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WHO recommendations Uterotonics for the prevention of postpartum haemorrhage: Web annex 3: Misoprostol versus placebo or no treatment

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WHO recommendations Uterotonics for the prevention of postpartum haemorrhage Web annex 3: Misoprostol versus placebo or no treatment EVIDENCE TO DECISION FRAMEWORK WHO recommendations Uterotonics for the prevention of postpartum haemorrhage Web annex 3: Misoprostol versus placebo or no treatment Evidence to Decision framework WHO/RHR/18.30 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. WHO recommendations: Uterotonics for the prevention of postpartum haemorrhage. Web annex 3: Misoprostol versus placebo or no treatment: Evidence to Decision framework. Geneva: World Health Organization; 2018 (WHO/RHR/18.30). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. 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It is being made publicly available as supplied by those responsible for its development for transparency purposes and information, as required by WHO (see the WHO handbook for guideline development, 2nd edition (2014)). iii CO N TE N TS Contents 1. Background 1 2. Question 1 3. Assessment 2 3.1 Effects of interventions 2 Research evidence 2 Desirable effects 4 Undesirable effects 5 Certainty of the evidence 5 3.2 Values 5 Research evidence 5 Balance of effects 6 3.3 Resources 6 Research evidence 6 Resources required 7 Certainty of evidence on required resources 7 Cost-effectiveness 8 3.4 Equity 8 Research evidence 8 3.5 Acceptability 9 Research evidence 9 3.6 Feasibility 10 Research evidence 10 4. Summary of judgements table 11 5. Summary of Findings table 12 6. References 17 1W EB A N N EX 3 : M IS O PR O ST O L V ER SU S PL A C EB O O R N O T RE AT M EN T – EV ID EN C E TO D EC IS IO N F RA M EW O RK 1. Background Misoprostol is a prostaglandin E1 analogue, which is licensed for the prevention and treatment of gastric ulcers. It is well known for its off-label use as a uterotonic agent. It is water-soluble and heat stable. It is absorbed 9–15 minutes after sublingual, oral, vaginal and rectal use. The half-life is about 20–40 minutes. Oral and sublingual routes have the advantage of rapid onset of action, while the vaginal and rectal routes result in prolonged activity and greater bioavailability. 2. Question Following is the question of interest in PICO (population, intervention, comparator, outcome) format: For women in the third stage of labour (P), does the use of misoprostol for prevention of postpartum haemorrhage (I), compared with placebo or no treatment (C), improve maternal and perinatal outcomes (O)? If so, what route of administration and dosing regimen should be used? Problem: Preventing the onset of postpartum haemorrhage (PPH) Perspective: Clinical practice recommendation – population perspective Population (P): All women in the third stage of labour Intervention (I): Misoprostol Comparator (C): Placebo or no treatment Setting: Hospital and community setting Subgroups: Women undergoing vaginal birth; women undergoing caesarean section Priority outcomes (O):1 Maternal death PPH ≥ 1000 ml Blood transfusion Severe maternal morbidity: intensive care unit (ICU) admissions Severe maternal morbidity: shock PPH ≥ 500 ml Use of additional uterotonics Blood loss (ml) Postpartum anaemia Breastfeeding Side-effects2 1 These outcomes reflect the prioritized outcomes used in the development of this recommendation, in the WHO recommendations for prevention and treatment of postpartum haemorrhage (2012) (1). The outcomes “shock”, “maternal well-being” and “maternal satisfaction” have been added as part of this update. 2 This includes nausea, vomiting, headache, abdominal pain, hypertension, shivering, fever and diarrhoea. W H O R EC O M M EN D AT IO N S: U TE RO TO N IC S FO R TH E PR EV EN TI O N O F PO ST PA RT U M H A EM O RR H A G E 2 Maternal well-being Maternal satisfaction 3. Assessment 3.1 Effects of interventions What is the effect of misoprostol for PPH prevention on the priority outcomes? Research evidence Summary of evidence Source and characteristics of studies Evidence on the efficacy and safety of misoprostol for prevention of postpartum haemorrhage (PPH) was extracted from an updated Cochrane systematic review with a network meta-analysis of all uterotonic agents for PPH prevention (2). The network meta-analysis included 196 trials (135 559 women) that were conducted across 53 countries (including high-, middle- and low-income countries). Most trials (187/196, 95.4%) were performed in a hospital setting, seven in a community setting (3.6%), one in a mixed setting (0.5%) and in one trial the setting was unclear. The majority of the trials included women undergoing a vaginal birth (140/196, 71.5%), while 53 trials (27.0%) involved women undergoing caesarean section, two trials (1.0%) included women undergoing either a vaginal birth or caesarean section, and one trial (0.5%) did not specify the mode of birth. A total of 124 trials (63.3%) included women with a singleton pregnancy, 36 trials (18.4%) included women with either singleton or multiple pregnancies, one trial (0.5%) included women with twin pregnancies only and the remaining 35 trials (17.9%) did not specify. A total of 108 trials (55.1%) included both nulliparous and multiparous women, six trials (3.1%) included only nulliparous or primigravida women, one trial included only multiparous women (0.5%), and 81 trials (41.3%) did not specify parity. Across all 196 trials (412 trial arms) in the network meta-analysis, the following agents were used either as intervention or comparator: 137 trial arms (33.3%) used oxytocin 96 trial arms (23.2%) used misoprostol 39 trial arms (9.4%) used ergometrine 35 trial arms (8.5%) used oxytocin plus ergometrine 33 trial arms (8%) used carbetocin 29 trial arms (7%) used placebo or no treatment 26 trial arms (6.3%) used misoprostol plus oxytocin 17 trial arms (4.1%) used injectable prostaglandins. Twelve randomized trials (involving 6105 women) in the network meta-analysis directly compared misoprostol with placebo or no treatment. Nine of the trials were conducted in hospital settings and three in community settings. The trials were conducted in China, Egypt, France, Guinea-Bissau, India (two studies), Pakistan, South Africa (three studies), Switzerland and Turkey. Seven trials recruited only women with singleton pregnancies while the other five trials did not specify this variable. All 12 trials included only women with vaginal births. 