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Fred A English,1 Louise C Kenny,1 Fergus P McCarthy1,2 1Irish Centre for Fetal and Neonatal Translational Research (INFANT), Department of Obstetrics and Gynaecology, University College Cork, Cork, Ireland; 2Women’s Health Academic Centre, King's Health Partners, St Thomas' Hospital, London, UK Abstract: Preeclampsia, a hypertensive disorder of pregnancy is estimated to complicate 2%–8% of pregnancies and remains a principal cause of maternal and fetal morbidity and mortality. Preeclampsia may present at any gestation but is more commonly encountered in the third trimester. Multiple risk factors have been documented, including: family history, nulliparity, egg donation, diabetes, and obesity. Significant progress has been made in developing tests to predict risk of preeclampsia in pregnancy, but these remain confined to clinical trial settings and center around measuring angiogenic profiles, including placental growth factor or newer tests involving metabolomics. Less progress has been made in developing new treatments and therapeutic targets, and aspirin remains one of the few agents shown to consistently reduce the risk of developing preeclampsia. This review serves to discuss recent advances in risk factor identification, prediction techniques, and management of preeclampsia in antenatal, intrapartum, and postnatal patients. Keywords: pregnancy, treatment, risk reduction, prediction

ObjectiveTo assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact.DesignIndividual participant data meta-analysis of 39 cohorts.SettingEurope, North America, and Oceania.Population265 270 births.MethodsInformation on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used.Main outcome measuresGestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth.ResultsHigher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain.ConclusionsMaternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity.Tweetable abstractPromoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

Objective: To develop a dichorionic twin pregnancy specific reference range for placental growth factor (PlGF), and to compare gestation‐specific placental growth factor levels in twin pregnancies later complicated by pre‐eclampsia, hypertensive disorder of pregnancy or fetal growth restriction with control pregnancies. Design: Prospective observational study. Setting: Single large tertiary maternity unit in Ireland. Population or Sample: Women with a twin pregnancy. Methods: Consenting pregnant women, across a variety of gestations, had a single blood sample taken at one time‐point only during their pregnancy. The plasma was initially biobanked and PlGF was measured later in batches using the point of care Triage® PlGF test. Main outcome measures: Development of pre‐eclampsia, hypertensive disorder of pregnancy or fetal growth restriction. Results: Placental growth factor levels in uncomplicated dichorionic twin pregnancies were significantly lower in the women who later developed pre‐eclampsia than in the controls at all gestational intervals. In those that later developed any hypertensive disorder of pregnancy, median PlGF was lower only in those recruited before 24 weeks of gestation, whereas in infants with a customised birthweight below the third centile, PlGF was lower only in those sampled after 24 weeks of gestation. Conclusions: Placental growth factor levels in twin pregnancy differ significantly between those women with a pregnancy that will later be complicated by pre‐eclampsia and those that will not. This difference is present many weeks before clinical signs or symptoms of disease are present. Using cross‐sectional values from uncomplicated twin pregnancies, we have developed a dichorionic twin pregnancy specific reference range for PlGF. Placental growth factor levels in twin pregnancy differ significantly between women that will later develop pre‐eclampsia and those that will not. Placental growth factor levels in twin pregnancy differ significantly between women that will later develop pre‐eclampsia and those that will not. [ABSTRACT FROM AUTHOR]

Objective: To investigate the parental physical and lifestyle determinants of newborn body composition.Design: Prospective cohort study.Setting: Cork University Maternity Hospital, a tertiary referral hospital in Cork, Ireland.Population: All babies were recruited as part of a prospective birth cohort, Babies AfterScope: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE). These babies were recruited from women who had participated in the Screening of Pregnancy Endpoints (SCOPE) study Ireland, a prospective, multicentre cohort studyMethods: Multivariate linear regression was used to analyse the effect of a range of maternal and paternal physical and lifestyle features on neonatal body fat percentage (BF%).Main Outcome Measures: Neonatal BF%. Neonatal adiposity was assessed within 48 hours of birth using air displacement plethysmography (PEAPOD(®) ).Results: In all, 1243 infants were enrolled in the study. Increasing maternal body mass index (adjusted mean difference 0.09; 0.04, 0.15) and waist height ratio (adjusted mean difference 6.59; 0.27, 12.92) were significantly associated with increased neonatal BF%. In contrast, maternal smoking was associated with reduced neonatal BF% compared with non smokers (adjusted mean difference -0.55; -1.07, -0.03). Infant sex significantly altered neonatal BF%, with female infants having higher neonatal BF% compared with male infants (adjusted mean difference 1.98; 1.54, 2.53). No association was observed between paternal body mass index (BMI), paternal age or paternal smoking and neonatal BF%.Conclusions: Maternal smoking, BMI, waist height ratio and infant sex were associated with altered BF%.Tweetable Abstract: Maternal smoking, BMI, waist height ratio and infant sex are associated with altered neonatal body fat percentage. [ABSTRACT FROM AUTHOR]

