OBG Management

Attributed to the ancient Greek philosopher Heraclitus, and often quoted in contemporary times, is the expression “the only constant is change.” This sentiment rings true for the field of obstetrics this past year, as several bread-and-butter guidelines for managing common obstetric conditions were either challenged or altered.

The publication of the PROLONG trial called into question the use of intramuscular progesterone for the prevention of preterm birth. Prophylaxis guidelines for group B streptococcal disease were updated, including several significant clinical practice changes. Finally, there was a comprehensive overhaul of the guidelines for hypertensive disorders of pregnancy, which replaced a landmark Task Force document from the American College of Obstetricians and Gynecologists (ACOG) that was published only a few years ago.

Change is constant, and in obstetrics it is vital to keep up with the changing guidelines that result as new data become available for digestion and implementation into everyday clinical practice.

Results from the PROLONG trial may shake up treatment options for recurrent preterm birth 

Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, et al. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): a multicenter, international, randomized double-blind trial. Am J Perinatol. 2019. doi: 10.1055/s-0039-3400227. 

The drug 17 α-hydroxyprogesterone caproate (17-OHPC, or 17P; Makena) was approved by the US Food and Drug Administration (FDA) in 2011 for the prevention of spontaneous preterm birth (PTB) in women with a singleton pregnancy and a history of singleton spontaneous PTB. The results of the trial by Meis and colleagues of 17-OHPC played a major role in achieving that approval, as it demonstrated a 34% reduction in recurrent PTB and a reduction in some neonatal morbidities.¹ Following the drug's approval, both ACOG and the Society for Maternal-Fetal Medicine (SMFM) published guidelines recommending progesterone therapy, including 17-OHPC, for the prevention of recurrent spontaneous PTB.²   

The FDA approval of 17-OHPC was granted under an accelerated conditional pathway that required a confirmatory trial evaluating efficacy, safety, and long-term infant follow-up to be performed by the sponsor. That trial, Progestin's Role in Optimizing Neonatal Gestation (PROLONG), was started in 2009, and its results were published on October 25, 2019.³ 

Continue to: Design of the trial...

Design of the trial 

PROLONG was a multicenter (93 sites), randomized, placebo-controlled, double-blind study conducted in 9 countries (23% of participants were in the United States, 60% were in Russia and Ukraine). The co-primary outcome was PTB < 35 weeks and a composite neonatal morbidity and mortality index. The primary safety outcome was fetal/early infant death. 

The study was designed to have 98% power to detect a 30% reduction in PTB < 35 weeks, and 90% power to detect a 35% reduction in the neonatal composite index. It included 1,708 participants (1,130 were treated with 17-OHPC, and 578 received placebo). 

Trial outcomes. There was no difference in PTB < 35 weeks between the 17-OHPC and the placebo groups (11.0% vs 11.5%; relative risk [RR], 0.95; 95% confidence interval [CI], 0.71-1.26). There was no difference in PTB < 32 or < 37 weeks. 

The study revealed also that there was no difference between groups in the neonatal composite index (5.6% for 17-OHPC vs 5.0% for placebo; RR, 1.12; 95% CI, 0.68-1.61). In addition, there was no difference in fetal/early infant death between the 17-OHPC and placebo groups (1.7% vs 1.9%; RR, 0.87; 95% CI, 0.4-1.81). 

Conclusions. The trial investigators concluded that 17-OHPC did not demonstrate a reduction in recurrent PTB and did not decrease neonatal morbidity. 

Study limitations included underpowering and selection bias 

The investigators noted that the PTB rate in PROLONG was unexpectedly almost 50% lower than that in the Meis trial, and that therefore the PROLONG trial was underpowered to assess the primary outcomes. 

Further, the study populations of the 2 trials were very different: The Meis trial included women at higher baseline risk for PTB (> 1 prior PTB and at least 1 other risk factor for PTB). Additionally, while the PROLONG trial included mostly white (90%), married (90%), nonsmoking women (8% smoked), the Meis trial population was 59% black and 50% married, and 20% were smokers.  

The availability and common use of 17-OHPC in the United States likely led to a selection bias for the PROLONG trial population, as the highest-risk patients were most likely already receiving treatment and were therefore excluded from the PROLONG trial. 

Society, and FDA, responses to the new data 

The results of the PROLONG trial call into question what has become standard practice for patients with a history of spontaneous PTB in the United States. While the safety profile of 17-OHPC has not been cited as a concern, whether or not the drug should be used at all has—as has its current FDA-approved status. 

In response to the publication of the PROLONG trial results, ACOG released a Practice Advisory that acknowledged the study's findings but did not alter the current recommendations to continue to offer progesterone for the prevention of preterm birth, upholding ACOG's current Practice Bulletin guidance.^2,4 Additional considerations for offering 17-OHPC use include the patients' preferences, available resources, and the setting for the intervention.  

SMFM's response was more specific, stating that it is reasonable to continue to use 17-OHPC in high-risk patient populations consistent with those in the Meis trial.⁵ In the rest of the general population at risk for recurrent PTB, SMFM recommends that, due to uncertain benefit with 17-OHPC, the high cost, patient discomfort, and increased visits should be taken into account.  

Four days after the publication of the PROLONG study, the FDA Bone, Reproductive, and Urologic Drugs Advisory Committee voted 9-7 to withdraw approval for 17-OHPC.⁶ In response, SMFM released a statement supporting continued access to 17-OHPC.⁷ The FDA's final decision on the status of the drug is expected within the next several months from this writing. 

Continue to: ACOG updates guidance on preventing early-onset GBS disease...

ACOG updates guidance on preventing early-onset GBS disease 

American College of Obstetricians and Gynecologists—Committee on Obstetric Practice. ACOG committee opinion no. 782: prevention of early-onset group B streptococcal disease in newborns. Obstet Gynecol. 2019;134:e19-e40. 

Group B streptococcus (GBS) is the leading cause of newborn infection and is associated with maternal infections as well as preterm labor and stillbirth. Early-onset GBS disease occurs within 7 days of birth and is linked to vertical transmission via maternal colonization of the genitourinary or gastrointestinal tract and fetal/neonatal aspiration at birth.  

Preventing early-onset GBS disease with maternal screening and intrapartum prophylaxis according to the Centers for Disease Control and Prevention (CDC) guidelines has reduced early-onset disease by 80% since the 1990s. By contrast, late-onset GBS infection, which occurs 7 days to 3 months after birth, usually is associated with horizontal maternal transmission or hospital or community infections, and it is not prevented by intrapartum treatment. 

In 2018, the CDC transferred responsibility for GBS prophylaxis guidelines to ACOG and the American Academy of Pediatrics (AAP). In July 2019, ACOG released its Committee Opinion on preventing early-onset GBS disease in newborns.⁸ This guidance replaces and updates the previous guidelines, with 3 notable changes.  

The screening timing has changed 

In the CDC's 2010 guidelines, GBS screening was recommended to start at 35 weeks' gestation. The new guidelines recommend universal vaginal-rectal screening at 36 to 37 6/7 weeks' gestation. The new timing of culture will shift the expected 5-week window in which GBS cultures are considered valid up to at least 41 weeks' gestation. The rationale  for this change is that any GBS-unknown patient who previously would have been cultured under 37 weeks' would be an automatic candidate for empiric therapy and the lower rate of birth in the 35th versus the 41st week of gestation. 

Identifying candidates for intrapartum treatment 

The usual indications for intrapartum antibiotic prophylaxis include a GBS-positive culture at 36 weeks or beyond, GBS bacteriuria at any point in pregnancy, a prior GBS-affected child, or unknown GBS status with any of the following: < 37 weeks, rupture of membranes ≥ 18 hours or temperature ≥ 100.4°F (38°C), and a positive rapid GBS culture in labor. In addition, antibiotics now should be considered for patients at term with unknown GBS status but with a history of GBS colonization in a prior pregnancy.  

This represents a major practice change for women at ≥ 37 weeks with unknown GBS status and no other traditional risk factors. The rationale for this recommendation is that women who have been positive for GBS in a prior pregnancy have a 50% chance of being colonized in the current pregnancy, and their newborns are therefore at higher risk for early-onset GBS disease.  

Managing patients with penicillin allergy 

Intravenous penicillin (or ampicillin) remains the antibiotic of choice for intrapartum prophylaxis against GBS due to its efficacy and specific, narrow coverage of gram-positive organisms. The updated recommendations emphasize that it is important to carefully evaluate patients with reported penicillin allergies for several reasons: determining risk of anaphylaxis and clindamycin susceptibility testing in GBS evaluations are often overlooked by obstetric providers, the need for antibiotic stewardship to reduce the development of antibiotic resistance, and clarification of allergy status for future health care needs. 

Three recommendations are made: 

• Laboratory requisitions for cultures should specifically note a penicillin allergy so that clindamycin susceptibility testing can be performed. 
• Penicillin allergy skin testing should be considered for patients at unknown or low risk for anaphylaxis, as it is considered safe in pregnancy and most patients (80%-90%) who report a penicillin allergy are actually penicillin tolerant. 
• For patients at high risk for anaphylaxis to penicillin, the recommended vancomycin dosing has been changed from 1 g IV every 12 hours to 20 mg/kg IV every 8 hours (maximum single dose, 2 g). Renal function should be assessed prior to dosing. This weight- and renal function-based dosing increased neonatal therapeutic levels in several studies of different doses.

Continue to: Managing hypertension in pregnancy: New recommendations...

Managing hypertension in pregnancy: New recommendations  

American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 202. Gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133:e1-e25. 

In 2013, ACOG released "Hypertension in pregnancy," a 99-page comprehensive document developed by their Task Force on Hypertension in Pregnancy, to summarize knowledge on the subject, provide guidelines for management, and identify needed areas of research.⁹ I summarized key points from that document in the 2014 "Update on Obstetrics" (OBG Manag. 2013;26[1]:28-36). Now, ACOG has released 2 Practice Bulletins—"Gestational hypertension and preeclampsia" and "Chronic hypertension in pregnancy"—that replace the 2013 document.^10,11 These Practice Bulletins are quite comprehensive and warrant a thorough read. Several noteworthy changes relevant to the practicing obstetrician are summarized below. 

Highlights of revised guidance 

Expectant management vs early delivery in preeclampsia with fetal growth restriction. Fetal growth restriction, which was removed from the definition of preeclampsia with severe features in 2013, is no longer an indication for delivery in preeclampsia with severe features (previously, if the estimated fetal weight was < 5th percentile for gestational age, delivery after steroid administration was recommended). Rather, expectant management is reasonable if fetal antenatal testing, amniotic fluid, and Doppler ultrasound studies are reassuring. Abnormal umbilical artery Doppler studies continue to be an indication for earlier delivery. 

Postpartum NSAID use in hypertension. The 2013 document cautioned against nonsteroidal anti-inflammatory drug (NSAID) use postpartum in women with hypertensive disorders of pregnancy because of concern for exacerbating hypertension. The updated Practice Bulletins recommend NSAIDs as the preferred choice over opioid analgesics as data have not shown these drugs to increase blood pressure, antihypertensive requirements, or other adverse events in postpartum patients with blood pressure issues. 

More women will be diagnosed with chronic hypertension. Recently, the American College of Cardiology and the American Heart Association changed the definition of hypertension. Stage 1 hypertension is now defined as a systolic blood pressure of 130-139 mm Hg or a diastolic blood pressure of 80-89 mm Hg. Treatment of stage 1 hypertension is recommended for nonpregnant adults with risk factors for current or future cardiovascular disease. The potential impact is that more women will enter pregnancy with a diagnosis of chronic hypertension, and more may be on prepregnancy antihypertensive therapy that will need to be addressed during the pregnancy.  

Blood pressure goals. The target blood pressure range for pregnant women with chronic hypertension is recommended to be ≥ 120/80 mm Hg and < 160/110 mm Hg (this represents a slight change, as previously diastolic blood pressure was to be < 105 mm Hg). Postpartum blood pressure goals of < 150/100 mm Hg remain the same. 

Managing acute hypertensive emergencies. Both Practice Bulletins emphasize the importance of aggressive management of acute hypertensive emergency, with options for 3 protocols: labetalol, nifedipine, and hydralazine. The goal is to administer antihypertensive therapy within 30 to 60 minutes, but administration as soon as feasibly possible after diagnosis of severe hypertension is ideal. 

Timing of delivery. Recommended delivery timing in patients with chronic hypertension was slightly altered (previous recommendations included a range of 37 to 39 6/7 weeks). The lower limit of gestational age for recommended delivery timing in chronic hypertension has not changed—it remains not before 38 weeks if no antihypertensive therapy and stable, and not before 37 weeks if antihypertensive therapy and stable.  

The upper limit of 39 6/7 weeks is challenged, however, because data support that induction of labor at either 38 or 39 weeks reduces the risk of severe hypertensive complications (such as superimposed preeclampsia and eclampsia) without increasing the risk of cesarean delivery. Therefore, for patients with chronic hypertension, expectant management beyond 39 weeks is cautioned, to be done only with careful consideration of risks and with close surveillance. 

Attributed to the ancient Greek philosopher Heraclitus, and often quoted in contemporary times, is the expression “the only constant is change.” This sentiment rings true for the field of obstetrics this past year, as several bread-and-butter guidelines for managing common obstetric conditions were either challenged or altered.

The publication of the PROLONG trial called into question the use of intramuscular progesterone for the prevention of preterm birth. Prophylaxis guidelines for group B streptococcal disease were updated, including several significant clinical practice changes. Finally, there was a comprehensive overhaul of the guidelines for hypertensive disorders of pregnancy, which replaced a landmark Task Force document from the American College of Obstetricians and Gynecologists (ACOG) that was published only a few years ago.

Change is constant, and in obstetrics it is vital to keep up with the changing guidelines that result as new data become available for digestion and implementation into everyday clinical practice.

Results from the PROLONG trial may shake up treatment options for recurrent preterm birth 

Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, et al. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): a multicenter, international, randomized double-blind trial. Am J Perinatol. 2019. doi: 10.1055/s-0039-3400227. 

The drug 17 α-hydroxyprogesterone caproate (17-OHPC, or 17P; Makena) was approved by the US Food and Drug Administration (FDA) in 2011 for the prevention of spontaneous preterm birth (PTB) in women with a singleton pregnancy and a history of singleton spontaneous PTB. The results of the trial by Meis and colleagues of 17-OHPC played a major role in achieving that approval, as it demonstrated a 34% reduction in recurrent PTB and a reduction in some neonatal morbidities.¹ Following the drug's approval, both ACOG and the Society for Maternal-Fetal Medicine (SMFM) published guidelines recommending progesterone therapy, including 17-OHPC, for the prevention of recurrent spontaneous PTB.²   

The FDA approval of 17-OHPC was granted under an accelerated conditional pathway that required a confirmatory trial evaluating efficacy, safety, and long-term infant follow-up to be performed by the sponsor. That trial, Progestin's Role in Optimizing Neonatal Gestation (PROLONG), was started in 2009, and its results were published on October 25, 2019.³ 

Continue to: Design of the trial...

Design of the trial 

PROLONG was a multicenter (93 sites), randomized, placebo-controlled, double-blind study conducted in 9 countries (23% of participants were in the United States, 60% were in Russia and Ukraine). The co-primary outcome was PTB < 35 weeks and a composite neonatal morbidity and mortality index. The primary safety outcome was fetal/early infant death. 

The study was designed to have 98% power to detect a 30% reduction in PTB < 35 weeks, and 90% power to detect a 35% reduction in the neonatal composite index. It included 1,708 participants (1,130 were treated with 17-OHPC, and 578 received placebo). 

Trial outcomes. There was no difference in PTB < 35 weeks between the 17-OHPC and the placebo groups (11.0% vs 11.5%; relative risk [RR], 0.95; 95% confidence interval [CI], 0.71-1.26). There was no difference in PTB < 32 or < 37 weeks. 

The study revealed also that there was no difference between groups in the neonatal composite index (5.6% for 17-OHPC vs 5.0% for placebo; RR, 1.12; 95% CI, 0.68-1.61). In addition, there was no difference in fetal/early infant death between the 17-OHPC and placebo groups (1.7% vs 1.9%; RR, 0.87; 95% CI, 0.4-1.81). 

Conclusions. The trial investigators concluded that 17-OHPC did not demonstrate a reduction in recurrent PTB and did not decrease neonatal morbidity. 

Study limitations included underpowering and selection bias 

The investigators noted that the PTB rate in PROLONG was unexpectedly almost 50% lower than that in the Meis trial, and that therefore the PROLONG trial was underpowered to assess the primary outcomes. 

Further, the study populations of the 2 trials were very different: The Meis trial included women at higher baseline risk for PTB (> 1 prior PTB and at least 1 other risk factor for PTB). Additionally, while the PROLONG trial included mostly white (90%), married (90%), nonsmoking women (8% smoked), the Meis trial population was 59% black and 50% married, and 20% were smokers.  

The availability and common use of 17-OHPC in the United States likely led to a selection bias for the PROLONG trial population, as the highest-risk patients were most likely already receiving treatment and were therefore excluded from the PROLONG trial. 

Society, and FDA, responses to the new data 

The results of the PROLONG trial call into question what has become standard practice for patients with a history of spontaneous PTB in the United States. While the safety profile of 17-OHPC has not been cited as a concern, whether or not the drug should be used at all has—as has its current FDA-approved status. 

In response to the publication of the PROLONG trial results, ACOG released a Practice Advisory that acknowledged the study's findings but did not alter the current recommendations to continue to offer progesterone for the prevention of preterm birth, upholding ACOG's current Practice Bulletin guidance.^2,4 Additional considerations for offering 17-OHPC use include the patients' preferences, available resources, and the setting for the intervention.  

SMFM's response was more specific, stating that it is reasonable to continue to use 17-OHPC in high-risk patient populations consistent with those in the Meis trial.⁵ In the rest of the general population at risk for recurrent PTB, SMFM recommends that, due to uncertain benefit with 17-OHPC, the high cost, patient discomfort, and increased visits should be taken into account.  

