BACKGROUND:The goal of this study was to determine whether metformin prevents gestational diabetes (GDM) and adverse pregnancy outcomes. METHODS:We searched Medline/Medline In-Process, Embase, and Evidence-Based Medicine Reviews databases through May 9, 2025, to identify double-blind randomized placebo-controlled trials using metformin in pregnancies without diabetes. Predefined primary maternal outcomes were GDM and glycemic indices from oral glucose tolerance tests (OGTTs). Primary neonatal outcomes were gestational age at delivery and neonatal anthropometry. One-stage mixed-effects models using individual participant data (IPD) were adjusted for maternal age, body mass index, gestational age at commencement, and baseline blood glucose level. RESULTS:Ten trials (N=2695) met inclusion criteria and seven provided IPD (n=2485; 92.2% of available IPD). After data harmonization, 2297 pregnancies (1159 participants randomly assigned to metformin and 1138 participants to placebo) were included. Metformin was not associated with reduced GDM in adjusted or unadjusted analyses, including by World Health Organization 1999 criteria (odds ratio, 1.04; 95% CI 0.80 to 1.36; adjusted odds ratio, 1.00; 95% CI 0.71 to 1.41) or by National Institute of Health and Care Excellence 2015 criteria (odds ratio 0.98; 95% CI, 0.76 to 1.27; adjusted odds ratio, 1.00; 95% CI 0.71 to 1.41), except on adjusted analysis using International Association of Diabetes and Pregnancy Study Groups thresholds (odds ratio 0.83; 95% CI, 0.65 to 1.06; adjusted odds ratio 0.71; 95% CI 0.52 to 0.98). Metformin was associated with marginally lower fasting blood glucose level (mean difference [MD], -0.06 mmol/l; 95% CI, -0.10 to -0.01), with no apparent difference in 2-hour postload blood glucose level. Metformin was also associated with longer gestation (MD, 0.30 weeks' gestation; 95% CI, 0.06 to 0.54), lower odds of preterm birth (adjusted odds ratio, 0.64; 95% CI, 0.47 to 0.89), and larger neonatal head circumference (MD, 2.43 percentile; 95% CI, 0.13 to 4.72). Gastrointestinal side effects were more commonly reported with metformin. CONCLUSIONS:In this IPD meta-analysis, metformin was not associated with a reduction in GDM, but was associated with an increase in gestational age at delivery.

The mechanisms by which vaginal microbiota shape spontaneous preterm birth (sPTB) risk remain poorly defined. Using electronic clinical records data from 74,913 maternities in conjunction with metaxanomic (n = 596) and immune profiling (n = 314) data, we show that the B blood group phenotype associates with increased risk of sPTB and adverse vaginal microbiota composition. The O blood group associates with sPTB in women who have a combination of a previous history of sPTB, an adverse vaginal microbial composition and pro-inflammatory cervicovaginal milieu. In contrast, women of blood group A have a higher prevalence of vaginal Lactobacillus crispatus, a lower risk of sPTB, with sPTB cases showing no association with vaginal microbiota composition or inflammation. We found that cervicovaginal fluid contains ABH(O) glycans and shows variable binding to key vaginal bacteria. This indicates that cervicovaginal ABH(O) glycans influence microbiota-host interactions implicated in sPTB risk, suggesting a novel target for sPTB prediction and prevention.

