Search

Lyndsay Creswell,1 Neil O’Gorman,1 Kirsten Rebecca Palmer,2 Fabricio da Silva Costa,3 Daniel Lorber Rolnik2 1Coombe Women and Infants University Hospital, Dublin, Ireland; 2Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia; 3Maternal Fetal Medicine Unit, Gold Coast University Hospital and School of Medicine and Dentistry, Griffith University, Gold Coast, Queensland, AustraliaCorrespondence: Lyndsay Creswell, Coombe Women and Infants University Hospital, Cork Street, Dublin, D08XW7X, Ireland, Tel +44 7754235257, Email lcreswell@coombe.ieAbstract: Pre-eclampsia (PE) is a complex multisystem disease of pregnancy that is becoming increasingly recognized as a state of angiogenic imbalance characterized by low concentrations of placental growth factor (PlGF) and elevated soluble fms-like tyrosine kinase (sFlt-1). PlGF is a protein highly expressed by the placenta with vasculogenic and angiogenic properties, which has a central role in spiral artery remodeling and the development of a low-resistance placental capillary network. PlGF concentrations are significantly lower in women with preterm PE, and these reduced levels have been shown to precede the clinical onset of disease. Subsequently, the clinical utility of maternal serum PlGF has been extensively studied in singleton gestations from as early as 11 to 13 weeks’ gestation, utilizing a validated multimarker prediction model, which performs superiorly to the National Institute for Health and Care Excellence (NICE) and American College of Obstetricians and Gynecologists (ACOG) guidelines in the detection of preterm PE. There is extensive research highlighting the role of PlGF-based testing utilizing commercially available assays in accelerating the diagnosis of PE in symptomatic women over 20 weeks’ gestation and predicting time-to-delivery, allowing individualized risk stratification and appropriate antenatal surveillance to be determined. “Real-world” data has shown that interpretation of PlGF-based test results can aid clinicians in improving maternal outcomes and a growing body of evidence has implied a role for sFlt-1/PlGF in the prognostication of adverse pregnancy and perinatal events. Subsequently, PlGF-based testing is increasingly being implemented into obstetric practice and is advocated by NICE. This literature review aims to provide healthcare professionals with an understanding of the role of angiogenic biomarkers in PE and discuss the evidence for PlGF-based screening and triage. Prospective studies are warranted to explore if its implementation significantly improves perinatal outcomes, explore the value of repeat PlGF testing, and its use in multiple pregnancies.Keywords: pre-eclampsia, biomarkers, PlGF, sFlt-1, screening, aspirin, prevention, prediction, pregnancy complications

As caesarean section rates around the world rise, attention has begun to turn to the impact of variations in surgical technique, particularly their effect on postoperative recovery and risk of future complications. This may have influenced the rates of niche formation observed, as single-layer closure with exclusion of endometrium had a significantly reduced niche prevalence. Conflicting evidence around optimal surgical technique is reflected in the study protocol - the single-layer closure arm was open to surgeon preference regarding endometrial inclusion due to inconclusive evidence. [Extracted from the article]

Background and Objective: Medication use is increasing to treat both pre-existing and pregnancy-related medical conditions or complications. This study aims to investigate factors associated with multiple medication use during pregnancy, as well as any increased risk of pregnancy complications for women taking multiple medications., Methods: A retrospective analysis of routinely collected medical records of singleton pregnant women was conducted in Southeast Melbourne, Australia, between 2016 and 2021. Self-reported medication use was recorded as part of routine medical care, starting from the first antenatal booking appointment and continuing for every subsequent antenatal appointment until birth. Multimorbidity was defined as having two or more medical conditions. Logistic regression was used to assess factors influencing multiple medication use (defined as taking two or more non-supplemental medications at any stage of pregnancy) and associations with pregnancy complications., Results: Of 48,502 participants, 34.9% used one medication, while 11.7% used multiple medications. Women of older age (30-34, 35-39, and ≥  40 years), higher body mass index (25.0-29.9 kg/m 2 and ≥  30 kg/m 2 ), born in Australasia and Oceania, higher socioeconomic status, and multimorbidity were more likely to use multiple medications during pregnancy. Women taking multiple medications had a higher risk of preterm and caesarean deliveries, fetal death, and neonatal admissions to intensive care. Sensitivity analyses exploring different morbidity categories produced no changes to findings., Conclusions: Medication use during pregnancy is prevalent, with many pregnant mothers taking multiple medications. Given the rising maternal age, body mass index, and morbidities in pregnancy, the use of medications during pregnancy is increasing. Such use correlates with an increased chance of adverse pregnancy outcomes. In the context of limited trials on the safety and efficacy of medications in pregnancy, timely harnessing of the information available within routine medical records for post-marketing surveillance is important., (© 2024. The Author(s).)

Importance: Transplant recipients experience high rates of adverse pregnancy outcomes; however, contemporary estimates of the association between solid organ transplantation and adverse pregnancy outcomes are lacking., Objective: To evaluate the association between solid organ transplantation and adverse pregnancy outcomes and to quantify the incidence of allograft rejection and allograft loss during pregnancy., Data Sources: PubMed/MEDLINE, EMBASE and Scopus databases were searched from January 1, 2000, to June 20, 2024, and reference lists were manually reviewed., Study Selection: Cohort and case-control studies that reported at least 1 adverse pregnancy outcome in pregnant women with solid organ transplantation vs without solid organ transplant or studies that reported allograft outcomes in pregnant women with solid organ transplantation were included following independent dual review of abstracts and full-text articles., Data Extraction and Synthesis: Two investigators abstracted data and independently appraised risk of bias using the Newcastle Ottawa Scale. A random-effects model was used to calculate overall pooled estimates using the DerSimonian-Laird estimator. Reporting followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline., Main Outcomes and Measures: Primary pregnancy outcomes were preeclampsia, preterm birth (<37 weeks), and low birth weight (<2500 g). Secondary pregnancy outcomes were live birth rate, gestation, very preterm birth (<32 weeks), very low birth weight (<1500 g), and cesarean delivery. Allograft outcomes were allograft loss and rejection during pregnancy., Results: Data from 22 studies and 93 565 343 pregnancies (4786 pregnancies in solid organ transplant recipients) were included; 14 studies reported adverse pregnancy outcomes, and 13 studies provided data for allograft outcomes. Pregnancies in organ transplant recipients were associated with significantly increased risk of preeclampsia (adjusted odds ratio [aOR], 5.83 [95% CI, 3.45-9.87]; I2 = 77.4%), preterm birth (aOR, 6.65 [95% CI, 4.09-12.83]; I2 = 81.8%), and low birth weight (aOR, 6.51 [95% CI, 2.85-14.88]; I2 = 90.6%). The incidence of acute allograft rejection was 2.39% (95% CI, 1.20%-3.96%; I2 = 68.5%), and the incidence of allograft loss during pregnancy was 1.55% (95% CI, 0.05%-4.44%; I2 = 69.2%)., Conclusions and Relevance: In this systematic review and meta-analysis, pregnancies in recipients of a solid organ transplant were associated with a 4 to 6 times increased risk of preeclampsia, preterm birth, and low birth weight during pregnancy. There was a low overall risk of graft rejection or loss during pregnancy.

Not discounting the important foetal or placental contribution, the endometrium is a key determinant of pregnancy outcomes. Given the inherently linked processes of menstruation, pregnancy and parturition with the endometrium, further understanding of menstruation will help to elucidate the maternal contribution to pregnancy. Endometrial health can be assessed via menstrual history and menstrual fluid, a cyclically shed, easily and non-invasively accessible biological sample that represents the distinct, heterogeneous composition of the endometrial environment. Menstrual fluid has been applied to the study of endometriosis, unexplained infertility and early pregnancy loss; however, it is yet to be examined regarding adverse pregnancy outcomes. These adverse outcomes, including preeclampsia, foetal growth restriction (FGR), spontaneous preterm birth and perinatal death (stillbirth and neonatal death), lay on a spectrum of severity and are often attributed to placental dysfunction. The source of this placental dysfunction is largely unknown and may be due to underlying endometrial abnormalities or endometrial interactions during placentation. We present existing evidence for the endometrial contribution to adverse pregnancy outcomes and propose that a more comprehensive understanding of menstruation can provide insight into the endometrial environment, offering great potential value as a diagnostic tool to assess pregnancy risk. As yet, this concept has hardly been explored.

