The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specifi c companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.# Introduction
Preterm babies are prone to serious illness or death during the neonatal period. Without appropriate treatment, those who survive are at increased risk of lifelong disability and poor quality of life.
Complications of prematurity are the single largest cause of neonatal death and the second leading cause of deaths among children under the age of 5 years. Global efforts to further reduce child mortality demand urgent action to address preterm birth.
Infant death and morbidity following preterm birth can be reduced through interventions provided to the mother before or during pregnancy, and to 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 cessation programmes) or used to minimize the risk in pregnant women with known risk factors (e.g. progestational agents, cervical cerclage). However, the most beneficial set of maternal interventions are those that could improve survival chances and health outcomes of preterm infants when preterm birth is inevitable. These interventions are provided to the mother shortly before or during the birth process with the aim of overcoming immediate and future health challenges of the preterm infant, such as lung immaturity, susceptibility to infection, and neurological complications. Essential and additional care of the preterm newborn to prevent or treat potential complications is also critical to newborn survival without disability.
WHO's Managing complications of pregnancy and childbirth: a guide for midwives and doctors (published in 2000) and Pocket book of hospital care for children (published in 2013) have, respectively, provided guidance on maternal and newborn interventions that could improve the outcomes of preterm birth.
In keeping with the WHO procedures for guideline development, these documents needed to be updated to include the current evidence-based practices and to respond to Member States' requests for guidance on controversial areas of practice. The present guideline is focused on interventions that could be provided during pregnancy, labour and during the newborn period with the aim of improving outcomes for preterm infants. Recommendations on interventions to prevent and reduce the risk of preterm birth or modify risk in at-risk pregnant women are outside the scope of this guideline.
"high". The GDG qualified the direction and strength of each recommendation by considering the quality of evidence and other factors, including balance between benefits and harms, values and preferences of stakeholders, and the resource implications of the intervention. To ensure that each recommendation is correctly understood and applied in practice, the contributing experts provided additional remarks where needed. Guideline users should refer to these remarks, as well as the evidence summaries in the full version of the guideline, if there is any doubt as to the basis for any of the recommendations.
The recommendations on maternal and newborn interventions to improve health outcomes for the preterm infants are summarized in the table below. In accordance with WHO guideline development procedures, these recommendations will be constantly reviewed and updated following identification of new evidence, with major reviews and updates at least every five years. WHO welcomes suggestions regarding additional questions for inclusion in future updates of the guideline.

# Summary list of WHO recommendations on interventions to improve preterm birth outcomes

# Maternal interventions Recommendations Strength of recommendation and quality of the evidence a
Antenatal cortico steroids to improve newborn outcomes 1.0. Antenatal corticosteroid therapy is recommended for women at risk of preterm birth from 24 weeks to 34 weeks of gestation when the following conditions are met:
n gestational age assessment can be accurately undertaken; n preterm birth is considered imminent; n there is no clinical evidence of maternal infection; n adequate childbirth care is available (including the capacity to recognize and safely manage preterm labour and birth);
n the preterm newborn can receive adequate care if needed (including resuscitation, thermal care, feeding support, infection treatment and safe oxygen use).

# Strong recommendation
based on moderate-quality evidence for newborn outcomes and low-quality evidence for maternal outcomes 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.

# Strong recommendation based on low-quality evidence
- 2. Antenatal corticosteroid therapy is recommended for women at risk of preterm birth irrespective of whether a single or multiple birth is anticipated.

# Strong recommendation based on low-quality evidence
- 3. Antenatal corticosteroid therapy is recommended in women with preterm prelabour rupture of membranes and no clinical signs of infection.

# Strong recommendation
based on moderate-quality evidence for newborn outcomes and low-quality evidence for maternal outcomes 1.4. Antenatal corticosteroid therapy is not recommended in women with chorioamnionitis who are likely to deliver preterm.

# Conditional recommendation based on very low-quality evidence
- 5. Antenatal corticosteroid therapy is not recommended in women undergoing planned caesarean section at late preterm gestations (34-36 +6 weeks).

# Conditional recommendation based on very low-quality evidence
- 6. Antenatal corticosteroid therapy is recommended in women with hypertensive disorders in pregnancy who are at risk of imminent preterm birth.

# Strong recommendation
based on moderate-quality evidence for newborn outcomes and low-quality evidence for maternal outcomes a For recommendations related to maternal interventions, the rating of the quality of evidence applies to both the maternal and newborn outcomes where the quality of the evidence for the two is not separately presented.  9.2. Administration of surfactant before the onset of respiratory distress syndrome (prophylactic administration) in preterm newborns is not recommended.

# Strong recommendation
based on low-quality evidence 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.

# Conditional recommendation (only in health-care facilities where intubation, ventilator care, blood gas analysis, newborn nursing care and monitoring are available) based on lowquality evidence
Oxygen therapy and concentration for preterm newborns 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 (if blended oxygen is not available), rather than with 100% oxygen.

# Strong recommendation based on very low-quality evidence
- 1. The use of progressively higher concentrations of oxygen should only be considered for newborns undergoing oxygen therapy if their heart rate is less than 60 beats per minute after 30 seconds of adequate ventilation with 30% oxygen or air.

# Strong recommendation based on very low-quality evidence
positive airway pressure (19) and surfactant therapy (20,21). It is therefore necessary to review and update the recommendations using the current WHO guideline development procedures.
The global agenda, as captured in the global action report on preterm birth, to substantially reduce preterm-related death, demands careful integration of the care of pregnant women and preterm newborns (22). However, this integration requires evidence-based guidance as an essential component to be effective in delaying preterm birth; providing appropriate intrapartum interventions to reduce complications in the preterm newborn; and providing effective care to the preterm newborn to reduce risk of death and long-term disability.
The purpose of this guideline is to provide evidencebased recommendations for interventions during pregnancy, labour and during the newborn period that are aimed at improving outcomes for preterm infants. Recommendations on interventions for the prevention of preterm birth are not within the scope of this guideline.

# Target audience
The target audience for this guideline includes health-care professionals responsible for developing national and local health-care protocols and policies, as well as managers of maternal and child health programmes and public health policy-makers in all settings. The guideline will also be useful to those directly providing care to pregnant women and preterm infants, such as obstetricians, paediatricians, midwives, nurses and general practitioners. This guideline is evidence-informed and covers topics related to interventions for improving outcomes of preterm birth that were selected and prioritized by an international, multidisciplinary group of health-care professionals, consumer representatives and other stakeholders. It provides specific recommendations for the management of imminent preterm birth and preterm infants, and is intended to inform the development of health-care protocols and policies related to interventions to improve preterm birth outcomes. It is not intended to provide a comprehensive practical guide for the management of preterm labour and preterm infants.

# Scope of the guideline

# Populations of interest
This guideline focuses on improving maternal and neonatal outcomes associated with preterm birth, 1. BACKGROUND
Preterm birth, defined as birth before 37 weeks of gestation, is the single most important determinant of adverse infant outcomes, in terms of survival and quality of life (1). Globally, it is the leading cause of perinatal and neonatal mortality and morbidity (2). Preterm infants are particularly vulnerable to complications due to impaired respiration, difficulty in feeding, poor body temperature regulation and high risk of infection (3)(4)(5). With the increasing contribution of neonatal deaths to overall child mortality, it is critical to address the determinants of poor outcomes related to preterm birth to achieve further reductions in child mortality (6)(7)(8).
Infant mortality and morbidity from preterm birth can be reduced through interventions delivered to the mother before or during pregnancy, and to the preterm infant after birth (9). Interventions can be directed at all women for primary prevention and reduction of the risk of preterm birth (e.g. smoking cessation programme) or aimed at minimizing the risk in women with known risk factors (e.g. progestational agents, cervical cerclage) (10). However, the most beneficial set of maternal interventions are those that are aimed at improving outcomes for preterm infants when preterm birth is inevitable (e.g. antenatal corticosteroids, magnesium sulfate and antibiotic prophylaxis) (9). Special care of the preterm newborn to prevent and treat complications of prematurity is also critical to newborn survival. In high-income countries, reductions in mortality rates in infants that were born preterm have been driven largely by improved care and, more importantly, by appropriate policy changes.
Existing World Health Organization (WHO) guidance on maternal interventions for preterm labour is available in the reference manual Managing complications of pregnancy and childbirth (11). This manual was published in 2000, and reprinted in 2013. In view of the changes to the WHO guideline development process since 2007, it is imperative that the recommendations are reviewed and updated accordingly. Similarly, the latest WHO guidance on neonatal interventions for management of preterm infants can be found in the Pocket book of hospital care for children (12). The second edition of this manual was published in 2013, but only a limited number of controversial areas were revised in accordance with the current WHO guideline development procedures. Moreover, a substantial amount of new evidence has emerged in recent years on preterm newborn interventions, including the use of Kangaroo mother care (KMC) (13)(14)(15)(16), plastic wraps (17,18), continuous and specifically includes both the care of pregnant women at imminent risk of preterm birth (birth < 37 weeks of gestation) and the care of preterm babies immediately after birth in all settings.
Women at imminent risk of preterm birth were defined as pregnant women who are very likely to deliver a preterm baby either as a result of onset of spontaneous preterm labour, preterm prelabour rupture of membranes or elective (or indicated) preterm birth. The guideline scope does not include preventive care for non-pregnant or pregnant women with previous history of preterm birth or other known risk factors of preterm birth.

# Critical outcomes
Critical maternal outcomes considered were: birth prior to 28, 32, 34 or 37 weeks of gestation; pregnancy prolongation (interval between randomization into the study and birth, birth within 48 hours or birth within 7 days); severe maternal morbidity or death; maternal sepsis (chorioamnionitis, puerperal sepsis); severe adverse effects of treatment.
Critical newborn outcomes considered were: neonatal death; fetal death or stillbirth; perinatal death (fetal or early neonatal death); severe neonatal morbidity (i.e. an illness in the neonatal period that is associated with a high risk of death or severe long-term disability among survivors); birth weight (mean; low or very low); infant or child death; long-term morbidity.

# Priority questions
The priority questions guiding the evidence review and synthesis for this guideline are listed below in PICO format -population (P), intervention (I), comparison (C) and outcome (O).
- Among pregnant women at risk of imminent preterm birth (P), is antenatal corticosteroid therapy (I), compared with no antenatal corticosteroid therapy (C), effective in reducing adverse newborn outcomes (O)? If so:
- Which population of pregnant women should be offered antenatal corticosteroids? (considering the gestational age at presentation or birth; interval between presentation and anticipated birth; single and multiple birth; status of amniotic membranes; and women undergoing elective caesarean section in late preterm) - Which population of pregnant women should not be offered antenatal corticosteroids? (considering conditions where there are concerns that associated risks may outweigh benefits: women with diabetes mellitus, hypertensive disorders, chorioamnionitis and growth-restricted babies) - Which corticosteroids (and regimens) should be used for eligible women? - Should repeat course(s) of corticosteroids be offered to a woman who has completed a course of corticosteroid but remains at risk of preterm birth 7 days or more after the initial treatment?
- Among pregnant women at risk of imminent preterm birth (P), is the use of tocolytic agent(s) (I), compared with no tocolytic agent, effective in delaying preterm birth and reducing adverse newborn outcomes? If so:
- Which population of pregnant women should be offered tocolytics? (considering gestational age at presentation or birth; interval between presentation and anticipated birth) - Which population of pregnant women should not be offered tocolytics? (considering potential contraindications: women with preterm prelabour rupture of membranes, multiple pregnancy, antepartum haemorrhage, fetal growth restriction and medical conditions) - Which tocolytic agents (and regimens) should be used for eligible women? - Should a tocolytic maintenance regimen be offered following successful first-line tocolysis of a preterm labour? If so, which maintenance regimen should be recommended?
- Among pregnant women at risk of imminent preterm birth (P), is magnesium sulfate therapy (I), compared with no magnesium sulfate therapy (C), effective in protecting the fetus from neurological complications (i.e. fetal neuroprotection) (O)? If so:
- Which population of pregnant women should be offered antenatal magnesium sulfate for fetal neuroprotection? (considering gestational age at presentation; interval between presentation and anticipated birth; single and multiple birth) - Which regimen of antenatal magnesium sulfate should be used for fetal neuroprotection in eligible women?
- 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?
- 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.)
- 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?
- 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?
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?
- 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 proteinfree?
- 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?
This document represents WHO's support for using evidence-informed norms, policies and practices in all countries. The guideline was developed using standard operating procedures in accordance with the process described in the WHO handbook for guideline development (23). In summary, the process included: (i) identification of priority questions and critical outcomes, (ii) retrieval of the evidence, (iii) assessment and synthesis of evidence, (iv) formulation of recommendations, and (v) planning for the dissemination, implementation, impact evaluation and updating of the guideline.
The guideline development process involved the formation of three main groups to guide the process; their specific roles are described in the following sections.

# WHO Steering Group
The WHO Steering Group, comprising WHO staff members from the Department of Maternal, Newborn, Child and Adolescent Health and the Department of Reproductive Health and Research, guided and managed the entire guideline development process. The group drafted the initial scope of the guideline and priority questions in PICO format (population, intervention, comparison, outcome) and identified systematic review teams, guideline methodologists and members of the Guideline Development Group (GDG). Additionally, the WHO Steering Group supervised the evidence retrieval and syntheses, organized the GDG meetings, prepared draft recommendations for the GDG and the final guideline document, and managed the guideline publication and dissemination. The members of the WHO Steering Group are presented in Annex 1.

# Guideline Development Group
The WHO Steering Group identified 27 external experts and stakeholders from the six WHO regions to constitute the GDG. This was a diverse and gender-balanced group of individuals with expertise in research, clinical policy and programmes relating to maternal and newborn interventions to improve outcomes of preterm birth. The group included clinical researchers, obstetricians, neonatologists, paediatricians, midwives, representatives of user groups and guideline methodology experts. Members of this group provided input into the drafting of the guideline scope and the PICO questions, and participated in prioritization of outcomes that guided the evidence reviews. In addition, the GDG appraised the evidence that was used to inform the recommendations, advised on the interpretation of the evidence, formulated the final recommendations based on the draft prepared by the WHO Steering Group, and reviewed and approved the final guideline document. The members of the GDG are presented in Annex 1.

