Jaimey M. Pauli, MD

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

In the musical Hamilton, there is a line from the song “The Election of 1800” in which, after a tumultuous time, Thomas Jefferson pleads for a sense of normalcy with, “Can we get back to politics?”

Trying to get back to “normal,” whatever that is, characterized the year 2022. Peeking out from under the constant shadow of the COVID-19 pandemic (not really gone, definitely not forgotten) were some blockbuster obstetrical headlines, including those on the CHAP (Chronic Hypertension and Pregnancy) trial and the impact of the Dobbs v Jackson Supreme Court decision. As these have been extensively covered in both OBG Management and other publications, in this Update we simply ask, “Can we get back to obstetrics?” as we focus on some straightforward patient care guidelines.

Thus, we offer updated information on the use of progesterone for preterm birth prevention, management of pregnancies that result from in vitro fertilization (IVF), and headache management in pregnant and postpartum patients.

Society guidance and FDA  advisement on the use of  progesterone for the prevention  of spontaneous preterm birth

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth. ACOG practice bulletin no. 234. Obstet Gynecol. 2021;138:e65-e90.

EPPPIC Group. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet. 2021;397:1183-1194.

This is not déjà vu! Progesterone and spontaneous preterm birth (sPTB) is a hot topic again. If you wonder what to tell your patients, you are not alone. Preterm birth (PTB) continues to pose a challenge in obstetrics, with a most recently reported overall rate of 10.49%¹ in the United States—a 4% increase from 2019. Preterm birth accounts for approximately 75% of perinatal mortality and more than half of neonatal morbidity.²

What has not changed

A recent practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) notes that some risk factors and screening assessments for PTB remain unchanged, including²:

• A history of PTB increases the risk for subsequent PTB. Risk increases with the number of prior preterm deliveries.
• A short cervix (<25 mm between 16 and  24 weeks’ gestation) is a risk factor for sPTB.
• The cervix should be visualized during the anatomy ultrasound exam (18 0/7 to 22 6/7 weeks’ gestation) in all pregnant patients regardless of prior birth history. If the cervix length (CL) appears shortened on transabdominal imaging, transvaginal (TV) imaging should be performed.
• Patients with a current singleton pregnancy and history of sPTB should have serial TV cervical measurements between 16 0/7 and 24 0/7 weeks’ gestation.²

EPPPIC changes and key takeaway points

In a meta-analysis of data from 31 randomized controlled trials, the EPPPIC (Evaluating Progestogens for Preventing Preterm birth International Collaborative) investigators compared vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate  (17-OHPC), or oral progesterone with control or with each other in women at risk for PTB.³ Outcomes included PTB and the associated adverse neonatal and maternal outcomes.

The EPPPIC study’s main findings were:

• Singleton pregnancies at high risk for PTB due to prior sPTB or short cervix who received 17-OHPC or vaginal progesterone were less likely to deliver before  34 weeks’ gestation compared with those who received no treatment.
• There is a benefit to both 17-OHPC and vaginal progesterone in reducing the risk of PTB, with no clear evidence to support one intervention’s effectiveness over the other.
• There is benefit to either 17-OHPC or vaginal progesterone for CL less than 25 mm. The shorter the CL, the greater the absolute risk reduction on PTB.
• In multifetal pregnancies, use of 17-OHPC, when compared with placebo, was shown to increase the risk of preterm premature rupture of membranes. Neither 17-OHPC nor vaginal progesterone was found to reduce the risk of sPTB in multifetal pregnancies.³

What continues to change

While the March 30, 2021, statement from the Society for Maternal-Fetal Medicine (SMFM), “Response to EPPPIC and consideration for the use of progestogens for the prevention of preterm birth” (https://www .smfm.org/publications/383-smfm-stat ement-response-to-epppic-and-consider ations-of-the-use-of-progestogens-for-the -prevention-of-preterm-birth), stands, ACOG has withdrawn its accompanying Practice Advisory on guidance for integrating the EPPPIC findings.

In August 2022, the US Food and Drug Administration (FDA) granted a hearing on the Center for Drug Evaluation and Research’s proposal to withdraw approval for Makena (hydroxyprogesterone caproate injection, 250 mg/mL, once weekly) on the basis that available evidence does not demonstrate that it is effective for its approved indication to reduce the risk of PTB in women with a singleton pregnancy with a history of singleton sPTB.⁴

The key takeaway points from the FDA hearing (October 17–19, 2022) were:

• A better designed randomized controlled confirmatory trial is needed in the most at-risk patients to determine if Makena is effective for its approved indication.
• Makena and its approved generic equivalents remain on the market until the FDA makes its final decision regarding approval.⁴

Continue to: Managing pregnancies that result from IVF...

Society for Maternal-Fetal Medicine (SMFM); Ghidini A, Gandhi M, McCoy J, et al; Publications Committee. Society for Maternal-Fetal Medicine consult series #60: management of pregnancies resulting from in vitro fertilization. Am J Obstet Gynecol. 2022;226:B2-B12.

Assisted reproductive technology contributes to 1.6% of all infant births, and although most pregnancies are uncomplicated, some specific risks alter management.^5–7 For example, IVF is associated with increased rates of prematurity and its complications, fetal growth restriction, low birth weight, congenital anomalies, genetic abnormalities, and placental abnormalities. In addition, there is doubling of the risk of morbidities to the pregnant IVF patient, including but not limited to hypertensive disorders and diabetes. These complications are thought to be related to both the process of IVF itself as well as to conditions that contribute to subfertility and infertility in the first place.

Genetic screening and diagnostic testing options

IVF pregnancies have a documented increase in chromosomal abnormalities compared with spontaneously conceived pregnancies due to the following factors:

• karyotypic abnormalities in couples with infertility
• microdeletions on the Y chromosome in patients with oligospermia or azoospermia
• de novo chromosomal abnormalities in IVF pregnancies that utilize intracytoplasmic sperm injection (ICSI)
• fragile X mutations in patients with reduced ovarian reserve
• imprinting disorders in patients with fertility issues.

A common misconception is that preimplantation genetic testing renders prenatal genetic screening or testing unnecessary. However, preimplantation testing can be anywhere from 43% to 84% concordant with prenatal diagnostic testing due to biologic and technical factors. Therefore, all pregnancies should be offered the same options of aneuploidy screening as well as diagnostic testing. Pretest counseling should include an increased risk in IVF pregnancies of false-positives for the first-trimester screen and “no-call” results for cell-free fetal DNA. Additionally, diagnostic testing is recommended specifically in cases where mosaic embryos are transferred when euploid embryos are not available.

Counseling on fetal reduction for multifetal pregnancies

The risks of multifetal pregnancies (particularly higher order multiples) are significant and well documented for both the patient and the fetuses. It is therefore recommended that the option of multifetal pregnancy reduction be discussed, including the risks and benefits of reduction versus pregnancy continuation, timing, procedural considerations, and genetic testing options.^5,8

Detailed anatomic survey and fetal echocardiogram are indicated

Fetal anomalies, including congenital cardiac defects, occur at a higher rate in IVF pregnancies compared with spontaneously conceived pregnancies (475/10,000 live births vs 317/10,000 live births). Placental anomalies (such as placenta previa, vasa previa, and velamentous cord insertion) are also more common in this population. A detailed anatomic survey is therefore recommended for all IVF pregnancies and it is suggested that a fetal echocardiogram is offered these patients as well.

Pregnancy management and delivery considerations

Despite an increased risk of preterm birth, preeclampsia, and fetal growth restriction in IVF pregnancies (odds ratios range, 1.4–2), serial cervical lengths, serial growth ultrasound exams, and low-dose aspirin are not recommended for the sole indication of IVF. Due to lack of data on the utility of serial exams, a single screening cervical length at the time of anatomic survey and a third-trimester growth assessment are recommended. For aspirin, IVF qualifies as a “moderate” risk factor for preeclampsia; it is therefore recommended if another moderate risk factor is present (for example, nulliparity, obesity, or family history of preeclampsia).⁹

There is a 2- to 3-fold increased risk of stillbirth in IVF pregnancies; therefore, antenatal surveillance in the third trimester is recommended (weekly starting at 36 weeks for the sole indication of IVF).¹⁰ As no specific studies have evaluated the timing of delivery in IVF pregnancies, delivery recommendations include the option of 39-week delivery with shared decision-making with the patient.

Continue to: Evaluating and treating headaches in pregnancy and postpartum...

Evaluating and treating headaches in pregnancy and postpartum

American College of Obstetricians and Gynecologists. Clinical practice guideline no. 3: headaches in pregnancy and postpartum. Obstet Gynecol. 2022;139:944-972.

For obstetricians, headaches are a common and often frustrating condition to treat, as many of the available diagnostic tools and medications are either not recommended or have no data on use in pregnancy and lactation. Additionally, a headache is not always just a headache but could be a sign of a time-sensitive serious complication. An updated guideline from the American College of Obstetricians and Gynecologists approaches the topic of headaches in a stepwise algorithm that promotes efficiency and efficacy in diagnosis  and treatment.¹¹

Types of headaches

The primary headache types—migraine, cluster, and tension—are distinguished from each other by patient characteristics, quality, duration, location, and related symptoms. Reassuringly, headache frequency decreases by 30% to 80% during pregnancy, which allows for the option to decrease, change, or stop current medications, ideally prior to pregnancy. Prevention via use of calcium channel blockers, antihistamines, or β-blockers is recommended, as requiring acute treatments more than 2 days per week increases the risk of medication overuse headaches.

Treating acute headache

For patients who present with an acute headache consistent with their usual type, treatment starts with known medications that are compatible with pregnancy and proceeds in a stepwise fashion:

1. Acetaminophen 1,000 mg orally with or without caffeine 130 mg orally (maximum dose, acetaminophen < 3.25–4 g per day, caffeine 200 mg per day)

2. Metoclopramide 10 mg intravenously with or without diphenhydramine 25 mg intravenously (for nausea and to counteract restlessness and offer sedation)

3. If headache continues after steps 1 and 2, consider the following secondary treatment options: magnesium sulfate 1–2 g intravenously, sumatriptan 6 mg subcutaneously or 20-mg nasal spray, ibuprofen 600 mg orally once, or ketorolac 30 mg intravenously once (second trimester only)

4. If continued treatment and/or hospitalization is required after step 3, steroids can be used: prednisone 20 mg 4 times a day for 2 days or methylprednisolone 4-mg dose pack over 6 days

5. Do not use butalbital, opioids, or ergotamines due to lack of efficacy in providing additional pain relief, potential for addiction, risk of medication overuse headaches, and association with fetal/ pregnancy abnormalities.

Consider secondary headache

An acute headache discordant from the patient’s usual type or with concerning symptoms (“red flags”) requires consideration of secondary headaches as well as a comprehensive symptom evaluation, imaging, and consultation as needed. While secondary headaches postpartum are most likely musculoskeletal in nature, the following symptoms need to be evaluated immediately:

• rapid onset/change from baseline
• “thunderclap” nature
• hypertension
• fever
• focal neurologic deficits (blurry vision or blindness, confusion, seizures)
• altered consciousness
• laboratory abnormalities.

The differential diagnosis includes preeclampsia, reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), infection, cerebral venous sinus thrombosis (CVST), post–dural puncture (PDP) headache, idiopathic intracranial hypertension (IIH), and less likely, carotid dissection, subarachnoid hemorrhage, intracranial hemorrhage, pituitary apoplexy, or neoplasm.

Treatment. Individualized treatment depends on the diagnosis. Preeclampsia with severe features is treated with antihypertensive medication, magnesium sulfate, and delivery planning. PDP headache is treated with epidural blood patch, sphenopalatine block, or occipital block with an anesthesiology consultation. If preeclampsia and PDP are ruled out, or if there are more concerning neurologic features, imaging is essential, as 25% of pregnant patients with acute headaches will have a secondary etiology. Magnetic resonance imaging without contrast is preferred due to concerns about gadolinium crossing the placenta and the lack of data on long-term accumulation in fetal  tissues. Once diagnosed on imaging, PRES and RCVS are treated with antihypertensives and delivery. CVST is treated with anticoagulation and a thrombophilia workup. IIH may be treated with acetazolamide after 20 weeks or serial lumbar punctures. Intracranial vascular abnormalities may be treated with endoscopic resection and steroids. ●

In the musical Hamilton, there is a line from the song “The Election of 1800” in which, after a tumultuous time, Thomas Jefferson pleads for a sense of normalcy with, “Can we get back to politics?”

Trying to get back to “normal,” whatever that is, characterized the year 2022. Peeking out from under the constant shadow of the COVID-19 pandemic (not really gone, definitely not forgotten) were some blockbuster obstetrical headlines, including those on the CHAP (Chronic Hypertension and Pregnancy) trial and the impact of the Dobbs v Jackson Supreme Court decision. As these have been extensively covered in both OBG Management and other publications, in this Update we simply ask, “Can we get back to obstetrics?” as we focus on some straightforward patient care guidelines.

Thus, we offer updated information on the use of progesterone for preterm birth prevention, management of pregnancies that result from in vitro fertilization (IVF), and headache management in pregnant and postpartum patients.

Society guidance and FDA  advisement on the use of  progesterone for the prevention  of spontaneous preterm birth

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth. ACOG practice bulletin no. 234. Obstet Gynecol. 2021;138:e65-e90.

EPPPIC Group. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet. 2021;397:1183-1194.

This is not déjà vu! Progesterone and spontaneous preterm birth (sPTB) is a hot topic again. If you wonder what to tell your patients, you are not alone. Preterm birth (PTB) continues to pose a challenge in obstetrics, with a most recently reported overall rate of 10.49%¹ in the United States—a 4% increase from 2019. Preterm birth accounts for approximately 75% of perinatal mortality and more than half of neonatal morbidity.²

What has not changed

A recent practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) notes that some risk factors and screening assessments for PTB remain unchanged, including²:

• A history of PTB increases the risk for subsequent PTB. Risk increases with the number of prior preterm deliveries.
• A short cervix (<25 mm between 16 and  24 weeks’ gestation) is a risk factor for sPTB.
• The cervix should be visualized during the anatomy ultrasound exam (18 0/7 to 22 6/7 weeks’ gestation) in all pregnant patients regardless of prior birth history. If the cervix length (CL) appears shortened on transabdominal imaging, transvaginal (TV) imaging should be performed.
• Patients with a current singleton pregnancy and history of sPTB should have serial TV cervical measurements between 16 0/7 and 24 0/7 weeks’ gestation.²

EPPPIC changes and key takeaway points

In a meta-analysis of data from 31 randomized controlled trials, the EPPPIC (Evaluating Progestogens for Preventing Preterm birth International Collaborative) investigators compared vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate  (17-OHPC), or oral progesterone with control or with each other in women at risk for PTB.³ Outcomes included PTB and the associated adverse neonatal and maternal outcomes.

The EPPPIC study’s main findings were:

• Singleton pregnancies at high risk for PTB due to prior sPTB or short cervix who received 17-OHPC or vaginal progesterone were less likely to deliver before  34 weeks’ gestation compared with those who received no treatment.
• There is a benefit to both 17-OHPC and vaginal progesterone in reducing the risk of PTB, with no clear evidence to support one intervention’s effectiveness over the other.
• There is benefit to either 17-OHPC or vaginal progesterone for CL less than 25 mm. The shorter the CL, the greater the absolute risk reduction on PTB.
• In multifetal pregnancies, use of 17-OHPC, when compared with placebo, was shown to increase the risk of preterm premature rupture of membranes. Neither 17-OHPC nor vaginal progesterone was found to reduce the risk of sPTB in multifetal pregnancies.³

What continues to change

While the March 30, 2021, statement from the Society for Maternal-Fetal Medicine (SMFM), “Response to EPPPIC and consideration for the use of progestogens for the prevention of preterm birth” (https://www .smfm.org/publications/383-smfm-stat ement-response-to-epppic-and-consider ations-of-the-use-of-progestogens-for-the -prevention-of-preterm-birth), stands, ACOG has withdrawn its accompanying Practice Advisory on guidance for integrating the EPPPIC findings.

In August 2022, the US Food and Drug Administration (FDA) granted a hearing on the Center for Drug Evaluation and Research’s proposal to withdraw approval for Makena (hydroxyprogesterone caproate injection, 250 mg/mL, once weekly) on the basis that available evidence does not demonstrate that it is effective for its approved indication to reduce the risk of PTB in women with a singleton pregnancy with a history of singleton sPTB.⁴

The key takeaway points from the FDA hearing (October 17–19, 2022) were:

• A better designed randomized controlled confirmatory trial is needed in the most at-risk patients to determine if Makena is effective for its approved indication.
• Makena and its approved generic equivalents remain on the market until the FDA makes its final decision regarding approval.⁴

Continue to: Managing pregnancies that result from IVF...

Society for Maternal-Fetal Medicine (SMFM); Ghidini A, Gandhi M, McCoy J, et al; Publications Committee. Society for Maternal-Fetal Medicine consult series #60: management of pregnancies resulting from in vitro fertilization. Am J Obstet Gynecol. 2022;226:B2-B12.

Assisted reproductive technology contributes to 1.6% of all infant births, and although most pregnancies are uncomplicated, some specific risks alter management.^5–7 For example, IVF is associated with increased rates of prematurity and its complications, fetal growth restriction, low birth weight, congenital anomalies, genetic abnormalities, and placental abnormalities. In addition, there is doubling of the risk of morbidities to the pregnant IVF patient, including but not limited to hypertensive disorders and diabetes. These complications are thought to be related to both the process of IVF itself as well as to conditions that contribute to subfertility and infertility in the first place.

Genetic screening and diagnostic testing options

IVF pregnancies have a documented increase in chromosomal abnormalities compared with spontaneously conceived pregnancies due to the following factors:

• karyotypic abnormalities in couples with infertility
• microdeletions on the Y chromosome in patients with oligospermia or azoospermia
• de novo chromosomal abnormalities in IVF pregnancies that utilize intracytoplasmic sperm injection (ICSI)
• fragile X mutations in patients with reduced ovarian reserve
• imprinting disorders in patients with fertility issues.

A common misconception is that preimplantation genetic testing renders prenatal genetic screening or testing unnecessary. However, preimplantation testing can be anywhere from 43% to 84% concordant with prenatal diagnostic testing due to biologic and technical factors. Therefore, all pregnancies should be offered the same options of aneuploidy screening as well as diagnostic testing. Pretest counseling should include an increased risk in IVF pregnancies of false-positives for the first-trimester screen and “no-call” results for cell-free fetal DNA. Additionally, diagnostic testing is recommended specifically in cases where mosaic embryos are transferred when euploid embryos are not available.

Counseling on fetal reduction for multifetal pregnancies

The risks of multifetal pregnancies (particularly higher order multiples) are significant and well documented for both the patient and the fetuses. It is therefore recommended that the option of multifetal pregnancy reduction be discussed, including the risks and benefits of reduction versus pregnancy continuation, timing, procedural considerations, and genetic testing options.^5,8

Detailed anatomic survey and fetal echocardiogram are indicated

Fetal anomalies, including congenital cardiac defects, occur at a higher rate in IVF pregnancies compared with spontaneously conceived pregnancies (475/10,000 live births vs 317/10,000 live births). Placental anomalies (such as placenta previa, vasa previa, and velamentous cord insertion) are also more common in this population. A detailed anatomic survey is therefore recommended for all IVF pregnancies and it is suggested that a fetal echocardiogram is offered these patients as well.

Pregnancy management and delivery considerations

Despite an increased risk of preterm birth, preeclampsia, and fetal growth restriction in IVF pregnancies (odds ratios range, 1.4–2), serial cervical lengths, serial growth ultrasound exams, and low-dose aspirin are not recommended for the sole indication of IVF. Due to lack of data on the utility of serial exams, a single screening cervical length at the time of anatomic survey and a third-trimester growth assessment are recommended. For aspirin, IVF qualifies as a “moderate” risk factor for preeclampsia; it is therefore recommended if another moderate risk factor is present (for example, nulliparity, obesity, or family history of preeclampsia).⁹

There is a 2- to 3-fold increased risk of stillbirth in IVF pregnancies; therefore, antenatal surveillance in the third trimester is recommended (weekly starting at 36 weeks for the sole indication of IVF).¹⁰ As no specific studies have evaluated the timing of delivery in IVF pregnancies, delivery recommendations include the option of 39-week delivery with shared decision-making with the patient.

Continue to: Evaluating and treating headaches in pregnancy and postpartum...

Evaluating and treating headaches in pregnancy and postpartum

American College of Obstetricians and Gynecologists. Clinical practice guideline no. 3: headaches in pregnancy and postpartum. Obstet Gynecol. 2022;139:944-972.

For obstetricians, headaches are a common and often frustrating condition to treat, as many of the available diagnostic tools and medications are either not recommended or have no data on use in pregnancy and lactation. Additionally, a headache is not always just a headache but could be a sign of a time-sensitive serious complication. An updated guideline from the American College of Obstetricians and Gynecologists approaches the topic of headaches in a stepwise algorithm that promotes efficiency and efficacy in diagnosis  and treatment.¹¹

Types of headaches

The primary headache types—migraine, cluster, and tension—are distinguished from each other by patient characteristics, quality, duration, location, and related symptoms. Reassuringly, headache frequency decreases by 30% to 80% during pregnancy, which allows for the option to decrease, change, or stop current medications, ideally prior to pregnancy. Prevention via use of calcium channel blockers, antihistamines, or β-blockers is recommended, as requiring acute treatments more than 2 days per week increases the risk of medication overuse headaches.

Treating acute headache

For patients who present with an acute headache consistent with their usual type, treatment starts with known medications that are compatible with pregnancy and proceeds in a stepwise fashion:

1. Acetaminophen 1,000 mg orally with or without caffeine 130 mg orally (maximum dose, acetaminophen < 3.25–4 g per day, caffeine 200 mg per day)

2. Metoclopramide 10 mg intravenously with or without diphenhydramine 25 mg intravenously (for nausea and to counteract restlessness and offer sedation)

3. If headache continues after steps 1 and 2, consider the following secondary treatment options: magnesium sulfate 1–2 g intravenously, sumatriptan 6 mg subcutaneously or 20-mg nasal spray, ibuprofen 600 mg orally once, or ketorolac 30 mg intravenously once (second trimester only)

4. If continued treatment and/or hospitalization is required after step 3, steroids can be used: prednisone 20 mg 4 times a day for 2 days or methylprednisolone 4-mg dose pack over 6 days

5. Do not use butalbital, opioids, or ergotamines due to lack of efficacy in providing additional pain relief, potential for addiction, risk of medication overuse headaches, and association with fetal/ pregnancy abnormalities.

Consider secondary headache

An acute headache discordant from the patient’s usual type or with concerning symptoms (“red flags”) requires consideration of secondary headaches as well as a comprehensive symptom evaluation, imaging, and consultation as needed. While secondary headaches postpartum are most likely musculoskeletal in nature, the following symptoms need to be evaluated immediately:

• rapid onset/change from baseline
• “thunderclap” nature
• hypertension
• fever
• focal neurologic deficits (blurry vision or blindness, confusion, seizures)
• altered consciousness
• laboratory abnormalities.

The differential diagnosis includes preeclampsia, reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), infection, cerebral venous sinus thrombosis (CVST), post–dural puncture (PDP) headache, idiopathic intracranial hypertension (IIH), and less likely, carotid dissection, subarachnoid hemorrhage, intracranial hemorrhage, pituitary apoplexy, or neoplasm.

