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Driven by a lack of appropriate human placenta models, recent years have seen the introduction of bioengineered in vitro models to better understand placental health and disease. Thus far, the focus has been on the maternal–foetal barrier. However, there are many other physiologically and pathologically significant aspects of the placenta that would benefit from state-of-the-art bioengineered models, in particular, integrating advanced culture systems with contemporary biological concepts such as organoids. This critical review defines and discusses the key parameters required for the development of physiologically relevant in vitro models of the placenta. Specifically, it highlights the importance of cell type, mechanical forces, and culture microenvironment towards the use of physiologically relevant models to improve the understanding of human placental function and dysfunction. Refereed/Peer-reviewed

To assess the independent and joint contribution of the individual components of metabolic syndrome, and known risk factors for gestational diabetes (GDM), on risk of GDM. Two thousand nine hundred and fifteen women from Australia and New Zealand, who participated in The Screening for Pregnancy Endpoints Study (SCOPE), were included. Using the SCOPE clinical data set and biomarkers obtained at 14–16 weeks’ gestation, a logistic regression model was fitted to the binary outcome GDM, with individual metabolic syndrome components (waist circumference, blood pressure, glucose, HDL-C, triglycerides), recruitment site, and other established factors associated with GDM. Hierarchical partitioning was used to assess the relative contribution of each variable. Of the 2915 women, 103 women (3.5%) developed GDM. The deviance explained by the logistic regression model containing all variables was 18.65% and the AUC was 0.809. Seventy percent of the independent effect was accounted for by metabolic syndrome components. The highest independent relative contribution to GDM was circulating triglycerides (17 ± 3%), followed by waist circumference (13 ± 3%). Glucose and maternal BMI contributed 12 ± 2% and 12 ± 3%, respectively. The remaining factors had an independent relative contribution of

Metabolic syndrome (MetS) is a cluster of risk factors which increases risk of cardiometabolic diseases in the adult population and increases risk for pregnancy complications such as gestational diabetes mellitus (GDM). Epidemiological data indicate that moderate-to-high levels of physical activity reduces the risk for GDM. The study aims to determine whether the association between MetS and GDM is affected by physical activity. We performed a prospective cohort study among 1373 pregnant nulliparous women in Adelaide, South Australia. At 9–16 weeks’ gestation, demographic, lifestyle and self-reported frequencies of physical activity were obtained, and a non-fasting blood sample was taken for assessment of MetS, defined using the International Diabetes Federation criteria. GDM was diagnosed at 24–28 weeks’ gestation using the World Health Organization classification. 1158 pregnant women were included: 107 (9%) women had MetS in early pregnancy, and 184 (16%) developed GDM. Having MetS increased the risk of developing GDM (37.4% vs. 13.7%, adjusted RR 2.5; 95% CI 1.7, 3.6). The interaction effect (RR; (95% CI) between MetS and physical activity was not significant (vigorous physical activity: 2.60; 0.46, 14.71) for ≥ 4 times per week; less vigorous activity; 0.77; 0.15, 4.02 for ≥ 4 times per week; stair climbing ≥ once day (1.16; 0.54, 2.51), all compared to no physical activity). Physical activity was not an effect modifier in the association between GDM and MetS. Information collected about the nature and extent of physical activity needs to be more detailed and granular to determine whether physical activity really has an effect.

Objective To evaluate the safety of maternal pertussis vaccination on pregnancy and birth outcomes. Methods The study population comprised 1272 healthy nulliparous pregnant women who participated in Screening Tests to identify poor Outcomes in Pregnancy (STOP) study at two obstetric hospitals in South Australia between 2015 and 2018. Participants were followed prospectively, with vaccination (confirmed by medical records), extensive amounts of pregnancy and birth outcome data collected by research midwives. Adjusted relative risks (aRRs) and hazard ratios (aHRs) were estimated accounting for time-varying vaccine exposure and the temporal nature of each outcome. Results Of the 1272 women included in this study, 80.1% (n = 1019) received maternal pertussis vaccination. Vaccinated women had an average 0.22 weeks (95% CI 0.001, 0.44) longer gestation at delivery compared to unvaccinated women. Maternal pertussis vaccination was not associated with chorioamnionitis (aRR 0.71, 95% CI 0.27,1.82), gestational hypertension (aHR 1.24, 95% CI, 0.66, 2.30), preeclampsia (aHR 0.75, 95% CI 0.47, 1.18) nor preterm birth (aHR 0.99, 95% CI 0.47, 2.07). Neither risk of low birth weight (aHR 0.72, 95% CI 0.41, 1.27) nor small for gestational age infants (aHR 0.67,95% CI 0.29, 1.55) were increased following maternal pertussis vaccination. No associations between pertussis vaccination during pregnancy and adverse birth outcomes including admission to the neonatal care unit, low Apgar scores, and mechanical ventilation were observed. Results were not materially changed after adjustment for maternal influenza vaccination. Conclusion Our study provides reassuring evidence of the safety of maternal pertussis vaccination with no increased risk of adverse pregnancy and birth outcomes. These findings support recommendations for pertussis vaccination during pregnancy to prevent morbidity and mortality associated with early-infant pertussis disease.

This systematic review and meta-analysis aimed to synthesize evidence on conventional cardiovascular disease (CVD) risk factors among women with previous Gestational Diabetes Mellitus (GDM). The review protocol is registered with PROSPERO (CRD42019118149). PubMed, CINAHL, SCOPUS, and EMBASE databases were searched. Studies reporting on CVD risk factors in women with previous GDM compared to women without previous GDM were selected. A total of 139 studies were eligible, of which 93 were included in the meta-analysis. Women with previous GDM have significantly higher systolic blood pressure (2.47 mmHg 95% CI 1.74 to 3.40, n = 48, 50,118 participants) diastolic blood pressure (1.89 mmHg 95% CI 1.32 to 2.46, n = 48, 49,495 participants), BMI (1.54 kg/m2 95% CI 1.32 to 2.46, n = 78, 255,308 participants), total cholesterol (0.26 SMD 95% CI 0.15 to 0.37, n = 48, 38,561 participants), LDL cholesterol (0.19 SMD 95% CI 0.08 to 0.30, n = 44, 16,980 participants), triglycerides (0.56 SMD 95% CI 0.42 to 0.70, n = 46, 13,175 participants), glucose (0.69 SMD 95% CI 0.56 to 0.81, n = 55, 127,900 participants), insulin (0.41 SMD 95% CI 0.23 to 0.59, n = 32, 8881 participants) and significantly lower HDL cholesterol (-0.28 SMD 95% CI -0.39 to -0.16, n = 56, 35,882 participants), compared to women without previous GDM. The increased blood pressure, total cholesterol, triglycerides and glucose are seen as early as

Preeclampsia (PE) and gestational hypertension (GH) are pregnancy-specific diseases that occur in around 10% of pregnancies worldwide. Increasing evidence suggests that women whose pregnancies were complicated by PE or GH, and their offspring, are at increased risk of cardiovascular disease (CVD) later in life. We hypothesised that PE and GH would associate with CVD risk factors 8–10 years after the first pregnancy in the mother and child and that differences in cardiovascular risk profile would be seen between 8- and 10-year-old male and female children. This is a follow-up study of the Adelaide SCOPE pregnancy cohort where 1164 nulliparous women and their babies were recruited between 2005 and 2008. Haemodynamic function was assessed using non-invasive USCOMBP+ and USCOM1A devices. Microvascular function was assessed by post-occlusive reactive hyperaemia. Of the 273 mother–child pairs followed up, 38 women had PE and 20 had GH during pregnancy. Augmentation index (Aix) and suprasystolic pulse pressure (ssPP) were increased, whereas measures of microvascular function were decreased in children who were born to PE compared to uncomplicated pregnancies. Female children had decreased Aix and ssPP compared to male children after in utero exposure to PE. Women who developed GH during their first pregnancy had increased systolic, diastolic and mean arterial pressures compared to women who had uncomplicated pregnancy. Our data suggest that GH is associated with increased cardiovascular risk in women 8–10 years after first pregnancy and PE is associated with increased offspring risk at 8–10 years of age, highlighting differences between these two hypertensive disorders of pregnancy.

