Factors influencing the participation of pregnant and lactating women in clinical trials: A mixed-methods systematic review.

BACKGROUND: Poor representation of pregnant and lactating women and people in clinical trials has marginalised their health concerns and denied the maternal-fetal/infant dyad benefits of innovation in therapeutic research and development. This mixed-methods systematic review synthesised factors affecting the participation of pregnant and lactating women in clinical trials, across all levels of the research ecosystem. METHODS AND FINDINGS: We searched 8 databases from inception to 14 February 2024 to identify qualitative, quantitative, and mixed-methods studies that described factors affecting participation of pregnant and lactating women in vaccine and therapeutic clinical trials in any setting. We used thematic synthesis to analyse the qualitative literature and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. We compared quantitative data against the thematic synthesis findings to assess areas of convergence or divergence. We mapped review findings to the Theoretical Domains Framework (TDF) and Capability, Opportunity, and Motivation Model of Behaviour (COM-B) to inform future development of behaviour change strategies. We included 60 papers from 27 countries. We grouped 24 review findings under 5 overarching themes: (a) interplay between perceived risks and benefits of participation in women's decision-making; (b) engagement between women and the medical and research ecosystems; (c) gender norms and decision-making autonomy; (d) factors affecting clinical trial recruitment; and (e) upstream factors in the research ecosystem. Women's willingness to participate in trials was affected by: perceived risk of the health condition weighed against an intervention's risks and benefits, therapeutic optimism, intervention acceptability, expectations of receiving higher quality care in a trial, altruistic motivations, intimate relationship dynamics, and power and trust in medicine and research. Health workers supported women's participation in trials when they perceived clinical equipoise, had hope for novel therapeutic applications, and were convinced an intervention was safe. For research staff, developing reciprocal relationships with health workers, having access to resources for trial implementation, ensuring the trial was visible to potential participants and health workers, implementing a woman-centred approach when communicating with potential participants, and emotional orientations towards the trial were factors perceived to affect recruitment. For study investigators and ethics committees, the complexities and subjectivities in risk assessments and trial design, and limited funding of such trials contributed to their reluctance in leading and approving such trials. All included studies focused on factors affecting participation of cisgender pregnant women in clinical trials; future research should consider other pregnancy-capable populations, including transgender and nonbinary people. CONCLUSIONS: This systematic review highlights diverse factors across multiple levels and stakeholders affecting the participation of pregnant and lactating women in clinical trials. By linking identified factors to frameworks of behaviour change, we have developed theoretically informed strategies that can help optimise pregnant and lactating women's engagement, participation, and trust in such trials.

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

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

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.

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 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.

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.].

Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth.

BACKGROUND: Postpartum hemorrhage is the most common cause of maternal death. Oxytocin is the standard therapy for the prevention of postpartum hemorrhage, but it requires cold storage, which is not available in many countries. In a large trial, we compared a novel formulation of heat-stable carbetocin with oxytocin. METHODS: We enrolled women across 23 sites in 10 countries in a randomized, double-blind, noninferiority trial comparing intramuscular injections of heat-stable carbetocin (at a dose of 100 µg) with oxytocin (at a dose of 10 IU) administered immediately after vaginal birth. Both drugs were kept in cold storage (2 to 8°C) to maintain double-blinding. There were two primary outcomes: the proportion of women with blood loss of at least 500 ml or the use of additional uterotonic agents, and the proportion of women with blood loss of at least 1000 ml. The noninferiority margins for the relative risks of these outcomes were 1.16 and 1.23, respectively. RESULTS: A total of 29,645 women underwent randomization. The frequency of blood loss of at least 500 ml or the use of additional uterotonic agents was 14.5% in the carbetocin group and 14.4% in the oxytocin group (relative risk, 1.01; 95% confidence interval [CI], 0.95 to 1.06), a finding that was consistent with noninferiority. The frequency of blood loss of at least 1000 ml was 1.51% in the carbetocin group and 1.45% in the oxytocin group (relative risk, 1.04; 95% CI, 0.87 to 1.25), with the confidence interval crossing the margin of noninferiority. The use of additional uterotonic agents, interventions to stop bleeding, and adverse effects did not differ significantly between the two groups. CONCLUSIONS: Heat-stable carbetocin was noninferior to oxytocin for the prevention of blood loss of at least 500 ml or the use of additional uterotonic agents. Noninferiority was not shown for the outcome of blood loss of at least 1000 ml; low event rates for this outcome reduced the power of the trial. (Funded by Merck Sharpe & Dohme; CHAMPION Australian New Zealand Clinical Trials Registry number, ACTRN12614000870651 ; EudraCT number, 2014-004445-26 ; and Clinical Trials Registry-India number, CTRI/2016/05/006969 .).

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.

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.

