Characterisation of Mid-Gestation Amniotic Fluid Cytokine and Bacterial DNA Profiles in Relation to Pregnancy Outcome in a Small Australian Cohort.

A well-established association exists between intrauterine bacteria and preterm birth. This study aimed to explore this further through documenting bacterial and cytokine profiles in Australian mid-gestation amniotic fluid samples from preterm and term births. Samples were collected during amniocenteses. DNA was extracted and the full-length 16S rRNA gene was amplified and sequenced. Levels of the cytokines IL-1ß, IL-6, IL-10, TNF-α and MCP-1 were determined using the Milliplex MAGPIX system. Bacterial DNA profiles were low in diversity and richness, with no significant differences observed between term and preterm samples. No differences in the relative abundance of individual OTUs between samples were identified. IL-1ß and TNF-α levels were significantly higher in samples containing reads mapping to Sphingomonas sp.; however, this result should be interpreted with caution as similar reads were also identified in extraction controls. IL-6 levels were significantly increased in samples with reads that mapped to Pelomonas sp., whilst TNF-α levels were elevated in fluid samples from pregnancies that subsequently delivered preterm. Bacterial DNA unlikely to have originated from extraction controls was identified in 20/31 (64.5%) mid-gestation amniotic fluid samples. Bacterial DNA profiles, however, were not predictive of preterm birth, and although cytokine levels were elevated in the presence of certain genera, the biological relevance of this remains unknown.

Maternal complications associated with second trimester medical abortion using mifepristone priming and subsequent misoprostol.

OBJECTIVES: To assess the frequency of maternal adverse events associated with second trimester medical abortion using sequential mifepristone and misoprostol. STUDY DESIGN: Retrospective analysis of medical abortions 13 to 28 weeks gestation using sequential mifepristone and misoprostol in a single center from January 2008 to December 2018. The main outcomes evaluated were the nature and incidence of adverse procedural events and the impact of gestation upon these outcomes. RESULTS: During the study period, 1393 people underwent a medical abortion with sequential mifepristone and misoprostol. The median maternal age was 31 years (IQR 27-36 years) and 21.8% had at least one prior cesarean delivery. The median gestational age at abortion commencement was 19 weeks (IQR 17-21). The main adverse maternal events were complete or partial placental retention greater than 60 minutes triggering removal in the operating room (19%), maternal hemorrhage>1000 cc (4.3%), blood transfusion (1.7%), hospital readmission (1.4%), uterine rupture (0.29%) and hysterectomy (0.07%). There were significant reductions in placental retention rates with increasing gestational age (23.3% at 13-16 weeks gestation declining to 10.1% at>23 weeks gestation, p < 0.001). CONCLUSIONS: Serious adverse maternal events associated with second trimester medical abortion with sequential mifepristone-misoprostol are uncommon. IMPLICATIONS: Second trimester medical abortion with mifepristone and misoprostol is generally safe, however, on occasions serious complications may occur. All health care units providing a medical abortion service require the facilities and expertise to deal with these adverse events in a timely manner.

Registry randomised trials: a methodological perspective.

Registry randomised clinical trials (RRCTs) have the potential to provide pragmatic answers to important clinical questions. RRCTs can be embedded into large population-based registries or smaller single site registries to provide timely answers at a reduced cost compared with traditional randomised controlled trials. RRCTs can take a number of forms in addition to the traditional individual-level randomised trial, including parallel group trials, platform or adaptive trials, cluster randomised trials and cluster randomised stepped-wedge trials. From an implementation perspective, initially it is advantageous to embed RRCT into well-established registries as these have typically already overcome any issues with end point validation and adjudication. With advances in data linkage and data quality, RRCTs can play an important role in answering clinical questions in a pragmatic, cost-effective way.

Mifepristone priming and subsequent misoprostol for second trimester medical abortion in women with previous caesarean delivery.