3W EB A N N EX 3 : M IS O PR O ST O L V ER SU S PL A C EB O O R N O T RE AT M EN T – EV ID EN C E TO D EC IS IO N F RA M EW O RK The studies differed in misoprostol dose and route of administration, although most administered misoprostol orally. Two studies used 400 µg orally. Five studies used 600 µg orally. One study used 200 µg sublingually. One study used 600 µg sublingually. One study used 400 µg rectally. One study used 800 µg rectally. One study used 400–800 µg administered orally, vaginally or rectally. Effects of misoprostol compared with placebo or no treatment The results below report the findings of the network meta-analysis for the priority outcomes (which generated effect estimates from both direct and indirect evidence). Maternal death: Low-certainty evidence suggests that the use of misoprostol may make little or no difference to the risk of maternal death when compared with placebo or no treatment (risk ratio [RR] 1.00, 95% CI 0.10–9.59). PPH ≥ 1000 ml: High-certainty evidence suggests that misoprostol reduces PPH ≥ 1000 ml compared with placebo or no treatment (RR 0.71, 95% CI 0.59–0.85). Blood transfusion: High-certainty evidence suggests that misoprostol reduces the use of blood transfusions compared with placebo or no treatment (RR 0.52, 95% CI 0.35–0.80). Severe maternal morbidity – ICU admission: Low-certainty evidence suggests that misoprostol may make little or no difference to ICU admissions (RR 1.00, 95% CI 0.14–7.05). There were no data for the outcome “shock” reported in the included trials. PPH ≥ 500 ml: Moderate-certainty evidence suggests that misoprostol probably reduces PPH ≥ 500 ml compared with placebo or no treatment (RR 0.63, 95% CI 0.52–0.76). Use of additional uterotonics: When compared with placebo or no treatment, moderate-certainty evidence suggests that misoprostol probably reduces the use of additional uterotonics (RR 0.44, 95% CI 0.33–0.59). Mean blood loss: Moderate-certainty evidence suggests that blood loss is probably slightly less among women receiving misoprostol compared with women receiving placebo or no treatment (mean difference [MD] 66.33 ml lower, 95% CI 106.96– 25.69 ml lower). Postpartum anaemia: This outcome was not directly reported in the review. However, there is moderate-certainty evidence to suggest that the mean change in haemoglobin level before versus after birth is probably less among women receiving misoprostol compared with those receiving placebo or no treatment (MD 2.22 g/L lower, 95% CI 3.94–0.50 g/L lower). Breastfeeding: No trials reported on this outcome. Any side-effect: Moderate-certainty evidence suggests that misoprostol probably makes little or no difference to the risk of experiencing nausea (RR 1.24, 95% CI 0.75–2.06) and vomiting (RR 1.61 95% CI 0.98–2.62). Low-certainty evidence suggests that misoprostol may make little or no difference to the risk of experiencing headache (RR 1.41, 95% CI 0.71–2.81). When compared with placebo or no treatment, moderate- certainty evidence suggests that misoprostol probably makes little or no difference to postpartum abdominal pain (RR 1.03, 95% CI 0.71–1.50). It is uncertain whether W H O R EC O M M EN D AT IO N S: U TE RO TO N IC S FO R TH E PR EV EN TI O N O F PO ST PA RT U M H A EM O RR H A G E 4 misoprostol reduces hypertension when compared with placebo or no treatment, because the certainty of the evidence is very low. High-certainty evidence suggests that when compared with placebo, misoprostol increases the risk of experiencing shivering (RR 2.91, 95% CI 1.78 –4.77). Moderate-certainty evidence suggests that misoprostol probably increases the risk of fever (RR 4.10, 95% CI 2.09–8.05). High- certainty evidence suggests that, when compared with placebo, misoprostol increases the risk of diarrhoea (RR 2.80, 95% CI 1.20–6.49). Maternal well-being: No trials reported on this outcome. Maternal satisfaction: No trials reported on this outcome. Additional considerations Subgroup analyses did not reveal a substantial difference in the effects of misoprostol on the above outcomes when compared with placebo or no treatment by mode of birth (vaginal versus caesarean section) or by setting (community versus hospital). A 2012 Cochrane review focused on the effects of prophylactic misoprostol versus placebo and other uterotonics, and found 11 trials comparing misoprostol to placebo/ no treatment (3). Results were similar to the above findings for maternal death and blood transfusion; however, due to significant statistical heterogeneity, the outcomes PPH ≥ 500 ml and PPH ≥ 1000 ml were not meta-analysed. The review authors noted that the misoprostol dosage most commonly used in trials to date is 600 µg oral. However, the review comparisons between 600 µg oral and 400 µg oral have not shown substantive differences for benefit outcomes (it should be noted that evidence was limited), although side-effects were slightly higher with 600 µg doses, as described in the data below. 600 µg oral versus 400 µg oral: Three studies (947 women) – no observed differences for PPH ≥ 1000 ml, PPH ≥ 500 ml, blood transfusion or use of additional uterotonics. Two trials (547 women) reported on mean blood loss – slight reduction with 600 µg dose (–30.00 ml, 95% CI –41.84 ml to –18. 