OBG Management

Pregnancy and the postpartum period are times of increased risk for venous thromboembolism (VTE). While VTE is a rare event overall, it is responsible for more than 9% of maternal deaths in the United States.¹ The increased risk of VTE exists throughout pregnancy, rising in the third trimester.² The highest-risk period is the first 6 weeks postpartum, likely peaking in the first 2 to 3 weeks and returning to baseline at about 12 weeks postpartum.^2,3

To reduce this source of maternal harm, the National Partnership for Maternal Safety and the Council on Patient Safety in Women’s Health Care recommend the use of VTE prevention bundles. Bundles include standard assessment of risk during prenatal care, any admission to the hospital, and postpartum coupled with standard recommendations for treatment.^4-6 Multiple published guidelines are available for prevention of VTE in pregnancy, and they provide varying recommendations on patient selection and treatment. Many of these recommendations are based on low quality of evidence, making the choice of standard practice difficult.

In this article, I attempt to simplify patient selection and treatment based on currently published guidelines from the American College of Obstetricians and Gynecologists (ACOG), Royal College of Obstetricians and Gynaecologists (RCOG), American College of Chest Physicians (CHEST), American Society of Hematology (ASH), and expert opinion.

Determining VTE risk and need for prophylaxis

CASE 1 Woman with factor V Leiden

A 25-year-old woman (G1P0) presents for her initial prenatal visit. She says she is a carrier for factor V Leiden but has never had a clot. She was tested after her sister had a VTE. She asks, does she need VTE prophylaxis before her delivery?

What are the considerations and options for this patient?

Options for VTE prophylaxis

Before considering patients at risk for VTE, it is helpful to review the options for prophylaxis. Patients can undergo clinical surveillance or routine care with attention to VTE symptoms and a low threshold for workup.

There are 3 categories of chemoprophylaxis for prevention of VTE. (TABLE 1 offers examples of dosing regimens.) No strategy has been proven optimal over another:

• prophylactic-dose: the lowest, fixed dose.
• intermediate-dose: lacks a standard definition and is any dose higher than prophylactic-dose but lower than therapeutic-dose. This includes fixed twice-daily doses, weight-based doses, and incrementally increasing doses.
• therapeutic-dose: typically used for treatment but mentioned here since patients with high-risk conditions may use it for prevention of VTE.

The preferred agent for VTE chemoprophylaxis is low molecular weight heparin (LMWH; dalteparin, enoxaparin). LMWH has a lower risk of complications than unfractionated heparin (UFH) and can be injected once daily. LMWH and UFH do not cross the placenta. LMWH and UFH are safe in breastfeeding. Oral direct thrombin inhibitors and anti-Xa inhibitors are not recommended in pregnancy or lactation at this time. Warfarin is avoided in pregnancy except in situations with mechanical heart valves, which will not be addressed here. Patients taking warfarin for long-term anticoagulation can transition back while breastfeeding with appropriate bridging.

Continue to: Risk factors for VTE...

Risk factors for VTE

History of VTE. The most important risk factor for VTE is a personal history of prior VTE.⁶ Recurrence risks have been widely reported and depend on the factors surrounding the initial event. For patients with a prior provoked deep vein thrombosis (DVT; associated with trauma or surgery), the antepartum VTE risk likely is less than 1%, and VTE chemoprophylaxis is not recommended antepartum.⁷

For patients with a prior VTE that was not associated with surgery or trauma (unprovoked), the risk is approximately 3%; for prior VTE related to pregnancy or hormonal contraception, the risk is approximately 6%.⁷ For both of these groups, prophylactic-dose antepartum is recommended. Patients with recurrent VTE are often taking long-term anticoagulation. Anyone on long-term anticoagulation should be placed on therapeutic-dose antepartum. For patients not receiving long-term anticoagulation, consider a hematology consultation when available, and begin an intermediate-dose or therapeutic-dose regimen after assessing other risk factors and the risk of bleeding and discussing treatment with the patient.

Thrombophilias. The next most important risk factor is the presence of inherited thrombophilias.⁶ Factor V homozygote, prothrombin G20210A mutation homozygote, antithrombin deficiency, and combined factor V heterozygote and prothrombin G20210A heterozygote (also called compound heterozygote) have the strongest association with VTE in pregnancy.⁸ It is recommended that patients with these high-risk thrombophilias receive prophylactic-dose antepartum.⁸

Factor V heterozygote, prothrombin G20210A mutation heterozygote, and protein C or protein S deficiency are considered low-risk thrombophilias. Patients with low-risk thrombophilias and no personal history of VTE or first-degree relative with VTE can be monitored with clinical surveillance antepartum. However, if a family history of VTE or other risk factors for VTE are present, antepartum prophylactic-dose is recommended. Clinical factors to consider antepartum include obesity, age older than 35 years, parity of 3 or higher, varicose veins, immobility, smoking, assisted reproductive technology use, multiple gestation, and preeclampsia.¹⁰

Antiphospholipid syndrome (APS) is another high-risk condition. For patients not taking long-term anticoagulation antepartum, prophylactic-dose is recommended. For patients on long-term anticoagulation, therapeutic-dose is recommended.

Other medical conditions. Patients with medical conditions that place them at high risk for VTE may warrant prophylactic-dose antepartum. These include active cancer, active systemic lupus erythematosus, sickle cell disease, nephropathy, and inflammatory bowel disease.¹⁰ This decision can be made in conjunction with other specialists caring for the patient.

Antepartum prophylactic-dose is not recommended for low-risk patients as there is less than 1% risk of VTE.⁷ (TABLE 2 summarizes antepartum chemoprophylaxis recommendations.)

CASE 1 continued Patient develops another VTE risk factor

The patient is being followed with clinical surveillance. At 19 weeks’ gestation, she presents to the emergency department with shortness of breath and fever. She is diagnosed with COVID-19 and is admitted by a medicine service. They call the OB team to ask for recommendations regarding anticoagulation.

What should the next steps include?

Hospitalization and nonobstetric surgery are risk factors for VTE. Many hospitals use a standardized assessment for all inpatients, such as the Padua or Caprini VTE risk assessment scores. These can be modified for use in pregnant patients, although neither scoring system is currently validated for use in pregnancy.⁵ For any pregnant patient admitted to the hospital, mechanical prophylaxis is recommended.

COVID-19. Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome, COVID-19, is associated with increased rates of VTE. Recommendations for pregnant patients with COVID-19 are the same as for the general population. During hospitalization for COVID-19, pregnant patients should be placed on prophylactic-dose chemoprophylaxis. Patients should not be discharged home on chemoprophylaxis, and patients managed as outpatients for their disease do not need chemoprophylaxis.¹¹

Management approach. Prophylactic-dose administration is recommended during hospital stay for all patients admitted with anticipated length of stay of 3 days or longer and who are not at high risk for bleeding or delivery.¹⁰ Both LMWH and UFH are options for inpatients. For any nonobstetric surgery or admission, LMWH may be most appropriate. However, as most obstetrics admissions are at increased risk for delivery, UFH 5,000 U twice daily to 3 times daily is the best option to increase the chances for neuraxial anesthesia. (I review anesthesia considerations for delivery later in this article.) For patients at high risk for bleeding or delivery, mechanical prophylaxis alone, with elastic stockings or pneumatic compression devices, can be used.

Continue to: CASE 1 continued Patient is discharged home...

CASE 1 continued Patient is discharged home

The patient received enoxaparin while she was in the hospital. She is now discharged and doing well. She asks, will she need anticoagulation prophylaxis after delivery?

How would you counsel her?

Chemoprophylaxis in the postpartum period

With no risk of fetal harm and a higher risk of VTE per day, the threshold for chemoprophylaxis is lower in the postpartum period. The risk of postpartum bleeding is less than 1%, with the most common complication being wound hematomas (0.61%).⁹ For this case patient, the COVID-19 diagnosis does not alter the recommendations for postpartum chemoprophylaxis. Additionally, as the need for neuraxial anesthesia has passed, the use of intermediate-dose chemoprophylaxis over prophylactic-dose is advocated in the postpartum period, especially in obese patients.¹²

As mentioned previously, there is no standard definition of intermediate-dose. Data suggest that a weight-based intermediate-dose is most likely to achieve therapeutic levels of anti-Xa in this high-risk population compared with a fixed dose.^13,14 For example, enoxaparin 0.5 mg/kg twice daily is recommended for patients with class 3 obesity or higher by the Society for Maternal-Fetal Medicine.¹²

As a rule, anyone who was on chemoprophylaxis antepartum should be continued on at least an equivalent dose for 6 weeks postpartum. Postpartum, patients with any prior DVT should take prophylactic-dose or intermediate-dose chemoprophylaxis for 6 weeks. Patients with a known high-risk thrombophilia should receive prophylactic-dose or intermediate-dose chemoprophylaxis postpartum for 6 weeks. For patients with a low-risk thrombophilia, prophylactic-dose or intermediate-dose chemoprophylaxis is recommended for 6 weeks.

For low-risk patients without prior VTE or thrombophilia, standardized risk assessment is recommended.

Cesarean delivery

Cesarean delivery (CD) is a risk factor for postpartum VTE.⁹ A universal chemoprophylaxis strategy has not been proven in this patient population. Mechanical prophylaxis with sequential compression devices is recommended for all patients undergoing CD pre-procedure and until patients are fully ambulatory.^8,9 Early ambulation also should be encouraged.

Many risk assessment models are available for postoperative VTE prevention, and they have widely different chemoprophylaxis rates. Studies have shown chemoprophylaxis rates of 85% by RCOG, 1% by ACOG, 35% by CHEST, 94% by Caprini, and less than 1% by Padua.^15,16 In addition to the antepartum patient-specific risk factors mentioned, postpartum risk factors include infection, postpartum hemorrhage, and transfusion. Based on data extrapolated from the nonobstetric literature, chemoprophylaxis is recommended until discharge from the hospital unless risk factors are expected to continue.⁹

Neuraxial anesthesia

For patients who require postpartum chemoprophylaxis, the Society for Obstetric Anesthesia and Perinatology (SOAP) offers evidence-based guidelines for use after neuraxial anesthesia. UFH can be initiated 1 hour or longer after a neuraxial procedure and 1 hour or longer after catheter removal. Prophylactic-dose LMWH can be restarted at 12 hours or longer after a neuraxial procedure and at 4 to 6 hours or longer after catheter removal. For patients restarting intermediate-dose or therapeutic-dose, the recommendations are to wait 24 hours or longer after a neuraxial procedure and 4 hours or longer after catheter removal.¹⁷ Timing can be individualized based on the patient’s risk of hemorrhage and surgical bleeding. Although it may be tempting to delay chemoprophylaxis in the setting of bleeding, postpartum hemorrhage and transfusion increase the risks of VTE. In this setting, it is best to consider the use of UFH, which safely can be started earlier than LMWH.

For patients without neuraxial anesthesia, ACOG recommends chemoprophylaxis 4 to 6 hours after vaginal delivery and 6 to 12 hours after CD.⁸ (TABLE 3 summarizes recommendations for postpartum chemoprophylaxis.)

Continue to: Adjusting the anticoagulation regimen...

CASE 2 Pregnant woman with prior VTE

A 36-year-old woman (G1P0) with prior VTE is taking enoxaparin 40 mg daily. She asks, does she need any blood work for her anticoagulation?

What would you test for?

Increased renal clearance of LMWH and increased volume of distribution during pregnancy has led to the consideration of monitoring anti-Xa levels. There are no published standards or recommendations for dose adjustment. At this time, anti-Xa level monitoring antepartum is not recommended, but it may be considered when a patient is at the extremes of weight. With a weight-based strategy in the postpartum period, monitoring is not recommended as studies show a higher likelihood of therapeutic anti-Xa levels with this approach.^13,14 This is an active area of research, and these recommendations may change.

For prophylactic-dose or intermediate-dose anticoagulation, a peak anti-Xa level of 0.2 to 0.6 U/mL is generally accepted as the target. For therapeutic-dose, a peak anti-Xa level of 0.6 to 1.2 U/mL is generally accepted as the therapeutic range. This blood draw must be collected 4 hours after the third dose.

CASE 2 continued Anticoagulation considerations nearing delivery

The patient is now at 36 weeks’ gestation, and she asks, what should be done regarding her anticoagulation prior to delivery?

What would be an appropriate approach?

Traditionally, patients were transitioned to UFH at 36 weeks and allowed to present in spontaneous labor to increase the likelihood of neuraxial anesthesia. The alternative is to continue prophylactic-dose LMWH until a scheduled delivery. While the SOAP guidelines establish the timeframe that is safe to proceed with neuraxial anesthesia, there is variation in practice, so consider discussing this with your anesthesia providers.

SOAP considers prophylactic-dose UFH to be 5,000 U 2 to 3 times per day. In this setting, neuraxial anesthesia can be placed more than 4 to 6 hours from the last dose.¹⁷ But due to the pharmacokinetics of pregnancy, ACOG recommends 10,000 U in the third trimester.⁸ This dose is considered intermediate-dose by SOAP, and 12 hours or longer plus a normal activated partial thromboplastin time (aPTT) or undetectable anti-Xa level are required prior to neuraxial anesthesia. This is the same time allowed for prophylactic-dose LMWH without lab work. Prophylactic-dose LMWH is considered to be enoxaparin 40 mg or less daily or 30 mg twice daily, and dalteparin 5,000 U daily. For therapeutic-dose LMWH or UFH, 24 hours or more from last dose is recommended prior to neuraxial anesthesia. For intermediate-dose LMWH, data are limited to recommend anything between 12 and 24 hours.¹⁷

In my practice, we favor a shared decision-making approach with patients. We discuss the likelihood of labor prior to 39 weeks based on a patient’s history, the importance of neuraxial anesthesia to the patient, and the importance of the number of daily injections. Most patients continue enoxaparin until a scheduled induction, and they are instructed to skip their dose if labor symptoms begin. Patients at high risk for preterm delivery can be transitioned to heparin earlier than 36 weeks. ●

Pregnancy and the postpartum period are times of increased risk for venous thromboembolism (VTE). While VTE is a rare event overall, it is responsible for more than 9% of maternal deaths in the United States.¹ The increased risk of VTE exists throughout pregnancy, rising in the third trimester.² The highest-risk period is the first 6 weeks postpartum, likely peaking in the first 2 to 3 weeks and returning to baseline at about 12 weeks postpartum.^2,3

To reduce this source of maternal harm, the National Partnership for Maternal Safety and the Council on Patient Safety in Women’s Health Care recommend the use of VTE prevention bundles. Bundles include standard assessment of risk during prenatal care, any admission to the hospital, and postpartum coupled with standard recommendations for treatment.^4-6 Multiple published guidelines are available for prevention of VTE in pregnancy, and they provide varying recommendations on patient selection and treatment. Many of these recommendations are based on low quality of evidence, making the choice of standard practice difficult.

