Highlights
– Discontinuation of GLP‑1 receptor agonists (GLP‑1RAs) before or in early pregnancy was associated with a mean 3.3‑kg greater gestational weight gain compared with propensity‑matched unexposed pregnancies.
– Exposed pregnancies had higher risks of excess gestational weight gain (65% vs 49%), preterm delivery (17% vs 13%), gestational diabetes (20% vs 15%), and hypertensive disorders of pregnancy (46% vs 36%).
– No differences were observed in birth length, rates of large or small for gestational age (LGA/SGA), or cesarean delivery.
Background
GLP‑1 receptor agonists (GLP‑1RAs) such as liraglutide and semaglutide are increasingly used to treat type 2 diabetes and obesity because of their potent glucose‑lowering, appetite‑suppressing, and weight‑reducing effects. GLP‑1RAs are, however, not recommended during pregnancy owing to limited human safety data and demonstrable fetal risks in some animal studies; professional guidance typically advises discontinuation when pregnancy is planned or confirmed.
For women of reproductive age who stop GLP‑1RA therapy immediately prior to or early in pregnancy, there are plausible clinical concerns: rebound weight gain after discontinuation, worsening insulin resistance, and metabolic shifts that could influence gestational weight gain (GWG) and maternal–fetal outcomes. Yet real‑world data examining pregnancy outcomes after GLP‑1RA discontinuation have been scarce.
Study design
This retrospective cohort study by Maya et al. analyzed 149,790 singleton pregnancies delivered within a single academic health system between June 1, 2016, and March 31, 2025. Exposure was defined as a GLP‑1RA order in the electronic health record between 3 years before conception and up to 90 days after conception. Propensity score matching (1:3) linked each exposed pregnancy with three unexposed pregnancies to balance measured confounders.
The primary outcome was total gestational weight gain. Secondary outcomes included excess gestational weight gain (by established thresholds), birth anthropometrics (birth weight percentile, LGA and SGA), birth length, preterm delivery, cesarean delivery, gestational diabetes mellitus (GDM), and hypertensive disorders of pregnancy (HDP).
Key findings
After matching, the primary analysis cohort included 1,792 pregnancies (448 exposed; 1,344 unexposed). The exposed group had a mean age of 34.0 years and mean prepregnancy BMI of 36.1 kg/m2; 84% had obesity and 23% had preexisting diabetes. Racial/ethnic distribution included 30% Hispanic, 11% non‑Hispanic Black, and 50% non‑Hispanic White.
Gestational weight gain
GLP‑1RA‑exposed pregnancies had greater mean gestational weight gain than matched unexposed pregnancies: 13.7 kg (SD 9.2) versus 10.5 kg (SD 8.0), respectively. The mean difference was 3.3 kg (95% CI, 2.3–4.2; P < .001).
Excess gestational weight gain was more frequent among exposed pregnancies (65%) than unexposed (49%), corresponding to a risk ratio (RR) of 1.32 (95% CI, 1.19–1.47).
Perinatal outcomes
Mean birth weight percentile was modestly higher in the exposed group (58.4% vs 54.8%; difference 3.6 percentage points; 95% CI, 0.2–6.9%). No significant differences were detected for birth length, or the proportion of infants who were LGA or SGA.
Pregnancy complications
Compared with matched unexposed pregnancies, GLP‑1RA‑exposed pregnancies had higher risks of:
- Preterm delivery: 17% vs 13% (RR 1.34; 95% CI, 1.06–1.69).
- Gestational diabetes: 20% vs 15% (RR 1.30; 95% CI, 1.01–1.68).
- Hypertensive disorders of pregnancy: 46% vs 36% (RR 1.29; 95% CI, 1.12–1.49).
There was no observed difference in cesarean delivery rates.
Interpretation and clinical significance
These findings suggest that discontinuation of GLP‑1RAs proximal to conception or during early pregnancy is associated with clinically meaningful increases in gestational weight gain and higher risks of several adverse pregnancy outcomes in a population predominantly affected by obesity.
The magnitude of the effect on GWG—about 3.3 kg on average—may be clinically relevant because even modest excess GWG is associated with higher rates of gestational diabetes, hypertensive disorders, and postpartum weight retention. The observed relative increases in preterm birth, GDM, and HDP (all RRs ≈1.3) are modest but potentially important at a population level given the growing use of GLP‑1RAs among women of reproductive age.