Treatment. Individualized treatment depends on the diagnosis. Preeclampsia with severe features is treated with antihypertensive medication, magnesium sulfate, and delivery planning. PDP headache is treated with epidural blood patch, sphenopalatine block, or occipital block with an anesthesiology consultation. If preeclampsia and PDP are ruled out, or if there are more concerning neurologic features, imaging is essential, as 25% of pregnant patients with acute headaches will have a secondary etiology. Magnetic resonance imaging without contrast is preferred due to concerns about gadolinium crossing the placenta and the lack of data on long-term accumulation in fetal  tissues. Once diagnosed on imaging, PRES and RCVS are treated with antihypertensives and delivery. CVST is treated with anticoagulation and a thrombophilia workup. IIH may be treated with acetazolamide after 20 weeks or serial lumbar punctures. Intracranial vascular abnormalities may be treated with endoscopic resection and steroids. ●

In the musical Hamilton, there is a line from the song “The Election of 1800” in which, after a tumultuous time, Thomas Jefferson pleads for a sense of normalcy with, “Can we get back to politics?”

Trying to get back to “normal,” whatever that is, characterized the year 2022. Peeking out from under the constant shadow of the COVID-19 pandemic (not really gone, definitely not forgotten) were some blockbuster obstetrical headlines, including those on the CHAP (Chronic Hypertension and Pregnancy) trial and the impact of the Dobbs v Jackson Supreme Court decision. As these have been extensively covered in both OBG Management and other publications, in this Update we simply ask, “Can we get back to obstetrics?” as we focus on some straightforward patient care guidelines.

Thus, we offer updated information on the use of progesterone for preterm birth prevention, management of pregnancies that result from in vitro fertilization (IVF), and headache management in pregnant and postpartum patients.

Society guidance and FDA  advisement on the use of  progesterone for the prevention  of spontaneous preterm birth

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth. ACOG practice bulletin no. 234. Obstet Gynecol. 2021;138:e65-e90.

EPPPIC Group. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet. 2021;397:1183-1194.

This is not déjà vu! Progesterone and spontaneous preterm birth (sPTB) is a hot topic again. If you wonder what to tell your patients, you are not alone. Preterm birth (PTB) continues to pose a challenge in obstetrics, with a most recently reported overall rate of 10.49%¹ in the United States—a 4% increase from 2019. Preterm birth accounts for approximately 75% of perinatal mortality and more than half of neonatal morbidity.²

What has not changed

A recent practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) notes that some risk factors and screening assessments for PTB remain unchanged, including²:

• A history of PTB increases the risk for subsequent PTB. Risk increases with the number of prior preterm deliveries.
• A short cervix (<25 mm between 16 and  24 weeks’ gestation) is a risk factor for sPTB.
• The cervix should be visualized during the anatomy ultrasound exam (18 0/7 to 22 6/7 weeks’ gestation) in all pregnant patients regardless of prior birth history. If the cervix length (CL) appears shortened on transabdominal imaging, transvaginal (TV) imaging should be performed.
• Patients with a current singleton pregnancy and history of sPTB should have serial TV cervical measurements between 16 0/7 and 24 0/7 weeks’ gestation.²

EPPPIC changes and key takeaway points

In a meta-analysis of data from 31 randomized controlled trials, the EPPPIC (Evaluating Progestogens for Preventing Preterm birth International Collaborative) investigators compared vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate  (17-OHPC), or oral progesterone with control or with each other in women at risk for PTB.³ Outcomes included PTB and the associated adverse neonatal and maternal outcomes.

The EPPPIC study’s main findings were:

• Singleton pregnancies at high risk for PTB due to prior sPTB or short cervix who received 17-OHPC or vaginal progesterone were less likely to deliver before  34 weeks’ gestation compared with those who received no treatment.
• There is a benefit to both 17-OHPC and vaginal progesterone in reducing the risk of PTB, with no clear evidence to support one intervention’s effectiveness over the other.
• There is benefit to either 17-OHPC or vaginal progesterone for CL less than 25 mm. The shorter the CL, the greater the absolute risk reduction on PTB.
• In multifetal pregnancies, use of 17-OHPC, when compared with placebo, was shown to increase the risk of preterm premature rupture of membranes. Neither 17-OHPC nor vaginal progesterone was found to reduce the risk of sPTB in multifetal pregnancies.³

What continues to change

While the March 30, 2021, statement from the Society for Maternal-Fetal Medicine (SMFM), “Response to EPPPIC and consideration for the use of progestogens for the prevention of preterm birth” (https://www .smfm.org/publications/383-smfm-stat ement-response-to-epppic-and-consider ations-of-the-use-of-progestogens-for-the -prevention-of-preterm-birth), stands, ACOG has withdrawn its accompanying Practice Advisory on guidance for integrating the EPPPIC findings.

In August 2022, the US Food and Drug Administration (FDA) granted a hearing on the Center for Drug Evaluation and Research’s proposal to withdraw approval for Makena (hydroxyprogesterone caproate injection, 250 mg/mL, once weekly) on the basis that available evidence does not demonstrate that it is effective for its approved indication to reduce the risk of PTB in women with a singleton pregnancy with a history of singleton sPTB.⁴

The key takeaway points from the FDA hearing (October 17–19, 2022) were:

• A better designed randomized controlled confirmatory trial is needed in the most at-risk patients to determine if Makena is effective for its approved indication.
• Makena and its approved generic equivalents remain on the market until the FDA makes its final decision regarding approval.⁴

Continue to: Managing pregnancies that result from IVF...

Society for Maternal-Fetal Medicine (SMFM); Ghidini A, Gandhi M, McCoy J, et al; Publications Committee. Society for Maternal-Fetal Medicine consult series #60: management of pregnancies resulting from in vitro fertilization. Am J Obstet Gynecol. 2022;226:B2-B12.

Assisted reproductive technology contributes to 1.6% of all infant births, and although most pregnancies are uncomplicated, some specific risks alter management.^5–7 For example, IVF is associated with increased rates of prematurity and its complications, fetal growth restriction, low birth weight, congenital anomalies, genetic abnormalities, and placental abnormalities. In addition, there is doubling of the risk of morbidities to the pregnant IVF patient, including but not limited to hypertensive disorders and diabetes. These complications are thought to be related to both the process of IVF itself as well as to conditions that contribute to subfertility and infertility in the first place.

Genetic screening and diagnostic testing options

IVF pregnancies have a documented increase in chromosomal abnormalities compared with spontaneously conceived pregnancies due to the following factors:

• karyotypic abnormalities in couples with infertility
• microdeletions on the Y chromosome in patients with oligospermia or azoospermia
• de novo chromosomal abnormalities in IVF pregnancies that utilize intracytoplasmic sperm injection (ICSI)
• fragile X mutations in patients with reduced ovarian reserve
• imprinting disorders in patients with fertility issues.

A common misconception is that preimplantation genetic testing renders prenatal genetic screening or testing unnecessary. However, preimplantation testing can be anywhere from 43% to 84% concordant with prenatal diagnostic testing due to biologic and technical factors. Therefore, all pregnancies should be offered the same options of aneuploidy screening as well as diagnostic testing. Pretest counseling should include an increased risk in IVF pregnancies of false-positives for the first-trimester screen and “no-call” results for cell-free fetal DNA. Additionally, diagnostic testing is recommended specifically in cases where mosaic embryos are transferred when euploid embryos are not available.

Counseling on fetal reduction for multifetal pregnancies

The risks of multifetal pregnancies (particularly higher order multiples) are significant and well documented for both the patient and the fetuses. It is therefore recommended that the option of multifetal pregnancy reduction be discussed, including the risks and benefits of reduction versus pregnancy continuation, timing, procedural considerations, and genetic testing options.^5,8

Detailed anatomic survey and fetal echocardiogram are indicated

Fetal anomalies, including congenital cardiac defects, occur at a higher rate in IVF pregnancies compared with spontaneously conceived pregnancies (475/10,000 live births vs 317/10,000 live births). Placental anomalies (such as placenta previa, vasa previa, and velamentous cord insertion) are also more common in this population. A detailed anatomic survey is therefore recommended for all IVF pregnancies and it is suggested that a fetal echocardiogram is offered these patients as well.

Pregnancy management and delivery considerations

Despite an increased risk of preterm birth, preeclampsia, and fetal growth restriction in IVF pregnancies (odds ratios range, 1.4–2), serial cervical lengths, serial growth ultrasound exams, and low-dose aspirin are not recommended for the sole indication of IVF. Due to lack of data on the utility of serial exams, a single screening cervical length at the time of anatomic survey and a third-trimester growth assessment are recommended. For aspirin, IVF qualifies as a “moderate” risk factor for preeclampsia; it is therefore recommended if another moderate risk factor is present (for example, nulliparity, obesity, or family history of preeclampsia).⁹

There is a 2- to 3-fold increased risk of stillbirth in IVF pregnancies; therefore, antenatal surveillance in the third trimester is recommended (weekly starting at 36 weeks for the sole indication of IVF).¹⁰ As no specific studies have evaluated the timing of delivery in IVF pregnancies, delivery recommendations include the option of 39-week delivery with shared decision-making with the patient.

Continue to: Evaluating and treating headaches in pregnancy and postpartum...

Evaluating and treating headaches in pregnancy and postpartum

American College of Obstetricians and Gynecologists. Clinical practice guideline no. 3: headaches in pregnancy and postpartum. Obstet Gynecol. 2022;139:944-972.

For obstetricians, headaches are a common and often frustrating condition to treat, as many of the available diagnostic tools and medications are either not recommended or have no data on use in pregnancy and lactation. Additionally, a headache is not always just a headache but could be a sign of a time-sensitive serious complication. An updated guideline from the American College of Obstetricians and Gynecologists approaches the topic of headaches in a stepwise algorithm that promotes efficiency and efficacy in diagnosis  and treatment.¹¹

Types of headaches

The primary headache types—migraine, cluster, and tension—are distinguished from each other by patient characteristics, quality, duration, location, and related symptoms. Reassuringly, headache frequency decreases by 30% to 80% during pregnancy, which allows for the option to decrease, change, or stop current medications, ideally prior to pregnancy. Prevention via use of calcium channel blockers, antihistamines, or β-blockers is recommended, as requiring acute treatments more than 2 days per week increases the risk of medication overuse headaches.

Treating acute headache

For patients who present with an acute headache consistent with their usual type, treatment starts with known medications that are compatible with pregnancy and proceeds in a stepwise fashion:

1. Acetaminophen 1,000 mg orally with or without caffeine 130 mg orally (maximum dose, acetaminophen < 3.25–4 g per day, caffeine 200 mg per day)

2. Metoclopramide 10 mg intravenously with or without diphenhydramine 25 mg intravenously (for nausea and to counteract restlessness and offer sedation)

3. If headache continues after steps 1 and 2, consider the following secondary treatment options: magnesium sulfate 1–2 g intravenously, sumatriptan 6 mg subcutaneously or 20-mg nasal spray, ibuprofen 600 mg orally once, or ketorolac 30 mg intravenously once (second trimester only)

4. If continued treatment and/or hospitalization is required after step 3, steroids can be used: prednisone 20 mg 4 times a day for 2 days or methylprednisolone 4-mg dose pack over 6 days

5. Do not use butalbital, opioids, or ergotamines due to lack of efficacy in providing additional pain relief, potential for addiction, risk of medication overuse headaches, and association with fetal/ pregnancy abnormalities.

Consider secondary headache

An acute headache discordant from the patient’s usual type or with concerning symptoms (“red flags”) requires consideration of secondary headaches as well as a comprehensive symptom evaluation, imaging, and consultation as needed. While secondary headaches postpartum are most likely musculoskeletal in nature, the following symptoms need to be evaluated immediately:

• rapid onset/change from baseline
• “thunderclap” nature
• hypertension
• fever
• focal neurologic deficits (blurry vision or blindness, confusion, seizures)
• altered consciousness
• laboratory abnormalities.

The differential diagnosis includes preeclampsia, reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), infection, cerebral venous sinus thrombosis (CVST), post–dural puncture (PDP) headache, idiopathic intracranial hypertension (IIH), and less likely, carotid dissection, subarachnoid hemorrhage, intracranial hemorrhage, pituitary apoplexy, or neoplasm.

Treatment. Individualized treatment depends on the diagnosis. Preeclampsia with severe features is treated with antihypertensive medication, magnesium sulfate, and delivery planning. PDP headache is treated with epidural blood patch, sphenopalatine block, or occipital block with an anesthesiology consultation. If preeclampsia and PDP are ruled out, or if there are more concerning neurologic features, imaging is essential, as 25% of pregnant patients with acute headaches will have a secondary etiology. Magnetic resonance imaging without contrast is preferred due to concerns about gadolinium crossing the placenta and the lack of data on long-term accumulation in fetal  tissues. Once diagnosed on imaging, PRES and RCVS are treated with antihypertensives and delivery. CVST is treated with anticoagulation and a thrombophilia workup. IIH may be treated with acetazolamide after 20 weeks or serial lumbar punctures. Intracranial vascular abnormalities may be treated with endoscopic resection and steroids. ●

Tita AT, Szychowski JM, Boggess K, et al. Treatment for mild chronic hypertension during pregnancy. N Engl J Med. 2022;386:1781-1792. doi: 10.1056/NEJMoa2201295.

Expert Commentary

In the nonpregnant population, medical management of hypertension >140/90 mm Hg is standard practice. By contrast, much higher blood pressures (BPs; up to 160/110 mm Hg) traditionally have been tolerated in pregnant patients with chronic hypertension without initiating treatment, and existing medications are often discontinued during pregnancy. Concern for impaired fetal growth as well as lack of data on improved outcomes have led to different recommendations for the management of mild chronic hypertension in pregnancy. However, chronic hypertension affects a substantial number of pregnant patients and is known to be a risk factor for severe short-term pregnancy and long-term health complications. With preliminary data suggesting that BPs >140/90 mm Hg prior to 20 weeks’ gestation are associated with an increase in adverse outcomes, Tita and colleagues sought to determine the effects of decreasing BP in pregnant patients with mild chronic hypertension.

Details about the study

This is an investigator-initiated, multicenter, pragmatic, open-label, randomized control trial of 2,408 patients with mild chronic hypertension. The active treatment group was treated with antihypertensive medication (including titration of existing medication), targeting a BP of <140/90 mm Hg. The control group only received medication for severe hypertension (≥160 mm Hg systolic or ≥105 mm Hg diastolic). The primary outcome of the study was a composite of preeclampsia with severe features, medically indicated preterm delivery prior to 35 weeks’ gestation (not spontaneous labor or rupture of membranes), placental abruption, and fetal or neonatal death. Birthweight that was less than the 10th percentile was used as a safety outcome. The hypothesis was that treatment would decrease the rate of adverse pregnancy and fetal/neonatal outcomes.

The patient population of singleton pregnancies at a gestational age of less than 23 weeks included 56% with known chronic hypertension on medications, 22% with known chronic hypertension without medications, and 22% with newly diagnosed (during pregnancy) chronic hypertension. The treatment group primarily received labetalol (61.7%) or nifedipine (35.6%); the maximum dose of a single agent was used as tolerated prior to adding a second agent. The control group only received an antihypertensive medication for severe hypertension.

Treatment of chronic hypertension demonstrated a decreased risk of the composite adverse outcome with an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<.001) and a number needed to treat (NNT) of 14.7. When analyzed separately, a similar risk reduction was noted for both preeclampsia with severe features and medically indicated preterm birth <35 weeks’ gestation. There was no statistical difference between the groups for birth weight <10th percentile and <5th percentile (adjusted risk ratio, 1.04 [0.82–1.31] vs 0.89 [0.62–1.26], respectively).

Planned subgroup analysis by type of chronic hypertension, race/ethnic group, diabetes status, gestational age at baseline, and body mass index (BMI) demonstrated a similar treatment effect to the overall composite primary outcome, with the exception of patients with newly diagnosed chronic hypertension or BMI ≥40 kg/m². Overall maternal and neonatal composite outcomes of severe complications did not differ between treatment and control groups; however, rates of severe preeclampsia, any preeclampsia, preterm birth rate, and birthweight <2,500 g were all lower in the treatment group.

Study strengths and weaknesses

The study strengths cited are a large sample size, multiple study sites, an independent data and safety monitoring board with close oversight, and centralized blinded confirmation of outcomes. Another strength is that the patient population of the study was similar to the overall population of pregnant patients in the United States with chronic hypertension in terms of age, race, and ethnicity.

The weaknesses of the study include the open-label design and the high ratio of screened to enrolled patients. Both of these issues appear related to the study design (ethics and logistics of a blinded treatment and gestational age cutoff) and the physiology of pregnancy (expected decrease in BP in the second trimester rendering patients ineligible due to lower BP). The study was also not powered to assess treatment effect in all of the subgroups, and further evaluation of patients with newly diagnosed chronic hypertension and BMI ≥ 40 kg/m² is needed. ●

Tita AT, Szychowski JM, Boggess K, et al. Treatment for mild chronic hypertension during pregnancy. N Engl J Med. 2022;386:1781-1792. doi: 10.1056/NEJMoa2201295.

Expert Commentary

In the nonpregnant population, medical management of hypertension >140/90 mm Hg is standard practice. By contrast, much higher blood pressures (BPs; up to 160/110 mm Hg) traditionally have been tolerated in pregnant patients with chronic hypertension without initiating treatment, and existing medications are often discontinued during pregnancy. Concern for impaired fetal growth as well as lack of data on improved outcomes have led to different recommendations for the management of mild chronic hypertension in pregnancy. However, chronic hypertension affects a substantial number of pregnant patients and is known to be a risk factor for severe short-term pregnancy and long-term health complications. With preliminary data suggesting that BPs >140/90 mm Hg prior to 20 weeks’ gestation are associated with an increase in adverse outcomes, Tita and colleagues sought to determine the effects of decreasing BP in pregnant patients with mild chronic hypertension.

Details about the study

This is an investigator-initiated, multicenter, pragmatic, open-label, randomized control trial of 2,408 patients with mild chronic hypertension. The active treatment group was treated with antihypertensive medication (including titration of existing medication), targeting a BP of <140/90 mm Hg. The control group only received medication for severe hypertension (≥160 mm Hg systolic or ≥105 mm Hg diastolic). The primary outcome of the study was a composite of preeclampsia with severe features, medically indicated preterm delivery prior to 35 weeks’ gestation (not spontaneous labor or rupture of membranes), placental abruption, and fetal or neonatal death. Birthweight that was less than the 10th percentile was used as a safety outcome. The hypothesis was that treatment would decrease the rate of adverse pregnancy and fetal/neonatal outcomes.

The patient population of singleton pregnancies at a gestational age of less than 23 weeks included 56% with known chronic hypertension on medications, 22% with known chronic hypertension without medications, and 22% with newly diagnosed (during pregnancy) chronic hypertension. The treatment group primarily received labetalol (61.7%) or nifedipine (35.6%); the maximum dose of a single agent was used as tolerated prior to adding a second agent. The control group only received an antihypertensive medication for severe hypertension.

Treatment of chronic hypertension demonstrated a decreased risk of the composite adverse outcome with an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<.001) and a number needed to treat (NNT) of 14.7. When analyzed separately, a similar risk reduction was noted for both preeclampsia with severe features and medically indicated preterm birth <35 weeks’ gestation. There was no statistical difference between the groups for birth weight <10th percentile and <5th percentile (adjusted risk ratio, 1.04 [0.82–1.31] vs 0.89 [0.62–1.26], respectively).

Planned subgroup analysis by type of chronic hypertension, race/ethnic group, diabetes status, gestational age at baseline, and body mass index (BMI) demonstrated a similar treatment effect to the overall composite primary outcome, with the exception of patients with newly diagnosed chronic hypertension or BMI ≥40 kg/m². Overall maternal and neonatal composite outcomes of severe complications did not differ between treatment and control groups; however, rates of severe preeclampsia, any preeclampsia, preterm birth rate, and birthweight <2,500 g were all lower in the treatment group.

Study strengths and weaknesses

The study strengths cited are a large sample size, multiple study sites, an independent data and safety monitoring board with close oversight, and centralized blinded confirmation of outcomes. Another strength is that the patient population of the study was similar to the overall population of pregnant patients in the United States with chronic hypertension in terms of age, race, and ethnicity.

The weaknesses of the study include the open-label design and the high ratio of screened to enrolled patients. Both of these issues appear related to the study design (ethics and logistics of a blinded treatment and gestational age cutoff) and the physiology of pregnancy (expected decrease in BP in the second trimester rendering patients ineligible due to lower BP). The study was also not powered to assess treatment effect in all of the subgroups, and further evaluation of patients with newly diagnosed chronic hypertension and BMI ≥ 40 kg/m² is needed. ●

Tita AT, Szychowski JM, Boggess K, et al. Treatment for mild chronic hypertension during pregnancy. N Engl J Med. 2022;386:1781-1792. doi: 10.1056/NEJMoa2201295.

Expert Commentary

In the nonpregnant population, medical management of hypertension >140/90 mm Hg is standard practice. By contrast, much higher blood pressures (BPs; up to 160/110 mm Hg) traditionally have been tolerated in pregnant patients with chronic hypertension without initiating treatment, and existing medications are often discontinued during pregnancy. Concern for impaired fetal growth as well as lack of data on improved outcomes have led to different recommendations for the management of mild chronic hypertension in pregnancy. However, chronic hypertension affects a substantial number of pregnant patients and is known to be a risk factor for severe short-term pregnancy and long-term health complications. With preliminary data suggesting that BPs >140/90 mm Hg prior to 20 weeks’ gestation are associated with an increase in adverse outcomes, Tita and colleagues sought to determine the effects of decreasing BP in pregnant patients with mild chronic hypertension.

Details about the study

This is an investigator-initiated, multicenter, pragmatic, open-label, randomized control trial of 2,408 patients with mild chronic hypertension. The active treatment group was treated with antihypertensive medication (including titration of existing medication), targeting a BP of <140/90 mm Hg. The control group only received medication for severe hypertension (≥160 mm Hg systolic or ≥105 mm Hg diastolic). The primary outcome of the study was a composite of preeclampsia with severe features, medically indicated preterm delivery prior to 35 weeks’ gestation (not spontaneous labor or rupture of membranes), placental abruption, and fetal or neonatal death. Birthweight that was less than the 10th percentile was used as a safety outcome. The hypothesis was that treatment would decrease the rate of adverse pregnancy and fetal/neonatal outcomes.

The patient population of singleton pregnancies at a gestational age of less than 23 weeks included 56% with known chronic hypertension on medications, 22% with known chronic hypertension without medications, and 22% with newly diagnosed (during pregnancy) chronic hypertension. The treatment group primarily received labetalol (61.7%) or nifedipine (35.6%); the maximum dose of a single agent was used as tolerated prior to adding a second agent. The control group only received an antihypertensive medication for severe hypertension.

Treatment of chronic hypertension demonstrated a decreased risk of the composite adverse outcome with an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<.001) and a number needed to treat (NNT) of 14.7. When analyzed separately, a similar risk reduction was noted for both preeclampsia with severe features and medically indicated preterm birth <35 weeks’ gestation. There was no statistical difference between the groups for birth weight <10th percentile and <5th percentile (adjusted risk ratio, 1.04 [0.82–1.31] vs 0.89 [0.62–1.26], respectively).

Planned subgroup analysis by type of chronic hypertension, race/ethnic group, diabetes status, gestational age at baseline, and body mass index (BMI) demonstrated a similar treatment effect to the overall composite primary outcome, with the exception of patients with newly diagnosed chronic hypertension or BMI ≥40 kg/m². Overall maternal and neonatal composite outcomes of severe complications did not differ between treatment and control groups; however, rates of severe preeclampsia, any preeclampsia, preterm birth rate, and birthweight <2,500 g were all lower in the treatment group.

