WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth

WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth WHO recommendation on routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth ISBN 978-92-4-001392-6 (electronic version) ISBN 978-92-4-001393-3 (print version) © World Health Organization 2020 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 (http://www.wipo.int/amc/en/ mediation/rules/). Suggested citation. WHO recommendation on routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/ about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Contents

Acknowledgements v Acronyms and abbreviations vi Executive summary vii Introduction vii Target audience vii Guideline development methods vii Recommendation viii 1. Introduction 1 1.1 Background 1 1.2 Rationale and objectives 1 1.3 Target audience 2 1.4 Scope of the recommendation 2 1.5 Persons affected by the recommendation 2 2. Methods 3 2.1 Executive Guideline Steering Group (GSG) 3 2.2 WHO Steering Group 3 2.3 Guideline Development Group (GDG) 3 2.4 Evidence Synthesis Group (ESG) 4 2.5 External partners and observers 4 2.6 External Review Group (ERG) 4 2.7 Identification of priority questions and outcomes 4 2.8 Evidence identification and retrieval 5 2.9 Certainty assessment and grading of the evidence 5 2.10 Formulation of the recommendation 6 2.11 Management of declarations of interests 8 2.12 Decision-making during the GDG meeting 8 2.13 Document preparation 9 2.14 Peer review 9 3. Recommendation and supporting evidence 10 4. Dissemination, adaptation and implementation of the recommendation 12 4.1 Recommendation dissemination 12 4.2 Adaptation 12 4.3 Implementation considerations 13 5. Research implications 13 6. Applicability issues 14 6.1. Anticipated impact on the organization of care and resources 14 6.2. Monitoring and evaluating guideline implementation 14 7. Updating the recommendation 15 8. References 16 Contents

iii iv WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth Annex 3. 3. Annex 4. Annex Annex 2. 2. Annex 1. Annex Summary and management of declared interests from gdg from interests of declared management and Summary framework toEvidence Decision indecision-making used outcomes Priority recommendation of the involvedpreparation in staff the who and experts External 19 members

22 25 23 Acknowledgements

The World Health Organization (WHO) Department of Sexual and Reproductive Health and Research and Department of Maternal, Newborn, Child and Adolescent Health and Ageing gratefully acknowledge the contributions of many individuals and organizations to the updating of this recommendation. Work on this update was coordinated by Fernando Althabe, Tina Lavin, Olufemi Oladapo, Joshua Vogel and Mariana Widmer of the Department of Sexual and Reproductive Health and Research. WHO extends its sincere thanks to Oluwarotimi Ireti Akinola, Brendan Carvalho, Melania Amorim, Catherine Deneux-Tharaux, Tippawan Liabsuetrakul, Martin Meremikwu, Suellen Miller, Mari Nagai, Hayfaa Wahabi, Dilys Walker and Andrew Weeks who served as members of the Guideline Development Group (GDG), and to Ashraf Nabhan (Chair) for leading the meeting. We also thank Christine East, Gill Gyte, Justus Hofmeyr, Syeda Batool Mazhar, Enrique Oyarzun and Qian Xu, who were members of the External Review Group (ERG). WHO also gratefully acknowledges the contribution of the members of the Executive Guideline Steering Group (GSG). Edgardo Abalos, Anna Cuthbert, Virginia Diaz, Kenneth Finlayson, Leanne Jones, Frances Kellie and Myfanwy Williams reviewed the scientific evidence, prepared the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tables and drafted the narrative summary of the evidence. Fernando Althabe, Olufemi Oladapo, Mariana Widmer and Joshua Vogel revised the narrative summaries and double-checked the corresponding GRADE tables and prepared the Evidence to Decision (EtD) frameworks. The ERG peer reviewed the final document prior to executive clearance by WHO and publication. We acknowledge the various organizations that were represented by observers, including Deborah Armbruster (United States Agency for International Development [USAID]), Ingela Wiklund (International Confederation of Midwives [ICM]) and Carlos Fuchtner (International Federation of Gynecology and Obstetrics [FIGO]). We also appreciate the contributions of staff at the WHO regional offices, including Nino Berdzuli, Bremen De Mucio, Hayfa Elamin, Chandani Anoma Jayathilaka, Ramez Khairi Mahaini, Howard Sobel and Claudio Sosa. WHO acknowledges the financial support for this work received from USAID and the UNDP–UNFPA–UNICEF–WHO–World Bank Special Programme of Research, Development and Research Training in Human Reproduction the Department of Sexual and Reproductive Health and Research. WHO emphasizes that donors do not participate in any decision related to the guideline development process, including the composition of research questions, membership of the guideline development groups, conducting and interpretation of systematic reviews, or formulation of the recommendations. The views of the funding bodies have not influenced the content of this recommendation. knowledgements c A

v vi WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth WHO USAID UNICEF UNFPA UNDP PPH PICO MPH-GDG IV intravenous IU IM ICM HRP GSG GRADE GDG FIGO EtD ESG ERG DOI CerQUAL Acronyms abbreviations and intramuscular

World Organization Health Development International for States Agency United Children’s Nations United Fund Fund Population Nations United United Nations Development Programme haemorrhage postpartum (P),population (I), intervention (C), comparator (O) outcome Group Development Guideline Health Perinatal and Maternal WHO units international of Midwives Confederation International Training Research and Reproduction inHuman Development of Research, Programme Special UNDP–UNFPA–UNICEF–WHO–World Bank Group Steering Guideline Evaluation and Development Assessment, of Recommendations Grading Group Development Guideline Obstetrics and of Gynecology Federation International toEvidence Decision Synthesis Group Evidence ReviewEvidence Group of interest declaration from ReviewsQualitative of Research in the Evidence Confidence Executive summary

Introduction Postpartum haemorrhage (PPH) is commonly defined as a blood loss of 500 mL or more within 24 hours after birth and affects about 5% of all women giving birth around the world. Globally, nearly one quarter of all maternal deaths are associated with PPH and, in most low-income countries, it is the main cause of maternal mortality. Improving care during childbirth to prevent PPH is a necessary step towards the achievement of the health targets of the third Sustainable Development Goal (SDG 3), particularly target 3.1: reduce the global maternal mortality ratio to less than 70 per 100 000 live births by 2030. Efforts to prevent and reduce morbidity and mortality due to PPH can help to address the profound inequities in maternal and perinatal health globally. To achieve this, skilled health personnel, health managers, policy-makers and other stakeholders need up-to-date and evidence-informed recommendations to guide clinical policies and practices. In 2019, the Executive Guideline Steering Group (GSG) for World Health Organization (WHO) maternal and perinatal health recommendations prioritized the updating of the existing WHO recommendations for intravenous (IV) versus intramuscular (IM) oxytocin for prevention of PPH after vaginal birth in response to the availability of new evidence. The recommendation in this document thus supersedes the previous WHO recommendations for the prevention of PPH as published in the 2012 guideline, WHO recommendations for the prevention and treatment of postpartum haemorrhage.

Target audience The primary audience for these recommendations includes health professionals who are responsible for developing national and local health-care guidelines and protocols (particularly those related to PPH prevention and treatment) and those involved in the provision of care to women and their newborns during labour and childbirth, including midwives, nurses, general medical practitioners and obstetricians, as well as managers of maternal and child health programmes, and relevant staff in ministries of health and training institutions, in all settings.

Guideline development methods The updating of these recommendations was guided by standardized operating procedures in accordance with the process described in the WHO handbook for guideline development. The recommendations were initially developed and updated using this process, namely: (i) identification of priority questions and outcomes; (ii) retrieval of evidence; (iii) assessment and synthesis of evidence; (iv) formulation of the recommendations; and (v) planning for the dissemination, implementation, impact evaluation and future updating of the recommendations. The scientific evidence supporting the recommendation was synthesized using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. An updated systematic review was used to prepare the evidence profiles for the prioritized question. WHO convened a meeting on 11–12 March 2020 where the Guideline Development Group (GDG) members reviewed, deliberated and achieved consensus on the strength and direction of the recommendation presented herein. Through a structured process, the GDG reviewed the balance between the desirable and undesirable effects and the overall certainty of supporting evidence, values and preferences of stakeholders, resource requirements and cost-effectiveness, acceptability, feasibility and equity. a ry utive summ utive c xe E

vii viii WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth postpartum haemorrhage after vaginal birth after haemorrhage postpartum of prevention the for administration oxytocin of routes on recommendation WHO implementation. on considerations the including summary, well as to as evidence the to to refer remarks, the may want users guideline inpractice, applied and understood is correctly recommendation To considerations. the that ensure implementation and with remarks birth, vaginal after prevention of for PPH oxytocin IM IVversus on recommendation new the issued GDG equity.The and acceptability, feasibility cost-effectiveness, and requirements resource of stakeholders, preferences and values evidence, of supporting overallthe certainty and effects undesirable and desirable the between reviewed balance the GDG The Recommendation     Justification (Context-specific recommendation) administration. intramuscular to preference in recommended is oxytocin IU 10 of administration intravenous slow the access, have intravenous already vaginally birth giving women where situations In births. all for haemorrhage postpartum of prevention the for recommended is /intravenous) intramuscular [IU], units international (10 oxytocin of use The Remarks     postpartum haemorrhage prevention. prevention. haemorrhage postpartum for oxytocin intravenous of administering purpose sole the for routinely placed be not should access intravenous that emphasized Group Development Guideline The use. resource on impacts and cost increases that settings high-income and low-middle in facilities health many in in labour all for women fluids intravenous of administration of routine use unnecessary and widespread the on emphasis with childbirth, and labour during fluids of intravenous use routine the against recommendations existing WHO acknowledged Group Development Guideline The intravenously. oxytocin administer to indication), medical is it (for recommended have access another intravenous already women where instances In of oxytocin. bolus intravenous with arapid concerns safety of possible suggestive women’s well as studies as comfort), and equity health resources, on impacts and feasibility (including considerations other on emphasis its placed Group Development Guideline the outcomes, health important for oxytocin intravenous favours of effects balance the that noting While this indication. for by WHO recommended currently are of administration routes both and haemorrhage preventingpostpartum in is effective oxytocin intramuscular or intravenous either that acknowledged Group Development Guideline The considerations. other these outweigh administration intravenous of benefits clinical the birth, vaginal at inplace is already access intravenous However, settings. where in situations indifferent vary may also administration of intravenous feasibility The inequities. health increase can and women’s comfort impact may negatively requirements, resource additional prevention imposes haemorrhage postpartum for use oxytocin intravenous routine cost-effective, more is administration intravenous whether uncertain it While is effects. undesirable in differences clear with no morbidity, severe maternal and transfusion blood haemorrhage, severe postpartum haemorrhage, of risk postpartum the reduces oxytocin intravenous oxytocin, to intramuscular compared When outcomes. of health interms oxytocin infavour of intravenous evidence is clear There  The Guideline Development Group noted that the previous trials considered for this question have all administered an oxytocin dose of 10 IU intravenously for postpartum haemorrhage prevention during vaginal birth. However, the speed of injection ranged from 1 minute (for bolus injection) to 40 minutes (for infusion) and volume of dilution from 1 mL (for bolus injection) to 1000 mL of saline (for infusion). There is no direct evidence comparing the different regimens for administering intravenous oxytocin during vaginal birth, and there were no safety concerns (such as hypotension or tachycardia) in trials comparing slow intravenous administration of 10 IU oxytocin over 1 minute with 10 IU intramuscular oxytocin. However, observational studies in women undergoing caesarean section suggest that rapid intravenous injection results in harmful haemodynamic effects. Therefore, the Guideline Development Group suggests avoiding a rapid injection, and agreed that the 10 IU oxytocin dose should preferably be diluted and administered slowly.  This recommendation reflects available evidence from direct comparison of intravenous versus intramuscular oxytocin during vaginal birth. For women undergoing caesarean section, WHO currently recommends 10 IU for postpartum haemorrhage prevention without preference for intravenous or intramuscular.  This recommendation does not relate to the use of oxytocin for other obstetric indications (such as labour induction, labour augmentation, or treatment of postpartum haemorrhage). a ry utive summ utive c xe E

