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.

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The increasing availability of multivariate data within biomedical research calls for appropriate statistical methods that can describe and model complex relationships between variables. The extended ANOVA simultaneous component analysis (ASCA+) framework combines general linear models and principal component analysis (PCA) to decompose and visualize the separate effects of experimental factors. It has recently been demonstrated how linear mixed models can be included in the framework to analyze data from longitudinal experimental designs with repeated measurements (RM-ASCA+). The ALASCA package for R makes the ASCA+ framework accessible for general use and includes multiple methods for validation and visualization. The package is especially useful for longitudinal data and the ability to easily adjust for covariates is an important strength. This paper demonstrates how the ALASCA package can be applied to gain insights into multivariate data from interventional as well as observational designs. Publicly available data sets from four studies are used to demonstrate the methods available (proteomics, metabolomics, and transcriptomics).

Context Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade inflammation and increased incidence of pregnancy complications, but its influence on the maternal immune system in pregnancy is unknown. Longitudinal serum cytokine profiling is a sensitive measure of the complex immunological dynamics of pregnancy. Objective Determine the immunological dynamics of serum cytokines throughout pregnancy in women with PCOS and compare it to pregnancy in women without PCOS. Design and setting A post hoc analysis of longitudinal serum samples from two randomized, placebo-controlled multicenter studies of pregnant women with PCOS and two studies of pregnant women without PCOS. Participants Pregnant women with PCOS (n = 358) and without PCOS (n = 258, controls) provided 1752 serum samples from four time points in pregnancy (weeks 10, 19, 32, 36). Main outcome measures Maternal serum levels of 22 cytokines and C-reactive protein (CRP) at four time points in pregnancy. Results Women with PCOS showed marked immunological changes in serum cytokines throughout pregnancy. Compared to controls, women with PCOS showed higher levels of 17 cytokines and CRP at week 10 of pregnancy and a distinct cytokine development throughout pregnancy. The immunological dynamics in women with PCOS was significantly affected by maternal BMI, smoking and fetal sex. Conclusion Pregnancy in women with PCOS was associated with a strong early mobilization of inflammatory and other serum cytokines persisting throughout pregnancy, indicating a more activated immune status. These findings provide a novel basis for further study of PCOS and pregnancy complications.