AIMS: To assess clinical outcomes and complications in women with ≥1 prior caesarean delivery (CS) during mid-pregnancy medical abortion with misoprostol following mifepristone priming. MATERIALS AND METHODS: Retrospective analysis of abortions at 13-28 weeks gestation using sequential mifepristone and misoprostol at a single centre from 1/2008-12/2018. Procedural outcomes were compared between cases with no prior CS, one prior and ≥2 prior CS. RESULTS: There were 1399 consecutive women who underwent a medical abortion, with 304 (21.7%) having ≥1 prior lower segment CS (241 one, 49 two, 12 three, one four) and one a prior classical CS. Median gestation was 19 weeks (interquartile range (IQR) 17-21) among nulliparas, multiparas with no prior CS and multiparas with prior CS, P = 0.505. Compared with nulliparas (median procedural duration 10.8 h, IQR 7.5-16.5; adjusted hazards ratio (aHR) = 1.20 95%CI 1.04-1.40, P = 0.015), multiparas with prior CS had a shorter procedural duration (9.5 h, IQR 6.5-13.5) while multiparas with no CS had the shortest duration (7.0 h, IQR 5.0-9.8; aHR = 2.28 95%CI 2.01-2.58, P < 0.001). Complications were more frequent with prior CS: estimated blood loss (medians: 100 cc no CS vs 150 cc ≥1 CS, P = 0.002), blood loss >1000 cc (3.6% no CS vs 7.2% ≥1 CS; odds ratio (OR) = 2.11 95%CI 1.23-3.62, P = 0.007) and placental retention (17.3% no CS vs 25.3% ≥1 CS; adjusted OR = 1.44 95%CI 1.05-1.99, P = 0.024). Uterine rupture occurred in 4/304 women with ≥1 prior CS (1.3%). CONCLUSIONS: Mifepristone-misoprostol abortion in women with prior CS is generally safe but associated with an increased risk of procedural complications. Lowering of the misoprostol dosage with prior CS may reduce uterine rupture, although this hypothesis requires ongoing research.

The Western Australian preterm birth prevention initiative: a whole of state singleton pregnancy cohort study showing the need to embrace alternative models of care for Aboriginal women.

BACKGROUND: Preterm birth (PTB) is the greatest cause of mortality and morbidity in children up to five years of age globally. The Western Australian (WA) PTB Prevention Initiative, the world's first whole-of-population whole-of-state program aimed at PTB prevention, was implemented across WA in 2014. METHODS: We conducted a prospective population-based cohort study using pregnancy data for singleton births in WA from 2009 to 2019. Logistic regression using the last full year before the Initiative (2013) as the reference, and run charts were used to examine changes in PTB rates compared to pre-Initiative levels, by gestational age group, hospital type, low and high risk of PTB in mid-pregnancy, and onset of labour (spontaneous/medically initiated). Analyses were stratified by Aboriginal and non-Aboriginal maternal ethnicity. RESULTS: Amongst non-Aboriginal women, there was initially a reduction in the PTB rate across the state, and in recent years it returned to pre-Initiative levels. Amongst Aboriginal women there was a small, non- significant reduction in the state-wide PTB rate in the first three years of the Initiative, followed by a rise in recent years. For non-Aboriginal women, the reduction in the rate of PTB at the tertiary centre was sustained and improved further for women of all risk levels and onsets of labour. This reduction was not observed for Aboriginal women giving birth at the tertiary centre, amongst whom there was an increase in the PTB rate overall and in all subgroups, with the exception of medically initiated PTB. Amongst Aboriginal women the PTB rate has also increased across the state. At non-tertiary hospitals there was a large increase in PTB amongst both Aboriginal and non-Aboriginal women, largely driven by medically initiated late PTB. Maternal risk factors cannot account for this increase. CONCLUSIONS: The reduction in PTB rates amongst non-Aboriginal women at the state's tertiary hospital demonstrates that with the right strategies, PTB can be reduced. A sustained collaborative model is required to realise this success in non-tertiary hospitals. The series of interventions was of limited use in Aboriginal women, and future efforts will need to be directed at strategies more likely to be successful, such as midwifery continuity of care models, with Aboriginal representation in the healthcare workforce.

Longitudinal effects of prenatal exposure to plastic-derived chemicals and their metabolites on asthma and lung function from childhood into adulthood.

