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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.

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.

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.

Phthalates are ubiquitous environmental endocrine disrupting chemicals suspected to interfere with developmental androgen action leading to adverse effects on male reproductive function. Prenatal exposure studies in rodents show cryptorchidism, hypospadias and reduced testicular volume, testosterone and anogenital distance in males. It is postulated that there is a developmental window in-utero when phthalate exposure has the most potent adverse effects. Some human studies show associations between prenatal phthalate exposure and reduced calculated ‘free’ serum testosterone in infant boys and shorter anogenital distance. However, there are no data available yet which link antenatal exposure to long-term effects in men. We aimed to correlate antenatal phthalate exposure with adult testicular volume (TV), semen parameters and serum reproductive hormone concentrations. 913 men from the Western Australian (Raine) Pregnancy Cohort were contacted aged 20-22 years. 423 (56%) agreed to participate; 404 underwent testicular ultrasound examination; 365 provided semen samples, and reproductive hormones were measured in 384. Maternal antenatal serum phthalate metabolite measurements were available for 185 and 111 men, who provided serum and semen respectively. Maternal serum collected at 18 and 34 weeks gestation, stored at -80oC, was pooled and analyzed for 32 phthalate metabolites by liquid chromatography-tandem mass spectrometry. TV was calculated, semen analysis performed by WHO approved methods, and serum concentrations of gonadotrophins, inhibin B and testosterone measured. Eleven phthalate metabolites were detected. Primary and secondary metabolites of di-(2-ethyl-hexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP) were positively correlated. After correction for adult height, BMI, presence of a varicocele and exposure to maternal smoking mono-iso-nonyl phthalate (MiNP) (r=-0.22) and sums of DEHP and DiNP metabolites (r=-0.24) and the sum of the metabolites of the high molecular weight phthalates (r=-0.21) were negatively correlated with testicular volume (all p

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.

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.

Background Contingent screening for trisomy 21 using non-invasive prenatal testing has the potential to reduce invasive diagnostic testing and increase the detection of trisomy 21. Aim To describe the diagnostic and economic performance of prenatal screening models for trisomy 21 that use non-invasive prenatal testing as a contingent screen across a range of combined first trimester screening risk cut-offs from a public health system perspective. Methods Using a hypothetical cohort of 300 000 pregnancies, we modelled the outcomes of 25 contingent non-invasive prenatal testing screening models and compared these to conventional screening, offering women with a high-risk (1 > 300) combined first trimester screening result an invasive test. The 25 models used a range of risk cut-offs. High-risk women were offered invasive testing. Intermediate-risk women were offered non-invasive prenatal testing. We report the cost of each model, detection rate, costs per diagnosis, invasive tests per diagnosis and the number of fetal losses per diagnosis. Results The cost per prenatal diagnosis of trisomy 21 using the conventional model was $51 876 compared to the contingent models which varied from $49 309–66 686. The number of diagnoses and cost per diagnosis increased as the intermediate-risk threshold was lowered. Results were sensitive to trisomy 21 incidence, uptake of testing and cost of non-invasive prenatal testing. Conclusion Contingent non-invasive prenatal testing models using more sensitive combined first trimester screening risk cut-offs than conventional screening improved the detection rate of trisomy 21, reduced procedure-related fetal loss and could potentially be provided at a lower cost per diagnosis than conventional screening.

Background Of the 5.54 million stillbirths and neonatal deaths occurring globally each year, a significant amount of these occur in the setting of inadequate intrapartum care. The introduction of universal umbilical artery lactate (UA) measurements in this setting may improve outcomes by providing an objective measurement of quality of care and stimulating case reflection, audit, and practice change. It is important that consideration is given to the barriers and facilitators to implementing this tool outside of a research setting. Methods During the period 16/11/2014 -13/01/2015, we conducted a training course in cardiotocograph (CTG) interpretation, fetal physiology, and the sampling and analysing of UA lactate, with a pre and post questionnaire aimed at assessing the barriers and facilitators to the introduction of universal UA lactate in a district hospital in the Eastern Cape, South Africa. Results Thirty-five pre-training questionnaires available (overall response rate 95 %) and 22 post training questionnaires (response rate 63 %) were available for analysis. Prior to training, the majority gave positive responses (strongly agree or agree) that measuring UA lactate assists neonatal care, is protective for staff medicolegally, and improves opportunities for audit and teaching of maternity practice (n = 33, 30, 32; 94.4 %, 85.7 %, 91.4 % respectively). Respondents remained positive about the benefits post training. An increased workload on medical or midwifery staff was less likely to be seen as barrier following training (71 vs. 38.9 % positive response, p = 0.038). A higher rate of respondents felt that expense and lack of equipment were likely to be barriers after completing training, although this wasn’t significant. There was a trend towards lack of time and expertise being less likely to be seen as barriers post training. Conclusion The majority of participants providing intrapartum care in this setting are positive about the role of universal UA lactate analysis and the potential benefits it provides. Training aids in overcoming some of the perceived barriers to implementation of universal UA lactate analysis.