Study strengths and weaknesses

The study strengths cited are a large sample size, multiple study sites, an independent data and safety monitoring board with close oversight, and centralized blinded confirmation of outcomes. Another strength is that the patient population of the study was similar to the overall population of pregnant patients in the United States with chronic hypertension in terms of age, race, and ethnicity.

The weaknesses of the study include the open-label design and the high ratio of screened to enrolled patients. Both of these issues appear related to the study design (ethics and logistics of a blinded treatment and gestational age cutoff) and the physiology of pregnancy (expected decrease in BP in the second trimester rendering patients ineligible due to lower BP). The study was also not powered to assess treatment effect in all of the subgroups, and further evaluation of patients with newly diagnosed chronic hypertension and BMI ≥ 40 kg/m² is needed. ●

Obstetrical practice saw updates in 2021 to 3 major areas of pregnancy management: preterm birth prevention, antepartum fetal surveillance, and the use of antenatal corticosteroids.

Updated guidance on predicting and preventing spontaneous PTB

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth: ACOG practice bulletin, number 234. Obstet Gynecol. 2021;138:e65-e90.

Preterm birth (PTB) continues to pose a challenge in clinical obstetrics, with the most recently reported rate of 10.2% in the United States.¹ This accounts for almost 75% of perinatal mortality and more than half of neonatal morbidity, in which effects last well past the neonatal period. PTB is classified as spontaneous (following preterm labor, preterm prelabor rupture of membranes, or cervical insufficiency) or iatrogenic (indicated due to maternal and/or fetal complications).

Assessing risk for PTB

The single strongest predictor of subsequent PTB is a history of spontaneous PTB. Recurrence risk is further increased by the number of prior PTBs and the gestational age at prior PTB. Identification of and intervention for a short cervix has been shown to prolong gestation. Transvaginal ultrasonography of the cervix is the most accurate method for evaluating cervical length (CL). Specific examination criteria exist to ensure that CL measurements are reproducible and reliable.² A short CL is generally defined as a measurement of less than 25 mm between 16 and 24 weeks’ gestation.

Screening strategies

The American College of Obstetricians and Gynecologists (ACOG), with an endorsement from the Society for Maternal-Fetal Medicine (SMFM), recommends cervical evaluation during the anatomy ultrasound exam between 18 0/7 and 22 6/7 weeks’ gestation in all pregnant patients regardless of prior PTB.³ If transabdominal imaging is concerning for a shortened cervix, transvaginal ultrasonography should be performed to assess the CL.

Serial transvaginal CL measurements are recommended between 16 0/7 and 24 0/7 weeks’ gestation for patients with a current singleton pregnancy and history of a spontaneous PTB, but not for patients with a history of iatrogenic or indicated PTB.

Interventions: Mind your p’s and c’s

Interventions to reduce the risk of spontaneous PTB depend on whether the current pregnancy is a singleton, twins, or higher-order multiples; CL measurement; and history of spontaneous PTB. Preconception optimization of underlying medical conditions also is important to reduce the risk of recurrent indicated PTB.

Continue to: Progesterone...

Progesterone

Vaginal administration. Several trials have shown that vaginal progesterone can be used to reduce the risk of spontaneous PTB in asymptomatic patients with a singleton pregnancy, incidental finding of a short cervix (<25 mm), and no history of spontaneous PTB. This is a change from the prior recommendation of CL of less than 20 mm. In the setting of a twin pregnancy, regardless of CL, data do not definitively support the use of vaginal progesterone.

Intramuscular administration.^4,5 The popularity of intramuscular progesterone has waxed and waned. At present, ACOG recommends that all patients with a singleton pregnancy and history of spontaneous PTB be offered progesterone beginning at 16 0/7 weeks’ gestation following a shared decision-making process that includes the limited data of efficacy noted in existing studies.

In a twin pregnancy with no history of spontaneous PTB, the use of intramuscular progesterone has been shown to potentially increase the risk of PTB and admission to the neonatal intensive care unit. As such, intramuscular progesterone in the setting of a twin gestation without a history of spontaneous PTB is not recommended. When a prior spontaneous PTB has occurred, there may be some benefit to intramuscular progesterone in twin gestations.

Cerclage

Ultrasound indicated. In a singleton pregnancy with an incidental finding of short cervix (<25 mm) and no history of PTB, the use of cerclage is of uncertain benefit. Effectiveness may be seen if the cervix is less than 10 mm. Ultrasound-indicated cerclage should be considered in a singleton pregnancy with a CL less than 25 mm and a history of spontaneous PTB.

Possibly one of the most controversial topics is ultrasound-indicated cerclage placement in twin gestation. As with many situations in obstetrics, data regarding ultrasound-indicated cerclage in twin gestation is based on small retrospective studies fraught with bias. Results from these studies range from no benefit, to potential benefit, to even possible increased risk of PTB. Since data are limited, as we await more evidence, it is recommended that the clinician and patient use shared decision making to decide on cerclage placement in a twin gestation.

Exam indicated. In a singleton pregnancy with a dilated cervix on digital or speculum exam between 16 0/7 to 23 6/7 weeks’ gestation, a physical exam–indicated cerclage should be offered. Exam-indicated cerclage also may reduce the incidence of PTB in twin gestations with cervical dilation between 16 0/7 and 23 6/7 weeks’ gestation. Indomethacin tocolysis and perioperative antibiotics should be considered when an exam-indicated cerclage is placed.

As the limits of viability are continually pushed earlier, more in-depth conversation is needed with patients who are considering an exam-indicated cerclage. The nuances of periviability and the likelihood that an exam-indicated cerclage will commit a pregnancy to a periviable or extremely preterm birth should be discussed in detail using a shared decision making model.

Regardless of whether the cerclage is ultrasound or exam indicated, once it is placed there is no utility in additional CL ultrasound monitoring.

Pessary

Vaginal pessaries for prevention of PTB have not gained popularity in the United States as they have in other countries. Trials are being conducted to determine the utility of vaginal pessary, but current data have not proven its effectiveness in preventing PTB in the setting of singleton pregnancy, short cervix, and no history of spontaneous PTB. So for now, pessary is not recommended. The same can be said for use in the twin gestation.

Which patients may benefit from antepartum fetal surveillance and when to initiate it

American College of Obstetricians and Gynecologists’ Committee on Obstetrics Practice, Society for Maternal-Fetal Medicine. Indications for outpatient antenatal surveillance: ACOG committee opinion, number 828. Obstet Gynecol. 2021;137:e177-e197.

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Antepartum fetal surveillance: ACOG practice bulletin, number 229. Obstet Gynecol. 2021;137:e116-e127.

The ultimate purpose of antenatal fetal surveillance is to prevent stillbirth. However, stillbirth has multiple etiologies, not all of which are preventable with testing. In June 2021, ACOG released a new Committee Opinion containing guidelines for fetal surveillance, including suggested gestational age at initiation and frequency of testing, for the most common high-risk conditions. ACOG also released an update to the Practice Bulletin on antepartum fetal surveillance; additions include randomized controlled trial level data on the utility of fetal kick counts (FKCs) and recommendations that align with the new Committee Opinion.

Data for the efficacy of antepartum fetal surveillance are lacking, mainly due to the difficulty of performing prospective studies in stillbirth. The existing evidence is subject to intervention bias, as deliveries increase in tested patients, and recommendations rely heavily on expert consensus and nonrandomized studies. Antenatal testing is also time, cost, and labor intensive, with the risk of intervention for a false-positive result. Despite these limitations, obstetrical practices routinely perform antenatal fetal surveillance.

The new guidelines: The why, when, and how often

Why. Antepartum fetal surveillance is suggested for conditions that have a risk of stillbirth greater than 0.8 per 1,000 (that is, the false-negative rate of a biophysical profile or a modified biophysical profile) and the relative risk or odds ratio is greater than 2.0 for stillbirth compared with unaffected pregnancies.

When. For most conditions, ACOG recommends initiation of testing at 32 weeks or later, with notable earlier exceptions for some of the highest-risk patients. For certain conditions, such as fetal growth restriction and hypertensive disorders of pregnancy, the recommendation is to start “at diagnosis,” with the corollary “or at a gestational age when delivery would be considered because of abnormal results.” Shared decision making with the patient about pregnancy goals therefore is required, particularly in cases of fetal anomalies, genetic conditions, or at very early gestational ages.

How often. The recommended frequency of testing is at least weekly. Testing frequency should be increased to twice-weekly outpatient or daily inpatient for the most complicated pregnancies (for example, fetal growth restriction with abnormal umbilical artery Doppler studies, preeclampsia with severe features).

Once or twice weekly is an option for many conditions, which gives the clinician the opportunity to assess clinical stability as well as the patient’s input in terms of logistics and anxiety.

Patients with multiple conditions may fall into the “individualized” category, as do patients with suboptimal control of conditions (for example, diabetes, hypertension) that may affect the fetus as the pregnancy progresses.

New diagnoses included for surveillance

Several diagnoses not previously included now qualify for antepartum fetal surveillance under the new guidelines, most notably:

• history of obstetrical complications in the immediate preceding pregnancy

—history of prior fetal growth restriction requiring preterm delivery

—history of prior preeclampsia requiring delivery

• alcohol use of 5 or more drinks per day
• in vitro fertilization
• abnormal serum markers

—pregnancy-associated plasma protein A (PAPP-A) in the fifth or lower percentile or 0.4 multiples of the median (MoM)

—second trimester inhibin A of 2 or greater MoM

• prepregnancy body mass index (BMI)

—this is divided into 2 categories for timing of initiation of testing:

1.  37 weeks for BMI of 35 to 39.9 kg/m²
2.  34 weeks for BMI of or greater than 40 kg/m².

Fetal kick counts

The major change to the updated Practice Bulletin on antenatal surveillance is the inclusion of data on FKCs, a simple modality of fetal surveillance that does not require a clinical visit. For FKCs, a meta-analysis of more than 450,000 patients did not demonstrate a difference in perinatal death between the FKC intervention group (0.54%) and the control group (0.59%). Of note, there were small but statistically significant increases in the rates of induction of labor, cesarean delivery, and preterm delivery in the FKC intervention group. Therefore, this update does not recommend a formal program of FKCs for all patients.

Continue to: Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation...

Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation

American College of Obstetricians and Gynecologists. Use of antenatal corticosteroids at 22 weeks of gestation: ACOG practice advisory. September 2021. https://www .acog.org/clinical/clinical-guidance/practice-advisory /articles/2021/09/use-of-antenatal-corticosteroids-at -22-weeks-of-gestation. Accessed December 11, 2021.

In September 2021, ACOG and SMFM released a Practice Advisory updating the current recommendations for the administration of antenatal corticosteroids in the periviable period (22 to 25 6/7 weeks’ gestation). Whereas the prior lower limit of gestational age for consideration of steroids was 23 weeks, the new recommendation now extends this consideration down to 22 weeks.

The cited data include a meta-analysis of more than 2,200 patients in which the survival rate of infants born between 22 and 22 6/7 weeks who were exposed to antenatal steroids was 39% compared with 19.5% in the unexposed group. Another study of more than 1,000 patients demonstrated a statistically significant increase in overall survival in patients treated with antenatal steroids plus life support compared with life support only (38.5% vs 17.7%). Survival without major morbidity in this study, although increased from 1% to 4.4%, was still low.

Recommendation carries caveats

Given this information, the Practice Advisory offers a 2C level recommendation (weak recommendation, low quality of evidence) for antenatal steroids at 22 to 22 6/7 weeks’ gestation if neonatal resuscitation is planned, acknowledging the limitations and potential bias of the available data.

The Practice Advisory emphasizes the importance of counseling and patient involvement in the decision making. This requires a multidisciplinary collaboration among the neonatology and obstetrical teams, flexibility in the plan after birth depending on the infant’s condition, and redirection of care if appropriate. Estimated fetal weight, the presence of multiple gestations, fetal biologic sex, and any anomalies are also important in helping families make an informed decision for their particular pregnancy. As described in the Obstetric Care Consensus on periviable birth,⁶ it is important to remember that considerations and recommendations are not the same as requirements, and redirection of care to comfort and family memory making is not the same as withholding care.

The rest of the recommendations for the administration of antenatal steroids remain the same: Antenatal steroids are not recommended at less than 22 weeks due to lack of evidence of benefit, and they continue to be recommended at 24 weeks and beyond. ●

Obstetrical practice saw updates in 2021 to 3 major areas of pregnancy management: preterm birth prevention, antepartum fetal surveillance, and the use of antenatal corticosteroids.

Updated guidance on predicting and preventing spontaneous PTB

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth: ACOG practice bulletin, number 234. Obstet Gynecol. 2021;138:e65-e90.

Preterm birth (PTB) continues to pose a challenge in clinical obstetrics, with the most recently reported rate of 10.2% in the United States.¹ This accounts for almost 75% of perinatal mortality and more than half of neonatal morbidity, in which effects last well past the neonatal period. PTB is classified as spontaneous (following preterm labor, preterm prelabor rupture of membranes, or cervical insufficiency) or iatrogenic (indicated due to maternal and/or fetal complications).

Assessing risk for PTB

The single strongest predictor of subsequent PTB is a history of spontaneous PTB. Recurrence risk is further increased by the number of prior PTBs and the gestational age at prior PTB. Identification of and intervention for a short cervix has been shown to prolong gestation. Transvaginal ultrasonography of the cervix is the most accurate method for evaluating cervical length (CL). Specific examination criteria exist to ensure that CL measurements are reproducible and reliable.² A short CL is generally defined as a measurement of less than 25 mm between 16 and 24 weeks’ gestation.

Screening strategies

The American College of Obstetricians and Gynecologists (ACOG), with an endorsement from the Society for Maternal-Fetal Medicine (SMFM), recommends cervical evaluation during the anatomy ultrasound exam between 18 0/7 and 22 6/7 weeks’ gestation in all pregnant patients regardless of prior PTB.³ If transabdominal imaging is concerning for a shortened cervix, transvaginal ultrasonography should be performed to assess the CL.

Serial transvaginal CL measurements are recommended between 16 0/7 and 24 0/7 weeks’ gestation for patients with a current singleton pregnancy and history of a spontaneous PTB, but not for patients with a history of iatrogenic or indicated PTB.

Interventions: Mind your p’s and c’s

Interventions to reduce the risk of spontaneous PTB depend on whether the current pregnancy is a singleton, twins, or higher-order multiples; CL measurement; and history of spontaneous PTB. Preconception optimization of underlying medical conditions also is important to reduce the risk of recurrent indicated PTB.

Continue to: Progesterone...

Progesterone

Vaginal administration. Several trials have shown that vaginal progesterone can be used to reduce the risk of spontaneous PTB in asymptomatic patients with a singleton pregnancy, incidental finding of a short cervix (<25 mm), and no history of spontaneous PTB. This is a change from the prior recommendation of CL of less than 20 mm. In the setting of a twin pregnancy, regardless of CL, data do not definitively support the use of vaginal progesterone.

Intramuscular administration.^4,5 The popularity of intramuscular progesterone has waxed and waned. At present, ACOG recommends that all patients with a singleton pregnancy and history of spontaneous PTB be offered progesterone beginning at 16 0/7 weeks’ gestation following a shared decision-making process that includes the limited data of efficacy noted in existing studies.

In a twin pregnancy with no history of spontaneous PTB, the use of intramuscular progesterone has been shown to potentially increase the risk of PTB and admission to the neonatal intensive care unit. As such, intramuscular progesterone in the setting of a twin gestation without a history of spontaneous PTB is not recommended. When a prior spontaneous PTB has occurred, there may be some benefit to intramuscular progesterone in twin gestations.

Cerclage

Ultrasound indicated. In a singleton pregnancy with an incidental finding of short cervix (<25 mm) and no history of PTB, the use of cerclage is of uncertain benefit. Effectiveness may be seen if the cervix is less than 10 mm. Ultrasound-indicated cerclage should be considered in a singleton pregnancy with a CL less than 25 mm and a history of spontaneous PTB.

Possibly one of the most controversial topics is ultrasound-indicated cerclage placement in twin gestation. As with many situations in obstetrics, data regarding ultrasound-indicated cerclage in twin gestation is based on small retrospective studies fraught with bias. Results from these studies range from no benefit, to potential benefit, to even possible increased risk of PTB. Since data are limited, as we await more evidence, it is recommended that the clinician and patient use shared decision making to decide on cerclage placement in a twin gestation.

Exam indicated. In a singleton pregnancy with a dilated cervix on digital or speculum exam between 16 0/7 to 23 6/7 weeks’ gestation, a physical exam–indicated cerclage should be offered. Exam-indicated cerclage also may reduce the incidence of PTB in twin gestations with cervical dilation between 16 0/7 and 23 6/7 weeks’ gestation. Indomethacin tocolysis and perioperative antibiotics should be considered when an exam-indicated cerclage is placed.

As the limits of viability are continually pushed earlier, more in-depth conversation is needed with patients who are considering an exam-indicated cerclage. The nuances of periviability and the likelihood that an exam-indicated cerclage will commit a pregnancy to a periviable or extremely preterm birth should be discussed in detail using a shared decision making model.

Regardless of whether the cerclage is ultrasound or exam indicated, once it is placed there is no utility in additional CL ultrasound monitoring.

Pessary

Vaginal pessaries for prevention of PTB have not gained popularity in the United States as they have in other countries. Trials are being conducted to determine the utility of vaginal pessary, but current data have not proven its effectiveness in preventing PTB in the setting of singleton pregnancy, short cervix, and no history of spontaneous PTB. So for now, pessary is not recommended. The same can be said for use in the twin gestation.

Which patients may benefit from antepartum fetal surveillance and when to initiate it

American College of Obstetricians and Gynecologists’ Committee on Obstetrics Practice, Society for Maternal-Fetal Medicine. Indications for outpatient antenatal surveillance: ACOG committee opinion, number 828. Obstet Gynecol. 2021;137:e177-e197.

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Antepartum fetal surveillance: ACOG practice bulletin, number 229. Obstet Gynecol. 2021;137:e116-e127.

The ultimate purpose of antenatal fetal surveillance is to prevent stillbirth. However, stillbirth has multiple etiologies, not all of which are preventable with testing. In June 2021, ACOG released a new Committee Opinion containing guidelines for fetal surveillance, including suggested gestational age at initiation and frequency of testing, for the most common high-risk conditions. ACOG also released an update to the Practice Bulletin on antepartum fetal surveillance; additions include randomized controlled trial level data on the utility of fetal kick counts (FKCs) and recommendations that align with the new Committee Opinion.

Data for the efficacy of antepartum fetal surveillance are lacking, mainly due to the difficulty of performing prospective studies in stillbirth. The existing evidence is subject to intervention bias, as deliveries increase in tested patients, and recommendations rely heavily on expert consensus and nonrandomized studies. Antenatal testing is also time, cost, and labor intensive, with the risk of intervention for a false-positive result. Despite these limitations, obstetrical practices routinely perform antenatal fetal surveillance.

The new guidelines: The why, when, and how often

Why. Antepartum fetal surveillance is suggested for conditions that have a risk of stillbirth greater than 0.8 per 1,000 (that is, the false-negative rate of a biophysical profile or a modified biophysical profile) and the relative risk or odds ratio is greater than 2.0 for stillbirth compared with unaffected pregnancies.

When. For most conditions, ACOG recommends initiation of testing at 32 weeks or later, with notable earlier exceptions for some of the highest-risk patients. For certain conditions, such as fetal growth restriction and hypertensive disorders of pregnancy, the recommendation is to start “at diagnosis,” with the corollary “or at a gestational age when delivery would be considered because of abnormal results.” Shared decision making with the patient about pregnancy goals therefore is required, particularly in cases of fetal anomalies, genetic conditions, or at very early gestational ages.

How often. The recommended frequency of testing is at least weekly. Testing frequency should be increased to twice-weekly outpatient or daily inpatient for the most complicated pregnancies (for example, fetal growth restriction with abnormal umbilical artery Doppler studies, preeclampsia with severe features).

Once or twice weekly is an option for many conditions, which gives the clinician the opportunity to assess clinical stability as well as the patient’s input in terms of logistics and anxiety.

Patients with multiple conditions may fall into the “individualized” category, as do patients with suboptimal control of conditions (for example, diabetes, hypertension) that may affect the fetus as the pregnancy progresses.

New diagnoses included for surveillance

Several diagnoses not previously included now qualify for antepartum fetal surveillance under the new guidelines, most notably:

• history of obstetrical complications in the immediate preceding pregnancy

—history of prior fetal growth restriction requiring preterm delivery

—history of prior preeclampsia requiring delivery

• alcohol use of 5 or more drinks per day
• in vitro fertilization
• abnormal serum markers

—pregnancy-associated plasma protein A (PAPP-A) in the fifth or lower percentile or 0.4 multiples of the median (MoM)

—second trimester inhibin A of 2 or greater MoM

• prepregnancy body mass index (BMI)

—this is divided into 2 categories for timing of initiation of testing:

1.  37 weeks for BMI of 35 to 39.9 kg/m²
2.  34 weeks for BMI of or greater than 40 kg/m².

Fetal kick counts

The major change to the updated Practice Bulletin on antenatal surveillance is the inclusion of data on FKCs, a simple modality of fetal surveillance that does not require a clinical visit. For FKCs, a meta-analysis of more than 450,000 patients did not demonstrate a difference in perinatal death between the FKC intervention group (0.54%) and the control group (0.59%). Of note, there were small but statistically significant increases in the rates of induction of labor, cesarean delivery, and preterm delivery in the FKC intervention group. Therefore, this update does not recommend a formal program of FKCs for all patients.

Continue to: Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation...

Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation

American College of Obstetricians and Gynecologists. Use of antenatal corticosteroids at 22 weeks of gestation: ACOG practice advisory. September 2021. https://www .acog.org/clinical/clinical-guidance/practice-advisory /articles/2021/09/use-of-antenatal-corticosteroids-at -22-weeks-of-gestation. Accessed December 11, 2021.

In September 2021, ACOG and SMFM released a Practice Advisory updating the current recommendations for the administration of antenatal corticosteroids in the periviable period (22 to 25 6/7 weeks’ gestation). Whereas the prior lower limit of gestational age for consideration of steroids was 23 weeks, the new recommendation now extends this consideration down to 22 weeks.

The cited data include a meta-analysis of more than 2,200 patients in which the survival rate of infants born between 22 and 22 6/7 weeks who were exposed to antenatal steroids was 39% compared with 19.5% in the unexposed group. Another study of more than 1,000 patients demonstrated a statistically significant increase in overall survival in patients treated with antenatal steroids plus life support compared with life support only (38.5% vs 17.7%). Survival without major morbidity in this study, although increased from 1% to 4.4%, was still low.

Recommendation carries caveats

Given this information, the Practice Advisory offers a 2C level recommendation (weak recommendation, low quality of evidence) for antenatal steroids at 22 to 22 6/7 weeks’ gestation if neonatal resuscitation is planned, acknowledging the limitations and potential bias of the available data.

The Practice Advisory emphasizes the importance of counseling and patient involvement in the decision making. This requires a multidisciplinary collaboration among the neonatology and obstetrical teams, flexibility in the plan after birth depending on the infant’s condition, and redirection of care if appropriate. Estimated fetal weight, the presence of multiple gestations, fetal biologic sex, and any anomalies are also important in helping families make an informed decision for their particular pregnancy. As described in the Obstetric Care Consensus on periviable birth,⁶ it is important to remember that considerations and recommendations are not the same as requirements, and redirection of care to comfort and family memory making is not the same as withholding care.