BACKGROUND AND OBJECTIVE: Environmental exposure to phthalates and bisphenol A (BPA), chemicals used in the production of plastics, may increase risk for asthma and allergies. However, little is known about the long-term effects of early life exposure to these compounds. We investigated if prenatal exposure to these compounds was associated with asthma, allergy and lung function outcomes from early childhood into adulthood in a cohort study. METHODS: Maternal serum samples collected from 846 pregnant women in the Raine Study were assayed for BPA and phthalate metabolites. The children of these women were followed up at 5, 13 and 22 years where spirometry and respiratory questionnaires were conducted to determine asthma and allergy status. Lung function trajectories were derived from longitudinal spirometry measurements. Multinomial logistic regression and weighted quantile sum regression was used to test associations of individual and chemical mixtures with asthma phenotypes and lung function trajectories. RESULTS: Effects of prenatal BPA and phthalates on asthma phenotypes were seen in male offspring, where BPA was associated with increased risk for persistent asthma, while mono-iso-butyl phthalate and mono-iso-decyl phthalate was associated with increased risk for adult asthma. Prenatal BPA had no effect on lung function trajectories, but prenatal phthalate exposure was associated with improved lung function. CONCLUSION: Prenatal BPA exposure was associated with increased likelihood of persistent asthma in males, while prenatal phthalate exposure was associated with increased likelihood of adult asthma in males. Results suggest that prenatal exposure to prenatal BPA and phthalates affect asthma risk, particularly in males, however lung function was not adversely affected.

Associations between Prenatal Exposure to Phthalates and Features of the Metabolic Syndrome in Males from Childhood into Adulthood.

Phthalate metabolites are detectable within the majority of the population. Evidence suggests that a prenatal exposure to phthalates may be associated with the subsequent risks of obesity and elevated blood pressure. We hypothesised that a prenatal exposure to phthalates would lead to an increase in adverse cardiometabolic parameters through childhood and adulthood. The maternal serum phthalate measurements from the stored samples taken from Gen1 mothers at 18 and 34 weeks gestation were examined in relation to the cardiometabolic measures in 387 male offspring from the Raine Study. Data from the Gen2 follow-ups between 3 and 27 years were used. The primary outcomes were analysed longitudinally using linear mixed models for the repeated measures. Non-alcoholic fatty liver disease (NAFLD) was assessed at 17 years using logistic regression. A consistent positive relationship was observed between a prenatal exposure to mono-carboxy-iso-octyl phthalate (MCiOP) through adolescence into adulthood with systolic blood pressure. There were no other consistent cardiovascular associations. Mid-levels of prenatal exposures to Mono-n-butyl phthalate (MnBP) were associated with a greater incidence of NAFLD. Detectable Mono-3-carboxypropyl phthalate (MCPP) was associated with a lower serum HDL-C through late childhood into adulthood, while a higher prenatal exposure to mono-iso-butyl phthalate (MiBP), was associated with a higher LDL-C at 22 years of age. A mid-level prenatal exposure to mono-2-ethylhexyl phthalate (MEHP) metabolites was associated with higher insulin in adulthood, while a higher prenatal exposure to the sum of the Di-(2-ethyl-hexyl) phthalate (DEHP) and Di-iso-nonyl phthalate (DiNP) metabolites was associated with higher fasting serum glucose in adulthood. In conclusion, our study demonstrated that higher prenatal phthalate exposures to some phthalate metabolites was associated with some adverse metabolic profiles through adolescence into adulthood, although the consistent themes were limited to a few metabolites and the outcomes of systolic blood pressure, fasting insulin and glucose.

Asthma and allergies in a cohort of adolescents conceived with ART.

