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Deferred (also known as delayed) cord clamping can improve survival of infants born preterm (before 37 weeks of gestation), but the optimal duration of deferral remains unclear. We conducted a systematic review and individual participant data network meta-analysis with the aim of comparing the effectiveness of umbilical cord clamping strategies with different timings of clamping or with cord milking for preterm infants.

Umbilical cord clamping strategies at preterm birth have the potential to affect important health outcomes. The aim of this study was to compare the effectiveness of deferred cord clamping, umbilical cord milking, and immediate cord clamping in reducing neonatal mortality and morbidity at preterm birth.

Existing evidence on the effects of race and ethnicity on pregnancy outcomes is restricted to individual studies done within specific countries and health systems. We aimed to assess the impact of race and ethnicity on perinatal outcomes in high-income and upper-middle-income countries, and to ascertain whether the magnitude of disparities, if any, varied across geographical regions.

ABSTRACTThe project ‘Quality Decision-making by women and providers’ (QUALI-DEC) combines four non-clinical interventions to promote informed decision-making surrounding mode of birth, improve women’s birth experiences, and reduce caesarean sections among low-risk women. QUALI-DEC is currently being implemented in 32 healthcare facilities across Argentina, Burkina Faso, Thailand, and Viet Nam. In this paper, we detail implementation processes and the planned process evaluation, which aims to assess how and for whom QUALI-DEC worked, the mechanisms of change and their interactions with context and setting; adaptations to intervention and implementation strategies, feasibility of scaling-up, and cost-effectiveness of the intervention. We developed a project theory of change illustrating how QUALI-DEC might lead to impact. The theory of change, together with on the ground observations of implementation processes, guided the process evaluation strategy including what research questions and perspectives to prioritise. Main data sources will include: 1) regular monitoring visits in healthcare facilities, 2) quantitative process and output indicators, 3) a before and after cross-sectional survey among post-partum women, 4) qualitative interviews with all opinion leaders, and 5) qualitative interviews with postpartum women and health workers in two healthcare facilities per country, as part of a case study approach. We foresee that the QUALI-DEC process evaluation will generate valuable information that will improve interpretation of the effectiveness evaluation. At the policy level, we anticipate that important lessons and methodological insights will be drawn, with application to other settings and stakeholders looking to implement complex interventions aiming to improve maternal and newborn health and wellbeing.Trial registration: ISRCTN67214403.

(Abstracted from BMJ2018;362:k3478)Preeclampsia is a serious medical condition, affecting approximately 3% to 5% of pregnancies, accounting for more than 35,000 maternal deaths annually worldwide and an important factor in maternal morbidity. Preeclampsia affects multiple organ systems and leads to an increased risk of other severe maternal and neonatal complications in pregnancy.

Despite the global burden of morbidity and mortality associated with preterm birth, little evidence is available for use of antenatal corticosteroids and tocolytic drugs in preterm births in low-income and middle-income countries. We analysed data from the WHO Multicountry Survey on Maternal and Newborn Health (WHOMCS) to assess coverage for these interventions in preterm deliveries.

We report the main findings of the WHO Multicountry Survey on Maternal and Newborn Health (WHOMCS), which aimed to assess the burden of complications related to pregnancy, the coverage of key maternal health interventions, and use of the maternal severity index (MSI) in a global network of health facilities.

Active management of the third stage of labour reduces the risk of post-partum haemorrhage. We aimed to assess whether controlled cord traction can be omitted from active management of this stage without increasing the risk of severe haemorrhage.

Post-partum haemorrhage is a leading cause of global maternal morbidity and mortality. Misoprostol, a prostaglandin analogue with uterotonic activity, is an attractive option for treatment because it is stable, active orally, and inexpensive. We aimed to assess the effectiveness of misoprostol as an adjunct to standard uterotonics compared with standard uterotonics alone for treatment of post-partum haemorrhage.

There has been concern about rising rates of caesarean section worldwide. This Article reports the third phase of the WHO global survey, which aimed to estimate the rate of different methods of delivery and to examine the relation between method of delivery and maternal and perinatal outcomes in selected facilities in Africa and Latin America in 2004–05, and in Asia in 2007–08.