16 ml). Three trials (945 women) – risk of shivering was higher with the 600 µg dose (RR 1.37, 95% CI 1.12–1.69). Three trials (944 women) – risk of fever was higher with the 600 µg dose (RR 2.04, 95% CI 1.45–2.88). Desirable effects How substantial are the desirable anticipated effects of misoprostol versus placebo or no treatment? Judgement — Don’t know — Varies — Trivial — Small ✓ Moderate — Large 5W EB A N N EX 3 : M IS O PR O ST O L V ER SU S PL A C EB O O R N O T RE AT M EN T – EV ID EN C E TO D EC IS IO N F RA M EW O RK Undesirable effects How substantial are the undesirable anticipated effects of misoprostol versus placebo or no treatment? Judgement — Don’t know — Varies — Large — Moderate ✓ Small — Trivial Certainty of the evidence What is the overall certainty of the evidence on effects of misoprostol versus placebo or no treatment? — No included studies — Very low — Low ✓ Moderate — High Additional considerations None. 3.2 Values Is there important uncertainty about, or variability in, how much women (and their families) value the main outcomes associated with misoprostol for PPH prevention? Research evidence In a review of qualitative studies looking at “what women want” from intrapartum care, findings indicate that most women want a normal birth (with good outcomes for mother and baby), but acknowledge that medical intervention may sometimes be necessary (high confidence) (4). Most women, especially those giving birth for the first time, are apprehensive about labour and birth (high confidence) and wary of medical interventions, although in certain contexts and/or situations, women welcome interventions to address recognized complications (low confidence). Where interventions are introduced, women would like to receive relevant information from technically competent health care providers who are sensitive to their needs (high confidence). Findings from another qualitative systematic review exploring perceptions of PPH prevention and treatment among women and providers suggest that women do not recognize the clinical definitions of blood loss or what might be considered “normal” blood loss (moderate confidence) (5). Furthermore, in some low- and middle-income countries (LMICs), women place a greater value on the expulsion of so-called “dirty blood”, which they perceive as a normal cleansing process and something that should not be prevented (moderate confidence). The same review also highlighted women’s need for information about PPH, ideally given during antenatal care (moderate confidence), and the importance of kind, clinically competent staff with a willingness to engage in shared decision-making around PPH management (moderate/low confidence). In addition, it was found that women are concerned about feelings of exhaustion and anxiety (at being separated from their babies) following PPH, as well as the long-term psychological effects of experiencing PPH and the negative impact this may have on their ability to breastfeed (moderate/low confidence). W H O R EC O M M EN D AT IO N S: U TE RO TO N IC S FO R TH E PR EV EN TI O N O F PO ST PA RT U M H A EM O RR H A G E 6 Additional considerations None. Judgement — Important uncertainty or variability — Possibly important uncertainty or variability ✓ Probably no important uncertainty or variability — No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favour misoprostol or placebo/ no treatment? Judgement — Don’t know — Varies — Favours placebo/no treatment — Probably favours placebo/no treatment — Does not favour either ✓ Probably favours misoprostol — Favours misoprostol 3.3 Resources How large are the resource requirements (costs) of misoprostol for PPH prevention? Research evidence A systematic review of the literature (6) identified six studies of the cost–effectiveness of misoprostol (7–12). All of these studies were conducted in settings with low access to modern birth facilities (i.e. with a shortage of skilled birth attendants, and inadequate transport and storage facilities for oxytocin, and where oxytocin was not available). These studies were of moderate to high quality according to Consensus Health Economic Criteria (CHEC) checklist and most used a model-based approach to estimate the incremental costs of introducing misoprostol to prevent PPH in these settings. Four studies evaluated misoprostol as a 600 µg dose (oral or sublingual), one used a 200 µg dose and one used a 1000 µg dose rectally administered. In most studies, administration of misoprostol was undertaken by lay health workers; in one study from Uganda it was distributed antenatally to pregnant women for self-administration following birth (8). Although cost–effectiveness measures and reporting differed (e.g. incremental cost–effectiveness ratio [ICER] per case of PPH avoided, per disability- adjusted life year [DALY] gained, per life saved, cost savings per 1000 births, etc.), findings were consistent across studies and showed that misoprostol was highly cost-effective or led to cost savings compared with no use of uterotonic agents in these settings. The cost of treating side-effects of misoprostol was reported to be negligible in two studies of misoprostol use in India (10,11). 7W EB A N N EX 3 : M IS O PR O ST O L V ER SU S PL A C EB O O R N O T RE AT M EN T – EV ID EN C E TO D EC IS IO N F RA M EW O RK Additional considerations One study from Senegal that compared the cost–effectiveness of misoprostol with oxytocin (10 IU provided via Uniject device) found misoprostol (600 µg orally) to be more cost-effective than oxytocin (12), partly because the Uniject devices were reported to be associated with high wastage costs (13). This evidence is derived from studies conducted in low-resource settings and it is not clear whether it applies to high-resource settings where the common side- effects of misoprostol might be managed differently and lead to higher costs. The evidence on the cost–effectiveness of misoprostol compared with no PPH prevention would probably also apply to caesarean section birth, as the evidence on effects in cases of caesarean section birth were consistent with