Infant Subcortical Brain Volumes Associated with Maternal Obesity and Diabetes: A Large Multicohort Study

ImportanceMaternal diabetes (MD) and maternal obesity (MO) have been robustly established to confer health risks in offspring. Additionally, mounting evidence suggests that these fetal programming effects vary by sex, but whether these factors independently or interactively influence infant brain development remains unclear. ObjectivesTo characterize interactions between MD, MO, and sex on offspring subcortical brain volumes. Design, setting and participantsThis was a cross-sectional study of 1,966 infants from six international cohorts. ExposuresMD and MO Main outcomes and measuresMRI-based subcortical brain volumes (thalamus, amygdala, hippocampus, pallidum, putamen, caudate) were segmented and mixed effects models were used to examine associations, controlling for age at scan, prematurity, birthweight, maternal education, and intracranial volume. Backward elimination regression was used to identify the best fitting model (3-way interaction, 2-way interaction, no interaction) for each region and false discovery rate (FDR) corrections were applied. ResultsOf 1,966 infants, 46% were female (N=909), 9% were exposed to MD (N=172), and 21% were exposed to MO (N=386). MRI scans were performed at (mean{+/-}SD) 25.9{+/-}18.8 days of age. There was a significant interaction between MD, MO and sex in the thalamus (standardized {beta}=-0.32, 95%CI -0.54 to -0.11, FDR corrected P=0.014). In female infants, MD (standardized {beta}=-0.10, 95%CI -0.02 to -0.003, P=0.04) and MO (standardized {beta} =-0.09, 95%CI -0.14 to -0.03, P=0.003) were independently and negatively associated with thalamic volume. In males, a significant interaction between MD and MO was observed (standardized {beta} =-0.20, 95%CI -0.34 to -0.06, P=0.005), with post hoc analysis showing that males with combined exposure to MD and MO had lower thalamic volume compared to those with one or neither exposure (all Ps<0.05). In the hippocampus, an interaction between MO and infant sex was identified (standardized {beta} =0.15, 95%CI 0.05 to 0.26, FDR corrected P=0.015), whereby MO (independent of MD) was associated with lower offspring hippocampal volume in females only (standardized {beta} =-0.12, 95%CI -0.2 to -0.05, P=0.002). Conclusion and relevanceOur results suggest independent, interactive associations of intrauterine exposure to MD and MO with infant subcortical brain volumes, varying by sex. This has implications for future metabolic disorders, among other health risks. SummaryThis study aims to investigate how sex modulates the influence of intrauterine exposure to maternal diabetes (MD) and maternal obesity (MO) on infant subcortical brain volumes. We observed sex-specific associations of gestational exposure to MD or MO with infant brain volumes in regions critical for motivation, emotion, and signal integration. In female offspring, MD and MO were negatively and independently associated with thalamic volume, while MO was negatively associated with hippocampal volume. In males, combined exposure to MD and MO was associated with lower thalamic volume. Sex modulates the influence of prenatal exposure to MD and/or MO on early brain development. This has implications for future metabolic disorders, among other health risks.