OBG Management

First trimester miscarriage, the presence of a nonviable intrauterine pregnancy before 13 weeks’ gestation, is a common complication occurring in approximately 15% of clinical pregnancies.^1,2 The goals for the holistic management of first-trimester miscarriage are to 1) reduce the risk of complications such as excessive bleeding and infection, 2) ensure that the patient is supported during a time of great distress, and 3) optimally counsel the patient about treatment options and elicit the patient’s preferences for care.³ To resolve a miscarriage, the intrauterine pregnancy tissue must be expelled, restoring normal reproductive function.

The options for the management of a nonviable intrauterine pregnancy include expectant management, medication treatment with mifepristone plus misoprostol or misoprostol-alone, or uterine aspiration. In the absence of uterine hemorrhage, infection, or another severe complication of miscarriage, the patient’s preferences should guide the choice of treatment. Many patients with miscarriage prioritize avoiding medical interventions and may prefer expectant management. A patient who prefers rapid and reliable completion of the pregnancy loss process may prefer uterine aspiration. If the patient prefers to avoid uterine aspiration but desires control over the time and location of the expulsion process, medication treatment may be optimal. Many other factors influence a patient’s choice of miscarriage treatment, including balancing work and childcare issues and the ease of scheduling a uterine aspiration. In counseling patients about the options for miscarriage treatment it is helpful to know the success rate of each treatment option.⁴ This editorial reviews miscarriage treatment outcomes as summarized in a recent Cochrane network meta-analysis.⁵

Uterine aspiration versus mifepristone-misoprostol

In 2 clinical trials that included 899 patients with miscarriage, successful treatment with uterine aspira-tion versus mifepristone-misoprostolwas reported in 95% and 66% of cases, respectively.^6,7

In the largest clinical trial comparing uterine aspiration to mifepristone-misoprostol, 801 patients with first-trimester miscarriage were randomly assigned to uterine aspiration or mifepristone-misoprostol.⁶ Uterine aspiration and mifepristone-misoprostol were associated with successful miscarriage treatment in 95% and 64% of cases, respectively. In the uterine aspiration group, a second uterine aspiration occurred in 5% of patients. Two patients in the uterine aspiration group needed a third uterine aspiration to resolve the miscarriage. In the mifepristone-misoprostol group, 36% of patients had a uterine aspiration. It should be noted that the trial protocol guided patients having a medication abortion to uterine aspiration if expulsion of miscarriage tissue had not occurred within 8 hours of receiving misoprostol. If the trial protocol permitted 1 to 4 weeks of monitoring after mifepristone-misoprostol treatment, the success rate with medication treatment would be greater. Six to 8 weeks following miscarriage treatment, patient-reported anxiety and depression symptoms were similar in both groups.⁶

Uterine aspiration versus misoprostol

Among 3 clinical trials that limited enrollment to patients with missed miscarriage, involving 308 patients, the success rates for uterine aspiration and misoprostol treatment was 95% and 62%, respectively.⁵

In a study sponsored by the National Institutes of Health, 652 patients with missed miscarriage or incomplete miscarriage were randomly assigned in a 1:3 ratioto uterine aspiration or misoprostol treatment (800 µg vaginally). After 8 days of follow-up, successful treatment rates among the patients treated with uterine evacuation or misoprostol was 97% and 84%, respectively.⁸ Of note, with misoprostol treatment the success rate increased from day 3 to day 8 of follow-up—from 71% to 84%.⁸

Continue to: Mifepristone-misoprostol versus misoprostol...

The combined results of 7 clinical trials of medication management of missed miscarriage that included 1,812 patients showed that successful treatment with mifepristone-misoprostol or misoprostol alone occurred in 80% and 70% of cases, respectively.⁵

Schreiber and colleagues⁹ reported a study of 300 patients with an anembryonic gestation or embryonic demise that were between 5 and 12 completed weeks of gestation and randomly assigned to treatment with mifepristone (200 mg) plus vaginal misoprostol (800 µg) administered 24 to 48 hours after mifepristone or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% CI, 1.09–1.43). Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment (9%) than with misoprostol monotherapy (24%) (RR, 0.37; 95% CI, 0.21 ̶ 0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors, including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁰ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹¹Chu and colleagues¹² reporteda study of medication treatmentof missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study, the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route; 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. At 7 days of follow-up, the success rates in the mifepristone-misoprostol and misoprostol-alone groups were 83% and 76%, respectively. Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53 ̶ 0.95; P=.021).¹² A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostolalone for the management of missed miscarriages.¹³

Photo: Getty Images

Expectant management versus uterine aspiration

The combined results of 7 clinical trials that included a total of 1,693 patients showed that successful treatment of miscarriage with expectant management or uterine aspiration occurred in 68% and 93% of cases, respectively.⁵ In one study, 700 patients with miscarriage were randomly assigned to expectant management or uterine aspiration. Treatment was successful for 56% and 95% of patients in the expectant management and uterine aspiration groups, respectively.⁶

The Cochrane network meta-analysis concluded that cervical preparation followed by uterine aspiration may be more effective than expectant management, with a reported risk ratio (RR) of 2.12 (95% CI, 1.41–3.20) with low-certainty evidence.⁵ In addition, uterine aspiration compared with expectant management may reduce the risk of serious complications (RR, 0.55; 95% CI, 0.23–1.32), with a wide range of treatment effects in reported trials and low-certainty evidence.⁵

In the treatment of miscarriage, the efficacy of expectant management may vary by the type of miscarriage. In one study, following the identification of a miscarriage, the percent of patients who have completed the expulsion of pregnancy tissue by 14 days was reported to be 84% for incomplete miscarriage, 59% for pregnancy loss with no expulsion of tissue, and 52% with ultrasound detection of a nonviable pregnancy with a gestational sac.¹⁴

Expectant management versus mifepristone-misoprostol

Aggregated data from 3 clinical trials that included a total of 910 patients showed that successful treatment with expectant management or mifepristone-misoprostol was reported in 48% and 68% of cases, respectively.⁵ The Cochrane network meta-analysis concluded that mifepristone-misoprostol may be more effective than expectant management, with a risk ratio of 1.42 (95% CI, 1.22–1.66) with low-certainty evidence. In addition, mifepristone-misoprostol compared with expectant management may reduce the risk for serious complications (RR, 0.76; 95% CI, 0.31–1.84) with wide range of treatment effects and low-certainty evidence.⁵

Continue to: Expectant management versus misoprostol...

The combined results of 10 clinical trials that included a total of 838 patients with miscarriage, showed that successful treatment with expectant management or misoprostol-alone occurred in 44% and 75% of cases, respectively.⁵ Among 3 studies limiting enrollment to patients with missed miscarriage, successful treatment with expectant management or misoprostol-alone occurred in 32% and 70%, respectively.⁵

The Cochrane analysis concluded that misoprostol-alone may be more effective than expectant management, with a reported risk ratio of 1.30 (95% CI, 1.16–1.46) with low-certainty evidence. In addition, misoprostol-alone compared with expectant management may reduce the risk of serious complications (RR, 0.50; 95% CI, 0.22–1.15) with a wide range of treatment effects and low-certainty evidence.⁵

Patient experience of miscarriage care

Pregnancy loss is often a distressing experience, which is associated with grief, anxiety, depression, and guilt, lasting up to 2 years for some patients.^15,16 Patient dissatisfaction with miscarriage care often focuses on 4 issues: a perceived lack of emotional support, failure to elicit patient preferences for treatment, insufficient provision of information, and inconsistent posttreatment follow-up.^17-19 When caring for patients with miscarriage, key goals are to communicate medical information with empathy and to provide emotional support. In the setting of a miscarriage, it is easy for patients to perceive that the clinician is insensitive and cold.¹⁵ Expressions of sympathy, compassion, and condolence help build an emotional connection and improve trust with the patient. Communications that may be helpful include: “I am sorry for your loss,” “I wish the outcome could be different,” “Our clinical team wants to provide you the best care possible,” and “May I ask how you are feeling?” Many patients report that they would like to have been offered mental health services as part of their miscarriage care.¹⁵

The Cochrane network meta-analysis of miscarriage concluded that uterine aspiration, misoprostol-mifepristone, and misoprostol-alone were likely more effective in resolving a miscarriage than expectant management.⁵ The strength of the conclusion was limited because of significant heterogeneity among studies, including different inclusion criteria, definition of success, and length of follow-up. Clinical trials with follow-up intervals more than 7 days generally reported greater success rates with expectant¹⁴ and medication management⁸ than studies with short follow-up intervals. Generally, expectant or medication management treatment is more likely to be successful in cases of incomplete abortion than in cases of missed miscarriage.⁵

In a rank analysis of treatment efficacy, uterine aspiration was top-ranked, followed by medication management. Expectant management had the greatest probability of being associated with unplanned uterine aspiration. Based on my analysis of available miscarriage studies, I estimate that the treatment success rates are approximately:

• uterine aspiration (93% to 99%)
• misoprostol-mifepristone (66% to 84%)
• misoprostol-alone (62% to 76%)
• expectant management (32% to 68%).

Although there may be significant differences in efficacy among the treatment options, offering patients all available approaches to treatment, providing information about the relative success of each approach, and eliciting the patient preference for care ensures an optimal patient experience during a major life event. ●
 

First trimester miscarriage, the presence of a nonviable intrauterine pregnancy before 13 weeks’ gestation, is a common complication occurring in approximately 15% of clinical pregnancies.^1,2 The goals for the holistic management of first-trimester miscarriage are to 1) reduce the risk of complications such as excessive bleeding and infection, 2) ensure that the patient is supported during a time of great distress, and 3) optimally counsel the patient about treatment options and elicit the patient’s preferences for care.³ To resolve a miscarriage, the intrauterine pregnancy tissue must be expelled, restoring normal reproductive function.

The options for the management of a nonviable intrauterine pregnancy include expectant management, medication treatment with mifepristone plus misoprostol or misoprostol-alone, or uterine aspiration. In the absence of uterine hemorrhage, infection, or another severe complication of miscarriage, the patient’s preferences should guide the choice of treatment. Many patients with miscarriage prioritize avoiding medical interventions and may prefer expectant management. A patient who prefers rapid and reliable completion of the pregnancy loss process may prefer uterine aspiration. If the patient prefers to avoid uterine aspiration but desires control over the time and location of the expulsion process, medication treatment may be optimal. Many other factors influence a patient’s choice of miscarriage treatment, including balancing work and childcare issues and the ease of scheduling a uterine aspiration. In counseling patients about the options for miscarriage treatment it is helpful to know the success rate of each treatment option.⁴ This editorial reviews miscarriage treatment outcomes as summarized in a recent Cochrane network meta-analysis.⁵

Uterine aspiration versus mifepristone-misoprostol

In 2 clinical trials that included 899 patients with miscarriage, successful treatment with uterine aspira-tion versus mifepristone-misoprostolwas reported in 95% and 66% of cases, respectively.^6,7

In the largest clinical trial comparing uterine aspiration to mifepristone-misoprostol, 801 patients with first-trimester miscarriage were randomly assigned to uterine aspiration or mifepristone-misoprostol.⁶ Uterine aspiration and mifepristone-misoprostol were associated with successful miscarriage treatment in 95% and 64% of cases, respectively. In the uterine aspiration group, a second uterine aspiration occurred in 5% of patients. Two patients in the uterine aspiration group needed a third uterine aspiration to resolve the miscarriage. In the mifepristone-misoprostol group, 36% of patients had a uterine aspiration. It should be noted that the trial protocol guided patients having a medication abortion to uterine aspiration if expulsion of miscarriage tissue had not occurred within 8 hours of receiving misoprostol. If the trial protocol permitted 1 to 4 weeks of monitoring after mifepristone-misoprostol treatment, the success rate with medication treatment would be greater. Six to 8 weeks following miscarriage treatment, patient-reported anxiety and depression symptoms were similar in both groups.⁶

Uterine aspiration versus misoprostol

Among 3 clinical trials that limited enrollment to patients with missed miscarriage, involving 308 patients, the success rates for uterine aspiration and misoprostol treatment was 95% and 62%, respectively.⁵

In a study sponsored by the National Institutes of Health, 652 patients with missed miscarriage or incomplete miscarriage were randomly assigned in a 1:3 ratioto uterine aspiration or misoprostol treatment (800 µg vaginally). After 8 days of follow-up, successful treatment rates among the patients treated with uterine evacuation or misoprostol was 97% and 84%, respectively.⁸ Of note, with misoprostol treatment the success rate increased from day 3 to day 8 of follow-up—from 71% to 84%.⁸

Continue to: Mifepristone-misoprostol versus misoprostol...