those for vaginal birth. Main resource requirements Resource Description Staff Most uterotonics require administration by trained maternity staff. However, lay health workers can administer misoprostol in community- based settings. In some settings, it has also been distributed to women antenatally for self-administration in the event of a home birth (8). Training Introduction of a new uterotonic agent or protocol might require additional training, particularly in settings where uterotonics have not previously been available. The costs of training of lay health workers to administer misoprostol are probably relatively low (7,10,12,14). Supplies Misoprostol indicative costs: Cost per 200 µg tablet: US$ 0.09–0.52 (7–12). Equipment and infrastructure Minimal requirements. Time Minimal requirements. Supervision and monitoring Supervision and monitoring to ensure appropriate use, stock availability and quality. Resources required Judgement — Don’t know — Varies — Large costs — Moderate costs — Negligible costs or savings ✓ Moderate savings — Large savings Certainty of evidence on required resources What is the certainty of the evidence on costs? Judgement — No included studies — Very low — Low ✓ Moderate — High W H O R EC O M M EN D AT IO N S: U TE RO TO N IC S FO R TH E PR EV EN TI O N O F PO ST PA RT U M H A EM O RR H A G E 8 Cost-effectiveness Judgement — Don’t know — Varies — Favours placebo/no treatment — Probably favours placebo/no treatment — Does not favour either ✓ Probably favours misoprostol — Favours misoprostol 3.4 Equity What would be the impact of misoprostol for PPH prevention on health equity? Research evidence Misoprostol is relatively inexpensive and widely available in a range of resource settings (low to high). Findings from a qualitative systematic review looking at prevention and treatment of PPH indicate that advanced distribution of misoprostol to women in lower-resource rural communities may be a useful approach in reducing maternal mortality (as a consequence of PPH) for women who may not ordinarily attend a health care facility to give birth (moderate confidence) (5). Additional considerations The 2015 World Health Organization (WHO) State of inequality report indicates that women who are poor, least educated, and who reside in rural areas have lower coverage of health interventions and worse health outcomes than more advantaged women (15). Therefore, reducing maternal morbidity due to PPH could have a positive impact on health equity and improve outcomes among disadvantaged women. Reducing the need for additional interventions to treat PPH (such as additional uterotonics and blood transfusion) would probably reduce inequities, especially in contexts where health services are covered through out-of-pocket means. Misoprostol is currently listed on the WHO Model List of Essential Medicines (16) as: 200 µg tablet: for the management of incomplete abortion and miscarriage; for the prevention and treatment of PPH where oxytocin is not available or cannot be safely used; and 25 µg tablet: for induction of labour (25 µg vaginal tablet). Judgement — Don’t know — Varies — Reduced — Probably reduced — Probably no impact ✓ Probably increased — Increased 9W EB A N N EX 3 : M IS O PR O ST O L V ER SU S PL A C EB O O R N O T RE AT M EN T – EV ID EN C E TO D EC IS IO N F RA M EW O RK 3.5 Acceptability Is misoprostol for PPH prevention acceptable to key stakeholders? Research evidence Findings from a qualitative systematic review exploring perceptions of PPH prevention and treatment by women and health care providers indicate that providers recognize the benefits of using misoprostol to prevent PPH, especially in rural areas of LMICs where community-based distribution programmes are in place (5). In these contexts, misoprostol was perceived to be safe, effective and more practical to use compared with oxytocin (low confidence). However, government officials and regional health care managers in some LMICs had concerns about the influence of civil society organizations, nongovernmental organizations and private providers in “pushing” misoprostol for other conditions (treatment of PPH) contrary to national guidelines (moderate confidence). The same review also showed that in some LMICs, providers (including government officials, health care managers and health care professionals) had concerns about the potential misuse of misoprostol in community contexts where it might be used to induce abortion or act as a deterrent to facility-based deliveries (moderate confidence). In addition, a number of providers, largely based in LMICs, felt they needed more information on the effectiveness of misoprostol and further guidance on successful implementation strategies for community distribution in LMICs (moderate confidence) (5). There were no findings from studies of women’s perspectives relating to the acceptability of misoprostol, although indirect evidence from providers in one study in Indonesia highlighted shivering as a potential concern for some women taking the tablets (moderate confidence) (17). Additional considerations A number of survey-based studies were identified looking at the potential benefits of advance misoprostol distribution in rural settings of LMICs where the maternal mortality ratio was relatively high (18–33). The studies were conducted in Afghanistan, Bangladesh, Ethiopia (two studies), Ghana, Liberia, Madagascar, Mozambique, Nepal, Nigeria (three studies), Pakistan, South Sudan and the United Republic of Tanzania (two studies). In most instances, misoprostol tablets were given to trained community health workers, community health volunteers or traditional birth attendants (TBAs) who then supplied the tablets (usually 3 x 200 µg tablets) to pregnant women in community settings during a home visit or antenatal appointment during the eighth month of pregnancy. During the home visit or appointment, women were also given information on PPH, the nature of the misoprostol tablets and