Obstetrics

Heart rate variability (HRV), as assessed during a deep breathing test, may lead to improved diagnosis of post-traumatic stress disorder, according to a study published in Frontiers in Psychiatry.

It is estimated that between 8% and 15% of clinically recognized pregnancies and up to 30% of all pregnancies result in miscarriage – a loss that can be devastating for everyone. There are limited data on the strength of the association between perinatal loss and subsequent common mental health disorders, such as anxiety, depression, and PTSD. The prevalence of PTSD among this group is still unknown, and one of the factors that contribute to the absence of data is that diagnostic evaluation is subjective.

To address this issue, researchers from Anhembi Morumbi University (UAM) in São José dos Campos, Brazil, along with teams in the United States and United Arab Emirates (UAE), investigated biomarkers for the severity of PTSD. The hope is that the research will enable psychiatrists to assess women who experience pregnancy loss more objectively. Study author Ovidiu Constantin Baltatu, MD, PhD, a professor at Brazil’s UAM and the UAE’s Khalifa University, spoke to this news organization about the study.

Under the guidance of Dr. Baltatu, psychologist Cláudia de Faria Cardoso carried out the research as part of her studies in biomedical engineering at UAM. Fifty-three women were recruited; the average age of the cohort was 33 years. All participants had a history of at least one perinatal loss. Pregnancy loss intervals ranged from less than 40 days to more than 6 months.

Participants completed a clinical interview and a questionnaire; PTSD symptoms were assessed on the basis of criteria in the DSM-5. The instrument used for the assessment was the Brazilian version of the Post-traumatic Stress Disorder Checklist (PCL-5). In addition, to evaluate general autonomic dysfunction, patients completed the Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire.

HRV was assessed during a deep breathing test using an HRV scanner system with wireless electrocardiography that enabled real-time data analysis and visualization. The investigators examined the following HRV measures: standard deviation (SD) of normal R-R wave intervals (SDNN), square root of the mean of the sum of the squares of differences between adjacent normal R wave intervals, and the number of all R-R intervals in which the change in consecutive normal sinus intervals exceeds 50 ms divided by the total number of R-R intervals measured.

Of the 53 participants, 25 had been diagnosed with pregnancy loss–induced PTSD. The results indicated a significant association between PCL-5 scores and HRV indices. The SDNN index effectively distinguished between patients with PTSD and those without.

To Dr. Baltatu, HRV indices reflect dysfunction of the autonomic nervous system (ANS), one of the major neural pathways activated by stress.

Although the deep breathing test has been around for a long time, it’s not widely used in current clinical practice, he said. According to him, maximum and minimum heart rates during breathing at six cycles per minute can typically be used to calculate the inspiratory-to-expiratory ratio, thus providing an indication of ANS function. “Our group introduced the study of HRV during deep breathing test, which is a step forward,” he said.

The methodology used by the team was well received by the participants. “With the deep breathing test, the women were able to look at a screen and see real-time graphics displaying the stress that they were experiencing after having suffered trauma. This visualization of objective measures was perceived as an improved care,” said Dr. Baltatu.

In general, HRV provides a more objective means of diagnosing PTSD. “Normally, PTSD is assessed through a questionnaire and an interview with psychologists,” said Dr. Baltatu. The subjectivity of the assessment is one of the main factors associated with the underdiagnosis of this condition, he explained.

It is important to remember that other factors, such as a lack of awareness about the problem, also hinder the diagnosis of PTSD in this population, Dr. Baltatu added. Women who have had a miscarriage often don’t think that their symptoms may result from PTSD. This fact highlights why it is so important that hospitals have a clinical psychologist on staff. In addition, Dr. Baltatu pointed out that a woman who experiences a pregnancy loss usually has negative memories of the hospital and is therefore reluctant to reach out for professional help. “In our study, all psychological care and assessments took place outside of a hospital setting, which the participants seemed to appreciate,” he emphasized.

Dr. Baltatu and his team are conducting follow-up research. The preliminary results indicate that the biomarkers identified in the study are promising in the assessment of patients’ clinical progress. This finding may reflect the fact that the HRV indices have proven useful not only in diagnosing but also in monitoring women in treatment, because they are able to identify which patients are responding better to treatment.

A version of this article first appeared on Medscape.com.

Heart rate variability (HRV), as assessed during a deep breathing test, may lead to improved diagnosis of post-traumatic stress disorder, according to a study published in Frontiers in Psychiatry.

It is estimated that between 8% and 15% of clinically recognized pregnancies and up to 30% of all pregnancies result in miscarriage – a loss that can be devastating for everyone. There are limited data on the strength of the association between perinatal loss and subsequent common mental health disorders, such as anxiety, depression, and PTSD. The prevalence of PTSD among this group is still unknown, and one of the factors that contribute to the absence of data is that diagnostic evaluation is subjective.

To address this issue, researchers from Anhembi Morumbi University (UAM) in São José dos Campos, Brazil, along with teams in the United States and United Arab Emirates (UAE), investigated biomarkers for the severity of PTSD. The hope is that the research will enable psychiatrists to assess women who experience pregnancy loss more objectively. Study author Ovidiu Constantin Baltatu, MD, PhD, a professor at Brazil’s UAM and the UAE’s Khalifa University, spoke to this news organization about the study.

Under the guidance of Dr. Baltatu, psychologist Cláudia de Faria Cardoso carried out the research as part of her studies in biomedical engineering at UAM. Fifty-three women were recruited; the average age of the cohort was 33 years. All participants had a history of at least one perinatal loss. Pregnancy loss intervals ranged from less than 40 days to more than 6 months.

Participants completed a clinical interview and a questionnaire; PTSD symptoms were assessed on the basis of criteria in the DSM-5. The instrument used for the assessment was the Brazilian version of the Post-traumatic Stress Disorder Checklist (PCL-5). In addition, to evaluate general autonomic dysfunction, patients completed the Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire.

HRV was assessed during a deep breathing test using an HRV scanner system with wireless electrocardiography that enabled real-time data analysis and visualization. The investigators examined the following HRV measures: standard deviation (SD) of normal R-R wave intervals (SDNN), square root of the mean of the sum of the squares of differences between adjacent normal R wave intervals, and the number of all R-R intervals in which the change in consecutive normal sinus intervals exceeds 50 ms divided by the total number of R-R intervals measured.

Of the 53 participants, 25 had been diagnosed with pregnancy loss–induced PTSD. The results indicated a significant association between PCL-5 scores and HRV indices. The SDNN index effectively distinguished between patients with PTSD and those without.

To Dr. Baltatu, HRV indices reflect dysfunction of the autonomic nervous system (ANS), one of the major neural pathways activated by stress.

Although the deep breathing test has been around for a long time, it’s not widely used in current clinical practice, he said. According to him, maximum and minimum heart rates during breathing at six cycles per minute can typically be used to calculate the inspiratory-to-expiratory ratio, thus providing an indication of ANS function. “Our group introduced the study of HRV during deep breathing test, which is a step forward,” he said.

The methodology used by the team was well received by the participants. “With the deep breathing test, the women were able to look at a screen and see real-time graphics displaying the stress that they were experiencing after having suffered trauma. This visualization of objective measures was perceived as an improved care,” said Dr. Baltatu.

In general, HRV provides a more objective means of diagnosing PTSD. “Normally, PTSD is assessed through a questionnaire and an interview with psychologists,” said Dr. Baltatu. The subjectivity of the assessment is one of the main factors associated with the underdiagnosis of this condition, he explained.

It is important to remember that other factors, such as a lack of awareness about the problem, also hinder the diagnosis of PTSD in this population, Dr. Baltatu added. Women who have had a miscarriage often don’t think that their symptoms may result from PTSD. This fact highlights why it is so important that hospitals have a clinical psychologist on staff. In addition, Dr. Baltatu pointed out that a woman who experiences a pregnancy loss usually has negative memories of the hospital and is therefore reluctant to reach out for professional help. “In our study, all psychological care and assessments took place outside of a hospital setting, which the participants seemed to appreciate,” he emphasized.

Dr. Baltatu and his team are conducting follow-up research. The preliminary results indicate that the biomarkers identified in the study are promising in the assessment of patients’ clinical progress. This finding may reflect the fact that the HRV indices have proven useful not only in diagnosing but also in monitoring women in treatment, because they are able to identify which patients are responding better to treatment.

A version of this article first appeared on Medscape.com.

Heart rate variability (HRV), as assessed during a deep breathing test, may lead to improved diagnosis of post-traumatic stress disorder, according to a study published in Frontiers in Psychiatry.

It is estimated that between 8% and 15% of clinically recognized pregnancies and up to 30% of all pregnancies result in miscarriage – a loss that can be devastating for everyone. There are limited data on the strength of the association between perinatal loss and subsequent common mental health disorders, such as anxiety, depression, and PTSD. The prevalence of PTSD among this group is still unknown, and one of the factors that contribute to the absence of data is that diagnostic evaluation is subjective.

To address this issue, researchers from Anhembi Morumbi University (UAM) in São José dos Campos, Brazil, along with teams in the United States and United Arab Emirates (UAE), investigated biomarkers for the severity of PTSD. The hope is that the research will enable psychiatrists to assess women who experience pregnancy loss more objectively. Study author Ovidiu Constantin Baltatu, MD, PhD, a professor at Brazil’s UAM and the UAE’s Khalifa University, spoke to this news organization about the study.

Under the guidance of Dr. Baltatu, psychologist Cláudia de Faria Cardoso carried out the research as part of her studies in biomedical engineering at UAM. Fifty-three women were recruited; the average age of the cohort was 33 years. All participants had a history of at least one perinatal loss. Pregnancy loss intervals ranged from less than 40 days to more than 6 months.

Participants completed a clinical interview and a questionnaire; PTSD symptoms were assessed on the basis of criteria in the DSM-5. The instrument used for the assessment was the Brazilian version of the Post-traumatic Stress Disorder Checklist (PCL-5). In addition, to evaluate general autonomic dysfunction, patients completed the Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire.

HRV was assessed during a deep breathing test using an HRV scanner system with wireless electrocardiography that enabled real-time data analysis and visualization. The investigators examined the following HRV measures: standard deviation (SD) of normal R-R wave intervals (SDNN), square root of the mean of the sum of the squares of differences between adjacent normal R wave intervals, and the number of all R-R intervals in which the change in consecutive normal sinus intervals exceeds 50 ms divided by the total number of R-R intervals measured.

Of the 53 participants, 25 had been diagnosed with pregnancy loss–induced PTSD. The results indicated a significant association between PCL-5 scores and HRV indices. The SDNN index effectively distinguished between patients with PTSD and those without.

To Dr. Baltatu, HRV indices reflect dysfunction of the autonomic nervous system (ANS), one of the major neural pathways activated by stress.

Although the deep breathing test has been around for a long time, it’s not widely used in current clinical practice, he said. According to him, maximum and minimum heart rates during breathing at six cycles per minute can typically be used to calculate the inspiratory-to-expiratory ratio, thus providing an indication of ANS function. “Our group introduced the study of HRV during deep breathing test, which is a step forward,” he said.

The methodology used by the team was well received by the participants. “With the deep breathing test, the women were able to look at a screen and see real-time graphics displaying the stress that they were experiencing after having suffered trauma. This visualization of objective measures was perceived as an improved care,” said Dr. Baltatu.

In general, HRV provides a more objective means of diagnosing PTSD. “Normally, PTSD is assessed through a questionnaire and an interview with psychologists,” said Dr. Baltatu. The subjectivity of the assessment is one of the main factors associated with the underdiagnosis of this condition, he explained.

It is important to remember that other factors, such as a lack of awareness about the problem, also hinder the diagnosis of PTSD in this population, Dr. Baltatu added. Women who have had a miscarriage often don’t think that their symptoms may result from PTSD. This fact highlights why it is so important that hospitals have a clinical psychologist on staff. In addition, Dr. Baltatu pointed out that a woman who experiences a pregnancy loss usually has negative memories of the hospital and is therefore reluctant to reach out for professional help. “In our study, all psychological care and assessments took place outside of a hospital setting, which the participants seemed to appreciate,” he emphasized.

Dr. Baltatu and his team are conducting follow-up research. The preliminary results indicate that the biomarkers identified in the study are promising in the assessment of patients’ clinical progress. This finding may reflect the fact that the HRV indices have proven useful not only in diagnosing but also in monitoring women in treatment, because they are able to identify which patients are responding better to treatment.

A version of this article first appeared on Medscape.com.

Between 2014 and 2020, the frequency of adverse pregnancy outcomes in the United States increased among women with gestational diabetes, with persisting differences in adverse outcomes by race and ethnicity, according to a report in JAMA

“[Previous] population-based studies on racial and ethnic disparities in gestational diabetes have focused on differences in the rate of diagnosis, rather than adverse pregnancy outcomes,” lead author Kartik K. Venkatesh, MD, PhD, of Ohio State University, Columbus, and colleagues explained.

The researchers conducted a cross-sectional, descriptive study to evaluate whether the frequency of adverse pregnancy outcomes with gestational diabetes changed over time and whether the risk of these outcomes differed by maternal race and ethnicity.

The data were obtained from the Centers for Disease Control and Prevention’s National Center for Health Statistics Natality Files. Exposures of interest were year of delivery, as well as race and ethnicity.
 

Results

The study cohort included 1,560,822 pregnant women with gestational diabetes aged 15-44 years. Among the study participants the mean age was 31 years (standard deviation, 5.5 years) and the majority were White (48%), followed by Hispanic/Latina (27%), Asian/Pacific Islander (13%), and Black (12%).

There was a significant increase in the overall frequency of transfusion (8.0%; 95% confidence interval, 3.8%-12.4%), preeclampsia or gestational hypertension (4.2%; 95% CI, 3.3%-5.2%), NICU admission (1.0%; 95% CI, 0.3%-1.7%), and preterm birth at less than 37 weeks (0.9%; 95% CI, 0.3%-1.5%) from 2014 to 2020 for these women and their infants.

