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ObjectiveTo determine if the presence or absence of sonographic sliding sign preoperatively is a good predictor of the presence and type of intra-abdominal adhesions; and to determine the time taken to demonstrate this sign.DesignA prospective, observational, triple-blind study using tests of diagnostic accuracy.SettingSingle-centre tertiary health institution in north-east Nigeria.Participants67 women in the third trimester scheduled for repeat elective caesarean sections (CS) had transabdominal sonography to determine the absence or presence and degree of sliding sign. The time taken to make these decisions were noted. Surgeons blinded to the ultrasound findings graded adhesions intraoperatively and comparison between sonographic and intraoperative findings made. Women who were scheduled for emergency CS were excluded.Main outcome measuresAccuracy of preoperative ultrasound to determine no/mild, moderate and severe adhesions. Secondary outcomes were interobserver correlations and time taken to determine sliding.ResultsWhen classified as adhesion and no adhesion, the sliding sign demonstrated a sensitivity of 100.00% (CI95 85.18% to 100.00%), specificity of 100.00% (CI95 92.13% to 100.00%). In predicting presence of moderate intra-abdominal adhesions, a sensitivity of 65.0% (CI95 40.78% to 84.61%) and specificity of 82.98% (CI95 69.19% to 92.35%) was found. For predicting severe intra-abdominal adhesions, it had a sensitivity of 25.00% (CI95 0.63% to 80.59%) and specificity of 98.41 (CI95 91.47 to 99.96). Disease prevalence for mild, moderate and severe adhesions was 33.82% (CI95 22.79% to 46.32%), 29.85% (CI95 19.28% to 42.27%) and 5.97% (CI95 1.65% to 14.59%), respectively. Interobserver Cohen’s kappa coefficient and PPA were 0.58 (CI95 0.39 to 0.76) and 58.82 (CI95 52.82 to 64.82), respectively. The mean duration to determine sliding sign was 7.56±2.86 s.ConclusionThis study supports the role of transabdominal sliding sign in preoperative prediction of intra-abdominal adhesions in women with previous CS without significant increase in sonography duration. This information can encourage planning for CS by ensuring that surgeons of appropriate seniority are deployed to undertake anticipated complex operations.

ObjectivesThis systematic review examined available literature on the prognostic accuracy of Doppler ultrasound for adverse perinatal outcomes in low/middle-income countries (LMIC).DesignWe searched PubMed, Embase, Cochrane Library and Scopus from inception to April 2020.SettingObservational or interventional studies from LMICs.ParticipantsSingleton pregnancies of any risk profile.InterventionsUmbilical artery (UA), middle cerebral artery (MCA), cerebroplacental ratio (CPR), uterine artery (UtA), fetal descending aorta (FDA), ductus venosus, umbilical vein and inferior vena cava.Primary and secondary outcome measuresPerinatal death, stillbirth, neonatal death, expedited delivery for fetal distress, meconium-stained amniotic fluid, low birth weight, fetal growth restriction, admission to neonatal intensive care unit, neonatal acidosis, Apgar scores, preterm birth, fetal anaemia, respiratory distress syndrome, length of hospital stay, birth asphyxia and composite adverse perinatal outcomes (CAPO).ResultsWe identified 2825 records, and 30 (including 4977 women) from Africa (40.0%, n=12), Asia (56.7%, n=17) and South America (3.3%, n=01) were included. Many individual studies reported associations and promising predictive values of UA Doppler for various adverse perinatal outcomes mostly in high-risk pregnancies, and moderate to high predictive values of MCA, CPR and UtA Dopplers for CAPO. A few studies suggested that the MCA and FDA may be potent predictors of fetal anaemia. No randomised clinical trial (RCT) was found. Most studies were of suboptimal quality, poorly powered and characterised by wide variations in outcome classifications, the timing for the Doppler tests and study populations.ConclusionLocal evidence to guide how antenatal Doppler ultrasound should be used in LMIC is lacking. Well-designed studies, preferably RCTs, are required. Standardisation of practice and classification of perinatal outcomes across countries, following the international standards, is imperative.PROSPERO registration numberCRD42019128546

ObjectivesTo evaluate the association between the urinary 8-hydroxy-2′-deoxyguanosine (U8-OHdG) levels and the incidence of small-for-gestational age (SGA) infants and to assess the utility of U8-OHdG as a biomarker to predict the incidence of SGA infants.DesignProspective cohort study.SettingThe Japan Environment and Children’s Study.ParticipantsData of participants enrolled in the Japan Environment and Children’s Study, a nationwide birth cohort study, between 2011 and 2014 were analysed; 104 062 fetal records were analysed. Data of women with singleton pregnancies ≥22 weeks of gestation were analysed.Primary and secondary outcome measuresU8-OHdG levels were assessed using liquid chromatography-tandem mass spectrometry. Participants were categorised into the following three groups according to the quartile of the distribution of U8-OHdG: low U8-OHdG (2.95 ng/mgCre) groups. Additionally, participants in the 90th percentile for U8-OHdG levels were analysed. Odds ratios (ORs) for SGA infants (ResultsData of 80 212 participants were analysed. The adjusted ORs for SGA infants (ConclusionsElevated U8-OHdG levels were associated with an increased incidence of SGA infants. However, this parameter would not be a useful screening tool for predicting SGA infants owing to its low sensitivity and specificity.

BackgroundThe 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.MethodsMulticentre 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 disseminationEthics 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 numberACTRN12620000878976; Pre-results.

