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IntroductionDespite recommendation that all women receive an ultrasound in pregnancy prior to 24 weeks', this remains unavailable to many women in low-income countries where trained practitioners are scarce. Although many programmes have demonstrated efficacy, few have achieved longterm sustainability, with a lack of information about how best to implement such programmes. This mixed-methods study aimed to evaluate the implementation of a novel education package to teach ultrasound-naive midwives in Malawi basic obstetric ultrasound, assessing its impact in the context of the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework.MethodsThe study ran across six sites in Malawi between October 2020 and June 2021, encompassing three phases; pre-implementation, implementation and post-implementation. Twenty nine midwives underwent a bespoke education package with matched pre and post course surveys assessed their knowledge, attitudes and confidence and “hands on” assessments evaluating practical skills. Training evaluation forms and in-depth interviews explored their satisfaction with the package, with repeat assessment and remote image review evaluating maintenance of skills.Results28/29 midwives completed the training, with significant increases in knowledge, confidence and practical skills. Adherence to the education package varied, however many changes to the proposed methodology were adaptive and appeared to facilitate the efficacy of the programme. Unfortunately, despite reporting approval regarding the training itself, satisfaction regarding supervision and follow up was mixed, reflecting the difficulties encountered with providing ongoing in-person and remote support.ConclusionThis programme was successful in improving trainees' knowledge, confidence and skill in performing basic obstetric ultrasound, largely on account of an adaptive approach to implementation. The maintenance of ongoing support was challenging, reflected by trainee dissatisfaction. By evaluating the success of this education package based on its implementation and not just its efficacy, we have generated new insights into the barriers to sustainable upscale, specifically those surrounding maintenance.

For women with a singleton or a multiple pregnancy in situations where active neonatal care is appropriate, and for whom preterm birth is anticipated between 24 and 34 weeks of gestation, one course of prenatal corticosteroids should ideally be offered 18 to 72 h before preterm birth is expected to improve outcomes for the baby. However, if preterm birth is expected within 18 h, prenatal corticosteroids should still be administered. One course of corticosteroids includes two doses of betamethasone acetate/phosphate 12 mg IM 24 h apart, or two doses of dexamethasone phosphate 12 mg IM 24 h apart. In women in whom preterm birth is expected within 72 h and who have had one course of corticosteroids more than a week previously, one single additional course of prenatal corticosteroids could be given at risk of imminent delivery. Prenatal corticosteroids should not be offered routinely to women in whom late preterm birth between 34 and 36 weeks is anticipated. In addition, prenatal corticosteroids should not be given routinely before cesarean delivery at term. Neither should prenatal corticosteroids be given "just in case". Instead, prenatal steroid administration should be reserved for women for whom preterm birth is expected within no more than 7 days, based on the woman's symptoms or an accurate predictive test.

Miscarriage in the second trimester and preterm birth are significant global problems. Vaginal cervical cerclage is performed to prevent pregnancy loss and preterm birth. We aimed to determine the effectiveness of a monofilament suture thread compared with braided suture thread on pregnancy loss rates in women undergoing a cervical cerclage.C-STICH was a pragmatic, randomised, controlled, superiority trial done at 75 obstetric units in the UK. Women with a singleton pregnancy who received a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were centrally randomised (1:1) using minimisation to receive a monofilament suture or braided suture thread for their cervical cerclage. Women and outcome assessors were masked to allocation as far as possible. The primary outcome was pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life, analysed in the intention-to-treat population (ie, all women who were randomly assigned). Safety was also assessed in the intention-to-treat population. The trial was registered with ISRCTN, ISRCTN15373349.Between Aug 21, 2015, and Jan 28, 2021, 2049 women were randomly assigned to receive a monofilament suture (n=1025) or braided suture (n=1024). The primary outcome was ascertained in 1003 women in the monofilament suture group and 993 women in the braided suture group. Pregnancy loss occurred in 80 (8·0%) of 1003 women in the monofilament suture group and 75 (7·6%) of 993 women in the braided suture group (adjusted risk ratio 1·05 [95% CI 0·79 to 1·40]; adjusted risk difference 0·002 [95% CI -0·02 to 0·03]).Monofilament suture did not reduce rate of pregnancy loss when compared with a braided suture. Clinicians should use the results of this trial to facilitate discussions around the choice of suture thread to optimise outcomes.National Institute of Health Research Health Technology Assessment Programme.