In addition, there was a significant decrease in the following outcomes: macrosomia (–4.7%; 95% CI, –5.3% to –4.0%), cesarean delivery (–1.4%; 95% CI, –1.7% to –1.1%), primary cesarean delivery (–1.2%; 95% CI, –1.5% to –0.9%), and large for gestational age (–2.3%; 95% CI, –2.8% to –1.8%), but there was no significant differences in maternal ICU admission and small-for-gestational-age infants.

From 2014 through 2020, differences in adverse outcomes by race and ethnicity persisted; in comparison with Whites, Black participants were at significantly higher risk of all evaluated outcomes, except for macrosomia and large for gestational age.

Hispanic/Latina and Asian/Pacific Islander individuals were also at significantly higher risk of preterm birth, NICU admission, maternal ICU admission, and small for gestational age. Furthermore, American Indian participants were at significantly higher risk of all evaluated outcomes, except for cesarean delivery and small for gestational age.
 

Results in context

Health policy researcher Felicia Hill-Briggs, PhD, at the Feinstein Institutes for Medical Research in Manhasset, N.Y. commented: “Two alarming trends highlighted by this study: 1) Racial and ethnic inequities in adverse gestational diabetes outcomes; and 2) the rising rates of gestational diabetes overall – both must and can be halted.”

“Optimizing medical management of gestational diabetes, whether through improved access to diabetes care in pregnancy, behavioral interventions, and pharmacotherapy can decrease the risk of adverse pregnancy outcomes,” Dr. Venkatesh commented. “It is possible that the equitable delivery of these interventions to address glycemic control could decrease racial and ethnic disparities in adverse pregnancy outcomes among individuals with gestational diabetes.”

Dr. Venkatesh and his colleagues acknowledged that a key limitation of the study was the use of administrative data; thus, inferences on maternal care improvements could not be determined.

“Further research could focus on greater understanding of racial and ethnic differences in the management of gestational diabetes,” the researchers concluded.

This study was supported by the Care Innovation and Community Improvement Program at Ohio State University. One author reported receiving grants from the National Institutes of Health outside of this study. The other authors reported no relevant disclosures. Dr. Hill-Briggs had no relevant disclosures.

Between 2014 and 2020, the frequency of adverse pregnancy outcomes in the United States increased among women with gestational diabetes, with persisting differences in adverse outcomes by race and ethnicity, according to a report in JAMA

“[Previous] population-based studies on racial and ethnic disparities in gestational diabetes have focused on differences in the rate of diagnosis, rather than adverse pregnancy outcomes,” lead author Kartik K. Venkatesh, MD, PhD, of Ohio State University, Columbus, and colleagues explained.

The researchers conducted a cross-sectional, descriptive study to evaluate whether the frequency of adverse pregnancy outcomes with gestational diabetes changed over time and whether the risk of these outcomes differed by maternal race and ethnicity.

The data were obtained from the Centers for Disease Control and Prevention’s National Center for Health Statistics Natality Files. Exposures of interest were year of delivery, as well as race and ethnicity.
 

Results

The study cohort included 1,560,822 pregnant women with gestational diabetes aged 15-44 years. Among the study participants the mean age was 31 years (standard deviation, 5.5 years) and the majority were White (48%), followed by Hispanic/Latina (27%), Asian/Pacific Islander (13%), and Black (12%).

There was a significant increase in the overall frequency of transfusion (8.0%; 95% confidence interval, 3.8%-12.4%), preeclampsia or gestational hypertension (4.2%; 95% CI, 3.3%-5.2%), NICU admission (1.0%; 95% CI, 0.3%-1.7%), and preterm birth at less than 37 weeks (0.9%; 95% CI, 0.3%-1.5%) from 2014 to 2020 for these women and their infants.

In addition, there was a significant decrease in the following outcomes: macrosomia (–4.7%; 95% CI, –5.3% to –4.0%), cesarean delivery (–1.4%; 95% CI, –1.7% to –1.1%), primary cesarean delivery (–1.2%; 95% CI, –1.5% to –0.9%), and large for gestational age (–2.3%; 95% CI, –2.8% to –1.8%), but there was no significant differences in maternal ICU admission and small-for-gestational-age infants.

From 2014 through 2020, differences in adverse outcomes by race and ethnicity persisted; in comparison with Whites, Black participants were at significantly higher risk of all evaluated outcomes, except for macrosomia and large for gestational age.

Hispanic/Latina and Asian/Pacific Islander individuals were also at significantly higher risk of preterm birth, NICU admission, maternal ICU admission, and small for gestational age. Furthermore, American Indian participants were at significantly higher risk of all evaluated outcomes, except for cesarean delivery and small for gestational age.
 

Results in context

Health policy researcher Felicia Hill-Briggs, PhD, at the Feinstein Institutes for Medical Research in Manhasset, N.Y. commented: “Two alarming trends highlighted by this study: 1) Racial and ethnic inequities in adverse gestational diabetes outcomes; and 2) the rising rates of gestational diabetes overall – both must and can be halted.”

“Optimizing medical management of gestational diabetes, whether through improved access to diabetes care in pregnancy, behavioral interventions, and pharmacotherapy can decrease the risk of adverse pregnancy outcomes,” Dr. Venkatesh commented. “It is possible that the equitable delivery of these interventions to address glycemic control could decrease racial and ethnic disparities in adverse pregnancy outcomes among individuals with gestational diabetes.”

Dr. Venkatesh and his colleagues acknowledged that a key limitation of the study was the use of administrative data; thus, inferences on maternal care improvements could not be determined.

“Further research could focus on greater understanding of racial and ethnic differences in the management of gestational diabetes,” the researchers concluded.

This study was supported by the Care Innovation and Community Improvement Program at Ohio State University. One author reported receiving grants from the National Institutes of Health outside of this study. The other authors reported no relevant disclosures. Dr. Hill-Briggs had no relevant disclosures.

Between 2014 and 2020, the frequency of adverse pregnancy outcomes in the United States increased among women with gestational diabetes, with persisting differences in adverse outcomes by race and ethnicity, according to a report in JAMA

“[Previous] population-based studies on racial and ethnic disparities in gestational diabetes have focused on differences in the rate of diagnosis, rather than adverse pregnancy outcomes,” lead author Kartik K. Venkatesh, MD, PhD, of Ohio State University, Columbus, and colleagues explained.

The researchers conducted a cross-sectional, descriptive study to evaluate whether the frequency of adverse pregnancy outcomes with gestational diabetes changed over time and whether the risk of these outcomes differed by maternal race and ethnicity.

The data were obtained from the Centers for Disease Control and Prevention’s National Center for Health Statistics Natality Files. Exposures of interest were year of delivery, as well as race and ethnicity.
 

Results

The study cohort included 1,560,822 pregnant women with gestational diabetes aged 15-44 years. Among the study participants the mean age was 31 years (standard deviation, 5.5 years) and the majority were White (48%), followed by Hispanic/Latina (27%), Asian/Pacific Islander (13%), and Black (12%).

There was a significant increase in the overall frequency of transfusion (8.0%; 95% confidence interval, 3.8%-12.4%), preeclampsia or gestational hypertension (4.2%; 95% CI, 3.3%-5.2%), NICU admission (1.0%; 95% CI, 0.3%-1.7%), and preterm birth at less than 37 weeks (0.9%; 95% CI, 0.3%-1.5%) from 2014 to 2020 for these women and their infants.

In addition, there was a significant decrease in the following outcomes: macrosomia (–4.7%; 95% CI, –5.3% to –4.0%), cesarean delivery (–1.4%; 95% CI, –1.7% to –1.1%), primary cesarean delivery (–1.2%; 95% CI, –1.5% to –0.9%), and large for gestational age (–2.3%; 95% CI, –2.8% to –1.8%), but there was no significant differences in maternal ICU admission and small-for-gestational-age infants.

From 2014 through 2020, differences in adverse outcomes by race and ethnicity persisted; in comparison with Whites, Black participants were at significantly higher risk of all evaluated outcomes, except for macrosomia and large for gestational age.

Hispanic/Latina and Asian/Pacific Islander individuals were also at significantly higher risk of preterm birth, NICU admission, maternal ICU admission, and small for gestational age. Furthermore, American Indian participants were at significantly higher risk of all evaluated outcomes, except for cesarean delivery and small for gestational age.
 

Results in context

Health policy researcher Felicia Hill-Briggs, PhD, at the Feinstein Institutes for Medical Research in Manhasset, N.Y. commented: “Two alarming trends highlighted by this study: 1) Racial and ethnic inequities in adverse gestational diabetes outcomes; and 2) the rising rates of gestational diabetes overall – both must and can be halted.”

“Optimizing medical management of gestational diabetes, whether through improved access to diabetes care in pregnancy, behavioral interventions, and pharmacotherapy can decrease the risk of adverse pregnancy outcomes,” Dr. Venkatesh commented. “It is possible that the equitable delivery of these interventions to address glycemic control could decrease racial and ethnic disparities in adverse pregnancy outcomes among individuals with gestational diabetes.”

Dr. Venkatesh and his colleagues acknowledged that a key limitation of the study was the use of administrative data; thus, inferences on maternal care improvements could not be determined.

“Further research could focus on greater understanding of racial and ethnic differences in the management of gestational diabetes,” the researchers concluded.

This study was supported by the Care Innovation and Community Improvement Program at Ohio State University. One author reported receiving grants from the National Institutes of Health outside of this study. The other authors reported no relevant disclosures. Dr. Hill-Briggs had no relevant disclosures.

In this question-and-answer article (the third in a series), our objective is to re­inforce for the clinician several practical points of management for common infectious diseases. The principal references for the answers to the questions are 2 textbook chapters written by Dr. Duff.^1,2 Other pertinent references are included in the text.

21. What prophylactic antibiotic should be administered intrapartum to a pregnant woman who is colonized with group B streptococci but who has a mild allergy to penicillin?

In this situation, the drug of choice is intravenous cefazolin, 2 g initially then 1 g every 8 hours until delivery. For patients with a severe allergy to penicillin, the drugs of choice are either clindamycin, 900 mg intravenously every 8 hours (if sensitivity of the organism is confirmed), or vancomycin, 20 mg/kg intravenously every 8 hours (maximum of 2 g per single dose).

22. In a pregnant woman who has a life-threatening allergy to penicillin, what is the most appropriate treatment for syphilis?

This patient should be admitted to the hospital and rapidly desensitized to penicillin. She then can be treated with the appropriate dose of penicillin, given her stage of syphilis. Of note, in the future, the patient’s allergy to penicillin will return, despite the brief period of desensitization.

23. What are the most common organisms that cause chorioamnionitis and puerperal endometritis?

Chorioamnionitis and puerperal endometritis are polymicrobial, mixed aerobic-anaerobic infections. The dominant organisms are anaerobic gram-negative bacilli (Bacteroides and Prevotella species); anaerobic gram-positive cocci (Peptococcus species and Peptostreptococcus species); aerobic gram-negative bacilli (principally, Escherichia coli, Klebsiella pneumoniae, and Proteus species); and aerobic gram-positive cocci (enterococci, staphylococci, and group B streptococci). ●

In this question-and-answer article (the third in a series), our objective is to re­inforce for the clinician several practical points of management for common infectious diseases. The principal references for the answers to the questions are 2 textbook chapters written by Dr. Duff.^1,2 Other pertinent references are included in the text.

21. What prophylactic antibiotic should be administered intrapartum to a pregnant woman who is colonized with group B streptococci but who has a mild allergy to penicillin?

In this situation, the drug of choice is intravenous cefazolin, 2 g initially then 1 g every 8 hours until delivery. For patients with a severe allergy to penicillin, the drugs of choice are either clindamycin, 900 mg intravenously every 8 hours (if sensitivity of the organism is confirmed), or vancomycin, 20 mg/kg intravenously every 8 hours (maximum of 2 g per single dose).

22. In a pregnant woman who has a life-threatening allergy to penicillin, what is the most appropriate treatment for syphilis?

This patient should be admitted to the hospital and rapidly desensitized to penicillin. She then can be treated with the appropriate dose of penicillin, given her stage of syphilis. Of note, in the future, the patient’s allergy to penicillin will return, despite the brief period of desensitization.

23. What are the most common organisms that cause chorioamnionitis and puerperal endometritis?

Chorioamnionitis and puerperal endometritis are polymicrobial, mixed aerobic-anaerobic infections. The dominant organisms are anaerobic gram-negative bacilli (Bacteroides and Prevotella species); anaerobic gram-positive cocci (Peptococcus species and Peptostreptococcus species); aerobic gram-negative bacilli (principally, Escherichia coli, Klebsiella pneumoniae, and Proteus species); and aerobic gram-positive cocci (enterococci, staphylococci, and group B streptococci). ●

In this question-and-answer article (the third in a series), our objective is to re­inforce for the clinician several practical points of management for common infectious diseases. The principal references for the answers to the questions are 2 textbook chapters written by Dr. Duff.^1,2 Other pertinent references are included in the text.

21. What prophylactic antibiotic should be administered intrapartum to a pregnant woman who is colonized with group B streptococci but who has a mild allergy to penicillin?

In this situation, the drug of choice is intravenous cefazolin, 2 g initially then 1 g every 8 hours until delivery. For patients with a severe allergy to penicillin, the drugs of choice are either clindamycin, 900 mg intravenously every 8 hours (if sensitivity of the organism is confirmed), or vancomycin, 20 mg/kg intravenously every 8 hours (maximum of 2 g per single dose).

22. In a pregnant woman who has a life-threatening allergy to penicillin, what is the most appropriate treatment for syphilis?

This patient should be admitted to the hospital and rapidly desensitized to penicillin. She then can be treated with the appropriate dose of penicillin, given her stage of syphilis. Of note, in the future, the patient’s allergy to penicillin will return, despite the brief period of desensitization.

