The effects of probiotics administration during pregnancy on preeclampsia and associated maternal, fetal, and newborn outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to synthesize the available evidence on probiotic administration during pregnancy for the prevention of preeclampsia and its effects on related maternal, fetal, and newborn outcomes. DATA SOURCES: Six databases were systematically searched for eligible studies, namely Ovid MEDLINE, Embase, CINAHL, Cochrane, Global Index Medicus, and the Maternity and Infant Care Database, from inception to August 2, 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials that evaluated the effects of probiotic administration on women during any stage of pregnancy were eligible for inclusion. METHODS: The protocol was registered with the International Prospective Register of Systematic Reviews under identifier CRD42023421613. Evaluating study eligibility, extracting data, assessing risk of bias (ROB-2 tool), and rating certainty (Grading of Recommendations, Assessment, Development and Evaluations) were conducted independently by 2 authors. The primary outcomes were incidence of preeclampsia, eclampsia, and maternal mortality. A meta-analysis was performed, and the results were reported as risk ratios with 95% confidence intervals. RESULTS: A total of 29 trials (7735 pregnant women) met the eligibility criteria. There was heterogeneity across the trials in the population of enrolled women and the type of probiotic tested (20 different strains), although most used oral administration. Probiotics may make no difference to the risk of preeclampsia (risk ratio, 1.14; 95% confidence interval, 0.84-1.53; 11 trials; 2401 women; low certainty evidence), preterm birth at <37 weeks' gestation (risk ratio, 0.93; 95% confidence interval, 0.66-1.30; 18 trials, 4016 women; low certainty evidence), or gestational age at delivery (mean difference, -0.03 weeks [≈0.2 days]; 95% confidence interval, -0.16 to 0.10 weeks [≈ -1.1 to 0.7 days]; 13 trials, 2194 women; low certainty evidence). It is difficult to assess the effects of probiotics on other secondary outcomes because the evidence was of very low certainty, however, no benefits or harms were observed. CONCLUSION: Limited evidence suggests that probiotic supplementation does not affect the risk for preeclampsia. Further high-quality trials are needed to definitively assess the benefits and possible harms of probiotic supplementation during pregnancy. There is also a lack of data from trials that included women who were undernourished or who experienced microbial dysbiosis and for whom probiotic supplementation might be useful.

Quality testing of mifepristone and misoprostol in 11 countries.

OBJECTIVE: Previous studies have demonstrated quality concerns with misoprostol. Mifepristone, however, has not been extensively assessed for quality. Between 2020 and 2021, Concept Foundation and the International Planned Parenthood Federation conducted a study to determine the quality of these medical abortion drugs in low- and middle-income countries (LMIC). METHODS: The collection of batch samples of misoprostol and mifepristone was carried out by trained sampling agents in selected LMIC. Single drug packs and combipacks were sampled. A World Health Organization prequalified laboratory conducted testing method verifications and subsequent sample analysis. Tests included identification, assay, related substances, and content uniformity for misoprostol, and identification, assay, related substances, and dissolution for mifepristone. RESULTS: Samples were collected from Burkina Faso, Cambodia, Democratic Republic of Congo, India, Kyrgyzstan, Moldova, Nepal, Nigeria, Pakistan, Uganda and Vietnam. Sixty-four pooled batch samples were tested, consisting of 31 combipacks, 26 misoprostol-only and seven mifepristone-only products. Overall, 54.7% of samples were non-compliant with one or more of the specifications, representing 51.6% of combipack products, 57.1% of misoprostol tablets analyzed and 23.7% of mifepristone tablets. One falsified misoprostol-only product was found. CONCLUSION: The present study confirms that a significant problem still exists in relation to the quality of medical abortion drugs in LMIC. For misoprostol, our findings suggest that historical concerns around primary packaging may have been largely resolved but that manufacturing processes for both finished product and active pharmaceutical ingredient need to be improved. The present study also provides evidence of mifepristone quality issues.

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.

Self-care interventions for preconception, antenatal, intrapartum and postpartum care: a scoping review.