Objective To establish a gestation-specific reference range for D-dimer in healthy pregnant women with a singleton pregnancy using the Auto-Dimer assay. Design Cross-sectional study Setting Cork University Maternity Hospital, Ireland. Population Healthy pregnant women attending for routine antenatal care. Methods Simultaneous-quantile regression was performed to construct a median, 5th percentile, and 95th percentile, model of normal pregnancy D-dimer concentration versus gestational week, ranging from week 6 to 42. Additionally, pair-wise Mann-Whitney U-tests were performed to compare distributions of D-dimer concentrations for each of the four discrete gestational sampling windows with the distribution of D-dimer concentrations 48 hours postpartum. Main outcome measures D-dimer concentrations (ng/ml) during normal gestation (approximately week 6 to week 42). Results Seven hundred and sixty healthy pregnant women were investigated between gestational age week 5 and 48 hours postpartum. There was a clear steady increase in median D-dimer concentrations over the complete gestational period. Additionally, the 95th centile estimates for all gestational time-points were above the accepted non-pregnancy normal cut-off concentration (224 ng/ml). The results of the Mann- Whitney U-tests suggested that the long-term postnatal return to normal D-dimer concentrations begins in the immediate postpartum period. Conclusions We found that there is a continuous increase in D-dimer concentrations across all gestations. This research is potentially beneficial to future diagnosis of venous thromboembolism ( VTE) in pregnancy using the new recommended 95th centile potential cut-offs. Possible further investigation involves an observational study comparing D-dimer concentrations in women with proven DVT with those that don't, generating likelihood ratios. [ABSTRACT FROM AUTHOR]

Objectives To assess the performance of clinical risk factors, uterine artery Doppler and angiogenic markers to predict preterm pre-eclampsia in nulliparous women. Design Predictive test accuracy study. Setting Prospective multicentre cohort study Screening for Pregnancy Endpoints ( SCOPE). Methods Low-risk nulliparous women with a singleton pregnancy were recruited. Clinical risk factor data were obtained and plasma placental growth factor ( Pl GF), soluble endoglin and soluble fms-like tyrosine kinase-1 (s Flt-1) were measured at 14-16 weeks of gestation. Prediction models were developed using multivariable stepwise logistic regression. Main outcome measure Preterm pre-eclampsia (delivered before 37+0 weeks of gestation). Results Of the 3529 women recruited, 187 (5.3%) developed pre-eclampsia of whom 47 (1.3%) delivered preterm. Controls ( n = 188) were randomly selected from women without preterm pre-eclampsia and included women who developed other pregnancy complications. An area under a receiver operating characteristic curve ( AUC) of 0.76 (95% CI 0.67-0.84) was observed using previously reported clinical risk variables. The AUC improved following the addition of Pl GF measured at 14-16 weeks (0.84; 95% CI 0.77-0.91), but no further improvement was observed with the addition of uterine artery Doppler or the other angiogenic markers. A sensitivity of 45% (95% CI 0.31-0.59) (5% false-positive rate) and post-test probability of 11% (95% CI 9-13) were observed using clinical risk variables and Pl GF measurement. Conclusions Addition of plasma Pl GF at 14-16 weeks of gestation to clinical risk assessment improved the identification of nulliparous women at increased risk of developing preterm pre-eclampsia, but the performance is not sufficient to warrant introduction as a clinical screening test. These findings are marker dependent, not assay dependent; additional markers are needed to achieve clinical utility. [ABSTRACT FROM AUTHOR]

