The association between in-utero exposure to stressful life events during pregnancy and male reproductive function in a cohort of 20-year-old offspring: The Raine Study.

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 (ß = -0.31, 95% CI -0.58; -0.03), number of progressive motile sperm (ß = -0.15, 95% CI -0.31; 0.00) and morning serum testosterone concentration (ß = -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 Bräuner's salary was supported by Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis foundation in Denmark. All authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Features of the metabolic syndrome in late adolescence are associated with impaired testicular function at 20 years of age.

STUDY QUESTION: Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: 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. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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 HOMA >4. 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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) (P < 0.001 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 P < 0.05 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-IR > 4 was associated with a lower serum testosterone (P = <0.001) and inhB (P = 0.010) and an increase in serum FSH (P = 0.015). LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): 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.

STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction.

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+0 to 29+6 weeks. METHODS: Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32+0 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.

Fetal middle cerebral artery Doppler to time intrauterine transfusion in red-cell alloimmunization: a randomized trial.

OBJECTIVES: 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. METHODS: 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 values >1.5 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. RESULTS: 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. CONCLUSION: 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 Wiley & Sons Ltd.

Health care experiences among women diagnosed with gestational breast cancer.

Gestational breast cancer (GBC) presents many challenges for women and the clinicians who care for them. The aim of this study was to explore the health care experiences of women diagnosed with GBC to inform and improve clinical care of women in this predicament. Semi-structured interviews were conducted with 17 women who had been diagnosed with GBC in the previous 5 years. The overarching themes for perceived quality of care were "communication" and "comprehensive care." "Communication" had two sub themes: "interdisciplinary communication" (the way health professionals from different disciplines communicated with each other about the management of the woman's care) and "patient communication" (how they communicated this to the woman). The "comprehensive care" theme incorporated three sub themes: "the spirit" (psychological care); "the mind" (information provision); and "the body" (management of treatment side effects). Women's own accounts of positive and negative experiences of GBC care provide unique and specific insights which improve understanding of their concerns and needs. The findings can inform advances in quality and efficacy of clinical care; offer guidance for obstetricians, oncologists and allied health professionals about the needs of women diagnosed with GBC and how care can be optimised; and inform the development of resources to assist women and their families.

Umbilical lactate as a measure of acidosis and predictor of neonatal risk: a systematic review.

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 < 0.001], base excess (ES -0.710; 95% CI -0.721 to -0.699, P < 0.001), and Apgar scores at 5 minutes (ES 0.300; 95% 0.193-0.407, P < 0.001). Umbilical lactate had pooled sensitivity and specificity for predicting neonatal neurological outcome including hypoxic ischaemic encephalopathy of 69.7% (95% CI 23.8-94.4%) and 93% (95% CI 86.8-96.3%). AUTHORS' CONCLUSION: Umbilical cord lactate is a clinically applicable, inexpensive and effective way to measure acidosis and is a tool that may be used in the assessment of neonatal outcome. TWEETABLE ABSTRACT: Umbilical cord lactate: a clinically applicable, inexpensive, effective way to measure intrapartum acidosis.

Testicular function in a birth cohort of young men.

