Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes.

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.

Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes.

OBJECTIVE: 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. STUDY DESIGN: 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). RESULTS: 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). CONCLUSION: 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.

The rebirth of progesterone in the prevention of preterm labor.

OBJECTIVE: To evaluate data since 2003 on the efficacy and safety of progesterone supplementation in the prevention of preterm labor. DATA SOURCES: A MEDLINE and Ovid database search (January 2003-September 2012) was performed using the search terms preterm, progesterone, and 17α-hydroxyprogesterone caproate. All relevant abstracts were reviewed. STUDY SELECTION: For efficacy and safety data, the search was limited to randomized, double-blind, placebo-controlled trials with the primary outcome of preterm delivery, fetal loss, or neonatal morbidity or mortality. Quality of the studies was assessed using the CONSORT (Consolidated Standards of Reporting Trials) guidelines for reporting parallel-group randomized trials. Eleven articles were selected for review. DATA SYNTHESIS: Preterm birth, prior to 37 weeks' gestation, remains the leading cause of neonatal morbidity and mortality in the US due to lack of treatment options. Recently, the use of progesterone to prevent preterm labor, deemed decades ago to be ineffective, has been reexamined. Progesterone formulations and dosage regimens varied greatly between studies. In patients with prior preterm birth or shortened cervix shown on transvaginal ultrasound, progesterone appears efficacious in reducing the rate of preterm birth. However, this benefit was not demonstrated in multiple-gestation pregnancies. Overall, progesterone was well tolerated and appeared safe for mother and fetus. More studies are needed to confirm the dosage regimen and population that will benefit most from progesterone. CONCLUSIONS: Progesterone appears to be safe and efficacious in reducing the risk of preterm birth in a select group of high-risk women with prior spontaneous preterm births and those with an ultrasound-confirmed short cervix. Women with multiple gestations do not benefit from progesterone supplementation.

Antenatal sexually transmitted infection screening in private and indigent clinics in a community hospital system.

OBJECTIVE: To determine whether clinics that serve indigent patients demonstrate equal compliance with sexually transmitted infection testing guidelines when compared with private clinics. STUDY DESIGN: One hundred eighty-three women were divided into cohorts based on whether they received prenatal care at a private or indigent clinic. Timing of required antenatal sexually transmitted infection screening was collected for 8 tests and compliance scores were calculated. Primary outcome was average compliance score compared between clinic types. Secondary outcomes included disease-specific compliance and percent of perfect compliance at different office types. RESULTS: Compliance was found to be different between clinic types (P = .023). Indigent clinics had the same median with slightly higher inner-quartile range than private clinics (7 [7-8], 7 [7-7]). Indigent clinics had higher mean compliance scores (7.1 vs 6.9) and a greater percentage of patients demonstrating perfect compliance (42% vs 14%, P < .001). CONCLUSION: Clinics serving indigent patient populations had a higher compliance with required testing compared to private clinics. HIV testing in the third trimester remains the greatest need for improvement for all practice types.

Depressive symptoms predict exaggerated inflammatory responses to an in vivo immune challenge among pregnant women.

OBJECTIVE: Stress and depressive symptoms predict exaggerated inflammatory responses to a biological challenge in nonpregnant humans and animals. The extent to which these findings generalize to pregnancy is unknown because the immune system exhibits substantial changes to support pregnancy. Notably, inflammatory responses to infectious agents play a causal role in the development of gestational hypertension as well as risk for preterm birth. Thus, depressive symptoms may increase susceptibility to these outcomes via sensitization of inflammatory processes. The current study was designed to test the hypothesis that depressive symptoms would predict an exaggerated proinflammatory response to an in vivo antigen challenge, influenza virus vaccination, among pregnant women. METHOD: Twenty-two pregnant women completed two study visits: baseline and 1week after receiving influenza virus vaccination. Depressive symptoms were measured with the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline. Serum levels of macrophage migration inhibitory factor (MIF) were determined using a high sensitivity immunoassay at both study visits. OUTCOMES: Analyses demonstrated that, as compared to those in the lowest tertile of CES-D scores, those in the highest tertile exhibited significantly higher levels of MIF 1week after influenza virus vaccination (p=.035). CONCLUSIONS: Depressive symptoms predicted exaggerated MIF production following influenza virus vaccination during pregnancy. These data support the hypothesis that depressive symptoms are associated with sensitization of the inflammatory response during pregnancy. Thus, women with greater depressive symptoms may be more vulnerable to negative sequelae of infectious illness during pregnancy.