In this article, I attempt to simplify patient selection and treatment based on currently published guidelines from the American College of Obstetricians and Gynecologists (ACOG), Royal College of Obstetricians and Gynaecologists (RCOG), American College of Chest Physicians (CHEST), American Society of Hematology (ASH), and expert opinion.

Determining VTE risk and need for prophylaxis

CASE 1 Woman with factor V Leiden

A 25-year-old woman (G1P0) presents for her initial prenatal visit. She says she is a carrier for factor V Leiden but has never had a clot. She was tested after her sister had a VTE. She asks, does she need VTE prophylaxis before her delivery?

What are the considerations and options for this patient?

Options for VTE prophylaxis

Before considering patients at risk for VTE, it is helpful to review the options for prophylaxis. Patients can undergo clinical surveillance or routine care with attention to VTE symptoms and a low threshold for workup.

There are 3 categories of chemoprophylaxis for prevention of VTE. (TABLE 1 offers examples of dosing regimens.) No strategy has been proven optimal over another:

• prophylactic-dose: the lowest, fixed dose.
• intermediate-dose: lacks a standard definition and is any dose higher than prophylactic-dose but lower than therapeutic-dose. This includes fixed twice-daily doses, weight-based doses, and incrementally increasing doses.
• therapeutic-dose: typically used for treatment but mentioned here since patients with high-risk conditions may use it for prevention of VTE.

The preferred agent for VTE chemoprophylaxis is low molecular weight heparin (LMWH; dalteparin, enoxaparin). LMWH has a lower risk of complications than unfractionated heparin (UFH) and can be injected once daily. LMWH and UFH do not cross the placenta. LMWH and UFH are safe in breastfeeding. Oral direct thrombin inhibitors and anti-Xa inhibitors are not recommended in pregnancy or lactation at this time. Warfarin is avoided in pregnancy except in situations with mechanical heart valves, which will not be addressed here. Patients taking warfarin for long-term anticoagulation can transition back while breastfeeding with appropriate bridging.

Continue to: Risk factors for VTE...

Risk factors for VTE

History of VTE. The most important risk factor for VTE is a personal history of prior VTE.⁶ Recurrence risks have been widely reported and depend on the factors surrounding the initial event. For patients with a prior provoked deep vein thrombosis (DVT; associated with trauma or surgery), the antepartum VTE risk likely is less than 1%, and VTE chemoprophylaxis is not recommended antepartum.⁷

For patients with a prior VTE that was not associated with surgery or trauma (unprovoked), the risk is approximately 3%; for prior VTE related to pregnancy or hormonal contraception, the risk is approximately 6%.⁷ For both of these groups, prophylactic-dose antepartum is recommended. Patients with recurrent VTE are often taking long-term anticoagulation. Anyone on long-term anticoagulation should be placed on therapeutic-dose antepartum. For patients not receiving long-term anticoagulation, consider a hematology consultation when available, and begin an intermediate-dose or therapeutic-dose regimen after assessing other risk factors and the risk of bleeding and discussing treatment with the patient.

Thrombophilias. The next most important risk factor is the presence of inherited thrombophilias.⁶ Factor V homozygote, prothrombin G20210A mutation homozygote, antithrombin deficiency, and combined factor V heterozygote and prothrombin G20210A heterozygote (also called compound heterozygote) have the strongest association with VTE in pregnancy.⁸ It is recommended that patients with these high-risk thrombophilias receive prophylactic-dose antepartum.⁸

Factor V heterozygote, prothrombin G20210A mutation heterozygote, and protein C or protein S deficiency are considered low-risk thrombophilias. Patients with low-risk thrombophilias and no personal history of VTE or first-degree relative with VTE can be monitored with clinical surveillance antepartum. However, if a family history of VTE or other risk factors for VTE are present, antepartum prophylactic-dose is recommended. Clinical factors to consider antepartum include obesity, age older than 35 years, parity of 3 or higher, varicose veins, immobility, smoking, assisted reproductive technology use, multiple gestation, and preeclampsia.¹⁰

Antiphospholipid syndrome (APS) is another high-risk condition. For patients not taking long-term anticoagulation antepartum, prophylactic-dose is recommended. For patients on long-term anticoagulation, therapeutic-dose is recommended.

Other medical conditions. Patients with medical conditions that place them at high risk for VTE may warrant prophylactic-dose antepartum. These include active cancer, active systemic lupus erythematosus, sickle cell disease, nephropathy, and inflammatory bowel disease.¹⁰ This decision can be made in conjunction with other specialists caring for the patient.

Antepartum prophylactic-dose is not recommended for low-risk patients as there is less than 1% risk of VTE.⁷ (TABLE 2 summarizes antepartum chemoprophylaxis recommendations.)

CASE 1 continued Patient develops another VTE risk factor

The patient is being followed with clinical surveillance. At 19 weeks’ gestation, she presents to the emergency department with shortness of breath and fever. She is diagnosed with COVID-19 and is admitted by a medicine service. They call the OB team to ask for recommendations regarding anticoagulation.

What should the next steps include?

Hospitalization and nonobstetric surgery are risk factors for VTE. Many hospitals use a standardized assessment for all inpatients, such as the Padua or Caprini VTE risk assessment scores. These can be modified for use in pregnant patients, although neither scoring system is currently validated for use in pregnancy.⁵ For any pregnant patient admitted to the hospital, mechanical prophylaxis is recommended.

COVID-19. Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome, COVID-19, is associated with increased rates of VTE. Recommendations for pregnant patients with COVID-19 are the same as for the general population. During hospitalization for COVID-19, pregnant patients should be placed on prophylactic-dose chemoprophylaxis. Patients should not be discharged home on chemoprophylaxis, and patients managed as outpatients for their disease do not need chemoprophylaxis.¹¹

Management approach. Prophylactic-dose administration is recommended during hospital stay for all patients admitted with anticipated length of stay of 3 days or longer and who are not at high risk for bleeding or delivery.¹⁰ Both LMWH and UFH are options for inpatients. For any nonobstetric surgery or admission, LMWH may be most appropriate. However, as most obstetrics admissions are at increased risk for delivery, UFH 5,000 U twice daily to 3 times daily is the best option to increase the chances for neuraxial anesthesia. (I review anesthesia considerations for delivery later in this article.) For patients at high risk for bleeding or delivery, mechanical prophylaxis alone, with elastic stockings or pneumatic compression devices, can be used.

Continue to: CASE 1 continued Patient is discharged home...

CASE 1 continued Patient is discharged home

The patient received enoxaparin while she was in the hospital. She is now discharged and doing well. She asks, will she need anticoagulation prophylaxis after delivery?

How would you counsel her?

Chemoprophylaxis in the postpartum period

With no risk of fetal harm and a higher risk of VTE per day, the threshold for chemoprophylaxis is lower in the postpartum period. The risk of postpartum bleeding is less than 1%, with the most common complication being wound hematomas (0.61%).⁹ For this case patient, the COVID-19 diagnosis does not alter the recommendations for postpartum chemoprophylaxis. Additionally, as the need for neuraxial anesthesia has passed, the use of intermediate-dose chemoprophylaxis over prophylactic-dose is advocated in the postpartum period, especially in obese patients.¹²

As mentioned previously, there is no standard definition of intermediate-dose. Data suggest that a weight-based intermediate-dose is most likely to achieve therapeutic levels of anti-Xa in this high-risk population compared with a fixed dose.^13,14 For example, enoxaparin 0.5 mg/kg twice daily is recommended for patients with class 3 obesity or higher by the Society for Maternal-Fetal Medicine.¹²

As a rule, anyone who was on chemoprophylaxis antepartum should be continued on at least an equivalent dose for 6 weeks postpartum. Postpartum, patients with any prior DVT should take prophylactic-dose or intermediate-dose chemoprophylaxis for 6 weeks. Patients with a known high-risk thrombophilia should receive prophylactic-dose or intermediate-dose chemoprophylaxis postpartum for 6 weeks. For patients with a low-risk thrombophilia, prophylactic-dose or intermediate-dose chemoprophylaxis is recommended for 6 weeks.

For low-risk patients without prior VTE or thrombophilia, standardized risk assessment is recommended.

Cesarean delivery

Cesarean delivery (CD) is a risk factor for postpartum VTE.⁹ A universal chemoprophylaxis strategy has not been proven in this patient population. Mechanical prophylaxis with sequential compression devices is recommended for all patients undergoing CD pre-procedure and until patients are fully ambulatory.^8,9 Early ambulation also should be encouraged.

Many risk assessment models are available for postoperative VTE prevention, and they have widely different chemoprophylaxis rates. Studies have shown chemoprophylaxis rates of 85% by RCOG, 1% by ACOG, 35% by CHEST, 94% by Caprini, and less than 1% by Padua.^15,16 In addition to the antepartum patient-specific risk factors mentioned, postpartum risk factors include infection, postpartum hemorrhage, and transfusion. Based on data extrapolated from the nonobstetric literature, chemoprophylaxis is recommended until discharge from the hospital unless risk factors are expected to continue.⁹

Neuraxial anesthesia

For patients who require postpartum chemoprophylaxis, the Society for Obstetric Anesthesia and Perinatology (SOAP) offers evidence-based guidelines for use after neuraxial anesthesia. UFH can be initiated 1 hour or longer after a neuraxial procedure and 1 hour or longer after catheter removal. Prophylactic-dose LMWH can be restarted at 12 hours or longer after a neuraxial procedure and at 4 to 6 hours or longer after catheter removal. For patients restarting intermediate-dose or therapeutic-dose, the recommendations are to wait 24 hours or longer after a neuraxial procedure and 4 hours or longer after catheter removal.¹⁷ Timing can be individualized based on the patient’s risk of hemorrhage and surgical bleeding. Although it may be tempting to delay chemoprophylaxis in the setting of bleeding, postpartum hemorrhage and transfusion increase the risks of VTE. In this setting, it is best to consider the use of UFH, which safely can be started earlier than LMWH.

For patients without neuraxial anesthesia, ACOG recommends chemoprophylaxis 4 to 6 hours after vaginal delivery and 6 to 12 hours after CD.⁸ (TABLE 3 summarizes recommendations for postpartum chemoprophylaxis.)

Continue to: Adjusting the anticoagulation regimen...

CASE 2 Pregnant woman with prior VTE

A 36-year-old woman (G1P0) with prior VTE is taking enoxaparin 40 mg daily. She asks, does she need any blood work for her anticoagulation?

What would you test for?

Increased renal clearance of LMWH and increased volume of distribution during pregnancy has led to the consideration of monitoring anti-Xa levels. There are no published standards or recommendations for dose adjustment. At this time, anti-Xa level monitoring antepartum is not recommended, but it may be considered when a patient is at the extremes of weight. With a weight-based strategy in the postpartum period, monitoring is not recommended as studies show a higher likelihood of therapeutic anti-Xa levels with this approach.^13,14 This is an active area of research, and these recommendations may change.

For prophylactic-dose or intermediate-dose anticoagulation, a peak anti-Xa level of 0.2 to 0.6 U/mL is generally accepted as the target. For therapeutic-dose, a peak anti-Xa level of 0.6 to 1.2 U/mL is generally accepted as the therapeutic range. This blood draw must be collected 4 hours after the third dose.

CASE 2 continued Anticoagulation considerations nearing delivery

The patient is now at 36 weeks’ gestation, and she asks, what should be done regarding her anticoagulation prior to delivery?

What would be an appropriate approach?

Traditionally, patients were transitioned to UFH at 36 weeks and allowed to present in spontaneous labor to increase the likelihood of neuraxial anesthesia. The alternative is to continue prophylactic-dose LMWH until a scheduled delivery. While the SOAP guidelines establish the timeframe that is safe to proceed with neuraxial anesthesia, there is variation in practice, so consider discussing this with your anesthesia providers.

SOAP considers prophylactic-dose UFH to be 5,000 U 2 to 3 times per day. In this setting, neuraxial anesthesia can be placed more than 4 to 6 hours from the last dose.¹⁷ But due to the pharmacokinetics of pregnancy, ACOG recommends 10,000 U in the third trimester.⁸ This dose is considered intermediate-dose by SOAP, and 12 hours or longer plus a normal activated partial thromboplastin time (aPTT) or undetectable anti-Xa level are required prior to neuraxial anesthesia. This is the same time allowed for prophylactic-dose LMWH without lab work. Prophylactic-dose LMWH is considered to be enoxaparin 40 mg or less daily or 30 mg twice daily, and dalteparin 5,000 U daily. For therapeutic-dose LMWH or UFH, 24 hours or more from last dose is recommended prior to neuraxial anesthesia. For intermediate-dose LMWH, data are limited to recommend anything between 12 and 24 hours.¹⁷

In my practice, we favor a shared decision-making approach with patients. We discuss the likelihood of labor prior to 39 weeks based on a patient’s history, the importance of neuraxial anesthesia to the patient, and the importance of the number of daily injections. Most patients continue enoxaparin until a scheduled induction, and they are instructed to skip their dose if labor symptoms begin. Patients at high risk for preterm delivery can be transitioned to heparin earlier than 36 weeks. ●

Pregnancy and the postpartum period are times of increased risk for venous thromboembolism (VTE). While VTE is a rare event overall, it is responsible for more than 9% of maternal deaths in the United States.¹ The increased risk of VTE exists throughout pregnancy, rising in the third trimester.² The highest-risk period is the first 6 weeks postpartum, likely peaking in the first 2 to 3 weeks and returning to baseline at about 12 weeks postpartum.^2,3

To reduce this source of maternal harm, the National Partnership for Maternal Safety and the Council on Patient Safety in Women’s Health Care recommend the use of VTE prevention bundles. Bundles include standard assessment of risk during prenatal care, any admission to the hospital, and postpartum coupled with standard recommendations for treatment.^4-6 Multiple published guidelines are available for prevention of VTE in pregnancy, and they provide varying recommendations on patient selection and treatment. Many of these recommendations are based on low quality of evidence, making the choice of standard practice difficult.

In this article, I attempt to simplify patient selection and treatment based on currently published guidelines from the American College of Obstetricians and Gynecologists (ACOG), Royal College of Obstetricians and Gynaecologists (RCOG), American College of Chest Physicians (CHEST), American Society of Hematology (ASH), and expert opinion.

Determining VTE risk and need for prophylaxis

CASE 1 Woman with factor V Leiden

A 25-year-old woman (G1P0) presents for her initial prenatal visit. She says she is a carrier for factor V Leiden but has never had a clot. She was tested after her sister had a VTE. She asks, does she need VTE prophylaxis before her delivery?

What are the considerations and options for this patient?

Options for VTE prophylaxis

Before considering patients at risk for VTE, it is helpful to review the options for prophylaxis. Patients can undergo clinical surveillance or routine care with attention to VTE symptoms and a low threshold for workup.