Objective: Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes., Design: Superiority, double-blind randomised controlled trial., Setting: A total of 20 UK fetal medicine units., Population: Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22 +0 and 29 +6  weeks of gestation., Methods: Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation., Main Outcome Measures: All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85., Results: In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm)., Conclusions: Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To predict birth weight at various potential gestational ages of delivery based on data routinely available at the first antenatal visit., Design: Individual participant data meta-analysis., Data Sources: Individual participant data of four cohorts (237 228 pregnancies) from the International Prediction of Pregnancy Complications (IPPIC) network dataset., Eligibility Criteria for Selecting Studies: Studies in the IPPIC network were identified by searching major databases for studies reporting risk factors for adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction, and stillbirth, from database inception to August 2019. Data of four IPPIC cohorts (237 228 pregnancies) from the US (National Institute of Child Health and Human Development, 2018; 233 483 pregnancies), UK (Allen et al, 2017; 1045 pregnancies), Norway (STORK Groruddalen research programme, 2010; 823 pregnancies), and Australia (Rumbold et al, 2006; 1877 pregnancies) were included in the development of the model., Results: The IPPIC birth weight model was developed with random intercept regression models with backward elimination for variable selection. Internal-external cross validation was performed to assess the study specific and pooled performance of the model, reported as calibration slope, calibration-in-the-large, and observed versus expected average birth weight ratio. Meta-analysis showed that the apparent performance of the model had good calibration (calibration slope 0.99, 95% confidence interval (CI) 0.88 to 1.10; calibration-in-the-large 44.5 g, -18.4 to 107.3) with an observed versus expected average birth weight ratio of 1.02 (95% CI 0.97 to 1.07). The proportion of variation in birth weight explained by the model (R 2 ) was 46.9% (range 32.7-56.1% in each cohort). On internal-external cross validation, the model showed good calibration and predictive performance when validated in three cohorts with a calibration slope of 0.90 (Allen cohort), 1.04 (STORK Groruddalen cohort), and 1.07 (Rumbold cohort), calibration-in-the-large of -22.3 g (Allen cohort), -33.42 (Rumbold cohort), and 86.4 g (STORK Groruddalen cohort), and observed versus expected ratio of 0.99 (Rumbold cohort), 1.00 (Allen cohort), and 1.03 (STORK Groruddalen cohort); respective pooled estimates were 1.00 (95% CI 0.78 to 1.23; calibration slope), 9.7 g (-154.3 to 173.8; calibration-in-the-large), and 1.00 (0.94 to 1.07; observed v expected ratio). The model predictions were more accurate (smaller mean square error) in the lower end of predicted birth weight, which is important in informing clinical decision making., Conclusions: The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other countries, settings, and subgroups is required., Trial Registration: PROSPERO CRD42019135045., Competing Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Institute for Health and Care Research Health Technology Assessment UK programme for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Improved Pregnancy Outcomes via Early Detection (IMPROvED) is a multi-centre, European phase IIa clinical study. The primary aim of IMPROvED is to enable the assessment and refinement of innovative prototype preeclampsia risk assessment tests based on emerging biomarker technologies. Here we describe IMPROvED's profile and invite researchers to collaborate., Methods: A total of 4,038 low-risk nulliparous singleton pregnancies were recruited from maternity units in Ireland (N=1,501), United Kingdom (N=1,108), The Netherlands (N=810), and Sweden (N=619) between November 2013 to August 2017. Participants were interviewed by a research midwife at ~11 weeks (optional visit), ~15 weeks, ~20 weeks, ~34 weeks' gestation (optional visit), and postpartum (within 72-hours following delivery)., Findings to Date: Clinical data included information on maternal sociodemographic, medical history, and lifestyle factors collected at ~15 weeks' gestation, and maternal measurements, collected at each study visit. Biobank samples included blood, urine, and hair collected at each study visit throughout pregnancy in all units plus umbilical cord/blood samples collected at birth in Ireland and Sweden. A total of 74.0% (N=2,922) had an uncomplicated pregnancy, 3.1% (N=122) developed preeclampsia, 3.6% (N=143) had a spontaneous preterm birth, and 10.5% (N=416) had a small for gestational age baby. We evaluated a panel of metabolite biomarkers and a panel of protein biomarkers at 15 weeks and 20 weeks' gestation for preeclampsia risk assessment. Their translation into tests with clinical application, as conducted by commercial entities, was hampered by technical issues and changes in test requirements. Work on the panel of proteins was abandoned, while work on the use of metabolite biomarkers for preeclampsia risk assessment is ongoing., Future Plans: In accordance with the original goals of the IMPROvED study, the data and biobank are now available for international collaboration to conduct high quality research into the cause and prevention of adverse pregnancy outcomes., Competing Interests: Competing interests: RT is an employee of Metabolomic Diagnostics. RT is a named inventor on several patent applications regarding the use of biomarkers to predict preeclampsia risk; the associated rights are assigned to Metabolomic Diagnostics. PNB and LCK are minority shareholders in Metabolomic Diagnostics, which seeks to develop predictive tests for major pregnancy complications. All other authors have no conflicts of interest to disclose, including financial interest., (Copyright: © 2024 Maher GM et al.)

Ergothioneine, an antioxidant nutraceutical mainly at present derived from the dietary intake of mushrooms, has been suggested as a preventive for pre-eclampsia (PE). We analysed early pregnancy samples from a cohort of 432 first time mothers as part of the Screening for Endpoints in Pregnancy (SCOPE, European branch) project to determine the concentration of ergothioneine in their plasma. There was a weak association between the ergothioneine levels and maternal age but none for BMI. Of these 432 women, 97 went on to develop pre-term (23) or term (74) PE. If a threshold was set at the 90th percentile of the reference range in the control population (≥462 ng/ml), only one of these 97 women (1%) developed PE, versus 96/397 (24.2%) whose ergothioneine level was below this threshold. One possible interpretation of these findings, consistent with previous experiments in a reduced uterine perfusion model in rats, is that ergothioneine may indeed prove protective against PE in humans. An intervention study of some kind now seems warranted., (© 2023 The Author(s).)