Depressive symptoms are associated with elevated serum proinflammatory cytokines among pregnant women.

Psychosocial stress and depressive symptoms are associated with increased risk of negative perinatal outcomes including preterm delivery and gestational hypertension. Inflammation is a likely mechanism by which distress may promote these outcomes. It is well-established that stress and depressive symptoms are associated with elevated serum inflammatory markers in nonpregnant populations. However, the immune system exhibits significant changes during pregnancy. Thus, the extent to which these findings extend to pregnancy is largely unknown. The current study examined associations among perceived stress, depressive symptoms, and serum inflammatory markers in a sample of 60 pregnant women. Fifty seven percent were African-American, 82% had completed high school or less education, and 63% reported an annual family income below $15,000. Participants completed the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression Scale (CES-D). Serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were determined using high sensitivity immunoassays. Regression analyses demonstrated that after controlling for pre-pregnancy Body Mass Index (BMI), higher scores on the CES-D were related to significantly higher levels of IL-6 (beta=.23, p=.05) and marginally higher TNF-alpha (beta=.24, p=.06). Perceived stress was not significantly related to serum levels of IL-6 or TNF-alpha. In sum, these results indicate that depressive symptoms are associated with higher levels of maternal serum inflammatory markers during pregnancy. These data are consistent with the contention that depressive symptoms may contribute to negative perinatal outcomes via inflammatory pathways.

Management of anti-Jka alloimmunization.

OBJECTIVE: To determine whether prenatal management using guidelines established for anti-D is applicable to anti-Jka. STUDY DESIGN: A computerized database containing the records of all alloimmunized pregnancies at The Ohio State University Medical Center with due dates from 1959 to 2008 was used to identify pregnancies affected only by anti-Jka. Only cases with evidence that the newborn was Jka antigen positive were included. RESULTS: Twenty affected pregnancies met inclusion criteria. Of those, 16 pregnancies required monitoring with serum titers only and 4 were followed with more diagnostic tests as recommended during that time period. One pregnancy with the highest titer of 32 and elevated middle cerebral artery peak systolic velocity (MCA PSV) required 4 intrauterine transfusions for fetal anemia. Another pregnancy with a titer of 32 had an infant who required phototherapy for hemolytic disease of the fetus/newborn (HDFN), with a hemoglobin value of 15.9 g/dL. None of the other 18 infants required any therapy for HDFN. CONCLUSION: Our case series identified severe disease in 1 of 20 pregnancies from anti-Jka using maternal antibody titer and MCA PSV. Criteria used for monitoring RhD alloimmunization were effective in detecting severe HDFN resulting from to anti-Jka.

Placental Alpha Microglobulin-1 Compared With Fetal Fibronectin to Predict Preterm Delivery in Symptomatic Women.