RESEARCH QUESTION: Are asthma and allergies more common in adolescents conceived with assisted reproductive technologies (ART) compared with adolescents conceived without? DESIGN: The Growing Up Healthy Study (GUHS) is a prospective cohort study including ART-conceived offspring born between 1991 and 2001 in Perth, Australia. Their long-term health outcomes, including asthma and allergy parameters, were compared with those of their counterparts conceived without ART from the Raine Study Generation 2 (Gen2), born in 1989-1991. At age 14, 152 GUHS and 1845 Gen2 participants completed the following assessments: the International Studies of Asthma and Allergies in Childhood (ISAAC) questionnaire, spirometry, methacholine challenge testing and skin prick testing (SPT). RESULTS: No differences were detected in the prevalence of current asthma (7.7% versus 10.8%, adjusted odds ratio [aOR] 0.82 (95% CI 0.44-1.52), P = 0.530). Spirometry-measured lung volumes were larger in the ART adolescents. Bronchial hyperresponsiveness was less prevalent in the ART cohort (8.8 versus 18.6%, P = 0.006). Current allergic rhinoconjunctivitis (ARC) rates were significantly higher in the ART cohort (32.4% versus 25.2%, aOR 1.52 [95% CI 1.03-2.26], P = 0.036), with no cohort differences in atopic dermatitis. Food allergies were more prevalent in the ART cohort (20.7 versus 10.9%, aOR 1.89 [95% CI 1.17-3.06], P = 0.010) with more adolescents having a positive SPT (68.0% versus 45.4%, aOR 3.03 [95% 1.99-4.63], P < 0.001). CONCLUSIONS: This study reports no differences in asthma prevalence, slightly altered lung function, an increase in ARC, food allergies and positive SPT in the ART-conceived adolescents. These findings are important to families and healthcare providers and may open up possibilities for targeted screening and treatment. Further studies are required to confirm these findings.

Consistency in the transabdominal ultrasound measurement of cervical length in mid-pregnancy.

Purpose: The Western Australian Preterm Birth Prevention Initiative recommends a transabdominal cervical length (TACL) measurement at the mid-pregnancy ultrasound to screen low-risk women for preterm birth risk. In view of this recommendation, we assessed the inter-observer consistency of TACL screening in mid-pregnancy. Methods: Routinely collected mid-pregnancy TACL ultrasound images were graded from 0 to 4 according to the anatomical landmarks identified by a single expert. A random selection of 10 images of each grade were disseminated in an electronic survey to determine inter- and intra-observer variations in the classification of the cervical image. Results: A total of 244 participants graded 50 TACL images. Six participants repeated the grading. Overall agreement to the exact initial grade for all images was 49.6%, highest for images at both ends of the spectrum (83% Grade 0 and 70.4% for Grade 4). Overall agreement to the initial diagnostic Grades 3 and 4 was 75.3% (95% CI 74.5-76.0%) and was higher when the maternal bladder was empty. There was moderate inter-rater agreement (κ = 0.42) for Grades 3 and 4 (diagnostic) or Grades 1 and 2 (non-diagnostic). The intra-rater agreement was fair to good (κ = 0.59, 95% CI 0.49-0.70) for those who repeated the assessment (including the expert grader). Conclusions: Sonographic CL screening is considered an important tool for the identification of women at high risk of preterm birth. Image classification of TACL performed poorly compared with previous studies assessing transvaginal cervical length. Improved reliability and measurement consistency may be achieved through high levels of quality assurance, ongoing training and image audit.

Health, social and economic implications of adolescent risk behaviours/states: protocol for Raine Study Gen2 cohort data linkage study.

Background: Risk-taking behaviours are a major contributor to youth morbidity and mortality. Vulnerability to these negative outcomes is constructed from individual behaviour including risk-taking, and from social context, ecological determinants, early life experience, developmental capacity and mental health, contributing to a state of higher risk. However, although risk-taking is part of normal adolescent development, there is no systematic way to distinguish young people with a high probability of serious adverse outcomes, hindering the capacity to screen and intervene. This study aims to explore the association between risk behaviours/states in adolescence and negative health, social and economic outcomes through young adulthood. Methods: The Raine Study is a prospective cohort study which recruited pregnant women in 1989-91, in Perth, Western Australia. The offspring cohort (N = 2,868) was followed up at regular intervals from 1 to 27 years of age. These data will be linked to State government health and welfare administrative data. We will empirically examine relationships across multiple domains of risk (for example, substance use, sexual behaviour, driving) with health and social outcomes (for instance, road-crash injury, educational underachievement). Microsimulation models will measure the impact of risk-taking on educational attainment and labour force outcomes. Discussion: Comprehensive preventive child health programmes and policy prioritise a healthy start to life. This is the first linkage study focusing on adolescence to adopt a multi-domain approach, and to integrate health economic modelling. This approach captures a more complete picture of health and social impacts of risk behaviour/​states in adolescence and young adulthood.