23. What are the most common organisms that cause chorioamnionitis and puerperal endometritis?

Chorioamnionitis and puerperal endometritis are polymicrobial, mixed aerobic-anaerobic infections. The dominant organisms are anaerobic gram-negative bacilli (Bacteroides and Prevotella species); anaerobic gram-positive cocci (Peptococcus species and Peptostreptococcus species); aerobic gram-negative bacilli (principally, Escherichia coli, Klebsiella pneumoniae, and Proteus species); and aerobic gram-positive cocci (enterococci, staphylococci, and group B streptococci). ●

Taglauer ES, Wachman EM, Juttukonda L, et al. Acute severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with placental angiotensin-converting enzyme 2 shedding. Am J Pathol. 2022;192:595-603. doi.org/10.1016/j.ajpath.2021.12.011

EXPERT COMMENTARY

Although transmission of SARS-CoV-2 virus from an infected mother to her fetus is rare, placental infection with SARS-CoV-2 can occur and has been observed in association with placental damage and adverse pregnancy outcomes, including stillbirth.¹ Understanding what mechanisms of defense protect the placenta and fetus from direct SARS-CoV-2 infection at the maternal-fetal interface, as well as the factors that might disturb or enhance that protection, is critical to gaining a deeper understanding of the potential impact of maternal COVID-19 on fetal well-being.

Details of the study

In a cohort of 24 pregnant individuals, Taglauer and colleagues investigated levels of placental angiotensin-converting enzyme (ACE)-2, placental ADAM17 (a disintegrin and metalloprotease domain 17) activity, and maternal serum soluble ACE2 in samples obtained at delivery from individuals with a history of second trimester COVID-19 infection, early third trimester COVID-19 infection, and no history of COVID-19 infection.

Results. Maternal COVID-19 infection in the early third trimester of pregnancy resulted in lower ACE2 protein levels in the placenta at delivery, higher ACE2 gene expression, and an increase in ADAM17 activity, compared with infection in the second trimester of pregnancy and compared with noninfected controls.

The authors postulated that increased ADAM17 activity—the enzyme responsible for ACE2 cleavage and shedding—may be responsible for lower ACE2 protein levels. Soluble ACE2 levels in maternal blood at delivery were increased in individuals with third trimester COVID-19 infection, although the source of soluble ACE2 (placental or otherwise) could not be determined with the methods employed. Levels of placental estrogen were no different between groups, which suggests that estrogen is not responsible for the observed differences.

Study strengths and limitations

ACE2 is the main receptor for the SARS-CoV-2 virus and facilitates viral entry into the cell.² Placental villous cells that are in direct contact with maternal blood express the ACE2 protein, rendering them potentially vulnerable to SARS-CoV-2 infection.³ In this study, the authors observed lower placental ACE2 protein in term placentas from recent (early third trimester) but not remote (second trimester) maternal SARS-CoV-2 infection, arguably the result of the observed increase in ADAM17 cleavage activity. Prior studies have shown conflicting results, with equal or higher ACE2 levels noted in the setting of maternal COVID-19 infection, which may be related to differences in COVID-19 disease severity, gestational age of infection, and/or fetal sex in these cohorts.^4-6

The concept that increased placental ACE2 shedding represents a protective defense mechanism that might last weeks beyond the acute infectious period is intriguing, but it requires further study. Observed differences in third but not second trimester COVID-19 infections could indicate either 1) an effect of maternal COVID-19 infection that lasts for several weeks but eventually normalizes over time, in the case of a remote infection; or 2) that second trimester maternal COVID-19 infection does not have the same pronounced effect on ACE2 levels as does third trimester infection. Observational studies of the human placenta are not able to answer this question, as directly sampling the placenta at the time of the exposure (or repeated sampling over time) in ongoing pregnancies is neither practical nor ethical. Further studies using animal or cellular models of SARS-CoV-2 infection in pregnancy may be necessary to fully understand the clinical relevance of these findings.

The study by Taglauer and colleagues provides a compelling argument for exploring how immune defenses at the maternal-fetal interface evolve over time and vary by trimester of exposure. ●

Taglauer ES, Wachman EM, Juttukonda L, et al. Acute severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with placental angiotensin-converting enzyme 2 shedding. Am J Pathol. 2022;192:595-603. doi.org/10.1016/j.ajpath.2021.12.011

EXPERT COMMENTARY

Although transmission of SARS-CoV-2 virus from an infected mother to her fetus is rare, placental infection with SARS-CoV-2 can occur and has been observed in association with placental damage and adverse pregnancy outcomes, including stillbirth.¹ Understanding what mechanisms of defense protect the placenta and fetus from direct SARS-CoV-2 infection at the maternal-fetal interface, as well as the factors that might disturb or enhance that protection, is critical to gaining a deeper understanding of the potential impact of maternal COVID-19 on fetal well-being.

Details of the study

In a cohort of 24 pregnant individuals, Taglauer and colleagues investigated levels of placental angiotensin-converting enzyme (ACE)-2, placental ADAM17 (a disintegrin and metalloprotease domain 17) activity, and maternal serum soluble ACE2 in samples obtained at delivery from individuals with a history of second trimester COVID-19 infection, early third trimester COVID-19 infection, and no history of COVID-19 infection.

Results. Maternal COVID-19 infection in the early third trimester of pregnancy resulted in lower ACE2 protein levels in the placenta at delivery, higher ACE2 gene expression, and an increase in ADAM17 activity, compared with infection in the second trimester of pregnancy and compared with noninfected controls.

The authors postulated that increased ADAM17 activity—the enzyme responsible for ACE2 cleavage and shedding—may be responsible for lower ACE2 protein levels. Soluble ACE2 levels in maternal blood at delivery were increased in individuals with third trimester COVID-19 infection, although the source of soluble ACE2 (placental or otherwise) could not be determined with the methods employed. Levels of placental estrogen were no different between groups, which suggests that estrogen is not responsible for the observed differences.

Study strengths and limitations

ACE2 is the main receptor for the SARS-CoV-2 virus and facilitates viral entry into the cell.² Placental villous cells that are in direct contact with maternal blood express the ACE2 protein, rendering them potentially vulnerable to SARS-CoV-2 infection.³ In this study, the authors observed lower placental ACE2 protein in term placentas from recent (early third trimester) but not remote (second trimester) maternal SARS-CoV-2 infection, arguably the result of the observed increase in ADAM17 cleavage activity. Prior studies have shown conflicting results, with equal or higher ACE2 levels noted in the setting of maternal COVID-19 infection, which may be related to differences in COVID-19 disease severity, gestational age of infection, and/or fetal sex in these cohorts.^4-6

The concept that increased placental ACE2 shedding represents a protective defense mechanism that might last weeks beyond the acute infectious period is intriguing, but it requires further study. Observed differences in third but not second trimester COVID-19 infections could indicate either 1) an effect of maternal COVID-19 infection that lasts for several weeks but eventually normalizes over time, in the case of a remote infection; or 2) that second trimester maternal COVID-19 infection does not have the same pronounced effect on ACE2 levels as does third trimester infection. Observational studies of the human placenta are not able to answer this question, as directly sampling the placenta at the time of the exposure (or repeated sampling over time) in ongoing pregnancies is neither practical nor ethical. Further studies using animal or cellular models of SARS-CoV-2 infection in pregnancy may be necessary to fully understand the clinical relevance of these findings.

The study by Taglauer and colleagues provides a compelling argument for exploring how immune defenses at the maternal-fetal interface evolve over time and vary by trimester of exposure. ●

Taglauer ES, Wachman EM, Juttukonda L, et al. Acute severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with placental angiotensin-converting enzyme 2 shedding. Am J Pathol. 2022;192:595-603. doi.org/10.1016/j.ajpath.2021.12.011

EXPERT COMMENTARY

Although transmission of SARS-CoV-2 virus from an infected mother to her fetus is rare, placental infection with SARS-CoV-2 can occur and has been observed in association with placental damage and adverse pregnancy outcomes, including stillbirth.¹ Understanding what mechanisms of defense protect the placenta and fetus from direct SARS-CoV-2 infection at the maternal-fetal interface, as well as the factors that might disturb or enhance that protection, is critical to gaining a deeper understanding of the potential impact of maternal COVID-19 on fetal well-being.

Details of the study

In a cohort of 24 pregnant individuals, Taglauer and colleagues investigated levels of placental angiotensin-converting enzyme (ACE)-2, placental ADAM17 (a disintegrin and metalloprotease domain 17) activity, and maternal serum soluble ACE2 in samples obtained at delivery from individuals with a history of second trimester COVID-19 infection, early third trimester COVID-19 infection, and no history of COVID-19 infection.

Results. Maternal COVID-19 infection in the early third trimester of pregnancy resulted in lower ACE2 protein levels in the placenta at delivery, higher ACE2 gene expression, and an increase in ADAM17 activity, compared with infection in the second trimester of pregnancy and compared with noninfected controls.

The authors postulated that increased ADAM17 activity—the enzyme responsible for ACE2 cleavage and shedding—may be responsible for lower ACE2 protein levels. Soluble ACE2 levels in maternal blood at delivery were increased in individuals with third trimester COVID-19 infection, although the source of soluble ACE2 (placental or otherwise) could not be determined with the methods employed. Levels of placental estrogen were no different between groups, which suggests that estrogen is not responsible for the observed differences.

Study strengths and limitations

ACE2 is the main receptor for the SARS-CoV-2 virus and facilitates viral entry into the cell.² Placental villous cells that are in direct contact with maternal blood express the ACE2 protein, rendering them potentially vulnerable to SARS-CoV-2 infection.³ In this study, the authors observed lower placental ACE2 protein in term placentas from recent (early third trimester) but not remote (second trimester) maternal SARS-CoV-2 infection, arguably the result of the observed increase in ADAM17 cleavage activity. Prior studies have shown conflicting results, with equal or higher ACE2 levels noted in the setting of maternal COVID-19 infection, which may be related to differences in COVID-19 disease severity, gestational age of infection, and/or fetal sex in these cohorts.^4-6

The concept that increased placental ACE2 shedding represents a protective defense mechanism that might last weeks beyond the acute infectious period is intriguing, but it requires further study. Observed differences in third but not second trimester COVID-19 infections could indicate either 1) an effect of maternal COVID-19 infection that lasts for several weeks but eventually normalizes over time, in the case of a remote infection; or 2) that second trimester maternal COVID-19 infection does not have the same pronounced effect on ACE2 levels as does third trimester infection. Observational studies of the human placenta are not able to answer this question, as directly sampling the placenta at the time of the exposure (or repeated sampling over time) in ongoing pregnancies is neither practical nor ethical. Further studies using animal or cellular models of SARS-CoV-2 infection in pregnancy may be necessary to fully understand the clinical relevance of these findings.

The study by Taglauer and colleagues provides a compelling argument for exploring how immune defenses at the maternal-fetal interface evolve over time and vary by trimester of exposure. ●

Pregnant women with HIV can be reassured that protease inhibitors are safer than previously thought in terms of risk to the fetus, according to research from the National Perinatal Epidemiology Unit (NPEU) at Oxford Population Health, a research institute based at the University of Oxford (England).

Antiretroviral therapy (ART) is recommended for all pregnant women living with HIV and plays a crucial role both in improving maternal health and in reducing transmission of HIV from mother to child. However, there has been a critical lack of evidence about the effects of ART on the risk of adverse pregnancy outcomes, with particular concern about protease inhibitors.

Current guidelines recommend that protease inhibitor-based therapies should be used in pregnancy only if first-line treatments (such as integrase and reverse-transcriptase based treatments) are either unsuitable or unavailable. These guidelines also often advise against the use of a specific protease inhibitor, lopinavir/ritonavir, citing an increased risk of preterm birth. However, such advice may restrict treatment options for pregnant women with HIV on the basis of limited evidence.
 

Largest review to date

The NPEU researchers, therefore, conducted the largest systematic review to date of adverse perinatal outcomes after a range of antiretroviral therapies. It included 34 cohort studies published between 1980 and 2020 and involving over 57,000 pregnant women with HIV in 22 different countries. The review, published in eClinicalMedicine, looked for evidence of 11 perinatal outcomes:

• Preterm birth, very preterm birth, and spontaneous preterm birth
• Low birth weight, very low birth weight, term low birth weight, and preterm low birth weight
• Small for gestational age and very small for gestational age
• Stillbirth, and neonatal death

Using pairwise random-effects meta-analyses, researchers compared protease inhibitor versus non-protease inhibitor-based ART, as well as specifically looking at the comparative risks associated with different protease inhibitor regimens.

They found that protease inhibitor-based ART significantly increased the risk of small or very small for gestational age babies, with relative risks of 1.24 (95% confidence interval, 1.08-1.43; I2 = 66.7%) and 1.40 (95% CI, 1.09-1.81; I2 = 0.0%), respectively. However there were no significant differences in other adverse pregnancy outcomes for protease inhibitors, compared with other therapies.

In addition, researchers found no significant differences in perinatal outcomes between ART regimens containing lopinavir/ritonavir, atazanavir/ritonavir, or darunavir/ritonavir, which are the most frequently used protease inhibitors.
 

No increased risk of preterm birth

Senior author Dr. Joris Hemelaar, senior clinical research fellow at the NPEU and honorary consultant in obstetrics at the John Radcliffe Hospital, Oxford (England), said: “Antiretroviral therapy in pregnancy has clear benefits for maternal health and prevention of HIV transmission to the child, but our study has shown for the first time that protease inhibitors are associated with babies being small or very small for their gestational age.”

“However, there was no increased risk of preterm birth, or any other adverse pregnancy outcomes. This means protease inhibitors remain an important option for pregnant women living with HIV if other treatments are unsuitable, for example due to drug resistance, or unavailable. The evidence presented here indicates that the commonly used protease inhibitors atazanavir, lopinavir, and darunavir are comparable with regard to perinatal outcomes, which should inform international treatment guidelines.”

