What is the association between preconception use of Glucagon-like peptide-1 (GLP-1) receptor agonists in patients without diabetes and the risk of gestational diabetes?

Preconception GLP-1 Receptor Agonist Use and Gestational Diabetes Risk

There is currently no evidence demonstrating that preconception GLP-1 receptor agonist use in patients without diabetes reduces the risk of gestational diabetes mellitus (GDM). While GLP-1 RAs are effective for weight management and metabolic health improvement, their role in preventing GDM remains unproven, and these medications should be discontinued before conception due to insufficient safety data during pregnancy.

Current Evidence Landscape

Lack of Data on GDM Prevention

• No studies have specifically examined whether preconception GLP-1 RA use in non-diabetic patients reduces GDM risk 1
• The available literature focuses primarily on inadvertent pregnancy exposure and safety concerns rather than GDM prevention outcomes 2, 3
• Current research demonstrates that GLP-1 RAs may facilitate weight loss and improve metabolic health prior to pregnancy, but there is insufficient evidence that this translates to improved pregnancy outcomes including reduced GDM rates 1

Safety Considerations During Pregnancy

• GLP-1 RAs are not approved for use during pregnancy and should be discontinued when pregnancy is planned or detected 2, 4
• The most recent large observational study (938 pregnancies) found no significantly increased risk of major congenital malformations with periconceptional GLP-1 RA exposure, though this study was limited to patients with type 2 diabetes and lacked data on maternal glycemic control 2
• A multicenter prospective cohort study of 168 pregnancies with first-trimester GLP-1 RA exposure showed no increased risk of major birth defects compared to reference groups (2.6% vs 2.3% in diabetic controls; adjusted OR 0.98,95% CI 0.16-5.82) 3
• Animal studies have shown concerning findings including decreased fetal growth, skeletal and visceral anomalies, and embryonic death, though human data have not confirmed these patterns 2

Clinical Recommendations for Preconception Care

For Non-Diabetic Patients Considering Pregnancy

• Discontinue GLP-1 RAs before attempting conception due to insufficient safety data and lack of proven benefit for GDM prevention 2, 4
• Focus on evidence-based preconception interventions including:
  • Weight optimization through lifestyle modification (diet and exercise) 5
  • Folic acid supplementation (400 mcg daily, or 4-5 mg for patients with obesity BMI >35) 5
  • Effective contraception until metabolic optimization is achieved 5

For Patients with Diabetes

• Preconception glycemic optimization is critical, with target A1C <6.5% (ideally <6%) to minimize congenital anomalies, preeclampsia, and other complications 5
• Transition from GLP-1 RAs to insulin before conception as insulin is the preferred agent with established safety data 5
• Multidisciplinary preconception care including endocrinology, maternal-fetal medicine, and diabetes education improves outcomes 5

Critical Knowledge Gaps

Areas Requiring Further Research

• No prospective studies exist examining GLP-1 RA use specifically for GDM prevention in non-diabetic patients 1
• Limited data on optimal timing of GLP-1 RA discontinuation before conception 2, 4
• Insufficient evidence regarding effects on fetal growth restriction, embryonic/fetal death, and long-term offspring outcomes 2
• The establishment of pregnancy registries to capture GLP-1 RA exposure data is a high priority 4

Common Pitfalls to Avoid

Contraception Counseling

• All patients of reproductive age taking GLP-1 RAs should use effective contraception to prevent unintended pregnancy 2
• Weight loss from GLP-1 RAs may restore fertility in women with oligomenorrhea from insulin resistance, increasing unplanned pregnancy risk 2
• Consider long-acting reversible contraception for highest efficacy 5

Inadvertent Exposure Management

• If pregnancy occurs during GLP-1 RA use, discontinue immediately upon detection 4
• Current evidence provides some reassurance regarding first-trimester exposure, though patients should be counseled that data remain limited 3
• Close monitoring and referral to maternal-fetal medicine is appropriate 2

Metabolic Optimization Strategy

• For patients with obesity planning pregnancy, prioritize proven interventions (lifestyle modification, bariatric surgery if appropriate) over GLP-1 RAs given the lack of pregnancy outcome data 5, 1
• Weight loss achieved through any method should be maintained through pregnancy planning period with lifestyle measures 5