ABSTRACTThere is limited data on immunity against varicella-zoster virus (VZV) in adults in different parts of Argentina, and it is not known which VZV strains are circulating in Argentina. The objectives of this study were as follows: (i) to evaluate seroprevalence of varicella among adults, assessing the accuracy of clinical history and determining the sociodemographic factors associated with seropositivity; and (ii) to determine the VZV strains circulating in Argentina. A cross-sectional serological survey enrolling 2,807 women aged 15 to 49 years attending public health-care settings in four cities in Argentina (i.e., Buenos Aires, Salta, Mendoza, and Rosario) and one rural area was conducted from August to November 2002. Specimens for identification of VZV strains were obtained from vesicular lesions from 13 pediatric patients with varicella from different areas of the country. PCR amplification was used for genotyping. The overall seroprevalence of varicella antibodies was 98.5% (95% confidence interval, 98.0 to 98.9), ranging from 97.2% in central Buenos Aires to 99.3% in southern Buenos Aires and Salta. Varicella seroprevalence increased with age. Crowding and length of residence in the same place were associated with seropositivity. The positive predictive value of varicella history for immunity to varicella was 99.4%; however, the negative predictive value was 2.5%. The European genotype was identified in all viral specimens. In Argentina, seroprevalence in women more than 15 years old was high regardless of the area of residence. Negative or uncertain varicella history was not a good predictor of immunity. VZV genotype was stable in all areas of the country.

Preeclampsia-eclampsia is a major cause of morbidity and mortality in mothers, fetuses, and neonates worldwide, most devastating in developing nations. Its cause is still uncertain, and many controversies exist concerning its management. The World Health Organization is aware of this and is coordinating a series of systematic reviews that focus on the etiology and the best strategies for the screening, prevention, and treatment of preeclampsia. This article summarizes results from systematic reviews of randomized trials to prevent and manage preeclampsia. There is a prophylactic role of modest magnitude for low-dose aspirin but the number to treat (90 women) to avoid one case of preeclampsia still is considered high. Antioxidant and calcium supplement trials remain to be completed before firm conclusions can be rendered on their efficacy for prevention. Magnesium sulfate is effective in preventing and treating eclampsia, while severe hypertension (with or without proteinuria) requires drug therapy, but there appears to be no benefits to treating mild to moderate hypertension without proteinuria in pregnancy. Finally, our review focuses on the quality of data reviewed, suggesting the need for better evidence, and discusses the use of systematic reviews as a strategy to focus future research on this important area of reproductive medicine.

There is a need for empirical work comparing the random effects model with the fixed effects model in the calculation of a pooled relative risk in the meta-analysis in systematic reviews of randomized controlled trials. Such comparisons are particularly important when trial results are heterogeneous. We considered 84 independent meta-analyses in which each trial included a set of different women/newborns. These meta-analyses were included in systematic reviews published in the Cochrane Library's pregnancy and childbirth module. Twenty-one of these 84 meta-analyses demonstrated statistical heterogeneity at p<0.10. The random effects model estimates showed wider confidence intervals, particularly in those meta-analyses showing heterogeneity in the trial results. The summary relative risk for the random effects model tended to show a larger protective treatment effect than the fixed effects model in the heterogeneous meta-analyses. In this set of meta-analyses, statistical evaluation of publication bias cannot be shown to account for heterogeneity. Our empirical conclusion is that there may be opposing effects if the random effects model is used in the meta-analysis of clinical trials showing heterogeneity in the results: stronger treatment effects reflected in the summary relative risk, but wider confidence intervals about this summary measure. Copyright © 2001 John Wiley & Sons, Ltd.

There is a need for empirical work comparing the random effects model with the fixed effects model in the calculation of a pooled relative risk in the meta‐analysis in systematic reviews of randomized controlled trials. Such comparisons are particularly important when trial results are heterogeneous. We considered 84 independent meta‐analyses in which each trial included a set of different women/newborns. These meta‐analyses were included in systematic reviews published in the Cochrane Library's pregnancy and childbirth module. Twenty‐one of these 84 meta‐analyses demonstrated statistical heterogeneity at p<0.10. The random effects model estimates showed wider confidence intervals, particularly in those meta‐analyses showing heterogeneity in the trial results. The summary relative risk for the random effects model tended to show a larger protective treatment effect than the fixed effects model in the heterogeneous meta‐analyses. In this set of meta‐analyses, statistical evaluation of publication bias cannot be shown to account for heterogeneity. Our empirical conclusion is that there may be opposing effects if the random effects model is used in the meta‐analysis of clinical trials showing heterogeneity in the results: stronger treatment effects reflected in the summary relative risk, but wider confidence intervals about this summary measure. Copyright © 2001 John Wiley & Sons, Ltd.

The World Health Organization and collaborating institutions in four developing countries have conducted a multi-centre randomized controlled trial, in which clinics were allocated at random to two antenatal care (ANC) models. These were the standard ‘Western’ ANC model and a ‘new’ ANC model consisting of tests, clinical procedures and follow-up actions scientifically demonstrated to be effective in improving maternal and newborn outcomes. The two models were compared using the equivalence approach. This paper discusses the implications of the equivalence approach in the sample size calculation, analysis and interpretation of results of this cluster randomized trial. It reviews the ethical aspects regarding informed consent, concluding that the Zelen design has a place in cluster randomization trials. It describes the estimation of the intracluster correlation coefficient (ICC) in a stratified cluster randomized trial using two methods and reports estimates of the ICC obtained for many maternal, newborn and perinatal outcomes. Finally, it discusses analytical problems that arose: issues encountered using a composite index, heterogeneity of the intervention effect across sites, the choice of the method of analysis and the importance of efficacy analyses. The choice of the clustered Woolf estimator and the generalized estimating equations (GEE) as the methods of analysis applied is discussed. Copyright © 2001 John Wiley & Sons, Ltd.

The World Health Organization and collaborating institutions in four developing countries have conducted a multi‐centre randomized controlled trial, in which clinics were allocated at random to two antenatal care (ANC) models. These were the standard ‘Western’ ANC model and a ‘new’ ANC model consisting of tests, clinical procedures and follow‐up actions scientifically demonstrated to be effective in improving maternal and newborn outcomes. The two models were compared using the equivalence approach. This paper discusses the implications of the equivalence approach in the sample size calculation, analysis and interpretation of results of this cluster randomized trial. It reviews the ethical aspects regarding informed consent, concluding that the Zelen design has a place in cluster randomization trials. It describes the estimation of the intracluster correlation coefficient (ICC) in a stratified cluster randomized trial using two methods and reports estimates of the ICC obtained for many maternal, newborn and perinatal outcomes. Finally, it discusses analytical problems that arose: issues encountered using a composite index, heterogeneity of the intervention effect across sites, the choice of the method of analysis and the importance of efficacy analyses. The choice of the clustered Woolf estimator and the generalized estimating equations (GEE) as the methods of analysis applied is discussed. Copyright © 2001 John Wiley & Sons, Ltd.

With more than 15 million infants born preterm annually, preterm birth is the largest cause of death among newborns and the second among children younger than 5 years. Antenatal corticosteroids can improve neonatal outcomes when given at 26 to 34 weeks plus 6 days’ gestation, even if given less than 24 hours before delivery. The use of antenatal corticosteroids outside this gestational age range is controversial, but they can be beneficial at 22 to 26 weeks. Tocolytic drugs inhibit labor progression, but their use alone does not reduce perinatal mortality. No reports have been published on patterns of tocolytic drug use in preterm labor in low- and middle-income countries. This analysis of the World Health Organization Multicountry Survey of Maternal and Newborn Health data set for facility-based deliveries in 29 countries was performed to assess patterns of use of antenatal corticosteroids in preterm deliveries and tocolytic drugs in spontaneous preterm deliveries.

Objective To determine whether intra‐umbilical vein injection with saline solution, with or without oxytocin, reduces the need for manual removal of placenta compared with expectant management.

Randomized controlled trials provide the most valid basis for comparing alternative treatment modalities. Unfortunately, the quality of many such trials has not been as high as our patients deserve. We offer here methodological and practical insights to key issues related to the design, implementation, and analysis of randomized controlled trials in obstetrics and gynecology, based on our experience in exploring research hypotheses in this field. Specifically, we present randomization as a method for the prevention of confounding; we discuss the process of randomization and the bias that can be introduced to randomized controlled trials by some popular methods of randomization. The strategies for presenting baseline comparisons and evaluating the impact of a treatment or intervention are also reviewed. We hope to contribute to a more rigorous selection of treatments for our clinical and public health armamentarium.

Women who have a retained placenta are at high risk of postpartum hemorrhage without prompt treatment. The facilities and skilled personnel needed to perform manual removal of the placenta, the current treatment, are often unavailable to women in rural resource-poor settings, and the case fatality rate is nearly 10% in such settings. Some investigators have suggested that administration of oxytocin via the umbilical vein and placenta is a low-cost low technology method that could increase placental expulsion. A number of small studies reported that umbilical injection of oxytocin was an effective intervention, while a meta-analysis (Cochrane review) suggested that this intervention was effective but the results were of borderline significance Two large, high quality studies found no reduction in the rates of retained placenta compared with expectant management.

(Abstracted from New Engl J Med2018;379:743–752)Postpartum hemorrhage is the most common cause of maternal death. Oxytocin is the standard therapy for the prevention of postpartum hemorrhage, but it requires cold storage, which is not available in many countries, and has unsatisfactory real-world efficacy as a result of heat sensitivity and quality issues such as insufficient active ingredient or impurities.

To determine the efficacy of high dose folic acid supplementation for prevention of preeclampsia in women with at least one of these risk factors: pre-existing hypertension, pre-pregnancy diabetes (type I or II), twin pregnancy, preeclampsia in a previous pregnancy, or body mass index (BMI) > 35 (kg/m2).

ObjectiveTo determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35.DesignRandomised, phase III, double blinded international, multicentre clinical trial.Setting70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK).Participants2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses.InterventionEligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation.Main outcome measureThe primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks’ gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets).ResultsPre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes.ConclusionSupplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition.Trial registrationCurrent Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.

A common prophylactic intervention used in the third stage of labor to reduce postpartum hemorrhage (PPH) can be labeled as active management. In the full management package used for active management, oxytocin is administered soon after delivery in combination with controlled cord traction. However, because the proper use of controlled cord traction requires manual skills, this procedure has been recommended only for skilled birth attendants. Unfortunately, a substantial proportion of maternal deaths from hemorrhage occur in settings in which skilled birth attendants are not available. Some evidence suggests that a simplified active package omitting controlled cord traction may have a similar effect on preventing blood loss, indicating that the uterotonic component in active management may be effective on its own. The contribution of controlled cord traction to blood loss is largely unknown.

In high-resource settings, standard treatment of postpartum hemorrhage relies heavily on hospital-based interventions, and maternal death from hemorrhage is rare. Simpler methods are needed for intervention at all levels of care, especially in low-resource settings in rural areas. Misoprostol, a prostaglandin E1 analog, has been used for the management of postpartum hemorrhage although it is less effective than oxytocin. But because it has a number of advantages including ease of administration, thermostability, and relatively low cost, it can be of benefit in low resource settings. Three placebo-controlled randomized trials compared the use of misoprostol plus uterotonics and uterotonics alone in women with postpartum hemorrhage. Although a meta-analysis of these trials reported that addition of misoprostol was associated with 40% to 50% reduction in blood loss of 500 mL or more, the sample sizes were too small in these studies to make a meaningful conclusion. Moreover, a systematic review concluded that evidence for any benefit of addition of misoprostol to standard uterotonic treatment was insufficient.

Over 20% of culture-positive untreated pregnant women develop pyelonephritis and other symptomatic disease. The risk of pyelonephritis in pregnant women with asymptomatic bacteriuria is reduced by treatment with antibiotics. It is unclear whether 1-day antibiotic therapy or treatment for several days has similar efficacy. Nitrofurantoin is one of several antibiotics used for treatment in such women. This multicenter, double-blind, placebo-controlled, randomized controlled trial compared the effectiveness of 1-day treatment and 7-day treatment with nitrofurantoin in eradicating asymptomatic bacteriuria in pregnant women. The study subjects were seen between 2004 and 2007 at antenatal clinics in Thailand, the Philippines, Vietnam, and Argentina that were part of the World Health Organization Maternal and Perinatal Research Network. Pregnant women were randomized to receive nitrofurantoin 100 mg twice daily either for 1 day (1-day group, n 386) or 7 days (7-day group, n 392). Bacteriologic cure was the primary study outcome.

Rates of cesarean section continue to increase throughout the world. The authors analyzed data from the 2005 World Health Organization global survey on maternal and perinatal health in an attempt to clarify the association between operative delivery and pregnancy outcome at the institutional level. The database consisted of a multistage stratified sample of 24 geographic regions in 8 Latin American countries. Data were collected for all women admitted to 120 institutions (randomly chosen from 410 hospitals) who were admitted for delivery over a 3-month period. Data were obtained for 97,095 of 106,546 deliveries—a coverage rate of 91%.

In present-day Western practice, the umbilical cord is clamped within 10 to 15 seconds after birth, but this has not proved to be better than waiting 1 to 3 minutes. Some studies show that delayed cord clamping prevents iron deficiency anemia in the first year of life, presumably because approximately 80 mL of blood is “transfused” within a minute after birth and 100 mL after 3 minutes. Other studies, however, suggest that delay in clamping the cord may increase the risk of polycythemia, respiratory symptoms, and hyperbilirubinemia. The present randomized, controlled study examined the effects of clamping the umbilical cord at different intervals after uneventful birth (15 seconds and 1 and 3 minutes) on the venous hematocrit of term newborn infants after 6 hours of life. Hematocrit was estimated in blood taken from the antecubital vein.