OBJECTIVE: To identify current and emerging self-care interventions to improve maternity healthcare. DESIGN: Scoping review. DATA SOURCES: MEDLINE, Embase, EmCare, PsycINFO, Cochrane CENTRAL/CDSR, CINAHL Plus (last searched on 17 October 2021). ELIGIBILITY CRITERIA: Evidence syntheses, interventional or observational studies describing any tool, resource or strategy to facilitate self-care in women preparing to get pregnant, currently pregnant, giving birth or post partum. DATA EXTRACTION/SYNTHESIS: Screening and data collection were conducted independently by two reviewers. Self-care interventions were identified based on predefined criteria and inductively organised into 11 categories. Characteristics of study design, interventions, participants and outcomes were recorded. RESULTS: We identified eligible 580 studies. Many included studies evaluated interventions in high-income countries (45%) and during antenatal care (76%). Self-care categories featuring highest numbers of studies were diet and nutrition (26% of all studies), physical activity (24%), psychosocial strategies (18%) and other lifestyle adjustments (17%). Few studies featured self-care interventions for sexual health and postpartum family planning (2%), self-management of medication (3%) and self-testing/sampling (3%). Several venues to introduce self-care were described: health facilities (44%), community venues (14%), digital platforms (18%), partner/peer support (7%) or over-the-counter products (13%). Involvement of health and community workers were described in 38% and 8% of studies, who supported self-care interventions by providing therapeutics for home use, training or counselling. The most common categories of outcomes evaluated were neonatal outcomes (eg, birth weight) (31%), maternal mental health (26%) and labour outcomes (eg, duration of labour) (22%). CONCLUSION: Self-care interventions in maternal care are diverse in their applications, implementation characteristics and intended outcomes. Many self-care interventions were implemented with support from the health system at initial stages of use and uptake. Some promising self-care interventions require further primary research, though several are matured and up-to-date evidence syntheses are needed. Research on self-care in the preconception period is lacking.

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.

Reclassifying contraceptives as over-the-counter medicines to improve access.

Self-care interventions include over-the-counter contraceptives, which enable individuals to make informed, autonomous decisions about fertility management. As there is a substantial unmet need for contraception in many countries, increasing access by establishing sound, affordable and effective regulation of over-the-counter contraceptives could help reduce unintended pregnancies and improve maternal health. We performed a review of 30 globally diverse countries: (i) to assess national regulatory procedures for changing oral contraceptives, emergency contraceptives and injectable contraceptives from prescription-only to over-the-counter products; and (ii) to determine whether national lists of over-the-counter medicines included contraceptives. Of the 30 countries, 13 (43%) had formal regulatory procedures in place for changing prescription-only medicines to over-the-counter medicines, 11 (36%) had national lists of over-the-counter medicines, and four (13%) included contraceptives on those lists. Changing from prescription-only to over-the-counter medicines presents challenges for national medicines regulatory authorities and manufacturers, involving, for example, reporting side-effects, quality control and the often poorly-defined process of switching to over-the-counter products. To facilitate the over-the-counter availability of contraceptives, countries should consider adopting a formal regulatory procedure for reclassifying prescription-only contraceptives as over-the-counter contraceptives. Although the availability of over-the-counter contraceptives can increase users' independence and anonymity and improve access, there may also be disadvantages, such as higher out-of-pocket costs and the need for accurate self-assessment. Basic remedial actions to improve, harmonize and standardize regulatory procedures for the reclassification of contraceptives are proposed with the aim of enabling national medicines regulatory authorities to manage the switch to over-the-counter contraceptives and to control their quality.

Les soins autoadministrés incluent les contraceptifs en vente libre, qui permettent aux individus de prendre des décisions réfléchies et autonomes concernant le contrôle de la fécondité. Vu le besoin criant de contraception dans de nombreux pays, faciliter l'accès en proposant des méthodes de régulation sûres, efficaces et abordables par le biais de contraceptifs en vente libre pourrait contribuer à diminuer le nombre de grossesses non désirées et à améliorer la santé maternelle. Nous avons passé en revue 30 pays aux profils variés: (i) pour évaluer les procédures réglementaires nationales visant à modifier le statut des contraceptifs oraux, d'urgence et injectables afin qu'ils soient en vente libre au lieu d'être considérés comme des médicaments sur ordonnance; et (ii) pour déterminer si les contraceptifs figuraient sur les listes nationales de médicaments en vente libre. Sur les 30 pays observés, 13 (43%) avaient mis en place des procédures réglementaires officielles en vue de modifier le statut des contraceptifs, 11 (36%) possédaient des listes nationales de médicaments en vente libre et quatre (13%) y avaient inscrit les contraceptifs. Le passage du statut de médicament sur ordonnance à celui de médicament en vente libre représente un défi pour les autorités nationales de réglementation pharmaceutique et les fabricants, notamment en matière de déclaration des effets secondaires, de contrôle de la qualité et en raison d'un processus souvent mal défini. S'ils souhaitent favoriser la disponibilité des contraceptifs en vente libre, les pays devraient envisager l'adoption d'une procédure réglementaire officielle destinée à reclassifier les contraceptifs sur ordonnance en contraceptifs en vente libre. Bien que cette disponibilité puisse accroître l'autonomie et l'anonymat des usagers et améliorer l'accès à la contraception, elle présente également des désavantages car elle entraîne une hausse des frais non remboursés et requiert une autoévaluation correcte. Le présent document formule des mesures correctrices élémentaires servant à améliorer, harmoniser et normaliser les procédures réglementaires de reclassification des contraceptifs. Objectif: permettre aux autorités nationales de réglementation pharmaceutique de superviser le passage au statut de médicament en vente libre et de contrôler la qualité.

