Changes in Serum Cytokines Throughout Pregnancy in Women With Polycystic Ovary Syndrome

Abstract

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: This work aimed to determine the immunological dynamics of serum cytokines throughout pregnancy in women with PCOS and compare it to pregnancy in women without PCOS.

Methods: A post hoc analysis was conducted of longitudinal serum samples from 2 randomized, placebo-controlled multicenter studies of pregnant women with PCOS and 2 studies of pregnant women without PCOS. Pregnant women with PCOS (n = 358) and without PCOS (n = 258, controls) provided 1752 serum samples from 4 time points in pregnancy (weeks 10, 19, 32, and 36). Main outcome measures included maternal serum levels of 22 cytokines and C-reactive protein (CRP) at 4 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 body mass index, 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.

Trial registration: ClinicalTrials.gov NCT00159536 NCT01587378 NCT00476567.

Keywords: C-reactive protein; PCOS; chemokine; cytokine; multivariate analysis; pregnancy.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.

Development of serum cytokine and CRP concentrations throughout pregnancy in women with PCOS. Cytokines are grouped according to main function. A, Trajectories from generalized additive mixed models displaying the relative development of cytokine and CRP concentrations in maternal serum throughout pregnancy in women with PCOS. Limits for the 3 trimesters are marked vertically with dotted lines. IL-17, G-CSF, GM-CSF, and TNFα are excluded from Fig. 1A because the gestational development could not be robustly modeled. B, Change in maternal log-transformed cytokine (pg/mL) and CRP (μg/mL) levels by trimester from univariate linear mixed models in pregnancies of women with PCOS. P values are adjusted using the Benjamini-Hochberg procedure. Asterisks indicate significant change from the first trimester. *P less than .05; **P less than .01; and ***P less than .001. C, Trajectories from multivariate RM-ASCA+ analyses compressing all cytokine developments by trimester into single variables called principal components (PCs). PC1 and PC2 explain most of the variation in cytokine development. A high PC score indicates higher concentrations of the cytokines with positive loadings and lower concentrations of the cytokines with negative loadings in the loadings score plot and vice versa. The vertical lines represent the error bars. CRP, C-reactive protein; FGF-b, basic fibroblastic growth factor; G-CSF, granulocyte colony-stimulating factor; GM, granulocyte macrophage; IL, interleukin; IP, interferon-γ–induced protein; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; PCOS, polycystic ovary syndrome; PDGF, platelet-derived growth factor; Ra, receptor antagonist; RM-ASCA+, repeated-measures analysis of variance simultaneous component analysis; TNF, tumor necrosis factor.

Figure 2.

Spearman rank correlation coefficients between cytokines within the third trimester in women with PCOS. Log-transformed cytokine values were used. Dark blue indicates a strong positive correlation, dark red indicates a strong negative correlation, and white indicates no correlation. Rho values are displayed in the figure tiles for correlations that remained significant after adjusting for multiple testing using the Benjamini-Hochberg procedure. The cytokines are grouped in bold squares by main function. CRP, C-reactive protein; FGF-b, basic fibroblastic growth factor; G-CSF, granulocyte colony-stimulating factor; GM, granulocyte macrophage; IL, interleukin; IP, interferon-γ–induced protein; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; PCOS, polycystic ovary syndrome; PDGF, platelet-derived growth factor; Ra, receptor antagonist; TNF, tumor necrosis factor.

Figure 3.

Influence of important clinical parameters on the serum cytokine pattern in pregnant women with PCOS by RM-ASCA+ for A, overweight and obese women relative to normal-weight women; B, women with a male compared to female fetus; C, smoking compared to nonsmoking women; and D, multiparous compared to nulliparous women. The first principal component (PC1) from the RM-ASCA+ analysis explains most of the variation of the comparisons, thus only PC1 is shown. Cytokine development in the clinical groups is shown relative to the indicated reference group and must be interpreted in relation to the corresponding reference trajectories in Supplementary Fig. 4. Samples with a high PC1 score have higher concentrations of the cytokines with positive loadings and lower concentrations of the cytokines with negative loadings in the loadings score plot compared to samples with low score values. The vertical lines represent the error bars. CRP, C-reactive protein; FGF-b, basic fibroblastic growth factor; G-CSF, granulocyte colony-stimulating factor; GM, granulocyte macrophage; IL, interleukin; IP, interferon-γ–induced protein; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; PC, principal component; PCOS, polycystic ovary syndrome; PDGF, platelet-derived growth factor; Ra, receptor antagonist; RM-ASCA+, repeated-measures analysis of variance simultaneous component analysis; TNF, tumor necrosis factor.