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Low-Carbohydrate and Ketogenic Dietary Patterns for Type 2 Diabetes Management
The prevalence of diabetes continues to increase despite advances in treatment options. In 2019, according to the Centers for Disease Control and Prevention (CDC), 37.1 million (14.7%) US adults had diabetes. Among adults aged ≥ 65 years, the prevalence is even higher at 29.2%.1 Research has also estimated that 45% of adults have evidence of prediabetes or diabetes.2 According to the Veterans Health Administration, almost 25% of enrolled veterans have diabetes.3
Background
Diabetes is associated with an increased risk of microvascular complications (eg, retinopathy, nephropathy, and neuropathy) and macrovascular complications (eg, atherosclerotic cardiovascular disease) and is one of the most common causes of morbidity and mortality in the US.4 In 2017, diabetes was estimated to cost $327 billion in the US, up from $261 billion in 2012.5 During this same period, the excess costs per person with diabetes increased from $8417 to $9601.5
Type 2 diabetes mellitus (T2DM) and its associated insulin resistance is typically considered a chronic disease with progressive loss of β-cell function. Controlling glycemia, delaying microvascular changes, and preventing macrovascular disease are major management goals. Lifestyle interventions are essential in the management and prevention of T2DM. Medication management for T2DM usually progresses through several medications, ending in insulin therapy.6 Within 10 years of diagnosis, almost half of all individuals with T2DM will require insulin to manage their glycemia.7
Bariatric surgery and nutrition approaches have been successful in reversing T2DM. Recently, there has been increased interest in nutritional approaches to place T2DM in remission, reverse the disease process, and improve insulin resistance. Contrary to popular belief, before the discovery of insulin in 1921, low-carbohydrate (LC) diets were the most common treatment for T2DM.8 With the discovery of insulin and the eventual development of low-fat dietary recommendations, LC diets were no longer favored by most clinicians.8 Low-fat diets are, by definition, also high-carbohydrate diets. By the early 1980s, low-fat diets had become the standard of care dietary recommendation, and the goal for clinicians became glycemic maintenance (with increased use of medications) rather than preventing hyperglycemia.8
With growing evidence regarding the use of LC diets for T2DM, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD), the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), Diabetes Canada, and Diabetes Australia all include LC diets as a viable option for treating T2DM.4,9-12 This article will highlight a case using a reduced carbohydrate approach in lifestyle management and provide clinicians with practical guidance in its implementation. We will review the evidence that informs these guidelines, describe a practical approach to nutritional counseling, and review medication management and deprescribing approaches. Finally, barriers to implementation will be explored.
ILLUSTRATIVE CASE
A 64-year-old woman presented to the clinical pharmacist for the management of T2DM after her tenth hospitalization related to hyperglycemia in 10 years. She had previously been managed by primary care clinicians, clinical dietitians, endocrinologists, and certified diabetes care and education specialists. Pertinent history included diabetic ketoacidosis, coronary artery disease, hyperlipidemia, hypertension, obstructive sleep apnea, obesity, metabolic dysfunction-associated steatotic liver disease, and mild nonproliferative diabetic retinopathy with clinically significant macular edema. The patient expressed frustration with poor glycemic control during her many years of insulin therapy and an inability to lose weight due to insulin dose titrations. The patient reported prior education including but not limited to standardized sample menus, consistent carbohydrate intake, calorie reduction, general healthful nutrition, and the “move more, eat less” approach. The patient was unable to titrate insulin dosage and did not experience weight loss despite compliance with these methods.
Her medications included glargine insulin 45 units once daily, aspart insulin 5 units before meals 3 times daily, and metformin 1000 mg twice daily. Her hemoglobin A1c (HbA1c) level was 11.8%. A review of prior therapies for T2DM included glyburide 5 mg twice daily, metformin 1000 mg twice daily, 70/30 insulin (up to 340 units/d), glargine insulin (range, 10-140 units/d), regular insulin (range, 30-240 units/d), aspart insulin (range, 15-45 units/d), and U-500 regular insulin (range, 125-390 units/d). She took metoprolol 25 mg extended release daily and hydrochlorothiazide 25 mg daily, but both were discontinued after the most recent hospitalization. A review of HbA1c readings showed poor glycemic control for > 12 years (range, 10.3% to > 12.3%).
Education for lifestyle modifications, including an LC diet, was presented to the patient to assist with weight loss, improve glycemic control, and reduce insulin resistance. In addition, a glucagon-like peptide-1 agonist (liraglutide) was added to her pharmacotherapy. Continued dietary modifications with LC intake led to consistent reductions in glargine and aspart insulin therapy. The patient remained motivated throughout clinic visits due to improved glycemic control with sustainable dietary modifications, consistently reported feeling better overall, and deprescribed diabetes drug therapies. She remained off her blood pressure medications. After4 months of LC dietary modifications, all insulin therapy was discontinued. She continued with liraglutide 1.8 mg daily and metformin 1000 mg twice daily with an HbA1c of 6.3%. Two months later, her HbA1c level was 6.0%. She also lost 8 lb and her body mass index improved from 31 to 29.
Low-Carbohydrate T2DM DIET MANAGEMENT
LC diets are commonly defined as < 130 g of carbohydrates per day.13 Very LC ketogenic (VLCK) diets often contain ≤ 50 g of carbohydrates per day to induce nutritional ketosis.13 One of the first randomized controlled trials (RCTs) that compared a VLCK diet (< 30 g of carbohydrates per day) with a low-fat diet for obesity demonstrated greater weight loss at 6 months with the LC diet. In addition, patients with diabetes randomized to the LC group also showed improved insulin sensitivity. Notably, this study was done in a population of veterans enrolled at the VA Philadelphia Health Care System.14
A 2008 study comparing an LC diet with a calorie-restricted, low-glycemic diet for individuals with T2DM found that the LC diet group experienced a greater reduction in HbA1c and insulin levels and weight.15 Comparing these 2 diet groups after 24 weeks, 95% of individuals in the LC group reduced or discontinued T2DM medications vs 62% in the low-glycemic group.15 Another study of individuals with T2DM compared a VLCK diet with a low-fat diet. After 34 weeks, 55% of individuals in the LC diet group achieved an HbA1c level below the threshold for diabetes vs 0% in the low-fat diet group.16 A 2018 study of patients with T2DM investigated the impact of a very LC diet compared with the standard of care.17 After 1 year, the LC diet group experienced a mean HbA1c reduction of 1.3%, and 60% of individuals who completed the study achieved an HbA1c level < 6.5% without T2DM medications (not including metformin). This study also demonstrated that medications were significantly reduced, including 100% discontinuation of sulfonylureas and 94% reduction or elimination of insulin.
A recent study of an LC diet (< 20% energy from carbohydrates) demonstrated reduced HbA1c levels, weight, and waist circumference vs a control diet after 6 months. The control diet derived 50% to 60% of energy from carbohydrates.18 This study is typical of other LC interventions, which did not calorie restrict and instead allowed ad libitum intake.14,15
With mounting evidence, the VA/DoD guidelines on T2DM management included LC diets as dietary options for treating T2DM. The ADA also determined that LC diets had the most evidence in improving glycemia and included LC diets as an option for medical nutrition therapy (Table 1).10,19
A systematic review and meta-analysis looking at RCTs of LC diets found evidence for remission of T2DM without significant adverse effects (AEs).20 Another recent systematic review and network meta-analysis of 42 RCTs found that the ketogenic diet was superior for a reduction in HbA1c levels compared with 9 other dietary patterns, including low-fat, Mediterranean, and vegetarian/vegan diets. Overall, ketogenic, Mediterranean, moderate-carbohydrate, and low-glycemic index diets demonstrated improved glycemic control.21
Ideally, a comprehensive behavioral program, such as the VA Move! or Whole Health program, should incorporate patient aligned care teams (PACTs), behavioral health clinicians, clinical pharmacists, and dietitians to provide medical-nutrition therapy using LC diets. However, many facilities may not have adequate experience, expertise, or support. We provide practical approaches to provide LC nutrition counseling, medication management, and deprescribing for any primary care clinician applying LC diets for their patients. For simplicity and practicality, we define 3 types of LC dietary patterns: (1) VLCK (< 50 g); (2) LC (50-100 g); and (3) moderate LC (101-150 g).
Nutrition
All nutrition approaches, including LC diets, should be patient centered, individualized, and sensitive to the patient's culture. Typically, many patients have previously been instructed to consume low-fat (and subsequently) high-carbohydrate (> 150 g) meals. Most well-meaning clinicians have provided common-approach diet education from mainstream health organizations in the form of standardized handouts. For example, the Carbohydrate Counting for People with Diabetes patient education handout from the Academy of Nutrition and Dietetics provides a sample menu with 3 meals and 1 snack totaling 195 g of carbohydrates.22 In contrast, an example ADA diet has sample diets with 3 meals and 2 snacks with approximately 20 to 70 g of carbohydrates.23 In the VA, there are excellent resources to review and standardize handouts that emphasize an LC nutrition approach to T2DM, including ketogenic versions.24,25 Table 2 shows example meal plans based on different LC patterns—VLCK, LC, and moderate LC.
Starting an LC dietary pattern should maximize nutrient-dense and minimally processed proteins. Clinicians should begin with a baseline nutritional assessment through a 24-hour recall or food diary. After this has been completed, the patient’s baseline diet is assessed, and a gradual carbohydrate reduction plan is discussed. Generally, carbohydrate reduction is recommended at 1 meal per day per week. High-carbohydrate meals and snacks are restructured to favor satiating, minimally processed, high-protein food sources. Individual food preferences are considered and included in the recommended LC plan. For example, LC diets can be formulated for vegetarians and vegans as well as those who prefer meat and seafood. Prioritizing satiating and nutrient-dense foods can help increase the probability of diet acceptance and adherence.
A recent studyshowed that restricting carbohydrates at breakfast reduces 24-hour postprandial hyperglycemia and improves glycemic variability.26 Many patients consume upward of 50 g of carbohydrates at breakfast.27 For example, it is not uncommon for a patient to consume cereal with milk or oatmeal, orange juice, a banana, and toast at breakfast. Instead, the patient is advised to consume any combination of eggs, meat, no-sugar-added Greek yogurt, or berries.
To keep things simple for lunch and dinner, the patient is offered high-quality, minimally processed protein of their choosing with any nonstarchy vegetable. Should a patient desire additional carbohydrates with meals, they may reduce the baseline serving of carbohydrates by 50%. For example, if a patient normally fills 50% of their plate with spaghetti, they may reduce the pasta portion to 25% and add a meatball or increase the amount of vegetables consumed with the meal to satiety.
Snacks may include cheese, eggs, peanut butter, nuts, seeds, berries, no-sugar-added Greek yogurt, or guacamole. Oftentimes, when LC meals are adopted, the desire or need for snacking is diminished due to the satiating effect of high-quality protein sources and nonstarchy vegetables.
Adverse Effects
AEs have been reported with VLCK diets, including headache, diarrhea, constipation, muscle cramps, halitosis, light-headedness, and muscle weakness.28 These AEs may be mitigated with increased fluid intake, sodium intake, and magnesium supplementation.29 Increasing fluids to a minimum of 2 L/d and adding sodium (eg, bouillon supplementation) can minimize AEs.30 Milk of magnesia (5 mL) or slow-release magnesium chloride 200 mEq/d is suggested to reduce muscle cramps.30 There have been no studies looking at sodium intake and worsening hypertension or chronic heart failure in the setting of an LC diet, but fluid and electrolyte intake should be monitored closely, especially in patients with uncontrolled hypertension and heart failure. Other concerns of higher protein on worsening kidney function have generally not been founded.31 In some individuals, an LC and higher fat diet may increase low-density lipoprotein cholesterol (LDL-C).32 Therefore a baseline lipid panel is recommended and should be monitored along with HbA1c levels. An elevated LDL-C response may be managed by increasing protein and reducing saturated fat intake while maintaining the reduced carbohydrate content of the diet.
Medication Management
The adoption of an LC diet can cause a swift and profound reduction in blood sugar.33 Utilizing PACTs can help prevent adverse drug events by involving clinical pharmacists to provide recommendations and dose reductions as patients adopt an LC diet. Each approach must be individualized to the patient and can depend on several factors, including the number and strength of medications, the degree of carbohydrate reduction, baseline blood glucose, as well as assessing for medical literacy and ability to implement recommendations. Additionally, patients should monitor their blood sugar regularly and communicate with their primary care team (pharmacist, PACT registered nurse, primary care clinician, and registered dietician). Ultimately, the goal when adopting an LC diet while taking antihyperglycemics is safely avoiding hypoglycemia while reducing the number of medications the patient is taking. We summarize a practical approach to medication management that was recently published (Table 3).33,34
Medications to Reduce or Discontinue
Medications that can cause hypoglycemia should be the first to be reduced or discontinued upon starting an LC diet, including bolus insulin (although a small amount may be needed to correct for high blood sugar), sulfonylureas, and meglitinides. Combination insulin should be stopped and changed to basal insulin to avoid the risk of hypoglycemia (see Table 4 for insulin deprescribing recommendations). The mechanism of action in preventing the breakdown of carbohydrates in the gastrointestinal tract makes the use of α-glucosidase inhibitors superfluous, and they can be discontinued, reducing pill burden and polypharmacy risks. Sodium-glucose transport protein 2 inhibitors (SGLT2i) should be discontinued for patients on VLCK diets due to the risk of euglycemic diabetic ketoacidosis. However, with LC and moderate LC plans, the SGLT2i may be used with caution as long as patients are made aware of ketoacidosis symptoms. To help prevent the risk of hypoglycemia, basal/long-acting insulin can be continued, but at a 50% reduced dose. Patients should closely monitor blood sugar to assess for appropriateness of dose reductions. While thiazolidinediones are not contraindicated, clinicians can consider discontinuation given both their penchant for inducing weight gain and their limited outcomes data.
Medications to Continue
Medications that pose minimal risk for hypoglycemia can be continued, including metformin, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide-1 agonists. However, even though these may pose a low risk of hypoglycemia, patients should still closely monitor their blood glucose so medications can be deprescribed as soon as safely and reasonably possible.
Other Medications
The improvement in metabolic health with the reduction of carbohydrates can render other classes of medications unnecessary or require adjustment. Patients should be counseled to monitor their blood pressure as significant and rapid improvements can occur. In the event of a systolic blood pressure of 100 to 110 mm Hg or signs of hypotension, down titration or discontinuation of antihypertensives should be initiated. Limited evidence exists on the preferred order of discontinuation but should be informed by other comorbidities, such as coronary artery disease and chronic kidney disease. Given an LC diet’s diuretic effect, tapering and stopping diuretics may be an option. Other medications requiring closer monitoring include lithium (can be affected by fluid and electrolyte shifts), warfarin (may alter vitamin K intake), valproate (which may be reduced), and zonisamide and topiramate (kidney stone risk).
Remission of T2DM with LC Diets
As patients adopt LC diets and medications are deprescribed and glycemia improves, HbA1c and fasting glucose levels may drop below the diagnostic threshold for T2DM.20 As new evidence emerges surrounding the management of T2DM from a lifestyle perspective, major health care organizations have acknowledged that T2DM is not necessarily an incurable, progressive disease, but rather a disease that can be reversed or put in remission.35-37 In 2016, the World Health Organization (WHO) global report on diabetes acknowledged that T2DM reversal can be achieved via weight loss and calorie restriction.35
In 2021, a consensus statement from the ADA, the Endocrine Society, the EASD, and Diabetes UK defined T2DM remission as an HbA1c level < 6.5% for at least 3 months with no T2DM medications.36 Diabetes Australia also published a position statement in 2021 about T2DM remission.37 Like the WHO, Diabetes Australia acknowledged that remission of T2DM is possible following intensive dietary changes or bariatric surgery.37 Before the 2021 consensus statement, some experts argued that excluding metformin from the T2DM medication list may not be warranted since metformin has indications beyond T2DM. In this case, remission of T2DM could be defined as an HbA1c level < 6.5% for at least 3 months and on metformin or no T2DM medications.8
Emerging Strategies
Emerging strategies, such as continuous glucose monitors (CGMs) and the use of intermittent fasting/time-restricted eating (TRE), can be used with the LC diet to help improve the monitoring and management of T2DM. In the recently published VA/DoD guidelines for T2DM, the work group suggested real-time CGMs for qualified patients with T2DM.4 These include patients on daily insulin who are not achieving glycemic control or to reduce the risk for hypoglycemia. CGMs have shown evidence of improved glycemic control and decreased hypoglycemia in those with T2DM.38,39 It is currently unknown if CGMs improve long-term glycemic control, but they appear promising for managing and reducing medications for those on an LC diet.40
TRE can be supplemented with an LC plan that incorporates “eating windows.” Common patterns include 14 hours of fasting and a 10-hour eating window (14F:10E), or 16 hours of fasting and an 8-hour eating window (16F:8E). By eating only in the specified window, patients generally reduce caloric intake and minimize insulin and glucose excursions during the fasting window. No changes need to be made to the macronutrient composition of the diet, and LC approaches can be used with TRE. The mechanism of action is likely multifactorial, targeting hyperinsulinemia and insulin resistance as well as producing a caloric deficit to enable weight loss.41 Eating windows may improve insulin sensitivity, reduce insulin resistance, and enhance overall glycemic control. The recent VA/DoD guidelines recommended against intermittent fasting due to concerns over the risk of hypoglycemia despite larger weight loss in TRE groups.4 Recently, a study using CGMs and TRE demonstrated both improved glycemic control and no hypoglycemic episodes in patients with T2DM on insulin.42 Patients who would like to supplement TRE with an LC plan as a strategy for improved glycemic control should work closely with their PACT to help manage their TRE and LC plan and consider a CGM adjunct, especially if on insulin.
Barriers
Managing T2DM often requires comprehensive lifestyle modifications of nutrition, exercise, sleep, stress management, and other psychosocial issues, as well as an interdisciplinary team-based approach.43 The advantage of working within the VA includes a uniform system within a network of care. However, many patients continue to use both federal and private health care. This use of out-of-network care may result in fragmented, potentially disjointed, or even contradictory dietary advice.
The VA PACT, whole health for holistic health, and weight loss interventions such as the MOVE! program provide lifestyle interventions like nutrition, physical activity, and behavior change. However, these well-intentioned approaches may provide alternative and even diverging recommendations, which place additional barriers to effective patient management. In patients who are advised and accept a trial of an LC plan, each member of the team should embrace the self-management decision of the patient and support the plan.29 Any conflicts, questions, or concerns should be communicated directly with the team in an interdisciplinary approach to provide a unified message and counsel.
The long-term effects and sustainability of an LC diet have been questioned in the literature.44-46 Recently, the use of an app-based coaching plan has demonstrated short- and long-term sustainability on an LC diet.47 In just 5 months in a large VA system, 590 patients using a virtual coaching platform and a VLCK diet plan were found to have lower HbA1c levels, reduced diabetic medication fills, lower body mass index, fewer outpatient visits, and lower prescription drug costs.
A 5-year follow-up found nearly 50% of participants sustained a VLCK diet for T2DM. For patients who participated in the study after 2 years, 72% sustained the VLCK diet in years 2 to 5. Most required nearly 50% fewer medications and in those that started with insulin, half did not require it at 5 years.48 Further research, however, is necessary to determine the long-term effects on cardiometabolic markers and health with LC diets. There are no long-term RCTs on outcomes data looking at T2DM morbidity or mortality. While there are prospective cohort studies on LC diets in the general population on mortality, they demonstrate mixed results. These studies may be confounded by heterogeneous definitions of LC diets, diet quality, and other health factors.49-51
Conclusions
The effective use of LC diets within a PACT with close and intensive lifestyle counseling and a safe approach to medication management and deprescribing can improve glycemic control, reduce the overall need for insulin, reduce medication use, and provide sustained weight loss. Additionally, the use of therapeutic carbohydrate reduction and subsequent medication deprescription may lead to sustained remission of T2DM. The current efficacy and sustainment of therapeutic carbohydrate reduction for patients with T2DM appears promising. Further research on LC diets, emerging strategies, and long-term effects on cardiometabolic risk factors, morbidity, and mortality will continue to inform future practice in our health care system.
Acknowledgments
We thank Cecile Seth who has been instrumental in pushing us forward and the Metabolic Multiplier group who has helped encourage and provide input into this article.
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45. Choi JH, Kang JH, Chon S. Comprehensive understanding for application in Korean patients with type 2 diabetes mellitus of the consensus statement on carbohydrate-restricted diets by Korean Diabetes Association, Korean Society for the Study of Obesity, and Korean Society of Hypertension. Diabetes Metab J. 2022;46(3):377. doi:10.4093/DMJ.2022.0051
46. Jayedi A, Zeraattalab-Motlagh S, Jabbarzadeh B, et al. Dose-dependent effect of carbohydrate restriction for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized controlled trials. Am J Clin Nutr. 2022;116(1). doi:10.1093/AJCN/NQAC066
47. Strombotne KL, Lum J, Ndugga NJ, et al. Effectiveness of a ketogenic diet and virtual coaching intervention for patients with diabetes: a difference-in-differences analysis. Diabetes Obes Metab. 2021;23(12):2643-2650. doi:10.1111/DOM.14515
48. Virta Health. Virta Health highlights lasting, transformative health improvements in 5-year diabetes reversal study. June 5, 2022. Accessed October 6, 2023. https://www.virtahealth.com/blog/virta-sustainable-health-improvements-5-year-diabetes-reversal-study
49. Wan Z, Shan Z, Geng T, et al. Associations of moderate low-carbohydrate diets with mortality among patients with type 2 diabetes: a prospective cohort study. J Clin Endocrinol Metab. 2022;107(7):E2702-E2709. doi:10.1210/CLINEM/DGAC235
50. Akter S, Mizoue T, Nanri A, et al. Low carbohydrate diet and all cause and cause-specific mortality. Clin Nutr. 2021;40(4):2016-2024. doi:10.1016/J.CLNU.2020.09.022
51. Shan Z, Guo Y, Hu FB, Liu L, Qi Q. Association of low-carbohydrate and low-fat diets with mortality among US adults. JAMA Intern Med. 2020;180(4):513-523. doi:10.1001/JAMAINTERNMED.2019.6980
The prevalence of diabetes continues to increase despite advances in treatment options. In 2019, according to the Centers for Disease Control and Prevention (CDC), 37.1 million (14.7%) US adults had diabetes. Among adults aged ≥ 65 years, the prevalence is even higher at 29.2%.1 Research has also estimated that 45% of adults have evidence of prediabetes or diabetes.2 According to the Veterans Health Administration, almost 25% of enrolled veterans have diabetes.3
Background
Diabetes is associated with an increased risk of microvascular complications (eg, retinopathy, nephropathy, and neuropathy) and macrovascular complications (eg, atherosclerotic cardiovascular disease) and is one of the most common causes of morbidity and mortality in the US.4 In 2017, diabetes was estimated to cost $327 billion in the US, up from $261 billion in 2012.5 During this same period, the excess costs per person with diabetes increased from $8417 to $9601.5
Type 2 diabetes mellitus (T2DM) and its associated insulin resistance is typically considered a chronic disease with progressive loss of β-cell function. Controlling glycemia, delaying microvascular changes, and preventing macrovascular disease are major management goals. Lifestyle interventions are essential in the management and prevention of T2DM. Medication management for T2DM usually progresses through several medications, ending in insulin therapy.6 Within 10 years of diagnosis, almost half of all individuals with T2DM will require insulin to manage their glycemia.7
Bariatric surgery and nutrition approaches have been successful in reversing T2DM. Recently, there has been increased interest in nutritional approaches to place T2DM in remission, reverse the disease process, and improve insulin resistance. Contrary to popular belief, before the discovery of insulin in 1921, low-carbohydrate (LC) diets were the most common treatment for T2DM.8 With the discovery of insulin and the eventual development of low-fat dietary recommendations, LC diets were no longer favored by most clinicians.8 Low-fat diets are, by definition, also high-carbohydrate diets. By the early 1980s, low-fat diets had become the standard of care dietary recommendation, and the goal for clinicians became glycemic maintenance (with increased use of medications) rather than preventing hyperglycemia.8
With growing evidence regarding the use of LC diets for T2DM, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD), the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), Diabetes Canada, and Diabetes Australia all include LC diets as a viable option for treating T2DM.4,9-12 This article will highlight a case using a reduced carbohydrate approach in lifestyle management and provide clinicians with practical guidance in its implementation. We will review the evidence that informs these guidelines, describe a practical approach to nutritional counseling, and review medication management and deprescribing approaches. Finally, barriers to implementation will be explored.
ILLUSTRATIVE CASE
A 64-year-old woman presented to the clinical pharmacist for the management of T2DM after her tenth hospitalization related to hyperglycemia in 10 years. She had previously been managed by primary care clinicians, clinical dietitians, endocrinologists, and certified diabetes care and education specialists. Pertinent history included diabetic ketoacidosis, coronary artery disease, hyperlipidemia, hypertension, obstructive sleep apnea, obesity, metabolic dysfunction-associated steatotic liver disease, and mild nonproliferative diabetic retinopathy with clinically significant macular edema. The patient expressed frustration with poor glycemic control during her many years of insulin therapy and an inability to lose weight due to insulin dose titrations. The patient reported prior education including but not limited to standardized sample menus, consistent carbohydrate intake, calorie reduction, general healthful nutrition, and the “move more, eat less” approach. The patient was unable to titrate insulin dosage and did not experience weight loss despite compliance with these methods.
Her medications included glargine insulin 45 units once daily, aspart insulin 5 units before meals 3 times daily, and metformin 1000 mg twice daily. Her hemoglobin A1c (HbA1c) level was 11.8%. A review of prior therapies for T2DM included glyburide 5 mg twice daily, metformin 1000 mg twice daily, 70/30 insulin (up to 340 units/d), glargine insulin (range, 10-140 units/d), regular insulin (range, 30-240 units/d), aspart insulin (range, 15-45 units/d), and U-500 regular insulin (range, 125-390 units/d). She took metoprolol 25 mg extended release daily and hydrochlorothiazide 25 mg daily, but both were discontinued after the most recent hospitalization. A review of HbA1c readings showed poor glycemic control for > 12 years (range, 10.3% to > 12.3%).
Education for lifestyle modifications, including an LC diet, was presented to the patient to assist with weight loss, improve glycemic control, and reduce insulin resistance. In addition, a glucagon-like peptide-1 agonist (liraglutide) was added to her pharmacotherapy. Continued dietary modifications with LC intake led to consistent reductions in glargine and aspart insulin therapy. The patient remained motivated throughout clinic visits due to improved glycemic control with sustainable dietary modifications, consistently reported feeling better overall, and deprescribed diabetes drug therapies. She remained off her blood pressure medications. After4 months of LC dietary modifications, all insulin therapy was discontinued. She continued with liraglutide 1.8 mg daily and metformin 1000 mg twice daily with an HbA1c of 6.3%. Two months later, her HbA1c level was 6.0%. She also lost 8 lb and her body mass index improved from 31 to 29.
Low-Carbohydrate T2DM DIET MANAGEMENT
LC diets are commonly defined as < 130 g of carbohydrates per day.13 Very LC ketogenic (VLCK) diets often contain ≤ 50 g of carbohydrates per day to induce nutritional ketosis.13 One of the first randomized controlled trials (RCTs) that compared a VLCK diet (< 30 g of carbohydrates per day) with a low-fat diet for obesity demonstrated greater weight loss at 6 months with the LC diet. In addition, patients with diabetes randomized to the LC group also showed improved insulin sensitivity. Notably, this study was done in a population of veterans enrolled at the VA Philadelphia Health Care System.14
A 2008 study comparing an LC diet with a calorie-restricted, low-glycemic diet for individuals with T2DM found that the LC diet group experienced a greater reduction in HbA1c and insulin levels and weight.15 Comparing these 2 diet groups after 24 weeks, 95% of individuals in the LC group reduced or discontinued T2DM medications vs 62% in the low-glycemic group.15 Another study of individuals with T2DM compared a VLCK diet with a low-fat diet. After 34 weeks, 55% of individuals in the LC diet group achieved an HbA1c level below the threshold for diabetes vs 0% in the low-fat diet group.16 A 2018 study of patients with T2DM investigated the impact of a very LC diet compared with the standard of care.17 After 1 year, the LC diet group experienced a mean HbA1c reduction of 1.3%, and 60% of individuals who completed the study achieved an HbA1c level < 6.5% without T2DM medications (not including metformin). This study also demonstrated that medications were significantly reduced, including 100% discontinuation of sulfonylureas and 94% reduction or elimination of insulin.
A recent study of an LC diet (< 20% energy from carbohydrates) demonstrated reduced HbA1c levels, weight, and waist circumference vs a control diet after 6 months. The control diet derived 50% to 60% of energy from carbohydrates.18 This study is typical of other LC interventions, which did not calorie restrict and instead allowed ad libitum intake.14,15
With mounting evidence, the VA/DoD guidelines on T2DM management included LC diets as dietary options for treating T2DM. The ADA also determined that LC diets had the most evidence in improving glycemia and included LC diets as an option for medical nutrition therapy (Table 1).10,19
A systematic review and meta-analysis looking at RCTs of LC diets found evidence for remission of T2DM without significant adverse effects (AEs).20 Another recent systematic review and network meta-analysis of 42 RCTs found that the ketogenic diet was superior for a reduction in HbA1c levels compared with 9 other dietary patterns, including low-fat, Mediterranean, and vegetarian/vegan diets. Overall, ketogenic, Mediterranean, moderate-carbohydrate, and low-glycemic index diets demonstrated improved glycemic control.21
Ideally, a comprehensive behavioral program, such as the VA Move! or Whole Health program, should incorporate patient aligned care teams (PACTs), behavioral health clinicians, clinical pharmacists, and dietitians to provide medical-nutrition therapy using LC diets. However, many facilities may not have adequate experience, expertise, or support. We provide practical approaches to provide LC nutrition counseling, medication management, and deprescribing for any primary care clinician applying LC diets for their patients. For simplicity and practicality, we define 3 types of LC dietary patterns: (1) VLCK (< 50 g); (2) LC (50-100 g); and (3) moderate LC (101-150 g).
Nutrition
All nutrition approaches, including LC diets, should be patient centered, individualized, and sensitive to the patient's culture. Typically, many patients have previously been instructed to consume low-fat (and subsequently) high-carbohydrate (> 150 g) meals. Most well-meaning clinicians have provided common-approach diet education from mainstream health organizations in the form of standardized handouts. For example, the Carbohydrate Counting for People with Diabetes patient education handout from the Academy of Nutrition and Dietetics provides a sample menu with 3 meals and 1 snack totaling 195 g of carbohydrates.22 In contrast, an example ADA diet has sample diets with 3 meals and 2 snacks with approximately 20 to 70 g of carbohydrates.23 In the VA, there are excellent resources to review and standardize handouts that emphasize an LC nutrition approach to T2DM, including ketogenic versions.24,25 Table 2 shows example meal plans based on different LC patterns—VLCK, LC, and moderate LC.
Starting an LC dietary pattern should maximize nutrient-dense and minimally processed proteins. Clinicians should begin with a baseline nutritional assessment through a 24-hour recall or food diary. After this has been completed, the patient’s baseline diet is assessed, and a gradual carbohydrate reduction plan is discussed. Generally, carbohydrate reduction is recommended at 1 meal per day per week. High-carbohydrate meals and snacks are restructured to favor satiating, minimally processed, high-protein food sources. Individual food preferences are considered and included in the recommended LC plan. For example, LC diets can be formulated for vegetarians and vegans as well as those who prefer meat and seafood. Prioritizing satiating and nutrient-dense foods can help increase the probability of diet acceptance and adherence.
A recent studyshowed that restricting carbohydrates at breakfast reduces 24-hour postprandial hyperglycemia and improves glycemic variability.26 Many patients consume upward of 50 g of carbohydrates at breakfast.27 For example, it is not uncommon for a patient to consume cereal with milk or oatmeal, orange juice, a banana, and toast at breakfast. Instead, the patient is advised to consume any combination of eggs, meat, no-sugar-added Greek yogurt, or berries.
To keep things simple for lunch and dinner, the patient is offered high-quality, minimally processed protein of their choosing with any nonstarchy vegetable. Should a patient desire additional carbohydrates with meals, they may reduce the baseline serving of carbohydrates by 50%. For example, if a patient normally fills 50% of their plate with spaghetti, they may reduce the pasta portion to 25% and add a meatball or increase the amount of vegetables consumed with the meal to satiety.
Snacks may include cheese, eggs, peanut butter, nuts, seeds, berries, no-sugar-added Greek yogurt, or guacamole. Oftentimes, when LC meals are adopted, the desire or need for snacking is diminished due to the satiating effect of high-quality protein sources and nonstarchy vegetables.
Adverse Effects
AEs have been reported with VLCK diets, including headache, diarrhea, constipation, muscle cramps, halitosis, light-headedness, and muscle weakness.28 These AEs may be mitigated with increased fluid intake, sodium intake, and magnesium supplementation.29 Increasing fluids to a minimum of 2 L/d and adding sodium (eg, bouillon supplementation) can minimize AEs.30 Milk of magnesia (5 mL) or slow-release magnesium chloride 200 mEq/d is suggested to reduce muscle cramps.30 There have been no studies looking at sodium intake and worsening hypertension or chronic heart failure in the setting of an LC diet, but fluid and electrolyte intake should be monitored closely, especially in patients with uncontrolled hypertension and heart failure. Other concerns of higher protein on worsening kidney function have generally not been founded.31 In some individuals, an LC and higher fat diet may increase low-density lipoprotein cholesterol (LDL-C).32 Therefore a baseline lipid panel is recommended and should be monitored along with HbA1c levels. An elevated LDL-C response may be managed by increasing protein and reducing saturated fat intake while maintaining the reduced carbohydrate content of the diet.
Medication Management
The adoption of an LC diet can cause a swift and profound reduction in blood sugar.33 Utilizing PACTs can help prevent adverse drug events by involving clinical pharmacists to provide recommendations and dose reductions as patients adopt an LC diet. Each approach must be individualized to the patient and can depend on several factors, including the number and strength of medications, the degree of carbohydrate reduction, baseline blood glucose, as well as assessing for medical literacy and ability to implement recommendations. Additionally, patients should monitor their blood sugar regularly and communicate with their primary care team (pharmacist, PACT registered nurse, primary care clinician, and registered dietician). Ultimately, the goal when adopting an LC diet while taking antihyperglycemics is safely avoiding hypoglycemia while reducing the number of medications the patient is taking. We summarize a practical approach to medication management that was recently published (Table 3).33,34
Medications to Reduce or Discontinue
Medications that can cause hypoglycemia should be the first to be reduced or discontinued upon starting an LC diet, including bolus insulin (although a small amount may be needed to correct for high blood sugar), sulfonylureas, and meglitinides. Combination insulin should be stopped and changed to basal insulin to avoid the risk of hypoglycemia (see Table 4 for insulin deprescribing recommendations). The mechanism of action in preventing the breakdown of carbohydrates in the gastrointestinal tract makes the use of α-glucosidase inhibitors superfluous, and they can be discontinued, reducing pill burden and polypharmacy risks. Sodium-glucose transport protein 2 inhibitors (SGLT2i) should be discontinued for patients on VLCK diets due to the risk of euglycemic diabetic ketoacidosis. However, with LC and moderate LC plans, the SGLT2i may be used with caution as long as patients are made aware of ketoacidosis symptoms. To help prevent the risk of hypoglycemia, basal/long-acting insulin can be continued, but at a 50% reduced dose. Patients should closely monitor blood sugar to assess for appropriateness of dose reductions. While thiazolidinediones are not contraindicated, clinicians can consider discontinuation given both their penchant for inducing weight gain and their limited outcomes data.
Medications to Continue
Medications that pose minimal risk for hypoglycemia can be continued, including metformin, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide-1 agonists. However, even though these may pose a low risk of hypoglycemia, patients should still closely monitor their blood glucose so medications can be deprescribed as soon as safely and reasonably possible.
Other Medications
The improvement in metabolic health with the reduction of carbohydrates can render other classes of medications unnecessary or require adjustment. Patients should be counseled to monitor their blood pressure as significant and rapid improvements can occur. In the event of a systolic blood pressure of 100 to 110 mm Hg or signs of hypotension, down titration or discontinuation of antihypertensives should be initiated. Limited evidence exists on the preferred order of discontinuation but should be informed by other comorbidities, such as coronary artery disease and chronic kidney disease. Given an LC diet’s diuretic effect, tapering and stopping diuretics may be an option. Other medications requiring closer monitoring include lithium (can be affected by fluid and electrolyte shifts), warfarin (may alter vitamin K intake), valproate (which may be reduced), and zonisamide and topiramate (kidney stone risk).
Remission of T2DM with LC Diets
As patients adopt LC diets and medications are deprescribed and glycemia improves, HbA1c and fasting glucose levels may drop below the diagnostic threshold for T2DM.20 As new evidence emerges surrounding the management of T2DM from a lifestyle perspective, major health care organizations have acknowledged that T2DM is not necessarily an incurable, progressive disease, but rather a disease that can be reversed or put in remission.35-37 In 2016, the World Health Organization (WHO) global report on diabetes acknowledged that T2DM reversal can be achieved via weight loss and calorie restriction.35
In 2021, a consensus statement from the ADA, the Endocrine Society, the EASD, and Diabetes UK defined T2DM remission as an HbA1c level < 6.5% for at least 3 months with no T2DM medications.36 Diabetes Australia also published a position statement in 2021 about T2DM remission.37 Like the WHO, Diabetes Australia acknowledged that remission of T2DM is possible following intensive dietary changes or bariatric surgery.37 Before the 2021 consensus statement, some experts argued that excluding metformin from the T2DM medication list may not be warranted since metformin has indications beyond T2DM. In this case, remission of T2DM could be defined as an HbA1c level < 6.5% for at least 3 months and on metformin or no T2DM medications.8
Emerging Strategies
Emerging strategies, such as continuous glucose monitors (CGMs) and the use of intermittent fasting/time-restricted eating (TRE), can be used with the LC diet to help improve the monitoring and management of T2DM. In the recently published VA/DoD guidelines for T2DM, the work group suggested real-time CGMs for qualified patients with T2DM.4 These include patients on daily insulin who are not achieving glycemic control or to reduce the risk for hypoglycemia. CGMs have shown evidence of improved glycemic control and decreased hypoglycemia in those with T2DM.38,39 It is currently unknown if CGMs improve long-term glycemic control, but they appear promising for managing and reducing medications for those on an LC diet.40
TRE can be supplemented with an LC plan that incorporates “eating windows.” Common patterns include 14 hours of fasting and a 10-hour eating window (14F:10E), or 16 hours of fasting and an 8-hour eating window (16F:8E). By eating only in the specified window, patients generally reduce caloric intake and minimize insulin and glucose excursions during the fasting window. No changes need to be made to the macronutrient composition of the diet, and LC approaches can be used with TRE. The mechanism of action is likely multifactorial, targeting hyperinsulinemia and insulin resistance as well as producing a caloric deficit to enable weight loss.41 Eating windows may improve insulin sensitivity, reduce insulin resistance, and enhance overall glycemic control. The recent VA/DoD guidelines recommended against intermittent fasting due to concerns over the risk of hypoglycemia despite larger weight loss in TRE groups.4 Recently, a study using CGMs and TRE demonstrated both improved glycemic control and no hypoglycemic episodes in patients with T2DM on insulin.42 Patients who would like to supplement TRE with an LC plan as a strategy for improved glycemic control should work closely with their PACT to help manage their TRE and LC plan and consider a CGM adjunct, especially if on insulin.
Barriers
Managing T2DM often requires comprehensive lifestyle modifications of nutrition, exercise, sleep, stress management, and other psychosocial issues, as well as an interdisciplinary team-based approach.43 The advantage of working within the VA includes a uniform system within a network of care. However, many patients continue to use both federal and private health care. This use of out-of-network care may result in fragmented, potentially disjointed, or even contradictory dietary advice.
The VA PACT, whole health for holistic health, and weight loss interventions such as the MOVE! program provide lifestyle interventions like nutrition, physical activity, and behavior change. However, these well-intentioned approaches may provide alternative and even diverging recommendations, which place additional barriers to effective patient management. In patients who are advised and accept a trial of an LC plan, each member of the team should embrace the self-management decision of the patient and support the plan.29 Any conflicts, questions, or concerns should be communicated directly with the team in an interdisciplinary approach to provide a unified message and counsel.
The long-term effects and sustainability of an LC diet have been questioned in the literature.44-46 Recently, the use of an app-based coaching plan has demonstrated short- and long-term sustainability on an LC diet.47 In just 5 months in a large VA system, 590 patients using a virtual coaching platform and a VLCK diet plan were found to have lower HbA1c levels, reduced diabetic medication fills, lower body mass index, fewer outpatient visits, and lower prescription drug costs.
A 5-year follow-up found nearly 50% of participants sustained a VLCK diet for T2DM. For patients who participated in the study after 2 years, 72% sustained the VLCK diet in years 2 to 5. Most required nearly 50% fewer medications and in those that started with insulin, half did not require it at 5 years.48 Further research, however, is necessary to determine the long-term effects on cardiometabolic markers and health with LC diets. There are no long-term RCTs on outcomes data looking at T2DM morbidity or mortality. While there are prospective cohort studies on LC diets in the general population on mortality, they demonstrate mixed results. These studies may be confounded by heterogeneous definitions of LC diets, diet quality, and other health factors.49-51
Conclusions
The effective use of LC diets within a PACT with close and intensive lifestyle counseling and a safe approach to medication management and deprescribing can improve glycemic control, reduce the overall need for insulin, reduce medication use, and provide sustained weight loss. Additionally, the use of therapeutic carbohydrate reduction and subsequent medication deprescription may lead to sustained remission of T2DM. The current efficacy and sustainment of therapeutic carbohydrate reduction for patients with T2DM appears promising. Further research on LC diets, emerging strategies, and long-term effects on cardiometabolic risk factors, morbidity, and mortality will continue to inform future practice in our health care system.
Acknowledgments
We thank Cecile Seth who has been instrumental in pushing us forward and the Metabolic Multiplier group who has helped encourage and provide input into this article.
The prevalence of diabetes continues to increase despite advances in treatment options. In 2019, according to the Centers for Disease Control and Prevention (CDC), 37.1 million (14.7%) US adults had diabetes. Among adults aged ≥ 65 years, the prevalence is even higher at 29.2%.1 Research has also estimated that 45% of adults have evidence of prediabetes or diabetes.2 According to the Veterans Health Administration, almost 25% of enrolled veterans have diabetes.3
Background
Diabetes is associated with an increased risk of microvascular complications (eg, retinopathy, nephropathy, and neuropathy) and macrovascular complications (eg, atherosclerotic cardiovascular disease) and is one of the most common causes of morbidity and mortality in the US.4 In 2017, diabetes was estimated to cost $327 billion in the US, up from $261 billion in 2012.5 During this same period, the excess costs per person with diabetes increased from $8417 to $9601.5
Type 2 diabetes mellitus (T2DM) and its associated insulin resistance is typically considered a chronic disease with progressive loss of β-cell function. Controlling glycemia, delaying microvascular changes, and preventing macrovascular disease are major management goals. Lifestyle interventions are essential in the management and prevention of T2DM. Medication management for T2DM usually progresses through several medications, ending in insulin therapy.6 Within 10 years of diagnosis, almost half of all individuals with T2DM will require insulin to manage their glycemia.7
Bariatric surgery and nutrition approaches have been successful in reversing T2DM. Recently, there has been increased interest in nutritional approaches to place T2DM in remission, reverse the disease process, and improve insulin resistance. Contrary to popular belief, before the discovery of insulin in 1921, low-carbohydrate (LC) diets were the most common treatment for T2DM.8 With the discovery of insulin and the eventual development of low-fat dietary recommendations, LC diets were no longer favored by most clinicians.8 Low-fat diets are, by definition, also high-carbohydrate diets. By the early 1980s, low-fat diets had become the standard of care dietary recommendation, and the goal for clinicians became glycemic maintenance (with increased use of medications) rather than preventing hyperglycemia.8
With growing evidence regarding the use of LC diets for T2DM, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD), the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), Diabetes Canada, and Diabetes Australia all include LC diets as a viable option for treating T2DM.4,9-12 This article will highlight a case using a reduced carbohydrate approach in lifestyle management and provide clinicians with practical guidance in its implementation. We will review the evidence that informs these guidelines, describe a practical approach to nutritional counseling, and review medication management and deprescribing approaches. Finally, barriers to implementation will be explored.
ILLUSTRATIVE CASE
A 64-year-old woman presented to the clinical pharmacist for the management of T2DM after her tenth hospitalization related to hyperglycemia in 10 years. She had previously been managed by primary care clinicians, clinical dietitians, endocrinologists, and certified diabetes care and education specialists. Pertinent history included diabetic ketoacidosis, coronary artery disease, hyperlipidemia, hypertension, obstructive sleep apnea, obesity, metabolic dysfunction-associated steatotic liver disease, and mild nonproliferative diabetic retinopathy with clinically significant macular edema. The patient expressed frustration with poor glycemic control during her many years of insulin therapy and an inability to lose weight due to insulin dose titrations. The patient reported prior education including but not limited to standardized sample menus, consistent carbohydrate intake, calorie reduction, general healthful nutrition, and the “move more, eat less” approach. The patient was unable to titrate insulin dosage and did not experience weight loss despite compliance with these methods.
Her medications included glargine insulin 45 units once daily, aspart insulin 5 units before meals 3 times daily, and metformin 1000 mg twice daily. Her hemoglobin A1c (HbA1c) level was 11.8%. A review of prior therapies for T2DM included glyburide 5 mg twice daily, metformin 1000 mg twice daily, 70/30 insulin (up to 340 units/d), glargine insulin (range, 10-140 units/d), regular insulin (range, 30-240 units/d), aspart insulin (range, 15-45 units/d), and U-500 regular insulin (range, 125-390 units/d). She took metoprolol 25 mg extended release daily and hydrochlorothiazide 25 mg daily, but both were discontinued after the most recent hospitalization. A review of HbA1c readings showed poor glycemic control for > 12 years (range, 10.3% to > 12.3%).
Education for lifestyle modifications, including an LC diet, was presented to the patient to assist with weight loss, improve glycemic control, and reduce insulin resistance. In addition, a glucagon-like peptide-1 agonist (liraglutide) was added to her pharmacotherapy. Continued dietary modifications with LC intake led to consistent reductions in glargine and aspart insulin therapy. The patient remained motivated throughout clinic visits due to improved glycemic control with sustainable dietary modifications, consistently reported feeling better overall, and deprescribed diabetes drug therapies. She remained off her blood pressure medications. After4 months of LC dietary modifications, all insulin therapy was discontinued. She continued with liraglutide 1.8 mg daily and metformin 1000 mg twice daily with an HbA1c of 6.3%. Two months later, her HbA1c level was 6.0%. She also lost 8 lb and her body mass index improved from 31 to 29.
Low-Carbohydrate T2DM DIET MANAGEMENT
LC diets are commonly defined as < 130 g of carbohydrates per day.13 Very LC ketogenic (VLCK) diets often contain ≤ 50 g of carbohydrates per day to induce nutritional ketosis.13 One of the first randomized controlled trials (RCTs) that compared a VLCK diet (< 30 g of carbohydrates per day) with a low-fat diet for obesity demonstrated greater weight loss at 6 months with the LC diet. In addition, patients with diabetes randomized to the LC group also showed improved insulin sensitivity. Notably, this study was done in a population of veterans enrolled at the VA Philadelphia Health Care System.14
A 2008 study comparing an LC diet with a calorie-restricted, low-glycemic diet for individuals with T2DM found that the LC diet group experienced a greater reduction in HbA1c and insulin levels and weight.15 Comparing these 2 diet groups after 24 weeks, 95% of individuals in the LC group reduced or discontinued T2DM medications vs 62% in the low-glycemic group.15 Another study of individuals with T2DM compared a VLCK diet with a low-fat diet. After 34 weeks, 55% of individuals in the LC diet group achieved an HbA1c level below the threshold for diabetes vs 0% in the low-fat diet group.16 A 2018 study of patients with T2DM investigated the impact of a very LC diet compared with the standard of care.17 After 1 year, the LC diet group experienced a mean HbA1c reduction of 1.3%, and 60% of individuals who completed the study achieved an HbA1c level < 6.5% without T2DM medications (not including metformin). This study also demonstrated that medications were significantly reduced, including 100% discontinuation of sulfonylureas and 94% reduction or elimination of insulin.
A recent study of an LC diet (< 20% energy from carbohydrates) demonstrated reduced HbA1c levels, weight, and waist circumference vs a control diet after 6 months. The control diet derived 50% to 60% of energy from carbohydrates.18 This study is typical of other LC interventions, which did not calorie restrict and instead allowed ad libitum intake.14,15
With mounting evidence, the VA/DoD guidelines on T2DM management included LC diets as dietary options for treating T2DM. The ADA also determined that LC diets had the most evidence in improving glycemia and included LC diets as an option for medical nutrition therapy (Table 1).10,19
A systematic review and meta-analysis looking at RCTs of LC diets found evidence for remission of T2DM without significant adverse effects (AEs).20 Another recent systematic review and network meta-analysis of 42 RCTs found that the ketogenic diet was superior for a reduction in HbA1c levels compared with 9 other dietary patterns, including low-fat, Mediterranean, and vegetarian/vegan diets. Overall, ketogenic, Mediterranean, moderate-carbohydrate, and low-glycemic index diets demonstrated improved glycemic control.21
Ideally, a comprehensive behavioral program, such as the VA Move! or Whole Health program, should incorporate patient aligned care teams (PACTs), behavioral health clinicians, clinical pharmacists, and dietitians to provide medical-nutrition therapy using LC diets. However, many facilities may not have adequate experience, expertise, or support. We provide practical approaches to provide LC nutrition counseling, medication management, and deprescribing for any primary care clinician applying LC diets for their patients. For simplicity and practicality, we define 3 types of LC dietary patterns: (1) VLCK (< 50 g); (2) LC (50-100 g); and (3) moderate LC (101-150 g).
Nutrition
All nutrition approaches, including LC diets, should be patient centered, individualized, and sensitive to the patient's culture. Typically, many patients have previously been instructed to consume low-fat (and subsequently) high-carbohydrate (> 150 g) meals. Most well-meaning clinicians have provided common-approach diet education from mainstream health organizations in the form of standardized handouts. For example, the Carbohydrate Counting for People with Diabetes patient education handout from the Academy of Nutrition and Dietetics provides a sample menu with 3 meals and 1 snack totaling 195 g of carbohydrates.22 In contrast, an example ADA diet has sample diets with 3 meals and 2 snacks with approximately 20 to 70 g of carbohydrates.23 In the VA, there are excellent resources to review and standardize handouts that emphasize an LC nutrition approach to T2DM, including ketogenic versions.24,25 Table 2 shows example meal plans based on different LC patterns—VLCK, LC, and moderate LC.
Starting an LC dietary pattern should maximize nutrient-dense and minimally processed proteins. Clinicians should begin with a baseline nutritional assessment through a 24-hour recall or food diary. After this has been completed, the patient’s baseline diet is assessed, and a gradual carbohydrate reduction plan is discussed. Generally, carbohydrate reduction is recommended at 1 meal per day per week. High-carbohydrate meals and snacks are restructured to favor satiating, minimally processed, high-protein food sources. Individual food preferences are considered and included in the recommended LC plan. For example, LC diets can be formulated for vegetarians and vegans as well as those who prefer meat and seafood. Prioritizing satiating and nutrient-dense foods can help increase the probability of diet acceptance and adherence.
A recent studyshowed that restricting carbohydrates at breakfast reduces 24-hour postprandial hyperglycemia and improves glycemic variability.26 Many patients consume upward of 50 g of carbohydrates at breakfast.27 For example, it is not uncommon for a patient to consume cereal with milk or oatmeal, orange juice, a banana, and toast at breakfast. Instead, the patient is advised to consume any combination of eggs, meat, no-sugar-added Greek yogurt, or berries.
To keep things simple for lunch and dinner, the patient is offered high-quality, minimally processed protein of their choosing with any nonstarchy vegetable. Should a patient desire additional carbohydrates with meals, they may reduce the baseline serving of carbohydrates by 50%. For example, if a patient normally fills 50% of their plate with spaghetti, they may reduce the pasta portion to 25% and add a meatball or increase the amount of vegetables consumed with the meal to satiety.
Snacks may include cheese, eggs, peanut butter, nuts, seeds, berries, no-sugar-added Greek yogurt, or guacamole. Oftentimes, when LC meals are adopted, the desire or need for snacking is diminished due to the satiating effect of high-quality protein sources and nonstarchy vegetables.
Adverse Effects
AEs have been reported with VLCK diets, including headache, diarrhea, constipation, muscle cramps, halitosis, light-headedness, and muscle weakness.28 These AEs may be mitigated with increased fluid intake, sodium intake, and magnesium supplementation.29 Increasing fluids to a minimum of 2 L/d and adding sodium (eg, bouillon supplementation) can minimize AEs.30 Milk of magnesia (5 mL) or slow-release magnesium chloride 200 mEq/d is suggested to reduce muscle cramps.30 There have been no studies looking at sodium intake and worsening hypertension or chronic heart failure in the setting of an LC diet, but fluid and electrolyte intake should be monitored closely, especially in patients with uncontrolled hypertension and heart failure. Other concerns of higher protein on worsening kidney function have generally not been founded.31 In some individuals, an LC and higher fat diet may increase low-density lipoprotein cholesterol (LDL-C).32 Therefore a baseline lipid panel is recommended and should be monitored along with HbA1c levels. An elevated LDL-C response may be managed by increasing protein and reducing saturated fat intake while maintaining the reduced carbohydrate content of the diet.
Medication Management
The adoption of an LC diet can cause a swift and profound reduction in blood sugar.33 Utilizing PACTs can help prevent adverse drug events by involving clinical pharmacists to provide recommendations and dose reductions as patients adopt an LC diet. Each approach must be individualized to the patient and can depend on several factors, including the number and strength of medications, the degree of carbohydrate reduction, baseline blood glucose, as well as assessing for medical literacy and ability to implement recommendations. Additionally, patients should monitor their blood sugar regularly and communicate with their primary care team (pharmacist, PACT registered nurse, primary care clinician, and registered dietician). Ultimately, the goal when adopting an LC diet while taking antihyperglycemics is safely avoiding hypoglycemia while reducing the number of medications the patient is taking. We summarize a practical approach to medication management that was recently published (Table 3).33,34
Medications to Reduce or Discontinue
Medications that can cause hypoglycemia should be the first to be reduced or discontinued upon starting an LC diet, including bolus insulin (although a small amount may be needed to correct for high blood sugar), sulfonylureas, and meglitinides. Combination insulin should be stopped and changed to basal insulin to avoid the risk of hypoglycemia (see Table 4 for insulin deprescribing recommendations). The mechanism of action in preventing the breakdown of carbohydrates in the gastrointestinal tract makes the use of α-glucosidase inhibitors superfluous, and they can be discontinued, reducing pill burden and polypharmacy risks. Sodium-glucose transport protein 2 inhibitors (SGLT2i) should be discontinued for patients on VLCK diets due to the risk of euglycemic diabetic ketoacidosis. However, with LC and moderate LC plans, the SGLT2i may be used with caution as long as patients are made aware of ketoacidosis symptoms. To help prevent the risk of hypoglycemia, basal/long-acting insulin can be continued, but at a 50% reduced dose. Patients should closely monitor blood sugar to assess for appropriateness of dose reductions. While thiazolidinediones are not contraindicated, clinicians can consider discontinuation given both their penchant for inducing weight gain and their limited outcomes data.
Medications to Continue
Medications that pose minimal risk for hypoglycemia can be continued, including metformin, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide-1 agonists. However, even though these may pose a low risk of hypoglycemia, patients should still closely monitor their blood glucose so medications can be deprescribed as soon as safely and reasonably possible.
Other Medications
The improvement in metabolic health with the reduction of carbohydrates can render other classes of medications unnecessary or require adjustment. Patients should be counseled to monitor their blood pressure as significant and rapid improvements can occur. In the event of a systolic blood pressure of 100 to 110 mm Hg or signs of hypotension, down titration or discontinuation of antihypertensives should be initiated. Limited evidence exists on the preferred order of discontinuation but should be informed by other comorbidities, such as coronary artery disease and chronic kidney disease. Given an LC diet’s diuretic effect, tapering and stopping diuretics may be an option. Other medications requiring closer monitoring include lithium (can be affected by fluid and electrolyte shifts), warfarin (may alter vitamin K intake), valproate (which may be reduced), and zonisamide and topiramate (kidney stone risk).
Remission of T2DM with LC Diets
As patients adopt LC diets and medications are deprescribed and glycemia improves, HbA1c and fasting glucose levels may drop below the diagnostic threshold for T2DM.20 As new evidence emerges surrounding the management of T2DM from a lifestyle perspective, major health care organizations have acknowledged that T2DM is not necessarily an incurable, progressive disease, but rather a disease that can be reversed or put in remission.35-37 In 2016, the World Health Organization (WHO) global report on diabetes acknowledged that T2DM reversal can be achieved via weight loss and calorie restriction.35
In 2021, a consensus statement from the ADA, the Endocrine Society, the EASD, and Diabetes UK defined T2DM remission as an HbA1c level < 6.5% for at least 3 months with no T2DM medications.36 Diabetes Australia also published a position statement in 2021 about T2DM remission.37 Like the WHO, Diabetes Australia acknowledged that remission of T2DM is possible following intensive dietary changes or bariatric surgery.37 Before the 2021 consensus statement, some experts argued that excluding metformin from the T2DM medication list may not be warranted since metformin has indications beyond T2DM. In this case, remission of T2DM could be defined as an HbA1c level < 6.5% for at least 3 months and on metformin or no T2DM medications.8
Emerging Strategies
Emerging strategies, such as continuous glucose monitors (CGMs) and the use of intermittent fasting/time-restricted eating (TRE), can be used with the LC diet to help improve the monitoring and management of T2DM. In the recently published VA/DoD guidelines for T2DM, the work group suggested real-time CGMs for qualified patients with T2DM.4 These include patients on daily insulin who are not achieving glycemic control or to reduce the risk for hypoglycemia. CGMs have shown evidence of improved glycemic control and decreased hypoglycemia in those with T2DM.38,39 It is currently unknown if CGMs improve long-term glycemic control, but they appear promising for managing and reducing medications for those on an LC diet.40
TRE can be supplemented with an LC plan that incorporates “eating windows.” Common patterns include 14 hours of fasting and a 10-hour eating window (14F:10E), or 16 hours of fasting and an 8-hour eating window (16F:8E). By eating only in the specified window, patients generally reduce caloric intake and minimize insulin and glucose excursions during the fasting window. No changes need to be made to the macronutrient composition of the diet, and LC approaches can be used with TRE. The mechanism of action is likely multifactorial, targeting hyperinsulinemia and insulin resistance as well as producing a caloric deficit to enable weight loss.41 Eating windows may improve insulin sensitivity, reduce insulin resistance, and enhance overall glycemic control. The recent VA/DoD guidelines recommended against intermittent fasting due to concerns over the risk of hypoglycemia despite larger weight loss in TRE groups.4 Recently, a study using CGMs and TRE demonstrated both improved glycemic control and no hypoglycemic episodes in patients with T2DM on insulin.42 Patients who would like to supplement TRE with an LC plan as a strategy for improved glycemic control should work closely with their PACT to help manage their TRE and LC plan and consider a CGM adjunct, especially if on insulin.
Barriers
Managing T2DM often requires comprehensive lifestyle modifications of nutrition, exercise, sleep, stress management, and other psychosocial issues, as well as an interdisciplinary team-based approach.43 The advantage of working within the VA includes a uniform system within a network of care. However, many patients continue to use both federal and private health care. This use of out-of-network care may result in fragmented, potentially disjointed, or even contradictory dietary advice.
The VA PACT, whole health for holistic health, and weight loss interventions such as the MOVE! program provide lifestyle interventions like nutrition, physical activity, and behavior change. However, these well-intentioned approaches may provide alternative and even diverging recommendations, which place additional barriers to effective patient management. In patients who are advised and accept a trial of an LC plan, each member of the team should embrace the self-management decision of the patient and support the plan.29 Any conflicts, questions, or concerns should be communicated directly with the team in an interdisciplinary approach to provide a unified message and counsel.
The long-term effects and sustainability of an LC diet have been questioned in the literature.44-46 Recently, the use of an app-based coaching plan has demonstrated short- and long-term sustainability on an LC diet.47 In just 5 months in a large VA system, 590 patients using a virtual coaching platform and a VLCK diet plan were found to have lower HbA1c levels, reduced diabetic medication fills, lower body mass index, fewer outpatient visits, and lower prescription drug costs.
A 5-year follow-up found nearly 50% of participants sustained a VLCK diet for T2DM. For patients who participated in the study after 2 years, 72% sustained the VLCK diet in years 2 to 5. Most required nearly 50% fewer medications and in those that started with insulin, half did not require it at 5 years.48 Further research, however, is necessary to determine the long-term effects on cardiometabolic markers and health with LC diets. There are no long-term RCTs on outcomes data looking at T2DM morbidity or mortality. While there are prospective cohort studies on LC diets in the general population on mortality, they demonstrate mixed results. These studies may be confounded by heterogeneous definitions of LC diets, diet quality, and other health factors.49-51
Conclusions
The effective use of LC diets within a PACT with close and intensive lifestyle counseling and a safe approach to medication management and deprescribing can improve glycemic control, reduce the overall need for insulin, reduce medication use, and provide sustained weight loss. Additionally, the use of therapeutic carbohydrate reduction and subsequent medication deprescription may lead to sustained remission of T2DM. The current efficacy and sustainment of therapeutic carbohydrate reduction for patients with T2DM appears promising. Further research on LC diets, emerging strategies, and long-term effects on cardiometabolic risk factors, morbidity, and mortality will continue to inform future practice in our health care system.
Acknowledgments
We thank Cecile Seth who has been instrumental in pushing us forward and the Metabolic Multiplier group who has helped encourage and provide input into this article.
