The quality of medicines for the prevention and management of hypertensive disorders of pregnancy: A systematic review.

The quality of medicines for the prevention and management of hypertensive disorders of pregnancy globally is a critical challenge in the reduction of maternal mortality rate. We aimed to conduct a systematic review of available studies on the quality of the eight medicines recommended globally for the prevention and management of hypertensive disorders of pregnancy. We searched five electronic databases- Ovid MEDLINE, EMBASE, CINAHL, ProQuest and Cochrane Library, and also grey literature, without year or language limitations. Any study assessing the quality parameters (Active Pharmaceutical Ingredients, pH, sterility, solubility, impurities) of medicines by using any valid laboratory methods was eligible. Two reviewers independently screened the studies, extracted data and applied Medicine Quality Assessment Reporting Guidelines tool for quality assessment. Results were narratively reported and stratified by the drug types. Of 5669 citations screened, 33 studies from 27 countries were included. Five studies reported on the quality of magnesium sulphate-two (Nigeria and USA) found substandard medicine due to failing API specification and contaminants, respectively. Another study from Nigeria and a multi-country study (10 lower-middle- and low-income countries) found poor-quality due to failing the pH criteria. Seven of eight studies evaluating aspirin found quality issues, including degraded medicines in five studies (Brazil, USA, Yugoslavia and Pakistan). Five studies of calcium supplements found quality issues, particularly heavy metal contamination. Of 15 antihypertensives quality studies, 12 found substandard medicines and one study identified counterfeit medicines. This systematic review identified pervasive issues of poor-quality medicines across all recommended medicines used to prevent or treat hypertensive disorders of pregnancy, raising concerns regarding their safety and effectiveness.

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.

The effect of selenium supplementation in pregnant women on maternal, fetal, and newborn outcomes: a systematic review and meta-analysis.

OBJECTIVE: Low maternal selenium status has been associated with poor pregnancy outcomes, including preterm birth. This study aimed to evaluate available evidence of the effects of selenium supplementation during pregnancy on preterm birth and related maternal, fetal, and newborn outcomes. DATA SOURCES: MEDLINE, Embase, CINAHL, Global Index Medicus, and the Cochrane Library were systematically searched on June 23, 2022, without language or time restrictions. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and nonrandomized interventional studies were included if they compared the effects of selenium supplementation with placebo or no treatment among pregnant women. The review protocol was registered in the International Prospective Register of Systematic Reviews (identification number: CRD42022383669). METHODS: For outcomes reported by ≥1 study, a meta-analysis was conducted. Because of the small number of studies and high clinical heterogeneity between populations, random-effects models were used. The Risk of Bias 2 and Risk Of Bias In Non-randomized Studies - of Interventions tools were used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation analysis was used to determine the certainty of evidence for each outcome. RESULTS: Literature searches identified 5105 unique records, and 32 studies met the eligibility criteria. Of note, 11 reports were not included for analysis following research integrity assessments. Moreover, 10 trials and 3 observational studies met the inclusion criteria; however, only 8 trials (1851 women) and 1 prospective cohort study (71,728 women) reported on at least 1 review outcome. Our results could not determine the effect of selenium supplementation on preterm birth at <37 weeks of gestation (relative risk, 0.65; 95% confidence interval, 0.26-1.63; very low certainty evidence) and <34 weeks of gestation (relative risk, 1.05; 95% confidence interval, 0.59-1.44; very low certainty evidence). CONCLUSION: There is limited evidence on the effects of selenium supplementation during pregnancy. Further trials, with larger sample sizes, more representative populations, and reliable assessment of maternal selenium status at trial entry, are required.

New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline.

BACKGROUND: There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product profiles (TPPs) for medicines to prevent spontaneous preterm birth and manage preterm labor. The objectives of this study were to 1) analyse the research and development pipeline of medicines for preterm birth and 2) compare these medicines to target product profiles for spontaneous preterm birth to identify the most promising candidates. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched to identify candidate medicines (including drugs, dietary supplements and biologics) and populate the Accelerating Innovations for Mothers (AIM) database. This database was screened for all candidates that have been investigated for preterm birth. Candidates in clinical development were ranked against criteria from TPPs, and classified as high, medium or low potential. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 178 candidates. Of the 71 candidates in clinical development, ten were deemed high potential (Prevention: Omega-3 fatty acid, aspirin, vaginal progesterone, oral progesterone, L-arginine, and selenium; Treatment: nicorandil, isosorbide dinitrate, nicardipine and celecoxib) and seven were medium potential (Prevention: pravastatin and lactoferrin; Treatment: glyceryl trinitrate, retosiban, relcovaptan, human chorionic gonadotropin and Bryophyllum pinnatum extract). 107 candidates were in preclinical development. CONCLUSIONS: This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals.