The perceptions of obstetric care providers about cervical length screening for preterm birth prevention.

BACKGROUND: Routine cervical length (CL) measurement at the mid-pregnancy ultrasound is a central recommendation of the Western Australian Preterm Birth Prevention Initiative (Initiative). AIM: To evaluate the perceptions and changes in practice of Western Australian obstetric care providers regarding routine CL screening for preterm birth (PTB) prevention following the Initiative introduction. METHODS: Two self-administered questionnaires were completed by providers from a range of practices. The first was during site visits with the Initiative Outreach team in 2015-2016. The questionnaire was re-issued in 2021 via online dissemination. Participant demographic data and opinions on CL screening for PTB prevention were collected. RESULTS: Two hundred and fourteen providers participated in 2015-2016 and 109 in 2021. In both surveys, providers were more likely to discuss transvaginal CL screening with high-risk women (48.1%, 76.1%; P < 0.001) compared with low-risk (7.5%, 18.3%; P = 0.002) and the importance of CL screening (13.5%, 40.4%; P < 0.001), in 2015-2016 and 2021, respectively. Responses relating to CL screening, including what constitutes a short cervix on ultrasound were varied. A transabdominal CL <35 mm was classified as short by 46.2% and 37.6% and <25 mm on transvaginal ultrasound by 49.1% and 64.2%, in the respective surveys. Most providers ceased progesterone (68.6%, 75.2%) at >28 weeks gestation. CONCLUSIONS: Providers focused on women with overt PTB risk factors, rather than a universal CL screening approach. Although there was improvement between the surveys, the definition of what constitutes a short cervix on ultrasound and how to treat and monitor women with a short CL remained varied.

The health and educational costs of preterm birth to 18 years of age in Australia.

BACKGROUND: Preterm birth is the greatest cause of death up to five years of age and an important contributor to lifelong disability. There is increasing evidence that a meaningful proportion of early births may be prevented, but widespread introduction of effective preventive strategies will require financial support. AIMS: This study estimated the economic cost to the Australian government of preterm birth, up to 18 years of age. MATERIALS AND METHODS: A decision-analytic model was developed to estimate the costs of preterm birth in Australia for a hypothetical cohort of 314 814 children, the number of live births in 2016. Costs to Australia's eight jurisdictions included medical expenditures and additional costs to educational services. RESULTS: The total cost of preterm birth to the Australian government associated with the annual cohort was estimated at $1.413 billion (95% CI 1047-1781). Two-thirds of the costs were borne by healthcare services during the newborn period and one-quarter of the costs by educational services providing special assistance. For each child, the costs were highest for those born at the earliest survivable gestational age, but the larger numbers of children born at later gestational ages contributed heavily to the overall economic burden. CONCLUSION: Preterm birth leaves many people with lifelong disabilities and generates a significant economic burden to society. The costs extend beyond those to the healthcare system and include additional educational needs. Assessments of economic costs should inform economic evaluations of interventions aimed at the prevention or treatment of preterm birth.

Asthma and allergies in offspring conceived by ART: a systematic review and meta-analysis.

