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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-1β, 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-1β 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.

Anorexia nervosa is a potentially severe, chronic, and relapsing mental disorder that is more common in women and girls during the reproductive years (usually defined as those aged 12-51 years). It is associated with suicide and mortality linked with the physical consequences of starvation. Although anorexia nervosa is a disorder of low prevalence, and even lower prevalence in pregnancy, it is associated with substantial risks for the mother and infant when under-recognised and undermanaged. Despite the complexity and risk of managing anorexia nervosa in pregnancy, few studies are available to guide care. We conducted a systematic review, identifying only eight studies that addressed the management of anorexia nervosa in pregnancy. These studies were case studies or case reports examining narrow aspects of management. Subsequently, we conducted a state-of-the-art review across research in relevant disciplines and areas of expertise for managing anorexia nervosa in pregnancy and synthesised the findings into recommendations and principles for multidisciplinary management of anorexia nervosa in pregnancy. These recommendations included a focus on the specialist mental health, obstetric, medical, and nutritional care required to ensure optimal outcomes for women and their infants. Despite the complexity and risks, a gap exists in the comprehensive guidelines and recommendations for managing anorexia nervosa in pregnancy. This Review provides multidisciplinary recommendations for clinical care in this area. Managing anorexia nervosa in pregnancy is an area of clinical care that requires a multidisciplinary approach and includes those experienced in managing high-risk pregnancies.

PURPOSE: The aim of this study was to investigate the applicability of four existing fetal growth charts to a local tertiary hospital obstetric population. METHOD: Four existing fetal growth charts (the Raine study reference charts, INTERGROWTH‐21st charts, World Health Organization (WHO) fetal growth study charts and Australasian Society for Ultrasound in Medicine (ASUM) endorsed Campbell Westerway charts were compared using data from 11651 singleton pregnancy ultrasound scans at King Edward Memorial Hospital (KEMH). The 3rd, 10th, 50th 90th and 97th percentile curves for abdominal circumference (AC) biometry for the KEMH data were calculated and the four primary correlation parameters from fitted 3rd order polynomials (a, b, c and d) were used to generate like‐for‐like comparisons for all charts. RESULTS: The overall comparisons showed a significant variation with different growth charts, giving different percentiles for the same fetal AC measurement. INTERGROWTH‐21st percentile curves tended to fall below those of other charts for AC measurements. Both the Raine Study charts and ASUM charts were the charts of closest overall fit to the local data. CONCLUSION: Our data show the Raine Study charts are the most appropriate for our population compared with the other three charts assessed suggesting the ‘one size fits all’ model may not be appropriate. However, additional analysis of biometry measurements, primarily AC, is needed to address the deficiency of data at 14‐18 weeks gestation which exists for the Raine Study data. A reasonable alternative may be to adopt the WHO charts with local calibration (including the 14 ‐ 18 week gestation period).

Background: Induction of labour is one of the most common obstetric interventions globally. Balloon catheters and vaginal prostaglandins are widely used to ripen the cervix in labour induction. We aimed to compare the effectiveness and safety profiles of these two induction methods. Methods: We did an individual participant data meta-analysis comparing balloon catheters and vaginal prostaglandins for cervical ripening before labour induction. We systematically identified published and unpublished randomised controlled trials that completed data collection between March 19, 2019, and May 1, 2021, by searching the Cochrane Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and PubMed. Further trials done before March 19, 2019, were identified through a recent Cochrane review. Data relating to the combined use of the two methods were not included, only data from women with a viable, singleton pregnancy were analysed, and no exclusion was made based on parity or membrane status. We contacted authors of individuals trials and participant-level data were harmonised and recoded according to predefined definitions of variables. Risk of bias was assessed with the ROB2 tool. The primary outcomes were caesarean delivery, indication for caesarean delivery, a composite adverse perinatal outcome, and a composite adverse maternal outcome. We followed the intention-to-treat principle for the main analysis. The primary meta-analysis used two-stage random-effects models and the sensitivity analysis used one-stage mixed models. All models were adjusted for maternal age and parity. This meta-analysis is registered with PROSPERO (CRD42020179924). Findings: Individual participant data were available from 12 studies with a total of 5460 participants. Balloon catheters, compared with vaginal prostaglandins, did not lead to a significantly different rate of caesarean delivery (12 trials, 5414 women; crude incidence 27·0%; adjusted OR [aOR] 1·09, 95% CI 0·95–1·24; I2=0%), caesarean delivery for failure to progress (11 trials, 4601 women; aOR 1·20, 95% CI 0·91–1·58; I2=39%), or caesarean delivery for fetal distress (10 trials, 4441 women; aOR 0·86, 95% CI 0·71–1·04; I2=0%). The composite adverse perinatal outcome was lower in women who were allocated to balloon catheters than in those allocated to vaginal prostaglandins (ten trials, 4452 neonates, crude incidence 13·6%; aOR 0·80, 95% CI 0·70–0·92; I2=0%). There was no significant difference in the composite adverse maternal outcome (ten trials, 4326 women, crude incidence 22·7%; aOR 1·02, 95% CI 0·89–1·18; I2=0%). Interpretation: In induction of labour, balloon catheters and vaginal prostaglandins have comparable caesarean delivery rates and maternal safety profiles, but balloon catheters lead to fewer adverse perinatal events. Funding: Australian National Health and Medical Research Council and Monash Health Emerging Researcher Fellowship.

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.

Non-invasive prenatal testing (NIPT) using cell-free DNA (cfDNA) has expanded from detecting chromosome aneuploidy to testing for a variety of genetic conditions, including some select single gene disorders. As next generation sequencing/whole exome sequencing technology develops, it may be possible to expand NIPT of cfDNA to identify hundreds of single gene and chromosomal disorders in a fetus, thereby increasing the complexity of pretest counselling and parental decision-making.The aim of this study was to assess the views of women on the phenotypes of genetic conditions potentially detectable with expanded NIPT that they would consider severe enough to warrant pregnancy termination.Using multiple clinical scenarios, we asked women via an online survey about the early detection of several well-described genetic phenotypes in pregnancy that in theory could be detected by expanded NIPT.Two hundred and nineteen women participated in this study. There was high support for early diagnosis and the option for termination of pregnancy in conditions perceived as severe (52-71%). Women expressed a preference for testing to be provided by general practitioners and assigned a high value to genetic counselling support (75-90%). In the case of a continuing pregnancy, women recognised the essential role of ongoing psychosocial counselling for family members and childhood early intervention programs.Women expressed clear preferences for termination of pregnancy for severe conditions and as early in gestation as feasible. Information and support from genetic counsellors are a highly valued resource in decision-making following a prenatal diagnosis of a fetal genetic abnormality.

