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.

Maternal and neonatal outcomes of women with gestational diabetes and without specific medical conditions: an Australian population-based study comparing induction of labor with expectant management.

BACKGROUND/AIMS: To evaluate maternal birth and neonatal outcomes among women with gestational diabetes mellitus (GDM), but without specific medical conditions and eligible for vaginal birth who underwent induction of labour (IOL) at term compared with those who were expectantly managed. MATERIALS AND METHODS: Population-based cohort study of women with GDM, but without medical conditions, who had a singleton, cephalic birth at 38-41 completed weeks gestation, in New South Wales, Australia between January 2010 and December 2016. Women who underwent IOL at 38, 39, 40 weeks gestation (38-, 39-, 40-induction groups) were compared with those who were managed expectantly and gave birth at and/or beyond the respective gestational age group (38-, 39-, 40-expectant groups). Multivariable logistic regression analysis was used to assess the association between IOL and adverse maternal birth and neonatal outcomes taking into account potential confounding by maternal age, country of birth, smoking, residential location, residential area of socioeconomic disadvantage and birth year. RESULTS: Of 676 762 women who gave birth during the study period, 66 606 (10%) had GDM; of these, 34799 met the inclusion criteria. Compared with expectant management, those in 38- (adjusted odds ratio (aOR) 1.11; 95% CI, 1.04-1.18), 39- (aOR 1.21; 95% CI, 1.14-1.28) and 40- (aOR 1.50; 95% CI, 1.40-1.60) induction groups had increased risk of caesarean section. Women in the 38-induction group also had an increased risk of composite neonatal morbidity (aOR 1.10; 95% CI, 1.01-1.21), which was not observed at 39- and 40-induction groups. We found no difference between groups in perinatal death or neonatal intensive care unit admission for births at any gestational age. CONCLUSION: In women with GDM but without specific medical conditions and eligible for vaginal birth, IOL at 38, 39, 40 weeks gestation is associated with an increased risk of caesarean section.

Dysregulation of Oxygen Sensing/Response Pathways in Pregnancies Complicated by Idiopathic Intrauterine Growth Restriction and Early-Onset Preeclampsia.

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are the leading causes of maternal and fetal morbidity/mortality. The central deficit in both conditions is impaired placentation due to poor trophoblast invasion, resulting in a hypoxic milieu in which oxidative stress contributes to the pathology. We examine the factors driving the hypoxic response in severely preterm PE (n = 19) and IUGR (n = 16) placentae compared to the spontaneous preterm (SPT) controls (n = 13) using immunoblotting, RT-PCR, immunohistochemistry, proximity ligation assays, and Co-IP. Both hypoxia-inducible factor (HIF)-1α and HIF-2α are increased at the protein level and functional in pathological placentae, as target genes prolyl hydroxylase domain (PHD)2, PHD3, and soluble fms-like tyrosine kinase-1 (sFlt-1) are increased. Accumulation of HIF-α-subunits occurs in the presence of accessory molecules required for their degradation (PHD1, PHD2, and PHD3 and the E3 ligase von Hippel-Lindau (VHL)), which were equally expressed or elevated in the placental lysates of PE and IUGR. However, complex formation between VHL and HIF-α-subunits is defective. This is associated with enhanced VHL/DJ1 complex formation in both PE and IUGR. In conclusion, we establish a significant mechanism driving the maladaptive responses to hypoxia in the placentae from severe PE and IUGR, which is central to the pathogenesis of both diseases.

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.

Variation in clinical decision-making for induction of labour: a qualitative study.

BACKGROUND: Unexplained variation in induction of labour (IOL) rates exist between hospitals, even after accounting for casemix and hospital differences. We aimed to explore factors that influence clinical decision-making for IOL that may be contributing to the variation in IOL rates between hospitals. METHODS: We undertook a qualitative study involving semi-structured, audio-recorded interviews with obstetricians and midwives. Using purposive sampling, participants known to have diverse opinions on IOL were selected from ten Australian maternity hospitals (based on differences in hospital IOL rate, size, location and case-mix complexities). Transcripts were indexed, coded, and analysed using the Framework Approach to identify main themes and subthemes. RESULTS: Forty-five participants were interviewed (21 midwives, 24 obstetric medical staff). Variations in decision-making for IOL were based on the obstetrician's perception of medical risk in the pregnancy (influenced by the obstetrician's personality and knowledge), their care relationship with the woman, how they involved the woman in decision-making, and resource availability. The role of a 'gatekeeper' in the procedural aspects of arranging an IOL also influenced decision-making. There was wide variation in the clinical decision-making practices of obstetricians and less accountability for decision-making in hospitals with a high IOL rate, with the converse occurring in hospitals with low IOL rates. CONCLUSION: Improved communication, standardised risk assessment and accountability for IOL offer potential for reducing variation in hospital IOL rates.