how/when to take them, as well as details of potential side-effects. Nearly all of the studies reported high levels of usage, acceptability and coverage with very few safety concerns. One study from Liberia found that 87/265 (32.8%) women took the misoprostol tablets after the delivery of the placenta but experienced few or no ill effects from doing so (29). W H O R EC O M M EN D AT IO N S: U TE RO TO N IC S FO R TH E PR EV EN TI O N O F PO ST PA RT U M H A EM O RR H A G E 10 Judgement — Don’t know ✓ Varies — No — Probably No — Probably Yes — Yes 3.6 Feasibility Is misoprostol for PPH prevention feasible to implement? Research evidence Findings from a qualitative systematic review exploring perceptions of PPH prevention and treatment by women and health care providers suggest that limited resources – particularly the limited availability of experienced, trained staff – may hinder effective distribution of misoprostol in some LMICs (high confidence) (5). In these countries, particularly in rural areas, task shifting strategies have been deployed to address staff shortages, and although these have been successful in some contexts, in others there was a perception that TBAs and community health workers were poorly trained and untrustworthy (moderate confidence). There were no findings from studies of women’s perspectives relating to the feasibility of this particular intervention. Additional considerations A number of survey-based studies were identified looking at the potential benefits of advance misoprostol distribution in rural settings of LMICs where the maternal mortality ratio was relatively high (18–33). The studies were conducted in Afghanistan, Bangladesh, Ethiopia (two studies), Ghana, Liberia, Madagascar, Mozambique, Nepal, Nigeria (three studies), Pakistan, South Sudan and the United Republic of Tanzania (two studies). In most instances, misoprostol tablets were given to trained community health workers, community health volunteers or TBAs who then supplied the tablets (usually 3 x 200 µg tablets) to pregnant women in community settings during a home visit or antenatal appointment during the eighth month of pregnancy. During the home visit or appointment, women were also given information on PPH, the nature of the misoprostol tablets and how/when to take them, as well as details of potential side-effects. In most of the studies the authors concluded that the programmes were effective and feasible, although inconsistent stocks of supplies and the delivery of inadequate information by community health volunteers were highlighted as concerns in Nepal (27). Judgement — Don’t know — Varies — No — Probably No ✓ Probably Yes — Yes 11 W EB A N N EX 3 : M IS O PR O ST O L V ER SU S PL A C EB O O R N O T RE AT M EN T – EV ID EN C E TO D EC IS IO N F RA M EW O RK 4. Summary of judgements table Desirable effects — Don’t know — Varies — Trivial — Small ✓ Moderate — Large Undesirable effects Don’t know — Varies — Large — Moderate ✓ Small — Trivial Certainty of the evidence — No included studies — Very low — Low ✓ Moderate — High Values — Important uncertainty or variability — Possibly important uncertainty or variability ✓ Probably no important uncertainty or variability — No important uncertainty or variability Balance of effects — Don’t know — Varies — Favours placebo/no treatment — Probably favours placebo/no treatment — Does not favour either ✓ Probably favours misoprostol — Favours misoprostol Resources required — Don’t know — Varies — Large costs — Moderate costs — Negligible costs or savings ✓ Moderate savings — Large savings Certainty of the evidence on required resources — No included studies — Very low Low ✓ Moderate — High Cost– effectiveness — Don’t know — Varies — Favours placebo/no treatment — Probably favours placebo/no treatment — Does not favour either ✓ Probably favours misoprostol — Favours misoprostol Equity — Don’t know — Varies — Reduced — Probably reduced — Probably no impact ✓ Probably increased — Increased Acceptability — Don’t know ✓ Varies — No — Probably No — Probably Yes — Yes Feasibility — Don’t know — Varies — No — Probably No ✓ Probably Yes — Yes Judgement We recommend against the intervention  We recommend considering the intervention only  in specific contexts  with targeted monitoring and evaluation  in the context of rigorous research We recommend the intervention  WH O R E C O M M E N D A T I O N S : U T E R O T O N I C S F O R T H E P R E V E N T I O N O F P O S T P A R T U M H A E M O R R H A G E 12 5. Summary of Findings table Patient or population: Women in the third stage of labour Setting: Hospital or community setting Intervention: Misoprostol Comparator: Placebo or no treatment Source: Gallos ID, Papadopoulou I, Man R, Athanasopoulos N, Tobias A, Price MJ, et al. Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis (Review). Cochrane Database Syst Rev. 2018:CD011689 (2). Outcome Direct evidence Indirect evidence Network meta to analysis Anticipated absolute effects for network meta-analysis estimate RR (95% CI) Certainty RR (95% CI) Certainty RR (95% CI) Certainty Risk with placebo or no treatment Risk with misoprostol Risk difference with misoprostol Maternal death 1.00 (0.10–9.59) ㊉㊉㊀㊀ LOW 0.79 (0.00–¥) ㊉㊉㊀㊀ VERY LOW 1.00 (0.10–9.59) ㊉㊉㊀㊀ LOW 1 per 1000 1 per 1000 0 fewer per 1000 (1 fewer to 9 more) 1 per 1000 (for vaginal birth) 1 per 1000 (for vaginal birth) 0 fewer per 1000 (1 fewer to 9 more) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc (for caesarean birth) PPH ≥ 1000 ml 0.73 (0.56–0.95) ㊉㊉㊉㊉ HIGH 0.68 (0.51–0.90) ㊉㊉㊉㊀ MODERATE 0.71 (0.59–0.85) ㊉㊉㊉㊉ HIGH 27 per 1000 19 per 1000 8 fewer per 1000 (11 fewer to 4 fewer) 27 per 1000 (for vaginal birth) 19 per 1000 (for vaginal birth) 8 fewer per 1000 (11 fewer to 4 fewer) (for vaginal birth) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc (for caesarean birth) Blood transfusion 0.46 (0.15–1.47) ㊉㊉㊉㊀ MODERATE 0.53 (0.34– 0.84) ㊉㊉㊀㊀ LOW 0.52 (0.35– 0.80) ㊉㊉㊉㊉ HIGH 27 per 1000 14 per 1000 