WHO recommendations on interventions to improve preterm outcomes

For more information, please contact: Department of Reproductive Health and Research World Health Organization ISBN 978 92 4 150898 8 Avenue Appia 20, CH-1211 Geneva 27, Switzerland Fax: +41 22 791 4171 E-mail: [email protected] www.who.int/reproductivehealth

WHO recommendations on interventions to improve outcomes WHO Library Cataloguing-in-Publication Data

WHO recommendations on interventions to improve preterm birth outcomes.

Contents: Appendix: WHO recommendations on interventions to improve preterm birth outcomes: evidence base

1.Premature Birth – prevention and control. 2., Premature. 3. – prevention and control. 4.. 5.Infant Care. 6.Guideline. I.World Health Organization.

ISBN 978 92 4 150898 8 (NLM Classifi cation: WQ 330)Contents

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Acknowledgements v Acronyms and abbreviations vi Executive summary 1 Introduction 1 Target audience 1 Guideline development methods 1 Recommendations 1 1. Background 5 1.1 Target audience 5 1.2 Scope of the guideline 5 2. Methods 8 2.1 WHO Steering Group 8 2.2 Guideline Development Group 8 2.3 External Review Group 8 2.4 Identification of priority questions and critical outcomes 8 2.5 Evidence identification and retrieval 9 2.6 Quality assessment and grading of the evidence 10 2.7 Formulation of recommendations 11 2.8 Declaration of interests by external contributors 11 2.9 Decision-making during the Technical Consultation 11 2.10 Document preparation and peer review 12 3. Evidence and recommendations 12 3.1 Maternal interventions 13 3.2 Newborn interventions 42 4. Research implications 51 4.1 Maternal research priorities 52 4.2 Newborn research priorities 52 5. Dissemination and implementation of the guideline 53 5.1 Guideline dissemination and evaluation 53 5.2 Guideline implementation 53 6. Applicability issues 54 6.1 Anticipated impact on the organization of care and resources 54 6.2 and evaluation of guideline impact 54 7. Updating the guideline 55 8. References 56 Annex 1. External experts and WHO staff involved in the preparation of the guideline 60 Annex 2. Considerations related to the direction and strength of the recommendations 64 Annex 3. Summary of declarations of interests from Guideline Development Group (GDG) members and how they were managed 96

The standardized criteria used in grading the evidence and GRADE tables are not included in this document although table numbers (prefixed with EB) are included for ease of reference. The tables have been published in a separate document – WHO recommendations on interventions to improve preterm birth outcomes: evidence base – which can be accessed online at www.who.int/reproductivehealth/publications/maternal_perinatal_health/ preterm-birth-guideline. CONTENTS

iii

Acknowledgements

The Department of Maternal, Newborn, Child and Adolescent Health, and the Department of Reproductive Health and Research of the World Health Organization (WHO) gratefully acknowledge the contributions that many individuals and organizations have made to the development of this guideline. Rajiv Bahl, A. Metin Gülmezoglu, Alexander Manu, Matthews Mathai, Olufemi Oladapo and Severin von Xylander were members of the WHO Steering Group that managed the guideline development process. Carl Bose, Wally Carlo, Agustin Conde-Agudelo, Caroline Crowther, Bissallah Ekele, Rogelio Gonzalez, Malik Goonewardene, Gill Gyte, William J. Keenan, , Pisake Lumbiganon, Silke Mader, Elizabeth Molyneux, Rintaro Mori, Ashraf Nabhan, Regina Obeng, Vinod Paul, Zahida Qureshi, Larry Rand, Ola Didrik Saugstad, Andrew Shennan, Jeffrey Smith, João Paulo Souza, Alan Tita and Khalid Yunis served as the members of the Guideline Development Group (GDG). James Neilson and Roger Soll served as chairs of the entire group and the newborn health subgroup, respectively. Therese Dowswell, Sonja Henderson, Nancy Medley, and Helen West coordinated and reviewed the scientific evidence, prepared the GRADE tables, and drafted the narrative summaries related to maternal interventions included in this guideline. Natasha Hezelgrave reviewed these narrative summaries and double-checked the corresponding GRADE tables. For evidence related to newborn interventions, Agustin Conde-Agudelo, Joy Lawn, and Jeeva Sankar conducted systematic reviews and prepared the corresponding GRADE tables. The WHO Steering Group members drafted the final guideline document before it was reviewed by the GDG and external reviewers. Special thanks are due to the authors of existing Cochrane systematic reviews used in this guideline for their assistance and collaboration in preparing or updating the reviews. We appreciate the feedback provided by a large number of international stakeholders during the scoping exercise that took place as part of the guideline development process. We acknowledge the various organizations that were represented as observers at the final GDG meeting, including Donna Vivio and Lily Kak ( Agency for International Development), Hora Soltani (International Confederation of Midwives), Gian Carlo Di Renzo (International Federation of Gynaecology and ) and Stephen Wall (Save the Children). The United Nations Children’s Fund (through a grant from Save the Children USA) and the United States Agency for International Development provided financial support for this work. The views of the funding bodies have not influenced the content of this guideline. Editing: Green Ink, United Kingdom. ACKNOWLEDGEMENTS

v vi WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES WHO USA SRT SGA RR RDS RCT PPV PPROM PICO OR NICU NEC MD LMP LMIC KMC IVH IV intravenous IUGR IM HIC GREAT GRADE GDG EDD EB CPAP CDP CI BPD Acronyms abbreviations and

intramuscular

knowledge (a WHO project and international partnership) international (a and knowledge project WHO World Organization Health States of America United age gestational for small syndrome distress respiratory randomized controlled trial ventilationpositive pressure of membranes rupture prelabour preterm outcome comparison, intervention, population, ratio odds intensive unit care neonatal necrotizing mean difference period menstrual last country low- middle-income and care intraventricular haemorrhage restriction growth intrauterine country high-income Transfer of evidence, of Applicability synthesis, Evidence priorities, Research development, Guideline Evaluation and Development Assessment, of Recommendations Grading Group Development Guideline date of delivery estimated base evidence pressure positive airway continuous pressure distending continuous bronchopulmonary dysplasia surfactant replacement surfactant confidence interval Executive summary

Introduction Target audience Preterm babies are prone to serious illness or death The primary audience for this guideline includes during the neonatal period. Without appropriate health-care professionals who are responsible for treatment, those who survive are at increased developing national and local health-care protocols risk of lifelong disability and poor quality of life. and policies, as well as managers of maternal and Complications of prematurity are the single largest child health programmes and policy-makers in all cause of neonatal death and the second leading settings. The guideline will also be useful to those cause of deaths among children under the age of 5 directly providing care to pregnant women and years. Global efforts to further reduce preterm , such as obstetricians, paediatricians, demand urgent action to address preterm birth. midwives, nurses and general practitioners. The information in this guideline will be useful for Infant death and morbidity following preterm birth developing job aids and tools for pre- and in-service can be reduced through interventions provided training of health workers to enhance their delivery of to the mother before or during , and to maternal and neonatal care relating to preterm birth. the preterm infant after birth. Interventions can be directed at all women for primary prevention and reduction of the risk of preterm birth (e.g. smoking Guideline development methods cessation programmes) or used to minimize the risk The guideline was developed using standard in pregnant women with known risk factors (e.g. operating procedures in accordance with the progestational agents, ). However, process described in the WHO handbook for guideline the most beneficial set of maternal interventions development. Briefly, these included (i) identification are those that could improve survival chances and of priority questions and critical outcomes, health outcomes of preterm infants when preterm (ii) retrieval of the evidence, (iii) assessment birth is inevitable. These interventions are provided and synthesis of evidence, (iv) formulation of to the mother shortly before or during the birth recommendations, and (v) planning for the process with the aim of overcoming immediate and dissemination, implementation, impact evaluation future health challenges of the preterm infant, such and updating of the guideline. The scientific evidence as immaturity, susceptibility to , and underpinning the recommendations was synthesized neurological complications. Essential and additional using the Grading of Recommendations Assessment, care of the preterm newborn to prevent or treat Development and Evaluation (GRADE) approach. potential complications is also critical to newborn Up-to-date systematic reviews were used to prepare survival without disability. evidence profiles for the priority questions. WHO then convened a Technical Consultation in May WHO’s Managing complications of pregnancy and 2014 where an international group of experts – the : a guide for midwives and doctors (published Guideline Development Group (GDG) – formulated in 2000) and Pocket book of hospital care for children and approved the recommendations based on the (published in 2013) have, respectively, provided evidence profiles. In November 2014, an online guidance on maternal and newborn interventions consultation of the GDG was conducted to review that could improve the outcomes of preterm birth. and revise the recommendations in the light of the In keeping with the WHO procedures for guideline findings of a large implementation trial of antenatal development, these documents needed to be in low-resource countries. updated to include the current evidence-based practices and to respond to Member States’ requests for guidance on controversial areas of practice. The Recommendations present guideline is focused on interventions that The WHO Technical Consultation led to the could be provided during pregnancy, labour and adoption of 10 main recommendations (and 17 during the newborn period with the aim of improving additional sub-recommendations) covering antenatal outcomes for preterm infants. Recommendations corticosteroids, tocolysis, sulfate, on interventions to prevent and reduce the risk prophylaxis, mode of preterm birth (for of preterm birth or modify risk in at-risk pregnant the mother) and Kangaroo mother care, plastic women are outside the scope of this guideline. wraps, continuous positive airway pressure therapy, surfactant and therapy (for the newborn). For each recommendation, the quality of evidence

was graded as “very low”, “low”, “moderate” or SUMMARY EXECUTIVE

1 2 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES a outcomes birth to improve preterm interventions on recommendations WHO listof Summary any recommendations. of basis for the the to as is any doubt if there guideline, of the version full inthe summaries evidence well as the as remarks, to refer these should users Guideline needed. where remarks additional provided experts contributing the inpractice, applied and understood is correctly Tointervention. recommendation each that ensure of the implications resource the and of stakeholders, between benefits and harms, values and preferences balance including factors, other and of evidence quality the by considering recommendation of each strength and direction the “high”. qualified GDG The

outcomes improve newborn cortico Antenatal interventions Maternal outcomes where the quality of the evidence for the two is not separately presented. separately not is two the for evidence the of quality the where outcomes For recommendations related to maternal interventions, the rating of the quality of evidence applies to both the maternal and newborn newborn and maternal the to both applies evidence of quality the of rating the interventions, to maternal related recommendations For tris to ­steroids

risk of imminent preterm birth. preterm of imminent risk at are who pregnancy in disorders hypertensive with women in is recommended therapy Antenatal 1.6. (34–36 gestations late at preterm section caesarean planned undergoing women therapy corticosteroid Antenatal 1.5. preterm. likely are to deliver who with women in therapy corticosteroid Antenatal 1.4. of infection. signs clinical no and of membranes rupture prelabour preterm with women in is recommended therapy corticosteroid Antenatal 1.3. is anticipated. birth multiple or asingle of whether irrespective birth of preterm risk at women for is recommended therapy corticosteroid Antenatal 1.2. 24 hours. first the within including treatment, of 7days starting within imminent is considered birth preterm when administered be should corticosteroid antenatal women, eligible For 1.1. n n n n n met: are conditions following the when gestation of weeks to 34 24 from weeks birth of preterm risk at women 1.0. Recommendations

infection treatment and safe oxygen use). oxygen safe and treatment infection support, feeding care, thermal , (including birth); and labour preterm manage safely to and recognize the preterm newborn can receive adequate care if needed ifneeded care adequate receive can newborn preterm the capacity the (including is available care childbirth adequate infection; of maternal evidence clinical is no there imminent; is considered birth preterm undertaken; accurately be can assessment age gestational Antenatal corticosteroid therapy is recommended for for is recommended therapy corticosteroid Antenatal +6 weeks). is not is is not is for inclusion in future updates of the guideline. guideline. of the updates infuture inclusion for questions additional regarding suggestions welcomes WHO five years. every least at updates and reviewsmajor with new of evidence, identification following reviewed updated and constantly will be development procedures, these recommendations guideline with WHO below. accordance In table inthe aresummarized infants preterm the for to outcomes improve health interventions newborn and maternal on recommendations The recommended in recommended outcomes maternal for evidence low-quality and outcomes evidence for newborn based on moderate-quality Strong recommendation evidence the of quality Strength of recommendation and outcomes maternal for evidence low-quality and outcomes evidence for newborn based on moderate-quality Strong recommendation evidence low-quality very recommendation Conditional evidence low-quality very recommendation Conditional outcomes maternal for evidence low-quality and outcomes evidence for newborn based on moderate-quality Strong recommendation evidence low-quality on based Strong recommendation evidence low-quality on based Strong recommendation based on on based on based a

Maternal Strength of recommendation and Recommendations interventions quality of the evidencea Antenatal 1.7. Antenatal corticosteroid therapy is recommended Strong recommendation cortico­steroids to for women at risk of imminent preterm birth of a growth- based on very low-quality improve newborn restricted . evidence outcomes 1.8. Antenatal corticosteroid therapy is recommended for Strong recommendation (continued) women with pre-gestational and gestational who based on very low-quality are at risk of imminent preterm birth, and this should be evidence accompanied by interventions to optimize maternal glucose control. 1.9. Either intramuscular (IM) or Strong recommendation IM (total 24 mg in divided doses) is based on low-quality recommended as the antenatal corticosteroid of choice when evidence preterm birth is imminent. 1.10. A single repeat course of antenatal corticosteroid is Conditional recommended if preterm birth does not occur within 7 days recommendation based on after the initial dose, and a subsequent clinical assessment moderate-quality evidence demonstrates that there is a high risk of preterm birth in the for newborn outcomes and next 7 days. low-quality evidence for maternal outcomes for 2.0. treatments (acute and maintenance Conditional inhibiting preterm treatments) are not recommended for women at risk of recommendation based on labour imminent preterm birth for the purpose of improving newborn very low-quality evidence outcomes. Magnesium 3.0. The use of is recommended for Strong recommendation sulfate for fetal women at risk of imminent preterm birth before 32 weeks of based on moderate-quality protection against gestation for prevention of in the infant and evidence neurological child. complications for 4.0. Routine antibiotic administration is not recommended for Strong recommendation preterm labour women in preterm labour with intact amniotic membranes based on moderate-quality and no clinical signs of infection. evidence 5.0. Antibiotic administration is recommended for women Strong recommendation with preterm prelabour rupture of membranes. based on moderate-quality evidence 5.1. is recommended as the antibiotic of choice Conditional for prophylaxis in women with preterm prelabour rupture of recommendation based on membranes. moderate-quality evidence 5.2. The use of a combination of and clavulanic Strong recommendation acid (“co-amoxiclav”) is not recommended for women with based on moderate-quality preterm prelabour rupture of membranes. evidence Optimal mode of 6.0. Routine delivery by for the purpose of Conditional delivery improving preterm newborn outcomes is not recommended, recommendation based on regardless of cephalic or breech presentation. very low-quality evidence Thermal care for 7.0. Kangaroo mother care is recommended for the routine Strong recommendation preterm newborns care of newborns weighing 2000 g or less at birth, and should based on moderate-quality be initiated in health-care facilities as soon as the newborns evidence are clinically stable. 7.1. Newborns weighing 2000 g or less at birth should be Strong recommendation provided as close to continuous Kangaroo mother care as based on moderate-quality possible. evidence 7.2. Intermittent Kangaroo mother care, rather than Strong recommendation conventional care, is recommended for newborns weighing based on moderate-quality 2000 g or less at birth, if continuous Kangaroo mother care is evidence not possible. EXECUTIVE SUMMARY EXECUTIVE

3 4 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES newborns preterm for and concentration therapy Oxygen distress syndrome with respiratory for newborns administration Surfactant distress syndrome respiratory newborns with pressure for positive airway Continuous ( preterm newborns for care Thermal interventions Maternal continued ) air. or oxygen 30% with ventilation of adequate seconds 30 after minute per beats 60 than is rate less heart iftheir therapy should only be considered for newborns undergoing oxygen of oxygen concentrations higher of progressively use The 10.1. oxygen. 100% with available), than rather is not oxygen (if blended air or oxygen 30% with therapy oxygen to start is recommended it of gestation, 32 weeks 10.0. therapy. rescue giving before to worsen symptoms the for waiting than rather birth) after hours 2 first (within early the administered be should surfactant syndrome, distress respiratory with newborns preterm intubated In 9.3. newborns preterm in administration) (prophylactic syndrome distress respiratory of onset the before of surfactant Administration 9.2. syndrome. distress respiratory with newborns preterm ventilated in therapy replacement surfactant for used be can surfactants synthetic protein-containing or 9.1. animal-derived Either syndrome. distress respiratory with newborns ventilated and intubated 9.0. is made. diagnosis the as soon as started be should syndrome distress respiratory with newborns for therapy pressure airway positive Continuous 8.1. syndrome. distress respiratory with newborns of preterm treatment the for recommended 8.0. tohypothermia. prevent alternative an as considered maybe bags/wraps plastic in wrapping wards, care neonatal to specialized newborns of preterm transfer and stabilization However, during birth. after immediately newborns preterm for care thermal providing in bags/wraps plastic of effectiveness the on evidence 7.4. is insufficient There incubators. in or warmers radiant under either environment neutral athermo- in for cared be should care, mother Kangaroo given be cannot who 2000 g than less weighing newborns stable or birth, at less or 2000 g weighing newborns 7.3. Unstable Recommendations Continuous positive airway pressure therapy is therapy pressure airway positive Continuous Surfactant replacement therapy is recommended for for is recommended therapy replacement Surfactant During ventilation of preterm babies born at or before before or at born babies of preterm ventilation During is not is recommended. blood gas analysis, newborn newborn analysis, gas blood care, intubation, facilities where health-care recommendation Conditional evidence low-quality very on based Strong recommendation evidence low-quality on based Strong recommendation evidence low-quality recommendation Conditional evidence low-quality very on based Strong recommendation evidence the of quality Strength of recommendation and evidence low-quality very on based Strong recommendation evidence low-quality very on based Strong recommendation evidence quality available are nursing care and monitoring newborn analysis, gas blood ventilator care, intubation, facilities where health-care recommendation Conditional evidence low-quality on based Strong recommendation moderate-quality evidence available are nursing care and monitoring newborn analysis, gas blood ventilator care, intubation, facilities where health-care recommendation Conditional moderate-quality evidence available are nursing care and monitoring ) based on low- on ) based on ) based on ) based ( on based ( ( only in in only only in in only in only a

1. Background

Preterm birth, defined as birth before 37 weeks of positive airway pressure (19) and surfactant therapy gestation, is the single most important determinant (20, 21). It is therefore necessary to review and of adverse infant outcomes, in terms of survival and update the recommendations using the current quality of life (1). Globally, it is the leading cause WHO guideline development procedures. of perinatal and neonatal mortality and morbidity The global agenda, as captured in the global action (2). Preterm infants are particularly vulnerable to report on preterm birth, to substantially reduce complications due to impaired respiration, difficulty preterm-related death, demands careful integration in feeding, poor body temperature regulation and of the care of pregnant women and preterm high risk of infection (3–5). With the increasing newborns (22). However, this integration requires contribution of neonatal deaths to overall child evidence-based guidance as an essential component mortality, it is critical to address the determinants of to be effective in delaying preterm birth; providing poor outcomes related to preterm birth to achieve appropriate intrapartum interventions to reduce further reductions in child mortality (6–8). complications in the preterm newborn; and providing Infant mortality and morbidity from preterm birth effective care to the preterm newborn to reduce risk can be reduced through interventions delivered to of death and long-term disability. the mother before or during pregnancy, and to the The purpose of this guideline is to provide evidence- preterm infant after birth (9). Interventions can be based recommendations for interventions during directed at all women for primary prevention and re- pregnancy, labour and during the newborn period duction of the risk of preterm birth (e.g. smoking ces- that are aimed at improving outcomes for preterm sation programme) or aimed at minimizing the risk in infants. Recommendations on interventions for the women with known risk factors (e.g. progestational prevention of preterm birth are not within the scope agents, cervical cerclage) (10). However, the most of this guideline. beneficial set of maternal interventions are those that are aimed at improving outcomes for preterm infants when preterm birth is inevitable (e.g. antena- 1.1 Target audience tal corticosteroids, magnesium sulfate and antibiotic The target audience for this guideline includes prophylaxis) (9). Special care of the preterm newborn health-care professionals responsible for developing to prevent and treat complications of prematurity national and local health-care protocols and policies, is also critical to newborn survival. In high-income as well as managers of maternal and child health countries, reductions in mortality rates in infants programmes and public health policy-makers in all that were born preterm have been driven largely by settings. The guideline will also be useful to those improved care and, more importantly, by appropriate directly providing care to pregnant women and policy changes. preterm infants, such as obstetricians, paediatricians, midwives, nurses and general practitioners. This Existing World Health Organization (WHO) guideline is evidence-informed and covers topics guidance on maternal interventions for preterm related to interventions for improving outcomes of labour is available in the reference manual Managing preterm birth that were selected and prioritized by an complications of pregnancy and childbirth (11). This international, multidisciplinary group of health-care manual was published in 2000, and reprinted in professionals, consumer representatives and other 2013. In view of the changes to the WHO guideline stakeholders. It provides specific recommendations development process since 2007, it is imperative for the management of imminent preterm birth that the recommendations are reviewed and updated and preterm infants, and is intended to inform accordingly. Similarly, the latest WHO guidance on the development of health-care protocols and neonatal interventions for management of preterm policies related to interventions to improve preterm infants can be found in the Pocket book of hospital care birth outcomes. It is not intended to provide a for children (12). The second edition of this manual comprehensive practical guide for the management was published in 2013, but only a limited number of of preterm labour and preterm infants. controversial areas were revised in accordance with the current WHO guideline development procedures. Moreover, a substantial amount of new evidence 1.2 Scope of the guideline has emerged in recent years on preterm newborn Populations of interest interventions, including the use of Kangaroo mother This guideline focuses on improving maternal and care (KMC) (13–16), plastic wraps (17, 18), continuous neonatal outcomes associated with preterm birth, 1. BACKGROUND

5 6 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES   Critical maternal outcomes considered were: Critical outcomes birth. of preterm risk factors known other or birth of preterm history with previous preventive care for non-pregnant or pregnant women include not does scope guideline The birth. preterm (or elective or indicated) of membranes rupture labour, preterm prelabour preterm of spontaneous of onset aresult as either baby apreterm deliver likely are to who very women pregnant as defined were birth riskof preterm Women imminent at inall settings. birth after immediately babies of preterm care the of gestation)and < 37 weeks (birth birth riskof preterm imminent at women pregnant care of both the includes specifically and 3. 2. 1.   hours or birth within 7 days); birth or hours within 48 birth birth, and into study the randomization between (interval prolongation pregnancy of gestation; 37 weeks or 34 to32, 28, prior birth Among pregnant women at risk of imminent preterm birth (P), is magnesium sulfate therapy (I), therapy sulfate (P), birth magnesium is preterm imminent of risk at women pregnant Among agent(s) (I), (P), tocolytic of use birth the is preterm imminent of risk at women pregnant Among therapy corticosteroid (P), birth antenatal is preterm imminent of risk at women pregnant Among • • complications (i.e. fetal neuroprotection) (O)? so: If neurological from fetus the protecting in (C), therapy effective sulfate magnesium no with compared • • • • so: If outcomes? newborn adverse reducing and birth preterm delaying in effective agent, tocolytic no with compared • • • • (O)?outcomes so: If newborn adverse reducing in (C), therapy effective corticosteroid antenatal no with (I), compared

Which regimen of antenatal magnesium sulfate should be used for fetal neuroprotection in eligible ineligible neuroprotection fetal for used be sulfate should magnesium of antenatal regimen Which sulfate fetal for magnesium antenatal offered be should women of pregnant population Which first-line tocolysisfollowingsuccessful preterm ofa offered be regimen maintenance atocolytic Should women? eligible for (and used agents be regimens) tocolytic should Which tocolytics? offered be not should women (c of pregnant population Which tocolytics? ( offered be should women of pregnant population Which of a course completed has who to a woman course(s)offered be repeat of corticosteroids Should women? eligible for (and used be corticosteroids regimens)Which should corticosteroids?antenatal ( offered be not should women of pregnant population Which corticosteroids?antenatal ( offered be should women of pregnant population Which labour? If so, which maintenance regimen should be recommended? be should regimen maintenance which so, If labour? conditions medical and restriction fetal growth haemorrhage, multiple pregnancy, antepartum of membranes, rupture contraindications: with women prelabour preterm anticipated and presentation birth interval between birth; or presentation initial the treatment? after more 7days or birth riskof at preterm remains but corticosteroid mellitus, hypertensive disorders, chorioamnionitis and growth-restricted babies with diabetes women benefits: outweigh may risks that associated concerns are there where conditions preterm inlate section electivecaesarean undergoing women and status of amniotic membranes; ; and single anticipated and presentation birth; interval between birth; or presentation at age gestational women? multiple birth and single birth; neuroprotection? ( ) considering at presentation; interval between presentation and anticipated and presentation presentation; at interval age between gestational considering ) comparison (C)comparison (O). outcome and (P), –population in PICO (I), format intervention arelisted below this for guideline synthesis and review evidence the guiding questions priority The questions Priority        were: considered outcomes Critical newborn              long-term morbidity. death; child or infant low); (mean; weight very low or birth survivors); among severe or long-termof death disability risk with ahigh is that associated period neonatal inthe illness an (i.e. morbidity severe neonatal death (fetalperinatal death); early or neonatal ; or death fetal death; neonatal of treatment. effects severe adverse ); (chorioamnionitis, sepsis puerperal ; or morbidity severe maternal ) ) considering gestational age at at age gestational considering ) onsidering potential onsidering considering the considering considering considering 4. Among pregnant women at risk of imminent preterm birth (P), is routine antibiotic prophylaxis (I), compared with no antibiotic prophylaxis (C), effective in improving maternal and newborn outcomes (O)? If so: • Which population of women should be offered antenatal prophylactic antibiotics? considering( women with preterm rupture of membranes) • Which population of pregnant women should not be offered antenatal prophylactic antibiotics? (considering women with intact amniotic membranes) • Which antibiotics (and regimens) should be used in eligible women? 5. Among women with refractory preterm labour (P), is a policy of routine caesarean delivery of preterm infants (I), compared with planned vaginal birth (C), effective in reducing adverse newborn outcomes (O)? If so: • What is the optimal mode of birth by fetal presentation? • What is the optimal mode of birth by gestational age? 6. Among preterm babies who require thermal care (P), is practicing Kangaroo mother care (I) compared with conventional care (C), effective in reducing adverse newborn outcomes (O)? If so: • How effective is continuous Kangaroo mother care (KMC) in the thermal care of preterm babies? • Is KMC equally effective when administered intermittently rather than continuously, with or without alternative conventional methods of care during the intervention periods? • In which subgroup of preterm newborns is KMC effective? considering( babies weighing < 2000 g; sick and unstable babies, with respiratory distress, feed intolerance, etc.) 7. In unstable preterm newborns who cannot be (exclusively) cared for by Kangaroo mother care (P), are there other superior methods for providing thermal care to maintain optimal body temperatures (I), compared with incubators (C), that are effective in improving newborn outcomes (O)? If so: • Are radiant warmers superior to incubators in the provision of thermal care for these preterm babies? 8. In newly born extremely preterm or very preterm infants (P), is the use of plastic wraps/caps (I), compared with conventional care including Kangaroo mother care (C), effective in improving newborn outcomes? If so: • Should these plastic wraps/caps be used instead of KMC immediately after birth in a subgroup of preterm infants? 9. In newly born preterm babies with or at risk of respiratory distress syndrome (P), is continuous positive airway pressure (I), compared with routine care (C), effective in preventing adverse newborn outcomes? If so: • Under what conditions and when should continuous positive airway pressure be provided? • What are the indications for additional interventions? 10.In newly born preterm babies who have or are at risk of respiratory distress syndrome (P), is surfactant therapy (I), compared with routine care without surfactants (C), effective in reducing adverse newborn outcomes (O)? If so: • How early should the surfactant therapy be started? • Should surfactants be given for prophylaxis in newborns where respiratory distress syndrome has not yet set in, or selectively when existing respiratory distress is worsening? • Which types of surfactant are effective – animal-derived or synthetic; protein-containing or protein- free? 11. In newly born preterm babies born before 32 weeks of gestation (P), is optimal oxygen therapy (O), compared to no guided administration (C), effective in improving newborn outcomes (O)? if so: • What concentration of oxygen should be administered? • What should guide the administration of the oxygen to these babies? 1. BACKGROUND

7 8 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES outcomes that guided the evidence reviews. In In reviews. evidence the guided that outcomes of inprioritization participated and questions, PICO the and scope guideline of the drafting into the input provided of this group Members experts. methodology guideline and groups user paediatricians, midwives, representatives of neonatologists, obstetricians, researchers, clinical included group The birth. of preterm outcomes to improve interventions newborn to and maternal relating programmes and policy clinical in research, with expertise of individuals group gender-balanced and adiverse was This to GDG. constitute the regions six the WHO from stakeholders and experts external 27 identified Group Steering WHO The 2.2 1. in Annex arepresented Group Steering WHO of the members The dissemination. and publication guideline the managed and document, guideline final the and GDG the for recommendations draft prepared meetings, GDG the organized syntheses, retrieval and evidence the supervised Group Steering WHO the (GDG). Group Development Additionally,Guideline of the members and methodologists guideline teams, outcome) identified and comparison, intervention, (population, PICO format in questions priority and guideline of the scope initial the drafted group The process. development entireguideline the managed and guided Research, and Health of Reproductive Department the and Health Adolescent Child and Newborn, staff members from the Department of Maternal, WHO comprising Group, Steering WHO The 2.1 sections. following in the described are roles specific their process; the to guide groups main of three formation involved the process development guideline The guideline. of the updating evaluationand impact (v) planning implementation, dissemination, the for evidence, (iv) formulation of recommendations, and of synthesis and (iii) assessment evidence, the (ii) retrieval of outcomes, critical and questions priority of (i) identification included: process development guideline for inthe described process with the inaccordance procedures operating standard using developed was guideline The in all countries. practices and policies norms, evidence-informed using for WHO’s support represents document This 2. Methods Methods Guideline Development Group Group Development Guideline Group Steering WHO

(23) . In summary, the the summary, . In WHO handbook values and preferences of potential users of the of the of potential users preferences and values contextual incorporated had processes making decision- guideline the that ensured group The implementation. for implications and issues contextual language, of the clarity the on commented and errors any factual to identify document guideline reviewed final group the The of interest. aconflict declared member no and representative gender- balanced, geographically was group The care. newborn and maternal of evidence-based provision inthe interest with an stakeholders other and experts six technical included group This 2.3 1. inAnnex are presented GDG of the members The document. guideline final the reviewed approved and and Group, Steering WHO by the prepared draft the on based recommendations final the formulated evidence, of the interpretation the on advised recommendations, to the inform used was that evidence the appraised GDG the addition, and formulation of recommendations. retrieval, grading searching, evidence for document of this scope inthe were included critical as rated outcomes prioritized The guideline. of the purposes the for to important be 4wereconsidered not than critical”, not lower with ascore but those while “important 6were considered 4and of between with ascore outcomes and Questions more. of 7or average score an ifgiven was it “critical” as ranked was 1 to from outcome 9. an a scale this In context, on outcomes of the relative the ranked importance stakeholders international The 2013. inApril Geneva aTechnical at prioritize outcomes the in Consultation and groups) questions of user to review draft the representatives and programmes inhealth experts midwives, obstetricians, researchers, neonatologists, (including stakeholders of international group larger a consulted then WHO birth. of preterm outcomes to improve related to interventions outcomes tant impor and potential critical and questions priority a list of drafted first Group Steering WHO The 2.4 1. inAnnex are presented Review Group External of the members The GDG. by the formulated recommendations the to change group’s within the not was It remit policy-makers. and professionals health-care recommendations,

critical outcomes External Review Group Review Group External Identification of priority questions and ­ 2.5 Evidence identification and retrieval editorial information about the Cochrane Pregnancy 2 The WHO Steering Group, in collaboration with and Childbirth Group. Trials identified through the an external team of systematic reviewers and search activities described above are each assigned guideline methodologists, retrieved evidence on to a review topic (or topics). Cochrane’s Trials Search the effectiveness of interventions from systematic Coordinator searches the register for each review reviews of randomized controlled trials (RCTs) and using the topic list rather than keywords. non-randomized studies as needed. The Steering Similar to the interventions, the Group provided the methodologists with standard evidence review and summary for the development operating procedures and a briefing on the desired of the guidelines on interventions for the newborn output of the systematic reviews, and together the were primarily based on Cochrane reviews. The members of these groups agreed on the format and newborn interventions, derived from the scoping timelines for reporting. Using the assembled list of questions, were based on studies identified from the priority questions and critical outcomes from the Cochrane Neonatal Review Group. This Cochrane scoping exercise, the WHO Steering Group, along group prepares and disseminates evidence-based with the external teams of systematic reviewers systematic reviews of RCTs of treatment for and guideline methodologists, identified systematic neonatal or conditions. These reviews are reviews that were either relevant or potentially prepared following standard methods, including relevant and assessed whether they needed to comprehensive searches for eligible trials using be updated. A systematic review was considered search engines such as Ovid and PubMed from to be out of date if the last search date was two key databases, as described for the maternal years or more prior to the date of assessment. The interventions. Cochrane reviews are regularly authors of reviews that were found to be out of date updated as new trials are published. were requested to update them within a specified The assessment of quality of individual intervention time period. In instances where the authors were studies included in Cochrane reviews follows a unable to do so, the updates were undertaken specific and explicit method for assessing the risk of by the external team of systematic reviewers, in bias. Briefly, using the criteria outlined in theCochrane consultation with the WHO Steering Group. handbook for systematic reviews of interventions, two Cochrane systematic reviews were the primary review authors independently assess the risk of bias source of evidence for the recommendations along six domains: sequence generation, allocation included in this guideline.1 The Cochrane reviews concealment, blinding of study personnel and relating to maternal interventions were based on participants, attrition, selective reporting, and other studies identified from searches of the Cochrane sources of bias such as publication bias (24). Each Pregnancy and Childbirth Group’s Trials Register. included study is assessed and rated to be at “low”, This Register is maintained by the Trials Search “high” or “unclear” risk of bias for each of these six Coordinator and contains trials identified from: domains, and these assessments together provide an monthly searches of the Cochrane Central Register overall risk of bias that indicates the likely magnitude of Controlled Trials (CENTRAL); weekly searches and direction of the bias and how it is likely to of Medline; weekly searches of Embase; hand impact the review findings. Each Cochrane review searches of 30 journals and the proceedings of major is preceded by a publication of a peer-reviewed conferences; weekly “current awareness” alerts for protocol describing the proposed methods and a further 44 journals; and monthly BioMed Central search strategy for that review. email alerts. The details of the search strategies The WHO Steering Group and methodologists for key databases such as CENTRAL, Medline and worked together to determine the appropriateness Embase, the list of hand searched journals and and suitability of each systematic review in providing conference proceedings, and the list of journals the evidence base for the key PICO questions, by reviewed via the current awareness service can be assessing the review’s relevance, timeliness and found in the “Specialized Register” section within the quality. Relevance was ascertained by examining 1 As part of the Cochrane pre-publication editorial whether the population, intervention, comparison process, reviews are commented on by three peers and outcomes considered in the full text of the (one editor and two referees external to the editorial review were compatible with those in the priority team) and the Group’s Statistical Adviser (see http:// question. The quality of each review was determined www.cochrane.org/cochrane-reviews). The Cochrane by assessing: the clarity of its primary question with handbook for systematic reviews of interventions describes in detail the process of preparing and maintaining Cochrane systematic reviews on the effects of health- 2 Available at: http://onlinelibrary.wiley.com/o/

care interventions. cochrane/clabout/articles/PREG/frame.html METHODS 2.

