Maternal immune gene expression trajectories and dynamic genetic regulation throughout pregnancy

Pregnancy involves profound changes to maternal immunity throughout gestation to simultaneously tolerate the fetus and protect both mother and baby from infection. Dysregulation of this process can lead to pregnancy complications and adverse outcomes. However, how the maternal peripheral immune system adapts throughout an uncomplicated pregnancy remains poorly understood, limiting our ability to identify and interpret alterations associated with pregnancy complications. Here, we longitudinally profiled maternal whole-blood transcriptomes of 1,305 nulliparous women at 12, 20, 28 and 36 weeks of gestation (n=3,776 samples) from the Pregnancy Outcome Prediction Study 2 (POPs2). Differential expression analysis revealed that the maternal immune system underwent its most pronounced remodeling in early pregnancy (between 12 and 20 weeks gestation). Co-expressed gene modules demonstrated immune-dominant programs were highly active in early stages, shifting towards increased cellular and metabolic activity in later pregnancy, reflecting maternal adaptation to increasing physiological demands. Through cis-eQTL mapping we found that genetic regulatory effects increasingly diverged from the non-pregnant state as pregnancy advanced. Colocalising with GWAS revealed putative mechanisms underlying genetic predisposition to pregnancy complications, with 58% of these colocalizations detectable only in the context of pregnancy. Finally, we identified eQTL that exhibit significant interactions with gestational age, implicating dynamic regulation of innate immune and metabolic pathways. These findings show that pregnancy is not only a state of changing gene expression, but also a dynamic regulatory environment that reshapes the effects of genetic variation. By characterizing these adaptations across gestation, this work provides a reference for interpreting maternal immune variation and genetic risk across gestation.