Analysis of a maternal health medicines pipeline database 2000-2021: New candidates for the prevention and treatment of fetal growth restriction.

OBJECTIVE: The Accelerating Innovation for Mothers project established a new database of candidate medicines under development between 2000 and 2021 for five pregnancy-related conditions, including fetal growth restriction. The objective was to assess medicines for fetal growth restriction and their potential for clinical use globally. DESIGN: Landscape analysis. SETTING: Global (focus on low- and middle-income countries, LMICs). SAMPLE: Drugs, dietary supplements and biologics under investigation for prevention or treatment of fetal growth restriction. METHODS: A research pipeline database of medicines was created through searching AdisInsight, PubMed and various grant and clinical trial databases. Analysis of clinical and preclinical candidates were descriptive. MAIN OUTCOMES MEASURES: Fetal growth restriction candidates in clinical development were identified and ranked as high, medium or low potential based on prespecified criteria, including efficacy, safety and accessibility. RESULTS: Of the 444 unique candidates in the database across all five pregnancy-related conditions, 63 were for fetal growth restriction. Of these, 31 were in clinical development (phases I, II or III) and 32 were in preclinical development. Three candidates, aspirin, l-arginine and vitamin D, were ranked as having high potential as preventive agents. There were no high-potential candidates for treating fetal growth restriction, although five candidates were ranked as having medium potential: allylestrenol, dalteparin, omega-3 fatty acids, tadalafil, and United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP). CONCLUSIONS: l-Arginine, aspirin and vitamin D are promising, high-potential preventative agents for fetal growth restriction. Based on the medicines pipeline, new pharmacological agents for fetal growth restriction are unlikely to emerge in the near future.

Systematic evaluation of the pre-eclampsia drugs, dietary supplements and biologicals pipeline using target product profiles.

BACKGROUND: The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five pregnancy-related conditions, including pre-eclampsia. In parallel, we published target product profiles (TPPs) that describe optimal characteristics of medicines for use in preventing/treating pre-eclampsia. The study objective was to use systematic double screening and extraction to identify all candidate medicines being investigated for pre-eclampsia prevention/treatment and rank their potential based on the TPPs. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched (Jan-May 2021). The AIM database was screened for all candidates being investigated for pre-eclampsia. Candidates in clinical development were evaluated against nine prespecified criteria from TPPs identified as key for wide-scale implementation, and classified as high, medium or low potential based on matching to the TPPs. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 153 candidates for pre-eclampsia. Of the 87 candidates in clinical development, seven were classified as high potential (prevention: esomeprazole, L-arginine, chloroquine, vitamin D and metformin; treatment: sulfasalazine and metformin) and eight as medium potential (prevention: probiotic lactobacilli, dalteparin, selenium and omega-3 fatty acid; treatment: sulforaphane, pravastatin, rosuvastatin and vitamin B3). Sixty-six candidates were in preclinical development, the most common being amino acid/peptides, siRNA-based medicines and polyphenols. CONCLUSIONS: This is a novel, evidence-informed approach to identifying promising candidates for pre-eclampsia prevention and treatment - a vital step in stimulating R&D of new medicines for pre-eclampsia suitable for real-world implementation.

Prevention and control of non-communicable diseases in antenatal, intrapartum, and postnatal care: a systematic scoping review of clinical practice guidelines since 2011.

