Obstetrics

Women with autoimmune disease are more likely to have perinatal depression (PND), according to findings from a new study that also suggested the reverse relationship is true: Women with a history of PND have a higher risk of developing autoimmune disease.

The research, published online on January 9, 2024, in Molecular Psychiatry, was led by Emma Bränn, PhD, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

The researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the group of approximately 815,000 women and 1.3 million pregnancies, just more than 55,000 women had been diagnosed with depression during their pregnancy or within a year after delivery.

The researchers then compared the incidence of 41 autoimmune diseases in women who had and did not have PND. They controlled for factors including genetic makeup and childhood environment.

Results indicated that women with autoimmune disease were 30% more likely to have PND (odds ratio, 1.30; 95% CI, 1.25-1.35). Conversely, women with PND were 30% more likely than women with no PND to develop an autoimmune disease (hazard ratio, 1.30; 95% CI, 1.25-1.36).

A sibling comparison helped confirm the results by controlling for some shared genetic and early life environmental factors related to the household in which sisters grew up.
 

Potential Shared Biological Mechanisms

The association was independent of psychiatric comorbidities, suggesting there may be shared biological mechanisms.

Dr. Bränn told this news organization that the research team wanted to do the study because previous research has shown involvement of the immune system in depression, with similarities in both the symptoms of immune system–activated diseases and depression and the molecular pathways activated by the immune system.

“Adding on top of the tremendous changes in the immune system that we see in the body of the woman during the perinatal period, we hypothesized that autoimmune diseases could be associated to perinatal depression,” she said. “This had also been shown in some previous literature but not to the extent as what we have investigated in this paper.”

She said their results help make a case for counseling women at several points in healthcare interactions — before and after conception and childbirth — and in rheumatology visits to inform women with autoimmune diseases who are contemplating motherhood of the association with developing PND. The results may also demonstrate a need for monitoring women in these groups for depression or autoimmune disease.

Fred Miller, MD, PhD, retired Scientist Emeritus of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences, who was not part of the study, said the results seem plausible as they build on early work that demonstrated selected associations between autoimmune conditions and mental illness.

“These associations may be the result of shared genetic and environmental risk factors, including stress, hormonal changes, medications, and the proinflammatory states that can lead to both,” he said.

The novelty, he said, is in the relatively strong associations of PND with autoimmune disease overall and with specific autoimmune diseases.
 

Strong Link Found With Multiple Sclerosis (MS)

According to the paper, a significant positive bidirectional link was found for autoimmune thyroid disease, psoriasis, MS, ulcerative colitis, and celiac disease.

Researchers found a particularly strong association — double the risk in both directions — between PND and MS.

Dr. Miller said though it is unclear from this study why the association of PND with MS was stronger than with other autoimmune diseases, people with MS are known to be at a high risk for depression in general. That may come from greater shared genetic and environmental risk factors, he added.

Additionally, MS is one of the more common autoimmune diseases, he noted, so the population is larger for study.

He said he was surprised the researchers didn’t investigate medication use because medications used in depression have immunologic effects and medications used in autoimmune diseases could have effects on mental conditions.

The study has implications for clinicians in a wide variety of specialties, Dr. Miller noted.

“It suggests that caregivers be more alert to the signs of developing autoimmune disease in women with perinatal depression and to the signs of developing perinatal depression in those with autoimmune disease,” Dr. Miller said, “so that appropriate screening, diagnostics, and interventions may be undertaken.”

The researchers say they will continue to examine the long-term effects of depression during pregnancy and in the year after childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” Dr. Bränn said. “We hope that our results will help decision-makers to steer funding toward maternal healthcare so that more women can get help and support in time.”

The study was financed by Karolinska Institute, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Council, and the Icelandic Research Fund.

The researchers and Dr. Miller reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Women with autoimmune disease are more likely to have perinatal depression (PND), according to findings from a new study that also suggested the reverse relationship is true: Women with a history of PND have a higher risk of developing autoimmune disease.

The research, published online on January 9, 2024, in Molecular Psychiatry, was led by Emma Bränn, PhD, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

The researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the group of approximately 815,000 women and 1.3 million pregnancies, just more than 55,000 women had been diagnosed with depression during their pregnancy or within a year after delivery.

The researchers then compared the incidence of 41 autoimmune diseases in women who had and did not have PND. They controlled for factors including genetic makeup and childhood environment.

Results indicated that women with autoimmune disease were 30% more likely to have PND (odds ratio, 1.30; 95% CI, 1.25-1.35). Conversely, women with PND were 30% more likely than women with no PND to develop an autoimmune disease (hazard ratio, 1.30; 95% CI, 1.25-1.36).

A sibling comparison helped confirm the results by controlling for some shared genetic and early life environmental factors related to the household in which sisters grew up.
 

Potential Shared Biological Mechanisms

The association was independent of psychiatric comorbidities, suggesting there may be shared biological mechanisms.

Dr. Bränn told this news organization that the research team wanted to do the study because previous research has shown involvement of the immune system in depression, with similarities in both the symptoms of immune system–activated diseases and depression and the molecular pathways activated by the immune system.

“Adding on top of the tremendous changes in the immune system that we see in the body of the woman during the perinatal period, we hypothesized that autoimmune diseases could be associated to perinatal depression,” she said. “This had also been shown in some previous literature but not to the extent as what we have investigated in this paper.”

She said their results help make a case for counseling women at several points in healthcare interactions — before and after conception and childbirth — and in rheumatology visits to inform women with autoimmune diseases who are contemplating motherhood of the association with developing PND. The results may also demonstrate a need for monitoring women in these groups for depression or autoimmune disease.

Fred Miller, MD, PhD, retired Scientist Emeritus of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences, who was not part of the study, said the results seem plausible as they build on early work that demonstrated selected associations between autoimmune conditions and mental illness.

“These associations may be the result of shared genetic and environmental risk factors, including stress, hormonal changes, medications, and the proinflammatory states that can lead to both,” he said.

The novelty, he said, is in the relatively strong associations of PND with autoimmune disease overall and with specific autoimmune diseases.
 

Strong Link Found With Multiple Sclerosis (MS)

According to the paper, a significant positive bidirectional link was found for autoimmune thyroid disease, psoriasis, MS, ulcerative colitis, and celiac disease.

Researchers found a particularly strong association — double the risk in both directions — between PND and MS.

Dr. Miller said though it is unclear from this study why the association of PND with MS was stronger than with other autoimmune diseases, people with MS are known to be at a high risk for depression in general. That may come from greater shared genetic and environmental risk factors, he added.

Additionally, MS is one of the more common autoimmune diseases, he noted, so the population is larger for study.

He said he was surprised the researchers didn’t investigate medication use because medications used in depression have immunologic effects and medications used in autoimmune diseases could have effects on mental conditions.

The study has implications for clinicians in a wide variety of specialties, Dr. Miller noted.

“It suggests that caregivers be more alert to the signs of developing autoimmune disease in women with perinatal depression and to the signs of developing perinatal depression in those with autoimmune disease,” Dr. Miller said, “so that appropriate screening, diagnostics, and interventions may be undertaken.”

The researchers say they will continue to examine the long-term effects of depression during pregnancy and in the year after childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” Dr. Bränn said. “We hope that our results will help decision-makers to steer funding toward maternal healthcare so that more women can get help and support in time.”

The study was financed by Karolinska Institute, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Council, and the Icelandic Research Fund.

The researchers and Dr. Miller reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Women with autoimmune disease are more likely to have perinatal depression (PND), according to findings from a new study that also suggested the reverse relationship is true: Women with a history of PND have a higher risk of developing autoimmune disease.

The research, published online on January 9, 2024, in Molecular Psychiatry, was led by Emma Bränn, PhD, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

The researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the group of approximately 815,000 women and 1.3 million pregnancies, just more than 55,000 women had been diagnosed with depression during their pregnancy or within a year after delivery.

The researchers then compared the incidence of 41 autoimmune diseases in women who had and did not have PND. They controlled for factors including genetic makeup and childhood environment.

Results indicated that women with autoimmune disease were 30% more likely to have PND (odds ratio, 1.30; 95% CI, 1.25-1.35). Conversely, women with PND were 30% more likely than women with no PND to develop an autoimmune disease (hazard ratio, 1.30; 95% CI, 1.25-1.36).

A sibling comparison helped confirm the results by controlling for some shared genetic and early life environmental factors related to the household in which sisters grew up.
 

Potential Shared Biological Mechanisms

The association was independent of psychiatric comorbidities, suggesting there may be shared biological mechanisms.

Dr. Bränn told this news organization that the research team wanted to do the study because previous research has shown involvement of the immune system in depression, with similarities in both the symptoms of immune system–activated diseases and depression and the molecular pathways activated by the immune system.

“Adding on top of the tremendous changes in the immune system that we see in the body of the woman during the perinatal period, we hypothesized that autoimmune diseases could be associated to perinatal depression,” she said. “This had also been shown in some previous literature but not to the extent as what we have investigated in this paper.”

She said their results help make a case for counseling women at several points in healthcare interactions — before and after conception and childbirth — and in rheumatology visits to inform women with autoimmune diseases who are contemplating motherhood of the association with developing PND. The results may also demonstrate a need for monitoring women in these groups for depression or autoimmune disease.

Fred Miller, MD, PhD, retired Scientist Emeritus of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences, who was not part of the study, said the results seem plausible as they build on early work that demonstrated selected associations between autoimmune conditions and mental illness.

“These associations may be the result of shared genetic and environmental risk factors, including stress, hormonal changes, medications, and the proinflammatory states that can lead to both,” he said.

The novelty, he said, is in the relatively strong associations of PND with autoimmune disease overall and with specific autoimmune diseases.
 

Strong Link Found With Multiple Sclerosis (MS)

According to the paper, a significant positive bidirectional link was found for autoimmune thyroid disease, psoriasis, MS, ulcerative colitis, and celiac disease.

Researchers found a particularly strong association — double the risk in both directions — between PND and MS.

Dr. Miller said though it is unclear from this study why the association of PND with MS was stronger than with other autoimmune diseases, people with MS are known to be at a high risk for depression in general. That may come from greater shared genetic and environmental risk factors, he added.

Additionally, MS is one of the more common autoimmune diseases, he noted, so the population is larger for study.

He said he was surprised the researchers didn’t investigate medication use because medications used in depression have immunologic effects and medications used in autoimmune diseases could have effects on mental conditions.

The study has implications for clinicians in a wide variety of specialties, Dr. Miller noted.

“It suggests that caregivers be more alert to the signs of developing autoimmune disease in women with perinatal depression and to the signs of developing perinatal depression in those with autoimmune disease,” Dr. Miller said, “so that appropriate screening, diagnostics, and interventions may be undertaken.”

The researchers say they will continue to examine the long-term effects of depression during pregnancy and in the year after childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” Dr. Bränn said. “We hope that our results will help decision-makers to steer funding toward maternal healthcare so that more women can get help and support in time.”

The study was financed by Karolinska Institute, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Council, and the Icelandic Research Fund.

The researchers and Dr. Miller reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

FAIRFAX, VIRGINIA — Pharmacologic treatment of gestational diabetes mellitus (GDM) remains challenged by overall poor trial quality, clinical practice guidelines that offer differing advice, and a limited ability to predict individual risk and treatment response, but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.

Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.

The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.

The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.  

“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.

The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.

The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.

The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.

The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
 

The State Of Knowledge About Oral Hypoglycemics

The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.

Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.

In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.

In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”

A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.

“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”

Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.

Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.

Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
 

The Challenge of Heterogeneity

In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.

Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.

A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.

Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”

Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.

There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)

“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”

Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.

The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
 

Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity

Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.

She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.

A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”

Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.

“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”

The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.

In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.

Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”

FAIRFAX, VIRGINIA — Pharmacologic treatment of gestational diabetes mellitus (GDM) remains challenged by overall poor trial quality, clinical practice guidelines that offer differing advice, and a limited ability to predict individual risk and treatment response, but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.

Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.

The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.

The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.  

“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.

The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.

The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.

The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.

The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
 

The State Of Knowledge About Oral Hypoglycemics

The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.

Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.

In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.

In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”

A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.

“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”

Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.

Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.

Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
 

The Challenge of Heterogeneity

In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.

Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.

A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.

Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”

Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.

There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)

“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”

Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.

The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
 

Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity

Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.

She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.

A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”

Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.

“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”

The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.

In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.

Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”

FAIRFAX, VIRGINIA — Pharmacologic treatment of gestational diabetes mellitus (GDM) remains challenged by overall poor trial quality, clinical practice guidelines that offer differing advice, and a limited ability to predict individual risk and treatment response, but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.

Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.

The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.

The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.  

“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.

The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.

The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.

The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.

The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
 

The State Of Knowledge About Oral Hypoglycemics

The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.

Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.

In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.

In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”

A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.

“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”

Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.

Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.

Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
 

The Challenge of Heterogeneity

In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.

Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.

A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.

Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”

Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.

There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)

“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”

Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.

The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
 

Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity

Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.

She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.

A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”

Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.

“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”

The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.

In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.

Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”

Taking 500 mg of calcium a day reduces the likelihood of pregnant women developing preeclampsia in pregnant women as much as higher doses, according to a study in The New England Journal of Medicine published on January 11. 

The study also shows that the lower dose of calcium protects against preterm birth almost as well as the higher dose recommended by the World Health Organization (WHO). 

Preeclampsia complicates up to 8% of pregnancies and may contribute to 45,000 maternal deaths globally every year. The US Centers for Disease Control and Prevention estimates that preeclampsia occurs in about 1 in 25 pregnancies, and Black women are 60% more likely to develop the condition than are White women.

Calcium supplementation reduces the risks for preeclampsia, per WHO guidelines. 

The WHO has recommended between 1500 mg and 2000 mg of calcium supplementation daily along with one 30- to 60-mg iron pill for pregnant women who receive insufficient calcium in their diets, which the WHO says generally occurs in lower-income nations and not wealthier nations, such as the United States. 

This dosage amounts to a minimum of three calcium pills per day because the dietary supplements generally come from suppliers in 500-mg doses. Researchers say the supplements are too expensive for many health authorities of low- and middle-income nations to provide, and that taking so many pills presents a barrier to use even if they were plentiful. In countries such as Tanzania and India, governments generally distribute supplements like calcium for free at health clinics, said Christopher Sudfeld, ScD, associate professor of global health and nutrition at Harvard University’s T.H. Chan School of Public Health, in Boston.

The WHO recommendation is “not implemented many places,” Dr. Sudfeld said. Due to the cost, Tanzania has never implemented WHO’s calcium recommendation, providing only the iron pill, he said. 

The randomized double-blinded study included 11,000 pregnant women in Tanzania and 11,000 pregnant women in India. None had yet given birth, which increased their risk for preeclampsia. All participants were older than 18 years and were less than 20 weeks pregnant, according to their most recent menstrual date. Half of participants received the three daily 500-mg calcium pills recommended by WHO; the other half received a single calcium pill and two placebo pills. 

Researchers measured blood pressure and urine protein levels starting at 20 weeks of gestation, at delivery, and 6 weeks after giving birth. 

Regardless of how much calcium people consumed daily, preeclampsia occurred approximately 3% of both the 500-mg and 1500-mg groups. Similar rates of preterm births occurred in both groups, although in Tanzanian, women in the 500-mg arm were somewhat more likely to give birth early. 

“We’re working with governments but we’re also going to disseminate the results to WHO, so that they can do their process for the next antenatal care guidelines, to potentially change the global guidelines,” to support a lower calcium supplement target, Dr. Sudfeld said. 
 

Does Calcium Actually Prevent Preeclampsia?

But Ahizechukwu Eke, MD, PhD, MPH, a pharmacologist who practices maternal fetal medicine at Johns Hopkins Medicine in Baltimore, questioned whether calcium really works to prevent preeclampsia. 

Eke said that the causes of preeclampsia are multifactorial, and researchers have yet to definitively demonstrate the mechanism of action by which calcium works to prevent the condition. One hypothesis is that calcium reduces the amount of contractions in a woman’s uterus, thereby lowering blood pressure. 

Low-dose aspirin is also used to prevent preeclampsia, and Dr. Eke said that the pharmacokinetic pathway by which this drug inhibits preeclampsia is more clear.

“I’m not saying we should stop using calcium, far from it,” Dr. Eke said. But as calcium supplementation to prevent preeclampsia continues, Dr. Eke called for pharmacokinetic studies to explore whether and how calcium works.

Dr. Sudfeld and Dr. Eke report no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Taking 500 mg of calcium a day reduces the likelihood of pregnant women developing preeclampsia in pregnant women as much as higher doses, according to a study in The New England Journal of Medicine published on January 11. 

The study also shows that the lower dose of calcium protects against preterm birth almost as well as the higher dose recommended by the World Health Organization (WHO). 

Preeclampsia complicates up to 8% of pregnancies and may contribute to 45,000 maternal deaths globally every year. The US Centers for Disease Control and Prevention estimates that preeclampsia occurs in about 1 in 25 pregnancies, and Black women are 60% more likely to develop the condition than are White women.

Calcium supplementation reduces the risks for preeclampsia, per WHO guidelines. 

The WHO has recommended between 1500 mg and 2000 mg of calcium supplementation daily along with one 30- to 60-mg iron pill for pregnant women who receive insufficient calcium in their diets, which the WHO says generally occurs in lower-income nations and not wealthier nations, such as the United States. 

This dosage amounts to a minimum of three calcium pills per day because the dietary supplements generally come from suppliers in 500-mg doses. Researchers say the supplements are too expensive for many health authorities of low- and middle-income nations to provide, and that taking so many pills presents a barrier to use even if they were plentiful. In countries such as Tanzania and India, governments generally distribute supplements like calcium for free at health clinics, said Christopher Sudfeld, ScD, associate professor of global health and nutrition at Harvard University’s T.H. Chan School of Public Health, in Boston.

The WHO recommendation is “not implemented many places,” Dr. Sudfeld said. Due to the cost, Tanzania has never implemented WHO’s calcium recommendation, providing only the iron pill, he said. 

The randomized double-blinded study included 11,000 pregnant women in Tanzania and 11,000 pregnant women in India. None had yet given birth, which increased their risk for preeclampsia. All participants were older than 18 years and were less than 20 weeks pregnant, according to their most recent menstrual date. Half of participants received the three daily 500-mg calcium pills recommended by WHO; the other half received a single calcium pill and two placebo pills. 

Researchers measured blood pressure and urine protein levels starting at 20 weeks of gestation, at delivery, and 6 weeks after giving birth. 

Regardless of how much calcium people consumed daily, preeclampsia occurred approximately 3% of both the 500-mg and 1500-mg groups. Similar rates of preterm births occurred in both groups, although in Tanzanian, women in the 500-mg arm were somewhat more likely to give birth early. 

“We’re working with governments but we’re also going to disseminate the results to WHO, so that they can do their process for the next antenatal care guidelines, to potentially change the global guidelines,” to support a lower calcium supplement target, Dr. Sudfeld said. 
 

Does Calcium Actually Prevent Preeclampsia?

But Ahizechukwu Eke, MD, PhD, MPH, a pharmacologist who practices maternal fetal medicine at Johns Hopkins Medicine in Baltimore, questioned whether calcium really works to prevent preeclampsia. 

Eke said that the causes of preeclampsia are multifactorial, and researchers have yet to definitively demonstrate the mechanism of action by which calcium works to prevent the condition. One hypothesis is that calcium reduces the amount of contractions in a woman’s uterus, thereby lowering blood pressure. 

Low-dose aspirin is also used to prevent preeclampsia, and Dr. Eke said that the pharmacokinetic pathway by which this drug inhibits preeclampsia is more clear.

“I’m not saying we should stop using calcium, far from it,” Dr. Eke said. But as calcium supplementation to prevent preeclampsia continues, Dr. Eke called for pharmacokinetic studies to explore whether and how calcium works.

Dr. Sudfeld and Dr. Eke report no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Taking 500 mg of calcium a day reduces the likelihood of pregnant women developing preeclampsia in pregnant women as much as higher doses, according to a study in The New England Journal of Medicine published on January 11. 

The study also shows that the lower dose of calcium protects against preterm birth almost as well as the higher dose recommended by the World Health Organization (WHO). 

Preeclampsia complicates up to 8% of pregnancies and may contribute to 45,000 maternal deaths globally every year. The US Centers for Disease Control and Prevention estimates that preeclampsia occurs in about 1 in 25 pregnancies, and Black women are 60% more likely to develop the condition than are White women.

Calcium supplementation reduces the risks for preeclampsia, per WHO guidelines. 

The WHO has recommended between 1500 mg and 2000 mg of calcium supplementation daily along with one 30- to 60-mg iron pill for pregnant women who receive insufficient calcium in their diets, which the WHO says generally occurs in lower-income nations and not wealthier nations, such as the United States. 

This dosage amounts to a minimum of three calcium pills per day because the dietary supplements generally come from suppliers in 500-mg doses. Researchers say the supplements are too expensive for many health authorities of low- and middle-income nations to provide, and that taking so many pills presents a barrier to use even if they were plentiful. In countries such as Tanzania and India, governments generally distribute supplements like calcium for free at health clinics, said Christopher Sudfeld, ScD, associate professor of global health and nutrition at Harvard University’s T.H. Chan School of Public Health, in Boston.

The WHO recommendation is “not implemented many places,” Dr. Sudfeld said. Due to the cost, Tanzania has never implemented WHO’s calcium recommendation, providing only the iron pill, he said. 

The randomized double-blinded study included 11,000 pregnant women in Tanzania and 11,000 pregnant women in India. None had yet given birth, which increased their risk for preeclampsia. All participants were older than 18 years and were less than 20 weeks pregnant, according to their most recent menstrual date. Half of participants received the three daily 500-mg calcium pills recommended by WHO; the other half received a single calcium pill and two placebo pills. 

Researchers measured blood pressure and urine protein levels starting at 20 weeks of gestation, at delivery, and 6 weeks after giving birth. 

Regardless of how much calcium people consumed daily, preeclampsia occurred approximately 3% of both the 500-mg and 1500-mg groups. Similar rates of preterm births occurred in both groups, although in Tanzanian, women in the 500-mg arm were somewhat more likely to give birth early. 

“We’re working with governments but we’re also going to disseminate the results to WHO, so that they can do their process for the next antenatal care guidelines, to potentially change the global guidelines,” to support a lower calcium supplement target, Dr. Sudfeld said. 
 

Does Calcium Actually Prevent Preeclampsia?

But Ahizechukwu Eke, MD, PhD, MPH, a pharmacologist who practices maternal fetal medicine at Johns Hopkins Medicine in Baltimore, questioned whether calcium really works to prevent preeclampsia. 

Eke said that the causes of preeclampsia are multifactorial, and researchers have yet to definitively demonstrate the mechanism of action by which calcium works to prevent the condition. One hypothesis is that calcium reduces the amount of contractions in a woman’s uterus, thereby lowering blood pressure. 