9 10 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES outcome. outcome. to the contributing studies of the by majority the met criteria quality minimum the on (“low”), depending two or level by (“moderate”) one downgraded then and “high” RCTs,rated For first was outcome. quality to the contributing studies across then and study level at individual the of the examined first bias was execution: and Limitations design inthe study below. described briefly factors of the consideration on dependent was of evidence quality of rating the The of criteria. aset on based “high”, as rated was “moderate”, “low”, low” “very or outcome each for of evidence quality the approach, approach Evaluation (GRADE) and of Recommendations Assessment, Development Grading the using performed was outcome each for of evidence body of the assessment Quality 2.6 solutions. on agree and challenges to discuss Group Steering WHO the with communicating constantly methodologists reviewers systematic and with the iterative, was process review entiresystematic development The restrictions. language were no there and considered were countries high-income and low-, middle- from Studies reviews. systematic individual in the were described exclusion of studies and inclusion criteria for specific the and studies the identify to employed strategies search The databases. regional Gateway WHO and NLM Popline, CINAHL, CENTRAL, Embase, Medline, including conducted, were databases electronic of various searches review.the systematic To studies, relevant identify on of reviewers embarked group the protocol before the reviewed endorsed then and members GDG the among experts content selected and Group Steering WHO The plan. analysis adata of biasand risk assessing for methods databases, bibliographic different for strategies search including of studies, identification for criteria and PICO question clear protocol with were asked astandard to prepare reviewers of systematic groups external the cases, such In recommendations. of the development the to inform groups to various were commissioned new systematic reviews question, priority specific reviews werethe that to relevant data lacked the where or reviews (Cochrane non-Cochrane) or systematic suitable were no there where situations In reporting. and syntheses of data methods the and riskof bias; the of assessing methods the processes; extraction data and selection study biasinthe for potential the databases; and strategies search the of to PICO; comprehensiveness the the respect of the evidence evidence the of Quality assessment and grading grading and assessment Quality (25) . Usingthis The riskof The

estimates) were downgraded for imprecision. imprecision. for estimates) were downgraded effect around intervals (and confidence wide thus events or with relatively few participants studies of events, size number of and sample a function As this was often assessed. was ofestimate effect Imprecision: or outcomes. comparisons interventions, to populations, instance, for were related, differences Such prepared. being are recommendations the which for context the and reported research the between differences were important there where i.e. evidence, of the directness the regarding concerns serious very or were serious there where were downgraded Indirectness: minimal showed overlap. limits confidence and directions were indifferent results the when downgraded was quality whereas overlapped, limits confidence and were similar findings of the directions the when downgraded not was of evidence quality The studies. different from observed size of effects and direction in the of differences magnitude the by exploring assessed was outcome agiven for of the results: Inconsistency for each priority question. priority each for generated were profiles evidence GRADE process, assessment step of the final the In evidence. of the above) to evaluate werequality applied the described (as criteria assessment GRADE outcome, each For reviews). non-Cochrane (for profilers GRADE the reviews)(for into Cochrane entered manually or RevMan the file from imported were then data The selected. and were identified outcomes critical the to relevant Secondly, analyses Library. Cochrane or the review from the authors file) obtained were and/or (e.g.date data review RevMan documents up-to- First, following the procedures. by applying question reviewssystematic priority relating to each the from manner inaconsistent were extracted data and information Relevant outcome. each for risks illustrative the comparative above and described relating to elements the judgements and assessments the include tables these question; priority each for tables of Findings” “Summary to construct used was software profiler GRADE level. by one downgraded was evidence suspected, strongly biaswas publication Where results. study on based publication selective of as a result an intervention of effect of the overestimation or may have to led underestimation of biasthat evidence statistical or by perceived Publication bias: The degree of uncertainty around the the around of uncertainty degree The Rating of the quality of evidence of evidence quality of the Rating Quality rating could also be affected affected be also could rating Quality The similarity in the results results inthe similarity The 2.7 Formulation of recommendations openly declare such conflict at the beginning of the The GRADE framework was applied to formulate Technical Consultation and no further action was each recommendation based on the synthesized taken. Conflict of interest that warranted action evidence (26). For each priority question, the WHO by WHO staff arose where experts had obtained Steering Group used the corresponding summaries funding from a body or an institution to perform of evidence for the critical outcomes, and the primary research or a systematic review directly assessments of the overall quality of the evidence, related to any of the guideline recommendations. At balance between benefits and risks, values and the Technical Consultation, the concerned experts preferences, and resource implications to draft the were restricted from participating in discussions recommendations. The draft recommendations, and/or formulation of recommendations pertaining evidence summaries, the corresponding GRADE to their conflicts of interest. A summary of the tables, and other related documents were provided DOI statements and how conflicts of interest were in advance to members of the GDG who were then managed is included in Annex 3. asked to comment on the document. The GDG members and other participants were then invited 2.9 Decision-making during the Technical to attend the Technical Consultation organized at Consultation WHO headquarters in Geneva, Switzerland, in May The Technical Consultation process was guided by 2014 (see Annex 1 for a full list of participants). a clear protocol, as described here. The meeting At the Technical Consultation, the GDG members was designed to allow participants to discuss systematically reviewed and discussed these each of the recommendations drafted by the documents to finalize the recommendations and WHO Steering Group. Where necessary, each determine their directions and strengths. of these recommendations was revised through group discussion. The final adoption of each 2.8 Declaration of interests by external recommendation was confirmed by consensus – contributors defined as the agreement of at least three quarters of According to WHO regulations, all experts must the participants – provided that those who disagreed declare their relevant interests prior to participation did not feel strongly about their position. Strong in WHO guideline development processes disagreements would have been recorded as such and meetings. All GDG members and external in the guideline. If the participants were unable to contributors were therefore required to complete reach a consensus, the disputed recommendation, a standard WHO Declaration of Interest (DOI) or any other decision, was put to a vote. Voting form before engaging in the guideline development was by a show of hand by members of the GDG. process and participating in related meetings. The A recommendation or decision stood if a simple WHO Steering Group reviewed all the DOI forms majority (more than half of the participants) voted in before finalizing experts’ invitations to participate support of it, unless the disagreement was related to in the guideline development. Where any conflict of a safety concern, in which case the WHO Secretariat interest was declared, the Steering Group determined would choose not to issue a recommendation at all. whether such conflicts were serious enough to affect WHO staff at the meeting, external technical experts objective judgement of the expert on the guideline involved in the collection and grading of the evidence, development process and recommendations. To and the observers (see list in Annex 1) were not ensure consistency, the Steering Group applied eligible to vote. If the issue to be voted upon involved the criteria for assessing the severity of a conflict primary research or systematic reviews conducted of interest in the WHO handbook for guideline by any of the participants who had declared an development for all experts (23). All statements on the academic conflict of interest, the participants in received DOI forms were managed in accordance question would be allowed to participate in the with the WHO DOI guidelines on a case-by-case discussion, but would not be allowed to vote on that basis and the decisions were communicated to the issue. experts. The Technical Consultation also determined the The procedures for the management of declared strength of each recommendation. By default, conflicts of interests were undertaken in accordance the strength of each recommendation under with the WHO guidelines for declaration of interests discussion was initially aligned with the quality (WHO experts). Where a conflict of interest was of the evidence (i.e. at the start of the discussion, not considered significant enough to pose any risk “strong recommendations” were based on evidence to the guideline development process or reduce of “moderate” and “high” quality, while “conditional its credibility, the experts were only required to recommendations” were based on evidence of “low” 2. METHODS 2.

11 12 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES Technicalapproval. final their for Consultation of the to participants the electronically returned was version revisedfinal of clarity. any lack The address to inlanguage improvement and errors of factual were limited to correction to guideline the Group Steering WHO by the made review, modifications the Technical the peer After and Consultation document. guideline inthe reviewers inclusion for peer of the input evaluated the carefully Group Steering WHO review. peer for Review The Group to External the sent itwas before comments further for members to GDG electronically sent then was document guideline draft The participants. of the decisions and deliberations the revisions to reflect accurately with document guideline full of the adraft prepared Group Steering WHO of the members meeting, the Following remarks. and deliberations participants’ with in line were modified recommendations draft the meeting, the During comments. their for meeting the before week one Consultation Technical of the available to participants the made was document draft The recommendations. of evidence summaries and corresponding version adraft prepared Group Steering WHO the to TechnicalPrior the inMay 2014, Consultation 2.10 GDG. by the agreed as into consideration, evidence new the taking revisions were made reviewed further and were recommendations Relevant countries. income inlow-middle- and mortality neonatal on therapy corticosteroid antenatal up to scale strategies of effects the on of evidence new implications to review held was the GDG of the consultation Web-based aspecial 2014, November In recommendations. of the strength to default the made changes for reasons the record and considerations to synthesize these noteused and were tables to Decision” “Evidence members. GDG of the opinions and well as experience as process retrieval evidence the during obtained estimates reported on evaluationrelied Cost GDG. of the of members opinions and experience the on based was preferences and of values consideration The resource/cost and issues implications. applicability relevant harms, versus of benefits balance the preferences, and values recommendation: final the of direction and strength the determining when were considered following the factors evidence, the quality). low” of to “very quality the addition and In Document preparation and peer review peer and preparation Document The participants at the WHO Technical WHO the at Consultation participants The inAnnex 2. arepresented recommendations of the direction and strength the indetermining considered that use were resource and harms, and benefits evidence, values and preferences, balance between of quality the summarizing tables to Decision” “Evidence perinatal_health/preterm-birth-guideline). int/reproductivehealth/publications/maternal_ evidence base outcomes: birth preterm to interventions on improve WHO recommendations (see to this document supplement electronic inthe separately arepresented 9. tables These (EB) base evidence as Tablesin this section 1to to arereferred recommendations the for tables GRADE corresponding The questions. priority the for of evidence summaries narrative corresponding the and recommendations the outline 3.2 3.1 and Sections inthis guideline. included recommendations the for base evidence the provided tables GRADE reviews in53 systematic summarized total,In 48 recommendations 3. necessary. where recommendation the under are included (GDG) Group Development by Guideline the discussion of the summary the reflecting remarks appropriately implemented in practice, additional each recommendation is correctly understood and To areindicated. “conditional” or that “strong” ensure as assessed recommendation of each strength low”, “very as “low”, the and “high” or “moderate” rated evidence supporting of the quality The 3.2.3). 3.2.1– (see therapy sections oxygen and therapy pressure (CPAP) therapy, replacement surfactant positive airway continuous (KMC), wraps, plastic care mother they relate of to Kangaroo use infant, the 3.1.1–3.1.5). preterm (see the For sections newborns of preterm of delivery mode optimal and antibiotics, sulfate, tocolysis, magnesium corticosteroids, relate of to antenatal use the recommendations mother, the For the birth. after infant preterm to and baby the preterm of the birth the before to mother provided the covering interventions recommendations and 17 sub-recommendations, main 10 inMay 2014 adopted this guideline on

Evidence and

www.who. 3.1 MATERNAL INTERVENTIONS n The GDG acknowledged that the conditions 3.1.1 Antenatal corticosteroids for improving listed above may not be operationalized in newborn outcomes a standard and consistent manner across RECOMMENDATION 1.0 settings. Identifying the most critical and Antenatal corticosteroid therapy is essential preconditions to achieve clinical recommended for women at risk of preterm benefits from antenatal corticosteroid is birth from 24 weeks to 34 weeks of gestation uncertain and would benefit from further when the following conditions are met: research. In setting these preconditions, the panel’s emphasis was on minimizing harm to n gestational age assessment can be accurately the mother and the baby. undertaken; n An appropriate standard of childbirth care n preterm birth is considered imminent; should be available to the mother in a facility n there is no clinical evidence of maternal that has a team of health-care providers infection; competent in recognizing and safely managing n adequate childbirth care is available (including preterm labour and imminent preterm the capacity to recognize and safely manage birth. Safe care during labour and childbirth preterm labour and birth); requires close monitoring of the mother and n the preterm newborn can receive adequate fetus to identify and appropriately manage care if needed (including resuscitation, complications, such as maternal infection and thermal care, feeding support, infection fetal . treatment and safe oxygen use). n Essential and special care for the management (Strong recommendation based on moderate-quality of preterm newborns should be available evidence for newborn outcomes and low-quality to prevent or address any newborn evidence for maternal outcomes) complications related to prematurity or REMARKS otherwise. n n This recommendation applies to all other The GDG made a strong recommendation, recommendations relating to the use of having placed its emphasis on: the benefits antenatal corticosteroids in this guideline (i.e. to the preterm infants, in terms of reducing Recommendations 1.1 to 1.10). early morbidity and mortality outcomes; the low-cost and wide availability of corticosteroid n The recommendation is largely based on globally; the feasibility of implementing the evidence derived from settings where the intervention; and the potential impact on certainty of gestational age estimation is health-care resource use across settings. high. Therefore, accurate and standardized gestational age assessment (ideally from first trimester ultrasound) is essential to Summary of evidence ensure that all eligible receive corticosteroids while avoiding unnecessary Antenatal corticosteroids versus placebo or no treatment (all women and babies) (EB Table 1a) treatment of ineligible mothers. Antenatal corticosteroid should not be routinely Evidence on the use of antenatal corticosteroids for administered in situations where the reducing adverse neonatal outcomes associated gestational age cannot be confirmed, with prematurity was extracted from a Cochrane particularly when gestational age is suspected systematic review of 26 trials (4469 women and to be more than 34 weeks, as the risk of harm 4853 babies) (27). This review included trials that may outweigh the benefits if mature compared corticosteroid treatment with placebo or are exposed to corticosteroid in-utero. no treatment in women expected to deliver between 24 and 37 weeks of gestation as a result of either n Due consideration should be given to local spontaneous preterm labour, preterm prelabour limits of when determining rupture of membranes (PPROM) or elective preterm the lowest limit of gestational age when birth. Exclusion criteria were variable but commonly antenatal steroids should be administered, included medical contraindications to steroid use, including reference to local data on newborn evidence of maternal infection, diabetes, lethal survival and morbidity. The GDG noted that fetal anomalies, advanced first stage of labour, and the probability of survival without residual any maternal or fetal indications requiring urgent morbidity (“intact survival”) at < 24 weeks is delivery. low, even in high-resource settings. 3. EVIDENCE AND RECOMMENDATIONS

13 14 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES placebo, corticosteroid therapy was associated associated was therapy corticosteroid placebo, Fetal and neonatal death: outcomes Infant 533 women). were reported studies, (4 effects side-effects: Maternal women). 1323 5studies, 0.64–1.33; women), fever 0.92, (RR postnatal 95% and CI 95% CI 0.93–1.95; 1003 1.35, (RR sepsis 8studies, women), 2525 of rates werepuerperal as the studies, 0.90, (RR 95% groups similar inboth CI 0.69–1.17; 13 were of rates chorioamnionitis the infection; maternal riskof with increased associated not was therapy morbidity: infectious Maternal women).95% 319 CI 0.26–2.05; (RR 0.74, groups the between difference significant to no was intensivethere admission care; maternal results). pooled of the Two arm each reported studies in 1death women, 365 3studies, 95% CI 0.06–15.50; 0.98, (RR mortality riskof maternal with increased associated not was therapy corticosteroid placebo, Severe or death: morbidity maternal Maternal outcomes mortality neonatal coverage on corticosteroid antenatal to increase strategy multifaceted population-based of a trial effects evaluating the cluster-randomized of a large findings the on based was main recommendation the for specified care of overarching context the regarding Evidence purpose. this for performed reviewssystematic were that specifically other from review, extracted was Cochrane evidence inthe included not was of interest population review. aspecific Cochrane Where same of the analyses subgroup from the extracted was benefits may outweigh risks associated that are concerns there inwhom those and corticosteroids antenatal from likely aremost to benefit babies preterm whose of women population specific the on Evidence babies). and (32 women dexamethasone or betamethasone either used study another and babies), and women (18 used corticosteroid the specify babies).not did 1514 study and One women (1391 dexamethasone six while trials used arm ment treat inthe 3289 babies)and corticosteroid the as (3028 women betamethasone trials used Eighteen Turkey, Tunisia Kingdom. United the and Spain, Africa, South Zealand, New Netherlands, the Jordan, Colombia, inCanada, trial each one and trials), (12 (USA) trials), States of America United the (2 Brazil trials), countries: in high-income (2 Finland settings inhospital trials of were the conducted Most No cases of maternal side- of maternal cases No Compared with Compared Corticosteroid Corticosteroid Compared with Compared (29) ­ . trial and results favoured the corticosteroids group group corticosteroids the favoured results trial and inone reported was supplementation of oxygen infants). 518 duration Mean 3studies, -2.28 to -0.56; (MD group -1.42 95% corticosteroids days, CIthe in ventilation reduced was of mechanical duration infants). mean 1686 The 6studies, CI 0.43–0.71; 95% 0.55, (RR reduced severealso was RDS and 4590 infants). studies, Moderate 25 0.58–0.73; 95% CI 0.65, (RR group corticosteroids in the by 35% (RDS) reduced was syndrome distress Severe morbidity: neonatal 1study, adults). 988 0.56–1.81; 95% CI 1.00, (RR adulthood during occurring deaths children) or 1010 4studies, 95% CI 0.36–1.27; 0.68, deaths (RR childhood of in terms differences death: Childhood infants). 3627 13 studies, 0.98, 95% CI 0.73–1.30; (RR groups inboth were comparable deaths fetal 14% versus controls), group for treatment whereas to 9.5% inthe corresponding infants, 4408 studies, 21 CI 98% 0.58–0.80; 0.68, (RR deaths neonatal in infants). to reduction a32% due largely was This 0.77,(RR 3627 95% CI 0.67–0.89; 13 studies, deaths neonatal and fewer fetal with significantly and behavioural or learning difficulties were were not difficulties learning or behavioural and delay, impairment intellectual neurodevelopmental impairment, hearing and visual for groups between children). 518 Differences 2 studies, 0.49, (RR delay developmental 95% CI 0.24–1.00; children), in 904 well as areduction as 5 studies, 95% CI 0.34–1.03; 0.60, (RR inchildhood palsy cerebral treated for of children number in the towards with atrend associated areduction was morbidity: Long-term infants). 641 4studies, 1.09; 95% stay(MD ofCI NICU -1.08 0.00, duration to infants) 629 mean or 95% CI 4studies, 0.73–1.06; 0.88, intensive (NICU) (RR unit care to aneonatal 2961 infants),-39.41 13 studies, admission to 25.55; 95% CI (MD weight -6.93 g, birth infant mean 95% CI 698 0.78–1.42; infants), 1.05, (RR 4studies, small-for-gestational-age for (SGA)observed infants was groups the between difference significant No with placebo. compared when 1675 infants) 95% 8studies, CI 0.29–0.74; 0.46, (RR 1359 infants) necrotizing enterocolitis and 6 studies, of 0.57, life (RR hours 48 95% 0.38–0.86; CI first the 2872 infants), in infection studies, systemic infant 13 95% CI 0.43–0.69; 0.54, (RR haemorrhage of cerebroventricular occurrence inthe a reduction with associated was infants). therapy Corticosteroid 818 6studies, 95% CI 0.61–1.22; 0.86, (RR lung chronic in difference significant no was There infants). 73 to -0.21; (MD -2.86 95% days, CI -5.51 There were no significant significant were no There Corticosteroid therapy therapy Corticosteroid The rate of respiratory rate of respiratory The statistically significant in children or adults, although : Birth weight was significantly reduced the relative risks were all in favour of a reduction. for those infants whose mothers received treatment from 30 to < 33 weeks of gestation (MD -190.64 g, Antenatal corticosteroids versus placebo or no 95% CI -359.98 to -21.3). No differences in birth treatment (analyses by gestational age at therapy) weight were observed in other gestational age (EB Table 1b) subgroups. In the same review (27), subgroup analyses were performed for six gestational age categories Antenatal corticosteroids versus placebo or no according to when corticosteroid therapy was treatment (analyses by gestational age at birth) initiated: < 26, 26 to < 30, 30 to < 33, 33 to < 35, (EB Table 1c) 35 to < 37, and > 36 weeks. However, each of these Subgroup analyses were also performed according analyses was based on one to three trials, and the to five categories of gestational age at birth of the number of participants per subgroup was generally preterm infant exposed to antenatal corticosteroid: small. Across the six subgroups, the number of < 28, < 30, < 32, < 34 and < 36 weeks. participants was lowest in the < 26 and > 36 weeks gestational age categories for the critical outcomes Maternal outcomes reported (with < 50 women in each category). Maternal infectious morbidity: No difference was observed in the rate of chorioamnionitis between Maternal outcomes those treated with corticosteroid and those given Maternal infectious morbidity: Chorioamnionitis placebo or no treatment across any of the gestational was significantly reduced in the women given age categories. corticosteroids between 30 and < 33 weeks of gestation (RR 0.19, 95% CI 0.04–0.86; 1 study, 294 Infant outcomes women), but not in other gestational age categories. Fetal and neonatal death: There was a significant reduction in combined fetal and neonatal deaths Infant outcomes among corticosteroid-exposed infants that were Fetal and neonatal death: Compared to controls, a born before 32 weeks of gestation (RR 0.71, 95% CI reduction in neonatal deaths for those infants whose 0.57–0.88; 3 studies, 453 infants), before 34 weeks mothers had been treated with corticosteroids (RR 0.73, 95% CI 0.58–0.91; 1 study, 598 infants) between 26 and < 30 weeks of gestation was and before 36 weeks (RR 0.75, 95% CI 0.61–0.94; observed (RR 0.67, 95% CI 0.45–0.99; 1 study, 227 2 studies, 969 infants). Neonatal deaths alone infants), while there were no significant differences were significantly reduced in the corticosteroid- in all other gestational age categories. No statistically exposed infants that were born before 32 weeks (RR significant differences were observed between 0.59, 95% CI 0.43–0.80; 3 studies, 378 infants), groups for combined fetal and neonatal deaths or before 34 weeks (RR 0.69, 95% CI 0.52–0.92; fetal deaths alone in the subgroups of gestational age 2 studies, 715 infants) and before 36 weeks (RR at which corticosteroid was administered. 0.68, 95% CI 0.50–0.92; 2 studies, 869 infants). However, the significant reduction in both fetal Severe neonatal morbidity: The frequency of and neonatal deaths, and in neonatal deaths alone RDS among infants of women receiving treatment was not observed for babies exposed to antenatal between 26 and 34+6 weeks of gestation was reduced corticosteroids who were born before 28 weeks by approximately 50% (26 to < 30 weeks: 2 studies, (fetal and neonatal death: RR 0.81, 95% CI 0.65–1.01, 242 women, RR 0.49, 95% CI 0.34–0.72; 30 to < 33 2 studies, 129 infants; neonatal death: RR 0.79, weeks: 2 studies, 361 women, RR 0.56, 95% CI 0.36– 95% CI 0.56–1.12, 2 studies, 89 infants) nor those 0.87; 33 to < 35 weeks: 2 studies, 434 women, RR born before 30 weeks (fetal and neonatal death: 0.53, 95% CI 0.31–0.91). There were no observed RR 0.86, 95% CI 0.70–1.05, 1 study, 201 infants; significant differences across other gestational age neonatal death: RR 0.82, 95% CI 0.60–1.11, 1 study, groups. Only those infants whose mothers were 150 infants). Likewise, mortality was not reduced for treated with corticosteroids between 26 and 29+6 infants born after 34 weeks of gestation (fetal and weeks of gestation showed a significant reduction neonatal death: RR 1.13, 95% CI 0.66–1.96, 1 study, in the incidence of cerebroventricular haemorrhage 770 infants; neonatal death: RR 1.58, 95% CI 0.71– (RR 0.45, 95% CI 0.21–0.95; 229 infants), while 3.50, 2 studies, 808 infants). there were no significant differences across all other gestational age subgroups. For infants born at 36 weeks of gestation or over, there was a non-significant trend towards an increase

in combined fetal and neonatal deaths (RR 3.25, 95% 3. EVIDENCE AND RECOMMENDATIONS

15 16 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES who were born at 23 weeks of gestation (adjusted of gestation weeks 23 at were born who infants lower in corticosteroid-exposed significantly Fetal and neonatal death: outcomes Infant impairment neurodevelopmental childhood or death on corticosteroid to antenatal exposure of investigated effect which the USA, 22–25 at inthe born infants weeks of 10 541 study cohort multicentre review aprospective found of 22–25This birth at age weeks. with gestational infants for reviewA separate conducted was weeks) 25 to 22 from birth at age (gestational treatment no or placebo versus corticosteroids Antenatal examined. were that birth at age of gestational subgroups different inthe weight birth for werecontrols seen and corticosteroids treated with antenatal groups the between differences significant statistically No in459 infants). (no reported events weeks 36 least at 0.07–17.92; 1study, 746 of infants) agestation at or 95% 1.13, (RR CI weeks 34 of least at agestation at 1study, 95% CI767 0.31–1.02; 0.56, (RR infants), 1study, infants), 150 0.29–1.10; weeks 36 before 95% CI 0.56, (RR weeks 30 before born in infants infants). However,observed not was this benefit 1study, 515 95% CI 0.29–0.95; 0.53, (RR weeks 34 1study, infants) before 277 and 95% CI 0.28–0.99; 1study, 62 infants), 0.52, 0.86; (RR 32 weeks before 95% CI 0.14– 0.34, (RR of gestation 28 weeks before born infants incorticosteroid-exposed reduced Cerebroventricular was significantly haemorrhage 102 infants). 4studies, 0.53–1.18; 0.79, (RR infants) 28 weeks 557 before or 95% CI 95% CI 0.03–2.67; 0.30, (RR weeks 36 5studies, 1261 5studies, 95% infants), CI 0.38–1.16; after 0.66, (RR of gestation weeks 34 after born infants all for analysed when RDS towere shown not reduce infants). 1022 corticosteroids Antenatal 4 studies, 95% CI 0.40–0.69; 0.52, (RR weeks 36 before and infants) 95% 1177 CI 0.47–0.72; 5studies, 0.58, (RR infants), weeks 583 34 before 6studies, 0.45–0.71; 95% CI infants), 0.56, (RR 218 32 weeks before 0.67, (RR gestation 95% 4studies, CI 0.52–0.87; of weeks 30 before were that born corticosteroids treated with of mothers ininfants reduced Severe morbidity: neonatal infants).514 95% CI 0.77–8.96; 2.62, (RR 3studies, alone deaths well as inneonatal as treatment, with corticosteroid 498 infants) CI associated 0.99–10.66; 2studies, Hospital deaths were deaths Hospital RDS was significantly significantly was RDS (28) . assessed the feasibility, effectiveness and safety safety and feasibility, the effectiveness assessed Trial Corticosteroids Antenatal (ACT). trial This cluster-randomized trial –the population-based multicountry of a large by findings the informed was corticosteroid of antenatal administration for relating toEvidence preconditions the (context care) of care Antenatal corticosteroidsversus usual scale-up weeks. 22 at born inthose not but of gestation, 23–25 at weeks born babies preterm in frequent less significantly also was impairment 95% CI 1.46–1.90). neurodevelopmental or Death 1.66, OR adjusted 18.5%, versus (35.8% controls to compared corticosteroids received mothers whose ininfants However, higher was survival intact 36%. was entirecohort inthe survival up, intact morbidity: Long-term this group. in size included sample to smaller the due may be (adjusted 0.61, 95% CI OR weeks 0.34–1.07), which 22 at born those 0.48–0.69), not but 95% CI 0.57 (adjusted OR weeks 25 95% and CI 0.54–0.76) 0.64, 0.49,OR (adjusted 24 95% CI 0.39–0.61), OR weeks was measured using a validated colour-coded tape colour-coded avalidated tape using measured was and age gestational for aproxy as used was height fundal uterine available, not was age gestational on information reliable When disk. obstetric designed aspecially using assessed was age gestational known, was EDD or LMP Where were known. EDD nor (EDD), LMP delivery if neither height uterine or date of estimated (LMP) and period menstrual last included that algorithm of an by use the determined was age respectively. Gestational settings, birth inhome or community inthe clinics, hospitals, at care providing delivery (TBAs) attendants birth traditional and workers health community nurses, physicians, including clusters, intervention in the working attendants all birth included this context in providers Health-care haemorrhage). antenatal or , or of pre-eclampsia labour, PPROM, with signs of gestation 24 weeks 36 and between (presenting birth riskof preterm high at women to and identify age gestational totraining assess provider involved health-care intervention The women. toclose 100 000 of records Zambia) with birth and Pakistan Kenya, low-resource countries (Argentina, India, Guatemala, in clusters semi-urban and rural geographical distinct hospitals)and dispensaries clinics, health community facilities, non-hospital and centres health (primary of care all at levels corticosteroids of antenatal use the to increase designed intervention of amultifaceted (29) . The study was conducted in102 conducted was study . The After 18–22 follow-After months with a red zone indicating estimated gestational age Infant outcomes +0 less than 36 weeks. For every woman identified to Neonatal death: Neonatal mortality among < 5th- be at high risk of preterm birth, health-care providers percentile-birth-weight infants was not significantly received training to administer a single course of different between intervention and control clusters four doses of 6 mg of dexamethasone at intervals of (RR 0.96, 95% CI 0.87–1.06; 4778 infants), and 12 hours. The control sites received no intervention neither were (RR 0.99, 95% CI 0.90–1.09; apart from training in essential newborn care as in 6262 infants) or perinatal deaths (RR 0.97, 95% CI the intervention clusters. 0.91–1.04; 6265 infants). However, there was a 12% Identification of women at risk of preterm birth increase in neonatal mortality among all liveborn and use of corticosteroids: A total of 6214 (13%) infants (regardless of birth weight) in the intervention of 48 219 women in the intervention cluster were clusters as compared with the control clusters (RR identified as being at high risk of preterm birth. 1.12, 95% CI 1.02–1.22; 98 137 infants). Likewise, Of these women, 87% were identified at the there was an 11% increase in the rate of stillbirth (RR community and primary health care levels, 77% 1.11, 95% CI 1.02–1.22; 100 705 infants) and perinatal were identified based on signs of preterm labour, death (RR 1.11, 95% CI 1.04–1.19; 100 705 infants) 50% were identified at 33–36 weeks of gestation, in the intervention clusters compared with control and 98% received antenatal corticosteroids (out of clusters. which 83% received the first dose at the community and primary health care levels). Only 16% of all women who received antenatal corticosteroids in the RECOMMENDATION 1.1 intervention clusters gave birth to a < 5th-percentile- For eligible women, antenatal corticosteroid birth-weight infant (a proxy for preterm infant). The should be administered when preterm birth is intervention strategy increased coverage of antenatal considered imminent within 7 days of starting corticosteroids in the intervention compared with treatment, including within the first 24 hours. the control clusters. Compared with 10% in control (Strong recommendation based on low-quality clusters, 45% of < 5th-percentile-birth-weight evidence) infants in the intervention clusters were exposed to at least one dose of corticosteroid. In the intervention REMARKS clusters, delivery care for < 5th-percentile-birth- n Antenatal corticosteroid therapy should be weight infants was provided by physicians, nurses, started even when the completion of a full TBAs and family members in 44%, 32%, 20% and course before preterm birth is uncertain. 5% of cases, respectively; and the location of birth n Tocolysis may be considered as an was in the hospital, clinic, and home or other birth intervention to gain time to complete a setting in 51%, 26% and 23% of cases, respectively. single course of antenatal corticosteroids (see also Recommendation 2.0 on tocolytic Maternal outcomes treatments). Maternal infectious morbidity: “Suspected maternal n The GDG acknowledged the limitations and infection” (a composite variable defined as antibiotic potential bias of evidence derived from the use plus hospital admission or referral, and use subgroup analyses according to interval of intravenous fluids, surgery or other treatment between steroid administration and preterm related to infection, and evidence of antepartum or birth, which led to rating of the quality of postpartum infection among mothers of infants with evidence as “low”. Nevertheless, the group birth weight < 2500 g) was used to assess maternal made a strong recommendation on the safety in relation to corticosteroid use. Among basis of the balance being in favour of the women who delivered < 5th-percentile-birth-weight benefits of antenatal corticosteroids (in infants, there was a significantly increased risk of terms of reducing respiratory morbidity and suspected maternal infection in intervention clusters mortality for babies born within 24 hours and as compared with control clusters (10% versus 6%; up to 7 days of starting treatment), the low OR 1.67, 95% CI 1.33–2.09). Likewise, suspected resource requirements, and the feasibility of maternal infection was significantly higher among implementing the intervention. all women in the intervention clusters compared with control clusters (3% versus 2%; OR 1.45, 95% 1.33–1.58; 99 737 women). 3. EVIDENCE AND RECOMMENDATIONS

17 18 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES infants). (MD -147.01 g, 95% CI -291.97 to -2.05; 1study, 486 dose first the 7days than after more were born who treatment to corticosteroid exposed infants among weight inbirth towards atrend was there areduction 7days, 1and between and hours, 48 24before hours, born of babies weights birth inthe demonstrated differences significant were no there While subgroups. in any other infants) of not the but 1study, 95% 339 CI 0.09–0.75; 0.26, of (RR steroids dose first of the hours within 48 born infants among haemorrhage of cerebroventricular incases observed also were infants). reductions 988 Significant studies, 8 95% 0.53–1.28; CI 0.82, dose (RR first the days after 7 than more born infants) 517 those or 1.15; 9studies, 0.87, (RR 24 before hours born those 95% CI 0.66– infants), 1110 among not but 9studies, 0.35–0.60; 95% CI 7days 0.46, (RR 1and infants) between and 0.67, (RR hours 374 95% CI 3studies, 0.49–0.93; 48 before born babies among of RDS fewer cases Severe morbidity: neonatal deaths. fetal for observed were differences no but alone deaths neonatal for subgroup the across consistent was pattern This 598 infants). 95% CI 3studies, 1.42, 0.91–2.23; (RR 7days after born infants) those or 606 3 studies, 95% CI 0.60–1.09; 7days 0.81, (RR 1and between born therapy, those infants) not but of corticosteroid 1study, 373 0.59, (RR 95% CI 0.41–0.86; hours infants) 293 within 48 and 3studies, 0.39–0.94; 95% CI 0.60, (RR within 24 born hours infants for deaths neonatal and fetal incombined reduction Fetal and neonatal death: outcomes Infant subgroups. all the across chorioamnionitis of occurrence in the observed were differences morbidity: infectious Maternal Maternal outcomes 1–7 > 7days dayscategories. and < 24 hours, the for to trials providing evidence nine eight had which exception of with the RDS, reported outcomes critical of the most for included be could to trials four one Only infant. preterm of the birth and treatment corticosteroid between to interval the (27) with placebo compared corticosteroids of antenatal review overall showed that benefits Cochrane the In days) Table (EB 1d) 1–7 > 7 days and hours, < 48 hours, < 24 birth: and treatment (interval between corticosteroid therapy no or placebo versus corticosteroids Antenatal of evidenceSummary , subgroup analyses were performed according according were performed analyses , subgroup There was a significant asignificant was There There were significantly significantly were There No significant significant No . with multiple inwomen or with pregnancies singleton inwomen chorioamnionitis, for groups comparison between differences significant statistically no morbidity: infectious Maternal Maternal outcomes related to pregnancies. multiple comparisons for todata trials provided two one only included in the same Cochrane review Cochrane same inthe included 12 were available from trials multiple or singleton was pregnancy the to according whether with placebo compared of corticosteroids effects the for Results Table(EB 1e) (singletontreatment versus multiple pregnancy) no or placebo versus corticosteroids Antenatal of evidenceSummary n n REMARKS recommendation based on low-quality evidence) is anticipated. birth or multiple a single of whether irrespective birth preterm of risk at women for recommended is therapy corticosteroid Antenatal RECOMMENDATION 1.2 n benefit in this group of women of group in thiswomen are (who benefit of any clinical potential impact the considered group The pregnancy. inmultiple reported outcomes critical of adverse risks of reduced were all infavour estimates point the that fact to the inaddition infants, singleton among outcomes incritical overall improvement the on judgement its based but fetuses, multiple carrying of women subgroup in the corticosteroids antenatal of benefits the on of clarity lack the acknowledged GDG The birth. preterm riskof basis of increased the on pregnancy, to with amultiple any woman corticosteroid (or of antenatal prophylactic)administration routine the precludes recommendation This be a research priority. aresearch be this to consider not does GDG the pregnancy, inmultiple corticosteroids antenatal of effectiveness the about uncertainty level of some remains there Although made a strong recommendation. therefore and rates, morbidity and survival overall newborn the preterm on modest, albeit likely more to preterm), deliver inherently The review showed showed review The (Strong (Strong (27) . Of these, these, . Of Infant outcomes Summary of evidence Fetal and neonatal death: The reduction in fetal and Antenatal corticosteroids versus placebo or neonatal deaths observed in singleton pregnancies no treatment (preterm prelabour rupture of (RR 0.79, 95% CI 0.65–0.96; 3 studies, 1425 babies) membranes) (EB Table 1f) was not demonstrated in the analysis for multiple In the same Cochrane review (27), the effects pregnancies (RR 0.71, 0.41–1.22; 2 studies, 252 of antenatal corticosteroids were examined in a babies), although there was a trend towards benefit. subgroup of women with PPROM. The same pattern was observed for neonatal deaths alone. Maternal outcomes Severe neonatal morbidity: The reduction in RDS for Severe morbidity or death: No significant singleton pregnancies treated with corticosteroids differences were observed between groups for (RR 0.60, 95% CI 0.51–0.70; 12 studies, 2907 maternal death, chorioamnionitis or puerperal sepsis infants) did not reach statistical significance for in mothers when the first dose of corticosteroids was multiple pregnancies (RR 0.85, 95% CI 0.60–1.20; given to women with PPROM or prolonged rupture of 4 studies, 320 infants). Similarly, no significant membranes (> 24 hours). reduction was demonstrated in the rate of cerebroventricular haemorrhage or mean infant birth Infant outcomes weight in women with multiple pregnancies treated Fetal and neonatal death: Combined fetal and with corticosteroids compared with placebo/no neonatal deaths were significantly reduced among treatment. infants exposed to antenatal corticosteroid and born following PPROM at the time of first dose (RR 0.62, 95% CI 0.46–0.82; 4 studies, 733 infants), but not RECOMMENDATION 1.3 following prolonged rupture of membranes > 24 Antenatal corticosteroid therapy is hours (RR 0.77, 95% CI 0.51–1.17; 2 studies, 508 recommended in women with preterm infants) or > 48 hours (RR 0.93, 95% CI 0.57–1.51; 1 prelabour rupture of membranes and no clinical study, 255 women). As with previous outcomes, this signs of infection. (Strong recommendation based reduction was due to the contribution of reduced on moderate-quality evidence for newborn outcomes neonatal mortality among corticosteroid-exposed and low-quality evidence for maternal outcomes) infants (RR 0.61, 95% CI 0.46–0.83; 8 studies, REMARKS 1024 infants), while no reduction in fetal deaths was observed for any of these subgroups. n The use of prophylactic antibiotics should be included as part of standard care for the Severe neonatal morbidity: RDS was significantly mother once preterm prelabour rupture reduced in infants whose mothers received of the membranes is confirmed (see corticosteroids at the time of PPROM (RR 0.68, Recommendation 5.0). 95% CI 0.57–0.83; 12 studies, 1129 infants), as was cerebroventricular haemorrhage (RR 0.47, 95% n The GDG noted the paucity of evidence on benefits with regard to the duration of CI 0.28–0.79; 5 studies, 895 infants), necrotizing membranes rupture due to the lack of such enterocolitis (NEC) (RR 0.39, 95% CI 0.18–0.86; 4 information from trials included in the review. studies, 583 infants), and duration of mechanical However, the group placed its emphasis on ventilation (MD -3.50 days, 95% CI -5.12 to -1.88 the overall balance favouring benefits over days; 1 study, 165 infants). No significant differences harms of using antenatal corticosteroids in were observed for , systemic terms of reducing severe adverse neonatal infection in the first 48 hours, or need for mechanical outcomes without evidence of increased ventilation or continuous positive airway pressure risk of infection to the mother or the baby, (CPAP). and with the consideration that a substantial proportion of women at risk of imminent preterm birth would present with ruptured membranes, and therefore made a strong recommendation.

n The GDG cautioned against the use of antenatal corticosteroids for women with prolonged rupture of the membranes and with

features of sepsis. 3. EVIDENCE AND RECOMMENDATIONS

19 20 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES with histological chorioamnionitis only, on two chorioamnionitis with histological of women ininfants therapy of corticosteroid effects the reported histologically. or clinically studies Four either were diagnosed studies inthese participants among Netherlands. the Korea and Canada, inAustralia, each one and inFrance, two USA, inthe two settings: inhigh-resource conducted of gestation weeks 35 before to or a total at deliver of 1424 expected mothers involving studies cohort eight review included that asystematic from extracted was birth of preterm risk areat who with chorioamnionitis in women outcomes newborn adverse reducing for therapy corticosteroid antenatal of effects the on Evidence Table(EB 1g) or no(women treatment with chorioamnionitis) Antenatal corticosteroids versus placebo of evidenceSummary n n n REMARKS evidence) low-quality very on based recommendation preterm. deliver to likely are who in womenrecommended with chorioamnionitis not is therapy corticosteroid Antenatal RECOMMENDATION 1.4 intervention in this situation. inthis situation. intervention the against recommendation conditional maketo chose a and context-specific be may harms and of benefits balance the that acknowledged They survival. newborn improving for is essential steroid use where of populations majority inthe corticosteroids antenatal of benefits known the outweigh this that potential riskmay felt group The generated. was with chorioamnionitis women on evidence the where settings ofthat the than is higher morbidity infectious maternal riskof baseline where settings middle-income inlow- and particularly infection, maternal riskof exacerbating the about concern the TrialCorticosteroids Antenatal the from of evidence light the In . or septicaemia e.g. infection, systemic of ongoing with evidence in women avoided be should corticosteroids Antenatal condition. fetal or by maternal indicated when delivery timely of initiated expense the at be not should therapy corticosteroid Antenatal is made. chorioamnionitis of clinical diagnosis the when priority the be should insult intrauterine to baby of the avoid further delivery Timely (29) (30) , the GDG reviewed GDG , the . All studies were . All studies (Conditional

