Prior Glucagon-like Peptide-1 Receptor Agonist Therapy and Pregnancy, Postpartum, and Child Cardiovascular Outcomes: A Target Trial

The goal of this proposal is to define the optimal interval for women to delay pregnancy after discontinuing long-acting, high-potency glucagon-like peptide-1 receptor agonists (GLP-1 RAs). While GLP-1 RAs are now established therapies for the prevention and management of cardiovascular disease in those with overweight, obesity, or diabetes outside of pregnancy, the impact of the timing of GLP-1 RA discontinuation on pregnancy, postpartum, and offspring outcomes is uncertain. This is critical to understand for several reasons. First, a majority of the >15 million adults currently using GLP-1 RAs are reproductive-aged women with another >30 million are eligible for treatment. Second, trial data in adults demonstrate rapid weight regain and worsening of cardiovascular health (CVH) parameters such as blood pressure and glycemic status following discontinuation of GLP-1 RAs whereby nearly all the CVH benefit from the therapy is lost. Third, worsening CVH in pregnancy, independent of baseline CVH, is associated with worse maternal and offspring outcomes. Therefore, the rapid weight regain and declining CVH expected when GLP-1 RAs are discontinued proximate to the beginning of pregnancy may be concentrated during a critical window for maternal and offspring health and lead to unintended short- and long-term harm with regards to pregnancy, postpartum, and offspring outcomes. Yet, a pre-pregnancy randomized trial of GLP-1 RA discontinuation is not feasible: it would require >10,000 women to be randomized to strategies that require prolonged delays in attempting pregnancy, and thus it is unlikely ever to be performed. There is, thus, a pressing need for high-quality observational data to rigorously and efficiently address this critical evidence gap and inform clinical guidelines and clinician-patient discussions. Therefore, our highly experienced multi-disciplinary team proposes an innovative application of the target trial framework to definitively answer this clinically relevant question. We will combine state-of-the-science methodologic approaches with a large, diverse, real-world dataset that contains granular data on >280,000 reproductive-aged women with repeated clinical and laboratory values, prescription fills, and linked mother-child records. We will conduct two target trials to examine the effect of varying intervals of delaying pregnancy after GLP-1 RA discontinuation in the two key populations eligible for GLP-1 RAs: (1) those with diabetes and (2) those with overweight or obesity but without diabetes. We will specifically examine the effect of delaying pregnancy after GLP-1 RA discontinuation on maternal cardiovascular outcomes in pregnancy (Aim 1) and the postpartum (Aim 2) and offspring CVH predictive of long-term cardiovascular disease risk (Aim 3). We will also use machine learning methods (e.g., SuperLearner models) to enhance the rigor of our study. Completion of these aims will yield novel and significant insights into the optimal timing of pregnancy after discontinuation of GLP-1 RAs to optimize intergenerational CVH. Project Number: 1R01HL180694-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Sadiya Khan (+2 co-PIs) | Institution: NORTHWESTERN UNIVERSITY AT CHICAGO, CHICAGO, IL | Award Amount: $772,581 | Activity Code: R01 | Study Section: Reproductive, Perinatal and Pediatric Health Study Section[RPPH] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18069401