Low-dose aspirin is also used to prevent preeclampsia, and Dr. Eke said that the pharmacokinetic pathway by which this drug inhibits preeclampsia is more clear.

“I’m not saying we should stop using calcium, far from it,” Dr. Eke said. But as calcium supplementation to prevent preeclampsia continues, Dr. Eke called for pharmacokinetic studies to explore whether and how calcium works.

Dr. Sudfeld and Dr. Eke report no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.

The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.

“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
 

ACOG Recommendations, Randomized Trials (New And Old)

The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).

In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.

ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.

The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.

The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)

Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).

Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.

What Retrospective Studies Reveal

Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.

Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”

The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.

However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).

In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)

The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.

Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.

In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).

Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”

Dr. Grantz reported no disclosures.

FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.

The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.

“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
 

ACOG Recommendations, Randomized Trials (New And Old)

The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).

In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.

ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.

The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.

The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)

Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).

Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.

What Retrospective Studies Reveal

Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.

Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”

The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.

However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).

In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)

The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.

Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.

In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).

Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”

Dr. Grantz reported no disclosures.

FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.

The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.

“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
 

ACOG Recommendations, Randomized Trials (New And Old)

The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).

In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.

ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.

The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.

The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)

Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).

Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.

What Retrospective Studies Reveal

Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.

Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”

The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.

However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).

In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)

The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.

Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.

In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).

Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”

Dr. Grantz reported no disclosures.

Delivered at 34 weeks’ gestation, Baby “Alex” had an enlarged liver and spleen on his initial newborn exam, poor tone, and a diffuse, peeling rash. Baby “Aaliyah” was born at term and appeared healthy. By 1 month of age, she was gaining weight poorly and developed copious nasal drainage and a salmon-colored rash on the soles of her feet.

The connection? Both babies were ultimately diagnosed with congenital syphilis. Infections in both babies could have been prevented if their mothers had been tested for syphilis and treated during pregnancy. Alex’s mom had no prenatal care. Aaliyah’s mom had tested negative for syphilis during her first trimester but had not been re-tested, despite sharing with her health care provider that she had a new sexual partner.

Alex and Aaliyah are representative of what Centers for Disease Control and Prevention (CDC) Chief Medical Officer Debra Houry, MD, MPH, calls a “family tragedy.” Cases of congenital syphilis are rising rapidly in the United States, reaching a 30-year high in 2021.¹ Cases increased by 755% between 2012 and 2021, from 335 in 2012 to 2,865 in 2021. In 2022, cases rose again: 3,761 cases of congenital syphilis were reported, including 231 stillbirths and 51 infant deaths. Infants with congenital syphilis are at risk for lifelong complications, including deafness, blindness, and intellectual disability.

Most of these cases were preventable. Congenital syphilis is rare when pregnant people complete adequate treatment at least 30 days before delivery. In 2022, lack of testing or timely testing contributed to 36.8% of congenital syphilis cases. Nearly 40% of birth parents of infected babies received inadequate treatment during pregnancy, and 11.2% received no treatment or treatment was not documented.

Cases of congenital syphilis have increased in all demographic groups and all US Census Bureau regions, but racial and geographic disparities exist, suggesting ongoing barriers to care related to social determinants of health. In 2021, the highest rates of congenital syphilis were among babies born to individuals who were non-Hispanic American Indian or Alaska Native (384 cases per 100,000 live births), non-Hispanic Native Hawaiian or other Pacific Islander (192 cases per 100,000 live births), and non-Hispanic Black or African American (169 cases per 100,000 live births). Six states had rates of congenital syphilis that exceeded 160 cases per 100,000 population, including Arizona, New Mexico, Louisiana, Mississippi, Texas, and Oklahoma. That is more than twice the national rate of 77.9 cases/100,000.
 

Reducing the Risk

To reduce rates of congenital syphilis in all people, barriers to testing must be eliminated. The CDC recommends that all pregnant people be tested early in pregnancy, with repeat testing at 28 weeks and at delivery for those at increased risk for infection based on individual risk factors or residence in a high-prevalence community. Rapid syphilis testing and treatment during pregnancy is recommended in settings such as emergency departments, syringe service programs, prisons/jails, and maternal and child health programs to minimize missed opportunities for care.

While pediatric clinicians rarely care for pregnant patients, they also have an essential role to play in reducing the adverse health outcomes associated with congenital syphilis. No infant should be discharged from the newborn nursery without confirming that the birth parent was tested for syphilis at least once and was treated appropriately if positive. Appropriate treatment during pregnancy is a single dose of benzathine penicillin G for primary, secondary, or early latent syphilis. Late-latent syphilis or syphilis of unknown duration is treated with three doses of benzathine penicillin G spaced 7-9 days apart. If the doses are given further than 9 days apart, treatment is considered inadequate, and the series of doses must be restarted. Benzathine penicillin G remains in short supply in the United States, but is the only drug recommended to treat syphilis during pregnancy.

Collaboration between obstetrical and newborn care providers is essential. Those who care for newborns need easy access to birthing parents’ syphilis treatment results. As more health care facilities implement routine syphilis testing at delivery, rapid syphilis testing must be available to avoid prolonging newborn hospital stays.

Pediatricians need to maintain an index of suspicion for congenital syphilis, regardless of maternal history, because symptomatic congenital syphilis can mimic a variety of infectious and noninfectious conditions. Most infected infants look normal at birth. While the majority of cases of congenital syphilis are identified in the newborn period, a 2021 paper published in Pediatrics described 84 infants born between 2014 and 2018 who were diagnosed beyond a month of age.² These represented 2.2% of all infants born with congenital syphilis. Common symptoms included rash, snuffles, and hepatomegaly. Sixty-nine percent of infants who had long bone radiographs obtained had findings consistent with congenital syphilis. Typical imaging findings include periostitis and demineralization of the metaphysis and diaphysis of long bones, although fractures can also occur. Case reports describe infants who presented with fractures and were initially evaluated for nonaccidental trauma.³

Another critical approach is to treat syphilis in people of childbearing age before pregnancy occurs. The CDC recommends syphilis testing for sexually active females 18-44 years of age and living in communities with high rates of syphilis. County-specific specific rates of syphilis rates are available at https://www.cdc.gov/nchhstp/atlas/syphilis/. Point-of-care tests are now available for syphilis and may facilitate timely treatment. 

Additional resources describing syphilis testing and treatment are available from the CDC and the American Academy of Pediatrics.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the AAP’s Committee on Infectious Diseases and one of the lead authors of the AAP’s Recommendations for Prevention and Control of Influenza in Children, 2022-2023. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta, and Gilead. Email her at [email protected]. (Also [email protected].)

References

1. McDonald R et al. Vital Signs: Missed Opportunities for Preventing Congenital Syphilis — United States, 2022. MMWR Morb Mortal Wkly Rep. 2023 Nov 17;72(46):1269-74. doi: 10.15585/mmwr.mm7246e1. 

2. Kimball A et al. Congenital Syphilis Diagnosed Beyond the Neonatal Period in the United States: 2014-2018. Pediatrics. 2021 Sep;148(3):e2020049080. doi: 10.1542/peds.2020-049080. 

3. Jacobs K et al. Congenital Syphilis Misdiagnosed as Suspected Nonaccidental Trauma. Pediatrics. 2019 Oct;144(4):e20191564. doi: 10.1542/peds.2019-1564. 

Delivered at 34 weeks’ gestation, Baby “Alex” had an enlarged liver and spleen on his initial newborn exam, poor tone, and a diffuse, peeling rash. Baby “Aaliyah” was born at term and appeared healthy. By 1 month of age, she was gaining weight poorly and developed copious nasal drainage and a salmon-colored rash on the soles of her feet.

The connection? Both babies were ultimately diagnosed with congenital syphilis. Infections in both babies could have been prevented if their mothers had been tested for syphilis and treated during pregnancy. Alex’s mom had no prenatal care. Aaliyah’s mom had tested negative for syphilis during her first trimester but had not been re-tested, despite sharing with her health care provider that she had a new sexual partner.

Alex and Aaliyah are representative of what Centers for Disease Control and Prevention (CDC) Chief Medical Officer Debra Houry, MD, MPH, calls a “family tragedy.” Cases of congenital syphilis are rising rapidly in the United States, reaching a 30-year high in 2021.¹ Cases increased by 755% between 2012 and 2021, from 335 in 2012 to 2,865 in 2021. In 2022, cases rose again: 3,761 cases of congenital syphilis were reported, including 231 stillbirths and 51 infant deaths. Infants with congenital syphilis are at risk for lifelong complications, including deafness, blindness, and intellectual disability.

Most of these cases were preventable. Congenital syphilis is rare when pregnant people complete adequate treatment at least 30 days before delivery. In 2022, lack of testing or timely testing contributed to 36.8% of congenital syphilis cases. Nearly 40% of birth parents of infected babies received inadequate treatment during pregnancy, and 11.2% received no treatment or treatment was not documented.

Cases of congenital syphilis have increased in all demographic groups and all US Census Bureau regions, but racial and geographic disparities exist, suggesting ongoing barriers to care related to social determinants of health. In 2021, the highest rates of congenital syphilis were among babies born to individuals who were non-Hispanic American Indian or Alaska Native (384 cases per 100,000 live births), non-Hispanic Native Hawaiian or other Pacific Islander (192 cases per 100,000 live births), and non-Hispanic Black or African American (169 cases per 100,000 live births). Six states had rates of congenital syphilis that exceeded 160 cases per 100,000 population, including Arizona, New Mexico, Louisiana, Mississippi, Texas, and Oklahoma. That is more than twice the national rate of 77.9 cases/100,000.
 

Reducing the Risk

To reduce rates of congenital syphilis in all people, barriers to testing must be eliminated. The CDC recommends that all pregnant people be tested early in pregnancy, with repeat testing at 28 weeks and at delivery for those at increased risk for infection based on individual risk factors or residence in a high-prevalence community. Rapid syphilis testing and treatment during pregnancy is recommended in settings such as emergency departments, syringe service programs, prisons/jails, and maternal and child health programs to minimize missed opportunities for care.

While pediatric clinicians rarely care for pregnant patients, they also have an essential role to play in reducing the adverse health outcomes associated with congenital syphilis. No infant should be discharged from the newborn nursery without confirming that the birth parent was tested for syphilis at least once and was treated appropriately if positive. Appropriate treatment during pregnancy is a single dose of benzathine penicillin G for primary, secondary, or early latent syphilis. Late-latent syphilis or syphilis of unknown duration is treated with three doses of benzathine penicillin G spaced 7-9 days apart. If the doses are given further than 9 days apart, treatment is considered inadequate, and the series of doses must be restarted. Benzathine penicillin G remains in short supply in the United States, but is the only drug recommended to treat syphilis during pregnancy.

Collaboration between obstetrical and newborn care providers is essential. Those who care for newborns need easy access to birthing parents’ syphilis treatment results. As more health care facilities implement routine syphilis testing at delivery, rapid syphilis testing must be available to avoid prolonging newborn hospital stays.

Pediatricians need to maintain an index of suspicion for congenital syphilis, regardless of maternal history, because symptomatic congenital syphilis can mimic a variety of infectious and noninfectious conditions. Most infected infants look normal at birth. While the majority of cases of congenital syphilis are identified in the newborn period, a 2021 paper published in Pediatrics described 84 infants born between 2014 and 2018 who were diagnosed beyond a month of age.² These represented 2.2% of all infants born with congenital syphilis. Common symptoms included rash, snuffles, and hepatomegaly. Sixty-nine percent of infants who had long bone radiographs obtained had findings consistent with congenital syphilis. Typical imaging findings include periostitis and demineralization of the metaphysis and diaphysis of long bones, although fractures can also occur. Case reports describe infants who presented with fractures and were initially evaluated for nonaccidental trauma.³

Another critical approach is to treat syphilis in people of childbearing age before pregnancy occurs. The CDC recommends syphilis testing for sexually active females 18-44 years of age and living in communities with high rates of syphilis. County-specific specific rates of syphilis rates are available at https://www.cdc.gov/nchhstp/atlas/syphilis/. Point-of-care tests are now available for syphilis and may facilitate timely treatment. 

