GLP-1 medications in gestational diabetes: safety review of 8 clinical trials

TL;DR

A 2025 systematic review published in Medicine (PMC12499737) analysed 8 clinical trials examining GLP-1 receptor agonist use in gestational diabetes mellitus (GDM). The pooled data found no statistically significant increase in major congenital malformations, perinatal mortality, or serious maternal adverse events. GLP-1 medications showed superior HbA1c and fasting glucose reductions compared to placebo and were comparable to metformin. The review notes significant limitations: trials were small, short, and used earlier-generation GLP-1 medications. Semaglutide and tirzepatide have not been specifically studied in GDM.

Gestational diabetes mellitus affects 14-17% of all pregnancies globally and is rising in line with obesity rates. Poorly controlled GDM increases the risk of macrosomia (large babies), caesarean delivery, neonatal hypoglycaemia, preeclampsia, and later type 2 diabetes in both mother and child. The standard treatment is dietary modification plus insulin when needed, with metformin used in some settings despite its own evidence limitations. As GLP-1 medications have become the dominant treatment for type 2 diabetes and obesity, the question of whether they can or should be used in GDM has become clinically urgent.

The 8 trials reviewed: what they actually tested

It is important to understand what was - and was not - in these 8 trials. The studies reviewed were conducted primarily in the 2015-2022 period and tested liraglutide and exenatide, not semaglutide or tirzepatide. The trials were generally small (ranging from 40 to 280 participants), short in duration (8-16 weeks), and used doses lower than the maximum approved doses for obesity management. They were conducted in women with GDM inadequately controlled on dietary management alone.

This context matters. The safety profile observed in these 8 trials reflects older, lower-dose GLP-1 medications used for short periods in the second and third trimester of pregnancy - the period when organogenesis (major organ development) has already completed. The first trimester, when teratogenic risk is highest, was generally excluded. Extrapolating these safety findings to semaglutide or tirzepatide used at higher doses or in the first trimester would be scientifically unjustified.

Efficacy findings: better glucose control than placebo

Pooled efficacy results across the 8 trials showed:

• HbA1c reduction: GLP-1 medications reduced HbA1c significantly more than placebo (weighted mean difference approximately -0.4 to -0.6%, p less than 0.01)
• Fasting plasma glucose: significantly lower in GLP-1-treated participants vs placebo
• Postprandial glucose: improved on GLP-1 therapy, reflecting the drug class's mechanism of augmenting insulin release in response to meals
• Comparison with metformin: GLP-1 medications produced similar glycaemic control to metformin in the trials that made this comparison directly
• Weight: GLP-1-treated women gained less gestational weight than placebo - a relevant finding given excessive gestational weight gain is itself a GDM risk factor and associated with adverse obstetric outcomes

Safety findings: no increase in congenital malformations

The primary safety concern with any drug used in pregnancy is teratogenicity - causing congenital malformations. Pooled safety data from the 8 trials showed:

• Major congenital malformations: no statistically significant difference between GLP-1 and comparator groups
• Perinatal mortality (stillbirth and neonatal death): no significant difference
• Neonatal hypoglycaemia: no increase on GLP-1 vs placebo (unlike some sulfonylureas, which can cause neonatal hypoglycaemia)
• Macrosomia (birth weight above 4 kg): no significant difference
• Preterm birth: no significant increase
• Maternal serious adverse events: no significant increase vs comparator

The most common adverse events on GLP-1 medications were gastrointestinal - nausea, vomiting, and diarrhoea - consistent with the known side effect profile. These were generally mild to moderate and did not lead to significant trial discontinuation.

Critical limitations: what this review cannot tell us

The review's authors are appropriately cautious about what these findings mean for clinical practice. Key limitations include:

• Sample sizes too small to detect rare adverse events: major congenital malformations occur in approximately 2-4% of pregnancies. To detect a 50% increase in that rate would require thousands of participants. None of these trials had sufficient power for this analysis.
• No first-trimester data: all trials used GLP-1 medications after organogenesis was complete. The most safety-critical period was excluded by design.
• Older drugs at lower doses: liraglutide and exenatide at doses used in GDM trials are pharmacologically different from semaglutide 2.4 mg or tirzepatide 15 mg. No data on high-dose GLP-1 exposure in pregnancy exists.
• Short follow-up: children in these trials were not followed long enough to detect developmental differences that might emerge later in childhood.

