Preterm infants have a gestational age below 37 weeks at birth and low-birth-weight (LBW) infants have a birth weight below 2.5 kg. Approximately 45% of all children under the age of five who die are newborns, and 60-80% of those newborns who die are premature and/or small for gestational age. Preterm and LBW infants have a 2-to 10-fold higher risk of mortality than infants born at term and with normal birth weight. Despite substantial progress over the last 10 years, the survival, health, growth and neurodevelopment of preterm and LBW infants remains concerning in many countries. Reasons include the complexities of caring for these vulnerable infants and preventing complications.
The care of preterm and LBW infants is a global priority. The WHO Departments of Maternal, Newborn, Child and Adolescent Health and Ageing (MCA) and Sexual and Reproductive Health and Research (SRH) have developed three guidelines for the care of preterm or LBW infants: n Guidelines on optimal feeding of low-birth-weight infants in low-and middle-income countries, 2011; n WHO recommendations on interventions to improve preterm birth outcomes, 2015; and n Recommendations for management of common childhood conditions, 2012.
However, new evidence has emerged in many areas since the development of those guidelines. A review of 203 studies from low-, middle-and high-income countries about "what matters" to families about the care of their preterm or LBW infant reported that families want a positive outcome for their baby, to be involved in delivering care and to take an active role in deciding what interventions are given to their baby (these family values are listed in Table 1.1 in Chapter 1).
In December 2020, an international group of experts defined the scope and priority questions for the development of updated guidance about the care of preterm or LBW infants (see Figure 1 below, Table 1.2 in Chapter 1, and Web Annex A).  1. Introduction
Preterm infants have a gestational age below 37 weeks at birth and low-birth-weight (LBW) infants have a birth weight below 2.5 kg (1)(2)(3). Global estimates of prematurity and LBW range from 15% to 20%. In 2015, an estimated 20.5 million live births were LBW, with 91% of those being from low-and middle-income countries (LMICs), mainly in southern Asia (48%) and sub-Saharan Africa (24%) (1)(2)(3).
Approximately 45% of all children under the age of five who die are newborns (2.7 out of 5.9 million in 2014), and 60-80% of those newborns who die are premature and/or small for gestational age (4).
Preterm and LBW infants have a 2-to 10-fold higher risk of mortality than infants born at term (at least 37 weeks' gestation) and with normal birth weight (at least 2.5 kg), and are particularly vulnerable to impaired respiration, difficulty feeding, growth failure, poor body temperature regulation, and infection (5)(6)(7). Preterm and LBW infants have a higher risk of developmental disabilities, including cerebral palsy and retinopathy of prematurity, and long-term adult-onset chronic conditions such as cardiovascular disease (8,9).
The survival, health, growth and neurodevelopment of preterm and LBW infants remains concerning in many countries and the pace of improvement has been slow (10)(11)(12)(13). Reasons include the complexities of caring for these vulnerable infants and preventing complications. A review of 203 studies from low-, middle-and high-income settings, about "what matters" to families about the care of preterm or LBW infants reported that families want a positive outcome for their baby, to be involved in providing care for their baby, and to take an active role in deciding what interventions are given to their baby (see values and preferences listed in Table 1.1) (14).  (20); and n Recommendations for management of common childhood conditions, 2012 (21).
However, new evidence has emerged in many areas since the development of those guidelines.

# Target audience
The recommendations in this guideline are intended to inform the development of national and subnational health policies, clinical protocols and programmatic guides. Therefore, the target audience includes national and subnational public health policy-makers, implementers and managers of maternal, newborn and child health programmes, health-care facility managers, supervisors/instructors for in-service training, health workers (including midwives, auxiliary nurse-midwives, nurses, paediatricians, neonatologists, general medical practitioners and community health workers), nongovernmental organizations, professional societies involved in the planning and management of maternal, newborn and child health services, academic staff involved in research and in the preservice education and training of health workers, and those involved in the education of parents.

# Scope of the guideline
The recommendations cover the care of the preterm or LBW infant in any health-care facility or community setting from birth to 24 months of age unless otherwise indicated (see Table 1.2 and Figure 1.1). There are 25 recommendations and 1 good practice statement. They are summarized in Table 1 in the executive summary and presented in detail in Chapter 3. Of the recommendations, 11 are new and 14 are updated. There are 11 strong recommendations for all preterm or LBW infants and 14 recommendations that are conditional on particular contexts or conditions. Sixteen recommendations are for preventive and promotive care (section A of Chapter 3), six are for care for complications (section B) and three are for family involvement and support (section C). A good practice statement was made for parental leave and entitlements because the GDG determined that these have obvious benefits, although there was little evidence available.
Other recommendations for care of the preterm or LBW infant (i.e. the items in Figure 1.1 that are in italics, not bold) are covered elsewhere, or will be included in a future update (see Annex 1).
The recommendations presented here are also complementary to existing WHO guidelines for antenatal, intrapartum and postnatal care (20,(22)(23)(24).

# Intervention period
From birth to 24 months of age

# Comparators (C)
Usual care or no intervention

# Comparator period
From birth to 24 months of age

# Outcomes (O)
- Critical outcomes: infant all-cause mortality, morbidity, growth, neurodevelopment at latest follow-up - Other outcomes: other infant outcomes that are specific for the intervention at latest follow-up

# Outcome period Unrestricted
Health-care facility or home, in any country or setting
- Very preterm (< 32 weeks' gestation) or very LBW (< 1.5 kg) - Other, specific for the intervention
This document was developed using the standard operating procedures described in the WHO handbook for guideline development, second edition (25). The process included: (i) identifying priority questions and outcomes, (ii) retrieval of the evidence, (iii) assessment and synthesis of the evidence, (iv) formulation of recommendations and write-up of the guideline, and (v) planning for the dissemination, implementation, impact evaluation and updating of the recommendations.

# Contributors to the guideline
The groups involved in the development of the guideline are described below. The members of these groups are listed in Annex 2.

# WHO Steering Group
The guideline development process was supervised by the WHO Steering Group, comprising staff members from four WHO departments: Maternal, Newborn, Child and Adolescent Health and Ageing; Mental Health and Substance Abuse; Nutrition and Food Safety; and Sexual and Reproductive Health and Research. The Steering Group drafted the initial scope of the guideline; identified priority questions in the "PICO" format (encompassing population, intervention, comparators and outcomes); prepared the guideline planning proposal; identified and invited systematic review teams, the guideline methodologist and members of the Guideline Development Group (GDG); supervised evidence retrieval, assessment and synthesis; organized the GDG meetings; prepared draft recommendations for the consideration of the GDG; compiled the final guideline document; and managed the guideline publication and dissemination.