Additional resources describing syphilis testing and treatment are available from the CDC and the American Academy of Pediatrics.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the AAP’s Committee on Infectious Diseases and one of the lead authors of the AAP’s Recommendations for Prevention and Control of Influenza in Children, 2022-2023. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta, and Gilead. Email her at [email protected]. (Also [email protected].)

References

1. McDonald R et al. Vital Signs: Missed Opportunities for Preventing Congenital Syphilis — United States, 2022. MMWR Morb Mortal Wkly Rep. 2023 Nov 17;72(46):1269-74. doi: 10.15585/mmwr.mm7246e1. 

2. Kimball A et al. Congenital Syphilis Diagnosed Beyond the Neonatal Period in the United States: 2014-2018. Pediatrics. 2021 Sep;148(3):e2020049080. doi: 10.1542/peds.2020-049080. 

3. Jacobs K et al. Congenital Syphilis Misdiagnosed as Suspected Nonaccidental Trauma. Pediatrics. 2019 Oct;144(4):e20191564. doi: 10.1542/peds.2019-1564. 

Delivered at 34 weeks’ gestation, Baby “Alex” had an enlarged liver and spleen on his initial newborn exam, poor tone, and a diffuse, peeling rash. Baby “Aaliyah” was born at term and appeared healthy. By 1 month of age, she was gaining weight poorly and developed copious nasal drainage and a salmon-colored rash on the soles of her feet.

The connection? Both babies were ultimately diagnosed with congenital syphilis. Infections in both babies could have been prevented if their mothers had been tested for syphilis and treated during pregnancy. Alex’s mom had no prenatal care. Aaliyah’s mom had tested negative for syphilis during her first trimester but had not been re-tested, despite sharing with her health care provider that she had a new sexual partner.

Alex and Aaliyah are representative of what Centers for Disease Control and Prevention (CDC) Chief Medical Officer Debra Houry, MD, MPH, calls a “family tragedy.” Cases of congenital syphilis are rising rapidly in the United States, reaching a 30-year high in 2021.¹ Cases increased by 755% between 2012 and 2021, from 335 in 2012 to 2,865 in 2021. In 2022, cases rose again: 3,761 cases of congenital syphilis were reported, including 231 stillbirths and 51 infant deaths. Infants with congenital syphilis are at risk for lifelong complications, including deafness, blindness, and intellectual disability.

Most of these cases were preventable. Congenital syphilis is rare when pregnant people complete adequate treatment at least 30 days before delivery. In 2022, lack of testing or timely testing contributed to 36.8% of congenital syphilis cases. Nearly 40% of birth parents of infected babies received inadequate treatment during pregnancy, and 11.2% received no treatment or treatment was not documented.

Cases of congenital syphilis have increased in all demographic groups and all US Census Bureau regions, but racial and geographic disparities exist, suggesting ongoing barriers to care related to social determinants of health. In 2021, the highest rates of congenital syphilis were among babies born to individuals who were non-Hispanic American Indian or Alaska Native (384 cases per 100,000 live births), non-Hispanic Native Hawaiian or other Pacific Islander (192 cases per 100,000 live births), and non-Hispanic Black or African American (169 cases per 100,000 live births). Six states had rates of congenital syphilis that exceeded 160 cases per 100,000 population, including Arizona, New Mexico, Louisiana, Mississippi, Texas, and Oklahoma. That is more than twice the national rate of 77.9 cases/100,000.
 

Reducing the Risk

To reduce rates of congenital syphilis in all people, barriers to testing must be eliminated. The CDC recommends that all pregnant people be tested early in pregnancy, with repeat testing at 28 weeks and at delivery for those at increased risk for infection based on individual risk factors or residence in a high-prevalence community. Rapid syphilis testing and treatment during pregnancy is recommended in settings such as emergency departments, syringe service programs, prisons/jails, and maternal and child health programs to minimize missed opportunities for care.

While pediatric clinicians rarely care for pregnant patients, they also have an essential role to play in reducing the adverse health outcomes associated with congenital syphilis. No infant should be discharged from the newborn nursery without confirming that the birth parent was tested for syphilis at least once and was treated appropriately if positive. Appropriate treatment during pregnancy is a single dose of benzathine penicillin G for primary, secondary, or early latent syphilis. Late-latent syphilis or syphilis of unknown duration is treated with three doses of benzathine penicillin G spaced 7-9 days apart. If the doses are given further than 9 days apart, treatment is considered inadequate, and the series of doses must be restarted. Benzathine penicillin G remains in short supply in the United States, but is the only drug recommended to treat syphilis during pregnancy.

Collaboration between obstetrical and newborn care providers is essential. Those who care for newborns need easy access to birthing parents’ syphilis treatment results. As more health care facilities implement routine syphilis testing at delivery, rapid syphilis testing must be available to avoid prolonging newborn hospital stays.

Pediatricians need to maintain an index of suspicion for congenital syphilis, regardless of maternal history, because symptomatic congenital syphilis can mimic a variety of infectious and noninfectious conditions. Most infected infants look normal at birth. While the majority of cases of congenital syphilis are identified in the newborn period, a 2021 paper published in Pediatrics described 84 infants born between 2014 and 2018 who were diagnosed beyond a month of age.² These represented 2.2% of all infants born with congenital syphilis. Common symptoms included rash, snuffles, and hepatomegaly. Sixty-nine percent of infants who had long bone radiographs obtained had findings consistent with congenital syphilis. Typical imaging findings include periostitis and demineralization of the metaphysis and diaphysis of long bones, although fractures can also occur. Case reports describe infants who presented with fractures and were initially evaluated for nonaccidental trauma.³

Another critical approach is to treat syphilis in people of childbearing age before pregnancy occurs. The CDC recommends syphilis testing for sexually active females 18-44 years of age and living in communities with high rates of syphilis. County-specific specific rates of syphilis rates are available at https://www.cdc.gov/nchhstp/atlas/syphilis/. Point-of-care tests are now available for syphilis and may facilitate timely treatment. 

Additional resources describing syphilis testing and treatment are available from the CDC and the American Academy of Pediatrics.

Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the AAP’s Committee on Infectious Diseases and one of the lead authors of the AAP’s Recommendations for Prevention and Control of Influenza in Children, 2022-2023. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta, and Gilead. Email her at [email protected]. (Also [email protected].)

References

1. McDonald R et al. Vital Signs: Missed Opportunities for Preventing Congenital Syphilis — United States, 2022. MMWR Morb Mortal Wkly Rep. 2023 Nov 17;72(46):1269-74. doi: 10.15585/mmwr.mm7246e1. 

2. Kimball A et al. Congenital Syphilis Diagnosed Beyond the Neonatal Period in the United States: 2014-2018. Pediatrics. 2021 Sep;148(3):e2020049080. doi: 10.1542/peds.2020-049080. 

3. Jacobs K et al. Congenital Syphilis Misdiagnosed as Suspected Nonaccidental Trauma. Pediatrics. 2019 Oct;144(4):e20191564. doi: 10.1542/peds.2019-1564. 

TOPLINE:

Among women diagnosed with rosacea, the impact of pregnancy on the disease is unpredictable.

METHODOLOGY:

• Few data beyond case reports exist about the course of rosacea during pregnancy.
• Researchers conducted a telephone survey of 39 women with a diagnosis of rosacea in the electronic medical records prior to the onset of pregnancy who had been admitted to Oregon Health & Science University for labor and delivery from June 27, 2015, to June 27, 2020.
• Patient global assessment of clear (0), mild (1), moderate (2), or severe (3) rosacea was rated across five timepoints: 1-3 months preconception; first, second, and third trimesters; and 6 weeks postpartum.

TAKEAWAY:

• The mean age of the survey participants was 35.5 years, the mean gestational age at delivery was 39.4 weeks, and most had singleton pregnancies.
• All but one study participant (97.4%) reported symptoms of erythematotelangiectatic rosacea, while 26 (67%) reported symptoms of papulopustular rosacea.
• Nearly half of the participants (19, 48.7%) said their rosacea worsened during pregnancy, 13 (33.3%) reported no change in rosacea severity during pregnancy, and 7 (17.9%) reported that their rosacea improved during pregnancy.
• Before conceiving, the mean rosacea severity score among participants was mild (1.10; 95% CI, 0.92-1.29) and did not change significantly over time, a reflection of individual variations. In addition, 83.3% of participants did not use prescription rosacea treatments prior to pregnancy, and 89.6% did not use them during pregnancy.

IN PRACTICE:

“Rosacea, like acne, lacks a predictable group effect, and instead, each individual may have a different response to the physiologic changes of pregnancy,” the authors concluded.

SOURCE:

Genevieve Benedetti, MD, MPP, of the Department of Dermatology at Oregon Health & Science University, Portland, Oregon, led the research, published as a research letter in the International Journal of Women’s Dermatology.

LIMITATIONS:

The small sample size, single-center design, and overall prevalence of mild disease limit the ability to detect change.

DISCLOSURES:

The researchers reported having no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Among women diagnosed with rosacea, the impact of pregnancy on the disease is unpredictable.

METHODOLOGY:

• Few data beyond case reports exist about the course of rosacea during pregnancy.
• Researchers conducted a telephone survey of 39 women with a diagnosis of rosacea in the electronic medical records prior to the onset of pregnancy who had been admitted to Oregon Health & Science University for labor and delivery from June 27, 2015, to June 27, 2020.
• Patient global assessment of clear (0), mild (1), moderate (2), or severe (3) rosacea was rated across five timepoints: 1-3 months preconception; first, second, and third trimesters; and 6 weeks postpartum.

TAKEAWAY:

• The mean age of the survey participants was 35.5 years, the mean gestational age at delivery was 39.4 weeks, and most had singleton pregnancies.
• All but one study participant (97.4%) reported symptoms of erythematotelangiectatic rosacea, while 26 (67%) reported symptoms of papulopustular rosacea.
• Nearly half of the participants (19, 48.7%) said their rosacea worsened during pregnancy, 13 (33.3%) reported no change in rosacea severity during pregnancy, and 7 (17.9%) reported that their rosacea improved during pregnancy.
• Before conceiving, the mean rosacea severity score among participants was mild (1.10; 95% CI, 0.92-1.29) and did not change significantly over time, a reflection of individual variations. In addition, 83.3% of participants did not use prescription rosacea treatments prior to pregnancy, and 89.6% did not use them during pregnancy.

IN PRACTICE:

“Rosacea, like acne, lacks a predictable group effect, and instead, each individual may have a different response to the physiologic changes of pregnancy,” the authors concluded.

SOURCE:

Genevieve Benedetti, MD, MPP, of the Department of Dermatology at Oregon Health & Science University, Portland, Oregon, led the research, published as a research letter in the International Journal of Women’s Dermatology.

LIMITATIONS:

The small sample size, single-center design, and overall prevalence of mild disease limit the ability to detect change.

DISCLOSURES:

The researchers reported having no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Among women diagnosed with rosacea, the impact of pregnancy on the disease is unpredictable.

