Antenatal care addressing gestational weight gain (GWG): a cross sectional study of pregnant women's reported receipt and acceptability of recommended GWG care and associated characteristics.

BACKGROUND: The Australian Clinical Practice Guidelines for Pregnancy Care recommend that during the first and subsequent antenatal visits all pregnant women are weighed; advised of recommended gestational weight gain (GWG), dietary intake and physical activity; and offered referrals for additional support if needed. The extent to which these recommendations are implemented and women's acceptability of recommended care is unknown. This study examines women's reported receipt and acceptability of guideline care for GWG, and characteristics associated with receipt of such care and its acceptability. METHODS: From September 2018 to February 2019 a telephone survey was undertaken with women who had recently had a baby and received antenatal care from five public maternity services within a health district in Australia. Women self-reported their demographic characteristics, and receipt and acceptability of recommended GWG care. Receipt and acceptability of such care, and their association with the characteristics of women and the maternity service they attended, were examined using descriptive statistics and multivariable logistic regression analyses. RESULTS: Of 514 women, 13.1% (95%CI:10.3-16.5) reported that they received an assessment of weight at both their first and a subsequent antenatal visit, and less than one third (30.0%; 95%CI:26.0-33.9) received advice on their recommended GWG range, dietary intake and physical activity. Just 6.6% (95%CI:4.8-9.1) of women reported receiving all assessment and advice components of recommended antenatal care, and 9.9% (95%CI:7.6-12.8) of women reported being referred for extra support. Women who were younger (OR = 1.13;95%CI:1.05-1.21), identifying as Aboriginal and Torres Strait Islander (OR = 24.54;95%CI:4.98-120.94), had a higher pre-pregnancy BMI (OR = 1.13;95%CI:1.05-1.21), were experiencing their first pregnancy (OR = 3.36;95%CI:1.27-8.86), and lived in a least disadvantaged area (compared to mid-disadvantaged area (OR = 18.5;95%CI:2.6-130.5) and most disadvantaged area (OR = 13.1;95%CI:2.09-82.4)) were more likely to receive recommended assessment and advice. Most Aboriginal (92%) and non-Aboriginal (93%) women agreed that recommended GWG care is acceptable. CONCLUSION: Most women perceive antenatal care for GWG as recommended by the Clinical Practice Guidelines as acceptable, but did not receive it. When provided, such care is not delivered consistently to all women regardless of their characteristics or those of the maternity service they attend. There is a need for service-wide practice change to increase routine GWG care in pregnancy for all women.

Preterm labor with and without chorioamnionitis is associated with activation of myometrial inflammatory networks: a comprehensive transcriptomic analysis.

BACKGROUND: The onset of preterm labor is associated with inflammation. Previous studies suggested that this is distinct from the inflammation observed during term labor. Our previous work on 44 genes differentially expressed in myometria in term labor demonstrated a different pattern of gene expression from that observed in preterm laboring and nonlaboring myometria. We found increased expression of inflammatory genes in preterm labor associated with chorioamnionitis, but in the absence of chorioamnionitis observed no difference in gene expression in preterm myometria regardless of laboring status, suggesting that preterm labor is associated with different myometrial genes or signals originating from outside the myometrium. Given that a small subset of genes were assessed, this study aimed to use RNA sequencing and bioinformatics to assess the myometrial transcriptome during preterm labor in the presence and absence of chorioamnionitis. OBJECTIVE: This study aimed to comprehensively determine protein-coding transcriptomic differences between preterm nonlaboring and preterm laboring myometria with and without chorioamnionitis. STUDY DESIGN: Myometria were collected at cesarean delivery from preterm patients not in labor (n=16) and preterm patients in labor with chorioamnionitis (n=8) or without chorioamnionitis (n=6). Extracted RNA from myometrial tissue was prepared and sequenced using Illumina NovaSeq. Gene expression was quantified by mapping the sequence reads to the human reference genome (hg38). Differential gene expression analysis, gene set enrichment analysis, and weighted gene coexpression network analysis were used to comprehensively interrogate transcriptomic differences and their associated biology. RESULTS: Differential gene expression analysis comparing preterm patients in labor with chorioamnionitis with preterm patients not in labor identified 931 differentially expressed genes, whereas comparing preterm patients in labor without chorioamnionitis with preterm patients not in labor identified no statistically significant gene expression changes. In contrast, gene set enrichment analysis and weighted gene coexpression network analysis demonstrated that preterm labor with and without chorioamnionitis was associated with enrichment of pathways involved in activation of the innate immune system and inflammation, and activation of G protein-coupled receptors. Key genes identified included chemotactic CYP4F3, CXCL8, DOCK2, and IRF1 in preterm labor with chorioamnionitis and CYP4F3, FCAR, CHUK, and IL13RA2 in preterm labor without chorioamnionitis. There was marked overlap in the pathways enriched in both preterm labor subtypes. CONCLUSION: Differential gene expression analysis demonstrated that myometria from preterm patients in labor without chorioamnionitis and preterm patients not in labor were transcriptionally similar, whereas the presence of chorioamnionitis was associated with marked gene changes. In contrast, comprehensive bioinformatic analysis indicated that preterm labor with or without chorioamnionitis was associated with innate immune activation. All causes of preterm labor were associated with activation of the innate immune system, but this was more marked in the presence of chorioamnionitis. These data suggest that anti-inflammatory therapy may be relevant in managing preterm labor of all etiologies.