ix 1. Introduction

1.1 Background An estimated 295 000 women and adolescent girls died as a result of pregnancy and childbirth-related complications in 2017, and around 99% of these deaths occurred in low-resource settings (1). Obstetric haemorrhage, especially postpartum haemorrhage (PPH), is responsible for more than a quarter of all maternal deaths worldwide (2). In most low-income countries, PPH is the leading cause of maternal deaths. Thus, improving access to safe and effective interventions to prevent PPH is critical to World Health Organization (WHO) strategic priorities (particularly universal health coverage) for achieving the targets of the third Sustainable Development Goal (SDG 3) (3). International human rights law includes fundamental commitments of States to enable women and adolescent girls to survive pregnancy and childbirth, as part of their enjoyment of sexual and reproductive health and rights, and living a life of dignity (4). WHO envisions a world where “every pregnant woman and newborn receives quality care throughout pregnancy, childbirth and the postnatal period” (5). To provide good-quality care, skilled health personnel at all levels of the health system need to have access to appropriate medications and training in relevant procedures (6). Health-care providers, health managers, health policy-makers and other stakeholders also need up-to-date, evidence-informed recommendations to guide clinical policies and practices to optimize quality of care and improve health-care outcomes. PPH is commonly defined as a blood loss of 500 mL or more within 24 hours after birth and affects about 5% of all women giving birth around the world (7,8). Severe maternal complications, such as organ dysfunction or death, generally occur following substantial blood loss that compromises maternal haemodynamic stability. Uterine atony is the most common cause of PPH and a leading cause of PPH-related maternal mortality worldwide (9). Genital tract trauma (including vaginal or cervical lacerations and uterine rupture), retained placental tissue or maternal bleeding disorders can cause PPH. Although PPH can occur in any woman, even those without risk factors, grand multiparity, prolonged labour, prior history of PPH and multiple gestation are associated with an increased risk of bleeding after birth (10). In addition, anaemia is a common aggravating factor (11). The majority of PPH- associated complications could be avoided by the use of prophylactic uterotonics during the third stage of labour (that is, the time between the delivery of the baby and complete expulsion of the placenta). Oxytocin is one such uterotonic and is listed on the WHO model list of essential medicines for this indication (12). It is a synthetic cyclic peptide form of the naturally occurring posterior pituitary hormone (13,14). Oxytocin binds to the oxytocin receptor in the uterine myometrium, stimulating contraction of the uterine smooth muscle. Oxytocin can be administered intravenously where its action is almost immediate with a peak in concentration after 30 minutes (13,14). It can also be administered intramuscularly with a slower onset of action taking 3–7 minutes, with a longer-lasting clinical effect of up to one hour (13,14). Oxytocin requires protection from light and must be stored at 2–8 °C (15).

1.2 Rationale and objectives WHO has established a new process for prioritizing and updating maternal and perinatal health recommendations, whereby an international group of independent experts – the Executive Guideline Steering Group (GSG) – oversees a systematic prioritization of maternal and perinatal health recommendations in most urgent need of updating (16,17). Recommendations are prioritized for updating on the basis of changes or important new uncertainties in the underlying evidence base on benefits, harms, values placed on outcomes, acceptability, feasibility, equity, resource use, cost-effectiveness or factors affecting implementation. The Executive GSG prioritized updating of the WHO

recommendations for intravenous (IV) versus intramuscular (IM) oxytocin for prevention c tion I ntrodu 1.

1 2 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth oxytocin for prevention of PPH after vaginal birth. vaginal prevention after of for PPH oxytocin IM of IVversus use for guidance provides thus recommendation This complications. they as relate its to and PPH birth, giving women for outcomes and of care quality the Research (GRADE-CerQUAL) Evaluation (GRADE) and Development Assessment, of Recommendations Grading of the use evidence, research WHO inthe for handbook guidelineprocedures development and standards with the inaccordance were developed recommendations updated These interventions. these on evidence potentially important of and new publication of the inanticipation birth vaginal after of PPH 2 1 settings. high-income or middle- low-, in women pregnant all includes by this recommendation affected population The 1.5  was: this recommendation for question the format, (P), Population the using Framed (I), (C), Intervention Comparison (O) Outcome (PICO) 1.4 centred maternal care, and implementers of programmes. people- promoting with concerned organizations nongovernmental of staff women, pregnant involved of care (low inthe societies to of high), professional settings well as members as of resource inarange birth giving to of interest women will be also recommendation This settings. all in institutions, training and health of ministries in staff relevant and programmes, health child and of maternal well as managers as obstetricians, and practitioners medical general nurses, midwives, including childbirth, and labour involved during provision to those inthe of care women and treatment) prevention and related to those PPH protocols (particularly and guidelines health-care local and national developing for responsible are who professionals health includes audience primary The 1.3 postpartum haemorrhage postpartum of the for prevention treatment and in2012 inWHOrecommendations werethat published birth vaginal prevention after of for PPH oxytocin IM IVversus for recommendations (18) stakeholders and (GDG) experts Group of international Development composed Guideline  Further information is available at: https://www.cerqual.org/. at: available is information Further Further information is available at: http://www.gradeworkinggroup.org/. (O)? (C) oxytocin withprevention IM (I) outcomes infant compared and improve maternal PPH for (P), of of third labour IVoxytocin inthe stage administration women For does . The recommendation published in this document thus supersedes the previous previous the supersedes thus inthis document published recommendation . The Persons affected Persons affected by the recommendation Scope of therecommendation Target audience 1 and GRADE Confidence in the Evidence from from ReviewsQualitative of in the Evidence Confidence GRADE and (19) . The primary aim of these recommendations is to improve recommendations aimof these primary . The 2 methodologies, and formulation of recommendations by a of recommendations formulation and methodologies, , including synthesis of available synthesis , including 2. Methods

The recommendation was developed using standardized operating procedures in accordance with the process described in the WHO handbook for guideline development (18). In summary, the process included: (i) identification of the priority question and critical outcomes; (ii) retrieval of evidence; (iii) assessment and synthesis of evidence; (iv) formulation of the recommendation; and (v) planning for the dissemination, implementation, impact evaluation and updating of the recommendation. In 2019, IV versus IM oxytocin for prevention of PPH after vaginal birth was identified by the Executive GSG as a high priority for development of a recommendation, in response to new, potentially important evidence on this question. Six main groups were involved in this process, with their specific roles described in the following sections.

2.1 Executive Guideline Steering Group (GSG) The Executive GSG is an independent panel of 14 external experts and relevant stakeholders from the six WHO regions: African Region, Region of the Americas, Eastern Mediterranean Region, European Region, South-East Asia Region and Western Pacific Region. The Executive GSG advises WHO on the prioritization of new and existing PICO questions in maternal and perinatal health for development or updating of recommendations (16,17).

2.2 WHO Steering Group The WHO Steering Group, comprising WHO staff members from the Department of Sexual and Reproductive Health and Research and the Department of Maternal, Newborn, Child and Adolescent Health and Ageing managed the process of updating the recommendations. The WHO Steering Group drafted the key recommendation questions in PICO format, engaged the systematic review teams and guideline methodologists (that is, the Evidence Synthesis Group [ESG]), as well as the members of the GDG and the External Review Group (ERG) (see below). In addition, the WHO Steering Group supervised the retrieval and syntheses of evidence, organized the GDG meetings, drafted and finalized the guideline document, and will also manage the guideline dissemination, implementation and impact assessment. The members of the WHO Steering Group are listed in Annex 1.

2.3 Guideline Development Group (GDG) The WHO Steering Group identified a pool of approximately 50 experts and relevant stakeholders from the six WHO regions to constitute the WHO Maternal and Perinatal Health Guideline Development Group (MPH-GDG). This pool consists of a diverse group of experts who are skilled in the critical appraisal of research evidence, implementation of evidence-informed recommendations, guideline development methods, and clinical practice, policy and programmes relating to maternal and perinatal health. Members of the MPH- GDG are identified in a way that ensures geographic representation and gender balance, and there were no perceived or real conflicts of interest. Members’ expertise cuts across thematic areas within maternal and perinatal health. From the MPH-GDG pool, 14 external experts and relevant stakeholders were invited to participate as members of the GDG for updating this recommendation. Those selected were a diverse group with expertise in research, guideline development methods, gender, equity and rights, clinical policy and programmes relating to PPH prevention and treatment. The 14 GDG members for this recommendation were also selected in a way that ensured geographic representation and gender balance, and there were no important conflicts of interest. The GDG appraised the evidence that was used to inform the recommendation, advised on the interpretation of this evidence, formulated the final recommendation based on the draft prepared by the WHO Steering Group and reviewed and reached unanimous ethods consensus for the recommendation in the final document. The members of the GDG are listed in Annex 1. M 2.

3 4 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth prevention and treatment of postpartum haemorrhage 2012 WHO the from recommendations with those were aligned outcomes for priority The 2.7 ERG of listed are inAnnex 1. the Members by GDG. the were formulated that recommendations the to of this remit change group within the not was It policy-makers. and professionals health-care recommendations, by the affected of persons preferences the and values contextual incorporated and considered had processes decision-making the that ensured They implementation. for implications and issues contextual of language, clarity on the commented and errors anyfactual identify to document reviewed final the experts The of interest. conflicts important no had members the and balanced, gender and diverse geographically was group The to PPH. treat care prevent and evidence-based provision inthe of expertise and with interests experts six technical ERG included The 2.6 inAnnex 1. included is meeting GDG inthe participated who list of observers The recommendations. of the potentialas implementers were identified implementation, and dissemination guideline perinatal and inmaternal with WHO of collaboration history long with their organizations, These observers. as meeting (FIGO) GDG inthe Obstetrics and participated Gynecology of Federation (ICM) of International Midwives the and Confederation International the (USAID), Development International for States Agency United of the Representatives 2.5 listed are inAnnex 1. ESG of the members The GDG. the from queries to technical to and respond evidence synthesized of the overview an (22) EtDin the framework (updated domain oxytocin to 2020) March cost-effectiveness inthe evidence for used was prevention (20,21) of PPH the for to inrelation interventions providers health-care and to women matters what and childbirth during to women matters what qualitative reviewsexisting systematic exploring two from were obtained EtD frameworks GRADE of the domains other the for Evidence GDG. the from queries to technical to and respond tables GRADE and available evidence of the to overview an provide meeting GDG the attended methodologist a and Group Childbirth and Pregnancy Cochrane of the Representatives methodology. GRADE the using evidence the to appraise Group Childbirth and Pregnancy Cochrane the with worked closely protocol and into updated the input reviewed provided and Group Steering WHO The Group. Childbirth and Pregnancy by Cochrane the supported updated, was (EtD) review to Asystematic Evidence thisthe question Decision on frameworks. develop and evidence the appraise reviews, systematic update or toteams conduct review systematic and methodologists of guideline composed ESG an convened WHO 2.4 recommendation. The list of priority outcomes is provided inAnnex 2. is provided outcomes list of priority The recommendation. of the formulation and grading retrieval, synthesis, searching, evidence for of this document scope inthe were included outcomes All the woman-centred. be would of recommendations set final the to that and ensure to women important are that were by driven outcomes GDG by the decision-making recommendation and synthesis evidence to that this update ensure for –were included satisfaction maternal and well-being –maternal outcomes additional (23) of PPH treatment prevention and for set outcome core published recently of the consideration due After 2012 guideline. the for by GDG the of outcomes aprioritization and systematic reviews published relevant, for databases scientific of search a through identified Identification priorityof questions outcomes and ReviewExternal (ERG) Group observers and partners External Evidence Synthesis (ESG) Group . A systematic review on the cost-effectiveness of IV versus IM of IV versus review cost-effectiveness . Asystematic the on . All members of the ESG attended the GDG meetings to provide meetings GDG the attended ESG of the . All members (19) . These outcomes were initially outcomes . These , two , two 2.8 Evidence identification and retrieval Evidence to support this update was derived from several sources by the ESG working in collaboration with the WHO Steering Group.

2.8.1 Evidence on the effects of IV versus IM oxytocin for PPH prevention after vaginal birth An existing systematic review was updated for the purpose of this update (24). This systematic review was the primary source of evidence for this recommendation. Randomized controlled trials relevant to the key question were screened by the review authors, and data on relevant outcomes and comparisons were entered into the Review Manager 5 (RevMan) software. The RevMan file was retrieved from the Cochrane Pregnancy and Childbirth Group and customized to reflect the key comparisons and outcomes (those that were not relevant to the recommendation were excluded). The RevMan file was then exported to GRADE profiler software (GRADEpro), and GRADE criteria were used to critically appraise the retrieved scientific evidence (25). Finally, evidence profiles (in the form of GRADE summary of findings tables) were prepared for comparisons of interest, including the assessment and judgements for each outcome and the estimated risks.