There are 3 categories of chemoprophylaxis for prevention of VTE. (TABLE 1 offers examples of dosing regimens.) No strategy has been proven optimal over another:

• prophylactic-dose: the lowest, fixed dose.
• intermediate-dose: lacks a standard definition and is any dose higher than prophylactic-dose but lower than therapeutic-dose. This includes fixed twice-daily doses, weight-based doses, and incrementally increasing doses.
• therapeutic-dose: typically used for treatment but mentioned here since patients with high-risk conditions may use it for prevention of VTE.

The preferred agent for VTE chemoprophylaxis is low molecular weight heparin (LMWH; dalteparin, enoxaparin). LMWH has a lower risk of complications than unfractionated heparin (UFH) and can be injected once daily. LMWH and UFH do not cross the placenta. LMWH and UFH are safe in breastfeeding. Oral direct thrombin inhibitors and anti-Xa inhibitors are not recommended in pregnancy or lactation at this time. Warfarin is avoided in pregnancy except in situations with mechanical heart valves, which will not be addressed here. Patients taking warfarin for long-term anticoagulation can transition back while breastfeeding with appropriate bridging.

Continue to: Risk factors for VTE...

Risk factors for VTE

History of VTE. The most important risk factor for VTE is a personal history of prior VTE.⁶ Recurrence risks have been widely reported and depend on the factors surrounding the initial event. For patients with a prior provoked deep vein thrombosis (DVT; associated with trauma or surgery), the antepartum VTE risk likely is less than 1%, and VTE chemoprophylaxis is not recommended antepartum.⁷

For patients with a prior VTE that was not associated with surgery or trauma (unprovoked), the risk is approximately 3%; for prior VTE related to pregnancy or hormonal contraception, the risk is approximately 6%.⁷ For both of these groups, prophylactic-dose antepartum is recommended. Patients with recurrent VTE are often taking long-term anticoagulation. Anyone on long-term anticoagulation should be placed on therapeutic-dose antepartum. For patients not receiving long-term anticoagulation, consider a hematology consultation when available, and begin an intermediate-dose or therapeutic-dose regimen after assessing other risk factors and the risk of bleeding and discussing treatment with the patient.

Thrombophilias. The next most important risk factor is the presence of inherited thrombophilias.⁶ Factor V homozygote, prothrombin G20210A mutation homozygote, antithrombin deficiency, and combined factor V heterozygote and prothrombin G20210A heterozygote (also called compound heterozygote) have the strongest association with VTE in pregnancy.⁸ It is recommended that patients with these high-risk thrombophilias receive prophylactic-dose antepartum.⁸

Factor V heterozygote, prothrombin G20210A mutation heterozygote, and protein C or protein S deficiency are considered low-risk thrombophilias. Patients with low-risk thrombophilias and no personal history of VTE or first-degree relative with VTE can be monitored with clinical surveillance antepartum. However, if a family history of VTE or other risk factors for VTE are present, antepartum prophylactic-dose is recommended. Clinical factors to consider antepartum include obesity, age older than 35 years, parity of 3 or higher, varicose veins, immobility, smoking, assisted reproductive technology use, multiple gestation, and preeclampsia.¹⁰

Antiphospholipid syndrome (APS) is another high-risk condition. For patients not taking long-term anticoagulation antepartum, prophylactic-dose is recommended. For patients on long-term anticoagulation, therapeutic-dose is recommended.

Other medical conditions. Patients with medical conditions that place them at high risk for VTE may warrant prophylactic-dose antepartum. These include active cancer, active systemic lupus erythematosus, sickle cell disease, nephropathy, and inflammatory bowel disease.¹⁰ This decision can be made in conjunction with other specialists caring for the patient.

Antepartum prophylactic-dose is not recommended for low-risk patients as there is less than 1% risk of VTE.⁷ (TABLE 2 summarizes antepartum chemoprophylaxis recommendations.)

CASE 1 continued Patient develops another VTE risk factor

The patient is being followed with clinical surveillance. At 19 weeks’ gestation, she presents to the emergency department with shortness of breath and fever. She is diagnosed with COVID-19 and is admitted by a medicine service. They call the OB team to ask for recommendations regarding anticoagulation.

What should the next steps include?

Hospitalization and nonobstetric surgery are risk factors for VTE. Many hospitals use a standardized assessment for all inpatients, such as the Padua or Caprini VTE risk assessment scores. These can be modified for use in pregnant patients, although neither scoring system is currently validated for use in pregnancy.⁵ For any pregnant patient admitted to the hospital, mechanical prophylaxis is recommended.

COVID-19. Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome, COVID-19, is associated with increased rates of VTE. Recommendations for pregnant patients with COVID-19 are the same as for the general population. During hospitalization for COVID-19, pregnant patients should be placed on prophylactic-dose chemoprophylaxis. Patients should not be discharged home on chemoprophylaxis, and patients managed as outpatients for their disease do not need chemoprophylaxis.¹¹

Management approach. Prophylactic-dose administration is recommended during hospital stay for all patients admitted with anticipated length of stay of 3 days or longer and who are not at high risk for bleeding or delivery.¹⁰ Both LMWH and UFH are options for inpatients. For any nonobstetric surgery or admission, LMWH may be most appropriate. However, as most obstetrics admissions are at increased risk for delivery, UFH 5,000 U twice daily to 3 times daily is the best option to increase the chances for neuraxial anesthesia. (I review anesthesia considerations for delivery later in this article.) For patients at high risk for bleeding or delivery, mechanical prophylaxis alone, with elastic stockings or pneumatic compression devices, can be used.

Continue to: CASE 1 continued Patient is discharged home...

CASE 1 continued Patient is discharged home

The patient received enoxaparin while she was in the hospital. She is now discharged and doing well. She asks, will she need anticoagulation prophylaxis after delivery?

How would you counsel her?

Chemoprophylaxis in the postpartum period

With no risk of fetal harm and a higher risk of VTE per day, the threshold for chemoprophylaxis is lower in the postpartum period. The risk of postpartum bleeding is less than 1%, with the most common complication being wound hematomas (0.61%).⁹ For this case patient, the COVID-19 diagnosis does not alter the recommendations for postpartum chemoprophylaxis. Additionally, as the need for neuraxial anesthesia has passed, the use of intermediate-dose chemoprophylaxis over prophylactic-dose is advocated in the postpartum period, especially in obese patients.¹²

As mentioned previously, there is no standard definition of intermediate-dose. Data suggest that a weight-based intermediate-dose is most likely to achieve therapeutic levels of anti-Xa in this high-risk population compared with a fixed dose.^13,14 For example, enoxaparin 0.5 mg/kg twice daily is recommended for patients with class 3 obesity or higher by the Society for Maternal-Fetal Medicine.¹²

As a rule, anyone who was on chemoprophylaxis antepartum should be continued on at least an equivalent dose for 6 weeks postpartum. Postpartum, patients with any prior DVT should take prophylactic-dose or intermediate-dose chemoprophylaxis for 6 weeks. Patients with a known high-risk thrombophilia should receive prophylactic-dose or intermediate-dose chemoprophylaxis postpartum for 6 weeks. For patients with a low-risk thrombophilia, prophylactic-dose or intermediate-dose chemoprophylaxis is recommended for 6 weeks.

For low-risk patients without prior VTE or thrombophilia, standardized risk assessment is recommended.

Cesarean delivery

Cesarean delivery (CD) is a risk factor for postpartum VTE.⁹ A universal chemoprophylaxis strategy has not been proven in this patient population. Mechanical prophylaxis with sequential compression devices is recommended for all patients undergoing CD pre-procedure and until patients are fully ambulatory.^8,9 Early ambulation also should be encouraged.

Many risk assessment models are available for postoperative VTE prevention, and they have widely different chemoprophylaxis rates. Studies have shown chemoprophylaxis rates of 85% by RCOG, 1% by ACOG, 35% by CHEST, 94% by Caprini, and less than 1% by Padua.^15,16 In addition to the antepartum patient-specific risk factors mentioned, postpartum risk factors include infection, postpartum hemorrhage, and transfusion. Based on data extrapolated from the nonobstetric literature, chemoprophylaxis is recommended until discharge from the hospital unless risk factors are expected to continue.⁹

Neuraxial anesthesia

For patients who require postpartum chemoprophylaxis, the Society for Obstetric Anesthesia and Perinatology (SOAP) offers evidence-based guidelines for use after neuraxial anesthesia. UFH can be initiated 1 hour or longer after a neuraxial procedure and 1 hour or longer after catheter removal. Prophylactic-dose LMWH can be restarted at 12 hours or longer after a neuraxial procedure and at 4 to 6 hours or longer after catheter removal. For patients restarting intermediate-dose or therapeutic-dose, the recommendations are to wait 24 hours or longer after a neuraxial procedure and 4 hours or longer after catheter removal.¹⁷ Timing can be individualized based on the patient’s risk of hemorrhage and surgical bleeding. Although it may be tempting to delay chemoprophylaxis in the setting of bleeding, postpartum hemorrhage and transfusion increase the risks of VTE. In this setting, it is best to consider the use of UFH, which safely can be started earlier than LMWH.

For patients without neuraxial anesthesia, ACOG recommends chemoprophylaxis 4 to 6 hours after vaginal delivery and 6 to 12 hours after CD.⁸ (TABLE 3 summarizes recommendations for postpartum chemoprophylaxis.)

Continue to: Adjusting the anticoagulation regimen...

CASE 2 Pregnant woman with prior VTE

A 36-year-old woman (G1P0) with prior VTE is taking enoxaparin 40 mg daily. She asks, does she need any blood work for her anticoagulation?

What would you test for?

Increased renal clearance of LMWH and increased volume of distribution during pregnancy has led to the consideration of monitoring anti-Xa levels. There are no published standards or recommendations for dose adjustment. At this time, anti-Xa level monitoring antepartum is not recommended, but it may be considered when a patient is at the extremes of weight. With a weight-based strategy in the postpartum period, monitoring is not recommended as studies show a higher likelihood of therapeutic anti-Xa levels with this approach.^13,14 This is an active area of research, and these recommendations may change.

For prophylactic-dose or intermediate-dose anticoagulation, a peak anti-Xa level of 0.2 to 0.6 U/mL is generally accepted as the target. For therapeutic-dose, a peak anti-Xa level of 0.6 to 1.2 U/mL is generally accepted as the therapeutic range. This blood draw must be collected 4 hours after the third dose.

CASE 2 continued Anticoagulation considerations nearing delivery

The patient is now at 36 weeks’ gestation, and she asks, what should be done regarding her anticoagulation prior to delivery?

What would be an appropriate approach?

Traditionally, patients were transitioned to UFH at 36 weeks and allowed to present in spontaneous labor to increase the likelihood of neuraxial anesthesia. The alternative is to continue prophylactic-dose LMWH until a scheduled delivery. While the SOAP guidelines establish the timeframe that is safe to proceed with neuraxial anesthesia, there is variation in practice, so consider discussing this with your anesthesia providers.

SOAP considers prophylactic-dose UFH to be 5,000 U 2 to 3 times per day. In this setting, neuraxial anesthesia can be placed more than 4 to 6 hours from the last dose.¹⁷ But due to the pharmacokinetics of pregnancy, ACOG recommends 10,000 U in the third trimester.⁸ This dose is considered intermediate-dose by SOAP, and 12 hours or longer plus a normal activated partial thromboplastin time (aPTT) or undetectable anti-Xa level are required prior to neuraxial anesthesia. This is the same time allowed for prophylactic-dose LMWH without lab work. Prophylactic-dose LMWH is considered to be enoxaparin 40 mg or less daily or 30 mg twice daily, and dalteparin 5,000 U daily. For therapeutic-dose LMWH or UFH, 24 hours or more from last dose is recommended prior to neuraxial anesthesia. For intermediate-dose LMWH, data are limited to recommend anything between 12 and 24 hours.¹⁷

In my practice, we favor a shared decision-making approach with patients. We discuss the likelihood of labor prior to 39 weeks based on a patient’s history, the importance of neuraxial anesthesia to the patient, and the importance of the number of daily injections. Most patients continue enoxaparin until a scheduled induction, and they are instructed to skip their dose if labor symptoms begin. Patients at high risk for preterm delivery can be transitioned to heparin earlier than 36 weeks. ●

CASE Pregnant woman with positive hepatitis B surface antigen

A 27-year-old primigravida at 9 weeks 3 days of gestation tests positive for the hepatitis B surface antigen at her first prenatal appointment. She is completely asymptomatic.

• What additional tests are indicated?

• Does she pose a risk to her sexual partner, and is her newborn at risk for acquiring hepatitis B?

• Can anything be done to protect her partner and newborn from infection?

Meet our perpetrator

Hepatitis is one of the more common viral infections that may occur during pregnancy. Two forms of hepatitis, notably hepatitis A and E, pose a primary threat to the mother. Three forms (B, C, and D) present dangers for the mother, fetus, and newborn. This article will review the epidemiology, clinical manifestations, perinatal implications, and management of the various forms of viral hepatitis. (TABLE 1).

Hepatitis A

Hepatitis A is caused by an RNA virus that is transmitted by fecal-oral contact. The disease is most prevalent in areas with poor sanitation and close living conditions. The incubation period ranges from 15 to 50 days. Most children who acquire this disease are asymptomatic. By contrast, most infected adults are acutely symptomatic. Clinical manifestations typically include low-grade fever, malaise, anorexia, right upper quadrant pain and tenderness, jaundice, and claycolored stools.^1,2

The diagnosis of acute hepatitis A infection is best confirmed by detection of immunoglobulin M (IgM)-specific antibodies. The serum transaminase concentrations and the serum bilirubin concentrations usually are significantly elevated. The international normalized ratio, prothrombin time, and partial thromboplastin time also may be elevated.^1,2

The treatment for acute hepatitis A largely is supportive care: maintaining hydration, optimizing nutrition, and correcting coagulation abnormalities. The appropriate measures for prevention of hepatitis A are adoption of sound sanitation practices, particularly water purification; minimizing overcrowded living conditions; and administering the hepatitis A vaccine for both pre and postexposure prophylaxis.^3,4 The hepatitis A vaccine is preferred over administration of immune globulin because it provides lifelong immunity.

The hepatitis A vaccine is produced in 2 monovalent formulations: Havrix (GlaxoSmithKline) and Vaqta (Merck & Co, Inc). The vaccine should be administered intramuscularly in 2 doses 6 to 12 months apart. The wholesale cost of the vaccine varies from $66 to $119 (according to http://www.goodrx.com). The vaccine also is available in a bivalent form, with recombinant hepatitis B vaccine (Twinrix, GlaxoSmithKline). When used in this form, 3 vaccine administrations are given—at 0, 1, and 6 months apart. The cost of the vaccine is approximately $150 (according to http://www.goodrx.com). TABLE 2 lists the individuals who are appropriate candidates for the hepatitis A vaccine.^3,4

Hepatitis B

Hepatitis B is caused by a DNA virus that is transmitted parenterally or perinatally or through sexual contact. Four genotypes have been identified: A, B, C, and D.