McDonald versus Shirodkar cerclage technique in the prevention of preterm birth: A systematic review and meta-analysis.

BACKGROUND: Cervical cerclage has been used for decades to reduce preterm birth. The Shirodkar and McDonald cerclage are the most commonly used techniques with no current consensus on the preferred technique. OBJECTIVE: To compare the efficacy of the Shirodkar and McDonald cerclage techniques in preventing preterm birth. SEARCH STRATEGY: Studies were sourced from six electronic databases and reference lists. SELECTION CRITERIA: Studies including women with a singleton pregnancy, requiring a cervical cerclage, using either the Shirodkar or McDonald technique that ran comparative analyses between the two techniques. DATA COLLECTION AND ANALYSIS: The primary outcome was preterm birth before 37 weeks, with analyses at 28, 32, 34 and 35 weeks. Secondary data were also collected on neonatal, maternal and obstetric outcomes. MAIN RESULTS: Seventeen papers were included: 16 were retrospective cohort studies and one was a randomised controlled trial. The Shirodkar technique was significantly less likely to result in preterm birth before 37 weeks than the McDonald technique (relative risk [RR] 0.91, 95% CI 0.85-0.98). This finding was supported by a statistically significant reduction in rates of preterm birth before 35, 34 and 32 weeks, PPROM, difference in cervical length, cerclage to delivery interval, and an increase in birthweight in the Shirodkar group. No difference was seen in preterm birth rates <28 weeks, neonatal mortality, chorioamnionitis, cervical laceration or caesarean section rates. The RR for preterm birth prior to 37 weeks was no longer significant when sensitivity analyses were performed removing studies with a serious risk of bias. However, similar analyses removing studies that utilised adjunctive progesterone strengthened the primary outcome (RR 0.83, 95% CI 0.74-0.93). CONCLUSION: Shirodkar cerclage reduces the rate of preterm birth prior to 35, 34 and 32 weeks' gestation when compared with McDonald cerclage; however, the overall quality of the studies in this review is low. Further, large, well-designed randomised controlled trials are required to address this important question to optimise care for women who may benefit from cervical cerclage.

Language and reading impairments are associated with increased prevalence of non-right-handedness.

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6-19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases  = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06-1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

Development and internal validation of a non-invasive clinical tool to predict sufficient omega-3 levels in early pregnancy.