# Guideline Development Group (GDG)
The WHO Steering Group identified 25 external experts and stakeholders from the six WHO regions to form the GDG. Criteria included geographic representation, gender balance and no conflicts of interest. The final GDG was a diverse group of individuals with expertise in research, clinical practice, policy and programmes, guideline development methods and service delivery approaches, including patient and consumer representatives.
The GDG participated in a virtual scoping meeting with the Steering Group in December 2020, and provided input on the PICO questions and related details that had been drafted to guide the evidence reviews. The GDG members examined and interpreted the evidence, formulated the wording of the final recommendations and provided related remarks and considerations at virtual GDG meetings between November 2021 and January 2022. The GDG also reviewed and approved the final guideline document.

# External Review Group (ERG)
The ERG included four technical experts and stakeholders with expertise and experience in the provision of care for the preterm or LBW infant.
The group was geographically representative and gender balanced. The ERG peer-reviewed the draft guideline document after the GDG had approved it.
They assessed and provided feedback on: factual errors; clarity of language; guideline decision-making processes; values and preferences of persons affected by the recommendations (including families, health workers, managers and policy-makers); and the implications for implementation. It was not within the remit of this group to change recommendations that had been formulated by the GDG.

# Evidence Synthesis Team (EST)
The EST comprised the guideline methodologist, systematic review teams and members of the WHO Steering Group. Within the EST, there were two work streams, each addressing multiple domains (see section 2.4). The work streams initially prepared an overview of systematic reviews (26) and a review of what matters to families about the care of their preterm or LBW infant (see Table 1.1) (14). They then appraised the quality of existing systematic reviews and commissioned new systematic reviews and structured searches. The EST members then reviewed each systematic review, prepared the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence-to-Decision (EtD) frameworks for each priority question and attended the GDG meetings.

# External partners and observers
Representatives of the United Nations Children's Fund (UNICEF), Save the Children, the Bill & Melinda Gates Foundation, the International Pediatric Association (IPA) and the United States Agency for International Development (USAID) were invited to the GDG meetings as observers. These organizations are potential partners in the implementation of the guideline, as they have a history of collaboration with WHO in guideline dissemination and implementation.
Observers were allowed to make comments during technical discussions at selected times during the GDG meetings. Observers did not participate in discussions on the final recommendations.

# Declarations of interests by external contributors
In accordance with WHO procedures for declarations of interests (DOIs) (27), all GDG, EST and ERG members and other external collaborators were asked to declare in writing any competing interests (whether academic, financial or other), using the standard WHO DOI form, before engaging in the guideline development process. All experts were instructed to notify the responsible technical officer of any change in relevant interests, in order to update and review potential conflicts of interest accordingly.
In addition, the GDG members were requested to submit an electronic copy of their curriculum vitae.
The names and short curriculum vitae of the GDG members were published on the WHO website for public review and comment two weeks prior to the first GDG meeting.
The WHO Steering Group reviewed all DOI forms and curriculum vitae to determine whether any conflicts of interest existed. All findings from the DOI forms were managed in accordance with the WHO DOI guidelines on a case-by-case basis. 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 (25).
For this guideline, none of the declared interests were considered serious enough to pose any risk to the guideline development process or to reduce its credibility. Thus, all experts were only required to declare such interests at the first GDG meeting. At each subsequent GDG meeting, GDG and EST members and observers were required to share any new potential conflicts of interest with the group. Some GDG members had performed primary research related to one or more of the guideline recommendations. In these cases, the experts were restricted from participating in discussions or formulating any recommendations related to that specific area of interest. There were no important conflicts of interest among the ERG members.
A summary of the GDG DOIs and how conflicts of interest were managed is provided in Annex 3.

# Identifying priority questions and outcomes
At the scoping meeting, the GDG decided on the priority questions in the PICO format (population, intervention, comparators, outcomes), based on the following criteria: n values and preferences of families as outlined in the systematic review, "What matters to families about the care of their preterm or low-birth-weight (LBW) infant" (see Table 1.1) (14); n public health importance; n availability of new evidence; and n questions not addressed by existing WHO guidelines or those identified for update.
The final scope of the guideline is presented in Table 1.2 and Figure 1.1. The PICO questions can be found in Web Annex A.

# Evidence search, retrieval and review
The DECIDE approach (Developing and Evaluating Communication strategies to support Informed Decisions and practice based on Evidence) (28) was used to guide the evidence search, evidence synthesis and judgements by the EST, and the formulation of recommendations by the GDG. The DECIDE framework has nine core domains: benefits, harms, balance of effects, certainty, values, acceptability, resources, feasibility and equity (Table 2.2). Yes, probably yes, probably no, no, varies, unknown a DECIDE = Developing and Evaluating Communication strategies to support Informed Decisions and practice based on Evidence (28).
b GRADE = Grading of Recommendations Assessment, Development and Evaluation (29).
c GRADE-CERQual = Confidence in the Evidence from Reviews of Qualitative Research (30).
d Searches = Structured searches in UNICEF supply catalogue (31), International Medical Products Price Guide (32) and the WHO compendium of innovative health technologies for low-resource settings (33).
For effects (benefits and harms), evidence was derived from systematic reviews of randomized controlled trials (RCTs) where possible. If reviews of RCTs were not available, then systematic reviews of non-randomized studies of interventions were used. An overview of systematic reviews was compiled to identify all eligible systematic reviews that had been conducted in the last three years (26). If systematic reviews were not available, they were commissioned from expert systematic review groups. All commissioned systematic reviews followed standard methods, including: a standard protocol published in advance; a clear PICO question; criteria for identification of studies, including search strategies for different bibliographic databases; methods for assessing risk of bias; and a data analysis plan. The protocols were reviewed and approved by members of the Steering Group. The language used to describe the evidence on effects was consistent with the Cochrane Effective Practice and Organisation of Care approach (EPOC) (34). The GDG carefully considered the benefits and harms, the balance of effects, and the certainty of the evidence of effectiveness for each PICO question.
For values and acceptability, a systematic review on what matters to families about the care of their preterm or LBW infant was commissioned (14). This systematic review also followed standard methods for qualitative reviews, including: a standard protocol published in advance; a clear research question; criteria for identification of studies, including search strategies for different bibliographic databases; methods for assessing quality; and a data analysis plan. The protocol was also reviewed and approved by members of the Steering Group.
For resources, feasibility and equity, structured searches were done using search terms from effectiveness reviews and guidance published in the last five years. Databases included: Excerpta Medica database (Embase), MEDLINE, UNICEF supply catalogue, International Medical Products Price Guide, and the WHO compendium of innovative health technologies for low-resource settings (31)(32)(33)35,36).
This evidence was then compiled into a GRADE EtD framework for each priority question (see section 2.8).

