Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth.

Immediately after birth, newborn babies experience rapid colonization by microorganisms from their mothers and the surrounding environment1. Diseases in childhood and later in life are potentially mediated by the perturbation of the colonization of the infant gut microbiota2. However, the effects of delivery via caesarean section on the earliest stages of the acquisition and development of the gut microbiota, during the neonatal period (≤1 month), remain controversial3,4. Here we report the disrupted transmission of maternal Bacteroides strains, and high-level colonization by opportunistic pathogens associated with the hospital environment (including Enterococcus, Enterobacter and Klebsiella species), in babies delivered by caesarean section. These effects were also seen, to a lesser extent, in vaginally delivered babies whose mothers underwent antibiotic prophylaxis and in babies who were not breastfed during the neonatal period. We applied longitudinal sampling and whole-genome shotgun metagenomic analysis to 1,679 gut microbiota samples (taken at several time points during the neonatal period, and in infancy) from 596 full-term babies born in UK hospitals; for a subset of these babies, we collected additional matched samples from mothers (175 mothers paired with 178 babies). This analysis demonstrates that the mode of delivery is a significant factor that affects the composition of the gut microbiota throughout the neonatal period, and into infancy. Matched large-scale culturing and whole-genome sequencing of over 800 bacterial strains from these babies identified virulence factors and clinically relevant antimicrobial resistance in opportunistic pathogens that may predispose individuals to opportunistic infections. Our findings highlight the critical role of the local environment in establishing the gut microbiota in very early life, and identify colonization with antimicrobial-resistance-containing opportunistic pathogens as a previously underappreciated risk factor in hospital births.

Maternal and neonatal outcomes among spontaneous vaginal births occurring in or out of water following intrapartum water immersion: The POOL cohort study.

OBJECTIVE: Warm water immersion during labour provides women with analgesia and comfort. This cohort study aimed to establish among women using intrapartum water immersion analgesia, without antenatal or intrapartum risk factors, whether waterbirth is as safe for them and their babies as leaving the water before birth. DESIGN: Cohort study with non-inferiority design. SETTING: Twenty-six UK NHS maternity services. SAMPLE: A total of 73 229 women without antenatal or intrapartum risk factors, using intrapartum water immersion, between 1 January 2015 and 30 June 2022. The analysis excluded 12 827 (17.5%) women who received obstetric or anaesthetic interventions before birth. METHODS: Non-inferiority analysis of retrospective and prospective data captured in NHS maternity and neonatal information systems. MAIN OUTCOME MEASURES: Maternal primary outcome: obstetric anal sphincter injury (OASI) by parity; neonatal composite primary outcome: fetal or neonatal death, neonatal unit admission with respiratory support or administration of antibiotics within 48 hours of birth. RESULTS: Rates of the primary outcomes were no higher among waterbirths compared with births out of water: rates of OASI among nulliparous women (waterbirth: 730/15 176 [4.8%] versus births out of water: 641/12 210 [5.3%]; adjusted odds ratio [aOR] 0.97, one-sided 95% CI, -∞ to 1.08); rates of OASI among parous women (waterbirth: 269/24 451 [1.1%] versus births out of water 144/8565 [1.7%]; aOR 0.64, one-sided 95% CI -∞ to 0.78) and rates of the composite adverse outcome among babies (waterbirth 263/9868 [2.7%] versus births out of water 224/5078 [4.4%]; aOR 0.65, one-sided 95% CI -∞ to 0.79). CONCLUSION: Among women using water immersion during labour, remaining in the pool and giving birth in water was not associated with an increase in the incidence of adverse primary maternal or neonatal outcomes.

Monofilament suture versus braided suture thread to improve pregnancy outcomes after vaginal cervical cerclage (C-STICH): a pragmatic randomised, controlled, phase 3, superiority trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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]). INTERPRETATION: 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. FUNDING: National Institute of Health Research Health Technology Assessment Programme.

Polypharmacy during pregnancy and associated risk factors: a retrospective analysis of 577 medication exposures among 1.5 million pregnancies in the UK, 2000-2019.