Over 70% of the studies assessed were conducted in high-income countries, and Dr. Hemelaar added that there is an urgent need for more research on pregnancy outcomes after different ART in low- to middle-income countries, where the burden of HIV is highest.

Professor Yvonne Gilleece, a spokesperson for the British HIV Association (BHIVA) and immediate past chair of the BHIVA guidelines on the management of HIV in pregnancy and the postpartum period commented: “Pregnancy is a unique life situation in which we must consider the safety of both the birthing parent and the baby. Due to ongoing under-representation of all women in clinical trials, but particularly pregnant women, we do not have enough evidence on which to base all our management decisions. This systematic review includes large numbers of pregnant women living with HIV and can, therefore, improve an informed discussion regarding the safety of the use of protease inhibitors during pregnancy.”

Dr. Hemelaar told Medscape UK: “Many international treatment guidelines cite adverse pregnancy outcomes, in particular preterm birth, associated with protease inhibitor (PI)-drugs as a reason for caution for their use in pregnancy. However, PI drugs are not associated with preterm birth in our analysis. This suggests that PI drugs may not be as detrimental as previously thought (and we found no differences between different PI drugs used), and, hence, these drugs may have a more favourable profile for use in pregnancy.

“However, many other aspects of treatment, including the extent to which the virus can be suppressed, adverse drug effects, adherence to drug prescriptions, antiretroviral drug resistance, drug interactions, drug cost, and availability, should also be taken into account by clinicians and guideline development committees.”

A version of this article first appeared on Medscape UK.

Pregnant women with HIV can be reassured that protease inhibitors are safer than previously thought in terms of risk to the fetus, according to research from the National Perinatal Epidemiology Unit (NPEU) at Oxford Population Health, a research institute based at the University of Oxford (England).

Antiretroviral therapy (ART) is recommended for all pregnant women living with HIV and plays a crucial role both in improving maternal health and in reducing transmission of HIV from mother to child. However, there has been a critical lack of evidence about the effects of ART on the risk of adverse pregnancy outcomes, with particular concern about protease inhibitors.

Current guidelines recommend that protease inhibitor-based therapies should be used in pregnancy only if first-line treatments (such as integrase and reverse-transcriptase based treatments) are either unsuitable or unavailable. These guidelines also often advise against the use of a specific protease inhibitor, lopinavir/ritonavir, citing an increased risk of preterm birth. However, such advice may restrict treatment options for pregnant women with HIV on the basis of limited evidence.
 

Largest review to date

The NPEU researchers, therefore, conducted the largest systematic review to date of adverse perinatal outcomes after a range of antiretroviral therapies. It included 34 cohort studies published between 1980 and 2020 and involving over 57,000 pregnant women with HIV in 22 different countries. The review, published in eClinicalMedicine, looked for evidence of 11 perinatal outcomes:

• Preterm birth, very preterm birth, and spontaneous preterm birth
• Low birth weight, very low birth weight, term low birth weight, and preterm low birth weight
• Small for gestational age and very small for gestational age
• Stillbirth, and neonatal death

Using pairwise random-effects meta-analyses, researchers compared protease inhibitor versus non-protease inhibitor-based ART, as well as specifically looking at the comparative risks associated with different protease inhibitor regimens.

They found that protease inhibitor-based ART significantly increased the risk of small or very small for gestational age babies, with relative risks of 1.24 (95% confidence interval, 1.08-1.43; I2 = 66.7%) and 1.40 (95% CI, 1.09-1.81; I2 = 0.0%), respectively. However there were no significant differences in other adverse pregnancy outcomes for protease inhibitors, compared with other therapies.

In addition, researchers found no significant differences in perinatal outcomes between ART regimens containing lopinavir/ritonavir, atazanavir/ritonavir, or darunavir/ritonavir, which are the most frequently used protease inhibitors.
 

No increased risk of preterm birth

Senior author Dr. Joris Hemelaar, senior clinical research fellow at the NPEU and honorary consultant in obstetrics at the John Radcliffe Hospital, Oxford (England), said: “Antiretroviral therapy in pregnancy has clear benefits for maternal health and prevention of HIV transmission to the child, but our study has shown for the first time that protease inhibitors are associated with babies being small or very small for their gestational age.”

“However, there was no increased risk of preterm birth, or any other adverse pregnancy outcomes. This means protease inhibitors remain an important option for pregnant women living with HIV if other treatments are unsuitable, for example due to drug resistance, or unavailable. The evidence presented here indicates that the commonly used protease inhibitors atazanavir, lopinavir, and darunavir are comparable with regard to perinatal outcomes, which should inform international treatment guidelines.”

Over 70% of the studies assessed were conducted in high-income countries, and Dr. Hemelaar added that there is an urgent need for more research on pregnancy outcomes after different ART in low- to middle-income countries, where the burden of HIV is highest.

Professor Yvonne Gilleece, a spokesperson for the British HIV Association (BHIVA) and immediate past chair of the BHIVA guidelines on the management of HIV in pregnancy and the postpartum period commented: “Pregnancy is a unique life situation in which we must consider the safety of both the birthing parent and the baby. Due to ongoing under-representation of all women in clinical trials, but particularly pregnant women, we do not have enough evidence on which to base all our management decisions. This systematic review includes large numbers of pregnant women living with HIV and can, therefore, improve an informed discussion regarding the safety of the use of protease inhibitors during pregnancy.”

Dr. Hemelaar told Medscape UK: “Many international treatment guidelines cite adverse pregnancy outcomes, in particular preterm birth, associated with protease inhibitor (PI)-drugs as a reason for caution for their use in pregnancy. However, PI drugs are not associated with preterm birth in our analysis. This suggests that PI drugs may not be as detrimental as previously thought (and we found no differences between different PI drugs used), and, hence, these drugs may have a more favourable profile for use in pregnancy.

“However, many other aspects of treatment, including the extent to which the virus can be suppressed, adverse drug effects, adherence to drug prescriptions, antiretroviral drug resistance, drug interactions, drug cost, and availability, should also be taken into account by clinicians and guideline development committees.”

A version of this article first appeared on Medscape UK.

Pregnant women with HIV can be reassured that protease inhibitors are safer than previously thought in terms of risk to the fetus, according to research from the National Perinatal Epidemiology Unit (NPEU) at Oxford Population Health, a research institute based at the University of Oxford (England).

Antiretroviral therapy (ART) is recommended for all pregnant women living with HIV and plays a crucial role both in improving maternal health and in reducing transmission of HIV from mother to child. However, there has been a critical lack of evidence about the effects of ART on the risk of adverse pregnancy outcomes, with particular concern about protease inhibitors.

Current guidelines recommend that protease inhibitor-based therapies should be used in pregnancy only if first-line treatments (such as integrase and reverse-transcriptase based treatments) are either unsuitable or unavailable. These guidelines also often advise against the use of a specific protease inhibitor, lopinavir/ritonavir, citing an increased risk of preterm birth. However, such advice may restrict treatment options for pregnant women with HIV on the basis of limited evidence.
 

Largest review to date

The NPEU researchers, therefore, conducted the largest systematic review to date of adverse perinatal outcomes after a range of antiretroviral therapies. It included 34 cohort studies published between 1980 and 2020 and involving over 57,000 pregnant women with HIV in 22 different countries. The review, published in eClinicalMedicine, looked for evidence of 11 perinatal outcomes:

• Preterm birth, very preterm birth, and spontaneous preterm birth
• Low birth weight, very low birth weight, term low birth weight, and preterm low birth weight
• Small for gestational age and very small for gestational age
• Stillbirth, and neonatal death

Using pairwise random-effects meta-analyses, researchers compared protease inhibitor versus non-protease inhibitor-based ART, as well as specifically looking at the comparative risks associated with different protease inhibitor regimens.

They found that protease inhibitor-based ART significantly increased the risk of small or very small for gestational age babies, with relative risks of 1.24 (95% confidence interval, 1.08-1.43; I2 = 66.7%) and 1.40 (95% CI, 1.09-1.81; I2 = 0.0%), respectively. However there were no significant differences in other adverse pregnancy outcomes for protease inhibitors, compared with other therapies.

In addition, researchers found no significant differences in perinatal outcomes between ART regimens containing lopinavir/ritonavir, atazanavir/ritonavir, or darunavir/ritonavir, which are the most frequently used protease inhibitors.
 

No increased risk of preterm birth

Senior author Dr. Joris Hemelaar, senior clinical research fellow at the NPEU and honorary consultant in obstetrics at the John Radcliffe Hospital, Oxford (England), said: “Antiretroviral therapy in pregnancy has clear benefits for maternal health and prevention of HIV transmission to the child, but our study has shown for the first time that protease inhibitors are associated with babies being small or very small for their gestational age.”

“However, there was no increased risk of preterm birth, or any other adverse pregnancy outcomes. This means protease inhibitors remain an important option for pregnant women living with HIV if other treatments are unsuitable, for example due to drug resistance, or unavailable. The evidence presented here indicates that the commonly used protease inhibitors atazanavir, lopinavir, and darunavir are comparable with regard to perinatal outcomes, which should inform international treatment guidelines.”

Over 70% of the studies assessed were conducted in high-income countries, and Dr. Hemelaar added that there is an urgent need for more research on pregnancy outcomes after different ART in low- to middle-income countries, where the burden of HIV is highest.

Professor Yvonne Gilleece, a spokesperson for the British HIV Association (BHIVA) and immediate past chair of the BHIVA guidelines on the management of HIV in pregnancy and the postpartum period commented: “Pregnancy is a unique life situation in which we must consider the safety of both the birthing parent and the baby. Due to ongoing under-representation of all women in clinical trials, but particularly pregnant women, we do not have enough evidence on which to base all our management decisions. This systematic review includes large numbers of pregnant women living with HIV and can, therefore, improve an informed discussion regarding the safety of the use of protease inhibitors during pregnancy.”

Dr. Hemelaar told Medscape UK: “Many international treatment guidelines cite adverse pregnancy outcomes, in particular preterm birth, associated with protease inhibitor (PI)-drugs as a reason for caution for their use in pregnancy. However, PI drugs are not associated with preterm birth in our analysis. This suggests that PI drugs may not be as detrimental as previously thought (and we found no differences between different PI drugs used), and, hence, these drugs may have a more favourable profile for use in pregnancy.

“However, many other aspects of treatment, including the extent to which the virus can be suppressed, adverse drug effects, adherence to drug prescriptions, antiretroviral drug resistance, drug interactions, drug cost, and availability, should also be taken into account by clinicians and guideline development committees.”

A version of this article first appeared on Medscape UK.

Despite the availability of effective direct-acting antivirals, very few a mothers with opioid use disorder (OUD) and hepatitis C virus (HCV) during pregnancy received follow-up care or treatment for the infection within 6 months of giving birth, a retrospective study of Medicaid maternity patients found.

The study pooled data on 23,780 Medicaid-enrolled pregnant women with OUD who had a live or stillbirth during 2016-2019 and were followed for 6 months after delivery. Among these women – drawn from six states in the Medicaid Outcomes Distributed Research Network – the pooled average probability of HCV testing during pregnancy was 70.3% (95% confidence interval, 61.5%-79.1%). Of these, 30.9% (95% CI, 23.8%-38%) tested positive. At 60 days postpartum, just 3.2% (95% CI, 2.6%-3.8%) had a follow-up visit or treatment for HCV. In a subset of patients followed for 6 months, only 5.9% (95% CI, 4.9%-6.9%) had any HCV follow-up visit or medication within 6 months of delivery.

While HCV screening and diagnosis rates varied across states, postpartum follow-up rates were universally low. The results suggest a need to improve the cascade of postpartum care for HCV and, ultimately perhaps, introduce antenatal HCV treatment, as is currently given safely for HIV, if current clinical research establishes safety, according to Marian P. Jarlenski, PhD, MPH, an associate professor of public health policy and management at the University of Pittsburgh. The study was published in Obstetrics & Gynecology.

HCV infection has risen substantially in people of reproductive age in tandem with an increase in OUDs. HCV is transmitted from an infected mother to her baby in about 6% of cases, according to the Centers for Disease Control and Prevention, which in 2020 expanded its HCV screening recommendations to include all pregnant women. Currently no treatment for HCV during pregnancy has been approved.

In light of those recent recommendations, Dr. Jarlenski said in an interview that her group was “interested in looking at high-risk screened people and estimating what proportion received follow-up care and treatment for HCV. What is the promise of screening? The promise is that you can treat. Otherwise why screen?”

She acknowledged, however, that the postpartum period is a challenging time for a mother to seek health information or care for herself, whether she’s a new parent or has other children in the home. Nevertheless, the low rate of follow-up and treatment was unexpected. “Even the 70% rate of screening was low – we felt it should have been closer to 100% – but the follow-up rate was surprisingly low,” Dr. Jarlenski said.

Mishka Terplan, MD, MPH, medical director of Friends Research Institute in Baltimore, was not surprised at the low follow-up rate. “The cascade of care for hep C is demoralizing,” said Dr. Terplan, who was not involved in the study. “We know that hep C is syndemic with OUD and other opioid crises and we know that screening is effective for identifying hep C and that antiviral medications are now more effective and less toxic than ever before. But despite this, we’re failing pregnant women and their kids at every step along the cascade. We do a better job with initial testing than with the follow-up testing. We do a horrible job with postpartum medication initiation.”

He pointed to the systemic challenges mothers face in getting postpartum HCV care. “They may be transferred to a subspecialist for treatment, and this transfer is compounded by issues of insurance coverage and eligibility.” With the onus on new mothers to submit the paperwork, “the idea that mothers would be able to initiate much less continue postpartum treatment is absurd,” Dr. Terplan said.

He added that the children born to HCV-positive mothers need surveillance as well, but data suggest that the rates of newborn testing are also low. “There’s a preventable public health burden in all of this.”