# Grading of the quality and certainty of the evidence
The GRADE approach was used to appraise the quality and certainty of the quantitative evidence for each priority question. GRADE is a standard systematic approach for developing and presenting summaries of evidence for clinical practice recommendations (29). It uses standard tools, which are published online, including GRADE protocols and risk-of-bias tools for assessing randomized and non-randomized studies. A GRADE EtD framework is prepared for each quantitative outcome and the certainty of evidence is rated as "high", "moderate", "low" or "very low". The standard criteria for baseline GRADE ratings are that RCTs provide high-certainty evidence while non-randomized trials and observational studies provide low-certainty evidence. This baseline certainty rating is then downgraded based on characteristics of the study design: risk of bias, inconsistency, imprecision, indirectness and publication bias. Magnitude of effect and dose response allow upgrading of certainty for observational studies. Further details of the standard GRADE approach can be found online (29). For this guideline, both the systematic review teams and the external guideline methodologist (members of the EST) independently performed grading of the quantitative evidence for each priority question and outcome. Consensus was reached through discussion among the methodologist and all members of the EST.
For the qualitative evidence, the reviews were appraised using the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative Research) tool (30). This tool uses an approach that is similar conceptually to other GRADE tools and provides a transparent method for assessing and assigning the level of confidence that can be applied to qualitative evidence. The three domains are values, acceptability and feasibility, and each of them has four components: methodological limitations of the individual studies; adequacy of data; coherence; and relevance to the review question.

# Review of evidence, decisionmaking and recommendations
The WHO Steering Group provided the EtD frameworks to the GDG members as soon as the documents had been drafted, and in advance of the virtual GDG meetings. The GDG was asked to review and provide comments on the documents electronically before the GDG meetings where possible. At the virtual meetings, under the leadership of the GDG chairs, GDG members collectively reviewed the EtD frameworks, the draft recommendations and any comments received through preliminary feedback.
The meetings included: presentation of the evidence and EtD frameworks by the EST; consideration of each EtD domain; presentation of draft recommendations by the WHO Steering Group; deliberations on each recommendation; and discussion about justification, caveats or difficulties, implementation considerations and research gaps.
The purpose of the GDG meetings was to reach consensus on each recommendation, including its direction, strength and conditions, based on explicit consideration of all the domains within the EtD frameworks.
Recommendations were developed using WHO Guidelines Review Committee (GRC) criteria (Box 2.1) (25):
The final adoption of each recommendation was made by consensus, defined as the agreement by three quarters or more of the GDG. Consensus was reached for all recommendations in this guideline and there were no strong disagreements.
The GDG also identified important research gaps and implications. Where the certainty of available evidence was rated as low or very low, the GDG considered whether further research should be prioritized, based on whether the research would: contribute to improvements in care of the preterm or LBW infant; fill a knowledge gap that would inform new recommendations or change an existing recommendation; be likely to promote equity; and be feasible to implement. The research implications are summarized in Chapter 6 and full details can be found in Web Annex B.

# Document preparation and peer review
Following the final GDG meeting, the WHO responsible technical officer prepared a draft of the full guideline document to accurately reflect the deliberations and decisions of the GDG. Other members of the WHO Steering Group provided comments on the draft document before it was sent electronically to the GDG members for review and further comment. Subsequently, the revised document was also sent to the ERG members for peer review. The Steering Group carefully evaluated the input of the GDG members and the ERG peer reviewers for inclusion in the guideline document and made revisions to the draft document as needed. Further modifications to the guideline were limited to corrections of factual errors and improvements in language to address any lack of clarity and to conform to WHO style.

# Presentation of the recommendations and evidence
The recommendations are presented in the summary table in the executive summary of this guideline (Table 1). In Chapter 3, the recommendations and associated GDG remarks are presented at the start of the sections about each intervention, followed by background information and definitions, and a summary of the evidence for each recommendation. The evidence summaries present the evidence

# Box 2.1 Approach for developing recommendations and good practice statements
The recommendation is:
A "strong recommendation" if the intervention is applicable to all preterm or low-birth-weight infants
- Strong recommendations should be phrased as "is recommended", "is not recommended", "should receive", "should not receive".
A "conditional recommendation" if the intervention is recommended under certain conditions, which could be shared decision-making, or in certain populations or settings
- Conditional recommendations should be phrased as "may be considered".
A "good practice statement" if the intervention is obviously beneficial and should be done in most circumstances, even though there is no, little or only very-low-certainty evidence
The recommendations should be accompanied by a description of the certainty of the body of evidence: "high", "moderate", "low", or "very low".
Source: WHO, 2014 (25).
-n effectiveness (benefits and harms) of the interventions (sources and characteristics of the evidence, critical outcomes, other outcomes and subgroup analysis) followed by a summary of other evidence (values and acceptability, resources, feasibility and equity). Finally for each intervention, a summary of judgements is presented in a table, including justifications for the recommendation made (if any) and the EtD summary.
The GRADE data tables for each priority question are presented in the Web Supplement. 1 The GRADE tables contain the grading of: bias, inconsistency, indirectness, imprecision, number of participants, relative and absolute effect, risk difference and 95% confidence intervals. Further detail on methods can be found in the WHO handbook for guideline development and other documents (25,29).
This guideline is also accompanied by three web annexes: 2 n Web Annex A: Priority questions and outcomes n Web Annex B: Detailed list of research implications n Web Annex C: Changes from approved scope of guideline.

# Evidence and recommendations
This guideline includes 25 recommendations and 1 good practice statement (summarized in Table 1 in the executive summary and presented in detail in this chapter) for care of the preterm (born before 37 weeks' gestation) or low-birth-weight (LBW; < 2.5 kg) infant. Of the recommendations, 11 are new and 14 are updated, and the good practice statement is new. There are 11 strong recommendations for all preterm or LBW infants and 14 recommendations that are conditional on particular contexts or conditions.
Sixteen recommendations are for preventive and promotive care, six are for care for complications, and three are for family involvement and support. A good practice statement was made for parental leave and entitlements because the Guideline Development Group (GDG) determined that these have obvious benefits, although there was little evidence available.
The GDG provided remarks related to all the recommendations and the good practice statement, where needed. Users of the guideline should refer to these remarks, which are presented prominently along with the recommendations in this chapter.
The recommendations have been divided into the following categories, as presented in this chapter:
- Any KMC -KMC can be given at home or at the health-care facility.
-Infants who receive KMC should be secured firmly to the mother's chest with a binder that ensures a patent airway. -Whenever possible, the mother should provide KMC. If the mother is not available, fathers, partners and other family members can also provide KMC. -Infants who need intensive care should be managed in special units, where mothers, fathers, partners and other family members can be with their preterm or LBW infants 24 hours a day.
- Immediate KMC -At home, immediate KMC should be given to infants who have no danger signs (22).
-At health-care facilities, immediate KMC can be initiated before the infant is clinically stable unless the infant is unable to breathe spontaneously after resuscitation, is in shock or needs mechanical ventilation. The infant's clinical condition (including heart rate, breathing, colour, temperature and oxygen saturation, where possible) must be monitored.

