Abstract
Pregnancy implies delicate immunological balance between two individuals, with constant changes and adaptions in response to maternal capacity and fetal demands. We performed cytokine profiling of 1149 longitudinal serum samples from 707 pregnant women to map immunological changes from first trimester to term and beyond. The serum levels of 22 cytokines and C-reactive protein (CRP) followed diverse but characteristic trajectories throughout pregnancy, consistent with staged immunological adaptions. Eotaxin showed a particularly robust decrease throughout pregnancy. A strong surge in cytokine levels developed when pregnancies progressed beyond term and the increase was amplified as labor approached. Maternal obesity, smoking and pregnancies with large fetuses showed sustained increase in distinct cytokines throughout pregnancy. Multiparous women had increased cytokine levels in the first trimester compared to nulliparous women with higher cytokine levels in the third trimester. Fetal sex affected first trimester cytokine levels with increased levels in pregnancies with a female fetus. These findings unravel important immunological dynamics of pregnancy, demonstrate how both maternal and fetal factors influence maternal systemic cytokines, and serve as a comprehensive reference for cytokine profiles in normal pregnancies.
Highlights
Pregnancy is a complex and dynamic process during which the immune system must balance tolerance towards the fetus and maternal immunological integrity [1], and serves as a key player for timing and orchestrating normal gestation [2, 3]
Nine additional women were excluded as outliers by visual inspection of principle component analysis (PCA) scores (Supplementary Figure 2), leaving a final set of 707 women (Supplementary Figure 1)
Maternal pre-pregnancy or first trimester body mass index (BMI) was distributed among the women as 64% normal weight (18.5-24.9 kg/m2), 26% overweight (25.0-29.9 kg/m2) and 10% obesity (≥ 30.0 kg/m2) [46]
Summary
Pregnancy is a complex and dynamic process during which the immune system must balance tolerance towards the fetus and maternal immunological integrity [1], and serves as a key player for timing and orchestrating normal gestation [2, 3]. Studies suggest that the maternal immune system is sensitive to factors such as obesity [4] and fetal sex [5]. While preterm labor has been studied extensively, less is known about late and post-term pregnancy and labor, even though 4-10% of all pregnancies continue beyond term [9]. Late term pregnancy may involve considerable stress for both mother and fetus, but the immunological development has not been characterized. Mapping the staged immunological adaptions throughout pregnancy and the impact of maternal and fetal factors can help mothers and clinicians make informed decisions to reduce the physiological burden of pregnancy and provide the fetus with an optimal outset for life
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