The rest of the recommendations for the administration of antenatal steroids remain the same: Antenatal steroids are not recommended at less than 22 weeks due to lack of evidence of benefit, and they continue to be recommended at 24 weeks and beyond. ●

Obstetrical practice saw updates in 2021 to 3 major areas of pregnancy management: preterm birth prevention, antepartum fetal surveillance, and the use of antenatal corticosteroids.

Updated guidance on predicting and preventing spontaneous PTB

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth: ACOG practice bulletin, number 234. Obstet Gynecol. 2021;138:e65-e90.

Preterm birth (PTB) continues to pose a challenge in clinical obstetrics, with the most recently reported rate of 10.2% in the United States.¹ This accounts for almost 75% of perinatal mortality and more than half of neonatal morbidity, in which effects last well past the neonatal period. PTB is classified as spontaneous (following preterm labor, preterm prelabor rupture of membranes, or cervical insufficiency) or iatrogenic (indicated due to maternal and/or fetal complications).

Assessing risk for PTB

The single strongest predictor of subsequent PTB is a history of spontaneous PTB. Recurrence risk is further increased by the number of prior PTBs and the gestational age at prior PTB. Identification of and intervention for a short cervix has been shown to prolong gestation. Transvaginal ultrasonography of the cervix is the most accurate method for evaluating cervical length (CL). Specific examination criteria exist to ensure that CL measurements are reproducible and reliable.² A short CL is generally defined as a measurement of less than 25 mm between 16 and 24 weeks’ gestation.

Screening strategies

The American College of Obstetricians and Gynecologists (ACOG), with an endorsement from the Society for Maternal-Fetal Medicine (SMFM), recommends cervical evaluation during the anatomy ultrasound exam between 18 0/7 and 22 6/7 weeks’ gestation in all pregnant patients regardless of prior PTB.³ If transabdominal imaging is concerning for a shortened cervix, transvaginal ultrasonography should be performed to assess the CL.

Serial transvaginal CL measurements are recommended between 16 0/7 and 24 0/7 weeks’ gestation for patients with a current singleton pregnancy and history of a spontaneous PTB, but not for patients with a history of iatrogenic or indicated PTB.

Interventions: Mind your p’s and c’s

Interventions to reduce the risk of spontaneous PTB depend on whether the current pregnancy is a singleton, twins, or higher-order multiples; CL measurement; and history of spontaneous PTB. Preconception optimization of underlying medical conditions also is important to reduce the risk of recurrent indicated PTB.

Continue to: Progesterone...

Progesterone

Vaginal administration. Several trials have shown that vaginal progesterone can be used to reduce the risk of spontaneous PTB in asymptomatic patients with a singleton pregnancy, incidental finding of a short cervix (<25 mm), and no history of spontaneous PTB. This is a change from the prior recommendation of CL of less than 20 mm. In the setting of a twin pregnancy, regardless of CL, data do not definitively support the use of vaginal progesterone.

Intramuscular administration.^4,5 The popularity of intramuscular progesterone has waxed and waned. At present, ACOG recommends that all patients with a singleton pregnancy and history of spontaneous PTB be offered progesterone beginning at 16 0/7 weeks’ gestation following a shared decision-making process that includes the limited data of efficacy noted in existing studies.

In a twin pregnancy with no history of spontaneous PTB, the use of intramuscular progesterone has been shown to potentially increase the risk of PTB and admission to the neonatal intensive care unit. As such, intramuscular progesterone in the setting of a twin gestation without a history of spontaneous PTB is not recommended. When a prior spontaneous PTB has occurred, there may be some benefit to intramuscular progesterone in twin gestations.

Cerclage

Ultrasound indicated. In a singleton pregnancy with an incidental finding of short cervix (<25 mm) and no history of PTB, the use of cerclage is of uncertain benefit. Effectiveness may be seen if the cervix is less than 10 mm. Ultrasound-indicated cerclage should be considered in a singleton pregnancy with a CL less than 25 mm and a history of spontaneous PTB.

Possibly one of the most controversial topics is ultrasound-indicated cerclage placement in twin gestation. As with many situations in obstetrics, data regarding ultrasound-indicated cerclage in twin gestation is based on small retrospective studies fraught with bias. Results from these studies range from no benefit, to potential benefit, to even possible increased risk of PTB. Since data are limited, as we await more evidence, it is recommended that the clinician and patient use shared decision making to decide on cerclage placement in a twin gestation.

Exam indicated. In a singleton pregnancy with a dilated cervix on digital or speculum exam between 16 0/7 to 23 6/7 weeks’ gestation, a physical exam–indicated cerclage should be offered. Exam-indicated cerclage also may reduce the incidence of PTB in twin gestations with cervical dilation between 16 0/7 and 23 6/7 weeks’ gestation. Indomethacin tocolysis and perioperative antibiotics should be considered when an exam-indicated cerclage is placed.

As the limits of viability are continually pushed earlier, more in-depth conversation is needed with patients who are considering an exam-indicated cerclage. The nuances of periviability and the likelihood that an exam-indicated cerclage will commit a pregnancy to a periviable or extremely preterm birth should be discussed in detail using a shared decision making model.

Regardless of whether the cerclage is ultrasound or exam indicated, once it is placed there is no utility in additional CL ultrasound monitoring.

Pessary

Vaginal pessaries for prevention of PTB have not gained popularity in the United States as they have in other countries. Trials are being conducted to determine the utility of vaginal pessary, but current data have not proven its effectiveness in preventing PTB in the setting of singleton pregnancy, short cervix, and no history of spontaneous PTB. So for now, pessary is not recommended. The same can be said for use in the twin gestation.

Which patients may benefit from antepartum fetal surveillance and when to initiate it

American College of Obstetricians and Gynecologists’ Committee on Obstetrics Practice, Society for Maternal-Fetal Medicine. Indications for outpatient antenatal surveillance: ACOG committee opinion, number 828. Obstet Gynecol. 2021;137:e177-e197.

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Antepartum fetal surveillance: ACOG practice bulletin, number 229. Obstet Gynecol. 2021;137:e116-e127.

The ultimate purpose of antenatal fetal surveillance is to prevent stillbirth. However, stillbirth has multiple etiologies, not all of which are preventable with testing. In June 2021, ACOG released a new Committee Opinion containing guidelines for fetal surveillance, including suggested gestational age at initiation and frequency of testing, for the most common high-risk conditions. ACOG also released an update to the Practice Bulletin on antepartum fetal surveillance; additions include randomized controlled trial level data on the utility of fetal kick counts (FKCs) and recommendations that align with the new Committee Opinion.

Data for the efficacy of antepartum fetal surveillance are lacking, mainly due to the difficulty of performing prospective studies in stillbirth. The existing evidence is subject to intervention bias, as deliveries increase in tested patients, and recommendations rely heavily on expert consensus and nonrandomized studies. Antenatal testing is also time, cost, and labor intensive, with the risk of intervention for a false-positive result. Despite these limitations, obstetrical practices routinely perform antenatal fetal surveillance.

The new guidelines: The why, when, and how often

Why. Antepartum fetal surveillance is suggested for conditions that have a risk of stillbirth greater than 0.8 per 1,000 (that is, the false-negative rate of a biophysical profile or a modified biophysical profile) and the relative risk or odds ratio is greater than 2.0 for stillbirth compared with unaffected pregnancies.

When. For most conditions, ACOG recommends initiation of testing at 32 weeks or later, with notable earlier exceptions for some of the highest-risk patients. For certain conditions, such as fetal growth restriction and hypertensive disorders of pregnancy, the recommendation is to start “at diagnosis,” with the corollary “or at a gestational age when delivery would be considered because of abnormal results.” Shared decision making with the patient about pregnancy goals therefore is required, particularly in cases of fetal anomalies, genetic conditions, or at very early gestational ages.

How often. The recommended frequency of testing is at least weekly. Testing frequency should be increased to twice-weekly outpatient or daily inpatient for the most complicated pregnancies (for example, fetal growth restriction with abnormal umbilical artery Doppler studies, preeclampsia with severe features).

Once or twice weekly is an option for many conditions, which gives the clinician the opportunity to assess clinical stability as well as the patient’s input in terms of logistics and anxiety.

Patients with multiple conditions may fall into the “individualized” category, as do patients with suboptimal control of conditions (for example, diabetes, hypertension) that may affect the fetus as the pregnancy progresses.

New diagnoses included for surveillance

Several diagnoses not previously included now qualify for antepartum fetal surveillance under the new guidelines, most notably:

• history of obstetrical complications in the immediate preceding pregnancy

—history of prior fetal growth restriction requiring preterm delivery

—history of prior preeclampsia requiring delivery

• alcohol use of 5 or more drinks per day
• in vitro fertilization
• abnormal serum markers

—pregnancy-associated plasma protein A (PAPP-A) in the fifth or lower percentile or 0.4 multiples of the median (MoM)

—second trimester inhibin A of 2 or greater MoM

• prepregnancy body mass index (BMI)

—this is divided into 2 categories for timing of initiation of testing:

1.  37 weeks for BMI of 35 to 39.9 kg/m²
2.  34 weeks for BMI of or greater than 40 kg/m².

Fetal kick counts

The major change to the updated Practice Bulletin on antenatal surveillance is the inclusion of data on FKCs, a simple modality of fetal surveillance that does not require a clinical visit. For FKCs, a meta-analysis of more than 450,000 patients did not demonstrate a difference in perinatal death between the FKC intervention group (0.54%) and the control group (0.59%). Of note, there were small but statistically significant increases in the rates of induction of labor, cesarean delivery, and preterm delivery in the FKC intervention group. Therefore, this update does not recommend a formal program of FKCs for all patients.

Continue to: Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation...

Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation

American College of Obstetricians and Gynecologists. Use of antenatal corticosteroids at 22 weeks of gestation: ACOG practice advisory. September 2021. https://www .acog.org/clinical/clinical-guidance/practice-advisory /articles/2021/09/use-of-antenatal-corticosteroids-at -22-weeks-of-gestation. Accessed December 11, 2021.

In September 2021, ACOG and SMFM released a Practice Advisory updating the current recommendations for the administration of antenatal corticosteroids in the periviable period (22 to 25 6/7 weeks’ gestation). Whereas the prior lower limit of gestational age for consideration of steroids was 23 weeks, the new recommendation now extends this consideration down to 22 weeks.

The cited data include a meta-analysis of more than 2,200 patients in which the survival rate of infants born between 22 and 22 6/7 weeks who were exposed to antenatal steroids was 39% compared with 19.5% in the unexposed group. Another study of more than 1,000 patients demonstrated a statistically significant increase in overall survival in patients treated with antenatal steroids plus life support compared with life support only (38.5% vs 17.7%). Survival without major morbidity in this study, although increased from 1% to 4.4%, was still low.

Recommendation carries caveats

Given this information, the Practice Advisory offers a 2C level recommendation (weak recommendation, low quality of evidence) for antenatal steroids at 22 to 22 6/7 weeks’ gestation if neonatal resuscitation is planned, acknowledging the limitations and potential bias of the available data.

The Practice Advisory emphasizes the importance of counseling and patient involvement in the decision making. This requires a multidisciplinary collaboration among the neonatology and obstetrical teams, flexibility in the plan after birth depending on the infant’s condition, and redirection of care if appropriate. Estimated fetal weight, the presence of multiple gestations, fetal biologic sex, and any anomalies are also important in helping families make an informed decision for their particular pregnancy. As described in the Obstetric Care Consensus on periviable birth,⁶ it is important to remember that considerations and recommendations are not the same as requirements, and redirection of care to comfort and family memory making is not the same as withholding care.

The rest of the recommendations for the administration of antenatal steroids remain the same: Antenatal steroids are not recommended at less than 22 weeks due to lack of evidence of benefit, and they continue to be recommended at 24 weeks and beyond. ●

Blanc J, Castel P, Mauviel F, et al. Prophylactic manual rotation of occiput posterior and transverse positions to decrease operative delivery: the PROPOP randomized clinical trial. Am J Obstet Gynecol. 2021;225:444.e1-444.e8. doi: 10.1016/j.ajog.2021.05.020.

EXPERT COMMENTARY

Occiput posterior or occiput transverse positions are reported at a rate of 20% in labor, with 5% persistent at the time of delivery. These lead to a higher risk of maternal complications, such as cesarean delivery (CD), prolonged second stage, severe perineal lacerations, postpartum hemorrhage, chorioamnionitis, and operative vaginal delivery.

Several options are available for rotation to occiput anterior (OA) to increase the likelihood of spontaneous delivery. These include instrument (which requires forceps or vacuum experience in rotation), maternal positioning changes, or manual rotation. Timing of manual rotation can be at full dilation (“prophylactic”) or at failure to progress (“therapeutic”), with the latter less likely to succeed.

Although the existing literature is somewhat limited, both the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommend consideration of manual rotation to reduce the rate of operative delivery. A recent study by Blanc and colleagues sought to add to the evidence for the effectiveness of manual rotation in reducing operative delivery.

Details of the study

The multicenter, open-label, randomized clinical trial included 257 patients at 4 French hospitals (2 academic, 2 community). The 126 patients in the intervention group underwent a trial of prophylactic manual rotation, while the 131 in the standard group had no trial of prophylactic manual rotation. The study’s primary objective was to determine the effect of prophylactic manual rotation on operative delivery (vaginal or cesarean). The hypothesis was that manual rotation would decrease the risk of operative delivery.

The inclusion criteria were patients with a singleton pregnancy at more than 37 weeks, epidural anesthesia, and OP or OT presentation (confirmed by ultrasonography) in the early second stage of labor at diagnosis of full dilation. Manual rotation was attempted using the previously described Tarnier and Chantreiul technique, and all investigators were trained in this technique at the beginning of the study using a mannequin.

The primary outcome was vaginal or cesarean operative delivery. Secondary outcomes included length of the second stage of labor as well as maternal and neonatal complications.

Results. The intervention group had a significantly lower rate of operative delivery (29.4%) compared with the standard group (41.2%). Length of the second stage was also lower in the intervention group (146.7 minutes) compared with that of the standard group (164.4 minutes). The 5-minute Apgar score was reported as significantly higher in the intervention group as well (9.8 vs 9.6). There were no other differences between the groups in either maternal or neonatal complications.

Study strengths and limitations

The strengths of this study included randomization and no loss to follow-up. The 4 different study sites with different levels of care and acuity added to the generalizability of the results. Given the potential for inaccuracy of digital exam for fetal head positioning, the use of ultrasonography for confirmation of the OP or OT position is a study strength. Additional strengths are the prestudy training in the maneuver using simulation and the high level of success in the rotations (89.7%).

The study’s main limitation is that it was not double blinded; therefore, bias in management was a possibility. Additionally, the study looked only at short-term outcomes for the delivery itself and not at the potential long-term pelvic floor outcomes. The authors reported that the study was underpowered for operative vaginal delivery and cesarean delivery separately, as well as the secondary outcomes. Other limitations were the high frequency of operative vaginal delivery, low rate of consent for the study, and lack of patient satisfaction data. ●

Blanc J, Castel P, Mauviel F, et al. Prophylactic manual rotation of occiput posterior and transverse positions to decrease operative delivery: the PROPOP randomized clinical trial. Am J Obstet Gynecol. 2021;225:444.e1-444.e8. doi: 10.1016/j.ajog.2021.05.020.

EXPERT COMMENTARY

Occiput posterior or occiput transverse positions are reported at a rate of 20% in labor, with 5% persistent at the time of delivery. These lead to a higher risk of maternal complications, such as cesarean delivery (CD), prolonged second stage, severe perineal lacerations, postpartum hemorrhage, chorioamnionitis, and operative vaginal delivery.

Several options are available for rotation to occiput anterior (OA) to increase the likelihood of spontaneous delivery. These include instrument (which requires forceps or vacuum experience in rotation), maternal positioning changes, or manual rotation. Timing of manual rotation can be at full dilation (“prophylactic”) or at failure to progress (“therapeutic”), with the latter less likely to succeed.

Although the existing literature is somewhat limited, both the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommend consideration of manual rotation to reduce the rate of operative delivery. A recent study by Blanc and colleagues sought to add to the evidence for the effectiveness of manual rotation in reducing operative delivery.

Details of the study

The multicenter, open-label, randomized clinical trial included 257 patients at 4 French hospitals (2 academic, 2 community). The 126 patients in the intervention group underwent a trial of prophylactic manual rotation, while the 131 in the standard group had no trial of prophylactic manual rotation. The study’s primary objective was to determine the effect of prophylactic manual rotation on operative delivery (vaginal or cesarean). The hypothesis was that manual rotation would decrease the risk of operative delivery.

The inclusion criteria were patients with a singleton pregnancy at more than 37 weeks, epidural anesthesia, and OP or OT presentation (confirmed by ultrasonography) in the early second stage of labor at diagnosis of full dilation. Manual rotation was attempted using the previously described Tarnier and Chantreiul technique, and all investigators were trained in this technique at the beginning of the study using a mannequin.

The primary outcome was vaginal or cesarean operative delivery. Secondary outcomes included length of the second stage of labor as well as maternal and neonatal complications.

Results. The intervention group had a significantly lower rate of operative delivery (29.4%) compared with the standard group (41.2%). Length of the second stage was also lower in the intervention group (146.7 minutes) compared with that of the standard group (164.4 minutes). The 5-minute Apgar score was reported as significantly higher in the intervention group as well (9.8 vs 9.6). There were no other differences between the groups in either maternal or neonatal complications.

Study strengths and limitations

The strengths of this study included randomization and no loss to follow-up. The 4 different study sites with different levels of care and acuity added to the generalizability of the results. Given the potential for inaccuracy of digital exam for fetal head positioning, the use of ultrasonography for confirmation of the OP or OT position is a study strength. Additional strengths are the prestudy training in the maneuver using simulation and the high level of success in the rotations (89.7%).

The study’s main limitation is that it was not double blinded; therefore, bias in management was a possibility. Additionally, the study looked only at short-term outcomes for the delivery itself and not at the potential long-term pelvic floor outcomes. The authors reported that the study was underpowered for operative vaginal delivery and cesarean delivery separately, as well as the secondary outcomes. Other limitations were the high frequency of operative vaginal delivery, low rate of consent for the study, and lack of patient satisfaction data. ●

Blanc J, Castel P, Mauviel F, et al. Prophylactic manual rotation of occiput posterior and transverse positions to decrease operative delivery: the PROPOP randomized clinical trial. Am J Obstet Gynecol. 2021;225:444.e1-444.e8. doi: 10.1016/j.ajog.2021.05.020.

EXPERT COMMENTARY

Occiput posterior or occiput transverse positions are reported at a rate of 20% in labor, with 5% persistent at the time of delivery. These lead to a higher risk of maternal complications, such as cesarean delivery (CD), prolonged second stage, severe perineal lacerations, postpartum hemorrhage, chorioamnionitis, and operative vaginal delivery.

Several options are available for rotation to occiput anterior (OA) to increase the likelihood of spontaneous delivery. These include instrument (which requires forceps or vacuum experience in rotation), maternal positioning changes, or manual rotation. Timing of manual rotation can be at full dilation (“prophylactic”) or at failure to progress (“therapeutic”), with the latter less likely to succeed.

Although the existing literature is somewhat limited, both the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommend consideration of manual rotation to reduce the rate of operative delivery. A recent study by Blanc and colleagues sought to add to the evidence for the effectiveness of manual rotation in reducing operative delivery.

Details of the study

The multicenter, open-label, randomized clinical trial included 257 patients at 4 French hospitals (2 academic, 2 community). The 126 patients in the intervention group underwent a trial of prophylactic manual rotation, while the 131 in the standard group had no trial of prophylactic manual rotation. The study’s primary objective was to determine the effect of prophylactic manual rotation on operative delivery (vaginal or cesarean). The hypothesis was that manual rotation would decrease the risk of operative delivery.

The inclusion criteria were patients with a singleton pregnancy at more than 37 weeks, epidural anesthesia, and OP or OT presentation (confirmed by ultrasonography) in the early second stage of labor at diagnosis of full dilation. Manual rotation was attempted using the previously described Tarnier and Chantreiul technique, and all investigators were trained in this technique at the beginning of the study using a mannequin.

The primary outcome was vaginal or cesarean operative delivery. Secondary outcomes included length of the second stage of labor as well as maternal and neonatal complications.

Results. The intervention group had a significantly lower rate of operative delivery (29.4%) compared with the standard group (41.2%). Length of the second stage was also lower in the intervention group (146.7 minutes) compared with that of the standard group (164.4 minutes). The 5-minute Apgar score was reported as significantly higher in the intervention group as well (9.8 vs 9.6). There were no other differences between the groups in either maternal or neonatal complications.

Study strengths and limitations

The strengths of this study included randomization and no loss to follow-up. The 4 different study sites with different levels of care and acuity added to the generalizability of the results. Given the potential for inaccuracy of digital exam for fetal head positioning, the use of ultrasonography for confirmation of the OP or OT position is a study strength. Additional strengths are the prestudy training in the maneuver using simulation and the high level of success in the rotations (89.7%).

The study’s main limitation is that it was not double blinded; therefore, bias in management was a possibility. Additionally, the study looked only at short-term outcomes for the delivery itself and not at the potential long-term pelvic floor outcomes. The authors reported that the study was underpowered for operative vaginal delivery and cesarean delivery separately, as well as the secondary outcomes. Other limitations were the high frequency of operative vaginal delivery, low rate of consent for the study, and lack of patient satisfaction data. ●

Gray KJ, Bordt EA, Atyeo C, et al. COVID-19 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol. 2021;S0002-9378(21)00187-3. doi: 10.1016/j.ajog.2021.03.023

EXPERT COMMENTARY

Pregnant women are among those at highest risk for severe disease and death from SARS-CoV-2 infection. However, exclusion of pregnant and lactating women from the initial COVID-19 vaccine trials has made counseling these patients challenging due to both the novelty of the vaccines themselves and the general lack of data in this vulnerable population. Data for the efficacy and risks of vaccination are needed to inform shared decision making between clinician and patient.

Details of the study

Gray and colleagues conducted a prospective cohort study of 84 pregnant, 31 lactating, and 16 nonpregnant women who received 1 of the 2 COVID-19 mRNA vaccines approved by the US Food and Drug Administration for emergency use authorization (BNT162b2 Pfizer/BioNTech or mRNA-1273 Moderna). The study’s primary objective was to evaluate the humoral immune response (antibody quantification) and adverse effects of these vaccines in the pregnant and lactating women compared with both nonpregnant women and a cohort of 37 women who had natural COVID-19 infection during pregnancy.

Antibody quantification from blood and breast milk was performed at 4 time points: V0, the first vaccine dose; V1, the second vaccine dose; V2, 2 to 6 weeks after the second vaccine dose; and at delivery. Umbilical cord blood also was collected from the subset of delivered patients (n = 13).

Results. The ultimately IgG-dominated antibody response to the vaccine in pregnant and lactating women was comparable to that in nonpregnant women, and all vaccine antibody responses were significantly higher than that in response to natural SARS-CoV-2 infection. IgG antibodies also were found in umbilical cord blood and breast milk, supporting the transfer of immunity to both the fetus and infant. There were no significant differences in adverse effects between pregnant and nonpregnant women.