# External Review Group
This group included six technical experts and other stakeholders with an interest in the provision of evidence-based maternal and newborn care.
The group was geographically balanced, genderrepresentative and no member declared a conflict of interest. The group reviewed the final guideline document to identify any factual errors and commented on the clarity of the language, contextual issues and implications for implementation.
The group ensured that the guideline decisionmaking processes had incorporated contextual values and preferences of potential users of the recommendations, health-care professionals and policy-makers. It was not within the group's remit to change the recommendations formulated by the GDG. The members of the External Review Group are presented in Annex 1.

# Identification of priority questions and critical outcomes
The WHO Steering Group first drafted a list of priority questions and potential critical and important outcomes related to interventions to improve outcomes of preterm birth. WHO then consulted a larger group of international stakeholders (including midwives, obstetricians, neonatologists, researchers, experts in health programmes and representatives of user groups) to review the draft questions and prioritize the outcomes at a Technical Consultation in Geneva in April 2013. The international stakeholders ranked the relative importance of the outcomes on a scale from 1 to 9. In this context, an outcome was ranked as "critical" if it was given an average score of 7 or more. Questions and outcomes with a score of between 4 and 6 were considered "important but not critical", while those with a score lower than 4 were not considered to be important for the purposes of the guideline. The prioritized outcomes rated as critical were included in the scope of this document for evidence searching, retrieval, grading and formulation of recommendations.

# Evidence identification and retrieval
The WHO Steering Group, in collaboration with an external team of systematic reviewers and guideline methodologists, retrieved evidence on the effectiveness of interventions from systematic reviews of randomized controlled trials (RCTs) and non-randomized studies as needed. The Steering Group provided the methodologists with standard operating procedures and a briefing on the desired output of the systematic reviews, and together the members of these groups agreed on the format and timelines for reporting. Using the assembled list of priority questions and critical outcomes from the scoping exercise, the WHO Steering Group, along with the external teams of systematic reviewers and guideline methodologists, identified systematic reviews that were either relevant or potentially relevant and assessed whether they needed to be updated. A systematic review was considered to be out of date if the last search date was two years or more prior to the date of assessment. The authors of reviews that were found to be out of date were requested to update them within a specified time period. In instances where the authors were unable to do so, the updates were undertaken by the external team of systematic reviewers, in consultation with the WHO Steering Group.
Cochrane systematic reviews were the primary source of evidence for the recommendations included in this guideline. 1 The Cochrane reviews relating to maternal interventions were based on studies identified from searches of the Cochrane Pregnancy and Childbirth Group's Trials Register. This Register is maintained by the Trials Search Coordinator and contains trials identified from: monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL); weekly searches of Medline; weekly searches of Embase; hand searches of 30 journals and the proceedings of major conferences; weekly "current awareness" alerts for a further 44 journals; and monthly BioMed Central email alerts. The details of the search strategies for key databases such as CENTRAL, Medline and Embase, the list of hand searched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the "Specialized Register" section within the The assessment of quality of individual intervention studies included in Cochrane reviews follows a specific and explicit method for assessing the risk of bias. Briefly, using the criteria outlined in the Cochrane handbook for systematic reviews of interventions, two review authors independently assess the risk of bias along six domains: sequence generation, allocation concealment, blinding of study personnel and participants, attrition, selective reporting, and other sources of bias such as publication bias (24). Each included study is assessed and rated to be at "low", "high" or "unclear" risk of bias for each of these six domains, and these assessments together provide an overall risk of bias that indicates the likely magnitude and direction of the bias and how it is likely to impact the review findings. Each Cochrane review is preceded by a publication of a peer-reviewed protocol describing the proposed methods and search strategy for that review.
The WHO Steering Group and methodologists worked together to determine the appropriateness and suitability of each systematic review in providing the evidence base for the key PICO questions, by assessing the review's relevance, timeliness and quality. Relevance was ascertained by examining whether the population, intervention, comparison and outcomes considered in the full text of the review were compatible with those in the priority question. The quality of each review was determined by assessing: the clarity of its primary question with 2 Available at: / cochrane/clabout/articles/PREG/frame.html respect to the PICO; the comprehensiveness of the search strategies and databases; the potential for bias in the study selection and data extraction processes; the methods of assessing the risk of bias; and the methods of data syntheses and reporting.
In situations where there were no suitable systematic reviews (Cochrane or non-Cochrane) or where the reviews lacked data that were relevant to the specific priority question, new systematic reviews were commissioned to various groups to inform the development of the recommendations. In such cases, the external groups of systematic reviewers were asked to prepare a standard protocol with clear PICO question and criteria for identification of studies, including search strategies for different bibliographic databases, methods for assessing risk of bias and a data analysis plan. The WHO Steering Group and selected content experts among the GDG members then reviewed and endorsed the protocol before the group of reviewers embarked on the review. To identify relevant studies, systematic searches of various electronic databases were conducted, including Medline, Embase, CENTRAL, CINAHL, Popline, NLM Gateway and WHO regional databases. The search strategies employed to identify the studies and the specific criteria for inclusion and exclusion of studies were described in the individual systematic reviews. Studies from low-, middle-and high-income countries were considered and there were no language restrictions. The entire systematic review development process was iterative, with the systematic reviewers and methodologists constantly communicating with the WHO Steering Group to discuss challenges and agree on solutions.

# Quality assessment and grading of the evidence
Quality assessment of the body of evidence for each outcome was performed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (25). Using this approach, the quality of evidence for each outcome was rated as "high", "moderate", "low", or "very low" based on a set of criteria. The rating of the quality of evidence was dependent on consideration of the factors briefly described below.
Limitations in the study design and execution: The risk of bias was first examined at the level of the individual study and then across studies contributing to the outcome. For RCTs, quality was first rated "high" and then downgraded by one level ("moderate") or two ("low"), depending on the minimum quality criteria met by the majority of the studies contributing to the outcome.
Inconsistency of the results: The similarity in the results for a given outcome was assessed by exploring the magnitude of differences in the direction and size of effects observed from different studies. The quality of evidence was not downgraded when the directions of the findings were similar and confidence limits overlapped, whereas quality was downgraded when the results were in different directions and confidence limits showed minimal overlap.
Indirectness: Rating of the quality of evidence were downgraded where there were serious or very serious concerns regarding the directness of the evidence, i.e. where there were important differences between the research reported and the context for which the recommendations are being prepared. Such differences were related, for instance, to populations, interventions, comparisons or outcomes.
The degree of uncertainty around the estimate of effect was assessed. As this was often a function of sample size and number of events, studies with relatively few participants or events (and thus wide confidence intervals around effect estimates) were downgraded for imprecision.
Publication bias: Quality rating could also be affected by perceived or statistical evidence of bias that may have led to underestimation or overestimation of the effect of an intervention as a result of selective publication based on study results. Where publication bias was strongly suspected, evidence was downgraded by one level.
GRADE profiler software was used to construct "Summary of Findings" tables for each priority question; these tables include the assessments and judgements relating to the elements described above and the illustrative comparative risks for each outcome. Relevant information and data were extracted in a consistent manner from the systematic reviews relating to each priority question by applying the following procedures. First, up-todate review documents and/or data (e.g. RevMan file) were obtained from the review authors or the Cochrane Library. Secondly, analyses relevant to the critical outcomes were identified and selected. The data were then imported from the RevMan file (for Cochrane reviews) or manually entered into the GRADE profilers (for non-Cochrane reviews).
For each outcome, GRADE assessment criteria (as described above) were applied to evaluate the quality of the evidence. In the final step of the assessment process, GRADE evidence profiles were generated for each priority question.

# Formulation of recommendations
The GRADE framework was applied to formulate each recommendation based on the synthesized evidence (26). For each priority question, the WHO Steering Group used the corresponding summaries of evidence for the critical outcomes, and the assessments of the overall quality of the evidence, balance between benefits and risks, values and preferences, and resource implications to draft the recommendations. The draft recommendations, evidence summaries, the corresponding GRADE tables, and other related documents were provided in advance to members of the GDG who were then asked to comment on the document. The GDG members and other participants were then invited to attend the Technical Consultation organized at WHO headquarters in Geneva, Switzerland, in May 2014 (see Annex 1 for a full list of participants). At the Technical Consultation, the GDG members systematically reviewed and discussed these documents to finalize the recommendations and determine their directions and strengths.

# Declaration of interests by external contributors
According to WHO regulations, all experts must declare their relevant interests prior to participation in WHO guideline development processes and meetings. All GDG members and external contributors were therefore required to complete a standard WHO Declaration of Interest (DOI) form before engaging in the guideline development process and participating in related meetings. The WHO Steering Group reviewed all the DOI forms before finalizing experts' invitations to participate in the guideline development. Where any conflict of interest was declared, the Steering Group determined whether such conflicts were serious enough to affect objective judgement of the expert on the guideline development process and recommendations. To ensure consistency, the Steering Group applied the criteria for assessing the severity of a conflict of interest in the WHO handbook for guideline development for all experts (23). All statements on the received DOI forms were managed in accordance with the WHO DOI guidelines on a case-by-case basis and the decisions were communicated to the experts.
The procedures for the management of declared conflicts of interests were undertaken in accordance with the WHO guidelines for declaration of interests (WHO experts). Where a conflict of interest was not considered significant enough to pose any risk to the guideline development process or reduce its credibility, the experts were only required to openly declare such conflict at the beginning of the Technical Consultation and no further action was taken. Conflict of interest that warranted action by WHO staff arose where experts had obtained funding from a body or an institution to perform primary research or a systematic review directly related to any of the guideline recommendations. At the Technical Consultation, the concerned experts were restricted from participating in discussions and/or formulation of recommendations pertaining to their conflicts of interest. A summary of the DOI statements and how conflicts of interest were managed is included in Annex 3.

# Decision-making during the Technical Consultation
The Technical Consultation process was guided by a clear protocol, as described here. The meeting was designed to allow participants to discuss each of the recommendations drafted by the WHO Steering Group. Where necessary, each of these recommendations was revised through group discussion. The final adoption of each recommendation was confirmed by consensusdefined as the agreement of at least three quarters of the participants -provided that those who disagreed did not feel strongly about their position. Strong disagreements would have been recorded as such in the guideline. If the participants were unable to reach a consensus, the disputed recommendation, or any other decision, was put to a vote. Voting was by a show of hand by members of the GDG.
A recommendation or decision stood if a simple majority (more than half of the participants) voted in support of it, unless the disagreement was related to a safety concern, in which case the WHO Secretariat would choose not to issue a recommendation at all. WHO staff at the meeting, external technical experts involved in the collection and grading of the evidence, and the observers (see list in Annex 1) were not eligible to vote. If the issue to be voted upon involved primary research or systematic reviews conducted by any of the participants who had declared an academic conflict of interest, the participants in question would be allowed to participate in the discussion, but would not be allowed to vote on that issue.
The Technical Consultation also determined the strength of each recommendation. By default, the strength of each recommendation under discussion was initially aligned with the quality of the evidence (i.e. at the start of the discussion, "strong recommendations" were based on evidence of "moderate" and "high" quality, while "conditional recommendations" were based on evidence of "low"

# Evidence and recommendations
In total, 48 systematic reviews summarized in 53 GRADE tables provided the evidence base for the recommendations included in this guideline. Sections 3.1 and 3.2 outline the recommendations and the corresponding narrative summaries of evidence for the priority questions. The corresponding GRADE tables for the recommendations are referred to in this section as evidence base (EB) Tables 1 to  9. These tables are presented separately in the electronic supplement to this document (see WHO recommendations on interventions to improve preterm birth outcomes: evidence base www.who. int/reproductivehealth/publications/maternal_ perinatal_health/preterm-birth-guideline). "Evidence to Decision" tables summarizing the quality of evidence, values and preferences, balance between benefits and harms, and resource use that were considered in determining the strength and direction of the recommendations are presented in Annex 2.
The participants at the WHO Technical Consultation on this guideline in May 2014 adopted 10 main recommendations and 17 sub-recommendations, covering interventions provided to the mother before the birth of the preterm baby and to the preterm infant after birth. For the mother, the recommendations relate to the use of antenatal corticosteroids, tocolysis, magnesium sulfate, antibiotics, and optimal mode of delivery of preterm newborns (see sections 3.1.1-3.1.5). For the preterm infant, they relate to the use of Kangaroo mother care (KMC), plastic wraps, continuous positive airway pressure (CPAP) therapy, surfactant replacement therapy and oxygen therapy (see sections 3.2.1-3.2.3). The quality of the supporting evidence rated as "very low", "low", "moderate" or "high" and the strength of each recommendation assessed as "strong" or "conditional" are indicated. To ensure that each recommendation is correctly understood and appropriately implemented in practice, additional remarks reflecting the summary of the discussion by the Guideline Development Group (GDG) are included under the recommendation where necessary.
and "very low" quality). In addition to the quality of the evidence, the following factors were considered when determining the strength and direction of the final recommendation: values and preferences, the balance of benefits versus harms, relevant applicability issues and resource/cost implications.
The consideration of values and preferences was based on the experience and opinions of members of the GDG. Cost evaluation relied on reported estimates obtained during the evidence retrieval process as well as experience and opinions of the GDG members. "Evidence to Decision" tables were used to note and synthesize these considerations and record the reasons for changes made to the default strength of the recommendations.
In November 2014, a special Web-based consultation of the GDG was held to review the implications of new evidence on the effects of strategies to scale up antenatal corticosteroid therapy on neonatal mortality in low-and middleincome countries. Relevant recommendations were reviewed and further revisions were made taking the new evidence into consideration, as agreed by the GDG.

# Document preparation and peer review
Prior to the Technical Consultation in May 2014, the WHO Steering Group prepared a draft version of evidence summaries and corresponding recommendations. The draft document was made available to the participants of the Technical Consultation one week before the meeting for their comments. During the meeting, the draft recommendations were modified in line with participants' deliberations and remarks. Following the meeting, members of the WHO Steering Group prepared a draft of the full guideline document with revisions to accurately reflect the deliberations and decisions of the participants. The draft guideline document was then sent electronically to GDG members for further comments before it was sent to the External Review Group for peer review. The WHO Steering Group carefully evaluated the input of the peer reviewers for inclusion in the guideline document. After the Technical Consultation and peer review, the modifications made by the WHO Steering Group to the guideline were limited to correction of factual errors and improvement in language to address any lack of clarity. The revised final version was returned electronically to the participants of the Technical Consultation for their final approval. n Due consideration should be given to local limits of fetal viability when determining the lowest limit of gestational age when antenatal steroids should be administered, including reference to local data on newborn survival and morbidity. The GDG noted that the probability of survival without residual morbidity ("intact survival") at < 24 weeks is low, even in high-resource settings.

