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WHO recommendation on Umbilical injection of for the treatment of retained

WHO recommendation on injection of oxytocin for the treatment of WHO recommendation on umbilical vein injection of oxytocin for the treatment of retained placenta ISBN 978-92-4-001394-0 (electronic version) ISBN 978-92-4-001395-7 (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 umbilical vein injection of oxytocin for the treatment of retained placenta. 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 6 2.10 Formulation of the recommendation 7 2.11 Management of declarations of interests 8 2.12 Decision-making during the GDG meeting 9 2.13 Document preparation 9 2.14 Peer review 9 3. Recommendation and supporting evidence 10 4. Dissemination, adaptation and implementation of the recommendation 11 4.1 Recommendation dissemination 11 4.2 Adaptation 11 4.3 Implementation research considerations 12 5. Research implications 12 6. Applicability issues 13 6.1 Anticipated impact on the organization of care and resources 13 6.2 Monitoring and evaluating guideline implementation 13 7. Updating the recommendation 13 8. References 14 Contents

iii iv WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta

4. Annex 3. Annex Annex 2. 2. Annex 1. Annex 4.2 management 4.1 frameworks toEvidence Decision members GDG from interests of declared management and Summary indecision-making used outcomes Priority recommendation of the involvedpreparation in staff the who and experts External regimens vein injection to umbilical other compared of oxytocin vein injection Umbilical Umbilical vein injection of oxytocin solution compared to expectant to expectant compared solution of oxytocin vein injection Umbilical 16

20 22 22 35 19 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, Joshua Vogel and Mariana Widmer 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 [ICM]) and Carlos Fuchtner (International Federation of Gynecology and [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, the UNDP– UNFPA–UNICEF–WHO–World Bank Special Programme of Research, Development and Research Training in (HRP) and 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 Umbilical vein injection of oxytocin for the treatment of retained placenta WHO UVI USAID UNICEF UNFPA UNDP SDG PPH PICO MPH-GDG IU ICM HRP GSG GRADE GDG FIGO EtD ESG ERG DOI CerQUAL Acronyms abbreviations and

World Organization Health vein injection umbilical Development International for States Agency United Children’s Nations United Fund Fund Population Nations United United Nations Development Programme Goal Development Sustainable 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 Review Group External of interest declaration from ReviewsQualitative of Research in the Evidence Confidence Executive summary

Introduction Postpartum haemorrhage (PPH) is commonly defined as a loss of 500 mL or more within 24 hours after 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 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 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 the World Health Organization (WHO) maternal and perinatal health recommendations prioritized updating of the existing WHO recommendation: Umbilical vein injection of oxytocin for the treatment of retained placenta, in response to the availability of new evidence. The recommendation in this document thus supersedes the previous WHO recommendations on “intraumbilical vein injection of oxytocin for treatment of retained placenta” 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 Umbilical vein injection of oxytocin for the treatment of retained placenta retained placentaretained of treatment the for oxytocin of injection vein umbilical 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 placenta, of retained treatment the for (UVI) of oxytocin vein injection umbilical on recommendation new the issued GDG equity.The and acceptability, feasibility cost-effectiveness, and requirements resource of stakeholders, preferences and values evidence, of supporting overall certainty the and effects undesirable and desirable the between reviewed balance the GDG The Recommendation    Remarks  Justification (Research-context recommendation) research. rigorous of context the in only placenta retained of treatment the for recommended is oxytocin of injection vein Umbilical     vein injection for retained placenta. retained for vein injection umbilical with of treatment of efficacy lack showing tohave results the contributed this may and treatment, before subtypes the have distinguished not studies date, To . retroplacental of the contraction of failed aresult as occurs which placenta, of retained type common most the adherens, placenta in effective only be is likely to vein injection umbilical and placenta, of retained types three are There bleeding. of abnormal absence inthe occurs placenta retained in which in situations of this intervention use the to consider is it safer context, inaresearch used When placenta. the of removal inmanual to areduction inaddition haemorrhage related to postpartum severe on morbidity impact its aimof demonstrating with the needed, are placenta with retained of women management of uterotonics with expectant vein injection umbilical trials comparing randomized high-quality that agreed group The practice. clinical routine for make to recommendation a insufficient outcomes priority other on impact without placenta of the removal manual of in terms of benefit evidence the considered but placenta of retained treatment inthe oxytocin injectionof vein potential of umbilical the acknowledged Group Development Guideline The oxytocin. of vein injection umbilical than better to clearly shown was be regimen vein injection umbilical other no uterotonics, and solutions of other with injection compared When negligible. probably are this intervention to implement required insupplies costs additional known, not is hospitalization) is unclear. cost-effectiveness the While of length and satisfaction maternal , (including outcomes priority on other However, of this intervention of placenta. removal manual effect the in to may areduction lead this that intervention suggest of saline vein injection umbilical versus of oxytocin vein injection umbilical and management expectant versus of oxytocin vein injection umbilical both trialscompared that from Evidence 1. Introduction

1.1 Background An estimated 295 000 women and adolescent girls died as a result of 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 and treat 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). Severe maternal complications, such as dysfunction or death, generally occur following substantial blood loss that compromises maternal haemodynamic stability. is the most common cause of PPH and a leading cause of PPH-related maternal mortality worldwide (8). Genital tract trauma (including vaginal or cervical lacerations and uterine rupture), retained placental tissue or maternal bleeding disorders can cause PPH. Although the majority of women presenting with PPH have no identifiable risk factor, grand multiparity, prolonged labour, prior history of PPH and multiple are obstetric conditions that are associated with an increased risk of bleeding after birth (9). In addition, anaemia is a common aggravating factor (10). Retained placenta is a potentially life-threatening of the third stage of labour when associated with PPH or . It complicates between 0.1 to 2% of births and is usually caused by a failed contraction of the retroplacental myometrium (11,12). The standard treatment for this complication is manual removal of placenta, which requires a surgical theatre and anaesthesia and entails the risks associated with surgical procedures. Umbilical vein injection (UVI) consists of the administration of a solution via the vein, with or without uterotonic drugs. It is proposed as a noninvasive way of treating retained placenta, which, if effective, could prevent the complications associated with manual removal of placenta. Directing uterotonic treatment to the placental bed and the uterine wall may facilitate uterine contractions and placental separation. Among the various proposed methods of UVI, the most commonly reported is an injection (directly into the umbilical vein or through a catheter) of oxytocin diluted in saline solution. Other methods use other uterotonics with saline solutions or plasma expanders.

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 (13,14). 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 c tion I ntrodu 1.

1 2 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta 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 of oxytocin UVI on recommendations WHO existing of the updating Executive prioritized the GSG The implementation. affecting factors or cost-effectiveness, acceptability, feasibility, use, equity, resource outcomes, 2 1 inany setting. birth vaginal after placenta with a retained all women includes by this recommendation affected population The 1.5   were: this recommendation for questions the format, (P), Population the using Framed (I), (C), Intervention Comparison (O) Outcome (PICO) 1.4 programmes. health perinatal and of maternal implementers and care, maternal centred 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 they relate to PPH and its complications. complications. they relate its to and PPH as birth, giving women for outcomes and of is care to improve quality the recommendation (16) haemorrhage of postpartum thefor prevention treatment and in2012 inWHO recommendations were that published of oxytocin UVI on recommendations (15) 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/. oxytocin (I) compared with other UVI regimens (C) regimens (O)? UVI with other (I) outcomes improve maternal compared oxytocin (P), of placenta of UVI use with retained the of third labour inthe does stage women For (C) (O)? management outcomes improve maternal with expectant (I) compared oxytocin (P), of placenta of UVI use with retained the of third labour inthe does stage women For . 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 2 methodologies, and formulation of recommendations by a of recommendations formulation and methodologies, , including synthesis of available synthesis , including . The primary aimof this primary . The 2. Methods

The recommendation was developed using standardized operating procedures in accordance with the process described in the WHO handbook for guideline development (15). 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, UVI of oxytocin 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 (13,14).

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 Umbilical vein injection of oxytocin for the treatment of retained placenta 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. is included meetings GDG inthe participated who list of observers The recommendations. of the implementers potentialas were identified implementation, and dissemination guideline health perinatal and in maternal with WHO of collaboration history long with their organizations, These observers. as meetings (FIGO) GDG inthe Obstetrics and participated of Gynecology Federation (ICM) of International Midwives the and Confederation International the (USAID), Development International for States Agency United of the Representatives 2.5 listed inAnnex 1. are ESG of the members The GDG. the from queries to technical to and respond evidence synthesized of the to overview an provide meetings GDG the attended ESG of the members All EtD frameworks. GRADE the prepare to and review ESG evidence of the the members with all worked closely members whose Group, Steering WHO with the in collaboration reviews conducted These were of use this intervention. on the studies cost-effectiveness no prevention (17) of the PPH for interventions on providers health-care and of women related to experiences views and qualitative studies review asystematic of conducted Kingdom, United Lancashire, of Central University the from Researchers EtD frameworks. GRADE of the domains other for evidence generate to commissioned were studies Systematic reviews cost-effectiveness of qualitative and 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 availability of drugs and treatment, and accuracy in blood loss assessment – as they –as were assessment loss inblood accuracy and treatment, and ofavailability drugs to implementation, decision-making of from time were –reduction removed outcomes Additionally,process three be woman-centred. would set of recommendations final the that to and ensure to women important are that were by driven outcomes by GDG the making decision- recommendation and synthesis evidence to that this update for ensure included –were satisfaction maternal and well-being maternal death, –maternal outcomes additional (18) 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 scoping search demonstrated that there were there that demonstrated search . Ascoping (16) . These outcomes were initially outcomes . These , three , three considered not relevant for this treatment intervention. All the outcomes were included in the scope of this document for evidence searching, retrieval, synthesis, grading and formulation of the recommendation. The list of priority outcomes is provided in Annex 2.

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 UVI of oxytocin An existing systematic review was updated for the purpose of this update with the support of the Cochrane Pregnancy and Childbirth Group (19). This systematic review was the primary source of evidence of effectiveness 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 (20). 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 For questions relating to the other domains of the GRADE EtD frameworks (other than effects – that is, resources, equity, acceptability and feasibility), new systematic reviews were commissioned from external experts. The external experts were asked to prepare a standard protocol before embarking on the review, including: (i) a clear and focused question; (ii) criteria for identification of studies, including search strategies for different bibliographic databases; (iii) methods for assessing risk of bias; and (iv) a data analysis plan. Each protocol was reviewed and endorsed by the WHO Steering Group before the respective review teams embarked on the review process. The entire systematic review development process was iterative, with the review teams in constant communication with the WHO Steering Group to discuss challenges and agree on solutions. In this regard, a qualitative systematic review was conducted on the views and experiences of women and health-care providers on interventions to prevent PPH (17). This review was used as the primary source of evidence on acceptability, feasibility and equity as they relate to the EtD frameworks for the uterotonic agents of interest. The search strategies for evidence identification and retrieval are detailed in this review (17). Evidence for these domains (acceptability, feasibility and equity) was also supplemented by findings from a qualitative systematic review on women’s views and experiences during intrapartum care (21). Evidence on resource use and cost-effectiveness was based on a systematic review of the literature. The review aimed to evaluate all available evidence regarding which uterotonic agents used for preventing PPH are cost-effective, according to the mode of birth and birth settings. Eligible studies were identified from the following databases from 1980 up to June 2018: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the National Health Services Economic Evaluation Database. Additional eligible studies were also identified from the reference lists of eligible studies identified via searches of these databases. Eligible studies included those evaluating costs and cost-effectiveness of the uterotonic agents of interest (alone or in combination) in comparison with standard care, placebo or another uterotonic agent for the prevention of PPH in women in the third stage of labour, in any setting. Unit costs were extracted, as well as measures of costs, incremental ethods

costs and incremental cost-effectiveness. M 2.

5 6 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta 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 alevel 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 tool (22) CERQual GRADE- using the quality for qualitative of reviewsthe appraised were findings The     Certainty 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 effect. estimate the around of uncertainty degree the Imprecision: assessed This of interest. outcomes or comparisons interventions, populations, to instance, for were related, differences Such prepared. being was recommendation the which for context the and reported research the between differences were important there whether is, that evidence, of the directness the regarding concerns serious very or were serious there when downgraded was of evidence certainty Indirectness: The no or showedoverlap. minimal limits confidence and directions were indifferent results the when was itdowngraded whereas limits overlapped, confidence and similar were findings of the directions the when downgraded not was of evidence certainty The studies. different in observed sizeand effects of direction in the of differences magnitude the by exploring assessed was outcome agiven Inconsistency for results inthe of the similarity results: The the outcome. to contributing studies of the by majority the met criteria minimum the on depending levels, two or (“low”) one by (“moderate”) downgraded then and “high” as rated first was certainty trials, randomized For to outcome. the contributing studies the across then and study individual level each at the of examined of risk first was bias The limitations: Study design below. described briefly factors on the dependent was of evidence rating of certainty final The criteria. “high”, as rated was low”, of established aset on “moderate”, “very based or “low” approach (20) the GRADE using performed was outcome each for of evidence body of the assessment certainty The 2.9     is likely to be substantially different from the estimateeffect. of from the is likely different to substantially be effect true The estimate. effect in the We confidence little have very 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 be close the to the to effect certainty: Moderate effect. of the High certainty: Certainty assessmentCertainty grading and of theevidence . The GRADE-CERQual tool, which uses a similar conceptual approach approach asimilar conceptual uses which tool, GRADE-CERQual . The estimate closethe that to of lies effect true the that We confident very are assessments are defined according to the GRADE approach: GRADE according to the defined are assessments We are moderately confident in the effect estimate. The true true The estimate. effect in the confident We moderately are . Using this approach, the certainty of evidence for each outcome outcome each for of evidence certainty the this. Using approach, 2.10 Formulation of the recommendation The WHO Steering Group supervised and finalized the preparation of summary of findings tables and narrative evidence summaries in collaboration with the ESG using the GRADE EtD framework. EtD frameworks include explicit and systematic consideration of evidence on prioritized interventions in terms of specified domains: effects, values, resources, equity, acceptability and feasibility. For the priority questions, judgements were made on the impact of the intervention on each domain to inform and guide the decision-making process. Using the EtD framework template, the WHO Steering Group and ESG created summary documents for each priority question covering evidence on each domain:  Effects: The evidence on the priority outcomes was summarized in this domain to answer the questions: “What are the desirable and undesirable effects of the intervention?” and “What is the certainty of the evidence on effects?” Where benefits clearly outweighed harms for outcomes that are highly valued by women, or vice versa, there was a greater likelihood of a clear judgement in favour of or against the intervention, respectively. Uncertainty about the net benefits or harms, or small net benefits, usually led to a judgement that did not favour the intervention or the comparator. The higher the certainty of the evidence of benefits across outcomes, the higher the likelihood of a judgement in favour of the intervention. In the absence of evidence of benefits, evidence of potential harm led to a recommendation against the intervention. Where the intervention showed evidence of potential harm and was also found to have evidence of important benefits, depending on the level of certainty and the likely impact of the harm, such evidence of potential harm was more likely to result in a context-specific recommendation, with the context explicitly stated within the recommendation.  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 UVI of oxytocin mainly include the costs of providing supplies, training, equipment and skilled human resources. 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 exploring perceptions of PPH prevention and treatment by women and health-care providers has informed the judgements for this domain (17). 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 systematic reviews exploring perceptions of PPH prevention and treatment by women and health-care providers was used to inform judgements for this domain (17). Where major barriers were identified, it was less likely that a judgement would be made in favour of the intervention. ethods 2. M 2.

