The impact of female fetal sex on preeclampsia and the maternal immune milieu

Objective: Small studies suggest that fetal sex alters maternal inflammation. We examined the association between fetal sex, preeclampsia and circulating maternal immune markers. Methods: This was a secondary data analysis within a nested case-control study of 216 preeclamptic women and 432 randomly selected normotensive controls from the Collaborative Perinatal Project. All women had singleton, primiparous pregnancies without chronic health conditions. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between female fetal sex and preeclampsia. Outcomes included preeclampsia, preterm preeclampsia (<37 and <34 weeks), and normotensive preterm birth <37 weeks. Associations between female fetal sex and immune markers [interleukin (IL)-6, IL4, IL5, IL12, IL10, IL8, IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-beta, and transforming growth factor-beta] were examined using a statistical method developed for large proportions of censored biomarker data. Models were adjusted for maternal age, race, body mass index, and smoking. Results: Women with early preterm preeclampsia (<34 weeks) had higher odds of having a female fetus (OR_adj. 3.2, 95% CI 1.1–9.6) and women with normotensive preterm birth had lower odds (OR_adj. 0.5, 95% CI 0.3–0.9). Female fetal sex was associated with lower first trimester pro-inflammatory IFNγ and IL-12 but higher second trimester pro-inflammatory IL1β and TNFβ, anti-inflammatory IL4r, and regulatory cytokines IL5 and IL10. Female fetal sex was associated with higher postpartum IL10 in preeclamptic women only. Conclusions: We identified sexual dimorphism in maternal inflammation. Longitudinal studies are needed to determine if fetal sex impacts the maternal immune milieu across pregnancy.