Gestational diabetes mellitus: modifier or mediator in the link between pre-pregnancy overweight/obesity and fetal overgrowth?

Pre-pregnancy overweight/obesity independently increases the risk of gestational diabetes mellitus (GDM) and fetal overgrowth. Furthermore, GDM itself is positively associated with fetal overgrowth. However, awareness of their relationships and the role of GDM remains limited. This study aims to examine the individual and combined effects of pre-pregnancy overweight/obesity and GDM on fetal overgrowth while investigating the underlying mechanisms, with a particular focus on the role of GDM in this association. This retrospective cohort study included pregnant women who delivered at the Affiliated Hospital of Southwest Medical University between January 2021 and February 2022. The exposures were pre-pregnancy overweight/obesity (body mass index [BMI] ≥ 24 kg/m2) and GDM. The participants were stratified into four groups: (1) the control group (neither pre-pregnancy overweight/obese nor GDM); (2) the GDM-only group; (3) the pre-pregnancy overweight/obese-only group; and (4) the combined exposure group. The primary outcome was fetal overgrowth, defined as macrosomia (birth weight ≥ 4000 g) or large for gestational age (LGA, birth weight > 90th percentile). Stratified analyses and additive interaction models were used to assess qualitative and quantitative interactions. A mediation analysis with interaction effects and four-way decomposition was further conducted to evaluate the mediating role of GDM. The cohort included 3733 pregnant women. Both pre-pregnancy overweight/obesity (adjusted odds ratio [aOR] 3.56, 95% confidence interval [CI]: 2.74-4.62) and GDM (aOR 2.05, 95% CI: 1.55-2.70) were independently associated with increased risks of fetal overgrowth. Compared with the control group, the GDM-only (aOR 1.69, 95% CI: 1.15-2.48) and pre-pregnancy overweight/obese-only groups (aOR 3.24, 95% CI: 2.34-4.48) presented elevated risks, with the highest risk in the combined exposure group (aOR 6.47, 95% CI: 4.42-9.48), which exceeded the sum of individual risks. A synergistic interaction was confirmed (synergy index 1.87, 95% CI: 1.13-3.09). Mediation analysis revealed that GDM mediated 7.99% (95% CI: 2.89-13.09) of the total association between maternal pre-pregnancy overweight/obesity and fetal overgrowth, with the pure mediation effect (independent of interaction) accounting for 2.33% (95% CI: 0.60-4.06). Pre-pregnancy overweight/obesity and GDM act as independent and synergistic risk factors for fetal overgrowth, with GDM mediating approximately 8% of adiposity-related risk through combined modification and mediation mechanisms.