The obvious way to increase eradicative therapy would be to treat women while they are getting antenatal care. A small phase 1 trial found that all pregnant participants who were HCV positive and given antivirals in their second trimester were safely treated and gave birth to healthy babies.

“If larger trials prove this treatment is safe and effective, then these results should be communicated to care providers and pregnant patients,” Dr. Jarlenski said. Otherwise, the public health potential of universal screening in pregnancy will not be realized.

This research was supported by the National Institute of Drug Abuse and by the Delaware Division of Medicaid and Medical Assistance and the University of Delaware, Center for Community Research & Service. Dr. Jarlenski disclosed no competing interests. One coauthor disclosed grant funding through her institution from Gilead Sciences and Organon unrelated to this work. Dr. Terplan reported no relevant competing interests.

Despite the availability of effective direct-acting antivirals, very few a mothers with opioid use disorder (OUD) and hepatitis C virus (HCV) during pregnancy received follow-up care or treatment for the infection within 6 months of giving birth, a retrospective study of Medicaid maternity patients found.

The study pooled data on 23,780 Medicaid-enrolled pregnant women with OUD who had a live or stillbirth during 2016-2019 and were followed for 6 months after delivery. Among these women – drawn from six states in the Medicaid Outcomes Distributed Research Network – the pooled average probability of HCV testing during pregnancy was 70.3% (95% confidence interval, 61.5%-79.1%). Of these, 30.9% (95% CI, 23.8%-38%) tested positive. At 60 days postpartum, just 3.2% (95% CI, 2.6%-3.8%) had a follow-up visit or treatment for HCV. In a subset of patients followed for 6 months, only 5.9% (95% CI, 4.9%-6.9%) had any HCV follow-up visit or medication within 6 months of delivery.

While HCV screening and diagnosis rates varied across states, postpartum follow-up rates were universally low. The results suggest a need to improve the cascade of postpartum care for HCV and, ultimately perhaps, introduce antenatal HCV treatment, as is currently given safely for HIV, if current clinical research establishes safety, according to Marian P. Jarlenski, PhD, MPH, an associate professor of public health policy and management at the University of Pittsburgh. The study was published in Obstetrics & Gynecology.

HCV infection has risen substantially in people of reproductive age in tandem with an increase in OUDs. HCV is transmitted from an infected mother to her baby in about 6% of cases, according to the Centers for Disease Control and Prevention, which in 2020 expanded its HCV screening recommendations to include all pregnant women. Currently no treatment for HCV during pregnancy has been approved.

In light of those recent recommendations, Dr. Jarlenski said in an interview that her group was “interested in looking at high-risk screened people and estimating what proportion received follow-up care and treatment for HCV. What is the promise of screening? The promise is that you can treat. Otherwise why screen?”

She acknowledged, however, that the postpartum period is a challenging time for a mother to seek health information or care for herself, whether she’s a new parent or has other children in the home. Nevertheless, the low rate of follow-up and treatment was unexpected. “Even the 70% rate of screening was low – we felt it should have been closer to 100% – but the follow-up rate was surprisingly low,” Dr. Jarlenski said.

Mishka Terplan, MD, MPH, medical director of Friends Research Institute in Baltimore, was not surprised at the low follow-up rate. “The cascade of care for hep C is demoralizing,” said Dr. Terplan, who was not involved in the study. “We know that hep C is syndemic with OUD and other opioid crises and we know that screening is effective for identifying hep C and that antiviral medications are now more effective and less toxic than ever before. But despite this, we’re failing pregnant women and their kids at every step along the cascade. We do a better job with initial testing than with the follow-up testing. We do a horrible job with postpartum medication initiation.”

He pointed to the systemic challenges mothers face in getting postpartum HCV care. “They may be transferred to a subspecialist for treatment, and this transfer is compounded by issues of insurance coverage and eligibility.” With the onus on new mothers to submit the paperwork, “the idea that mothers would be able to initiate much less continue postpartum treatment is absurd,” Dr. Terplan said.

He added that the children born to HCV-positive mothers need surveillance as well, but data suggest that the rates of newborn testing are also low. “There’s a preventable public health burden in all of this.”

The obvious way to increase eradicative therapy would be to treat women while they are getting antenatal care. A small phase 1 trial found that all pregnant participants who were HCV positive and given antivirals in their second trimester were safely treated and gave birth to healthy babies.

“If larger trials prove this treatment is safe and effective, then these results should be communicated to care providers and pregnant patients,” Dr. Jarlenski said. Otherwise, the public health potential of universal screening in pregnancy will not be realized.

This research was supported by the National Institute of Drug Abuse and by the Delaware Division of Medicaid and Medical Assistance and the University of Delaware, Center for Community Research & Service. Dr. Jarlenski disclosed no competing interests. One coauthor disclosed grant funding through her institution from Gilead Sciences and Organon unrelated to this work. Dr. Terplan reported no relevant competing interests.

Despite the availability of effective direct-acting antivirals, very few a mothers with opioid use disorder (OUD) and hepatitis C virus (HCV) during pregnancy received follow-up care or treatment for the infection within 6 months of giving birth, a retrospective study of Medicaid maternity patients found.

The study pooled data on 23,780 Medicaid-enrolled pregnant women with OUD who had a live or stillbirth during 2016-2019 and were followed for 6 months after delivery. Among these women – drawn from six states in the Medicaid Outcomes Distributed Research Network – the pooled average probability of HCV testing during pregnancy was 70.3% (95% confidence interval, 61.5%-79.1%). Of these, 30.9% (95% CI, 23.8%-38%) tested positive. At 60 days postpartum, just 3.2% (95% CI, 2.6%-3.8%) had a follow-up visit or treatment for HCV. In a subset of patients followed for 6 months, only 5.9% (95% CI, 4.9%-6.9%) had any HCV follow-up visit or medication within 6 months of delivery.

While HCV screening and diagnosis rates varied across states, postpartum follow-up rates were universally low. The results suggest a need to improve the cascade of postpartum care for HCV and, ultimately perhaps, introduce antenatal HCV treatment, as is currently given safely for HIV, if current clinical research establishes safety, according to Marian P. Jarlenski, PhD, MPH, an associate professor of public health policy and management at the University of Pittsburgh. The study was published in Obstetrics & Gynecology.

HCV infection has risen substantially in people of reproductive age in tandem with an increase in OUDs. HCV is transmitted from an infected mother to her baby in about 6% of cases, according to the Centers for Disease Control and Prevention, which in 2020 expanded its HCV screening recommendations to include all pregnant women. Currently no treatment for HCV during pregnancy has been approved.

In light of those recent recommendations, Dr. Jarlenski said in an interview that her group was “interested in looking at high-risk screened people and estimating what proportion received follow-up care and treatment for HCV. What is the promise of screening? The promise is that you can treat. Otherwise why screen?”

She acknowledged, however, that the postpartum period is a challenging time for a mother to seek health information or care for herself, whether she’s a new parent or has other children in the home. Nevertheless, the low rate of follow-up and treatment was unexpected. “Even the 70% rate of screening was low – we felt it should have been closer to 100% – but the follow-up rate was surprisingly low,” Dr. Jarlenski said.

Mishka Terplan, MD, MPH, medical director of Friends Research Institute in Baltimore, was not surprised at the low follow-up rate. “The cascade of care for hep C is demoralizing,” said Dr. Terplan, who was not involved in the study. “We know that hep C is syndemic with OUD and other opioid crises and we know that screening is effective for identifying hep C and that antiviral medications are now more effective and less toxic than ever before. But despite this, we’re failing pregnant women and their kids at every step along the cascade. We do a better job with initial testing than with the follow-up testing. We do a horrible job with postpartum medication initiation.”

He pointed to the systemic challenges mothers face in getting postpartum HCV care. “They may be transferred to a subspecialist for treatment, and this transfer is compounded by issues of insurance coverage and eligibility.” With the onus on new mothers to submit the paperwork, “the idea that mothers would be able to initiate much less continue postpartum treatment is absurd,” Dr. Terplan said.

He added that the children born to HCV-positive mothers need surveillance as well, but data suggest that the rates of newborn testing are also low. “There’s a preventable public health burden in all of this.”

The obvious way to increase eradicative therapy would be to treat women while they are getting antenatal care. A small phase 1 trial found that all pregnant participants who were HCV positive and given antivirals in their second trimester were safely treated and gave birth to healthy babies.

“If larger trials prove this treatment is safe and effective, then these results should be communicated to care providers and pregnant patients,” Dr. Jarlenski said. Otherwise, the public health potential of universal screening in pregnancy will not be realized.

This research was supported by the National Institute of Drug Abuse and by the Delaware Division of Medicaid and Medical Assistance and the University of Delaware, Center for Community Research & Service. Dr. Jarlenski disclosed no competing interests. One coauthor disclosed grant funding through her institution from Gilead Sciences and Organon unrelated to this work. Dr. Terplan reported no relevant competing interests.

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

The first comprehensive guidelines to manage pregnant women with anorexia nervosa (AN) have been released.

Pregnant women with AN are at greater risk of poor outcomes, including stillbirth, underweight infant, or pre-term birth, yet there are no clear guidelines on the management of the condition.

“Anorexia in pregnancy has been an overlooked area of clinical care, as many believed only women in remission become pregnant, and it is clear that is not the case,” lead author Megan Galbally, MBBS, PhD, professor and director, Centre of Women’s and Children’s Mental Health at Monash University School of Clinical Sciences, Melbourne, told this news organization.

“There are great opportunities to support women in their mental health and give them and their babies a healthier start to parenthood and life,” said Dr. Galbally.

“For instance, reducing the likelihood of prematurity or low birth weight at birth that can be associated with anorexia in pregnancy has extraordinary benefits for that child for lifelong health and well-being,” she added.

The guidelines were published online in Lancet Psychiatry.
 

Spike in cases

Dr. Galbally noted that during her 20 years of working in perinatal mental health within tertiary maternity services, she only ever saw an occasional pregnant woman with current AN.

In contrast, over the last 3 to 4 years, there has been a “steep increase in women presenting in pregnancy with very low body mass index (BMI) and current anorexia nervosa requiring treatment in pregnancy,” Dr. Galbally said.

Despite the complexity of managing AN in pregnancy, few studies are available to guide care. In a systematic literature review, the researchers identified only eight studies that addressed the management of AN in pregnancy. These studies were case studies or case reports examining narrow aspects of management.

Digging deeper, the researchers conducted a state-of-the-art research review in relevant disciplines and areas of expertise for managing anorexia nervosa in pregnancy. They synthesized their findings into “recommendations and principles” for multidisciplinary care of pregnant women with AN.

The researchers note that AN in pregnancy is associated with increased risks of pregnancy complications and poorer outcomes for infants, and measures such as BMI are less accurate in pregnancy for assessing severity or change in anorexia nervosa.

Anorexia affects pregnancy and neonatal outcomes through low calorie intake, nutritional and vitamin deficiencies, stress, fasting, low body mass, and poor placentation and uteroplacental function.

The authors note that managing AN in pregnancy requires multidisciplinary care that considers the substantial physiological changes for women and requirements for monitoring fetal growth and development.

At a minimum, they recommend monitoring the following:

• Sodium, potassium, magnesium, phosphate, and chloride concentration
• Iron status, vitamin D and bone mineral density, blood sugar concentration (fasting or random), and A1c
• Liver function (including bilirubin, aspartate transaminase, alanine aminotransferase, and gamma-glutamyl transferase) and bone marrow function (including full blood examination, white cell count, neutrophil count, platelets, and hemoglobin)
• Inflammatory markers (C-reactive protein and erythrocyte sedimentation rate)
• Cardiac function (electrocardiogram and echocardiogram)
• Blood pressure and heart rate (lying and standing) and body temperature

“There are considerable risks for women and their unborn child in managing moderate to severe AN in pregnancy,” said Dr. Galbally.

“While we have provided some recommendations, it still requires considerable adaptation to individual presentations and circumstances, and this is best done with a maternity service that manages other high-risk pregnancies such as through maternal-fetal medicine teams,” she said.

“While this area of clinical care can be new to high-risk pregnancy teams, it is clearly important that high-risk pregnancy services and mental health work together to improve care for women with anorexia in pregnancy,” Dr. Galbally added.
 

A nightmare, a dream come true

Reached for comment, Kamryn T. Eddy, PhD, co-director, Eating Disorders Clinical and Research Program, Massachusetts General Hospital, said, “for many with anorexia nervosa, pregnancy realizes their greatest nightmare and dream come true, both at once.”

“The physical demands of pregnancy can be taxing, and for those with anorexia nervosa, closer clinical management makes sense and may help to support patients who are at risk for return to or worsening of symptoms with the increased nutritional needs and weight gain that occur in pregnancy,” Dr. Eddy, associate professor, department of psychiatry, Harvard Medical School, Boston, told this news organization.

“At the same time, the desire to have a child can be a strong motivator for patients to make the changes needed to recover, and for some, the transition to mother can also help in recovery by broadening the range of things that influence their self-worth,” Dr. Eddy added.

This research had no specific funding. Dr. Galbally and Dr. Eddy report no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

The first comprehensive guidelines to manage pregnant women with anorexia nervosa (AN) have been released.

Pregnant women with AN are at greater risk of poor outcomes, including stillbirth, underweight infant, or pre-term birth, yet there are no clear guidelines on the management of the condition.

“Anorexia in pregnancy has been an overlooked area of clinical care, as many believed only women in remission become pregnant, and it is clear that is not the case,” lead author Megan Galbally, MBBS, PhD, professor and director, Centre of Women’s and Children’s Mental Health at Monash University School of Clinical Sciences, Melbourne, told this news organization.

“There are great opportunities to support women in their mental health and give them and their babies a healthier start to parenthood and life,” said Dr. Galbally.