2.8.2 Evidence on values, resource use and cost-effectiveness, equity, acceptability and feasibility Evidence from two systematic reviews were used to inform the acceptability, feasibility and equity domains as they relate to the EtD framework for IV versus IM oxytocin administration for the prevention of PPH (20,21). A review of qualitative studies evaluating “what women want” from intrapartum care was used for the acceptability and equity domains relating to medical interventions, feelings about labour and birth, recognition of complications and receiving information on introduced interventions (20). Another qualitative review explored the perceptions on PPH prevention and treatment of health-care providers and women, including the benefits of oxytocin use to prevent PPH and the factors influencing effective use of oxytocin (21). A systematic review of the literature found no direct evidence on the relative cost-effectiveness of IV oxytocin compared with IM oxytocin to prevent PPH (22).

2.9 Certainty assessment and grading of the evidence The certainty assessment of the body of evidence for each outcome was performed using the GRADE approach (26). Using this approach, the certainty of evidence for each outcome was rated as ”high”, ”moderate”, ”low” or ”very low” based on a set of established criteria. The final rating of certainty of evidence was dependent on the factors briefly described below. Study design limitations: The risk of bias was first examined at the level of each individual study and then across the studies contributing to the outcome. For randomized trials, certainty was first rated as “high” and then downgraded by one (“moderate”) or two (“low”) levels, depending on the minimum criteria met by the majority of the studies contributing to the outcome. Inconsistency of the results: The similarity in the results for a given outcome was assessed by exploring the magnitude of differences in the direction and size of effects observed in different studies. The certainty of evidence was not downgraded when the direction of the findings were similar and confidence limits overlapped, whereas it was downgraded when the results were in different directions and confidence limits showed minimal or no overlap. Indirectness: The certainty of evidence was downgraded when there were serious or very serious concerns regarding the directness of the evidence – that is, whether there were important differences between the research reported and the context for which the recommendation was being prepared. Such differences were related, for instance, to populations, interventions, comparisons or outcomes of interest. ethods 2. M 2.

5 6 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth  domain: each on covering evidence question priority each for documents summary created ESG and Group Steering WHO the template, EtD the Using framework process. decision-making the guide to and inform domain each on intervention of the impact the on were made judgements questions, feasibility. priority and the For acceptability equity, resources, values, effects, domains: of specified interms interventions prioritized on of evidence consideration systematic and explicit include EtD frameworks EtD framework. GRADE the using ESG with the incollaboration summaries evidence narrative and tables findings of summary of preparation finalized the and supervised Group Steering WHO The 2.10 comparison of interest. comparison each for narratively were reported studies cost-effectiveness individual from Findings to areview contributing finding. studies individual of the torelevance review the question and coherence; of data; adequacy studies; individual of the limitations methodological low) very low and according components: review toto four moderate, finding each (high, tool to a level of assign confidence GRADE-CERQual the review systematic team used The from reviews qualitative of in research. evidence placed be can that level of confidence the assigning and assessing for method atransparent provides tools, to GRADE other CERQual tool (27) CERQual GRADE- using the quality for qualitative of reviewsthe appraised were findings The     of evidence Certainty bias. of publication suspicion strong was there where considered level by was one evidence Downgrading results. study on based publication of selective as a result an intervention of overestimate effect or the of to bias evidence underestimate statistical or perceived by affected be also could rating certainty The bias: Publication downgraded for imprecision. were estimates, effect around intervals confidence wide thus and events, or participants with relatively few studies of events, size number and of sample afunction this is often As of estimate effect. the around of uncertainty degree the Imprecision: assessed This      context explicitly stated within the recommendation. recommendation. within the explicitly stated context with the likely more was to ina context-specific recommendation, potential harm result of evidence such harm, of the likely the impact and level the of certainty on depending benefits, to of have important found also was evidence and of potential harm evidence showed intervention the Where intervention. the against to arecommendation led harm potential of evidence of benefits, of evidence absence the In favour intervention. of the in judgement of a likelihood the higher the outcomes, across of benefits evidence of the certainty the comparator. the higher or The intervention favour the not did that judgement led usually toa benefits, net small or harms, or benefits net the about Uncertainty respectively. intervention, the against infavour of or judgement of aclear likelihood agreater was there vice versa, or by women, valued highly are that outcomes for harms outweighed clearly benefits Where effects?” on evidence of the certainty is the “What and intervention?” of the effects undesirable and desirable the are “What questions: the to answer inthis domain summarized was outcomes priority the on Effects: evidence The is likely to be substantially different from the estimateeffect. of from the is likely different to substantially be Very low certainty: effect. estimate of the from the different substantially be may effect true The estimate is limited. effect in the confidence Our Low certainty: different. substantially itthat is possibility isa there but is effect, likelyestimate of close the be to the to effect true The estimate. effect in the confident We moderately are certainty: Moderate effect. of the estimate closethe that to of lies effect true the that We confident very are certainty: High Formulation of therecommendation . The GRADE-CERQual tool, which uses a similar conceptual approach approach asimilar conceptual uses which tool, GRADE-CERQual . The assessments are defined according to the GRADE approach: GRADE according to the defined are assessments We have very little confidence in the effect estimate. The true effect effect true The estimate. effect in the We confidence little have very  Values: This domain relates to the relative importance assigned to the outcomes associated with the intervention by those affected, how such importance varies within and across settings, and whether this importance is surrounded by any uncertainty. The question asked was: “Is there important uncertainty or variability in how much women value the main outcomes associated with the intervention?” When the intervention resulted in benefit for outcomes that most women consistently value (regardless of setting), this was more likely to lead to a judgement in favour of the intervention. This domain, together with the “effects” domain (see above), informed the “balance of effects” judgement.  Resources: For this domain, the questions asked were: “What are the resources associated with the intervention?” and “Is the intervention cost-effective?” The resources required to implement IV oxytocin mainly include the costs of providing supplies and training. A judgement in favour of or against the intervention was likely where the resource implications were clearly advantageous or disadvantageous, respectively.  Acceptability: For this domain, the question was: “Is the intervention acceptable to women and health-care providers?” Qualitative evidence from systematic reviews on the views and experiences of women and providers with the prevention and treatment of PPH informed the judgements for this domain (20,21). The lower the acceptability, the lower the likelihood of a judgement in favour of the intervention.  Feasibility: The feasibility of implementing this intervention depends on factors such as the resources, infrastructure and training requirements, and the perceptions of health- care providers responsible for administering it. The question addressed was: “Is it feasible for the relevant stakeholders to implement the intervention?” Qualitative evidence from the systematic reviews on women’s and providers’ views and experiences with treatment of PPH was used to inform judgements for this domain (20,21). Where major barriers were identified, it was less likely that a judgement would be made in favour of the intervention.  Equity: This domain encompasses evidence or considerations as to whether or not the intervention would reduce health inequities. Therefore, this domain addressed the question: “What is the anticipated impact of the intervention on equity?” The findings of qualitative reviews of evidence and two rapid reviews, as well as the experiences and experiences of the GDG members, were used to inform judgements for this domain (20,21). The intervention was likely to be recommended if its proven (or anticipated) effects reduce (or could reduce) health inequalities among different groups of women and their families. For each of the above domains, additional evidence of potential harms or unintended consequences are described in the Additional considerations subsections. Such considerations were derived from studies that might not have directly addressed the priority question but provided pertinent information in the absence of direct evidence. These considerations were extracted from single studies, systematic reviews or other relevant sources. The WHO Steering Group provided the EtD frameworks, including evidence summaries, summary of findings tables and other documents related to each recommendation, to the GDG members two weeks in advance of the GDG meeting. The GDG members were asked to review and provide comments (electronically) on the documents before the GDG meeting. During the GDG meeting (11–12 March 2020), which was conducted under the leadership of the GDG chairperson, the GDG members collectively reviewed the EtD frameworks, and any comments received through preliminary feedback, and formulated the recommendations. The purpose of the meeting was to reach consensus on each recommendation, including its direction and in some instances the specific context, based on explicit consideration of the range of evidence presented in each EtD framework and the judgement of the GDG members. The GDG was asked to select one of the following categories for the recommendation: ethods 2. M 2.

7 8 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth recommendation. to the opposition expressed members GDG of the None participants. of the more or quarters by three agreement as the defined consensus, on based were made Decisions considerations. these synthesize and to describe were used EtD tables available. where a literature search from by evidence supported and members GDG of the opinions and experiences the on were based equity. Considerations and acceptability, feasibility implications, resource values, stakeholders’ included criteria These recommendation. the to EtD determine framework GRADE the on based criteria additional applied GDG the of evidence, the the overall certainty and intervention of the effects undesirable and desirable the between balance addition to In the evaluating clarification. sought and summary evidence the reviewed discussed and GDG the meeting, the During 2.12 Group. Steering WHO by the managed were by invitedexperts declared of interest how conflicts and statements DOI of the asummary 3shows Annex were taken. actions further no and meeting GDG the of beginning at the of interest conflicts such declare to openly required were only experts credibility, its to the or reduce process development any to risk to guideline the pose enough significant not considered was of interest aconflict Where to meeting. the prior weeks four online were published of individuals biographies and names The independent. and objective ostensibly, and actually is, experts of its contributions the and of WHO work the assure to procedures WHO with the inaccordance were managed received statements DOI the WHO forthe handbook guideline development in outlined as of interests of conflicts severity the assessing for criteria the applied Group To process. Steering consistency, WHO ensure the development recommendation and guideline the in judgement objective expert’s an affect to enough serious were conflicts such whether determined Group Steering WHO the declared, was of interest any conflict Where invitations participate. to experts’ finalizing the before reviewed all declarations Group Steering WHO The processes. guideline-related inthe participating before and process development guideline inthe engaging before form DOI WHO astandard complete (18) experts WHO (DOI) for of interest declaration for to according guidelines the meetings and processes development guideline inWHO to participation prior interests their declare must all experts to regulations, WHO According WHO. at development of guideline part acritical are contributors and experts external other and members GDG of of interest conflicts non-financial and financial relevant of management appropriate the and disclosure The of interest. conflicts ostensible or give to rise could that actual any circumstances disclose role advisory inan serving experts that requires WHO collaborates. it with whom experts of individual integrity the protect well as to as work normative of its integrity tothe protect process arobust has WHO 2.11         Recommended: or option, and its acceptability and feasibility. and acceptability its and option, or intervention of the to related both effectiveness uncertainties and questions unanswered addresses that of research form the takes it provided scale, alarge on undertaken be still can implementation of recommendation, this With category intervention. the about uncertainties important are recommendation): there that indicates category This Recommended only in the context of rigorous research (research-context contexts. in these be implemented only should and recommendation in the specified population or setting to condition, only the is applicable intervention the that indicates category Recommended only in specific contexts (context-specific recommendation): This implemented. Not recommended: Decision-making during meeting theGDG ofManagement declarations of interests This category indicates that the intervention should be implemented. be should intervention the that indicates category This This category indicates that the intervention should not be be not should intervention the that indicates category This . All GDG members were therefore required to required were therefore members . All GDG to all participating experts. All findings from from All findings experts. to all participating 2.13 Document preparation Prior to the online meeting, the WHO Steering Group prepared a draft version of the GRADE evidence profiles, the evidence summary and other documents relevant to the GDG’s deliberation. The draft documents were made available to the participants of the meeting two weeks before the meeting for their comments. During the meeting, these documents were modified in line with the participants’ deliberations and remarks. Following the meeting, members of the WHO Steering Group drafted a full guideline document to accurately reflect the deliberations and decisions of the participants. The draft document was sent electronically to the GDG and the ERG for their final review and approval.

2.14 Peer review Following review and approval by GDG members, the final document was sent to eight external independent experts (comprising the ERG) who were not involved in the guideline panel for peer review. The WHO Steering Group evaluated the inputs of the peer reviewers for inclusion in this document. After the meeting and external peer review, the modifications made by the WHO Steering Group to the document consisted only of the correction of factual errors and improving language to address any lack of clarity. ethods 2. M 2.