Background: Fetal growth restriction (FGR) is a condition of poor growth of the fetus in utero. One of the causes of FGR is placental insufficiency. Severe early-onset FGR at < 32 weeks of gestation occurs in an estimated 0.4% of pregnancies. This extreme phenotype is associated with a high risk of fetal death, neonatal mortality, and neonatal morbidity. Currently, there is no causal treatment, and management is focused on indicated preterm birth to prevent fetal death. Interest has risen in interventions that aim to improve placental function by administration of pharmacological agents affecting the nitric oxide pathway causing vasodilatation., Objectives: The objective of this systematic review and aggregate data meta-analysis is to assess the beneficial and harmful effects of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or different drugs affecting this pathway against each other, in pregnant women with severe early-onset FGR., Search Methods: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 July 2022), and reference lists of retrieved studies., Selection Criteria: We considered all randomised controlled comparisons of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or another drug affecting this pathway in pregnant women with severe early-onset FGR of placental origin, for inclusion in this review., Data Collection and Analysis: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis., Main Results: We included a total of eight studies (679 women) in this review, all of which contributed to the data and analysis. The identified studies report on five different comparisons: sildenafil compared with placebo or no therapy, tadalafil compared with placebo or no therapy, L-arginine compared with placebo or no therapy, nitroglycerin compared with placebo or no therapy and sildenafil compared with nitroglycerin. The risk of bias of included studies was judged as low or unclear. In two studies the intervention was not blinded. The certainty of evidence for our primary outcomes was judged as moderate for the intervention sildenafil and low for tadalafil and nitroglycerine (due to low number of participants and low number of events). For the intervention L-arginine, our primary outcomes were not reported. Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women) Five studies (Canada, Australia and New Zealand, the Netherlands, the UK and Brazil) involving 516 pregnant women with FGR were included. We assessed the certainty of the evidence as moderate. Compared with placebo or no therapy, sildenafil probably has little or no effect on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.80 to 1.27, 5 studies, 516 women); may reduce fetal mortality (RR 0.82, 95% CI 0.60 to 1.12, 5 studies, 516 women), and increase neonatal mortality (RR 1.45, 95% CI 0.90 to 2.33, 5 studies, 397 women), although the results are uncertain for fetal and neonatal mortality as 95% confidence intervals are wide crossing the line of no effect. Tadalafil compared with placebo or no therapy (1 study, 87 women) One study (Japan) involving 87 pregnant women with FGR was included. We assessed the certainty of the evidence as low. Compared with placebo or no therapy, tadalafil may have little or no effect on all-cause mortality (risk ratio 0.20, 95% CI 0.02 to 1.60, one study, 87 women); fetal mortality (RR 0.11, 95% CI 0.01 to 1.96, one study, 87 women); and neonatal mortality (RR 0.89, 95% CI 0.06 to 13.70, one study, 83 women). L-Arginine compared with placebo or no therapy (1 study, 43 women) One study (France) involving 43 pregnant women with FGR was included. This study did not assess our primary outcomes. Nitroglycerin compared to placebo or no therapy (1 studies, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. Sildenafil citrate compared to nitroglycerin (1 study, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups., Authors' Conclusions: Interventions affecting the nitric oxide pathway probably do not seem to influence all-cause (fetal and neonatal) mortality in pregnant women carrying a baby with FGR, although more evidence is needed. The certainty of this evidence is moderate for sildenafil and low for tadalafil and nitroglycerin. For sildenafil a fair amount of data are available from randomised clinical trials, but with low numbers of participants. Therefore, the certainty of evidence is moderate. For the other interventions investigated in this review there are insufficient data, meaning we do not know whether these interventions improve perinatal and maternal outcomes in pregnant women with FGR., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment., (© 2021. The Author(s).)