Acute hepatitis B affects 1 to 2 of 1,000 pregnancies in the United States. Approximately 6 to 10 patients per 1,000 pregnancies are asymptomatic but chronically infected.⁴ The natural history of hepatitis B infection is shown in the FIGURE. The diagnosis of acute and chronic hepatitis B is best established by serology and polymerase chain reaction (PCR; TABLE 3).

Continue to: Hepatitis C...

Hepatitis C

Hepatitis C is caused by an RNA virus that has 6 genotypes. The most common genotype is HCV1, which affects 79% of patients; approximately 13% of patients have HCV2, and 6% have HCV3.⁹ Of note, the 3 individuals who discovered this virus—Drs. Harvey Alter, Michael Houghton, and Charles Rice—received the 2020 Nobel Prize in Medicine.¹⁰

Hepatitis C is transmitted via sexual contact, parenterally, and perinatally. In many patient populations in the United States, hepatitis C is now more prevalent than hepatitis B. Only about half of all infected persons are aware of their infection. If patients go untreated, approximately 15% to 30% eventually develop cirrhosis. Of these individuals, 1% to 3% develop hepatocellular cancer. Chronic hepatitis C is now the most common indication for liver transplantation in the United States.^1,9

In the initial stages of infection, hepatitis C usually is asymptomatic. The best screening test is detection of hepatitis C antibody. Because of the increasing prevalence of this disease, the seriousness of the infection, and the recent availability of remarkably effective treatment, routine screening, rather than screening on the basis of risk factors, for hepatitis C in pregnancy is now indicated.^11,12

The best tests for confirmation of infection are detection of antibody by enzyme immunoassay and recombinant immuno-blot assay and detection of viral RNA in serum by PCR. Seroconversion may not occur for up to 16 weeks after infection. Therefore, in at-risk patients who initially test negative, retesting is advisable. Patients with positive test results should have tests to identify the specific genotype, determine the viral load, and assess liver function.¹

In patients who have undetectable viral loads and who do not have coexisting HIV infection, the risk of perinatal transmission of hepatitis C is less than 5%. If HIV infection is present, the risk of perinatal transmission approaches 20%.^1,13,14

If the patient is coinfected with HIV, a scheduled cesarean delivery should be performed at 38 weeks’ gestation.¹ If the viral load is undetectable, vaginal delivery is appropriate. If the viral load is high, however (arbitrarily defined as >2.5 millioncopies/mL), the optimal method of delivery is controversial. Several small, nonrandomized noncontrolled cohort studies support elective cesarean delivery in such patients.¹⁴

There is no contraindication to breastfeeding in women with hepatitis C unless they are coinfected with HIV. In such a circumstance, formula feeding should be chosen. After delivery, patients with hepatitis C should be referred to a gastroenterology specialist to receive antiviral treatment. Multiple new single-agent and combination regimens have produced cures in more than 90% of patients. These regimens usually require 8 to 12 weeks of treatment, and they are very expensive. They have not been widely tested in pregnant women.¹

Hepatitis D

Hepatitis D, or delta hepatitis, is caused by an RNA virus. This virus is unique because it is incapable of independent replication. It must be present in association with hepatitis B to replicate and cause clinical infection. Therefore, the epidemiology of hepatitis D closely mirrors that of hepatitis B.^1,2

Patients with hepatitis D typically present in one of two ways. Some individuals are acutely infected with hepatitis D at the same time that they acquire hepatitis B (coinfection). The natural history of this infection usually is spontaneous resolution without sequelae. Other patients have chronic hepatitis D superimposed on chronic hepatitis B (superinfection). Unfortunately, patients with the latter condition are at a notably increased risk for developing severe persistent liver disease.^1,2

The diagnosis of hepatitis D may be confirmed by identifying the delta antigen in serum or in liver tissue obtained by biopsy or by identifying IgM- and IgG-specific antibodies in serum. In conjunction with hepatitis B, the delta virus can cause a chronic carrier state. Perinatal transmission is possible but uncommon. Of greatest importance, the immunoprophylaxis described for hepatitis B is almost perfectly protective against perinatal transmission of hepatitis D.^1,2

Continue to: Hepatitis E...

Hepatitis E

Hepatitis E is an RNA virus that has 1 serotype and 4 genotypes. Its epidemiology is similar to that of hepatitis A. It is the most common waterborne illness in the world. The incubation period varies from 21 to 56 days. This disease is quite rare in the United States but is endemic in developing nations. In those countries, maternal infection has an alarmingly high mortality rate (5%–25%). For example, in Bangladesh, hepatitis E is responsible for more than 1,000 deaths per year in pregnant women. When hepatitis E is identified in more affluent countries, the individual cases and small outbreaks usually are linked to consumption of undercooked pork or wild game.^1,15-17

The clinical presentation of acute hepatitis E also is similar to that of hepatitis A. The usual manifestations are fever, malaise, anorexia, nausea, right upper quadrant pain and tenderness, jaundice, darkened urine, and clay-colored stools. The most useful diagnostic tests are serologic detection of viral-specific antibodies (positive IgM or a 4-fold increase in the prior IgG titer) and PCR-RNA.^1,17

Hepatitis E usually does not cause a chronic carrier state, and perinatal transmission is rare. Fortunately, a highly effective vaccine was recently developed (Hecolin, Xiamen Innovax Biotech). This recombinant vaccine is specifically directed against the hepatitis E genotype 1. In the initial efficacy study, healthy adults aged 16 to 65 years were randomly assigned to receive either the hepatitis E vaccine or the hepatitis B vaccine. The vaccine was administered at time point 0, and 1 and 6 months later. Patients were followed for up to 4.5 years to assess efficacy, immunogenicity, and safety. During the study period, 7 cases of hepatitis E occurred in the vaccine group, compared with 53 in the control group. Approximately 56,000 patients were included in each group. The efficacy of the vaccine was 86.8% (P<.001).¹⁸

Hepatitis G

Hepatitis G is caused by 2 single-stranded RNA viruses that are virtually identical—hepatitis G virus and GB virus type C. The viruses share approximately 30% homology with hepatitis C virus. The organism is present throughout the world and infects approximately 1.5% to 2.0% of the population. The virus is transmitted by blood and sexual contact. It replicates preferentially in mononuclear cells and the bone marrow rather than in the liver.^19-21

Hepatitis G is much less virulent than hepatitis C. Hepatitis G often coexists with hepatitis A, B, and C, as well as with HIV. Coinfection with hepatitis G does not adversely affect the clinical course of the other conditions.^22,23

Most patients with hepatitis G are asymptomatic, and no treatment is indicated. The virus can cause a chronic carrier state. Perinatal transmission is distinctly uncommon. When it does occur, however, injury to mother, fetus, or neonate is unlikely.^1,24

The diagnosis of hepatitis G can be established by detection of virus with PCR and by the identification of antibody by enzyme immunoassay. Routine screening for this infection in pregnancy is not indicated.^1,2

CASE Resolved

Hepatitis B is highly contagious and can be transmitted from the patient to her sexual partner and neonate. Testing for hepatitis B surface antigen and antibody is indicated in her partner. If these tests are negative, the partner should immediately receive hepatitis B immune globulin and then be started on the 3-dose hepatitis B vaccination series. The patient’s newborn also should receive hepatitis B immune globulin within 12 hours of delivery and should receive the first dose of the hepatitis B vaccine prior to discharge from the hospital. The second and third doses should be administered 1 and 6 months after delivery.

The patient also should have the following tests:

• liver function tests

-serum transaminases

-direct and indirect bilirubin

-coagulation profile

• hepatitis D antigen

• hepatitis B genotype

• hepatitis B viral load

• HIV serology.

If the hepatitis B viral load exceeds 1 million copies/mL, the patient should be treated with tenofovir 200 mg daily from 28 weeks’ gestation until delivery. In addition, she should be referred to a liver disease specialist after delivery for consideration of treatment with directly-acting antiviral agents. ●

CASE Pregnant woman with positive hepatitis B surface antigen

A 27-year-old primigravida at 9 weeks 3 days of gestation tests positive for the hepatitis B surface antigen at her first prenatal appointment. She is completely asymptomatic.

• What additional tests are indicated?

• Does she pose a risk to her sexual partner, and is her newborn at risk for acquiring hepatitis B?

• Can anything be done to protect her partner and newborn from infection?

Meet our perpetrator

Hepatitis is one of the more common viral infections that may occur during pregnancy. Two forms of hepatitis, notably hepatitis A and E, pose a primary threat to the mother. Three forms (B, C, and D) present dangers for the mother, fetus, and newborn. This article will review the epidemiology, clinical manifestations, perinatal implications, and management of the various forms of viral hepatitis. (TABLE 1).

Hepatitis A

Hepatitis A is caused by an RNA virus that is transmitted by fecal-oral contact. The disease is most prevalent in areas with poor sanitation and close living conditions. The incubation period ranges from 15 to 50 days. Most children who acquire this disease are asymptomatic. By contrast, most infected adults are acutely symptomatic. Clinical manifestations typically include low-grade fever, malaise, anorexia, right upper quadrant pain and tenderness, jaundice, and claycolored stools.^1,2

The diagnosis of acute hepatitis A infection is best confirmed by detection of immunoglobulin M (IgM)-specific antibodies. The serum transaminase concentrations and the serum bilirubin concentrations usually are significantly elevated. The international normalized ratio, prothrombin time, and partial thromboplastin time also may be elevated.^1,2

The treatment for acute hepatitis A largely is supportive care: maintaining hydration, optimizing nutrition, and correcting coagulation abnormalities. The appropriate measures for prevention of hepatitis A are adoption of sound sanitation practices, particularly water purification; minimizing overcrowded living conditions; and administering the hepatitis A vaccine for both pre and postexposure prophylaxis.^3,4 The hepatitis A vaccine is preferred over administration of immune globulin because it provides lifelong immunity.

The hepatitis A vaccine is produced in 2 monovalent formulations: Havrix (GlaxoSmithKline) and Vaqta (Merck & Co, Inc). The vaccine should be administered intramuscularly in 2 doses 6 to 12 months apart. The wholesale cost of the vaccine varies from $66 to $119 (according to http://www.goodrx.com). The vaccine also is available in a bivalent form, with recombinant hepatitis B vaccine (Twinrix, GlaxoSmithKline). When used in this form, 3 vaccine administrations are given—at 0, 1, and 6 months apart. The cost of the vaccine is approximately $150 (according to http://www.goodrx.com). TABLE 2 lists the individuals who are appropriate candidates for the hepatitis A vaccine.^3,4

Hepatitis B

Hepatitis B is caused by a DNA virus that is transmitted parenterally or perinatally or through sexual contact. Four genotypes have been identified: A, B, C, and D.

Acute hepatitis B affects 1 to 2 of 1,000 pregnancies in the United States. Approximately 6 to 10 patients per 1,000 pregnancies are asymptomatic but chronically infected.⁴ The natural history of hepatitis B infection is shown in the FIGURE. The diagnosis of acute and chronic hepatitis B is best established by serology and polymerase chain reaction (PCR; TABLE 3).

Continue to: Hepatitis C...

Hepatitis C

Hepatitis C is caused by an RNA virus that has 6 genotypes. The most common genotype is HCV1, which affects 79% of patients; approximately 13% of patients have HCV2, and 6% have HCV3.⁹ Of note, the 3 individuals who discovered this virus—Drs. Harvey Alter, Michael Houghton, and Charles Rice—received the 2020 Nobel Prize in Medicine.¹⁰

Hepatitis C is transmitted via sexual contact, parenterally, and perinatally. In many patient populations in the United States, hepatitis C is now more prevalent than hepatitis B. Only about half of all infected persons are aware of their infection. If patients go untreated, approximately 15% to 30% eventually develop cirrhosis. Of these individuals, 1% to 3% develop hepatocellular cancer. Chronic hepatitis C is now the most common indication for liver transplantation in the United States.^1,9

In the initial stages of infection, hepatitis C usually is asymptomatic. The best screening test is detection of hepatitis C antibody. Because of the increasing prevalence of this disease, the seriousness of the infection, and the recent availability of remarkably effective treatment, routine screening, rather than screening on the basis of risk factors, for hepatitis C in pregnancy is now indicated.^11,12

The best tests for confirmation of infection are detection of antibody by enzyme immunoassay and recombinant immuno-blot assay and detection of viral RNA in serum by PCR. Seroconversion may not occur for up to 16 weeks after infection. Therefore, in at-risk patients who initially test negative, retesting is advisable. Patients with positive test results should have tests to identify the specific genotype, determine the viral load, and assess liver function.¹

In patients who have undetectable viral loads and who do not have coexisting HIV infection, the risk of perinatal transmission of hepatitis C is less than 5%. If HIV infection is present, the risk of perinatal transmission approaches 20%.^1,13,14

If the patient is coinfected with HIV, a scheduled cesarean delivery should be performed at 38 weeks’ gestation.¹ If the viral load is undetectable, vaginal delivery is appropriate. If the viral load is high, however (arbitrarily defined as >2.5 millioncopies/mL), the optimal method of delivery is controversial. Several small, nonrandomized noncontrolled cohort studies support elective cesarean delivery in such patients.¹⁴

There is no contraindication to breastfeeding in women with hepatitis C unless they are coinfected with HIV. In such a circumstance, formula feeding should be chosen. After delivery, patients with hepatitis C should be referred to a gastroenterology specialist to receive antiviral treatment. Multiple new single-agent and combination regimens have produced cures in more than 90% of patients. These regimens usually require 8 to 12 weeks of treatment, and they are very expensive. They have not been widely tested in pregnant women.¹

Hepatitis D

Hepatitis D, or delta hepatitis, is caused by an RNA virus. This virus is unique because it is incapable of independent replication. It must be present in association with hepatitis B to replicate and cause clinical infection. Therefore, the epidemiology of hepatitis D closely mirrors that of hepatitis B.^1,2

Patients with hepatitis D typically present in one of two ways. Some individuals are acutely infected with hepatitis D at the same time that they acquire hepatitis B (coinfection). The natural history of this infection usually is spontaneous resolution without sequelae. Other patients have chronic hepatitis D superimposed on chronic hepatitis B (superinfection). Unfortunately, patients with the latter condition are at a notably increased risk for developing severe persistent liver disease.^1,2

The diagnosis of hepatitis D may be confirmed by identifying the delta antigen in serum or in liver tissue obtained by biopsy or by identifying IgM- and IgG-specific antibodies in serum. In conjunction with hepatitis B, the delta virus can cause a chronic carrier state. Perinatal transmission is possible but uncommon. Of greatest importance, the immunoprophylaxis described for hepatitis B is almost perfectly protective against perinatal transmission of hepatitis D.^1,2

Continue to: Hepatitis E...