Histological chorioamnionitis outcomes Infant on maternal outcomes. review systematic inthe reported studies of the None Maternal outcomes settings income inlow- mortality neonatal coverage on corticosteroid antenatal on increasing trial effects evaluating the cluster-randomized of a large findings of the context inthe reviewed was interpreted evidence and This (267 infants). and used was mothers dexamethasone or betamethasone either studies, two remaining infants) inthe and and (161 mothers used was infants), dexamethasone studies, intwo and (996 mothers used was betamethasone studies, incomplete/suboptimal treatment). four In (or treatment with no compared corticosteroid review of inthe a use evaluated the All studies women separately. of groups inboth infants on studies further two and only, chorioamnionitis with clinical of women infants 3 studies, 427 babies).3 studies, 95% CI 0.38–1.14; 0.66, dysplasia (BPD) OR (pooled babies) or chronic lung disease/bronchopulmonary 0.93, OR 95% CI 720 0.67–1.30;(pooled 3studies, use babies), 1084 CI surfactant 0.78–2.26; 5studies, 95% babies), 1.33, OR 1084 NEC(pooled 5 studies, 95% CI 0.72–1.48; 1.03, OR (pooled sepsis neonatal 0.74,OR 419 babies), 95% 3studies, CI 0.26–2.09; (pooled leukomalacia inperiventricular observed were differences babies). 88 significant No 0.23; ventilation (MD -2.00,mechanical 95% CI -4.23– CI 0.08–1.07; of duration babies) inthe 121 nor 95% ventilation (OR mechanical 0.30, for need inthe were observed groups control and exposed between differences study, significant another no In 527 babies). (OR 95%therapy CI 0.28–0.70; 0.45, with corticosteroid < 7associated score with Apgar babies of incidence in the reduction a significant 491 babies). found study 4studies, One 0.20–0.79; 95% CI 0.40, OR 3–4) (pooled severe (grade IVH babies) 621 and 5studies, 95%0.41, CI 0.24–0.69; OR (IVH) (pooled haemorrhage intraventricular babies), 1084 5studies, 95% CI 0.44–0.76; 0.58, OR RDS (pooled in reductions with significant associated was chorioamnionitis with histological inwomen use Severe morbidity: neonatal infants). 1156 studies, 6 0.49, OR 95% (pooled CIdeaths 0.34–0.73; neonatal in reduction with asignificant associated was chorioamnionitis with histological inwomen use Fetal and neonatal death: (29) . Antenatal corticosteroid corticosteroid Antenatal Antenatal corticosteroid corticosteroid Antenatal Long-term morbidity: One small study that in babies of treated women, but corticosteroid followed participants through childhood was unable therapy had no significant effect on the duration of to show any difference in incidence of cerebral (MD -2.00, 95% CI -4.23 palsy (OR 0.35, 95% CI 0.07–1.67; 72 children) or to 0.23; 88 babies). No significant difference was neurodevelopmental outcome (general development observed in (pooled OR 1.02, 95% quotient) at the ages of 1 year (MD 6.00, 95% -9.94 CI 0.73–1.42; 5 studies, 1234 babies), NEC (pooled to 20.94; 72 children) and 3 years (MD 13.00, 95% OR 1.49, 95% CI 0.91–2.53; 5 studies, 1234 babies) CI -3.75 to 29.75; 72 children). or chronic lung disease/BPD (pooled OR 0.74, 95% CI 0.48–1.15; 4 studies, 659 babies). Clinical chorioamnionitis Fetal and neonatal death: Antenatal corticosteroid therapy in women with clinical chorioamnionitis RECOMMENDATION 1.5 was not associated with a significant difference in Antenatal corticosteroid therapy is not neonatal mortality (pooled OR 0.77, 95% 0.36–1.65; recommended in women undergoing planned 3 studies, 247 babies). caesarean section at late preterm gestations (34–36+6 weeks). (Conditional recommendation Severe neonatal morbidity: Corticosteroid therapy based on very low-quality evidence for newborn and in women with clinical chorioamnionitis was not maternal outcomes) associated with significant differences in RDS (pooled OR 0.73, 95% CI 0.73–1.12; 4 studies, 417 REMARKS babies), neonatal sepsis (pooled OR 0.94, 95% CI n The GDG noted the paucity of evidence on 0.40–2.18; 2 studies, 150 babies) or NEC (pooled the balance of benefits versus harms when OR 2.63, 95% CI 0.72–9.68; 2 studies, 150 babies). antenatal corticosteroid is administered Significant reductions in IVH (pooled OR 0.36, 95% to mothers undergoing elective caesarean CI 0.16–0.82; 3 studies, 318 babies), severe IVH section (CS) in late preterm. The group (pooled OR 0.29, 95% CI 0.10–0.89; 3 studies, 318 acknowledged that while there might be some babies) and periventricular leukomalacia (pooled benefits, there might also be harms. Reference OR 0.35, 95% CI 0.14–0.85; 3 studies, 318 babies) was made to the overall evidence on antenatal were observed among babies of mothers who were corticosteroid, which suggests potential treated with antenatal corticosteroids. In one study, harms in late preterm infants, and the fact that corticosteroid therapy significantly decreased the the population providing the evidence also need for mechanical ventilation (OR 0.05; 95% included provider-initiated (elective) preterm CI 0.00–0.94; 93 babies), but had no significant birth. effect on the duration of mechanical ventilation n Elective CS should not normally be performed (MD -2.00, 95% CI -4.23 to 0.23; 88 babies). at any gestational age < 39 weeks. No significant differences were observed in the frequencies of chronic lung disease/BPD (pooled OR n The GDG considered this to be a research 0.91, 95% CI 0.44–1.86; 3 studies, 232 babies). priority but chose to recommend against the practice until further evidence becomes available. Clinical and/or histological chorioamnionitis Fetal and neonatal death: Corticosteroid treatment in mothers with clinical and/or histological Summary of evidence chorioamnionitis was associated with significant reductions in neonatal mortality (pooled OR 0.54, Antenatal corticosteroids versus placebo or no 95% CI 0.38–0.76; 7 studies, 1403 babies). treatment (elective caesarean section in late preterm birth) (EB Table 1h) Corticosteroid therapy Severe neonatal morbidity: A systematic review of randomized and non- was associated with significant reductions in RDS randomized studies evaluating the effectiveness (pooled OR 0.62, 95% CI 0.49–0.78; 7 studies, 1501 of antenatal corticosteroid therapy for reducing babies), IVH (pooled OR 0.39, 95% CI 0.25–0.61; 6 adverse newborn outcomes in women undergoing studies, 939 babies), severe IVH (grade 3–4) (pooled elective caesarean section (CS) in the late preterm OR 0.36, 95% CI 0.20–0.65; 5 studies, 854 babies) period (i.e. > 34 weeks to 36+6 weeks of gestation) and periventricular leukomalacia (pooled OR 0.47, identified no eligible studies (30). Indirect evidence 95% CI 0.24–0.90; 4 studies, 737 babies). One study was extracted from a Cochrane systematic review found a significantly decreased need for mechanical that assessed the effects of corticosteroid therapy ventilation (OR 0.18, 95% CI 0.06–0.57; 214 babies) 3. EVIDENCE AND RECOMMENDATIONS

21 22 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES between the comparison groups. differences clear were no there childhood; through followed 407 infants for reported was childhood morbidity: Long-term 95% CI 0.49–1.33). 0.81, (RR indication respiratory (all care special levels) non- or any respiratory for overallto the rate neonatal of admission reduce significantly not did betamethasone Antenatal outcomes. low two of the rates the underscoring 95% CI -5% to -0%), reduction, 3% (i.e. respectively, 95% CI -5% to -1%) reduction, 3% (i.e. -0.03 and -0.03 were riskdifferences 0.64). corresponding The 0.15, 95% (RR CI 0.03– complications respiratory 95% CIfor 0.22–0.90), 0.45, (RR particularly and (all units care special levels) to neonatal admission risk of in the reduction with significant associated was betamethasone to Antenatal 1.30). CI -5.58 (MD NICU of stayinthe -2.14duration 95% days, ventilation 4.07, (RR or 95% CI 0.46–36.27), 95% CI mechanical 0.25–1.11), for 0.52, need (RR CI 0.07–1.58), newborn of the tachypnea transient 95% 0.32, RR respectively; infants, unexposed and 1.1% and (0.2% incorticosteroid-exposed of RDS incidence in the was found reduction significant Severe morbidity: neonatal group. ineither sepsis neonatal or death perinatal for Fetal and neonatal death: outcomes Infant infection. wound including infections, maternal for reported morbidity: infectious Maternal Maternal outcomes CS elective undergoing women in corticosteroids without treatment with usual babies), their betamethasone and compared which (involving 942 Kingdom mother United trial inthe (31) CS elective term after morbidity respiratory neonatal prevention of the on treatment with usual compared evidence for maternal outcomes) low-quality and outcomes evidence newborn for recommendation based on moderate-quality birth. preterm of imminent risk at are who pregnancy in disorders hypertensive with women in recommended is therapy corticosteroid Antenatal RECOMMENDATION 1.6 . This review included one unblinded randomized randomized unblinded one review. This included Academic ability during during ability Academic No events were reported were events reported No No statistically statistically No (Strong (Strong (32) No events were events No . women with hypertensive disorders in pregnancy. inpregnancy. disorders with hypertensive women in effectiveness its to examine were performed were observed between groups for birth weight weight birth for groups between were observed 278differences infants). significant statistically No 95% CI 0.17–0.87; 0.38, (RR 2studies, haemorrhage infants) cerebroventricular 382 and 5 studies, 95% CI 0.35–0.72; 0.50, (RR inRDS reductions Severe morbidity: neonatal infants). 313 95% 2studies, CI 0.57–1.20; 0.83, (RR death neonatal and fetal infants) combined or 331 95% 3studies, CI 0.91–3.28; 1.73, (RR only death fetal for groups between observed were differences 278 infants). significant 2 studies, statistically No 95% CI 0.29–0.87; 0.50, (RR deaths in neonatal reductions were significant there corticosteroids, to antenatal exposed disorders with hypertensive Fetal and neonatal death: outcomes Infant treatment. no or placebo received who those and corticosteroids received who those between 0.74,(RR 95% 1study, CI women) 0.26–2.05; 218 to intensive admission unit care maternal women) or 1study, 218 95% CI 0.30–1.52; 0.68, (RR sepsis women), 311 puerperal 2studies, 95% CI 0.36–15.73; 1 study, 2.36, women),(RR 218 chorioamnionitis 0.98, (RR 95% death CI 0.06–15.50; in maternal differences significant were no of there pregnancy, disorders with hypertensive of women subgroup Severe or death: morbidity maternal Maternal outcomes of antenatal corticosteroid corticosteroid of antenatal review effectiveness evaluating the Cochrane the In Table(EB 1i) pregnancy) in disorders (hypertensive treatment no or placebo versus corticosteroids Antenatal of evidenceSummary n n REMARKS therefore made a strong recommendation. and settings, across use resource health-care on potential impact the and intervention, the globally, of implementing feasibility the of availability corticosteroid wide low and cost the outcomes, mortality and morbidity early of reducing interms to infants preterm the benefits the on emphasis its placed GDG The setting. inahospital therapy to corticosteroid inaddition to mother the provided be should inpregnancy disorders with hypertensive of women management the for of care standard appropriate An Among infants of mothers of mothers infants Among (27) There were significant were significant There , subgroup analyses analyses , subgroup In the the In (MD -131.72 g, 95% CI -319.68 to 56.24; 1 study, 95 Maternal outcomes infants). Maternal morbidity: There were no significant differences in the rates of chorioamnionitis (OR 0.77, 95% CI 0.36–1.63; 1 study, 220 women) or RECOMMENDATION 1.7 caesarean section (OR 0.48, 95% CI 0.03–8.68; 1 Antenatal corticosteroid therapy is study, 165 women) between women with SGA or recommended for women at risk of imminent IUGR infants exposed to antenatal corticosteroids preterm birth of a growth-restricted fetus. versus no antenatal corticosteroids (or incomplete (Strong recommendation based on very low-quality corticosteroid treatment). evidence) Infant outcomes REMARKS Fetal and neonatal death: There was no observed n The GDG noted the limited evidence on the difference in (fetal or neonatal benefits of antenatal corticosteroid in this death) between groups in any of the IUGR studies subgroup of women. However, the group (pooled OR 0.81, 95% CI 0.58–1.04; 4 studies, 504 placed its emphasis on the overall benefits babies), nor in the majority of reports on SGA infants of antenatal corticosteroid, the potential (pooled OR 0.78, 95% CI 0.58–1.04; 6 studies, 958 benefits in terms of reduced handicap among babies). surviving intrauterine growth-restricted (IUGR) infants, and evidence of reduced odds Child death: No significant difference in childhood of adverse newborn mortality and morbidity deaths was observed in the study that reported long- outcomes, and therefore made a strong term follow-up (OR 0.79, 95% CI 0.20–3.08; 124 recommendation. babies). n The GDG acknowledged the concern about Severe neonatal morbidity: No significant the effect of antenatal corticosteroids on difference was observed for RDS between treated fetal growth, but agreed that there is no and untreated groups in any of the IUGR studies evidence to suggest that steroids will perform (pooled OR 0.81, 95% CI 0.59–1.11; 4 studies, 504 differently in this subgroup compared to the babies), nor in the majority of reports on SGA overall preterm population. infants, though pooled analyses showed a trend in favour of antenatal corticosteroid-exposed infants (pooled OR 0.83, 95% CI 0.66–1.05; 8 studies, 1126 Summary of evidence babies). No difference was observed in the risk of Antenatal corticosteroids versus placebo or no major cerebral morbidity between corticosteroid- treatment (growth-restricted fetus and small-for- exposed compared with unexposed IUGR infants in gestational-age infant) (EB Table 1j) two studies (pooled OR 0.86, 95% CI 0.35–2.10; 211 Evidence relating to the effectiveness and safety babies), but a reduction in lesions was observed of antenatal corticosteroid therapy for reducing for SGA infants who were exposed to antenatal adverse newborn outcomes in women with small-for- corticosteroids (OR 0.57, 95% CI 0.41–0.78; 5 gestational-age (SGA) infants, including intrauterine studies, 761 babies). growth-restricted (IUGR) infants, was extracted There was no significant difference noted in exposed from one systematic review of nine observational versus control groups for other neonatal outcomes studies (30). The studies included women who (neonatal sepsis, BPD, NEC, Apgar < 7 at 5 minutes, were pregnant with babies diagnosed with IUGR use of mechanical ventilation, chronic lung disease, through confirmation of and or defined as < 3rd percentile for those identified as SGA (a total of 2846 mothers gestational age). and infants). Three of the studies were specifically on IUGR only, five were on SGA infants only, and Long-term morbidity: Only one study reported on one study included both IUGR and SGA infants. The long-term outcomes after antenatal corticosteroid studies evaluated betamethasone or dexamethasone treatment. Survival without handicap at two years compared with no treatment (or incomplete was more likely in IUGR infants exposed to antenatal treatment) in women expected to deliver at or before steroids (82% in the exposed versus 65% in the 35 weeks of gestation. All studies were conducted in unexposed group: OR 2.55, 95% CI 1.11–5.87; 124 high-resource countries: Canada (1 study), France (1 babies). However, physical growth beneath the 10th study), Italy (2 studies), the Netherlands (3 studies), percentile appears more likely after Sweden (1 study) and the USA (1 study). exposure (OR 5.20, 95% CI 1.38–19.62). 3. EVIDENCE AND RECOMMENDATIONS

23 24 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES and diabetes mellitus. diabetes and diabetes gestational with women excluded have generally newborns in outcomes adverse reducing for corticosteroids studies eligible no identified birth riskof at preterm women diabetic gestational and in pre-gestational outcomes adverse reducing for treatment no or with placebo compared therapy corticosteroid of antenatal effectiveness evaluating the studies randomized non- and reviewA systematic of randomized diabetes) and gestational no (pre-gestational treatment Antenatal corticosteroids versus placebo or of evidenceSummary n n n n REMARKS evidence) low-quality very on based recommendation maternal blood glucose control. optimize to by interventions accompanied be should this and birth, preterm imminent of risk at are who diabetes gestational and for women recommended with pre-gestational is therapy corticosteroid Antenatal RECOMMENDATION 1.8 evidence of fetal lung immaturity. lung of fetal evidence is laboratory if there of gestation weeks > 34 at considered be also should corticosteroids of use the diabetes, controlled with poorly women inpregnant Therefore, population. obstetric general with the compared women diabetic inpregnant frequent more is generally maturity lung infetal Delay respiratory distress syndrome. riskof newborn the to reduce pregnancy to and/or prior glucose during blood maternal of control strict ensure Clinicians should control. are takento glycaemic ensure measures babyappropriate if the for benefits potentialthe counterbalance to insufficient itwas that agreed but corticosteroids, maternalofantenatal hyperglycaemic effect the about concern the considered group The strong recommendation. a made therefore and survival, newborn overall on potential impact the and diabetes, by maternal posed morbidity respiratory riskof newborn higher the of reducing in terms potential benefits the in preterm, steroid antenatal of overall the benefits on However, emphasis its placed group the of women. inthis subgroup corticosteroid antenatal of benefits the on evidence of paucity the acknowledged GDG The (30) . Importantly, previous trials on antenatal antenatal trials on previous . Importantly, (Strong (Strong type 2 diabetes treated with diet or diet and insulin. insulin. and diet or treated with diet diabetes type 2 with women among 26–64% increased and diabetes 39–112% with diet-plus-insulin-treated inwomen increased was dose insulin while administration, with diet-treated novo de insulin required diabetes of therapy, women 40% betamethasone antenatal membranes of the rupture riskof at premature women diabetic in of betamethasone use following antenatal control glycaemic on reported inMexico women 30 among study Additionally, observational one infants inpreterm corticosteroids antenatal of review benefit showed that Cochrane of the findings with the consistent was study same inthe betamethasone receiving women among innewborns outcomes adverse other and in RDS women). 123 However, reduction the 1.14–6.46; 95% CI 2.71, (RR controls with the compared betamethasone receiving women among mellitus diabetes riskof gestational increased showed study of gestation weeks 34 26 and between with severe pre-eclampsia women pregnant diabetic innon- treatment with no betamethasone antenatal compared inBrazil trial conducted randomized One treatment. 4 following betamethasone days 2and between occurred changes greatest The n n REMARKS evidence) quality imminent. is birth preterm when choice of corticosteroid antenatal the as recommended doses) is divided in (total 24 mg betamethasone IM or (IM)dexamethasone intramuscular Either RECOMMENDATION 1.9 administered in divided doses 12 hours or 24 or 12 hours doses individed administered of atotal 24 mg steroid dose was majority inthe that noted but two, the comparing trials slightly across varied betamethasone and dexamethasone both for regimens and doses the that acknowledged GDG The midwives for doctors guide and a childbirth: and complications inpregnancy inWHO’s and List Medicine Essential WHO the on women inpregnant use availability, listedwider for itis currently and of lowerand in terms cost betamethasone over advantage an has dexamethasone that over other. acknowledged the group The of one arecommendation support would that betamethasone and dexamethasone of efficacy comparative the on evidence conclusive is no there that noted GDG The (34) (Strong recommendation based on low- . The study showed that following that showed study . The Managing Managing

(27) (11) . . (33) . This . This conducted in the USA, two in France and one trial hours apart. Four doses of dexamethasone each in Iran, Israel, the Netherlands, Poland, Taiwan 6 mg IM 12 hours apart or two doses of and the United Kingdom, as well as a two-centre betamethasone 12 mg IM 24 hours apart were study in Italy and Israel. the preferred choice in most of the studies. When deciding on the dosing frequency, Dexamethasone versus betamethasone (any dose consideration should be given to the likely or regimen) timing of preterm birth to ensure that the woman completes the total dose of steroid or Maternal outcomes receives a substantial amount of the total dose Pregnancy prolongation: Pregnancy prolongation before birth. Although there were no data on was reported in only one trial with results reported women’s satisfaction, women are likely to separately for women with intact and ruptured prefer fewer injections. membranes. For women with ruptured membranes, the mean interval between hospital admission and n The GDG reviewed the important differences in the type and preparation of steroids birth was identical (7.1 days) in the two groups (MD across settings and emphasized that local 0.00 days, 95% CI -0.99 to 0.99; 120 women). protocols on the type and dosing regimen of However, for women with intact membranes, antenatal steroid should be informed by the pregnancy was prolonged for a mean difference of 7 preparations that are readily available in the days in the dexamethasone group compared with the setting. This will not only encourage uptake betamethasone group (MD 7.0 days, 95% CI 5.56 to and ease their use by health-care providers 8.44; 120 women). but also avoid incorrect dosing and wastage of resources. Infant outcomes

n The panel felt there might be important There were no significant differences in most differences in pharmacological properties of critical infant outcomes between groups receiving dexamethasone and betamethasone dosage dexamethasone and those receiving betamethasone. regimens and therefore considered this as a Neonatal death: Neonatal death was similar in the research priority. two groups (RR 1.41, 95% CI 0.54–3.67; 4 studies, 596 infants). Summary of evidence Severe neonatal morbidity: There were no significant differences in RDS (RR 1.06, 95% Different corticosteroid regimens for women at risk of preterm birth (EB Table 1k) CI 0.88–1.27; 5 studies, 753 infants), neonatal sepsis (RR 1.30, 95% CI 0.78–2.19; 2 studies, 516 infants), Evidence on the effectiveness and safety of different NEC (RR 1.29, 95% CI 0.38–4.40; 3 studies, 598 corticosteroids and different drug regimens was infants), retinopathy of prematurity (RR 0.93, 95% extracted from a Cochrane systematic review that CI 0.59–1.47; 2 studies, 516 infants), periventricular included 12 trials (1557 women and 1661 infants) leukomalacia (RR 0.83, 95% CI 0.23–3.03; 4 studies, evaluating antenatal corticosteroid therapy for 703 infants) or BPD (RR 2.50, 95% CI 0.10–61.34; preterm birth (35). 2 studies, 464 infants). The use of dexamethasone Ten trials compared dexamethasone with was associated with a reduction in the frequency of betamethasone and two trials compared different any IVH (all grades) (RR 0.44, 95% CI 0.21–0.92; 4 regimens of the same drug in women at high risk of studies, 549 infants), but no difference was observed giving birth between 23 and 35 weeks of gestation. between the drugs for severe IVH (RR 0.40, 95% In the comparison between dexamethasone and CI 0.13–1.24; 4 studies, 549 infants). betamethasone, both drugs were administered There was no significant difference in the rate of intramuscularly (IM); betamethasone was given low infant Apgar score (< 7) at 5 minutes after as 24 mg in two to four divided doses 12–24 hours birth (RR 0.97, 95% CI 0.43–2.18; 2 studies, 207 apart and dexamethasone was given as 24 mg infants) or admission to NICU (RR 1.72, 95% (except in one trial which used 16 mg) in two to four CI 0.44–6.72; 2 studies, 345 infants) between the divided doses 12 hours apart. However, 6 of the 10 groups. In one trial (70 infants), the mean duration studies in this comparison used two doses of 12 mg of NICU stay was reduced by approximately 1 day betamethasone 24 hours apart and four doses of in the dexamethasone group as compared to the 6 mg dexamethasone 12 hours apart. betamethasone group (MD -0.91, 95% CI -1.77 to In four of the trials, women may have received repeat -0.05). doses of corticosteroid. Three of the trials were 3. EVIDENCE AND RECOMMENDATIONS

25 26 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES not be clinically significant (mean of 2.82 versus 3.55 3.55 versus 2.82 of significant clinically (mean be not may groups between of this difference magnitude the although treatment, 24-hourly receiving group to the 12-hourly compared as betamethasone receiving group inthe reduced staywas hospital morbidity: Maternal Maternal outcomes hours. 24 versus 12 hours every of betamethasone doses 12 mg compared women 255 for trial with data One 12 mg 24-hourly Betamethasone 12 mg 12-hourly versus betamethasone 95%1.11–64.93). CI 8.48, (RR significant was groups between difference the thisfor outcome and group, dexamethasone IM with the compared oral inthe increased was sepsis Neonatal weight. birth infant or IVH NEC, death, of neonatal terms in dexamethasone IM or oral receiving groups between differences significant were no There Neonatal death and severe neonatal morbidity: outcomes Infant inthis trial. were reported outcomes maternal No Maternal outcomes 12-hourly) dexamethasone. 12-hourly) (32 mg oral (24 mg with intramuscular compared women 183 for with data study One Oral versus intramuscular dexamethasone differences. subgroup possible to power statistical lacked identify studies that low event or meant rates subgroup, one available werefor only data estimable outcomes, most For morbidity. severe or infant death neonatal with regard to dosing regimens different the betamethasone. There were no differencesbetween and dexamethasone of dosing regimens different comparing were conducted analyses Subgroup groups. comparison the between differences meaningful powerstatistical detect to sufficient have trialnot did The months. 18 at disability children) reported assessment of neurosensory morbidity: Long-term infants). 95% 734 CI to -0.11 0.12; 3studies, 0.01 kg, (MD identical were almost groups betamethasone and dexamethasone inthe weights birth mean the infants). infive trials, 105 addition, 0.65–1.24; In 0.89, 95%(RR groups CI between difference no significant (< 2500 g)weight identified and birth low in infant difference the trial reported One Maternal postpartum Only one trial (with one Only 12

differencesbetween groups for most outcomes. to power statistical lacked identify study the although reported, outcomes critical all newborn for regimens two the between differences significant were no and earlyNeonatal mortality morbidity: outcomes Infant 2.02). 95% CI 0.25– 0.71, (RR feverof > 100.4ºF maternal rates the in observed difference significant no was 95% days, CI to -1.28 -0.18). -0.73 days; MD There evidence for maternal outcomes) low-quality and outcomes evidence newborn for recommendation based on moderate-quality 7days. next the in birth preterm of risk ahigh is there that demonstrates assessment clinical asubsequent and dose, initial the 7days after within occur not does birth preterm if recommended is corticosteroid antenatal of course repeat A single RECOMMENDATION 1.10 n n n n REMARKS antenatal corticosteroid regimens. on recommendation previous with the align should recommendation the that agreed but used, of betamethasone doses and of courses number inthe variations the noted also group recommendation to dexamethasone. The the to not extend reasons were no there that concluded but testedinthiswas context, betamethasone only that noted GDG The gestation. of weeks 24 34 and between to women applied be only should recommendation This inthis guideline. recommended as corticosteroid of antenatal dose a full to refers inthis context course A single conditional. it made and recommendation of the strength lowered the GDG the settings, system health across values likely inthese to variations be are there that Given of steroid. course repeat asingle recommended therefore and weight, birth inneonatal reduction small the on value (which save lower costs) could placed and use surfactant less and morbidity respiratory inthe reduction further associated the on However, emphasis its placed group the corticosteroids. of repeat use with the mortality of neonatal reduction further on of evidence lack the acknowledged GDG The (Conditional There There Repeat course(s) versus a single course of (RR 0.82, 95% CI 0.24–2.84; 7 studies, 2755 antenatal corticosteroids (EB Table 1l) fetuses), neonatal deaths (RR 0.91, 95% CI 0.62– Data on repeat course(s) compared with a single 1.34; 7 studies, 2713 infants) or fetal and neonatal course of antenatal corticosteroids were extracted deaths combined (RR 0.94, 95% CI 0.71–1.23; 9 from a Cochrane systematic review of 10 trials studies, 5554 infants). with data for 4733 women and 5700 babies (36). Severe neonatal morbidity: A repeat course of The review evaluated the use of repeat doses antenatal corticosteroids was associated with a of betamethasone compared with no repeat reduction in RDS in infants compared with placebo or corticosteroid treatment in women who had no treatment (RR 0.83, 95% CI 0.75–0.91; 8 studies, received one course of corticosteroid at trial entry 3206 infants). A repeat course was also associated and remained at risk of preterm birth for 7 or more with a reduction in surfactant use in preterm infants days after initial treatment. Studies were mainly (RR 0.78, 95% CI 0.65–0.95; 9 studies 5525 infants). conducted in high-resource settings: Australia and There was no significant difference in the duration of New Zealand, Canada, Finland and India (1 study respiratory support between the groups (MD 0.30 each) and the USA (5 studies). One multicentre days, 95% CI -0.90 to 1.50; 1 study, 37 infants). trial took place in 20 countries (including a number of middle-income countries): Argentina, Brazil, “Serious infant outcome”, a composite outcome Bolivia, Canada, Chile, China, Columbia, Denmark, that variably included infant mortality and serious Germany, Hungary, Israel, Jordan, the Netherlands, morbidity outcomes, was significantly reduced in Peru, Poland, Russia, Spain, Switzerland, the United infants of women treated with repeat courses of Kingdom and the USA. corticosteroids compared to controls (RR 0.84, 95% CI 0.75–0.94; 7 studies, 5094 infants). However, Additional comparisons included a subgroup no significant differences were seen between of women with PPROM, and subgroup analysis comparison groups for individual severe infant compared different dosing regimens and intervals morbidity outcomes: any grade of IVH (RR 0.94, between initial treatment and repeat doses. Women 95% CI 0.75–1.18; 6 studies, 3065 infants), severe included in the trials were between 23 and 34 weeks IVH (RR 1.13, 95% CI 0.69–1.86; 6 studies, 4819 pregnant, though the specific criteria varied between infants), NEC (RR 0.74, 95% CI 0.51–1.08; 8 studies, studies. 5394 infants), retinopathy of prematurity (RR 1.02, 95% CI 0.81–1.28; 7 studies, 4883 infants), chronic Repeat course(s) of antenatal corticosteroids versus lung disease (RR 1.06, 95% CI 0.87–1.30; 8 studies, placebo or no treatment 5393 infants), periventricular leukomalacia (RR Maternal outcomes 0.77, 95% CI 0.43–1.37; 7 studies, 4888 infants) Prolongation of pregnancy: Repeat courses of or systemic neonatal infection (RR 0.93, 95% CI corticosteroids were not associated with reduction 0.79–1.11; 3 studies, 1544 infants). Rates of admission in the rates of preterm birth before 28, 34 or 37 to NICU were very similar in the two groups (RR 1.01, completed weeks of gestation (RR 1.07, 95% CI 95% CI 0.95–1.07; 2 studies, 3448 infants). 0.83–1.38; 2 studies, 1632 women; RR 1.01, 95% CI Infants whose mothers had received repeat courses 0.95–1.07; 4 studies, 2140 women; RR 0.97, 95% of corticosteroids compared to those who had a CI 0.92–1.02; 2 studies, 1181 women, respectively). single course had on average slightly lower birth Mean gestational age at delivery was not significantly weight (MD -75.79 g, 95% CI -117.63 to -33.96; 9 different between comparison groups (MD -0.09 studies, 5626 infants). There was no significant weeks, 95% CI -0.33 to 0.15; 8 studies, 3179 infants). difference between groups for frequency of SGA Maternal infectious morbidity: There were no babies (RR 1.18, 95% CI 0.97–1.43; 7 studies, 3975 significant differences between groups for rates infants). of puerperal sepsis (RR 1.15, 95% CI 0.83–1.60; 5 Long-term morbidity: Long-term outcomes were studies, 3091 women) or maternal chorioamnionitis also similar in the two groups: survival free of any (RR 1.16, 95% CI 0.92–1.46; 6 studies, 4261 women). disability (RR 1.01, 95% CI 0.97–1.05; 2 studies, 3155 Maternal side-effects: Maternal side-effects were children); any neurosensory disability (RR 1.01, 95% not significantly different in the two groups (RR 0.97, CI 0.92–1.11; 2 studies, 1317 children); childhood 95% CI 0.24–3.90; 2 studies, 1474 women). disability at early childhood follow-up (RR 0.98, 95% CI 0.83–1.16; 1 study, 999 children); or development Infant outcomes delay at early childhood follow-up (RR 0.97, 95% CI 0.84–1.13; 3 studies, 3202 children). Rates of Fetal and neonatal death: There were no significant blindness and deafness were very similar in the two

differences between groups in terms of fetal deaths 3. EVIDENCE AND RECOMMENDATIONS

27 28 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES differences between different dosing regimens for dosing regimens different between differences significant no showed tests interaction Subgroup compared. also were dosing regimens Different CI -290 to -31.48). (MD weight -161.00 g, 95% birth mean with reduced associated were also study, doses same repeat the 95% CI 1.07–3.73; 2.00, (RR infants).course 368 In to asingle were exposed who with those compared age gestational for small of being frequency in the increase an had of corticosteroids courses repeat more to or four exposed babies that indicated study infants). 399 one from Data 2studies, CI 0.73–0.99; 95% 0.85, (RR group course repeat inthe reduced (as which analysis) RDS, main from inthe was apart outcomes most for groups course single and course repeat the between differences significant were no there of corticosteroids course repeat one receiving For women analysis. main the reflected largely Findings received. group courses repeat in the women of corticosteroids courses of repeat number by the conducted also was analysis Subgroup course(s).repeat the and initial the treatment between interval of the irrespective weights birth slightly lowerhad mean course(s) repeat inthe group babies the weight: birth for infant sample whole the for findings the reflected Similarly, analysis subgroup of corticosteroids. course asingle receiving to group the compared group course(s) repeat inthe inRDS areduction showed bothsubgroups sample: whole the for findings the reflected RDS for results The IVH. or mortality, neonatal and fetal chorioamnionitis, for subgroups between differences significant were no There 14 days). after course repeat 7days versus after course repeat (i.e. adifference made course repeat the and course one between interval the whether to examine conducted was analysis Subgroup 95% CI 1.05–2.31). 1.56, (RR course single a received who with those compared corticosteroids course(s) repeat the receiving of inwomen increased However,disease. was rate of chorioamnionitis lung chronic and RDS mortality, perinatal sepsis, puerperal for including reported, outcomes of the most for groups between differences significant were no There following PPROM. in women outcomes examined women 160 for with data Maternal and perinatal outcomes: courses) of repeat number course, repeat (PPROM, treatment no 7-day 14-day interval for versus course(s) or placebo Repeat versus of corticosteroids children). 3883 5 studies, 95% CI 0.71–1.49; follow-up 1.03, (RR childhood early at palsy of cerebral frequency the was as groups, One study study One 3.1.2 sample. whole the for findings the overall reflected largely findings and reported, any outcomes of the n REMARKS evidence) quality (Conditional recommendation based very low- outcomes. newborn improving of purpose the for birth preterm imminent of risk at women for recommended not are treatments) Tocolytic treatments (acute and maintenance RECOMMENDATION 2.0 n neonatal outcomes. to improve critical demonstrated been not has that agents) outcome intermediate is an 2–7 days (which by few is achievable tocolytic agreed that prolongation of pregnancy for GDG The outcomes. neonatal and perinatal adverse of reducing interms treatment, tocolytic with no compared treatment of tocolytic benefits of substantive lack the by informed was recommendation This — — outcomes. improves neonatal to this showthat measure evidence direct no is currently there although setting, care health- neonatal to appropriate an transfer and/or fetal corticosteroid in-utero antenatal of to administration for awindow provide (up considered be pregnancy hours) can to 48 to prolong drug of atocolytic use acute otherwise uncomplicated pregnancy, the have who an birth preterm of imminent risk at inwomen that agreed GDG The

Tocolysis and labour preterm inhibiting for improving newborn outcomes outcomes newborn improving Although betamimetics do appear appear do betamimetics Although inthis tocolysis is considered When sometimes be life-threatening. may which reactions, drug of adverse risk higher of the tocolysis because for used be not they should hours, 48 more than for delayingbirth in effective comes first. whichever is completed, until transfer or hours to up for 48 hours 4–8 every 20 mg of followed 20 mg by dose 10– initial oral an suggested GDG The hours. toup 48 for or ceased until contractions hours 4–8 followed by 10–20initial dose, every mg an as mg 10–30 was treatment tocolytic acute intrials for used regimen common most The trials. inrelevant used regimens inthe variation considerable is blocker) There agent. preferred is the (a nifedipine channel calcium context, the use of oral or intravenous (IV) hydration as a — There is no evidence of additional benefit treatment for preterm labour (45). The methodology of using a combination of tocolytic agents of many of the tocolytic studies was limited over single agents. Therefore, when by insufficient numbers of participants, lack of tocolysis is considered, a combination of comparison with a placebo, and inconsistent use of tocolytic agents should not be used. . For specific subgroups (e.g. women — The available evidence regarding the with multiple pregnancies, PPROM), evidence was potential risks and the lack of information sought from commissioned systematic reviews that on the long-term outcomes following considered both randomized and non-randomized tocolysis should be discussed with the studies. The summary of evidence for these woman and her partner in order for them subgroups is not included in this document as the to take an informed decision regarding the overall recommendation is not in favour of tocolysis. woman’s care. — Consideration of the use of tocolytics Betamimetics versus placebo or no treatment should be individualized and tocolytics (EB Table 2a) should not be used when there is any Twelve trials compared any betamimetics with obstetric or medical contraindication to placebo (1366 women). Eligible women were prolonging the pregnancy. Specifically, between 20 and 37 weeks of pregnancy, but the tocolytics may be associated with harm majority of women were recruited after 32 weeks. and should not be used in the following Three trials included women with PPROM and six conditions: included pregnancies in addition to singletons. n preterm prelabour rupture of Two trials administered steroids to women in both membranes (PPROM) arms, use of steroids was not clear in one trial, and the remaining trials did not state whether or not n chorioamnionitis women received steroids in addition to tocolytic n abruption therapy. Nine trials compared the betamimetic n cardiac disease. with placebo, two compared n The GDG agreed that considerable with placebo, and one trial compared isoxsuprine uncertainty still exists around the value of with placebo. tocolysis for newborns, particularly as it relates to taking advantage of the time gained Maternal outcomes for administration of antenatal corticosteroids Maternal death: There were no maternal deaths and/or in-utero transfer, and whether a short reported in trials that evaluated this outcome (2 prolongation of pregnancy of 2–7 days is studies, 907 women). more advantageous in one setting compared to another. The group considered studies Pregnancy prolongation: While there was no on tocolytics (e.g. ) observed effect on preterm birth before 37 weeks + antenatal corticosteroids versus placebo (RR 0.95, 95% CI 0.88–1.03; 10 studies, 1212 + antenatal corticosteroids for improving women), betamimetics reduced the chances of neonatal outcomes a research priority. In women in threatened preterm labour giving birth addition, the GDG stressed the need for within 48 hours (RR 0.68, 95% CI 0.53–0.88; 10 systematic collection of data on critical studies, 1209 women) and within 7 days of entering neonatal outcomes following tocolysis. the trial (RR 0.80, 95% CI 0.65–0.98; 5 studies, 911 women), compared with women who received placebo. Summary of evidence Adverse drug reaction and side-effects: More Any tocolytic agent versus placebo or no treatment women on betamimetics stopped treatment due to Evidence related to the use of tocolytic drugs versus adverse drug reaction (RR 11.38, 95% CI 5.21–24.86; no tocolysis for improving pregnancy outcomes 5 studies, 1081 women). Betamimetics were also in women with threatened preterm labour was associated with a number of maternal side-effects, extracted from eight Cochrane reviews examining including palpitation (RR 9.91; 95% CI 6.46–15.20; 5 the relative effects of tocolytic (37–44). studies, 1089 women) and chest (RR 11.29, 95% Each systematic review originally examined the CI 3.81–33.46; 2 studies, 814 women). In addition, effectiveness of a particular class of tocolytic agent more women in the treatment group experienced (as described below), rather than tocolysis as an headache (RR 4.07; 95% CI 2.60–6.35; 3 studies, intervention. Another systematic review examined 936 women), hyperglycaemia (RR 2.90, 95% CI 3. EVIDENCE AND RECOMMENDATIONS