Objective: Examine the association between alcohol consumption before and during pregnancy and neurodevelopmental outcomes in the offspring at two and five years., Study Design: Retrospective analysis of a prospective longitudinal cohort; SCOPE-BASELINE. Data on pre-conception and prenatal alcohol consumption were obtained at 15 weeks' gestation and categorised as abstinent, occasional-low (1-7units/week) and moderate-heavy (≥8units/week). Binge drinking was defined as ≥6 units/session. Outcome measures (Child Behaviour Checklist and Kaufman Brief Intelligence Test) were obtained at two and five years. Linear regression examined an alcohol consumption and Child Behaviour Checklist and Kaufman Brief Intelligence Test relationship, adjusting for several potential confounders., Results: Data on alcohol consumption was available for 1,507 women. Adjusted linear regression suggested few associations: pre-pregnancy occasional-low alcohol consumption was associated with lower log externalizing Child Behaviour Checklist scores (-0.264, 95% CI: -0.009, -0.520), while pre-pregnancy moderate-high levels of alcohol consumption was associated with lower Kaufman Brief Intelligence Test verbal standard scores (-0.034, 95% CI: -0.001, -0.068) and composite IQ scores (-0.028, 95% CI: -0.056, -0.0004) at five-years. In the first trimester, moderate-high levels of alcohol consumption was associated with lower internalizing Child Behaviour Checklist scores at two-years (-0.252, 95% CI: -0.074, -0.430). No significant associations were observed between number of binge episodes pre-pregnancy or binge drinking in the first trimester and Child Behaviour Checklist or Kaufman Brief Intelligence Test., Conclusions: We did not find strong evidence of associations between pre-pregnancy and early pregnancy maternal alcohol consumption and adverse neurodevelopmental outcomes at age two and five years overall. Further research examining alcohol consumption (including binge drinking) beyond 15 weeks' gestation and subsequent neurodevelopmental outcomes is needed to examine the potential effect of alcohol consumption in later pregnancy., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Preeclampsia causes substantial maternal and perinatal morbidity and mortality and significant societal economic impact. Effective screening would facilitate timely and appropriate prevention and management of preeclampsia., Objectives: To develop an early cost-effectiveness analysis to assess both costs and health outcomes of a new screening test for preeclampsia from a healthcare payer perspective, in the United Kingdom (UK), Ireland, the Netherlands and Sweden., Methods: A decision tree over a 9-month time horizon was developed to explore the cost-effectiveness of the new screening test for preeclampsia compared to the current screening strategy. The new test strategy is being developed so that it can stratify healthy low risk nulliparous women early in pregnancy to either a high-risk group with a risk of 1 in 6 or more of developing preeclampsia, or a low-risk group with a risk of 1 in 100 or less. The model simulated 25 plausible scenarios in a hypothetical cohort of 100,000 pregnant women, in which the sensitivity and specificity of the new test were varied to set a benchmark for the minimum test performance that is needed for the test to become cost-effective. The input parameters and costs were mainly derived from published literature. The main outcome was incremental costs per preeclampsia case averted, expressed as an incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty., Results: Base case results showed that the new test strategy would be more effective and less costly compared to the current situation in the UK. In the Netherlands, the majority of scenarios would be cost-effective from a threshold of €50,000 per preeclampsia case averted, while in Ireland and Sweden, the vast majority of scenarios would be considered cost-effective only when a threshold of €100,000 was used. In the best case analyses, ICERs were more favourable in all four participating countries. Aspirin effectiveness, prevalence of preeclampsia, accuracy of the new screening test and cost of regular antenatal care were identified as driving factors for the cost-effectiveness of screening for preeclampsia., Conclusion: The results indicate that the new screening test for preeclampsia has potential to be cost-effective. Further studies based on proven accuracy of the test will confirm whether the new screening test is a cost-effective additional option to the current situation., Competing Interests: NZ performed the major part of this project as an PhD researcher at the University of Groningen. ADIvA and RT report grants from 7th Framework Programme of the European Union, during the conduct of the study. PNB and LCK are minority shareholders in Metabolomic Diagnostics, a company that seeks to develop screening tests for preeclampsia based on analyses of metabolites.; RT is employee of Metabolomic Diagnostics, outside the submitted work. MJP reports grants and personal fees from various pharmaceutical industries, all outside the submitted work. MJP holds stocks in Health Ecore and Pharmacoeconomics Advice Groningen (PAG Ltd) and is advisor to Asc Academics, all pharmacoeconomic consultancy companies. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

All units managing hypertensive pregnant women should maintain and review uniform departmental management protocols and conduct regular audits of maternal & fetal outcomes. The cause(s) of pre-eclampsia and the optimal clinical management of the hypertensive disorders of pregnancy remain uncertain; therefore, we recommend that every hypertensive pregnant woman be offered an opportunity to participate in research, clinical trials and follow-up studies., (Copyright © 2021 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized human trophoblst cells) cell invasion in a Hippo-signaling-dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA (Ras homolog gene family, member A)/ROCK (Rho-associated protein kinase) induced actin polymerization. Mutation-based YAP-5SA (S61A, S109A, S127A, S164A, S381A) demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