METHODOLOGY:

• Few data beyond case reports exist about the course of rosacea during pregnancy.
• Researchers conducted a telephone survey of 39 women with a diagnosis of rosacea in the electronic medical records prior to the onset of pregnancy who had been admitted to Oregon Health & Science University for labor and delivery from June 27, 2015, to June 27, 2020.
• Patient global assessment of clear (0), mild (1), moderate (2), or severe (3) rosacea was rated across five timepoints: 1-3 months preconception; first, second, and third trimesters; and 6 weeks postpartum.

TAKEAWAY:

• The mean age of the survey participants was 35.5 years, the mean gestational age at delivery was 39.4 weeks, and most had singleton pregnancies.
• All but one study participant (97.4%) reported symptoms of erythematotelangiectatic rosacea, while 26 (67%) reported symptoms of papulopustular rosacea.
• Nearly half of the participants (19, 48.7%) said their rosacea worsened during pregnancy, 13 (33.3%) reported no change in rosacea severity during pregnancy, and 7 (17.9%) reported that their rosacea improved during pregnancy.
• Before conceiving, the mean rosacea severity score among participants was mild (1.10; 95% CI, 0.92-1.29) and did not change significantly over time, a reflection of individual variations. In addition, 83.3% of participants did not use prescription rosacea treatments prior to pregnancy, and 89.6% did not use them during pregnancy.

IN PRACTICE:

“Rosacea, like acne, lacks a predictable group effect, and instead, each individual may have a different response to the physiologic changes of pregnancy,” the authors concluded.

SOURCE:

Genevieve Benedetti, MD, MPP, of the Department of Dermatology at Oregon Health & Science University, Portland, Oregon, led the research, published as a research letter in the International Journal of Women’s Dermatology.

LIMITATIONS:

The small sample size, single-center design, and overall prevalence of mild disease limit the ability to detect change.

DISCLOSURES:

The researchers reported having no disclosures.

A version of this article appeared on Medscape.com.

The past year has been a challenging time for many, both at the local level and globally, with divisive undercurrents across many communities. Many times, the end of the year is an opportunity for reflection. As I reflect on the state of perinatal psychiatry in the new year, I see several evolving issues that I’d like to share in this first column of 2024.

In 2023, the American College of Obstetricians and Gynecologists published new recommendations meant to enhance the well-being of pregnant and postpartum women and families. A main message from discussion papers borne out of these recommendations was that as a field, we should be doing more than identifying perinatal illness. We should be screening women at risk for postpartum psychiatric illness and see that those suffering from posttraumatic stress disorder (PTSD) have access to care and “wrap-around services” from clinicians with varying expertise.

Screening is a primary way we identify patients at risk for psychiatric illness and also those who are suffering at the time of a screen. One problem I see in the near future is our disparate collection and management of data. When we look closely across health care systems, it’s not clear how screening data are captured, let alone managed. What is being done in one hospital system may be very different from what is being done elsewhere. Some clinicians are adopting digital platforms to identify those with postpartum depression, while others are practicing as they always have, either through a paper screening process or with queries as part of a clinical encounter.

Given this amalgam of methods for collecting and storing information, there does not appear to be a systematic way clinicians and researchers are recording whether women are meeting criteria for significant depressive symptoms or frank postpartum psychiatric illness. It is clear a more cohesive method for collection and management is needed to optimize the likelihood that next steps can be taken to get patients the care they need.

However, screening is only one part of the story. Certainly, in our own center, one of our greatest interests, both clinically and on the research side, is what happens after screening. Through our center’s initiation of the Screening and Treatment Enhancement for Postpartum Depression (STEPS for PPD) project funded by the Marriott Foundation, we are evaluating the outcomes of women who are screened at 6 weeks postpartum with significant depressive symptoms, and who are then given an opportunity to engage with a perinatal social worker who can assist with direct psychotherapy, arranging for referrals, and navigating care for a new mother.

What we are learning as we enroll women through the initial stages of STEPS for PPD is that screening and identifying women who likely suffer from PPD simply is not enough. In fact, once identified with a depression screening tool, women who are suffering from postpartum depression can be very challenging to engage clinically. What I am learning decades after starting to work with perinatal patients is that even with a screening system and effective tools for treatment of PPD, optimizing engagement with these depressed women seems a critical and understudied step on the road to optimizing positive clinical outcomes.

A recent study published in the Journal of Women’s Health explored gaps in care for perinatal depression and found that patients without a history of psychiatric illness prior to pregnancy were less likely to be screened for depression and 80% less likely to receive care if they developed depression compared with women with a previous history of psychiatric illness (J Womens Health (Larchmt). 2023 Oct;32[10]:1111-9).

That history may help women navigate to care, while women for whom psychiatric illness is a new experience may be less likely to engage, be referred for care, and receive appropriate treatment. The study indicates that, as a field, we must strive to ensure universal screening for depression in perinatal populations.

While we have always been particularly interested in populations of patients at highest risk for PPD, helping women at risk for PPD in the general population without a history of psychiatric illness is a large public health issue and will be an even larger undertaking. As women’s mental health is gaining more appropriate focus, both at the local level and even in the recent White House Initiative on Women’s Health Research, the focus has been on screening and developing new treatments.

We are not lacking in pharmacologic agents nor nonpharmacologic options as treatments for women experiencing PPD. Newer alternative treatments are being explored, such as transcranial magnetic stimulation (TMS) and even psychedelics as a potential therapy for PPD. But perhaps what we’ve learned in 2023 and as we move into a new year, is that the problem of tackling PPD is not only about having the right tools, but is about helping women navigate to the care that they need.

The COVID-19 pandemic brought with it an explosion of telehealth options that have enhanced the odds women can find support during such a challenging time; as society has returned to some semblance of normal, nearly all support groups for postpartum women have remained online.

When we set up Virtual Rounds at the Center for Women’s Mental Health at the beginning of the pandemic, I was struck by the community of colleagues at various stages of their careers dedicated to mitigating the suffering associated with perinatal psychiatric illness. As I’ve often said, it takes a village to care for these patients. We need help from colleagues with varying expertise — from lactation consultants, psychiatrists, psychologists, obstetricians, nurse practitioners, support group leaders, and a host of others — who can help reach these women.

At the end of the day, helping depressed women find resources is a challenge that we have not met in this country. We should be excited that we have so many treatment options to offer patients — whether it be a new first-in-class medication, TMS, or digital apps to ensure patients are receiving effective treatment. But there should also be a focus on reaching women who still need treatment, particularly in underserved communities where resources are sparse or nonexistent. Identifying the path to reaching these women where they are and getting them well should be a top priority in 2024.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. STEPS for PPD is funded by the Marriott Foundation. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

The past year has been a challenging time for many, both at the local level and globally, with divisive undercurrents across many communities. Many times, the end of the year is an opportunity for reflection. As I reflect on the state of perinatal psychiatry in the new year, I see several evolving issues that I’d like to share in this first column of 2024.

In 2023, the American College of Obstetricians and Gynecologists published new recommendations meant to enhance the well-being of pregnant and postpartum women and families. A main message from discussion papers borne out of these recommendations was that as a field, we should be doing more than identifying perinatal illness. We should be screening women at risk for postpartum psychiatric illness and see that those suffering from posttraumatic stress disorder (PTSD) have access to care and “wrap-around services” from clinicians with varying expertise.

Screening is a primary way we identify patients at risk for psychiatric illness and also those who are suffering at the time of a screen. One problem I see in the near future is our disparate collection and management of data. When we look closely across health care systems, it’s not clear how screening data are captured, let alone managed. What is being done in one hospital system may be very different from what is being done elsewhere. Some clinicians are adopting digital platforms to identify those with postpartum depression, while others are practicing as they always have, either through a paper screening process or with queries as part of a clinical encounter.

Given this amalgam of methods for collecting and storing information, there does not appear to be a systematic way clinicians and researchers are recording whether women are meeting criteria for significant depressive symptoms or frank postpartum psychiatric illness. It is clear a more cohesive method for collection and management is needed to optimize the likelihood that next steps can be taken to get patients the care they need.

However, screening is only one part of the story. Certainly, in our own center, one of our greatest interests, both clinically and on the research side, is what happens after screening. Through our center’s initiation of the Screening and Treatment Enhancement for Postpartum Depression (STEPS for PPD) project funded by the Marriott Foundation, we are evaluating the outcomes of women who are screened at 6 weeks postpartum with significant depressive symptoms, and who are then given an opportunity to engage with a perinatal social worker who can assist with direct psychotherapy, arranging for referrals, and navigating care for a new mother.

What we are learning as we enroll women through the initial stages of STEPS for PPD is that screening and identifying women who likely suffer from PPD simply is not enough. In fact, once identified with a depression screening tool, women who are suffering from postpartum depression can be very challenging to engage clinically. What I am learning decades after starting to work with perinatal patients is that even with a screening system and effective tools for treatment of PPD, optimizing engagement with these depressed women seems a critical and understudied step on the road to optimizing positive clinical outcomes.

A recent study published in the Journal of Women’s Health explored gaps in care for perinatal depression and found that patients without a history of psychiatric illness prior to pregnancy were less likely to be screened for depression and 80% less likely to receive care if they developed depression compared with women with a previous history of psychiatric illness (J Womens Health (Larchmt). 2023 Oct;32[10]:1111-9).

That history may help women navigate to care, while women for whom psychiatric illness is a new experience may be less likely to engage, be referred for care, and receive appropriate treatment. The study indicates that, as a field, we must strive to ensure universal screening for depression in perinatal populations.

While we have always been particularly interested in populations of patients at highest risk for PPD, helping women at risk for PPD in the general population without a history of psychiatric illness is a large public health issue and will be an even larger undertaking. As women’s mental health is gaining more appropriate focus, both at the local level and even in the recent White House Initiative on Women’s Health Research, the focus has been on screening and developing new treatments.

We are not lacking in pharmacologic agents nor nonpharmacologic options as treatments for women experiencing PPD. Newer alternative treatments are being explored, such as transcranial magnetic stimulation (TMS) and even psychedelics as a potential therapy for PPD. But perhaps what we’ve learned in 2023 and as we move into a new year, is that the problem of tackling PPD is not only about having the right tools, but is about helping women navigate to the care that they need.

The COVID-19 pandemic brought with it an explosion of telehealth options that have enhanced the odds women can find support during such a challenging time; as society has returned to some semblance of normal, nearly all support groups for postpartum women have remained online.

When we set up Virtual Rounds at the Center for Women’s Mental Health at the beginning of the pandemic, I was struck by the community of colleagues at various stages of their careers dedicated to mitigating the suffering associated with perinatal psychiatric illness. As I’ve often said, it takes a village to care for these patients. We need help from colleagues with varying expertise — from lactation consultants, psychiatrists, psychologists, obstetricians, nurse practitioners, support group leaders, and a host of others — who can help reach these women.

At the end of the day, helping depressed women find resources is a challenge that we have not met in this country. We should be excited that we have so many treatment options to offer patients — whether it be a new first-in-class medication, TMS, or digital apps to ensure patients are receiving effective treatment. But there should also be a focus on reaching women who still need treatment, particularly in underserved communities where resources are sparse or nonexistent. Identifying the path to reaching these women where they are and getting them well should be a top priority in 2024.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. STEPS for PPD is funded by the Marriott Foundation. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

The past year has been a challenging time for many, both at the local level and globally, with divisive undercurrents across many communities. Many times, the end of the year is an opportunity for reflection. As I reflect on the state of perinatal psychiatry in the new year, I see several evolving issues that I’d like to share in this first column of 2024.