9 10 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth included under the recommendation. are GDG by the discussion of the summary the reflecting remarks additional in practice, implemented appropriately and understood To is correctly recommendation the that ensure outcomes. critical of the most for “moderate” as rated was evidence supporting of the 4). (Annex certainty tables The GRADE in review summarized systematic and updated the from derived was of this intervention effectiveness the on Evidence by GDG. the adopted was following recommendation The 4). (Annex EtD inthe framework is presented recommendation, the determining in considered that were equity and acceptability, feasibility effectiveness, supporting evidence, values and preferences of stakeholders, resource requirements, cost- of the the overall certainty and effects undesirable and desirable the between balance the summarizing EtD table, The question. prioritized the for of evidence summary narrative corresponding the and recommendation the outlines following section The evidence 3.    Justification (Context-specific recommendation) administration. intramuscular to preference in recommended is oxytocin IU 10 of administration intravenous slow the access, have intravenous already vaginally birth giving women where situations In births. all for haemorrhage postpartum of prevention the for recommended is intramuscular/intravenous) [IU], units international (10 oxytocin of use The Remarks    administer oxytocin intravenously. oxytocin administer to indication), medical is it (for recommended have access another intravenous already women where instances In of oxytocin. bolus intravenous with arapid concerns safety of possible suggestive women’s well as studies as comfort), and equity health resources, on impacts and feasibility (including considerations other on emphasis its placed Group Development Guideline the outcomes, health important for oxytocin intravenous favours of effects balance the that noting While (19) this indication for by WHO recommended currently are of administration routes both and haemorrhage preventingpostpartum in is effective oxytocin intramuscular or intravenous either that acknowledged Group Development Guideline The considerations. other these outweigh administration intravenous of benefits clinical the birth, vaginal at inplace is already access intravenous However, settings. where in situations indifferent vary may also administration of intravenous feasibility The inequities. health increase can and women’s comfort impact may negatively requirements, resource additional prevention imposes haemorrhage postpartum for use oxytocin intravenous routine cost-effective, more is administration intravenous whether uncertain it While is effects. undesirable in differences clear with no morbidity, severe maternal and transfusion blood haemorrhage, severe postpartum haemorrhage, of risk postpartum the reduces oxytocin intravenous oxytocin, to intramuscular compared When outcomes. of health interms oxytocin infavour of intravenous evidence is clear There Recommendation and supporting .  The Guideline Development Group acknowledged existing WHO recommendations against the routine use of intravenous fluids during labour and childbirth, with emphasis on the widespread and unnecessary use of routine administration of intravenous fluids for all women in labour in many health facilities in low-, middle- and high-income settings that increases cost and impacts on resource use (28). The Guideline Development Group emphasized that intravenous access should not be placed routinely for the sole purpose of administering intravenous oxytocin for postpartum haemorrhage prevention.  The Guideline Development Group noted that the previous trials considered for this question have all administered an oxytocin dose of 10 IU intravenously for postpartum haemorrhage prevention during vaginal birth. However, the speed of injection ranged from 1 minute (for bolus injection) to 40 minutes (for infusion) and volume of dilution from 1 mL (for bolus injection) to 1000 mL of saline (for infusion). There is no direct evidence comparing the different regimens for administering intravenous oxytocin during vaginal birth, and there were no safety concerns (such as hypotension or tachycardia) in trials comparing slow intravenous administration of 10 IU oxytocin over 1 minute with 10 IU intramuscular oxytocin (29,30). However, observational studies in women undergoing caesarean section suggest that rapid intravenous results in harmful haemodynamic effects (30,31). Therefore, the Guideline Development Group suggests avoiding a rapid injection, and agreed that the 10 IU oxytocin dose should preferably be diluted and administered slowly.  This recommendation reflects available evidence from direct comparison of intravenous versus intramuscular oxytocin during vaginal birth. For women undergoing caesarean section, WHO currently recommends 10 IU for postpartum haemorrhage prevention without preference for intravenous or intramuscular (19).  This recommendation does not relate to the use of oxytocin for other obstetric indications (such as labour induction, labour augmentation, or treatment of postpartum haemorrhage). e c nd supporting eviden tion a a ommend c e 3. R

11 12 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth 1 be mayrequired and Context-specific toolkits tools made. be should preferences, and values their including settings, inemergency of women needs to unique the considerations Additional strategies. response with other alignment and integration the consider should recommendation current of the adaptation emergencies, of humanitarian context the In practices. evidence-based of use the to enable practitioners of health-care behaviour inthe changes including of this recommendation, use the for created be should environment enabling An groups. leadership relevant other and societies professional local agencies, Nations United of health, by ministries supported often protocols, and guidelines local revision or of existing national or development the may include processes These implementation. and of adaptation recommendations) depends on well-planned and participatory consensus-driven processes (relating policies to updated of evidence-based introduction successful The documents and tools. levels appropriate into locally local and country regional, at partners and by stakeholders to adapted be intended are and recommendations of WHO implementation support thus models These user-level and policy, health organizational relevant considerations. address models Both countries. and systems health across may within that exist and policies generic of baby, influence of the her and woman irrespective the for outcomes psychological and emotional physical, possible by to aiming best achieve the care, health of maternal quality inthe is to drive improvements models basis of these conceptual The women. of preferences and needs individual and contexts countries, to different adapted be can guidelines care intrapartum and antenatal WHO for those as such models global Existing recommendation. updated the on protocols based or revision guidelines or of existing national development the may include process existing strategy. an This on based this recommendation implement and to adapt established may be subgroups subnational and National Adaptation 4.2 Library. Health Reproductive WHO website the WHO and the available on will be also recommendation This others. among organizations, nongovernmental and agencies Nations United other centres, collaborating WHO organizations, professional of health, ministries offices, country and regional WHO through disseminated will be recommendation The 4.1 appropriate. where levels, facility care health- and country at programmes and into packages translated care be recommendation this that crucial is therefore It birth. giving to all women services high-quality provide can of all levels facilities to they ensure health-care at capacity the to and strengthen care health to women’s maternal to access increase need is avital There levels. local and national international, the at women involved pregnant provision for inthe of care all stakeholders by to are considered be of this recommendation implementation and dissemination The 4. languages. into these any of willingfull office recommendation translatethe to to regional any WHO provided be will assistance offices. regional Technical WHO the through disseminated and languages into Nations six translated will the United be document recommendation The staff. health perinatal and maternal by WHO attended conferences scientific or meetings during disseminated routinely also are recommendations Updated Available at: www.who.int/rhl.

implementation of therecommendation Dissemination, adaptation and Recommendation dissemination dissemination Recommendation 1 in addition to standard tools to support the implementation of the recommendation in humanitarian emergencies by stakeholders.

4.3 Implementation considerations  Oxytocin should only be given by skilled health personnel who have been trained to safely administer injectable uterotonics.  Oxytocin is relatively inexpensive and widely available; however, it requires cold chain, refrigerated transport and storage (2–8 °C). In settings where this cannot be guaranteed, the quality, efficacy and effectiveness of oxytocin may be adversely affected.  It is advised that programmes to implement uterotonics for PPH prevention ensure women are adequately informed in advance about the need to use a uterotonic to prevent PPH, the available uterotonic options, the possible side effects of these options and their rights to choose what care they receive.  An enabling environment should be created for the implementation of this recommendation, including education to support behaviour change among skilled health personnel to facilitate the use of evidence-based practices.  National health systems need to ensure that supplies of good-quality uterotonics and the necessary equipment are available wherever maternity services are provided. This includes establishing robust and sustainable regulatory, procurement and effective cold chain, and logistics processes that can ensure good-quality medicines and equipment are obtained, transported and stored correctly.  Procurement agencies at all levels of supply chains should procure only quality-assured uterotonic medicines, that are labelled for storage at 2–8 °C, in single-use ampoules or vials of oxytocin of 10 IU per mL (10 IU/mL). While some manufacturer labelling may seem to indicate that oxytocin is stable at room temperature, stability may not have been tested in the much warmer conditions that may be prevalent in some countries, and different formulations have different stability characteristics. To prevent its degradation and to safeguard its quality, oxytocin should always be stored in refrigeration, regardless of labelling.

5. Research implications

The GDG identified important knowledge gaps that need to be addressed through primary research, which may have an impact on this recommendation. The following question was identified as one that demands urgent priority:  What is the optimal effective regimen of IV oxytocin for PPH prevention after vaginal birth? tions ca impli h c a r ese 5. R 5.

13 14 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth recommendation included in this guideline. inthis guideline. included recommendation to the of adherence overall an assessment provides indicator This birth. giving all women by divided of third labour the stage uterotonics during prophylactic receiving of women number the as is calculated uterotonic “prophylactic coverage indicator” suggested The prevention (19) of PPH and monitoring the for indicator aprocess as used uterotonics be coverage of the prophylactic that recommends WHO to regard With prevention, PPH guideline. inthis contained of interventions use the on data relevant to the obtain used be could audits criterion-based or audits clinical series, time Interrupted States. Member WHO individual of policies national on impact its to term assess to medium short evaluated inthe and collected will be recommendation of the implementation regional-level and country- on data Ageing, and Health Adolescent Child and Newborn, of Maternal, Department WHO the and Research and Health Reproductive and of Sexual Department WHO of the teams evaluation and monitoring with the collaboration In targets. agreed with locally aligned be should that and indicators and criteria quality-of-care to define used be can that measures outcome and facilities inhealth care newborn (32) and of maternal Standards quality improving for document WHO The care. newborn and of maternal quality improve and the monitor to efforts of broader part as levels, regional and country service, health the at monitored will be of this recommendation impact and implementation The 6.2 4. insection considerations implementation under provided are implementation facilitating and barriers these addressing Various for strategies        to application: their following the potential barriers to consider may wish stakeholders system health this recommendation, to implement of efforts part As providers. inhealth-care change behaviour encourage can packages, care postpartum immediate and existing intrapartum into this recommendation by including of care, Standardization implementation. facilitate its and impact its increase would recommendation the on providing training and curricula training updating that noted GDG The of uterotonic storage drugs. and procurement sustainable for resources requires recommendation this evidence-based Implementing 6.1 6.        recommended practices (such as patient records and registers). (such and records patient as practices recommended monitor and to document designed systems management information of health lack pathways; and management PPH trigger order to in PPH, areexperiencing who women identify to mechanisms of effective lack and uterotonics); gloves syringes, (such needles, as medicines and supplies equipment, of essential lack temperature-sensitive uterotonics); for refrigeration and (such electricity as interventions to support of infrastructure lack practices; evidence-based to of non-evidence-based use the from to changing personnel care of skilled resistance managers; systems and personnel care skilled among interventions inrecommended of changes of understanding lack recommendedand support practices; supervise skills to and implement, expertise necessary with the resources of human lack

Applicability issues Applicability Anticipated impact on theorganization of care resources and Monitoring and evaluating guideline implementation evaluating guideline and Monitoring provides a list of prioritized input, output output alist of input, prioritized provides . The use of other locally agreed and more specific indicators (for example, the proportion of pregnant women with IV access already in place given IV oxytocin after vaginal birth) may be necessary to obtain a more complete assessment of the quality of care related to the prevention and treatment of PPH. WHO has developed specific guidance for evaluating the quality of care for severe maternal complications (including PPH) based on the near miss and criterion-based clinical audit concepts (33). Monitoring of the quality of uterotonic drugs available in low-resource settings may help to guide skilled health personnel in selecting the most effective uterotonic option for PPH prevention in the context in which they are working.

7. Updating the recommendation

The Executive GSG convenes annually to review WHO’s current portfolio of maternal and perinatal health recommendations and to help WHO prioritize new and existing questions for recommendation development and updating. Accordingly, this recommendation will be reviewed along with other recommendations and prioritized as needed by the Executive GSG. If new evidence that could potentially impact the current evidence base is identified, the recommendation may be updated. If no new reports or information is identified, the recommendation may be revalidated. Following publication and dissemination of the updated recommendation, any concerns about the validity of the recommendation should be promptly communicated to the guideline implementers, in addition to any plans to update the recommendation. WHO welcomes suggestions regarding additional questions for inclusion in the updated recommendation. Please email your suggestions to [email protected]. tion a ommend c ting the re a pd 7. U 7.