BACKGROUND: The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy. METHODS: A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy. RESULTS: During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese [aOR: 1.16 (1.14-1.18) and 1.55 (1.53-1.57)], belonging to an ethnic minority group [aOR: 2.40 (2.33-2.47), 1.71 (1.65-1.76), 1.41 (1.35-1.47) and 1.39 (1.30-1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women] and smoking or previously smoking [aOR: 1.19 (1.18-1.20) and 1.05 (1.03-1.06)]. Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy. CONCLUSIONS: The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.

The development of a core outcome set for studies of pregnant women with multimorbidity.

BACKGROUND: Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as a minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. METHODS: We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last 5 years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. RESULTS: Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were as follows: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care and development of new mental health conditions. The six child outcomes were as follows: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight and separation of baby from mother for health care needs. CONCLUSIONS: Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process, this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group.

Management and implications of severe COVID-19 in pregnancy in the UK: data from the UK Obstetric Surveillance System national cohort.

INTRODUCTION: There is a lack of population level data on risk factors and impact of severe COVID-19 in pregnancy. The aims of this study were to determine the characteristics, and maternal and perinatal outcomes associated with severe COVID-19 in pregnancy compared with those with mild and moderate COVID-19 and to explore the impact of timing of birth. MATERIAL AND METHODS: This was a secondary analysis of a national, prospective cohort study. All pregnant women admitted to hospital in the UK with symptomatic SARS-CoV-2 from March 1, 2020 to October 31, 2021 were included. The severity of maternal infection (need for high flow or invasive ventilation, intensive care admission or died), pregnancy and perinatal outcomes, and the impact of timing of birth were analyzed using multivariable logistic regression. RESULTS: Of 4436 pregnant women, 13.9% (n = 616) had severe infection. Women with severe infection were more likely to be aged ≥30 years (adjusted odds ratio [aOR] aged 30-39 1.48, 95% confidence interval [CI] 1.20-1.83), be overweight or obese (aOR 1.73, 95% CI 1.34-2.25 and aOR 2.52 95% CI 1.97-3.23, respectively), be of mixed ethnicity (aOR 1.93, 95% CI 1.17-3.21) or have gestational diabetes (aOR 1.43, 95% CI 1.09-1.87) compared with those with mild or moderate infection. Women with severe infection were more likely to have a pre-labor cesarean birth (aOR 8.84, 95% CI 6.61-11.83), a very or extreme preterm birth (28-31+ weeks' gestation, aOR 18.97, 95% CI 7.78-14.85; <28 weeks' gestation, aOR 12.35, 95% CI 6.34-24.05) and their babies were more likely to be stillborn (aOR 2.51, 95% CI 1.35-4.66) or admitted to a neonatal unit (aOR 11.61, 95% CI 9.28-14.52). Of 112 women with severe infection who were discharged and gave birth at a later admission, the majority gave birth ≥36 weeks (85.7%), noting that three women in this group (2.7%) had a stillbirth. CONCLUSIONS: Severe COVID-19 in pregnancy increases the risk of adverse outcomes. Information to promote uptake of vaccination should specifically target those at greatest risk of severe outcomes. Decisions about timing of birth should be informed by multidisciplinary team discussion; however, our data suggest that women with severe infection who do not require early delivery have mostly good outcomes but that those with severe infection at term may warrant rapid delivery.

Epidemiology of pre-existing multimorbidity in pregnant women in the UK in 2018: a population-based cross-sectional study.

BACKGROUND: Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland). STUDY DESIGN: Pregnant women aged 15-49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians. RESULTS: The prevalence of multimorbidity was 44.2% (95% CI 43.7-44.7%), 46.2% (45.6-46.8%) and 19.8% (18.8-20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% [23.8-24.6%], 23.5% [23.0-24.0%] and 17.0% [16.0 to 17.9%] in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% [30.8-31.8%]). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 [95% CI 1.04-3.17] 45-49 years vs 15-19 years), multigravid (1.68 [1.50-1.89] gravidity ≥ five vs one), have raised body mass index (1.59 [1.44-1.76], body mass index 30+ vs body mass index 18.5-24.9) and smoked preconception (1.61 [1.46-1.77) vs non-smoker). CONCLUSION: Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.

Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines).

Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this Review is to provide a summary of knowledge on placebo controls in surgical trials. A placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. This Review outlines what a placebo control entails and present understanding of this tool in the context of surgery. We consider when placebo controls in surgery are acceptable (and when they are desirable) in terms of ethical arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be done and interpreted. Use of placebo controls is justified in randomised controlled trials of surgical interventions provided there is a strong scientific and ethical rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with high risk of bias, particularly because of the placebo effect. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. This Review forms an outline for best practice and provides guidance, in the form of the Applying Surgical Placebo in Randomised Evaluations (known as ASPIRE) checklist, for those considering the use of a placebo control in a surgical randomised controlled trial.

