Cytokine Changes in Maternal Peripheral Blood Correlate With Time-to-Delivery in Pregnancies Complicated by Premature Prelabor Rupture of the Membranes Stefania Ronzoni, MD, PhD 1 , Valerie Steckle, BSc 2,3 , Rohan D’Souza, MD 2,4 , Kellie E. Murphy, MD 2,4 , Stephen Lye, PhD 2,3,4 , and Oksana Shynlova, PhD 2,3,4 Abstract Premature prelabor rupture of the membranes (PPROM) causes one-third of preterm births worldwide and is most likely caused by subclinical intrauterine infection and/or inflammation. We proposed that women with systemic inflammation at the time of PPROM would have shorter latency. Peripheral blood samples were collected from 20 singleton pregnant women with PPROM between 23 + 1 and 33 + 6 weeks. The first sample was drawn within 48 hours of admission, followed by weekly blood draws until delivery. Pregnancies complicated with acute chorioamnionitis, preeclampsia, intrauterine growth restriction, obesity, substance abuse, and chronic maternal disease were excluded. Twenty uncomplicated, gestational age-matched pregnancies served as controls. Plasma concentration of 39 cytokines was measured longitudinally using Luminex assays to investigate their value as predictive biomarkers of latency. Women with PPROM exhibited significantly lower plasma concentration of interferon- g-inducible protein 10-Chemokine (c-x-c motif; IP10/CXCL10), Chemokine (c-x-c motif) Ligand 9 (MIG/CXCL9), Platelet- derived growth factor BB (PDGFbb), and cutaneous T cell-attracting chemokine, also known as CCL27/CCL27 than controls at admission but significantly elevated interleukin (IL)1RA, tumor necrosis factor a, monocyte chemotactic protein-1/CCL2 at delivery compared to admission. Women with PPROM who delivered within 7 days had significantly lower plasma concentration of anti-inflammatory cytokine IL1RA than those with latency periods >7 days. The IL1RA and endotoxin activity in conjunction with clinical parameters results in excellent prediction of latency to delivery (area under the receiver–operating characteristic curve ¼ 0.91). We concluded that higher levels of anti-inflammatory cytokines in women with PPROM were associated with increased latency until delivery, likely due to counterbalancing of proinflammatory load. When used in conjunction with other predictive characteristics of time until delivery, cytokines may further assist clinical decision-making and optimize pregnancy outcomes in women with PPROM. Keywords premature rupture of fetal membranes, premature birth, cytokines, biomarkers, latency to delivery, intrauterine infection/ inflammation Introduction Premature prelabor rupture of the fetal membranes (PPROM) precedes approximately 40% of preterm births (PTB), the preg- nancy complication that is the leading cause of morbidity and mortality for children younger than 5 years of age worldwide. 1 It is well established that both the maternal and the fetal immune systems play a key role in the onset of term parturition and that localized physiological uterine inflammation during the last phase of gestation is particularly important for labor initiation and progression. 2 Spontaneous labor at term (>37 weeks’ gestation) is associated with the infiltration of inflam- matory cells into the cervix, myometrium, chorioamniotic 1 Department of Obstetrics and Gynecology, Sunnybrook Health Science Centre, University of Toronto, Ontario, Canada 2 Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, Ontario, Canada 3 Department of Physiology, University of Toronto, Ontario, Canada 4 Department of Obstetrics and Gynecology, University of Toronto, Ontario, Canada Corresponding Author: Stefania Ronzoni, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N3M5. Email: stefania.ronzoni@sunnybrook.ca Reproductive Sciences 1-11 ª The Author(s) 2018 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1933719118815590 journals.sagepub.com/home/rsx