BACKGROUND: Currently, 1 in 25 children born in Australia are conceived through ARTs such as IVF and ICSI. Worldwide over 8 million children have been born after ART. There is evidence that these children are at an increased risk of congenital malformations, preterm birth, low birth weight and neonatal morbidity. However, studies on long-term health outcomes of offspring conceived after ART are lacking. Atopic disorders, such as asthma, atopic dermatitis and various allergies are increasingly common within society, and concerns have been raised that ART increases the risk of atopy amongst offspring. OBJECTIVE AND RATIONALE: The aim of this study was to systematically summarise and quantify the risk of atopic disorders in offspring conceived with ART compared to those conceived without ART. SEARCH METHODS: A systematic review was conducted according to the PRISMA guidelines. Several systematic searches were performed in the following international databases: Medline, Embase, Cinahl, PsychINFO, AMED, Global Health and ISI Web of Science. Search terms utilised were all terms pertaining to ART, IVF, ICSI, asthma, atopic dermatitis and allergies. The search period was 1978-2021. Included observational studies stated a primary outcome of asthma or allergies in offspring conceived after ART, with a comparison group conceived without ART. Individual studies were scored on quality and risk of bias, using the Newcastle-Ottawa scale (NOS). OUTCOMES: There were 26 studies which met the inclusion criteria; of these, 24 studies investigated asthma in offspring conceived after ART. While 10 studies, including the two largest population-based studies, reported a significantly increased risk of asthma in offspring conceived after ART (adjusted odds ratio (aOR) range: 1.20-2.38), 14 smaller cohort studies found no difference (aOR range 0.70-1.27). In the meta-analysis of the 14 highest-quality studies (NOS ≥ 7), a modest yet significantly increased risk of asthma was demonstrated in offspring conceived after ART [risk ratio (RR) 1.28 (1.08-1.51)]. Although heterogeneity in these 14 studies was high (I2 = 85%), the removal of outliers and high weight studies significantly reduced heterogeneity (I2 = 0% and I2 = 34% respectively) while still demonstrating a significantly increased risk [RR 1.19 (1.10-1.28) and RR 1.31 (1.03-1.65), respectively]. The increased asthma risk was also observed in most subgroup and sensitivity analyses. The allergy rates were not increased in offspring conceived after ART in 9 of 12 studies (aOR range 0.60-1.30). In summary, the findings of this systematic review and meta-analysis suggest a trend towards a significantly increased risk of asthma, but not allergies, in offspring conceived after ART. There was no evidence of publication bias in the asthma studies and minimal evidence of publication bias in the allergy studies (both P > 0.05). WIDER IMPLICATIONS: Asthma brings considerable burden to the quality of life of individuals and to society. Hence, it is of great importance to untangle potential causal pathways. Although ART use is common, knowledge about its long-term health effects is required to provide evidence-based advice to couples considering ART, and to be vigilant for any potential adverse health effects on offspring conceived after ART.

Associations between Prenatal Exposure to Phthalates and Timing of Menarche and Growth and Adiposity into Adulthood: A Twenty-Years Birth Cohort Study.

Phthalates are ubiquitous environmental chemicals with endocrine disrupting properties and potentially obesogenic effects. We hypothesised that antenatal phthalate exposure may influence growth and adiposity patterns in girls through childhood into adolescence. Among 1342 Raine Study singleton females, 462 had maternal serum and at least one outcome available up to 20 years of age. Individuals' maternal serum collected at 18 and 34 weeks gestation was pooled and analyzed for concentrations of 32 metabolites of 15 phthalate diesters. Cox regression and linear models were used to determine associations between maternal phthalate levels and age at menarche, change in height and weight z-scores between birth and two years, height from birth to 20 years, BMI from two to 20 years, deviation from mid-parental height at age 20 and DEXA scan measures at age 20. Weak negative associations were detected with some phthalate metabolites and change in height and weight z-score during infancy. Weak positive associations between some of the high molecular weight phthalate metabolites and height z-score were detected during childhood. While still within the normal range, age at menarche was slightly delayed in girls with higher prenatal exposure to the higher molecular weight phthalate metabolites. We derived some associations between prenatal phthalate exposure with early growth patterns and age at menarche.

The perceptions of pregnant women about cervical length screening for preterm birth prevention.