In 2023, the American College of Obstetricians and Gynecologists published new recommendations meant to enhance the well-being of pregnant and postpartum women and families. A main message from discussion papers borne out of these recommendations was that as a field, we should be doing more than identifying perinatal illness. We should be screening women at risk for postpartum psychiatric illness and see that those suffering from posttraumatic stress disorder (PTSD) have access to care and “wrap-around services” from clinicians with varying expertise.

Screening is a primary way we identify patients at risk for psychiatric illness and also those who are suffering at the time of a screen. One problem I see in the near future is our disparate collection and management of data. When we look closely across health care systems, it’s not clear how screening data are captured, let alone managed. What is being done in one hospital system may be very different from what is being done elsewhere. Some clinicians are adopting digital platforms to identify those with postpartum depression, while others are practicing as they always have, either through a paper screening process or with queries as part of a clinical encounter.

Given this amalgam of methods for collecting and storing information, there does not appear to be a systematic way clinicians and researchers are recording whether women are meeting criteria for significant depressive symptoms or frank postpartum psychiatric illness. It is clear a more cohesive method for collection and management is needed to optimize the likelihood that next steps can be taken to get patients the care they need.

However, screening is only one part of the story. Certainly, in our own center, one of our greatest interests, both clinically and on the research side, is what happens after screening. Through our center’s initiation of the Screening and Treatment Enhancement for Postpartum Depression (STEPS for PPD) project funded by the Marriott Foundation, we are evaluating the outcomes of women who are screened at 6 weeks postpartum with significant depressive symptoms, and who are then given an opportunity to engage with a perinatal social worker who can assist with direct psychotherapy, arranging for referrals, and navigating care for a new mother.

What we are learning as we enroll women through the initial stages of STEPS for PPD is that screening and identifying women who likely suffer from PPD simply is not enough. In fact, once identified with a depression screening tool, women who are suffering from postpartum depression can be very challenging to engage clinically. What I am learning decades after starting to work with perinatal patients is that even with a screening system and effective tools for treatment of PPD, optimizing engagement with these depressed women seems a critical and understudied step on the road to optimizing positive clinical outcomes.

A recent study published in the Journal of Women’s Health explored gaps in care for perinatal depression and found that patients without a history of psychiatric illness prior to pregnancy were less likely to be screened for depression and 80% less likely to receive care if they developed depression compared with women with a previous history of psychiatric illness (J Womens Health (Larchmt). 2023 Oct;32[10]:1111-9).

That history may help women navigate to care, while women for whom psychiatric illness is a new experience may be less likely to engage, be referred for care, and receive appropriate treatment. The study indicates that, as a field, we must strive to ensure universal screening for depression in perinatal populations.

While we have always been particularly interested in populations of patients at highest risk for PPD, helping women at risk for PPD in the general population without a history of psychiatric illness is a large public health issue and will be an even larger undertaking. As women’s mental health is gaining more appropriate focus, both at the local level and even in the recent White House Initiative on Women’s Health Research, the focus has been on screening and developing new treatments.

We are not lacking in pharmacologic agents nor nonpharmacologic options as treatments for women experiencing PPD. Newer alternative treatments are being explored, such as transcranial magnetic stimulation (TMS) and even psychedelics as a potential therapy for PPD. But perhaps what we’ve learned in 2023 and as we move into a new year, is that the problem of tackling PPD is not only about having the right tools, but is about helping women navigate to the care that they need.

The COVID-19 pandemic brought with it an explosion of telehealth options that have enhanced the odds women can find support during such a challenging time; as society has returned to some semblance of normal, nearly all support groups for postpartum women have remained online.

When we set up Virtual Rounds at the Center for Women’s Mental Health at the beginning of the pandemic, I was struck by the community of colleagues at various stages of their careers dedicated to mitigating the suffering associated with perinatal psychiatric illness. As I’ve often said, it takes a village to care for these patients. We need help from colleagues with varying expertise — from lactation consultants, psychiatrists, psychologists, obstetricians, nurse practitioners, support group leaders, and a host of others — who can help reach these women.

At the end of the day, helping depressed women find resources is a challenge that we have not met in this country. We should be excited that we have so many treatment options to offer patients — whether it be a new first-in-class medication, TMS, or digital apps to ensure patients are receiving effective treatment. But there should also be a focus on reaching women who still need treatment, particularly in underserved communities where resources are sparse or nonexistent. Identifying the path to reaching these women where they are and getting them well should be a top priority in 2024.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. STEPS for PPD is funded by the Marriott Foundation. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

TOPLINE:

Pregnancy weight gain is lower in women with a history of gastric bypass or sleeve gastrectomy than in those without such a history, especially when the interval between surgery and conception is shorter, new data suggest.

METHODOLOGY:

• Using Swedish national registers, researchers investigated the association of pregnancy weight gain with  history in 12,776 pregnancies — 6388 in women with a history of bariatric surgery and 6388 in women without such a history.
• Pregnancies were propensity score matched to patients’ early-pregnancy body mass index (BMI), prepregnancy diabetes, , smoking status, education, height, country of birth, and delivery year.
• Post-gastric bypass pregnancies were matched to post-sleeve gastrectomy pregnancies using the same matching strategy.
• Time from surgery to conception was also assessed.

TAKEAWAY:

• Across all early-pregnancy BMI strata, women with a history of bariatric surgery had lower pregnancy weight gain than matched controls.
• The magnitude of difference was largest for women with normal weight or overweight early-pregnancy BMI status (adjusted mean difference in z score, −0.33), which then decreased stepwise within the  subclasses (−0.21, −0.16, and −0.08 for obesity classes I, II, and III, respectively).
• Pregnancy weight gain did not differ by surgery type, but lower pregnancy weight gain was associated with a shorter surgery-to-conception interval (particularly within 1 year) or lower surgery-to-conception weight loss.

IN PRACTICE:

“The highest proportion of weight gain below the recommendations was found among women with a normal weight status. Hence, clinical attention to women with history of bariatric surgery and a normal weight status in early pregnancy might be warranted,” the authors advised.

SOURCE:

The study, with the first author Huiling Xu, MD, MSc, Karolinska Institutet, Stockholm, Sweden, was published online in JAMA Network Open.

LIMITATIONS:

Despite rigorous matching, residual confounding was possible. The sample size was limited for some subgroups, possibly affecting statistical power. Although the study provides an overview of pregnancy outcomes within surgery-to-conception interval and pregnancy weight gain z scores, a more in-depth investigation is needed to understand the associations among bariatric surgery, pregnancy weight gain, and pregnancy outcomes.

DISCLOSURES:

Research for this study was supported by the Swedish Research Council for Health, Working Life and Welfare, and the Swedish Research Council. The authors have no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Pregnancy weight gain is lower in women with a history of gastric bypass or sleeve gastrectomy than in those without such a history, especially when the interval between surgery and conception is shorter, new data suggest.

METHODOLOGY:

• Using Swedish national registers, researchers investigated the association of pregnancy weight gain with  history in 12,776 pregnancies — 6388 in women with a history of bariatric surgery and 6388 in women without such a history.
• Pregnancies were propensity score matched to patients’ early-pregnancy body mass index (BMI), prepregnancy diabetes, , smoking status, education, height, country of birth, and delivery year.
• Post-gastric bypass pregnancies were matched to post-sleeve gastrectomy pregnancies using the same matching strategy.
• Time from surgery to conception was also assessed.

TAKEAWAY:

• Across all early-pregnancy BMI strata, women with a history of bariatric surgery had lower pregnancy weight gain than matched controls.
• The magnitude of difference was largest for women with normal weight or overweight early-pregnancy BMI status (adjusted mean difference in z score, −0.33), which then decreased stepwise within the  subclasses (−0.21, −0.16, and −0.08 for obesity classes I, II, and III, respectively).
• Pregnancy weight gain did not differ by surgery type, but lower pregnancy weight gain was associated with a shorter surgery-to-conception interval (particularly within 1 year) or lower surgery-to-conception weight loss.

IN PRACTICE:

“The highest proportion of weight gain below the recommendations was found among women with a normal weight status. Hence, clinical attention to women with history of bariatric surgery and a normal weight status in early pregnancy might be warranted,” the authors advised.

SOURCE:

The study, with the first author Huiling Xu, MD, MSc, Karolinska Institutet, Stockholm, Sweden, was published online in JAMA Network Open.

LIMITATIONS:

Despite rigorous matching, residual confounding was possible. The sample size was limited for some subgroups, possibly affecting statistical power. Although the study provides an overview of pregnancy outcomes within surgery-to-conception interval and pregnancy weight gain z scores, a more in-depth investigation is needed to understand the associations among bariatric surgery, pregnancy weight gain, and pregnancy outcomes.

DISCLOSURES:

Research for this study was supported by the Swedish Research Council for Health, Working Life and Welfare, and the Swedish Research Council. The authors have no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Pregnancy weight gain is lower in women with a history of gastric bypass or sleeve gastrectomy than in those without such a history, especially when the interval between surgery and conception is shorter, new data suggest.

METHODOLOGY:

• Using Swedish national registers, researchers investigated the association of pregnancy weight gain with  history in 12,776 pregnancies — 6388 in women with a history of bariatric surgery and 6388 in women without such a history.
• Pregnancies were propensity score matched to patients’ early-pregnancy body mass index (BMI), prepregnancy diabetes, , smoking status, education, height, country of birth, and delivery year.
• Post-gastric bypass pregnancies were matched to post-sleeve gastrectomy pregnancies using the same matching strategy.
• Time from surgery to conception was also assessed.

TAKEAWAY:

• Across all early-pregnancy BMI strata, women with a history of bariatric surgery had lower pregnancy weight gain than matched controls.
• The magnitude of difference was largest for women with normal weight or overweight early-pregnancy BMI status (adjusted mean difference in z score, −0.33), which then decreased stepwise within the  subclasses (−0.21, −0.16, and −0.08 for obesity classes I, II, and III, respectively).
• Pregnancy weight gain did not differ by surgery type, but lower pregnancy weight gain was associated with a shorter surgery-to-conception interval (particularly within 1 year) or lower surgery-to-conception weight loss.

IN PRACTICE:

“The highest proportion of weight gain below the recommendations was found among women with a normal weight status. Hence, clinical attention to women with history of bariatric surgery and a normal weight status in early pregnancy might be warranted,” the authors advised.

SOURCE:

The study, with the first author Huiling Xu, MD, MSc, Karolinska Institutet, Stockholm, Sweden, was published online in JAMA Network Open.

LIMITATIONS:

Despite rigorous matching, residual confounding was possible. The sample size was limited for some subgroups, possibly affecting statistical power. Although the study provides an overview of pregnancy outcomes within surgery-to-conception interval and pregnancy weight gain z scores, a more in-depth investigation is needed to understand the associations among bariatric surgery, pregnancy weight gain, and pregnancy outcomes.

DISCLOSURES:

Research for this study was supported by the Swedish Research Council for Health, Working Life and Welfare, and the Swedish Research Council. The authors have no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Among adolescent pregnancies in the United States, the prevalence of e-cigarette use during the third trimester increased from 0.8% in 2016 to 4.1% in 2021, according to research published online on December 13 in JAMA Network Open. 

METHODOLOGY:

• Researchers analyzed data from the 2016-2021 Pregnancy Risk Assessment Monitoring System.
• They focused on 10,428 adolescents aged 10-19 years who had had a singleton birth and provided information about their use of e-cigarettes or cigarettes.