7 8 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta to affect an expert’s objective judgement in the guideline and recommendation development development recommendation and guideline in the judgement objective expert’s an to affect enough serious were conflicts such whether determined Group Steering WHO the declared, was interest of any conflict Where invitations participate. to experts’ finalizing the before reviewed all DOI Group Steering WHO The processes. guideline-related inthe participating before and process development guideline inthe engaging before form DOI WHO standard (15) 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 regulations, According WHO. at to WHO development of guideline part acritical are contributors and experts external other and members GDG of of interest conflicts non-financial and financial of relevant 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 well as to as work normative protect of its integrity tothe protect process arobust has WHO 2.11  recommendation: the for following of categories the one asked was to select GDG The members. GDG of the judgement the and EtD framework ineach presented of evidence range of the explicit consideration on based context, specific the instances insome and direction its including recommendation, each on to consensus was reach meeting of the purpose The recommendations. the formulated and feedback, preliminary through received comments any and reviewed EtD the collectively frameworks members GDG the chairperson, GDG the of (11–12 meeting 2020), GDG leadership March the the During under conducted was which meeting. (electronically) GDG the before to review comments provide and documents the on were asked members GDG The meeting. GDG of the inadvance weeks two members GDG to the recommendation, related each to documents other and tables of findings summary summaries, evidence including EtD the frameworks, provided Group Steering WHO The sources. relevant reviews systematic other or studies, single from were extracted considerations These evidence. of direct absence inthe information pertinent provided but question priority the addressed have not directly might that studies from were derived considerations Such subsections. considerations Additional inthe described are consequences unintended or of potential harms evidence additional above of the domains, each For          Recommended: families. their and of groups women different among reduce) inequalities could health proven (orreduce if its (or likely was effects anticipated) to recommended intervention be The this domain. for to judgements inform were used members GDG of the opinions and experiences The equity?” on intervention of the impact anticipated is the “What question: the addressed this domain Therefore, inequities. health reduce would intervention the not or to as whether considerations or evidence encompasses domain Equity: This 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: Management 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 a complete required were therefore members . All GDG process. To ensure consistency, the WHO Steering Group applied the criteria for assessing the severity of conflicts of interest as outlined in the WHO handbook for guideline development to all participating experts. All findings from the DOI statements received were managed in accordance with the WHO procedures to assure the work of WHO and the contributions of its experts is, actually and ostensibly, objective and independent. The names and biographies of individuals were published online four weeks prior to the meeting. Where a conflict of interest was not considered significant enough to pose any risk to the guideline development process or to reduce its credibility, the experts were only required to openly declare such conflicts of interest at the beginning of the GDG meeting, and no further actions were taken. Annex 3 shows a summary of the DOI statements and how conflicts of interest declared by invited experts were managed by the WHO Steering Group.

2.12 Decision-making during the GDG meeting During the meeting, the GDG reviewed and discussed the evidence summary and sought clarification. In addition to evaluating the balance between the desirable and undesirable effects of the intervention and the overall certainty of the evidence, the GDG applied additional criteria based on the GRADE EtD framework to determine the direction and strength of the recommendation. These criteria included stakeholders’ values, resource implications, acceptability, feasibility and equity. Considerations were based on the experiences and opinions of the GDG members and supported by evidence from a literature search where available. EtD tables were used to describe and synthesize these considerations. Decisions were made based on consensus, defined as the agreement by three quarters or more of the participants. None of the GDG members expressed opposition to the recommendation.

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 Umbilical vein injection of oxytocin for the treatment of retained placenta 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 (Annex 4). EtD inthe framework is presented recommendation, of the direction and strength 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 (Research-context recommendation) research. rigorous of context the in only placenta retained of treatment the for recommended is oxytocin of injection vein Umbilical Remarks     with umbilical vein injection for retained placenta. retained for vein injection with umbilical of treatment of efficacy lack showing this to may have results and the contributed treatment, before Tomyometrial. subtypes the have distinguished not studies date, retroplacental of the contraction of failed aresult as occurs which placenta, retained of type common most the adherens, placenta in treating is likely effective to only be of oxytocin vein injection umbilical and placenta of retained types three are There bleeding. of abnormal absence inthe occurs placenta retained which in insituations of this intervention use the to consider itis safer context, research In placenta. of the removal inmanual to areduction inaddition morbidity haemorrhage-related postpartum severe on impact its aimof demonstrating with the needed, are placenta retained with of women management of uterotonics with expectant vein injection umbilical trials comparing randomized high-quality that agreed group The practice. clinical routine for make to recommendation a insufficient outcomes priority other on impact without placenta of the removal manual of in terms of benefit evidence the considered but placenta of retained treatment inthe solution oxytocin injectionof vein potential of umbilical the acknowledged Group Development Guideline The oxytocin. of vein injection umbilical than better to clearly shown was be regimen vein injection umbilical other no uterotonics, and solutions of other with injection compared When negligible. probably are this intervention to implement required insupplies costs additional known, not is hospitalization) is unclear. cost-effectiveness the While of length and satisfaction maternal infections, (including outcomes priority other on However, of this intervention of placenta. removal manual effect in the the to may areduction lead this that intervention suggests of saline vein injection umbilical versus of oxytocin vein injection umbilical and management expectant versus of oxytocin vein injection umbilical both trialscompared that from Evidence Recommendation and supporting 4. Dissemination, adaptation and implementation of the recommendation

The dissemination and the implementation of this recommendation are to be considered by all stakeholders involved in the provision of care for pregnant women at the international, national and local levels. There is a vital need to increase women’s access to maternal health care and to strengthen the capacity at health-care facilities of all levels to ensure they can provide high-quality services to all women giving birth. It is therefore crucial that this recommendation be translated into care packages and programmes at country and health- care facility levels, where appropriate.

4.1 Recommendation dissemination The recommendation will be disseminated through WHO regional and country offices, ministries of health, professional organizations, WHO collaborating centres, other United Nations agencies and nongovernmental organizations, among others. This recommendation will also be available on the WHO website and the WHO Reproductive Health Library.1 Updated recommendations are also routinely disseminated during meetings or scientific conferences attended by WHO maternal and perinatal health staff. The recommendation document will be translated into the six United Nations languages and disseminated through the WHO regional offices. Technical assistance will be provided to any WHO regional office willing to translate the full recommendation into any of these languages.

4.2 Adaptation National and subnational subgroups may be established to adapt and implement this recommendation based on an existing strategy. This process may include the development or revision of existing national guidelines or protocols based on the updated recommendation. Existing global models such as those for WHO antenatal and intrapartum care guidelines can be adapted to different countries, contexts and individual needs and preferences of tion women. The conceptual basis of these models is to drive improvements in the quality a of maternal health care, by aiming to achieve the best possible physical, emotional and psychological outcomes for the woman and her baby, irrespective of the influence of ommend generic policies that may exist within and across health systems and countries. Both models c address relevant health policy, organizational and user-level considerations. These models thus support implementation of WHO recommendations and are intended to be adapted by stakeholders and partners at regional, country and local levels into locally appropriate documents and tools. tion of the re the of tion a The successful introduction of evidence-based policies (relating to updated recommendations) depends on well-planned and participatory consensus-driven processes of adaptation and implementation. These processes may include the development or revision of existing national or local guidelines and protocols, often supported by ministries of health, United Nations agencies, local professional societies and other relevant leadership groups. An enabling environment should be created for the use of this recommendation, nd implement a nd tion including changes in the behaviour of health-care practitioners to enable the use of a

evidence-based practices. a pt In the context of humanitarian emergencies, adaptation of the current recommendation should consider the integration and alignment with other response strategies. Additional tion, a d tion, considerations for the unique needs of women in emergency settings, including their values and preferences, should be made. Context-specific tools and toolkits may be required issemin a

1 Available at: www.who.int/rhl. D 4.

11 12 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta humanitarian emergencies by stakeholders. in recommendation of the implementation the tools to to support standard in addition     placenta, with retained women In priority: urgent demand that as those identified were following questions The this recommendation. on may have which impact an research, primary through addressed be to need that gaps knowledge important identified GDG The 5.       4.3           accurately diagnosed clinically prior to the UVI? to UVI? the prior clinically diagnosed accurately be type that can so, if and, placenta of retained types only certain in effective is UVI morbidity? and mortality maternal PPH-related inreducing oxytocin UVI of than uterotonics (carbetocin, of other is effective UVI ) more morbidity? and mortality maternal PPH-related inreducing administration oxytocin or intravenous intramuscular than effective more of oxytocin is UVI morbidity? and mortality maternal PPH-related in reducing management expectant than effective more of oxytocin is UVI (23) injection direct than bed placental the to reach effective more proven has solution, of saline mL catheter, of the use 30 The additional with an insertion. placental vein to the from umbilical 5cm the along introduced catheter aspiration mucus infant via vein an or into umbilical the injection direct either are methods injection The tomL. mL 30 10 from ranges dilution for used of saline volume the Likewise, IU. (IU) to 100 units international 10 from ranged available evidence from dose Oxytocin UVI. for oxytocin for regimen dilution standardized no is currently There randomized trials. through done be case in this should research rigorous To effectiveness, assess products. blood and fluids intravenous acid, tranexamic of uterotonics, use the including to PPH, treat prevent and childbirth after care of good-quality importance the from detract not should recommendation This uncertainties. of these informed (and is it be given) to to this intervention whom use women should elect who Providers placenta. of retained treatment the for of oxytocin of UVI use the against favour of or in recommend to evidence insufficient is currently there that informed be PPH) should to treat prevent and involved those inprogrammes (particularly stakeholders Relevant feasibility.and acceptability as as well effectiveness, related to uncertainties and questions unanswered to is able address that of research form the ittakes that provided scale, alarge at undertaken still be can implementation The this intervention. about uncertainties important are there that indicates category rating This research. of rigorous context inthe only is recommended of oxytocin UVI

Research implicationsResearch Implementation research considerations . 6. Applicability issues

6.1 Anticipated impact on the organization of care and resources If UVI of oxytocin was proven effective to treat retained placenta, updated training curricula and provision of training to relevant health workers will be required. In addition, measures to ensure sustainable supply of oxytocin and the necessary injection equipment (which are typically available in maternity care settings) are required.

6.2 Monitoring and evaluating guideline implementation As this is a recommendation in the context of rigorous research, implementation of this recommendation should ideally be conducted in the context of high-quality randomized controlled trials that could help to address the uncertainties around benefits and harms of this intervention. However, if UVI of oxytocin is implemented into care for women with retained placenta, the impact of this recommendation on important health outcomes should be monitored at health service, district and national level. The uncertainties regarding the benefits and potential harms of this intervention should not detract from the importance of broader efforts to monitor and evaluate the quality of maternal and newborn health care. Any such monitoring and evaluation activities should adopt clearly defined review criteria and indicators; these could be associated with locally agreed targets and aligned with the standards and indicators described in the WHO document Standards for improving quality of maternal and newborn care in health facilities (24).