BACKGROUND: Complications from preterm birth (PTB) are the leading cause of death and disability in those under five years. Whilst the role of omega-3 (n-3) supplementation in reducing PTB is well-established, growing evidence suggests supplementation use in those replete may increase the risk of early PTB. AIM: To develop a non-invasive tool to identify individuals with total n-3 serum levels above 4.3% of total fatty acids in early pregnancy. METHODS: We conducted a prospective observational study recruiting 331 participants from three clinical sites in Newcastle, Australia. Eligible participants (n = 307) had a singleton pregnancy between 8 and 20 weeks' gestation at recruitment. Data on factors associated with n-3 serum levels were collected using an electronic questionnaire; these included estimated intake of n-3 (including food type, portion size, frequency of consumption), n-3 supplementation, and sociodemographic factors. The optimal cut-point of estimated n-3 intake that predicted mothers with total serum n-3 levels likely above 4.3% was developed using multivariate logistic regression, adjusting for maternal age, body mass index, socioeconomic status, and n-3 supplementation use. Total serum n-3 levels above 4.3% was selected as previous research has demonstrated that mothers with these levels are at increased risk of early PTB if they take additional n-3 supplementation during pregnancy. Models were evaluated using various performance metrics including sensitivity, specificity, area under receiver operator characteristic (AUROC) curve, true positive rate (TPR) at 10% false positive rate (FPR), Youden Index, Closest to (0,1) Criteria, Concordance Probability, and Index of Union. Internal validation was performed using 1000-bootstraps to generate 95% confidence intervals for performance metrics generated. RESULTS: Of 307 eligible participants included for analysis, 58.6% had total n-3 serum levels above 4.3%. The optimal model had a moderate discriminative ability (AUROC 0.744, 95% CI 0.742-0.746) with 84.7% sensitivity, 54.7% specificity and 37.6% TPR at 10% FPR. CONCLUSIONS: Our non-invasive tool was a moderate predictor of pregnant women with total serum n-3 levels above 4.3%; however, its performance is not yet adequate for clinical use. TRIAL REGISTRATION: This trial was approved by the Hunter New England Human Research Ethics Committee of the Hunter New England Local Health District (Reference 2020/ETH00498 on 07/05/2020 and 2020/ETH02881 on 08/12/2020).

Double-vs single-balloon catheter for induction of labor: Systematic review and individual participant data meta-analysis.

INTRODUCTION: Evidence comparing double-balloon vs single-balloon catheter for induction of labor is divided. We aim to compare the efficacy and safety of double-vs single-balloon catheters using individual participant data. MATERIAL AND METHODS: A search of Ovid MEDLINE, Embase, Ovid Emcare, CINAHL Plus, Scopus, and clinicaltrials.gov was conducted for randomized controlled trials published from March 2019 until April 13, 2021. Earlier trials were identified from the Cochrane Review on Mechanical Methods for Induction of Labour. Randomized controlled trials that compared double-balloon with single-balloon catheters for induction of labor in singleton gestations were eligible. Participant-level data were sought from trial investigators and an individual participant data meta-analysis was performed. The primary outcomes were rates of vaginal birth achieved, a composite measure of adverse maternal outcomes and a composite measure of adverse perinatal outcomes. We used a two-stage random-effects model. Data were analyzed from the intention-to-treat perspective. RESULTS: Of the eight eligible randomized controlled trials, three shared individual-level data with a total of 689 participants, 344 women in the double-balloon catheter group and 345 women in the single-balloon catheter group. The difference in the rate of vaginal birth between double-balloon catheter and single-balloon catheter was not statistically significant (relative risk [RR] 0.93, 95% confidence interval [CI] 0.86-1.00, p = 0.050; I2 0%; moderate-certainty evidence). Both perinatal outcomes (RR 0.81, 95% CI 0.54-1.21, p = 0.691; I2 0%; moderate-certainty evidence) and maternal composite outcomes (RR 0.65, 95% CI 0.15-2.87, p = 0.571; I2 55.46%; low-certainty evidence) were not significantly different between the two groups. CONCLUSIONS: Single-balloon catheter is at least comparable to double-balloon catheter in terms of vaginal birth rate and maternal and perinatal safety outcomes.

Preterm labor is a distinct process from term labor following computational analysis of human myometrium.