# MATERNAL INTERVENTIONS

# EVIDENCE AND RECOMMENDATIONS
n The GDG acknowledged that the conditions listed above may not be operationalized in a standard and consistent manner across settings. Identifying the most critical and essential preconditions to achieve clinical benefits from antenatal corticosteroid is uncertain and would benefit from further research. In setting these preconditions, the panel's emphasis was on minimizing harm to the mother and the baby.
n An appropriate standard of childbirth care should be available to the mother in a facility that has a team of health-care providers competent in recognizing and safely managing preterm labour and imminent preterm birth. Safe care during labour and childbirth requires close monitoring of the mother and fetus to identify and appropriately manage complications, such as maternal infection and fetal hypoxia.
n Essential and special care for the management of preterm newborns should be available to prevent or address any newborn complications related to prematurity or otherwise.
n The GDG made a strong recommendation, having placed its emphasis on: the benefits to the preterm infants, in terms of reducing early 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.

# Summary of evidence

# Antenatal corticosteroids versus placebo or no treatment (all women and babies) (EB Table 1a)
Evidence on the use of antenatal corticosteroids for reducing adverse neonatal outcomes associated with prematurity was extracted from a Cochrane systematic review of 26 trials (4469 women and 4853 babies) (27). This review included trials that compared corticosteroid treatment with placebo or no treatment in women expected to deliver between 24 and 37 weeks of gestation as a result of either spontaneous preterm labour, preterm prelabour rupture of membranes (PPROM) or elective preterm birth. Exclusion criteria were variable but commonly included medical contraindications to steroid use, evidence of maternal infection, diabetes, lethal fetal anomalies, advanced first stage of labour, and any maternal or fetal indications requiring urgent delivery.
Most of the trials were conducted in hospital settings in high-income countries: Brazil (2 trials), Finland (2 trials), the United States of America (USA) (12 trials), and one trial each in Canada, Colombia, Jordan, the Netherlands, New Zealand, South Africa, Spain, Turkey, Tunisia and the United Kingdom.
Eighteen trials used betamethasone (3028 women and 3289 babies) as the corticosteroid in the treatment arm while six trials used dexamethasone (1391 women and 1514 babies). One study did not specify the corticosteroid used (18 women and babies), and another study used either betamethasone or dexamethasone (32 women and babies).
Evidence on the specific population of women whose preterm babies are most likely to benefit from antenatal corticosteroids and those in whom there are concerns that associated risks may outweigh benefits was extracted from the subgroup analyses of the same Cochrane review. Where a specific population of interest was not included in the Cochrane review, evidence was extracted from other systematic reviews that were specifically performed for this purpose.
Evidence regarding the overarching context of care specified for the main recommendation was based on the findings of a large cluster-randomized trial evaluating the effects of a population-based multifaceted strategy to increase antenatal corticosteroid coverage on neonatal mortality (29).

# Maternal outcomes
Severe No statistically significant differences between the groups treated with antenatal corticosteroids and controls were seen for birth weight in the different subgroups of gestational age at birth that were examined.

# Antenatal corticosteroids versus placebo or no treatment (gestational age at birth from 22 to 25 weeks)
A separate review was conducted for infants with gestational age at birth of 22-25 weeks. This review found a prospective multicentre cohort study of 10 541 infants born at 22-25 weeks in the USA, which investigated the effect of exposure to antenatal corticosteroid on death or childhood neurodevelopmental impairment (28). Identification of women at risk of preterm birth and use of corticosteroids: A total of 6214 (13%) of 48 219 women in the intervention cluster were identified as being at high risk of preterm birth. Of these women, 87% were identified at the community and primary health care levels, 77% were identified based on signs of preterm labour, 50% were identified at 33-36 weeks of gestation, and 98% received antenatal corticosteroids (out of 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 intervention clusters gave birth to a < 5th-percentilebirth-weight infant (a proxy for preterm infant). The intervention strategy increased coverage of antenatal corticosteroids in the intervention compared with the control clusters. Compared with 10% in control clusters, 45% of < 5th-percentile-birth-weight infants in the intervention clusters were exposed to at least one dose of corticosteroid. In the intervention clusters, delivery care for < 5th-percentile-birthweight infants was provided by physicians, nurses, TBAs and family members in 44%, 32%, 20% and 5% of cases, respectively; and the location of birth was in the hospital, clinic, and home or other birth setting in 51%, 26% and 23% of cases, respectively.

# Infant outcomes

# Maternal outcomes
Maternal infectious morbidity: "Suspected maternal infection" (a composite variable defined as antibiotic use plus hospital admission or referral, and use of intravenous fluids, surgery or other treatment related to infection, and evidence of antepartum or postpartum infection among mothers of infants with birth weight < 2500 g) was used to assess maternal safety in relation to corticosteroid use. Among women who delivered < 5th-percentile-birth-weight infants, there was a significantly increased risk of suspected maternal infection in intervention clusters as compared with control clusters (10% versus 6%; OR 1.67, 95% CI 1.33-2.09). Likewise, suspected maternal infection was significantly higher among all women in the intervention clusters compared with control clusters (3% versus 2%; OR 1.
n Antenatal corticosteroid therapy should be started even when the completion of a full course before preterm birth is uncertain.
n Tocolysis may be considered as an intervention to gain time to complete a single course of antenatal corticosteroids (see also Recommendation 2.0 on tocolytic treatments).
n The GDG acknowledged the limitations and potential bias of evidence derived from the subgroup analyses according to interval between steroid administration and preterm birth, which led to rating of the quality of evidence as "low". Nevertheless, the group made a strong recommendation on the basis of the balance being in favour of the benefits of antenatal corticosteroids (in terms of reducing respiratory morbidity and mortality for babies born within 24 hours and up to 7 days of starting treatment), the low resource requirements, and the feasibility of implementing the intervention.

# Summary of evidence
Antenatal corticosteroids versus placebo or no treatment (interval between corticosteroid therapy and birth:  7 days) (EB Table 1d)
In the Cochrane review that showed overall benefits of antenatal corticosteroids compared with placebo (27), subgroup analyses were performed according to the interval between corticosteroid treatment and birth of the preterm infant. Only one to four trials could be included for most of the critical outcomes reported with the exception of RDS, which had eight to nine trials providing evidence for the  7 days categories.

# Maternal outcomes
Maternal infectious morbidity: No significant differences were observed in the occurrence of chorioamnionitis across all the subgroups.

# Infant outcomes
Fetal and neonatal death: There was a significant reduction in combined fetal and neonatal deaths for infants born within 24 hours (RR 0.
n This recommendation precludes the routine (or prophylactic) administration of antenatal corticosteroid to any woman with a multiple pregnancy, on the basis of increased risk of preterm birth.
n The GDG acknowledged the lack of clarity on the benefits of antenatal corticosteroids in the subgroup of women carrying multiple fetuses, but based its judgement on the overall improvement in critical outcomes among singleton infants, in addition to the fact that the point estimates were all in favour of reduced risks of adverse critical outcomes reported in multiple pregnancy. The group considered the potential impact of any clinical benefit in this group of women (who are inherently more likely to deliver preterm), albeit modest, on the overall preterm newborn survival and morbidity rates, and therefore made a strong recommendation.
n Although there remains some level of uncertainty about the effectiveness of antenatal corticosteroids in multiple pregnancy, the GDG does not consider this to be a research priority.

# Summary of evidence

# Antenatal corticosteroids versus placebo or no treatment (singleton versus multiple pregnancy) (EB Table 1e)
Results for the effects of corticosteroids compared with placebo according to whether the pregnancy was singleton or multiple were available from 12 trials included in the same Cochrane review (27). Of these, only one to two trials provided data for comparisons related to multiple pregnancies.

# Maternal outcomes
Maternal infectious morbidity: The review showed no statistically significant differences between comparison groups for chorioamnionitis, in women with singleton pregnancies or in women with multiple pregnancies.
n The use of prophylactic antibiotics should be included as part of standard care for the mother once preterm prelabour rupture of the membranes is confirmed (see Recommendation 5.0).
n The GDG noted the paucity of evidence on benefits with regard to the duration of membranes rupture due to the lack of such information from trials included in the review. However, the group placed its emphasis on the overall balance favouring benefits over harms of using antenatal corticosteroids in terms of reducing severe adverse neonatal outcomes without evidence of increased risk of infection to the mother or the baby, 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.

# Summary of evidence

# Antenatal corticosteroids versus placebo or no treatment (preterm prelabour rupture of membranes) (EB Table 1f)
In the same Cochrane review (27), the effects of antenatal corticosteroids were examined in a subgroup of women with PPROM.

# Maternal outcomes
Severe morbidity or death: No significant differences were observed between groups for maternal death, chorioamnionitis or puerperal sepsis in mothers when the first dose of corticosteroids was given to women with PPROM or prolonged rupture of membranes (> 24 hours). n Antenatal corticosteroids should be avoided in women with evidence of ongoing systemic infection, e.g. septicaemia or tuberculosis.
n In the light of evidence from the Antenatal Corticosteroids Trial (29), the GDG reviewed the concern about the risk of exacerbating maternal infection, particularly in low-and middle-income settings where baseline risk of maternal infectious morbidity is higher than that of the settings where the evidence on women with chorioamnionitis was generated.
The group felt that this potential risk may outweigh the known benefits of antenatal corticosteroids in the majority of populations where steroid use is essential for improving newborn survival. They acknowledged that the balance of benefits and harms may be context-specific and chose to make a conditional recommendation against the intervention in this situation.

# Summary of evidence

# Antenatal corticosteroids versus placebo or no treatment (women with chorioamnionitis) (EB Table 1g)
Evidence on the effects of antenatal corticosteroid therapy for reducing adverse newborn outcomes in women with chorioamnionitis who are at risk of preterm birth was extracted from a systematic review that included eight cohort studies involving a total of 1424 mothers expected to deliver at or before 35 weeks of gestation (30). All studies were conducted in high-resource settings: two in the USA, two in France, and one each in Australia, Canada, Korea and the Netherlands. Infections among participants in these studies were diagnosed either clinically or histologically. Four studies reported the effects of corticosteroid therapy in infants of women with histological chorioamnionitis only, two on infants of women with clinical chorioamnionitis only, and two further studies on infants in both groups of women separately.
All studies in the review evaluated the use of a corticosteroid compared with no treatment (or incomplete/suboptimal treatment). In four studies, betamethasone was used (996 mothers and infants), in two studies, dexamethasone was used (161 mothers and infants) and in the remaining two studies, either betamethasone or dexamethasone was used (267 mothers and infants).
This evidence was reviewed and interpreted in the context of the findings of a large cluster-randomized trial evaluating the effects on increasing antenatal corticosteroid coverage on neonatal mortality in lowincome settings (29).

# Maternal outcomes
None of the studies in the systematic review reported on maternal outcomes.

# Infant outcomes

# Histological chorioamnionitis
n The GDG noted the paucity of evidence on the balance of benefits versus harms when antenatal corticosteroid is administered to mothers undergoing elective caesarean section (CS) in late preterm. The group acknowledged that while there might be some benefits, there might also be harms. Reference was made to the overall evidence on antenatal corticosteroid, which suggests potential harms in late preterm infants, and the fact that the population providing the evidence also included provider-initiated (elective) preterm birth.
n Elective CS should not normally be performed at any gestational age < 39 weeks.
n The GDG considered this to be a research priority but chose to recommend against the practice until further evidence becomes available.

# Summary of evidence

# Antenatal corticosteroids versus placebo or no treatment (elective caesarean section in late preterm birth) (EB Table 1h)
A systematic review of randomized and nonrandomized studies evaluating the effectiveness of antenatal corticosteroid therapy for reducing adverse newborn outcomes in women undergoing elective caesarean section (CS) in the late preterm period (i.e. > 34 weeks to 36 +6 weeks of gestation) identified no eligible studies (30). Indirect evidence was extracted from a Cochrane systematic review that assessed the effects of corticosteroid therapy compared with usual treatment on the prevention of neonatal respiratory morbidity after term elective CS (31). This review included one unblinded randomized trial in the United Kingdom (involving 942 mother and their babies), which compared betamethasone with usual treatment without corticosteroids in women undergoing elective CS (32).

# Maternal outcomes
Maternal infectious morbidity: No events were reported for maternal infections, including wound infection.

# Infant outcomes
Fetal and neonatal death: No events were reported for perinatal death or neonatal sepsis in either group.
Severe neonatal morbidity: No statistically significant reduction was found in the incidence of RDS (0.2% and 1.1% in corticosteroid-exposed and unexposed infants, respectively; RR 0.32, 95% CI 0.07-1.58), transient tachypnea of the newborn (RR 0.52, 95% CI 0.25-1.11), need for mechanical ventilation (RR 4.07, 95% CI 0.46-36.27), or duration of stay in the NICU (MD -2.14 days, 95% CI -5.58 to 1.30). Antenatal betamethasone was associated with significant reduction in the risk of admission to neonatal special care units (all levels) (RR 0.45, 95% CI 0.22-0.90), and particularly for respiratory complications (RR 0.15, 95% CI 0.03-0.64). The corresponding risk differences were -0.03 (i.e. 3% reduction, 95% CI -5% to -1%) and -0.03 (i.e. 3% reduction, 95% CI -5% to -0%), respectively, underscoring the low rates of the two outcomes. Antenatal betamethasone did not significantly reduce the overall rate of admission to neonatal special care (all levels) for any respiratory or nonrespiratory indication (RR 0.81, 95% CI 0.49-1.33).
Long-term morbidity: Academic ability during childhood was reported for 407 infants followed through childhood; there were no clear differences between the comparison groups.

