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Objective: This study was undertaken to determine whether the interleukin-1 receptor antagonist (IL-1RN) variable number tandem repeat polymorphism is associated with preterm birth., Study Design: A case-control study was performed. Cases (n = 95) delivered before 37 weeks after preterm labor (PTL) or preterm premature rupture of membranes (PPROM) and controls (n = 105) delivered after 37 weeks. Maternal DNA was genotyped by polymerase chain reaction for a length polymorphism in intron 2 of the IL-1RN gene., Results: There was no significant difference in maternal age, ethnicity, insurance status, or parity between groups. Allele and genotype frequencies did not differ significantly from that expected under Hardy-Weinberg equilibrium (P = .59) in the total group as well as study groups. Of the 95 cases, 26.8% had at least 1 copy of allele 2 present compared with 12.4% in the control group (P < .0004)., Conclusion: Maternal carriage of at least 1 copy of the IL-1RN allele 2 appears to be associated with increased risk of preterm birth.

Objective: The purpose of this study was to examine the association between Gram stain findings of vaginal fluid and the concentration of vaginal fluid neutrophil defensins., Study Design: Vaginal fluid specimens obtained from 749 women at 24 to 29 weeks of gestation were tested for bacterial vaginosis and assayed for neutrophil defensins. Bacterial vaginosis was studied as a categoric variable (negative, intermediate, and positive), whereas defensins were examined as a continuous measure and dichotomized on the basis of presence versus absence and at the 90th percentile. Multiple linear and logistic regression models were used to assess the relationship between bacterial vaginosis and defensins., Results: Women with intermediate bacterial vaginosis were more likely to have elevated vaginal fluid neutrophil defensins (>90th percentile) than women with normal vaginal flora (adjusted odds ratio, 2.3; 95% CI, 1.3, 4.2), whereas women with frank bacterial vaginosis were not (adjusted odds ratio, 1.3; 95% CI, 0.7, 2.6). Among women with any detectable defensin (69.5% of the study population), intermediate bacterial vaginosis was associated positively with defensin concentrations in multiple linear regression models (P =.007). Women with intermediate and frank bacterial vaginosis had 5.9 microg/mL and 2.2 microg/mL higher defensin concentrations, respectively, than women who did not have bacterial vaginosis. The presence of leukocytes in vaginal fluids was associated positively with defensin concentrations (P <.0001)., Conclusion: Changes in vaginal microflora during mid pregnancy are associated with an increased concentration of vaginal fluid neutrophil defensins.

Clinical pharmacology studies that describe the pharmacokinetics and pharmacodynamics of drugs in pregnant women are critical for informing on the safe and effective use of drugs during pregnancy. That being said, multiple factors have hindered the ability to study drugs in pregnant patients. These include concerns for maternal and fetal safety, ethical considerations, the difficulty in designing appropriate trials to assess the study objectives, and funding limitations. This document summarizes the recommendations of a panel of experts convened by the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. These experts were charged with reviewing the issues related to the development of preclinical and clinical drug studies in pregnant women and to develop strategies for addressing these issues. These findings may also be utilized in the development of future drug studies involving pregnant women and their fetus/neonate.

Objective: The number of women aged 45 and older who become pregnant is increasing. The objective of this study was to estimate the risk of medical and obstetric complications among women aged 45 and older. Methods: The Nationwide Inpatient Sample was used to identify pregnant woman during admission for delivery. Deliveries were identified using International Classification of Diseases, Ninth Revision (ICD-9-CM) codes. Using ICD-9-CM codes, pre-existing medical conditions and medical and obstetric complications were identified in women at the time of delivery and were compared for women aged 45 years and older to women under age 35. Outcomes among women aged 35–44 were also compared to women under age 35 to determine if women in this group demonstrated intermediate risk between the older and younger groups. Logistic regression analyses were used to calculate odds ratios with 95% confidence intervals for pre-existing medical conditions and medical and obstetric complications for both older groups relative to women under 35. Multivariable logistic regression analyses were also developed for outcomes at delivery among older women, while controlling for pre-existing medical conditions, multiple gestation, and insurance status, to determine the effect of age on the studied outcomes. Results: Women aged 45 and older had higher adjusted odds for death, transfusion, myocardial infarction/ischemia, cardiac arrest, acute heart failure, pulmonary embolism, deep vein thrombosis, acute renal failure, cesarean delivery, gestational diabetes, fetal demise, fetal chromosomal anomaly, and placenta previa compared to women under 35. Conclusion: Pregnant women aged 45 and older experience significantly more medical and obstetric complications and are more likely to die at the time of a delivery than women under age 35, though the absolute risks are low and these events are rare. Further research is needed to determine what associated factors among pregnant women aged 45 and older may contribute to these findings. [ABSTRACT FROM AUTHOR]