STUDY QUESTION: By investigating a birth cohort with a high ongoing participation rate to derive an unbiased population, what are the parameters and influences upon testicular function for a population not selected with regard to fertility? SUMMARY ANSWER: While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have no or minimal adverse impact. WHAT IS KNOWN ALREADY: The majority of previous attempts to develop valid reference populations for spermatogenesis have relied on potentially biased sources such as recruits from infertility clinics, self-selected volunteer sperm donors for research or artificial insemination or once-fertile men seeking vasectomy. It is well known that studies requiring semen analysis have low recruitment rates which consequently question their validity. However, there has been some concern that a surprisingly high proportion of young men may have semen variables that do not meet all the WHO reference range criteria for fertile men, with some studies reporting that up to one half of participants have not meet the reference range for fertile men. Reported median sperm concentrations have ranged from 40 to 60 million sperm/ml. STUDY DESIGN, SIZE AND DURATION: The Western Australian Pregnancy Cohort (Raine) was established in 1989. At 20-22 years of age, members of the cohort were contacted to attend for a general follow-up, with 753 participating out of the 913 contactable men. Of these, 423 men (56% of participants in the 20-22 years cohort study, 46% of contactable men) participated in a testicular function study. Of the 423 men, 404 had a testicular ultrasound, 365 provided at least one semen sample, 287 provided a second semen sample and 384 provided a blood sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testicular ultrasound examinations were performed at King Edward Memorial Hospital, Subiaco, Perth, for testicular volume and presence of epididymal cysts and varicoceles. Semen samples were provided and analysed by standard semen assessment and a sperm chromatin structural assay (SCSA) at Fertility Specialists of Western Australia, Claremont, Perth. Serum blood samples were provided at the University of Western Australia, Crawley, Perth and were analysed for serum luteinizing hormone (LH), follicular stimulating hormone (FSH), inhibin B, testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), estradiol, estrone and the primary metabolites of DHT: 5α-androstane-3α,17ß-diol (3α-diol) and 5-α androstane-3-ß-17-beta-diol (3ß-diol). Serum steroids were measured by liquid chromatography, mass spectrometry and LH, FSH and inhibin B were measured by ELISA assays. MAIN RESULTS AND THE ROLE OF CHANCE: Cryptorchidism was associated with a significant reduction in testicular (P = 0.047) and semen (P = 0.027) volume, sperm concentration (P = 0.007) and sperm output (P = 0.003). Varicocele was associated with smaller testis volume (P < 0.001), lower sperm concentration (P = 0.012) and total sperm output (P = 0.030) and lower serum inhibin B levels (P = 0.046). Smoking, alcohol intake, herniorrhaphy, an epididymal cyst, medication and illicit drugs were not associated with any significant semen variables, testicular volume or circulating reproductive hormones. BMI had a significantly negative correlation with semen volume (r = -0.12, P = 0.048), sperm output (r = -0.13, P = 0.02), serum LH (r = -0.16, P = 0.002), inhibin B (r = -0.16, P < 0.001), testosterone (r = -0.23, P < 0.001) and DHT (r = -0.22, P < 0.001) and a positive correlation with 3αD (r = 0.13, P = 0.041) and DHEA (r = 0.11, P = 0.03). Second semen samples compared with the first semen samples in the 287 participants who provided two samples, with no significant bias by Bland-Altman analysis. Testis volume was significantly correlated positively with sperm concentration (r = 0.25, P < 0.001) and sperm output (r = 0.29, P < 0.001) and inhibin B (r = 0.42, P < 0.001), and negatively correlated with serum LH (r = -0.24, P < 0.001) and FSH (r = -0.32, P < 0.001). SCSA was inversely correlated with sperm motility (r = -0.20, P < 0.001) and morphology (r = -0.16, P = 0.005). WHO semen reference criteria were all met by only 52 men (14.4%). Some criteria were not met at first analysis in 15-20% of men, including semen volume (<1.5 ml, 14.8%), total sperm output (<39 million, 18.9%), sperm concentration (<15 million/ml, 17.5%), progressive motility (<32%, 14.4%) and morphologically normal sperm (<4%, 26.4%), while all five WHO criteria were not met in four participants (1.1%). LIMITATIONS AND REASONS FOR CAUTION: This was a large cohort study; however, potential for recruitment bias still exists. Men who did not participate in the testicular evaluation study (n = 282) did not differ from those who did (n = 423) with regard to age, weight, BMI, smoking or circulating reproductive hormones (LH, FSH, inhibin B, T, DHT, E2, E1, DHEA, 3α-diol, 3ß-diol), but were significantly shorter (178 versus 180 cm, P = 0.008) and had lower alcohol consumption (P = 0.019) than those who did participate. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated the feasibility of establishing a birth cohort to provide a relatively unbiased insight into population-representative sperm output and function and of investigating its determinants from common exposures. While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have little adverse impact, and this study suggests that discrepancies from the WHO reference ranges are expected, due to its derivation from non-population-representative fertile populations.

The risk of placenta accreta following primary elective caesarean delivery: a case-control study.