# RECOMMENDATION 1.6
Antenatal corticosteroid therapy is recommended in women with hypertensive disorders in pregnancy who are at risk of imminent preterm birth. (Strong recommendation based on moderate-quality evidence for newborn outcomes and low-quality evidence for maternal outcomes)
n An appropriate standard of care for the management of women with hypertensive disorders in pregnancy should be provided to the mother in addition to corticosteroid therapy in a hospital setting.
n The GDG placed its emphasis on the benefits to the preterm infants in terms of reducing early 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.

# Summary of evidence Antenatal corticosteroids versus placebo or no treatment (hypertensive disorders in pregnancy) (EB Table 1i)
In the Cochrane review evaluating the effectiveness of antenatal corticosteroid (27), subgroup analyses were performed to examine its effectiveness in women with hypertensive disorders in pregnancy.

# Maternal outcomes
Severe maternal morbidity or death: In the subgroup of women with hypertensive disorders of pregnancy, there were no significant differences in maternal death (RR 0.98, 95% CI 0.
n The GDG noted the limited evidence on the benefits of antenatal corticosteroid in this subgroup of women. However, the group placed its emphasis on the overall benefits of antenatal corticosteroid, the potential benefits in terms of reduced handicap among surviving intrauterine growth-restricted (IUGR) infants, and evidence of reduced odds of adverse newborn mortality and morbidity outcomes, and therefore made a strong recommendation.
n The GDG acknowledged the concern about the effect of antenatal corticosteroids on fetal growth, but agreed that there is no evidence to suggest that steroids will perform differently in this subgroup compared to the overall preterm population.

# Summary of evidence

# Antenatal corticosteroids versus placebo or no treatment (growth-restricted fetus and small-forgestational-age infant) (EB Table 1j)
Evidence relating to the effectiveness and safety of antenatal corticosteroid therapy for reducing adverse newborn outcomes in women with small-forgestational-age (SGA) infants, including intrauterine growth-restricted (IUGR) infants, was extracted from one systematic review of nine observational studies (30). The studies included women who were pregnant with babies diagnosed with IUGR through confirmation of placental insufficiency and those identified as SGA (a total of 2846 mothers and infants). Three of the studies were specifically on IUGR only, five were on SGA infants only, and one study included both IUGR and SGA infants. The studies evaluated betamethasone or dexamethasone compared with no treatment (or incomplete treatment) in women expected to deliver at or before 35 weeks of gestation. All studies were conducted in high-resource countries: Canada (1 study), France (1 study), Italy (2 studies), the Netherlands (3 studies), Sweden (1 study) and the USA (1 study).

# Maternal outcomes
Maternal morbidity: There were no significant differences in the rates of chorioamnionitis (OR 0.77, 95% CI 0. There was no significant difference noted in exposed versus control groups for other neonatal outcomes (neonatal sepsis, BPD, NEC, Apgar < 7 at 5 minutes, use of mechanical ventilation, chronic lung disease, or low birth weight defined as < 3rd percentile for gestational age).

# Long-term morbidity:
n The GDG acknowledged the paucity of evidence on the benefits of antenatal corticosteroid in this subgroup of women. However, the group placed its emphasis on the overall benefits of antenatal steroid in preterm, the potential benefits in terms of reducing the higher risk of newborn respiratory morbidity posed by maternal diabetes, and the potential impact on overall newborn survival, and therefore made a strong recommendation.
n The group considered the concern about the maternal hyperglycaemic effect of antenatal corticosteroids, but agreed that it was insufficient to counterbalance the potential benefits for the baby if appropriate measures are taken to ensure glycaemic control.
n Clinicians should ensure strict control of maternal blood glucose prior to and/or during pregnancy to reduce the risk of newborn respiratory distress syndrome.
n Delay in fetal lung maturity is generally more frequent in pregnant diabetic women compared with the general obstetric population. Therefore, in pregnant women with poorly controlled diabetes, the use of corticosteroids should also be considered at > 34 weeks of gestation if there is laboratory evidence of fetal lung immaturity.

# Summary of evidence

# Antenatal corticosteroids versus placebo or no treatment (pre-gestational and gestational diabetes)
A systematic review of randomized and nonrandomized studies evaluating the effectiveness of antenatal corticosteroid therapy compared with placebo or no treatment for reducing adverse outcomes in pre-gestational and gestational diabetic women at risk of preterm birth identified no eligible studies (30). Importantly, previous trials on antenatal corticosteroids for reducing adverse outcomes in newborns have generally excluded women with gestational diabetes and diabetes mellitus.
One randomized trial conducted in Brazil compared antenatal betamethasone with no treatment in nondiabetic pregnant women with severe pre-eclampsia between 26 and 34 weeks of gestation (33). This study showed increased risk of gestational diabetes mellitus among women receiving betamethasone compared with the controls (RR 2.71, 95% CI 1.14-6.46; 123 women). However, the reduction in RDS and other adverse outcomes in newborns among women receiving betamethasone in the same study was consistent with the findings of the Cochrane review that showed benefit of antenatal corticosteroids in preterm infants (27).
Additionally, one observational study among 30 women in Mexico reported on glycaemic control following antenatal use of betamethasone in diabetic women at risk of premature rupture of the membranes (34). The study showed that following antenatal betamethasone therapy, 40% of women with diet-treated diabetes required de novo insulin administration, while insulin dose was increased 39-112% in women with diet-plus-insulin-treated diabetes and increased 26-64% among women with type 2 diabetes treated with diet or diet and insulin.
The greatest changes occurred between days 2 and 4 following betamethasone treatment.

# RECOMMENDATION 1.9 Either intramuscular (IM) dexamethasone or IM betamethasone (total 24 mg in divided doses) is recommended as the antenatal corticosteroid of choice when preterm birth is imminent. (Strong recommendation based on lowquality evidence)
n The GDG noted that there is no conclusive evidence on the comparative efficacy of dexamethasone and betamethasone that would support a recommendation of one over the other. The group acknowledged that dexamethasone has an advantage over betamethasone in terms of lower cost and wider availability, and it is currently listed for use in pregnant women on the WHO Essential Medicine List and in WHO's Managing complications in pregnancy and childbirth: a guide for midwives and doctors (11).
n The GDG acknowledged that the doses and regimens for both dexamethasone and betamethasone varied slightly across trials comparing the two, but noted that in the majority a total steroid dose of 24 mg was administered in divided doses 12 hours or 24 hours apart. Four doses of dexamethasone 6 mg IM hours apart or two doses of betamethasone 12 mg IM 24 hours apart were the preferred choice in most of the studies. When deciding on the dosing frequency, consideration should be given to the likely timing of preterm birth to ensure that the woman completes the total dose of steroid or receives a substantial amount of the total dose before birth. Although there were no data on women's satisfaction, women are likely to prefer fewer injections.
n The GDG reviewed the important differences in the type and preparation of steroids across settings and emphasized that local protocols on the type and dosing regimen of antenatal steroid should be informed by the preparations that are readily available in the setting. This will not only encourage uptake and ease their use by health-care providers but also avoid incorrect dosing and wastage of resources.
n The panel felt there might be important differences in pharmacological properties of dexamethasone and betamethasone dosage regimens and therefore considered this as a research priority.

# Summary of evidence

# Different corticosteroid regimens for women at risk of preterm birth (EB Table 1k)
Evidence on the effectiveness and safety of different corticosteroids and different drug regimens was extracted from a Cochrane systematic review that included 12 trials (1557 women and 1661 infants) evaluating antenatal corticosteroid therapy for preterm birth (35).
Ten trials compared dexamethasone with betamethasone and two trials compared different regimens of the same drug in women at high risk of giving birth between 23 and 35 weeks of gestation.
In the comparison between dexamethasone and betamethasone, both drugs were administered intramuscularly (IM); betamethasone was given as 24 mg in two to four divided doses 12-24 hours apart and dexamethasone was given as 24 mg (except in one trial which used 16 mg) in two to four divided doses 12 hours apart. However, 6 of the 10 studies in this comparison used two doses of 12 mg betamethasone 24 hours apart and four doses of 6 mg dexamethasone 12 hours apart.
In four of the trials, women may have received repeat doses of corticosteroid. Three of the trials were conducted in the USA, two in France and one trial each in Iran, Israel, the Netherlands, Poland, Taiwan and the United Kingdom, as well as a two-centre study in Italy and Israel.

# Dexamethasone versus betamethasone (any dose or regimen)

# Maternal outcomes
Pregnancy prolongation: Pregnancy prolongation was reported in only one trial with results reported separately for women with intact and ruptured membranes. For women with ruptured membranes, the mean interval between hospital admission and birth was identical (7.1 days) in the two groups (MD 0.00 days, 95% CI -0.99 to 0.99; 120 women). However, for women with intact membranes, pregnancy was prolonged for a mean difference of 7 days in the dexamethasone group compared with the betamethasone group (MD 7.0 days, 95% CI 5.56 to 8.44; 120 women).

# Infant outcomes
There were no significant differences in most critical infant outcomes between groups receiving dexamethasone and those receiving betamethasone. There was no significant difference in the rate of low infant Apgar score (< 7) at 5 minutes after birth (RR 0.97, 95% CI 0.43-2.18; 2 studies, 207 infants) or admission to NICU (RR 1.72, 95% CI 0.44-6.72; 2 studies, 345 infants) between the groups. In one trial (70 infants), the mean duration of NICU stay was reduced by approximately 1 day in the dexamethasone group as compared to the betamethasone group (MD -0.91, 95% CI -1.77 to -0.05).
One trial reported the difference in low infant birth weight (< 2500 g) and identified no significant difference between groups (RR 0.89, 95% CI 0.65-1.24; 105 infants). In addition, in five trials, the mean birth weights in the dexamethasone and betamethasone groups were almost identical (MD 0.01 kg, 95% CI -0.11 to 0.12; 3 studies, 734 infants).
Long-term morbidity: Only one trial (with 12 children) reported assessment of neurosensory disability at 18 months. The trial did not have sufficient statistical power to detect meaningful differences between the comparison groups.
Subgroup analyses were conducted comparing different dosing regimens of dexamethasone and betamethasone. There were no differences between the different dosing regimens with regard to neonatal death or severe infant morbidity. For most outcomes, estimable data were only available for one subgroup, or low event rates meant that studies lacked statistical power to identify possible subgroup differences.

# Oral versus intramuscular dexamethasone
One study with data for 183 women compared oral (32 mg 12-hourly) with intramuscular (24 mg 12-hourly) dexamethasone.

# Maternal outcomes
No maternal outcomes were reported in this trial.

# Infant outcomes
Neonatal death and severe neonatal morbidity: There were no significant differences between groups receiving oral or IM dexamethasone in terms of neonatal death, NEC, IVH or infant birth weight. Neonatal sepsis was increased in the oral compared with the IM dexamethasone group, and for this outcome the difference between groups was significant (RR 8.48, 95% CI 1.11-64.93).

# Betamethasone 12 mg 12-hourly versus betamethasone 12 mg 24-hourly
One trial with data for 255 women compared 12 mg doses of betamethasone every 12 hours versus 24 hours.

# Maternal outcomes
Maternal morbidity: Maternal postpartum hospital stay was reduced in the group receiving betamethasone 12-hourly as compared to the group receiving 24-hourly treatment, although the magnitude of this difference between groups may not be clinically significant (mean of 2.82 versus 3.55 days; MD -0.73 days, 95% CI -1.28 to -0.18). There was no significant difference observed in the rates of maternal fever > 100.4oF (RR 0.71, 95% CI 0.25-2.02).

# Infant outcomes
Neonatal mortality and early morbidity: There were no significant differences between the two regimens for all newborn critical outcomes reported, although the study lacked statistical power to identify differences between groups for most 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. (Conditional recommendation based on moderate-quality evidence for newborn outcomes and low-quality evidence for maternal outcomes)
n The GDG acknowledged the lack of evidence on further reduction of neonatal mortality with the use of repeat corticosteroids. However, the group placed its emphasis on the associated further reduction in the respiratory morbidity and less surfactant use (which could save costs) and placed lower value on the small reduction in neonatal birth weight, and therefore recommended a single repeat course of steroid. Given that there are likely to be variations in these values across health system settings, the GDG lowered the strength of the recommendation and made it conditional.
n A single course in this context refers to a full dose of antenatal corticosteroid as recommended in this guideline.
n This recommendation should only be applied to women between 24 and 34 weeks of gestation.
n The GDG noted that only betamethasone was tested in this context, but concluded that there were no reasons not to extend the recommendation to dexamethasone. The group also noted the variations in the number of courses and doses of betamethasone used, but agreed that the recommendation should align with the previous recommendation on antenatal corticosteroid regimens.

# Repeat course(s) versus a single course of antenatal corticosteroids (EB Table 1l)
Data on repeat course(s) compared with a single course of antenatal corticosteroids were extracted from a Cochrane systematic review of 10 trials with data for 4733 women and 5700 babies (36).
The review evaluated the use of repeat doses of betamethasone compared with no repeat corticosteroid treatment in women who had received one course of corticosteroid at trial entry and remained at risk of preterm birth for 7 or more days after initial treatment. Studies were mainly conducted in high-resource settings: Australia and New Zealand, Canada, Finland and India (1 study each) and the USA (5 studies). One multicentre trial took place in 20 countries (including a number of middle-income countries): Argentina, Brazil, Bolivia, Canada, Chile, China, Columbia, Denmark, Germany, Hungary, Israel, Jordan, the Netherlands, Peru, Poland, Russia, Spain, Switzerland, the United Kingdom and the USA.
Additional comparisons included a subgroup of women with PPROM, and subgroup analysis compared different dosing regimens and intervals between initial treatment and repeat doses. Women included in the trials were between 23 and 34 weeks pregnant, though the specific criteria varied between studies.