Las intervenciones de cuidado personal incluyen los anticonceptivos de venta libre, que permiten a las personas tomar decisiones informadas y autónomas sobre la gestión de la fertilidad. Dado que en muchos países existe una importante necesidad insatisfecha de anticoncepción, aumentar el acceso mediante el establecimiento de una normativa sólida, asequible y eficaz de los anticonceptivos de venta libre podría ayudar a reducir los embarazos no deseados y mejorar la salud materna. Se realizó una revisión de 30 países de todo el mundo: (i) para evaluar los procedimientos normativos nacionales relativos al cambio de los anticonceptivos orales, los anticonceptivos de urgencia y los anticonceptivos inyectables de medicamentos de venta con receta a productos de venta libre; y (ii) para determinar si las listas nacionales de medicamentos de venta libre incluían los anticonceptivos. De los 30 países, 13 (43 %) contaban con procedimientos normativos formales para el cambio de medicamentos de venta con receta a medicamentos de venta libre, 11 (36 %) tenían listas nacionales de medicamentos de venta libre, y cuatro (13 %) incluían los anticonceptivos en esas listas. El cambio de los medicamentos de venta con receta a los de venta libre supone un desafío para las autoridades nacionales de regulación de medicamentos y para los fabricantes, ya que implica, por ejemplo, la notificación de los efectos secundarios, el control de calidad y el proceso, que suele estar mal definido, de pasar a los productos de venta libre. Para facilitar la disponibilidad de los anticonceptivos sin receta, los países deberían considerar la adopción de un procedimiento normativo formal para reclasificar los anticonceptivos de venta con receta como anticonceptivos de venta sin receta. Aunque la disponibilidad de los anticonceptivos de venta libre puede aumentar la independencia y el anonimato de los usuarios y mejorar el acceso, también puede haber desventajas, como los mayores costos de bolsillo y la necesidad de una autoevaluación precisa. Se proponen acciones correctivas básicas para mejorar, armonizar y estandarizar los procedimientos normativos para la reclasificación de los anticonceptivos, con el objetivo de que las autoridades nacionales de regulación de medicamentos puedan gestionar el cambio a los anticonceptivos sin receta y controlar su calidad.

Challenges in updating national guidelines and essential medicines lists in Sub-Saharan African countries to include WHO-recommended postpartum hemorrhage medicines.

Despite the 2017 WHO recommendations on tranexamic acid (TXA) for the treatment of postpartum hemorrhage (PPH), the 2018 uterotonic recommendations (which included heat-stable carbetocin (HSC) for the prevention of PPH) and their inclusion in the WHO Essential Medicines List (EML), both drugs are still underused or not used at all to manage PPH in many countries with a high burden. HSC is currently being registered in low- and middle-income countries and its policy inclusion is limited and slow. TXA (also heat stable) is available in many countries but is not registered for PPH treatment, which may have contributed to the delay in its inclusion in national guidelines and EMLs. For both drugs, national guidelines will need to be revised and updated for their optimal uptake. We implemented an advocacy initiative to accelerate the necessary normative policy change to ensure access to quality-assured and heat-stable medicines for the prevention and treatment of PPH in Sub-Saharan African countries. Our initiative aimed to raise awareness of the importance of recently recommended medicines for the prevention and treatment of PPH and support the process to update PPH guidelines and EMLs to include these drugs. We highlight the lessons learned during the initiative, including the challenges and opportunities identified in updating PPH policies at the national level.