Background: During the COVID-19 pandemic, mitigation measures were associated with a reduction in preterm birth rates; while not clearly proven, this observation has sparked significant interest., Aim: To understand the cause of this reduction by exploring the characteristics of preterm birth cohorts., Material and Methods: We performed a retrospective cohort study where we compared women who delivered preterm in three Melbourne maternity hospitals and conceived between November 2019 and February 2020 (mitigation measures-exposed cohort) to women who delivered preterm and conceived between November 2018 and February 2019 (non-exposed cohort). We compared maternal characteristics, pregnancy complications, antenatal interventions, intrapartum care, and indications for delivery., Results: In the exposed cohort, 252/3129 women delivered preterm (8.1%), vs 298/3154 (9.4%) in the non-exposed cohort (odds ratio (OR) 0.84, 95% CI 0.70-1.00, P = 0.051). The baseline characteristic of two cohorts were comparable. Rates of spontaneous preterm labour (sPTL) without preterm pre-labour rupture of membranes (PPROM) were lower in the exposed cohort (13.1% vs 24.2%, OR 0.47, P = 0.001) while PPROM occurred more often (48.0% vs 35.6%, OR 1.67, P = 0.003). With a non-statistically significant prolongation of pregnancy in the cohort exposed to mitigation measures for both sPTL without PPROM (35.4 vs 34.9 weeks, P = 0.703) and PPROM (35.6 vs 34.9 weeks, P = 0.184). The rate of spontaneous labour after PPROM was higher in the exposed cohort compared to the non-exposed cohort (40.1% vs 24.1%, OR 2.09, P < 0.001)., Conclusion: The reduction in preterm delivery during mitigation measures may have been driven by a reduction in spontaneous labour without PPROM, which seemed to result in more PPROM later in pregnancy., (© 2024 Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: Physiological adaptations during pregnancy alter nutrient and energy metabolism. Creatine may be important for maintaining cellular energy homeostasis throughout pregnancy. However, the impact of pregnancy on endogenous and exogenous creatine availability has never been comprehensively explored., Objectives: To undertake a prospective cohort study and determine the physiological ranges of creatine and associated metabolites throughout human pregnancy., Methods: Females with a singleton low-risk pregnancy were recruited at an Australian health service. Maternal blood and urine were collected at 5-time points from 10-36 weeks of gestation, and cord blood and placental samples were collected at birth. Creatine and associated amino acids and metabolites of creatine synthesis were analyzed. Dietary data were captured to determine effects of exogenous creatine intake. Associations between creatine metabolism and neonatal growth parameters were examined., Results: Two hundred and eighty-two females were included. Maternal plasma creatine remained stable throughout pregnancy [β: -0.003 μM; 95% confidence interval (CI): -0.07, 0.07; P = 0.94], though urinary creatine declined in late gestation (β: 0.38 μM/mmol/L creatinine (CRN); 95% CI: -0.47, -0.29; P < 0.0001). Plasma guanidinoacetate (GAA; the precursor to creatine during endogenous synthesis) fell from 10-29 weeks of gestation before rising until birth (β: -0.38 μM/mmol/L CRN; 95% CI: -0.47, -0.29; P < 0.0001). Urinary GAA followed an opposing pattern (β: 2.52 μM/mmol/L CRN; 95% CI: 1.47, 3.58, P < 0.001). Animal protein intake was positively correlated with maternal plasma creatine until ∼32 weeks of gestation (β: 0.07-0.18 μM; 95% CI: 0.006, 0.25; P ≤ 0.001). There were no links between creatine and neonatal growth, but increased urinary GAA in early pregnancy was associated with a slight reduction in head circumference at birth (β: -0.01 cm; 95% CI: -0.02, -0.004; P = 0.003)., Conclusions: Although maternal plasma creatine concentrations were highly conserved, creatine metabolism appears to adjust throughout pregnancy. An ability to maintain creatine concentrations through diet and shifts in endogenous synthesis may impact fetal growth. This trial was registered at [registry name] as ACTRN12618001558213., (Copyright © 2023 American Society for Nutrition. All rights reserved.)

Introduction: Preterm birth is a leading cause of perinatal morbidity and mortality. During the COVID-19 pandemic, reduction in rates of preterm birth in women exposed to viral mitigation measures was reported by multiple studies. In addition, others and we observed a more pronounced reduction of preterm birth in women who had previously experienced a preterm birth. The aim of this pilot study is to establish the feasibility of a lifestyle intervention based on viral mitigation measures in high-risk pregnancies, with the ultimate aim to reduce the incidence of preterm birth., Methods and Analysis: One hundred pregnant women, enrolled in antenatal clinics at two tertiary maternity centres in Melbourne, Australia, who have had a previous preterm birth between 22 and 34 weeks gestation will be recruited. This is a two-arm, parallel group, open-label randomised controlled feasibility trial: 50 women will be randomised to the intervention group, where they will be requested to comply with a set of lifestyle changes (similar to the viral mitigation measures observed during the pandemic). Another 50 women will be randomised to the control group, where they will undergo standard pregnancy care. The primary outcome of this trial is feasibility, which will be assessed by measuring patient eligibility rate, recruitment rate, compliance rate and data completion rate. Secondary outcomes include incidence of preterm birth, maternal satisfaction, maternal quality of life and other pregnancy outcomes. Standard methods in statistical analysis for randomised controlled trials on an intention to treat basis will be followed., Ethics and Dissemination: This trial has been approved by the Monash Human Research Ethics Committee; approval reference number RES-22-0000-122A. Study findings will be reported and submitted to peer-reviewed journals for publication, and presentation at conferences., Trial Registration Number: ACTRN12622000753752; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2023. The Author(s).)

