Glucagon-Like Peptide-1 Receptor Agonists and Pregnancy: Weighing the Benefits and Risks

Abstract

GLP-1 RAs are used extensively in the treatment of T2DM and obesity, not only because of their good effects on glycemic control, but also due to their weight-reducing and cardiovascular protective effects. Despite these benefits, safety concerns have been expressed concerning the use of such medications during pregnancy, especially when the pregnancy is unintentional. Although some women with oligomenorrhea by history have reported pregnancies during GLP-1 RA, there is limited evidence on the safety of periconceptional exposure to GLP-1 RAs. Fetal growth restriction and embryonic anomalies have been reported in some animal studies, but congenital malformations are not evident, or at least not patterned, in human studies. This paper strives to complete a literature review of GLP-1 receptor agonists in pregnancy with a view to safety issues and possible risks alongside suggestions for daily clinical practice.

Introduction

GLP-1 RAs have transformed the management of T2DM and obesity. These drugs, including exenatide, liraglutide, and semaglutide, offer substantial benefits in improving glycemic control, promoting weight loss, and reducing cardiovascular risks. However, with their increasing use, questions about their safety during pregnancy have arisen. Some women who were previously unable to conceive due to metabolic disturbances have reported unplanned pregnancies while on GLP-1 RAs. This article discusses the possible implications of GLP-1 RAs exposed periconceptionally, reviews what is known in animal and human studies, and provides recommendations to clinicians.

Literature Review

Mechanism of Action of GLP-1 RAs

GLP-1 RAs mimic the effects of endogenous GLP-1, enhancing insulin secretion, reducing glucagon levels, slowing gastric emptying, and promoting satiety. These mechanisms contribute to improved glycemic control and significant weight loss, which can have implications for reproductive health in women with metabolic disorders.

GLP-1 RAs and Reproductive Health

Weight loss associated with GLP-1 RAs has been correlated with the resumption of ovulatory cycles in women with obesity-related oligomenorrhea or PCOS. This unexpected return of fertility has led to unintended pregnancies in women who were previously considered subfertile. The increasing use of GLP-1 RAs necessitates a better understanding of their impact on reproductive health and pregnancy outcomes.

Animal Studies on GLP-1 RAs in Pregnancy

Studies on small animals exposed to GLP-1 RAs during pregnancy have reported potential risks, including:

• Decreased fetal growth

• Skeletal and visceral anomalies

• Embryonic and fetal death

While these findings raise concerns, their applicability to human pregnancy remains uncertain due to species-specific physiological differences.

Human Studies and Clinical Data

Human data on GLP-1 RAs in pregnancy are scarce. A recent population-based cohort study involving 938 pregnancies compared periconceptional exposure to GLP-1 RAs and insulin in women with T2DM. The study did not find a significantly increased risk of major congenital anomalies. However, limitations included:

• Lack of maternal glycemic control data

• Insufficient information on diabetic embryopathy

• Limited data on fetal growth restriction or fetal mortality

Several retrospective cohort studies and case series have attempted to assess the impact of GLP-1 RA exposure in early pregnancy, but findings remain inconclusive due to small sample sizes and variability in study design.

Clinical Implications and Recommendations

Counseling Patients on GLP-1 RAs and Pregnancy

Given the limited data on human pregnancy outcomes, clinicians should provide comprehensive counseling to women of reproductive age taking GLP-1 RAs. Key recommendations include:

• Advising contraception to prevent unintended pregnancies

• Discussing alternative treatment options for women planning pregnancy

• Monitoring closely if pregnancy occurs while on GLP-1 RAs

• Assessing glycemic control before discontinuing therapy to prevent maternal hyperglycemia

Alternative Treatment Options

Alternative therapies, such as insulin, metformin, or sulfonylureas, may be preferred for women with T2DM who are planning pregnancy, given their well-established safety profiles in pregnancy. Such alternatives should be considered when weighing the risks and benefits of continuing GLP-1 RAs.

Monitoring and Risk Management

Such patients who get pregnant on GLP-1 RAs need a multidisciplinary approach to monitoring the fetus and the mother. Among them are periodic ultrasounds and growth assessment of the fetus that will facilitate earlier detection of any complication, thus providing adequate opportunity for interventions.

Future Directions and Research Needs

Further studies are needed to clarify the safety profile of GLP-1 RAs in pregnancy. Prospective human studies should evaluate:

• The impact of maternal glycemic control on fetal outcomes

• The risk of fetal growth restriction and embryonic loss

• Long-term effects on offspring development

• The potential need for dosage adjustments during pregnancy

Given the growing use of GLP-1 RAs for both diabetes management and weight loss, establishing a comprehensive risk assessment framework will be essential to guide clinical decision-making.

Conclusion

Indeed, GLP-1 RAs have revolutionized the treatment of T2DM and obesity but remain a thorny issue related to their use in pregnancy. The available human data do not raise a substantial concern for a major risk in congenital anomalies, but, due to the current limitation of study sizes, firm conclusions cannot be drawn. To date, based on the available studies, clinicians can only advise and counsel patients on potential risks associated with the treatment, and recommend contraceptives and alternative therapies before pregnancy. Optimal health outcomes for mother and fetus, while maintaining effective glycemic control, will be ensured through this approach. Continued research studies into the long-term effects of GLP-1 RAs on pregnancy and fetal development will strengthen clinical guidelines and clarify practice recommendations for the affected patients.