The combined results of 7 clinical trials of medication management of missed miscarriage that included 1,812 patients showed that successful treatment with mifepristone-misoprostol or misoprostol alone occurred in 80% and 70% of cases, respectively.⁵

Schreiber and colleagues⁹ reported a study of 300 patients with an anembryonic gestation or embryonic demise that were between 5 and 12 completed weeks of gestation and randomly assigned to treatment with mifepristone (200 mg) plus vaginal misoprostol (800 µg) administered 24 to 48 hours after mifepristone or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% CI, 1.09–1.43). Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment (9%) than with misoprostol monotherapy (24%) (RR, 0.37; 95% CI, 0.21 ̶ 0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors, including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁰ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹¹Chu and colleagues¹² reporteda study of medication treatmentof missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study, the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route; 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. At 7 days of follow-up, the success rates in the mifepristone-misoprostol and misoprostol-alone groups were 83% and 76%, respectively. Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53 ̶ 0.95; P=.021).¹² A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostolalone for the management of missed miscarriages.¹³

Photo: Getty Images

Expectant management versus uterine aspiration

The combined results of 7 clinical trials that included a total of 1,693 patients showed that successful treatment of miscarriage with expectant management or uterine aspiration occurred in 68% and 93% of cases, respectively.⁵ In one study, 700 patients with miscarriage were randomly assigned to expectant management or uterine aspiration. Treatment was successful for 56% and 95% of patients in the expectant management and uterine aspiration groups, respectively.⁶

The Cochrane network meta-analysis concluded that cervical preparation followed by uterine aspiration may be more effective than expectant management, with a reported risk ratio (RR) of 2.12 (95% CI, 1.41–3.20) with low-certainty evidence.⁵ In addition, uterine aspiration compared with expectant management may reduce the risk of serious complications (RR, 0.55; 95% CI, 0.23–1.32), with a wide range of treatment effects in reported trials and low-certainty evidence.⁵

In the treatment of miscarriage, the efficacy of expectant management may vary by the type of miscarriage. In one study, following the identification of a miscarriage, the percent of patients who have completed the expulsion of pregnancy tissue by 14 days was reported to be 84% for incomplete miscarriage, 59% for pregnancy loss with no expulsion of tissue, and 52% with ultrasound detection of a nonviable pregnancy with a gestational sac.¹⁴

Expectant management versus mifepristone-misoprostol

Aggregated data from 3 clinical trials that included a total of 910 patients showed that successful treatment with expectant management or mifepristone-misoprostol was reported in 48% and 68% of cases, respectively.⁵ The Cochrane network meta-analysis concluded that mifepristone-misoprostol may be more effective than expectant management, with a risk ratio of 1.42 (95% CI, 1.22–1.66) with low-certainty evidence. In addition, mifepristone-misoprostol compared with expectant management may reduce the risk for serious complications (RR, 0.76; 95% CI, 0.31–1.84) with wide range of treatment effects and low-certainty evidence.⁵

Continue to: Expectant management versus misoprostol...

The combined results of 10 clinical trials that included a total of 838 patients with miscarriage, showed that successful treatment with expectant management or misoprostol-alone occurred in 44% and 75% of cases, respectively.⁵ Among 3 studies limiting enrollment to patients with missed miscarriage, successful treatment with expectant management or misoprostol-alone occurred in 32% and 70%, respectively.⁵

The Cochrane analysis concluded that misoprostol-alone may be more effective than expectant management, with a reported risk ratio of 1.30 (95% CI, 1.16–1.46) with low-certainty evidence. In addition, misoprostol-alone compared with expectant management may reduce the risk of serious complications (RR, 0.50; 95% CI, 0.22–1.15) with a wide range of treatment effects and low-certainty evidence.⁵

Patient experience of miscarriage care

Pregnancy loss is often a distressing experience, which is associated with grief, anxiety, depression, and guilt, lasting up to 2 years for some patients.^15,16 Patient dissatisfaction with miscarriage care often focuses on 4 issues: a perceived lack of emotional support, failure to elicit patient preferences for treatment, insufficient provision of information, and inconsistent posttreatment follow-up.^17-19 When caring for patients with miscarriage, key goals are to communicate medical information with empathy and to provide emotional support. In the setting of a miscarriage, it is easy for patients to perceive that the clinician is insensitive and cold.¹⁵ Expressions of sympathy, compassion, and condolence help build an emotional connection and improve trust with the patient. Communications that may be helpful include: “I am sorry for your loss,” “I wish the outcome could be different,” “Our clinical team wants to provide you the best care possible,” and “May I ask how you are feeling?” Many patients report that they would like to have been offered mental health services as part of their miscarriage care.¹⁵

The Cochrane network meta-analysis of miscarriage concluded that uterine aspiration, misoprostol-mifepristone, and misoprostol-alone were likely more effective in resolving a miscarriage than expectant management.⁵ The strength of the conclusion was limited because of significant heterogeneity among studies, including different inclusion criteria, definition of success, and length of follow-up. Clinical trials with follow-up intervals more than 7 days generally reported greater success rates with expectant¹⁴ and medication management⁸ than studies with short follow-up intervals. Generally, expectant or medication management treatment is more likely to be successful in cases of incomplete abortion than in cases of missed miscarriage.⁵

In a rank analysis of treatment efficacy, uterine aspiration was top-ranked, followed by medication management. Expectant management had the greatest probability of being associated with unplanned uterine aspiration. Based on my analysis of available miscarriage studies, I estimate that the treatment success rates are approximately:

• uterine aspiration (93% to 99%)
• misoprostol-mifepristone (66% to 84%)
• misoprostol-alone (62% to 76%)
• expectant management (32% to 68%).

Although there may be significant differences in efficacy among the treatment options, offering patients all available approaches to treatment, providing information about the relative success of each approach, and eliciting the patient preference for care ensures an optimal patient experience during a major life event. ●
 

First trimester miscarriage, the presence of a nonviable intrauterine pregnancy before 13 weeks’ gestation, is a common complication occurring in approximately 15% of clinical pregnancies.^1,2 The goals for the holistic management of first-trimester miscarriage are to 1) reduce the risk of complications such as excessive bleeding and infection, 2) ensure that the patient is supported during a time of great distress, and 3) optimally counsel the patient about treatment options and elicit the patient’s preferences for care.³ To resolve a miscarriage, the intrauterine pregnancy tissue must be expelled, restoring normal reproductive function.

The options for the management of a nonviable intrauterine pregnancy include expectant management, medication treatment with mifepristone plus misoprostol or misoprostol-alone, or uterine aspiration. In the absence of uterine hemorrhage, infection, or another severe complication of miscarriage, the patient’s preferences should guide the choice of treatment. Many patients with miscarriage prioritize avoiding medical interventions and may prefer expectant management. A patient who prefers rapid and reliable completion of the pregnancy loss process may prefer uterine aspiration. If the patient prefers to avoid uterine aspiration but desires control over the time and location of the expulsion process, medication treatment may be optimal. Many other factors influence a patient’s choice of miscarriage treatment, including balancing work and childcare issues and the ease of scheduling a uterine aspiration. In counseling patients about the options for miscarriage treatment it is helpful to know the success rate of each treatment option.⁴ This editorial reviews miscarriage treatment outcomes as summarized in a recent Cochrane network meta-analysis.⁵

Uterine aspiration versus mifepristone-misoprostol

In 2 clinical trials that included 899 patients with miscarriage, successful treatment with uterine aspira-tion versus mifepristone-misoprostolwas reported in 95% and 66% of cases, respectively.^6,7

In the largest clinical trial comparing uterine aspiration to mifepristone-misoprostol, 801 patients with first-trimester miscarriage were randomly assigned to uterine aspiration or mifepristone-misoprostol.⁶ Uterine aspiration and mifepristone-misoprostol were associated with successful miscarriage treatment in 95% and 64% of cases, respectively. In the uterine aspiration group, a second uterine aspiration occurred in 5% of patients. Two patients in the uterine aspiration group needed a third uterine aspiration to resolve the miscarriage. In the mifepristone-misoprostol group, 36% of patients had a uterine aspiration. It should be noted that the trial protocol guided patients having a medication abortion to uterine aspiration if expulsion of miscarriage tissue had not occurred within 8 hours of receiving misoprostol. If the trial protocol permitted 1 to 4 weeks of monitoring after mifepristone-misoprostol treatment, the success rate with medication treatment would be greater. Six to 8 weeks following miscarriage treatment, patient-reported anxiety and depression symptoms were similar in both groups.⁶

Uterine aspiration versus misoprostol

Among 3 clinical trials that limited enrollment to patients with missed miscarriage, involving 308 patients, the success rates for uterine aspiration and misoprostol treatment was 95% and 62%, respectively.⁵

In a study sponsored by the National Institutes of Health, 652 patients with missed miscarriage or incomplete miscarriage were randomly assigned in a 1:3 ratioto uterine aspiration or misoprostol treatment (800 µg vaginally). After 8 days of follow-up, successful treatment rates among the patients treated with uterine evacuation or misoprostol was 97% and 84%, respectively.⁸ Of note, with misoprostol treatment the success rate increased from day 3 to day 8 of follow-up—from 71% to 84%.⁸

Continue to: Mifepristone-misoprostol versus misoprostol...

The combined results of 7 clinical trials of medication management of missed miscarriage that included 1,812 patients showed that successful treatment with mifepristone-misoprostol or misoprostol alone occurred in 80% and 70% of cases, respectively.⁵

Schreiber and colleagues⁹ reported a study of 300 patients with an anembryonic gestation or embryonic demise that were between 5 and 12 completed weeks of gestation and randomly assigned to treatment with mifepristone (200 mg) plus vaginal misoprostol (800 µg) administered 24 to 48 hours after mifepristone or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% CI, 1.09–1.43). Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment (9%) than with misoprostol monotherapy (24%) (RR, 0.37; 95% CI, 0.21 ̶ 0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors, including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁰ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹¹Chu and colleagues¹² reporteda study of medication treatmentof missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study, the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route; 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. At 7 days of follow-up, the success rates in the mifepristone-misoprostol and misoprostol-alone groups were 83% and 76%, respectively. Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53 ̶ 0.95; P=.021).¹² A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostolalone for the management of missed miscarriages.¹³

Photo: Getty Images

Expectant management versus uterine aspiration

The combined results of 7 clinical trials that included a total of 1,693 patients showed that successful treatment of miscarriage with expectant management or uterine aspiration occurred in 68% and 93% of cases, respectively.⁵ In one study, 700 patients with miscarriage were randomly assigned to expectant management or uterine aspiration. Treatment was successful for 56% and 95% of patients in the expectant management and uterine aspiration groups, respectively.⁶

The Cochrane network meta-analysis concluded that cervical preparation followed by uterine aspiration may be more effective than expectant management, with a reported risk ratio (RR) of 2.12 (95% CI, 1.41–3.20) with low-certainty evidence.⁵ In addition, uterine aspiration compared with expectant management may reduce the risk of serious complications (RR, 0.55; 95% CI, 0.23–1.32), with a wide range of treatment effects in reported trials and low-certainty evidence.⁵

In the treatment of miscarriage, the efficacy of expectant management may vary by the type of miscarriage. In one study, following the identification of a miscarriage, the percent of patients who have completed the expulsion of pregnancy tissue by 14 days was reported to be 84% for incomplete miscarriage, 59% for pregnancy loss with no expulsion of tissue, and 52% with ultrasound detection of a nonviable pregnancy with a gestational sac.¹⁴

Expectant management versus mifepristone-misoprostol

Aggregated data from 3 clinical trials that included a total of 910 patients showed that successful treatment with expectant management or mifepristone-misoprostol was reported in 48% and 68% of cases, respectively.⁵ The Cochrane network meta-analysis concluded that mifepristone-misoprostol may be more effective than expectant management, with a risk ratio of 1.42 (95% CI, 1.22–1.66) with low-certainty evidence. In addition, mifepristone-misoprostol compared with expectant management may reduce the risk for serious complications (RR, 0.76; 95% CI, 0.31–1.84) with wide range of treatment effects and low-certainty evidence.⁵

Continue to: Expectant management versus misoprostol...

The combined results of 10 clinical trials that included a total of 838 patients with miscarriage, showed that successful treatment with expectant management or misoprostol-alone occurred in 44% and 75% of cases, respectively.⁵ Among 3 studies limiting enrollment to patients with missed miscarriage, successful treatment with expectant management or misoprostol-alone occurred in 32% and 70%, respectively.⁵

The Cochrane analysis concluded that misoprostol-alone may be more effective than expectant management, with a reported risk ratio of 1.30 (95% CI, 1.16–1.46) with low-certainty evidence. In addition, misoprostol-alone compared with expectant management may reduce the risk of serious complications (RR, 0.50; 95% CI, 0.22–1.15) with a wide range of treatment effects and low-certainty evidence.⁵

Patient experience of miscarriage care

Pregnancy loss is often a distressing experience, which is associated with grief, anxiety, depression, and guilt, lasting up to 2 years for some patients.^15,16 Patient dissatisfaction with miscarriage care often focuses on 4 issues: a perceived lack of emotional support, failure to elicit patient preferences for treatment, insufficient provision of information, and inconsistent posttreatment follow-up.^17-19 When caring for patients with miscarriage, key goals are to communicate medical information with empathy and to provide emotional support. In the setting of a miscarriage, it is easy for patients to perceive that the clinician is insensitive and cold.¹⁵ Expressions of sympathy, compassion, and condolence help build an emotional connection and improve trust with the patient. Communications that may be helpful include: “I am sorry for your loss,” “I wish the outcome could be different,” “Our clinical team wants to provide you the best care possible,” and “May I ask how you are feeling?” Many patients report that they would like to have been offered mental health services as part of their miscarriage care.¹⁵

The Cochrane network meta-analysis of miscarriage concluded that uterine aspiration, misoprostol-mifepristone, and misoprostol-alone were likely more effective in resolving a miscarriage than expectant management.⁵ The strength of the conclusion was limited because of significant heterogeneity among studies, including different inclusion criteria, definition of success, and length of follow-up. Clinical trials with follow-up intervals more than 7 days generally reported greater success rates with expectant¹⁴ and medication management⁸ than studies with short follow-up intervals. Generally, expectant or medication management treatment is more likely to be successful in cases of incomplete abortion than in cases of missed miscarriage.⁵

In a rank analysis of treatment efficacy, uterine aspiration was top-ranked, followed by medication management. Expectant management had the greatest probability of being associated with unplanned uterine aspiration. Based on my analysis of available miscarriage studies, I estimate that the treatment success rates are approximately:

• uterine aspiration (93% to 99%)
• misoprostol-mifepristone (66% to 84%)
• misoprostol-alone (62% to 76%)
• expectant management (32% to 68%).

Although there may be significant differences in efficacy among the treatment options, offering patients all available approaches to treatment, providing information about the relative success of each approach, and eliciting the patient preference for care ensures an optimal patient experience during a major life event. ●
 

Due to an increasing incidence of colon cancer among men and women aged 45 and younger, in 2018 the American Cancer Society, and in 2021 the US Preventive Services Task Force, recommended that screening for colon cancer begin at age 45 rather than age 50. More than half of the US population reports being up to date with these screening guidelines.

Source: Barbieri R. Colorectal cancer screening, 2021: An update. OBG Manag. 2021;33:9-11, 15. doi: 10.12788/obgm.0119.

