Male fetal sex is associated with low maternal plasma anti-inflammatory cytokine profile in the first trimester of healthy pregnancies

Male fetal sex associates with higher rates of materno-fetal complications. Inflammation and inadequate vasoactive responses are mechanisms implicated in obstetric complications, and alterations in maternal plasma cytokine profile and nitric oxide (NO) metabolites are potential predictive biomarkers. We aimed to assess if these parameters are influenced by fetal sex. A prospective, observational study was carried out in 85 healthy pregnant women with singleton pregnancies in the first trimester of gestation. A blood sample was extracted at the tenth week of gestation. In plasma, we assessed: 1) cytokines (micro-array): pro-inflammatory (IL1α, IL1 β, IL6, TNFα), anti-inflammatory (IL4, IL10, IL13), and chemoattractant (IL8, MCP1, IFNγ), and 2) NO metabolites (liquid chromatography–tandem mass spectrometry and Griess reaction): L-arginine, ADMA, SDMA, nitrates (NOx). Women with a male fetus (n = 50) exhibited, compared with those with a female (n = 35): higher IL1β (OR = 1.09 with 95% CI: 0.97–1.28), and lower IL13 (OR = 0.93 with 95% CI: 0.87–0.99), and higher plasma NOx (OR = 1.14 with 95% CI: 1.03–1.31). Our data suggest that fetal sex influences maternal plasma cytokine profile and NO in early pregnancy. Women with a male fetus may have a worse capacity to counteract an inflammatory response. They may have better vasodilator capacity, but in the presence of an oxidative environment, a higher nitrosative damage may occur. These data reinforce the need to include sex as variable in predictive models.
This research was funded by Universidad Autónoma de Madrid; Multidisciplinary Research Project (CEMU, 2013-10; Spain), Ministerio de Economía y Competitividad (FEM2015-63631-R; Spain) and Ministerio de Ciencia y Universidades (RTI2018-097504-B-I00; Spain), co-founded by FEDER funds.