J. Perinat. Med. 2020; 48(3): 249–255 Mateusz Mikołajczyk*, Przemysław Wirstlein, Magdalena Adamczyk, Jana Skrzypczak and Ewa Wender-Ożegowska Value of cervicovaginal fluid cytokines in prediction of fetal inflammatory response syndrome in pregnancies complicated with preterm premature rupture of membranes (pPROM) https://doi.org/10.1515/jpm-2019-0280 Received July 25, 2019; accepted January 19, 2020 ; previously published online February 18, 2020 Abstract Background: Preterm premature rupture of membranes (pPROM) is associated with a high risk of prematurity and complications of fetal inflammatory response syndrome (FIRS). The aim of the study is to determine any correla- tions between the concentration of selected cytokines contained in the cervicovaginal secretion eluates and in the umbilical cord plasma in patients with pPROM and to find the noninvasive markers of FIRS in order to pinpoint the optimal time of the delivery. Methods: The study included 80 patients with pPROM between the 24 th and 34 th week of gestation. The cervico- vaginal fluid and umbilical cord blood were collected. Interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 19 (IL-19) and tumor necrosis factor-α (TNF-α) concentra- tions were measured in both materials. For the statistical analysis, SigmaStat3.5 software was used. Results: There was no direct association in levels of IL-6, TNF-α, IL-10 and IL-19 between the cord blood and cervi- covaginal secretions within the studied group. The cut-off point of IL-6 of 26.8 pg/mL in the vaginal fluid had high sensitivity and specificity in order to discriminate between newborns with and without FIRS (81.08%; 76.74%). Conclusion: Further studies are needed on a larger group of participants to demonstrate that an elevated concen- tration of IL-6 above 26.8 pg/mL in the cervicovaginal secretion eluate is an indirect noninvasive marker of FIRS. Keywords: fetal inflammatory response syndrome; funisi- tis; histologic chorioamnionitis; interleukin 6; interleu- kin 19; premature rupture of membranes; prematurity; preterm birth; tumor necrosis factor-α. Introduction Preterm premature rupture of membranes (pPROM) is a serious complication of pregnancy. It is estimated to occur in 2–4% of pregnancies, yet it might be responsible for over 30% of preterm deliveries [1]. The main cause of PROM is an infection that may cause as well as compli- cate the management of pPROM. It can lead to a preterm labor, may cause intraamniotic infections and affect both the fetus and the newborn [2–4]. However, even without any symptomatic maternal infection, the fetus is at risk of developing the fetal inflammatory response syndrome (FIRS), which is a response of the fetal innate immune system to stressors [5, 6]. The syndrome can cause multio- rgan damage, worsening the prognosis for both short- and long-term fetal survival. It can lead to detrimental effects on the development of the fetal brain, lung, kidneys, and also on the heart function [4, 7]. There are two types of FIRS, one associated with infections and the other one free of them [8, 9]. One of the hallmark features of FIRS is an elevated level of interleukin 6 (IL-6) in the umbilical blood (>17.5 pg/ mL) of the newborn with or without the signs of funisitis [10]. IL-6 is the main inflammatory cytokine produced by many cells, including T-cells, B-cells and endothelial cells [6]. It regulates acute phase responses during inflamma- tory processes. However, there are other cytokines that might be implicated in enhancing or suppressing the ongoing FIRS. These are tumor necrosis factor-α (TNF-α), interleukin 10 (IL-10) and interleukin 19 (IL-19) [11–13]. TNF-α is secreted mostly by monocytes and macrophages. It induces cytotoxic reactions and increases the release of C-reactive protein [13, 14]. On the other hand, IL-10 and IL-19 are considered Th2 cytokines that are anti-inflamma- tory, with actions that mitigate the effect of IL-6 and TNF-α [12]. IL-19 belongs to the IL-10 family. It can induce the pro- duction of IL-10 from blood mononuclear cells and activate monocytes to release IL-6, TNF-α, IL-8 and oxygen radicals. Savasan et al. found a higher concentration of IL-19 in the blood of children with FIRS compared to newborns without FIRS [11]. It is known that there are two independent risk factors for the newborn’s development: the gestational age at delivery and the condition in which the newborn is delivered. It is clear that the prolongation of pregnancies *Corresponding author: Mateusz Mikołajczyk, MD, PhD, Department of Reproduction, Poznan University of Medical Sciences, ul. Polna 33, 60-535 Poznań, Poland, Tel.: +48 61 8419302, Fax: +48 61 8419625, E-mail: oddzpiv@gmail.com. https://orcid.org/0000-0003-4599-7003 Przemysław Wirstlein, Magdalena Adamczyk, Jana Skrzypczak and Ewa Wender-Ożegowska: Department of Reproduction, Poznan University of Medical Sciences, Poznań, Poland Brought to you by | Karolinska Institute Authenticated Download Date | 3/2/20 2:31 PM