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 and prioritized 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]. bility issues ca 6. Appli

13 14 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. 8. References July 2020).July reproductivehealth/publications/updating-mnh-recommendations/en/, 9 accessed (https://www.who.int/ 2019 World Organization; Health Geneva: recommendations. health perinatal and maternal WHO updating for Group Steering Guideline Executive 6736(09)61752-9. randomised controlled trial. Lancet. 2010;375(9709):141–7. doi:10.1016/S0140- Study): (Release placenta of retained adouble-blind, treatment the for vein oxytocin T, Majeed Umbilical al. et R, Gosakan A, VernonNamayanja AD,Weeks Alia G, G, 2008;22(6):1103–17. doi:10.1016/j.bpobgyn.2008.07.005. Clin Gynaecol. Res Obstet Pract Best placenta. retained AD.Weeks The 109X(18)30078-0. doi:10.1016/S2214- 6(5):e548–54. 2018; 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 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 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. 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. 15. WHO handbook for guideline development, second edition. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/145714, accessed 9 July 2020). 16. 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). 17. 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. 18. 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. 19. Nardin JM, Weeks A, Carroli G. Umbilical vein injection for management of retained placenta. Cochrane Database Syst Rev. 2011(5):CD001337. doi:10.1002/14651858. CD001337.pub2. 20. 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. 21. 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. 22. 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 the series. Implement Sci. 2018;13(Suppl 1):2. doi:10.1186/s13012-017-0688-3. 23. Pipingas A, Gulmezoglu AM, Mitri FF, Hofmeyr GJ. Umbilical vein injection for retained placenta: clinical feasibility study of a new technique. East Afr Med J. 1994;71(6):396–7. 24. Standards for improving quality of maternal and newborn care in health facilities. Geneva: World Health Organization; 2016 (https://www.who.int/maternal_child_ adolescent/documents/improving-maternal-newborn-care-quality/en/, accessed 6 August 2020). es c eferen 8. R

15 16 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta San Francisco,San USA (UCSF) Francisco San of California, University Reproductive Sciences and Gynecology of Obstetrics, Department Program Director, Motherhood Safe * MILLER Suellen Calabar, Nigeria of Calabar University Epidemiology &Clinical of Paediatrics Professor * MEREMIKWU Martin Songkhla, Thailand University of Songkhla Prince Faculty of Medicine of Epidemiology Professor * Tippawan LIABSUETRAKUL France Paris, Statistics Sorbonne and inEpidemiology ofCentre Research Team Research Epidemiology Obstetrical, Perinatal Pediatric and Catherine DENEUX-THARAUX * (USA) States of America United Stanford, of Medicine School University Stanford PainMedicine and Perioperative Department of Anaesthesiology, Chief, Anaesthesia of Division Obstetric CARVALHOBrendan * Brazil Paraiba, Figueira Fernando Professor Integral Medicina Instituto de Neto and Amorim Joaquim Professor Pesquisa de Instituto Paraibano Obstetrician & Gynaecologist AMORIM Melania Nigeria Abuja, (SOGON) Nigeria in Obstetrics and of Gynaecology Society President AKINOLA Ireti Oluwarotimi (GDG) GROUP DEVELOPMENT GUIDELINE 2020)(11–12 March Participants at theWHO Guideline Development (GDG) Group meeting Annex 1. recommendation involved in preparation the of the External and experts WHO staff Santa Cruz, Bolivia Cruz, Santa (FIGO)Obstetrics International and Federation of Gynecology President * Carlos FUCHTNER IndonesiaJakarta, Health (USAID) Global for Development Bureau International for States Agency United Advisor Health Newborn and Maternal Senior * Deborah ARMBRUSTER OBSERVERS by* Participated conference. video Kingdom) (United Ireland Northern and Britain of Great Kingdom United Liverpool, University of Liverpool Professor Andrew WEEKS Francisco,San USA UCSF Reproductive Sciences & Gynecology of Obstetrics, Department Professor * WALKER Dilys Arabia Saudi Riyadh, University Saud King ofCollege Medicine, Translation Knowledge and Healthcare Evidence-based Chair and Professor Hayfaa WAHABI * Tokyo, Medicine and Health Global for Center National Cooperation Health of International Bureau Director, System Team Health Deputy Lead Mari NAGAI Egypt Cairo, University Shams Ain Gynecology and of Obstetrics Department Professor Ashraf NABHAN

Ingela WIKLUND EXTERNAL REVIEW GROUP (ERG) Representative Christine EAST International Confederation of Midwives Professor of Nursing and , (ICM) Nursing Stockholm, Sweden La Trobe University, * Participated by video conference. Melbourne, Australia

EVIDENCE SYNTHESIS GROUP (ESG) Gill GYTE Consumer Editor for Cochrane Pregnancy & Edgardo ABALOS * Childbirth Group Vice Director University of Liverpool Centro Rosarino de Estudios Perinatales Liverpool Women’s Hospital NHS Trust Rosario, Argentina Crown Street Virginia DIAZ ** Liverpool, United Kingdom Researcher Justus HOFMEYR Centro Rosarino de Estudios Perinatales Director Rosario, Argentina Effective Care Research Unit Kenneth FINLAYSON (Methodologist) University of the Witwatersrand/University Research Associate of Fort Hare/ Research in Childbirth and Health Unit Eastern Cape Department of Health (ReaCH) Eastern Cape, South Africa University of Central Lancashire Syeda Batool MAZHAR Preston, United Kingdom Professor of Obstetrics and Gynaecology Leanne JONES (Methodologist) Mother and Child Health Centre (MCH) Research Associate Pakistan Institute of Medical Sciences Islamabad, Pakistan Cochrane Pregnancy and Childbirth Group tion a Editorial Office Enrique OYARZUN University of Liverpool Chairman

Liverpool, United Kingdom Department Obstetrics and Gynaecology ommend c Frances KELLIE ** Facultad de Medicina Pontificia Managing Editor Universidad Católica de Chile Cochrane Pregnancy and Childbirth Group Santiago, Chile Editorial Office Qian XU tion of the re

University of Liverpool Department of Maternal, Child and a r Liverpool, United Kingdom Adolescent Health a School of Public Health, Fudan University Myfanwy WILLIAMS (Methodologist) Shanghai, Research Associate Cochrane Pregnancy and Childbirth Group Editorial Office University of Liverpool Liverpool, United Kingdom ff involved in the prep a * Participated by video conference ** Unable to attend nd WHO st l experts a a xtern Annex 1. E

17 18 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta ** Unable to attend to Unable attend ** Montevideo, Uruguay Americas the for Office Regional WHO Health Reproductive and Sexual Advisor,Regional AMRO/CLP Claudio SOSA** Philippines Manila, thefor Pacific Western Office Regional Life-Course through Health and of NCD Division Health Adolescent and Reproductive, Maternal, Newborn, Child SOBEL**Howard Egypt Cairo, Mediterranean Eastern the for Office Regional WHO Reproductive and Maternal Health Ramez Khairi MAHAINI** India Delhi, New Asia South-East for Office Regional WHO Course Life and Gender Family Health, Chandani Anoma JAYATHILAKA** Harare, Zimbabwe Region theAfrican for Office Regional WHO Ageing and Health Maternal Adviser,Regional Reproductive, ELAMIN Hayfa Montevideo, Uruguay Americas the of Office Regional WHO Health Reproductive and Sexual MUCIO** DE Bremen Copenhagen, Denmark Europe for Office Regional WHO course Noncommunicable Diseases and Life- Health Reproductive and Sexual BERDZULI** Nino OFFICERS COUNTRY REGIONAL WHO AND

H Health and Ageing and Health Child Maternal, Adolescent and Newborn, Unit Health Maternal Officer Medical Maurice BUCAGO H Adolescent and D GROUP STEERING WHO D Research and Health Reproductive and Sexual Health Perinatal and Maternal Technical Officer Mariana WIDMER Research and Health Reproductive and Sexual Health Perinatal and Maternal Consultant Joshua P. VOGEL Research and Health Reproductive and Sexual Health Perinatal and Maternal a.i. Head Unit T. Olufemi OLADAPO Research and Health Reproductive and Sexual Health Perinatal and Maternal Technical Officer LAVIN Tina Research and Health Reproductive and Sexual Health Perinatal and Maternal Officer Medical Fernando ALTHABE epartment of S epartment epartment of M epartment ealth and R and ealth esearch exual and R and exual aternal, N aternal, ealth and Ageing Ageing and ealth ewborn, Child ewborn, eproductive eproductive Annex 2. Priority outcomes used in decision-making

Critical outcomes:  Maternal death  Additional blood loss ≥ 500 mL  Additional blood loss ≥ 1 000 mL  Blood transfusion  Additional uterotonics  Invasive nonsurgical interventions (including manual removal of placenta, curettage and embolization)  Surgical interventions (including hysterectomy)  Maternal temperature ≥ 40 °C  Procedure-related complications  Infections  Severe morbidity  Maternal transfer

Important outcomes:  Mean blood loss  Postpartum anaemia  Additional non-surgical interventions (for example, external aortic compression and compression garments)  Nausea, vomiting or shivering  Maternal temperature ≥ 38 °C  Delayed initiation of breastfeeding  Prolonged hospitalization  Maternal well-being  Maternal satisfaction king a ision-m c omes used in de c riority out Annex 2. P

19 20 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Annex 3. Dilys Walker Dilys WahabiHayfaa Nagai Mari Ashraf Nabhan Suellen Miller Meremikwu Martin Liabsuetrakul Tippawan Tharaux Catherine Deneux- CarvalhoBrendan Amorim Melania Akinola I Oluwarotimi N ame

interests members from GDG management and of declared Summary guideline development E end-user and expert Content end-user and expert Content end-user and expert Content implementer and expert Content end-user and expert Content end-user and expert Content end-user and expert Content end-user and expert Content end-user and expert Content end-user and expert Content end-user and expert Content xpertise contributed to contributed xpertise D Pack simulation training kit. training simulation Pack PARTO PRONTO the and Pants simulator, low-techthe birth International has to the rights PRONTO organization. the toWalker funds donated has Professorhaemorrhage. postpartum including and neonatal emergencies, obstetric for team training and simulation implements and International. PRONTO designs PRONTO organization nongovernmental of the Co-founder and President None declared None declared None declared trademark. the royalty for LifeWrap. a receives UCSF anti-shock the garment, one brand of non-pneumatic distributes and manufactures who Fuzionto Group Blue the advisor atechnical as Serves None declared None declared None declared Gauss Surgical. from options share Receives operative loss). blood and peripartum measures that for Gauss Surgical (company consultant technical as Serves None declared None declared eclared interest eclared participation. or membership GDG to affect enough serious considered not was conflict The applicable Not applicable Not applicable Not participation. or membership GDG to affect enough serious considered not was conflict The applicable Not applicable Not applicable Not participation. (GDG) or membership Development Group Guideline affect to enough serious considered not was conflict The applicable Not applicable Not interest M anagement of conflict of conflict of anagement Andrew Weeks Content expert and Chief investigator of the The conflict was not end-user COPE trial, and co-inventor of considered serious the Butterfly device to treat enough to affect postpartum haemorrhage GDG membership or as well as chief investigator participation. of the development study. Both funded by NIHR (United Kingdom) research grants to the University of Liverpool. The University is the device patent holder but, as co-inventor, Professor Weeks would receive a share of the profits. red interests from GDG members a l c gement of de a n a nd m ry a ry a umm Annex 3. S

21 22 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta             1 Subgroups: setting community or Hospital Setting: (C): Comparator (I): of oxytocin UVI Intervention (P):Population of Women third labour, placenta inthe stage of retained with adiagnosis perspective –population Perspective: recommendation Clinical practice Problem: Critical outcomes: Priority outcomes (O): (O))outcome format: (P), inPICO of interest (population (I),Following question is the intervention (C), comparator Question 4.1 Annex 4.             update. this of part as added have been satisfaction” “maternal and well-being” “maternal outcomes The (2012). haemorrhage postpartum of treatment and prevention the for recommendations WHO in recommendation, this of development the in used outcomes prioritized the reflect outcomes These Maternal transfer Severe morbidity Infections Procedure-related complications Maternal temperature ≥40 °C hysterectomy) (including interventions Surgical embolization) artery and curettage [MROP], of placenta removal manual (including interventions Invasive nonsurgical Additional uterotonics transfusion Blood ≥1000 loss mL blood Additional mL ≥500 loss blood Additional Maternal death   outcomes (O)? (C) management improve maternal to (I) expectant of compared oxytocin UVI (P), placenta of with use retained the of third labour inthe does stage women For Treating placenta retained management management solution compared to expectant Umbilical vein injection of oxytocin If required. If Expectant management management Expectant Evidence to Decision frameworks 1 Important outcomes:  Mean blood loss  Postpartum anaemia  Additional nonsurgical interventions (for example, external aortic compression and compression garments)  Nausea, vomiting or shivering  Maternal temperature ≥ 38 °C  Delayed initiation of breastfeeding  Prolonged hospitalization  Maternal well-being  Maternal satisfaction

Assessment Effects of interventions What is the effect of treating retained placenta with UVI with oxytocin on the priority outcomes?

Research evidence

Summary of evidence Source and characteristics of studies Evidence on the effects of UVI for treating retained placenta is from an update of gement

a Cochrane Review that now includes 24 trials (2348 women) (1). Twenty-three of a n

these trials (2302 women) included women who received UVI with oxytocin to treat a retained placenta. However, two trials did not contribute data to the analyses, one nt m because of inconsistencies in the reported data (44 women), and another due to a lack a of information about the number of women in each group in the only available abstract (37 women). Two groups (16 women) from one four-arm trial were also excluded from the analyses because those trial arms did not meet the review inclusion criteria. red expect to

The trials that contributed data to the analyses took place in hospital settings in a Argentina, Belgium, Denmark (four trials), Egypt (two trials), Finland, Hong Kong SAR (China), India, Israel, Italy, Malaysia (two trials), the Netherlands, Pakistan (two trials), Uganda and the United Kingdom (four trials). The largest trial involved 13 centres tion comp

across Pakistan, Uganda and the United Kingdom. Ten trials involved multiple centres u in single countries, ranging from two to 11 sites. The remaining 11 trials were undertaken in a single hospital. The number of women randomized in the trials ranged from 30 to 577 women. Thirteen trials included only women with singleton and, in the other eight trials contributing data, this was not described. Some trials specified a minimum or age range in the inclusion criteria: ≥ 20 weeks (one trial); ≥ 28 weeks (four trials); ≥ 34 weeks (three trials); 34–42 weeks (one trial); ≥ 37 weeks (two trials). One trial described women as both term and preterm, and in nine trials gestational age was not reported. l vein injection of oxytocin sol

Fourteen studies excluded women with postpartum haemorrhage (PPH) or bleeding a requiring immediate treatment, hypovolaemic shock or haemodynamic instability. However, PPH status at trial entry was not explicit in the remaining studies. In terms of management of the third stage of labour, 15 trials reported that women in both the treatment and control groups experienced active management of the third stage of labour, although the oxytocic drug, dose and route varied considerably; in three trials, Annex 4.1. Umbilic