OBJECTIVE: To determine the epidemiology, clinical management, and outcomes of women with gestational breast cancer (GBC). METHODS: A population-based prospective cohort study was conducted in Australia and New Zealand between 2013 and 2014 using the Australasian Maternity Outcomes Surveillance System (AMOSS). Women who gave birth with a primary diagnosis of breast cancer during pregnancy were included. Data were collected on demographic and pregnancy factors, GBC diagnosis, obstetric and cancer management, and perinatal outcomes. The main outcome measures were preterm birth, maternal complications, breastfeeding, and death. RESULTS: Forty women with GBC (incidence 7.5/100 000 women giving birth) gave birth to 40 live-born babies. Thirty-three (82.5%) women had breast symptoms at diagnosis. Of 27 women diagnosed before 30 weeks' gestation, 85% had breast surgery and 67% had systemic therapy during pregnancy. In contrast, all 13 women diagnosed from 30 weeks had their cancer management delayed until postdelivery. There were 17 preterm deliveries; 15 were planned. Postpartum complications included the following: hemorrhage (n = 4), laparotomy (n = 1), and thrombocytopenia (n = 1). There was one late maternal death. Eighteen (45.0%) women initiated breastfeeding, including 12 of 23 women who had antenatal breast surgery. There were no perinatal deaths or congenital malformations, but 42.5% of babies were preterm, and 32.5% were admitted for higher-level neonatal care. CONCLUSIONS: Gestational breast cancer diagnosed before 30 weeks' gestation was associated with surgical and systemic cancer care during pregnancy and planned preterm birth. In contrast, cancer treatment was deferred to postdelivery for women diagnosed from 30 weeks, reflecting the complexity of managing expectant mothers with GBC in multidisciplinary care settings.

Purpose: To highlight the various options available for the management of breast cancer diagnosed during pregnancy by describing the investigations, treatment, and outcomes in relation to these women. Methods: This is a narrative review of the literature to describe the issues related to pregnancy and obstetric management in patients with breast cancer. It incorporates a description of six cases of women (aged 29-39 years) with a first-time diagnosis of breast cancer during pregnancy to illustrate a number of issues that need to be considered during different trimesters. Results: Of the six cases, two were diagnosed in each pregnancy trimester. A painless breast mass was the presenting symptom in five cases (83%). In all cases, breast ultrasound was the primary diagnostic imaging procedure. Chest X-ray was performed in 3 (50%) and computed tomography in 2 (33%). A core needle biopsy was performed in all cases, and sentinel lymph node biopsy in 3 (50%) cases. Four women had grade 3 tumor; five had estrogen receptor-positive tumors. Four women had breast surgery during pregnancy. Five women gave birth after the induction of labor and/or cesarean section. In all six cases, a multidisciplinary team was involved in the delivery of health care. Conclusion: Regular breast examinations are needed for all pregnant woman during prenatal visits. Breast ultrasonography should be offered if a breast lump or other symptoms are detected. Breast surgery can be safely performed during all pregnancy trimesters, and some systemic therapeutic agents can be administered safely in the second and third trimesters.

INTRODUCTION AND OBJECTIVES: Estimation of the umbilical venous blood flow volume relies on the diameter of the vein, which has been reported to be reduced in severely growth restricted fetuses. However, there is only limited information on the growth pattern of this vessel in the normal human fetus. The aim of this study is to examine the growth pattern of the umbilical vein across gestation in low‐risk human pregnancies. METHODS: In a prospective, longitudinal ultrasound study of 136 low‐risk pregnancies, the internal diameter of the intra‐amniotic portion of the umbilical vein was measured at 18, 26 and 34 weeks of gestation. To investigate the growth pattern of the venous diameter, the ratios of diameters at 26 weeks to diameters at 18 weeks (ratio 1) and the ratios at 34 to 26 weeks (ratio 2) were also calculated. A paired‐sample t‐test was performed to compare the means of the two ratios. RESULTS: The mean diameter of the umbilical vein at 18 weeks was 2.8 mm (SD 0.40), 5.8 mm (SD 0.67) at 26 weeks and 7.6 mm (SD 0.98) at 34 weeks. The mean of ratio 1 was 2.06 (95% CI 2.01–2.14), which was significantly higher than ratio 2 (mean 1.33, 95% CI 1.29–1.36), P < 0.001. CONCLUSION: The umbilical venous diameter demonstrates a non‐linear growth pattern between 18 and 34 weeks of gestation. The diameter doubled in size between 18 and 26 weeks but grew at a slower rate between 26 and 34 weeks of gestation. This study provides new data on the normal growth pattern of the umbilical vein by identifying a period of gestation where its growth is accelerated.

ObjectiveSurvival rates for congenital diaphragmatic hernia (CDH) are increasing. The long-term outcomes of CDH survivors were compared with a healthy control group to assess the morbidity for guidance of antenatal counselling and long-term follow-up programmes.Participants and designParticipants born with CDH in Western Australia 1993–2008 were eligible with matched controls from the general population. Participants had comprehensive lung function tests, echocardiogram, low-dose chest CT scan and completed a Strengths and Difficulties Questionnaire (SDQ) and quality of life (QOL) questionnaire.Results34 matched case–control pairs were recruited. Demographic data between groups were similar. Cases were smaller at follow-up (weight Z-score of −0.2vs0.3; p=0.03; height Z-score of −0.3vs0.6; p=0.01). Cases had lower mean Z-scores for forced expiratory volume in 1 s (FEV1) (−1.49 vs −0.01; p=0.004), FEV1/forced vital capacity (−1.92 vs −1.2; p=0.009) and forced expiratory flow at 25-75% (FEF25-75) (−1.18vs0.23; p=0.007). Cases had significantly worse respiratory mechanics using forced oscillation technique. Subpleural triangles architectural distortion, linear opacities and scoliosis on chest CT were significantly higher in cases. Prosthetic patch requirement was associated with worse lung mechanics and peak cough flow. Cases had significantly higher rates of gastro-oesophageal reflux disease (GORD) and GORD medication usage. Developmental delay was significantly higher in cases. More cases had a total difficulties score in the high to very high range (25% vs 0%, p=0.03) on the SDQ and reported lower objective QOL scores (70.2 vs 79.8, p=0.02).ConclusionSurvivors of CDH may have significant adverse long-term medical and psychosocial issues that would be better recognised and managed in a multidisciplinary clinic.

Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood?Adolescents with features of metabolic disorder at 17 years, or insulin resistance (IR) at 20 years of age, show impaired testicular function and altered hormone levels compared to those without metabolic disorder.Controversial evidence suggests a recent decline in sperm production potentially linked to environmental influences, but its cause remains unclear. Concomitant increases in obesity and diabetes suggest that lifestyle factors may contribute to this decline in testicular function. Although obesity has been associated with adverse testicular function in some studies, it remains unclear whether poor testicular function merely reflects, or causes, poor metabolic health. If metabolic disorder were present in adolescence, prior to the onset of obesity, this may suggest that metabolic disorder maybe a precursor of impaired testicular function.The Western Australian Pregnancy Cohort (Raine) Study is a longitudinal study of children born in 1989-1991 who have undergone detailed physical assessments since birth (1454 male infants born). At 17 years of age, 490 boys underwent a hepatic ultrasound examination, serum cytokine assessment (n = 520) and a metabolic assessment (n = 544). A further metabolic assessment was performed at 20 years (n = 608). Testicular assessment was performed at 20 years; 609 had reproductive hormones measured, 404 underwent a testicular ultrasound and 365 produced a semen sample.Testicular volume was estimated by ultrasonography, and semen analysis was performed according to World Health Organization guidelines. Concentrations of LH, FSH and inhibin B (inhB) in serum were measured by immunoassay and total testosterone by liquid chromatography-mass spectrometry.At 17 years of age, a liver ultrasound examination was performed to determine the presence of non-alcoholic fatty liver disease (NAFLD), and serum analysed for the cytokines interleukin-18 and soluble tumour necrosis factor receptor 1 and 2 (sTNFR1, sTNFR2).At 17 and 20 years of age, fasting blood samples were analysed for serum liver enzymes, insulin, glucose, triglycerides (TG), total cholesterol, high density lipoprotein and low density lipoprotein cholesterol, high sensitivity C-reactive protein and uric acid. The homoeostatic model assessment (HOMA) was calculated and approximated IR was defined by a HOMA4. Anthropometric data was collected and dual energy X-ray absorptiometry measurement performed for lean and total fat mass. As at this young age the prevalence of metabolic syndrome was expected to be low, a two-step cluster analysis was used using waist circumference, TGs, insulin, and systolic blood pressure to derive a distinct high-risk group with features consistent with the metabolic syndrome and increased cardiometabolic risk.Men at age 17 years with increased cardiometabolic risk had lower concentrations of serum testosterone (medians: 4.0 versus 4.9 ng/mL) and inhB (193.2 versus 221.9 pg/mL) (P0.001 for both) compared to those within the low risk metabolic cluster. Men with ultrasound evidence of NAFLD (n = 45, 9.8%) had reduced total sperm output (medians: 68.0 versus 126.00 million, P = 0.044), testosterone (4.0 versus 4.7 ng/mL, P = 0.005) and inhB (209.1 versus 218.4 pg/mL, P = 0.032) compared to men without NAFLD.Men with higher concentrations of sTNFR1 at 17 years of age had a lower sperm output and serum concentration of inhB, with an increase in LH and FSH (all P0.05 after adjustment for age, BMI, abstinence and a history of cryptorchidism, varicocele, cigarette smoking, alcohol and drug use), compared to those without an elevated sTNFR1. Multivariable regression analysis, adjusting for confounders, demonstrated that men in the high-risk metabolic cluster at 20 years had a lower serum testosterone and inhB (P = 0.003 and P = 0.001, respectively). A HOMA-IR4 was associated with a lower serum testosterone (P =0.001) and inhB (P = 0.010) and an increase in serum FSH (P = 0.015).This study is limited by the sample size and multiple comparisons, and causality cannot be proven from an observational study. Due to a 3-year interval between some metabolic assessments and assessment of testicular function, we cannot exclude the introduction of a bias into the study, as some of the participants and their testicular function will not have been fully mature at the 17-year assessment.Irrespective of a proven causation, our study findings are important in that a significant minority of the men, prior to seeking parenthood, presented co-existent features of metabolic disorder and signs of testicular impairment. Of particular note is that the presence of NAFLD at 17 years of age, although only present in a minority of men, was associated with an almost 50% reduction in sperm output at 20 years of age, and that the presence of IR at 20 years was associated with a 20% reduction in testicular volume.This study was supported by Australian NHMRC (Grant Numbers 634457, 35351417 and 403981) and received support from the Raine Medical Research Foundation, The Telethon Kids Institute, University of Western Australia, Women and Infants Research Foundation, Curtin University and Edith Cowan University. D.A.D., J.E.D., N.M., L.A.A., R.-C.H., T.A.M., J.K.O., L.J.B. have nothing to declare. R.J.H. is Medical Director of Fertility Specialists of Western Australia, has equity interests in Western IVF, and has received grant support from MSD, Merck-Serono and Ferring Pharmaceuticals. RMcL has equity interests in the Monash IVF Group. R.J.N. has equity interests in FertilitySA, and has received grant support from Merck Serono and Ferring Pharmaceuticals. D.J.H. has received institutional grant funding (but no personal income) for investigator-initiated testosterone pharmacology studies from Lawley and Besins Healthcare and has provided expert testimony to anti-doping tribunals and for testosterone litigation.This abstract was awarded the Fertility Society of Australia clinical exchange award for the oral presentation at ESHRE, Barcelona, in 2018.

We report three babies from two families with a severe lethal form of congenital cutis laxa. All three had redundant and doughy-textured skin and two siblings from one family had facial dysmorphism. Echocardiograms showed thickened and poorly contractile hearts, arterial dilatation and tortuosity. Post-mortem examination in two of the babies further revealed widespread ectasia and tortuosity of medium and large sized arteries, myocardial hypertrophy, rib and skull fractures. The presence of fractures initially suggested a diagnosis of osteogenesis imperfecta. Under light microscopy bony matrices were abnormal and arterial wall architecture was grossly abnormal showing fragmented elastic fibres. Molecular analysis of known cutis laxa genes did not yield any pathogenic defects. Whole exome sequencing of DNA following informed consent identified two separate homozygous variants in the LOX (Lysyl Oxidase) gene. LOX belongs to the 5-lysyl oxidase gene family involved in initiation of cross-linking of elastin and collagen. A mouse model of a different variant in this gene recapitulates the phenotype seen in the three babies. Our findings suggest that the LOX gene is a novel cause of severe congenital cutis laxa with arterial tortuosity, bone fragility and respiratory failure.

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.

Background Experimental studies suggest that prenatal stress affects reproductive function in female offspring, but human evidence is sparse and inconsistent. In this present study, we aim to investigate whether maternal psychological stress, quantified as stressful life events during pregnancy, affect reproductive function in the female offspring. Method In a large population-based pregnancy cohort study (The Raine Study) continuously followed from prenatal life through to adolescence we examined the association between the number of maternal stressful life events in both early and late gestation and subsequent ovarian and uterine function in 228 female adolescent offspring. Mothers prospectively reported stressful life events during pregnancy at 18 and 34 weeks using a standardized 10-point questionnaire. Female offspring (n ​= ​228) age 14–16 years underwent gynecological examination including transabdominal abdominal ultrasound (TAUS) to measure uterine volume and ovarian AFC. Plasma samples on day 2–6 of the spontaneous menstrual cycle measured circulating AMH and inhibin B. Multivariate linear regression analysis was used to examine the associations between maternal stressful life events and reproductive function in female offspring. Adolescents taking hormonal contraception were excluded. Results Most adolescents (145/228, 64%) were exposed to at least one stressful life event in early gestation and around half (125/228, 55%) were exposed to at least one in later gestation. Exposure to one or more maternal stressful life events in late gestation was associated with a greater uterine volume (β ​= ​0.13, 95% CI 0.04; 0.23) and higher ovarian AFC (β ​= ​0.19, 95% CI 0.02; 0.35) at age 14–16 years. No associations between maternal stressful events in late gestation and reproductive function were identified. No associations between stressful life events in early or late gestation and circulating AMH or Inhibin B were observed. Conclusion Maternal psychological stress in late, but not early gestation was associated with a significantly greater uterine volume and ovarian antral follicle count (AFC) in adolescent offspring but did not affect ovarian production of antimullerian hormone (AMH) or Inhibin B. These findings suggest that female reproductive function is influenced by prenatal exposure to stress.

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.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.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.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.Australian New Zealand Clinical Trials Registry, ACTRN12612000884808.