29 30 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES 173 women).173 2studies, 95% CI 0.21–0.43; 0.30, (RR recruitment of hours within 48 birth giving of women number in the reduction with asignificant were associated blockers channel calcium with placebo, Compared 95% CI 0.18–2.43). 0.65, average RR (pooled groups between difference no was there Overall, 0.96, 95% (RR CI 0.89–1.03). 37 weeks before birth given had included women 89 2of the all but women), study, 84 in another while CI 0.31–0.62; 95% 0.44, (RR group blockers channel calcium the in reduced significantly was of gestation 37 weeks before study, one In birth rate birth. the of preterm prolongation:Pregnancy Maternal outcomes given. details further with no weeks, 35 28 and between women included second the membranes; intact with and of gestation weeks 34 and 30 between pregnancies singleton carrying women included study One were reported. outcomes relevant three (nifedipine) only blockers and with placebo channel calcium women) compared (173 studies two Only (EB Table 2b) treatment no or placebo blockerCalcium versus channel infants). 95% CI 1.12–5.13; 2.40, (RR group treatment 30 in the increased significantly fetal was palsy). cerebral or hypoglycaemia trial, asmall In neonatal infection, or sepsis neonatal NEC, (RDS, reported morbidity any severe for neonatal groups significant differences between comparison Severe morbidity: neonatal 1study, infants). 750 95% CI 0.05–5.64; 0.51, (RR 1174CI 6studies, 0.27–3.00; death infants) infant or 0.90, infants), (RR 1332 death 95% studies, neonatal 11 95% CI 0.46–1.55; 0.84, (RR death perinatal for significant differences between comparison groups Perinatal, neonatal or infant death: outcomes Infant 52 controls. the among with none compared betamimetic-treated women of 54 in6out occurred Myocardial infarction . or arrhythmias cardiac tachycardia, oedema, pulmonary for women in differences 708 observed women). were no There 1study, 10.74, (RR tremor and 95% CI 6.20–18.59; 1study, 2.90, 708(RR women) 95% CI 1.64–5.12; 932 women), stuffiness 3studies, nasal 1.29–2.42; women), 1.76, vomiting814 (RR or 95% CI nausea 2studies, 95% CI 2.21–6.77; 3.86, (RR dyspnoea 6.07,(RR 1study, 708 women), 95% CI 4.00–9.20; 1study, 708 women), 2.05–4.09; hypokalaemia Both studies reported on on reported studies Both There were no were no There There were no were no There pregnancies from two of the trials. of the two from pregnancies with multiple those trials and all three from were excluded membranes Women with ruptured of gestation. weeks 35 and 23 between in labour trials were to Womensuppository. these recruited third inthe arectal as and orally administered was indomethacin trials, two In with placebo. (a of indomethacin COXcomparisons inhibitor) included women involving 106 studies Three (EB Tabletreatment 2c) Cyclo-oxygenase (COX) no or placebo versus inhibitors studies. inthese werereported not outcomes Infant outcomes Infant 95% CI 3.13–795.02). 49.89, (RR group placebo inthe with none compared andvertigo) headache (flushing, side-effects had tocolysis inthe group women of half the than more with placebo: compared group blockers channel calcium inthe were increased these and reactions, drug adverse maternal reported women with 89 side-effects: and reaction drug Adverse including IVH, neonatal sepsis, NEC, RDS, persistent persistent RDS, NEC, sepsis, neonatal IVH, including morbidity infant serious or mortality perinatal for groups between differences significant were no Perinatal death or severe neonatal morbidity: outcomes Infant 101 women). 3studies, 95% CI 0.66–3.78; 1.58, (RR reactions drug adverse maternal for COX placebo versus inhibitors receiving women between differences significant no side-effects: and reaction drug Adverse women). 64 2studies, 95% CI 0.44–8.60; 1.94, RR (chorioamnionitis : or infection maternal for groups comparison between observed morbidity: Maternal 67 women). (95% with controls compared CI 1.13–5.92; 2studies, daysCOX inthe group inhibitors by 3.53 increased was respectively). birth at age gestational Mean 70 women, 95% 0.41, CIRR 0.1–1.66, 2studies, 70 women; 2studies, 95% CI 0.03–1.28, 0.20, (RR within 7days or of initiation of treatment hours within 48 delivery for groups treatment between CI 0.07–0.62; differences women). were no 36 There 95% 0.21, (RR 37 weeks before gaveinhibitors birth COX received who size, fewer women sample small with a study one In were inconsistent. prolongation pregnancy on findings with placebo, inhibitors prolongation:Pregnancy Maternal outcomes No significant differences were differences significant No In trials comparing COX trialsIn comparing One study study One There were were There There There pulmonary of the newborn, or chronic Infant outcomes neonatal lung disease; for all of these outcomes, Perinatal death: Infant mortality was low in these trials studies lacked sufficient power to demonstrate and the trials lacked power to identify any possible differences between groups. Admission to NICU differences between groups. There were no significant was comparable in the two groups (RR 0.80, 95% differences between groups receiving magnesium CI 0.56–1.15; 1 study, 39 infants), as was low infant sulfate or no active treatment in terms of fetal deaths Apgar score (< 7) at 5 minutes (RR 0.53, 95% CI (RR 5.70, 95% CI 0.28–116.87; 2 studies, 257 infants), 0.05–5.34; 1 study, 39 infants). neonatal deaths (RR 1.37, 95% CI 0.48–3.97; 3 studies, In two studies with a total sample size of 67, mean 290 infants) or in terms of a composite outcome, infant birth weight was 716.34 g greater in the COX including serious neonatal outcomes and death (RR inhibitors group (95% CI 425.52–1007.16). 1.74, 95% CI 0.63–4.77; 3 studies, 292 infants). For all deaths (fetal, neonatal and infant) there was no Magnesium sulfate versus placebo or no treatment significant difference between groups, although (EB Table 2d) there was a trend towards fewer deaths in the group not receiving magnesium sulfate (RR 4.56, 95% CI Four trials compared magnesium sulphate with 1.00–20.86; 2 studies, 257 infants). placebo or no tocolytic treatment (346 women). The loading dose of IV magnesium sulfate was 4–5 g and Severe neonatal morbidity: There was no the maintenance dose was 2–4 g per hour. In two of statistically significant difference between the group the trials, women with ruptured membranes were receiving magnesium sulfate and the group receiving explicitly excluded. no active treatment for any of the measures of serious infant morbidity reported: RDS (RR 1.09, 95% Maternal outcomes CI 0.98–1.22; 3 studies, 289 infants), proven neonatal Pregnancy prolongation: There was limited evidence infection (RR 6.25, 95% CI 0.32–121.14; 1 study, 34 that magnesium sulfate was effective in prolonging infants), severe IVH (Grade 3 or 4) or periventricular pregnancy, as compared with no treatment. There leukomalacia (no events, 1 study, 90 infants), any was no significant evidence that birth within 24 or 48 grade IVH (RR 0.86, 95% CI 0.28 to 2.62; 3 studies, hours of trial entry was reduced in the magnesium 289 infants), NEC (RR 1.19, 95% CI 0.33 to 4.29; 3 sulfate group (RR 1.05, 95% CI 0.64–1.74, 1 study, studies, 289 infants), respiratory arrest (RR 3.16, 156 women; RR 0.57, 95% CI 0.28–1.15; 3 studies, 95% CI 0.13–76.30; 2 study, 156 infants) or use of 190 women, respectively). There was also no mechanical ventilation (RR 1.17, 95% CI 0.61–2.24; significant difference between groups for the mean 2 study, 165 infants). There was also no significant interval between trial entry and birth (MD 0.08 days, difference between groups for admission to NICU 95% CI -4.08 to 4.24; 3 studies, 281 women). One (RR 0.49, 95% CI 0.18–1.32; 2 study, 165 infants). trial with a small sample size (65 women) showed a reduction in preterm birth (before 37 weeks of Oxytocin receptor antagonists versus placebo or no gestation) in the group receiving magnesium sulfate treatment (EB Table 2e) (RR 0.62, 95% CI 0.46–0.83). However, the mean Three studies involving 691 women compared the gestational age at birth was higher (approximately 5 use of the oxytocin receptor antagonist days) in the group receiving no active treatment (MD with placebo. The minimum gestational age at -0.78 weeks, 95% CI -1.40 to -0.17; 3 studies, 281 recruitment was 20 weeks in all three studies and the women). maximum varied between 34 and 36 weeks. All three studies excluded women with ruptured membranes Maternal morbidity: Serious maternal complications and one excluded women with multiple pregnancies. were evaluated in one study and there were no events reported in either comparison group. Three Maternal outcomes studies reported the frequency of caesarean birth and there were no differences observed between the Pregnancy prolongation: There was an observed groups (RR 1.08, 95% CI 0.63–1.85; 280 women). reduction in extremely preterm birth, defined as birth before 28 weeks of gestation (RR 3.11, 95% Adverse drug reaction and side-effects: Four CI 1.02–9.51; 1 study, 501 women), but not preterm trials reported maternal adverse effects leading birth, defined as birth before 37 weeks (RR 1.17, 95% to treatment discontinuation and there were no CI 0.99–1.37; 1 study, 501 women). Compared with significant differences between groups (RR 1.31, 95% placebo there was no observed reduction in birth CI 0.01–221.68; 310 women). Maternal tachycardia within 48 hours using oxytocin receptor antagonists and hypotension were assessed in one study (156 for tocolysis (RR 1.05, 95% CI 0.15–7.43; 2 studies, women) but no events were reported.

152 women). 3. EVIDENCE AND RECOMMENDATIONS

31 32 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES including dizziness, flushing and hypotension, were and hypotension, flushing dizziness, including 1.14–1.94). side-effects, of individual Frequency 1.49, (RR reactions 95% CI adverse experience likely were more to group nitricoxidethe donors in women with controls, Compared reactions. drug adverse women) reported (186 studies side-effects: Adverse and drug reaction respectively). women, 303 2 studies, 0.57, RR 1 study, women; 95% 153 CI 0.16 to 2.01, 0.93, RR 1 study, 95% CI women; 0.61–1.41, 153 to 1.09, 95% CI 0.23 0.50, (RR of gestation weeks 37 completed or 34 28, before of birth frequency CI 0.74–1.90; reduced women) nor 186 2studies, 1.19, (RR hours 95% 48 than more for pregnancy of with prolongation associated not was donors Prolongation of pregnancy: Maternal outcomes data. trial contributed asingle outcomes most For weeks. 36 32 and between was maximum the and weeks 24 33 and trials between was inthe recruitment at age lowestgestational The explicitly excluded. were membranes with ruptured trials women two in and were recruited, with pregnancies singleton women trials, of the two In patches. transdermal trinitrate glycerine used two dinitrate and isosorbide sublingual women). trial used (336 One placebo with nitric oxide donors trials compared Three (EB Table 2f) treatment no or placebo versus Nitric oxide donors to intensiveadmission care). IVF, (RDS, outcomes infant NEC, in adverse Severe morbidity: neonatal infants). 95% CI583 1.39–27.22; 6.15, (RR age) study inone (up deaths ininfant increase with an to of 12 months However, atosiban of associated was the use the 4.10, 95% CI 0.88–19.13; 1 study, infants). 583 (RR death neonatal for groups treatment between Perinatal or infant death: outcomes Infant 613 women). 95% CI 1.02–2.32; 2studies, 1.54, (RR treated arm in the reactions drug maternal in increase significant 2.05–7.85; 613 a women). also was 2studies, There 95% CI 4.02, (RR antagonists receptor oxytocin using women in those increased significantly were of treatment cessation requiring effects adverse drug reaction: Maternal inany studies. of the reported deaths maternal or death: morbidity Maternal There was no difference difference no was There There was no difference difference no was There Use of nitricoxideUse There were no were no There Maternal side- Two Two

oxide and control groups (RR 0.43, 95% CI 0.06– 0.43, (RR groups control oxide and nitricthe in different significantly not also was death rate neonatal The of groups. between difference eventsignificant asingle with no reported and lities abnorma to unrelated congenital stillbirths reported infants 153 for with data study One mortality. or morbidity infant relating to serious any outcomes for groups between differences significant were no Perinatal death or severe neonatal morbidity: outcomes Infant 1.20). 95% 0.90– CI 1.04, (RR groups between difference significant no was there –again, corticosteroids of antenatal course afull completed had women CI 0.14–1.57; 1study, whether women) –and 33 0.47, (RR nitricoxide donors receiving women 95% in different significantly not was –which section rate of caesarean included reported outcomes Severe morbidity: maternal women). 1.95,95% 1study, (RR CI group 1.31–2.90; 153 donors nitricoxide inthe inwomen of headache incidence ahigher was there although groups, two similar inthe differences between groups for birth within 48 hours hours 48 within birth for groups between differences infants). 293 were no There 4studies, 0.39–0.98; 95% CI 0.62, (RR of gestation 37 weeks before babies delivered agents progestational received had Prolongation of pregnancy: Maternal outcomes used. agents tocolytic additional and administration, of method dosage, used, of form inthe varied studies included The agent. tocolytic addition to a in offered was agent progestational tocolysis a inall is, trials; that adjuvant received Women of interest. outcomes critical the report not did of these four although studies, eight included review systematic that aCochrane from extracted was this for question Evidence birth. and labour preterm on agents progestational of effects the considered women involving 300 studies Four (EB Table 2g) Progestational agents versus placebo or no treatment 95% CI -272.13 to 926.13; 1study, infants). 33 (MD weight 327.00 g, birth infant of mean in terms groups between difference significant no was There 0.15, 95%(RR CI 0.02–1.21; 1study, infants). 153 1study, disease lung infants) chronic 153 or 23.06; 1 study, infants), 33 2.14, (RR IVH 95% CI 0.20– 0.47, (RR RDS for groups between 95% CI 0.14–1.57; difference significant no was there morbidity, infants). neonatal 186 serious For 2studies, 2.89; Fewer mothers who who Fewer mothers Other relevant relevant Other There There ­ of intervention (RR 0.76, 95% CI 0.38–1.50; 1 study, Intravenous or oral hydration versus alone or no 110 women). There was no significant difference treatment (EB Table 2i) in the number of babies born before 34 weeks (RR A Cochrane systematic review examined the 0.62, 95% CI 0.30–1.27; 1 study, 62 infants) or 35 evidence for the use of IV or oral hydration therapy weeks (RR 0.43, 95% CI 0.12–1.5; 1 study, 60 infants). as a treatment for preterm labour (45). Included trials recruited women less than 37 weeks pregnant with Infant outcomes intact membranes, preterm contractions and cervical Perinatal death or severe neonatal morbidity: There changes to receive oral or IV hydration therapy were no significant differences in perinatal mortality versus bed rest alone. The review included two (RR 0.31, 95% CI 0.01–7.41; 1 study, 83 infants), RDS studies involving 228 women. Approximately 30% (RR 0.93, 95% CI 0.06–14.38; 1 study, 83 infants), of women from both the intervention and control low birth weight (< 2500 g) (RR 1.01, 95% CI 0.61– groups in these trials were treated with tocolytic 1.65; 1 study, 105 infants) or admission to NICU (RR drugs. There were no significant differences between 1.08, 95% CI 0.59–1.97; 2 studies, 187 infants). groups for any relevant outcome reported. No differences were observed between groups Maternal outcomes for IVH (RR 3.12, 95% CI 0.13–74.76; 1 study, 104 infants), NEC (RR 1.04, 95% CI 0.07–16.18; 1 study, Pregnancy prolongation: There were no differences 104 infants), mechanical ventilation (RR 1.18, 95% between groups for rates of preterm birth before 32, CI 0.41–3.37; 2 studies, 187 infants) or oxygen 34 or 37 weeks of gestation (RR 0.76, 95% CI 0.29– requirement on day 7 and day 28 of life (RR 0.69, 1.97, 1 study, 110 women; RR 0.72, 95% CI 0.20–2.56, 95% CI 0.21–2.31, 1 study, 104 infants; and RR 0.42, 1 study, 118 women; RR 1.09, 95% CI 0.71–1.68, 2 95% CI 0.08–2.05, 1 study, 104 infants, respectively). studies, 228 women, respectively). Hydration had no significant effect on time to delivery in days (MD Infants whose mothers had received progestational -0.99 days, 95% CI -7.85 to 5.87; 2 studies, 228 agents had a significantly higher average birth weight women). than those whose mothers had not (MD 324.7 g, 95% CI 155.05–494.34; 2 studies, 143 infants). Infant outcomes Severe neonatal morbidity: For infants, the rates versus placebo or no treatment of NICU admission were comparable between the (EB Table 2h) intervention and control groups (RR 0.99, 95% Three studies (149 women) considered the effects CI 0.46–2.16; 1 study, 118 infants). Other critical of relaxin. All three were quasi-randomized trials and outcomes were not reported. thus were at high risk of bias, had small sample sizes and low event rates. All studies recruited women Tocolytic maintenance therapy for preterm labour in preterm labour but excluded women with any after first-line tocolysis (EB Tables 2j to 2m) complications that necessitated immediate delivery. Available evidence related to the use of tocolytic drugs as maintenance therapy to improve pregnancy Maternal outcomes outcomes after initial treatment of preterm labour Prolongation of pregnancy: One trial reported a consisted of five systematic reviews of 27 RCTs, significant reduction in the number of women who each evaluating a particular class of tocolytic went on to give birth within 7 days of treatment in the agent: oral betamimetics (13 RCTs, 1551 women) relaxin group (RR 0.50, 95% CI 0.29–0.87; 1 study, (46), terbutaline pump (3 RCTs, 166 women) (47), 30 women). There were no differences between magnesium as magnesium sulfate, chloride or oxide groups in any of the other relevant outcomes (4 RCTS, 422 women) (48), calcium channel blockers reported, including preterm birth (0.92 95% CI 0.81– (6 RCTs, 794 women) (49) and oxytocin antagonists 1.05; 1 study, 69 women). (1 RCT, 513 women) (50). The interventions in these studies used different doses, regimens and drug, Infant outcomes within each class of tocolytic agent. Most compared Perinatal death or severe neonatal morbidity: There maintenance therapy with no treatment or placebo, were no differences between groups for perinatal while others conducted within-class and between- mortality (RR 0.83, 0.32–2.15; 1 study, 30 infants), class comparisons of tocolytic agents. All studies neonatal death (RR 0.80, 0.27–2.41; 1 study, 30 were hospital based. Twenty-six were conducted in infants), fetal death (RR 1.00, 95% CI 0.07–14.55; 1 high-income countries (Croatia, Japan, Netherlands, study, 30 infants) or low birth weight (< 2500 g) (RR New Zealand, Turkey, the United Kingdom and the 2.0, 0.43 to 9.32; 1 study, 30 infants). USA) and one in a low-income country (Malaysia). 3. EVIDENCE AND RECOMMENDATIONS

33 34 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES stopped treatment due to severe side-effects. For For to severe due side-effects. treatment stopped of 141 out 1woman trials only intwo although CI respectively), 1.32–24.40, 1study, women, 140 5.67, RR CI 1.13–3.19, and women; 166 95% 2studies, 95% 1.89, RR women; 260 2studies, CI 1.20–10.33, 95% 3.52, CI 414 1.52–2.98, RR women; 4studies, 2.13, 95% (RR betamimetics oral receiving women palpitations)and likely were more toin occur hypotension tachypnea, (tachycardia, effects side-effects: and reaction drug Adverse with nifedipine. or treatment active with no compared when therapy maintenance betamimetic oral of commencing hours within 24 48 birth or of frequency on effects significant were no There prolongation. pregnancy of measure any other affect to CI appear 0.49–10.21),not did this therapy but average days(95% on by 5.35 recruitment after of pregnancy with aprolongation associated was therapy women). maintenance of nifedipine Use 681 5studies, 95% CIto -0.61 1.25, 0.32, MD nifedipine: women; 183 2studies, to 95% 0.25, CI -1.34 -0.55, MD (magnesium: treatment no or with placebo compared therapy maintenance tocolytic receiving (weeks) birth at age gestational women for mean in difference significant no was There of gestation. 32 weeks or 28 weeks before of rates birth in the reduction to led a significant therapies maintenance of the none treatment, no or with placebo Compared     treatment. no or with placebo compared when therapy maintenance blocker)channel atosiban (oxytocin or as antagonist) (calcium nifedipine magnesium, betamimetics, oral receiving women for of gestation 37 weeks before birth preterm rates of in the differences prolongation:Pregnancy evaluated. therapies any maintenance of for the groups between differences significant were no there reported when and rare, was morbidity maternal Serious observed. deaths were no there deaths, maternal report did that inthose and reported not were generally deaths Severe or death: morbidity maternal Maternal outcomes treatment Tocolytic no or placebo therapy maintenance versus     women): RR 0.89,women): 95% RR CI 0.71–1.12. (atosiban; antagonists 1study, oxytocin 510 0.97, women): RR 681 95% CI 0.87–1.09 (nifedipine; 5studies, blockers channel calcium 0.80–1.40 CI 95% 1.05, women): RR 99 (2 studies, magnesium 95% 1.11, women): CI RR 0.91–1.35 644 6studies, (ritodrine terbutaline; and betamimetics There were no significant significant were no There Maternal Side- periventricular haemorrhage, admission to NICU or to or NICU admission haemorrhage, periventricular sepsis, neonatal NEC, of rates RDS, (including therapy of maintenance any type receiving infants for insevere morbidity reduction observed no was There     treatment. no or placebo and therapy tocolytic maintenance receiving groups between mortality perinatal in difference significant statistically no was Perinatal death or severe neonatal morbidity: outcomes Infant treatment. active receiving ingroups labour of preterm episode arepeat for readmission maternal morbidity: Maternal were identified groups other side-effects, no significant differencesbetween 3.1.3 treatment. no or placebo received had mothers whose with infants compared antagonists) oxytocin or blockers channel calcium sulphate, magnesium (betamimetics, therapy maintenance received had mothers whose infants for different weresignificantly weight not birth mean (< 2500 g) weight of low and birth frequency The stay). of NICU length mean     cerebral palsy in the infant and child. child. and infant the in palsy cerebral of prevention for gestation of weeks 32 before birth preterm imminent of risk at women for recommended is sulfate magnesium of use The RECOMMENDATION 3.0 n n REMARKS evidence) recommendation based on moderate-quality infants): 0.77, RR 95% CI 0.21–2.83. (atosiban; antagonist oxytocin 1study, 512 95% CI 0.45–4.86 infants): 1.48, RR 466 (nifedipine; 2studies, blockers channel calcium 95% CI 0.25–99.16 study, (1 infants): therapy 5.00, 50 RR magnesium infants):95% 2.41, CI 0.86–6.74 RR 681 6studies, (ritodrine terbutaline; and betamimetics the next 24 hours. The median time from time median The 24 hours. next the is likely within birth if given preterm be only should sulfate neuroprotection for Magnesium weeks. 34 below ages gestational at sulfate magnesium of effects neuroprotective the trial on is aware ongoing of an GDG The ages. gestational earlier at to increased be (neuroprotection) arelikelycomplications neurological sulfateon magnesium of effects protective the that suggests Evidence neurological complications neurological Magnesium sulfate for fetal protection from from protection fetal for sulfate Magnesium There was no difference in difference no was There (Strong (Strong There There these trials ranged from below 30 weeks up to 37 magnesium sulfate administration to birth weeks. Corticosteroids were given to more than 50% was reported in only two of the trials that of women in three of the trials. generated the evidence (1 hour 38 minutes and 3.7 hours). However, the GDG felt that Magnesium sulfate versus no active treatment administering magnesium sulfate at any time (all women and babies) (EB Table 3a) from immediately prior to birth, up to 24 hours prior to anticipated birth is appropriate. Maternal outcomes Maternal morbidity or death: There were no n Three dosing regimens (IV 4 g over 20 minutes, then 1 g/hour until delivery or for significant differences between women receiving 24 hours, whichever came first; IV 4 g over magnesium sulfate versus placebo or no active 30 minutes or IV bolus of 4 g given as single treatment in terms of maternal mortality or serious dose; and IV 6 g over 20–30 minutes, followed maternal morbidity in four studies with a total of by IV maintenance of 2 g/hour) have been more than 5000 women. Risks of maternal death, tested in the available studies, which – on , respiratory depression or arrest, and meta-analysis – show effect on cerebral admission to intensive care were not significantly palsy, and death or cerebral palsy. There different between groups. The cases of maternal was insufficient evidence to recommend one deaths and serious morbidity that were recorded specific dosing regimen over others. The were largely confined to the study that recruited GDG is aware that an individual patient data women with severe pre-eclampsia rather than those analysis of these studies is underway, which studies that randomized women with preterm labour. may affect this guidance in the future. There were no significant differences between the groups for rates of postpartum haemorrhage, n This recommendation applies to women caesarean or length of maternal hospital stay. carrying either singleton or multiple pregnancies. Maternal adverse effects: Cessation of therapy as a result of maternal adverse effects was increased n In women at imminent risk of preterm birth, magnesium sulfate should be considered as in the magnesium sulfate group compared with the the preferred option whenever there is a valid placebo group (RR 3.26, 95% CI 2.46–4.31; 3 studies, obstetric indication (e.g. pre-eclampsia) and 4847 women). Maternal hypotension (RR 1.51, 95% where it is considered safe and effective. CI 1.09–2.09; 2 studies, 1626 women) and maternal tachycardia (RR 1.53, 95% CI 1.03–2.29; 1 study, 1062 n There is a need for further research to women) were also more frequent in women who had establish whether repeated treatment with received magnesium sulfate. magnesium sulfate for neuroprotection is appropriate (i.e. in the event that delivery Infant outcomes does not occur). Fetal and infant death: For overall infant mortality (including fetal mortality), there was no significant Summary of evidence difference between women who had received Magnesium sulfate versus placebo or no treatment magnesium sulfate and controls (RR 1.02, 95% CI for fetal neuroprotection 0.90–1.15; 5 studies, 6039 infants). Rates for other Evidence on the use of magnesium sulfate for measures of fetal and infant mortality were also neuroprotection in preterm infants was extracted comparable in both groups (i.e. fetal death, infant from a Cochrane systematic review (five studies death during hospitalization, infant death), to the including 6145 infants) investigating whether the latest age of follow up. administration of magnesium sulfate to women at Severe neonatal morbidity and long-term risk of preterm labour conferred neuroprotective morbidity: There were also no significant differences advantage to the fetus (51). One trial was conducted between groups for a range of composite outcomes in Australia and New Zealand, one in France, two (i.e. death or cerebral palsy, death or neurological in the USA, and the fifth was a multicentre study impairment, death or serious motor dysfunction, conducted in countries across the world. The final and death or major neurological disability). There “Magpie” study was designed to prevent eclampsia were no significant differences between women who by magnesium sulfate administration, but data received magnesium sulfate and those in the control relevant to the effect on preterm infants were group with regard to infant IVH, periventricular included in the analysis. All studies were placebo leukomalacia, major or any neurological impairment, controlled. The gestational age at recruitment to blindness or deafness, or developmental delay or 3. EVIDENCE AND RECOMMENDATIONS

35 36 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES at < 30 weeks (RR 0.86, 0.56–1.31; 2 studies, 1537 1537 2studies, 0.56–1.31; 0.86, (RR weeks < 30 at randomized inwomen not women) 5192 but studies, 4 0.69, (RR of gestation 0.54–0.88; weeks < 34 at treatment no or placebo sulfate versus magnesium to randomized inwomen reduced was palsy cerebral However,analysis. main the in findings the reflected largely findings analysis subgroup the Overall, size power. statistical and sample to increased due this partly was of gestation, weeks to up 34 women trials recruiting inthe outcomes for demonstrated be more likely was to significance statistical Although clear. not was weeks to < 34 opposed as gestation of weeks sulfate < 30 at of magnesium use the on evidence randomization). at The weeks < 34 versus (< 30 administration at age gestational weeks to according performed was analysis Subgroup administration) at (gestational age (EB Table 3c) sulfateMagnesium placebo treatment no or versus pregnancies. multiple and singleton for were comparable impairment neurological major on and impairment) serious or death (i.e. outcomes composite on rates, overall sulfate on death of magnesium effects The benefit. favoured estimate point the 527 babies), 2studies, although 95% CI 0.21–1.25; 0.52, (RR pregnancies inmultiple observed not was pregnancies insingleton palsy of cerebral risk sulfateon magnesium of positive effects The reported. outcomes critical of the most for pregnancies multiple and singleton women). There were no clear differencesbetween 527 (2 werestudies, smaller pregnancies singleton for with those compared pregnancies multiple for size event rate and sample the allFor comparisons, (single multiple pregnancy) versus (EB Table 3b) sulfateMagnesium placebo treatment no or versus infants). 6039 5studies, CI 0.55–0.89; 0.70, (RR sulfate group 30%) 95% magnesium inthe (by reduced significantly also was palsy cerebral 5980 infants). riskof 4studies, The CI 0.44–0.85; to 0.61, 95% (RR controls compared dysfunction risk(39%) motor gross ofreduced substantial sulfate were at to magnesium exposed Infants 3 months. at and 28 at days oxygen requiring disease lung of chronic stay, hospital incidence inthe of infant nor in length difference infants). clear 4387 no was There studies, 3 0.94, (RR 95% outcome CI 0.89–1.00; latter the for sulfate group magnesium riskinthe towards reduced atrend was there although support, respiratory ongoing for requirement or neonatal convulsions, neonatal for groups between differences significant were no There impairment. intellectual in the group receiving magnesium sulfate (RR 0.84, sulfate 0.84, (RR magnesium receiving group in the towards atrend was –there reduction dysfunction motor gross or –death outcome composite another infants). 4837 For 3studies, 95% CI 0.44–0.92; 0.64, (RR consistent remained treated group in the inriskof palsy moderate/severe cerebral reduction infants). Similarly,0.74–0.98; the 4446 4studies, 95% CI 0.85, (RR treated group inthe reduced significantly was palsy cerebral or of death outcome composite The death. infant or death fetal mortality, paediatric for overall groups between differences significant were no there neuroprotection, for explicitly was treatment of intention the the where studies to confined When outcomes. critical most for consistent meta-analysis remained of the findings the analysis, the from excluded was severe pre-eclampsia) with inwomen preventing at eclampsia aimed was (where study sulfate Magpie the magnesium When complications)neurologic (EB Table 3d) (with the intention to prevent birth-related preterm sulfateMagnesium placebo treatment no or versus sulfate inthis population. magnesium of use with the palsy incerebral a reduction favoured estimate women), point the although responsible for the overall point estimate related estimate overall the point for responsible was study This 0.59, (RR palsy 95% CI 0.40–0.85). of cerebral incidence in the reduction significant astatistically showed doses maintenance and loading high of therapy, used trial that only a course the completing after allowednot was or retreatment to according analysis whether subgroup the In maintenance. higher-dose (2 g/hour) and dose 6 gloading and any maintenance; plus dose loading 4–6 g subgroups: following the for significance statistical reached only palsy However, incerebral reduction reported. the outcomes critical of the most for regimens various the between differences clear were no There route of administration. intravenous the intentused All trials with neuroprotective imminent. was birth whenever permitted with retreatment 12 for hours, of 2g/hour infusion by maintenance (v) and 4 g; followed IV6gover minutes, 20–30 (iv)of minutes; IV4gover 30 of IVbolus single (iii) 24 for dose single hours; 4hours 5gevery IM by or 24 for hours, IV1g/hour followed by either (ii) IV4g 10–15over minutes, first; came whichever 24 for or hours, until delivery 1g/hour then minutes, trials: (i) inthese IV4goversulfate 20 varied of magnesium dose and route of administration The (EB Table 3e) sulfate fetal for of magnesium neuroprotection Regimens infants). 4387 3studies, 95% CI 0.71–1.00; to cerebral palsy in the review. For the composite Most of the results of meta-analysis were dominated outcome of death or cerebral palsy, the results were by the findings of this latter placebo-controlled trial consistent across the two subgroups: retreatment with data for more than 6000 women (the ORACLE allowed (RR 0.90, 95% CI 0.73–1.10) and retreatment II trial) (53). not allowed (RR 0.91, 95% CI 0.74–1.13). All studies recruited women with uterine Maternal adverse effects related to magnesium contractions and cervical dilatation, with intact sulfate appear to be dose dependent. However, membranes and no clinical signs of infection. The the available evidence also points to better mean gestational age at recruitment was between 30 neuroprotection with higher dosing. Importantly, and 32 weeks. Women received only oral antibiotics there is evidence to suggest that a maintenance in three trials, only IV antibiotics in another three dose is essential in order to observe an effect. It trials, and IV followed by oral antibiotics in eight is unclear whether the effects on cerebral palsy of trials. Antibiotics examined included ampicillin (with higher loading and higher maintenance dosing with or without sulbactam or clavulanic acid), amoxicillin a repeat treatment are due to the dosage regimen or (with or without sulbactam or clavulanic acid), a reflection of the size of the trial. However, as this erythromycin, , mezlocillin, ceftizoxime protective effect was not demonstrated in terms of or , mostly as combinations. The incidence of death or cerebral palsy, the relationship duration of treatment varied from 3 to 10 days. In to dose is unlikely to be strong. 13 of the 14 trials, antibiotics were administered alongside tocolytic therapy to women in both 3.1.4 Antibiotics for women in preterm labour intervention and control groups, according to local (with and without prelabour rupture of protocol at the study sites. Women participating in membranes) most of the trials conducted in the mid-1990s also RECOMMENDATION 4.0 received corticosteroids. Routine antibiotic administration is not Any prophylactic antibiotic versus placebo or recommended for women in preterm labour no antibiotics (EB Table 4a) with intact amniotic membranes and no clinical Maternal outcomes signs of infection. (Strong recommendation based moderate-quality evidence) Pregnancy prolongation: Overall, there was no clear evidence that prophylactic antibiotics prolong REMARKS pregnancy. No statistically significant differences n It is important that women with any diagnostic were observed in birth prior to 36 or 37 weeks (RR or clinical signs of infection are treated 0.98, 95% CI 0.92–1.05; 10 studies, 7387 women), accordingly with antibiotics. birth within 48 hours of randomization (RR 1.04,

n Management of group B streptococcal 95% CI 0.89–1.23; 4 studies, 6800 women), birth colonization is not within the scope of this within 7 days of randomization (RR 0.98, 95% recommendation. CI 0.87–1.10; 8 studies, 7053 women) or gestational age at birth (MD 0.53 weeks, 95% CI 0.00–1.06; n The GDG placed its emphasis on the potential 10 studies, 986 women). However, the interval risk of harm to the baby and placed less between randomization and birth was on average value on the minimal benefit to mothers, 5 days longer among women receiving prophylactic and therefore recommended against the antibiotics (MD 5.59 days, 95% CI 0.31–10.87; 6 intervention. studies, 2499 women). Maternal morbidity: There was a significant Summary of evidence reduction in the frequency of maternal infection in the group receiving antibiotics (RR 0.74, 95% Prophylactic antibiotics for women in preterm CI 0.63–0.86; 10 studies, 7371 women). labour with intact amniotic membranes Evidence on the use of antibiotics for women in Adverse effects: There was no significant difference preterm labour with intact amniotic membranes was between groups for maternal adverse drug reaction extracted from a Cochrane systematic review of 14 requiring cessation of treatment (RR 1.32, 95% RCTs involving more than 7800 women (52). Studies CI 0.92–1.89; 5 studies, 626 women). were mainly conducted in high-resource settings: six trials in the USA, and one trial each in Canada, Infant outcomes Chile, Denmark, Germany, Iran, South Africa and Perinatal death: There were no significant Uruguay, as well as a large multicentre trial with data differences between groups for perinatal death (RR predominantly from women in the United Kingdom. 1.22, 95% CI 0.88–1.69; 10 studies, 7304 infants), 3. EVIDENCE AND RECOMMENDATIONS

37 38 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES     antibiotics: of types different comparing subgroups review examined also The (EB Table 4b) antibioticsno antibiotics of versus Specific classes labour. preterm for antibiotics received had mothers whose children children) those for 3173 CI 0.99–3.34; 95% 1.82, (RR palsy cerebral children) and 3052 1.10, 95% 7(RR age at CI 0.99–1.23; impairment) mild (including impairment inany functional increase an towards children). atrend was 3052 There 0.89–1.28; 1.07, (RR impairment severeor functional 95% CI to moderate with respect placebo received had ­ anti received had mothers whose children between difference significant no was there At 7years, age 7years. for infants and followed women up Kingdom morbidity: Long-term infants). 7531 12-26.24 studies, to 143.00; 95% CI (MD weight 58.38 g, birth infant in mean groups between difference significant no also was 0.97,(RR infants). 6628 There 0.81–1.15; 5studies, (< 2500 g) weight of low birth incidence inthe reduction with asignificant wereassociated not Antibiotics CI 0.62–1.10; infants). 6875 5studies, 95% 0.82, (RR groups two inthe comparable 1 study, 6241 infants). to were Admissions NICU 95% 95%ventilation CI 1.02, (RR CI 1.02, 0.84–1.24; CI 0.78–1.76; 1study, 6241 children) mechanical or discharge) 1.17, (RR hospital before ultrasound 95% (on disease infants), lung 6813 neonatal chronic infants), 0.76 (RR IVH 95% CI 0.48–1.19; 5studies, 7386 95% studies, CI 10 0.64–1.16; 0.86, (RR sepsis infants), 6880 neonatal 6studies, CI 0.64–1.73; infants), 95% 7200 1.06, NEC(RR 1.16; 9studies, with to regard 0.99, (RR RDS groups 95% CI 0.84– differences were observedbetween comparison significant No morbidity. infant serious reduced significantly antibiotics prophylactic that evidence Severe morbidity: neonatal infants). 7248 studies, 1.57, (RR antibiotics receiving 95% 9 CI 1.03–2.40; however, of women death, ininfants increased was 95% CI 0.68–1.67; infants). 1study, Neonatal 4654 28 days 1.06, (RR after 7080 death infants) infant or 8studies, 95% CI 0.43–1.26; 0.73. (RR stillbirth     clindamycin) antibiotics. no versus (e.g. anaerobic against active antibiotics antibiotics no versus antibiotics betalactam and macrolide combined antibiotics no versus alone (e.g. antibiotics erythromycin) macrolide co-amoxiclav) antibiotics no versus alone (e.g. antibiotics amoxicillin, ampicillin, betalactam biotics compared with those whose mothers mothers whose with those compared biotics One study in the United United inthe study One Overall, there was no no was there Overall,