15 16 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. 8. References 2018;46(D1):D1074–82. doi:10.1093/nar/gkx1037. Acids Res. Nucleic 2018. for database to update DrugBank the amajor 5.0: DrugBank al. et JR, Grant A, Marcu Lo EJ, AC, YD, Guo Feunang DS, Wishart essentialmedicines/en/, accessed 14 July 2020). (https://www.who.int/medicines/publications/ 2019 World Organization; Health Geneva: list. –21st medicines list of essential model World Organization Health 109X(18)30078-0. doi:10.1016/S2214- 2018;6(5):e548–54. Health. Glob Lancet a multilevel analysis. partum: post and pregnancy during with severe anaemia inwomen mortality maternal OT, Vogel of Risk al. et Oladapo BM, J, N, Fernandez-Felix J, Morisaki Zamora J, Daru 2010;53(1):147–56. Clin Gynecol. Obstet doi:10.1097/GRF.0b013e3181cc406d.causes. and factors, risk Y,Oyelese epidemiology, CV. Ananth hemorrhage: Postpartum 2013;381(9879):1747–55.Lancet. doi:10.1016/S0140-6736(13)60686-8. study. Health): across-sectional Newborn and Maternal on Survey Multicountry (the WHO mortality of maternal reduction for interventions essential beyond P, JP,Souza Lumbiganon Vogel Moving G, al. et Carroli Z, AM, J, Qureshi Gulmezoglu 2020). 14 July accessed (https://apps.who.int/iris/handle/10665/277276, 2018 World Organization; Health haemorrhage. prevention of the postpartum for Uterotonics recommendations: WHO 2008;22(6):999–1012. doi:10.1016/j.bpobgyn.2008.08.004. Clin Gynaecol. Res Obstet review. asystematic Pract Best haemorrhage: of postpartum Epidemiology AM. Gulmezoglu E, Abalos C, Cuesta G, Carroli professionals/en/, 2020). July 9 accessed (https://www.who.int/reproductivehealth/publications/statement-competent-mnh- 2018 World Organization; IPA. Health Geneva: and FIGO ICN, ICM, UNICEF, by WHO, UNFPA, statement joint 2018 the childbirth: during providing care personnel health skilled of FIGO, IPA. UNICEF, Definition WHO, ICN, UNFPA, ICM, 2015;122(8):1045–9. doi:10.1111/1471-0528.13451. BJOG. vision. WHO –the newborns and women pregnant for of care Quality al. et OT, R, Bahl Tuncalp Oladapo C, AM, Ö, Gulmezoglu Were MacLennan WM, mortality/en/, 2020). 9July accessed 2012 (https://www.who.int/gender-equity-rights/knowledge/reduce-maternal- Assembly; York New General Nations United session. twentieth (NY): Council, Rights Human mortality. and morbidity maternal preventable to reduce programmes and of policies to implementation the approach rights-based of ahuman application the on guidance Rights.Human Technical for Commissioner High Nations United the of Office (https://unstats.un.org/sdgs/report/2019/, 9 accessed July 2020). York New 2019 Nations; United (NY): report. Goals Development Sustainable The doi:10.1016/S2214-109X(14)70227-X. 2014;2(6):e323–33. Health. Glob Lancet analysis. systematic aWHO death: maternal of causes Global Tuncalp al. et J, Daniels A, D, AB, Chou O, Gemmill Moller L, Say 2020). 9July accessed (https://apps.who.int/iris/handle/10665/327596, 2019 World Organization; Health Geneva: executive Division: Population summary. Nations United the and Group World Bank to 2017: by 2000 WHO, UNICEF, estimates Trends UNFPA, mortality inmaternal 14. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, et al. PubChem substance and compound databases. Nucleic Acids Res. 2016;44(D1):D1202–13. doi:10.1093/nar/ gkv951. 15. 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. 16. Vogel JP, Dowswell T, Lewin S, Bonet M, Hampson L, Kellie F, et al. Developing and applying a ‘living guidelines’ approach to WHO recommendations on maternal and perinatal health. BMJ Glob Health. 2019;4(4):e001683. doi:10.1136/ bmjgh-2019-001683. 17. Executive Guideline Steering Group for updating WHO maternal and perinatal health recommendations. Geneva: World Health Organization; 2019 (https://www.who.int/ reproductivehealth/publications/updating-mnh-recommendations/en/, accessed 9 July 2020). 18. WHO handbook for guideline development, second edition. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/145714, accessed 9 July 2020). 19. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva: World Health Organization; 2012 (https://www.who.int/ reproductivehealth/publications/maternal_perinatal_health/9789241548502/en/, accessed 9 July 2020). 20. Downe S, Finlayson K, Oladapo OT, Bonet M, Gulmezoglu AM. What matters to women during childbirth: a systematic qualitative review. PloS One. 2018;13(4):e0194906. doi:10.1371/journal.pone.0194906. 21. 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. PloS One. 2019;14(5):e0215919. doi:10.1371/journal. pone.0215919. 22. Lawrie TA, Rogozinska E, Sobiesuo P, Vogel JP, Ternent L, Oladapo OT. A systematic review of the cost-effectiveness of uterotonic agents for the prevention of postpartum hemorrhage. Int J Gynaecol Obstet. 2019;146(1):56–64. doi:10.1002/ijgo.12836. 23. Meher S, Cuthbert A, Kirkham JJ, Williamson P, Abalos E, Aflaifel N, et al. Core outcome sets for prevention and treatment of postpartum haemorrhage: an international Delphi consensus study. BJOG. 2019;126(1):83–93. doi:10.1111/1471- 0528.15335. 24. Oladapo OT, Okusanya BO, Abalos E. Intramuscular versus intravenous prophylactic oxytocin for the third stage of labour. Cochrane Database Syst Rev. 2018;9:CD009332. doi:10.1002/14651858.CD009332.pub3. 25. GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University (developed by Evidence Prime, Inc.); 2015 (https://www.gradepro.org, accessed 14 July 2020). 26. Alonso-Coello P, Schunemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016;353:i2016. doi:10.1136/bmj.i2016. 27. Lewin S, Booth A, Glenton C, Munthe-Kaas H, Rashidian A, Wainwright M, et al. Applying GRADE-CERQual to qualitative evidence synthesis findings: introduction to es the series. Implement Sci. 2018;13(Suppl 1):2. doi:10.1186/s13012-017-0688-3. c eferen 8. R

17 18 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth 33. 32. 31. 30. 29. 28. (https://apps.who.int/iris/handle/10665/44692, accessed 14 July 2020). 14 July (https://apps.who.int/iris/handle/10665/44692, accessed 2011 World Organization; Health Geneva: health. maternal for approach near-miss WHO the complications: severe for pregnancy of care Evaluating quality the 2020).July adolescent/documents/improving-maternal-newborn-care-quality/en/, 14 accessed (https://www.who.int/maternal_child_ 2016 World Organization; Health Geneva: facilities. inhealth care newborn and of maternal quality improving for Standards 2002;11(3):156–9. Anesth. J Obstet doi:10.1054/ijoa.2002.0970. Int anaesthesia. spinal under section caesarean during by oxytocin caused changes Haemodynamic R. Johnson J, GD, O’Riordan Shorten C, Calow M, Dresner AJ, Pinder doi:10.1093/bja/ael302. 2007;98(1):116–9. JAnaesth. Br section. Caesarean undergoing women on infusion or i.v.givenas of oxytocin bolus effects Haemodynamic GM. Cooper Koh SH, JS, Thomas 2016;84(5):306–13. Mex. Obstet trial]. Ginecol clinical randomised of oxytocin: schemes Three labor: Pedraza-Aviles [Active AG. M, of third ofNeri-Mejia the stage management randomised controlled doi:10.1136/bmj.k3546. trial. 2018;362:k3546. BMJ. delivery: vaginal at haemorrhage to prevent postpartum oxytocin intravenous F, Conlan-Trant N, Boland Adnan versus C, DJ. Intramuscular Murphy McCormick R, Annex 1. External experts and WHO staff involved in the preparation of the recommendation

Participants at the Who Guideline Development Group (Gdg) Meeting (11–12 March 2020)

GUIDELINE DEVELOPMENT GROUP Ashraf NABHAN (GDG) Professor Oluwarotimi Ireti AKINOLA Department of Obstetrics and Gynecology President Ain Shams University Society of Gynaecology and Obstetrics in Cairo, Egypt Nigeria (SOGON) Mari NAGAI Abuja, Nigeria Deputy Director, Health System Team Lead Melania AMORIM Bureau of International Health Cooperation Obstetrician & Gynaecologist National Center for Global Health and Instituto Paraibano de Pesquisa Professor Medicine Joaquim Amorim Neto and Instituto de Tokyo, Japan Medicina Integral Professor Fernando Hayfaa WAHABI * Figueira Professor and Chair Paraiba, Brazil Evidence-based Healthcare and Knowledge Brendan CARVALHO * Translation Chief, Division of Obstetric Anaesthesia College of Medicine, King Saud University

Riyadh, Saudi Arabia tion Department of Anaesthesiology, a Perioperative and Pain Medicine Dilys WALKER * Stanford University School of Medicine Professor ommend

Stanford, United States of America (USA) Department of Obstetrics, Gynecology & c Catherine DENEUX-THARAUX * Reproductive Sciences Obstetrical, Perinatal and Pediatric UCSF Epidemiology Research Team San Francisco, USA

Centre of Research in Epidemiology and Andrew WEEKS tion of the re a

Statistics Sorbonne r Professor a Paris, France University of Liverpool Tippawan LIABSUETRAKUL * Liverpool, United Kingdom of Great Britain Professor of Epidemiology and Northern Ireland (United Kingdom) Faculty of Medicine, Prince of Songkhla * Participated by video conference. University Songkhla, Thailand OBSERVERS ff involved in the prep

Martin MEREMIKWU * Deborah ARMBRUSTER * a Professor of Paediatrics & Clinical Senior Maternal and Newborn Health Epidemiology Advisor United States Agency for International University of Calabar nd WHO st Calabar, Nigeria Development (USAID) Bureau for Global Health Suellen MILLER * Jakarta, Indonesia

Director, Safe Motherhood Program l experts a Department of Obstetrics, Gynecology and Carlos FUCHTNER * a Reproductive Sciences President xtern University of California, San Francisco International Federation of Gynaecology San Francisco, USA and Obstetrics (FIGO) Santa Cruz, Bolivia Annex 1. E

19 20 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth *Participated by conference. video Stockholm, Sweden (ICM) of Midwives Confederation International Representative WIKLUND Ingela ** Unable to Unable attend ** by* Participated conference video Liverpool, United Kingdom University of Liverpool Editorial Office Group Childbirth and Pregnancy Cochrane Research Associate (Methodologist) WILLIAMS Myfanwy Liverpool, United Kingdom University of Liverpool Editorial Office Group Childbirth and Pregnancy Cochrane Editor Managing ** KELLIE Frances Liverpool, United Kingdom University of Liverpool Editorial Office Group Childbirth and Pregnancy Cochrane Research Associate Leanne (Methodologist) JONES Kingdom United Preston, Lancashire of Central University (ReaCH) Unit Health and inChildbirth Research Research Associate Kenneth FINLAYSON (Methodologist) Argentina Rosario, Perinatales Estudios de Rosarino Centro ** DIAZ Virginia Argentina Rosario, Perinatales Estudios de Rosarino Centro Director Vice Edgardo ABALOS * (ESG) GROUP SYNTHESIS EVIDENCE Shanghai, ChinaShanghai, University Fudan Health, of Public School Health Adolescent Child and of Maternal, Department XU Qian Chile Santiago, Chile de Católica Universidad Pontificia Medicina Facultad de Gynaecology and Obstetrics Department Chairman Enrique OYARZUN Islamabad, Pakistan Sciences Institute of Medical Pakistan (MCH) Centre Child Health and Mother Professor of Obstetrics Gynaecology and Syeda Batool MAZHAR Africa South Cape, Eastern of Health Department Cape Eastern Hare/ of Fort of Witwatersrand/University the University Unit Care Research Effective Director HOFMEYR Justus Liverpool, United Kingdom Street Crown Trust Women’s NHS Liverpool Hospital University of Liverpool Group Childbirth & Pregnancy Cochrane Editor for Consumer GYTE Gill AustraliaMelbourne, TrobeLa University Nursing Midwifery, and of Nursing Professor Christine EAST (ERG) GROUP REVIEW EXTERNAL WHO COUNTRY AND REGIONAL WHO STEERING GROUP OFFICERS Department of Sexual and Reproductive Nino BERDZULI** Health and Research Sexual and Reproductive Health, Fernando ALTHABE Noncommunicable Diseases and life-course Medical Officer WHO Regional Office for Europe Maternal and Perinatal Health Copenhagen, Denmark Sexual and Reproductive Health and Bremen DE MUCIO** Research Sexual and Reproductive Health Tina LAVIN WHO Regional Office of the Americas Technical Officer Montevideo, Uruguay Maternal and Perinatal Health Hayfa ELAMIN Sexual and Reproductive Health and Regional Adviser, Reproductive, Maternal Research Health and Ageing Olufemi T. OLADAPO WHO Regional Office for the African Region Unit Head a.i. Harare, Zimbabwe Maternal and Perinatal Health Chandani Anoma JAYATHILAKA** Sexual and Reproductive Health and Family Health, Gender and Life Course Research WHO Regional Office for South-East Asia Joshua P. VOGEL New Delhi, India Consultant Ramez Khairi MAHAINI** Maternal and Perinatal Health Reproductive and Maternal Health Sexual and Reproductive Health and WHO Regional Office for the Eastern Research Mediterranean Mariana WIDMER