# Repeat course(s) of antenatal corticosteroids versus placebo or no treatment

# Repeat course(s) of corticosteroids versus placebo or no treatment (PPROM, 7-day versus 14-day interval for repeat course, number of repeat courses)
Maternal and perinatal outcomes: One study with data for 160 women examined outcomes in women following PPROM. There were no significant differences between groups for most of the outcomes reported, including for puerperal sepsis, perinatal mortality, RDS and chronic lung disease. However, rate of chorioamnionitis was increased in women receiving the repeat course(s) of corticosteroids compared with those who received a single course (RR 1.56, 95% CI 1.05-2.31).
Subgroup analysis was conducted to examine whether the interval between one course and the repeat course made a difference (i.e. repeat course after 7 days versus repeat course after 14 days). There were no significant differences between subgroups for chorioamnionitis, fetal and neonatal mortality, or IVH. The results for RDS reflected the findings for the whole sample: both subgroups showed a reduction in RDS in the repeat course(s) group compared to the group receiving a single course of corticosteroids. Similarly, subgroup analysis reflected the findings for the whole sample for infant birth weight: the babies in the repeat course(s) group had slightly lower mean birth weights irrespective of the interval between the initial treatment and the repeat course(s).
Subgroup analysis was also conducted by the number of repeat courses of corticosteroids women in the repeat courses group received. Findings largely reflected the main analysis. For women receiving one repeat course of corticosteroids there were no significant differences between the repeat course and single course groups for most outcomes apart from RDS, which (as in the main analysis) was reduced in the repeat course group (RR 0.85, 95% CI 0.73-0.99; 2 studies, 399 infants). Data from one study indicated that babies exposed to four or more repeat courses of corticosteroids had an increase in the frequency of being small for gestational age compared with those who were exposed to a single course (RR 2.00, 95% CI 1.07-3.73; 368 infants). In the same study, repeat doses were also associated with reduced mean birth weight (MD -161.00 g, 95% CI -290 to -31.48).
Different dosing regimens were also compared. Subgroup interaction tests showed no significant differences between different dosing regimens for any of the outcomes reported, and findings largely reflected the overall findings for the whole sample. n The GDG agreed that in women at risk of imminent preterm birth who have an otherwise uncomplicated pregnancy, the acute use of a tocolytic drug to prolong pregnancy (up to 48 hours) can be considered to provide a window for administration of antenatal corticosteroid and/or in-utero fetal transfer to an appropriate neonatal healthcare setting, although there is currently no direct evidence to show that this measure improves neonatal outcomes.

# Tocolysis for inhibiting preterm labour
-When tocolysis is considered in this context, nifedipine (a calcium channel blocker) is the preferred agent. There is considerable variation in the nifedipine regimens used in relevant trials. The most common regimen used in trials for acute tocolytic treatment was 10-30 mg as an initial dose, followed by 10-20 mg every 4-8 hours until contractions ceased or for up to 48 hours. The GDG suggested an initial oral dose of 20 mg followed by 10-20 mg every 4-8 hours for up to 48 hours or until transfer is completed, whichever comes first.
-Although betamimetics do appear effective in delaying birth for more than 48 hours, they should not be used for tocolysis because of the higher risk of adverse drug reactions, which may sometimes be life-threatening.
-There is no evidence of additional benefit of using a combination of tocolytic agents over single agents. Therefore, when tocolysis is considered, a combination of tocolytic agents should not be used.
-The available evidence regarding the potential risks and the lack of information on the long-term outcomes following tocolysis should be discussed with the woman and her partner in order for them to take an informed decision regarding the woman's care.
-Consideration of the use of tocolytics should be individualized and tocolytics should not be used when there is any obstetric or medical contraindication to prolonging the pregnancy. Specifically, tocolytics may be associated with harm and should not be used in the following conditions:
n preterm prelabour rupture of membranes (PPROM) n chorioamnionitis n placenta abruption n cardiac disease.
n The GDG agreed that considerable uncertainty still exists around the value of tocolysis for newborns, particularly as it relates to taking advantage of the time gained for administration of antenatal corticosteroids and/or in-utero transfer, and whether a short prolongation of pregnancy of 2-7 days is more advantageous in one setting compared to another. The group considered studies on tocolytics (e.g. calcium channel blocker) + antenatal corticosteroids versus placebo + antenatal corticosteroids for improving neonatal outcomes a research priority. In addition, the GDG stressed the need for systematic collection of data on critical neonatal outcomes following tocolysis.

# Summary of evidence Any tocolytic agent versus placebo or no treatment
Evidence related to the use of tocolytic drugs versus no tocolysis for improving pregnancy outcomes in women with threatened preterm labour was extracted from eight Cochrane reviews examining the relative effects of tocolytic therapies (37)(38)(39)(40)(41)(42)(43)(44).
Each systematic review originally examined the effectiveness of a particular class of tocolytic agent (as described below), rather than tocolysis as an intervention. Another systematic review examined the use of oral or intravenous (IV) hydration as a treatment for preterm labour (45). The methodology of many of the tocolytic studies was limited by insufficient numbers of participants, lack of comparison with a placebo, and inconsistent use of glucocorticoids. For specific subgroups (e.g. women with multiple pregnancies, PPROM), evidence was sought from commissioned systematic reviews that considered both randomized and non-randomized studies. The summary of evidence for these subgroups is not included in this document as the overall recommendation is not in favour of tocolysis.

# Betamimetics versus placebo or no treatment (EB Table 2a)
Twelve trials compared any betamimetics with placebo (1366 women). Eligible women were between 20 and 37 weeks of pregnancy, but the majority of women were recruited after 32 weeks. Three trials included women with PPROM and six included twin pregnancies in addition to singletons. Two trials administered steroids to women in both arms, use of steroids was not clear in one trial, and the remaining trials did not state whether or not women received steroids in addition to tocolytic therapy. Nine trials compared the betamimetic ritodrine with placebo, two compared terbutaline with placebo, and one trial compared isoxsuprine with placebo.

# Maternal outcomes
Maternal death: There were no maternal deaths reported in trials that evaluated this outcome (2 studies, 907 women). Adverse drug reaction and side-effects: One study with 89 women reported maternal adverse drug reactions, and these were increased in the calcium channel blockers group compared with placebo: more than half of the women in the tocolysis group had side-effects (flushing, headache and vertigo) compared with none in the placebo group (RR 49.89, 95% CI 3.13-795.02).

# Infant outcomes
Infant outcomes were not reported in these studies.

# Cyclo-oxygenase (COX) inhibitors versus placebo or no treatment (EB Table 2c)
Three studies involving 106 women included comparisons of indomethacin (a COX inhibitor) with placebo. In two trials, indomethacin was administered orally and in the third as a rectal suppository. Women recruited to these trials were in labour between 23 and 35 weeks of gestation.
Women with ruptured membranes were excluded from all three trials and those with multiple pregnancies from two of the trials. Adverse drug reaction and side-effects: There were no significant differences between women receiving COX inhibitors versus placebo for maternal adverse drug reactions (RR 1.58, 95% CI 0.66-3.78; 3 studies, 101 women).

# Maternal outcomes

# Infant outcomes
Perinatal death or severe neonatal morbidity: There were no significant differences between groups for perinatal mortality or serious infant morbidity including IVH, neonatal sepsis, NEC, RDS, persistent pulmonary hypertension of the newborn, or chronic neonatal lung disease; for all of these outcomes, studies lacked sufficient power to demonstrate differences between groups. Admission to NICU was comparable in the two groups (RR 0.80, 95% CI 0.56-1.15; 1 study, 39 infants), as was low infant Apgar score (< 7) at 5 minutes (RR 0.53, 95% CI 0.05-5.34; 1 study, 39 infants).
In two studies with a total sample size of 67, mean infant birth weight was 716.34 g greater in the COX inhibitors group (95% CI 425.52-1007.16).

# Magnesium sulfate versus placebo or no treatment (EB Table 2d)
Four trials compared magnesium sulphate with placebo or no tocolytic treatment (346 women). The loading dose of IV magnesium sulfate was 4-5 g and the maintenance dose was 2-4 g per hour. In two of the trials, women with ruptured membranes were explicitly excluded.

# Maternal outcomes
Pregnancy prolongation: There was limited evidence that magnesium sulfate was effective in prolonging pregnancy, as compared with no treatment. There was no significant evidence that birth within 24 or 48 hours of trial entry was reduced in the magnesium sulfate group (RR 1.05, 95% CI 0.64-1.74, 1 study, 156 women; RR 0.57, 95% CI 0.28-1.15; 3 studies, 190 women, respectively). There was also no significant difference between groups for the mean interval between trial entry and birth (MD 0.08 days, 95% CI -4.08 to 4.24; 3 studies, 281 women). One trial with a small sample size (65 women) showed a reduction in preterm birth (before 37 weeks of gestation) in the group receiving magnesium sulfate (RR 0.62, 95% CI 0.46-0.83). However, the mean gestational age at birth was higher (approximately 5 days) in the group receiving no active treatment (MD -0.78 weeks, 95% CI -1.40 to -0.17; 3 studies, 281 women).
Maternal morbidity: Serious maternal complications were evaluated in one study and there were no events reported in either comparison group. Three studies reported the frequency of caesarean birth and there were no differences observed between the groups (RR 1.08, 95% CI 0.63-1.85; 280 women).
Adverse drug reaction and side-effects: Four trials reported maternal adverse effects leading to treatment discontinuation and there were no significant differences between groups (RR 1.31, 95% CI 0.01-221.68; 310 women). Maternal tachycardia and hypotension were assessed in one study (156 women) but no events were reported.

# Infant outcomes
Perinatal death: Infant mortality was low in these trials and the trials lacked power to identify any possible differences between groups. There were no significant differences between groups receiving magnesium sulfate or no active treatment in terms of fetal deaths (RR 5.70, 95% CI 0. There was no significant difference between groups in terms of mean infant birth weight (MD 327.00 g, 95% CI -272.13 to 926.13; 1 study, 33 infants).

# Progestational agents versus placebo or no treatment (EB Table 2g)
Four studies involving 300 women considered the effects of progestational agents on preterm labour and birth. Evidence for this question was extracted from a Cochrane systematic review that included eight studies, although four of these did not report the critical outcomes of interest. Women received adjuvant tocolysis in all trials; that is, a progestational agent was offered in addition to a tocolytic agent. The included studies varied in the form of progesterone used, dosage, method of administration, and additional tocolytic agents used.

# Maternal outcomes
Prolongation of pregnancy: Fewer mothers who had received progestational agents delivered babies before 37 weeks of gestation (RR 0.62, 95% CI 0.39-0.98; 4 studies, 293 infants). There were no differences between groups for birth within 48 hours of intervention (RR 0.76, 95% CI 0.38-1.50; 1 study, women). There was no significant difference in the number of babies born before 34 weeks (RR 0.62, 95% CI 0.30-1.27; 1 study, 62 infants) or 35 weeks (RR 0.43, 95% CI 0.12-1.5; 1 study, 60 infants).

# Infant outcomes
Perinatal death or severe neonatal morbidity: There were no significant differences in perinatal mortality (RR 0.31, 95% CI 0.01-7.41; 1 study, 83 infants), RDS (RR 0.93, 95% CI 0.06-14.38; 1 study, 83 infants), low birth weight (< 2500 g) (RR 1.01, 95% CI 0.61-1.65; 1 study, 105 infants) or admission to NICU (RR 1.08, 95% CI 0.59-1.97; 2 studies, 187 infants).
No differences were observed between groups 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, 104 infants), mechanical ventilation (RR 1.18, 95% CI 0.41-3.37; 2 studies, 187 infants) or oxygen requirement on day 7 and day 28 of life (RR 0.69, 95% CI 0.21-2.31, 1 study, 104 infants; and RR 0.42, 95% CI 0.08-2.05, 1 study, 104 infants, respectively).
Infants whose mothers had received progestational agents had a significantly higher average birth weight than those whose mothers had not (MD 324.7 g, 95% CI 155.05-494.34; 2 studies, 143 infants).

# Relaxin versus placebo or no treatment (EB Table 2h)
Three studies (149 women) considered the effects of relaxin. All three were quasi-randomized trials and thus were at high risk of bias, had small sample sizes and low event rates. All studies recruited women in preterm labour but excluded women with any complications that necessitated immediate delivery.

# Maternal outcomes
Prolongation of pregnancy: One trial reported a significant reduction in the number of women who went on to give birth within 7 days of treatment in the relaxin group (RR 0.50, 95% CI 0.29-0.87; 1 study, 30 women). There were no differences between groups in any of the other relevant outcomes reported, including preterm birth (0.92 95% CI 0.81-1.05; 1 study, 69 women).

# Infant outcomes
Perinatal death or severe neonatal morbidity: There were no differences between groups for perinatal mortality (RR 0.83, 0.32-2.15; 1 study, 30 infants), neonatal death (RR 0.80, 0.27-2.41; 1 study, 30 infants), fetal death (RR 1.00, 95% CI 0.07-14.55; 1 study, 30 infants) or low birth weight (< 2500 g) (RR 2.0, 0.43 to 9.32; 1 study, 30 infants).

# Intravenous or oral hydration versus bed rest alone or no treatment (EB Table 2i)
A Cochrane systematic review examined the evidence for the use of IV or oral hydration therapy as a treatment for preterm labour (45). Included trials recruited women less than 37 weeks pregnant with intact membranes, preterm contractions and cervical changes to receive oral or IV hydration therapy versus bed rest alone. The review included two studies involving 228 women. Approximately 30% of women from both the intervention and control groups in these trials were treated with tocolytic drugs. There were no significant differences between groups for any relevant outcome reported.

# Maternal outcomes
Pregnancy prolongation: There were no differences between groups for rates of preterm birth before 32, 34 or 37 weeks of gestation (RR 0.76, 95% CI 0.29-1.97, 1 study, 110 women; RR 0.72, 95% CI 0.20-2.56, 1 study, 118 women; RR 1.09, 95% CI 0.71-1.68, 2 studies, 228 women, respectively). Hydration had no significant effect on time to delivery in days (MD -0.99 days, 95% CI -7.85 to 5.87; 2 studies, 228 women).

# Infant outcomes
Severe neonatal morbidity: For infants, the rates of NICU admission were comparable between the intervention and control groups (RR 0.99, 95% CI 0.46-2.16; 1 study, 118 infants). Other critical outcomes were not reported.