BACKGROUND: Non-communicable diseases (NCDs) are a leading cause of maternal mortality and morbidity worldwide. The World Health Organization is developing new recommendations focusing on the management of NCDs for pregnant, intrapartum, and postnatal women. Thus, to support the development of new guidelines and recommendations, we aimed to determine the availability, focus, and scope of recommendations of current guidelines for the management of NCDs during pregnancy, intrapartum, and postnatal period. METHODS: PubMed, Global Index Medicus, TRIP, and Guideline International Network databases were searched on 31 May 2021, to identify any NCD-related guidelines published between 2011 and 2021 with no language or country restrictions. Websites of 165 professional organizations were also searched. Characteristics of included guidelines were analyzed, and recommendations were extracted from guidelines of five high-priority NCD conditions (diabetes, chronic hypertension, respiratory conditions, hemoglobinopathies and sickle cell disease, and mental and substance use disorders). RESULTS: From 6026 citations and 165 websites, 405 guidelines were included of which 132 (33%) were pregnancy-specific and 285 (88%) were developed in high-income countries. Among pregnancy-specific guidelines, the most common conditions for which recommendations were provided were gestational diabetes, circulatory diseases, thyroid disorders, and hypertensive disorders of pregnancy. For the five high-priority conditions, 47 guidelines were identified which provided 1834 recommendations, largely focused on antenatal care interventions (62%) such as early detection, screening tools, pharmacological treatment, and lifestyle education. Postnatal recommendations largely covered postnatal clinical assessments, lifestyle education, and breastfeeding. Health system recommendations largely covered multidisciplinary care teams and strengthening referral pathways. CONCLUSIONS: This study provides a robust assessment of currently available guidelines and mapping of recommendations on NCD management within maternal health services, which will inform the scope of the World Health Organization's future guideline development activities. This study identified a need to develop guidelines that consider NCDs holistically, with an integrated approach to antenatal, intrapartum, and postnatal care, and that are relevant for resource-limited contexts. Any such guidelines should consider what interventions are most essential to improving outcomes for women with NCDs and their newborns, and how variations in quality of NCD-related care can be addressed.

Enhancing quality midwifery care in humanitarian and fragile settings: a systematic review of interventions, support systems and enabling environments.

INTRODUCTION: Women and children bear a substantial burden of the impact of conflict and instability. The number of people living in humanitarian and fragile settings (HFS) has increased significantly over the last decade. The provision of essential maternal and newborn healthcare by midwives is crucial everywhere, especially in HFS. There is limited knowledge about the interventions, support systems and enabling environments that enhance midwifery care in these settings. The aim of this paper is to identify the factors affecting an enabling environment for midwives in HFS and to explore the availability and effectiveness of support systems for midwives. METHODS: A structured systematic review was undertaken to identify peer-reviewed primary research articles published between 1995 and 2020. RESULTS: In total, 24 papers were included from Afghanistan, Bangladesh, Nigeria, Democratic Republic of Congo, South Sudan and Sudan, Ethiopia, Pakistan, Uganda and Liberia. There were two broad themes: (1) the facilitators of, and barriers to, an enabling environment, and (2) the importance of effective support systems for midwives. Facilitators were: community involvement and engagement and an adequate salary, incentives or benefits. Barriers included: security and safety concerns, culture and gender norms and a lack of infrastructure and supplies. Support systems were: education, professional development, supportive supervision, mentorship and workforce planning. CONCLUSION: More efforts are needed to develop and implement quality midwifery services in HFS. There is an urgent need for more action and financing to ensure better outcomes and experiences for all women, girls and families living in these settings. PROSPERO REGISTRATION NUMBER: CRD42021226323.

Formative research to design an implementation strategy for a postpartum hemorrhage initial response treatment bundle (E-MOTIVE): study protocol.

BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal death worldwide. When PPH occurs, early identification of bleeding and prompt management using evidence-based guidelines, can avert most PPH-related severe morbidities and deaths. However, adherence to the World Health Organization recommended practices remains a critical challenge. A potential solution to inefficient and inconsistent implementation of evidence-based practices is the application of a 'clinical care bundle' for PPH management. A clinical care bundle is a set of discrete, evidence-based interventions, administered concurrently, or in rapid succession, to every eligible person, along with teamwork, communication, and cooperation. Once triggered, all bundle components must be delivered. The E-MOTIVE project aims to improve the detection and first response management of PPH through the implementation of the "E-MOTIVE" bundle, which consists of (1) Early PPH detection using a calibrated drape, (2) uterine Massage, (3) Oxytocic drugs, (4) Tranexamic acid, (5) Intra Venous fluids, and (6) genital tract Examination and escalation when necessary. The objective of this paper is to describe the protocol for the formative phase of the E-MOTIVE project, which aims to design an implementation strategy to support the uptake of this bundle into practice. METHODS: We will use behavior change and implementation science frameworks [e.g. capability, opportunity, motivation and behavior (COM-B) and theoretical domains framework (TDF)] to guide data collection and analysis, in Kenya, Nigeria, South Africa, Sri Lanka, and Tanzania. There are four methodological components: qualitative interviews; surveys; systematic reviews; and design workshops. We will triangulate findings across data sources, participant groups, and countries to explore factors influencing current PPH detection and management, and potentially influencing E-MOTIVE bundle implementation. We will use these findings to develop potential strategies to improve implementation, which will be discussed and agreed with key stakeholders from each country in intervention design workshops. DISCUSSION: This formative protocol outlines our strategy for the systematic development of the E-MOTIVE implementation strategy. This focus on implementation considers what it would take to support roll-out and implementation of the E-MOTIVE bundle. Our approach therefore aims to maximize internal validity in the trial alongside future scalability, and implementation of the E-MOTIVE bundle in routine practice, if proven to be effective. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04341662.

Excessive bleeding after birth is the leading cause of maternal death globally. The World Health Organization (WHO) has recommended several treatment options for bleeding after birth. However, these treatments are not used regularly, or consistently for all women. A key underlying issue is that it is challenging for health workers to identify when women are bleeding too much, because measuring the amount of blood loss is difficult.Maternal health experts have proposed a new clinical 'care bundle' for caring for women with excessive bleeding after birth. A care bundle is a way to group together multiple treatments (e.g. 3­5 treatments). These treatments are then given to the woman at the same time, or one after another in quick succession, and supported by strategies to improve teamwork, communication, and cooperation.This is a research protocol for the preliminary phase of our study ("E-MOTIVE"), which means that it is a description of what we plan to do and how we plan to do it. The aim of our study is to develop a strategy for how we will test whether the E-MOTIVE bundle works through collaborative activities with midwives and doctors in five countries (Kenya, Nigeria, South Africa, Sri Lanka, and Tanzania) to develop a strategy for how we will test whether the E-MOTIVE bundle works. We plan to do this by conducting interviews and surveys with midwives and doctors, and reviewing other research conducted on PPH to understand what works in different settings. We will discuss our research findings in a workshop, with midwives and doctors in the study countries to co-create a strategy that will work for them, based on their needs and preferences.

What matters to women and healthcare providers in relation to interventions for the prevention of postpartum haemorrhage: A qualitative systematic review.

BACKGROUND: Postpartum haemorrhage (PPH) is a leading cause of maternal mortality and morbidity. Reducing deaths from PPH is a global challenge. The voices of women and healthcare providers have been missing from the debate around best practices for PPH prevention. The aim of this review was to identify, appraise and synthesize available evidence about the views and experiences of women and healthcare providers on interventions to prevent PPH. METHODS: We searched eight electronic databases and reference lists of eligible studies published between 1996 and 2018, reporting qualitative data on views and experiences of PPH in general, and of any specific preventative intervention(s). Authors' findings were extracted and synthesised using meta-ethnographic techniques. Confidence in the quality, coherence, relevance and adequacy of data underpinning the resulting themes was assessed using GRADE-CERQual. A line of argument synthesis was developed. RESULTS: Thirty-five studies from 29 countries met our inclusion criteria. Our results indicate that women and healthcare providers recognise the dangers of severe blood loss in the perinatal and postpartum period, but don't always share the same beliefs about the causes and consequences of PPH. Skilled birth attendants and traditional birth attendants (TBA's) want to prevent PPH but may lack the required resources and training. Women generally appreciate PPH prevention strategies, especially where their individual needs, beliefs and values are taken into account. Women and healthcare providers also recognize the value of using uterotonics (medications that contract the uterus) to prevent PPH but highlight safety concerns and potential misuse of the drugs as acceptability and implementation issues. CONCLUSIONS: Based on stakeholder views and experiences, PPH prevention strategies are more likely to be successful where all stakeholders agree on the causes and consequences of severe postpartum blood loss, especially in the context of sufficient resources and effective implementation by competent, suitably trained providers.