BACKGROUND: Preterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce preterm birth and adverse neonatal outcomes.METHODS: We did a systematic review of randomised trials comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth. We identified published and unpublished trials that completed primary data collection before July 30, 2016, (12 months before data collection began), by searching MEDLINE, Embase, CINAHL, the Maternity and Infant Care Database, and relevant trial registers between inception and July 30, 2019. Trials of progestogen to prevent early miscarriage or immediately-threatened preterm birth were excluded. Individual participant data were requested from investigators of eligible trials. Outcomes included preterm birth, early preterm birth, and mid-trimester birth. Adverse neonatal sequelae associated with early births were assessed using a composite of serious neonatal complications, and individually. Adverse maternal outcomes were investigated as a composite and individually. Individual participant data were checked and risk of bias assessed independently by two researchers. Primary meta-analyses used one-stage generalised linear mixed models that incorporated random effects to allow for heterogeneity across trials. This meta-analysis is registered with PROSPERO, CRD42017068299.FINDINGS: Initial searches identified 47 eligible trials. Individual participant data were available for 30 of these trials. An additional trial was later included in a targeted update. Data were therefore available from a total of 31 trials (11 644 women and 16185 offspring). Trials in singleton pregnancies included mostly women with previous spontaneous preterm birth or short cervix. Preterm birth before 34 weeks was reduced in such women who received vaginal progesterone (nine trials, 3769 women; relative risk [RR] 0·78, 95% CI 0·68-0·90), 17-OHPC (five trials, 3053 women; 0·83, 0·68-1·01), and oral progesterone (two trials, 181 women; 0·60, 0·40-0·90). Results for other birth and neonatal outcomes were consistently favourable, but less certain. A possible increase in maternal complications was suggested, but this was uncertain. We identified no consistent evidence of treatment interaction with any participant characteristics examined, although analyses within subpopulations questioned efficacy in women who did not have a short cervix. Trials in multifetal pregnancies mostly included women without additional risk factors. For twins, vaginal progesterone did not reduce preterm birth before 34 weeks (eight trials, 2046 women: RR 1·01, 95% CI 0·84-1·20) nor did 17-OHPC for twins or triplets (eight trials, 2253 women: 1·04, 0·92-1·18). Preterm premature rupture of membranes was increased with 17-OHPC exposure in multifetal gestations (rupture INTERPRETATION: Vaginal progesterone and 17-OHPC both reduced birth before 34 weeks' gestation in high-risk singleton pregnancies. Given increased underlying risk, absolute risk reduction is greater for women with a short cervix, hence treatment might be most useful for these women. Evidence for oral progesterone is insufficient to support its use. Shared decision making with woman with high-risk singleton pregnancies should discuss an individual's risk, potential benefits, harms and practicalities of intervention. Treatment of unselected multifetal pregnancies with a progestogen is not supported by the evidence.FUNDING: Patient-Centered Outcomes Research Institute.

Background Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. Objectives (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. Design A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. Setting A total of 48 hospitals in the UK. Participants Women aged 16–39 years with early pregnancy bleeding. Interventions Women aged 16–39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. Main outcome measures The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. Results A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval –£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation. Conclusions Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets. Trial registration Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326. 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. 24, No. 33. See the NIHR Journals Library website for further project information.

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.