# Tocolytic maintenance therapy for preterm labour after first-line tocolysis (EB Tables 2j to 2m)
Available evidence related to the use of tocolytic drugs as maintenance therapy to improve pregnancy outcomes after initial treatment of preterm labour consisted of five systematic reviews of 27 RCTs, each evaluating a particular class of tocolytic agent: oral betamimetics (13 RCTs, 1551 women) (46), terbutaline pump (3 RCTs, 166 women) (47), magnesium as magnesium sulfate, chloride or oxide (4 RCTS, 422 women) (48), calcium channel blockers (6 RCTs, 794 women) (49) and oxytocin antagonists (1 RCT, 513 women) (50). The interventions in these studies used different doses, regimens and drug, within each class of tocolytic agent. Most compared maintenance therapy with no treatment or placebo, while others conducted within-class and betweenclass comparisons of tocolytic agents. All studies were hospital based. Twenty-six were conducted in high-income countries (Croatia, Japan, Netherlands, New Zealand, Turkey, the United Kingdom and the USA) and one in a low-income country (Malaysia).

# Tocolytic maintenance therapy versus placebo or no treatment

# Maternal outcomes
Severe maternal morbidity or death: Maternal deaths were generally not reported and in those that did report maternal deaths, there were no deaths observed. Serious maternal morbidity was rare, and when reported there were no significant differences between groups for any of the maintenance therapies evaluated.
Pregnancy prolongation: There were no significant differences in the rates of preterm birth before 37
n Evidence suggests that the protective effects of magnesium sulfate on neurological complications (neuroprotection) are likely to be increased at earlier gestational ages.
The GDG is aware of an ongoing trial on the neuroprotective effects of magnesium sulfate at gestational ages below 34 weeks.
n Magnesium sulfate for neuroprotection should only be given if preterm birth is likely within the next 24 hours. The median time from magnesium sulfate administration to birth was reported in only two of the trials that generated the evidence (1 hour 38 minutes and 3.7 hours). However, the GDG felt that administering magnesium sulfate at any time from immediately prior to birth, up to 24 hours prior to anticipated birth is appropriate.
n Three dosing regimens (IV 4 g over 20 minutes, then 1 g/hour until delivery or for 24 hours, whichever came first; IV 4 g over 30 minutes or IV bolus of 4 g given as single dose; and IV 6 g over 20-30 minutes, followed by IV maintenance of 2 g/hour) have been tested in the available studies, which -on meta-analysis -show effect on cerebral palsy, and death or cerebral palsy. There was insufficient evidence to recommend one specific dosing regimen over others. The GDG is aware that an individual patient data analysis of these studies is underway, which may affect this guidance in the future.
n This recommendation applies to women carrying either singleton or multiple pregnancies.
n In women at imminent risk of preterm birth, magnesium sulfate should be considered as the preferred option whenever there is a valid obstetric indication (e.g. pre-eclampsia) and where it is considered safe and effective.
n There is a need for further research to establish whether repeated treatment with magnesium sulfate for neuroprotection is appropriate (i.e. in the event that delivery does not occur).

# Summary of evidence

# Magnesium sulfate versus placebo or no treatment for fetal neuroprotection
Evidence on the use of magnesium sulfate for neuroprotection in preterm infants was extracted from a Cochrane systematic review (five studies including 6145 infants) investigating whether the administration of magnesium sulfate to women at risk of preterm labour conferred neuroprotective advantage to the fetus (51). One trial was conducted in Australia and New Zealand, one in France, two in the USA, and the fifth was a multicentre study conducted in countries across the world. The final "Magpie" study was designed to prevent eclampsia by magnesium sulfate administration, but data relevant to the effect on preterm infants were included in the analysis. All studies were placebo controlled. The gestational age at recruitment to these trials ranged from below 30 weeks up to 37 weeks. Corticosteroids were given to more than 50% of women in three of the trials.

# Magnesium sulfate versus no active treatment (all women and babies) (EB Table 3a)

# Maternal outcomes
Maternal morbidity or death: There were no significant differences between women receiving magnesium sulfate versus placebo or no active treatment in terms of maternal mortality or serious maternal morbidity in four studies with a total of more than 5000 women. Risks of maternal death, cardiac arrest, respiratory depression or arrest, and admission to intensive care were not significantly different between groups. The cases of maternal deaths and serious morbidity that were recorded were largely confined to the study that recruited women with severe pre-eclampsia rather than those studies that randomized women with preterm labour. There were no significant differences between the groups for rates of postpartum haemorrhage, caesarean births or length of maternal hospital stay. Severe neonatal morbidity and long-term morbidity: There were also no significant differences between groups for a range of composite outcomes (i.e. death or cerebral palsy, death or neurological impairment, death or serious motor dysfunction, and death or major neurological disability). There were no significant differences between women who received magnesium sulfate and those in the control group with regard to infant IVH, periventricular leukomalacia, major or any neurological impairment, blindness or deafness, or developmental delay or intellectual impairment. There were no significant differences between groups for neonatal convulsions, neonatal hypotonia or requirement for ongoing respiratory support, although there was a trend towards reduced risk in the magnesium sulfate group for the latter outcome (RR 0.94, 95% CI 0.89-1.00; 3 studies, 4387 infants). There was no clear difference in length of infant hospital stay, nor in the incidence of chronic lung disease requiring oxygen at 28 days and at 3 months.
Infants exposed to magnesium sulfate were at reduced risk (39%) of substantial gross motor dysfunction compared to controls (RR 0.61, 95% CI 0.44-0.85; 4 studies, 5980 infants). The risk of cerebral palsy was also significantly reduced (by 30%) in the magnesium sulfate group (RR 0.70, 95% CI 0.55-0.89; 5 studies, 6039 infants).

# Magnesium sulfate versus placebo or no treatment (single versus multiple pregnancy) (EB Table 3b)
For all comparisons, the sample size and event rate for multiple pregnancies compared with those for singleton pregnancies were smaller (2 studies, 527 women). There were no clear differences between singleton and multiple pregnancies for most of the critical outcomes reported.
The positive effects of magnesium sulfate on risk of cerebral palsy in singleton pregnancies was not observed in multiple pregnancies (RR 0.52, 95% CI 0.21-1.25; 2 studies, 527 babies), although the point estimate favoured benefit. The effects of magnesium sulfate on overall death rates, on composite outcomes (i.e. death or serious impairment) and on major neurological impairment were comparable for singleton and multiple pregnancies.

# Magnesium sulfate versus placebo or no treatment (gestational age at administration) (EB Table 3c)
Subgroup analysis was performed according to gestational age at administration (< 30 weeks versus < 34 weeks at randomization). The evidence on the use of magnesium sulfate at < 30 weeks of gestation as opposed to < 34 weeks was not clear.
Although statistical significance was more likely to be demonstrated for outcomes in the trials recruiting women up to 34 weeks of gestation, this was partly due to increased sample size and statistical power.
Overall, the subgroup analysis findings largely reflected the findings in the main analysis. However, cerebral palsy was reduced in women randomized to magnesium sulfate versus placebo or no treatment at < 34 weeks of gestation (RR 0.69, 0.54-0.88; 4 studies, 5192 women) but not in women randomized at < 30 weeks (RR 0.86, 0.56-1.31; 2 studies, 1537 women), although the point estimate favoured a reduction in cerebral palsy with the use of magnesium sulfate in this population.

# Magnesium sulfate versus placebo or no treatment (with the intention to prevent preterm birth-related neurologic complications) (EB Table 3d)
When the Magpie study (where magnesium sulfate was aimed at preventing eclampsia in women with severe pre-eclampsia) was excluded from the analysis, the findings of the meta-analysis remained consistent for most critical outcomes. When confined to studies where the intention of the treatment was explicitly for neuroprotection, there were no significant differences between groups for overall paediatric mortality, fetal death or infant death. The composite outcome of death or cerebral palsy was significantly reduced in the treated group (RR 0.85, 95% CI 0.74-0.98; 4 studies, 4446 infants). Similarly, the reduction in risk of moderate/severe cerebral palsy in the treated group remained consistent (RR 0.64, 95% CI 0.44-0.92; 3 studies, 4837 infants). For another composite outcome -death or gross motor dysfunction -there was a trend towards reduction in the group receiving magnesium sulfate (RR 0.84, 95% CI 0.71-1.00; 3 studies, 4387 infants).

# Regimens of magnesium sulfate for fetal neuroprotection (EB Table 3e)
The route of administration and dose of magnesium sulfate varied in these trials: (i) IV 4 g over 20 minutes, then 1 g/hour until delivery or for 24 hours, whichever came first; (ii) IV 4 g over 10-15 minutes, followed by either IV 1 g/hour for 24 hours, or by IM 5 g every 4 hours for 24 hours; (iii) single dose of IV 4 g over 30 minutes; (iv) single IV bolus of 4 g; and (v) IV 6 g over 20-30 minutes, followed by maintenance infusion of 2 g/hour for 12 hours, with retreatment permitted whenever birth was imminent. All trials with neuroprotective intent used the intravenous route of administration.
There were no clear differences between the various regimens for most of the critical outcomes reported. However, the reduction in cerebral palsy only reached statistical significance for the following subgroups: 4-6 g loading dose plus any maintenance; and 6 g loading dose and higher-dose (2 g/hour) maintenance.
In the subgroup analysis according to whether retreatment was allowed or not after completing a course of therapy, the only trial that used high loading and maintenance doses showed a statistically significant reduction in the incidence of cerebral palsy (RR 0.59, 95% CI 0.40-0.85). This study was responsible for the overall point estimate related to cerebral palsy in the review. For the composite outcome of death or cerebral palsy, the results were consistent across the two subgroups: retreatment allowed (RR 0.90, 95% CI 0.73-1.10) and retreatment not allowed (RR 0.91, 95% CI 0.74-1.13).
Maternal adverse effects related to magnesium sulfate appear to be dose dependent. However, the available evidence also points to better neuroprotection with higher dosing. Importantly, there is evidence to suggest that a maintenance dose is essential in order to observe an effect. It is unclear whether the effects on cerebral palsy of higher loading and higher maintenance dosing with a repeat treatment are due to the dosage regimen or a reflection of the size of the trial. However, as this protective effect was not demonstrated in terms of incidence of death or cerebral palsy, the relationship to dose is unlikely to be strong.

# Antibiotics for women in preterm labour
n It is important that women with any diagnostic or clinical signs of infection are treated accordingly with antibiotics.
n Management of group B streptococcal colonization is not within the scope of this recommendation.
n The GDG placed its emphasis on the potential risk of harm to the baby and placed less value on the minimal benefit to mothers, and therefore recommended against the intervention.

# Summary of evidence

# Prophylactic antibiotics for women in preterm labour with intact amniotic membranes
Evidence on the use of antibiotics for women in preterm labour with intact amniotic membranes was extracted from a Cochrane systematic review of 14 RCTs involving more than 7800 women (52). Studies were mainly conducted in high-resource settings: six trials in the USA, and one trial each in Canada, Chile, Denmark, Germany, Iran, South Africa and Uruguay, as well as a large multicentre trial with data predominantly from women in the United Kingdom.

# EVIDENCE AND RECOMMENDATIONS
Most of the results of meta-analysis were dominated by the findings of this latter placebo-controlled trial with data for more than 6000 women (the ORACLE II trial) (53).
All studies recruited women with uterine contractions and cervical dilatation, with intact membranes and no clinical signs of infection. The mean gestational age at recruitment was between 30 and 32 weeks. Women received only oral antibiotics in three trials, only IV antibiotics in another three trials, and IV followed by oral antibiotics in eight trials. Antibiotics examined included ampicillin (with or without sulbactam or clavulanic acid), amoxicillin (with or without sulbactam or clavulanic acid), erythromycin, clindamycin, mezlocillin, ceftizoxime or metronidazole, mostly as combinations. The duration of treatment varied from 3 to 10 days. In 13 of the 14 trials, antibiotics were administered alongside tocolytic therapy to women in both intervention and control groups, according to local protocol at the study sites. Women participating in most of the trials conducted in the mid-1990s also received corticosteroids.

# Any prophylactic antibiotic versus placebo or no antibiotics (EB

# Specific classes of antibiotics versus no antibiotics (EB Table 4b)
The review also examined subgroups comparing different types of antibiotics: betalactam antibiotics (e.g. ampicillin, amoxicillin, co-amoxiclav) alone versus no antibiotics macrolide antibiotics (e.g. erythromycin) alone versus no antibiotics combined macrolide and betalactam antibiotics versus no antibiotics antibiotics active against anaerobic bacteria (e.g. clindamycin) versus no antibiotics.
Pregnancy prolongation: There was no statistically significant evidence that any specific class of antibiotics reduced the number of preterm births (< 37 weeks), or delayed birth by 48 hours compared with no antibiotics. While macrolide and betalactam antibiotics had no significant impact on the interval between randomization and birth, three small trials indicated that the mean interval between randomization and birth was increased in women receiving antibiotics active against anaerobic bacteria (MD 10.50 days, 95% CI 4.95-16.06; 293 women).

# Adverse effects:
There was no evidence that maternal adverse drug reactions were significantly increased with the use of any particular class of antibiotic.
Perinatal or infant death: For stillbirth, perinatal, neonatal and infant death, there were no statistically significant subgroup differences, although there were few events in some subgroups and many effect estimates were imprecise.
Severe neonatal morbidity: There was no evidence of subgroup differences for RDS, NEC or IVH.
Long-term morbidity: Long-term morbidity outcomes were measured in a single factorial study; there was no evidence that different antibiotics had a differential impact on moderate or severe functional impairment, or any functional impairment when children were 7 years of age. Compared with placebo, there was an increased risk of cerebral palsy observed at 7 years in association with macrolide and betalactam antibiotics combined (erythromycin plus co-amoxiclav) (RR 2.83, 95% CI 1.02-7.88; 1 study, 1052 children).

# RECOMMENDATION 5.0
Antibiotic administration is recommended for women with preterm prelabour rupture of membranes. (Strong recommendation based moderate-quality evidence)
n In order to avoid inadvertent antibiotics administration to women with intact amniotic membranes, antibiotics should not be prescribed unless a definite diagnosis of preterm prelabour rupture of membranes (PPROM) has been made. Therefore, a policy of prescribing antibiotics for women with PPROM should be accompanied by a protocol for reliably diagnosing PPROM.
n Women should be monitored for signs of clinical chorioamnionitis.