23 24 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta 1 groups for all trials included in this comparison. this in included trials all for groups both in available were data whom for women of number total the is detailed women of number The confidence interval interval [CI]0.47 confidence 1.38). to 95% [RR] ratio risk 24/171; 0.81, versus 20/168 women; (four 339 trials, management withexpectant compared when transfusion blood to difference no or may make little Blood transfusion: low certainty. of as very approach Evaluation (GRADE) and Development Assessment, of Recommendations Grading uterotonics additional mL ≥ 500 loss blood additional on maternal death effect an has solution of oxytocin UVI whether is unclear It management expectant versus solution of UVI oxytocin of Effects       management expectant versus solution of oxytocin UVI placenta”. of the removal manual with planned ‘conservatively’ were “treated women trial groups), inboth by received all women trial, further one inone and described; (detail groups), inboth by placenta received all the women to care expel not standard (two trials), treatment active no (one between cord traction controlled trial, varied, also strategies management expectant The trials. between varied of solution volume total the and dose the but solution, insaline women), administered was 554 oxytocin (seven trials, management expectant versus of oxytocin UVI trials comparing the In reports. trial inthe trials (117 two women), described remaining not was MROP protocol for the inthe obstetrician; attending of the judgement the on women), based was MROP trial (81 inone women). minutes 45 trial at women); (200 trial (200 and one In one in minutes trial (37 women); 30–45 inone at minutes women); 40 at trialsin 11 (1388 minutes post-treatment/diagnosis women); 30 at 163 on data trials (reporting infour group) MROP. for management expectant minutes 15 inthe at was MROP placenta post-treatment point a time post-diagnosis trials prespecified Most (or of retained trial (28 minutes. one women) 60 at and women) minutes; 45 at trial (54 one minutes; women) 30 at trials 11 (1736 minutes; 30 at administered was treatment trials (81 of these women), inone although six trials women) (295 20 minutes, at post-birth; minutes 15 placenta retained women) diagnosed 73 on data (reporting Two trials. between varied diagnosis trials for point time the post-birth, minutes 30 placenta retained diagnosed to analyses data the trials contributing most Although third of the stage. management about information provide not did studies six remaining the and drugs; oxytocic received groups inboth all women not but some       61 women). (one trial, management expectant versus 30 mL solution saline plus IU 100 Oxytocin 42trial, women) (one management expectant versus 20 mL solution saline plus IU 100 Oxytocin 52 women) (one trial, management expectant versus 20 mL solution saline plus 20 IU Oxytocin 191 women) (one trial, management expectant versus 18 mL solution saline plus 20 IU Oxytocin women) 173 (two trials, management expectant versus solution 20 mL saline plus 10 IU Oxytocin 35 women) (one trial, management expectant versus solution 10 mL saline plus 10 IU Oxytocin 1 Low-certainty evidence suggests that UVI of oxytocin solution solution of oxytocin UVI that suggests evidence Low-certainty . The evidence for all four outcomes was assessed by using the by the using assessed was outcomes all four for evidence . The and the use of use the and mL ≥ 1000 loss blood , additional , Invasive nonsurgical interventions: Low-certainty evidence suggests that UVI of oxytocin solution may reduce the need for MROP when compared with expectant management (seven trials, 546 women; 131/282 versus 159/264; average RR 0.73, 95% CI 0.56 to 0.95). It is unclear what effect the intervention has on the risk of women requiring instrumental evacuation of retained products of conception (very- low-certainty evidence). It is also unclear what effect UVI of oxytocin solution has on the priority outcomes infections, severe maternal morbidity, mean blood loss (in mL), postpartum anaemia (the Cochrane review reported the proxy outcomes haemoglobin 24–48 hours postpartum and haemoglobin 40–45 days postpartum), prolonged hospitalization (stay in hospital for more than two days was reported), and maternal satisfaction (maternal dissatisfaction with third stage management was reported). The evidence for all of these outcomes was of very low certainty. No other priority outcomes were reported under this comparison.

Additional considerations

A separate 2012 Cochrane review assessed the effectiveness of UVI (alone or with any uterotonic drug) for the routine management of the third stage of labour and identified nine studies (1118 women) (2). Comparing UVI of normal saline plus oxytocin with UVI of saline only (six studies, 394 women), there was no evidence of difference in any of the relevant outcomes. Other comparisons included only one study for each, and there was no relevant information available. The authors concluded that there was insufficient evidence to support the routine use of oxytocin (or other uterotonics) with normal saline via UVI for the active management of the third stage of labour until new evidence is available. gement a n a Desirable effects nt m

How substantial are the desirable anticipated effects of UVI of oxytocin versus expectant a management?

Judgement red expect to

— — — — ✓ — a Don’t know Varies Trivial Small Moderate Large

Undesirable effects tion comp How substantial are the undesirable anticipated effects of UVI of oxytocin versus expectant u management?

Judgement ✓ — — — — — Don’t know Varies Large Moderate Small Trivial

Certainty of the evidence What is the overall certainty of the evidence on effects of UVI of oxytocin versus expectant management? l vein injection of oxytocin sol a

— ✓ — — — No included Very low Low Moderate High studies Annex 4.1. Umbilic

25 26 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Judgement Additional considerations expectant management? expectant or UVI of favour oxytocin effects undesirable and desirable between balance the Does of effects Balance Research evidence placenta? retained for of oxytocin with UVI associated outcomes main the value (and women families) their how much in, variability or about, uncertainty important there Is Values Important uncertainty uncertainty Important None. confidence) (moderate/low to this breastfeed may ability have their on impact negative the and PPH experiencing of effects long-term well as the babies) as psychological following PPH, their from (at anxiety separated and being of exhaustion feelings about concerned management (moderate/low confidence) PPH around decision-making shared in engage to with awillingness staff competent during antenatal care (moderate confidence) given ideally PPH, about information for review women’s highlighted need same The prevented (moderate be not should confidence) that something and process cleansing anormal as they blood”, perceive which “dirty of so-called expulsion the on (LMICs), value agreater place countries women income (moderate loss blood “normal” confidence) be considered might what or loss blood of definitions recognize clinical not the do women that suggest providers and women among treatment prevention and PPH of perceptions of review aqualitative systematic update an exploring from Findings confidence) (high sensitive are to needs who their providers health-care competent technically like would from women to receiveinformation relevant introduced, are interventions (low complications recognized to confidence) address interventions welcome and/or women contexts situations, incertain although, interventions, of medical (highbirth and confidence) labour about apprehensive are time, first the be necessary (high confidence) necessary be may sometimes intervention baby) medical that and mother for acknowledge but birth outcomes normal a (with good want most women that indicate findings care, intrapartum from want” women evaluating areviewIn “what of qualitative studies or variability or — . . Possibly important Possibly important uncertainty or or uncertainty variability (3) — . Most women, especially those giving birth for for birth giving those especially women, . Most . In addition, it was found that women are are women that found was it addition, . In (4) , and the importance of kind, clinically of kind, importance the , and . Furthermore, in some low- and middle- low- and insome . Furthermore, Probably no important important no Probably . uncertainty or or uncertainty variability ✓ and wary wary and uncertainty or or uncertainty No important important No variability . Where . Where — Judgement ✓ — — — — — — Don’t know Varies Favours Probably Does not Probably Favours UVI expectant favours favour favours UVI of oxytocin manage- expectant either of oxytocin ment manage- ment

Resources How large are the resource requirements (costs) of favouring UVI of oxytocin?

Research evidence

The Cochrane review on UVI for retained placenta did not prespecify any cost or economic outcomes. A literature search did not identify any cost-effectiveness studies related to this intervention.

Additional considerations

This intervention requires items (oxytocin, needle, syringe, normal saline, gloves) that are typically available in adequately equipped hospital settings. Performing this intervention would be considered part of the expertise of skilled health personnel. While no cost-effectiveness evidence was identified, reduction in the need for MROP (an invasive procedure requiring general anaesthesia, which may also necessitate transfer to a higher level of care) would likely reduce costs. gement a

Main resource requirements n a Resource Description nt m

Staff Oxytocin administered via UVI by skilled health-care personnel. a Training Training to administer injections, and to monitor and manage expected and unexpected side-effects, is part of standard maternity staff training. However, additional training would be required if this intervention red expect to

is to be introduced in settings where it has not previously been a available. Supplies  Oxytocin indicative cost per 10 IU: US$ 0.22–1.19 (5,6)

 Needle and syringe cost: Approximately US$ 0.07 (6) tion comp  Normal saline: Median price of USD$ 1 per litre (7) u  Gloves. Equipment and Oxytocin cold chain storage and transport costs infrastructure Cost per birth: Possibly US$ 0.84 in a low-resource setting (8). Time Minimal Supervision and Supervision and monitoring to ensure appropriate use, stock monitoring availability and quality.

Resources required

Judgement l vein injection of oxytocin sol a ✓ — — — — — — Don’t know Varies Large costs Moderate Negligible Moderate Large costs costs or savings savings savings Annex 4.1. Umbilic

27 28 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Judgement Additional considerations Research evidence to key acceptable stakeholders? of oxytocin UVI Is Acceptability Research evidence equity? health on of oxytocin of UVI impact the be would What Equity Judgement Cost-effectiveness Judgement costs? on evidence of the certainty is the What resources required on evidence of the Certainty Don’t know Don’t know low-resource settings. in feasible less be might which level expertise, have would health to another acquire primary at personnel health skilled the hand, other the On facilities. health primary in birth giving women for inequities level ofto care) reduce ahigher probably would (which placenta to retained treat transfer may curettage require or MROP for need the Reducing women. disadvantaged among improve outcomes and equity health on (9) 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 identified. was evidence direct No (4) (low to high) settings of resource inarange and internationally used is widely oxytocin However, identified. was intravenous providers or women either from placenta retained of treatment the for of oxytocin of UVI relating to acceptability the evidence direct No No included included No — . . Therefore, reducing maternal morbidity due to PPH could have a positive impact have to could apositive PPH due impact morbidity maternal reducing . Therefore, ✓ studies ✓ Varies Varies — ✓ Very low Very — placebo/no treatment Reduced Favours Favours — — placebo/no treatment Probably Probably reduced favours favours Low — — — Probably no no Probably Does not not Does impact favour favour either either — — Moderate — increased Probably Probably oxytocin favours favours — — High Increased oxytocin — Favours Favours — — Additional considerations

Findings from a qualitative systematic review exploring perceptions of PPH prevention and treatment by women and health-care providers has provided indirect evidence in relation to oxytocin use in the (4). Findings indicate that providers recognize the benefits of using oxytocin to prevent PPH and hasten the delivery of the placenta (moderate confidence). However, in some LMIC settings, providers hold the perception that the intravenous oxytocin may actually cause retained placenta when administered preventatively or may contribute to PPH when given to induce labour (moderate confidence). In rural LMIC settings where access to health facilities may be limited, community-based health providers (usually traditional birth attendants) prefer to use traditional techniques (massage) and herbal medicines to treat retained placenta (moderate confidence). There were no findings from studies of women’s perceptions relating to the acceptability of oxytocin.

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

Feasibility Is UVI of oxytocin feasible to implement?

Research evidence

No direct evidence relating to the feasibility of using a uterotonic for the treatment of gement a

retained placenta from either women or providers was identified. However, intravenous n a oxytocin is widely used internationally and in a range of resource settings (low to high)

(4). nt m a

Additional considerations

This intervention requires items (oxytocin, needle, syringe, normal saline, gloves) that red expect to a are typically available in adequately equipped health facilities providing normal delivery care by a skilled . Performing this intervention would be considered part of the expertise of skilled health personnel. tion comp Indirect findings from a qualitative systematic review exploring perceptions of PPH u prevention and treatment among women and health-care providers suggest that resource constraints may influence effective use of oxytocin for retained placenta, particularly in LMICs (high confidence) (4). 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 use in certain contexts (high confidence). In a wide variety of settings, health-care providers feel they need more training in third-stage management as well as specific training on when/how to administer oxytocin (high confidence). Injectable oxytocin is already widely available in a range of resource settings (low to l vein injection of oxytocin sol

high) and has multiple applications (such as for PPH prevention and treatment as well a as labour induction). Oxytocin (10 IU in 1 mL for injection) is listed in the WHO Model list of essential medicines (10). Annex 4.1. Umbilic

29 30 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Summary of judgements table Summary effects Desirable Feasibility Acceptability Equity effectiveness Cost- resources required on evidence the of Certainty the evidence of Certainty effects Undesirable effects of Balance Values required Resources Judgement Don’t know — No included included No 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 — — — — — — — — management placebo/no Large costs Large expectant expectant treatment Reduced Favours Favours Favours Favours No — — — — — uncertainty or or uncertainty management placebo/no Probably No Important Important expectant expectant treatment Moderate variability Probably Probably Probably Very low Very Very low Very reduced favours favours favours favours 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 Negligible important important 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 with oxytocin Probably Yes Probably Yes favours UVI UVI favours Probably no no Probably important important Moderate Moderate Moderate Moderate variability increased Probably Probably Probably oxytocin savings favours favours Small — — — — — — ✓ ✓ ✓ ✓ ✓ Yes — uncertainty or or uncertainty Large savings Large No important important No with oxytocin Favours UVI UVI Favours variability Increased oxytocin Favours Favours Trivial Large High High Yes Yes — — — — — — — — — — — Summary of findings table Question: UVI of oxytocin compared with expectant management for management of retained placenta Setting: Hospital (Argentina, Belgium, Denmark, Malaysia, Netherlands, United Kingdom) Reference: Kumar N, Jahanfar S, Haas DM, Weeks AD. Umbilical vein injection for management of retained placenta. Cochrane Database Syst Rev (in press). ent

Certainty assessment No. of patients Effect m ge

UVI with a No. of Other Expectant Relative Absolute Certainty Importance Study design Risk of bias Inconsistency Indirectness Imprecision oxytocin n studies considerations management (95% CI) (95% CI) solution

Maternal death nt ma a 2 randomized seriousa not serious not serious very none 0/45 (0.0%) 0/48 (0.0%) not estimable ㊉㊀㊀㊀ CRITICAL trials seriousb VERY LOW Additional blood loss ≥ 500 mL

c 3 randomized serious not serious not serious very none 32/126 26/119 RR 1.00 0 fewer per ㊉㊀㊀㊀ CRITICAL expectd to e trials seriousd (25.4%) (21.8%) (0.45 to 1000 VERY LOW ar

