Maternal Hyperglycemia and Adult Offspring Overweight and Obesity: Is Birthweight a Mediator?

Objectives We and others have shown that maternal hyperglycemia during pregnancy in women with insulin-dependent diabetes mellitus (IDDM) influences fetal growth. Less is understood regarding how trimester-specific glycemic patterns, particularly glucose variability, shape offspring obesity risk across the life course and whether this is mediated by birthweight. Leveraging data from the Diabetes in Pregnancy Program Grant (PPG; 1978-1995) and the Transgenerational Effects on Adult Morbidity (TEAM Study; 2017-2023) cohort, we aimed to evaluate whether the association between maternal glycemic control and adult offspring obesity status was mediated in part through infant birthweight. Study Design Maternal glycohemoglobinA1 levels were collected monthly during pregnancy and harmonized across laboratories using standard deviation units (HbA ₁SD). Functional principal component analysis characterized patterns in blood glucose level and variability. TEAM Study participants, adult offspring of PPG women, completed in-person or online assessments (via Zoom) of body anthropometrics. Linear mixed-effects models and generalized estimating equations estimated associations between maternal glycemia and adult offspring outcomes. Classical mediation methods tested whether birthweight mediated observed relationships. Results Consistent with prior findings, third-trimester HbA ₁SD demonstrated the most consistent positive associations with adult offspring body mass index (BMI) outcomes, after adjustment for maternal BMI at last menstrual period, maternal education, gestational weight gain, and sex of offspring (for offspring weight only). There was no evidence that birthweight mediated the relationship between maternal glycemic patterns and adult offspring overweight and obesity; however, birthweight exhibited an independent direct effect on adult offspring BMI in fully adjusted models. Conclusion Infant birthweight was not shown to be a mediator in the association of maternal gestational glycemic control and overweight/obesity in adult offspring of women with IDDM. Although birthweight does not appear to mediate these long-term associations, the findings underscore the importance of trimester-specific evaluation of blood glucose level and variability, motivating further investigation into transgenerational metabolic risk pathways. Key Points It is unlikely that birthweight mediates the association between gestational blood glucose levels and offspring adult obesity. Higher birthweight is an important risk factor for overweight and obesity in the adult offspring. Early gestation hyperglycemia may program obesity in adult offspring of IDDM women.