1. Centers for Disease Control and Prevention. Prevalence of Both Diagnosed and Undiagnosed Diabetes. Updated September 30, 2022. Accessed October 6, 2023. https://www.cdc.gov/diabetes/data/statistics-report/diagnosed-undiagnosed-diabetes.html
2. Centers for Disease Control and Prevention. Diabetes and Prediabetes. Updated September 6, 2022. Accessed October 6, 2023. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm 3. US Department of Veterans Affairs. Diabetes information - Nutrition and food services. Updated May 4, 2023. Accessed October 6, 2023. https://www.nutrition.va.gov/diabetes.asp
4. US Department of Veterans Affairs. Management of Type 2 Diabetes Mellitus (2023) - VA/DoD Clinical Practice Guidelines. Updated September 1, 2023. Accessed October 6, 2023. https://www.healthquality.va.gov/guidelines/CD/diabetes/
5. American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2017. Diabetes Care. 2018;41(5):917-928. doi:10.2337/dci18-0007
6. Home P, Riddle M, Cefalu WT, et al. Insulin therapy in people with type 2 diabetes: opportunities and challenges?. Diabetes Care. 2014;37(6):1499-1508. doi:10.2337/dc13-2743
7. Donath MY, Ehses JA, Maedler K, et al. Mechanisms of β-cell death in type 2 diabetes. Diabetes. 2005;54(suppl 2):S108-S113. doi:10.2337/DIABETES.54.SUPPL_2.S108
8. Hallberg SJ, Gershuni VM, Hazbun TL, Athinarayanan SJ. Reversing type 2 diabetes: a narrative review of the evidence. Nutrients. 2019;11(4):766. Published 2019 Apr 1. doi:10.3390/nu11040766
9. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669. doi:10.2337/DCI18-0033
10. Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019;42(5):731-754. doi:10.2337/DCI19-0014
11. Diabetes Canada position statement on low-carbohydrate diets for adults with diabetes: a rapid review. Can J Diabetes. 2020;44(4):295-299. doi:10.1016/J.JCJD.2020.04.001
12. Diabetes Australia. Position statements. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/research-advocacy/position-statements/
13. Feinman RD, Pogozelski WK, Astrup A, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2014;31(1):1-13. doi:10.1016/j.nut.2014.06.011
14. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003;348(21):2074-2081. doi:10.1056/NEJMOA02263715. Westman EC, Yancy WS, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond). 2008;5(1):36. doi:10.1186/1743-7075-5-36
16. Saslow LR, Mason AE, Kim S, et al. An online intervention comparing a very low-carbohydrate ketogenic diet and lifestyle recommendations versus a plate method diet in overweight individuals with type 2 diabetes: a randomized controlled trial. J Med Internet Res. 2017;19(2). doi:10.2196/JMIR.5806
17. Hallberg SJ, McKenzie AL, Williams PT, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Ther. 2018;9(2):583-612. doi:10.1007/S13300-018-0373-9
18. Gram-Kampmann EM, Hansen CD, Hugger MB, et al. Effects of a 6-month, low-carbohydrate diet on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes: An open-label randomized controlled trial. Diabetes Obes Metab. 2022;24(4):693-703. doi:10.1111/DOM.14633
19. Committee ADAPP. 5. Facilitating behavior change and well-being to improve health outcomes: standards of medical care in diabetes—2022. Diabetes Care. 2022;45(suppl 1):S60-S82. doi:10.2337/DC22-S005
20. Goldenberg JZ, Johnston BC. Low and very low carbohydrate diets for diabetes remission. BMJ. 2021;373:m4743. doi:10.1136/BMJ.N262
21. Jing T, Zhang S, Bai M, et al. Effect of dietary approaches on glycemic control in patients with type 2 diabetes: a systematic review with network meta-analysis of randomized trials. Nutrients. 2023;15(14):3156. doi:10.3390/nu15143156
22. Academy of Nutrition and Dietetics. Nutrition care manual. Accessed October 6, 2023. https://www.nutritioncaremanual.org/
23. Low carbohydrate and very low carbohydrate eating patterns in adults with diabetes. ShopDiabetes.org. Accessed August 5, 2022. https://shopdiabetes.org/products/low-carbohydrate-and-very-low-carbohydrate-eating-patterns-in-adults-with-diabetes-a-guide-for-health-care-providers
24. US Department of Veterans Affairs. Diabetes education - nutrition and food services. Published July 31, 2022. http://vaww.nutrition.va.gov/docs/pted/ModifiedKetogenicDiet.pdf [Source not verified]
25. US Department of Veterans Affairs, My HealtheVet. Lowdown on low-carb diets. Updated June 1, 2021. Accessed October 6, 2023. https://www.myhealth.va.gov/mhv-portal-web/ss20190724-low-carb-diet
26. Chang CR, Francois ME, Little JP. Restricting carbohydrates at breakfast is sufficient to reduce 24-hour exposure to postprandial hyperglycemia and improve glycemic variability. Am J Clin Nutr. 2019;109(5):1302-1309. doi:10.1093/AJCN/NQY261
27. Hall KD, Ayuketah A, Brychta R, et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metab. 2019;30(1):226. doi:10.1016/j.cmet.2019.05.020
28. Harvey CJ d. C, Schofield GM, Zinn C, Thornley S. Effects of differing levels of carbohydrate restriction on mood achievement of nutritional ketosis, and symptoms of carbohydrate withdrawal in healthy adults: a randomized clinical trial. Nutrition. 2019;67-68:100005. doi:10.1016/J.NUTX.2019.100005
29. Griauzde DH, Standafer Lopez K, Saslow LR, Richardson CR. A pragmatic approach to translating low- and very low-carbohydrate diets into clinical practice for patients with obesity and type 2 diabetes. Front Nutr. 2021;8:416. doi:10.3389/FNUT.2021.682137/BIBTEX
30. Westman EC, Tondt J, Maguire E, Yancy WS. Implementing a low-carbohydrate, ketogenic diet to manage type 2 diabetes mellitus. Expert Rev Endocrinol Metab. 2018;13(5):263-272. doi:10.1080/17446651.2018.1523713
31. Suyoto PST. Effect of low-carbohydrate diet on markers of renal function in patients with type 2 diabetes: a meta-analysis. Diabetes Metab Res Rev. 2018;34(7). doi:10.1002/DMRR.3032
32. Norwitz NG, Feldman D, Soto-Mota A, Kalayjian T, Ludwig DS. Elevated LDL cholesterol with a carbohydrate-restricted diet: evidence for a “lean mass hyper-responder” phenotype. Curr Dev Nutr. 2021;6(1). doi:10.1093/CDN/NZAB144
33. Murdoch C, Unwin D, Cavan D, Cucuzzella M, Patel M. Adapting diabetes medication for low carbohydrate management of type 2 diabetes: a practical guide. Br J Gen Pract. 2019;69(684):360-361. doi:10.3399/bjgp19X704525
34. Cucuzzella M, Riley K, Isaacs D. Adapting medication for type 2 diabetes to a low carbohydrate diet. Front Nutr. 2021;8:486. doi:10.3389/FNUT.2021.688540/BIBTEX
35. World Health Organization. Global report on diabetes. 2016. Accessed October 6, 2023. https://iris.who.int/bitstream/handle/10665/204871/9789241565257_eng.pdf?sequence=1
36. Riddle MC, Cefalu WT, Evans PH, et al. Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetes Care. 2021;44(10):2438-2444. doi:10.2337/DCI21-0034
37. Diabetes Australia. Type 2 Diabetes remission position statement. 2021. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/wp-content/uploads/2021_Diabetes-Australia-Position-Statement_Type-2-diabetes-remission_2.pdf
38. Martens T, Beck RW, Bailey R, et al. Effect of continuous glucose monitoring on glycemic control in patients with type 2 diabetes treated with basal insulin: a randomized clinical trial. JAMA. 2021;325(22):2262-2272. doi:10.1001/JAMA.2021.7444
39. Jackson MA, Ahmann A, Shah VN. Type 2 diabetes and the use of real-time continuous glucose monitoring. Diabetes Technol Ther. 2021;23(S1):S27-S34. doi:10.1089/DIA.2021.0007
40. Oser TK, Cucuzzella M, Stasinopoulos M, Moncrief M, McCall A, Cox DJ. An innovative, paradigm-shifting lifestyle intervention to reduce glucose excursions with the use of continuous glucose monitoring to educate, motivate, and activate adults with newly diagnosed type 2 diabetes: pilot feasibility study. JMIR Diabetes. 2022;7(1). doi:10.2196/34465
41. Światkiewicz I, Woźniak A, Taub PR. Time-restricted eating and metabolic syndrome: current status and future perspectives. Nutrients. 2021;13(1):221. doi:10.3390/NU13010221
42. Obermayer A, Tripolt NJ, Pferschy PN, et al. Efficacy and safety of intermittent fasting in people with insulin-treated type 2 diabetes (INTERFAST-2)—a randomized controlled trial. Diabetes Care. 2023;46(2):463-468. doi:10.2337/dc22-1622
43. American Diabetes Association. 5. Lifestyle management: standards of medical care in diabetes—2019. Diabetes Care. 2019;42(suppl 1):S46-S60. doi:10.2337/DC19-S005
44. Li S, Ding L, Xiao X. Comparing the efficacy and safety of low-carbohydrate diets with low-fat diets for type 2 diabetes mellitus patients: a systematic review and meta-analysis of randomized clinical trials. Int J Endocrinol. 2021;2021:8521756. Published 2021 Dec 6. doi:10.1155/2021/8521756
45. Choi JH, Kang JH, Chon S. Comprehensive understanding for application in Korean patients with type 2 diabetes mellitus of the consensus statement on carbohydrate-restricted diets by Korean Diabetes Association, Korean Society for the Study of Obesity, and Korean Society of Hypertension. Diabetes Metab J. 2022;46(3):377. doi:10.4093/DMJ.2022.0051
46. Jayedi A, Zeraattalab-Motlagh S, Jabbarzadeh B, et al. Dose-dependent effect of carbohydrate restriction for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized controlled trials. Am J Clin Nutr. 2022;116(1). doi:10.1093/AJCN/NQAC066
47. Strombotne KL, Lum J, Ndugga NJ, et al. Effectiveness of a ketogenic diet and virtual coaching intervention for patients with diabetes: a difference-in-differences analysis. Diabetes Obes Metab. 2021;23(12):2643-2650. doi:10.1111/DOM.14515
48. Virta Health. Virta Health highlights lasting, transformative health improvements in 5-year diabetes reversal study. June 5, 2022. Accessed October 6, 2023. https://www.virtahealth.com/blog/virta-sustainable-health-improvements-5-year-diabetes-reversal-study
49. Wan Z, Shan Z, Geng T, et al. Associations of moderate low-carbohydrate diets with mortality among patients with type 2 diabetes: a prospective cohort study. J Clin Endocrinol Metab. 2022;107(7):E2702-E2709. doi:10.1210/CLINEM/DGAC235
50. Akter S, Mizoue T, Nanri A, et al. Low carbohydrate diet and all cause and cause-specific mortality. Clin Nutr. 2021;40(4):2016-2024. doi:10.1016/J.CLNU.2020.09.022
51. Shan Z, Guo Y, Hu FB, Liu L, Qi Q. Association of low-carbohydrate and low-fat diets with mortality among US adults. JAMA Intern Med. 2020;180(4):513-523. doi:10.1001/JAMAINTERNMED.2019.6980
1. Centers for Disease Control and Prevention. Prevalence of Both Diagnosed and Undiagnosed Diabetes. Updated September 30, 2022. Accessed October 6, 2023. https://www.cdc.gov/diabetes/data/statistics-report/diagnosed-undiagnosed-diabetes.html
2. Centers for Disease Control and Prevention. Diabetes and Prediabetes. Updated September 6, 2022. Accessed October 6, 2023. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm 3. US Department of Veterans Affairs. Diabetes information - Nutrition and food services. Updated May 4, 2023. Accessed October 6, 2023. https://www.nutrition.va.gov/diabetes.asp
4. US Department of Veterans Affairs. Management of Type 2 Diabetes Mellitus (2023) - VA/DoD Clinical Practice Guidelines. Updated September 1, 2023. Accessed October 6, 2023. https://www.healthquality.va.gov/guidelines/CD/diabetes/
5. American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2017. Diabetes Care. 2018;41(5):917-928. doi:10.2337/dci18-0007
6. Home P, Riddle M, Cefalu WT, et al. Insulin therapy in people with type 2 diabetes: opportunities and challenges?. Diabetes Care. 2014;37(6):1499-1508. doi:10.2337/dc13-2743
7. Donath MY, Ehses JA, Maedler K, et al. Mechanisms of β-cell death in type 2 diabetes. Diabetes. 2005;54(suppl 2):S108-S113. doi:10.2337/DIABETES.54.SUPPL_2.S108
8. Hallberg SJ, Gershuni VM, Hazbun TL, Athinarayanan SJ. Reversing type 2 diabetes: a narrative review of the evidence. Nutrients. 2019;11(4):766. Published 2019 Apr 1. doi:10.3390/nu11040766
9. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669. doi:10.2337/DCI18-0033
10. Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019;42(5):731-754. doi:10.2337/DCI19-0014
11. Diabetes Canada position statement on low-carbohydrate diets for adults with diabetes: a rapid review. Can J Diabetes. 2020;44(4):295-299. doi:10.1016/J.JCJD.2020.04.001
12. Diabetes Australia. Position statements. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/research-advocacy/position-statements/
13. Feinman RD, Pogozelski WK, Astrup A, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2014;31(1):1-13. doi:10.1016/j.nut.2014.06.011
14. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003;348(21):2074-2081. doi:10.1056/NEJMOA02263715. Westman EC, Yancy WS, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond). 2008;5(1):36. doi:10.1186/1743-7075-5-36
16. Saslow LR, Mason AE, Kim S, et al. An online intervention comparing a very low-carbohydrate ketogenic diet and lifestyle recommendations versus a plate method diet in overweight individuals with type 2 diabetes: a randomized controlled trial. J Med Internet Res. 2017;19(2). doi:10.2196/JMIR.5806
17. Hallberg SJ, McKenzie AL, Williams PT, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Ther. 2018;9(2):583-612. doi:10.1007/S13300-018-0373-9
18. Gram-Kampmann EM, Hansen CD, Hugger MB, et al. Effects of a 6-month, low-carbohydrate diet on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes: An open-label randomized controlled trial. Diabetes Obes Metab. 2022;24(4):693-703. doi:10.1111/DOM.14633
19. Committee ADAPP. 5. Facilitating behavior change and well-being to improve health outcomes: standards of medical care in diabetes—2022. Diabetes Care. 2022;45(suppl 1):S60-S82. doi:10.2337/DC22-S005
20. Goldenberg JZ, Johnston BC. Low and very low carbohydrate diets for diabetes remission. BMJ. 2021;373:m4743. doi:10.1136/BMJ.N262
21. Jing T, Zhang S, Bai M, et al. Effect of dietary approaches on glycemic control in patients with type 2 diabetes: a systematic review with network meta-analysis of randomized trials. Nutrients. 2023;15(14):3156. doi:10.3390/nu15143156
22. Academy of Nutrition and Dietetics. Nutrition care manual. Accessed October 6, 2023. https://www.nutritioncaremanual.org/
23. Low carbohydrate and very low carbohydrate eating patterns in adults with diabetes. ShopDiabetes.org. Accessed August 5, 2022. https://shopdiabetes.org/products/low-carbohydrate-and-very-low-carbohydrate-eating-patterns-in-adults-with-diabetes-a-guide-for-health-care-providers
24. US Department of Veterans Affairs. Diabetes education - nutrition and food services. Published July 31, 2022. http://vaww.nutrition.va.gov/docs/pted/ModifiedKetogenicDiet.pdf [Source not verified]
25. US Department of Veterans Affairs, My HealtheVet. Lowdown on low-carb diets. Updated June 1, 2021. Accessed October 6, 2023. https://www.myhealth.va.gov/mhv-portal-web/ss20190724-low-carb-diet
26. Chang CR, Francois ME, Little JP. Restricting carbohydrates at breakfast is sufficient to reduce 24-hour exposure to postprandial hyperglycemia and improve glycemic variability. Am J Clin Nutr. 2019;109(5):1302-1309. doi:10.1093/AJCN/NQY261
27. Hall KD, Ayuketah A, Brychta R, et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metab. 2019;30(1):226. doi:10.1016/j.cmet.2019.05.020
28. Harvey CJ d. C, Schofield GM, Zinn C, Thornley S. Effects of differing levels of carbohydrate restriction on mood achievement of nutritional ketosis, and symptoms of carbohydrate withdrawal in healthy adults: a randomized clinical trial. Nutrition. 2019;67-68:100005. doi:10.1016/J.NUTX.2019.100005
29. Griauzde DH, Standafer Lopez K, Saslow LR, Richardson CR. A pragmatic approach to translating low- and very low-carbohydrate diets into clinical practice for patients with obesity and type 2 diabetes. Front Nutr. 2021;8:416. doi:10.3389/FNUT.2021.682137/BIBTEX
30. Westman EC, Tondt J, Maguire E, Yancy WS. Implementing a low-carbohydrate, ketogenic diet to manage type 2 diabetes mellitus. Expert Rev Endocrinol Metab. 2018;13(5):263-272. doi:10.1080/17446651.2018.1523713
31. Suyoto PST. Effect of low-carbohydrate diet on markers of renal function in patients with type 2 diabetes: a meta-analysis. Diabetes Metab Res Rev. 2018;34(7). doi:10.1002/DMRR.3032
32. Norwitz NG, Feldman D, Soto-Mota A, Kalayjian T, Ludwig DS. Elevated LDL cholesterol with a carbohydrate-restricted diet: evidence for a “lean mass hyper-responder” phenotype. Curr Dev Nutr. 2021;6(1). doi:10.1093/CDN/NZAB144
33. Murdoch C, Unwin D, Cavan D, Cucuzzella M, Patel M. Adapting diabetes medication for low carbohydrate management of type 2 diabetes: a practical guide. Br J Gen Pract. 2019;69(684):360-361. doi:10.3399/bjgp19X704525
34. Cucuzzella M, Riley K, Isaacs D. Adapting medication for type 2 diabetes to a low carbohydrate diet. Front Nutr. 2021;8:486. doi:10.3389/FNUT.2021.688540/BIBTEX
35. World Health Organization. Global report on diabetes. 2016. Accessed October 6, 2023. https://iris.who.int/bitstream/handle/10665/204871/9789241565257_eng.pdf?sequence=1
36. Riddle MC, Cefalu WT, Evans PH, et al. Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetes Care. 2021;44(10):2438-2444. doi:10.2337/DCI21-0034
37. Diabetes Australia. Type 2 Diabetes remission position statement. 2021. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/wp-content/uploads/2021_Diabetes-Australia-Position-Statement_Type-2-diabetes-remission_2.pdf
38. Martens T, Beck RW, Bailey R, et al. Effect of continuous glucose monitoring on glycemic control in patients with type 2 diabetes treated with basal insulin: a randomized clinical trial. JAMA. 2021;325(22):2262-2272. doi:10.1001/JAMA.2021.7444
39. Jackson MA, Ahmann A, Shah VN. Type 2 diabetes and the use of real-time continuous glucose monitoring. Diabetes Technol Ther. 2021;23(S1):S27-S34. doi:10.1089/DIA.2021.0007
40. Oser TK, Cucuzzella M, Stasinopoulos M, Moncrief M, McCall A, Cox DJ. An innovative, paradigm-shifting lifestyle intervention to reduce glucose excursions with the use of continuous glucose monitoring to educate, motivate, and activate adults with newly diagnosed type 2 diabetes: pilot feasibility study. JMIR Diabetes. 2022;7(1). doi:10.2196/34465
41. Światkiewicz I, Woźniak A, Taub PR. Time-restricted eating and metabolic syndrome: current status and future perspectives. Nutrients. 2021;13(1):221. doi:10.3390/NU13010221
42. Obermayer A, Tripolt NJ, Pferschy PN, et al. Efficacy and safety of intermittent fasting in people with insulin-treated type 2 diabetes (INTERFAST-2)—a randomized controlled trial. Diabetes Care. 2023;46(2):463-468. doi:10.2337/dc22-1622
43. American Diabetes Association. 5. Lifestyle management: standards of medical care in diabetes—2019. Diabetes Care. 2019;42(suppl 1):S46-S60. doi:10.2337/DC19-S005
44. Li S, Ding L, Xiao X. Comparing the efficacy and safety of low-carbohydrate diets with low-fat diets for type 2 diabetes mellitus patients: a systematic review and meta-analysis of randomized clinical trials. Int J Endocrinol. 2021;2021:8521756. Published 2021 Dec 6. doi:10.1155/2021/8521756
45. Choi JH, Kang JH, Chon S. Comprehensive understanding for application in Korean patients with type 2 diabetes mellitus of the consensus statement on carbohydrate-restricted diets by Korean Diabetes Association, Korean Society for the Study of Obesity, and Korean Society of Hypertension. Diabetes Metab J. 2022;46(3):377. doi:10.4093/DMJ.2022.0051
46. Jayedi A, Zeraattalab-Motlagh S, Jabbarzadeh B, et al. Dose-dependent effect of carbohydrate restriction for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized controlled trials. Am J Clin Nutr. 2022;116(1). doi:10.1093/AJCN/NQAC066
47. Strombotne KL, Lum J, Ndugga NJ, et al. Effectiveness of a ketogenic diet and virtual coaching intervention for patients with diabetes: a difference-in-differences analysis. Diabetes Obes Metab. 2021;23(12):2643-2650. doi:10.1111/DOM.14515
48. Virta Health. Virta Health highlights lasting, transformative health improvements in 5-year diabetes reversal study. June 5, 2022. Accessed October 6, 2023. https://www.virtahealth.com/blog/virta-sustainable-health-improvements-5-year-diabetes-reversal-study
49. Wan Z, Shan Z, Geng T, et al. Associations of moderate low-carbohydrate diets with mortality among patients with type 2 diabetes: a prospective cohort study. J Clin Endocrinol Metab. 2022;107(7):E2702-E2709. doi:10.1210/CLINEM/DGAC235
50. Akter S, Mizoue T, Nanri A, et al. Low carbohydrate diet and all cause and cause-specific mortality. Clin Nutr. 2021;40(4):2016-2024. doi:10.1016/J.CLNU.2020.09.022
51. Shan Z, Guo Y, Hu FB, Liu L, Qi Q. Association of low-carbohydrate and low-fat diets with mortality among US adults. JAMA Intern Med. 2020;180(4):513-523. doi:10.1001/JAMAINTERNMED.2019.6980
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>0124 FED Keto</fileName> <TBEID>0C02EE34.SIG</TBEID> <TBUniqueIdentifier>NJ_0C02EE34</TBUniqueIdentifier> <newsOrJournal>Journal</newsOrJournal> <publisherName>Frontline Medical Communications Inc.</publisherName> <storyname/> <articleType>1</articleType> <TBLocation>Copyfitting-FED</TBLocation> <QCDate/> <firstPublished>20240103T212824</firstPublished> <LastPublished>20240103T212824</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20240103T212824</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline/> <bylineText>Robert C. Oh, MD, MPHa; Kendrick C. Murphy, PharmD, BCACP, MHPb; Cory M. Jenks, PharmD, MHP, BCPS, BCACPc; Kathleen B. Lopez, RDN, CDCES, CNSCd; Mahendra A. Patel, PharmD, BCPSe; Emily E. Scotland, MSN, FNP-Ce; Monu Khanna, MD, MHPf</bylineText> <bylineFull/> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType/> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>The prevalence of diabetes continues to increase despite advances in treatment options. In 2019, according to the Centers for Disease Control and Prevention (CD</metaDescription> <articlePDF/> <teaserImage/> <title>Low-Carbohydrate and Ketogenic Dietary Patterns for Type 2 Diabetes Management</title> <deck/> <eyebrow>Clinical Review</eyebrow> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear>2024</pubPubdateYear> <pubPubdateMonth>January</pubPubdateMonth> <pubPubdateDay/> <pubVolume>41</pubVolume> <pubNumber>1</pubNumber> <wireChannels/> <primaryCMSID/> <CMSIDs> <CMSID>2967</CMSID> <CMSID>3639</CMSID> </CMSIDs> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>FED</publicationCode> <pubIssueName>January 2024</pubIssueName> <pubArticleType>Feature Articles | 3639</pubArticleType> <pubTopics/> <pubCategories/> <pubSections> <pubSection>Clinical Review | 2967<pubSubsection/></pubSection> </pubSections> <journalTitle>Fed Pract</journalTitle> <journalFullTitle>Federal Practitioner</journalFullTitle> <copyrightStatement>Copyright 2017 Frontline Medical Communications Inc., Parsippany, NJ, USA. All rights reserved.</copyrightStatement> </publicationData> </publications_g> <publications> <term canonical="true">16</term> </publications> <sections> <term canonical="true">49</term> </sections> <topics> <term canonical="true">205</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Low-Carbohydrate and Ketogenic Dietary Patterns for Type 2 Diabetes Management</title> <deck/> </itemMeta> <itemContent> <p class="abstract"><b>Background:</b> Type 2 diabetes mellitus (T2DM) has been traditionally considered a chronic, progressive disease. Since 2017, guidelines from the US Department of Veterans Affairs and US Department of Defense have included low-carbohydrate (LC) dietary patterns in managing T2DM. Recently, carbohydrate reduction, including ketogenic diets, has gained renewed interest in the management and remission of T2DM. <br/><br/><b>Observations:</b> This narrative review examines the evidence behind carbohydrate reduction in T2DM and a practical guide for clinicians starting patients on therapeutic LC diets. We present an illustrative case and provide practical approaches to prescribing a very LC ketogenic (< 50 g), LC (50-100 g), or a moderate LC (101-150 g) dietary plan and discuss adverse effects and management of LC diets. We provide a medication management and deprescription approach and discuss strategies to consider in conjunction with LC diets. As patients adopt LC diets, glycemia improves, and medications are deprescribed, hemoglobin A<sub>1c</sub> levels and fasting glucose may drop below the diagnostic threshold for T2DM. Remission of T2DM may occur with LC diets (hemoglobin A<sub>1c</sub> < 6.5% for ≥ 3 months without T2DM medications). Finally, we describe barriers and limitations to applying therapeutic carbohydrate reduction in a federal health care system. <br/><br/><b>Conclusions:</b> The effective use of LC diets with close and intensive lifestyle counseling and a safe approach to medication management and deprescribing can improve glycemic control, reduce the overall need for insulin and medication and provide sustained weight loss. The efficacy and continuation of therapeutic carbohydrate reduction for patients with T2DM appears promising. Further research on LC diets, emerging strategies, and long-term effects on cardiometabolic risk factors, morbidity, and mortality will continue to inform practice.</p> <p><span class="Drop">T</span>he prevalence of diabetes continues to increase despite advances in treatment options. In 2019, according to the Centers for Disease Control and Prevention (CDC), 37.1 million (14.7%) US adults had diabetes. Among adults aged ≥ 65 years, the prevalence is even higher at 29.2%.<sup>1</sup> Research has also estimated that 45% of adults have evidence of prediabetes or diabetes.<sup>2</sup> According to the Veterans Health Administration, almost 25% of enrolled veterans have diabetes.<sup>3</sup></p> <h2>Background</h2> <p>Diabetes is associated with an increased risk of microvascular complications (eg, retinopathy, nephropathy, and neuropathy) and macrovascular complications (eg, atherosclerotic cardiovascular disease) and is one of the most common causes of morbidity and mortality in the US.<sup>4</sup> In 2017, diabetes was estimated to cost $327 billion in the US, up from $261 billion in 2012.<sup>5</sup> During this same period, the excess costs per person with diabetes increased from $8417 to $9601.<sup>5</sup></p> <p>Type 2 diabetes mellitus (T2DM) and its associated insulin resistance is typically considered a chronic disease with progressive loss of β-cell function. Controlling glycemia, delaying microvascular changes, and preventing macrovascular disease are major management goals. Lifestyle interventions are essential in the management and prevention of T2DM. Medication management for T2DM usually progresses through several medications, ending in insulin therapy.<sup>6</sup> Within 10 years of diagnosis, almost half of all individuals with T2DM will require insulin to manage their glycemia.<sup>7<br/><br/></sup>Bariatric surgery and nutrition approaches have been successful in reversing T2DM. Recently, there has been increased interest in nutritional approaches to place T2DM in remission, reverse the disease process, and improve insulin resistance. Contrary to popular belief, before the discovery of insulin in 1921, low-carbohydrate (LC) diets were the most common treatment for T2DM.<sup>8</sup> With the discovery of insulin and the eventual development of low-fat dietary recommendations, LC diets were no longer favored by most clinicians.<sup>8</sup> Low-fat diets are, by definition, also high-carbohydrate diets. By the early 1980s, low-fat diets had become the standard of care dietary recommendation, and the goal for clinicians became glycemic maintenance (with increased use of medications) rather than preventing hyperglycemia.<sup>8<br/><br/></sup>With growing evidence regarding the use of LC diets for T2DM, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD), the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), Diabetes Canada, and Diabetes Australia all include LC diets as a viable option for treating T2DM.<sup>4,9-12</sup> This article will highlight a case using a reduced carbohydrate approach in lifestyle management and provide clinicians with practical guidance in its implementation. We will review the evidence that informs these guidelines, describe a practical approach to nutritional counseling, and review medication management and deprescribing approaches. Finally, barriers to implementation will be explored.</p> <h2>ILLUSTRATIVE CASE</h2> <p>A 64-year-old woman presented to the clinical pharmacist for the management of T2DM after her tenth hospitalization related to hyperglycemia in 10 years. She had previously been managed by primary care clinicians, clinical dietitians, endocrinologists, and certified diabetes care and education specialists. Pertinent history included diabetic ketoacidosis, coronary artery disease, hyperlipidemia, hypertension, obstructive sleep apnea, obesity, metabolic dysfunction-associated steatotic liver disease, and mild nonproliferative diabetic retinopathy with clinically significant macular edema. The patient expressed frustration with poor glycemic control during her many years of insulin therapy and an inability to lose weight due to insulin dose titrations. The patient reported prior education including but not limited to standardized sample menus, consistent carbohydrate intake, calorie reduction, general healthful nutrition, and the “move more, eat less” approach. The patient was unable to titrate insulin dosage and did not experience weight loss despite compliance with these methods.</p> <p>Her medications included glargine insulin 45 units once daily, aspart insulin 5 units before meals 3 times daily, and metformin 1000 mg twice daily. Her hemoglobin A<sub>1c</sub> (HbA<sub>1c</sub>) level was 11.8%. A review of prior therapies for T2DM included glyburide 5 mg twice daily, metformin 1000 mg twice daily, 70/30 insulin (up to 340 units/d), glargine insulin (range, 10-140 units/d), regular insulin (range, 30-240 units/d), aspart insulin (range, 15-45 units/d), and U-500 regular insulin (range, 125-390 units/d). She took metoprolol 25 mg extended release daily and hydrochlorothiazide 25 mg daily, but both were discontinued after the most recent hospitalization. A review of HbA<sub>1c</sub> readings showed poor glycemic control for > 12 years (range, 10.3% to > 12.3%).Education for lifestyle modifications, including an LC diet, was presented to the patient to assist with weight loss, improve glycemic control, and reduce insulin resistance. In addition, a glucagon-like peptide-1 agonist (liraglutide) was added to her pharmacotherapy. Continued dietary modifications with LC intake led to consistent reductions in glargine and aspart insulin therapy. The patient remained motivated throughout clinic visits due to improved glycemic control with sustainable dietary modifications, consistently reported feeling better overall, and deprescribed diabetes drug therapies. She remained off her blood pressure medications. After4 months of LC dietary modifications, all insulin therapy was discontinued. She continued with liraglutide 1.8 mg daily and metformin 1000 mg twice daily with an HbA<sub>1c</sub> of 6.3%. Two months later, her HbA<sub>1c</sub> level was 6.0%. She also lost 8 lb and her body mass index improved from 31 to 29.</p> <h2>Low-Carbohydrate T2DM DIET MANAGEMENT</h2> <p>LC diets are commonly defined as < 130 g of carbohydrates per day.<sup>13</sup> Very LC ketogenic (VLCK) diets often contain ≤ 50 g of carbohydrates per day to induce nutritional ketosis.<sup>13</sup> One of the first randomized controlled trials (RCTs) that compared a VLCK diet (< 30 g of carbohydrates per day) with a low-fat diet for obesity demonstrated greater weight loss at 6 months with the LC diet. In addition, patients with diabetes randomized to the LC group also showed improved insulin sensitivity. Notably, this study was done in a population of veterans enrolled at the VA Philadelphia Health Care System.<sup>14</sup> </p> <p>A 2008 study comparing an LC diet with a calorie-restricted, low-glycemic diet for individuals with T2DM found that the LC diet group experienced a greater reduction in HbA<sub>1c</sub> and insulin levels and weight.<sup>15</sup> Comparing these 2 diet groups after 24 weeks, 95% of individuals in the LC group reduced or discontinued T2DM medications vs 62% in the low-glycemic group.<sup>15</sup> Another study of individuals with T2DM compared a VLCK diet with a low-fat diet. After 34 weeks, 55% of individuals in the LC diet group achieved an HbA<sub>1c</sub> level below the threshold for diabetes vs 0% in the low-fat diet group.<sup>16</sup> A 2018 study of patients with T2DM investigated the impact of a very LC diet compared with the standard of care.<sup>17</sup> After 1 year, the LC diet group experienced a mean HbA<sub>1c</sub> reduction of 1.3%, and 60% of individuals who completed the study achieved an HbA<sub>1c</sub> level < 6.5% without T2DM medications (not including metformin). This study also demonstrated that medications were significantly reduced, including 100% discontinuation of sulfonylureas and 94% reduction or elimination of insulin.<br/><br/>A recent study of an LC diet (< 20% energy from carbohydrates) demonstrated reduced HbA<sub>1c</sub> levels, weight, and waist circumference vs a control diet after 6 months. The control diet derived 50% to 60% of energy from carbohydrates.<sup>18</sup> This study is typical of other LC interventions, which did not calorie restrict and instead allowed ad libitum intake.<sup>14,15<br/><br/></sup>With mounting evidence, the VA/DoD guidelines on T2DM management included LC diets as dietary options for treating T2DM. The ADA also determined that LC diets had the most evidence in improving glycemia and included LC diets as an option for medical nutrition therapy (Table 1).<sup>10,19<br/><br/></sup>A systematic review and meta-analysis looking at RCTs of LC diets found evidence for remission of T2DM without significant adverse effects (AEs).<sup>20</sup> Another recent systematic review and network meta-analysis of 42 RCTs found that the ketogenic diet was superior for a reduction in HbA<sub>1c</sub> levels compared with 9 other dietary patterns, including low-fat, Mediterranean, and vegetarian/vegan diets. Overall, ketogenic, Mediterranean, moderate-carbohydrate, and low-glycemic index diets demonstrated improved glycemic control.<sup>21<br/><br/></sup>Ideally, a comprehensive behavioral program, such as the VA Move! or Whole Health program, should incorporate patient aligned care teams (PACTs), behavioral health clinicians, clinical pharmacists, and dietitians to provide medical-nutrition therapy using LC diets. However, many facilities may not have adequate experience, expertise, or support. We provide practical approaches to provide LC nutrition counseling, medication management, and deprescribing for any primary care clinician applying LC diets for their patients. For simplicity and practicality, we define 3 types of LC dietary patterns: (1) VLCK (< 50 g); (2) LC (50-100 g); and (3) moderate LC (101-150 g).</p> <h2>Nutrition</h2> <p>All nutrition approaches, including LC diets, should be patient centered, individualized, and sensitive to the patient's culture. Typically, many patients have previously been instructed to consume low-fat (and subsequently) high-carbohydrate (> 150 g) meals. Most well-meaning clinicians have provided common-approach diet education from mainstream health organizations in the form of standardized handouts. For example, the Carbohydrate Counting for People with Diabetes patient education handout from the Academy of Nutrition and Dietetics provides a sample menu with 3 meals and 1 snack totaling 195 g of carbohydrates.<sup>22</sup> In contrast, an example ADA diet has sample diets with 3 meals and 2 snacks with approximately 20 to 70 g of carbohydrates.<sup>23</sup> In the VA, there are excellent resources to review and standardize handouts that emphasize an LC nutrition approach to T2DM, including ketogenic versions.<sup>24,25</sup> Table 2 shows example meal plans based on different LC patterns—VLCK, LC, and moderate LC.</p> <p>Starting an LC dietary pattern should maximize nutrient-dense and minimally processed proteins. Clinicians should begin with a baseline nutritional assessment through a 24-hour recall or food diary. After this has been completed, the patient’s baseline diet is assessed, and a gradual carbohydrate reduction plan is discussed. Generally, carbohydrate reduction is recommended at 1 meal per day per week. High-carbohydrate meals and snacks are restructured to favor satiating, minimally processed, high-protein food sources. Individual food preferences are considered and included in the recommended LC plan. For example, LC diets can be formulated for vegetarians and vegans as well as those who prefer meat and seafood. Prioritizing satiating and nutrient-dense foods can help increase the probability of diet acceptance and adherence. <br/><br/>A recent study<sup> </sup>showed that restricting carbohydrates at breakfast reduces 24-hour postprandial hyperglycemia and improves glycemic variability.<sup>26</sup> Many patients consume upward of 50 g of carbohydrates at breakfast.<sup>27</sup> For example, it is not uncommon for a patient to consume cereal with milk or oatmeal, orange juice, a banana, and toast at breakfast. Instead, the patient is advised to consume any combination of eggs, meat, no-sugar-added Greek yogurt, or berries. <br/><br/>To keep things simple for lunch and dinner, the patient is offered high-quality, minimally processed protein of their choosing with any nonstarchy vegetable. Should a patient desire additional carbohydrates with meals, they may reduce the baseline serving of carbohydrates by 50%. For example, if a patient normally fills 50% of their plate with spaghetti, they may reduce the pasta portion to 25% and add a meatball or increase the amount of vegetables consumed with the meal to satiety.<br/><br/>Snacks may include cheese, eggs, peanut butter, nuts, seeds, berries, no-sugar-added Greek yogurt, or guacamole. Oftentimes, when LC meals are adopted, the desire or need for snacking is diminished due to the satiating effect of high-quality protein sources and nonstarchy vegetables.</p> <h3>Adverse Effects</h3> <p>AEs have been reported with VLCK diets, including headache, diarrhea, constipation, muscle cramps, halitosis, light-headedness, and muscle weakness.<sup>28</sup> These AEs may be mitigated with increased fluid intake, sodium intake, and magnesium supplementation.<sup>29</sup> Increasing fluids to a minimum of 2 L/d and adding sodium (eg, bouillon supplementation) can minimize AEs.<sup>30</sup> Milk of magnesia (5 mL) or slow-release magnesium chloride 200 mEq/d is suggested to reduce muscle cramps.<sup>30</sup> There have been no studies looking at sodium intake and worsening hypertension or chronic heart failure in the setting of an LC diet, but fluid and electrolyte intake should be monitored closely, especially in patients with uncontrolled hypertension and heart failure. Other concerns of higher protein on worsening kidney function have generally not been founded.<sup>31</sup> In some individuals, an LC and higher fat diet may increase low-density lipoprotein cholesterol (LDL-C).<sup>32</sup> Therefore a baseline lipid panel is recommended and should be monitored along with HbA<sub>1c</sub> levels. An elevated LDL-C response may be managed by increasing protein and reducing saturated fat intake while maintaining the reduced carbohydrate content of the diet. </p> <h2>Medication Management</h2> <p>The adoption of an LC diet can cause a swift and profound reduction in blood sugar.<sup>33</sup> Utilizing PACTs can help prevent adverse drug events by involving clinical pharmacists to provide recommendations and dose reductions as patients adopt an LC diet. Each approach must be individualized to the patient and can depend on several factors, including the number and strength of medications, the degree of carbohydrate reduction, baseline blood glucose, as well as assessing for medical literacy and ability to implement recommendations. Additionally, patients should monitor their blood sugar regularly and communicate with their primary care team (pharmacist, PACT registered nurse, primary care clinician, and registered dietician). Ultimately, the goal when adopting an LC diet while taking antihyperglycemics is safely avoiding hypoglycemia while reducing the number of medications the patient is taking. We summarize a practical approach to medication management that was recently published (Table 3).<sup>33,34</sup> </p> <h3>Medications to Reduce or Discontinue</h3> <p>Medications that can cause hypoglycemia should be the first to be reduced or discontinued upon starting an LC diet, including bolus insulin (although a small amount may be needed to correct for high blood sugar), sulfonylureas, and meglitinides. Combination insulin should be stopped and changed to basal insulin to avoid the risk of hypoglycemia (see Table 4 for insulin deprescribing recommendations). The mechanism of action in preventing the breakdown of carbohydrates in the gastrointestinal tract makes the use of α-glucosidase inhibitors superfluous, and they can be discontinued, reducing pill burden and polypharmacy risks. Sodium-glucose transport protein 2 inhibitors (SGLT2i) should be discontinued for patients on VLCK diets due to the risk of euglycemic diabetic ketoacidosis. However, with LC and moderate LC plans, the SGLT2i may be used with caution as long as patients are made aware of ketoacidosis symptoms. To help prevent the risk of hypoglycemia, basal/long-acting insulin can be continued, but at a 50% reduced dose. Patients should closely monitor blood sugar to assess for appropriateness of dose reductions. While thiazolidinediones are not contraindicated, clinicians can consider discontinuation given both their penchant for inducing weight gain and their limited outcomes data.</p> <h3>Medications to Continue</h3> <p>Medications that pose minimal risk for hypoglycemia can be continued, including metformin, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide-1 agonists. However, even though these may pose a low risk of hypoglycemia, patients should still closely monitor their blood glucose so medications can be deprescribed as soon as safely and reasonably possible.</p> <h3>Other Medications</h3> <p>The improvement in metabolic health with the reduction of carbohydrates can render other classes of medications unnecessary or require adjustment. Patients should be counseled to monitor their blood pressure as significant and rapid improvements can occur. In the event of a systolic blood pressure of 100 to 110 mm Hg or signs of hypotension, down titration or discontinuation of antihypertensives should be initiated. Limited evidence exists on the preferred order of discontinuation but should be informed by other comorbidities, such as coronary artery disease and chronic kidney disease. Given an LC diet’s diuretic effect, tapering and stopping diuretics may be an option. Other medications requiring closer monitoring include lithium (can be affected by fluid and electrolyte shifts), warfarin (may alter vitamin K intake), valproate (which may be reduced), and zonisamide and topiramate (kidney stone risk).</p> <h2>Remission of T2DM with LC Diets</h2> <p>As patients adopt LC diets and medications are deprescribed and glycemia improves, HbA<sub>1c</sub> and fasting glucose levels may drop below the diagnostic threshold for T2DM.<sup>20</sup> As new evidence emerges surrounding the management of T2DM from a lifestyle perspective, major health care organizations have acknowledged that T2DM is not necessarily an incurable, progressive disease, but rather a disease that can be reversed or put in remission.<sup>35-37</sup> In 2016, the World Health Organization (WHO) global report on diabetes acknowledged that T2DM reversal can be achieved via weight loss and calorie restriction.<sup>35</sup></p> <p>In 2021, a consensus statement from the ADA, the Endocrine Society, the EASD, and Diabetes UK defined T2DM remission as an HbA<sub>1c</sub> level < 6.5% for at least 3 months with no T2DM medications.<sup>36</sup> Diabetes Australia also published a position statement in 2021 about T2DM remission.<sup>37</sup> Like the WHO, Diabetes Australia acknowledged that remission of T2DM is possible following intensive dietary changes or bariatric surgery.<sup>37</sup> Before the 2021 consensus statement, some experts argued that excluding metformin from the T2DM medication list may not be warranted since metformin has indications beyond T2DM. In this case, remission of T2DM could be defined as an HbA<sub>1c</sub> level < 6.5% for at least 3 months and on metformin or no T2DM medications.<sup>8</sup> </p> <h2>Emerging Strategies</h2> <p>Emerging strategies, such as continuous glucose monitors (CGMs) and the use of intermittent fasting/time-restricted eating (TRE), can be used with the LC diet to help improve the monitoring and management of T2DM. In the recently published VA/DoD guidelines for T2DM, the work group suggested real-time CGMs for qualified patients with T2DM.<sup>4</sup> These include patients on daily insulin who are not achieving glycemic control or to reduce the risk for hypoglycemia. CGMs have shown evidence of improved glycemic control and decreased hypoglycemia in those with T2DM.<sup>38,39</sup> It is currently unknown if CGMs improve long-term glycemic control, but they appear promising for managing and reducing medications for those on an LC diet.<sup>40</sup></p> <p>TRE can be supplemented with an LC plan that incorporates “eating windows.” Common patterns include 14 hours of fasting and a 10-hour eating window (14F:10E), or 16 hours of fasting and an 8-hour eating window (16F:8E). By eating only in the specified window, patients generally reduce caloric intake and minimize insulin and glucose excursions during the fasting window. No changes need to be made to the macronutrient composition of the diet, and LC approaches can be used with TRE. The mechanism of action is likely multifactorial, targeting hyperinsulinemia and insulin resistance as well as producing a caloric deficit to enable weight loss.<sup>41</sup> Eating windows may improve insulin sensitivity, reduce insulin resistance, and enhance overall glycemic control. The recent VA/DoD guidelines recommended against intermittent fasting due to concerns over the risk of hypoglycemia despite larger weight loss in TRE groups.<sup>4</sup> Recently, a study using CGMs and TRE demonstrated both improved glycemic control and no hypoglycemic episodes in patients with T2DM on insulin.<sup>42</sup> Patients who would like to supplement TRE with an LC plan as a strategy for improved glycemic control should work closely with their PACT to help manage their TRE and LC plan and consider a CGM adjunct, especially if on insulin.</p> <h2>Barriers</h2> <p>Managing T2DM often requires comprehensive lifestyle modifications of nutrition, exercise, sleep, stress management, and other psychosocial issues, as well as an interdisciplinary team-based approach.<sup>43</sup> The advantage of working within the VA includes a uniform system within a network of care. However, many patients continue to use both federal and private health care. This use of out-of-network care may result in fragmented, potentially disjointed, or even contradictory dietary advice.</p> <p>The VA PACT, whole health for holistic health, and weight loss interventions such as the MOVE! program provide lifestyle interventions like nutrition, physical activity, and behavior change. However, these well-intentioned approaches may provide alternative and even diverging recommendations, which place additional barriers to effective patient management. In patients who are advised and accept a trial of an LC plan, each member of the team should embrace the self-management decision of the patient and support the plan.<sup>29</sup> Any conflicts, questions, or concerns should be communicated directly with the team in an interdisciplinary approach to provide a unified message and counsel.<br/><br/>The long-term effects and sustainability of an LC diet have been questioned in the literature.<sup>44-46</sup> Recently, the use of an app-based coaching plan has demonstrated short- and long-term sustainability on an LC diet.<sup>47</sup> In just 5 months in a large VA system, 590 patients using a virtual coaching platform and a VLCK diet plan were found to have lower HbA<sub>1c</sub> levels, reduced diabetic medication fills, lower body mass index, fewer outpatient visits, and lower prescription drug costs. <br/><br/>A 5-year follow-up found nearly 50% of participants sustained a VLCK diet for T2DM. For patients who participated in the study after 2 years, 72% sustained the VLCK diet in years 2 to 5. Most required nearly 50% fewer medications and in those that started with insulin, half did not require it at 5 years.<sup>48</sup> Further research, however, is necessary to determine the long-term effects on cardiometabolic markers and health with LC diets. There are no long-term RCTs on outcomes data looking at T2DM morbidity or mortality. While there are prospective cohort studies on LC diets in the general population on mortality, they demonstrate mixed results. These studies may be confounded by heterogeneous definitions of LC diets, diet quality, and other health factors.<sup>49-51</sup></p> <h2>Conclusions</h2> <p>The effective use of LC diets within a PACT with close and intensive lifestyle counseling and a safe approach to medication management and deprescribing can improve glycemic control, reduce the overall need for insulin, reduce medication use, and provide sustained weight loss. Additionally, the use of therapeutic carbohydrate reduction and subsequent medication deprescription may lead to sustained remission of T2DM. The current efficacy and sustainment of therapeutic carbohydrate reduction for patients with T2DM appears promising. Further research on LC diets, emerging strategies, and long-term effects on cardiometabolic risk factors, morbidity, and mortality will continue to inform future practice in our health care system.</p> <h3> Acknowledgments </h3> <p> <em>We thank Cecile Seth who has been instrumental in pushing us forward and the Metabolic Multiplier group who has helped encourage and provide input into this article.</em> </p> <h3> Author affiliations </h3> <p> <em><sup>a</sup>Veterans Affairs Palo Alto Health Care System, California<br/><br/><sup>b</sup>Western North Carolina Veterans Affairs Health Care System, Asheville<br/><br/><sup>c</sup>Ambulatory Care Clinical Pharmacist Society of Metabolic Health Practitioners, Tucson, Arizona<br/><br/><sup>d</sup>Veterans Affairs Boston Health Care System, Massachusetts<br/><br/><sup>e</sup>Southern Arizona Veterans Affairs Health Care System, Tucson<br/><br/><sup>f</sup>Veterans Affairs St Louis Health Care System, Missouri</em> </p> <h3> Author disclosures </h3> <p> <em>CM Jenks is married to an employee of Virta Medical, which provides care related to type 2 diabetes and ketogenic diets. </em> </p> <h3> Disclaimer </h3> <p> <em>The opinions expressed herein are those of the authors and do not necessarily reflect those of <i>Federal Practitioner</i>, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.</em> </p> <h3> Ethics and consent </h3> <p> <em>Written consent for publication has been obtained from the patient reported in the illustrative case.</em> </p> <h3> References </h3> <p class="reference"> 1. Centers for Disease Control and Prevention. Prevalence of Both Diagnosed and Undiagnosed Diabetes. Updated September 30, 2022. Accessed October 6, 2023. https://www.cdc.gov/diabetes/data/statistics-report/diagnosed-undiagnosed-diabetes.html<br/><br/> 2. Centers for Disease Control and Prevention. Diabetes and Prediabetes. Updated September 6, 2022. Accessed October 6, 2023. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm 3. US Department of Veterans Affairs. Diabetes information - Nutrition and food services. Updated May 4, 2023. Accessed October 6, 2023. https://www.nutrition.va.gov/diabetes.asp<br/><br/> 4. US Department of Veterans Affairs. Management of Type 2 Diabetes Mellitus (2023) - VA/DoD Clinical Practice Guidelines. Updated September 1, 2023. Accessed October 6, 2023. https://www.healthquality.va.gov/guidelines/CD/diabetes/<br/><br/> 5. American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2017. <i>Diabetes Care</i>. 2018;41(5):917-928. doi:10.2337/dci18-0007<br/><br/> 6. Home P, Riddle M, Cefalu WT, et al. Insulin therapy in people with type 2 diabetes: opportunities and challenges?. <i>Diabetes Care</i>. 2014;37(6):1499-1508. doi:10.2337/dc13-2743<br/><br/> 7. Donath MY, Ehses JA, Maedler K, et al. Mechanisms of β-cell death in type 2 diabetes. <i>Diabetes</i>. 2005;54(suppl 2):S108-S113. doi:10.2337/DIABETES.54.SUPPL_2.S108<br/><br/> 8. Hallberg SJ, Gershuni VM, Hazbun TL, Athinarayanan SJ. Reversing type 2 diabetes: a narrative review of the evidence. <i>Nutrients</i>. 2019;11(4):766. Published 2019 Apr 1. doi:10.3390/nu11040766<br/><br/> 9. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). <i>Diabetes Care</i>. 2018;41(12):2669. doi:10.2337/DCI18-0033<br/><br/>10. Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. <i>Diabetes Care</i>. 2019;42(5):731-754. doi:10.2337/DCI19-0014<br/><br/>11. Diabetes Canada position statement on low-carbohydrate diets for adults with diabetes: a rapid review. <i>Can J Diabetes</i>. 2020;44(4):295-299. doi:10.1016/J.JCJD.2020.04.001<br/><br/>12. Diabetes Australia. Position statements. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/research-advocacy/position-statements/<br/><br/>13. Feinman RD, Pogozelski WK, Astrup A, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. <i>Nutrition</i>. 2014;31(1):1-13. doi:10.1016/j.nut.2014.06.011<br/><br/>14. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. <i>N Engl J Med</i>. 2003;348(21):2074-2081. doi:10.1056/NEJMOA02263715. Westman EC, Yancy WS, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. <i>Nutr Metab (Lond)</i>. 2008;5(1):36. doi:10.1186/1743-7075-5-36<br/><br/>16. Saslow LR, Mason AE, Kim S, et al. An online intervention comparing a very low-carbohydrate ketogenic diet and lifestyle recommendations versus a plate method diet in overweight individuals with type 2 diabetes: a randomized controlled trial. <i>J Med Internet Res</i>. 2017;19(2). doi:10.2196/JMIR.5806<br/><br/>17. Hallberg SJ, McKenzie AL, Williams PT, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. <i>Diabetes Ther</i>. 2018;9(2):583-612. doi:10.1007/S13300-018-0373-9<br/><br/>18. Gram-Kampmann EM, Hansen CD, Hugger MB, et al. Effects of a 6-month, low-carbohydrate diet on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes: An open-label randomized controlled trial. <i>Diabetes Obes Metab</i>. 2022;24(4):693-703. doi:10.1111/DOM.14633<br/><br/>19. Committee ADAPP. 5. Facilitating behavior change and well-being to improve health outcomes: standards of medical care in diabetes—2022. <i>Diabetes Care</i>. 2022;45(suppl 1):S60-S82. doi:10.2337/DC22-S005<br/><br/>20. Goldenberg JZ, Johnston BC. Low and very low carbohydrate diets for diabetes remission. <i>BMJ</i>. 2021;373:m4743. doi:10.1136/BMJ.N262</p> <p class="reference">21. Jing T, Zhang S, Bai M, et al. Effect of dietary approaches on glycemic control in patients with type 2 diabetes: a systematic review with network meta-analysis of randomized trials. <i>Nutrients</i>. 2023;15(14):3156. doi:10.3390/nu15143156<br/><br/>22. Academy of Nutrition and Dietetics. Nutrition care manual. Accessed October 6, 2023. https://www.nutritioncaremanual.org/<br/><br/>23. Low carbohydrate and very low carbohydrate eating patterns in adults with diabetes. ShopDiabetes.org. Accessed August 5, 2022. https://shopdiabetes.org/products/low-carbohydrate-and-very-low-carbohydrate-eating-patterns-in-adults-with-diabetes-a-guide-for-health-care-providers<br/><br/>24. US Department of Veterans Affairs. Diabetes education - nutrition and food services. Published July 31, 2022. http://vaww.nutrition.va.gov/docs/pted/ModifiedKetogenicDiet.pdf [Source not verified] <br/><br/>25. US Department of Veterans Affairs, My HealtheVet. Lowdown on low-carb diets. Updated June 1, 2021. Accessed October 6, 2023. https://www.myhealth.va.gov/mhv-portal-web/ss20190724-low-carb-diet<br/><br/>26. Chang CR, Francois ME, Little JP. Restricting carbohydrates at breakfast is sufficient to reduce 24-hour exposure to postprandial hyperglycemia and improve glycemic variability. <i>Am J Clin Nutr</i>. 2019;109(5):1302-1309. doi:10.1093/AJCN/NQY261<br/><br/>27. Hall KD, Ayuketah A, Brychta R, et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. <i>Cell Metab</i>. 2019;30(1):226. doi:10.1016/j.cmet.2019.05.020<br/><br/>28. Harvey CJ d. C, Schofield GM, Zinn C, Thornley S. Effects of differing levels of carbohydrate restriction on mood achievement of nutritional ketosis, and symptoms of carbohydrate withdrawal in healthy adults: a randomized clinical trial. <i>Nutrition</i>. 2019;67-68:100005. doi:10.1016/J.NUTX.2019.100005<br/><br/>29. Griauzde DH, Standafer Lopez K, Saslow LR, Richardson CR. A pragmatic approach to translating low- and very low-carbohydrate diets into clinical practice for patients with obesity and type 2 diabetes. <i>Front Nutr</i>. 2021;8:416. doi:10.3389/FNUT.2021.682137/BIBTEX<br/><br/>30. Westman EC, Tondt J, Maguire E, Yancy WS. Implementing a low-carbohydrate, ketogenic diet to manage type 2 diabetes mellitus. <i>Expert Rev Endocrinol Metab</i>. 2018;13(5):263-272. doi:10.1080/17446651.2018.1523713<br/><br/>31. Suyoto PST. Effect of low-carbohydrate diet on markers of renal function in patients with type 2 diabetes: a meta-analysis. <i>Diabetes Metab Res Rev</i>. 2018;34(7). doi:10.1002/DMRR.3032<br/><br/>32. Norwitz NG, Feldman D, Soto-Mota A, Kalayjian T, Ludwig DS. Elevated LDL cholesterol with a carbohydrate-restricted diet: evidence for a “lean mass hyper-responder” phenotype. <i>Curr Dev Nutr</i>. 2021;6(1). doi:10.1093/CDN/NZAB144<br/><br/>33. Murdoch C, Unwin D, Cavan D, Cucuzzella M, Patel M. Adapting diabetes medication for low carbohydrate management of type 2 diabetes: a practical guide. <i>Br J Gen Pract</i>. 2019;69(684):360-361. doi:10.3399/bjgp19X704525<br/><br/>34. Cucuzzella M, Riley K, Isaacs D. Adapting medication for type 2 diabetes to a low carbohydrate diet. <i>Front Nutr</i>. 2021;8:486. doi:10.3389/FNUT.2021.688540/BIBTEX<br/><br/>35. World Health Organization. Global report on diabetes. 2016. Accessed October 6, 2023. https://iris.who.int/bitstream/handle/10665/204871/9789241565257_eng.pdf?sequence=1<br/><br/>36. Riddle MC, Cefalu WT, Evans PH, et al. Consensus report: definition and interpretation of remission in type 2 diabetes. <i>Diabetes Care</i>. 2021;44(10):2438-2444. doi:10.2337/DCI21-0034</p> <p class="reference">37. Diabetes Australia. Type 2 Diabetes remission position statement. 2021. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/wp-content/uploads/2021_Diabetes-Australia-Position-Statement_Type-2-diabetes-remission_2.pdf<br/><br/>38. Martens T, Beck RW, Bailey R, et al. Effect of continuous glucose monitoring on glycemic control in patients with type 2 diabetes treated with basal insulin: a randomized clinical trial. <i>JAMA</i>. 2021;325(22):2262-2272. doi:10.1001/JAMA.2021.7444<br/><br/>39. Jackson MA, Ahmann A, Shah VN. Type 2 diabetes and the use of real-time continuous glucose monitoring. <i>Diabetes Technol Ther</i>. 2021;23(S1):S27-S34. doi:10.1089/DIA.2021.0007<br/><br/>40. Oser TK, Cucuzzella M, Stasinopoulos M, Moncrief M, McCall A, Cox DJ. An innovative, paradigm-shifting lifestyle intervention to reduce glucose excursions with the use of continuous glucose monitoring to educate, motivate, and activate adults with newly diagnosed type 2 diabetes: pilot feasibility study. <i>JMIR Diabetes</i>. 2022;7(1). doi:10.2196/34465<br/><br/>41. Światkiewicz I, Woźniak A, Taub PR. Time-restricted eating and metabolic syndrome: current status and future perspectives. <i>Nutrients</i>. 2021;13(1):221. doi:10.3390/NU13010221<br/><br/>42. Obermayer A, Tripolt NJ, Pferschy PN, et al. Efficacy and safety of intermittent fasting in people with insulin-treated type 2 diabetes (INTERFAST-2)—a randomized controlled trial. <i>Diabetes Care</i>. 2023;46(2):463-468. doi:10.2337/dc22-1622<br/><br/>43. American Diabetes Association. 5. Lifestyle management: standards of medical care in diabetes—2019. <i>Diabetes Care</i>. 2019;42(suppl 1):S46-S60. doi:10.2337/DC19-S005<br/><br/>44. Li S, Ding L, Xiao X. Comparing the efficacy and safety of low-carbohydrate diets with low-fat diets for type 2 diabetes mellitus patients: a systematic review and meta-analysis of randomized clinical trials. <i>Int J Endocrinol</i>. 2021;2021:8521756. Published 2021 Dec 6. doi:10.1155/2021/8521756<br/><br/>45. Choi JH, Kang JH, Chon S. Comprehensive understanding for application in Korean patients with type 2 diabetes mellitus of the consensus statement on carbohydrate-restricted diets by Korean Diabetes Association, Korean Society for the Study of Obesity, and Korean Society of Hypertension. <i>Diabetes Metab J</i>. 2022;46(3):377. doi:10.4093/DMJ.2022.0051<br/><br/>46. Jayedi A, Zeraattalab-Motlagh S, Jabbarzadeh B, et al. Dose-dependent effect of carbohydrate restriction for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized controlled trials. <i>Am J Clin Nutr</i>. 2022;116(1). doi:10.1093/AJCN/NQAC066<br/><br/>47. Strombotne KL, Lum J, Ndugga NJ, et al. Effectiveness of a ketogenic diet and virtual coaching intervention for patients with diabetes: a difference-in-differences analysis. <i>Diabetes Obes Metab</i>. 2021;23(12):2643-2650. doi:10.1111/DOM.14515<br/><br/>48. Virta Health. Virta Health highlights lasting, transformative health improvements in 5-year diabetes reversal study. June 5, 2022. Accessed October 6, 2023. https://www.virtahealth.com/blog/virta-sustainable-health-improvements-5-year-diabetes-reversal-study<br/><br/>49. Wan Z, Shan Z, Geng T, et al. Associations of moderate low-carbohydrate diets with mortality among patients with type 2 diabetes: a prospective cohort study. <i>J Clin Endocrinol Metab</i>. 2022;107(7):E2702-E2709. doi:10.1210/CLINEM/DGAC235<br/><br/>50. Akter S, Mizoue T, Nanri A, et al. Low carbohydrate diet and all cause and cause-specific mortality. <i>Clin Nutr</i>. 2021;40(4):2016-2024. doi:10.1016/J.CLNU.2020.09.022<br/><br/>51. Shan Z, Guo Y, Hu FB, Liu L, Qi Q. Association of low-carbohydrate and low-fat diets with mortality among US adults. <i>JAMA Intern Med</i>. 2020;180(4):513-523. doi:10.1001/JAMAINTERNMED.2019.6980</p> </itemContent> </newsItem> </itemSet></root>
The Role of Toluidine Blue in Mohs Micrographic Surgery: A Systematic Review
Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.1 Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.2 The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.3
Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.2 Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.4 Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.5 We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.
Methods
We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.
Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.
Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.
Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.
Results
A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).
A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.
Comment
Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.20 The advantages and limitations of TB staining of BCC are presented in Table 2.
Humphreys et al6 suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.6 The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.21 This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.6
The margin behavior of BCC stained with TB was further characterized by Goldberg et al,8 who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.8
The nasal surface has a predilection for BCC.22 The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.22 When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.10 None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.10
The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.9 Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.9
Bennett and Taher7 described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.7
Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues6 of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.6
Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.12 All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.12 The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.13 Drosou et al13 suggested that TB may enhance the diagnostic accuracy for perineural SCC.
Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.15
Although PCACC is rare, the recurrence rate is high.23 Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.14
Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.17 In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.6
Conclusion
Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.
- Culling CF, Allison TR. Cellular Pathology Technique. 4th ed. Butterworths; 1985.
- Bergeron JA, Singer M. Metachromasy: an experimental and theoretical reevaluation. J Biophys Biochem Cytol. 1958;4:433-457. doi:10.1083/jcb.4.4.433
- Epstein JB, Scully C, Spinelli J. Toluidine blue and Lugol’s iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. J Oral Pathol Med. 1992;21:160-163. doi:10.1111/j.1600-0714.1992.tb00094.x
- Warnakulasuriya KA, Johnson NW. Sensitivity and specificity of OraScan (R) toluidine blue mouthrinse in the detection of oral cancer and precancer. J Oral Pathol Med. 1996;25:97-103. doi:10.1111/j.1600-0714.1996.tb00201.x
- Silapunt S, Peterson SR, Alcalay J, et al. Mohs tissue mapping and processing: a survey study. Dermatol Surg. 2003;29:1109-1112; discussion 1112.
- Humphreys TR, Nemeth A, McCrevey S, et al. A pilot study comparing toluidine blue and hematoxylin and eosin staining of basal cell and squamous cell carcinoma during Mohs surgery. Dermatol Surg. 1996;22:693-697. doi:10.1111/j.1524-4725.1996.tb00619.x
- Bennett R, Taher M. Restylane persistent for 23 months found during Mohs micrographic surgery: a source of confusion with hyaluronic acid surrounding basal cell carcinoma. Dermatol Surg. 2005;31:1366-1369. doi:10.1111/j.1524-4725.2005.31223
- Goldberg LH, Wang SQ, Kimyai-Asadi A. The setting sun sign: visualizing the margins of a basal cell carcinoma on serial frozen sections stained with toluidine blue. Dermatol Surg. 2007;33:761-763. doi:10.1111/j.1524-4725.2007.33158.x
- Tehrani H, May K, Morris A, et al. Does the dual use of toluidine blue and hematoxylin and eosin staining improve basal cell carcinoma detection by Mohs surgery trainees? Dermatol Surg. 2013;39:995-1000. doi:10.1111/dsu.12180
- Donaldson MR, Weber LA. Toluidine blue supports differentiation of folliculocentric basaloid proliferation from basal cell carcinoma on frozen sections in a small single-practice cohort. Dermatol Surg. 2017;43:1303-1306. doi:10.1097/DSS.0000000000001107
- Styperek AR, Goldberg LH, Goldschmidt LE, et al. Toluidine blue and hematoxylin and eosin stains are comparable in evaluating squamous cell carcinoma during Mohs. Dermatol Surg. 2016;42:1279-1284. doi:10.1097/DSS.0000000000000872
- Trieu D, Drosou A, Goldberg LH, et al. Detecting spindle cell squamous cell carcinomas with toluidine blue on frozen sections. Dermatol Surg. 2014;40:1259-1260. doi:10.1097/DSS.0000000000000147
- Drosou A, Trieu D, Goldberg LH, et al. The perineural corona sign: enhancing detection of perineural squamous cell carcinoma during Mohs micrographic surgery with toluidine blue stain. J Am Acad Dermatol. 2014;71:826-827. doi:10.1016/j.jaad.2014.04.076
- Chesser RS, Bertler DE, Fitzpatrick JE, et al. Primary cutaneous adenoid cystic carcinoma treated with Mohs micrographic surgery toluidine blue technique. J Dermatol Surg Oncol. 1992;18:175-176. doi:10.1111/j.1524-4725.1992.tb02794.x
- Wang SQ, Goldberg LH, Nemeth A. The merits of adding toluidine blue-stained slides in Mohs surgery in the treatment of a microcystic adnexal carcinoma. J Am Acad Dermatol. 2007;56:1067-1069. doi:10.1016/j.jaad.2007.01.008
- Chen CL, Wilson S, Afzalneia R, et al. Topical aluminum chloride and Monsel’s solution block toluidine blue staining in Mohs frozen sections: mechanism and solution. Dermatol Surg. 2019;45:1019-1025. doi:10.1097/DSS.0000000000001761
- Todd MM, Lee JW, Marks VJ. Rapid toluidine blue stain for Mohs’ micrographic surgery. Dermatol Surg. 2005;31:244-245. doi:10.1111/j.1524-4725.2005.31053
- Picoto AM, Picoto A. Technical procedures for Mohs fresh tissue surgery. J Derm Surg Oncol. 1986;12:134-138. doi:10.1111/j.1524-4725.1986.tb01442.x
- Sperling LC, Winton GB. The transverse anatomy of androgenic alopecia. J Derm Surg Oncol. 1990;16:1127-1133. doi:10.1111/j.1524 -4725.1990.tb00024.x
- Smith-Zagone MJ, Schwartz MR. Frozen section of skin specimens. Arch Pathol Lab Med. 2005;129:1536-1543. doi:10.5858/2005-129-1536-FSOSS
- Moy RL, Potter TS, Uitto J. Increased glycosaminoglycans production in sclerosing basal cell carcinoma–derived fibroblasts and stimulation of normal skin fibroblast glycosaminoglycans production by a cytokine-derived from sclerosing basal cell carcinoma. Dermatol Surg. 2000;26:1029-1036. doi:10.1046/j.1524-4725.2000.0260111029.x
- Leshin B, White WL. Folliculocentric basaloid proliferation. The bulge (der Wulst) revisited. Arch Dermatol. 1990;126:900-906. doi:10.1001/archderm.126.7.900
- Seab JA, Graham JH. Primary cutaneous adenoid cystic carcinoma.J Am Acad Dermatol. 1987;17:113-118. doi:10.1016/s0190 -9622(87)70182-0
Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.1 Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.2 The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.3
Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.2 Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.4 Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.5 We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.
Methods
We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.
Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.
Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.
Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.
Results
A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).
A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.
Comment
Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.20 The advantages and limitations of TB staining of BCC are presented in Table 2.
Humphreys et al6 suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.6 The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.21 This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.6
The margin behavior of BCC stained with TB was further characterized by Goldberg et al,8 who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.8
The nasal surface has a predilection for BCC.22 The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.22 When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.10 None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.10
The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.9 Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.9
Bennett and Taher7 described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.7
Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues6 of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.6
Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.12 All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.12 The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.13 Drosou et al13 suggested that TB may enhance the diagnostic accuracy for perineural SCC.
Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.15
Although PCACC is rare, the recurrence rate is high.23 Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.14
Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.17 In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.6
Conclusion
Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.
Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.1 Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.2 The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.3
Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.2 Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.4 Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.5 We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.
Methods
We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.
Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.
Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.
Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.
Results
A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).
A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.
Comment
Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.20 The advantages and limitations of TB staining of BCC are presented in Table 2.
Humphreys et al6 suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.6 The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.21 This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.6
The margin behavior of BCC stained with TB was further characterized by Goldberg et al,8 who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.8
The nasal surface has a predilection for BCC.22 The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.22 When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.10 None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.10
The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.9 Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.9
Bennett and Taher7 described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.7
Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues6 of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.6
Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.12 All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.12 The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.13 Drosou et al13 suggested that TB may enhance the diagnostic accuracy for perineural SCC.
Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.15
Although PCACC is rare, the recurrence rate is high.23 Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.14
Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.17 In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.6
Conclusion
Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.
- Culling CF, Allison TR. Cellular Pathology Technique. 4th ed. Butterworths; 1985.
- Bergeron JA, Singer M. Metachromasy: an experimental and theoretical reevaluation. J Biophys Biochem Cytol. 1958;4:433-457. doi:10.1083/jcb.4.4.433
- Epstein JB, Scully C, Spinelli J. Toluidine blue and Lugol’s iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. J Oral Pathol Med. 1992;21:160-163. doi:10.1111/j.1600-0714.1992.tb00094.x
- Warnakulasuriya KA, Johnson NW. Sensitivity and specificity of OraScan (R) toluidine blue mouthrinse in the detection of oral cancer and precancer. J Oral Pathol Med. 1996;25:97-103. doi:10.1111/j.1600-0714.1996.tb00201.x
- Silapunt S, Peterson SR, Alcalay J, et al. Mohs tissue mapping and processing: a survey study. Dermatol Surg. 2003;29:1109-1112; discussion 1112.
- Humphreys TR, Nemeth A, McCrevey S, et al. A pilot study comparing toluidine blue and hematoxylin and eosin staining of basal cell and squamous cell carcinoma during Mohs surgery. Dermatol Surg. 1996;22:693-697. doi:10.1111/j.1524-4725.1996.tb00619.x
- Bennett R, Taher M. Restylane persistent for 23 months found during Mohs micrographic surgery: a source of confusion with hyaluronic acid surrounding basal cell carcinoma. Dermatol Surg. 2005;31:1366-1369. doi:10.1111/j.1524-4725.2005.31223
- Goldberg LH, Wang SQ, Kimyai-Asadi A. The setting sun sign: visualizing the margins of a basal cell carcinoma on serial frozen sections stained with toluidine blue. Dermatol Surg. 2007;33:761-763. doi:10.1111/j.1524-4725.2007.33158.x
- Tehrani H, May K, Morris A, et al. Does the dual use of toluidine blue and hematoxylin and eosin staining improve basal cell carcinoma detection by Mohs surgery trainees? Dermatol Surg. 2013;39:995-1000. doi:10.1111/dsu.12180
- Donaldson MR, Weber LA. Toluidine blue supports differentiation of folliculocentric basaloid proliferation from basal cell carcinoma on frozen sections in a small single-practice cohort. Dermatol Surg. 2017;43:1303-1306. doi:10.1097/DSS.0000000000001107
- Styperek AR, Goldberg LH, Goldschmidt LE, et al. Toluidine blue and hematoxylin and eosin stains are comparable in evaluating squamous cell carcinoma during Mohs. Dermatol Surg. 2016;42:1279-1284. doi:10.1097/DSS.0000000000000872
- Trieu D, Drosou A, Goldberg LH, et al. Detecting spindle cell squamous cell carcinomas with toluidine blue on frozen sections. Dermatol Surg. 2014;40:1259-1260. doi:10.1097/DSS.0000000000000147
- Drosou A, Trieu D, Goldberg LH, et al. The perineural corona sign: enhancing detection of perineural squamous cell carcinoma during Mohs micrographic surgery with toluidine blue stain. J Am Acad Dermatol. 2014;71:826-827. doi:10.1016/j.jaad.2014.04.076
- Chesser RS, Bertler DE, Fitzpatrick JE, et al. Primary cutaneous adenoid cystic carcinoma treated with Mohs micrographic surgery toluidine blue technique. J Dermatol Surg Oncol. 1992;18:175-176. doi:10.1111/j.1524-4725.1992.tb02794.x
- Wang SQ, Goldberg LH, Nemeth A. The merits of adding toluidine blue-stained slides in Mohs surgery in the treatment of a microcystic adnexal carcinoma. J Am Acad Dermatol. 2007;56:1067-1069. doi:10.1016/j.jaad.2007.01.008
- Chen CL, Wilson S, Afzalneia R, et al. Topical aluminum chloride and Monsel’s solution block toluidine blue staining in Mohs frozen sections: mechanism and solution. Dermatol Surg. 2019;45:1019-1025. doi:10.1097/DSS.0000000000001761
- Todd MM, Lee JW, Marks VJ. Rapid toluidine blue stain for Mohs’ micrographic surgery. Dermatol Surg. 2005;31:244-245. doi:10.1111/j.1524-4725.2005.31053
- Picoto AM, Picoto A. Technical procedures for Mohs fresh tissue surgery. J Derm Surg Oncol. 1986;12:134-138. doi:10.1111/j.1524-4725.1986.tb01442.x
- Sperling LC, Winton GB. The transverse anatomy of androgenic alopecia. J Derm Surg Oncol. 1990;16:1127-1133. doi:10.1111/j.1524 -4725.1990.tb00024.x
- Smith-Zagone MJ, Schwartz MR. Frozen section of skin specimens. Arch Pathol Lab Med. 2005;129:1536-1543. doi:10.5858/2005-129-1536-FSOSS
- Moy RL, Potter TS, Uitto J. Increased glycosaminoglycans production in sclerosing basal cell carcinoma–derived fibroblasts and stimulation of normal skin fibroblast glycosaminoglycans production by a cytokine-derived from sclerosing basal cell carcinoma. Dermatol Surg. 2000;26:1029-1036. doi:10.1046/j.1524-4725.2000.0260111029.x
- Leshin B, White WL. Folliculocentric basaloid proliferation. The bulge (der Wulst) revisited. Arch Dermatol. 1990;126:900-906. doi:10.1001/archderm.126.7.900
- Seab JA, Graham JH. Primary cutaneous adenoid cystic carcinoma.J Am Acad Dermatol. 1987;17:113-118. doi:10.1016/s0190 -9622(87)70182-0
- Culling CF, Allison TR. Cellular Pathology Technique. 4th ed. Butterworths; 1985.
- Bergeron JA, Singer M. Metachromasy: an experimental and theoretical reevaluation. J Biophys Biochem Cytol. 1958;4:433-457. doi:10.1083/jcb.4.4.433
- Epstein JB, Scully C, Spinelli J. Toluidine blue and Lugol’s iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. J Oral Pathol Med. 1992;21:160-163. doi:10.1111/j.1600-0714.1992.tb00094.x
- Warnakulasuriya KA, Johnson NW. Sensitivity and specificity of OraScan (R) toluidine blue mouthrinse in the detection of oral cancer and precancer. J Oral Pathol Med. 1996;25:97-103. doi:10.1111/j.1600-0714.1996.tb00201.x
- Silapunt S, Peterson SR, Alcalay J, et al. Mohs tissue mapping and processing: a survey study. Dermatol Surg. 2003;29:1109-1112; discussion 1112.