Long-term morbidity: Long-term NECor IVH. RDS, for differences of subgroup Severe morbidity: neonatal were imprecise. estimates effect many and subgroups were few insome events there although differences, subgroup significant statistically were no there death, infant and neonatal Perinatal or infant death: antibiotic. of class of any particular use with the increased were significantly reactions drug adverse maternal Adverse effects: 95% women). days, CI 293 4.95–16.06; (MD 10.50 bacteria anaerobic against active antibiotics receiving inwomen increased was birth and randomization between interval mean the that trials indicated small three birth, and randomization between interval on the impact significant no had antibiotics betalactam and macrolide While antibiotics. with no (< 37 compared hours weeks), by 48 birth delayed or births of preterm number the reduced antibiotics of class any specific that evidence significant prolongation:Pregnancy 1052 children). 1052 co-amoxiclav) 95% CI 1.02–7.88; 2.83, (RR 1study, (erythromycin plus combined antibiotics betalactam and with macrolide inassociation 7years at observed palsy riskof cerebral increased an was there placebo, with Compared of age. were 7years children when impairment any functional or impairment, functional severeor moderate on impact adifferential had antibiotics different that evidence no was there study; factorial inasingle were measured outcomes n n REMARKS moderate-quality evidence) of membranes. for women with preterm prelabour rupture Antibiotic administration is recommended RECOMMENDATION 5.0 clinical chorioamnionitis. of signs for monitored be Women should PPROM. diagnosing reliably for by aprotocol accompanied be PPROM should with women for antibiotics of prescribing apolicy Therefore, made. (PPROM) been has of membranes rupture prelabour preterm of diagnosis adefinite unless prescribed be not should antibiotics membranes, amniotic with intact to women administration antibiotics to avoid order In inadvertent There was no evidence that that evidence no was There (Strong recommendation based Long-term morbidity Long-term morbidity There was no statistically statistically no was There For stillbirth, perinatal, perinatal, stillbirth, For There was no evidence evidence no was There Summary of evidence Maternal adverse effects: No women were reported to have suffered a major adverse drug reaction (3 Prophylactic antibiotics for women with preterm studies, 5487 women). prelabour rupture of membranes Evidence on the use of antibiotics for women with Infant outcomes PPROM was extracted from a Cochrane review that included 22 RCTs and a total of more than 7000 Perinatal death: There was no significant difference women (54). between groups in terms of perinatal death (RR 0.89, 95% CI 0.74–1.08; 18 studies, 6872 infants). In a Data were mainly for women cared for in high- sensitivity analysis including only placebo-controlled resource settings: 14 trials in the USA, and one trial trials, the difference between groups remained non- each in Denmark, Finland, Germany, Spain, Turkey, significant (RR 0.93, 95% CI 0.76–1.14; 12 studies, Zimbabwe, as well as two multicentre trials, one 6301 infants). mostly recruiting women from Chile and the other one from the United Kingdom. Most of the results Severe neonatal morbidity: Infants whose mothers were dominated by the findings of the United received antibiotics had a reduced risk of infection, Kingdom trial with data for more than 4800 women including (RR 0.67, 95% CI 0.52–0.85; (the ORACLE I trial) (55). 12 studies, 1680 infants), and a reduced risk of having a positive (RR 0.79, 95% CI Most women recruited into the trials were not in 0.63–0.99; 3 studies, 4961 infants). Infants whose active labour. Trials recruited women between 20 mothers received antibiotics were also at reduced and 37 weeks of gestation. For the 16 placebo- risk of major cerebral abnormality (RR 0.81, 95% controlled trials, women received oral antibiotics CI 0.68–0.98; 12 studies, 6289 infants). In one study, in three trials, IV antibiotics in four trials, and antibiotics slightly reduced the risk of the infant IV therapy followed by oral antibiotics in the requiring treatment with a surfactant (RR 0.83, 95% remaining trials. Ten of these trials examined broad- CI 0.72–0.96; 1 study, 4809 infants). There were no spectrum antibiotics and five compared macrolide significant differences between groups receiving or antibiotics (erythromycin) with placebo. In some not receiving antibiotics with regard to RDS (RR 0.95, trials combinations of different drugs were used. 95% CI 0.83–1.09; 12 studies, 6287 infants), NEC The duration of the course of antibiotics varied (RR 1.09, 95% CI 0.65–1.83; 11 studies, 6229 infants) considerably across trials, from two doses through to or need for mechanical ventilation (RR 0.90, 95% continued antibiotic therapy until delivery. CI 0.80–1.02; 2 studies, 4924 infants). There were no instances of neonatal in one trial Any prophylactic antibiotic versus placebo or no with a small sample size reporting this outcome. antibiotics (EB Tables 5a) Admissions to the NICU were similar in the two Maternal outcomes groups (RR 0.98, 95% CI 0.84–1.13; 4 studies, 5023 Pregnancy prolongation: Compared with placebo, infants). Data on length of NICU stay were reported there was no statistically significant evidence that in three trials with small sample sizes; infants in antibiotics reduced the likelihood of preterm birth the group whose mothers received antibiotics, on (< 37 weeks) (RR 1.00, 95% CI 0.98–1.03; 3 studies, average, had five fewer days in special care (MD 4931 women). Antibiotics were associated with -5.05 days, 95% CI -9.77 to -0.33; 225 infants). a reduction in the chances of women giving birth Antibiotics were not associated with a reduction within 48 hours (RR 0.71, 95% CI 0.58–0.87; 7 in the incidence of low birth weight (< 2500 g) (RR studies, 5927 women) and within 7 days (RR 0.79, 1.00, 0.96–1.04; 2 studies, 4876 infants). Mean birth 95% CI 0.71–0.89; 7 studies, 5965 women). weight was slightly increased in those infants whose Maternal death: There were no maternal deaths in mothers had received antibiotics (MD 53.83 g, 95% any of the three trials that reported this outcome CI 7.06–100.60; 12 studies, 6374 infants). (763 women). Long-term morbidity: One study followed up women Maternal infectious morbidity: Fewer women and infants for seven years. At age 7, there were no in the group receiving antibiotics developed significant differences in serious disability between chorioamnionitis (RR 0.66, 95% CI 0.46–0.96; children whose mothers had received antibiotics in 11 studies, 1559 women). Four studies with data pregnancy versus placebo (RR 1.01, 95% CI 0.91–1.12; for 5547 women reported on maternal infection 3171 children). following delivery (before hospital discharge); there was no significant difference between groups for this outcome (RR 0.91, 95% CI 0.8–1.02). 3. EVIDENCE AND RECOMMENDATIONS

39 40 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES n n n REMARKS recommendation based moderate-quality evidence) prelabour rupture of membranes. preterm with women for recommended not is (“co-amoxiclav”) acid clavulanic and amoxicillin of acombination of use The RECOMMENDATION 5.2 n n n REMARKS evidence) quality (Conditional recommendation based on moderate- preterm prelabour rupture of membranes with women in prophylaxis for choice of antibiotic the as recommended is Erythromycin RECOMMENDATION 5.1 Penicillins (excluding amoxiclav) were used pregnancy. co-amoxiclavusing during to avoid sensible seem would it antibiotics, aresensitive to other organisms Where erythromycin. with and with placebo compared when riskof NECwith co-amoxiclav increased the on based was recommendation This sensitivities. coverage and microbiological adequate on takenbased be should decisions management Bstreptococcus, with group However, colonization line. considering when of this guide scope the is outside colonization Bstreptococcal of group management The Itrial. ORACLE inthe used by regimen the informed was of this regimen choice The used. a day(or 10 days for until delivery) be should times four 250 mg erythromycin oral PPROM, with antibioticFor inwomen prophylaxis organisms. of prevalent sensitivities and drug of availability the local on dependent may be antibiotic choice because conditional made was to co-amoxiclav. recommendation The compared (NEC)enterocolitis newborn inthe riskof necrotizing the lessens erythromycin that showed which women, with over 2000 I trial) ORACLE study of a (the findings the on However, based was of erythromycin choice the (PPROM). of membranes rupture prelabour with preterm inwomen prophylaxis for used antibiotics of regimens and classes different demonstrate comparative effectiveness of to analysis subgroup the from evidence of paucity the acknowledged GDG The as amoxicillin)as used. be can (such penicillin available, is not erythromycin where Therefore, inthisantibiotics context. of benefits trialsshowed that pooled in the (Strong (Strong ­ NEC was increased for those infants whose mothers mothers whose infants those for increased NEC was riskof with placebo, compared of antibiotics types most for groups between differences significant Severe morbidity: neonatal examined). any subgroups of for the groups between differences significant were no there (i.e. with placebo compared death perinatal on impact an had of antibiotic used type the that evidence Perinatal death:       antibiotics: of types different comparing review Cochrane The Tables (EB 5d) to PPROM 5b with women for antibiotics prophylactic of Regimens of evidenceSummary study, women). 2395 1 95% CI 0.23–0.94; riskof0.46, NEC(RR reduced significantly at were co-amoxiclav than rather erythromycin received had mothers whose Infants co-amoxiclav and groups. erythromycin the between comparable was of gestation 37 weeks before CI 1.02–1.28; 1study,women). 2395 However, birth antibiotic 1.14,95% the (RR of receiving hours 48 within riskof birth were slightly at increased group 7years).at However, erythromycin inthe women disability childhood serious and admission NICU discharge, before ultrasound on abnormality cerebral major with surfactant, treatment RDS, death, perinatal (i.e. outcomes morbidity neonatal serious most the or for mortality perinatal for differences significant were no there infants, and women 2000 than more for with data study amoxiclav inone with co- compared was erythromycin When subgroups. for other not significant were differences the but ultrasound, on abnormality cerebral of major amoxiclav) occurrence with reduced were associated Similarly, (excluding all penicillins subgroups. co- for other not significant infants), were differences but 521 5studies, 95% CI 0.13–0.68; 0.30, (RR placebo (excludingpenicillins co-amoxiclav) with compared broad-spectrum received mothers whose infants inthe to reduced be appeared pneumonia, including infections, infants). neonatal riskof other 1880 The amoxiclav) 2studies, 95% CI 1.57–14.23; 4.72, (RR co- (including antibiotics beta-lactam received had       3-day versus 7-day versus of3-day ampicillin. regimens co-amoxiclav versus erythromycin placebo versus antibiotics other versus placebo erythromycin) (including antibiotics macrolide versus placebo co-amoxiclav) (including antibiotics beta-lactam placebo (exceptall penicillins co-amoxiclav) versus There was no statistically significant significant statistically no was There (54) also examined subgroups subgroups examined also While there were no were no there While One trial with data for 82 women compared 3- trials were stopped early, due to difficulties with versus 7-day regimens. The study did not have recruitment. sufficient statistical power to identify any significant differences for most outcomes. Maternal outcomes The overall quality of the evidence varied across Severe maternal morbidity: Women with breech the subgroup comparisons. For comparisons of all presentation were more likely to experience major penicillins (except co-amoxiclav) versus placebo, postpartum complications in the immediate CS and for other antibiotics versus placebo, the quality group compared to those in the of evidence was rated as low to high. The quality group (RR 7.21, 95% CI 1.37–38.08; 3 studies, 78 was rated as moderate for all outcomes reported in women). Women with breech presentation and in the comparison of macrolide antibiotics (including the CS group were at higher risk of puerperal pyrexia erythromycin) versus placebo and for most (RR 2.98, 95% CI 1.18–7.53; 2 studies, 51 women). No outcomes reported in the comparison of beta-lactam woman with (by either mode antibiotics (including co-amoxiclav) versus placebo. of delivery) had major complications or any reported For the comparison between erythromycin versus maternal morbidity (1 study, 38 women). co-amoxiclav, the quality of evidence was rated as Overall, there was no significant difference between moderate to high, while for 3- versus 7-day regimen groups for rates of maternal wound infection (RR 1.16, comparisons, it was mostly rated as low. 95% CI 0.18–7.70; 3 studies 103 women), although for women with breech presentation, the risk of other 3.1.5 Optimal mode of birth for women in maternal infection was increased among women in refractory preterm labour the CS group (RR 2.63, 95% CI 1.02–6.78; 2 studies, RECOMMENDATION 6.0 65 women). Another outcome reported in these trials Routine delivery by caesarean section for was length of maternal hospital stay: there was no the purpose of improving preterm newborn difference between women in the two trial arms in outcomes is not recommended, regardless of the proportion of women with a hospital stay longer cephalic or breech presentation. (Conditional than 10 days (RR 1.27, 95% CI 0.35–4.65; 3 studies, recommendation based very low-quality evidence) 78 women). Timing of birth after trial entry: Two trials (both REMARKS recruiting women with breech presentation) reported n There is insufficient evidence to support delivery within 7 days of entry to trials: out of 51 the routine delivery of preterm infants by women, all but one had delivered within this time. caesarean section instead of vaginal delivery, regardless of fetal presentation. Infant outcomes n Caesarean section should only be performed Perinatal death: Perinatal mortality was reported in for obstetric indications. three trials comparing immediate CS versus vaginal delivery, with data for 89 infants. There was no Summary of evidence statistically significant difference between groups (RR 0.29, 95% CI 0.07–1.14). Planned immediate caesarean section versus vaginal delivery for preterm birth (EB Table 6a) Severe neonatal morbidity: There were no cases of head entrapment in any of the trials, and Evidence on the optimal mode of delivery for the event rates were low for cord prolapse, with no preterm infant was extracted from one Cochrane significant differences between women randomized systematic review of four trials involving a total of 116 to immediate CS versus vaginal delivery for this women (56). These trials compared two policies for outcome (RR 0.25, 95% CI 0.03–1.92; 4 studies, delivery of the preterm infant: planned immediate 116 women). One study with a small sample size caesarean section (CS) versus vaginal delivery for reported rates of birth asphyxia: there was no women with refractory preterm labour with singleton significant difference between groups (RR 1.63, 95% pregnancies. One trial was conducted in Singapore, CI 0.84–3.14; 12 infants). There were no significant one in the United Kingdom and two in the USA. differences between groups in rates of RDS (RR One of the trials included women with cephalic 0.55, 95% CI 0.27–1.10; 3 studies, 103 women) or presentation only, while three included women with neonatal (RR 0.22, 95% CI 0.01–4.32; 3 breech presentation only. All women were in labour studies, 77 infants). There were few data on hypoxic (experiencing regular contractions) at recruitment, ischemic encephalopathy and intracranial pathology and all were less than 37 weeks pregnant. All four and no significant differences between groups for 3. EVIDENCE AND RECOMMENDATIONS

41 42 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES 1.73). 95% CI 0.03– 0.22, RR presentation: breech infants, (38 weeks 36 28 and 95% CI between 0.03–3.29) or 0.33, RR presentation: cephalic infants, (38 weeks 95% CI 0.02–10.34), 0.50, RR 33 26 and between presentation: breech (12 infants, of gestation weeks 32 26 and between birth vaginal or CS by planned delivered ininfants deaths perinatal in differences Perinatal death: age. toaccording gestational complications postpartum major for groups birth vaginal and caesarean between were observed Severe morbidity: maternal infants). (38 (12 weeks infants) 33 and of 32 weeks limits (66 gestation infants), upper had two other the while of to up weeks 36 women pregnant recruited Two sizes. to sample small trials included of the review systematic due Cochrane inthe performed not was age by analysis gestational Subgroup age by gestational birth of mode Optimal children).95% CI38 0.19–2.22; 0.65, (RR groups between differences significant no were trial: there one in was reported (not defined) morbidity: Long-term infants). 115 95% 4studies, CI 0.43–1.6; 0.83, (< 7) score Apgar lowfor infant (RR 5minutes at groups between difference significant no was There infants). 95%days, CI -19.90 1study, 12 respectively; to 56.42, 18.26 MD and 1.87, (RR different 95% 0.71–4.88 CI ventilation weresignificantly not mechanical used of days infants number mean the ventilation and mechanical requiring of infants number The infrequently. were reported outcomes these although women), 0.92, 103 (RR 95% CI 0.57–1.48;3studies, neonatal women) 103 or 3studies, 4.66; 0.76, (RR 95% infection CI 0.12–proven neonatal 6.67,(RR 95%1study, CI 0.39–114.78; 12 infants), of rates NEC for delivery vaginal and CS immediate between differences significant were no There infants). 38 95% CI 0.05–5.62; 0.56, (RR outcome for this groups between difference significant no was there presentation: following breech injury birth respectively). reported study infants, 110 One 0.92, RR 95%12 infants; CI 0.27–3.14, 4studies 1study, 95% CI 4.0, 0.2–82.01, (RR outcome either There were no significant significant were no There Abnormal childhood follow-up Abnormal No differences 3.2.1 3.2 started early before stabilization of the baby; for what what for baby; of the stabilization before early started be can KMC whether questions: specific answering with aview to continuously or intermittently either practiced KMC of effects the review examined The birth. at < 1500 g weighing to only babies KMC to singletons)addition six while trials provided (in pregnancies following multiple born babies (HICs). included countries Five studies high-income in (LMICs) five while conducted were countries inlow-middle-income and trials were conducted of these Thirteen outcomes. morbidity and mortality neonatal on care conventional versus of KMC effects trialsevaluated 18 that the review included review16). (13, Cochrane updated an The from extracted was KMC of effectiveness the on Evidence 7a) Table (EB newborns stable of care routine for care conventional versus (KMC) care mother Kangaroo evidence of Summary n n n REMARKS on moderate-quality evidence) clinically stable. are newborns the as soon as facilities care health- in initiated be should and birth, at less or 2000 g weighing newborns of care routine the for recommended is care mother Kangaroo RECOMMENDATION 7.0 n n recommendation to provide KMC to unstable to unstable to KMC provide recommendation make to a evidence is insufficient There middle-incomecountries. and low- from mainly studies, facility-based on based was this for recommendation Evidence with breastmilk. feeding (ideally)baby, exclusive and or the and mother the between contact to-skin skin- prolonged early,and include continuous mother. with the keyskin-to-skin Its features carried infants of preterm is care (KMC) care mother Kangaroo of definition The discharge should continue to applied. be continue should discharge existingfor criteria the recommendation, inthe any change for need the suggesting evidence no is currently there that Given implementation. for guidance or manual in the included be follow-up –should and discharge for criteria competencies, their and resources human requirements, system health as –such relating to KMC issues system Health neonates.

Thermal care for preterm newborns Newborn interventions Newborn (Strong recommendation based minimum duration per day KMC should be practiced; RECOMMENDATION 7.1 at what level of care and what resources are needed Newborns weighing 2000 g or less at birth for effective KMC; what criteria have been used for should be provided as close to continuous discharge of babies initiated on KMC in the facility; Kangaroo mother care as possible. (Strong and what is the optimum frequency of follow-up recommendation based on moderate-quality contact after discharge. evidence) Neonatal death: Compared with conventional care, KMC was associated with a 40% lower risk of RECOMMENDATION 7.2 mortality at discharge or 40–41 weeks postmenstrual Intermittent Kangaroo mother care, rather age (RR 0.60, 95% CI 0.39–0.92; 8 studies, 1736 than conventional care, is recommended for babies). A comparable result was obtained when newborns weighing 2000 g or less at birth, analysis was limited to the seven trials conducted in if continuous Kangaroo mother care is not LMICs. In these seven trials, KMC was associated possible. (Strong recommendation based on with a 43% reduction in mortality at discharge moderate-quality evidence) or 40–41 weeks postmenstrual age, compared to conventional care (RR 0.57, 95% CI 0.37–0.89). The Summary of evidence only study from HICs that evaluated this outcome found no protective effect for KMC compared with Continuous or intermittent Kangaroo mother care conventional care. (KMC) versus conventional care KMC, as compared with conventional care, was The Cochrane review summarized data on also associated with a 33% lower risk of all-cause effectiveness by subgroups of studies that had mortality for infants at the latest follow-up (RR used either continuous or intermittent KMC (13). 0.67; 95% CI 0.48–0.95; 11 studies, 2167 babies). Continuous KMC is defined as the practice of skin- Nine studies conducted in LMICs showed that KMC to-skin care continuously throughout the day without resulted in a 35% reduction in the risk of mortality breaking the contact between mother and baby, at the latest follow-up (RR 0.65, 95% CI 0.45–0.93; while intermittent KMC is the practice of skin-to- 2036 babies). In the two trials from HICs (with 131 skin care alternated with the use of either a radiant preterm newborns), the evidence of an effect on warmer or an incubator care for the baby. mortality was inconclusive, with confidence intervals consistent with a possible 71% reduction as well as Continuous KMC practice versus conventional care over five-fold higher risk of mortality at the latest (EB Table 7b) follow-up (RR 1.25, 95% CI 0.29–5.42). Five trials evaluated the effect of continuous KMC practice on neonatal mortality or severe neonatal Severe neonatal morbidity: Compared with morbidity. conventional care, KMC was associated with a 44% reduction in the risk of severe infection at the latest Neonatal death: Continuous KMC was associated follow-up (RR 0.56, 95% CI 0.40–0.78; 7 studies, with a 40% lower risk of mortality at the time of 1343 babies). The intervention was also associated discharge or at 40–41 weeks postmenstrual age with a 55% lower risk of nosocomial infection at the compared to conventional care (RR 0.60, 95% time of discharge or at 40–41 weeks postmenstrual CI 0.39–0.92; 3 studies, 1117 babies). Continuous age (RR 0.45, 95% CI 0.27–0.76; 3 studies, 913 KMC was also associated with a 33% reduction in babies). All the studies that reported on the risk of the risk of mortality at the latest follow-up contact, hypo- and hyperthermia implemented intermittent compared with conventional care (RR 0.67, 95% rather than continuous KMC. Six studies (with 698 CI 0.46–0.98; 4 studies, 1384 babies). babies) showed that KMC was associated with Severe neonatal morbidity: Only one trial (663 a 66% lower risk of hypothermia at the time of babies) reported the effects of continuous KMC discharge or at 40–41 weeks postmenstrual age (RR on severe infection at the latest follow-up and the 0.34, 95% CI 0.17–0.67). There was inconclusive finding was inconclusive (RR 0.69, 95% CI 0.43–1.12). evidence on the risk of hyperthermia at the time One study reported on the risk of nosocomial of discharge or at 40–41 weeks postmenstrual infections until the time of discharge or 40–41 age. The point estimate of data from two studies weeks postmenstrual age: there was a 51% lower also suggested a possible reduction in the risk of risk with continuous KMC compared to conventional readmission at the latest follow-up for babies that care (RR 0.49, 95% CI 0.25–0.93). The evidence were provided with KMC (RR 0.60, 95% CI 0.34– of effectiveness of continuous KMC in terms of 1.06). reducing the risk of readmission was inconclusive

(RR 0.60, 95% CI 0.34–1.06). 3. EVIDENCE AND RECOMMENDATIONS

43 44 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES CI 0.16–0.67; 2 studies, 250 infants). 250 CI 0.16–0.67; 2studies, 95% 0.39, (RR age postmenstrual weeks 40–41 at or of time discharge the at infections risk of nosocomial babies) 61% and 680 lower 6studies, CI 0.28–0.73; 95% follow-up latest visit 0.45, the at (RR infection with a55% lower riskof associated was severe KMC intermittent care, with conventional 1.05). Compared 0.79, (RR 95% CI riskof0.59– hyperthermia in the 95CI 0.17–0.67), reduction 0.34, significant no but (RR age postmenstrual weeks 40–41 at or discharge of time the at a 66% lower riskof hypothermia was There KMC. intermittent used hyperthermia and on hypo- KMC of effects the reported that Severe morbidity: neonatal 95% CI 0.26–1.77). 0.68, (RR up follow- latest the at riskof mortality inthe reduction of evidence inconclusive showed also babies preterm 0.59,(RR 95% CI 0.19–1.81). trials Seven with 783 care with conventional compared age, postmenstrual weeks 40–41 or to up of time discharge the mortality reducing for KMC of intermittent benefit the regarding evidence inconclusive was there babies, Neonatal death: intermittentimplemented KMC. main review trials in the identified 18 of the Thirteen (EB Table 7c) conventional practice care versus KMC Intermittent n n n REMARKS low-quality evidence)very in incubators. environment either under radiant warmers or athermo-neutral in for cared be should care, mother Kangaroo given be cannot who 2000 g than less weighing newborns stable or birth, at less or 2000 g weighing newborns Unstable RECOMMENDATION 7.3 The selection of a device for creating the the of creating adevice for selection The considered. be should costs and preferences providers’ health-care the devices, two the between any choice making In babies. preterm of care the for over other the incubators or warmers radiant of either superiority support to evidence is insufficient There rate. metabolic minimum at range a normal in temperature maintains ababy which under conditions to environmental be considered A thermo-neutral environment was personnel, costpersonnel, and other resources. illnesses), environment, physical the concurrent and size, maturity (including population patient the i.e. context, relevant inthe assessed carefully be should use, its for strategy the and environment, thermo-neutral From five studies involving From studies five 619 (Strong recommendation based on All the studies studies All the

phototherapy was also provided to some babies in babies to provided some also was phototherapy and groups, control inthe babies for were employed incubators the for shields heat or humidification as such interventions additional trials, some In trials. remaining inthe (or 1.8 kg) weighed baby until the birth days after 35 7and between six trials and 3days in and 1hour between varied intervention to the Exposure birth. at 1.1–1.6 kg weighed and of 28–32 ages weeks gestational had studies the into recruited Infants (NICUs) units care inHICs. intensive inneonatal review all were conducted and inthe were included babies preterm involving 156 trials Eight by or servo-mechanism. manually singleheated, double-walled or incubator, controlled air- inan nursed was and nappies) clothed for or (except naked either was infant the group, control with controls clothed) or naked either (with warmers inradiant baby the newborns preterm nursing review compared that Cochrane one from obtained was incubators and warmers radiant of effects related toEvidence comparative the unstable neonates (EB Table 7d) or sick for incubator versus warmer Radiant evidence of Summary 95% CI -1.49 to days). 3.10 days, trials similar was inboth (MD weight 0.86 birth takento time (0% regain mean 2.2%). versus The (IVH) ofrates severe haemorrhage intraventricular on intervention of the impact significant no showed Two wide. very (with studies newborns) preterm 90 was interval confidence the few and events very dysplasia(BPD), were there but bronchopulmonary and of sepsis risks reported newborns preterm 60 Severe morbidity: neonatal CI 0.05–1.59). (absolute 2.1% 0.27, 10.6%; RR risks: versus 95% inincubators nursed with those compared warmers radiant under nursed babies for mortality of neonatal risk the on evidence inconclusive yielded newborns Neonatal death: low. very was of evidence quality the were limited and data the Overall found. review were Cochrane of the publication the after studies relevant additional No group. intervention the recommendation based on low-quality evidence) alternative to prevent hypothermia. an as considered maybe bags/wraps plastic in wrapping wards, care neonatal specialized to newborns preterm of transfer and stabilization However, during birth. after immediately newborns preterm for care thermal providing in bags/wraps plastic of effectiveness the on evidence insufficient is There RECOMMENDATION 7.4 Two trials involving preterm 94 One study involving study One (57) (Conditional . In the the . In Summary of evidence Severe neonatal morbidity: Three studies, including one randomized controlled trial (RCT) and two Plastic wraps or bags before stabilization for observational studies, examined the impact of thermal care versus conventional thermal care for preterm infants (EB Table 7e) wrapping in plastic bags compared with conventional care on the risk of necrotizing enterocolitis (NEC). A systematic review that addressed this question The RCT involving 110 preterm newborns (born at identified 24 hospital-based studies (58). Twenty of 24–34 weeks of gestation) had only two reported these studies involved preterm babies exclusively events – both in the intervention group – and thus while the other four had results for term babies. lacked power to detect meaningful differences Sixteen of the 20 studies with preterm babies between the groups (RR 5.98, 95% CI 0.29–121.80). involved very preterm babies with either birth weight Similarly, results from the two observational studies < 1500 g or gestational age below 32 weeks, while did not demonstrate any significant difference with two included moderately preterm babies (32–34 regard to the risk of NEC in neonates < 1500 g (RR weeks of gestation) and two involved late preterm 1.29, 95% CI 0.85–1.97; 273 neonates). babies (34–37 weeks). Nine of the 24 studies were conducted in LMICs. The intervention consisted of Four studies (including two RCTs from Malaysia and wrapping of the neonate in a plastic bag, wrap or Uruguay) examined the impact of the intervention cap immediately following vaginal birth or caesarean on severe IVH (grade 3–4). The results from the section (prior to drying), and keeping the bag, wrap RCTs showed no statistically significant effects of or cap on until the neonate had been stabilized or the intervention on the risk of IVH. The study from had a normal body temperature. Materials used Malaysia, which involved 110 preterm newborns for wrapping included saran wraps (a transparent < 1000 g, showed no significant difference in the risk polythene film or sheet), shopping bags and other of IVH when wrapping in plastic bags was compared manufactured plastic sheets. In the control group, to keeping the baby under a radiant warmer (RR thermal care was provided using incubators or 0.30, 95% CI 0.03–2.60). In the study from Uruguay, radiant warmers, or by keeping the baby wrapped which compared the intervention with every other in clothes in a warm room. No study compared this means of thermal care, there was a trend towards intervention with provision of KMC. a reduction in the incidence of IVH (RR 0.38, 95% CI 0.15–1.02; 77 neonates). Neonatal death: Five trials involving 341 very preterm neonates (< 29 weeks) from HICs showed Two RCTs conducted in HICs assessed the impact no significant difference in terms of all-cause of the intervention on other major brain injuries in neonatal mortality when plastic wrapping was preterm neonates born at ≤ 29 weeks of gestation: compared with wrapping in a blanket (absolute risks: no evidence of an effect was found (RR 1.10, 95% 16.3% versus 19.4%; RR 0.84, 95% CI 0.54–1.30). CI 0.41–2.98; 152 neonates). When the analysis was restricted to three studies An RCT of plastic bags used for neonates with where radiant warmers were used for the control gestational ages of 24–34 weeks in Malaysia found group, the overall effect on neonatal mortality no evidence of a difference in incidence of respiratory was similar in the intervention and control groups distress syndrome (RDS) between the intervention (RR 0.86; 95% CI 0.49–1.49; 290 neonates). A and control groups (RR 1.04, 95% CI 0.78–1.38; study from Zambia, among 104 newborns born at 110 neonates). Similarly, an observational study 26–36 weeks or weighing < 2500 g, found absolute of neonates < 1000 g showed no evidence of a mortality risks of 14.3% versus 5.5% for wrapping reduced risk of BPD (RR 0.98, 95% CI 0.57–1.69; 209 versus conventional thermal care although the neonates). study lacked sufficient power to detect a statistically significant difference in mortality (RR 2.62, 95% Three RCTs involving 229 very preterm neonates CI 0.72–9.58). Another small trial conducted in (≤ 29 weeks) showed a 42% reduction in the risk of Malaysia, among 110 neonates born at 24–34 weeks hypothermia (temperature < 36.5 °C) with plastic of gestation admitted to the NICU, showed absolute bag use compared to controls (absolute risks: 46.0% mortality risks of 10.0% versus 16.7% for wrapping versus 79.0%; RR 0.58, 95% CI 0.46–0.72). Plastic versus conventional thermal care (RR 0.60, 95% wraps were also associated with a reduction in risk CI 0.22–1.64). There were six observational studies of hypothermia in more mature preterm neonates: that evaluated mortality outcomes comparing plastic one RCT of preterm neonates born at 24–34 weeks wrapping with wrapping in a blanket; the results reported a 21% reduction in the risk of hypothermia were again similar (RR 1.10, 95% CI 0.84–1.46; 849 (RR 0.79, 95% CI 0.67–0.93; 110 neonates). Two neonates). RCTs in neonates ranging in gestational age from 26 to 36 weeks showed a 46% reduction in the 3. EVIDENCE AND RECOMMENDATIONS

45 46 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES 3.2.2 group. control inthe infants of 312 none and group, intervention inthe of infants 286 out cases eight inonly reported was It studies. inall the outcome RCTs innine arare was reported was but °C, 38.0 Hyperthermia, defined as temperature hypothermia. of definition in the of differences because pooled were not studies observational of these results The in hypothermia. 85%to reduction effect no from ranging impacts estimated riskof hypothermia the 194 neonates). reporting Ten studies observational 95% CI 0.36–0.79; 0.54, (RR risk of hypothermia n n n n REMARKS evidence) (Strong recommendation based on low-quality newborns with respiratory distress syndrome. preterm of treatment the for recommended is therapy pressure airway positive Continuous RECOMMENDATION 8.0 radiological criteria. or basis of clinical the on diagnosed be can syndrome distress Respiratory demonstrable harms. of because used never be should oxygen 100% used; be airshould available, are not No. 10.1). blenders Where Recommendation levels (see saturation oxygen blood targeted titrated upwards to and maintain used be should oxygen of blended low concentrations with CPAP, is to delivered therapy be oxygen If to care newborns. supportive quality provide can that facilities in health-care implemented be should recommendation This benefit. than to harm more lead have potential to the interventions these as settings, medical inless-developed neonates [CPAP] to ill critically ventilator or support) pressure positive airway continuous oxygen, (supplemental intervention any respiratory to instituting prior considered be must status, cardiorespiratory and saturation oxygen to monitor ability the including of care, context technological the that strongly felt GDG The respiratory distress syndrome with newborns for administration surfactant Continuous positive airway pressure and and pressure airway positive Continuous ≥ 37.5 or °C in-hospital neonatal mortality (17.9% mortality 9.1%; neonatal versus in-hospital inoverall CPAP reduction with a48% associated was Neonatal death: one. in were used surfactants trials of and the intwo used were additionally corticosteroids Antenatal cannula. nasal or facemask box, by head delivered oxygen with were compared These pressure. negative nasopharyngeal/endotracheal tubes or continuous (CDP), pressure distending CPAP prongs, nasal using continuous included interventions the and RDS, of features clinical or with radiological babies preterm trials enrolled The quasi-randomized. one and trials five randomized which of were six HICs, trials from review included The studies. relevant additional no inMay 2014 found search review aCochrane from extracted was this for recommendation Evidence Table 8a) (EB newborns (RDS)preterm in syndrome distress respiratory for cannula nasal or facemask box, by head therapy oxygen versus therapy (CPAP) pressure airway positive continuous Any evidence of Summary neonates). preterm 260 3studies, 95% CI 0.44–3.39; 1.22, 95% CI 0.12–1.48) 0.43, (RR therapy (RR BPD or surfactant for need of the interms therapy oxygen treated with CPAP groups the standard or between differences of significant evidence no was There 95% 2.42, CI 6.1% 1.26–4.65). RR incontrols; versus CPAP on neonates preterm (14.5% among increased also was Similarly, riskof airleaks the 1.39–5.04). 95% CI 2.64, (RR two-fold than more increased CPAP-treated inthe of neonates However, 95% CI 0.72, (RR 0.56–0.91). risk the therapy CPAP oxygen on on to 52.5% compared in36.4% ventilation assisted occurred requiring failure respiratory neonates, preterm with 314 five In trials airleaks. and risk of pneumothorax with ahigher associated also was but ventilation, assisted requiring failure lower riskof respiratory therapy, withoxygen asignificantly associated was Severe morbidity: neonatal mortality. hospital in- RDS-specific in differences significant no showed 32–36 (28–32 age and gestational weeks weeks) by analysis Subgroup 95% CI 0.52–0.81). 0.65, (RR with RDS ventilation babies assisted inpreterm for need the or of death outcome combined of the risk inthe babies). a35%reduction also was There preterm 355 95%6studies, CI 0.32–0.87; 0.52, RR Compared to the comparison arm, arm, to comparison the Compared (59) CPAP, to compared as . An updated literature updated . An RECOMMENDATION 8.1 included in this analysis, the evidence for mortality reduction from the pooled results was inconclusive: Continuous positive airway pressure therapy 13.8% of those initiated early on CPAP died in- for newborns with respiratory distress hospital, as compared to 18.8% of those receiving syndrome should be started as soon as the delayed CPAP (RR 0.70, 95% CI 0.40–1.24). diagnosis is made. (Strong recommendation based on very low-quality evidence) Severe neonatal morbidity: Six studies (involving 165 neonates) showed that early rather than delayed REMARKS initiation of CPAP therapy was associated with n In view of the high proportion of neonatal reduced risk of respiratory failure requiring mechanical deaths that are caused by respiratory ventilation (17.8% versus 31.5%; RR 0.55, 95% CI distress syndrome, the GDG made a strong 0.32–0.96). Only one study (60) reported on the need recommendation despite the low quality of for surfactant therapy and the incidence of sepsis in the evidence showing the benefits of early neonates on early or late CPAP. Early initiation was continuous positive airway pressure (CPAP) associated with a 36% lower risk of complications therapy. requiring surfactant therapy (RR 0.64, 95% CI 0.44–0.93) and a 54% lower incidence of sepsis (RR 0.46, 95% CI 0.27–0.79). Finally, the incidence of IVH Summary of evidence was also lower with the use of early CPAP compared Early versus late initiation of continuous positive with delayed CPAP (58.3 versus 83.0%, P = 0.037). airway pressure (CPAP) therapy for respiratory However, there was no conclusive evidence of distress syndrome (RDS) in preterm infants (EB reduction in the risks of BPD (RR 0.70, 95% CI Table 8b) 0.12–3.98) or air leaks (RR 0.84, 95% CI 0.37–1.91). Evidence on the timing of initiation of CPAP therapy for preterm newborns with RDS was derived from a Cochrane review by Ho et al. (59). This review RECOMMENDATION 9.0 included five randomized trials and one quasi- Surfactant replacement therapy is randomized trial, all from HICs. The included recommended for intubated and ventilated studies were conducted between the mid-1970s newborns with respiratory distress syndrome. and the early 1980s, before the era of surfactant (Conditional recommendation [only in health-care treatment. Criteria for enrolment differed somewhat facilities where intubation, ventilator care, blood gas between trials but essentially all preterm babies with analysis, newborn nursing care and monitoring are radiological or clinical features of RDS were included. available] based on moderate-quality evidence) The intervention involved initiation of CPAP therapy (either with continuous distending pressure or REMARKS continuous negative pressure) immediately following n The GDG members were of the opinion that the diagnosis of RDS, and these neonates required the benefits of the intervention in reducing fraction of inspired oxygen (FiO2) between 0.3 mortality clearly outweighed the possible and 0.7. In the comparison arm, CPAP was initiated increased risk of pulmonary haemorrhage. only when RDS was worsening and babies required n The recommendation should be used in relatively higher FiO2 (between 0.5 and 1.0). An higher-level health-care facilities because it updated search in May 2014 identified one additional applies to preterm newborns with respiratory RCT (60), conducted in Iran in 2013. In the study, distress syndrome who have access to early CPAP was defined as CPAP initiated within 5 intubation and mechanical ventilation. minutes of birth, and late CPAP was that initiated at least 30 minutes after birth. This trial was the largest n In high-income countries, surfactant of all the seven studies included and contributed over treatment may reduce overall hospital costs, 30% of the total preterm newborns in the review. but this might not be the case in low- and middle-income countries (LMICs). Neonatal death: Only two trials (involving 61 preterm n In many LMICs, resource implications (both babies) reported mortality in the neonatal period. human and material) may make the use of The trials suggested no evidence of a reduction in surfactant a lower priority. neonatal mortality with early initiation of CPAP as compared to delayed initiation (RR 0.93, 95% CI 0.13–6.81). All seven trials reported the effect of early initiation of CPAP on in-hospital neonatal mortality. However, with a total of only 237 preterm babies 3. EVIDENCE AND RECOMMENDATIONS

