Metabolic differences in the maternal gut microbiome precede the birth of large-for-gestational-age infants: A nested case-control study

BackgroundNeonatal size influences newborn health and is affected by prenatal factors, such as the maternal gut microbiome, which impacts maternal metabolism and fetal growth. MethodsA nested case-control study (1:2 matched) was conducted within the Swedish Maternal Microbiome (SweMaMi, 2017-2021) cohort to investigate the associations between maternal gut microbiome profiles during pregnancy and the risk of delivering large-for-gestational-age (LGA; birth weight >90th percentile) infants compared to appropriate-for-gestational-age (AGA; birth weight 10-90th percentile) infants, with a focus on dietary influence. Shotgun metagenomics enabled taxonomic and functional profiling of fecal samples collected during early (TP1: 10-20 weeks; n = 245:490) and late pregnancy (TP2: 28-32 weeks; n = 157:314). Additionally, we analyzed within-group changes in microbiome diversity from TP1 to TP2 to compare longitudinal patterns between the groups. ResultsAt TP1, microbial species richness was higher in mothers of LGA infants (p = 0.01, 95% CI: 3.26 to 24.9), but this difference was not observed at TP2 (p = 0.30, 95% CI: -7.04 to 22.7). Beta diversity (overall microbial structure) did not differ significantly between groups at either time point. Within-sample diversity, as measured by the Shannon index, showed a significantly greater decline in the LGA group compared to the AGA group (p = 0.03, 95% CI: -0.13 to -0.007), suggesting a loss of microbial diversity specific to the LGA group over time. Evenness also declined in both groups, but the change was significantly more pronounced in the LGA group (p = 0.047, 95% CI: -0.02 to -0.0001. At TP1, the LGA group was functionally enriched in proteolytic pathways, while the AGA, group was associated with short-chain fatty acid (SCFA) production, a connection that remained at TP2. In contrast, the LGA group displayed a shift toward a pathway involved in glucose production. LimitationsReliance on self-reported dietary data, lack of physical activity and pre-pregnancy diet information, and a highly educated study population may limit generalizability. ConclusionEarly pregnancy gut microbiome diversity and function, along with maternal factors, may contribute to the risk of fetal overgrowth. While microbiome diversity converges between cases and controls at a later time-point, this is not enough to mitigate risk.