Effect of asthma management with exhaled nitric oxide versus usual care on perinatal outcomes.

INTRODUCTION: Asthma exacerbations in pregnancy are associated with adverse perinatal outcomes. We aimed to determine whether fractional exhaled nitric oxide (F ENO)-based asthma management improves perinatal outcomes compared to usual care. METHODS: The Breathing for Life Trial was a multicentre, parallel-group, randomised controlled trial conducted in six hospital antenatal clinics, which compared asthma management guided by F ENO (adjustment of asthma treatment according to exhaled nitric oxide and symptoms each 6-12 weeks) to usual care (no treatment adjustment as part of the trial). The primary outcome was a composite of adverse perinatal events (preterm birth, small for gestational age (SGA), perinatal mortality or neonatal hospitalisation) assessed using hospital records. Secondary outcomes included maternal asthma exacerbations. Concealed random allocation, stratified by study site and self-reported smoking status was used, with blinded outcome assessment and statistical analysis (intention to treat). RESULTS: Pregnant women with current asthma were recruited; 599 to the control group (608 infants) and 601 to the intervention (615 infants). There were no significant group differences for the primary composite perinatal outcome (152 (25.6%) out of 594 control, 177 (29.4%) out of 603 intervention; OR 1.21, 95% CI 0.94-1.56; p=0.15), preterm birth (OR 1.14, 95% CI 0.78-1.68), SGA (OR 1.06, 95% CI 0.78-1.68), perinatal mortality (OR 3.62, 95% CI 0.80-16.5), neonatal hospitalisation (OR 1.24, 95% CI 0.89-1.72) or maternal asthma exacerbations requiring hospital admission or emergency department presentation (OR 1.19, 95% CI 0.69-2.05). CONCLUSION: F ENO-guided asthma pharmacotherapy delivered by a nurse or midwife in the antenatal clinic setting did not improve perinatal outcomes.

Factors Associated with Nonadherence to Inhaled Corticosteroids for Asthma During Pregnancy.

BACKGROUND: Nonadherence is common among pregnant women prescribed inhaled corticosteroids (ICS) for asthma and may have serious consequences for mother and baby. Factors associated with ICS nonadherence have not been determined in this population. OBJECTIVES: To determine factors associated with {1} nonadherence to ICS in early-mid pregnancy (cross-sectional) and {2} persistent nonadherence to ICS during pregnancy (longitudinal). METHODS: Data used come from 3 prospective studies (2004-2019) involving women with asthma recruited by 23 weeks' gestation (N = 1614). Demographics, asthma history, and current symptoms were assessed, and spirometry was performed at baseline and throughout pregnancy. Women self-reported current medication use and number of ICS doses missed in the past week. Nonadherence was defined as ≥20% of prescribed dosages missed in the past week (baseline) and on at least 2 occasions during follow-up (persistent). Factors associated with ICS nonadherence were examined using backward stepwise logistic regression. RESULTS: Of 610 (38%) women prescribed ICS at baseline, 236 (39%) were classified as nonadherent. Of 612 (38%) women prescribed ICS during at least 2 follow-up visits, 149 (24%) were classified as persistent nonadherent. Factors associated with nonadherence at baseline were current or ex-smoking, non-Caucasian/non-Indigenous ethnicity, adult diagnosis of asthma, and lower lung function. Factors associated with persistent nonadherence to ICS were lower maternal age, higher parity, and no prescribed ICS at baseline. CONCLUSION: Young multiparous non-Caucasian/non-Indigenous mothers are at increased risk of being nonadherent to ICS during pregnancy. Strategies to improve ICS nonadherence should address maternal smoking and target women who (re-)initiate ICS use in pregnancy.

Trends in asthma self-management skills and inhaled corticosteroid use during pregnancy and postpartum from 2004 to 2017.