Cairo, Egypt tion Technical Officer a Howard SOBEL** Maternal and Perinatal Health Reproductive, Maternal, Newborn, Child Sexual and Reproductive Health and Research ommend and Adolescent Health Division c of NCD and Health through Life-Course Department of Maternal, Newborn, Child, Regional Office for the Western Pacific Adolescent Health and Ageing Manila, Philippines Maurice BUCAGO

Claudio SOSA** tion of the re Medical Officer a r

Regional Advisor, AMRO/CLP Maternal Health Unit, Maternal, Newborn, a Sexual and Reproductive Health Child and Adolescent Health and Ageing WHO Regional Office for the Americas Montevideo, Uruguay

** Unable to attend ff involved in the prep a nd WHO st l experts a a xtern Annex 1. E

21 22 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth 1           outcomesImportant    outcomes Critical Annex 2.              nausea, vomiting, headache, abdominal pain, hypotension, shivering, fever and diarrhoea. diarrhoea. and fever shivering, hypotension, pain, abdominal headache, vomiting, nausea, including: treatment, requiring side-effect or intervention the of side-effect any includes This Maternal satisfaction Maternal well-being Side-effects Breastfeeding anaemia Postpartum (mL) loss Blood uterotonics of additional Use mL ≥500 haemorrhage Postpartum shock Severe morbidity: maternal intensive admission unit care morbidity: Severe maternal transfusion Blood mL PPH ≥ 1000 Maternal death 1 decision-making Priority outcomes used in Annex 3. Summary and management of declared interests from GDG members

Expertise contributed to Management of conflict of Name Declared interest guideline development interest Oluwarotimi I Content expert and None declared Not applicable Akinola end-user Melania Amorim Content expert and None declared Not applicable end-user Brendan Carvalho Content expert and Serves as technical consultant The conflict was end-user for Gauss Surgical (company not considered that measures peripartum and serious enough to operative blood loss). affect Guideline Development Group Receives share options from (GDG) membership or Gauss Surgical. participation. Catherine Deneux- Content expert and None declared Not applicable Tharaux end-user Tippawan Content expert and None declared Not applicable Liabsuetrakul end-user Martin Meremikwu Content expert and None declared Not applicable end-user Suellen Miller Content expert and Serves as a technical advisor The conflict was not end-user to the Blue Fuzion Group who considered serious manufactures and distributes enough to affect one brand of non-pneumatic GDG membership or anti-shock garment, the participation. LifeWrap. UCSF receives a royalty for the trademark. Ashraf Nabhan Content expert and None declared Not applicable implementer Mari Nagai Content expert and None declared Not applicable end-user Hayfaa Wahabi Content expert and None declared Not applicable end-user Dilys Walker Content expert and Co-founder and President The conflict was not end-user of the nongovernmental considered serious red interests from GDG members

organization PRONTO enough to affect a l

International. PRONTO designs GDG membership or c and implements simulation and participation. team training for obstetric and neonatal emergencies, including

postpartum haemorrhage. gement of de a

Professor Walker has donated n a funds to the organization.

PRONTO International has the nd m rights to the low-tech birth ry a ry simulator, PARTO Pants and a the PRONTO Pack simulation umm training kit. Annex 3. S

23 24 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth Andrew Weeks N ame end-user and expert Content guideline development E xpertise contributed to contributed xpertise D a share of the profits. of the a share receive would Weeks Professor co-inventor, as but, holder device patent is the University The of Liverpool. University the to grants research Kingdom) (United by NIHR funded Both study. development of the investigator wellas chief as haemorrhage postpartum device to treat Butterfly the co-inventor of and COPE trial, Chief investigator of the eclared interest eclared interest M participation. or membership GDG to affect enough serious considered not was conflict The anagement of conflict of conflict of anagement Annex 4. Evidence to Decision framework

Question Following is the question of interest in PICO (population (P), intervention (I), comparator (C), outcome (O)) format:  For women in the third stage of labour (P), does administration of IV oxytocin for postpartum haemorrhage (PPH) prevention (I) compared with IM oxytocin (C) improve maternal and infant outcomes (O)? Problem: Preventing the onset of PPH Perspective: Clinical practice recommendation – population perspective Population (P): Women in the third stage of labour with vaginal birth Intervention (I): IV oxytocin Comparator (C): IM oxytocin Setting: Hospital or community setting Subgroups: By type of IV administration; by type of further management.

Priority outcomes (O):1 Critical outcomes  Maternal death  PPH ≥ 1000 mL  Blood transfusion

Important outcomes  Severe maternal morbidity: intensive care unit (ICU) admission  Severe maternal morbidity: shock  PPH ≥ 500 mL  Use of additional uterotonics  Blood loss (mL)  Postpartum anaemia  Breastfeeding  Side-effects2  Maternal well-being  Maternal satisfaction mework a ision fr c e e to D e to c 1 These outcomes reflect the prioritized outcomes used in the development of this recommendation, in WHO recommendations for the prevention and treatment of postpartum haemorrhage (2012). The viden outcomes “maternal well-being” and “maternal satisfaction” have been added as part of this update. 2 This includes any side-effect of the intervention or side-effect requiring treatment, including

nausea, vomiting, headache, abdominal pain, hypotension, shivering, fever and diarrhoea. Annex 4. E

25 26 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth Research evidence evidence Research outcomes? priority preventionon the PPH for IM oxytocin versus of IV oxytocin effect is the What Effects of interventions Assessment included seven randomized trials (7840 women) (4) trials (7840 seven randomized included review, systematic of aCochrane update which an from derived was birth vaginal prevention followingPPH of the for IM oxytocin of IV versus effects the on Evidence of studies characteristics and Source roller clamp fully open, with women receiving IV oxytocin 10 IU over 1 minute. over 1minute. IU 10 IVoxytocin receiving with women open, fully clamp roller with the infusion agravity-driven through saline in500 mL 10 IU IVoxytocin receiving women combining meta-analysis, for IVarms two the review pooled Cochrane – the (one over 2 minutes slowly arms administered three solution trial had trial). largest The arate at (one of 12 mL/min solution saline of saline trial);trial); in10 mL in500 mL trials: (one over arate at (three ofacross 1minute 1 mL/min saline trials); in1000 mL differed of IVoxytocin of rates administration The oxytocin. IM as frame time same within the given of IVoxytocin, 10 IU All trials used birth. following the immediately or shoulder anterior of the birth with the either oxytocin, of IM 10 IU All seven trials used wise comparison. to make point pair- time asingle each at IVgroups and groups IM the review combined The cord. of the clamping at and shoulder anterior of the birth the at IVbolus and IM of third labour. take inthe four-arm not stage did place The one trial compared because inclusion for were eligible arms two only trial, three-arm other the In comparison. into pair-wise asingle were combined IVarms the trials, of these one In IVinfusion. an and IVbolus with an oxytocin IM four-arm trialscompared both three-arm The trial. a was one trials and were three-arm two trials, were two-arm four seven trials, the Of unclear. study, final inthe again this was and, implemented not was management active massage). of uterine studies, use two the In mention trials also two and cord clamping; trials delayed two cord (all traction; controlled studies trials used of these included of the infour actively managed was clear.this not was of third labour stage The trial, remaining inthe and, allocation clinicians to or treatment the women mask not Two trials did four while to all women, aplacebo women) administered trials (1555 labour. were inactive women the when was it suggests available information the though occurred, randomization as when to specific were not two and ward inlabour; while labour or unit assessment to an were admitted women when randomized three imminent; was delivery when or labour were inactive women when either trials randomized two inlabour: women were term). at (although women ages most All trials recruited all at gestational women included three other the and term at women trials included four only; pregnancies with singleton women All trials included total of the sample. 63% trial contributed to largest 4913; the 66 from trials ranged inthe included of women number The (two hospitals). Egypt except for were single-centre Turkey and Thailand Mexico, Ireland, (two trials), 2019. and 2010 All trials between ofthird labour). Egypt, stage inArgentina, Trials settings inhospital were conducted the after IVinfusion theyoxytocin were an given because trial were excluded another from 23 and recruitment, after section by caesarean they gave birth because included trial were not one from women 40 were analysed; women seven trials (data 7777 for Summary of evidence Summary . Data were extracted from all from were. Data extracted Effects of IV oxytocin compared with IM oxytocin Maternal death: It is unclear whether the route of administration of oxytocin has an impact on the risk of this outcome as there were no maternal deaths in either group (very low certainty). PPH ≥ 1000 mL: Moderate-certainty evidence suggests that the risk of this outcome is probably decreased with IV oxytocin when compared with IM oxytocin (four trials, 6681 women; 47/3692 versus 69/2989; average risk ratio [RR] 0.65, 95% confidence interval [CI] 0.39 to 1.08). However, the 95% CI crosses the line of no effect. Blood transfusion: High-certainty evidence suggests that women are less likely to need a blood transfusion if they receive IV oxytocin when compared with IM oxytocin (four trials, 6684 women; 19/3693 versus 40/2991; average RR 0.44, 95% CI 0.26 to 0.77). Severe maternal morbidity – ICU admission: The Cochrane review reported a combined outcome of serious maternal morbidity; however, 94% of the pooled effect estimate came from one trial reporting high-dependency unit admissions. Moderate- certainty evidence suggests that IV oxytocin probably decreases the risk of this outcome when compared with IM oxytocin (four trials, 7028 women; 9/3 865 versus 20/3163; average RR 0.47, 95% CI 0.22 to 1.00). However, the 95% CI touches the line of no effect. PPH ≥ 500 mL: High-certainty evidence suggests that the risk of blood loss ≥ 500 mL decreases when women receive IV oxytocin compared with IM oxytocin (six trials, 7731 women; 201/4 217 versus 253/3514; average RR 0.78, 95% CI 0.66 to 0.92). Use of additional uterotonics: Low-certainty evidence suggests that the need for additional uterotonics may decrease with IV oxytocin when compared with IM oxytocin (six trials, 7327 women; 179/4014 versus 207/3313; average RR 0.78, 95% CI 0.49 to 1.25). However, the 95% CI crosses the line of no effect. Blood loss: Six trials (7541 women) in the Cochrane review reported on mean blood loss. The review authors did not pool the data to perform a meta-analysis because the standard deviations (SDs) in the six studies varied considerably. The individual studies suggest that mean blood loss may decrease with IV oxytocin compared with IM oxytocin. However, the review authors observed that the mean blood loss was low across studies, and the difference between the groups is unlikely to be clinically important. The studies contributing data to this outcome varied in their risk of bias, and only two of six trials were at low risk of bias. Postpartum anaemia: High-certainty evidence suggests that there is little or no difference in the incidence of postpartum anaemia in women who have received IV or IM oxytocin (three trials, 6178 women; 227/3444 versus 222/2744; average RR 0.99, 95% CI 0.84 to 1.16). Breastfeeding: High-certainty evidence suggests that the route of administration of oxytocin in the third stage of labour makes little or no difference to whether women

are not breastfeeding at hospital discharge (one trial, 1035 women; 228/517 versus mework 238/518; average RR 0.96, 95% CI 0.84 to 1.10). a Side-effects: Moderate-certainty evidence suggests that IV oxytocin probably ision fr c

decreases the risk of any adverse effect reported when compared with IM e administration (one trial, 1035 women; 21/517 versus 27/518; average RR 0.78, 95% CI