# Background and definitions
Kangaroo mother care (KMC) is defined by WHO as early, continuous and prolonged skin-to-skin contact between the mother (or other caregiver) and the baby, and exclusive breastfeeding (20).
In 2015, WHO recommended that KMC be given to hospitalized babies under 2.0 kg as soon as the babies were clinically stable (20). However, there has been wide variation among care providers (i.e. parents/primary caregivers and health workers) in the timing and duration of KMC (37,38). New studies have also been published that assess the effects of KMC provided before clinical stabilization and also KMC initiated in community settings (39,40). and two studies were from a low-income country (Ethiopia). Twenty-five studies were conducted in health-care facilities and two were communitybased. In all but one of the studies, the infants were stabilized before enrolment. KMC was started within 24 hours after birth in two studies, between 1 and 7 days after birth in 10 studies, and more than 7 days after birth in 12 studies, but 3 studies did not report the timing of initiation of KMC. The duration of KMC was less than 8 hours in nine studies, between 8 and 16 hours in nine studies and more than 16 hours in four studies, while five studies did not report the duration of KMC.

# Summary of the evidence

# Critical outcomes
Sixteen trials reported all-cause mortality, 11 reported severe morbidity (

# Subgroup analyses
Subgroup differences for morbidity, growth and neurodevelopmental outcomes could not be assessed as there were insufficient studies. For all-cause mortality, no subgroup differences were seen for setting (health-care facility, community), gestational age (mean gestational age  16 hours/ day), although the analysis for daily duration of less than 8 hours was limited by small sample size and imprecision.

# Effectiveness: Comparison 2 -KMC initiated early versus later

# Sources and characteristics of the evidence
For the second comparison of KMC initiated early (< 24 hours after birth) versus KMC initiated late ( 24 hours after birth), the effectiveness evidence was derived from a systematic review of four RCTs totalling 3603 infants (41). One study was from a high-income country (Sweden), two were from lowincome countries (Gambia and Madagascar) and one was a multicountry study conducted in Ghana, India, Malawi, Nigeria and the United Republic of Tanzania. All studies were conducted in health-care facilities. Two studies enrolled babies irrespective of clinical stability, while one study enrolled only stable infants and one study enrolled only unstable babies. KMC was started as soon after birth as possible in all studies. The mean age at initiation of KMC was 1.3 hours, 13.6 hours and 19 hours after birth in three studies, while one study did not report the age of initiation of KMC. The duration of KMC was less than 8 hours in one study, more than 16 hours in two studies and not reported in one study.

# Critical outcomes

# Subgroup analyses
Differences for morbidity, growth and neurodevelopment could not be assessed as there were insufficient studies. For all-cause mortality, no subgroup differences were seen for setting (facility, community), gestational age (mean gestational age  16 hours/day).

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants and want to take an active role in deciding what interventions are given to infants, including skin-to-skin contact and feeding (14). A systematic review of caregivers' perspectives on KMC reported that social support, access to care and cultural norms were important drivers of family perceptions, practices, attitudes and values about KMC (38). Important elements included: services free of charge for users; support from health workers; parents allowed unlimited visiting hours at the health-care facility; a private, quiet space in the hospital to provide KMC; and involvement of fathers and partners. Another synthesis of qualitative studies suggested that providing KMC can be restorative as well as energy-draining for mothers, fathers and partners (37).

# Resources required and implementation considerations
Organization of care KMC can be implemented at home and at all levels of newborn care (primary, secondary and tertiary) (42).
Health services should ensure family involvement in the care of their preterm or LBW infant, irrespective of the infant's clinical condition. This should include a policy of "zero separation" between families and their preterm or LBW infant. This needs close collaboration between families and newborn and maternity care providers. Health-care facilities should ensure that families have access to beds, food, bathing and toilet facilities throughout the infant's hospital stay.
KMC is ideally initiated immediately after birth, or after initial resuscitation if that is needed. When it is not possible for the mother to provide KMC, other family members should provide it. To prepare for this situation, family members should be identified before delivery, counselled and allowed access to maternity and newborn care areas. If the infant needs to be transferred to a special or intensive care unit, the infant should be transported safely in KMC with the mother or another family member.   is being developed and will be published separately.

# Feasibility and equity
Facility-based studies have shown that KMC can be provided to small babies, for more than 8 hours per day, and that it can be initiated immediately after birth irrespective of clinical stability (39,43,45,46). These studies were conducted in poor, remote and urban communities in "real world pragmatic" settings (40,51). However, community-initiated KMC and KMC for unstable babies have not been implemented outside research settings and global coverage remains low (52,53).

# Summary of judgements
- The GDG made a strong recommendation despite low-certainty evidence because of the consistent harm from infant formula on two critical outcomes (necrotizing enterocolitis and infection) and lack of evidence of benefit from infant formula.
- The GDG also considered that providing mother's own milk is the standard of care across all countries and the core of many national policies and programmes.
- Mothers should also be encouraged and supported before and after birth to provide their own breastmilk (including colostrum) for their infants.

# Background and definitions
Mother's own milk confers important immune and nutritional advantages for preterm and LBW infants (54)(55)(56). Artificial formulas can be manipulated to contain higher amounts of important nutrients (such as protein) than mother's own milk (55,57). However, formula milks do not contain the antibodies and immune modulators and primers present in human milk that protect the immature gastro intestinal tract' of preterm and LBW infants (19,58,59). In 2011, WHO recommended that mother's own milk should be given to all preterm and LBW infants (19). All the included studies were observational; there were no RCTs. Thirty-six studies were from hospitals and six were from the "whole population" (all infants born in the study area regardless of whether they were admitted to hospital). The largest study (72 997 participants) was an observational study of all infants under 32 weeks' gestation admitted to 777 neonatal intensive care units (NICUs) in the USA. The studies used a combination of milks in the intervention and comparison groups.