Early-onset preeclampsia appears to discourage subsequent pregnancy but the risks may be overestimated.

BACKGROUND: Early-onset preeclampsia is associated with adverse maternal and perinatal outcomes. For women who consider another pregnancy after one complicated by early-onset preeclampsia, the likelihood of recurrence and the subsequent pregnancy outcome for themselves and their babies are pertinent considerations. OBJECTIVES: The purpose of this study was to determine the subsequent pregnancy rate after a nulliparous pregnancy that was complicated by early-onset preeclampsia and among those who have a subsequent pregnancy, the risk of recurrence by gestational week, and adverse pregnancy outcomes. STUDY DESIGN: This was a population-based record linkage cohort study. The study population included nulliparous women with a singleton pregnancy and early-onset preeclampsia (<34 weeks gestation) who gave birth in New South Wales Australia from 2001-2010 (the index birth), with follow-up data for a subsequent birth through 2012. Early-onset in the index birth was further categorized as <28 vs 28-33 weeks gestation. Subsequent pregnancy outcomes that were assessed included the pregnancy rate, preeclampsia recurrence, and maternal and perinatal morbidity and mortality rates. The risk of preeclampsia necessitating delivery at each gestational week for women who were at risk was plotted, and the net gain or loss of gestational age when comparing the index with the subsequent pregnancy was calculated. RESULTS: Among 361,031 nulliparous women with singleton pregnancies, 1473 (0.4%) had early-onset preeclampsia. Women with early-onset preeclampsia in their first pregnancy had a lower subsequent pregnancy rate (59.7%) than women without preeclampsia (67.7%). Of the 758 women with a subsequent singleton birth, 256 (33.8%) experienced preeclampsia in the next pregnancy; 57 women (7.5%) with recurrent early-onset preeclampsia were included. Cumulative rates of preeclampsia in the subsequent pregnancy were higher at every gestation from 23 weeks gestation when the index birth was <28 weeks compared with 28-33 weeks gestation. The cumulative rate and gestation-specific risk of recurrent preeclampsia rose most steeply at 32-38 weeks gestation. Most women (94.6%) progressed to a later gestational age in their subsequent pregnancy. The median overall increase in gestational age at delivery was 6 weeks (interquartile range, 4-8); among women with recurrent preeclampsia, the median increase was 5 weeks (interquartile range, 2-7). Women with index birth <28 weeks gestation compared with 28-33 weeks gestation were more likely to deliver preterm (38.8% vs 28.7%; relative risk, 1.35; 95% confidence interval, 1.04-1.75) and have a perinatal death (4.3% vs 1.2%; relative risk, 3.46; 95% confidence interval, 1.15-10.39) at the subsequent birth, but live born infants had similar rates of severe morbidity (17.1% vs 15.0%; relative risk, 1.14; 95% confidence interval, 0.73-1.79). CONCLUSION: Women with early-onset preeclampsia in a first pregnancy appear less likely than women without preeclampsia to have a subsequent pregnancy. Maternal and perinatal outcomes in the subsequent pregnancy are generally better than in the first; most women will not have recurrent preeclampsia, and those who do usually will give birth at a greater gestational age compared with their index birth.

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 .

Venous thromboembolism prophylaxis during and following caesarean section: a survey of clinical practice.