BACKGROUND: The onset of the term human parturition involves myometrial gene expression changes to transform the uterus from a quiescent to a contractile phenotype. It is uncertain whether the same changes occur in the uterus during preterm labor. OBJECTIVE: This study aimed to compare the myometrial gene expression between term and preterm labor and to determine whether the presence of acute clinical chorioamnionitis or twin gestation affects these signatures. STUDY DESIGN: Myometrial specimens were collected during cesarean delivery from the following 7 different groups of patients: term not in labor (n=31), term labor (n=13), preterm not in labor (n=21), preterm labor with acute clinical chorioamnionitis (n=6), preterm labor with no acute clinical chorioamnionitis (n=9), twin preterm not in labor (n=8), and twin preterm labor with no acute clinical chorioamnionitis (n=5). RNA was extracted, reverse transcribed and quantitative polymerase chain reactions were performed on 44 candidate genes (with evidence for differential expression in human term labor) using the Fluidigm platform. Computational analysis was performed using 2-class unpaired Wilcoxon tests and principal component analysis. RESULTS: Computational analysis revealed that gene expression in the preterm myometrium, irrespective of whether in labor or not in labor, clustered tightly and is clearly different from the term labor and term not-in-labor groups. This was true for both singleton and twin pregnancies. Principal component analysis showed that 57% of the variation was explained by 3 principal components. These 44 genes interact in themes of prostaglandin activity and inflammatory signaling known to be important during term labor, but are not a full representation of the myometrium transcriptional activity. CONCLUSION: The myometrial contractions associated with preterm labor are associated with a pattern of gene expression that is distinct from term labor. Therefore, preterm labor may be initiated by a different myometrial process or processes outside the myometrium.

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Healthcare factors associated with the risk of antepartum and intrapartum stillbirth in migrants in Western Australia (2005-2013): A retrospective cohort study.

BACKGROUND: Migrant women, especially from Indian and African ethnicity, have a higher risk of stillbirth than native-born populations in high-income countries. Differential access or timing of ANC and the uptake of other services may play a role. We investigated the pattern of healthcare utilisation among migrant women and its relationship with the risk of stillbirth (SB)-antepartum stillbirth (AnteSB) and intrapartum stillbirth (IntraSB)-in Western Australia (WA). METHODS AND FINDINGS: A retrospective cohort study using de-identified linked data from perinatal, birth, death, hospital, and birth defects registrations through the WA Data Linkage System was undertaken. All (N = 260,997) non-Indigenous births (2005-2013) were included. Logistic regression analysis was used to estimate odds ratios and 95% CI for AnteSB and IntraSB comparing migrant women from white, Asian, Indian, African, Maori, and 'other' ethnicities with Australian-born women controlling for risk factors and potential healthcare-related covariates. Of all the births, 66.1% were to Australian-born and 33.9% to migrant women. The mean age (years) was 29.5 among the Australian-born and 30.5 among the migrant mothers. For parity, 42.3% of Australian-born women, 58.2% of Indian women, and 29.3% of African women were nulliparous. Only 5.3% of Maori and 9.2% of African migrants had private health insurance in contrast to 43.1% of Australian-born women. Among Australian-born women, 14% had smoked in pregnancy whereas only 0.7% and 1.9% of migrants from Indian and African backgrounds, respectively, had smoked in pregnancy. The odds of AnteSB was elevated in African (odds ratio [OR] 2.22, 95% CI 1.48-2.13, P < 0.001), Indian (OR 1.64, 95% CI 1.13-2.44, P = 0.013), and other women (OR 1.46, 95% CI 1.07-1.97, P = 0.016) whereas IntraSB was higher in African (OR 5.24, 95% CI 3.22-8.54, P < 0.001) and 'other' women (OR 2.18, 95% CI 1.35-3.54, P = 0.002) compared with Australian-born women. When migrants were stratified by timing of first antenatal visit, the odds of AnteSB was exclusively increased in those who commenced ANC later than 14 weeks gestation in women from Indian (OR 2.16, 95% CI 1.18-3.95, P = 0.013), Maori (OR 3.03, 95% CI 1.43-6.45, P = 0.004), and 'other' (OR 2.19, 95% CI 1.34-3.58, P = 0.002) ethnicities. With midwife-only intrapartum care, the odds of IntraSB for viable births in African and 'other' migrants (combined) were more than 3 times that of Australian-born women (OR 3.43, 95% CI 1.28-9.19, P = 0.014); however, with multidisciplinary intrapartum care, the odds were similar to that of Australian-born group (OR 1.34, 95% CI 0.30-5.98, P = 0.695). Compared with Australian-born women, migrant women who utilised interpreter services had a lower risk of SB (OR 0.51, 95% CI 0.27-0.96, P = 0.035); those who did not utilise interpreters had a higher risk of SB (OR 1.20, 95% CI 1.07-1.35, P < 0.001). Covariates partially available in the data set comprised the main limitation of the study. CONCLUSION: Late commencement of ANC, underutilisation of interpreter services, and midwife-only intrapartum care are associated with increased risk of SB in migrant women. Education to improve early engagement with ANC, better uptake of interpreter services, and the provision of multidisciplinary-team intrapartum care to women specifically from African and 'other' backgrounds may reduce the risk of SB in migrants.

Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero.

The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N = 15 661, with replication N = 75 821), we identified 11 loci (9 novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (ß = 0.06; P = 0.02) between 2D:4D ratio and sensitivity to testosterone [length of the CAG microsatellite repeat in the androgen receptor (AR) gene] in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population.

Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium.

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

Sex differences between parental pregnancy characteristics and nonalcoholic fatty liver disease in adolescents.

Nonalcoholic fatty liver disease (NAFLD) is a complex chronic liver disorder. Examination of parental pregnancy-related characteristics may provide insights into the origins of risk of NAFLD in offspring. We examined relationships between parental pregnancy-related characteristics and NAFLD in 1,170 adolescent offspring aged 17 years participating in the Western Australian Pregnancy (Raine) Cohort Study. Fatty liver was diagnosed using liver ultrasound. NAFLD was diagnosed in 15.2% of adolescents at age 17 years. In univariate analysis, maternal factors associated with NAFLD in female offspring were younger maternal age (P = 0.02), higher maternal prepregnancy BMI (P < 0.001), higher maternal weight gain by 18 weeks' gestation (P < 0.001), and maternal smoking during pregnancy (P = 0.04). Paternal age or body mass index (BMI) were not associated with NAFLD in female offspring. In contrast, higher paternal BMI (P < 0.001), maternal prepregnancy BMI (P < 0.001), and lower family socioeconomic status (SES) at time of birth (P = 0.001), but not parental age nor maternal gestational weight gain, were associated with NAFLD in male offspring. Using multivariate logistic regression, factors independently associated with NAFLD after adjusting for obesity in adolescent females included maternal obesity (odds ratio [OR], 3.46; 95% confidence interval [CI], 1.49-8.05; P = 0.004) and maternal weight gain ≥6.0 kg by the 18th week of gestation (OR, 1.10; 95% CI, 1.04-1.15; P < 0.001). In adolescent males, family SES at the time of birth (OR, 9.07; 95% CI, 1.54-53.29; P = 0.02) remained significantly associated with NAFLD after multivariate modeling adjusted for adolescent obesity. CONCLUSION: Early-life contributors to NAFLD show considerable sexual dimorphism. Maternal obesity and higher early-mid gestational weight gain were associated with NAFLD in female offspring, whereas lower family SES at birth was associated with NAFLD in male offspring independent of adolescent obesity. (Hepatology 2018;67:108-122).

Single dose v two-dose antenatal anti-D prophylaxis: a randomised controlled trial.

OBJECTIVE: To compare rates of detectability of circulating Rh(D)-immunoglobulin (anti-D) at delivery with single and two-dose antenatal anti-D prophylaxis (RAADP) regimens; to compare compliance with the two regimens. DESIGN: Open label, randomised controlled trial between May 2013 and November 2015. SETTING, PARTICIPANTS: 277 women who attended a tertiary obstetric referral hospital in Perth for antenatal care and were at least 18 years of age, less than 30 weeks pregnant and yet to receive RAADP, Rh(D)-negative (negative antibody screen), and who intended to deliver their baby at the hospital. Exclusion criteria were prior anti-D sensitisation, any contraindication of anti-D administration, and a history of isolated IgA deficiency. INTERVENTIONS: One 1500 IU anti-D dose at 28 weeks of pregnancy (single dose regimen); two doses of 625 IU each at 28 and 34 weeks of pregnancy (two-dose regimen). MAIN OUTCOME MEASURES: The primary outcome was the proportion of women with detectable anti-D levels at delivery; the secondary outcome was compliance with the allocated RAADP regimen. RESULTS: Circulating anti-D was detectable at delivery in a greater proportion of women in the two-dose group (111 of 129, 86%) than in the single dose group (70 of 125, 56%; P < 0.001). Compliance was not significantly different between the single dose (86 of 138, 61%) and two-dose groups (70 of 139, 50%; P = 0.06). CONCLUSIONS: The two-dose RAADP schedule currently recommended in Australia provides better protection against Rh(D) sensitisation than a one-dose regimen. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12613000661774).

Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis.

AIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (ß ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10-3) and higher fasting insulin (0.030 ± 0.005 [log e pmol/l], p = 2.0 × 10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the ß-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant. CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis. TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study).

The impact of antenatal Bisphenol A exposure on male reproductive function at 20-22 years of age.

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.

Does perinatal exposure to exogenous oxytocin influence child behavioural problems and autistic-like behaviours to 20 years of age?

BACKGROUND: The neuropeptide and hormone oxytocin is known to have a significant impact on social cognition and behaviour in humans. There is growing concern regarding the influence of exogenous oxytocin (OT) administration in early life on later social and emotional development, including autism spectrum disorder (ASD). No study has examined offspring development in relation to the dose of exogenous oxytocin administered during labour. METHODS: Between 1989 and 1992, 2,900 mothers were recruited prior to the 18th week of pregnancy, delivering 2,868 live offspring. The Child Behaviour Checklist was used to measure offspring behavioural difficulties at ages 5, 8, 10, 14 and 17 years. Autism spectrum disorder was formally diagnosed by consensus of a team of specialists. At 20 years, offspring completed a measure of autistic-like traits, the Autism Spectrum Quotient (AQ). Oxytocin exposure prior to birth was analysed using categorical and continuous approaches (maternal oxytocin dose) with univariate and multivariate statistical techniques. RESULTS: Categorical analyses of oxytocin exposure prior to birth demonstrated no group differences in any measures of child behaviour. A small in magnitude dose-response association was observed for clinically significant total behaviour symptoms (adjusted odds ratio 1.03; 95% CI: 1.01-1.06, p < .01). Exogenous oxytocin administration prior to birth was not associated with ASD (OR: 0.64; 95% CI: 0.15-2.12, p = .46) or high levels of autistic-like traits (p = .93), as assessed by the AQ. CONCLUSIONS: This study is the first to investigate longitudinal mental health outcomes associated with the use of oxytocin-based medications during labour. The results do not provide evidence to support the theory that exogenous OT has a clinically significant negative impact on the long-term mental health of children.

Stillbirth in Western Australia, 2005-2013: the influence of maternal migration and ethnic origin.

OBJECTIVE: To investigate prevalence rates and the risk of ante- and intrapartum stillbirth in Western Australia with respect to maternal country of birth and ethnic origin. DESIGN, SETTING AND PARTICIPANTS: Whole population retrospective cohort analysis of de-identified, linked routinely collected birth, perinatal and mortality data for all births to non-Indigenous women in WA during 2005-2013. MAIN OUTCOME MEASURES: Crude and adjusted odds ratios (aORs) with 95% confidence intervals were estimated by logistic regression and adjusted for confounding factors, for all stillbirths, antepartum stillbirths and intrapartum stillbirths, stratified by migrant status and ethnic background (white, Asian, Indian, African, Maori, other). RESULTS: Women born overseas were more likely to have a stillbirth than Australian-born women (aOR, 1.26; 95% CI, 1.09-1.37). There was no significant difference for any type of stillbirth between Australian-born women of white and non-white backgrounds, but non-white migrant women were more likely than white migrants to have a stillbirth (OR, 1.42; 95% CI, 1.19-1.70). Compared with Australian-born women, migrants of Indian (aOR, 1.71; 95% CI, 1.17-2.47), African (aOR, 2.12; 95% CI, 1.46-3.08), and "other" ethnic origins (aOR, 1.43; 95% CI, 1.06-1.93) were more likely to have antepartum stillbirths; women of African (aOR, 5.08; 95% CI, 3.14-8.22) and "other" (aOR, 1.86; 95% CI, 1.15-3.00) background were more likely to have an intrapartum stillbirth. CONCLUSIONS: Immigrants of African or Indian background appear to be at greater risk of ante- and intrapartum stillbirth in WA. Specific strategies are needed reduce the prevalence of stillbirth in these communities.

Shared genetic variants suggest common pathways in allergy and autoimmune diseases.

BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood. OBJECTIVE: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. METHODS: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. RESULTS: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.

WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness.

Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5)).