OBJECTIVE: Asthma exacerbations and medication non-adherence are significant clinical problems during pregnancy. While asthma self-management education is effective, the number of education sessions required to maximise asthma management knowledge and inhaler technique and whether improvements persist postpartum, are unknown. This paper describes how asthma knowledge, skills, and inhaled corticosteroid (ICS) use have changed over time. METHODS: Data were obtained from 3 cohorts of pregnant women with asthma recruited in Newcastle, Australia between 2004 and 2017 (N = 895). Medication use, adherence, knowledge, and inhaler technique were compared between cohorts. Changes in self-management knowledge/skills and women's perception of medication risk to the fetus were assessed in 685 women with 5 assessments during pregnancy, and 95 women who had a postpartum assessment. RESULTS: At study entry, 41%, 29%, and 38% of participants used ICS in the 2004, 2007, and 2013 cohorts, respectively (p = 0.017), with 40% non-adherence in each cohort. Self-management skills of pregnant women with asthma did not improve between 2004 and 2017 and possession of a written action plan remained low. Maximum improvements were reached by 3 sessions for medications knowledge and one session for inhaler technique, and were maintained postpartum. ICS adherence was maximally improved after one session, but not maintained postpartum. Perceived risk of asthma medications on the fetus was highest for corticosteroid-containing medication; and was significantly reduced following education. CONCLUSIONS: There was a high prevalence of non-adherence and poor self-management skills in all cohorts. More awareness of the importance of optimal asthma management during pregnancy is warranted, since no improvements were observed over the past decade.

The Breathing for Life Trial: a randomised controlled trial of fractional exhaled nitric oxide (FENO)-based management of asthma during pregnancy and its impact on perinatal outcomes and infant and childhood respiratory health.

BACKGROUND: Asthma exacerbations are common during pregnancy and associated with an increased risk of adverse perinatal outcomes. Adjusting asthma treatment based on airway inflammation rather than symptoms reduces the exacerbation rate by 50 %. The Breathing for Life Trial (BLT) will test whether this approach also improves perinatal outcomes. METHODS/DESIGN: BLT is a multicentre, parallel group, randomised controlled trial of asthma management guided by fractional exhaled nitric oxide (FENO, a marker of eosinophilic airway inflammation) compared to usual care, with prospective infant follow-up. Women with physician-diagnosed asthma, asthma symptoms and/or medication use in the previous 12 months, who are 12-22 weeks gestation, will be eligible for inclusion. Women randomised to the control group will have one clinical assessment of their asthma, including self-management education. Any treatment changes will be made by their general practitioner. Women randomised to the intervention group will have clinical assessments every 3-6 weeks during pregnancy, and asthma treatments will be adjusted every second visit based on an algorithm which uses FENO to adjust inhaled corticosteroid (ICS) dose (increase in dose when FENO >29 parts per billion (ppb), decrease in dose when FENO <19 ppb, and no change when FENO is between 19 and 29 ppb). A long acting beta agonist (LABA) will be added when symptoms remain uncontrolled. Both the control and intervention groups will report on exacerbations at a postpartum phone interview. The primary outcome is adverse perinatal outcome (a composite measure including preterm birth, intrauterine growth restriction, neonatal hospitalisation at birth or perinatal mortality), assessed from hospital records. Secondary outcomes will be each component of the primary outcome, maternal exacerbations requiring medical intervention during pregnancy (both smokers and non-smokers), and hospitalisation and emergency department presentation for wheeze, bronchiolitis or croup in the first 12 months of infancy. Outcome assessment and statistical analysis of the primary outcome will be blinded. To detect a reduction in adverse perinatal outcomes from 35 % to 26 %, 600 pregnant women with asthma per group are required. DISCUSSION: This trial will provide evidence for the effectiveness of a FENO-based management strategy in improving perinatal outcomes in pregnant women with asthma. If successful, this would improve the management of pregnant women with asthma worldwide. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000202763 .

Dietary balance during pregnancy is associated with fetal adiposity and fat distribution.

