Although the use of glucagon-like peptide 1 (GLP-1) receptor agonists and other antidiabetic medications continues to increase among pregnant women with type 2 diabetes, current evidence suggests no increased risk for birth defects associated with the use of the drugs in early pregnancy compared with insulin use.
"Our findings are significant for clinicians because they provide initial reassurance of safety for infants exposed to these medications during pregnancy," senior author Sonia Hernández-Díaz, MD, a professor of epidemiology at Harvard Chan School, Boston, Massachusetts, told Medscape Medical News.
She notes the caveat that with relatively few women using the antidiabetic drugs over the broader course of the study, "some estimates were imprecise, and further studies are needed to confirm the results."
The study, the largest of its kind to date, was published this month in JAMA Internal Medicine.
Poor glycemic control during pregnancy is a known risk factor for major congenital malformations, and while some guidelines support the consideration of metformin in pregnancy, data are lacking on the safety of other noninsulin antidiabetic medications in pregnancy.
The recommended treatment has therefore remained insulin, which does not cross the placenta and is not considered to pose the risk for birth defects.
"Pregnant women are typically excluded from clinical trials; hence, treatment guidelines do not recommend these [antidiabetic] agents in pregnancy," Hernández-Díaz explained.
Meanwhile, with their rising popularity, antidiabetes drugs are increasingly being used when women have unplanned pregnancies; "therefore, it is critical to generate evidence on the safety these medications," she said.
Sulfonylurea Exposure Associated With the Highest Rate of Malformations
To investigate the safety of periconceptual exposure of the drugs through the first trimester of pregnancy, Hernández-Díaz and her colleagues conducted the observational, population-based cohort study that included data from four Nordic countries from 2009 to 2020, the US MarketScan Database (2012 to 2021) and the Israeli Maccabi Health Services database (2009-2020).
Periconceptional exposure was defined in the study as having had one or more prescription fill of sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, GLP-1 receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors or insulin (active comparator) from 90 days prior to pregnancy until the end of the first trimester.
The rate of periconceptional exposure to the second-line noninsulin antidiabetic medications ranged from 32 per 100,000 pregnancies in the Nordics, 73 per 100,000 in Israel, and 295 per 100,000 in the United States, with increases over the study period that were notably high in the United States.
In a follow-up of the women and live-born infants until 1 year after birth, the standardized prevalence of major congenital malformations was 3.7% in the full population of 3,514,865 infants.
The rate of the malformations was 5.3% among infants born to women with type 2 diabetes (n = 51,826) and was the highest, at 9.7%, among infants exposed to sulfonylureas (n = 1362).
Major congenital malformations for those exposed to GLP-1 receptor agonists occurred in 8.3% (n = 938); SGLT2 inhibitors, 7.0% (n = 335); insulin, 7.8% (n = 5078); and DPP-4 inhibitors, 6.1% (n = 687).
The adjusted risk ratios for the drug exposures, compared with insulin, for major congenital malformations in infants were 1.18 for exposure to sulfonylureas, 0.83 for DPP-4 inhibitors, 0.95 for GLP-1 receptor agonists, and 0.98 for SGLT2 inhibitors.
In other findings, "those treated with insulin or other second-line treatments had a higher risk of major congenital malformations compared with those treated with metformin or not treated pharmacologically; however, the higher risk is most likely due to the underlying indication," Hernández-Díaz said.
However, in further comparison of second-line treatment using GLP-1 with second-line treatment using insulin, no elevated risk for major congenital malformations was observed with either treatment.
"In infants born to women with type 2 diabetes treated with second-line antidiabetic medications, we did not observe a greater risk of major congenital malformations after periconceptional exposure to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors compared with insulin," the authors reported.
"Although reassuring, confirmation from other studies is needed, and continuous monitoring will provide more precise risk estimates in the future as data accumulate."
Commenting on the study, Linda Barbour, MD, professor of medicine and obstetrics and gynecology, Divisions of Endocrinology, Metabolism, and Diabetes and Maternal-Fetal Medicine, and Medical Director of the OB Diabetes Clinic at the University of Colorado School of Medicine, in Denver, Colorado, agreed that the study, although important, has some notable limitations.
Caveats include that "it is not clear what the actual exposure to these agents was during the critical time of organogenesis, which is 5-10 weeks of pregnancy, given the exposures were based on prescription refills from 90 days prior to conception and through the first trimester," she told Medscape Medical News.
Furthermore, as the study only included pregnancies that resulted in a live infant, "it is unknown if any of these agents caused more lethal anomalies or if women decided to terminate the pregnancy based on any malformations," she said.
"But the study does clearly add to the very miniscule literature on this extremely important subject."
Barbour is on the Endocrine Society and European Endocrine Society Guidelines Committee on Diabetes in Pregnancy and noted that the issue of the antidiabetic drugs in pregnancy is among the 10 top pressing questions that are anticipated to be addressed.
Hernández-Díaz reported grants from Takeda to her institution, personal fees from Johnson & Johnson for methods consulting, personal fees from Moderna for methods consulting, and personal fees from UCB for methods consulting outside the submitted work. The other authors' disclosures are detailed in the study.
This study was published online on December 20, 2023, in JAMA Internal Medicine.
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