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.

Systematic review on the cost and cost-effectiveness of mHealth interventions supporting women during pregnancy.

OBJECTIVES: The increased integration of digital health into maternity care-alongside growing use of, and access to, personal digital technology among pregnant women-warrants an investigation of the cost-effectiveness of mHealth interventions used by women during pregnancy and the methodological quality of the cost-effectiveness studies. METHODS: A systematic search was conducted to identify peer-reviewed studies published in the last ten years (2011-2021) reporting on the costs or cost-effectiveness of mHealth interventions used by women during pregnancy. Available data related to program costs, total incremental costs and incremental cost-effectiveness ratios (ICERs) were reported in 2020 United States Dollars. The quality of cost-effectiveness studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). FINDINGS: Nine articles reporting on eight studies met the inclusion criteria. Direct intervention costs ranged from $7.04 to $86 per woman, total program costs ranged from $241,341 to $331,136 and total incremental costs ranged from -$21.16 to $1.12 million per woman. The following ICERs were reported: $2168 per DALY averted, $203.44 per woman ceasing smoking, and $3475 per QALY gained. The full economic evaluation studies (n = 4) were moderate to high in quality and all reported the mHealth intervention as cost-effective. Other studies (n = 4) were low to moderate in quality and reported low costs or cost savings associated with the implementation of the mHealth intervention. CONCLUSIONS FOR PRACTICE: Preliminary evidence suggests mHealth interventions may be cost-effective and "low-cost" but more evidence is needed to ascertain the cost-effectiveness of mHealth interventions regarding positive maternal and child health outcomes and longer-term health service utilisation.

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.

Healthcare providers experiences of using uterine balloon tamponade (UBT) devices for the treatment of post-partum haemorrhage: A meta-synthesis of qualitative studies.

BACKGROUND: Postpartum haemorrhage (PPH) is a leading cause of maternal mortality and severe morbidity globally. When PPH cannot be controlled using standard medical treatments, uterine balloon tamponade (UBT) may be used to arrest bleeding. While UBT is used by healthcare providers in hospital settings internationally, their views and experiences have not been systematically explored. The aim of this review is to identify, appraise and synthesize available evidence about the views and experiences of healthcare providers using UBT to treat PPH. METHODS: Using a pre-determined search strategy, we searched MEDLINE, CINAHL, PsycINFO, EMBASE, LILACS, AJOL, and reference lists of eligible studies published 1996-2019, reporting qualitative data on the views and experiences of health professionals using UBT to treat PPH. Author findings were extracted and synthesised using techniques derived from thematic synthesis and confidence in the findings was assessed using GRADE-CERQual. RESULTS: Out of 89 studies we identified 5 that met our inclusion criteria. The studies were conducted in five low- and middle-income countries (LMICs) in Africa and reported on the use of simple UBT devices for the treatment of PPH. A variety of cadres (including midwives, medical officers and clinical officers) had experience with using UBTs and found them to be effective, convenient, easy to assemble and relatively inexpensive. Providers also suggested regular, hands-on training was necessary to maintain skills and highlighted the importance of community engagement in successful implementation. CONCLUSIONS: Providers felt that administration of a simple UBT device offered a practical and cost-effective approach to the treatment of uncontrolled PPH, especially in contexts where uterotonics were ineffective or unavailable or where access to surgery was not possible. The findings are limited by the relatively small number of studies contributing to the review and further research in other contexts is required to address wider acceptability and feasibility issues.

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.

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.

Implementation of effective practices in health facilities: a systematic review of cluster randomised trials.

BACKGROUND: The capacity for health systems to support the translation of research in to clinical practice may be limited. The cluster randomised controlled trial (cluster RCT) design is often employed in evaluating the effectiveness of implementation of evidence-based practices. We aimed to systematically review available evidence to identify and evaluate the components in the implementation process at the facility level using cluster RCT designs. METHODS: All cluster RCTs where the healthcare facility was the unit of randomisation, published or written from 1990 to 2014, were assessed. Included studies were analysed for the components of implementation interventions employed in each. Through iterative mapping and analysis, we synthesised a master list of components used and summarised the effects of different combinations of interventions on practices. RESULTS: Forty-six studies met the inclusion criteria and covered the specialty groups of obstetrics and gynaecology (n=9), paediatrics and neonatology (n=4), intensive care (n=4), internal medicine (n=20), and anaesthetics and surgery (n=3). Six studies included interventions that were delivered across specialties. Nine components of multifaceted implementation interventions were identified: leadership, barrier identification, tailoring to the context, patient involvement, communication, education, supportive supervision, provision of resources, and audit and feedback. The four main components that were most commonly used were education (n=42, 91%), audit and feedback (n=26, 57%), provision of resources (n=23, 50%) and leadership (n=21, 46%). CONCLUSIONS: Future implementation research should focus on better reporting of multifaceted approaches, incorporating sets of components that facilitate the translation of research into practice, and should employ rigorous monitoring and evaluation.

A qualitative study of women's and health providers' attitudes and acceptability of mistreatment during childbirth in health facilities in Guinea.