Four days after the publication of the PROLONG study, the FDA Bone, Reproductive, and Urologic Drugs Advisory Committee voted 9-7 to withdraw approval for 17-OHPC.⁶ In response, SMFM released a statement supporting continued access to 17-OHPC.⁷ The FDA's final decision on the status of the drug is expected within the next several months from this writing. 

Continue to: ACOG updates guidance on preventing early-onset GBS disease...

ACOG updates guidance on preventing early-onset GBS disease 

American College of Obstetricians and Gynecologists—Committee on Obstetric Practice. ACOG committee opinion no. 782: prevention of early-onset group B streptococcal disease in newborns. Obstet Gynecol. 2019;134:e19-e40. 

Group B streptococcus (GBS) is the leading cause of newborn infection and is associated with maternal infections as well as preterm labor and stillbirth. Early-onset GBS disease occurs within 7 days of birth and is linked to vertical transmission via maternal colonization of the genitourinary or gastrointestinal tract and fetal/neonatal aspiration at birth.  

Preventing early-onset GBS disease with maternal screening and intrapartum prophylaxis according to the Centers for Disease Control and Prevention (CDC) guidelines has reduced early-onset disease by 80% since the 1990s. By contrast, late-onset GBS infection, which occurs 7 days to 3 months after birth, usually is associated with horizontal maternal transmission or hospital or community infections, and it is not prevented by intrapartum treatment. 

In 2018, the CDC transferred responsibility for GBS prophylaxis guidelines to ACOG and the American Academy of Pediatrics (AAP). In July 2019, ACOG released its Committee Opinion on preventing early-onset GBS disease in newborns.⁸ This guidance replaces and updates the previous guidelines, with 3 notable changes.  

The screening timing has changed 

In the CDC's 2010 guidelines, GBS screening was recommended to start at 35 weeks' gestation. The new guidelines recommend universal vaginal-rectal screening at 36 to 37 6/7 weeks' gestation. The new timing of culture will shift the expected 5-week window in which GBS cultures are considered valid up to at least 41 weeks' gestation. The rationale  for this change is that any GBS-unknown patient who previously would have been cultured under 37 weeks' would be an automatic candidate for empiric therapy and the lower rate of birth in the 35th versus the 41st week of gestation. 

Identifying candidates for intrapartum treatment 

The usual indications for intrapartum antibiotic prophylaxis include a GBS-positive culture at 36 weeks or beyond, GBS bacteriuria at any point in pregnancy, a prior GBS-affected child, or unknown GBS status with any of the following: < 37 weeks, rupture of membranes ≥ 18 hours or temperature ≥ 100.4°F (38°C), and a positive rapid GBS culture in labor. In addition, antibiotics now should be considered for patients at term with unknown GBS status but with a history of GBS colonization in a prior pregnancy.  

This represents a major practice change for women at ≥ 37 weeks with unknown GBS status and no other traditional risk factors. The rationale for this recommendation is that women who have been positive for GBS in a prior pregnancy have a 50% chance of being colonized in the current pregnancy, and their newborns are therefore at higher risk for early-onset GBS disease.  

Managing patients with penicillin allergy 

Intravenous penicillin (or ampicillin) remains the antibiotic of choice for intrapartum prophylaxis against GBS due to its efficacy and specific, narrow coverage of gram-positive organisms. The updated recommendations emphasize that it is important to carefully evaluate patients with reported penicillin allergies for several reasons: determining risk of anaphylaxis and clindamycin susceptibility testing in GBS evaluations are often overlooked by obstetric providers, the need for antibiotic stewardship to reduce the development of antibiotic resistance, and clarification of allergy status for future health care needs. 

Three recommendations are made: 

• Laboratory requisitions for cultures should specifically note a penicillin allergy so that clindamycin susceptibility testing can be performed. 
• Penicillin allergy skin testing should be considered for patients at unknown or low risk for anaphylaxis, as it is considered safe in pregnancy and most patients (80%-90%) who report a penicillin allergy are actually penicillin tolerant. 
• For patients at high risk for anaphylaxis to penicillin, the recommended vancomycin dosing has been changed from 1 g IV every 12 hours to 20 mg/kg IV every 8 hours (maximum single dose, 2 g). Renal function should be assessed prior to dosing. This weight- and renal function-based dosing increased neonatal therapeutic levels in several studies of different doses.

Continue to: Managing hypertension in pregnancy: New recommendations...

Managing hypertension in pregnancy: New recommendations  

American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 202. Gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133:e1-e25. 

In 2013, ACOG released "Hypertension in pregnancy," a 99-page comprehensive document developed by their Task Force on Hypertension in Pregnancy, to summarize knowledge on the subject, provide guidelines for management, and identify needed areas of research.⁹ I summarized key points from that document in the 2014 "Update on Obstetrics" (OBG Manag. 2013;26[1]:28-36). Now, ACOG has released 2 Practice Bulletins—"Gestational hypertension and preeclampsia" and "Chronic hypertension in pregnancy"—that replace the 2013 document.^10,11 These Practice Bulletins are quite comprehensive and warrant a thorough read. Several noteworthy changes relevant to the practicing obstetrician are summarized below. 

Highlights of revised guidance 

Expectant management vs early delivery in preeclampsia with fetal growth restriction. Fetal growth restriction, which was removed from the definition of preeclampsia with severe features in 2013, is no longer an indication for delivery in preeclampsia with severe features (previously, if the estimated fetal weight was < 5th percentile for gestational age, delivery after steroid administration was recommended). Rather, expectant management is reasonable if fetal antenatal testing, amniotic fluid, and Doppler ultrasound studies are reassuring. Abnormal umbilical artery Doppler studies continue to be an indication for earlier delivery. 

Postpartum NSAID use in hypertension. The 2013 document cautioned against nonsteroidal anti-inflammatory drug (NSAID) use postpartum in women with hypertensive disorders of pregnancy because of concern for exacerbating hypertension. The updated Practice Bulletins recommend NSAIDs as the preferred choice over opioid analgesics as data have not shown these drugs to increase blood pressure, antihypertensive requirements, or other adverse events in postpartum patients with blood pressure issues. 

More women will be diagnosed with chronic hypertension. Recently, the American College of Cardiology and the American Heart Association changed the definition of hypertension. Stage 1 hypertension is now defined as a systolic blood pressure of 130-139 mm Hg or a diastolic blood pressure of 80-89 mm Hg. Treatment of stage 1 hypertension is recommended for nonpregnant adults with risk factors for current or future cardiovascular disease. The potential impact is that more women will enter pregnancy with a diagnosis of chronic hypertension, and more may be on prepregnancy antihypertensive therapy that will need to be addressed during the pregnancy.  

Blood pressure goals. The target blood pressure range for pregnant women with chronic hypertension is recommended to be ≥ 120/80 mm Hg and < 160/110 mm Hg (this represents a slight change, as previously diastolic blood pressure was to be < 105 mm Hg). Postpartum blood pressure goals of < 150/100 mm Hg remain the same. 

Managing acute hypertensive emergencies. Both Practice Bulletins emphasize the importance of aggressive management of acute hypertensive emergency, with options for 3 protocols: labetalol, nifedipine, and hydralazine. The goal is to administer antihypertensive therapy within 30 to 60 minutes, but administration as soon as feasibly possible after diagnosis of severe hypertension is ideal. 

Timing of delivery. Recommended delivery timing in patients with chronic hypertension was slightly altered (previous recommendations included a range of 37 to 39 6/7 weeks). The lower limit of gestational age for recommended delivery timing in chronic hypertension has not changed—it remains not before 38 weeks if no antihypertensive therapy and stable, and not before 37 weeks if antihypertensive therapy and stable.  

The upper limit of 39 6/7 weeks is challenged, however, because data support that induction of labor at either 38 or 39 weeks reduces the risk of severe hypertensive complications (such as superimposed preeclampsia and eclampsia) without increasing the risk of cesarean delivery. Therefore, for patients with chronic hypertension, expectant management beyond 39 weeks is cautioned, to be done only with careful consideration of risks and with close surveillance. 

Attributed to the ancient Greek philosopher Heraclitus, and often quoted in contemporary times, is the expression “the only constant is change.” This sentiment rings true for the field of obstetrics this past year, as several bread-and-butter guidelines for managing common obstetric conditions were either challenged or altered.

The publication of the PROLONG trial called into question the use of intramuscular progesterone for the prevention of preterm birth. Prophylaxis guidelines for group B streptococcal disease were updated, including several significant clinical practice changes. Finally, there was a comprehensive overhaul of the guidelines for hypertensive disorders of pregnancy, which replaced a landmark Task Force document from the American College of Obstetricians and Gynecologists (ACOG) that was published only a few years ago.

Change is constant, and in obstetrics it is vital to keep up with the changing guidelines that result as new data become available for digestion and implementation into everyday clinical practice.

Results from the PROLONG trial may shake up treatment options for recurrent preterm birth 

Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, et al. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): a multicenter, international, randomized double-blind trial. Am J Perinatol. 2019. doi: 10.1055/s-0039-3400227. 

The drug 17 α-hydroxyprogesterone caproate (17-OHPC, or 17P; Makena) was approved by the US Food and Drug Administration (FDA) in 2011 for the prevention of spontaneous preterm birth (PTB) in women with a singleton pregnancy and a history of singleton spontaneous PTB. The results of the trial by Meis and colleagues of 17-OHPC played a major role in achieving that approval, as it demonstrated a 34% reduction in recurrent PTB and a reduction in some neonatal morbidities.¹ Following the drug's approval, both ACOG and the Society for Maternal-Fetal Medicine (SMFM) published guidelines recommending progesterone therapy, including 17-OHPC, for the prevention of recurrent spontaneous PTB.²   

The FDA approval of 17-OHPC was granted under an accelerated conditional pathway that required a confirmatory trial evaluating efficacy, safety, and long-term infant follow-up to be performed by the sponsor. That trial, Progestin's Role in Optimizing Neonatal Gestation (PROLONG), was started in 2009, and its results were published on October 25, 2019.³ 

Continue to: Design of the trial...

Design of the trial 

PROLONG was a multicenter (93 sites), randomized, placebo-controlled, double-blind study conducted in 9 countries (23% of participants were in the United States, 60% were in Russia and Ukraine). The co-primary outcome was PTB < 35 weeks and a composite neonatal morbidity and mortality index. The primary safety outcome was fetal/early infant death. 

The study was designed to have 98% power to detect a 30% reduction in PTB < 35 weeks, and 90% power to detect a 35% reduction in the neonatal composite index. It included 1,708 participants (1,130 were treated with 17-OHPC, and 578 received placebo). 

Trial outcomes. There was no difference in PTB < 35 weeks between the 17-OHPC and the placebo groups (11.0% vs 11.5%; relative risk [RR], 0.95; 95% confidence interval [CI], 0.71-1.26). There was no difference in PTB < 32 or < 37 weeks. 

The study revealed also that there was no difference between groups in the neonatal composite index (5.6% for 17-OHPC vs 5.0% for placebo; RR, 1.12; 95% CI, 0.68-1.61). In addition, there was no difference in fetal/early infant death between the 17-OHPC and placebo groups (1.7% vs 1.9%; RR, 0.87; 95% CI, 0.4-1.81). 

Conclusions. The trial investigators concluded that 17-OHPC did not demonstrate a reduction in recurrent PTB and did not decrease neonatal morbidity. 

Study limitations included underpowering and selection bias 

The investigators noted that the PTB rate in PROLONG was unexpectedly almost 50% lower than that in the Meis trial, and that therefore the PROLONG trial was underpowered to assess the primary outcomes. 

Further, the study populations of the 2 trials were very different: The Meis trial included women at higher baseline risk for PTB (> 1 prior PTB and at least 1 other risk factor for PTB). Additionally, while the PROLONG trial included mostly white (90%), married (90%), nonsmoking women (8% smoked), the Meis trial population was 59% black and 50% married, and 20% were smokers.  

The availability and common use of 17-OHPC in the United States likely led to a selection bias for the PROLONG trial population, as the highest-risk patients were most likely already receiving treatment and were therefore excluded from the PROLONG trial. 

Society, and FDA, responses to the new data 

The results of the PROLONG trial call into question what has become standard practice for patients with a history of spontaneous PTB in the United States. While the safety profile of 17-OHPC has not been cited as a concern, whether or not the drug should be used at all has—as has its current FDA-approved status. 

In response to the publication of the PROLONG trial results, ACOG released a Practice Advisory that acknowledged the study's findings but did not alter the current recommendations to continue to offer progesterone for the prevention of preterm birth, upholding ACOG's current Practice Bulletin guidance.^2,4 Additional considerations for offering 17-OHPC use include the patients' preferences, available resources, and the setting for the intervention.  

SMFM's response was more specific, stating that it is reasonable to continue to use 17-OHPC in high-risk patient populations consistent with those in the Meis trial.⁵ In the rest of the general population at risk for recurrent PTB, SMFM recommends that, due to uncertain benefit with 17-OHPC, the high cost, patient discomfort, and increased visits should be taken into account.  

Four days after the publication of the PROLONG study, the FDA Bone, Reproductive, and Urologic Drugs Advisory Committee voted 9-7 to withdraw approval for 17-OHPC.⁶ In response, SMFM released a statement supporting continued access to 17-OHPC.⁷ The FDA's final decision on the status of the drug is expected within the next several months from this writing. 

Continue to: ACOG updates guidance on preventing early-onset GBS disease...

ACOG updates guidance on preventing early-onset GBS disease 

American College of Obstetricians and Gynecologists—Committee on Obstetric Practice. ACOG committee opinion no. 782: prevention of early-onset group B streptococcal disease in newborns. Obstet Gynecol. 2019;134:e19-e40. 

Group B streptococcus (GBS) is the leading cause of newborn infection and is associated with maternal infections as well as preterm labor and stillbirth. Early-onset GBS disease occurs within 7 days of birth and is linked to vertical transmission via maternal colonization of the genitourinary or gastrointestinal tract and fetal/neonatal aspiration at birth.  

Preventing early-onset GBS disease with maternal screening and intrapartum prophylaxis according to the Centers for Disease Control and Prevention (CDC) guidelines has reduced early-onset disease by 80% since the 1990s. By contrast, late-onset GBS infection, which occurs 7 days to 3 months after birth, usually is associated with horizontal maternal transmission or hospital or community infections, and it is not prevented by intrapartum treatment. 

In 2018, the CDC transferred responsibility for GBS prophylaxis guidelines to ACOG and the American Academy of Pediatrics (AAP). In July 2019, ACOG released its Committee Opinion on preventing early-onset GBS disease in newborns.⁸ This guidance replaces and updates the previous guidelines, with 3 notable changes.  

The screening timing has changed 

In the CDC's 2010 guidelines, GBS screening was recommended to start at 35 weeks' gestation. The new guidelines recommend universal vaginal-rectal screening at 36 to 37 6/7 weeks' gestation. The new timing of culture will shift the expected 5-week window in which GBS cultures are considered valid up to at least 41 weeks' gestation. The rationale  for this change is that any GBS-unknown patient who previously would have been cultured under 37 weeks' would be an automatic candidate for empiric therapy and the lower rate of birth in the 35th versus the 41st week of gestation. 

Identifying candidates for intrapartum treatment 

The usual indications for intrapartum antibiotic prophylaxis include a GBS-positive culture at 36 weeks or beyond, GBS bacteriuria at any point in pregnancy, a prior GBS-affected child, or unknown GBS status with any of the following: < 37 weeks, rupture of membranes ≥ 18 hours or temperature ≥ 100.4°F (38°C), and a positive rapid GBS culture in labor. In addition, antibiotics now should be considered for patients at term with unknown GBS status but with a history of GBS colonization in a prior pregnancy.  

This represents a major practice change for women at ≥ 37 weeks with unknown GBS status and no other traditional risk factors. The rationale for this recommendation is that women who have been positive for GBS in a prior pregnancy have a 50% chance of being colonized in the current pregnancy, and their newborns are therefore at higher risk for early-onset GBS disease.  

Managing patients with penicillin allergy 

Intravenous penicillin (or ampicillin) remains the antibiotic of choice for intrapartum prophylaxis against GBS due to its efficacy and specific, narrow coverage of gram-positive organisms. The updated recommendations emphasize that it is important to carefully evaluate patients with reported penicillin allergies for several reasons: determining risk of anaphylaxis and clindamycin susceptibility testing in GBS evaluations are often overlooked by obstetric providers, the need for antibiotic stewardship to reduce the development of antibiotic resistance, and clarification of allergy status for future health care needs. 

Three recommendations are made: 

• Laboratory requisitions for cultures should specifically note a penicillin allergy so that clindamycin susceptibility testing can be performed. 
• Penicillin allergy skin testing should be considered for patients at unknown or low risk for anaphylaxis, as it is considered safe in pregnancy and most patients (80%-90%) who report a penicillin allergy are actually penicillin tolerant. 
• For patients at high risk for anaphylaxis to penicillin, the recommended vancomycin dosing has been changed from 1 g IV every 12 hours to 20 mg/kg IV every 8 hours (maximum single dose, 2 g). Renal function should be assessed prior to dosing. This weight- and renal function-based dosing increased neonatal therapeutic levels in several studies of different doses.

Continue to: Managing hypertension in pregnancy: New recommendations...

Managing hypertension in pregnancy: New recommendations  

American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 202. Gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133:e1-e25. 

In 2013, ACOG released "Hypertension in pregnancy," a 99-page comprehensive document developed by their Task Force on Hypertension in Pregnancy, to summarize knowledge on the subject, provide guidelines for management, and identify needed areas of research.⁹ I summarized key points from that document in the 2014 "Update on Obstetrics" (OBG Manag. 2013;26[1]:28-36). Now, ACOG has released 2 Practice Bulletins—"Gestational hypertension and preeclampsia" and "Chronic hypertension in pregnancy"—that replace the 2013 document.^10,11 These Practice Bulletins are quite comprehensive and warrant a thorough read. Several noteworthy changes relevant to the practicing obstetrician are summarized below. 