Due to an increasing incidence of colon cancer among men and women aged 45 and younger, in 2018 the American Cancer Society, and in 2021 the US Preventive Services Task Force, recommended that screening for colon cancer begin at age 45 rather than age 50. More than half of the US population reports being up to date with these screening guidelines.

Source: Barbieri R. Colorectal cancer screening, 2021: An update. OBG Manag. 2021;33:9-11, 15. doi: 10.12788/obgm.0119.

Due to an increasing incidence of colon cancer among men and women aged 45 and younger, in 2018 the American Cancer Society, and in 2021 the US Preventive Services Task Force, recommended that screening for colon cancer begin at age 45 rather than age 50. More than half of the US population reports being up to date with these screening guidelines.

Source: Barbieri R. Colorectal cancer screening, 2021: An update. OBG Manag. 2021;33:9-11, 15. doi: 10.12788/obgm.0119.

Medical library access

During most of my clinical career I had an affiliation with a local medical school as a “Clinical Instructor” and then “Assistant Clinical Professor.” In addition to teaching medical students and residents from that institution that rotated through my hospital, it also gave me certain privileges, the most important of which was access to that institution’s electronic medical library. Using that access, even as an “LMD,” I have been able to contribute to the medical literature on subjects of interest to me and to others in my specialty. 

Recently, now as an older clinician, I gave up my hospital privileges, although I continue my office practice. Giving up my hospital privileges meant that I no longer qualified as a faculty member—and therefore lost online access to the medical library. Still wishing to continue my medical writing, I have attempted to attain access to the medical literature by special request to that library, by contacting my state medical society, by contacting my national specialty organization, by contacting the department chair at the institution to which I had been affiliated, and by calling the Dean of the medical school to which my hospital was affiliated. Although meaning well, none was able to get me access to an online medical library. Thus, I am greatly hampered in my attempts to do research and to continue to write further papers on those areas in which I have previously published. 

Is there no remedy for this? Should all clinicians who “age out” of institutional affiliations no longer be able to pursue research interests? And what about community physicians who have no academic affiliations? Can they not access the latest information they need to practice evidence-based, up-to-date medicine? 

It makes no sense to me that access to the latest and most current aspects of medical care should be withheld from any clinician. For every clinician not to have access to such medical knowledge does a disservice to all those practicing medicine who wish to keep up to date and to all patients of American clinicians whose providers are prevented from practicing the best, evidence-based care.

Henry Lerner, MD

Boston, Massachusetts

Medical library access

During most of my clinical career I had an affiliation with a local medical school as a “Clinical Instructor” and then “Assistant Clinical Professor.” In addition to teaching medical students and residents from that institution that rotated through my hospital, it also gave me certain privileges, the most important of which was access to that institution’s electronic medical library. Using that access, even as an “LMD,” I have been able to contribute to the medical literature on subjects of interest to me and to others in my specialty. 

Recently, now as an older clinician, I gave up my hospital privileges, although I continue my office practice. Giving up my hospital privileges meant that I no longer qualified as a faculty member—and therefore lost online access to the medical library. Still wishing to continue my medical writing, I have attempted to attain access to the medical literature by special request to that library, by contacting my state medical society, by contacting my national specialty organization, by contacting the department chair at the institution to which I had been affiliated, and by calling the Dean of the medical school to which my hospital was affiliated. Although meaning well, none was able to get me access to an online medical library. Thus, I am greatly hampered in my attempts to do research and to continue to write further papers on those areas in which I have previously published. 

Is there no remedy for this? Should all clinicians who “age out” of institutional affiliations no longer be able to pursue research interests? And what about community physicians who have no academic affiliations? Can they not access the latest information they need to practice evidence-based, up-to-date medicine? 

It makes no sense to me that access to the latest and most current aspects of medical care should be withheld from any clinician. For every clinician not to have access to such medical knowledge does a disservice to all those practicing medicine who wish to keep up to date and to all patients of American clinicians whose providers are prevented from practicing the best, evidence-based care.

Henry Lerner, MD

Boston, Massachusetts

Medical library access

During most of my clinical career I had an affiliation with a local medical school as a “Clinical Instructor” and then “Assistant Clinical Professor.” In addition to teaching medical students and residents from that institution that rotated through my hospital, it also gave me certain privileges, the most important of which was access to that institution’s electronic medical library. Using that access, even as an “LMD,” I have been able to contribute to the medical literature on subjects of interest to me and to others in my specialty. 

Recently, now as an older clinician, I gave up my hospital privileges, although I continue my office practice. Giving up my hospital privileges meant that I no longer qualified as a faculty member—and therefore lost online access to the medical library. Still wishing to continue my medical writing, I have attempted to attain access to the medical literature by special request to that library, by contacting my state medical society, by contacting my national specialty organization, by contacting the department chair at the institution to which I had been affiliated, and by calling the Dean of the medical school to which my hospital was affiliated. Although meaning well, none was able to get me access to an online medical library. Thus, I am greatly hampered in my attempts to do research and to continue to write further papers on those areas in which I have previously published. 

Is there no remedy for this? Should all clinicians who “age out” of institutional affiliations no longer be able to pursue research interests? And what about community physicians who have no academic affiliations? Can they not access the latest information they need to practice evidence-based, up-to-date medicine? 

It makes no sense to me that access to the latest and most current aspects of medical care should be withheld from any clinician. For every clinician not to have access to such medical knowledge does a disservice to all those practicing medicine who wish to keep up to date and to all patients of American clinicians whose providers are prevented from practicing the best, evidence-based care.

Henry Lerner, MD

Boston, Massachusetts

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Clinical care for fetal demise is complex and multidimensional, including empathic emotional support for the patient and family members who are experiencing a tragedy, investigation of the cause of the demise, and a plan for emptying the uterus. This editorial narrowly focuses on the options for treatment of fetal demise with the goal of emptying the uterus while minimizing complications.

When planning treatment of fetal demise, focus on fetal size and gestational age

Most guidelines for the treatment of fetal demise use gestational age to guide selection of a treatment.^1,2 I believe that fetal size is as important as gestational age for selecting a treatment plan. When considering treatment, there are 2 reasons why fetal size is as important as gestational age:

• The physiologic processes that caused fetal demise may have caused fetal growth restriction, resulting in a fetal size that is 2 or more weeks below expected fetal size for gestational age.
• Fetal demise may have occurred weeks before the diagnosis was made, resulting in gestational age being greater than fetal size. This editorial will use ultrasonography estimate of fetal size in gestational weeks to guide treatment recommendations. When discussing fetal size, we will use the convention of weeks-days (w-d). Twenty-five weeks and zero days gestation is represented as 25w0d.

Treatment in the second and third trimester is a 2-step process

Step 1: Cervical preparation

In most cases of first trimester fetal demise, no cervical preparation is necessary. Cervical dilation with metal dilators followed by uterine evacuation with an appropriately sized vacuum catheter is a highly successful treatment.³ However for second and third trimester fetal demise, it is best to use a 2-step process, beginning with cervical preparation followed by emptying the uterus. For example, at a fetal size of 13w0d to 16w0d, cervical preparation can be achieved by administering a single buccal dose of misoprostol 400 µg 3 to 4 hours prior to uterine evacuation or by inserting a Dilapan-S (Medicem Inc) osmotic cervical dilator 3 to 6 hours prior to uterine evacuation.^4-7 At a fetal size of 16w0d to 19w6d, cervical preparation can be achieved by placing osmotic cervical dilators 4 to 6 hours before surgical evacuation and administering buccal misoprostol 400 µg 3 hours before surgical evacuation.⁸

Alternatively, from 16w0d to 25w0d osmotic cervical dilators can be placed on day 1 of a 2-day process, and the patient can return on day 2 to have the cervical dilators removed followed by surgical evacuation of the uterus. Mifepristone 200 mg oral dose can be administered on day 1 to facilitate cervical preparation. In my practice, I use mifepristone 200 mg on day 1 when the fetal size is ≥20w0d gestation. Options for cervical preparation include use of osmotic dilators, cervical balloons, misoprostol, and/or mifepristone. These options are discussed below. With fetal demise, natural physiologic processes often have caused sufficient cervical softening and dilation that no cervical preparation is necessary and immediate uterine surgical evacuation or induction of labor can be initiated.

Step 2: Emptying the uterus

In the second and third trimesters, the approach to uterine evacuation is based on fetal size. At fetal sizes <25w0d, options for emptying the uterus include surgical evacuation with a vacuum catheter and grasping forceps or induction of labor with misoprostol followed by vaginal birth and expulsion of the placenta. At fetal sizes ˃25w0d gestation, following completion of cervical preparation, the most common approaches to uterine evacuation are induction of labor with misoprostol or oxytocin. Rarely, with a stillbirth at term, some clinicians will select hysterotomy to empty the uterus, avoiding uterine rupture during labor induction for patients at the highest risk, including those with a prior classical cesarean birth or more than 2 prior cesarean births with a low-transverse uterine incision.

Osmotic cervical dilators

The 2 most used cervical dilators are Dilapan-S, a polyacrylate-based hydrogel rod, and laminaria, dried compressed seaweed stipe (stalk) from Laminaria japonica or Laminaria digitata. Dilapan-S rods are available in diameters of 3 mm and 4 mm and rod lengths of 55 mm and 65 mm. Laminaria dilators are available in diameters of 2, 3, 4, 5, 6, 8 and 10 mm and rod length of 60 and 70 mm. Dilapan-S dilators reach near-maximal dilation in approximately 4 to 6 hours but continue to expand over the following 18 hours to achieve a maximum dilation of 3.3 to 3.6 times their dry diameter.⁹ Laminaria dilators expand to 2.7 to 2.9 times their dry diameter over 24 hours.⁹

A general rule is that as many dilators as possible should be placed until significant resistance to the placement of additional dilators is encountered.¹⁰ In my practice, for fetal size ≥20 weeks’ gestation, I place 2 Dilapan-S rods, 4 mm in diameter, 55 mm in length, and then encircle the Dilapan-S with laminaria rods that are 4 mm in diameter and 60 mm in length. Once cervical resistance to the placement of the 4 mm laminaria rods is observed, I encircle those laminaria with laminaria 2 mm in diameter, filling in the interstices between the 4 mm laminaria. The next day, cervical dilation is routinely ≥3 cm.

In a retrospective study of 491 patients undergoing pregnancy termination after 14 weeks’ gestation, with a mean gestational age of 24 weeks, compared with no osmotic cervical dilators, inserting osmotic cervical dilators the day before initiating misoprostol for induction of labor resulted in a decrease in time to delivery (428 min vs 640 min; P<.001) and a decrease in total misoprostol dose (990 µg vs 1,449 µg; P<.0001).¹¹

Cervical balloons

All clinicians know that a Foley catheter or a Cook cervical ripening balloon can be used for cervical preparation in the third trimester.^12,13 The Foley catheter also has been reported to be useful for cervical preparation in the second trimester. In one study of 43 patients 17 to 24 weeks’ gestation scheduled for a second-trimester dilation and evacuation, an intracervical Foley catheter was placed the evening before evacuation, and the balloon was inflated with 30 mL to 50 mL of saline. At the same time, mifepristone 200 mg was administered to the patients.¹⁴ The following day, dilation and evacuation was performed. In 72% of cases no additional cervical dilation was required on the day of evacuation. The investigators concluded that if osmotic cervical dilators are not available, the placement of an intracervical Foley catheter plus administration of mifepristone facilitates performance of an evacuation on the following day. If the patient prefers a 1-day procedure, the Foley can be inserted in the morning to facilitate cervical preparation, and the uterus can be evacuated in the afternoon.

Continue to: Misoprostol...

Misoprostol

Misoprostol, a derivative of prostaglandin E1, is useful for both cervical preparation and induction of labor. The dose of misoprostol and the route of administration are major determinants of uterine response.^15-19 When administered by an oral route, misoprostol has fast onset and offset of action and often does not cause sustained uterine contractions. Hence, oral misoprostol, at a low dose is useful for cervical ripening, but not as useful for stimulation of sustained uterine contractions for induction of labor. When administered by a buccal or vaginal route, misoprostol has prolonged activity and often results in sustained uterine contractions. At any given dose of misoprostol, buccal and vaginal misoprostol administration are more effective than oral administration in inducing sustained uterine contractions sufficient to empty the uterus.^15-19

Mifepristone

Mifepristone, an anti-progestin, is useful for cervical preparation and sensitizing myocytes to the action of uterotonics. Progesterone reduces cell-to-cell communication among uterine myocytes, facilitating uterine quiescence by suppressing connexin 43 and other proteins. Mifepristone blocks the effect of progesterone, inducing the production of myocyte connexin 43, enhancing efficient cell-to-cell communication, permitting uterine myoctes to contract in unison, creating the potential for powerful and sustained contractions.^20-23 Randomized clinical trials report that administration of mifepristone 200 mg prior to misoprostol induced labor results in more rapid emptying of the uterus.^24-27

It takes time for mifepristone to have its full effect on uterine myocytes. Hence, most protocols recommend waiting 24 hours following mifepristone administration before initiating treatment with an agent to stimulate uterine contractions such as misoprostol or oxytocin. However, preliminary data suggest that partial benefit of mifepristone can be obtained when initiating misoprostol 3 to 5 hours after mifepristone administration.²⁸ In a study of 481 patients undergoing induction of labor in the second or third trimester, the time from initiation of misoprostol to vaginal birth was 15 hours with no mifepristone pretreatment, 13.2 hours if mifepristone was administered 3 to 5 hours before initiating misoprostol, 9.3 hours if mifepristone was administered 24 hours before initiating misoprostol, and 10.5 hours if mifepristone was administered 48 hours before initiating misoprostol.²⁸

Fetal size <25w0d gestation: Cervical preparation and surgical evacuation

For fetal demise at a fetal size less than 25w0d, if clinical experts are available, the best treatment option is cervical preparation followed by surgical evacuation of the uterus using a vacuum catheter and grasping forceps to empty the uterus.^29,30 A disadvantage of surgical evacuation of the uterus is that an intact fetus is not available for the patient to hold and mourn, and pathologic examination of an intact fetus is not possible. An alternative approach is cervical preparation followed by induction of labor using misoprostol with the goal of delivering an intact fetus. Although no prospective clinical trials are available comparing these 2 options, retrospective studies have reported that, at fetal size <25w0d gestation, compared with induction of labor, surgical evacuation of the uterus results in fewer complications,³⁰ including fewer cases of retained placenta requiring an unplanned procedure and fewer presumed uterine infections.²⁹

For surgical evacuation of fetal demise with a fetal size of <25w0d gestation, the first step on day 1 is placement of osmotic cervical dilators. In addition to osmotic cervical dilators, if the gestational age or fetal size is ≥19 weeks’ gestation an oral dose of mifepristone 200 mg to facilitate cervical preparation may be considered. On day 2, the osmotic dilators are removed and surgical evacuation is performed. In one randomized study, for pregnancies at 19 to 24 weeks’ gestation, compared with osmotic dilators alone, administration of mifepristone 200 mg at the time of placement of osmotic dilators resulted in fewer procedures that were difficult to complete.³¹ In some cases, 2 consecutive days of cervical preparation with osmotic dilators may be needed to properly prepare the cervix for uterine evacuation. For example, the cervix of a nulliparous teenage patient may require 2 days of cervical preparation with osmotic dilators to facilitate uterine evacuation. In some cases of fetal demise, the cervix is already dilated to ≥3 cm and surgical evacuation of the uterus or induction of labor can be initiated without the need for cervical preparation.