Primary and secondary prevention of preterm birth: a review of systematic reviews and ongoing randomized controlled trials.

BACKGROUND: Preterm birth (PTB) is a leading cause of perinatal morbidity and mortality. Interventions aimed at preventing PTB can be classified as primary, secondary, or tertiary prevention. OBJECTIVE: To conduct a review of systematic reviews on the effectiveness and safety of primary and secondary preterm birth prevention interventions. SEARCH STRATEGY: A systematic literature search of the Cochrane, PubMed/Medline, EMBASE and CINAHL databases was conducted on 2 September 2015, and updated on 21 November 2016. SELECTION CRITERIA: We included any published systematic review of randomized controlled trials (RCTs) or individual patient data (IPD) of RCTs related to primary or secondary prevention of PTB, published between 2005-2016 where gestational age at birth (of any interval) was a pre-specified outcome. Individual trials and non-systematic reviews were not eligible. DATA COLLECTION AND ANALYSIS: The population of interest was all pregnant women, regardless of PTB risk. The primary outcome was PTB < 37 weeks. MAIN RESULTS: In total, 112 reviews were included in this study. Overall there were 49 Cochrane and 63 non-Cochrane reviews. Eight were individual participant data (IPD) reviews. Sixty reviews assessed the effect of primary prevention interventions on risk of PTB. Positive effects were reported for lifestyle and behavioural changes (including diet and exercise); nutritional supplements (including calcium and zinc supplementation); nutritional education; screening for lower genital tract infections. Eighty-three systematic reviews were identified relating to secondary PTB prevention interventions. Positive effects were found for low dose aspirin among women at risk of preeclampsia; clindamycin for treatment of bacterial vaginosis; treatment of vaginal candidiasis; progesterone in women with prior spontaneous PTB and in those with short midtrimester cervical length; L-arginine in women at risk for preeclampsia; levothyroxine among women with tyroid disease; calcium supplementation in women at risk of hypertensive disorders; smoking cessation; cervical length screening in women with history of PTB with placement of cerclage in those with short cervix; cervical pessary in singleton gestations with short cervix; and treatment of periodontal disease. CONCLUSION: The overview serves as a guide to current evidence relevant to PTB prevention. Only a few interventions have been demononstrated to be effective, including cerclage, progesterone, low dose aspirin, and lifestyle and behavioural changes. For several of the interventions evaluated, there was insufficient evidence to assess whether they were effective or not.

Research prioritization of interventions for the primary prevention of preterm birth: An international survey.

OBJECTIVE: To identify research priorities of interventions for the primary prevention of preterm birth (PTB), by conducting an international stakeholder survey. STUDY DESIGN: A prospective cross-sectional online survey was conducted in November 2016. Fifteen interventions to prevent spontaneous PTB were identified and ranked by stakeholders (n = 159) in the field of maternal and perinatal health research, using nine equally weighted criteria. Medians and interquartile ranges (IQRs) were calculated and the interventions ranked accordingly. RESULTS: Respondents to the survey were from 46 different countries, mostly from low and middle-income countries (62%, 99/159) and were mainly clinicians (80%, 127/159). Of the fifteen interventions ranked, the following five were identified as research priorities in the primary prevention of PTB: dietary counselling and nutritional education, risk scoring, vitamin D supplementation, exercise and antioxidant supplementation. CONCLUSION: We have identified research priorities of interventions to prevent spontaneous PTB through a global stakeholder survey. The interventions prioritized in this exercise can be used by researchers, grant funding bodies and research-policy decision makers to inform calls on future clinical trials or individual patient data meta-analyses on the primary prevention of PTB.

Interventions during pregnancy to prevent preterm birth: an overview of Cochrane systematic reviews.