Creatine metabolism likely contributes to energy homeostasis in the human uterus, but whether this organ synthesizes creatine and whether creatine metabolism is adjusted throughout the menstrual cycle and with pregnancy are largely unknown. This study determined endometrial protein expression of creatine-synthesizing enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), creatine kinase (CKBB), and the creatine transporter (SLC6A8) throughout the menstrual cycle in fertile and primary infertile women. It also characterized creatine metabolism at term pregnancy, measuring aspects of creatine metabolism in myometrial and decidual tissue. In endometrial samples, AGAT, GAMT, SLC6A8, and CKBB were expressed in glandular and luminal epithelial cells. Except for SLC6A8, the other proteins were also located in stromal cells. Irrespective of fertility, AGAT, GAMT, and SLC6A8 high-intensity immunohistochemical staining was greatest in the early secretory phase of the menstrual cycle. During the proliferative phase, staining for SLC6A8 protein was greater (P = 0.01) in the primary infertile compared with the fertile group. Both layers of the term pregnant uterus contained creatine, phosphocreatine, guanidinoacetic acid, arginine, glycine, and methionine; detectable gene and protein expression of AGAT, GAMT, CKBB, and ubiquitous mitochondrial CK (uMt-CK); and gene expression of SLC6A8. The proteins AGAT, GAMT, CKBB, and SLC6A8 were uniformly distributed in the myometrium and localized to the decidual glands. In conclusion, endometrial tissue has the capacity to produce creatine and its capacity is highest around the time of fertilization and implantation. Both layers of the term pregnant uterus also contained all the enzymatic machinery and substrates of creatine metabolism., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: To compare pharmacokinetics (PK) and safety of heat-stable inhaled (IH) oxytocin with intramuscular (IM) oxytocin in women in third stage of labour (TSL), the primary endpoint being PK profiles of oxytocin IH and secondary endpoint of safety., Methods: A phase 1, randomized, cross-over study was undertaken in 2 UK and 1 Australian centres. Subjects were recruited into 2 groups: Group 1, women in TSL; Group 2, nonpregnant women of childbearing potential (Cohort A, combined oral contraception; Cohort B, nonhormonal contraception). Participants were randomized 1:1 to: Group 1, oxytocin 10 IU (17 μg) IM or oxytocin 240 IU (400 μg) IH immediately after delivery; Group 2, oxytocin 5 IU (8.5 μg) intravenously and oxytocin 240 IU (400 μg) IH at 2 separate dosing sessions., Results: Participants were recruited between 23 November 2016 to 4 March 2019. In Group 1, 17 participants were randomized; received either IH (n = 9) or IM (n = 8) oxytocin. After IH and IM administration, most plasma oxytocin concentrations were below quantification limits (2 pg/mL). In Group 2 (n = 14), oxytocin IH concentrations remained quantifiable ≤3 h postdose. Adverse events were reported in both groups, with no deaths reported: Group 1, IH n = 3 (33%) and IM n = 2 (25%); Group 2, n = 14 (100%)., Conclusion: Safety profiles of oxytocin IH and IM were similar. However, PK profiles could not be established for oxytocin IH or IM in women in TSL, despite using a highly sensitive and specific assay., (© 2023 GSK. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: During the COVID-19 pandemic, rapid integration of telehealth into antenatal care occurred to support ongoing maternity care. A programme of this scale had not been previously implemented. We evaluated whether telehealth-integrated antenatal care in an Australian public health system could achieve pregnancy outcomes comparable to those of conventional care to assess its safety and efficacy., Methods: Routinely collected data for individuals who gave birth at Monash Health (Melbourne, VIC, Australia) during a conventional care period (Jan 1, 2018, to March 22, 2020) and telehealth-integrated period (April 20, 2020, to April 25, 2021) were analysed. We included all births that occurred at 20 weeks' gestation or later or with a birthweight of at least 400 g (if duration of gestation was unknown). We excluded multiple births, births for which private antenatal care was received, and births to individuals transferred from other hospitals or who had no antenatal care. Baseline demographics, telehealth uptake, and pregnancy complications (related to pre-eclampsia, fetal growth restriction [FGR], gestational diabetes, stillbirth, neonatal intensive care [NICU] admission, and preterm birth [<37 weeks' gestation]) were compared using comparative statistics and an interrupted time-series analysis. Results were stratified by care stream, with high-risk models consisting of obstetric specialist-led care, and all other streams categorised as low-risk models. The impact of the integrated period on outcomes was also assessed with stratification by parity., Findings: 17 873 births occurred in the conventional period and 8131 in the integrated period. Compared with the conventional period, women giving birth during the integrated period were slightly older (30·63 years vs 30·88 years) and had slightly higher BMI (25·52 kg/m 2 vs 26·14 kg/m 2 ), and more Australian-born women gave birth during the integrated period (37·37% vs 39·79%). There were no significant differences in smoking status or parity between the two groups. 107 (0·08%) of 129 514 antenatal consultations in the conventional period and 34 444 (45·94%) of 74 982 in the integrated period were delivered by telehealth. No significant differences between the conventional and integrated periods were seen in median gestational age at pre-eclampsia diagnosis (low-risk models 37·4 weeks in the conventional period vs 37·1 weeks in the integrated period, difference -0·3 weeks [-0·7 to 0·1]; high-risk models 35·5 weeks vs 36·3 weeks, difference 0·3 weeks [-0·3 to 1·1]), incidence of FGR below the 3rd birthweight percentile (low-risk models 1·62% vs 1·74%, difference 0·12 percentage points [-0·26 to 0·50]; high-risk 4·04% vs 4·13%, difference 0·089 percentage points [-1·08 to 1·26]), and incidence of preterm birth (low-risk models 4·99% vs 5·01%, difference 0·02% [-0·62 to 0·66]; high-risk models 15·76% vs 14·43%, difference -1·33% [-3·42 to 0·77]). Parity did not affect these findings. Interrupted time-series analysis showed a significant reduction in induction of labour for singletons with suspected FGR among women in low-risk models during the integrated period (-0·04% change per week [95% CI -0·07 to -0·01], p=0·0040), and NICU admission declined after telehealth integration (low-risk models -0·02% change per week [-0·03 to -0·003], p=0·018; high-risk models -0·10% change per week, -0·19 to -0·001; p=0·047). No significant differences in stillbirth rates were observed. The proportion of women diagnosed with gestational diabetes was significantly higher in the integrated period compared with the conventional period for both low-risk care models (22·28% vs 25·13%, difference 2·85 percentage points [1·60 to 4·11]) and high-risk care models (28·70% vs 34·02%, difference 5·32 percentage points [2·57 to 8·07]). However overall, when compared with the conventional period, there was no significant difference in proportion of women with gestational diabetes requiring insulin therapy (low-risk models 8·08% vs 7·73%, difference -0·35 percentage points [-1·13 vs 0·44]; high-risk models 14·81% vs 15·71%, difference 0·89 percentage points [-1·23 to 3·02]), or proportion of women with gestational diabetes who gave birth to a baby with macrosomia in the integrated period (low-risk models 3·16% vs 2·33%, difference -0·83 percentage points [-1·77 to 0·12]; high-risk models 5·58% vs 4·81%, difference -0·77 percentage points [-3·06 to 1·52])., Interpretation: Telehealth-integrated antenatal care replaced around 46% of in-person consultations without compromising pregnancy outcomes. It might be associated with a reduction in labour induction for suspected FGR, particularly for women in low-risk models, without compromising FGR detection or perinatal morbidity. These findings support the ongoing use of telehealth in providing flexible antenatal care., Funding: None., Competing Interests: Declaration of interests BWM and KRP are supported by National Health and Medical Research Council Investigator grants (GNT1176437 and GNT2009765, respectively). BWM reports consultancy for ObsEva, Guerbet, and Merck, and travel support from Merck. KRP has provided consultancy for Janssen. DLR reports consultancy for Alexion Pharmaceutical, as well as conference support from the International Society of Ultrasound in Obstetrics and Gynaecology and Asia Pacific Congress. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Evidence comparing double-balloon vs single-balloon catheter for induction of labor is divided. We aim to compare the efficacy and safety of double-vs single-balloon catheters using individual participant data., Material and Methods: A search of Ovid MEDLINE, Embase, Ovid Emcare, CINAHL Plus, Scopus, and clinicaltrials.gov was conducted for randomized controlled trials published from March 2019 until April 13, 2021. Earlier trials were identified from the Cochrane Review on Mechanical Methods for Induction of Labour. Randomized controlled trials that compared double-balloon with single-balloon catheters for induction of labor in singleton gestations were eligible. Participant-level data were sought from trial investigators and an individual participant data meta-analysis was performed. The primary outcomes were rates of vaginal birth achieved, a composite measure of adverse maternal outcomes and a composite measure of adverse perinatal outcomes. We used a two-stage random-effects model. Data were analyzed from the intention-to-treat perspective., Results: Of the eight eligible randomized controlled trials, three shared individual-level data with a total of 689 participants, 344 women in the double-balloon catheter group and 345 women in the single-balloon catheter group. The difference in the rate of vaginal birth between double-balloon catheter and single-balloon catheter was not statistically significant (relative risk [RR] 0.93, 95% confidence interval [CI] 0.86-1.00, p = 0.050; I 2 0%; moderate-certainty evidence). Both perinatal outcomes (RR 0.81, 95% CI 0.54-1.21, p = 0.691; I 2 0%; moderate-certainty evidence) and maternal composite outcomes (RR 0.65, 95% CI 0.15-2.87, p = 0.571; I 2 55.46%; low-certainty evidence) were not significantly different between the two groups., Conclusions: Single-balloon catheter is at least comparable to double-balloon catheter in terms of vaginal birth rate and maternal and perinatal safety outcomes., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Excess inflammation and oxidative stress are common themes in many pathologies of pregnancy including preeclampsia and more recently severe COVID-19. The risk of preeclampsia increases following maternal infection with COVID-19, potentially relating to significant overlap in pathophysiology with endothelial, vascular and immunological dysfunction common to both. Identifying a therapy which addresses these injurious processes and stabilises the endothelial and vascular maternal system would help address the significant global burden of maternal and neonatal morbidity and mortality they cause. Sulforaphane is a naturally occurring phytonutrient found most densely within cruciferous vegetables. It has anti-inflammatory, antioxidant and immune modulating properties via upregulation of phase-II detoxification enzymes. This review will cover the common pathways shared by COVID-19 and preeclampsia and offer a potential therapeutic target via nuclear factor erythroid 2-related factor upregulation in the form of sulforaphane., Competing Interests: Declaration of competing interest All authors disclose no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Since its discovery in late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been estimated to be responsible for at least 769.3 million infections and over 6.95 million deaths. Despite significant global vaccination efforts, there are limited therapies that are considered safe and effective for use in the management of COVID-19 during pregnancy despite the common knowledge that pregnant patients have a much higher risk of adverse outcomes. A bioactive compound found in broccoli sprout-sulforaphane-is a potent inducer of phase-II detoxification enzymes promoting a series of potentially beneficial effects notably as an antioxidant, anti-inflammatory, and anti-viral. A pilot, double-blinded, placebo-controlled randomised trial is to be conducted in Melbourne, Australia, across both public and private hospital sectors. We will assess a commercially available broccoli sprout extract in pregnant women between 20 +0 and 36 +0 weeks gestation with SARS-CoV-2 infection to investigate (i) the duration of COVID-19 associated symptoms, (ii) maternal and neonatal outcomes, and (iii) biomarkers of infection and inflammation. We plan to enrol 60 outpatient women with COVID-19 irrespective of vaccination status diagnosed by PCR swab or RAT (rapid antigen test) within five days and randomised to 14 days of oral broccoli sprout extract (42 mg of sulforaphane daily) or identical microcrystalline cellulose placebo. The primary outcome of this pilot trial will be to assess the feasibility of conducting a larger trial investigating the duration (days) of COVID-19-associated symptoms using a broccoli sprout supplement for COVID-19-affected pregnancies. Pregnant patients remain an at-risk group for severe disease following infection with SARS-CoV-2 and currently unclear consequences for the offspring. Therefore, this study will assess feasibility of using a broccoli sprout supplement, whilst providing important safety data for the use of sulforaphane in pregnancy.

Background: Following the development of the Royal Australian College of Obstetricians and Gynaecologists Intrapartum Fetal Surveillance Guideline in 2003, an education program was developed to support guideline implementation and clinical practice. It was intended that improved clinician knowledge, particularly of cardiotocography, would reduce rates of intrapartum fetal morbidity and mortality. The program contains a multiple-choice assessment, designed to assess fetal surveillance knowledge and the application of that knowledge. We used the results of this assessment over time to evaluate the impact of the education program on clinicians' fetal surveillance knowledge and interpretive skills, in the immediate and longer-term. Methods: We undertook a retrospective analysis of the assessment results for all participants in the Fetal Surveillance Education Program, between 2004 and 2018. Classical Test Theory and Rasch Item Response Theory analysis were used to evaluate the statistical reliability and quality of the assessment, and the measurement invariance or stability of the assessments over time. Clinicians' assessment scores were then reviewed by craft group and previous exposure to the program. Results: The results from 64,430, broadly similar assessments, showed that participation in the education program was associated with an immediate improvement in clinician performance in the assessment. Performance improvement was sustained for up to 18 months following participation in the program and recurrent participation was associated with progressive improvements. These trends were observed for all craft groups (consultant obstetricians, doctors in training, general practitioners, midwives, student midwives). Conclusions: These findings suggest that the Fetal Surveillance Education Program has improved clinician knowledge and the associated cognitive skills over time. The stable difficulty of the assessment tool means any improvement in clinician's results, with ongoing exposure to the program, can be reliably assessed and demonstrated. Importantly this holds true for all craft groups involved in intrapartum care and the interpretation of cardiotocography., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Beaves M et al.)

Introduction: Current research aimed at understanding and preventing stillbirth focuses almost exclusively on the role of the placenta. The underlying origins of poor placental function leading to stillbirth, however, remain poorly understood. There is evidence demonstrating that the endometrial environment in which the embryo implants impacts not only the establishment of pregnancy but also the development of some pregnancy outcomes. Menstrual fluid has recently been applied to the study of menstrual disorders such as heavy menstrual bleeding or endometriosis, however, it has great potential in the study of adverse pregnancy outcomes. This study aims to identify differences in menstrual fluid and menstrual cycle characteristics of women who have experienced preterm stillbirth and other associated adverse pregnancy outcomes, compared with those who have not. The association between menstrual fluid composition and menstrual cycle characteristics will also be determined., Methods and Analysis: This is a case-control study of women who have experienced a late miscarriage, spontaneous preterm birth or preterm stillbirth or a pregnancy complicated by placental insufficiency (fetal growth restriction or pre-eclampsia), compared with those who have had a healthy term birth. Cases will be matched for maternal age, body mass index and gravidity. Participants will not currently be on hormonal therapy. Women will be provided with a menstrual cup and will collect their sample on day 2 of menstruation. Primary exposure measures include morphological and functional differences in decidualisation of the endometrium (cell types, immune cell subpopulations and protein composition secreted from the decidualised endometrium). Women will complete a menstrual history survey to capture menstrual cycle length, regularity, level of pain and heaviness of flow., Ethics and Dissemination: Ethics approval was obtained from Monash University Human Research Ethics Committee (27900) on 14/07/2021 and will be conducted in accordance with these conditions. Findings from this study will be disseminated through peer-reviewed publications and conference presentations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Multiple studies have suggested a likely association between breech presentation and assisted reproductive technology (ART) for conception. The aims were to determine whether conception via in vitro fertilisation (IVF) and ovulation induction (OI) is associated with fetal malpresentation at birth and to ascertain what mediating factors most significantly contribute to fetal malpresentation., Methods: This whole-population-based cohort study included 355 990 singleton pregnancies born in Queensland, Australia, between July 2012 and July 2018. Multinomial logistic regression models estimated the adjusted odds of breech, transverse/shoulder and face/brow malpresentations in pregnancies conceived via spontaneous conception, OI (OI group) and IVF with or without intracytoplasmic sperm injection (ART group)., Results: After adjustment for potential confounding factors, breech presentation occurred approximately 20% more often in singleton pregnancies conceived via both ART (adjusted odds ratio: 1.20, 95% confidence interval: 1.10-1.30, P < 0.001) and OI (1.21, 95% confidence interval: 1.04-1.39, P < 0.05). No significant associations were observed between the three modes of conception and transverse/shoulder or face/brow presentations. Low birthweight was found to be the most significant mediating factor for breech presentation in pregnancies conceived via ART and OI., Conclusions: Similar levels of increased odds of breech presentation are present in pregnancies conceived via OI and ART, suggesting a shared underlying mechanism for the aetiology of breech presentation. For women who are considering or have conceived via these methods, counselling with respect to this increased risk is recommended., (© 2023 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Activin A is a two-subunit protein belonging to the transforming growth factor β superfamily. First discovered almost three decades ago, it has since been implicated in diverse physiological roles, ranging from wound repair to reproduction. After 30 years of research, altered activin A levels are now understood to be associated with the development of various diseases, making activin A a potential therapeutic target. In pregnancy, the placenta and fetal membranes are major producers of activin A, with significantly enhanced serum concentrations now recognised as a contributor to numerous gestational disorders. Evidence now suggests that circulating levels of activin A may be clinically relevant in the early detection of pregnancy complications, including miscarriage and preeclampsia. This review aims to summarise our current understanding of activin A as a potential diagnostic marker in common pregnancy pathologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways., (© 2023. The Author(s).)

Background: Mechanical methods were the first methods developed to ripen the cervix and induce labour. During recent decades they have been substituted by pharmacological methods. Potential advantages of mechanical methods, compared with pharmacological methods may include reduction in side effects that could improve neonatal outcomes. This is an update of a review first published in 2001, last updated in 2012., Objectives: To determine the effectiveness and safety of mechanical methods for third trimester (> 24 weeks' gestation) induction of labour in comparison with prostaglandin E2 (PGE2) (vaginal and intracervical), low-dose misoprostol (oral and vaginal), amniotomy or oxytocin., Search Methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies (9 January 2018). We updated the search in March 2019 and added the search results to the awaiting classification section of the review., Selection Criteria: Clinical trials comparing mechanical methods used for third trimester cervical ripening or labour induction with pharmacological methods. Mechanical methods include: (1) the introduction of a catheter through the cervix into the extra-amniotic space with balloon insufflation; (2) introduction of laminaria tents, or their synthetic equivalent (Dilapan), into the cervical canal; (3) use of a catheter to inject fluid into the extra-amniotic space (EASI). This review includes the following comparisons: (1) specific mechanical methods (balloon catheter, laminaria tents or EASI) compared with prostaglandins (different types, different routes) or with oxytocin; (2) single balloon compared to a double balloon; (3) addition of prostaglandins or oxytocin to mechanical methods compared with prostaglandins or oxytocin alone., Data Collection and Analysis: Two review authors independently assessed trials for inclusion and assessed risk of bias. Two review authors independently extracted data and assessed the quality of the evidence using the GRADE approach., Main Results: This review includes a total of 112 trials, with 104 studies contributing data (22,055 women; 21 comparisons). Risk of bias of trials varied. Overall, the evidence was graded from very-low to moderate quality. All evidence was downgraded for lack of blinding and, for many comparisons, the effect estimates were too imprecise to make a valid judgement.   Balloon versus vaginal PGE2: there may be little or no difference in vaginal deliveries not achieved within 24 hours (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.82 to 1.26; 7 studies; 1685 women; low-quality evidence) and there probably is little or no difference in caesarean sections (RR 1.00, 95% CI 0.92 to 1.09; 28 studies; 6619 women; moderate-quality evidence) between induction of labour with a balloon catheter and vaginal PGE2. A balloon catheter probably reduces the risk of uterine hyperstimulation with fetal heart rate (FHR) changes (RR 0.35, 95% CI 0.18 to 0.67; 6 studies; 1966 women; moderate-quality evidence), serious neonatal morbidity or perinatal death (RR 0.48, 95% CI 0.25 to 0.93; 8 studies; 2757 women; moderate-quality evidence) and may slightly reduce the risk of aneonatal intensive care unit (NICU) admission (RR 0.82, 95% CI 0.65 to 1.04; 3647 women; 12 studies; low-quality evidence). It is uncertain whether there is a difference in serious maternal morbidity or death (RR 0.20, 95% CI 0.01 to 4.12; 4 studies; 1481 women) or five-minute Apgar score < 7 (RR 0.74, 95% CI 0.49 to 1.14; 4271 women; 14 studies) because the quality of the evidence was found to be very low and low, respectively. Balloon versus low-dose vaginal misoprostol: it is uncertain whether there is a difference in vaginal deliveries not achieved within 24 hours between induction of labour with a balloon catheter and vaginal misoprostol (RR 1.09, 95% CI 0.85 to 1.39; 340 women; 2 studies; low-quality evidence). A balloon catheter probably reduces the risk of uterine hyperstimulation with FHR changes (RR 0.39, 95% CI 0.18 to 0.85; 1322 women; 8 studies; moderate-quality evidence) but may increase the risk of a caesarean section (RR 1.28, 95% CI 1.02 to 1.60; 1756 women; 12 studies; low-quality evidence). It is uncertain whether there is a difference in serious neonatal morbidity or perinatal death (RR 0.58, 95% CI 0.12 to 2.66; 381 women; 3 studies), serious maternal morbidity or death (no events; 4 studies, 464 women), both very low-quality evidence, and five-minute Apgar score < 7 (RR 1.00, 95% CI 0.50 to 1.97; 941 women; 7 studies) and NICU admissions (RR 1.00, 95% CI 0.61 to 1.63; 1302 women; 9 studies) both low-quality evidence. Balloon versus low-dose oral misoprostol: a balloon catheter probably increases the risk of a vaginal delivery not achieved within 24 hours (RR 1.28, 95% CI 1.13 to 1.46; 782 women, 2 studies, and probably slightly increases the risk of a caesarean section (RR 1.17, 95% CI 1.04 to 1.32; 3178 women; 7 studies; both moderate-quality evidence) when compared to oral misoprostol. It is uncertain whether there is a difference in uterine hyperstimulation with FHR changes (RR 0.81, 95% CI 0.48 to 1.38; 2033 women; 2 studies), serious neonatal morbidity or perinatal death (RR 1.11, 95% CI 0.60 to 2.06; 2627 women; 3 studies), both low-quality evidence, serious maternal morbidity or death (RR 0.50, 95% CI 0.05 to 5.52; 2627 women; 3 studies), very low-quality evidence, five-minute Apgar scores < 7 (RR 0.71, 95% CI 0.38 to 1.32; 2693 women; 4 studies) and NICU admissions (RR 0.82, 95% CI 0.58 to 1.17; 2873 women; 5 studies) both low-quality evidence., Authors' Conclusions: Low- to moderate-quality evidence shows mechanical induction with a balloon is probably as effective as induction of labour with vaginal PGE2. However, a balloon seems to have a more favourable safety profile. More research on this comparison does not seem warranted. Moderate-quality evidence shows a balloon catheter may be slightly less effective as oral misoprostol, but it remains unclear if there is a difference in safety outcomes for the neonate. When compared to low-dose vaginal misoprostol, low-quality evidence shows a balloon may be less effective, but probably has a better safety profile. Future research could be focused more on safety aspects for the neonate and maternal satisfaction., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: School readiness includes cognitive, socio-emotional, language and physical growth and development domains which share strong associations with life-course opportunities. Children with cerebral palsy (CP) are at increased risk of poor school readiness compared with their typically developing peers. Recently, earlier diagnosis of CP has allowed interventions to commence sooner, harnessing neuroplasticity. First, we hypothesise that early referral to intervention for children at-risk of CP will lead to improved school readiness at 4-6 years relative to placebo or care as usual. Second, we hypothesise that receipt of early diagnosis and early intervention will lead to cost-savings in the form of reduced healthcare utilisation., Methods and Analysis: Infants identified as at-risk of CP ≤6 months corrected age (n=425) recruited to four randomised trials of neuroprotectants (n=1), early neurorehabilitation (n=2) or early parenting support (n=1) will be re-recruited to one overarching follow-up study at age 4-6 years 3 months. A comprehensive battery of standardised assessments and questionnaires will be administered to assess all domains of school readiness and associated risk factors. Participants will be compared with a historical control group of children (n=245) who were diagnosed with CP in their second year of life. Mixed-effects regression models will be used to compare school readiness outcomes between those referred for early intervention versus placebo/care-as-usual. We will also compare health-resource use associated with early diagnosis and intervention versus later diagnosis and intervention., Ethics and Dissemination: The Children's Health Queensland Hospital and Health Service, The University of Queensland, University of Sydney, Monash University and Curtin University Human Research Ethics Committees have approved this study. Informed consent will be sought from the parent or legal guardian of every child invited to participate. Results will be disseminated in peer-reviewed journals, scientific conferences and professional organisations, and to people with lived experience of CP and their families., Trial Registration Number: ACTRN12621001253897., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Infection during pregnancy can increase the risk of neurodevelopmental disorders in offspring. The impact of maternal SARS-CoV-2 infection on infant neurodevelopment is poorly understood. The maternal immune response to infection may be mimicked in rodent models of maternal immune activation which recapitulate altered neurodevelopment and behavioural disturbances in the offspring. In these models, epigenetic mechanisms, in particular DNA methylation, are one pathway through which this risk is conferred in utero to offspring. We hypothesised that in utero exposure to SARS-CoV-2 in humans may alter infant DNA methylation, particularly in genes associated with neurodevelopment. We aimed to test this hypothesis in a pilot sample of children in Victoria, Australia, who were exposed in utero to SARS-CoV-2., Methods: DNA was extracted from buccal swab specimens from (n = 4) SARS-CoV-2 in utero exposed and (n = 4) non-exposed infants and methylation status assessed across 850,000 methylation sites using an Illumina EPIC BeadChip. We also conducted an exploratory enrichment analysis using Gene Ontology annotations., Results: 1962 hypermethylated CpG sites were identified with an unadjusted p-value of 0.05, where 1133 CpGs mapped to 959 unique protein coding genes, and 716 hypomethylated CpG sites mapped to 559 unique protein coding genes in SARS-CoV-2 exposed infants compared to non-exposed. One differentially methylated position (cg06758191), located in the gene body of AFAP1 that was hypomethylated in the SARS-CoV-2 exposed cohort was significant after correction for multiple testing (FDR-adjusted p-value <0.00083). Two significant differentially methylated regions were identified; a hypomethylated intergenic region located in chromosome 6p proximal to the genes ZP57 and HLA-F (fwer <0.004), and a hypomethylated region in the promoter and body of the gene GAREM2 (fwer <0.036). Gene network enrichment analysis revealed differential methylation in genes corresponding to pathways relevant to neurodevelopment, including the ERBB pathway., Conclusion: These pilot data suggest that exposure to SARS-CoV-2 in utero differentially alters methylation of genes in pathways that play a role in human neurodevelopment., Competing Interests: The authors declare no conflicts of interest., (© 2022 Published by Elsevier Inc.)