Continue to: Fetal size 14w0d to 28w6d gestation: Cervical preparation and induction of labor...

Treatment of fetal demise at 14w0d to 28w6d gestation with the goal of the vaginal birth of an intact fetus is optimized by the administration of mifepristone for cervical preparation followed by induction of labor with misoprostol.^26,27

In one clinical trial, 66 patients with fetal demise between 14w0d and 28w6d gestation were randomly assigned to receive mifepristone 200 mg or placebo followed 24 to 48 hours later with initiation of misoprostol induction of labor.²⁶ Among the patients from 14w0d to 24 weeks’ gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24w0d to 28 weeks’ gestation, the misoprostol dose was 200 µg vaginally every 4 hours. At 24 hours, a consultant obstetrician determined if additional misoprostol should be given. The median time from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups was 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P= .002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage, 4 in the placebo group and 1 in the mifepristone group.²⁶

In a second clinical trial, 105 patients with fetal demise after 20 weeks of gestation were randomly assigned to receive mifepristone 200 mg or placebo.²⁷ In this study, 86% of the patients were ≥26w0d gestation, with a mean gestational age of approximately 32w2d. Thirty-six to 48 hours later, misoprostol induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostoldose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients from ≥26 weeks’ gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours, respectively (P=.001). Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg; P<.001). Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.²⁷

Fetal size ≥29w0d gestation

At a fetal size ≥29w0d gestation, if the cervix is ripe with a Bishop score of ≥7, oxytocin induction of labor is often used as a first-line treatment. If the cervix is not ripe, misoprostol induction of labor may be considered at doses less than those used in the second trimester of pregnancy.³²TABLES 1,^{1, 26, 33–36}2,³⁷ and 3³⁷ summarize regimens proposed for fetal size ≥29w0d. One regimen begins with an initial misoprostol dose of 50 µg. If adequate uterine contractions occur, the 50 µg dose is repeated every 4 hours up to 6 total doses. If contractions are inadequate, the dose can be increased to 100 µg every 4 hours for 5 additional doses.

For fetal demise after 28w0d gestation, the American College of Obstetricians and Gynecologists (ACOG)¹ recommends standard obstetric protocols for induction of labor, including standard protocols for induction of labor following a previous cesarean birth. For a patient with a history of a prior cesarean birth or major uterine surgery, ACOG recommends that management of fetal demise should prioritize the use of mechanical cervical ripening, for example with a balloon catheter, and induction of uterine contractions with oxytocin.³⁸ ACOG recommends against the use of misoprostol for cervical ripening or labor induction for patients with a stillbirth at term with a history of a cesarean birth.³⁸ Preliminary experience suggests that stillbirth protocols using misoprostol doses modestly greater than those used in the management of a pregnancy with a viable fetus may be safe.⁹ See TABLES 2 and 3.

A multidisciplinary approach can optimize compassionate care

There are many gaps in the holistic care of patients and partners experiencing fetal demise. Patients with fetal demise often report that they did not receive sufficient information about the cause of the demise and wanted more opportunity to be involved in decision making about their care.³⁹ The patient’s partner often reports feeling unacknowledged as a grieving parent.⁴⁰ Fetal demise is experienced by many patients as a tragedy, triggering feelings of grief, anger, denial, anxiety and depression, sometimes resulting in isolation and substance misuse.

Using a 5-round Delphi process, experts identified 8 core goals in the care of patients with fetal demise:

1. reduce stigma
2. provide respectful care
3. involve patients in care planning
4. attempt to provide an explanation for the demise¹
5. acknowledge the depth of the grief response and provide emotional support
6. offer information about ongoing psychological support
7. provide information about future pregnancy planning
8. provide opportunities for specialized training and support for care providers.⁴¹

Management of stillbirth is optimized by a multidisciplinary approach that includes the expert care of obstetrician-gynecologists, obstetric nurses, anesthesiologists, and expert consultation from social work, chaplaincy, and pathology. A heart-to-heart connection between clinician and patient is a key component of stillbirth care. ●

Clinical care for fetal demise is complex and multidimensional, including empathic emotional support for the patient and family members who are experiencing a tragedy, investigation of the cause of the demise, and a plan for emptying the uterus. This editorial narrowly focuses on the options for treatment of fetal demise with the goal of emptying the uterus while minimizing complications.

When planning treatment of fetal demise, focus on fetal size and gestational age

Most guidelines for the treatment of fetal demise use gestational age to guide selection of a treatment.^1,2 I believe that fetal size is as important as gestational age for selecting a treatment plan. When considering treatment, there are 2 reasons why fetal size is as important as gestational age:

• The physiologic processes that caused fetal demise may have caused fetal growth restriction, resulting in a fetal size that is 2 or more weeks below expected fetal size for gestational age.
• Fetal demise may have occurred weeks before the diagnosis was made, resulting in gestational age being greater than fetal size. This editorial will use ultrasonography estimate of fetal size in gestational weeks to guide treatment recommendations. When discussing fetal size, we will use the convention of weeks-days (w-d). Twenty-five weeks and zero days gestation is represented as 25w0d.

Treatment in the second and third trimester is a 2-step process

Step 1: Cervical preparation

In most cases of first trimester fetal demise, no cervical preparation is necessary. Cervical dilation with metal dilators followed by uterine evacuation with an appropriately sized vacuum catheter is a highly successful treatment.³ However for second and third trimester fetal demise, it is best to use a 2-step process, beginning with cervical preparation followed by emptying the uterus. For example, at a fetal size of 13w0d to 16w0d, cervical preparation can be achieved by administering a single buccal dose of misoprostol 400 µg 3 to 4 hours prior to uterine evacuation or by inserting a Dilapan-S (Medicem Inc) osmotic cervical dilator 3 to 6 hours prior to uterine evacuation.^4-7 At a fetal size of 16w0d to 19w6d, cervical preparation can be achieved by placing osmotic cervical dilators 4 to 6 hours before surgical evacuation and administering buccal misoprostol 400 µg 3 hours before surgical evacuation.⁸

Alternatively, from 16w0d to 25w0d osmotic cervical dilators can be placed on day 1 of a 2-day process, and the patient can return on day 2 to have the cervical dilators removed followed by surgical evacuation of the uterus. Mifepristone 200 mg oral dose can be administered on day 1 to facilitate cervical preparation. In my practice, I use mifepristone 200 mg on day 1 when the fetal size is ≥20w0d gestation. Options for cervical preparation include use of osmotic dilators, cervical balloons, misoprostol, and/or mifepristone. These options are discussed below. With fetal demise, natural physiologic processes often have caused sufficient cervical softening and dilation that no cervical preparation is necessary and immediate uterine surgical evacuation or induction of labor can be initiated.

Step 2: Emptying the uterus

In the second and third trimesters, the approach to uterine evacuation is based on fetal size. At fetal sizes <25w0d, options for emptying the uterus include surgical evacuation with a vacuum catheter and grasping forceps or induction of labor with misoprostol followed by vaginal birth and expulsion of the placenta. At fetal sizes ˃25w0d gestation, following completion of cervical preparation, the most common approaches to uterine evacuation are induction of labor with misoprostol or oxytocin. Rarely, with a stillbirth at term, some clinicians will select hysterotomy to empty the uterus, avoiding uterine rupture during labor induction for patients at the highest risk, including those with a prior classical cesarean birth or more than 2 prior cesarean births with a low-transverse uterine incision.

Osmotic cervical dilators

The 2 most used cervical dilators are Dilapan-S, a polyacrylate-based hydrogel rod, and laminaria, dried compressed seaweed stipe (stalk) from Laminaria japonica or Laminaria digitata. Dilapan-S rods are available in diameters of 3 mm and 4 mm and rod lengths of 55 mm and 65 mm. Laminaria dilators are available in diameters of 2, 3, 4, 5, 6, 8 and 10 mm and rod length of 60 and 70 mm. Dilapan-S dilators reach near-maximal dilation in approximately 4 to 6 hours but continue to expand over the following 18 hours to achieve a maximum dilation of 3.3 to 3.6 times their dry diameter.⁹ Laminaria dilators expand to 2.7 to 2.9 times their dry diameter over 24 hours.⁹

A general rule is that as many dilators as possible should be placed until significant resistance to the placement of additional dilators is encountered.¹⁰ In my practice, for fetal size ≥20 weeks’ gestation, I place 2 Dilapan-S rods, 4 mm in diameter, 55 mm in length, and then encircle the Dilapan-S with laminaria rods that are 4 mm in diameter and 60 mm in length. Once cervical resistance to the placement of the 4 mm laminaria rods is observed, I encircle those laminaria with laminaria 2 mm in diameter, filling in the interstices between the 4 mm laminaria. The next day, cervical dilation is routinely ≥3 cm.

In a retrospective study of 491 patients undergoing pregnancy termination after 14 weeks’ gestation, with a mean gestational age of 24 weeks, compared with no osmotic cervical dilators, inserting osmotic cervical dilators the day before initiating misoprostol for induction of labor resulted in a decrease in time to delivery (428 min vs 640 min; P<.001) and a decrease in total misoprostol dose (990 µg vs 1,449 µg; P<.0001).¹¹

Cervical balloons

All clinicians know that a Foley catheter or a Cook cervical ripening balloon can be used for cervical preparation in the third trimester.^12,13 The Foley catheter also has been reported to be useful for cervical preparation in the second trimester. In one study of 43 patients 17 to 24 weeks’ gestation scheduled for a second-trimester dilation and evacuation, an intracervical Foley catheter was placed the evening before evacuation, and the balloon was inflated with 30 mL to 50 mL of saline. At the same time, mifepristone 200 mg was administered to the patients.¹⁴ The following day, dilation and evacuation was performed. In 72% of cases no additional cervical dilation was required on the day of evacuation. The investigators concluded that if osmotic cervical dilators are not available, the placement of an intracervical Foley catheter plus administration of mifepristone facilitates performance of an evacuation on the following day. If the patient prefers a 1-day procedure, the Foley can be inserted in the morning to facilitate cervical preparation, and the uterus can be evacuated in the afternoon.

Continue to: Misoprostol...

Misoprostol

Misoprostol, a derivative of prostaglandin E1, is useful for both cervical preparation and induction of labor. The dose of misoprostol and the route of administration are major determinants of uterine response.^15-19 When administered by an oral route, misoprostol has fast onset and offset of action and often does not cause sustained uterine contractions. Hence, oral misoprostol, at a low dose is useful for cervical ripening, but not as useful for stimulation of sustained uterine contractions for induction of labor. When administered by a buccal or vaginal route, misoprostol has prolonged activity and often results in sustained uterine contractions. At any given dose of misoprostol, buccal and vaginal misoprostol administration are more effective than oral administration in inducing sustained uterine contractions sufficient to empty the uterus.^15-19

Mifepristone

Mifepristone, an anti-progestin, is useful for cervical preparation and sensitizing myocytes to the action of uterotonics. Progesterone reduces cell-to-cell communication among uterine myocytes, facilitating uterine quiescence by suppressing connexin 43 and other proteins. Mifepristone blocks the effect of progesterone, inducing the production of myocyte connexin 43, enhancing efficient cell-to-cell communication, permitting uterine myoctes to contract in unison, creating the potential for powerful and sustained contractions.^20-23 Randomized clinical trials report that administration of mifepristone 200 mg prior to misoprostol induced labor results in more rapid emptying of the uterus.^24-27

It takes time for mifepristone to have its full effect on uterine myocytes. Hence, most protocols recommend waiting 24 hours following mifepristone administration before initiating treatment with an agent to stimulate uterine contractions such as misoprostol or oxytocin. However, preliminary data suggest that partial benefit of mifepristone can be obtained when initiating misoprostol 3 to 5 hours after mifepristone administration.²⁸ In a study of 481 patients undergoing induction of labor in the second or third trimester, the time from initiation of misoprostol to vaginal birth was 15 hours with no mifepristone pretreatment, 13.2 hours if mifepristone was administered 3 to 5 hours before initiating misoprostol, 9.3 hours if mifepristone was administered 24 hours before initiating misoprostol, and 10.5 hours if mifepristone was administered 48 hours before initiating misoprostol.²⁸

Fetal size <25w0d gestation: Cervical preparation and surgical evacuation

For fetal demise at a fetal size less than 25w0d, if clinical experts are available, the best treatment option is cervical preparation followed by surgical evacuation of the uterus using a vacuum catheter and grasping forceps to empty the uterus.^29,30 A disadvantage of surgical evacuation of the uterus is that an intact fetus is not available for the patient to hold and mourn, and pathologic examination of an intact fetus is not possible. An alternative approach is cervical preparation followed by induction of labor using misoprostol with the goal of delivering an intact fetus. Although no prospective clinical trials are available comparing these 2 options, retrospective studies have reported that, at fetal size <25w0d gestation, compared with induction of labor, surgical evacuation of the uterus results in fewer complications,³⁰ including fewer cases of retained placenta requiring an unplanned procedure and fewer presumed uterine infections.²⁹

For surgical evacuation of fetal demise with a fetal size of <25w0d gestation, the first step on day 1 is placement of osmotic cervical dilators. In addition to osmotic cervical dilators, if the gestational age or fetal size is ≥19 weeks’ gestation an oral dose of mifepristone 200 mg to facilitate cervical preparation may be considered. On day 2, the osmotic dilators are removed and surgical evacuation is performed. In one randomized study, for pregnancies at 19 to 24 weeks’ gestation, compared with osmotic dilators alone, administration of mifepristone 200 mg at the time of placement of osmotic dilators resulted in fewer procedures that were difficult to complete.³¹ In some cases, 2 consecutive days of cervical preparation with osmotic dilators may be needed to properly prepare the cervix for uterine evacuation. For example, the cervix of a nulliparous teenage patient may require 2 days of cervical preparation with osmotic dilators to facilitate uterine evacuation. In some cases of fetal demise, the cervix is already dilated to ≥3 cm and surgical evacuation of the uterus or induction of labor can be initiated without the need for cervical preparation.