The impact of early life events on testicular function in adulthood is not well understood.To study the early influences of fetal growth, exposures to cigarette smoke in utero and cord blood estrogens, and the influences of growth and adiposity in childhood through adolescence; on testicular function in adulthood.Male members of the Western Australian Pregnancy Cohort (Raine) were contacted at 20-22 years of age. Of 913 contacted, 423 (56%) agreed to participate; 404 underwent a testicular ultrasound, 365 provided a semen sample, and reproductive hormones were measured (384). Fetal growth measurements (n = 137), umbilical cord estrogen concentrations (n = 128), cord testosterone (T) (n = 125), and child-adulthood growth charts (n = 395) were available.Median sperm output for the 18.6% of men exposed in utero to smoking was lower than nonexposed (82.4 × 10(6) vs 123.1 × 10(6); P = .029). Sperm output in adulthood was inversely correlated with cord serum estradiol (P = .019) and estrone (P = .018). The sperm output of men whose cord blood estradiol and estrone were less than 50th percentile vs more than 50th percentile was 191.1 × 10(6) vs 100.5 × 10(6) (P = .002) and 190.0 × 10(6) vs 106.0 × 10(6) (P = .012), respectively. Men with favorable fetal growth patterns in utero were less likely to have total motile sperm counts within the lowest quartile (P = .011), and men born prematurely had reduced serum T levels in adulthood (13.4 vs 16.6nmol/L, P = .024). Consistent height above the 50th percentile for age through childhood was associated with larger adult mean testicular volume (P.001). Optimal body mass index trajectory through childhood and adolescence was associated with larger testicular volume (P = .009) and higher serum inhibin B (P = .010) and T (P = .003) in adulthood.Exposures to maternal smoking and higher cord blood estrogens at delivery were associated with a reduced sperm output in adulthood. Optimal adult testicular function depends on being born at or above average weight, and maintaining optimal growth and adiposity into adulthood.

Cervical length (CL) screening has been successfully utilised to identify asymptomatic women, with a singleton pregnancy, at risk of preterm birth (PTB), thereby providing an opportunity to offer interventions that may reduce that risk. Cervical length screening with ultrasound is most effectively performed with a transvaginal approach. Universal cervical length screening, encompassing all singleton pregnancies rather than restricting screening to those considered at increased risk of PTB, is currently not widely used, despite a growing body of evidence in support of its utility for PTB prevention. There are a number of barriers that may prevent or restrict the implementation of a universal CL screening program. These include cost, availability of vaginal progesterone and other treatment options, reluctance of women to undergo transvaginal ultrasound and the perceptions and beliefs of medical practitioners. Given that mid-pregnancy CL measurement is a recognised predictor of spontaneous PTB, that most cases of PTB occur with no prior maternal history and that there are interventions available that may reduce the risk of PTB, we believe there is a clear role for routine CL screening to be adopted as a component of the fetal morphology ultrasound examination. As a strategy to reduce PTB rates, discussion and counselling about PTB prevention and CL screening should be adopted as a core element of prenatal care.

Developmental stage-specific differentiation of stem or progenitor cells into safe and functional cells is of fundamental importance in regenerative medicine, including β-cell replacement. However, the differentiation of islet progenitor cells (IPCs) into insulin-secreting β cells remains elusive. Here, we report that the multifunctional molecule nicotinamide (NIC) is a specific differentiation regulator of mouse IPCs. The differentiated cells regulated by NIC exhibited many characteristics of adult β cells, including ameliorating preclinical diabetes and a highly comparable transcriptome profile. Gene set enrichment analysis showed that during differentiation, numerous IPC transcription factor genes, including Ngn3, Pax4, Fev, and Mycl1, were all down regulated. Pharmacological, biochemical, and gene knockdown analyses collectively demonstrated that NIC regulated the differentiation via inhibiting Sirt1 (silent information regulator transcript 1). Finally, NIC also regulates human IPC differentiation. Thus, our study advances islet developmental biology and impacts on translational research and regenerative therapies to diabetes and other diseases.