BACKGROUND: The Western Australian Preterm Birth Prevention Initiative was officially launched in November 2014. It demonstrated an initial decrease in the preterm birth rate in Western Australia. One of the key points of this initiative is the routine ultrasound measurement of the cervical length in mid-pregnancy. AIM: The aim of this study was to evaluate the perceptions and attitudes of Western Australian women regarding transvaginal cervical length (TVCL) screening for preterm birth prevention. MATERIALS AND METHODS: Self-administered questionnaires were completed by pregnant women before and after their mid-trimester obstetric ultrasound. Maternal demographical and medical data were collected in addition to opinions of TVCL screening. RESULTS: A total of 598 women participated with the maternal age range representative of the Western Australian obstetric population. There was a high rate of acceptance of TVCL imaging, with 2% of the 149 women declining a transvaginal ultrasound (TVU) offered in this study, 1.5% refusing a TVU in the past and 5.7% reporting that they would have a concern in having a TVU in the future. Women stated that they either had declined TVCL in the past (11%) or would decline in the future (30.7%) as they wanted to discuss the procedure with their clinician first, had been advised not to have a TVU by their clinician (11% in the past and 47.7% in the future) or felt uncomfortable with the operator (22% at a previous TVU and 34.4% in the future). CONCLUSION: Pregnant women participating in this study had a high acceptance of TVCL screening for preterm birth prevention.

Pretreatment With Mifepristone Compared With Misoprostol Alone for Delivery After Fetal Death Between 14 and 28 Weeks of Gestation: A Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy of pretreatment with mifepristone before misoprostol, compared with misoprostol alone, for termination of pregnancy after a fetal death in the second trimester. METHODS: This prospective, double blind, placebo-controlled trial randomized women requiring a termination of pregnancy after fetal death between 14 and 28 weeks of gestation to placebo or 200 mg mifepristone orally 24-48 hours before the termination of pregnancy with misoprostol (400 micrograms every 6 hours vaginally for women at 24 weeks of gestation or less, and 200 micrograms every 4 hours vaginally for women at 24 weeks of gestation or more). Based on a median labor with misoprostol alone in the second trimester of 13 hours, a sample size of 116 women per group was planned to compare the primary outcome of time from administration of misoprostol to delivery. The trial was ceased after 66 women were enrolled secondary to prolonged time to achieve recruitment. RESULTS: From April 2013 to November 2016, 66 women were randomized (34 to placebo and 32 to mifepristone). There were no differences in the characteristics between the two groups. The median time for the primary outcome of administration of misoprostol to delivery in the placebo group was 10.5 hours, compared with 6.8 hours in the treatment group (hazard ratio 2.41 95% CI 1.39-4.17, P=.002). Women in the placebo group required more doses of misoprostol (3.4 vs 2.1, P=.002) and more misoprostol overall (1,181.8 micrograms, vs 767.7 micrograms, P=.003). There was no difference in maternal complications between the two groups. Women in the mifepristone group reported improved perception of the procedure. CONCLUSION: The sequential use of mifepristone and misoprostol for the termination of pregnancy after fetal deaths between 14 and 28 weeks of gestation reduces the time to delivery, compared with the use of misoprostol alone, with no worsening of maternal complications. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12612000884808.

Preventing early births in a regional tertiary maternity unit: Evaluating preterm and early term birth rates before and after implementation of the Preterm Birth Prevention Initiative in the Australian Capital Territory.

BACKGROUND: A multifaceted preterm birth (PTB) prevention initiative was launched in the Australian Capital Territory (ACT) in 2019. The aim of this initiative was to safely lower the rate of early births across the ACT and the surrounding areas in New South Wales. Modelled on the Western Australian PTB Prevention Initiative, the program included new clinical guidelines and a new PTB prevention clinic at the main tertiary hospital. AIM: To evaluate the initiative and its effects on preterm and early term birth rates at the main tertiary hospital after 16 months of implementation. MATERIALS AND METHODS: A before and after intervention study was conducted. Rates of preterm and early term birth before (previous five years) and after 16 months of implementation of the ACT PTB Prevention Initiative were evaluated. RESULTS: At the main tertiary hospital in The Canberra Hospital, the rate of PTB was significantly reduced by 10% after 16 months of implementation of the initiative. Rates of PTB were lower than any of the preceding five years and resulted in 45 averted or delayed PTBs. The number of planned early term births with no medical indication was significantly reduced by 34.5% and resulted in 77 averted or delayed early term births. CONCLUSIONS: The multifaceted PTB Prevention Initiative safely lowered the rates of early birth in the ACT context. These results highlight the importance of prioritising early birth prevention, education, research and expanding the initiative nationwide.