Continue to: Fetal size 14w0d to 28w6d gestation: Cervical preparation and induction of labor...

Treatment of fetal demise at 14w0d to 28w6d gestation with the goal of the vaginal birth of an intact fetus is optimized by the administration of mifepristone for cervical preparation followed by induction of labor with misoprostol.^26,27

In one clinical trial, 66 patients with fetal demise between 14w0d and 28w6d gestation were randomly assigned to receive mifepristone 200 mg or placebo followed 24 to 48 hours later with initiation of misoprostol induction of labor.²⁶ Among the patients from 14w0d to 24 weeks’ gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24w0d to 28 weeks’ gestation, the misoprostol dose was 200 µg vaginally every 4 hours. At 24 hours, a consultant obstetrician determined if additional misoprostol should be given. The median time from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups was 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P= .002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage, 4 in the placebo group and 1 in the mifepristone group.²⁶

In a second clinical trial, 105 patients with fetal demise after 20 weeks of gestation were randomly assigned to receive mifepristone 200 mg or placebo.²⁷ In this study, 86% of the patients were ≥26w0d gestation, with a mean gestational age of approximately 32w2d. Thirty-six to 48 hours later, misoprostol induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostoldose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients from ≥26 weeks’ gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours, respectively (P=.001). Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg; P<.001). Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.²⁷

Fetal size ≥29w0d gestation

At a fetal size ≥29w0d gestation, if the cervix is ripe with a Bishop score of ≥7, oxytocin induction of labor is often used as a first-line treatment. If the cervix is not ripe, misoprostol induction of labor may be considered at doses less than those used in the second trimester of pregnancy.³²TABLES 1,^{1, 26, 33–36}2,³⁷ and 3³⁷ summarize regimens proposed for fetal size ≥29w0d. One regimen begins with an initial misoprostol dose of 50 µg. If adequate uterine contractions occur, the 50 µg dose is repeated every 4 hours up to 6 total doses. If contractions are inadequate, the dose can be increased to 100 µg every 4 hours for 5 additional doses.

For fetal demise after 28w0d gestation, the American College of Obstetricians and Gynecologists (ACOG)¹ recommends standard obstetric protocols for induction of labor, including standard protocols for induction of labor following a previous cesarean birth. For a patient with a history of a prior cesarean birth or major uterine surgery, ACOG recommends that management of fetal demise should prioritize the use of mechanical cervical ripening, for example with a balloon catheter, and induction of uterine contractions with oxytocin.³⁸ ACOG recommends against the use of misoprostol for cervical ripening or labor induction for patients with a stillbirth at term with a history of a cesarean birth.³⁸ Preliminary experience suggests that stillbirth protocols using misoprostol doses modestly greater than those used in the management of a pregnancy with a viable fetus may be safe.⁹ See TABLES 2 and 3.

A multidisciplinary approach can optimize compassionate care

There are many gaps in the holistic care of patients and partners experiencing fetal demise. Patients with fetal demise often report that they did not receive sufficient information about the cause of the demise and wanted more opportunity to be involved in decision making about their care.³⁹ The patient’s partner often reports feeling unacknowledged as a grieving parent.⁴⁰ Fetal demise is experienced by many patients as a tragedy, triggering feelings of grief, anger, denial, anxiety and depression, sometimes resulting in isolation and substance misuse.

Using a 5-round Delphi process, experts identified 8 core goals in the care of patients with fetal demise:

1. reduce stigma
2. provide respectful care
3. involve patients in care planning
4. attempt to provide an explanation for the demise¹
5. acknowledge the depth of the grief response and provide emotional support
6. offer information about ongoing psychological support
7. provide information about future pregnancy planning
8. provide opportunities for specialized training and support for care providers.⁴¹

Management of stillbirth is optimized by a multidisciplinary approach that includes the expert care of obstetrician-gynecologists, obstetric nurses, anesthesiologists, and expert consultation from social work, chaplaincy, and pathology. A heart-to-heart connection between clinician and patient is a key component of stillbirth care. ●

Clinical care for fetal demise is complex and multidimensional, including empathic emotional support for the patient and family members who are experiencing a tragedy, investigation of the cause of the demise, and a plan for emptying the uterus. This editorial narrowly focuses on the options for treatment of fetal demise with the goal of emptying the uterus while minimizing complications.

When planning treatment of fetal demise, focus on fetal size and gestational age

Most guidelines for the treatment of fetal demise use gestational age to guide selection of a treatment.^1,2 I believe that fetal size is as important as gestational age for selecting a treatment plan. When considering treatment, there are 2 reasons why fetal size is as important as gestational age:

• The physiologic processes that caused fetal demise may have caused fetal growth restriction, resulting in a fetal size that is 2 or more weeks below expected fetal size for gestational age.
• Fetal demise may have occurred weeks before the diagnosis was made, resulting in gestational age being greater than fetal size. This editorial will use ultrasonography estimate of fetal size in gestational weeks to guide treatment recommendations. When discussing fetal size, we will use the convention of weeks-days (w-d). Twenty-five weeks and zero days gestation is represented as 25w0d.

Treatment in the second and third trimester is a 2-step process

Step 1: Cervical preparation

In most cases of first trimester fetal demise, no cervical preparation is necessary. Cervical dilation with metal dilators followed by uterine evacuation with an appropriately sized vacuum catheter is a highly successful treatment.³ However for second and third trimester fetal demise, it is best to use a 2-step process, beginning with cervical preparation followed by emptying the uterus. For example, at a fetal size of 13w0d to 16w0d, cervical preparation can be achieved by administering a single buccal dose of misoprostol 400 µg 3 to 4 hours prior to uterine evacuation or by inserting a Dilapan-S (Medicem Inc) osmotic cervical dilator 3 to 6 hours prior to uterine evacuation.^4-7 At a fetal size of 16w0d to 19w6d, cervical preparation can be achieved by placing osmotic cervical dilators 4 to 6 hours before surgical evacuation and administering buccal misoprostol 400 µg 3 hours before surgical evacuation.⁸

Alternatively, from 16w0d to 25w0d osmotic cervical dilators can be placed on day 1 of a 2-day process, and the patient can return on day 2 to have the cervical dilators removed followed by surgical evacuation of the uterus. Mifepristone 200 mg oral dose can be administered on day 1 to facilitate cervical preparation. In my practice, I use mifepristone 200 mg on day 1 when the fetal size is ≥20w0d gestation. Options for cervical preparation include use of osmotic dilators, cervical balloons, misoprostol, and/or mifepristone. These options are discussed below. With fetal demise, natural physiologic processes often have caused sufficient cervical softening and dilation that no cervical preparation is necessary and immediate uterine surgical evacuation or induction of labor can be initiated.

Step 2: Emptying the uterus

In the second and third trimesters, the approach to uterine evacuation is based on fetal size. At fetal sizes <25w0d, options for emptying the uterus include surgical evacuation with a vacuum catheter and grasping forceps or induction of labor with misoprostol followed by vaginal birth and expulsion of the placenta. At fetal sizes ˃25w0d gestation, following completion of cervical preparation, the most common approaches to uterine evacuation are induction of labor with misoprostol or oxytocin. Rarely, with a stillbirth at term, some clinicians will select hysterotomy to empty the uterus, avoiding uterine rupture during labor induction for patients at the highest risk, including those with a prior classical cesarean birth or more than 2 prior cesarean births with a low-transverse uterine incision.

Osmotic cervical dilators

The 2 most used cervical dilators are Dilapan-S, a polyacrylate-based hydrogel rod, and laminaria, dried compressed seaweed stipe (stalk) from Laminaria japonica or Laminaria digitata. Dilapan-S rods are available in diameters of 3 mm and 4 mm and rod lengths of 55 mm and 65 mm. Laminaria dilators are available in diameters of 2, 3, 4, 5, 6, 8 and 10 mm and rod length of 60 and 70 mm. Dilapan-S dilators reach near-maximal dilation in approximately 4 to 6 hours but continue to expand over the following 18 hours to achieve a maximum dilation of 3.3 to 3.6 times their dry diameter.⁹ Laminaria dilators expand to 2.7 to 2.9 times their dry diameter over 24 hours.⁹

A general rule is that as many dilators as possible should be placed until significant resistance to the placement of additional dilators is encountered.¹⁰ In my practice, for fetal size ≥20 weeks’ gestation, I place 2 Dilapan-S rods, 4 mm in diameter, 55 mm in length, and then encircle the Dilapan-S with laminaria rods that are 4 mm in diameter and 60 mm in length. Once cervical resistance to the placement of the 4 mm laminaria rods is observed, I encircle those laminaria with laminaria 2 mm in diameter, filling in the interstices between the 4 mm laminaria. The next day, cervical dilation is routinely ≥3 cm.

In a retrospective study of 491 patients undergoing pregnancy termination after 14 weeks’ gestation, with a mean gestational age of 24 weeks, compared with no osmotic cervical dilators, inserting osmotic cervical dilators the day before initiating misoprostol for induction of labor resulted in a decrease in time to delivery (428 min vs 640 min; P<.001) and a decrease in total misoprostol dose (990 µg vs 1,449 µg; P<.0001).¹¹

Cervical balloons

All clinicians know that a Foley catheter or a Cook cervical ripening balloon can be used for cervical preparation in the third trimester.^12,13 The Foley catheter also has been reported to be useful for cervical preparation in the second trimester. In one study of 43 patients 17 to 24 weeks’ gestation scheduled for a second-trimester dilation and evacuation, an intracervical Foley catheter was placed the evening before evacuation, and the balloon was inflated with 30 mL to 50 mL of saline. At the same time, mifepristone 200 mg was administered to the patients.¹⁴ The following day, dilation and evacuation was performed. In 72% of cases no additional cervical dilation was required on the day of evacuation. The investigators concluded that if osmotic cervical dilators are not available, the placement of an intracervical Foley catheter plus administration of mifepristone facilitates performance of an evacuation on the following day. If the patient prefers a 1-day procedure, the Foley can be inserted in the morning to facilitate cervical preparation, and the uterus can be evacuated in the afternoon.

Continue to: Misoprostol...

Misoprostol

Misoprostol, a derivative of prostaglandin E1, is useful for both cervical preparation and induction of labor. The dose of misoprostol and the route of administration are major determinants of uterine response.^15-19 When administered by an oral route, misoprostol has fast onset and offset of action and often does not cause sustained uterine contractions. Hence, oral misoprostol, at a low dose is useful for cervical ripening, but not as useful for stimulation of sustained uterine contractions for induction of labor. When administered by a buccal or vaginal route, misoprostol has prolonged activity and often results in sustained uterine contractions. At any given dose of misoprostol, buccal and vaginal misoprostol administration are more effective than oral administration in inducing sustained uterine contractions sufficient to empty the uterus.^15-19

Mifepristone

Mifepristone, an anti-progestin, is useful for cervical preparation and sensitizing myocytes to the action of uterotonics. Progesterone reduces cell-to-cell communication among uterine myocytes, facilitating uterine quiescence by suppressing connexin 43 and other proteins. Mifepristone blocks the effect of progesterone, inducing the production of myocyte connexin 43, enhancing efficient cell-to-cell communication, permitting uterine myoctes to contract in unison, creating the potential for powerful and sustained contractions.^20-23 Randomized clinical trials report that administration of mifepristone 200 mg prior to misoprostol induced labor results in more rapid emptying of the uterus.^24-27

It takes time for mifepristone to have its full effect on uterine myocytes. Hence, most protocols recommend waiting 24 hours following mifepristone administration before initiating treatment with an agent to stimulate uterine contractions such as misoprostol or oxytocin. However, preliminary data suggest that partial benefit of mifepristone can be obtained when initiating misoprostol 3 to 5 hours after mifepristone administration.²⁸ In a study of 481 patients undergoing induction of labor in the second or third trimester, the time from initiation of misoprostol to vaginal birth was 15 hours with no mifepristone pretreatment, 13.2 hours if mifepristone was administered 3 to 5 hours before initiating misoprostol, 9.3 hours if mifepristone was administered 24 hours before initiating misoprostol, and 10.5 hours if mifepristone was administered 48 hours before initiating misoprostol.²⁸

Fetal size <25w0d gestation: Cervical preparation and surgical evacuation

For fetal demise at a fetal size less than 25w0d, if clinical experts are available, the best treatment option is cervical preparation followed by surgical evacuation of the uterus using a vacuum catheter and grasping forceps to empty the uterus.^29,30 A disadvantage of surgical evacuation of the uterus is that an intact fetus is not available for the patient to hold and mourn, and pathologic examination of an intact fetus is not possible. An alternative approach is cervical preparation followed by induction of labor using misoprostol with the goal of delivering an intact fetus. Although no prospective clinical trials are available comparing these 2 options, retrospective studies have reported that, at fetal size <25w0d gestation, compared with induction of labor, surgical evacuation of the uterus results in fewer complications,³⁰ including fewer cases of retained placenta requiring an unplanned procedure and fewer presumed uterine infections.²⁹

For surgical evacuation of fetal demise with a fetal size of <25w0d gestation, the first step on day 1 is placement of osmotic cervical dilators. In addition to osmotic cervical dilators, if the gestational age or fetal size is ≥19 weeks’ gestation an oral dose of mifepristone 200 mg to facilitate cervical preparation may be considered. On day 2, the osmotic dilators are removed and surgical evacuation is performed. In one randomized study, for pregnancies at 19 to 24 weeks’ gestation, compared with osmotic dilators alone, administration of mifepristone 200 mg at the time of placement of osmotic dilators resulted in fewer procedures that were difficult to complete.³¹ In some cases, 2 consecutive days of cervical preparation with osmotic dilators may be needed to properly prepare the cervix for uterine evacuation. For example, the cervix of a nulliparous teenage patient may require 2 days of cervical preparation with osmotic dilators to facilitate uterine evacuation. In some cases of fetal demise, the cervix is already dilated to ≥3 cm and surgical evacuation of the uterus or induction of labor can be initiated without the need for cervical preparation.