ContextMany studies assert a negative influence of inappropriate maternal diet and nutritional status during pregnancy on offspring, not only in utero but throughout life, because of the role in the programing of noncommunicable diseases. Telomere length is a biomarker of aging, and shorter telomeres are associated with chronic disease later in life. Maternal nutrition and nutritional status may be an important determinant of offspring telomere length.ObjectiveA systematic review was conducted to determine the effect of maternal nutrition and nutritional status in pregnancy on offspring telomere length.Data SourcesThis systematic review was conducted according to PRISMA guidelines. Database searches of PubMed, CINAHL, Scopus, Medline, and Web of Science were performed.Study SelectionIncluded studies assessed the association between maternal nutrition (dietary intake and nutritional status) during pregnancy and offspring telomere length measured in cord blood, serum, plasma, and peripheral blood mononuclear cells.Data ExtractionThree authors screened and determined the quality of the articles; disagreements were resolved by a fourth author. All authors compared the compiled data.ResultsSeven studies were extracted and evaluated. Studies comprised a double-blind placebo-controlled trial (n = 1), prospective cohort studies (n = 5), and a cross-sectional study (n = 1). Higher circulating maternal folate and 25-hydroxyvitamin D3 concentrations, along with higher maternal dietary caffeine intakes, were associated with longer offspring telomere length, whereas higher dietary intake of carbohydrate, folate, n-3 polyunsaturated fatty acids, vitamin C, or sodium was not.ConclusionThe limited but suggestive evidence highlights the need for further research to be conducted in this area, particularly longitudinal studies involving larger cohorts of pregnant women.Systematic review registrationPROSPERO registration no. CRD42019136506

The primary aim of this systematic review and meta-analysis was to determine the association between gestational diabetes mellitus (GDM) and metabolic syndrome (MetS) in women and children. Our secondary aim was to assess the development of MetS with respect to the elapsed time postpartum at which MetS was diagnosed. This review is registered with PROSPERO (CRD42020173319). PubMed, CINHAL, SCOPUS, and EMBASE databases were searched. Studies reporting on the rate of MetS in pregnant women with GDM, the rate of MetS in women with a history of GDM, and the rate of MetS in offspring exposed to GDM in utero compared to healthy controls were selected. We identified 588 articles from the literature search. Fifty-one studies were included in the review and of those 35 were included in the meta-analysis. Quantitative summary measures showed that women with a history of GDM had an increased risk of developing MetS compared to those without a history of GDM (RR 2.36, 95% CI 1.77–3.14, 29 studies, 13,390 participants; heterogeneity: χ2 p

The aim of this study was to determine whether presence of the metabolic syndrome in pregnancy associates with child telomere length or child anthropometry (weight, BMI) and BP, measured at 10 years of age. The Screening for Pregnancy Endpoints study (SCOPE) was a multicentre, international prospective cohort of nulliparous pregnant women recruited from Australia, New Zealand, Ireland and the UK (N = 5628). The current analysis is a 10 year follow-up of SCOPE pregnant women and their children, from the Australian cohort. Clinical data collected at 14–16 weeks’ gestation during the SCOPE study were used to diagnose the metabolic syndrome using IDF criteria. Telomere length, a biomarker of ageing, was assessed by quantitative PCR from children’s saliva collected at 10 years of age. In women who completed follow-up (n = 255), 20% had the metabolic syndrome in pregnancy. After adjusting for a range of confounders, children of mothers who had the metabolic syndrome in pregnancy had 14% shorter telomeres than children of mothers without the metabolic syndrome in pregnancy (mean difference −0.36 [95% CI −0.74, 0.01]). Height- and weight-for-age, and BMI z scores were similar in children of mothers who did and did not have the metabolic syndrome during pregnancy. Children of mothers who had the metabolic syndrome in pregnancy have shorter telomeres, a biomarker of accelerated ageing. These findings warrant further studies in larger cohorts of children, as well as investigations into whether telomere length measured in cord blood associates with telomere length in childhood.

Preeclampsia is a common pregnancy complication, affecting 2% to 8% of pregnancies worldwide, and is an important cause of both maternal and fetal morbidity and mortality. Importantly, although aspirin and calcium are able to prevent preeclampsia in some women, there is no cure apart from delivery of the placenta and fetus, often necessitating iatrogenic preterm birth. Preclinical models of preeclampsia are widely used to investigate the causes and consequences of preeclampsia and to evaluate safety and efficacy of potential preventative and therapeutic interventions. In this review, we provide a summary of the published preclinical models of preeclampsia that meet human diagnostic criteria, including the development of maternal hypertension, together with new-onset proteinuria, maternal organ dysfunction, and uteroplacental dysfunction. We then discuss evidence from preclinical models for multiple causal factors of preeclampsia, including those implicated in early-onset and late-onset preeclampsia. Next, we discuss the impact of exposure to a preeclampsia-like environment for later maternal and progeny health. The presence of long-term impairment, particularly cardiovascular outcomes, in mothers and progeny after an experimentally induced preeclampsia-like pregnancy, implies that later onset or reduced severity of preeclampsia will improve later maternal and progeny health. Finally, we summarize published intervention studies in preclinical models and identify gaps in knowledge that we consider should be targets for future research.

Objective To identify the psychosocial factors influencing women’s uptake and willingness to receive pertussis and influenza vaccine during pregnancy. Methods The study population comprised 1364 healthy nulliparous pregnant women who participated in a prospective cohort study at two obstetric hospitals in South Australia between 2015 and 2017. Information on women's vaccination status, sociodemographic, lifestyle and psychological state were collected at 9–16 weeks’ gestation and medical case notes were checked post-delivery to verify the reported vaccination status. Poisson regression models were used to estimate the crude and adjusted prevalence ratios (aPRs) to identify psychosocial factors influencing uptake of vaccination during pregnancy. Results Willingness to receive the recommended maternal vaccines was high (90%). Overall, 79% and 48% received maternal pertussis and influenza vaccines respectively. There was no evidence to support the influence of psychosocial factors on women’s willingness to receive immunization during pregnancy. High levels of anxiety (aPR 0.98, 95% CI: 0.87–1.09) was not associated with uptake of maternal pertussis vaccine. However, elevated depressive symptoms (aPR 1.14, 95% CI: 1.00–1.30) and very high-perceived stress during pregnancy were significantly associated with receipt of pertussis vaccination (aPR 0.87; 95% CI 0.76–0.99). Women with mild depressive symptoms (aPR 1.21, 95% CI 1.00–1.44) and mild anxiety symptoms (aPR 1.21, 95% CI: 0.99–1.48) were more likely to receive influenza vaccine during pregnancy (aPR 1.27, 95% CI: 1.08–1.49). A history of major depressive disorder was independently associated with receipt of pertussis (aPR 1.16, 95% CI 1.06–1.26) and influenza vaccination during pregnancy (aPR 1.32; 95% CI 1.14–1.58). Conclusion Regardless of psychosocial factors, most women reported a positive willingness to receive the recommended vaccinations during pregnancy. However, psychosocial factors influenced the uptake of pertussis and influenza vaccines during pregnancy. Psychosocial factors should be taken into consideration in designing interventions and implementation of maternal pertussis and influenza immunization programs.

Preeclampsia (PE) is now recognised as a cardiovascular risk factor for women. Emerging evidence suggests that children exposed to PE in utero may also be at increased risk of cardiovascular disease (CVD) in later life. Individuals exposed to PE in utero have higher systolic and diastolic blood pressure and higher body mass index (BMI) compared to those not exposed to PE in utero. The aim of this review is to discuss the potential mechanisms driving the relationship between PE and offspring CVD. Exposure to an adverse intrauterine environment as a consequence of the pathophysiological changes that occur during a pregnancy complicated by PE is proposed as one mechanism that programs the fetus for future CVD risk. Consistent with this hypothesis, animal models of PE where progeny have been studied demonstrate causality for programming of offspring cardiovascular health by the preeclamptic environment. Shared alleles between mother and offspring, and shared lifestyle factors between mother and offspring provide alternate pathways explaining associations between PE and offspring CVD risk. In addition, adverse lifestyle habits can also act as second hits for those programmed for increased CVD risk. PE and CVD are both multifactorial diseases and, hence, identifying the relative contribution of PE to offspring risk for CVD is a very complex task. However, considering the emerging strong association between PE and CVD, those exposed to PE in utero may benefit from targeted primary CVD preventive strategies.

Gestational diabetes mellitus (GDM) is a pregnancy complication that affects one in seven pregnancies. Emerging evidence demonstrates that children born of pregnancies complicated by GDM may be at increased risk of cardiovascular disease (CVD) in adulthood. Therefore, the aim of this study was to determine cardiovascular risk factors in offspring exposed to GDM in utero. PubMed, CINAHL, SCOPUS, and EMBASE databases were searched. Information was extracted on established CVD risk factors including blood pressure, lipids, blood glucose, fasting insulin, body mass index (BMI), and endothelial/microvascular function. The review protocol is registered in PROSPERO (CRD42018094983). Prospective and retrospective studies comparing offspring exposed to GDM compared to controls (non-GDM pregnancies) were considered. We included studies that defined GDM based on the International Association of Diabetes and Pregnancy Study Groups (IADPSG) definition, or prior definitions. The PRISMA guidelines were followed in conducting this systematic review. Methodological quality was assessed using the Newcastle–Ottawa Quality Assessment Scale. Study selection, data extraction, and quality assessment were done by two independent reviewers. The data were pooled using a random-effects model. Of 59 eligible studies, 24 were included in the meta-analysis. Offspring exposed to GDM had higher systolic blood pressure (mean difference (MD): 1.75 mmHg, 95% CI 0.57–2.94; eight studies, 7264 participants), BMI z-score (MD 0.11, 95% CI 0.02–0.20; nine studies, 8759 participants), and glucose (standard MD 0.43, 95% CI 0.08–0.77; 11 studies, 6423 participants) than control participants. In conclusion, offspring exposed to GDM have elevated systolic blood pressure, BMI, and glucose. Those exposed to GDM in utero may benefit from early childhood blood pressure measurements.

Vitamin D and calcium are essential micronutrients for reproductive success. Vitamin D deficiency during pregnancy is associated with increased risk of pregnancy complications including pre-eclampsia and preterm birth (PTB). However, inconsistencies in the literature reflect uncertainties regarding the true biological importance of vitamin D but may be explained by maternal calcium intakes. We aimed to determine whether low dietary consumption of calcium along with vitamin D deficiency had an additive effect on adverse pregnancy outcome by investigating placental morphogenesis and foetal growth in a mouse model.Female mice were randomly assigned to one of four diets: control-fed (+Ca+VD), reduced vitamin D only (+Ca−VD), reduced calcium only (−Ca+VD) and reduced calcium and vitamin D (−Ca−VD), and sacrificed at gestational day (GD) 18.5. Maternal serum 25-hydroxy vitamin D (25(OH)D3) levels were lower in each reduced diet group when compared with levels in +Ca+VD fed mice. While the pregnancy rate did not differ between groups, in the −Ca−VD-fed group, 55% (5 out of 9 pregnant of known gestational age) gave birth preterm (

This study questioned whether raised pre-pregnancy two-hour (2 h) insulin levels, measured in recurrent embryonic miscarriage (RM) patients via a 75 g Oral Glucose Tolerance Test (OGTT), are associated with an increased risk of gestational diabetes mellitus (GDM) in a subsequent pregnancy. Patients had a 75 g OGTT and insulin levels evaluated (

Background: There is evidence that breastfeeding may provide protection against cardiovascular risk factors in mothers with a history of gestational diabetes mellitus and their children who were exposed in utero. Research Aim: To perform a systematic review and meta-analysis of observational studies to ascertain the effects of breastfeeding on cardiovascular risk factors in women with previous gestational diabetes mellitus and their children exposed in utero. Methods: Studies assessing conventional cardiovascular risk factors in women with previous gestational diabetes mellitus and children exposed in utero stratified by breastfeeding/no breastfeeding or breastfed/not breastfed were included. Gestational diabetes mellitus was defined based on the International Association of Diabetes in Pregnancy Study Group definition or previous accepted definitions. Breastfeeding was defined as reported in each study. Results: The literature search yielded 260 titles, of which 17 studies were selected to be in the review. Women with previous gestational diabetes mellitus who did not breastfeed had higher blood glucose ( SMD: 0.32, 95% CI [0.12, 0.53]) and a greater risk of developing Type 2 diabetes mellitus ( RR: 2.08 95% CI [1.44, 3.00]) compared to women with no history. There were not enough studies to conduct a meta-analysis on the effects of breastfeeding on risk factors for cardiovascular disease among children exposed to gestational diabetes mellitus in utero. Conclusion: Breastfeeding appears to be protective against cardiovascular risk factors among women who experience gestational diabetes mellitus.

Poor infection control practices during childbirth are recognised as a critical factor leading to life-threatening maternal and newborn sepsis. Therefore, this paper assesses the effectiveness of clean birth kits (CBKs) to ensure a safe birthing environment. We searched PubMed, Cochrane Library and CINAHL, as well as Google Scholar, to identify both qualitative and quantitative studies on CBKs published in English up to November 2018. Studies were included if the pregnant women or women giving birth intended to use or used a CBK. The methodological quality of included papers was assessed. A total of 37 studies, 26 quantitative and 11 qualitative studies, were included. Quantitative studies showed a positive impact of CBKs on reducing the incidence of puerperal sepsis and neonatal tetanus. The review also identified CBK use to be associated with a reduction in perinatal, neonatal and young infant mortality. Qualitative studies suggested that a lack of awareness of the importance of CBKs and clean delivery practices, unavailability of CBKs and financial constraints to purchase CBKs were the potential barriers. CBKs appear to be a promising strategy to reduce maternal and neonatal morbidity and mortality. However, the current evidence is limited and further large-scale trials are required.

Objectives: The objective of this study was to compare three automated blood pressure devices (Microlife VSA, Uscom BP + and Tensiomed Arteriograph) with an aneroid device in an Australian antenatal population to determine an accurate and reliable alternative method of measuring blood pressure in pregnant women.Study design: This observational, prospective study recruited a random sample of 200 pregnant women of any gestation attending an antenatal clinic in an Australian hospital. Each participant had two peripheral blood pressure measurements per instrument performed, resulting in eight measurements per participant.Main outcome measurements: Infra- and inter-device reliability of peripheral blood pressure measurements made by the aneroid device and the three automated brachial-cuff oscillometric devices were assessed. The agreement between devices was graded according to standardised criteria.Results: Both intra- and inter-device reliability of blood pressure measurements of the four devices in this study were found to be 'excellent' (ICCs > 0.75). Microlife VSA and Uscom BP + showed acceptable levels of agreement (+/- 5mmHg) when compared to the aneroid device. Arteriograph did not show an acceptable level of agreement with the aneroid device for systolic blood pressure, but did for diastolic blood pressure.Conclusion: Accurate automated devices may ensure consistent assessment of blood pressure in the antenatal setting. Our results suggest that Microlife VSA and Uscom BP + may be suitable alternatives to the aneroid device for use in the antenatal setting. Further studies assessing both auscultatory and oscillometric blood pressure devices in pregnancy, and especially in hypertensive cohorts, are required.

Objective: The aim of this study was to investigate the potential utility of serum HtrA1 and HtrA3, serine proteases that are highly expressed in the developing placenta, at 15 and 20 weeks of gestation for predicting later development of adverse pregnancy outcomes of preeclampsia (PE), gestational hypertension (GHT), preterm birth (PTB), and small for gestational age (SGA) birth. Methods: This is a nested case control study of 665 samples (330 controls, 335 cases) from the Adelaide SCOPE cohort. The cases included were 92 PE, 71 GHT, 56 PTB, and 116 SGA. Samples were assessed by ELISA and data adjusted for maternal age, BMI, socioeconomic index, hCG, and smoking status. Multivariate logistic regression was performed with other biochemical and biophysical parameters available for these samples. Results: HtrA1 did not differ between the controls and cases. In contrast, HtrA3 was significantly lower at 15 weeks in pregnancies that later developed late-onset PE (LPE) or resulted in SGA birth, with an area under the ROC curve (AUC) of 0.716 and 0.790, respectively. The combination of HtrA3 with PAPP-A, uterine, and umbilical Doppler improved the AUC to 0.755 for LPE and 0.844 for SGA. Conclusion: HtrA3 at 15 weeks is associated with, and may be useful for, the early detection of LPE development and SGA birth.

Background Asymmetric fetal growth and male sex are both associated with adverse neonatal outcome. However, less is known about the influence of asymmetric growth and fetal sex within SGA neonates, a group of infants already at increased risk for adverse neonatal outcomes. The aim of the present study was to provide insight into variance in risk factors for SGA in a fetal sex- and growth symmetry-specific way. Methods For this prospective, multicenter cohort study, data from the Screening for Pregnancy Endpoints (SCOPE) study were used with 5628 nulliparous participants, of which 633 (11.3%) pregnancies were complicated with SGA and 3376 (60.0%) women had uncomplicated pregnancies. Association between risk factors for SGA, SGA subgroups, and uncomplicated pregnancies were assessed with multivariable analyses. Results Prevalence of asymmetric growth varied from 45.8% of SGA infants to 5.5% of infants with a customized birthweight > 90th percentile (p < 0.001). Significantly more SGA males had asymmetric growth compared to SGA female infants (51.2% vs 40.4%, p = 0.009). Maternal pre-pregnancy diet and BMI < 20 and ≥ 30 were significantly associated with symmetric SGA but not with asymmetric SGA. Asymmetric SGA infants had not only lower customized birthweight percentile (4.4 (SD 2.8) vs 5.0 (SD 3.0), p < 0.001), but also lower rates of stillbirth (p = 0.041) and less often Apgar scores < 7 (p = 0.060). Conclusions Among SGA infants, low customized birthweight percentiles and male sex are associated with asymmetric growth. Only symmetric SGA is significantly associated with maternal risk factors in early pregnancy. There is a substantial variance in risk factors and neonatal outcomes for SGA based on growth symmetry, implying a different pathogenesis. Trial registration ACTRN12607000551493

This commentary is an author response to Lu and Wang, regarding the manuscript entitled ‘Cardiovascular risk factors in offspring exposed to gestational diabetes mellitus in utero: Systematic review and meta-analysis’. We address their concern regarding duplication of studies in the meta-analysis and the quality of included studies.

Background There is currently no concise systematic review or meta-analysis addressing cardio-metabolic risk factors in women experiencing infertility. Objectives To determine whether infertile women have higher levels of cardiovascular risk factors compared with fertile women. Search strategy We performed a systematic literature search using PubMed, Embase and CINAHL, Scopus and additional manual and bibliographic searches for relevant articles (end search date 6 November 2019). Selection criteria We selected studies that compared cardio-metabolic risk factors in fertile and infertile women of reproductive age. Data collection and analysis At least two authors independently screened potentially eligible studies. Main results There was an increased presence of several cardio-metabolic risk factors in infertile women compared with fertile women. Infertile women had statistically significant higher body mass index (BMI), increased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) compared with fertile women. Fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR) and mean arterial pressure were not found to be different between fertile and infertile women. A subgroup analysis revealed that TC, fasting glucose and fasting insulin were increased, and high-density lipoprotein was decreased only in women with polycystic ovarian syndrome compared with fertile women, whereas BMI, TG and LDL-C were statistically significantly increased in women with any indication of infertility compared with fertile women. Conclusions Infertile women have a higher level of cardio-metabolic risk factors compared with fertile women. This finding has clinical implications for infertile women in general, and those attempting to conceive through medically assisted reproduction. Tweetable abstract Infertile women appear to have a higher level of cardio-metabolic risk factors compared with fertile women.

Background: Women who experience pregnancy complications have an increased risk of future cardiovascular disease when compared to their healthy counterparts. Despite recommendations, there is no standardized cardiovascular follow-up in the postpartum period for these women, and the Australian follow-up protocols that have been previously described are research-based. This study proposes a new model of care for a nurse practitioner-led postpartum intervention clinic for women who experience severe hypertensive disorders of pregnancy, gestational diabetes mellitus requiring medication, severe intrauterine growth restriction, idiopathic preterm delivery, or placental abruption, in a socioeconomically disadvantaged population. Methods: All women receiving antenatal care or who deliver at the Lyell McEwin Hospital, a tertiary acute care facility located in the northern Adelaide metropolitan area, following a severe complication of pregnancy are referred to the intervention clinic for review at 6 months postpartum. A comprehensive assessment is conducted from demographics, medical history, diet and exercise habits, psychosocial information, health literacy, pathology results, and physical measurements. Subsequently, patient-specific education and clinical counseling are provided by a specialized nurse practitioner. Clinic appointments are repeated at 18 months and 5 years postpartum. All data is also collated into a registry, which aims to assess the efficacy of the intervention at improving modifiable cardiovascular risk factors and reducing cardiovascular risk. Discussion: There is limited information on the efficacy of postpartum intervention clinics in reducing cardiovascular risk in women who have experienced pregnancy complications. Analyses of the data collected in the registry will provide essential information about how best to reduce cardiovascular risk in women in socioeconomically disadvantaged and disease-burdened populations.

Objective: To determine the association between parental MTHFR 677C > T (RS1801133) and 1298A > C (RS1801131), and fetal loss (FL).Design: Case–control study.Setting: Department of Obstetrics and G...

AIMS The aims of the present study were to examine the association between late pregnancy exposure to serotonin reuptake inhibitor (SRI) antidepressants and difficulties in achieving an adequate breast milk supply in women who have given birth to preterm infants, while accounting for the potential impacts of underlying maternal psychiatric illness. METHODS A retrospective cohort study was carried out of 3024 women delivering liveborn preterm infants (

The intrarenal renin-angiotensin system (iRAS) is implicated in the pathogenesis of hypertension, chronic kidney disease and diabetic nephropathy. Urinary angiotensinogen (uAGT) levels reflect the activity of the iRAS and are altered in women with preeclampsia. Since Indigenous Australians suffer high rates and early onset of renal disease, we hypothesised that Indigenous Australian pregnant women, like non-Indigenous women with pregnancy complications, would have altered uAGT levels. The excretion of RAS proteins was measured in non-Indigenous and Indigenous Australian women with uncomplicated or complicated pregnancies (preeclampsia, diabetes/gestational diabetes, proteinuria/albuminuria, hypertension, small/large for gestational age, preterm birth), and in non-pregnant non-Indigenous women.Non-Indigenous pregnant women with uncomplicated pregnancies, had higher uAGT/creatinine levels than non-Indigenous non-pregnant women (P < 0.01), and levels increased as pregnancy progressed (P < 0.001). In non-Indigenous pregnant women with pregnancy complications, uAGT/creatinine was suppressed in the third trimester (P < 0.01). In Indigenous pregnant women with uncomplicated pregnancies, there was no change in uAGT/creatinine with gestational age and uAGT/creatinine was lower in the 2nd and 3rd trimesters than in nonIndigenous pregnant women with uncomplicated pregnancies (P < 0.03, P < 0.007, respectively). The uAGT/creatinine ratios of Indigenous women with uncomplicated or complicated pregnancies were the same.A decrease in uAGT/creatinine with advancing gestational age was associated with increased urinary albumin/creatinine, as is seen in preeclampsia, but it was not specific for this disorder. The reduced uAGT/creatinine in Indigenous pregnant women may reflect subclinical renal dysfunction which limits the ability of the kidney to maintain sodium balance and could indicate an increased risk of pregnancy complications and/or future renal disease.

To describe long-term trends in the prevalence of preterm birth and rates of preterm birth in singleton pregnancies complicated by hypertensive disorders of pregnancy, small for gestational age (SGA), and preterm prelabor rupture of membranes (PROM) in South Australia.We conducted a retrospective population study including all singleton live births in the state of South Australia from 1986 to 2014. Long-term trends for preterm birth, hypertensive disorders of pregnancy, SGA, preterm PROM as well as stillbirth were assessed using joinpoint regression analyses. Trends in maternal age, body mass index (BMI), ethnic diversity, parity, and smoking over time were also assessed.From 1986 to 2014, with a total of 539,234 singleton births, the overall preterm birth rates increased from 5.1% to 7.1% (P.001) and for iatrogenic preterm birth increased from 1.6% to 3.2% (P.001). The incidence of hypertensive disorders of pregnancy decreased from 8.7% to 7.2%. Among pregnancies complicated by hypertensive disorders of pregnancy, the proportion of preterm birth increased (10.4-17.5%, P.001). The incidence of SGA decreased from 11.1% to 8.0%. Among pregnancies complicated by SGA, the proportion of preterm birth increased (2.9-5.4%, P.001). The incidence of preterm PROM increased from 1.4% to 2.2%. Among pregnancies complicated by preterm PROM, the proportion of preterm birth remained stable. Preterm stillbirth rates declined (4.23-2.32%, P.001). Maternal age, BMI, and ethnic diversity have all increased since 1986, whereas maternal smoking has decreased.In South Australia, the preterm birth rate among singletons increased from 1986 to 2014 by 40%, with iatrogenic preterm birth being responsible for 80% of this increase. Incidence of hypertensive disorders of pregnancy and SGA declined. Among pregnancies complicated by hypertensive disorders of pregnancy and SGA, the proportions of preterm birth increased, indicating earlier interventions in these women. The diagnosis of preterm PROM increased from 1% to 2%, and greater than 80% of preterm PROM was associated with preterm birth after 1990. Increasing iatrogenic delivery may be attributable, in part, to changing maternal phenotype and to altered clinicians' behavior. However, improvements in fetal surveillance, particularly ultrasonography, and advanced neonatal care may underpin perinatal clinical decision-making and the likelihood of iatrogenic birth.

The COVID-19 pandemic has infected nearly 178 million people and claimed the lives of over 3.8 million in less than 15 months. This has prompted a flurry of research studies into the mechanisms and effects of SARS-CoV-2 viral infection in humans. However, studies examining the effects of COVID-19 in pregnant women, their placentae and their babies remain limited. Furthermore, reports of safety and efficacy of vaccines for SARS-CoV-2 in pregnancy are limited. This review concisely summarises the case studies and research on COVID-19 in pregnancy, to date. It also reviews the mechanism of infection with SARS-CoV-2, and its reliance and effects upon the renin-angiotensin-aldosterone system. Overall, the data suggest that infection during pregnancy can be dangerous at any time, but this risk to both the mother and fetus, as well as placental damage, increases during the third trimester. The possibility of vertical transmission, which is explored in this review, remains contentious. However, maternal infection with SARS-CoV-2 can increase risk of miscarriage, preterm birth and stillbirth, which is likely due to damage to the placenta.

Placenta-derived hormones including growth hormone (GH) in humans contribute to maternal adaptation to pregnancy, and intermittent maternal GH administration increases foetal growth in several species. Both patterns and abundance of circulating GH are important for its activity, but their changes during pregnancy have only been reported in humans and rats. The aim of the present study was to characterise circulating profiles and secretory characteristics of GH in non-pregnant female mice and throughout murine pregnancy. Circulating GH concentrations were measured in whole blood (2 μL) collected every 10 min for 6 h in non-pregnant diestrus female C57Bl/6J mice (n = 9), and pregnant females at day 8.5–9.5 (early pregnancy, n = 8), day 12.5–13.5 (mid-pregnancy, n = 7) and day 17.5 after mating (late pregnancy, n = 7). Kinetics and secretory patterns of GH secretion were determined by deconvolution analysis, while orderliness and regularity of serial GH concentrations were calculated by approximate entropy analysis. Circulating GH was pulsatile in all groups. Mean circulating GH and total and basal GH secretion rates increased markedly from early to mid-pregnancy, and then remained elevated. Pulse frequency and pulsatile GH secretion rate were similar between groups. The irregularity of GH pulses was higher in all pregnant groups than that in non-pregnant mice. Increased circulating GH in murine pregnancy is consistent with an important role for this hormone in maternal adaptation to pregnancy and placental development. The timing of increased basal secretion from mid-pregnancy, concurrent with the formation of the chorioallantoic placenta and initiation of maternal blood flow through it, suggests regulation of pituitary secretion by placenta-derived factors.

Objective To compare early pregnancy clinical and biomarker risk factors for later development of preeclampsia between women with obesity (body mass index, BMI ≥30 kg/m2 ) and those with a normal BMI (20-25 kg/m2 ). Methods In 3,940 eligible nulliparous women from the Screening for Pregnancy Endpoints (SCOPE) study, a total of 53 biomarkers of glucose and lipid metabolism, placental function, and known markers of preeclampsia were measured at 14 to 16 weeks' gestation. Logistic regression was performed to identify clinical and biomarker risk factors for preeclampsia in women with and without obesity. Results Among 834 women with obesity and 3,106 with a normal BMI, 77 (9.2%) and 105 (3.4%) developed preeclampsia, respectively. In women with obesity, risk factors included a family history of thrombotic disease, low plasma placental growth factor, and higher uterine artery resistance index at 20 weeks. In women with a normal BMI, a family history of preeclampsia or gestational hypertension, mean arterial blood pressure, plasma endoglin and cystatin C, and uterine artery resistance index were associated with preeclampsia, while high fruit intake was protective. Conclusions Women with obesity and a normal BMI have different early pregnancy clinical and biomarker risk factors for preeclampsia.

Workshops are an integral component of the annual International Federation of Placenta Association (IFPA) meeting, allowing for networking and focused discussion related to specialized topics on the placenta. At the 2015 IFPA meeting (Brisbane, Australia) twelve themed workshops were held, three of which are summarized in this report. These workshops focused on various aspects of placental function, particularly in cases of placenta-mediated disease. Collectively, these inter-connected workshops highlighted the role of the placenta in fetal programming, the use of various biomarkers to monitor placental function across pregnancy, and the clinical impact of novel diagnostic and surveillance modalities in instances of late onset fetal growth restriction (FGR).

Single nucleotide polymorphisms and pre‐ and peri‐conception folic acid (FA) supplementation and dietary data were used to identify one‐carbon metabolic factors associated with pregnancy outcomes in 3196 nulliparous women. In 325 participants, we also measured circulating folate, vitamin B12 and homocysteine. Pregnancy outcomes included preeclampsia (PE), gestational hypertension (GHT), small for gestational age (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). Study findings show that maternal genotype MTHFR A1298C(CC) was associated with increased risk for PE, whereas TCN2 C766G(GG) had a reduced risk for sPTB. Paternal MTHFR A1298C(CC) and MTHFD1 G1958A(AA) genotypes were associated with reduced risk for sPTB, whereas MTHFR C677T(CT) genotype had an increased risk for GHT. FA supplementation was associated with higher serum folate and vitamin B12 concentrations, reduced uterine artery resistance index and increased birth weight. Women who supplemented with

Background Chronic obstructive pulmonary disease (COPD) is the second-leading cause of death in the United Kingdom and accounts for 1.7% of bed days in acute hospitals. An estimated two-third of patients with COPD remain undiagnosed. Objective Modern Innovative Solutions in Improving Outcomes in Chronic Obstructive Pulmonary Disease (MISSION COPD) aimed to proactively identify patients from primary care who were undiagnosed or had uncontrolled COPD and to provide a comprehensive integrated multidisciplinary clinic to address the needs of this complex group for improving diagnosis, personalizing therapy, and empowering patients to self-manage their condition. Methods This clinic was led by a respiratory specialist team from Portsmouth Hospitals NHS Trust working with five primary care surgeries in Wessex. A total of 108 patients were reviewed, with 98 patients consenting to provide additional data for research. Diagnoses were changed in 14 patients, and 32 new diagnoses were made. Results Reductions were seen across all aspects of unscheduled care as compared to the prior 12 months, including in emergency general practitioner visits (3.37-0.79 visits per patient, P Conclusions This pilot demonstrates that the MISSION model may be an effective way to provide comprehensive gold-standard care that is valued by patients and to promote integration across sectors.

OBJECTIVES To evaluate whether cannabis use during pregnancy is associated with adverse neonatal outcomes that are independent of cigarette smoking. DESIGN Prospective cohort study. SETTING Adelaide (Australia), Auckland (New Zealand), Cork (Ireland), and Leeds, London and Manchester (United Kingdom). PARTICIPANTS 5610 pregnant nulliparous women with low risk pregnancies recruited for the Screening for Pregnancy Endpoints (SCOPE) study, November 2004 - February 2011. At 14-16 weeks of pregnancy, women were grouped by self-reported cannabis use. MAIN OUTCOME MEASURES Infant birthweight, head circumference, birth length, gestational age, and severe neonatal morbidity or mortality. RESULTS 314 women (5.6%) reported using cannabis in the 3 months before or during their pregnancy; 97 (31%) stopped using it before and 157 (50%) during the first 15 weeks of pregnancy, while 60 (19%) were still using cannabis at 15 weeks. Compared with babies of mother who had never used cannabis, infants of those who still used it at 15 weeks had lower mean values for birthweight (adjusted mean difference [aMD], -127 g; 95% CI, -238 to -17 g), head circumference (aMD, -0.5 cm; 95% CI, -0.8 to -0.1 cm), birth length (aMD, -0.8 cm; 95% CI, -1.4 to -0.2 cm), and gestational age at birth (aMD, -8.1 days; 95% CI, -12.1 to -4.0 days). The differences for all outcomes except gestational age were greater for women who used cannabis more than once a week than for those who used it less frequently. CONCLUSIONS Continuing to use cannabis during pregnancy is an independent risk factor for poorer neonatal outcomes.

Trace elements such as zinc, copper, and selenium are essential for reproductive health, but there is limited work examining how circulating trace elements may associate with fertility in humans. The aim of this study was to determine the association between maternal plasma concentrations of zinc, copper, and selenium, and time to pregnancy and subfertility. Australian women (n = 1060) who participated in the multi-centre prospective Screening for Pregnancy Endpoints study were included. Maternal plasma concentrations of copper, zinc and selenium were assessed at 15 &plusmn, 1 weeks&rsquo, gestation. Estimates of retrospectively reported time to pregnancy were documented as number of months to conceive, subfertility was defined as taking more than 12 months to conceive. A range of maternal and paternal adjustments were included. Women who had lower zinc (time ratio, 1.20 (0.99&ndash, 1.44)) or who had lower selenium concentrations (1.19 (1.01&ndash, 1.40)) had a longer time to pregnancy, equivalent to a median difference in time to pregnancy of around 0.6 months. Women with low selenium concentrations were also at a 1.46 (1.06&ndash, 2.03) greater relative risk for subfertility compared to women with higher selenium concentrations. There were no associations between copper and time to pregnancy or subfertility. Lower selenium and zinc trace element concentrations, which likely reflect lower dietary intakes, associate with a longer time to pregnancy. Further research supporting our work is required, which may inform recommendations to increase maternal trace element intake in women planning a pregnancy.

Background Severe asthma exacerbations are costly to patients and the NHS, and occur frequently in severely allergic patients. Objective To ascertain whether or not nocturnal temperature-controlled laminar airflow (TLA) device usage over 12 months can reduce severe exacerbations and improve asthma control and quality of life compared with a placebo device, while being cost-effective and acceptable to adults with severe allergic asthma. Design A pragmatic, multicentre, randomised, double-blind, placebo-controlled, parallel-group, superiority trial with qualitative interviews. The trial included an internal pilot with qualitative focus groups. Setting Fourteen hospitals in the UK that manage patients with severe asthma. Participants Adults (16–75 years) with severe, poorly controlled, exacerbation-prone asthma despite high-intensity treatment, and who are sensitised to a perennial indoor aeroallergen. Intervention Nocturnal, home-based TLA treatment using an Airsonett® (Airsonett AB, Ängelholm, Sweden) device. The comparator was a placebo device that was identical to the active device except that it did not deliver the laminar airflow. Participants were allocated 1 : 1 to TLA therapy or placebo, minimised by site, origin of case, baseline severe exacerbation frequency, maintenance oral corticosteroid use and pre-bronchodilator forced expiratory volume in 1 second. Main outcome measures Primary outcome – frequency of severe asthma exacerbations occurring within the 12-month follow-up period, defined as worsening of asthma requiring systemic corticosteroids [≥ 30 mg of prednisolone or equivalent daily (or ≥ 50% increase in dose if on maintenance dose of ≥ 30 mg of prednisolone)] for ≥ 3 days. Secondary outcomes – changes in asthma control, lung function, asthma-specific and global quality of life for participants, adherence to the intervention, device acceptability, health-care resource use and cost-effectiveness. Results Between May 2014 and January 2016, 489 patients consented to participate in the trial, of whom 249 failed screening and 240 were randomised (n = 119 in the treatment group and n = 121 in the placebo group); all were analysed. In total, 202 participants (84%) reported use of the device for 9–12 months. Qualitative analyses showed high levels of acceptability. The mean [standard deviation (SD)] rate of severe exacerbations did not differ between groups [active 1.39 (1.57), placebo 1.48 (2.03); risk ratio 0.92, 95% CI 0.66 to 1.27; p = 0.616]. There were no significant differences in secondary outcomes for lung function, except for a reduction in mean daily peak expiratory flow [mean (SD) difference 14.7 l/minute (7.35 l/minute), 95% CI 0.32 to 29.1 l/minute; p = 0.045) for those in the active device group. There were no differences in asthma control or airway inflammation and no serious harms related to the device. No significant difference between the groups in quality-adjusted life-years gained over 1 year was observed. In addition, there was no difference in generic or disease-specific health-related quality of life overall, although statistically significant higher quality of life at month 6 was observed. Increases in quality of life were not sufficient to offset the annual costs associated with use of the TLA device. Limitations Missing outcome data could have resulted in an underestimation of exacerbations and rendered the study inconclusive. Conclusions Within the limits of the data, no consistent benefits of the active device were demonstrated, and the differences observed were not sufficient to make the device cost-effective. The types of patients who may benefit from the TLA device, and the reasons for large reductions in exacerbation frequency in severe asthma trials, which also incorporate other methods of recording exacerbations, need to be explored. Trial registration Current Controlled Trials ISRCTN46346208. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 29. See the NIHR Journals Library website for further project information.

Objectives Evaluating maternal haemodynamics across pregnancy in uncomplicated pregnancies and those complicated by hypertensive disorders of pregnancy (HDP). Study design Prospective cohort study from 2015 to 2018 of healthy, nulliparous, singleton-bearing women. Maternal haemodynamics assessed by Uscom BP+ at 9–16 and 32–36 weeks’ gestation in pregnancies complicated by HDP [preeclampsia with severe (sPE n = 12) and without severe clinical features (nsPE n = 49), gestational hypertension (GH n = 25), transient gestational hypertension (TGH n = 33)] were compared to uncomplicated pregnancies (n = 286) using mixed-effects linear modelling. Main outcome measures Maternal haemodynamic adaptation in uncomplicated pregnancies and those complicated by HDP. Results Between the two measurements, haemodynamic adaptation in women with sPE and nsPE was significantly different compared to those with uncomplicated pregnancies. An additional increase was observed for peripheral systolic blood pressure [SBP; 14.3 mmHg, 8.6–20.1 (sPE)], peripheral diastolic blood pressure [DBP; 7.7 mmHg, 3.3–12.1 (sPE); 2.6 mmHg, 3.3–12.1 (nsPE)] peripheral mean arterial pressure [MAP; 10.6 mmHg, 5.8–15.5 (sPE); 3.4 mmHg, 0.8–6.0 (nsPE)], peripheral pulse pressure [PP; 6.6 mmHg, 2.1–11.1 (sPE)], central SBP [15.8 mmHg, 10.4–21.2 (sPE); 2.9 mmHg, 0.1–5.8 (nsPE)], central DBP [8.3 mmHg, 3.9–12.6 (sPE); 2.5 mmHg, 0.2–4.8 (nsPE), central MAP [10.8 mmHg, 6.4–15.2 (sPE); 2.6 mmHg, 0.3–5.0 (nsPE)] and central PP [7.6 mmHg, 3.9–11.3 (sPE)]. Augmentation index (AIx) decreased less (15.5%, 6.3–24.6 (sPE); 9.0%, 4.2–13.6 (nsPE)] compared to uncomplicated pregnancies. Haemodynamic adaptation across pregnancy in women with GH and TGH was not different from those with uncomplicated pregnancies. Conclusion Women who develop preeclampsia show an altered, while those who develop GH or TGH demonstrate a comparable haemodynamic adaptation compared to uncomplicated pregnancies. TGH is not a benign condition.

This prospective cohort study measured anti-Müllerian hormone (AMH) levels in recurrent miscarriage (RM) patients, compared them to a normal population, and assessed the pregnancy outcomes. The RM patients demonstrated AMH levels that were significantly lower than the normal population, both in women aged ≤35 years, and those aged35 years. AMH percentiles were found to be significantly lower in the study group of RM patients ≤35 years (p .004) in the 5th and 50th percentiles, and in all percentiles in women35 years (p .03), were compared to women from a normal population. Serum AMH levels may reflect quality, and quantity of the remaining oocytes in these patients, and RM patients may have a low ovarian reserve, and a potentially poor oocyte quality, as shown by low circulating AMH. The evaluation of AMH levels in a RM work up may allow realistic counselling and possible ART referral in RM patients. Impact statement What is already known on this subject? There is some evidence to show that low AMH levels are associated with recurrent miscarriages and this is thought to be due to a decreased oocyte quality. The AMH levels are lower in the patients with endometriosis, and are often significantly higher in the patients with polycystic ovarian syndrome. Both conditions are independently associated with miscarriages. What the results of this study add? Anti-Müllerian hormone (AMH) levels were found to be significantly lower in recurrent miscarriage patients, compared to a normal population. This may be another factor contributing to miscarriages. The spontaneous pregnancy rates in the miscarriage group significantly improved with increasing AMH levels. This may confirm that patients with low AMH levels have poorer quality oocytes, and thus may be considered 'sub-fertile'. It was also found that the utilisation of assisted reproductive technologies (ART) to achieve a pregnancy was significantly reduced in the groups with a higher serum AMH. What the implications are of these findings for clinical practice and/or further research? Serum AMH levels should be offered to all patients as part of a recurrent miscarriage work up. Detecting the low AMH levels and counselling the patients on these findings may allow them the option of accessing ART. ART may have the ability to expedite conception rates, and with pre-implantation genetic analyses, could possibly select the embryos with the greatest chance of survival. Further research is needed to establish how the decreased AMH levels contribute to recurrent miscarriages.

Objectives: To investigate the risk of pregnancy complications in women with and without polycystic ovary syndrome after consideration of lifestyle factors.Design: Prospective cohort Patients and measurements: Participants (n=5628) were apparently healthy nulliparous women with singleton pregnancies from the Screening for Pregnancy Endpoints study in New Zealand, Australia, United Kingdom and Ireland. Multivariable regression models were performed assessing the association of self-reported polycystic ovary syndrome status with pregnancy complications with consideration of lifestyle factors at the 15th week of gestation.Results: Women with polycystic ovary syndrome (n=354) were older, had a higher socioeconomic index and body mass index and were less likely to consume alcohol and smoke but more likely to do vigorous exercise and take multivitamins. In univariable analysis polycystic ovary syndrome was associated with increased risk of gestational diabetes [OR: 2.2, 95% CI: 1.2,4.0]. In multivariable models, polycystic ovary syndrome was only significantly associated with decreased risk of large for gestational age [OR: 0.62, 95% CI: 0.40, 0.98] with a population attributable risk of 0.22%. None of the other outcomes were attributable to polycystic ovary syndrome status.Conclusions: Polycystic ovary syndrome is associated with a lower risk of large for gestational age infants. In this low risk population, the risk of pregnancy complications was not increased in women with polycystic ovary syndrome who were following a healthy lifestyle. Further studies are warranted assessing the contribution of lifestyle factors to the risk of pregnancy complications in higher risk groups of women with and without polycystic ovary syndrome.

OBJECTIVE: This study investigated the influence of birth weight on the risk of pregnancy complications, including preeclampsia (PE), gestational hypertension (GH), small for gestational age (SGA) pregnancy, spontaneous preterm birth, and gestational diabetes mellitus (GDM), and assessed the effect of early pregnancy BMI on this relationship.METHODS: A total of 5,336 nulliparous women from the SCreening fOr Pregnancy Endpoints (SCOPE) study were included. Women's birth weights were self-reported and confirmed via medical records when possible. A birth weight of 3,000 to 3,499 g was considered the reference.RESULTS: After adjusting for confounders, birth weight < 2,500 g was associated with increased risk of GH (adjusted odds ratio [aOR] = 2.2, 95% CI = 1.3-3.7), PE (aOR = 1.7, 95% CI = 1.0-2.9), small for gestational age (aOR = 1.9, 95% CI = 1.1-3.2), and GDM (aOR = 2.4, 95% CI = 1.0-5.8) compared with the referent. Women born with birth weight < 2,500 g and who subsequently developed overweight or were diagnosed with obesity were at increased risk of GH (aOR = 2.2, 95% CI = 1.1-4.5), PE (aOR = 2.3, 95% CI = 1.2-4.5), and GDM (aOR = 3.2, 95% CI = 1.1-9.5) compared with women with birth weight ≥ 2,500 g and remained lean.CONCLUSIONS: Women who were born with a low birth weight are at increased risk of pregnancy complications. Those born small may have undergone "programming" in response to unfavorable intrauterine conditions. In such women, the physiological demands of pregnancy may act as a "second hit," leading to pregnancy complications.

Objective To determine: (1) the association between metabolic syndrome (MetS), time to pregnancy (TTP), and infertility; (2) associations between individual and an increasing number of MetS components, TTP, and infertility; and (3) whether these relationships differ by body mass index (BMI Design Retrospective cohort study. Setting Multiple centres (in Australia, Ireland, New Zealand, and the UK). Population Five thousand five hundred and nineteen low-risk nulliparous pregnant women. Methods Data on retrospectively reported TTP (number of months to conceive) and a blood sample to assess metabolic health were collected between 14 and 16 weeks of gestation. MetS was defined according to the International Diabetes Federation criteria. Accelerated failure time models with log-normal distribution were conducted to estimate time ratios (TRs) and 95% CIs. Differences in MetS on infertility (TTP > 12 months) were compared using a generalised linear model (Poisson distribution) with robust variance estimates (relative risks, RRs; 95% CIs). All analyses (entire cohort and split by BMI) were controlled for a range of maternal and paternal confounding factors. Main outcome measures Time to pregnancy and infertility. Results Of the 5519 women included, 12.4% (n = 684) had MetS. Compared with women without MetS, women with MetS had a longer TTP (adjusted TR 1.30; 95% CI 1.15-1.46), which was similar in women who were obese and in women who were not obese. Marginal estimates for median TTP in women with MetS versus without MetS was 3.1 months (3.0-3.3 months) versus 4.1 months (3.6-4.5 months), respectively. Women with MetS were at a 62% greater risk for infertility and were at a greater risk for infertility whether they were obese (adjusted RR 1.62; 95% CI 1.15-2.29) or not (adjusted RR 1.73; 95% CI 1.33-2.23). Reduced high-density lipoprotein cholesterol (HDL-C) and raised triglycerides (TGs) were the main individual components associated with risk for infertility. Conclusion Metabolic syndrome is associated with longer TTP and infertility, independent of obesity. Additional studies, before pregnancy, are required to support our findings and to determine the applicability of which combinations of metabolic abnormalities pose the greatest risk to delayed fertility, or whether individual components are amenable to modification. Tweetable abstract Metabolic syndrome is associated with longer time to pregnancy and infertility, independent of obesity.

Adverse pregnancy outcomes including prematurity and low birth weight (LBW) have been associated with life-long chronic disease risk for the infant. Stress during pregnancy increases the risk of adverse pregnancy outcomes. Many studies have reported the incidence of adverse pregnancy outcomes in Indigenous populations and a smaller number of studies have measured rates of stress and depression in these populations. This study sought to examine the potential association between stress during pregnancy and the rate of adverse pregnancy outcomes in Australian Indigenous women residing in rural and remote communities in New South Wales. This study found a higher rate of post-traumatic stress disorder, depression and anxiety symptoms during pregnancy than the general population. There was also a higher incidence of prematurity and LBW deliveries. Unfortunately, missing post-traumatic stress disorder and depressive symptomatology data impeded the examination of associations of interest. This was largely due to the highly sensitive nature of the issues under investigation, and the need to ensure adequate levels of trust between Indigenous women and research staff before disclosure and recording of sensitive research data. We were unable to demonstrate a significant association between the level of stress and the incidence of adverse pregnancy outcomes at this stage. We recommend this longitudinal study continue until complete data sets are available. Future research in this area should ensure prioritization of building trust in participants and overestimating sample size to ensure no undue pressure is placed upon an already stressed participant.

Background Obesity increases the risk for developing gestational diabetes mellitus (GDM) and preeclampsia (PE), which both associate with increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in women in later life. In the general population, metabolic syndrome (MetS) associates with T2DM and CVD. The impact of maternal MetS on pregnancy outcomes, in nulliparous pregnant women, has not been investigated. Methods and findings Low-risk, nulliparous women were recruited to the multi-centre, international prospective Screening for Pregnancy Endpoints (SCOPE) cohort between 11 November 2004 and 28 February 2011. Women were assessed for a range of demographic, lifestyle, and metabolic health variables at 15 ± 1 weeks’ gestation. MetS was defined according to International Diabetes Federation (IDF) criteria for adults: waist circumference ≥80 cm, along with any 2 of the following: raised trigycerides (≥1.70 mmol/l [≥150 mg/dl]), reduced high-density lipoprotein cholesterol (, Claire Trelford Roberts and colleagues report on the association of metabolic syndrome in pregnant women with increased risk for adverse pregnancy outcomes such as gestational diabetes and preeclampsia., Author summary Why was this study done? Obesity increases the risk for developing gestational diabetes mellitus (GDM) and preeclampsia (PE), which both associate with increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in women in later life. In the general population, metabolic syndrome (MetS) associates with T2DM and CVD. The impact of maternal MetS on pregnancy outcomes in nulliparous pregnant women has not been thoroughly investigated. What did the researchers do and find? We assessed the association between MetS, measured at 15 ± 1 weeks’ gestation, and a range of pregnancy complications in low-risk, nulliparous women recruited to the multi-centre, international prospective Screening for Pregnancy Endpoints (SCOPE) study. Women with MetS in early pregnancy had an increased risk for GDM and PE, after adjustment for a range of demographic and lifestyle variables. What do these findings mean? Diagnosis of MetS may be useful to broadly identify a group of women at risk for pregnancy complications, which may additionally associate with future CVD risk. Future studies are required to substantiate our findings and to determine whether MetS is a useful discriminator of pregnancy complications in lean and obese women. Future studies are also encouraged to define clear metabolic health phenotypes that will produce the optimal probability threshold for each outcome.

Background Women who suffer recurrent miscarriage are a heterogeneous group. Known causes include genetic and endocrine abnormalities, anti-phospholipid syndrome and autoimmune disease. Congenital uterine abnormalities (CUAs) such as bicornuate, unicornuate, septate and arcuate uterine abnormalities are known to negatively impact on pregnancy rates, and to increase the miscarriage rates of genetically normal pregnancies. In some countries, such as Britain, 3D ultrasound of the pelvis is offered routinely to women with recurrent miscarriages. Aim To determine the prevalence of CUAs and other pelvic pathology, in women attending a South Australian recurrent miscarriage clinic. Materials and methods 3D transvaginal ultrasounds performed during the luteal phase of the menstrual cycle were offered to all patients attending the recurrent miscarriage clinic, who had not previously had a hysteroscopy, laparoscopy, HyCoSy or MRI study of their pelvis. A Philips IUI 8 MHz transvaginal probe for freehand sweep, and dedicated 3D transvaginal probe was used. 3D scans provide a coronal view of the uterus, ideal for detecting abnormalities which may be missed during routine conventional 2D scanning. Results A total of 210 women were recruited, 200 results were available, and 29% were found to have a CUA. 15% had polycystic ovaries detected, 15% were found to have fibroids, 12% adenomyosis and 1.5% Asherman's syndrome. Conclusions 3D ultrasound evaluation of patients attending a recurrent miscarriage clinic detects CUAs, and has a high detection rate of other pelvic abnormalities that may contribute to recurrent miscarriages.

Objective To investigate whether the FTO rs9939609 single nucleotide polymorphism (SNP), which is a risk factor for obesity and vascular diseases, is also associated with pregnancy complications including pre-eclampsia, gestational hypertension, small for gestational age pregnancy (SGA), and spontaneous preterm birth (sPTB). Methods A case-control study of 1,741 nulliparous Caucasian women, their partners, and infants was conducted. DNA was extracted from peripheral blood or saliva from parents and cord blood from infants and genotyped using the Sequenom MassARRAY system. Results The prevalence of maternal and infant AA genotype of FTO rs9939609 was increased in the SGA group compared with the uncomplicated pregnancy group (19.2% vs. 13.4%, OR = 1.7, 95% CI = 1.1-2.6, P = 0.02 and 24.6% vs. 12.5%, OR = 2.7, 95% CI = 1.6-4.6, P = 0.0002). The prevalence of maternal and infant AA genotype of FTO rs9939609 was also increased in the sPTB group compared with the uncomplicated pregnancy group (20.8% vs. 13.4%, OR = 2.1, 95% CI = 1.2-3.8, P = 0.009 and 20.0% vs. 12.5%, OR = 2.4, 95% CI = 1.0-5.3, P = 0.03). Conclusions The maternal and infant AA genotype of the obesity associated FTO rs9939609 SNP associates with increased risk for SGA and sPTB. This SNP may be important in predicting the risk of these pregnancy complications and subsequent vascular diseases.

Background Our study aimed to assess the safety and protective effect of maternal influenza vaccination on pregnancy and birth outcomes. Methods The study population comprised 1253 healthy nulliparous pregnant women in South Australia between 2015 and 2018. Participants were followed prospectively, with vaccination status (confirmed by medical records), pregnancy, and birth outcome data collected by midwives. Adjusted relative risks (aRRs) and adjusted hazard ratios (aHRs) were estimated accounting for time-varying vaccine exposure and temporal nature of each outcome. Findings Maternal influenza vaccination (48%, 603 of 1253) reduced the risk for pre-delivery hospitalisation with influenza like illness (aHR 0•61; 95% CI 0•39, 0•97). Maternal influenza vaccination was not associated with spontaneous abortion (aHR 0•42, 95% CI 0•12, 1•45), chorioamnionitis (aRR 0•78, 95% CI, 0•32, 1•88), gestational hypertension (aHR 0•78, 95% CI 0•47, 1•29), pre-eclampsia (aHR 0.84, 95% CI 0•54, 1•27), gestational diabetes (aHR 1•16, 95% CI 0•82, 1•66) nor preterm birth (aHR 0•94, 95% CI 0•59, 1•49). No associations between antenatal influenza vaccination and congenital anomalies, admission to the neonatal care unit, low Apgar scores, and mechanical ventilation were observed. Results were not materially changed after adjustment for pertussis vaccination. We observed a protective effect of maternal influenza vaccination on low birth weight (aHR 0•46, 95% CI 0•23, 0•94) and a marginal protective effect on small for gestational age births (aHR 0•65, 95% CI 0•40, 1•04) during periods of high influenza activity. Interpretation These results support the safety of maternal influenza vaccination and suggest a protective effect in reducing the rates of low birthweight and small for gestational age births. Funding There was no funding for this study.

Background Small-for-gestational-age (SGA) is a significant cause of morbidity and mortality, and there are currently few preventive strategies. Aim The aim of this study was to investigate the relationship between maternal folic acid supplement (FAS) use pre-conception through to the second trimester, and small-for-gestational age (SGA) and birth size parameters. Study design Women were recruited as part of the Screening for Pregnancy Endpoints (SCOPE) international prospective multi-centre cohort study: New Zealand, Australia, United Kingdom and Ireland. Information on FAS use pre-conception, during the first trimester and at 15 ± 1 weeks' gestation was collected via interview administered questionnaire. Participants were followed through to delivery. Pregnancy outcome data and birth measurements were collected within 72 h of birth. Multivariable regression analysis was used to investigate relationships between FAS and outcomes, adjusting for maternal sociodemographic and lifestyle factors. Subjects Nulliparous women with singleton pregnancies. Outcome measures SGA ( Results 5606 women were included. SGA prevalence was 11.3%. Pre-conception FAS was associated with a significantly lower risk of SGA: aOR = 0.82 (95% CI: 0.67–01.00 p = 0.047). Although the association between FAS at 15 weeks' gestation and SGA did not reach significance, FAS at 15 weeks was associated with a significantly higher customised birthweight centile (β 2.56 (95% CI: 0.87–4.26; p = 0.003). There was no significant effect of FAS on large-for-gestational-age births or head circumference. Conclusions In this international cohort, FAS was positively associated with fetal growth, without increasing risks associated with LGA. Further studies are required to confirm whether continuing FAS beyond the first trimester might lower the risk of SGA.