Fetal sex is associated with maternal stimulated cytokine production, but not serum cytokine levels, in human pregnancy

- Data examining associations between fetal sex and maternal immune function are lacking.
- Women with female vs male fetuses had greater LPS-stimulated cytokine production.
- Effects were seen in each trimester for IL-6, select timepoints for TNF-α and IL-1β.
- These findings have implications for maternal health (e.g., asthma) during pregnancy.
- Studies of maternal immune function should consider fetal sex, statistically and conceptually.

Some studies suggest that fetal sex plays a role in maternal physiological processes during pregnancy including glycemic control, blood pressure, and cortisol regulation. However, data examining fetal sex-specific differences in maternal immune parameters is lacking. In the current study, serum levels of interleukin(IL)-6, IL-8, and tumor necrosis factor(TNF)-α as well as LPS-stimulated production of IL-6, IL-8, TNF-α, and IL-1β by PBMCs incubated for 24 h were assessed in early, mid, and late pregnancy among 80 women (46 with male and 34 with female fetuses). Linear mixed models showed that women carrying females versus males exhibited greater stimulated production of IL-6 at each timepoint (ps ⩽ 0.03), TNF-α in early pregnancy (p = 0.04), and IL-1β in mid- and late pregnancy (ps ⩽ 0.05). Despite changes in serum levels of IL-8 (p = 0.002) and TNF-α (p < 0.0001) across pregnancy, no differences in any serum cytokines were observed in relation to fetal sex (ps > 0.85). In conclusion, in pregnant women, those carrying female versus male fetuses exhibited greater stimulated cytokine production across pregnancy. Differential inflammatory responses could affect maternal health and fetal development. Fetal sex should be considered as a factor in studies of maternal inflammation. These findings have relevance both clinically and conceptually. For example, maternal asthma is exacerbated among women carrying female versus male fetuses. In addition, data on associations between fetal sex and maternal immune function among women with health conditions (e.g., preeclampsia) and adverse pregnancy outcomes (e.g., preterm birth) would be informative.