Objective To predict birth weight at various potential gestational ages of delivery based on data routinely available at the first antenatal visit.Design Individual participant data meta-analysis.Data sources Individual participant data of four cohorts (237 228 pregnancies) from the International Prediction of Pregnancy Complications (IPPIC) network dataset.Eligibility criteria for selecting studies Studies in the IPPIC network were identified by searching major databases for studies reporting risk factors for adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction, and stillbirth, from database inception to August 2019. Data of four IPPIC cohorts (237 228 pregnancies) from the US (National Institute of Child Health and Human Development, 2018; 233 483 pregnancies), UK (Allen et al, 2017; 1045 pregnancies), Norway (STORK Groruddalen research programme, 2010; 823 pregnancies), and Australia (Rumbold et al, 2006; 1877 pregnancies) were included in the development of the model.Results The IPPIC birth weight model was developed with random intercept regression models with backward elimination for variable selection. Internal-external cross validation was performed to assess the study specific and pooled performance of the model, reported as calibration slope, calibration-in-the-large, and observed versus expected average birth weight ratio. Meta-analysis showed that the apparent performance of the model had good calibration (calibration slope 0.99, 95% confidence interval (CI) 0.88 to 1.10; calibration-in-the-large 44.5 g, -18.4 to 107.3) with an observed versus expected average birth weight ratio of 1.02 (95% CI 0.97 to 1.07). The proportion of variation in birth weight explained by the model (R2) was 46.9% (range 32.7-56.1% in each cohort). On internal-external cross validation, the model showed good calibration and predictive performance when validated in three cohorts with a calibration slope of 0.90 (Allen cohort), 1.04 (STORK Groruddalen cohort), and 1.07 (Rumbold cohort), calibration-in-the-large of -22.3 g (Allen cohort), -33.42 (Rumbold cohort), and 86.4 g (STORK Groruddalen cohort), and observed versus expected ratio of 0.99 (Rumbold cohort), 1.00 (Allen cohort), and 1.03 (STORK Groruddalen cohort); respective pooled estimates were 1.00 (95% CI 0.78 to 1.23; calibration slope), 9.7 g (-154.3 to 173.8; calibration-in-the-large), and 1.00 (0.94 to 1.07; observed v expected ratio). The model predictions were more accurate (smaller mean square error) in the lower end of predicted birth weight, which is important in informing clinical decision making.Conclusions The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other countries, settings, and subgroups is required.Trial registration PROSPERO CRD42019135045

Introduction The aim of the STOPPIT-3 study is to determine the clinical and cost effectiveness of antenatal corticosteroids (ACS) prior to planned birth of twins in a multicentre placebo-controlled trial with internal pilot.Methods and analysis This study will comprise a multicentre, double-blinded, randomised, placebo-controlled trial in at least 50 UK obstetric units. The target population is 1552 women with a twin pregnancy and a planned birth between 35 and 38+6 weeks’ gestation recruited from antenatal clinics. Women will be randomised to Dexamethasone Phosphate (24 mg) or saline administered via two intramuscular injections 24 hours apart, 24–120 hours prior to scheduled birth.Outcomes The primary outcome is need for respiratory support within 72 hours of birth. Secondary and safety outcomes will be included. Cognitive and language development at age 2 years will be assessed in a subset of participants using the Parent report of Children’s Abilities-Revised questionnaire. We will also determine the cost effectiveness of the treatment with ACS compared with placebo.Ethics and dissemination STOPPIT-3 has been funded and approved by the National Institute of Healthcare Research. It has been approved by the West Midlands Research Ethics Committee (22/WM/0018). The results will be disseminated via publication in peer-reviewed journals and conference presentation and will also be communicated to the public via links with charity partners and social media.Trial sponsor The University of Edinburgh and Lothian Health Board ACCORD, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ.Trial registration number ISRCTN59959611.

Abstract Background Incidence of gestational diabetes mellitus (GDM) is increasing and is associated with adverse perinatal outcomes including macrosomia, pre-eclampsia, and pre-term delivery. Optimum glycaemic control can reduce these adverse perinatal outcomes. Continuous glucose monitoring (CGM) informs users about interstitial glucose levels allowing early detection of glycaemic excursions and pharmacological or behavioural intervention. Few adequately powered RCTs to evaluate the impact of using CGM in women with GDM on perinatal outcomes have been undertaken. We aim to establish the feasibility of a multi-site RCT to evaluate the clinical- and cost-effectiveness of an intermittently scanned continuous glucose monitor (isCGM) compared with self-monitored blood glucose (SMBG) in women with GDM for reducing fetal macrosomia and improving maternal and fetal outcomes. We will evaluate recruitment and retention rates, adherence to device requirements, adequacy of data capture and acceptability of trial design and isCGM devices. Methods Open-label multicentre randomised controlled feasibility trial. Inclusion criteria: pregnant women, singleton pregnancy, recent diagnosis of GDM (within 14 days of commencing medication, up to 34 weeks gestation) prescribed metformin and/or insulin. Women will be consecutively recruited and randomised to isCGM (FreestyleLibre2) or SMBG. At every antenatal visit, glucose measurements will be evaluated. The SMBG group will use blinded isCGM for 14 days at baseline (~ 12–32 weeks) and ~ 34–36 weeks. The primary outcome is the recruitment rate and absolute number of women participating. Clinical assessments of maternal and fetal/infant health will be undertaken at baseline, birth, up to ~ 13 weeks post-natal. Psychological, behavioural and health economic measures will be assessed at baseline and ~ 34–36 weeks gestation. Qualitative interviews will be undertaken with study decliners, participants, and professionals to explore trial acceptability, of using isCGM and SMBG. Discussion GDM can be associated with adverse pregnancy outcomes. isCGM could offer a timely, easy-to-engage-with intervention, to improve glycaemic control, potentially reducing adverse pregnancy, birth and long-term health outcomes for mother and child. This study will determine the feasibility of conducting a large-scale multisite RCT of isCGM in women with GDM. Trial registration This study has been registered with the ISRCTN (reference: ISRCTN42125256 , Date registered: 07/11/2022).