Background: A considerable challenge for maternity care providers is recognising clinical deterioration early in pregnant women. Professional bodies recommend the use of clinical assessment protocols or evaluation tools, commonly referred to as physiological track-and-trigger systems (TTS) or early warning systems (EWS), as a means of helping maternity care providers recognise actual or potential clinical deterioration early. TTS/EWS are clinician-administered (midwife, obstetrician), bedside physiological assessment protocols, charts or tools designed to record routinely assessed clinical parameters; that is, blood pressure, temperature, heart rate, urine output and mental/neurological alertness. In general, these systems involve the application of scores or alert indicators to the observed physiological parameters based on their prespecified limits of normality. The overall system score or alert limit is then used to assist the maternity care provider identify a need to escalate care. This, in turn, may allow for earlier intervention(s) to alter the course of the emerging critical illness and ultimately reduce or avoid mortality and morbidity sequelae., Objectives: To evaluate the clinical- and cost-effectiveness of maternal physiological TTS/EWS on pregnancy, labour and birth, postpartum (up to 42 days) and neonatal outcomes., Search Methods: We searched Cochrane Pregnancy and Childbirth's Trials Register (28 May 2021), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (7 June 2021), OpenGrey, the ProQuest Dissertations and Theses database (7 June 2021), and reference lists of retrieved studies., Selection Criteria: We included randomised and quasi-randomised controlled trials (RCTs), including cluster-RCTs, comparing physiological TTS/EWS with no system or another system. Participants were women who were pregnant or had given birth within the previous 42 days, at high risk and low risk for pregnancy, labour and birth, and postpartum complications., Data Collection and Analysis: Two review authors (VS and MN) independently assessed all identified papers for inclusion and performed risk of bias assessments. Any discrepancies were resolved through discussion and consensus. Data extraction was also conducted independently by two review authors (VS and MN) and checked for accuracy. We used the summary odds ratio (OR) with 95% confidence intervals (CIs) to present the results for dichotomous data and the mean difference (MD) with 95% CI to present the results for continuous data., Main Results: We included two studies, a parallel RCT involving 700 women and a stepped-wedge cluster trial involving 536,233 women. Both studies were published in 2019, and both were conducted in low-resource settings. The interventions were the 'Saving Mothers Score' (SMS) and the CRADLE Vital Sign Alert (VSA) device, and both interventions were compared with standard care. Both studies had low or unclear risk of bias on all seven risk of bias criteria. Evidence certainty, assessed using GRADE, ranged from very low to moderate certainty, mainly due to other bias as well as inconsistency and imprecision. For women randomised to TTS/EWS compared to standard care there is probably little to no difference in maternal death (OR 0.80, 95% CI 0.30 to 2.11; 1 study, 536,233 participants; moderate-certainty evidence). Use of TTS/EWS compared to standard care may reduce total haemorrhage (OR 0.36, 95% CI 0.19 to 0.69; 1 study, 700 participants; low-certainty evidence). For women randomised to TTS/EWS compared to standard care there may be little to no difference in sepsis (OR 0.21, 95% CI 0.02 to 1.80; 1 study, 700 participants; low-certainty evidence), eclampsia (OR 1.50, 95% CI 0.74 to 3.03; 2 studies, 536,933 participants; low-certainty evidence) and HELLP (OR 0.21, 95% CI 0.01 to 4.40; 1 study, 700 participants; very low-certainty evidence), and probably little to no difference in maternal admission to the intensive care unit (ICU) (OR 0.78, 95% CI  0.53 to 1.15; 2 studies, 536,933 participants; moderate-certainty evidence). Use of TTS/EWS compared to standard care may reduce a woman's length of hospital stay (MD -1.21, 95% CI -1.78 to -0.64; 1 study, 700 participants; low-certainty evidence) but may result in little to no difference in neonatal death (OR 1.06, 95% CI 0.62 to 1.84; 1 study, 700 participants; low-certainty evidence). Cost-effectiveness measures were not measured in either of the two studies.  AUTHORS' CONCLUSIONS: Use of TTS/EWS in maternity care may be helpful in reducing some maternal outcomes such as haemorrhage and maternal length of hospital stay, possibly through early identification of clinical deterioration and escalation of care. The evidence suggests that the use of TTS/EWS compared to standard care probably results in little to no difference in maternal death and may result in little to no difference in neonatal death. Both of the included studies were conducted in low-resource settings where the use of TTS/EWS might potentially confer a different effect to TTS/EWS use in high-resource settings. Further high-quality trials in high- and middle-resource settings, as well as in discrete populations of high- and low-risk women, are required., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