Highlights of revised guidance 

Expectant management vs early delivery in preeclampsia with fetal growth restriction. Fetal growth restriction, which was removed from the definition of preeclampsia with severe features in 2013, is no longer an indication for delivery in preeclampsia with severe features (previously, if the estimated fetal weight was < 5th percentile for gestational age, delivery after steroid administration was recommended). Rather, expectant management is reasonable if fetal antenatal testing, amniotic fluid, and Doppler ultrasound studies are reassuring. Abnormal umbilical artery Doppler studies continue to be an indication for earlier delivery. 

Postpartum NSAID use in hypertension. The 2013 document cautioned against nonsteroidal anti-inflammatory drug (NSAID) use postpartum in women with hypertensive disorders of pregnancy because of concern for exacerbating hypertension. The updated Practice Bulletins recommend NSAIDs as the preferred choice over opioid analgesics as data have not shown these drugs to increase blood pressure, antihypertensive requirements, or other adverse events in postpartum patients with blood pressure issues. 

More women will be diagnosed with chronic hypertension. Recently, the American College of Cardiology and the American Heart Association changed the definition of hypertension. Stage 1 hypertension is now defined as a systolic blood pressure of 130-139 mm Hg or a diastolic blood pressure of 80-89 mm Hg. Treatment of stage 1 hypertension is recommended for nonpregnant adults with risk factors for current or future cardiovascular disease. The potential impact is that more women will enter pregnancy with a diagnosis of chronic hypertension, and more may be on prepregnancy antihypertensive therapy that will need to be addressed during the pregnancy.  

Blood pressure goals. The target blood pressure range for pregnant women with chronic hypertension is recommended to be ≥ 120/80 mm Hg and < 160/110 mm Hg (this represents a slight change, as previously diastolic blood pressure was to be < 105 mm Hg). Postpartum blood pressure goals of < 150/100 mm Hg remain the same. 

Managing acute hypertensive emergencies. Both Practice Bulletins emphasize the importance of aggressive management of acute hypertensive emergency, with options for 3 protocols: labetalol, nifedipine, and hydralazine. The goal is to administer antihypertensive therapy within 30 to 60 minutes, but administration as soon as feasibly possible after diagnosis of severe hypertension is ideal. 

Timing of delivery. Recommended delivery timing in patients with chronic hypertension was slightly altered (previous recommendations included a range of 37 to 39 6/7 weeks). The lower limit of gestational age for recommended delivery timing in chronic hypertension has not changed—it remains not before 38 weeks if no antihypertensive therapy and stable, and not before 37 weeks if antihypertensive therapy and stable.  

The upper limit of 39 6/7 weeks is challenged, however, because data support that induction of labor at either 38 or 39 weeks reduces the risk of severe hypertensive complications (such as superimposed preeclampsia and eclampsia) without increasing the risk of cesarean delivery. Therefore, for patients with chronic hypertension, expectant management beyond 39 weeks is cautioned, to be done only with careful consideration of risks and with close surveillance. 

Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939.

EXPERT COMMENTARY

Ovarian cancer represents the most lethal gynecologic cancer, with an estimated 14,000 deaths in 2019.¹ While the incidence of this disease is low in comparison to uterine cancer, the advanced stage at diagnosis portends poor prognosis. While stage is an independent risk factor for death, it is also a risk for recurrence, with more than 80% of women developing recurrent disease.^2-4 Secondary cytoreduction remains an option for patients in which disease recurs; up until now this management option was driven by retrospective data.⁵

Details of the study

Coleman and colleagues conducted the Gynecologic Oncology Group (GOG) 0213 trial—a phase 3, multicenter, randomized clinical trial that included 485 women with recurrent ovarian cancer. The surgical objective of the trial was to determine whether secondary cytoreduction in operable, platinum-sensitive (PS) patients improved overall survival (OS).

Patients were eligible to participate in the surgical portion of the trial if they had PS measurable disease and had the intention to achieve complete gross resection. Women with ascites, evidence of extraabdominal disease, and “diffuse carcinomatosis” were excluded. The primary and secondary end points were OS and progression-free survival (PFS), respectively.

Results. There were no statistical differences between the surgery and no surgery groups with regard to median OS (50.6 months vs 64.7 months, respectively; hazard ratio [HR], 1.29; 95% confidence interval [CI], 0.97–1.72) or median PFS (18.9 months vs 16.2 months; HR, 0.82; 95% CI, 0.66 to 1.01). When comparing patients in which complete gross resection was achieved (150 patients vs 245 who did not receive surgery), there was only a statistical difference in PFS in favor of the surgical group (22.4 months vs 16.2 months; HR, 0.62; 95% CI, 0.48–0.80).

Of note, 67% of the patients who received surgery (63% intention-to-treat) were debulked to complete gross resection. There were 33% more patients with extraabdominal disease (10% vs 7% of total patients in each group) and 15% more patients with upper abdominal disease (40% vs 33% of total patients in each group) included in the surgical group. Finally, the median time to chemotherapy was 40 days in the surgery group versus 7 days in the no surgery group.

Continue to: Study strengths and weaknesses...

Study strengths and weaknesses

The authors deserve to be commended for this well-designed and laborious trial, which is the first of its kind. The strength of the study is its randomized design producing level I data.

Study weaknesses include lack of reporting of BRCA status and the impact of receiving targeted therapies after the trial was over. It is well established that BRCA-mutated patients have an independent survival advantage, even when taking into account platinum sensitivity.^6-8BRCA status of the study population is not specifically addressed in this paper. The authors noted in the first GOG 0213 trial publication, which assessed bevacizumab in the recurrent setting, that BRCA status has an impact on patient outcomes. Subsequently, they state that they do not report BRCA status because “…its independent effect on response to an anti-angiogenesis agent was unknown,” but it clearly would affect survival analysis if unbalanced between groups.⁹

Similarly, in the introduction to their study, Coleman and colleagues list availability of maintenance therapy, for instance poly ADP (adenosine diphosphate–ribose) polymerase (PARP) inhibitors, as rationale for conducting their trial. They subsequently cite this as a possible reason that the median overall survival was 3 times longer than expected. However, they provide no data on which patients received maintenance therapy, which again could have drastically affected survival outcomes.¹⁰ They do report in the supplementary information that, when stratifying those receiving bevacizumab adjuvantly during the trial, the median OS was comparable between the surgical and nonsurgical groups (58.5 months vs 61.7 months).

The authors discuss the presence of patient selection bias as a weakness in the study. Selection bias is evident in this trial (as in many surgical trials) because patients with a limited volume of disease were selected to participate over those with large-volume disease. It is reasonable to conclude that this study is likely selecting patients with less aggressive tumor biology, not only evident by low-volume disease at recurrence but also by the 20.4-month median platinum-free interval in the surgical group, which certainly affects the trial’s validity. Despite being considered PS, the disease biology in a patient with a platinum-free interval of 20.4 months is surely different from the disease biology in a patient with a 6.4-month platinum-free interval; therefore, it is difficult to generalize these data to all PS recurrent ovarian cancer patients. Similarly, other research has suggested strict selection criteria, which was not apparent in this study’s methodology.¹¹ While the number of metastatic sites were relatively equal between the surgery and no surgery groups, there were more patients in the surgical group with extraabdominal disease, which the authors used as an exclusion criterion.

Lastly, the time to treatment commencement in each arm, which was 40 days for the surgical arm and 7 days in the nonsurgical arm, could represent a flaw in this trial. While we expect a difference in duration to account for recovery time, many centers start chemotherapy as soon as 21 days after surgery, which is almost half of the median interval in the surgical group in this trial. While the authors address this by stating that they completed a landmark analysis, no data or information about what time points they used for the analysis are provided. They simply report an interquartile range of 28 to 51 days. It is hard to know what effect this may have had on the outcome.

Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939.

EXPERT COMMENTARY

Ovarian cancer represents the most lethal gynecologic cancer, with an estimated 14,000 deaths in 2019.¹ While the incidence of this disease is low in comparison to uterine cancer, the advanced stage at diagnosis portends poor prognosis. While stage is an independent risk factor for death, it is also a risk for recurrence, with more than 80% of women developing recurrent disease.^2-4 Secondary cytoreduction remains an option for patients in which disease recurs; up until now this management option was driven by retrospective data.⁵

Details of the study

Coleman and colleagues conducted the Gynecologic Oncology Group (GOG) 0213 trial—a phase 3, multicenter, randomized clinical trial that included 485 women with recurrent ovarian cancer. The surgical objective of the trial was to determine whether secondary cytoreduction in operable, platinum-sensitive (PS) patients improved overall survival (OS).

Patients were eligible to participate in the surgical portion of the trial if they had PS measurable disease and had the intention to achieve complete gross resection. Women with ascites, evidence of extraabdominal disease, and “diffuse carcinomatosis” were excluded. The primary and secondary end points were OS and progression-free survival (PFS), respectively.

Results. There were no statistical differences between the surgery and no surgery groups with regard to median OS (50.6 months vs 64.7 months, respectively; hazard ratio [HR], 1.29; 95% confidence interval [CI], 0.97–1.72) or median PFS (18.9 months vs 16.2 months; HR, 0.82; 95% CI, 0.66 to 1.01). When comparing patients in which complete gross resection was achieved (150 patients vs 245 who did not receive surgery), there was only a statistical difference in PFS in favor of the surgical group (22.4 months vs 16.2 months; HR, 0.62; 95% CI, 0.48–0.80).

Of note, 67% of the patients who received surgery (63% intention-to-treat) were debulked to complete gross resection. There were 33% more patients with extraabdominal disease (10% vs 7% of total patients in each group) and 15% more patients with upper abdominal disease (40% vs 33% of total patients in each group) included in the surgical group. Finally, the median time to chemotherapy was 40 days in the surgery group versus 7 days in the no surgery group.

Continue to: Study strengths and weaknesses...

Study strengths and weaknesses

The authors deserve to be commended for this well-designed and laborious trial, which is the first of its kind. The strength of the study is its randomized design producing level I data.

Study weaknesses include lack of reporting of BRCA status and the impact of receiving targeted therapies after the trial was over. It is well established that BRCA-mutated patients have an independent survival advantage, even when taking into account platinum sensitivity.^6-8BRCA status of the study population is not specifically addressed in this paper. The authors noted in the first GOG 0213 trial publication, which assessed bevacizumab in the recurrent setting, that BRCA status has an impact on patient outcomes. Subsequently, they state that they do not report BRCA status because “…its independent effect on response to an anti-angiogenesis agent was unknown,” but it clearly would affect survival analysis if unbalanced between groups.⁹

Similarly, in the introduction to their study, Coleman and colleagues list availability of maintenance therapy, for instance poly ADP (adenosine diphosphate–ribose) polymerase (PARP) inhibitors, as rationale for conducting their trial. They subsequently cite this as a possible reason that the median overall survival was 3 times longer than expected. However, they provide no data on which patients received maintenance therapy, which again could have drastically affected survival outcomes.¹⁰ They do report in the supplementary information that, when stratifying those receiving bevacizumab adjuvantly during the trial, the median OS was comparable between the surgical and nonsurgical groups (58.5 months vs 61.7 months).

The authors discuss the presence of patient selection bias as a weakness in the study. Selection bias is evident in this trial (as in many surgical trials) because patients with a limited volume of disease were selected to participate over those with large-volume disease. It is reasonable to conclude that this study is likely selecting patients with less aggressive tumor biology, not only evident by low-volume disease at recurrence but also by the 20.4-month median platinum-free interval in the surgical group, which certainly affects the trial’s validity. Despite being considered PS, the disease biology in a patient with a platinum-free interval of 20.4 months is surely different from the disease biology in a patient with a 6.4-month platinum-free interval; therefore, it is difficult to generalize these data to all PS recurrent ovarian cancer patients. Similarly, other research has suggested strict selection criteria, which was not apparent in this study’s methodology.¹¹ While the number of metastatic sites were relatively equal between the surgery and no surgery groups, there were more patients in the surgical group with extraabdominal disease, which the authors used as an exclusion criterion.

Lastly, the time to treatment commencement in each arm, which was 40 days for the surgical arm and 7 days in the nonsurgical arm, could represent a flaw in this trial. While we expect a difference in duration to account for recovery time, many centers start chemotherapy as soon as 21 days after surgery, which is almost half of the median interval in the surgical group in this trial. While the authors address this by stating that they completed a landmark analysis, no data or information about what time points they used for the analysis are provided. They simply report an interquartile range of 28 to 51 days. It is hard to know what effect this may have had on the outcome.

Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939.

EXPERT COMMENTARY

Ovarian cancer represents the most lethal gynecologic cancer, with an estimated 14,000 deaths in 2019.¹ While the incidence of this disease is low in comparison to uterine cancer, the advanced stage at diagnosis portends poor prognosis. While stage is an independent risk factor for death, it is also a risk for recurrence, with more than 80% of women developing recurrent disease.^2-4 Secondary cytoreduction remains an option for patients in which disease recurs; up until now this management option was driven by retrospective data.⁵

Details of the study

Coleman and colleagues conducted the Gynecologic Oncology Group (GOG) 0213 trial—a phase 3, multicenter, randomized clinical trial that included 485 women with recurrent ovarian cancer. The surgical objective of the trial was to determine whether secondary cytoreduction in operable, platinum-sensitive (PS) patients improved overall survival (OS).

Patients were eligible to participate in the surgical portion of the trial if they had PS measurable disease and had the intention to achieve complete gross resection. Women with ascites, evidence of extraabdominal disease, and “diffuse carcinomatosis” were excluded. The primary and secondary end points were OS and progression-free survival (PFS), respectively.

Results. There were no statistical differences between the surgery and no surgery groups with regard to median OS (50.6 months vs 64.7 months, respectively; hazard ratio [HR], 1.29; 95% confidence interval [CI], 0.97–1.72) or median PFS (18.9 months vs 16.2 months; HR, 0.82; 95% CI, 0.66 to 1.01). When comparing patients in which complete gross resection was achieved (150 patients vs 245 who did not receive surgery), there was only a statistical difference in PFS in favor of the surgical group (22.4 months vs 16.2 months; HR, 0.62; 95% CI, 0.48–0.80).

Of note, 67% of the patients who received surgery (63% intention-to-treat) were debulked to complete gross resection. There were 33% more patients with extraabdominal disease (10% vs 7% of total patients in each group) and 15% more patients with upper abdominal disease (40% vs 33% of total patients in each group) included in the surgical group. Finally, the median time to chemotherapy was 40 days in the surgery group versus 7 days in the no surgery group.

Continue to: Study strengths and weaknesses...

Study strengths and weaknesses

The authors deserve to be commended for this well-designed and laborious trial, which is the first of its kind. The strength of the study is its randomized design producing level I data.

Study weaknesses include lack of reporting of BRCA status and the impact of receiving targeted therapies after the trial was over. It is well established that BRCA-mutated patients have an independent survival advantage, even when taking into account platinum sensitivity.^6-8BRCA status of the study population is not specifically addressed in this paper. The authors noted in the first GOG 0213 trial publication, which assessed bevacizumab in the recurrent setting, that BRCA status has an impact on patient outcomes. Subsequently, they state that they do not report BRCA status because “…its independent effect on response to an anti-angiogenesis agent was unknown,” but it clearly would affect survival analysis if unbalanced between groups.⁹

Similarly, in the introduction to their study, Coleman and colleagues list availability of maintenance therapy, for instance poly ADP (adenosine diphosphate–ribose) polymerase (PARP) inhibitors, as rationale for conducting their trial. They subsequently cite this as a possible reason that the median overall survival was 3 times longer than expected. However, they provide no data on which patients received maintenance therapy, which again could have drastically affected survival outcomes.¹⁰ They do report in the supplementary information that, when stratifying those receiving bevacizumab adjuvantly during the trial, the median OS was comparable between the surgical and nonsurgical groups (58.5 months vs 61.7 months).

The authors discuss the presence of patient selection bias as a weakness in the study. Selection bias is evident in this trial (as in many surgical trials) because patients with a limited volume of disease were selected to participate over those with large-volume disease. It is reasonable to conclude that this study is likely selecting patients with less aggressive tumor biology, not only evident by low-volume disease at recurrence but also by the 20.4-month median platinum-free interval in the surgical group, which certainly affects the trial’s validity. Despite being considered PS, the disease biology in a patient with a platinum-free interval of 20.4 months is surely different from the disease biology in a patient with a 6.4-month platinum-free interval; therefore, it is difficult to generalize these data to all PS recurrent ovarian cancer patients. Similarly, other research has suggested strict selection criteria, which was not apparent in this study’s methodology.¹¹ While the number of metastatic sites were relatively equal between the surgery and no surgery groups, there were more patients in the surgical group with extraabdominal disease, which the authors used as an exclusion criterion.

Lastly, the time to treatment commencement in each arm, which was 40 days for the surgical arm and 7 days in the nonsurgical arm, could represent a flaw in this trial. While we expect a difference in duration to account for recovery time, many centers start chemotherapy as soon as 21 days after surgery, which is almost half of the median interval in the surgical group in this trial. While the authors address this by stating that they completed a landmark analysis, no data or information about what time points they used for the analysis are provided. They simply report an interquartile range of 28 to 51 days. It is hard to know what effect this may have had on the outcome.