The growing population this review addresses

GDM disproportionately affects women with obesity - the same population that is increasingly prescribed GLP-1 medications before pregnancy. As discussed in our companion article on semaglutide in pregnancy, GLP-1 medications may restore fertility in women with PCOS-related anovulation, creating a population of women who conceive while on these drugs. Some will discover their pregnancy in the second trimester while still taking medication prescribed for weight management. This review provides the best available reassurance for cases of inadvertent GLP-1 exposure in mid-to-late pregnancy - while emphasising that the data does not support intentional first-trimester use.

The review also frames the longer-term question: as GDM rates rise and insulin resistance during pregnancy worsens with increasing obesity prevalence, there will be growing pressure to find better GDM pharmacotherapies. GLP-1 medications - with their superior efficacy to metformin and their complementary mechanisms addressing the insulin resistance and beta-cell dysfunction of GDM - are a logical future candidate, pending adequately powered safety trials in the current drug generation.

Nutrition in GDM and GLP-1 therapy: a compounding challenge

Women with gestational diabetes who are on GLP-1 medications face a triple nutritional challenge. Pregnancy increases requirements for folate, iron, calcium, vitamin D, and omega-3 fatty acids. GDM management through dietary restriction further reduces food intake. GLP-1 medication-induced appetite suppression compounds the reduction further. The risk of nutrient deficiency in this population is substantially higher than in non-pregnant GLP-1 users.

Iron deficiency anaemia, vitamin D deficiency, and folate insufficiency are all associated with adverse GDM outcomes - including preterm birth, impaired fetal neurodevelopment, and increased infection risk. While GLP-1 Shield is not a prenatal supplement, the documented nutrient depletion risks of GLP-1 therapy overlap with pregnancy nutritional needs. Women of childbearing age on GLP-1 medications should discuss comprehensive nutritional assessment and supplementation with their prescriber - both before conception and during pregnancy.

Frequently asked questions

Can GLP-1 medications be used to treat gestational diabetes?

GLP-1 medications are not currently approved for gestational diabetes mellitus (GDM). A 2025 systematic review of 8 clinical trials found that older GLP-1 medications (liraglutide, exenatide) used in the second and third trimester of pregnancy showed no significant increase in congenital malformations or perinatal mortality, with better glucose control than placebo. However, the trials were small, used lower-dose older drugs, and did not study semaglutide or tirzepatide. GDM treatment currently relies on dietary modification, insulin, and metformin.

Is it safe to take Ozempic or Wegovy if you have gestational diabetes?

No clinical trials have tested semaglutide (Ozempic, Wegovy) specifically for gestational diabetes. Semaglutide is contraindicated in pregnancy based on animal safety data showing developmental risks at human-comparable doses, and the FDA label requires stopping it before pregnancy. The 2025 systematic review data on GLP-1 safety in GDM relates only to older medications at lower doses in mid-to-late pregnancy and should not be used to justify semaglutide use in pregnancy.

What is gestational diabetes and what are the risks?

Gestational diabetes mellitus (GDM) is a form of diabetes that develops during pregnancy in women who did not have diabetes before. It affects 14-17% of pregnancies globally. Risks include macrosomia (oversized baby), caesarean delivery, neonatal hypoglycaemia, preeclampsia, and an elevated long-term risk of type 2 diabetes in both mother and child. It is strongly associated with obesity and typically resolves after delivery, though women who have had GDM have a 50% lifetime risk of developing type 2 diabetes.

What nutrients are most important for women with GDM on GLP-1 medications?

Women with GDM on any GLP-1-based therapy face compounding nutritional risks from pregnancy requirements, dietary GDM management, and GLP-1-driven appetite suppression. The most critical nutrients to monitor are iron (preventing anaemia and supporting fetal development), folate (neural tube development, critical in early pregnancy), vitamin D (glucose metabolism, immune function, fetal bone development), and calcium. B12 deficiency risk from GLP-1 therapy is also relevant given its role in neurological development. Comprehensive nutritional assessment is essential in this population.