Continue to: Fetal size 14w0d to 28w6d gestation: Cervical preparation and induction of labor...

Treatment of fetal demise at 14w0d to 28w6d gestation with the goal of the vaginal birth of an intact fetus is optimized by the administration of mifepristone for cervical preparation followed by induction of labor with misoprostol.^26,27

In one clinical trial, 66 patients with fetal demise between 14w0d and 28w6d gestation were randomly assigned to receive mifepristone 200 mg or placebo followed 24 to 48 hours later with initiation of misoprostol induction of labor.²⁶ Among the patients from 14w0d to 24 weeks’ gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24w0d to 28 weeks’ gestation, the misoprostol dose was 200 µg vaginally every 4 hours. At 24 hours, a consultant obstetrician determined if additional misoprostol should be given. The median time from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups was 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P= .002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage, 4 in the placebo group and 1 in the mifepristone group.²⁶

In a second clinical trial, 105 patients with fetal demise after 20 weeks of gestation were randomly assigned to receive mifepristone 200 mg or placebo.²⁷ In this study, 86% of the patients were ≥26w0d gestation, with a mean gestational age of approximately 32w2d. Thirty-six to 48 hours later, misoprostol induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostoldose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients from ≥26 weeks’ gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours, respectively (P=.001). Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg; P<.001). Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.²⁷

Fetal size ≥29w0d gestation

At a fetal size ≥29w0d gestation, if the cervix is ripe with a Bishop score of ≥7, oxytocin induction of labor is often used as a first-line treatment. If the cervix is not ripe, misoprostol induction of labor may be considered at doses less than those used in the second trimester of pregnancy.³²TABLES 1,^{1, 26, 33–36}2,³⁷ and 3³⁷ summarize regimens proposed for fetal size ≥29w0d. One regimen begins with an initial misoprostol dose of 50 µg. If adequate uterine contractions occur, the 50 µg dose is repeated every 4 hours up to 6 total doses. If contractions are inadequate, the dose can be increased to 100 µg every 4 hours for 5 additional doses.

For fetal demise after 28w0d gestation, the American College of Obstetricians and Gynecologists (ACOG)¹ recommends standard obstetric protocols for induction of labor, including standard protocols for induction of labor following a previous cesarean birth. For a patient with a history of a prior cesarean birth or major uterine surgery, ACOG recommends that management of fetal demise should prioritize the use of mechanical cervical ripening, for example with a balloon catheter, and induction of uterine contractions with oxytocin.³⁸ ACOG recommends against the use of misoprostol for cervical ripening or labor induction for patients with a stillbirth at term with a history of a cesarean birth.³⁸ Preliminary experience suggests that stillbirth protocols using misoprostol doses modestly greater than those used in the management of a pregnancy with a viable fetus may be safe.⁹ See TABLES 2 and 3.

A multidisciplinary approach can optimize compassionate care

There are many gaps in the holistic care of patients and partners experiencing fetal demise. Patients with fetal demise often report that they did not receive sufficient information about the cause of the demise and wanted more opportunity to be involved in decision making about their care.³⁹ The patient’s partner often reports feeling unacknowledged as a grieving parent.⁴⁰ Fetal demise is experienced by many patients as a tragedy, triggering feelings of grief, anger, denial, anxiety and depression, sometimes resulting in isolation and substance misuse.

Using a 5-round Delphi process, experts identified 8 core goals in the care of patients with fetal demise:

1. reduce stigma
2. provide respectful care
3. involve patients in care planning
4. attempt to provide an explanation for the demise¹
5. acknowledge the depth of the grief response and provide emotional support
6. offer information about ongoing psychological support
7. provide information about future pregnancy planning
8. provide opportunities for specialized training and support for care providers.⁴¹

Management of stillbirth is optimized by a multidisciplinary approach that includes the expert care of obstetrician-gynecologists, obstetric nurses, anesthesiologists, and expert consultation from social work, chaplaincy, and pathology. A heart-to-heart connection between clinician and patient is a key component of stillbirth care. ●

CASE Patient inquires about new technology to detect cancer

A 51-year-old woman (para 2) presents to your clinic for a routine gynecology exam. She is up to date on her screening mammogram and Pap testing. She has her first colonoscopy scheduled for next month. She has a 10-year remote smoking history, but she stopped smoking in her late twenties. Her cousin was recently diagnosed with skin cancer, her father had prostate cancer and is now in remission, and her paternal grandmother died of ovarian cancer. She knows ovarian cancer does not have an effective screening test, and she recently heard on the news about a new blood test that can detect cancer before symptoms start. She would like to know more about this test. Could it replace her next Pap, mammogram, and future colonoscopies? She also wants to know—How can a simple blood test detect cancer?

The power of genomics in cancer care

Since the first human genome was sequenced in 2000, the power of genomics has been evident across many aspects of medicine, including cancer care.¹ Whereas the first human genome to be sequenced took more than 10 years to sequence and cost over  $1 billion, sequencing of your entire genome can now be obtained for less than $400—with results in a week.²

Genomics is now an integral part of cancer care, with results having implications for both cancer risk and prevention as well as more individualized treatment. For example, a healthy 42-year-old patient with a strong family history of breast cancer may undergo genetic testing and discover she has a mutation in the tumor suppression gene BRCA1, which carries a 39% to 58% lifetime risk of ovarian cancer.³ By undergoing a risk-reducing bilateral salpingooophorectomy she will lower her ovarian cancer risk by up to 96%.^4,5 A 67-year-old with a new diagnosis of stage III ovarian cancer and a BRCA2 mutation may be in remission for 5+ years due to her BRCA2 mutation, which makes her eligible for the use of the poly(ADPribose) polymerase (PARP) inhibitor olaparib.⁶ Genetic testing as illustrated above has led to decreased cancer-related mortality and prolonged survival.⁷ However, many women with such germline mutations are faced with difficult choices about surgical risk reduction, with the potential harms of early menopause and quality of life concerns. Having a test that does not just predict cancer risk but in fact quantifies that risk for the individual would greatly help in these decisions. Furthermore, more than 75% of ovarian cancers occur without a germline mutation. 

Advances in genetic testing technology also have led to the ability to obtain genetic information from a simple blood test. For example, cell-free DNA (cfDNA), which is DNA fragments that are normally found to be circulating in the bloodstream, is routinely used as a screening tool for prenatal genetic testing to detect chromosomal abnormalities in the fetus.⁸ This technology relies on analyzing fetal free (non-cellular) DNA that is naturally found circulating in maternal blood. More recently, similar technology using cfDNA has been applied for the screening and characterization of certain cancers.⁹ This powerful technology can detect cancer before symptoms begin—all from a simple blood test, often referred to as a “liquid biopsy.” However, understanding the utility, supporting data, and target population for these tests is important before employing them as part of routine clinical practice. 

Continue to: Current methods of cancer screening are limited...

Current methods of cancer screening are limited 

Cancer is a leading cause of death worldwide, with nearly 10 million cancer-related deaths annually, and it may surpass cardiovascular disease as the leading cause over the course of the century.^10,11 Many cancer deaths are in part due to late-stage diagnosis, when the cancer has already metastasized.¹² Early detection of cancer improves outcomes and survival rates, but it is often difficult to detect early due to the lack of early symptoms with many cancers, which can limit cancer screening and issues with access to care.¹³

 Currently, there are only 5 cancers: cervical, prostate, breast, colon, and lung (for high-risk adults) that are screened for in the general population (see "Cancer screening has helped save countless lives" at the end of this article).¹⁴ The Pap test to screen for cervical cancer, developed in the 1940s, has saved millions of women’s lives and reduced the mortality of cervical cancer by 70%.¹⁵ Coupled with the availability and implementation of the human papillomavirus (HPV) vaccine, cervical cancer rates are decreasing at substantial rates.¹⁶ However, there are no validated screening tests for uterine cancer, the most common gynecologic malignancy in the United States, or ovarian cancer, the most lethal. 

Screening tests for cervical, prostate, breast, colon, and lung cancer have helped save millions of lives; however, these tests also come with high false-positive rates and the potential for overdiagnosis and overtreatment. For example, half of women undergoing mammograms will receive a false-positive result over a 10-year time period,¹⁷ and up to 50% of men undergoing prostate cancer screening have a positive prostate-specific antigen (PSA) test result when they do not actually have prostate cancer.¹⁸ Additionally, the positive predictive value of the current standard-of-care screening tests can be as low as <5%. Most diagnoses of cancer are made from a surgical biopsy, but these types of procedures can be difficult depending on the location or size of the tumor.¹⁹ 

The liquid biopsy. Given the limitations of current cancer screening and diagnostic tests, there is a great need for a more sensitive test that also can detect cancer from multiple organ sites. Liquid biopsy-based biomarkers can include circulating tumor cells, exosomes, microRNAs, and circulating tumor DNA (ctDNA). With advances in next-generation sequencing, ctDNA techniques remain the most promising.²⁰ 

Methylation-based MCED testing: A new way of  cancer screening 

Multi-cancer early detection (MCED) technology was developed to address the need for better cancer screening and has the potential to detect up to 50 cancers with a simple blood test. This new technology opens the possibility for early detection of multiple cancers before symptoms even begin. MCED testing is sometimes referred to as “GRAIL” testing, after the American biotechnology company that developed the first commercially available MCED test, called the Galleri test (Galleri, Menlo Park, California). Although other biotechnology companies are developing similar technology (Exact Sciences, Madison, Wisconsin, and Freenome, South San Francisco, California, for example), this is the first test of its kind available to the public.²¹

The MCED test works by detecting the cfDNA fragments that are released into the blood passively by necrotic or apoptotic cells or secreted actively from tumor cells. The DNA from tumor cells is also known as circulating tumor DNA (ctDNA). CtDNA is found in much lower quantities in the blood stream compared with cfDNA from cells, making it difficult to distinguish a cancer versus a noncancer cell and to determine the tumor site of origin.²²

Through innovation, the first example of detecting cancer through this method in fact came as a surprise result from an abnormal cfDNA test. A pregnant 37-yearold woman had a cfDNA result suggestive of aneuploidy for chromosomes 18 and 13; however, she gave birth to a normal male fetus. Shortly thereafter, a vaginal biopsy confirmed small-cell carcinoma with alterations in chromosomes 18 and 13.²³ GRAIL testing for this patient was subsequently able to optimize their methods of detecting both the presence of cancer cells and the tumor site of origin by utilizing next-generation genomic sequencing and methylation. Their development of a methylation-based assay combined with 46 machine-learning allowed the test to determine, first, if there is cancer present or not, and second, the tissue of origin prediction. It is important to note that these tests are meant to be used in addition to standard-of-care screening tests, not as an alternative, and this is emphasized throughout the company’s website and the medical literature.²⁴ 

Continue to: The process to develop and validate GRAIL’s blood-based cancer screening test...

The process to develop and validate GRAIL’s blood-based cancer screening test includes 4 large clinical trials of more than 180,000 participants, including those with cancer and those without. The Circulating Cell-Free Genome Atlas (CCGA) Study, was a prospective, case-controlled, observational study enrolling approximately 15,000 participants with 3 prespecified sub-studies. The first sub-study developed the machine-learning classifier for both early detection and tumor of origin detection.^25,26 

The highest performing assay from the first sub-study then went on to be further validated in the 2nd and 3rd sub-studies. The 3rd sub-study, published in the Annals of Oncology in 2021 looked at a cohort of 4,077 participants with and without cancer, and found the specificity of cancer signal detection to be 99.5% and the overall sensitivity to be 51.5%, with increasing sensitivity by cancer stage (stage I - 17%, stage II - 40%, stage III - 77%, and stage IV - 90.1%).²⁴ The false-positive rate was low, at 0.7%, and the true positive rate was 88.7%. Notably, the test was able to correctly identify the tumor of origin for 93% of samples.²⁴ The study overall demonstrated high specificity and accuracy of tumor site of origin and supported the use of this blood-based MCED assay. 

The PATHFINDER study was another prospective, multicenter clinical trial that enrolled more than 6,000 participants in the United States. The participants were aged >50 years with or without additional cancer risk factors. The goal of this study was to determine the extent of testing required to achieve diagnosis after a “cancer signal detected” result. The study results found that, when MCED testing was added to the standard-of-care screening, the number of cancers detected doubled when compared with standard cancer screening alone.^27,28 Of the 92 participants with positive cancer signals, 35 were diagnosed with cancer, and 71% of these cancer types did not have standard-ofcare screening. The tumor site of origin was correctly detected in 97% of cases, and there were less than 1% of false positives. Overall, the test led to diagnostic evaluation of 1.4% of patients and a cancer diagnosis in 0.5%. 