Hepatitis E

Hepatitis E is an RNA virus that has 1 serotype and 4 genotypes. Its epidemiology is similar to that of hepatitis A. It is the most common waterborne illness in the world. The incubation period varies from 21 to 56 days. This disease is quite rare in the United States but is endemic in developing nations. In those countries, maternal infection has an alarmingly high mortality rate (5%–25%). For example, in Bangladesh, hepatitis E is responsible for more than 1,000 deaths per year in pregnant women. When hepatitis E is identified in more affluent countries, the individual cases and small outbreaks usually are linked to consumption of undercooked pork or wild game.^1,15-17

The clinical presentation of acute hepatitis E also is similar to that of hepatitis A. The usual manifestations are fever, malaise, anorexia, nausea, right upper quadrant pain and tenderness, jaundice, darkened urine, and clay-colored stools. The most useful diagnostic tests are serologic detection of viral-specific antibodies (positive IgM or a 4-fold increase in the prior IgG titer) and PCR-RNA.^1,17

Hepatitis E usually does not cause a chronic carrier state, and perinatal transmission is rare. Fortunately, a highly effective vaccine was recently developed (Hecolin, Xiamen Innovax Biotech). This recombinant vaccine is specifically directed against the hepatitis E genotype 1. In the initial efficacy study, healthy adults aged 16 to 65 years were randomly assigned to receive either the hepatitis E vaccine or the hepatitis B vaccine. The vaccine was administered at time point 0, and 1 and 6 months later. Patients were followed for up to 4.5 years to assess efficacy, immunogenicity, and safety. During the study period, 7 cases of hepatitis E occurred in the vaccine group, compared with 53 in the control group. Approximately 56,000 patients were included in each group. The efficacy of the vaccine was 86.8% (P<.001).¹⁸

Hepatitis G

Hepatitis G is caused by 2 single-stranded RNA viruses that are virtually identical—hepatitis G virus and GB virus type C. The viruses share approximately 30% homology with hepatitis C virus. The organism is present throughout the world and infects approximately 1.5% to 2.0% of the population. The virus is transmitted by blood and sexual contact. It replicates preferentially in mononuclear cells and the bone marrow rather than in the liver.^19-21

Hepatitis G is much less virulent than hepatitis C. Hepatitis G often coexists with hepatitis A, B, and C, as well as with HIV. Coinfection with hepatitis G does not adversely affect the clinical course of the other conditions.^22,23

Most patients with hepatitis G are asymptomatic, and no treatment is indicated. The virus can cause a chronic carrier state. Perinatal transmission is distinctly uncommon. When it does occur, however, injury to mother, fetus, or neonate is unlikely.^1,24

The diagnosis of hepatitis G can be established by detection of virus with PCR and by the identification of antibody by enzyme immunoassay. Routine screening for this infection in pregnancy is not indicated.^1,2

CASE Resolved

Hepatitis B is highly contagious and can be transmitted from the patient to her sexual partner and neonate. Testing for hepatitis B surface antigen and antibody is indicated in her partner. If these tests are negative, the partner should immediately receive hepatitis B immune globulin and then be started on the 3-dose hepatitis B vaccination series. The patient’s newborn also should receive hepatitis B immune globulin within 12 hours of delivery and should receive the first dose of the hepatitis B vaccine prior to discharge from the hospital. The second and third doses should be administered 1 and 6 months after delivery.

The patient also should have the following tests:

• liver function tests

-serum transaminases

-direct and indirect bilirubin

-coagulation profile

• hepatitis D antigen

• hepatitis B genotype

• hepatitis B viral load

• HIV serology.

If the hepatitis B viral load exceeds 1 million copies/mL, the patient should be treated with tenofovir 200 mg daily from 28 weeks’ gestation until delivery. In addition, she should be referred to a liver disease specialist after delivery for consideration of treatment with directly-acting antiviral agents. ●

CASE Pregnant woman with positive hepatitis B surface antigen

A 27-year-old primigravida at 9 weeks 3 days of gestation tests positive for the hepatitis B surface antigen at her first prenatal appointment. She is completely asymptomatic.

• What additional tests are indicated?

• Does she pose a risk to her sexual partner, and is her newborn at risk for acquiring hepatitis B?

• Can anything be done to protect her partner and newborn from infection?

Meet our perpetrator

Hepatitis is one of the more common viral infections that may occur during pregnancy. Two forms of hepatitis, notably hepatitis A and E, pose a primary threat to the mother. Three forms (B, C, and D) present dangers for the mother, fetus, and newborn. This article will review the epidemiology, clinical manifestations, perinatal implications, and management of the various forms of viral hepatitis. (TABLE 1).

Hepatitis A

Hepatitis A is caused by an RNA virus that is transmitted by fecal-oral contact. The disease is most prevalent in areas with poor sanitation and close living conditions. The incubation period ranges from 15 to 50 days. Most children who acquire this disease are asymptomatic. By contrast, most infected adults are acutely symptomatic. Clinical manifestations typically include low-grade fever, malaise, anorexia, right upper quadrant pain and tenderness, jaundice, and claycolored stools.^1,2

The diagnosis of acute hepatitis A infection is best confirmed by detection of immunoglobulin M (IgM)-specific antibodies. The serum transaminase concentrations and the serum bilirubin concentrations usually are significantly elevated. The international normalized ratio, prothrombin time, and partial thromboplastin time also may be elevated.^1,2

The treatment for acute hepatitis A largely is supportive care: maintaining hydration, optimizing nutrition, and correcting coagulation abnormalities. The appropriate measures for prevention of hepatitis A are adoption of sound sanitation practices, particularly water purification; minimizing overcrowded living conditions; and administering the hepatitis A vaccine for both pre and postexposure prophylaxis.^3,4 The hepatitis A vaccine is preferred over administration of immune globulin because it provides lifelong immunity.

The hepatitis A vaccine is produced in 2 monovalent formulations: Havrix (GlaxoSmithKline) and Vaqta (Merck & Co, Inc). The vaccine should be administered intramuscularly in 2 doses 6 to 12 months apart. The wholesale cost of the vaccine varies from $66 to $119 (according to http://www.goodrx.com). The vaccine also is available in a bivalent form, with recombinant hepatitis B vaccine (Twinrix, GlaxoSmithKline). When used in this form, 3 vaccine administrations are given—at 0, 1, and 6 months apart. The cost of the vaccine is approximately $150 (according to http://www.goodrx.com). TABLE 2 lists the individuals who are appropriate candidates for the hepatitis A vaccine.^3,4

Hepatitis B

Hepatitis B is caused by a DNA virus that is transmitted parenterally or perinatally or through sexual contact. Four genotypes have been identified: A, B, C, and D.

Acute hepatitis B affects 1 to 2 of 1,000 pregnancies in the United States. Approximately 6 to 10 patients per 1,000 pregnancies are asymptomatic but chronically infected.⁴ The natural history of hepatitis B infection is shown in the FIGURE. The diagnosis of acute and chronic hepatitis B is best established by serology and polymerase chain reaction (PCR; TABLE 3).

Continue to: Hepatitis C...

Hepatitis C

Hepatitis C is caused by an RNA virus that has 6 genotypes. The most common genotype is HCV1, which affects 79% of patients; approximately 13% of patients have HCV2, and 6% have HCV3.⁹ Of note, the 3 individuals who discovered this virus—Drs. Harvey Alter, Michael Houghton, and Charles Rice—received the 2020 Nobel Prize in Medicine.¹⁰

Hepatitis C is transmitted via sexual contact, parenterally, and perinatally. In many patient populations in the United States, hepatitis C is now more prevalent than hepatitis B. Only about half of all infected persons are aware of their infection. If patients go untreated, approximately 15% to 30% eventually develop cirrhosis. Of these individuals, 1% to 3% develop hepatocellular cancer. Chronic hepatitis C is now the most common indication for liver transplantation in the United States.^1,9

In the initial stages of infection, hepatitis C usually is asymptomatic. The best screening test is detection of hepatitis C antibody. Because of the increasing prevalence of this disease, the seriousness of the infection, and the recent availability of remarkably effective treatment, routine screening, rather than screening on the basis of risk factors, for hepatitis C in pregnancy is now indicated.^11,12

The best tests for confirmation of infection are detection of antibody by enzyme immunoassay and recombinant immuno-blot assay and detection of viral RNA in serum by PCR. Seroconversion may not occur for up to 16 weeks after infection. Therefore, in at-risk patients who initially test negative, retesting is advisable. Patients with positive test results should have tests to identify the specific genotype, determine the viral load, and assess liver function.¹

In patients who have undetectable viral loads and who do not have coexisting HIV infection, the risk of perinatal transmission of hepatitis C is less than 5%. If HIV infection is present, the risk of perinatal transmission approaches 20%.^1,13,14

If the patient is coinfected with HIV, a scheduled cesarean delivery should be performed at 38 weeks’ gestation.¹ If the viral load is undetectable, vaginal delivery is appropriate. If the viral load is high, however (arbitrarily defined as >2.5 millioncopies/mL), the optimal method of delivery is controversial. Several small, nonrandomized noncontrolled cohort studies support elective cesarean delivery in such patients.¹⁴

There is no contraindication to breastfeeding in women with hepatitis C unless they are coinfected with HIV. In such a circumstance, formula feeding should be chosen. After delivery, patients with hepatitis C should be referred to a gastroenterology specialist to receive antiviral treatment. Multiple new single-agent and combination regimens have produced cures in more than 90% of patients. These regimens usually require 8 to 12 weeks of treatment, and they are very expensive. They have not been widely tested in pregnant women.¹

Hepatitis D

Hepatitis D, or delta hepatitis, is caused by an RNA virus. This virus is unique because it is incapable of independent replication. It must be present in association with hepatitis B to replicate and cause clinical infection. Therefore, the epidemiology of hepatitis D closely mirrors that of hepatitis B.^1,2

Patients with hepatitis D typically present in one of two ways. Some individuals are acutely infected with hepatitis D at the same time that they acquire hepatitis B (coinfection). The natural history of this infection usually is spontaneous resolution without sequelae. Other patients have chronic hepatitis D superimposed on chronic hepatitis B (superinfection). Unfortunately, patients with the latter condition are at a notably increased risk for developing severe persistent liver disease.^1,2

The diagnosis of hepatitis D may be confirmed by identifying the delta antigen in serum or in liver tissue obtained by biopsy or by identifying IgM- and IgG-specific antibodies in serum. In conjunction with hepatitis B, the delta virus can cause a chronic carrier state. Perinatal transmission is possible but uncommon. Of greatest importance, the immunoprophylaxis described for hepatitis B is almost perfectly protective against perinatal transmission of hepatitis D.^1,2

Continue to: Hepatitis E...

Hepatitis E

Hepatitis E is an RNA virus that has 1 serotype and 4 genotypes. Its epidemiology is similar to that of hepatitis A. It is the most common waterborne illness in the world. The incubation period varies from 21 to 56 days. This disease is quite rare in the United States but is endemic in developing nations. In those countries, maternal infection has an alarmingly high mortality rate (5%–25%). For example, in Bangladesh, hepatitis E is responsible for more than 1,000 deaths per year in pregnant women. When hepatitis E is identified in more affluent countries, the individual cases and small outbreaks usually are linked to consumption of undercooked pork or wild game.^1,15-17

The clinical presentation of acute hepatitis E also is similar to that of hepatitis A. The usual manifestations are fever, malaise, anorexia, nausea, right upper quadrant pain and tenderness, jaundice, darkened urine, and clay-colored stools. The most useful diagnostic tests are serologic detection of viral-specific antibodies (positive IgM or a 4-fold increase in the prior IgG titer) and PCR-RNA.^1,17

Hepatitis E usually does not cause a chronic carrier state, and perinatal transmission is rare. Fortunately, a highly effective vaccine was recently developed (Hecolin, Xiamen Innovax Biotech). This recombinant vaccine is specifically directed against the hepatitis E genotype 1. In the initial efficacy study, healthy adults aged 16 to 65 years were randomly assigned to receive either the hepatitis E vaccine or the hepatitis B vaccine. The vaccine was administered at time point 0, and 1 and 6 months later. Patients were followed for up to 4.5 years to assess efficacy, immunogenicity, and safety. During the study period, 7 cases of hepatitis E occurred in the vaccine group, compared with 53 in the control group. Approximately 56,000 patients were included in each group. The efficacy of the vaccine was 86.8% (P<.001).¹⁸

Hepatitis G

Hepatitis G is caused by 2 single-stranded RNA viruses that are virtually identical—hepatitis G virus and GB virus type C. The viruses share approximately 30% homology with hepatitis C virus. The organism is present throughout the world and infects approximately 1.5% to 2.0% of the population. The virus is transmitted by blood and sexual contact. It replicates preferentially in mononuclear cells and the bone marrow rather than in the liver.^19-21

Hepatitis G is much less virulent than hepatitis C. Hepatitis G often coexists with hepatitis A, B, and C, as well as with HIV. Coinfection with hepatitis G does not adversely affect the clinical course of the other conditions.^22,23

Most patients with hepatitis G are asymptomatic, and no treatment is indicated. The virus can cause a chronic carrier state. Perinatal transmission is distinctly uncommon. When it does occur, however, injury to mother, fetus, or neonate is unlikely.^1,24

The diagnosis of hepatitis G can be established by detection of virus with PCR and by the identification of antibody by enzyme immunoassay. Routine screening for this infection in pregnancy is not indicated.^1,2

CASE Resolved

Hepatitis B is highly contagious and can be transmitted from the patient to her sexual partner and neonate. Testing for hepatitis B surface antigen and antibody is indicated in her partner. If these tests are negative, the partner should immediately receive hepatitis B immune globulin and then be started on the 3-dose hepatitis B vaccination series. The patient’s newborn also should receive hepatitis B immune globulin within 12 hours of delivery and should receive the first dose of the hepatitis B vaccine prior to discharge from the hospital. The second and third doses should be administered 1 and 6 months after delivery.

The patient also should have the following tests:

• liver function tests

-serum transaminases

-direct and indirect bilirubin

-coagulation profile

• hepatitis D antigen

• hepatitis B genotype

• hepatitis B viral load

• HIV serology.

If the hepatitis B viral load exceeds 1 million copies/mL, the patient should be treated with tenofovir 200 mg daily from 28 weeks’ gestation until delivery. In addition, she should be referred to a liver disease specialist after delivery for consideration of treatment with directly-acting antiviral agents. ●

Sentilhes L, Senat MV, Le Lous M, et al; Groupe de Recherche en Obstetrique et Gynecologie. Tranexamic acid for the prevention of blood loss after cesarean delivery. N Engl J Med. 2021;384:1623-1634. doi: 10.1056/NEJMoa2028788.

EXPERT COMMENTARY

Postpartum hemorrhage is the leading cause of maternal mortality worldwide.¹ Many preventive strategies, including tranexamic acid administration, have been studied in an attempt to reduce the risk of PPH. Tranexamic acid prevents the conversion of plasminogen to plasmin, preventing the breakdown of fibrin, and ultimately stabilizing the fibrin matrix of clot.² It has been shown to be an effective approach to treating hemorrhage in patients after trauma as well as cardiac surgery.^3,4 The use of tranexamic acid in obstetric hemorrhage has reduced mortality in previous trials,⁵ but its prophylactic use has had mixed results in preventing obstetric hemorrhage.^6-8

Recently, Sentilhes and colleagues published the largest prospective study to date addressing the efficacy of tranexamic acid for the primary prevention of PPH.