# Summary of the
In the intervention group, all 42 studies used formula milk as the sole or predominant (> 50%) diet. Among these studies, 24 studies gave formula milk as the sole diet, 13 mixed formula with mother's own milk, 5 mixed formula with donor milk and mother's own milk, and 6 did not state whether they mixed formula milk with other milks. Twenty-one studies used preterm formula, 5 used term formula, 2 used a combination of preterm and term formula, and 14 did not state which type of formula was used.
In the comparison group, all 42 studies used mother's own milk as the sole or predominant (> 50%) diet. Among these studies, 9 studies gave mother's own milk as the sole diet, 17 mixed mother's own milk with donor human milk, and the remainder did not state if they mixed mother's own milk with other milks. Twenty studies used fortifier, 6 did not use fortifier and 16 did not state whether fortifier was provided.
Babies all received their feeds from birth until discharge or 28 days of age. Twenty-five used parenteral nutrition, 10 did not use parenteral nutrition and the remainder did not state if parenteral nutrition was used.

# Critical outcomes

# Subgroup analyses
There was no evidence of a subgroup difference by gestational age, birth weight, or type of milk in the control group for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see  (14). Two qualitative reviews reported that parents understood the importance of expressing breast-milk for the care of their baby but also found it challenging to express breast-milk unless supported by hospital staff and adequately informed about resources (61,62).
Reviews also report that families value having formula available if their circumstances demand it -for example, work commitments, maternity leave, nighttime feeding, father/partner support (14).

# Resources required and implementation considerations

# Organization of care
Mother's own milk should be provided through direct breastfeeding wherever possible. If direct breastfeeding is not possible, then breast-milk can be expressed and provided using cups and gastric tubes.

# Infrastructure, equipment and supplies
Breastfeeding requires no specific infrastructure, equipment or supplies. If expressed breast-milk is needed, milk can be expressed by hand or using a manual breast pump. Supplies are also needed for cup and gastric tube feeding. National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can provide breastfeeding support to mothers and families. Standardized packages are needed for training, supervision and monitoring.

# Feasibility and equity
Difficulties related to breastfeeding and expressing breast-milk in hospitals can include lack of privacy, inadequate training from busy health workers, and feelings of stress and inadequacy from mothers and families (63). There are also studies that report difficulties in providing mother's own milk when the mother and baby return home from hospital, including difficulties balancing work commitments, maternity leave, night-time feeding and father and partner support (14). There are many studies that report problems in sourcing clean water to reconstitute infant formula and wash receptacles in resource-limited settings (64,65).

# Summary of judgements
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The potential harm of necrotizing enterocolitis from infant formula was considered by the GDG to be more clinically important than the benefit of increased growth from infant formula.
- Donor human milk was pasteurized in all but one trial, so the GDG was not able to make a recommendation on the use of unpasteurized milk.
- Safe and affordable milk-banking facilities are needed for the provision of donor human milk.
- Mothers should also be encouraged and supported before and after birth to provide their own breastmilk (including colostrum) for their infants.

# Background and definitions
When mother's own milk is not available, preterm or LBW infants must be given other milks. Donor human milk is provided through human milk banks (i.e. places where human milk is collected, treated and/ or distributed) (56,66). Donor milk has differences in immune composition to mother's own milk.
Human milk banks also usually pasteurize milk to remove infective organisms, which further alters milk components (56,66). WHO LBW feeding guidelines in 2011 recommended feeding donor human milk rather than infant formula to preterm or LBW babies who cannot be fed mother's own milk (19). However, new studies have been published since that time.  (7 trials). A mix of term and preterm formula was used. The donor milk was a mix of preterm and term donor milk and a mix of fortified and unfortified milk. In all trials except one, the donor human milk was pasteurized. In general, feeds were allocated for several weeks, or until participating infants reached a specified body weight (generally > 2 kg). One trial used the allocated feed for less than 10 days after birth. Infants then received preterm formula if their mother's own milk was insufficient.

# Summary of the

# Critical outcomes

# Subgroup analyses
For the analyses by gestational age and birth weight and amount of donor milk in the control arm, differences for all critical outcomes could not be assessed as there were insufficient studies.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). A number of studies report the facilitators and barriers to donating and receiving donor human milk (68)(69)(70)(71). These include preferences for receiving human rather than artificial milk, concerns about the effect of pasteurization and transportation, and concerns that the mother's own breast-milk supply will reduce (68)(69)(70)(71). A large cross-sectional survey among health workers in urban Zimbabwe reported that the concept of donor human milk banking was acceptable, and that the participants would accept donor human milk for their children, and many would encourage their clients to donate human milk (68).

# Resources required and implementation considerations

# Organization of care
The provision of donor human milk requires access to a human milk bank where milk can be tested, pasteurized and transported safely.

# Infrastructure, equipment and supplies
Infrastructure, equipment and supplies are needed for donor assessment (screening, informed consent, serological testing), milk expression, handling, storage, transport, pre-pasteurization testing, pasteurization, and post-pasteurization testing. Supplies are also needed for safe cup and gastric tube feeding.

# Workforce, training, supervision and monitoring
Specialized staff are needed for the operation of donor human milk banks. Standardized packages are needed for training, supervision and monitoring. More detailed guidance on the operation of donor human milk banks is being developed and will be published separately. Health workers at all levels can provide feeding support.

# Feasibility and equity
A census of milk banks from a systematic literature review reported 572 milk banks globally in 60 countries, with the majority in high-income countries (68). It is well known that safe and affordable milkbanking facilities are needed for the provision of donor human milk. However, the base resources for donor milk feeding (i.e. donor recruitment, donor assessment milk expression, handling, storage, transport, pre-pasteurization testing, pasteurization, postpasteurization testing) are much less available in lowand middle-income countries (LMICs), especially in smaller towns and villages (66,72). The use of donor milk varies widely within and between countries and is influenced by cultural practices, access, costs, awareness, supportive policies and resources (66,72).

# Summary of judgements Comparison: Infant formula vs donor human milk (A.3) Justification
In trials where most participants are very preterm (< 32 weeks' gestation) or VLBW (< 1.5 kg):
- Evidence of small benefits from using infant formula instead of donor human milk: increased in-hospital weight gain, length and head circumference (moderate-certainty evidence) - Evidence of moderate harms from using infant formula instead of donor human milk: increased necrotizing enterocolitis and feed intolerance (moderate-certainty evidence) - Evidence of little or no effect of using infant formula on mortality and neurodevelopment (moderate-certainty evidence)
- The potential harm of mortality and necrotizing enterocolitis from fortification was considered by the GDG to be very uncertain due to the low quality of the included trials. The GDG also considered that the benefits of multicomponent fortifier were clinically important for the weight, length and head circumference of very preterm (< 32 weeks) or very-low-birth-weight (VLBW) (< 1.5 kg) infants. Thus, the GDG decided not to routinely recommend multicomponent fortifier for all preterm or LBW infants and suggested that fortification may be considered for very preterm or VLBW infants. This recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The GDG noted that there were limited data on the type of fortifier used in the studies. Based on most trials included in the evidence review, the GDG suggests that commercially available multicomponent fortifiers specifically formulated for preterm infants may be considered.
- The GDG also noted that there were limited data on the timing of initiation and duration of fortification in the studies. The GDG suggests that the initiation and duration of multicomponent fortification should be based on clinical judgement.
- Mothers should also be encouraged and supported before and after birth to provide their own breastmilk (including colostrum) for their infants.