Polycystic ovary syndrome (PCOS) is the triad of oligo-ovulation resulting in oligomenorrhea, hyperandrogenism and, often, an excess number of small antral follicles on high-resolution pelvic ultrasound. One meta-analysis reported that, in women of reproductive age, the prevalence of PCOS was 10% using the Rotterdam-European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) criteria¹ and 6% using the National Institutes of Health 1990 diagnostic criteria.² (See “The PCOS trinity—3 findings in one syndrome: oligo-ovulation, hyperandrogenism, and a multifollicular ovary.”³)

PCOS is caused by abnormalities in 3 systems: reproductive, metabolic, and dermatologic. Reproductive abnormalities commonly observed in women with PCOS include⁴:

• an increase in pituitary secretion of luteinizing hormone (LH), resulting from both an increase in LH pulse amplitude and LH pulse frequency, suggesting a primary hypothalamic disorder
• an increase in ovarian secretion of androstenedione and testosterone due to stimulation by LH and possibly insulin
• oligo-ovulation with chronically low levels of progesterone that can result in endometrial hyperplasia
• ovulatory infertility.

Metabolic abnormalities commonly observed in women with PCOS include^5,6:

• insulin resistance and hyperinsulinemia
• excess adipose tissue in the liver
• excess visceral fat
• elevated adipokines
• obesity
• an increased prevalence of glucose intolerance and frank diabetes.

Dermatologic abnormalities commonly observed in women with PCOS include⁷:

• facial hirsutism
• acne
• androgenetic alopecia.

Given that PCOS is caused by abnormalities in the reproductive, metabolic, and dermatologic systems, it is appropriate to consider multimodal hormonal therapy that addresses all 3 problems. In my practice, I believe that the best approach to the long-term hormonal treatment of PCOS for many women is to prescribe a combination of 3 medicines: a combination estrogen-progestin oral contraceptive (COC), an insulin sensitizer, and an antiandrogen.

The COC reduces pituitary secretion of LH, decreases ovarian androgen production, and prevents the development of endometrial hyperplasia. When taken cyclically, the COC treatment also restores regular withdrawal uterine bleeding.

An insulin sensitizer, such as metformin or pioglitazone, helps to reduce insulin resistance, glucose intolerance, and hepatic adipose content, rebalancing central metabolism. It is important to include diet and exercise in the long-term treatment of PCOS, and I always encourage these lifestyle changes. However, my patients usually report that they have tried multiple times to restrict dietary caloric intake and increase exercise and have been unable to rebalance their metabolism with these interventions alone. Of note, in the women with PCOS and a body mass index >35 kg/m², bariatric surgery, such as a sleeve gastrectomy, often results in marked improvement of their PCOS.⁸

The antiandrogen spironolactone provides effective treatment for the dermatologic problems of facial hirsutism and acne. Some COCs containing the progestins drospirenone, norgestimate, and norethindrone acetate are approved by the US Food and Drug Administration for the treatment of acne. A common approach I use in practice is to prescribe a COC, plus spironolactone 100 mg daily plus metformin extended-release 750 mg to 1,500 mg daily.

Continue to: Which COCs have low androgenicity?...

Which COCs have low androgenicity?

I believe that every COC is an effective treatment for PCOS, regardless of the androgenicity of the progestin in the contraceptive. However, some dermatologists believe that combination contraceptives containing progestins with low androgenicity, such as drospirenone, norgestimate, and desogestrel, are more likely to improve acne than contraceptives with an androgenic progestin such as levonorgestrel. In one study in which 2,147 women with acne were treated by one dermatologic practice, the percentage of women reporting that a birth control pill helped to improve their acne was 66% for pills containing drospirenone, 53% for pills containing norgestimate, 44% for pills containing desogestrel, 30% for pills containing norethindrone, and 25% for pills containing levonorgestrel. In the same study, the percent of women reporting that a birth control pill made their acne worse was 3% for pills containing drospirenone, 6% for pills containing norgestimate, 2% for pills containing desogestrel, 8% for pills containing norethindrone, and 10% for pills containing levonorgestrel.⁹ Given these findings, when treating a woman with PCOS, I generally prescribe a contraceptive that does not contain levonorgestrel.

Why is a spironolactone dose of 100 mg a good choice for PCOS treatment?

Spironolactone, an antiandrogen and inhibitor of 5-alpha-reductase, is commonly prescribed for the treatment of hirsutism and acne at doses ranging from 50 mg to 200 mg daily.^10,11 In my clinical experience, spironolactone at a dose of 200 mg daily commonly causes irregular and bothersome uterine bleeding while spironolactone at a dose of 100 mg daily is seldom associated with irregular bleeding. I believe that spironolactone at a dose of 100 mg daily results in superior clinical efficacy than a 50-mg daily dose, although studies report that both doses are effective in the treatment of acne and hirsutism. Spironolactone should not be prescribed to women with renal failure because it can result in severe hyperkalemia. In a study of spironolactone safety in the treatment of acne, no adverse effects on the kidney, liver, or adrenal glands were reported over 8 years of use.¹²

What insulin sensitizers are useful in rebalancing the metabolic abnormalities observed with PCOS?

Diet and exercise are superb approaches to rebalancing metabolic abnormalities, but for many of my patients they are insufficient and treatment with an insulin sensitizer is warranted. The most commonly utilized insulin sensitizer for the treatment of PCOS is metformin because it is very inexpensive and has a low risk of serious adverse effects such as lactic acidosis. Metformin increases peripheral glucose uptake and reduces gastrointestinal glucose absorption. Insulin sensitizers also decrease visceral fat, a major source of adipokines. One major disadvantage of metformin is that at doses in the range of 1,500 mg to 2,250 mg it often causes gastrointestinal adverse effects such as borborygmi, nausea, abdominal discomfort, and loose stools.

Thiazolidinediones, including pioglitazone, have been reported to be effective in rebalancing central metabolism in women with PCOS. Pioglitazone carries a black box warning of an increased risk of congestive heart failure and nonfatal myocardial infarction. Pioglitazone is also associated with a risk of hepatotoxicity. However, at the pioglitazone dose commonly used in the treatment of PCOS (7.5 mg daily), these serious adverse effects are rare. In practice, I initiate metformin at a dose of 750 mg daily using the extended-release formulation. I increase the metformin dose to 1,500 mg daily if the patient has no bothersome gastrointestinal symptoms on the lower dose. If the patient cannot tolerate metformin treatment because of adverse effects, I will use pioglitazone 7.5 mg daily.

Continue to: Treatment of PCOS in women who are carriers of the Factor V Leiden mutation...

Treatment of PCOS in women who are carriers of the Factor V Leiden mutation

The Factor V Leiden allele is associated with an increased risk of venous thromboembolism. Estrogen-progestin contraception is contraindicated in women with the Factor V Leiden mutation. The prevalence of this mutation varies by race and ethnicity. It is present in about 5% of white, 2% of Hispanic, 1% of black, 1% of Native American, and 0.5% of Asian women. In women with PCOS who are known to be carriers of the mutation, dual therapy with metformin and spironolactone is highly effective.^13-15 For these women I also offer a levonorgestrel IUD to provide contraception and reduce the risk of endometrial hyperplasia.

Combination triple medication treatment of PCOS

Optimal treatment of the reproductive, metabolic, and dermatologic problems associated with PCOS requires multimodal medications including an estrogen-progestin contraceptive, an antiandrogen, and an insulin sensitizer. In my practice, I initiate treatment of PCOS by offering patients 3 medications: a COC, spironolactone 100 mg daily, and metformin extended-release formulation 750 mg daily. Some patients elect dual medication therapy (COC plus spironolactone or COC plus metformin), but many patients select treatment with all 3 medications. Although triple medication treatment of PCOS has not been tested in large randomized clinical trials, small trials report that triple medication treatment produces optimal improvement in the reproductive, metabolic, and dermatologic problems associated with PCOS.^16-18

Polycystic ovary syndrome (PCOS) is the triad of oligo-ovulation resulting in oligomenorrhea, hyperandrogenism and, often, an excess number of small antral follicles on high-resolution pelvic ultrasound. One meta-analysis reported that, in women of reproductive age, the prevalence of PCOS was 10% using the Rotterdam-European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) criteria¹ and 6% using the National Institutes of Health 1990 diagnostic criteria.² (See “The PCOS trinity—3 findings in one syndrome: oligo-ovulation, hyperandrogenism, and a multifollicular ovary.”³)

PCOS is caused by abnormalities in 3 systems: reproductive, metabolic, and dermatologic. Reproductive abnormalities commonly observed in women with PCOS include⁴:

• an increase in pituitary secretion of luteinizing hormone (LH), resulting from both an increase in LH pulse amplitude and LH pulse frequency, suggesting a primary hypothalamic disorder
• an increase in ovarian secretion of androstenedione and testosterone due to stimulation by LH and possibly insulin
• oligo-ovulation with chronically low levels of progesterone that can result in endometrial hyperplasia
• ovulatory infertility.

Metabolic abnormalities commonly observed in women with PCOS include^5,6:

• insulin resistance and hyperinsulinemia
• excess adipose tissue in the liver
• excess visceral fat
• elevated adipokines
• obesity
• an increased prevalence of glucose intolerance and frank diabetes.

Dermatologic abnormalities commonly observed in women with PCOS include⁷:

• facial hirsutism
• acne
• androgenetic alopecia.

Given that PCOS is caused by abnormalities in the reproductive, metabolic, and dermatologic systems, it is appropriate to consider multimodal hormonal therapy that addresses all 3 problems. In my practice, I believe that the best approach to the long-term hormonal treatment of PCOS for many women is to prescribe a combination of 3 medicines: a combination estrogen-progestin oral contraceptive (COC), an insulin sensitizer, and an antiandrogen.

The COC reduces pituitary secretion of LH, decreases ovarian androgen production, and prevents the development of endometrial hyperplasia. When taken cyclically, the COC treatment also restores regular withdrawal uterine bleeding.

An insulin sensitizer, such as metformin or pioglitazone, helps to reduce insulin resistance, glucose intolerance, and hepatic adipose content, rebalancing central metabolism. It is important to include diet and exercise in the long-term treatment of PCOS, and I always encourage these lifestyle changes. However, my patients usually report that they have tried multiple times to restrict dietary caloric intake and increase exercise and have been unable to rebalance their metabolism with these interventions alone. Of note, in the women with PCOS and a body mass index >35 kg/m², bariatric surgery, such as a sleeve gastrectomy, often results in marked improvement of their PCOS.⁸

The antiandrogen spironolactone provides effective treatment for the dermatologic problems of facial hirsutism and acne. Some COCs containing the progestins drospirenone, norgestimate, and norethindrone acetate are approved by the US Food and Drug Administration for the treatment of acne. A common approach I use in practice is to prescribe a COC, plus spironolactone 100 mg daily plus metformin extended-release 750 mg to 1,500 mg daily.

Continue to: Which COCs have low androgenicity?...

Which COCs have low androgenicity?

I believe that every COC is an effective treatment for PCOS, regardless of the androgenicity of the progestin in the contraceptive. However, some dermatologists believe that combination contraceptives containing progestins with low androgenicity, such as drospirenone, norgestimate, and desogestrel, are more likely to improve acne than contraceptives with an androgenic progestin such as levonorgestrel. In one study in which 2,147 women with acne were treated by one dermatologic practice, the percentage of women reporting that a birth control pill helped to improve their acne was 66% for pills containing drospirenone, 53% for pills containing norgestimate, 44% for pills containing desogestrel, 30% for pills containing norethindrone, and 25% for pills containing levonorgestrel. In the same study, the percent of women reporting that a birth control pill made their acne worse was 3% for pills containing drospirenone, 6% for pills containing norgestimate, 2% for pills containing desogestrel, 8% for pills containing norethindrone, and 10% for pills containing levonorgestrel.⁹ Given these findings, when treating a woman with PCOS, I generally prescribe a contraceptive that does not contain levonorgestrel.

Why is a spironolactone dose of 100 mg a good choice for PCOS treatment?

Spironolactone, an antiandrogen and inhibitor of 5-alpha-reductase, is commonly prescribed for the treatment of hirsutism and acne at doses ranging from 50 mg to 200 mg daily.^10,11 In my clinical experience, spironolactone at a dose of 200 mg daily commonly causes irregular and bothersome uterine bleeding while spironolactone at a dose of 100 mg daily is seldom associated with irregular bleeding. I believe that spironolactone at a dose of 100 mg daily results in superior clinical efficacy than a 50-mg daily dose, although studies report that both doses are effective in the treatment of acne and hirsutism. Spironolactone should not be prescribed to women with renal failure because it can result in severe hyperkalemia. In a study of spironolactone safety in the treatment of acne, no adverse effects on the kidney, liver, or adrenal glands were reported over 8 years of use.¹²

What insulin sensitizers are useful in rebalancing the metabolic abnormalities observed with PCOS?

Diet and exercise are superb approaches to rebalancing metabolic abnormalities, but for many of my patients they are insufficient and treatment with an insulin sensitizer is warranted. The most commonly utilized insulin sensitizer for the treatment of PCOS is metformin because it is very inexpensive and has a low risk of serious adverse effects such as lactic acidosis. Metformin increases peripheral glucose uptake and reduces gastrointestinal glucose absorption. Insulin sensitizers also decrease visceral fat, a major source of adipokines. One major disadvantage of metformin is that at doses in the range of 1,500 mg to 2,250 mg it often causes gastrointestinal adverse effects such as borborygmi, nausea, abdominal discomfort, and loose stools.

Thiazolidinediones, including pioglitazone, have been reported to be effective in rebalancing central metabolism in women with PCOS. Pioglitazone carries a black box warning of an increased risk of congestive heart failure and nonfatal myocardial infarction. Pioglitazone is also associated with a risk of hepatotoxicity. However, at the pioglitazone dose commonly used in the treatment of PCOS (7.5 mg daily), these serious adverse effects are rare. In practice, I initiate metformin at a dose of 750 mg daily using the extended-release formulation. I increase the metformin dose to 1,500 mg daily if the patient has no bothersome gastrointestinal symptoms on the lower dose. If the patient cannot tolerate metformin treatment because of adverse effects, I will use pioglitazone 7.5 mg daily.

Continue to: Treatment of PCOS in women who are carriers of the Factor V Leiden mutation...

Treatment of PCOS in women who are carriers of the Factor V Leiden mutation

The Factor V Leiden allele is associated with an increased risk of venous thromboembolism. Estrogen-progestin contraception is contraindicated in women with the Factor V Leiden mutation. The prevalence of this mutation varies by race and ethnicity. It is present in about 5% of white, 2% of Hispanic, 1% of black, 1% of Native American, and 0.5% of Asian women. In women with PCOS who are known to be carriers of the mutation, dual therapy with metformin and spironolactone is highly effective.^13-15 For these women I also offer a levonorgestrel IUD to provide contraception and reduce the risk of endometrial hyperplasia.

Combination triple medication treatment of PCOS

Optimal treatment of the reproductive, metabolic, and dermatologic problems associated with PCOS requires multimodal medications including an estrogen-progestin contraceptive, an antiandrogen, and an insulin sensitizer. In my practice, I initiate treatment of PCOS by offering patients 3 medications: a COC, spironolactone 100 mg daily, and metformin extended-release formulation 750 mg daily. Some patients elect dual medication therapy (COC plus spironolactone or COC plus metformin), but many patients select treatment with all 3 medications. Although triple medication treatment of PCOS has not been tested in large randomized clinical trials, small trials report that triple medication treatment produces optimal improvement in the reproductive, metabolic, and dermatologic problems associated with PCOS.^16-18

Polycystic ovary syndrome (PCOS) is the triad of oligo-ovulation resulting in oligomenorrhea, hyperandrogenism and, often, an excess number of small antral follicles on high-resolution pelvic ultrasound. One meta-analysis reported that, in women of reproductive age, the prevalence of PCOS was 10% using the Rotterdam-European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) criteria¹ and 6% using the National Institutes of Health 1990 diagnostic criteria.² (See “The PCOS trinity—3 findings in one syndrome: oligo-ovulation, hyperandrogenism, and a multifollicular ovary.”³)

PCOS is caused by abnormalities in 3 systems: reproductive, metabolic, and dermatologic. Reproductive abnormalities commonly observed in women with PCOS include⁴:

• an increase in pituitary secretion of luteinizing hormone (LH), resulting from both an increase in LH pulse amplitude and LH pulse frequency, suggesting a primary hypothalamic disorder
• an increase in ovarian secretion of androstenedione and testosterone due to stimulation by LH and possibly insulin
• oligo-ovulation with chronically low levels of progesterone that can result in endometrial hyperplasia
• ovulatory infertility.

Metabolic abnormalities commonly observed in women with PCOS include^5,6:

• insulin resistance and hyperinsulinemia
• excess adipose tissue in the liver
• excess visceral fat
• elevated adipokines
• obesity
• an increased prevalence of glucose intolerance and frank diabetes.

Dermatologic abnormalities commonly observed in women with PCOS include⁷:

• facial hirsutism
• acne
• androgenetic alopecia.

Given that PCOS is caused by abnormalities in the reproductive, metabolic, and dermatologic systems, it is appropriate to consider multimodal hormonal therapy that addresses all 3 problems. In my practice, I believe that the best approach to the long-term hormonal treatment of PCOS for many women is to prescribe a combination of 3 medicines: a combination estrogen-progestin oral contraceptive (COC), an insulin sensitizer, and an antiandrogen.

The COC reduces pituitary secretion of LH, decreases ovarian androgen production, and prevents the development of endometrial hyperplasia. When taken cyclically, the COC treatment also restores regular withdrawal uterine bleeding.

An insulin sensitizer, such as metformin or pioglitazone, helps to reduce insulin resistance, glucose intolerance, and hepatic adipose content, rebalancing central metabolism. It is important to include diet and exercise in the long-term treatment of PCOS, and I always encourage these lifestyle changes. However, my patients usually report that they have tried multiple times to restrict dietary caloric intake and increase exercise and have been unable to rebalance their metabolism with these interventions alone. Of note, in the women with PCOS and a body mass index >35 kg/m², bariatric surgery, such as a sleeve gastrectomy, often results in marked improvement of their PCOS.⁸

The antiandrogen spironolactone provides effective treatment for the dermatologic problems of facial hirsutism and acne. Some COCs containing the progestins drospirenone, norgestimate, and norethindrone acetate are approved by the US Food and Drug Administration for the treatment of acne. A common approach I use in practice is to prescribe a COC, plus spironolactone 100 mg daily plus metformin extended-release 750 mg to 1,500 mg daily.