Study strengths and limitations

This study’s main strength is that it demonstrated a similar increase in humoral immune response to the COVID-19 mRNA vaccines in a previously unstudied population of pregnant and lactating women, supporting the potential efficacy of the vaccines in this group at high risk for complications from SARS-CoV-2. Other data to support this include the increased vaccine antibody response compared with the antibody response after SARS-CoV-2 infection in pregnant women as well as the presence of maternal-infant transfer of antibodies via cord blood and breast milk. All of these are important data to inform patients and practitioners who are trying to make shared, informed decisions about a novel vaccine during a global pandemic.

The main limitation of this study is a limited patient population of mostly White, non-Hispanic, health care workers with few comorbidities and only 13 delivered vaccinated patients within the study period. Long-term immunity, immune responses other than antibody titers, and potential fetal effects also were not explored in this study. ●

Gray KJ, Bordt EA, Atyeo C, et al. COVID-19 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol. 2021;S0002-9378(21)00187-3. doi: 10.1016/j.ajog.2021.03.023

EXPERT COMMENTARY

Pregnant women are among those at highest risk for severe disease and death from SARS-CoV-2 infection. However, exclusion of pregnant and lactating women from the initial COVID-19 vaccine trials has made counseling these patients challenging due to both the novelty of the vaccines themselves and the general lack of data in this vulnerable population. Data for the efficacy and risks of vaccination are needed to inform shared decision making between clinician and patient.

Details of the study

Gray and colleagues conducted a prospective cohort study of 84 pregnant, 31 lactating, and 16 nonpregnant women who received 1 of the 2 COVID-19 mRNA vaccines approved by the US Food and Drug Administration for emergency use authorization (BNT162b2 Pfizer/BioNTech or mRNA-1273 Moderna). The study’s primary objective was to evaluate the humoral immune response (antibody quantification) and adverse effects of these vaccines in the pregnant and lactating women compared with both nonpregnant women and a cohort of 37 women who had natural COVID-19 infection during pregnancy.

Antibody quantification from blood and breast milk was performed at 4 time points: V0, the first vaccine dose; V1, the second vaccine dose; V2, 2 to 6 weeks after the second vaccine dose; and at delivery. Umbilical cord blood also was collected from the subset of delivered patients (n = 13).

Results. The ultimately IgG-dominated antibody response to the vaccine in pregnant and lactating women was comparable to that in nonpregnant women, and all vaccine antibody responses were significantly higher than that in response to natural SARS-CoV-2 infection. IgG antibodies also were found in umbilical cord blood and breast milk, supporting the transfer of immunity to both the fetus and infant. There were no significant differences in adverse effects between pregnant and nonpregnant women.

Study strengths and limitations

This study’s main strength is that it demonstrated a similar increase in humoral immune response to the COVID-19 mRNA vaccines in a previously unstudied population of pregnant and lactating women, supporting the potential efficacy of the vaccines in this group at high risk for complications from SARS-CoV-2. Other data to support this include the increased vaccine antibody response compared with the antibody response after SARS-CoV-2 infection in pregnant women as well as the presence of maternal-infant transfer of antibodies via cord blood and breast milk. All of these are important data to inform patients and practitioners who are trying to make shared, informed decisions about a novel vaccine during a global pandemic.

The main limitation of this study is a limited patient population of mostly White, non-Hispanic, health care workers with few comorbidities and only 13 delivered vaccinated patients within the study period. Long-term immunity, immune responses other than antibody titers, and potential fetal effects also were not explored in this study. ●

Gray KJ, Bordt EA, Atyeo C, et al. COVID-19 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol. 2021;S0002-9378(21)00187-3. doi: 10.1016/j.ajog.2021.03.023

EXPERT COMMENTARY

Pregnant women are among those at highest risk for severe disease and death from SARS-CoV-2 infection. However, exclusion of pregnant and lactating women from the initial COVID-19 vaccine trials has made counseling these patients challenging due to both the novelty of the vaccines themselves and the general lack of data in this vulnerable population. Data for the efficacy and risks of vaccination are needed to inform shared decision making between clinician and patient.

Details of the study

Gray and colleagues conducted a prospective cohort study of 84 pregnant, 31 lactating, and 16 nonpregnant women who received 1 of the 2 COVID-19 mRNA vaccines approved by the US Food and Drug Administration for emergency use authorization (BNT162b2 Pfizer/BioNTech or mRNA-1273 Moderna). The study’s primary objective was to evaluate the humoral immune response (antibody quantification) and adverse effects of these vaccines in the pregnant and lactating women compared with both nonpregnant women and a cohort of 37 women who had natural COVID-19 infection during pregnancy.

Antibody quantification from blood and breast milk was performed at 4 time points: V0, the first vaccine dose; V1, the second vaccine dose; V2, 2 to 6 weeks after the second vaccine dose; and at delivery. Umbilical cord blood also was collected from the subset of delivered patients (n = 13).

Results. The ultimately IgG-dominated antibody response to the vaccine in pregnant and lactating women was comparable to that in nonpregnant women, and all vaccine antibody responses were significantly higher than that in response to natural SARS-CoV-2 infection. IgG antibodies also were found in umbilical cord blood and breast milk, supporting the transfer of immunity to both the fetus and infant. There were no significant differences in adverse effects between pregnant and nonpregnant women.

Study strengths and limitations

This study’s main strength is that it demonstrated a similar increase in humoral immune response to the COVID-19 mRNA vaccines in a previously unstudied population of pregnant and lactating women, supporting the potential efficacy of the vaccines in this group at high risk for complications from SARS-CoV-2. Other data to support this include the increased vaccine antibody response compared with the antibody response after SARS-CoV-2 infection in pregnant women as well as the presence of maternal-infant transfer of antibodies via cord blood and breast milk. All of these are important data to inform patients and practitioners who are trying to make shared, informed decisions about a novel vaccine during a global pandemic.

The main limitation of this study is a limited patient population of mostly White, non-Hispanic, health care workers with few comorbidities and only 13 delivered vaccinated patients within the study period. Long-term immunity, immune responses other than antibody titers, and potential fetal effects also were not explored in this study. ●

Practicing evidence-based medicine, as obstetricians know, is not always possible when one does not have evidence due to lack of data or long-term experience in pregnancy. During the COVID-19 pandemic, the evidence changed so rapidly that we were compelled to alter our strategy frequently as we learned more about the impact of this disease on our vulnerable patient population. The COVID-19 pandemic taught us that, in unprecedented times, centering the safety of the patient, her child, and the health care team requires quick thinking, flexibility, and above all effective communication between team members.

Here, I share our institutional experience in providing practical obstetric care through various stages of the still-evolving COVID-19 pandemic. We based our strategy on guidance from the Centers for Disease Control and Prevention (CDC), the American College of Obstetricians and Gynecologists (ACOG),^1,2 and the Society for Maternal-Fetal Medicine (SMFM).^3-5 We were reminded yet again that the only constant is change and that timely but thoughtful adjustments were needed to keep up with the coronavirus.

Changes to prenatal care

Like many others, our institution has provided continued in-person outpatient prenatal care to both our low- and high-risk patients throughout each stage of the pandemic. While continuing to provide the necessary obstetric care, we made alterations to limit exposure and practice social distancing when possible.

Limiting patient support persons. One significant change was to restrict or limit support persons in the outpatient clinics based on guidelines reflecting community infection rates. Recognizing that this was not optimal for our patients’ emotional well-being, we needed to become more flexible in using technology to include family or support persons in prenatal visits and ultrasonography exams.

Altering test frequency. Using the guidance from SMFM,¹ we changed the frequency of our antenatal testing and ultrasonography exams in the following ways: We increased the duration between indicated growth ultrasonography to every 4 weeks and decreased fetal antenatal testing to weekly, with twice-weekly testing continued for the highest-risk patients. Early first-trimester ultrasonography exams were limited and, when possible, delayed until after 10 to 12 weeks’ gestation or combined with other indications (nuchal translucency). Prenatal visits for low-risk patients were spaced out using existing models if the patient was amenable, especially in early pregnancy.

Adjusting staff assignments and using telehealth. In the early part of the pandemic, we divided into 2 groups to limit the number of clinicians at any one site: a dedicated group of outpatient clinicians who saw patients in the clinic only and a dedicated group of inpatient clinicians who staffed labor and delivery and the inpatient antepartum service. Additionally, our consultative maternal-fetal medicine service transitioned to a telehealth platform and performed the majority of consults remotely. Ultrasonography exams at various sites were read remotely and pertinent findings were communicated directly to patients via phone or the telehealth platform. Amniocentesis continued to be offered.

Responding to lower COVID-19 case numbers. When the number of COVID-19 cases decreased in the summer and fall of 2020, we returned to our prepandemic in-person practices, but we continued to offer telehealth visits as an option for patients who desired it. Patients were limited to one support person.

Shifting gears again. During the second surge of COVID-19 in our region, we used our experiences from the first to transition our practices to reduce in-person contact. Appointment frequency was decreased if appropriate, and we developed a tiered system of antenatal testing frequency based on risk factors. Visitors were again restricted, with exceptions made for extenuating circumstances. Consults were transitioned to telemedicine as appropriate and ultrasonography exams were read remotely when possible to limit exposures. Given the varied experiences with telemedicine and patient preferences, patients who desired in-person consult were (and are still) offered this option.

Some patients who were interested in telehealth but unable to access the technology were offered appointments via telehealth with the use of our clinic devices. Telemedicine increased our flexibility in offering consults as one provider could see patients at different office sites in one session. We continued our routine inpatient and outpatient coverage during this time as this kept our coverage options more flexible and expanded our obstetric backup plan in response to increased rates of community infection that affected both clinicians and patients.

Coordinating care for infected patients. One vital part of our prenatal care during the COVID-19 pandemic was to coordinate with our colleagues in medical specialties to provide outpatient care for patients with confirmed or suspected COVID-19 during their period of isolation or quarantine. Patients could be seen as outpatients in a dedicated space that used appropriate personal protective equipment (PPE) for not only prenatal care but also any needed in-person evaluation for COVID-19. Our obstetric clinicians and sonographers performed exams, antenatal testing (in the form of biophysical profiles), and indicated ultrasonography exams (such as umbilical artery Doppler studies and fetal growth assessments). This required a concerted effort and excellent communication between teams to provide the necessary care in the safest manner possible.

Continue to: Universal testing on labor and delivery...

Not surprisingly, obstetric delivery volumes in our institution were not affected in the same way as elective surgery volumes. Our inpatient team continued to bring babies into the world at the same if not a higher rate than in prepandemic times. We continued elective inductions when space allowed. Our first COVID-19–positive patient was already at 40 weeks’ gestation when the result of her test, done due to exposure, was received. Creative effort among multiple specialties quickly developed her delivery plan, and she and her infant did well.

As data started coming out of the New York City obstetric experience, concern for preservation of the PPE supply and the potential for asymptomatic/presymptomatic patients led us, in consultation with our infectious disease colleagues, to institute universal testing for all antepartum and laboring patients. At first, all patients were tested on admission with our rapid in-house test. Eventually, we moved toward preoperative testing 3 to 5 days prior to scheduled cesarean deliveries in alignment with the surgical services when elective cases were reinstituted. Finally, we instituted preprocedure testing for all scheduled labor and delivery procedures, including inductions, cerclages, and fetal blood transfusions, while we still used rapid testing for patients who presented urgently or in labor.

We needed to address several considerations almost immediately after instituting universal testing, including:

• what to do in case of patient refusal to be tested
• which precautions to institute while awaiting test results
• potential postponement of elective delivery if a patient tested positive, and
• where best to deliver patients.

What we did at the beginning of the pandemic was not necessarily the same as we do in our current practice, and we expect that our procedures may need to change in the future. Derived from what we learned from others’ experience, we tailored our protocols to our own physical space, staffing capabilities, and testing limitations. We adjusted them often, with input from multiple services, based on updated policy, recommendation for isolation and quarantine durations, rates of community infection, and changes in the unit spaces. As with many things, one protocol did not fit every patient, necessitating case-by-case flexibility.

Delivery considerations

To answer some of the above questions, all patients who declined testing, were awaiting test results while in labor, or were in triage were placed in droplet and contact isolation on our unit, a practice we continue currently. Given the concern of potential aerosolization during the second stage of labor or during intubation, for any patients in those categories who required delivery, we limited the number of staff in their rooms as possible. Additional pediatric staff waited in close proximity of the room and were ready to come in if needed depending on fetal complications and gestational age. For delivery, all team members used full special pathogens precautions (N95 masks, face shields, gowns, and gloves).

Patients who were asymptomatic and tested negative for COVID-19 had and continue to have routine care from a PPE (standard gowns, gloves, face mask, and eye protection) and health care team perspective. We have allowed visitation of one support person per hospital stay for these patients throughout the pandemic.

For the majority of our experience during the pandemic, adult patients who tested positive for COVID-19 were cohorted within dedicated negative pressure units of varying levels of care. As these units included the same intensive care unit (ICU) we utilized in non-COVID times for critical obstetric patients, we had already operationalized their use and they were wired for our electronic fetal monitoring system. These rooms are adjacent to the main operating room (OR) complex, which allows for transition to a dedicated COVID-19 OR for cesarean delivery. We worked with the primary COVID-19 team, ICU team, anesthesia, and neonatal ICU team to develop a written protocol that detailed the care for our COVID-19–positive laboring and postpartum patients in this critical care COVID-19 unit.

For a time, admitted COVID-19–positive patients were not permitted to have support persons. The health care team therefore stepped in to be the patients’ support during the delivery of their child. Care of these patients required a great deal of coordination and communication between teams as well as the addition of a dedicated obstetric physician—separate from the regular labor and delivery team—assigned to care for these patients.

For pregnant patients in the emergency room or in the intermediate or floor COVID-19 units, portable fetal monitors and ultrasonography equipment were used for obstetric consults, fetal testing, and obstetrical ultrasonography as appropriate based on gestational age and medical conditions. Again, communication between teams was essential to provide seamless and timely patient care. Patients usually were admitted to the COVID-19 teams with maternal-fetal medicine or obstetric consult teams following daily; they were admitted and transferred to the ICU COVID-19 unit if delivery was necessary. To limit exposures whenever possible, coordinated care (such as exams and telephone evaluation) was performed outside of the room with the nursing and primary teams.

Continue to: Staying flexible to the changing COVID-19 environment...

Postponed in-person visits. Whenever possible, deliveries that were not medically indicated and in-person outpatient care visits were postponed until isolation/quarantine precautions could be lifted to avoid the need for special pathogens precautions, separation of mother and infant, and visitor restrictions. We did not postpone any medically indicated deliveries or appropriate care due to COVID-19 alone. As the CDC guidelines changed regarding the timing of infectivity, we had to continually re-evaluate when a patient could return to regular outpatient care instead of the COVID-19 clinic and/or be delivered.

Mother-infant separation. As outlined in an article we wrote with our pediatric colleagues, originally all infants were immediately separated from their COVID-19–positive mothers, and delayed cord clamping was not performed.⁶ We adjusted our protocols as experience and data grew regarding the risk of transmission to the newborn from asymptomatic mothers and as updated recommendations were made by ACOG and the CDC. Currently, if desired, asymptomatic mothers are not separated from their well term infants. We practice our standard delayed cord clamping technique for all patients. Masking, hand hygiene, and physical distancing are used to reduce the risk of infection transmission. Breastfeeding is encouraged if the patient desires it, either directly using precautions or supported via pumping.

Reduced workplace exposure. Along with many others, we are even more cognizant of reducing the risk of workplace exposure; thus, we conduct our daily multidisciplinary huddle and physician transition of care sign-outs. We use multiple rooms for our larger group with secure video chats, and we limit huddles to a single representative from each specialty.

Medication protocols. Early in the pandemic in our area, we limited antenatal corticosteroids for fetal lung maturity to patients who were at less than 34 weeks’ gestation, per ACOG recommendations, carefully considering necessity in the critically ill. Now, we continue to administer antenatal steroids according to our usual protocols up to 36 6/7 weeks, per ACOG and SMFM recommendations, regardless of illness severity.⁷ Nonsteroidal anti-inflammatory drug use, once limited in COVID-19–positive patients, are now used again. Additionally, we had a comprehensive venous thromboembolism (VTE) prophylaxis protocol for our obstetric patients, and we have added special consideration for prophylaxis for patients with moderate to severe illness or other VTE risk factors. While we do not perform routine circumcisions on infants of COVID-19–positive mothers, we have a process in place to provide that service after discharge when isolation precautions are lifted.

Labor accommodations. As COVID-19 cases increased in our hospital during recent months, we made one more significant change in our care protocols. To open up space in the ICU, we moved our care for asymptomatic COVID-19–positive laboring patients to our new labor and delivery unit with implemented special pathogens precautions. This is not revolutionary; many other hospitals did not have the same capability we did with our existing collaboration with the ICU for critical obstetric care. However, this change again required communication and collaboration among multiple care teams, agreement on the qualifications for delivery on labor and delivery versus in the ICU, and physical alteration of our unit to accommodate additional isolation precautions.

Visitor policy. Another change is that we have opened up the visitor policy to welcome an asymptomatic support person for the COVID-19–positive labor patient, giving special attention to adherence to isolation precautions. Our staff members have embraced this change as they have everything else, with cautious optimism and focus on keeping both the patients and the health care team safe. Our moderate to severely ill patients continue to be cared for in the COVID-19 unit in close collaboration with our infectious disease and ICU colleagues.

It’s all about teamwork

I hope I have given a clear example of our approach to providing obstetric care in the ever-changing landscape of the COVID-19 pandemic. We embraced this period of necessary change as practically and safely as possible for both our patients and our health care workers. We learned multiple times along the way that what seemed to be a good idea was not feasible, or not the ideal option, or that COVID-19 had changed the rules of the game again. Our team met daily if not more frequently, as we found we had to constantly adapt and change to each new challenge or new clinical scenario. When we struggled, it generally related to a gap in communication.

I am privileged to work with a dedicated, selfless, multidisciplinary team that rose to the occasion. They had the focused goal to provide the highest quality and safety in obstetric care while offering compassion and empathy for the experience of having a baby during a pandemic. ●

The author would like to acknowledge Danielle Prentice, DO, and Jaimie Maines, MD, for their manuscript review.

Practicing evidence-based medicine, as obstetricians know, is not always possible when one does not have evidence due to lack of data or long-term experience in pregnancy. During the COVID-19 pandemic, the evidence changed so rapidly that we were compelled to alter our strategy frequently as we learned more about the impact of this disease on our vulnerable patient population. The COVID-19 pandemic taught us that, in unprecedented times, centering the safety of the patient, her child, and the health care team requires quick thinking, flexibility, and above all effective communication between team members.

Here, I share our institutional experience in providing practical obstetric care through various stages of the still-evolving COVID-19 pandemic. We based our strategy on guidance from the Centers for Disease Control and Prevention (CDC), the American College of Obstetricians and Gynecologists (ACOG),^1,2 and the Society for Maternal-Fetal Medicine (SMFM).^3-5 We were reminded yet again that the only constant is change and that timely but thoughtful adjustments were needed to keep up with the coronavirus.

Changes to prenatal care

Like many others, our institution has provided continued in-person outpatient prenatal care to both our low- and high-risk patients throughout each stage of the pandemic. While continuing to provide the necessary obstetric care, we made alterations to limit exposure and practice social distancing when possible.

Limiting patient support persons. One significant change was to restrict or limit support persons in the outpatient clinics based on guidelines reflecting community infection rates. Recognizing that this was not optimal for our patients’ emotional well-being, we needed to become more flexible in using technology to include family or support persons in prenatal visits and ultrasonography exams.

Altering test frequency. Using the guidance from SMFM,¹ we changed the frequency of our antenatal testing and ultrasonography exams in the following ways: We increased the duration between indicated growth ultrasonography to every 4 weeks and decreased fetal antenatal testing to weekly, with twice-weekly testing continued for the highest-risk patients. Early first-trimester ultrasonography exams were limited and, when possible, delayed until after 10 to 12 weeks’ gestation or combined with other indications (nuchal translucency). Prenatal visits for low-risk patients were spaced out using existing models if the patient was amenable, especially in early pregnancy.

Adjusting staff assignments and using telehealth. In the early part of the pandemic, we divided into 2 groups to limit the number of clinicians at any one site: a dedicated group of outpatient clinicians who saw patients in the clinic only and a dedicated group of inpatient clinicians who staffed labor and delivery and the inpatient antepartum service. Additionally, our consultative maternal-fetal medicine service transitioned to a telehealth platform and performed the majority of consults remotely. Ultrasonography exams at various sites were read remotely and pertinent findings were communicated directly to patients via phone or the telehealth platform. Amniocentesis continued to be offered.

Responding to lower COVID-19 case numbers. When the number of COVID-19 cases decreased in the summer and fall of 2020, we returned to our prepandemic in-person practices, but we continued to offer telehealth visits as an option for patients who desired it. Patients were limited to one support person.

Shifting gears again. During the second surge of COVID-19 in our region, we used our experiences from the first to transition our practices to reduce in-person contact. Appointment frequency was decreased if appropriate, and we developed a tiered system of antenatal testing frequency based on risk factors. Visitors were again restricted, with exceptions made for extenuating circumstances. Consults were transitioned to telemedicine as appropriate and ultrasonography exams were read remotely when possible to limit exposures. Given the varied experiences with telemedicine and patient preferences, patients who desired in-person consult were (and are still) offered this option.

Some patients who were interested in telehealth but unable to access the technology were offered appointments via telehealth with the use of our clinic devices. Telemedicine increased our flexibility in offering consults as one provider could see patients at different office sites in one session. We continued our routine inpatient and outpatient coverage during this time as this kept our coverage options more flexible and expanded our obstetric backup plan in response to increased rates of community infection that affected both clinicians and patients.

Coordinating care for infected patients. One vital part of our prenatal care during the COVID-19 pandemic was to coordinate with our colleagues in medical specialties to provide outpatient care for patients with confirmed or suspected COVID-19 during their period of isolation or quarantine. Patients could be seen as outpatients in a dedicated space that used appropriate personal protective equipment (PPE) for not only prenatal care but also any needed in-person evaluation for COVID-19. Our obstetric clinicians and sonographers performed exams, antenatal testing (in the form of biophysical profiles), and indicated ultrasonography exams (such as umbilical artery Doppler studies and fetal growth assessments). This required a concerted effort and excellent communication between teams to provide the necessary care in the safest manner possible.

Continue to: Universal testing on labor and delivery...

Not surprisingly, obstetric delivery volumes in our institution were not affected in the same way as elective surgery volumes. Our inpatient team continued to bring babies into the world at the same if not a higher rate than in prepandemic times. We continued elective inductions when space allowed. Our first COVID-19–positive patient was already at 40 weeks’ gestation when the result of her test, done due to exposure, was received. Creative effort among multiple specialties quickly developed her delivery plan, and she and her infant did well.

As data started coming out of the New York City obstetric experience, concern for preservation of the PPE supply and the potential for asymptomatic/presymptomatic patients led us, in consultation with our infectious disease colleagues, to institute universal testing for all antepartum and laboring patients. At first, all patients were tested on admission with our rapid in-house test. Eventually, we moved toward preoperative testing 3 to 5 days prior to scheduled cesarean deliveries in alignment with the surgical services when elective cases were reinstituted. Finally, we instituted preprocedure testing for all scheduled labor and delivery procedures, including inductions, cerclages, and fetal blood transfusions, while we still used rapid testing for patients who presented urgently or in labor.

We needed to address several considerations almost immediately after instituting universal testing, including:

• what to do in case of patient refusal to be tested
• which precautions to institute while awaiting test results
• potential postponement of elective delivery if a patient tested positive, and
• where best to deliver patients.