Currently, there are 2 ongoing clinical trials to further evaluate the Galleri MCED test. The STRIVE trial that aims to prospectively validate the MCED test in a population of nearly 100,000 women undergoing mammography,²⁹ and the SUMMIT trial,³⁰ which is similarly aiming to validate the test in a group of individuals, half of whom have a significantly elevated risk of lung cancer. 

With the promising results described above, the Galleri test became the first MCED test available for commercial use starting in 2022. It is only available for use in people who are aged 50 and older, have a family history of cancer, or are at an increased risk for cancer (although GRAIL does not elaborate on what constitutes increased risk). However, the Galleri test is only available through prescription—therefore, if interested, patients must ask their health care provider to register with GRAIL and order the test (https://www .galleri.com/hcp/the-galleri-test/ordering). Additionally, the test will cost the patient $949 and is not yet covered by insurances. Currently, several large health care groups such as the United States Department of Veterans Affairs, Cleveland Clinic, and Mercy hospitals have partnered with GRAIL to offer their test to certain patients for use as part of clinical trials. Currently, no MCED test, including the Galleri, is approved by the US Food and  Drug Administration. 

Incorporating MCED testing into clinical practice

The Galleri MCED test has promising potential to make multi-cancer screening feasible and obtainable, which could ultimately reduce late-stage cancer diagnosis and decrease mortality from all cancers. The compelling data from large cohorts and numerous clinical trials demonstrate its accuracy, reliability, reproducibility, and specificity. It can detect up to 50 different types of cancers, including cancers that affect our gynecologic patients, including breast, cervical, ovarian, and uterine. Additionally, its novel methylation-based assay accurately identifies the tumor site of origin in 97% of cases.²⁸ Ongoing and future clinical trials will continue to validate and refine these methods and improve the sensitivity and positive-predictive value of this assay. As mentioned, although it has been incorporated into various large health care systems, it is not FDA approved and has not been validated in the general population. Additionally, it should not be used as a replacement for recommended screening. 

CASE Resolved

The patient is eligible for the Galleri MCED test if ordered by her physician. However, she will need to pay for the test out-of-pocket. Due to her family history, she should consider germline genetic testing (either for herself, or if possible, for her father, who should meet criteria based on his prostate cancer).³ Panel testing for germline mutations has become much more accessible, and until MCED testing is ready for prime time, it remains one of the best ways to predict and prevent cancers. Additionally, she should continue to undergo routine screening for cervical, breast, and colon cancer as indicated. ●

CASE Patient inquires about new technology to detect cancer

A 51-year-old woman (para 2) presents to your clinic for a routine gynecology exam. She is up to date on her screening mammogram and Pap testing. She has her first colonoscopy scheduled for next month. She has a 10-year remote smoking history, but she stopped smoking in her late twenties. Her cousin was recently diagnosed with skin cancer, her father had prostate cancer and is now in remission, and her paternal grandmother died of ovarian cancer. She knows ovarian cancer does not have an effective screening test, and she recently heard on the news about a new blood test that can detect cancer before symptoms start. She would like to know more about this test. Could it replace her next Pap, mammogram, and future colonoscopies? She also wants to know—How can a simple blood test detect cancer?

The power of genomics in cancer care

Since the first human genome was sequenced in 2000, the power of genomics has been evident across many aspects of medicine, including cancer care.¹ Whereas the first human genome to be sequenced took more than 10 years to sequence and cost over  $1 billion, sequencing of your entire genome can now be obtained for less than $400—with results in a week.²

Genomics is now an integral part of cancer care, with results having implications for both cancer risk and prevention as well as more individualized treatment. For example, a healthy 42-year-old patient with a strong family history of breast cancer may undergo genetic testing and discover she has a mutation in the tumor suppression gene BRCA1, which carries a 39% to 58% lifetime risk of ovarian cancer.³ By undergoing a risk-reducing bilateral salpingooophorectomy she will lower her ovarian cancer risk by up to 96%.^4,5 A 67-year-old with a new diagnosis of stage III ovarian cancer and a BRCA2 mutation may be in remission for 5+ years due to her BRCA2 mutation, which makes her eligible for the use of the poly(ADPribose) polymerase (PARP) inhibitor olaparib.⁶ Genetic testing as illustrated above has led to decreased cancer-related mortality and prolonged survival.⁷ However, many women with such germline mutations are faced with difficult choices about surgical risk reduction, with the potential harms of early menopause and quality of life concerns. Having a test that does not just predict cancer risk but in fact quantifies that risk for the individual would greatly help in these decisions. Furthermore, more than 75% of ovarian cancers occur without a germline mutation. 

Advances in genetic testing technology also have led to the ability to obtain genetic information from a simple blood test. For example, cell-free DNA (cfDNA), which is DNA fragments that are normally found to be circulating in the bloodstream, is routinely used as a screening tool for prenatal genetic testing to detect chromosomal abnormalities in the fetus.⁸ This technology relies on analyzing fetal free (non-cellular) DNA that is naturally found circulating in maternal blood. More recently, similar technology using cfDNA has been applied for the screening and characterization of certain cancers.⁹ This powerful technology can detect cancer before symptoms begin—all from a simple blood test, often referred to as a “liquid biopsy.” However, understanding the utility, supporting data, and target population for these tests is important before employing them as part of routine clinical practice. 

Continue to: Current methods of cancer screening are limited...

Current methods of cancer screening are limited 

Cancer is a leading cause of death worldwide, with nearly 10 million cancer-related deaths annually, and it may surpass cardiovascular disease as the leading cause over the course of the century.^10,11 Many cancer deaths are in part due to late-stage diagnosis, when the cancer has already metastasized.¹² Early detection of cancer improves outcomes and survival rates, but it is often difficult to detect early due to the lack of early symptoms with many cancers, which can limit cancer screening and issues with access to care.¹³

 Currently, there are only 5 cancers: cervical, prostate, breast, colon, and lung (for high-risk adults) that are screened for in the general population (see "Cancer screening has helped save countless lives" at the end of this article).¹⁴ The Pap test to screen for cervical cancer, developed in the 1940s, has saved millions of women’s lives and reduced the mortality of cervical cancer by 70%.¹⁵ Coupled with the availability and implementation of the human papillomavirus (HPV) vaccine, cervical cancer rates are decreasing at substantial rates.¹⁶ However, there are no validated screening tests for uterine cancer, the most common gynecologic malignancy in the United States, or ovarian cancer, the most lethal. 

Screening tests for cervical, prostate, breast, colon, and lung cancer have helped save millions of lives; however, these tests also come with high false-positive rates and the potential for overdiagnosis and overtreatment. For example, half of women undergoing mammograms will receive a false-positive result over a 10-year time period,¹⁷ and up to 50% of men undergoing prostate cancer screening have a positive prostate-specific antigen (PSA) test result when they do not actually have prostate cancer.¹⁸ Additionally, the positive predictive value of the current standard-of-care screening tests can be as low as <5%. Most diagnoses of cancer are made from a surgical biopsy, but these types of procedures can be difficult depending on the location or size of the tumor.¹⁹ 

The liquid biopsy. Given the limitations of current cancer screening and diagnostic tests, there is a great need for a more sensitive test that also can detect cancer from multiple organ sites. Liquid biopsy-based biomarkers can include circulating tumor cells, exosomes, microRNAs, and circulating tumor DNA (ctDNA). With advances in next-generation sequencing, ctDNA techniques remain the most promising.²⁰ 

Methylation-based MCED testing: A new way of  cancer screening 

Multi-cancer early detection (MCED) technology was developed to address the need for better cancer screening and has the potential to detect up to 50 cancers with a simple blood test. This new technology opens the possibility for early detection of multiple cancers before symptoms even begin. MCED testing is sometimes referred to as “GRAIL” testing, after the American biotechnology company that developed the first commercially available MCED test, called the Galleri test (Galleri, Menlo Park, California). Although other biotechnology companies are developing similar technology (Exact Sciences, Madison, Wisconsin, and Freenome, South San Francisco, California, for example), this is the first test of its kind available to the public.²¹

The MCED test works by detecting the cfDNA fragments that are released into the blood passively by necrotic or apoptotic cells or secreted actively from tumor cells. The DNA from tumor cells is also known as circulating tumor DNA (ctDNA). CtDNA is found in much lower quantities in the blood stream compared with cfDNA from cells, making it difficult to distinguish a cancer versus a noncancer cell and to determine the tumor site of origin.²²

Through innovation, the first example of detecting cancer through this method in fact came as a surprise result from an abnormal cfDNA test. A pregnant 37-yearold woman had a cfDNA result suggestive of aneuploidy for chromosomes 18 and 13; however, she gave birth to a normal male fetus. Shortly thereafter, a vaginal biopsy confirmed small-cell carcinoma with alterations in chromosomes 18 and 13.²³ GRAIL testing for this patient was subsequently able to optimize their methods of detecting both the presence of cancer cells and the tumor site of origin by utilizing next-generation genomic sequencing and methylation. Their development of a methylation-based assay combined with 46 machine-learning allowed the test to determine, first, if there is cancer present or not, and second, the tissue of origin prediction. It is important to note that these tests are meant to be used in addition to standard-of-care screening tests, not as an alternative, and this is emphasized throughout the company’s website and the medical literature.²⁴ 

Continue to: The process to develop and validate GRAIL’s blood-based cancer screening test...

The process to develop and validate GRAIL’s blood-based cancer screening test includes 4 large clinical trials of more than 180,000 participants, including those with cancer and those without. The Circulating Cell-Free Genome Atlas (CCGA) Study, was a prospective, case-controlled, observational study enrolling approximately 15,000 participants with 3 prespecified sub-studies. The first sub-study developed the machine-learning classifier for both early detection and tumor of origin detection.^25,26 

The highest performing assay from the first sub-study then went on to be further validated in the 2nd and 3rd sub-studies. The 3rd sub-study, published in the Annals of Oncology in 2021 looked at a cohort of 4,077 participants with and without cancer, and found the specificity of cancer signal detection to be 99.5% and the overall sensitivity to be 51.5%, with increasing sensitivity by cancer stage (stage I - 17%, stage II - 40%, stage III - 77%, and stage IV - 90.1%).²⁴ The false-positive rate was low, at 0.7%, and the true positive rate was 88.7%. Notably, the test was able to correctly identify the tumor of origin for 93% of samples.²⁴ The study overall demonstrated high specificity and accuracy of tumor site of origin and supported the use of this blood-based MCED assay. 

The PATHFINDER study was another prospective, multicenter clinical trial that enrolled more than 6,000 participants in the United States. The participants were aged >50 years with or without additional cancer risk factors. The goal of this study was to determine the extent of testing required to achieve diagnosis after a “cancer signal detected” result. The study results found that, when MCED testing was added to the standard-of-care screening, the number of cancers detected doubled when compared with standard cancer screening alone.^27,28 Of the 92 participants with positive cancer signals, 35 were diagnosed with cancer, and 71% of these cancer types did not have standard-ofcare screening. The tumor site of origin was correctly detected in 97% of cases, and there were less than 1% of false positives. Overall, the test led to diagnostic evaluation of 1.4% of patients and a cancer diagnosis in 0.5%. 

Currently, there are 2 ongoing clinical trials to further evaluate the Galleri MCED test. The STRIVE trial that aims to prospectively validate the MCED test in a population of nearly 100,000 women undergoing mammography,²⁹ and the SUMMIT trial,³⁰ which is similarly aiming to validate the test in a group of individuals, half of whom have a significantly elevated risk of lung cancer. 

With the promising results described above, the Galleri test became the first MCED test available for commercial use starting in 2022. It is only available for use in people who are aged 50 and older, have a family history of cancer, or are at an increased risk for cancer (although GRAIL does not elaborate on what constitutes increased risk). However, the Galleri test is only available through prescription—therefore, if interested, patients must ask their health care provider to register with GRAIL and order the test (https://www .galleri.com/hcp/the-galleri-test/ordering). Additionally, the test will cost the patient $949 and is not yet covered by insurances. Currently, several large health care groups such as the United States Department of Veterans Affairs, Cleveland Clinic, and Mercy hospitals have partnered with GRAIL to offer their test to certain patients for use as part of clinical trials. Currently, no MCED test, including the Galleri, is approved by the US Food and  Drug Administration. 

Incorporating MCED testing into clinical practice

The Galleri MCED test has promising potential to make multi-cancer screening feasible and obtainable, which could ultimately reduce late-stage cancer diagnosis and decrease mortality from all cancers. The compelling data from large cohorts and numerous clinical trials demonstrate its accuracy, reliability, reproducibility, and specificity. It can detect up to 50 different types of cancers, including cancers that affect our gynecologic patients, including breast, cervical, ovarian, and uterine. Additionally, its novel methylation-based assay accurately identifies the tumor site of origin in 97% of cases.²⁸ Ongoing and future clinical trials will continue to validate and refine these methods and improve the sensitivity and positive-predictive value of this assay. As mentioned, although it has been incorporated into various large health care systems, it is not FDA approved and has not been validated in the general population. Additionally, it should not be used as a replacement for recommended screening. 

CASE Resolved

The patient is eligible for the Galleri MCED test if ordered by her physician. However, she will need to pay for the test out-of-pocket. Due to her family history, she should consider germline genetic testing (either for herself, or if possible, for her father, who should meet criteria based on his prostate cancer).³ Panel testing for germline mutations has become much more accessible, and until MCED testing is ready for prime time, it remains one of the best ways to predict and prevent cancers. Additionally, she should continue to undergo routine screening for cervical, breast, and colon cancer as indicated. ●

CASE Patient inquires about new technology to detect cancer

A 51-year-old woman (para 2) presents to your clinic for a routine gynecology exam. She is up to date on her screening mammogram and Pap testing. She has her first colonoscopy scheduled for next month. She has a 10-year remote smoking history, but she stopped smoking in her late twenties. Her cousin was recently diagnosed with skin cancer, her father had prostate cancer and is now in remission, and her paternal grandmother died of ovarian cancer. She knows ovarian cancer does not have an effective screening test, and she recently heard on the news about a new blood test that can detect cancer before symptoms start. She would like to know more about this test. Could it replace her next Pap, mammogram, and future colonoscopies? She also wants to know—How can a simple blood test detect cancer?