13 fewer per 1000 (18 fewer to 5 fewer) 27 per 1000 (for vaginal birth) 14 per 1000 (for vaginal birth) 13 fewer per 1000 (18 fewer to 5 fewer) (for vaginal birth) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc (for caesarean birth) 13 W E B A N N E X 3 : M I S O P R O S T O L V E R S U S P L A C E B O O R N O T R E A T M E N T – E V I D E N C E T O D E C I S I O N F R A M E W O R K Outcome Direct evidence Indirect evidence Network meta to analysis Anticipated absolute effects for network meta-analysis estimate RR (95% CI) Certainty RR (95% CI) Certainty RR (95% CI) Certainty Risk with placebo or no treatment Risk with misoprostol Risk difference with misoprostol Intensive care unit (ICU) admission 1.00 (0.14–7.05) ㊉㊉㊀㊀ LOW 1.10 (0.00 to ¥) ㊉㊉㊀㊀ VERY LOW 1.00 (0.14–7.05) ㊉㊉㊀㊀ LOW 2 per 1000 2 per 1000 0 fewer per 1000 (2 fewer to 12 more) 2 per 1000 (for vaginal birth) 2 per 1000 (for vaginal birth) 0 fewer per 1000 (2 fewer to 12 more) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc (for caesarean birth) Maternal shock Not reported — — — — — — — — PPH ≥ 500 ml 0.75 (0.59–0.94) ㊉㊉㊉㊉ HIGH 0.57 (0.45–0.73) ㊉㊉㊀㊀ LOW 0.63 (0.52–0.76) ㊉㊉㊉㊀ MODERATE 255 per 1000 161 per 1000 94 fewer per 1000 (122 fewer to 61 fewer) 255 per 1000 (for vaginal birth) 161 per 1000 (for vaginal birth) 94 fewer per 1000 (122 fewer to 61 fewer) 320 per 1000 (for caesarean birth) 202 per 1000 (for caesarean birth) 118 fewer per 1000 (154 fewer to 77 fewer) (for caesarean birth) Use of additional uterotonics 0.67 (0.52–0.87) ㊉㊉㊉㊉ HIGH 0.36 (0.25–0.52) ㊉㊉㊀㊀ LOW 0.44 (0.33– 0.59) ㊉㊉㊉㊀ MODERATE 211 per 1000 93 per 1000 118 fewer per 1000 (141 fewer to 87 fewer) 211 per 1000 (for vaginal birth) 93 per 1000 (for vaginal birth) 108 fewer per 1000 (129 fewer to 79 fewer) (for vaginal birth) 746 per 1000 (for caesarean birth) 328 per 1000 (for caesarean birth) 418 per 1000 (500 fewer to 306 fewer) (for caesarean birth) Mean blood loss (ml) MD 42.07 lower (52.47 lower to 31.68 lower) ㊉㊉㊉㊀ MODERATE MD 88.91 lower (148.00 lower to 29.81 lower) ㊉㊉㊀㊀ VERY LOW MD 66.33 lower (106.96 lower to 25.69 lower) ㊉㊉㊉㊀ MODERATE The mean blood loss was 295 ml (range across placebo groups: 167.4–853 ml) The mean blood loss in the misoprostol group was on average 66.33 ml lower (range: 106.96 lower to 25.69 ml lower) The mean blood loss for vaginal birth was 294 ml (range: 167.4–680 ml) The mean blood loss with misoprostol was on average 66.33 ml lower (range: 106.96 lower to 25.69 ml lower) The mean blood loss for caesarean birth was 815 ml (range: 800–853 ml) The mean blood loss with misoprostol was on average 66.33 ml lower (range: 106.96 lower to 25.69 ml lower) WH O R E C O M M E N D A T I O N S : U T E R O T O N I C S F O R T H E P R E V E N T I O N O F P O S T P A R T U M H A E M O R R H A G E 14 Outcome Direct evidence Indirect evidence Network meta to analysis Anticipated absolute effects for network meta-analysis estimate RR (95% CI) Certainty RR (95% CI) Certainty RR (95% CI) Certainty Risk with placebo or no treatment Risk with misoprostol Risk difference with misoprostol Change in haemoglobin (Hb) (g/L) MD 2.53 lower (3.53 lower to 1.52 lower) ㊉㊉㊉㊀ MODERATE MD 2.53 lower (4.94 lower to 0.11 lower) ㊉㊉㊀㊀ VERY LOW MD 2.22 lower (3.94 lower to 0.50 lower) ㊉㊉㊉㊀ MODERATE The mean change in Hb was 8.1 g/L (range: 6.0–13.5 g/L) The mean change in Hb with misoprostol was on average 2.22 g/L lower (range: 3.94 g/L lower to 0.50 g/L lower) The mean change in Hb for vaginal birth was 8.1 g/L (range: 6.0–13.5 g/L) The mean change in Hb with misoprostol was on average 2.22 g/L lower (range: 3.94 g/L lower to 0.50 g/L lower) The mean change in Hb for caesarean birth was 8.4 g/L The mean change in Hb with misoprostol was on average 2.22 g/L lower (range: 3.94 g/L lower to 0.50 g/L lower) Breastfeeding Not reported — — — — — — — — Nausea 1.18 (0.78–1.78) ㊉㊉㊉㊀ MODERATE 1.30 (0.63–2.67) ㊉㊉㊀㊀ LOW 1.24 (0.75–2.06) ㊉㊉㊉㊀ MODERATE 37 per 1000 46 per 1000 9 more per 1000 (9 fewer to 39 more) 37 per 1000 (for vaginal birth) 46 per 1000 (for vaginal birth) 9 more per 1000 (9 fewer to 39 more) (for vaginal birth) 67 per 1000 (for caesarean birth) 83 per 1000 (for caesarean birth) 16 more per 1000 (17 fewer to 71 more) (for caesarean birth) Vomiting 1.41 (0.92–2.16) ㊉㊉㊉㊀ MODERATE 1.48 (0.73–3.03) ㊉㊉㊀㊀ VERY LOW 1.61 (0.98–2.62) ㊉㊉㊉㊀ MODERATE 34 per 1000 55 per 1000 21 more per 1000 (1 fewer to 55 more) 34 per 1000 (for vaginal birth) 55 per 1000 (for vaginal birth) 21 more per 1000 (1 fewer to 55 more) (for vaginal birth) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc (for caesarean birth) Headache 0.94 (0.32–2.77) ㊉㊉㊀㊀ LOW 1.62 (0.72–3.66) ㊉㊉㊀㊀ LOW 1.41 (0.71–2.81) ㊉㊉㊀㊀ LOW 12 per 1000 17 per 1000 5 more per 1000 (3 fewer to 22 more) 12 per 1000 (for vaginal birth) 17 per 1000 (for vaginal birth) 5 more per 1000 (3 fewer to 22 more) (for vaginal birth) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc (for caesarean birth) 15 W E B A N N E X 3 : M I S O P R O S T O L V E R S U S P L A C E B O O R N O T R E A T M E N T – E V I D E N C E T O D E C I S I O N F R A M E W O R K Outcome Direct evidence Indirect evidence Network meta to analysis Anticipated absolute effects for network meta-analysis estimate RR (95% CI) Certainty RR (95% CI) Certainty RR (95% CI) Certainty Risk with placebo or no treatment Risk with misoprostol Risk difference with misoprostol Abdominal pain 0.98 (0.29–3.37) ㊉㊉㊉㊀ MODERATE 0.87 (0.54–1.41) ㊉㊉㊉㊀ MODERATE 1.03 (0.71–1.50) ㊉㊉㊉㊀ MODERATE 339 per 1000 349 per 1000 10 more per 1000 (98 fewer to 169 more) 339 per 1000 (for vaginal birth) 349 per 1000 (for vaginal birth) 10 more per 1000 (98 fewer to 169 more) (for vaginal birth) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc Hypertension Not reported — 1.27 (0.15–10.44) d ㊉㊉㊀㊀ VERY LOW 1.27 (0.15–10.44) ㊉㊉㊀㊀ VERY LOW 7 per 1000 9 per 1000 2 more per 1000 (6 fewer to 65 more) 7 per 1000 (for vaginal birth) 9 per 1000 (for vaginal birth) 2 more per 1000 (6 fewer to 65 