Host-vaginal-microbial interactions have been shown to influence spontaneous preterm birth (sPTB) risk(1,2). In other body niches, histo-blood group antigens are associated with microbiota composition and disease risk(3,4). To investigate whether ABO blood group influences sPTB risk, and if this is associated with changes in vaginal microbial composition and host immune response. Prospective study of women defined as at-risk of sPTB (n=1935), where cervicovaginal fluid (CVF) was collected in pregnancy (20-24 weeks). Bacterial DNA was extracted, and the composition assessed using 16 S rRNA gene sequencing surveying the V1-V2 region (n=238). Cytokine immunoassays were performed on matched CVF supernatant (n=103). Results were analysed according to ABO blood group status and risk factor for sPTB. In women at risk of sPTB with previous cervical treatment blood group B was associated with a higher risk of sPTB<34weeks than A (RR 2.94(1.22-7.64), p=0.01), yet no correlation was seen with CVF cytokine concentration. In women with previous mid-trimester loss (MTL)/PTB those with blood group O were at increased risk of sPTB <34 weeks compared to those of blood group A (RR 1.42(0.94-2.17), p=0.04). IL-8 levels were higher in women of blood group O with a previous MTL/PTB than those of blood group A or B. IL-8 was also correlated with L. iners and bacterial vaginosis-associated taxa in women of blood group O with sPTB. ABO blood groups influence vaginal microbial composition, local inflammation and risk of sPTB, and provide mechanistic insight on the different aetiologies of PTB.