47 48 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES receiving SRT versus no SRT. no versus SRT receiving 95% CI 0.79–1.10)those between were observed 0.95, 95% CI severe0.93, (RR or 0.84–1.08) IVH 95% CI 0.77–2.15), 1.29, (RR haemorrhage (RR BPD 1.14, 95% (RR of CI sepsis 0.87–1.48), pulmonary therisks on effects the in differences significant no neonates). 1380 However, 7studies, CI 0.39–0.58; 0.47, RR 31.0%; versus (14.7% 95% surfactant no to compared as riskof airleaks inthe reduction with a53% associated was SRT for surfactant Severe morbidity: neonatal 421 neonates). 7studies, CI 0.44–0.90; 95% 0.63, (RR with controls compared mortality neonatal a37% showed loweralso riskof in-hospital surfactants with SRT animal-derived CI 0.57–0.82). 95% 0.68, RR 28.4%; SRT(19.5%with no versus compared mortality, lower riskof overall neonatal a32% showed trials involvingbabies preterm 1469 Ten mortality. neonatal in-hospital overall and with lower to associated be found was surfactants Neonatal death: therapy. surfactant no received or sources fluid amniotic or porcine bovine, from treated with surfactants were of either RDS evidence radiological or with clinical neonates preterm which al. reviewet byThe Seger (EB TableAnimal-derived surfactants 9a) countries. available inmost commercially longer no are surfactants protein-free synthetic because and (animal-derived used surfactants versus synthetic) source of the in the ofdifferences the because pooled reviews were not Cochrane two of the results The treatment. no or placebo receiving babies included groups comparison The of RDS. features radiological or with clinical babies for tube by endotracheal surfactants synthetic or animal-derived exogenous of doses multiple or dose of asingle administration the included interventions The inHICs. hospitals within inintensive units care were conducted studies All included studies. relevant additional no found reviews both for conducted search updated An treatment. no or to placebo treatment the compared that studies reviews both included surfactants; Soll by second, the whilst surfactants, animal-derived al. et Seger by first, The this for recommendation. evidence provided morbidity and mortality neonatal on SRT Two of reviews effects evaluated that the Cochrane established respiratory distress syndrome (RDS) and/or clinical with neonates radiologically preterm for (SRT) therapy replacement Surfactant evidence of Summary (62) , focused on the use of protein-free use synthetic the on , focused (61) , evaluated the effects of the use of use of the effects , evaluated the SRT using animal-derived animal-derived using SRT (61) Animal-derived Animal-derived included 13 RCTs included in severe IVH when compared to no SRT (RR 0.84, 95% to0.84, (RR SRT no compared severe when IVH lower risk of with asignificantly associated not was neonates). However, therapy synthetic surfactant 95% 0.75, (RR CIlower 0.61–0.92; risk of BPD 2248 neonates) a25% 2328 and 95% CI 0.55–0.76; 0.64, 36% (RR lower risk leaks of air significant ina resulted surfactants synthetic using SRT that Severe morbidity: neonatal 0.79, (RR 95% CI 0.68–0.92). mortality neonatal lower a21% riskof in-hospital demonstrated also results 95% CI 0.61–0.88). 0.73, These (RR SRT to no compared when death of overall neonatal with a27% lower risk associated was surfactants synthetic using SRT that showed neonates Neonatal death: preparation. phosphatidylglycerol and 2-dipalmitoyl-sn-glycero-3-phosphocholine 1, dry used other the and discontinued been has production whose formulation a surfactant trials used Five of these were SRT included. no with SRT for surfactants protein-free synthetic review the In by Soll (EBProtein-free Table synthetic surfactants 9b) preterm babies at risk of RDS or with radiological/ or riskof at RDS babies preterm in SRT for surfactants natural versus synthetic of doses multiple or dose of a single effects the compared reviews directly that Cochrane two from derived was this for recommendation evidence The respiratory distress syndrome (RDS) and/or clinical with radiologically established neonates preterm for surfactants derived) Synthetic versus surfactants natural (animal- of evidenceSummary CI 0.63–1.12; neonates). 2328 n REMARKS evidence) available] are monitoring moderate-quality on based and care nursing newborn analysis, gas blood care, health-care facilities where intubation, ventilator syndrome. preterm newborns with respiratory distress ventilated in therapy replacement surfactant for used be can surfactants synthetic or animal-derived Either protein-containing RECOMMENDATION 9.1 no longer commercially available. available. commercially longer no of This is type synthetic surfactant surfactant. with animal-derived compared when riskof pneumothorax the increase surfactants protein-free that noted synthetic GDG The (Conditional recommendation [only in Six trials involving 2352 preterm preterm Six trials involving 2352 (62) , six trials that compared , six trialscompared that Five trials showed clinical features of RDS. The surfactants were differences in the risks of pulmonary haemorrhage administered by the intra-tracheal route. The first (RR 0.73, 95% CI 0.51–1.06; 1028 neonates), BPD review by Soll et al. (63) evaluated the effects of (RR 0.99, 95% CI 0.84–1.18; 1028 neonates), air leaks SRT with protein-free synthetics whilst the second, (RR 1.00, 95% CI 0.73–1.37; 1028 neonates), sepsis by Pfister et al.(64) , evaluated the use of protein- (RR 1.01, 95% CI 0.85–1.19; 785 neonates) and IVH containing synthetic surfactants, both compared to (RR 1.52, 95% CI 0.73–3.13; 243 neonates). natural surfactants.

RECOMMENDATION 9.2 Protein-free synthetic versus natural surfactants (EB Table 9c) Administration of surfactant before the onset The review by Soll et al. (63) included 11 studies of respiratory distress syndrome (prophylactic that used protein-free synthetic surfactant in the administration) in preterm newborns is not intervention group and compared its effects with recommended. (Strong recommendation based on the use of natural surfactants. These studies were low-quality evidence) conducted within intensive care units of hospitals REMARKS in HICs. An updated search found two additional n The GDG did not recommend prophylactic studies, which were included in the pooled analysis. administration of surfactants despite evidence Neonatal death: Neonates who received protein- of benefit in older studies because: free synthetic surfactant had similar risk of overall — the control group in these older studies neonatal mortality compared to natural surfactants did not receive continuous positive airway (RR 1.07, 95% CI 0.99–1.17; 12 studies, 5447 babies). pressure (CPAP), which is now part of Severe neonatal morbidity: The risk of standard care; and pneumothorax (including pneumo-mediastinum and — recent studies in which CPAP was given to pneumo-pericardium) was 49% higher with the use control group did not show any evidence of the protein-free synthetic surfactants compared of benefit for prophylactic surfactant with the use of natural ones (RR 1.49, 95% CI administration, and a possibility of harm 1.26–1.77; 5381 neonates). There were no significant could not be ruled out. differences in the risks of BPD (RR 1.00, 95% CI 0.92–1.10; 7 studies, 4006 preterm neonates), IVH (RR 0.95, 95% CI 0.83–1.09; 9 studies, 4969 Summary of evidence neonates) or sepsis (RR 0.99, 95% CI 0.90–1.08; Prophylactic versus rescue surfactant therapy for 10 studies, 5244 neonates) between the groups respiratory distress syndrome (RDS) in preterm receiving the two types of surfactants. neonates (EB Tables 9e to 9g) Evidence for this recommendation was based on Protein-containing synthetic versus natural surfactants a Cochrane review that evaluated the effects of (EB Table 9d) prophylactic administration of surfactants compared The systematic review by Pfister et al. (64) included with selective rescue therapy on mortality and two studies that compared the effects of the newer morbidity in preterm newborns with or without generation of protein-containing surfactants with evidence of RDS (65). The review included 11 studies, those of natural surfactants on mortality and all from intensive care units of hospitals in HICs, and morbidity outcomes when used in newborns with all using animal-derived surfactants. Surfactants clinical or radiological features of RDS or at risk of were administered with or without CPAP; two studies RDS. An updated search identified no additional routinely administered CPAP to stabilize babies in studies eligible for inclusion. the comparison arm, whereas the other nine were conducted in the pre-CPAP era. Neonatal death: There was no significant difference in the risk of mortality between the use of protein- Neonatal death: The use of prophylactic surfactant containing synthetic surfactant compared to natural administration was not associated with benefit in surfactants (RR 0.79, 95% CI 0.61–1.02; 2 studies, terms of neonatal death (RR 0.89, 95% CI 0.76–1.04; 1028 neonates). 10 studies, 4507 preterm neonates). However, there was substantial heterogeneity among studies Severe neonatal morbidity: Among preterm babies depending on whether the control group receive with RDS, use of protein-containing synthetic CPAP or not. In recent studies in which CPAP was surfactants was associated with a lower risk of NEC given to control infants, prophylactic administration compared with natural surfactants (RR 0.60, 95% of surfactants did not reduce neonatal death (RR CI 0.42–0.86). There was inconclusive evidence of 1.24, 95% CI 0.97–1.58; 2 studies, 1746 neonates). 3. EVIDENCE AND RECOMMENDATIONS

49 50 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES one from Brazil. Four studies used animal-derived animal-derived used studies Four Brazil. from one and HICs from –five six studies review included The RDS. established they developed when only administered therapy surfactant selective delayed ventilation assisted and/or requiring of RDS features radiological clinical for intubated newborns preterm for of birth) 2 hours (within administration first the surfactant of early review effects evaluated that the a Cochrane from extracted was this for recommendation Evidence Tables (EB RDS 9h) or clinically radiologically for established intubated neonates preterm for RDS) worsening with 2 hours after (given therapy surfactant selective delayed versus birth) after 2 hours first (within the Early evidence of Summary group. intervention neonates) 2013 inthe 5studies, CI 0.03–0.33; 2760 0.1, (RR 95% neonates) sepsis 8 studies, and 0.79, (RR riskof airleaks 95% CIreduced 0.63–0.98; receive CPAP not did infants group control a showed 1.04). However, inwhich studies older nine the 0.64–1.08) severe0.87, (RR or IVH 95% CI 0.74– 95% CI 95% 0.71–1.04), CI 0.86, 0.83, (RR sepsis (RR airleaks for groups control and intervention between of adifference evidence provide not did outcomes morbidity reported that all studies 11 Severe morbidity: neonatal (95% CI 0.79–3.94; 428 neonates). arelative riskof 1.76 reported and infants, control CPAPused studies fiveneonates). offor these One 1458 0.79, (RR therapy 5studies, 95% CI 0.63–1.00; to selective compared administration surfactant of prophylactic use with the mortality of in-hospital inrisk towards atrend was areduction There studies. infive reported as outcomes mortality in-hospital 27610.85; for were similar neonates). findings The 0.69, (RR significant was 95% 0.56– CI reduction mortality the to infants, control administered not CPAPHowever, where studies was older ineight evidence) available] are monitoring low-quality on based and care nursing newborn analysis, gas blood care, health-care facilities where intubation, ventilator therapy. rescue giving before worsen to symptoms the for waiting than rather birth) after 2 hours first (within the early administered be should respiratory distress syndrome, surfactant with newborns preterm intubated In RECOMMENDATION 9.3 (Conditional recommendation [only in (66) . The comparison group had had group comparison . The The pooled effect across across effect pooled The single study from Brazil Brazil from study single inthe reported were only which sepsis, bacterial riskof confirmed severe inthe or IVH observed neonates). was association 463 No 2 studies, 95% CI 0.48–0.78; 0.64, (RR neonates) airleaks and 3082 4studies, 0.67, (RR BPD 95% CI 0.54–0.84; with alower riskof associated was administration Severe morbidity: neonatal 75 neonates). 0.76, (RR 95% LMIC CI inan 0.46–1.26; conducted study only inthe withtherapy delayed compared administration surfactant riskwith early mortality respectively). on evidence inconclusive was There 95% CI 0.74–0.95; 95% CI 0.78–0.99, 0.88; RR to 0.84; (RR controls compared mortality neonatal with lower riskof in-hospital overallassociated and was RDS for intubated newborns preterm for birth of hours 2 first within the administration surfactant Neonatal death: criteria. eligibility the met that studies anyadditional review find not did Cochrane the for search updated An surfactant. asynthetic used two other the and surfactants 3.2.3 n n REMARKS low-quality evidence) very on based air. or oxygen 30% with ventilation adequate of seconds 30 after minute per beats 60 than less is rate heart their if therapy oxygen undergoing newborns for considered be only should oxygen of concentrations higher progressively of use The RECOMMENDATION 10.1 evidence) low-quality very on (Strong based recommendation oxygen. 100% with than available), rather not is oxygen (if blended air or oxygen 30% with therapy oxygen start to recommended is it gestation, of weeks 32 before or at born babies preterm of ventilation During RECOMMENDATION 10.0 initiated 2 minutes after birth. after initiated 2 minutes be should monitoring saturation-level hence and newborn preterm of the resuscitation at efforts early supersede not should levels saturation of these measurement However, levels. saturation oxygen blood by guided be should concentration Oxygen resuscitation inthe those as same arethe recommendations These Oxygen therapy for preterm newborns preterm for therapy Oxygen In six trials (3577 babies), six In trials (3577 early

WHO guidelines on basic newborn newborn basic on WHO guidelines (68) . (Strong recommendation (67) . Early surfactant surfactant Early Subgroup analysis (preterm babies born at 32–36 n The target oxygen saturation levels are as weeks versus < 32 weeks of gestation) follows: Except for two of the studies – Saugstad et al. (70) Time (after birth) All preterm infants and Kapadia et al. (71) – all other studies in the 2 minutes 55% – 75% review enrolled preterm babies born before 32 weeks 3 minutes 65% – 80% of gestation. Saugstad et al. included both term 4 minutes 70% – 85% and preterm neonates, with approximately 95% of 5 minutes 80% – 90% enrolled neonates being born at 32 weeks or later. 10 minutes 85% – 95% For the purpose of this review, the results of the study were stratified into those born at 32–36 weeks n The adjustment of the concentration of and those born before 32 weeks, and low versus high oxygen levels should be by 10% (FiO2=0.1) oxygen concentrations were compared. Kapadia et per 30 seconds and must be guided by oxygen al. enrolled preterm infants born before 35 weeks of saturation levels reached. gestation (the mean gestation being 30 weeks) but was excluded because of non-availability of data for Summary of evidence the two subgroups of interest. Preterm babies born at 32–36 weeks of gestation: Lower oxygen concentration (room air to ≤ 50%) versus higher oxygen concentrations (> 50%) for There was a 42% lower risk of in-hospital mortality positive pressure ventilation (PPV) of preterm observed in the lower oxygen concentration group neonates at birth compared to the higher oxygen concentration group Evidence related to the starting and progression (RR 0.58, 95% CI 0.34–0.97). No morbidity outcomes of oxygen concentration during ventilation was were available from the Saugstad et al. study. extracted from a systematic review of six RCTs Preterm babies born at < 32 weeks of gestation: involving 484 newborns. (69). An updated literature There was inconclusive evidence regarding the risk of search did not identify any additional eligible studies. mortality (RR 0.69, 95% CI 0.39–1.22) and the same Five of the included trials were conducted among was true for all the critical outcomes, including BPD, neonates born at a gestational age less than 32 NEC, IVH, retinopathy of prematurity (ROP), and weeks in HICs. The sixth was a multicentre trial that the proportion reaching target saturation by 5 or 10 was conducted among preterm and term neonates minutes after birth. in high- and low-income countries. Most of the studies had serious methodological limitations that affected the overall quality of the evidence. Low oxygen concentration was defined as receiving room air (21% oxygen concentration, 4 studies), 30% (1 4. Research implications study) or 50% (1 study) oxygen concentration. High oxygen concentration was defined as receiving 100% The Guideline Development Group identified (4 studies), 90% (1 study) or 80% (1 study) oxygen important knowledge gaps that need to be addressed concentration. through primary research. The quality of evidence Neonatal death: There was significant benefit of was rated as “low” or “very low” for a number using low oxygen concentrations for resuscitation in of recommendations, particularly those relating terms of overall and in-hospital neonatal mortality: to questions about sub-populations. According eight trials demonstrated that the use of low oxygen to GRADE methodology, evidence quality that concentration or air for preterm babies resuscitated was rated as “low” or “very low” implies that with PPV immediately after birth was associated with further research is likely to have an impact on the a 37% lower risk of overall or in-hospital mortality corresponding recommendation(s). Conversely, (RR 0.63, 95% CI 0.44–0.92). further research is not a priority for those recommendations based on evidence of “moderate” Severe neonatal morbidity: There was no or “high” quality. The knowledge gaps identified association between ventilation with low oxygen based on this concept were prioritized by considering concentrations for and whether such research would be original and severe morbidities, including BPD, retinopathy innovative, feasible to implement, likely to promote of prematurity, NEC, severe IVH, the proportion equity, and likely to contribute to improvements in of infants reaching target oxygen saturation by care for mothers and infants at risk of preterm birth. 10 minutes after birth, the duration (in days) of The priority research questions are listed as they mechanical ventilation or the need for endotracheal relate to maternal and newborn interventions. intubation during resuscitation. 3. EVIDENCE AND RECOMMENDATIONS

51 52 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES  Tocolysis             Antenatal corticosteroids 4.1              antenatal corticosteroids?antenatal (Consider calcium + placebo versus corticosteroids antenatal with incombination ofmorbidity, tocolytics and mortality maternal on and morbidity, and mortality neonatal on effects arethe What countries? low-income in effectively and safely used be antenatalIn can what contexts corticosteroids corticosteroids? antenatal for dose and regimen effective most is the What corticosteroids? of antenatal courses repeat for required dose effective minimum improved outcomes? other is the and What to maturation achieve lung fetal corticosteroids of dose effective minimum is the What outcomes? neonatal and maternal both on therapy antibiotic receive appropriate also who infection of with evidence mothers among administration corticosteroid of antenatal impact is the What used)? they areroutinely where insettings available data (consider phosphate using betamethasone acetate versus of betamethasone properties pharmacokinetic in the differences there Are facility)? to ahealth-care referral followed by community in the dose first the using (e.g. administration corticosteroid of antenatal context in the shifting task of effects arethe What inlate preterm? section caesarean prelabour undergoing inwomen administration corticosteroid antenatal of effects arethe What settings). (in events LMIC of adverse monitoring and strategies of implementation Assessment mortality).neonatal in (and reduction associated implementation guideline after and before corticosteroids of coverage of antenatal Assessment patient data analysis)?independent birth at ages (using gestational different at corticosteroid antenatal of effects arethe What outcomes? to improve settings (LMIC) country income inlow-middle- and of corticosteroids use the increase safely and effectively can strategies What infants)?term (including to corticosteroids antenatal exposed of all infants long-term arethe outcomes What Maternal research priorities research Maternal Antibiotic prophylaxis Antibiotic      Magnesium sulfate for fetal neuroprotection   administration surfactant (CPAP) pressure airway and positive Continuous    (KMC) care mother Kangaroo 4.2  infant preterm the for delivery of mode Optimal              (particularly on resuscitation)? on (particularly period postpartum immediate inthe newborn the sulfateon magnesium of effects arethe What facility)? to ahealth-care referral followed by community in the dose first the (e.g. sulfate using administration of magnesium context in the shifting task of effects arethe What regimen)? of intramuscular effectiveness (including neuroprotection fetal for used when sulfate of magnesium alternative regimens of effectiveness comparative is the What neuroprotection? sulfate fetal for magnesium of dose effective minimum is the What dose? first the completing after occur not does event birth inthe that neuroprotection fetal for sulfate safe of magnesium doses repeated Are regimens) dosing including outcomes, to improve placebo versus blockers channel methylxanthines/? giving despite persists that of prematurity of role is CPAP the What with apnoea babies for etc. cannulas, flow nasal ventilation, positive pressure intermittent nasal providing CPAP? for modality e.g. best is the What inLMICs? setting initiated community in the effectively be KMC Can outcomes? important other and mortality neonatal on to achieve impact an needed exposure of KMC threshold minimum is the What health-care facility? the from discharge after providing KMC mothers of follow-up for frequency optimal is the What presentation? and age by gestational delivery caesarean versus vaginal of safety and effects comparative arethe What and macrolide)? with betalactam therapy torelation combination in (particularly prophylaxis for used be should that regimen and dose appropriate is the What Newborn research priorities research Newborn  What is the efficacy of surfactants in a context and nongovernmental organizations. After the final where antenatal corticosteroids and early CPAP approval of the guideline, technical meetings will be is provided (without immediate obligatory held at WHO within the Department of Maternal, mechanical ventilation) for babies who are at risk Newborn, Child and Adolescent Health and the of respiratory distress syndrome (e.g. InSURE – Department of Reproductive Health and Research intubation, surfactant replacement therapy and to share the recommendations and other related extubation)? products with the teams responsible for policy and programme implementation. The recommendations Infection treatment will be published on the websites of these two WHO departments, as well as in the WHO Reproductive  What is the role of emollient therapy in reducing infections and mortality among preterm infants? Health Library, where they will be accompanied by an independent critical appraisal based on the AGREE instrument (Appraisal of Guidelines Research and Evaluation)1. Evidence briefs will also be developed  What are the optimal feeding methods for preterm for a wide range of policy-makers, programme infants with birth weight < 1200 grams? managers and clinicians, and then disseminated  Is there a role for total parenteral nutrition in the through WHO regional and country offices. management of preterm infants? The executive summary of the guideline will be translated into the six United Nations languages and Growth and development disseminated through the WHO regional offices and during meetings organized by or attended by relevant  Are there effective interventions for the care and WHO staff. Technical assistance will be provided development of preterm infants and what are as needed to any WHO regional office willing to these? translate the full guideline into any of the six United Nations languages. To also increase awareness of the guideline, the recommendations will be published as commentaries in peer-reviewed journals, in 5. Dissemination and compliance with WHO’s open access and copyright implementation policies. of the guideline 5.2 Guideline implementation The successful introduction of evidence-based The ultimate goal of this guideline is to improve policies related to the interventions to improve the quality of care and health outcomes related preterm birth outcomes into national programmes to preterm birth. The dissemination and and health services depends on well planned implementation of this guideline are therefore crucial and participatory consensus-driven processes of steps that should be undertaken by the international adaptation and implementation. These processes community as well as by national and local health may include the development or revision of existing services. In this context, the WHO Department of national guidelines or protocols based on this Reproductive Health and Research has adopted document. The Department of Maternal, Newborn, a formal knowledge-to-action framework for the Child and Adolescent Health and the Department dissemination, adaptation and implementation of of Reproductive Health and Research at WHO will guidelines (72). In addition to this framework, a support national and subnational subgroups to list of priority actions and events, advocacy and adapt and implement the guideline based on existing promotion opportunities identified during the WHO strategies. Technical Consultation will be used by WHO and Within this context, the WHO Department of other partners to facilitate the dissemination and Reproductive Health will involve its international implementation of this guideline. partnership called the GREAT Network (Guideline- driven, Research priorities, Evidence synthesis, 5.1 Guideline dissemination and evaluation Application of evidence, and Transfer of knowledge) The recommendations in this guideline will to adapt and implement guidelines particularly in be disseminated through a broad network of LMICs (72). The GREAT Network uses a unique international partners, including WHO country evidence-based knowledge translation approach to and regional offices, ministries of health, WHO 1 Available at: http://www.agreecollaboration.org/ collaborating centres, other United Nations agencies, instrument GUIDELINE THE OF IMPLEMENTATION AND DISSEMINATION 5.

53 54 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES   following: the include to implementation barriers potential The countries. in low-middle-income and particularly resources, of health-care redistribution and of care re-organization may require this guideline in recommendations of the implementation Effective 6.1 6. encouraged. be should process all-inclusiveparticipatory an and and inthis process roles may important societies professional Local practices. of evidence-based use the to enable managers and practitioners of health-care behaviour inthe changes including areavailablehospitals), at corticosteroids antenatal (e.g.that ensuring recommendations of these use the for created be should environment enabling An manner. transparent and explicit an in made be should anychanges for justifications and recommendations, limited tobe conditional should necessary, where to recommendations, the Modifications service. health its and country of each needs specific the to areable meet that documents appropriate into locally adapted be should guideline present inthe contained recommendations The meetings. stakeholder in well as participation as indicators, quality and flowcharts manuals, of training development inthe implementers guideline local for support technical includes This context. to local the tailored strategies implementation and adaptation guideline develop to stakeholders of efforts the supports and implementation, to facilitators guideline and barriers priorities, the assess and to system identify care health of the stakeholders relevant together brings GREAT Specifically, the Network countries. many in guidelines WHO other for employed successfully been has and health, newborn and perinatal maternal, relating to reproductive, of guidelines implementation and adaptation inthe LMICs support   recommended practices and monitor recipients’ the skillsto and implement expertise necessary with the resources of human Lack and radiant warmers); oximeter, pulse administration, oxygen incubators, for masks (e.g. oxygen, supplies and equipment of lack and surfactant) and sulfate, magnesium (e.g.corticosteroids, antibiotics, medicine of essential supply irregular or Non-availability

of care and resources and care of Anticipated impact on the organization organization the on impact Anticipated Applicability issues Applicability   areapplied: inthis guideline made recommendations the before considered be should following issues (GDG) Group Development the that noted Guideline the barriers, to overcome order these In   with the monitoring and evaluation teams of the of evaluationteams the and monitoring with the collaboration In recommendations. to guideline the adherence and implementation of guideline impact the levels to assess country and regional at adapted be can that indicators and measures of outcomes aset suggested GDG the inMay 2014, Consultation At Technical the targets. agreed with locally areassociated that indicators and criteria defined clearly on based levels, country and regional service, health- the at monitored will be recommendations of these impact and implementation The 6.2             early antenatal care visits. available during method best with the pregnancy to paid of dating be should attention Careful survival. newborn preterm influence that factors contextual for consideration with due continuum, within a infants preterm and birth preterm riskof at imminent of women management the integrate that developed be protocols should Local continuum. within a infants preterm and labour with preterm of women management pathways ensure that care and mechanisms referral of effective Lack countries; resource inlow- population obstetric inthe particularly estimation age of gestational Low certainty therapy); oxygen intubation, pressure, positive airway of (e.g. continuous application response clinical within the health-care facility. health-care within the established be should birth preterm imminent riskof at pathways women for referral Clear (KMC). care mother Kangaroo and warmers of radiant provision the level, including facility health-care the at quality care newborn and of maternal to given aspects be all other should Consideration (macrolideantibiotics penicillin). or sulfate and betamethasone),or magnesium (dexamethasone corticosteroids antenatal of supplies consistent and ample ensure to made be should arrangements Local birth. preterm of imminent features clinical and age of estimate gestational best the determine howon to be trained should staff Health-care impact Monitoring and evaluation of guideline guideline evaluation of and Monitoring WHO Department of Maternal, Newborn, Child and Adolescent Health and the Department 7. Updating the guideline of Reproductive Health and Research, data on country- and regional-level implementation of the In accordance with the guidance of the WHO recommendations will be collected and evaluated Guidelines Review Committee, which ensures a in the short to medium term to evaluate its impact systematic and continuous process of identifying on the national policies of individual WHO Member and bridging evidence gaps following guideline States. implementation, this guideline will be updated in five years after publication, unless new evidence Interrupted time series, clinical audits or criterion- emerges which necessitates earlier revision. WHO based clinical audits could be used to obtain relevant welcomes suggestions regarding additional questions data related to the interventions contained in for inclusion in the updated guideline. Please this guideline. Clearly defined review criteria and e-mail your suggestions to: [email protected]. The indicators are needed and these could be associated WHO Steering Group will continue to follow the with locally agreed targets. In this context, the research developments in the area of preterm birth, following indicators are suggested: particularly those relating to questions for which no  The proportion of all babies at risk of being born evidence was found and those that are supported by from 24 to < 34 weeks of gestation who were low-quality evidence, where new recommendations exposed to antenatal corticosteroids (numerator: or a change in the published recommendation may all babies at risk of being born from 24 to < 34 be warranted, respectively. Following publication and weeks whose mothers received antenatal dissemination of the guideline, any concern about corticosteroids; denominator: all babies at risk of validity of any recommendation will be promptly being born from 24 to < 34 weeks in the facility). communicated to the guideline implementers in addition to plans to update the recommendation.  The proportion of all babies at risk of being born at ≥ 34 weeks of gestation who were exposed to antenatal corticosteroids (numerator: all babies at risk of being born at ≥ 34 weeks of gestation whose mothers received antenatal corticosteroids; denominator: all babies at risk of being born at ≥ 34 weeks in the facility).  The proportion of all babies born before 32 weeks of gestation and exposed in-utero to magnesium sulfate for fetal neuroprotection (numerator: all babies born before 32 weeks whose mothers received magnesium sulfate for fetal neuroprotection; denominator: all babies born before 32 weeks in the facility).  The proportion of women with preterm prelabour rupture of membranes (PPROM) who received prophylactic antibiotics (numerator: all women with PPROM who received antibiotic prophylaxis; denominator: all women with PPROM giving birth in the facility).  The proportion of clinically stable neonates weighing ≤ 2000 g at birth who received KMC (numerator: clinically stable neonates weighing ≤ 2000 g at birth who received KMC; denominator: all clinically stable neonates weighing ≤ 2000 g managed in the facility). 7. UPDATING THE GUIDELINE THE UPDATING 7.

55 56 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES 1 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. 8.

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R, Soll Syst Rev. Database Cochrane 2002;2:CD002271. infants. inpreterm syndrome distress respiratory for pressure distending Continuous Davis PG. 2009;98(2):256–60. lower at they work gestations?do Paediatr. Acta – infants inpreterm birth at prevent hypothermia CP,Ibrahim Yoxall CW. to of bags plastic Use 34. 2013;132(1):e128– Pediatrics. infants. weight birth low and inpreterm prevention of hypothermia for Plastic bags al. et R, Schelonka AA, Salas E, Syst Rev.Database 2011;3:CD002771. Cochrane infants. inlow birthweight mortality and morbidity to care reduce mother Kangaroo Diaz-Rossello J. JM, Belizan A, Conde-Agudelo 1:i144–54. Suppl 2010;39 JEpidemiol. Int complications. to birth preterm due deaths to prevent neonatal care’ mother ‘Kangaroo S. Cousens FC, Barros BL, Horta J, Mwansa-Kambafwile JE, Lawn 21. Pfister RH, Soll R, Wiswell TE. Protein- 30. Amiya RM ML, Ota E, Suwa T, Mori R, Oladapo containing synthetic surfactant versus OT. 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(ASTECS) Research Team. Antenatal 23. WHO Handbook for guideline development. betamethasone and incidence of neonatal Geneva: World Health Organization; respiratory distress after elective caesarean 2012 (http://apps.who.int/iris/ section: pragmatic randomised trial. BMJ. bitstream/10665/75146/1/9789241548441_ 2005;331(7518):662. eng.pdf, accessed 9 July, 2015). 33. Amorim MM, Santos LC, Faundes A. 24. Higgins JPT, Green S, editors. Cochrane Corticosteroid therapy for prevention of handbook for systematic reviews of respiratory distress syndrome in severe interventions, version 5.1.0. The Cochrane preeclampsia. Am J Obstet Gynecol. Collaboration; updated 2011. 1999;180(5):1283–8. 25. Balshem H, Helfand M, Schunemann HJ, Oxman 34. Ramirez-Torres MA, Perez-Monter SE, Espino y AD, Kunz R, Brozek J, et al. GRADE guidelines: Sosa S, Ibarguengoitia-Ochoa F. Effect of 3. Rating the quality of evidence. 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2001;357(9261):979–88. Lancet. Group. Collaborative ORACLE trial. Irandomised ORACLE the membranes: fetal of rupture prelabour preterm, for antibiotics CollaborativeORACLE Group. Broad-spectrum TaylorKenyon SL, DJ, Tarnow-Mordi W; Syst Rev.Database 2013;12:CD001058. Cochrane of membranes. rupture preterm for JP. Neilson M, Boulvain Kenyon Antibiotics S, 2001;357(9261):989–94. Lancet. Group. Collaborative ORACLE trial. randomised II ORACLE the labour: preterm spontaneous for antibiotics Broad-spectrum OC. TaylorKenyon SL, DJ, Tarnow-Mordi W, Group 2013;12:CD000246. Syst Rev. Database Cochrane membranes. with intact labour preterm inhibiting for antibiotics Prophylactic N. Badawi S, V,Flenady Kenyon Stock OM, Hawley G, Syst Rev. Database Cochrane 2009;1:CD004661. fetus. of the neuroprotection for birth of preterm risk at women for sulphate D.Rouse Magnesium †Doyle LW, P, Middleton CA, Crowther S, Marret 2009;2:CD007836. Syst Rev. Database Cochrane syndrome. distress of respiratory treatment for extract surfactant derived Animal R. Soll N, †Seger 2013;2:4. Res. Adv Biomed trial. clinical a randomized newborns: inpremature syndrome distress of respiratory treatment for pressure airway positive continuous initiationdelayed of nasal versus Early F, Naseri A. Z, Badiee Sadeghnia Syst Rev.Database 2002;2:CD002975. Cochrane infants. inpreterm syndrome distress respiratory for pressure distending initiation delayed of continuous versus Early DJ, Davis PG. Henderson-Smart JJ, †Ho 2014 (unpublished). neonates. term and preterm in morbidity and mortality on wraps and bags plastic including of coverings review effect of the Systematic JE. Lawn H, Blencowe Oatley H, Syst Rev.Database 2003;4:CD000435. Cochrane infants. innewborn temperature body regulating for incubators versus VJ, warmers Radiant †Flenady Woodgate PG. 2013;9:CD000078. Syst Rev. Database Cochrane singletons. in birth preterm for delivery vaginal versus section Caesarean S. Livio SJ, Milan Z, Alfirevic 62. †Soll R. Synthetic surfactant for respiratory 68. Guidelines on basic newborn resuscitation. distress syndrome in preterm infants. Cochrane Geneva: World Health Organization; 2012 Database Syst Rev. 2000;2:CD001149. (http://www.who.int/maternal_child_ adolescent/documents/basic_newborn_ 63. †Soll R, Blanco F. Natural surfactant extract resuscitation/en/2014, accessed 19 March versus synthetic surfactant for neonatal 2015). respiratory distress syndrome. Cochrane Database Syst Rev. 2001;2:CD000144. 69. †Brown JV, Moe-Byrne T, Harden M, McGuire W. Lower versus higher oxygen concentration for 64. †Pfister RH, Soll RF, Wiswell T. Protein delivery room stabilisation of preterm neonates: containing synthetic surfactant versus animal systematic review. PloS One. 2012;7(12):e52033. derived surfactant extract for the prevention and treatment of respiratory distress 70. Saugstad OD, Rootwelt T, Aalen O. Resuscitation syndrome. Cochrane Database Syst Rev. of asphyxiated newborn infants with room air 2007;3:CD006069. or oxygen: an international controlled trial: the Resair 2 study. Pediatrics. 1998;102(1):e1. 65. †Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing 71. Kapadia VS, Chalak LF, Sparks JE, Allen JR, morbidity and mortality in preterm infants. Savani RC, Wyckoff MH. Resuscitation of Cochrane Database Syst Rev. 2012;3:CD000510. preterm neonates with limited versus high oxygen strategy. Pediatrics. 2013;132(6):e1488– 66. †Bahadue FL, Soll R. Early versus delayed 96. selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane 72. Knowledge to action framework and the Database Syst Rev. 2012;11:CD001456. G.R.E.A.T project. Geneva: World Health Organization; 2010. (http://www.who.int/ 67. Lefort S, Diniz EM, Vaz FA. Clinical course of reproductivehealth/topics/best_practices/ premature infants intubated in the delivery greatproject_KTAframework/en/index.html, room, submitted or not to porcine-derived lung accessed 21 March 2015). surfactant therapy within the first hour of life. J Matern Fetal Neonatal Med. 2003;14(3):187–96. 8. REFERENCE

59 60 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES Sri Lanka 70, Box PO Galle of Ruhuna University Faculty of Medicine, Gynecology and of Obstetrics Department Professor Malik Goonewardene Chile Santiago Chile of University Catholic Center for Perinatal Diagnosis Hospital Rio del Sotero of Obstetrics Gynaecology, and Department Dr Rogelio Gonzalez Nigeria Abuja Gwagwalada, Teaching of Abuja University Hospital of Obstetrics Gynaecology and Department BissallahProfessor Ekele Australia 5006 Australia, South Adelaide North William Road, King Women’s Children’s and Hospital of Adelaide University of Obstetrics Gynaecology and Department Professor Caroline Crowther Colombia Bogotá Palmira 26-60 58, Calle Bogotá Fe de Santa Fundación Gynecology and of Obstetrics Department and Salud en eInvestigación Estudios de Centro Dr Agustin Conde-Agudelo USA AL Birmingham, 619, South Street 19th Birmingham at of Alabama University Director, Division of Wally Carlo Dr USA NC Hill Chapel of Medicine School Carolina of North University Medicine ofDivision Neonatal-Perinatal Department of Pediatrics Bose Carl Professor Guideline Development Group Annex 1.

preparation of guideline the andWHO staff experts External involved the in

Keppel Street Keppel &Tropical of Hygiene School Medicine London Director, Centre MARCH JoyProfessor Lawn USA 63104 MO St Louis, Blvd Grand South 1465 Medicine Neonatal–Perinatal Children’s Glennon Cardinal Hospital of Medicine School St University Louis Department of Pediatrics Keenan J. William Professor Kingdom United 7SS L8 Crown Liverpool, Street, Trust Women’s Floor, Foundation First Liverpool NHS of Liverpool University The Group Childbirth and Pregnancy Cochrane Editor Consumer Gyte Gill Ms Japan Tokyo Development and Child Institute for Health Research National Policy, of Health Department Mori Rintaro Dr Malawi Queen Elizabeth Central ofCollege Medicine Paediatric Department Professor Elizabeth Molyneux Germany Munich 81379 Hofmannstrasse 7a Infants of Newborn Care the for Foundation European Board Executive of the Chairwoman Mader Silke Dr Thailand Kaen Khon University Kaen Khon Faculty of Medicine of Obstetrics Gynaecology and Department Lumbiganon Pisake Professor Kingdom United London WC1E 7HT