# Summary of evidence

# Prophylactic antibiotics for women with preterm prelabour rupture of membranes
Evidence on the use of antibiotics for women with PPROM was extracted from a Cochrane review that included 22 RCTs and a total of more than 7000 women (54).
Data were mainly for women cared for in highresource settings: 14 trials in the USA, and one trial each in Denmark, Finland, Germany, Spain, Turkey, Zimbabwe, as well as two multicentre trials, one mostly recruiting women from Chile and the other one from the United Kingdom. Most of the results were dominated by the findings of the United Kingdom trial with data for more than 4800 women (the ORACLE I trial) (55).
Most women recruited into the trials were not in active labour. Trials recruited women between 20 and 37 weeks of gestation. For the 16 placebocontrolled trials, women received oral antibiotics in three trials, IV antibiotics in four trials, and IV therapy followed by oral antibiotics in the remaining trials. Ten of these trials examined broadspectrum antibiotics and five compared macrolide antibiotics (erythromycin) with placebo. In some trials combinations of different drugs were used.
The duration of the course of antibiotics varied considerably across trials, from two doses through to continued antibiotic therapy until delivery.

# Any prophylactic antibiotic versus placebo or no antibiotics (EB Tables 5a)
Maternal outcomes Long-term morbidity: One study followed up women and infants for seven years. At age 7, there were no significant differences in serious disability between children whose mothers had received antibiotics in pregnancy versus placebo (RR 1.01, 95% CI 0.91-1.12; 3171 children).

# RECOMMENDATION 5.1 Erythromycin is recommended as the antibiotic of choice for prophylaxis in women with preterm prelabour rupture of membranes (Conditional recommendation based on moderatequality evidence)
n The GDG acknowledged the paucity of evidence from the subgroup analysis to demonstrate comparative effectiveness of different classes and regimens of antibiotics used for prophylaxis in women with preterm prelabour rupture of membranes (PPROM). However, the choice of erythromycin was based on the findings of a study (the ORACLE I trial) with over 2000 women, which showed that erythromycin lessens the risk of necrotizing enterocolitis (NEC) in the newborn compared to co-amoxiclav. The recommendation was made conditional because antibiotic choice may be dependent on local availability of the drug and sensitivities of prevalent organisms.
n For antibiotic prophylaxis in women with PPROM, oral erythromycin 250 mg four times a day for 10 days (or until delivery) should be used. The choice of this regimen was informed by the regimen used in the ORACLE I trial.
n The management of group B streptococcal colonization is outside the scope of this guideline. However, when considering colonization with group B streptococcus, management decisions should be taken based on adequate microbiological coverage and sensitivities.

# 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. (Strong recommendation based moderate-quality evidence)
n This recommendation was based on the increased risk of NEC with co-amoxiclav when compared with placebo and with erythromycin.
n Where organisms are sensitive to other antibiotics, it would seem sensible to avoid using co-amoxiclav during pregnancy.
n Penicillins (excluding amoxiclav) were used in the pooled trials that showed benefits of antibiotics in this context. Therefore, where erythromycin is not available, penicillin (such as amoxicillin) can be used.

# Summary of evidence

# Regimens of prophylactic antibiotics for women with PPROM (EB Tables 5b to 5d)
The Cochrane review (54) also examined subgroups comparing different types of antibiotics: all penicillins (except co-amoxiclav) versus placebo beta-lactam antibiotics (including co-amoxiclav) versus placebo macrolide antibiotics (including erythromycin) versus placebo other antibiotics versus placebo erythromycin versus co-amoxiclav 3-day versus 7-day regimens of ampicillin.

# Perinatal death:
There was no statistically significant evidence that the type of antibiotic used had an impact on perinatal death compared with placebo (i.e. there were no significant differences between groups for any of the subgroups examined).
Severe neonatal morbidity: While there were no significant differences between groups for most types of antibiotics compared with placebo, risk of NEC was increased for those infants whose mothers had received beta-lactam antibiotics (including coamoxiclav) (RR 4.72, 95% CI 1.57-14.23; 2 studies, 1880 infants). The risk of other neonatal infections, including pneumonia, appeared to be reduced in the infants whose mothers received broad-spectrum penicillins (excluding co-amoxiclav) compared with placebo (RR 0.30, 95% CI 0.13-0.68; 5 studies, 521 infants), but differences were not significant for other subgroups. Similarly, all penicillins (excluding coamoxiclav) were associated with reduced occurrence of major cerebral abnormality on ultrasound, but the differences were not significant for other subgroups.
When erythromycin was compared with coamoxiclav in one study with data for more than 2000 women and infants, there were no significant differences for perinatal mortality or for the most serious neonatal morbidity outcomes (i.e. perinatal death, RDS, treatment with surfactant, major cerebral abnormality on ultrasound before discharge, NICU admission and serious childhood disability at 7 years). However, women in the erythromycin group were at slightly increased risk of birth within 48 hours of receiving the antibiotic (RR 1.14, 95% CI 1.02-1.28; 1 study, 2395 women). However, birth before 37 weeks of gestation was comparable between the erythromycin and co-amoxiclav groups.
Infants whose mothers had received erythromycin rather than co-amoxiclav were at significantly reduced risk of NEC (RR 0.46, 95% CI 0.23-0.94; 1 study, 2395 women).
One trial with data for 82 women compared 3versus 7-day regimens. The study did not have sufficient statistical power to identify any significant differences for most outcomes.
The overall quality of the evidence varied across the subgroup comparisons. For comparisons of all penicillins (except co-amoxiclav) versus placebo, and for other antibiotics versus placebo, the quality of evidence was rated as low to high. The quality was rated as moderate for all outcomes reported in the comparison of macrolide antibiotics (including erythromycin) versus placebo and for most outcomes reported in the comparison of beta-lactam antibiotics (including co-amoxiclav) versus placebo.
For the comparison between erythromycin versus co-amoxiclav, the quality of evidence was rated as moderate to high, while for 3-versus 7-day regimen comparisons, it was mostly rated as low.

# Optimal mode of birth for women in refractory preterm labour RECOMMENDATION 6.0

# Routine delivery by caesarean section for the purpose of improving preterm newborn outcomes is not recommended, regardless of cephalic or breech presentation. (Conditional recommendation based very low-quality evidence)
n There is insufficient evidence to support the routine delivery of preterm infants by caesarean section instead of vaginal delivery, regardless of fetal presentation.
n Caesarean section should only be performed for obstetric indications.

# Summary of evidence

# Planned immediate caesarean section versus vaginal delivery for preterm birth (EB Table 6a)
Evidence on the optimal mode of delivery for the preterm infant was extracted from one Cochrane systematic review of four trials involving a total of 116 women (56). These trials compared two policies for delivery of the preterm infant: planned immediate caesarean section (CS) versus vaginal delivery for women with refractory preterm labour with singleton pregnancies. One trial was conducted in Singapore, one in the United Kingdom and two in the USA. One of the trials included women with cephalic presentation only, while three included women with breech presentation only. All women were in labour (experiencing regular contractions) at recruitment, and all were less than 37 weeks pregnant. All four There was no significant difference between groups for low infant Apgar score (< 7) at 5 minutes (RR 0.83, 95% CI 0.43-1.6; 4 studies, 115 infants).
Long-term morbidity: Abnormal childhood follow-up (not defined) was reported in one trial: there were no significant differences between groups (RR 0.65, 95% CI 0.19-2.22; 38 children).

# Optimal mode of birth by gestational age
Subgroup analysis by gestational age was not performed in the Cochrane systematic review due to small sample sizes. Two of the included trials recruited pregnant women up to 36 weeks of gestation (66 infants), while the other two had upper limits of 32 weeks (12 infants) and 33 weeks (38 infants).
Severe maternal morbidity: No differences were observed between caesarean and vaginal birth groups for major postpartum complications according to gestational age. n There is insufficient evidence to make a recommendation to provide KMC to unstable neonates.
n Health system issues relating to KMC -such as health system requirements, human resources and their competencies, criteria for discharge and follow-up -should be included in the manual or guidance for implementation.
n Given that there is currently no evidence suggesting the need for any change in the recommendation, the existing criteria for discharge should continue to be applied.

# Summary of evidence

# Summary of evidence Continuous or intermittent Kangaroo mother care (KMC) versus conventional care
The Cochrane review summarized data on effectiveness by subgroups of studies that had used either continuous or intermittent KMC (13).
Continuous KMC is defined as the practice of skinto-skin care continuously throughout the day without breaking the contact between mother and baby, while intermittent KMC is the practice of skin-toskin care alternated with the use of either a radiant warmer or an incubator care for the baby.

# Continuous KMC practice versus conventional care (EB Table 7b)
Five trials evaluated the effect of continuous KMC practice on neonatal mortality or severe neonatal morbidity.
n A thermo-neutral environment was considered to be environmental conditions under which a baby maintains temperature in a normal range at minimum metabolic rate.
n There is insufficient evidence to support superiority of either radiant warmers or incubators over the other for the care of preterm babies. In making any choice between the two devices, the health-care providers' preferences and costs should be considered.
n The selection of a device for creating the thermo-neutral environment, and the strategy for its use, should be carefully assessed in the relevant context, i.e. the patient population (including size, maturity and concurrent illnesses), the physical environment, personnel, cost and other resources.

# Summary of evidence

# Radiant warmer versus incubator for sick or unstable neonates (EB Table 7d)
Evidence related to the comparative effects of radiant warmers and incubators was obtained from one Cochrane review that compared nursing preterm newborns in radiant warmers (with the baby either naked or clothed) with controls (57). In the control group, the infant was either naked (except for nappies) or clothed and was nursed in an airheated, single or double-walled incubator, controlled manually or by servo-mechanism. Eight trials involving 156 preterm babies were included in the review and all were conducted in neonatal intensive care units (NICUs) in HICs. Infants recruited into the studies had gestational ages of 28-32 weeks and weighed 1.1-1.6 kg at birth. Exposure to the intervention varied between 1 hour and 3 days in six trials and between 7 and 35 days after birth (or until the baby weighed 1.8 kg) in the remaining trials. In some trials, additional interventions such as humidification or heat shields for the incubators were employed for babies in the control groups, and phototherapy was also provided to some babies in the intervention group. No additional relevant studies after the publication of the Cochrane review were found. Overall the data were limited and the quality of evidence was very low.
Neonatal death: Two trials involving 94 preterm newborns yielded inconclusive evidence on the risk of neonatal mortality for babies nursed under radiant warmers compared with those nursed in incubators (absolute risks: 2.1% versus 10.6%; RR 0.27, 95% CI 0.05-1.59).
Severe neonatal morbidity: One study involving 60 preterm newborns reported risks of sepsis and bronchopulmonary dysplasia (BPD), but there were very few events and the confidence interval was very wide. Two studies (with 90 preterm newborns) showed no significant impact of the intervention on rates of severe intraventricular haemorrhage (IVH) (0% versus 2.2%). The mean time taken to regain birth weight was similar in both trials (MD 0.86 days, 95% CI -1.49 to 3.10 days).

# 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. (Conditional recommendation based on low-quality evidence)

# Summary of evidence Plastic wraps or bags before stabilization for thermal care versus conventional thermal care for preterm infants (EB Table 7e)
A systematic review that addressed this question identified 24 hospital-based studies (58). Twenty of these studies involved preterm babies exclusively while the other four had results for term babies.
Sixteen of the 20 studies with preterm babies involved very preterm babies with either birth weight < 1500 g or gestational age below 32 weeks, while two included moderately preterm babies (32-34 weeks of gestation) and two involved late preterm babies (34-37 weeks). Nine of the 24 studies were conducted in LMICs. The intervention consisted of wrapping of the neonate in a plastic bag, wrap or cap immediately following vaginal birth or caesarean section (prior to drying), and keeping the bag, wrap or cap on until the neonate had been stabilized or had a normal body temperature. Materials used for wrapping included saran wraps (a transparent polythene film or sheet), shopping bags and other manufactured plastic sheets. In the control group, thermal care was provided using incubators or radiant warmers, or by keeping the baby wrapped in clothes in a warm room. No study compared this intervention with provision of KMC.

# Summary of evidence Early versus late initiation of continuous positive airway pressure (CPAP) therapy for respiratory distress syndrome (RDS) in preterm infants (EB Table 8b)
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 included five randomized trials and one quasirandomized trial, all from HICs. The included studies were conducted between the mid-1970s and the early 1980s, before the era of surfactant treatment. Criteria for enrolment differed somewhat between trials but essentially all preterm babies with radiological or clinical features of RDS were included.
The intervention involved initiation of CPAP therapy (either with continuous distending pressure or continuous negative pressure) immediately following the diagnosis of RDS, and these neonates required fraction of inspired oxygen (FiO2) between 0.3 and 0.7. In the comparison arm, CPAP was initiated only when RDS was worsening and babies required relatively higher FiO2 (between 0.5 and 1.0). An updated search in May 2014 identified one additional RCT (60), conducted in Iran in 2013. In the study, early CPAP was defined as CPAP initiated within 5 minutes of birth, and late CPAP was that initiated at least 30 minutes after birth. This trial was the largest of all the seven studies included and contributed over 30% of the total preterm newborns in the review.
n The GDG members were of the opinion that the benefits of the intervention in reducing mortality clearly outweighed the possible increased risk of pulmonary haemorrhage.
n The recommendation should be used in higher-level health-care facilities because it applies to preterm newborns with respiratory distress syndrome who have access to intubation and mechanical ventilation.

# Summary of evidence

# Surfactant replacement therapy (SRT) for preterm neonates with clinical and/or radiologically established respiratory distress syndrome (RDS)
Two Cochrane reviews that evaluated the effects of SRT on neonatal mortality and morbidity provided evidence for this recommendation. The first, by Seger et al. (61), evaluated the effects of the use of animal-derived surfactants, whilst the second, by Soll (62), focused on the use of protein-free synthetic surfactants; both reviews included studies that compared the treatment to placebo or no treatment. An updated search conducted for both reviews found no additional relevant studies. All included studies were conducted in intensive care units within hospitals in HICs. The interventions included the administration of a single dose or multiple doses of exogenous animal-derived or synthetic surfactants by endotracheal tube for babies with clinical or radiological features of RDS. The comparison groups included babies receiving placebo or no treatment.
The results of the two Cochrane reviews were not pooled because of the differences in the source of the surfactants used (animal-derived versus synthetic) and because protein-free synthetic surfactants are no longer commercially available in most countries.