Details of the study

Multiple hospitals throughout France participated in the investigators’ double-blind randomized, placebo-controlled trial. Women undergoing CD at 34 or more weeks’ gestation (N = 4,551) were randomly assigned to receive 1 g of intravenous (IV) tranexamic acid or placebo after cord clamping. Both groups received IV prophylactic uterotonics. The primary outcome was PPH, defined by estimated blood loss (EBL) greater than 1 L or receipt of red blood cell transfusion within the first 2 days after surgery.

Results. The rate of PPH was significantly lower in women who received tranexamic acid compared with those who received placebo. Yet, the mean EBL between the 2 groups differed by only 100 mL. The rates of blood transfusions, additional uterotonic administration, arterial embolization, and hysterectomy did not differ between groups.

The clinicians responsible for the care of these patients did not observe a difference in the rate of “clinically significant” PPH between those who received tranexamic acid and those who received placebo. Women who received tranexamic acid were more likely to experience nausea and vomiting, but they did not have any increased risk of venous thromboembolic disease.

Study strengths and limitations

Sentilhes and colleagues’ study findings contradict those of an earlier meta-analysis on the topic.⁹ This may be due to the effect of publication bias on meta-analyses, which makes them prone to supporting the findings of published positive trials while missing data from negative trials that did not reach publication. The gold standard for addressing a research question such as this is a randomized controlled trial (RCT). The study reviewed here is an excellent example of a well-designed and executed RCT.

There may be a benefit to prophylactic tranexamic acid in certain populations not well captured among these study participants. The inclusion criteria were broad, including both prelabor and intrapartum CDs, making the results generalizable. However, the population studied, with a mean body mass index of 26 kg/m² and age of 33, may not resemble some readers’ patient population. Prespecified subgroup analyses did not find a benefit to tranexamic acid in patients considered at high risk for PPH or in those undergoing intrapartum CD. ●

Sentilhes L, Senat MV, Le Lous M, et al; Groupe de Recherche en Obstetrique et Gynecologie. Tranexamic acid for the prevention of blood loss after cesarean delivery. N Engl J Med. 2021;384:1623-1634. doi: 10.1056/NEJMoa2028788.

EXPERT COMMENTARY

Postpartum hemorrhage is the leading cause of maternal mortality worldwide.¹ Many preventive strategies, including tranexamic acid administration, have been studied in an attempt to reduce the risk of PPH. Tranexamic acid prevents the conversion of plasminogen to plasmin, preventing the breakdown of fibrin, and ultimately stabilizing the fibrin matrix of clot.² It has been shown to be an effective approach to treating hemorrhage in patients after trauma as well as cardiac surgery.^3,4 The use of tranexamic acid in obstetric hemorrhage has reduced mortality in previous trials,⁵ but its prophylactic use has had mixed results in preventing obstetric hemorrhage.^6-8

Recently, Sentilhes and colleagues published the largest prospective study to date addressing the efficacy of tranexamic acid for the primary prevention of PPH.

Details of the study

Multiple hospitals throughout France participated in the investigators’ double-blind randomized, placebo-controlled trial. Women undergoing CD at 34 or more weeks’ gestation (N = 4,551) were randomly assigned to receive 1 g of intravenous (IV) tranexamic acid or placebo after cord clamping. Both groups received IV prophylactic uterotonics. The primary outcome was PPH, defined by estimated blood loss (EBL) greater than 1 L or receipt of red blood cell transfusion within the first 2 days after surgery.

Results. The rate of PPH was significantly lower in women who received tranexamic acid compared with those who received placebo. Yet, the mean EBL between the 2 groups differed by only 100 mL. The rates of blood transfusions, additional uterotonic administration, arterial embolization, and hysterectomy did not differ between groups.

The clinicians responsible for the care of these patients did not observe a difference in the rate of “clinically significant” PPH between those who received tranexamic acid and those who received placebo. Women who received tranexamic acid were more likely to experience nausea and vomiting, but they did not have any increased risk of venous thromboembolic disease.

Study strengths and limitations

Sentilhes and colleagues’ study findings contradict those of an earlier meta-analysis on the topic.⁹ This may be due to the effect of publication bias on meta-analyses, which makes them prone to supporting the findings of published positive trials while missing data from negative trials that did not reach publication. The gold standard for addressing a research question such as this is a randomized controlled trial (RCT). The study reviewed here is an excellent example of a well-designed and executed RCT.

There may be a benefit to prophylactic tranexamic acid in certain populations not well captured among these study participants. The inclusion criteria were broad, including both prelabor and intrapartum CDs, making the results generalizable. However, the population studied, with a mean body mass index of 26 kg/m² and age of 33, may not resemble some readers’ patient population. Prespecified subgroup analyses did not find a benefit to tranexamic acid in patients considered at high risk for PPH or in those undergoing intrapartum CD. ●

Sentilhes L, Senat MV, Le Lous M, et al; Groupe de Recherche en Obstetrique et Gynecologie. Tranexamic acid for the prevention of blood loss after cesarean delivery. N Engl J Med. 2021;384:1623-1634. doi: 10.1056/NEJMoa2028788.

EXPERT COMMENTARY

Postpartum hemorrhage is the leading cause of maternal mortality worldwide.¹ Many preventive strategies, including tranexamic acid administration, have been studied in an attempt to reduce the risk of PPH. Tranexamic acid prevents the conversion of plasminogen to plasmin, preventing the breakdown of fibrin, and ultimately stabilizing the fibrin matrix of clot.² It has been shown to be an effective approach to treating hemorrhage in patients after trauma as well as cardiac surgery.^3,4 The use of tranexamic acid in obstetric hemorrhage has reduced mortality in previous trials,⁵ but its prophylactic use has had mixed results in preventing obstetric hemorrhage.^6-8

Recently, Sentilhes and colleagues published the largest prospective study to date addressing the efficacy of tranexamic acid for the primary prevention of PPH.

Details of the study

Multiple hospitals throughout France participated in the investigators’ double-blind randomized, placebo-controlled trial. Women undergoing CD at 34 or more weeks’ gestation (N = 4,551) were randomly assigned to receive 1 g of intravenous (IV) tranexamic acid or placebo after cord clamping. Both groups received IV prophylactic uterotonics. The primary outcome was PPH, defined by estimated blood loss (EBL) greater than 1 L or receipt of red blood cell transfusion within the first 2 days after surgery.

Results. The rate of PPH was significantly lower in women who received tranexamic acid compared with those who received placebo. Yet, the mean EBL between the 2 groups differed by only 100 mL. The rates of blood transfusions, additional uterotonic administration, arterial embolization, and hysterectomy did not differ between groups.

The clinicians responsible for the care of these patients did not observe a difference in the rate of “clinically significant” PPH between those who received tranexamic acid and those who received placebo. Women who received tranexamic acid were more likely to experience nausea and vomiting, but they did not have any increased risk of venous thromboembolic disease.

Study strengths and limitations

Sentilhes and colleagues’ study findings contradict those of an earlier meta-analysis on the topic.⁹ This may be due to the effect of publication bias on meta-analyses, which makes them prone to supporting the findings of published positive trials while missing data from negative trials that did not reach publication. The gold standard for addressing a research question such as this is a randomized controlled trial (RCT). The study reviewed here is an excellent example of a well-designed and executed RCT.

There may be a benefit to prophylactic tranexamic acid in certain populations not well captured among these study participants. The inclusion criteria were broad, including both prelabor and intrapartum CDs, making the results generalizable. However, the population studied, with a mean body mass index of 26 kg/m² and age of 33, may not resemble some readers’ patient population. Prespecified subgroup analyses did not find a benefit to tranexamic acid in patients considered at high risk for PPH or in those undergoing intrapartum CD. ●

There are dozens of medications containing combinations of estrogen and progestin. I am often confused by the bewildering proliferation of generic brand names used to describe the same estrogen-progestin (E-P) regimen. For example, the combination medication containing ethinyl estradiol 20 µg plus norethindrone acetate (NEA) 1 mg is available under at least 5 different names: Lo Estrin 1/20 (Warner Chilcot), Junel 1/20 (Teva Pharmaceuticals), Microgestin Fe 1/20 (Mayne Pharma), Gildess 1/20 (Qualitest Pharmaceuticals), and Larin 1/20 (Novast Laboratories). To reduce the confusion, it is often useful to select a single preferred estrogen and progestin and use the dose combinations that are available to treat a wide range of gynecology problems (TABLE). In this editorial I focus on using various dose combinations of ethinyl estradiol and NEA to treat 3 common gynecologic problems.

CASE 1 Polycystic ovary syndrome

A 19-year-old woman reports 4 spontaneous menses in the past year and bothersome facial hair and acne. Her total testosterone concentration is at the upper limit of normal (0.46 ng/mL) and her sex hormone binding globulin (SHBG) concentration is at the lower limit of normal (35 nM). For treatment of the patient’s menstrual disorder, what is an optimal E-P combination?

Prioritize the use of an estrogen-dominant medication

Based on the Rotterdam criteria this woman has polycystic ovary syndrome (PCOS).¹ In women with PCOS, luteinizing hormone (LH) secretion is increased, stimulating excessive ovarian production of testosterone.² In addition, many women with PCOS have decreased hepatic secretion of SHBG, a binding protein that prevents testosterone from entering cells, resulting in excessive bioavailable testosterone.³ The Endocrine Society recommends that women with PCOS who have menstrual dysfunction or hirsutism be treated initially with a combination E-P hormone medication.¹ Combination E-P medications suppress pituitary secretion of LH, thereby reducing ovarian production of testosterone, and ethinyl estradiol increases hepatic secretion of SHBG, reducing bioavailable testosterone. These two goals are best accomplished with an oral E-P hormone medication containing ethinyl estradiol doses of 20 µg to 30 µg per pill. An E-P hormone medication containing pills with an ethinyl estradiol dose ≤ 10 µg-daily may stimulate less hepatic production of SHBG than a pill with an ethinyl estradiol dose of 20 µg or 30 µg daily.^4,5 In addition, E-P pills containing levonorgestrel suppress SHBG hormone secretion compared with E-P pills with other progestins.⁶ Therefore, levonorgestrel-containing E-P pills should not be prioritized for use in women with PCOS because the estrogen-induced increase in SHBG will be blunted by levonorgestrel.

CASE 2 Moderate to severe pelvic pain caused by endometriosis

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis lesions in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy showed endometriosis. Postoperatively, the patient was treated with an E-P pill containing 30 µg ethinyl estradiol and 0.15 mg desogestrel per pill using a continuous-dosing protocol. During the year following the laparoscopy, her pelvic pain symptoms gradually increased until they became severe, preventing her from performing daily activities on multiple days per month. She was prescribed elagolix but her insurance did not approve the treatment. What alternative treatment would you prescribe?

Continue to: Use progestin-dominant pills to treat pelvic pain...

Use progestin-dominant pills to treat pelvic pain

Cellular activity in endometriosis lesions is stimulated by estradiol and inhibited by a high concentration of androgenic progestins or androgens. This simplified endocrine paradigm explains the effectiveness of hormonal treatments that suppress ovarian estradiol production, including leuprolide, elagolix, medroxyprogesterone acetate, and NEA. For the woman in the above case, I would advocate for elagolix treatment but, following the insurance denial of the prescription, an alternative treatment for moderate or severe pelvic pain caused by endometriosis would be a progestin-dominant hormone medication (for example, NEA 5 mg daily). Norethindrone acetate 5 mg daily may be associated with bothersome adverse effects including weight gain (16% of patients; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%).⁷

I sometimes see women with moderate to severe pelvic pain caused by endometriosis being treated with norethindrone 0.35 mg daily. This dose of norethindrone is suboptimal for pain treatment because it does not reliably suppress ovarian production of estradiol. In addition, the cells in endometriosis lesions are often resistant to the effects of progesterone, requiring higher dosages to produce secretory or decidual changes. In most situations, I recommend against the use of norethindrone 0.35 mg daily for the treatment of pelvic pain caused by endometriosis.

Patients commonly ask if NEA 5 mg daily has contraceptive efficacy. Although it is not approved at this dosage by the US Food and Drug Administration as a contraceptive,⁸ norethindrone 0.35 mg daily is approved as a progestin-only contraceptive.⁹ Norethindrone acetate is rapidly and completely deacetylated to norethindrone and the disposition of oral NEA is indistinguishable from that of norethindrone (which is the FDA-approved dosage mentioned above). Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg daily has contraceptive efficacy, especially if there is good adherence with the daily medication.

CASE 3 Perimenopausal AUB

A 45-year-old woman reports varying menstrual cycle lengths from 24 to 60 days with very heavy menses in some cycles. Pelvic ultrasonography shows no abnormality. Endometrial biopsy shows a proliferative endometrium. Her serum progesterone level, obtained 1 week before the onset of menses, is < 3 ng/mL. She has no past history of heavy menses, easy bruising, excessive bleeding with procedures, or a family history of bleeding problems. She also reports occasional hot flashes that wake her from sleep.

Use an estrogen step-down regimen to manage postmenopause transition

This patient is likely in the perimenopause transition, and the abnormal uterine bleeding (AUB) is caused, in part, by oligo- or anovulation. Perimenopausal women with AUB may have cycles characterized by above normal ovarian estradiol production and below normal progesterone production, or frank anovulation.¹⁰ Elevated ovarian estrogen and low progesterone production sets the stage for heavy bleeding in the perimenopause, regardless of the presence of uterine pathology such as fibroids.

For perimenopausal women, one option for treatment of AUB due to anovulation is to prescribe an estrogen step-down regimen. For the 45-year-old woman in this case, initiating treatment with an E-P pill containing ethinyl estradiol 10 µg and NEA 1 mg will likely control the AUB and her occasional hot flash.¹¹ As the woman ages, the ethinyl estradiol dose can be decreased to pills containing 5 µg and then 2.5 µg, covering the transition into postmenopause. Once the woman is in the postmenopause, treatment with transdermal estradiol and oral micronized progesterone is an option to treat menopausal vasomotor symptoms.