Innovations in the prevention and treatment of postpartum hemorrhage: Analysis of a novel medicines development pipeline database.

BACKGROUND: A significant barrier to improving prevention and treatment of postpartum hemorrhage (PPH) is a lack of innovative medicines that meet the needs of women and providers, particularly those in low-and middle-income countries (LMICs). The Accelerating Innovation for Mothers (AIM) project established a new database of candidate medicines under development for five pregnancy-related conditions between 2000 and 2021. OBJECTIVE: To systematically identify and rank candidates for prevention and treatment of PPH. SEARCH STRATEGY: Adis Insight, Pharmaprojects, WHO ICTRP, PubMed, and grant databases were searched to develop the AIM database. SELECTION CRITERIA: AIM database was searched for candidates being evaluated for PPH prevention and treatment, regardless of phase. DATA COLLECTION AND ANALYSIS: Candidates were ranked as high, medium, or low potential based on prespecified criteria. Analysis was primarily descriptive, describing candidates and development potential. MAIN RESULTS: Of the 444 unique candidates, only 39 pertained to PPH. One was high potential (heat-stable/inhaled oxytocin) and three were medium potential (melatonin, vasopressin and dofetilide via nanoparticle delivery). CONCLUSION: The pipeline for new PPH medicines is concerningly limited, lacking diversity, and showing little evidence of novel technologies. Without significant investment in early-phase research, it is unlikely that new products will emerge.

Quality of oxytocin and tranexamic acid for the prevention and treatment of postpartum hemorrhage in Kenya, Nigeria, South Africa, and Tanzania.

OBJECTIVE: To check the quality of oxytocin and tranexamic acid-two recommended products for prevention and treatment of postpartum hemorrhage (PPH)-used in facilities taking part in an implementation research project to improve PPH diagnosis and management. METHODS: Between September 2020 and August 2021, oxytocin and tranexamic acid products used in the study facilities in Kenya, Nigeria, South Africa, and Tanzania were collected and transported in cold storage for analysis. Samples were analyzed according to the International (oxytocin) and British Pharmacopeia (tranexamic acid) standards. RESULTS: Of the 17 unique oxytocin products, 33 individual measurements were made. Only six unique products had adequate content and no related substances exceeding the recommended limits. Of 14 tranexamic acid samples, 10 showed adequate content. One product in Kenya and two products in Nigeria from different manufacturers had a high content of related substances, which classified them as substandard. CONCLUSION: While we were unable to investigate the origin regarding poor manufacturing or poor storage or both, the high number of substandard oxytocin samples is of great concern. Most of the tranexamic acid samples had adequate content but the presence of impurities in multiple products is worrying and requires further study.

Target product profiles for novel medicines to prevent and treat preeclampsia: An expert consensus.

BACKGROUND: Preeclampsia and eclampsia are a leading cause of global maternal and newborn mortality. Currently, there are few effective medicines that can prevent or treat preeclampsia. Target Product Profiles (TPPs) are important tools for driving new product development by specifying upfront the characteristics that new products should take. Considering the lack of investment and innovation around new medicines for obstetric conditions, we aimed to develop two new TPPs for medicines to prevent and treat preeclampsia. METHODS AND FINDINGS: We used a multi-methods approach comprised of a literature review, stakeholder interviews, online survey, and public consultation. Following an initial literature review, diverse stakeholders (clinical practice, research, academia, international organizations, funders, consumer representatives) were invited for in-depth interviews and an online international survey, as well as public consultation on draft TPPs. The level of stakeholder agreement with TPPs was assessed, and findings from interviews were synthesised to inform the final TPPs. We performed 23 stakeholder interviews and received 46 survey responses. A high level of agreement was observed in survey results, with 89% of TPP variables reaching consensus (75% agree or strongly agree). Points of discussion were raised around the target population for preeclampsia prevention and treatment, as well as the acceptability of cold-chain storage and routes of administration. CONCLUSION: There is consensus within the maternal health research community on the parameters that new medicines for preeclampsia prevention and treatment must achieve to meet real-world health needs. These TPPs provide necessary guidance to spur interest, innovation and investment in the development of new medicines to prevent and treat preeclampsia.

Regulatory standards and processes for over-the-counter availability of hormonal contraception and drugs for medical abortion in five countries in the Eastern Mediterranean Region.

