Concept Foundation

IntroductionPostpartum haemorrhage (PPH) remains the leading cause of maternal death. Yet there is a lack of clarity around what research is needed to determine what works and how best to deliver proven PPH interventions. This article describes a WHO-led effort to develop a global PPH research agenda for 2023–2030, to reinvigorate research and innovation while avoiding duplication and waste.MethodsPotential questions were culled from evidence gaps in a forthcoming Lancet PPH series, a pipeline analysis on PPH medicines and devices, international PPH guidelines, previous research prioritisation efforts and submissions from a reference group of PPH experts and stakeholders. Questions were deduplicated and consolidated, categorised into three tracks (innovation, implementation and cross-cutting) and subjected to an online prioritisation survey. Survey participants (n=120) assessed these questions using five criteria (answerability, effectiveness, deliverability, maximum potential for disease burden reduction and equity) following the Child Health and Nutrition Research Initiative methodology. The outcome of this exercise was complemented by an in-person consensus meeting (Global PPH Summit from 7 March 2023 to 10 March 2023 in Dubai, United Arab Emirates) to finalise the research agenda.ResultsFifteen research questions (five per track) were identified as top priority. The top question per track called for research on the comparative effectiveness and safety of alternative routes of administration (other than the intravenous route) of tranexamic acid in the treatment of PPH (innovation); identifying barriers and facilitators affecting the adoption and use of evidence-based recommendations for PPH management (implementation) and the effectiveness of a strategy of early detection and first response treatment using a bundle of recommended interventions for improving PPH-related outcomes (cross-cutting).ConclusionThis shared research agenda should guide future investments into PPH studies with high potential to transform policy and clinical practice in the near term to medium term. Funding for the new research priorities is urgently needed.

Uterotonics are essential in preventing postpartum hemorrhage (PPH), the leading direct cause of maternal death worldwide. However, uterotonics are often substandard in low- and middle-income countries, contributing to poor maternal health outcomes. This study examines the health and economic impact of substandard uterotonics in Ghana. A decision-tree model was built to simulate vaginal and cesarean section births across health facilities, uterotonic quality and utilization, PPH risk and diagnosis, and resulting health and economic outcomes. We utilized delivery data from Ghana's maternal health survey, risks of health outcomes from a Cochrane review, and E-MOTIVE trial data for health outcomes related to oxytocin quality. We compared scenarios with and without substandard uterotonics, as well as scenarios altering uterotonic use and care-seeking behaviors. We found that substandard uterotonic use contributes to $18.8 million in economic burden annually, including $6.3 million and $4.8 million in out-of-pocket expenditures in public and private sectors, respectively. Annually, the National Health Insurance Scheme bears $1.6 million in costs due to substandard uterotonic use. Substandard uterotonics contribute to $6 million in long-term productivity losses from maternal mortality annually. Improving the quality of uterotonics could reduce 20,000 (11%) PPH cases, 5,000 (11%) severe PPH cases, and 100 (11%) deaths due to PPH annually in Ghana. Ensuring the quality of uterotonics would result in millions of dollars in cost savings and improve maternal health outcomes for the government and families in Ghana. Cost savings from improving uterotonic quality would provide financial protection and help Ghana advance toward Universal Health Coverage.

BackgroundPreeclampsia 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 findingsWe 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.ConclusionThere 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.

To develop target product profiles (TPPs) for new medicines for preterm birth prevention and preterm labour management that address the real-world need of women and healthcare providers, informed by views and agreement amongst globally diverse stakeholders. Mixed methods. Global (with a focus on low- and middle-income countries, LMICs). Global stakeholders with diverse expertise in preterm labour/birth and drug development. Following an initial literature review, diverse stakeholders were invited to participate in an online international survey and in-depth interviews. The level of stakeholder agreement with TPPs was assessed, and findings from interviews were synthesised to inform the final TPPs. Level of stakeholder agreement on the minimum and preferred requirements for preterm labour/birth medicines. We performed 21 interviews. Interview participants demonstrated strong agreement on room temperature stability, no additional drug-specific clinical monitoring, and affordability in LMICs being the minimal acceptable requirements. Points of discussion were raised around the target population. Survey respondents included clinicians, researchers, funding agency staff, international public organisation staff, programme implementers, policymakers, representatives of consumer advocacy organisations and other relevant stakeholders from maternal health systems. Survey results indicated strong agreement amongst stakeholders, with only one variable in each TPP not reaching consensus (i.e. 25% disagree or strongly disagree). There is strong consensus within the preterm labour/birth community on the characteristics that new medicines for preterm birth prevention and preterm labour management must achieve. These TPPs provide necessary guidance to evaluate new candidates and their potential for implementation in a range of settings.

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.

ObjectivesTo evaluate uterine tamponade devices’ effectiveness for atonic refractory postpartum haemorrhage (PPH) after vaginal birth and the effect of including them in institutional protocols.Search strategyPubMed, EMBASE, CINAHL, LILACS, POPLINE, from inception to January 2021.Study selectionRandomised and non‐randomised comparative studies.OutcomesComposite outcome including surgical interventions (artery ligations, compressive sutures or hysterectomy) or maternal death, and hysterectomy.ResultsAll included studies were at high risk of bias. The certainty of the evidence was rated as very low to low. One randomised study measured the effect of the condom‐catheter balloon compared with standard care and found unclear results for the composite outcome (relative risk [RR] 2.33, 95% CI 0.76–7.14) and hysterectomy (RR 4.14, 95% CI 0.48–35.93). Three comparative studies assessed the effect of including uterine balloon tamponade in institutional protocols. A stepped wedge cluster randomised controlled trial suggested an increase in the composite outcome (RR 4.08, 95% CI 1.07–15.58) and unclear results for hysterectomy (RR 4.38, 95% CI 0.47–41.09) with the use of the condom‐catheter or surgical glove balloon. One non‐randomised study showed unclear effects on the composite outcome (RR 0.33, 95% CI 0.11–1.03) and hysterectomy (RR 0.49, 95% CI 0.04–5.38) after the inclusion of the Bakri balloon. The second non‐randomised study found unclear effects on the composite outcome (RR 0.95, 95% CI 0.32–2.81) and hysterectomy (RR 1.84, 95% CI 0.44–7.69) after the inclusion of Ebb or Bakri balloon.ConclusionsThe effect of uterine tamponade devices for the management of atonic refractory PPH after vaginal delivery is unclear, as is the role of the type of device and the setting.Tweetable abstractUnclear effects of uterine tamponade devices and their inclusion in institutional protocols for atonic refractory PPH after vaginal delivery.

ObjectiveAccess 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.MethodsThe 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 findingsThe 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.ConclusionOur 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 2014Plain English summaryAccess 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 available evidence suggests that oxytocin used as first-line treatment of PPH probably is more effective than misoprostol with less side-effects. Adding misoprostol to the conventional treatment of oxytocin probably makes little or no difference to effectiveness outcomes, and is also associated with more side-effects. The evidence for most uterotonic agents used as first-line treatment of PPH is limited, with no evidence found for commonly used agents, such as injectable prostaglandins, ergometrine, and Syntometrine®.

BackgroundExtracorporeal shock wave therapy has been successfully introduced for the treatment of cellulite in recent years. However, it is still unknown whether the individual clinical outcome of cellulite treatment with extracorporeal shock wave therapy can be predicted by the patient’s individual cellulite grade at baseline, individual patient age, body mass index (BMI), weight, and/or height.MethodsFourteen Caucasian females with cellulite were enrolled in a prospective, single-center, randomized, open-label Phase II study. The mean (± standard error of the mean) cellulite grade at baseline was 2.5±0.09 and mean BMI was 22.8±1.17. All patients were treated with radial extracorporeal shock waves using the Swiss DolorClast® device (Electro Medical Systems, S.A., Nyon, Switzerland). Patients were treated unilaterally with 2 weekly treatments for 4 weeks on a randomly selected side (left or right), totaling eight treatments on the selected side. Treatment was performed at 3.5–4.0 bar, with 15,000 impulses per session applied at 15 Hz. Impulses were homogeneously distributed over the posterior thigh and buttock area (resulting in 7,500 impulses per area). Treatment success was evaluated after the last treatment and 4 weeks later by clinical examination, photographic documentation, contact thermography, and patient satisfaction questionnaires.ResultsThe mean cellulite grade improved from 2.5±0.09 at baseline to 1.57±0.18 after the last treatment (ie, mean δ-1 was 0.93 cellulite grades) and 1.68±0.16 at follow-up (ie, mean δ-2 was 0.82 cellulite grades). Compared with baseline, no patient’s condition worsened, the treatment was well tolerated, and no unwanted side effects were observed. No statistically significant (ie, P<0.05) correlation was found between individual values for δ-1 and δ-2 and cellulite grade at baseline, BMI, weight, height, or age.ConclusionRadial shock wave therapy is a safe and effective treatment option for cellulite. The individual clinical outcome cannot be predicted by the patient’s individual cellulite grade at baseline, BMI, weight, height, or age.