Objective: Bacterial colonization of the fetal membranes and its role in pathogenesis of membrane rupture is poorly understood. Prior retrospective work revealed chorion layer thinning in preterm premature rupture of membranes (PPROM) subjects. Our objective was to prospectively examine fetal membrane chorion thinning and to correlate to bacterial presence in PPROM, preterm, and term subjects. Study Design: Paired membrane samples (membrane rupture and membrane distant) were prospectively collected from: PPROM = 14, preterm labor (PTL = 8), preterm no labor (PTNL = 8), term labor (TL = 10), and term no labor (TNL = 8), subjects. Sections were probed with cytokeratin to identify fetal trophoblast layer of the chorion using immunohistochemistry. Fluorescence in situ hybridization was performed using broad range 16 s ribosomal RNA probe. Images were evaluated, chorion and choriodecidua were measured, and bacterial fluorescence scored. Chorion thinning and bacterial presence were compared among and between groups using Student's t-test, linear mixed effect model, and Poisson regression model (SAS Cary, NC). Results: In all groups, the fetal chorion cellular layer was thinner at rupture compared to distant site (147.2 vs. 253.7 µm, p<0.0001). Further, chorion thinning was greatest among PPROM subjects compared to all other groups combined, regardless of site sampled [PPROM(114.9) vs. PTL(246.0) vs. PTNL(200.8) vs. TL(217.9) vs. TNL(246.5)]. Bacteria counts were highest among PPROM subjects compared to all other groups regardless of site sampled or histologic infection [PPROM(31) vs. PTL(9) vs. PTNL(7) vs. TL(7) vs. TNL(6)]. Among all subjects at both sites, bacterial counts were inversely correlated with chorion thinning, even excluding histologic chorioamnionitis (p<0.0001 and p = 0.05). Conclusions: Fetal chorion was uniformly thinner at rupture site compared to distant sites. In PPROM fetal chorion, we demonstrated pronounced global thinning. Although cause or consequence is uncertain, bacterial presence is greatest and inversely correlated with chorion thinning among PPROM subjects. [ABSTRACT FROM AUTHOR]

Smoking in pregnancy reduces preeclampsia risk, but the mechanism of this effect is unknown. Prior studies have demonstrated that women with preeclampsia have lower placental adrenomedullin (AM) expression, and cigarette smoke extract (CSE) treatment of placental trophoblast cells in culture increases AM cellular production. We hypothesized that CSE alters trophoblast invasion through an AM-mediated mechanism, and that placental AM expression is greater among smokers. HTR-8/SVneo trophoblast cells were incubated for 24 hours in Matrigel-invasion chambers with 6 treatment groups: nonstimulated (NS), AM, AM inhibitor (AM22-52), 1% CSE, AM + AM22-52, and 1% CSE + AM22-52. Cells that penetrated the lower surface of the chambers were quantified, invasion indices were calculated, and compared using a 1-way analysis of variance with Bonferroni corrections for multiple comparisons. Trophoblast cells treated with both AM and 1% CSE demonstrated increased cellular invasion compared to NS controls (1.5-fold [P < .01] and 1.45-fold [P < .01], respectively). Cotreatment with the AM inhibitor significantly attenuated the increased invasion seen with both AM and CSE alone. Next, the placental tissue was obtained from 11 smokers and 11 nonsmokers at term and processed for immunohistochemistry (IHC) and real-time quantitative polymerase chain reaction (PCR) for AM. Placentas from smokers demonstrated more intense AM staining and increased AM gene (ADM) expression compared to placentas from nonsmokers (P = .004 for IHC, P = .022 for PCR). The CSE increases trophoblast cell invasion through an AM-mediated process, and placental AM expression is increased among term smokers compared to nonsmokers. These findings provide evidence that the AM pathway may play a role in the protection from preeclampsia seen in smokers. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate cervical ripening with foley balloon combined with a fixed vs. incremental low-dose oxytocin infusion. Methods: Women presenting for term labor induction were randomized to fixed low-dose or standard incremental low-dose oxytocin infusion following foley balloon placement. The primary outcome was time from foley balloon placement to delivery. Results: Among 116 subjects, there was no difference in median time to delivery among subjects receiving fixed low-dose vs. standard incremental low-dose oxytocin during induction of labor with a foley balloon (23.7 vs. 19.2 hours). There were no differences between the two groups in median time to foley bulb extrusion, active labor and second stage of labor or incidence of uterine tachysystole, fetal heart rate abnormalities, mode of delivery or maternal hemorrhage. Conclusions: There is no difference in median time to delivery in women undergoing cervical ripening with a foley balloon combined with a fixed low-dose or standard incremental low-dose oxytocin. [ABSTRACT FROM AUTHOR]

Desensitization of the oxytocin receptor (OXTR) in the setting of prolonged oxytocin exposure may lead to dysfunctional labor, which increases the risk for cesarean delivery, and uterine atony, which may result in postpartum hemorrhage. The molecular mechanism for OXTR desensitization is through the agonist-mediated recruitment of the multifunctional protein β-arrestin. In addition to its desensitizing function, β-arrestins have recently been shown to simultaneously activate downstream signaling. We tested whether oxytocin stimulation promotes β-arrestin-mediated OXTR desensitization in vivo and activates β-arrestin-mediated mitogen-activated protein kinase (MAPK) growth signaling. Uterine muscle strips isolated from wild-type mice exhibited diminished uterine contractility following repeated exposure to oxytocin, whereas uterine muscle strips from β-arrestin-1 and β-arrestin-2 knockout mice showed no desensitization. Utilizing siRNA knockdown of β-arrestin-1 and β-arrestin-2 in HEK-293 cells expressing the OXTR, we demonstrated oxytocin-mediated MAPK signaling that was dependent on β-arrestin-1 and β-arrestin-2. Wild-type and β-arrestin-1 and β-arrestin-2 knockout mice receiving intravenous oxytocin also demonstrated oxytocin-mediated MAPK signaling that was dependent on β-arrestin-1 and β-arrestin-2. Finally, to test the significance of β-arrestin-mediated signaling from the OXTR, HEK-293 cells expressing the OXTR showed β-arrestin-dependent proliferation in a cell migration assay following oxytocin treatment. In conclusion, β-arrestin is a multifunctional scaffold protein that mediates both desensitization of the OXTR, leading to decreases in uterine contractility, and MAPK growth signaling following stimulation by oxytocin. The development of unique OXTR ligands that prevent receptor desensitization may be a novel approach in the treatment of adverse clinical events secondary to prolonged oxytocin therapy. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to estimate the nationwide prevalence of cystic fibrosis (CF) in pregnancy and determine what medical complications exist at delivery among pregnant women with CF. Study Design The Nationwide Inpatient Sample (NIS) was queried for all delivery-related discharges. Women with CF were identified by International Classification of Diseases, 9th revision, Clinical Modifications codes and compared with women without CF. The prevalence of selected severe medical complications was compared between the 2 groups (NIS years 2008-2010) using multivariable logistic regression and the linear change in prevalence of CF at delivery determined (NIS years 2000-2010). Results From 2000 to 2010, there was a significant linear increase in the prevalence of CF at delivery from 3.0 to 9.8 per 100,000 deliveries, in 2000 and 2010, respectively (R 2 = 0.92, P < .0001). From 2008-2010, there were 1119 deliveries to women with CF and 12,627,627 to women without CF. Women with CF were more likely to be white ( P < .0001) and have diabetes (odds ratio [OR], 14.0; 95% confidence interval [CI], 11.8–16.7) or asthma (OR, 5.1; 95% CI, 4.3–6.1). Multivariable logistic regression demonstrated that women with CF were more likely to die (adjusted OR [aOR], 76.0; 95% CI, 31.6–183), require mechanical ventilation (aOR, 18.3; 95% CI, 10.8–31.2), or have pneumonia (aOR, 56.5; 95% CI, 43.2−74.1), acute renal failure (aOR, 17.3; 95% CI, 9.1–32.6), preterm labor (aOR, 2.2; 95% CI, 1.9–2.6), or an adverse composite CF outcome (aOR, 28.1; 95% CI, 21.8–36.3). Conclusion Pregnant women with CF are more likely to die, require mechanical ventilation, and have infectious complications compared with women without CF, although the absolute risks are low and these events are relatively rare. [ABSTRACT FROM AUTHOR]

Despite evidence regarding the benefits of influenza immunization during pregnancy for both the pregnant woman and her infant, as well as reassuring safety data, influenza vaccination rates in pregnancy have lagged. The 2009 influenza pandemic was accompanied by increased maternal vaccination rates. In this article, we review programmatic and research priorities with regard to overcoming barriers to influenza immunization of pregnant women. [ABSTRACT FROM AUTHOR]

Abstract Objective Tetanus toxoid, reduced diphtheria toxoid, and acellular pertusiss (Tdap) vaccine is recommended during each pregnancy, regardless of prior receipt. Data on reactogenicity and immunogenicity, particularly after repeated Tdap, are limited. We compared local injection-site and systemic reactions and serologic response following Tdap in (1) pregnant and nonpregnant women and (2) pregnant women by self-reported prior Tdap receipt. Study design Pregnant women (gestational age 20–34 weeks) and nonpregnant women receiving Tdap were enrolled in this observational study. Injection-site and systemic reactions were assessed for one week post-vaccination. Pertussis toxin, filamentous hemagglutinin, pertactin, fimbriae, tetanus and diphtheria specific IgG antibody titers were determined by standardized enzyme-linked immunosorbent assay at baseline and 28 days post-vaccination. Reactogenicity and serologic responses were compared by pregnancy status, and within pregnant women by self-reported prior Tdap receipt. Results 374 pregnant and 225 nonpregnant women were vaccinated. Severe local or systemic reactions or "any" fever were uncommon (≤3% for both groups). Moderate/severe injection-site pain was significantly higher in pregnant (17.9%) versus nonpregnant (11.1%) women, but did not prompt a healthcare visit. Proportions of other moderate/severe or any severe reactions were not significantly higher in pregnant compared to nonpregnant women. Moderate/severe (including pain) and severe reactions were not significantly higher in pregnant women receiving repeat versus first-time Tdap. Antibody titers increased from baseline to post-vaccination for all vaccine antigens in pregnant and nonpregnant women; post-vaccination titers against pertussis toxin and filamentous hemagglutinin were significantly higher in nonpregnant versus pregnant women (p < 0.01). Conclusion Tdap was well-tolerated in pregnant and nonpregnant women. Pregnant women were more likely to report moderate/severe pain at the Tdap injection-site compared with nonpregnant women, but did not necessitate medical visits. Prior Tdap receipt did not increase occurrence of moderate/severe local or systemic reactions in pregnant women. Serologic responses to all vaccine antigens were robust. Clinical Trial Registration@ClinicalTrials.gov. NCT02209623. https://clinicaltrials.gov/ct2/show/NCT02209623. [ABSTRACT FROM AUTHOR]