Universal third-trimester ultrasonic screening using fetal macrosomia in the prediction of adverse perinatal outcome: A systematic review and meta-analysis of diagnostic test accuracy.

BACKGROUND: The effectiveness of screening for macrosomia is not well established. One of the critical elements of an effective screening program is the diagnostic accuracy of a test at predicting the condition. The objective of this study is to investigate the diagnostic effectiveness of universal ultrasonic fetal biometry in predicting the delivery of a macrosomic infant, shoulder dystocia, and associated neonatal morbidity in low- and mixed-risk populations. METHODS AND FINDINGS: We conducted a predefined literature search in Medline, Excerpta Medica database (EMBASE), the Cochrane library and ClinicalTrials.gov from inception to May 2020. No language restrictions were applied. We included studies where the ultrasound was performed as part of universal screening and those that included low- and mixed-risk pregnancies and excluded studies confined to high risk pregnancies. We used the estimated fetal weight (EFW) (multiple formulas and thresholds) and the abdominal circumference (AC) to define suspected large for gestational age (LGA). Adverse perinatal outcomes included macrosomia (multiple thresholds), shoulder dystocia, and other markers of neonatal morbidity. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was carried out using the hierarchical summary receiver operating characteristic (ROC) and the bivariate logit-normal (Reitsma) models. We identified 41 studies that met our inclusion criteria involving 112,034 patients in total. These included 11 prospective cohort studies (N = 9986), one randomized controlled trial (RCT) (N = 367), and 29 retrospective cohort studies (N = 101,681). The quality of the studies was variable, and only three studies blinded the ultrasound findings to the clinicians. Both EFW >4,000 g (or 90th centile for the gestational age) and AC >36 cm (or 90th centile) had >50% sensitivity for predicting macrosomia (birthweight above 4,000 g or 90th centile) at birth with positive likelihood ratios (LRs) of 8.74 (95% confidence interval [CI] 6.84-11.17) and 7.56 (95% CI 5.85-9.77), respectively. There was significant heterogeneity at predicting macrosomia, which could reflect the different study designs, the characteristics of the included populations, and differences in the formulas used. An EFW >4,000 g (or 90th centile) had 22% sensitivity at predicting shoulder dystocia with a positive likelihood ratio of 2.12 (95% CI 1.34-3.35). There was insufficient data to analyze other markers of neonatal morbidity. CONCLUSIONS: In this study, we found that suspected LGA is strongly predictive of the risk of delivering a large infant in low- and mixed-risk populations. However, it is only weakly (albeit statistically significantly) predictive of the risk of shoulder dystocia. There was insufficient data to analyze other markers of neonatal morbidity.

Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial.

BACKGROUND: In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unclear because limitation of maternal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of neonatal or infant outcomes, compared with expectant management (usual care) in women with late preterm pre-eclampsia. METHODS: In this parallel-group, non-masked, multicentre, randomised controlled trial done in 46 maternity units across England and Wales, we compared planned delivery versus expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia from 34 to less than 37 weeks' gestation and a singleton or dichorionic diamniotic twin pregnancy. The co-primary maternal outcome was a composite of maternal morbidity or recorded systolic blood pressure of at least 160 mm Hg with a superiority hypothesis. The co-primary perinatal outcome was a composite of perinatal deaths or neonatal unit admission up to infant hospital discharge with a non-inferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were by intention to treat, together with a per-protocol analysis for the perinatal outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN01879376. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: Between Sept 29, 2014, and Dec 10, 2018, 901 women were recruited. 450 women (448 women and 471 infants analysed) were allocated to planned delivery and 451 women (451 women and 475 infants analysed) to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group (289 [65%] women) compared with the expectant management group (338 [75%] women; adjusted relative risk 0·86, 95% CI 0·79-0·94; p=0·0005). The incidence of the co-primary perinatal outcome by intention to treat was significantly higher in the planned delivery group (196 [42%] infants) compared with the expectant management group (159 [34%] infants; 1·26, 1·08-1·47; p=0·0034). The results from the per-protocol analysis were similar. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. INTERPRETATION: There is strong evidence to suggest that planned delivery reduces maternal morbidity and severe hypertension compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater neonatal morbidity. This trade-off should be discussed with women with late preterm pre-eclampsia to allow shared decision making on timing of delivery. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Vaginal preparation with chlorhexidine at cesarean section to reduce endometritis and prevent sepsis: A randomized pilot trial (PREPS).

INTRODUCTION: Cesarean sections are the most common major operation worldwide. One in 10 women develops a surgical-site infection after cesarean section. The PREPS pilot trial was developed to assess the feasibility of a randomized controlled trial of vaginal cleansing with chlorhexidine before cesarean section, to reduce infectious morbidity. MATERIAL AND METHODS: A multi-center, open-label, parallel-group pilot randomized controlled trial across 4 UK maternity units. Women aged ≥16 years, undergoing elective or emergency cesarean section, ≥34 weeks of gestation, and able to give informed consent were eligible. Women were randomized 1:1 to chlorhexidine 0.05% or no cleansing and were followed up until 6 weeks after cesarean section. The feasibility of a larger randomized controlled trial was assessed by the pilot trial's recruitment, ability to use verbal consent in an emergency, adherence, follow-up and withdrawal rates. The main clinical outcome collected was Center for Disease Control and Prevention (CDC) classification of endometritis at 30 days. Trial registration number is ISRCTN33435996. RESULTS: A total of 320 women (128% of target) were randomized. Of these, 93% (95% CI 89%-95%) received their allocated intervention. Of the 88 women who had an emergency cesarean section, verbal consent was initially given by 32 (36%) women, with the remainder having sufficient time to give written consent. Endometritis (CDC definition) was collected from medical notes of 96% of women, 68% (95% CI 63%-73%) were followed up at both 14 and 30 days by telephone, and we were able to collect patient-reported outcomes. In the vaginal cleansing arm 2/152 (1.3%) women had endometritis compared with 1/155 (0.7%) in the no cleansing arm (RR 2.08, 95% CI 0.19-22.31). CONCLUSIONS: It is possible to perform a randomized controlled trial in women undergoing an elective or emergency cesarean section, using a verbal-followed-by-written consent process, while maintaining high adherence and retaining women in the trial.

Uncertainties in Screening and Prevention of Group B Streptococcus Disease.

In autumn 2016, the UK Department of Health (now Department of Health and Social Care) convened 2 meetings to discuss how to address research evidence gaps in order to minimize the impact of infant group B streptococcus (GBS) disease in the United Kingdom. At that meeting, a number of research priorities were highlighted, including improving the screening for GBS colonization in pregnant women, offering intrapartum antibiotic prophylaxis and point-of-care testing, and understanding the effect of widespread intrapartum antibiotic use on long-term infant health. Further discussions involved investigating the feasibility of a large prospective study of pregnant women and their infants in order to understand the role of antibodies in the protection against GBS disease in infancy following maternal exposure to GBS colonization. Here, we summarize the research uncertainties identified at that meeting.

Effects of repeat prenatal corticosteroids given to women at risk of preterm birth: An individual participant data meta-analysis.

BACKGROUND: Infants born preterm compared with infants born at term are at an increased risk of dying and of serious morbidities in early life, and those who survive have higher rates of neurological impairments. It remains unclear whether exposure to repeat courses of prenatal corticosteroids can reduce these risks. This individual participant data (IPD) meta-analysis (MA) assessed whether repeat prenatal corticosteroid treatment given to women at ongoing risk of preterm birth in order to benefit their infants is modified by participant or treatment factors. METHODS AND FINDINGS: Trials were eligible for inclusion if they randomised women considered at risk of preterm birth who had already received an initial, single course of prenatal corticosteroid seven or more days previously and in which corticosteroids were compared with either placebo or no placebo. The primary outcomes for the infants were serious outcome, use of respiratory support, and birth weight z-scores; for the children, they were death or any neurosensory disability; and for the women, maternal sepsis. Studies were identified using the Cochrane Pregnancy and Childbirth search strategy. Date of last search was 20 January 2015. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. IPD were analysed using a one-stage approach. Eleven trials, conducted between 2002 and 2010, were identified as eligible, with five trials being from the United States, two from Canada, and one each from Australia and New Zealand, Finland, India, and the United Kingdom. All 11 trials were included, with 4,857 women and 5,915 infants contributing data. The mean gestational age at trial entry for the trials was between 27.4 weeks and 30.2 weeks. There was no significant difference in the proportion of infants with a serious outcome (relative risk [RR] 0.92, 95% confidence interval [CI] 0.82 to 1.04, 5,893 infants, 11 trials, p = 0.33 for heterogeneity). There was a reduction in the use of respiratory support in infants exposed to repeat prenatal corticosteroids compared with infants not exposed (RR 0.91, 95% CI 0.85 to 0.97, 5,791 infants, 10 trials, p = 0.64 for heterogeneity). The number needed to treat (NNT) to benefit was 21 (95% CI 14 to 41) women/fetus to prevent one infant from needing respiratory support. Birth weight z-scores were lower in the repeat corticosteroid group (mean difference -0.12, 95%CI -0.18 to -0.06, 5,902 infants, 11 trials, p = 0.80 for heterogeneity). No statistically significant differences were seen for any of the primary outcomes for the child (death or any neurosensory disability) or for the woman (maternal sepsis). The treatment effect varied little by reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, the gestational age when first trial treatment course was given, or the time prior to birth that the last dose was given. Infants exposed to between 2-5 courses of repeat corticosteroids showed a reduction in both serious outcome and the use of respiratory support compared with infants exposed to only a single repeat course. However, increasing numbers of repeat courses of corticosteroids were associated with larger reductions in birth z-scores for weight, length, and head circumference. Not all trials could provide data for all of the prespecified subgroups, so this limited the power to detect differences because event rates are low for some important maternal, infant, and childhood outcomes. CONCLUSIONS: In this study, we found that repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduced the likelihood of their infant needing respiratory support after birth and led to neonatal benefits. Body size measures at birth were lower in infants exposed to repeat prenatal corticosteroids. Our findings suggest that to provide clinical benefit with the least effect on growth, the number of repeat treatment courses should be limited to a maximum of three and the total dose to between 24 mg and 48 mg.

Outcomes of Two Trials of Oxygen-Saturation Targets in Preterm Infants.

BACKGROUND: The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS: In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS: After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001). CONCLUSIONS: Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).

When to keep it simple - adaptive designs are not always useful.

BACKGROUND: Adaptive designs are a wide class of methods focused on improving the power, efficiency and participant benefit of clinical trials. They do this through allowing information gathered during the trial to be used to make changes in a statistically robust manner - the changes could include which treatment arms patients are enrolled to (e.g. dropping non-promising treatment arms), the allocation ratios, the target sample size or the enrolment criteria of the trial. Generally, we are enthusiastic about adaptive designs and advocate their use in many clinical situations. However, they are not always advantageous. In some situations, they provide little efficiency advantage or are even detrimental to the quality of information provided by the trial. In our experience, factors that reduce the efficiency of adaptive designs are routinely downplayed or ignored in methodological papers, which may lead researchers into believing they are more beneficial than they actually are. MAIN TEXT: In this paper, we discuss situations where adaptive designs may not be as useful, including situations when the outcomes take a long time to observe, when dropping arms early may cause issues and when increased practical complexity eliminates theoretical efficiency gains. CONCLUSION: Adaptive designs often provide notable efficiency benefits. However, it is important for investigators to be aware that they do not always provide an advantage. There should always be careful consideration of the potential benefits and disadvantages of an adaptive design.

Pulse Oximeter Saturation Targeting and Oximeter Changes in the Benefits of Oxygen Saturation Targeting (BOOST)-II Australia and BOOST-II UK Oxygen Trials.

Infants in the Australian and UK Benefits of Oxygen Saturation Targeting-II trials treated using revised oximeters spent more time within their planned pulse oximeter saturation target ranges than infants treated using the original oximeters (P < .001). This may explain the larger mortality difference seen with revised oximeters. If so, average treatment effects from the Neonatal Oxygen Prospective Meta-analysis trials may be underestimates.

Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration.

Importance: There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. Objective: To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. Design, Setting, and Participants: Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks' gestation. Exposures: Spo2 target range that was lower (85%-89%) vs higher (91%-95%). Main Outcomes and Measures: The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities. Results: A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% [95% CI, -1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, -4.0% [95% CI, -6.1% to -2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Spo2 target group and 170 of 2465 infants (6.9%) in the higher Spo2 target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], P = .003). Conclusions and Relevance: In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

Effects of hypothermia for perinatal asphyxia on childhood outcomes.

BACKGROUND: In the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), newborns with asphyxial encephalopathy who received hypothermic therapy had improved neurologic outcomes at 18 months of age, but it is uncertain whether such therapy results in longer-term neurocognitive benefits. METHODS: We randomly assigned 325 newborns with asphyxial encephalopathy who were born at a gestational age of 36 weeks or more to receive standard care alone (control) or standard care with hypothermia to a rectal temperature of 33 to 34°C for 72 hours within 6 hours after birth. We evaluated the neurocognitive function of these children at 6 to 7 years of age. The primary outcome of this analysis was the frequency of survival with an IQ score of 85 or higher. RESULTS: A total of 75 of 145 children (52%) in the hypothermia group versus 52 of 132 (39%) in the control group survived with an IQ score of 85 or more (relative risk, 1.31; P=0.04). The proportions of children who died were similar in the hypothermia group and the control group (29% and 30%, respectively). More children in the hypothermia group than in the control group survived without neurologic abnormalities (65 of 145 [45%] vs. 37 of 132 [28%]; relative risk, 1.60; 95% confidence interval, 1.15 to 2.22). Among survivors, children in the hypothermia group, as compared with those in the control group, had significant reductions in the risk of cerebral palsy (21% vs. 36%, P=0.03) and the risk of moderate or severe disability (22% vs. 37%, P=0.03); they also had significantly better motor-function scores. There was no significant between-group difference in parental assessments of children's health status and in results on 10 of 11 psychometric tests. CONCLUSIONS: Moderate hypothermia after perinatal asphyxia resulted in improved neurocognitive outcomes in middle childhood. (Funded by the United Kingdom Medical Research Council and others; TOBY ClinicalTrials.gov number, NCT01092637.).

A comparison of intrapartum interventions and adverse outcomes by parity in planned freestanding midwifery unit and alongside midwifery unit births: secondary analysis of 'low risk' births in the birthplace in England cohort.

BACKGROUND: For low risk women, there is good evidence that planned birth in a midwifery unit is associated with a reduced risk of maternal interventions compared with planned birth in an obstetric unit. Findings from the Birthplace cohort study have been interpreted by some as suggesting a reduced risk of interventions in planned births in freestanding midwifery units (FMUs) compared with planned births in alongside midwifery units (AMUs). However, possible differences have not been robustly investigated using individual-level Birthplace data. METHODS: This was a secondary analysis of data on 'low risk' women with singleton, term, 'booked' pregnancies collected in the Birthplace national prospective cohort study. We used logistic regression to compare interventions and outcomes by parity in 11,265 planned FMU births and 16,673 planned AMU births, adjusted for potential confounders, using planned AMU birth as the reference group. Outcomes considered included adverse perinatal outcomes (Birthplace primary outcome measure), instrumental delivery, intrapartum caesarean section, 'straightforward vaginal birth', third or fourth degree perineal trauma, blood transfusion and maternal admission for higher-level care. We used a significance level of 1% for all secondary outcomes. RESULTS: There was no significant difference in adverse perinatal outcomes between planned AMU and FMU births. The odds of instrumental delivery were reduced in planned FMU births (nulliparous: aOR 0.63, 99% CI 0.46-0.86; multiparous: aOR 0.41, 99% CI 0.25-0.68) and the odds of having a 'straightforward vaginal birth' were increased in planned FMU births compared with planned AMU births (nulliparous: aOR 1.47, 99% CI 1.17-1.85; multiparous: 1.86, 99% CI 1.35-2.57). The odds of intrapartum caesarean section did not differ significantly between the two settings (nulliparous: p = 0.147; multiparous: p = 0.224). The overall pattern of findings suggested a trend towards lower intervention rates and fewer adverse maternal outcomes in planned FMU births compared with planned AMU births. CONCLUSIONS: The findings support the recommendation that 'low risk' women can be informed that planned birth in an FMU is associated with a lower rate of instrumental delivery and a higher rate of 'straightforward vaginal birth' compared with planned birth in an AMU; and that outcomes for babies do not appear to differ between FMUs and AMUs.