Pulmonary Gas Exchange Improves over the First Year in Preterm Infants with and without Bronchopulmonary Dysplasia.

BACKGROUND: Right shift of the peripheral oxyhaemoglobin saturation (SpO2) versus inspired oxygen pressure (PIO2) curve is a sensitive marker of pulmonary gas exchange. OBJECTIVES: The aim of this study was to assess the impact of prematurity and bronchopulmonary dysplasia (BPD) on gas exchange and right-to-left shunt in the neonatal period, and its evolution over the first year of life. METHOD: We assessed shift and shunt in extremely preterm (EP) and very preterm (VP) infants at 36 and 44 weeks' postmenstrual age (PMA), and at 1-year corrected postnatal age (cPNA). PIO2 was decreased stepwise to achieve SpO2 between 85 and 98%. Shift and shunt were calculated from paired SpO2/PIO2 measurements using customized software. Results were examined cross-sectionally at each time point, and longitudinally using generalized linear regression. Term infants were assessed at 44 wk PMA as a comparative reference. RESULTS: Longitudinal modelling showed continuous decline in shift in EP and VP infants during the first year of life. There was no difference in shift compared to term infants at 44 wk PMA (p = 0.094). EP infants with BPD had higher shift than infants without BPD at 36 wk PMA (p < 0.001) and 44 wk PMA (p = 0.005) but not at 1-year cPNA. CONCLUSIONS: In the absence of lung disease, prematurity per se did not result in reduced gas exchange at 1-year cPNA. We report ongoing, significant improvements in pulmonary gas exchange in all preterm infants during the first year of life, despite evidence of early deficits in gas exchange in EP infants with BPD.

Effect of shift work on fatigue and sleep in neonatal registrars.

OBJECTIVE: We aimed to study fatigue and sleep in registrars working 12-hour rotating shifts in our tertiary neonatal intensive unit. METHODS AND PARTICIPANTS: This study involved neonatal registrar's working day (08:00-21:00) and night (20:30-08:30) shifts. Participants maintained a sleep diary, answered a self-reported sleepiness questionnaire assessing subjective sleepiness, and performed a 10-minute psychomotor vigilance task (PVT) at the start and end of each shift. Primary outcomes: (1) Fatigue at the (i) "start vs end" of day and night shifts, (ii) end of the "day vs night" shifts, and (iii) end of "first vs last shift" in block of day and night shifts. (2) Duration and quality of sleep before the "day vs night" shifts. Mean reaction time (RTM), relative coefficient of variation (RTCV), and lapses (reaction time > 500ms) were used as measures of fatigue on PVT. Secondary outcome: Subjective sleepiness (self-reported sleepiness questionnaire) at the 'start vs end" of day and night shifts. RESULTS: Fifteen registrars completed the study. Acuity was comparable for all shifts. (1) Psychomotor responses were impaired at the end vs start of day shifts [RTM (p = 0.014), lapses (p = 0.001)], end vs start of night shifts [RTM (p = 0.007), RTCV (p = 0.003), lapses (p<0.001)] and end of night vs day shifts [RTM (p = 0.007), RTCV (p = 0.046), lapses (p = 0.001)]. Only lapses were significantly increased at the end of the last (p = 0.013) vs first shift (p = 0.009) in a block of day and night shifts. (2) Duration of sleep before the night (p = 0.019) and consecutive night shifts was decreased significantly (p = 0.034). Subjective sleepiness worsened after day (p = 0.014) and night shifts (p<0.001). CONCLUSION: Fatigue worsened after the 12-hour day and night shifts with a greater change after night shifts. Lapses increased after block of day and night shifts. Sleep was decreased before night shifts. Our findings need to be confirmed in larger studies.