ObjectivesThe association between hypertensive disorders in pregnancy (HDP) and an increased risk of asthma in offspring remains controversial. No systematic review of this topic has been performed. The aim of this systematic review was to summarise the available evidence regarding the association between HDP and the risk of asthma in offspring.DesignSystematic review and meta-analysis.MethodsOn the basis of a prepared protocol, a systematic search of PubMed, EMBASE, the Cochrane Library and Web of Science was performed using a detailed search strategy from the database inception to 17 January 2020. Cohort, case–control and cross-sectional studies published in English reporting the diagnoses of maternal HDP and asthma in offspring were included. The Meta-analysis of Observational Studies in Epidemiology guidelines were followed throughout the study. The estimated pooled ORs of HDP and asthma in offspring were calculated from the studies, and the meta-analysis was performed using random-effects models.ResultsTen cohort studies involving a total of 6 270 430 participants were included. According to the Newcastle-Ottawa Scale, the overall methodological quality was good since 8 studies were of high quality and 2 studies were of moderate quality. After controlling for potential confounders, HDP was associated with a possible increased risk of asthma in offspring, with a pooled adjusted OR (aOR) of 1.19 (95% CI 1.12 to 1.26). The subgroup analyses according to HDP subgroups, sibling design, study quality, study location, offspring ages, singleton status, exposure assessment, outcome assessment and adjusted factors showed similar results.ConclusionsExposure to HDP may be associated with an increased risk of asthma in offspring. Further research is needed to verify the results and determine whether the observed relationship is causal.PROSPERO registration numberCRD42020148250.

Introduction The majority of women admitted with threatened preterm labour (PTL) do not delivery prematurely. While those with microbial invasion of the amniotic cavity (MIAC) represent the highest risk group, this is a condition that is not routinely ruled out since it requires amniocentesis. Identification of low-risk or high-risk cases might allow individualisation of care, that is, reducing overtreatment with corticosteroids and shorten hospital stay in low-risk women, while allowing early antibiotic therapy in those with MIAC. Benefits versus risks of amniocentesis-based predictor models of spontaneous delivery within 7 days and/or MIAC have not been evaluated. Methods and analysis This will be a Spanish randomised, multicentre clinical trial in singleton pregnancies (23.0-34.6 weeks) with PTL, conducted in 13 tertiary centres. The intervention arm will consist in the use of amniocentesis-based predictor models: if low risk, hospital discharge within 24 hours of results with no further medication will be recommended. If high risk, antibiotics will be added to standard management. The control group will be managed according to standard institutional protocols, without performing amniocentesis for this indication. The primary outcome will be total antenatal doses of corticosteroids, and secondary outcomes will be days of maternal stay and the occurrence of clinical chorioamnionitis. A cost analysis will be undertaken. To observe a reduction from 90% to 70% in corticosteroid doses, a reduction in 1 day of hospital stay (SD of 2) and a reduction from 24% to 12% of clinical chorioamnionitis, a total of 340 eligible patients randomised 1 to 1 to each study arm is required (power of 80%, with type I error alpha=0.05 and two-sided test, considering a dropout rate of 20%). Randomisation will be stratified by gestational age and centre. Ethics and dissemination Prior to receiving approval from the Ethics Committee (HCB/2020/1356) and the Spanish Agency of Medicines and Medical Devices (AEMPS) (identification number: 2020-005-202-26), the trial was registered in the European Union Drug Regulating Authorities Clinical Trials database (2020-005202-26). AEMPS approved the trial as a low-intervention trial. All participants will be required to provide written informed consent. Findings will be disseminated through workshops, peer-reviewed publications and national/international conferences. Protocol version V.4 10 May 2021., This research has received a grant from the Instituto Carlos III (PI21/00972)

IntroductionPreterm birth is one of the main problems in obstetrics, and the most important cause of neonatal mortality, morbidity and neurodevelopmental impairment. Multiple gestation is an important risk factor for preterm birth, with up to 50% delivering before 37 weeks. Progesterone has a role in maintaining pregnancy and is frequently prescribed to prevent (recurrent) preterm birth and improve pregnancy outcomes in high-risk patients. However, little is known about its long-term effects in multiple gestations. The objective of this follow-up study is to assess long-term benefits and harms of prenatal exposure to progesterone treatment in multiple gestations on child development.Methods and analysisThis is a follow-up study of a multicentre, double-blind, placebo-controlled randomised trial (AMPHIA trial, ISRCTN40512715). Between 2006 and 2009 women with a multiple gestation were randomised at 16–20 weeks of gestation to weekly injections 250 mg 17α-hydroxyprogesterone caproate or placebo, until 36 weeks of gestation or delivery. The current long-term follow-up will assess all children (n=1355) born to mothers who participated in the AMPHIA trial, at 11–14 years of age, with internationally validated questionnaires, completed by themselves, their parents and their teachers.Main outcomes are child cognition and behaviourAdditional outcomes are death (perinatal and up to age 14), gender identity, educational performance and health-related problems. We will use intention-to-treat analyses comparing experimental and placebo group. To adjust for the correlation between twins, general linear mixed-effects models will be used.Ethics and disseminationAmsterdam UMC MEC provided a waiver for the Medical Research Involving Human Subjects Act (W20_234#20.268). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders, patients and participants. This protocol is published before analysis of the results.Trial registration numberNL8933.

ObjectivesA third of pregnant women in the UK are vitamin D deficient, which may confer deleterious consequences, including an increased risk of pre-eclampsia, gestational diabetes mellitus and intrauterine growth restriction. This study aims to determine the proportion of women that met National Institute for Health and Care Excellence (NICE) standards for vitamin D supplementation in pregnancy and compare biochemical and obstetrical outcomes according to supplementation status.Design and settingThis is a single-centre cross-sectional study in an antenatal centre in Birmingham, UK. Participants received a questionnaire regarding their experiences with vitamin D supplementation during their pregnancy with their general practitioner. Serum 25-hydroxyvitamin D and bone profile results were obtained during the same appointment and obstetrical outcomes were collected retrospectively once participants had delivered.Results41.8% of participants (n=61) received written and/or verbal advice about supplementation, (NICE standards=100%). 72.6% (n=106) had one or more risk factors for vitamin D deficiency, of which 38.7% (n=41, NICE standards=100%) were asked about supplementation. Among those asked, 85.4% (n=41, NICE standards=100%) received the correct dosage. Compared with the supplementation group, the non-supplementation group had offspring that were 1.40 cm (95% CI 0.01 to 2.80, p=0.04) longer at birth; which was significant after adjusting for confounding factors. No significant differences in any biochemical parameters were observed between supplementation categories (p>0.05).ConclusionsAdherence to NICE standards was suboptimal. This may be attributed to insufficient training for general practitioners on the importance of supplementation, causing them to underestimate the consequences of gestational vitamin D deficiency. Recommendations include implementing a mandatory screening tool to identify ‘at-risk’ women and providing more clinician training to ensure that supplementation during pregnancy is standard of care.