Introduction: Since the early 1980s, prenatal screening using ultrasound and biochemical markers has been used to refine the risk of Down syndrome and other fetal anomalies prior to considering fetal karyotyping. The performance of prenatal screening is subject to ongoing monitoring in Western Australia. The collection of these data can also assist in the identification of any potential inequities of access to prenatal screening within the state-wide programme. Methods: Prenatal screening data (2005–2006) were collected from accredited ultrasound and pathology laboratories in Western Australia. Screening data were linked to diagnostic and pregnancy outcome data. Performance characteristics of screening and uptake by socio-demographic characteristics were analysed. Results: Complete screening data were collected for 35,142 of the estimated 38,081 women screened during 2005 and 2006. There were 59,999 births related to this screening period. The lowest uptake of screening was among women who were Aboriginal (14.9%), living in remote areas (38.0%), under the age of 25 (40.2%), in the lowest quintile of the SEIFA index (41.6%) and with three or more children (48.4%). Logistic regression analysis showed all socio-demographic factors to be strongly associated with screening behaviour, with adjustment for ethnicity, socio-economic status, age, parity and area of residence. Discussion: Our results have important implications for the delivery of prenatal screening services in Western Australia. While the screening programme meets international and national performance standards, the disparities in screening uptake suggest inequity in access to services, particularly for Aboriginal, remote and socio-economically disadvantaged women.

To estimate the long-term effects of anemia on the fetal heart by echocardiography of children who received intrauterine blood transfusions for red cell isoimmunization.Surviving children who received intrauterine transfusions during the period from 1992 to 2003 were identified. Children matched for age and sex were chosen for the control group to create a 1:1 case-control study design. A clinical interview, physical examination, and echocardiography assessment (corrected for body surface area) were performed.Twenty-five children were recruited for the case group and matched to 25 healthy children for the control group. Children in the case group had received a median of four intrauterine transfusion procedures (range 1-7), with a median gestation at initial intrauterine transfusion of 28 weeks (range 22-34 weeks). Hydrops was present in 32%. Median initial hemoglobin was 76 g/L (range 25-133 g/L). Median gestation at delivery was 36 weeks (range 29-38 weeks). The median age of children in the case group was 10.1 years (range 3.6-15.8 years) and of those in the control group was 10.5 years (range 3.8-16.4 years; P=.122). There was no difference in body surface area, baseline heart rate, systolic blood pressure, or diastolic blood pressure between children in the case group and those in the control group. Echocardiography demonstrated three main differences: children in the case group had 9% less left atrial area (95% confidence interval [CI] 2-16% less; P=.02), 10% less ventricular mass (95% CI 1-19% less; P=.039), and an average 11 ms less mitral valve atrial duration (95% CI 3-19 ms less; P=.009) than did those in the control group. These results did not alter when adjusted for isoimmunization severity.Fetal anemia secondary to red cell isoimmunization is associated with a reduction in left ventricular mass and left atrial area in childhood, although resting ventricular function is maintained. We speculate this may be secondary to the prenatal effects of anemia on cardiomyocyte proliferation and differentiation.III.

This prospective study was established to determine the impact of maternal circulating androgen levels during normal pregnancy on ovarian function, as determined by early follicular phase antimüllerian hormone (AMH) levels, inhibin B levels, and antral follicle count (AFC) in 244 female offspring in adolescence. Maternal circulating total testosterone levels at 18 weeks' gestation were statistically significantly correlated with early follicular-phase circulating AMH levels in female adolescent offspring, but no other statistically significant correlations were determined among the maternal androgens at 18 or 34 weeks of gestation and the markers of adolescent ovarian function.

Abnormally formed lower limbs with varying degrees of fusion are the major feature of sirenomelia whereas maldeveloped lower limbs without fusion are found in association with caudal dysgenesis (CD). The relationship between these two entities has been a topic of debate for many years. The presence of a single umbilical artery originating from the abdominal aorta was considered a major feature distinguishing sirenomelia from CD. Based on this finding, the vascular steal theory was put forward as the causative mechanism of sirenomelia. CD and sirenomelia were considered to be two entirely different entities with distinct pathogenic mechanisms. However, it is now clear that a single umbilical artery can be found in some patients of CD and normal umbilical arteries in some patients of sirenomelia. The hypothesis of primary deficiency of caudal mesoderm caused by early developmental disruption suggests that sirenomelia and CD are two ends of a spectrum of maldevelopment of caudal mesoderm. In this paper we report on the clinical and pathological features of 16 patients of CD and 9 patients of sirenomelia from our institution and review the literature. This series of cases is notable for the significant association with neural tube defects, refining the renal and urogenital pathology associated with these conditions, and supporting the concept of a continuum of the disease spectrum.

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in adolescents, with potentially significant lifelong consequences. This prospective study set out to determine if the investigators could derive a threshold value of antimullerian hormone (AMH) that would predict its presence according to two internationally recognized definitions using a simple measurement, avoiding more extensive and potentially more invasive investigations. The study failed to demonstrate, in a general adolescent population, that serum AMH is a reliable predictor of PCO morphology or for the presence of PCOS.