BACKGROUND: The prenatal environment can induce permanent changes in offspring phenotype. Thinness at birth is associated with adult risk of cardiometabolic disease. OBJECTIVE: The objective was to investigate the association between maternal nutrition during pregnancy and intrauterine development of fetal body composition. DESIGN: We used prospective data from 179 Australian women with singleton pregnancies from the Women and Their Children's Health Study. A validated food-frequency questionnaire was used at 18-24 wk and 36-40 wk of gestation to quantify maternal diet during the previous 3 mo of pregnancy. Fetal body-composition measurements were ascertained from abdominal and midthigh sites by ultrasound performed at 19, 25, 30, and 36 wk. The subcutaneous fat area at each site was calculated by subtracting the lean/visceral area from the total area. RESULTS: In linear mixed-model regressions, maternal intakes of protein (b = -0.13; P = 0.04) and starch (b = 0.10; P = 0.02) and the protein:carbohydrate ratio (b = -3.61; P = 0.02) were associated with the percentage of abdominal fat, whereas SFA (b = 0.27; P = 0.04) and PUFA (b = -0.48; P = 0.03) were associated with the percentage of midthigh fat. Response surfaces for fetal adiposity were maximized at different macronutrient intakes. Abdominal fat was highest with low protein intakes (<16% of energy), and midthigh fat was highest at intermediate protein (18-21% of energy), high fat (>40% of energy), and low carbohydrate (<40% of energy) intakes. CONCLUSION: Fetal body composition may be modifiable via nutritional intervention in the mother and thus may play an important role in influencing the offspring's risk of future disease.

Protocol for the Women And Their Children's Health (WATCH) study: a cohort of pregnancy and beyond.

BACKGROUND: The developmental origins of health and disease is a conceptual framework that helps explain the links between our early life exposures and later health outcomes, and is a burgeoning field of research. In this report, we describe the study protocol used in a prospective cohort of women recruited during pregnancy, with postnatal follow-up of the mothers and offspring. METHODS: The Women And Their Children's Health (WATCH) cohort (n = 180 women) is being conducted at the John Hunter Hospital, Australia (from June 2006). Women attended study visits during pregnancy at 19, 24, 30, and 36 weeks' gestation. Postnatal follow-up of the women and their offspring occurred at 3-month intervals during the first year after birth and annually thereafter, until age 4 years. Fetal ultrasound scans were performed at each pregnancy visit. Pregnancy and birth data were obtained from hospital records. Data collection has included maternal and child anthropometric, biochemical, dietary, physical activity, socioeconomic, medical, and other variables. CONCLUSIONS: The 2 most novel components of our prospective cohort study are (1) the regular and systematic tracking of fetal and child growth and body composition, starting in the second trimester of pregnancy and continuing to age 4 years, and (2) the detailed maternal and child dietary data collection, including biochemical parameters. Detailed cohorts that collect data on the early nutritional, physiological, and social determinants of health are valuable. Despite its relatively small sample size, many hypotheses on developmental origins can be tested or piloted using data collected from the WATCH cohort.

Protocol for a randomised controlled trial of treatment of asymptomatic candidiasis for the prevention of preterm birth [ACTRN12610000607077].

BACKGROUND: Prevention of preterm birth remains one of the most important challenges in maternity care. We propose a randomised trial with: a simple Candida testing protocol that can be easily incorporated into usual antenatal care; a simple, well accepted, treatment intervention; and assessment of outcomes from validated, routinely-collected, computerised databases. METHODS/DESIGN: Using a prospective, randomised, open-label, blinded-endpoint (PROBE) study design, we aim to evaluate whether treating women with asymptomatic vaginal candidiasis early in pregnancy is effective in preventing spontaneous preterm birth. Pregnant women presenting for antenatal care<20 weeks gestation with singleton pregnancies are eligible for inclusion. The intervention is a 6-day course of clotrimazole vaginal pessaries (100 mg) and the primary outcome is spontaneous preterm birth<37 weeks gestation.The study protocol draws on the usual antenatal care schedule, has been pilot-tested and the intervention involves only a minor modification of current practice. Women who agree to participate will self-collect a vaginal swab and those who are culture positive for Candida will be randomised (central, telephone) to open-label treatment or usual care (screening result is not revealed, no treatment, routine antenatal care). Outcomes will be obtained from population databases.A sample size of 3,208 women with Candida colonisation (1,604 per arm) is required to detect a 40% reduction in the spontaneous preterm birth rate among women with asymptomatic candidiasis from 5.0% in the control group to 3.0% in women treated with clotrimazole (significance 0.05, power 0.8). Analyses will be by intention to treat. DISCUSSION: For our hypothesis, a placebo-controlled trial had major disadvantages: a placebo arm would not represent current clinical practice; knowledge of vaginal colonisation with Candida may change participants' behaviour; and a placebo with an alcohol preservative may have an independent affect on vaginal flora. These disadvantages can be overcome by the PROBE study design.This trial will provide definitive evidence on whether screening for and treating asymptomatic candidiasis in pregnancy significantly reduces the rate of spontaneous preterm birth. If it can be demonstrated that treating asymptomatic candidiasis reduces preterm births this will change current practice and would directly impact the management of every pregnant woman. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000607077.

