GLP-1 exposure in pregnancy does not clearly raise major birth defect risk

Large-scale evidence offers cautious reassurance after inadvertent GLP-1 exposure in pregnancy, but unresolved risks and low-certainty data mean routine use cannot yet be considered safe.

Study: Pregnancy outcomes following maternal GLP-1 receptor agonist exposure: a systematic review and meta-analysis. Image Credit: While of My Desk / Shutterstock

Want to read later? Download your PDF copy by clicking here.

Background

As the use of weight-loss and diabetes medications continues to rise worldwide, more women of reproductive age are becoming pregnant while receiving these treatments, often before realizing they are expecting. GLP-1 receptor agonists are increasingly used to treat type 2 diabetes and obesity.

About the Study

The researchers conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, and the study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) prior to data collection.

The electronic search encompassed a number of databases, including PubMed, MEDLINE, Embase, Web of Science, and Reprotox, covering the period from database inception through January 2026. Additionally, the references of eligible studies and relevant reviews were examined to identify further potentially relevant publications.

Eligible studies were cohort or case-control studies that assessed maternal exposure to GLP-1 receptor agonists from 90 days before conception through the end of pregnancy and included an appropriate unexposed comparator group.

Reviews, editorials, animal studies, and studies based solely on spontaneous pharmacovigilance reports were excluded when pooling data for scientific analyses. Risk of bias was assessed using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool, and methodological quality was evaluated using the Newcastle-Ottawa Scale. The Grading of Recommendations Assessment, Development and Evaluation framework (GRADE) system was applied to assess the certainty of evidence for each outcome. The research also included qualitative assessments of data from case reports, case series, pharmacovigilance analyses, and other studies unsuitable for quantitative pooling.

Study Results

Seven cohort studies that included over 40,000 pregnancies exposed to GLP-1 receptor agonists satisfied the criteria for quantitative assessment. The timing of exposure varied across the studies: two analyzed any exposure during pregnancy, whereas the other five focused on first-trimester exposure.

Studies reporting adjusted analyses had low to moderate risk of bias, whereas those reporting only crude estimates had a serious risk of bias, mainly due to confounding. Overall, the certainty of the evidence for the evaluated outcomes was rated as low or very low due to study limitations and imprecise estimates.

The analysis of any congenital malformations included seven studies with 42,282 exposed pregnancies and 723,892 comparator pregnancies. Maternal exposure to GLP-1 receptor agonists during pregnancy was not associated with a statistically significant increase in the overall risk of congenital disabilities, with an odds ratio (OR) of 1.11 and a 95% confidence interval (CI) of 0.82-1.51.

A sensitivity analysis focused only on four studies reporting adjusted effect estimates, including 793 exposed and 488,871 comparator pregnancies, produced similar findings (OR 1.40; 95% CI, 0.63-3.12).

Three studies comprising 41,984 exposed pregnancies and 136,485 comparator pregnancies found no statistically significant association with cardiac congenital malformations (OR 0.92; 95% CI, 0.67-1.27).

In contrast, two studies, including 41,046 exposed pregnancies and 131,407 comparator pregnancies, identified a statistically significant association with urinary congenital malformations (OR 1.24; 95% CI, 1.05-1.47), although these findings were based solely on unadjusted estimates. The result was largely driven by one large cohort, and neither study reported specific urinary malformation subtypes, limiting causal interpretation.

None of the other pooled adverse pregnancy outcomes reached statistical significance, although several estimates remained imprecise.

Four studies, including 41,225 exposed pregnancies and 232,786 comparator pregnancies, also reported no statistically significant increase in preterm birth (OR 1.17; 95% CI, 0.79-1.72). However, substantial heterogeneity across the studies indicated considerable uncertainty in this estimate. The qualitative review found no consistent, recurrent, or biologically plausible pattern of congenital anomalies across case reports and case series.

Conclusion

The authors concluded that maternal exposure to GLP-1 receptor agonists did not have a significant association with major congenital malformations, stillbirth, spontaneous abortion, small for gestational age, or preterm birth. Although an association with urinary congenital malformations was identified, it was based on limited unadjusted data and may reflect confounding by maternal diabetes or obesity rather than a true treatment effect.

Overall, the findings provide cautious, low-certainty reassurance regarding inadvertent maternal exposure, particularly during early pregnancy, but do not establish that these drugs are safe for routine use throughout pregnancy. Comparator groups and exposure definitions also varied across studies, and prescription records did not always confirm that the medications were taken. Nevertheless, the low or very low certainty of evidence underscores the need for larger population studies with standardized exposure definitions, detailed outcome classification, and comprehensive adjustment for confounding. Further research is needed to strengthen the available evidence on pregnancy safety.

Journal reference:

• Uysal, N., Horoz, E., Gungor, M., Timarci, I., Sozmen, M. K., Karadas, B., & Kaplan, Y. C. (2026). Pregnancy outcomes following maternal GLP-1 receptor agonist exposure: A systematic review and meta-analysis. Scientific Reports. DOI: 10.1038/s41598-026-61582-8, https://www.nature.com/articles/s41598-026-61582-8