Optimize estrogen and progestin treatment for your patients

Many gynecologic problems are effectively treated by estrogen and/or progestin steroids. The dose of estrogen and progestin should be tailored to the specific problem. For PCOS, the estrogen dose selected should be sufficient to safely stimulate hepatic SHBG production. For endometriosis, if a GnRH antagonist is not available to the patient, a high-dose progestin, such as NEA 5 mg, may be an effective treatment. During the perimenopause transition in a woman with AUB, a treatment plan using a sequential E-P step-down program might control symptoms and help smoothly glide the patient into the postmenopause. ●

There are dozens of medications containing combinations of estrogen and progestin. I am often confused by the bewildering proliferation of generic brand names used to describe the same estrogen-progestin (E-P) regimen. For example, the combination medication containing ethinyl estradiol 20 µg plus norethindrone acetate (NEA) 1 mg is available under at least 5 different names: Lo Estrin 1/20 (Warner Chilcot), Junel 1/20 (Teva Pharmaceuticals), Microgestin Fe 1/20 (Mayne Pharma), Gildess 1/20 (Qualitest Pharmaceuticals), and Larin 1/20 (Novast Laboratories). To reduce the confusion, it is often useful to select a single preferred estrogen and progestin and use the dose combinations that are available to treat a wide range of gynecology problems (TABLE). In this editorial I focus on using various dose combinations of ethinyl estradiol and NEA to treat 3 common gynecologic problems.

CASE 1 Polycystic ovary syndrome

A 19-year-old woman reports 4 spontaneous menses in the past year and bothersome facial hair and acne. Her total testosterone concentration is at the upper limit of normal (0.46 ng/mL) and her sex hormone binding globulin (SHBG) concentration is at the lower limit of normal (35 nM). For treatment of the patient’s menstrual disorder, what is an optimal E-P combination?

Prioritize the use of an estrogen-dominant medication

Based on the Rotterdam criteria this woman has polycystic ovary syndrome (PCOS).¹ In women with PCOS, luteinizing hormone (LH) secretion is increased, stimulating excessive ovarian production of testosterone.² In addition, many women with PCOS have decreased hepatic secretion of SHBG, a binding protein that prevents testosterone from entering cells, resulting in excessive bioavailable testosterone.³ The Endocrine Society recommends that women with PCOS who have menstrual dysfunction or hirsutism be treated initially with a combination E-P hormone medication.¹ Combination E-P medications suppress pituitary secretion of LH, thereby reducing ovarian production of testosterone, and ethinyl estradiol increases hepatic secretion of SHBG, reducing bioavailable testosterone. These two goals are best accomplished with an oral E-P hormone medication containing ethinyl estradiol doses of 20 µg to 30 µg per pill. An E-P hormone medication containing pills with an ethinyl estradiol dose ≤ 10 µg-daily may stimulate less hepatic production of SHBG than a pill with an ethinyl estradiol dose of 20 µg or 30 µg daily.^4,5 In addition, E-P pills containing levonorgestrel suppress SHBG hormone secretion compared with E-P pills with other progestins.⁶ Therefore, levonorgestrel-containing E-P pills should not be prioritized for use in women with PCOS because the estrogen-induced increase in SHBG will be blunted by levonorgestrel.

CASE 2 Moderate to severe pelvic pain caused by endometriosis

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis lesions in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy showed endometriosis. Postoperatively, the patient was treated with an E-P pill containing 30 µg ethinyl estradiol and 0.15 mg desogestrel per pill using a continuous-dosing protocol. During the year following the laparoscopy, her pelvic pain symptoms gradually increased until they became severe, preventing her from performing daily activities on multiple days per month. She was prescribed elagolix but her insurance did not approve the treatment. What alternative treatment would you prescribe?

Continue to: Use progestin-dominant pills to treat pelvic pain...

Use progestin-dominant pills to treat pelvic pain

Cellular activity in endometriosis lesions is stimulated by estradiol and inhibited by a high concentration of androgenic progestins or androgens. This simplified endocrine paradigm explains the effectiveness of hormonal treatments that suppress ovarian estradiol production, including leuprolide, elagolix, medroxyprogesterone acetate, and NEA. For the woman in the above case, I would advocate for elagolix treatment but, following the insurance denial of the prescription, an alternative treatment for moderate or severe pelvic pain caused by endometriosis would be a progestin-dominant hormone medication (for example, NEA 5 mg daily). Norethindrone acetate 5 mg daily may be associated with bothersome adverse effects including weight gain (16% of patients; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%).⁷

I sometimes see women with moderate to severe pelvic pain caused by endometriosis being treated with norethindrone 0.35 mg daily. This dose of norethindrone is suboptimal for pain treatment because it does not reliably suppress ovarian production of estradiol. In addition, the cells in endometriosis lesions are often resistant to the effects of progesterone, requiring higher dosages to produce secretory or decidual changes. In most situations, I recommend against the use of norethindrone 0.35 mg daily for the treatment of pelvic pain caused by endometriosis.

Patients commonly ask if NEA 5 mg daily has contraceptive efficacy. Although it is not approved at this dosage by the US Food and Drug Administration as a contraceptive,⁸ norethindrone 0.35 mg daily is approved as a progestin-only contraceptive.⁹ Norethindrone acetate is rapidly and completely deacetylated to norethindrone and the disposition of oral NEA is indistinguishable from that of norethindrone (which is the FDA-approved dosage mentioned above). Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg daily has contraceptive efficacy, especially if there is good adherence with the daily medication.

CASE 3 Perimenopausal AUB

A 45-year-old woman reports varying menstrual cycle lengths from 24 to 60 days with very heavy menses in some cycles. Pelvic ultrasonography shows no abnormality. Endometrial biopsy shows a proliferative endometrium. Her serum progesterone level, obtained 1 week before the onset of menses, is < 3 ng/mL. She has no past history of heavy menses, easy bruising, excessive bleeding with procedures, or a family history of bleeding problems. She also reports occasional hot flashes that wake her from sleep.

Use an estrogen step-down regimen to manage postmenopause transition

This patient is likely in the perimenopause transition, and the abnormal uterine bleeding (AUB) is caused, in part, by oligo- or anovulation. Perimenopausal women with AUB may have cycles characterized by above normal ovarian estradiol production and below normal progesterone production, or frank anovulation.¹⁰ Elevated ovarian estrogen and low progesterone production sets the stage for heavy bleeding in the perimenopause, regardless of the presence of uterine pathology such as fibroids.

For perimenopausal women, one option for treatment of AUB due to anovulation is to prescribe an estrogen step-down regimen. For the 45-year-old woman in this case, initiating treatment with an E-P pill containing ethinyl estradiol 10 µg and NEA 1 mg will likely control the AUB and her occasional hot flash.¹¹ As the woman ages, the ethinyl estradiol dose can be decreased to pills containing 5 µg and then 2.5 µg, covering the transition into postmenopause. Once the woman is in the postmenopause, treatment with transdermal estradiol and oral micronized progesterone is an option to treat menopausal vasomotor symptoms.

Optimize estrogen and progestin treatment for your patients

Many gynecologic problems are effectively treated by estrogen and/or progestin steroids. The dose of estrogen and progestin should be tailored to the specific problem. For PCOS, the estrogen dose selected should be sufficient to safely stimulate hepatic SHBG production. For endometriosis, if a GnRH antagonist is not available to the patient, a high-dose progestin, such as NEA 5 mg, may be an effective treatment. During the perimenopause transition in a woman with AUB, a treatment plan using a sequential E-P step-down program might control symptoms and help smoothly glide the patient into the postmenopause. ●

There are dozens of medications containing combinations of estrogen and progestin. I am often confused by the bewildering proliferation of generic brand names used to describe the same estrogen-progestin (E-P) regimen. For example, the combination medication containing ethinyl estradiol 20 µg plus norethindrone acetate (NEA) 1 mg is available under at least 5 different names: Lo Estrin 1/20 (Warner Chilcot), Junel 1/20 (Teva Pharmaceuticals), Microgestin Fe 1/20 (Mayne Pharma), Gildess 1/20 (Qualitest Pharmaceuticals), and Larin 1/20 (Novast Laboratories). To reduce the confusion, it is often useful to select a single preferred estrogen and progestin and use the dose combinations that are available to treat a wide range of gynecology problems (TABLE). In this editorial I focus on using various dose combinations of ethinyl estradiol and NEA to treat 3 common gynecologic problems.

CASE 1 Polycystic ovary syndrome

A 19-year-old woman reports 4 spontaneous menses in the past year and bothersome facial hair and acne. Her total testosterone concentration is at the upper limit of normal (0.46 ng/mL) and her sex hormone binding globulin (SHBG) concentration is at the lower limit of normal (35 nM). For treatment of the patient’s menstrual disorder, what is an optimal E-P combination?

Prioritize the use of an estrogen-dominant medication

Based on the Rotterdam criteria this woman has polycystic ovary syndrome (PCOS).¹ In women with PCOS, luteinizing hormone (LH) secretion is increased, stimulating excessive ovarian production of testosterone.² In addition, many women with PCOS have decreased hepatic secretion of SHBG, a binding protein that prevents testosterone from entering cells, resulting in excessive bioavailable testosterone.³ The Endocrine Society recommends that women with PCOS who have menstrual dysfunction or hirsutism be treated initially with a combination E-P hormone medication.¹ Combination E-P medications suppress pituitary secretion of LH, thereby reducing ovarian production of testosterone, and ethinyl estradiol increases hepatic secretion of SHBG, reducing bioavailable testosterone. These two goals are best accomplished with an oral E-P hormone medication containing ethinyl estradiol doses of 20 µg to 30 µg per pill. An E-P hormone medication containing pills with an ethinyl estradiol dose ≤ 10 µg-daily may stimulate less hepatic production of SHBG than a pill with an ethinyl estradiol dose of 20 µg or 30 µg daily.^4,5 In addition, E-P pills containing levonorgestrel suppress SHBG hormone secretion compared with E-P pills with other progestins.⁶ Therefore, levonorgestrel-containing E-P pills should not be prioritized for use in women with PCOS because the estrogen-induced increase in SHBG will be blunted by levonorgestrel.

CASE 2 Moderate to severe pelvic pain caused by endometriosis

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis lesions in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy showed endometriosis. Postoperatively, the patient was treated with an E-P pill containing 30 µg ethinyl estradiol and 0.15 mg desogestrel per pill using a continuous-dosing protocol. During the year following the laparoscopy, her pelvic pain symptoms gradually increased until they became severe, preventing her from performing daily activities on multiple days per month. She was prescribed elagolix but her insurance did not approve the treatment. What alternative treatment would you prescribe?

Continue to: Use progestin-dominant pills to treat pelvic pain...

Use progestin-dominant pills to treat pelvic pain

Cellular activity in endometriosis lesions is stimulated by estradiol and inhibited by a high concentration of androgenic progestins or androgens. This simplified endocrine paradigm explains the effectiveness of hormonal treatments that suppress ovarian estradiol production, including leuprolide, elagolix, medroxyprogesterone acetate, and NEA. For the woman in the above case, I would advocate for elagolix treatment but, following the insurance denial of the prescription, an alternative treatment for moderate or severe pelvic pain caused by endometriosis would be a progestin-dominant hormone medication (for example, NEA 5 mg daily). Norethindrone acetate 5 mg daily may be associated with bothersome adverse effects including weight gain (16% of patients; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%).⁷

I sometimes see women with moderate to severe pelvic pain caused by endometriosis being treated with norethindrone 0.35 mg daily. This dose of norethindrone is suboptimal for pain treatment because it does not reliably suppress ovarian production of estradiol. In addition, the cells in endometriosis lesions are often resistant to the effects of progesterone, requiring higher dosages to produce secretory or decidual changes. In most situations, I recommend against the use of norethindrone 0.35 mg daily for the treatment of pelvic pain caused by endometriosis.

Patients commonly ask if NEA 5 mg daily has contraceptive efficacy. Although it is not approved at this dosage by the US Food and Drug Administration as a contraceptive,⁸ norethindrone 0.35 mg daily is approved as a progestin-only contraceptive.⁹ Norethindrone acetate is rapidly and completely deacetylated to norethindrone and the disposition of oral NEA is indistinguishable from that of norethindrone (which is the FDA-approved dosage mentioned above). Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg daily has contraceptive efficacy, especially if there is good adherence with the daily medication.

CASE 3 Perimenopausal AUB

A 45-year-old woman reports varying menstrual cycle lengths from 24 to 60 days with very heavy menses in some cycles. Pelvic ultrasonography shows no abnormality. Endometrial biopsy shows a proliferative endometrium. Her serum progesterone level, obtained 1 week before the onset of menses, is < 3 ng/mL. She has no past history of heavy menses, easy bruising, excessive bleeding with procedures, or a family history of bleeding problems. She also reports occasional hot flashes that wake her from sleep.

Use an estrogen step-down regimen to manage postmenopause transition

This patient is likely in the perimenopause transition, and the abnormal uterine bleeding (AUB) is caused, in part, by oligo- or anovulation. Perimenopausal women with AUB may have cycles characterized by above normal ovarian estradiol production and below normal progesterone production, or frank anovulation.¹⁰ Elevated ovarian estrogen and low progesterone production sets the stage for heavy bleeding in the perimenopause, regardless of the presence of uterine pathology such as fibroids.

For perimenopausal women, one option for treatment of AUB due to anovulation is to prescribe an estrogen step-down regimen. For the 45-year-old woman in this case, initiating treatment with an E-P pill containing ethinyl estradiol 10 µg and NEA 1 mg will likely control the AUB and her occasional hot flash.¹¹ As the woman ages, the ethinyl estradiol dose can be decreased to pills containing 5 µg and then 2.5 µg, covering the transition into postmenopause. Once the woman is in the postmenopause, treatment with transdermal estradiol and oral micronized progesterone is an option to treat menopausal vasomotor symptoms.

Optimize estrogen and progestin treatment for your patients

Many gynecologic problems are effectively treated by estrogen and/or progestin steroids. The dose of estrogen and progestin should be tailored to the specific problem. For PCOS, the estrogen dose selected should be sufficient to safely stimulate hepatic SHBG production. For endometriosis, if a GnRH antagonist is not available to the patient, a high-dose progestin, such as NEA 5 mg, may be an effective treatment. During the perimenopause transition in a woman with AUB, a treatment plan using a sequential E-P step-down program might control symptoms and help smoothly glide the patient into the postmenopause. ●

Hereditary cancer risk assessment is the key to identifying patients and families who are at increased risk for developing cancer. The knowledge generated by cancer risk assessment impacts clinical decisions that obstetricians and gynecologists and their patients make every day. Previvors—patients predisposed to developing cancer, because of their family history or a pathogenic gene variant, who have not had cancer—benefit from counseling, heightened surveillance, and medical and surgical options.

For the last 25 years, this field has been growing dramatically, and although the scientific advances are present, only 15.3% of patients with a personal history of breast or ovarian cancer who meet hereditary cancer testing criteria have been tested.¹ As many as 1 in 4 women who present for a gynecologic examination may have a personal history or a family history that qualifies them for genetic testing.²

Cancer risk app considerations

The ability to leverage mobile device applications can provide clinicians and patients with a useful screening tool to identify women who are at increased cancer risk. Only a handful of apps are available today and most are geared to patients. Such apps explore the different testing modalities, including genetic testing, as well as treatment options. When evaluating the best app for patients, using the ACOG-recommended rubric shown on page 35, the qualities to keep in mind and that should score 4 out of 4 include design, authority, usefulness, and accuracy.