Professor Ashraf Nabhan Dr Jeffrey Smith Department of Obstetrics and Gynaecology Maternal and Child Health Integrated Program Ain Shams University (MCHIP) 16 Ali Fahmi Kamel Street United States Agency for International Development Heliopolis, Cairo, 11351 Washington, DC 20036 Egypt USA

Professor James Neilson Professor Roger F. Soll NIHR Dean for Faculty of Trainees H. Wallace Professor of Neonatology Professor of Obstetrics & Gynaecology Department of Pediatrics, Smith, Rm 552A Department of Women’s & Children’s Health University of Vermont College of Medicine University of Liverpool S-253 Given Courtyard Crown Street 89 Beaumont Avenue Liverpool L8 7SS Burlington, VT 05405 United Kingdom USA

Ms Regina Obeng Dr João Paulo Souza Deputy Director of Nursing Services Department of Social Medicine Department of Child Health Ribeirão Preto Medical School Komfo Anokye Teaching Hospital University of São Paulo Kumasi São Paulo Ghana Brazil

Professor Vinod Paul Professor Alan Tita Head Department of Obstetrics and Gynecology Department of Pediatrics & WHO Collaborating Division of Maternal–Fetal Medicine Centre for Training & Research in Newborn Care University of Alabama at Birmingham All India Institute of Medical 619 19th St. South Sciences, Delhi 110029 Birmingham, AL 35249 India USA

Professor Zahida Qureshi Dr Khalid Yunis Chairperson Department of Pediatrics and Adolescent Medicine Department of Obstetrics & Gynaecology American University of Beirut Medical Center University of Nairobi PO Box 113-6044 Nairobi Beirut Kenya Lebanon

Dr Larry Rand Guideline methodologists Department of Obstetrics Dr Therese Dowswell University of California Cochrane Pregnancy and Childbirth Group San Francisco, CA Department of Women’s and Children’s Health USA The University of Liverpool Professor Ola Didrik Saugstad Liverpool Women’s NHS Foundation Trust Head, Department of Paediatrics Crown Street University of Oslo Liverpool, L8 7SS Rikshospitalet, 0027 United Kingdom Oslo Ms Sonja Henderson Norway Cochrane Pregnancy and Childbirth Group Professor Andrew Shennan Department of Women’s and Children’s Health Women’s Health Academic Centre The University of Liverpool Kings College London, St Thomas’ Hospital Liverpool Women’s NHS Foundation Trust Westminster Bridge Rd, SE1 7EH, London Crown Street United Kingdom Liverpool, L8 7SS United Kingdom ANNEX 1. EXTERNAL EXPERTS AND WHO IN INVOLVED STAFF THE PREPARATION OF THE GUIDELINE

61 62 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES USA 20523 DC Washington, Ave., NW, Pennsylvania 3.07-811300 Rm Ronald Reagan Building for InternationalUnited States Development Agency Nutrition and Diseases Infectious Health, of Office Health Newborn and Partnerships Global for Advisor Senior Kak Lily Dr Italy 06132 Sisto Perugia San Hospital MisericordiaUniversity della Maria Santa Medicine Reproductive and Perinatal for Centre and Gynaecology and of Obstetrics Department Chairman and Professor (FIGO);Obstetrics International and Federation of Gynecology Hon. Secretary General Renzo Di Carlo Gian Professor Observers India 110029 Delhi Sciences Institute ofAll India Medical Care in Newborn Training for Centre Collaborating WHO &Research Dr Jeeva Sankar Kingdom United Liverpool, L8 7SS Street Crown Trust Women’s Foundation Liverpool NHS of Liverpool University The Department of Women’s and Children’s Health Group Childbirth and Pregnancy Cochrane West Helen Dr Kingdom United Liverpool, L8 7SS Street Crown Trust Women’s Foundation Liverpool NHS of Liverpool University The Department of Women’s and Children’s Health Group Childbirth and Pregnancy Cochrane Medley Nancy Ms Kingdom United London 7EH, SE1 Rd, Westminster Bridge Hospital St Thomas’ London College Kings Obstetrics Gynaecology and Doctoral Research Fellow (NIHR) Research InstituteHealth for National Dr Natasha Hezelgrave 1

USA DC Washington, USA Children, Lives/Savethe Newborn Saving of Technical Director Senior Leadership Dr Stephen Wall USA 20523 DC, Washington, 320 Twenty-First NW Street, Health Global for InternationalUnited States Development Agency Vivio Donna Ms Netherlands The Hague The AN 2517 Laan van Meerdervoort 70 of Midwives Confederation International Representative Dr Hora Soltani Canada 6A8 T3B AB Calgary, Trail, Shaganappi NW 2888 Children’s Hospital Alberta of Neonatology Department Professor Nalini Singhal 1 Health Adolescent Child and Newborn, of Maternal, Department Research and Development Officer Medical Dr Alexander Manu Health Adolescent Child and Newborn, of Maternal, Department Epidemiology, Monitoring Evaluation and Coordinator Mathai Matthews Dr Research and Health of Reproductive Department &Preventing Unsafe Health Perinatal and Maternal Coordinator Gülmezoglu Metin Dr Health Adolescent Child and Newborn, of Maternal, Department Research and Development Coordinator Bahl Rajiv Dr Group Steering WHO the recommendations. the guideline development process or formulation of to experience or expertise technical contribute not did and organizations of representatives were Observers Dr Olufemi Oladapo External Review Group Medical Officer Dr Edgardo Abalos Maternal and Perinatal Health & Preventing Unsafe Vice Director Abortion Centro Rosarino de Estudios Perinatales (CREP) Department of Reproductive Health and Research Rosario Argentina Dr Severin von Xylander Medical Officer Professor Zulfiqar A. Bhutta Policy, Planning and Programmes Husein Laljee Dewraj Professor and Chairman Department of Maternal, Newborn, Child and Department of Pediatrics and Child Health Adolescent Health Aga Khan University Medical Center Karachi WHO regional offices Pakistan Dr Léopold Ouedraogo Regional Adviser Professor Karen Edmond Research and Program Development School of Paediatrics and Child Health (SPACH) Reproductive Health The University of Western Australia (M561) Health Promotion Cluster 35 Stirling Highway WHO Regional Office for Africa Crawley WA 6009 BP. 06 Brazzaville Australia Republic of Congo Dr David Haas Dr Assumpta Muriithi Associate Professor Health Promotion/Family and Reproductive Health Wishard Memorial Hospital, WHO Regional Office for Africa 1001 W 10th Street, F5102 WHO Kenya Indianapolis, IN 46202 PO Box 45335-00160 USA Waurolr Professor Suneeta Mittal Kenya Department of Obstetrics and Gynecology, Dr Martin Weber All India Institute of Medical Sciences, Medical Officer New Delhi Making Pregnancy Safer and Reproductive Health India Department of Family and Research Professor Siddharth Ramji WHO Regional Office for South-East Asia Maulana Azad Medical College World Health House, Indraprastha Estate New Delhi Mahatma Gandhi Marg India New Delhi 110 002 India

Dr Howard Sobel Acting WHO Representative in the WHO Regional Office for the Western Pacific PO Box 2932 1000 Manila Philippines ANNEX 1. EXTERNAL EXPERTS AND WHO IN INVOLVED STAFF THE PREPARATION OF THE GUIDELINE

63 weeks for respiratory distress syndrome The (RDS). quality of evidence from the subgroup analyses based on gestational age at birth +6 EXPLANATION Based on the main analysis, the overall quality of evidence for maternal outcomes was mostly rated whereas as low, for newborn severe morbidity and mortality outcomes it was rated as moderate or high. Long-term outcomes during childhood and adulthood were rated as Thelow. quality of evidence from the subgroup analyses based on gestational age at first dose was rated forlow most newborn morbidity and mortality outcomes due few trials to and small sample it sizes. was rated However, as moderate or high for categories between and 26 34 was quite variable, ranging from high low to across the different age categories for severe neonatal morbidity and mortality outcomes. it was moderateHowever, high to for RDS for babies born < 30 weeks, < 32 weeks, < 34 weeks and < 36 weeks. The Guideline Development acknowledged Group (GDG) the differences in the qualityevidence of between maternal and early newborn critical outcomes and between early and late newborn critical outcomes. The panel interpreted the overall quality of evidence within the context of the recommendation question and the main review findings, and favoured a distinction between the qualityevidence of for the mother and the newborn. Thus, the overall quality of evidence was rated as moderate for newborn outcomes and low for maternal outcomes. Health-care providers, policy-makers, and pregnant women and their families in all settings are likelyplace to a high value on the survival of a preterm newborn without residual morbidity. The GDG is confident that there is no variation in this value among mothers, health-care providers and policy-makers in middle- low-, and high-income settings. High (newborn) Moderate (mother) Low Very low No significant variability Significantvariability

      DECISION Considerations related to the direction and strength the therecommendations direction of to related Considerations gestational age assessment can be accurately undertaken; preterm birth considered is imminent; there no is clinical evidence maternal of infection; adequate childbirth care (including available is the capacity and recognize safely to manage preterm labour and birth); the preterm newborn can adequate receive care needed if (including resuscitation, thermal care, feeding support, infection treatment and safe oxygen use).      Recommendation. 1: Antenatal corticosteroid therapy is recommended for women at risk of preterm birth from 24 weeks to 34 weeks of gestation when the following met: are conditions      FACTOR Quality of the evidence Values and preferences Annex 2.Annex

64 Antenatal corticosteroid reduces the risk of death and serious short-term morbidities and is probably beneficial in reducing long-term adverse neurological outcomes for preterm infants. For the there mother, is no evidence of benefits or harms. While the Cochrane systematic review demonstrated these benefits across a broad range of gestational ages(largely to the24 weeks), 36 fromsubgroup analyses for the most part lack sufficientpower to show consistent statistically significant results for specific gestational age categories. These inconsistencies were more pronounced at the two extremes weeks of prematurity and > 34 (< 26 weeks) because the sample sizes were even Nevertheless, smaller. the subgroup analyses showed consistent evidence of reduction in neonatal death when the infant is born before 34 weeks of gestation. Likewise, the data indicated that corticosteroid does not reduce infant mortality when born after 34 weeks and there is an increasing likelihood of fetal and newborn death when born at 36 weeks or after. With regard the to lower end of gestational age limit, corticosteroid may likely reduce neonatal mortality for infants born as early as 23 weeks of gestation, but the overall rate of survival without residual morbidity is generally low among infants born before weeks. 24 Overall, the desirable consequences for preterm infants whose mothers receive antenatal corticosteroid between and 24 34 weeks are substantial (including reduction in the risks of death and serious short-term morbidities and possibly better long-term neurological outcomes) and highly valued. For eligible mothers, these benefits are achievable without increased harmto mother and Beyondbaby. this gestational age range, the undesirable consequences for the preterm infant (including survival with residual long-term morbidity and increased risk of death) outweigh the potential benefits. Antenatal corticosteroids are relatively cheap, easy administer, to and readily available in at least one preparation in all settings. It is feasible include to antenatal corticosteroid therapy into existing health structures and protocols that are designed manage to women at imminent birth preterm of minimal costs. risk with The moderate-to-high confidence in the magnitude of effects of a relatively cheap intervention on highly valued criticalnewborn intervention. the favoured outcomes The GDG placed its emphasis on the benefitsto the preterm infantsterms in of reducing severe morbidity and mortality outcomes, the low cost and wide availability of corticosteroid globally, the feasibility of implementing the intervention and the potential impact on health- care resource use across settings, and therefore made a strong recommendation. Benefits outweigh Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

        

Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

65 66 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES

Recommendation 1.1: For eligible women, antenatal corticosteroid should be administered when preterm birth is considered imminent within 7 days of starting treatment, including within the first 24 hours. FACTOR DECISION EXPLANATION Quality of the  High The quality of evidence was variable for critical outcomes reported, ranging from low to high across the different categories of intervals evidence between first dose of corticosteroid and preterm birth. Overall, the quality of evidence was rated low for both newborn and maternal  Moderate outcomes.  Low  Very low Values and  No significant Health-care providers, policy-makers, and pregnant women and their families in all settings are likely to place a high value on the benefits preferences variability of an intervention with the potential to reduce the risk of newborn death and serious morbidity even when given at short interval before birth. The GDG is confident that mothers, health-care providers and policy-makers in any setting will invariably place a higher value on  Significant variability these benefits compared to any inconvenience that incomplete dosing of steroids might cause to the mother or the health system. Balance of  Benefits outweigh There is evidence of benefit in terms of reduction in neonatal death for infants born within 24 hours and within 48 hours after the first benefits versus disadvantages corticosteroid dose. This benefit was not clearly demonstrated in those born between 1 and 7 days and after 7 days of first steroid dose. disadvantages However, there is a 54% reduction in the likelihood of RDS among those born within 1 and 7 days after the first dose of corticosteroid.  Benefits and Overall, there is variable evidence of benefits regarding newborn death and RDS for infants born within 7 days of receiving the first disadvantages are corticosteroid dose, while there is consistently no evidence of benefits for these outcomes in infants born 7 days after the first dose. The balanced risk of intrapartum maternal infection is independent of the time interval between the first corticosteroid dose and birth.  Disadvantages Overall, the desirable consequences for preterm infants whose mothers receive antenatal corticosteroids and who are born within 7 days outweigh benefits after the first dose are substantial. Even for preterm infants born within 24 hours of exposure to steroid, the balance is in the favour of these benefits, as they are not associated with any inconvenience or harm to the mother. Resource use  Less resource Antenatal corticosteroids are relatively cheap, easy to administer, and readily available in at least one preparation in all settings. Available intensive preparations of dexamethasone and betamethasone are often compatible with standard dosing regimen and inability to complete a full course is unlikely to result in waste of health resources.  More resource intensive Recommendation  In favour of the The magnitude of beneficial effects of a relatively cheap intervention on highly valued critical newborn outcomes favoured the direction intervention intervention.  Against the intervention Overall  Strong The GDG acknowledged the limitations and potential bias of evidence derived from the subgroup analysis according to the interval strength of the recommendation between steroid administration and preterm birth, which led to low quality evidence for critical outcomes. Nevertheless, the group made recommendation a strong recommendation on the basis of the balance in favour of benefits of antenatal steroids (in terms of reducing respiratory morbidity  Conditional and mortality for babies born within 24 hours and up 7 days of starting treatment), the low resource requirements, and feasibility of recommendation implementing the intervention. EXPLANATION The overall quality of evidence was rated low for both newborn and maternal outcomes. Health-care providers, policy-makers, and pregnant women and their families in all settings are place likely to a high value on the modest benefits of antenatal steroids on the risk of newborn death and serious morbidities, particularly because of higher baseline risk of preterm birth in multiple pregnancy. The GDG is confident that mothers, health-care providers and policy-makers in any setting will invariably place a higher value on these benefits,even if modest, and will choseto use the intervention. The positive effects of corticosteroids on preterm infants resulting from multiple pregnancies are not as clear as in singleton pregnancies. It is uncertain whether the lack of a statistical difference was only relatedto the small sample of this size subgroup in the systematic review or as a result of different pharmacokinetic properties leadingto sub-therapeutic levels of steroids in multiple pregnancies. for However, the outcomes reported, the point estimates were consistent for risk reduction in both singleton and multiple pregnancies. Given that the evidence base demonstrating benefits of antenatal corticosteroids was extracted from studies that includedwomen with multiple pregnancies, it is plausible for corticosteroids also to improve survival and reduce the risk of morbidity of preterm infants resulting from multiple pregnancies. Overall, the desirable consequences for preterm infants whose mothers receive antenatal corticosteroids are likelybe to substantial. Appropriate use in eligible mothers is not known constitute to any inconvenience or harm among populations of women carrying either singleton or multiple pregnancies. Antenatal corticosteroids are relatively cheap, easy administer, to and readily available in at least one preparation in all settings. The same dosage is required for treatment of a woman with a multiple pregnancy as for a woman with a singleton pregnancy. The potential beneficial effects of a relatively cheap intervention on highly valued criticalnewborn outcomesfavoured the intervention. The GDG acknowledged the lack of clarity on the benefits of antenatal steroids in this subgroupwomen, of but felt there is no reasonto suggest that antenatal corticosteroids are not beneficial, given that the point estimateswere all in favour of reduced risks of adverse critical outcomes reported. The group considered the impact of any benefit, albeit modest, on the critical outcomes in this groupwomen, of who are inherently more likelydeliver to preterm, on the overall preterm newborn survival and morbidity rates, and therefore made a strong recommendation. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation 1.2: Antenatal corticosteroid therapy is recommended for women at risk of preterm birth irrespective of whether a single or multiple birth is anticipated. FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

67 68 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES

Recommendation 1.3: Antenatal corticosteroid therapy is recommended in women with preterm prelabour rupture of membranes and no clinical signs of infection. FACTOR DECISION EXPLANATION Quality of the  High The quality of evidence was variable for the reported critical outcomes for preterm prelabour rupture of membranes as a group, and evidence for prolonged rupture of membranes for more than 24 hours and 48 hours. However, for preterm prelabour rupture of membranes as  Moderate (newborn) a subgroup, the quality of evidence was generally low for maternal infectious morbidity and moderate for early newborn death and  Low (mother) infectious morbidity. The overall quality of evidence was rated moderate for newborn outcomes and low for maternal outcomes.  Very low Values and  No significant Health-care providers, policy-makers, and pregnant women and their families in all settings are likely to place a high value on the preferences variability reduction in the risk of newborn death and serious morbidity and less value on the potential for increased risk of maternal infection. The panel is confident that mothers, health-care providers and policy-makers in any setting will invariably place a higher value on these  Significant variability benefits, and will chose to use the intervention. Balance of  Benefits outweigh Corticosteroid administration is associated with reduction in the risk of neonatal death and serious short-term morbidity in women with benefits versus disadvantages preterm prelabour rupture of membranes at the time of the first dose without increasing the risk of maternal or neonatal infection. While disadvantages it is unclear whether these benefits remain consistent for women with ruptured membranes for more than 24 or 48 hours, the risk of  Benefits and intrapartum infection was not any worse even in these women. disadvantages are balanced  Disadvantages outweigh benefits Resource use  Less resource intensive Antenatal corticosteroids are relatively cheap, easy to administer, and readily available in at least one preparation in all settings. It is feasible to include antenatal corticosteroid therapy into existing health structures and protocols that are designed to manage women at  More resource risk of imminent preterm birth with minimal costs. intensive Recommendation  In favour of the In spite of the low confidence in the magnitude of effects, the overall balance is in favour of benefits. direction intervention  Against the intervention Overall  Strong The GDG noted the paucity of evidence on benefits around the duration of membrane rupture due to the lack of such information from strength of the recommendation trials included in the review. However, the group placed its emphasis on the overall balance of benefits versus harm of using antenatal recommendation steroids in terms of reducing severe adverse neonatal outcomes without evidence of increased risk of infection to the mother or the baby,  Conditional and with consideration that a substantial proportion of women at risk of imminent preterm birth would present with ruptured membranes, recommendation and therefore made a strong recommendation. recommended in women with chorioamnionitis who are likely to deliver preterm. is not EXPLANATION Available evidence on newborn critical outcomes was obtained from observational studies with some design limitations. No maternal outcomes were reported. Health-care providers, policy-makers, and pregnant women and their families in high-income settings might place a higher value on the potential benefits of antenatal steroidsterms in of reduction in RDS and neonatal mortality(regardless of the limitedevidence on benefits in this context) over concerns about exacerbation of maternal infections, and therefore chose not adhere to the to recommendation in all women; whereas those in low- and middle-income settings might put a higher value on the potential risk of increasing maternal infectious morbidity over unclear benefits for clinical chorioamnionitis and thus choseto adhereto the recommendation in the majoritywomen. of Corticosteroids are known suppress to the , and so the concern that their use may activate latent infections is reasonable. In a pregnant woman with ongoing infection, it may theoretically suppress the natural immune response and exacerbate infectious morbidities. there is no However, direct evidence from randomized and observational studies on the effects of corticosteroid therapy on mothers with chorioamnionitis who are at risk of giving birth preterm to neonates either to confirm or refute this theory.Evidence from the reviewed observational studies from high-income countries suggests that in women with histological chorioamnionitis, there are some benefits for the preterm neonates without increasing potential harm of steroid therapy, particularly neonatal sepsis. However, no convincing evidence of benefits was shown for neonatal mortality and RDS womenin with clinical chorioamnionitis. In view of the evidence from low-income settings showing a significant67% increase in suspected maternal infections among mothers of preterm infants who received antenatal corticosteroid, the potential harm of worsening infectious morbidities may outweigh the potential benefits, especially in settings where the baseline risk of maternal infection is high. This concern is further supported a 35% by increased risk of puerperal sepsis (albeit not statistically significant) among womenall receiving corticosteroid compared with placebo as shown in the main Cochrane review of antenatal corticosteroid for improving adverse neonatal outcomes. It is unclear whether the desirable consequences (possible reduction in mortality and severe morbidity) for the preterm newborn associated with corticosteroid use outweigh the potential harm for the mother (in terms of puerperal sepsis and other infection-related severe maternal morbidity). Although it is feasible administer to antenatal corticosteroid, it might not be cost–effective if it has adverse impact on maternal infectious morbidity. The GDG acknowledged that while there might be some benefits for the newborn, there might also be harmto the mother. The decisionto recommend against the intervention was based on the lack of clear evidence on the benefits for the baby in clinical chorioamnionitis which could be outweighed potential by harm the to mother in the majority of the population that will use the guideline. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention

             DECISION Recommendation 1.4: Antenatal corticosteroid therapy 1.4: therapy Recommendation corticosteroid Antenatal FACTOR Quality of the evidence Values and preferences benefits of Balance versus disadvantages use Resource Recommendation direction ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

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Recommendation 1.4: Antenatal corticosteroid therapy is not recommended in women with chorioamnionitis who are likely to deliver preterm (continued). FACTOR DECISION EXPLANATION Overall  Strong The GDG reviewed the concern about risk of exacerbating maternal infection, particularly in low- and middle-income settings where strength of the recommendation baseline risks of maternal infectious morbidity is higher than those of settings where the current evidence was generated. The group recommendation acknowledged the variability in the balance between benefits and harms according to context and the variation in clinical practice, and  Conditional chose to make a conditional recommendation against the intervention. recommendation

+6 recommended in women undergoing planned caesarean section at late preterm gestations (34–36 is not EXPLANATION Current evidence comes from a single study without major methodological concerns apart from its non-blind design. However, indirectness was a major issue as the population studied (i.e. mothers undergoing elective caesarean section at term) differs from the population of interest. The quality of the evidence was graded as very low across all critical outcomes. Health-care providers, policy-makers, and pregnant women and their families in high-income settings might place a higher value on the potential cost saving of antenatal steroids in terms of reduction in neonatal (NICU) admission and therefore chose the intervention regardless of the lack of evidence on mortality outcomes; whereas those in low- and middle-income settings might put a higher value on the potential maternal harm related caesarean to section and lower value on modest reduction in NICU admission – which may not be available in such settings. As a result of variability in these values and preferences across settings, clinical practice and choice made women by and their families are likelyvary to across settings. There is insufficient evidence to conclude on the benefits or harms of usingantenatal corticosteroids in women undergoing elective caesarean section in late preterm. There may be some benefits with regardto reducing NICU admission for respiratory complications, although this was not supported the by comparable frequencies of respiratory complications reported in In the view review. of the lower risk of respiratory complications for babies born in late preterm, much larger sample sizes and longer follow-up would be needed examine to the potential differences regarding benefits or harms of antenatal corticosteroid. Given that overall the evidence on the effectiveness of antenatal corticosteroid suggests possible harmto preterm infants born after weeks,34 it is unclear whether the desirable consequences of administering corticosteroid outweigh the potential harm for the preterm infant born through elective caesarean section after 34 weeks. Although it is feasible administer to antenatal corticosteroid, it might not be cost–effective if it has little or no impact on serious adverse outcomes. newborn The GDG acknowledged that while there might be some benefits, there might also be harm. The decision was based on the potential for harm as suggested the by overall evidence on antenatal corticosteroid. The GDG made a conditional recommendation based on the very low quality of evidence, the variability in the values and preferences across settings, and the lack of clear benefits or harms. The group considered to this be a research priority, but choseto recommend against the practice until further evidence becomes available. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation 1.5: Antenatal corticosteroid therapy 1.5: therapy Recommendation corticosteroid Antenatal weeks). FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

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Recommendation 1.6: Antenatal corticosteroid therapy is recommended in women with hypertensive disorders in pregnancy who are at risk of imminent preterm birth. FACTOR DECISION EXPLANATION Quality of the  High The quality of evidence was rated as low for all maternal critical outcomes reported, but was rated as moderate to high for most mortality evidence and serious early newborn morbidities. Therefore, the overall quality of evidence was rated as moderate for newborn outcomes and low  Moderate (newborn) for maternal outcomes.  Low (mother)  Very low Values and  No significant Health-care providers, policy-makers, and pregnant women and their families in all settings are likely to place a high value on the survival preferences variability of a preterm baby born to a mother with a hypertensive disorder during pregnancy. The GDG is confident that there is little or no variation of this value among mothers, health-care providers and policy-makers in low-, middle- and high-income settings, particularly because  Significant variability hypertensive disorders pose further risk of morbidity and mortality for the preterm newborn. Balance of  Benefits outweigh Antenatal corticosteroid therapy in women with hypertension during pregnancy is associated with reduction in both neonatal mortality benefits versus disadvantages and serious short-term morbidities, without any evidence of harm to the mother or the baby. disadvantages  Benefits and Overall, the desirable consequences of administering antenatal corticosteroids to hypertensive mothers are substantial and highly valued. disadvantages are balanced  Disadvantages outweigh benefits Resource use  Less resource intensive Antenatal corticosteroids are relatively cheap, easy to administer, and readily available in at least one preparation in all settings. It is feasible to include antenatal corticosteroid therapy into existing structures and protocols for the management of women with hypertensive  More resource disorders and at imminent risk of preterm birth at minimal cost. intensive Recommendation  In favour of the The moderate-to-high confidence in the magnitude of effects of a relatively cheap intervention on highly valued critical newborn outcomes direction intervention favoured the intervention.  Against the intervention Overall  Strong The GDG placed its emphasis on the benefits to the preterm infants in terms of reducing mortality and serious early morbidities, the low strength of the recommendation cost and wide availability of corticosteroid globally, the feasibility of implementing the intervention and the potential impact on health- recommendation care resource use across settings, and therefore made a strong recommendation.  Conditional recommendation EXPLANATION The overall quality of evidence was rated very low for both newborn and maternal outcomes. Evidence was extracted from observational studies that had some design limitations. Health-care providers, policy-makers, and pregnant women and their families in all settings are likelyplace to a high value on the potential benefits of antenatal steroids on babies’ survival without handicap and less value on potential effect onphysical growth. The GDG is confident that mothers, health-care providers and policy-makers in any setting will invariably place a higher value on these benefits in the light of overall benefits of antenatal steroids for preterm population, and will choseto use the intervention. The potential benefitsterms in of reduced handicap among surviving intrauterine growth-restricted(IUGR) preterm infants at the age of two years, evidence of reduced likelihood of newborn mortality and morbidity outcomes outweigh the potential adverse effects on growth. physical Antenatal corticosteroids are relatively cheap, easy administer, to and readily available in at least one preparation in all settings. It is feasible include to antenatal corticosteroid therapy into existing protocols for the management of women at imminent risk of giving birth preterm a growth-restricted to fetus at minimal costs. In spite of the low confidence in the magnitude of effects, overall the balance is infavour of benefits. There is limited evidence on the use antenatal corticosteroids in growth-restricted fetuses. in light of the However, considerable beneficial effects of antenatal corticosteroids for preterm infantsoverall, coupled with lack of clearevidence of harm in growth-restricted fetuses, the GDG made a strong recommendation. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation 1.7: Antenatal corticosteroid therapy is recommended for women at risk of imminent preterm birth of a growth-restricted fetus. FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

73 74 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES

Recommendation 1.8: Antenatal corticosteroid therapy is recommended for women with pre-gestational and gestational diabetes who are at risk of imminent preterm birth, and this should be accompanied by interventions to optimize maternal blood glucose control. FACTOR DECISION EXPLANATION Quality of the  High Only indirect evidence was available. The quality of the evidence was graded as very low. evidence  Moderate  Low  Very low Values and  No significant Health-care providers, policy-makers, and pregnant women and their families in all settings are likely to place a high value on the survival preferences variability of preterm newborns who are at higher risk of respiratory morbidities from maternal diabetes. The panel is confident that there is little or no variation of this value among mothers, health-care providers and policy-makers in low-, middle- and high-income settings.  Significant variability Balance of  Benefits outweigh There is insufficient evidence to conclude on the benefits or harms of antenatal corticosteroid in pre-gestational or gestational diabetic benefits versus disadvantages women at risk of imminent preterm birth. However, in diabetic women, preterm birth and RDS are both more frequent than in the disadvantages general obstetric population. The need for antenatal corticosteroid therapy is thus likely to be greater in women with pre-gestational and  Benefits and gestational diabetes. While there is no evidence to clearly demonstrate the benefits of antenatal corticosteroid in this subgroup of women, disadvantages are available evidence suggests hyperglycaemic effect of corticosteroids in pregnant women. It is known that maternal hyperglycaemia balanced can adversely affect fetal lung maturity and therefore it is possible that any benefit of corticosteroids to the baby could be offset by  Disadvantages corticosteroid-induced hyperglycaemia, although there is no direct evidence. In particular, corticosteroid-induced hyperglycaemia may outweigh benefits be greater in insulin-treated women with gestational or type 2 diabetes, with the potential for abnormal glucose metabolism and risk of ketoacidosis if the insulin dose is not adjusted accordingly. Overall, the desirable consequences for preterm infants of women with gestational diabetes are substantial and highly valued. Resource use  Less resource intensive Antenatal corticosteroids are relatively cheap, easy to administer, and readily available in at least one preparation in all settings. Monitoring and maintaining normal blood glucose in mothers during antenatal corticosteroid administration will increase the demand on  More resource health resources. However, these added costs are outweighed by the cost savings for managing the respiratory morbidities and ensuring intensive survival among preterm babies of women with abnormal glucose metabolism. Recommendation  In favour of the The potential beneficial effects of a relatively cheap intervention on highly valued critical newborn outcomes favoured the intervention. direction intervention  Against the intervention Overall  Strong The GDG acknowledged the paucity of evidence on the benefits of antenatal corticosteroid in this subgroup of women. However, the strength of the recommendation group placed its emphasis on the overall benefits of antenatal steroid in preterm, the potential benefits in terms of reducing the higher risk recommendation of newborn respiratory morbidity posed by maternal diabetes, and potential impact on the overall newborn survival, and therefore made a  Conditional strong recommendation. recommendation EXPLANATION The quality of evidence was based on the comparison of any dose or regimen of dexamethasone and betamethasone. In spite of the total number of trials included, few of them reported on critical maternal and newborn outcomes. Overall, the quality of the evidence was rated as low. Health-care providers, policy-makers, and pregnant women and their families in all settings are likelyplace to a higher value on the overall clinical benefits of either drug well-testedas corticosteroidsterms (in of reduction preterm morbidity and mortality)over subtle pharmacological differences that might exist, and therefore choseto adhereto the recommendation. The GDG is confident that there is no variation of this value among mothers, health-care providers and policy-makers in middle- low-, and high-income settings. theFrom available evidence, it appears there are no major differences in the effectiveness and safety of dexamethasone and betamethasone, although dexamethasone may be slightly advantageous with regard all grades to of intraventricular haemorrhage (IVH) and duration of stay in NICU. There is insufficient evidence on tested dosing regimens to draw conclusions on their effectiveness and safety although one small trial suggested that 12-hour and 24-hour dosing regimens of betamethasone may be equally effective. Another small study suggested that IVH and neonatal sepsis may be reduced with IM as opposed oral to dexamethasone. There is a paucity of data assessto the long-term benefits or harms of the commonlytwo used antenatal corticosteroids. No proof of efficacy exists for any other steroids or regimen. Both steroid preparations are already available and used in one form or the other in all countries and implementing this recommendation is not expected increase to current health-care costs. as dexamethasone However, is cheaper than betamethasone, health systems switching from betamethasone dexamethasone to based on this recommendation are likelysave costs. to The lack of significant differences in clinical benefits of either preparation on highly valued critical newbornoutcomes favoured the use of intervention. either The GDG acknowledged the low quality of evidence on the comparative benefits of the two popular corticosteroid preparations with one it placedanother. However, its emphasis on the overall evidence of clinical benefits of antenatal corticosteroids(which was based on both preparations), the lack of safety concerns when one is compared with and the other, the potential impact of recommending either preparation on uptake of antenatal corticosteroids, and therefore made a strong recommendation. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation 1.9: Either intramuscular (IM) dexamethasone or IM betamethasone 24 (total mg in divided is doses) recommended as the antenatal corticosteroid of choice when preterm birth is imminent. FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

75 76 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES

Recommendation 1.10: A single repeat course of antenatal corticosteroid is recommended if preterm birth does not occur within 7 days after the initial dose, and a subsequent clinical assessment demonstrates that there is a high risk of preterm birth in the next 7 days. FACTOR DECISION EXPLANATION Quality of the  High The quality of evidence was rated as low to moderate for reported maternal critical outcomes, but was rated as moderate to high for evidence newborn critical outcomes (mortality and serious early and late newborn morbidities). Therefore, the overall quality of evidence was rated  Moderate (newborn) as moderate for newborn outcomes and low for maternal outcomes.  Low (mother)  Very low Values and  No significant Health-care providers, policy-makers, and pregnant women and their families in high-income settings might place a higher value on the preferences variability potential cost saving of antenatal corticosteroids in terms of further reduction in newborn RDS and surfactant use, and therefore chose the intervention regardless of the lack of further benefits on newborn mortality outcomes; whereas those in low- and middle-income settings  Significant variability might place a higher value on the concern about potential harm to the mother and lower value on reducing surfactant use – which is often not part of standard care in such settings. Balance of  Benefits outweigh There are short-term benefits for infants exposed to repeat course(s) of corticosteroids in terms of less respiratory distress (17% benefits versus disadvantages reduction) and surfactant use (22% reduction), and fewer serious morbidities (when considered as a composite) compared to infants disadvantages exposed to a single course. However, these apparent short-term benefits do not translate into a reduction in neonatal death. The downside  Benefits and of repeat course is a reduction in the weight at birth, which is independent of whether the interval before the repeat course is 7 or 14 days. disadvantages are While there seems to be no apparent long-term benefits, available data did not show any increase in harm during childhood. Although this balanced evidence supports the concern about restriction of growth of the preterm infants with repeat corticosteroid from animal studies, it neither  Disadvantages confirms nor refutes the concern regarding brain developmental delay and behavioural abnormalities. For women with preterm prelabour outweigh benefits rupture of membranes, there may be no added benefits, but the risk of intrapartum infection may be increased with repeat courses of corticosteroids. Overall, the desirable consequences of a repeat course of corticosteroid for the newborn outweigh the undesirable effect on newborn birth weight or concern about childhood development. However, antenatal exposure to four or more repeat courses may likely nullify these benefits as the undesirable effects become more frequent and clinically significant. Resource use  Less resource intensive Additional course of steroid for women who are likely to give birth preterm is likely to increase human resource needs and supply costs. However, this interventions is likely to be cost–effective in settings where standard neonatal support attracts significant health-care costs  More resource (e.g. for surfactant or other interventions relating to RDS in the newborn). intensive Recommendation  In favour of the The overall balance of desirable versus undesirable effects is in favour of a single repeat course of antenatal corticosteroids. direction intervention  Against the intervention Overall  Strong The GDG placed its emphasis on further reduction in the respiratory morbidity and less surfactant use (which could save costs) and lower strength of the recommendation value on the concern about reduction in neonatal birth weight, and therefore recommended the intervention. As there are likely to be recommendation significant variations in these values across countries and health-system settings, the group lowered the strength of the recommendation  Conditional and made it conditional. recommendation recommended for women at risk of imminent preterm birth for the purpose of are not EXPLANATION There were design limitations and insufficient data on critical maternal and neonatal outcomes for of many the studies comparing first-line tocolytic or maintenance therapy with placebo. Health-care providers, policy-makers and pregnant women and their families in high-income settings are likelyplace to a higher value on the potential harms (maternal adverse effects) that are associated tocolyticwith therapy; and less value on the benefit of short delay in preterm birth which does not improve neonatal outcomes and therefore chose adhere to the to recommendation in most women; whereas those in low- and middle-income settings are likelyplace to a higher value on the potential benefits of delaying birthto complete corticosteroids and in-utero fetal transfer and thus chose not adhere to the to recommendation in most women. There is no convincing evidence that first-linetocolysis improve substantive perinatal outcomes as there is no clear reduction in perinatal death or neonatal morbidities associated with preterm birth RDS (e.g. and Compared IVH). with no tocolytic treatment, betamimetics and calcium-channel blockers appear beneficial in delaying birth for more than 48 hours, whereas for othertocolytics, theevidence on pregnancy prolongation is inconclusive. Most tocolytics are associated with side-effects that are often dependent on their class and mechanism of action. These side-effects veryare frequent, more disturbing and importanthave medical implications particularly with betamimetics, but are also considerable for calcium-channel blockers, oxytocin-receptor antagonists and nitric-oxide donors. There are no data assess to long-term benefits or harmstocolytic of therapy compared with tocolyticno therapy. Similarly, there is no consistent evidence that any tocolytic maintenance therapy prolonged pregnancy duration or had any positive effect on maternal and infant outcomes. Some maintenance therapies were associated with considerable side-effects. Overall, the undesirable consequences (maternal side-effects and life-threatening adverse reactions, inconvenience of administrationto outweighthe mother) the benefit of short prolongation of thetime of birth for the newborn. The implementation of this recommendation issave likely health-care to costs. The decision recommend to against the intervention was based on the lack of substantive benefitsterms in of neonatal critical outcomes; the benefits are outweighedby potential harmto the mother. The GDG considered the quality of the evidence and the variability in values and preferences of mothers, health-care providers and policy- makers across different settings, and choseto a make conditional recommendation. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation 2.0: Tocolytic treatments (acute and maintenance treatments) treatments) maintenance and (acute treatments 2.0: Tocolytic Recommendation outcomes. neonatal improving FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