“For instance, reducing the likelihood of prematurity or low birth weight at birth that can be associated with anorexia in pregnancy has extraordinary benefits for that child for lifelong health and well-being,” she added.

The guidelines were published online in Lancet Psychiatry.
 

Spike in cases

Dr. Galbally noted that during her 20 years of working in perinatal mental health within tertiary maternity services, she only ever saw an occasional pregnant woman with current AN.

In contrast, over the last 3 to 4 years, there has been a “steep increase in women presenting in pregnancy with very low body mass index (BMI) and current anorexia nervosa requiring treatment in pregnancy,” Dr. Galbally said.

Despite the complexity of managing AN in pregnancy, few studies are available to guide care. In a systematic literature review, the researchers identified only eight studies that addressed the management of AN in pregnancy. These studies were case studies or case reports examining narrow aspects of management.

Digging deeper, the researchers conducted a state-of-the-art research review in relevant disciplines and areas of expertise for managing anorexia nervosa in pregnancy. They synthesized their findings into “recommendations and principles” for multidisciplinary care of pregnant women with AN.

The researchers note that AN in pregnancy is associated with increased risks of pregnancy complications and poorer outcomes for infants, and measures such as BMI are less accurate in pregnancy for assessing severity or change in anorexia nervosa.

Anorexia affects pregnancy and neonatal outcomes through low calorie intake, nutritional and vitamin deficiencies, stress, fasting, low body mass, and poor placentation and uteroplacental function.

The authors note that managing AN in pregnancy requires multidisciplinary care that considers the substantial physiological changes for women and requirements for monitoring fetal growth and development.

At a minimum, they recommend monitoring the following:

• Sodium, potassium, magnesium, phosphate, and chloride concentration
• Iron status, vitamin D and bone mineral density, blood sugar concentration (fasting or random), and A1c
• Liver function (including bilirubin, aspartate transaminase, alanine aminotransferase, and gamma-glutamyl transferase) and bone marrow function (including full blood examination, white cell count, neutrophil count, platelets, and hemoglobin)
• Inflammatory markers (C-reactive protein and erythrocyte sedimentation rate)
• Cardiac function (electrocardiogram and echocardiogram)
• Blood pressure and heart rate (lying and standing) and body temperature

“There are considerable risks for women and their unborn child in managing moderate to severe AN in pregnancy,” said Dr. Galbally.

“While we have provided some recommendations, it still requires considerable adaptation to individual presentations and circumstances, and this is best done with a maternity service that manages other high-risk pregnancies such as through maternal-fetal medicine teams,” she said.

“While this area of clinical care can be new to high-risk pregnancy teams, it is clearly important that high-risk pregnancy services and mental health work together to improve care for women with anorexia in pregnancy,” Dr. Galbally added.
 

A nightmare, a dream come true

Reached for comment, Kamryn T. Eddy, PhD, co-director, Eating Disorders Clinical and Research Program, Massachusetts General Hospital, said, “for many with anorexia nervosa, pregnancy realizes their greatest nightmare and dream come true, both at once.”

“The physical demands of pregnancy can be taxing, and for those with anorexia nervosa, closer clinical management makes sense and may help to support patients who are at risk for return to or worsening of symptoms with the increased nutritional needs and weight gain that occur in pregnancy,” Dr. Eddy, associate professor, department of psychiatry, Harvard Medical School, Boston, told this news organization.

“At the same time, the desire to have a child can be a strong motivator for patients to make the changes needed to recover, and for some, the transition to mother can also help in recovery by broadening the range of things that influence their self-worth,” Dr. Eddy added.

This research had no specific funding. Dr. Galbally and Dr. Eddy report no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

The first comprehensive guidelines to manage pregnant women with anorexia nervosa (AN) have been released.

Pregnant women with AN are at greater risk of poor outcomes, including stillbirth, underweight infant, or pre-term birth, yet there are no clear guidelines on the management of the condition.

“Anorexia in pregnancy has been an overlooked area of clinical care, as many believed only women in remission become pregnant, and it is clear that is not the case,” lead author Megan Galbally, MBBS, PhD, professor and director, Centre of Women’s and Children’s Mental Health at Monash University School of Clinical Sciences, Melbourne, told this news organization.

“There are great opportunities to support women in their mental health and give them and their babies a healthier start to parenthood and life,” said Dr. Galbally.

“For instance, reducing the likelihood of prematurity or low birth weight at birth that can be associated with anorexia in pregnancy has extraordinary benefits for that child for lifelong health and well-being,” she added.

The guidelines were published online in Lancet Psychiatry.
 

Spike in cases

Dr. Galbally noted that during her 20 years of working in perinatal mental health within tertiary maternity services, she only ever saw an occasional pregnant woman with current AN.

In contrast, over the last 3 to 4 years, there has been a “steep increase in women presenting in pregnancy with very low body mass index (BMI) and current anorexia nervosa requiring treatment in pregnancy,” Dr. Galbally said.

Despite the complexity of managing AN in pregnancy, few studies are available to guide care. In a systematic literature review, the researchers identified only eight studies that addressed the management of AN in pregnancy. These studies were case studies or case reports examining narrow aspects of management.

Digging deeper, the researchers conducted a state-of-the-art research review in relevant disciplines and areas of expertise for managing anorexia nervosa in pregnancy. They synthesized their findings into “recommendations and principles” for multidisciplinary care of pregnant women with AN.

The researchers note that AN in pregnancy is associated with increased risks of pregnancy complications and poorer outcomes for infants, and measures such as BMI are less accurate in pregnancy for assessing severity or change in anorexia nervosa.

Anorexia affects pregnancy and neonatal outcomes through low calorie intake, nutritional and vitamin deficiencies, stress, fasting, low body mass, and poor placentation and uteroplacental function.

The authors note that managing AN in pregnancy requires multidisciplinary care that considers the substantial physiological changes for women and requirements for monitoring fetal growth and development.

At a minimum, they recommend monitoring the following:

• Sodium, potassium, magnesium, phosphate, and chloride concentration
• Iron status, vitamin D and bone mineral density, blood sugar concentration (fasting or random), and A1c
• Liver function (including bilirubin, aspartate transaminase, alanine aminotransferase, and gamma-glutamyl transferase) and bone marrow function (including full blood examination, white cell count, neutrophil count, platelets, and hemoglobin)
• Inflammatory markers (C-reactive protein and erythrocyte sedimentation rate)
• Cardiac function (electrocardiogram and echocardiogram)
• Blood pressure and heart rate (lying and standing) and body temperature

“There are considerable risks for women and their unborn child in managing moderate to severe AN in pregnancy,” said Dr. Galbally.

“While we have provided some recommendations, it still requires considerable adaptation to individual presentations and circumstances, and this is best done with a maternity service that manages other high-risk pregnancies such as through maternal-fetal medicine teams,” she said.

“While this area of clinical care can be new to high-risk pregnancy teams, it is clearly important that high-risk pregnancy services and mental health work together to improve care for women with anorexia in pregnancy,” Dr. Galbally added.
 

A nightmare, a dream come true

Reached for comment, Kamryn T. Eddy, PhD, co-director, Eating Disorders Clinical and Research Program, Massachusetts General Hospital, said, “for many with anorexia nervosa, pregnancy realizes their greatest nightmare and dream come true, both at once.”

“The physical demands of pregnancy can be taxing, and for those with anorexia nervosa, closer clinical management makes sense and may help to support patients who are at risk for return to or worsening of symptoms with the increased nutritional needs and weight gain that occur in pregnancy,” Dr. Eddy, associate professor, department of psychiatry, Harvard Medical School, Boston, told this news organization.

“At the same time, the desire to have a child can be a strong motivator for patients to make the changes needed to recover, and for some, the transition to mother can also help in recovery by broadening the range of things that influence their self-worth,” Dr. Eddy added.

This research had no specific funding. Dr. Galbally and Dr. Eddy report no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

SEATTLE – Use of antiseizure medications while breastfeeding is not associated with differences in child cognitive outcomes at age 3, according to new results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

The study follows results from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, which found no evidence of cognitive harm in children who were exposed in utero to antiepileptic drugs. “[In the NEAD study] we followed our cohort to age 6 and found them to have actually an improvement in cognition by about 4 IQ points by the time they got to age 6,” Kimford J. Meador, MD, said during a presentation of the results of the MONEAD study at the 2022 annual meeting of the American Academy of Neurology.

Breastfeeding has health benefits for both mothers and children, including reduced risk of respiratory tract infections, atopic dermatitis, asthma, and diabetes in children, and reduced risk of diabetes, breast cancer, ovarian cancer, and postpartum depression in mothers. Despite those benefits, concerns about harms from exposure to antiepileptic drugs may prompt some women to avoid breastfeeding.

The results of NEAD and MONEAD should reassure patients, according to Dr. Meador, professor of neurology at Stanford (Calif.) University. “Given the known multiple benefits of breastfeeding … women with epilepsy should be encouraged to breastfeed,” he said.
 

A responsibility to ‘engage and educate’ patients

Jennifer Hopp, MD, who served as a discussant for the presentation, underscored the need for neurologists to address pregnancy with female patients of childbearing agents. “The issues may include fertility, peripartum management, and outcomes that really go through the lifespan to also include issues of menopause,” Dr. Hopp, associate professor of neurology at the University of Maryland, Baltimore, said during her presentation.

Dr. Hopp noted one study showing lower rates of breastfeeding among mothers with epilepsy. “Breastfeeding rates in women with epilepsy are strikingly lower than in women who do not have epilepsy,” said Dr. Hopp. Another study showed that women with epilepsy were less likely to sustain breastfeeding after 6 weeks.

Dr. Hopp implored neurologists to address this. “It’s our responsibility to engage and educate our patients. These data provide us messaging to our patients that the newer drugs do not adversely affect outcome independently of their other exposure, and really support well-informed choices in breastfeeding,” said Dr. Hopp.
 

Outdated attitudes still persist

Dr. Meador referred to the stigma that surrounds epilepsy, including some state laws that called for sterilization of women with epilepsy that lasted until the 1960s. One might think that such attitudes are gone, “but it’s still there,” said Dr. Meador, who recounted a story a colleague told him about a woman on antiseizure medication. In the hospital, the nurse told her not to breastfeed. The neurological consult told her not to breastfeed. She breastfed anyway. “Then they reported her for child neglect, and that was just a few years ago. So I think the message needs to be loud and clear that we encourage [women with epilepsy] to breastfeed because we have the known benefits, and now several studies showing clearly no adverse effects of breastfeeding while taking antiseizure medications,” said Dr. Meador.

MONEAD findings

The MONEAD study included women from 20 different sites, with 145 participating investigators. The researchers compared outcomes in 284 women with epilepsy and 87 healthy women. The maternal mean IQ was 98 among women with epilepsy (95% confidence interval [CI], 96-99), and 105 (95% CI, 102-107) among healthy women. Seventy-six percent of women with epilepsy breastfed, versus 89% of controls.

Among the study cohort, 79% of women with epilepsy were on monotherapy, and 21% were on polytherapy. Thirty-five percent received lamotrigine, 28% levetiracetam, 16% were on another monotherapy, 10% received a combination of lamotrigine and levetiracetam, and 11% received a different combination.

At age 3, there was no association between the verbal index score of the child and whether the mother had epilepsy or not (difference, 0.4; P = .770). The researchers did find associations with the mother’s IQ (0.3; P < .001), male versus female child sex (–4.9; P < .001), Hispanic or Latino ethnicity (vs. Non-Hispanic, –5.5; P < .001), mother without college degree (–7.0; P < .001), average Beck Anxiety Inventory score after birth (–0.4; P < .001), and weeks of gestational age at enrollment.

The researchers found no association between third trimester antiseizure medication blood levels and verbal index score after adjustment (–2.9; P = .149), with the exception of levetiracetam (–9.0; P = .033). “This is interesting (but) not to be overblown, because overall the children on levetiracetam did well. But it must be remembered that teratogens act in an exposure dependent manner, so we’re constantly in this balancing act of trying to make sure you get enough medication on board to stop the seizures and protect the mother and the child, and at the same time, not too much on board where we increase the risk of teratogenicity in the child,” said Dr. Meador.

The study was funded by the National Institutes of Health. Dr. Meador and Dr. Hopp have no relevant financial disclosures.

SEATTLE – Use of antiseizure medications while breastfeeding is not associated with differences in child cognitive outcomes at age 3, according to new results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

The study follows results from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, which found no evidence of cognitive harm in children who were exposed in utero to antiepileptic drugs. “[In the NEAD study] we followed our cohort to age 6 and found them to have actually an improvement in cognition by about 4 IQ points by the time they got to age 6,” Kimford J. Meador, MD, said during a presentation of the results of the MONEAD study at the 2022 annual meeting of the American Academy of Neurology.

Breastfeeding has health benefits for both mothers and children, including reduced risk of respiratory tract infections, atopic dermatitis, asthma, and diabetes in children, and reduced risk of diabetes, breast cancer, ovarian cancer, and postpartum depression in mothers. Despite those benefits, concerns about harms from exposure to antiepileptic drugs may prompt some women to avoid breastfeeding.

The results of NEAD and MONEAD should reassure patients, according to Dr. Meador, professor of neurology at Stanford (Calif.) University. “Given the known multiple benefits of breastfeeding … women with epilepsy should be encouraged to breastfeed,” he said.
 

A responsibility to ‘engage and educate’ patients

Jennifer Hopp, MD, who served as a discussant for the presentation, underscored the need for neurologists to address pregnancy with female patients of childbearing agents. “The issues may include fertility, peripartum management, and outcomes that really go through the lifespan to also include issues of menopause,” Dr. Hopp, associate professor of neurology at the University of Maryland, Baltimore, said during her presentation.

Dr. Hopp noted one study showing lower rates of breastfeeding among mothers with epilepsy. “Breastfeeding rates in women with epilepsy are strikingly lower than in women who do not have epilepsy,” said Dr. Hopp. Another study showed that women with epilepsy were less likely to sustain breastfeeding after 6 weeks.

