Mothers with overweight or obesity exposed to semaglutide before and during pregnancy had higher risks for excessive gestational weight gain, gestational diabetes, excessive fetal growth, and cesarean delivery than nonusers, a national database study in Obstetrics and Gynecology found.
Study investigators led by Yang Yu, PhD, MPH, MNS, an assistant professor at the University of Rochester School of Nursing in Rochester, New York, noted that current drug labeling advises discontinuing the drug at least 2 months before attempting to conceive, a warning based on animal research linking use in pregnancy to miscarriage, impaired fetal growth, and congenital anomalies.
However, unintended exposure during pregnancy is likely common, given the growth of GLP-1 use in reproductive-age women because strict contraceptive use is not mandated during treatment and approximately 40% of US pregnancies are unplanned. Additionally, the GLP-1 receptor agonist may have fertility-enhancing effects (as suggested by murine studies) via alleviation of ovarian inflammation and oxidative stress.
“Most previous studies have focused on birth defects in relatively small numbers of exposed pregnancies,” Yu told Medscape Medical News. “We wanted to better understand how semaglutide use before and during pregnancy relates to a broader range of pregnancy outcomes.”
Drawing on electronic medical records and pharmacy dispensing data, her group classified women aged 18-45 years with prepregnancy overweight or obesity who were delivering from January 2022 to January 2026 into three categories. These were: semaglutide users before and into pregnancy, former users before pregnancy only, and nonusers.Exposed women — whether prescribed semaglutide for weight loss or diabetes treatment — were on average 32.7 years of age at delivery and had a mean prepregnancy BMI of 36.9, with 61.3% using semaglutide for diabetes.
Compared with nonusers (n = 2203), pregnancy-exposed users (n = 429) experienced an average 5.12-kg greater gestational weight gain (95% CI, 3.44-6.80), for an adjusted odds ratio (aOR) of 2.88 (95% CI, 2.04-4.05). They also had a higher risk for gestational diabetes (aOR, 1.59; 95% CI, 1.03-2.44), excessive fetal growth (aOR, 1.78; 95% CI, 1.03-3.08), and cesarean delivery (aOR, 3.35; 95% CI, 2.15-5.22).
Similarly, compared with nonusers, former users (n = 801) also had higher risks for excessive gestational weight gain (aOR, 1.98; 95% CI, 1.56-2.51), gestational diabetes (aOR, 1.43; 95% CI, 1.05-1.93), excessive fetal growth (aOR, 1.54; 95% CI, 1.01-2.36), and cesarean delivery (aOR, 3.92; 95% CI, 2.81-5.47) than nonusers.
About a third of those on semaglutide before pregnancy were also exposed to it after conception, with a median exposure of 44 days. No statistically significant differences in weight gain or outcomes were observed between pregnancy-exposed users and former users.
Consistent with earlier studies, the elevated risk for obstetric complications supports the hypothesis that weight gain and adverse metabolic changes after discontinuation rather than gestational exposure may drive obstetric risks. “One important mechanism may be weight rebound after semaglutide discontinuation. Excessive gestational weight gain is a well-established risk factor for a range of adverse pregnancy outcomes, and women who stop semaglutide often experience rapid weight regain,” Yu said.
Research is needed to determine whether these changes contribute to pregnancy risks. “We need to better understand the biological mechanisms linking semaglutide use and discontinuation to pregnancy outcomes, determine whether there are effects on long-term child health, clarify the risk of congenital malformations in larger human studies, and identify the optimal timing for discontinuation before pregnancy,” Yu said. “We are also interested in studying GLP-1 use during the postpartum period to see whether it may help reduce long-term cardiometabolic risk among women who experience pregnancy complications.”
Commenting on the study for Medscape Medical News but not involved in it, Henriette Svarre Nielsen, MD, DMSc, chair and professor of ob/gyn in the Department of Medicine at the University of Copenhagen in Copenhagen, Denmark, noted that two recent real-world studies — one American and one Danish (on which she was the senior author) — point the same way.
“The risks seen around GLP-1 medicines in early pregnancy don’t seem to come from the drug reaching the baby. The American study finds that women who stopped before pregnancy and those who continued it had similar risks, while our Danish national study shows the preterm use signal is underlying diabetes treatment, not weight-loss use,” she said.
What concerns her most as a reproductive medicine specialist is post-discontinuation rebound. “When these medicines are stopped, rapid weight regain and a return of metabolic disturbance may themselves worsen pregnancy outcomes.”
In addition to a mechanistic understanding of the molecular actions in human vs animal early pregnancy, Svarre Nielsen added, “I believe research must now focus on how we manage the transition off treatment before conception. Women who conceive unexpectedly need reassurance, not alarm.”
In the meantime, said Yu, with insufficient evidence to suggest a safer prepregnancy discontinuation interval, women should follow the minimum 2-month cessation recommendation. “This recommendation is based on the drug’s long half-life and the time required for it to be cleared from the body,” she said.
Effective contraception is critical because GLP-1s may boost fertility through weight loss and metabolic improvements. “And gastrointestinal side effects such as vomiting may reduce the effectiveness of oral contraceptives,” said Yu.
In the context of diabetes treatment, decisions should be made in consultation with the healthcare team after carefully weighing the potential risks and benefits.
This study was supported by the Heilbrunn Family Center for Research Nursing at Rockefeller University. Yu disclosed having no conflicts of interest. Study co-author Chao reported having served on advisory boards for Eli Lilly and Company, Novo Nordisk, and Boehringer Ingelheim and receiving grant support from Lilly through the University of Pennsylvania and Johns Hopkins University. Svarre Nielsen reported receiving lecture fees from Novo Nordisk, Ferring Pharmaceuticals, Gedeon Richter, Cook Medical, and IBSA Nordic.
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