Effect of maternal asthma, inhaled glucocorticoids and cigarette use during pregnancy on the newborn insulin-like growth factor axis.

BACKGROUND: Fetal growth varies in a sex-specific manner in response to maternal asthma during pregnancy, but the mechanisms are unclear. OBJECTIVE: We examined the influence of maternal asthma severity and associated exposures, inhaled glucocorticoid treatment, maternal cigarette use, and fetal sex on fetal growth and placental function during pregnancy and on the newborn insulin-like growth factor (IGF) axis. STUDY SUBJECTS AND DESIGN: Fetal growth was assessed in a prospective cohort of asthmatic and non-asthmatic women (n=145). At delivery, umbilical vein plasma was collected from male (n=61, controls n=16 and asthmatic n=45) or female (n=84, controls n=22 and asthmatic n=62) fetuses. Cord plasma insulin-like growth factor (IGF) binding protein (BP)-1, IGFBP-3, IGF-1 and IGF-2 were measured by radioimmunoassay and ELISA. RESULTS: Cord plasma IGF-1 was the main component of the neonatal IGF axis altered by asthma and cigarette use. IGF-1 was increased in the presence of mild asthma and a male fetus and decreased in the presence of a female fetus and maternal asthma with cigarette use. IGFBP-3 was also decreased in the female fetuses of pregnancies complicated by asthma and cigarette use. Inhaled glucocorticoid use for the treatment of asthma did not affect the IGF axis. The strongest overall predictor of female birth weight after accounting for asthma severity, inhaled glucocorticoid treatment and cigarette use was IGF-1. For males, the strongest predictor of birth weight was IGFBP-3. CONCLUSION: The data suggest male and female fetuses institute different strategies in response to adverse pregnancy conditions such as asthma and cigarette use.

Regional block versus general anaesthesia for caesarean section and neonatal outcomes: a population-based study.

BACKGROUND: Anaesthesia guidelines recommend regional anaesthesia for most caesarean sections due to the risk of failed intubation and aspiration with general anaesthesia. However, general anaesthesia is considered to be safe for the foetus, based on limited evidence, and is still used for caesarean sections. METHODS: Cohorts of caesarean sections by indication (that is, planned repeat caesarean section, failure to progress, foetal distress) were selected from the period 1998 to 2004 (N = 50,806). Deliveries performed under general anaesthesia were compared with those performed under spinal or epidural, for the outcomes of neonatal intubation and 5-minute Apgar (Apgar5) <7. RESULTS: The risk of adverse outcomes was increased for caesarean sections under general anaesthesia for all three indications and across all levels of hospital. The relative risks were largest for low-risk planned repeat caesarean deliveries: resuscitation with intubation relative risk was 12.8 (95% confidence interval 7.6, 21.7), and Apgar5 <7 relative risk was 13.4 (95% confidence interval 9.2, 19.4). The largest absolute increase in risk was for unplanned caesareans due to foetal distress: there were five extra intubations per 100 deliveries and six extra Apgar5 <7 per 100 deliveries. CONCLUSION: The infants most affected by general anaesthesia were those already compromised in utero, as evidenced by foetal distress. The increased rate of adverse neonatal outcomes should be weighed up when general anaesthesia is under consideration.

Patterns of plasma corticotropin-releasing hormone, progesterone, estradiol, and estriol change and the onset of human labor.