2.22) (from 120 p fewer to 267 m more) Additional blood loss ≥ 1000 mL tion co 2 randomized seriousc not serious not serious very none 7/100 (7.0%) 5/90 (5.6%) RR 1.23 13 more per ㊉㊀㊀㊀ CRITICAL u trials seriouse (0.41 to 3.74) 1000 VERY LOW (from 33 fewer to 152 more) Blood transfusion 4 randomized seriousf not serious not serious seriousg none 20/168 24/171 RR 0.81 27 fewer per ㊉㊉㊀㊀ CRITICAL trials (11.9%) (14.0%) (0.47 to 1.38) 1000 LOW (from 74 ection of oxytocin sol fewer to 53 j more) Additional uterotonics l vein in

1 randomized seriousc not serious not serious very none 10/30 20/30 RR 0.50 333 fewer ㊉㊀㊀㊀ CRITICAL a trials serioush (33.3%) (66.7%) (0.28 to per 1000 VERY LOW 0.88) (from 480 bilic m fewer to 80 fewer) Annex 4.1. U

31 32 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta M S I Surgic P I oth e nf nv e o ea riou s studies N as tp e ction n bloo o. of of o. r th 2 2 7 2 1 1 iv artu s ma a e non l int a n ma d lo m t e e anaem s rn rv S randomized randomized randomized randomized randomized randomized urgic tudy design ( ss nu a e trials trials trials trials trials trials trials trials trials trials trials ntion l m a mL l r i a orbi a ) l int – haem em s – in ov d e ity (hy ity rv very serious very very serious very a Risk of bias of Risk s l of pl l of seriousc tru oglobin 24–48 hour oglobin 24–48 serious serious serious e ntion me s t c a f f e nt c r s –ma i l C e e a nt ertainty assessment ertainty cto l e I nconsistency a not serious serious not serious not serious not serious not not serious serious not v seriousm nu , r m a y, adm cu e a l l r a a t tion of ret em to th to ed s po i ss ov s ion to int to ion I tp a ndirectness not serious serious not serious not serious not serious not not serious serious not not serious serious not l of th l of artu e r a a in n m e pl ed d , g% e o n prod m s a very serious very I iv not serious serious not mprecision c iz serious serious serious serious e e c int ed nt very very very very very very very uct a a r b n d e s k e of conc , r rv j e n e considerations ntion a l or r l or O none none none none none none e ther ther ption s es ) pir a tory f tory 0/45 (0.0%) 5/93 (5.4%) 5/93 U oxytocin oxytocin (46.5%) (46.5%) 131/282 131/282 solution (18.5%) (18.5%) 23/124 23/124 with with VI 88 88 85 85 a N ilur o. of patients of o. e , a management 0/45 (0.0%) 4/86 (4.7%)4/86 n E d oth 159/264 159/264 (60.2%) (60.2%) xpectant xpectant (27.1%) (27.1%) 32/118 32/118 84 84 81 81 e r add (0.43 to 1.06) to 1.06) (0.43 not estimable estimable not (0.32 to 4.16) (0.32 ition (95% CI (95% 0.68 RR (0.56 to (0.56 Relative RR 0.73 RR 1.16 RR 0.95) 0.95) – – a l s

)

Effect urgic 163 fewer per per fewer 163 (0.61 lower to (0.61 lower 191.71 higher) higher) 191.71 87 fewer per per fewer 87 fewer to 147 fewer 0.61 higher) higher) 0.61 fewer to 30 to 30 fewer 7 more per per 7 more fewer to 16 to 16 fewer MD 20.92 20.92 MD (from 265 265 (from (from 155 155 (from (95% CI (95% Absolute (from 32 32 (from (233.56 (233.56 lower to lower fewer) fewer) a more) more) more) more) MD 0 MD lower 1000 1000 1000 l proc

)

ed ur ㊉㊀㊀㊀ ㊉㊀㊀㊀ ㊉㊀㊀㊀ ㊉㊀㊀㊀ ㊉㊀㊀㊀ ㊉㊉㊀㊀ VERY LOW VERY LOW VERY LOW VERY LOW VERY VERY LOW VERY C to tr to es ertainty LOW LOW ◯

ea t PPH IMPORTANT IMPORTANT I mportance CRITICAL CRITICAL CRITICAL CRITICAL Certainty assessment No. of patients Effect UVI with No. of Other Expectant Relative Absolute Certainty Importance Study design Risk of bias Inconsistency Indirectness Imprecision oxytocin studies considerations management (95% CI) (95% CI) solution Postpartum anaemia – haemoglobin 40-45 days postpartum, g% 1 randomized seriousf not serious not serious very none 47 49 – MD 0.5 ㊉㊀㊀㊀ IMPORTANT n

trials serious higher VERY LOW ent

(0.14 lower to m

1.14 higher) ge a Prolonged hospitalization (stay at hospital more than two days) n 1 randomized seriousc not serious not serious very none 19/94 16/86 RR 1.09 17 more per ㊉㊀㊀㊀ IMPORTANT trials seriouso (20.2%) (18.6%) (0.60 to 1.97) 1000 nt ma

VERY LOW a (from 74 fewer to 180 more) Maternal dissatisfaction with third-stage management to expectd to 1 randomized very seriousl not serious not serious very none 6/18 (33.3%) 21/24 RR 0.38 543 fewer ㊉㊀㊀㊀ IMPORTANT e

h ar trials serious (87.5%) (0.19 to 0.74) per 1000 VERY LOW p (from 709 m fewer to 228 fewer) tion co

CI: confidence interval;RR : risk ratio; MD: mean difference;UVI : umbilical vein injection u a Data provided by studies at moderate and high risk of bias. b Small sample size. No events, not estimable. c All of pooled effect provided by study (or studies) at moderate risk of bias. d Small sample size. Wide CI including both appreciable reduction and appreciable increase in risk with oxytocin injection. e Small sample size, few events. Wide CI including both appreciable reduction and appreciable increase in risk with oxytocin injection. f Majority of pooled effect provided by study (or studies) at moderate risk of bias. g Wide CI including both appreciable reduction and appreciable increase in risk with oxytocin injection.

h ection of oxytocin sol Single study with small sample size and few events. j i Majority of pooled effect provided by studies at high risk of bias for this outcome. j Small sample size. Wide CI crossing the line of no effect and also including appreciable reduction in risk with oxytocin injection. k

Single study with small sample size and few events. Wide CI including both appreciable reduction and appreciable increase in risk with oxytocin injection. l vein in l Majority of pooled effect provided by study at high risk of bias. a m Severe statistical heterogeneity (I²=80%). bilic n Single study with small sample size. m o Single study with small sample size. Wide CI including both appreciable reduction and appreciable increase in risk with oxytocin injection. Annex 4.1. U

33 34 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. R eferences 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 2020). July 10 accessed (https://www.who.int/gho/health_equity/report_2015, 2015 Organization; Health World Geneva: health. child and newborn maternal, reproductive, State of inequality: 2016;133(3):307–11.Obstet. doi: 10.1016/j.ijgo.2015.10.015. JGynaecol Int inSenegal. hemorrhage prevention of the postpartum for interventions two of A. Cost-effectiveness Bankole K, J, Philbin Kost A, Diallo M, Vlassoff 2020). July 10 accessed (http://mshpriceguide.org/en/home/, 2015 Health. for Sciences Management guide. price products medical International Health. for Sciences Management doi:10.1186/s12884-015-0749-z. 2015;15(1):305. Childbirth. Pregnancy BMC settings. inlow-resource of analysis misoprostol consequences cost haemorrhage: Prevention of postpartum J. Robertson FL, Zhao DL, Lang doi:10.1002/ijgo.12836. 2019;146(1):56–64. Obstet. JGynaecol Int hemorrhage. preventionpostpartum of the for uterotonic of reviewagents cost-effectiveness of the P, TA,Lawrie Sobiesuo Rogozinska E, Vogel JP, OT. Ternent Oladapo L, Asystematic pone.0215919. review.A qualitative systematic 2019;14(5):e0215919. PLoS One. doi:10.1371/journal. haemorrhage: prevention of the postpartum for to inrelation interventions providers Vogel S, Downe JP, K, Finlayson OT. healthcare Oladapo and to women matters What 2018;13(4):e0194906. doi:10.1371/journal.pone.0194906. qualitative review. Asystematic childbirth: PLoS One. during to women matters What OT, AM. Gulmezoglu Oladapo M, K, Finlayson Bonet S, Downe 2012(3):CD006176. doi:10.1002/14651858.CD006176.pub2. Syst Rev. Database of of third labour. stage Cochrane management routine the for vein injection Umbilical A. Yamamoto Weeks G, JM, Carroli Nardin N, R, Mori CD001337.pub2. Cochraneplacenta. Database Syst Rev. 2011(5):CD001337. doi:10.1002/14651858. of retained management for vein injection Umbilical G. Carroli A, Weeks JM, Nardin 4.2 Umbilical vein injection of oxytocin compared to other umbilical vein injection regimens

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 with retained placenta (P), does the use of UVI of oxytocin (I) compared to other UVI regimens (C) improve maternal outcomes (O)? Problem: Retained placenta Perspective: Clinical practice recommendation – population perspective Population (P): Women in the third stage of labour, with a retained placenta Intervention (I): UVI of oxytocin Comparator (C): UVI of solution without uterotonics; with another uterotonics; UVI of plasma expander Setting: Hospital or community setting.

Priority outcomes (O):1 Critical outcomes:  Maternal death  Additional blood loss ≥ 500 mL  Additional blood loss ≥ 1000 mL  Blood transfusion l vein injection regimens  Additional uterotonics a

 Invasive nonsurgical interventions (including manual removal of placenta [MROP], mbilic curettage and artery embolization)  Surgical interventions (including hysterectomy)  Maternal temperature ≥ 40 °C red other to u

 Procedure-related complications a  Infections  Severe morbidity  Maternal transfer

Important outcomes:  Mean blood loss  Postpartum anaemia  Additional nonsurgical interventions (for example, external aortic compression and l vein injection of oxytocin comp

compression garments) a  Nausea, vomiting or shivering

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 outcomes “maternal well-being” and “maternal satisfaction” have been added as part of this

update. Annex 4.2. Umbilic

35 36 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Research evidence evidence Research regimens? UVI with other compared when outcomes, priority on the UVI of with oxytocin placenta of treating retained effect is the What Effects of interventions Assessment           women), MROP was based on the judgement of the attending obstetrician; in the inthe obstetrician; attending of the judgement the on women), based was MROP trial (81 inone women). minutes 45 trial at women); (200 trial (200 and one In one in minutes trial (37 women); 30–45 inone at minutes women); 40 at trialsin 11 (1388 minutes post-treatment/diagnosis women); 30 at 163 on data trials (reporting infour group) MROP. for management expectant minutes 15 inthe at was MROP placenta post-treatment point a time post-diagnosis trials prespecified Most (or of retained trial (28 minutes. one women) 60 at women) minutes; 45 at trial (54 one minutes; women) 30 at trials 11 (1736 minutes; 30 at administered was treatment trials (81 of these women), inone although six trials women) (295 20 minutes, at birth; after minutes 15 placenta retained women) diagnosed 73 on data (reporting Two trials. between varied diagnosis trials for point time the birth, after minutes 30 placenta retained diagnosed to analyses data the trials contributing most Although reported. not was age trials gestational innine and preterm, and term both as women trial described One (three (one(four trials); trials); weeks (two weeks trial); ≥34 trials). ≥ 37 34–42 weeks (one ≥20 weeks criteria: trial); inclusion inthe ≥ 28 weeks range age or age gestational minimum a trials specified Some described. this not was data, trials contributing eight other inthe and, with pregnancies singleton women only trials included Thirteen women. to 30 577 from trials ranged inthe randomized of women number The hospital. in asingle trials 11 were undertaken remaining The to two sites. 11 from ranging countries, in single Ten Kingdom. United the trials involved and centres multiple Uganda Pakistan, across (four trials). Kingdom trial United involved the 13 centres and largest Uganda The (China), Italy, Israel, Malaysia (two (two India, trials), trials), Pakistan Netherlands, the (four trials), (two Denmark trials), KongSAR Belgium, Egypt Hong Argentina, Finland, in settings inhospital place took to analyses data the trialscontributed that The review criteria. the inclusion meet not did trial arms those because analyses, women). Two four-arm one women) (16 from the from groups trial excluded were also (37 available abstract inthe group ineach of women number the about information (44 data to of alack due women), another reported inthe and of inconsistencies because However, one toplacenta. analyses, data the contribute trials not did two to retained treat of oxytocin UVI received who women women)trials (2302 included women) (1) 24 Review trials (2348 includes that Cochrane updated an from is placenta treating retained for UVI of effects the on Evidence of studies characteristics and Source Maternal satisfaction Maternal well-being Prolonged hospitalization initiationDelayed of breastfeeding Maternal temperature ≥ 38 °C Summary of evidence Summary . Twenty-three of these remaining two trials (117 women), the protocol for MROP was not described in the trial reports. The trials considered in this evidence summary compared UVI of oxytocin solution versus UVI of saline solution; plasma expander; solution; solution; and carbetocin solution (although in the comparison with prostaglandins and carbetocin, women receiving oxytocin were analysed as the control group). Five trials (all oxytocin versus saline) administered a placebo. All drugs were administered in saline solution, but the dose and the total volume of solution administered varied between trials, and different types of prostaglandins were used:

UVI of oxytocin solution versus UVI of saline solution  Oxytocin 10 IU plus saline solution 10 mL versus saline solution 10 mL (one trial, 35 women)1  Oxytocin 10 IU plus saline solution 19 mL versus saline solution 20 mL (one trial, 30 women)  Oxytocin 10 IU plus saline solution 20 mL versus saline placebo 1 mL plus saline solution 20 mL (four trials, 284 women)  Oxytocin 20 IU plus saline solution 18 mL versus saline solution 20 mL (one trial, 193 women)  Oxytocin 20 IU plus saline solution 20 mL versus saline solution 20 mL (one trial, 52 women)  Oxytocin 30 IU plus saline solution 20 mL versus saline solution 20 mL (one trial, 18 women)  Oxytocin 30 IU plus saline solution 27 mL versus saline solution 30 mL (one trial, 35 women)  Oxytocin 50 IU plus saline solution 25 mL versus sterile water placebo 5 mL plus saline solution 25 mL (one trial, 577 women) l vein injection regimens a  Oxytocin 50 IU plus saline solution 25 mL versus saline solution 30 mL (two trials, 91 women) mbilic  Oxytocin 100 IU plus saline solution 20 mL versus saline solution 30 mL (two trials, 79 women).

