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

Abstract

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 24h 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.

Keywords: Cytokines; Fetal sex; Longitudinal; Maternal inflammation; Pregnancy; Stimulated cytokine production.

Fig. 1

LPS-stimulated proinflammatory cytokine production among women during pregnancy based on fetal sex. Numerical values on X-axis refer to early, mid, and late pregnancy. Asterisks signify significant differences by fetal sex at that timepoint. Linear mixed models showed that women carrying females versus males exhibited higher 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 ≤ 0.054).