CONTEXT: Clinical prediction of preterm delivery is largely ineffective, and the mechanism mediating progesterone (P) withdrawal and estrogen activation at the onset of human labor is unclear. OBJECTIVES: Our objectives were to determine associations of rates of change of circulating maternal CRH in midpregnancy with preterm delivery, CRH with estriol (E3) concentrations in late pregnancy, and predelivery changes in the ratios of E3, estradiol (E2), and P. DESIGN AND SETTING: A cohort of 500 pregnant women was followed from first antenatal visits to delivery during the period 2000-2004 at John Hunter Hospital, New South Wales, Australia, a tertiary care obstetric hospital. PATIENTS: Unselected subjects were recruited (including women with multiple gestations) and serial blood samples obtained. MAIN OUTCOME MEASURES: CRH daily percentage change in term and preterm singletons at 26 wk, ratios E3/E2, P/E3, and P/E2 and the association between E3 and CRH concentrations in the last month of pregnancy (with spontaneous labor onset) were assessed. RESULTS: CRH percentage daily change was significantly higher in preterm than term singletons at 26 wk (medians 3.09 and 2.73; P = 0.003). In late pregnancy, CRH and E3 concentrations were significantly positively associated (P = 0.003). E3/E2 increased, P/E3 decreased, and P/E2 was unchanged in the month before delivery (medians: E3/E2, 7.04 and 10.59, P < 0.001; P/E3, 1.55 and 0.98, P < 0.001; P/E2, 11.78 and 10.79, P = 0.07). CONCLUSIONS: The very rapid rise of CRH in late pregnancy is associated with an E3 surge and critically altered P/E3 and E3/E2 ratios that create an estrogenic environment at the onset of labor. Our evidence provides a rationale for the use of CRH in predicting preterm birth and informs approaches to delaying labor using P supplementation.

Maternal and neonatal outcomes of pregnancies complicated by asthma in an Australian population.

OBJECTIVE: To determine if there are sex differences in risk and incidence of stillbirth, preterm delivery and small-for-gestational age (SGA) in pregnancies complicated by maternal asthma relative to a non-asthmatic population. STUDY DESIGN: Univariant and multiple regression analysis of the incidence of preterm delivery, SGA and stillbirth in singleton pregnancies complicated by asthma in Newcastle, NSW, Australia, from 1995 to 1999. RESULTS: Asthma complicated 12% of all singleton pregnancies. The incidence of preterm delivery was not significantly different between asthmatic (13%) and non-asthmatic (11%) pregnancies. Male fetuses (53%) were more likely to deliver preterm than female fetuses (47%) in both asthmatic and non-asthmatic populations. There were significantly more male neonates of pregnancies complicated by asthma that were SGA at term relative to those of the non-asthmatic population. There were significantly more preterm female neonates that were SGA in pregnancies complicated by asthma relative to those of the non-asthmatic population. Male fetuses were more likely to be associated with a stillbirth in pregnancies complicated by asthma than female fetuses. CONCLUSION: The presence of maternal asthma during pregnancy increases the risk of stillbirth for the male fetus and is associated with changes in fetal growth, but does not increase the incidence of a preterm delivery.

Institution of universal screening for Group B streptococcus (GBS) from a risk management protocol results in reduction of early-onset GBS disease in a tertiary obstetric unit.

AIM: To determine the effect of institution of a universal screening protocol as per CDC 2002 guidelines had on the incidence of early-onset Group B streptococcal (GBS) and non-GBS disease in a tertiary obstetric unit. METHODS: A prospective study with historical control data reporting the incidence of early-onset GBS and non-GBS disease following institution of a universal screening strategy at John Hunter Hospital, Newcastle, Australia. We compared the incidence of early-onset GBS and non-GBS disease during prescreening (1994-2002) with screening period (2004 to June 2006). The outcome measure was the incidence of early-onset GBS disease. We specifically reported the number of women needed to treat (NNT) with antibiotics and the number of women needed to screen. RESULTS: The incidence of early-onset GBS and non-GBS during the prescreening period was 0.84/1000 and 0.94/1000 live births, respectively. After institution of universal screening, the incidence was 0.00/1000 and 0.72/1000 live births, respectively. This is a statistically significant reduction in early-onset GBS disease by 84% (chi(2) = 5.75; P = 0.016). There was no difference in non-GBS disease (chi2 = 0.14; P = 0.71). The NNT is 1191 and we needed to screen 5704 women to prevent one case of early-onset GBS disease. CONCLUSION: Screening for GBS rather than by assessing risk factors has significantly reduced the incidence of early-onset GBS disease in our unit. Despite low incidence of early-onset GBS prior to screening period, we still found a significant decrease in early-onset GBS disease after institution of universal screening protocol. These results support the screening-based approach at 34-37 weeks gestation.

Mechanisms regulating prostaglandin H2 synthase-2 mRNA level in the amnion and chorion during pregnancy.