OBJECTIVE: To evaluate the risk of placenta praevia accreta following primary (first) elective or primary emergency caesarean section in a pregnancy complicated by placenta praevia. DESIGN: Retrospective matched case-control study, employing variable matching. SETTING: Tertiary referral centre between 1993 and 2008. POPULATION: Sixty-five cases and 102 controls were used for the analysis from a total of 82 667 births during the study period. METHODS: Relevant data were abstracted from clinical records. Matching of cases with controls was based on co-existing placenta praevia, number of previous caesarean sections, and age, with one or two controls per case. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). MAIN OUTCOME MEASURES: Placenta accreta in a pregnancy complicated by placenta praevia following a primary elective or emergency caesarean section, and morbidity associated with pregnancies complicated by placenta accreta. RESULTS: Significantly more cases than controls had an elective caesarean section for their primary caesarean delivery (46.2 versus 18.6%; P < 0.001). There were no differences between groups for previous pregnancy loss, uterine surgery, and vaginal delivery, before or after the primary caesarean section. Compared with primary emergency caesarean section, primary elective caesarean section significantly increased the risk of placenta accreta in a subsequent pregnancy in the presence of placenta praevia (OR 3.00; 95% CI 1.47-6.12; P = 0.025). CONCLUSIONS: Our results suggest that women with a primary elective caesarean section without labour are more likely, compared with those undergoing primary emergency caesarean section with labour, to develop an accreta in a subsequent pregnancy with placenta praevia.

The association between in utero exposure to maternal psychological stress and female reproductive function in adolescence: A prospective cohort study.

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 â€‹= â€‹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 (ߠ​= â€‹0.13, 95% CI 0.04; 0.23) and higher ovarian AFC (ߠ​= â€‹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.

Neonatal outcomes following previable prelabour rupture of membranes before 23 weeks of gestation - A retrospective cohort study.

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 < 23 weeks and were grouped as: Group 1 (n = 28) with PPROM < 20 weeks and Group 2 (n = 54) with PPROM between 20-22 + 6 weeks. Median latency following PPROM was significantly longer in Group 1 infants [69(Interquartile range (IQR): 43-74; Range (R): 25-100 vs. 29(IQR: 10-53; R: 2-72) days, p < 0.001]. Median gestation at delivery was 27.4 weeks (Group 1) vs. 25.1 weeks (Group 2). Group 1 had a significantly higher incidence of oligohydramnios [13(46.4%) vs. 8(14.8%), p = 0.002], lower Apgar scores (<7) at 5 minutes [19(67.9%) vs. 24(44.4%), p = 0.044], increased pulmonary hypoplasia [13(46.4%) vs. 5(9.3%), p < 0.001], joint contractures [3(10.7%) vs. 0, p = 0.037] and mortality [10(35.7%) vs. 7(13.0%), p = 0.016]. Neurodevelopmental outcomes at 24 months corrected age were comparable in the 36 surviving infants (9/18 vs. 27/547). CONCLUSION: Morbidity and mortality is high in infants born after previable PPROM; specifically, in those with PPROM < 20 weeks although early childhood neurodevelopmental outcomes were comparable. Larger prospective studies focussing on long term neonatal outcomes are needed to confirm these findings.

In utero exposure to maternal stressful life events and risk of polycystic ovary syndrome in the offspring: The Raine Study.

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 (ß = -0.05, 95% CI: -0.09; -0.004) and androstenedione (ß = -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.

Induction of labour in nulliparous women with an unfavourable cervix: a randomised controlled trial comparing double and single balloon catheters and PGE2 gel.