- Humphreys TR, Nemeth A, McCrevey S, et al. A pilot study comparing toluidine blue and hematoxylin and eosin staining of basal cell and squamous cell carcinoma during Mohs surgery. Dermatol Surg. 1996;22:693-697. doi:10.1111/j.1524-4725.1996.tb00619.x
- Bennett R, Taher M. Restylane persistent for 23 months found during Mohs micrographic surgery: a source of confusion with hyaluronic acid surrounding basal cell carcinoma. Dermatol Surg. 2005;31:1366-1369. doi:10.1111/j.1524-4725.2005.31223
- Goldberg LH, Wang SQ, Kimyai-Asadi A. The setting sun sign: visualizing the margins of a basal cell carcinoma on serial frozen sections stained with toluidine blue. Dermatol Surg. 2007;33:761-763. doi:10.1111/j.1524-4725.2007.33158.x
- Tehrani H, May K, Morris A, et al. Does the dual use of toluidine blue and hematoxylin and eosin staining improve basal cell carcinoma detection by Mohs surgery trainees? Dermatol Surg. 2013;39:995-1000. doi:10.1111/dsu.12180
- Donaldson MR, Weber LA. Toluidine blue supports differentiation of folliculocentric basaloid proliferation from basal cell carcinoma on frozen sections in a small single-practice cohort. Dermatol Surg. 2017;43:1303-1306. doi:10.1097/DSS.0000000000001107
- Styperek AR, Goldberg LH, Goldschmidt LE, et al. Toluidine blue and hematoxylin and eosin stains are comparable in evaluating squamous cell carcinoma during Mohs. Dermatol Surg. 2016;42:1279-1284. doi:10.1097/DSS.0000000000000872
- Trieu D, Drosou A, Goldberg LH, et al. Detecting spindle cell squamous cell carcinomas with toluidine blue on frozen sections. Dermatol Surg. 2014;40:1259-1260. doi:10.1097/DSS.0000000000000147
- Drosou A, Trieu D, Goldberg LH, et al. The perineural corona sign: enhancing detection of perineural squamous cell carcinoma during Mohs micrographic surgery with toluidine blue stain. J Am Acad Dermatol. 2014;71:826-827. doi:10.1016/j.jaad.2014.04.076
- Chesser RS, Bertler DE, Fitzpatrick JE, et al. Primary cutaneous adenoid cystic carcinoma treated with Mohs micrographic surgery toluidine blue technique. J Dermatol Surg Oncol. 1992;18:175-176. doi:10.1111/j.1524-4725.1992.tb02794.x
- Wang SQ, Goldberg LH, Nemeth A. The merits of adding toluidine blue-stained slides in Mohs surgery in the treatment of a microcystic adnexal carcinoma. J Am Acad Dermatol. 2007;56:1067-1069. doi:10.1016/j.jaad.2007.01.008
- Chen CL, Wilson S, Afzalneia R, et al. Topical aluminum chloride and Monsel’s solution block toluidine blue staining in Mohs frozen sections: mechanism and solution. Dermatol Surg. 2019;45:1019-1025. doi:10.1097/DSS.0000000000001761
- Todd MM, Lee JW, Marks VJ. Rapid toluidine blue stain for Mohs’ micrographic surgery. Dermatol Surg. 2005;31:244-245. doi:10.1111/j.1524-4725.2005.31053
- Picoto AM, Picoto A. Technical procedures for Mohs fresh tissue surgery. J Derm Surg Oncol. 1986;12:134-138. doi:10.1111/j.1524-4725.1986.tb01442.x
- Sperling LC, Winton GB. The transverse anatomy of androgenic alopecia. J Derm Surg Oncol. 1990;16:1127-1133. doi:10.1111/j.1524 -4725.1990.tb00024.x
- Smith-Zagone MJ, Schwartz MR. Frozen section of skin specimens. Arch Pathol Lab Med. 2005;129:1536-1543. doi:10.5858/2005-129-1536-FSOSS
- Moy RL, Potter TS, Uitto J. Increased glycosaminoglycans production in sclerosing basal cell carcinoma–derived fibroblasts and stimulation of normal skin fibroblast glycosaminoglycans production by a cytokine-derived from sclerosing basal cell carcinoma. Dermatol Surg. 2000;26:1029-1036. doi:10.1046/j.1524-4725.2000.0260111029.x
- Leshin B, White WL. Folliculocentric basaloid proliferation. The bulge (der Wulst) revisited. Arch Dermatol. 1990;126:900-906. doi:10.1001/archderm.126.7.900
- Seab JA, Graham JH. Primary cutaneous adenoid cystic carcinoma.J Am Acad Dermatol. 1987;17:113-118. doi:10.1016/s0190 -9622(87)70182-0
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>Long</fileName> <TBEID>0C02EF03.SIG</TBEID> <TBUniqueIdentifier>NJ_0C02EF03</TBUniqueIdentifier> <newsOrJournal>Journal</newsOrJournal> <publisherName>Frontline Medical Communications Inc.</publisherName> <storyname>Long</storyname> <articleType>1</articleType> <TBLocation>Copyfitting-CT</TBLocation> <QCDate/> <firstPublished>20231221T075529</firstPublished> <LastPublished>20231221T075529</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20231221T075529</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline>Tyler Long, DO; Austin Dunn, DO; Dane Hill, MD</byline> <bylineText>Tyler Long, DO; Austin Dunn, DO; Dane Hill, MD; Leonard H. Goldberg, MD; Russel Akin, MD</bylineText> <bylineFull>Tyler Long, DO; Austin Dunn, DO; Dane Hill, MD</bylineFull> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType/> <journalDocType/> <linkLabel/> <pageRange>E6-E11</pageRange> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.1 Metachromasia is a perceptible change in the </metaDescription> <articlePDF>299750</articlePDF> <teaserImage/> <title>The Role of Toluidine Blue in Mohs Micrographic Surgery: A Systematic Review</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear>2023</pubPubdateYear> <pubPubdateMonth>December</pubPubdateMonth> <pubPubdateDay/> <pubVolume>112</pubVolume> <pubNumber>6</pubNumber> <wireChannels/> <primaryCMSID/> <CMSIDs> <CMSID>2163</CMSID> </CMSIDs> <keywords> <keyword>nonmelanoma skin cancer</keyword> <keyword> mohs micrographic surgery</keyword> </keywords> <seeAlsos/> <publications_g> <publicationData> <publicationCode>CT</publicationCode> <pubIssueName>December 2023</pubIssueName> <pubArticleType>Online Exclusive | 2163</pubArticleType> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Cutis</journalTitle> <journalFullTitle>Cutis</journalFullTitle> <copyrightStatement>Copyright 2015 Frontline Medical Communications Inc., Parsippany, NJ, USA. All rights reserved.</copyrightStatement> </publicationData> </publications_g> <publications> <term canonical="true">12</term> </publications> <sections> <term canonical="true">49</term> </sections> <topics> <term>204</term> <term canonical="true">245</term> </topics> <links> <link> <itemClass qcode="ninat:composite"/> <altRep contenttype="application/pdf">images/18002689.pdf</altRep> <description role="drol:caption"/> <description role="drol:credit"/> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>The Role of Toluidine Blue in Mohs Micrographic Surgery: A Systematic Review</title> <deck/> </itemMeta> <itemContent> <p class="abstract">Toluidine blue (TB) is a metachromatic dye used as a stain in frozen sections in Mohs micrographic surgery (MMS). The current literature on the use of TB is sparse and generally qualitative in nature. The aim of this systematic review was to summarize and evaluate the existing literature analyzing TB use in MMS. The PubMed and Cochrane databases were searched for relevant studies published before December 1, 2019. Studies that analyzed the use of TB in frozen sections applicable to MMS were included. A total of 25 articles were reviewed, of which 12 fit the inclusion criteria. Our analysis showed that TB may play an important role in the successful diagnosis and treatment of particular cutaneous tumors. </p> <p> <em><em>Cutis.</em> 2023;112:E6-E11.</em> </p> <p><span class="body">T</span>oluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.<sup>1</sup> Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.<sup>2</sup> The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.<sup>3</sup> </p> <p>Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.<sup>2</sup> Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.<sup>4</sup> Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.<sup>5</sup> We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS. </p> <h3>Methods</h3> <p>We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms <i>toluidine blue</i> and <i>Mohs</i> or <i>Mohs micrographic surgery</i>. We manually checked the bibliographies of the identified articles to further identify eligible studies. </p> <p><i>Eligibility Criteria</i>—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.<br/><br/><i>Data Extraction and Outcomes</i>—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.<br/><br/><i>Quality Assessment</i>—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review. </p> <h3>Results</h3> <p>A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).</p> <p>A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.</p> <h3>Comment</h3> <p><i>Basal Cell Carcinoma</i>—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.<sup>18,19</sup> In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.<sup>20</sup> The advantages and limitations of TB staining of BCC are presented in Table 2.</p> <p>Humphreys et al<sup>6</sup> suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.<sup>6</sup> The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.<sup>21</sup> This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.<sup>6<br/><br/></sup>The margin behavior of BCC stained with TB was further characterized by Goldberg et al,<sup>8</sup> who coined the term <i>setting sun sign</i>, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.<sup>8</sup> <br/><br/>The nasal surface has a predilection for BCC.<sup>22</sup> The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.<sup>22</sup> When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.<sup>10</sup> None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N<span class="body">=</span>279) of BCCs confirmed on H&E<span class="Emphasis"> </span>did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.<sup>10<br/><br/></sup>The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.<sup>9</sup> Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.<sup>9<br/><br/></sup>Bennett and Taher<sup>7</sup> described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.<sup>7<br/><br/></sup><i>Squamous Cell Carcinoma</i>—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues<sup>6</sup> of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.<sup>6</sup> <br/><br/>Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.<sup>12</sup> All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.<sup>12</sup> The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the <i>perineural corona sign</i> because of the bright magenta stain that forms around affected nerves.<sup>13</sup> Drosou et al<sup>13</sup> suggested that TB may enhance the diagnostic accuracy for perineural SCC.<br/><br/><i>Rare Tumors</i>—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.<sup>15<br/><br/></sup>Although PCACC is rare, the recurrence rate is high.<sup>23</sup> Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.<sup>14<br/><br/></sup><i>Technical Aspects</i>—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.<sup>17</sup> In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.<sup>6</sup></p> <h3>Conclusion</h3> <p>Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.</p> <h2>References</h2> <p class="reference"> 1. Culling CF, Allison TR. <i>Cellular Pathology Technique</i>. 4th ed. Butterworths; 1985. </p> <p class="reference"> 2. Bergeron JA, Singer M. Metachromasy: an experimental and theoretical reevaluation. <i>J Biophys Biochem Cytol</i>. 1958;4:433-457. doi:10.1083/jcb.4.4.433<br/><br/> 3. Epstein JB, Scully C, Spinelli J. Toluidine blue and Lugol’s iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. <i>J Oral Pathol Med</i>. 1992;21:160-163. doi:10.1111/j.1600-0714.1992.tb00094.x<br/><br/> 4. Warnakulasuriya KA, Johnson NW. Sensitivity and specificity of OraScan (R) toluidine blue mouthrinse in the detection of oral cancer and precancer. <i>J Oral Pathol Med</i>. 1996;25:97-103. doi:10.1111/j.1600-0714.1996.tb00201.x<br/><br/> 5. Silapunt S, Peterson SR, Alcalay J, et al. Mohs tissue mapping and processing: a survey study. <i>Dermatol Surg</i>. 2003;29:1109-1112; discussion 1112.<br/><br/> 6. Humphreys TR, Nemeth A, McCrevey S, et al. A pilot study comparing toluidine blue and hematoxylin and eosin staining of basal cell and squamous cell carcinoma during Mohs surgery. <i>Dermatol Surg</i>. 1996;22:693-697. doi:10.1111/j.1524-4725.1996.tb00619.x</p> <p class="reference"> 7. Bennett R, Taher M. Restylane persistent for 23 months found during Mohs micrographic surgery: a source of confusion with hyaluronic acid surrounding basal cell carcinoma. <i>Dermatol Surg</i>. 2005;31:1366-1369. doi:10.1111/j.1524-4725.2005.31223<br/><br/> 8. Goldberg LH, Wang SQ, Kimyai-Asadi A. The setting sun sign: visualizing the margins of a basal cell carcinoma on serial frozen sections stained with toluidine blue. <i>Dermatol Surg</i>. 2007;33:761-763. doi:10.1111/j.1524-4725.2007.33158.x<br/><br/> 9. Tehrani H, May K, Morris A, et al. Does the dual use of toluidine blue and hematoxylin and eosin staining improve basal cell carcinoma detection by Mohs surgery trainees? <i>Dermatol Surg</i>. 2013;39:995-1000. doi:10.1111/dsu.12180<br/><br/>10. Donaldson MR, Weber LA. Toluidine blue supports differentiation of folliculocentric basaloid proliferation from basal cell carcinoma on frozen sections in a small single-practice cohort. <i>Dermatol Surg</i>. 2017;43:1303-1306. doi:10.1097/DSS.0000000000001107<br/><br/>11. Styperek AR, Goldberg LH, Goldschmidt LE, et al. Toluidine blue and hematoxylin and eosin stains are comparable in evaluating squamous cell carcinoma during Mohs. <i>Dermatol Surg</i>. 2016;42:1279-1284. doi:10.1097/DSS.0000000000000872<br/><br/>12. Trieu D, Drosou A, Goldberg LH, et al. Detecting spindle cell squamous cell carcinomas with toluidine blue on frozen sections. <i>Dermatol Surg</i>. 2014;40:1259-1260. doi:10.1097/DSS.0000000000000147<br/><br/>13. Drosou A, Trieu D, Goldberg LH, et al. The perineural corona sign: enhancing detection of perineural squamous cell carcinoma during Mohs micrographic surgery with toluidine blue stain. <i>J Am Acad Dermatol</i>. 2014;71:826-827. doi:10.1016/j.jaad.2014.04.076<br/><br/>14. Chesser RS, Bertler DE, Fitzpatrick JE, et al. Primary cutaneous adenoid cystic carcinoma treated with Mohs micrographic surgery toluidine blue technique. <i>J Dermatol Surg Oncol</i>. 1992;18:175-176. doi:10.1111/j.1524-4725.1992.tb02794.x<br/><br/>15. Wang SQ, Goldberg LH, Nemeth A. The merits of adding toluidine blue-stained slides in Mohs surgery in the treatment of a microcystic adnexal carcinoma. <i>J Am Acad Dermatol</i>. 2007;56:1067-1069. doi:10.1016/j.jaad.2007.01.008<br/><br/>16. Chen CL, Wilson S, Afzalneia R, et al. Topical aluminum chloride and Monsel’s solution block toluidine blue staining in Mohs frozen sections: mechanism and solution. <i>Dermatol Surg</i>. 2019;45:1019-1025. doi:10.1097/DSS.0000000000001761<br/><br/>17. Todd MM, Lee JW, Marks VJ. Rapid toluidine blue stain for Mohs’ micrographic surgery. <i>Dermatol Surg</i>. 2005;31:244-245. doi:10.1111/j.1524-4725.2005.31053<br/><br/>18. Picoto AM, Picoto A. Technical procedures for Mohs fresh tissue surgery. <i>J Derm Surg Oncol</i>. 1986;12:134-138. doi:10.1111/j.1524-4725.1986.tb01442.x<br/><br/>19. Sperling LC, Winton GB. The transverse anatomy of androgenic alopecia. <i>J Derm Surg Oncol</i>. 1990;16:1127-1133. doi:10.1111/j.1524 -4725.1990.tb00024.x<br/><br/>20. Smith-Zagone MJ, Schwartz MR. Frozen section of skin specimens. <i>Arch Pathol Lab Med</i>. 2005;129:1536-1543. doi:10.5858/2005-129-1536-FSOSS<br/><br/>21. Moy RL, Potter TS, Uitto J. Increased glycosaminoglycans production in sclerosing basal cell carcinoma–derived fibroblasts and stimulation of normal skin fibroblast glycosaminoglycans production by a cytokine-derived from sclerosing basal cell carcinoma. <i>Dermatol Surg</i>. 2000;26:1029-1036. doi:10.1046/j.1524-4725.2000.0260111029.x<br/><br/>22. Leshin B, White WL. Folliculocentric basaloid proliferation. The bulge (der Wulst) revisited. <i>Arch Dermatol</i>. 1990;126:900-906. doi:10.1001/archderm.126.7.900<br/><br/>23. Seab JA, Graham JH. Primary cutaneous adenoid cystic carcinoma.<i>J Am Acad Dermatol</i>. 1987;17:113-118. doi:10.1016/s0190 -9622(87)70182-0</p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>bio</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p class="disclosure">Dr. Long is from the Health Corporation of America and Virginia College of Osteopathic Medicine, Blacksburg. Dr. Dunn is in private practice, Tampa, Florida. Drs. Hill and Akin are from the Department of Dermatology, Texas Tech University Health Sciences Center, Lubbock. Dr. Akin also is from Midland Dermatology and Skin Cancer Center, Texas. Dr. Goldberg is from DermSurgery Associates, Houston, Texas.</p> <p class="disclosure">The authors report no conflicts of interest.Correspondence: Tyler Long, DO, HCA LewisGale Hospital Montgomery Medical Education, 700 S Main St, Blacksburg, VA 24060 (longjtyler@yahoo.com).<br/><br/>doi:10.12788/cutis.0915</p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>in</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p class="insidehead">Practice <strong>Points</strong></p> <ul class="insidebody"> <li>Toluidine blue (TB) staining can be integrated into Mohs micrographic surgery (MMS) for enhanced diagnosis of cutaneous tumors. Its metachromatic properties can aid in differentiating tumor cells from surrounding tissues, especially in basal cell carcinomas and squamous cell carcinomas.</li> <li>It is important to develop expertise in interpreting TB-stained sections, as it may offer clearer visualization of nuclear details and stromal components, potentially leading to more accurate diagnosis and effective tumor margin identification.</li> <li>Toluidine blue staining can be incorporated into routine MMS practice considering its quick staining process and low disruption to workflow. This can potentially improve diagnostic efficiency without significantly lengthening surgery time.</li> </ul> </itemContent> </newsItem> </itemSet></root>
Practice Points
- Toluidine blue (TB) staining can be integrated into Mohs micrographic surgery (MMS) for enhanced diagnosis of cutaneous tumors. Its metachromatic properties can aid in differentiating tumor cells from surrounding tissues, especially in basal cell carcinomas and squamous cell carcinomas.
- It is important to develop expertise in interpreting TB-stained sections, as it may offer clearer visualization of nuclear details and stromal components, potentially leading to more accurate diagnosis and effective tumor margin identification.
- Toluidine blue staining can be incorporated into routine MMS practice considering its quick staining process and low disruption to workflow. This can potentially improve diagnostic efficiency without significantly lengthening surgery time.
2023 Update on minimally invasive gynecologic surgery
It has been an incredible year for complex gynecology and minimally invasive gynecologic surgery (MIGS), with several outstanding new findings and reviews in 2023. The surgical community continues to push the envelope and emphasize the value of this specialty for women’s health.
Endometriosis and adenomyosis were at the center of several large cohort studies and systematic reviews that reassessed what we know about how to evaluate and treat these challenging diseases, including both surgical and nonsurgical approaches, with an emphasis on fertility-sparing modalities.1-8 In addition, a focus on quality of life, patient-centered care, and racial biases allowed us to reflect on our own practice patterns and keep the patient at the center of care models.9-13 Finally, there was a clear expansion in the use of technologies such as artificial intelligence (AI) and machine learning for care and novel minimally invasive tools.14
In this Update, we highlight and expand on how several particularly important developments are likely to make a difference in our clinical management.
New classification system for cesarean scar ectopic pregnancy with defined surgical guidance has 97% treatment success rate
Ban Y, Shen J, Wang X, et al. Cesarean scar ectopic pregnancy clinical classification system with recommended surgical strategy. Obstet Gynecol. 2023;141:927-936. doi:10.1097/AOG.0000000000005113
A large multiarmed study by Ban and colleagues used multivariable modeling to formulate and test a classification system and recommended surgical treatment strategies for patients with a cesarean scar ectopic pregnancy (CSP).15 In the study, 273 patients were included in the predictive modeling group, 118 in the internal validation group, and 564 within the model testing cohort. Classifications were based on 2 independent risk factors for intraoperative hemorrhage: anterior myometrial thickness and mean diameter of gestational sac (MSD).
Classification types
The 3 main CSP types were defined based on the anterior myometrial thickness at the cesarean section scar (type I, > 3 mm; type II, 1–3 mm; type III, ≤ 1 mm) and subtyped based on the MSD (type IIa, MSD ≤ 30 mm; type IIb, MSD > 30 mm; type IIIa, MSD ≤ 50 mm; type IIIb, MSD > 50 mm).
The subgroups were matched with recommended surgical strategy using expert opinion: Type I CSP was treated with suction dilation and aspiration (D&A) under ultrasound guidance, with or without hysteroscopy. Type IIa CSP was treated with suction D&A with hysteroscopy under ultrasound guidance. Type IIb CSP was treated with hysteroscopy with laparoscopic monitoring or excision, or transvaginal excision. Type IIIa CSP was treated with laparoscopic excision or transvaginal excision. Type IIIb CSP was treated with laparoscopic excision after uterine artery embolization or laparotomy (TABLE).15
Treatment outcomes
These guidelines were tested on a cohort of 564 patients between 2014 and 2022. Using these treatment guidelines, the overall treatment success rate was 97.5%; 85% of patients had a negative serum ß-human chorionic gonadotropin (ß-hCG) level within 3 weeks, and 95.2% of patients resumed menstrual cycles within 8 weeks. Successful treatment was defined as:
- complete resection of the products of conception
- no need to shift to a second-line surgical strategy
- no major complications
- no readmission for additional treatment
- serum ß-hCG levels that returned to normal within 4 weeks.
Although the incidence of CSP is reported to be around 1:2,000 pregnancies, these rare findings frequently cause a clinical conundrum.16 This thoughtful study by Ban and colleagues provides guidance with the creation of a classification system aimed at decreasing the severe morbidity that can come from mismanagement of these problematic pregnancies using predictive quantitative measures. In our own practice, we have used classification (type 1 endogenic or type 2 exogenic), mean gestational sac diameter, and overlying myometrial thickness when weighing options for treatment. However, decisions have been made on a case-by-case basis and expert opinion without specific cutoffs. Having defined parameters to more accurately classify the type of ectopic pregnancy is essential for communicating risk factors with all team members and for research purposes. The treatment algorithm proposed and tested in this study is logical with good outcomes in the test group. We applaud the authors of this study on a rare but potentially morbid pregnancy outcome. Of note, this study does not discuss nonsurgical alternatives for treatment, such as intra-sac methotrexate injection, which is another option used in select patients at our institution.
Continue to: Pre-op hormonal treatment of endometriosis found to be protective against post-op complications...
Pre-op hormonal treatment of endometriosis found to be protective against post-op complications
Casarin J, Ghezzi F, Mueller M, et al. Surgical outcomes and complications of laparoscopic hysterectomy for endometriosis: a multicentric cohort study. J Minim Invasive Gynecol. 2023;30:587-592. doi:1016/j.jmig.2023.03.018
In a large European multicenter retrospective cohort study, Casarin and colleagues evaluated perioperative complications during laparoscopic hysterectomy for endometriosis or adenomyosis in 995 patients treated from 2010 to 2020.2
Reported intraoperative data included the frequency of ureterolysis (26.8%), deep nodule resection (30%) and posterior adhesiolysis (38.9%), unilateral salpingo-oophorectomy (15.1%), bilateral salpingo-oophorectomy (26.8%), estimated blood loss (mean, 100 mL), and adverse events. Intraoperative complications occurred in 3% of cases (including bladder/bowel injury or need for transfusion).
Postoperative complications occurred in 13.8% of cases, and 9.3% had a major event, including vaginal cuff dehiscence, fever, abscess, and fistula.
Factors associated with postoperative complications
In a multivariate analysis, the authors found that increased operative time, younger age at surgery, previous surgery for endometriosis, and occurrence of intraoperative complications were associated with Clavien-Dindo score grade 2 or greater postoperative complications.
Medical treatment for endometriosis with estro-progestin or progestin medications, however, was found to be protective, with an odds ratio of 0.50 (95% confidence interval, 0.31–0.81).
It is well known that endometriosis is a risk factor for surgical complications. The reported complication rates in this cohort were relatively high, with nearly 10% of patients sustaining a major event postoperatively. While surgical risk is multifactorial and includes factors that are difficult to capture, including surgeon experience and patient population baseline risk, the relatively high incidence reported should be cause for pause and be incorporated in patient counseling. Of note, this cohort did undergo a large number of higher order dissections and a high number of bilateral salpingo-oophorectomies (26.8%), which suggests a high-risk population.
What we found most interesting, however, was the positive finding that medication administration was protective against complications. The authors suggested that the antiinflammatory effects of hormone suppressive medications may be the key. Although this was a retrospective cohort study, the significant risk reduction seen is extremely compelling. A randomized clinical trial corroborating these findings would be instrumental. Endometriosis acts similarly to cancer in its progressive spread and destruction of surrounding tissues. As is increasingly supported in the oncologic literature, perhaps neoadjuvant therapy should be the standard for our “benign” high-risk endometriosis surgeries, with hormonal suppression serving as our chemotherapy. In our own practices, we may be more likely to encourage preoperative medication management, citing this added benefit to patients.
Diaphragmatic endometriosis prevalence higher than previously reported
Pagano F, Schwander A, Vaineau C, et al. True prevalence of diaphragmatic endometriosis and its association with severe endometriosis: a call for awareness and investigation. J Minim Invasive Gynecol. 2023;30:329-334. doi:10.1016/j.jmig.2023.01.006
Pagano and colleagues conducted an impressive large prospective cohort study that included more than 1,300 patients with histologically proven endometriosis.1 Each patient underwent a systematic evaluation and reporting of intraoperative findings, including bilateral evaluation for diaphragmatic endometriosis (DE).
Patients with DE had high rates of infertility and high-stage disease
In this cohort, 4.7% of patients were found to have diaphragmatic disease; 92.3% of these cases had DE involving the right diaphragm. Patients with DE had a higher rate of infertility than those without DE (nearly 50%), but otherwise they had no difference in typical endometriosis symptoms (dysmenorrhea, dyspareunia, dyschezia, dysuria). In this cohort, 27.4% had diaphragmatic symptoms (right shoulder pain, cough, cyclic dyspnea).
Patients found to have DE had higher rates of stage III/IV disease (78.4%), and the left pelvis was affected in more patients (73.8%).
The prevalence of DE in this large cohort evaluated by endometriosis surgeons was far higher than previously reported rates of DE (0.19%–1.5% for abdominal endometriosis cases).17,18 Although admittedly this center cares for a larger portion of women with high-stage disease than many nonspecialty centers do, it still begs the question: Are we as a specialty underdiagnosing diaphragmatic endometriosis, especially in our patients with more severe endometriosis? Because nearly 5% of endometriosis patients could have DE, a thoughtful and systematic approach to the abdominal survey and diaphragm should be performed for each case. Adding questions about diaphragmatic symptoms to our preoperative evaluation may help to identify about one-quarter of these complicated patients preoperatively to aid in counseling and surgical planning. Patients to be specifically mindful about include those with high-stage disease, especially left-sided disease, and those with infertility (although this could be a secondary association given the larger proportion of patients with stage III/IV disease with infertility, and no multivariate analysis was performed). This study serves as a thoughtful reminder of this important subject.
A word on fertility-sparing treatments for adenomyosis
Several interesting and thoughtful studies were published on the fertility-sparing management of adenomyosis.6-8 These included a comparison of fertility outcomes following excisional and nonexcisional therapies,6 a systematic review of the literature that compared recurrence rates following procedural and surgical treatments,8 and outcomes after use of a novel therapy (percutaneous microwave ablation) for the treatment of adenomyosis.7
Although our critical evaluation of these studies found that they are not robust enough to yet change our practice, we want to applaud the authors on their discerning questions and on taking the initial steps to answer critical questions, including:
- What is the best uterine-sparing method for treatment of diffuse adenomyosis?
- Are radiofrequency or microwave ablation procedures the future of adenomyosis care?
- How do we counsel patients about fertility potential following procedural treatments?
- Pagano F, Schwander A, Vaineau C, et al. True prevalence of diaphragmatic endometriosis and its association with severe endometriosis: a call for awareness and investigation. J Minim Invasive Gynecol. 2023;30:329-334. doi:10.1016 /j.jmig.2023.01.006
- Casarin J, Ghezzi F, Mueller M, et al. Surgical outcomes and complications of laparoscopic hysterectomy for endometriosis: a multicentric cohort study. J Minim Invasive Gynecol. 2023;30:587-592. doi:1016/j.jmig.2023.03.018
- Abrao MS, Andres MP, Gingold JA, et al. Preoperative ultrasound scoring of endometriosis by AAGL 2021 endometriosis classification is concordant with laparoscopic surgical findings and distinguishes early from advanced stages. J Minim Invasive Gynecol. 2023;30:363-373. doi:10.1016 /j.jmig.2022.11.003
- Meyer R, Siedhoff M, Truong M, et al. Risk factors for major complications following minimally invasive surgeries for endometriosis in the United States. J Minim Invasive Gynecol. 2023;30:820-826. doi:10.1016/j.jmig.2023.06.002
- Davenport S, Smith D, Green DJ. Barriers to a timely diagnosis of endometriosis. Obstet Gynecol. 2023;142:571-583. doi:10.1097/AOG.0000000000005255
- Jiang L, Han Y, Song Z, et al. Pregnancy outcomes after uterus-sparing operative treatment for adenomyosis: a systematic review and meta-analysis. J Minim Invasive Gynecol. 2023:30:543-554. doi:10.1016/j.jmig.2023.03.015
- Li S, Li Z, Lin M, et al. Efficacy of transabdominal ultrasoundguided percutaneous microwave ablation in the treatment of symptomatic adenomyosis: a retrospective cohort study. J Minim Invasive Gynecol. 2023;30:137-146. doi:10.1016/j.jmig.2022.11.004
- Liu L, Tian H, Lin D, et al. Risk of recurrence and reintervention after uterine-sparing interventions for symptomatic adenomyosis: a systematic review and metaanalysis. Obstet Gynecol. 2023;141:711-723. doi:10.1097 /AOG.0000000000005080
- Chang OH, Tewari S, Yao M, et al. Who places high value on the uterus? A cross-sectional survey study evaluating predictors for uterine preservation. J Minim Invasive Gynecol. 2023;30:131-136. doi:10.1016/j.jmig.2022.10.012
- Carey ET, Moore KJ, McClurg AB, et al. Racial disparities in hysterectomy route for benign disease: examining trends and perioperative complications from 2007 to 2018 using the NSQIP database. J Minim Invasive Gynecol. 2023;30:627-634. doi:10.1016/j.jmig.2023.03.024
- Frisch EH, Mitchell J, Yao M, et al. The impact of fertility goals on long-term quality of life in reproductive-aged women who underwent myomectomy versus hysterectomy for uterine fibroids. J Minim Invasive Gynecol. 2023;30:642-651. doi:10.1016/j.jmig.2023.04.003 1
- Robinson WR, Mathias JG, Wood ME, et al. Ethnoracial differences in premenopausal hysterectomy: the role of symptom severity. Obstet Gynecol. 2023;142:350-359. doi:10.1097 /AOG.0000000000005225
- Harris HR, Peres LC, Johnson CE, et al. Racial differences in the association of endometriosis and uterine leiomyomas with the risk of ovarian cancer. Obstet Gynecol. 2023;141:11241138. doi:10.1097/AOG.0000000000005191
- Atia O, Hazan E, Rotem R, et al. A scoring system developed by a machine learning algorithm to better predict adnexal torsion. J Minim Invasive Gynecol. 2023;30:486-493. doi:10.1016/j.jmig.2023.02.008
- Ban Y, Shen J, Wang X, et al. Cesarean scar ectopic pregnancy clinical classification system with recommended surgical strategy. Obstet Gynecol. 2023;141:927-936. doi:10.1097 /AOG.0000000000005113
- Rotas MA, Haberman S, Levgur M. Cesarean scar ectopic pregnancies. Obstet Gynecol. 2006;107:1373-1381. doi:10.1097/01.AOG.0000218690.24494.ce
- Scioscia M, Bruni F, Ceccaroni M, et al. Distribution of endometriotic lesions in endometriosis stage IV supports the menstrual reflux theory and requires specific preoperative assessment and therapy. Acta Obstet Gynecol Scand. 2011;90:136-139. doi:10.1111/j.1600-0412.2010.01008.x
- Wetzel A, Philip C-A, Golfier F, et al. Surgical management of diaphragmatic and thoracic endometriosis: a French multicentric descriptive study. J Gynecol Obstet Hum Reprod. 2021;50:102147. doi:10.1016/j.jogoh.2021.102147
It has been an incredible year for complex gynecology and minimally invasive gynecologic surgery (MIGS), with several outstanding new findings and reviews in 2023. The surgical community continues to push the envelope and emphasize the value of this specialty for women’s health.
Endometriosis and adenomyosis were at the center of several large cohort studies and systematic reviews that reassessed what we know about how to evaluate and treat these challenging diseases, including both surgical and nonsurgical approaches, with an emphasis on fertility-sparing modalities.1-8 In addition, a focus on quality of life, patient-centered care, and racial biases allowed us to reflect on our own practice patterns and keep the patient at the center of care models.9-13 Finally, there was a clear expansion in the use of technologies such as artificial intelligence (AI) and machine learning for care and novel minimally invasive tools.14
In this Update, we highlight and expand on how several particularly important developments are likely to make a difference in our clinical management.
New classification system for cesarean scar ectopic pregnancy with defined surgical guidance has 97% treatment success rate
Ban Y, Shen J, Wang X, et al. Cesarean scar ectopic pregnancy clinical classification system with recommended surgical strategy. Obstet Gynecol. 2023;141:927-936. doi:10.1097/AOG.0000000000005113
A large multiarmed study by Ban and colleagues used multivariable modeling to formulate and test a classification system and recommended surgical treatment strategies for patients with a cesarean scar ectopic pregnancy (CSP).15 In the study, 273 patients were included in the predictive modeling group, 118 in the internal validation group, and 564 within the model testing cohort. Classifications were based on 2 independent risk factors for intraoperative hemorrhage: anterior myometrial thickness and mean diameter of gestational sac (MSD).
Classification types
The 3 main CSP types were defined based on the anterior myometrial thickness at the cesarean section scar (type I, > 3 mm; type II, 1–3 mm; type III, ≤ 1 mm) and subtyped based on the MSD (type IIa, MSD ≤ 30 mm; type IIb, MSD > 30 mm; type IIIa, MSD ≤ 50 mm; type IIIb, MSD > 50 mm).
The subgroups were matched with recommended surgical strategy using expert opinion: Type I CSP was treated with suction dilation and aspiration (D&A) under ultrasound guidance, with or without hysteroscopy. Type IIa CSP was treated with suction D&A with hysteroscopy under ultrasound guidance. Type IIb CSP was treated with hysteroscopy with laparoscopic monitoring or excision, or transvaginal excision. Type IIIa CSP was treated with laparoscopic excision or transvaginal excision. Type IIIb CSP was treated with laparoscopic excision after uterine artery embolization or laparotomy (TABLE).15
Treatment outcomes
These guidelines were tested on a cohort of 564 patients between 2014 and 2022. Using these treatment guidelines, the overall treatment success rate was 97.5%; 85% of patients had a negative serum ß-human chorionic gonadotropin (ß-hCG) level within 3 weeks, and 95.2% of patients resumed menstrual cycles within 8 weeks. Successful treatment was defined as:
- complete resection of the products of conception
- no need to shift to a second-line surgical strategy
- no major complications
- no readmission for additional treatment
- serum ß-hCG levels that returned to normal within 4 weeks.
Although the incidence of CSP is reported to be around 1:2,000 pregnancies, these rare findings frequently cause a clinical conundrum.16 This thoughtful study by Ban and colleagues provides guidance with the creation of a classification system aimed at decreasing the severe morbidity that can come from mismanagement of these problematic pregnancies using predictive quantitative measures. In our own practice, we have used classification (type 1 endogenic or type 2 exogenic), mean gestational sac diameter, and overlying myometrial thickness when weighing options for treatment. However, decisions have been made on a case-by-case basis and expert opinion without specific cutoffs. Having defined parameters to more accurately classify the type of ectopic pregnancy is essential for communicating risk factors with all team members and for research purposes. The treatment algorithm proposed and tested in this study is logical with good outcomes in the test group. We applaud the authors of this study on a rare but potentially morbid pregnancy outcome. Of note, this study does not discuss nonsurgical alternatives for treatment, such as intra-sac methotrexate injection, which is another option used in select patients at our institution.
Continue to: Pre-op hormonal treatment of endometriosis found to be protective against post-op complications...
Pre-op hormonal treatment of endometriosis found to be protective against post-op complications
Casarin J, Ghezzi F, Mueller M, et al. Surgical outcomes and complications of laparoscopic hysterectomy for endometriosis: a multicentric cohort study. J Minim Invasive Gynecol. 2023;30:587-592. doi:1016/j.jmig.2023.03.018
In a large European multicenter retrospective cohort study, Casarin and colleagues evaluated perioperative complications during laparoscopic hysterectomy for endometriosis or adenomyosis in 995 patients treated from 2010 to 2020.2
Reported intraoperative data included the frequency of ureterolysis (26.8%), deep nodule resection (30%) and posterior adhesiolysis (38.9%), unilateral salpingo-oophorectomy (15.1%), bilateral salpingo-oophorectomy (26.8%), estimated blood loss (mean, 100 mL), and adverse events. Intraoperative complications occurred in 3% of cases (including bladder/bowel injury or need for transfusion).
Postoperative complications occurred in 13.8% of cases, and 9.3% had a major event, including vaginal cuff dehiscence, fever, abscess, and fistula.
Factors associated with postoperative complications
In a multivariate analysis, the authors found that increased operative time, younger age at surgery, previous surgery for endometriosis, and occurrence of intraoperative complications were associated with Clavien-Dindo score grade 2 or greater postoperative complications.
Medical treatment for endometriosis with estro-progestin or progestin medications, however, was found to be protective, with an odds ratio of 0.50 (95% confidence interval, 0.31–0.81).
It is well known that endometriosis is a risk factor for surgical complications. The reported complication rates in this cohort were relatively high, with nearly 10% of patients sustaining a major event postoperatively. While surgical risk is multifactorial and includes factors that are difficult to capture, including surgeon experience and patient population baseline risk, the relatively high incidence reported should be cause for pause and be incorporated in patient counseling. Of note, this cohort did undergo a large number of higher order dissections and a high number of bilateral salpingo-oophorectomies (26.8%), which suggests a high-risk population.
What we found most interesting, however, was the positive finding that medication administration was protective against complications. The authors suggested that the antiinflammatory effects of hormone suppressive medications may be the key. Although this was a retrospective cohort study, the significant risk reduction seen is extremely compelling. A randomized clinical trial corroborating these findings would be instrumental. Endometriosis acts similarly to cancer in its progressive spread and destruction of surrounding tissues. As is increasingly supported in the oncologic literature, perhaps neoadjuvant therapy should be the standard for our “benign” high-risk endometriosis surgeries, with hormonal suppression serving as our chemotherapy. In our own practices, we may be more likely to encourage preoperative medication management, citing this added benefit to patients.
Diaphragmatic endometriosis prevalence higher than previously reported
Pagano F, Schwander A, Vaineau C, et al. True prevalence of diaphragmatic endometriosis and its association with severe endometriosis: a call for awareness and investigation. J Minim Invasive Gynecol. 2023;30:329-334. doi:10.1016/j.jmig.2023.01.006
Pagano and colleagues conducted an impressive large prospective cohort study that included more than 1,300 patients with histologically proven endometriosis.1 Each patient underwent a systematic evaluation and reporting of intraoperative findings, including bilateral evaluation for diaphragmatic endometriosis (DE).
Patients with DE had high rates of infertility and high-stage disease
In this cohort, 4.7% of patients were found to have diaphragmatic disease; 92.3% of these cases had DE involving the right diaphragm. Patients with DE had a higher rate of infertility than those without DE (nearly 50%), but otherwise they had no difference in typical endometriosis symptoms (dysmenorrhea, dyspareunia, dyschezia, dysuria). In this cohort, 27.4% had diaphragmatic symptoms (right shoulder pain, cough, cyclic dyspnea).
Patients found to have DE had higher rates of stage III/IV disease (78.4%), and the left pelvis was affected in more patients (73.8%).
The prevalence of DE in this large cohort evaluated by endometriosis surgeons was far higher than previously reported rates of DE (0.19%–1.5% for abdominal endometriosis cases).17,18 Although admittedly this center cares for a larger portion of women with high-stage disease than many nonspecialty centers do, it still begs the question: Are we as a specialty underdiagnosing diaphragmatic endometriosis, especially in our patients with more severe endometriosis? Because nearly 5% of endometriosis patients could have DE, a thoughtful and systematic approach to the abdominal survey and diaphragm should be performed for each case. Adding questions about diaphragmatic symptoms to our preoperative evaluation may help to identify about one-quarter of these complicated patients preoperatively to aid in counseling and surgical planning. Patients to be specifically mindful about include those with high-stage disease, especially left-sided disease, and those with infertility (although this could be a secondary association given the larger proportion of patients with stage III/IV disease with infertility, and no multivariate analysis was performed). This study serves as a thoughtful reminder of this important subject.
A word on fertility-sparing treatments for adenomyosis
Several interesting and thoughtful studies were published on the fertility-sparing management of adenomyosis.6-8 These included a comparison of fertility outcomes following excisional and nonexcisional therapies,6 a systematic review of the literature that compared recurrence rates following procedural and surgical treatments,8 and outcomes after use of a novel therapy (percutaneous microwave ablation) for the treatment of adenomyosis.7
Although our critical evaluation of these studies found that they are not robust enough to yet change our practice, we want to applaud the authors on their discerning questions and on taking the initial steps to answer critical questions, including:
- What is the best uterine-sparing method for treatment of diffuse adenomyosis?
- Are radiofrequency or microwave ablation procedures the future of adenomyosis care?
- How do we counsel patients about fertility potential following procedural treatments?
It has been an incredible year for complex gynecology and minimally invasive gynecologic surgery (MIGS), with several outstanding new findings and reviews in 2023. The surgical community continues to push the envelope and emphasize the value of this specialty for women’s health.
Endometriosis and adenomyosis were at the center of several large cohort studies and systematic reviews that reassessed what we know about how to evaluate and treat these challenging diseases, including both surgical and nonsurgical approaches, with an emphasis on fertility-sparing modalities.1-8 In addition, a focus on quality of life, patient-centered care, and racial biases allowed us to reflect on our own practice patterns and keep the patient at the center of care models.9-13 Finally, there was a clear expansion in the use of technologies such as artificial intelligence (AI) and machine learning for care and novel minimally invasive tools.14
In this Update, we highlight and expand on how several particularly important developments are likely to make a difference in our clinical management.
New classification system for cesarean scar ectopic pregnancy with defined surgical guidance has 97% treatment success rate
Ban Y, Shen J, Wang X, et al. Cesarean scar ectopic pregnancy clinical classification system with recommended surgical strategy. Obstet Gynecol. 2023;141:927-936. doi:10.1097/AOG.0000000000005113
A large multiarmed study by Ban and colleagues used multivariable modeling to formulate and test a classification system and recommended surgical treatment strategies for patients with a cesarean scar ectopic pregnancy (CSP).15 In the study, 273 patients were included in the predictive modeling group, 118 in the internal validation group, and 564 within the model testing cohort. Classifications were based on 2 independent risk factors for intraoperative hemorrhage: anterior myometrial thickness and mean diameter of gestational sac (MSD).
Classification types
The 3 main CSP types were defined based on the anterior myometrial thickness at the cesarean section scar (type I, > 3 mm; type II, 1–3 mm; type III, ≤ 1 mm) and subtyped based on the MSD (type IIa, MSD ≤ 30 mm; type IIb, MSD > 30 mm; type IIIa, MSD ≤ 50 mm; type IIIb, MSD > 50 mm).
The subgroups were matched with recommended surgical strategy using expert opinion: Type I CSP was treated with suction dilation and aspiration (D&A) under ultrasound guidance, with or without hysteroscopy. Type IIa CSP was treated with suction D&A with hysteroscopy under ultrasound guidance. Type IIb CSP was treated with hysteroscopy with laparoscopic monitoring or excision, or transvaginal excision. Type IIIa CSP was treated with laparoscopic excision or transvaginal excision. Type IIIb CSP was treated with laparoscopic excision after uterine artery embolization or laparotomy (TABLE).15
Treatment outcomes
These guidelines were tested on a cohort of 564 patients between 2014 and 2022. Using these treatment guidelines, the overall treatment success rate was 97.5%; 85% of patients had a negative serum ß-human chorionic gonadotropin (ß-hCG) level within 3 weeks, and 95.2% of patients resumed menstrual cycles within 8 weeks. Successful treatment was defined as:
- complete resection of the products of conception
- no need to shift to a second-line surgical strategy
- no major complications
- no readmission for additional treatment
- serum ß-hCG levels that returned to normal within 4 weeks.
Although the incidence of CSP is reported to be around 1:2,000 pregnancies, these rare findings frequently cause a clinical conundrum.16 This thoughtful study by Ban and colleagues provides guidance with the creation of a classification system aimed at decreasing the severe morbidity that can come from mismanagement of these problematic pregnancies using predictive quantitative measures. In our own practice, we have used classification (type 1 endogenic or type 2 exogenic), mean gestational sac diameter, and overlying myometrial thickness when weighing options for treatment. However, decisions have been made on a case-by-case basis and expert opinion without specific cutoffs. Having defined parameters to more accurately classify the type of ectopic pregnancy is essential for communicating risk factors with all team members and for research purposes. The treatment algorithm proposed and tested in this study is logical with good outcomes in the test group. We applaud the authors of this study on a rare but potentially morbid pregnancy outcome. Of note, this study does not discuss nonsurgical alternatives for treatment, such as intra-sac methotrexate injection, which is another option used in select patients at our institution.
Continue to: Pre-op hormonal treatment of endometriosis found to be protective against post-op complications...
Pre-op hormonal treatment of endometriosis found to be protective against post-op complications
Casarin J, Ghezzi F, Mueller M, et al. Surgical outcomes and complications of laparoscopic hysterectomy for endometriosis: a multicentric cohort study. J Minim Invasive Gynecol. 2023;30:587-592. doi:1016/j.jmig.2023.03.018
In a large European multicenter retrospective cohort study, Casarin and colleagues evaluated perioperative complications during laparoscopic hysterectomy for endometriosis or adenomyosis in 995 patients treated from 2010 to 2020.2
Reported intraoperative data included the frequency of ureterolysis (26.8%), deep nodule resection (30%) and posterior adhesiolysis (38.9%), unilateral salpingo-oophorectomy (15.1%), bilateral salpingo-oophorectomy (26.8%), estimated blood loss (mean, 100 mL), and adverse events. Intraoperative complications occurred in 3% of cases (including bladder/bowel injury or need for transfusion).
Postoperative complications occurred in 13.8% of cases, and 9.3% had a major event, including vaginal cuff dehiscence, fever, abscess, and fistula.
Factors associated with postoperative complications
In a multivariate analysis, the authors found that increased operative time, younger age at surgery, previous surgery for endometriosis, and occurrence of intraoperative complications were associated with Clavien-Dindo score grade 2 or greater postoperative complications.
Medical treatment for endometriosis with estro-progestin or progestin medications, however, was found to be protective, with an odds ratio of 0.50 (95% confidence interval, 0.31–0.81).
It is well known that endometriosis is a risk factor for surgical complications. The reported complication rates in this cohort were relatively high, with nearly 10% of patients sustaining a major event postoperatively. While surgical risk is multifactorial and includes factors that are difficult to capture, including surgeon experience and patient population baseline risk, the relatively high incidence reported should be cause for pause and be incorporated in patient counseling. Of note, this cohort did undergo a large number of higher order dissections and a high number of bilateral salpingo-oophorectomies (26.8%), which suggests a high-risk population.
What we found most interesting, however, was the positive finding that medication administration was protective against complications. The authors suggested that the antiinflammatory effects of hormone suppressive medications may be the key. Although this was a retrospective cohort study, the significant risk reduction seen is extremely compelling. A randomized clinical trial corroborating these findings would be instrumental. Endometriosis acts similarly to cancer in its progressive spread and destruction of surrounding tissues. As is increasingly supported in the oncologic literature, perhaps neoadjuvant therapy should be the standard for our “benign” high-risk endometriosis surgeries, with hormonal suppression serving as our chemotherapy. In our own practices, we may be more likely to encourage preoperative medication management, citing this added benefit to patients.
Diaphragmatic endometriosis prevalence higher than previously reported
Pagano F, Schwander A, Vaineau C, et al. True prevalence of diaphragmatic endometriosis and its association with severe endometriosis: a call for awareness and investigation. J Minim Invasive Gynecol. 2023;30:329-334. doi:10.1016/j.jmig.2023.01.006
Pagano and colleagues conducted an impressive large prospective cohort study that included more than 1,300 patients with histologically proven endometriosis.1 Each patient underwent a systematic evaluation and reporting of intraoperative findings, including bilateral evaluation for diaphragmatic endometriosis (DE).
Patients with DE had high rates of infertility and high-stage disease
In this cohort, 4.7% of patients were found to have diaphragmatic disease; 92.3% of these cases had DE involving the right diaphragm. Patients with DE had a higher rate of infertility than those without DE (nearly 50%), but otherwise they had no difference in typical endometriosis symptoms (dysmenorrhea, dyspareunia, dyschezia, dysuria). In this cohort, 27.4% had diaphragmatic symptoms (right shoulder pain, cough, cyclic dyspnea).
Patients found to have DE had higher rates of stage III/IV disease (78.4%), and the left pelvis was affected in more patients (73.8%).
The prevalence of DE in this large cohort evaluated by endometriosis surgeons was far higher than previously reported rates of DE (0.19%–1.5% for abdominal endometriosis cases).17,18 Although admittedly this center cares for a larger portion of women with high-stage disease than many nonspecialty centers do, it still begs the question: Are we as a specialty underdiagnosing diaphragmatic endometriosis, especially in our patients with more severe endometriosis? Because nearly 5% of endometriosis patients could have DE, a thoughtful and systematic approach to the abdominal survey and diaphragm should be performed for each case. Adding questions about diaphragmatic symptoms to our preoperative evaluation may help to identify about one-quarter of these complicated patients preoperatively to aid in counseling and surgical planning. Patients to be specifically mindful about include those with high-stage disease, especially left-sided disease, and those with infertility (although this could be a secondary association given the larger proportion of patients with stage III/IV disease with infertility, and no multivariate analysis was performed). This study serves as a thoughtful reminder of this important subject.
A word on fertility-sparing treatments for adenomyosis
Several interesting and thoughtful studies were published on the fertility-sparing management of adenomyosis.6-8 These included a comparison of fertility outcomes following excisional and nonexcisional therapies,6 a systematic review of the literature that compared recurrence rates following procedural and surgical treatments,8 and outcomes after use of a novel therapy (percutaneous microwave ablation) for the treatment of adenomyosis.7
Although our critical evaluation of these studies found that they are not robust enough to yet change our practice, we want to applaud the authors on their discerning questions and on taking the initial steps to answer critical questions, including:
- What is the best uterine-sparing method for treatment of diffuse adenomyosis?
- Are radiofrequency or microwave ablation procedures the future of adenomyosis care?
- How do we counsel patients about fertility potential following procedural treatments?
- Pagano F, Schwander A, Vaineau C, et al. True prevalence of diaphragmatic endometriosis and its association with severe endometriosis: a call for awareness and investigation. J Minim Invasive Gynecol. 2023;30:329-334. doi:10.1016 /j.jmig.2023.01.006
- Casarin J, Ghezzi F, Mueller M, et al. Surgical outcomes and complications of laparoscopic hysterectomy for endometriosis: a multicentric cohort study. J Minim Invasive Gynecol. 2023;30:587-592. doi:1016/j.jmig.2023.03.018
- Abrao MS, Andres MP, Gingold JA, et al. Preoperative ultrasound scoring of endometriosis by AAGL 2021 endometriosis classification is concordant with laparoscopic surgical findings and distinguishes early from advanced stages. J Minim Invasive Gynecol. 2023;30:363-373. doi:10.1016 /j.jmig.2022.11.003
- Meyer R, Siedhoff M, Truong M, et al. Risk factors for major complications following minimally invasive surgeries for endometriosis in the United States. J Minim Invasive Gynecol. 2023;30:820-826. doi:10.1016/j.jmig.2023.06.002
- Davenport S, Smith D, Green DJ. Barriers to a timely diagnosis of endometriosis. Obstet Gynecol. 2023;142:571-583. doi:10.1097/AOG.0000000000005255
- Jiang L, Han Y, Song Z, et al. Pregnancy outcomes after uterus-sparing operative treatment for adenomyosis: a systematic review and meta-analysis. J Minim Invasive Gynecol. 2023:30:543-554. doi:10.1016/j.jmig.2023.03.015
- Li S, Li Z, Lin M, et al. Efficacy of transabdominal ultrasoundguided percutaneous microwave ablation in the treatment of symptomatic adenomyosis: a retrospective cohort study. J Minim Invasive Gynecol. 2023;30:137-146. doi:10.1016/j.jmig.2022.11.004
- Liu L, Tian H, Lin D, et al. Risk of recurrence and reintervention after uterine-sparing interventions for symptomatic adenomyosis: a systematic review and metaanalysis. Obstet Gynecol. 2023;141:711-723. doi:10.1097 /AOG.0000000000005080
- Chang OH, Tewari S, Yao M, et al. Who places high value on the uterus? A cross-sectional survey study evaluating predictors for uterine preservation. J Minim Invasive Gynecol. 2023;30:131-136. doi:10.1016/j.jmig.2022.10.012
- Carey ET, Moore KJ, McClurg AB, et al. Racial disparities in hysterectomy route for benign disease: examining trends and perioperative complications from 2007 to 2018 using the NSQIP database. J Minim Invasive Gynecol. 2023;30:627-634. doi:10.1016/j.jmig.2023.03.024
- Frisch EH, Mitchell J, Yao M, et al. The impact of fertility goals on long-term quality of life in reproductive-aged women who underwent myomectomy versus hysterectomy for uterine fibroids. J Minim Invasive Gynecol. 2023;30:642-651. doi:10.1016/j.jmig.2023.04.003 1
- Robinson WR, Mathias JG, Wood ME, et al. Ethnoracial differences in premenopausal hysterectomy: the role of symptom severity. Obstet Gynecol. 2023;142:350-359. doi:10.1097 /AOG.0000000000005225
- Harris HR, Peres LC, Johnson CE, et al. Racial differences in the association of endometriosis and uterine leiomyomas with the risk of ovarian cancer. Obstet Gynecol. 2023;141:11241138. doi:10.1097/AOG.0000000000005191
- Atia O, Hazan E, Rotem R, et al. A scoring system developed by a machine learning algorithm to better predict adnexal torsion. J Minim Invasive Gynecol. 2023;30:486-493. doi:10.1016/j.jmig.2023.02.008
- Ban Y, Shen J, Wang X, et al. Cesarean scar ectopic pregnancy clinical classification system with recommended surgical strategy. Obstet Gynecol. 2023;141:927-936. doi:10.1097 /AOG.0000000000005113
- Rotas MA, Haberman S, Levgur M. Cesarean scar ectopic pregnancies. Obstet Gynecol. 2006;107:1373-1381. doi:10.1097/01.AOG.0000218690.24494.ce
- Scioscia M, Bruni F, Ceccaroni M, et al. Distribution of endometriotic lesions in endometriosis stage IV supports the menstrual reflux theory and requires specific preoperative assessment and therapy. Acta Obstet Gynecol Scand. 2011;90:136-139. doi:10.1111/j.1600-0412.2010.01008.x
- Wetzel A, Philip C-A, Golfier F, et al. Surgical management of diaphragmatic and thoracic endometriosis: a French multicentric descriptive study. J Gynecol Obstet Hum Reprod. 2021;50:102147. doi:10.1016/j.jogoh.2021.102147
- Pagano F, Schwander A, Vaineau C, et al. True prevalence of diaphragmatic endometriosis and its association with severe endometriosis: a call for awareness and investigation. J Minim Invasive Gynecol. 2023;30:329-334. doi:10.1016 /j.jmig.2023.01.006
- Casarin J, Ghezzi F, Mueller M, et al. Surgical outcomes and complications of laparoscopic hysterectomy for endometriosis: a multicentric cohort study. J Minim Invasive Gynecol. 2023;30:587-592. doi:1016/j.jmig.2023.03.018
- Abrao MS, Andres MP, Gingold JA, et al. Preoperative ultrasound scoring of endometriosis by AAGL 2021 endometriosis classification is concordant with laparoscopic surgical findings and distinguishes early from advanced stages. J Minim Invasive Gynecol. 2023;30:363-373. doi:10.1016 /j.jmig.2022.11.003
- Meyer R, Siedhoff M, Truong M, et al. Risk factors for major complications following minimally invasive surgeries for endometriosis in the United States. J Minim Invasive Gynecol. 2023;30:820-826. doi:10.1016/j.jmig.2023.06.002
- Davenport S, Smith D, Green DJ. Barriers to a timely diagnosis of endometriosis. Obstet Gynecol. 2023;142:571-583. doi:10.1097/AOG.0000000000005255
- Jiang L, Han Y, Song Z, et al. Pregnancy outcomes after uterus-sparing operative treatment for adenomyosis: a systematic review and meta-analysis. J Minim Invasive Gynecol. 2023:30:543-554. doi:10.1016/j.jmig.2023.03.015
- Li S, Li Z, Lin M, et al. Efficacy of transabdominal ultrasoundguided percutaneous microwave ablation in the treatment of symptomatic adenomyosis: a retrospective cohort study. J Minim Invasive Gynecol. 2023;30:137-146. doi:10.1016/j.jmig.2022.11.004
- Liu L, Tian H, Lin D, et al. Risk of recurrence and reintervention after uterine-sparing interventions for symptomatic adenomyosis: a systematic review and metaanalysis. Obstet Gynecol. 2023;141:711-723. doi:10.1097 /AOG.0000000000005080
- Chang OH, Tewari S, Yao M, et al. Who places high value on the uterus? A cross-sectional survey study evaluating predictors for uterine preservation. J Minim Invasive Gynecol. 2023;30:131-136. doi:10.1016/j.jmig.2022.10.012
- Carey ET, Moore KJ, McClurg AB, et al. Racial disparities in hysterectomy route for benign disease: examining trends and perioperative complications from 2007 to 2018 using the NSQIP database. J Minim Invasive Gynecol. 2023;30:627-634. doi:10.1016/j.jmig.2023.03.024
- Frisch EH, Mitchell J, Yao M, et al. The impact of fertility goals on long-term quality of life in reproductive-aged women who underwent myomectomy versus hysterectomy for uterine fibroids. J Minim Invasive Gynecol. 2023;30:642-651. doi:10.1016/j.jmig.2023.04.003 1
- Robinson WR, Mathias JG, Wood ME, et al. Ethnoracial differences in premenopausal hysterectomy: the role of symptom severity. Obstet Gynecol. 2023;142:350-359. doi:10.1097 /AOG.0000000000005225
- Harris HR, Peres LC, Johnson CE, et al. Racial differences in the association of endometriosis and uterine leiomyomas with the risk of ovarian cancer. Obstet Gynecol. 2023;141:11241138. doi:10.1097/AOG.0000000000005191
- Atia O, Hazan E, Rotem R, et al. A scoring system developed by a machine learning algorithm to better predict adnexal torsion. J Minim Invasive Gynecol. 2023;30:486-493. doi:10.1016/j.jmig.2023.02.008
- Ban Y, Shen J, Wang X, et al. Cesarean scar ectopic pregnancy clinical classification system with recommended surgical strategy. Obstet Gynecol. 2023;141:927-936. doi:10.1097 /AOG.0000000000005113
- Rotas MA, Haberman S, Levgur M. Cesarean scar ectopic pregnancies. Obstet Gynecol. 2006;107:1373-1381. doi:10.1097/01.AOG.0000218690.24494.ce
- Scioscia M, Bruni F, Ceccaroni M, et al. Distribution of endometriotic lesions in endometriosis stage IV supports the menstrual reflux theory and requires specific preoperative assessment and therapy. Acta Obstet Gynecol Scand. 2011;90:136-139. doi:10.1111/j.1600-0412.2010.01008.x
- Wetzel A, Philip C-A, Golfier F, et al. Surgical management of diaphragmatic and thoracic endometriosis: a French multicentric descriptive study. J Gynecol Obstet Hum Reprod. 2021;50:102147. doi:10.1016/j.jogoh.2021.102147
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>Update1223docx</fileName> <TBEID>0C02EF48.SIG</TBEID> <TBUniqueIdentifier>NJ_0C02EF48</TBUniqueIdentifier> <newsOrJournal>Journal</newsOrJournal> <publisherName>Frontline Medical Communications Inc.</publisherName> <storyname/> <articleType>1</articleType> <TBLocation>Copyfitting-OBGM</TBLocation> <QCDate/> <firstPublished>20231212T140909</firstPublished> <LastPublished>20231212T140909</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20231212T140909</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline/> <bylineText/> <bylineFull/> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType>(choose one)</newsDocType> <journalDocType>(choose one)</journalDocType> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>It has been an incredible year for complex gynecology and minimally invasive gynecologic surgery (MIGS), with several outstanding new findings and reviews in 20</metaDescription> <articlePDF/> <teaserImage/> <title/> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gyn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle>MDedge ObGyn</journalFullTitle> <copyrightStatement>2018</copyrightStatement> </publicationData> <publicationData> <publicationCode>obgm</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">49726</term> <term>24</term> </publications> <sections> <term canonical="true">49</term> </sections> <topics> <term canonical="true">262</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p class="abstract">Focused guidance on treating cesarean scar pregnancy, preventing complications from laparoscopic hysterectomy for endometriosis, and large study outcomes on the prevalence of diaphragmatic endometriosis</p> <p>It has been an incredible year for complex gynecology and minimally invasive gynecologic surgery (MIGS), with several outstanding new findings and reviews in 2023. The surgical community continues to push the envelope and emphasize the value of this specialty for women’s health.</p> <p>Endometriosis and adenomyosis were at the center of several large cohort studies and systematic reviews that reassessed what we know about how to evaluate and treat these challenging diseases, including both surgical and nonsurgical approaches, with an emphasis on fertility-sparing modalities.<sup>1-8</sup> In addition, a focus on quality of life, patient-centered care, and racial biases allowed us to reflect on our own practice patterns and keep the patient at the center of care models.<sup>9-13</sup> Finally, there was a clear expansion in the use of technologies such as artificial intelligence (AI) and machine learning for care and novel minimally invasive tools.<sup>14<br/><br/></sup>In this Update, we highlight and expand on how several particularly important developments are likely to make a difference in our clinical management.</p> </itemContent> </newsItem> </itemSet></root>
Norgestrel for nonprescription contraception: What you and your patients need to know
On July 13, 2023, the US Food and Drug Administration (FDA) approved norgestrel 0.075 mg (Opill, HRA Pharma, Paris, France) as the first nonprescription oral contraceptive pill (FIGURE). This progestin-only pill was originally FDA approved in 1973, with prescription required, and was available as Ovrette until 2005, when product distribution ceased for marketing reasons and not for safety or effectiveness concerns.1 In recent years, studies have been conducted to support converted approval from prescription to nonprescription to increase access to safe and effective contraception. Overall, norgestrel is more effective than other currently available nonprescription contraceptive options when used as directed, and widespread accessibility to this method has the potential to decrease the risk of unintended pregnancies. This product is expected to be available in drugstores, convenience stores, grocery stores, and online in 2024.
How it works
The indication for norgestrel 0.075 mg is pregnancy prevention in people with the capacity to become pregnant; this product is not intended for emergency contraception. Norgestrel is a racemic mixture of 2 isomers, of which only levonorgestrel is bioactive. The mechanism of action for contraception is primarily through cervical mucus thickening, which inhibits sperm movement through the cervix. About 50% of users also have an additional contraceptive effect of ovulation suppression.2
Instructions for use. In the package label, users are instructed to take the norgestrel 0.075 mg pill daily, preferably at the same time each day and no more than 3 hours from the time taken on the previous day. This method can be started on any day of the cycle, and backup contraception (a barrier method) should be used for the first 48 hours after starting the method if it has been more than 5 days since menstrual bleeding started.3 Product instructions indicate that, if users miss a dose, they should take the next dose as soon as possible. If a pill is taken 3 hours or more later than the usual time, they should take a pill immediately and then resume the next pill at the usual time. In addition, backup contraception is recommended for 48 hours.2
Based on the Centers for Disease Control and Prevention (CDC) Selected Practice Recommendations for Contraceptive Use, no examinations or tests are required prior to initiation of progestin-only pills for safe and effective use.3
Efficacy
The product label indicates that the pregnancy rate is approximately 2 per 100 women-years based on over 21,000 28-day exposure cycles from 8 US clinical studies.2 In a recent review by Glasier and colleagues, the authors identified 13 trials that assessed the efficacy of the norgestrel 0.075 mg pill, all published several decades ago.4 Given that breastfeeding can have contraceptive impact through ovulation inhibition, studies that included breastfeeding participants were evaluated separately. Six studies without breastfeeding participants included 3,184 women who provided more than 35,000 months of use. The overall failure rates ranged from 0 to 2.4 per hundred woman-years with typical use; an aggregate Pearl Index was calculated to be 2.2 based on the total numbers of pregnancies and cycles. The remaining 7 studies included individuals who were breastfeeding for at least part of their study participation. These studies included 5,445 women, and the 12-month life table cumulative pregnancy rates in this group ranged from 0.0% to 3.4%. This review noted that the available studies are limited by incomplete descriptions of study participant information and differences in reporting of failure rates; however, the overall data support the effectiveness of the norgestrel 0.075 mg pill for pregnancy prevention.
Continue to: Norgestrel’s mechanism of action on ovarian activity and cervical mucus...
Norgestrel’s mechanism of action on ovarian activity and cervical mucus
More recently, a prospective, multicenter randomized, crossover study was performed to better understand this pill’s impact on cervical mucus and ovulation during preparation for nonprescription approval. In this study, participants were evaluated with frequent transvaginal ultrasonography, cervical mucus, and blood assessments (including levels of follicular-stimulating hormone, luteinizing hormone, progesterone, and estradiol) for three 28-day cycles. Cervical mucus was scored on a modified Insler scale to indicate if the mucus was favorable (Insler score ≥9), intermediate (Insler score 5-8), or unfavorable to fertility (Insler score ≤4).5
In the first cycle, participants were instructed to use the pills as prescribed (described as “correct use”). During this cycle, most participants (n = 34/51; 67%) did not ovulate, confirming that norgestrel 0.075 mg does impact ovulation.6 Most participants also had unfavorable cervical mucus (n = 39/51; 76%).6 Overall, 94% had full protection against pregnancy, either through lack of ovulation (n = 9), unfavorable mucus (n = 14), or both (n = 25). The remaining 3 participants ovulated and had intermediate mucus scores; ultimately, these participants were considered to have medium protection against pregnancy.7,8 (See the contraceptive protection algorithm [TABLE]).8
In the second and third cycles, the investigators evaluated ovulation and cervical mucus changes in the setting of either a delayed (by 6 hours) or missed dose midcycle.8 Of the 46 participants with evaluable data during the intervention cycles, 32 (70%) did not ovulate in each of the delayed- and missed-dose cycles. Most participants (n = 27; 59%) also demonstrated unfavorable mucus scores (modified Insler score ≤4) over the entire cycle despite delaying or missing a pill. There was no significant change to the cervical mucus score when comparing the scores on the days before, during, and after the delayed or missed pills (P = .26), nor when comparing between delayed pill use and missed pill use (P = .45). With the delayed pill intervention, 4 (9%) had reduced contraceptive protection (ie, medium protection) based on ovulation with intermediate mucus scores. With the missed pill intervention, 5 (11%) had reduced protection, of whom 3 had medium protection and 2 had minimum protection with ovulation and favorable mucus scores. Overall, this study shows that delaying or missing one pill may not impact contraceptive efficacy as much as previously thought given the strict 3-hour window for progestin-only pills. However, these findings are theoretical as information about pregnancy outcomes with delaying or missing pills are lacking.
Safety
Progestin-only methods are one of the safest options for contraception, with few contraindications to use; those listed include known or suspected pregnancy, known or suspected carcinoma of the breast or other progestinsensitive cancer, undiagnosed abnormal uterine bleeding, hypersensitivity to any component of the product, benign or malignant liver tumors, and acute liver disease.2
The CDC Medical Eligibility Criteria for Contraceptive Use guidelines offer guidance for progestin-only pills, indicating a category 3 (theoretical or proven risks usually outweigh the advantages) or category 4 (unacceptable health risk, method not to be used) for only a select number of additional conditions. These conditions include a history of malabsorptive bariatric surgery (category 3) and concurrent use of medications that induce hepatic enzyme activity (category 3)— such as phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine, rifampin, and rifabutin.9 These conditions are included primarily due to concerns of decreased effectivenessof the contraception and not necessarily because of evidence of harm with use.
The prevalence of consumers with contraindications to progestin-only pills appears to be low. In a large database study, only 4.36% seeking preventive care and 2.29% seeking both preventive and contraceptive services had a contraindication to progestin-only pills.10 Therefore, candidates for norgestrel use include individuals who have commonly encountered conditions, including those who9:
- have recently given birth
- are breastfeeding
- have a history of venous thromboembolism
- smoke
- have cardiovascular disease, hypertension, migraines with aura, or longstanding diabetes.
Adverse effects
The most common adverse effects (AEs) related to norgestrel use are bleeding changes.2 In the initial clinical studies for FDA approval, about half of enrolled participants reported a change in bleeding; about 9% discontinued the contraceptive due to bleeding. Breakthrough bleeding and spotting were reported by 48.6% and 47.3% of participants, respectively. About 6.1% had amenorrhea in their first cycle; 28.7% of participants had amenorrhea overall. Other reported AEs were headache, dizziness, nausea, increased appetite, abdominal pain, cramps or bloating, breast tenderness, and acne.
- Brand name: Opill
- Class: Progestin-only contraception
- Indication: Pregnancy prevention
- Approval date: Initial approval in 1973, nonprescription approval on July 13, 2023
- Availability date: 2024
- Manufacturer: Perrigo Company, HRA Pharma, Paris, France
- Dosage forms: 0.075 mg tablet
Continue to: FDA approval required determining appropriate direct-to-patient classification...
FDA approval required determining appropriate direct-to-patient classification
As part of the process for obtaining nonprescription approval, studies needed to determine that patients can safely and effectively use norgestrel without talking to a health care provider first. As part of that process, label comprehension, self-selection, and actualuse studies were required to demonstrate that consumers can use the package information to determine their eligibility and take the medication appropriately.
The ACCESS study Research Q: Do patients appropriately determine if the contraceptive is right for them?
Study A: Yes, 99% of the time. In the Adherence with Continuous-dose Oral Contraceptive: Evaluation of Self-Selection and Use (ACCESS) pivotal study, which evaluated prescription to nonprescription approval, participants were asked to review the label and determine whether the product was appropriate for them to use based on their health history.11 Approximately 99% of participants (n = 1,234/1,246) were able to correctly self-select whether norgestrel was appropriate for their own use.12
Research Q: After beginning the contraceptive, do patients adhere to correct use?
Study A: Yes, more than 90% of the time (and that remained true for subpopulations).
In the next phase of the ACCESS study, eligible participants from the self-selection population who purchased norgestrel and reported using the product at least once in their e-diary over a 6-month study period comprised the “User Population.”12 The overall adherence to daily pill intake was 92.5% (95% confidence interval [CI], 92.3–92.6%) among the 883 participants who contributed more than 90,000 days of study participation, and adherence was similarly high in subpopulations of individuals with low health literacy (92.6%; 95% CI, 92.1–93.0), adolescents aged 12–14 years (91.8%; 95% CI, 91.0–92.5%), and adolescents aged 15–17 years (91.9%; 95% CI, 91.4%–92.3%).
Research Q: When a pill was missed, did patients use backup contraception?
Study A: Yes, 97% of the time.
When including whether participants followed label instructions for mitigating behaviors when the pill was missed (eg, take a pill as soon as they remember, use backup contraception for 2 days after restarting the pill), adherence was 97.1% (95% CI, 97.0–97.2%). Most participants missed a single day of taking pills, and the most common reported reason for missing pills was issues with resupply as participants needed to get new packs from their enrolled research site, which should be less of a barrier when these pills are available over the counter.
Clinical implications of expanded access
Opportunities to expand access to effective contraception have become more critical in the increasingly restrictive environment for abortion care in the post-Dobbs era, and the availability of norgestrel to patients without prescription can advance contraceptive equity. Patients encounter many barriers to accessing prescription contraception, such as lack of insurance; difficulty with scheduling an appointment or getting to a clinic; not having a regular clinician or clinic; or health care providers requiring a visit, exam, or test prior to prescribing contraception.13,14 For patients who face these challenges, an alternative option is to use a nonprescription contraceptive, such as barrier or fertility awareness–based methods, which are typically associated with higher failure rates. With the introduction of norgestrel as a nonprescription contraceptive product, people can have direct access to a more effective contraceptive option.
A follow-up study of participants who had participated in the ACCESS actual-use study demonstrated that most (83%) would be likely to use the nonprescription method if available in the future for many reasons, including convenience, ease of access, ability to save time and money, not needing to visit a clinic, and flexibility of accessing the pills while traveling or having someone else get their pills for them.14 Furthermore, a nonprescription method could be beneficial for people who have concerns about privacy, such as adolescents or individuals affected by contraception sabotage (an act that can intentionally limit or prohibit a person's contraception access or use, ie, damaging condoms or hiding a person’s contraception method). This expansion of access can ultimately lead to a decrease in unintended pregnancies. In a model using the ACCESS actual-use data, about 1,500 to 34,000 unintended pregnancies would be prevented per year based on varying model parameters, with all scenarios demonstrating a benefit to nonprescription access to norgestrel.15
After norgestrel is available, where will patients be able to seek more information?
Patients who have questions or concerns about starting or taking norgestrel should talk to their clinician or a pharmacist for additional information (FIGURE 2). Examples of situations when additional clinical evaluation or counseling are recommended include:
- when a person is taking any medications with possible drug-drug interactions
- if a person is starting norgestrel after taking an emergency contraceptive in the last 5 days
- if there is a concern about pregnancy
- when there are any questions about adverse effects while taking norgestrel.