TAKEAWAY:

• Whereas the researchers found a roughly fivefold increase in the exclusive use of e-cigarettes, the percentage of patients using only cigarettes decreased from 9.2% in 2017 to 3.2% in 2021.
• The percentage of patients who both vaped and smoked fluctuated between 0.6% and 1.6%.
• The rate of small-for-gestational-age (SGA) births for adolescents who did not smoke or vape (12.9%) did not differ significantly from that among adolescents who exclusively used e-cigarettes (16.8%) or those who used both cigarettes and e-cigarettes (17.6%).
• The researchers found use of cigarettes only was associated with a significantly higher rate of SGA births: 24.6%.

IN PRACTICE:

“Exclusive e-cigarette use and dual use of cigarettes and e-cigarettes did not seem to be statistically significantly associated with SGA birth in our analysis, but this finding should be interpreted with caution given the low prevalence of use and the limited sample size,” the study authors wrote.

SOURCE:

Xiaozhong Wen, MD, PhD, with the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo, was the corresponding author of the study. 

LIMITATIONS:

Participants may have underreported their use of e-cigarettes and cigarettes because of fears of social stigma. The researchers lacked information about vaping in the first and second trimesters, exposure to secondhand smoke, cannabis use, and diet. 

DISCLOSURES:

The research was supported by the National Institute on Drug Abuse; the Food and Drug Administration Center for Tobacco Products; the National Heart, Lung, and Blood Institute; and the American Heart Association. A study coauthor has received grants from Pfizer and personal fees from Johnson & Johnson, the World Health Organization, and the Campaign for Tobacco-Free Kids.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Among adolescent pregnancies in the United States, the prevalence of e-cigarette use during the third trimester increased from 0.8% in 2016 to 4.1% in 2021, according to research published online on December 13 in JAMA Network Open. 

METHODOLOGY:

• Researchers analyzed data from the 2016-2021 Pregnancy Risk Assessment Monitoring System.
• They focused on 10,428 adolescents aged 10-19 years who had had a singleton birth and provided information about their use of e-cigarettes or cigarettes.

TAKEAWAY:

• Whereas the researchers found a roughly fivefold increase in the exclusive use of e-cigarettes, the percentage of patients using only cigarettes decreased from 9.2% in 2017 to 3.2% in 2021.
• The percentage of patients who both vaped and smoked fluctuated between 0.6% and 1.6%.
• The rate of small-for-gestational-age (SGA) births for adolescents who did not smoke or vape (12.9%) did not differ significantly from that among adolescents who exclusively used e-cigarettes (16.8%) or those who used both cigarettes and e-cigarettes (17.6%).
• The researchers found use of cigarettes only was associated with a significantly higher rate of SGA births: 24.6%.

IN PRACTICE:

“Exclusive e-cigarette use and dual use of cigarettes and e-cigarettes did not seem to be statistically significantly associated with SGA birth in our analysis, but this finding should be interpreted with caution given the low prevalence of use and the limited sample size,” the study authors wrote.

SOURCE:

Xiaozhong Wen, MD, PhD, with the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo, was the corresponding author of the study. 

LIMITATIONS:

Participants may have underreported their use of e-cigarettes and cigarettes because of fears of social stigma. The researchers lacked information about vaping in the first and second trimesters, exposure to secondhand smoke, cannabis use, and diet. 

DISCLOSURES:

The research was supported by the National Institute on Drug Abuse; the Food and Drug Administration Center for Tobacco Products; the National Heart, Lung, and Blood Institute; and the American Heart Association. A study coauthor has received grants from Pfizer and personal fees from Johnson & Johnson, the World Health Organization, and the Campaign for Tobacco-Free Kids.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Among adolescent pregnancies in the United States, the prevalence of e-cigarette use during the third trimester increased from 0.8% in 2016 to 4.1% in 2021, according to research published online on December 13 in JAMA Network Open. 

METHODOLOGY:

• Researchers analyzed data from the 2016-2021 Pregnancy Risk Assessment Monitoring System.
• They focused on 10,428 adolescents aged 10-19 years who had had a singleton birth and provided information about their use of e-cigarettes or cigarettes.

TAKEAWAY:

• Whereas the researchers found a roughly fivefold increase in the exclusive use of e-cigarettes, the percentage of patients using only cigarettes decreased from 9.2% in 2017 to 3.2% in 2021.
• The percentage of patients who both vaped and smoked fluctuated between 0.6% and 1.6%.
• The rate of small-for-gestational-age (SGA) births for adolescents who did not smoke or vape (12.9%) did not differ significantly from that among adolescents who exclusively used e-cigarettes (16.8%) or those who used both cigarettes and e-cigarettes (17.6%).
• The researchers found use of cigarettes only was associated with a significantly higher rate of SGA births: 24.6%.

IN PRACTICE:

“Exclusive e-cigarette use and dual use of cigarettes and e-cigarettes did not seem to be statistically significantly associated with SGA birth in our analysis, but this finding should be interpreted with caution given the low prevalence of use and the limited sample size,” the study authors wrote.

SOURCE:

Xiaozhong Wen, MD, PhD, with the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo, was the corresponding author of the study. 

LIMITATIONS:

Participants may have underreported their use of e-cigarettes and cigarettes because of fears of social stigma. The researchers lacked information about vaping in the first and second trimesters, exposure to secondhand smoke, cannabis use, and diet. 

DISCLOSURES:

The research was supported by the National Institute on Drug Abuse; the Food and Drug Administration Center for Tobacco Products; the National Heart, Lung, and Blood Institute; and the American Heart Association. A study coauthor has received grants from Pfizer and personal fees from Johnson & Johnson, the World Health Organization, and the Campaign for Tobacco-Free Kids.
 

A version of this article appeared on Medscape.com.

For the last 30 years, the Center for Women’s Mental Health at Massachusetts General Hospital (MGH) has had as part of its mission, the conveying of accurate information about the reproductive safety of psychiatric medications. There has been a spectrum of medicines developed across psychiatric indications over the last several decades, and many studies over those decades have attempted to delineate the reproductive safety of these agents.

With the development of new antidepressants and second-generation antipsychotics has come an appreciation of the utility of these agents across a wide range of psychiatric disease states and psychiatric symptoms. More and more data demonstrate the efficacy of these medicines for mood and anxiety disorders; these agents are also used for a broad array of symptoms from insomnia, irritability, and symptoms of posttraumatic stress disorder (PTSD) just as examples — even absent formal approval by the US Food and Drug Administration (FDA) for these specific indications. With the growing use of medicines, including new antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors, and second-generation atypical antipsychotics, there has been a greater interest and appreciation of the need to provide women with the best information about reproductive safety of these medicines as well.

When I began working in reproductive psychiatry, the FDA was using the pregnancy labeling categories introduced in 1979. The categories were simple, but also oversimplified in terms of incompletely conveying information about reproductive safety. For instance, category labels of B and C under the old labeling system could be nebulous, containing sparse information (in the case of category B) or animal data and some conflicting human data (in the case of category C) that may not have translated into relevant or easily interpretable safety information for patients and clinicians.

It was on that basis the current Pregnancy and Lactation Labeling (PLLR) Final Rule was published in 2014, which was a shift from categorical labeling to more descriptive labeling, including updated actual information on the package insert about available reproductive safety data, animal data, and data on lactation.

Even following the publication of the PLLR, there has still been an acknowledgment in the field that our assessment tools for postmarketing reproductive safety surveillance are incomplete. A recent 2-day FDA workshop hosted by the Duke-Margolis Center for Health Policy on optimizing the use of postapproval pregnancy safety studies sought to discuss the many questions that still surround this issue. Based on presentations at this workshop, a framework emerged for the future of assessing the reproductive safety of medications, which included an effort to develop the most effective model using tools such as pregnancy registries and harnessing “big data,” whether through electronic health records or large administrative databases from public and private insurers. Together, these various sources of information can provide signals of potential concern, prompting the need for a more rigorous look at the reproductive safety of a medication, or provide reassurance if data fail to indicate the absence of a signal of risk.

FDA’s new commitments under the latest reauthorization of the Prescription Drug User Fee Act (PDUFA VII) include pregnancy-specific postmarketing safety requirements as well as the creation of a framework for how data from pregnancy-specific postmarketing studies can be used. The agency is also conducting demonstration projects, including one for assessing the performance of pregnancy registries for the potential to detect safety signals for medications early in pregnancy. FDA is expanding its Sentinel Initiative to help accomplish these aims, and is implementing an Active Risk Identification and Analysis (ARIA) system to conduct active safety surveillance of medications used during pregnancy.

Pregnancy registries have now been available for decades, and some have been more successful than others across different classes of medicines, with the most rigorous registries including prospective follow-up of women across pregnancies and careful documentation of malformations (at best with original source data and with a blinded dysmorphologist). Still, with all of its rigor, even the best-intentioned efforts with respect to pregnancy registries have limitations. As I mentioned in my testimony during the public comment portion of the workshop, the sheer volume of pregnancy data from administrative databases we now have access to is attractive, but the quality of these data needs to be good enough to ascertain a signal of risk if they are to be used as a basis for reproductive safety determination.

The flip side of using data from large administrative databases is using carefully collected data from pregnancy registries. With a pregnancy registry, accrual of a substantial number of participants can also take a considerable period of time, and initial risk estimates of outcomes can have typically large confidence intervals, which can make it difficult to discern whether a drug is safe for women of reproductive age.

Another key issue is a lack of participation from manufacturers with respect to commitment to collection of high-quality reproductive safety data. History has shown that many medication manufacturers, unless required to have a dedicated registry as part of a postmarketing requirement or commitment, will invest sparse resources to track data on safety of fetal drug exposure. Participation is typically voluntary and varies from company to company unless, as noted previously, there is a postmarketing requirement or commitment tied to the approval of a medication. Just as a recent concrete example, the manufacturer of a new medication recently approved by the FDA for the treatment of postpartum depression (which will include presumably sexually active women well into the first postpartum year) has no plan to support the collection of reproductive safety data on this new medication because it is not required to, based on current FDA guidelines and the absence of a postmarketing requirement to do so.
 

Looking ahead

While the PLLR was a huge step forward in the field from the old pregnancy category system that could misinform women contemplating pregnancy, it also sets the stage for the next iteration of a system that allows us to generate information more quickly about the reproductive safety of medications. In psychiatry, as many as 10% of women use SSRIs during pregnancy. With drugs like atypical antipsychotics being used across disease states — in schizophrenia, bipolar disorder, depression, anxiety, insomnia, and PTSD — and where new classes of medicine are becoming available, like with ketamine or steroids, we need to have a system by which we can more quickly ascertain reproductive safety information. This information informs treatment decisions during a critical life event of deciding to try to become pregnant or during an actual pregnancy.

In my mind, it is reassuring when a registry has even as few as 50-60 cases of fetal exposure without an increase in the risk for malformation, because it can mean we are not seeing a repeat of the past with medications like thalidomide and sodium valproate. However, patients and clinicians are starved for better data. Risk assessment is also different from clinician to clinician and patient to patient. We want to empower patients to make decisions that work for them based on more rapidly accumulating information and help inform their decisions.

To come out on the “other side” of the PLLR, we will need to find a way to accelerate our ability to identify signals of risk or information that is reassuring (or not reassuring) so that clinicians and patients are not left waiting for the next paper to come out, which can be confusing when study results frequently conflict. I believe we have an obligation today to do this better, because the areas of reproductive toxicology and pharmacovigilance are growing incredibly quickly, and clinicians and patients are seeing these volumes of data being published without the ability to integrate that information in a systematic way.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

For the last 30 years, the Center for Women’s Mental Health at Massachusetts General Hospital (MGH) has had as part of its mission, the conveying of accurate information about the reproductive safety of psychiatric medications. There has been a spectrum of medicines developed across psychiatric indications over the last several decades, and many studies over those decades have attempted to delineate the reproductive safety of these agents.