Background PCOS is the most common endocrine disorder in reproductive age women. The origins of PCOS are unknown but experimental and limited human evidence suggests that greater prenatal exposure to androgens may predispose to PCOS. Experimental evidence suggests that maternal stressors may affect reproductive function in the offspring via changes in prenatal androgen exposure. In this present study, we aim to investigate whether maternal stressful life events during pregnancy are associated with polycystic ovary morphology (PCOM) or polycystic ovary syndrome (PCOS) in adolescent offspring. Method In a large population-based pregnancy cohort study (The Raine Study) continuously followed from prenatal life through to adolescence we examined the association between maternal stressful life events during pregnancy in both early and late gestation, and subsequent circulating concentrations of ovarian and adrenal androgens, PCOM and PCOS in the normal menstrual cycle of offspring age 14–16 years. Maternal stressful life events were prospectively recorded during pregnancy at 18 and 34 weeks using a 10-point questionnaire. Female offspring (n = 223) completed a questionnaire about their menstrual cycles, underwent a clinical examination for hirsutism (Ferriman-Gallwey score) and transabdominal pelvic ultrasound examination to determine ovarian morphology according to standardized criteria for classification of PCOM. Plasma samples were obtained at day 2–6 of the normal menstrual cycle for measurement of androgens. PCOM was defined according to the international consensus definition, 2003 and the evidence-based guideline for the assessment and management of PCOS, 2018. PCOS was diagnosed according to Rotterdam criteria and National Institute of Health (NIH) criteria. Multivariate linear and logistic regression analyses were used to examine the associations between maternal stressful life event exposure and ovarian morphology (PCOM), circulating ovarian and adrenal androgens (clinical and biochemical hyperandrogenism (hirsutism)) and presence of PCOS. Results Of 223 recruited adolescent girls, 78 (35.9%) and 68 (31.3%) had PCOM by the 2003 and 2018 criteria respectively, while 66 (29.6%) and 37 (16.6%) had PCOS, using Rotterdam and NIH criteria, respectively. Most girls (141/223, 63.2%) were exposed to at least one stressful life event in early gestation and around half (121/223, 54.3%) were exposed to at least one stressful life event in late gestation. Maternal stressful life events in early gestation were associated with a statistically significant lower prevalence of PCOM when applying the 2003 criteria [adjusted odds ratio [aOR] and 95% confidence intervals (CI): 0.74 (95% CI: 0.55; 0.99)], and a similar association was detected when applying the 2018 PCOM criteria (aOR, 0.69, 95% CI: 0.50; 0.95)]. Maternal stressful life events in early gestation were also associated with lower circulating concentrations of testosterone (β = −0.05, 95% CI: −0.09; −0.004) and androstenedione (β = −0.05, 95% CI: −0.10; −0.002) in the offspring. No similar effects for PCOM or circulating androgens were detected in late gestation. No statistically significant associations between maternal stressful life events in early or late gestation with PCOS (neither Rotterdam nor NIH criteria) in adolescence were detected. The prospective collection of maternal stressful life events during both early and late gestation and direct measurement of PCOM, PCOS and circulating androgens in adolescence and key co-variates implies minimal possibility of recall, information bias and selection bias. Conclusion Maternal exposure to stressful life events in early gestation is associated with significantly reduced circulating ovarian and adrenal androgen concentrations in adolescence (testosterone and androstenedione), and an indication of fewer cases of polycystic ovary morphology (PCOM) defined by the 2003 international consensus definition and by the 2018 international evidence-based guideline, but has no effect on polycystic ovary syndrome (PCOS), diagnosed using either Rotterdam or NIH criteria.

OBJECTIVE: To compare outcomes of hospitalized preterm infants following previable prelabour rupture of membranes (PPROM) at≤23 weeks of gestation. METHODS: Retrospective cohort study of preterm infants admitted for intensive care, between January 2006 and December 2016 following PPROM, was conducted. Short term clinical outcomes included severity of respiratory morbidity, length of hospital stay and mortality. Neurodevelopment in survivors was assessed using Bayley’s Scales of Infant Development (3rd edition) at 24 months corrected age. RESULTS: A total of 82 preterm infants were admitted following PPROM at

Background In 2014, a whole-of-population and multi-faceted preterm birth prevention program was introduced in Western Australia with the single aim of safely lowering the rate of preterm birth. The program included new clinical guidelines, print and social media, and a dedicated new clinic. In the first full calendar year the rate of preterm birth fell by 7.6% and the reduction extended from the 28–31 week gestational age group upwards. Objective The objective of this study was to evaluate outcomes in greater depth and to also include the first three years of the program. Study design This was a prospective population-based cohort study of perinatal outcomes in singleton pregnancies before and after commencement of the program. Results There was a significant reduction in preterm birth in the tertiary center which extended from 28 weeks gestation onwards and was ongoing. In non-tertiary centers there was an initial reduction, but this was not sustained past the first year. The greatest reduction was observed in pregnancies classified at first attendance as low risk. No benefit was observed in the private sector, but a significant reduction was seen in the remote region of the Kimberley where the program was first launched and vaginal progesterone had been made free-of-charge. Conclusion Preterm birth rates can be safely reduced by a multi-faceted and whole-of-population program but the effectiveness requires continuing effort and will be greatest where the strategies are most targeted.

Non-invasive prenatal testing (NIPT) for a panel of 25 single gene disorders became available in Western Australia in 2020 and potentially may be able to test for panels of hundreds of disorders as is the case with reproductive carrier screening. How this information would be used by parents in a population screening model is unknown. We used a phenomenological approach to explore retrospectively whether mothers of children with single gene or chromosomal disorders would have wanted to know about their child’s genetic diagnosis prior to delivery. Themes were identified such as having a child with a de novo disorder and effect on pregnancy outcomes in hypothetical situations, impact on family function, the diagnostic journey and personal growth. These themes related to both the concept of expanded NIPT (ENIPT) and the situation of having a child with a de novo genetic disorder that could now hypothetically be detected through ENIPT. Opinions were divided about whether participants would have wanted to know about their affected child’s condition, indicating any expanded NIPT testing panels would need to be offered in the context of an appropriate comprehensive counselling program. How this would be provided on a population screening level and the role of genetic counselling needs further exploration.

In order to explore the impact of potential new technologies in the area of prenatal screening, we conducted a baseline study using qualitative interviews to explore women's attitudes and knowledge regarding current and future prenatal screening technology and methods. Three cohorts were interviewed, including healthy women without children, healthy women with healthy children, and healthy women with children who have de novo genetic disorders. This study aimed to assess the baseline understanding and attitudes of women in Western Australia. Women from each cohort demonstrated adequate knowledge of the differences between screening and diagnostic tests, but were mostly unaware of the conditions for which screening is currently available except Down syndrome. Women who had children with de novo genetic conditions were generally aware of more genetic conditions than women with or without healthy children. Most women recognised the genetic basis for the conditions mentioned. Two thirds of women understood that Down syndrome is a chromosomal condition; just one third recognised that the phenotype is variable. Most women expressed a positive attitude towards Down syndrome. Social acceptance of children with Down syndrome was commonly mentioned as a concern. While the majority of women with children supported screening for Down syndrome, they emphasised that it must be an autonomous choice. General knowledge of genetic conditions illustrated that women are exposed to diverse conditions from lived experience as well as the media.