A few apps provide reminders for appointments, such as mammograms, magnetic resonance imaging, or breast self-exams, and allow patients to track treatment plans. To date, no app addresses prevention and treatment opportunities that are specific to patients who have a hereditary predisposition. At least one app lists hereditary cancer testing guidelines. Many more apps are geared toward individuals with cancer rather than toward previvors.

As ObGyns, we have an opportunity to educate and identify women and, subsequently, better counsel women identified as at increased risk for developing cancer. We can utilize medical apps to efficiently incorporate this screening into clinical practice. ●

Hereditary cancer risk assessment is the key to identifying patients and families who are at increased risk for developing cancer. The knowledge generated by cancer risk assessment impacts clinical decisions that obstetricians and gynecologists and their patients make every day. Previvors—patients predisposed to developing cancer, because of their family history or a pathogenic gene variant, who have not had cancer—benefit from counseling, heightened surveillance, and medical and surgical options.

For the last 25 years, this field has been growing dramatically, and although the scientific advances are present, only 15.3% of patients with a personal history of breast or ovarian cancer who meet hereditary cancer testing criteria have been tested.¹ As many as 1 in 4 women who present for a gynecologic examination may have a personal history or a family history that qualifies them for genetic testing.²

Cancer risk app considerations

The ability to leverage mobile device applications can provide clinicians and patients with a useful screening tool to identify women who are at increased cancer risk. Only a handful of apps are available today and most are geared to patients. Such apps explore the different testing modalities, including genetic testing, as well as treatment options. When evaluating the best app for patients, using the ACOG-recommended rubric shown on page 35, the qualities to keep in mind and that should score 4 out of 4 include design, authority, usefulness, and accuracy.

A few apps provide reminders for appointments, such as mammograms, magnetic resonance imaging, or breast self-exams, and allow patients to track treatment plans. To date, no app addresses prevention and treatment opportunities that are specific to patients who have a hereditary predisposition. At least one app lists hereditary cancer testing guidelines. Many more apps are geared toward individuals with cancer rather than toward previvors.

As ObGyns, we have an opportunity to educate and identify women and, subsequently, better counsel women identified as at increased risk for developing cancer. We can utilize medical apps to efficiently incorporate this screening into clinical practice. ●

Hereditary cancer risk assessment is the key to identifying patients and families who are at increased risk for developing cancer. The knowledge generated by cancer risk assessment impacts clinical decisions that obstetricians and gynecologists and their patients make every day. Previvors—patients predisposed to developing cancer, because of their family history or a pathogenic gene variant, who have not had cancer—benefit from counseling, heightened surveillance, and medical and surgical options.

For the last 25 years, this field has been growing dramatically, and although the scientific advances are present, only 15.3% of patients with a personal history of breast or ovarian cancer who meet hereditary cancer testing criteria have been tested.¹ As many as 1 in 4 women who present for a gynecologic examination may have a personal history or a family history that qualifies them for genetic testing.²

Cancer risk app considerations

The ability to leverage mobile device applications can provide clinicians and patients with a useful screening tool to identify women who are at increased cancer risk. Only a handful of apps are available today and most are geared to patients. Such apps explore the different testing modalities, including genetic testing, as well as treatment options. When evaluating the best app for patients, using the ACOG-recommended rubric shown on page 35, the qualities to keep in mind and that should score 4 out of 4 include design, authority, usefulness, and accuracy.

A few apps provide reminders for appointments, such as mammograms, magnetic resonance imaging, or breast self-exams, and allow patients to track treatment plans. To date, no app addresses prevention and treatment opportunities that are specific to patients who have a hereditary predisposition. At least one app lists hereditary cancer testing guidelines. Many more apps are geared toward individuals with cancer rather than toward previvors.

As ObGyns, we have an opportunity to educate and identify women and, subsequently, better counsel women identified as at increased risk for developing cancer. We can utilize medical apps to efficiently incorporate this screening into clinical practice. ●

Evolutionary changes in ObGyn

Preventive medicine guidelines have evolved to reflect enhanced cervical cancer screening tests, longer-acting contraceptive options, and better data on the lack of utility of the annual pelvic exam that has changed the focus of the annual visit for both physicians and patients.¹ These changes allow us to pivot and leverage the trust we build with our patients to make meaningful impacts in preventing chronic disease, improving prepregnancy health, reducing maternal mortality and morbidity, and improving the quality and longevity of our patients’ lives. New guidelines, coupled with the knowledge of the leading causes of morbidity for women, provide the chance to incorporate areas of screening and intervention that, while we are capable of addressing, we traditionally have not done so for various reasons.

The ACOG Presidential Task Force identified 5 areas of preventive health that significantly influence the long-term morbidity of women: obesity, cardiovascular disease, preconception counseling, diabetes, and cancer risk. ObGyns are uniquely positioned to identify and initiate the conversation and subsequently manage, treat, and address these critical health areas. To make this daunting task more manageable, the Task Force not only published webinars to address the clinical knowledge pertaining to these areas of health but also specifically looked at how to use technology to aid obstetrician-gynecologists in addressing them with patients.

Making use of technology in clinical practice

Technology is emerging as an influential player in health care. Major corporations, such as Amazon, Google, Apple, and Facebook, are making headlines in health care as they consider strategies (moves) to revolutionize technology and, in turn, patient visits like we have never seen before. Examples include incorporating artificial intelligence in a patient’s care and allowing better access for primary care.

The changes that we will see over the next 10 years, influenced by industry, will be more than those seen in our lifetime. To prepare for these changes, we need to incorporate technology into our daily practice. This encompasses much more than just the electronic medical record. Consequently, the Task Force intentionally looked at mobile medical apps to aid physicians in addressing the 5 specific areas of preventive health identified.

While a small step compared with what is to come, apps are a great resource to leverage in making this transition. However, with hundreds of thousands of medical apps available in app stores and the constant updates and iterations of each, it would be impossible to recommend any single app. There is much value in having a framework to use to efficiently measure the benefit of an app that you or your patient comes across in clinical practice. The objective of this series was to provide clinicians with an effective tool to evaluate a medical app that could be used, for example, when addressing obesity or optimizing prepregnancy health.

Continue to: The recommended rubric for evaluating apps...

The recommended rubric for evaluating apps

To evaluate mobile drug information apps, the Task Force members recommend a user-friendly, convenient rubric developed by the American Society of Health-System Pharmacists (ASHP) (see page 35). The rubric can help obstetrician-gynecologists evaluate and compare the value of various medical apps that specifically address obesity, diabetes mellitus, cardiovascular disease, improving maternal morbidity with enhanced preconception counseling, and cancer risk assessment.

The authors of this Task Force series have attempted to highlight the key features of an app as it pertains to a particular area of focus. It is important to keep in mind the primary user and the goal when choosing or recommending an app for practice or for patient use. The ASHP’s rubric is a tool meant to aid clinicians in evaluating medical apps, but it is ultimately the user’s decision to determine if the deficiencies of an app should deter its use. Although all the criteria are relevant and important, as medical experts it is incumbent on us to pay careful attention to the accuracy, authority, objectivity, timeliness, and security of any app we consider incorporating into clinical practice.

While integrating the use of medical apps into clinical practice will be novel for some, for others, junior Fellows in particular, it has become part of their practice and education. Dr. Eva Hoffmann, Chief Resident in the NYU Langone Health System, offers this perspective: “As medical trainees we use mobile apps to enhance our patient interaction and guide high-quality, continuous care. In today’s modern technological world, apps help keep us up to date with the ever-changing guidelines in pregnancy and routine gynecologic care as well as communicate directly and discreetly with a patient whenever the need arises. The most significant apps provide guidance on abnormal Pap results, indicated deliveries prior to 39 weeks, and the ability to respond to obstetrical emergencies. They also allow for quick society-endorsed references in seconds. Apps have changed the way that we practice by providing evidence-based medicine literally at our fingertips—in a shareable and communicable way—making the practice of medicine even more efficient and effective.”

Opportunity to reaffirm expertise

Dr. Chalas’ initiative was meant to shed light on the opportunity obstetrician-gynecologists have to reassert themselves as women’s health experts, to consider redefining their practice by incorporating new preventive guidelines, and to leverage medical apps for achieving better health outcomes for women across their lifetime. We hope that by opening a dialogue about how ubiquitous medical apps are (for both physicians and patients) in today’s health arena, how many apps are inaccurate and/or misused, and how a simple rubric can be used to assess an app’s value, you are inspired and feel more comfortable to incorporate medical apps into your practice.

Health care will continually undergo advancements, and as a specialty we must evolve to address women’s needs. Obstetrician-gynecologists are well suited to contribute significantly to the well-being of women and mothers. We can leverage technology-based apps to help us redefine our roles and priorities at the patient’s annual visit. We can reaffirm ourselves as the leading women’s health care physicians.

An additional resource

To enhance your understanding of apps and how to evaluate them, Dr. Katherine Chen’s App Review series in OBG Management is a great resource and building block for enhancing your toolbox for the annual visit. Dr. Chen’s own research and APPLICATIONS scoring system is used to evaluate selected mobile apps.² In addition, each article includes a table that details the apps’ features based on a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature used, and important special features).

In appreciation

The members of this Task Force want to thank the Editorial Board and staff of OBG Management for their support and assistance in publishing this series. We especially want to thank Dr. Robert Barbieri for his support and appreciation for the role technology and medical mobile apps play in our daily practice. ●

Evolutionary changes in ObGyn

Preventive medicine guidelines have evolved to reflect enhanced cervical cancer screening tests, longer-acting contraceptive options, and better data on the lack of utility of the annual pelvic exam that has changed the focus of the annual visit for both physicians and patients.¹ These changes allow us to pivot and leverage the trust we build with our patients to make meaningful impacts in preventing chronic disease, improving prepregnancy health, reducing maternal mortality and morbidity, and improving the quality and longevity of our patients’ lives. New guidelines, coupled with the knowledge of the leading causes of morbidity for women, provide the chance to incorporate areas of screening and intervention that, while we are capable of addressing, we traditionally have not done so for various reasons.

The ACOG Presidential Task Force identified 5 areas of preventive health that significantly influence the long-term morbidity of women: obesity, cardiovascular disease, preconception counseling, diabetes, and cancer risk. ObGyns are uniquely positioned to identify and initiate the conversation and subsequently manage, treat, and address these critical health areas. To make this daunting task more manageable, the Task Force not only published webinars to address the clinical knowledge pertaining to these areas of health but also specifically looked at how to use technology to aid obstetrician-gynecologists in addressing them with patients.

Making use of technology in clinical practice

Technology is emerging as an influential player in health care. Major corporations, such as Amazon, Google, Apple, and Facebook, are making headlines in health care as they consider strategies (moves) to revolutionize technology and, in turn, patient visits like we have never seen before. Examples include incorporating artificial intelligence in a patient’s care and allowing better access for primary care.

The changes that we will see over the next 10 years, influenced by industry, will be more than those seen in our lifetime. To prepare for these changes, we need to incorporate technology into our daily practice. This encompasses much more than just the electronic medical record. Consequently, the Task Force intentionally looked at mobile medical apps to aid physicians in addressing the 5 specific areas of preventive health identified.

While a small step compared with what is to come, apps are a great resource to leverage in making this transition. However, with hundreds of thousands of medical apps available in app stores and the constant updates and iterations of each, it would be impossible to recommend any single app. There is much value in having a framework to use to efficiently measure the benefit of an app that you or your patient comes across in clinical practice. The objective of this series was to provide clinicians with an effective tool to evaluate a medical app that could be used, for example, when addressing obesity or optimizing prepregnancy health.

Continue to: The recommended rubric for evaluating apps...

The recommended rubric for evaluating apps

To evaluate mobile drug information apps, the Task Force members recommend a user-friendly, convenient rubric developed by the American Society of Health-System Pharmacists (ASHP) (see page 35). The rubric can help obstetrician-gynecologists evaluate and compare the value of various medical apps that specifically address obesity, diabetes mellitus, cardiovascular disease, improving maternal morbidity with enhanced preconception counseling, and cancer risk assessment.

The authors of this Task Force series have attempted to highlight the key features of an app as it pertains to a particular area of focus. It is important to keep in mind the primary user and the goal when choosing or recommending an app for practice or for patient use. The ASHP’s rubric is a tool meant to aid clinicians in evaluating medical apps, but it is ultimately the user’s decision to determine if the deficiencies of an app should deter its use. Although all the criteria are relevant and important, as medical experts it is incumbent on us to pay careful attention to the accuracy, authority, objectivity, timeliness, and security of any app we consider incorporating into clinical practice.

While integrating the use of medical apps into clinical practice will be novel for some, for others, junior Fellows in particular, it has become part of their practice and education. Dr. Eva Hoffmann, Chief Resident in the NYU Langone Health System, offers this perspective: “As medical trainees we use mobile apps to enhance our patient interaction and guide high-quality, continuous care. In today’s modern technological world, apps help keep us up to date with the ever-changing guidelines in pregnancy and routine gynecologic care as well as communicate directly and discreetly with a patient whenever the need arises. The most significant apps provide guidance on abnormal Pap results, indicated deliveries prior to 39 weeks, and the ability to respond to obstetrical emergencies. They also allow for quick society-endorsed references in seconds. Apps have changed the way that we practice by providing evidence-based medicine literally at our fingertips—in a shareable and communicable way—making the practice of medicine even more efficient and effective.”

Opportunity to reaffirm expertise

Dr. Chalas’ initiative was meant to shed light on the opportunity obstetrician-gynecologists have to reassert themselves as women’s health experts, to consider redefining their practice by incorporating new preventive guidelines, and to leverage medical apps for achieving better health outcomes for women across their lifetime. We hope that by opening a dialogue about how ubiquitous medical apps are (for both physicians and patients) in today’s health arena, how many apps are inaccurate and/or misused, and how a simple rubric can be used to assess an app’s value, you are inspired and feel more comfortable to incorporate medical apps into your practice.

Health care will continually undergo advancements, and as a specialty we must evolve to address women’s needs. Obstetrician-gynecologists are well suited to contribute significantly to the well-being of women and mothers. We can leverage technology-based apps to help us redefine our roles and priorities at the patient’s annual visit. We can reaffirm ourselves as the leading women’s health care physicians.

An additional resource

To enhance your understanding of apps and how to evaluate them, Dr. Katherine Chen’s App Review series in OBG Management is a great resource and building block for enhancing your toolbox for the annual visit. Dr. Chen’s own research and APPLICATIONS scoring system is used to evaluate selected mobile apps.² In addition, each article includes a table that details the apps’ features based on a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature used, and important special features).

In appreciation

The members of this Task Force want to thank the Editorial Board and staff of OBG Management for their support and assistance in publishing this series. We especially want to thank Dr. Robert Barbieri for his support and appreciation for the role technology and medical mobile apps play in our daily practice. ●