more) (for vaginal birth) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc (for caesarean birth) Shivering 2.94 (2.38–3.64) ㊉㊉㊉㊉ HIGH 0.68 (0.00– 189.35) ㊉㊉㊀㊀ VERY LOW 2.91 (1.78–4.77) ㊉㊉㊉㊉ HIGH 148 per 1000 431 per 1000 283 more per 1000 (115 more to 558 more) 148 per 1000 (for vaginal birth) 431 per 1000 (for vaginal birth) 283 more per 1000 (115 more to 558 more) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc (for caesarean birth) Fever 4.09 (2.01–8.32) ㊉㊉㊉㊀ MODERATE 0.49 (0.00– 202.19) ㊉㊉㊀㊀ VERY LOW 4.10 (2.09–8.05) ㊉㊉㊉㊀ MODERATE 29 per 1000 119 per 1000 90 more per 1000 (32 more to 204 more) 29 per 1000 (for vaginal birth) 119 per 1000 (for vaginal birth) 90 more per 1000 (32 more to 204 more) (for vaginal birth) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc (for caesarean birth) WH O R E C O M M E N D A T I O N S : U T E R O T O N I C S F O R T H E P R E V E N T I O N O F P O S T P A R T U M H A E M O R R H A G E 16 Outcome Direct evidence Indirect evidence Network meta to analysis Anticipated absolute effects for network meta-analysis estimate RR (95% CI) Certainty RR (95% CI) Certainty RR (95% CI) Certainty Risk with placebo or no treatment Risk with misoprostol Risk difference with misoprostol Diarrhoea 2.80 (1.21–6.49)e ㊉㊉㊉㊉ HIGH Not reported — 2.80 (1.20–6.49) ㊉㊉㊉㊉ HIGH 6 per 1000 17 per 1000 11 more per 1000 (1 more to 33 more) 6 per 1000 (for vaginal birth) 17 per 1000 (for vaginal birth) 11 more per 1000 (1 more to 33 more) (for vaginal birth) See commentsa (for caesarean birth) See commentsb (for caesarean birth) See commentsc (for caesarean birth) Note: The assumed risks in the placebo or no treatment group are based on weighted means of baseline risks from the studies with placebo or no treatment groups in the network meta-analysis. The corresponding risks in the misoprostol group (and their 95% confidence interval) are based on the assumed risks in the placebo or no treatment group and the relative effects of misoprostol (and its 95% CI) derived from the network meta-analysis. a There were no included studies or there were no events in the included studies to estimate the baseline risk. b Absolute risk with misoprostol cannot be estimated in the absence of absolute risk with placebo or no treatment. c Risk difference cannot be estimated in the absence of absolute risks with placebo or no treatment and misoprostol. d The included studies did not provide any direct evidence for this outcome, therefore the effect estimate from the indirect evidence is identical to the network effect estimate. e The included studies did not provide any indirect evidence on this outcome, therefore the effect estimate from the direct evidence is identical to the effect estimate generated by the whole network. CI: confidence interval; Hb: haemoglobin; MD: mean difference; RR: risk ratio Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group grades of evidence1 High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. 1 Further information available at: http://www.gradeworkinggroup.org/ 17 W EB A N N EX 3 : M IS O PR O ST O L V ER SU S PL A C EB O O R N O T RE AT M EN T – EV ID EN C E TO D EC IS IO N F RA M EW O RK 6. References 1. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva: World Health Organization; 2012 (http://apps.who.int/iris/bitstream/handle/10665/75411/9789241548502_eng.pdf, accessed 5 November 2018). 2. Gallos ID, Papadopoulou A, Man R, Athanasopoulos N, Tobias A, Price MJ, et al. Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis (Review). Cochrane Database Syst Rev 2018: CD011689. doi:10.1002/14651858. CD011689.pub3. 3. Tunçalp Ö, Hofmeyr GJ, Gülmezoglu AM. Prostaglandins for preventing postpartum haemorrhage. Cochrane Database Syst Rev. 2012;(8):CD000494. 4. Downe S, Finlayson K, Oladapo O, Bonet M, Gülmezoglu A. What matters to women during childbirth: a systematic qualitative review. PLoS One. 2018;13(5):e0197791. doi:10.1371/journal.pone.0194906. 5. Finlayson K, Downe S, Vogel JP, Oladapo OT. What matters to women and healthcare providers in relation to interventions for the prevention of postpartum haemorrhage: a qualitative systematic review. 2018 (unpublished). 6. Lawrie TA, Rogozinska E, Vogel JP, Oladapo OT. The cost-effectiveness of uterotonic agents to prevent postpartum haemorrhage: a systematic review. 2018 (unpublished). 7. Bradley SE, Prata N, Young-Lin N, Bishai DM. Cost-effectiveness of misoprostol to control postpartum hemorrhage in low-resource settings. Int J Gynaecol Obstet. 2007;97(1):52-6. doi:10.1016/j.ijgo.2006.12.005. 8. Lubinga SJ, Atukunda EC, Wasswa-Ssalongo G, Babigumira JB. Potential cost- effectiveness of prenatal distribution of misoprostol for prevention of postpartum hemorrhage in Uganda. PLoS One. 2015;10(11):e0142550. doi:10.1371/journal. pone.0142550. [Erratum appears in PLoS One. 2016;11(3):e0152955]. 9. Lang DL, Zhao FL, Robertson J. Prevention of postpartum haemorrhage: cost consequences analysis of misoprostol in low-resource settings. BMC Pregnancy Childbirth. 2015;15(1):305. doi:10.1186/s12884-015-0749-z. 10. Sutherland T, Meyer C, Bishai DM, Geller S, Miller S. Community-based distribution of misoprostol for treatment or prevention of postpartum hemorrhage: cost-effectiveness, mortality, and morbidity reduction analysis. Int J Gynaecol Obstet. 2010;108(3):289- 94. doi:10.1016/j.ijgo.2009.11.007. 11. Sutherland T, Bishai DM. Cost-effectiveness of misoprostol and prenatal iron supplementation as maternal mortality interventions in home births in rural India. Int J Gynaecol Obstet. 2009;104(3):189-93. doi:10.1016/j.ijgo.2008.10.011. 12. Vlassoff M, Diallo A, Philbin J, Kost K, Bankole A. Cost-effectiveness of two interventions for the prevention of postpartum hemorrhage in senegal. Int J Gynaecol Obstet. 2016;133(3):307-11. doi:10.1016/j.ijgo.2015.10.015. 13. Diop A, Daff B, Sow M, Blum J, Diagne M, Sloan NL, et al. Oxytocin via Uniject (a prefilled single-use injection) versus oral misoprostol for prevention of postpartum haemorrhage at the community level: a cluster-randomised controlled trial. Lancet Glob Health. 