Biological plausibility and potential mechanisms
Several mechanisms could explain these associations. GLP‑1RAs reduce appetite, slow gastric emptying, and improve glycemic control; abrupt cessation can lead to rebound increases in energy intake, weight regain, and worsened glucose metabolism. In pregnancy, increased GWG and worsening insulin resistance may predispose to GDM and hypertensive disorders. Additionally, metabolic instability and systemic inflammation associated with rapid weight change could contribute to preterm birth risk. However, direct causal pathways remain speculative without mechanistic studies.
Strengths
- Large contemporary cohort drawn from an integrated electronic health record system covering nearly a decade.
- Propensity score matching to address measured confounding and balance baseline characteristics.
- Comprehensive assessment of clinically important maternal and neonatal outcomes.
Limitations and sources of bias
Important limitations constrain interpretation:
- Observational design: residual confounding by unmeasured factors (e.g., intention to conceive, timing and duration of GLP‑1RA use, adherence, lifestyle behaviors, provider practices) cannot be excluded.
- Exposure ascertainment relied on medication orders in the EHR; this does not confirm ingestion, dose, or exact timing of discontinuation relative to conception.
- Single academic health system: findings may not generalize to other populations, particularly those with lower obesity prevalence or different access to preconception care.
- Heterogeneity of GLP‑1RA agents and indications (obesity versus diabetes) were not fully dissected; concomitant medications and glycemic control trajectories were not fully detailed in the summary data.
- Potential for detection bias: women previously on GLP‑1RAs may have increased surveillance for metabolic complications.
Implications for clinical practice
For clinicians caring for reproductive‑aged women on GLP‑1RAs, these data underscore the need for proactive reproductive counseling and pregnancy planning:
- Discuss contraception and pregnancy intentions before initiating GLP‑1RA therapy.
- If pregnancy is planned or suspected, counsel about current recommendations to discontinue GLP‑1RAs and discuss potential for weight rebound; plan for close follow‑up.
- When GLP‑1RA is discontinued, institute intensified lifestyle support (nutrition, physical activity), early pregnancy weight monitoring, and targeted interventions to limit excessive GWG.
- Consider earlier metabolic screening (e.g., early pregnancy glucose testing) and closer blood pressure monitoring given increased risks of GDM and HDP observed in this study.
- Coordinate care among primary care, endocrinology, and obstetrics to develop individualized transition plans for glucose and weight management where appropriate.
There is no evidence to suggest restarting GLP‑1RAs during pregnancy; current labels and guidance recommend avoiding these agents while pregnant.
Research priorities
Key gaps that warrant further study include:
- Prospective studies to quantify timing and magnitude of weight rebound after GLP‑1RA discontinuation and to link these dynamics with pregnancy outcomes.
- Registry‑based surveillance to capture periconception exposures, agent‑specific effects (e.g., semaglutide vs liraglutide), dose‑response relationships, and breastfeeding outcomes.
- Mechanistic research into metabolic and inflammatory changes after GLP‑1RA withdrawal in early pregnancy.
- Intervention trials for women discontinuing GLP‑1RAs who are planning pregnancy to test strategies that mitigate weight regain and metabolic risk (behavioral programs, pharmacologic alternatives with safety data in pregnancy where appropriate).
Conclusion
In this large matched cohort dominated by women with obesity, GLP‑1RA exposure defined by an order within 3 years before to 90 days after conception followed by discontinuation was associated with greater gestational weight gain and higher risks of preterm delivery, gestational diabetes, and hypertensive disorders of pregnancy. While causality cannot be established from observational data, these findings have immediate relevance for counseling and managing women of reproductive age who are receiving GLP‑1RA therapy. Clinicians should prioritize preconception counseling, proactive transition plans, and intensified monitoring when GLP‑1RAs are stopped around the time of conception.
Funding and clinicaltrials.gov
Funding and trial registration details are reported in the original publication.
References
1. Maya J, Pant D, Fu Y, et al. Gestational Weight Gain and Pregnancy Outcomes After GLP‑1 Receptor Agonist Discontinuation. JAMA. 2025 Nov 24. doi:10.1001/jama.2025.20951. PMID: 41284263.