Continue to: Which COCs have low androgenicity?...

Which COCs have low androgenicity?

I believe that every COC is an effective treatment for PCOS, regardless of the androgenicity of the progestin in the contraceptive. However, some dermatologists believe that combination contraceptives containing progestins with low androgenicity, such as drospirenone, norgestimate, and desogestrel, are more likely to improve acne than contraceptives with an androgenic progestin such as levonorgestrel. In one study in which 2,147 women with acne were treated by one dermatologic practice, the percentage of women reporting that a birth control pill helped to improve their acne was 66% for pills containing drospirenone, 53% for pills containing norgestimate, 44% for pills containing desogestrel, 30% for pills containing norethindrone, and 25% for pills containing levonorgestrel. In the same study, the percent of women reporting that a birth control pill made their acne worse was 3% for pills containing drospirenone, 6% for pills containing norgestimate, 2% for pills containing desogestrel, 8% for pills containing norethindrone, and 10% for pills containing levonorgestrel.⁹ Given these findings, when treating a woman with PCOS, I generally prescribe a contraceptive that does not contain levonorgestrel.

Why is a spironolactone dose of 100 mg a good choice for PCOS treatment?

Spironolactone, an antiandrogen and inhibitor of 5-alpha-reductase, is commonly prescribed for the treatment of hirsutism and acne at doses ranging from 50 mg to 200 mg daily.^10,11 In my clinical experience, spironolactone at a dose of 200 mg daily commonly causes irregular and bothersome uterine bleeding while spironolactone at a dose of 100 mg daily is seldom associated with irregular bleeding. I believe that spironolactone at a dose of 100 mg daily results in superior clinical efficacy than a 50-mg daily dose, although studies report that both doses are effective in the treatment of acne and hirsutism. Spironolactone should not be prescribed to women with renal failure because it can result in severe hyperkalemia. In a study of spironolactone safety in the treatment of acne, no adverse effects on the kidney, liver, or adrenal glands were reported over 8 years of use.¹²

What insulin sensitizers are useful in rebalancing the metabolic abnormalities observed with PCOS?

Diet and exercise are superb approaches to rebalancing metabolic abnormalities, but for many of my patients they are insufficient and treatment with an insulin sensitizer is warranted. The most commonly utilized insulin sensitizer for the treatment of PCOS is metformin because it is very inexpensive and has a low risk of serious adverse effects such as lactic acidosis. Metformin increases peripheral glucose uptake and reduces gastrointestinal glucose absorption. Insulin sensitizers also decrease visceral fat, a major source of adipokines. One major disadvantage of metformin is that at doses in the range of 1,500 mg to 2,250 mg it often causes gastrointestinal adverse effects such as borborygmi, nausea, abdominal discomfort, and loose stools.

Thiazolidinediones, including pioglitazone, have been reported to be effective in rebalancing central metabolism in women with PCOS. Pioglitazone carries a black box warning of an increased risk of congestive heart failure and nonfatal myocardial infarction. Pioglitazone is also associated with a risk of hepatotoxicity. However, at the pioglitazone dose commonly used in the treatment of PCOS (7.5 mg daily), these serious adverse effects are rare. In practice, I initiate metformin at a dose of 750 mg daily using the extended-release formulation. I increase the metformin dose to 1,500 mg daily if the patient has no bothersome gastrointestinal symptoms on the lower dose. If the patient cannot tolerate metformin treatment because of adverse effects, I will use pioglitazone 7.5 mg daily.

Continue to: Treatment of PCOS in women who are carriers of the Factor V Leiden mutation...

Treatment of PCOS in women who are carriers of the Factor V Leiden mutation

The Factor V Leiden allele is associated with an increased risk of venous thromboembolism. Estrogen-progestin contraception is contraindicated in women with the Factor V Leiden mutation. The prevalence of this mutation varies by race and ethnicity. It is present in about 5% of white, 2% of Hispanic, 1% of black, 1% of Native American, and 0.5% of Asian women. In women with PCOS who are known to be carriers of the mutation, dual therapy with metformin and spironolactone is highly effective.^13-15 For these women I also offer a levonorgestrel IUD to provide contraception and reduce the risk of endometrial hyperplasia.

Combination triple medication treatment of PCOS

Optimal treatment of the reproductive, metabolic, and dermatologic problems associated with PCOS requires multimodal medications including an estrogen-progestin contraceptive, an antiandrogen, and an insulin sensitizer. In my practice, I initiate treatment of PCOS by offering patients 3 medications: a COC, spironolactone 100 mg daily, and metformin extended-release formulation 750 mg daily. Some patients elect dual medication therapy (COC plus spironolactone or COC plus metformin), but many patients select treatment with all 3 medications. Although triple medication treatment of PCOS has not been tested in large randomized clinical trials, small trials report that triple medication treatment produces optimal improvement in the reproductive, metabolic, and dermatologic problems associated with PCOS.^16-18

Eating disorders affect nearly 1% of US adults,¹ and disordered eating, or unspecified eating disorder, affects at least 1% of all pregnancies.² Among 739 pregnant women assessed with the Eating Disorder Diagnostic scale, 7.5% of patients met criteria for an eating disorder, with 8.8% of women reporting binge eating and 2.3% of pregnant women engaging in regular compensatory behaviors. In fact, 23.4% of the study population expressed concerns about pregnancy-related weight gain and body shape.³ Eating disorders during pregnancy are more common than previously thought, and they create unique clinical challenges for obstetric providers.

Types of eating disorders

There are 3 major types of eating disorders: anorexia nervosa, bulimia nervosa, and binge eating disorder, with significant fluidity existing between all 3 conditions.

Anorexia nervosa is a condition in which an individual believes he or she is significantly overweight despite being underweight. Patients with anorexia nervosa often restrict food intake and have compulsive rituals around eating and exercise, leading to weight loss and starvation.⁴

Bulimia nervosa is marked by intensive dieting, uncontrolled episodes of overeating, and compensatory behaviors.⁴ Compensatory behaviors include self-induced vomiting; excessive exercise; and misuse of laxatives, diuretics, or other medications.

Binge eating disorder is classified as recurrent episodes of uncontrolled overeating without compensatory purging behaviors, leading to excessive weight gain.⁴

Eating disorders and pregnancy

Pregnancy can impact the course of pre­existing eating disorders, and women also can develop symptoms of eating disorders for the first time during pregnancy. This is clinically significant as there are both maternal and fetal consequences to a mother’s disordered eating.

The risks of anorexia nervosa include vitamin deficiencies (vitamin B12/folate), dehydration leading to renal injury and electrolyte imbalances, hypoglycemia, abnormal lipid profiles, cardiac arrhythmia, and even death. The mortality rate of patients with anorexia nervosa may approach 10%; however, death during pregnancy is quite rare.² Bulimia nervosa also carries the risks of protein and vitamin deficiencies, hypoglycemia and hyperglycemia, and death, with mortality estimated at 7% for those with a 5-year history of the illness. However, death in pregnancy due to the condition is again quite rare.⁵

Eating disorders can cause significant maternal and fetal complications during pregnancy and postpartum.

Maternal complications. When women with eating disorders become pregnant, they have increased risks of some pregnancy complications. Approximately 10% to 25% of pregnant women with eating disorders develop hyperemesis gravidarum.⁶ The nausea can serve as a trigger for a woman with an eating disorder, particularly among women with a history of purging behaviors.

Cesarean delivery is more common among women with eating disorders, which may be due to preexisting fetal compromise, leading to poor tolerance of labor, or to clinicians perceiving these pregnancies as higher risk.⁷

It is well known that eating disorders are highly comorbid with depression and other psychiatric conditions. In fact, 30% to 40% of women with an eating disorder develop symptoms of postpartum depression.⁸

Continue to: Fetal risks and complications...

Fetal risks and complications. Excessive caloric restriction and dieting can lead to folate deficiency, which in turn increases the risk of neural tube defects. Such defects are more common among women with eating disorders.⁹ Intrauterine growth restriction also can be a concern, most likely because of maternal malnutrition and poor maternal weight gain.¹⁰ In addition, women with eating disorders are more likely to have a preterm delivery or experience perinatal mortality or stillbirth.¹⁰

Bulimia nervosa is associated with low birthweight, while anorexia nervosa is associated with the very premature birth, low birthweight, and perinatal death.¹¹ Eating disorders during pregnancy can have long-term psychological impacts on children, including increased likelihood of childhood hyperactivity, conduct, and adjustment disorder.¹²

Assessing patients for an eating disorder

Diagnosis of eating disorders is an interview-guided process using clinical criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.⁴ The Eating Disorder Examination is a semi-structured interview composed of 4 subsections (restraint, eating concern, shape concern, and weight concern). The interview’s aim is to assess the psychopathology associated with eating disorders, and it is used in research settings rather than clinically.

1. Do you make yourself sick because you feel uncomfortably full?
2. Do you worry that you have lost control over how much you eat?
3. Have you recently lost more than one stone (14 lb) in a 3-month period?
4. Do you believe yourself to be fat when others say you are too thin?
5. Would you say that food dominates your life?

Referral. Patients for whom you have a concern for any eating disorder should be referred to a psychiatrist for formal diagnosis. Integrated multidisciplinary care of pregnant patients with eating disorders is necessary to improve maternal and fetal outcomes. Care teams should include obstetricians or maternal-fetal medicine clinicians experienced in caring for patients with eating disorders, psychiatrists, psychologists, nutritionists, and social workers. General treatment principles require an assessment for appropriate setting of intervention, which depends on presentation severity, assessment of nutritional status, treatment of psychiatric comorbidity, and psychotherapeutic intervention.

Overall management strategy

The initial treatment strategy for pregnant women with eating disorders should involve evaluating for severe illness and life-threatening complications of the specific disorder. All patients should be screened for suicidal ideation, severe malnutrition, electrolyte abnormalities, dehydration, hemodynamic instability, and cardiac arrhythmia. Patients with any of these severe features should be admitted for medical hospitalization and psychiatric evaluation.¹⁴ Patients that are hospitalized should be watched closely for refeeding syndrome—potentially life threatening metabolic disturbances that occur when nutrition is reinstituted to patients who are severely malnourished.

Patients without severe features or acute life-threatening complications can be managed safely on an outpatient basis with close medical monitoring. Psychiatric providers should be involved to assess for treatment needs including psychotherapy and psychotropic medications. There are numerous pharmacologic options available for patients, with the use of selective serotonin reuptake inhibitors (SSRIs) most common. While SSRI use has been controversial in pregnancy in the past, the risks of untreated illness carry risk to the mother and unborn child that outweigh the small risks associated with SSRI exposure in pregnancy.¹⁵

Women should have established care with a nutritionist or dietician who can ensure adequate counseling regarding meal planning and multivitamin supplementation. The numerous food restrictions in pregnancy, such as avoidance of unpasteurized cheese or deli meats, may be triggering for many patients with a history of restrictive eating.

One of the greatest difficulties for women with disordered eating in pregnancy revolves around weight gain. Many patients find the various measurements of pregnancy (maternal weight gain, fetal weight, fetal heart rate, and fundal height) triggering, which can make appropriate maternal and fetal weight gain in pregnancy very challenging. One strategy for managing this includes using fetal weight and growth as a surrogate for appropriate maternal gestational weight gain. One other strategy involves blind weights, where the woman is turned away from the scale so her weight is not disclosed to her. Patients often will not be able to achieve the expected 28 to 40 lb of pregnancy weight gain. It is best to have an open, honest conversation in early pregnancy to discuss how she would like to address weight in her pregnancy.

Continue to: Postpregnancy concerns...

Postpregnancy concerns

Patients with eating disorders are at high risk of relapse in the postpartum period, even if they are able to achieve full remission in pregnancy. Rapid postpartum weight loss may be a sign of disordered eating. Postpartum depression also is a concern, and women should be followed closely for surveillance of symptoms. Finally, postpartum contraception is extremely important. The menstrual irregularities that are common among women with eating disorders along with common misconceptions regarding fertility in the postpartum period increase the risk of unplanned pregnancy.

Remain cognizant of eating disorders

A clear surveillance plan early in the pregnancy that is developed in conjunction with the patient and her care team is crucial in improving maternal and fetal outcomes among women with an eating disorder. Clinician knowledge of complications and risks specific to disordered eating and pregnancy can affect outcomes for both mother and baby.

Eating disorders affect nearly 1% of US adults,¹ and disordered eating, or unspecified eating disorder, affects at least 1% of all pregnancies.² Among 739 pregnant women assessed with the Eating Disorder Diagnostic scale, 7.5% of patients met criteria for an eating disorder, with 8.8% of women reporting binge eating and 2.3% of pregnant women engaging in regular compensatory behaviors. In fact, 23.4% of the study population expressed concerns about pregnancy-related weight gain and body shape.³ Eating disorders during pregnancy are more common than previously thought, and they create unique clinical challenges for obstetric providers.

Types of eating disorders

There are 3 major types of eating disorders: anorexia nervosa, bulimia nervosa, and binge eating disorder, with significant fluidity existing between all 3 conditions.

Anorexia nervosa is a condition in which an individual believes he or she is significantly overweight despite being underweight. Patients with anorexia nervosa often restrict food intake and have compulsive rituals around eating and exercise, leading to weight loss and starvation.⁴

Bulimia nervosa is marked by intensive dieting, uncontrolled episodes of overeating, and compensatory behaviors.⁴ Compensatory behaviors include self-induced vomiting; excessive exercise; and misuse of laxatives, diuretics, or other medications.

Binge eating disorder is classified as recurrent episodes of uncontrolled overeating without compensatory purging behaviors, leading to excessive weight gain.⁴

Eating disorders and pregnancy

Pregnancy can impact the course of pre­existing eating disorders, and women also can develop symptoms of eating disorders for the first time during pregnancy. This is clinically significant as there are both maternal and fetal consequences to a mother’s disordered eating.

The risks of anorexia nervosa include vitamin deficiencies (vitamin B12/folate), dehydration leading to renal injury and electrolyte imbalances, hypoglycemia, abnormal lipid profiles, cardiac arrhythmia, and even death. The mortality rate of patients with anorexia nervosa may approach 10%; however, death during pregnancy is quite rare.² Bulimia nervosa also carries the risks of protein and vitamin deficiencies, hypoglycemia and hyperglycemia, and death, with mortality estimated at 7% for those with a 5-year history of the illness. However, death in pregnancy due to the condition is again quite rare.⁵

Eating disorders can cause significant maternal and fetal complications during pregnancy and postpartum.

Maternal complications. When women with eating disorders become pregnant, they have increased risks of some pregnancy complications. Approximately 10% to 25% of pregnant women with eating disorders develop hyperemesis gravidarum.⁶ The nausea can serve as a trigger for a woman with an eating disorder, particularly among women with a history of purging behaviors.

Cesarean delivery is more common among women with eating disorders, which may be due to preexisting fetal compromise, leading to poor tolerance of labor, or to clinicians perceiving these pregnancies as higher risk.⁷

It is well known that eating disorders are highly comorbid with depression and other psychiatric conditions. In fact, 30% to 40% of women with an eating disorder develop symptoms of postpartum depression.⁸

Continue to: Fetal risks and complications...

Fetal risks and complications. Excessive caloric restriction and dieting can lead to folate deficiency, which in turn increases the risk of neural tube defects. Such defects are more common among women with eating disorders.⁹ Intrauterine growth restriction also can be a concern, most likely because of maternal malnutrition and poor maternal weight gain.¹⁰ In addition, women with eating disorders are more likely to have a preterm delivery or experience perinatal mortality or stillbirth.¹⁰

Bulimia nervosa is associated with low birthweight, while anorexia nervosa is associated with the very premature birth, low birthweight, and perinatal death.¹¹ Eating disorders during pregnancy can have long-term psychological impacts on children, including increased likelihood of childhood hyperactivity, conduct, and adjustment disorder.¹²

Assessing patients for an eating disorder

Diagnosis of eating disorders is an interview-guided process using clinical criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.⁴ The Eating Disorder Examination is a semi-structured interview composed of 4 subsections (restraint, eating concern, shape concern, and weight concern). The interview’s aim is to assess the psychopathology associated with eating disorders, and it is used in research settings rather than clinically.

1. Do you make yourself sick because you feel uncomfortably full?
2. Do you worry that you have lost control over how much you eat?
3. Have you recently lost more than one stone (14 lb) in a 3-month period?
4. Do you believe yourself to be fat when others say you are too thin?
5. Would you say that food dominates your life?

Referral. Patients for whom you have a concern for any eating disorder should be referred to a psychiatrist for formal diagnosis. Integrated multidisciplinary care of pregnant patients with eating disorders is necessary to improve maternal and fetal outcomes. Care teams should include obstetricians or maternal-fetal medicine clinicians experienced in caring for patients with eating disorders, psychiatrists, psychologists, nutritionists, and social workers. General treatment principles require an assessment for appropriate setting of intervention, which depends on presentation severity, assessment of nutritional status, treatment of psychiatric comorbidity, and psychotherapeutic intervention.

Overall management strategy

The initial treatment strategy for pregnant women with eating disorders should involve evaluating for severe illness and life-threatening complications of the specific disorder. All patients should be screened for suicidal ideation, severe malnutrition, electrolyte abnormalities, dehydration, hemodynamic instability, and cardiac arrhythmia. Patients with any of these severe features should be admitted for medical hospitalization and psychiatric evaluation.¹⁴ Patients that are hospitalized should be watched closely for refeeding syndrome—potentially life threatening metabolic disturbances that occur when nutrition is reinstituted to patients who are severely malnourished.