How women are treated during facility-based childbirth in four countries: a cross-sectional study with labour observations and community-based surveys.

BACKGROUND: Women across the world are mistreated during childbirth. We aimed to develop and implement evidence-informed, validated tools to measure mistreatment during childbirth, and report results from a cross-sectional study in four low-income and middle-income countries. METHODS: We prospectively recruited women aged at least 15 years in twelve health facilities (three per country) in Ghana, Guinea, Myanmar, and Nigeria between Sept 19, 2016, and Jan 18, 2018. Continuous observations of labour and childbirth were done from admission up to 2 h post partum. Surveys were administered by interviewers in the community to women up to 8 weeks post partum. Labour observations were not done in Myanmar. Data were collected on sociodemographics, obstetric history, and experiences of mistreatment. FINDINGS: 2016 labour observations and 2672 surveys were done. 838 (41·6%) of 2016 observed women and 945 (35·4%) of 2672 surveyed women experienced physical or verbal abuse, or stigma or discrimination. Physical and verbal abuse peaked 30 min before birth until 15 min after birth (observation). Many women did not consent for episiotomy (observation: 190 [75·1%] of 253; survey: 295 [56·1%] of 526) or caesarean section (observation: 35 [13·4%] of 261; survey: 52 [10·8%] of 483), despite receiving these procedures. 133 (5·0%) of 2672 women or their babies were detained in the facility because they were unable to pay the bill (survey). Younger age (15-19 years) and lack of education were the primary determinants of mistreatment (survey). For example, younger women with no education (odds ratio [OR] 3·6, 95% CI 1·6-8·0) and younger women with some education (OR 1·6, 1·1-2·3) were more likely to experience verbal abuse, compared with older women (≥30 years), adjusting for marital status and parity. INTERPRETATION: More than a third of women experienced mistreatment and were particularly vulnerable around the time of birth. Women who were younger and less educated were most at risk, suggesting inequalities in how women are treated during childbirth. Understanding drivers and structural dimensions of mistreatment, including gender and social inequalities, is essential to ensure that interventions adequately account for the broader context. FUNDING: United States Agency for International Development and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, WHO.

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.

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.

Self-care and remote care during pregnancy: a new paradigm?

Self-care interventions and remote care offer innovative and equitable ways to strengthen access to sexual and reproductive health services. Self-isolation during COVID-19 provided the opportunity for obstetric facilities and healthcare providers to integrate and increase the usage of interventions for self-care and remote care for pregnant women and to improve the quality of care overall.

Correction to: Self-care and remote care during pregnancy: a new paradigm?

An amendment to this paper has been published and can be accessed via the original article.

Progression of the first stage of spontaneous labour: A prospective cohort study in two sub-Saharan African countries.

BACKGROUND: Escalation in the global rates of labour interventions, particularly cesarean section and oxytocin augmentation, has renewed interest in a better understanding of natural labour progression. Methodological advancements in statistical and computational techniques addressing the limitations of pioneer studies have led to novel findings and triggered a re-evaluation of current labour practices. As part of the World Health Organization's Better Outcomes in Labour Difficulty (BOLD) project, which aimed to develop a new labour monitoring-to-action tool, we examined the patterns of labour progression as depicted by cervical dilatation over time in a cohort of women in Nigeria and Uganda who gave birth vaginally following a spontaneous labour onset. METHODS AND FINDINGS: This was a prospective, multicentre, cohort study of 5,606 women with singleton, vertex, term gestation who presented at ≤ 6 cm of cervical dilatation following a spontaneous labour onset that resulted in a vaginal birth with no adverse birth outcomes in 13 hospitals across Nigeria and Uganda. We independently applied survival analysis and multistate Markov models to estimate the duration of labour centimetre by centimetre until 10 cm and the cumulative duration of labour from the cervical dilatation at admission through 10 cm. Multistate Markov and nonlinear mixed models were separately used to construct average labour curves. All analyses were conducted according to three parity groups: parity = 0 (n = 2,166), parity = 1 (n = 1,488), and parity = 2+ (n = 1,952). We performed sensitivity analyses to assess the impact of oxytocin augmentation on labour progression by re-examining the progression patterns after excluding women with augmented labours. Labour was augmented with oxytocin in 40% of nulliparous and 28% of multiparous women. The median time to advance by 1 cm exceeded 1 hour until 5 cm was reached in both nulliparous and multiparous women. Based on a 95th percentile threshold, nulliparous women may take up to 7 hours to progress from 4 to 5 cm and over 3 hours to progress from 5 to 6 cm. Median cumulative duration of labour indicates that nulliparous women admitted at 4 cm, 5 cm, and 6 cm reached 10 cm within an expected time frame if the dilatation rate was ≥ 1 cm/hour, but their corresponding 95th percentiles show that labour could last up to 14, 11, and 9 hours, respectively. Substantial differences exist between actual plots of labour progression of individual women and the 'average labour curves' derived from study population-level data. Exclusion of women with augmented labours from the study population resulted in slightly faster labour progression patterns. CONCLUSIONS: Cervical dilatation during labour in the slowest-yet-normal women can progress more slowly than the widely accepted benchmark of 1 cm/hour, irrespective of parity. Interventions to expedite labour to conform to a cervical dilatation threshold of 1 cm/hour may be inappropriate, especially when applied before 5 cm in nulliparous and multiparous women. Averaged labour curves may not truly reflect the variability associated with labour progression, and their use for decision-making in labour management should be de-emphasized.