BACKGROUND: Caesarean section (CS) is a significant risk factor for venous thromboembolism; however, the optimal method of thromboprophylaxis around the time of CS is unknown. AIMS: To examine current thromboprophylaxis practice during and following CS in Australia and New Zealand, and the willingness of obstetricians to participate in a randomised controlled trial (RCT) comparing different methods of thromboprophylaxis after CS. MATERIALS AND METHODS: An online survey was sent to fellows and trainees of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists. RESULTS: There were 488 responses from currently practising obstetricians (response rate 23.4%). During CS, 48% and 80% of obstetricians recommended intermittent pneumatic compression (IPC) and elastic stockings (ES), respectively. Following CS, 96-97% of obstetricians recommended early ambulation, 87-90% recommended ES, 23-36% recommended IPC, and 42-65% recommended low molecular weight heparin (LMWH) depending on clinical factors. Increased BMI (OR 3.42; 95% CI 2.87-4.06), emergency CS (OR 1.88; 95% CI 1.67-2.16) and older maternal age (OR 1.37; 95% CI 1.26-1.49) were associated with more frequent LMWH use. Of obstetricians who prescribed LMWH, 70% adjusted the dose depending on maternal weight. LMWH therapy was most commonly recommended until discharge from hospital (31%), <5 days (24%) and 5-7 days (15%). Most obstetricians (58-79%) were willing to enrol women in a RCT, but less likely if the woman had an increased BMI or emergency CS. CONCLUSIONS: There is considerable variation in clinical practice regarding thromboprophylaxis during and following CS. Obstetricians support a RCT to assess different methods of thromboprophylaxis following CS.

Trends and outcomes of postpartum haemorrhage, 2003-2011.

BACKGROUND: While rates of postpartum haemorrhage (PPH) have continued to rise, it is not clear if the association with other morbidity and transfusion has changed over time. This study explores the recent trend in postpartum haemorrhage and whether postpartum haemorrhage is associated with increased transfusions or adverse outcomes over time. METHODS: Linked birth and hospital data were used to examine ICD-10 AM coded PPH and outcomes in maternal birth admission records, 2003--2011 in hospitals in New South Wales (NSW), Australia (N = 818,965 pregnancies). Trends were calculated on the whole population, and among subgroups, and tested using the Cochran Armitage test for trend. Logistic regression models were developed separately for vaginal and caesarean births, and for a maternal morbidity composite indicator (excluding transfusion) and red cell transfusion. Adjusted odds ratios (aOR) for each year relative to 2003 and 95% confidence intervals (CI) are presented with adjustment for maternal (eg. age, country of birth) and pregnancy factors (eg. parity, interventions, pregnancy complications). RESULTS: Overall, there was a significant increase in the PPH rate, from 6.1% in 2003 to 8.3% in 2011 (p < 0.0001). Crude rates of postpartum haemorrhage with transfusion increased from 0.75% (n = 636) to 1.21% (n = 1145) (p < 0.0001) while crude rates of postpartum haemorrhage with maternal morbidity increased from 0.18% (n = 149) to 0.23% (n = 221) (p = 0.02). Having accounted for maternal and pregnancy factors, there were significant overall decreases in the odds of morbidity among women with a PPH delivering vaginally (in 2006, 2007 and 2010, aORs were 0.70 (95 % CI 0.52, 0.96) 0.69 (0.51, 0.94) and 0.64 (0.47, 0.87) relative to 2003; p < 0.05), and no significant decrease among women delivered by caesarean section (aOR 0.87 (0.58, 1.29) in 2011; p = 0.37). Among women with a PPH delivering vaginally, there was a trend towards a non-linear increase in the adjusted odds of transfusion by birth year. Compared to women who had vaginal births with PPH in 2003, the adjusted odds for transfusion was between 1.1 and 1.2 fold higher for those with a PPH delivering vaginally in 2007, 2009, 2010 and 2011. However there was no significant trend amongst caesarean births (aOR 0.84 (0.66, 1.06) in 2011; p = 0.29). CONCLUSIONS: PPH has become more frequent, however this has not been associated with a clear pattern of increased severe maternal morbidity. This suggests that the increase in PPH may represent fewer severe haemorrhages, better management of severe haemorrhage or better recording of PPH. The increase in transfusions following vaginal births with PPH warrants further investigation.

Pre-eclampsia in a first pregnancy and subsequent pregnancy outcomes: a nationwide cohort study.