Background Increasingly couples are travelling overseas to access assisted reproductive technology, known as cross border reproductive care, although the incidence, pregnancy outcomes and healthcare costs are unknown. Aims To determine obstetric and neonatal outcomes for multiple pregnancies conceived through fertility treatment overseas, and estimate cost of these pregnancies to the health system. Materials and methods Retrospective study of women receiving care for a multiple gestation between July 2013 and June 2015 at Western Australia's sole tertiary obstetric hospital, where conception was by overseas fertility treatment. Obstetric and neonatal outcomes were recorded and cost estimates calculated. Results Of 11 710 births, 422 were multiple pregnancies. Thirty-seven pregnancies were conceived with fertility treatment, with 11 (29.7%) conceived overseas. Median antenatal clinic attendances, ultrasound examinations, and fetal assessments for the overseas fertility cases were six, 10, and nine, respectively. The gestational age at delivery ranged from 30 to 38 weeks (median 34 + 1). Median neonatal admission duration was 18 days (range 0–47). Cost for obstetric care was estimated between $170 000 and $216 000, and cost of neonatal care was estimated as $810 000, giving a combined total cost of between $980 000 and $1 026 000. Conclusion At the sole tertiary obstetric centre in WA, approximately one-third of all multiple pregnancies conceived with fertility treatment resulted from treatment overseas. The Australian healthcare cost for these 11 women and their infants exceeded $1 000 000. This study suggests that overseas fertility treatment has a significant health-related cost to the mother and infant, and the local healthcare system.

Introduction Rates of cesarean section (CS) are increasing and abnormal fetal heart rate tracing and concern about consequent acidosis remain one of the most common indications for primary CS. Umbilical artery (UA) lactate sampling provides clinicians with point of care feedback on CTG interpretation and intrapartum care and may result in altered future practice. Materials and methods From 3rd March - 12th November 2014 we undertook a before and after study in Pretoria, South Africa, to determine the impact of introducing a clinical package of fetal heart rate monitoring education and prompt feedback with UA cord lactate sampling, using a hand-held meter, on maternal and perinatal outcomes. Results Nine hundred thirty-six consecutive samples were analyzed (pre n = 374 and post n = 562). There was no difference in mean lactate (4.6 mmol/L [95%CI 4.4–4.8] compared with 4.9 mmol/L [95%CI 4.7–5.1], p = 0.089). Suspected fetal compromise was reduced in the post-intervention period: 30·2% vs 22·1%, aOR 0·71, 95% CI 0·52–0·96, p = 0·027. Cesarean section rates were significantly reduced in the univariate analysis: pre- 40·3% vs post-intervention 31·6% (p = 0·007). This reduction remained significant when adjusted for previous cesarean section, primiparity, maternal HIV infection and preterm birth (aOR 0·72, 95%CI 0·54–0·98, p = 0·035). Neonatal outcomes did not differ between the two groups. Conclusion The introduction of a clinical practice package of fetal heart rate monitoring education combined with routine UA cord lactate sampling has the potential to reduce the cesarean section rate without increasing adverse neonatal outcomes in a low-resource setting.

Background Information is scarce regarding effects of antihypertensive medication on blood pressure variability ( BPV ) and associated clinical outcomes. We examined whether antihypertensive treatment changes BPV over time and whether such change (decline or increase) has any association with long‐term mortality in an elderly hypertensive population. Methods and Results We used data from a subset of participants in the Second Australian National Blood Pressure study (n=496) aged ≥65 years who had 24‐hour ambulatory blood pressure recordings at study entry (baseline) and then after a median of 2 years while on treatment (follow‐up). Weighted day‐night systolic BPV was calculated for both baseline and follow‐up as a weighted mean of daytime and nighttime blood pressure standard deviations. The annual rate of change in BPV over time was calculated from these BPV estimates. Furthermore, we classified both BPV estimates as high and low based on the baseline median BPV value and then classified BPV changes into stable: low BPV , stable: high BPV , decline: high to low , and increase: low to high . We observed an annual decline (mean± SD : −0.37±1.95; 95% CI, −0.54 to −0.19; P BPV between baseline and follow‐up. Having constant stable: high BPV was associated with an increase in all‐cause mortality (hazard ratio: 3.03; 95% CI, 1.67–5.52) and cardiovascular mortality (hazard ratio: 3.70; 95% CI, 1.62–8.47) in relation to the stable: low BPV group over a median 8.6 years after the follow‐up ambulatory blood pressure monitoring. Similarly, higher risk was observed in the decline: high to low group. Conclusions Our results demonstrate that in elderly hypertensive patients, average BPV declined over 2 years of follow‐up after initiation of antihypertensive therapy, and having higher BPV (regardless of any change) was associated with increased long‐term mortality.

This retrospective study assessed maternal and perinatal outcomes for women with rheumatic heart disease (RHD) admitted to the largest tertiary obstetric hospital in Western Australia from 2009 to 2016. Of 54 women identified, 75.9% were Indigenous, 59.3% lived in rural areas and 40.7% had severe RHD. Heart failure developed in 10% who gave birth. Indigenous women were younger, had higher gravidity (P = 0.0305), were more likely to receive secondary prophylaxis (P = 0.0041) and have sub-optimal antenatal clinic attendance (P = 0.0078). There were no maternal deaths and two perinatal deaths (4.0%), reflecting vigilance in the obstetric management of women with RHD in Western Australia.

Chemotherapy during a viable pregnancy may be associated with adverse perinatal outcomes. We conducted a prospective cohort study to examine the perinatal outcomes of babies born following in utero exposure to chemotherapy in Australia and New Zealand. Over 18 months we identified 24 births, of >400 g and/or >20-weeks’ gestation, to women diagnosed with breast cancer in the first or second trimesters. Eighteen babies were exposed in utero to chemotherapy. Chemotherapy commenced at a median of 20 weeks gestation, for a mean duration of 10 weeks. Twelve exposed infants were born preterm with 11 by induced labour or pre-labour caesarean section. There were no perinatal deaths or congenital malformations. Our findings show that breast cancer diagnosed during mid-pregnancy is often treated with chemotherapy. Other than induced preterm births, there were no serious adverse perinatal outcomes.

Objective: To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction. Design: A randomised placebo-controlled trial. Setting: Thirteen maternal–fetal medicine units across New Zealand and Australia. Population: Women with singleton pregnancies affected by fetal growth restriction at 22 to 29 weeks. Methods: Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32 weeks, birth or fetal death (whichever occurred first). Main Outcome Measures: The primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia. Results: Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23–1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80–7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84–4.45); and new-onset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26–1.75). Conclusions: Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing. Tweetable abstract: Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.