The World Health Organization 2019 WHO consolidated guideline on self-care interventions for health: sexual and reproductive health and rights includes recommendations on self-administration of injectable contraception, over-the-counter (OTC) oral contraception and self-management of medical abortion. A review of the regulatory status of these two self-care interventions can highlight processes required to ensure that the quality of the medicines and safety of individuals are safeguarded in the introduction and scale-up in countries. This review outlines the legal regulatory status of prescription-only medicine (POM) and OTC contraceptives, including emergency contraception, and drugs for medical abortion in Egypt, Jordan, Lebanon, Morocco and Tunisia using information obtained from internet searches, regulatory information databases and personal contacts. In addition, the review examines whether the national medicines regulatory authorities have documented procedures available to allow for a change in status from a POM to OTC to allow for increased accessibility, availability and uptake of self-care interventions recommended by WHO. Egypt, Jordan and Lebanon have a documented national OTC list available. The only contraceptive product mentioned in the OTC lists across all five countries is ellaOne (ulipristal acetate for emergency contraception), which is publicly registered in Lebanon. None of the five countries has an official documented procedure to apply for the change of POM to OTC. Informal procedures exist, such as the ability to apply to the national medicines regulatory authority for OTC status if the product has OTC status in the original country of manufacture. However, many of these procedures are not officially documented, highlighting the need for establishing sound, affordable and effective regulation of medical products as an important part of health system strengthening. From a public health perspective, it would be advantageous for licensed products to be available OTC. This is particularly the case for settings where the health system is under-resourced or over-stretched due to health emergencies. Readiness of national regulatory guidelines and OTC procedures could lead to increased access, availability and usage of essential self-care interventions for sexual and reproductive health and rights.

Mobile apps for detecting falsified and substandard drugs: A systematic review.

The use of substandard and counterfeit medicines (SCM) leads to significant health and economic consequences, like treatment failure, rise of antimicrobial resistance, extra expenditures of individuals or households and serious adverse drug reactions including death. Our objective was to systematically search, identify and compare relevant available mobile applications (apps) for smartphones and tablets, which use could potentially affect clinical and public health outcomes. We carried out a systematic review of the literature in January 2020, including major medical databases, and app stores. We used the validated Mobile App Rating Scale (MARS) to assess the quality of apps, (1 worst score, 3 acceptable score, and 5 best score). We planned to evaluate the accuracy of the mobile apps to detect SCM. We retrieved 335 references through medical databases and 42 from Apple, Google stores and Google Scholar. We finally included two studies of the medical database, 25 apps (eight from the App Store, eight from Google Play, eight from both stores, and one from Google Scholar), and 16 websites. We only found one report on the accuracy of a mobile apps detecting SCMs. Most apps use the imprint, color or shape for pill identification, and only a few offer pill detection through photographs or bar code. The MARS mean score for the apps was 3.17 (acceptable), with a maximum of 4.9 and a minimum of 1.1. The 'functionality' dimension resulted in the highest mean score (3.4), while the 'engagement' and 'information' dimensions showed the lowest one (3.0). In conclusion, we found a remarkable evidence gap about the accuracy of mobile apps in detecting SCMs. However, mobile apps could potentially be useful to screen for SCM by assessing the physical characteristics of pills, although this should still be assessed in properly designed research studies.

Correction: The World Health Organization Fetal Growth Charts: A Multinational Longitudinal Study of Ultrasound Biometric Measurements and Estimated Fetal Weight.

[This corrects the article DOI: 10.1371/journal.pmed.1002220.].

Cost of hospital care of women with postpartum haemorrhage in India, Kenya, Nigeria and Uganda: a financial case for improved prevention.