ObjectivesKnowledge on the impact of heated tobacco product (HTP) use in pregnant women with associated maternal and neonatal risks for hypertensive disorders of pregnancy (HDP) and low birth weight (LBW) is limited. We aimed to assess the status of HTP use among pregnant women in Japan and explore the association of HTP use with HDP and LBW.DesignCross-sectional study.SettingData from the Japan ‘COVID-19 and Society’ Internet Survey study, a web-based nationwide survey.ParticipantsWe investigated 558 postdelivery and 365 currently pregnant women in October 2020.Primary and secondary outcome measuresInformation on HDP and LBW was collected from the postdelivery women’s Maternal and Child Health Handbooks (maternal and newborn records). We estimated the age-adjusted ORs and 95% CIs of ever HTP smokers for HDP and LBW and compared them with those of never HTP smokers in a logistic regression analysis.ResultsThe prevalence of ever and current HTP use were 11.7% and 2.7% in postdelivery women and 12.6% and 1.1% in currently pregnant women, respectively. Among currently pregnant women who were former combustible cigarette smokers, 4.4% (4/91) were current HTP smokers. Among postdelivery women, ever HTP smokers had a higher HDP incidence (13.8% vs 6.5%, p=0.03; age-adjusted OR=2.48, 95% CI 1.11 to 5.53) and higher LBW incidence (18.5% vs 8.9%, p=0.02; age-adjusted OR=2.36, 95% CI 1.16 to 4.87).ConclusionsIn Japan, the incidence of ever HTP use exceeded 10% among pregnant women, and HTP smoking may be associated with maternal and neonatal risks.

ObjectiveTo determine the maternal and newborn characteristics associated with high umbilical artery lactate levels at Mulago National Referral Hospital.DesignCross-sectional observational study.SettingDepartment of Obstetrics and Gynecology at a national referral hospital located in the capital of Uganda, Kampala.ParticipantsWe randomly selected 720 pregnant mothers at term who presented in labour and their newborn babies.Primary outcomeUmbilical artery lactate level.ResultsDuring the study, there were 579 vaginal deliveries (18 instrumental) and 141 caesarean sections which met the inclusion criteria. One hundred and eighty-seven neonates (187) had high arterial lactate levels. The following factors were associated with an increased likelihood of high lactate concentration: male sex (adjusted OR (aOR)=1.71; 95% CI 1.16 to 2.54; p<0.05), primigravidity (aOR=2.78; 95% CI 1.89 to 4.08; p<0.05).ConclusionAbout a fifth of the babies born in Mulago National Referral Hospital during the study period had high umbilical artery lactate. The maternal-fetal factors significantly associated with high umbilical artery lactate levels included: baby’s sex, mother’s gravidity, meconium-stained amniotic fluid and oxytocin administration during labour.

ObjectivesThe primary aim of this study was to establish the normal reference ranges of the fetal left ventricular (LV) Modified Myocardial Performance Index (Mod-MPI). A secondary aim was to evaluate the agreement between manual and automatic measurements for fetal Mod-MPI.DesignA prospective, multicentre, cross-sectional study.ParticipantsNormal singleton pregnancies.MethodsThe LV functions of normal singleton pregnancies were assessed in nine centres covering eight provinces in China using unified ultrasound protocols and settings and standardised measurements by pulsed Doppler at 20–24, 28–32 and 34–38 weeks of gestation. The isovolumetric relaxation time (IRT), isovolumetric contraction time, ejection time (ET) and Mod-MPI were measured both automatically and manually.ResultsThis cross-sectional study included 2081 fetuses, and there was a linear correlation between gestational age (GA) and Mod-MPI (0.416+0.001×GA (weeks), p2=0.013), IRT (36.201+0.162× GA (weeks), p2=0.021) and ET (171.418–0.078*GA (weeks), p2=0.002). This finding was verified using longitudinal data in a subgroup of 610 women. The agreement between the manual and automated measurements for Mod-MPI was good.ConclusionsWe constructed normal reference values of fetal LV Mod-MPI. Automatic measurement can be considered for ease of measurement in view of the good agreement between the automatic and manual values.

IntroductionPreterm birth (PTB) is the leading cause of death in children under 5 years. Preventive therapies targeted towards women with risk factors such as a prior PTB or a short cervix reduce the rate of PTB. Cervical cerclage, vaginal progesterone and a combination of the two have been used with no consensus as to whether combined treatment is more effective than any single treatment alone. The objective of this review is to determine the efficacy of combined treatment compared with cerclage alone and combined treatment compared with progesterone alone.Methods and analysisStudies will be sourced from the electronic databases Medline (Ovid), EMBASE (Ovid), PsycINFO (Ovid), Scopus, CINAHL (EBSCOhost) and Cochrane Library (Wiley) and reference lists. We will not exclude any papers due to publication date. Randomised control trials (RCTs), non-RCTs and cohort studies assessing single therapy (either progesterone or cerclage) versus combined therapy in women with a singleton pregnancy will be included. Two independent reviewers will conduct study screening (at abstract and full-text level), data extraction and risk of bias assessment with disagreements resolved by an experienced researcher. Random or fixed effects models will be used depending on data heterogeneity and data will be presented as risk ratio for dichotomous data or mean difference for continuous data with a CI of 95% used for all outcomes.Ethics and disseminationNot applicable due to nature of the study type.PROSPERO registration numberCRD42020195975.