Increasing prostaglandin H(2) synthase (PGHS)-2 expression in the fetal membranes is implicated in the production of prostaglandins (PGs) that stimulate labour. We have determined the activity of the PGHS-2 gene in the amnion and chorion throughout gestation and defined the contribution of transcriptional and post-transcriptional mechanisms to the increase of PGHS-2 mRNA levels. We also measured PGHS-1 mRNA abundance to assess the participation of the two isoenzymes in fetal membrane PG-production during pregnancy. Amnion and chorion were collected from non-labouring women at 10-19 weeks (early), at 28-36 weeks (preterm) and at term (37-41 weeks). We determined PGHS-1 and -2 mRNA abundance and assessed PGHS-2 gene activity by measuring PGHS-2 heterogeneous nuclear RNA levels using real-time RT-PCR. PGHS-2 gene activity and mRNA levels were up-regulated in both tissues with advancing gestation. Path analysis demonstrated that the PGHS-2 mRNA up-regulation involved both transcriptional and post-transcriptional components. PGHS-2 mRNA abundance increased 9-11 fold between the early (10-19 weeks) and preterm (28-36 weeks) groups and remained high at term. The underlying mechanism was predominantly transcriptional in the amnion and post-transcriptional in the chorion. PGHS-1 mRNA expression precipitously decreased between early gestation and term. Thus, PGHS-2 mRNA abundance is up-regulated well in advance of term and is not a trigger for labour. There is a switch in PGHS mRNA expression during pregnancy with PGHS-1 dominating in the early period and PGHS-2 dominating at term.

Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus.

The environment in which the fetus develops is critical for its survival and long-term health. The regulation of normal human fetal growth involves many multidirectional interactions between the mother, placenta, and fetus. The mother supplies nutrients and oxygen to the fetus via the placenta. The fetus influences the provision of maternal nutrients via the placental production of hormones that regulate maternal metabolism. The placenta is the site of exchange between mother and fetus and regulates fetal growth via the production and metabolism of growth-regulating hormones such as IGFs and glucocorticoids. Adequate trophoblast invasion in early pregnancy and increased uteroplacental blood flow ensure sufficient growth of the uterus, placenta, and fetus. The placenta may respond to fetal endocrine signals to increase transport of maternal nutrients by growth of the placenta, by activation of transport systems, and by production of placental hormones to influence maternal physiology and even behavior. There are consequences of poor fetal growth both in the short term and long term, in the form of increased mortality and morbidity. Endocrine regulation of fetal growth involves interactions between the mother, placenta, and fetus, and these effects may program long-term physiology.

Maternal asthma is associated with reduced female fetal growth.

Asthma during pregnancy is associated with a low birth weight, although the mechanisms contributing to this outcome remain unknown. The relationship between maternal asthma and its treatment, placental function, fetal sex, and low birth weight was examined to establish the effect of asthma on fetal growth. Glucocorticoid intake by women with asthma was assessed throughout pregnancy. The placenta was collected after delivery, and 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity was measured. Fetal cortisol and estriol were measured in the umbilical vein plasma at delivery. Those with asthma were compared with a nonasthmatic control group. In women with asthma who did not use inhaled steroids and were pregnant with a female fetus, we observed significantly reduced birth weights, whereas male birth weights were unaffected. The presence of a female fetus was associated with significantly increased maternal circulating monocytes, significantly reduced placental 11beta-HSD2 activity and fetal estriol, and a trend toward elevated fetal plasma cortisol. This study provides evidence that in pregnancies complicated by asthma there is a fetal sex-specific effect on the maternal immune system with adverse effects on placental function and female fetal growth.

The control of prostaglandin endoperoxide H-Synthase-2 expression in the human chorion laeve at term.