Background: The Coronavirus disease (COVID-19) pandemic has created unprecedented acute global health challenges. However, it also presents a set of unquantified and poorly understood risks in the medium to long term, specifically, risks to children whose mothers were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Infections during pregnancy can increase the risk of atypical neurodevelopment in the offspring, but the long-term neurodevelopmental impact of in utero COVID-19 exposure is unknown. Prospective, longitudinal studies are needed to evaluate children exposed in utero to SARS-CoV2 to define this risk., Methods: We have designed a prospective, case-controlled study to investigate the long-term impacts of SARS-CoV2 exposure on children exposed in utero. Women infected with SARS-CoV-2 during pregnancy will be recruited from Monash Health, the Royal Women's Hospital and Western Health (Melbourne, Australia) and Londrina Municipal Maternity Hospital Lucilla Ballalai and PUCPR Medical Clinical (Londrina, Brazil). A control group in a 2:1 ratio (2 non-exposed: 1 exposed mother infant dyad) comprising women who gave birth in the same month of delivery, are of similar age but did not contract SARS-CoV-2 during their pregnancy will also be recruited. We aim to recruit 170 exposed and 340 non-exposed mother-infant dyads. Clinical and socio-demographic data will be collected directly from the mother and medical records. Biospecimens and clinical and epidemiological data will be collected from the mothers and offspring at multiple time points from birth through to 15 years of age using standardised sample collection, and neurological and behavioural measures., Discussion: The mapped neurodevelopmental trajectories and comparisons between SARS-CoV-2 exposed and control children will indicate the potential for an increase in atypical neurodevelopment. This has significant implications for strategic planning in the mental health and paediatrics sectors and long-term monitoring of children globally., (© 2023. The Author(s).)

Nutritional deficits or excesses affect a huge proportion of pregnant women worldwide. Maternal nutrition has a significant influence on the fetal environment and can dramatically impact fetal brain development. This paper reviews current nutritional supplements that can be used to optimise fetal neurodevelopment and prevent neurodevelopmental morbidities, including folate, iodine, vitamin B12, iron, and vitamin D. Interestingly, while correcting nutritional deficits can prevent neurodevelopmental adversity, overcorrecting them can in some cases be detrimental, so care needs to be taken when recommending supplementation in pregnancy. The potential benefits of using nutrition to prevent neurodiversity is shown by promising nutraceuticals, sulforaphane and creatine, both currently under investigation. They have the potential to promote improved neurodevelopmental outcomes through mitigation of pathological processes, including hypoxia, inflammation, and oxidative stress. Neurodevelopment is a complex process and whilst the role of micronutrients and macronutrients on the developing fetal brain is not completely understood, this review highlights the key findings thus far., Competing Interests: Author SE serves as a member of the Scientific Advisory Board on creatine in health and medicine (AlzChem LLC). The company had no oversight of the content included in this narrative review. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Heland, Fields, Ellery, Fahey and Palmer.)

Background: Induction of labour is one of the most common obstetric interventions globally. Balloon catheters and vaginal prostaglandins are widely used to ripen the cervix in labour induction. We aimed to compare the effectiveness and safety profiles of these two induction methods., Methods: We did an individual participant data meta-analysis comparing balloon catheters and vaginal prostaglandins for cervical ripening before labour induction. We systematically identified published and unpublished randomised controlled trials that completed data collection between March 19, 2019, and May 1, 2021, by searching the Cochrane Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and PubMed. Further trials done before March 19, 2019, were identified through a recent Cochrane review. Data relating to the combined use of the two methods were not included, only data from women with a viable, singleton pregnancy were analysed, and no exclusion was made based on parity or membrane status. We contacted authors of individuals trials and participant-level data were harmonised and recoded according to predefined definitions of variables. Risk of bias was assessed with the ROB2 tool. The primary outcomes were caesarean delivery, indication for caesarean delivery, a composite adverse perinatal outcome, and a composite adverse maternal outcome. We followed the intention-to-treat principle for the main analysis. The primary meta-analysis used two-stage random-effects models and the sensitivity analysis used one-stage mixed models. All models were adjusted for maternal age and parity. This meta-analysis is registered with PROSPERO (CRD42020179924)., Findings: Individual participant data were available from 12 studies with a total of 5460 participants. Balloon catheters, compared with vaginal prostaglandins, did not lead to a significantly different rate of caesarean delivery (12 trials, 5414 women; crude incidence 27·0%; adjusted OR [aOR] 1·09, 95% CI 0·95-1·24; I 2 =0%), caesarean delivery for failure to progress (11 trials, 4601 women; aOR 1·20, 95% CI 0·91-1·58; I 2 =39%), or caesarean delivery for fetal distress (10 trials, 4441 women; aOR 0·86, 95% CI 0·71-1·04; I 2 =0%). The composite adverse perinatal outcome was lower in women who were allocated to balloon catheters than in those allocated to vaginal prostaglandins (ten trials, 4452 neonates, crude incidence 13·6%; aOR 0·80, 95% CI 0·70-0·92; I 2 =0%). There was no significant difference in the composite adverse maternal outcome (ten trials, 4326 women, crude incidence 22·7%; aOR 1·02, 95% CI 0·89-1·18; I 2 =0%)., Interpretation: In induction of labour, balloon catheters and vaginal prostaglandins have comparable caesarean delivery rates and maternal safety profiles, but balloon catheters lead to fewer adverse perinatal events., Funding: Australian National Health and Medical Research Council and Monash Health Emerging Researcher Fellowship., Competing Interests: Declaration of interests BWM has received grants from the Australian National Health and Medical Research Council (NHMRC), personal fees from ObsEva, personal fees from Merck, personal fees from Guerbet, and grants from Merck, outside the submitted work. BWM was also an investigator for one of the trials included in the individual participant data meta-analysis. DLR has received fees to participate in advisory boards from Alexion and travel support and lecture fees from the International Society of Ultrasound in Obstetrics and Gynecology, unrelated to this work. KRP has received research grant funds from GlaxoSmithKline and consultancy fees from Janssen Pharmaceuticals unrelated to this work. WL has received research grant funds from the Norman Beischer Medical Research Foundation, unrelated to this work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Research indicates that soluble fms-like tyrosine kinase 1 (sFLT-1) and placental growth factor (PLGF) have diagnostic and prognostic significance for women with preeclampsia. However, sparse research has studied these biomarkers in women with preexisting comorbidities such as chronic hypertension, diabetes mellitus, systemic lupus erythematosus and chronic kidney disease. We undertook a prospective longitudinal cohort study to compare the sFLT-1: PlGF ratio between women with and without comorbidities who did and did not go on to develop preeclampsia. We found that women with comorbidities may develop preeclampsia with a milder elevation in sFLT-1: PlGF than do women without comorbidities. This has clinical and research implications., (Copyright © 2022 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Introduction: Soluble fms-like tyrosine kinase 1 (sFLT-1), a circulating anti-angiogenic factor that binds and antagonizes placental growth factor (PlGF), appears key to preeclamptic pathophysiology. Two main sFLT-1 splice variants exist: sFLT-1 e15a and sFLT-1 i13. Total sFLT-1/PlGF ratios are increasingly used clinically; we explore whether using placental-specific sFLT-1 e15a improves test performance compared with total sFLT-1 in preeclampsia diagnosis., Methods: Consent was obtained for serum sampling from 96 women with suspected preeclampsia. Total sFLT-1 and PlGF were quantified using the B.R.A.H.M.S Kryptor Compact Plus automated immunoassay platform, and sFLT-1 e15a by custom enzyme-linked immunosorbent assay. Test performance was then assessed by subsequent diagnosis., Results: Of 96 participants, 32 did not develop preeclampsia, 32 had early-onset (<34 weeks') disease and 32 had late-onset (≥34 weeks') disease. In those with preeclampsia, median sFLT-1 and sFLT-1 e15a were significantly increased (7361.0 vs 2463.0 pg/mL, and 946.6 vs 305.4 ng/mL respectively; p < 0.001 for both), and PlGF significantly reduced (43.5 vs 154.4 pg/mL; p < 0.001) compared to those without preeclampsia. Those with early-onset, compared to late-onset, preeclampsia chiefly had lower median PlGF levels (16.0 vs 57.3; p < 0.001), which contributed to higher sFLT-1/PlGF and sFLT-1 e15a/PlGF ratios (830.1 vs 86.7, and 109258.9 vs 12608.7 respectively; p < 0.001 for both)., Discussion: sFLT-1 e15a performs comparably to total sFLT-1 in women with suspected preeclampsia, however with higher translational burden. Our results support the expanding clinical use of the sFLT-1/PlGF ratio in suspected preeclampsia, particularly early-onset, to assist with disease diagnosis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate how medical comorbidities - chronic hypertension, pre-gestational or gestational diabetes and obesity - influence maternal and neonatal complications from preeclampsia., Study Design: We undertook a retrospective cohort study of women delivering in Victoria, Australia, between 2009 and 2017. We compared the likelihood of having a maternal complication before delivery or neonatal complication after birth between women with and without comorbidities. We used causal mediation analysis for neonatal outcomes to separate the effects of comorbidities and of prematurity on morbidity., Main Outcome Measures: Pregnancy complications (eclampsia; haemolysis, elevated liver enzymes, low platelets syndrome; placental abruption; stillbirth) and neonatal complications (respiratory distress syndrome; neonatal sepsis; a 5-minute APGAR < 5; neonatal intensive care unit admission)., Results: Women with comorbidities delivered at a median (interquartile range) of 37.0 (36.0-39.0) weeks gestation, earlier than women without comorbidities (38.0 (36.0-39.0) weeks, p < 0.001). Women with comorbidities were less likely than those without to suffer any pregnancy complication prior to delivery (adjusted relative risk 0.78, 95% confidence interval 0.72-0.86); however, their neonates suffered more respiratory distress syndrome (aRR 1.43, 95% CI 1.31-1.57), neonatal sepsis (aRR 1.42, 95% CI 1.17-1.72) and NICU admission (aRR 1.37, 95% CI 1.23-1.53). Earlier delivery was a major contributor to worse neonatal outcomes., Conclusions: Medical comorbidities are associated with earlier delivery among women with preeclampsia. This is associated with fewer maternal complications, but worse neonatal outcomes., (Copyright © 2021 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background Community lockdowns during the coronavirus disease 2019 (COVID-19) pandemic may influence preterm birth rates, but mechanisms are unclear. Methods We compared neonatal outcomes of preterm infants born to mothers exposed to community lockdowns in 2020 (exposed group) to those born in 2019 (control group). Main outcome studied was composite of significant neonatal morbidity or death. Results Median gestational age was 35 + 4 weeks (295 infants, exposed group) vs. 35 + 0 weeks (347 infants, control group) ( p = 0.108). The main outcome occurred in 36/295 (12.2%) infants in exposed group vs. 46/347 (13.3%) in control group ( p = 0.69). Continuous positive airway pressure (CPAP) use, jaundice requiring phototherapy, hypoglycaemia requiring treatment, early neonatal white cell and neutrophil counts were significantly reduced in the exposed group. Conclusions COVID-19 community lockdowns did not alter composite neonatal outcomes in preterm infants, but reduced rates of some common outcomes as well as early neonatal inflammatory markers.

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., Competing Interests: Competing interests: BWM reports consultancy for ObsEva and received research funding from Ferring and Merck. KRP has received consultancy fees from GSK and Janssen Pharmaceuticals. LH has received research funding from Ferring Pharmaceuticals outside the scope of this study. All other investigators do not declare any financial or competing interests for the overall study., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the effect of restriction measures implemented to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission during the coronavirus disease 2019 (COVID-19) pandemic on pregnancy duration and outcome., Methods: A before-and-after study was conducted with cohort sampling in three maternity hospitals in Melbourne, Australia, including women who were pregnant when restriction measures were in place during the COVID-19 pandemic (estimated conception date between 1 November 2019 and 29 February 2020) and women who were pregnant before the restrictions (estimated conception date between 1 November 2018 and 28 February 2019). The primary outcome was delivery before 34 weeks' gestation or stillbirth. The main secondary outcome was a composite of adverse perinatal outcomes. Pregnancy outcomes were compared between women exposed to restriction measures and unexposed controls using the χ-square test and modified Poisson regression models, and duration of pregnancy was compared between the groups using survival analysis., Results: In total, 3150 women who were exposed to restriction measures during pregnancy and 3175 unexposed controls were included. Preterm birth before 34 weeks or stillbirth occurred in 95 (3.0%) exposed pregnancies and in 130 (4.1%) controls (risk ratio (RR), 0.74 (95% CI, 0.57-0.96); P = 0.021). Preterm birth before 34 weeks occurred in 2.4% of women in the exposed group and in 3.4% of women in the control group (RR, 0.71 (95% CI, 0.53-0.95); P = 0.022), without evidence of an increase in the rate of stillbirth in the exposed group (0.7% vs 0.9%; RR, 0.83 (95% CI, 0.48-1.44); P = 0.515). Competing-risks regression analysis showed that the effect of the restriction measures on spontaneous preterm birth was stronger and started earlier (subdistribution hazard ratio (HR), 0.81 (95% CI, 0.64-1.03); P = 0.087) than the effect on medically indicated preterm birth (subdistribution HR, 0.89 (95% CI, 0.70-1.12); P = 0.305). The effect was stronger in women with a previous preterm birth (RR, 0.42 (95% CI, 0.21-0.82); P = 0.008) than in parous women without a previous preterm birth (RR, 0.93 (95% CI, 0.63-1.38); P = 0.714) (P for interaction = 0.044). Composite adverse perinatal outcome was less frequent in the exposed group than in controls (all women: 2.1% vs 2.9%; RR, 0.73 (95% CI, 0.54-0.99); P = 0.042); women with a previous preterm birth: 4.5% vs 8.4%; RR, 0.54 (95% CI, 0.25-1.18); P = 0.116)., Conclusions: Restriction measures implemented to mitigate SARS-CoV-2 transmission during the COVID-19 pandemic were associated with a reduced rate of preterm birth before 34 weeks. This reduction was mainly due to a lower rate of spontaneous prematurity. The effect was more substantial in women with a previous preterm birth and was not associated with an increased stillbirth rate. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To compare the effect of comorbidities on the phenotype and outcomes of preeclampsia. Methods: A matched retrospective cohort study of women delivering at a tertiary maternity center following a diagnosis of preeclampsia. We collected data on signs and symptoms, biochemical markers, and maternal and perinatal outcomes. Results: We studied 474 women; 158 women with and 316 without comorbidities. Compared to women without comorbidities, women with comorbidities delivered earlier. They suffered fewer maternal but more neonatal complications. Conclusion: Women with comorbidities receive earlier intervention than women without comorbidities, which may lead to fewer maternal complications but worse neonatal outcomes.

Background: Universal screening has been proposed as a strategy to identify asymptomatic individuals infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mitigate transmission., Aim: To investigate the rate of positive tests among pregnant women in Melbourne, Australia., Methods: We performed a cross-sectional prevalence study at three maternity hospitals (one tertiary referral hospital and two secondary maternities) in Melbourne, Australia. SARS-CoV-2 testing was offered to all pregnant women attending face-to-face antenatal visits and to those attending the hospital with symptoms of possible coronavirus disease, between 6th and 19th of May 2020. Testing was performed by multiplex-tandem polymerase chain reaction (PCR) on combined oropharyngeal and nasopharyngeal swabs. The primary outcome was the proportion of positive SARS-CoV-2 tests., Findings: SARS-CoV-2 testing was performed in 350 women, of whom 19 had symptoms of possible COVID-19. The median maternal age was 32 years (IQR 28-35 years), and the median gestational age at testing was 33 weeks and four days (IQR 28 weeks to 36 weeks and two days). All 350 tests returned negative results (p̂=0%, 95% CI 0-1.0%)., Conclusion: In a two-week period of low disease prevalence, the rate of asymptomatic coronavirus infection among pregnant women in Australia during the study period was negligible, reflecting low levels of community transmission., (Copyright © 2020 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.)

Background: Little evidence is available on the use of telehealth for antenatal care. In response to the COVID-19 pandemic, we developed and implemented a new antenatal care schedule integrating telehealth across all models of pregnancy care. To inform this clinical initiative, we aimed to assess the effectiveness and safety of telehealth in antenatal care., Methods: We analysed routinely collected health data on all women giving birth at Monash Health, a large health service in Victoria (Australia), using an interrupted time-series design. We assessed the impact of telehealth integration into antenatal care from March 23, 2020, across low-risk and high-risk care models. Allowing a 1-month implementation period from March 23, 2020, we compared the first 3 months of telehealth integrated care delivered between April 20 and July 26, 2020, with conventional care delivered between Jan 1, 2018, and March 22, 2020. The primary outcomes were detection and outcomes of fetal growth restriction, pre-eclampsia, and gestational diabetes. Secondary outcomes were stillbirth, neonatal intensive care unit admission, and preterm birth (birth before 37 weeks' gestation)., Findings: Between Jan 1, 2018, and March 22, 2020, 20 031 women gave birth at Monash Health during the conventional care period and 2292 women gave birth during the telehealth integrated care period. Of 20 154 antenatal consultations provided in the integrated care period, 10 731 (53%) were delivered via telehealth. Overall, compared with the conventional care period, no significant differences were identified in the integrated care period with regard to the number of babies with fetal growth restriction (birthweight below the 3rd percentile; 2% in the integrated care period vs 2% in the conventional care period, p=0·72, for low-risk care models; 5% in the integrated care period vs 5% in the conventional care period, p=0·50 for high-risk care models), number of stillbirths (1% vs 1%, p=0·79; 2% vs 2%, p=0·70), or pregnancies complicated by pre-eclampsia (3% vs 3%, p=0·70; 9% vs 7%, p=0·15), or gestational diabetes (22% vs 22%, p=0·89; 30% vs 26%, p=0·06). Interrupted time-series analysis showed a significant reduction in preterm birth among women in high-risk models (-0·68% change in incidence per week [95% CI -1·37 to -0·002]; p=0·049), but no significant differences were identified in other outcome measures for low-risk or high-risk care models after telehealth integration compared with conventional care., Interpretation: Telehealth integrated antenatal care enabled the reduction of in-person consultations by 50% without compromising pregnancy outcomes. This care model can help to minimise in-person interactions during the COVID-19 pandemic, but should also be considered in post-pandemic health-care models., Funding: None., Competing Interests: Declaration of interests BWM is a consultant for Guerbet, and has received research grants from Guerbet and Merck. KRP has received consultancy fees from Janssen. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cardiac ventricular aneurysms affect 1 in 200,000 live births. To the best of our knowledge, no reported cases of a left ventricular pseudoaneurym and in utero rupture exist to guide optimal management., Case Presentation: We present a case of fetal left ventricular rupture with a large pericardial effusion, cardiac tamponade and subsequent pseudoaneurysm formation with concerns for a poor prognosis. Interventional drainage of the pericardial effusion led to resolution of tamponade and significant improvement in fetal condition. A multidisciplinary team was utilised to plan birth to minimise risk of pseudoaneurysmal rupture and a catastrophic bleed at birth., Conclusion: For similar cases we recommend consideration of birth by caesarean section, delayed cord clamping and a prostaglandin E1 infusion, to reduce the systemic pressures on the left ventricle during transition from fetal to neonatal circulations, until definitive surgical repair. In this case, this resulted in a successful outcome.

Sulforaphane, an isothiocyanate found in cruciferous vegetables such as broccoli, shows promise as an adjuvant therapy for preeclampsia. To inform future clinical trials, we set out to determine the bioavailability of sulforaphane in non-pregnant and preeclamptic women. In six healthy female volunteers, we performed a crossover trial to compare the bioavailability of sulforaphane and metabolites afforded by an activated and non-activated broccoli extract preparation. We then undertook a dose escalation study of the activated broccoli extract in 12 women with pregnancy hypertension. In non-pregnant women, an equivalent dose of activated broccoli extract gave higher levels of sulforaphane and metabolites than a non-activated extract (p < 0.0001) and greater area under the curve (AUC) (3559 nM vs. 2172 nM, p = 0.03). Compared to non-pregnant women, in women with preeclampsia, the same dose of activated extract gave lower levels of total metabolites (p < 0.000) and AUC (3559 nM vs. 1653 nM, p = 0.007). Doubling the dose of the activated extract in women with preeclampsia doubled levels of sulforaphane and metabolites (p = 0.02) and AUC (1653 nM vs. 3333 nM, p = 0.02). In women with preeclampsia, activated broccoli extract was associated with modest decreases in diastolic blood pressure (p = 0.05) and circulating levels of sFlt-1 (p = 0.0002). A myrosinase-activated sulforaphane formulation affords better sulforaphane bioavailability than a non-activated formulation. Higher doses of sulforaphane are required to achieve likely effective doses in pregnant women than in non-pregnant women. Sulforaphane may improve endothelial function and blood pressure in women with pregnancy hypertension.

Preeclampsia is a disease specific to pregnancy characterised by new-onset hypertension with maternal organ dysfunction and/or fetal growth restriction. It remains a major cause of maternal and perinatal morbidity and mortality. For sixty years, antihypertensives have been the mainstay of treating preeclampsia and only recently have insights into the pathogenesis of the disease opened new avenues for novel therapies. Melatonin is one such option, an endogenous and safe antioxidant, that may improve the maternal condition in preeclampsia while protecting the fetus from a hostile intrauterine environment. Here we review the evidence for melatonin as a possible adjuvant therapy for preeclampsia, including in vitro evidence supporting a role for melatonin in protecting the human placenta, preclinical models, vascular studies, and clinical studies in hypertension and pregnancy.

Competing Interests: Financial Disclosure Kirsten R. Palmer reports that money was paid to her institution from GlaxoSmithKline, the Cerebral Palsy Alliance, and the National Health & Medical Research Council. Ben W. Mol reports that he is supported by a NHMRC Investigator grant (GNT1176437), and has been a consultant for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. He has received research support from Merck and Guerbet. The other authors did not report any potential conflicts of interest.

Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread "natural experiment" of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide critical new information to shape prenatal care strategies throughout (and well beyond) the pandemic., Competing Interests: Competing interests: Helga Zoega is an employee of the Centre for Big Data Research in Health, UNSW Sydney which has received funding from AbbVie Australia to conduct research unrelated to the submitted work. Andrew Morris reports grants from the Bill & Melinda Gates Foundation during the conduct of this work. Kristin Palmer reports grants from GlaxoSmithKline, grants from Cerebral Palsy Alliance, grants from Equity Trustees, outside the submitted work. Clare Whitehead reports research funding from Bill & Melinda Gates Foundation Ferring International, unrelated to the submitted work. Aziz Sheikh reports grants from Health Data Research UK. He is a member of the ICODA Executive Leadership Team and Director of the Health Data Research UK BREATHE Hub., (Copyright: © 2021 Stock SJ et al.)