Metabolic Health and Heterogenous Outcomes of Prenatal Interventions: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Prenatal intensive behavioral therapy (IBT) interventions that promote adequate gestational weight gain (GWG) have had variable and mostly modest effects on clinically relevant maternal and infant outcomes. It is unknown whether different maternal obesity metabolic phenotypes underlie the heterogeneity in response. Objective: To examine GWG, adverse perinatal outcomes, substrate changes, and differential changes in each in a prenatal IBT intervention conducted among pregnant individuals with 2 identified obesity phenotypes. Design, Setting, and Participants: The Lifestyle Interventions for Expectant Moms (LIFE-Moms) trial was a consortium of 7 independent but collaborative multicenter randomized clinical trials that took place between November 1, 2012, and December 31, 2017, and evaluated a prenatal IBT intervention on GWG and perinatal outcomes among women with overweight and obesity. Statistical analysis for the present preplanned secondary analysis was conducted from March 29, 2023, to June 4, 2025. Participants (n = 1150) had a confirmed viable singleton pregnancy and no previous diagnosis of cardiometabolic diseases. This analysis was limited to those with obesity. Participants were classified into 2 groups: obesity with no additional qualifying cardiometabolic disease risk factors (metabolically healthy obesity [MHO]) or obesity with 2 qualifying risk factors (metabolically unhealthy obesity [MUO]) in early pregnancy. Intervention: A behavioral lifestyle intervention incorporating diet and physical activity was delivered to increase adherence to the National Academy of Medicine GWG guidelines. Main Outcomes and Measures: GWG (total and adherence to guidelines), adverse perinatal outcomes, substrate changes, and infant body composition. Analysis was conducted on an intent-to-treat basis. Results: The mean (SD) age of the 640 participants was 30.2 (5.6) years, and the participants presented in early pregnancy with a mean (SD) body mass index of 35.2 (4.1). Participants in the MUO (n = 172) and MHO (n = 228) groups did not differ in response to treatment in weight outcomes, adverse perinatal outcomes, or substrate changes, with the exception that patients in the intervention group experienced smaller mean (SE) triglyceride increases more in the MUO group than in the MHO group (90.3% [7.4%] vs 81.8% [8.3%]; P = .02). After adjustment for maternal baseline demographics and treatment group, individuals with MUO had lower GWG (0.30 [0.23] kg/wk) compared with individuals with MHO (0.41 [0.27] kg/wk; P < .001), a 36.7% difference, and had a lower proportion exceed weight gain guidelines (57.0% [98 of 172] vs 68.0% [155 of 228]; P = .03). Participants with MUO had a higher incidence of gestational diabetes (23.8% [41 of 172] vs 9.8% [22 of 228]; P = .001) and had infants with a higher proportion of adiposity (mean [SD], 12.5% [3.9%] vs 11.7% [3.7%] fat; P = .05) compared with participants with MHO. Conclusions and Relevance: In this preplanned secondary analysis of a randomized clinical trial of an IBT on GWG among pregnant individuals, those with MUO experienced less GWG, had a higher incidence of gestational diabetes, and had infants with a higher proportion of adiposity compared with those who MHO. Data supported that the maternal obesity metabolic phenotype has a greater clinical effect on adverse maternal and infant clinical outcomes compared with GWG alone and did not contribute to a differential response to a lifestyle intervention. Future interventions should identify methods to better optimize the maternal metabolic milieu as early in pregnancy as possible to reduce the intergenerational transmission of metabolic disease. Trial Registration: ClinicalTrials.gov Identifiers: NCT01545934, NCT01616147, NCT01771133, NCT01631747, NCT01768793, NCT01610752, NCT01812694.