Bottom line
The nonprescription approval of norgestrel, a progestin-only pill, has the potential to greatly expand patient access to a safe and effective contraceptive method and advance contraceptive equity. The availability of informational materials for consumers about potential issues that may arise (for instance, changes in bleeding) will be important for initiation and continuation of this method. As this product is not yet available for purchase, several unknown factors remain, such as the cost and ease of accessibility in stores or online, that will ultimately determine its public health impact on unintended pregnancies. ●
- US Food and Drug Administration. 82 FR 49380. Determination that Ovrette (norgestrel) tablet, 0.075 milligrams, was not withdrawn from sale for reasons of safety or effectiveness. October 25, 2017. Accessed December 5, 2023. https://www.federalregister.gov/d/2017-23125
- US Food and Drug Administration. Opill tablets (norgestrel tablets) package label. August 2017. Accessed December 5, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label /2017/017031s035s036lbl.pdf
- Curtis KM, Jatlaoui TC, Tepper NK, et al. US selected practice recommendations for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(No. RR-4):1-66.
- Glasier A, Sober S, Gasloli R, et al. A review of the effectiveness of a progestogen-only pill containing norgestrel 75 µg/day. Contraception. 2022;105:1-6.
- Edelman A, Hemon A, Creinin M, et al. Assessing the pregnancy protective impact of scheduled nonadherence to a novel progestin-only pill: protocol for a prospective, multicenter, randomized, crossover study. JMIR Res Protoc. 2021;10:e292208.
- Glasier A, Edelman A, Creinin MD, et al. Mechanism of action of norgestrel 0.075 mg a progestogen-only pill. I. Effect on ovarian activity. Contraception. 2022;112:37-42.
- Han L, Creinin MD, Hemon A, et al. Mechanism of action of a 0.075 mg norgestrel progestogen-only pill 2. Effect on cervical mucus and theoretical risk of conception. Contraception. 2022;112:43-47.
- Glasier A, Edelman A, Creinin MD, et al. The effect of deliberate non-adherence to a norgestrel progestin-only pill: a randomized, crossover study. Contraception. 2023;117:1-6.
- Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(No RR-3):1-104.
- Dutton C, Kim R, Janiak E. Prevalence of contraindications to progestin-only contraceptive pills in a multi-institution patient database. Contraception. 2021;103:367-370.
- Clinicaltrials.gov. Adherence with Continuous-dose Oral Contraceptive Evaluation of Self-Selection and Use (ACCESS). Accessed December 5, 2023. https://clinicaltrials.gov/study /NCT04112095
- HRA Pharma. Opill (norgestrel 0.075 mg tablets) for Rx-toOTC switch. Sponsor Briefing Documents. Joint Meeting of the Nonprescription Drugs Advisory Committee and the Obstetrics, Reproductive, and Urology Drugs Advisory Committee. Meeting dates: 9-10 May 2023. Accessed December 5, 2023. https://www.fda.gov/media/167893 /download
- American College of Obstetricians and Gynecologists. Committee Opinion No. 788: Over-the-counter access to hormonal contraception. Obstet Gynecol. 2019;134:e96-105.
- Grindlay K, Key K, Zuniga C, et al. Interest in continued use after participation in a study of over-the-counter progestin-only pills in the United States. Womens Health Rep. 2022;3:904-914.
- Guillard H, Laurora I, Sober S, et al. Modeling the potential benefit of an over-the-counter progestin-only pill in preventing unintended pregnancies in the U.S. Contraception. 2023;117:7-12.
On July 13, 2023, the US Food and Drug Administration (FDA) approved norgestrel 0.075 mg (Opill, HRA Pharma, Paris, France) as the first nonprescription oral contraceptive pill (FIGURE). This progestin-only pill was originally FDA approved in 1973, with prescription required, and was available as Ovrette until 2005, when product distribution ceased for marketing reasons and not for safety or effectiveness concerns.1 In recent years, studies have been conducted to support converted approval from prescription to nonprescription to increase access to safe and effective contraception. Overall, norgestrel is more effective than other currently available nonprescription contraceptive options when used as directed, and widespread accessibility to this method has the potential to decrease the risk of unintended pregnancies. This product is expected to be available in drugstores, convenience stores, grocery stores, and online in 2024.
How it works
The indication for norgestrel 0.075 mg is pregnancy prevention in people with the capacity to become pregnant; this product is not intended for emergency contraception. Norgestrel is a racemic mixture of 2 isomers, of which only levonorgestrel is bioactive. The mechanism of action for contraception is primarily through cervical mucus thickening, which inhibits sperm movement through the cervix. About 50% of users also have an additional contraceptive effect of ovulation suppression.2
Instructions for use. In the package label, users are instructed to take the norgestrel 0.075 mg pill daily, preferably at the same time each day and no more than 3 hours from the time taken on the previous day. This method can be started on any day of the cycle, and backup contraception (a barrier method) should be used for the first 48 hours after starting the method if it has been more than 5 days since menstrual bleeding started.3 Product instructions indicate that, if users miss a dose, they should take the next dose as soon as possible. If a pill is taken 3 hours or more later than the usual time, they should take a pill immediately and then resume the next pill at the usual time. In addition, backup contraception is recommended for 48 hours.2
Based on the Centers for Disease Control and Prevention (CDC) Selected Practice Recommendations for Contraceptive Use, no examinations or tests are required prior to initiation of progestin-only pills for safe and effective use.3
Efficacy
The product label indicates that the pregnancy rate is approximately 2 per 100 women-years based on over 21,000 28-day exposure cycles from 8 US clinical studies.2 In a recent review by Glasier and colleagues, the authors identified 13 trials that assessed the efficacy of the norgestrel 0.075 mg pill, all published several decades ago.4 Given that breastfeeding can have contraceptive impact through ovulation inhibition, studies that included breastfeeding participants were evaluated separately. Six studies without breastfeeding participants included 3,184 women who provided more than 35,000 months of use. The overall failure rates ranged from 0 to 2.4 per hundred woman-years with typical use; an aggregate Pearl Index was calculated to be 2.2 based on the total numbers of pregnancies and cycles. The remaining 7 studies included individuals who were breastfeeding for at least part of their study participation. These studies included 5,445 women, and the 12-month life table cumulative pregnancy rates in this group ranged from 0.0% to 3.4%. This review noted that the available studies are limited by incomplete descriptions of study participant information and differences in reporting of failure rates; however, the overall data support the effectiveness of the norgestrel 0.075 mg pill for pregnancy prevention.
Continue to: Norgestrel’s mechanism of action on ovarian activity and cervical mucus...
Norgestrel’s mechanism of action on ovarian activity and cervical mucus
More recently, a prospective, multicenter randomized, crossover study was performed to better understand this pill’s impact on cervical mucus and ovulation during preparation for nonprescription approval. In this study, participants were evaluated with frequent transvaginal ultrasonography, cervical mucus, and blood assessments (including levels of follicular-stimulating hormone, luteinizing hormone, progesterone, and estradiol) for three 28-day cycles. Cervical mucus was scored on a modified Insler scale to indicate if the mucus was favorable (Insler score ≥9), intermediate (Insler score 5-8), or unfavorable to fertility (Insler score ≤4).5
In the first cycle, participants were instructed to use the pills as prescribed (described as “correct use”). During this cycle, most participants (n = 34/51; 67%) did not ovulate, confirming that norgestrel 0.075 mg does impact ovulation.6 Most participants also had unfavorable cervical mucus (n = 39/51; 76%).6 Overall, 94% had full protection against pregnancy, either through lack of ovulation (n = 9), unfavorable mucus (n = 14), or both (n = 25). The remaining 3 participants ovulated and had intermediate mucus scores; ultimately, these participants were considered to have medium protection against pregnancy.7,8 (See the contraceptive protection algorithm [TABLE]).8
In the second and third cycles, the investigators evaluated ovulation and cervical mucus changes in the setting of either a delayed (by 6 hours) or missed dose midcycle.8 Of the 46 participants with evaluable data during the intervention cycles, 32 (70%) did not ovulate in each of the delayed- and missed-dose cycles. Most participants (n = 27; 59%) also demonstrated unfavorable mucus scores (modified Insler score ≤4) over the entire cycle despite delaying or missing a pill. There was no significant change to the cervical mucus score when comparing the scores on the days before, during, and after the delayed or missed pills (P = .26), nor when comparing between delayed pill use and missed pill use (P = .45). With the delayed pill intervention, 4 (9%) had reduced contraceptive protection (ie, medium protection) based on ovulation with intermediate mucus scores. With the missed pill intervention, 5 (11%) had reduced protection, of whom 3 had medium protection and 2 had minimum protection with ovulation and favorable mucus scores. Overall, this study shows that delaying or missing one pill may not impact contraceptive efficacy as much as previously thought given the strict 3-hour window for progestin-only pills. However, these findings are theoretical as information about pregnancy outcomes with delaying or missing pills are lacking.
Safety
Progestin-only methods are one of the safest options for contraception, with few contraindications to use; those listed include known or suspected pregnancy, known or suspected carcinoma of the breast or other progestinsensitive cancer, undiagnosed abnormal uterine bleeding, hypersensitivity to any component of the product, benign or malignant liver tumors, and acute liver disease.2
The CDC Medical Eligibility Criteria for Contraceptive Use guidelines offer guidance for progestin-only pills, indicating a category 3 (theoretical or proven risks usually outweigh the advantages) or category 4 (unacceptable health risk, method not to be used) for only a select number of additional conditions. These conditions include a history of malabsorptive bariatric surgery (category 3) and concurrent use of medications that induce hepatic enzyme activity (category 3)— such as phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine, rifampin, and rifabutin.9 These conditions are included primarily due to concerns of decreased effectivenessof the contraception and not necessarily because of evidence of harm with use.
The prevalence of consumers with contraindications to progestin-only pills appears to be low. In a large database study, only 4.36% seeking preventive care and 2.29% seeking both preventive and contraceptive services had a contraindication to progestin-only pills.10 Therefore, candidates for norgestrel use include individuals who have commonly encountered conditions, including those who9:
- have recently given birth
- are breastfeeding
- have a history of venous thromboembolism
- smoke
- have cardiovascular disease, hypertension, migraines with aura, or longstanding diabetes.
Adverse effects
The most common adverse effects (AEs) related to norgestrel use are bleeding changes.2 In the initial clinical studies for FDA approval, about half of enrolled participants reported a change in bleeding; about 9% discontinued the contraceptive due to bleeding. Breakthrough bleeding and spotting were reported by 48.6% and 47.3% of participants, respectively. About 6.1% had amenorrhea in their first cycle; 28.7% of participants had amenorrhea overall. Other reported AEs were headache, dizziness, nausea, increased appetite, abdominal pain, cramps or bloating, breast tenderness, and acne.
- Brand name: Opill
- Class: Progestin-only contraception
- Indication: Pregnancy prevention
- Approval date: Initial approval in 1973, nonprescription approval on July 13, 2023
- Availability date: 2024
- Manufacturer: Perrigo Company, HRA Pharma, Paris, France
- Dosage forms: 0.075 mg tablet
Continue to: FDA approval required determining appropriate direct-to-patient classification...
FDA approval required determining appropriate direct-to-patient classification
As part of the process for obtaining nonprescription approval, studies needed to determine that patients can safely and effectively use norgestrel without talking to a health care provider first. As part of that process, label comprehension, self-selection, and actualuse studies were required to demonstrate that consumers can use the package information to determine their eligibility and take the medication appropriately.
The ACCESS study Research Q: Do patients appropriately determine if the contraceptive is right for them?
Study A: Yes, 99% of the time. In the Adherence with Continuous-dose Oral Contraceptive: Evaluation of Self-Selection and Use (ACCESS) pivotal study, which evaluated prescription to nonprescription approval, participants were asked to review the label and determine whether the product was appropriate for them to use based on their health history.11 Approximately 99% of participants (n = 1,234/1,246) were able to correctly self-select whether norgestrel was appropriate for their own use.12
Research Q: After beginning the contraceptive, do patients adhere to correct use?
Study A: Yes, more than 90% of the time (and that remained true for subpopulations).
In the next phase of the ACCESS study, eligible participants from the self-selection population who purchased norgestrel and reported using the product at least once in their e-diary over a 6-month study period comprised the “User Population.”12 The overall adherence to daily pill intake was 92.5% (95% confidence interval [CI], 92.3–92.6%) among the 883 participants who contributed more than 90,000 days of study participation, and adherence was similarly high in subpopulations of individuals with low health literacy (92.6%; 95% CI, 92.1–93.0), adolescents aged 12–14 years (91.8%; 95% CI, 91.0–92.5%), and adolescents aged 15–17 years (91.9%; 95% CI, 91.4%–92.3%).
Research Q: When a pill was missed, did patients use backup contraception?
Study A: Yes, 97% of the time.
When including whether participants followed label instructions for mitigating behaviors when the pill was missed (eg, take a pill as soon as they remember, use backup contraception for 2 days after restarting the pill), adherence was 97.1% (95% CI, 97.0–97.2%). Most participants missed a single day of taking pills, and the most common reported reason for missing pills was issues with resupply as participants needed to get new packs from their enrolled research site, which should be less of a barrier when these pills are available over the counter.
Clinical implications of expanded access
Opportunities to expand access to effective contraception have become more critical in the increasingly restrictive environment for abortion care in the post-Dobbs era, and the availability of norgestrel to patients without prescription can advance contraceptive equity. Patients encounter many barriers to accessing prescription contraception, such as lack of insurance; difficulty with scheduling an appointment or getting to a clinic; not having a regular clinician or clinic; or health care providers requiring a visit, exam, or test prior to prescribing contraception.13,14 For patients who face these challenges, an alternative option is to use a nonprescription contraceptive, such as barrier or fertility awareness–based methods, which are typically associated with higher failure rates. With the introduction of norgestrel as a nonprescription contraceptive product, people can have direct access to a more effective contraceptive option.
A follow-up study of participants who had participated in the ACCESS actual-use study demonstrated that most (83%) would be likely to use the nonprescription method if available in the future for many reasons, including convenience, ease of access, ability to save time and money, not needing to visit a clinic, and flexibility of accessing the pills while traveling or having someone else get their pills for them.14 Furthermore, a nonprescription method could be beneficial for people who have concerns about privacy, such as adolescents or individuals affected by contraception sabotage (an act that can intentionally limit or prohibit a person's contraception access or use, ie, damaging condoms or hiding a person’s contraception method). This expansion of access can ultimately lead to a decrease in unintended pregnancies. In a model using the ACCESS actual-use data, about 1,500 to 34,000 unintended pregnancies would be prevented per year based on varying model parameters, with all scenarios demonstrating a benefit to nonprescription access to norgestrel.15
After norgestrel is available, where will patients be able to seek more information?
Patients who have questions or concerns about starting or taking norgestrel should talk to their clinician or a pharmacist for additional information (FIGURE 2). Examples of situations when additional clinical evaluation or counseling are recommended include:
- when a person is taking any medications with possible drug-drug interactions
- if a person is starting norgestrel after taking an emergency contraceptive in the last 5 days
- if there is a concern about pregnancy
- when there are any questions about adverse effects while taking norgestrel.
Bottom line
The nonprescription approval of norgestrel, a progestin-only pill, has the potential to greatly expand patient access to a safe and effective contraceptive method and advance contraceptive equity. The availability of informational materials for consumers about potential issues that may arise (for instance, changes in bleeding) will be important for initiation and continuation of this method. As this product is not yet available for purchase, several unknown factors remain, such as the cost and ease of accessibility in stores or online, that will ultimately determine its public health impact on unintended pregnancies. ●
On July 13, 2023, the US Food and Drug Administration (FDA) approved norgestrel 0.075 mg (Opill, HRA Pharma, Paris, France) as the first nonprescription oral contraceptive pill (FIGURE). This progestin-only pill was originally FDA approved in 1973, with prescription required, and was available as Ovrette until 2005, when product distribution ceased for marketing reasons and not for safety or effectiveness concerns.1 In recent years, studies have been conducted to support converted approval from prescription to nonprescription to increase access to safe and effective contraception. Overall, norgestrel is more effective than other currently available nonprescription contraceptive options when used as directed, and widespread accessibility to this method has the potential to decrease the risk of unintended pregnancies. This product is expected to be available in drugstores, convenience stores, grocery stores, and online in 2024.
How it works
The indication for norgestrel 0.075 mg is pregnancy prevention in people with the capacity to become pregnant; this product is not intended for emergency contraception. Norgestrel is a racemic mixture of 2 isomers, of which only levonorgestrel is bioactive. The mechanism of action for contraception is primarily through cervical mucus thickening, which inhibits sperm movement through the cervix. About 50% of users also have an additional contraceptive effect of ovulation suppression.2
Instructions for use. In the package label, users are instructed to take the norgestrel 0.075 mg pill daily, preferably at the same time each day and no more than 3 hours from the time taken on the previous day. This method can be started on any day of the cycle, and backup contraception (a barrier method) should be used for the first 48 hours after starting the method if it has been more than 5 days since menstrual bleeding started.3 Product instructions indicate that, if users miss a dose, they should take the next dose as soon as possible. If a pill is taken 3 hours or more later than the usual time, they should take a pill immediately and then resume the next pill at the usual time. In addition, backup contraception is recommended for 48 hours.2
Based on the Centers for Disease Control and Prevention (CDC) Selected Practice Recommendations for Contraceptive Use, no examinations or tests are required prior to initiation of progestin-only pills for safe and effective use.3
Efficacy
The product label indicates that the pregnancy rate is approximately 2 per 100 women-years based on over 21,000 28-day exposure cycles from 8 US clinical studies.2 In a recent review by Glasier and colleagues, the authors identified 13 trials that assessed the efficacy of the norgestrel 0.075 mg pill, all published several decades ago.4 Given that breastfeeding can have contraceptive impact through ovulation inhibition, studies that included breastfeeding participants were evaluated separately. Six studies without breastfeeding participants included 3,184 women who provided more than 35,000 months of use. The overall failure rates ranged from 0 to 2.4 per hundred woman-years with typical use; an aggregate Pearl Index was calculated to be 2.2 based on the total numbers of pregnancies and cycles. The remaining 7 studies included individuals who were breastfeeding for at least part of their study participation. These studies included 5,445 women, and the 12-month life table cumulative pregnancy rates in this group ranged from 0.0% to 3.4%. This review noted that the available studies are limited by incomplete descriptions of study participant information and differences in reporting of failure rates; however, the overall data support the effectiveness of the norgestrel 0.075 mg pill for pregnancy prevention.
Continue to: Norgestrel’s mechanism of action on ovarian activity and cervical mucus...
Norgestrel’s mechanism of action on ovarian activity and cervical mucus
More recently, a prospective, multicenter randomized, crossover study was performed to better understand this pill’s impact on cervical mucus and ovulation during preparation for nonprescription approval. In this study, participants were evaluated with frequent transvaginal ultrasonography, cervical mucus, and blood assessments (including levels of follicular-stimulating hormone, luteinizing hormone, progesterone, and estradiol) for three 28-day cycles. Cervical mucus was scored on a modified Insler scale to indicate if the mucus was favorable (Insler score ≥9), intermediate (Insler score 5-8), or unfavorable to fertility (Insler score ≤4).5
In the first cycle, participants were instructed to use the pills as prescribed (described as “correct use”). During this cycle, most participants (n = 34/51; 67%) did not ovulate, confirming that norgestrel 0.075 mg does impact ovulation.6 Most participants also had unfavorable cervical mucus (n = 39/51; 76%).6 Overall, 94% had full protection against pregnancy, either through lack of ovulation (n = 9), unfavorable mucus (n = 14), or both (n = 25). The remaining 3 participants ovulated and had intermediate mucus scores; ultimately, these participants were considered to have medium protection against pregnancy.7,8 (See the contraceptive protection algorithm [TABLE]).8
In the second and third cycles, the investigators evaluated ovulation and cervical mucus changes in the setting of either a delayed (by 6 hours) or missed dose midcycle.8 Of the 46 participants with evaluable data during the intervention cycles, 32 (70%) did not ovulate in each of the delayed- and missed-dose cycles. Most participants (n = 27; 59%) also demonstrated unfavorable mucus scores (modified Insler score ≤4) over the entire cycle despite delaying or missing a pill. There was no significant change to the cervical mucus score when comparing the scores on the days before, during, and after the delayed or missed pills (P = .26), nor when comparing between delayed pill use and missed pill use (P = .45). With the delayed pill intervention, 4 (9%) had reduced contraceptive protection (ie, medium protection) based on ovulation with intermediate mucus scores. With the missed pill intervention, 5 (11%) had reduced protection, of whom 3 had medium protection and 2 had minimum protection with ovulation and favorable mucus scores. Overall, this study shows that delaying or missing one pill may not impact contraceptive efficacy as much as previously thought given the strict 3-hour window for progestin-only pills. However, these findings are theoretical as information about pregnancy outcomes with delaying or missing pills are lacking.
Safety
Progestin-only methods are one of the safest options for contraception, with few contraindications to use; those listed include known or suspected pregnancy, known or suspected carcinoma of the breast or other progestinsensitive cancer, undiagnosed abnormal uterine bleeding, hypersensitivity to any component of the product, benign or malignant liver tumors, and acute liver disease.2
The CDC Medical Eligibility Criteria for Contraceptive Use guidelines offer guidance for progestin-only pills, indicating a category 3 (theoretical or proven risks usually outweigh the advantages) or category 4 (unacceptable health risk, method not to be used) for only a select number of additional conditions. These conditions include a history of malabsorptive bariatric surgery (category 3) and concurrent use of medications that induce hepatic enzyme activity (category 3)— such as phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine, rifampin, and rifabutin.9 These conditions are included primarily due to concerns of decreased effectivenessof the contraception and not necessarily because of evidence of harm with use.
The prevalence of consumers with contraindications to progestin-only pills appears to be low. In a large database study, only 4.36% seeking preventive care and 2.29% seeking both preventive and contraceptive services had a contraindication to progestin-only pills.10 Therefore, candidates for norgestrel use include individuals who have commonly encountered conditions, including those who9:
- have recently given birth
- are breastfeeding
- have a history of venous thromboembolism
- smoke
- have cardiovascular disease, hypertension, migraines with aura, or longstanding diabetes.
Adverse effects
The most common adverse effects (AEs) related to norgestrel use are bleeding changes.2 In the initial clinical studies for FDA approval, about half of enrolled participants reported a change in bleeding; about 9% discontinued the contraceptive due to bleeding. Breakthrough bleeding and spotting were reported by 48.6% and 47.3% of participants, respectively. About 6.1% had amenorrhea in their first cycle; 28.7% of participants had amenorrhea overall. Other reported AEs were headache, dizziness, nausea, increased appetite, abdominal pain, cramps or bloating, breast tenderness, and acne.
- Brand name: Opill
- Class: Progestin-only contraception
- Indication: Pregnancy prevention
- Approval date: Initial approval in 1973, nonprescription approval on July 13, 2023
- Availability date: 2024
- Manufacturer: Perrigo Company, HRA Pharma, Paris, France
- Dosage forms: 0.075 mg tablet
Continue to: FDA approval required determining appropriate direct-to-patient classification...
FDA approval required determining appropriate direct-to-patient classification
As part of the process for obtaining nonprescription approval, studies needed to determine that patients can safely and effectively use norgestrel without talking to a health care provider first. As part of that process, label comprehension, self-selection, and actualuse studies were required to demonstrate that consumers can use the package information to determine their eligibility and take the medication appropriately.
The ACCESS study Research Q: Do patients appropriately determine if the contraceptive is right for them?
Study A: Yes, 99% of the time. In the Adherence with Continuous-dose Oral Contraceptive: Evaluation of Self-Selection and Use (ACCESS) pivotal study, which evaluated prescription to nonprescription approval, participants were asked to review the label and determine whether the product was appropriate for them to use based on their health history.11 Approximately 99% of participants (n = 1,234/1,246) were able to correctly self-select whether norgestrel was appropriate for their own use.12
Research Q: After beginning the contraceptive, do patients adhere to correct use?
Study A: Yes, more than 90% of the time (and that remained true for subpopulations).
In the next phase of the ACCESS study, eligible participants from the self-selection population who purchased norgestrel and reported using the product at least once in their e-diary over a 6-month study period comprised the “User Population.”12 The overall adherence to daily pill intake was 92.5% (95% confidence interval [CI], 92.3–92.6%) among the 883 participants who contributed more than 90,000 days of study participation, and adherence was similarly high in subpopulations of individuals with low health literacy (92.6%; 95% CI, 92.1–93.0), adolescents aged 12–14 years (91.8%; 95% CI, 91.0–92.5%), and adolescents aged 15–17 years (91.9%; 95% CI, 91.4%–92.3%).
Research Q: When a pill was missed, did patients use backup contraception?
Study A: Yes, 97% of the time.
When including whether participants followed label instructions for mitigating behaviors when the pill was missed (eg, take a pill as soon as they remember, use backup contraception for 2 days after restarting the pill), adherence was 97.1% (95% CI, 97.0–97.2%). Most participants missed a single day of taking pills, and the most common reported reason for missing pills was issues with resupply as participants needed to get new packs from their enrolled research site, which should be less of a barrier when these pills are available over the counter.
Clinical implications of expanded access
Opportunities to expand access to effective contraception have become more critical in the increasingly restrictive environment for abortion care in the post-Dobbs era, and the availability of norgestrel to patients without prescription can advance contraceptive equity. Patients encounter many barriers to accessing prescription contraception, such as lack of insurance; difficulty with scheduling an appointment or getting to a clinic; not having a regular clinician or clinic; or health care providers requiring a visit, exam, or test prior to prescribing contraception.13,14 For patients who face these challenges, an alternative option is to use a nonprescription contraceptive, such as barrier or fertility awareness–based methods, which are typically associated with higher failure rates. With the introduction of norgestrel as a nonprescription contraceptive product, people can have direct access to a more effective contraceptive option.
A follow-up study of participants who had participated in the ACCESS actual-use study demonstrated that most (83%) would be likely to use the nonprescription method if available in the future for many reasons, including convenience, ease of access, ability to save time and money, not needing to visit a clinic, and flexibility of accessing the pills while traveling or having someone else get their pills for them.14 Furthermore, a nonprescription method could be beneficial for people who have concerns about privacy, such as adolescents or individuals affected by contraception sabotage (an act that can intentionally limit or prohibit a person's contraception access or use, ie, damaging condoms or hiding a person’s contraception method). This expansion of access can ultimately lead to a decrease in unintended pregnancies. In a model using the ACCESS actual-use data, about 1,500 to 34,000 unintended pregnancies would be prevented per year based on varying model parameters, with all scenarios demonstrating a benefit to nonprescription access to norgestrel.15
After norgestrel is available, where will patients be able to seek more information?
Patients who have questions or concerns about starting or taking norgestrel should talk to their clinician or a pharmacist for additional information (FIGURE 2). Examples of situations when additional clinical evaluation or counseling are recommended include:
- when a person is taking any medications with possible drug-drug interactions
- if a person is starting norgestrel after taking an emergency contraceptive in the last 5 days
- if there is a concern about pregnancy
- when there are any questions about adverse effects while taking norgestrel.
Bottom line
The nonprescription approval of norgestrel, a progestin-only pill, has the potential to greatly expand patient access to a safe and effective contraceptive method and advance contraceptive equity. The availability of informational materials for consumers about potential issues that may arise (for instance, changes in bleeding) will be important for initiation and continuation of this method. As this product is not yet available for purchase, several unknown factors remain, such as the cost and ease of accessibility in stores or online, that will ultimately determine its public health impact on unintended pregnancies. ●
- US Food and Drug Administration. 82 FR 49380. Determination that Ovrette (norgestrel) tablet, 0.075 milligrams, was not withdrawn from sale for reasons of safety or effectiveness. October 25, 2017. Accessed December 5, 2023. https://www.federalregister.gov/d/2017-23125
- US Food and Drug Administration. Opill tablets (norgestrel tablets) package label. August 2017. Accessed December 5, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label /2017/017031s035s036lbl.pdf
- Curtis KM, Jatlaoui TC, Tepper NK, et al. US selected practice recommendations for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(No. RR-4):1-66.
- Glasier A, Sober S, Gasloli R, et al. A review of the effectiveness of a progestogen-only pill containing norgestrel 75 µg/day. Contraception. 2022;105:1-6.
- Edelman A, Hemon A, Creinin M, et al. Assessing the pregnancy protective impact of scheduled nonadherence to a novel progestin-only pill: protocol for a prospective, multicenter, randomized, crossover study. JMIR Res Protoc. 2021;10:e292208.
- Glasier A, Edelman A, Creinin MD, et al. Mechanism of action of norgestrel 0.075 mg a progestogen-only pill. I. Effect on ovarian activity. Contraception. 2022;112:37-42.
- Han L, Creinin MD, Hemon A, et al. Mechanism of action of a 0.075 mg norgestrel progestogen-only pill 2. Effect on cervical mucus and theoretical risk of conception. Contraception. 2022;112:43-47.
- Glasier A, Edelman A, Creinin MD, et al. The effect of deliberate non-adherence to a norgestrel progestin-only pill: a randomized, crossover study. Contraception. 2023;117:1-6.
- Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(No RR-3):1-104.
- Dutton C, Kim R, Janiak E. Prevalence of contraindications to progestin-only contraceptive pills in a multi-institution patient database. Contraception. 2021;103:367-370.
- Clinicaltrials.gov. Adherence with Continuous-dose Oral Contraceptive Evaluation of Self-Selection and Use (ACCESS). Accessed December 5, 2023. https://clinicaltrials.gov/study /NCT04112095
- HRA Pharma. Opill (norgestrel 0.075 mg tablets) for Rx-toOTC switch. Sponsor Briefing Documents. Joint Meeting of the Nonprescription Drugs Advisory Committee and the Obstetrics, Reproductive, and Urology Drugs Advisory Committee. Meeting dates: 9-10 May 2023. Accessed December 5, 2023. https://www.fda.gov/media/167893 /download
- American College of Obstetricians and Gynecologists. Committee Opinion No. 788: Over-the-counter access to hormonal contraception. Obstet Gynecol. 2019;134:e96-105.
- Grindlay K, Key K, Zuniga C, et al. Interest in continued use after participation in a study of over-the-counter progestin-only pills in the United States. Womens Health Rep. 2022;3:904-914.
- Guillard H, Laurora I, Sober S, et al. Modeling the potential benefit of an over-the-counter progestin-only pill in preventing unintended pregnancies in the U.S. Contraception. 2023;117:7-12.
- US Food and Drug Administration. 82 FR 49380. Determination that Ovrette (norgestrel) tablet, 0.075 milligrams, was not withdrawn from sale for reasons of safety or effectiveness. October 25, 2017. Accessed December 5, 2023. https://www.federalregister.gov/d/2017-23125
- US Food and Drug Administration. Opill tablets (norgestrel tablets) package label. August 2017. Accessed December 5, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label /2017/017031s035s036lbl.pdf
- Curtis KM, Jatlaoui TC, Tepper NK, et al. US selected practice recommendations for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(No. RR-4):1-66.
- Glasier A, Sober S, Gasloli R, et al. A review of the effectiveness of a progestogen-only pill containing norgestrel 75 µg/day. Contraception. 2022;105:1-6.
- Edelman A, Hemon A, Creinin M, et al. Assessing the pregnancy protective impact of scheduled nonadherence to a novel progestin-only pill: protocol for a prospective, multicenter, randomized, crossover study. JMIR Res Protoc. 2021;10:e292208.
- Glasier A, Edelman A, Creinin MD, et al. Mechanism of action of norgestrel 0.075 mg a progestogen-only pill. I. Effect on ovarian activity. Contraception. 2022;112:37-42.
- Han L, Creinin MD, Hemon A, et al. Mechanism of action of a 0.075 mg norgestrel progestogen-only pill 2. Effect on cervical mucus and theoretical risk of conception. Contraception. 2022;112:43-47.
- Glasier A, Edelman A, Creinin MD, et al. The effect of deliberate non-adherence to a norgestrel progestin-only pill: a randomized, crossover study. Contraception. 2023;117:1-6.
- Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(No RR-3):1-104.
- Dutton C, Kim R, Janiak E. Prevalence of contraindications to progestin-only contraceptive pills in a multi-institution patient database. Contraception. 2021;103:367-370.
- Clinicaltrials.gov. Adherence with Continuous-dose Oral Contraceptive Evaluation of Self-Selection and Use (ACCESS). Accessed December 5, 2023. https://clinicaltrials.gov/study /NCT04112095
- HRA Pharma. Opill (norgestrel 0.075 mg tablets) for Rx-toOTC switch. Sponsor Briefing Documents. Joint Meeting of the Nonprescription Drugs Advisory Committee and the Obstetrics, Reproductive, and Urology Drugs Advisory Committee. Meeting dates: 9-10 May 2023. Accessed December 5, 2023. https://www.fda.gov/media/167893 /download
- American College of Obstetricians and Gynecologists. Committee Opinion No. 788: Over-the-counter access to hormonal contraception. Obstet Gynecol. 2019;134:e96-105.
- Grindlay K, Key K, Zuniga C, et al. Interest in continued use after participation in a study of over-the-counter progestin-only pills in the United States. Womens Health Rep. 2022;3:904-914.
- Guillard H, Laurora I, Sober S, et al. Modeling the potential benefit of an over-the-counter progestin-only pill in preventing unintended pregnancies in the U.S. Contraception. 2023;117:7-12.
Recruiting ObGyns: Starting salary considerations
Evidence continues to show that the number of practicing ObGyns lags the growing and diverse US population of women.1 Furthermore, approximately 1 in every 3 ObGyns will move usually once or twice every 10 years.2 Knowing what to expect in being recruited requires a better understanding of your needs and capabilities and what they may be worth in real time. Some ObGyns elect to use a recruitment firm to begin their search to more objectively assess what is fair and equitable.
Understanding physician compensation involves many factors, such as patient composition, sources of reimbursement, impact of health care systems, and geography.3 Several sources report trends in annual physician compensation, most notably the American Medical Association, medical specialty organizations, and recruitment firms. Sources such as the Medical Group Management Association (MGMA), the American Medical Group Association (AMGA), and Medscape report total compensation.
Determining salaries for new positions
A standard and comprehensive benchmarking resource for salaries in new positions has been the annual review of physician and advanced practitioner recruiting incentives by AMN Healthcare (formerly Merritt Hawkins) Physician Solutions.4 This resource is used by hospitals, medical groups, academics, other health care systems, and others who track trends in physician supply, demand, and compensation. Their 2023 report considered starting salaries for more than 20 medical or surgical specialties.
Specialists’ revenue-generating potential is tracked by annual billings to commercial payers. The average annual billing by a full-time ObGyn ($3.8 million) is about the same as that of other specialties combined.5 As in the past, ObGyns are among the most consistently requested specialists in searches. In 2023, ObGyns were ranked the third most common physician specialists being recruited and tenth as the percentage of physicians per specialty (TABLE).4
Full-time salaries for ObGyns have remained within the middle third of all specialties. They consistently have been higher than primary care physicians’ salaries but remain among the lowest of the surgical specialties. This impression is reinforced by 2023 data shown in FIGURE 1.4 In the past, salaries remained flat compared with other surgical specialties. As with other specialties, starting salaries decreased during the peak 2020 and 2021 COVID-19 years. It is encouraging that averaged full-time salaries for recruiting ObGyns increased by 14.1% from 2020–2021 to 2021–2022 and by 10.5% from 2021–2022 to 2022–2023 (FIGURE 2).4
Special considerations
Incomes tended to be highest for ObGyns practicing in metropolitan areas with population sizes less than 1 million rather than in larger metropolitan areas.3 However, differences in reported incomes do not control for cost of living and other determinants of income (for example, surgeries, deliveries, patient care hours worked). Averaged salaries can vary regionally in the following order from highest to lowest: Midwest/Great Plains, West, Southwest, and Northeast and Southeast.4
Differences in starting salaries between male and female ObGyns are often not reported, although they are a very important consideration.6,7 Both men and women desire “controllable lifestyles” with more flexibility and working in shifts. Sex-based differences in physician salary and compensation can be complex. Explanations may deal with the number of patients seen, number of procedures and surgeries performed, and frequency of after-hours duties. Women constitute most ObGyns, and their salary being at any lower end of the income spectrum may be partially explained by fewer desired work hours or less seniority.
Annual earnings can vary and are positively related to the number of working hours, being in the middle of one’s career (aged 42–51 years), working in a moderately large practice rather than in a solo or self-employed practice, and being board certified.3 A lower starting salary would be anticipated for a recent graduate. However, the resident going into a hard-to-fill position may be offered a higher salary than an experienced ObGyn who takes a relatively easy-to-fill position in a popular location. Practices would be more desirable in which patient volume is sufficient to invest in nonphysician clinicians and revenue-generating ancillary services that do not require costly layers of administration.
Information on physician salaries for new positions from individual recruiting or research firms can serve as a starting point for negotiation, although it may not entirely be representative. Sample sizes can be small, and information in some specialties may not separate salaries of physicians in academic versus nonacademic positions and generalists versus subspecialists. The information in this article reflects the average salaries offered to attract physicians to new practice settings rather than what they might earn and report on their tax return.
Continue to: Incentives...
Incentives
Negotiations involve incentives along with a starting salary. Signing bonuses, movingallowances, continuing education time and allowances, and medical education loan repayments are important incentives. Recent signing bonuses (average, $37,472) likely reflect efforts to bring physicians back to health care facilities post-COVID-19 or, more commonly, when candidates are considering multiple opportunities.4 It is important to clarify at the beginning any coverage for health insurance and professional liability insurance.
Relocation allowances are for those being recruited outside their current area of residence. The average continuing medical education allowance was $3,840 in 2023.4 Medical school debt is common, being approximately $200,000 at graduation for many. An educational loan repayment (average, $98,665) is typically an exchange for a commitment to stay in the community for a given period.
Starting employment contracts with hospitals or large medical groups often feature a production bonus to reward additional clinical work performed or an adherence to quality protocol or guidelines, rather than income guarantees alone. Metrics are usually volume driven (for example, relative value units, net collections, gross billings, patients seen). Initiatives by payers and health care organizations have included quality metrics, such as high patient satisfaction scores, low morbidity rates, and low readmission rates. Production-based formulas are straightforward, while use of quality-based formulas (up to 14% of total compensation) can be less clear to define.4 ●
- Rayburn WF, Xierali IM. Expanded fellowship training and residency graduates’ availability for women’s general health needs. Obstet Gynecol. 2021;137:1119-1121.
- Xierali IM, Nivett MA, Rayburn WF. Relocation of obstetriciangynecologists in the United States, 2005-2015. Obstet Gynecol. 2017;129:543-550.
- Rayburn WF. The Obstetrician-Gynecologist Workforce in the United States: Facts, Figures, and Implications. 2nd ed. American College of Obstetricians and Gynecologists; 2017.
- AMN Healthcare. 2023 Review of physician and advanced practitioner recruiting incentives. July 24, 2023. Accessed October 3, 2023. https://www.amnhealthcare.com/amn -insights/physician/surveys/2023-physician-and-ap -recruiting-incentives/
- AMN Healthcare. 2023 Physician billing report. March 21, 2023. Accessed October 7, 2023. https://www.amnhealthcare. com/amn-insights/physician/whitepapers/2023-physician -billing-report/
- Bravender T, Selkie E, Sturza J, et al. Association of salary differences between medical specialties with sex distribution. JAMA Pediatr. 2021;175:524-525.
- Lo Sasso AT, Armstrong D, Forte G, et al. Differences in starting pay for male and female physicians persist; explanations for the gender gap remain elusive. Health Aff. 2020;39:256-263.
Evidence continues to show that the number of practicing ObGyns lags the growing and diverse US population of women.1 Furthermore, approximately 1 in every 3 ObGyns will move usually once or twice every 10 years.2 Knowing what to expect in being recruited requires a better understanding of your needs and capabilities and what they may be worth in real time. Some ObGyns elect to use a recruitment firm to begin their search to more objectively assess what is fair and equitable.
Understanding physician compensation involves many factors, such as patient composition, sources of reimbursement, impact of health care systems, and geography.3 Several sources report trends in annual physician compensation, most notably the American Medical Association, medical specialty organizations, and recruitment firms. Sources such as the Medical Group Management Association (MGMA), the American Medical Group Association (AMGA), and Medscape report total compensation.
Determining salaries for new positions
A standard and comprehensive benchmarking resource for salaries in new positions has been the annual review of physician and advanced practitioner recruiting incentives by AMN Healthcare (formerly Merritt Hawkins) Physician Solutions.4 This resource is used by hospitals, medical groups, academics, other health care systems, and others who track trends in physician supply, demand, and compensation. Their 2023 report considered starting salaries for more than 20 medical or surgical specialties.
Specialists’ revenue-generating potential is tracked by annual billings to commercial payers. The average annual billing by a full-time ObGyn ($3.8 million) is about the same as that of other specialties combined.5 As in the past, ObGyns are among the most consistently requested specialists in searches. In 2023, ObGyns were ranked the third most common physician specialists being recruited and tenth as the percentage of physicians per specialty (TABLE).4
Full-time salaries for ObGyns have remained within the middle third of all specialties. They consistently have been higher than primary care physicians’ salaries but remain among the lowest of the surgical specialties. This impression is reinforced by 2023 data shown in FIGURE 1.4 In the past, salaries remained flat compared with other surgical specialties. As with other specialties, starting salaries decreased during the peak 2020 and 2021 COVID-19 years. It is encouraging that averaged full-time salaries for recruiting ObGyns increased by 14.1% from 2020–2021 to 2021–2022 and by 10.5% from 2021–2022 to 2022–2023 (FIGURE 2).4
Special considerations
Incomes tended to be highest for ObGyns practicing in metropolitan areas with population sizes less than 1 million rather than in larger metropolitan areas.3 However, differences in reported incomes do not control for cost of living and other determinants of income (for example, surgeries, deliveries, patient care hours worked). Averaged salaries can vary regionally in the following order from highest to lowest: Midwest/Great Plains, West, Southwest, and Northeast and Southeast.4
Differences in starting salaries between male and female ObGyns are often not reported, although they are a very important consideration.6,7 Both men and women desire “controllable lifestyles” with more flexibility and working in shifts. Sex-based differences in physician salary and compensation can be complex. Explanations may deal with the number of patients seen, number of procedures and surgeries performed, and frequency of after-hours duties. Women constitute most ObGyns, and their salary being at any lower end of the income spectrum may be partially explained by fewer desired work hours or less seniority.
Annual earnings can vary and are positively related to the number of working hours, being in the middle of one’s career (aged 42–51 years), working in a moderately large practice rather than in a solo or self-employed practice, and being board certified.3 A lower starting salary would be anticipated for a recent graduate. However, the resident going into a hard-to-fill position may be offered a higher salary than an experienced ObGyn who takes a relatively easy-to-fill position in a popular location. Practices would be more desirable in which patient volume is sufficient to invest in nonphysician clinicians and revenue-generating ancillary services that do not require costly layers of administration.
Information on physician salaries for new positions from individual recruiting or research firms can serve as a starting point for negotiation, although it may not entirely be representative. Sample sizes can be small, and information in some specialties may not separate salaries of physicians in academic versus nonacademic positions and generalists versus subspecialists. The information in this article reflects the average salaries offered to attract physicians to new practice settings rather than what they might earn and report on their tax return.
Continue to: Incentives...
Incentives
Negotiations involve incentives along with a starting salary. Signing bonuses, movingallowances, continuing education time and allowances, and medical education loan repayments are important incentives. Recent signing bonuses (average, $37,472) likely reflect efforts to bring physicians back to health care facilities post-COVID-19 or, more commonly, when candidates are considering multiple opportunities.4 It is important to clarify at the beginning any coverage for health insurance and professional liability insurance.
Relocation allowances are for those being recruited outside their current area of residence. The average continuing medical education allowance was $3,840 in 2023.4 Medical school debt is common, being approximately $200,000 at graduation for many. An educational loan repayment (average, $98,665) is typically an exchange for a commitment to stay in the community for a given period.
Starting employment contracts with hospitals or large medical groups often feature a production bonus to reward additional clinical work performed or an adherence to quality protocol or guidelines, rather than income guarantees alone. Metrics are usually volume driven (for example, relative value units, net collections, gross billings, patients seen). Initiatives by payers and health care organizations have included quality metrics, such as high patient satisfaction scores, low morbidity rates, and low readmission rates. Production-based formulas are straightforward, while use of quality-based formulas (up to 14% of total compensation) can be less clear to define.4 ●
Evidence continues to show that the number of practicing ObGyns lags the growing and diverse US population of women.1 Furthermore, approximately 1 in every 3 ObGyns will move usually once or twice every 10 years.2 Knowing what to expect in being recruited requires a better understanding of your needs and capabilities and what they may be worth in real time. Some ObGyns elect to use a recruitment firm to begin their search to more objectively assess what is fair and equitable.
Understanding physician compensation involves many factors, such as patient composition, sources of reimbursement, impact of health care systems, and geography.3 Several sources report trends in annual physician compensation, most notably the American Medical Association, medical specialty organizations, and recruitment firms. Sources such as the Medical Group Management Association (MGMA), the American Medical Group Association (AMGA), and Medscape report total compensation.
Determining salaries for new positions
A standard and comprehensive benchmarking resource for salaries in new positions has been the annual review of physician and advanced practitioner recruiting incentives by AMN Healthcare (formerly Merritt Hawkins) Physician Solutions.4 This resource is used by hospitals, medical groups, academics, other health care systems, and others who track trends in physician supply, demand, and compensation. Their 2023 report considered starting salaries for more than 20 medical or surgical specialties.
Specialists’ revenue-generating potential is tracked by annual billings to commercial payers. The average annual billing by a full-time ObGyn ($3.8 million) is about the same as that of other specialties combined.5 As in the past, ObGyns are among the most consistently requested specialists in searches. In 2023, ObGyns were ranked the third most common physician specialists being recruited and tenth as the percentage of physicians per specialty (TABLE).4
Full-time salaries for ObGyns have remained within the middle third of all specialties. They consistently have been higher than primary care physicians’ salaries but remain among the lowest of the surgical specialties. This impression is reinforced by 2023 data shown in FIGURE 1.4 In the past, salaries remained flat compared with other surgical specialties. As with other specialties, starting salaries decreased during the peak 2020 and 2021 COVID-19 years. It is encouraging that averaged full-time salaries for recruiting ObGyns increased by 14.1% from 2020–2021 to 2021–2022 and by 10.5% from 2021–2022 to 2022–2023 (FIGURE 2).4
Special considerations
Incomes tended to be highest for ObGyns practicing in metropolitan areas with population sizes less than 1 million rather than in larger metropolitan areas.3 However, differences in reported incomes do not control for cost of living and other determinants of income (for example, surgeries, deliveries, patient care hours worked). Averaged salaries can vary regionally in the following order from highest to lowest: Midwest/Great Plains, West, Southwest, and Northeast and Southeast.4
Differences in starting salaries between male and female ObGyns are often not reported, although they are a very important consideration.6,7 Both men and women desire “controllable lifestyles” with more flexibility and working in shifts. Sex-based differences in physician salary and compensation can be complex. Explanations may deal with the number of patients seen, number of procedures and surgeries performed, and frequency of after-hours duties. Women constitute most ObGyns, and their salary being at any lower end of the income spectrum may be partially explained by fewer desired work hours or less seniority.
Annual earnings can vary and are positively related to the number of working hours, being in the middle of one’s career (aged 42–51 years), working in a moderately large practice rather than in a solo or self-employed practice, and being board certified.3 A lower starting salary would be anticipated for a recent graduate. However, the resident going into a hard-to-fill position may be offered a higher salary than an experienced ObGyn who takes a relatively easy-to-fill position in a popular location. Practices would be more desirable in which patient volume is sufficient to invest in nonphysician clinicians and revenue-generating ancillary services that do not require costly layers of administration.
Information on physician salaries for new positions from individual recruiting or research firms can serve as a starting point for negotiation, although it may not entirely be representative. Sample sizes can be small, and information in some specialties may not separate salaries of physicians in academic versus nonacademic positions and generalists versus subspecialists. The information in this article reflects the average salaries offered to attract physicians to new practice settings rather than what they might earn and report on their tax return.
Continue to: Incentives...
Incentives
Negotiations involve incentives along with a starting salary. Signing bonuses, movingallowances, continuing education time and allowances, and medical education loan repayments are important incentives. Recent signing bonuses (average, $37,472) likely reflect efforts to bring physicians back to health care facilities post-COVID-19 or, more commonly, when candidates are considering multiple opportunities.4 It is important to clarify at the beginning any coverage for health insurance and professional liability insurance.
Relocation allowances are for those being recruited outside their current area of residence. The average continuing medical education allowance was $3,840 in 2023.4 Medical school debt is common, being approximately $200,000 at graduation for many. An educational loan repayment (average, $98,665) is typically an exchange for a commitment to stay in the community for a given period.
Starting employment contracts with hospitals or large medical groups often feature a production bonus to reward additional clinical work performed or an adherence to quality protocol or guidelines, rather than income guarantees alone. Metrics are usually volume driven (for example, relative value units, net collections, gross billings, patients seen). Initiatives by payers and health care organizations have included quality metrics, such as high patient satisfaction scores, low morbidity rates, and low readmission rates. Production-based formulas are straightforward, while use of quality-based formulas (up to 14% of total compensation) can be less clear to define.4 ●
- Rayburn WF, Xierali IM. Expanded fellowship training and residency graduates’ availability for women’s general health needs. Obstet Gynecol. 2021;137:1119-1121.
- Xierali IM, Nivett MA, Rayburn WF. Relocation of obstetriciangynecologists in the United States, 2005-2015. Obstet Gynecol. 2017;129:543-550.
- Rayburn WF. The Obstetrician-Gynecologist Workforce in the United States: Facts, Figures, and Implications. 2nd ed. American College of Obstetricians and Gynecologists; 2017.
- AMN Healthcare. 2023 Review of physician and advanced practitioner recruiting incentives. July 24, 2023. Accessed October 3, 2023. https://www.amnhealthcare.com/amn -insights/physician/surveys/2023-physician-and-ap -recruiting-incentives/
- AMN Healthcare. 2023 Physician billing report. March 21, 2023. Accessed October 7, 2023. https://www.amnhealthcare. com/amn-insights/physician/whitepapers/2023-physician -billing-report/
- Bravender T, Selkie E, Sturza J, et al. Association of salary differences between medical specialties with sex distribution. JAMA Pediatr. 2021;175:524-525.
- Lo Sasso AT, Armstrong D, Forte G, et al. Differences in starting pay for male and female physicians persist; explanations for the gender gap remain elusive. Health Aff. 2020;39:256-263.
- Rayburn WF, Xierali IM. Expanded fellowship training and residency graduates’ availability for women’s general health needs. Obstet Gynecol. 2021;137:1119-1121.
- Xierali IM, Nivett MA, Rayburn WF. Relocation of obstetriciangynecologists in the United States, 2005-2015. Obstet Gynecol. 2017;129:543-550.
- Rayburn WF. The Obstetrician-Gynecologist Workforce in the United States: Facts, Figures, and Implications. 2nd ed. American College of Obstetricians and Gynecologists; 2017.
- AMN Healthcare. 2023 Review of physician and advanced practitioner recruiting incentives. July 24, 2023. Accessed October 3, 2023. https://www.amnhealthcare.com/amn -insights/physician/surveys/2023-physician-and-ap -recruiting-incentives/
- AMN Healthcare. 2023 Physician billing report. March 21, 2023. Accessed October 7, 2023. https://www.amnhealthcare. com/amn-insights/physician/whitepapers/2023-physician -billing-report/
- Bravender T, Selkie E, Sturza J, et al. Association of salary differences between medical specialties with sex distribution. JAMA Pediatr. 2021;175:524-525.
- Lo Sasso AT, Armstrong D, Forte G, et al. Differences in starting pay for male and female physicians persist; explanations for the gender gap remain elusive. Health Aff. 2020;39:256-263.
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>Rayburn1223docx</fileName> <TBEID>0C02EE5F.SIG</TBEID> <TBUniqueIdentifier>NJ_0C02EE5F</TBUniqueIdentifier> <newsOrJournal>Journal</newsOrJournal> <publisherName>Frontline Medical Communications Inc.</publisherName> <storyname/> <articleType>1</articleType> <TBLocation>Copyfitting-OBGM</TBLocation> <QCDate/> <firstPublished>20231211T205925</firstPublished> <LastPublished>20231211T205925</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20231211T205925</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline/> <bylineText>William F. Rayburn, MD, MBA; Phillip Miller, BA, BS</bylineText> <bylineFull/> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType>(choose one)</newsDocType> <journalDocType>(choose one)</journalDocType> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>Evidence continues to show that the number of practicing ObGyns lags the growing and diverse US population of women.1 Furthermore, approximately 1 in every 3 Ob</metaDescription> <articlePDF/> <teaserImage/> <title>Recruiting ObGyns: Starting salary considerations</title> <deck/> <eyebrow>OBG WORKFORCE CONSULT</eyebrow> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gyn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle>MDedge ObGyn</journalFullTitle> <copyrightStatement>2018</copyrightStatement> </publicationData> <publicationData> <publicationCode>obgm</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">49726</term> <term>24</term> </publications> <sections> <term canonical="true">49</term> </sections> <topics> <term canonical="true">27442</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Recruiting ObGyns: Starting salary considerations</title> <deck/> </itemMeta> <itemContent> <p class="abstract">The competitive nature of ObGyn recruiting is reflected in rising starting salaries. It remains one of the most recruited specialties. Starting salaries have increased in recent years. Here, considerations about incentives and bonuses are provided to begin the negotiating.</p> <p>Evidence continues to show that the number of practicing ObGyns lags the growing and diverse US population of women.<sup>1</sup> Furthermore, approximately 1 in every 3 ObGyns will move usually once or twice every 10 years.<sup>2</sup> Knowing what to expect in being recruited requires a better understanding of your needs and capabilities and what they may be worth in real time. Some ObGyns elect to use a recruitment firm to begin their search to more objectively assess what is fair and equitable.</p> <p>Understanding physician compensation involves many factors, such as patient composition, sources of reimbursement, impact of health care systems, and geography.<sup>3</sup> Several sources report trends in annual physician compensation, most notably the American Medical Association, medical specialty organizations, and recruitment firms. Sources such as the Medical Group Management Association (MGMA), the American Medical Group Association (AMGA), and Medscape report total compensation.</p> <h2>Determining salaries for new positions</h2> <p>A standard and comprehensive benchmarking resource for salaries in new positions has been the annual review of physician and advanced practitioner recruiting incentives by AMN Healthcare (formerly Merritt Hawkins) Physician Solutions.<sup>4</sup> This resource is used by hospitals, medical groups, academics, other health care systems, and others who track trends in physician supply, demand, and compensation. Their 2023 report considered starting salaries for more than 20 medical or surgical specialties.</p> <p>Specialists’ revenue-generating potential is tracked by annual billings to commercial payers. The average annual billing by a full-time ObGyn ($3.8 million) is about the same as that of other specialties combined.<sup>5</sup> As in the past, ObGyns are among the most consistently requested specialists in searches. In 2023, ObGyns were ranked the third most common physician specialists being recruited and tenth as the percentage of physicians per specialty (<strong>TABLE</strong>).<sup>4</sup><br/><br/>Full-time salaries for ObGyns have remained within the middle third of all specialties. They consistently have been higher than primary care physicians’ salaries but remain among the lowest of the surgical specialties. This impression is reinforced by 2023 data shown in <strong>Figure 1</strong>.<sup>4</sup> In the past, salaries remained flat compared with other surgical specialties. As with other specialties, starting salaries decreased during the peak 2020 and 2021 COVID-19 years. It is encouraging that averaged full-time salaries for recruiting ObGyns increased by 14.1% from 2020–2021 to 2021–2022 and by 10.5% from 2021–2022 to 2022–2023 (<strong>figure 2, </strong>page 14).<sup>4</sup></p> <h2>Special considerations</h2> <p>Incomes tended to be highest for ObGyns practicing in metropolitan areas with population sizes less than 1 million rather than in larger metropolitan areas.<sup>3</sup> However, differences in reported incomes do not control for cost of living and other determinants of income (for example, surgeries, deliveries, patient care hours worked). Averaged salaries can vary regionally in the following order from highest to lowest: Midwest/Great Plains, West, Southwest, and Northeast and Southeast.<sup>4</sup></p> <p>Differences in starting salaries between male and female ObGyns are often not reported, although they are a very important consideration.<sup>6,7</sup> Both men and women desire “controllable lifestyles” with more flexibility and working in shifts. Sex-based differences in physician salary and compensation can be complex. Explanations may deal with the number of patients seen, number of procedures and surgeries performed, and frequency of after-hours duties. Women constitute most ObGyns, and their salary being at any lower end of the income spectrum may be partially explained by fewer desired work hours or less seniority.<br/><br/>Annual earnings can vary and are positively related to the number of working hours, being in the middle of one’s career (aged 42–51 years), working in a moderately large practice rather than in a solo or self-employed practice, and being board certified.<sup>3</sup> A lower starting salary would be anticipated for a recent graduate. However, the resident going into a hard-to-fill position may be offered a higher salary than an experienced ObGyn who takes a relatively easy-to-fill position in a popular location. Practices would be more desirable in which patient volume is sufficient to invest in nonphysician clinicians and revenue-generating ancillary services that do not require costly layers of administration.<br/><br/>Information on physician salaries for new positions from individual recruiting or research firms can serve as a starting point for negotiation, although it may not entirely be representative. Sample sizes can be small, and information in some specialties may not separate salaries of physicians in academic versus nonacademic positions and generalists versus subspecialists. The information in this article reflects the average salaries offered to attract physicians to new practice settings rather than what they might earn and report on their tax return.</p> <h2>Incentives</h2> <p>Negotiations involve incentives along with a starting salary. Signing bonuses, movingallowances, continuing education time and allowances, and medical education loan repayments are important incentives. Recent signing bonuses (average, $37,472) likely reflect efforts to bring physicians back to health care facilities post-COVID-19 or, more commonly, when candidates are considering multiple opportunities.<sup>4</sup> It is important to clarify at the beginning any coverage for health insurance and professional liability insurance.</p> <p>Relocation allowances are for those being recruited outside their current area of residence. The average continuing medical education allowance was $3,840 in 2023.<sup>4</sup> Medical school debt is common, being approximately $200,000 at graduation for many. An educational loan repayment (average, $98,665) is typically an exchange for a commitment to stay in the community for a given period.<br/><br/>Starting employment contracts with hospitals or large medical groups often feature a production bonus to reward additional clinical work performed or an adherence to quality protocol or guidelines, rather than income guarantees alone. Metrics are usually volume driven (for example, relative value units, net collections, gross billings, patients seen). Initiatives by payers and health care organizations have included quality metrics, such as high patient satisfaction scores, low morbidity rates, and low readmission rates. Production-based formulas are straightforward, while use of quality-based formulas (up to 14% of total compensation) can be less clear to define.<sup>4 </sup>●</p> </itemContent> </newsItem> </itemSet></root>
Patient counseling for breast cancer screening: Taking changes to USPSTF recommendations into account
Breast cancer represents the most commonly diagnosed cancer in the nation.1 However, unlike other cancers, most breast cancers are identified at stage I and have a 90% survival rate 5-year prognosis.2 These outcomes are attributable to various factors, one of the most significant being screening mammography—a largely accessible, highly sensitive and specific screening tool.3 Data demonstrate that malignant tumors detected on screening mammography have more favorable profiles in tumor size and nodal status compared with symptomatic breast cancers,4 which make it critical for early diagnosis. Most importantly, the research overwhelmingly demonstrates that screening mammography decreases breast cancer–related mortality.5-7
The USPSTF big change: Mammography starting at age 40 for all recommended
Despite the general accessibility and mortality benefits of screening mammography (in light of the high lifetime 12% prevalence of breast cancer in the United States8), recommendations still conflict across medical societies regarding optimal timing and frequency.9-12 Previously, the US Preventive Services Task Force (USPSTF) recommended that screening mammography should occur at age 50 biennially and that screening between ages 40 and 49 should be an individualized decision.13,14 In the draft recommendation statement issued on May 9, 2023, however, the USPSTF now recommends screening every other year starting at age 40 to decrease the risk of dying from breast cancer.15
This change represents a critically important shift. The new guidance:
- acknowledges the increasing incidence of early-onset breast cancer
- reinforces a national consciousness toward screening mammography in decreasing mortality,17 even among a younger age group for whom the perception of risk may be lower.
The USPSTF statement represents a significant change in how patients should be counseled. Practitioners now have more direct guidance that is concordant with what other national medical organizations offer or recommend, including the American College of Obstetricians and Gynecologists (ACOG), the American College of Radiology (ACR), and the National Comprehensive Cancer Network (NCCN).
However, while the USPSTF statement can and should encourage health care practitioners to initiate mammography earlier than prior recommendations, ongoing discussion regarding the optimal screening interval is warranted. The USPSTF recommendations state that mammography should be performed biennially. While the age at initiation represents a step in the right direction, this recommended screening interval should be reevaluated.
Annual vs biennial screening?
The debate between annual and biennial screening mammography is not new. While many randomized trials on screening mammography have evaluated such factors as breast cancer mortality by age or rate of false positives,18 fewer trials have evaluated the optimal screening interval.
One randomized trial from the United Kingdom evaluated 99,389 people aged 50 to 62 from 1989 to 1996 who underwent annual screening (study arm) versus 3 years later (control).19 Findings demonstrated a significantly smaller tumor size in the study arm (P=.05) as well as an increased total cancer detection rate. However, the authors concluded that shortening the screening interval (from 3 years) would not yield a statistically significant decrease in mortality.19
In a randomized trial from Finland, researchers screened those aged older than 50 at biennial intervals and those aged younger than 50 at either annual or triennial intervals.20 Results demonstrated that, among those aged 40 to 49, the frequency of stage I cancers was not significantly different from screen-detected cancers, interval cancers, or cancers detected outside of screening (50%, 42%, and 44%, respectively; P=.73). Furthermore, there was a greater likelihood of interval cancers among those aged 40 to 49 at 1-year (27%) and 3-year (39%) screening intervals compared with those aged older than 50 screened biennially (18%; P=.08 and P=.0009, respectively).20
These randomized trials, however, have been scrutinized because of factors such as discrepancies in screening intervals by country as well as substantial improvements made in screening mammography since the time these trials were conducted.5 Due to the dearth of more contemporary randomized controlled trials accounting for more up-to-date training and technology, most of the more recent data has been largely observational, retrospective, or used modeling.21 The TABLE outlines some of the major studies on this topic.
False-positive results, biopsy rates. The arguments against more frequent screening include the possibility of false positives that require callbacks and biopsies, which may be more frequent among those who undergo annual mammography.22 A systematic review from the Breast Cancer Surveillance Consortium demonstrated a 61.3% annual (confidence interval [CI], 59.4%–63.1%) versus 41.6% biennial (CI, 40.6%–42.5%) false-positive rate, resulting in a 7% (CI, 6.1%–7.8%) versus 4.8% (CI, 4.4–5.2%) rate of biopsy, respectively.23 This false-positive rate, however, also may be increased in younger patients aged 40 to 49 and in those with dense breasts.22,24 These callbacks and biopsies could induce significant patient stress, pain, and anxiety, as well as carry financial implications related to subsequent diagnostic imaging.
Overdiagnosis. There is also the risk of overdiagnosis, in which an indolent breast cancer that otherwise would not grow or progress to become symptomatic is identified. This could lead to overtreatment. While the exact incidence of overdiagnosis is unclear (due to recommendations for universal treatment of ductal carcinoma in situ), some data suggest that overdiagnosis could be decreased with biennial screening.25
While discomfort could also be a barrier, it may not necessarily be prohibitive for some to continue with future screening mammograms.22 Further, increased radiation with annual mammography is a concern. However, modeling studies have shown that the mortality benefit for annual mammography starting at age 40 outweighs (by 60-fold) the mortality risk from a radiation-induced breast cancer.26
Benefit from biennial screening
Some research suggests overall benefit from biennial screening. One study that used Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer microsimulation was adapted to measure the incidence, mortality, and life-years gained for Canadian patients.27 This model demonstrated that mortality reduction was linked to greater lifetime screens for breast cancer, but this applied primarily to patients aged 50 and older. Overall, a larger impact was observed by initiating screening at age 40 than by decreasing screening intervals.27
Using modeling, Mandelblatt and colleagues demonstrated that biennial screening could capture most of the benefit of annual screening with less harm.28 In another study in 2016, Mandelblatt and colleagues used updated and revised versions of these simulation models and maintained that biennial screening upheld 79.8% to 81.3% of the benefits of annual screening mammography but with fewer overdiagnoses and false-positive results.25 The authors concluded that while biennial screening is equally effective for average-risk populations, there should be an evaluation of benefits and harms based on the clinical scenario (suggesting that annual screening for those at age 40 who carried elevated risk was similar to biennial screening for average-risk patients starting at age 50).25
Another study that served to inform the European Commission Initiative on Breast Cancer recommendations evaluated randomized controlled trials and observational and modeling studies that assessed breast screening intervals.29 The authors concluded that each screening interval has risks and benefits, with data suggesting more benefit with biennial screening for people aged 50 to 69 years and more possible harm with annual screening in younger people (aged 45–49).29
Continue to: Benefit from annual screening...
Benefit from annual screening
However, these data conflict with other studies that demonstrate the benefit of annual compared with biennial screening mammography. One large retrospective review of prospectively collected data evaluated outcome differences based on mammography frequency.30 For those undergoing annual versus biennial screening, the median tumor size was 11 mm (versus 15 mm), the percentage of lymph node metastasis was 14% (versus 24%), and cancer stage II or higher was 17% (versus 29%). The study overall demonstrated that annual screening resulted in lower recall rates (P<.0001) and detection of smaller tumors that carried a more favorable prognosis (P<.04).30
Another observational study from 2004 that assessed data from 7 different mammography registries nationwide noted that, among those aged 40 to 49, patients who underwent biennial screening had an increased likelihood of late-stage disease compared with those with annual screening (28% vs 21%, respectively; odds ratio [OR], 1.35; 95% CI, 1.01–1.81), although this discrepancy was not observed in people aged 50 or older.31
A study that critiqued the previous 2012 version of the USPSTF guidelines used CISNET modeling, which demonstrated a 39.6% mortality reduction with annual screening for those aged 40 to 84 versus 23.2% for biennial screening for those aged 50 to 74.5
More recent data also reflect these findings. A retrospective cohort study that evaluated patients aged 40 to 84 diagnosed with breast cancer found that those who previously underwent annual versus biennial screening mammography had lower incidences of late-stage diagnoses (24.0% vs 43.8%, respectively; P=.02), fewer interval cancers (10.5% vs 37.5%; P<.001), and smaller mean (SD) tumor diameter (1.4 [1.2] cm vs 1.8 [1.6] cm; P=.04).21 Postmenopausal patients in this cohort also demonstrated similar findings when comparing mammogram frequency. Although not significant, biennial (or greater) frequency of screening mammography also resulted in an increased likelihood of axillary lymph node dissection and chemotherapy.
Similarly, authors of another large prospective cohort study concluded that breast cancers diagnosed in premenopausal patients were more likely to be larger with less favorable prognostic characteristics (tumor size >15 mm, relative risk [RR], 1.21 [95% CI, 1.07–1.37]; P=.002); any less favorable prognostic characteristics (RR, 1.11 [95% CI, 1.00–1.22]; P=.047), and higher stage (stage IIB or higher, RR, 1.28 [95% CI, 1.01–1.63]; P=.04) for those who underwent biennial screening compared with breast cancers diagnosed by annual screening.32 However, this trend was not observed in postmenopausal patients not taking hormone therapy.32
Some international studies also show more favorable outcomes with annual screening mammography. A Swedish study evaluated mammography screening intervals of 21 months compared with 18 or 12 months in patients aged 40 to 49.33 Data showed an improved effectiveness of 1.6% to 9.8% for interval cancers and 2.9% to 17.4% for both interval and screening-detected cancers by reducing the screening frequency to 12 months, with authors suggesting a further reduction in breast cancer–related mortality rates for this age group.33
Results from another descriptive study from Europe also showed increasing interval breast cancer rates with increasing screening intervals.34 After a negative screen, the interval cancer rates and regional ranges for 0 to less than 12 months, 12 to less than 24 months, and 24 to less than 36 months per 1,000 screened were 0.55 (0.43–0.76), 1.13 (0.92–1.47), and 1.22 (0.93–1.57), respectively.34
Finally, a study conducted in Canada evaluated interval breast cancers among people with dense breasts screened between 2008 and 2010.35 Those with screening programs with policies that offered annual screening reported fewer interval cancers (interval cancer rate, 0.89 per 1,000; 95% CI, 0.67–1.11) compared with those who had policies that used biennial screening (interval cancer rate, 1.45 per 1,000 [annualized]; 95% CI, 1.19–1.72), which was 63% higher (P=.002). For those for whom radiologists recommended screening, interval cancer was lower for annual (0.93 per 1,000; 95% CI, 0.71–1.16) versus biennial screening (1.70 per 1,000 [annualized]; 95% CI, 0.70–2.71) (P=.061).35
Continue to: Black patients have a worse breast cancer prognosis...
Black patients have a worse breast cancer prognosis
Additional consideration should be given to populations with worse survival outcomes at baseline for whom screening mammography could play a significant role. In particular, Black people have similar rates of breast cancer compared with White people (127.8 cases per 100,000 vs 133.7 cases per 100,000, respectively) but have a 40% increased breast cancer–related mortality.8 The USPSTF recognizes this disparity and mentions it in their recommendations, encouraging health care clinicians to engage in shared decision making with Black patients and asserting that more research is needed on screening mammography in Black communities.15
While the age modification to the new guidelines better addresses the disparities that impact the Black community (such as increased likelihood of early-onset breast cancer36 and increased rate of breast cancer diagnosis at first mammogram37), the next obvious question is: Can groups with higher breast cancer mortality such as Black communities afford to undergo mammography every 2 years (as opposed to every year)?
Although some data specifically have evaluated the age of initiation and frequency of screening mammography among Black patients,38,39 little data have specifically assessed outcomes for annual versus biennial screening among Black people. Despite these research gaps, risk factors among the Black community should be considered. There is an increased risk of triple-negative breast cancer that can contribute to higher mortality among Black communities.40 Black people also tend to be diagnosed with more aggressive subtypes overall,41,42 are more likely to have dense breasts,43,44 have a higher likelihood of advanced stages at the time of diagnosis compared with White people,8,45 and have a greater chance of diagnosis of a second primary or contralateral breast cancer46-48—all risk factors that support the importance of regular and early-screening mammography.