OBJECTIVE: To compare the efficacy and patient satisfaction of three methods of labour induction (double balloon catheters, single balloon catheters and prostaglandin gel) in term nulliparous women with unfavourable cervices. DESIGN: Randomised controlled trial. POPULATION: A total of 330 nulliparous women with unfavourable cervices induced at term. METHODS: Three cervical ripening study arms were used: double balloon catheter (107 women); 16F Foley catheter (110 women) and PGE(2) gel (2 mg) (113 women). MAIN OUTCOME MEASURES: Caesarean section, induction to delivery interval, adverse reactions and patient satisfaction. RESULTS: There was no difference in caesarean delivery rates between groups (double balloon 43%, single balloon 36%, PGE(2) 37%, P = 0.567). The induction to delivery interval was longer in the double balloon group (median 24.5; 95% CI 23.7, 30.6 hours) than the single balloon (23.2; 20.8, 25.8 hours) or PGE(2) (23.8; 21.7, 26.8 hours) (P = 0.043). Uterine hyperstimulation occurred in 14% of the PGE(2) group with none occurring with mechanical cervical ripening. Cord blood gases were worse in the PGE(2) group: median arterial pH double balloon 7.26 (range 7.03-7.40); single balloon 7.26 (7.05-7.44); PGE(2) 7.25 (6.91-7.41) (P = 0.050). Cervical ripening with the single balloon catheter was associated with significantly less pain (pain score > or =4: double balloon 55%, single balloon 36%, PGE(2) 63%, P < 0.001). CONCLUSIONS: Labour induction in nullipara with unfavourable cervices results in high caesarean delivery rates. Although all methods in this study had similar efficacy, the single balloon catheter offers the best combination of safety and patient comfort.

Antenatal intravenous immunoglobulin in chronic immune thrombocytopenic purpura: case report and literature review.

Immune thrombocytopenic purpura (ITP) may complicate pregnancy and, uncommonly, may cause severe neonatal thrombocytopenia. However, it is difficult to predict which neonates are at risk of severe thrombocytopenia. Direct fetal sampling is not commonly done, as it poses significant risks to the fetus. Furthermore, appropriate antenatal treatment of neonates is controversial. We describe the case of a 32-year-old woman with chronic severe ITP and a previous severely affected infant, pregnant with trichorionic triplets, who was successfully managed with the use of weekly intravenous immunoglobulin 1 g/kg without recourse to direct fetal sampling.

The introduction of umbilical cord lactate measurement and associated neonatal outcomes in a South African tertiary hospital labor ward.

PURPOSE: To investigate the utility of umbilical artery (UA) lactate measurements in a South African hospital for assessing intrapartum care and predicting neonatal outcomes. MATERIALS AND METHODS: 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. RESULTS: 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 score <7 at 5 min and the optimal lactate for this outcome was 5.65 mmol/L (sensitivity 64%, specificity of 69%). CONCLUSIONS: 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.

The effect of preterm birth on umbilical cord blood gases.

Apgar scores are used routinely to assess early neonatal status, but are less accurate in the preterm neonate because of developmental immaturity. Attention has been directed to umbilical cord gases as a method of neonatal evaluation. Using a retrospective chart review of all viable preterm births (24-36 weeks' gestation) between January 1986 and December 1989, we tabulated the umbilical cord gas indices of these infants. Fetuses with lethal congenital anomalies and those with abnormal heart rate tracings on admission were excluded from the data base, leaving 1872 infants. Cord arterial blood gas values were available for analysis in 74.4% of cases and cord venous gas values in 81.8%. The mean (+/- standard deviation [SD]) arterial and venous umbilical cord blood gas values for the preterm infants, were, respectively: pH, 7.26 +/- 0.08 and 7.33 +/- 0.07; oxygen pressure, 19.0 +/- 7.9 and 29.2 +/- 9.7 mmHg; carbon dioxide pressure, 53.0 +/- 10.0 and 43.4 +/- 8.3 mmHg; bicarbonate, 24.0 +/- 2.3 and 22.8 +/- 2.1 mEq/L; and base excess, -3.2 +/- 2.9 and -2.6 +/- 2.5 mEq/L. Acidemia was defined statistically as 2 SDs or more below the population mean. The incidence of 5-minute Apgar scores below 7 in the preterm infants was 8.5% and within this group, 17.8% were acidemic (arterial pH 7.10 or lower). More than 82% of neonates with 5-minute Apgar scores less than 7 had normal umbilical cord blood gases. There was no significant difference in umbilical arterial blood gas values between preterm infants and 1924 term deliveries at our institution between 1986-1988.(ABSTRACT TRUNCATED AT 250 WORDS)

The progression of disease stage in twin-twin transfusion syndrome.