Methodological development of tools to measure how women are treated during facility-based childbirth in four countries: labor observation and community survey.

BACKGROUND: Efforts to improve maternal health are increasingly focused on improving the quality of care provided to women at health facilities, including the promotion of respectful care and eliminating mistreatment of women during childbirth. A WHO-led multi-country research project aims to develop and validate two tools (labor observation and community survey) to measure how women are treated during facility-based childbirth. This paper describes the development process for these measurement tools, and how they were implemented in a multi-country study (Ghana, Guinea, Myanmar and Nigeria). METHODS: An iterative mixed-methods approach was used to develop two measurement tools. Methodological development was conducted in four steps: (1) initial tool development; (2) validity testing, item adjustment and piloting of paper-based tools; (3) conversion to digital, tablet-based tools; and (4) data collection and analysis. These steps included systematic reviews, primary qualitative research, mapping of existing tools, item consolidation, peer review by key stakeholders and piloting. RESULTS: The development, structure, administration format, and implementation of the labor observation and community survey tools are described. For the labor observations, a total of 2016 women participated: 408 in Nigeria, 682 in Guinea, and 926 in Ghana. For the community survey, a total of 2672 women participated: 561 in Nigeria, 644 in Guinea, 836 in Ghana, and 631 in Myanmar. Of the 2016 women who participated in the labor observations, 1536 women (76.2%) also participated in the community survey and have linked data: 779 in Ghana, 425 in Guinea, and 332 in Nigeria. CONCLUSIONS: An important step to improve the quality of maternity care is to understand the magnitude and burden of mistreatment across contexts. Researchers and healthcare providers in maternal health are encouraged to use and implement these tools, to inform the development of more women-centered, respectful maternity healthcare services. By measuring the prevalence of mistreatment of women during childbirth, we will be able to design and implement programs and policies to transform maternity services.

Distribution of postpartum blood loss: modeling, estimation and application to clinical trials.

BACKGROUND: The loss of large amounts of blood postpartum can lead to severe maternal morbidity and mortality. Understanding the nature of postpartum blood loss distribution is critical for the development of efficient analysis techniques when comparing treatments to prevent this event. When blood loss is measured, resulting in a continuous volume measure, often this variable is categorized in classes, and reduced to an indicator of volume greater than a cutoff point. This reduction of volume to classes entails a substantial loss of information. As a consequence, very large trials are needed to assess clinically important differences between treatments to prevent postpartum haemorrhage. METHODS: The authors explore the nature of postpartum blood loss distribution, assuming that the physical properties of blood loss lead to a lognormal distribution. Data from four clinical trials and one observational study are used to confirm this empirically. Estimates of probabilities of postpartum haemorrhage events 'blood loss greater than a cutoff point' and relative risks are obtained from the fitted lognormal distributions. Confidence intervals for relative risk are obtained by bootstrap techniques. RESULTS: A variant of the lognormal distribution, the three-parameter lognormal distribution, showed an excellent fit to postpartum blood loss data of the four trials and the observational study. A measurement quality assessment showed that problems of digit preference and lower limit of detection were well handled by the lognormal fit. The analysis of postpartum haemorrhage events based on a lognormal distribution improved the efficiency of the estimates. Sample size calculation for a hypothetical future trial showed that the application of this procedure permits a reduction of sample size for treatment comparison. CONCLUSION: A variant of the lognormal distribution fitted very well postpartum blood loss data from different geographical areas, suggesting that the lognormal distribution might fit postpartum blood loss universally. An approach of analysis of postpartum haemorrhage events based on the lognormal distribution improves efficiency of estimates of probabilities and relative risk, and permits a reduction of sample size for treatment comparison. TRIAL REGISTRATION: This paper reports secondary analyses for trials registered at Australian New Zealand Clinical Trials Registry (ACTRN 12608000434392 and ACTRN12614000870651); and at clinicaltrials.gov (NCT00781066).

Odon device for instrumental vaginal deliveries: results of a medical device pilot clinical study.