How I counsel my patients
As Director of the Cancer Genetics and Breast Health Clinic, I am a gynecologist who primarily evaluates patients at increased risk for breast cancer (and other cancers). As an initial step, I strongly encourage all patients (especially Black patients and those of Ashkenazi Jewish ancestry as per the American College of Radiology recommendations9) to undergo risk assessment at age 25 to determine if they may be at increased risk for breast cancer. This first step may include genetic testing if the patient meets NCCN testing criteria based on personal or family history. If results are positive for a germline pathogenic variant, the timing and nature of breast screening would be based on NCCN recommendations for that particular variant (with possible modification of age of initiation based on family history). If testing is negative, lifetime risk assessment would then be performed using risk calculators—such as Tyrer-Cuzick—to determine if the patient meets criteria for intensive surveillance with supplemental breast magnetic resonance imaging. If the patient is subsequently determined to be at average risk after these assessments, I recommend they undergo screening mammography annually starting at age 40. However, it must be recognized that risk may change over time. A patient’s risk can continue to be assessed over a lifetime—with changing family history, personal risk factors, and new discoveries in genetics.
Summary
Ultimately, it is reassuring that the USPSTF guidelines have been updated to be concordant with other national medical society recommendations. They reflect the increasing nationwide trends that clearly demonstrate the high overall prevalence of breast cancer as well as the increasing incidence of early-onset breast cancer.
The updated guidelines, however, do not reflect the entirety of breast cancer trends in this country. With breast cancer being the most commonly diagnosed cancer in the United States, it is imperative to consider the data that demonstrate improved prognostics with annual compared with biennial mammography. Furthermore, the guidelines only begin to explore the disparities that Black patients face regarding breast cancer–related mortality. The risks of younger age at diagnosis, greater likelihood of aggressive subtypes, increased risk of second primary and contralateral breast cancer, and later stage at diagnosis must be seriously evaluated when counseling this patient population.
While the USPSTF recommendations for age at initiation reflect national statistics, recommendations by the ACR and NCCN more appropriately recognize that the benefits of annual screening outweigh the potential risks. Annual screening frequency should be adopted when counseling patients, particularly for the Black community. ●
- Cancer stat facts: Common cancer sites. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Accessed November 7, 2023. https://seer .cancer.gov/statfacts/html/common.html#:~:text=An%20 estimated%20297%2C790%20women%20and,overall%20 with%20288%2C300%20expected%20cases
- Survival rates for breast cancer. American Cancer Society. March 1, 2023. Accessed November 16, 2023. https://www .cancer.org/cancer/breast-cancer/understanding-a-breast -cancer-diagnosis/breast-cancer-survival-rates.html
- Ambinder EB, Lee E, Nguyen DL, et al. Interval breast cancers versus screen detected breast cancers: a retrospective cohort study. Acad Radiol. 2023;30(suppl 2):S154-S160.
- Allgood PC, Duffy SW, Kearins O, et al. Explaining the difference in prognosis between screen-detected and symptomatic breast cancers. Br J Cancer. 2011;104:1680-1685.
- Hendrick RE, Helvie MA. United States Preventive Services Task Force screening mammography recommendations: science ignored. AJR Am J Roentgenol. 2011;196:W112-W116.
- Oeffinger KC, Fontham ETH, Etzioni R, et al; American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314:1599-1614.
- Hendrick RE, Baker JA, Helvie MA. Breast cancer deaths averted over 3 decades. Cancer. 2019;125:1482-1488.
- Breast cancer facts & figures 2022-2024. American Cancer Society. 2022. Accessed September 7, 2023. https://www .cancer.org/content/dam/cancer-org/research/cancer-facts -and-statistics/breast-cancer-facts-and-figures/2022-2024 -breast-cancer-fact-figures-acs.pdf
- New ACR breast cancer screening guidelines call for earlier and more-intensive screening for high-risk women. American College of Radiology. May 3, 2023. Accessed October 8, 2023. https://www.acr.org/Media-Center/ACR -News-Releases/2023/New-ACR-Breast-Cancer-Screening -Guidelines-call-for-earlier-screening-for-high-risk-women
- American Cancer Society recommendations for the early detection of breast cancer. American Cancer Society. January 14, 2022. Accessed October 30, 2023. https://www.cancer .org/cancer/types/breast-cancer/screening-tests-and-early -detection/american-cancer-society-recommendations-for -the-early-detection-of-breast-cancer.html
- Breast cancer screening and diagnosis. National Comprehensive Cancer Network. Published Version 1.2023. June 19, 2023. Accessed September 21, 2023. https://www .nccn.org/professionals/physician_gls/pdf/breast-screening .pdf
- ACOG Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No 179. Breast cancer risk assessment and screening in average-risk women. Obstet Gynecol. 2017;130:e1-e16.
- Final recommendation statement. Breast cancer: screening. US Preventive Services Task Force. January 11, 2016. Accessed September 1, 2023. https://www .uspreventiveservicestaskforce.org/uspstf/recommendation breast-cancer-screening
- Siu AL; US Preventive Services Task Force. Screening for breast cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164:279-296.
- Breast cancer: screening. US Preventive Services Task Force. May 9, 2023. Accessed October 7, 2023. https://www .uspreventiveservicestaskforce.org/uspstf/document/draft -evidence-review/breast-cancer-screening-adults
- Breast cancer in young women. Centers for Disease Control and Prevention. June 21, 2023. Accessed October 30, 2023. https://www.cdc.gov/cancer/breast/young_women/index .htm
- Arleo EK, Hendrick RE, Helvie MA, et al. Comparison of recommendations for screening mammography using CISNET models. Cancer. 2017;123:3673-3680.
- Nelson HD, Tyne K, Naik A, et al; US Preventive Services Task Force. Screening for breast cancer: an update for the US Preventive Services Task Force. Ann Intern Med. 2009;151:727737, W237-W242.
- Breast Screening Frequency Trial Group. The frequency of breast cancer screening: results from the UKCCCR randomised trial. United Kingdom Co-ordinating Committee on Cancer Research. Eur J Cancer. 2002;38:1458-1464.
- Klemi PJ, Toikkanen S, Räsänen O, et al. Mammography screening interval and the frequency of interval cancers in a population-based screening. Br J Cancer. 1997;75:762-766.
- Moorman SEH, Pujara AC, Sakala MD, et al. Annual screening mammography associated with lower stage breast cancer compared with biennial screening. AJR Am J Roentgenol. 2021;217:40-47.
- Nelson HD, Pappas M, Cantor A, et al. Harms of breast cancer screening: systematic review to update the 2009 US Preventive Services Task Force recommendation. Ann Intern Med. 2016;164:256-267.
- Hubbard RA, Kerlikowske K, Flowers CI, et al. Cumulative probability of false-positive recall or biopsy recommendation after 10 years of screening mammography: a cohort study. Ann Intern Med. 2011;155:481-492.
- Kerlikowske K, Zhu W, Hubbard RA, et al; Breast Cancer Surveillance Consortium. Outcomes of screening mammography by frequency, breast density, and postmenopausal hormone therapy. JAMA Intern Med. 2013;173:807-816.
- Mandelblatt JS, Stout NK, Schechter CB, et al. Collaborative modeling of the benefits and harms associated with different US breast cancer screening strategies. Ann Intern Med. 2016;164:215-225.
- Miglioretti DL, Lange J, van den Broek JJ, et al. Radiationinduced breast cancer incidence and mortality from digital mammography screening: a modeling study. Ann Intern Med. 2016;164:205-214.
- Yaffe MJ, Mittmann N, Lee P, et al. Clinical outcomes of modelling mammography screening strategies. Health Rep. 2015;26:9-15.
- Mandelblatt JS, Cronin KA, Bailey S, et al; Breast Cancer Working Group of the Cancer Intervention and Surveillance Modeling Network. Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms. Ann Intern Med. 2009;151: 738-747.
- Canelo-Aybar C, Posso M, Montero N, et al. Benefits and harms of annual, biennial, or triennial breast cancer mammography screening for women at average risk of breast cancer: a systematic review for the European Commission Initiative on Breast Cancer (ECIBC). Br J Cancer. 2022;126:673-688.
- Hunt KA, Rosen EL, Sickles EA. Outcome analysis for women undergoing annual versus biennial screening mammography: a review of 24,211 examinations. AJR Am J Roentgenol. 1999;173:285-289.
- White E, Miglioretti DL, Yankaskas BC, et al. Biennial versus annual mammography and the risk of late-stage breast cancer. J Natl Cancer Inst. 2004;96:1832-1839.
- Miglioretti DL, Zhu W, Kerlikowske K, et al; Breast Cancer Surveillance Consortium. Breast tumor prognostic characteristics and biennial vs annual mammography, age, and menopausal status. JAMA Oncol. 2015;1:1069-1077.
- Mao Z, Nyström L, Jonsson H. Breast cancer screening with mammography in women aged 40-49 years: impact of length of screening interval on effectiveness of the program. J Med Screen. 2021;28:200-206.
- Bennett RL, Sellars SJ, Moss SM. Interval cancers in the NHS breast cancer screening programme in England, Wales and Northern Ireland. Br J Cancer. 2011;104:571-577.
- Seely JM, Peddle SE, Yang H, et al. Breast density and risk of interval cancers: the effect of annual versus biennial screening mammography policies in Canada. Can Assoc Radiol J. 2022;73:90-100.
- Liu Q, Yao S, Zhao H, et al. Early-onset triple-negative breast cancer in multiracial/ethnic populations: distinct trends of prevalence of truncation mutations. Cancer Med. 2019;8:1845-1853.
- Wilkerson AD, Obi M, Ortega C, et al. Young Black women may be more likely to have first mammogram cancers: a new perspective in breast cancer disparities. Ann Surg Oncol. 2023;30:2856-2869.
- Chen T, Kharazmi E, Fallah M. Race and ethnicity-adjusted age recommendation for initiating breast cancer screening. JAMA Netw Open. 2023;6:e238893.
- Chapman CH, Schechter CB, Cadham CJ, et al. Identifying equitable screening mammography strategies for Black women in the United States using simulation modeling. Ann Intern Med. 2021;174:1637-1646.
- Howard FM, Olopade OI. Epidemiology of triple-negative breast cancer: a review. Cancer J. 2021;27:8-16.
- Stringer-Reasor EM, Elkhanany A, Khoury K, et al. Disparities in breast cancer associated with African American identity. Am Soc Clin Oncol Educ Book. 2021;41:e29-e46.
- Newman LA. Parsing the etiology of breast cancer disparities. J Clin Oncol. 2016;34:1013-1014.
- Moore JX, Han Y, Appleton C, et al. Determinants of mammographic breast density by race among a large screening population. JNCI Cancer Spectr. 2020;4:pkaa010.
- McCarthy AM, Keller BM, Pantalone LM, et al. Racial differences in quantitative measures of area and volumetric breast density. J Natl Cancer Inst. 2016;108:djw104.
- Chen L, Li CI. Racial disparities in breast cancer diagnosis and treatment by hormone receptor and HER2 status. Cancer Epidemiol Biomarkers Prev. 2015;24:1666-1672.
- Terman E, Sheade J, Zhao F, et al. The impact of race and age on response to neoadjuvant therapy and long-term outcomes in Black and White women with early-stage breast cancer. Breast Cancer Res Treat. 2023;200:75-83.
- Watt GP, John EM, Bandera EV, et al. Race, ethnicity and risk of second primary contralateral breast cancer in the United States. Int J Cancer. 2021;148:2748-2758.
- Giannakeas V, Lim DW, Narod SA. The risk of contralateral breast cancer: a SEER-based analysis. Br J Cancer. 2021;125:601-610.
Dr. Pleasant is Clinical Assistant Professor and Director, Breast Health and Cancer Genetics Clinic, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor.
The author reports being the recipient of a MICHR K12 award through the following grants: UM1TR004404, K12TR004374, and T32TR004371.
Dr. Pleasant is Clinical Assistant Professor and Director, Breast Health and Cancer Genetics Clinic, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor.
The author reports being the recipient of a MICHR K12 award through the following grants: UM1TR004404, K12TR004374, and T32TR004371.
Dr. Pleasant is Clinical Assistant Professor and Director, Breast Health and Cancer Genetics Clinic, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor.
The author reports being the recipient of a MICHR K12 award through the following grants: UM1TR004404, K12TR004374, and T32TR004371.
Breast cancer represents the most commonly diagnosed cancer in the nation.1 However, unlike other cancers, most breast cancers are identified at stage I and have a 90% survival rate 5-year prognosis.2 These outcomes are attributable to various factors, one of the most significant being screening mammography—a largely accessible, highly sensitive and specific screening tool.3 Data demonstrate that malignant tumors detected on screening mammography have more favorable profiles in tumor size and nodal status compared with symptomatic breast cancers,4 which make it critical for early diagnosis. Most importantly, the research overwhelmingly demonstrates that screening mammography decreases breast cancer–related mortality.5-7
The USPSTF big change: Mammography starting at age 40 for all recommended
Despite the general accessibility and mortality benefits of screening mammography (in light of the high lifetime 12% prevalence of breast cancer in the United States8), recommendations still conflict across medical societies regarding optimal timing and frequency.9-12 Previously, the US Preventive Services Task Force (USPSTF) recommended that screening mammography should occur at age 50 biennially and that screening between ages 40 and 49 should be an individualized decision.13,14 In the draft recommendation statement issued on May 9, 2023, however, the USPSTF now recommends screening every other year starting at age 40 to decrease the risk of dying from breast cancer.15
This change represents a critically important shift. The new guidance:
- acknowledges the increasing incidence of early-onset breast cancer
- reinforces a national consciousness toward screening mammography in decreasing mortality,17 even among a younger age group for whom the perception of risk may be lower.
The USPSTF statement represents a significant change in how patients should be counseled. Practitioners now have more direct guidance that is concordant with what other national medical organizations offer or recommend, including the American College of Obstetricians and Gynecologists (ACOG), the American College of Radiology (ACR), and the National Comprehensive Cancer Network (NCCN).
However, while the USPSTF statement can and should encourage health care practitioners to initiate mammography earlier than prior recommendations, ongoing discussion regarding the optimal screening interval is warranted. The USPSTF recommendations state that mammography should be performed biennially. While the age at initiation represents a step in the right direction, this recommended screening interval should be reevaluated.
Annual vs biennial screening?
The debate between annual and biennial screening mammography is not new. While many randomized trials on screening mammography have evaluated such factors as breast cancer mortality by age or rate of false positives,18 fewer trials have evaluated the optimal screening interval.
One randomized trial from the United Kingdom evaluated 99,389 people aged 50 to 62 from 1989 to 1996 who underwent annual screening (study arm) versus 3 years later (control).19 Findings demonstrated a significantly smaller tumor size in the study arm (P=.05) as well as an increased total cancer detection rate. However, the authors concluded that shortening the screening interval (from 3 years) would not yield a statistically significant decrease in mortality.19
In a randomized trial from Finland, researchers screened those aged older than 50 at biennial intervals and those aged younger than 50 at either annual or triennial intervals.20 Results demonstrated that, among those aged 40 to 49, the frequency of stage I cancers was not significantly different from screen-detected cancers, interval cancers, or cancers detected outside of screening (50%, 42%, and 44%, respectively; P=.73). Furthermore, there was a greater likelihood of interval cancers among those aged 40 to 49 at 1-year (27%) and 3-year (39%) screening intervals compared with those aged older than 50 screened biennially (18%; P=.08 and P=.0009, respectively).20
These randomized trials, however, have been scrutinized because of factors such as discrepancies in screening intervals by country as well as substantial improvements made in screening mammography since the time these trials were conducted.5 Due to the dearth of more contemporary randomized controlled trials accounting for more up-to-date training and technology, most of the more recent data has been largely observational, retrospective, or used modeling.21 The TABLE outlines some of the major studies on this topic.
False-positive results, biopsy rates. The arguments against more frequent screening include the possibility of false positives that require callbacks and biopsies, which may be more frequent among those who undergo annual mammography.22 A systematic review from the Breast Cancer Surveillance Consortium demonstrated a 61.3% annual (confidence interval [CI], 59.4%–63.1%) versus 41.6% biennial (CI, 40.6%–42.5%) false-positive rate, resulting in a 7% (CI, 6.1%–7.8%) versus 4.8% (CI, 4.4–5.2%) rate of biopsy, respectively.23 This false-positive rate, however, also may be increased in younger patients aged 40 to 49 and in those with dense breasts.22,24 These callbacks and biopsies could induce significant patient stress, pain, and anxiety, as well as carry financial implications related to subsequent diagnostic imaging.
Overdiagnosis. There is also the risk of overdiagnosis, in which an indolent breast cancer that otherwise would not grow or progress to become symptomatic is identified. This could lead to overtreatment. While the exact incidence of overdiagnosis is unclear (due to recommendations for universal treatment of ductal carcinoma in situ), some data suggest that overdiagnosis could be decreased with biennial screening.25
While discomfort could also be a barrier, it may not necessarily be prohibitive for some to continue with future screening mammograms.22 Further, increased radiation with annual mammography is a concern. However, modeling studies have shown that the mortality benefit for annual mammography starting at age 40 outweighs (by 60-fold) the mortality risk from a radiation-induced breast cancer.26
Benefit from biennial screening
Some research suggests overall benefit from biennial screening. One study that used Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer microsimulation was adapted to measure the incidence, mortality, and life-years gained for Canadian patients.27 This model demonstrated that mortality reduction was linked to greater lifetime screens for breast cancer, but this applied primarily to patients aged 50 and older. Overall, a larger impact was observed by initiating screening at age 40 than by decreasing screening intervals.27
Using modeling, Mandelblatt and colleagues demonstrated that biennial screening could capture most of the benefit of annual screening with less harm.28 In another study in 2016, Mandelblatt and colleagues used updated and revised versions of these simulation models and maintained that biennial screening upheld 79.8% to 81.3% of the benefits of annual screening mammography but with fewer overdiagnoses and false-positive results.25 The authors concluded that while biennial screening is equally effective for average-risk populations, there should be an evaluation of benefits and harms based on the clinical scenario (suggesting that annual screening for those at age 40 who carried elevated risk was similar to biennial screening for average-risk patients starting at age 50).25
Another study that served to inform the European Commission Initiative on Breast Cancer recommendations evaluated randomized controlled trials and observational and modeling studies that assessed breast screening intervals.29 The authors concluded that each screening interval has risks and benefits, with data suggesting more benefit with biennial screening for people aged 50 to 69 years and more possible harm with annual screening in younger people (aged 45–49).29
Continue to: Benefit from annual screening...
Benefit from annual screening
However, these data conflict with other studies that demonstrate the benefit of annual compared with biennial screening mammography. One large retrospective review of prospectively collected data evaluated outcome differences based on mammography frequency.30 For those undergoing annual versus biennial screening, the median tumor size was 11 mm (versus 15 mm), the percentage of lymph node metastasis was 14% (versus 24%), and cancer stage II or higher was 17% (versus 29%). The study overall demonstrated that annual screening resulted in lower recall rates (P<.0001) and detection of smaller tumors that carried a more favorable prognosis (P<.04).30
Another observational study from 2004 that assessed data from 7 different mammography registries nationwide noted that, among those aged 40 to 49, patients who underwent biennial screening had an increased likelihood of late-stage disease compared with those with annual screening (28% vs 21%, respectively; odds ratio [OR], 1.35; 95% CI, 1.01–1.81), although this discrepancy was not observed in people aged 50 or older.31
A study that critiqued the previous 2012 version of the USPSTF guidelines used CISNET modeling, which demonstrated a 39.6% mortality reduction with annual screening for those aged 40 to 84 versus 23.2% for biennial screening for those aged 50 to 74.5
More recent data also reflect these findings. A retrospective cohort study that evaluated patients aged 40 to 84 diagnosed with breast cancer found that those who previously underwent annual versus biennial screening mammography had lower incidences of late-stage diagnoses (24.0% vs 43.8%, respectively; P=.02), fewer interval cancers (10.5% vs 37.5%; P<.001), and smaller mean (SD) tumor diameter (1.4 [1.2] cm vs 1.8 [1.6] cm; P=.04).21 Postmenopausal patients in this cohort also demonstrated similar findings when comparing mammogram frequency. Although not significant, biennial (or greater) frequency of screening mammography also resulted in an increased likelihood of axillary lymph node dissection and chemotherapy.
Similarly, authors of another large prospective cohort study concluded that breast cancers diagnosed in premenopausal patients were more likely to be larger with less favorable prognostic characteristics (tumor size >15 mm, relative risk [RR], 1.21 [95% CI, 1.07–1.37]; P=.002); any less favorable prognostic characteristics (RR, 1.11 [95% CI, 1.00–1.22]; P=.047), and higher stage (stage IIB or higher, RR, 1.28 [95% CI, 1.01–1.63]; P=.04) for those who underwent biennial screening compared with breast cancers diagnosed by annual screening.32 However, this trend was not observed in postmenopausal patients not taking hormone therapy.32
Some international studies also show more favorable outcomes with annual screening mammography. A Swedish study evaluated mammography screening intervals of 21 months compared with 18 or 12 months in patients aged 40 to 49.33 Data showed an improved effectiveness of 1.6% to 9.8% for interval cancers and 2.9% to 17.4% for both interval and screening-detected cancers by reducing the screening frequency to 12 months, with authors suggesting a further reduction in breast cancer–related mortality rates for this age group.33
Results from another descriptive study from Europe also showed increasing interval breast cancer rates with increasing screening intervals.34 After a negative screen, the interval cancer rates and regional ranges for 0 to less than 12 months, 12 to less than 24 months, and 24 to less than 36 months per 1,000 screened were 0.55 (0.43–0.76), 1.13 (0.92–1.47), and 1.22 (0.93–1.57), respectively.34
Finally, a study conducted in Canada evaluated interval breast cancers among people with dense breasts screened between 2008 and 2010.35 Those with screening programs with policies that offered annual screening reported fewer interval cancers (interval cancer rate, 0.89 per 1,000; 95% CI, 0.67–1.11) compared with those who had policies that used biennial screening (interval cancer rate, 1.45 per 1,000 [annualized]; 95% CI, 1.19–1.72), which was 63% higher (P=.002). For those for whom radiologists recommended screening, interval cancer was lower for annual (0.93 per 1,000; 95% CI, 0.71–1.16) versus biennial screening (1.70 per 1,000 [annualized]; 95% CI, 0.70–2.71) (P=.061).35
Continue to: Black patients have a worse breast cancer prognosis...
Black patients have a worse breast cancer prognosis
Additional consideration should be given to populations with worse survival outcomes at baseline for whom screening mammography could play a significant role. In particular, Black people have similar rates of breast cancer compared with White people (127.8 cases per 100,000 vs 133.7 cases per 100,000, respectively) but have a 40% increased breast cancer–related mortality.8 The USPSTF recognizes this disparity and mentions it in their recommendations, encouraging health care clinicians to engage in shared decision making with Black patients and asserting that more research is needed on screening mammography in Black communities.15
While the age modification to the new guidelines better addresses the disparities that impact the Black community (such as increased likelihood of early-onset breast cancer36 and increased rate of breast cancer diagnosis at first mammogram37), the next obvious question is: Can groups with higher breast cancer mortality such as Black communities afford to undergo mammography every 2 years (as opposed to every year)?
Although some data specifically have evaluated the age of initiation and frequency of screening mammography among Black patients,38,39 little data have specifically assessed outcomes for annual versus biennial screening among Black people. Despite these research gaps, risk factors among the Black community should be considered. There is an increased risk of triple-negative breast cancer that can contribute to higher mortality among Black communities.40 Black people also tend to be diagnosed with more aggressive subtypes overall,41,42 are more likely to have dense breasts,43,44 have a higher likelihood of advanced stages at the time of diagnosis compared with White people,8,45 and have a greater chance of diagnosis of a second primary or contralateral breast cancer46-48—all risk factors that support the importance of regular and early-screening mammography.
How I counsel my patients
As Director of the Cancer Genetics and Breast Health Clinic, I am a gynecologist who primarily evaluates patients at increased risk for breast cancer (and other cancers). As an initial step, I strongly encourage all patients (especially Black patients and those of Ashkenazi Jewish ancestry as per the American College of Radiology recommendations9) to undergo risk assessment at age 25 to determine if they may be at increased risk for breast cancer. This first step may include genetic testing if the patient meets NCCN testing criteria based on personal or family history. If results are positive for a germline pathogenic variant, the timing and nature of breast screening would be based on NCCN recommendations for that particular variant (with possible modification of age of initiation based on family history). If testing is negative, lifetime risk assessment would then be performed using risk calculators—such as Tyrer-Cuzick—to determine if the patient meets criteria for intensive surveillance with supplemental breast magnetic resonance imaging. If the patient is subsequently determined to be at average risk after these assessments, I recommend they undergo screening mammography annually starting at age 40. However, it must be recognized that risk may change over time. A patient’s risk can continue to be assessed over a lifetime—with changing family history, personal risk factors, and new discoveries in genetics.
Summary
Ultimately, it is reassuring that the USPSTF guidelines have been updated to be concordant with other national medical society recommendations. They reflect the increasing nationwide trends that clearly demonstrate the high overall prevalence of breast cancer as well as the increasing incidence of early-onset breast cancer.
The updated guidelines, however, do not reflect the entirety of breast cancer trends in this country. With breast cancer being the most commonly diagnosed cancer in the United States, it is imperative to consider the data that demonstrate improved prognostics with annual compared with biennial mammography. Furthermore, the guidelines only begin to explore the disparities that Black patients face regarding breast cancer–related mortality. The risks of younger age at diagnosis, greater likelihood of aggressive subtypes, increased risk of second primary and contralateral breast cancer, and later stage at diagnosis must be seriously evaluated when counseling this patient population.
While the USPSTF recommendations for age at initiation reflect national statistics, recommendations by the ACR and NCCN more appropriately recognize that the benefits of annual screening outweigh the potential risks. Annual screening frequency should be adopted when counseling patients, particularly for the Black community. ●
Breast cancer represents the most commonly diagnosed cancer in the nation.1 However, unlike other cancers, most breast cancers are identified at stage I and have a 90% survival rate 5-year prognosis.2 These outcomes are attributable to various factors, one of the most significant being screening mammography—a largely accessible, highly sensitive and specific screening tool.3 Data demonstrate that malignant tumors detected on screening mammography have more favorable profiles in tumor size and nodal status compared with symptomatic breast cancers,4 which make it critical for early diagnosis. Most importantly, the research overwhelmingly demonstrates that screening mammography decreases breast cancer–related mortality.5-7
The USPSTF big change: Mammography starting at age 40 for all recommended
Despite the general accessibility and mortality benefits of screening mammography (in light of the high lifetime 12% prevalence of breast cancer in the United States8), recommendations still conflict across medical societies regarding optimal timing and frequency.9-12 Previously, the US Preventive Services Task Force (USPSTF) recommended that screening mammography should occur at age 50 biennially and that screening between ages 40 and 49 should be an individualized decision.13,14 In the draft recommendation statement issued on May 9, 2023, however, the USPSTF now recommends screening every other year starting at age 40 to decrease the risk of dying from breast cancer.15
This change represents a critically important shift. The new guidance:
- acknowledges the increasing incidence of early-onset breast cancer
- reinforces a national consciousness toward screening mammography in decreasing mortality,17 even among a younger age group for whom the perception of risk may be lower.
The USPSTF statement represents a significant change in how patients should be counseled. Practitioners now have more direct guidance that is concordant with what other national medical organizations offer or recommend, including the American College of Obstetricians and Gynecologists (ACOG), the American College of Radiology (ACR), and the National Comprehensive Cancer Network (NCCN).
However, while the USPSTF statement can and should encourage health care practitioners to initiate mammography earlier than prior recommendations, ongoing discussion regarding the optimal screening interval is warranted. The USPSTF recommendations state that mammography should be performed biennially. While the age at initiation represents a step in the right direction, this recommended screening interval should be reevaluated.
Annual vs biennial screening?
The debate between annual and biennial screening mammography is not new. While many randomized trials on screening mammography have evaluated such factors as breast cancer mortality by age or rate of false positives,18 fewer trials have evaluated the optimal screening interval.
One randomized trial from the United Kingdom evaluated 99,389 people aged 50 to 62 from 1989 to 1996 who underwent annual screening (study arm) versus 3 years later (control).19 Findings demonstrated a significantly smaller tumor size in the study arm (P=.05) as well as an increased total cancer detection rate. However, the authors concluded that shortening the screening interval (from 3 years) would not yield a statistically significant decrease in mortality.19
In a randomized trial from Finland, researchers screened those aged older than 50 at biennial intervals and those aged younger than 50 at either annual or triennial intervals.20 Results demonstrated that, among those aged 40 to 49, the frequency of stage I cancers was not significantly different from screen-detected cancers, interval cancers, or cancers detected outside of screening (50%, 42%, and 44%, respectively; P=.73). Furthermore, there was a greater likelihood of interval cancers among those aged 40 to 49 at 1-year (27%) and 3-year (39%) screening intervals compared with those aged older than 50 screened biennially (18%; P=.08 and P=.0009, respectively).20
These randomized trials, however, have been scrutinized because of factors such as discrepancies in screening intervals by country as well as substantial improvements made in screening mammography since the time these trials were conducted.5 Due to the dearth of more contemporary randomized controlled trials accounting for more up-to-date training and technology, most of the more recent data has been largely observational, retrospective, or used modeling.21 The TABLE outlines some of the major studies on this topic.
False-positive results, biopsy rates. The arguments against more frequent screening include the possibility of false positives that require callbacks and biopsies, which may be more frequent among those who undergo annual mammography.22 A systematic review from the Breast Cancer Surveillance Consortium demonstrated a 61.3% annual (confidence interval [CI], 59.4%–63.1%) versus 41.6% biennial (CI, 40.6%–42.5%) false-positive rate, resulting in a 7% (CI, 6.1%–7.8%) versus 4.8% (CI, 4.4–5.2%) rate of biopsy, respectively.23 This false-positive rate, however, also may be increased in younger patients aged 40 to 49 and in those with dense breasts.22,24 These callbacks and biopsies could induce significant patient stress, pain, and anxiety, as well as carry financial implications related to subsequent diagnostic imaging.
Overdiagnosis. There is also the risk of overdiagnosis, in which an indolent breast cancer that otherwise would not grow or progress to become symptomatic is identified. This could lead to overtreatment. While the exact incidence of overdiagnosis is unclear (due to recommendations for universal treatment of ductal carcinoma in situ), some data suggest that overdiagnosis could be decreased with biennial screening.25
While discomfort could also be a barrier, it may not necessarily be prohibitive for some to continue with future screening mammograms.22 Further, increased radiation with annual mammography is a concern. However, modeling studies have shown that the mortality benefit for annual mammography starting at age 40 outweighs (by 60-fold) the mortality risk from a radiation-induced breast cancer.26
Benefit from biennial screening
Some research suggests overall benefit from biennial screening. One study that used Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer microsimulation was adapted to measure the incidence, mortality, and life-years gained for Canadian patients.27 This model demonstrated that mortality reduction was linked to greater lifetime screens for breast cancer, but this applied primarily to patients aged 50 and older. Overall, a larger impact was observed by initiating screening at age 40 than by decreasing screening intervals.27
Using modeling, Mandelblatt and colleagues demonstrated that biennial screening could capture most of the benefit of annual screening with less harm.28 In another study in 2016, Mandelblatt and colleagues used updated and revised versions of these simulation models and maintained that biennial screening upheld 79.8% to 81.3% of the benefits of annual screening mammography but with fewer overdiagnoses and false-positive results.25 The authors concluded that while biennial screening is equally effective for average-risk populations, there should be an evaluation of benefits and harms based on the clinical scenario (suggesting that annual screening for those at age 40 who carried elevated risk was similar to biennial screening for average-risk patients starting at age 50).25
Another study that served to inform the European Commission Initiative on Breast Cancer recommendations evaluated randomized controlled trials and observational and modeling studies that assessed breast screening intervals.29 The authors concluded that each screening interval has risks and benefits, with data suggesting more benefit with biennial screening for people aged 50 to 69 years and more possible harm with annual screening in younger people (aged 45–49).29
Continue to: Benefit from annual screening...
Benefit from annual screening
However, these data conflict with other studies that demonstrate the benefit of annual compared with biennial screening mammography. One large retrospective review of prospectively collected data evaluated outcome differences based on mammography frequency.30 For those undergoing annual versus biennial screening, the median tumor size was 11 mm (versus 15 mm), the percentage of lymph node metastasis was 14% (versus 24%), and cancer stage II or higher was 17% (versus 29%). The study overall demonstrated that annual screening resulted in lower recall rates (P<.0001) and detection of smaller tumors that carried a more favorable prognosis (P<.04).30
Another observational study from 2004 that assessed data from 7 different mammography registries nationwide noted that, among those aged 40 to 49, patients who underwent biennial screening had an increased likelihood of late-stage disease compared with those with annual screening (28% vs 21%, respectively; odds ratio [OR], 1.35; 95% CI, 1.01–1.81), although this discrepancy was not observed in people aged 50 or older.31
A study that critiqued the previous 2012 version of the USPSTF guidelines used CISNET modeling, which demonstrated a 39.6% mortality reduction with annual screening for those aged 40 to 84 versus 23.2% for biennial screening for those aged 50 to 74.5
More recent data also reflect these findings. A retrospective cohort study that evaluated patients aged 40 to 84 diagnosed with breast cancer found that those who previously underwent annual versus biennial screening mammography had lower incidences of late-stage diagnoses (24.0% vs 43.8%, respectively; P=.02), fewer interval cancers (10.5% vs 37.5%; P<.001), and smaller mean (SD) tumor diameter (1.4 [1.2] cm vs 1.8 [1.6] cm; P=.04).21 Postmenopausal patients in this cohort also demonstrated similar findings when comparing mammogram frequency. Although not significant, biennial (or greater) frequency of screening mammography also resulted in an increased likelihood of axillary lymph node dissection and chemotherapy.
Similarly, authors of another large prospective cohort study concluded that breast cancers diagnosed in premenopausal patients were more likely to be larger with less favorable prognostic characteristics (tumor size >15 mm, relative risk [RR], 1.21 [95% CI, 1.07–1.37]; P=.002); any less favorable prognostic characteristics (RR, 1.11 [95% CI, 1.00–1.22]; P=.047), and higher stage (stage IIB or higher, RR, 1.28 [95% CI, 1.01–1.63]; P=.04) for those who underwent biennial screening compared with breast cancers diagnosed by annual screening.32 However, this trend was not observed in postmenopausal patients not taking hormone therapy.32
Some international studies also show more favorable outcomes with annual screening mammography. A Swedish study evaluated mammography screening intervals of 21 months compared with 18 or 12 months in patients aged 40 to 49.33 Data showed an improved effectiveness of 1.6% to 9.8% for interval cancers and 2.9% to 17.4% for both interval and screening-detected cancers by reducing the screening frequency to 12 months, with authors suggesting a further reduction in breast cancer–related mortality rates for this age group.33
Results from another descriptive study from Europe also showed increasing interval breast cancer rates with increasing screening intervals.34 After a negative screen, the interval cancer rates and regional ranges for 0 to less than 12 months, 12 to less than 24 months, and 24 to less than 36 months per 1,000 screened were 0.55 (0.43–0.76), 1.13 (0.92–1.47), and 1.22 (0.93–1.57), respectively.34
Finally, a study conducted in Canada evaluated interval breast cancers among people with dense breasts screened between 2008 and 2010.35 Those with screening programs with policies that offered annual screening reported fewer interval cancers (interval cancer rate, 0.89 per 1,000; 95% CI, 0.67–1.11) compared with those who had policies that used biennial screening (interval cancer rate, 1.45 per 1,000 [annualized]; 95% CI, 1.19–1.72), which was 63% higher (P=.002). For those for whom radiologists recommended screening, interval cancer was lower for annual (0.93 per 1,000; 95% CI, 0.71–1.16) versus biennial screening (1.70 per 1,000 [annualized]; 95% CI, 0.70–2.71) (P=.061).35
Continue to: Black patients have a worse breast cancer prognosis...
Black patients have a worse breast cancer prognosis
Additional consideration should be given to populations with worse survival outcomes at baseline for whom screening mammography could play a significant role. In particular, Black people have similar rates of breast cancer compared with White people (127.8 cases per 100,000 vs 133.7 cases per 100,000, respectively) but have a 40% increased breast cancer–related mortality.8 The USPSTF recognizes this disparity and mentions it in their recommendations, encouraging health care clinicians to engage in shared decision making with Black patients and asserting that more research is needed on screening mammography in Black communities.15
While the age modification to the new guidelines better addresses the disparities that impact the Black community (such as increased likelihood of early-onset breast cancer36 and increased rate of breast cancer diagnosis at first mammogram37), the next obvious question is: Can groups with higher breast cancer mortality such as Black communities afford to undergo mammography every 2 years (as opposed to every year)?
Although some data specifically have evaluated the age of initiation and frequency of screening mammography among Black patients,38,39 little data have specifically assessed outcomes for annual versus biennial screening among Black people. Despite these research gaps, risk factors among the Black community should be considered. There is an increased risk of triple-negative breast cancer that can contribute to higher mortality among Black communities.40 Black people also tend to be diagnosed with more aggressive subtypes overall,41,42 are more likely to have dense breasts,43,44 have a higher likelihood of advanced stages at the time of diagnosis compared with White people,8,45 and have a greater chance of diagnosis of a second primary or contralateral breast cancer46-48—all risk factors that support the importance of regular and early-screening mammography.
How I counsel my patients
As Director of the Cancer Genetics and Breast Health Clinic, I am a gynecologist who primarily evaluates patients at increased risk for breast cancer (and other cancers). As an initial step, I strongly encourage all patients (especially Black patients and those of Ashkenazi Jewish ancestry as per the American College of Radiology recommendations9) to undergo risk assessment at age 25 to determine if they may be at increased risk for breast cancer. This first step may include genetic testing if the patient meets NCCN testing criteria based on personal or family history. If results are positive for a germline pathogenic variant, the timing and nature of breast screening would be based on NCCN recommendations for that particular variant (with possible modification of age of initiation based on family history). If testing is negative, lifetime risk assessment would then be performed using risk calculators—such as Tyrer-Cuzick—to determine if the patient meets criteria for intensive surveillance with supplemental breast magnetic resonance imaging. If the patient is subsequently determined to be at average risk after these assessments, I recommend they undergo screening mammography annually starting at age 40. However, it must be recognized that risk may change over time. A patient’s risk can continue to be assessed over a lifetime—with changing family history, personal risk factors, and new discoveries in genetics.
Summary
Ultimately, it is reassuring that the USPSTF guidelines have been updated to be concordant with other national medical society recommendations. They reflect the increasing nationwide trends that clearly demonstrate the high overall prevalence of breast cancer as well as the increasing incidence of early-onset breast cancer.
The updated guidelines, however, do not reflect the entirety of breast cancer trends in this country. With breast cancer being the most commonly diagnosed cancer in the United States, it is imperative to consider the data that demonstrate improved prognostics with annual compared with biennial mammography. Furthermore, the guidelines only begin to explore the disparities that Black patients face regarding breast cancer–related mortality. The risks of younger age at diagnosis, greater likelihood of aggressive subtypes, increased risk of second primary and contralateral breast cancer, and later stage at diagnosis must be seriously evaluated when counseling this patient population.
While the USPSTF recommendations for age at initiation reflect national statistics, recommendations by the ACR and NCCN more appropriately recognize that the benefits of annual screening outweigh the potential risks. Annual screening frequency should be adopted when counseling patients, particularly for the Black community. ●
- Cancer stat facts: Common cancer sites. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Accessed November 7, 2023. https://seer .cancer.gov/statfacts/html/common.html#:~:text=An%20 estimated%20297%2C790%20women%20and,overall%20 with%20288%2C300%20expected%20cases
- Survival rates for breast cancer. American Cancer Society. March 1, 2023. Accessed November 16, 2023. https://www .cancer.org/cancer/breast-cancer/understanding-a-breast -cancer-diagnosis/breast-cancer-survival-rates.html
- Ambinder EB, Lee E, Nguyen DL, et al. Interval breast cancers versus screen detected breast cancers: a retrospective cohort study. Acad Radiol. 2023;30(suppl 2):S154-S160.
- Allgood PC, Duffy SW, Kearins O, et al. Explaining the difference in prognosis between screen-detected and symptomatic breast cancers. Br J Cancer. 2011;104:1680-1685.
- Hendrick RE, Helvie MA. United States Preventive Services Task Force screening mammography recommendations: science ignored. AJR Am J Roentgenol. 2011;196:W112-W116.
- Oeffinger KC, Fontham ETH, Etzioni R, et al; American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314:1599-1614.
- Hendrick RE, Baker JA, Helvie MA. Breast cancer deaths averted over 3 decades. Cancer. 2019;125:1482-1488.
- Breast cancer facts & figures 2022-2024. American Cancer Society. 2022. Accessed September 7, 2023. https://www .cancer.org/content/dam/cancer-org/research/cancer-facts -and-statistics/breast-cancer-facts-and-figures/2022-2024 -breast-cancer-fact-figures-acs.pdf
- New ACR breast cancer screening guidelines call for earlier and more-intensive screening for high-risk women. American College of Radiology. May 3, 2023. Accessed October 8, 2023. https://www.acr.org/Media-Center/ACR -News-Releases/2023/New-ACR-Breast-Cancer-Screening -Guidelines-call-for-earlier-screening-for-high-risk-women
- American Cancer Society recommendations for the early detection of breast cancer. American Cancer Society. January 14, 2022. Accessed October 30, 2023. https://www.cancer .org/cancer/types/breast-cancer/screening-tests-and-early -detection/american-cancer-society-recommendations-for -the-early-detection-of-breast-cancer.html
- Breast cancer screening and diagnosis. National Comprehensive Cancer Network. Published Version 1.2023. June 19, 2023. Accessed September 21, 2023. https://www .nccn.org/professionals/physician_gls/pdf/breast-screening .pdf
- ACOG Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No 179. Breast cancer risk assessment and screening in average-risk women. Obstet Gynecol. 2017;130:e1-e16.
- Final recommendation statement. Breast cancer: screening. US Preventive Services Task Force. January 11, 2016. Accessed September 1, 2023. https://www .uspreventiveservicestaskforce.org/uspstf/recommendation breast-cancer-screening
- Siu AL; US Preventive Services Task Force. Screening for breast cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164:279-296.
- Breast cancer: screening. US Preventive Services Task Force. May 9, 2023. Accessed October 7, 2023. https://www .uspreventiveservicestaskforce.org/uspstf/document/draft -evidence-review/breast-cancer-screening-adults
- Breast cancer in young women. Centers for Disease Control and Prevention. June 21, 2023. Accessed October 30, 2023. https://www.cdc.gov/cancer/breast/young_women/index .htm
- Arleo EK, Hendrick RE, Helvie MA, et al. Comparison of recommendations for screening mammography using CISNET models. Cancer. 2017;123:3673-3680.
- Nelson HD, Tyne K, Naik A, et al; US Preventive Services Task Force. Screening for breast cancer: an update for the US Preventive Services Task Force. Ann Intern Med. 2009;151:727737, W237-W242.
- Breast Screening Frequency Trial Group. The frequency of breast cancer screening: results from the UKCCCR randomised trial. United Kingdom Co-ordinating Committee on Cancer Research. Eur J Cancer. 2002;38:1458-1464.
- Klemi PJ, Toikkanen S, Räsänen O, et al. Mammography screening interval and the frequency of interval cancers in a population-based screening. Br J Cancer. 1997;75:762-766.
- Moorman SEH, Pujara AC, Sakala MD, et al. Annual screening mammography associated with lower stage breast cancer compared with biennial screening. AJR Am J Roentgenol. 2021;217:40-47.
- Nelson HD, Pappas M, Cantor A, et al. Harms of breast cancer screening: systematic review to update the 2009 US Preventive Services Task Force recommendation. Ann Intern Med. 2016;164:256-267.
- Hubbard RA, Kerlikowske K, Flowers CI, et al. Cumulative probability of false-positive recall or biopsy recommendation after 10 years of screening mammography: a cohort study. Ann Intern Med. 2011;155:481-492.
- Kerlikowske K, Zhu W, Hubbard RA, et al; Breast Cancer Surveillance Consortium. Outcomes of screening mammography by frequency, breast density, and postmenopausal hormone therapy. JAMA Intern Med. 2013;173:807-816.
- Mandelblatt JS, Stout NK, Schechter CB, et al. Collaborative modeling of the benefits and harms associated with different US breast cancer screening strategies. Ann Intern Med. 2016;164:215-225.
- Miglioretti DL, Lange J, van den Broek JJ, et al. Radiationinduced breast cancer incidence and mortality from digital mammography screening: a modeling study. Ann Intern Med. 2016;164:205-214.
- Yaffe MJ, Mittmann N, Lee P, et al. Clinical outcomes of modelling mammography screening strategies. Health Rep. 2015;26:9-15.
- Mandelblatt JS, Cronin KA, Bailey S, et al; Breast Cancer Working Group of the Cancer Intervention and Surveillance Modeling Network. Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms. Ann Intern Med. 2009;151: 738-747.
- Canelo-Aybar C, Posso M, Montero N, et al. Benefits and harms of annual, biennial, or triennial breast cancer mammography screening for women at average risk of breast cancer: a systematic review for the European Commission Initiative on Breast Cancer (ECIBC). Br J Cancer. 2022;126:673-688.
- Hunt KA, Rosen EL, Sickles EA. Outcome analysis for women undergoing annual versus biennial screening mammography: a review of 24,211 examinations. AJR Am J Roentgenol. 1999;173:285-289.
- White E, Miglioretti DL, Yankaskas BC, et al. Biennial versus annual mammography and the risk of late-stage breast cancer. J Natl Cancer Inst. 2004;96:1832-1839.
- Miglioretti DL, Zhu W, Kerlikowske K, et al; Breast Cancer Surveillance Consortium. Breast tumor prognostic characteristics and biennial vs annual mammography, age, and menopausal status. JAMA Oncol. 2015;1:1069-1077.
- Mao Z, Nyström L, Jonsson H. Breast cancer screening with mammography in women aged 40-49 years: impact of length of screening interval on effectiveness of the program. J Med Screen. 2021;28:200-206.
- Bennett RL, Sellars SJ, Moss SM. Interval cancers in the NHS breast cancer screening programme in England, Wales and Northern Ireland. Br J Cancer. 2011;104:571-577.
- Seely JM, Peddle SE, Yang H, et al. Breast density and risk of interval cancers: the effect of annual versus biennial screening mammography policies in Canada. Can Assoc Radiol J. 2022;73:90-100.
- Liu Q, Yao S, Zhao H, et al. Early-onset triple-negative breast cancer in multiracial/ethnic populations: distinct trends of prevalence of truncation mutations. Cancer Med. 2019;8:1845-1853.
- Wilkerson AD, Obi M, Ortega C, et al. Young Black women may be more likely to have first mammogram cancers: a new perspective in breast cancer disparities. Ann Surg Oncol. 2023;30:2856-2869.
- Chen T, Kharazmi E, Fallah M. Race and ethnicity-adjusted age recommendation for initiating breast cancer screening. JAMA Netw Open. 2023;6:e238893.
- Chapman CH, Schechter CB, Cadham CJ, et al. Identifying equitable screening mammography strategies for Black women in the United States using simulation modeling. Ann Intern Med. 2021;174:1637-1646.
- Howard FM, Olopade OI. Epidemiology of triple-negative breast cancer: a review. Cancer J. 2021;27:8-16.
- Stringer-Reasor EM, Elkhanany A, Khoury K, et al. Disparities in breast cancer associated with African American identity. Am Soc Clin Oncol Educ Book. 2021;41:e29-e46.
- Newman LA. Parsing the etiology of breast cancer disparities. J Clin Oncol. 2016;34:1013-1014.
- Moore JX, Han Y, Appleton C, et al. Determinants of mammographic breast density by race among a large screening population. JNCI Cancer Spectr. 2020;4:pkaa010.
- McCarthy AM, Keller BM, Pantalone LM, et al. Racial differences in quantitative measures of area and volumetric breast density. J Natl Cancer Inst. 2016;108:djw104.
- Chen L, Li CI. Racial disparities in breast cancer diagnosis and treatment by hormone receptor and HER2 status. Cancer Epidemiol Biomarkers Prev. 2015;24:1666-1672.
- Terman E, Sheade J, Zhao F, et al. The impact of race and age on response to neoadjuvant therapy and long-term outcomes in Black and White women with early-stage breast cancer. Breast Cancer Res Treat. 2023;200:75-83.
- Watt GP, John EM, Bandera EV, et al. Race, ethnicity and risk of second primary contralateral breast cancer in the United States. Int J Cancer. 2021;148:2748-2758.
- Giannakeas V, Lim DW, Narod SA. The risk of contralateral breast cancer: a SEER-based analysis. Br J Cancer. 2021;125:601-610.
- Cancer stat facts: Common cancer sites. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Accessed November 7, 2023. https://seer .cancer.gov/statfacts/html/common.html#:~:text=An%20 estimated%20297%2C790%20women%20and,overall%20 with%20288%2C300%20expected%20cases
- Survival rates for breast cancer. American Cancer Society. March 1, 2023. Accessed November 16, 2023. https://www .cancer.org/cancer/breast-cancer/understanding-a-breast -cancer-diagnosis/breast-cancer-survival-rates.html
- Ambinder EB, Lee E, Nguyen DL, et al. Interval breast cancers versus screen detected breast cancers: a retrospective cohort study. Acad Radiol. 2023;30(suppl 2):S154-S160.
- Allgood PC, Duffy SW, Kearins O, et al. Explaining the difference in prognosis between screen-detected and symptomatic breast cancers. Br J Cancer. 2011;104:1680-1685.
- Hendrick RE, Helvie MA. United States Preventive Services Task Force screening mammography recommendations: science ignored. AJR Am J Roentgenol. 2011;196:W112-W116.
- Oeffinger KC, Fontham ETH, Etzioni R, et al; American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314:1599-1614.
- Hendrick RE, Baker JA, Helvie MA. Breast cancer deaths averted over 3 decades. Cancer. 2019;125:1482-1488.
- Breast cancer facts & figures 2022-2024. American Cancer Society. 2022. Accessed September 7, 2023. https://www .cancer.org/content/dam/cancer-org/research/cancer-facts -and-statistics/breast-cancer-facts-and-figures/2022-2024 -breast-cancer-fact-figures-acs.pdf
- New ACR breast cancer screening guidelines call for earlier and more-intensive screening for high-risk women. American College of Radiology. May 3, 2023. Accessed October 8, 2023. https://www.acr.org/Media-Center/ACR -News-Releases/2023/New-ACR-Breast-Cancer-Screening -Guidelines-call-for-earlier-screening-for-high-risk-women
- American Cancer Society recommendations for the early detection of breast cancer. American Cancer Society. January 14, 2022. Accessed October 30, 2023. https://www.cancer .org/cancer/types/breast-cancer/screening-tests-and-early -detection/american-cancer-society-recommendations-for -the-early-detection-of-breast-cancer.html
- Breast cancer screening and diagnosis. National Comprehensive Cancer Network. Published Version 1.2023. June 19, 2023. Accessed September 21, 2023. https://www .nccn.org/professionals/physician_gls/pdf/breast-screening .pdf
- ACOG Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No 179. Breast cancer risk assessment and screening in average-risk women. Obstet Gynecol. 2017;130:e1-e16.
- Final recommendation statement. Breast cancer: screening. US Preventive Services Task Force. January 11, 2016. Accessed September 1, 2023. https://www .uspreventiveservicestaskforce.org/uspstf/recommendation breast-cancer-screening
- Siu AL; US Preventive Services Task Force. Screening for breast cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164:279-296.
- Breast cancer: screening. US Preventive Services Task Force. May 9, 2023. Accessed October 7, 2023. https://www .uspreventiveservicestaskforce.org/uspstf/document/draft -evidence-review/breast-cancer-screening-adults
- Breast cancer in young women. Centers for Disease Control and Prevention. June 21, 2023. Accessed October 30, 2023. https://www.cdc.gov/cancer/breast/young_women/index .htm
- Arleo EK, Hendrick RE, Helvie MA, et al. Comparison of recommendations for screening mammography using CISNET models. Cancer. 2017;123:3673-3680.
- Nelson HD, Tyne K, Naik A, et al; US Preventive Services Task Force. Screening for breast cancer: an update for the US Preventive Services Task Force. Ann Intern Med. 2009;151:727737, W237-W242.
- Breast Screening Frequency Trial Group. The frequency of breast cancer screening: results from the UKCCCR randomised trial. United Kingdom Co-ordinating Committee on Cancer Research. Eur J Cancer. 2002;38:1458-1464.
- Klemi PJ, Toikkanen S, Räsänen O, et al. Mammography screening interval and the frequency of interval cancers in a population-based screening. Br J Cancer. 1997;75:762-766.
- Moorman SEH, Pujara AC, Sakala MD, et al. Annual screening mammography associated with lower stage breast cancer compared with biennial screening. AJR Am J Roentgenol. 2021;217:40-47.
- Nelson HD, Pappas M, Cantor A, et al. Harms of breast cancer screening: systematic review to update the 2009 US Preventive Services Task Force recommendation. Ann Intern Med. 2016;164:256-267.
- Hubbard RA, Kerlikowske K, Flowers CI, et al. Cumulative probability of false-positive recall or biopsy recommendation after 10 years of screening mammography: a cohort study. Ann Intern Med. 2011;155:481-492.
- Kerlikowske K, Zhu W, Hubbard RA, et al; Breast Cancer Surveillance Consortium. Outcomes of screening mammography by frequency, breast density, and postmenopausal hormone therapy. JAMA Intern Med. 2013;173:807-816.
- Mandelblatt JS, Stout NK, Schechter CB, et al. Collaborative modeling of the benefits and harms associated with different US breast cancer screening strategies. Ann Intern Med. 2016;164:215-225.
- Miglioretti DL, Lange J, van den Broek JJ, et al. Radiationinduced breast cancer incidence and mortality from digital mammography screening: a modeling study. Ann Intern Med. 2016;164:205-214.
- Yaffe MJ, Mittmann N, Lee P, et al. Clinical outcomes of modelling mammography screening strategies. Health Rep. 2015;26:9-15.
- Mandelblatt JS, Cronin KA, Bailey S, et al; Breast Cancer Working Group of the Cancer Intervention and Surveillance Modeling Network. Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms. Ann Intern Med. 2009;151: 738-747.
- Canelo-Aybar C, Posso M, Montero N, et al. Benefits and harms of annual, biennial, or triennial breast cancer mammography screening for women at average risk of breast cancer: a systematic review for the European Commission Initiative on Breast Cancer (ECIBC). Br J Cancer. 2022;126:673-688.
- Hunt KA, Rosen EL, Sickles EA. Outcome analysis for women undergoing annual versus biennial screening mammography: a review of 24,211 examinations. AJR Am J Roentgenol. 1999;173:285-289.
- White E, Miglioretti DL, Yankaskas BC, et al. Biennial versus annual mammography and the risk of late-stage breast cancer. J Natl Cancer Inst. 2004;96:1832-1839.
- Miglioretti DL, Zhu W, Kerlikowske K, et al; Breast Cancer Surveillance Consortium. Breast tumor prognostic characteristics and biennial vs annual mammography, age, and menopausal status. JAMA Oncol. 2015;1:1069-1077.
- Mao Z, Nyström L, Jonsson H. Breast cancer screening with mammography in women aged 40-49 years: impact of length of screening interval on effectiveness of the program. J Med Screen. 2021;28:200-206.
- Bennett RL, Sellars SJ, Moss SM. Interval cancers in the NHS breast cancer screening programme in England, Wales and Northern Ireland. Br J Cancer. 2011;104:571-577.
- Seely JM, Peddle SE, Yang H, et al. Breast density and risk of interval cancers: the effect of annual versus biennial screening mammography policies in Canada. Can Assoc Radiol J. 2022;73:90-100.
- Liu Q, Yao S, Zhao H, et al. Early-onset triple-negative breast cancer in multiracial/ethnic populations: distinct trends of prevalence of truncation mutations. Cancer Med. 2019;8:1845-1853.
- Wilkerson AD, Obi M, Ortega C, et al. Young Black women may be more likely to have first mammogram cancers: a new perspective in breast cancer disparities. Ann Surg Oncol. 2023;30:2856-2869.
- Chen T, Kharazmi E, Fallah M. Race and ethnicity-adjusted age recommendation for initiating breast cancer screening. JAMA Netw Open. 2023;6:e238893.
- Chapman CH, Schechter CB, Cadham CJ, et al. Identifying equitable screening mammography strategies for Black women in the United States using simulation modeling. Ann Intern Med. 2021;174:1637-1646.
- Howard FM, Olopade OI. Epidemiology of triple-negative breast cancer: a review. Cancer J. 2021;27:8-16.
- Stringer-Reasor EM, Elkhanany A, Khoury K, et al. Disparities in breast cancer associated with African American identity. Am Soc Clin Oncol Educ Book. 2021;41:e29-e46.
- Newman LA. Parsing the etiology of breast cancer disparities. J Clin Oncol. 2016;34:1013-1014.
- Moore JX, Han Y, Appleton C, et al. Determinants of mammographic breast density by race among a large screening population. JNCI Cancer Spectr. 2020;4:pkaa010.
- McCarthy AM, Keller BM, Pantalone LM, et al. Racial differences in quantitative measures of area and volumetric breast density. J Natl Cancer Inst. 2016;108:djw104.
- Chen L, Li CI. Racial disparities in breast cancer diagnosis and treatment by hormone receptor and HER2 status. Cancer Epidemiol Biomarkers Prev. 2015;24:1666-1672.
- Terman E, Sheade J, Zhao F, et al. The impact of race and age on response to neoadjuvant therapy and long-term outcomes in Black and White women with early-stage breast cancer. Breast Cancer Res Treat. 2023;200:75-83.
- Watt GP, John EM, Bandera EV, et al. Race, ethnicity and risk of second primary contralateral breast cancer in the United States. Int J Cancer. 2021;148:2748-2758.
- Giannakeas V, Lim DW, Narod SA. The risk of contralateral breast cancer: a SEER-based analysis. Br J Cancer. 2021;125:601-610.
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>Pleasant1223docx</fileName> <TBEID>0C02EE6C.SIG</TBEID> <TBUniqueIdentifier>NJ_0C02EE6C</TBUniqueIdentifier> <newsOrJournal>Journal</newsOrJournal> <publisherName>Frontline Medical Communications Inc.</publisherName> <storyname/> <articleType>1</articleType> <TBLocation>Copyfitting-OBGM</TBLocation> <QCDate/> <firstPublished>20231211T203547</firstPublished> <LastPublished>20231211T203547</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20231211T203547</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline/> <bylineText>Versha Pleasant, MD, MPH</bylineText> <bylineFull/> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType>(choose one)</newsDocType> <journalDocType>(choose one)</journalDocType> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>Breast cancer represents the most commonly diagnosed cancer in the nation.1 However, unlike other cancers, most breast cancers are identified at stage I and hav</metaDescription> <articlePDF/> <teaserImage/> <title>Patient counseling for breast cancer screening: Taking changes to USPSTF recommendations into account</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gyn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle>MDedge ObGyn</journalFullTitle> <copyrightStatement>2018</copyrightStatement> </publicationData> <publicationData> <publicationCode>obgm</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">49726</term> <term>24</term> </publications> <sections> <term canonical="true">49</term> </sections> <topics> <term canonical="true">192</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Patient counseling for breast cancer screening: Taking changes to USPSTF recommendations into account</title> <deck/> </itemMeta> <itemContent> <p class="abstract">The US Preventive Services Task Force now recommends mammography screening every other year starting at age 40 to decrease the risk of dying from breast cancer, but questions remain regarding biennial versus annual screening as well as disparities in risk factors and outcomes among Black people</p> <p>Breast cancer represents the most commonly diagnosed cancer in the nation.<sup><a href="https://paperpile.com/c/wiWWJx/xnMwb">1</a></sup> However, unlike other cancers, most breast cancers are identified at stage I and have a 90% survival rate 5-year prognosis.<sup><a href="https://paperpile.com/c/wiWWJx/DgY3D">2</a></sup> These outcomes are attributable to various factors, one of the most significant being screening mammography—a largely accessible, highly sensitive and specific screening tool.<sup><a href="https://paperpile.com/c/wiWWJx/QVqK7">3</a></sup> Data demonstrate that malignant tumors detected on screening mammography have more favorable profiles in tumor size and nodal status compared with symptomatic breast cancers,<sup><a href="https://paperpile.com/c/wiWWJx/Kgiyg">4</a></sup> which make it critical for early diagnosis. Most importantly, the research overwhelmingly demonstrates that screening mammography decreases breast cancer–related mortality.<sup><a href="https://paperpile.com/c/wiWWJx/Ur7Do+QnMTe+44pUB">5-7</a></sup></p> <h2>The USPSTF big change: Mammography starting at age 40 for all recommended</h2> <p>Despite the general accessibility and mortality benefits of screening mammography (in light of the high lifetime 12% prevalence of breast cancer in the United States<sup><a href="https://paperpile.com/c/wiWWJx/f7iIp">8</a></sup>), recommendations still conflict across medical societies regarding optimal timing and frequency.<sup><a href="https://paperpile.com/c/wiWWJx/2SvFw+ZESfI+bnwRG+EH0vL">9-12</a></sup> Previously, the US Preventive Services Task Force (USPSTF) recommended that screening mammography should occur at age 50 biennially and that screening between ages 40 and 49 should be an individualized decision.<sup><a href="https://paperpile.com/c/wiWWJx/itABE+uuy9A">13,14</a></sup> In the draft recommendation statement issued on May 9, 2023, however, the USPSTF now recommends screening every other year starting at age 40 to decrease the risk of dying from breast cancer.<sup><a href="https://paperpile.com/c/wiWWJx/DugZ0">15</a></sup></p> <p>This change represents a critically important shift. The new guidance:</p> <ul class="body"> <li>acknowledges the increasing incidence of early-onset breast cancer</li> <li>reinforces a national consciousness toward screening mammography in decreasing mortality,<a href="https://paperpile.com/c/wiWWJx/pW8Pc">17</a> even among a younger age group for whom the perception of risk may be lower.</li> </ul> <p>The USPSTF statement represents a significant change in how patients should be counseled. Practitioners now have more direct guidance that is concordant with what other national medical organizations offer or recommend, including the American College of Obstetricians and Gynecologists (ACOG), the American College of Radiology (ACR), and the National Comprehensive Cancer Network (NCCN).<br/><br/>However, while the USPSTF statement can and should encourage health care practitioners to initiate mammography earlier than prior recommendations, ongoing discussion regarding the optimal screening interval is warranted. The USPSTF recommendations state that mammography should be performed biennially. While the age at initiation represents a step in the right direction, this recommended screening interval should be reevaluated.</p> <h2>Annual vs biennial screening?</h2> <p>The debate between annual and biennial screening mammography is not new. While many randomized trials on screening mammography have evaluated such factors as breast cancer mortality by age or rate of false positives,<sup><a href="https://paperpile.com/c/wiWWJx/nOy1X">18</a></sup> fewer trials have evaluated the optimal screening interval.</p> <p>One randomized trial from the United Kingdom evaluated 99,389 people aged 50 to 62 from 1989 to 1996 who underwent annual screening (study arm) versus 3 years later (control).<sup>19</sup> Findings demonstrated a significantly smaller tumor size in the study arm (<i>P</i>=.05) as well as an increased total cancer detection rate. However, the authors concluded that shortening the screening interval (from 3 years) would not yield a statistically significant decrease in mortality.<sup><a href="https://paperpile.com/c/wiWWJx/nXuQF">19</a><br/><br/></sup>In a randomized trial from Finland, researchers screened those aged older than 50 at biennial intervals and those aged younger than 50 at either annual or triennial intervals.<sup>20</sup> Results demonstrated that, among those aged 40 to 49, the frequency of stage I cancers was not significantly different from screen-detected cancers, interval cancers, or cancers detected outside of screening (50%, 42%, and 44%, respectively; <i>P</i>=.73). Furthermore, there was a greater likelihood of interval cancers among those aged 40 to 49 at 1-year (27%) and 3-year (39%) screening intervals compared with those aged older than 50 screened biennially (18%; <i>P</i>=.08 and <i>P</i>=.0009, respectively).<sup><a href="https://paperpile.com/c/wiWWJx/8WXcp">20</a><br/><br/></sup>These randomized trials, however, have been scrutinized because of factors such as discrepancies in screening intervals by country as well as substantial improvements made in screening mammography since the time these trials were conducted.<sup><a href="https://paperpile.com/c/wiWWJx/Ur7Do">5</a></sup> Due to the dearth of more contemporary randomized controlled trials accounting for more up-to-date training and technology, most of the more recent data has been largely observational, retrospective, or used modeling.<sup><a href="https://paperpile.com/c/wiWWJx/266Wr">21</a></sup> The <strong>TABLE</strong> outlines some of the major studies on this topic.</p> <p><span class="intro">False-positive results, biopsy rates</span>. The arguments against more frequent screening include the possibility of false positives that require callbacks and biopsies, which may be more frequent among those who undergo annual mammography.<sup><a href="https://paperpile.com/c/wiWWJx/HXUvL">22</a></sup> A systematic review from the Breast Cancer Surveillance Consortium demonstrated a 61.3% annual (confidence interval [CI], 59.4%–63.1%) versus 41.6% biennial (CI, 40.6%–42.5%) false-positive rate, resulting in a 7% (CI, 6.1%–7.8%) versus 4.8% (CI, 4.4–5.2%) rate of biopsy, respectively.<sup><a href="https://paperpile.com/c/wiWWJx/Cdruf">23</a></sup> This false-positive rate, however, also may be increased in younger patients aged 40 to 49 and in those with dense breasts.<sup><a href="https://paperpile.com/c/wiWWJx/HXUvL+9u9oj">22,24</a></sup> These callbacks and biopsies could induce significant patient stress, pain, and anxiety, as well as carry financial implications related to subsequent diagnostic imaging.<br/><br/><span class="intro">Overdiagnosis. </span>There is also the risk of overdiagnosis, in which an indolent breast cancer that otherwise would not grow or progress to become symptomatic is identified. This could lead to overtreatment. While the exact incidence of overdiagnosis is unclear (due to recommendations for universal treatment of ductal carcinoma in situ), some data suggest that overdiagnosis could be decreased with biennial screening.<sup><a href="https://paperpile.com/c/wiWWJx/GhKae">25</a></sup> </p> <p>While discomfort could also be a barrier, it may not necessarily be prohibitive for some to continue with future screening mammograms.<sup><a href="https://paperpile.com/c/wiWWJx/HXUvL">22</a></sup> Further, increased radiation with annual mammography is a concern. However, modeling studies have shown that the mortality benefit for annual mammography starting at age 40 outweighs (by 60-fold) the mortality risk from a radiation-induced breast cancer.<sup><a href="https://paperpile.com/c/wiWWJx/OFKsf">26</a></sup></p> <h2>Benefit from biennial screening</h2> <p>Some research suggests overall benefit from biennial screening. One study that used Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer microsimulation was adapted to measure the incidence, mortality, and life-years gained for Canadian patients.<sup>27</sup> This model demonstrated that mortality reduction was linked to greater lifetime screens for breast cancer, but this applied primarily to patients aged 50 and older. Overall, a larger impact was observed by initiating screening at age 40 than by decreasing screening intervals.<sup><a href="https://paperpile.com/c/wiWWJx/tbbqq">27</a></sup></p> <p>Using modeling, Mandelblatt and colleagues demonstrated that biennial screening could capture most of the benefit of annual screening with less harm.<sup><a href="https://paperpile.com/c/wiWWJx/u3ESD">28</a></sup> In another study in 2016, Mandelblatt and colleagues used updated and revised versions of these simulation models and maintained that biennial screening upheld 79.8% to 81.3% of the benefits of annual screening mammography but with fewer overdiagnoses and false-positive results.<sup>25</sup> The authors concluded that while biennial screening is equally effective for average-risk populations, there should be an evaluation of benefits and harms based on the clinical scenario (suggesting that annual screening for those at age 40 who carried elevated risk was similar to biennial screening for average-risk patients starting at age 50).<sup><a href="https://paperpile.com/c/wiWWJx/GhKae">25</a><br/><br/></sup>Another study that served to inform the European Commission Initiative on Breast Cancer recommendations evaluated randomized controlled trials and observational and modeling studies that assessed breast screening intervals.<sup>29</sup> The authors concluded that each screening interval has risks and benefits, with data suggesting more benefit with biennial screening for people aged 50 to 69 years and more possible harm with annual screening in younger people (aged 45–49).<sup><a href="https://paperpile.com/c/wiWWJx/9XkOu">29</a></sup></p> <h2>Benefit from annual screening</h2> <p>However, these data conflict with other studies that demonstrate the benefit of annual compared with biennial screening mammography. One large retrospective review of prospectively collected data evaluated outcome differences based on mammography frequency.<sup>30</sup> For those undergoing annual versus biennial screening, the median tumor size was 11 mm (versus 15 mm), the percentage of lymph node metastasis was 14% (versus 24%), and cancer stage II or higher was 17% (versus 29%). The study overall demonstrated that annual screening resulted in lower recall rates (<i>P</i><.0001) and detection of smaller tumors that carried a more favorable prognosis (<i>P</i><.04).<sup><a href="https://paperpile.com/c/wiWWJx/yJcze">30</a></sup></p> <p>Another observational study from 2004 that assessed data from 7 different mammography registries nationwide noted that, among those aged 40 to 49, patients who underwent biennial screening had an increased likelihood of late-stage disease compared with those with annual screening (28% vs 21%, respectively; odds ratio [OR], 1.35; 95% CI, 1.01–1.81), although this discrepancy was not observed in people aged 50 or older.<sup><a href="https://paperpile.com/c/wiWWJx/euQPl">31</a><br/><br/></sup>A study that critiqued the previous 2012 version of the USPSTF guidelines used CISNET modeling, which demonstrated a 39.6% mortality reduction with annual screening for those aged 40 to 84 versus 23.2% for biennial screening for those aged 50 to 74.<sup><a href="https://paperpile.com/c/wiWWJx/Ur7Do">5</a><br/><br/></sup>More recent data also reflect these findings. A retrospective cohort study that evaluated patients aged 40 to 84 diagnosed with breast cancer found that those who previously underwent annual versus biennial screening mammography had lower incidences of late-stage diagnoses (24.0% vs 43.8%, respectively; <i>P</i>=.02), fewer interval cancers (10.5% vs 37.5%; <i>P</i><.001), and smaller mean (SD) tumor diameter (1.4 [1.2] cm vs 1.8 [1.6] cm; <i>P</i>=.04).<sup><a href="https://paperpile.com/c/wiWWJx/266Wr">21</a></sup> Postmenopausal patients in this cohort also demonstrated similar findings when comparing mammogram frequency. Although not significant, biennial (or greater) frequency of screening mammography also resulted in an increased likelihood of axillary lymph node dissection and chemotherapy.<br/><br/>Similarly, authors of another large prospective cohort study concluded that breast cancers diagnosed in premenopausal patients were more likely to be larger with less favorable prognostic characteristics (tumor size >15 mm, relative risk [RR], 1.21 [95% CI, 1.07–1.37]; <i>P</i>=.002); any less favorable prognostic characteristics (RR, 1.11 [95% CI, 1.00–1.22]; <i>P</i>=.047), and higher stage (stage IIB or higher, RR, 1.28 [95% CI, 1.01–1.63]; <i>P</i>=.04) for those who underwent biennial screening compared with breast cancers diagnosed by annual screening.<sup>32</sup> However, this trend was not observed in postmenopausal patients not taking hormone therapy.<sup><a href="https://paperpile.com/c/wiWWJx/e4cdu">32</a><br/><br/></sup>Some international studies also show more favorable outcomes with annual screening mammography. A Swedish study evaluated mammography screening intervals of 21 months compared with 18 or 12 months in patients aged 40 to 49.<sup>33</sup> Data showed an improved effectiveness of 1.6% to 9.8% for interval cancers and 2.9% to 17.4% for both interval and screening-detected cancers by reducing the screening frequency to 12 months, with authors suggesting a further reduction in breast cancer–related mortality rates for this age group.<sup><a href="https://paperpile.com/c/wiWWJx/cjzBM">33</a><br/><br/></sup>Results from another descriptive study from Europe also showed increasing interval breast cancer rates with increasing screening intervals.<sup>34</sup> After a negative screen, the interval cancer rates and regional ranges for 0 to less than 12 months, 12 to less than 24 months, and 24 to less than 36 months per 1,000 screened were 0.55 (0.43–0.76), 1.13 (0.92–1.47), and 1.22 (0.93–1.57), respectively.<sup><a href="https://paperpile.com/c/wiWWJx/9wGYP">34</a><br/><br/></sup>Finally, a study conducted in Canada evaluated interval breast cancers among people with dense breasts screened between 2008 and 2010.<sup>35</sup> Those with screening programs with policies that offered annual screening reported fewer interval cancers (interval cancer rate, 0.89 per 1,000; 95% CI, 0.67–1.11) compared with those who had policies that used biennial screening (interval cancer rate, 1.45 per 1,000 [annualized]; 95% CI, 1.19–1.72), which was 63% higher (<i>P</i>=.002). For those for whom radiologists recommended screening, interval cancer was lower for annual (0.93 per 1,000; 95% CI, 0.71–1.16) versus biennial screening (1.70 per 1,000 [annualized]; 95% CI, 0.70–2.71) (<i>P</i>=.061).<sup><a href="https://paperpile.com/c/wiWWJx/a7prT">35</a></sup></p> <h2>Black patients have a worse breast cancer prognosis</h2> <p>Additional consideration should be given to populations with worse survival outcomes at baseline for whom screening mammography could play a significant role. In particular, Black people have similar rates of breast cancer compared with White people (127.8 cases per 100,000 vs 133.7 cases per 100,000, respectively) but have a 40% increased breast cancer–related mortality.<sup><a href="https://paperpile.com/c/wiWWJx/f7iIp">8</a></sup> The USPSTF recognizes this disparity and mentions it in their recommendations, encouraging health care clinicians to engage in shared decision making with Black patients and asserting that more research is needed on screening mammography in Black communities.<sup><a href="https://paperpile.com/c/wiWWJx/DugZ0">15</a></sup></p> <p>While the age modification to the new guidelines better addresses the disparities that impact the Black community (such as increased likelihood of early-onset breast cancer<sup><a href="https://paperpile.com/c/wiWWJx/zwQ0y">36</a></sup> and increased rate of breast cancer diagnosis at first mammogram<sup><a href="https://paperpile.com/c/wiWWJx/iQlAI">37</a></sup>), the next obvious question is: Can groups with higher breast cancer mortality such as Black communities afford to undergo mammography every 2 years (as opposed to every year)?<br/><br/>Although some data specifically have evaluated the age of initiation and frequency of screening mammography among Black patients,<sup><a href="https://paperpile.com/c/wiWWJx/Y67Dv+5Dny6">38,39</a></sup> little data have specifically assessed outcomes for annual versus biennial screening among Black people. Despite these research gaps, risk factors among the Black community should be considered. There is an increased risk of triple-negative breast cancer that can contribute to higher mortality among Black communities.<sup><a href="https://paperpile.com/c/wiWWJx/7T5WT">40</a></sup> Black people also tend to be diagnosed with more aggressive subtypes overall,<sup><a href="https://paperpile.com/c/wiWWJx/SDrrq+YrfeC">41,42</a></sup> are more likely to have dense breasts,<sup><a href="https://paperpile.com/c/wiWWJx/1QQSI+r6vhr">43,44</a></sup> have a higher likelihood of advanced stages at the time of diagnosis compared with White people,<sup><a href="https://paperpile.com/c/wiWWJx/cTjjd+f7iIp">8,45</a></sup> and have a greater chance of diagnosis of a second primary or contralateral breast cancer<sup><a href="https://paperpile.com/c/wiWWJx/kocI5+4N6aw+4UjGH">46-48</a></sup>—all risk factors that support the importance of regular and early-screening mammography.</p> <h2>How I counsel my patients</h2> <p>As Director of the Cancer Genetics and Breast Health Clinic, I am a gynecologist who primarily evaluates patients at increased risk for breast cancer (and other cancers). As an initial step, I strongly encourage all patients (especially Black patients and those of Ashkenazi Jewish ancestry as per the American College of Radiology recommendations<sup>9</sup>) to undergo risk assessment at age 25 to determine if they may be at increased risk for breast cancer. This first step may include genetic testing if the patient meets NCCN testing criteria based on personal or family history. If results are positive for a germline pathogenic variant, the timing and nature of breast screening would be based on NCCN recommendations for that particular variant (with possible modification of age of initiation based on family history). If testing is negative, lifetime risk assessment would then be performed using risk calculators—such as Tyrer-Cuzick—to determine if the patient meets criteria for intensive surveillance with supplemental breast magnetic resonance imaging. If the patient is subsequently determined to be at average risk after these assessments, I recommend they undergo screening mammography annually starting at age 40. However, it must be recognized that risk may change over time. A patient’s risk can continue to be assessed over a lifetime—with changing family history, personal risk factors, and new discoveries in genetics.</p> <h2>Summary</h2> <p>Ultimately, it is reassuring that the USPSTF guidelines have been updated to be concordant with other national medical society recommendations. They reflect the increasing nationwide trends that clearly demonstrate the high overall prevalence of breast cancer as well as the increasing incidence of early-onset breast cancer.</p> <p>The updated guidelines, however, do not reflect the entirety of breast cancer trends in this country. With breast cancer being the most commonly diagnosed cancer in the United States, it is imperative to consider the data that demonstrate improved prognostics with annual compared with biennial mammography. Furthermore, the guidelines only begin to explore the disparities that Black patients face regarding breast cancer–related mortality. The risks of younger age at diagnosis, greater likelihood of aggressive subtypes, increased risk of second primary and contralateral breast cancer, and later stage at diagnosis must be seriously evaluated when counseling this patient population.<br/><br/>While the USPSTF recommendations for age at initiation reflect national statistics, recommendations by the ACR and NCCN more appropriately recognize that the benefits of annual screening outweigh the potential risks. Annual screening frequency should be adopted when counseling patients, particularly for the Black community. ●</p> </itemContent> </newsItem> </itemSet></root>
Focus on long-COVID: Perimenopause and post-COVID chronic fatigue
Long COVID (postacute sequelae of SARS-CoV-2 infection, or PASC) is an emerging syndrome that affects 50% to 70% of people who survive COVID-19 for up to 3 months or longer after acute disease.1 It is a multisystem condition that causes dysfunction of respiratory, cardiac, and nervous tissue, at least in part likely due to alterations in cellular energy metabolism and reduced oxygen supply to tissue.3 Patients who have had SARS-CoV-2 infection report persistent symptoms and signs that affect their quality of life. These may include neurocognitive, cardiorespiratory, gastrointestinal, and musculoskeletal symptoms; loss of taste and smell; and constitutional symptoms.2 There is no one test to determine if symptoms are due to COVID-19.3
Acute COVID-19 mortality risk factors include increasing age, chronic comorbidities, and male sex. However, long COVID risk factors are quite different. A meta-analysis and review of 20 articles that met inclusion criteria (n = 13,340 study participants), limited by pooling of crude estimates, found that risk factors were female sex and severity of acute disease.4 A second meta-analysis of 37 studies with 1 preprint found that female sex and comorbidities such as pulmonary disease, diabetes, and obesity were risk factors for long COVID.5 Qualitative analysis of single studies (n = 18 study participants) suggested that older adults can develop more long COVID symptoms than younger adults, but this association between advancing age and long COVID was not supported when data were pooled into a meta-analysis.3 However, both single studies (n = 16 study participants) and the meta-analysis (n = 7 study participants) did support female sex as a risk factor for long COVID, along with single studies suggesting increased risk with medical comorbidities for pulmonary disease, diabetes, and organ transplantation.
Perimenopause
Perimenopause: A temporary disruption to physiologic ovarian steroid hormone production following COVID could acutely exacerbate symptoms of perimenopause and menopause.
JoAnn V. Pinkerton, MD, MSCP
The higher prevalence of long COVID in women younger than 50 years6 supports the overlap that studies have shown between symptoms of long COVID and perimenopause,7 as the median age of natural menopause is 51 years. Thus, health care providers need to differentiate between long COVID and other conditions, such as perimenopause, which share similar symptoms (FIGURE). Perimenopause might be diagnosed as long COVID, or the 2 might affect each other.
Symptoms of long COVID include fatigue, brain fog, and increased heart rate after recovering from COVID-19 and may continue or increase after an initial infection.8 Common symptoms of perimenopause and menopause, which also could be seen with long COVID, include typical menopausal symptoms such as hot flashes, night sweats, or disrupted sleep; changes in mood including dysthymia, depression, anxiety, or emotional lability; cognitive concerns such as brain fog or decreased concentration; and decreased stamina, fatigue, joint and muscle pains, or more frequent headaches. Therefore, women in their 40s or 50s with persistent symptoms after having COVID-19 without an alternative diagnosis, and who present with menstrual irregularity,9hot flashes, or night sweats, could be having an exacerbation of perimenopausal symptoms, or they could be experiencing a combination of long COVID and perimenopausal symptoms.
- Consider long COVID, versus perimenopause, or both, in women aged younger than 50 years
- Estradiol, which has been shown to alleviate perimenopausal and menopausal symptoms, also has been shown to have beneficial effects during acute COVID-19 infection
- Hormone therapy could improve symptoms of perimenopause and long COVID if some of the symptoms are due to changes in ovary function
Continue to: Potential pathophysiology...
Potential pathophysiology
Inflammation is likely to be critical in the pathogenesis of postacute sequelae of SARS-CoV-2 infection, or PASC. Individuals with long COVID have elevated inflammatory markers for several months.10 The chronic inflammation associated with long COVID could cause disturbances in the ovary and ovarian hormone production.2,10,11
During perimenopause, the ovary is more sensitive to illnesses such as COVID-19and to stress. The current theory is that COVID-19 affects the ovary with declines in ovarian reserve and ovarian function7 and with potential disruptions to the menstrual cycle, gonadal function, and ovarian sufficiency that lead to issues with menopause or fertility, as well as symptom exacerbation around menstruation.12 Another theory is that SARS-CoV-2 infection affects ovary hormone production, as there is an abundance of angiotensin-converting enzyme-2 receptors on ovarian and endometrial tissue.11 Thus, it makes sense that long COVID could bring on symptoms of perimenopause or menopause more acutely or more severely or lengthen the duration of perimenopausal symptoms.
Perimenopause is the transitional period prior to menopause, when the ovaries gradually produce fewer hormones and is associated with erratic hormonal fluctuations. The length of this transitional period varies from 4 to 10 years. Ethnic variations in the duration of hot flashes have been found, noting that Black and Hispanic women have them for an average of 8 to 10 years (longer), White women for an average of 7 years, and Asian, Japanese, and Chinese women for an average of 5 to 6 years (shorter).17
What should health care providers ask?
Distinguishing perimenopause from long COVID. It is important to try to differentiate between perimenopause and long COVID, and it is possible to have both, with long COVID exacerbating the menopausal symptoms.7,8 Health care providers should be alert to consider perimenopause if women present with shorter or longer cycles (21-40 days), missed periods (particularly 60 days or 2 months), or worsening perimenopausal mood, migraines, insomnia, or hot flashes. Clinicians should actively enquire about all of these symptoms.
Moreover, if a perimenopausal woman reports acutely worsening symptoms after COVID-19, health care providers should address the perimenopausal symptoms and determine whether hormone therapy is appropriate and could improve their symptoms. Women do not need to wait until they go 1 year without a period to be treated with hormone therapy to improve perimenopausal and menopausal symptoms. If women with long COVID have perimenopause or menopause symptoms, they should have access to evidence-based information and discuss menopausal hormone therapy if appropriate. Hormone therapy could improve both perimenopausal symptoms and the long COVID symptoms if some of the symptoms are due to changes in ovary function. Health care providers could consider progesterone or antidepressants during the second half of the cycle (luteal phase) or estrogen combined with progesterone for the entire cycle.18
For health care providers working in long COVID clinics, in addition to asking when symptoms started, what makes symptoms worse, the frequency of symptoms, and which activities are affected, ask about perimenopausal and menopausal symptoms. If a woman has irregular periods, sleep disturbances, fatigue, or mood changes, consider that these could be related to long COVID, perimenopause, or both.8,18 Be able to offer treatment or refer patients to a women’s health specialist who can assess and offer treatment.
A role for vitamin D? A recent retrospective case-matched study found that 6 months after hospital discharge, patients with long COVID had lower levels of 25(OH) vitamin D with the most notable symptom being brain fog.19 Thus, there may be a role for vitamin D supplementation as a preventive strategy in those being discharged after hospitalization. Vitamin D levels and supplementation have not been otherwise evaluated to date.
Lifestyle strategies for women with perimenopause and long COVID
Lifestyle strategies should be encouraged for women during perimenopause and long COVID. This includes good nutrition (avoiding carbs and sweets, particularly before menses), getting at least 7 hours of sleep and using sleep hygiene (regular bedtimes, sleep regimen, no late screens), getting regular exercise 5 days per week, reducing stress, avoiding excess alcohol, and not smoking. All of these factors can help women and their ovarian function during this period of ovarian fluctuations.
The timing of menopause and COVID may coincide with midlife stressors, including relationship issues (separations or divorce), health issues for the individual or their partner, widowhood, parenting challenges (care of young children, struggles with adolescents, grown children returning home), being childless, concerns about aging parents and caregiving responsibilities, as well as midlife career, community, or education issues—all of which make both long COVID and perimenopause more challenging to navigate.
Need for research
There is a need for future research to understand the epidemiologic basis and underlying biological mechanisms of sex differences seen in women with long COVID. Studying the effects of COVID-19 on ovarian function could lead to a better understanding of perimenopause, what causes ovarian failure to speed up, and possibly ways to slow it down8 since there are health risks of early menopause.16
References
- Fernández-de-Las-Peñas C, Palacios-Ceña D, GómezMayordomo V, et al. Defining post-COVID symptoms (postacute COVID, long COVID, persistent post-COVID): an integrative classification. Int J Environ Res Public Health. 2021;18:2621. doi: 10.3390/ijerph18052621
- Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601-615. doi: 10.1038/s41591 -021-01283-z
- Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022-00846-2
- Maglietta G, Diodati F, Puntoni M, et al. Prognostic factors for post-COVID-19 syndrome: a systematic review and meta-analysis. J Clin Med. 2022;11:1541. doi: 10.3390 /jcm11061541
- Notarte KI, de Oliveira MHS, Peligro PJ, et al. Age, sex and previous comorbidities as risk factors not associated with SARS-CoV-2 infection for long COVID-19: a systematic review and meta-analysis. J Clin Med. 2022;11:7314. doi: 10.3390 /jcm11247314
- Sigfrid L, Drake TM, Pauley E, et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. 2021;8:100186. doi: 10.1016/j.lanepe.2021.100186
- Pollack B, von Saltza E, McCorkell L, et al. Female reproductive health impacts of long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Front Rehabil Sci. 2023;4:1122673. doi: 10.3389/fresc.2023.1122673
- Stewart S, Newson L, Briggs TA, et al. Long COVID risk - a signal to address sex hormones and women’s health. Lancet Reg Health Eur. 2021;11:100242. doi: 10.1016 /j.lanepe.2021.100242
- Li K, Chen G, Hou H, et al. Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reprod Biomed Online. 2021;42:260-267. doi: 10.1016 /j.rbmo.2020.09.020
- Phetsouphanh C, Darley DR, Wilson DB, et al. Immunological dysfunction persists for 8 months following initial mild-tomoderate SARS-CoV-2 infection. Nat Immunol. 2022;23:210216. doi: 10.1038/s41590-021-01113-x
- Sharp GC, Fraser A, Sawyer G, et al. The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities. Int J Epidemiol. 2022;51:691-700. doi: 10.1093/ije/dyab239
- Ding T, Wang T, Zhang J, et al. Analysis of ovarian injury associated with COVID-19 disease in reproductive-aged women in Wuhan, China: an observational study. Front Med (Lausanne). 2021;8:635255. doi: 10.3389/fmed.2021.635255
- Huang B, Cai Y, Li N, et al. Sex-based clinical and immunological differences in COVID-19. BMC Infect Dis. 2021;21:647. doi: 10.1186/s12879-021-06313-2
- Connor J, Madhavan S, Mokashi M, et al. Health risks and outcomes that disproportionately affect women during the Covid-19 pandemic: a review. Soc Sci Med. 2020;266:113364. doi: 10.1016/j.socscimed.2020.113364
- Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, progesterone, immunomodulation, and COVID-19 outcomes. Endocrinology. 2020;161:bqaa127. doi:10.1210/endocr/bqaa127
- The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29:767-794. doi: 10.1097/GME.0000000000002028
- Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175:531-539. doi:10.1001 /jamainternmed.2014.8063
- Newson L, Lewis R, O’Hara M. Long COVID and menopause - the important role of hormones in long COVID must be considered. Maturitas. 2021;152:74. doi: 10.1016 /j.maturitas.2021.08.026
- di Filippo L, Frara S, Nannipieri F, et al. Low Vitamin D levels are associated with long COVID syndrome in COVID-19 survivors. J Clin Endocrinol Metab. 2023;108:e1106-e1116. doi: 10.1210/clinem/dgad207
Continue to: Chronic fatigue syndrome...
Chronic fatigue syndrome
Chronic fatigue syndrome: A large number of patients have “post-COVID conditions” affecting everyday function, including depression/anxiety, insomnia, and chronic fatigue (with a 3:1 female predominance)
Alexandra Kadl, MD
After 3 years battling acute COVID-19 infections, we encounter now a large number of patients with PASC— also known as “long COVID,” “COVID long-hauler syndrome,” and “post-COVID conditions”—a persistent multisystem syndrome that impacts everyday function.1 As of October 2023, there are more than 100 million COVID-19 survivors reported in the United States; 10% to 85% of COVID survivors2-4 may show lingering, life-altering symptoms after recovery. Common reported symptoms include fatigue, depression/ anxiety, insomnia, and brain fog/difficulty concentrating, which are particularly high in women who often had experienced only mild acute COVID-19 disease and were not even hospitalized. More recently, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as major component of PASC5 with a 3:1 female predominance.6 Up to 75% of patients with this diagnosis are not able to maintain their jobs and normal life, and up to 25% are so disabled that they are bedbound.6
Diagnosis
Although illnesses resembling CFS have been reported for more than 200 years,7 the diagnosis of CFS/ME remains difficult to make. There is a likely underreporting due to fear of being labeled as malingering when reaching out to health care providers, and there is a reporting bias toward higher socioeconomic groups due to better access to health care. The current criteria for the diagnosis of CFS/ME include the following 3 components8:
- substantial impairment in the ability to function for more than 6 months, accompanied by profound fatigue, not alleviated by rest
- post-exertional malaise (PEM; prolonged, disabling exacerbation of the patient’s baseline symptoms after exercise)
- non-refreshing sleep, PLUS either cognitive impairment or orthostatic intolerance.
Pathophysiology
Originally found to evolve in a small patient population with Epstein-Barr virus infection and Lyme disease, CFS/ME has moved to centerstage after the COVID-19 pandemic. While the diagnosis of COVID-19–related CFS/ME has advanced in the field, a clear mechanistic explanation of why it occurs is still missing. Certain risk factors have been identified for the development of CFS/ME, including female sex, reactivation of herpesviruses, and presence of connective tissue disorders; however, about one-third of patients with CFS/ME do not have identifiable risk factors.9,10 Persistence of viral particles11 and prolonged inflammatory states are speculated to affect the nervous system and mitochondrial function and metabolism. Interestingly, there is no correlation between severity of initial COVID-19 illness and the development of CFS/ME, similar to observations in non–COVID-19–related CFS/ME.
Proposed therapy
There is currently no proven therapy for CFS/ME. At this time, several immunomodulatory, antiviral, and neuromodulator drugs are being tested in clinical trial networks around the world.12 Usual physical therapy with near maximum intensity has been shown to exacerbate symptoms and often results in PEM, which is described as a “crash” or “full collapse” by patients. The time for recovery after such episodes can be several days.13
Instead, the focus should be on addressing “treatable” concomitant symptoms, such as sleep disorders, anxiety and depression, and chronic pain. Lifestyle changes, avoidance of triggers, and exercise without over exertion are currently recommended to avoid incapacitating PEM.
Gaps in knowledge
There is a large knowledge gap regarding the pathophysiology, prevention, and therapy for CFS/ME. Many health care practitioners are not familiar with the disease and have focused on measurable parameters of exercise limitations and fatigue, such as anemias and lung and cardiac impairments, thus treating CFS/ME as a form of deconditioning. Given the large number of patients who recovered from acute COVID-19 that are now disabled due to CFS/ME, a patient-centered research opportunity has arisen. Biomedical/mechanistic research is ongoing, and well-designed clinical trials evaluating pharmacologic intervention as well as tailored exercise programs are needed.
Conclusion
General practitioners and women’s health specialists need to be aware of CFS/ME, especially when managing patients with long COVID. They also need to know that typical physical therapy may worsen symptoms. Furthermore, clinicians should shy away from trial drugs with a theoretical benefit outside of a clinical trial. ●
- Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as a major component of PASC
- Typical physical therapy has been shown to exacerbate symptoms of CFS/ME
- Treatment should focus on addressing “treatable” concomitant symptoms, lifestyle changes, avoidance of triggers, and exercise without over exertion
References
- Soriano JB, Murthy S, Marshall JC, et al. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22:e102-e107. doi: 10.1016 /S1473-3099(21)00703-9
- Chen C, Haupert SR, Zimmermann L, et al. Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: a meta-analysis and systematic review. J Infect Dis. 2022;226:1593-1607. doi: 10.1093/infdis/jiac136
- Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022 -00846-2
- Pavli A, Theodoridou M, Maltezou HC. Post-COVID syndrome: incidence, clinical spectrum, and challenges for primary healthcare professionals. Arch Med Res. 2021;52:575-581. doi: 10.1016/j.arcmed.2021.03.010
- Kedor C, Freitag H, Meyer-Arndt L, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13:5104. doi: 10.1038/s41467-022-32507-6
- Bateman L, Bested AC, Bonilla HF, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin Proc. 2021;96:28612878. doi: 10.1016/j.mayocp.2021.07.004
- Wessely S. History of postviral fatigue syndrome. Br Med Bull. 1991;47:919-941. doi: 10.1093/oxfordjournals.bmb.a072521
- Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. National Academies Press; 2015. doi: 10.17226/19012
- Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93135. doi: 10.1016/j.bbi.2021.12.020
- Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019. doi: 10.1016/j.eclinm.2021.101019
- Hanson MR. The viral origin of myalgic encephalomyelitis/ chronic fatigue syndrome. PLoS Pathog. 2023;19:e1011523. doi: 10.1371/journal.ppat.1011523
- Scheibenbogen C, Bellmann-Strobl JT, Heindrich C, et al. Fighting post-COVID and ME/CFS—development of curative therapies. Front Med (Lausanne). 2023;10:1194754. doi: 10.3389/fmed.2023.1194754
- Stussman B, Williams A, Snow J, et al. Characterization of post-exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol. 2020;11:1025. doi: 10.3389/fneur.2020.01025
Long COVID (postacute sequelae of SARS-CoV-2 infection, or PASC) is an emerging syndrome that affects 50% to 70% of people who survive COVID-19 for up to 3 months or longer after acute disease.1 It is a multisystem condition that causes dysfunction of respiratory, cardiac, and nervous tissue, at least in part likely due to alterations in cellular energy metabolism and reduced oxygen supply to tissue.3 Patients who have had SARS-CoV-2 infection report persistent symptoms and signs that affect their quality of life. These may include neurocognitive, cardiorespiratory, gastrointestinal, and musculoskeletal symptoms; loss of taste and smell; and constitutional symptoms.2 There is no one test to determine if symptoms are due to COVID-19.3
Acute COVID-19 mortality risk factors include increasing age, chronic comorbidities, and male sex. However, long COVID risk factors are quite different. A meta-analysis and review of 20 articles that met inclusion criteria (n = 13,340 study participants), limited by pooling of crude estimates, found that risk factors were female sex and severity of acute disease.4 A second meta-analysis of 37 studies with 1 preprint found that female sex and comorbidities such as pulmonary disease, diabetes, and obesity were risk factors for long COVID.5 Qualitative analysis of single studies (n = 18 study participants) suggested that older adults can develop more long COVID symptoms than younger adults, but this association between advancing age and long COVID was not supported when data were pooled into a meta-analysis.3 However, both single studies (n = 16 study participants) and the meta-analysis (n = 7 study participants) did support female sex as a risk factor for long COVID, along with single studies suggesting increased risk with medical comorbidities for pulmonary disease, diabetes, and organ transplantation.
Perimenopause
Perimenopause: A temporary disruption to physiologic ovarian steroid hormone production following COVID could acutely exacerbate symptoms of perimenopause and menopause.
JoAnn V. Pinkerton, MD, MSCP
The higher prevalence of long COVID in women younger than 50 years6 supports the overlap that studies have shown between symptoms of long COVID and perimenopause,7 as the median age of natural menopause is 51 years. Thus, health care providers need to differentiate between long COVID and other conditions, such as perimenopause, which share similar symptoms (FIGURE). Perimenopause might be diagnosed as long COVID, or the 2 might affect each other.
Symptoms of long COVID include fatigue, brain fog, and increased heart rate after recovering from COVID-19 and may continue or increase after an initial infection.8 Common symptoms of perimenopause and menopause, which also could be seen with long COVID, include typical menopausal symptoms such as hot flashes, night sweats, or disrupted sleep; changes in mood including dysthymia, depression, anxiety, or emotional lability; cognitive concerns such as brain fog or decreased concentration; and decreased stamina, fatigue, joint and muscle pains, or more frequent headaches. Therefore, women in their 40s or 50s with persistent symptoms after having COVID-19 without an alternative diagnosis, and who present with menstrual irregularity,9hot flashes, or night sweats, could be having an exacerbation of perimenopausal symptoms, or they could be experiencing a combination of long COVID and perimenopausal symptoms.
- Consider long COVID, versus perimenopause, or both, in women aged younger than 50 years
- Estradiol, which has been shown to alleviate perimenopausal and menopausal symptoms, also has been shown to have beneficial effects during acute COVID-19 infection
- Hormone therapy could improve symptoms of perimenopause and long COVID if some of the symptoms are due to changes in ovary function
Continue to: Potential pathophysiology...
Potential pathophysiology
Inflammation is likely to be critical in the pathogenesis of postacute sequelae of SARS-CoV-2 infection, or PASC. Individuals with long COVID have elevated inflammatory markers for several months.10 The chronic inflammation associated with long COVID could cause disturbances in the ovary and ovarian hormone production.2,10,11
During perimenopause, the ovary is more sensitive to illnesses such as COVID-19and to stress. The current theory is that COVID-19 affects the ovary with declines in ovarian reserve and ovarian function7 and with potential disruptions to the menstrual cycle, gonadal function, and ovarian sufficiency that lead to issues with menopause or fertility, as well as symptom exacerbation around menstruation.12 Another theory is that SARS-CoV-2 infection affects ovary hormone production, as there is an abundance of angiotensin-converting enzyme-2 receptors on ovarian and endometrial tissue.11 Thus, it makes sense that long COVID could bring on symptoms of perimenopause or menopause more acutely or more severely or lengthen the duration of perimenopausal symptoms.
Perimenopause is the transitional period prior to menopause, when the ovaries gradually produce fewer hormones and is associated with erratic hormonal fluctuations. The length of this transitional period varies from 4 to 10 years. Ethnic variations in the duration of hot flashes have been found, noting that Black and Hispanic women have them for an average of 8 to 10 years (longer), White women for an average of 7 years, and Asian, Japanese, and Chinese women for an average of 5 to 6 years (shorter).17
What should health care providers ask?
Distinguishing perimenopause from long COVID. It is important to try to differentiate between perimenopause and long COVID, and it is possible to have both, with long COVID exacerbating the menopausal symptoms.7,8 Health care providers should be alert to consider perimenopause if women present with shorter or longer cycles (21-40 days), missed periods (particularly 60 days or 2 months), or worsening perimenopausal mood, migraines, insomnia, or hot flashes. Clinicians should actively enquire about all of these symptoms.
Moreover, if a perimenopausal woman reports acutely worsening symptoms after COVID-19, health care providers should address the perimenopausal symptoms and determine whether hormone therapy is appropriate and could improve their symptoms. Women do not need to wait until they go 1 year without a period to be treated with hormone therapy to improve perimenopausal and menopausal symptoms. If women with long COVID have perimenopause or menopause symptoms, they should have access to evidence-based information and discuss menopausal hormone therapy if appropriate. Hormone therapy could improve both perimenopausal symptoms and the long COVID symptoms if some of the symptoms are due to changes in ovary function. Health care providers could consider progesterone or antidepressants during the second half of the cycle (luteal phase) or estrogen combined with progesterone for the entire cycle.18
For health care providers working in long COVID clinics, in addition to asking when symptoms started, what makes symptoms worse, the frequency of symptoms, and which activities are affected, ask about perimenopausal and menopausal symptoms. If a woman has irregular periods, sleep disturbances, fatigue, or mood changes, consider that these could be related to long COVID, perimenopause, or both.8,18 Be able to offer treatment or refer patients to a women’s health specialist who can assess and offer treatment.
A role for vitamin D? A recent retrospective case-matched study found that 6 months after hospital discharge, patients with long COVID had lower levels of 25(OH) vitamin D with the most notable symptom being brain fog.19 Thus, there may be a role for vitamin D supplementation as a preventive strategy in those being discharged after hospitalization. Vitamin D levels and supplementation have not been otherwise evaluated to date.
Lifestyle strategies for women with perimenopause and long COVID
Lifestyle strategies should be encouraged for women during perimenopause and long COVID. This includes good nutrition (avoiding carbs and sweets, particularly before menses), getting at least 7 hours of sleep and using sleep hygiene (regular bedtimes, sleep regimen, no late screens), getting regular exercise 5 days per week, reducing stress, avoiding excess alcohol, and not smoking. All of these factors can help women and their ovarian function during this period of ovarian fluctuations.
The timing of menopause and COVID may coincide with midlife stressors, including relationship issues (separations or divorce), health issues for the individual or their partner, widowhood, parenting challenges (care of young children, struggles with adolescents, grown children returning home), being childless, concerns about aging parents and caregiving responsibilities, as well as midlife career, community, or education issues—all of which make both long COVID and perimenopause more challenging to navigate.
Need for research
There is a need for future research to understand the epidemiologic basis and underlying biological mechanisms of sex differences seen in women with long COVID. Studying the effects of COVID-19 on ovarian function could lead to a better understanding of perimenopause, what causes ovarian failure to speed up, and possibly ways to slow it down8 since there are health risks of early menopause.16
References
- Fernández-de-Las-Peñas C, Palacios-Ceña D, GómezMayordomo V, et al. Defining post-COVID symptoms (postacute COVID, long COVID, persistent post-COVID): an integrative classification. Int J Environ Res Public Health. 2021;18:2621. doi: 10.3390/ijerph18052621
- Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601-615. doi: 10.1038/s41591 -021-01283-z
- Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022-00846-2
- Maglietta G, Diodati F, Puntoni M, et al. Prognostic factors for post-COVID-19 syndrome: a systematic review and meta-analysis. J Clin Med. 2022;11:1541. doi: 10.3390 /jcm11061541
- Notarte KI, de Oliveira MHS, Peligro PJ, et al. Age, sex and previous comorbidities as risk factors not associated with SARS-CoV-2 infection for long COVID-19: a systematic review and meta-analysis. J Clin Med. 2022;11:7314. doi: 10.3390 /jcm11247314
- Sigfrid L, Drake TM, Pauley E, et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. 2021;8:100186. doi: 10.1016/j.lanepe.2021.100186
- Pollack B, von Saltza E, McCorkell L, et al. Female reproductive health impacts of long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Front Rehabil Sci. 2023;4:1122673. doi: 10.3389/fresc.2023.1122673
- Stewart S, Newson L, Briggs TA, et al. Long COVID risk - a signal to address sex hormones and women’s health. Lancet Reg Health Eur. 2021;11:100242. doi: 10.1016 /j.lanepe.2021.100242
- Li K, Chen G, Hou H, et al. Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reprod Biomed Online. 2021;42:260-267. doi: 10.1016 /j.rbmo.2020.09.020
- Phetsouphanh C, Darley DR, Wilson DB, et al. Immunological dysfunction persists for 8 months following initial mild-tomoderate SARS-CoV-2 infection. Nat Immunol. 2022;23:210216. doi: 10.1038/s41590-021-01113-x
- Sharp GC, Fraser A, Sawyer G, et al. The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities. Int J Epidemiol. 2022;51:691-700. doi: 10.1093/ije/dyab239
- Ding T, Wang T, Zhang J, et al. Analysis of ovarian injury associated with COVID-19 disease in reproductive-aged women in Wuhan, China: an observational study. Front Med (Lausanne). 2021;8:635255. doi: 10.3389/fmed.2021.635255
- Huang B, Cai Y, Li N, et al. Sex-based clinical and immunological differences in COVID-19. BMC Infect Dis. 2021;21:647. doi: 10.1186/s12879-021-06313-2
- Connor J, Madhavan S, Mokashi M, et al. Health risks and outcomes that disproportionately affect women during the Covid-19 pandemic: a review. Soc Sci Med. 2020;266:113364. doi: 10.1016/j.socscimed.2020.113364
- Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, progesterone, immunomodulation, and COVID-19 outcomes. Endocrinology. 2020;161:bqaa127. doi:10.1210/endocr/bqaa127
- The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29:767-794. doi: 10.1097/GME.0000000000002028
- Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175:531-539. doi:10.1001 /jamainternmed.2014.8063
- Newson L, Lewis R, O’Hara M. Long COVID and menopause - the important role of hormones in long COVID must be considered. Maturitas. 2021;152:74. doi: 10.1016 /j.maturitas.2021.08.026
- di Filippo L, Frara S, Nannipieri F, et al. Low Vitamin D levels are associated with long COVID syndrome in COVID-19 survivors. J Clin Endocrinol Metab. 2023;108:e1106-e1116. doi: 10.1210/clinem/dgad207
Continue to: Chronic fatigue syndrome...
Chronic fatigue syndrome
Chronic fatigue syndrome: A large number of patients have “post-COVID conditions” affecting everyday function, including depression/anxiety, insomnia, and chronic fatigue (with a 3:1 female predominance)
Alexandra Kadl, MD
After 3 years battling acute COVID-19 infections, we encounter now a large number of patients with PASC— also known as “long COVID,” “COVID long-hauler syndrome,” and “post-COVID conditions”—a persistent multisystem syndrome that impacts everyday function.1 As of October 2023, there are more than 100 million COVID-19 survivors reported in the United States; 10% to 85% of COVID survivors2-4 may show lingering, life-altering symptoms after recovery. Common reported symptoms include fatigue, depression/ anxiety, insomnia, and brain fog/difficulty concentrating, which are particularly high in women who often had experienced only mild acute COVID-19 disease and were not even hospitalized. More recently, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as major component of PASC5 with a 3:1 female predominance.6 Up to 75% of patients with this diagnosis are not able to maintain their jobs and normal life, and up to 25% are so disabled that they are bedbound.6
Diagnosis
Although illnesses resembling CFS have been reported for more than 200 years,7 the diagnosis of CFS/ME remains difficult to make. There is a likely underreporting due to fear of being labeled as malingering when reaching out to health care providers, and there is a reporting bias toward higher socioeconomic groups due to better access to health care. The current criteria for the diagnosis of CFS/ME include the following 3 components8:
- substantial impairment in the ability to function for more than 6 months, accompanied by profound fatigue, not alleviated by rest
- post-exertional malaise (PEM; prolonged, disabling exacerbation of the patient’s baseline symptoms after exercise)
- non-refreshing sleep, PLUS either cognitive impairment or orthostatic intolerance.
Pathophysiology
Originally found to evolve in a small patient population with Epstein-Barr virus infection and Lyme disease, CFS/ME has moved to centerstage after the COVID-19 pandemic. While the diagnosis of COVID-19–related CFS/ME has advanced in the field, a clear mechanistic explanation of why it occurs is still missing. Certain risk factors have been identified for the development of CFS/ME, including female sex, reactivation of herpesviruses, and presence of connective tissue disorders; however, about one-third of patients with CFS/ME do not have identifiable risk factors.9,10 Persistence of viral particles11 and prolonged inflammatory states are speculated to affect the nervous system and mitochondrial function and metabolism. Interestingly, there is no correlation between severity of initial COVID-19 illness and the development of CFS/ME, similar to observations in non–COVID-19–related CFS/ME.
Proposed therapy
There is currently no proven therapy for CFS/ME. At this time, several immunomodulatory, antiviral, and neuromodulator drugs are being tested in clinical trial networks around the world.12 Usual physical therapy with near maximum intensity has been shown to exacerbate symptoms and often results in PEM, which is described as a “crash” or “full collapse” by patients. The time for recovery after such episodes can be several days.13
Instead, the focus should be on addressing “treatable” concomitant symptoms, such as sleep disorders, anxiety and depression, and chronic pain. Lifestyle changes, avoidance of triggers, and exercise without over exertion are currently recommended to avoid incapacitating PEM.
Gaps in knowledge
There is a large knowledge gap regarding the pathophysiology, prevention, and therapy for CFS/ME. Many health care practitioners are not familiar with the disease and have focused on measurable parameters of exercise limitations and fatigue, such as anemias and lung and cardiac impairments, thus treating CFS/ME as a form of deconditioning. Given the large number of patients who recovered from acute COVID-19 that are now disabled due to CFS/ME, a patient-centered research opportunity has arisen. Biomedical/mechanistic research is ongoing, and well-designed clinical trials evaluating pharmacologic intervention as well as tailored exercise programs are needed.
Conclusion
General practitioners and women’s health specialists need to be aware of CFS/ME, especially when managing patients with long COVID. They also need to know that typical physical therapy may worsen symptoms. Furthermore, clinicians should shy away from trial drugs with a theoretical benefit outside of a clinical trial. ●
- Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as a major component of PASC
- Typical physical therapy has been shown to exacerbate symptoms of CFS/ME
- Treatment should focus on addressing “treatable” concomitant symptoms, lifestyle changes, avoidance of triggers, and exercise without over exertion
References
- Soriano JB, Murthy S, Marshall JC, et al. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22:e102-e107. doi: 10.1016 /S1473-3099(21)00703-9
- Chen C, Haupert SR, Zimmermann L, et al. Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: a meta-analysis and systematic review. J Infect Dis. 2022;226:1593-1607. doi: 10.1093/infdis/jiac136
- Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022 -00846-2
- Pavli A, Theodoridou M, Maltezou HC. Post-COVID syndrome: incidence, clinical spectrum, and challenges for primary healthcare professionals. Arch Med Res. 2021;52:575-581. doi: 10.1016/j.arcmed.2021.03.010
- Kedor C, Freitag H, Meyer-Arndt L, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13:5104. doi: 10.1038/s41467-022-32507-6
- Bateman L, Bested AC, Bonilla HF, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin Proc. 2021;96:28612878. doi: 10.1016/j.mayocp.2021.07.004
- Wessely S. History of postviral fatigue syndrome. Br Med Bull. 1991;47:919-941. doi: 10.1093/oxfordjournals.bmb.a072521
- Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. National Academies Press; 2015. doi: 10.17226/19012
- Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93135. doi: 10.1016/j.bbi.2021.12.020
- Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019. doi: 10.1016/j.eclinm.2021.101019
- Hanson MR. The viral origin of myalgic encephalomyelitis/ chronic fatigue syndrome. PLoS Pathog. 2023;19:e1011523. doi: 10.1371/journal.ppat.1011523
- Scheibenbogen C, Bellmann-Strobl JT, Heindrich C, et al. Fighting post-COVID and ME/CFS—development of curative therapies. Front Med (Lausanne). 2023;10:1194754. doi: 10.3389/fmed.2023.1194754
- Stussman B, Williams A, Snow J, et al. Characterization of post-exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol. 2020;11:1025. doi: 10.3389/fneur.2020.01025
Long COVID (postacute sequelae of SARS-CoV-2 infection, or PASC) is an emerging syndrome that affects 50% to 70% of people who survive COVID-19 for up to 3 months or longer after acute disease.1 It is a multisystem condition that causes dysfunction of respiratory, cardiac, and nervous tissue, at least in part likely due to alterations in cellular energy metabolism and reduced oxygen supply to tissue.3 Patients who have had SARS-CoV-2 infection report persistent symptoms and signs that affect their quality of life. These may include neurocognitive, cardiorespiratory, gastrointestinal, and musculoskeletal symptoms; loss of taste and smell; and constitutional symptoms.2 There is no one test to determine if symptoms are due to COVID-19.3
Acute COVID-19 mortality risk factors include increasing age, chronic comorbidities, and male sex. However, long COVID risk factors are quite different. A meta-analysis and review of 20 articles that met inclusion criteria (n = 13,340 study participants), limited by pooling of crude estimates, found that risk factors were female sex and severity of acute disease.4 A second meta-analysis of 37 studies with 1 preprint found that female sex and comorbidities such as pulmonary disease, diabetes, and obesity were risk factors for long COVID.5 Qualitative analysis of single studies (n = 18 study participants) suggested that older adults can develop more long COVID symptoms than younger adults, but this association between advancing age and long COVID was not supported when data were pooled into a meta-analysis.3 However, both single studies (n = 16 study participants) and the meta-analysis (n = 7 study participants) did support female sex as a risk factor for long COVID, along with single studies suggesting increased risk with medical comorbidities for pulmonary disease, diabetes, and organ transplantation.
Perimenopause
Perimenopause: A temporary disruption to physiologic ovarian steroid hormone production following COVID could acutely exacerbate symptoms of perimenopause and menopause.
JoAnn V. Pinkerton, MD, MSCP
The higher prevalence of long COVID in women younger than 50 years6 supports the overlap that studies have shown between symptoms of long COVID and perimenopause,7 as the median age of natural menopause is 51 years. Thus, health care providers need to differentiate between long COVID and other conditions, such as perimenopause, which share similar symptoms (FIGURE). Perimenopause might be diagnosed as long COVID, or the 2 might affect each other.
Symptoms of long COVID include fatigue, brain fog, and increased heart rate after recovering from COVID-19 and may continue or increase after an initial infection.8 Common symptoms of perimenopause and menopause, which also could be seen with long COVID, include typical menopausal symptoms such as hot flashes, night sweats, or disrupted sleep; changes in mood including dysthymia, depression, anxiety, or emotional lability; cognitive concerns such as brain fog or decreased concentration; and decreased stamina, fatigue, joint and muscle pains, or more frequent headaches. Therefore, women in their 40s or 50s with persistent symptoms after having COVID-19 without an alternative diagnosis, and who present with menstrual irregularity,9hot flashes, or night sweats, could be having an exacerbation of perimenopausal symptoms, or they could be experiencing a combination of long COVID and perimenopausal symptoms.
- Consider long COVID, versus perimenopause, or both, in women aged younger than 50 years
- Estradiol, which has been shown to alleviate perimenopausal and menopausal symptoms, also has been shown to have beneficial effects during acute COVID-19 infection
- Hormone therapy could improve symptoms of perimenopause and long COVID if some of the symptoms are due to changes in ovary function
Continue to: Potential pathophysiology...
Potential pathophysiology
Inflammation is likely to be critical in the pathogenesis of postacute sequelae of SARS-CoV-2 infection, or PASC. Individuals with long COVID have elevated inflammatory markers for several months.10 The chronic inflammation associated with long COVID could cause disturbances in the ovary and ovarian hormone production.2,10,11
During perimenopause, the ovary is more sensitive to illnesses such as COVID-19and to stress. The current theory is that COVID-19 affects the ovary with declines in ovarian reserve and ovarian function7 and with potential disruptions to the menstrual cycle, gonadal function, and ovarian sufficiency that lead to issues with menopause or fertility, as well as symptom exacerbation around menstruation.12 Another theory is that SARS-CoV-2 infection affects ovary hormone production, as there is an abundance of angiotensin-converting enzyme-2 receptors on ovarian and endometrial tissue.11 Thus, it makes sense that long COVID could bring on symptoms of perimenopause or menopause more acutely or more severely or lengthen the duration of perimenopausal symptoms.
Perimenopause is the transitional period prior to menopause, when the ovaries gradually produce fewer hormones and is associated with erratic hormonal fluctuations. The length of this transitional period varies from 4 to 10 years. Ethnic variations in the duration of hot flashes have been found, noting that Black and Hispanic women have them for an average of 8 to 10 years (longer), White women for an average of 7 years, and Asian, Japanese, and Chinese women for an average of 5 to 6 years (shorter).17
What should health care providers ask?
Distinguishing perimenopause from long COVID. It is important to try to differentiate between perimenopause and long COVID, and it is possible to have both, with long COVID exacerbating the menopausal symptoms.7,8 Health care providers should be alert to consider perimenopause if women present with shorter or longer cycles (21-40 days), missed periods (particularly 60 days or 2 months), or worsening perimenopausal mood, migraines, insomnia, or hot flashes. Clinicians should actively enquire about all of these symptoms.
Moreover, if a perimenopausal woman reports acutely worsening symptoms after COVID-19, health care providers should address the perimenopausal symptoms and determine whether hormone therapy is appropriate and could improve their symptoms. Women do not need to wait until they go 1 year without a period to be treated with hormone therapy to improve perimenopausal and menopausal symptoms. If women with long COVID have perimenopause or menopause symptoms, they should have access to evidence-based information and discuss menopausal hormone therapy if appropriate. Hormone therapy could improve both perimenopausal symptoms and the long COVID symptoms if some of the symptoms are due to changes in ovary function. Health care providers could consider progesterone or antidepressants during the second half of the cycle (luteal phase) or estrogen combined with progesterone for the entire cycle.18
For health care providers working in long COVID clinics, in addition to asking when symptoms started, what makes symptoms worse, the frequency of symptoms, and which activities are affected, ask about perimenopausal and menopausal symptoms. If a woman has irregular periods, sleep disturbances, fatigue, or mood changes, consider that these could be related to long COVID, perimenopause, or both.8,18 Be able to offer treatment or refer patients to a women’s health specialist who can assess and offer treatment.
A role for vitamin D? A recent retrospective case-matched study found that 6 months after hospital discharge, patients with long COVID had lower levels of 25(OH) vitamin D with the most notable symptom being brain fog.19 Thus, there may be a role for vitamin D supplementation as a preventive strategy in those being discharged after hospitalization. Vitamin D levels and supplementation have not been otherwise evaluated to date.
Lifestyle strategies for women with perimenopause and long COVID
Lifestyle strategies should be encouraged for women during perimenopause and long COVID. This includes good nutrition (avoiding carbs and sweets, particularly before menses), getting at least 7 hours of sleep and using sleep hygiene (regular bedtimes, sleep regimen, no late screens), getting regular exercise 5 days per week, reducing stress, avoiding excess alcohol, and not smoking. All of these factors can help women and their ovarian function during this period of ovarian fluctuations.
The timing of menopause and COVID may coincide with midlife stressors, including relationship issues (separations or divorce), health issues for the individual or their partner, widowhood, parenting challenges (care of young children, struggles with adolescents, grown children returning home), being childless, concerns about aging parents and caregiving responsibilities, as well as midlife career, community, or education issues—all of which make both long COVID and perimenopause more challenging to navigate.
Need for research
There is a need for future research to understand the epidemiologic basis and underlying biological mechanisms of sex differences seen in women with long COVID. Studying the effects of COVID-19 on ovarian function could lead to a better understanding of perimenopause, what causes ovarian failure to speed up, and possibly ways to slow it down8 since there are health risks of early menopause.16
References
- Fernández-de-Las-Peñas C, Palacios-Ceña D, GómezMayordomo V, et al. Defining post-COVID symptoms (postacute COVID, long COVID, persistent post-COVID): an integrative classification. Int J Environ Res Public Health. 2021;18:2621. doi: 10.3390/ijerph18052621
- Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601-615. doi: 10.1038/s41591 -021-01283-z
- Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022-00846-2
- Maglietta G, Diodati F, Puntoni M, et al. Prognostic factors for post-COVID-19 syndrome: a systematic review and meta-analysis. J Clin Med. 2022;11:1541. doi: 10.3390 /jcm11061541
- Notarte KI, de Oliveira MHS, Peligro PJ, et al. Age, sex and previous comorbidities as risk factors not associated with SARS-CoV-2 infection for long COVID-19: a systematic review and meta-analysis. J Clin Med. 2022;11:7314. doi: 10.3390 /jcm11247314
- Sigfrid L, Drake TM, Pauley E, et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. 2021;8:100186. doi: 10.1016/j.lanepe.2021.100186
- Pollack B, von Saltza E, McCorkell L, et al. Female reproductive health impacts of long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Front Rehabil Sci. 2023;4:1122673. doi: 10.3389/fresc.2023.1122673
- Stewart S, Newson L, Briggs TA, et al. Long COVID risk - a signal to address sex hormones and women’s health. Lancet Reg Health Eur. 2021;11:100242. doi: 10.1016 /j.lanepe.2021.100242
- Li K, Chen G, Hou H, et al. Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reprod Biomed Online. 2021;42:260-267. doi: 10.1016 /j.rbmo.2020.09.020
- Phetsouphanh C, Darley DR, Wilson DB, et al. Immunological dysfunction persists for 8 months following initial mild-tomoderate SARS-CoV-2 infection. Nat Immunol. 2022;23:210216. doi: 10.1038/s41590-021-01113-x
- Sharp GC, Fraser A, Sawyer G, et al. The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities. Int J Epidemiol. 2022;51:691-700. doi: 10.1093/ije/dyab239
- Ding T, Wang T, Zhang J, et al. Analysis of ovarian injury associated with COVID-19 disease in reproductive-aged women in Wuhan, China: an observational study. Front Med (Lausanne). 2021;8:635255. doi: 10.3389/fmed.2021.635255
- Huang B, Cai Y, Li N, et al. Sex-based clinical and immunological differences in COVID-19. BMC Infect Dis. 2021;21:647. doi: 10.1186/s12879-021-06313-2
- Connor J, Madhavan S, Mokashi M, et al. Health risks and outcomes that disproportionately affect women during the Covid-19 pandemic: a review. Soc Sci Med. 2020;266:113364. doi: 10.1016/j.socscimed.2020.113364
- Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, progesterone, immunomodulation, and COVID-19 outcomes. Endocrinology. 2020;161:bqaa127. doi:10.1210/endocr/bqaa127
- The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29:767-794. doi: 10.1097/GME.0000000000002028
- Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175:531-539. doi:10.1001 /jamainternmed.2014.8063
- Newson L, Lewis R, O’Hara M. Long COVID and menopause - the important role of hormones in long COVID must be considered. Maturitas. 2021;152:74. doi: 10.1016 /j.maturitas.2021.08.026
- di Filippo L, Frara S, Nannipieri F, et al. Low Vitamin D levels are associated with long COVID syndrome in COVID-19 survivors. J Clin Endocrinol Metab. 2023;108:e1106-e1116. doi: 10.1210/clinem/dgad207
Continue to: Chronic fatigue syndrome...
Chronic fatigue syndrome
Chronic fatigue syndrome: A large number of patients have “post-COVID conditions” affecting everyday function, including depression/anxiety, insomnia, and chronic fatigue (with a 3:1 female predominance)
Alexandra Kadl, MD
After 3 years battling acute COVID-19 infections, we encounter now a large number of patients with PASC— also known as “long COVID,” “COVID long-hauler syndrome,” and “post-COVID conditions”—a persistent multisystem syndrome that impacts everyday function.1 As of October 2023, there are more than 100 million COVID-19 survivors reported in the United States; 10% to 85% of COVID survivors2-4 may show lingering, life-altering symptoms after recovery. Common reported symptoms include fatigue, depression/ anxiety, insomnia, and brain fog/difficulty concentrating, which are particularly high in women who often had experienced only mild acute COVID-19 disease and were not even hospitalized. More recently, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as major component of PASC5 with a 3:1 female predominance.6 Up to 75% of patients with this diagnosis are not able to maintain their jobs and normal life, and up to 25% are so disabled that they are bedbound.6
Diagnosis
Although illnesses resembling CFS have been reported for more than 200 years,7 the diagnosis of CFS/ME remains difficult to make. There is a likely underreporting due to fear of being labeled as malingering when reaching out to health care providers, and there is a reporting bias toward higher socioeconomic groups due to better access to health care. The current criteria for the diagnosis of CFS/ME include the following 3 components8:
- substantial impairment in the ability to function for more than 6 months, accompanied by profound fatigue, not alleviated by rest
- post-exertional malaise (PEM; prolonged, disabling exacerbation of the patient’s baseline symptoms after exercise)
- non-refreshing sleep, PLUS either cognitive impairment or orthostatic intolerance.
Pathophysiology
Originally found to evolve in a small patient population with Epstein-Barr virus infection and Lyme disease, CFS/ME has moved to centerstage after the COVID-19 pandemic. While the diagnosis of COVID-19–related CFS/ME has advanced in the field, a clear mechanistic explanation of why it occurs is still missing. Certain risk factors have been identified for the development of CFS/ME, including female sex, reactivation of herpesviruses, and presence of connective tissue disorders; however, about one-third of patients with CFS/ME do not have identifiable risk factors.9,10 Persistence of viral particles11 and prolonged inflammatory states are speculated to affect the nervous system and mitochondrial function and metabolism. Interestingly, there is no correlation between severity of initial COVID-19 illness and the development of CFS/ME, similar to observations in non–COVID-19–related CFS/ME.
Proposed therapy
There is currently no proven therapy for CFS/ME. At this time, several immunomodulatory, antiviral, and neuromodulator drugs are being tested in clinical trial networks around the world.12 Usual physical therapy with near maximum intensity has been shown to exacerbate symptoms and often results in PEM, which is described as a “crash” or “full collapse” by patients. The time for recovery after such episodes can be several days.13
Instead, the focus should be on addressing “treatable” concomitant symptoms, such as sleep disorders, anxiety and depression, and chronic pain. Lifestyle changes, avoidance of triggers, and exercise without over exertion are currently recommended to avoid incapacitating PEM.
Gaps in knowledge
There is a large knowledge gap regarding the pathophysiology, prevention, and therapy for CFS/ME. Many health care practitioners are not familiar with the disease and have focused on measurable parameters of exercise limitations and fatigue, such as anemias and lung and cardiac impairments, thus treating CFS/ME as a form of deconditioning. Given the large number of patients who recovered from acute COVID-19 that are now disabled due to CFS/ME, a patient-centered research opportunity has arisen. Biomedical/mechanistic research is ongoing, and well-designed clinical trials evaluating pharmacologic intervention as well as tailored exercise programs are needed.
Conclusion
General practitioners and women’s health specialists need to be aware of CFS/ME, especially when managing patients with long COVID. They also need to know that typical physical therapy may worsen symptoms. Furthermore, clinicians should shy away from trial drugs with a theoretical benefit outside of a clinical trial. ●
- Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as a major component of PASC
- Typical physical therapy has been shown to exacerbate symptoms of CFS/ME
- Treatment should focus on addressing “treatable” concomitant symptoms, lifestyle changes, avoidance of triggers, and exercise without over exertion
References
- Soriano JB, Murthy S, Marshall JC, et al. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22:e102-e107. doi: 10.1016 /S1473-3099(21)00703-9
- Chen C, Haupert SR, Zimmermann L, et al. Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: a meta-analysis and systematic review. J Infect Dis. 2022;226:1593-1607. doi: 10.1093/infdis/jiac136
- Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022 -00846-2
- Pavli A, Theodoridou M, Maltezou HC. Post-COVID syndrome: incidence, clinical spectrum, and challenges for primary healthcare professionals. Arch Med Res. 2021;52:575-581. doi: 10.1016/j.arcmed.2021.03.010
- Kedor C, Freitag H, Meyer-Arndt L, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13:5104. doi: 10.1038/s41467-022-32507-6
- Bateman L, Bested AC, Bonilla HF, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin Proc. 2021;96:28612878. doi: 10.1016/j.mayocp.2021.07.004
- Wessely S. History of postviral fatigue syndrome. Br Med Bull. 1991;47:919-941. doi: 10.1093/oxfordjournals.bmb.a072521
- Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. National Academies Press; 2015. doi: 10.17226/19012
- Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93135. doi: 10.1016/j.bbi.2021.12.020
- Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019. doi: 10.1016/j.eclinm.2021.101019
- Hanson MR. The viral origin of myalgic encephalomyelitis/ chronic fatigue syndrome. PLoS Pathog. 2023;19:e1011523. doi: 10.1371/journal.ppat.1011523
- Scheibenbogen C, Bellmann-Strobl JT, Heindrich C, et al. Fighting post-COVID and ME/CFS—development of curative therapies. Front Med (Lausanne). 2023;10:1194754. doi: 10.3389/fmed.2023.1194754
- Stussman B, Williams A, Snow J, et al. Characterization of post-exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol. 2020;11:1025. doi: 10.3389/fneur.2020.01025
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Pinkerton, MD, MSCP</bylineText> <bylineFull/> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType>(choose one)</newsDocType> <journalDocType>(choose one)</journalDocType> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>Long COVID (postacute sequelae of SARS-CoV-2 infection, or PASC) is an emerging syndrome that affects 50% to 70% of people who survive COVID-19 for up to 3 mont</metaDescription> <articlePDF/> <teaserImage/> <title>Focus on long-COVID: Perimenopause and post-COVID chronic fatigue</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gyn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle>MDedge ObGyn</journalFullTitle> <copyrightStatement>2018</copyrightStatement> </publicationData> <publicationData> <publicationCode>obgm</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">49726</term> <term>24</term> </publications> <sections> <term canonical="true">49</term> </sections> <topics> <term canonical="true">63993</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Focus on long-COVID: Perimenopause and post-COVID chronic fatigue</title> <deck/> </itemMeta> <itemContent> <p>Long COVID (postacute sequelae of SARS-CoV-2 infection, or PASC) is an emerging syndrome that affects 50% to 70% of people who survive COVID-19 for up to 3 months or longer after acute disease.<sup>1</sup> It is a multisystem condition that causes dysfunction of respiratory, cardiac, and nervous tissue, at least in part likely due to alterations in cellular energy metabolism and reduced oxygen supply to tissue.<sup>3</sup> Patients who have had SARS-CoV-2 infection report persistent symptoms and signs that affect their quality of life. These may include neurocognitive, cardiorespiratory, gastrointestinal, and musculoskeletal symptoms; loss of taste and smell; and constitutional symptoms.<sup>2</sup> There is no one test to determine if symptoms are due to COVID-19.<sup>3</sup> </p> <p>Acute COVID-19 mortality risk factors include increasing age, chronic comorbidities, and male sex. However, long COVID risk factors are quite different. A meta-analysis and review of 20 articles that met inclusion criteria (n = 13,340 study participants), limited by pooling of crude estimates, found that risk factors were female sex and severity of acute disease.<sup>4</sup> A second meta-analysis of 37 studies with 1 preprint found that<i> </i>female sex and comorbidities such as pulmonary disease, diabetes, and obesity were risk factors for long COVID.<sup>5</sup> Qualitative analysis of single studies (n = 18 study participants) suggested that older adults can develop more long COVID symptoms than younger adults, but this association between advancing age and long COVID was not supported when data were pooled into a meta-analysis.<sup>3</sup> However, both single studies (n = 16 study participants) and the meta-analysis (n = 7 study participants) did support female sex as a risk factor for long COVID, along with single studies suggesting increased risk with medical comorbidities for pulmonary disease, diabetes, and organ transplantation.<sup><caps>5</caps></sup> In this discussion, we focus on long COVID and its relationship with perimenopause and chronic fatigue syndrome. </p> <h2> Perimenopause </h2> <p class="abstract"><b>Perimenopause:</b> A temporary disruption to physiologic ovarian steroid hormone production following COVID could acutely exacerbate symptoms of perimenopause and menopause. </p> <p>The higher prevalence of long COVID in women younger than 50 years<sup>6</sup> supports the overlap that studies have shown between symptoms of long COVID and perimenopause,<sup>7</sup> as the median age of natural menopause is 51 years. Thus, health care providers need to differentiate between long COVID and other conditions, such as perimenopause, which share similar symptoms (<strong>figure, </strong>page 16). Perimenopause might be diagnosed as long COVID, or the 2 might affect each other. </p> <p>Symptoms of long COVID include fatigue, brain fog, and increased heart rate after recovering from COVID-19 and may continue or increase after an initial infection.<sup>8</sup> Common symptoms of perimenopause and menopause, which also could be seen with long COVID, include typical menopausal symptoms such as hot flashes, night sweats, or disrupted sleep; changes in mood including dysthymia, depression, anxiety, or emotional lability; cognitive concerns such as brain fog or decreased concentration; and decreased stamina, fatigue, joint and muscle pains, or more frequent headaches. Therefore, women in their 40s or 50s with persistent symptoms after having COVID-19 without an alternative diagnosis, and who present with menstrual irregularity,<sup>9</sup><span class="element-citation"><sup> </sup></span>hot flashes, or night sweats, could be having an exacerbation of perimenopausal symptoms, or they could be experiencing a combination of long COVID and perimenopausal symptoms. </p> <h2>Potential pathophysiology</h2> <p>Inflammation is likely to be critical in the pathogenesis of postacute sequelae of SARS-CoV-2 infection, or PASC. Individuals with long COVID have elevated inflammatory markers for several months.<sup>10</sup> The chronic inflammation associated with long COVID could cause disturbances in the ovary and ovarian hormone production.<sup>2,10,11</sup> </p> <p>During perimenopause, the ovary is more sensitive to illnesses such as COVID-19and to stress. The current theory is that COVID-19 affects the ovary with declines in ovarian reserve and ovarian function<sup>7</sup> and with potential disruptions to the menstrual cycle, gonadal function, and ovarian sufficiency that lead to issues with menopause or fertility, as well as symptom exacerbation around menstruation.<sup>12</sup> Another theory is that SARS-CoV-2 infection affects ovary hormone production, as there is an abundance of angiotensin-converting enzyme-2 receptors on ovarian and endometrial tissue.<sup>11</sup> Thus, it makes sense that long COVID could bring on symptoms of perimenopause or menopause more acutely or more severely or lengthen the duration of perimenopausal symptoms. <br/><br/><hl name="377"/>Sex differentiation has been seen with regard to symptomatic COVID-19, with women generally faring better.<sup>13,14</sup><span class="element-citation"><sup> </sup></span>Estradiol has been shown to have beneficial effects during acute COVID-19.<sup>15</sup> With acute COVID-19 infection, women had lower mortality, lower levels of inflammation, higher lymphocyte counts, and faster antibody responses than men.<sup>13,14</sup> In addition, estradiol has been shown to help perimenopausal and menopausal hot flashes, night sweats, and sleep and to improve mood during perimenopause.<sup>16</sup> So it is likely that perimenopausal or menopausal symptomatic women with long COVID treated with estrogen would see improvements in their symptoms both due to the action of estradiol on the ovary as seen during COVID-19 and in perimenopause.<br/><br/>Perimenopause is the transitional period prior to menopause, when the ovaries gradually produce fewer hormones and is associated with erratic hormonal fluctuations. The length of this transitional period varies from 4 to 10 years. Ethnic variations in the duration of hot flashes have been found, noting that Black and Hispanic women have them for an average of 8 to 10 years (longer), White women for an average of 7 years, and Asian, Japanese, and Chinese women for an average of 5 to 6 years (shorter).<sup>17<hl name="378"/></sup> </p> <h2>What should health care providers ask?</h2> <p><span class="intro">Distinguishing perimenopause from long COVID.</span> It is important to try to differentiate between perimenopause and long COVID, and it is possible to have both, with long COVID exacerbating the menopausal symptoms.<sup>7,8</sup> Health care providers should be alert to consider perimenopause if women present with shorter or longer cycles (21-40 days), missed periods (particularly 60 days or 2 months), or worsening perimenopausal mood, migraines, insomnia, or hot flashes. Clinicians should actively enquire about all of these symptoms.</p> <p>Moreover, if a perimenopausal woman reports acutely worsening symptoms after COVID-19, health care providers should address the perimenopausal symptoms and determine whether hormone therapy is appropriate and could improve their symptoms. Women do not need to wait until they go 1 year without a period to be treated with hormone therapy to improve perimenopausal and menopausal symptoms. If women with long COVID have perimenopause or menopause symptoms, they should have access to evidence-based information and discuss menopausal hormone therapy if appropriate. Hormone therapy could improve both perimenopausal symptoms and the long COVID symptoms if some of the symptoms are due to changes in ovary function. Health care providers could consider progesterone or antidepressants during the second half of the cycle (luteal phase) or estrogen combined with progesterone for the entire cycle.<sup>18</sup></p> <p><span class="intro">For health care providers working in long COVID clinics,</span> in addition to asking when symptoms started, what makes symptoms worse, the frequency of symptoms, and which activities are affected, ask about perimenopausal and menopausal symptoms. If a woman has irregular periods, sleep disturbances, fatigue, or mood changes, consider that these could be related to long COVID, perimenopause, or both.<sup>8,18 </sup>Be able to offer treatment or refer patients to a women’s health specialist who can assess and offer treatment.<br/><br/><span class="intro">A role for vitamin D?</span> A recent retrospective case-matched study found that 6 months after hospital discharge, patients with long COVID had lower levels of 25(OH) vitamin D with the most notable symptom being brain fog.<sup>19</sup> Thus, there may be a role for vitamin D supplementation as a preventive strategy in those being discharged after hospitalization. Vitamin D levels and supplementation have not been otherwise evaluated to date.</p> <h2>Lifestyle strategies for women with perimenopause and long COVID</h2> <p>Lifestyle strategies should be encouraged for women during perimenopause and long COVID. This includes good nutrition (avoiding carbs and sweets, particularly before menses), getting at least 7 hours of sleep and using sleep hygiene (regular bedtimes, sleep regimen, no late screens), getting regular exercise 5 days per week, reducing stress, avoiding excess alcohol, and not smoking. All of these factors can help women and their ovarian function during this period of ovarian fluctuations.</p> <p>The timing of menopause and COVID may coincide with midlife stressors, including relationship issues (separations or divorce), health issues for the individual or their partner, widowhood, parenting challenges (care of young children, struggles with adolescents, grown children returning home), being childless, concerns about aging parents and caregiving responsibilities, as well as midlife career, community, or education issues—all of which make both long COVID and perimenopause more challenging to navigate. </p> <h2>Need for research</h2> <p>There is a need for future research to understand the epidemiologic basis and underlying biological mechanisms of sex differences seen in women with long COVID. Studying the effects of COVID-19 on ovarian function could lead to a better understanding of perimenopause, what causes ovarian failure to speed up, and possibly ways to slow it down<sup>8</sup> since there are health risks of early menopause.<sup>16</sup> </p> <p>After 3 years battling acute COVID-19 infections, we encounter now a large number of patients with PASC—also known as “long COVID,” “COVID long-hauler syndrome,” and “post-COVID conditions”—a persistent multisystem syndrome that impacts everyday function.<sup>1</sup> As of October 2023, there are more than 100 million COVID-19 survivors reported in the United States; 10% to 85% of COVID survivors<sup>2-4</sup> may show lingering, life-altering symptoms after recovery. Common reported symptoms include fatigue, depression/anxiety, insomnia, and brain fog/difficulty concentrating, which are particularly high in women who often had experienced only mild acute COVID-19 disease and were not even hospitalized. More recently, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as major component of PASC<sup>5</sup> with a 3:1 female predominance.<sup>6</sup> Up to 75% of patients with this diagnosis are not able to maintain their jobs and normal life, and up to 25% are so disabled that they are bedbound.<sup>6</sup></p> <h2>Diagnosis</h2> <p>Although illnesses resembling CFS have been reported for more than 200 years,<sup>7</sup> the diagnosis of CFS/ME remains difficult to make. There is a likely underreporting due to fear of being labeled as malingering when reaching out to health care providers, and there is a reporting bias toward higher socioeconomic groups due to better access to health care. The current criteria for the diagnosis of CFS/ME include the following 3 components<sup>8</sup>: </p> <ol class="Body"> <li>substantial impairment in the ability to function for more than 6 months, accompanied by profound fatigue, not alleviated by rest</li> <li>post-exertional malaise (PEM; prolonged, disabling exacerbation of the patient’s baseline symptoms after exercise)</li> <li>non-refreshing sleep, PLUS either cognitive impairment or orthostatic intolerance.</li> </ol> <h2>Pathophysiology</h2> <p>Originally found to evolve in a small patient population with Epstein-Barr virus infection and Lyme disease, CFS/ME has moved to centerstage after the COVID-19 pandemic. While the diagnosis of COVID-19–related CFS/ME has advanced in the field, a clear mechanistic explanation of why it occurs is still missing. Certain risk factors have been identified for the development of CFS/ME, including female sex, reactivation of herpesviruses, and presence of connective tissue disorders; however, about one-third of patients with CFS/ME do not have identifiable risk factors.<sup>9,10</sup> Persistence of viral particles<sup>11</sup> and prolonged inflammatory states are speculated to affect the nervous system and mitochondrial function and metabolism. Interestingly, there is no correlation between severity of initial COVID-19 illness and the development of CFS/ME, similar to observations in non–COVID-19–related CFS/ME.</p> <h2>Proposed therapy</h2> <p>There is currently no proven therapy for CFS/ME. At this time, several immunomodulatory, antiviral, and neuromodulator drugs are being tested in clinical trial networks around the world.<sup>12</sup> Usual physical therapy with near maximum intensity has been shown to exacerbate symptoms and often results in PEM, which is described as a “crash” or “full collapse” by patients. The time for recovery after such episodes can be several days.<sup>13</sup> </p> <p>Instead, the focus should be on addressing “treatable” concomitant symptoms, such as sleep disorders, anxiety and depression, and chronic pain. Lifestyle changes, avoidance of triggers, and exercise without over exertion are currently recommended to avoid incapacitating PEM.</p> <h2>Gaps in knowledge</h2> <p>There is a large knowledge gap regarding the pathophysiology, prevention, and therapy for CFS/ME. Many health care practitioners are not familiar with the disease and have focused on measurable parameters of exercise limitations and fatigue, such as anemias and lung and cardiac impairments, thus treating CFS/ME as a form of deconditioning. Given the large number of patients who recovered from acute COVID-19 that are now disabled due to CFS/ME, a patient-centered research opportunity has arisen. Biomedical/mechanistic research is ongoing, and well-designed clinical trials evaluating pharmacologic intervention as well as tailored exercise programs are needed. </p> <h2>Conclusion</h2> <p>General practitioners and women’s health specialists need to be aware of CFS/ME, especially when managing patients with long COVID. They also need to know that typical physical therapy may worsen symptoms. Furthermore, clinicians should shy away from trial drugs with a theoretical benefit outside of a clinical trial. ●</p> </itemContent> </newsItem> </itemSet></root>
Time to rethink endometrial ablation: A gyn oncology perspective on the sequelae of an overused procedure
CASE New patient presents with a history of endometrial hyperplasia
A 51-year-old patient (G2P2002) presents to a new gynecologist’s office after moving from a different state. In her medical history, the gynecologist notes that 5 years ago she underwent dilation and curettage and endometrial ablation procedures for heavy menstrual bleeding (HMB). Ultrasonography performed prior to those procedures showed a slightly enlarged uterus, a simple left ovarian cyst, and a non ̶ visualized right ovary. The patient had declined a 2-step procedure due to concerns with anesthesia, and surgical pathology at the time of ablation revealed hyperplasia without atypia. The patient’s medical history was otherwise notable for prediabetes (recent hemoglobin A1c [HbA1c] measurement, 6.0%) and obesity (body mass index, 43 kg/m2). Pertinent family history included her mother’s diagnosis of endometrial cancer at age 36. Given the patient’s diagnosis of endometrial hyperplasia, she was referred to gynecologic oncology, but she ultimately declined hysterectomy, stating that she was happy with the resolution of her abnormal bleeding. At the time of her initial gynecologic oncology consultation, the consultant suggested lifestyle changes to combat prediabetes and obesity to reduce the risk of endometrial cancer, as future signs of cancer, namely bleeding, may be masked by the endometrial ablation. The patient was prescribed metformin given these medical comorbidities.
