Highlight
- Maternal obesity metabolic phenotypes—metabolically healthy obesity (MHO) versus metabolically unhealthy obesity (MUO)—influence gestational weight gain (GWG), gestational diabetes incidence, and infant adiposity.
- Despite intensive behavioral therapy (IBT) aiming to optimize GWG, no differential treatment response was observed between MHO and MUO groups in weight or adverse perinatal outcomes.
- Maternal metabolic health status exerts a stronger effect on adverse outcomes than GWG alone, highlighting the need for early metabolic optimization during pregnancy.
Study Background and Disease Burden
Obesity during pregnancy poses significant risks for adverse maternal and neonatal outcomes, including gestational diabetes mellitus (GDM), large-for-gestational-age infants, and long-term metabolic disease predisposition. Prenatal intensive behavioral therapy (IBT) interventions focusing on controlled gestational weight gain (GWG) have shown variable efficacy in improving clinically relevant outcomes. Notably, this variability may stem from differences in maternal metabolic health phenotypes. Metabolically healthy obesity (MHO) is characterized by obesity without significant metabolic risk factors, whereas metabolically unhealthy obesity (MUO) presents with multiple cardiometabolic risks, including insulin resistance and dyslipidemia. Understanding how these phenotypes affect responses to prenatal interventions is critical to personalized maternal care and improving offspring health.
Study Design
The Lifestyle Interventions for Expectant Moms (LIFE-Moms) consortium comprised seven multicenter randomized controlled trials conducted between November 2012 and December 2017. These trials assessed the effects of behavioral lifestyle interventions, combining diet modification and physical activity, aimed at promoting adherence to National Academy of Medicine GWG guidelines among overweight and obese pregnant individuals.
This secondary analysis, encompassing 640 participants with obesity, categorized women early in pregnancy into MHO and MUO groups based on cardiometabolic risk factor presence. MHO included obese women without additional cardiometabolic disease risk factors, whereas MUO included those with at least two qualifying risk factors. The intervention aimed to reduce excessive weight gain and improve perinatal outcomes. Outcomes assessed included total and guideline-adherent GWG, adverse perinatal events, substrate changes (e.g., lipid profiles), and infant body composition, analyzed on an intent-to-treat basis.
Key Findings
Participants’ mean age was 30.2 years with an average BMI of 35.2 kg/m² at early pregnancy. Comparing MUO (n=172) and MHO (n=228) groups revealed several notable differences:
– GWG: After adjustment for baseline demographics and treatment, MUO had a significantly lower GWG rate (0.30 ± 0.23 kg/wk) compared to MHO (0.41 ± 0.27 kg/wk), a 36.7% reduction (P < .001). Additionally, fewer MUO individuals exceeded GWG guidelines (57.0%) vs MHO individuals (68.0%) (P = .03).
– Adverse Perinatal Outcomes: MUO participants had a markedly higher gestational diabetes incidence (23.8%) relative to MHO (9.8%) (P = .001).
– Infant Outcomes: Infants born to MUO mothers exhibited greater adiposity (12.5% ± 3.9%) compared with those of MHO mothers (11.7% ± 3.7%) (P = .05).
– Substrate Changes: Both groups experienced changes in metabolic substrates, but triglyceride increases were significantly smaller in the intervention MUO group compared to MHO (90.3% vs 81.8%, P = .02), signifying some differential metabolic response.
– Response to Intervention: No other significant differences in weight-related outcomes or adverse perinatal events were observed between MUO and MHO in response to the IBT, suggesting metabolic phenotype did not modify intervention efficacy.
Expert Commentary
These findings underscore the complexity of obesity in pregnancy and the intricate interplay between maternal metabolic health and prenatal intervention outcomes. The higher gestational diabetes rate and increased infant adiposity in the MUO group reflect the profound influence of maternal metabolic dysfunction beyond mere excess weight gain. Interestingly, despite the intervention’s efforts to modulate GWG, the metabolic phenotype did not predict differential responsiveness, implying that IBT focused on behavioral factors alone may be insufficient to counteract underlying metabolic derangements.
Current guidelines emphasize controlling GWG to mitigate risk, but this study suggests that early metabolic profiling could better stratify risk and guide targeted therapeutics. Interventions incorporating early metabolic optimization—potentially including pharmacologic means or more tailored nutritional strategies—may be necessary to improve outcomes in MUO pregnancies. These results parallel broader evidence indicating that cardiometabolic health is a pivotal determinant of pregnancy outcomes in obese populations.
Limitations include the secondary nature of the analysis and potential residual confounders. Additionally, broader metabolic phenotyping may further clarify heterogeneity within obesity subtypes.
Conclusion
The secondary analysis of the LIFE-Moms trial illustrates that the metabolic health phenotype in obese pregnant individuals substantially influences maternal and infant outcomes, particularly gestational diabetes risk and infant adiposity, independent of gestational weight gain. While behavioral interventions prompt adherence to GWG guidelines, they do not differentially benefit MUO versus MHO groups. These insights advocate for early metabolic assessment in pregnancy and the development of interventions beyond lifestyle modifications, aimed at optimizing the maternal metabolic environment to potentially reduce adverse intergenerational metabolic outcomes.
References
1. Flanagan EW, Drews KL, Cade WT, et al. Metabolic Health and Heterogenous Outcomes of Prenatal Interventions: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2025;8(8):e2528264. doi:10.1001/jamanetworkopen.2025.28264
2. National Academy of Medicine. Weight Gain During Pregnancy: Reexamining the Guidelines. The National Academies Press; 2009.
3. Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child. BMJ. 2017;356:j1. doi:10.1136/bmj.j1
4. Black MH, Sacks DA, Xiang AH, Lawrence JM. Clinical outcomes of pregnancies complicated by obesity for infants and mothers. Obstet Gynecol. 2013;122(2 Pt 1):341-348. doi:10.1097/AOG.0b013e318299a2c9