The power of genomics in cancer care

Since the first human genome was sequenced in 2000, the power of genomics has been evident across many aspects of medicine, including cancer care.¹ Whereas the first human genome to be sequenced took more than 10 years to sequence and cost over  $1 billion, sequencing of your entire genome can now be obtained for less than $400—with results in a week.²

Genomics is now an integral part of cancer care, with results having implications for both cancer risk and prevention as well as more individualized treatment. For example, a healthy 42-year-old patient with a strong family history of breast cancer may undergo genetic testing and discover she has a mutation in the tumor suppression gene BRCA1, which carries a 39% to 58% lifetime risk of ovarian cancer.³ By undergoing a risk-reducing bilateral salpingooophorectomy she will lower her ovarian cancer risk by up to 96%.^4,5 A 67-year-old with a new diagnosis of stage III ovarian cancer and a BRCA2 mutation may be in remission for 5+ years due to her BRCA2 mutation, which makes her eligible for the use of the poly(ADPribose) polymerase (PARP) inhibitor olaparib.⁶ Genetic testing as illustrated above has led to decreased cancer-related mortality and prolonged survival.⁷ However, many women with such germline mutations are faced with difficult choices about surgical risk reduction, with the potential harms of early menopause and quality of life concerns. Having a test that does not just predict cancer risk but in fact quantifies that risk for the individual would greatly help in these decisions. Furthermore, more than 75% of ovarian cancers occur without a germline mutation. 

Advances in genetic testing technology also have led to the ability to obtain genetic information from a simple blood test. For example, cell-free DNA (cfDNA), which is DNA fragments that are normally found to be circulating in the bloodstream, is routinely used as a screening tool for prenatal genetic testing to detect chromosomal abnormalities in the fetus.⁸ This technology relies on analyzing fetal free (non-cellular) DNA that is naturally found circulating in maternal blood. More recently, similar technology using cfDNA has been applied for the screening and characterization of certain cancers.⁹ This powerful technology can detect cancer before symptoms begin—all from a simple blood test, often referred to as a “liquid biopsy.” However, understanding the utility, supporting data, and target population for these tests is important before employing them as part of routine clinical practice. 

Continue to: Current methods of cancer screening are limited...

Current methods of cancer screening are limited 

Cancer is a leading cause of death worldwide, with nearly 10 million cancer-related deaths annually, and it may surpass cardiovascular disease as the leading cause over the course of the century.^10,11 Many cancer deaths are in part due to late-stage diagnosis, when the cancer has already metastasized.¹² Early detection of cancer improves outcomes and survival rates, but it is often difficult to detect early due to the lack of early symptoms with many cancers, which can limit cancer screening and issues with access to care.¹³

 Currently, there are only 5 cancers: cervical, prostate, breast, colon, and lung (for high-risk adults) that are screened for in the general population (see "Cancer screening has helped save countless lives" at the end of this article).¹⁴ The Pap test to screen for cervical cancer, developed in the 1940s, has saved millions of women’s lives and reduced the mortality of cervical cancer by 70%.¹⁵ Coupled with the availability and implementation of the human papillomavirus (HPV) vaccine, cervical cancer rates are decreasing at substantial rates.¹⁶ However, there are no validated screening tests for uterine cancer, the most common gynecologic malignancy in the United States, or ovarian cancer, the most lethal. 

Screening tests for cervical, prostate, breast, colon, and lung cancer have helped save millions of lives; however, these tests also come with high false-positive rates and the potential for overdiagnosis and overtreatment. For example, half of women undergoing mammograms will receive a false-positive result over a 10-year time period,¹⁷ and up to 50% of men undergoing prostate cancer screening have a positive prostate-specific antigen (PSA) test result when they do not actually have prostate cancer.¹⁸ Additionally, the positive predictive value of the current standard-of-care screening tests can be as low as <5%. Most diagnoses of cancer are made from a surgical biopsy, but these types of procedures can be difficult depending on the location or size of the tumor.¹⁹ 

The liquid biopsy. Given the limitations of current cancer screening and diagnostic tests, there is a great need for a more sensitive test that also can detect cancer from multiple organ sites. Liquid biopsy-based biomarkers can include circulating tumor cells, exosomes, microRNAs, and circulating tumor DNA (ctDNA). With advances in next-generation sequencing, ctDNA techniques remain the most promising.²⁰ 

Methylation-based MCED testing: A new way of  cancer screening 

Multi-cancer early detection (MCED) technology was developed to address the need for better cancer screening and has the potential to detect up to 50 cancers with a simple blood test. This new technology opens the possibility for early detection of multiple cancers before symptoms even begin. MCED testing is sometimes referred to as “GRAIL” testing, after the American biotechnology company that developed the first commercially available MCED test, called the Galleri test (Galleri, Menlo Park, California). Although other biotechnology companies are developing similar technology (Exact Sciences, Madison, Wisconsin, and Freenome, South San Francisco, California, for example), this is the first test of its kind available to the public.²¹

The MCED test works by detecting the cfDNA fragments that are released into the blood passively by necrotic or apoptotic cells or secreted actively from tumor cells. The DNA from tumor cells is also known as circulating tumor DNA (ctDNA). CtDNA is found in much lower quantities in the blood stream compared with cfDNA from cells, making it difficult to distinguish a cancer versus a noncancer cell and to determine the tumor site of origin.²²

Through innovation, the first example of detecting cancer through this method in fact came as a surprise result from an abnormal cfDNA test. A pregnant 37-yearold woman had a cfDNA result suggestive of aneuploidy for chromosomes 18 and 13; however, she gave birth to a normal male fetus. Shortly thereafter, a vaginal biopsy confirmed small-cell carcinoma with alterations in chromosomes 18 and 13.²³ GRAIL testing for this patient was subsequently able to optimize their methods of detecting both the presence of cancer cells and the tumor site of origin by utilizing next-generation genomic sequencing and methylation. Their development of a methylation-based assay combined with 46 machine-learning allowed the test to determine, first, if there is cancer present or not, and second, the tissue of origin prediction. It is important to note that these tests are meant to be used in addition to standard-of-care screening tests, not as an alternative, and this is emphasized throughout the company’s website and the medical literature.²⁴ 

Continue to: The process to develop and validate GRAIL’s blood-based cancer screening test...

The process to develop and validate GRAIL’s blood-based cancer screening test includes 4 large clinical trials of more than 180,000 participants, including those with cancer and those without. The Circulating Cell-Free Genome Atlas (CCGA) Study, was a prospective, case-controlled, observational study enrolling approximately 15,000 participants with 3 prespecified sub-studies. The first sub-study developed the machine-learning classifier for both early detection and tumor of origin detection.^25,26 

The highest performing assay from the first sub-study then went on to be further validated in the 2nd and 3rd sub-studies. The 3rd sub-study, published in the Annals of Oncology in 2021 looked at a cohort of 4,077 participants with and without cancer, and found the specificity of cancer signal detection to be 99.5% and the overall sensitivity to be 51.5%, with increasing sensitivity by cancer stage (stage I - 17%, stage II - 40%, stage III - 77%, and stage IV - 90.1%).²⁴ The false-positive rate was low, at 0.7%, and the true positive rate was 88.7%. Notably, the test was able to correctly identify the tumor of origin for 93% of samples.²⁴ The study overall demonstrated high specificity and accuracy of tumor site of origin and supported the use of this blood-based MCED assay. 

The PATHFINDER study was another prospective, multicenter clinical trial that enrolled more than 6,000 participants in the United States. The participants were aged >50 years with or without additional cancer risk factors. The goal of this study was to determine the extent of testing required to achieve diagnosis after a “cancer signal detected” result. The study results found that, when MCED testing was added to the standard-of-care screening, the number of cancers detected doubled when compared with standard cancer screening alone.^27,28 Of the 92 participants with positive cancer signals, 35 were diagnosed with cancer, and 71% of these cancer types did not have standard-ofcare screening. The tumor site of origin was correctly detected in 97% of cases, and there were less than 1% of false positives. Overall, the test led to diagnostic evaluation of 1.4% of patients and a cancer diagnosis in 0.5%. 

Currently, there are 2 ongoing clinical trials to further evaluate the Galleri MCED test. The STRIVE trial that aims to prospectively validate the MCED test in a population of nearly 100,000 women undergoing mammography,²⁹ and the SUMMIT trial,³⁰ which is similarly aiming to validate the test in a group of individuals, half of whom have a significantly elevated risk of lung cancer. 

With the promising results described above, the Galleri test became the first MCED test available for commercial use starting in 2022. It is only available for use in people who are aged 50 and older, have a family history of cancer, or are at an increased risk for cancer (although GRAIL does not elaborate on what constitutes increased risk). However, the Galleri test is only available through prescription—therefore, if interested, patients must ask their health care provider to register with GRAIL and order the test (https://www .galleri.com/hcp/the-galleri-test/ordering). Additionally, the test will cost the patient $949 and is not yet covered by insurances. Currently, several large health care groups such as the United States Department of Veterans Affairs, Cleveland Clinic, and Mercy hospitals have partnered with GRAIL to offer their test to certain patients for use as part of clinical trials. Currently, no MCED test, including the Galleri, is approved by the US Food and  Drug Administration. 

Incorporating MCED testing into clinical practice

The Galleri MCED test has promising potential to make multi-cancer screening feasible and obtainable, which could ultimately reduce late-stage cancer diagnosis and decrease mortality from all cancers. The compelling data from large cohorts and numerous clinical trials demonstrate its accuracy, reliability, reproducibility, and specificity. It can detect up to 50 different types of cancers, including cancers that affect our gynecologic patients, including breast, cervical, ovarian, and uterine. Additionally, its novel methylation-based assay accurately identifies the tumor site of origin in 97% of cases.²⁸ Ongoing and future clinical trials will continue to validate and refine these methods and improve the sensitivity and positive-predictive value of this assay. As mentioned, although it has been incorporated into various large health care systems, it is not FDA approved and has not been validated in the general population. Additionally, it should not be used as a replacement for recommended screening. 

CASE Resolved

The patient is eligible for the Galleri MCED test if ordered by her physician. However, she will need to pay for the test out-of-pocket. Due to her family history, she should consider germline genetic testing (either for herself, or if possible, for her father, who should meet criteria based on his prostate cancer).³ Panel testing for germline mutations has become much more accessible, and until MCED testing is ready for prime time, it remains one of the best ways to predict and prevent cancers. Additionally, she should continue to undergo routine screening for cervical, breast, and colon cancer as indicated. ●

REVIEW

FEMCERV^®: Well-designed technology that can minimize patient discomfort

The FemCerv^® Endocervical Sampler, developed by Femasys, Inc (Suwanee, Georgia) expands options for colposcopy biopsy.


Background. In the United States, approximately 3 million women per year undergo colposcopic evaluation to work-up abnormal screening cytology. While some controversy exists regarding the exact role of endocervical curettage (ECC) within each age group and clinical situation, it is nonetheless an important component of the colposcopy-biopsy examination in many cases. For over a century, the 3 mm metal endocervical curette has been the primary tool employed to obtain the tissue sample from the endocervical canal. Unfortunately, sharp curettage with a metal curette can have inadequate sampling rates as high as 14%,¹ it runs the risk of ectocervical contamination, and it is painful, with almost half the participants in one study rating the procedural pain 3 ̶ 5 out of 8 on a VAS scale.² So, maybe there is a better way.


Design/Functionality. According to Femasys, the FemCerv^® Endocervical Sampler was designed to be the better way of performing an endocervical curettage. FemCerv is a single-use sterile device that comes in a standard 13 F size as well as an 11 F size for the narrower/stenotic os. In truth, at first glance it looks pretty complicated compared with a Kevorkian curette or an endocervical brush. The user end has a handle with a rotatable knob that transitions to a shaft with a flange at the end right before the sampling mechanism. To use the device, the sampling end is inserted into the endocervical canal up to the flange. The knob on the handle is then turned clockwise to open the sheath, thereby exposing sharp rigid plastic edges. The device is then rotated 360° clockwise and then 360° counterclockwise to “curette” the endocervical canal. Finally, the knob on the handle is turned counterclockwise to close the sheath and the device is removed. The specimen is then transferred to a standard vial for processing.

In my experience with its use, it actually exceeded my expectations. The device was easy to use, and the specimens were more than adequate. Truth be told, I came into the trial with a negative mindset having already convinced myself that this device was a waste of money given that doing an ECC with traditional methods is so straightforward. What I had not anticipated was the complete lack of patient discomfort when I used the FemCerv compared with a Kevorkian device.

Innovation. From an innovation standpoint, FemCerv is not super-disruptive technology, but it is well designed and pretty clever in that the opening and closing sheath prevents ectocervical cellular contamination, and the rotational sampling, rather than in-and-out sampling, does dramatically reduce the patient discomfort.


Summary. As I previously noted, before trying it, I did not anticipate liking FemCerv as much as I did. Does it add some non-reimbursable cost to a relatively low-reimbursing procedure? Absolutely. But it is not too expensive and, for me, making a painful procedure relatively painless is good value every time. I think all our patients would agree.

For more information, visit https://femasys.com/.

UPDATE

Hologic, Inc. announces that they received the following 2022 IMV ServiceTrak^TM Awards for Mammography: Best Service, Best Customer Satisfaction, and Best System Performance. In addition, Hologic announces that their Affirm Contrast Biopsy software is commercially available in the United States. Tissue samples may be targeted and acquired using the Affirm Contrast Biopsy software from lesions identified using Hologic’s I-View Contrast Enhanced Mammography software. The latter software allows health care facilities an alternative to breast magnetic resonance imaging, which is used as supplemental imaging to mammography and/or ultrasonography.

For more information, visit https://www.hologic.com/