UVI of oxytocin solution versus plasma expander

 Oxytocin 50 IU plus saline solution 15 mL versus Dextran 70, 20 mL (one trial, 109 red other to u a women).

UVI of prostaglandin solution versus UVI of oxytocin solution  Prostaglandin F2α (carboprost) 20 mg plus saline solution 20 mL versus oxytocin 30 IU plus saline solution 20 mL (one trial, 21 women) Misoprostol 800 μg plus saline solution 30 mL versus oxytocin 20 IU plus saline 30 mL (one trial, 51 women) Misoprostol 800 μg plus saline solution 30 mL versus oxytocin 50 IU plus saline 25 mL (one trial, 41 women) Misoprostol 800 μg plus saline solution 30 mL versus oxytocin 50 IU plus saline 30 l vein injection of oxytocin comp mL (one trial, 60 women). a

1 The number of women detailed is the total number of women for whom data were available in both groups for all trials included in this comparison. Annex 4.2. Umbilic

37 38 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta 43/417 95% to CI 2.09). 0.87 31/403; versus 1.35, RR (three inrisk 820 women; trials, reduction appreciable with an CI compatible is also however, solution; with saline compared 95% the when infections increase probably solution of oxytocin UVI that suggests evidence Infections: Moderate-certainty low certainty. of was very outcomes both for evidence the only, solution of because saline injection with compared following when injections hypertension pain and abdominal both on has solution UVI of oxytocin effect complications: what Procedure-related is unclear It to0.01 2.69). 0.14, 95% RR CI 3/355; (four 724 0/369CIs this versus outcome for trials, women; wide the considering known not is intervention of the effect the that suggests evidence MROP, than (PPH) other Low-certainty interventions. related to randomized the haemorrhage to postpartum treat procedures surgical additional other and failure, respiratory hysterectomy, as or renal to intensive morbidities admission care, maternal of severe maternal morbidity inreporting were included review; however, Cochrane inthe outcome hysterectomy on data independent an as (including interventions Surgical hysterectomy): to 1.40). CI 0.56 27/420 (four 826 women; trials, solution of saline UVI 29/406; versus 0.89, 95% RR to instrumental difference evacuation no or of retained products may make little solution of oxytocin UVI that suggests 0.97). evidence Low-certainty 95% CI 418/668; 0.69 to versus 0.82, average RR 1370 388/702 (14 trials, women; of risk MROP the may reduce solution oxytocin of UVI that Invasive suggests nonsurgical evidence interventions: Low-certainty to 1.23). CI 0.59 95% 0.85, RR 46/332; versus (four 678 trials, solution 43/346 of saline women; UVI with compared when outcome to this difference no or little makes probably solution of oxytocin UVI that suggests evidence Moderate-certainty uterotonics: Additional 974 64/493 women; 95% CI 58/481; 0.78 versus to 1.08, 1.49). RR transfusion (seven trials, blood for need to the difference no or little makes probably this that intervention suggests evidence Blood transfusion: Moderate-certainty 95% CI 0.70 1.08, toRR 1.68). (four 766 37/391 trials, solution women; of saline with UVI 33/375; compared versus when outcome to this difference no or little makes probably solution of oxytocin ≥1000 mL: loss blood Additional evidence). 129/434;versus high-certainty to 0.98, 1.20; 95% RR CI 0.80 (six 132/453 solution women; 887 of saline trials, with UVI compared when mL 500 ≥ loss blood additional risk of to the difference little or no makes solution of oxytocin ≥500 loss mL: blood Additional evidence). interval [RR] ratio risk low-certainty [CI] 2.93,0.12 95% 0/384; confidence 71.59; to versus 1/398 (five solution 782 trials, ofwomen; saline with UVI compared when death maternal on has solution UVI of oxytocin effect what is unclear It Maternal death: solution saline of UVI versus solution of UVI oxytocin of Effects (one 20 mL women). saline plus 200 trial, Carbetocin 1 mL (containing 1mL µ Carbetocin 100 solution of oxytocin UVI versus solution of carbetocin UVI (one mL 30 women). 53 trial, solution insaline mg 0.2 ergometrine versus mL 30 solution saline plus 20 IU Oxytocin solution of ergometrine UVI versus solution of oxytocin UVI High-certainty evidence suggests that the use of UVI of UVI use the that suggests evidence High-certainty Moderate-certainty evidence suggests that UVI UVI that suggests evidence Moderate-certainty g) plus saline solution 20 mL versus oxytocin 20 IU 20 IU oxytocin versus 20 mL solution saline plus g) compared with UVI of saline solution solution of saline with UVI compared Hysterectomy was not reported reported not was Hysterectomy . The review defined serious serious review defined . The when compared with compared when Mean blood loss: It is unclear what effect UVI of oxytocin has on mean blood loss when compared with saline solution only, because the evidence was of very low certainty. Postpartum anaemia: The review reported three proxy outcomes relevant to consideration of postpartum anaemia. High-certainty evidence suggests that the intervention makes little or no difference to afall in haemoglobin level > 10% from time of randomization to first day postpartum (one trial, 541 women; 185/274 versus 178/267; RR 1.01, 95% CI 0.90 to 1.14). However, the evidence on haemoglobin 24–48 hours postpartum and haemoglobin 40–45 days postpartum was of very low certainty. Nausea, vomiting or shivering: Although both nausea following injection and shivering following injection were reported, the evidence was of very low certainty. Maternal temperature ≥ 38 °C: The review reported fever, but the parameters were defined differently in two trials (>38 °C; > 37.5 °C on two successive occasions between 1 and 12 hours apart or one reading of more than 38 °C in the 24 hours after birth), and not defined at all in the other two trials. The available evidence suggests that UVI of oxytocin solution may increase the risk of fever when compared with saline solution alone (four trials, 707 women; 16/360 versus 9/347; RR 1.67, 95% CI 0.76 to 3.64; low-certainty evidence). The review reported prolonged hospitalization (stay in hospital for more than 2 days was reported), and maternal satisfaction (maternal dissatisfaction with third-stage management was reported), but the evidence for both of these outcomes was of very low certainty. The priority outcomes maternal temperature ≥ 40 °C, maternal transfer, additional nonsurgical interventions (for example, external aortic compression and compression garments), artery embolization, delayed initiation of breastfeeding and maternal well-being were not reported for this comparison.

Effects of UVI of oxytocin solution versus UVI of plasma expander l vein injection regimens a One small trial included in the Cochrane review reported evidence relevant to only two

priority outcomes for this comparison. However, the evidence on both additional blood mbilic loss ≥ 1000 mL (the trial reported blood loss > 1000 mL) and invasive nonsurgical interventions (MROP reported) was of very low certainty.

Effects of UVI of oxytocin solution versus UVI of prostaglandin solution

Only six priority outcomes were reported for this comparison: additional uterotonics; red other to u invasive nonsurgical interventions (MROP reported); procedure-related a complications (abdominal pain reported); mean blood loss; nausea, vomiting or shivering (shivering following injection reported); maternal temperature ≥ 38 °C (fever reported). However, the evidence for all these outcomes was of very low certainty.

Effects of UVI of oxytocin solution versus UVI of ergometrine solution One outcome was reported for this comparison in a single, very small trial. Evidence for invasive nonsurgical interventions reported as MROP was of very low certainty. No other priority outcomes were reported for this comparison. l vein injection of oxytocin comp

Effects of UVI of carbetocin solution versus UVI of oxytocin solution a One trial of 200 women contributed data to this comparison. It is unclear what effect UVI of carbetocin solution has on blood loss > 500 mL (proxy for additional blood loss ≥ 500 mL), blood transfusion, and invasive nonsurgical interventions: MROP, and adherent placenta, piecemeal removal and uterine curettage in comparison with oxytocin injection (very-low-certainty evidence). Annex 4.2. Umbilic

39 40 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Additional considerations Judgement regimens? UVI other versus UVI of of oxytocin effects anticipated undesirable the are substantial How Undesirable effects Judgement regimens? UVI other versus UVI of of oxytocin effects anticipated desirable the are substantial How effects Desirable regimens? UVI other versus UVI of of oxytocin effects on evidence of the overall is the certainty What evidence of the Certainty Don’t know Don’t know third stage of labour until new evidence is available. until evidence new ofthird labour stage of the (or management active the for via uterotonics) UVI other saline with normal oxytocin use of routine the support to evidence insufficient was there that concluded authors The reviewoutcomes. specified the available for information relevant no was there and each, for study one only included comparisons Other outcomes. relevant the any in of women), of difference (six 394 only evidence no was of saline there studies, women) (2) (1118 studies nine identified and of third labour of the stage management routine the for uterotonic drug) UVI of anyor with (alone effectiveness the review assessed 2012 Cochrane A separate this comparison. for were reported outcomes priority other No oxytocin. g/dL lower, g/dL 0.55 lower)MD g/dL 95% with lower CI to 0.59 0.51 compared when higher) changes in may reduce Hb concentration and (g/dL) g/dL higher, g/dL 0.87 (one MD to 95% women; g/dL 1.66 CI higher 0.08 200 trial, Hb concentration postpartum may increase (g/dL) injection carbetocin that suggests concentration (g/dL) anaemia: Postpartum solution. with oxytocin compared [MD] difference lower,mean mL 98 lower)mL 95% CI 192.47 lower3.53 mL when to (one women; postpartum) 200 trial, to 2hours placenta of retained diagnosis from (measured (in mL) loss 95% blood CI 0.17 mean total to reduce 0.40) may also and uterotonics of additional use the may reduce solution of carbetocin UVI that suggests evidence Low-certainty — ✓ Varies Varies — ✓ and change and in Hb concentration (g/dL) postpartum haemoglobin (Hb) haemoglobin postpartum review reported The (one trial, 200 women; 18/100 versus 69/100; RR 0.26, 0.26, 69/100; RR versus (one 18/100 women; 200 trial, . Comparing UVI of normal saline plus oxytocin with UVI with UVI oxytocin plus saline of normal UVI . Comparing Trivial Large — — Moderate Small — — (one women; 200 trial, Moderate . Low-certainty evidence evidence . Low-certainty Small — — Trivial Large — —

Judgement — ✓ — — — 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 UVI of oxytocin solution versus other UVI regimens for retained placenta?

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) (3). 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 an update of a qualitative systematic review exploring perceptions of

PPH prevention and treatment among women and providers suggest that women l vein injection regimens a do not recognize the clinical definitions of blood loss or what might be considered “normal” blood loss (moderate confidence) (4). Furthermore, in some low- and middle- mbilic 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 red other to u

during antenatal care (moderate confidence), and the importance of kind, clinically a competent staff with a willingness to engage in shared decision-making around PPH management (moderate/low confidence). In addition, it was found that women are concerned about feelings of exhaustion and anxiety (at being separated from their babies) following PPH, as well as the long-term psychological effects of experiencing PPH and the negative impact this may have on their ability to breastfeed (moderate/low confidence).

Additional considerations

None. l vein injection of oxytocin comp a Annex 4.2. Umbilic

41 42 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Additional considerations Research evidence placenta retained for regimens (costs) UVI other requirements versus resource the are of large oxytocin How of UVI Resources Judgement regimens? UVI other or solution UVI of favour oxytocin effects undesirable and desirable between balance the Does of effects Balance Judgement Don’t know Important uncertainty uncertainty Important this intervention would be considered part of the expertise of skilled health personnel. health of skilled expertise of the part considered be would this intervention Performing settings. hospital equipped gloves) available inadequately typically are that saline, normal syringe, (uterotonic items requires needle, intervention This solution, related to this intervention. studies any cost-effectiveness identify not did Aliterature search outcomes. economic or any cost prespecify not did placenta retained for review UVI on Cochrane The — or variability or — Varies ✓ Possibly important Possibly important uncertainty or or uncertainty other UVI UVI other regimens Favours Favours variability — — other UVI UVI other regimens Probably favours favours — Probably no important important no Probably uncertainty or or uncertainty variability Does not not Does favour favour either either ✓ — favours UVI UVI favours of oxytocin oxytocin of Probably solution solution — uncertainty or or uncertainty No important important No variability — Favours UVI UVI Favours of oxytocin oxytocin of solution — Main resource requirements Resource Description Staff Uterotonic solution administered via UVI 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, additional training would be required if this intervention is to be introduced in settings where it has not previously been available. Supplies Indicative costs:  Oxytocin per 10 IU: US$ 0.22–1.19 (5,6)  Carboprost per 250 μg: US$ 23.84 (7)  Misoprostol per 200 μg: US$ 0.09–0.52 (5)  Ergometrine per 500 μg: US$ 1.97 (7)  Carbetocin per 100 μg: US$ 13.10 –25.60 (8–11)  Plasma expander: Dextran 70 6% in normal saline, 20 mL: US$ 0.20 (12)  Needle and syringe: approximately US$ 0.07 (6)7  Normal saline – median price of USD$1 per litre (12)  Gloves. Equipment and Oxytocin cold chain storage and transport costs: infrastructure Cost per birth: possibly US$ 0.84 in a low-resource setting (13). Time Minimal Supervision and Supervision and monitoring to ensure appropriate use, stock monitoring availability and quality.