Patients without severe features or acute life-threatening complications can be managed safely on an outpatient basis with close medical monitoring. Psychiatric providers should be involved to assess for treatment needs including psychotherapy and psychotropic medications. There are numerous pharmacologic options available for patients, with the use of selective serotonin reuptake inhibitors (SSRIs) most common. While SSRI use has been controversial in pregnancy in the past, the risks of untreated illness carry risk to the mother and unborn child that outweigh the small risks associated with SSRI exposure in pregnancy.¹⁵

Women should have established care with a nutritionist or dietician who can ensure adequate counseling regarding meal planning and multivitamin supplementation. The numerous food restrictions in pregnancy, such as avoidance of unpasteurized cheese or deli meats, may be triggering for many patients with a history of restrictive eating.

One of the greatest difficulties for women with disordered eating in pregnancy revolves around weight gain. Many patients find the various measurements of pregnancy (maternal weight gain, fetal weight, fetal heart rate, and fundal height) triggering, which can make appropriate maternal and fetal weight gain in pregnancy very challenging. One strategy for managing this includes using fetal weight and growth as a surrogate for appropriate maternal gestational weight gain. One other strategy involves blind weights, where the woman is turned away from the scale so her weight is not disclosed to her. Patients often will not be able to achieve the expected 28 to 40 lb of pregnancy weight gain. It is best to have an open, honest conversation in early pregnancy to discuss how she would like to address weight in her pregnancy.

Continue to: Postpregnancy concerns...

Postpregnancy concerns

Patients with eating disorders are at high risk of relapse in the postpartum period, even if they are able to achieve full remission in pregnancy. Rapid postpartum weight loss may be a sign of disordered eating. Postpartum depression also is a concern, and women should be followed closely for surveillance of symptoms. Finally, postpartum contraception is extremely important. The menstrual irregularities that are common among women with eating disorders along with common misconceptions regarding fertility in the postpartum period increase the risk of unplanned pregnancy.

Remain cognizant of eating disorders

A clear surveillance plan early in the pregnancy that is developed in conjunction with the patient and her care team is crucial in improving maternal and fetal outcomes among women with an eating disorder. Clinician knowledge of complications and risks specific to disordered eating and pregnancy can affect outcomes for both mother and baby.

Eating disorders affect nearly 1% of US adults,¹ and disordered eating, or unspecified eating disorder, affects at least 1% of all pregnancies.² Among 739 pregnant women assessed with the Eating Disorder Diagnostic scale, 7.5% of patients met criteria for an eating disorder, with 8.8% of women reporting binge eating and 2.3% of pregnant women engaging in regular compensatory behaviors. In fact, 23.4% of the study population expressed concerns about pregnancy-related weight gain and body shape.³ Eating disorders during pregnancy are more common than previously thought, and they create unique clinical challenges for obstetric providers.

Types of eating disorders

There are 3 major types of eating disorders: anorexia nervosa, bulimia nervosa, and binge eating disorder, with significant fluidity existing between all 3 conditions.

Anorexia nervosa is a condition in which an individual believes he or she is significantly overweight despite being underweight. Patients with anorexia nervosa often restrict food intake and have compulsive rituals around eating and exercise, leading to weight loss and starvation.⁴

Bulimia nervosa is marked by intensive dieting, uncontrolled episodes of overeating, and compensatory behaviors.⁴ Compensatory behaviors include self-induced vomiting; excessive exercise; and misuse of laxatives, diuretics, or other medications.

Binge eating disorder is classified as recurrent episodes of uncontrolled overeating without compensatory purging behaviors, leading to excessive weight gain.⁴

Eating disorders and pregnancy

Pregnancy can impact the course of pre­existing eating disorders, and women also can develop symptoms of eating disorders for the first time during pregnancy. This is clinically significant as there are both maternal and fetal consequences to a mother’s disordered eating.

The risks of anorexia nervosa include vitamin deficiencies (vitamin B12/folate), dehydration leading to renal injury and electrolyte imbalances, hypoglycemia, abnormal lipid profiles, cardiac arrhythmia, and even death. The mortality rate of patients with anorexia nervosa may approach 10%; however, death during pregnancy is quite rare.² Bulimia nervosa also carries the risks of protein and vitamin deficiencies, hypoglycemia and hyperglycemia, and death, with mortality estimated at 7% for those with a 5-year history of the illness. However, death in pregnancy due to the condition is again quite rare.⁵

Eating disorders can cause significant maternal and fetal complications during pregnancy and postpartum.

Maternal complications. When women with eating disorders become pregnant, they have increased risks of some pregnancy complications. Approximately 10% to 25% of pregnant women with eating disorders develop hyperemesis gravidarum.⁶ The nausea can serve as a trigger for a woman with an eating disorder, particularly among women with a history of purging behaviors.

Cesarean delivery is more common among women with eating disorders, which may be due to preexisting fetal compromise, leading to poor tolerance of labor, or to clinicians perceiving these pregnancies as higher risk.⁷

It is well known that eating disorders are highly comorbid with depression and other psychiatric conditions. In fact, 30% to 40% of women with an eating disorder develop symptoms of postpartum depression.⁸

Continue to: Fetal risks and complications...

Fetal risks and complications. Excessive caloric restriction and dieting can lead to folate deficiency, which in turn increases the risk of neural tube defects. Such defects are more common among women with eating disorders.⁹ Intrauterine growth restriction also can be a concern, most likely because of maternal malnutrition and poor maternal weight gain.¹⁰ In addition, women with eating disorders are more likely to have a preterm delivery or experience perinatal mortality or stillbirth.¹⁰

Bulimia nervosa is associated with low birthweight, while anorexia nervosa is associated with the very premature birth, low birthweight, and perinatal death.¹¹ Eating disorders during pregnancy can have long-term psychological impacts on children, including increased likelihood of childhood hyperactivity, conduct, and adjustment disorder.¹²

Assessing patients for an eating disorder

Diagnosis of eating disorders is an interview-guided process using clinical criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.⁴ The Eating Disorder Examination is a semi-structured interview composed of 4 subsections (restraint, eating concern, shape concern, and weight concern). The interview’s aim is to assess the psychopathology associated with eating disorders, and it is used in research settings rather than clinically.

1. Do you make yourself sick because you feel uncomfortably full?
2. Do you worry that you have lost control over how much you eat?
3. Have you recently lost more than one stone (14 lb) in a 3-month period?
4. Do you believe yourself to be fat when others say you are too thin?
5. Would you say that food dominates your life?

Referral. Patients for whom you have a concern for any eating disorder should be referred to a psychiatrist for formal diagnosis. Integrated multidisciplinary care of pregnant patients with eating disorders is necessary to improve maternal and fetal outcomes. Care teams should include obstetricians or maternal-fetal medicine clinicians experienced in caring for patients with eating disorders, psychiatrists, psychologists, nutritionists, and social workers. General treatment principles require an assessment for appropriate setting of intervention, which depends on presentation severity, assessment of nutritional status, treatment of psychiatric comorbidity, and psychotherapeutic intervention.

Overall management strategy

The initial treatment strategy for pregnant women with eating disorders should involve evaluating for severe illness and life-threatening complications of the specific disorder. All patients should be screened for suicidal ideation, severe malnutrition, electrolyte abnormalities, dehydration, hemodynamic instability, and cardiac arrhythmia. Patients with any of these severe features should be admitted for medical hospitalization and psychiatric evaluation.¹⁴ Patients that are hospitalized should be watched closely for refeeding syndrome—potentially life threatening metabolic disturbances that occur when nutrition is reinstituted to patients who are severely malnourished.

Patients without severe features or acute life-threatening complications can be managed safely on an outpatient basis with close medical monitoring. Psychiatric providers should be involved to assess for treatment needs including psychotherapy and psychotropic medications. There are numerous pharmacologic options available for patients, with the use of selective serotonin reuptake inhibitors (SSRIs) most common. While SSRI use has been controversial in pregnancy in the past, the risks of untreated illness carry risk to the mother and unborn child that outweigh the small risks associated with SSRI exposure in pregnancy.¹⁵

Women should have established care with a nutritionist or dietician who can ensure adequate counseling regarding meal planning and multivitamin supplementation. The numerous food restrictions in pregnancy, such as avoidance of unpasteurized cheese or deli meats, may be triggering for many patients with a history of restrictive eating.

One of the greatest difficulties for women with disordered eating in pregnancy revolves around weight gain. Many patients find the various measurements of pregnancy (maternal weight gain, fetal weight, fetal heart rate, and fundal height) triggering, which can make appropriate maternal and fetal weight gain in pregnancy very challenging. One strategy for managing this includes using fetal weight and growth as a surrogate for appropriate maternal gestational weight gain. One other strategy involves blind weights, where the woman is turned away from the scale so her weight is not disclosed to her. Patients often will not be able to achieve the expected 28 to 40 lb of pregnancy weight gain. It is best to have an open, honest conversation in early pregnancy to discuss how she would like to address weight in her pregnancy.

Continue to: Postpregnancy concerns...

Postpregnancy concerns

Patients with eating disorders are at high risk of relapse in the postpartum period, even if they are able to achieve full remission in pregnancy. Rapid postpartum weight loss may be a sign of disordered eating. Postpartum depression also is a concern, and women should be followed closely for surveillance of symptoms. Finally, postpartum contraception is extremely important. The menstrual irregularities that are common among women with eating disorders along with common misconceptions regarding fertility in the postpartum period increase the risk of unplanned pregnancy.

Remain cognizant of eating disorders

A clear surveillance plan early in the pregnancy that is developed in conjunction with the patient and her care team is crucial in improving maternal and fetal outcomes among women with an eating disorder. Clinician knowledge of complications and risks specific to disordered eating and pregnancy can affect outcomes for both mother and baby.

Whether or not women experience symptoms from uterine fibroid(s) can be dependent on a fibroid’s size and location. Heavy menstrual bleeding (HMB) is the most common symptom resulting from fibroids, and it occurs in up to one-third of women with fibroids. For fibroids that are large (>10 cm), “bulk” symptoms may occur, including pelvic pressure, urinary urgency or frequency, incontinence, constipation, abdominal protrusion, etc.¹

Elagolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was US Food and Drug Administration–approved in 2018 to treat moderate to severe pain caused by endometriosis. ² Elagolix is being evaluated in 2 phase 3 randomized, double-blind trials for the additional treatment of HMB associated with uterine fibroids. The results of these studies were presented at the 2019 AAGL meeting on November 12, in Vancouver, Canada.
 

Phase 3 study details

Premenopausal women aged 18 to 51 years were included in the Elaris UF-1 and UF-2 studies if they had HMB (defined using the alkaline hematin methodology as menstrual blood loss [MBL] >80 mL/cycle) and uterine fibroids as confirmed through ultrasound. Because elagolix suppresses estrogen and progesterone, treatment results in dose- and duration-dependent decreases in bone mineral density (BMD),² and add-back therapy can lessen these adverse effects. Subsequently, participants were randomly assigned 1:1:2 to placebo, elagolix 300 mg twice daily, or elagolix 300 mg twice daily with add-back therapy (1 mg estradiol/0.5 mg norethidrone acetate [E2/NETA]) once daily. Uterine volume and size and location of uterine fibroid(s) were assessed by ultrasound. Subgroups were defined by baseline FIGO categories, grouped FIGO 0-3, FIGO 4, or FIGO 5-8.³

Over the 6-month studies, 72.2% (95% confidence interval [CI], 67.65–76.73) of the 395 women who received elagolix plus E2/NETA achieved < 80 mL MBL during the final month and ≥ 50% MBL reduction from baseline to the final month. When stratified by FIGO classification, the results were similar for all subgroups: FIGO 0-3, 77.7% (95% CI, 67.21–80.85). Similar results were seen in women with a primary fibroid volume of either greater or less than 36.2 cm³ (median).³



The most frequently reported adverse events among women taking elagolix plus E2/NETA were hot flushes, night sweats, nausea, and headache. Changes in BMD among these women were not significant compared with women taking placebo.³

The Elaris UF-1 and UF-2 studies are funded by AbbVie Inc.

Whether or not women experience symptoms from uterine fibroid(s) can be dependent on a fibroid’s size and location. Heavy menstrual bleeding (HMB) is the most common symptom resulting from fibroids, and it occurs in up to one-third of women with fibroids. For fibroids that are large (>10 cm), “bulk” symptoms may occur, including pelvic pressure, urinary urgency or frequency, incontinence, constipation, abdominal protrusion, etc.¹

Elagolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was US Food and Drug Administration–approved in 2018 to treat moderate to severe pain caused by endometriosis. ² Elagolix is being evaluated in 2 phase 3 randomized, double-blind trials for the additional treatment of HMB associated with uterine fibroids. The results of these studies were presented at the 2019 AAGL meeting on November 12, in Vancouver, Canada.
 

Phase 3 study details

Premenopausal women aged 18 to 51 years were included in the Elaris UF-1 and UF-2 studies if they had HMB (defined using the alkaline hematin methodology as menstrual blood loss [MBL] >80 mL/cycle) and uterine fibroids as confirmed through ultrasound. Because elagolix suppresses estrogen and progesterone, treatment results in dose- and duration-dependent decreases in bone mineral density (BMD),² and add-back therapy can lessen these adverse effects. Subsequently, participants were randomly assigned 1:1:2 to placebo, elagolix 300 mg twice daily, or elagolix 300 mg twice daily with add-back therapy (1 mg estradiol/0.5 mg norethidrone acetate [E2/NETA]) once daily. Uterine volume and size and location of uterine fibroid(s) were assessed by ultrasound. Subgroups were defined by baseline FIGO categories, grouped FIGO 0-3, FIGO 4, or FIGO 5-8.³

Over the 6-month studies, 72.2% (95% confidence interval [CI], 67.65–76.73) of the 395 women who received elagolix plus E2/NETA achieved < 80 mL MBL during the final month and ≥ 50% MBL reduction from baseline to the final month. When stratified by FIGO classification, the results were similar for all subgroups: FIGO 0-3, 77.7% (95% CI, 67.21–80.85). Similar results were seen in women with a primary fibroid volume of either greater or less than 36.2 cm³ (median).³



The most frequently reported adverse events among women taking elagolix plus E2/NETA were hot flushes, night sweats, nausea, and headache. Changes in BMD among these women were not significant compared with women taking placebo.³

The Elaris UF-1 and UF-2 studies are funded by AbbVie Inc.

Whether or not women experience symptoms from uterine fibroid(s) can be dependent on a fibroid’s size and location. Heavy menstrual bleeding (HMB) is the most common symptom resulting from fibroids, and it occurs in up to one-third of women with fibroids. For fibroids that are large (>10 cm), “bulk” symptoms may occur, including pelvic pressure, urinary urgency or frequency, incontinence, constipation, abdominal protrusion, etc.¹

Elagolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was US Food and Drug Administration–approved in 2018 to treat moderate to severe pain caused by endometriosis. ² Elagolix is being evaluated in 2 phase 3 randomized, double-blind trials for the additional treatment of HMB associated with uterine fibroids. The results of these studies were presented at the 2019 AAGL meeting on November 12, in Vancouver, Canada.
 

Phase 3 study details

Premenopausal women aged 18 to 51 years were included in the Elaris UF-1 and UF-2 studies if they had HMB (defined using the alkaline hematin methodology as menstrual blood loss [MBL] >80 mL/cycle) and uterine fibroids as confirmed through ultrasound. Because elagolix suppresses estrogen and progesterone, treatment results in dose- and duration-dependent decreases in bone mineral density (BMD),² and add-back therapy can lessen these adverse effects. Subsequently, participants were randomly assigned 1:1:2 to placebo, elagolix 300 mg twice daily, or elagolix 300 mg twice daily with add-back therapy (1 mg estradiol/0.5 mg norethidrone acetate [E2/NETA]) once daily. Uterine volume and size and location of uterine fibroid(s) were assessed by ultrasound. Subgroups were defined by baseline FIGO categories, grouped FIGO 0-3, FIGO 4, or FIGO 5-8.³

Over the 6-month studies, 72.2% (95% confidence interval [CI], 67.65–76.73) of the 395 women who received elagolix plus E2/NETA achieved < 80 mL MBL during the final month and ≥ 50% MBL reduction from baseline to the final month. When stratified by FIGO classification, the results were similar for all subgroups: FIGO 0-3, 77.7% (95% CI, 67.21–80.85). Similar results were seen in women with a primary fibroid volume of either greater or less than 36.2 cm³ (median).³



The most frequently reported adverse events among women taking elagolix plus E2/NETA were hot flushes, night sweats, nausea, and headache. Changes in BMD among these women were not significant compared with women taking placebo.³

The Elaris UF-1 and UF-2 studies are funded by AbbVie Inc.

CASE New mother receives unneeded opioids after CD

A house officer wrote orders for a healthy patient who had just had an uncomplicated cesarean delivery (CD). The hospital’s tradition dictates orders for oxycodone plus acetaminophen tablets in addition to ibuprofen for all new mothers. At the time of the patient’s discharge, the same house officer prescribed 30 tablets of oxycodone plus acetaminophen “just in case,” although the patient had required only a few tablets while in the hospital on postoperative day 2 and none on the day of discharge.

Stuck in the habit

Prescribing postpartum opioids in the United States is almost habitual. Both optimizing patient satisfaction and minimizing patient phone calls may be driving this well-established pattern. Interestingly, a survey study of obstetric providers in 14 countries found that clinicians in 13 countries prescribe opioids “almost never” after vaginal delivery.¹ The United States was the 1 outlier, with providers reporting prescribing opioids “on a regular basis” after vaginal birth. Similarly, providers in 10 countries reported prescribing opioids “almost never” after CD, while those in the United States reported prescribing opioids “almost always” in this context.

Moreover, mounting data suggest that many patients do not require the quantity of opioids prescribed and that our overprescribing may be causing more harm than good.