BACKGROUND: Preterm birth (PTB) is a major factor contributing to global rates of neonatal death and to longer-term health problems for surviving infants. Both the World Health Organization and the United Nations consider prevention of PTB as central to improving health care for pregnant women and newborn babies. Current preventative clinical strategies show varied efficacy in different populations of pregnant women, frustrating women and health providers alike, while researchers call for better understanding of the underlying mechanisms that lead to PTB. OBJECTIVES: We aimed to summarise all evidence for interventions relevant to the prevention of PTB as reported in Cochrane systematic reviews (SRs). We intended to highlight promising interventions and to identify SRs in need of an update. METHODS: We searched the Cochrane Database of Systematic Reviews (2 November 2017) with key words to capture any Cochrane SR that prespecified or reported a PTB outcome. Inclusion criteria focused on pregnant women without signs of preterm labour or ruptured amniotic membranes. We included reviews of interventions for pregnant women irrespective of their risk status. We followed standard Cochrane methods.We applied GRADE criteria to evaluate the quality of SR evidence. We assigned graphic icons to classify the effectiveness of interventions as: clear evidence of benefit; clear evidence of harm; clear evidence of no effect or equivalence; possible benefit; possible harm; or unknown benefit or harm. We defined clear evidence of benefit and clear evidence of harm to be GRADE moderate- or high-quality evidence with a confidence interval (CI) that does not cross the line of no effect. Clear evidence of no effect or equivalence is GRADE moderate- or high-quality evidence with a narrow CI crossing the line of no effect. Possible benefit and possible harm refer to GRADE low-quality evidence with a clear effect (CI does not cross the line of no effect) or GRADE moderate- or high-quality evidence with a wide CI. Unknown harm or benefit refers to GRADE low- or very low-quality evidence with a wide CI. MAIN RESULTS: We included 83 SRs; 70 had outcome data. Below we highlight key results from a subset of 36 SRs of interventions intended to prevent PTB. OUTCOME: preterm birthClear evidence of benefitFour SRs reported clear evidence of benefit to prevent specific populations of pregnant women from giving birth early, including midwife-led continuity models of care versus other models of care for all women; screening for lower genital tract infections for pregnant women less than 37 weeks' gestation and without signs of labour, bleeding or infection; and zinc supplementation for pregnant women without systemic illness. Cervical cerclage showed clear benefit for women with singleton pregnancy and high risk of PTB only.Clear evidence of harmNo included SR reported clear evidence of harm.No effect or equivalenceFor pregnant women at high risk of PTB, bedrest for women with singleton pregnancy and antibiotic prophylaxis during the second and third trimester were of no effect or equivalent to a comparator.Possible benefitFour SRs found possible benefit in: group antenatal care for all pregnant women; antibiotics for pregnant women with asymptomatic bacteriuria; pharmacological interventions for smoking cessation for pregnant women who smoke; and vitamin D supplements alone for women without pre-existing conditions such as diabetes.Possible harmOne SR reported possible harm (increased risk of PTB) with intramuscular progesterone, but this finding is only relevant to women with multiple pregnancy and high risk of PTB. Another review found possible harm with vitamin D, calcium and other minerals for pregnant women without pre-existing conditions. OUTCOME: perinatal deathClear evidence of benefitTwo SRs reported clear evidence of benefit to reduce pregnant women's risk of perinatal death: midwife-led continuity models of care for all pregnant women; and fetal and umbilical Doppler for high-risk pregnant women.Clear evidence of harmNo included SR reported clear evidence of harm.No effect or equivalenceFor pregnant women at high risk of PTB, antibiotic prophylaxis during the second and third trimester was of no effect or equivalent to a comparator.Possible benefitOne SR reported possible benefit with cervical cerclage for women with singleton pregnancy and high risk of PTB.Possible harmOne SR reported possible harm associated with a reduced schedule of antenatal visits for pregnant women at low risk of pregnancy complications; importantly, these women already received antenatal care in settings with limited resources. OUTCOMES: preterm birth and perinatal deathUnknown benefit or harmFor pregnant women at high risk of PTB for any reason including multiple pregnancy, home uterine monitoring was of unknown benefit or harm. For pregnant women at high risk due to multiple pregnancy: bedrest, prophylactic oral betamimetics, vaginal progesterone and cervical cerclage were all of unknown benefit or harm. AUTHORS' CONCLUSIONS: Implications for practiceThe overview serves as a map and guide to all current evidence relevant to PTB prevention published in the Cochrane Library. Of 70 SRs with outcome data, we identified 36 reviews of interventions with the aim of preventing PTB. Just four of these SRs had evidence of clear benefit to women, with an additional four SRs reporting possible benefit. No SR reported clear harm, which is an important finding for women and health providers alike.The overview summarises no evidence for the clinically important interventions of cervical pessary, cervical length assessment and vaginal progesterone because these Cochrane Reviews were not current. These are active areas for PTB research.The graphic icons we assigned to SR effect estimates do not constitute clinical guidance or an endorsement of specific interventions for pregnant women. It remains critical for pregnant women and their healthcare providers to carefully consider whether specific strategies to prevent PTB will be of benefit for individual women, or for specific populations of women.Implications for researchFormal consensus work is needed to establish standard language for overviews of reviews and to define the limits of their interpretation.Clinicians, researchers and funders must address the lack of evidence for interventions relevant to women at high risk of PTB due to multiple pregnancy.