BACKGROUND: For women whose first pregnancy was complicated by pre-eclampsia (PE), particularly if severe and requiring early birth, the risk of recurrence and maternal and neonatal outcomes at subsequent birth are important considerations. METHODS: In this observational cohort study, all primiparous women who gave birth in Denmark between 1997 and 2016 were identified using nationwide registries. Women were stratified by whether they developed PE and followed from date of birth until subsequent birth, emigration, death or end of study (December 2016). The cumulative incidences of subsequent birth among women with versus without PE were assessed using the Aalen-Johansen estimator. Subsequent outcomes including PE recurrence and maternal and neonatal morbidity and mortality were also examined. Factors associated with subsequent birth and recurrent PE were examined using multivariable Cox regression models. RESULTS: Among 510 615 primiparous women with singleton pregnancies, 21 683 (4.2%) developed PE, with 1819 (0.4%) being early-onset PE (birth <34 weeks). Women with PE had a lower subsequent birth rate (57.4%) compared with women without PE (61.2%), and it was considerably lower among women with early-onset PE (49.4%). Among women with PE who had a subsequent birth, the overall recurrence rate of PE was 15.8% and higher among those with early-onset PE (31.5%). The gestational age increased with a median of 3 days (IQR -5 to 14) overall and 50 days (IQR 35-67) among those with early-onset PE. Moreover, neonatal and maternal morbidity and mortality were substantially improved in a subsequent pregnancy. CONCLUSIONS: Primiparous women with PE have a significantly lower rate of a subsequent birth than women without PE, yet the absolute difference was modest. Although the overall risk of recurrent PE is 1 in 6, maternal and neonatal morbidity and mortality at subsequent birth are substantially improved.

Vernix Caseosa Peritonitis Causing Acute Abdomen After Cesarean Section: A Case Series.

BACKGROUND Vernix caseosa peritonitis (VCP) is a rare complication that typically presents following an otherwise uneventful cesarean section. Leakage of vernix caseosa into the peritoneum is thought to elicit a granulomatous foreign body reaction. Symptoms can be similar to other acute abdominal conditions, and diagnosis is confirmed by intraoperative findings and histological examination. Peritoneal lavage with supportive measures is the mainstay of treatment and recovery. CASE REPORT Case 1 was a 30-year-old woman who developed right iliac fossa pain, fever, tachycardia, and tachypnea less than a week after her lower segment cesarean section (LSCS). She underwent a laparoscopy for a peritonitic abdomen and concern for intra-abdominal sepsis. A peritoneal biopsy demonstrated histological changes consistent with VCP. Case 2 was a 39-year-old woman who underwent a LSCS. After discharge, she re-presented with generalized abdominal pain. With computed tomography (CT) scan findings suggestive of appendicitis, an appendectomy was performed, and vernix caseosa was detected in all quadrants. Case 3 was a 33-year-old woman who presented with fever, vomiting, diarrhea, and iliac fossa pain 9 days following an LSCS. She was given analgesia and antibiotics for a pelvic fluid collection noted on CT scan. She re-presented with tense swelling and pain above her cesarean section incision. Laparoscopy revealed adhesions over the lower abdomen and pelvis and white plaques suggestive of vernix caseosa along the peritoneal side walls. CONCLUSIONS The rising incidence of cesarean births worldwide creates the potential for increased numbers of VCP cases. Greater recognition of VCP is warranted to prevent unnecessary procedures.

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.

Stillbirth in Australia 2: Working together to reduce stillbirth in Australia: The Safer Baby Bundle initiative.

The rate of late gestation stillbirth in Australia is unacceptably high. Up to one third of stillbirths are preventable, particularly beyond 28 weeks' gestation. The aim of this second paper in the Stillbirth in Australia series is to highlight one key national initiative, the Safer Baby Bundle (SBB), which has been led by the Centre of Research Excellence in Stillbirth in partnership with state health departments. Addressing commonly identified evidence practice gaps, the SBB contains five elements that, when implemented together, should result in better outcomes than if performed individually. This paper describes the development of the SBB, what the initiative aims to achieve, and progress to date. By collaborating with Departments of Health and other partners to amplify uptake of the SBB, we anticipate a reduction of at least 20% in Australia's stillbirth rate after 28 weeks' gestation is achievable.