IntroductionThe aim of the cervical ripening at home or in-hospital—prospective cohort study and process evaluation (CHOICE) study is to compare home versus in-hospital cervical ripening to determine whether home cervical ripening is safe (for the primary outcome of neonatal unit (NNU) admission), acceptable to women and cost-effective from the perspective of both women and the National Health Service (NHS).Methods and analysisWe will perform a prospective multicentre observational cohort study with an internal pilot phase. We will obtain data from electronic health records from at least 14 maternity units offering only in-hospital cervical ripening and 12 offering dinoprostone home cervical ripening. We will also conduct a cost-effectiveness analysis and a mixed methods study to evaluate processes and women/partner experiences. Our primary sample size is 8533 women with singleton pregnancies undergoing induction of labour (IOL) at 39+0 weeks’ gestation or more. To achieve this and contextualise our findings, we will collect data relating to a cohort of approximately 41 000 women undergoing IOL after 37 weeks. We will use mixed effects logistic regression for the non-inferiority comparison of NNU admission and propensity score matched adjustment to control for treatment indication bias. The economic analysis will be undertaken from the perspective of the NHS and Personal Social Services (PSS) and the pregnant woman. It will include a within-study cost-effectiveness analysis and a lifetime cost–utility analysis to account for any long-term impacts of the cervical ripening strategies. Outcomes will be reported as incremental cost per NNU admission avoided and incremental cost per quality adjusted life year gained.Research ethics approval and disseminationCHOICE has been funded and approved by the National Institute of Healthcare Research Health Technology and Assessment, and the results will be disseminated via publication in peer-reviewed journals.Trial registration numberISRCTN32652461.

ObjectivesGlobally, half of all stillbirths occur during birth. Detection of fetal distress with fetal heart rate monitoring (FHRM), followed by appropriate and timely management, might reduce fresh stillbirths and neonatal morbidity. This study aimed to investigate the barriers and facilitators for the implementation of Moyo FHRM use in Bihar state, and secondarily, the feasibility of collecting reliable obstetrical and neonatal outcome data to assess the effect of implementation.SettingCARE Bihar and the hospital management at four district hospitals (DHs) in Bihar state, each with 6500 to 15 000 deliveries a year, agreed to testing the implementation of Moyo FHRM through a process of meetings, training sessions and collecting data. At each hospital, a clinical training expert was trained to train others, while a clinical assessment facilitator collected data.MethodologyObservational notes were taken at all training sessions and meetings. Individual interviews (n=4) were conducted with clinical training experts (CTEs) on training experiences and barriers and facilitators for Moyo FHRM implementation. The CTEs recoded field notes in diaries. Descriptive analyses performed on pre-implementation and post-implementation data (n=521) assessed quality and completeness.ResultsMain barriers to implementation of Moyo FHRM were health system and cultural challenges involving (1) existing practices, (2) insufficient human resources, (3) action delays and (4) cultural and local challenges. Another barrier was insufficient involvement of doctors. Facilitators for implementation were easy use of the Moyo FHRM device and adequate training for staff.Electronic collection of obstetrical data worked well but had substantial missing data.ConclusionHealth system and cultural challenges are a major constraint to Moyo FHRM implementation in low-resource settings. Improvements at all levels of infrastructure, practices and skills will be critical in busy DHs in Bihar. Full-scale implementation needs doctor-led leadership and ownership. Obstetrical data collection for the purpose of scientific analysis needs to be improved.

ObjectivesThe secondary impacts of the COVID-19 pandemic on adverse maternal and neonatal outcomes remain unclear. In this study, we aimed to evaluate the association between the COVID-19 pandemic and the risk for adverse pregnancy outcomes.DesignWe conduced retrospective analyses on two cohorts comprising 7699 pregnant women in Beijing, China, and compared pregnancy outcomes between the pre-COVID-2019 cohort (women who delivered from 20 May 2019 to 30 November 2019) and the COVID-2019 cohort (women who delivered from 20 January 2020 to 31 July 2020). The secondary impacts of the COVID-2019 pandemic on pregnancy outcomes were assessed by using multivariate log-binomial regression models, and we used interrupted time-series (ITS) regression analysis to further control the effects of time-trends.SettingOne tertiary-level centre in Beijing, ChinaParticipants7699 pregnant women.ResultsCompared with women in the pre-COVID-19 pandemic group, pregnant women during the COVID-2019 pandemic were more likely to be of advanced age, exhibit insufficient or excessive gestational weight gain and show a family history of chronic disease (all p<0.05). After controlling for other confounding factors, the risk of premature rupture of membranes and foetal distress was increased by 11% (95% CI, 1.04 to 1.18; p0.05).ConclusionsDuring the COVID-19 pandemic, more women manifested either insufficient or excessive gestational weight gain; and the risk of premature rupture of membranes and foetal distress was also higher during the pandemic.

Introduction The majority of women admitted with threatened preterm labour (PTL) do not delivery prematurely. While those with microbial invasion of the amniotic cavity (MIAC) represent the highest risk group, this is a condition that is not routinely ruled out since it requires amniocentesis. Identification of low-risk or high-risk cases might allow individualisation of care, that is, reducing overtreatment with corticosteroids and shorten hospital stay in low-risk women, while allowing early antibiotic therapy in those with MIAC. Benefits versus risks of amniocentesis-based predictor models of spontaneous delivery within 7 days and/or MIAC have not been evaluated. Methods and analysis This will be a Spanish randomised, multicentre clinical trial in singleton pregnancies (23.0-34.6 weeks) with PTL, conducted in 13 tertiary centres. The intervention arm will consist in the use of amniocentesis-based predictor models: if low risk, hospital discharge within 24 hours of results with no further medication will be recommended. If high risk, antibiotics will be added to standard management. The control group will be managed according to standard institutional protocols, without performing amniocentesis for this indication. The primary outcome will be total antenatal doses of corticosteroids, and secondary outcomes will be days of maternal stay and the occurrence of clinical chorioamnionitis. A cost analysis will be undertaken. To observe a reduction from 90% to 70% in corticosteroid doses, a reduction in 1 day of hospital stay (SD of 2) and a reduction from 24% to 12% of clinical chorioamnionitis, a total of 340 eligible patients randomised 1 to 1 to each study arm is required (power of 80%, with type I error alpha=0.05 and two-sided test, considering a dropout rate of 20%). Randomisation will be stratified by gestational age and centre. Ethics and dissemination Prior to receiving approval from the Ethics Committee (HCB/2020/1356) and the Spanish Agency of Medicines and Medical Devices (AEMPS) (identification number: 2020-005-202-26), the trial was registered in the European Union Drug Regulating Authorities Clinical Trials database (2020-005202-26). AEMPS approved the trial as a low-intervention trial. All participants will be required to provide written informed consent. Findings will be disseminated through workshops, peer-reviewed publications and national/international conferences. Protocol version V.4 10 May 2021.

ObjectivesAfter introduction of a more proactive post-term induction practice, stillbirth rates have decreased substantially throughout the first decade of this century in Denmark. The aim was to follow up on induction and stillbirth rates in Denmark.DesignHistorical ecological study.ParticipantsWe included all delivering women in Denmark during the period 2007–2018.InterventionInduction rates from 41 weeks of gestation.Main outcome measureStillbirth rates from 41+0 weeks.ResultsOf 739 570 delivered children, 179 734 (24.3%) were born from 41+0 weeks. The proportion of deliveries after 41 weeks which were induced increased from 25.4% in 2007 to 44.4% in 2012. From 2012 to 2015, the induction rates decreased from 44.4% to 39.4%. After 2015 rates were stable.During the same period, stillbirth rates decreased from 1.30 in 2007/2008 to 0.38 per 1000 newborn in 2011/12; -54%. From 2012, however, the rates were doubled from 0.38 per 1000 in 2011/2012 to 0.74 per 1000 in 2015/2018; RR 1.97 (95% CI 1.02 to 3.81), p=0.033.Changes in the included potential confounders cannot explain neither the substantial fall in stillbirth rates from 2007/2008 to 2011/2012, nor the doubling in stillbirth rates after 41 weeks since 2012.During the whole study period, the cumulated risk of intrauterine foetal death increased from week 41+0 to 41+6 from 0.16 to 1.25 per 1000 ongoing pregnancies or 7.8 folds. Going beyond 42 weeks further increased the risk to 2.46 per 1000 ongoing pregnancies.ConclusionWe found a consistent inverse correlation between the proportion of women with induction of labour after 41 weeks of gestation and the stillbirth rates during the same period and same gestational ages. This Danish update on post-term inductions and corresponding stillbirth rates thus confirm previous findings suggesting a causal link between these two parameters.

ObjectiveTo determine the association of prenatal exposure to intimate partner violence (IPV) with birth weight as a continuous variable among term births in a Nigerian population.DesignCross-sectional study.SettingMother–child pairs recruited when their newborns were brought for BCG or other vaccines shortly after birth at the Child Welfare Clinic of Barau Dikko Teaching Hospital, Kaduna, Nigeria.Participants293 women with term birth infants.Main exposure and outcome measuresEmotional, physical and sexual IPV were measured postnatally by interview using the Conflict Tactics Scale. Birth weight in grams was the main outcome measure. Linear regression, with adjustment for covariates, was used to estimate associations between birth weight and exposure to the presence, and frequency, of IPV.ResultsSixty-seven per cent of mothers experienced at least one of the three forms of IPV during pregnancy. Relative to the 33% of women with no prenatal exposure to any form of IPV, we observed a reduction in birth weight of 94 g (95% CI: −202 to 15) for prenatal exposure to emotional IPV, 162 g (95% CI −267 to −58) for physical IPV and 139 g (95% CI −248 to −30) for sexual IPV. The combination of all three forms of IPV was associated with a 223 g reduction in birth weight (95% CI −368 to −77). Increasing occurrences of each of the three types of IPV were associated with greater reductions in birth weight. For physical IPV, relative to no exposure to any form of IPV, birth weight was lower by 112 g (95% CI −219 to −4) with 1–5 instances and 380 g (95% CI −553 to −206) for >5 instances over the pregnancy.ConclusionsMaternal exposure to IPV was associated with shifting of the birth weight distribution among term newborns. A dose–response relationship was observed between frequency of IPV and birth weight.

IntroductionReal-time continuous glucose monitoring (rt-CGM) informs users about current interstitial glucose levels and allows early detection of glycaemic excursions and timely adaptation by behavioural change or pharmacological intervention. Randomised controlled studies adequately powered to evaluate the impact of long-term application of rt-CGM systems on the reduction of adverse obstetric outcomes in women with gestational diabetes (GDM) are missing. We aim to assess differences in the proportion of large for gestational age newborns in women using rt-CGM as compared with women with self-monitored blood glucose (primary outcome). Rates of neonatal hypoglycaemia, caesarean section and shoulder dystocia are secondary outcomes. A comparison of glucose metabolism and quality of life during and after pregnancy completes the scope of this study.Methods and analysisOpen-label multicentre randomised controlled trial with two parallel groups including 372 female patients with a recent diagnosis of GDM (between 24+0 until 31+6 weeks of gestation): 186 with rt-CGM (Dexcom G6) and 186 with self-monitored blood glucose (SMBG). Women with GDM will be consecutively recruited and randomised to rt-CGM or control (SMBG) group after a run-in period of 6–8 days. The third visit will be scheduled 8–10 days later and then every 2 weeks. At every visit, glucose measurements will be evaluated and all patients will be treated according to the standard care. The control group will receive a blinded CGM for 10 days between the second and third visit and between week 36+0 and 38+6. Cord blood will be sampled immediately after delivery. 48 hours after delivery neonatal biometry and maternal glycosylated haemoglobin A1c (HbA1c) will be assessed, and between weeks 8 and 16 after delivery all patients receive a re-examination of glucose metabolism including blinded CGM for 8–10 days.Ethics and disseminationThis study received ethical approval from the main ethic committee in Vienna. Data will be presented at international conferences and published in peer-reviewed journals.Trial registration numberNCT03981328; Pre-results.

IntroductionPre-eclampsia (PE) and intrauterine growth restriction (IUGR) are two major pregnancy complications, related to chronic uteroplacental hypoperfusion. Nowadays, there is no screening or diagnostic test for uteroplacental vascularisation deficiency in pregnant women. Since 2004, 3 three-imensional power Doppler (3DPD) angiography has been used for the evaluation of uteroplacental vascularisation and three vascular indices are usually calculated: Vascularisation Index (VI), Flow Index (FI) and vascularisation-FI (VFI). A high intraobserver and interobserver reproducibility and a potential interest for placental function study were reported by our team and others.The main objective of our study is to determine differences in 3DPD indices at first trimester between pregnancies defined at their outcome as uncomplicated pregnancy, PE (mild and severe) and IUGR in nulliparous women.Methods and analysisThis is a national multicentre prospective cohort study conducted in four French maternity units. We expect to include 2200 women in a period of 36 months. The nulliparous pregnant women will be recruited during their first trimester consultation (11–13+6 gestation week (GW)).The 3DPD and uterine artery Doppler acquisition will be included in the current routine 11–13+6 GW ultrasound. Also, additional blood samples will be taken for biomarker analysis (PAPP-A and P1GF) and biological collection. Uteroplacental VIs (FI and VFI) will be measured. For each subgroup (uncomplicated pregnancy, PE and IUGR), mean values in 3DPD indices will be computed and compared using a pairwise t test with a Bonferroni correction p value adjustment.Ethics and disseminationThe study was approved by the French Ethics Committee, the Comité de Protection des Personnes SUD MEDITERRANEE IV on 13 February 2018 with reference number 17 12 03. The results of this study will be published in a peer-reviewed journal and will be presented at relevant conferences.Trial registration numberNCT03342014; Pre-results. PHRCN-16-0567.

IntroductionWomen with twin pregnancies and a short cervix are at increased risk for preterm birth (PTB). Given the burden of prematurity and its attendant risks, the quest for effective interventions in twins has been an area of considerable research. Studies investigating the effectiveness of cervical cerclage, cervical pessary and vaginal progesterone in preventing PTB have yielded conflicting results. The aim of this study is to compare the effectiveness of cervical pessary and cervical cerclage with or without vaginal progesterone to prevent PTB in women with twin pregnancies and a cervical length (CL) ≤ 28 mm.Methods and analysisThis multicentre, randomised clinical trial will be conducted at My Duc Hospital and My Duc Phu Nhuan Hospital, Vietnam. Asymptomatic women with twin pregnancies and a CL ≤28 mm, measured at 16–22 weeks’ gestation, will be randomised in a 1:1:1:1 ratio to receive a cerclage, pessary, cerclage plus progesterone or pessary plus progesterone. Primary outcome will be PTB Ethics and disseminationEthical approval was obtained from the Institutional Ethics Committee of My Duc Hospital and informed patient consent was obtained before study enrolment. Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT03863613(date of registration: 4 March 2019).

IntroductionOver 310 000 women gave birth in Australia in 2016, with approximately 80 000 births in the state of Victoria. While most of these births occur in metropolitan Melbourne and other large regional centres, a significant proportion of Victorian women birth in local rural health services. The Victorian state government recently mandated the provision of a maternal and neonatal emergency training programme, called Maternal and Newborn Emergencies (MANE), to rural and regional maternity service providers across the state. MANE aims to educate maternity and newborn care clinicians about recognising and responding to clinical deterioration in an effort to improve clinical outcomes. This paper describes the protocol for an evaluation of the MANE programme.Methods and analysisThis study will evaluate the effectiveness of MANE in relation to: clinician confidence, skills and knowledge; changes in teamwork and collaboration; and consumer experience and satisfaction, and will explore and describe any governance changes within the organisations after MANE implementation. The Kirkpatrick Evaluation Model will provide a framework for the evaluation. The participants of MANE, 27 rural and regional Victorian health services ranging in size from approximately 20 to 1000 births per year, will be invited to participate. Baseline data will be collected from maternity service staff and consumers at each health service before MANE delivery, and at four time-points post-MANE delivery. There will be four components to data collection: a survey of maternity services staff; follow-up interviews with Maternity Managers at health services 4 months after MANE delivery; consumer feedback from all health services collected through the Victorian Healthcare Experience Survey; case studies with five regional or rural health service providers.Ethics and disseminationThis evaluation has been approved by the La Trobe University Science, Health and Engineering College Human Ethics Sub-Committee. Findings will be presented to project stakeholders in a deidentified report, and disseminated through peer-reviewed publications and conference presentations.

IntroductionLabour induction in women with a previous caesarean delivery currently uses vaginal prostaglandin E2 (PGE2), which carries the risks of uterine hyperstimulation and scar rupture. We aim to compare the efficacy of mechanical labour induction using a transcervically applied Foley catheter balloon (FCB) with PGE2 in affected women attempting trial of labour after caesarean (TOLAC).Methods and analysisThis single-centre non-inferiority prospective, randomised, open, blinded-endpoint study conducted at an academic maternity unit in Singapore will recruit a total of 100 women with one previous uncomplicated caesarean section and no contraindications to vaginal delivery. Eligible consented participants with term singleton pregnancies and unfavourable cervical scores (≤5) requiring labour induction undergo stratified randomisation based on parity and are assigned either FCB (n=50) or PGE2 (n=50). Treatments are applied for up to 12 hours with serial monitoring of the mother and the fetus and serial assessment for improved cervical scores. If the cervix is still unfavourable, participants are allowed a further 12 hours’ observation for cervical ripening. Active labour is initiated by amniotomy at cervical scores of ≥6. The primary outcome is the rate of change in the cervical score, and secondary outcomes include active labour within 24 hours of induction, vaginal delivery, time-to-delivery interval and uterine hyperstimulation. All analyses will be intention-to-treat. The data generated in this trial may guide a change in practice towards mechanical labour induction if this proves efficient and safer for women attempting TOLAC compared with PGE2, to improve labour management in this high-risk population.Ethics and disseminationEthical approval is granted by the Domain Specific Review Board (Domain D) of the National Healthcare Group, Singapore. All adverse events will be reported within 24 hours of notification for assessment of causality. Data will be published and will be available for future meta-analyses.Trial registration numberNCT03471858; Pre-results.

IntroductionFetal growth restriction (FGR) is a serious pregnancy complication, associated with increased rates of perinatal death and morbidity among survivors. Most commonly FGR results from placental insufficiency, where the placenta fails to deliver the oxygen and nutrients required for normal fetal growth. This leads to fetal oxidative stress, resulting in organ damage through lipid peroxidation. The early developing brain is particularly susceptible, such that FGR is associated with poorer neurodevelopment, witnessed as cognitive and behavioural dysfunction, and cerebral palsy. Promisingly, melatonin, a lipid soluble antioxidant is neuroprotective in animal models of FGR. We present a protocol outlining a randomised, placebo-controlled trial to explore whether antenatal maternal melatonin supplementation in pregnancies with severe, early-onset FGR can improve neurodevelopment among survivors at 2 years of age.Methods and analysesWe will recruit 336 women with a singleton pregnancy complicated by FGR between 23+0 and 31+6 weeks gestation. Participants will be randomised, stratified by gestational age, to either 30 mg melatonin per day or a visually identical placebo, continued until birth. Measures of maternal and fetal health will be collected until birth. Timing of birth will be determined by the treating clinical team in discussion with the woman. Neonatal and infant neurodevelopmental assessments will be undertaken, consisting of brain MRI at term corrected age, general movements assessment at term and 3 months’ corrected age, and Bayley Scales of Infant & Toddler Development-III and Infant Toddler Social Emotional Assessment at 2.5 years corrected age. Analyses will be on intention to treat. The primary outcome is a difference of 5 points in the cognitive domain of the Bayley-III. Secondary outcomes address maternal and fetal safety.Ethics and disseminationThis trial has Monash Health Human Research and Ethics committee approval (17-0000-583A). Findings will be disseminated through peer-reviewed publications, conference presentations and to participants.Trial registration numberACTRN12617001515381; Pre-results

ObjectivesTo investigate if centre-specific levels of perinatal interventional activity were associated with neonatal and neurodevelopmental outcome at 2 years of age in two separately analysed cohorts of infants: cohort A born at 22–25 and cohort B born at 26–27 gestational weeks, respectively.DesignGeographically defined, retrospective cohort study.SettingAll nine level III perinatal centres (neonatal intensive care units and affiliated obstetrical services) in Switzerland.PatientsAll live-born infants in Switzerland in 2006–2013 below 28 gestational weeks, excluding infants with major congenital malformation.Outcome measuresOutcomes at 2 years corrected for prematurity were mortality, survival with any major neonatal morbidity and with severe-to-moderate neurodevelopmental impairment (NDI).ResultsCohort A associated birth in a centre with high perinatal activity with low mortality adjusted OR (aOR 0.22; 95% CI 0.16 to 0.32), while no association was observed with survival with major morbidity (aOR 0.74; 95% CI 0.46 to 1.19) and with NDI (aOR 0.97; 95% CI 0.46 to 2.02). Median age at death (8 vs 4 days) and length of stay (100 vs 73 days) were higher in high than in low activity centres. The results for cohort B mirrored those for cohort A.ConclusionsCentres with high perinatal activity in Switzerland have a significantly lower risk for mortality while having comparable outcomes among survivors. This confirms the results of other studies but in a geographically defined area applying a more restrictive approach to initiation of perinatal intensive care than previous studies. The study adds that infants up to 28 weeks benefited from a higher perinatal activity and why further research is required to better estimate the added burden on children who ultimately do not survive.

ObjectivesTo examine how pregnant couples experience receiving a prenatal diagnosis of Down syndrome (DS) by phone—a practice that has been routine care in the Central Denmark Region for years.DesignQualitative interview study.SettingParticipants were recruited from hospitals in Central Denmark Region, Denmark.ParticipantsCouples who had received a prenatal diagnosis of DS by phone and decided to terminate the pregnancy. They were recruited from the obstetric department where the termination was undertaken. During the study period (February 2016 to July 2017), 21 semistructured, audio-recorded interviews were conducted by an experienced anthropologist. Interviews were conducted 4–22 weeks after the diagnosis and analysed using thematic analysis.ResultsA prearranged phone call was considered an acceptable practice. However, the first theme’Expected but unexpected'shows how the call often came earlier than expected. Consequently, most women were not with their partner and were thus initially alone with their grief and furthermore responsible for informing their partner, which some considered difficult. The second theme’Now what?'shows how during the phone calls, physicians were quick to enquire about the couples’ agendas. As the majority had already decided to seek termination of pregnancy, the dialogue focused on related questions and arrangements. Only half of the couples received additional counselling.ConclusionA prearranged phone call was considered an acceptable and appropriate practice. However, some aspects of this practice (particularly related to the context of the call) showed to be less than optimal for the couples. To make sure that a diagnostic result is delivered in accordance with the couples' needs and requests, the context of the call could be addressed and agreed on in advance by physicians and couples.

IntroductionPreterm birth (PTB) results from heterogeneous influences and is a major contributor to neonatal mortality and morbidity that continues to have adverse effects on infants beyond the neonatal period. This protocol describes the procedures to determine molecular signatures predictive of PTB through high-frequency sampling during pregnancy, at delivery and the postpartum period.Methods and analysisFour hundred first trimester pregnant women from either Myanmar or Thailand of either Karen or Burman ethnicity, with a viable, singleton pregnancy will be enrolled in this non-interventional, prospective pregnancy birth cohort study and will be followed through to the postpartum period. Fortnightly finger prick capillary blood sampling will allow the monitoring of genome-wide transcript abundance in whole blood. Collection of stool samples and vaginal swabs each trimester, at delivery and postpartum will allow monitoring of intestinal and vaginal microbial composition. In a nested case–control analysis, perturbations of transcript abundance in capillary blood as well as longitudinal changes of the gut, vaginal and oral microbiome will be compared between mothers giving birth to preterm and matched cases giving birth to term neonates. Placenta tissue of preterm and term neonates will be used to determine bacterial colonisation as well as for the establishment of coding and non-coding RNA profiles. In addition, RNA profiles of circulating, non-coding RNA in cord blood serum will be compared with those of maternal peripheral blood serum at time of delivery.Ethics and disseminationThis research protocol that aims to detect perturbations in molecular trajectories preceding adverse pregnancy outcomes was approved by the ethics committee of the Faculty of Tropical Medicine, Mahidol University in Bangkok, Thailand (Ethics Reference: TMEC 15–062), the Oxford Tropical Research Ethics Committee (Ethics Reference: OxTREC: 33–15) and the local Tak Province Community Ethics Advisory Board. The results of this cooperative project will be disseminated in multiple publications staggered over time in international peer-reviewed scientific journals.Trial registration numberNCT02797327; Pre-results.

IntroductionThe incidence of intrauterine growth restriction (IUGR) is estimated at about 3% of pregnancies, and it is associated with 30% of all perinatal mortality and severe morbidity with adverse neurodevelopmental and cardiovascular health consequences in adult life. Early onset IUGR represents 20%–30% of all cases and is highly associated with severe placental insufficiency. The existing evidence suggests that low molecular weight heparin (LMWH) has effects beyond its antithrombotic action, improving placental microvessel structure and function of pregnant women with vascular obstetric complications by normalising proangiogenic and antiapoptotic protein levels, cytokines and inflammatory factors. The objective of our study is to demonstrate the effectiveness of LMWH in prolonging gestation in pregnancies with early-onset IUGR.Methods and analysisThis is a multicentre, triple-blind, parallel-arm randomised clinical trial. Singleton pregnancies qualifying for early (20–32 weeks at diagnosis) placental IUGR (according to Delphi criteria) will be randomised to subcutaneous treatment with bemiparin 3500 IU/0.2 mL/day or placebo from inclusion at diagnosis to the time of delivery. Analyses will be based on originally assigned groups (intention-to-treat). The primary objective will be analysed by comparing gestational age and prolongation of pregnancy (days) in each group with Student’s t-tests for independent samples and by comparing Kaplan-Maier survival curves (from inclusion to delivery, log-rank test). A linear regression model for gestational age at birth will consider the following covariates: gestational age at inclusion (continuous) and pre-eclampsia (binary).Ethics and disseminationThe study will be conducted in accordance with the principles of Good Clinical Practice. This study was approved by the Clinical Research Ethics Committee (CEIC) of Sant Joan de Déu Hospital, on 13 July 2017. The trial is registered in the public registrywww.clinicaltrial.gov. according to Science Law 14/2011, and the results will be published in an open access journal.Trial registration numberNCT03324139; Pre-results.

This case report describes a baby who was diagnosed antenatally with a significant left-sided congenital cystic adenomatoid malformation. Following diagnosis of a fluid-filled, macrocystic structure on the left side of the chest, the mother was referred at 27 weeks’ gestation to her regional fetal medicine unit for assessment and ongoing management. Fetal MRI demonstrated a cyst measuring 6.7 mm × 4.3 mm, associated with mediastinal shift and affecting cardiac contractility. Scalp …

A 32-year-old primigravida, with low background risk at booking, referred to our fetal medicine department after a missing left lower limb in the fetus was diagnosed on scan at 26 weeks gestation. Hypoplastic left thigh and limb reduction defect were confirmed (figures 1 and 2) using 4D scan, and parents counselled. They remained committed to the pregnancy. …

Introduction Fetal growth restriction (FGR) affects 5%–10% of all pregnancies, contributing to 30%–50% of stillbirths. Unfortunately, growth restriction often is not detected antenatally. The last weeks of pregnancy are critical for preventing stillbirth among babies with FGR because there is a pronounced increase in stillbirths among growth-restricted fetuses after 37 weeks of pregnancy. Here we present a protocol (V.1, 23 May 2016) for the RATIO37 trial, which evaluates an integrated strategy for accurately selecting at-risk fetuses for delivery at term. The protocol is based on the combination of fetal biometry and cerebroplacental ratio (CPR). The primary objective is to reduce stillbirth rates. The secondary aims are to detect low birth weights and adverse perinatal outcomes. Methods and analysis The study is designed as multicentre (Spain, Chile, Mexico,Czech Republic and Israel), open-label, randomised trial with parallel groups. Singleton pregnancies will be invited to participate after routine second-trimester ultrasound scan (19 +0 –22 +6 weeks of gestation), and participants will be randomly allocated to receive revealed or concealed CPR evaluation. Then, a routine ultrasound and Doppler scan will be performed at 36 +0 –37 +6 weeks. Sociodemographic and clinical data will be collected at enrolment. Ultrasound and Doppler variables will be recorded at 36 +0 –37 +6 weeks of pregnancy. Perinatal outcomes will be recorded after delivery. Univariate (with estimated effect size and its 95% CI) and multivariate (mixed-effects logistic regression) comparisons between groups will be performed. Ethics and dissemination The study will be conducted in accordance with the principles of Good Clinical Practice. This study was accepted by the Clinical Research Ethics Committee of Hospital Clinic Barcelona on 23May 2016. Subsequent approval by individual ethical committees and competent authorities was granted. The study results will be published in peer-reviewed journals and disseminated at international conferences. Trial registration number NCT02907242; pre-results.