Pharmacological and mechanical interventions for labour induction in outpatient settings.

BACKGROUND: Induction of labour is carried out for a variety of indications and using a range of methods. For women at low risk of pregnancy complications, some methods of induction of labour or cervical ripening may be suitable for use in outpatient settings. OBJECTIVES: To examine pharmacological and mechanical interventions to induce labour or ripen the cervix in outpatient settings in terms of effectiveness, maternal satisfaction, healthcare costs and, where information is available, safety. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials examining outpatient cervical ripening or induction of labour with pharmacological agents or mechanical methods. Cluster trials were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed evidence using the GRADE approach. MAIN RESULTS: This updated review included 34 studies of 11 different methods for labour induction with 5003 randomised women, where women received treatment at home or were sent home after initial treatment and monitoring in hospital.Studies examined vaginal and intracervical prostaglandin E2 (PGE2), vaginal and oral misoprostol, isosorbide mononitrate, mifepristone, oestrogens, amniotomy and acupuncture, compared with placebo, no treatment, or routine care. Trials generally recruited healthy women with a term pregnancy. The risk of bias was mostly low or unclear, however, in 16 trials blinding was unclear or not attempted. In general, limited data were available on the review's main and additional outcomes. Evidence was graded low to moderate quality. 1. Vaginal PGE2 versus expectant management or placebo (5 studies)Fewer women in the vaginal PGE2 group needed additional induction agents to induce labour, however, confidence intervals were wide (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.27 to 0.99; 150 women; 2 trials). There were no clear differences between groups in uterine hyperstimulation (with or without fetal heart rate (FHR) changes) (RR 3.76, 95% CI 0.64 to 22.24; 244 women; 4 studies; low-quality evidence), caesarean section (RR 0.80, 95% CI 0.49 to 1.31; 288 women; 4 studies; low-quality evidence), or admission to a neonatal intensive care unit (NICU) (RR 0.32, 95% CI 0.10 to 1.03; 230 infants; 3 studies; low-quality evidence).There was no information on vaginal birth within 24, 48 or 72 hours, length of hospital stay, use of emergency services or maternal or caregiver satisfaction. Serious maternal and neonatal morbidity or deaths were not reported. 2. Intracervical PGE2 versus expectant management or placebo (7 studies) There was no clear difference between women receiving intracervical PGE2 and no treatment or placebo in terms of need for additional induction agents (RR 0.98, 95% CI 0.74 to 1.32; 445 women; 3 studies), vaginal birth not achieved within 48 to 72 hours (RR 0.83, 95% CI 0.68 to 1.02; 43 women; 1 study; low-quality evidence), uterine hyperstimulation (with FHR changes) (RR 2.66, 95% CI 0.63 to 11.25; 488 women; 4 studies; low-quality evidence), caesarean section (RR 0.90, 95% CI 0.72 to 1.12; 674 women; 7 studies; moderate-quality evidence), or babies admitted to NICU (RR 1.61, 95% CI 0.43 to 6.05; 215 infants; 3 studies; low-quality evidence). There were no uterine ruptures in either the PGE2 group or placebo group.There was no information on vaginal birth not achieved within 24 hours, length of hospital stay, use of emergency services, mother or caregiver satisfaction, or serious morbidity or neonatal morbidity or perinatal death. 3. Vaginal misoprostol versus placebo (4 studies)One small study reported on the rate of perinatal death with no clear differences between groups; there were no deaths in the treatment group compared with one stillbirth (reason not reported) in the control group (RR 0.34, 95% CI 0.01 to 8.14; 77 infants; 1 study; low-quality evidence).There was no clear difference between groups in rates of uterine hyperstimulation with FHR changes (RR 1.97, 95% CI 0.43 to 9.00; 265 women; 3 studies; low-quality evidence), caesarean section (RR 0.94, 95% CI 0.61 to 1.46; 325 women; 4 studies; low-quality evidence), and babies admitted to NICU (RR 0.89, 95% CI 0.54 to 1.47; 325 infants; 4 studies; low-quality evidence).There was no information on vaginal birth not achieved within 24, 48 or 72 hours, additional induction agents required, length of hospital stay, use of emergency services, mother or caregiver satisfaction, serious maternal, and other neonatal, morbidity or death.No substantive differences were found for other comparisons. One small study found that women who received oral misoprostol were more likely to give birth within 24 hours (RR 0.65, 95% CI 0.48 to 0.86; 87 women; 1 study) and were less likely to require additional induction agents (RR 0.60, 95% CI 0.37 to 0.97; 127 women; 2 studies). Women who received mifepristone were also less likely to require additional induction agents (average RR 0.59, 95% CI 0.37 to 0.95; 311 women; 4 studies; I² = 74%); however, this result should be interpreted with caution due to high heterogeneity. One trial each of acupuncture and outpatient amniotomy were included, but few review outcomes were reported. AUTHORS' CONCLUSIONS: Induction of labour in outpatient settings appears feasible and important adverse events seem rare, however, in general there is insufficient evidence to detect differences. There was no strong evidence that agents used to induce labour in outpatient settings had an impact (positive or negative) on maternal or neonatal health. There was some evidence that compared to placebo or no treatment, induction agents administered on an outpatient basis reduced the need for further interventions to induce labour, and shortened the interval from intervention to birth.We do not have sufficient evidence to know which induction methods are preferred by women, the interventions that are most effective and safe to use in outpatient settings, or their cost effectiveness. Further studies where various women-friendly outpatient protocols are compared head-to-head are required. As part of such work, women should be consulted on what sort of management they would prefer.