Dr. Hopp implored neurologists to address this. “It’s our responsibility to engage and educate our patients. These data provide us messaging to our patients that the newer drugs do not adversely affect outcome independently of their other exposure, and really support well-informed choices in breastfeeding,” said Dr. Hopp.
 

Outdated attitudes still persist

Dr. Meador referred to the stigma that surrounds epilepsy, including some state laws that called for sterilization of women with epilepsy that lasted until the 1960s. One might think that such attitudes are gone, “but it’s still there,” said Dr. Meador, who recounted a story a colleague told him about a woman on antiseizure medication. In the hospital, the nurse told her not to breastfeed. The neurological consult told her not to breastfeed. She breastfed anyway. “Then they reported her for child neglect, and that was just a few years ago. So I think the message needs to be loud and clear that we encourage [women with epilepsy] to breastfeed because we have the known benefits, and now several studies showing clearly no adverse effects of breastfeeding while taking antiseizure medications,” said Dr. Meador.

MONEAD findings

The MONEAD study included women from 20 different sites, with 145 participating investigators. The researchers compared outcomes in 284 women with epilepsy and 87 healthy women. The maternal mean IQ was 98 among women with epilepsy (95% confidence interval [CI], 96-99), and 105 (95% CI, 102-107) among healthy women. Seventy-six percent of women with epilepsy breastfed, versus 89% of controls.

Among the study cohort, 79% of women with epilepsy were on monotherapy, and 21% were on polytherapy. Thirty-five percent received lamotrigine, 28% levetiracetam, 16% were on another monotherapy, 10% received a combination of lamotrigine and levetiracetam, and 11% received a different combination.

At age 3, there was no association between the verbal index score of the child and whether the mother had epilepsy or not (difference, 0.4; P = .770). The researchers did find associations with the mother’s IQ (0.3; P < .001), male versus female child sex (–4.9; P < .001), Hispanic or Latino ethnicity (vs. Non-Hispanic, –5.5; P < .001), mother without college degree (–7.0; P < .001), average Beck Anxiety Inventory score after birth (–0.4; P < .001), and weeks of gestational age at enrollment.

The researchers found no association between third trimester antiseizure medication blood levels and verbal index score after adjustment (–2.9; P = .149), with the exception of levetiracetam (–9.0; P = .033). “This is interesting (but) not to be overblown, because overall the children on levetiracetam did well. But it must be remembered that teratogens act in an exposure dependent manner, so we’re constantly in this balancing act of trying to make sure you get enough medication on board to stop the seizures and protect the mother and the child, and at the same time, not too much on board where we increase the risk of teratogenicity in the child,” said Dr. Meador.

The study was funded by the National Institutes of Health. Dr. Meador and Dr. Hopp have no relevant financial disclosures.

SEATTLE – Use of antiseizure medications while breastfeeding is not associated with differences in child cognitive outcomes at age 3, according to new results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

The study follows results from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, which found no evidence of cognitive harm in children who were exposed in utero to antiepileptic drugs. “[In the NEAD study] we followed our cohort to age 6 and found them to have actually an improvement in cognition by about 4 IQ points by the time they got to age 6,” Kimford J. Meador, MD, said during a presentation of the results of the MONEAD study at the 2022 annual meeting of the American Academy of Neurology.

Breastfeeding has health benefits for both mothers and children, including reduced risk of respiratory tract infections, atopic dermatitis, asthma, and diabetes in children, and reduced risk of diabetes, breast cancer, ovarian cancer, and postpartum depression in mothers. Despite those benefits, concerns about harms from exposure to antiepileptic drugs may prompt some women to avoid breastfeeding.

The results of NEAD and MONEAD should reassure patients, according to Dr. Meador, professor of neurology at Stanford (Calif.) University. “Given the known multiple benefits of breastfeeding … women with epilepsy should be encouraged to breastfeed,” he said.
 

A responsibility to ‘engage and educate’ patients

Jennifer Hopp, MD, who served as a discussant for the presentation, underscored the need for neurologists to address pregnancy with female patients of childbearing agents. “The issues may include fertility, peripartum management, and outcomes that really go through the lifespan to also include issues of menopause,” Dr. Hopp, associate professor of neurology at the University of Maryland, Baltimore, said during her presentation.

Dr. Hopp noted one study showing lower rates of breastfeeding among mothers with epilepsy. “Breastfeeding rates in women with epilepsy are strikingly lower than in women who do not have epilepsy,” said Dr. Hopp. Another study showed that women with epilepsy were less likely to sustain breastfeeding after 6 weeks.

Dr. Hopp implored neurologists to address this. “It’s our responsibility to engage and educate our patients. These data provide us messaging to our patients that the newer drugs do not adversely affect outcome independently of their other exposure, and really support well-informed choices in breastfeeding,” said Dr. Hopp.
 

Outdated attitudes still persist

Dr. Meador referred to the stigma that surrounds epilepsy, including some state laws that called for sterilization of women with epilepsy that lasted until the 1960s. One might think that such attitudes are gone, “but it’s still there,” said Dr. Meador, who recounted a story a colleague told him about a woman on antiseizure medication. In the hospital, the nurse told her not to breastfeed. The neurological consult told her not to breastfeed. She breastfed anyway. “Then they reported her for child neglect, and that was just a few years ago. So I think the message needs to be loud and clear that we encourage [women with epilepsy] to breastfeed because we have the known benefits, and now several studies showing clearly no adverse effects of breastfeeding while taking antiseizure medications,” said Dr. Meador.

MONEAD findings

The MONEAD study included women from 20 different sites, with 145 participating investigators. The researchers compared outcomes in 284 women with epilepsy and 87 healthy women. The maternal mean IQ was 98 among women with epilepsy (95% confidence interval [CI], 96-99), and 105 (95% CI, 102-107) among healthy women. Seventy-six percent of women with epilepsy breastfed, versus 89% of controls.

Among the study cohort, 79% of women with epilepsy were on monotherapy, and 21% were on polytherapy. Thirty-five percent received lamotrigine, 28% levetiracetam, 16% were on another monotherapy, 10% received a combination of lamotrigine and levetiracetam, and 11% received a different combination.

At age 3, there was no association between the verbal index score of the child and whether the mother had epilepsy or not (difference, 0.4; P = .770). The researchers did find associations with the mother’s IQ (0.3; P < .001), male versus female child sex (–4.9; P < .001), Hispanic or Latino ethnicity (vs. Non-Hispanic, –5.5; P < .001), mother without college degree (–7.0; P < .001), average Beck Anxiety Inventory score after birth (–0.4; P < .001), and weeks of gestational age at enrollment.

The researchers found no association between third trimester antiseizure medication blood levels and verbal index score after adjustment (–2.9; P = .149), with the exception of levetiracetam (–9.0; P = .033). “This is interesting (but) not to be overblown, because overall the children on levetiracetam did well. But it must be remembered that teratogens act in an exposure dependent manner, so we’re constantly in this balancing act of trying to make sure you get enough medication on board to stop the seizures and protect the mother and the child, and at the same time, not too much on board where we increase the risk of teratogenicity in the child,” said Dr. Meador.

The study was funded by the National Institutes of Health. Dr. Meador and Dr. Hopp have no relevant financial disclosures.

Pregnant women with a history of migraine are at elevated risk for gestational hypertension and preeclampsia, and of delivering their baby preterm, new research suggests. In a large prospective study, researchers also found a link between migraine with aura and increased preeclampsia risk.

Overall, the findings suggest women with a history of migraine may benefit from enhanced monitoring during pregnancy, said coinvestigator Alexandra Purdue-Smithe, PhD, associate epidemiologist at Brigham and Women’s Hospital and instructor of medicine at Harvard Medical School, Boston. “Our results suggest that migraine history may be an important consideration in  obstetric risk assessment,” Dr. Purdue-Smithe added.

The findings will be presented at the 2022 annual meeting of the American Academy of Neurology.
 

Common neurovascular disorder

Migraine is a common neurovascular disorder, affecting about 15% of adults. The condition carries “a pretty remarkable sex bias” as it affects up to three times more women than men, and about a quarter of women in the reproductive age bracket of 18-44 years, Dr. Purdue-Smithe noted.

Despite this, relatively little is known about migraine and pregnancy risks, she said.

What is known is that women with migraine have a higher burden of cardiovascular risk factors such as obesity and chronic hypertension, and these factors can also increase risk for pregnancy complications, she added.

In the study, researchers analyzed data on 30,555 pregnancies in about 19,000 women without a history of cardiovascular disease, type 2 diabetes, or cancer during a 20-year period ending in 2009.

The data came from the Nurses’ Health Study II, a large prospective cohort study established in 1989 when it enrolled women aged 25-42 years. Participants in the ongoing study complete questionnaires every 2 years, reporting information on various health conditions as well as pregnancy and reproductive events.

The investigators estimated associations of physician-diagnosed prepregnancy migraine with preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, and low birth weight (<2,500 grams [5.5 lb]).

About 11% of the women in the study had migraine diagnosed by a physician before pregnancy.

Researchers adjusted for age at pregnancy, race/ethnicity, age at menarche, and prepregnancy chronic hypertension, body mass index, physical activity, smoking status, alcohol intake, history of infertility, parity, oral contraceptive use, and analgesic use.
 

‘A bit surprising’

Results showed that compared with women without a history of migraine, those with such a history had higher risk for preterm delivery (relative risk [RR], 1.17; 95% confidence interval [CI], 1.05-1.30), gestational hypertension (RR, 1.28; 95% CI, 1.11-1.48), and preeclampsia (RR, 1.40; 95% CI, 1.19-1.65).

Prepregnancy migraine was not associated with low birth weight (RR, 0.99; 95% CI, 0.85-1.16) or gestational diabetes (RR, 1.05; 95% CI, .91-1.22).

It was a “bit surprising” that women with migraine had a higher risk for preterm delivery but their babies were not necessarily underweight – although some prior literature had similar findings, said Dr. Purdue-Smithe.

She noted that in her study the association was limited to moderate preterm delivery (gestational age, 32-37 weeks) and not with very preterm births (before 32 weeks).

Researchers also assessed adverse pregnancy outcomes by aura phenotype. “Women with migraine with aura have a higher risk of cardiovascular disease later in life, so we hypothesized that aura might be more strongly associated with adverse pregnancy outcomes with underlying vascular pathology,” Dr. Purdue-Smithe said.

Women with and without aura had elevated risks for preterm delivery and gestational hypertension. Those with aura had a slightly higher risk for preeclampsia (RR, 1.51; 95% CI, 1.22-1.88) than those without aura (RR, 1.29; 95% CI, 1.04-1.61).

As the association between migraine and adverse pregnancy outcomes persisted after adjustment for established cardiovascular and obstetric risk factors, “this suggests there may be subclinical factors that are contributing to elevated risks of these outcomes in women with migraine,” said Dr. Purdue-Smithe.

Such factors could include platelet activation, chronic inflammation, and endothelial dysfunction, she added.

While findings of some previous case-control and retrospective studies suggested a possible link between migraine and adverse pregnancy outcomes, until now few large prospective studies have examined the association.

“Strengths of our study include its prospective design, very large sample size, and more complete adjustment for potential prepregnancy confounders,” Dr. Purdue-Smithe said.
 

Independent risk factor?

In the past, it has been somewhat unclear whether migraine is an independent risk factor for these complications or whether women with migraine just have greater risk factors for adverse pregnancy outcomes.

“Our preliminary findings suggest that migraine is independently associated with these adverse pregnancy outcomes, or at least that’s what it seems,” said Dr. Purdue-Smithe.

The new results could be used by clinicians to “flag” women who may be at risk for complications, she added. “These women may benefit from closer monitoring in pregnancy so that if issues arise, physicians can act quickly.”

She noted that preeclampsia “can come on suddenly and escalate rapidly,” and there are few interventions to treat it besides delivery.

However, low-dose aspirin may be worth investigating. Various health care groups and the U.S. Preventive Services Task Force recommend pregnant women at high risk for preeclampsia take low-dose aspirin (81 mg/d) after 12 weeks’ gestation.

“It would be interesting to see if women with migraine who take aspirin in pregnancy can reduce their risk of preeclampsia, and future research should address this question,” said Dr. Purdue-Smithe.

Additional testing showed that associations with preeclampsia and gestational hypertension did not vary according to age and other obstetrical risks.

The Nurses’ Health Study II did not have information on number and severity of migraine attacks, so the researchers were unable to determine if these factors affect pregnancy outcomes.

“Understanding whether specific migraine features, such as attack frequency, are associated with adverse pregnancy outcomes will be an important area for future research,” said Dr. Purdue-Smithe. She noted prior studies showed the frequency of migraine attacks is related to ischemic stroke and other cardiovascular outcomes.

The authors acknowledged a limitation for the current study: Although migraine history was reported prior to pregnancy, information on migraine aura was collected after most of the pregnancies in the cohort were over. So the findings for migraine aura may have been influenced by participants’ ability to accurately remember their experiences.
 

Collaboration is key

Commenting on the research, Nina Riggins, MD, PhD, director of the Headache and Traumatic Brain Injury Center in the department of neurosciences at the University of California, San Diego, said the study “stands out” because it distinguishes pregnancy complications between those with and without aura among women with migraine. 

Dr. Riggins noted the investigators found the risk of preeclampsia, which on average occurs in about 3%-5% of pregnancies, is higher among women with migraine with aura.  

“The good news is that treatments are available,” she said. “Preconception planning should include this discussion for patients living with migraine.”

However, the study did not compare risks for patients who have frequent migraine attacks versus episodic migraine, Dr. Riggins noted. “We need to learn more about whether any treatments can be safe and effective to decrease risks of complications during pregnancy in this population,” she said.

