Importance: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are contraindicated in pregnancy. Discontinuation of GLP-1RAs proximal to pregnancy could affect gestational weight gain and pregnancy outcomes. Objective: To compare gestational weight gain and pregnancy outcomes with and without exposure to GLP-1RAs before or during early pregnancy. Design, Setting, and Participants: Retrospective cohort study of 149 790 singleton pregnancies delivered between June 1, 2016, and March 31, 2025, within a single academic health system. Exposure: A GLP-1RA order between 3 years before and 90 days after conception, with propensity score matching of each exposed pregnancy to 3 unexposed pregnancies. Main Outcomes and Measures: The primary outcome was gestational weight gain. Secondary outcomes were excess gestational weight gain, large and small for gestational age birth weight, birth weight percentile for gestational age and sex, birth length, preterm delivery, cesarean delivery, gestational diabetes, and hypertensive disorders of pregnancy. Results: Among 149 790 pregnancies during the study period, 1792 (448 exposed and 1344 unexposed) were matched for the primary analysis. Exposed pregnancies had mean maternal age of 34.0 years (SD, 4.7 years) and prepregnancy body mass index of 36.1 (SD, 6.5; calculated as weight in kilograms divided by height in meters squared); 378 of 448 (84%) had obesity and 104 of 448 (23%) had preexisting diabetes; 136 (30%) were Hispanic, 49 (11%) were non-Hispanic Black, and 223 (50%) were non-Hispanic White; and 43 (10%) had public insurance. The GLP-1RA–exposed pregnancies had greater gestational weight gain (mean, 13.7 kg [SD, 9.2]) than propensity score–matched unexposed pregnancies (mean, 10.5 kg [SD, 8.0]), a difference of 3.3 kg (95% CI, 2.3-4.2; P < .001). The GLP-1RA–exposed group had a higher risk of excess gestational weight gain (65% vs 49%; risk ratio [RR], 1.32; 95% CI, 1.19-1.47), greater mean birth weight percentile (58.4% vs 54.8%; difference, 3.6%; 95% CI, 0.2%-6.9%), and higher risk 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), and hypertensive disorders of pregnancy (46% vs 36%; RR, 1.29; 95% CI, 1.12-1.49). There was no difference in birth length, risk of large or small for gestational age birth weight, or cesarean delivery. Conclusions and Relevance: In a cohort composed primarily of women with obesity, GLP-1RA use with subsequent prepregnancy or early pregnancy discontinuation was associated with more gestational weight gain and a higher risk of preterm delivery, gestational diabetes, and hypertensive disorders of pregnancy.

Attention to precision medicine in type 2 diabetes (T2D) has provided two favored approaches to subclassifying affected individuals and parsing heterogeneity apparent in this condition: phenotype-based and genotype-based. Gestational diabetes mellitus (GDM) shares phenotypic characteristics with T2D. However, unlike T2D, GDM emerges in the setting of profound pregnancy-related physiologic changes in glucose metabolism. T2D and GDM also share common genetic architecture, but there are likely to be unique genetic influences on pregnancy glycemic regulation that contribute to GDM. In this Perspective, we describe efforts to decipher heterogeneity in T2D and detail how we and others are applying approaches developed for T2D to the study of heterogeneity in GDM. Emerging results reveal the potential of phenotype- and genotype-based subclassification of GDM to deliver the promise of precision medicine to the obstetric population.

OBJECTIVE: To evaluate changes in insulin physiology in euglycemic pregnancy and gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: Participants underwent oral glucose tolerance tests at ≤15 weeks’ gestation (early pregnancy), 24–32 weeks’ gestation (mid-late pregnancy), and 6–24 weeks postpartum. We evaluated longitudinal changes in insulin secretory response (log Stumvoll first-phase estimate) and insulin sensitivity (log Matsuda index) using linear mixed models. We then evaluated participants who met GDM criteria in early pregnancy (early GDM) and mid-late pregnancy (classic GDM) separately from those without GDM. We derived the pregnancy insulin physiology (PIP) index to quantify β-cell compensation for insulin resistance. RESULTS: Among 166 participants, 21 had early GDM and 24 developed classic GDM. Insulin sensitivity was reduced slightly in early pregnancy (β = −0.20, P < 0.001) and substantially in mid-late pregnancy (β = −0.47, P < 0.001) compared with postpartum. Insulin secretory response (adjusted for insulin sensitivity) was augmented in early pregnancy (β = 0.16, P < 0.001) and mid-late pregnancy (β = 0.16, P = 0.001) compared with postpartum. Compared with postpartum, the PIP index was augmented in early pregnancy (β = 215, P = 0.04) but not mid-late pregnancy (β = 55, P = 0.64). Early GDM was distinguished by a substantial reduction in early pregnancy insulin sensitivity (β = −0.59, P < 0.001) compared with postpartum. Both early and classic GDM lacked evidence of early pregnancy augmentation of insulin secretory response (adjusted for insulin sensitivity) and the PIP index (P > 0.1 vs. postpartum). Early pregnancy PIP index predicted GDM independent of participant characteristics (area under the curve without PIP index 0.70 [95% CI 0.61–0.79], area under the curve with PIP index 0.87 [95% CI 0.80–0.93]). CONCLUSIONS: β-Cell function is enhanced in early pregnancy. Deficient first-trimester β-cell function predicts GDM.

The placenta participates in maternal insulin sensitivity changes during pregnancy; however, mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75-g oral glucose tolerance tests at ∼26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using Illumina EPIC arrays. Using linear regression models to quantify associations at 720,077 cytosine-guanine dinucleotides (CpGs), with adjustment for maternal age, gravidity, smoking, BMI, child sex, and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index (P < 6.94 × 10−8). Among genes annotated to these 188 CpGs, we found enrichment in targets for miRNAs, in histone modifications, and in parent-of-origin DNA methylation including the H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1. Mendelian randomization analyses revealed five loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy.