Randomized Trial of Early Detection and Treatment of Postpartum Hemorrhage.

BACKGROUND: Delays in the detection or treatment of postpartum hemorrhage can result in complications or death. A blood-collection drape can help provide objective, accurate, and early diagnosis of postpartum hemorrhage, and delayed or inconsistent use of effective interventions may be able to be addressed by a treatment bundle. METHODS: We conducted an international, cluster-randomized trial to assess a multicomponent clinical intervention for postpartum hemorrhage in patients having vaginal delivery. The intervention included a calibrated blood-collection drape for early detection of postpartum hemorrhage and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination, and escalation), supported by an implementation strategy (intervention group). Hospitals in the control group provided usual care. The primary outcome was a composite of severe postpartum hemorrhage (blood loss, ≥1000 ml), laparotomy for bleeding, or maternal death from bleeding. Key secondary implementation outcomes were the detection of postpartum hemorrhage and adherence to the treatment bundle. RESULTS: A total of 80 secondary-level hospitals across Kenya, Nigeria, South Africa, and Tanzania, in which 210,132 patients underwent vaginal delivery, were randomly assigned to the intervention group or the usual-care group. Among hospitals and patients with data, a primary-outcome event occurred in 1.6% of the patients in the intervention group, as compared with 4.3% of those in the usual-care group (risk ratio, 0.40; 95% confidence interval [CI], 0.32 to 0.50; P<0.001). Postpartum hemorrhage was detected in 93.1% of the patients in the intervention group and in 51.1% of those in the usual-care group (rate ratio, 1.58; 95% CI, 1.41 to 1.76), and the treatment bundle was used in 91.2% and 19.4%, respectively (rate ratio, 4.94; 95% CI, 3.88 to 6.28). CONCLUSIONS: Early detection of postpartum hemorrhage and use of bundled treatment led to a lower risk of the primary outcome, a composite of severe postpartum hemorrhage, laparotomy for bleeding, or death from bleeding, than usual care among patients having vaginal delivery. (Funded by the Bill and Melinda Gates Foundation; E-MOTIVE ClinicalTrials.gov number, NCT04341662.).

Outcomes and quality of care for women and their babies after caesarean section in Nigeria.

OBJECTIVE: To describe the outcomes and quality of care for women and their babies after caesarean section (CS) in Nigerian referral-level hospitals. DESIGN: Secondary analysis of a nationwide cross-sectional study. SETTING: Fifty-four referral-level hospitals. POPULATION: All women giving birth in the participating facilities between 1 September 2019 and 31 August 2020. METHODS: Data for the women were extracted, including sociodemographic data, clinical information, mode of birth, and maternal and perinatal outcomes. A conceptual hierarchical framework was employed to explore the sociodemographic and clinical factors associated with maternal and perinatal death in women who had an emergency CS. MAIN OUTCOME MEASURES: Overall CS rate, outcomes for women who had CS, and factors associated with maternal and perinatal mortality. RESULTS: The overall CS rate was 33.3% (22 838/68 640). The majority of CS deliveries were emergency cases (62.8%) and 8.1% of CS deliveries had complications after delivery, which were more common after an emergency CS. There were 179 (0.8%) maternal deaths in women who had a CS and 29.6% resulted from complications of hypertensive disorders of pregnancy. The overall maternal mortality rate in women who delivered by CS was 778 per 100 000 live births, whereas the perinatal mortality at birth was 51 per 1000 live births. Factors associated with maternal mortality in women who had an emergency CS were being <20 or >35 years of age, having a lower level of education and being referred from another facility or informal setting. CONCLUSIONS: One-third of births were delivered via CS (mostly emergency), with almost one in ten women experiencing a complication after a CS. To improve outcomes, hospitals should invest in care and remove obstacles to accessible quality CS services.

Burden and outcomes of postpartum haemorrhage in Nigerian referral-level hospitals.

OBJECTIVE: To determine the prevalence of primary postpartum haemorrhage (PPH), risk factors, and maternal and neonatal outcomes in a multicentre study across Nigeria. DESIGN: A secondary data analysis using a cross-sectional design. SETTING: Referral-level hospitals (48 public and six private facilities). POPULATION: Women admitted for birth between 1 September 2019 and 31 August 2020. METHODS: Data collected over a 1-year period from the Maternal and Perinatal Database for Quality, Equity and Dignity programme in Nigeria were analysed, stratified by mode of delivery (vaginal or caesarean), using a mixed-effects logistic regression model. MAIN OUTCOME MEASURES: Prevalence of PPH and maternal and neonatal outcomes. RESULTS: Of 68 754 women, 2169 (3.2%, 95% CI 3.07%-3.30%) had PPH, with a prevalence of 2.7% (95% CI 2.55%-2.85%) and 4.0% (95% CI 3.75%-4.25%) for vaginal and caesarean deliveries, respectively. Factors associated with PPH following vaginal delivery were: no formal education (aOR 2.2, 95% CI 1.8-2.6, P < 0.001); multiple pregnancy (aOR 2.7, 95% CI 2.1-3.5, P < 0.001); and antepartum haemorrhage (aOR 11.7, 95% CI 9.4-14.7, P < 0.001). Factors associated with PPH in a caesarean delivery were: maternal age of >35 years (aOR 1.7, 95% CI 1.5-2.0, P < 0.001); referral from informal setting (aOR 2.4, 95% CI 1.4-4.0, P = 0.002); and antepartum haemorrhage (aOR 3.7, 95% CI 2.8-4.7, P < 0.001). Maternal mortality occurred in 4.8% (104/2169) of deliveries overall, and in 8.5% (101/1182) of intensive care unit admissions. One-quarter of all infants were stillborn (570/2307), representing 23.9% (429/1796) of neonatal intensive care unit admissions. CONCLUSIONS: A PPH prevalence of 3.2% can be reduced with improved access to skilled birth attendants.

Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries.

BACKGROUND: The safety and efficacy of antenatal glucocorticoids in women in low-resource countries who are at risk for preterm birth are uncertain. METHODS: We conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at risk for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal death, and possible maternal bacterial infection; neonatal death alone and stillbirth or neonatal death were evaluated with superiority analyses, and possible maternal bacterial infection was evaluated with a noninferiority analysis with the use of a prespecified margin of 1.25 on the relative scale. RESULTS: A total of 2852 women (and their 3070 fetuses) from 29 secondary- and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan underwent randomization. The trial was stopped for benefit at the second interim analysis. Neonatal death occurred in 278 of 1417 infants (19.6%) in the dexamethasone group and in 331 of 1406 infants (23.5%) in the placebo group (relative risk, 0.84; 95% confidence interval [CI], 0.72 to 0.97; P = 0.03). Stillbirth or neonatal death occurred in 393 of 1532 fetuses and infants (25.7%) and in 444 of 1519 fetuses and infants (29.2%), respectively (relative risk, 0.88; 95% CI, 0.78 to 0.99; P = 0.04); the incidence of possible maternal bacterial infection was 4.8% and 6.3%, respectively (relative risk, 0.76; 95% CI, 0.56 to 1.03). There was no significant between-group difference in the incidence of adverse events. CONCLUSIONS: Among women in low-resource countries who were at risk for early preterm birth, the use of dexamethasone resulted in significantly lower risks of neonatal death alone and stillbirth or neonatal death than the use of placebo, without an increase in the incidence of possible maternal bacterial infection. (Funded by the Bill and Melinda Gates Foundation and the World Health Organization; Australian and New Zealand Clinical Trials Registry number, ACTRN12617000476336; Clinical Trials Registry-India number, CTRI/2017/04/008326.).

Tranexamic acid at cesarean delivery: drug-error deaths.

The use of tranexamic acid for postpartum hemorrhage has entered obstetrical practice globally with the evidence-based expectation of saving lives. This improvement in the care of women with postpartum hemorrhage has come at a price. For the anesthetist, having tranexamic acid ampoules close at hand would seem an obvious strategy to facilitate its use during cesarean delivery, an important setting for severe hemorrhage. Tragically, we have identified a number of recent instances of inadvertent intrathecal administration of tranexamic acid instead of local anesthetic for spinal anesthesia. Reported cases of this catastrophic error seem to be increasing. The profound neurotoxicity of tranexamic acid causes rapid-onset convulsions, with mortality of 50%. How can these tragic errors be averted? Drug safety alerts have been issued by the US Food and Drug Administration and the World Health Organization, but that is not enough. We recommend extensive dissemination of information to raise awareness of this potential hazard, and local hospital protocols to ensure that tranexamic acid is stored separately from anesthetic drugs, preferably outside the operating room and with an auxiliary warning label. Implementation of safety strategies on a very large scale will be needed to ensure that the life-saving potential of tranexamic acid is not eclipsed by drug-error mortality.

New insights on labor progression: a systematic review.

The past 20 years witnessed an invigoration of research on labor progression and a change of thinking regarding normal labor. New evidence is emerging, and more advanced statistical methods are applied to labor progression analyses. Given the wide variations in the onset of active labor and the pattern of labor progression, there is an emerging consensus that the definition of abnormal labor may not be related to an idealized or average labor curve. Alternative approaches to guide labor management have been proposed; for example, using an upper limit of a distribution of labor duration to define abnormally slow labor. Nonetheless, the methods of labor assessment are still primitive and subject to error; more objective measures and more advanced instruments are needed to identify the onset of active labor, monitor labor progression, and define when labor duration is associated with maternal/child risk. Cervical dilation alone may be insufficient to define active labor, and incorporating more physical and biochemical measures may improve accuracy of diagnosing active labor onset and progression. Because the association between duration of labor and perinatal outcomes is rather complex and influenced by various underlying and iatrogenic conditions, future research must carefully explore how to integrate statistical cut-points with clinical outcomes to reach a practical definition of labor abnormalities. Finally, research regarding the complex labor process may benefit from new approaches, such as machine learning technologies and artificial intelligence to improve the predictability of successful vaginal delivery with normal perinatal outcomes.

Tranexamic acid at cesarean delivery: drug-error deaths.

The use of tranexamic acid for postpartum hemorrhage has entered obstetrical practice globally with the evidence-based expectation of saving lives. This improvement in the care of women with postpartum hemorrhage has come at a price. For the anesthetist, having tranexamic acid ampoules close at hand would seem an obvious strategy to facilitate its use during cesarean delivery, an important setting for severe hemorrhage. Tragically, we have identified a number of recent instances of inadvertent intrathecal administration of tranexamic acid instead of local anesthetic for spinal anesthesia. Reported cases of this catastrophic error seem to be increasing. The profound neurotoxicity of tranexamic acid causes rapid-onset convulsions, with mortality of 50%. How can these tragic errors be averted? Drug safety alerts have been issued by the US Food and Drug Administration and the World Health Organization, but that is not enough. We recommend extensive dissemination of information to raise awareness of this potential hazard, and local hospital protocols to ensure that tranexamic acid is stored separately from anesthetic drugs, preferably outside the operating room and with an auxiliary warning label. Implementation of safety strategies on a very large scale will be needed to ensure that the life-saving potential of tranexamic acid is not eclipsed by drug-error mortality.

A core outcome set for trials in miscarriage management and prevention: An international consensus development study.

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage.

Alternative magnesium sulphate regimens for women with pre-eclampsia and eclampsia.

BACKGROUND: Magnesium sulphate is the drug of choice for the prevention and treatment of women with eclampsia. Regimens for administration of this drug have evolved over the years, but there is no clarity on the comparative benefits or harm of alternative regimens. This is an update of a review first published in 2010. OBJECTIVES: To assess if one magnesium sulphate regimen is better than another when used for the care of women with pre-eclampsia or eclampsia, or both, to reduce the risk of severe morbidity and mortality for the woman and her baby. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (29 April 2022), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised trials and cluster-randomised trials comparing different regimens for administration of magnesium sulphate used in women with pre-eclampsia or eclampsia, or both. Comparisons included different dose regimens, intramuscular versus intravenous route for maintenance therapy, and different durations of therapy. We excluded studies with quasi-random or cross-over designs. We included abstracts of conference proceedings if compliant with the trustworthiness assessment. DATA COLLECTION AND ANALYSIS: For this update, two review authors assessed trials for inclusion, performed risk of bias assessment, and extracted data. We checked data for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: For this update, a total of 16 trials (3020 women) met our inclusion criteria: four trials (409 women) compared regimens for women with eclampsia, and 12 trials (2611 women) compared regimens for women with pre-eclampsia. Most of the included trials had small sample sizes and were conducted in low- and middle-income countries. Eleven trials reported adequate randomisation and allocation concealment. Blinding of participants and clinicians was not possible in most trials. The included studies were for the most part at low risk of attrition and reporting bias. Treatment of women with eclampsia (four comparisons) One trial compared a loading dose-alone regimen with a loading dose plus maintenance dose regimen (80 women). It is uncertain whether either regimen has an effect on the risk of recurrence of convulsions or maternal death (very low-certainty evidence). One trial compared a lower-dose regimen with standard-dose regimen over 24 hours (72 women). It is uncertain whether either regimen has an effect on the risk of recurrence of convulsion, severe morbidity, perinatal death, or maternal death (very low-certainty evidence). One trial (137 women) compared intravenous (IV) versus standard intramuscular (IM) maintenance regimen. It is uncertain whether either route has an effect on recurrence of convulsions, death of the baby before discharge (stillbirth and neonatal death), or maternal death (very low-certainty evidence). One trial (120 women) compared a short maintenance regimen with a standard (24 hours after birth) maintenance regimen. It is uncertain whether the duration of the maintenance regimen has an effect on recurrence of convulsions, severe morbidity, or side effects such as nausea and respiratory failure. A short maintenance regimen may reduce the risk of flushing when compared to a standard 24 hours maintenance regimen (risk ratio (RR) 0.27, 95% confidence interval (CI) 0.08 to 0.93; 1 trial, 120 women; low-certainty evidence). Many of our prespecified critical outcomes were not reported in the included trials. Prevention of eclampsia for women with pre-eclampsia (five comparisons) Two trials (462 women) compared loading dose alone with loading dose plus maintenance therapy. Low-certainty evidence suggests an uncertain effect with either regimen on the risk of eclampsia (RR 2.00, 95% CI 0.61 to 6.54; 2 trials, 462 women) or perinatal death (RR 0.50, 95% CI 0.19 to 1.36; 2 trials, 462 women). One small trial (17 women) compared an IV versus IM maintenance regimen for 24 hours. It is uncertain whether IV or IM maintenance regimen has an effect on eclampsia or stillbirth (very low-certainty evidence). Four trials (1713 women) compared short postpartum maintenance regimens with continuing for 24 hours after birth. Low-certainty evidence suggests there may be a wide range of benefit or harm between groups regarding eclampsia (RR 1.99, 95% CI 0.18 to 21.87; 4 trials, 1713 women). Low-certainty evidence suggests there may be little or no effect on severe morbidity (RR 0.96, 95% CI 0.71 to 1.29; 2 trials, 1233 women) or side effects such as respiratory depression (RR 0.80, 95% CI 0.25 to 2.61; 2 trials, 1424 women). Three trials (185 women) compared a higher-dose maintenance regimen versus a lower-dose maintenance regimen. It is uncertain whether either regimen has an effect on eclampsia (very low-certainty evidence). Low-certainty evidence suggests that a higher-dose maintenance regimen has little or no effect on side effects when compared to a lower-dose regimen (RR 0.79, 95% CI 0.61 to 1.01; 1 trial 62 women). One trial (200 women) compared a maintenance regimen by continuous infusion versus a serial IV bolus regimen. It is uncertain whether the duration of the maintenance regimen has an effect on eclampsia, side effects, perinatal death, maternal death, or other neonatal morbidity (very low-certainty evidence). Many of our prespecified critical outcomes were not reported in the included trials. AUTHORS' CONCLUSIONS: Despite the number of trials evaluating various magnesium sulphate regimens for eclampsia prophylaxis and treatment, there is still no compelling evidence that one particular regimen is more effective than another. Well-designed randomised controlled trials are needed to answer this question.

Perceptions and experiences of the prevention, detection, and management of postpartum haemorrhage: a qualitative evidence synthesis.

BACKGROUND: Postpartum haemorrhage (PPH), defined as blood loss of 500 mL or more after childbirth, is the leading cause of maternal mortality worldwide. It is possible to prevent complications of PPH with timely and appropriate detection and management. However, implementing the best methods of PPH prevention, detection and management can be challenging, particularly in low- and middle-income countries. OBJECTIVES: Our overall objective was to explore the perceptions and experiences of women, community members, lay health workers, and skilled healthcare providers who have experience with PPH or with preventing, detecting, and managing PPH, in community or health facility settings. SEARCH METHODS: We searched MEDLINE, CINAHL, Scopus, and grey literature on 13 November 2022 with no language restrictions. We then performed reference checking and forward citation searching of the included studies. SELECTION CRITERIA: We included qualitative studies and mixed-methods studies with an identifiable qualitative component. We included studies that explored perceptions and experiences of PPH prevention, detection, and management among women, community members, traditional birth attendants, healthcare providers, and managers. DATA COLLECTION AND ANALYSIS: We used three-stage maximum variation sampling to ensure diversity in terms of relevance of the study to the review objectives, richness of data, and coverage of critical contextual elements: setting (region, country income level), perspective (type of participant), and topic (prevention, detection, management). We extracted data using a data extraction form designed for this review. We used thematic synthesis to analyse and synthesise the evidence, and we used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach to assess our confidence in each finding. To identify factors that may influence intervention implementation, we mapped each review finding to the Theoretical Domains Framework (TDF) and the Capability, Motivation, and Opportunity model of Behaviour change (COM-B). We used the Behaviour Change Wheel to explore implications for practice. MAIN RESULTS: We included 67 studies and sampled 43 studies for our analysis. Most were from low- or middle-income countries (33 studies), and most included the perspectives of women and health workers. We downgraded our confidence in several findings from high confidence to moderate, low, or very-low confidence, mainly due to concerns about how the studies were conducted (methodological limitations) or concerns about missing important perspectives from some types of participants or in some settings (relevance). In many communities, bleeding during and after childbirth is considered "normal" and necessary to expel "impurities" and restore and cleanse the woman's body after pregnancy and birth (moderate confidence). In some communities, people have misconceptions about causes of PPH or believe that PPH is caused by supernatural powers or evil spirits that punish women for ignoring or disobeying social rules or for past mistakes (high confidence). For women who give birth at home or in the community, female family members or traditional birth attendants are the first to recognise excess bleeding after birth (high confidence). Family members typically take the decision of whether and when to seek care if PPH is suspected, and these family members are often influenced by trusted traditional birth attendants or community midwives (high confidence). If PPH is identified for women birthing at home or in the community, decision-making about the subsequent referral and care pathway can be multifaceted and complex (high confidence). First responders to PPH are not always skilled or trained healthcare providers (high confidence). In health facilities, midwives may consider it easy to implement visual estimation of blood loss with a kidney dish or under-pad, but difficult to accurately interpret the amount of blood loss (very low confidence). Quantifying (rather than estimating) blood loss may be a complex and contentious change of practice for health workers (low confidence). Women who gave birth in health facilities and experienced PPH described it as painful, embarrassing, and traumatic. Partners or other family members also found the experience stressful. While some women were dissatisfied with their level of involvement in decision-making for PPH management, others felt health workers were best placed to make decisions (moderate confidence). Inconsistent availability of resources (drugs, medical supplies, blood) causes delays in the timely management of PPH (high confidence). There is limited availability of misoprostol in the community owing to stockouts, poor supply systems, and the difficulty of navigating misoprostol procurement for community health workers (moderate confidence). Health workers described working on the maternity ward as stressful and intense due to short staffing, long shifts, and the unpredictability of emergencies. Exhausted and overwhelmed staff may be unable to appropriately monitor all women, particularly when multiple women are giving birth simultaneously or on the floor of the health facility; this could lead to delays in detecting PPH (moderate confidence). Inadequate staffing, high turnover of skilled health workers, and appointment of lower-level cadres of health workers are key challenges to the provision of quality PPH care (high confidence). Through team-based simulation training, health workers of different cadres (doctors, midwives, lay health workers) can develop a shared mental model to help them work quickly, efficiently, and amicably as a team when managing women with PPH (moderate confidence). AUTHORS' CONCLUSIONS: Our findings highlight how improving PPH prevention, detection, and management is underpinned by a complex system of interacting roles and behaviours (community, women, health workers of different types and with different experiences). Multiple individual, sociocultural, and environmental factors influence the decisions and behaviours of women, families, communities, health workers, and managers. It is crucial to consider the broader health and social systems when designing and implementing PPH interventions to change or influence these behaviours. We have developed a set of prompts that may help programme managers, policymakers, researchers, and other key stakeholders to identify and address factors that affect implementation and scale-up of interventions to improve PPH prevention, detection, and management.

Factors influencing appropriate use of interventions for management of women experiencing preterm birth: A mixed-methods systematic review and narrative synthesis.

BACKGROUND: Preterm birth-related complications are the leading cause of death in newborns and children under 5. Health outcomes of preterm newborns can be improved with appropriate use of antenatal corticosteroids (ACSs) to promote fetal lung maturity, tocolytics to delay birth, magnesium sulphate for fetal neuroprotection, and antibiotics for preterm prelabour rupture of membranes. However, there are wide disparities in the rate and consistency in the use of these interventions across settings, which may underlie the differential health outcomes among preterm newborns. We aimed to assess factors (barriers and facilitators) affecting the appropriate use of ACS, tocolytics, magnesium sulphate, and antibiotics to improve preterm birth management. METHODS AND FINDINGS: We conducted a mixed-methods systematic review including primary qualitative, quantitative, and mixed-methods studies. We searched MEDLINE, EMBASE, CINAHL, Global Health, and grey literature from inception to 16 May 2022. Eligible studies explored perspectives of women, partners, or community members who experienced preterm birth or were at risk of preterm birth and/or received any of the 4 interventions, health workers providing maternity and newborn care, and other stakeholders involved in maternal care (e.g., facility managers, policymakers). We used an iterative narrative synthesis approach to analysis, assessed methodological limitations using the Mixed Methods Appraisal Tool, and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. Behaviour change models (Theoretical Domains Framework; Capability, Opportunity, and Motivation (COM-B)) were used to map barriers and facilitators affecting appropriate use of these interventions. We included 46 studies from 32 countries, describing factors affecting use of ACS (32/46 studies), tocolytics (13/46 studies), magnesium sulphate (9/46 studies), and antibiotics (5/46 studies). We identified a range of barriers influencing appropriate use of the 4 interventions globally, which include the following: inaccurate gestational age assessment, inconsistent guidelines, varied knowledge, perceived risks and benefits, perceived uncertainties and constraints in administration, confusion around prescribing and administering authority, and inadequate stock, human resources, and labour and newborn care. Women reported hesitancy in accepting interventions, as they typically learned about them during emergencies. Most included studies were from high-income countries (37/46 studies), which may affect the transferability of these findings to low- or middle-income settings. CONCLUSIONS: In this study, we identified critical factors affecting implementation of 4 interventions to improve preterm birth management globally. Policymakers and implementers can consider these barriers and facilitators when formulating policies and planning implementation or scale-up of these interventions. Study findings can inform clinical preterm birth guidelines and implementation to ensure that barriers are addressed, and enablers are reinforced to ensure these interventions are widely available and appropriately used globally.

Correction: Factors influencing appropriate use of interventions for management of women experiencing preterm birth: A mixed-methods systematic review and narrative synthesis.

[This corrects the article DOI: 10.1371/journal.pmed.1004074.].

Sporadic miscarriage: evidence to provide effective care.

The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units.

Recurrent miscarriage: evidence to accelerate action.

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.

A Randomized Trial of Prophylactic Antibiotics for Miscarriage Surgery.

BACKGROUND: Surgical intervention is needed in some cases of spontaneous abortion to remove retained products of conception. Antibiotic prophylaxis may reduce the risk of pelvic infection, which is an important complication of this surgery, particularly in low-resource countries. METHODS: We conducted a double-blind, placebo-controlled, randomized trial investigating whether antibiotic prophylaxis before surgery to complete a spontaneous abortion would reduce pelvic infection among women and adolescents in low-resource countries. We randomly assigned patients to a single preoperative dose of 400 mg of oral doxycycline and 400 mg of oral metronidazole or identical placebos. The primary outcome was pelvic infection within 14 days after surgery. Pelvic infection was defined by the presence of two or more of four clinical features (purulent vaginal discharge, pyrexia, uterine tenderness, and leukocytosis) or by the presence of one of these features and the clinically identified need to administer antibiotics. The definition of pelvic infection was changed before the unblinding of the data; the original strict definition was two or more of the clinical features, without reference to the administration of antibiotics. RESULTS: We enrolled 3412 patients in Malawi, Pakistan, Tanzania, and Uganda. A total of 1705 patients were assigned to receive antibiotics and 1707 to receive placebo. The risk of pelvic infection was 4.1% (68 of 1676 pregnancies) in the antibiotics group and 5.3% (90 of 1684 pregnancies) in the placebo group (risk ratio, 0.77; 95% confidence interval [CI], 0.56 to 1.04; P = 0.09). Pelvic infection according to original strict criteria was diagnosed in 1.5% (26 of 1700 pregnancies) and 2.6% (44 of 1704 pregnancies), respectively (risk ratio, 0.60; 95% CI, 0.37 to 0.96). There were no significant between-group differences in adverse events. CONCLUSIONS: Antibiotic prophylaxis before miscarriage surgery did not result in a significantly lower risk of pelvic infection, as defined by pragmatic broad criteria, than placebo. (Funded by the Medical Research Council and others; AIMS Current Controlled Trials number, ISRCTN97143849.).

Tocolytics for delaying preterm birth: a network meta-analysis (0924).

BACKGROUND: Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for administration of corticosteroids for fetal lung maturation, magnesium sulphate for neuroprotection, and transport to a facility with appropriate neonatal care facilities. However, there is still uncertainty about their effectiveness and safety. OBJECTIVES: To estimate relative effectiveness and safety profiles for different classes of tocolytic drugs for delaying preterm birth, and provide rankings of the available drugs. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov (21 April 2021) and reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials assessing effectiveness or adverse effects of tocolytic drugs for delaying preterm birth. We excluded quasi- and non-randomised trials. We evaluated all studies against predefined criteria to judge their trustworthiness. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the trials for inclusion and risk of bias, and extracted data. We performed pairwise and network meta-analyses, to determine the relative effects and rankings of all available tocolytics. We used GRADE to rate the certainty of the network meta-analysis effect estimates for each tocolytic versus placebo or no treatment. MAIN RESULTS: This network meta-analysis includes 122 trials (13,697 women) involving six tocolytic classes, combinations of tocolytics, and placebo or no treatment. Most trials included women with threatened preterm birth, singleton pregnancy, from 24 to 34 weeks of gestation. We judged 25 (20%) studies to be at low risk of bias. Overall, certainty in the evidence varied. Relative effects from network meta-analysis suggested that all tocolytics are probably effective in delaying preterm birth compared with placebo or no tocolytic treatment. Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio (RR) 1.12, 95% confidence interval (CI) 1.05 to 1.20; low-certainty evidence), and 7 days (RR 1.14, 95% CI 1.03 to 1.25; low-certainty evidence). COX inhibitors are possibly effective in delaying preterm birth by 48 hours (RR 1.11, 95% CI 1.01 to 1.23; low-certainty evidence). Calcium channel blockers are possibly effective in delaying preterm birth by 48 hours (RR 1.16, 95% CI 1.07 to 1.24; low-certainty evidence), probably effective in delaying preterm birth by 7 days (RR 1.15, 95% CI 1.04 to 1.27; moderate-certainty evidence), and prolong pregnancy by 5 days (0.1 more to 9.2 more; high-certainty evidence). Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12, 95% CI 1.02 to 1.23; moderate-certainty evidence). Oxytocin receptor antagonists are probably effective in delaying preterm birth by 48 hours (RR 1.13, 95% CI 1.05 to 1.22; moderate-certainty evidence), are effective in delaying preterm birth by 7 days (RR 1.18, 95% CI 1.07 to 1.30; high-certainty evidence), and possibly prolong pregnancy by 10 days (95% CI 2.3 more to 16.7 more). Nitric oxide donors are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.05 to 1.31; moderate-certainty evidence), and 7 days (RR 1.18, 95% CI 1.02 to 1.37; moderate-certainty evidence). Combinations of tocolytics are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.07 to 1.27; moderate-certainty evidence), and 7 days (RR 1.19, 95% CI 1.05 to 1.34; moderate-certainty evidence). Nitric oxide donors ranked highest for delaying preterm birth by 48 hours and 7 days, and delay in birth (continuous outcome), followed by calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics. Betamimetics (RR 14.4, 95% CI 6.11 to 34.1; moderate-certainty evidence), calcium channel blockers (RR 2.96, 95% CI 1.23 to 7.11; moderate-certainty evidence), magnesium sulphate (RR 3.90, 95% CI 1.09 to 13.93; moderate-certainty evidence) and combinations of tocolytics (RR 6.87, 95% CI 2.08 to 22.7; low-certainty evidence) are probably more likely to result in cessation of treatment. Calcium channel blockers possibly reduce the risk of neurodevelopmental morbidity (RR 0.51, 95% CI 0.30 to 0.85; low-certainty evidence), and respiratory morbidity (RR 0.68, 95% CI 0.53 to 0.88; low-certainty evidence), and result in fewer neonates with birthweight less than 2000 g (RR 0.49, 95% CI 0.28 to 0.87; low-certainty evidence). Nitric oxide donors possibly result in neonates with higher birthweight (mean difference (MD) 425.53 g more, 95% CI 224.32 more to 626.74 more; low-certainty evidence), fewer neonates with birthweight less than 2500 g (RR 0.40, 95% CI 0.24 to 0.69; low-certainty evidence), and more advanced gestational age (MD 1.35 weeks more, 95% CI 0.37 more to 2.32 more; low-certainty evidence). Combinations of tocolytics possibly result in fewer neonates with birthweight less than 2500 g (RR 0.74, 95% CI 0.59 to 0.93; low-certainty evidence). In terms of maternal adverse effects, betamimetics probably cause dyspnoea (RR 12.09, 95% CI 4.66 to 31.39; moderate-certainty evidence), palpitations (RR 7.39, 95% CI 3.83 to 14.24; moderate-certainty evidence), vomiting (RR 1.91, 95% CI 1.25 to 2.91; moderate-certainty evidence), possibly headache (RR 1.91, 95% CI 1.07 to 3.42; low-certainty evidence) and tachycardia (RR 3.01, 95% CI 1.17 to 7.71; low-certainty evidence) compared with placebo or no treatment. COX inhibitors possibly cause vomiting (RR 2.54, 95% CI 1.18 to 5.48; low-certainty evidence). Calcium channel blockers (RR 2.59, 95% CI 1.39 to 4.83; low-certainty evidence), and nitric oxide donors probably cause headache (RR 4.20, 95% CI 2.13 to 8.25; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Compared with placebo or no tocolytic treatment, all tocolytic drug classes that we assessed (betamimetics, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, nitric oxide donors) and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days. Tocolytic drugs were associated with a range of adverse effects (from minor to potentially severe) compared with placebo or no tocolytic treatment, although betamimetics and combination tocolytics were more likely to result in cessation of treatment. The effects of tocolytic use on neonatal outcomes such as neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection were uncertain.

Antenatal corticosteroids for early preterm birth: implementation strategy lessons from the WHO ACTION-I trial.

The WHO ACTION-I trial, the largest placebo-controlled trial on antenatal corticosteroids (ACS) efficacy and safety to date, reaffirmed the benefits of ACS on mortality reduction among early preterm newborns in low-income settings. We discuss here lessons learned from ACTION-I trial that are relevant to a strategy for ACS implementation to optimize impact. Key elements included (i) gestational age dating by ultrasound (ii) application of appropriate selection criteria by trained obstetric physicians to identify women with a likelihood of preterm birth for ACS administration; and (iii) provision of a minimum package of care for preterm newborns in facilities. This strategy accurately identified a large proportion of women who eventually gave birth preterm, and resulted in a 16% reduction in neonatal mortality from ACS use. Policy-makers, programme managers and clinicians are encouraged to consider this implementation strategy to effectively scale and harness the benefits of ACS in saving preterm newborn lives.

Usability, acceptability, and feasibility of the World Health Organization Labour Care Guide: A mixed-methods, multicountry evaluation.

INTRODUCTION: The World Health Organization's (WHO) Labour Care Guide (LCG) is a "next-generation" partograph based on WHO's latest intrapartum care recommendations. It aims to optimize clinical care provided to women and their experience of care. We evaluated the LCG's usability, feasibility, and acceptability among maternity care practitioners in clinical settings. METHODS: Mixed-methods evaluation with doctors, midwives, and nurses in 12 health facilities across Argentina, India, Kenya, Malawi, Nigeria, and Tanzania. Purposively sampled and trained practitioners applied the LCG in low-risk women during labor and rated experiences, satisfaction, and usability. Practitioners were invited to focus group discussions (FGDs) to share experiences and perceptions of the LCG, which were subjected to framework analysis. RESULTS: One hundred and thirty-six practitioners applied the LCG in managing labor and birth of 1,226 low-risk women. The majority of women had a spontaneous vaginal birth (91.6%); two cases of intrapartum stillbirths (1.63 per 1000 births) occurred. Practitioner satisfaction with the LCG was high, and median usability score was 67.5%. Practitioners described the LCG as supporting precise and meticulous monitoring during labor, encouraging critical thinking in labor management, and improving the provision of woman-centered care. CONCLUSIONS: The LCG is feasible and acceptable to use across different clinical settings and can promote woman-centered care, though some design improvements would benefit usability. Implementing the LCG needs to be accompanied by training and supportive supervision, and strategies to promote an enabling environment (including updated policies on supportive care interventions, and ensuring essential equipment is available).

The development of the WHO Labour Care Guide: an international survey of maternity care providers.

BACKGROUND: The partograph is the most commonly used labour monitoring tool in the world. However, it has been used incorrectly or inconsistently in many settings. In 2018, a WHO expert group reviewed and revised the design of the partograph in light of emerging evidence, and they developed the first version of the Labour Care Guide (LCG). The objective of this study was to explore opinions of skilled health personnel on the first version of the WHO Labour Care Guide. METHODS: Skilled health personnel (including obstetricians, midwives and general practitioners) of any gender from Africa, Asia, Europe and Latin America were identified through a large global research network. Country coordinators from the network invited 5 to 10 mid-level and senior skilled health personnel who had worked in labour wards anytime in the last 5 years. A self-administered, anonymous, structured, online questionnaire including closed and open-ended questions was designed to assess the clarity, relevance, appropriateness of the frequency of recording, and the completeness of the sections and variables on the LCG. RESULTS: A total of 110 participants from 23 countries completed the survey between December 2018 and January 2019. Variables included in the LCG were generally considered clear, relevant and to have been recorded at the appropriate frequency. Most sections of the LCG were considered complete. Participants agreed or strongly agreed with the overall design, structure of the LCG, and the usefulness of reference thresholds to trigger further assessment and actions. They also agreed that LCG could potentially have a positive impact on clinical decision-making and respectful maternity care. Participants disagreed with the value of some variables, including coping, urine, and neonatal status. CONCLUSIONS: Future end-users of WHO Labour Care Guide considered the variables to be clear, relevant and appropriate, and, with minor improvements, to have the potential to positively impact clinical decision-making and respectful maternity care.