Reaching the unreached through trained and skilled birth attendants in Ethiopia: a cluster randomized controlled trial study protocol.

BACKGROUND: Despite improvements since 1990 to 2014, maternal mortality ratio (MMR) remains high in Ethiopia. One of the key drivers of maternal mortality in Ethiopia is the very low coverage of Skilled Birth attendance (SBA) in rural Ethiopia. This cluster randomized trial piloted an innovative approach of deploying trained community reproductive nurses (CORN) to hard to reach/unreachable rural Ethiopia to improve the coverage of SBA. METHODS: We used a three-arm cluster randomized trial to test the effect of deploying CORN in rural communities in South Ethiopia to improve SBA and other maternal health indicators. A total of 282 villages/clusters (94 from each arm) were randomly selected in the three districts of the zone for the study. The intervention was implemented in four consecutive phases that aimed at of provision of essential maternal, neonatal and child health (MNCH) services mainly focusing on SBA. The CORN were trained and deployed in health centres (arm 1) and in the community/health posts (arm2). A third arm (arm 3) consisting control villages without the intervention. A baseline and end line assessment was conducted to compare the difference in the proportion of SBA and other MNCH service uptake across the three arms Data was entered into computer, edited, cleaned, and analyzed using Epi-data statistical software. The presentation followed the Consolidated Standards of Reporting Trials (CONSORT) statement guidelines for cluster-randomized trials. DISCUSSION: This trial is designed to test the impact of an innovative and newly designed means of distribution for the national health extension program strategy with additional service package with no change to the target population. The focus is on effect of CORN in revitalizing the Health Extension Program (HEP) through improving SBA service uptake and other maternal health service uptake indicators. The study findings may guide national policy to strengthen and shape the already existing HEP that has certain limitations to improve maternal health indicators. The competency based training methodology could provide feedback for health science colleges to improve the national nursing or midwifery training curriculum. TRIAL REGISTRATION: clinicaltrails.gov NCT02501252 dated on July 14, 2015.