Although the majority of pregnancies progress smoothly and result in the birth of a healthy baby, this is not always the case. Pregnancy can have severe complications, including stillbirth, affecting eight in 1000 pregnancies in France;1Cinelli H Lelong N Le Ray C Enquête nationale périnatale. Rapport 2021.https://enp.inserm.fr/wp-content/uploads/2022/10/rapport-2022-v5.pdfDate: 2022Date accessed: March 3, 2023Google Scholar maternal hypertension, affecting 74 in 1000,2Olié V Moutengou E Grave C et al.Prevalence of hypertensive disorders during pregnancy in France (2010–2018): the Nationwide CONCEPTION Study.J Clin Hypertens. 2021; 23: 1344-1353Crossref Scopus (17) Google Scholar or neonatal death, affecting three in 1000. Obstetrics and midwifery are the fields of study focused on pregnancy, childbirth, and the post-partum period. They aim to identify, by screening or diagnosis, pregnant women at risk of complications and offer ways to prevent or treat complications to improve outcomes. Recently, Richard Horton commented3Horton R Offline: FRENCH-ARRIVE—elles accusent.Lancet. 2022; 4001911Summary Full Text Full Text PDF Scopus (4) Google Scholar on the FRENCH-ARRIVE trial (NCT04799912). This large, nationwide, randomised trial in France aims to replicate or refute the findings of the US ARRIVE trial.4Grobman WA Rice MM Reddy UM et al.Labor induction versus expectant management in low-risk nulliparous women.N Engl J Med. 2018; 379: 513-523Crossref PubMed Scopus (666) Google Scholar The US trial showed that induction of labour in nulliparous women with uncomplicated pregnancies between 39 weeks (+0 days) and 39 weeks (+4 days) resulted in improved outcomes for the newborn baby than expectant management. Women induced also had lower rates of caesarean birth and hypertensive disorders of pregnancy. Horton responds to a book by Claudine Schalck and Raymonde Gagnon5Schalck C Gagnon R When inducing labor compromises a woman's motherhood: a psycho-sociological analysis of maternity as labor. Editions L'Harmattan, France2022Google Scholar that posits “induction of labour without any medically justified reason can be considered nothing less than ‘obstetric violence’”. Of note, Horton highlights emotive quotes from the French authors 13 times (eg, “control” and “abuse” are a “form of domination over women”; the woman “has neither body, nor power, nor place, nor role in childbirth”). By contrast, he quotes the FRENCH-ARRIVE investigators twice. This, we think, reflects his bias in the debate for which he calls. Horton's Comment deserves a rebuttal. The French research network Groupe de Recherche en Obstétrique et Gynécologie (GROG) is an excellent network that has done landmark trials that have improved care for mothers and babies. The FRENCH-ARRIVE study adds valuable obstetric knowledge to support decision making by women and their families. The best way to provide high-quality information for consumers and clinicians is with randomised controlled trials, such as ARRIVE and FRENCH-ARRIVE, and other studies, such as SWEPIS and INDEX, both of which assess induction at 41 weeks.6Alkmark M Keulen JKJ Kortekaas JC et al.Induction of labour at 41 weeks or expectant management until 42 weeks: a systematic meta-analysis of randomised trials.PLoS Med. 2020; 17e1003436Crossref Scopus (20) Google Scholar We are particularly concerned that Horton implies pregnant women lack capacity to consent. This contention echoes historical, paternalistic, patriarchal, and prejudicial attitudes about women and begs the question why he believes their consent capacity is any different than any other individual in the context of a research trial? We contend this attitude additionally promotes the exclusion of pregnant women from research, with the resultant impairment of maternal and child health. Suggesting that pregnant women should not be presented with information (eg, about the risks and benefits of an intervention, such as induction) and allowed to make decisions based on their own preferences and values is disrespectful. Instead, it is proposed that a higher authority should decide the philosophy to which they should adhere or the information with which they are permitted to engage. We would posit that just as it is problematic when women have interventions that they do not want, withholding information from women so they cannot make decisions for themselves as to what intervention (or non-intervention) is best for them is also problematic. In fact, in a recent UK law case, the judge upheld the right for women to have information about any material risk to make autonomous decisions about how to give birth.7Chan SW Tulloch Cooper ES Smith A Wojcik W Norman JE Montgomery and informed consent: where are we now?.BMJ. 2017; 12: 357Google Scholar The debate about the medicalisation of pregnancy (and medicalisation of life in general) is important, but that debate should never be conflated with good research or used to impugn researchers and clinicians who address important questions in an appropriate and ethical manner. In fact, GROG and other research networks have identified many interventions that are ineffective; these studies have protected women from the possible harm of such interventions.8Schmitz T Fuchs F Closset E et al.Outpatient cervical ripening by nitric oxide donors for prolonged pregnancy: a randomized controlled trial.Obstet Gynecol. 2014; 124: 1089-1097Crossref PubMed Scopus (22) Google Scholar, 9Senat MV Affres H Letourneau A et al.Effect of glyburide vs subcutaneous insulin on perinatal complications among women with gestational diabetes: a randomized clinical trial.JAMA. 2018; 319: 1773-1780Crossref PubMed Scopus (67) Google Scholar Additionally, the use of terms such as “obstetric violence” from The Lancet's Editor-in-Chief is unfortunate. Such inflammatory language shreds the ability for the nuanced, scientific debate that Horton is calling for. Similarly, we are surprised by the title of Horton's Offline, including the words ”elles accusent”, making a parallel between the FRENCH-ARRIVE study and the 1890's Dreyfus affair, a notable example of antisemitism in France. All in all, we welcome the debate that Horton wants to initiate, but, for reasons mentioned, we feel that this biased, provocative Offline comment is a false start. CdG is President of the Dutch Society of Obstetrics & Gynecology. BWM reports an investigator grant from the National Health and Medical Research Council (NHMRC; GN1176437); consultancy fees at an hourly rate for ObsEva, Merck KGaA, Guerbet, iGenomix, and Merck; and travel support from Merck KGaA. JEN is Deputy Vice-Chancellor and Provost at the University of Nottingham and a non-executive Director of a UK National Health Service Trust, and reports funding from UK charities and the UK Government to conduct clinical trials into improving outcomes for pregnant women and their babies. KP reports an investigator grant from the NHMRC (GNT2009765). SJS declares grants from the National Institute of Healthcare Research Health Technology and Assessment, Wellcome Trust, Medical Research Council, The Chief Scientist Office of Scotland, and Tommy's Charity, all paid to her institution; consulting fees on pre-term birth treatments to Natera; honoraria for educational speaking from Hologic, all paid to her institution; participation in the National Institute of Healthcare Research Health Technology and Assessment data monitoring committee and trial steering committee in the past 36 months; and a leadership role in the Trustee of Sands charity. All other authors declare no competing interests. Offline: FRENCH-ARRIVE—elles accusentThe accusation is direct and unflinching. The FRENCH-ARRIVE trial “obeys a pseudo-scientific rational logic” that is “a denial of what childbirth and motherhood mean to women”. Claudine Schalck and Raymonde Gagnon are both registered midwives. Their book, When Inducing Labor Compromises a Woman's Motherhood (L’Harmattan, 2022), is one of the most remarkable denunciations of an ongoing research study ever published. It is also a sustained critique of the contemporary approach to obstetric care in many western nations today. Full-Text PDF

Luke Carter-Brzezinski , Elizabeth Davies , Jane Norman, Lourdes Rubio, Christopher Dixon, Sarah Brett, Tony Dunne, Shahid Iqbal, Fiona L. Dignan, Shazaad Ahmad, Nicholas Machin, Henry Morriss, Anthony Wilson and Eleni Tholouli Department of Clinical Haematology, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK; Department of Critical Care Medicine, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK; Department of Virology, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK

Introduction Although ultrasound to determine gestational age is fundamental to the optimum management of pregnancy and is recommended for all women by the World Health Organisation, it remains unavailable to many women in low-income countries where trained practitioners are scarce. This study aimed to evaluate a novel, context-specific education package to teach midwives basic obstetric ultrasound, including the determination of gestational age by measurement of fetal femur length. Methods The study was conducted across six sites in Malawi in January 2021. Following a virtual “training of the trainers”, local teams delivered a 10-day programme encompassing both didactic and “hands on” components. Matched pre and post course tests assessed participants' knowledge of key concepts, with Objective Structured Clinical Examinations used to evaluate practical skills. To achieve a pass, trainees were required to establish the gestational age to within ±7 days of an experienced practitioner and achieve an overall score of >65% on five consecutive occasions. A matched pre and post course survey explored participants' attitudes and confidence in performing ultrasound examinations. Results Of the 29 midwives who participated, 28 finished the programme and met the criteria specified to pass. 22 midwives completed the matched knowledge tests, with the mean (SD) score increasing from 10.2 (3.3) to 18 (2.5) after training (P <0.0001). Mean difference 7.9, 95% CI 6.5–9.2. Midwives passed 87% of the Observed Structured Clinical Examinations, establishing the gestational age to within ±7 days of an experienced practitioner in 89% of assessments. Beliefs regarding the importance of antenatal ultrasound increased post course (p = 0.02), as did confidence in performing ultrasound examinations (p <0.0001). Conclusion This study demonstrates not only that ultrasound-naive practitioners can be taught to perform basic obstetric ultrasound dating scans, confidently and competently, after 10 days of training, but also that local teams can be orientated to successfully deliver the programme virtually. Previous ultrasound training initiatives, while often more comprehensive in their syllabus, have been of considerably longer duration and this is likely to be a barrier to upscaling opportunities. We propose that this focused training increases the potential for widescale and sustainable implementation.

There has been a surge in studies implicating a role of vaginal microbiota in spontaneous preterm birth (sPTB), but most are associative without mechanistic insight. Here we show a comprehensive approach to understand the causative factors of preterm birth, based on the integration of longitudinal vaginal microbiota and cervicovaginal fluid (CVF) immunophenotype data collected from 133 women at high-risk of sPTB. We show that vaginal depletion of Lactobacillus species and high bacterial diversity leads to increased mannose binding lectin (MBL), IgM, IgG, C3b, C5, IL-8, IL-6 and IL-1β and to increased risk of sPTB. Cervical shortening, which often precedes preterm birth, is associated with Lactobacillus iners and elevated levels of IgM, C3b, C5, C5a and IL-6. These data demonstrate a role for the complement system in microbial-driven sPTB and provide a scientific rationale for the development of live biotherapeutics and complement therapeutics to prevent sPTB.

Abstract Background The AFFIRM intervention aimed to reduce stillbirth and neonatal deaths by increasing awareness of reduced fetal movements (RFM) and implementing a care pathway when women present with RFM. Although there is uncertainty regarding the clinical effectiveness of the intervention, the aim of this analysis was to evaluate the cost-effectiveness. Methods A stepped-wedge, cluster-randomised trial was conducted in thirty-three hospitals in the United Kingdom (UK) and Ireland. All women giving birth at the study sites during the analysis period were included in the study. The costs associated with implementing the intervention were estimated from audits of RFM attendances and electronic healthcare records. Trial data were used to estimate a cost per stillbirth prevented was for AFFIRM versus standard care. A decision analytic model was used to estimate the costs and number of perinatal deaths (stillbirths + early neonatal deaths) prevented if AFFIRM were rolled out across Great Britain for one year. Key assumptions were explored in sensitivity analyses. Results Direct costs to implement AFFIRM were an estimated £95,126 per 1,000 births. Compared to standard care, the cost per stillbirth prevented was estimated to be between £86,478 and being dominated (higher costs, no benefit). The estimated healthcare budget impact of implementing AFFIRM across Great Britain was a cost increase of £61,851,400/year. Conclusions Perinatal deaths are relatively rare events in the UK which can increase uncertainty in economic evaluations. This evaluation estimated a plausible range of costs to prevent baby deaths which can inform policy decisions in maternity services. Trial registration The trial was registered with www.ClinicalTrials.gov, number NCT01777022.

The Ockenden review 1 Ockenden DC Final findings, conclusions and essential actions from the Ockenden review of maternity services at Shrewsbury and Telford Hospital NHS Trust. Department of Health and Social Care, London2022https://www.gov.uk/government/publications/final-report-of-the-ockenden-reviewDate accessed: April 27, 2022 Google Scholar into the failings in maternity care at Shrewsbury and Telford Hospital NHS Trust in the UK makes for sobering reading. 2 The LancetThe Ockenden review and women's health in the UK. Lancet. 2022; 3991359 Summary Full Text Full Text PDF Scopus (2) Google Scholar The review focuses predominantly on the period from 2000 to 2019 and estimates that there were significant or major concerns in the care of nine women and more than 200 babies who died while receiving care at the Trust. Many more women and babies suffered serious injuries. It was clear that the Shrewsbury and Telford Hospital NHS Trust did not investigate, learn, change, or listen to families when adverse events occurred. 1 Ockenden DC Final findings, conclusions and essential actions from the Ockenden review of maternity services at Shrewsbury and Telford Hospital NHS Trust. Department of Health and Social Care, London2022https://www.gov.uk/government/publications/final-report-of-the-ockenden-reviewDate accessed: April 27, 2022 Google Scholar The conclusions of the Ockenden review make it clear that safe staffing levels, a well trained workforce, an ability to learn from incidents, and a willingness and ability to listen to families are all crucial for safe maternity care.

IntroductionEstablishing an accurate gestational age is essential for the optimum management of pregnancy, delivery and neonatal care, with improved estimates of gestational age considered a public health priority by the World Health Organization (WHO). Although ultrasound is considered the most precise method to achieve this, it is unavailable to many women in low- and middle- income countries (LMICs), where the lack of trained practitioners is considered a major barrier. This systematic review explores what initiatives have previously been undertaken to train staff to date pregnancies using ultrasound, which were successful and what barriers and facilitators influenced training.MethodsThe systematic review was conducted according to PRISMA guidelines and the protocol registered (PROSPERO CRD42019154619). Searches were last performed in July 2021. Studies were screened independently by two assessors, with data extracted by one and verified by the other. Both reviewers graded the methodological quality using the Mixed Methods Assessment Tool. Results were collated within prespecified domains, generating a narrative synthesis.Results25/1,262 studies were eligible for inclusion, all of which were programme evaluations. Eighteen were undertaken in Africa, three in South-East Asia, one in South America, and three across multiple sites, including those in Africa, Asia, and South America. Five programs specified criteria to pass, and within these 96% of trainees did so. Trainee follow up was undertaken in 18 studies. Ten met recommendations for training outlined by the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) but only 1 met the current standards set by the WHO.DiscussionThis systematic review is the first to evaluate this topic and has uncovered major inconsistencies in the delivery and reporting of basic obstetric ultrasound training in LMICs, with the majority of programs not meeting minimum recommendations. By identifying these issues, we have highlighted key areas for improvement and made recommendations for reporting according to the RE-AIM framework. With an increasing focus on the importance of improving estimates of gestational age in LMICs, we believe these findings will be of significance to those seeking to develop and expand the provision of sustainable obstetric ultrasound in LMICs.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019154619, PROSPERO CRD42019154619.

Background: Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. Objective: STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. Design: STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group – the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. Setting: Antenatal clinics in the UK and elsewhere in Europe. Participants: Women with twin pregnancy at < 21 weeks’ gestation with known chorionicity and gestation established by scan at ≤ 16 weeks’ gestation. Interventions: Ultrasound scan to establish cervical length. Women with a cervical length of ≤ 35 mm at 18+ 0–20+ 6 weeks’ gestation were randomised to standard care or Arabin pessary plus standard care. Randomisation was performed by computer and accessed through a web-based browser. Main outcome measures: Obstetric – all births before 34+ 0 weeks’ gestation following the spontaneous onset of labour; and neonatal – composite of adverse outcomes, including stillbirth or neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis or proven sepsis, all measured up to 28 days after the expected date of delivery. Results: A total of 2228 participants were recruited to the screening phase, of whom 2170 received a scan and 503 were randomised: 250 to Arabin pessary and 253 to standard care alone. The rate of the primary obstetric outcome was 18.4% (46/250) in the intervention group and 20.6% (52/253) in the control group (adjusted odds ratio 0.87, 95% confidence interval 0.55 to 1.38; p = 0.54). The rate of the primary neonatal outcome was 13.4% (67/500) and 15.0% (76/506) in the intervention group and control group, respectively (adjusted odds ratio 0.86, 95% confidence interval 0.54 to 1.36; p = 0.52). The pessary was largely well tolerated and clinicians found insertion and removal ‘easy’ or ‘fairly easy’ in the majority of instances. The simple costs analysis showed that pessary treatment is no more costly than standard care. Limitations: There was the possibility of a type II error around smaller than anticipated benefit. Conclusions: In this study, the Arabin pessary did not reduce preterm birth or adverse neonatal outcomes in women with a twin pregnancy and a short cervix. The pessary either is ineffective at reducing preterm birth or has an effect size of < 0.4. Future work: Women with twin pregnancy remain at risk of preterm birth; work is required to find treatments for this. Trial registration: Current Controlled Trials ISRCTN98835694 and ClinicalTrials.gov NCT02235181. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 44. See the NIHR Journals Library website for further project information.

Metformin is widely used in pregnancy, despite lack of long-term safety for children. We hypothesised that metformin exposure in utero is associated with increased cardiovascular risk. We tested this hypothesis in a follow-up study of children born to obese mothers who had participated in a randomised controlled trial of metformin versus placebo in pregnancy (EMPOWaR). We measured body composition, peripheral blood pressure (BP), arterial pulse wave velocity and central haemodynamics (central BP and augmentation index) using an oscillometric device in 40 children of mean (SD) age 5.78 (0.93) years, exposed to metformin (n = 19) or placebo (n = 21) in utero. There were no differences in any of the anthropometric or vascular measures between metformin and placebo-exposed groups in univariate analyses, or after adjustment for potential confounders including the child's behaviour, diet and activity levels. Post-hoc sample size calculation indicated we would have detected large clinically significant differences between the groups but would need an unfeasible large number to detect possible subtle differences in key cardiovascular risk parameters in children at this age of follow-up. Our findings suggest no evidence of increased cardiovascular risk in children born to obese mothers who took metformin in pregnancy and increase available knowledge of the long-term safety of metformin on childhood outcomes.

The pregnancy vaginal microbiome contributes to risk of preterm birth, the primary cause of death in children under 5 years of age. Here we describe direct on-swab metabolic profiling by Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) for sample preparation-free characterisation of the cervicovaginal metabolome in two independent pregnancy cohorts (VMET, n = 160; 455 swabs; VMET II, n = 205; 573 swabs). By integrating metataxonomics and immune profiling data from matched samples, we show that specific metabolome signatures can be used to robustly predict simultaneously both the composition of the vaginal microbiome and host inflammatory status. In these patients, vaginal microbiota instability and innate immune activation, as predicted using DESI-MS, associated with preterm birth, including in women receiving cervical cerclage for preterm birth prevention. These findings highlight direct on-swab metabolic profiling by DESI-MS as an innovative approach for preterm birth risk stratification through rapid assessment of vaginal microbiota-host dynamics.

Background Around 60,000 babies are born preterm (prior to 37 weeks’ gestation) each year in the UK. There is little evidence on the optimal birth mode (vaginal or caesarean section). Objective The overall aim of the CASSAVA project was to determine if a trial to define the optimal mode of preterm birth could be carried out and, if so, determine what sort of trial could be conducted and how it could best be performed. We aimed to determine the specific groups of preterm women and babies for whom there are uncertainties about the best planned mode of birth, and if there would be willingness to recruit to, and participate in, a randomised trial to address some, but not all, of these uncertainties. This project was conducted in response to a Heath Technology Assessment programme commissioning call (17/22 ‘Mode of delivery for preterm infants’). Methods We conducted clinician and patient surveys ( n = 224 and n = 379, respectively) to identify current practice and opinion, and a consensus survey and Delphi workshop ( n = 76 and n = 22 participants, respectively) to inform the design of a hypothetical clinical trial. The protocol for this clinical trial/vignette was used in telephone interviews with clinicians ( n = 24) and in focus groups with potential participants ( n = 13). Results Planned sample size and data saturation was achieved for all groups except for focus groups with participants, as this had to be curtailed because of the COVID-19 pandemic and data saturation was not achieved. There was broad agreement from parents and health-care professionals that a trial is needed. The clinician survey demonstrated a variety of practice and opinion. The parent survey suggested that women and their families generally preferred vaginal birth at later gestations and caesarean section for preterm infants. The interactive workshop and Delphi consensus process confirmed the need for more evidence (hence the case for a trial) and provided rich information on what a future trial should entail. It was agreed that any trial should address the areas with most uncertainty, including the management of women at 26–32 weeks’ gestation, with either spontaneous preterm labour (cephalic presentation) or where preterm birth was medically indicated. Clear themes around the challenges inherent in conducting any trial emerged, including the concept of equipoise itself. Specific issues were as follows: different clinicians and participants would be in equipoise for each clinical scenario, effective conduct of the trial would require appropriate resources and expertise within the hospital conducting the trial, potential participants would welcome information on the trial well before the onset of labour and minority ethnic groups would require tailored approaches. Conclusion Given the lack of evidence and the variation of practice and opinion in this area, and having listened to clinicians and potential participants, we conclude that a trial should be conducted and the outlined challenges resolved. Future work The CASSAVA project could be used to inform the design of a randomised trial and indicates how such a trial could be carried out. Any future trial would benefit from a pilot with qualitative input and a study within a trial to inform optimal recruitment. Limitations Certainty that a trial could be conducted can be determined only when it is attempted. Trial registration Current Controlled Trials ISRCTN12295730. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 61. See the NIHR Journals Library website for further project information.