OBJECTIVE: Prostaglandin endoperoxide H synthase-2 (PGHS-2), the key enzyme of prostaglandin biosynthesis in gestational tissues, is expressed in the chorion laeve at term. We have determined the mechanisms that control the level of PGHS-2 mRNA in the chorion membrane in order to assess the significance of chorion-derived prostaglandins in term labor. METHODS: Chorion membranes were collected after elective cesarean delivery (CD, n = 21) and after spontaneous labor (SL, n = 20) at term. The PGHS-2 gene transcription rate was measured by transcriptional run-on, and PGHS-2 mRNA and heterogeneous RNA (hnRNA) abundance was determined by quantitative real-time reverse transcriptase polymerase chain reaction. PGHS-2 mRNA stability, PGHS-2 hnRNA processing rate, and the short-term dynamics of the two RNA species were characterized in 0-24-hour-long tissue incubations. RESULTS: The transcriptional activity of the PGHS-2 gene predicted (P <.02) the abundance of PGHS-2 mRNA and hnRNA in individual tissues. PGHS-2 gene activity and hnRNA processing rate were not different in the CD and SL groups. PGHS-2 mRNA was constitutively stable before and after labor, and its abundance spontaneously increased sixfold in tissues incubated for 24 hours. At the same time, PGHS-2 gene activity decreased by 80% within 2 hours and rebounded to 60% of its initial level by 24 hours. CONCLUSIONS: PGHS-2 mRNA is highly stable, and its abundance is transcriptionally controlled in the chorion laeve at term. Labor is not associated with changing PGHS-2 gene activity. Endogenous factors drive PGHS-2 gene transcription in the chorion, and the stable PGHS-2 mRNA accumulates in the tissue at term. This accumulation has little or no impact on the timing of labor.

The in vivo control of prostaglandin H synthase-2 messenger ribonucleic acid expression in the human amnion at parturition.

Prostaglandin H synthase-2 (PGHS-2) activity and mRNA rise in the human amnion at late gestation, contributing to the increase in intrauterine PG production crucial for labor and delivery. In the present investigation we have determined the mechanism that controls amniotic PGHS-2 mRNA levels in vivo at term parturition. Amnion membranes were collected after elective cesarean section (n = 20), and after spontaneous labor (n = 20). PGHS-2 relative gene transcription rates were determined by transcriptional run-on, and PGHS-2 mRNA and heterogeneous nuclear RNA (hnRNA) relative abundance were measured by quantitative real-time RT-PCR. The PGHS-2 mRNA degradation rate was determined by incubating amnion in the presence of the transcription inhibitor 5,6-dichlorobenzimidazole riboside. The dynamics of PGHS-2 hnRNA and mRNA abundance were characterized in 0- to 24-h tissue incubations. The PGHS-2 relative gene transcription rate was a significant (P < 0.05) predictor of PGHS-2 hnRNA and mRNA abundance, and PGHS-2 hnRNA was also a predictor (P < 0.01) of PGHS-2 mRNA levels both before and after labor. Interestingly, even though PGHS-2 gene activity remained unchanged, PGHS-2 mRNA abundance increased with labor and displayed constitutive stability before and after labor. PGHS-2 mRNA levels spontaneously increased by 400% (P < 0.01) upon incubation for 24 h, whereas the transcription rate dropped by 95% during the first 2 h, then rebounded significantly between 6-24 h. Thus, PGHS-2 mRNA abundance is transcriptionally controlled in term amnion. Labor does not increase PGHS-2 gene activity or mRNA stability. The PGHS-2 gene is probably induced before labor by a factor(s) originating in the amnion membrane, and the resulting stable mRNA accumulates progressively in the tissue throughout labor and delivery.

Reduced 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma.

Pregnancies complicated by asthma are associated with an increased risk of low birth weight. Currently, the mechanisms causing this outcome are unknown. To investigate whether impaired placental function may be a determinant, we measured placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity, protein and mRNA, placental CRH mRNA, fetal cortisol, and fetal estriol concentrations at delivery. Asthmatic subjects were classified according to inhaled glucocorticoid intake during pregnancy and compared with a control nonasthmatic group. There was a 25% reduction in neonatal birth weight centile in asthmatic women who did not use inhaled glucocorticoid treatment. This was accompanied by significantly reduced placental 11beta-HSD2 activity, significantly increased fetal cortisol, and a trend toward increased placental CRH mRNA and reduced fetal estriol concentrations. The use of inhaled glucocorticoids for treatment was associated with birth weight centile, 11beta-HSD2 activity, CRH mRNA, fetal cortisol, and estriol concentrations similar to control levels. There was a significant inverse correlation between fetal cortisol and fetal estriol concentrations across all groups. These studies demonstrate that inhaled glucocorticoid intake for the treatment of asthma is associated with improved placental function and fetal outcome, suggesting that inflammatory factors associated with asthma may be detrimental to fetal growth and development in these pregnancies.