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Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth.This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth).The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of.05.In total, we identified 1728 genes for which placental expression was associated with spontaneous preterm birth with more differences in expression in early preterm samples than late preterm samples when compared with full-term samples. Of those, 9 genes were significantly decreased in both early and late spontaneous preterm birth, and the strongest associations involved placental expression of IL1B, ALPL, and CRLF1. In early and late preterm samples, we observed decreased expression of genes involved in immune signaling, signal transduction, and endocrine function.This study provides a comprehensive assessment of the differences in the placental transcriptome associated with spontaneous preterm birth with robust adjustment for confounding. Results of this study are in alignment with the known etiology of spontaneous preterm birth, because we identified multiple genes and pathways for which the placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways that are essential for placental growth and function, which may be related to the etiology of spontaneous preterm birth. We identified increased expression of genes within metabolic pathways associated exclusively with early preterm birth. These signaling and metabolic pathways may provide clinically targetable pathways and biomarkers. The findings presented here can be used to understand underlying pathologic changes in premature placentas, which can inform and improve clinical obstetrics practice.

Background Preeclampsia is a major pregnancy complication that results in significant maternal and infant mortality, most of which occurs in low and middle-income countries. The accurate and timely diagnosis of preeclampsia is critical in management of affected pregnancies to reduce maternal and fetal/neonatal morbidity and mortality, yet difficulties remain in establishing the rigorous diagnosis of preeclampsia based on clinical parameters alone. Biomarkers that detect biochemical disease have been proposed as complements or alternatives to clinical criteria to improve diagnostic accuracy. This cohort study assessed the performance of several biomarkers, including glycosylated fibronectin (GlyFn), to rule-in or rule-out preeclampsia within 4 weeks in a cohort of women at increased risk for preeclampsia. Methods 151 women with risk factors for or clinical signs and symptoms of preeclampsia were selected from a prospective cohort. Maternal serum samples were collected between 20 and 37 weeks of gestation. Clinical suspicion of preeclampsia was defined as presence of new-onset proteinuria, or clinical symptoms of preeclampsia. Subjects with a clinical diagnosis of preeclampsia at the time of enrollment were excluded. GlyFn, pregnancy-associated plasma protein-A2 (PAPPA2), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured by immunoassay. GlyFn was also determined using a rapid point-of care (POC) test format. Receiver-operating characteristic (ROC) curves derived from logistic regression analysis were used to determine the classification performance for each analyte. Results 32 of 151 (21%) women developed a clinical diagnosis of preeclampsia within 4 weeks. All biomarkers exhibited good classification performance [GlyFn (area under the curve (AUROC) = 0.94, 91% sensitivity, 86% specificity); PAPPA2 AUC = 0.92, 87% sensitivity, 77% specificity; PlGF AUC = 0.90, 81% sensitivity, 83% specificity; sFlt-1 AUC = 0.92, 84% sensitivity, 91% specificity. The GlyFn immunoassay and the rapid POC test showed a correlation of r = 0.966. Conclusions In this prospective cohort, serum biomarkers of biochemical disease were effective in short-term prediction of preeclampsia, and the performance of GlyFn in particular as a POC test may meet the needs of rapid and accurate triage and intervention.

The interleukin (IL)-1 system plays a major role in immune responses and inflammation. The IL-1 system components include IL-1α, IL-1β, IL-1 receptor type 1 and IL-1 receptor type 2 (decoy receptor), IL-1 receptor accessory protein, and IL-1 receptor antagonist (IL-1Ra). These components have been shown to play a role in pregnancy, specifically in embryo-maternal communication for implantation, placenta development, and protection against infections. As gestation advances, maternal tissues experience increasing fetal demand and physical stress and IL-1β is induced. Dependent on the levels of IL-1Ra, which regulates IL-1β activity, a pro-inflammatory response may or may not occur. If there is an inflammatory response, prostaglandins are synthesized that may lead to myometrial contractions and the initiation of labor. Many studies have examined the role of the IL-1 system in pregnancy by independently measuring plasma, cervical, and amniotic fluid IL-1β or IL-1Ra levels. Other studies have tested for polymorphisms in IL-1β and IL-1Ra genes in women experiencing pregnancy complications such as early pregnancy loss, in vitro fertilization failure, pre-eclampsia and preterm delivery. Data from those studies suggest a definite role for the IL-1 system in successful pregnancy outcomes. However, as anticipated, the results varied among different experimental models, ethnicities, and disease states. Here, we review the current literature and propose that measurement of IL-1Ra in relation to IL-1 may be useful in predicting the risk of poor pregnancy outcomes.Summary SentenceThe IL-1 system has been shown to have an important role in pregnancy, and an IL-1 system assay may be used as a method to screen for women who are more likely to have a high-risk pregnancy and pregnancy complications.

