BACKGROUND: Despite expectant management, preeclampsia remote from term usually results in preterm delivery. Antithrombin, which displays antiinflammatory and anticoagulant properties, may have a therapeutic role in treating preterm preeclampsia, a disorder characterized by endothelial dysfunction, inflammation, and activation of the coagulation system. OBJECTIVE: This randomized, placebo-controlled clinical trial aimed to evaluate whether intravenous recombinant human antithrombin could prolong gestation and therefore improve maternal and fetal outcomes. STUDY DESIGN: We performed a double-blind, placebo-controlled trial at 23 hospitals. Women were eligible if they had a singleton pregnancy, early-onset or superimposed preeclampsia at 23 0/7 to 30 0/7 weeks' gestation, and planned expectant management. In addition to standard therapy, patients were randomized to receive either recombinant human antithrombin 250 mg loading dose followed by a continuous infusion of 2000 mg per 24 hours or an identical saline infusion until delivery. The primary outcome was days gained from randomization until delivery. The secondary outcome was composite neonatal morbidity score. A total of 120 women were randomized. RESULTS: There was no difference in median gestational age at enrollment (27.3 weeks' gestation for the recombinant human antithrombin group [range, 23.1-30.0] and 27.6 weeks' gestation for the placebo group [range, 23.0-30.0]; P=.67). There were no differences in median increase in days gained (5.0 in the recombinant human antithrombin group [range, 0-75] and 6.0 for the placebo group [range, 0-85]; P=.95). There were no differences between groups in composite neonatal morbidity scores or in maternal complications. No safety issues related to recombinant human antithrombin were noted in this study, despite the achievement of supraphysiological antithrombin concentrations. CONCLUSION: The administration of recombinant human antithrombin in preterm preeclampsia neither prolonged pregnancy nor improved neonatal or maternal outcomes.

Asthma is a common and potentially life-threatening lung disease. The prevalence of asthma is higher in women than in men. This monograph provides an overview of the pathophysiology, evaluation, and management of asthma in women. Management approaches in reproductive-aged, pregnant, and postmenopausal patients are addressed.

Objective To assess the risk of ischemic placental disease (IPD) including preeclampsia, small for gestational age (SGA), and abruption, in relation to preeclampsia in maternal grandmother, mother, and sister(s). Study Design We performed a secondary analysis of data from a randomized trial of vitamins C and E for preeclampsia prevention. Data on family history of preeclampsia were based on recall by the proband. The associations between family history of preeclampsia and the odds of IPD were evaluated from alternating logistic regressions. Results Of the 9,686 women who delivered nonmalformed, singleton live births, 17.1% had IPD. Probands provided data on preeclampsia in 55.5% ( n =5,374) on all three family members, 26.5% ( n =2,562) in mother and sister(s) only, and 11.6% ( n =1,125) in sister(s) only. The pairwise odds ratio (pOR) of IPD was 1.16 (95% confidence interval [CI]: 1.00-1.36) if one or more of the female relatives had preeclampsia. The pORs of preeclampsia were 1.54 (95% CI: 1.12-2.13) and 1.35 (95% CI: 1.03-1.77) if the proband's mother or sister(s) had a preeclamptic pregnancy, respectively, but no associations were seen for SGA infant or abruption. Conclusion This study suggests that IPD may share a predisposition with preeclampsia, suggesting a familial inheritance.

THE EFFECT OF SEDENTARY CONDITIONS ON GABAERGIC TRANSMISSION IN THE RVLM by MARYETTA DONNA DOMBROWSKI December 2015 Advisor: Patrick Mueller, Ph.D. Major: Physiology Degree: Doctor of Philosophy Physical inactivity is detrimental to our health and is a major risk factor for the development of CVD (138). Our laboratory has shown that physical inactivity leads to elevated resting splanchnic sympathetic nerve activity when compared to physically active conditions(91). Our laboratory has also shown that in response to glutamate microinjected into RVLM sedentary rats have greater increases in SSNA (enhanced sympathoexcitation) when compared to physically active rats (91). Negrao et al showed that in response to angiotensin II and sodium nitroprusside infusion lead to sympathoexcitation but the exercise trained rats had greater increases in SSNA when compared to the unexercised rats (105). Roveda et al showed that muscle sympathetic nerve activity (MSNA) is elevated in heart failure patients when compared to healthy individuals (60). Following a single bout of exercise MSNA was lower in the heart failure patients (60). This enhanced sympathoexcitation has been suggested to lead to overactivity of the sympathetic nervous system (28; 39; 117). The mechanisms that lead to alterations in the central nervous system in response to sedentary and physically active conditions are not completely understood. This project is aimed to help provide

OBJECTIVE:To determine if tobacco use increases the incidence of preterm premature rupture of the membranes (pPROM) or alters perinatal outcomes after pPROM.STUDY DESIGN:This is a secondary analysis of the databases of three completed Eunice Kennedy Shriver National Institute of Child Health and Human Development-supported Maternal Fetal Medicine Units Network studies. Self-reported tobacco exposure data was obtained. Its relationship with the incidence of pPROM and associated neonatal outcome measures were assessed.RESULTS:There was no difference in the incidence of pPROM when comparing nonsmokers to those using tobacco. Although a trend was seen between the incidence of pPROM and the amount smoked, this did not reach statistical significance. Among the patients with pPROM, the use of tobacco was not associated with an increase in perinatal morbidity.CONCLUSION:Our data do not support a significant relationship between tobacco use and pPROM.

OBJECTIVE: We sought to correlate maternal and cord blood cytokine and intercellular adhesion molecule-1 levels with antibiotic exposure and perinatal outcomes after conservatively managed preterm premature rupture of the membranes.STUDY DESIGN: Conservatively managed women with preterm premature rupture of the membranes at 24-32 weeks had blood sampling at randomization (n = 222) and delivery (n = 121). Plasma from these, and umbilical cord blood (n = 196), was stored at -70 degrees C. Interleukin (IL)-6, IL-10, granulocyte colony-stimulating factor (G-CSF), tumor necrosis factor-alpha, and intercellular adhesion molecule-1 levels were assessed for associations with antibiotic treatment, latency, amnionitis, neonatal sepsis, pneumonia, and composite neonatal morbidity.RESULTS: Cord blood IL-6 and G-CSF were higher than maternal levels. Antibiotic treatment lowered only maternal G-CSF (P = .01). Elevated maternal cytokine levels were associated with delivery within 7 days and with development of chorioamnionitis. All umbilical cord blood markers were increased with amnionitis (P <= .01 for each). No maternal marker was associated with neonatal morbidities. Cord G-CSF and IL-6 were increased with neonatal sepsis within 72 hours of birth (P = .004 for both), and with composite neonatal morbidity (P = .001 and .002, respectively). Maternal and umbilical cord cytokine levels demonstrated low predictive values for perinatal outcomes.CONCLUSION: Umbilical cord blood cytokine values are higher than maternal levels, suggesting significant fetal/placental contribution. Maternal and umbilical cord cytokine levels are not adequately predictive to be used clinically.

OBJECTIVE: Seventeen-alpha-hydroxyprogesterone caproate (17-OHPC) reduces recurrent preterm birth (PTB). We hypothesized that single nucleotide polymorphisms in the human progesterone receptor (PGR) affect response to 17-OHPC in the prevention of recurrent PTB.STUDY DESIGN: We conducted secondary analysis of a study of 17-OHPC vs placebo for recurrent PTB prevention. Twenty PGR gene single nucleotide polymorphisms were studied. Multivariable logistic regression assessed for an interaction between PGR genotype and treatment status in modulating the risk of recurrent PTB.RESULTS: A total of 380 women were included; 253 (66.6%) received 17-OHPC and 127 (33.4%) received placebo. In all, 61.1% of women were African American. Multivariable logistic regression demonstrated significant treatment-genotype interactions (either a beneficial or harmful treatment response) for African Americans delivering <37 weeks' gestation for rs471767 and rs578029, and for Hispanics/Caucasians delivering <37 weeks' gestation for rs500760 and <32 weeks' gestation for rs578029, rs503362, and rs666553.CONCLUSION: The clinical efficacy and safety of 17-OHPC for recurrent PTB prevention may be altered by PGR gene polymorphisms.

OBJECTIVE:We sought to identify serum markers of subsequent spontaneous preterm birth (SPTB) in asymptomatic women prior to labor.STUDY DESIGN:Serum proteomics was applied to sera from 80 pregnant women sampled at 24 weeks and an additional 80 pregnant women sampled at 28 weeks. Half had uncomplicated pregnancies and half had SPTB.RESULTS:Three specific peptides arising from inter-alpha-trypsin inhibitor heavy chain 4 protein were significantly reduced in women at 24 and 28 weeks having subsequent SPTB. The most discriminating peptide had a sensitivity of 65.0% and specificity of 82.5%; odds ratio, 8.8; and 95% confidence interval, 3.1-24.8. A combination of the 3 new biomarkers and 6 previously studied biomarkers increased sensitivity to 86.5%, with a specificity of 80.6% at 28 weeks.CONCLUSION:Three novel serum markers of SPTB have been identified using serum proteomics. Using a combination of these new markers with additional markers, women at risk of SPTB can be identified weeks prior to SPTB.

Objective: The aim of this study was to determine the interrelationship between cervical concentration of interleukin 6 and detection of fetal fibronectin and other risk factors for spontaneous preterm birth. Study Design: All patients with spontaneous preterm birth at <35 weeks’ gestation (case patients; n = 125) and subjects matched for race, parity, and center delivered at ≥37 weeks’ gestation (n = 125; control subjects) were selected from women enrolled in the National Institute of Child Health and Human Development’s Preterm Prediction Study. Interleukin 6 concentrations were determined by enzyme-linked immunosorbent assay in cervical swabs obtained at 22 weeks’ to 24 weeks 6 days’ gestation. Cutoffs to define an elevated interleukin 6 concentration included the 90th and 95th percentiles for control subjects (>305 and >538 pg/mL, respectively). Results: The mean (±SD) interleukin 6 concentration was significantly higher in case patients than in control subjects (212 ± 339 vs 111 ± 186 pg/mL; P =.008). With either cutoff value elevated interleukin 6 concentration was significantly associated with spontaneous preterm birth (90th percentile, 20% vs 9.6%; P =.02; 95th percentile, 12% vs 4.8%; P =.04). Cervical interleukin 6 levels were highest within 4 weeks of delivery, and the trend continued until term. Elevated interleukin 6 concentration was not significantly associated with bacterial vaginosis, maternal body mass index <19.8 kg/m2, or a short cervix (≤25 mm), but it was significantly associated with a positive cervicovaginal fetal fibronectin test result (90th percentile, odds ratio, 5.5; 95% confidence interval, 2.6-11.9; 95th percentile, odds ratio, 5.3, 95% confidence interval, 2.1-12.9). The mean interleukin 6 concentration among women with a positive fibronectin test result was 373 ± 406 pg/mL; that among women with a negative fetal fibronectin test result was 130 ± 239 pg/mL (P =.001). In a regression analysis that adjusted for risk factors significantly associated with spontaneous preterm birth in this population (positive fetal fibronectin test result, body mass index <19.8 kg/m2, vaginal bleeding in the first or second trimester, previous spontaneous preterm birth, and short cervix) elevated cervical interleukin 6 concentration was not independently associated with spontaneous preterm birth (odds ratio, 1.8; 95% confidence interval, 0.8-4.3). Conclusions: At 24 weeks’ gestation cervical interleukin 6 concentration in women who subsequently had a spontaneous preterm birth at <35 weeks’ gestation was significantly elevated relative to those who were delivered at term. The association was particularly strong within 4 weeks of testing. A positive fetal fibronectin test result was strongly associated with elevated cervical interleukin 6 concentration, but bacterial vaginosis was not. (Am J Obstet Gynecol 2001;184:483-8.)

BACKGROUND:The article was designed to estimate the effect of active and passive household cigarette smoke exposure on asthma severity and obstetric and neonatal outcomes in pregnant women with asthma.METHODS:We used a secondary observational analysis of pregnant women with mild and moderate-severe asthma enrolled in a prospective observational cohort study of asthma in pregnancy and a randomized clinical trial (RCT) comparing inhaled beclomethasone and oral theophylline. A baseline questionnaire detailing smoking history and passive household smoke exposure was given to each patient. Smoking status was confirmed in the RCT using cotinine levels. Data on asthma severity and obstetric and neonatal outcomes were collected and analyzed with respect to self-reported tobacco smoke exposure. Kruskal-Wallis and Pearson chi(2) statistics were used to test for significance.RESULTS:A total of 2,210 women were enrolled: 1,812 in the observational study and 398 in the RCT. Four hundred and eight (18%) women reported current active smoking. Of the nonsmokers, 790 (36%) women reported passive household smoke exposure. Active smoking was associated with more total symptomatic days (P < .001) and nights of sleep disturbance (P < .001). Among the newborns of active smokers, there was a greater risk of small for gestational age < 10th percentile (P < .001), and a lower mean birth weight (P < .001). There were no differences in symptom exacerbation or outcome between nonsmokers with and without passive household cigarette smoke exposure.CONCLUSIONS:Among pregnant women with asthma, active but not passive smoking is associated with increased asthma symptoms and fetal growth abnormalities.

Asthma is an increasingly common problem during pregnancy. Mild and moderate asthma can be associated with excellent maternal and perinatal pregnancy outcomes, especially if patients are managed according to contemporary recommendations of National Asthma Education and Prevention Program. Severe and poorly controlled asthma may be associated with increased prematurity, need for cesarean delivery, preeclampsia, and growth restriction. Severe asthma exacerbations can result in maternal morbidity and mortality, and can have commensurate adverse pregnancy outcomes. The management of asthma during pregnancy should be based upon objective assessment, trigger avoidance, patient education, and step therapy. Asthma medications should be continued during pregnancy and while breast-feeding.

Objective. To determine whether asthma-specific quality of life during pregnancy is related to asthma exacerbations and to perinatal outcomes. Methods. This was a secondary analysis of data from a randomized controlled trial of inhaled beclomethasone versus theophylline in the treatment of moderate asthma during pregnancy. The Juniper Asthma Quality of Life Questionnaire (AQLQ) was administered to patients at enrollment. Exacerbations were defined as asthma symptoms requiring a hospitalization, unscheduled medical visit, or oral corticosteroid course. Results. Quality of life assessments were provided by 310 of the 385 participants who completed the study. There was more than a 25% decrease in the odds of a subsequent asthma exacerbation for every 1-point increase in AQLQ score for the overall score (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.55–0.96), emotion domain (OR 0.72, 95% CI 0.59–0.88), and symptoms domain (OR 0.73, 95% CI 0.57–0.94). These relationships were not significantly influenced by initial symptom frequency or forced expiratory volume in 1 s (FEV1). No significant relationships were demonstrated between enrollment AQLQ scores and preeclampsia, preterm birth, low birth weight, or small for gestational age. Conclusion. Asthma-specific quality of life in early pregnancy is related to subsequent asthma morbidity during pregnancy but not to perinatal outcomes.

OBJECTIVE:Evaluate association of the inflammatory marker C-reactive protein with recurrent preeclampsia.METHODS:Serum samples collected longitudinally in women with previous preeclampsia from the Maternal-Fetal Medicine Units Network trial of aspirin to prevent preeclampsia were assayed for CRP.RESULTS:Of 255 women studied, 50 developed recurrence. Baseline C-reactive protein concentration was similar between women who did and did not recur. After adjusting for confounders, neither elevated baseline C-reactive protein nor its change over gestation was associated with recurrence.CONCLUSION:In this group of women with previous preeclampsia, neither baseline C-reactive protein concentration nor change in concentration over gestation was associated with recurrent preeclampsia.