Resources required Judgement ✓ — — — — — —

Don’t know l vein injection regimens

Varies Large costs Moderate Negligible Moderate Large a costs costs or savings savings savings mbilic

Certainty of the evidence on required resources What is the certainty of the evidence on costs? red other to u

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

Cost-effectiveness Judgement ✓ — — — — — — Don’t know Varies Favours Probably Does not Probably Favours UVI other UVI favours favour favours UVI of oxytocin regimens other UVI either of oxytocin solution l vein injection of oxytocin comp

regimens solution a Annex 4.2. Umbilic

43 44 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Additional considerations Judgement Additional considerations Research evidence to key acceptable stakeholders? of oxytocin UVI Is Acceptability Research evidence equity? health on placenta of retained treatment for regimens of other UVI versus solution of oxytocin of UVI impact the be would What Equity Don’t know perceptions relating to the acceptability of oxytocin. relating to acceptability the perceptions placenta (moderate confidence) to retained treat medicines (massage) herbal techniques and to traditional prefer use (usually attendants) providers health birth traditional community-based limited, be (moderate confidence) labour to given induce to preventatively may when contribute PPH or administered when placenta retained cause may actually oxytocin intravenous the that perception placenta (moderate confidence) of the delivery the hasten preventand to PPH using of oxytocin recognize benefits the (4) period postpartum inthe use torelation oxytocin in evidence indirect provided has providers health-care and by women treatment and prevention of PPH perceptions review aqualitative systematic from exploring Findings settings. (low to high) (4) settings of resource inarange and internationally used is widely oxytocin Intravenous identified. was providers or women either from placenta of retained treatment the for of UVI relating to acceptability the evidence direct No primary health facilities. health primary in birth giving women for inequities level ofto care) reduce ahigher probably would (which placenta to retained treat transfer may curettage require or MROP for need the Reducing women. disadvantaged among improve outcomes and equity health on (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 (WHO) State World Organization report 2015 Health The of inequality identified. was evidence direct No ✓ . Therefore, reducing maternal morbidity due to PPH could have a positive impact have to could apositive PPH due impact morbidity maternal reducing . Therefore, Varies — . Some uterotonics (such available inall be may carbetocin) not as . Some . In rural LMIC settings where access to health facilities may facilities to health access where settings LMIC rural . In Reduced — . There were no findings from studies of women’s studies from findings were no . There the hold providers . However, settings, LMIC insome Probably reduced — Probably no no Probably . Findings indicate that providers providers that indicate . Findings impact — increased Probably — Increased — Judgement ✓ — — — — — Don’t know Varies No Probably No Probably Yes Yes

Feasibility Is UVI of oxytocin solution for treatment of retained placenta feasible to implement?

Research evidence

No direct evidence relating to the feasibility of using UVI of an uterotonic for the treatment of retained placenta from either women or providers was identified. However, intravenous oxytocin is widely used internationally and in a range of resource settings (low to high) (4).

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 retained placenta, particularly in LMICs (high confidence) (4). 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 use in certain contexts (high confidence). In a wide variety of settings, health-care providers feel they need more training in third-stage management as well as specific training on when/how to administer oxytocin (high confidence). This intervention requires items (needle, syringe, normal saline, gloves) that are typically available in adequately equipped hospital settings. Performing this intervention would be considered part of the expertise of skilled health personnel. Injectable oxytocin is already widely available in a range of resource settings (low to l vein injection regimens

high) and has multiple applications (such as for PPH prevention and treatment as well a as labour induction). Oxytocin (10 IU in 1 mL for injection) is listed in the WHO model

list of essential medicines (15). mbilic

Judgement — — — — ✓ — red other to u

Don’t know Varies No Probably No Probably Yes Yes a l vein injection of oxytocin comp a Annex 4.2. Umbilic

45 46 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Summary of judgements table Summary Feasibility Acceptability Equity effectiveness Cost- resources required on evidence the of Certainty effects Desirable the evidence of Certainty effects Undesirable effects of Balance Values required Resources 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 — — — — — — ✓ ✓ UVI regimens UVI regimens Favours other other Favours Favours other other Favours Large costs Large Reduced — — — — uncertainty or or uncertainty UVI regimens UVI regimens favours other other favours favours other other favours Important Important Moderate variability Probably Probably Very low Very Probably Very low Very 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 Negligible important important Moderate variability Does not not Does Does not not Does Possibly costs or or costs savings impact Small Low Low — — — — — — — — — — — uncertainty or or uncertainty Probably Yes Probably Yes favours UVI UVI favours favours UVI UVI favours Probably no no Probably of oxytocin of of oxytocin of important important Moderate Moderate Moderate Moderate variability increased Probably Probably Probably savings Small — — — — — — — — — ✓ ✓ uncertainty or or uncertainty Large savings Large No important important No Favours UVI UVI Favours Favours UVI UVI Favours of oxytocin of of oxytocin of variability Increased Trivial Large High High Yes Yes — — — — — — — — — — — Summary of findings table ens

Question: UVI of oxytocin solution compared with UVI of saline solution for management of retained placenta m Setting: Hospital (Argentina, Denmark, Hong Kong, India, Italy, Malaysia, Netherlands, Pakistan, Uganda, United Kingdom) Reference: Kumar N, Jahanfar S, Haas DM, Weeks AD. UVI for management of retained placenta. Cochrane Database Syst Rev (in press). ection regi

Certainty assessment No. of patients Effect j UVI of Other UVI of saline Relative Absolute Certainty Importance No. of studies Study design Risk of bias Inconsistency Indirectness Imprecision oxytocin considerations solution (95% CI) (95% CI) solution l vein in a Maternal death

5 randomized not serious not serious not serious very none 1/398 (0.3%) 0/384 RR 2.93 0 fewer per ㊉㊉㊀㊀ CRITICAL bilic trials seriousa,b (0.0%) (0.12 to 1000 LOW 71.59) (from 0 fewer to 0 fewer) Additional blood loss ≥ 500 mL 6 randomized not serious not serious not serious not serious none 132/453 129/434 RR 0.98 6 fewer per ㊉㊉㊉㊉ CRITICAL

trials (29.1%) (29.7%) (0.80 to 1.20) 1000 HIGH red other to um a (from 59 p fewer to 59 m more) Additional blood loss ≥ 1000 mL 4 randomized not serious not serious not serious seriousa none 37/391 33/375 RR 1.08 7 more per ㊉㊉㊉㊀ CRITICAL trials (9.5%) (8.8%) (0.70 to 1.68) 1000 MODERATE (from 26 fewer to 60 more) ection of oxytocin co

Blood transfusion j 7 randomized not serious not serious not serious seriousc none 64/493 58/481 RR 1.08 10 more per ㊉㊉㊉㊀ CRITICAL trials (13.0%) (12.1%) (0.78 to 1.49) 1000 MODERATE

(from 27 l vein in fewer to 59 a more) bilic m Annex 4.2. U

47 48 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Additional uterotonic I Procedure-rel P Surgic I N nfection nv rocedure-rel o. of studies of o. as 14 14 4 4 3 1 1 ive non ive a l intervention s S randomized randomized randomized randomized randomized randomized urgic tudy design a a ted coted m ted co trials trials trials trials trials trials trials trials trials trials trials trials a l intervention m s s : s plic plic urgic very serious very R not serious serious not not serious serious not a a isk of bias of isk serious serious serious tion tion a l ev s s g g f – abdo : hyperten s –ma C e a ertainty assessment ertainty cu I nconsistency a not serious serious not not serious serious not serious not serious not not serious serious not not serious serious not tion of ret m nu alin p a s l re ion following injection a m in ov a I ndirectness not serious serious not not serious serious not serious not serious not not serious serious not not serious serious not a ined product l of the pl the l of a very serious very I not serious serious not mprecision cent serious serious serious serious s very very of conception a a,h d c j i considerations O none none none none none none ther ther 0/32 (0.0%) 0/32 1/11 (9.1%)1/11 388/702 388/702 oxytocin oxytocin (55.3%) (55.3%) (10.3%) (10.3%) solution 43/346 (12.4%) (12.4%) 27/420 27/420 43/417 (6.4%) (6.4%) U of of VI N o. of patients of o. U 0/28 (0.0%)0/28 0/7 (0.0%) 0/7 of saline saline of VI 418/668 418/668 (62.6%) (62.6%) solution (13.9%) (13.9%) 29/406 29/406 46/332 46/332 31/403 31/403 (7.7%) (7.7%) (7.1%) (7.1%) (0.87 to 2.09) to 2.09) (0.87 (0.69 to 0.97) (0.69 to 0.97) (0.56 to 1.40) to 1.40) (0.56 not estimable estimable not (0.59 to 1.23) to 1.23) (0.59 (95% CI (95% 2.00 RR (0.09 to (0.09 0.89 RR RR 0.85 0.82 RR Relative 1.35 RR 43.22) 43.22) )

Effect (from 0 fewer 0fewer (from 113 fewer per per fewer 113 21 fewer per per fewer 21 27 more per per more 27 0 fewer per per 0 fewer 8 fewer per per 8 fewer fewer to 84 to 84 fewer fewer to 29 to 29 fewer fewer to 32 to 32 fewer to 0fewer) fewer to 19 to 19 fewer (from 194 194 (from (95% CI (95% Absolute (from 57 57 (from (from 10 10 (from (from 31 31 (from fewer) fewer) more) more) more) more) more) more) 1000 1000 1000 1000 1000

)

MODERATE MODERATE MODERATE MODERATE ㊉㊉㊉㊀ ㊉㊀㊀㊀ ㊉㊀㊀㊀ ㊉㊉㊀㊀ ㊉㊉㊀㊀ ㊉㊉㊉㊀ VERY LOW VERY LOW VERY C ertainty LOW LOW LOW

I mportance CRITICAL CRITICAL CRITICAL CRITICAL CRITICAL CRITICAL Certainty assessment No. of patients Effect UVI of Other UVI of saline Relative Absolute Certainty Importance No. of studies Study design Risk of bias Inconsistency Indirectness Imprecision oxytocin considerations solution (95% CI) (95% CI) solution

Serious maternal morbidity (hysterectomy, admission to intensive care, renal or respiratory failure, and other additional surgical procedures to treat PPH ens other than manual removal of placenta, related to the randomized interventions) m 4 randomized not serious not serious not serious very none 0/369 3/355 (0.8%) RR 0.14 7 fewer per ㊉㊉㊀㊀ CRITICAL trials seriousa,b (0.0%) (0.01 to 2.69) 1000 LOW (from 8 fewer ection regi

to 14 more) j Mean blood loss (mL) 5 randomized seriousf seriousk not serious very seriousl none 143 131 – MD 13.56 ㊉㊀㊀㊀ IMPORTANT l vein in

trials lower VERY LOW a (118.83 lower

to 91.71 bilic higher) Postpartum anaemia – fall in haemoglobin level > 10% from time of randomization to first day postpartum 1 randomized not serious not serious not serious not serious none 185/274 178/267 RR 1.01 7 more per ㊉㊉㊉㊉ IMPORTANT trials (67.5%) (66.7%) (0.90 to 1.14) 1000 HIGH (from 67

fewer to 93 red other to um a

more) p m Postpartum anaemia – haemoglobin 24–48 hours postpartum, g% 1 randomized seriousm not serious not serious very seriousn none 85 82 – MD 0.1 lower ㊉㊀㊀㊀ IMPORTANT trials (0.76 lower to VERY LOW 0.56 higher) Postpartum anaemia – haemoglobin 40–45 days postpartum, g% 1 randomized seriousm not serious not serious very seriousn none 47 44 – MD 0.1 higher ㊉㊀㊀㊀ IMPORTANT trials (0.58 lower VERY LOW to 0.78 ection of oxytocin co higher) j Nausea following injection

g o

1 randomized serious not serious not serious very serious none 0/32 (0.0%) 0/28 (0.0%) not estimable ㊉㊀㊀㊀ IMPORTANT l vein in trials VERY LOW a

Shivering following injection bilic m 1 randomized seriousg not serious not serious very seriouso none 0/32 (0.0%) 0/28 (0.0%) not estimable ㊉㊀㊀㊀ IMPORTANT trials VERY LOW Annex 4.2. U

49 50 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta q p o n m l k j i h g f e d c b a CI Fever M P N : confidence interval; RR interval; : confidence rolonged ho rolonged o. of studies of o. One study contributing data, at high risk of bias. bias. of risk high at data, contributing study One injection. with oxytocin risk in increase appreciable including and effect no of line the CI crossing Wide estimable. not events, no size, sample small with study Single meaningful. clinically not is Effect size. sample small with study Single bias. of risk moderate with studies from effect pooled All size. sample small and injection, oxytocin with risk in increase appreciable and reduction appreciable both CI including Wide (I²>60%). heterogeneity statistical Severe injection. with oxytocin risk in increase appreciable and effect, no of line the CI crossing Wide estimable. not events, No size. sample Small events. few size, sample Small bias. of risk moderate at data, contributing study One bias. of risk moderate at study by studies) (or provided effect pooled of Majority outcome. this for bias of risk high at studies by provided effect pooled of Majority injection. with oxytocin risk in reduction appreciable including and effect, no of line the CI crossing Wide injection. oxytocin with risk in increase appreciable and reduction appreciable both CI including Wide Few events. injection. oxytocin with risk in increase appreciable and reduction appreciable both CI including Wide a altern di 4 1 1 ssa S randomized randomized randomized s tudy design pit ti trials trials trials trials trials trials s a f liz a ction with third- a : risk ratio; MD ratio; : risk tion ( tion very serious very R not serious serious not isk of bias of isk serious s t a y a g t ho : mean difference; PPH difference; : mean C q ertainty assessment ertainty s I s t nconsistency not serious serious not not serious serious not serious not pit a na ge ma a l m ore th ore ge I m ndirectness not serious serious not not serious serious not serious not a ent n two d n two : postpartum haemorrhage; UVI a y very serious very serious very I mprecision s serious ) very very b,p l l considerations O none none none ther ther : umbilical vein injection vein : umbilical 6/18 (33.3%) (33.3%) 6/18 oxytocin oxytocin (20.2%) (20.2%) solution 16/360 16/360 (4.4%) (4.4%) U 19/94 of of VI N o. of patients of o. 8/18 (44.4%) 8/18 9/347 (2.6%)9/347 U of saline saline of VI (22.2%) (22.2%) solution 20/90 20/90 (0.76 to 3.64) (0.76 to 3.64) (0.52 to 1.59) to 1.59) (0.52 (0.33 to 1.72) to 1.72) (0.33 (95% CI (95% Relative 0.75 RR RR 0.91 RR RR 1.67 RR