# Background and definitions
Commercially available multicomponent fortifiers for infant human milk feeding can be human or animal (often cows' milk) protein based, and contain carbohydrate, fat, protein, multivitamins, iron, zinc, calcium and phosphorous in varying amounts (56,73). They are provided as liquid or powder and mixed with mother's own or donor human milk (74,75). Some health workers advise families to add multicomponent fortifier to human milk feeds for preterm and LBW infants with the intent to increase nutrient accretion (76,77). However, there are concerns that multicomponent fortifiers are associated with adverse events such as feed intolerance and necrotizing enterocolitis (56). WHO guidelines in 2011 recommended against the use of multicomponent fortifiers for all preterm and LBW babies but to use them for very-low-birth-weight (VLBW) babies (< 1.5 kg) or very preterm babies (< 32 weeks' gestation) who fail to gain weight (19).
There have been new trials since that time. Trials used a range of different "base" milks to feed the infants which were identical in the intervention and the control arms. Six trials used only mother's own milk, one trial used only donor human milk, seven trials used a mixture of mother's own milk and donor milk, and four trials used a mixture of mother's own milk, donor milk and preterm formula. Participants received the intervention once they were tolerating a specified quantity of milk feeding, typically at least 100 ml/kg per day, or when receiving "full" enteral feeds, typically 150 ml/kg per day.
In the intervention arm in all trials, multicomponent fortifier was mixed into the base milk and was provided according to the manufacturer's specifications. Fourteen trials used a commercially available, bovine-milk-based, powdered preparation and four trials used preterm formula powder as the multicomponent fortifier. No trials used humanmilk-derived fortifier. The fortifier was provided until a prespecified body weight was attained (most commonly, 1.8-2.0 kg), until a prespecified PMA (most commonly 34-36 weeks) or until discharge home from hospital.
In the control arm, eight trials gave infants multiple supplements (i.e. multivitamins, iron, zinc, calcium and phosphorus) in similar quantities to the nutrients in multicomponent fortifier, five trials gave infants only vitamin D, and five trials gave no supplements at all. No trials gave infants additional carbohydrate or protein in the control arm.

# Critical outcomes
For multicomponent fortification compared with unfortified breast-milk, two trials reported allcause mortality, 13

# Other outcomes
There was little or no effect on length of hospital stay in weeks (MD -0.07, 95% CI -0.35 to 0.21; 6 trials, 526 infants), or feed intolerance (RR 1.05, 95% CI 0.65 to 1.67; 7 trials, 453 infants).

# Subgroup analyses
The effect of gestational age and birth weight and type of fortifier could not be assessed as there were insufficient studies.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). No other specific evidence was located about whether families value fortified feeds rather than unfortified feeds for their preterm or LBW baby, or find fortified feeds more or less acceptable than unfortified feeds.

# Resources required and implementation considerations
Organization of care Health-care facilities can provide multicomponent fortifier for preterm or LBW infants.

# Infrastructure, equipment and supplies
The main commodity required is the fortifier, which should be a standard, nationally approved, multicomponent fortifier specially formulated for preterm or LBW infants. Commonly used fortifiers have similar amounts of carbohydrate, protein and micronutrients. Facilities for expressing breast-milk are also needed, as are facilities for the safe mixing of fortifier into expressed breast-milk. Supplies are also needed for cup or gastric tube feeding.

# Workforce, training, supervision and monitoring
Health workers at all levels can provide support to mothers and families. Standardized packages are needed for training, supervision and monitoring.

# Feasibility and equity
There was no specific evidence on the feasibility and equity of providing multicomponent fortifier for preterm or LBW infants.

# Summary of judgements Comparison: Multicomponent fortification vs unfortified breast-milk (A.4) Justification
In trials where most participants are very preterm (< 32 weeks' gestation) or VLBW (< 1.
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The GDG was not able to recommend a particular type of preterm formula. Based on most trials included in the evidence review, the GDG suggests that commercially available nutrient-enriched formulas specifically formulated for preterm infants may be considered.
- There was insufficient evidence to make a recommendation for infants who were born at 32-36 weeks' gestation or with birth weight of 1.5-2.4 kg. For these infants, the GDG considered that standard term formula or nutrient-enriched preterm formula may be considered, depending on clinical judgement.
- The GDG also noted that there was limited information on the timing of initiation and duration of preterm formula in the studies. The GDG suggests initiation and duration should be based on clinical judgement.
- Mothers should also be encouraged and supported before and after birth to provide their own breastmilk (including colostrum) for their infants.

# Background and definitions
If human milk is not available, then preterm and LBW infants need to be given infant formula in the first six months after birth (56). Some studies suggest that feeding preterm infants with nutrient-enriched formula (or preterm formula) rather than formula developed for term infants (also called term formula, or non-nutrient-enriched formula) might increase nutrient accretion, growth and neurodevelopmental outcomes (76,79,80). Preterm formula often has energy content over 72 kcal/100 ml and protein content over 1.7 g/100 ml (56,81). Term formula milks have varying energy and protein content, usually below these values (56,81). In 2011, WHO did not recommend preterm formula for feeding preterm and LBW infants (19).

# Summary of the

# Sources and characteristics of the evidence
The effectiveness evidence was derived from a 2019 Cochrane systematic review of seven trials including 590 infants (81). An updated search conducted on 1 September 2021 located no new trials. The trials were undertaken during the 1970s and 1980s in neonatal units in South Africa, Thailand, Turkiye, the United Kingdom and the USA. All infants were clinically stable preterm infants. Most were very low birth weight (< 1.5 kg). Few participants were extremely preterm (< 28 weeks), extremely low birth weight (< 1.0 kg) or growth restricted. The trials excluded infants with congenital anomalies, or respiratory, gastrointestinal or neurological problems.
Preterm formula was defined in the systematic review as a formula with both energy content over 72 kcal/100 ml and protein content over 1.7 g/100 ml and term formula was defined as a formula with both energy content below 72 kcal/100 ml and protein content below 1.7 g/100 ml. In six trials, the formula was the sole diet while in one trial the formula was used in addition to human milk. The milk feeds were started when infants were clinically stable and able to tolerate enteral feeds in all trials. Trial participants continued to receive the intervention or control formula for two weeks or until they reached 2.0 kg. The target volume of milk intake for both groups was 150-180 ml/kg per day.