It has been widely observed that adult men of all ages are at higher risk of developing serious complications from COVID-19 when compared with women. This study aimed to investigate the association of COVID-19 positivity and severity with estrogen exposure in women, in a population based matched cohort study of female users of the COVID Symptom Study application in the UK. Analyses included 152,637 women for menopausal status, 295,689 women for exogenous estrogen intake in the form of the combined oral contraceptive pill (COCP), and 151,193 menopausal women for hormone replacement therapy (HRT). Data were collected using the COVID Symptom Study in May-June 2020. Analyses investigated associations between predicted or tested COVID-19 status and menopausal status, COCP use, and HRT use, adjusting for age, smoking and BMI, with follow-up age sensitivity analysis, and validation in a subset of participants from the TwinsUK cohort. Menopausal women had higher rates of predicted COVID-19 (P = 0.003). COCP-users had lower rates of predicted COVID-19 (P = 8.03E-05), with reduction in hospital attendance (P = 0.023). Menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P = 2.22E-05) for HRT users alone. The findings support a protective effect of estrogen exposure on COVID-19, based on positive association between predicted COVID-19 with menopausal status, and negative association with COCP use. HRT use was positively associated with COVID-19, but the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential unaccounted for confounders and comorbidities., Competing Interests: Zoe Global Limited co-developed the app pro bono for non-commercial purposes. JCP and JW work for Zoe Global, and TDS is a consultant to Zoe Global. IB is Chief Data Scientist Advisor for AstraZeneca. These do not alter our adherence to PLoS ONE policies on sharing data and materials.

Background: Iron is critical to the developing brain, but fetal iron accretion is compromised by several maternal and pregnancy-related factors. Little consideration has been given to the long-term neurologic consequences of neonatal iron deficiency, especially in generally healthy, low-risk populations., Objective: We aimed to investigate the association between neonatal iron deficiency and neurologic development at 2 and 5 y of age., Design: We measured umbilical cord serum ferritin concentrations in the prospective maternal-infant Cork BASELINE (Babies after SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints) Birth Cohort. Lifestyle and clinical data were collected from 15 weeks of gestation to 5 y of age. Standardized neurologic assessments were performed at 2 y [Bayley Scales of Infant Development/Child Behavior Checklist (CBCL)] and 5 y (Kaufman Brief Intelligence Test/CBCL)., Results: Among 697 maternal-infant pairs, median (IQR) cord ferritin concentrations were 200.9 (139.0, 265.8) µg/L; 8% had neonatal iron deficiency (ferritin <76 µg/L). Using fully adjusted models, there was no association between neonatal iron deficiency and cognitive or behavioral outcomes at 2 or 5 y. We conducted an a priori sensitivity analysis in 306 high-risk children, selected using known risk factors for neonatal iron deficiency (smoking/obesity/cesarean section delivery/small-for-gestational age birth). In this high-risk subgroup, children with iron deficiency at birth (12%) had similar cognitive outcomes, but the behavioral assessments showed higher internalizing [9.0 (5.3, 12.0) compared with 5.0 (3.0, 10.0), P = 0.006; adjusted estimate (95% CI): 2.8 (0.5, 5.1), P = 0.015] and total [24.5 (15.3, 40.8) compared with 16.0 (10.0, 30.0), P = 0.009; adjusted estimate (95% CI): 6.6 (0.1, 13.1), P = 0.047] problem behavior scores at 5 y compared with those born iron sufficient., Conclusions: We have demonstrated lasting behavioral consequences of neonatal iron deficiency in high-risk children from our generally healthy, low-risk maternal-infant cohort. Although larger investigations are warranted, this study provides strong association data to suggest that interventions and strategies targeting the fetal and neonatal period should be prioritized for the prevention of iron deficiency and associated neurologic consequences., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Psychological stress affects maternal gastrointestinal (GI) permeability, leading to low-grade inflammation, which can negatively affect fetal development. We investigated a panel of circulating markers as a biological signature of this stress exposure in pregnant women with and without the stress-related GI disorder irritable bowel syndrome (IBS). Markers of GI permeability and inflammation were measured in plasma from healthy and IBS cohorts of women at 15 and 20 weeks' gestation. Biomarkers were evaluated with respect to their degree of association to levels of stress, anxiety, and depression as indicated by responses from the Perceived Stress Scale, State-Trait Anxiety Inventory, and Edinburgh Postnatal Depression Scale. High levels of stress were associated with elevations of soluble CD14, lipopolysaccharide binding protein (LBP), and tumor necrosis factor-α, while anxiety was associated with elevated concentrations of C-reactive protein (CRP) in otherwise healthy pregnancies. Prenatal depression was associated with higher levels of soluble CD14, LBP, and CRP in the healthy cohort. High levels of prenatal anxiety and depression were also associated with lower concentrations of tryptophan and kynurenine, respectively, in the IBS cohort. These markers may represent a core maternal biological signature of active prenatal stress, which can be used to inform intervention strategies via stress reduction techniques or other lifestyle approaches. Such interventions may need to be tailored to reflect underlying GI conditions, such as IBS.

