The long-term impact of elevated C-reactive protein levels during pregnancy on brain morphology in late childhood

Importance: Animal studies show that Maternal Immune Activation (MIA) may have detrimental effects on fetal brain development. Clinical studies provide evidence for structural brain abnormalities in human neonates following MIA, but no study has investigated the long-term effects of MIA (as measured with biomarkers) on human brain morphology ten years after the exposure. Objective: Our aim was to evaluate the long-term impact of MIA on brain morphology in 10-year-old children, including the possible mediating role of gestational age at birth. Design: We leveraged data from Generation R, a large-scale prospective pregnancy cohort study. Pregnant women were included between 2002 and 2006, and their children were invited to participate in the MRI study between 2013 and 2015. To be included, mother-child dyads had to have data on maternal C-reactive protein levels during gestation and a good quality MRI-scan of the child's brain at age 10 years. Of the 3,992 children scanned, a total of 2,053 10-year-old children were included in this study. Exposure: Maternal C-reactive protein was measured in the first 18 weeks of gestation. For the analyses we used both a continuous approach as well as a categorical approach based on clinical cut-offs to determine if there was a dose-response relationship. Main outcomes and measures: High-resolution MRI brain morphology measures were used as the primary outcome. Gestational age at birth, established using ultrasound, was included as a mediator using a causal mediation analysis. Corrections were made for relevant confounders and multiple comparisons. Biological sex was investigated as moderator. Results: We found a direct association between continuous MIA and lower cerebellar volume. In girls, we demonstrated a negative indirect association between continuous MIA and total brain volume, through the mediator gestational age at birth. We observed no associations with categorical MIA after multiple testing correction. Conclusion and relevance: Our results suggest sex-specific long-term effects in brain morphology after MIA. Categorical analyses suggest that this association might be driven by acute infections or other sources of severe inflammation, which is of clinical relevance given that the COVID-19 pandemic is currently affecting millions of pregnant women worldwide.