Maternal plasma cytokines in early- and mid-gestation of normal human pregnancy and their association with maternal factors

Few studies have assessed longitudinal changes in circulating cytokine levels during normal pregnancy. We have examined the natural history of maternal plasma cytokines from early- to mid-pregnancy in a large, longitudinal cohort. Multiplex flow cytometry was used to measure interleukin (IL)-2, IL-6, IL-12, tumor necrosis factor (TNF)-α, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) in early- (median [IQR]: 8.5 weeks [7.1, 10.0]) and mid-pregnancy (25.0 [24.1, 26.1]) from 1274 Danish women delivering singleton term infants. GM-CSF decreased from early- to mid-pregnancy (median percent change [95% CI]: −51.3% [−59.1%, −41.8%]), while increases were observed in IL-6 (24.3% [4.6%, 43.9%]), IL-12 (21.3% [8.9%, 35.7%]) and IFN-γ (131.7% [100.2%, 171.6%]); IL-2 (−2.8% [−11.5%, 0.0%]) and TNF-α (0% [−5.9%, 25.6%]) remained stable. Positive correlations were found between all cytokines, both in early- and mid-pregnancy (all p < 0.001). Early- and mid-pregnancy levels were rank-correlated for IL-2, IL-12, TNF-α and GM-CSF, but not IL-6 and IFN-γ; these correlations were generally weaker than correlations between different cytokines at a single time point in pregnancy. Women with a pre-pregnancy BMI <18.5 had reduced levels of IFN-γ and GM-CSF compared to women in other BMI categories, while women aged ≥35 years had elevated IL-2, IL-6, TNF-α and IFN-γ. Early-pregnancy levels of TNF-α were higher in women with a prior preterm delivery. Cytokine levels were not associated with gravidity. In conclusion, cytokines were detected in plasma during early- and mid-pregnancy, with IL-6, IL-12, IFN-γ and GM-CSF concentrations varying over pregnancy. Concentrations may depend on BMI, maternal age and prior preterm delivery.