Aims: Although preeclampsia (PE) has been attributed to excessive oxidative stress (OS) in the placenta, mild antioxidants failed to prevent PE in clinical trials. As mitochondria are a major source of OS, this study assessed the potential of a potent mitochondria-targeting antioxidant MitoQ in the prevention of PE. Results: Placentas from women with PE and from reduced uterine perfusion pressure (RUPP) mice demonstrated significantly higher OS, along with increased mitochondrial damage and compromised glutathione peroxidase (GPx) activities. MitoQ administration during late gestation alleviated RUPP-induced PE; whereas early-pregnancy MitoQ treatment not only exacerbated blood pressure, fetal growth restriction, and proteinuria but also reduced the labyrinth/spongiotrophoblast ratio and blood sinuses in the labyrinth. Invasion (Matrigel transwell) and migration (wound healing assay) of trophoblasts were greatly improved by 1 μ M hydrogen peroxide (H 2 O 2 ), but this improvement was abolished by MitoQ or MitoTempo. Mild OS enhanced the expression of miR-29b-3p, which regulates five genes involved in viability and mobility, in HTR8-S/Vneo cells. Innovation and Conclusions: Although the potent mitochondrial-targeting antioxidant MitoQ protects against hypertension and kidney damage induced by RUPP in mice when administered in late gestation, it exacerbates the PE-like phenotype when given in early gestation by interfering with placenta formation because mild OS is required to stimulate trophoblast proliferation, invasion, and migration. Eliminating trophoblastic OS during early pregnancy may lead to compromised placentation and a risk of diseases of placental origin. Therefore, antioxidant therapy for pregnant women should be carefully considered.

Introduction: Small for gestational age (SGA) may be associated with neonatal morbidity and mortality. Our understanding of the molecular pathways implicated is poor., Objectives: Our aim was to determine the metabolic pathways involved in the pathophysiology of SGA and examine their variation between maternal biofluid samples., Methods: Plasma (Cork) and urine (Cork, Auckland) samples were collected at 20 weeks' gestation from nulliparous low-risk pregnant women participating in the SCOPE study. Women who delivered an SGA infant (birthweight < 10th percentile) were matched to controls (uncomplicated pregnancies). Metabolomics (urine) and lipidomics (plasma) analyses were performed using ultra performance liquid chromatography-mass spectrometry. Features were ranked based on FDR adjusted p-values from empirical Bayes analysis, and significant features putatively identified., Results: Lipidomics plasma analysis revealed that 22 out of the 33 significantly altered lipids annotated were glycerophospholipids; all were detected in higher levels in SGA. Metabolomic analysis identified reduced expression of metabolites associated with detoxification (D-Glucuronic acid, Estriol-16-glucuronide), nutrient absorption and transport (Sulfolithocholic acid) pathways., Conclusions: This study suggests higher levels of glycerophospholipids, and lower levels of specific urine metabolites are implicated in the pathophysiology of SGA. Further research is needed to confirm these findings in independent samples.

Objective: To develop a dichorionic twin pregnancy specific reference range for placental growth factor (PlGF), and to compare gestation-specific placental growth factor levels in twin pregnancies later complicated by pre-eclampsia, hypertensive disorder of pregnancy or fetal growth restriction with control pregnancies., Design: Prospective observational study., Setting: Single large tertiary maternity unit in Ireland., Population or Sample: Women with a twin pregnancy., Methods: Consenting pregnant women, across a variety of gestations, had a single blood sample taken at one time-point only during their pregnancy. The plasma was initially biobanked and PlGF was measured later in batches using the point of care Triage ® PlGF test., Main Outcome Measures: Development of pre-eclampsia, hypertensive disorder of pregnancy or fetal growth restriction., Results: Placental growth factor levels in uncomplicated dichorionic twin pregnancies were significantly lower in the women who later developed pre-eclampsia than in the controls at all gestational intervals. In those that later developed any hypertensive disorder of pregnancy, median PlGF was lower only in those recruited before 24 weeks of gestation, whereas in infants with a customised birthweight below the third centile, PlGF was lower only in those sampled after 24 weeks of gestation., Conclusions: Placental growth factor levels in twin pregnancy differ significantly between those women with a pregnancy that will later be complicated by pre-eclampsia and those that will not. This difference is present many weeks before clinical signs or symptoms of disease are present. Using cross-sectional values from uncomplicated twin pregnancies, we have developed a dichorionic twin pregnancy specific reference range for PlGF., Tweetable Abstract: Placental growth factor levels in twin pregnancy differ significantly between women that will later develop pre-eclampsia and those that will not., (© 2020 John Wiley & Sons Ltd.)