# Animal-derived surfactants (EB

# Protein-free synthetic surfactants (EB Table 9b)
In the review by Soll (62), six trials that compared protein-free synthetic surfactants for SRT with no SRT were included. Five of these trials used a surfactant formulation whose production has been discontinued and the other used dry 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine and phosphatidylglycerol preparation.
n The GDG noted that protein-free synthetic surfactants increase the risk of pneumothorax when compared with animal-derived surfactant. This type of synthetic surfactant is no longer commercially available.

# Summary of evidence

# Synthetic surfactants versus natural (animalderived) surfactants for preterm neonates with clinical and/or radiologically established respiratory distress syndrome (RDS)
The evidence for this recommendation was derived from two Cochrane reviews that directly compared the effects of a single dose or multiple doses of synthetic versus natural surfactants for SRT in preterm babies at risk of RDS or with radiological/ clinical features of RDS. The surfactants were administered by the intra-tracheal route. The first review by Soll et al. (63) evaluated the effects of SRT with protein-free synthetics whilst the second, by Pfister et al. (64), evaluated the use of proteincontaining synthetic surfactants, both compared to natural surfactants.

# Protein-free synthetic versus natural surfactants (EB Table 9c)
The review by Soll et al. (63) included 11 studies that used protein-free synthetic surfactant in the intervention group and compared its effects with the use of natural surfactants. These studies were conducted within intensive care units of hospitals in HICs. An updated search found two additional studies, which were included in the pooled analysis.
n The GDG did not recommend prophylactic administration of surfactants despite evidence of benefit in older studies because:
-the control group in these older studies did not receive continuous positive airway pressure (CPAP), which is now part of standard care; and -recent studies in which CPAP was given to control group did not show any evidence of benefit for prophylactic surfactant administration, and a possibility of harm could not be ruled out.

# Summary of evidence

# Prophylactic versus rescue surfactant therapy for respiratory distress syndrome (RDS) in preterm neonates (EB Tables 9e to 9g)
Evidence for this recommendation was based on a Cochrane review that evaluated the effects of prophylactic administration of surfactants compared with selective rescue therapy on mortality and morbidity in preterm newborns with or without evidence of RDS (65). The review included 11 studies, all from intensive care units of hospitals in HICs, and all using animal-derived surfactants. Surfactants were administered with or without CPAP; two studies routinely administered CPAP to stabilize babies in the comparison arm, whereas the other nine were conducted in the pre-CPAP era. n The adjustment of the concentration of oxygen levels should be by 10% (FiO2=0.1) per 30 seconds and must be guided by oxygen saturation levels reached.

# Summary of evidence Lower oxygen concentration (room air to  50%) versus higher oxygen concentrations (> 50%) for positive pressure ventilation (PPV) of preterm neonates at birth
Evidence related to the starting and progression of oxygen concentration during ventilation was extracted from a systematic review of six RCTs involving 484 newborns. (69). An updated literature search did not identify any additional eligible studies. Five of the included trials were conducted among neonates born at a gestational age less than 32 weeks in HICs. The sixth was a multicentre trial that was conducted among preterm and term neonates 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 study) or 50% (1 study) oxygen concentration. High oxygen concentration was defined as receiving 100% (4 studies), 90% (1 study) or 80% (1 study) oxygen concentration.
Neonatal death: There was significant benefit of using low oxygen concentrations for resuscitation in terms of overall and in-hospital neonatal mortality: eight trials demonstrated that the use of low oxygen concentration or air for preterm babies resuscitated with PPV immediately after birth was associated with a 37% lower risk of overall or in-hospital mortality (RR 0.63, 95% CI 0.44-0.92).

# Severe neonatal morbidity:
There was no association between ventilation with low oxygen concentrations for neonatal resuscitation and severe morbidities, including BPD, retinopathy of prematurity, NEC, severe IVH, the proportion of infants reaching target oxygen saturation by 10 minutes after birth, the duration (in days) of mechanical ventilation or the need for endotracheal intubation during resuscitation.

# EVIDENCE AND RECOMMENDATIONS
Subgroup analysis (preterm babies born at 32-36 weeks versus < 32 weeks of gestation)

# Preterm babies born at 32-36 weeks of gestation:
There was a 42% lower risk of in-hospital mortality observed in the lower oxygen concentration group compared to the higher oxygen concentration group (RR 0.58, 95% CI 0.34-0.97). No morbidity outcomes were available from the Saugstad et al. study.

# Preterm babies born at < 32 weeks of gestation:
There was inconclusive evidence regarding the risk of mortality (RR 0.69, 95% CI 0.39-1.22) and the same was true for all the critical outcomes, including BPD, NEC, IVH, retinopathy of prematurity (ROP), and the proportion reaching target saturation by 5 or 10 minutes after birth.

# Research implications
The Guideline Development Group identified important knowledge gaps that need to be addressed through primary research. The quality of evidence was rated as "low" or "very low" for a number of recommendations, particularly those relating to questions about sub-populations. According to GRADE methodology, evidence quality that was rated as "low" or "very low" implies that further research is likely to have an impact on the corresponding recommendation(s). Conversely, further research is not a priority for those recommendations based on evidence of "moderate" or "high" quality. The knowledge gaps identified based on this concept were prioritized by considering whether such research would be original and innovative, feasible to implement, likely to promote equity, and likely to contribute to improvements in care for mothers and infants at risk of preterm birth. The priority research questions are listed as they relate to maternal and newborn interventions. What are the effects of task shifting in the context of magnesium sulfate administration (e.g. using the first dose in the community followed by referral to a health-care facility)? What are the effects of magnesium sulfate on the newborn in the immediate postpartum period (particularly on resuscitation)?

# Maternal research priorities

# Antibiotic prophylaxis
What is the appropriate dose and regimen that should be used for prophylaxis (particularly in relation to combination therapy with betalactam and macrolide)?

# Optimal mode of delivery for the preterm infant
What are the comparative effects and safety of vaginal versus caesarean delivery by gestational age and presentation?

# Newborn research priorities Kangaroo mother care (KMC)
What is the optimal frequency of follow-up for mothers providing KMC after discharge from the health-care facility? What is the minimum threshold of KMC exposure needed to achieve an impact on neonatal mortality and other important outcomes? Can KMC be effectively initiated in the community setting in LMICs?

# Continuous positive airway pressure (CPAP) and surfactant administration
What is the best modality for providing CPAP? e.g. nasal intermittent positive pressure ventilation, nasal flow cannulas, etc. What is the role of CPAP for babies with apnoea of prematurity that persists despite giving methylxanthines/caffeine? What is the efficacy of surfactants in a context where antenatal corticosteroids and early CPAP is provided (without immediate obligatory mechanical ventilation) for babies who are at risk of respiratory distress syndrome (e.g. InSUREintubation, surfactant replacement therapy and extubation)?

# Infection treatment
What is the role of emollient therapy in reducing infections and mortality among preterm infants?
What are the optimal feeding methods for preterm infants with birth weight < 1200 grams? Is there a role for total parenteral nutrition in the management of preterm infants?

# Growth and development
Are there effective interventions for the care and development of preterm infants and what are these?

# Dissemination and implementation of the guideline
The ultimate goal of this guideline is to improve the quality of care and health outcomes related to preterm birth. The dissemination and implementation of this guideline are therefore crucial steps that should be undertaken by the international community as well as by national and local health services. In this context, the WHO Department of Reproductive Health and Research has adopted a formal knowledge-to-action framework for the dissemination, adaptation and implementation of guidelines (72). In addition to this framework, a list of priority actions and events, advocacy and promotion opportunities identified during the WHO Technical Consultation will be used by WHO and other partners to facilitate the dissemination and implementation of this guideline.

# Guideline dissemination and evaluation
The recommendations in this guideline will be disseminated through a broad network of international partners, including WHO country and regional offices, ministries of health, WHO collaborating centres, other United Nations agencies, and nongovernmental organizations. After the final approval of the guideline, technical meetings will be held at WHO within the Department of Maternal, Newborn, Child and Adolescent Health and the Department of Reproductive Health and Research to share the recommendations and other related products with the teams responsible for policy and programme implementation. The recommendations will be published on the websites of these two WHO departments, as well as in the WHO Reproductive 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 for a wide range of policy-makers, programme managers and clinicians, and then disseminated through WHO regional and country offices.
The executive summary of the guideline will be translated into the six United Nations languages and disseminated through the WHO regional offices and during meetings organized by or attended by relevant WHO staff. Technical assistance will be provided as needed to any WHO regional office willing to 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 compliance with WHO's open access and copyright policies.

# Guideline implementation
The successful introduction of evidence-based policies related to the interventions to improve preterm birth outcomes into national programmes and health services depends on well planned and participatory consensus-driven processes of adaptation and implementation. These processes may include the development or revision of existing national guidelines or protocols based on this document. The Department of Maternal, Newborn, Child and Adolescent Health and the Department of Reproductive Health and Research at WHO will support national and subnational subgroups to adapt and implement the guideline based on existing strategies.
Within this context, the WHO Department of Reproductive Health will involve its international partnership called the GREAT Network (Guidelinedriven, Research priorities, Evidence synthesis, Application of evidence, and Transfer of knowledge) to adapt and implement guidelines particularly in LMICs (72). The GREAT Network uses a unique evidence-based knowledge translation approach to 1 Available at: / instrument

# DISSEMINATION AND IMPLEMENTATION OF THE GUIDELINE
support LMICs in the adaptation and implementation of guidelines relating to reproductive, maternal, perinatal and newborn health, and has been successfully employed for other WHO guidelines in many countries. Specifically, the GREAT Network brings together relevant stakeholders of the health care system to identify and assess the priorities, barriers and facilitators to guideline implementation, and supports the efforts of stakeholders to develop guideline adaptation and implementation strategies tailored to the local context. This includes technical support for local guideline implementers in the development of training manuals, flowcharts and quality indicators, as well as participation in stakeholder meetings.
The recommendations contained in the present guideline should be adapted into locally appropriate documents that are able to meet the specific needs of each country and its health service. Modifications to the recommendations, where necessary, should be limited to conditional recommendations, and justifications for any changes should be made in an explicit and transparent manner.
An enabling environment should be created for the use of these recommendations (e.g. ensuring that antenatal corticosteroids are available at hospitals), including changes in the behaviour of health-care practitioners and managers to enable the use of evidence-based practices. Local professional societies may play important roles in this process and an all-inclusive and participatory process should be encouraged.

# Applicability issues 6.1 Anticipated impact on the organization of care and resources
Effective implementation of the recommendations in this guideline may require re-organization of care and redistribution of health-care resources, particularly in low-and middle-income countries. The potential barriers to implementation include the following: Non-availability or irregular supply of essential medicine (e.g. antibiotics, corticosteroids, magnesium sulfate, and surfactant) and lack of equipment and supplies (e.g. oxygen, masks for oxygen administration, pulse oximeter, incubators, and radiant warmers); Lack of human resources with the necessary expertise and skills to implement the recommended practices and monitor recipients' clinical response (e.g. application of continuous positive airway pressure, intubation, oxygen therapy); Low certainty of gestational age estimation particularly in the obstetric population in lowresource countries; Lack of effective referral mechanisms and care pathways that ensure management of women with preterm labour and preterm infants within a continuum.
In order to overcome these barriers, the Guideline Development Group (GDG) noted that the following issues should be considered before the recommendations made in this guideline are applied: Local protocols should be developed that integrate the management of women at risk of imminent preterm birth and preterm infants within a continuum, with due consideration for contextual factors that influence preterm newborn survival. Careful attention should be paid to dating of pregnancy with the best method available during early antenatal care visits. Health-care staff should be trained on how to determine the best estimate of gestational age and clinical features of imminent preterm birth. Local arrangements should be made to ensure ample and consistent supplies of antenatal corticosteroids (dexamethasone or betamethasone), magnesium sulfate and antibiotics (macrolide or penicillin). Consideration should be given to all other aspects of maternal and newborn care quality at the health-care facility level, including the provision of radiant warmers and Kangaroo mother care (KMC). Clear referral pathways for women at risk of imminent preterm birth should be established within the health-care facility.

# Monitoring and evaluation of guideline impact
The implementation and impact of these recommendations will be monitored at the healthservice, regional and country levels, based on clearly defined criteria and indicators that are associated with locally agreed targets. At the Technical Consultation in May 2014, the GDG suggested a set of outcomes measures and indicators that can be adapted at regional and country levels to assess the impact of guideline implementation and adherence to the guideline recommendations. In collaboration with the monitoring and evaluation teams of the WHO Department of Maternal, Newborn, Child and Adolescent Health and the Department of Reproductive Health and Research, data on country-and regional-level implementation of the recommendations will be collected and evaluated in the short to medium term to evaluate its impact on the national policies of individual WHO Member States.
Interrupted time series, clinical audits or criterionbased clinical audits could be used to obtain relevant data related to the interventions contained in this guideline. Clearly defined review criteria and indicators are needed and these could be associated with locally agreed targets. In this context, the following indicators are suggested:
The proportion of all babies at risk of being born from 24 to < 34 weeks of gestation who were exposed to antenatal corticosteroids (numerator: all babies at risk of being born from 24 to < 34 weeks whose mothers received antenatal corticosteroids; denominator: all babies at risk of being born from 24 to < 34 weeks in the facility).
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).

# UPDATING THE GUIDELINE

# Updating the guideline
In accordance with the guidance of the WHO Guidelines Review Committee, which ensures a systematic and continuous process of identifying and bridging evidence gaps following guideline implementation, this guideline will be updated in five years after publication, unless new evidence emerges which necessitates earlier revision. WHO welcomes suggestions regarding additional questions for inclusion in the updated guideline. Please e-mail your suggestions to: mpa-info@who.int. The WHO Steering Group will continue to follow the research developments in the area of preterm birth, particularly those relating to questions for which no evidence was found and those that are supported by low-quality evidence, where new recommendations or a change in the published recommendation may be warranted, respectively. Following publication and dissemination of the guideline, any concern about validity of any recommendation will be promptly communicated to the guideline implementers in addition to plans to update the recommendation.