BACKGROUND: A prolonged and complicated second stage of labour is associated with serious perinatal complications. The Odon device is an innovation intended to perform instrumental vaginal delivery presently under development. We present an evaluation of the feasibility and safety of delivery with early prototypes of this device from an early terminated clinical study. METHODS: Hospital-based, multi-phased, open-label, pilot clinical study with no control group in tertiary hospitals in Argentina and South Africa. Multiparous and nulliparous women, with uncomplicated singleton pregnancies, were enrolled during the third trimester of pregnancy. Delivery with Odon device was attempted under non-emergency conditions during the second stage of labour. The feasibility outcome was delivery with the Odon device defined as successful expulsion of the fetal head after one-time application of the device. RESULTS: Of the 49 women enrolled, the Odon device was inserted successfully in 46 (93%), and successful Odon device delivery as defined above was achieved in 35 (71%) women. Vaginal, first and second degree perineal tears occurred in 29 (59%) women. Four women had cervical tears. No third or fourth degree perineal tears were observed. All neonates were born alive and vigorous. No adverse maternal or infant outcomes were observed at 6-weeks follow-up for all dyads, and at 1 year for the first 30 dyads. CONCLUSIONS: Delivery using the Odon device is feasible. Observed genital tears could be due to the device or the process of delivery and assessment bias. Evaluating the effectiveness and safety of the further developed prototype of the BD Odon Device™ will require a randomized-controlled trial. TRIAL REGISTRATION: ANZCTR ACTRN12613000141741 Registered 06 February 2013. Retrospectively registered.

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

BACKGROUND: Perinatal mortality and morbidity continue to be major global health challenges strongly associated with prematurity and reduced fetal growth, an issue of further interest given the mounting evidence that fetal growth in general is linked to degrees of risk of common noncommunicable diseases in adulthood. Against this background, WHO made it a high priority to provide the present fetal growth charts for estimated fetal weight (EFW) and common ultrasound biometric measurements intended for worldwide use. METHODS AND FINDINGS: We conducted a multinational prospective observational longitudinal study of fetal growth in low-risk singleton pregnancies of women of high or middle socioeconomic status and without known environmental constraints on fetal growth. Centers in ten countries (Argentina, Brazil, Democratic Republic of the Congo, Denmark, Egypt, France, Germany, India, Norway, and Thailand) recruited participants who had reliable information on last menstrual period and gestational age confirmed by crown-rump length measured at 8-13 wk of gestation. Participants had anthropometric and nutritional assessments and seven scheduled ultrasound examinations during pregnancy. Fifty-two participants withdrew consent, and 1,387 participated in the study. At study entry, median maternal age was 28 y (interquartile range [IQR] 25-31), median height was 162 cm (IQR 157-168), median weight was 61 kg (IQR 55-68), 58% of the women were nulliparous, and median daily caloric intake was 1,840 cal (IQR 1,487-2,222). The median pregnancy duration was 39 wk (IQR 38-40) although there were significant differences between countries, the largest difference being 12 d (95% CI 8-16). The median birthweight was 3,300 g (IQR 2,980-3,615). There were differences in birthweight between countries, e.g., India had significantly smaller neonates than the other countries, even after adjusting for gestational age. Thirty-one women had a miscarriage, and three fetuses had intrauterine death. The 8,203 sets of ultrasound measurements were scrutinized for outliers and leverage points, and those measurements taken at 14 to 40 wk were selected for analysis. A total of 7,924 sets of ultrasound measurements were analyzed by quantile regression to establish longitudinal reference intervals for fetal head circumference, biparietal diameter, humerus length, abdominal circumference, femur length and its ratio with head circumference and with biparietal diameter, and EFW. There was asymmetric distribution of growth of EFW: a slightly wider distribution among the lower percentiles during early weeks shifted to a notably expanded distribution of the higher percentiles in late pregnancy. Male fetuses were larger than female fetuses as measured by EFW, but the disparity was smaller in the lower quantiles of the distribution (3.5%) and larger in the upper quantiles (4.5%). Maternal age and maternal height were associated with a positive effect on EFW, particularly in the lower tail of the distribution, of the order of 2% to 3% for each additional 10 y of age of the mother and 1% to 2% for each additional 10 cm of height. Maternal weight was associated with a small positive effect on EFW, especially in the higher tail of the distribution, of the order of 1.0% to 1.5% for each additional 10 kg of bodyweight of the mother. Parous women had heavier fetuses than nulliparous women, with the disparity being greater in the lower quantiles of the distribution, of the order of 1% to 1.5%, and diminishing in the upper quantiles. There were also significant differences in growth of EFW between countries. In spite of the multinational nature of the study, sample size is a limiting factor for generalization of the charts. CONCLUSIONS: This study provides WHO fetal growth charts for EFW and common ultrasound biometric measurements, and shows variation between different parts of the world.