At today’s appointment, the patient notes continued resolution of bleeding since the procedure. She does, however, note a 6-month history of vasomotor symptoms and one episode of spotting 3 months ago. Three years ago she was diagnosed with type 2 diabetes mellitus, and her current HbA1c is 6.9%. She has gained 10 lb since being diagnosed with endometrial cancer 5 years ago, and she has continued to take metformin.
An in-office endometrial biopsy is unsuccessful due to cervical stenosis. The treating gynecologist orders a transvaginal ultrasound, which reveals a small left ovarian cyst and a thickened endometrium (measuring 10 mm). Concerned that these findings could represent endometrial cancer, the gynecologist refers the patient to gynecologic oncology for further evaluation.
Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology (SGO) members revealed that 93.8% of respondents had received such a referral, and almost 20% of respondents were managing more than 20 patients with post-ablation complications in their practices.1 These complications, including hematometra, post-ablation tubal sterilization syndrome, other pain syndromes associated with retrograde menstruation, and thickened endometrium with scarring leading to an inability to sample the endometrium to investigate post-ablation bleeding are symptoms and findings that often lead to further surgery, including hysterectomy.2 General gynecologists faced with these complications may refer patients to gynecologic oncology given an inability to sample the post-ablation endometrium or anticipated difficulties with hysterectomy. A recent meta-analysis revealed a 12.4% hysterectomy rate 5 years after endometrial ablation. Among these patients, the incidence of endometrial cancer ranged from 0% to 1.6%.3
In 2023, endometrial cancer incidence continues to increase, as does the incidence of obesity in women of all ages. Endometrial cancer mortality rates are also increasing, and these trends disproportionately affects non-Hispanic Black women.4 As providers and advocates work to narrow these disparities, gynecologic oncologists are simultaneously noting increased referrals for very likely benign conditions.5 Patients referred for post-ablation bleeding are a subset of these, as most patients who undergo endometrial ablation will not develop cancer. Considering the potential bottlenecks created en route to a gynecologic oncology evaluation, it seems prudent to minimize practices, like endometrial ablation, that may directly or indirectly prevent timely referral of patients with cancer to a gynecologic oncologist.
In this review we focus on the current use of endometrial ablation, associated complications, the incidence of treatment failure, and patient selection. Considering these issues in the context of the current endometrial cancer landscape, we posit best practices aimed at optimizing patient outcomes, and empowering general gynecologists to practice cancer prevention and to triage their surgical patients.
- Before performing endometrial ablation, consider whether alternatives such as hysterectomy or insertion of a progestin-containing IUD would be appropriate.
- Clinical management of patients with abnormal bleeding with indications for endometrial ablation should be guidelinedriven.
- Post-ablation bleeding or pain does not inherently require referral to oncology.
- General gynecologists can perform hysterectomy in this setting if appropriate.
- Patients with endometrial hyperplasia at endometrial ablation should be promptly offered hysterectomy. If atypia is not present, this hysterectomy, too, can be performed by a general gynecologist if appropriate, as the chance for malignancy is minimal.
Continue to: Current use of endometrial ablation in the US...
Current use of endometrial ablation in the US
In 2015, more than 500,000 endometrial ablations were performed in the United States.Given the ability to perform in-office ablation, this number is growing and potentially underestimated each year.6 In 2022, the global endometrial ablation market was valued at $3.4 billion, a figure projected to double in 10 years.7 The procedure has evolved as different devices and approaches have developed, offering patients different means to manage bleeding without hysterectomy. The minimally invasive procedure, performed in premenopausal patients with heavy menstrual bleeding (HMB) due to benign causes who have completed childbearing, has been associated with faster recovery times and fewer short-term complications compared with more invasive surgery.8 There are several non-resectoscope ablative devices approved by the US Food and Drug Administration (FDA), and each work to destroy the endometrial lining via thermal or cryoablation. Endometrial ablation can be performed in premenopausal patients with HMB due to benign causes who have completed childbearing.
Recently, promotional literature has begun to report on so-called overuse of hysterectomy, despite decreasing overall hysterectomy rates. This reporting proposes and applies “appropriateness criteria,” accounting for the rate of preoperative counseling regarding alternatives to hysterectomy, as well as the rate of “unsupportive” final pathology.9 The adoption of endometrial ablation and increasing market value of such vendors suggest that this campaign is having its desired effect. From the oncology perspective, we are concerned the pendulum could swing too far away from hysterectomy, a procedure that definitively cures abnormal uterine bleeding, toward endometrial ablation without explicit acknowledgement of the trade-offs involved.
Endometrial ablation complications: Late-onset procedure failure
A number of post-ablation syndromes may present at least 1 month following the procedure. Collectively known as late-onset endometrial ablation failure (LOEAF), these syndromes are characterized by recurrent vaginal bleeding, and/or new cyclic pelvic pain.10 It is difficult to measure the true incidence of LOEAF. Thomassee and colleagues examined a Canadian retrospective cohort of 437 patients who underwent endometrial ablation; 20.8% reported post-ablation pelvic pain after a median 301 days.11 The subsequent need for surgical intervention, often hysterectomy, is a surrogate for LOEAF.
It should be noted that LOEAF is distinct from post-ablation tubal sterilization syndrome (PATSS), which describes cornual menstrual bleeding impeded by the ligated proximal fallopian tube.12 Increased awareness of PATSS, along with the discontinuation of Essure (a permanent hysteroscopic sterilization device) in 2018, has led some surgeons to advocate for concomitant salpingectomy at the time of endometrial ablation.13 The role of opportunistic salpingectomy in primary prevention of epithelial ovarian cancer is well described, and while we strongly support this practice at the time of endometrial ablation, we do not feel that it effectively prevents LOEAF.14
The post-ablation inability to adequately sample the endometrium is also considered a LOEAF. A prospective study of 57 women who underwent endometrial ablation assessed post-ablation sampling feasibility via transvaginal ultrasonography, saline infusion sonohysterography (SIS), and in-office endometrial biopsies. In 23% of the cohort, endometrial sampling failed, and the authors noted decreased reliability of pathologic assessment.15 One systematic review, in which authors examined the incidence of endometrial cancer following endometrial ablation, characterized 38 cases of endometrial cancer and reported a post-ablation endometrial sampling success rate of 89%. This figure was based on a self-selected sample of 18 patients; cases in which endometrial sampling was thought to be impossible were excluded. The study also had a 30% missing data rate and several other biases.16
In the previously mentioned poll of SGO members,1 84% of the surveyed gynecologic oncologists managing post-ablation patients reported that endometrial sampling following endometrial ablation was “moderately” or “extremely” difficult. More than half of the survey respondents believed that hysterectomy was required for accurate diagnosis.1 While we acknowledge the likely sampling bias affecting the survey results, we are not comforted by any data that minimizes this diagnostic challenge.
Appropriate patient selection and contraindications
The ideal candidate for endometrial ablation is a premenopausal patient with HMB who does not desire future fertility. According to the FDA, absolute contraindications include pregnancy or desired fertility, prior ablation, current IUD in place, inadequate preoperative endometrial assessment, known or suspected malignancy, active infection, or unfavorable anatomy.17
What about patients who may be at increased risk for endometrial cancer?
There is a paucity of data regarding the safety of endometrial ablation in patients at increased risk for developing endometrial cancer in the future. The American College of Obstetricians and Gynecologists (ACOG) 2007 practice bulletin on endometrial ablation (no longer accessible online) alludes to this concern and other contraindications,18 but there are no established guidelines. Currently, no ACOG practice bulletin or committee opinion lists relative contraindications to endometrial ablation, long-term complications (except risks associated with future pregnancy), or risk of subsequent hysterectomy. The risk that “it may be harder to detect endometrial cancer after ablation” is noted on ACOG’s web page dedicated to frequently asked questions (FAQs) regarding abnormal uterine bleeding.19 It is not mentioned on their web page dedicated to the FAQs regarding endometrial ablation.20
In the absence of high-quality published data on established contraindications for endometrial ablation, we advocate for the increased awareness of possible relative contraindications—namely well-established risk factors for endometrial cancer (TABLE 1).For example, in a pooled analysis of 24 epidemiologic studies, authors found that the odds of developing endometrial cancer was 7 times higher among patients with a body mass index (BMI) ≥ 40 kg/m2, compared with controls (odds ratio [OR], 7.14; 95% confidence interval [CI], 6.33–8.06).21 Additionally, patients with Lynch syndrome, a history of extended tamoxifen use, or those with a history of chronic anovulation or polycystic ovary syndrome are at increased risk for endometrial cancer.22-24 If the presence of one or more of these factors does not dissuade general gynecologists from performing an endometrial ablation (even armed with a negative preoperative endometrial biopsy), we feel they should at least prompt thoughtful guideline-driven pause.
Continue to: Hysterectomy—A disincentivized option...
Hysterectomy—A disincentivized option
The annual number of hysterectomies performed by general gynecologists has declined over time. One study by Cadish and colleagues revealed that recent residency graduates performed only 3 to 4 annually.25 These numbers partly reflect the decreasing number of hysterectomies performed during residency training. Furthermore, other factors—including the increasing rate of placenta accreta spectrum, the focus on risk stratification of adnexal masses via the ovarian-adnexal reporting and data classification system (O-RADs), and the emphasis on minimally invasive approaches often acquired in subspecialty training—have likely contributed to referral patterns to such specialists as minimally invasive gynecologic surgeons and gynecologic oncologists.26 This trend is self-actualizing, as quality metrics funnel patients to high-volume surgeons, and general gynecologists risk losing hysterectomy privileges.
These factors lend themselves to a growing emphasis on endometrial ablation. Endometrial ablations can be performed in several settings, including in the hospital, in outpatient clinics, and more and more commonly, in ambulatory surgery centers. This increased access to endometrial ablation in the ambulatory surgery setting has corresponded with an annual endometrial ablation market value growth rate of 5% to 7%.27 These rates are likely compounded by payer reimbursement policies that promote endometrial ablation and other alternatives to hysterectomy that are cost savings in the short term.28 While the actual payer models are unavailable to review, they may not consider the costs of LOEAFs, including subsequent hysterectomy up to 5 years after initial ablation procedures. Provocatively, they almost certainly do not consider the costs of delayed care of patients with endometrial cancer vying for gynecologic oncology appointment slots occupied by post-ablation patients.
We urge providers, patients, and advocates to question who benefits from the uptake of ablation procedures: Patients? Payors? Providers? And how will the field of gynecology fare if hysterectomy skills and privileges are supplanted by ablation?
Post-ablation bleeding: Management by the gyn oncologist
Patients with post-ablation bleeding, either immediately or years later, are sometimes referred to a gynecologic oncologist given the possible risk for cancer and need for surgical staging if cancer is found on the hysterectomy specimen. In practice, assuming normal preoperative ultrasonography and no other clinical or radiologic findings suggestive of malignancy (eg, computed tomography findings concerning for metastases, abnormal cervical cytology, etc.), the presence of cancer is extremely unlikely to be determined at the time of surgery. Frozen section is not generally performed on the endometrium; intraoperative evaluation of even the unablated endometrium is notoriously unreliable; and histologic assessment of the ablated endometrium is limited by artifact (FIGURE 1). The abnormalities caused by ablation further impede selection of a representative focus, obfuscating any actionable result.
Some surgeons routinely bivalve the excised uterus prior to fixation to assess presence of tumor, tumor size, and the degree of myometrial invasion.29 A combination of factors may compel surgeons to perform lymphadenectomy if not already performed, or if sentinel lymph node mapping was unsuccessful. But this practice has not been studied in patients with post-ablation bleeding, and applying these principles relies on a preoperative diagnosis establishing the presence and grade of a cancer. Furthermore, the utility of frozen section and myometrial assessment to decide whether or not to proceed with lymphadenectomy is less relevant in the era of molecular classification guiding adjuvant therapy. In summary, assuming no pathologic or radiologic findings suggestive of cancer, gynecologic oncologists are unlikely to perform lymphadenectomy at the time of hysterectomy in these post-ablation cases, which therefore can safely be performed by general gynecologists.
Our recommendations
Consider the LNG-IUD as an alternative to ablation. A recent randomized controlled trial by Beelen and colleagues compared the effectiveness of LNG-releasing IUDs with endometrial ablation in patients with HMB. While the LNG-IUD was inferior to endometrial ablation, quality-of-life measures were similar up to 2 years.31 Realizing that the hysterectomy rate following endometrial ablation increases significantly beyond that time point (2 years), this narrative may be incomplete. A 5- to 10-year follow-up time-frame may be a more helpful gauge of long-term outcomes. This prolonged time-frame also may allow study of the LNG-IUD’s protective effects on the endometrium in the prevention of endometrial hyperplasia and cancer.
Consider hysterectomy. A 2021 Cochrane review revealed that, compared with endometrial ablation, minimally invasive hysterectomy is associated with higher quality-of-life metrics, higher self-reported patient satisfaction, and similar rates of adverse events.32 While patient autonomy is paramount, the developing step-wise approach from endometrial ablation to hysterectomy, and its potential effects on the health care system at a time when endometrial cancer incidence and mortality rates are rising, is troubling.
Postablation, consider hysterectomy by the general gynecologist. Current trends appear to disincentivize general gynecologists from performing hysterectomy either for HMB or LOEAF. We would offer reassurance that they can safely perform this procedure. Referral to oncology may not be necessary since, in the absence of an established diagnosis of cancer, a lymphadenectomy is not typically required. A shift away from referral for these patients can preserve access to oncology for those women, especially minority women, with an explicit need for oncologic care.
In FIGURE 2, we propose a management algorithm for the patient who presents with post–ablation bleeding. We acknowledge that the evidence base for our management recommendations is limited. Still, we hope providers, ACOG, and other guidelines-issuing organizations consider them as they adapt their own practices and recommendations. We believe this is one of many steps needed to improve outcomes for patients with gynecologic cancer, particularly those in marginalized communities disproportionately impacted by current trends.
CASE Resolution
After reviewing the relevant documentation and examining the patient, the gynecologic oncology consultant contacts the referring gynecologist. They review the low utility of frozen section and the overall low risk of cancer on the final hysterectomy specimen if the patient were to undergo hysterectomy. The consultant clarifies that there is no other concern for surgical complexity beyond the skill of the referring provider, and they discuss the possibility of referral to a minimally invasive specialist for the surgery.
Ultimately, the patient undergoes uncomplicated laparoscopic hysterectomy performed by the original referring gynecologist. Final pathology reveals inactive endometrium with ablative changes and cornual focus of endometrial hyperplasia without atypia. ●
Acknowledgement
The authors acknowledge Ian Hagemann, MD, PhD, for his review of the manuscript.
- Chen H, Saiz AM, McCausland AM, et al. Experience of gynecologic oncologists regarding endometrial cancer after endometrial ablation. J Clin Oncol. 2018;36:e17566-e.
- McCausland AM, McCausland VM. Long-term complications of endometrial ablation: cause, diagnosis, treatment, and prevention. J Minim Invasive Gynecol. 2007;14:399-406.
- Oderkerk TJ, Beelen P, Bukkems ALA, et al. Risk of hysterectomy after endometrial ablation: a systematic review and meta-analysis. Obstet Gynecol. 2023;142:51-60.
- Clarke MA, Devesa SS, Hammer A, et al. Racial and ethnic differences in hysterectomy-corrected uterine corpus cancer mortality by stage and histologic subtype. JAMA Oncol. 2022;8:895-903.
- Barber EL, Rossi EC, Alexander A, et al. Benign hysterectomy performed by gynecologic oncologists: is selection bias altering our ability to measure surgical quality? Gynecol Oncol. 2018;151:141-144.
- Wortman M. Late-onset endometrial ablation failure. Case Rep Womens Health. 2017;15:11-28.
- Insights FM. Endometrial Ablation Market Outlook.Accessed July 26, 2023. https://www.futuremarketinsights.com/reports/endometrial-ablation -market
- Famuyide A. Endometrial ablation. J Minim Invasive Gynecol. 2018;25:299-307.
- Corona LE, Swenson CW, Sheetz KH, et al. Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative. Am J Obstet Gynecol. 2015;212:304.e1-e7.
- Wortman M, Cholkeri A, McCausland AM, et al. Late-onset endometrial ablation failure—etiology, treatment, and prevention. J Minim Invasive Gynecol. 2015;22:323-331.
- Thomassee MS, Curlin H, Yunker A, et al. Predicting pelvic pain after endometrial ablation: which preoperative patient characteristics are associated? J Minim Invasive Gynecol. 2013;20:642-647.
- Townsend DE, McCausland V, McCausland A, et al. Post-ablation-tubal sterilization syndrome. Obstet Gynecol. 1993;82:422-424.
- Greer Polite F, DeAgostino-Kelly M, Marchand GJ. Combination of laparoscopic salpingectomy and endometrial ablation: a potentially underused procedure. J Gynecol Surg. 2021;37:89-91.
- Hanley GE, Pearce CL, Talhouk A, et al. Outcomes from opportunistic salpingectomy for ovarian cancer prevention. JAMA Network Open. 2022;5:e2147343-e.
- Ahonkallio SJ, Liakka AK, Martikainen HK, et al. Feasibility of endometrial assessment after thermal ablation. Eur J Obstet Gynecol Reprod Biol. 2009;147:69-71.
- Tamara JO, Mileen RDvdK, Karlijn MCC, et al. Endometrial cancer after endometrial ablation: a systematic review. Int J Gynecol Cancer. 2022;32:1555.
- US Food and Drug Administration. Endometrial ablation for heavy menstrual bleeding.Accessed July 26, 2023. https://www.fda.gov/medical-devices /surgery-devices/endometrial-ablation-heavy-menstrual-bleeding
- ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists. Number 81, May 2007. Obstet Gynecol. 2007;109:1233-1248.
- The American College of Obstetricians and Gynecologists. Abnormal uterine bleeding frequently asked questions. Accessed July 26, 2023. https://www.acog .org/womens-health/faqs/abnormal-uterine-bleeding
- The American College of Obstetricians and Gynecologists. Endometrial ablation frequently asked questions. Accessed November 28, 2023. https://www.acog. org/womens-health/faqs/endometrial-ablation#:~:text=Can%20I%20still%20 get%20pregnant,should%20not%20have%20this%20procedure
- Setiawan VW, Yang HP, Pike MC, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol. 2013;31:2607-2618.
- National Comprehensive Cancer Network. Lynch Syndrome (Version 2.2023). Accessed November 15, 2023. https://www.nccn.org/professionals /physician_gls/pdf/genetics_colon.pdf
- Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305: 2304-2310.
- Fleming CA, Heneghan HM, O’Brien D, et al. Meta-analysis of the cumulative risk of endometrial malignancy and systematic review of endometrial surveillance in extended tamoxifen therapy. Br J Surg. 2018;105:1098-1106.
- Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2014;20:748-758.
- Cadish LA, Kropat G, Muffly TM. Hysterectomy volume among recent obstetrics and gynecology residency graduates. Urogynecology. 2021;27.
- Blank SV, Huh WK, Bell M, et al. Doubling down on the future of gynecologic oncology: the SGO future of the profession summit report. Gynecol Oncol. 2023;171:76-82.
- Reports MI. Global endometrial ablation market growth, trends and forecast 2023 to 2028 by types, by application, by regions and by key players like Boston Scientific, Hologic, Olympus, Minerva Surgical. Accessed July 30, 2023. https://www.marketinsightsreports.com/single-report/061612632440/global -endometrial-ablation-market-growth-trends-and-forecast-2023-to-2028-by -types-by-application-by-regions-and-by-key-players-like-boston-scientific -hologic-olympus-minerva-surgical
- London R, Holzman M, Rubin D, et al. Payer cost savings with endometrial ablation therapy. Am J Manag Care. 1999;5:889-897.
- Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11-18.
- Beelen P, van den Brink MJ, Herman MC, et al. Levonorgestrel-releasing intrauterine system versus endometrial ablation for heavy menstrual bleeding. Am J Obstet Gynecol. 2021;224:187.e1-e10.
- Bofill Rodriguez M, Lethaby A, Fergusson RJ. Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2021;2:Cd000329.
CASE New patient presents with a history of endometrial hyperplasia
A 51-year-old patient (G2P2002) presents to a new gynecologist’s office after moving from a different state. In her medical history, the gynecologist notes that 5 years ago she underwent dilation and curettage and endometrial ablation procedures for heavy menstrual bleeding (HMB). Ultrasonography performed prior to those procedures showed a slightly enlarged uterus, a simple left ovarian cyst, and a non ̶ visualized right ovary. The patient had declined a 2-step procedure due to concerns with anesthesia, and surgical pathology at the time of ablation revealed hyperplasia without atypia. The patient’s medical history was otherwise notable for prediabetes (recent hemoglobin A1c [HbA1c] measurement, 6.0%) and obesity (body mass index, 43 kg/m2). Pertinent family history included her mother’s diagnosis of endometrial cancer at age 36. Given the patient’s diagnosis of endometrial hyperplasia, she was referred to gynecologic oncology, but she ultimately declined hysterectomy, stating that she was happy with the resolution of her abnormal bleeding. At the time of her initial gynecologic oncology consultation, the consultant suggested lifestyle changes to combat prediabetes and obesity to reduce the risk of endometrial cancer, as future signs of cancer, namely bleeding, may be masked by the endometrial ablation. The patient was prescribed metformin given these medical comorbidities.
At today’s appointment, the patient notes continued resolution of bleeding since the procedure. She does, however, note a 6-month history of vasomotor symptoms and one episode of spotting 3 months ago. Three years ago she was diagnosed with type 2 diabetes mellitus, and her current HbA1c is 6.9%. She has gained 10 lb since being diagnosed with endometrial cancer 5 years ago, and she has continued to take metformin.
An in-office endometrial biopsy is unsuccessful due to cervical stenosis. The treating gynecologist orders a transvaginal ultrasound, which reveals a small left ovarian cyst and a thickened endometrium (measuring 10 mm). Concerned that these findings could represent endometrial cancer, the gynecologist refers the patient to gynecologic oncology for further evaluation.
Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology (SGO) members revealed that 93.8% of respondents had received such a referral, and almost 20% of respondents were managing more than 20 patients with post-ablation complications in their practices.1 These complications, including hematometra, post-ablation tubal sterilization syndrome, other pain syndromes associated with retrograde menstruation, and thickened endometrium with scarring leading to an inability to sample the endometrium to investigate post-ablation bleeding are symptoms and findings that often lead to further surgery, including hysterectomy.2 General gynecologists faced with these complications may refer patients to gynecologic oncology given an inability to sample the post-ablation endometrium or anticipated difficulties with hysterectomy. A recent meta-analysis revealed a 12.4% hysterectomy rate 5 years after endometrial ablation. Among these patients, the incidence of endometrial cancer ranged from 0% to 1.6%.3
In 2023, endometrial cancer incidence continues to increase, as does the incidence of obesity in women of all ages. Endometrial cancer mortality rates are also increasing, and these trends disproportionately affects non-Hispanic Black women.4 As providers and advocates work to narrow these disparities, gynecologic oncologists are simultaneously noting increased referrals for very likely benign conditions.5 Patients referred for post-ablation bleeding are a subset of these, as most patients who undergo endometrial ablation will not develop cancer. Considering the potential bottlenecks created en route to a gynecologic oncology evaluation, it seems prudent to minimize practices, like endometrial ablation, that may directly or indirectly prevent timely referral of patients with cancer to a gynecologic oncologist.
In this review we focus on the current use of endometrial ablation, associated complications, the incidence of treatment failure, and patient selection. Considering these issues in the context of the current endometrial cancer landscape, we posit best practices aimed at optimizing patient outcomes, and empowering general gynecologists to practice cancer prevention and to triage their surgical patients.
- Before performing endometrial ablation, consider whether alternatives such as hysterectomy or insertion of a progestin-containing IUD would be appropriate.
- Clinical management of patients with abnormal bleeding with indications for endometrial ablation should be guidelinedriven.
- Post-ablation bleeding or pain does not inherently require referral to oncology.
- General gynecologists can perform hysterectomy in this setting if appropriate.
- Patients with endometrial hyperplasia at endometrial ablation should be promptly offered hysterectomy. If atypia is not present, this hysterectomy, too, can be performed by a general gynecologist if appropriate, as the chance for malignancy is minimal.
Continue to: Current use of endometrial ablation in the US...
Current use of endometrial ablation in the US
In 2015, more than 500,000 endometrial ablations were performed in the United States.Given the ability to perform in-office ablation, this number is growing and potentially underestimated each year.6 In 2022, the global endometrial ablation market was valued at $3.4 billion, a figure projected to double in 10 years.7 The procedure has evolved as different devices and approaches have developed, offering patients different means to manage bleeding without hysterectomy. The minimally invasive procedure, performed in premenopausal patients with heavy menstrual bleeding (HMB) due to benign causes who have completed childbearing, has been associated with faster recovery times and fewer short-term complications compared with more invasive surgery.8 There are several non-resectoscope ablative devices approved by the US Food and Drug Administration (FDA), and each work to destroy the endometrial lining via thermal or cryoablation. Endometrial ablation can be performed in premenopausal patients with HMB due to benign causes who have completed childbearing.
Recently, promotional literature has begun to report on so-called overuse of hysterectomy, despite decreasing overall hysterectomy rates. This reporting proposes and applies “appropriateness criteria,” accounting for the rate of preoperative counseling regarding alternatives to hysterectomy, as well as the rate of “unsupportive” final pathology.9 The adoption of endometrial ablation and increasing market value of such vendors suggest that this campaign is having its desired effect. From the oncology perspective, we are concerned the pendulum could swing too far away from hysterectomy, a procedure that definitively cures abnormal uterine bleeding, toward endometrial ablation without explicit acknowledgement of the trade-offs involved.
Endometrial ablation complications: Late-onset procedure failure
A number of post-ablation syndromes may present at least 1 month following the procedure. Collectively known as late-onset endometrial ablation failure (LOEAF), these syndromes are characterized by recurrent vaginal bleeding, and/or new cyclic pelvic pain.10 It is difficult to measure the true incidence of LOEAF. Thomassee and colleagues examined a Canadian retrospective cohort of 437 patients who underwent endometrial ablation; 20.8% reported post-ablation pelvic pain after a median 301 days.11 The subsequent need for surgical intervention, often hysterectomy, is a surrogate for LOEAF.
It should be noted that LOEAF is distinct from post-ablation tubal sterilization syndrome (PATSS), which describes cornual menstrual bleeding impeded by the ligated proximal fallopian tube.12 Increased awareness of PATSS, along with the discontinuation of Essure (a permanent hysteroscopic sterilization device) in 2018, has led some surgeons to advocate for concomitant salpingectomy at the time of endometrial ablation.13 The role of opportunistic salpingectomy in primary prevention of epithelial ovarian cancer is well described, and while we strongly support this practice at the time of endometrial ablation, we do not feel that it effectively prevents LOEAF.14
The post-ablation inability to adequately sample the endometrium is also considered a LOEAF. A prospective study of 57 women who underwent endometrial ablation assessed post-ablation sampling feasibility via transvaginal ultrasonography, saline infusion sonohysterography (SIS), and in-office endometrial biopsies. In 23% of the cohort, endometrial sampling failed, and the authors noted decreased reliability of pathologic assessment.15 One systematic review, in which authors examined the incidence of endometrial cancer following endometrial ablation, characterized 38 cases of endometrial cancer and reported a post-ablation endometrial sampling success rate of 89%. This figure was based on a self-selected sample of 18 patients; cases in which endometrial sampling was thought to be impossible were excluded. The study also had a 30% missing data rate and several other biases.16
In the previously mentioned poll of SGO members,1 84% of the surveyed gynecologic oncologists managing post-ablation patients reported that endometrial sampling following endometrial ablation was “moderately” or “extremely” difficult. More than half of the survey respondents believed that hysterectomy was required for accurate diagnosis.1 While we acknowledge the likely sampling bias affecting the survey results, we are not comforted by any data that minimizes this diagnostic challenge.
Appropriate patient selection and contraindications
The ideal candidate for endometrial ablation is a premenopausal patient with HMB who does not desire future fertility. According to the FDA, absolute contraindications include pregnancy or desired fertility, prior ablation, current IUD in place, inadequate preoperative endometrial assessment, known or suspected malignancy, active infection, or unfavorable anatomy.17
What about patients who may be at increased risk for endometrial cancer?
There is a paucity of data regarding the safety of endometrial ablation in patients at increased risk for developing endometrial cancer in the future. The American College of Obstetricians and Gynecologists (ACOG) 2007 practice bulletin on endometrial ablation (no longer accessible online) alludes to this concern and other contraindications,18 but there are no established guidelines. Currently, no ACOG practice bulletin or committee opinion lists relative contraindications to endometrial ablation, long-term complications (except risks associated with future pregnancy), or risk of subsequent hysterectomy. The risk that “it may be harder to detect endometrial cancer after ablation” is noted on ACOG’s web page dedicated to frequently asked questions (FAQs) regarding abnormal uterine bleeding.19 It is not mentioned on their web page dedicated to the FAQs regarding endometrial ablation.20
In the absence of high-quality published data on established contraindications for endometrial ablation, we advocate for the increased awareness of possible relative contraindications—namely well-established risk factors for endometrial cancer (TABLE 1).For example, in a pooled analysis of 24 epidemiologic studies, authors found that the odds of developing endometrial cancer was 7 times higher among patients with a body mass index (BMI) ≥ 40 kg/m2, compared with controls (odds ratio [OR], 7.14; 95% confidence interval [CI], 6.33–8.06).21 Additionally, patients with Lynch syndrome, a history of extended tamoxifen use, or those with a history of chronic anovulation or polycystic ovary syndrome are at increased risk for endometrial cancer.22-24 If the presence of one or more of these factors does not dissuade general gynecologists from performing an endometrial ablation (even armed with a negative preoperative endometrial biopsy), we feel they should at least prompt thoughtful guideline-driven pause.
Continue to: Hysterectomy—A disincentivized option...
Hysterectomy—A disincentivized option
The annual number of hysterectomies performed by general gynecologists has declined over time. One study by Cadish and colleagues revealed that recent residency graduates performed only 3 to 4 annually.25 These numbers partly reflect the decreasing number of hysterectomies performed during residency training. Furthermore, other factors—including the increasing rate of placenta accreta spectrum, the focus on risk stratification of adnexal masses via the ovarian-adnexal reporting and data classification system (O-RADs), and the emphasis on minimally invasive approaches often acquired in subspecialty training—have likely contributed to referral patterns to such specialists as minimally invasive gynecologic surgeons and gynecologic oncologists.26 This trend is self-actualizing, as quality metrics funnel patients to high-volume surgeons, and general gynecologists risk losing hysterectomy privileges.
These factors lend themselves to a growing emphasis on endometrial ablation. Endometrial ablations can be performed in several settings, including in the hospital, in outpatient clinics, and more and more commonly, in ambulatory surgery centers. This increased access to endometrial ablation in the ambulatory surgery setting has corresponded with an annual endometrial ablation market value growth rate of 5% to 7%.27 These rates are likely compounded by payer reimbursement policies that promote endometrial ablation and other alternatives to hysterectomy that are cost savings in the short term.28 While the actual payer models are unavailable to review, they may not consider the costs of LOEAFs, including subsequent hysterectomy up to 5 years after initial ablation procedures. Provocatively, they almost certainly do not consider the costs of delayed care of patients with endometrial cancer vying for gynecologic oncology appointment slots occupied by post-ablation patients.
We urge providers, patients, and advocates to question who benefits from the uptake of ablation procedures: Patients? Payors? Providers? And how will the field of gynecology fare if hysterectomy skills and privileges are supplanted by ablation?
Post-ablation bleeding: Management by the gyn oncologist
Patients with post-ablation bleeding, either immediately or years later, are sometimes referred to a gynecologic oncologist given the possible risk for cancer and need for surgical staging if cancer is found on the hysterectomy specimen. In practice, assuming normal preoperative ultrasonography and no other clinical or radiologic findings suggestive of malignancy (eg, computed tomography findings concerning for metastases, abnormal cervical cytology, etc.), the presence of cancer is extremely unlikely to be determined at the time of surgery. Frozen section is not generally performed on the endometrium; intraoperative evaluation of even the unablated endometrium is notoriously unreliable; and histologic assessment of the ablated endometrium is limited by artifact (FIGURE 1). The abnormalities caused by ablation further impede selection of a representative focus, obfuscating any actionable result.
Some surgeons routinely bivalve the excised uterus prior to fixation to assess presence of tumor, tumor size, and the degree of myometrial invasion.29 A combination of factors may compel surgeons to perform lymphadenectomy if not already performed, or if sentinel lymph node mapping was unsuccessful. But this practice has not been studied in patients with post-ablation bleeding, and applying these principles relies on a preoperative diagnosis establishing the presence and grade of a cancer. Furthermore, the utility of frozen section and myometrial assessment to decide whether or not to proceed with lymphadenectomy is less relevant in the era of molecular classification guiding adjuvant therapy. In summary, assuming no pathologic or radiologic findings suggestive of cancer, gynecologic oncologists are unlikely to perform lymphadenectomy at the time of hysterectomy in these post-ablation cases, which therefore can safely be performed by general gynecologists.
Our recommendations
Consider the LNG-IUD as an alternative to ablation. A recent randomized controlled trial by Beelen and colleagues compared the effectiveness of LNG-releasing IUDs with endometrial ablation in patients with HMB. While the LNG-IUD was inferior to endometrial ablation, quality-of-life measures were similar up to 2 years.31 Realizing that the hysterectomy rate following endometrial ablation increases significantly beyond that time point (2 years), this narrative may be incomplete. A 5- to 10-year follow-up time-frame may be a more helpful gauge of long-term outcomes. This prolonged time-frame also may allow study of the LNG-IUD’s protective effects on the endometrium in the prevention of endometrial hyperplasia and cancer.
Consider hysterectomy. A 2021 Cochrane review revealed that, compared with endometrial ablation, minimally invasive hysterectomy is associated with higher quality-of-life metrics, higher self-reported patient satisfaction, and similar rates of adverse events.32 While patient autonomy is paramount, the developing step-wise approach from endometrial ablation to hysterectomy, and its potential effects on the health care system at a time when endometrial cancer incidence and mortality rates are rising, is troubling.
Postablation, consider hysterectomy by the general gynecologist. Current trends appear to disincentivize general gynecologists from performing hysterectomy either for HMB or LOEAF. We would offer reassurance that they can safely perform this procedure. Referral to oncology may not be necessary since, in the absence of an established diagnosis of cancer, a lymphadenectomy is not typically required. A shift away from referral for these patients can preserve access to oncology for those women, especially minority women, with an explicit need for oncologic care.
In FIGURE 2, we propose a management algorithm for the patient who presents with post–ablation bleeding. We acknowledge that the evidence base for our management recommendations is limited. Still, we hope providers, ACOG, and other guidelines-issuing organizations consider them as they adapt their own practices and recommendations. We believe this is one of many steps needed to improve outcomes for patients with gynecologic cancer, particularly those in marginalized communities disproportionately impacted by current trends.
CASE Resolution
After reviewing the relevant documentation and examining the patient, the gynecologic oncology consultant contacts the referring gynecologist. They review the low utility of frozen section and the overall low risk of cancer on the final hysterectomy specimen if the patient were to undergo hysterectomy. The consultant clarifies that there is no other concern for surgical complexity beyond the skill of the referring provider, and they discuss the possibility of referral to a minimally invasive specialist for the surgery.
Ultimately, the patient undergoes uncomplicated laparoscopic hysterectomy performed by the original referring gynecologist. Final pathology reveals inactive endometrium with ablative changes and cornual focus of endometrial hyperplasia without atypia. ●
Acknowledgement
The authors acknowledge Ian Hagemann, MD, PhD, for his review of the manuscript.
CASE New patient presents with a history of endometrial hyperplasia
A 51-year-old patient (G2P2002) presents to a new gynecologist’s office after moving from a different state. In her medical history, the gynecologist notes that 5 years ago she underwent dilation and curettage and endometrial ablation procedures for heavy menstrual bleeding (HMB). Ultrasonography performed prior to those procedures showed a slightly enlarged uterus, a simple left ovarian cyst, and a non ̶ visualized right ovary. The patient had declined a 2-step procedure due to concerns with anesthesia, and surgical pathology at the time of ablation revealed hyperplasia without atypia. The patient’s medical history was otherwise notable for prediabetes (recent hemoglobin A1c [HbA1c] measurement, 6.0%) and obesity (body mass index, 43 kg/m2). Pertinent family history included her mother’s diagnosis of endometrial cancer at age 36. Given the patient’s diagnosis of endometrial hyperplasia, she was referred to gynecologic oncology, but she ultimately declined hysterectomy, stating that she was happy with the resolution of her abnormal bleeding. At the time of her initial gynecologic oncology consultation, the consultant suggested lifestyle changes to combat prediabetes and obesity to reduce the risk of endometrial cancer, as future signs of cancer, namely bleeding, may be masked by the endometrial ablation. The patient was prescribed metformin given these medical comorbidities.
At today’s appointment, the patient notes continued resolution of bleeding since the procedure. She does, however, note a 6-month history of vasomotor symptoms and one episode of spotting 3 months ago. Three years ago she was diagnosed with type 2 diabetes mellitus, and her current HbA1c is 6.9%. She has gained 10 lb since being diagnosed with endometrial cancer 5 years ago, and she has continued to take metformin.
An in-office endometrial biopsy is unsuccessful due to cervical stenosis. The treating gynecologist orders a transvaginal ultrasound, which reveals a small left ovarian cyst and a thickened endometrium (measuring 10 mm). Concerned that these findings could represent endometrial cancer, the gynecologist refers the patient to gynecologic oncology for further evaluation.
Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology (SGO) members revealed that 93.8% of respondents had received such a referral, and almost 20% of respondents were managing more than 20 patients with post-ablation complications in their practices.1 These complications, including hematometra, post-ablation tubal sterilization syndrome, other pain syndromes associated with retrograde menstruation, and thickened endometrium with scarring leading to an inability to sample the endometrium to investigate post-ablation bleeding are symptoms and findings that often lead to further surgery, including hysterectomy.2 General gynecologists faced with these complications may refer patients to gynecologic oncology given an inability to sample the post-ablation endometrium or anticipated difficulties with hysterectomy. A recent meta-analysis revealed a 12.4% hysterectomy rate 5 years after endometrial ablation. Among these patients, the incidence of endometrial cancer ranged from 0% to 1.6%.3
In 2023, endometrial cancer incidence continues to increase, as does the incidence of obesity in women of all ages. Endometrial cancer mortality rates are also increasing, and these trends disproportionately affects non-Hispanic Black women.4 As providers and advocates work to narrow these disparities, gynecologic oncologists are simultaneously noting increased referrals for very likely benign conditions.5 Patients referred for post-ablation bleeding are a subset of these, as most patients who undergo endometrial ablation will not develop cancer. Considering the potential bottlenecks created en route to a gynecologic oncology evaluation, it seems prudent to minimize practices, like endometrial ablation, that may directly or indirectly prevent timely referral of patients with cancer to a gynecologic oncologist.
In this review we focus on the current use of endometrial ablation, associated complications, the incidence of treatment failure, and patient selection. Considering these issues in the context of the current endometrial cancer landscape, we posit best practices aimed at optimizing patient outcomes, and empowering general gynecologists to practice cancer prevention and to triage their surgical patients.
- Before performing endometrial ablation, consider whether alternatives such as hysterectomy or insertion of a progestin-containing IUD would be appropriate.
- Clinical management of patients with abnormal bleeding with indications for endometrial ablation should be guidelinedriven.
- Post-ablation bleeding or pain does not inherently require referral to oncology.
- General gynecologists can perform hysterectomy in this setting if appropriate.
- Patients with endometrial hyperplasia at endometrial ablation should be promptly offered hysterectomy. If atypia is not present, this hysterectomy, too, can be performed by a general gynecologist if appropriate, as the chance for malignancy is minimal.
Continue to: Current use of endometrial ablation in the US...
Current use of endometrial ablation in the US
In 2015, more than 500,000 endometrial ablations were performed in the United States.Given the ability to perform in-office ablation, this number is growing and potentially underestimated each year.6 In 2022, the global endometrial ablation market was valued at $3.4 billion, a figure projected to double in 10 years.7 The procedure has evolved as different devices and approaches have developed, offering patients different means to manage bleeding without hysterectomy. The minimally invasive procedure, performed in premenopausal patients with heavy menstrual bleeding (HMB) due to benign causes who have completed childbearing, has been associated with faster recovery times and fewer short-term complications compared with more invasive surgery.8 There are several non-resectoscope ablative devices approved by the US Food and Drug Administration (FDA), and each work to destroy the endometrial lining via thermal or cryoablation. Endometrial ablation can be performed in premenopausal patients with HMB due to benign causes who have completed childbearing.
Recently, promotional literature has begun to report on so-called overuse of hysterectomy, despite decreasing overall hysterectomy rates. This reporting proposes and applies “appropriateness criteria,” accounting for the rate of preoperative counseling regarding alternatives to hysterectomy, as well as the rate of “unsupportive” final pathology.9 The adoption of endometrial ablation and increasing market value of such vendors suggest that this campaign is having its desired effect. From the oncology perspective, we are concerned the pendulum could swing too far away from hysterectomy, a procedure that definitively cures abnormal uterine bleeding, toward endometrial ablation without explicit acknowledgement of the trade-offs involved.
Endometrial ablation complications: Late-onset procedure failure
A number of post-ablation syndromes may present at least 1 month following the procedure. Collectively known as late-onset endometrial ablation failure (LOEAF), these syndromes are characterized by recurrent vaginal bleeding, and/or new cyclic pelvic pain.10 It is difficult to measure the true incidence of LOEAF. Thomassee and colleagues examined a Canadian retrospective cohort of 437 patients who underwent endometrial ablation; 20.8% reported post-ablation pelvic pain after a median 301 days.11 The subsequent need for surgical intervention, often hysterectomy, is a surrogate for LOEAF.
It should be noted that LOEAF is distinct from post-ablation tubal sterilization syndrome (PATSS), which describes cornual menstrual bleeding impeded by the ligated proximal fallopian tube.12 Increased awareness of PATSS, along with the discontinuation of Essure (a permanent hysteroscopic sterilization device) in 2018, has led some surgeons to advocate for concomitant salpingectomy at the time of endometrial ablation.13 The role of opportunistic salpingectomy in primary prevention of epithelial ovarian cancer is well described, and while we strongly support this practice at the time of endometrial ablation, we do not feel that it effectively prevents LOEAF.14
The post-ablation inability to adequately sample the endometrium is also considered a LOEAF. A prospective study of 57 women who underwent endometrial ablation assessed post-ablation sampling feasibility via transvaginal ultrasonography, saline infusion sonohysterography (SIS), and in-office endometrial biopsies. In 23% of the cohort, endometrial sampling failed, and the authors noted decreased reliability of pathologic assessment.15 One systematic review, in which authors examined the incidence of endometrial cancer following endometrial ablation, characterized 38 cases of endometrial cancer and reported a post-ablation endometrial sampling success rate of 89%. This figure was based on a self-selected sample of 18 patients; cases in which endometrial sampling was thought to be impossible were excluded. The study also had a 30% missing data rate and several other biases.16
In the previously mentioned poll of SGO members,1 84% of the surveyed gynecologic oncologists managing post-ablation patients reported that endometrial sampling following endometrial ablation was “moderately” or “extremely” difficult. More than half of the survey respondents believed that hysterectomy was required for accurate diagnosis.1 While we acknowledge the likely sampling bias affecting the survey results, we are not comforted by any data that minimizes this diagnostic challenge.
Appropriate patient selection and contraindications
The ideal candidate for endometrial ablation is a premenopausal patient with HMB who does not desire future fertility. According to the FDA, absolute contraindications include pregnancy or desired fertility, prior ablation, current IUD in place, inadequate preoperative endometrial assessment, known or suspected malignancy, active infection, or unfavorable anatomy.17
What about patients who may be at increased risk for endometrial cancer?
There is a paucity of data regarding the safety of endometrial ablation in patients at increased risk for developing endometrial cancer in the future. The American College of Obstetricians and Gynecologists (ACOG) 2007 practice bulletin on endometrial ablation (no longer accessible online) alludes to this concern and other contraindications,18 but there are no established guidelines. Currently, no ACOG practice bulletin or committee opinion lists relative contraindications to endometrial ablation, long-term complications (except risks associated with future pregnancy), or risk of subsequent hysterectomy. The risk that “it may be harder to detect endometrial cancer after ablation” is noted on ACOG’s web page dedicated to frequently asked questions (FAQs) regarding abnormal uterine bleeding.19 It is not mentioned on their web page dedicated to the FAQs regarding endometrial ablation.20
In the absence of high-quality published data on established contraindications for endometrial ablation, we advocate for the increased awareness of possible relative contraindications—namely well-established risk factors for endometrial cancer (TABLE 1).For example, in a pooled analysis of 24 epidemiologic studies, authors found that the odds of developing endometrial cancer was 7 times higher among patients with a body mass index (BMI) ≥ 40 kg/m2, compared with controls (odds ratio [OR], 7.14; 95% confidence interval [CI], 6.33–8.06).21 Additionally, patients with Lynch syndrome, a history of extended tamoxifen use, or those with a history of chronic anovulation or polycystic ovary syndrome are at increased risk for endometrial cancer.22-24 If the presence of one or more of these factors does not dissuade general gynecologists from performing an endometrial ablation (even armed with a negative preoperative endometrial biopsy), we feel they should at least prompt thoughtful guideline-driven pause.
Continue to: Hysterectomy—A disincentivized option...
Hysterectomy—A disincentivized option
The annual number of hysterectomies performed by general gynecologists has declined over time. One study by Cadish and colleagues revealed that recent residency graduates performed only 3 to 4 annually.25 These numbers partly reflect the decreasing number of hysterectomies performed during residency training. Furthermore, other factors—including the increasing rate of placenta accreta spectrum, the focus on risk stratification of adnexal masses via the ovarian-adnexal reporting and data classification system (O-RADs), and the emphasis on minimally invasive approaches often acquired in subspecialty training—have likely contributed to referral patterns to such specialists as minimally invasive gynecologic surgeons and gynecologic oncologists.26 This trend is self-actualizing, as quality metrics funnel patients to high-volume surgeons, and general gynecologists risk losing hysterectomy privileges.
These factors lend themselves to a growing emphasis on endometrial ablation. Endometrial ablations can be performed in several settings, including in the hospital, in outpatient clinics, and more and more commonly, in ambulatory surgery centers. This increased access to endometrial ablation in the ambulatory surgery setting has corresponded with an annual endometrial ablation market value growth rate of 5% to 7%.27 These rates are likely compounded by payer reimbursement policies that promote endometrial ablation and other alternatives to hysterectomy that are cost savings in the short term.28 While the actual payer models are unavailable to review, they may not consider the costs of LOEAFs, including subsequent hysterectomy up to 5 years after initial ablation procedures. Provocatively, they almost certainly do not consider the costs of delayed care of patients with endometrial cancer vying for gynecologic oncology appointment slots occupied by post-ablation patients.
We urge providers, patients, and advocates to question who benefits from the uptake of ablation procedures: Patients? Payors? Providers? And how will the field of gynecology fare if hysterectomy skills and privileges are supplanted by ablation?
Post-ablation bleeding: Management by the gyn oncologist
Patients with post-ablation bleeding, either immediately or years later, are sometimes referred to a gynecologic oncologist given the possible risk for cancer and need for surgical staging if cancer is found on the hysterectomy specimen. In practice, assuming normal preoperative ultrasonography and no other clinical or radiologic findings suggestive of malignancy (eg, computed tomography findings concerning for metastases, abnormal cervical cytology, etc.), the presence of cancer is extremely unlikely to be determined at the time of surgery. Frozen section is not generally performed on the endometrium; intraoperative evaluation of even the unablated endometrium is notoriously unreliable; and histologic assessment of the ablated endometrium is limited by artifact (FIGURE 1). The abnormalities caused by ablation further impede selection of a representative focus, obfuscating any actionable result.
Some surgeons routinely bivalve the excised uterus prior to fixation to assess presence of tumor, tumor size, and the degree of myometrial invasion.29 A combination of factors may compel surgeons to perform lymphadenectomy if not already performed, or if sentinel lymph node mapping was unsuccessful. But this practice has not been studied in patients with post-ablation bleeding, and applying these principles relies on a preoperative diagnosis establishing the presence and grade of a cancer. Furthermore, the utility of frozen section and myometrial assessment to decide whether or not to proceed with lymphadenectomy is less relevant in the era of molecular classification guiding adjuvant therapy. In summary, assuming no pathologic or radiologic findings suggestive of cancer, gynecologic oncologists are unlikely to perform lymphadenectomy at the time of hysterectomy in these post-ablation cases, which therefore can safely be performed by general gynecologists.
Our recommendations
Consider the LNG-IUD as an alternative to ablation. A recent randomized controlled trial by Beelen and colleagues compared the effectiveness of LNG-releasing IUDs with endometrial ablation in patients with HMB. While the LNG-IUD was inferior to endometrial ablation, quality-of-life measures were similar up to 2 years.31 Realizing that the hysterectomy rate following endometrial ablation increases significantly beyond that time point (2 years), this narrative may be incomplete. A 5- to 10-year follow-up time-frame may be a more helpful gauge of long-term outcomes. This prolonged time-frame also may allow study of the LNG-IUD’s protective effects on the endometrium in the prevention of endometrial hyperplasia and cancer.
Consider hysterectomy. A 2021 Cochrane review revealed that, compared with endometrial ablation, minimally invasive hysterectomy is associated with higher quality-of-life metrics, higher self-reported patient satisfaction, and similar rates of adverse events.32 While patient autonomy is paramount, the developing step-wise approach from endometrial ablation to hysterectomy, and its potential effects on the health care system at a time when endometrial cancer incidence and mortality rates are rising, is troubling.
Postablation, consider hysterectomy by the general gynecologist. Current trends appear to disincentivize general gynecologists from performing hysterectomy either for HMB or LOEAF. We would offer reassurance that they can safely perform this procedure. Referral to oncology may not be necessary since, in the absence of an established diagnosis of cancer, a lymphadenectomy is not typically required. A shift away from referral for these patients can preserve access to oncology for those women, especially minority women, with an explicit need for oncologic care.
In FIGURE 2, we propose a management algorithm for the patient who presents with post–ablation bleeding. We acknowledge that the evidence base for our management recommendations is limited. Still, we hope providers, ACOG, and other guidelines-issuing organizations consider them as they adapt their own practices and recommendations. We believe this is one of many steps needed to improve outcomes for patients with gynecologic cancer, particularly those in marginalized communities disproportionately impacted by current trends.
CASE Resolution
After reviewing the relevant documentation and examining the patient, the gynecologic oncology consultant contacts the referring gynecologist. They review the low utility of frozen section and the overall low risk of cancer on the final hysterectomy specimen if the patient were to undergo hysterectomy. The consultant clarifies that there is no other concern for surgical complexity beyond the skill of the referring provider, and they discuss the possibility of referral to a minimally invasive specialist for the surgery.
Ultimately, the patient undergoes uncomplicated laparoscopic hysterectomy performed by the original referring gynecologist. Final pathology reveals inactive endometrium with ablative changes and cornual focus of endometrial hyperplasia without atypia. ●
Acknowledgement
The authors acknowledge Ian Hagemann, MD, PhD, for his review of the manuscript.
- Chen H, Saiz AM, McCausland AM, et al. Experience of gynecologic oncologists regarding endometrial cancer after endometrial ablation. J Clin Oncol. 2018;36:e17566-e.
- McCausland AM, McCausland VM. Long-term complications of endometrial ablation: cause, diagnosis, treatment, and prevention. J Minim Invasive Gynecol. 2007;14:399-406.
- Oderkerk TJ, Beelen P, Bukkems ALA, et al. Risk of hysterectomy after endometrial ablation: a systematic review and meta-analysis. Obstet Gynecol. 2023;142:51-60.
- Clarke MA, Devesa SS, Hammer A, et al. Racial and ethnic differences in hysterectomy-corrected uterine corpus cancer mortality by stage and histologic subtype. JAMA Oncol. 2022;8:895-903.
- Barber EL, Rossi EC, Alexander A, et al. Benign hysterectomy performed by gynecologic oncologists: is selection bias altering our ability to measure surgical quality? Gynecol Oncol. 2018;151:141-144.
- Wortman M. Late-onset endometrial ablation failure. Case Rep Womens Health. 2017;15:11-28.
- Insights FM. Endometrial Ablation Market Outlook.Accessed July 26, 2023. https://www.futuremarketinsights.com/reports/endometrial-ablation -market
- Famuyide A. Endometrial ablation. J Minim Invasive Gynecol. 2018;25:299-307.
- Corona LE, Swenson CW, Sheetz KH, et al. Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative. Am J Obstet Gynecol. 2015;212:304.e1-e7.
- Wortman M, Cholkeri A, McCausland AM, et al. Late-onset endometrial ablation failure—etiology, treatment, and prevention. J Minim Invasive Gynecol. 2015;22:323-331.
- Thomassee MS, Curlin H, Yunker A, et al. Predicting pelvic pain after endometrial ablation: which preoperative patient characteristics are associated? J Minim Invasive Gynecol. 2013;20:642-647.
- Townsend DE, McCausland V, McCausland A, et al. Post-ablation-tubal sterilization syndrome. Obstet Gynecol. 1993;82:422-424.
- Greer Polite F, DeAgostino-Kelly M, Marchand GJ. Combination of laparoscopic salpingectomy and endometrial ablation: a potentially underused procedure. J Gynecol Surg. 2021;37:89-91.
- Hanley GE, Pearce CL, Talhouk A, et al. Outcomes from opportunistic salpingectomy for ovarian cancer prevention. JAMA Network Open. 2022;5:e2147343-e.
- Ahonkallio SJ, Liakka AK, Martikainen HK, et al. Feasibility of endometrial assessment after thermal ablation. Eur J Obstet Gynecol Reprod Biol. 2009;147:69-71.
- Tamara JO, Mileen RDvdK, Karlijn MCC, et al. Endometrial cancer after endometrial ablation: a systematic review. Int J Gynecol Cancer. 2022;32:1555.
- US Food and Drug Administration. Endometrial ablation for heavy menstrual bleeding.Accessed July 26, 2023. https://www.fda.gov/medical-devices /surgery-devices/endometrial-ablation-heavy-menstrual-bleeding
- ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists. Number 81, May 2007. Obstet Gynecol. 2007;109:1233-1248.
- The American College of Obstetricians and Gynecologists. Abnormal uterine bleeding frequently asked questions. Accessed July 26, 2023. https://www.acog .org/womens-health/faqs/abnormal-uterine-bleeding
- The American College of Obstetricians and Gynecologists. Endometrial ablation frequently asked questions. Accessed November 28, 2023. https://www.acog. org/womens-health/faqs/endometrial-ablation#:~:text=Can%20I%20still%20 get%20pregnant,should%20not%20have%20this%20procedure
- Setiawan VW, Yang HP, Pike MC, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol. 2013;31:2607-2618.
- National Comprehensive Cancer Network. Lynch Syndrome (Version 2.2023). Accessed November 15, 2023. https://www.nccn.org/professionals /physician_gls/pdf/genetics_colon.pdf
- Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305: 2304-2310.
- Fleming CA, Heneghan HM, O’Brien D, et al. Meta-analysis of the cumulative risk of endometrial malignancy and systematic review of endometrial surveillance in extended tamoxifen therapy. Br J Surg. 2018;105:1098-1106.
- Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2014;20:748-758.
- Cadish LA, Kropat G, Muffly TM. Hysterectomy volume among recent obstetrics and gynecology residency graduates. Urogynecology. 2021;27.
- Blank SV, Huh WK, Bell M, et al. Doubling down on the future of gynecologic oncology: the SGO future of the profession summit report. Gynecol Oncol. 2023;171:76-82.
- Reports MI. Global endometrial ablation market growth, trends and forecast 2023 to 2028 by types, by application, by regions and by key players like Boston Scientific, Hologic, Olympus, Minerva Surgical. Accessed July 30, 2023. https://www.marketinsightsreports.com/single-report/061612632440/global -endometrial-ablation-market-growth-trends-and-forecast-2023-to-2028-by -types-by-application-by-regions-and-by-key-players-like-boston-scientific -hologic-olympus-minerva-surgical
- London R, Holzman M, Rubin D, et al. Payer cost savings with endometrial ablation therapy. Am J Manag Care. 1999;5:889-897.
- Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11-18.
- Beelen P, van den Brink MJ, Herman MC, et al. Levonorgestrel-releasing intrauterine system versus endometrial ablation for heavy menstrual bleeding. Am J Obstet Gynecol. 2021;224:187.e1-e10.
- Bofill Rodriguez M, Lethaby A, Fergusson RJ. Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2021;2:Cd000329.
- Chen H, Saiz AM, McCausland AM, et al. Experience of gynecologic oncologists regarding endometrial cancer after endometrial ablation. J Clin Oncol. 2018;36:e17566-e.
- McCausland AM, McCausland VM. Long-term complications of endometrial ablation: cause, diagnosis, treatment, and prevention. J Minim Invasive Gynecol. 2007;14:399-406.
- Oderkerk TJ, Beelen P, Bukkems ALA, et al. Risk of hysterectomy after endometrial ablation: a systematic review and meta-analysis. Obstet Gynecol. 2023;142:51-60.
- Clarke MA, Devesa SS, Hammer A, et al. Racial and ethnic differences in hysterectomy-corrected uterine corpus cancer mortality by stage and histologic subtype. JAMA Oncol. 2022;8:895-903.
- Barber EL, Rossi EC, Alexander A, et al. Benign hysterectomy performed by gynecologic oncologists: is selection bias altering our ability to measure surgical quality? Gynecol Oncol. 2018;151:141-144.
- Wortman M. Late-onset endometrial ablation failure. Case Rep Womens Health. 2017;15:11-28.
- Insights FM. Endometrial Ablation Market Outlook.Accessed July 26, 2023. https://www.futuremarketinsights.com/reports/endometrial-ablation -market
- Famuyide A. Endometrial ablation. J Minim Invasive Gynecol. 2018;25:299-307.
- Corona LE, Swenson CW, Sheetz KH, et al. Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative. Am J Obstet Gynecol. 2015;212:304.e1-e7.
- Wortman M, Cholkeri A, McCausland AM, et al. Late-onset endometrial ablation failure—etiology, treatment, and prevention. J Minim Invasive Gynecol. 2015;22:323-331.
- Thomassee MS, Curlin H, Yunker A, et al. Predicting pelvic pain after endometrial ablation: which preoperative patient characteristics are associated? J Minim Invasive Gynecol. 2013;20:642-647.
- Townsend DE, McCausland V, McCausland A, et al. Post-ablation-tubal sterilization syndrome. Obstet Gynecol. 1993;82:422-424.
- Greer Polite F, DeAgostino-Kelly M, Marchand GJ. Combination of laparoscopic salpingectomy and endometrial ablation: a potentially underused procedure. J Gynecol Surg. 2021;37:89-91.
- Hanley GE, Pearce CL, Talhouk A, et al. Outcomes from opportunistic salpingectomy for ovarian cancer prevention. JAMA Network Open. 2022;5:e2147343-e.
- Ahonkallio SJ, Liakka AK, Martikainen HK, et al. Feasibility of endometrial assessment after thermal ablation. Eur J Obstet Gynecol Reprod Biol. 2009;147:69-71.
- Tamara JO, Mileen RDvdK, Karlijn MCC, et al. Endometrial cancer after endometrial ablation: a systematic review. Int J Gynecol Cancer. 2022;32:1555.
- US Food and Drug Administration. Endometrial ablation for heavy menstrual bleeding.Accessed July 26, 2023. https://www.fda.gov/medical-devices /surgery-devices/endometrial-ablation-heavy-menstrual-bleeding
- ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists. Number 81, May 2007. Obstet Gynecol. 2007;109:1233-1248.
- The American College of Obstetricians and Gynecologists. Abnormal uterine bleeding frequently asked questions. Accessed July 26, 2023. https://www.acog .org/womens-health/faqs/abnormal-uterine-bleeding
- The American College of Obstetricians and Gynecologists. Endometrial ablation frequently asked questions. Accessed November 28, 2023. https://www.acog. org/womens-health/faqs/endometrial-ablation#:~:text=Can%20I%20still%20 get%20pregnant,should%20not%20have%20this%20procedure
- Setiawan VW, Yang HP, Pike MC, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol. 2013;31:2607-2618.
- National Comprehensive Cancer Network. Lynch Syndrome (Version 2.2023). Accessed November 15, 2023. https://www.nccn.org/professionals /physician_gls/pdf/genetics_colon.pdf
- Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305: 2304-2310.
- Fleming CA, Heneghan HM, O’Brien D, et al. Meta-analysis of the cumulative risk of endometrial malignancy and systematic review of endometrial surveillance in extended tamoxifen therapy. Br J Surg. 2018;105:1098-1106.
- Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2014;20:748-758.
- Cadish LA, Kropat G, Muffly TM. Hysterectomy volume among recent obstetrics and gynecology residency graduates. Urogynecology. 2021;27.
- Blank SV, Huh WK, Bell M, et al. Doubling down on the future of gynecologic oncology: the SGO future of the profession summit report. Gynecol Oncol. 2023;171:76-82.
- Reports MI. Global endometrial ablation market growth, trends and forecast 2023 to 2028 by types, by application, by regions and by key players like Boston Scientific, Hologic, Olympus, Minerva Surgical. Accessed July 30, 2023. https://www.marketinsightsreports.com/single-report/061612632440/global -endometrial-ablation-market-growth-trends-and-forecast-2023-to-2028-by -types-by-application-by-regions-and-by-key-players-like-boston-scientific -hologic-olympus-minerva-surgical
- London R, Holzman M, Rubin D, et al. Payer cost savings with endometrial ablation therapy. Am J Manag Care. 1999;5:889-897.
- Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11-18.
- Beelen P, van den Brink MJ, Herman MC, et al. Levonorgestrel-releasing intrauterine system versus endometrial ablation for heavy menstrual bleeding. Am J Obstet Gynecol. 2021;224:187.e1-e10.
- Bofill Rodriguez M, Lethaby A, Fergusson RJ. Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2021;2:Cd000329.