Objective The truncated mitochondrial progesterone receptor (PR-M) is homologous to nuclear PRs with the exception of an amino terminus hydrophobic membrane localization sequence, which localizes PR-M to mitochondria. Given the matrilineal inheritance of both spontaneous preterm birth (SPTB) and the mitochondrial genome, we hypothesized that (a) PR-M is polymorphic and (b) PR-M localization sequence polymorphisms could result in variable progesterone-mitochondrial effects and variable responsiveness to progesterone prophylaxis. Methods Secondary analysis of DNA from women enrolled in a multicenter, prospective, study of 17 alpha-hydroxyprogesterone caproate (17OHPC) versus placebo for the prevention of recurrent SPTB. DNA was extracted from stored saliva. Results The PR-M localization sequence was sequenced on 344 patients. Sequences were compared with the previously published 48 base-pair sequence, and all were identical. Conclusions We did not detect genetic variation in the mitochondrial localization sequence of the truncated PR-M in a group of women at high risk for SPTB.

OBJECTIVE: Soluble receptor levels of tumor necrosis factor (sTNF-R)-1 and -2 are increased during preeclampsia. We postulated the increase preceded overt disease.STUDY DESIGN: Archived plasma from the Eunice Kennedy Shriver National Institute of Child Health and Human Development aspirin to prevent preeclampsia in high risk women trial were used to measure serial sTNF-R1 and sTNF-R2 (enrollment, 24-28 week's gestation) in 986 women (577 also sampled at 34- 38 weeks).RESULTS: Preeclampsia incidence was 21.2%. sTNF-R2 levels were higher at enrollment (P = .02) and weeks 24-28 (P = .01) in women who eventually developed preeclampsia. The magnitude of increase from baseline of both receptors was significantly greater in women who developed preeclampsia in the future. Women with week 24-28 sTNF-R2 levels in the highest quartile had significantly increased odds to develop preeclampsia (P = .03 vs quartile 1). This association was observed in the placebo but not the aspirin arm (P <= .002). Sensitivities and positive predictive values were low.CONCLUSION: sTNF-R2 levels are elevated prior to overt preeclampsia, suggesting a pathogenetic role for these proinflammatory cytokines.

OBJECTIVE: To assess the associations among maternal obesity, uterine contraction frequency, and spontaneous preterm birth in women at risk for spontaneous preterm birth.METHODS: In a secondary analysis, we analyzed data from 253 women at risk for spontaneous preterm birth (prior spontaneous preterm birth, vaginal bleeding) enrolled in a multicenter observational study of home uterine activity monitoring at 11 centers. All women wore a uterine activity monitor twice daily from 22 weeks through 34 weeks of gestation. Mean and maximal contractions/hour at 22-24, 25-26, 27-28, 29-30, 31-32 weeks, and at or after 33 weeks of gestation were compared between overweight/obese women (a body mass index [BMI] at 22-24 weeks greater than 25 kg/m(2)) and normal/underweight women (a BMI of 25 kg/m(2) or less) at each gestational age interval. Multivariable analysis evaluated the influences of BMI, contractions, fetal fibronectin, and transvaginal cervical length on spontaneous preterm birth before 35 weeks.RESULTS: Obese/overweight women (n=156) were significantly less likely to experience spontaneous preterm birth before 35 weeks (8.3% compared with 21.7%, P<.01). For each gestational age interval before 32 weeks, obese/overweight women had fewer mean contractions/hour (P<.01 for each) and maximal contractions/hour (P<.01 for each) than normal/underweight women, although their mean cervical lengths (34.3 mm compared with 33.1 mm, P=.25), and fetal fibronectin levels (7.1% compared with 7.2% 50 ng/mL or more, P=.97) were similar at study enrollment. Obese/overweight status was associated with a lower risk of spontaneous preterm birth before 35 weeks after controlling for contraction frequency and other factors evaluated at 22-24 weeks, but not at later periods.CONCLUSION: Obese/overweight women at risk for spontaneous preterm birth exhibit less uterine activity and less frequent spontaneous preterm birth before 35 weeks of gestation than normal/underweight women.