The problem of overprescribing opioids after childbirth

Opioid analgesia has long been the mainstay of treatment for postpartum pain, which when poorly controlled is associated with the development of postpartum depression and chronic pain.² However, common adverse effects of opioids, including nausea, drowsiness, and dizziness, similarly can interfere with self-care and infant care. Of additional concern, a 2016 claims data study found that 1 of 300 opioid-naïve women who were prescribed opioids at discharge after CD used these medications persistently in the first year postpartum.³

Many women do not use the opioids that are prescribed to them at discharge, thus making tablets available for potential diversion into the community—a commonly recognized source of opioid misuse and abuse.^4,5 In a 2018 Committee Opinion on postpartum pain management, the American College of Obstetricians and Gynecologists (ACOG) stated that “a stepwise, multimodal approach emphasizing nonopioid analgesia as first-line therapy is safe and effective for vaginal deliveries and cesarean deliveries.”⁶ The Committee Opinion also asserted that “opioid medication is an adjunct for patients with uncontrolled pain despite adequate first-line therapy.”⁶

Despite efforts by the Centers for Disease Control and Prevention (CDC) and ACOG to improve opioid prescribing patterns after childbirth, the vast majority of women receive opioids in the hospital and at discharge not only after CD, but after vaginal delivery as well.^4,7 Why has tradition prevailed over data, and why have we not changed?

Continue to: Common misconceptions about reducing opioid use...

Common misconceptions about reducing opioid use

Two misconceptions persist regarding reducing opioid prescriptions for postpartum pain.

Misconception #1: Patients will be in pain

Randomized controlled trials that compared nonopioid with opioid regimens in the emergency room setting and opioid use after outpatient general surgery procedures have demonstrated that pain control for patients receiving opioids was equivalent to that for patients with pain managed with nonopioid regimens.^8-10 In the obstetric setting, a survey study of 720 women who underwent CD found that higher quantities of opioid tablets prescribed at discharge were not associated with improved pain, higher satisfaction, or lower refill rates at 2 weeks postpartum.⁴ However, greater quantities of opioids prescribed at the time of discharge were associated with greater opioid consumption.

Recently, several quality improvement studies implemented various interventions and successfully decreased postpartum opioid consumption without compromising pain management. One quality improvement project eliminated the routine use of opioids after CD and decreased the proportion of patients using any opioids in the hospital from 68% to 45%, with no changes in pain scores.¹¹ A similar study implemented an enhanced recovery after surgery (ERAS) program for women after CD; mean in-patient opioid use decreased from 10.7 to 5.4 average daily morphine equivalents, with improvement in the proportion of time that patients reported their pain as acceptable.¹²

Misconception #2: Clinicians will be overwhelmed with pages and phone calls

Providers commonly fear that decreasing opioid use will lead to an increased volume of pages and phone calls from patients requesting additional medication. However, data suggest otherwise. For example, a quality improvement study that eliminated the routine use of opioids after CD tracked the number of phone calls that were received requesting rescue opioid prescriptions after discharge.¹¹ Although the percentage of women discharged with opioids decreased from 90.6% to 40.3%, the requests for rescue opioid prescriptions did not change. Of 191 women, 4 requested a rescue prescription prior to the intervention compared with no women after the intervention. At the same time, according to unpublished data (Dr. Holland), satisfaction among nurses, house staff, and faculty did not change.

Similarly, a quality improvement project that implemented shared decision-making to inform the quantity of opioids prescribed at discharge demonstrated that the number of tablets prescribed decreased from 33.2 to 26.5, and there was no change in the rate of patients requesting opioid refills.¹³

Success stories: Strategies for reducing opioid use after childbirth

While overall rates of opioid prescribing after vaginal delivery and CD remain high throughout the United States, various institutions have developed successful and reproducible strategies to reduce opioid use after childbirth both in the hospital and at discharge. We highlight 3 strategies below.

Strategy 1: ERAS initiatives

An integrated health care system in northern California studied the effects of an ERAS protocol for CD across 15 medical centers.¹² The intervention centered on 4 pillars: multimodal pain management, early mobility, optimal nutrition, and patient engagement through education. Specifically, multimodal pain management consisted of the following:

• intrathecal opioids during CD
• scheduled intravenous acetaminophen for 24 hours followed by oral acetaminophen every 6 hours
• nonsteroidal anti-inflammatory drugs (NSAIDs) every 6 hours
• oral oxycodone for breakthrough pain
• decoupling of opioid medication from nonopioids in the post-CD order set
• decoupling of opioid and nonopioid medications in the discharge order set along with a reduction from 30 to 20 tablets as the default discharge quantity.

Continue to: Among 4,689 and 4,624 patients who underwent CD...

Among 4,689 and 4,624 patients who underwent CD before and after the intervention, the daily morphine milligram equivalents (MME) consumed in the hospital decreased from 10.7 to 5.4. The percentage of women who required no opioids while in the hospital increased from 8.3% to 21.4% after ERAS implementation, while the percentage of time that patients reported acceptable pain scores increased from 82.1% to 86.4%. The average number of opioid tablets prescribed at discharge also decreased, from 37 to 26 MME.¹² (The TABLE shows oxycodone doses converted to MMEs.)

Strategy 2: Order set change to eliminate routine use of opioids

A tertiary care center in Boston, Massachusetts, implemented a quality improvement project aimed at eliminating the routine use of opioid medication after CD through an order set change.¹¹ The intervention consisted of the following:

• intrathecal morphine
• multimodal postoperative pain management including scheduled oral acetaminophen for 72 hours followed by as-needed oral acetaminophen, scheduled NSAIDs for 72 hours followed by as-needed NSAIDs
• no postoperative order for opioids unless the patient had a contraindication to acetaminophen or NSAIDs, had a history of opioid dependence, or underwent complex surgery
• counseling patients that opioids were available for breakthrough pain if needed. In this case, nursing staff would page the responding clinician, who would order oxycodone 5 mg every 6 hours for 6 doses.
• specific criteria for discharge quantities of opioids: if the patient required no opioids in the hospital, she received no opioids at discharge; if the patient required opioids in the hospital but none at the time of discharge, she received no more than 10 tablets of oxycodone 5 mg; if the patient required opioids at the time of discharge, she received a maximum of 20 tablets of oxycodone 5 mg.

Among 191 and 181 women undergoing CD before and after the intervention, the percentage of patients who received any opioids in the hospital decreased from 68.1% to 45.3%.¹¹ Similarly, the percentage of patients receiving a discharge prescription for opioids decreased from 90.6% to 40.3%, while patient pain scores and satisfaction with pain control remained unchanged.

Strategy 3: Shared decision-making tool

Another tertiary care center in Boston evaluated the effects of a shared decision-making tool on opioid discharge prescribing after CD.¹⁵ The intervention consisted of a 10-minute clinician-facilitated session incorporating:

• education around anticipated patterns of postoperative pain
• expected outpatient opioid use after CD
• risks and benefits of opioids and nonopioids
• education around opioid disposal and access to refills.

Among the 50 women enrolled in the study, the number of oxycodone 5-mg tablets prescribed at discharge decreased from the institutional standard of 40 to 20. Ninety percent of women reported being satisfied or very satisfied with their pain control, while only 4 of 50 women required an opioid refill. A follow-up quality improvement project, which implemented the shared decision-making model along with a standardized multimodal pain management protocol, demonstrated a similar decrease in the quantity of opioids prescribed at discharge.¹³

Continue to: Change is here to stay: A new culture of postpartum analgesia...

Change is here to stay: A new culture of postpartum analgesia

The CDC continues to champion responsible opioid prescribing, while ACOG advocates for a reassessment of the way that opioids are utilized postpartum. The majority of women in the United States, however, continue to receive opioids after both vaginal delivery and CD. Consciously or not, we clinicians may be contributing to an outdated tradition that is potentially harmful both to patients and society. Reproducible strategies exist to reduce opioid use without compromising pain control or overwhelming clinicians with phone calls. It is time to embrace the change.

CASE New mother receives unneeded opioids after CD

A house officer wrote orders for a healthy patient who had just had an uncomplicated cesarean delivery (CD). The hospital’s tradition dictates orders for oxycodone plus acetaminophen tablets in addition to ibuprofen for all new mothers. At the time of the patient’s discharge, the same house officer prescribed 30 tablets of oxycodone plus acetaminophen “just in case,” although the patient had required only a few tablets while in the hospital on postoperative day 2 and none on the day of discharge.

Stuck in the habit

Prescribing postpartum opioids in the United States is almost habitual. Both optimizing patient satisfaction and minimizing patient phone calls may be driving this well-established pattern. Interestingly, a survey study of obstetric providers in 14 countries found that clinicians in 13 countries prescribe opioids “almost never” after vaginal delivery.¹ The United States was the 1 outlier, with providers reporting prescribing opioids “on a regular basis” after vaginal birth. Similarly, providers in 10 countries reported prescribing opioids “almost never” after CD, while those in the United States reported prescribing opioids “almost always” in this context.

Moreover, mounting data suggest that many patients do not require the quantity of opioids prescribed and that our overprescribing may be causing more harm than good.

The problem of overprescribing opioids after childbirth

Opioid analgesia has long been the mainstay of treatment for postpartum pain, which when poorly controlled is associated with the development of postpartum depression and chronic pain.² However, common adverse effects of opioids, including nausea, drowsiness, and dizziness, similarly can interfere with self-care and infant care. Of additional concern, a 2016 claims data study found that 1 of 300 opioid-naïve women who were prescribed opioids at discharge after CD used these medications persistently in the first year postpartum.³

Many women do not use the opioids that are prescribed to them at discharge, thus making tablets available for potential diversion into the community—a commonly recognized source of opioid misuse and abuse.^4,5 In a 2018 Committee Opinion on postpartum pain management, the American College of Obstetricians and Gynecologists (ACOG) stated that “a stepwise, multimodal approach emphasizing nonopioid analgesia as first-line therapy is safe and effective for vaginal deliveries and cesarean deliveries.”⁶ The Committee Opinion also asserted that “opioid medication is an adjunct for patients with uncontrolled pain despite adequate first-line therapy.”⁶

Despite efforts by the Centers for Disease Control and Prevention (CDC) and ACOG to improve opioid prescribing patterns after childbirth, the vast majority of women receive opioids in the hospital and at discharge not only after CD, but after vaginal delivery as well.^4,7 Why has tradition prevailed over data, and why have we not changed?

Continue to: Common misconceptions about reducing opioid use...

Common misconceptions about reducing opioid use

Two misconceptions persist regarding reducing opioid prescriptions for postpartum pain.

Misconception #1: Patients will be in pain

Randomized controlled trials that compared nonopioid with opioid regimens in the emergency room setting and opioid use after outpatient general surgery procedures have demonstrated that pain control for patients receiving opioids was equivalent to that for patients with pain managed with nonopioid regimens.^8-10 In the obstetric setting, a survey study of 720 women who underwent CD found that higher quantities of opioid tablets prescribed at discharge were not associated with improved pain, higher satisfaction, or lower refill rates at 2 weeks postpartum.⁴ However, greater quantities of opioids prescribed at the time of discharge were associated with greater opioid consumption.

Recently, several quality improvement studies implemented various interventions and successfully decreased postpartum opioid consumption without compromising pain management. One quality improvement project eliminated the routine use of opioids after CD and decreased the proportion of patients using any opioids in the hospital from 68% to 45%, with no changes in pain scores.¹¹ A similar study implemented an enhanced recovery after surgery (ERAS) program for women after CD; mean in-patient opioid use decreased from 10.7 to 5.4 average daily morphine equivalents, with improvement in the proportion of time that patients reported their pain as acceptable.¹²

Misconception #2: Clinicians will be overwhelmed with pages and phone calls

Providers commonly fear that decreasing opioid use will lead to an increased volume of pages and phone calls from patients requesting additional medication. However, data suggest otherwise. For example, a quality improvement study that eliminated the routine use of opioids after CD tracked the number of phone calls that were received requesting rescue opioid prescriptions after discharge.¹¹ Although the percentage of women discharged with opioids decreased from 90.6% to 40.3%, the requests for rescue opioid prescriptions did not change. Of 191 women, 4 requested a rescue prescription prior to the intervention compared with no women after the intervention. At the same time, according to unpublished data (Dr. Holland), satisfaction among nurses, house staff, and faculty did not change.

Similarly, a quality improvement project that implemented shared decision-making to inform the quantity of opioids prescribed at discharge demonstrated that the number of tablets prescribed decreased from 33.2 to 26.5, and there was no change in the rate of patients requesting opioid refills.¹³

Success stories: Strategies for reducing opioid use after childbirth

While overall rates of opioid prescribing after vaginal delivery and CD remain high throughout the United States, various institutions have developed successful and reproducible strategies to reduce opioid use after childbirth both in the hospital and at discharge. We highlight 3 strategies below.

Strategy 1: ERAS initiatives

An integrated health care system in northern California studied the effects of an ERAS protocol for CD across 15 medical centers.¹² The intervention centered on 4 pillars: multimodal pain management, early mobility, optimal nutrition, and patient engagement through education. Specifically, multimodal pain management consisted of the following:

• intrathecal opioids during CD
• scheduled intravenous acetaminophen for 24 hours followed by oral acetaminophen every 6 hours
• nonsteroidal anti-inflammatory drugs (NSAIDs) every 6 hours
• oral oxycodone for breakthrough pain
• decoupling of opioid medication from nonopioids in the post-CD order set
• decoupling of opioid and nonopioid medications in the discharge order set along with a reduction from 30 to 20 tablets as the default discharge quantity.

Continue to: Among 4,689 and 4,624 patients who underwent CD...

Among 4,689 and 4,624 patients who underwent CD before and after the intervention, the daily morphine milligram equivalents (MME) consumed in the hospital decreased from 10.7 to 5.4. The percentage of women who required no opioids while in the hospital increased from 8.3% to 21.4% after ERAS implementation, while the percentage of time that patients reported acceptable pain scores increased from 82.1% to 86.4%. The average number of opioid tablets prescribed at discharge also decreased, from 37 to 26 MME.¹² (The TABLE shows oxycodone doses converted to MMEs.)

Strategy 2: Order set change to eliminate routine use of opioids

A tertiary care center in Boston, Massachusetts, implemented a quality improvement project aimed at eliminating the routine use of opioid medication after CD through an order set change.¹¹ The intervention consisted of the following:

• intrathecal morphine
• multimodal postoperative pain management including scheduled oral acetaminophen for 72 hours followed by as-needed oral acetaminophen, scheduled NSAIDs for 72 hours followed by as-needed NSAIDs
• no postoperative order for opioids unless the patient had a contraindication to acetaminophen or NSAIDs, had a history of opioid dependence, or underwent complex surgery
• counseling patients that opioids were available for breakthrough pain if needed. In this case, nursing staff would page the responding clinician, who would order oxycodone 5 mg every 6 hours for 6 doses.
• specific criteria for discharge quantities of opioids: if the patient required no opioids in the hospital, she received no opioids at discharge; if the patient required opioids in the hospital but none at the time of discharge, she received no more than 10 tablets of oxycodone 5 mg; if the patient required opioids at the time of discharge, she received a maximum of 20 tablets of oxycodone 5 mg.

Among 191 and 181 women undergoing CD before and after the intervention, the percentage of patients who received any opioids in the hospital decreased from 68.1% to 45.3%.¹¹ Similarly, the percentage of patients receiving a discharge prescription for opioids decreased from 90.6% to 40.3%, while patient pain scores and satisfaction with pain control remained unchanged.

Strategy 3: Shared decision-making tool

Another tertiary care center in Boston evaluated the effects of a shared decision-making tool on opioid discharge prescribing after CD.¹⁵ The intervention consisted of a 10-minute clinician-facilitated session incorporating:

• education around anticipated patterns of postoperative pain
• expected outpatient opioid use after CD
• risks and benefits of opioids and nonopioids
• education around opioid disposal and access to refills.

Among the 50 women enrolled in the study, the number of oxycodone 5-mg tablets prescribed at discharge decreased from the institutional standard of 40 to 20. Ninety percent of women reported being satisfied or very satisfied with their pain control, while only 4 of 50 women required an opioid refill. A follow-up quality improvement project, which implemented the shared decision-making model along with a standardized multimodal pain management protocol, demonstrated a similar decrease in the quantity of opioids prescribed at discharge.¹³

Continue to: Change is here to stay: A new culture of postpartum analgesia...

Change is here to stay: A new culture of postpartum analgesia

The CDC continues to champion responsible opioid prescribing, while ACOG advocates for a reassessment of the way that opioids are utilized postpartum. The majority of women in the United States, however, continue to receive opioids after both vaginal delivery and CD. Consciously or not, we clinicians may be contributing to an outdated tradition that is potentially harmful both to patients and society. Reproducible strategies exist to reduce opioid use without compromising pain control or overwhelming clinicians with phone calls. It is time to embrace the change.

CASE New mother receives unneeded opioids after CD

A house officer wrote orders for a healthy patient who had just had an uncomplicated cesarean delivery (CD). The hospital’s tradition dictates orders for oxycodone plus acetaminophen tablets in addition to ibuprofen for all new mothers. At the time of the patient’s discharge, the same house officer prescribed 30 tablets of oxycodone plus acetaminophen “just in case,” although the patient had required only a few tablets while in the hospital on postoperative day 2 and none on the day of discharge.

Stuck in the habit

Prescribing postpartum opioids in the United States is almost habitual. Both optimizing patient satisfaction and minimizing patient phone calls may be driving this well-established pattern. Interestingly, a survey study of obstetric providers in 14 countries found that clinicians in 13 countries prescribe opioids “almost never” after vaginal delivery.¹ The United States was the 1 outlier, with providers reporting prescribing opioids “on a regular basis” after vaginal birth. Similarly, providers in 10 countries reported prescribing opioids “almost never” after CD, while those in the United States reported prescribing opioids “almost always” in this context.

Moreover, mounting data suggest that many patients do not require the quantity of opioids prescribed and that our overprescribing may be causing more harm than good.