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Hagemann, MD</bylineText> <bylineFull/> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType>(choose one)</newsDocType> <journalDocType>(choose one)</journalDocType> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology </metaDescription> <articlePDF/> <teaserImage/> <title>Time to rethink endometrial ablation: A gyn oncology perspective on the sequelae of an overused procedure</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gyn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle>MDedge ObGyn</journalFullTitle> <copyrightStatement>2018</copyrightStatement> </publicationData> <publicationData> <publicationCode>obgm</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">49726</term> <term>24</term> </publications> <sections> <term canonical="true">49</term> </sections> <topics> <term canonical="true">218</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Time to rethink endometrial ablation: A gyn oncology perspective on the sequelae of an overused procedure</title> <deck/> </itemMeta> <itemContent> <p class="abstract">For lower-volume general gynecologists, several factors have led to an overemphasis on endometrial ablation for patients with HMB when alternatives, such as hysterectomy or IUD, should be considered</p> <h3><span class="intro">CASE</span> New patient presents with a history of endometrial hyperplasia</h3> <p> <strong>A 51-year-old patient (G2P2002) presents to a new gynecologist’s office after moving from a different state. In her medical history, the gynecologist notes that 5 years ago she underwent dilation and curettage and endometrial ablation procedures for heavy menstrual bleeding (HMB). Ultrasonography performed prior to those procedures showed a slightly enlarged uterus, a simple left ovarian cyst, and a non ̶ visualized right ovary. The patient had declined a 2-step procedure due to concerns with anesthesia, and surgical pathology at the time of ablation revealed hyperplasia without atypia. The patient’s medical history was otherwise notable for prediabetes (recent hemoglobin A<sub>1c</sub> [HbA<sub>1c</sub>] measurement, 6.0%) and obesity (body mass index, 43 kg/m<sup>2</sup>). Pertinent family history included her mother’s diagnosis of endometrial cancer at age 36. Given the patient’s diagnosis of endometrial hyperplasia, she was referred to gynecologic oncology, but she ultimately declined hysterectomy, stating that she was happy with the resolution of her abnormal bleeding. At the time of her initial gynecologic oncology consultation, the consultant suggested lifestyle changes to combat prediabetes and obesity to reduce the risk of endometrial cancer, as future signs of cancer, namely bleeding, may be masked by the endometrial ablation. The patient was prescribed metformin given these medical comorbidities. </strong> </p> <p> <strong>At today’s appointment, the patient notes continued resolution of bleeding since the procedure. She does, however, note a 6-month history of vasomotor symptoms and one episode of spotting 3 months ago. Three years ago she was diagnosed with type 2 diabetes mellitus, and her current HbA<sub>1c</sub> is 6.9%. She has gained 10 lb since being diagnosed with endometrial cancer 5 years ago, and she has continued to take metformin. <br/><br/>An in-office endometrial biopsy is unsuccessful due to cervical stenosis. The treating gynecologist orders a transvaginal ultrasound, which reveals a small left ovarian cyst and a thickened endometrium (measuring 10 mm). Concerned that these findings could represent endometrial cancer, the gynecologist refers the patient to gynecologic oncology for further evaluation.</strong> </p> <p><br/><br/>Sequelae and complications following endometrial ablation are often managed by a gynecologic oncologist. Indeed, a 2018 poll of Society of Gynecologic Oncology (SGO) members revealed that 93.8% of respondents had received such a referral, and almost 20% of respondents were managing more than 20 patients with post-ablation complications in their practices.<sup>1</sup> These complications, including hematometra, post-ablation tubal sterilization syndrome, other pain syndromes associated with retrograde menstruation, and thickened endometrium with scarring leading to an inability to sample the endometrium to investigate post-ablation bleeding are symptoms and findings that often lead to further surgery, including hysterectomy.<sup>2</sup> General gynecologists faced with these complications may refer patients to gynecologic oncology given an inability to sample the post-ablation endometrium or anticipated difficulties with hysterectomy. A recent meta-analysis revealed a 12.4% hysterectomy rate 5 years after endometrial ablation. Among these patients, the incidence of endometrial cancer ranged from 0% to 1.6%.<sup>3</sup> </p> <p>In 2023, endometrial cancer incidence continues to increase, as does the incidence of obesity in women of all ages. Endometrial cancer mortality rates are also increasing, and these trends disproportionately affects non-Hispanic Black women.<sup>4</sup> As providers and advocates work to narrow these disparities, gynecologic oncologists are simultaneously noting increased referrals for very likely benign conditions.<sup>5</sup> Patients referred for post-ablation bleeding are a subset of these, as most patients who undergo endometrial ablation will not develop cancer. Considering the potential bottlenecks created en route to a gynecologic oncology evaluation, it seems prudent to minimize practices, like endometrial ablation, that may directly or indirectly prevent timely referral of patients with cancer to a gynecologic oncologist. <br/><br/>In this review we focus on the current use of endometrial ablation, associated complications, the incidence of treatment failure, and patient selection. Considering these issues in the context of the current endometrial cancer landscape, we posit best practices aimed at optimizing patient outcomes, and empowering general gynecologists to practice cancer prevention and to triage their surgical patients. </p> <h2>Current use of endometrial ablation in the US</h2> <p>In 2015, more than 500,000 endometrial ablations were performed in the United States.Given the ability to perform in-office ablation, this number is growing and potentially underestimated each year.<sup>6</sup> In 2022, the global endometrial ablation market was valued at $3.4 billion, a figure projected to double in 10 years.<sup>7</sup> The procedure has evolved as different devices and approaches have developed, offering patients different means to manage bleeding without hysterectomy. The minimally invasive procedure, performed in premenopausal patients with heavy menstrual bleeding (HMB) due to benign causes who have completed childbearing, has been associated with faster recovery times and fewer short-term complications compared with more invasive surgery.<sup>8</sup> There are several non-resectoscope ablative devices approved by the US Food and Drug Administration (FDA), and each work to destroy the endometrial lining via thermal or cryoablation. Endometrial ablation can be performed in premenopausal patients with HMB due to benign causes who have completed childbearing. </p> <p>Recently, promotional literature has begun to report on so-called overuse of hysterectomy, despite decreasing overall hysterectomy rates. This reporting proposes and applies “appropriateness criteria,” accounting for the rate of preoperative counseling regarding alternatives to hysterectomy, as well as the rate of “unsupportive” final pathology.<sup>9</sup> The adoption of endometrial ablation and increasing market value of such vendors suggest that this campaign is having its desired effect. From the oncology perspective, we are concerned the pendulum could swing too far away from hysterectomy, a procedure that definitively cures abnormal uterine bleeding, toward endometrial ablation without explicit acknowledgement of the trade-offs involved.</p> <h2>Endometrial ablation complications: Late-onset procedure failure</h2> <p>A number of post-ablation syndromes may present at least 1 month following the procedure. Collectively known as late-onset endometrial ablation failure (LOEAF), these syndromes are characterized by recurrent vaginal bleeding, and/or new cyclic pelvic pain.<sup>10</sup> It is difficult to measure the true incidence of LOEAF. Thomassee and colleagues examined a Canadian retrospective cohort of 437 patients who underwent endometrial ablation; 20.8% reported post-ablation pelvic pain after a median 301 days.<sup>11</sup> The subsequent need for surgical intervention, often hysterectomy, is a surrogate for LOEAF. </p> <p>It should be noted that LOEAF is distinct from post-ablation tubal sterilization syndrome (PATSS), which describes cornual menstrual bleeding impeded by the ligated proximal fallopian tube.<sup>12</sup> Increased awareness of PATSS, along with the discontinuation of Essure (a permanent hysteroscopic sterilization device) in 2018, has led some surgeons to advocate for concomitant salpingectomy at the time of endometrial ablation.<sup>13</sup> The role of opportunistic salpingectomy in primary prevention of epithelial ovarian cancer is well described, and while we strongly support this practice at the time of endometrial ablation, we do not feel that it effectively prevents LOEAF.<sup>14</sup> <br/><br/>The post-ablation inability to adequately sample the endometrium is also considered a LOEAF. A prospective study of 57 women who underwent endometrial ablation assessed post-ablation sampling feasibility via transvaginal ultrasonography, saline infusion sonohysterography (SIS), and in-office endometrial biopsies. In 23% of the cohort, endometrial sampling failed, and the authors noted decreased reliability of pathologic assessment.<sup>15</sup> One systematic review, in which authors examined the incidence of endometrial cancer following endometrial ablation, characterized 38 cases of endometrial cancer and reported a post-ablation endometrial sampling success rate of 89%. This figure was based on a self-selected sample of 18 patients; cases in which endometrial sampling was thought to be impossible were excluded. The study also had a 30% missing data rate and several other biases.<sup>16</sup> <br/><br/>In the previously mentioned poll of SGO members,<sup>1</sup> 84% of the surveyed gynecologic oncologists managing post-ablation patients reported that endometrial sampling following endometrial ablation was “moderately” or “extremely” difficult. More than half of the survey respondents believed that hysterectomy was required for accurate diagnosis.<sup>1</sup> While we acknowledge the likely sampling bias affecting the survey results, we are not comforted by any data that minimizes this diagnostic challenge. </p> <h2>Appropriate patient selection and contraindications</h2> <p>The ideal candidate for endometrial ablation is a premenopausal patient with HMB who does not desire future fertility. According to the FDA, absolute contraindications include pregnancy or desired fertility, prior ablation, current IUD in place, inadequate preoperative endometrial assessment, known or suspected malignancy, active infection, or unfavorable anatomy.<sup>17</sup> </p> <h3>What about patients who may be at increased risk for endometrial cancer? </h3> <p>There is a paucity of data regarding the safety of endometrial ablation in patients at increased risk for developing endometrial cancer in the future. The American College of Obstetricians and Gynecologists (ACOG) 2007 practice bulletin on endometrial ablation (no longer accessible online) alludes to this concern and other contraindications,<sup>18</sup> but there are no established guidelines. Currently, no ACOG practice bulletin or committee opinion lists relative contraindications to endometrial ablation, long-term complications (except risks associated with future pregnancy), or risk of subsequent hysterectomy. The risk that “it may be harder to detect endometrial cancer after ablation” is noted on ACOG’s web page dedicated to frequently asked questions (FAQs) regarding abnormal uterine bleeding.<sup>19</sup> It is not mentioned on their web page dedicated to the FAQs regarding endometrial ablation.<sup>20</sup> </p> <p>In the absence of high-quality published data on established contraindications for endometrial ablation, we advocate for the increased awareness of possible relative contraindications—namely well-established risk factors for endometrial cancer (<strong>TABLE 1</strong>).For example, in a pooled analysis of 24 epidemiologic studies, authors found that the odds of developing endometrial cancer was 7 times higher among patients with a body mass index (BMI) ≥ 40 kg/m<sup>2</sup>, compared with controls (odds ratio [OR], 7.14; 95% confidence interval [CI], 6.33–8.06).<sup>21</sup> Additionally, patients with Lynch syndrome, a history of extended tamoxifen use, or those with a history of chronic anovulation or polycystic ovary syndrome are at increased risk for endometrial cancer.<sup>22-24</sup> If the presence of one or more of these factors does not dissuade general gynecologists from performing an endometrial ablation (even armed with a negative preoperative endometrial biopsy), we feel they should at least prompt thoughtful guideline-driven pause. </p> <h2>Hysterectomy—A disincentivized option</h2> <p>The annual number of hysterectomies performed by general gynecologists has declined over time. One study by Cadish and colleagues revealed that recent residency graduates performed only 3 to 4 annually.<sup>25</sup> These numbers partly reflect the decreasing number of hysterectomies performed during residency training. Furthermore, other factors—including the increasing rate of placenta accreta spectrum, the focus on risk stratification of adnexal masses via the ovarian-adnexal reporting and data classification system (O-RADs), and the emphasis on minimally invasive approaches often acquired in subspecialty training—have likely contributed to referral patterns to such specialists as minimally invasive gynecologic surgeons and gynecologic oncologists.<sup>26</sup> This trend is self-actualizing, as quality metrics funnel patients to high-volume surgeons, and general gynecologists risk losing hysterectomy privileges. <br/><br/><span class="intro">These factors lend themselves to a growing emphasis on endometrial ablation.</span><b> </b>Endometrial ablations can be performed in several settings, including in the hospital, in outpatient clinics, and more and more commonly, in ambulatory surgery centers. This increased access to endometrial ablation in the ambulatory surgery setting has corresponded with an annual endometrial ablation market value growth rate of 5% to 7%.<sup>27</sup> These rates are likely compounded by payer reimbursement policies that promote endometrial ablation and other alternatives to hysterectomy that are cost savings in the short term.<sup>28</sup> While the actual payer models are unavailable to review, they may not consider the costs of LOEAFs, including subsequent hysterectomy up to 5 years after initial ablation procedures. Provocatively, they almost certainly do not consider the costs of delayed care of patients with endometrial cancer vying for gynecologic oncology appointment slots occupied by post-ablation patients. <br/><br/><span class="intro">We urge providers, patients, and advocates to question</span><b> </b>who benefits from the uptake of ablation procedures: Patients? Payors? Providers? And how will the field of gynecology fare if hysterectomy skills and privileges are supplanted by ablation?</p> <h2>Post-ablation bleeding: Management by the gyn oncologist</h2> <p>Patients with post-ablation bleeding, either immediately or years later, are sometimes referred to a gynecologic oncologist given the possible risk for cancer and need for surgical staging if cancer is found on the hysterectomy specimen. In practice, assuming normal preoperative ultrasonography and no other clinical or radiologic findings suggestive of malignancy (eg, computed tomography findings concerning for metastases, abnormal cervical cytology, etc.), the presence of cancer is extremely unlikely to be determined at the time of surgery. Frozen section is not generally performed on the endometrium; intraoperative evaluation of even the unablated endometrium is notoriously unreliable; and histologic assessment of the ablated endometrium is limited by artifact (<strong>FIGURE 1</strong>). The abnormalities caused by ablation further impede selection of a representative focus, obfuscating any actionable result. </p> <p>Some surgeons routinely bivalve the excised uterus prior to fixation to assess presence of tumor, tumor size, and the degree of myometrial invasion.<sup>29</sup> A combination of factors may compel surgeons to perform lymphadenectomy if not already performed, or if sentinel lymph node mapping was unsuccessful. But this practice has not been studied in patients with post-ablation bleeding, and applying these principles relies on a preoperative diagnosis establishing the presence and grade of a cancer. Furthermore, the utility of frozen section and myometrial assessment to decide whether or not to proceed with lymphadenectomy is less relevant in the era of molecular classification guiding adjuvant therapy. In summary, assuming no pathologic or radiologic findings suggestive of cancer, gynecologic oncologists are unlikely to perform lymphadenectomy at the time of hysterectomy in these post-ablation cases, which therefore can safely be performed by general gynecologists. </p> <h2>Our recommendations</h2> <p><span class="intro">Consider the LNG-IUD as an alternative to ablation.</span> A recent randomized controlled trial by Beelen and colleagues compared the effectiveness of LNG-releasing IUDs with endometrial ablation in patients with HMB. While the LNG-IUD was inferior to endometrial ablation, quality-of-life measures were similar up to 2 years.<sup>31</sup> Realizing that the hysterectomy rate following endometrial ablation increases significantly beyond that time point (2 years), this narrative may be incomplete. A 5- to 10-year follow-up time-frame may be a more helpful gauge of long-term outcomes. This prolonged time-frame also may allow study of the LNG-IUD’s protective effects on the endometrium in the prevention of endometrial hyperplasia and cancer. <br/><br/><span class="intro">Consider hysterectomy.</span> A 2021 Cochrane review revealed that, compared with endometrial ablation, minimally invasive hysterectomy is associated with higher quality-of-life metrics, higher self-reported patient satisfaction, and similar rates of adverse events.<sup>32</sup> While patient autonomy is paramount, the developing step-wise approach from endometrial ablation to hysterectomy, and its potential effects on the health care system at a time when endometrial cancer incidence and mortality rates are rising, is troubling. <br/><br/><span class="intro">Postablation, consider hysterectomy by the general gynecologist</span>. Current trends appear to disincentivize general gynecologists from performing hysterectomy either for HMB or LOEAF. We would offer reassurance that they can safely perform this procedure. Referral to oncology may not be necessary since, in the absence of an established diagnosis of cancer, a lymphadenectomy is not typically required. A shift away from referral for these patients can preserve access to oncology for those women, especially minority women, with an explicit need for oncologic care. <br/><br/><span class="intro">In </span><strong>FIGURE 2</strong><span class="intro">, we propose a management algorithm for the patient who presents with post–ablation bleeding. </span> We acknowledge that the evidence base for our management recommendations is limited. Still, we hope providers, ACOG, and other guidelines-issuing organizations consider them as they adapt their own practices and recommendations. We believe this is one of many steps needed to improve outcomes for patients with gynecologic cancer, particularly those in marginalized communities disproportionately impacted by current trends. </p> <h3><span class="intro">CASE</span> Resolution</h3> <p> <strong>After reviewing the relevant documentation and examining the patient, the gynecologic oncology consultant contacts the referring gynecologist. They review the low utility of frozen section and the overall low risk of cancer on the final hysterectomy specimen if the patient were to undergo hysterectomy. The consultant clarifies that there is no other concern for surgical complexity beyond the skill of the referring provider, and they discuss the possibility of referral to a minimally invasive specialist for the surgery. </strong> </p> <p> <strong>Ultimately, the patient undergoes uncomplicated laparoscopic hysterectomy performed by the original referring gynecologist. Final pathology reveals inactive endometrium with ablative changes and cornual focus of endometrial hyperplasia without atypia. ●</strong> </p> <h3> <b> <i>Acknowledgement</i> </b> </h3> <p> <i>The authors acknowledge Ian Hagemann, MD, PhD, for his review of the manuscript.</i> </p> </itemContent> </newsItem> </itemSet></root>
LGBTQI+: Special considerations for reproductive health care
CASE A new patient office visit
A new patient is waiting for you in the exam room. You review the chart and see the sex demographic field is blank, and the patient’s name is Alex. As an ObGyn, most of your patients are female, but you have treated your patients’ partners for sexually transmitted infections. As you enter the room, you see 2 androgynously dressed individuals; you introduce yourself and ask,
“What brings you in today, and who is your friend?”
“This is my partner Charlie, and we are worried I have an STD.”
Estimates suggest that between 7% to 12% of the US population identifies as lesbian, gay, bisexual, transgender/non-binary, queer/questioning, intersex, or asexual (LGBTQI+).1 If you practice in an urban area, the odds are quite high that you have encountered an LGBTQI+ person who openly identified as such; if you are in a rural area, you also likely have had an LGBTQI+ patient, but they may not have disclosed this about themselves.2 Maybe you have had training in cultural relevance or are a member of this community and you feel confident in providing quality care to LGBTQI+ patients. Or maybe you think that, as a responsibly practicing health care clinician, you treat all patients the same, so whether or not you know their sexual orientation or gender identity does not impact the care you provide. As the proportion of US adults who identify as LGBTQI+ increases,1 it becomes more important for health care clinicians to understand the challenges these patients face when trying to access health care. To start, let’s review the meaning of LGBTQI+, the history of the community, what it means to be culturally relevant or humble, and how to create a welcoming and safe practice environment.
LGBTQI+ terms and definitions
The first step in providing quality care to LGBTQI+ patients is to understand the terminology associated with sexual orientation, gender identity, and gender expression.3–5
Sexual orientation refers to whom a person is sexually attracted. The term straight/heterosexual suggests a person is sexually attracted to a person of the opposite gender. Lesbian or gay refers to those who are attracted to their same gender. Some people use bisexual (attracted to both the same and opposite gender) and pansexual (attracted to all humans regardless of gender). Still others refer to themselves as queer—people who identify as someone who is not heterosexual or cisgender. A variety of other terms exist to describe one’s sexual attraction. There are also some people who identify as asexual, which suggests they are not sexually attracted to anyone.
Gender identity relates to how one views their own gender. If you were assigned female at birth and identify as a woman, you are cisgender. If you were assigned male at birth and identify as a woman, you may identify as transgender whether or not you have had gender transitioning surgery or have taken hormones. Some people do not identify with the terms male or female and may view themselves as nonbinary. The terms gender queer, gender fluid, gender diverse, and gender non-conforming also may be used to describe various ways that an individual may not identify as male or female. We also can refer to people as “assigned female at birth” or “assigned male at birth”. People with intersex conditions may require taking a unique medical history that includes asking about genetic testing (eg, 46,XX congenital adrenal hyperplasia or 46,XY complete gonadal dysgenesis).
Gender expression refers to how one pre-sents themselves to others through appearance, dress, and behavior. A person may be assigned female at birth, dress in a conventional male fashion, and still identify as a woman. Still others may choose to express their gender in a variety of ways that may not have anything to do with their sexual orientation or gender identity, such as dressing in ways that represent their culture.
People may be fluid in their sexual orientation or gender identity; it may change from day to day, month to month, or even year to year.6,7
*The term LGBTQI+ is not used consistently in the literature. Throughout this article, the terminology used matches that used in the cited reference(s).
Continue to: Health care and the LGBTQI+ community...
Health care and the LGBTQI+ community
The LGBTQI+ community has a history of experiencing societal discrimination and stigma, which stems from medical mistrust often due to a lack of understanding of their medical and psychosocial needs.8,9 A 2019 survey of US LGBTQ adults, found that about 50% of people who identified as transgender reported having negative or discriminatory experiences with a health care clinician.10 About 18% of transgender people anticipated being refused medical care due to their gender identity.10 About 18% of LGBTQ individuals avoid any type of medical care, fearing discrimination.10 Lesbian women are 3 times more likely to have not seen an ObGyn than women who identify as straight.11 Sixty-two percent of lesbian women have biological children and received prenatal care; however, of those, 47% do not receive routine cancer screenings.10,11 Only 45% of age-eligible lesbian women have received at least 1 dose of the HPV vaccine, compared with 60% of straight women.10,11
Due to societal stigma, more than 40% of transgender people have attempted suicide.12 Felt or perceived stigma is also associated with risky health behaviors that contribute to health disparities. LGBTQI+ people are more likely to use substances,13 lesbian women are more likely to be obese,14 and 19% of transgender men are living with HIV/AIDS.15 Rates of unintended pregnancy among lesbian women and transgender men are 28%, compared with 6% in straight women, and 12% in heterosexual teens.15,16
In addition to real or perceived discrimination, there are medical misperceptions among the LGBTQI+ community. For instance, sexual minority women (SMW) are less likely to receive regular screening for cervical cancer. In one survey of more than 400 SMW, about 25% reported not receiving regular screening. SMW may mistakenly believe they do not need Pap testing and pelvic exams because they do not have penile-vaginal intercourse.17,18 Transgender men may not identify with having a cervix, or may perceive ObGyns to be “gendered” toward people who identify as women.18
Embracing cultural humility
Cultural humility expands upon the term cultural competence, with the idea that one can never be fully competent in the culture of another person.19,20 The National Institutes of Health defines cultural humility as “a lifelong process of self-reflection and self-critique whereby the individual not only learns about another’s culture, but one starts with an examination of his/her own beliefs and cultural identities.”21
Having cultural humility is the recognition that, in order to treat your ObGyn patient as a whole person and engage in shared medical decision making in the office setting, you need to know their sexual orientation and gender identity. Treating each patient the same is not providing equitable care (equality does not equal equity) because each patient has different medical and psychosocial needs. Embracing cultural humility is the first step in creating safe and welcoming spaces in the ObGyn office.20
CASE Ways to better introduce yourself
To revisit the case, what options does the clinician have to start off on a best foot to create a safe space for Alex?
- Open with your own preferred pronouns. For instance, for an introduction, consider: “I’m Dr. X, my pronouns are she/her.”
- Don’t assume. Do not make assumptions about the relationship between Alex and the person accompanying them.
4 ways for creating welcoming and affirming spaces in ObGyn
- Make sure your intake form is inclusive. Include a space for pronouns and the patient’s preferred name (which may differ from their legal name). Also allow patients to choose more than 1 sexual orientation and gender identity.20 (An example form is available from the LGBT National Health Education Center: https://www.lgbtqiahealtheducation.org/publication/focus-forms-policy-creating-inclusive-environment-lgbt-patients/.)
- Create a safe environment in the waiting area. Try to ensure that at least 1 bathroom is labeled “All Gender” or “Family.” Gendered bathrooms (eg, Ladies’ or Men’s rooms) are not welcoming. Make sure your non-discrimination policy is displayed and includes sexual orientation and gender identity. Review the patient education and reading materials in your waiting room to ensure they are inclusive. Do they show people with varied gender expression? Do they show same-sex couples or interracial couples?
- Use a trauma-informed approach when taking a sexual history and while conducting a physical exam. Determine if a pelvic exam is necessary at this visit or can it be postponed for another visit, when trust has been established with the patient. Explain each part of the pelvic/vaginal exam prior to conducting and again while performing the exam. Before taking a sexual history, explain why you are asking the questions and be sure to remain neutral with your questioning. For instance, you can say, “It’s important for me to understand your medical history in detail to provide you with the best health care possible.” Instead of asking, “Do you have sex with men, women, or both?” ask, “Do you have sex with people with a penis, vagina, or both? Do you have anal sex?” Recognize that some patients may be in a polyamorous relationship and may have more than 1 committed partner. For sexually active patients consider asking if they have ever exchanged sex for money or other goods, making sure to avoid judgmental body language or wording. Patients who do engage in “survival sex” may benefit from a discussion on pre-exposure prophylaxis to reduce HIV transmission.22
- Provide appropriate counsel based on their feedback.
- Explain their risk for HPV infection and vaccination options.
- Respectfully ask if there is a need for contraception and review options appropriate for their situation.
- Ask about the use of “toys” and provide guidance on sanitation and risk of infection with shared toys.
- Determine current or past hormone use for patients who identify as transgender and nonbinary (although many do not take hormones and have not had gender-affirming procedures, some may be considering these procedures). Be sure to ask these patients if they have had any surgeries or other procedures.
The receipt of gynecologic care can be traumatic for some LGBTQI+ people. Explain to the patient why you are doing everything during your examination and how it might feel. If a pelvic exam is not absolutely necessary that day, perhaps the patient can return another time. For transgender men who have been taking testosterone,vaginal atrophy may be a concern, and you could consider a pediatric speculum.
In summary, the number of people who identify as lesbian, gay, bisexual, transgender/nonbinary, queer/questioning, intersex, or asexual is not insignificant. Many of these patients or their partners may present for ObGyn care at your office. Clinicians need to understand that there is a new language relative to sexual orientation and gender identity. Incorporating cultural humility into one’s practice requires personal introspection and is a first step to creating safe and welcoming spaces in the ObGyn office. ●
- Jones JM. LGBT identification in US ticks up to 7.1%. Gallup News. February 17, 2022. Accessed July 11, 2023. https://news.gallup .com/poll/389792/lgbt-identification-ticks -up.aspx
- Patterson JG, Tree JMJ, and Kamen C. Cultural competency and microaggressions in the provision of care to LGBT patients in rural and Appalachian Tennessee. Patient Educ Couns. 2019;102:2081-2090. doi: 10.1016/j.pec .2019.06.003
- Grasso C, Funk D. Collecting sexual orientation and gender identity (SO/GI) data in electronic health records. The National LGBT Health Education Center. Accessed October 12, 2023. https://fenwayhealth.org/wp-content/uploads /4.-Collecting-SOGI-Data.pdf
- Glossary of terms: LGBTQ. GLAAD website. Accessed October 16, 2023. https://glaad.org /reference/terms.
- LGBTQI+. Social protection and human rights website. Accessed November 2, 2023. https ://socialprotection-humanrights.org/key -issues/disadvantaged-and-vulnerable-groups /lgbtqi/
- Goldberg AE, Manley MH, Ellawala T, et al. Sexuality and sexual identity across the first year of parenthood among male-partnered plurisexual women. Psychol Sex Orientat Gend Divers. 2019;6:75.
- Campbell A, Perales F, Hughes TL, et al. Sexual fluidity and psychological distress: what happens when young women’s sexual identities change? J Health Soc Behav. 2022;63:577-593.
- Gessner M, Bishop MD, Martos A, et al. Sexual minority people’s perspectives of sexual health care: understanding minority stress in sexual health settings. Sex Res Social Policy. 2020;17:607618. doi: 10.1007/s13178-019-00418-9
- Carpenter E. “The health system just wasn’t built for us”: queer cisgender women and gender expansive individuals’ strategies for navigating reproductive health care. Womens Health Issues. 2021;31:478-484. doi: 10.1016 /j.whi.2021.06.004
- Casey LS, Reisner SL, Findling MG, et al. Discrimination in the United States: experiences of lesbian, gay, bisexual, transgender, and queer Americans. Health Serv Res. 2019;54(suppl 2):1454-1466. doi: 10.1111/1475-6773.13229
- Grasso C, Goldhammer H, Brown RJ, et al. Using sexual orientation and gender identity data in electronic health records to assess for disparities in preventive health screening services. Int J Med Inform. 2020:142:104245. doi: 10.1016 /j.ijmedinf.2020.104245
- Austin A, Craig SL, D’Souza S, et al. Suicidality among transgender youth: elucidating the role of interpersonal risk factors. J Interpers Violence. 2022;37:NP2696-NP2718. doi: 10.1177 /0886260520915554. Published correction appears in J Interpers Violence. 2020:8862 60520946128.
- Hibbert MP, Hillis A, Brett CE, et al. A narrative systematic review of sexualised drug use and sexual health outcomes among LGBT people. Int J Drug Policy. 2021;93:103187. doi: 10.1016 /j.drugpo.2021.103187
- Azagba S, Shan L, Latham K. Overweight and obesity among sexual minority adults in the United States. Int J Environ Res Public Health. 2019;16:1828. doi: 10.3390/ijerph16101828
- Klein PW, Psihopaidas D, Xavier J, et al. HIVrelated outcome disparities between transgender women living with HIV and cisgender people living with HIV served by the Health Resources and Services Administration’s Ryan White HIV/ AIDS Program: a retrospective study. PLoS Med. 2020;17:e1003125. doi: 10.1371/journal.pmed .1003125
- Jung C, Hunter A, Saleh M, et al. Breaking the binary: how clinicians can ensure everyone receives high quality reproductive health services. Open Access J Contracept. 2023:14:23-39. doi: 10.2147/OAJC.S368621
- Bustamante G, Reiter PL, McRee AL. Cervical cancer screening among sexual minority women: findings from a national survey. Cancer Causes Control. 2021;32:911-917. doi: 10.1007 /s10552-021-01442-0
- Dhillon N, Oliffe JL, Kelly MT, et al. Bridging barriers to cervical cancer screening in transgender men: a scoping review. Am J Mens Health. 2020;14:1557988320925691. doi: 10.1177/1557988320925691
- Stubbe DE. Practicing cultural competence and cultural humility in the care of diverse patients. Focus (Am Psychiatr Publ). 2020;18:49-51. doi: 10.1176/appi.focus.20190041
- Alpert A, Kamen C, Schabath MB, et al. What exactly are we measuring? Evaluating sexual and gender minority cultural humility training for oncology care clinicians. J Clin Oncol. 2020;38:2605-2609. doi: 10.1200/JCO.19.03300
- Yeager KA, Bauer-Wu S. Cultural humility: essential foundation for clinical researchers. Appl Nurs Res. 2013;26:251-256. doi: 10.1016 /j.apnr.2013.06.008
- Nagle-Yang S, Sachdeva J, Zhao LX, et al. Traumainformed care for obstetric and gynecologic settings. Matern Child Health J. 2022;26:2362-2369.
CASE A new patient office visit
A new patient is waiting for you in the exam room. You review the chart and see the sex demographic field is blank, and the patient’s name is Alex. As an ObGyn, most of your patients are female, but you have treated your patients’ partners for sexually transmitted infections. As you enter the room, you see 2 androgynously dressed individuals; you introduce yourself and ask,
“What brings you in today, and who is your friend?”
“This is my partner Charlie, and we are worried I have an STD.”
Estimates suggest that between 7% to 12% of the US population identifies as lesbian, gay, bisexual, transgender/non-binary, queer/questioning, intersex, or asexual (LGBTQI+).1 If you practice in an urban area, the odds are quite high that you have encountered an LGBTQI+ person who openly identified as such; if you are in a rural area, you also likely have had an LGBTQI+ patient, but they may not have disclosed this about themselves.2 Maybe you have had training in cultural relevance or are a member of this community and you feel confident in providing quality care to LGBTQI+ patients. Or maybe you think that, as a responsibly practicing health care clinician, you treat all patients the same, so whether or not you know their sexual orientation or gender identity does not impact the care you provide. As the proportion of US adults who identify as LGBTQI+ increases,1 it becomes more important for health care clinicians to understand the challenges these patients face when trying to access health care. To start, let’s review the meaning of LGBTQI+, the history of the community, what it means to be culturally relevant or humble, and how to create a welcoming and safe practice environment.
LGBTQI+ terms and definitions
The first step in providing quality care to LGBTQI+ patients is to understand the terminology associated with sexual orientation, gender identity, and gender expression.3–5
Sexual orientation refers to whom a person is sexually attracted. The term straight/heterosexual suggests a person is sexually attracted to a person of the opposite gender. Lesbian or gay refers to those who are attracted to their same gender. Some people use bisexual (attracted to both the same and opposite gender) and pansexual (attracted to all humans regardless of gender). Still others refer to themselves as queer—people who identify as someone who is not heterosexual or cisgender. A variety of other terms exist to describe one’s sexual attraction. There are also some people who identify as asexual, which suggests they are not sexually attracted to anyone.
Gender identity relates to how one views their own gender. If you were assigned female at birth and identify as a woman, you are cisgender. If you were assigned male at birth and identify as a woman, you may identify as transgender whether or not you have had gender transitioning surgery or have taken hormones. Some people do not identify with the terms male or female and may view themselves as nonbinary. The terms gender queer, gender fluid, gender diverse, and gender non-conforming also may be used to describe various ways that an individual may not identify as male or female. We also can refer to people as “assigned female at birth” or “assigned male at birth”. People with intersex conditions may require taking a unique medical history that includes asking about genetic testing (eg, 46,XX congenital adrenal hyperplasia or 46,XY complete gonadal dysgenesis).
Gender expression refers to how one pre-sents themselves to others through appearance, dress, and behavior. A person may be assigned female at birth, dress in a conventional male fashion, and still identify as a woman. Still others may choose to express their gender in a variety of ways that may not have anything to do with their sexual orientation or gender identity, such as dressing in ways that represent their culture.
People may be fluid in their sexual orientation or gender identity; it may change from day to day, month to month, or even year to year.6,7
*The term LGBTQI+ is not used consistently in the literature. Throughout this article, the terminology used matches that used in the cited reference(s).
Continue to: Health care and the LGBTQI+ community...
Health care and the LGBTQI+ community
The LGBTQI+ community has a history of experiencing societal discrimination and stigma, which stems from medical mistrust often due to a lack of understanding of their medical and psychosocial needs.8,9 A 2019 survey of US LGBTQ adults, found that about 50% of people who identified as transgender reported having negative or discriminatory experiences with a health care clinician.10 About 18% of transgender people anticipated being refused medical care due to their gender identity.10 About 18% of LGBTQ individuals avoid any type of medical care, fearing discrimination.10 Lesbian women are 3 times more likely to have not seen an ObGyn than women who identify as straight.11 Sixty-two percent of lesbian women have biological children and received prenatal care; however, of those, 47% do not receive routine cancer screenings.10,11 Only 45% of age-eligible lesbian women have received at least 1 dose of the HPV vaccine, compared with 60% of straight women.10,11
Due to societal stigma, more than 40% of transgender people have attempted suicide.12 Felt or perceived stigma is also associated with risky health behaviors that contribute to health disparities. LGBTQI+ people are more likely to use substances,13 lesbian women are more likely to be obese,14 and 19% of transgender men are living with HIV/AIDS.15 Rates of unintended pregnancy among lesbian women and transgender men are 28%, compared with 6% in straight women, and 12% in heterosexual teens.15,16
In addition to real or perceived discrimination, there are medical misperceptions among the LGBTQI+ community. For instance, sexual minority women (SMW) are less likely to receive regular screening for cervical cancer. In one survey of more than 400 SMW, about 25% reported not receiving regular screening. SMW may mistakenly believe they do not need Pap testing and pelvic exams because they do not have penile-vaginal intercourse.17,18 Transgender men may not identify with having a cervix, or may perceive ObGyns to be “gendered” toward people who identify as women.18
Embracing cultural humility
Cultural humility expands upon the term cultural competence, with the idea that one can never be fully competent in the culture of another person.19,20 The National Institutes of Health defines cultural humility as “a lifelong process of self-reflection and self-critique whereby the individual not only learns about another’s culture, but one starts with an examination of his/her own beliefs and cultural identities.”21
Having cultural humility is the recognition that, in order to treat your ObGyn patient as a whole person and engage in shared medical decision making in the office setting, you need to know their sexual orientation and gender identity. Treating each patient the same is not providing equitable care (equality does not equal equity) because each patient has different medical and psychosocial needs. Embracing cultural humility is the first step in creating safe and welcoming spaces in the ObGyn office.20
CASE Ways to better introduce yourself
To revisit the case, what options does the clinician have to start off on a best foot to create a safe space for Alex?
- Open with your own preferred pronouns. For instance, for an introduction, consider: “I’m Dr. X, my pronouns are she/her.”
- Don’t assume. Do not make assumptions about the relationship between Alex and the person accompanying them.
4 ways for creating welcoming and affirming spaces in ObGyn
- Make sure your intake form is inclusive. Include a space for pronouns and the patient’s preferred name (which may differ from their legal name). Also allow patients to choose more than 1 sexual orientation and gender identity.20 (An example form is available from the LGBT National Health Education Center: https://www.lgbtqiahealtheducation.org/publication/focus-forms-policy-creating-inclusive-environment-lgbt-patients/.)
- Create a safe environment in the waiting area. Try to ensure that at least 1 bathroom is labeled “All Gender” or “Family.” Gendered bathrooms (eg, Ladies’ or Men’s rooms) are not welcoming. Make sure your non-discrimination policy is displayed and includes sexual orientation and gender identity. Review the patient education and reading materials in your waiting room to ensure they are inclusive. Do they show people with varied gender expression? Do they show same-sex couples or interracial couples?
- Use a trauma-informed approach when taking a sexual history and while conducting a physical exam. Determine if a pelvic exam is necessary at this visit or can it be postponed for another visit, when trust has been established with the patient. Explain each part of the pelvic/vaginal exam prior to conducting and again while performing the exam. Before taking a sexual history, explain why you are asking the questions and be sure to remain neutral with your questioning. For instance, you can say, “It’s important for me to understand your medical history in detail to provide you with the best health care possible.” Instead of asking, “Do you have sex with men, women, or both?” ask, “Do you have sex with people with a penis, vagina, or both? Do you have anal sex?” Recognize that some patients may be in a polyamorous relationship and may have more than 1 committed partner. For sexually active patients consider asking if they have ever exchanged sex for money or other goods, making sure to avoid judgmental body language or wording. Patients who do engage in “survival sex” may benefit from a discussion on pre-exposure prophylaxis to reduce HIV transmission.22
- Provide appropriate counsel based on their feedback.
- Explain their risk for HPV infection and vaccination options.
- Respectfully ask if there is a need for contraception and review options appropriate for their situation.
- Ask about the use of “toys” and provide guidance on sanitation and risk of infection with shared toys.
- Determine current or past hormone use for patients who identify as transgender and nonbinary (although many do not take hormones and have not had gender-affirming procedures, some may be considering these procedures). Be sure to ask these patients if they have had any surgeries or other procedures.
The receipt of gynecologic care can be traumatic for some LGBTQI+ people. Explain to the patient why you are doing everything during your examination and how it might feel. If a pelvic exam is not absolutely necessary that day, perhaps the patient can return another time. For transgender men who have been taking testosterone,vaginal atrophy may be a concern, and you could consider a pediatric speculum.
In summary, the number of people who identify as lesbian, gay, bisexual, transgender/nonbinary, queer/questioning, intersex, or asexual is not insignificant. Many of these patients or their partners may present for ObGyn care at your office. Clinicians need to understand that there is a new language relative to sexual orientation and gender identity. Incorporating cultural humility into one’s practice requires personal introspection and is a first step to creating safe and welcoming spaces in the ObGyn office. ●
CASE A new patient office visit
A new patient is waiting for you in the exam room. You review the chart and see the sex demographic field is blank, and the patient’s name is Alex. As an ObGyn, most of your patients are female, but you have treated your patients’ partners for sexually transmitted infections. As you enter the room, you see 2 androgynously dressed individuals; you introduce yourself and ask,
“What brings you in today, and who is your friend?”
“This is my partner Charlie, and we are worried I have an STD.”
Estimates suggest that between 7% to 12% of the US population identifies as lesbian, gay, bisexual, transgender/non-binary, queer/questioning, intersex, or asexual (LGBTQI+).1 If you practice in an urban area, the odds are quite high that you have encountered an LGBTQI+ person who openly identified as such; if you are in a rural area, you also likely have had an LGBTQI+ patient, but they may not have disclosed this about themselves.2 Maybe you have had training in cultural relevance or are a member of this community and you feel confident in providing quality care to LGBTQI+ patients. Or maybe you think that, as a responsibly practicing health care clinician, you treat all patients the same, so whether or not you know their sexual orientation or gender identity does not impact the care you provide. As the proportion of US adults who identify as LGBTQI+ increases,1 it becomes more important for health care clinicians to understand the challenges these patients face when trying to access health care. To start, let’s review the meaning of LGBTQI+, the history of the community, what it means to be culturally relevant or humble, and how to create a welcoming and safe practice environment.
LGBTQI+ terms and definitions
The first step in providing quality care to LGBTQI+ patients is to understand the terminology associated with sexual orientation, gender identity, and gender expression.3–5
Sexual orientation refers to whom a person is sexually attracted. The term straight/heterosexual suggests a person is sexually attracted to a person of the opposite gender. Lesbian or gay refers to those who are attracted to their same gender. Some people use bisexual (attracted to both the same and opposite gender) and pansexual (attracted to all humans regardless of gender). Still others refer to themselves as queer—people who identify as someone who is not heterosexual or cisgender. A variety of other terms exist to describe one’s sexual attraction. There are also some people who identify as asexual, which suggests they are not sexually attracted to anyone.
Gender identity relates to how one views their own gender. If you were assigned female at birth and identify as a woman, you are cisgender. If you were assigned male at birth and identify as a woman, you may identify as transgender whether or not you have had gender transitioning surgery or have taken hormones. Some people do not identify with the terms male or female and may view themselves as nonbinary. The terms gender queer, gender fluid, gender diverse, and gender non-conforming also may be used to describe various ways that an individual may not identify as male or female. We also can refer to people as “assigned female at birth” or “assigned male at birth”. People with intersex conditions may require taking a unique medical history that includes asking about genetic testing (eg, 46,XX congenital adrenal hyperplasia or 46,XY complete gonadal dysgenesis).
Gender expression refers to how one pre-sents themselves to others through appearance, dress, and behavior. A person may be assigned female at birth, dress in a conventional male fashion, and still identify as a woman. Still others may choose to express their gender in a variety of ways that may not have anything to do with their sexual orientation or gender identity, such as dressing in ways that represent their culture.
People may be fluid in their sexual orientation or gender identity; it may change from day to day, month to month, or even year to year.6,7
*The term LGBTQI+ is not used consistently in the literature. Throughout this article, the terminology used matches that used in the cited reference(s).
Continue to: Health care and the LGBTQI+ community...
Health care and the LGBTQI+ community
The LGBTQI+ community has a history of experiencing societal discrimination and stigma, which stems from medical mistrust often due to a lack of understanding of their medical and psychosocial needs.8,9 A 2019 survey of US LGBTQ adults, found that about 50% of people who identified as transgender reported having negative or discriminatory experiences with a health care clinician.10 About 18% of transgender people anticipated being refused medical care due to their gender identity.10 About 18% of LGBTQ individuals avoid any type of medical care, fearing discrimination.10 Lesbian women are 3 times more likely to have not seen an ObGyn than women who identify as straight.11 Sixty-two percent of lesbian women have biological children and received prenatal care; however, of those, 47% do not receive routine cancer screenings.10,11 Only 45% of age-eligible lesbian women have received at least 1 dose of the HPV vaccine, compared with 60% of straight women.10,11
Due to societal stigma, more than 40% of transgender people have attempted suicide.12 Felt or perceived stigma is also associated with risky health behaviors that contribute to health disparities. LGBTQI+ people are more likely to use substances,13 lesbian women are more likely to be obese,14 and 19% of transgender men are living with HIV/AIDS.15 Rates of unintended pregnancy among lesbian women and transgender men are 28%, compared with 6% in straight women, and 12% in heterosexual teens.15,16
In addition to real or perceived discrimination, there are medical misperceptions among the LGBTQI+ community. For instance, sexual minority women (SMW) are less likely to receive regular screening for cervical cancer. In one survey of more than 400 SMW, about 25% reported not receiving regular screening. SMW may mistakenly believe they do not need Pap testing and pelvic exams because they do not have penile-vaginal intercourse.17,18 Transgender men may not identify with having a cervix, or may perceive ObGyns to be “gendered” toward people who identify as women.18
Embracing cultural humility
Cultural humility expands upon the term cultural competence, with the idea that one can never be fully competent in the culture of another person.19,20 The National Institutes of Health defines cultural humility as “a lifelong process of self-reflection and self-critique whereby the individual not only learns about another’s culture, but one starts with an examination of his/her own beliefs and cultural identities.”21
Having cultural humility is the recognition that, in order to treat your ObGyn patient as a whole person and engage in shared medical decision making in the office setting, you need to know their sexual orientation and gender identity. Treating each patient the same is not providing equitable care (equality does not equal equity) because each patient has different medical and psychosocial needs. Embracing cultural humility is the first step in creating safe and welcoming spaces in the ObGyn office.20
CASE Ways to better introduce yourself
To revisit the case, what options does the clinician have to start off on a best foot to create a safe space for Alex?
- Open with your own preferred pronouns. For instance, for an introduction, consider: “I’m Dr. X, my pronouns are she/her.”
- Don’t assume. Do not make assumptions about the relationship between Alex and the person accompanying them.
4 ways for creating welcoming and affirming spaces in ObGyn
- Make sure your intake form is inclusive. Include a space for pronouns and the patient’s preferred name (which may differ from their legal name). Also allow patients to choose more than 1 sexual orientation and gender identity.20 (An example form is available from the LGBT National Health Education Center: https://www.lgbtqiahealtheducation.org/publication/focus-forms-policy-creating-inclusive-environment-lgbt-patients/.)
- Create a safe environment in the waiting area. Try to ensure that at least 1 bathroom is labeled “All Gender” or “Family.” Gendered bathrooms (eg, Ladies’ or Men’s rooms) are not welcoming. Make sure your non-discrimination policy is displayed and includes sexual orientation and gender identity. Review the patient education and reading materials in your waiting room to ensure they are inclusive. Do they show people with varied gender expression? Do they show same-sex couples or interracial couples?
- Use a trauma-informed approach when taking a sexual history and while conducting a physical exam. Determine if a pelvic exam is necessary at this visit or can it be postponed for another visit, when trust has been established with the patient. Explain each part of the pelvic/vaginal exam prior to conducting and again while performing the exam. Before taking a sexual history, explain why you are asking the questions and be sure to remain neutral with your questioning. For instance, you can say, “It’s important for me to understand your medical history in detail to provide you with the best health care possible.” Instead of asking, “Do you have sex with men, women, or both?” ask, “Do you have sex with people with a penis, vagina, or both? Do you have anal sex?” Recognize that some patients may be in a polyamorous relationship and may have more than 1 committed partner. For sexually active patients consider asking if they have ever exchanged sex for money or other goods, making sure to avoid judgmental body language or wording. Patients who do engage in “survival sex” may benefit from a discussion on pre-exposure prophylaxis to reduce HIV transmission.22
- Provide appropriate counsel based on their feedback.
- Explain their risk for HPV infection and vaccination options.
- Respectfully ask if there is a need for contraception and review options appropriate for their situation.
- Ask about the use of “toys” and provide guidance on sanitation and risk of infection with shared toys.
- Determine current or past hormone use for patients who identify as transgender and nonbinary (although many do not take hormones and have not had gender-affirming procedures, some may be considering these procedures). Be sure to ask these patients if they have had any surgeries or other procedures.
The receipt of gynecologic care can be traumatic for some LGBTQI+ people. Explain to the patient why you are doing everything during your examination and how it might feel. If a pelvic exam is not absolutely necessary that day, perhaps the patient can return another time. For transgender men who have been taking testosterone,vaginal atrophy may be a concern, and you could consider a pediatric speculum.
In summary, the number of people who identify as lesbian, gay, bisexual, transgender/nonbinary, queer/questioning, intersex, or asexual is not insignificant. Many of these patients or their partners may present for ObGyn care at your office. Clinicians need to understand that there is a new language relative to sexual orientation and gender identity. Incorporating cultural humility into one’s practice requires personal introspection and is a first step to creating safe and welcoming spaces in the ObGyn office. ●
- Jones JM. LGBT identification in US ticks up to 7.1%. Gallup News. February 17, 2022. Accessed July 11, 2023. https://news.gallup .com/poll/389792/lgbt-identification-ticks -up.aspx
- Patterson JG, Tree JMJ, and Kamen C. Cultural competency and microaggressions in the provision of care to LGBT patients in rural and Appalachian Tennessee. Patient Educ Couns. 2019;102:2081-2090. doi: 10.1016/j.pec .2019.06.003
- Grasso C, Funk D. Collecting sexual orientation and gender identity (SO/GI) data in electronic health records. The National LGBT Health Education Center. Accessed October 12, 2023. https://fenwayhealth.org/wp-content/uploads /4.-Collecting-SOGI-Data.pdf
- Glossary of terms: LGBTQ. GLAAD website. Accessed October 16, 2023. https://glaad.org /reference/terms.
- LGBTQI+. Social protection and human rights website. Accessed November 2, 2023. https ://socialprotection-humanrights.org/key -issues/disadvantaged-and-vulnerable-groups /lgbtqi/
- Goldberg AE, Manley MH, Ellawala T, et al. Sexuality and sexual identity across the first year of parenthood among male-partnered plurisexual women. Psychol Sex Orientat Gend Divers. 2019;6:75.
- Campbell A, Perales F, Hughes TL, et al. Sexual fluidity and psychological distress: what happens when young women’s sexual identities change? J Health Soc Behav. 2022;63:577-593.
- Gessner M, Bishop MD, Martos A, et al. Sexual minority people’s perspectives of sexual health care: understanding minority stress in sexual health settings. Sex Res Social Policy. 2020;17:607618. doi: 10.1007/s13178-019-00418-9
- Carpenter E. “The health system just wasn’t built for us”: queer cisgender women and gender expansive individuals’ strategies for navigating reproductive health care. Womens Health Issues. 2021;31:478-484. doi: 10.1016 /j.whi.2021.06.004
- Casey LS, Reisner SL, Findling MG, et al. Discrimination in the United States: experiences of lesbian, gay, bisexual, transgender, and queer Americans. Health Serv Res. 2019;54(suppl 2):1454-1466. doi: 10.1111/1475-6773.13229
- Grasso C, Goldhammer H, Brown RJ, et al. Using sexual orientation and gender identity data in electronic health records to assess for disparities in preventive health screening services. Int J Med Inform. 2020:142:104245. doi: 10.1016 /j.ijmedinf.2020.104245
- Austin A, Craig SL, D’Souza S, et al. Suicidality among transgender youth: elucidating the role of interpersonal risk factors. J Interpers Violence. 2022;37:NP2696-NP2718. doi: 10.1177 /0886260520915554. Published correction appears in J Interpers Violence. 2020:8862 60520946128.
- Hibbert MP, Hillis A, Brett CE, et al. A narrative systematic review of sexualised drug use and sexual health outcomes among LGBT people. Int J Drug Policy. 2021;93:103187. doi: 10.1016 /j.drugpo.2021.103187
- Azagba S, Shan L, Latham K. Overweight and obesity among sexual minority adults in the United States. Int J Environ Res Public Health. 2019;16:1828. doi: 10.3390/ijerph16101828
- Klein PW, Psihopaidas D, Xavier J, et al. HIVrelated outcome disparities between transgender women living with HIV and cisgender people living with HIV served by the Health Resources and Services Administration’s Ryan White HIV/ AIDS Program: a retrospective study. PLoS Med. 2020;17:e1003125. doi: 10.1371/journal.pmed .1003125
- Jung C, Hunter A, Saleh M, et al. Breaking the binary: how clinicians can ensure everyone receives high quality reproductive health services. Open Access J Contracept. 2023:14:23-39. doi: 10.2147/OAJC.S368621
- Bustamante G, Reiter PL, McRee AL. Cervical cancer screening among sexual minority women: findings from a national survey. Cancer Causes Control. 2021;32:911-917. doi: 10.1007 /s10552-021-01442-0
- Dhillon N, Oliffe JL, Kelly MT, et al. Bridging barriers to cervical cancer screening in transgender men: a scoping review. Am J Mens Health. 2020;14:1557988320925691. doi: 10.1177/1557988320925691
- Stubbe DE. Practicing cultural competence and cultural humility in the care of diverse patients. Focus (Am Psychiatr Publ). 2020;18:49-51. doi: 10.1176/appi.focus.20190041
- Alpert A, Kamen C, Schabath MB, et al. What exactly are we measuring? Evaluating sexual and gender minority cultural humility training for oncology care clinicians. J Clin Oncol. 2020;38:2605-2609. doi: 10.1200/JCO.19.03300
- Yeager KA, Bauer-Wu S. Cultural humility: essential foundation for clinical researchers. Appl Nurs Res. 2013;26:251-256. doi: 10.1016 /j.apnr.2013.06.008
- Nagle-Yang S, Sachdeva J, Zhao LX, et al. Traumainformed care for obstetric and gynecologic settings. Matern Child Health J. 2022;26:2362-2369.
- Jones JM. LGBT identification in US ticks up to 7.1%. Gallup News. February 17, 2022. Accessed July 11, 2023. https://news.gallup .com/poll/389792/lgbt-identification-ticks -up.aspx
- Patterson JG, Tree JMJ, and Kamen C. Cultural competency and microaggressions in the provision of care to LGBT patients in rural and Appalachian Tennessee. Patient Educ Couns. 2019;102:2081-2090. doi: 10.1016/j.pec .2019.06.003
- Grasso C, Funk D. Collecting sexual orientation and gender identity (SO/GI) data in electronic health records. The National LGBT Health Education Center. Accessed October 12, 2023. https://fenwayhealth.org/wp-content/uploads /4.-Collecting-SOGI-Data.pdf
- Glossary of terms: LGBTQ. GLAAD website. Accessed October 16, 2023. https://glaad.org /reference/terms.
- LGBTQI+. Social protection and human rights website. Accessed November 2, 2023. https ://socialprotection-humanrights.org/key -issues/disadvantaged-and-vulnerable-groups /lgbtqi/
- Goldberg AE, Manley MH, Ellawala T, et al. Sexuality and sexual identity across the first year of parenthood among male-partnered plurisexual women. Psychol Sex Orientat Gend Divers. 2019;6:75.
- Campbell A, Perales F, Hughes TL, et al. Sexual fluidity and psychological distress: what happens when young women’s sexual identities change? J Health Soc Behav. 2022;63:577-593.
- Gessner M, Bishop MD, Martos A, et al. Sexual minority people’s perspectives of sexual health care: understanding minority stress in sexual health settings. Sex Res Social Policy. 2020;17:607618. doi: 10.1007/s13178-019-00418-9
- Carpenter E. “The health system just wasn’t built for us”: queer cisgender women and gender expansive individuals’ strategies for navigating reproductive health care. Womens Health Issues. 2021;31:478-484. doi: 10.1016 /j.whi.2021.06.004
- Casey LS, Reisner SL, Findling MG, et al. Discrimination in the United States: experiences of lesbian, gay, bisexual, transgender, and queer Americans. Health Serv Res. 2019;54(suppl 2):1454-1466. doi: 10.1111/1475-6773.13229
- Grasso C, Goldhammer H, Brown RJ, et al. Using sexual orientation and gender identity data in electronic health records to assess for disparities in preventive health screening services. Int J Med Inform. 2020:142:104245. doi: 10.1016 /j.ijmedinf.2020.104245
- Austin A, Craig SL, D’Souza S, et al. Suicidality among transgender youth: elucidating the role of interpersonal risk factors. J Interpers Violence. 2022;37:NP2696-NP2718. doi: 10.1177 /0886260520915554. Published correction appears in J Interpers Violence. 2020:8862 60520946128.
- Hibbert MP, Hillis A, Brett CE, et al. A narrative systematic review of sexualised drug use and sexual health outcomes among LGBT people. Int J Drug Policy. 2021;93:103187. doi: 10.1016 /j.drugpo.2021.103187
- Azagba S, Shan L, Latham K. Overweight and obesity among sexual minority adults in the United States. Int J Environ Res Public Health. 2019;16:1828. doi: 10.3390/ijerph16101828
- Klein PW, Psihopaidas D, Xavier J, et al. HIVrelated outcome disparities between transgender women living with HIV and cisgender people living with HIV served by the Health Resources and Services Administration’s Ryan White HIV/ AIDS Program: a retrospective study. PLoS Med. 2020;17:e1003125. doi: 10.1371/journal.pmed .1003125
- Jung C, Hunter A, Saleh M, et al. Breaking the binary: how clinicians can ensure everyone receives high quality reproductive health services. Open Access J Contracept. 2023:14:23-39. doi: 10.2147/OAJC.S368621
- Bustamante G, Reiter PL, McRee AL. Cervical cancer screening among sexual minority women: findings from a national survey. Cancer Causes Control. 2021;32:911-917. doi: 10.1007 /s10552-021-01442-0
- Dhillon N, Oliffe JL, Kelly MT, et al. Bridging barriers to cervical cancer screening in transgender men: a scoping review. Am J Mens Health. 2020;14:1557988320925691. doi: 10.1177/1557988320925691
- Stubbe DE. Practicing cultural competence and cultural humility in the care of diverse patients. Focus (Am Psychiatr Publ). 2020;18:49-51. doi: 10.1176/appi.focus.20190041
- Alpert A, Kamen C, Schabath MB, et al. What exactly are we measuring? Evaluating sexual and gender minority cultural humility training for oncology care clinicians. J Clin Oncol. 2020;38:2605-2609. doi: 10.1200/JCO.19.03300
- Yeager KA, Bauer-Wu S. Cultural humility: essential foundation for clinical researchers. Appl Nurs Res. 2013;26:251-256. doi: 10.1016 /j.apnr.2013.06.008
- Nagle-Yang S, Sachdeva J, Zhao LX, et al. Traumainformed care for obstetric and gynecologic settings. Matern Child Health J. 2022;26:2362-2369.
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Goldstein, MD, MSCP, CCD</bylineText> <bylineFull/> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType>(choose one)</newsDocType> <journalDocType>(choose one)</journalDocType> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>Estimates suggest that between 7% to 12% of the US population identifies as lesbian, gay, bisexual, transgender/non-binary, queer/questioning, intersex, or asex</metaDescription> <articlePDF/> <teaserImage/> <title>LGBTQI+: Special considerations for reproductive health care</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gyn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle>MDedge ObGyn</journalFullTitle> <copyrightStatement>2018</copyrightStatement> </publicationData> <publicationData> <publicationCode>obgm</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">49726</term> <term>24</term> </publications> <sections> <term canonical="true">49</term> </sections> <topics> <term canonical="true">27442</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>LGBTQI+: Special considerations for reproductive health care</title> <deck/> </itemMeta> <itemContent> <p class="abstract">Creating a welcoming practice means inclusivity, and evaluating how you present yourself to patients to consider their gender expression and identity is part of contemporary practice</p> <h3><span class="intro">CASE</span> A new patient office visit</h3> <p> <strong>A new patient is waiting for you in the exam room. You review the chart and see the sex demographic field is blank, and the patient’s name is Alex. As an ObGyn, most of your patients are female, but you have treated your patients’ partners for sexually transmitted infections. As you enter the room, you see 2 androgynously dressed individuals; you introduce yourself and ask, </strong> </p> <p> <strong>“What brings you in today, and who is your friend?”<br/><br/>“This is my partner Charlie, and we are worried I have an STD.”</strong> </p> <p>Estimates suggest that between 7% to 12% of the US population identifies as lesbian, gay, bisexual, transgender/non-binary, queer/questioning, intersex, or asexual (LGBTQI+).<sup>1</sup> If you practice in an urban area, the odds are quite high that you have encountered an LGBTQI+ person who openly identified as such; if you are in a rural area, you also likely have had an LGBTQI+ patient, but they may not have disclosed this about themselves.<sup>2</sup> Maybe you have had training in cultural relevance or are a member of this community and you feel confident in providing quality care to LGBTQI+ patients. Or maybe you think that, as a responsibly practicing health care clinician, you treat all patients the same, so whether or not you know their sexual orientation or gender identity does not impact the care you provide. As the proportion of US adults who identify as LGBTQI+ increases,<sup>1</sup> it becomes more important for health care clinicians to understand the challenges these patients face when trying to access health care. To start, let’s review the meaning of LGBTQI+, the history of the community, what it means to be culturally relevant or humble, and how to create a welcoming and safe practice environment. </p> <h2><caps>LGBTQI+</caps> terms and definitions</h2> <p>The first step in providing quality care to LGBTQI+ patients is to understand the terminology associated with sexual orientation, gender identity, and gender expression.<sup>3–5</sup><span class="intro">Sexual orientation</span> refers to whom a person is sexually attracted. The term straight/heterosexual suggests a person is sexually attracted to a person of the opposite gender. Lesbian or gay refers to those who are attracted to their same gender. Some people use bisexual (attracted to both the same and opposite gender) and pansexual (attracted to all humans regardless of gender). Still others refer to themselves as queer—people who identify as someone who is not heterosexual or cisgender. A variety of other terms exist to describe one’s sexual attraction. There are also some people who identify as asexual, which suggests they are not sexually attracted to anyone. <br/><br/><span class="intro">Gender identity </span>relates to how one views their own gender. If you were assigned female at birth and identify as a woman, you are cisgender. If you were assigned male at birth and identify as a woman, you may identify as transgender whether or not you have had gender transitioning surgery or have taken hormones. Some people do not identify with the terms male or female and may view themselves as nonbinary. The terms gender queer, gender fluid, gender diverse, and gender non-conforming also may be used to describe various ways that an individual may not identify as male or female. We also can refer to people as “assigned female at birth” or “assigned male at birth”. People with intersex conditions may require taking a unique medical history that includes asking about genetic testing (eg, 46,XX congenital adrenal hyperplasia or 46,XY complete gonadal dysgenesis). <br/><br/><span class="intro">Gender expression</span> refers to how one pre-sents themselves to others through appearance, dress, and behavior. A person may be assigned female at birth, dress in a conventional male fashion, and still identify as a woman. Still others may choose to express their gender in a variety of ways that may not have anything to do with their sexual orientation or gender identity, such as dressing in ways that represent their culture. <br/><br/><span class="intro">People may be fluid</span><b> </b>in their sexual orientation or gender identity; it may change from day to day, month to month, or even year to year.<sup>6,7</sup> </p> <h2>Health care and the <caps>LGBTQI+</caps> community</h2> <p>The LGBTQI+ community has a history of experiencing societal discrimination and stigma, which stems from medical mistrust often due to a lack of understanding of their medical and psychosocial needs.<sup>8,9</sup> A 2019 survey of US LGBTQ adults, found that about 50% of people who identified as transgender reported having negative or discriminatory experiences with a health care clinician.<sup>10</sup> About 18% of transgender people anticipated being refused medical care due to their gender identity.<sup>10</sup> About 18% of LGBTQ individuals avoid any type of medical care, fearing discrimination.<sup>10</sup> Lesbian women are 3 times more likely to have not seen an ObGyn than women who identify as straight.<sup>11</sup> Sixty-two percent of lesbian women have biological children and received prenatal care; however, of those, 47% do not receive routine cancer screenings.<sup>10,11</sup> Only 45% of age-eligible lesbian women have received at least 1 dose of the HPV vaccine, compared with 60% of straight women.<sup>10,11</sup> </p> <p>Due to societal stigma, more than 40% of transgender people have attempted suicide.<sup>12</sup> Felt or perceived stigma is also associated with risky health behaviors that contribute to health disparities. LGBTQI+ people are more likely to use substances,<sup>13</sup> lesbian women are more likely to be obese,<sup>14</sup> and 19% of transgender men are living with HIV/AIDS.<sup>15</sup> Rates of unintended pregnancy among lesbian women and transgender men are 28%, compared with 6% in straight women, and 12% in heterosexual teens.<sup>15,16 </sup>In addition to real or perceived discrimination, there are medical misperceptions among the LGBTQI+ community. For instance, sexual minority women (SMW) are less likely to receive regular screening for cervical cancer. In one survey of more than 400 SMW, about 25% reported not receiving regular screening. SMW may mistakenly believe they do not need Pap testing and pelvic exams because they do not have penile-vaginal intercourse.<sup>17,18</sup> Transgender men may not identify with having a cervix, or may perceive ObGyns to be “gendered” toward people who identify as women.<sup>18</sup> </p> <h2>Embracing cultural humility</h2> <p>Cultural humility expands upon the term cultural competence, with the idea that one can never be fully competent in the culture of another person.<sup>19,20</sup> The National Institutes of Health defines cultural humility as “a lifelong process of self-reflection and self-critique whereby the individual not only learns about another’s culture, but one starts with an examination of his/her own beliefs and cultural identities.”<sup>21</sup></p> <p>Having cultural humility is the recognition that, in order to treat your ObGyn patient as a whole person and engage in shared medical decision making in the office setting, you need to know their sexual orientation and gender identity. Treating each patient the same is not providing equitable care (equality does not equal equity) because each patient has different medical and psychosocial needs. Embracing cultural humility is the first step in creating safe and welcoming spaces in the ObGyn office.<sup>20</sup></p> <h3><span class="intro">CASE</span> Ways to better introduce yourself</h3> <p> <strong>To revisit the case, what options does the clinician have to start off on a best foot to create a safe space for Alex? </strong> </p> <ul class="bbody"> <li>Open with your own preferred pronouns. For instance, for an introduction, consider: </li> </ul> <p> <strong> “<i>I’m Dr. X, my pronouns are she/her.</i>”</strong> </p> <ul class="bbody"> <li>Don’t assume. Do not make assumptions about the relationship between Alex and the person accompanying them.<i> </i></li> </ul> <h2>4 ways for creating welcoming and affirming spaces in ObGyn</h2> <ol class="Body"> <li><span class="intro">Make sure your intake form is inclusive.</span> Include a space for pronouns and the patient’s preferred name (which may differ from their legal name). Also allow patients to choose more than 1 sexual orientation and gender identity.<sup>20 </sup>(An example form is available from the LGBT National Health Education Center: https://www.lgbtqiahealtheducation.org/publication/focus-forms-policy-creating-inclusive-environment-lgbt-patients/.) </li> <li><span class="intro">Create a safe environment in the waitingarea.</span> Try to ensure that at least 1 bathroom is labeled “All Gender” or “Family.” Gendered bathrooms (eg, Ladies’ or Men’s rooms) are not welcoming. Make sure your non-discrimination policy is displayed and includes sexual orientation and gender identity. Review the patient education and reading materials in your waiting room to ensure they are inclusive. Do they show people with varied gender expression? Do they show same-sex couples or interracial couples?</li> <li><span class="intro">Use a trauma-informed approach when taking a sexual history and while conducting a physical exam. </span> Determine if a pelvic exam is necessary at this visit or can it be postponed for another visit, when trust has been established with the patient. Explain each part of the pelvic/vaginal exam prior to conducting and again while performing the exam. Before taking a sexual history, explain why you are asking the questions and be sure to remain neutral with your questioning. For instance, you can say, “It’s important for me to understand your medical history in detail to provide you with the best health care possible.” Instead of asking, “Do you have sex with men, women, or both?” ask, “Do you have sex with people with a penis, vagina, or both? Do you have anal sex?” Recognize that some patients may be in a polyamorous relationship and may have more than 1 committed partner. For sexually active patients consider asking if they have ever exchanged sex for money or other goods, making sure to avoid judgmental body language or wording. Patients who do engage in “survival sex” may benefit from a discussion on pre-exposure prophylaxis to reduce HIV transmission.<sup>22</sup> </li> <li> <span class="intro">Provide appropriate counsel based on their feedback. </span> </li> </ol> <ul class="body"> <li>Explain their risk for HPV infection and vaccination options. </li> <li>Respectfully ask if there is a need for contraception and review options appropriate for their situation. </li> <li>Ask about the use of “toys” and provide guidance on sanitation and risk of infection with shared toys. </li> <li>Determine current or past hormone use<b> </b>for patients who identify as transgender and nonbinary (although many do not take hormones and have not had gender-affirming procedures, some may be considering these procedures). Be sure to ask these patients if they have had any surgeries or other procedures. </li> </ul> <p>The receipt of gynecologic care can be traumatic for some LGBTQI+ people. Explain to the patient why you are doing everything during your examination and how it might feel. If a pelvic exam is not absolutely necessary that day, perhaps the patient can return another time. For transgender men who have been taking testosterone,vaginal atrophy may be a concern, and you could consider a pediatric speculum. </p> <h2><hl name="369"/>Personal introspection may be necessary</h2> <p>In summary, the number of people who identify as lesbian, gay, bisexual, transgender/nonbinary, queer/questioning, intersex, or asexual is not insignificant. Many of these patients or their partners may present for ObGyn care at your office. Clinicians need to understand that there is a new language relative to sexual orientation and gender identity. Incorporating cultural humility into one’s practice requires personal introspection and is a first step to creating safe and welcoming spaces in the ObGyn office. ●</p> </itemContent> </newsItem> </itemSet></root>
Announcement from the publisher
Dear OBG Management Reader:
Frontline Medical Communications Inc has made the difficult decision to discontinue publication of
The online archive of clinical content for
For the latest news and information on obstetrics and gynecology, continue to turn to MDedge ObGyn.
Goodbye to OBG Management
Robert L. Barbieri, MD
OBG
Over 4 decades, the work of the
Our editorial board members are nationally recognized experts in our field and innovators in clinical care. Our editorial members include: Arnold P. Advincula, MD; Linda D. Bradley, MD; Amy L. Garcia, MD; Steven R. Goldstein, MD, MSCP, CCD; Andrew M. Kaunitz, MD, MSCP; Barbara Levy, MD; David G. Mutch, MD; Errol R. Norwitz, MD, PhD, MBA; Jaimey Pauli, MD; JoAnn V. Pinkerton, MD, MSCP; Joseph S. Sanfilippo, MD; and James A. Simon, MD, CCD, IF, MSCP. Prior to his retirement, Dr. John Repke was an important member of our editorial board. Over the past decade our editorial team—Lila O’Connor, Editorial Manager, and Kathy Christie, Senior Medical Content Editor—have ensured that the articles written by our authors are expertly prepared for publication and presentation to our readers.
In clinical practice, we sometimes do not achieve the optimal patient outcomes we desire. Over the past 4 decades, the
Dear OBG Management Reader:
Frontline Medical Communications Inc has made the difficult decision to discontinue publication of
The online archive of clinical content for
For the latest news and information on obstetrics and gynecology, continue to turn to MDedge ObGyn.
Goodbye to OBG Management
Robert L. Barbieri, MD
OBG
Over 4 decades, the work of the
Our editorial board members are nationally recognized experts in our field and innovators in clinical care. Our editorial members include: Arnold P. Advincula, MD; Linda D. Bradley, MD; Amy L. Garcia, MD; Steven R. Goldstein, MD, MSCP, CCD; Andrew M. Kaunitz, MD, MSCP; Barbara Levy, MD; David G. Mutch, MD; Errol R. Norwitz, MD, PhD, MBA; Jaimey Pauli, MD; JoAnn V. Pinkerton, MD, MSCP; Joseph S. Sanfilippo, MD; and James A. Simon, MD, CCD, IF, MSCP. Prior to his retirement, Dr. John Repke was an important member of our editorial board. Over the past decade our editorial team—Lila O’Connor, Editorial Manager, and Kathy Christie, Senior Medical Content Editor—have ensured that the articles written by our authors are expertly prepared for publication and presentation to our readers.
In clinical practice, we sometimes do not achieve the optimal patient outcomes we desire. Over the past 4 decades, the
Dear OBG Management Reader:
Frontline Medical Communications Inc has made the difficult decision to discontinue publication of
The online archive of clinical content for
For the latest news and information on obstetrics and gynecology, continue to turn to MDedge ObGyn.
Goodbye to OBG Management
Robert L. Barbieri, MD
OBG
Over 4 decades, the work of the
Our editorial board members are nationally recognized experts in our field and innovators in clinical care. Our editorial members include: Arnold P. Advincula, MD; Linda D. Bradley, MD; Amy L. Garcia, MD; Steven R. Goldstein, MD, MSCP, CCD; Andrew M. Kaunitz, MD, MSCP; Barbara Levy, MD; David G. Mutch, MD; Errol R. Norwitz, MD, PhD, MBA; Jaimey Pauli, MD; JoAnn V. Pinkerton, MD, MSCP; Joseph S. Sanfilippo, MD; and James A. Simon, MD, CCD, IF, MSCP. Prior to his retirement, Dr. John Repke was an important member of our editorial board. Over the past decade our editorial team—Lila O’Connor, Editorial Manager, and Kathy Christie, Senior Medical Content Editor—have ensured that the articles written by our authors are expertly prepared for publication and presentation to our readers.
In clinical practice, we sometimes do not achieve the optimal patient outcomes we desire. Over the past 4 decades, the
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>Farewell1223docx</fileName> <TBEID>0C02EE95.SIG</TBEID> <TBUniqueIdentifier>NJ_0C02EE95</TBUniqueIdentifier> <newsOrJournal>Journal</newsOrJournal> <publisherName>Frontline Medical Communications Inc.</publisherName> <storyname/> <articleType>1</articleType> <TBLocation>Copyfitting-OBGM</TBLocation> <QCDate/> <firstPublished>20231211T144536</firstPublished> <LastPublished>20231211T144536</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20231211T144536</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline/> <bylineText/> <bylineFull/> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType>(choose one)</newsDocType> <journalDocType>(choose one)</journalDocType> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:"> <name/> <rightsInfo> <copyrightHolder> <name/> </copyrightHolder> <copyrightNotice/> </rightsInfo> </provider> <abstract/> <metaDescription>Frontline Medical Communications Inc has made the difficult decision to discontinue publication of OBG Management, effective with this issue. We thank OBG Manag</metaDescription> <articlePDF/> <teaserImage/> <title>Announcement from the publisher</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gyn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle>MDedge ObGyn</journalFullTitle> <copyrightStatement>2018</copyrightStatement> </publicationData> <publicationData> <publicationCode>obgm</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">49726</term> <term>24</term> </publications> <sections> <term canonical="true">49</term> </sections> <topics> <term canonical="true">27442</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Announcement from the publisher</title> <deck/> </itemMeta> <itemContent> <h2>Dear <scaps>OBG Management</scaps> Reader:</h2> <p>Frontline Medical Communications Inc has made the difficult decision to discontinue publication of <scaps>OBG Management</scaps>, effective with this issue. We thank <scaps>OBG Management</scaps>’s esteemed Editorial Board, loyal readers, and dedicated authors for their support. It has been our privilege to publish <scaps>OBG Management</scaps> for 35 years. </p> <p>The online archive of clinical content for <scaps>OBG Management</scaps> (2002–2023) remains accessible on MDedge ObGyn. Reprint requests can be directed to Wright’s Media via email frontline@wrightsmedia.com or telephone (877-652-5295). <br/><br/>For the latest news and information on obstetrics and gynecology, continue to turn to MDedge ObGyn. </p> <h2>Goodbye to OBG <scaps>Management</scaps></h2> <p><b>Robert L. Barbieri, MD <br/><br/></b>OBG <scaps>Management</scaps> was founded in 1988 by Carroll Dowden, a giant in the field of medical publishing. During his career he served as the editor or publisher of <i>Medical Economics</i>, <i>Physician’s Desk Reference</i>, and <i>Mayo Clinic Proceedings.</i> In creating OBG <scaps>Management</scaps>, Mr. Dowden’s vision was to edit and publish a monthly magazine focused on issues that impact the practice of obstetrics and gynecology, including patient care and practice management. Dr. Jeffrey Phelan was the founding editor-in-chief of OBG <scaps>Management</scaps>, serving from 1988 through 2000, when I became the editor-in-chief. It is with the greatest sadness that we announce that publication of OBG <scaps>Management</scaps> will cease with the December 2023 issue, 35 years after its inception. </p> <p>Over 4 decades, the work of the <scaps>OBG Management</scaps> editorial team and authors has been guided by our mission to “enhance the quality of women’s health care and the professional development of ObGyns and all women’s health care clinicians.” The teamwork of our editorial board is the primary reason for the success of <scaps>OBG Management</scaps>, ensuring that we consistently provided practical clinical guidance on the most important topics in our field with the goal of improving the health care of our patients. We are proud that <scaps>OBG Management </scaps>has been recognized as #1 in readership among obstetrics and gynecology publications. <br/><br/>Our editorial board members are nationally recognized experts in our field and innovators in clinical care. Our editorial members include: Arnold P. Advincula, MD; Linda D. Bradley, MD; Amy L. Garcia, MD; Steven R. Goldstein, MD, MSCP, CCD; Andrew M. Kaunitz, MD, MSCP; Barbara Levy, MD; David G. Mutch, MD; Errol R. Norwitz, MD, PhD, MBA; Jaimey Pauli, MD; JoAnn V. Pinkerton, MD, MSCP; Joseph S. Sanfilippo, MD; and James A. Simon, MD, CCD, IF, MSCP. Prior to his retirement, Dr. John Repke was an important member of our editorial board. Over the past decade our editorial team—Lila O’Connor, Editorial Manager, and Kathy Christie, Senior Medical Content Editor—have ensured that the articles written by our authors are expertly prepared for publication and presentation to our readers. <br/><br/>In clinical practice, we sometimes do not achieve the optimal patient outcomes we desire. Over the past 4 decades, the <scaps>OBG Management</scaps> team has strived to identify opportunities to improve patient outcomes and offer practical approaches to optimize practice. We will miss the opportunity to work with you, our community of clinical experts in women’s health care. ●</p> </itemContent> </newsItem> </itemSet></root>