What we did at the beginning of the pandemic was not necessarily the same as we do in our current practice, and we expect that our procedures may need to change in the future. Derived from what we learned from others’ experience, we tailored our protocols to our own physical space, staffing capabilities, and testing limitations. We adjusted them often, with input from multiple services, based on updated policy, recommendation for isolation and quarantine durations, rates of community infection, and changes in the unit spaces. As with many things, one protocol did not fit every patient, necessitating case-by-case flexibility.

Delivery considerations

To answer some of the above questions, all patients who declined testing, were awaiting test results while in labor, or were in triage were placed in droplet and contact isolation on our unit, a practice we continue currently. Given the concern of potential aerosolization during the second stage of labor or during intubation, for any patients in those categories who required delivery, we limited the number of staff in their rooms as possible. Additional pediatric staff waited in close proximity of the room and were ready to come in if needed depending on fetal complications and gestational age. For delivery, all team members used full special pathogens precautions (N95 masks, face shields, gowns, and gloves).

Patients who were asymptomatic and tested negative for COVID-19 had and continue to have routine care from a PPE (standard gowns, gloves, face mask, and eye protection) and health care team perspective. We have allowed visitation of one support person per hospital stay for these patients throughout the pandemic.

For the majority of our experience during the pandemic, adult patients who tested positive for COVID-19 were cohorted within dedicated negative pressure units of varying levels of care. As these units included the same intensive care unit (ICU) we utilized in non-COVID times for critical obstetric patients, we had already operationalized their use and they were wired for our electronic fetal monitoring system. These rooms are adjacent to the main operating room (OR) complex, which allows for transition to a dedicated COVID-19 OR for cesarean delivery. We worked with the primary COVID-19 team, ICU team, anesthesia, and neonatal ICU team to develop a written protocol that detailed the care for our COVID-19–positive laboring and postpartum patients in this critical care COVID-19 unit.

For a time, admitted COVID-19–positive patients were not permitted to have support persons. The health care team therefore stepped in to be the patients’ support during the delivery of their child. Care of these patients required a great deal of coordination and communication between teams as well as the addition of a dedicated obstetric physician—separate from the regular labor and delivery team—assigned to care for these patients.

For pregnant patients in the emergency room or in the intermediate or floor COVID-19 units, portable fetal monitors and ultrasonography equipment were used for obstetric consults, fetal testing, and obstetrical ultrasonography as appropriate based on gestational age and medical conditions. Again, communication between teams was essential to provide seamless and timely patient care. Patients usually were admitted to the COVID-19 teams with maternal-fetal medicine or obstetric consult teams following daily; they were admitted and transferred to the ICU COVID-19 unit if delivery was necessary. To limit exposures whenever possible, coordinated care (such as exams and telephone evaluation) was performed outside of the room with the nursing and primary teams.

Continue to: Staying flexible to the changing COVID-19 environment...

Postponed in-person visits. Whenever possible, deliveries that were not medically indicated and in-person outpatient care visits were postponed until isolation/quarantine precautions could be lifted to avoid the need for special pathogens precautions, separation of mother and infant, and visitor restrictions. We did not postpone any medically indicated deliveries or appropriate care due to COVID-19 alone. As the CDC guidelines changed regarding the timing of infectivity, we had to continually re-evaluate when a patient could return to regular outpatient care instead of the COVID-19 clinic and/or be delivered.

Mother-infant separation. As outlined in an article we wrote with our pediatric colleagues, originally all infants were immediately separated from their COVID-19–positive mothers, and delayed cord clamping was not performed.⁶ We adjusted our protocols as experience and data grew regarding the risk of transmission to the newborn from asymptomatic mothers and as updated recommendations were made by ACOG and the CDC. Currently, if desired, asymptomatic mothers are not separated from their well term infants. We practice our standard delayed cord clamping technique for all patients. Masking, hand hygiene, and physical distancing are used to reduce the risk of infection transmission. Breastfeeding is encouraged if the patient desires it, either directly using precautions or supported via pumping.

Reduced workplace exposure. Along with many others, we are even more cognizant of reducing the risk of workplace exposure; thus, we conduct our daily multidisciplinary huddle and physician transition of care sign-outs. We use multiple rooms for our larger group with secure video chats, and we limit huddles to a single representative from each specialty.

Medication protocols. Early in the pandemic in our area, we limited antenatal corticosteroids for fetal lung maturity to patients who were at less than 34 weeks’ gestation, per ACOG recommendations, carefully considering necessity in the critically ill. Now, we continue to administer antenatal steroids according to our usual protocols up to 36 6/7 weeks, per ACOG and SMFM recommendations, regardless of illness severity.⁷ Nonsteroidal anti-inflammatory drug use, once limited in COVID-19–positive patients, are now used again. Additionally, we had a comprehensive venous thromboembolism (VTE) prophylaxis protocol for our obstetric patients, and we have added special consideration for prophylaxis for patients with moderate to severe illness or other VTE risk factors. While we do not perform routine circumcisions on infants of COVID-19–positive mothers, we have a process in place to provide that service after discharge when isolation precautions are lifted.

Labor accommodations. As COVID-19 cases increased in our hospital during recent months, we made one more significant change in our care protocols. To open up space in the ICU, we moved our care for asymptomatic COVID-19–positive laboring patients to our new labor and delivery unit with implemented special pathogens precautions. This is not revolutionary; many other hospitals did not have the same capability we did with our existing collaboration with the ICU for critical obstetric care. However, this change again required communication and collaboration among multiple care teams, agreement on the qualifications for delivery on labor and delivery versus in the ICU, and physical alteration of our unit to accommodate additional isolation precautions.

Visitor policy. Another change is that we have opened up the visitor policy to welcome an asymptomatic support person for the COVID-19–positive labor patient, giving special attention to adherence to isolation precautions. Our staff members have embraced this change as they have everything else, with cautious optimism and focus on keeping both the patients and the health care team safe. Our moderate to severely ill patients continue to be cared for in the COVID-19 unit in close collaboration with our infectious disease and ICU colleagues.

It’s all about teamwork

I hope I have given a clear example of our approach to providing obstetric care in the ever-changing landscape of the COVID-19 pandemic. We embraced this period of necessary change as practically and safely as possible for both our patients and our health care workers. We learned multiple times along the way that what seemed to be a good idea was not feasible, or not the ideal option, or that COVID-19 had changed the rules of the game again. Our team met daily if not more frequently, as we found we had to constantly adapt and change to each new challenge or new clinical scenario. When we struggled, it generally related to a gap in communication.

I am privileged to work with a dedicated, selfless, multidisciplinary team that rose to the occasion. They had the focused goal to provide the highest quality and safety in obstetric care while offering compassion and empathy for the experience of having a baby during a pandemic. ●

The author would like to acknowledge Danielle Prentice, DO, and Jaimie Maines, MD, for their manuscript review.

Practicing evidence-based medicine, as obstetricians know, is not always possible when one does not have evidence due to lack of data or long-term experience in pregnancy. During the COVID-19 pandemic, the evidence changed so rapidly that we were compelled to alter our strategy frequently as we learned more about the impact of this disease on our vulnerable patient population. The COVID-19 pandemic taught us that, in unprecedented times, centering the safety of the patient, her child, and the health care team requires quick thinking, flexibility, and above all effective communication between team members.

Here, I share our institutional experience in providing practical obstetric care through various stages of the still-evolving COVID-19 pandemic. We based our strategy on guidance from the Centers for Disease Control and Prevention (CDC), the American College of Obstetricians and Gynecologists (ACOG),^1,2 and the Society for Maternal-Fetal Medicine (SMFM).^3-5 We were reminded yet again that the only constant is change and that timely but thoughtful adjustments were needed to keep up with the coronavirus.

Changes to prenatal care

Like many others, our institution has provided continued in-person outpatient prenatal care to both our low- and high-risk patients throughout each stage of the pandemic. While continuing to provide the necessary obstetric care, we made alterations to limit exposure and practice social distancing when possible.

Limiting patient support persons. One significant change was to restrict or limit support persons in the outpatient clinics based on guidelines reflecting community infection rates. Recognizing that this was not optimal for our patients’ emotional well-being, we needed to become more flexible in using technology to include family or support persons in prenatal visits and ultrasonography exams.

Altering test frequency. Using the guidance from SMFM,¹ we changed the frequency of our antenatal testing and ultrasonography exams in the following ways: We increased the duration between indicated growth ultrasonography to every 4 weeks and decreased fetal antenatal testing to weekly, with twice-weekly testing continued for the highest-risk patients. Early first-trimester ultrasonography exams were limited and, when possible, delayed until after 10 to 12 weeks’ gestation or combined with other indications (nuchal translucency). Prenatal visits for low-risk patients were spaced out using existing models if the patient was amenable, especially in early pregnancy.

Adjusting staff assignments and using telehealth. In the early part of the pandemic, we divided into 2 groups to limit the number of clinicians at any one site: a dedicated group of outpatient clinicians who saw patients in the clinic only and a dedicated group of inpatient clinicians who staffed labor and delivery and the inpatient antepartum service. Additionally, our consultative maternal-fetal medicine service transitioned to a telehealth platform and performed the majority of consults remotely. Ultrasonography exams at various sites were read remotely and pertinent findings were communicated directly to patients via phone or the telehealth platform. Amniocentesis continued to be offered.

Responding to lower COVID-19 case numbers. When the number of COVID-19 cases decreased in the summer and fall of 2020, we returned to our prepandemic in-person practices, but we continued to offer telehealth visits as an option for patients who desired it. Patients were limited to one support person.

Shifting gears again. During the second surge of COVID-19 in our region, we used our experiences from the first to transition our practices to reduce in-person contact. Appointment frequency was decreased if appropriate, and we developed a tiered system of antenatal testing frequency based on risk factors. Visitors were again restricted, with exceptions made for extenuating circumstances. Consults were transitioned to telemedicine as appropriate and ultrasonography exams were read remotely when possible to limit exposures. Given the varied experiences with telemedicine and patient preferences, patients who desired in-person consult were (and are still) offered this option.

Some patients who were interested in telehealth but unable to access the technology were offered appointments via telehealth with the use of our clinic devices. Telemedicine increased our flexibility in offering consults as one provider could see patients at different office sites in one session. We continued our routine inpatient and outpatient coverage during this time as this kept our coverage options more flexible and expanded our obstetric backup plan in response to increased rates of community infection that affected both clinicians and patients.

Coordinating care for infected patients. One vital part of our prenatal care during the COVID-19 pandemic was to coordinate with our colleagues in medical specialties to provide outpatient care for patients with confirmed or suspected COVID-19 during their period of isolation or quarantine. Patients could be seen as outpatients in a dedicated space that used appropriate personal protective equipment (PPE) for not only prenatal care but also any needed in-person evaluation for COVID-19. Our obstetric clinicians and sonographers performed exams, antenatal testing (in the form of biophysical profiles), and indicated ultrasonography exams (such as umbilical artery Doppler studies and fetal growth assessments). This required a concerted effort and excellent communication between teams to provide the necessary care in the safest manner possible.

Continue to: Universal testing on labor and delivery...

Not surprisingly, obstetric delivery volumes in our institution were not affected in the same way as elective surgery volumes. Our inpatient team continued to bring babies into the world at the same if not a higher rate than in prepandemic times. We continued elective inductions when space allowed. Our first COVID-19–positive patient was already at 40 weeks’ gestation when the result of her test, done due to exposure, was received. Creative effort among multiple specialties quickly developed her delivery plan, and she and her infant did well.

As data started coming out of the New York City obstetric experience, concern for preservation of the PPE supply and the potential for asymptomatic/presymptomatic patients led us, in consultation with our infectious disease colleagues, to institute universal testing for all antepartum and laboring patients. At first, all patients were tested on admission with our rapid in-house test. Eventually, we moved toward preoperative testing 3 to 5 days prior to scheduled cesarean deliveries in alignment with the surgical services when elective cases were reinstituted. Finally, we instituted preprocedure testing for all scheduled labor and delivery procedures, including inductions, cerclages, and fetal blood transfusions, while we still used rapid testing for patients who presented urgently or in labor.

We needed to address several considerations almost immediately after instituting universal testing, including:

• what to do in case of patient refusal to be tested
• which precautions to institute while awaiting test results
• potential postponement of elective delivery if a patient tested positive, and
• where best to deliver patients.

What we did at the beginning of the pandemic was not necessarily the same as we do in our current practice, and we expect that our procedures may need to change in the future. Derived from what we learned from others’ experience, we tailored our protocols to our own physical space, staffing capabilities, and testing limitations. We adjusted them often, with input from multiple services, based on updated policy, recommendation for isolation and quarantine durations, rates of community infection, and changes in the unit spaces. As with many things, one protocol did not fit every patient, necessitating case-by-case flexibility.

Delivery considerations

To answer some of the above questions, all patients who declined testing, were awaiting test results while in labor, or were in triage were placed in droplet and contact isolation on our unit, a practice we continue currently. Given the concern of potential aerosolization during the second stage of labor or during intubation, for any patients in those categories who required delivery, we limited the number of staff in their rooms as possible. Additional pediatric staff waited in close proximity of the room and were ready to come in if needed depending on fetal complications and gestational age. For delivery, all team members used full special pathogens precautions (N95 masks, face shields, gowns, and gloves).

Patients who were asymptomatic and tested negative for COVID-19 had and continue to have routine care from a PPE (standard gowns, gloves, face mask, and eye protection) and health care team perspective. We have allowed visitation of one support person per hospital stay for these patients throughout the pandemic.

For the majority of our experience during the pandemic, adult patients who tested positive for COVID-19 were cohorted within dedicated negative pressure units of varying levels of care. As these units included the same intensive care unit (ICU) we utilized in non-COVID times for critical obstetric patients, we had already operationalized their use and they were wired for our electronic fetal monitoring system. These rooms are adjacent to the main operating room (OR) complex, which allows for transition to a dedicated COVID-19 OR for cesarean delivery. We worked with the primary COVID-19 team, ICU team, anesthesia, and neonatal ICU team to develop a written protocol that detailed the care for our COVID-19–positive laboring and postpartum patients in this critical care COVID-19 unit.

For a time, admitted COVID-19–positive patients were not permitted to have support persons. The health care team therefore stepped in to be the patients’ support during the delivery of their child. Care of these patients required a great deal of coordination and communication between teams as well as the addition of a dedicated obstetric physician—separate from the regular labor and delivery team—assigned to care for these patients.

For pregnant patients in the emergency room or in the intermediate or floor COVID-19 units, portable fetal monitors and ultrasonography equipment were used for obstetric consults, fetal testing, and obstetrical ultrasonography as appropriate based on gestational age and medical conditions. Again, communication between teams was essential to provide seamless and timely patient care. Patients usually were admitted to the COVID-19 teams with maternal-fetal medicine or obstetric consult teams following daily; they were admitted and transferred to the ICU COVID-19 unit if delivery was necessary. To limit exposures whenever possible, coordinated care (such as exams and telephone evaluation) was performed outside of the room with the nursing and primary teams.

Continue to: Staying flexible to the changing COVID-19 environment...

Postponed in-person visits. Whenever possible, deliveries that were not medically indicated and in-person outpatient care visits were postponed until isolation/quarantine precautions could be lifted to avoid the need for special pathogens precautions, separation of mother and infant, and visitor restrictions. We did not postpone any medically indicated deliveries or appropriate care due to COVID-19 alone. As the CDC guidelines changed regarding the timing of infectivity, we had to continually re-evaluate when a patient could return to regular outpatient care instead of the COVID-19 clinic and/or be delivered.

Mother-infant separation. As outlined in an article we wrote with our pediatric colleagues, originally all infants were immediately separated from their COVID-19–positive mothers, and delayed cord clamping was not performed.⁶ We adjusted our protocols as experience and data grew regarding the risk of transmission to the newborn from asymptomatic mothers and as updated recommendations were made by ACOG and the CDC. Currently, if desired, asymptomatic mothers are not separated from their well term infants. We practice our standard delayed cord clamping technique for all patients. Masking, hand hygiene, and physical distancing are used to reduce the risk of infection transmission. Breastfeeding is encouraged if the patient desires it, either directly using precautions or supported via pumping.

Reduced workplace exposure. Along with many others, we are even more cognizant of reducing the risk of workplace exposure; thus, we conduct our daily multidisciplinary huddle and physician transition of care sign-outs. We use multiple rooms for our larger group with secure video chats, and we limit huddles to a single representative from each specialty.

Medication protocols. Early in the pandemic in our area, we limited antenatal corticosteroids for fetal lung maturity to patients who were at less than 34 weeks’ gestation, per ACOG recommendations, carefully considering necessity in the critically ill. Now, we continue to administer antenatal steroids according to our usual protocols up to 36 6/7 weeks, per ACOG and SMFM recommendations, regardless of illness severity.⁷ Nonsteroidal anti-inflammatory drug use, once limited in COVID-19–positive patients, are now used again. Additionally, we had a comprehensive venous thromboembolism (VTE) prophylaxis protocol for our obstetric patients, and we have added special consideration for prophylaxis for patients with moderate to severe illness or other VTE risk factors. While we do not perform routine circumcisions on infants of COVID-19–positive mothers, we have a process in place to provide that service after discharge when isolation precautions are lifted.

Labor accommodations. As COVID-19 cases increased in our hospital during recent months, we made one more significant change in our care protocols. To open up space in the ICU, we moved our care for asymptomatic COVID-19–positive laboring patients to our new labor and delivery unit with implemented special pathogens precautions. This is not revolutionary; many other hospitals did not have the same capability we did with our existing collaboration with the ICU for critical obstetric care. However, this change again required communication and collaboration among multiple care teams, agreement on the qualifications for delivery on labor and delivery versus in the ICU, and physical alteration of our unit to accommodate additional isolation precautions.

Visitor policy. Another change is that we have opened up the visitor policy to welcome an asymptomatic support person for the COVID-19–positive labor patient, giving special attention to adherence to isolation precautions. Our staff members have embraced this change as they have everything else, with cautious optimism and focus on keeping both the patients and the health care team safe. Our moderate to severely ill patients continue to be cared for in the COVID-19 unit in close collaboration with our infectious disease and ICU colleagues.

It’s all about teamwork

I hope I have given a clear example of our approach to providing obstetric care in the ever-changing landscape of the COVID-19 pandemic. We embraced this period of necessary change as practically and safely as possible for both our patients and our health care workers. We learned multiple times along the way that what seemed to be a good idea was not feasible, or not the ideal option, or that COVID-19 had changed the rules of the game again. Our team met daily if not more frequently, as we found we had to constantly adapt and change to each new challenge or new clinical scenario. When we struggled, it generally related to a gap in communication.

I am privileged to work with a dedicated, selfless, multidisciplinary team that rose to the occasion. They had the focused goal to provide the highest quality and safety in obstetric care while offering compassion and empathy for the experience of having a baby during a pandemic. ●

The author would like to acknowledge Danielle Prentice, DO, and Jaimie Maines, MD, for their manuscript review.

While 2020 was a challenge to say the least, obstetrician-gynecologists remained on the frontline caring for women through it all. Life continued despite the COVID-19 pandemic: prenatal care was delivered, albeit at times in different ways; babies were born; and our role in improving outcomes for women and their children became even more important. This year’s Update focuses on clinical guidelines centered on safety and optimal outcomes for women and children.

ACOG and SMFM update guidance on FGR management

American College of Obstetricians and Gynecologists. Practice advisory: Updated guidance regarding fetal growth restriction. September 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/09/updated-guidance-regarding-fetal-growth-restriction. Accessed December 18, 2020.

Fetal growth restriction (FGR) affects up to 10% of pregnancies and is a leading cause of infant morbidity and mortality. Suboptimal fetal growth can have lasting negative effects on development into early childhood and, some hypothesize, even into adulthood.^1,2 Antenatal detection of fetuses with FGR is critical so that antenatal testing can be implemented in an attempt to deliver improved clinical outcomes. FGR is defined by several different diagnostic criteria, and many studies have been conducted to determine how best to diagnose this condition.

In September 2020, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory regarding guidance on FGR in an effort to align the ACOG Practice Bulletin No. 204, ACOG Committee Opinion No. 764, and SMFM (Society for Maternal-Fetal Medicine) Consult Series No. 52.^3-5 This guidance updates and replaces prior guidelines, with an emphasis on 3 notable changes.

FGR definition, workup have changed

While the original definition of FGR was an estimated fetal weight (EFW) of less than the 10th percentile for gestational age, a similar level of accuracy in prediction of subsequent small for gestational age (SGA) at birth has been shown when this or an abdominal circumference (AC) of less than the 10th percentile is used. Based on these findings, SMFM now recommends that FGR be defined as an EFW or AC of less than the 10th percentile for gestational age.

Recent studies have done head-to-head comparisons of different methods of estimating fetal weight to determine the best detection and pregnancy outcome improvement in FGR. In all instances, the Hadlock formula has continued to more accurately estimate fetal weight, prediction of SGA, and composite neonatal morbidity. As such, new guidelines recommend that population-based fetal growth references (that is, the Hadlock formula) should be used to determine ultrasonography-derived fetal weight percentiles.

The new guidance also suggests classification of FGR based on gestational age at onset, with early FGR at less than 32 weeks and late FGR at 32 or more weeks. The definition of severe FGR is reserved for fetuses with an EFW of less than the 3rd percentile. A diagnosis of FGR should prompt the recommendation for a detailed obstetric ultrasonography. Diagnostic genetic testing should be offered in cases of early-onset FGR, concomitant sonographic abnormalities, and/or polyhydramnios. Routine serum screening for toxoplasmosis, rubella, herpes, or cytomegalovirus (CMV) should not be done unless there are risk factors for infection. If amniocentesis is performed for genetic diagnostic testing, consideration can be made for polymerase chain reaction for CMV in the amniotic fluid.

Continue to: Timing of delivery in isolated FGR...

Timing of delivery in isolated FGR

A complicating factor in diagnosing FGR is distinguishing between the pathologically growth-restricted fetus and the constitutionally small fetus. Antenatal testing and serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for evidence of fetal compromise until delivery is planned.

The current ACOG Practice Bulletin No. 204 and Committee Opinion No. 764 recommend delivery between 38 0/7 and 39 6/7 weeks in the setting of isolated FGR with reassuring fetal testing and umbilical artery Doppler assessment.To further refine this, the new recommendations use the growth percentiles. In cases of isolated FGR with EFW between the 3rd and 10th percentile in the setting of normal umbilical artery Doppler, delivery is recommended between 38 and 39 weeks’ gestation. In cases of isolated FGR with EFW of less than the 3rd percentile (severe FGR) in the setting of normal umbilical artery Doppler, delivery is recommended at 37 weeks.

Timing of delivery in complicated FGR

A normal umbilical artery Doppler reflects the low impedance that is necessary for continuous forward flow of blood to the fetus. Abnormal umbilical artery Doppler signifies aberrations of this low-pressure system that affect the amount of continuous forward flow during diastole of the cardiac cycle. With continued compromise, there is progression to absent end-diastolic velocity (AEDV) and, most concerning, reversed end-diastolic velocity (REDV).

Serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for progression that is associated with perinatal mortality, since intervention can be initiated in the form of delivery. Delivery at 37 weeks is recommended for FGR with elevated umbilical artery Doppler of greater than the 95th percentile for gestational age. For FGR with AEDV, delivery is recommended between 33 and 34 weeks of gestation and for FGR with REDV between 30 and 32 weeks, as the neonatal morbidity and mortality associated with continuing the pregnancy outweighs the risks of prematurity in this setting. Because of the abnormal placental-fetal circulation in FGR complicated by AEDV/REDV, there may be a higher likelihood of fetal intolerance of labor and cesarean delivery (CD) may be considered.