The purpose of this study was to compare intraamniotic inflammation vs microbial invasion of the amniotic cavity (MIAC) as predictors of adverse outcome in preterm labor with intact membranes.Interleukin-6 (IL-6) was measured in prospectively collected amniotic fluid from 305 women with preterm labor. MIAC was defined by amniotic fluid culture and/or detection of microbial 16S ribosomal DNA. Cases were categorized into 5 groups: infection (MIAC; IL-6, ≥11.3 ng/mL); severe inflammation (no MIAC; IL-6, ≥11.3 ng/mL); mild inflammation (no MIAC; IL-6, 2.6-11.2 ng/mL); colonization (MIAC; IL-6,2.6 ng/mL); negative (no MIAC; IL-6,2.6 ng/mL).The infection (n = 27) and severe inflammation (n = 36) groups had similar latency (median,1 day and 2 days, respectively) and similar rates of composite perinatal morbidity and mortality (81% and 72%, respectively). The colonization (n = 4) and negative (n = 195) groups had similar outcomes (median latency, 23.5 and 25 days; composite morbidity and mortality rates, 21% and 25%, respectively). The mild inflammation (n = 47) groups had outcomes that were intermediate to the severe inflammation and negative groups (median latency, 7 days; composite morbidity and mortality rates, 53%). In logistic regression adjusting for gestational age at enrollment, IL-6 ≥11.3 and 2.6-11.2 ng/mL, but not MIAC, were associated significantly with composite morbidity and mortality rates (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.2-11.2, OR, 3.1; 95% CI, 1.5-6.4, and OR, 1.8; 95% CI, 0.6-5.5, respectively).We confirmed previous reports that intraamniotic inflammation is associated with adverse perinatal outcomes whether or not intraamniotic microbes are detected. Colonization without inflammation appears relatively benign. Intraamniotic inflammation is not simply present or absent but also has degrees of severity that correlate with adverse outcomes. We propose the designation amniotic inflammatory response syndrome to denote the adverse outcomes that are associated with intraamniotic inflammation.

Objective Preterm rupture of membranes (PROM) is associated with an increased risk of preterm birth and neonatal morbidity. Prophylactic 17-hydroxyprogesterone caproate (17OHP-C) reduces the risk of preterm birth in some women who are at risk for preterm birth. We sought to test whether 17OHP-C would prolong pregnancy or improve perinatal outcome when given to mothers with preterm rupture of the membranes. Study Design This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. The study included singleton pregnancies with gestational ages from 23 0/7 to 30 6/7 weeks at enrollment, documented PROM, and no contraindication to expectant management. Consenting women were assigned randomly to receive weekly intramuscular injections of 17OHP-C (250 mg) or placebo. The primary outcome was continuation of pregnancy until a favorable gestational age, which was defined as either 34 0/7 weeks of gestation or documentation of fetal lung maturity at 32 0/7 to 33 6/7 weeks of gestation. The 2 prespecified secondary outcomes were interval from randomization to delivery and composite adverse perinatal outcome. The planned sample size was 222 total women. Results From October 2011 to April 2014, 152 women were enrolled; 74 women were allocated randomly to 17OHP-C, and 78 were allocated randomly to placebo. The trial was stopped when results of a planned interim analysis suggested that continuation was futile. The primary outcome was achieved in 3% of the 17OHP-C group and 8% of the placebo group ( P = .18). There was no significant between-group difference in the prespecified secondary outcomes, randomization-to-delivery interval (17.1 ± 16.1 vs 17.0 ± 15.8 days, respectively; P = .76) or composite adverse perinatal outcome (63% vs 61%, respectively; P = .93). No significant differences were found in other outcomes, which included rates of chorioamnionitis, postpartum endometritis, cesarean delivery, individual components of the composite outcome, or prolonged neonatal length of stay. Conclusion Compared with placebo, weekly 17OHP-C injections did not prolong pregnancy or reduce perinatal morbidity in patients with PROM in this trial.

Objective Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (phase 1) and to validate the test in an independent cohort (phase 2). Study Design This was a prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S ribosomal DNA results. Nine candidate CVF proteins were analyzed by enzyme-linked immunosorbent assay. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the phase 1 cohort (N = 108) into those with or without MIAC. The best models, selected by area under the curve (AUC) of the receiver operating characteristic curve in phase 1, included various combinations of interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), alpha fetoprotein, and insulin-like growth factor binding protein-1. Model performance was then tested in the phase 2 cohort (N = 306). Results MIAC was present in 15% of cases in phase 1 and 9% in phase 2. A 3-marker CVF model using IL-6 plus CXCL1 plus insulin-like growth factor binding protein-1 had AUC 0.87 in phase 1 and 0.78 in phase 2. Two-marker models using IL-6 plus CXCL1 or alpha fetoprotein plus CXCL1 performed similarly in phase 2 (AUC 0.78 and 0.75, respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cutoff value of CVF IL-6 ≥463 pg/mL (which had 81% sensitivity in phase 1) predicted MIAC in phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%. Conclusion High levels of IL-6 in CVF are strongly associated with MIAC. If developed into a bedside test or rapid laboratory assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials.