Simplified gestational diabetes screening with a triaging fasting plasma glucose reduces the burden of oral glucose tolerance tests during pregnancy - A large tertiary comparative cohort study.

AIMS: The study aimed to evaluate the impact of a simplified screeningapproach for gestational diabetes (GDM) compared to conventional screening on OGTT rates, GDM prevalence, and perinatal outcomes. METHOD: A retrospective comparative cohort study included singleton births from 20 weeks' gestation. Pregnancies without diagnostic glucose results from 13 weeks' gestation or incomplete screenings were excluded. Simplified screening consisted of a triaging fasting plasma glucose (FPG), where only those with FPG levels between 4.7 and 5.0 mmol/L proceeded to the 2hr 75 g oral glucose tolerance test (OGTT).The study period was divided into conventional screening (1st January 2019-30th June 2020) and simplified screening (1st January 2021-31st December 2021). RESULTS: Out of 15,138 pregnancies, 12,035 met the inclusion criteria: 7385 underwent conventional and 4650 underwent simplified screening. In the simplified group, 82.9 % avoided an OGTT. The simplified screening group also had a lower GDM prevalence compared to the conventional group ((18.7 % vs. 21.7 %, p < 0.001). Perinatal outcomes, including the rate of large-for-gestational-age infants, were similar between the groups. CONCLUSION: The simplified GDM screening strategy for significantly reduced OGTTs by over 80% without impacting perinatal outcomes. It suggests that prospective studies are necessary to further evaluate this approach.

Pregnant women with diabetes and their clinician's experience of participating in a pilot randomised controlled trial of corticosteroid administration in late pregnancy: A qualitative study.

BACKGROUND: Little research exists to support the administration of corticosteroids to pregnant women with diabetes. Pregnant women are often excluded from clinical trials due to concerns of harm to the foetus. AIM: This study aimed to understand the experiences of women and clinicians of participating in the Prevention of neonatal Respiratory distress with antenatal corticosteroids before Elective Caesarean section in women with Diabetes pilot randomised controlled trial to determine the acceptability of the study protocol. METHODS: Women and clinicians participating in the pilot trial were invited to complete a telephone interview regarding their experiences of participating. Qualitative data were collected and subsequently analysed using thematic analysis. RESULTS: A total of 13 women and nine clinicians were recruited between June 2020 and May 2022 for a telephone interview. Participating in the study was deemed acceptable by women and clinicians. Women chose to participate in the study due to the perceived low risk of harm associated with the intervention and for altruistic reasons. The high level of clinical support and information provided for the duration of the pilot trial was valued by women and clinicians. All clinicians highlighted the importance of conducting the trial to inform evidence-based practice. CONCLUSIONS: Pregnant women are more likely to participate in clinical trials when perceived risks are low and they are well-informed during decision-making. Clinicians will support clinical trials when they perceive a benefit to practice and feel assured that women receive extensive monitoring and support. Incorporating these factors into study protocols is more likely to be successful in recruiting pregnant women and maintaining the engagement of clinical staff for the duration of clinical trials. PATIENT OR PUBLIC CONTRIBUTIONS: Patients were invited to be participants in this study. A consumer has been included in the planning and oversite of the large multicentre trial.

Reduction in spontaneous and iatrogenic preterm births in twin pregnancies during COVID-19 lockdown in Melbourne, Australia: a multicenter cohort study.

BACKGROUND: Melbourne, Australia, recorded one of the longest and most stringent pandemic lockdowns in 2020, which was associated with an increase in preterm stillbirths among singleton pregnancies. Twin pregnancies may be particularly susceptible to the impacts of pandemic disruptions to maternity care due to their higher background risk of adverse perinatal outcomes. METHODS: Multicenter retrospective cohort study of all twin pregnancies birthing in public maternity hospitals in Melbourne. Multivariable log-binomial regression models were used to compare perinatal outcomes between a pre-pandemic group to women in whom weeks 20+0 to 40+0 of gestation occurred entirely during one of two lockdown-exposure periods: exposure 1 from 22 March 2020 to 21 March 2021 and exposure 2 from 22 March 2021 to 27 March 2022. RESULTS: Total preterm births < 37 weeks were significantly lower in exposure 1 compared with the pre-pandemic period (63.1% vs 68.3%; adjusted risk ratio 0.92 95% CI 0.87-0.98, p = 0.01). This was mainly driven by fewer spontaneous preterm births (18.9% vs 20.3%; adjusted risk ratio 0.95 95% CI 0.90-0.99, p = 0.04). There were also lower rates of preterm birth < 34 weeks (19.9% vs 23.0%, adjusted risk ratio 0.93 95% CI 0.89-0.98 p = 0.01) and total iatrogenic births for fetal compromise (13.4% vs 20.4%; adjusted risk ratio 0.94 95% CI 0.89-0.98, p = 0.01). There were fewer special care nursery admissions (38.5% vs 43.4%; adjusted risk ratio 0.91 95% CI 0.87-0.95, p < 0.001) but no significant changes in stillbirth (1.5% vs 1.6%; adjusted risk ratio 1.00 95% CI 0.99-1.01, p = 0.82). Compared with the pre-pandemic period, there were more preterm births < 28 weeks and neonatal intensive care unit admissions in exposure 2. CONCLUSIONS: Melbourne's first lockdown-exposure period was associated with lower preterm births in twins without significant differences in adverse newborn outcomes. Our findings provide insights into the influences on preterm birth and the optimal timing of delivery for twins.

Variation in clinical practice guideline recommendations for medication use in pregnancy in Australia: A systematic review.

BACKGROUND: Medication use in pregnancy is common; however, it is unknown if clinical practice guideline (CPG) prescribing recommendations referred to in Australia at the state, national and international level are consistent. AIMS: This systematic review aimed to: (1) identify sources of CPGs that inform prescribing during pregnancy in Australia; (2) assess CPG quality; and (3) evaluate variation within CPG recommendations for medication use in three common conditions in pregnancy: prophylactic antibiotics following premature rupture of membranes (PROM) at term, antidepressants in pregnancy and metformin in gestational diabetes mellitus (GDM). MATERIALS AND METHODS: A literature search was conducted across PubMed, Scopus and EMBASE databases. Grey literature was identified through publicly available Australian policy statements. Prescribing recommendations for prophylactic antibiotics following PROM at term, antidepressants in pregnancy and metformin in GDM, were compared at the state, national and international levels. CPG quality was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. RESULTS: We identified 39 CPG sources that inform prescribing during pregnancy in Australia. CPG quality varied between resources. There was minor variation in recommendations for antibiotic prophylaxis in PROM at term. Recommendations regarding metformin use in GDM were also variable, with CPGs either recommending its use as a first-line agent when lifestyle modifications are not effective or when insulin therapy is not practicable. Recommendations for antidepressant use were consistent across CPGs analysed. CONCLUSION: Multiple CPGs exist to inform prescribing during pregnancy in Australia, with variation present within CPG quality and recommendations. These findings offer insight into potential sources of variation in maternal and neonatal health outcomes.

PRECeDe Pilot: Prevention of neonatal respiratory distress with antenatal corticosteroids before elective caesarean section in women with diabetes - a feasibility randomised trial.

OBJECTIVE: The PRECeDe Pilot Trial was designed to determine the feasibility of undertaking a multicentre, randomised controlled trial (RCT) to assess the efficacy of antenatal corticosteroids administration within 7 days before elective caesarean section (CS) in women with pre-gestational diabetes (PGDM) or gestational diabetes (GDM). DESIGN: Triple blind, parallel group, placebo-controlled, pilot RCT. SETTING: Single-centre tertiary maternity hospital in Melbourne, Australia. POPULATION: Pregnant women with PGDM (type 1 or type 2 diabetes) or GDM booked for a planned CS scheduled between 35+0 and 38+6 weeks of gestation. METHODS: Eligible participants were randomised to receive two injections of either betamethasone 11.4 mg or normal saline placebo, 24 hours apart within 7 days before CS scheduled between 35+0 and 38+6 weeks of gestation. MAIN OUTCOME MEASURE: The proportion of eligible women who consented and were randomised. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12619001475134. RESULTS: Of 537 women eligible, 182 were approached and 47 (26%) were recruited. Of these, 22 were allocated to the betamethasone group and 25 were allocated to the placebo group. There were no serious adverse events related to participation. CONCLUSION: It is feasible to undertake a triple-blind, placebo-controlled RCT investigating the efficacy of antenatal corticosteroids in preventing respiratory morbidity in infants of women with PGDM or GDM who are undergoing an elective CS between 35+0 and 38+6 weeks.

My Baby's Movements: An assessment of the effectiveness of the My Baby's Movements phone program in reducing late-gestation stillbirth rates.

BACKGROUND: Delayed reporting of decreased fetal movements (DFM) could represent a missed opportunity to prevent stillbirth. Mobile phone applications (apps) have the potential to improve maternal awareness and reporting of DFM and contribute to stillbirth prevention. AIMS: To evaluate the effectiveness of the My Baby's Movements (MBM) app on late-gestation stillbirth rates. MATERIALS AND METHODS: The MBM trial evaluated a multifaceted fetal movements awareness package across 26 maternity services in Australia and New Zealand between 2016 and 2019. In this secondary analysis, generalised linear mixed models were used to compare rates of late-gestation stillbirth, obstetric interventions, and neonatal outcomes between app users and non-app users including calendar time, cluster, primiparity and other potential confounders as fixed effects, and hospital as a random effect. RESULTS: Of 140 052 women included, app users comprised 9.8% (n = 13 780). The stillbirth rate was not significantly lower among app users (1.67/1000 vs 2.29/1000) (adjusted odds ratio (aOR) 0.79; 95% CI 0.51-1.23). App users were less likely to have a preterm birth (aOR 0.81; 0.75-0.88) or a composite adverse neonatal outcome (aOR 0.87; 0.81-0.93); however, they had higher rates of induction of labour (IOL) (aOR 1.27; 1.22-1.32) and early term birth (aOR 1.08; 1.04-1.12). CONCLUSIONS: The MBM app had low uptake and its use was not associated with stillbirth rates but was associated with some neonatal benefit, and higher rates of IOL and early term birth. Use and acceptability of tools designed to promote fetal movement awareness is an important knowledge gap. The implications of increased IOL and early term births warrant consideration in future studies.

Reductions in stillbirths and preterm birth in COVID-19-vaccinated women: a multicenter cohort study of vaccination uptake and perinatal outcomes.

BACKGROUND: COVID-19 infection in pregnancy is associated with a higher risk of progression to severe disease, but vaccine uptake by pregnant women is hindered by persistent safety concerns. COVID-19 vaccination in pregnancy has been shown to reduce stillbirth, but its relationship with preterm birth is uncertain. OBJECTIVE: This study aimed to measure the rate of COVID-19 vaccine uptake among women giving birth in Melbourne, Australia, and to compare perinatal outcomes by vaccination status. STUDY DESIGN: This was a retrospective multicenter cohort study conducted after the June 2021 government recommendations for messenger RNA COVID-19 vaccination during pregnancy. Routinely collected data from all 12 public maternity hospitals in Melbourne were extracted on births at ≥20 weeks' gestation from July 1, 2021 to March 31, 2022. Maternal sociodemographic characteristics were analyzed from the total birth cohort. Perinatal outcomes were compared between vaccinated and unvaccinated women for whom weeks 20 to 43 of gestation fell entirely within the 9-month data collection period. The primary outcomes were the rates of stillbirth and preterm birth (spontaneous and iatrogenic) in singleton pregnancies of at least 24 weeks' gestation, after exclusion of congenital anomalies. Secondary perinatal outcomes included the rate of congenital anomalies among infants born at ≥20 weeks' gestation and birthweight ≤third centile and newborn intensive care unit admissions among infants born without congenital anomalies at ≥24 weeks' gestation. We calculated the adjusted odds ratio of perinatal outcomes among vaccinated vs unvaccinated women using inverse propensity score-weighting regression adjustment with multiple covariates; P<.05 was considered statistically significant. RESULTS: Births from 32,536 women were analyzed: 17,365 (53.4%) were vaccinated and 15,171 (47.6%) were unvaccinated. Vaccinated women were more likely to be older, nulliparous, nonsmoking, not requiring an interpreter, of higher socioeconomic status, and vaccinated against pertussis and influenza. Vaccination status also varied by region of birth. Vaccinated women had a significantly lower rate of stillbirth compared with unvaccinated women (0.2% vs 0.8%; adjusted odds ratio, 0.18; 95% confidence interval, 0.09-0.37; P<.001). Vaccination was associated with a significant reduction in total preterm births at <37 weeks (5.1% vs 9.2%; adjusted odds ratio, 0.60; 95% confidence interval, 0.51-0.71; P<.001), spontaneous preterm birth (2.4% vs 4.0%; adjusted odds ratio, 0.73; 95% confidence interval, 0.56-0.96; P=.02), and iatrogenic preterm birth (2.7% vs 5.2%; adjusted odds ratio, 0.52; 95% confidence interval, 0.41-0.65; P<.001). Infants born to vaccinated mothers also had lower rates of admission to the neonatal intensive care unit. There was no significant increase in the rate of congenital anomalies or birthweight ≤3rd centile in vaccinated women. Vaccinated women were significantly less likely to have an infant with a major congenital anomaly compared with the unvaccinated group (2.4% vs 3.0%; adjusted odds ratio, 0.72; 95% confidence interval, 0.56-0.94; P=.02). This finding remained significant even when the analysis was restricted to women vaccinated before 20 weeks' gestation. CONCLUSION: COVID-19 vaccination during pregnancy was associated with a reduction in stillbirth and preterm birth, and not associated with any adverse impact on fetal growth or development. Vaccine coverage was substantially influenced by known social determinants of health.

Neonatal outcomes following antenatal corticosteroid administration prior to elective caesarean delivery in women with pre-gestational diabetes: A retrospective cohort study.

BACKGROUND: The benefit of antenatal corticosteroid (ACS) administration for the prevention of neonatal morbidity and mortality has been well described for preterm infants. Some studies have demonstrated a benefit for infants born by elective caesarean section (CS) at late preterm or term gestations. However, the neonatal benefits of ACS are not well described when given to pregnant women with diabetes. AIMS: The aim of this study was to evaluate the neonatal outcomes following ACS administration in women with pre-gestational diabetes mellitus (PGDM) when administered prior to elective CS after 36 weeks gestation. METHODS: This retrospective observational study included all women with PGDM who gave birth by elective CS between 36+0 and 38+6 weeks gestation. Neonatal outcomes for exposed participants were compared to outcomes for non-exposed participants. RESULTS: Of the 306 women identified, 65 (21.2%) were exposed to ACS within seven days prior to birth and 241 (78.8%) were not. Although not statistically significant, ACS-exposed infants born prior to 38+0 weeks were less likely to require respiratory support or neonatal nursery admission compared to those who were not exposed; however, exposed infants born after 37+0 weeks were more likely to require parenteral treatment for neonatal hypoglycaemia. CONCLUSION: This study did not demonstrate any statistically significant beneficial or harmful effects of ACS in neonates of women with PGDM who are born by elective CS. While it is plausible that ACS could reduce neonatal respiratory morbidity in this population, further prospective studies evaluating the benefits and harms are required before recommending this practice.

Improving Cohort-Hospital Matching Accuracy through Standardization and Validation of Participant Identifiable Information.

Linking very large, consented birth cohorts to birthing hospitals clinical data could elucidate the lifecourse outcomes of health care and exposures during the pregnancy, birth and newborn periods. Unfortunately, cohort personally identifiable information (PII) often does not include unique identifier numbers, presenting matching challenges. To develop optimized cohort matching to birthing hospital clinical records, this pilot drew on a one-year (December 2020-December 2021) cohort for a single Australian birthing hospital participating in the whole-of-state Generation Victoria (GenV) study. For 1819 consented mother-baby pairs and 58 additional babies (whose mothers were not themselves participating), we tested the accuracy and effort of various approaches to matching. We selected demographic variables drawn from names, DOB, sex, telephone, address (and birth order for multiple births). After variable standardization and validation, accuracy rose from 10% to 99% using a deterministic-rule-based approach in 10 steps. Using cohort-specific modifications of the Australian Statistical Linkage Key (SLK-581), it took only 3 steps to reach 97% (SLK-5881) and 98% (SLK-5881.1) accuracy. We conclude that our SLK-5881 process could safely and efficiently achieve high accuracy at the population level for future birth cohort-birth hospital matching in the absence of unique identifier numbers.

Placental OLAH Levels Are Altered in Fetal Growth Restriction, Preeclampsia and Models of Placental Dysfunction.

Previously, we identified elevated transcripts for the gene Oleoyl-ACP Hydrolase (OLAH) in the maternal circulation of pregnancies complicated by preterm fetal growth restriction. As placental dysfunction is central to the pathogenesis of both fetal growth restriction and preeclampsia, we aimed to investigate OLAH levels and function in the human placenta. We assessed OLAH mRNA expression (qPCR) throughout pregnancy, finding placental expression increased as gestation progressed. OLAH mRNA and protein levels (Western blot) were elevated in placental tissue from cases of preterm preeclampsia, while OLAH protein levels in placenta from growth-restricted pregnancies were comparatively reduced in the preeclamptic cohort. OLAH expression was also elevated in placental explant tissue, but not isolated primary cytotrophoblast cultured under hypoxic conditions (as models of placental dysfunction). Further, we discovered that silencing cytotrophoblast OLAH reduced the expression of pro- and anti-apoptosis genes, BAX and BCL2, placental growth gene, IGF2, and oxidative stress gene, NOX4. Collectively, these findings suggest OLAH could play a role in placental dysfunction and may be a therapeutic target for mitigating diseases associated with this vital organ. Further research is required to establish the role of OLAH in the placenta, and whether these changes may be a maternal adaptation or consequence of disease.

The role of Australian clinical quality registries in pregnancy care: A scoping review.

BACKGROUND: Pregnancy represents a time of increased morbidity and mortality for women and their infants. Clinical quality registries (CQRs) collect, analyse and report key healthcare quality indicators for patient cohorts to improve patient care. There are limited data regarding existing CQRs in pregnancy. This scoping review aimed to: (1) identify Australian CQRs specific to pregnancy care and describe their general characteristics; and (2) outline their aims and measured outcomes METHODS: The scoping review was undertaken according to Joanna Briggs Institute guidelines. CQRs were identified using a systematic approach from publications (Ovid MEDLINE, PubMed, Google Scholar), peer consultation, the Australian register of clinical registries and web searches. Details surrounding general characteristics, aims and outcomes were collated. RESULTS: We identified two primary sources of information about pregnancy care. (1) Six CQRs are specific to pregnancy (Australia and New Zealand twin-twin transfusion syndrome registry, Australian Pregnancy Register for women with epilepsy and those taking anti-epileptic drugs, National Register of Antipsychotic Medication in Pregnancy, Australasian Maternity Outcomes Surveillance System, Neonatal Alloimmune Thrombocytopaenia Registry and the Diabetes in Pregnancy clinical register). (2) Fourteen observational cohort studies were facilitated by non-pregnancy-specific CQRs where a subsection of patients underwent pregnancy. CONCLUSIONS: Australian CQRs currently report varied information regarding some selected conditions during pregnancy and offer therapeutic and epidemiological insight into their care. Further research into their effectiveness is warranted. We note the lack of a CQR spanning the common problems of pregnancy in general, where significant health, service and economic gains are possible.

Increase in preterm stillbirths in association with reduction in iatrogenic preterm births during COVID-19 lockdown in Australia: a multicenter cohort study.

BACKGROUND: The COVID-19 pandemic has been associated with a worsening of perinatal outcomes in many regions around the world. Melbourne, Australia, had one of the longest and most stringent lockdowns worldwide in 2020 while recording only rare instances of COVID-19 infection in pregnant women. OBJECTIVE: This study aimed to compare the stillbirth and preterm birth rates in women who were exposed or unexposed to lockdown restrictions during pregnancy. STUDY DESIGN: This was a retrospective, multicenter cohort study of perinatal outcomes in Melbourne before and during the COVID-19 lockdown. The lockdown period was defined as the period from March 23, 2020 to March 14, 2021. Routinely-collected maternity data on singleton pregnancies ≥24 weeks gestation without congenital anomalies were obtained from all the 12 public hospitals in Melbourne. We defined the lockdown-exposed cohort as those women for whom weeks 20 to 40 of gestation occurred during the lockdown and the unexposed control group as women from the corresponding calendar periods 12 and 24 months before. The main outcome measures were stillbirth, preterm birth, fetal growth restriction (birthweight < third centile), and iatrogenic preterm birth for fetal compromise. We performed multivariable logistic regression analysis to compare the odds of stillbirth, preterm birth, fetal growth restriction, and iatrogenic preterm birth for fetal compromise, adjusting for multiple covariates. RESULTS: There were 24,817 births in the exposed group and 50,017 births in the control group. There was a significantly higher risk of preterm stillbirth in the exposed group than the control group (0.26% vs 0.18%; adjusted odds ratio, 1.49; 95% confidence interval, 1.08-2.05; P=.015). There was also a significant reduction in the preterm birth of live infants <37 weeks (5.68% vs 6.07%; adjusted odds ratio, 0.93; 95% confidence interval, 0.87-0.99; P=.02), which was largely mediated by a significant reduction in iatrogenic preterm birth (3.01% vs 3.27%; adjusted odds ratio, 0.91; 95% confidence interval, 0.83-0.99; P=.03), including iatrogenic preterm birth for fetal compromise (1.25% vs 1.51%; adjusted odds ratio, 0.82; 95% confidence interval, 0.71-0.93; P=.003). There were also significant reductions in special care nursery admissions during lockdown (11.53% vs 12.51%; adjusted odds ratio, 0.90; 95% confidence interval, 0.86-0.95; P<.0001). There was a trend to fewer spontaneous preterm births <37 weeks in the exposed group of a similar magnitude to that reported in other countries (2.69% vs 2.82%; adjusted odds ratio, 0.95; 95% confidence interval, 0.87-1.05; P=.32). CONCLUSION: Lockdown restrictions in Melbourne, Australia were associated with a significant reduction in iatrogenic preterm birth for fetal compromise and a significant increase in preterm stillbirths. This raises concerns that pandemic conditions in 2020 may have led to a failure to identify and appropriately care for pregnant women at an increased risk of antepartum stillbirth. Further research is required to understand the relationship between these 2 findings and to inform our ongoing responses to the pandemic.

Collaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia.

BACKGROUND: The COVID-19 pandemic has resulted in a range of unprecedented disruptions to maternity care with documented impacts on perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne has endured one of the longest and most stringent lockdowns in globally. This paper presents the protocol for a multicentre study to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic. METHODS: Multicentre observational study analysing monthly deidentified maternal and newborn outcomes from births >20 weeks at all 12 public maternity services in Melbourne. Data will be merged centrally to analyse outcomes and create run charts according to established methods for detecting non-random 'signals' in healthcare. Perinatal outcomes will include weekly rates of total births, stillbirths, preterm births, neonatal intensive care admissions, low Apgar scores and fetal growth restriction. Maternal outcomes will include weekly rates of: induced labour, caesarean section, births before arrival to hospital, postpartum haemorrhage, length of stay, general anaesthesia for caesarean birth, influenza and COVID-19 vaccination status, and gestation at first antenatal visit. A prepandemic median for all outcomes will be calculated for the period of January 2018 to March 2020. A significant shift is defined as ≥6 consecutive weeks, all above or below the prepandemic median. Additional statistical analyses such as regression, time series and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests. ETHICS AND DISSEMINATION: Ethics approval for the collaborative maternity and newborn dashboard project has been obtained from the Austin Health (HREC/64722/Austin-2020) and Mercy Health (ref. 2020-031). TRIAL REGISTRATION NUMBER: ACTRN12620000878976; Pre-results.

NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast.

Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O2 compared to 8% O2) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2.

LOX-1 expression is reduced in placenta from pregnancies complicated by preeclampsia and in hypoxic cytotrophoblast.

OBJECTIVES: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is upregulated in the maternal vasculature in preeclampsia, and contributes to oxidative stress and endothelial dysfunction. However, its function in the placenta is unclear. This paper investigated LOX-1 expression in models of placental dysfunction and preeclampsia, and whether candidate therapeutics for preeclampsia could alter its expression. STUDY DESIGN: Placentas were collected from preterm pregnancies and cases of preterm preeclampsia and fetal growth restriction. Blood was collected from participants whose pregnancies were complicated by preterm fetal growth restriction and/or preeclampsia. Primary cytotrophoblast and placental explant tissue were cultured under hypoxic (1% O2) or normoxic (8% O2) conditions. Cytotrophoblast were exposed to 10% preeclamptic or control serum. Cytotrophoblast and preeclamptic explant tissue were treated with 100 µM esomeprazole, lansoprazole or rabeprazole. MAIN OUTCOME MEASURES: LOX-1 expression was assessed in all samples via qPCR. RESULTS: LOX-1 expression was reduced in placentas from cases of preterm preeclampsia, but not fetal growth restriction, compared to controls. LOX-1 expression was reduced in cytotrophoblast under hypoxia, but not in explant tissue. Treatment with preeclamptic serum in vitro did not alter cytotrophoblast LOX-1 expression. Circulating LOX-1 mRNA was unaltered in patients with fetal growth restriction, preeclampsia, and fetal hypoxia, compared to controls. Treatment with esomeprazole or lansoprazole in vitro increased placental LOX-1 expression. CONCLUSIONS: LOX-1 expression is reduced in preeclamptic placentas and hypoxic cytotrophoblast. Esomeprazole and lansoprazole increase placental LOX-1 expression. These findings demonstrate a role for LOX-1 in the placenta, and improve our understanding of maternal adaptations in pregnancy complications.

Maternal thrombin generation and D-dimer levels in obesity and pregnancy: results from the maternal thrombin generation in obesity and pregnancy (MaTOPs) study.

Venous thromboembolic disease (VTE) risk increases five-fold antenatally and 14-fold during the puerperium. Obesity significantly increases this risk. The D-dimer assay and more novel Calibrated Automated Thrombogram (CAT) assay laboratory tests display potential for use in VTE risk stratification in pregnancy, although to date, research in the performance characteristics of these tests in obese and nonobese pregnant populations is limited. The aim of this study was to compare D-dimer and thrombin generation levels in obese and nonobese pregnant women. Pregnant women were recruited and categorised, as obese (BMI ≥30) or nonobese (BMI 18.5-25). Blood was collected at 26-28 weeks' gestation, 36-40 weeks' gestation and 6-12 weeks postpartum and D-dimer concentrations and endogenous thrombin potential (ETP) were determined. Student's t-test was used to analyse differences in mean D-dimer and ETP. At 36-40 weeks, obese pregnant women had higher D-dimer concentrations (P = 0.001) but lower ETP levels compared with nonobese women (P = 0.044). D-dimer was higher in nonobese than in obese women at 6-12 weeks postpartum (P = 0.026). There was no difference in mean D-dimer (P  = 0.825) and mean ETP (P  = 0.424) between obese and nonobese women at 26-28 weeks. No difference was observed in mean ETP at 6-12 weeks postpartum (P  = 0.472). ETP was lower in both obese and nonobese women postpartum than during pregnancy. D-dimer was lower in obese women but not in nonobese women postpartum. D-dimer concentrations and ETP were not significantly different during multiple time points in pregnancy and postpartum between obese and nonobese pregnant women suggesting limited utility in VTE risk assessment in obese pregnant women.

Enhancing Value and Uptake for Whole-Population Cohorts of Children and Parents: Methods to Integrate Registries into the Generation Victoria Cohort.

Health registries are critical to understanding, benchmarking and improving quality of care for specific diseases and conditions, but face hurdles including funding, bias towards clinical rather than population samples, lack of pre-morbid and outcomes data, and absent cross-registry harmonisation and coordination. Children are particularly under-represented in registry research. This paper lays out novel principles, methods and governance to integrate diverse registries within or alongside a planned children's mega-cohort to rapidly generate translatable evidence. GenV (Generation Victoria) will approach for recruitment parents of all newborns (estimated 150,000) over two years from mid-2021 in the state of Victoria (population 6.5 million), Australia. Its sample size and population denominator mean it will contain almost all children with uncommon or co-morbid conditions as they emerge over time. By design, it will include linked datasets, biosamples (including from pregnancy), phenotypes and participant-reported measures, all of which will span pre-morbid to long-term outcomes. We provide a vignette of a planned new registry for high-risk pregnancies to illustrate the possibilities. To our knowledge, this is the first paper to describe such a methodology designed prospectively to enhance both the clinical relevance of a large multipurpose cohort and the value and inclusivity of registries in a population.

DAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia.

Previously, we identified increased maternal circulating DAAM2 mRNA in pregnancies complicated by preterm fetal growth restriction (FGR). Here, we assessed whether circulating DAAM2 mRNA could detect FGR, and whether the DAAM2 gene, known to play roles in the Wnt signalling pathway is expressed in human placenta and associated with dysfunction and FGR. We performed linear regression analysis to calculate area under the ROC curve (AUC) for DAAM2 mRNA expression in the maternal circulation of pregnancies complicated by preterm FGR. DAAM2 mRNA expression was assessed across gestation by qPCR. DAAM2 protein and mRNA expression was assessed in preterm FGR placenta using western blot and qPCR. DAAM2 expression was assessed in term cytotrophoblasts and placental explant tissue cultured under hypoxic and normoxic conditions by qPCR. Small interfering RNAs were used to silence DAAM2 in term primary cytotrophoblasts. Expression of growth, apoptosis and oxidative stress genes were assessed by qPCR. Circulating DAAM2 mRNA was elevated in pregnancies complicated by preterm FGR [p < 0.0001, AUC = 0.83 (0.78-0.89)]. Placental DAAM2 mRNA was detectable across gestation, with highest expression at term. DAAM2 protein was increased in preterm FGR placentas but demonstrated no change in mRNA expression. DAAM2 mRNA expression was increased in cytotrophoblasts and placental explants under hypoxia. Silencing DAAM2 under hypoxia decreased expression of pro-survival gene, BCL2 and oxidative stress marker, NOX4, whilst increasing expression of antioxidant enzyme, HMOX-1. The increased DAAM2 associated with FGR and hypoxia implicates a potential role in placental dysfunction. Decreasing DAAM2 may have cytoprotective effects, but further research is required to elucidate its role in healthy and dysfunctional placentas.

Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth.

BACKGROUND: Fetuses affected by placental insufficiency do not receive adequate nutrients and oxygenation, become growth restricted and acidemic, and can demise. Preterm fetal growth restriction is a severe form of placental insufficiency with a high risk of stillbirth. We set out to identify maternal circulating mRNA transcripts that are differentially expressed in preterm pregnancies complicated by very severe placental insufficiency, in utero fetal acidemia, and are at very high risk of stillbirth. METHODS: We performed a cohort study across six hospitals in Australia and New Zealand, prospectively collecting blood from 128 pregnancies complicated by preterm fetal growth restriction (delivery < 34 weeks' gestation) and 42 controls. RNA-sequencing was done on all samples to discover circulating mRNAs associated with preterm fetal growth restriction and fetal acidemia in utero. We used RT-PCR to validate the associations between five lead candidate biomarkers of placental insufficiency in an independent cohort from Europe (46 with preterm fetal growth restriction) and in a third cohort of pregnancies ending in stillbirth. RESULTS: In the Australia and New Zealand cohort, we identified five mRNAs that were highly differentially expressed among pregnancies with preterm fetal growth restriction: NR4A2, EMP1, PGM5, SKIL, and UGT2B1. Combining three yielded an area under the receiver operative curve (AUC) of 0.95. Circulating NR4A2 and RCBTB2 in the maternal blood were dysregulated in the presence of fetal acidemia in utero. We validated the association between preterm fetal growth restriction and circulating EMP1, NR4A2, and PGM5 mRNA in a cohort from Europe. Combining EMP1 and PGM5 identified fetal growth restriction with an AUC of 0.92. Several of these genes were differentially expressed in the presence of ultrasound parameters that reflect placental insufficiency. Circulating NR4A2, EMP1, and RCBTB2 mRNA were differentially regulated in another cohort destined for stillbirth, compared to ongoing pregnancies. EMP1 mRNA appeared to have the most consistent association with placental insufficiency in all cohorts. CONCLUSIONS: Measuring circulating mRNA offers potential as a test to identify pregnancies with severe placental insufficiency and at very high risk of stillbirth. Circulating mRNA EMP1 may be promising as a biomarker of severe placental insufficiency.

Controversies in antenatal corticosteroid treatment.

Antenatal corticosteroids are now established as one of the cornerstones of therapy in the prevention of neonatal morbidity and mortality prior to preterm birth. Although this practice is widely accepted, a significant number of controversies exist. This review explores the knowledge gaps regarding the use of antenatal corticosteroids in the preterm, late preterm and term populations. Furthermore, the role of antenatal corticosteroids in special populations, such as diabetes, multiple pregnancies and periviable gestations, where high-quality data from randomized controlled trials are lacking, is also considered.