Continue to: New recommendations for PROM management...

New recommendations for PROM management

American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Obstetrics. ACOG practice bulletin no. 217: Prelabor rupture of membranes. Obstet Gynecol. 2020;135:e80-e97.

Rupture of membranes prior to the onset of labor occurs at term in 8% of pregnancies and in the preterm period in 2% to 3% of pregnancies.⁶ Accurate diagnosis, gestational age, evidence of infection, and discussion of the risks and benefits to the mother and fetus/neonate are necessary to optimize outcomes. In the absence of other indications for delivery, a gestational age of 34 or more weeks traditionally has been the cutoff to proceed with delivery, although this has not been globally agreed on and/or practiced.

ACOG has published a comprehensive update that incorporates the results of the PPROMT trial and other recommendations for the diagnosis and management of both term and preterm prelabor rupture of membranes (PROM).^6,7

Making the diagnosis

Diagnosis of PROM usually can be made clinically via history and the classic triad of physical exam findings—pooling of fluid, basic pH, and ferning; some institutions also use commercially available tests that detect placental-derived proteins. Both ACOG and the US Food and Drug Administration caution against using these tests alone without clinical evaluation due to concern for false-positives and false-negatives that lead to adverse maternal and fetal/neonatal outcomes. For equivocal cases, ultrasonography for amniotic fluid evaluation and ultrasonography-guided dye tests can be used to assist in accurate diagnosis, especially in the preterm period in which there are significant implications for pregnancy management.

PROM management depends on gestational age

All management recommendations require reassuring fetal testing, evaluation for infection, and no other contraindications to expectant management. Once these are established, the most important determinant of PROM management then becomes gestational age.

Previable PROM

Previable PROM (usually defined as less than 23–24 weeks) has high risks of both maternal and fetal/neonatal morbidity and mortality from infection, hemorrhage, pulmonary hypoplasia, and extreme prematurity. These very difficult cases benefit from a multidisciplinary approach to patient counseling regarding expectant management versus immediate delivery.

If expectant management is chosen, outpatient management with close monitoring for signs of maternal infection may be done until an agreed on gestational age of viability. Then inpatient management with fetal monitoring, corticosteroids, tocolysis, magnesium for neuroprotection, and group B streptococcus (GBS) prophylaxis may be considered as appropriate.

Preterm PROM at less than 34 weeks

If the mother and fetus are otherwise stable, PROM at less than 34 weeks warrants inpatient expectant management with close maternal and fetal monitoring for signs of infection and labor. Management includes latency antibiotics, antenatal corticosteroids, magnesium for neuroprotection if less than 32 weeks’ gestation and at risk for imminent delivery, and GBS prophylaxis. While tocolysis may increase latency and help with steroid course completion, it should be used cautiously and avoided in cases of abruption or chorioamnionitis. Although there is no definitive recommendation published, a rescue course of steroids may be considered as appropriate but should not delay an indicated delivery.

Continue to: Late preterm PROM...

Late preterm PROM

The biggest change to clinical management in this ACOG Practice Bulletin is for late preterm (34–36 6/7 weeks) PROM, with the recommendation for either immediate delivery or expectant management up to 37 weeks stemming from the PPROMPT study by Morris and colleagues.⁷

From the neonatal perspective, no difference has been demonstrated between immediate delivery and expectant management for neonatal sepsis or a composite neonatal morbidity and mortality. Expectant management may be preferred from the neonatal point of view as immediate delivery was associated with an increased rate of neonatal respiratory distress, mechanical ventilation, and length of stay in the neonatal intensive care unit. The potential for long-term neurodevelopmental outcomes of delivery at 34 versus 37 weeks also should be considered.

From the maternal perspective, expectant management has an increased risk of antepartum and postpartum hemorrhage, fever, antibiotic use, and maternal length of stay, but a decreased risk of CD.

A late preterm steroid course can be considered if delivery is planned in no less than 24 hours and likely to occur in the next 7 days and if the patient has not already received a course of steroids. A rescue course of steroids is not indicated if the patient received a steroid course prior in the pregnancy. While appropriate GBS prophylaxis is recommended, latency antibiotics and tocolysis are not, and delivery should not be delayed if chorioamnionitis is diagnosed.

Ultimately, preterm PROM management with a stable mother and fetus at or beyond 34 weeks requires comprehensive counseling of the risks and benefits for both mother and fetus/neonate. A multidisciplinary team that together counsels the patient also may help with this shared decision making.

Term PROM

For patients with term PROM, delivery is recommended. Although a short period of expectant management for 12 to 24 hours is reported as “reasonable,” the risk of infection increases with the length of rupture of membranes. Therefore, induction of labor or CD soon after rupture of membranes is recommended for patients who are GBS positive and is preferred for all others.

VTE prophylaxis in pregnancy: Regimen adjustments, CD strategies, and COVID-19 considerations

Birsner ML, Turrentine M, Pettker CM, et al. ACOG practice advisory: Options for peripartum anticoagulation in areas affected by shortage of unfractionated heparin. March 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/options-for-peripartum-anticoagulation-in-areas-affected-by-shortage-of-unfractionated-heparin. Accessed December 8, 2020.

Pacheco LD, Saade G, Metz TD. Society for Maternal-Fetal Medicine Consult Series No. 51: Thromboembolism prophylaxis for cesarean delivery. Am J Obstet Gynecol. 2020;223:B11-B17

Venous thromboembolism (VTE) prophylaxis is a timely topic for a number of reasons. First, a shortage of unfractionated heparin prompted an ACOG Practice Advisory, endorsed by SMFM and the Society for Obstetric Anesthesia and Perinatology, regarding use of low molecular weight heparin (LMWH) in the peripartum period.⁸ In addition, SMFM released updated recommendations for VTE prophylaxis for CD as part of the SMFM Consult Series.⁹ Finally, there is evidence that COVID-19 infection may increase the risk of coagulopathy, leading to consideration of additional VTE prophylaxis for pregnant and postpartum women with COVID-19.

Candidates for prophylaxis

As recommended by the ACOG Practice Bulletin on thromboembolism in pregnancy, women who may require VTE prophylaxis during pregnancy and/or the postpartum period include those with¹⁰:

• VTE diagnosed during pregnancy
• a history of VTE, including during pregnancy or with use of hormonal contraception
• a history of thrombophilia with or without a personal or family history of VTE.

For these patients, LMWH has many advantages over unfractionated heparin, including ease of use and reliability of dosing. It generally is preferred in pregnancy and postpartum (for both prophylactic and therapeutic anticoagulation) by patients and providers.

The Practice Bulletin references a strategy that describes converting LMWH to unfractionated heparin at around 36 weeks’ gestation in preparation for delivery because unfractionated heparin has the advantage of a shorter half-life and the option for anticoagulation reversal with protamine sulfate. In the Practice Advisory, a global shortage of unfractionated heparin and an argument that the above conversion was less about concern for maternal hemorrhage and more about avoiding spinal and epidural hematomas led to the following recommendations for continued use of LMWH through delivery:

• LMWH heparin can be discontinued in a planned fashion prior to scheduled induction of labor or CD (generally 12 hours for prophylactic dosing and 24 hours for intermediate dosing).
• Patients in spontaneous labor may receive neuraxial anesthesia 12 hours after the last prophylactic dose and 24 hours after the last intermediate dose of LMWH.
• Patients who require anticoagulation during pregnancy should be counseled that if they have vaginal bleeding, leakage of fluid, or regular contractions they should be evaluated prior to taking their next dose of anticoagulant.
• In the absence of other complications, delivery should not be before 39 weeks for the indication of anticoagulation requirement alone.

Continue to: Managing VTE risk in CD...

Managing VTE risk in CD

Recognizing that VTE is a major cause of maternal morbidity and mortality, as well as the variety of the published guidelines for VTE prophylaxis after CD, the SMFM Consult Series provides recommendations to assist clinicians caring for postpartum women after CD. As reviewed in the ACOG Practice Bulletin, there are good data to support pharmacologic prophylaxis during pregnancy and the postpartum period for women with a history of VTE or a thrombophilia. Solid evidence is lacking, however, for what to do for women who have a CD without this history but may have other potential risk factors for VTE, such as obesity, preeclampsia, and transfusion requirement. Universal pharmacologic prophylaxis also is not yet supported by evidence. SMFM supports LMWH as the preferred medication in pregnancy and postpartum and provides these additional recommendations:

• All women who have a CD should have sequential compression devices (SCDs) placed prior to surgery and continued until they are ambulatory.
• Women with a history of VTE or thrombophilia without history of VTE should have SCDs and pharmacologic VTE prophylaxis for 6 weeks postpartum.
• Intermediate dosing of LMWH is recommended for patients with class III obesity.
• Institutions should develop patient safety bundles for VTE prophylaxis to identify additional risk factors that may warrant pharmacologic prophylaxis after CD in select patients.

Our approach to patients with COVID-19 infection

At our institution, we recently incorporated a VTE prophylaxis protocol into our electronic medical record that provides risk stratification for each patient. In addition to the above recommendations, our patients may qualify for short-term in-house or longer postpartum prophylaxis depending on risk factors.

A new risk factor in recent months is COVID-19 infection, which appears to increase the risk of coagulopathy, especially in patients with disease severe enough to warrant hospitalization. Given the potential for additive risk in pregnancy, in consult with our medicine colleagues, we have placed some of our more ill hospitalized pregnant patients on a course of prophylactic LMWH both in the hospital and after discharge independent of delivery status or mode of delivery. ●

While 2020 was a challenge to say the least, obstetrician-gynecologists remained on the frontline caring for women through it all. Life continued despite the COVID-19 pandemic: prenatal care was delivered, albeit at times in different ways; babies were born; and our role in improving outcomes for women and their children became even more important. This year’s Update focuses on clinical guidelines centered on safety and optimal outcomes for women and children.

ACOG and SMFM update guidance on FGR management

American College of Obstetricians and Gynecologists. Practice advisory: Updated guidance regarding fetal growth restriction. September 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/09/updated-guidance-regarding-fetal-growth-restriction. Accessed December 18, 2020.

Fetal growth restriction (FGR) affects up to 10% of pregnancies and is a leading cause of infant morbidity and mortality. Suboptimal fetal growth can have lasting negative effects on development into early childhood and, some hypothesize, even into adulthood.^1,2 Antenatal detection of fetuses with FGR is critical so that antenatal testing can be implemented in an attempt to deliver improved clinical outcomes. FGR is defined by several different diagnostic criteria, and many studies have been conducted to determine how best to diagnose this condition.

In September 2020, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory regarding guidance on FGR in an effort to align the ACOG Practice Bulletin No. 204, ACOG Committee Opinion No. 764, and SMFM (Society for Maternal-Fetal Medicine) Consult Series No. 52.^3-5 This guidance updates and replaces prior guidelines, with an emphasis on 3 notable changes.

FGR definition, workup have changed

While the original definition of FGR was an estimated fetal weight (EFW) of less than the 10th percentile for gestational age, a similar level of accuracy in prediction of subsequent small for gestational age (SGA) at birth has been shown when this or an abdominal circumference (AC) of less than the 10th percentile is used. Based on these findings, SMFM now recommends that FGR be defined as an EFW or AC of less than the 10th percentile for gestational age.

Recent studies have done head-to-head comparisons of different methods of estimating fetal weight to determine the best detection and pregnancy outcome improvement in FGR. In all instances, the Hadlock formula has continued to more accurately estimate fetal weight, prediction of SGA, and composite neonatal morbidity. As such, new guidelines recommend that population-based fetal growth references (that is, the Hadlock formula) should be used to determine ultrasonography-derived fetal weight percentiles.

The new guidance also suggests classification of FGR based on gestational age at onset, with early FGR at less than 32 weeks and late FGR at 32 or more weeks. The definition of severe FGR is reserved for fetuses with an EFW of less than the 3rd percentile. A diagnosis of FGR should prompt the recommendation for a detailed obstetric ultrasonography. Diagnostic genetic testing should be offered in cases of early-onset FGR, concomitant sonographic abnormalities, and/or polyhydramnios. Routine serum screening for toxoplasmosis, rubella, herpes, or cytomegalovirus (CMV) should not be done unless there are risk factors for infection. If amniocentesis is performed for genetic diagnostic testing, consideration can be made for polymerase chain reaction for CMV in the amniotic fluid.

Continue to: Timing of delivery in isolated FGR...

Timing of delivery in isolated FGR

A complicating factor in diagnosing FGR is distinguishing between the pathologically growth-restricted fetus and the constitutionally small fetus. Antenatal testing and serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for evidence of fetal compromise until delivery is planned.

The current ACOG Practice Bulletin No. 204 and Committee Opinion No. 764 recommend delivery between 38 0/7 and 39 6/7 weeks in the setting of isolated FGR with reassuring fetal testing and umbilical artery Doppler assessment.To further refine this, the new recommendations use the growth percentiles. In cases of isolated FGR with EFW between the 3rd and 10th percentile in the setting of normal umbilical artery Doppler, delivery is recommended between 38 and 39 weeks’ gestation. In cases of isolated FGR with EFW of less than the 3rd percentile (severe FGR) in the setting of normal umbilical artery Doppler, delivery is recommended at 37 weeks.

Timing of delivery in complicated FGR

A normal umbilical artery Doppler reflects the low impedance that is necessary for continuous forward flow of blood to the fetus. Abnormal umbilical artery Doppler signifies aberrations of this low-pressure system that affect the amount of continuous forward flow during diastole of the cardiac cycle. With continued compromise, there is progression to absent end-diastolic velocity (AEDV) and, most concerning, reversed end-diastolic velocity (REDV).

Serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for progression that is associated with perinatal mortality, since intervention can be initiated in the form of delivery. Delivery at 37 weeks is recommended for FGR with elevated umbilical artery Doppler of greater than the 95th percentile for gestational age. For FGR with AEDV, delivery is recommended between 33 and 34 weeks of gestation and for FGR with REDV between 30 and 32 weeks, as the neonatal morbidity and mortality associated with continuing the pregnancy outweighs the risks of prematurity in this setting. Because of the abnormal placental-fetal circulation in FGR complicated by AEDV/REDV, there may be a higher likelihood of fetal intolerance of labor and cesarean delivery (CD) may be considered.

Continue to: New recommendations for PROM management...

New recommendations for PROM management

American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Obstetrics. ACOG practice bulletin no. 217: Prelabor rupture of membranes. Obstet Gynecol. 2020;135:e80-e97.

Rupture of membranes prior to the onset of labor occurs at term in 8% of pregnancies and in the preterm period in 2% to 3% of pregnancies.⁶ Accurate diagnosis, gestational age, evidence of infection, and discussion of the risks and benefits to the mother and fetus/neonate are necessary to optimize outcomes. In the absence of other indications for delivery, a gestational age of 34 or more weeks traditionally has been the cutoff to proceed with delivery, although this has not been globally agreed on and/or practiced.

ACOG has published a comprehensive update that incorporates the results of the PPROMT trial and other recommendations for the diagnosis and management of both term and preterm prelabor rupture of membranes (PROM).^6,7

Making the diagnosis

Diagnosis of PROM usually can be made clinically via history and the classic triad of physical exam findings—pooling of fluid, basic pH, and ferning; some institutions also use commercially available tests that detect placental-derived proteins. Both ACOG and the US Food and Drug Administration caution against using these tests alone without clinical evaluation due to concern for false-positives and false-negatives that lead to adverse maternal and fetal/neonatal outcomes. For equivocal cases, ultrasonography for amniotic fluid evaluation and ultrasonography-guided dye tests can be used to assist in accurate diagnosis, especially in the preterm period in which there are significant implications for pregnancy management.

PROM management depends on gestational age

All management recommendations require reassuring fetal testing, evaluation for infection, and no other contraindications to expectant management. Once these are established, the most important determinant of PROM management then becomes gestational age.

Previable PROM

Previable PROM (usually defined as less than 23–24 weeks) has high risks of both maternal and fetal/neonatal morbidity and mortality from infection, hemorrhage, pulmonary hypoplasia, and extreme prematurity. These very difficult cases benefit from a multidisciplinary approach to patient counseling regarding expectant management versus immediate delivery.

If expectant management is chosen, outpatient management with close monitoring for signs of maternal infection may be done until an agreed on gestational age of viability. Then inpatient management with fetal monitoring, corticosteroids, tocolysis, magnesium for neuroprotection, and group B streptococcus (GBS) prophylaxis may be considered as appropriate.

Preterm PROM at less than 34 weeks

If the mother and fetus are otherwise stable, PROM at less than 34 weeks warrants inpatient expectant management with close maternal and fetal monitoring for signs of infection and labor. Management includes latency antibiotics, antenatal corticosteroids, magnesium for neuroprotection if less than 32 weeks’ gestation and at risk for imminent delivery, and GBS prophylaxis. While tocolysis may increase latency and help with steroid course completion, it should be used cautiously and avoided in cases of abruption or chorioamnionitis. Although there is no definitive recommendation published, a rescue course of steroids may be considered as appropriate but should not delay an indicated delivery.

Continue to: Late preterm PROM...

Late preterm PROM

The biggest change to clinical management in this ACOG Practice Bulletin is for late preterm (34–36 6/7 weeks) PROM, with the recommendation for either immediate delivery or expectant management up to 37 weeks stemming from the PPROMPT study by Morris and colleagues.⁷

From the neonatal perspective, no difference has been demonstrated between immediate delivery and expectant management for neonatal sepsis or a composite neonatal morbidity and mortality. Expectant management may be preferred from the neonatal point of view as immediate delivery was associated with an increased rate of neonatal respiratory distress, mechanical ventilation, and length of stay in the neonatal intensive care unit. The potential for long-term neurodevelopmental outcomes of delivery at 34 versus 37 weeks also should be considered.

From the maternal perspective, expectant management has an increased risk of antepartum and postpartum hemorrhage, fever, antibiotic use, and maternal length of stay, but a decreased risk of CD.

A late preterm steroid course can be considered if delivery is planned in no less than 24 hours and likely to occur in the next 7 days and if the patient has not already received a course of steroids. A rescue course of steroids is not indicated if the patient received a steroid course prior in the pregnancy. While appropriate GBS prophylaxis is recommended, latency antibiotics and tocolysis are not, and delivery should not be delayed if chorioamnionitis is diagnosed.

Ultimately, preterm PROM management with a stable mother and fetus at or beyond 34 weeks requires comprehensive counseling of the risks and benefits for both mother and fetus/neonate. A multidisciplinary team that together counsels the patient also may help with this shared decision making.

Term PROM

For patients with term PROM, delivery is recommended. Although a short period of expectant management for 12 to 24 hours is reported as “reasonable,” the risk of infection increases with the length of rupture of membranes. Therefore, induction of labor or CD soon after rupture of membranes is recommended for patients who are GBS positive and is preferred for all others.

VTE prophylaxis in pregnancy: Regimen adjustments, CD strategies, and COVID-19 considerations

Birsner ML, Turrentine M, Pettker CM, et al. ACOG practice advisory: Options for peripartum anticoagulation in areas affected by shortage of unfractionated heparin. March 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/options-for-peripartum-anticoagulation-in-areas-affected-by-shortage-of-unfractionated-heparin. Accessed December 8, 2020.

Pacheco LD, Saade G, Metz TD. Society for Maternal-Fetal Medicine Consult Series No. 51: Thromboembolism prophylaxis for cesarean delivery. Am J Obstet Gynecol. 2020;223:B11-B17

Venous thromboembolism (VTE) prophylaxis is a timely topic for a number of reasons. First, a shortage of unfractionated heparin prompted an ACOG Practice Advisory, endorsed by SMFM and the Society for Obstetric Anesthesia and Perinatology, regarding use of low molecular weight heparin (LMWH) in the peripartum period.⁸ In addition, SMFM released updated recommendations for VTE prophylaxis for CD as part of the SMFM Consult Series.⁹ Finally, there is evidence that COVID-19 infection may increase the risk of coagulopathy, leading to consideration of additional VTE prophylaxis for pregnant and postpartum women with COVID-19.

Candidates for prophylaxis

As recommended by the ACOG Practice Bulletin on thromboembolism in pregnancy, women who may require VTE prophylaxis during pregnancy and/or the postpartum period include those with¹⁰:

• VTE diagnosed during pregnancy
• a history of VTE, including during pregnancy or with use of hormonal contraception
• a history of thrombophilia with or without a personal or family history of VTE.

For these patients, LMWH has many advantages over unfractionated heparin, including ease of use and reliability of dosing. It generally is preferred in pregnancy and postpartum (for both prophylactic and therapeutic anticoagulation) by patients and providers.

The Practice Bulletin references a strategy that describes converting LMWH to unfractionated heparin at around 36 weeks’ gestation in preparation for delivery because unfractionated heparin has the advantage of a shorter half-life and the option for anticoagulation reversal with protamine sulfate. In the Practice Advisory, a global shortage of unfractionated heparin and an argument that the above conversion was less about concern for maternal hemorrhage and more about avoiding spinal and epidural hematomas led to the following recommendations for continued use of LMWH through delivery:

• LMWH heparin can be discontinued in a planned fashion prior to scheduled induction of labor or CD (generally 12 hours for prophylactic dosing and 24 hours for intermediate dosing).
• Patients in spontaneous labor may receive neuraxial anesthesia 12 hours after the last prophylactic dose and 24 hours after the last intermediate dose of LMWH.
• Patients who require anticoagulation during pregnancy should be counseled that if they have vaginal bleeding, leakage of fluid, or regular contractions they should be evaluated prior to taking their next dose of anticoagulant.
• In the absence of other complications, delivery should not be before 39 weeks for the indication of anticoagulation requirement alone.

Continue to: Managing VTE risk in CD...

Managing VTE risk in CD

Recognizing that VTE is a major cause of maternal morbidity and mortality, as well as the variety of the published guidelines for VTE prophylaxis after CD, the SMFM Consult Series provides recommendations to assist clinicians caring for postpartum women after CD. As reviewed in the ACOG Practice Bulletin, there are good data to support pharmacologic prophylaxis during pregnancy and the postpartum period for women with a history of VTE or a thrombophilia. Solid evidence is lacking, however, for what to do for women who have a CD without this history but may have other potential risk factors for VTE, such as obesity, preeclampsia, and transfusion requirement. Universal pharmacologic prophylaxis also is not yet supported by evidence. SMFM supports LMWH as the preferred medication in pregnancy and postpartum and provides these additional recommendations:

• All women who have a CD should have sequential compression devices (SCDs) placed prior to surgery and continued until they are ambulatory.
• Women with a history of VTE or thrombophilia without history of VTE should have SCDs and pharmacologic VTE prophylaxis for 6 weeks postpartum.
• Intermediate dosing of LMWH is recommended for patients with class III obesity.
• Institutions should develop patient safety bundles for VTE prophylaxis to identify additional risk factors that may warrant pharmacologic prophylaxis after CD in select patients.

Our approach to patients with COVID-19 infection

At our institution, we recently incorporated a VTE prophylaxis protocol into our electronic medical record that provides risk stratification for each patient. In addition to the above recommendations, our patients may qualify for short-term in-house or longer postpartum prophylaxis depending on risk factors.