Study question Is exposure to gestational stress in the critical time window for the normal differentiation and growth of male reproductive tissue associated with male reproductive function in offspring in later life? Summary answer Exposure to stressful life events (SLEs) in early, but not late gestation, are associated with reduced adult male reproductive function, consistent with the hypothesis that events during early prenatal life programme adult male reproductive function. What is already known Animal studies suggest that gestational stress may impact on the reproductive function of male offspring, but human evidence is sparse. Study design, size, duration Using a prospective longitudinal cohort, we examined the association between number and type of maternal stressors during pregnancy in both early and late gestation and reproductive function in 643 male Generation 2 (offspring) at age 20 years. Mothers and their male Generation 2 (offspring) from The Raine Study participated. Mothers prospectively reported SLEs during pregnancy recorded at gestational weeks 18 and 34 using a standardized 10-point questionnaire. Participants/materials, setting, methods The 643 male Generation 2 (offspring) underwent testicular ultrasound examination and semen analysis and provided serum for reproductive hormone analysis. Multivariate linear regression analysis was used to examine associations. Main results and role of chance Of 643 recruited males, 407 (63%) were exposed to at least one SLE in early gestation. Fewer SLEs were reported in late gestation (n = 343, 53%). Maternal SLE exposure in early gestation was negatively associated with total sperm count (β = -0.31, 95% CI -0.58; -0.03), number of progressive motile sperm (β = -0.15, 95% CI -0.31; 0.00) and morning serum testosterone concentration (β = -0.04, 95% CI -0.09; -0.00). No similar effects of maternal SLE exposure in late pregnancy were detected. The large sample size and an objective detailed direct assessment of adult male reproductive function with strict external quality control for sperm quality, as well as detailed prospectively collected information on prenatal SLEs in two distinct time windows of pregnancy reported by the women in early and late gestation along with other risk factors, imply minimal possibility of recall, information bias and selection bias. When assessing our results, we adjusted for a priori chosen confounders, but residual confounding or confounding by factors unbeknown to us cannot be ruled out. Limitations, reasons for caution It is not possible to measure how SLEs impacted differently on the mother's experience or perception of stress. Resilience (coping) gradients may alter cortisol levels and thus modify the associations we observed and the mothers' own perception of stress severity may have provided a more precise estimate of her exposure. Wider implications of the findings Our findings suggest that exposure to SLEs in early, but not late gestation, are associated with reduced adult male reproductive function. Improved support for women with exposure to SLEs during pregnancy, particularly during the first trimester, may improve the reproductive health of their male offspring in later life. Intervention studies of improved pregnancy support could provide more insight into this association and more information is needed about the potential specific epigenetic mechanisms underlying this association. Study funding/competing interest(s) The male fertility sub-study was funded by NHMRC Grant 634 457. The core management of the Raine Study is funded by University of Western Australia, Curtin University, Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, The University of Notre Dame Australia and Raine Medical Research foundation. Dr Brauner's salary was supported by Laege Sofus Carl Emil Friis og Hustru Olga Doris Friis foundation in Denmark. All authors declare no competing interests. Trial registration number N/A.

Background Umbilical cord lactate is one approach to measuring acidosis and intrapartum hypoxia, knowledge of which may be helpful for clinicians involved in the care of women and newborns. Objective To synthesise the evidence on accuracy of umbilical cord lactate in measuring acidosis and predicting poor neonatal outcome. Search strategy Studies published and unpublished between 1990 and 2014 from PubMed/Medline, EMBASE, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov were assessed. Selection criteria Cross-sectional and randomised studies that assessed fetal acidosis (using lactate as the index test) with or without an assessment of neonatal outcome. Data collection and analysis Correlations between index and reference test(s) were recorded, as were the raw data to classify the predictive ability of umbilical lactate for neonatal outcomes. Meta-analysis of correlation was performed. We plotted estimates of the studies' observed sensitivities and specificities on Forest plots with 95% confidence intervals (CI). Where possible, we combined data using meta-analysis, applying the hierarchical summary receiver operating characteristics model and a bivariate model. Main results Twelve studies were included. Umbilical lactate correlated with pH [pooled effect size (ES) −0.650; 95% CI −0.663 to −0.637, P

Background/purpose This study aims to retrospectively review outcomes, including neurodevelopmental outcomes, of neonatal right sided congenital diaphragmatic hernias (RCDH) compared with left sided congenital diaphragmatic hernias (L-CDH) treated surgically at our institute. Methods A retrospective review was undertaken of all cases of congenital diaphragmatic hernia (CDH) treated at Princess Margaret Hospital for Children (PMH), Perth, born between 1st January 2002 and 1st August 2012. The outcomes of R-CDH cases were compared with L-CDH cases. We examined duration of ventilatory support, use of patch versus primary closure, the CDH recurrence rates, the number of reoperations and neurodevelopmental follow-up at one year of age. Results Forty-nine cases of CDH were operated on at PMH during the 10-year period. Of these, ten cases were R-CDH with 39 L-CDH cases. Of 49 cases, 34 were diagnosed antenatally, 5 R-CDH versus 29 L-CDH. Only 8/39 cases of L-CDH required patch repair for larger defects, while 5/10 R-CDH required patch repair. Postoperative mortality was 6/49 (1/10 right sided versus 5/39 left sided). Recurrence was observed in 5/10 R-CDH versus 6/39 L-CDH with p=0.03. Thirty-three of 43 surviving patients received one-year follow-up with Griffiths general quotient (GQ) assessment demonstrating a median score of 98 for L-CDH (IQR 86 to 104.25) and 91 for R-CDH (IQR 76.5 to 93). Conclusions R-CDH required patch repair more commonly than L-CDH because of larger defect size or complete agenesis. The rate of recurrent herniation was the only morbidity significantly higher in the R-CDH group. Survivors of R-CDH did not have a significant difference in neurodevelopmental outcome compared to L-CDH cases, with both groups exhibiting normal median GQ scores at one year of age.

Background: Controversial speculation suggestions that dietary intake may affect semen quality and testicular function, however, there are limited comprehensive studies observing dietary patterns. Objective: To study associations between major dietary patterns and markers of testicular function in adulthood. Material and Methods: Observational cross-sectional study of two hundred and ninety men with an average age of 20 years, from the Western Australian Pregnancy Cohort (Raine) Study. Usual dietary intake assessed using a semi-quantitative food frequency questionnaire at 20 years of age. Two dietary patterns previously identified using exploratory factor analysis ("Healthy" or "Western") and participants received z-scores for each dietary pattern. Primary endpoints were testicular volume, total sperm per ejaculate, morning serum testosterone concentration. Secondary endpoints were semen sample parameters, inhibin B and sex steroids (DHT: 3α-diol, 3β-diol; LH; FSH; DHEA; estradiol; estrone). Result(s): Participants were on average 20.0 ± 0.4 years old, had a median of 2 days sexual abstinence and a body mass index of 24.1 ± 3.9 kg/m 2 , 13% were smokers, 52% were 'moderate' alcohol drinkers, 23% frequently used recreational drugs and 68% reported 'high' physical activity levels. Sperm concentration and DHT 3α-diol were negatively associated with a greater z-score for the "Western" dietary pattern ( p = 0.007 and; p = 0.044, respectively), and serum estradiol concentration was positively associated with a "Western" dietary pattern ( p = 0.007) after adjustment for BMI, varicocele, cryptorchidism and sexual abstinence. Discussion: Despite associations between greater intake of the "Western" dietary pattern and a decreased male reproductive health markers, our lack of consistent associations of either a "Healthy" or a "Western" dietary pattern, limit clinical or biological significance in isolation. Conclusions: A potential negative association of a "Western" dietary pattern with male reproductive health was detected and should be studied further in population-based studies.