2016;4(1):e37-44. doi:10.1016/S2214-109X(15)00219-3. 14. Chatterjee S, Sarkar A, Rao KD. Using misoprostol for primary versus secondary prevention of postpartum haemorrhage – do costs matter? PLoS One. 2016;11(10):e0164718. doi:10.1371/journal.pone.0164718. W H O R EC O M M EN D AT IO N S: U TE RO TO N IC S FO R TH E PR EV EN TI O N O F PO ST PA RT U M H A EM O RR H A G E 18 15. State of inequality: reproductive, maternal, newborn and child health. Geneva: World Health Organization; 2015 (http://apps.who.int/iris/bitstream/handle/10665/164590/9789241564908_eng. pdf, accessed 5 November 2018). 16. WHO model list of essential medicines (20th List). March 2017 (Amended August 2017). Geneva: World Health Organization; 2017 (http://apps.who.int/iris/bitstream/handle/10665/273826/EML-20-eng.pdf, accessed 5 November 2018). 17. Sanghvi H, Wiknjosastro G, Chanpong G, Fishel J, Ahmed S, Zulkarnain M. Prevention of postpartum haemorrhage study, West Java, Indonesia. Baltimore, MD: Jhpiego; 2004 (https://www.k4health.org/sites/default/files/10%20MNH%20PPH%20study%20 West%20Java%202004_0.pdf, accessed 12 November 2018). 18. Ejembi C, Shittu O, Moran M, Adiri F, Oguntunde O, Saadatu B, et al. Community- level distribution of misoprostol to prevent postpartum hemorrhage at home births in northern Nigeria. Afr J Reprod Health. 2014;18(2):166-75. 19. Geller S, Carnahan L, Akosah E, Asare G, Agyemang R, Dickson R, et al. Community- based distribution of misoprostol to prevent postpartum haemorrhage at home births: results from operations research in rural Ghana. BJOG. 2014;121(3):319-26. doi:10.1111/1471-0528.12447. 20. Haver J, Ansari N, Zainullah P, Kim YM, Tappis H. Misoprostol for prevention of postpartum hemorrhage at home birth in Afghanistan: program expansion experience. J Midwifery Womens Health. 2016;61(2):196-202. doi:10.1111/jmwh.12413 21. Mayer Hashi Project. Preventing postpartum hemorrhage: community-based distribution of misoprostol in Tangail District, Bangladesh. Project Brief No. 2, May. New York, NY: The RESPOND Project at EngenderHealth; 2010 (http://www.respond-project.org/pages/files/6_pubs/project_briefs/Project-Brief-2- Bangladesh-PPH-final.pdf, accessed 31 October 2018). 22. Mir AM, Wajid A, Gull S. Helping rural women in Pakistan to prevent postpartum hemorrhage: a quasi experimental study. BMC Pregnancy Childbirth. 2012;12:120. doi:10.1186/1471-2393-12-120. 23. Orobaton N, Abdulazeez J, Abegunde D, Shoretire K, Maishanu A, Ikoro N, et al. Implementing at-scale, community-based distribution of misoprostol tablets to mothers in the third stage of labor for the prevention of postpartum haemorrhage in Sokoto State, Nigeria: early results and lessons learned. PLoS One. 2017;12(2):e0170739. doi:10.1371/journal.pone.0170739. 24. Prata N, Mbaruku G, Grossman AA, Holston M, Hsieh K. Community-based availability of misoprostol: is it safe? Afr J Reprod Health. 2009;13(2):117-28. 25. Prata N, Gessessew A, Abraha AK, Holston M, Potts M. Prevention of postpartum hemorrhage: options for home births in rural Ethiopia. Afr J Reprod Health. 2009;13(2):87-95. 26. Prata N, Ejembi C, Fraser A, Shittu O, Minkler M. Community mobilization to reduce postpartum hemorrhage in home births in northern Nigeria. Soc Sci Med. 2012;74(8):1288-96. doi: 10.1016/j.socscimed.2011.11.035. 27. Rajbhandari SP, Aryal K, Sheldon WR, Ban B, Upreti SR, Regmi K, et al. Postpartum hemorrhage prevention in Nepal: a program assessment. BMC Pregnancy Childbirth. 2017;17(1):169. doi:10.1186/s12884-017-1347-z. 19 W EB A N N EX 3 : M IS O PR O ST O L V ER SU S PL A C EB O O R N O T RE AT M EN T – EV ID EN C E TO D EC IS IO N F RA M EW O RK 28. Sibley LM, Spangler SA, Barry D, Tesfaye S, Desta BF, Gobezayehu AG. A regional comparison of distribution strategies and women’s awareness, receipt, and use of misoprostol to prevent postpartum hemorrhage in rural Amhara and Oromiya regions of Ethiopia. J Midwifery Womens Health. 2014;59(Suppl 1):S73-82. doi:10.1111/ jmwh.12136. 29. Smith JM, Baawo SD, Subah M, Sirtor-Gbassie V, Howe CJ, Ishola G, et al. Advance distribution of misoprostol for prevention of postpartum hemorrhage (PPH) at home births in two districts of Liberia. BMC Pregnancy Childbirth. 2014;14:189. doi:10.1186/1471-2393-14-189. 30. Smith JM, Dimiti A, Dwivedi V, Ochieng I, Dalaka M, Currie S, et al. Advance distribution of misoprostol for the prevention of postpartum hemorrhage in South Sudan. Int J Gynaecol Obstet. 2014;127(2):183-8. doi:10.1016/j.ijgo.2014.05.016. 31. Misoprostol policy and scale-up for the prevention of postpartum hemorrhage in Madagascar: country report. Arlington, VA: African Strategies for Health; 2016 (https://www.msh.org/sites/msh.org/files/misoprostol_policy_and_scale_up_in_ madagascar_aug_2016.pdf, accessed 31 October 2018). 32. Misoprostol policy and scale-up for the prevention of postpartum hemorrhage in Mozambique: country report. Arlington, VA: African Strategies for Health; 2016 (https://www.msh.org/sites/msh.org/files/misoprostol_policy_and_scale_up_in_ mozambique_aug_2016.pdf, accessed 31 October 2018). 33. Webber GC, Chirangi B. Women’s health in women’s hands: a pilot study assessing the feasibility of providing women with medications to reduce postpartum hemorrhage and sepsis in rural Tanzania. Health Care Women Int. 2014;35(7-9):758-70. doi:10.1080/07 399332.2014.915843. For more information, please contact: Department of Reproductive Health and Research E-mail: reproductivehealth@who.int www.who.int/reproductivehealth Maternal, Newborn, Child and Adolescent Health E-mail: mncah@who.int www.who.int/maternal_child_adolescent World Health Organization Avenue Appia 20, CH-1211 Geneva 27 Switzerland

Основные сведения

Организация Всемирная организация здравоохранения (ВОЗ / WHO)

Тип документа Technical Documents

Дата принятия 20 декабря 2018 г.

Источник Всемирная организация здравоохранения