A new risk factor in recent months is COVID-19 infection, which appears to increase the risk of coagulopathy, especially in patients with disease severe enough to warrant hospitalization. Given the potential for additive risk in pregnancy, in consult with our medicine colleagues, we have placed some of our more ill hospitalized pregnant patients on a course of prophylactic LMWH both in the hospital and after discharge independent of delivery status or mode of delivery. ●

While 2020 was a challenge to say the least, obstetrician-gynecologists remained on the frontline caring for women through it all. Life continued despite the COVID-19 pandemic: prenatal care was delivered, albeit at times in different ways; babies were born; and our role in improving outcomes for women and their children became even more important. This year’s Update focuses on clinical guidelines centered on safety and optimal outcomes for women and children.

ACOG and SMFM update guidance on FGR management

American College of Obstetricians and Gynecologists. Practice advisory: Updated guidance regarding fetal growth restriction. September 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/09/updated-guidance-regarding-fetal-growth-restriction. Accessed December 18, 2020.

Fetal growth restriction (FGR) affects up to 10% of pregnancies and is a leading cause of infant morbidity and mortality. Suboptimal fetal growth can have lasting negative effects on development into early childhood and, some hypothesize, even into adulthood.^1,2 Antenatal detection of fetuses with FGR is critical so that antenatal testing can be implemented in an attempt to deliver improved clinical outcomes. FGR is defined by several different diagnostic criteria, and many studies have been conducted to determine how best to diagnose this condition.

In September 2020, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory regarding guidance on FGR in an effort to align the ACOG Practice Bulletin No. 204, ACOG Committee Opinion No. 764, and SMFM (Society for Maternal-Fetal Medicine) Consult Series No. 52.^3-5 This guidance updates and replaces prior guidelines, with an emphasis on 3 notable changes.

FGR definition, workup have changed

While the original definition of FGR was an estimated fetal weight (EFW) of less than the 10th percentile for gestational age, a similar level of accuracy in prediction of subsequent small for gestational age (SGA) at birth has been shown when this or an abdominal circumference (AC) of less than the 10th percentile is used. Based on these findings, SMFM now recommends that FGR be defined as an EFW or AC of less than the 10th percentile for gestational age.

Recent studies have done head-to-head comparisons of different methods of estimating fetal weight to determine the best detection and pregnancy outcome improvement in FGR. In all instances, the Hadlock formula has continued to more accurately estimate fetal weight, prediction of SGA, and composite neonatal morbidity. As such, new guidelines recommend that population-based fetal growth references (that is, the Hadlock formula) should be used to determine ultrasonography-derived fetal weight percentiles.

The new guidance also suggests classification of FGR based on gestational age at onset, with early FGR at less than 32 weeks and late FGR at 32 or more weeks. The definition of severe FGR is reserved for fetuses with an EFW of less than the 3rd percentile. A diagnosis of FGR should prompt the recommendation for a detailed obstetric ultrasonography. Diagnostic genetic testing should be offered in cases of early-onset FGR, concomitant sonographic abnormalities, and/or polyhydramnios. Routine serum screening for toxoplasmosis, rubella, herpes, or cytomegalovirus (CMV) should not be done unless there are risk factors for infection. If amniocentesis is performed for genetic diagnostic testing, consideration can be made for polymerase chain reaction for CMV in the amniotic fluid.

Continue to: Timing of delivery in isolated FGR...

Timing of delivery in isolated FGR

A complicating factor in diagnosing FGR is distinguishing between the pathologically growth-restricted fetus and the constitutionally small fetus. Antenatal testing and serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for evidence of fetal compromise until delivery is planned.

The current ACOG Practice Bulletin No. 204 and Committee Opinion No. 764 recommend delivery between 38 0/7 and 39 6/7 weeks in the setting of isolated FGR with reassuring fetal testing and umbilical artery Doppler assessment.To further refine this, the new recommendations use the growth percentiles. In cases of isolated FGR with EFW between the 3rd and 10th percentile in the setting of normal umbilical artery Doppler, delivery is recommended between 38 and 39 weeks’ gestation. In cases of isolated FGR with EFW of less than the 3rd percentile (severe FGR) in the setting of normal umbilical artery Doppler, delivery is recommended at 37 weeks.

Timing of delivery in complicated FGR

A normal umbilical artery Doppler reflects the low impedance that is necessary for continuous forward flow of blood to the fetus. Abnormal umbilical artery Doppler signifies aberrations of this low-pressure system that affect the amount of continuous forward flow during diastole of the cardiac cycle. With continued compromise, there is progression to absent end-diastolic velocity (AEDV) and, most concerning, reversed end-diastolic velocity (REDV).

Serial umbilical artery Doppler assessment should be done following diagnosis of FGR to monitor for progression that is associated with perinatal mortality, since intervention can be initiated in the form of delivery. Delivery at 37 weeks is recommended for FGR with elevated umbilical artery Doppler of greater than the 95th percentile for gestational age. For FGR with AEDV, delivery is recommended between 33 and 34 weeks of gestation and for FGR with REDV between 30 and 32 weeks, as the neonatal morbidity and mortality associated with continuing the pregnancy outweighs the risks of prematurity in this setting. Because of the abnormal placental-fetal circulation in FGR complicated by AEDV/REDV, there may be a higher likelihood of fetal intolerance of labor and cesarean delivery (CD) may be considered.

Continue to: New recommendations for PROM management...

New recommendations for PROM management

American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Obstetrics. ACOG practice bulletin no. 217: Prelabor rupture of membranes. Obstet Gynecol. 2020;135:e80-e97.

Rupture of membranes prior to the onset of labor occurs at term in 8% of pregnancies and in the preterm period in 2% to 3% of pregnancies.⁶ Accurate diagnosis, gestational age, evidence of infection, and discussion of the risks and benefits to the mother and fetus/neonate are necessary to optimize outcomes. In the absence of other indications for delivery, a gestational age of 34 or more weeks traditionally has been the cutoff to proceed with delivery, although this has not been globally agreed on and/or practiced.

ACOG has published a comprehensive update that incorporates the results of the PPROMT trial and other recommendations for the diagnosis and management of both term and preterm prelabor rupture of membranes (PROM).^6,7

Making the diagnosis

Diagnosis of PROM usually can be made clinically via history and the classic triad of physical exam findings—pooling of fluid, basic pH, and ferning; some institutions also use commercially available tests that detect placental-derived proteins. Both ACOG and the US Food and Drug Administration caution against using these tests alone without clinical evaluation due to concern for false-positives and false-negatives that lead to adverse maternal and fetal/neonatal outcomes. For equivocal cases, ultrasonography for amniotic fluid evaluation and ultrasonography-guided dye tests can be used to assist in accurate diagnosis, especially in the preterm period in which there are significant implications for pregnancy management.

PROM management depends on gestational age

All management recommendations require reassuring fetal testing, evaluation for infection, and no other contraindications to expectant management. Once these are established, the most important determinant of PROM management then becomes gestational age.

Previable PROM

Previable PROM (usually defined as less than 23–24 weeks) has high risks of both maternal and fetal/neonatal morbidity and mortality from infection, hemorrhage, pulmonary hypoplasia, and extreme prematurity. These very difficult cases benefit from a multidisciplinary approach to patient counseling regarding expectant management versus immediate delivery.

If expectant management is chosen, outpatient management with close monitoring for signs of maternal infection may be done until an agreed on gestational age of viability. Then inpatient management with fetal monitoring, corticosteroids, tocolysis, magnesium for neuroprotection, and group B streptococcus (GBS) prophylaxis may be considered as appropriate.

Preterm PROM at less than 34 weeks

If the mother and fetus are otherwise stable, PROM at less than 34 weeks warrants inpatient expectant management with close maternal and fetal monitoring for signs of infection and labor. Management includes latency antibiotics, antenatal corticosteroids, magnesium for neuroprotection if less than 32 weeks’ gestation and at risk for imminent delivery, and GBS prophylaxis. While tocolysis may increase latency and help with steroid course completion, it should be used cautiously and avoided in cases of abruption or chorioamnionitis. Although there is no definitive recommendation published, a rescue course of steroids may be considered as appropriate but should not delay an indicated delivery.

Continue to: Late preterm PROM...

Late preterm PROM

The biggest change to clinical management in this ACOG Practice Bulletin is for late preterm (34–36 6/7 weeks) PROM, with the recommendation for either immediate delivery or expectant management up to 37 weeks stemming from the PPROMPT study by Morris and colleagues.⁷

From the neonatal perspective, no difference has been demonstrated between immediate delivery and expectant management for neonatal sepsis or a composite neonatal morbidity and mortality. Expectant management may be preferred from the neonatal point of view as immediate delivery was associated with an increased rate of neonatal respiratory distress, mechanical ventilation, and length of stay in the neonatal intensive care unit. The potential for long-term neurodevelopmental outcomes of delivery at 34 versus 37 weeks also should be considered.

From the maternal perspective, expectant management has an increased risk of antepartum and postpartum hemorrhage, fever, antibiotic use, and maternal length of stay, but a decreased risk of CD.

A late preterm steroid course can be considered if delivery is planned in no less than 24 hours and likely to occur in the next 7 days and if the patient has not already received a course of steroids. A rescue course of steroids is not indicated if the patient received a steroid course prior in the pregnancy. While appropriate GBS prophylaxis is recommended, latency antibiotics and tocolysis are not, and delivery should not be delayed if chorioamnionitis is diagnosed.

Ultimately, preterm PROM management with a stable mother and fetus at or beyond 34 weeks requires comprehensive counseling of the risks and benefits for both mother and fetus/neonate. A multidisciplinary team that together counsels the patient also may help with this shared decision making.

Term PROM

For patients with term PROM, delivery is recommended. Although a short period of expectant management for 12 to 24 hours is reported as “reasonable,” the risk of infection increases with the length of rupture of membranes. Therefore, induction of labor or CD soon after rupture of membranes is recommended for patients who are GBS positive and is preferred for all others.

VTE prophylaxis in pregnancy: Regimen adjustments, CD strategies, and COVID-19 considerations

Birsner ML, Turrentine M, Pettker CM, et al. ACOG practice advisory: Options for peripartum anticoagulation in areas affected by shortage of unfractionated heparin. March 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/options-for-peripartum-anticoagulation-in-areas-affected-by-shortage-of-unfractionated-heparin. Accessed December 8, 2020.

Pacheco LD, Saade G, Metz TD. Society for Maternal-Fetal Medicine Consult Series No. 51: Thromboembolism prophylaxis for cesarean delivery. Am J Obstet Gynecol. 2020;223:B11-B17

Venous thromboembolism (VTE) prophylaxis is a timely topic for a number of reasons. First, a shortage of unfractionated heparin prompted an ACOG Practice Advisory, endorsed by SMFM and the Society for Obstetric Anesthesia and Perinatology, regarding use of low molecular weight heparin (LMWH) in the peripartum period.⁸ In addition, SMFM released updated recommendations for VTE prophylaxis for CD as part of the SMFM Consult Series.⁹ Finally, there is evidence that COVID-19 infection may increase the risk of coagulopathy, leading to consideration of additional VTE prophylaxis for pregnant and postpartum women with COVID-19.

Candidates for prophylaxis

As recommended by the ACOG Practice Bulletin on thromboembolism in pregnancy, women who may require VTE prophylaxis during pregnancy and/or the postpartum period include those with¹⁰:

• VTE diagnosed during pregnancy
• a history of VTE, including during pregnancy or with use of hormonal contraception
• a history of thrombophilia with or without a personal or family history of VTE.

For these patients, LMWH has many advantages over unfractionated heparin, including ease of use and reliability of dosing. It generally is preferred in pregnancy and postpartum (for both prophylactic and therapeutic anticoagulation) by patients and providers.

The Practice Bulletin references a strategy that describes converting LMWH to unfractionated heparin at around 36 weeks’ gestation in preparation for delivery because unfractionated heparin has the advantage of a shorter half-life and the option for anticoagulation reversal with protamine sulfate. In the Practice Advisory, a global shortage of unfractionated heparin and an argument that the above conversion was less about concern for maternal hemorrhage and more about avoiding spinal and epidural hematomas led to the following recommendations for continued use of LMWH through delivery:

• LMWH heparin can be discontinued in a planned fashion prior to scheduled induction of labor or CD (generally 12 hours for prophylactic dosing and 24 hours for intermediate dosing).
• Patients in spontaneous labor may receive neuraxial anesthesia 12 hours after the last prophylactic dose and 24 hours after the last intermediate dose of LMWH.
• Patients who require anticoagulation during pregnancy should be counseled that if they have vaginal bleeding, leakage of fluid, or regular contractions they should be evaluated prior to taking their next dose of anticoagulant.
• In the absence of other complications, delivery should not be before 39 weeks for the indication of anticoagulation requirement alone.

Continue to: Managing VTE risk in CD...

Managing VTE risk in CD

Recognizing that VTE is a major cause of maternal morbidity and mortality, as well as the variety of the published guidelines for VTE prophylaxis after CD, the SMFM Consult Series provides recommendations to assist clinicians caring for postpartum women after CD. As reviewed in the ACOG Practice Bulletin, there are good data to support pharmacologic prophylaxis during pregnancy and the postpartum period for women with a history of VTE or a thrombophilia. Solid evidence is lacking, however, for what to do for women who have a CD without this history but may have other potential risk factors for VTE, such as obesity, preeclampsia, and transfusion requirement. Universal pharmacologic prophylaxis also is not yet supported by evidence. SMFM supports LMWH as the preferred medication in pregnancy and postpartum and provides these additional recommendations:

• All women who have a CD should have sequential compression devices (SCDs) placed prior to surgery and continued until they are ambulatory.
• Women with a history of VTE or thrombophilia without history of VTE should have SCDs and pharmacologic VTE prophylaxis for 6 weeks postpartum.
• Intermediate dosing of LMWH is recommended for patients with class III obesity.
• Institutions should develop patient safety bundles for VTE prophylaxis to identify additional risk factors that may warrant pharmacologic prophylaxis after CD in select patients.

Our approach to patients with COVID-19 infection

At our institution, we recently incorporated a VTE prophylaxis protocol into our electronic medical record that provides risk stratification for each patient. In addition to the above recommendations, our patients may qualify for short-term in-house or longer postpartum prophylaxis depending on risk factors.

A new risk factor in recent months is COVID-19 infection, which appears to increase the risk of coagulopathy, especially in patients with disease severe enough to warrant hospitalization. Given the potential for additive risk in pregnancy, in consult with our medicine colleagues, we have placed some of our more ill hospitalized pregnant patients on a course of prophylactic LMWH both in the hospital and after discharge independent of delivery status or mode of delivery. ●

Van Bavel J, Ravelli AC, Abu-Hanna A, et al. Risk factors for the recurrence of obstetrical anal sphincter injury and the role of a mediolateral episiotomy: an analysis of a national registry. BJOG. 2020;127:951-956.

EXPERT COMMENTARY

Women with a history of OASI are at increased risk for recurrence in a subsequent delivery. Higher rates of anal and fecal incontinence are reported in women with recurrent OASI (rOASI) compared with women who had an OASI only in their first delivery. Previous studies have reported recurrence rates of 5% to 7%,¹ and some suggested that MLE may be protective, but standardized recommendations for mode of delivery and use of MLE currently are not available.

Recently, van Bavel and colleagues sought to determine the rate of rOASI in their population as well as the factors that increase and decrease the risk of this complication.

Details of the study

This cohort study used data from the Dutch Perinatal Registry (Perined) that included 268,607 women who had their first and second deliveries (singleton, term, vertex, < 43 weeks) vaginally in 2000–2009. The study’s primary objective was to determine the rate of rOASI in women who had OASI in their first delivery. The secondary objectives were to identify risk factors for rOASI and to assess the effect of MLE. For the purposes of this study, OASI was defined as subtotal and total rupture of the perineum, or grades 3A-4 as defined by the Royal College of Obstetricians and Gynaecologists.²

Within this cohort, 9,943 women had an OASI in their first delivery (4%), and the rate of rOASI was 5.8% (579 of 9,943). After multivariate analysis, the risk factors for rOASI were birth weight of 4,000 g or greater (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.6–2.6) and duration of the second stage of labor of 30 minutes or longer (OR, 1.8; 95% CI, 1.4–2.3).

The MLE rate was 40.8% (4,054 of 9,943) and was associated with a lower rate of rOASI (OR, 0.3; 95% CI, 0.3–0.4). This association persisted when delivery type was separated into spontaneous and operative vaginal deliveries, with the number of MLEs needed to prevent one rOASI of 22 and 8, respectively. Birth weight of less than 3,000 g also was noted to be protective against rOASI (OR, 0.5; 95% CI, 0.3–0.9).

Based on these findings, as well as comparisons to previous studies, the authors concluded that MLE could be considered for routine use or at least discussed with all women with a prior OASI for prevention of rOASI.

Continue to: Study strengths and limitations...

Study strengths and limitations

A strength of this study was the large number of deliveries and the wide variation of practice included in the registry database, which promotes the generalizability of the results and reduces bias. This also provides an adequate base on which to determine an accurate rate of rOASI in the Dutch population.

One study limitation is that information is not available regarding how the episiotomies were performed (specifically, angle of incision), delivery techniques (“hands on” vs “hands off”), and indication for the episiotomy. Additional limitations suggested are that clinicians who perform an episiotomy may have an inherent bias regarding the protective nature of the procedure and may miss a rOASI due to inadequate examination postprocedure, overestimating its protective effect.

Finally, the relatively high rate of MLE and low rate of cesarean delivery (6.9%) in this study are specific to the Netherlands and do not reflect the obstetric practices used in many other countries. Generalizability of these results in the context of much lower MLE and higher cesarean delivery rates (as in the United States) would therefore be in question.●

Van Bavel J, Ravelli AC, Abu-Hanna A, et al. Risk factors for the recurrence of obstetrical anal sphincter injury and the role of a mediolateral episiotomy: an analysis of a national registry. BJOG. 2020;127:951-956.

EXPERT COMMENTARY

Women with a history of OASI are at increased risk for recurrence in a subsequent delivery. Higher rates of anal and fecal incontinence are reported in women with recurrent OASI (rOASI) compared with women who had an OASI only in their first delivery. Previous studies have reported recurrence rates of 5% to 7%,¹ and some suggested that MLE may be protective, but standardized recommendations for mode of delivery and use of MLE currently are not available.

Recently, van Bavel and colleagues sought to determine the rate of rOASI in their population as well as the factors that increase and decrease the risk of this complication.

Details of the study

This cohort study used data from the Dutch Perinatal Registry (Perined) that included 268,607 women who had their first and second deliveries (singleton, term, vertex, < 43 weeks) vaginally in 2000–2009. The study’s primary objective was to determine the rate of rOASI in women who had OASI in their first delivery. The secondary objectives were to identify risk factors for rOASI and to assess the effect of MLE. For the purposes of this study, OASI was defined as subtotal and total rupture of the perineum, or grades 3A-4 as defined by the Royal College of Obstetricians and Gynaecologists.²

Within this cohort, 9,943 women had an OASI in their first delivery (4%), and the rate of rOASI was 5.8% (579 of 9,943). After multivariate analysis, the risk factors for rOASI were birth weight of 4,000 g or greater (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.6–2.6) and duration of the second stage of labor of 30 minutes or longer (OR, 1.8; 95% CI, 1.4–2.3).

The MLE rate was 40.8% (4,054 of 9,943) and was associated with a lower rate of rOASI (OR, 0.3; 95% CI, 0.3–0.4). This association persisted when delivery type was separated into spontaneous and operative vaginal deliveries, with the number of MLEs needed to prevent one rOASI of 22 and 8, respectively. Birth weight of less than 3,000 g also was noted to be protective against rOASI (OR, 0.5; 95% CI, 0.3–0.9).

Based on these findings, as well as comparisons to previous studies, the authors concluded that MLE could be considered for routine use or at least discussed with all women with a prior OASI for prevention of rOASI.

Continue to: Study strengths and limitations...

Study strengths and limitations

A strength of this study was the large number of deliveries and the wide variation of practice included in the registry database, which promotes the generalizability of the results and reduces bias. This also provides an adequate base on which to determine an accurate rate of rOASI in the Dutch population.

One study limitation is that information is not available regarding how the episiotomies were performed (specifically, angle of incision), delivery techniques (“hands on” vs “hands off”), and indication for the episiotomy. Additional limitations suggested are that clinicians who perform an episiotomy may have an inherent bias regarding the protective nature of the procedure and may miss a rOASI due to inadequate examination postprocedure, overestimating its protective effect.

Finally, the relatively high rate of MLE and low rate of cesarean delivery (6.9%) in this study are specific to the Netherlands and do not reflect the obstetric practices used in many other countries. Generalizability of these results in the context of much lower MLE and higher cesarean delivery rates (as in the United States) would therefore be in question.●

Van Bavel J, Ravelli AC, Abu-Hanna A, et al. Risk factors for the recurrence of obstetrical anal sphincter injury and the role of a mediolateral episiotomy: an analysis of a national registry. BJOG. 2020;127:951-956.

EXPERT COMMENTARY

Women with a history of OASI are at increased risk for recurrence in a subsequent delivery. Higher rates of anal and fecal incontinence are reported in women with recurrent OASI (rOASI) compared with women who had an OASI only in their first delivery. Previous studies have reported recurrence rates of 5% to 7%,¹ and some suggested that MLE may be protective, but standardized recommendations for mode of delivery and use of MLE currently are not available.

Recently, van Bavel and colleagues sought to determine the rate of rOASI in their population as well as the factors that increase and decrease the risk of this complication.

Details of the study

This cohort study used data from the Dutch Perinatal Registry (Perined) that included 268,607 women who had their first and second deliveries (singleton, term, vertex, < 43 weeks) vaginally in 2000–2009. The study’s primary objective was to determine the rate of rOASI in women who had OASI in their first delivery. The secondary objectives were to identify risk factors for rOASI and to assess the effect of MLE. For the purposes of this study, OASI was defined as subtotal and total rupture of the perineum, or grades 3A-4 as defined by the Royal College of Obstetricians and Gynaecologists.²

Within this cohort, 9,943 women had an OASI in their first delivery (4%), and the rate of rOASI was 5.8% (579 of 9,943). After multivariate analysis, the risk factors for rOASI were birth weight of 4,000 g or greater (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.6–2.6) and duration of the second stage of labor of 30 minutes or longer (OR, 1.8; 95% CI, 1.4–2.3).

The MLE rate was 40.8% (4,054 of 9,943) and was associated with a lower rate of rOASI (OR, 0.3; 95% CI, 0.3–0.4). This association persisted when delivery type was separated into spontaneous and operative vaginal deliveries, with the number of MLEs needed to prevent one rOASI of 22 and 8, respectively. Birth weight of less than 3,000 g also was noted to be protective against rOASI (OR, 0.5; 95% CI, 0.3–0.9).

Based on these findings, as well as comparisons to previous studies, the authors concluded that MLE could be considered for routine use or at least discussed with all women with a prior OASI for prevention of rOASI.

Continue to: Study strengths and limitations...

Study strengths and limitations

A strength of this study was the large number of deliveries and the wide variation of practice included in the registry database, which promotes the generalizability of the results and reduces bias. This also provides an adequate base on which to determine an accurate rate of rOASI in the Dutch population.

One study limitation is that information is not available regarding how the episiotomies were performed (specifically, angle of incision), delivery techniques (“hands on” vs “hands off”), and indication for the episiotomy. Additional limitations suggested are that clinicians who perform an episiotomy may have an inherent bias regarding the protective nature of the procedure and may miss a rOASI due to inadequate examination postprocedure, overestimating its protective effect.

Finally, the relatively high rate of MLE and low rate of cesarean delivery (6.9%) in this study are specific to the Netherlands and do not reflect the obstetric practices used in many other countries. Generalizability of these results in the context of much lower MLE and higher cesarean delivery rates (as in the United States) would therefore be in question.●