OBJECTIVE: Access to quality, effective lifesaving uterotonics in low and middle-income countries (LMICs) remains a major barrier to reducing maternal deaths from postpartum haemorrhage (PPH). Our objective was to assess the costs of care for women who receive different preventative uterotonics, and with PPH and no-PPH so that the differences, if significant, can inform better resource allocation for maternal health care. METHODS: The costs of direct hospital care of women who received oxytocin or heat-stable carbetocin for prevention of PPH in selected tertiary care facilities in India, Kenya, Nigeria, and Uganda were assessed. We collected data from all women who had PPH, as well as a random sample of women without PPH. Cost data was collected for the cost of stay, PPH interventions, transfusions and medications for 2966 women. We analyzed the difference in cost of care at a facility level between women who experienced a PPH event and those who did not. Key findings The mean cost of care of a woman experiencing PPH in the study sites in India, Kenya, Nigeria, and Uganda exceeded the cost of care of a woman who did not experience PPH by between 21% and 309%. There was a large variation in cost across hospitals within a country and across countries. CONCLUSION: Our results quantify the increased cost of PPH of up to 4.1 times that for a birth without PPH. PPH cost information can help countries to evaluate options across different conditions and in the formulation of appropriate guidelines for intrapartum care, including rational selection of quality-assured, effective medicines. This information can be applied to national assessment and adaptation of international recommendations such as the World Health Organization's recommendations on uterotonics for the prevention of PPH or other interventions used to treat PPH. Trial registration HRP Trial A65870; UTN U1111-1162-8519; ACTRN12614000870651; CTRI/2016/05/006969, EUDRACT 2014-004445-26. Date of registration 14 August 2014 Access to quality, effective lifesaving medicines in low and middle-income countries remains a major barrier to reducing maternal deaths from bleeding after childbirth. Information on to what extent treatments for bleeding increases the cost of care of women after childbirth is important for informed resource allocation. We collected data from all women who had bleeding after childbirth, as well as a random sample of women without bleeding in selected hospitals in India, Kenya, Nigeria, and Uganda. Cost data was collected for the cost of stay and interventions to manage bleeding for 2966 women. We compared the difference in cost of care between women who experienced a bleeding event and those who did not. The mean cost of care of a woman with bleeding in the study sites exceeded the cost of care of a woman who did not experience PPH by between 21% and 309%. There was a large variation in cost across hospitals within a country and across countries. Our results indicate an increased cost of bleeding of up to 4.1 times that for birth without bleeding. Effective prevention reduces the cost of care. Cost information can help countries to evaluate options across different conditions and in the formulation of appropriate guidelines for intrapartum care, including rational selection of quality-assured, effective medicines. This information can be applied to national assessment and adaptation of international recommendations such as the World Health Organization's recommendations on medications for the prevention of bleeding after childbirth or other interventions used to treat bleeding.

The first 2 h after birth: prevalence and factors associated with neonatal care practices from a multicountry, facility-based, observational study.

BACKGROUND: Amid efforts to improve the quality of care for women and neonates during childbirth, there is growing interest in the experience of care, including respectful care practices. However, there is little research on the prevalence of practices that might constitute mistreatment of neonates. This study aims to describe the care received by neonates up to 2 h after birth in a sample of three countries in west Africa. METHODS: Data from this multicountry, facility-based, observational study were collected on 15 neonatal care practices across nine facilities in Ghana, Guinea, and Nigeria, as part of WHO's wider multicountry study on how women are treated during childbirth. Women were eligible if they were admitted to the participating health facilities for childbirth, in early established labour or active labour, aged 15 years or older, and provided written informed consent on behalf of themselves and their neonate. All labour observations were continuous, one-to-one observations of women and neonates by independent data collectors. Descriptive statistics and multivariate logistic regressions were used to examine associations between these neonatal care practices, maternal and neonate characteristics, and maternal mistreatment. Early neonate deaths, stillbirths, and higher order multiple births were excluded from analysis. FINDINGS: Data collection took place from Sept 19, 2016, to Feb 26, 2017, in Nigeria; from Aug 1, 2017, to Jan 18, 2018, in Ghana; and from July 1 to Oct 30, 2017, in Guinea. We included data for 362 women-neonate dyads (356 [98%] with available data for neonatal care practices) in Nigeria, 760 (749 [99%]) in Ghana, and 558 (522 [94%]) in Guinea. Delayed cord clamping was done for most neonates (1493 [91·8%] of 1627); other practices, such as skin-to-skin contact, were less commonly done (1048 [64·4%]). During the first 2 h after birth, separation of the mother and neonate occurred in 844 (51·9%) of 1627 cases; and was more common for mothers who were single (adjusted odds ratio [AOR; adjusting for country, maternal age, education, marital status, neonate weight at birth, and neonate sex] 1·8, 95% CI 1·3-2·6) than those who were married or cohabiting. Lack of maternal education was associated with increased likelihood of neonates not receiving recommended breastfeeding practices. Neonates with a low birthweight (<2·5 kg) were more likely (1·7, 1·1-2·8) to not begin breastfeeding on demand than full weight neonates. When women experienced physical abuse from providers within 1 h before childbirth, their neonates were more likely to be slapped (AOR 1·9, 1·1-3·9). INTERPRETATION: A high proportion of neonates did not receive recommended care practices, and some received practices that might constitute mistreatment. Further research is needed on understanding and measuring mistreatment to improve care, including respectful care, for mothers and neonates. FUNDING: US Agency for International Development, and the UNDP/UN Population Fund/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, WHO.