OBJECTIVE: To compare the rapid bedside test for placental α microglobulin-1 with the instrumented fetal fibronectin test for prediction of imminent spontaneous preterm delivery among women with symptoms of preterm labor. METHODS: We conducted a prospective observational study on pregnant women with signs or symptoms suggestive of preterm labor between 24 and 35 weeks of gestation with intact membranes and cervical dilatation less than 3 cm. Participants were prospectively enrolled at 15 U.S. academic and community centers. Placental α microglobulin-1 samples did not require a speculum examination. Health care providers were blinded to placental α microglobulin-1 results. Fetal fibronectin samples were collected through speculum examination per manufacturer requirements and sent to a certified laboratory for testing using a cutoff of 50 ng/mL. The coprimary endpoints were positive predictive value (PPV) superiority and negative predictive value (NPV) noninferiority of placental α microglobulin-1 compared with fetal fibronectin for the prediction of spontaneous preterm birth within 7 days and within 14 days. RESULTS: Of 796 women included in the study cohort, 711 (89.3%) had both placental α microglobulin-1 and fetal fibronectin results and valid delivery outcomes available for analysis. The overall rate of preterm birth was 2.4% (17/711) within 7 days of testing and 4.2% (30/711) within 14 days of testing with respective rates of spontaneous preterm birth of 1.3% (9/703) and 2.9% (20/701). Fetal fibronectin was detected in 15.5% (110/711), and placental α microglobulin-1 was detected in 2.4% (17/711). The PPVs for spontaneous preterm delivery within 7 days or less among singleton gestations (n=13) for placental α microglobulin-1 and fetal fibronectin were 23.1% (3/13) and 4.3% (4/94), respectively (P<.025 for superiority). The NPVs were 99.5% (619/622) and 99.6% (539/541) for placental α microglobulin-1 and fetal fibronectin, respectively (P<.001 for noninferiority). CONCLUSION: Although placental α microglobulin-1 performed the same as fetal fibronectin in ruling out spontaneous preterm delivery among symptomatic women, it demonstrated statistical superiority in predicting it.

Monochorionic diamniotic infants without twin-to-twin transfusion syndrome.

BACKGROUND: Monochorionic-diamniotic twins (MoDi) occur in 0.3% of all pregnancies. Twin-to-twin transfusion syndrome (TTS) that occurs in 20% of MoDi pregnancies is associated with high perinatal morbidity and mortality. MoDi twins without TTS are more frequent (80%) but have been scarcely reported. OBJECTIVE: To study perinatal morbidity and mortality of 74 MoDi twin sets without TTS and to compare it to that of 38 sets of MoDi twins with TTS. METHODS: Chorionicity was determined by gender and placental examination. Gestational age (GA) was set by sonography and pediatric examination. TTS was diagnosed clinically and by sonography, discordance was defined by twins birth weight difference > or =20%, and fetal growth restriction was determined by using a twin-specific nomogram. RESULTS: MoDi twin pregnancies without and with TTS were similar in demographics, live births, history of preeclampsia, fetal distress and cesarean delivery. They were different (p<0.01) in discordant pregnancies (36 and 79%), GA at delivery (32 and 29 weeks) intrauterine growth restriction (39 and 89%) and neonatal mortality (12 and 36%). Concordant (47 sets) and discordant (27 sets) MoDi twins without TTS were clinically similar. CONCLUSIONS: MoDi twins without TTS have high rates of birth weight discordance, fetal growth restriction, fetal distress, prematurity and cesarean delivery. Although their perinatal mortality is low, the reported occurrence and the short- and long-term impacts of fetal and neonatal morbidities warrants attention.

Adverse pregnancy outcomes in women with nausea and vomiting of pregnancy.

OBJECTIVE: To examine the influence of nausea and vomiting of pregnancy (NVP) on pregnancy outcomes. METHODS: Outcomes were compared for primigravidas with a current singleton gestation enrolled at <20 weeks' gestation in a maternity risk screening and education program (n = 81 486). Patient-reported maternal characteristics and pregnancy outcomes were compared for women with and without NVP and within the NVP group for those with and without poor weight gain. RESULTS: 6.4% of women reported NVP as a pregnancy complication. Women reporting NVP were more likely to be younger, obese, single and smoke. They had higher rates of preterm delivery, pregnancy-induced hypertension and low birth weight <2500 g. Almost one-quarter of women with NVP had lower than recommended weight gain. Poor weight gain was associated with a higher incidence of adverse outcomes. Obesity, tobacco use and poor pregnancy weight gain independently increased the odds of an adverse outcome. CONCLUSION: NVP and subsequent poor weight gain may be associated with adverse pregnancy outcomes.