“I believe, ultimately, what this study reveals is that collaboration among primary care, ob.gyn., maternal-fetal medicine specialists, and neurologists will likely benefit pregnant patients with migraine,” Dr. Riggins said.

The study received funding from the National Institutes of Health. Dr. Purdue-Smithe has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Pregnant women with a history of migraine are at elevated risk for gestational hypertension and preeclampsia, and of delivering their baby preterm, new research suggests. In a large prospective study, researchers also found a link between migraine with aura and increased preeclampsia risk.

Overall, the findings suggest women with a history of migraine may benefit from enhanced monitoring during pregnancy, said coinvestigator Alexandra Purdue-Smithe, PhD, associate epidemiologist at Brigham and Women’s Hospital and instructor of medicine at Harvard Medical School, Boston. “Our results suggest that migraine history may be an important consideration in  obstetric risk assessment,” Dr. Purdue-Smithe added.

The findings will be presented at the 2022 annual meeting of the American Academy of Neurology.
 

Common neurovascular disorder

Migraine is a common neurovascular disorder, affecting about 15% of adults. The condition carries “a pretty remarkable sex bias” as it affects up to three times more women than men, and about a quarter of women in the reproductive age bracket of 18-44 years, Dr. Purdue-Smithe noted.

Despite this, relatively little is known about migraine and pregnancy risks, she said.

What is known is that women with migraine have a higher burden of cardiovascular risk factors such as obesity and chronic hypertension, and these factors can also increase risk for pregnancy complications, she added.

In the study, researchers analyzed data on 30,555 pregnancies in about 19,000 women without a history of cardiovascular disease, type 2 diabetes, or cancer during a 20-year period ending in 2009.

The data came from the Nurses’ Health Study II, a large prospective cohort study established in 1989 when it enrolled women aged 25-42 years. Participants in the ongoing study complete questionnaires every 2 years, reporting information on various health conditions as well as pregnancy and reproductive events.

The investigators estimated associations of physician-diagnosed prepregnancy migraine with preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, and low birth weight (<2,500 grams [5.5 lb]).

About 11% of the women in the study had migraine diagnosed by a physician before pregnancy.

Researchers adjusted for age at pregnancy, race/ethnicity, age at menarche, and prepregnancy chronic hypertension, body mass index, physical activity, smoking status, alcohol intake, history of infertility, parity, oral contraceptive use, and analgesic use.
 

‘A bit surprising’

Results showed that compared with women without a history of migraine, those with such a history had higher risk for preterm delivery (relative risk [RR], 1.17; 95% confidence interval [CI], 1.05-1.30), gestational hypertension (RR, 1.28; 95% CI, 1.11-1.48), and preeclampsia (RR, 1.40; 95% CI, 1.19-1.65).

Prepregnancy migraine was not associated with low birth weight (RR, 0.99; 95% CI, 0.85-1.16) or gestational diabetes (RR, 1.05; 95% CI, .91-1.22).

It was a “bit surprising” that women with migraine had a higher risk for preterm delivery but their babies were not necessarily underweight – although some prior literature had similar findings, said Dr. Purdue-Smithe.

She noted that in her study the association was limited to moderate preterm delivery (gestational age, 32-37 weeks) and not with very preterm births (before 32 weeks).

Researchers also assessed adverse pregnancy outcomes by aura phenotype. “Women with migraine with aura have a higher risk of cardiovascular disease later in life, so we hypothesized that aura might be more strongly associated with adverse pregnancy outcomes with underlying vascular pathology,” Dr. Purdue-Smithe said.

Women with and without aura had elevated risks for preterm delivery and gestational hypertension. Those with aura had a slightly higher risk for preeclampsia (RR, 1.51; 95% CI, 1.22-1.88) than those without aura (RR, 1.29; 95% CI, 1.04-1.61).

As the association between migraine and adverse pregnancy outcomes persisted after adjustment for established cardiovascular and obstetric risk factors, “this suggests there may be subclinical factors that are contributing to elevated risks of these outcomes in women with migraine,” said Dr. Purdue-Smithe.

Such factors could include platelet activation, chronic inflammation, and endothelial dysfunction, she added.

While findings of some previous case-control and retrospective studies suggested a possible link between migraine and adverse pregnancy outcomes, until now few large prospective studies have examined the association.

“Strengths of our study include its prospective design, very large sample size, and more complete adjustment for potential prepregnancy confounders,” Dr. Purdue-Smithe said.
 

Independent risk factor?

In the past, it has been somewhat unclear whether migraine is an independent risk factor for these complications or whether women with migraine just have greater risk factors for adverse pregnancy outcomes.

“Our preliminary findings suggest that migraine is independently associated with these adverse pregnancy outcomes, or at least that’s what it seems,” said Dr. Purdue-Smithe.

The new results could be used by clinicians to “flag” women who may be at risk for complications, she added. “These women may benefit from closer monitoring in pregnancy so that if issues arise, physicians can act quickly.”

She noted that preeclampsia “can come on suddenly and escalate rapidly,” and there are few interventions to treat it besides delivery.

However, low-dose aspirin may be worth investigating. Various health care groups and the U.S. Preventive Services Task Force recommend pregnant women at high risk for preeclampsia take low-dose aspirin (81 mg/d) after 12 weeks’ gestation.

“It would be interesting to see if women with migraine who take aspirin in pregnancy can reduce their risk of preeclampsia, and future research should address this question,” said Dr. Purdue-Smithe.

Additional testing showed that associations with preeclampsia and gestational hypertension did not vary according to age and other obstetrical risks.

The Nurses’ Health Study II did not have information on number and severity of migraine attacks, so the researchers were unable to determine if these factors affect pregnancy outcomes.

“Understanding whether specific migraine features, such as attack frequency, are associated with adverse pregnancy outcomes will be an important area for future research,” said Dr. Purdue-Smithe. She noted prior studies showed the frequency of migraine attacks is related to ischemic stroke and other cardiovascular outcomes.

The authors acknowledged a limitation for the current study: Although migraine history was reported prior to pregnancy, information on migraine aura was collected after most of the pregnancies in the cohort were over. So the findings for migraine aura may have been influenced by participants’ ability to accurately remember their experiences.
 

Collaboration is key

Commenting on the research, Nina Riggins, MD, PhD, director of the Headache and Traumatic Brain Injury Center in the department of neurosciences at the University of California, San Diego, said the study “stands out” because it distinguishes pregnancy complications between those with and without aura among women with migraine. 

Dr. Riggins noted the investigators found the risk of preeclampsia, which on average occurs in about 3%-5% of pregnancies, is higher among women with migraine with aura.  

“The good news is that treatments are available,” she said. “Preconception planning should include this discussion for patients living with migraine.”

However, the study did not compare risks for patients who have frequent migraine attacks versus episodic migraine, Dr. Riggins noted. “We need to learn more about whether any treatments can be safe and effective to decrease risks of complications during pregnancy in this population,” she said.

“I believe, ultimately, what this study reveals is that collaboration among primary care, ob.gyn., maternal-fetal medicine specialists, and neurologists will likely benefit pregnant patients with migraine,” Dr. Riggins said.

The study received funding from the National Institutes of Health. Dr. Purdue-Smithe has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Pregnant women with a history of migraine are at elevated risk for gestational hypertension and preeclampsia, and of delivering their baby preterm, new research suggests. In a large prospective study, researchers also found a link between migraine with aura and increased preeclampsia risk.

Overall, the findings suggest women with a history of migraine may benefit from enhanced monitoring during pregnancy, said coinvestigator Alexandra Purdue-Smithe, PhD, associate epidemiologist at Brigham and Women’s Hospital and instructor of medicine at Harvard Medical School, Boston. “Our results suggest that migraine history may be an important consideration in  obstetric risk assessment,” Dr. Purdue-Smithe added.

The findings will be presented at the 2022 annual meeting of the American Academy of Neurology.
 

Common neurovascular disorder

Migraine is a common neurovascular disorder, affecting about 15% of adults. The condition carries “a pretty remarkable sex bias” as it affects up to three times more women than men, and about a quarter of women in the reproductive age bracket of 18-44 years, Dr. Purdue-Smithe noted.

Despite this, relatively little is known about migraine and pregnancy risks, she said.

What is known is that women with migraine have a higher burden of cardiovascular risk factors such as obesity and chronic hypertension, and these factors can also increase risk for pregnancy complications, she added.

In the study, researchers analyzed data on 30,555 pregnancies in about 19,000 women without a history of cardiovascular disease, type 2 diabetes, or cancer during a 20-year period ending in 2009.

The data came from the Nurses’ Health Study II, a large prospective cohort study established in 1989 when it enrolled women aged 25-42 years. Participants in the ongoing study complete questionnaires every 2 years, reporting information on various health conditions as well as pregnancy and reproductive events.

The investigators estimated associations of physician-diagnosed prepregnancy migraine with preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, and low birth weight (<2,500 grams [5.5 lb]).

About 11% of the women in the study had migraine diagnosed by a physician before pregnancy.

Researchers adjusted for age at pregnancy, race/ethnicity, age at menarche, and prepregnancy chronic hypertension, body mass index, physical activity, smoking status, alcohol intake, history of infertility, parity, oral contraceptive use, and analgesic use.
 

‘A bit surprising’

Results showed that compared with women without a history of migraine, those with such a history had higher risk for preterm delivery (relative risk [RR], 1.17; 95% confidence interval [CI], 1.05-1.30), gestational hypertension (RR, 1.28; 95% CI, 1.11-1.48), and preeclampsia (RR, 1.40; 95% CI, 1.19-1.65).

Prepregnancy migraine was not associated with low birth weight (RR, 0.99; 95% CI, 0.85-1.16) or gestational diabetes (RR, 1.05; 95% CI, .91-1.22).

It was a “bit surprising” that women with migraine had a higher risk for preterm delivery but their babies were not necessarily underweight – although some prior literature had similar findings, said Dr. Purdue-Smithe.

She noted that in her study the association was limited to moderate preterm delivery (gestational age, 32-37 weeks) and not with very preterm births (before 32 weeks).

Researchers also assessed adverse pregnancy outcomes by aura phenotype. “Women with migraine with aura have a higher risk of cardiovascular disease later in life, so we hypothesized that aura might be more strongly associated with adverse pregnancy outcomes with underlying vascular pathology,” Dr. Purdue-Smithe said.

Women with and without aura had elevated risks for preterm delivery and gestational hypertension. Those with aura had a slightly higher risk for preeclampsia (RR, 1.51; 95% CI, 1.22-1.88) than those without aura (RR, 1.29; 95% CI, 1.04-1.61).

As the association between migraine and adverse pregnancy outcomes persisted after adjustment for established cardiovascular and obstetric risk factors, “this suggests there may be subclinical factors that are contributing to elevated risks of these outcomes in women with migraine,” said Dr. Purdue-Smithe.

Such factors could include platelet activation, chronic inflammation, and endothelial dysfunction, she added.

While findings of some previous case-control and retrospective studies suggested a possible link between migraine and adverse pregnancy outcomes, until now few large prospective studies have examined the association.

“Strengths of our study include its prospective design, very large sample size, and more complete adjustment for potential prepregnancy confounders,” Dr. Purdue-Smithe said.
 

Independent risk factor?

In the past, it has been somewhat unclear whether migraine is an independent risk factor for these complications or whether women with migraine just have greater risk factors for adverse pregnancy outcomes.

“Our preliminary findings suggest that migraine is independently associated with these adverse pregnancy outcomes, or at least that’s what it seems,” said Dr. Purdue-Smithe.

The new results could be used by clinicians to “flag” women who may be at risk for complications, she added. “These women may benefit from closer monitoring in pregnancy so that if issues arise, physicians can act quickly.”

She noted that preeclampsia “can come on suddenly and escalate rapidly,” and there are few interventions to treat it besides delivery.

However, low-dose aspirin may be worth investigating. Various health care groups and the U.S. Preventive Services Task Force recommend pregnant women at high risk for preeclampsia take low-dose aspirin (81 mg/d) after 12 weeks’ gestation.

“It would be interesting to see if women with migraine who take aspirin in pregnancy can reduce their risk of preeclampsia, and future research should address this question,” said Dr. Purdue-Smithe.

Additional testing showed that associations with preeclampsia and gestational hypertension did not vary according to age and other obstetrical risks.

The Nurses’ Health Study II did not have information on number and severity of migraine attacks, so the researchers were unable to determine if these factors affect pregnancy outcomes.

“Understanding whether specific migraine features, such as attack frequency, are associated with adverse pregnancy outcomes will be an important area for future research,” said Dr. Purdue-Smithe. She noted prior studies showed the frequency of migraine attacks is related to ischemic stroke and other cardiovascular outcomes.

The authors acknowledged a limitation for the current study: Although migraine history was reported prior to pregnancy, information on migraine aura was collected after most of the pregnancies in the cohort were over. So the findings for migraine aura may have been influenced by participants’ ability to accurately remember their experiences.
 

Collaboration is key

Commenting on the research, Nina Riggins, MD, PhD, director of the Headache and Traumatic Brain Injury Center in the department of neurosciences at the University of California, San Diego, said the study “stands out” because it distinguishes pregnancy complications between those with and without aura among women with migraine. 

Dr. Riggins noted the investigators found the risk of preeclampsia, which on average occurs in about 3%-5% of pregnancies, is higher among women with migraine with aura.  

“The good news is that treatments are available,” she said. “Preconception planning should include this discussion for patients living with migraine.”

However, the study did not compare risks for patients who have frequent migraine attacks versus episodic migraine, Dr. Riggins noted. “We need to learn more about whether any treatments can be safe and effective to decrease risks of complications during pregnancy in this population,” she said.

“I believe, ultimately, what this study reveals is that collaboration among primary care, ob.gyn., maternal-fetal medicine specialists, and neurologists will likely benefit pregnant patients with migraine,” Dr. Riggins said.

The study received funding from the National Institutes of Health. Dr. Purdue-Smithe has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.