Cost of goods sold analysis and recommendations to reduce costs of co-packaged mifepristone-misoprostol for medical abortion.

OBJECTIVE: Understanding the price components of the mifepristone/misoprostol (combi-pack) for medical abortion to improve access is critical for identifying strategies to reduce product costs for quality-assured formulations and expanding its availability and use. METHODS: We constructed a cost of goods sold analysis using data collected from manufacturing companies in Bangladesh, China and India supported by publicly available information related to the product formulation, active pharmaceutical ingredients (API), manufacturing location, manufacturer profiles and other individual model components. Key model components were the active pharmaceutical ingredients (quality-assured or not), excipients, labour cost, operating cost and packaging. RESULTS: Combi-pack direct production cost ranges from US$1.08 for finished products which are not quality assured to US$3.05 for products containing quality assured active pharmaceutical ingredients, which means that with a 30% administrative fee applied to those prices, it could be made available between US$1.40 and US$3.97 depending on location, manufacturer's profile, optimal market situation and the quality of the active pharmaceutical ingredients. The main model component impacting on the cost range is the purchase price of mifepristone active pharmaceutical ingredient and the current differential between quality-assured material supported by adequate documentation and API for which quality assurance cannot be demonstrated. Compared to India cost of goods sold is lower in Bangladesh primarily due to lower operating costs, including the cost of labour. CONCLUSIONS: It is feasible to lower the cost of quality-assured combi-packs, through reducing mifepristone API cost and selection of the manufacturing location. However, manufacturers need to be incentivised to achieve WHO pre-qualification with a carefully built business case and require support in identifying and sourcing competitively priced material and manufacturing products to the necessary standard.

Risk factors associated with adverse maternal outcomes following intrapartum cesarean birth: a secondary analysis of the WHO global survey on maternal and perinatal health, 2004-2008.

BACKGROUND: To identify risk factors associated with a composite adverse maternal outcomes in women undergoing intrapartum cesarean birth. METHODS: We used the facility-based, multi-country, cross-sectional WHO Global Survey of Maternal and Perinatal Health (2004-2008) to examine associations between woman-, labor/obstetric-, and facility-level characteristics and a composite adverse maternal outcome of postpartum morbidity and mortality. This analysis was performed among women who underwent intrapartum cesarean birth during the course of labor. RESULTS: We analyzed outcomes of 29,516 women from low- and middle-income countries who underwent intrapartum cesarean birth between the gestational ages of 24 and 43 weeks, 3.5% (1040) of whom experienced the composite adverse maternal outcome. In adjusted analyses, factors associated with a decreased risk of the adverse maternal outcome associated with intrapartum cesarean birth included having four or more antenatal visits (AOR 0.60; 95% CI: 0.43-0.84; p = 0.003), delivering in a medium- or high-human development index country (vs. low-human development index country: AOR 0.07; 95% CI: 0.01-0.85 and AOR 0.02; 95% CI: 0.001-0.39, respectively; p = 0.03), and malpresentation (vs. cephalic: breech AOR 0.52; CI: 0.31-0.87; p = 0.04). Women who were medically high risk (vs. not medically high risk: AOR 1.81; CI: 1.30-2.51, p < 0.0004), had less education (0-6 years) (vs. 13+ years; AOR 1.64; CI: 1.03-2.63; p = 0.01), were obstetrically high risk (vs. not high risk; AOR 3.67; CI: 2.58-5.23; p < 0.0001), or had a maternal or obstetric indication (vs. elective: AOR 4.74; CI: 2.36-9.50; p < 0.0001) had increased odds of the adverse outcome. CONCLUSION: We found reduced adverse maternal outcomes of intrapartum cesarean birth in women with ≥ 4 antenatal visits, those who delivered in a medium or high human development index country, and those with malpresenting fetuses. Maternal adverse outcomes associated with intrapartum cesarean birth were medically and obstetrically high risk women, those with less education, and those with a maternal or obstetric indication for intrapartum cesarean birth.