Maternal inflammation and oxidative stress during pregnancy in relation to early childhood neurodevelopment

Pregnancy is a critical period for fetal brain development. Previous animal studies suggest that maternal immune activation can lead to long-term neurodevelopmental issues in offspring. Inflammation and oxidative stress are key upstream pathways leading to immune activation, and both can be triggered by multiple environmental and social stressors. However, a limited number of epidemiological studies have examined the associations of maternal inflammation and oxidative stress during pregnancy with child neurodevelopment.

We used data from the PROTECT birth cohort in Puerto Rico, including 193 mother-child pairs for inflammation analyses and 247 pairs for oxidative stress analyses, to evaluate associations with early childhood neurodevelopment (ages 1 year to 3 years). Maternal serum concentrations of inflammation biomarkers were measured up to two times during pregnancy (median 18 and 27 weeks gestation), while urinary markers of oxidative stress were measured up to three times (median 18, 23, and 27 weeks). Child neurodevelopment was assessed between ages 1 and 3 years using the Battelle Developmental Inventory-2 Spanish edition (BDI-2), which evaluates adaptive, cognitive, communication, personal-social, and motor domains. Linear mixed-effects models with subject-specific random intercepts were used to account for repeated outcome measurements, while adjusting for potential confounders. Additionally, effect modifications by child sex, age, and gestational timing of biomarker measurements were explored.

Multiple associations were observed between maternal inflammation biomarkers and BDI-2 outcomes. For instance, a doubling in maternal matrix metalloproteinase-1 (MMP1) was associated with a 2.16% lower (95% CI: -3.44, -0.87) adaptive domain score, indicating poorer performance in this domain. We also noted sex-specific findings-generally stronger among males-in both the inflammation and oxidative stress analyses. For example, a doubling of free 8-iso-prostaglandin-F2α (IsoP) concentrations was significantly associated with lower adaptive (-2.96%, 95% CI: -5.43, -0.49) and personal-social (-3.21%, 95% CI: -5.35, -1.07) domain scores among male children, but not among female children. Several gestational timing- and child-age-specific associations were also identified, particularly in the oxidative stress analyses. Overall, the negative association between maternal oxidative stress and BDI-2 tended to be stronger at the third gestational visit (∼27 weeks of gestation) and at older child ages for most observed associations.

These findings suggest that gestational inflammation and oxidative stress may adversely affect early neurodevelopment, with associations potentially modified by gestational timing, child age, and child sex. Future research should prioritize investigating the mediating roles of inflammation and oxidative stress in the relationship between multiple stressors during pregnancy and child neurodevelopment.