0.45 to 1.36). However, the 95% CI crosses the line of no effect. D e to c In terms of specific side-effects, moderate-certainty evidence suggests that the route of oxytocin administration probably makes little or no difference tohypotension (four viden trials, 6468 women; 389/3585 versus 321/2883; average RR 1.01, 95% CI 0.88 to 1.15) and tachycardia (two trials, 1513 women; 75/756 versus 85/757; average RR 0.89, Annex 4. E

27 28 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth How substantial are the undesirable anticipated effects of IV oxytocin versus IM oxytocin? versus of IV oxytocin effects anticipated undesirable the are substantial How Undesirable effects Judgement IM oxytocin? versus of IV oxytocin effects anticipated desirable the are substantial How effects Desirable Additional considerations Don’t know headache 95% to CI 0.06 15.98),risk of to the difference no or may make little IVoxytocin while to nausea difference no route or may the that make little to suggests 95% 1.16). CI evidence 0.68 Low-certainty has on diarrhoea on has administration route the of 95%oxytocin to CI 0.08 2.06). effect what is unclear It shivering and to 3.34) 1515 women; 9/756 versus 19/759; 9/756 versus women; 0.47, RR 1515 to 1.04). 95% CI 0.22 trials, (two effect of no line the 95% the CI crosses with inrisk IVoxytocin, decrease aprobable suggests morbidity However, maternal serious for estimate point the while 95% to CI 0.43 0.94). 0.64, 60/757; average RR versus 38/755 women; (two 1512 trials, oxytocin with IM compared ≥ 1000 mL of risk PPH the decreases of IVoxytocin administration that trials low at of risk from biassuggest Results morbidity. maternal serious and ≥1000 mL PPH outcomes the for bias, ofrisk selection to trials low at restricted analysis asensitivity conducted review authors Cochrane The management. of further by type of subgroups comparison labour). ameaningful However, insize were to too imbalanced support subgroups the of third of the stage (with management active management without or of further type by morbidity maternal serious and ≥1000 mL PPH for results review analysed also The Subgroup analyses by type of management by IV infusion. oxytocin trials administering the in no events were there because morbidity maternal serious for unclear were effects subgroup The loss. severe blood for subgroups the between of adifference evidence infusion). no was or (bolus There morbidity) of IVadministration maternal by type serious and (PPH ≥1000 mL outcomes two for results the review analysed The of IV administration by type analyses Subgroup review. Cochrane inthe reported were not shock outcomes priority The this outcome. trials reported included Maternal satisfaction: No sizes were relatively small. sample while outcomes, these on trials reporting inthe events were no there because vomiting low certainty) and women; 480 trial, — (two trials, 1515 women; 3/756 versus 4/759; average RR 0.75, 95% 0.75, CI average RR 0.17 4/759; versus 3/756 women; (two 1515 trials, (one trial, 480 women; low certainty), (one women; fever 480 trial, Varies — (two trials, 1515 women; 2/756 versus 5/759; average RR 0.40, 0.40, average RR 5/759; versus 2/756 women; (two 1515 trials, (two trials, 1515 women; 1/756 versus 1/759; average RR 1.00, 1.00, average RR 1/759; versus 1/756 women; (two 1515 trials, abdominal pain , abdominal Trivial — , hypertension (two trials, 1515 women; low certainty) women; (two 1515 trials, Small — and maternal well-being and (> 38 Moderate ✓ ° C reported) (one C reported) Large — Judgement — — — — — ✓ Don’t know Varies Large Moderate Small Trivial

Certainty of the evidence What is the overall certainty of the evidence on effects of IV oxytocin versus IM oxytocin?

— — — ✓ — No included Very low Low Moderate High studies

Additional considerations

None.

Values Is there important uncertainty about, or variability in, how much women (and their families) value the main outcomes associated with the route of oxytocin for PPH prevention?

Research evidence

In a review of qualitative studies evaluating “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) (5). 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) (6). 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 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 mework management (moderate/low confidence). In addition, it was found that women are a 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 ision fr c PPH and the negative impact this may have on their ability to breastfeed (moderate/low e confidence). e to D e to c viden Annex 4. E

29 30 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth Research evidence (costs) requirements prevention? PPH for resource the are large How of IVoxytocin Resources Judgement oxytocin? IM or favour IV oxytocin effects undesirable and desirable between balance the Does of effects Balance Judgement Additional considerations Additional considerations Don’t know Important uncertainty uncertainty Important PPH (7) preventto with IV oxytocin compared IM of oxytocin cost-effectiveness and costs the on evidence direct review until no 2020A systematic literature of updated found the None. (9) reported have been expiry and compromise to heat due wastage and supplies oxytocin (8) settings low-resource available inmany readily not are which transport, and storage refrigerated require oxytocin IM IVand Both higher- and between lower-resource likelywould settings. differ cost-effectiveness the Group However, cost-effective. Development (GDG)noted more that be Guideline the would IV effects), that possible oxytocin it is adverse and ICU admission transfusion, (such costs blood as with management associated are that outcomes priority on effectiveness in their IM and oxytocin IV between differences the Considering IVfluids). and (such cannulae as IVequipment for to need the due cost increase may slightly which access, intravenous requires of IVoxytocin administration the However, personnel. health by skilled administration require oxytocin IM IVand Both — . or variability or — . Varies — Possibly important Possibly important Favours IM IM Favours uncertainty or or uncertainty oxytocin variability — — favours IM IM favours Probably oxytocin — Probably no important important no Probably uncertainty or or uncertainty . Concerns about the quality of quality the about . Concerns variability Does not not Does favour favour either either ✓ — favours IV IV favours Probably oxytocin — uncertainty or or uncertainty No important important No variability — Favours IV IV Favours oxytocin ✓ Main resource requirements

Resource Description Staff Oxytocin requires parenteral administration (IV or IM) by skilled health-care personnel. Training Training to administer injections, and to monitor and manage expected and unexpected side-effects, is part of standard maternity staff training. However, some additional training may be required if a route of administration of oxytocin is introduced in settings where it has not previously been available. Supplies Oxytocin indicative cost: Cost per 10 IU: US$ 0.22–1.19 (10,11) IM administration: Needle and syringe IV administration:  IV-giving/infusion set, with needle  Sterile, disposable IV cannula  IV fluids. Equipment and Cold chain storage and transport costs: Cost per birth is possibly infrastructure US$ 0.84 in a low-resource setting (12). Time IM administration takes 2 minutes. IV administration takes longer, if an IV cannula needs to be put in place for this purpose (13). Supervision and Supervision and monitoring to ensure appropriate use, stock monitoring availability and quality.

Resources required Judgement — — — ✓ — — — Don’t know Varies Large costs Moderate Negligible Moderate Large costs costs or savings savings savings

Certainty of the evidence on required resources What is the certainty of the evidence on costs?

Judgement ✓ — — — — No included Very low Low Moderate High studies

Cost-effectiveness Judgement mework ✓ — — — — — — a Don’t know Varies Favours IM Probably Does not Probably Favours IV oxytocin favours IM favour favours IV oxytocin ision fr

oxytocin either oxytocin c e e to D e to

Equity c What would be the impact of IV oxytocin for PPH prevention on health equity? viden Annex 4. E

31 32 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth Judgement Additional considerations Additional considerations Research evidence to key prevention acceptable PPH for stakeholders? IVoxytocin Is Acceptability Research evidence Don’t know to the need for IV access). for to need the it access to forwomen difficult more (due be equity, can it as may decrease IV oxytocin (14) women advantaged more than outcomes health worse and interventions of health have areas lower coverage inrural reside who and poor, are educated who least women that indicates report (WHO) State World Organization of 2015 inequality Health The IM and oxytocin. both IV oxytocin affect are likely challenges to These recommendations. guideline to fulfil inorder themselves, to cost additional at oxytocin, to purchase to turning private suppliers professionals health-care and Leone), have inwomen resulted Sierra issues and supply India (moderate greatest is arguably need confidence) (6) the where areas rural inisolated particularly inLMICs, settings inlow-resource use its may limit medication of the sensitivity heat the levels stock and inconsistent of PPH, treatment preventionand at the qualitative systematic a reviewfrom looking findings (low to settings high) of resource available inarange widely (whether form IM), IVor is ininjectable already and is relatively inexpensive Oxytocin, identified. evidence direct No use expectant management and make selective use of guideline recommendations recommendations of guideline use make selective and management expectant use (moderate confidence) with uterotonic properties medicines to herbal prefer use attendants) birth traditional (usually providers health community-based limited, may be facilities to health access (moderate labour to given induce when confidence) preventatively may to even or contribute PPH administered when placenta retained may cause medication the that perception the hold providers settings, LMIC some (moderate placenta of the delivery the hasten and confidence)PPH (6) using of oxytocin prevent IVinjection) via to a (usually single recognize benefits the providers that indicate providers health-care and by women treatment prevention and PPH of perceptions qualitative systematic a reviewfrom exploring findings Indirect high) (low to settings of resource inarange and internationally used is widely IV oxytocin identified. was providers health-care or women either from oxytocin route for administration of (or relating to acceptability for) the evidence preference direct No aparticular — . Varies — , while in several high-income countries, experienced midwives midwives experienced countries, high-income inseveral , while Reduced — Probably reduced ✓ . In rural LMIC settings where where settings LMIC rural . In . In some contexts (for example, (for example, contexts some . In Probably no no Probably impact — . However, to according the increased Probably . However, in — Increased — . (ignoring oxytocin use), especially if the birth is perceived to be normal (moderate confidence). There were no findings from studies of women’s perceptions relating to the acceptability of oxytocin. The GDG noted the lack of direct evidence on acceptability. However, they noted the aforementioned evidence that women prefer a normal birth and considered that, in some situations, the presence of an IV line and/or the administration of IV fluids around the time of childbirth may cause some discomfort or restrict a woman’s mobility. However, in situations where a woman already has IV access in place (for other medical reasons), it is likely that women would find IV oxytocin administration to be acceptable.

Judgement ✓ — — — — — Don’t know Varies No Probably No Probably Yes Yes

Feasibility Is IV oxytocin for PPH prevention feasible to implement?

Research evidence

No direct evidence relating to the feasibility of a particular administration route for oxytocin from either women or health-care providers was identified. However, IV oxytocin is widely used internationally and in a range of resource settings (low to high).

Additional considerations

Indirect findings from a qualitative systematic review exploring perceptions of PPH prevention and treatment among women and health-care providers suggest that resource constraints may influence effective use of oxytocin for PPH prevention, particularly in LMICs (high confidence) (6) . Inconsistent supplies and concerns about oxytocin storage in areas with limited/inconsistent electricity hinder utilization, and a lack of experienced staff to administer the injection limits its use in certain contexts (high confidence). In a wide variety of settings, health-care providers feel they need more training in PPH management, as well as specific training on when/ how to administer oxytocin (high confidence). In some LMIC settings, task shifting had been introduced to address staff shortages or increase coverage, and the success of this strategy was largely dependent on the ability of health-care professionals to build trustworthy relationships with traditional birth attendants or community health workers (moderate confidence) (6). There were no findings from the reviewed studies on women’s perceptions relating to the feasibility of this particular intervention.