The problem of overprescribing opioids after childbirth

Opioid analgesia has long been the mainstay of treatment for postpartum pain, which when poorly controlled is associated with the development of postpartum depression and chronic pain.² However, common adverse effects of opioids, including nausea, drowsiness, and dizziness, similarly can interfere with self-care and infant care. Of additional concern, a 2016 claims data study found that 1 of 300 opioid-naïve women who were prescribed opioids at discharge after CD used these medications persistently in the first year postpartum.³

Many women do not use the opioids that are prescribed to them at discharge, thus making tablets available for potential diversion into the community—a commonly recognized source of opioid misuse and abuse.^4,5 In a 2018 Committee Opinion on postpartum pain management, the American College of Obstetricians and Gynecologists (ACOG) stated that “a stepwise, multimodal approach emphasizing nonopioid analgesia as first-line therapy is safe and effective for vaginal deliveries and cesarean deliveries.”⁶ The Committee Opinion also asserted that “opioid medication is an adjunct for patients with uncontrolled pain despite adequate first-line therapy.”⁶

Despite efforts by the Centers for Disease Control and Prevention (CDC) and ACOG to improve opioid prescribing patterns after childbirth, the vast majority of women receive opioids in the hospital and at discharge not only after CD, but after vaginal delivery as well.^4,7 Why has tradition prevailed over data, and why have we not changed?

Continue to: Common misconceptions about reducing opioid use...

Common misconceptions about reducing opioid use

Two misconceptions persist regarding reducing opioid prescriptions for postpartum pain.

Misconception #1: Patients will be in pain

Randomized controlled trials that compared nonopioid with opioid regimens in the emergency room setting and opioid use after outpatient general surgery procedures have demonstrated that pain control for patients receiving opioids was equivalent to that for patients with pain managed with nonopioid regimens.^8-10 In the obstetric setting, a survey study of 720 women who underwent CD found that higher quantities of opioid tablets prescribed at discharge were not associated with improved pain, higher satisfaction, or lower refill rates at 2 weeks postpartum.⁴ However, greater quantities of opioids prescribed at the time of discharge were associated with greater opioid consumption.

Recently, several quality improvement studies implemented various interventions and successfully decreased postpartum opioid consumption without compromising pain management. One quality improvement project eliminated the routine use of opioids after CD and decreased the proportion of patients using any opioids in the hospital from 68% to 45%, with no changes in pain scores.¹¹ A similar study implemented an enhanced recovery after surgery (ERAS) program for women after CD; mean in-patient opioid use decreased from 10.7 to 5.4 average daily morphine equivalents, with improvement in the proportion of time that patients reported their pain as acceptable.¹²

Misconception #2: Clinicians will be overwhelmed with pages and phone calls

Providers commonly fear that decreasing opioid use will lead to an increased volume of pages and phone calls from patients requesting additional medication. However, data suggest otherwise. For example, a quality improvement study that eliminated the routine use of opioids after CD tracked the number of phone calls that were received requesting rescue opioid prescriptions after discharge.¹¹ Although the percentage of women discharged with opioids decreased from 90.6% to 40.3%, the requests for rescue opioid prescriptions did not change. Of 191 women, 4 requested a rescue prescription prior to the intervention compared with no women after the intervention. At the same time, according to unpublished data (Dr. Holland), satisfaction among nurses, house staff, and faculty did not change.

Similarly, a quality improvement project that implemented shared decision-making to inform the quantity of opioids prescribed at discharge demonstrated that the number of tablets prescribed decreased from 33.2 to 26.5, and there was no change in the rate of patients requesting opioid refills.¹³

Success stories: Strategies for reducing opioid use after childbirth

While overall rates of opioid prescribing after vaginal delivery and CD remain high throughout the United States, various institutions have developed successful and reproducible strategies to reduce opioid use after childbirth both in the hospital and at discharge. We highlight 3 strategies below.

Strategy 1: ERAS initiatives

An integrated health care system in northern California studied the effects of an ERAS protocol for CD across 15 medical centers.¹² The intervention centered on 4 pillars: multimodal pain management, early mobility, optimal nutrition, and patient engagement through education. Specifically, multimodal pain management consisted of the following:

• intrathecal opioids during CD
• scheduled intravenous acetaminophen for 24 hours followed by oral acetaminophen every 6 hours
• nonsteroidal anti-inflammatory drugs (NSAIDs) every 6 hours
• oral oxycodone for breakthrough pain
• decoupling of opioid medication from nonopioids in the post-CD order set
• decoupling of opioid and nonopioid medications in the discharge order set along with a reduction from 30 to 20 tablets as the default discharge quantity.

Continue to: Among 4,689 and 4,624 patients who underwent CD...

Among 4,689 and 4,624 patients who underwent CD before and after the intervention, the daily morphine milligram equivalents (MME) consumed in the hospital decreased from 10.7 to 5.4. The percentage of women who required no opioids while in the hospital increased from 8.3% to 21.4% after ERAS implementation, while the percentage of time that patients reported acceptable pain scores increased from 82.1% to 86.4%. The average number of opioid tablets prescribed at discharge also decreased, from 37 to 26 MME.¹² (The TABLE shows oxycodone doses converted to MMEs.)

Strategy 2: Order set change to eliminate routine use of opioids

A tertiary care center in Boston, Massachusetts, implemented a quality improvement project aimed at eliminating the routine use of opioid medication after CD through an order set change.¹¹ The intervention consisted of the following:

• intrathecal morphine
• multimodal postoperative pain management including scheduled oral acetaminophen for 72 hours followed by as-needed oral acetaminophen, scheduled NSAIDs for 72 hours followed by as-needed NSAIDs
• no postoperative order for opioids unless the patient had a contraindication to acetaminophen or NSAIDs, had a history of opioid dependence, or underwent complex surgery
• counseling patients that opioids were available for breakthrough pain if needed. In this case, nursing staff would page the responding clinician, who would order oxycodone 5 mg every 6 hours for 6 doses.
• specific criteria for discharge quantities of opioids: if the patient required no opioids in the hospital, she received no opioids at discharge; if the patient required opioids in the hospital but none at the time of discharge, she received no more than 10 tablets of oxycodone 5 mg; if the patient required opioids at the time of discharge, she received a maximum of 20 tablets of oxycodone 5 mg.

Among 191 and 181 women undergoing CD before and after the intervention, the percentage of patients who received any opioids in the hospital decreased from 68.1% to 45.3%.¹¹ Similarly, the percentage of patients receiving a discharge prescription for opioids decreased from 90.6% to 40.3%, while patient pain scores and satisfaction with pain control remained unchanged.

Strategy 3: Shared decision-making tool

Another tertiary care center in Boston evaluated the effects of a shared decision-making tool on opioid discharge prescribing after CD.¹⁵ The intervention consisted of a 10-minute clinician-facilitated session incorporating:

• education around anticipated patterns of postoperative pain
• expected outpatient opioid use after CD
• risks and benefits of opioids and nonopioids
• education around opioid disposal and access to refills.

Among the 50 women enrolled in the study, the number of oxycodone 5-mg tablets prescribed at discharge decreased from the institutional standard of 40 to 20. Ninety percent of women reported being satisfied or very satisfied with their pain control, while only 4 of 50 women required an opioid refill. A follow-up quality improvement project, which implemented the shared decision-making model along with a standardized multimodal pain management protocol, demonstrated a similar decrease in the quantity of opioids prescribed at discharge.¹³

Continue to: Change is here to stay: A new culture of postpartum analgesia...

Change is here to stay: A new culture of postpartum analgesia

The CDC continues to champion responsible opioid prescribing, while ACOG advocates for a reassessment of the way that opioids are utilized postpartum. The majority of women in the United States, however, continue to receive opioids after both vaginal delivery and CD. Consciously or not, we clinicians may be contributing to an outdated tradition that is potentially harmful both to patients and society. Reproducible strategies exist to reduce opioid use without compromising pain control or overwhelming clinicians with phone calls. It is time to embrace the change.

Medical malpractice (more formally, professional liability, but we will use the term malpractice) has been of concern to ObGyns for many years, and for good reasons. This specialty has some of the highest incidents of malpractice claims, some of the largest verdicts, and some of the highest malpractice insurance rates. We look more closely at ObGyn malpractice issues in a 3-part “What’s the Verdict” series over the next few months.

In part 1, we discuss the background on malpractice and reasons why malpractice rates have been so high—including large verdicts and lawsuit-prone physicians. In the second part we will look at recent experience and developments in malpractice exposure—who is sued and why. Finally, in the third part we will consider suggestions for reducing the likelihood of a malpractice lawsuit, with a special focus on recent research regarding apologies.

Two reports of recent trials involving ObGyn care illustrate the risk of “the big verdict.”^1,2 (Note that the following vignettes are drawn from actual cases but are outlines of those cases and not complete descriptions of the claims. Because the information does not come from formal court records, the facts may be inaccurate and are incomplete; they should be viewed as illustrations only.)

CASE 1 Delayed delivery, $19M verdict

At 39 weeks’ gestation, a woman was admitted to the hospital in spontaneous labor. Artificial rupture of membranes with clear amniotic fluid was noted. Active contractions occurred for 11 hours. Oxytocin was then initiated, and 17 minutes later, profound fetal bradycardia was detected. There was recurrent evidence of fetal distress with meconium. After a nursing staff change a second nurse restarted oxytocin for a prolonged period. The physician allowed labor to continue despite fetal distress, and performed a cesarean delivery (CD) 4.5 hours later. Five hours postdelivery the neonate was noted to have a pneumothorax, lung damage, and respiratory failure. The infant died at 18 days of age.

The jury felt that there was negligence—failure to timely diagnose fetal distress and failure to timely perform CD, all of which resulted in a verdict for the plaintiff. The jury awarded in excess of $19 million.¹

CASE 2 An undiagnosed tumor, $20M verdict

A patient underwent bilateral mastectomy. Following surgery, she reported pain and swelling at the surgical site for 2 years, and the defendant physician “dismissed” her complaint, refusing to evaluate it as the provider felt it was related to scar tissue. Three years after the mastectomies, the patient underwent surgical exploration and removal of 3 ribs and sternum secondary to a desmoid tumor. Surgical mesh and chest reconstruction was required, necessitating long-term opioids and sleeping medications that “will slow her wits, dull her senses and limit activities of daily living.” Of note, discrepancies were found in the medical records maintained by the defendant. (There was, for example, no report in the record of the plaintiff’s pain until late in the process.) The plaintiff based her claim on the fact that her pain and lump were neither evaluated nor discovered until it was too late.

The jury awarded $20 million. The verdict was reduced to $2 million by the court based on state statutory limits on malpractice damages.^2,3

Continue to: Medical malpractice: Evolution of a standard of care...

Medical malpractice: Evolution of a standard of care

Medical malpractice is not a modern invention. Some historians trace malpractice to the Code of Hammurabi (2030 BC), through Roman law,⁴ into English common law.⁵ It was sufficiently established by 1765 that the classic legal treatise of the century referred to medical malpractice.^6,7 Although medical malpractice existed for a long time, actual malpractice cases were relatively rare before the last half of the 20th century.⁸

Defensive medicine born out of necessity. The number of malpractice cases increased substantially—described as a “geometric increase”—after 1960, with a 300% rise between 1965 and 1970.^7,9 This “malpractice maelstrom of the 70s”⁷ resulted in dramatic increases in malpractice insurance costs and invited the practice of defensive medicine—medically unnecessary or unjustified tests and services.¹⁰Although there is controversy about what is defensive medicine and what is reasonably cautious medicine, the practice may account for 3% of total health care spending.¹¹ Mello and others have estimated that there may be a $55 billion annual cost related to the medical malpractice system.¹²

Several malpractice crises and waves of malpractice or tort reform ensued,¹³ beginning in the 1970s and extending into the 2000s.¹¹ Malpractice law is primarily a matter of state law, so reform essentially has been at the state level—as we will see in the second part in this series.

Defining a standard of care

Medical malpractice is the application of standard legal principles to medical practice. Those principles generally are torts (intentional torts and negligence), and sometimes contracts.¹⁴ Eventually, medical malpractice came to focus primarily on negligence. The legal purposes of imposing negligence liability are compensation (to repay the plaintiff the costs of the harm caused by the defendant) and deterrence (to discourage careless conduct that can harm others.)

Negligence is essentially carelessness that falls below the acceptable standard of care. Negligence may arise, for example, from¹⁵:

• doing something (giving a drug to a patient with a known allergy to it)
• not doing something (failing to test for a possible tumor, as in the second case above)
• not giving appropriate informed consent
• failing to conduct an adequate examination
• abandoning a patient
• failing to refer a patient to a specialist (or conduct a consultation).

(In recent years, law reforms directed specifically at medical malpractice have somewhat separated medical malpractice from other tort law.)

In malpractice cases, the core question is whether the provider did (or did not) do something that a reasonably careful physician would have done. It is axiomatic that not all bad outcomes are negligent. Indeed, not all mistakes are negligent—only the mistakes that were unreasonable given all of the circumstances. In the first case above, for example, given all of the facts that preceded it, the delay of the physician for 4.5 hours after the fetal distress started was, as seen by the jury, not just a mistake but an unreasonable mistake. Hence, it was negligent. In the second case, the failure to investigate the pain and swelling in the surgical site for 2 years (or failure to refer the patient to another physician) was seen by the jury as an unreasonable mistake—one that would not have been made by a reasonably careful practitioner.

Continue to: The big verdict...

The big verdict

Everyone—every professional providing service, every manufacturer, every driver—eventually will make an unreasonable mistake (ie, commit negligence). If that negligence results in harming someone else, our standard legal response is that the negligent person should be financially responsible for the harm to the other. So, a driver who fails to stop at a red light and hits another car is responsible for those damages. But the damages may vary—perhaps a banged-up fender, or, in another instance, with the same negligence, perhaps terrible personal injuries that will disable the other driver for life. Thus, the damages can vary for the same level of carelessness. The “big verdict” may therefore fall on someone who was not especially careless.

Big verdicts often involve long-term care. The opening case vignettes illustrate a concern of medical malpractice generally—especially for ObGyn practice—the very high verdict. Very high verdicts generally reflect catastrophic damages that will continue for a long time. Bixenstine and colleagues found, for example, that catastrophic payouts often involved “patient age less than 1 year, quadriplegia, brain damage, or lifelong care.”¹⁶ In the case of serious injuries during delivery, for example, the harm to the child may last a lifetime and require years and years of intensive medical services.

Million-dollar-plus payouts are on the rise. The percentage of paid claims (through settlement or trial) that are above $1 million is increasing. These million-dollar cases represent 36% of the total dollars paid in ObGyn malpractice claims, even though they represent only 8% of the number of claims paid.¹⁶ The increase in the big verdict cases (above $1 million) suggests that ObGyn practition­ers should consider their malpractice policy limits—a million dollars may not be enough.

In big verdict cases, the great harm to the plaintiff is often combined with facts that produce extraordinary sympathy for the plaintiff. Sometimes there is decidedly unsympathetic conduct by the defendant as well. In the second case, for example, the problems with the medical record may have suggested to the jury that the doctor was either trying to hide something or did not care enough about the patient even to note a serious complaint. In a case we reviewed in an earlier “What’s the Verdict” column, a physician left the room for several minutes during a critical time—to take a call from a stockbroker.^16-18

The big verdict does not necessarily suggest that the defendant was especially or grossly negligent.¹⁶ It was a bad injury that occurred, for instance. On the other hand, the physician with several malpractice judgments may suggest that this is a problem physician.

Physicians facing multiple lawsuits are the exceptions

A number of studies have demonstrated that only a small proportion of physicians are responsible for a disproportionate number of paid medical malpractice claims. (“Paid claims” are those in which the plaintiff receives money from the doctor’s insurance. “Filed claims” are all malpractice lawsuits filed. Many claims are filed, but few are paid.)

ObGyn has high number of paid claims and high risk of claim payment recurrence. Studdert and colleagues found that the probability of future paid malpractice climbed with each past paid claim.¹⁹ They also found that 1% of physicians accounted for 32% of all paid claims. The number of paid claims varied by specialty—obstetrics and gynecology accounted for the second largest number of paid claims (13%). The risk of recurrence (more than one paid claim) was highest among 4 surgical specialties and ObGyns (about double the recurrence rate in these specialties compared with internal medicine).¹⁹

A minority of physicians responsible for lion share of paid claims. Black and colleagues followed up the Studdert study. Although there were some differences in what they found, the results were very similar.²⁰ For example, they found that having even a single prior paid claim strongly predicted future claims over the next 5 years. They also found that some “outlier” physicians with multiple paid claims “are responsible for a significant share of paid claims.” They specifically found that, even for physicians in high-risk specialties in high-risk states, “bad luck is highly unlikely to explain” multiple claims within 5 years.

Continue to: Both of the studies just mentioned relied on...

Both of the studies just mentioned relied on the National Practitioner Data Bank for information about paid claims. This source has some limitations in capturing claims or payments made by hospitals or other institutions for the actions of its agent-physicians. Some of these limitations were resolved in another recent study that looked at Indiana state insurance and licensing discipline records (over a 41-year period).²¹ Not surprisingly, this study found that claims paid increase with more severe licensure discipline. On the other hand, although, the “frequent fliers” in terms of malpractice claims made and paid could be identified as a “small number of repeat defendants,” these physicians were not routinely disciplined by the state medical board. This was only a single state study, of course, but it also found that a few physicians accounted for a significant number of the claims. The state board was not taking licensing action against this small group, however.

Should the few bad apples be picked from the orchard?

Collectively, these studies are fairly overwhelming in demonstrating that there are some physicians who are “prone” to malpractice claims (for whom all physicians in the specialty are probably paying higher malpractice rates), but who do not attract the attention of licensing agencies for careful examination. In addition to its self-interest in eliminating physicians prone to malpractice claims and payments, the obligation of professions to protect the public interest suggests that state boards should be more aggressive in pursuing those physicians practicing risky medicine.

This medical malpractice series will continue next month with a look at how to reduce malpractice exposure.