BACKGROUND: Reducing maternal morbidity and mortality remains a key health challenge in Guinea. Anecdotal evidence suggests that women in Guinea are subjected to mistreatment during childbirth in health facilities, but limited research exists on this topic. This study was conducted to better understand the social norms and the acceptability of four scenarios of mistreatment during childbirth, from the perspectives of women and service providers. METHODS: This study used qualitative methods including in-depth interviews (IDIs) and focus group discussions (FGDs) with women of reproductive age, midwives, nurses and doctors. This study was conducted in one urban area (Mamou) and one peri-urban area (Pita) in Guinea. Participants were presented with four scenarios of mistreatment during childbirth, including a provider: (1) slapping a woman; (2) verbally abusing a woman; (3) refusing to help a woman; and (4) forcing a woman to give birth on the floor. Data were collected in local languages (Pular and Malinké) and French, and transcribed and analyzed in French. We used a thematic analysis approach and manually coded the data using a codebook developed for the project. RESULTS: A total of 40 IDIs and eight FGDs were conducted with women of reproductive age, 5 IDIs with doctors, and 13 IDIs with midwives. Most women were not accepting of any of the scenarios, unless the action was perceived to be used to save the life of the mother or child. However, they perceived a woman's disobedience and uncooperativeness to contribute to her poor treatment. Women reacted to this mistreatment by accepting poor treatment, refusal to use the same hospital, revenge against the provider or complaints to hospital management. Service providers were accepting of mistreatment when women were disobedient, uncooperative, or to save the life of the baby. CONCLUSIONS: This is the first known study on mistreatment of women during childbirth to be conducted in Guinea. Both women and service providers were accepting of mistreatment during childbirth under certain conditions. Any approach to preventing and eliminating mistreatment during childbirth must consider these important contextual and social norms and develop a comprehensive intervention that addresses root causes. Further research is needed on how to measure mistreatment during childbirth in Guinea.

Use of the Robson classification to assess caesarean section trends in 21 countries: a secondary analysis of two WHO multicountry surveys.

BACKGROUND: Rates of caesarean section surgery are rising worldwide, but the determinants of this increase, especially in low-income and middle-income countries, are controversial. In this study, we aimed to analyse the contribution of specific obstetric populations to changes in caesarean section rates, by using the Robson classification in two WHO multicountry surveys of deliveries in health-care facilities. The Robson system classifies all deliveries into one of ten groups on the basis of five parameters: obstetric history, onset of labour, fetal lie, number of neonates, and gestational age. METHODS: We studied deliveries in 287 facilities in 21 countries that were included in both the WHO Global Survey of Maternal and Perinatal Health (WHOGS; 2004-08) and the WHO Multi-Country Survey of Maternal and Newborn Health (WHOMCS; 2010-11). We used the data from these surveys to establish the average annual percentage change (AAPC) in caesarean section rates per country. Countries were stratified according to Human Development Index (HDI) group (very high/high, medium, or low) and the Robson criteria were applied to both datasets. We report the relative size of each Robson group, the caesarean section rate in each Robson group, and the absolute and relative contributions made by each to the overall caesarean section rate. FINDINGS: The caesarean section rate increased overall between the two surveys (from 26.4% in the WHOGS to 31.2% in the WHOMCS, p=0.003) and in all countries except Japan. Use of obstetric interventions (induction, prelabour caesarean section, and overall caesarean section) increased over time. Caesarean section rates increased across most Robson groups in all HDI categories. Use of induction and prelabour caesarean section increased in very high/high and low HDI countries, and the caesarean section rate after induction in multiparous women increased significantly across all HDI groups. The proportion of women who had previously had a caesarean section increased in moderate and low HDI countries, as did the caesarean section rate in these women. INTERPRETATION: Use of the Robson criteria allows standardised comparisons of data across countries and timepoints and identifies the subpopulations driving changes in caesarean section rates. Women who have previously had a caesarean section are an increasingly important determinant of overall caesarean section rates in countries with a moderate or low HDI. Strategies to reduce the frequency of the procedure should include avoidance of medically unnecessary primary caesarean section. Improved case selection for induction and prelabour caesarean section could also reduce caesarean section rates. FUNDING: None.

Assessment of cesarean delivery availability in 26 low- and middle-income countries: a cross-sectional study.

OBJECTIVE: We sought to assess the capacity to provide cesarean delivery (CD) in health facilities in low- and middle-income countries. STUDY DESIGN: We conducted secondary analysis of 719 health facilities, in 26 countries in Africa, the Pacific, Asia, and the Mediterranean, using facility-based cross-sectional data from the World Health Organization Situational Analysis Tool to Assess Emergency and Essential Surgical Care. RESULTS: A total of 531 (73.8%) facilities reported performing CD. In all, 126 (17.5%) facilities did not perform but referred CD; the most common reasons for doing so were lack of skills (53.2%) and nonfunctioning equipment (42.9%). All health facilities surveyed had at least 1 operating room. Of the facilities performing CD, 47.3% did not report the presence of any type of anesthesia provider and 17.9% did not report the presence of any type of obstetric/gynecological or surgical care provider. In facilities reporting a lack of functioning equipment, 26.4% had no access to an oxygen supply, 60.8% had no access to an anesthesia machine, and 65.9% had no access to a blood bank. CONCLUSION: Provision of CD in facilities in low- and middle-income countries is hindered by a lack of an adequate anesthetic and surgical workforce and availability of oxygen, anesthesia, and blood banks.