With the development of new antidepressants and second-generation antipsychotics has come an appreciation of the utility of these agents across a wide range of psychiatric disease states and psychiatric symptoms. More and more data demonstrate the efficacy of these medicines for mood and anxiety disorders; these agents are also used for a broad array of symptoms from insomnia, irritability, and symptoms of posttraumatic stress disorder (PTSD) just as examples — even absent formal approval by the US Food and Drug Administration (FDA) for these specific indications. With the growing use of medicines, including new antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors, and second-generation atypical antipsychotics, there has been a greater interest and appreciation of the need to provide women with the best information about reproductive safety of these medicines as well.

When I began working in reproductive psychiatry, the FDA was using the pregnancy labeling categories introduced in 1979. The categories were simple, but also oversimplified in terms of incompletely conveying information about reproductive safety. For instance, category labels of B and C under the old labeling system could be nebulous, containing sparse information (in the case of category B) or animal data and some conflicting human data (in the case of category C) that may not have translated into relevant or easily interpretable safety information for patients and clinicians.

It was on that basis the current Pregnancy and Lactation Labeling (PLLR) Final Rule was published in 2014, which was a shift from categorical labeling to more descriptive labeling, including updated actual information on the package insert about available reproductive safety data, animal data, and data on lactation.

Even following the publication of the PLLR, there has still been an acknowledgment in the field that our assessment tools for postmarketing reproductive safety surveillance are incomplete. A recent 2-day FDA workshop hosted by the Duke-Margolis Center for Health Policy on optimizing the use of postapproval pregnancy safety studies sought to discuss the many questions that still surround this issue. Based on presentations at this workshop, a framework emerged for the future of assessing the reproductive safety of medications, which included an effort to develop the most effective model using tools such as pregnancy registries and harnessing “big data,” whether through electronic health records or large administrative databases from public and private insurers. Together, these various sources of information can provide signals of potential concern, prompting the need for a more rigorous look at the reproductive safety of a medication, or provide reassurance if data fail to indicate the absence of a signal of risk.

FDA’s new commitments under the latest reauthorization of the Prescription Drug User Fee Act (PDUFA VII) include pregnancy-specific postmarketing safety requirements as well as the creation of a framework for how data from pregnancy-specific postmarketing studies can be used. The agency is also conducting demonstration projects, including one for assessing the performance of pregnancy registries for the potential to detect safety signals for medications early in pregnancy. FDA is expanding its Sentinel Initiative to help accomplish these aims, and is implementing an Active Risk Identification and Analysis (ARIA) system to conduct active safety surveillance of medications used during pregnancy.

Pregnancy registries have now been available for decades, and some have been more successful than others across different classes of medicines, with the most rigorous registries including prospective follow-up of women across pregnancies and careful documentation of malformations (at best with original source data and with a blinded dysmorphologist). Still, with all of its rigor, even the best-intentioned efforts with respect to pregnancy registries have limitations. As I mentioned in my testimony during the public comment portion of the workshop, the sheer volume of pregnancy data from administrative databases we now have access to is attractive, but the quality of these data needs to be good enough to ascertain a signal of risk if they are to be used as a basis for reproductive safety determination.

The flip side of using data from large administrative databases is using carefully collected data from pregnancy registries. With a pregnancy registry, accrual of a substantial number of participants can also take a considerable period of time, and initial risk estimates of outcomes can have typically large confidence intervals, which can make it difficult to discern whether a drug is safe for women of reproductive age.

Another key issue is a lack of participation from manufacturers with respect to commitment to collection of high-quality reproductive safety data. History has shown that many medication manufacturers, unless required to have a dedicated registry as part of a postmarketing requirement or commitment, will invest sparse resources to track data on safety of fetal drug exposure. Participation is typically voluntary and varies from company to company unless, as noted previously, there is a postmarketing requirement or commitment tied to the approval of a medication. Just as a recent concrete example, the manufacturer of a new medication recently approved by the FDA for the treatment of postpartum depression (which will include presumably sexually active women well into the first postpartum year) has no plan to support the collection of reproductive safety data on this new medication because it is not required to, based on current FDA guidelines and the absence of a postmarketing requirement to do so.
 

Looking ahead

While the PLLR was a huge step forward in the field from the old pregnancy category system that could misinform women contemplating pregnancy, it also sets the stage for the next iteration of a system that allows us to generate information more quickly about the reproductive safety of medications. In psychiatry, as many as 10% of women use SSRIs during pregnancy. With drugs like atypical antipsychotics being used across disease states — in schizophrenia, bipolar disorder, depression, anxiety, insomnia, and PTSD — and where new classes of medicine are becoming available, like with ketamine or steroids, we need to have a system by which we can more quickly ascertain reproductive safety information. This information informs treatment decisions during a critical life event of deciding to try to become pregnant or during an actual pregnancy.

In my mind, it is reassuring when a registry has even as few as 50-60 cases of fetal exposure without an increase in the risk for malformation, because it can mean we are not seeing a repeat of the past with medications like thalidomide and sodium valproate. However, patients and clinicians are starved for better data. Risk assessment is also different from clinician to clinician and patient to patient. We want to empower patients to make decisions that work for them based on more rapidly accumulating information and help inform their decisions.

To come out on the “other side” of the PLLR, we will need to find a way to accelerate our ability to identify signals of risk or information that is reassuring (or not reassuring) so that clinicians and patients are not left waiting for the next paper to come out, which can be confusing when study results frequently conflict. I believe we have an obligation today to do this better, because the areas of reproductive toxicology and pharmacovigilance are growing incredibly quickly, and clinicians and patients are seeing these volumes of data being published without the ability to integrate that information in a systematic way.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

For the last 30 years, the Center for Women’s Mental Health at Massachusetts General Hospital (MGH) has had as part of its mission, the conveying of accurate information about the reproductive safety of psychiatric medications. There has been a spectrum of medicines developed across psychiatric indications over the last several decades, and many studies over those decades have attempted to delineate the reproductive safety of these agents.

With the development of new antidepressants and second-generation antipsychotics has come an appreciation of the utility of these agents across a wide range of psychiatric disease states and psychiatric symptoms. More and more data demonstrate the efficacy of these medicines for mood and anxiety disorders; these agents are also used for a broad array of symptoms from insomnia, irritability, and symptoms of posttraumatic stress disorder (PTSD) just as examples — even absent formal approval by the US Food and Drug Administration (FDA) for these specific indications. With the growing use of medicines, including new antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors, and second-generation atypical antipsychotics, there has been a greater interest and appreciation of the need to provide women with the best information about reproductive safety of these medicines as well.

When I began working in reproductive psychiatry, the FDA was using the pregnancy labeling categories introduced in 1979. The categories were simple, but also oversimplified in terms of incompletely conveying information about reproductive safety. For instance, category labels of B and C under the old labeling system could be nebulous, containing sparse information (in the case of category B) or animal data and some conflicting human data (in the case of category C) that may not have translated into relevant or easily interpretable safety information for patients and clinicians.

It was on that basis the current Pregnancy and Lactation Labeling (PLLR) Final Rule was published in 2014, which was a shift from categorical labeling to more descriptive labeling, including updated actual information on the package insert about available reproductive safety data, animal data, and data on lactation.

Even following the publication of the PLLR, there has still been an acknowledgment in the field that our assessment tools for postmarketing reproductive safety surveillance are incomplete. A recent 2-day FDA workshop hosted by the Duke-Margolis Center for Health Policy on optimizing the use of postapproval pregnancy safety studies sought to discuss the many questions that still surround this issue. Based on presentations at this workshop, a framework emerged for the future of assessing the reproductive safety of medications, which included an effort to develop the most effective model using tools such as pregnancy registries and harnessing “big data,” whether through electronic health records or large administrative databases from public and private insurers. Together, these various sources of information can provide signals of potential concern, prompting the need for a more rigorous look at the reproductive safety of a medication, or provide reassurance if data fail to indicate the absence of a signal of risk.

FDA’s new commitments under the latest reauthorization of the Prescription Drug User Fee Act (PDUFA VII) include pregnancy-specific postmarketing safety requirements as well as the creation of a framework for how data from pregnancy-specific postmarketing studies can be used. The agency is also conducting demonstration projects, including one for assessing the performance of pregnancy registries for the potential to detect safety signals for medications early in pregnancy. FDA is expanding its Sentinel Initiative to help accomplish these aims, and is implementing an Active Risk Identification and Analysis (ARIA) system to conduct active safety surveillance of medications used during pregnancy.

Pregnancy registries have now been available for decades, and some have been more successful than others across different classes of medicines, with the most rigorous registries including prospective follow-up of women across pregnancies and careful documentation of malformations (at best with original source data and with a blinded dysmorphologist). Still, with all of its rigor, even the best-intentioned efforts with respect to pregnancy registries have limitations. As I mentioned in my testimony during the public comment portion of the workshop, the sheer volume of pregnancy data from administrative databases we now have access to is attractive, but the quality of these data needs to be good enough to ascertain a signal of risk if they are to be used as a basis for reproductive safety determination.

The flip side of using data from large administrative databases is using carefully collected data from pregnancy registries. With a pregnancy registry, accrual of a substantial number of participants can also take a considerable period of time, and initial risk estimates of outcomes can have typically large confidence intervals, which can make it difficult to discern whether a drug is safe for women of reproductive age.

Another key issue is a lack of participation from manufacturers with respect to commitment to collection of high-quality reproductive safety data. History has shown that many medication manufacturers, unless required to have a dedicated registry as part of a postmarketing requirement or commitment, will invest sparse resources to track data on safety of fetal drug exposure. Participation is typically voluntary and varies from company to company unless, as noted previously, there is a postmarketing requirement or commitment tied to the approval of a medication. Just as a recent concrete example, the manufacturer of a new medication recently approved by the FDA for the treatment of postpartum depression (which will include presumably sexually active women well into the first postpartum year) has no plan to support the collection of reproductive safety data on this new medication because it is not required to, based on current FDA guidelines and the absence of a postmarketing requirement to do so.
 

Looking ahead

While the PLLR was a huge step forward in the field from the old pregnancy category system that could misinform women contemplating pregnancy, it also sets the stage for the next iteration of a system that allows us to generate information more quickly about the reproductive safety of medications. In psychiatry, as many as 10% of women use SSRIs during pregnancy. With drugs like atypical antipsychotics being used across disease states — in schizophrenia, bipolar disorder, depression, anxiety, insomnia, and PTSD — and where new classes of medicine are becoming available, like with ketamine or steroids, we need to have a system by which we can more quickly ascertain reproductive safety information. This information informs treatment decisions during a critical life event of deciding to try to become pregnant or during an actual pregnancy.

In my mind, it is reassuring when a registry has even as few as 50-60 cases of fetal exposure without an increase in the risk for malformation, because it can mean we are not seeing a repeat of the past with medications like thalidomide and sodium valproate. However, patients and clinicians are starved for better data. Risk assessment is also different from clinician to clinician and patient to patient. We want to empower patients to make decisions that work for them based on more rapidly accumulating information and help inform their decisions.

To come out on the “other side” of the PLLR, we will need to find a way to accelerate our ability to identify signals of risk or information that is reassuring (or not reassuring) so that clinicians and patients are not left waiting for the next paper to come out, which can be confusing when study results frequently conflict. I believe we have an obligation today to do this better, because the areas of reproductive toxicology and pharmacovigilance are growing incredibly quickly, and clinicians and patients are seeing these volumes of data being published without the ability to integrate that information in a systematic way.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].