Mid-pregnancy circulating cytokine levels, histologic chorioamnionitis and spontaneous preterm birth

Abstract

Some spontaneous preterm deliveries (PTD) are caused by occult infections of the fetal membranes (histologic chorioamnionitis [HCA]). High levels of infection-related markers, including some cytokines, sampled from maternal circulation in mid-pregnancy have been linked to PTD, but whether these specifically identify HCA has not been established. We have tested associations between 13 Th1, Th2 and Th17 cytokines and PTD with and without HCA in a prospective cohort study. The study sample included 926 Pregnancy Outcomes and Community Health Study subcohort women; women with medically indicated PTD or incomplete data excluded. A panel of cytokines was assessed using a multiplex assay in maternal plasma collected at 15-27 weeks of gestation. Severe HCA was scored by a placental pathologist blinded to clinical variables. Multivariable polytomous logistic regression was used to estimate adjusted odds ratios (OR) per 1 standard deviation (S.D.) increase in cytokine levels using a 5 level outcome variable: PTD <35 weeks with HCA, PTD <35 weeks without HCA, PTD 35-36 weeks with HCA, PTD 35-36 weeks without HCA, and term (referent). Interleukin (IL)-1beta, IL-2, IL-12, interferon-gamma, IL-4, IL-6 and transforming growth factor-beta were all significantly associated with PTD <35 weeks with HCA, with ORs of 1.6-2.3 per S.D. increase. None of these were associated with PTD <35 weeks without HCA or PTD 35-36 weeks with HCA. Although the tissues of origin of circulating cytokines are unclear, the observed elevations across many cytokines among women who later delivered <35 weeks with HCA may represent a robust immune response to infection within gestational tissues. These results suggest that women with HCA could be identified using relatively non-invasive means.

Figure 1

Derivation of the study sample

Figure 2

Boxplots of standardized cytokine values for 7 cytokines by delivery week and HCA categories: (A) IL-1β, (B) IL-2, (C) IL-12, (D) IFN-γ, (E) IL-4, (F) IL-6, (G) TGF-β. Y-axis scale is standard deviation of log-transformed cytokine value. Solid horizontal lines denote median and interquartile range; + denotes mean. Extreme values (> 75^th percentile + 2x interquartile range or < 25^th percentile - 2x interquartile range) not shown (clipping indicated by open circle).