Injectable oxytocin is already widely available in a range of resource settings (low to mework high) and has multiple applications (such as PPH prevention and treatment as well as a labour induction). Oxytocin (10 IU in 1 mL for injection) is listed in the WHO model list

of essential medicines (3). ision fr c e The GDG noted, however, that lack of access to equipment and fluids for IV

administration, as well as the need to have staff that can safely manage IV infusions, D e to c may limit feasibility of IV oxytocin, particularly in lower-level facilities in limited- resource settings. viden Annex 4. E

33 34 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth Summary of judgements table ofjudgements Summary Feasibility effects Desirable Acceptability Equity effects Undesirable effectiveness Cost- effects of Balance the evidence of Certainty resources required on evidence the of Certainty required Resources Values Judgement Don’t know — No included included No No included included No Don’t know Don’t know Don’t know Don’t know Don’t know Don’t know Don’t know know Don’t Don’t know studies studies — — — — — — — ✓ ✓ ✓ Varies ✓ Varies Varies Varies Varies Varies Varies Varies Varies — — — — — — — ✓ Large costs Large Favours IM IM Favours Favours IM IM Favours Reduced oxytocin oxytocin No — — — — — uncertainty or or uncertainty Probably No favours IM IM favours favours IM IM favours Important Important Moderate variability Probably Probably Probably Very low Very Very low Very oxytocin oxytocin reduced Trivial Large costs No No — — — — — — — — — ✓ ✓ — uncertainty or or uncertainty favour either either favour favour either either favour Probably No Probably No Probably no no Probably important important Negligible Moderate variability Does not not Does Does not not Does Possibly costs or or costs Probably Yes savings impact Small Low Low — — — — — — — — — — — — uncertainty or or uncertainty Probably Yes Probably Yes Probably no no Probably favours IV IV favours favours IV IV favours important important Moderate Moderate Moderate Moderate variability increased Probably Probably Probably oxytocin oxytocin savings Small — — — — — — — — ✓ ✓ ✓ Yes — uncertainty or or uncertainty Large savings Large No important important No Favours IV IV Favours Favours IV IV Favours variability Increased oxytocin oxytocin Trivial Large High High Yes Yes — — — — — — — — — ✓ ✓ Summary of findings table Question: IV compared with IM oxytocin for the third stage of labour Setting: Hospitals (Argentina, Egypt, Ireland, Mexico, Thailand and Turkey) Reference: Oladapo OT, Okusanya BO, Abalos E, Gallos ID, Papadopoulou A. Intramuscular versus intravenous prophylactic oxytocin for the third stage of labour. Cochrane Database Syst Rev (in press).

Certainty assessment No. of patients Effect No. of Other consid- Relative Absolute Certainty Importance Study design Risk of bias Inconsistency Indirectness Imprecision IV oxytocin IM oxytocin studies erations (95% CI) (95% CI) Maternal death 4 randomized seriousa not serious not serious very seriousb none 0/3865 0/3163 not estimable ㊉㊀㊀㊀ CRITICAL trials (0.0%) (0.0%) VERY LOW

Severe PPH ≥ 1000 mL 4 randomized not serious not serious not serious seriousc none 47/3692 69/2989 Average RR 8 fewer per ㊉㊉㊉㊀ CRITICAL trials (1.3%) (2.3%) 0.65 1000 MODERATE (0.39 to 1.08) (from 14 fewer to 2 more) Blood transfusion 4 randomized not serious not serious not serious not serious none 19/3693 40/2991 Average RR 7 fewer per ㊉㊉㊉㊉ CRITICAL trials (0.5%) (1.3%) 0.44 1000 HIGH (0.26 to 0.77) (from 10 fewer to 3 fewer) Serious maternal morbidity (organ failure, coma, ICU admission, hysterectomy or as defined by the study authors) mework

4 randomized not serious not serious not serious seriousd none 9/3865 20/3163 Average RR 3 fewer per ㊉㊉㊉㊀ IMPORTANT a trials (0.2%) (0.6%) 0.47 1000 MODERATE (0.22 to 1.00) (from 5 fewer to 0 fewer) ecision fr Blood loss ≥ 500 mL 6 randomized not serious not serious not serious not serious none 201/4217 253/3514 Average RR 16 fewer per ㊉㊉㊉㊉ IMPORTANT trials (4.8%) (7.2%) 0.78 1000 HIGH (0.66 to 0.92) (from 24

fewer to 6 vidence D to fewer) Annex 4. E

35 36 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth Fe P U A Any ad Not D studies N ostpartum se bdomi iarrhoea v o. of of o. — 6 3 1 1 1 1 > 38 °C >38 er o breast f additio verse n a S randomized randomized randomized randomized randomized randomized l pai tudy design f eedi anaemia trials trials trials trials trials trials trials trials trials trials trials trials e — ff nal uteroto n – ect n g reported ot at reported hospitaldischarge R not serious serious not not serious serious not not serious serious not not serious serious not not serious serious not not serious serious not isk of bias of isk n — ics Certainty assessment Certainty I nconsistency not serious serious not not serious serious not not serious serious not not serious serious not not serious serious not serious — e I ndirectness not serious serious not not serious serious not not serious serious not not serious serious not not serious serious not not serious serious not — very serious very very serious very I not serious serious not not serious serious not mprecision serious serious — c f b b O ther consid erations none none none none none none — - 0/239 (0.0%) 0/239 (0.0%) 0/239 21/517 (4.1%) oxytocin IV 227/3444 179/4014 179/4014 228/517 228/517 (44.1%) (4.5%) (6.6%) — N o. of patients of o.

0/241 (0.0%) 0/241 (0.0%) oxytocin IM 222/2744 207/3313 238/518 238/518 (45.9%) (45.9%) 27/518 27/518 (5.2%) (6.2%) (8.1%) (8.1%) — (0.49 to 1.25) (0.49 to 1.25) (0.45 to 1.36) to 1.36) (0.45 not estimable estimable not estimable not (0.84 to 1.10) (0.84 (0.84 to 1.16) (0.84 Average RR RR Average Average RR RR Average Average RR RR Average Average RR RR Average (95% C (95% Relative 0.96 0.78 0.78 0.99 —

I )

Effect (from 13 fewer fewer 13 (from 14 fewer per per fewer 14 18 fewer per per fewer 18 11 fewer per per fewer 11 fewer to 46 to 46 fewer to 13 more) to 13 1 fewer per per 1 fewer fewer to 16 to 16 fewer fewer to 19 to 19 fewer (95% C (95% Absolute (from 29 29 (from (from 74(from (from 32 32 (from more) more) more) 1000 1000 1000 1000 —

I )

MODERATE MODERATE ㊉㊉㊉㊀ ㊉㊉㊉㊉ ㊉㊉㊉㊉ Certainty ㊉㊉㊀ ㊉㊉㊀ ㊉㊉㊀ HIGH HIGH HIGH LOW LOW LOW LOW LOW —

IMPORTANT IMPORTANT IMPORTANT IMPORTANT IMPORTANT IMPORTANT IMPORTANT I mportance Certainty assessment No. of patients Effect No. of Other consid- Relative Absolute Certainty Importance Study design Risk of bias Inconsistency Indirectness Imprecision IV oxytocin IM oxytocin studies erations (95% CI) (95% CI) Headache 2 randomized not serious not serious not serious very seriousf,g none 3/756 (0.4%) 4/759 (0.5%) Average RR 1 fewer per ㊉㊉㊀ IMPORTANT trials 0.75 1000 LOW (0.17 to 3.34) (from 4 fewer to 12 more) Hypertension – not reported – – – – – – – – – – – IMPORTANT – Hypotension 4 randomized seriousa not serious not serious not serious none 389/3585 321/2883 Average RR 1 more per ㊉㊉㊉㊀ IMPORTANT trials (10.9%) (11.1%) 1.01 1000 MODERATE (0.88 to 1.15) (from 13 fewer to 17 more) Nausea 2 randomized not serious not serious not serious very seriousf,g none 1/756 (0.1%) 1/759 (0.1%) Average RR 0 fewer per ㊉㊉㊀ IMPORTANT trials 1.00 1000 LOW (0.06 to (from 1 fewer 15.98) to 20 more) Shivering 2 randomized not serious not serious not serious very seriousf,g none 2/756 (0.3%) 5/759 (0.7%) Average RR 4 fewer per ㊉㊉㊀ IMPORTANT trials 0.40 1000 LOW (0.08 to 2.06) (from 6 fewer to 7 more) mework Tachycardia a 2 randomized not serious not serious not serious seriousc none 75/756 85/757 Average RR 12 fewer per ㊉㊉㊉㊀ IMPORTANT trials (9.9%) (11.2%) 0.89 1000 MODERATE

(0.68 to 1.16) (from 36 ecision fr fewer to 18 more) Vomiting 2 randomized not serious not serious not serious very seriousb none 0/756 (0.0%) 0/759 (0.0%) not estimable ㊉㊉㊀ IMPORTANT trials LOW vidence D to Annex 4. E

37 38 WHO recommendation on Routes of oxytocin administration for the prevention of postpartum haemorrhage after vaginal birth g f e d c b a CI M M studies : confidence interval; ICU interval; : confidence N Few events. Few events. oxytocin. IV with risk in increase appreciable and decrease appreciable both CI including Wide (I²=61%). heterogeneity statistical Severe IV oxytocin. with risk in decrease appreciable including also and effect, no of line CI touching Wide IV oxytocin. with risk in decrease appreciable and effect, no of line both CI including Wide estimable. not events, No bias. of risk moderate at study by studies) (or provided effect pooled of Majority atern atern o. of of o. — — a a l we l satis S tudy design ll- — — f bei actio ng – not n – not : intensive care unit; IM unit; care : intensive R isk of bias of isk reported — — reported Certainty assessment Certainty I nconsistency — — : intramuscular; IV : intramuscular; I ndirectness — — : intravenous; RR : intravenous; I mprecision — — : risk ratio : risk O ther consid erations — — - oxytocin IV — — N o. of patients of o. oxytocin IM — — (95% C (95% Relative — — I )

Effect (95% C (95% Absolute — — I )

Certainty — — IMPORTANT IMPORTANT I mportance References 1. Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074–82. doi:10.1093/nar/gkx1037. 2. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, et al. PubChem Substance and Compound databases. Nucleic Acids Res. 2016;44(D1):D1202–13. doi:10.1093/ nar/gkv951. 3. World Health Organization model list of essential medicines – 21st list. Geneva: World Health Organization; 2019 (https://www.who.int/medicines/publications/ essentialmedicines/en/, accessed 14 July 2020). 4. Oladapo OT, Okusanya BO, Abalos E. Intramuscular versus intravenous prophylactic oxytocin for the third stage of labour. Cochrane Database Syst Rev. 2018;9:CD009332. doi:10.1002/14651858.CD009332.pub3. 5. Downe S, Finlayson K, Oladapo OT, Bonet M, Gulmezoglu AM. What matters to women during childbirth: A systematic qualitative review. PloS One. 2018;13(4):e0194906. doi:10.1371/journal.pone.0194906. 6. 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. PloS One. 2019;14(5):e0215919. doi:10.1371/journal. pone.0215919. 7. Lawrie TA, Rogozinska E, Sobiesuo P, Vogel JP, Ternent L, Oladapo OT. A systematic review of the cost-effectiveness of uterotonic agents for the prevention of postpartum hemorrhage. Int J Gynaecol Obstet. 2019;146(1):56–64. doi:10.1002/ijgo.12836. 8. Natarajan A, Ahn R, Nelson BD, Eckardt M, Kamara J, Kargbo S, et al. Use of prophylactic uterotonics during the third stage of labor: a survey of provider practices in community health facilities in Sierra Leone. BMC pregnancy and childbirth. 2016;16(1):23. doi:10.1186/s12884-016-0809-z. 9. Braddick L, Tuckey V, Abbas Z, Lissauer D, Ismail K, Manaseki-Holland S, et al. A mixed-methods study of barriers and facilitators to the implementation of postpartum hemorrhage guidelines in Uganda. Int J Gynaecol Obstet. 2016;132(1):89–93. doi:10.1016/j.ijgo.2015.06.047. 10. 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. 11. Gallos ID, Papadopoulou A, Man R, Athanasopoulos N, Tobias A, Price MJ, et al. Uterotonic drugs for preventing postpartum haemorrhage: a network meta-analysis and cost-effectiveness analysis. Cochrane Database Syst Rev. 2018;12(12):CD011689. doi:10.1002/14651858.CD011689.pub3. 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 mework Obstet. 2016;133(3):307–11. doi:10.1016/j.ijgo.2015.10.015. a 13. Avenir Health. OneHealth Tool: intervention assumptions. Avenir Health; 2016 ision fr

(https://www.avenirhealth.org/software-onehealth, accessed 14 July 2020). c e 14. State of inequality: reproductive, maternal, newborn and child health. Geneva: World e to D e to

Health Organization; 2015 (https://www.who.int/gho/health_equity/report_2015, c accessed 10 July 2020). viden Annex 4. E

39 For more information, please contact: World Health Organization Avenue Appia 20, CH-1211 Geneva 27, Switzerland

Maternal and Perinatal Health Unit, Department of Sexual and Reproductive Health and Research E-mail: [email protected]. Website: www.who.int/reproductivehealth

Department of Maternal, Newborn, Child, Adolescent Health, and Ageing Email: [email protected] Website: www.who.int/maternal_child_adolescent