Background Preterm birth is associated with significant mortality and morbidity for mothers and babies. Women are identified as high risk for preterm birth based on either previous medical/pregnancy history or on ultrasound assessment of the cervix. Women identified as high risk can be offered a cervical cerclage (a purse string stitch) around the cervix (neck of the womb) to reduce the risk of preterm birth. In women who have a cervical cerclage, the procedure can be performed using either a monofilament (single-stranded) or braided (woven) suture material. Both suture materials are routinely used for cervical cerclage and there is uncertainty as to which is superior. Methods A multicentre, open, randomised controlled superiority trial of 2050 women presenting at obstetric units, deemed to be at risk of preterm birth and already scheduled to have a cervical cerclage as part of their standard care. Inclusion criteria include singleton pregnancies and an indication for cervical cerclage for either a history of three or more previous mid-trimester losses or premature births (≤ 28 weeks), insertion of cervical sutures in previous pregnancies, a history of mid trimester loss or premature birth with a (current) shortened (≤ 25 mm) cervix, or women whom clinicians deem to be at risk of preterm birth either by history or the results of an ultrasound scan. Exclusion criteria include women who have taken part in C-STICH previously, are aged less than 18 years old at the time of presentation, require a rescue cerclage, and are unwilling or unable to give informed consent and in whom a cerclage will be placed by any route other than vaginally (e.g. via an abdominal route). Following informed consent, women are randomised on a 1:1 basis to either monofilament or braided suture, by minimisation. The primary outcome is pregnancy loss (miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life), and secondary outcomes include the core outcome set for preterm birth trials. Discussion Optimising established interventions to prevent preterm birth is important in reducing perinatal mortality rates. Trial registration ISRCTN 15373349. Registered before recruitment on 03 December 2014 prior to first recruit.

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., Here, the authors apply DESI-MS, a sample preparation-free, direct on-swab mass spectrometry analytical tool, to profile the cervicovaginal metabolome of two independent cohorts of pregnant women and, combined with matched metataxonomic and immuno-profiling data, show that DESI-MS predicts vaginal microbiota composition and local inflammatory status associated with preterm birth and clinical interventions used during pregnancy.

Background The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth. Objectives To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness. Design The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an individual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin. Data sources/setting The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres. Participants Pregnant women at 22+0–34+6 weeks’ gestation with signs and symptoms of preterm labour. Health technology being assessed Quantitative fetal fibronectin. Main outcome measures Spontaneous preterm birth within 7 days. Results The individual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke R 2 of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days. Limitations The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation. Conclusions A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour. Future work The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model. Study registration This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423. 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. 52. See the NIHR Journals Library website for further project information.

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 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 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.

Background Retained placenta is associated with postpartum haemorrhage and can lead to significant maternal morbidity if untreated. The only effective treatment is the surgical procedure of manual removal of placenta, which is costly, requires skilled staff, requires an operative environment and is unpleasant for women. Small studies suggest that glyceryl trinitrate may be an effective medical alternative. Objective To determine the clinical effectiveness and cost-effectiveness of sublingual glyceryl trinitrate spray compared with placebo in reducing the need for manual removal of placenta in women with retained placenta after vaginal delivery following the failure of current management. Design A group-sequential randomised double-blind placebo-controlled trial with a cost-effectiveness analysis. Setting There were 29 obstetric units in the UK involved in the study. Participants There were 1107 women (glyceryl trinitrate group, n = 543; placebo group, n = 564) randomised between October 2014 and July 2017. Interventions Glyceryl trinitrate spray was administered to 541 women in the intervention group, and a placebo was administered to 563 women in the control group. Main outcome measures Four primary outcomes were defined: (1) clinical – the need for manual removal of placenta, (2) safety – measured blood loss, (3) patient sided – satisfaction with treatment and side effects and (4) economic – cost-effectiveness of both treatments using the UK NHS perspective. Secondary clinical outcomes included a > 15% decrease in haemoglobin level, time from randomisation to delivery of placenta in theatre, the need for earlier manual removal of placenta than planned, increase in heart rate or decrease in blood pressure, requirement for blood transfusion, requirement for general anaesthesia, maternal pyrexia, and sustained uterine relaxation requiring additional uterotonics. Results No difference was observed between the glyceryl trinitrate group and the control group for the placenta remaining undelivered within 15 minutes of study treatment (93.3% vs. 92%; odds ratio 1.01, 95% confidence interval 0.98 to 1.04; p = 0.393). There was no difference in blood loss of > 1000 ml between the glyceryl trinitrate group and the control group (22.2% vs. 15.5%; odds ratio 1.14, 95% confidence interval 0.88 to 1.48; p = 0.314). Palpitations were more common in the glyceryl trinitrate group than in the control group after taking the study drug (9.8% vs. 4.0%; odds ratio 2.60, 95% confidence interval 1.40 to 4.84; p = 0.003). There was no difference in any other measures of patient satisfaction between the groups. There was no difference in costs to the health service between groups (mean difference £55.30, 95% confidence interval –£199.20 to £309.79). Secondary outcomes revealed that a fall in systolic or diastolic blood pressure, or an increase in heart rate, was more common in the glyceryl trinitrate group than in the control group (odds ratio 4.9, 95% confidence interval 3.7 to 6.4; p p = 0.033). Conclusions Glyceryl trinitrate spray did not increase the delivery of retained placenta within 15 minutes of administration when compared with the placebo, and was not cost-effective for medical management of retained placenta. More participants reported palpitations and required a blood transfusion in the glyceryl trinitrate group. Further research into alternative methods of medical management of retained placenta is required. Trial registration Current Controlled Trials ISRCTN88609453. 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. 23, No. 70. See the NIHR Journals Library website for further project information.

Patients with relapsed follicular lymphoma (FL) following first-line therapy have an increasing number of management strategies ranging from observation through to stem cell transplantation. There has been an exciting expansion in novel agents to treat FL, but at present there is not a universally accepted standard of care in the relapse setting. Decision-making can be difficult for the clinician as there is a paucity of data to compare the various relapse therapies available. This review will discuss conventional therapy for relapsed FL, consider the use of novel agents and explore the role and timing of autologous and allogeneic stem cell transplantation.

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.

IDH wild-type glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. Tackling this, we investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti- apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non- malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti- apoptotic BCL-2 family members. Surprisingly, high anti-apoptotic BCL-xL and MCL-1 expression correlated with heightened susceptibility of GBM to BCL-2 family protein- targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3- mimetics.

Objective The My Baby’s Movements (MBM) trial aimed to evaluate the impact on stillbirth rates of a multifaceted awareness package (MBM intervention). Design Stepped-wedge cluster-randomised controlled trial. Setting Twenty-seven maternity hospitals in Australia and New Zealand. Population Women with a singleton pregnancy without major fetal anomaly ≥28 weeks’ gestation from August 2016-May 2019. Methods The MBM intervention was implemented at randomly assigned time points with sequential introduction into 8 clusters of 3-5 hospitals at four-monthly intervals. The stillbirth rate was compared in the control and intervention periods. Generalised linear mixed models controlled for calendar time, clustering, and hospital effects. Outcome Measures Stillbirth at ≥28 weeks’ gestation. Results There were 304,853 births with 290,219 meeting inclusion criteria: 150,079 in control and 140,140 in intervention periods. The stillbirth rate during the intervention was lower than the control period (2.2/1000 births versus 2.4, odds ratio [OR] 0.91, 95% Confidence Intervals [CI] 0.78-1.06, p=0.22). The decrease was larger across calendar time with 2.7/1000 in the first 18 months versus 2.0/1000 in the last 18 months (OR 0.74; 95% CI 0.63-0.86; p≤0.01). Following adjustment, stillbirth rates between the control and intervention periods were not significantly different: (aOR 1.18, 95% CI 0.93-1.50; p=0.18). No increase in secondary outcomes, including obstetric intervention or adverse neonatal outcome, was evident. Conclusion The MBM intervention did not reduce stillbirths beyond the downward trend over time, suggesting hospitals may have implemented best practice in DFM management outside their randomisation schedule. The role of interventions for raising awareness of DFM remains unclear

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.

Background Timely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness. Methods and findings Pregnant women included in the analyses were 22+0 to 34+6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an individual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016; 1,783 women; mean age 29.7 years; median BMI 24.8 kg/m2; 67.6% White; 11.7% smokers; 51.8% nulliparous; 10.4% with multiple pregnancy; 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018; 2,924 women; mean age 28.2 years; median BMI 25.4 kg/m2; 88.2% White; 21% smokers; 35.2% nulliparous; 3.5% with multiple pregnancy; 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R2 of 36% (95% CI: 34% to 38%). Recalibration of the model’s intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than “treat all” or “treat none” strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset. Conclusions In this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice. Trial registration The study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry (ISRCTN 41598423) and NIHR Portfolio (CPMS: 31277)., Sarah J Stock and colleagues develop and validate a risk prediction model of spontaneous preterm birth for women with preterm labour symptoms, based on vaginal fluid fetal fibronectin and clinical risk factors., Author summary Why was this study done? Preterm labour is notoriously challenging for clinicians to diagnose due to the nonspecific nature of presenting signs and symptoms. The outcomes and health of preterm babies can be significantly improved by well-timed and appropriate interventions, but unnecessary overtreatment of women is common and costly. Qualitative fetal fibronectin (fFN) is one test used to aid the diagnosis of preterm labour. What did the researchers do and find? We developed and validated a risk prediction model to improve the prediction of impending preterm birth using a combination of qualitative fFN results and additional clinical risk factors. The primary outcome was spontaneous preterm birth within 7 days of fFN testing. We developed and internally validated the model using data from 1783 European women and externally validated the model in a prospective cohort study of 2,924 UK women. Women with signs and symptoms of preterm labour were included in the analysis between 22+0 to 34+6 weeks gestation. At a threshold of ≥2% risk of birth within 7 days of testing, we found the prognostic model to be cost effective in comparison to fFN alone. What do these findings mean? Our findings indicate that the prognostic model has promising potential to improve prediction of spontaneous preterm birth. The model is well placed to aid management decisions and discussions with women presenting with signs and symptoms of preterm labour. Limitations were that there were low numbers of participants in the studies who were not White, and there were some missing data in the risk predictor development cohort.

Background: Maternal perception of decreased fetal movements (DFM) is associated with stillbirth. The My Baby’s Movements (MBM) trial aimed to evaluate the impact on stillbirth rates of a multifaceted awareness package for women and clinicians. Methods: A stepped wedge cluster randomised controlled trial was undertaken with 8 groups of 3-5 hospitals in Australia and New Zealand at four-monthly intervals, targeting women with a singleton pregnancy without major fetal anomaly at ≥28 weeks’ gestation. The primary outcome was stillbirth at ≥28 weeks’ gestation. Secondary outcomes included obstetric and neonatal outcomes. Analysis was undertaken using generalised linear mixed models controlling for calendar time, clustering, and hospital effects. Findings: From August 2016 to May 2019 there were 304,853 births with 290,219 meeting inclusion criteria: 150,079 in control and 140,140 in intervention periods. The stillbirth rate during the intervention was lower than the control period, although not statistically significant (2·2/1000 births versus 2·4, odds ratio [OR] 0·91, 95% Confidence Intervals [CI] 0·78-1·06, p=0·22). The decrease was larger across calendar time with 2·7/1000 in the first 18 months versus 2·0/1000 in the last 18 months (OR 0·74; 95% CI 0·63-0·86; p≤0·01). Adjusting for calendar time, stillbirth rates between the control and intervention periods were not significantly different: (aOR 1·18, 95% CI 0·93-1·50; p=0·18). No increase in obstetric intervention or adverse neonatal outcome was evident. Interpretation: The MBM intervention did not reduce stillbirths beyond the downward trend over time, suggesting hospitals may have implemented best practice in DFM management outside their randomisation schedule. Based on these findings, the role of interventions for raising awareness of DFM remains unclear. Trial Registration: ACTRN12614000291684. Funding Statement: National Health and Medical Research Council (NHMRC) Project Grant Application (APP1067363). Stillbirth Foundation Australia provided funding to develop the MBM application. Dr Glenn Gardener was provided a Betty McGrath Fellowship through the Mater Research Institute. Additional support was provided by Mater Foundation and the NHMRC Stillbirth Centre of Research Excellence. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Primary ethics approval was obtained from Mater Misericordiae Ltd Human Research Ethics Committee (EC00332) (MML HREC) in 2015. Further jurisdictional ethics approval was obtained from seven participating HRECs include the ACT Health, Northern Sydney Local Health District (NSLHD), Northern Territory Department of Health and Menzies School of Health Research, The Central Health and Disability Ethics Committee (NZ), Melbourne Health, and the Mercy Health. Governance clearance was obtained from all 26 sites involved in the trial.

Background Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. Objectives To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. Design This was an individual participant data meta-analysis of cohort studies. Setting Source data from secondary and tertiary care. Predictors We identified predictors from systematic reviews, and prioritised for importance in an international survey. Primary outcomes Early-onset (delivery at Analysis We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I 2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. Results The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. Limitations Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. Conclusion For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. Future work Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. Study registration This study is registered as PROSPERO CRD42015029349. 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. 24, No. 72. See the NIHR Journals Library website for further project information.

Background Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. Methods IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. Results Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model’s calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. Conclusions The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Background Preterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix. Methods and findings We conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55–1.38], p = 0.54). The primary neonatal outcome—a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery—was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54–1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50–1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses. Conclusions These results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out. Trial registration ISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181., Jane Norman and co-workers report an evaluation of a cervical pessary for prevention of preterm birth in women with a short cervix bearing twins., Author summary Why was this study done? Preterm-labour-associated preterm birth is common in twin pregnancy, and is an important cause of perinatal mortality and morbidity. There is controversy on the clinical effectiveness and cost-effectiveness of the Arabin pessary for the prevention of preterm birth in women with a twin pregnancy and a short cervix. What did the researchers do and find? We randomised 503 women with a cervical length of 35 mm or less to either standard care (according to National Institute for Health and Care Excellence [NICE] guidelines) or standard care and an Arabin pessary, inserted before 21 weeks gestation. The primary obstetric outcome was spontaneous onset of labour and birth before 34 weeks 0 days of gestation; the primary neonatal outcome was a composite adverse outcome. We found no differences in rates of the primary obstetric and neonatal outcomes between the 2 groups. What do these findings mean? Our findings indicate that any reduction in preterm-labour-associated preterm birth conferred by the Arabin pessary is less than 40%. Our findings indicate that a cervical length scan between 18 weeks 0 days and 20 weeks 6 days in women with a twin pregnancy and using a threshold length of 35 mm was ineffective at ruling in or ruling out preterm-labour-associated preterm birth.

IntroductionGestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use individual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps.Methods and analysisMEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD.Ethics and disseminationAll IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, providing much needed evidence to inform clinical and public health actions in this area.

IMPORTANCE Twin pregnancies account for 3% of live births but experience substantially more perinatal morbidity and mortality than singleton pregnancies. Optimizing the timing of birth is a key strategy in improving twin pregnancy outcomes. Current UK and US policies are based on observational studies of perinatal mortality and not on longer-term effects. The association of timing of birth with long-term childhood outcomes among twins is uncertain.OBJECTIVE To identify the optimal gestation week for birth of twin infants by calculating the week of birth associated with the lowest risk of short-term and long-term adverse outcomes (perinatal mortality and special educational need [SEN] at school).DESIGN, SETTING, AND PARTICIPANTS This population-based, data-linkage cohort study included 43 133 twin infants born at a gestational age of 34 weeks onward between January 1, 1980, and December 31, 2015, in Scotland. The data were analyzed from June 1, 2017, to March 1, 2019.EXPOSURES Gestational age (in weeks) at the time of birth.MAIN OUTCOMES AND MEASURESThe primary outcomes were extended perinatal mortalityand a record of SEN (1 of intellectual disabilities, dyslexia, physical or motor impairment, language or speech disorder, autistic spectrum disorder, and social, emotional, or behavioraldifficulties) at school (children aged 4-18 years). To infer the consequence of the gestational age at birth, clinical outcomes of twin infants born at each week of gestation from 34 weeksonward were compared with those of twin infants remaining in utero thereafter.RESULTS Of the total 43 133 twin infants included in the study, 21 696 (50.3%) were females. Although maternity records were available for all infants, 9519 sex-discordant twin children were linked to their educational data, of whom 1069 (13.8%) had a record of SEN. Compared with twins remaining in utero (n = 26 172), birth at any gestational age from 34 to 37 weeks was associated with increased odds of perinatal death (ie, adjusted odds ratio [AOR], 1.99;95% CI, 1.53-2.69 at 36 weeks [n = 8056]) and increased risk of SEN at school (AOR, 1.39; 95% CI, 1.11-1.74, for birth at 36 weeks compared with 37 weeks). In a competing risk analysis,the risks of stillbirth and neonatal death were balanced at 37 weeks (risk difference, 2.05; 95% CI, 0.8-3.3).CONCLUSIONS AND RELEVANCE The findings of this study suggest that, in the absence of amedical complication, twins should not be routinely delivered before 37 completed weeks of gestation. These findings may help optimize shared decision-making around the timing oftwin birth. These findings may help optimize shared decision-making around the timing of twin birth.

Progestogens (vaginal progesterone and intramuscular 17‐hydroxyprogesterone acetate) are widely recommended for women at high risk of preterm birth. Typical regimens include 17‐hydroxyprogesterone caproate (250 mg intramuscularly weekly), starting at 16–20 gestational weeks until 36 weeks or delivery for women with a singleton gestation and a history of spontaneous preterm birth, or vaginal progesterone (90‐mg vaginal gel or 200‐mg micronized vaginal soft capsules) for women with a short cervix (typically ≤25 mm). Although some randomized trials support this approach, neither of the largest trials (PROLONG for 17‐hydroxyprogesterone acetate or OPPTIMUM for vaginal progesterone) demonstrated efficacy. There are almost no data on long‐term effects, and none that shows benefit beyond the neonatal period. Although some analyses suggest the cost‐effectiveness of the approach, a cervical length screening program followed by progesterone for those with a short cervix will reduce preterm birth rates by less than 0.5%. The present review assesses evidence on the efficacy, likely impact, and long‐term effects of implementing the recommendations for progestogens in full. Clinicians and pregnant women can look forward to resolution of the conflicting views on efficacy once the Patient‐Centered Outcomes Research Initiative (PCORI)‐funded individual patient data meta‐analysis is published., The efficacy, probable impact, and long‐term effects of progesterone or 17‐hydroxyprogesterone acetate on the prevention of preterm labor are uncertain.

Friedman and colleagues1 outline a vision of the learning health system founded on the sharing of data and achieved through alignment of information technology, advanced analytics and clinical expertise. The Institute of Medicine2 recognises the potential of the learning health system to generate new information automatically during the delivery of healthcare, offering continual opportunities to improve healthcare processes for the benefit of public health. The learning health system is promoted as a mechanism to accelerate the adoption of effective treatments into clinical practice, shortening the extended delay3 from publication of research findings to implementation. Furthermore, it harbours the ambition to deliver personalised medicine to each service user, rather than the systematic provision of identical care to groups of patients who share the same characteristics. Worldwide escalating costs in healthcare provision due to demographic changes, compounded by ongoing use of ineffective tests and treatments, make it critically important to harness the efficiency gains of a learning health system. Of its many potential characteristics, one distinct attribute of the learning health system is to enable efficient investigation of whether strategies promoting implementation of best practice (such as educational initiatives or care bundles) actually work. A systematic review identifying a low frequency of reports on the evaluation and impact of learning health systems4 prompted us here to reconsider the central requirements for evaluation of improvement interventions within the learning health system. Here, we reflect on two recent implementation studies, both using efficiencies of the learning health system (minimising data acquisition and relying heavily on data acquisition from existing medical records), to illustrate the key issues arising when incorporating this type of research into the learning health system. In this paper, we argue that the presence of infrastructure which facilitates data sharing, combined with appropriate research design, analysis and reporting, …

Background: Preterm birth (PTB) represents the leading cause of neonatal death. Large-scale genetic studies are necessary to determine genetic influences on PTB risk, but prospective cohort studies are expensive and time-consuming. We investigated the feasibility of retrospective recruitment of post-partum women for efficient collection of genetic samples, with self-collected saliva for DNA extraction from themselves and their babies, alongside self-recollection of pregnancy and birth details to phenotype PTB. Methods: 708 women who had participated in the OPPTIMUM trial (a randomised trial of progesterone pessaries to prevent PTB [ISRCTN14568373]) and consented to further contact were invited to provide self-collected saliva from themselves and their babies. DNA was extracted from Oragene OG-500 (adults) and OG-575 (babies) saliva kits and the yield measured by Qubit. Samples were analysed using a panel of Taqman single nucleotide polymorphism (SNP) assays. A questionnaire designed to meet the minimum data set required for phenotyping PTB was included. Questionnaire responses were transcribed and analysed for concordance with prospective trial data using Cohen’s kappa (k). Results: Recruitment rate was 162/708 (23%) for self-collected saliva samples and 157/708 (22%) for questionnaire responses. 161 samples from the mother provided DNA with median yield 59.0µg (0.4-148.9µg). 156 samples were successfully genotyped (96.9%). 136 baby samples had a median yield 11.5µg (0.1-102.7µg); two samples failed DNA extraction. 131 baby samples (96.3%) were successfully genotyped. Concordance between self-recalled birth details and prospective birth details was excellent (k>0.75) in 4 out of 10 key fields for phenotyping PTB (mode of delivery, labour onset, ethnicity and maternal age at birth). Conclusion: This feasibility study demonstrates that self-collected DNA samples from mothers and babies were sufficient for genetic analysis but yields were variable. Self-recollection of pregnancy and birth details was inadequate for accurately phenotyping PTB, highlighting the need for alternative strategies for investigating genetic links with PTB.

Objectives To assess the cost‐effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. Design Economic evaluation alongside a large multi‐centre randomised placebo‐controlled trial. Setting Forty‐eight UK NHS early pregnancy units. Population Four thousand one hundred and fifty‐three women aged 16–39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. Methods An incremental cost‐effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. Main outcome measures Cost per additional live birth at ≥34 weeks of gestation. Results Progesterone intervention led to an effect difference of 0.022 (95% CI −0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI −£559 to £711) more than the mean cost in the placebo group. The incremental cost‐effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014–0.096) and this was associated with a cost saving of £322 (95% CI −£1318 to £673). Conclusions The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost‐effective intervention, particularly for women with previous miscarriage(s). Tweetable abstract Progesterone treatment is likely to be cost‐effective in women with early pregnancy bleeding and a history of miscarriage., Tweetable abstract Progesterone treatment is likely to be cost‐effective in women with early pregnancy bleeding and a history of miscarriage.

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth., Ureaplasma parvum is often isolated from intrauterine infections, which are associated with 40% of preterm births. Here, Pavlidis et al. present a mouse model of ascending U. parvum infection that resembles human disease, and show that mild cervical damage promotes intrauterine infection, inflammation and preterm birth.