# Critical outcomes

# Subgroup analyses
For the analysis by gestational age and birth weight, differences for all critical outcomes could not be assessed as there were insufficient studies.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). No other specific evidence was located about whether families value preterm formula rather than term formula for their preterm or LBW baby, or find preterm formula more or less acceptable than term formula.

# Resources required and implementation considerations
Organization of care Health workers and staff at other care facilities can provide preterm (nutrient-enriched) formula for preterm or LBW infants.

# Infrastructure, equipment and supplies
The main commodity required is the preterm formula, which should be a standard, nationally approved formula, specially formulated for preterm or LBW infants. Facilities are needed for safe reconstitution of preterm formula. Supplies are also needed for cup or gastric tube feeding.

# Workforce, training, supervision and monitoring
Health workers at all levels can provide support to mothers and families. Standardized packages are needed for training, supervision and monitoring.

# Feasibility and equity
There was no specific evidence on the feasibility and equity of providing preterm formula for preterm or LBW infants.

# Summary of judgements
Comparison: Preterm formula vs term formula (A.5) Preterm and low-birth-weight (LBW) infants, including very preterm (< 32 weeks' gestation) and very LBW (< 1.5 kg) infants, should be fed as early as possible from the first day after birth. Infants who are able to breastfeed should be put to the breast as soon as possible after birth. Infants who are unable to breastfeed should be given expressed mother's own milk as soon as it becomes available. If mother's own milk is not available, donor human milk should be given wherever possible. (Strong recommendation, moderate-certainty evidence)
- Enteral feeding includes direct breastfeeding and feeding by cups, naso-or orogastric tubes.
- The trials included in the systematic review mostly did not state the stability of the babies, so careful consideration is needed in applying these recommendations to unstable babies. The GDG considers that initiation of enteral feeding in unstable babies should be based on clinical judgement.
- Infants should be given mother's own milk wherever possible. The provision of colostrum is especially important. If mother's own milk is not available, then donor human milk should be given wherever possible. If human milk is not available, infants can be fed formula as this is preferable to delayed initiation of enteral feeding and the use of parenteral nutrition.
- There was no difference in effectiveness by volume of initial feed, so a recommendation was not made on restricting the volume of feed.
- In all but one of the trials, the control group received parenteral nutrition. The benefits of early initiation of enteral feeding may be even greater when the alternatives are intravenous fluids or dextrose water rather than parenteral nutrition.

# Background and definitions
WHO and UNICEF recommend early initiation of breastfeeding within 1 hour of birth for all healthy term infants (63). Clinicians continue to debate the optimal timing of feeding initiation for preterm and LBW infants for fear of potential health complications, including necrotizing enterocolitis (13,82,83). Additionally, women in communities around the world may delay feeding due to the cultural practices of discarding colostrum, pain and discomfort after delivery, and concern about the developmental maturity of the infant, including the infant's inability to digest milk feeds (84,85). In 2011, WHO recommended early initiation of enteral feeding for stable preterm or LBW infants (19). However, there have been new studies since that time. Effectiveness: Comparison -Early versus delayed initiation of enteral feeding

# Summary of the

# Sources and characteristics of the evidence
The effectiveness evidence was derived from a systematic review of 14 trials enrolling 1511 preterm or LBW infants, which compared early initiation of enteral feeding (< 72 hours) with delayed initiation of enteral feeding ( 72 hours). The trials were from nine countries (Canada, Chile, Colombia, India, the Netherlands, Spain, the United Arab Emirates, the United Kingdom and the USA) (86). All trials were based in hospital NICUs. Ten trials restricted enrolment to very preterm infants (< 32 weeks' gestation) or VLBW infants (< 1.5 kg) and five enrolled all preterm or LBW infants. Three studies enrolled only small-for-gestational-age (SGA) infants.
Early initiation time ranged from 1 to 3 days after birth and delayed initiation time ranged from 4 to 15 days after birth. Two studies initiated feeding by day 1 (i.e.  15 ml/kg per day. Only one trial provided direct breastfeeding while the remaining 13 gave feeds by naso-or orogastric tube. Three studies gave the babies formula milk, one gave mother's own milk and the remaining 10 gave a mixture of milks (i.e. mother's own, donor human milk and/or formula). All infants received supplemental parenteral nutrition in the delayed initiation group, except for one study which did not specify.

# Critical outcomes
For early feeding compared with delayed feeding for preterm or LBW infants, 12 studies reported allcause mortality outcomes, 14 reported morbidity (14 reported necrotizing enterocolitis, 6 sepsis, 1 intraventricular haemorrhage), 7 reported growth outcomes (7 reported time to regain birth weight, 1 weight, 1 length and 3 head circumference). None of the trials reported on neurodevelopment. (Full details are provided in GRADE

# Other outcomes
There was little or no effect on feed intolerance at discharge (RR 1.03, 95% CI 0.66 to 1.60; 2 trials, 187 participants) or length of hospital stay (days to discharge) (MD -3.2, 95% CI -5.74 to -0.66; 10 trials, 1100 participants).

# Subgroup analyses
For the analyses by gestational age and birth weight, subgroup differences could not be assessed as there were insufficient studies on any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). There have been studies of the barriers, facilitators, preferences, values and acceptability of early and late initiation of enteral feeding for preterm or LBW infants (84,85).
Reasons for delay in initiation of feeding include cultural practices of discarding colostrum, pain and discomfort after delivery, and concern about the developmental maturity of the baby, including the baby's inability to digest milk feeds. Reasons for early initiation include the importance of providing nurturing care to the baby as soon as possible, and concerns about the use of intravenous lines, dextrose water, total parenteral nutrition and lack of other nutritional support (84,85).

# Resources required and implementation considerations
Organization of care Early initiation of enteral feeding from the first day of life (the day of birth) can be implemented at home and at all levels of newborn care (primary, secondary and tertiary).
Infrastructure, equipment and supplies National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can provide early initiation support to mothers and families. Standardized packages are needed for training, supervision and monitoring.

# Feasibility and equity
There was no specific evidence on the feasibility and equity of early initiation of feeding for preterm or LBW infants.

# Summary of judgements
Comparison: Early vs delayed initiation of enteral feeding (A.

# A.7 RESPONSIVE AND SCHEDULED FEEDING Recommendation and remarks RECOMMENDATION A.7 (UPDATED)
In health-care facilities, scheduled feeding may be considered rather than responsive feeding for preterm infants born before 34 weeks' gestation, until the infant is discharged. (Conditional recommendation, lowcertainty evidence)
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- In making this decision, the GDG considered that the harms from responsive feeding (i.e. poor weight gain) outweighed the benefits (i.e. decreased length of hospital stay).
- Most data were about infants born before 34 weeks' gestation, so recommendations could not be made for infants born at or after 34 weeks' gestation.
- The included trials used a range of different feeding schedules and it was not possible to recommend a particular schedule. The GDG suggests 2-3 hourly scheduled feeding may be used for infants born before 34 weeks' gestation as this is a commonly used and feasible schedule.
- All studies were in hospitalized infants, so the GDG could not make a recommendation on feeding outside the hospital.
- Nurturing care and responsive caregiving are critical to the well-being of every preterm and LBW infant and should be implemented regardless of the type of feeding regime.