OBJECTIVE: To estimate the frequency of progression or regression of disease stage in pregnancies complicated by twin-twin transfusion syndrome (TTTS) managed with non-placental laser techniques. METHODS: A cohort of TTTS pregnancies within the sole perinatal center for the state of Western Australia was examined. All cases of prenatally identified TTTS from 1992 to 2002 were staged at diagnosis (retrospectively prior to 2000, prospectively since). Amnioreduction and septostomy were the principal therapies used. Features associated with progression, regression or stability were identified. RESULTS: During the study period, 71 cases of TTTS were managed. Amnioreduction was performed in 73.2%, with no difference in the median number of procedures by stage (p = 0.178). In 21.1% of cases, TTTS resolved completely with persistent normalization of amniotic fluid volumes after amnioreduction (median number of procedures: 2). Disease resolution was associated with pregnancy prolongation, greater gestational age at delivery (36 weeks vs. 28.4 weeks, p < 0.001) and increased perinatal survival (100% vs. 42.6%, p < 0.001) compared with stage progression. Logistic regression analysis predicted that the probability of both infants surviving was 80% if the pregnancy remained at Stage I or II throughout, compared with a probability of 50% if it reached Stage III or more at 26 weeks, and only 25% if the disease reached Stage III or more at 16 weeks' gestation. CONCLUSION: Pregnancy outcome for TTTS managed with amnioreduction techniques is correlated with stage at diagnosis and the subsequent disease evolution. However, the progression of stage in TTTS is unpredictable and the likelihood of spontaneous fetal demise was not different between stages.

Neonatal necrotizing enterocolitis following intrauterine transfusions: is there an association?

The case of a neonate with necrotizing enterocolitis (NEC) following intrauterine transfusions (IUTs) for Rhesus hemolytic disease (RHD) prompted us to undertake a retrospective study (1995-2002) to determine whether there is an association between IUT and NEC. Maternal and neonatal demographics, and details concerning IUT and definite (> or =Stage II) NEC, were collected. Chi2 tests of association were performed. In our population 281/38,200 (0.73%) pregnancies were complicated by RHD. Fetal anemia necessitated IUT in 25/281 pregnancies. Definite NEC occurred in 59/11,814 (very low birth weight=1874) neonatal admissions. Except for the index case, no other neonate developed NEC following IUT. No significant association was found between IUT and NEC.

Dilated and echogenic fetal bowel and postnatal outcomes: a surgical perspective. Case series and literature review.

INTRODUCTION: Foetal dilated or echogenic bowel have been described as markers for a variety of conditions including bowel obstruction, chromosomal and infectious disorders and cystic fibrosis. We aim to describe possible surgical interventions and outcomes. METHODS: A 5-year review was performed of the clinical course of infants with antenatally diagnosed isolated echogenic bowel and/or dilated bowel or intraabdominal echogenic foci presenting at Princess Margaret Hospital for Children, Perth, Western Australia. RESULTS: Abnormal antenatal findings were present in 35 foetuses. Twelve babies underwent surgery for intestinal atresia, meconium ileus and duplication cysts. Postoperative courses and outcomes were good. CONCLUSIONS: Echogenic bowel on antenatal ultrasound is a non-specific marker for a variety of disorders. Although associated with higher rates of foetal loss, the majority of neonates are normal at delivery. Bowel dilatation with or without echogenicity is often predictive of bowel obstruction requiring surgery. Surgical outcomes are, however, very good. Echogenic foci elsewhere in the abdomen have little postnatal significance.

The expression of apoptosis related genes in the first trimester human placenta using a short term in vitro model.

Using in vitro model for studying the induction and inhibition of spontaneous apoptosis in human first trimester placental villi, mediated by the free radical scavenger SOD, we have examined the expression of bcl-xL, bax, Caspase-3 and PARP (Poly ADP-ribosyl). An increase in apoptosis was associated with activation of PARP and an increase and activation of Caspase-3. There was no significant change in bcl-x or bax. Therefore bcl-x and bax do not appear to have a significant role in apoptosis in the first trimester in vitro. Cleavage of Caspase-3 rather than transcriptional regulation appears to be the main determinant of Caspase-3 activity in first trimester placental villi.