Objective This study aims to review temporal changes in perinatal management and 1-year survival outcomes of cases of congenital diaphragmatic hernia (CDH) from 1996 to 2015 in Western Australia (WA). Method This research is a retrospective study of all cases of CDH in WA from 1996 to 2015 identified from five independent databases within the WA health network. Detailed information pertaining to pregnancy and survival outcomes were obtained from review of maternal and infant medical records. Results There were 215 cases of CDH with 164 diagnosed prenatally. Between 1996 and 2010, a decline in live birth rates for CDH-affected pregnancies was observed, reaching a nadir of 5.3 per 10 000 births before increasing to a peak of 9.73 per 10 000 births in 2011-2015. A corresponding decline was seen in the number of pregnancies terminated in the same period from 8.3 to 4.6 per 10 000 births (P = 0.14) and an increase in survival of live births from 38.9% to 81.3% (P = 0.01). Conclusion The improved overall survival rate in infants with CDH over the last 20 years may have resulted in an increased tendency for women to continue their pregnancy with a concomitant decline in termination rates. Information from this study will help in the counselling of women following prenatal detection of CDH.

Background Nontypeable Haemophilus influenzae (NTHi) bacteraemia in pregnant women is strongly associated with pregnancy loss and preterm delivery. However, the clinical significance of isolation of NTHi from nonsterile sites is unknown. Aims To examine the hypothesis that isolation of NTHi from any specimen is associated with adverse perinatal outcomes and to investigate the impression that NTHi is disproportionately isolated from indigenous women and their neonates. Materials and Methods Cases where NTHi was isolated from maternal, fetal or neonatal specimens during the period from 1 July 1997 to 1 July 2009 were identified. Demographic and clinical data were extracted from case notes. Histopathological material was re-reviewed by a perinatal pathologist. Demographic and clinical features of the affected group were compared with the hospital obstetric population. Results NTHi was isolated from maternal, fetal or neonatal specimens in 97 pregnancies. Two women had NTHi isolated during different pregnancies. Two mothers and 10 neonates were bacteraemic. Indigenous women comprised 28% of pregnancies where NTHi was isolated, compared with 6% of the hospital obstetric population (P < 0.001). Pregnancy loss occurred in six cases (6%). Median gestation at delivery was 33 weeks. Of 96 liveborn neonates, 88 (92%) required admission to a neonatal special care unit. Four liveborn neonates died (4%). Chorioamnionitis was confirmed by histology in 31/33 (93.9%) of placentas examined. Conclusions Isolation of NTHi occurred more commonly in indigenous women and neonates. Isolation of NTHi from any obstetric or neonatal specimen is associated with chorioamnionitis, preterm birth, pregnancy loss, early-onset neonatal sepsis and neonatal death.

Aim To describe the potential impact of using noninvasive prenatal testing (NIPT) as a second-tier test, on the diagnosis and outcomes of pregnancies identified as high risk through first trimester screening (FTS) in a cohort of real pregnancies. Materials and Methods Western Australian FTS and diagnostic data (2007–2009) were linked to pregnancy outcomes. Karyotype results from invasive prenatal testing in high-risk women were analysed. The outcomes of abnormal results that would not be detected by NIPT, assuming a panel of trisomy 21/18/13 and sex chromosome aneuploidies, and the likelihood of diagnosis in a screening model using NIPT as a second-tier test are described. Results Abnormal karyotype results were reported in 224 of 1488 (15%) women with high-risk pregnancies having invasive diagnostic testing. NIPT potentially would have identified 85%. The 33 abnormalities unidentifiable by NIPT were triploidies (n = 7, 21%), balanced (n = 8, 24%) and unbalanced rearrangements (n = 10, 30%) and level III mosaicisms (n = 8, 24%). For conditions not identifiable by NIPT, fetal sonographic appearance was likely to have led to invasive testing for 10 of 17 (59%) pathogenic abnormalities. If a policy was adopted recommending invasive testing for FTS risk >1:50 and/or ultrasound detected abnormality, the residual risk of an unidentified pathogenic chromosomal abnormality in those without a diagnosis would have been 0.33% (95% CI 0.01–0.65%). Conclusions A screening model with NIPT as a second-tier for high-risk pregnancies would be unlikely to have changed the outcome for the majority of pregnancies. Optimising the diagnosis of rare pathogenic abnormalities requires clear indicators for invasive testing over NIPT.

CONTEXT:\ud Intronic DNA frequently encodes potential exonic sequences called pseudoexons. In recent years, mutations resulting in aberrant pseudoexon inclusion have been increasingly recognized to cause disease.\ud OBJECTIVES:\ud To find the genetic cause of familial glucocorticoid deficiency (FGD) in two siblings.\ud PATIENTS:\ud The proband and his affected sibling, from nonconsanguineous parents of East Asian and South African origin, were diagnosed with FGD at the ages of 21 and 8 months, respectively.\ud DESIGN:\ud Whole exome sequencing was performed on genomic DNA (gDNA) of the siblings. Variants in genes known to cause FGD were assessed for causality. Further analysis of gDNA and cDNA was performed by PCR/RT-PCR followed by automated Sanger sequencing.\ud RESULTS:\ud Whole exome sequencing identified a single, novel heterozygous variant (p.Arg71*) in nicotinamide nucleotide transhydrogenase (NNT) in both affected individuals. Follow-up cDNA analysis in the proband identified a 69-bp pseudoexon inclusion event, and Sanger sequencing of his gDNA identified a 4-bp duplication responsible for its activation. The variants segregated with the disease: p.Arg71* was inherited from the mother, the pseudoexon change was inherited from the father, and an unaffected sibling had inherited only the p.Arg71* variant.\ud CONCLUSIONS:\ud FGD in these siblings is caused by compound heterozygous mutations in NNT; one causing pseudoexon inclusion in combination with another leading to Arg71*. Discovery of this pseudoexon activation mutation highlights the importance of identifying sequence changes in introns by cDNA analysis. The clinical implications of these findings include: facilitation of antenatal genetic diagnosis, early institution of potentially lifesaving therapy, and the possibility of preventative or curative intervention

Objective To assess umbilical artery lactate levels and perinatal outcomes among women with and without HIV infection. Methods The present prospective cohort study recruited women planning to undergo vaginal delivery at Kalafong Hospital, South Africa, between March 3 and November 12, 2014. Umbilical artery lactate levels were measured and perinatal outcome data were recorded. Outcome analyses were stratified by maternal HIV status, and a subgroup analysis was performed where women with a CD4 count below 350 × 106 cells/L were compared with women without HIV. Results In total, 936 women with singleton fetuses were enrolled. Maternal HIV status was available for 897 (95.8%) participants, of whom 202 (21.6%) had HIV infections. Overall, 186 (92.1%) women with HIV infections received prophylaxis or treatment. There was no difference between participants with and without HIV infections in the preterm delivery rate (P=0.770), mode of delivery (P=0.354), neonatal resuscitation rate (P=0.717), 1- or 5-minute Apgar scores below 7 (P=0.353), or the rate of having an umbilical artery lactate level above 5.45 mmol/L (P=0.301). Similarly, there were no differences in outcomes in the subgroup analysis of women with a CD4 count below 350 × 106 cells/L. Conclusion Umbilical artery lactate levels and perinatal outcomes were found to be comparable between patients with and without HIV infections in a South African setting.

Bisphenol A (BPA) is a ubiquitous chemical suspected to possess oestrogenic hormonal activities. Male population studies suggest a negative impact on testicular function. As Sertoli cell proliferation occurs during fetal or early postnatal life, it is speculated that oestrogenic environmental exposures may influence mature testicular function. Among 705 Western Australian Pregnancy Cohort (Raine) Study men aged 20-22 years, 404 underwent testicular ultrasound examination (149 had maternal serum available), and/or 365 provided semen (136 had maternal serum) and/or 609 serum samples for sex steroids, gonadotrophins and inhibin B analysis (244 had maternal serum). Maternal serum collected at 18 and 34 weeks' gestation was pooled and assayed for concentrations of total BPA (free plus conjugated) as an estimate of antenatal exposure. Testicular volume was calculated by ultrasonography, and semen analysis performed. Serum LH, FSH and inhibin B were measured by immunoassay; testosterone, oestradiol, oestrone andBPA were measured by liquid chromatography-mass spectrometry. BPA levels were detectable in most (89%) maternal serum samples. After adjustment for maternal smoking, abstinence and varicocele, sperm concentration and motility were significantly correlated to maternal serum BPA (r = 0.18; P = 0.04 for both). No other associations of maternal serum BPA with testicular function were observed.

To evaluate whether Doppler measurement of middle cerebral artery peak systolic velocity (MCA-PSV) for timing subsequent intrauterine transfusions (IUTs) in fetuses that had undergone one IUT for anemia secondary to red-cell alloimmunization is non-inferior to timing based on expected decrease in fetal hematocrit (Hct) or fetal hemoglobin level, without compromising infant hemoglobin at birth.This was an international, pragmatic multicenter randomized controlled trial. Women with a pregnancy complicated by fetal anemia secondary to red-cell alloimmunization (due to any antibody alone or in combination), as indicated by the need to undergo a single IUT, were eligible for inclusion. Women were randomized to the determination of timing of further transfusion(s) by Doppler measurement of MCA-PSV (MCA-PSV Group), with a serial upward trend of values1.5 multiples of the median considered indicative of the need for another IUT, or timing of transfusion by a decrease in fetal Hct (fetal Hct Group), with subsequent IUTs timed according to an estimated fall in fetal Hct of 1% per day or fetal hemoglobin of 0.3 g/dL per day, to maintain fetal hemoglobin level between 7 and 10 g/dL. The primary outcome was infant hemoglobin level measured at birth.A total of 71 women were randomized, 36 to the MCA-PSV Group and 35 to the fetal Hct Group. Median gestational age at randomization was 30.3 weeks, the majority of women were Caucasian and non-smokers, 9.9% of women had Kell alloimmunization, and 14% of fetuses were hydropic at their first IUT. No statistically significant differences between the two treatment groups were observed with regard to mean hemoglobin levels at birth (MCA-PSV Group, 10.36 ± 3.82 g/dL vs fetal Hct Group, 12.03 ± 3.14 g/dL; adjusted mean difference -1.56 g/dL (95% CI, -3.24 to 0.13 g/dL); P = 0.070), or the number of IUTs performed after randomization (MCA-PSV Group, 1.75 ± 1.79 vs fetal Hct Group 1.80 ± 1.32; adjusted relative risk 0.88 (95% CI, 0.61-1.26); P = 0.474). There was no statistically significant difference between the two groups with respect to the risk of adverse infant outcomes related to alloimmunization or procedure-related complications.Both Doppler measurement of MCA-PSV and estimation of the decrease in fetal Hct or hemoglobin can be used to determine the timing of second and subsequent IUTs in fetuses with red-cell alloimmunization. Copyright © 2017 ISUOG. Published by John WileySons Ltd.

To investigate the utility of umbilical artery (UA) lactate measurements in a South African hospital for assessing intrapartum care and predicting neonatal outcomes.From 3 March-12 November 2014, we conducted a prospective cohort study of UA lactate levels at Kalafong Hospital, Pretoria, South Africa. Following birth, a UA blood sample (0.5uL) was taken from a double-clamped segment of cord and the lactate measured. Maternal and neonatal characteristics and outcomes were recorded.During the study, there were 4668 deliveries; including 1091 emergency cesarean and 154 instrumental deliveries. A lactate was recorded for 946 deliveries (20.3%). 190 babies required neonatal resuscitation, with an optimal cutoff for lactate of 5.45 mmol/L (sensitivity 68%, specificity 72%). 124 babies required nursery admission with the optimal cutoff for lactate 4.95 mmol/L (sensitivity 61%, specificity 59%). 55 babies had an Apgar score7 at 5 min and the optimal lactate for this outcome was 5.65 mmol/L (sensitivity 64%, specificity of 69%).Umbilical lactate can be used in a middle-low resource setting as a measurement of intrapartum hypoxia, with reasonable sensitivity and specificity for the prediction of, or need for, resuscitation, admission to the nursery, and low Apgar scores.

Objective To compare the efficacy of the vaginal and sublingual administration of the synthetic prostaglandin misoprostol with the currently used oral administration route in second-trimester medical abortion. Methods This was a prospective randomized trial of medical abortion with misoprostol after mifepristone priming at 14-24 weeks of gestation. From 2009 to 2013, recruited women received 200 mg mifepristone orally followed 24-48 hours later by an 800-microgram vaginal loading dose of misoprostol. Women were then randomized to receive additional 400-microgram misoprostol doses orally every 3 hours, vaginally every 4 hours, or sublingually every 3 hours. The main outcome was the duration of abortion with emphasis on the proportion of women undelivered 12 hours after the misoprostol loading dose in the three groups. Results A total of 302 women were randomized: 100 to oral, 100 to vaginal, and 102 to sublingual misoprostol. The median gestation at recruitment was oral 19.1 weeks (interquartile range 17.2-20.8), vaginal 19.4 weeks (interquartile range 17.3-20.4), and sublingual 19.7 weeks (interquartile range 17.6-21.0). The overall abortion duration was longer in women receiving oral misoprostol: oral 9.5 hours (95% confidence interval [CI] 8.5-11.4), vaginal 7.4 hours (95% CI 6.5-8.2), and sublingual 7.8 hours (95% CI 7.0-9.2). Overall, 84 of 302 (27.8%) women were undelivered at 12 hours, comprising 37.0% (95% CI 28.7-47.8) oral, 20.5% (95% CI 14.0-30.1) vaginal, and 21.0% (95% CI 14.3-30.7) sublingual groups. Conclusion Vaginal or sublingual misoprostol administered after a vaginal loading dose in second-trimester medical abortion with mifepristone priming is associated with a shorter time to pregnancy termination compared with an oral regimen. Clinical trial registration ClinicalTrials.gov, www.clinicaltrials.gov, NCT00864799. Level of evidence I.