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Recommendation 3.0: The use of magnesium sulfate is recommended for women at risk of imminent preterm birth before 32 weeks of gestation for prevention of cerebral palsy in the infant and child. FACTOR DECISION EXPLANATION Quality of the  High The quality of the evidence was moderate to high for critical outcomes relating to infant mortality and serious morbidity and maternal evidence outcomes. Overall, the quality of evidence was rated as moderate.  Moderate  Low  Very low Values and  No significant Health-care providers, policy-makers, and pregnant women and their families in all settings are likely to place a high value on the survival preferences variability of a preterm newborn without cerebral palsy. The panel is confident that there is little or no variation of this value among mothers, health- care providers and policy-makers in low-, middle- and high-income settings.  Significant variability Balance of  Benefits outweigh Magnesium sulfate was associated with reductions in cerebral palsy and gross motor dysfunction. Magnesium sulfate increased the risk of benefits versus disadvantages minor maternal adverse effects, including hypotension and tachycardia, and in some cases adverse effects led to cessation of treatment. disadvantages None of the potential harms (including death and serious morbidity) for the fetus, infant or child were increased with antenatal exposure  Benefits and to magnesium sulfate. The neuroprotective benefit of magnesium sulfate was demonstrated in infants up to 33 weeks and 6 days, but disadvantages are the available evidence regarding fetuses less than 30 weeks is less clear. Considering the fact that the risk of neurodevelopmental delay balanced is inversely proportional to the gestational age at birth, it is likely that fetuses less than 30 weeks also benefit. Although the evidence  Disadvantages regarding benefits is less clear in the subgroup of women carrying a multiple pregnancy, it is likely that magnesium sulfate would have outweigh benefits similar neuroprotective effects in infants resulting from multiple pregnancies as in those of singletons, given the point and direction of the effect estimate. Overall, the desirable consequences for preterm infants whose mothers receive magnesium sulfate at gestation of less than 32 weeks are substantial. These benefits outweigh the potential risk of maternal adverse effects. Beyond 32 weeks, the undesirable consequences for the mother are likely to outweigh the potential benefits. Resource use  Less resource intensive Implementation of this recommendation is likely to increase costs where it is not currently in practice. However, the application of the intervention is likely to be cost–effective.  More resource intensive Recommendation  In favour of the The moderate-to-high confidence in the magnitude of effects on highly valued critical newborn outcomes favoured the intervention. direction intervention  Against the intervention Overall  Strong The GDG placed its emphasis on the long-term benefits to the preterm infants in terms of reducing gross motor dysfunction and cerebral strength of the recommendation palsy, the feasibility of implementing the intervention where it is already being used for other maternal indications (e.g. pre-eclampsia), recommendation and the potential long-term impact on resource use across settings, and therefore made a strong recommendation.  Conditional recommendation recommended for women in preterm labour with intact amniotic membranes and no clinical signs of is not EXPLANATION The overall quality of the evidence was graded as moderate for newborn and maternal outcomes. Health-care providers, policy-makers, and pregnant women and their families in all settings are likelyplace to a high value on preterm infant survival without long-term morbidity and less value on clinical benefitsterms in of reduction in maternal infection. The panel is confident that there is no variation of this value among mothers, health-care providers and policy-makers in any setting. Compared with placebo or no treatment, prophylactic antibiotics did not appear have a significant to impact on most of the critical outcomes examined in including the review, severe infant morbidity. Antibiotic prophylaxis appears reduce to maternal infection; however, it may be associated with an increase in neonatal death, and poorer long-term outcomes in children. Although the observed differences between groups were not statistically significant for cerebral palsy or any functional impairment years,at 7 there was a trendtowards increased risk in children whose mothers had received antibiotics. Overall, the undesirable consequences for preterm infants considerably mother. the for consequences desirable the outweigh Implementation of this recommendation is likelyreduce to costs where routine antibiotic prophylaxis is currently the norm. intervention. the against is outcomes newborn critical valued highly on effects of magnitude the in confidence moderate-to-high The The GDG placed its emphasis on the considerable short- and long-term harm this intervention could cause the to preterm infant, and the need curb to the widespread use of routine antibiotic prophylaxis globally, and therefore made a strong recommendation. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation 4.0: Routine antibiotic administration administration antibiotic 4.0: Routine Recommendation infection. FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

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Recommendation 5.0: Antibiotic administration is recommended for women with preterm prelabour rupture of membranes. FACTOR DECISION EXPLANATION Quality of the  High The overall quality of the evidence for the main comparison was graded as moderate for newborn and maternal outcomes. evidence  Moderate  Low  Very low Values and  No significant Health-care providers, policy-makers, and pregnant women and their families in all settings are likely to place a high value on the benefits preferences variability in short-term outcomes for the mother and infant (reduction in maternal and neonatal infection). The GDG is confident that there is no variation of this value among mothers, health-care providers and policy-makers in any setting.  Significant variability Balance of  Benefits outweigh Compared with placebo, antibiotics for preterm prelabour rupture of membranes (PPROM) reduced the risk of women giving birth within benefits versus disadvantages 48 hours and 7 days, and reduced the risk of chorioamnionitis in the mother. Antibiotics also reduced the risk of neonatal infections disadvantages including pneumonia, and cerebral abnormality, and were associated with a shorter stay in NICU. On the other hand, antibiotics did not  Benefits and appear to have an impact on other infant mortality or severe morbidity or on longer-term outcomes. Overall, there are desirable short- disadvantages are term benefits for the mother and preterm infants without evidence of harms in the short or long term. balanced  Disadvantages outweigh benefits Resource use  Less resource intensive Antibiotics are widely available in oral and parenteral forms in all settings. It is feasible to include prophylactic antibiotic therapy into existing health structures that are designed to manage women at risk of imminent preterm birth with minimal costs.  More resource intensive Recommendation  In favour of the The moderate confidence in the magnitude of effects on highly valued critical maternal and newborn outcomes is in favour of the direction intervention intervention.  Against the intervention Overall  Strong The GDG placed its emphasis on the short-term benefits to the mother and preterm infants in terms of reducing infection without strength of the recommendation evidence of harm, the moderate quality of evidence, an even stronger argument for antibiotic use in low-income settings, and wide recommendation availability of the recommended antibiotics globally, and therefore made a strong recommendation.  Conditional recommendation EXPLANATION The overall quality of the evidence was graded as moderate. Health-care providers, policy-makers, and pregnant women and their families in different settings may choose different types of antibiotics based on costs, availability and many other considerations. The desirable consequences for preterm infants whose mothers receive erythromycin for PPROM are substantial without increased risk of harm as (such necrotizing enterocolitis) and highly valued. It is feasible include to erythromycin treatment into existing protocols but at extra costs the to health systems. The moderate confidence in the magnitude of protective effects on highly valuednewborn outcomes (necrotizing enterocolitis) is infavour of the intervention. The GDG considered the variability in values and preferences of mothers, health-care providers and policy-makers across different recommendation. conditional a make to chose and settings High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation 5.1: Erythromycin is recommended as the antibiotic of choice for prophylaxis in women with preterm prelabour rupture of membranes. FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

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Recommendation 5.2: The use of a combination of amoxicillin and clavulanic acid (“co-amoxiclav”) is not recommended for women with preterm prelabour rupture of membranes. FACTOR DECISION EXPLANATION Quality of the  High The overall quality of the evidence was graded as moderate. evidence  Moderate  Low  Very low Values and  No significant Health-care providers, policy-makers, and pregnant women and their families in all settings are likely to place a high value on the risk preferences variability of harms to the preterm infant (increased risk of necrotizing enterocolitis). The GDG is confident that there is no variation of this value among mothers, health-care providers and policy-makers in any setting.  Significant variability Balance of  Benefits outweigh Broad-spectrum penicillins (excluding co-amoxiclav) are beneficial in reducing neonatal infection (including pneumonia) and major benefits versus disadvantages cerebral abnormality detected on ultrasound before discharge. There is a high risk of necrotizing enterocolitis in infants whose mothers disadvantages received co-amoxiclav compared with either placebo or erythromycin. The undesirable consequences associated with co-amoxiclav  Benefits and outweigh its benefits as an antibiotic for PPROM. disadvantages are balanced  Disadvantages outweigh benefits Resource use  Less resource intensive It is feasible to exclude co-amoxiclav from the choice of antibiotics for PPROM since other suitable and less harmful options exist. Other penicillins (excluding co-amoxiclav) are readily available and could be easily incorporated into existing protocols for management of  More resource women at risk of imminent preterm birth at minimal costs. intensive Recommendation  In favour of the The moderate confidence in the magnitude of effects on highly valued critical newborn outcomes is against the use of the intervention. direction intervention  Against the intervention Overall  Strong The GDG placed its emphasis on the very high risk of necrotizing enterocolitis among infants of mothers treated with co-amoxiclav, when strength of the recommendation compared with placebo or erythromycin, the moderate confidence in the effect size, and global availability of other antibiotics that are recommendation effective without harm, and therefore made a strong recommendation.  Conditional recommendation recommended, regardless of cephalic or is not EXPLANATION The overall quality of evidence was rated as very low for maternal and newborn critical outcomes mainly because of the small sample sizes of the studies in the review. Health-care providers, policy-makers, pregnant women and their families in different settings are to likely prefer different mode of birth for preterm infants as this choice is likelybe to influencedby health system, social and cultural considerations. With the uncertainty of benefitsto the preterm infants, pregnantwomen and their families in low- and middle-income settings are to likely prefer vaginal birthover caesarean section. Pregnant women in settings where there are fewer cultural restrictions caesarean to birth and good perinatal outcomes for preterm infants may prefer caesarean section over vaginal birth. Women with breech presentation and planned vaginal birth were less likelyexperience to major postpartum complications, puerperal pyrexia and other maternal infections. For other critical outcomes, including neonatal mortality and serious neonatal morbidity, there was insufficient evidence to assess the harms and benefits of planned caesarean versus vaginal birth for preterm infants. The small sample sizes in the studies meant that they generally lacked statistical power detect to clinically important differences. Overall, there is insufficient evidence assess to the harms and benefits of planned caesareanversus vaginal birth for preterm infants. there are However, known undesirable consequences associated with caesarean birth for the mother irrespective of gestational age at birth. A policy of routine caesarean birth rather than vaginal birth for all preterm infants will significantly increase health-care costs, not justto perform the intervention but also manage to potential maternal morbidities. Additionally, it will further contribute the to rising global rates section. caesarean of The overall balance of desirable versus undesirable effects is against a policy routineof caesarean birth for all preterm infants. The GDG considered the very low confidence in the qualityevidence of and the variations in values and preferences relatingto the interventions across settings, and therefore chose make a conditional to recommendation. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation 6.0: Routine delivery caesarean by section for the purpose of improving preterm newborn outcomes presentation. breech FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

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Recommendation 7.0: Kangaroo mother care is recommended for the routine care of newborns weighing 2000 g or less at birth, and should be initiated in health-care facilities as soon as the newborns are clinically stable. FACTOR DECISION EXPLANATION Quality of the  High The quality of evidence for most of the critical outcomes, including that for mortality, neonatal infections and hypothermia, was high. evidence However, the GDG decided to rate the overall quality of evidence as moderate because the quality of evidence was moderate for  Moderate hyperthermia and re-admission to hospital.  Low  Very low Values and  No significant Kangaroo mother care (KMC) provides a very simple-to-implement method for care of low-birth-weight babies. Mothers can be taught to preferences variability practise at facilities and even continue at home upon discharge. The benefits of KMC go beyond just mortality and morbidity and include improved breastfeeding practices and bonding between mother and baby. These are desired values with known health and social benefits  Significant variability for families, communities as a whole, health-service providers and policy-makers. Balance of  Benefits outweigh There was conclusive evidence that, compared to conventional care, KMC reduces mortality, prevents severe infections and nosocomial benefits versus disadvantages infections, and reduces the risk of hypothermia; there was some evidence, though inconclusive, of a reduced risk of hyperthermia. No clear disadvantages harms have been demonstrated with KMC compared to conventional care.  Benefits and disadvantages are balanced  Disadvantages outweigh benefits Resource use  Less resource intensive Apart from initial set-up costs, the cost of the maintaining implementation of KMC could be low in terms of finance but may require some amount of health workers’ time to educate mothers to initiate KMC and maintain the practice.  More resource intensive Recommendation  In favour of the The moderate-to-high confidence in the magnitude of effects of a relatively cheap intervention on highly valued critical newborn outcomes direction intervention favoured the intervention.  Against the intervention Overall  Strong The GDG made a strong recommendation considering the moderate- to high-quality evidence, the benefits outweighing the risks, the lack strength of the recommendation of variability in the values and preferences which were all in favour of the intervention, the low cost, the feasibility of implementing the recommendation intervention and the potential impact on health-care resource use across all settings.  Weak recommendation EXPLANATION The quality of evidence for most of the critical outcomes, including that for mortality, neonatal infections and hypothermia, was high. the GDGHowever, decided rate the to overall quality of evidence as moderate, because the quality of evidence was moderate for hyperthermia and re-admission hospital. to Providing KMC for low-birth-weight and preterm newborns is crucial for . When KMC is practised continuously, the newborn maintains a uniform body temperature, which reduces stress and promotes growth and survival. require however, the It may, carry to mother/carer the baby for all activities. If initiated within facilities, where mothers/carers do not engage in any activity except caring of their the inconvenience baby, may be minimal. Knowing that their baby needs their thermal support for survival and the feeling of being involved in the care of the baby continually may be of value mothers/carers. to The benefits of increased survival will be valuedby health-service providers and policy-makers. The evidence from the review suggests that providing continuous KMC has benefits in reducing mortality and morbidity for the preterm newborn. There was no evidence of harmful effects of continuous KMC practice. The cost of providing continuous KMC depends on the human resources of the facility invested in the care. That said, it is a relatively cheap intervention and may not cost more than practising intermittent KMC. In the with latter, interspersed use of incubators and radiant warmers, stafftime and resource use may be much more. The confidence in the positive of effects of the continuous (with no added KMC costs to the health systems between continuous or intermittent KMC practice, but the potential for less morbidity which will reduce facility resource on use) highly critical newborn intervention. the favoured outcomes The GDG emphasized the moderate- high-quality to evidence, the benefits outweighing the risks, the lack of variability in the values and preferences which were all in favour of the intervention, the fact that there will be no additional costs in implementing continuous compared intermittent to KMC, the feasibility of implementing the intervention and the potential impact on health-care resource use across settings, and therefore made a strong recommendation. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Weak recommendation

               DECISION Recommendation Newborns weighing 2000 g 7.1: or less at birth should be provided as close to continuous Kangaroo mother care as possible. FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

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Recommendation 7.2: Intermittent Kangaroo mother care, rather than conventional care, is recommended for newborns weighing 2000 g or less at birth, if continuous Kangaroo mother care is not possible. FACTOR DECISION EXPLANATION Quality of the  High The quality of evidence was moderate for neonatal mortality and hyperthermia, but high for all other critical outcomes. The GDG rated evidence the overall quality of evidence as moderate because of imprecision around the mortality effect estimates.  Moderate  Low  Very low Values and  No significant variability Providing KMC for low-birth-weight and preterm newborns is crucial for thermoregulation. The benefits and absence of harm with preferences intermittent KMC will be particularly valued by mothers/carers since it will enable them to carry out many of their routine activities.  Significant variability If initiated within facilities, where mothers/carers do not engage in any activity except caring of their baby, the inconvenience may be minimal. It also maintains the satisfaction these mothers/carers will derive from knowing that they are being directly involved in the care of their baby. These benefits will be valued by the mothers/carers, health-care providers and policy-makers. Balance of  Benefits outweigh While the evidence suggests some benefits of intermittent KMC practice with respect to morbidity reduction, the overall evidence was benefits versus disadvantages inconclusive for mortality benefits. There was, however, no clear evidence of harm. disadvantages  Benefits and disadvantages are balanced  Disadvantages outweigh benefits Resource use  Less resource intensive The cost of providing intermittent KMC depends on the human resources of the facility invested in the care. That said, it is a relatively cheap intervention. However, if intermittent KMC is interspersed with the use of incubators and radiant warmers, staff time and facility  More resource intensive resource use may be relatively more. Recommendation  In favour of the The GDG considered that there was enough confidence in the positive of effects of the intermittent KMC (with relatively low costs to direction intervention the health systems and potential for increased compliance and less morbidity, which will reduce facility human resource use) on highly critical newborn outcomes and therefore favoured the intervention.  Against the intervention Overall  Strong recommendation The GDG made a strong recommendation, based on the moderate- to high-quality evidence suggesting that the benefits to the preterm strength of the newborn in terms of reducing morbidity and mortality outcomes outweighs the risks. The group also considered the low cost and recommendation  Weak recommendation feasibility of implementing the intervention, as well as the lack of suitable alternatives, across many low- and middle-income settings. EXPLANATION The evidence was from only one study conducted in a high-income setting and the mortality effect estimateswere imprecise. The overall quality of evidence was rated very low. Given the very low quality of evidence and, more importantly, the paucity of data on the relative benefits and harms in sick preterm neonates, health-care providers and policy-makers from both high-income countries (HICs) and low- and middle-income countries (LMICs) are likelyconsider to the relatively cheaper costs of radiant warmers incubators) (compared to as well as the relative safety in terms of water loss with the incubators. It is very difficult to determine what their choice would be between incubators and radiant warmers and either may be valued on the basis of other factors. The GDG thought incubators are neither superior nor inferior radiant to warmers for the provision of routine thermal care for stable preterm neonates weighing < 2000 g and both will be of value. There was very low-quality evidence suggesting no difference in morbidity and mortality between nursing under radiant warmers or in incubators for these unstable preterm newborns. The risk of insensible water losses increased with the use of radiant warmers compared incubators. to The generalizability of the effectsvery is the(a) all included low as studieswere from HIC settings, and(b) all the studies had enrolled relatively stable preterm infants who were on enteral feeds and gaining weight, and excluded sick infants with respiratory distress. Only one study included infants from day of birth. Incubators are more expensive than radiant warmers. They may not be easily available and may be difficult to maintain in many resource-restricted settings where reliable power supply and adequate human resources check to the proper functioning may be serious challenges. The GDG considered the paucity of evidence, the urgency in attending the to health of unstable preterm babies and recommended the thermo-neutral environment and thought both radiant warmers and incubators could be used provide to such an environment. Based on the benefitsto sick or unstable preterm newborns,even though the quality of theevidence wasvery the low, GDG made a strong recommendation. The group considered that the benefits outweigh the risks and the intervention will be valued in all settings because KMC cannot be practised for these babies. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against intervention the recommendation Strong recommendation Weak

               DECISION Recommendation Unstable 7.3: newborns weighing 2000 g or less at birth, or stable newborns weighing less than 2000 g who cannot be given Kangaroo mother care, should be cared for in a thermo-neutral environment either under radiant warmers or in incubators. FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

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Recommendation 7.4: There is insufficient evidence on the effectiveness of plastic bags/wraps in providing thermal care for preterm newborns immediately after birth. However, during stabilization and transfer of preterm newborns to specialized neonatal care wards, wrapping in plastic bags/wraps may be considered as an alternative to prevent hypothermia. FACTOR DECISION EXPLANATION Quality of the  High The evidence was derived from component studies that had methodological biases, with inconsistent and imprecise effect estimates or evidence were conducted in high-income settings; hence the GDG graded the overall evidence quality as low.  Moderate  Low  Very low Values and  No significant Health-care providers and policy-makers in developing-country settings are likely to accept the intervention or value the benefits on preferences variability hypothermia reduction because it is cheap and easy to apply. Other forms of thermal care such as incubators are not affordable or readily available in these settings and, even where they are, unreliable power supply and poor maintenance as well as difficulty in ensuring  Significant variability aseptic conditions makes these less pragmatic. No study reported a comparison with KMC, but plastic wraps could have competed as another cheap alternative for thermal care. However, with preterm babies already having relatively higher mortality rates, it will be difficult to manage perceptions of mothers/carers and community members that babies placed in these plastic bags are being considered as moribund. This will impact on the acceptability of the intervention. Balance of  Benefits outweigh There was a significant reduction in the risk of hypothermia for preterm babies, irrespective of the gestational age, who were wrapped benefits versus disadvantages in plastic bags compared with controls. No conclusive evidence of mortality reduction was shown, as most of the trials that assessed disadvantages the outcome lacked sufficient power to show statistical significance; however, the effect was in the direction of mortality reduction. The  Benefits and only reported adverse outcome with the intervention was hyperthermia, but this was resolved when the wrap was taken off. There was, disadvantages are however, a non-significant increase in the risk of necrotizing enterocolitis. balanced  Disadvantages outweigh benefits Resource use  Less resource The intervention is low cost, and would be easily accessible and feasible to implement in all settings, including low- and middle-income intensive settings.  More resource intensive Recommendation  In favour of the The GDG considered the paucity of evidence and decided against the intervention. There was a conditional recommendation specific for direction intervention facility settings where specialized neonatal care can be provided.  Against the intervention Overall  Strong The GDG could not make a recommendation for the routine use of the plastic bags/wraps. It did, however, make a conditional strength of the recommendation recommendation for the use of the plastic bags and wraps within hospitals to prevent hypothermia in situations where KMC cannot be recommendation applied.  Conditional recommendation EXPLANATION The GDG rated the quality of evidence as low because of methodological biases and imprecise effect estimates in the component studies. The studies were also conducted mainly in high-income settings. In spite of the low-quality evidence, the reduction in mortality with the use of continuous positive is likelybe to airway pressure (CPAP) valued health-care by providers and policy-makers. may be more CPAP expensive than oxygen therapy, but the cost would be justifiable policy-makers.to It presents a potential life-saving intervention and will be preferred oxygen to therapy or might be used and augmented with oxygen therapy. There was low-quality evidence of reduction in in-hospital mortality as well as the need for mechanical ventilation. There was also inconclusive evidence of a possible reduction in the need for surfactant the intervention therapy. However, increased the risk of pneumothorax and air leaks, as well as a possible increase in the risk of bronchopulmonary dysplasia for which (BPD) the evidence was inconclusive. The treatment will require with CPAP more resources – human and material as well as time – than just oxygen face by mask or nasal prongs. The GDG recommendation was in favour of the use of the intervention. This was informed its by potential save many to lives in spite of the costs. The GDG acknowledged the low quality of evidence for this recommendation, but considered that the potential for the intervention to improve newborn outcomes was substantial and outweighs the risks. The group felt that though the costs may be high, the intervention will be highly valued in settings where it can be implemented, and were unanimous in making a strong recommendation. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Weak recommendation

               DECISION Recommendation 8.0: Continuous positive airway pressure therapy is recommended for the treatment of preterm newborns with respiratory distress syndrome. FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

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Recommendation 8.1: Continuous positive airway pressure therapy for newborns with respiratory distress syndrome should be started as soon as the diagnosis is made. FACTOR DECISION EXPLANATION Quality of the  High The GDG rated the overall quality of evidence as very low because there were only few trials conducted in high-income settings which had evidence methodological biases and their effect estimates were imprecise.  Moderate  Low  Very low Values and  No significant Policy-makers and health-care providers will likely place value on the effects of early initiation of CPAP on severe morbidity even if there preferences variability was inconclusive evidence of a benefit on mortality because of the paucity of data.  Significant variability Balance of  Benefits outweigh There was no conclusive evidence for mortality effects in early versus delayed initiation of CPAP because of lack of sufficient data. There benefits versus disadvantages was a significant benefit with early therapy in that it showed a lower risk of respiratory failure requiring mechanical ventilation, the need for disadvantages surfactant therapy and a lower risk of sepsis. These effects could be linked to later mortality benefits. There was no evidence of harm with  Benefits and early initiation of CPAP. disadvantages are balanced  Disadvantages outweigh benefits Resource use  Less resource Treatment with CPAP will require more resources – human and material as well as time – than just oxygen by face mask or nasal prongs, but intensive starting early or late does not change the material input; rather the evidence of reduced morbidity will mean less facility resources in the long term.  More resource intensive Recommendation  In favour of the The GDG recommendation was in favour of the use of early rather than delayed CPAP. This was informed by its potential to save many lives. direction intervention  Against the intervention Overall  Strong In spite of the very low quality of evidence, the GDG considered the potential for the intervention to improve newborn outcomes strength of the recommendation and the fact that, if CPAP can be administered, there will be no additional cost in starting it early or late and therefore made a strong recommendation recommendation.  Weak recommendation EXPLANATION The GDG rated the overall quality of evidence as moderate. The evidence quality was moderate for the mortality outcomes, but low for morbidity outcomes. The trials either were conducted mainly in high-income settings or had imprecise effect estimates. Health-care providers and policy-makers will place value on the significant one third reduction in the risk of mortality from the animal- derived surfactants. Since preterm birth is one the most important contributors neonatal to mortality and RDS is a significant contributor this,to this significant effect is especially noteworthy. In many LMICs, the scale of preference and other resource implicationsmay make the surfactant a lower priority. Synthetic surfactants are not commercially available and there are differences in the quality of those available. While new research will be identifying more refined synthetic ones, the benefits of the animal-derived onesoverall will make them a preferred option in settings where they can be used. There was conclusive evidence of reduced mortality in preterm babies with RDS who are given surfactant replacement therapy (SRT) whether with synthetic or animal-source surfactants. The emphasis of the balance of benefitsversus harms was placed on the animal- derived surfactants because of the non-availability of the synthetic products used There in this review. was also evidence of reduction in the incidence of air leaks with SRT compared the evidence However, with no was SRT. inconclusive on the beneficial effects of the animal- derived surfactants on severe morbidities such as IVH, BPD and sepsis. That said, there was no clear evidence of harm the to preterm even though there were suggestions of a possible increase in the risk of pulmonary haemorrhage. The cost of surfactants is relatively high, especially the synthetic ones. The GDG noted that In HIC settings, surfactant treatment may reduce overall hospital costs, but this might not be the case in LMICs. The GDG recommendation was in favour whether of the use of SRT, animal derived or synthetic, since the intervention has the potential of outcomes. newborn improving The GDG considered the potential for the intervention improve to newborn outcomes, and the value that health-care providers and policy- makers will place on its use, make recommendation to conditional on the availability of the right environment and resources (human and implementation. for other) High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation Surfactant 9.0: replacement therapy is recommended for intubated and ventilated newborns with respiratory distress syndrome. FACTOR Quality of the evidence and Values preferences benefits of Balance versus disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

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Recommendation 9.1: Either animal-derived or protein-containing synthetic surfactants can be used for surfactant replacement therapy in ventilated preterm newborns with respiratory distress syndrome. FACTOR DECISION EXPLANATION Quality of the  High The GDG rated the overall quality of evidence as moderate because all the evidence was derived from trials conducted solely in HICs. evidence  Moderate  Low  Very low Values and  No significant The results of the review indicate no value in using synthetic surfactants over animal-derived ones in preterm newborns with RDS. The evidence for the newer-generation protein-containing synthetic surfactants was very scanty and the fact that there are already preferences variability suggestions of protection from severe morbidities like NEC is promising, but the higher costs of these newer-generation surfactants would  Significant variability not make them preferable to natural ones at this time. Balance of benefits  Benefits outweigh There was insufficient evidence of mortality benefits for preterm babies treated with synthetic surfactants compared with those treated with animal-derived ones even though the very low-quality evidence suggested possible mortality benefits from the protein-containing versus disadvantages surfactants compared to animal-derived ones. However, protein-containing synthetic surfactants are not available in many countries. disadvantages  Benefits and There was also evidence that the protein-containing surfactants offered some protection against the incidence of necrotizing enterocolitis disadvantages are in preterm infants. Determinations of differences in the effects of the synthetic surfactants compared to the natural ones on other balanced morbidities were inconclusive.  Disadvantages outweigh benefits Resource use  Less resource intensive The cost of surfactants is relatively high, especially the synthetic ones.  More resource intensive Recommendation  In favour of the The GDG recommendation was in favour of the use of either animal-derived or synthetic surfactants since the intervention has the direction intervention potential of improving newborn outcomes.  Against the intervention Overall  Strong The GDG considered the potential for the intervention to improve newborn outcomes and placed emphasis on the basic requirements in strength of the recommendation any setting that will enable the use of SRT. The group thought the recommendation should be conditional and should only be implemented recommendation in health-care facilities where intubation, ventilator care, blood gas analysis, newborn nursing care and monitoring are available.  Conditional recommendation is not EXPLANATION The GDG considered there were methodological biases in the studies and many were conducted in HICs, and therefore rated the overall quality of evidence as low. In settings can where be CPAP routinely administered preterm to newborns for stabilization, the evidence suggests that there will be no value in routine prophylaxis with surfactants. cannot Where CPAP be given, there will be value in routinely administering prophylactic surfactants preterm to babies even before the onset of RDS, but considerations of the costs, the resource requirement and the invasiveness of the procedure compared will guide CPAP provider to preferences and hence policy. The evidence for mortality reduction with routine prophylactic surfactant administration compared rescue to therapy was inconclusive. In settings was where used stabilize CPAP to the infant within the control group and rescue surfactant therapy was given, the evidence showed that routine prophylactic surfactant had no effect on mortality or morbidity. There was also inconclusiveevidence of possible increased harm with respect increased to risks of BPD and pulmonary haemorrhage in the intervention was group given the to if CPAP controls. In settings where prophylactic surfactant administration was compared directly some with rescue evidence therapy with no CPAP, of mortality reduction as well as reduction in air leaks was found. The cost of surfactants is relatively high, especially the synthetic ones, and may require additional human resources for administration. The GDG considered the risks, costs and resource investment in SRT and recommended against its prophylactic use, especially since it has no added benefits(a relatively cheaper when CPAP option) can be administered. recommendation the thought and considerations, resource the and intervention the from harm for potential the considered GDG The against prophylactic use should be strong. High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation 9.2: Administration of surfactant before the onset of respiratory distress syndrome (prophylactic administration) in preterm newborns recommended. FACTOR Quality of the evidence and Values preferences benefits of Balance versus disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

93 94 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES

Recommendation 9.3: In intubated preterm newborns with respiratory distress syndrome, surfactant should be administered early (within the first 2 hours after birth) rather than waiting for the symptoms to worsen before giving rescue therapy. FACTOR DECISION EXPLANATION Quality of the  High There was a lack of studies from LMICs and the included studies had methodological limitations. The GDG rated the overall quality of evidence as low. Evidence  Moderate  Low  Very low Values and  No significant The evidence seems to suggest that for preterm neonates with established RDS and with no CPAP, there will be no value in withholding surfactant therapy within the first 2–3 hours after birth only to give it when the symptoms worsen. Mortality impact is seen when the preferences variability surfactant is administered early, irrespective of the type of surfactant used. With the reduced risk of air leaks and BPD, early intervention  Significant variability will be preferred by many providers. Balance of benefits  Benefits outweigh The evidence from this review suggests mortality benefits for preterm babies with RDS when they are intubated and surfactant administration is commenced early (within 2–3 hours after birth). There was also conclusive evidence of beneficial effects on morbidities versus disadvantages such as BPD and air leaks. The evidence was, however, inconclusive for the reduction in the risk of IVH or sepsis, although for the latter disadvantages  Benefits and there was some very low-quality and inconclusive evidence of a possible increase in the risk. No conclusive evidence of harm with early disadvantages are surfactant administration compared to delayed therapy for worsening RDS was demonstrated. balanced  Disadvantages outweigh benefits Resource use  Less resource The cost of surfactants is relatively high, especially the synthetic ones, but there will be no extra costs in administration of the surfactant intensive whether it is given early or late.  More resource intensive Recommendation  In favour of the The GDG agreed that, under the right conditions, the benefits of early therapy would favour its choice over late rescue therapy. direction intervention  Against the intervention Overall  Strong The GDG placed its emphasis on the added benefits of early SRT within 2 hours of onset of RDS and therefore made a strong strength of the recommendation recommendation. recommendation  Conditional recommendation EXPLANATION There was a paucity of evidence from trials specifically addressing this question. Effect estimates could not be directly assessed or were imprecise, and the trials were all conducted in HICs. The GDG rated the overall quality of evidence as very low. Notwithstanding the very low quality of the evidence, the mortality benefit observed with using oxygenlower concentration during resuscitation isbe likely to valued health-care by providers as well as policy-makers. although Moreover, not able demonstrate to significant differences, the known effect of higher concentrations of oxygen on criticaloutcomes such asretinopathy of prematurity and the ease of use of air or lower concentrations of oxygen for resuscitation will be preferred both by providers and policy-makers. There is very low-quality evidence that initiating resuscitation with lower oxygen would concentration reduce the mortality (< 50%) in preterm neonates requiring positive pressure ventilation at birth, when compared initiating to resuscitation with higher oxygen concentrations The confidence (> 50%). in this result low as the is, only however, study that showed significant reduction in mortality contributed(and half to of the total weightage in the pooled analysis) had significant risk of selection bias. Therevery is low-quality and inconclusive evidence of lower risk of severe morbidity such as BPD, IVH and need for mechanical ventilation. Use of air requires significantly less resources than 100%oxygen; it can be administered evenat the most remote health-care facilities. using slightlyHowever, higher oxygen concentrations – up 50% to – would require use of blenders, which are not easily available in most LMIC settings and therefore require additional resources. The GDG was unanimous in favour of low concentration (30%) of oxygen or air at the start and then a progressive increase in concentration guided the by newborn’s vital signs, including persisting . The GDG acknowledged the paucity of evidence, but made a strong recommendation considering that the demonstrated benefits outweigh the harms for an intervention which will be valued in all settings partly because it is also easy use. to High Moderate Low Very low No significant variability Significantvariability Benefits outweigh disadvantages and Benefits disadvantages are balanced Disadvantages benefits outweigh Less resource intensive More resource intensive In favour of the intervention Against the intervention Strong recommendation Conditional recommendation

               DECISION Recommendation 10.0: During ventilation of preterm babies born at or before 32 weeks of gestation, it is recommended to start oxygen therapy with 30% oxygen or air blended (if oxygen is not rather available), than with 100% oxygen. Recommendation 10.1: The use of progressively higher concentrations of oxygen should only be considered for newborns undergoing oxygen therapy if their is less than 60 beats per minute after 30 seconds of adequate ventilation with 30% oxygen or air. FACTOR Quality of the evidence Values and preferences Balance of versus benefits disadvantages use Resource Recommendation direction Overall strength of the recommendation ANNEX 2. CONSIDERATIONS RELATED TO THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS THE OF STRENGTH AND DIRECTION THE TO RELATED CONSIDERATIONS 2. ANNEX

95 96 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES Annex 3. user end- and expert Content Expertise: Mader Silke Dr user end- and expert Content Expertise: Professor Pisake Lumbiganon user end- and expert Content Expertise: Lawn Joy Professor user end- and expert Content Expertise: William J.Keenan Professor Methodologist Expertise: Dr Natasha Hezelgrave representative Consumer Expertise: Gyte Gill Ms user end- and expert Content Expertise: Professor Malik Goonewardene user end- and expert Content Expertise: Dr Rogelio Gonzalez user end- and expert Content Expertise: BissallahProfessor Ekele Dr Therese Dowswell user end- and expert Content Expertise: Professor Caroline Crowther Dr Agustin Conde-Agudelo user end- and expert Content Expertise: Carlo Wally Dr user end- and expert Content Expertise: CarlBose Professor the guideline development to contributed expertise and Name Expertise: Methodologist Expertise: user end- and expert Content Expertise: and how they were managed Guideline Development (GDG) Group members of declarationsSummary of interests from Declared interest(s) None declared None declared None declared None declared birth. preterm in afellowship of part as grant received and birth preterm on (i) talks gave None declared None declared None declared None declared reviews. systematic on work support to grants received institution (i) her None declared None declared investigator. aprincipal was he which for research for grants large received (i) institution his materials. training care newborn essential of development for agrant (ii) received registry; health newborn and maternal a of development for agrant (i) received As one of the methodologists for for methodologists the of one As Not applicable Not applicable Consultation. Technical the in participation or membership GDG to affect enough serious considered not was conflict The the Technical Consultation. during session any chair not did Bose Consultation. Nevertheless, Professor Technical the in participation or membership GDG to affect enough serious considered not was conflict The Management of conflict(s) of interest Not applicable Not applicable Not applicable Not applicable Consultation. Technical the at rights have voting not did Hezelgrave Dr guideline, this for methodologists the of one As Not applicable Not applicable Not applicable Not applicable Consultation. Technical the at rights have voting not did Dowswell Dr guideline, this

Name and expertise contributed to Declared interest(s) Management of conflict(s) of interest the guideline development Dr Silke Mader None declared Not applicable Expertise: Content expert and end- user Professor Elizabeth Molyneux (i) received significant grants for The conflict was not considered serious implementing interventions relating to enough to affect GDG membership. Expertise: Content expert and end- topics covered in the guidelines. Nevertheless, Professor Molyneux user did not vote on or chair discussions of those topics during the Technical Consultation. Dr Rintaro Mori None declared Not applicable Expertise: Content expert and end- user Professor Ashraf Nabhan None declared Not applicable Expertise: Content expert and end- user Professor James Neilson None declared Not applicable Expertise: Content expert and end- user Ms Regina Obeng None declared Not applicable Expertise: Content expert and end- user Professor Vinod Paul (i) an academic who takes positions The conflict was not considered serious within government and stakeholder enough to affect GDG membership Expertise: Content expert and end- decision-making. or participation in the Technical user Consultation. Professor Zahida Qureshi None declared Not applicable Expertise: Content expert and end- user Dr Larry Rand None declared Not applicable Expertise: Content expert and end- user Dr Jeeva Sankar None declared As one of the methodologists for this guideline, Dr Sankar did not have voting Expertise: Methodologist rights at the Technical Consultation. Professor Ola Didrik Saugstad (i) has published research on some of The conflict was not considered serious. the topics covered by the guidelines. Nevertheless, Professor Saugstad Expertise: Content expert and end- did not vote on or chair discussions user of those topics during the Technical Consultation. Professor Andrew Shennan (i) received sponsorship for research; The conflict was not considered serious enough to affect GDG membership. Expertise: Content expert and end- (ii) his institution also received Nevertheless, Professor Shennan user grants from GlaxoSmithKline, etc., for did not chair any session during the research. Technical Consultation. Dr Jeffrey Smith (i) works for Jhpiego, which receives Dr Smith was accepted as a member money and donations for research and of the GDG, but was not allowed to Expertise: Content expert and programmes in preterm birth; chair any session during the Technical implementer Consultation. (ii) works with the United States Agency for International Development, Laerdal Foundation and the United Nations Commission on Life-Saving Commodities – all entities with active projects relating to preterm birth . ANNEX 3. SUMMARY OF DECLARATIONS OF INTERESTS FROM GUIDELINE DEVELOPMENT GROUP MEMBERS (GDG) AND HOW THEY WERE MANAGED

97 98 WHO RECOMMENDATIONS ON INTERVENTIONS TO IMPROVE PRETERM BIRTH OUTCOMES user end- and expert Content Expertise: Dr Khalid Yunis user end- and expert Content Expertise: Professor Alan Tita user end- and expert Content Expertise: Souza Paulo João Dr user end- and expert Content Expertise: Professor Roger F. Soll the guideline development to contributed expertise and Name None declared research. for grants received (ii) institution his sponsorship; personal (i) received Declared interest(s) None declared None declared Not applicable Not applicable Not applicable Consultation. Technical the in participation or membership GDG to affect enough serious considered not was conflict The Management of conflict(s) of interest

WHO recommendations on interventions to improve preterm birth outcomes

For more information, please contact: Department of Reproductive Health and Research E-mail: [email protected] www.who.int/reproductivehealth

Department of Maternal, Newborn, Child and Adolescent Health E-mail: [email protected] ISBN 978 92 4 150898 8 www.who.int/maternal_child_adolescent

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