)

Effect (from 6 fewer 6fewer (from 20 fewer per per fewer 20 fewer to 320 to 320 fewer 111 fewer per per fewer 111 to 68 more) more) to 68 17 more per per more 17 fewer to 131 to 131 fewer (from 298 298 (from (from 107 107 (from (95% CI (95% Absolute more) more) more) more) 1000 1000 1000

)

㊉㊀㊀㊀ ㊉㊀㊀㊀ ㊉㊉㊀㊀ VERY LOW VERY LOW VERY C ertainty LOW LOW

IMPORTANT IMPORTANT I mportance CRITICAL Question: UVI of oxytocin solution compared with UVI of plasma expander for management of retained placenta

Setting: Hospital (Finland) ens Reference: Kumar N, Jahanfar S, Haas DM, Weeks AD. UVI for management of retained placenta. Cochrane Database of Systematic Reviews (in press). m

Certainty assessment No. of patients Effect

UVI of UVI of Certainty Importance

Other Relative Absolute ection regi

No. of studies Study design Risk of bias Inconsistency Indirectness Imprecision oxytocin plasma j considerations (95% CI) (95% CI) solution expander Blood loss > 1000 mL during third stage of labour

a b l vein in

1 randomized very serious not serious not serious very serious none 8/68 (11.8%) 5/41 (12.2%) RR 0.96 5 fewer per ㊉㊀㊀㊀ a trials (0.34 to 2.75) 1000 VERY LOW

(from 80 bilic fewer to 213 more) Invasive nonsurgical interventions – manual removal of the placenta 1 randomized very seriousa not serious not serious very seriousc none 49/68 22/41 RR 1.34 182 more per ㊉㊀㊀㊀ trials (72.1%) (53.7%) (0.97 to 1.85) 1000 VERY LOW

(from 16 red other to um a

fewer to 456 p more) m CI: confidence interval;RR : risk ratio; UVI: umbilical vein injection a Single study with high risk of bias. b Small sample size, few events. Wide CI including both appreciable benefit and appreciable harm with oxytocin injection. c Small sample size. Wide CI including both appreciable benefit and appreciable harm with oxytocin injection. ection of oxytocin co j l vein in a bilic m Annex 4.2. U

51 52 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta Kumar N, Jahanfar S, Haas DM, Weeks AD. UVI for management of retained placenta. Cochrane Database of Systematic Database Reviews (in press). Cochrane placenta. of retained management for AD. Weeks UVI DM, Haas S, Jahanfar N, Kumar Reference: Pakistan) Israel, Kong, Hong (Egypt, Hospital Setting: placenta of retained management for solution of oxytocin with UVI compared solution of prostaglandin UVI Question: Additional uterotonic Shivering following injection Me P I nv rocedure-rel studies a N as n blood lo n blood o. of of o. 4 1 1 1 1 ive non ive s S randomized randomized randomized randomized randomized urgic tudy design ( ss a ted co trials trials trials trials trials trials trials trials trials trials mL a ) l intervention m s plic very serious very very serious very R a isk of bias of isk serious serious serious tion s a a a – abdo s –ma C c f ertainty assessment ertainty I nconsistency not serious serious not serious not not serious serious not serious not not serious serious not m nu alin p a l re a m in ov I ndirectness not serious serious not serious not not serious serious not serious not not serious serious not a l of the pl the l of very serious very serious very very serious very very serious very a I mprecision cent serious a d b b b e considerations O none none none none none ther ther 6/10 (60.0%) 6/10 3/10 (30.0%) (30.0%) 3/10 prostaglandin 1/30 (3.3%) (3.3%) 1/30 solution (24.1%) (24.1%) U 21/87 21/87 of of VI 10 10 N o. of patients of o. 0/30 (0.0%) 0/30 5/11 (45.5%) (45.5%) 5/11 1/11 (9.1%)1/11 oxytocin oxytocin (44.2%) (44.2%) solution U 38/86 38/86 of of VI 11 11 Average RR RR Average (95% CI (95% 3.00 RR (0.58 to (0.58 (0.36 to (0.36 RR 3.30 Relative (0.41 to (0.13 to 1.32 RR 70.83) 70.83) 26.81) 26.81) 0.84) 0.84) 3.00) 3.00) 0.55 –

)

Effect fewer to 1000 to 1000 fewer 209 more per per more 209 199 fewer per per fewer 199 (from 0 fewer 0fewer (from 145 more per per more 145 fewer to 909 to 909 fewer (118.19 lower lower (118.19 Average MD MD Average 0 fewer per per 0 fewer to 0fewer) fewer to 71 to 71 fewer (from 283 283 (from (95% CI (95% (from 191 191 (from Absolute (from 54 54 (from 19 lower 19 to 80.19 to 80.19 higher) fewer) fewer) more) more) more) more) 1000 1000 1000 1000

)

㊉㊀㊀㊀ ㊉㊀㊀㊀ ㊉㊀㊀㊀ ㊉㊀㊀㊀ ㊉㊀㊀㊀ VERY LOW VERY VERY LOW VERY VERY LOW VERY LOW VERY LOW VERY C ertainty

IMPORTANT IMPORTANT I mportance CRITICAL CRITICAL CRITICAL Certainty assessment No. of patients Effect Certainty Importance

UVI of UVI of ens No. of Other Relative Absolute m Study design Risk of bias Inconsistency Indirectness Imprecision prostaglandin oxytocin studies considerations (95% CI) (95% CI) solution solution Fever 1 randomized seriousa not serious not serious very seriousb none 1/10 (10.0%) 1/11 (9.1%) RR 1.10 9 more per ㊉㊀㊀㊀ IMPORTANT ection regi trials (0.08 to 1000 VERY LOW j 15.36) (from 84 fewer to 1000

more) l vein in a CI: confidence interval;RR : risk ratio; MD: mean difference;UVI : umbilical vein injection bilic a Single study at moderate risk of bias. b Small sample size, few events. Wide CI including both appreciable benefit and appreciable harm with prostaglandins. c Majority of pooled effect from studies at high risk of bias. d Small sample size. e Very small sample size, single study. f Single study at high risk of bias. red other to um a p m ection of oxytocin co j l vein in a bilic m Annex 4.2. U

53 54 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta b a CI Kumar N, Jahanfar S, Haas DM, Weeks AD. UVI for management of retained placenta. Cochrane Database of Systematic Database Reviews (in press). Cochrane placenta. of retained management for AD. Weeks UVI DM, Haas S, Jahanfar N, Kumar Reference: (Egypt) Hospital Setting: placenta of retained management for solution to of ergometrine UVI compared solution of oxytocin UVI Question: I N nv : confidence interval; RR interval; : confidence o. of studies of o. Small sample size, few events. events. few size, sample Small bias. of risk moderate at study Single as 1 ive non ive s S randomized urgic tudy design trials trials a l intervention : risk ratio; UVI ratio; : risk R isk of bias of isk serious a : umbilical vein injection vein : umbilical s –ma C ertainty assessment ertainty I nconsistency not serious serious not nu a l re m ov I ndirectness not serious serious not a l of the pl the l of a very serious very I cent mprecision a b considerations O none ther ther 7/26 (26.9%) oxytocin oxytocin solution U of of VI N o. of patients of o. ergometrine ergometrine (63.0%) (63.0%) solution U 17/27 17/27 of of VI (0.21 to 0.86) to 0.86) (0.21 (95% CI (95% 0.43 RR Relative )

Effect 359 fewer per per fewer 359 fewer to 88 to 88 fewer (from 497 497 (from (95% CI (95% Absolute fewer) fewer) 1000

)

㊉㊀㊀㊀ VERY LOW VERY C ertainty

I mportance CRITICAL Question: UVI of carbetocin solution compared with UVI of oxytocin solution for management of retained placenta Setting: Hospital (Egypt) Reference: Kumar N, Jahanfar S, Haas DM, Weeks AD. UVI for management of retained placenta. Cochrane Database of Systematic Reviews (in press). ens m Certainty assessment No. of patients Effect UVI of UVI of Other Relative Absolute Certainty Importance No. of studies Study design Risk of bias Inconsistency Indirectness Imprecision carbetocin oxytocin considerations (95% CI) (95% CI) solution solution ection regi Blood loss > 500 mL j 1 randomized seriousa not serious not serious very seriousb,c none 3/100 (3.0%) 10/100 RR 0.30 70 fewer per ㊉㊀㊀㊀ CRITICAL trials (10.0%) (0.09 to 1.06) 1000 VERY LOW l vein in

(from 91 a fewer to 6

more) bilic Blood transfusion 1 randomized seriousa not serious not serious very seriousb,c none 1/100 (1.0%) 7/100 (7.0%) RR 0.14 60 fewer per ㊉㊀㊀㊀ CRITICAL trials (0.02 to 1.14) 1000 VERY LOW (from 69 fewer to 10

more) red other to um a p

Additional uterotonics m 1 randomized seriousa not serious not serious seriousd none 18/100 69/100 RR 0.26 511 fewer per ㊉㊉㊀㊀ CRITICAL trials (18.0%) (69.0%) (0.17 to 0.40) 1000 LOW (from 573 fewer to 414 fewer) Invasive nonsurgical interventions – manual removal of the placenta 1 randomized seriousa not serious not serious very seriousb,c none 9/100 (9.0%) 17/100 RR 0.53 80 fewer per ㊉㊀㊀㊀ CRITICAL trials (17.0%) (0.25 to 1.13) 1000 VERY LOW ection of oxytocin co (from 128 j fewer to 22 more) l vein in

Invasive nonsurgical interventions – adherent placenta, piecemeal removal and uterine curettage a 1 randomized seriousa not serious not serious very none 2/100 5/100 (5.0%) RR 0.40 30 fewer per ㊉㊀㊀㊀ CRITICAL b,e bilic

trials serious (2.0%) (0.08 to 2.01) 1000 VERY LOW m (from 46 fewer to 50 more) Annex 4.2. U

55 56 WHO recommendation on Umbilical vein injection of oxytocin for the treatment of retained placenta b a CI e d c Me P P N : confidence interval; RR interval; : confidence o o o. of studies of o. Wide CI including both appreciable reduction and appreciable increase in risk with carbetocin injection. injection. carbetocin with risk in increase appreciable and reduction appreciable both CI including Wide size. sample Small injection. carbetocin with risk in reduction appreciable including and effect no of line the CI crossing Wide events. few and size, sample Small bias. of risk moderate at trial single from effect pooled of All s s a tp tp n tot 1 1 1 artu artu a l blood lo l blood m m ane ane S randomized randomized randomized tudy design trials trials trials trials trials trials m m i i a a ( ss –ange ch inae h – po : risk ratio; MD ratio; : risk mL s tp ) R isk of bias of isk serious serious serious artu m a a a : mean difference : mean hae C m ertainty assessment ertainty oglobin concentr I m nconsistency not serious serious not serious not serious not oglobin concentr I ndirectness not serious serious not serious not serious not a tion, g/dL a tion, g/dL I mprecision serious serious serious d d d considerations O none none none ther ther carbetocin solution U 100 100 100 100 100 of of VI N o. of patients of o. oxytocin oxytocin solution U 100 100 100 100 100 of of VI (95% CI (95% Relative – – – )

Effect (0.59 lower to lower (0.59 to 3.53 lower) to 3.53 (192.47 lower lower (192.47 lower 98 MD (0.08 higher higher (0.08 0.51 lower) 0.51 (95% CI (95% Absolute MD 0.87 0.87 MD MD 0.55 0.55 MD higher) to 1.66 to 1.66 higher lower

)

㊉㊉㊀㊀ ㊉㊉㊀㊀ ㊉㊉㊀㊀ C ertainty LOW LOW LOW LOW

IMPORTANT IMPORTANT IMPORTANT I mportance References 1. Nardin JM, Weeks A, Carroli G. Umbilical vein injection for management of retained placenta. Cochrane Database Syst Rev. 2011(5):CD001337. doi:10.1002/14651858. CD001337.pub2. 2. Mori R, Nardin JM, Yamamoto N, Carroli G, Weeks A. Umbilical vein injection for the routine management of third stage of labour. Cochrane Database Syst Rev. 2012(3):CD006176. doi:10.1002/14651858.CD006176.pub2. 3. 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. 4. 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. 5. 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. 6. 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. 7. Joint Formulary Committee. British National Formulary 72 (September 2016–March 2017). London: BMJ Group and Pharmaceutical Press; 2017. 8. 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. 9. Henríquez-Trujillo AR, Lucio-Romero RA, Bermúdez-Gallegos K. Analysis of the l vein injection regimens

cost-effectiveness of carbetocin for the prevention of hemorrhage following cesarean a delivery in Ecuador. J Comp Eff Res. 2017;6(6):529–36. doi:10.2217/cer-2017-0004. mbilic 10. Voon HY, Shafie AA, Bujang MA, Suharjono HN. Cost effectiveness analysis of carbetocin during cesarean section in a high volume maternity unit. J Obstet Gynaecol Res. 2018;44(1):109–16. doi:10.1111/jog.13486. 11. Luni Y, Borakati A, Matah A, Skeats K, Eedarapalli P. A prospective cohort study red other to u

evaluating the cost-effectiveness of carbetocin for prevention of postpartum a haemorrhage in caesarean sections. J Obstet Gynaecol. 2017;37(5):601–4. doi:10.1080 /01443615.2017.1284188. 12. Management Sciences for Health. International medical products price guide. Management Sciences for Health; 2015 (http://mshpriceguide.org/en/home/, accessed 10 July 2020). 13. 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. 14. State of inequality: reproductive, maternal, newborn and child health. Geneva: World

Health Organization; 2015 (https://www.who.int/gho/health_equity/report_2015, l vein injection of oxytocin comp a accessed 10 July 2020). 15. 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). Annex 4.2. Umbilic

57 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