# Background and definitions
Responsive feeding is often defined as feeding in response to infant visual and auditory cues (or signals) of hunger and satiety (87)(88)(89). Infant cues include crying, hand-mouth motions, suckling and awakeness. Scheduled feeding is defined in many studies as enteral feeding at regularly timed intervals, irrespective of infant cues (87)(88)(89). A 2016 Cochrane review suggested that responsive feeding led to slower weight gain, but decreased the transition time from enteral tube to oral feeding (90). However, another systematic review reported that responsive feeding decreased the length of hospitalization and increased weight gain in infants (91). In 2011, WHO recommended that LBW infants who are orally fed but not breastfed should be fed based on infants' hunger cues, except when the infant remains asleep beyond three hours since the last feed (19). The studies were all conducted in NICUs and the responsive feeding was provided by health staff and not by families -that is, the health workers directly implemented a protocol of scheduled or responsive feeding regardless of whether a family member was present. The scheduled feeding regimes were mostly 2-to 3-hourly and the feeding volumes ranged from 120 to 180 ml/kg per day. The studies implemented the intervention for variable durations, with the minimum being 3 days and the maximum lasting until hospital discharge. Only one study recruited very preterm infants (< 32 weeks' gestation) while the remainder recruited preterm infants.

# Summary of the

# Critical outcomes
For responsive feeding compared with scheduled feeding for preterm or LBW infants, seven studies assessed growth outcomes (7 reported weight gain, 3 weight

# Other outcomes
Very-low-certainty evidence from three trials totalling 342 participants suggests a decrease in duration of hospitalization (days to discharge) (MD -1.42, 95% CI -5.43 to 2.59).

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient studies.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). No other specific evidence was located about whether families value responsive feeding more than scheduled feeding for their preterm or LBW baby or whether they find it more or less acceptable.

# Resources required and implementation considerations

# Organization of care
In facilities, infants born before 34 weeks' gestation can be fed every 2-3 hours. Infants born at 34 weeks' gestation or more can be fed every 3-4 hours or by responsive feeding. At home, there is no recommended scheduling; families and health workers can decide together, depending on clinical judgement and their preferences.

# Infrastructure, equipment and supplies
National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring.

# Feasibility and equity
Administration of scheduled feeds for preterm and LBW babies varies markedly but common scheduling is 2-to 3-hourly feeding with volumes of 80-200 ml/kg per day for babies born before 34 weeks' gestation. Responsive feeding requires sensitivity and careful observation of the baby's behaviour and is more commonly implemented in settings with well staffed special care nurseries and NICUs (87). There was no specific evidence on the feasibility and equity of responsive and scheduled feeding for preterm or LBW infants.

# Summary of judgements
Comparison: Responsive feeding vs scheduled feeding (A.7)
In trials where most participants are hospitalized infants born < 34 weeks' gestation:
- Evidence of small benefits from responsive feeding: decreased length of hospital stay (very-lowcertainty evidence) in trials of infants born < 34 weeks' gestation - Evidence of small harms from responsive feeding: decreased weight gain velocity in grams per day, and grams per kilogram per day (low-to very-low-certainty evidence), decreased weight gain in grams at discharge (very-low-certainty evidence) - No evidence on other critical outcomes Evidence-to-Decision summary
Benefits of responsive feeding are trivial to none
Harms of responsive feeding are small

# Very low to low
Balance Probably does not favour responsive feeding, probably favours scheduled feeding
Uncertainty or variability about outcomes
Acceptability of responsive feeding and scheduled feeding varies
Resources needed for responsive feeding and scheduled feeding vary
Feasibility of responsive feeding and scheduled feeding varies
Equity of responsive feeding and scheduled feeding varies

# A.8 FAST AND SLOW ADVANCEMENT OF FEEDING Recommendation and remarks RECOMMENDATION A.8 (UPDATED)
In preterm or low-birth-weight (LBW) infants, including very preterm (< 32 weeks' gestation) or very LBW (< 1.5 kg) infants, who need to be fed by an alternative feeding method to breastfeeding (e.g. gastric tube feeding or cup feeding), feed volumes can be increased by up to 30 ml/kg per day. (Conditional recommendation, moderate-certainty evidence)
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The GDG noted that the trials enrolled infants immediately after birth (i.e. day 1 -within 24 hours of birth) so results are generalizable to very early feeding of LBW infants from this time.
- All trials excluded babies with congenital anomalies and birth asphyxia, so careful consideration is needed in applying these recommendations to infants with these conditions. Feed advancement should be based on clinical judgement for these infants.
- All trials compared fast advancement (increments of 30-40 ml/kg per day) with slow advancement (increments of 15-25 ml/kg per day). So the GDG took the conservative value of 30 ml/kg per day as the threshold for fast feed advancement. This value is also consistent with many national guidelines.
- All studies were in hospitalized infants, so the GDG could not make a recommendation on feeding outside the hospital.
- The GDG did not make separate recommendations for babies fed formula milk versus human milk as there was insufficient evidence (only one trial gave formula as the sole diet while the remainder gave human milk only or a mix of human milk and formula).
- The GDG considered that advancement should continue until full maintenance feed volumes are reached. These volumes should be based on local guidelines.
- The GDG noted that further research is needed to understand the neurodevelopmental effects of fast feed advancement.

# Background and definitions
There is substantial variation in the definitions of fast and slow advancement of enteral feeding volumes for preterm and LBW babies in the first weeks after birth. Advancement increments commonly vary between 10 and 40 ml/kg per day (93,94). Up to the 1990s, the standard of care was a conservative ("slow rate") approach because of concerns about feed intolerance (e.g. gagging, vomiting and apnoea post-feed) and necrotizing enterocolitis (56). In 2011, WHO recommended that feeds could be advanced by up to 30 ml/kg per day with careful monitoring for feed intolerance in infants weighing under 1.5 kg (19). However, there have been new studies published since that time (95).

# Summary of the evidence

# Subgroup analyses
No subgroup differences were seen for gestational age and birth weight for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). No specific evidence was located about whether families value fast versus slow feed advancement for their preterm or LBW baby or whether they find the different rates more or less acceptable.

# Resources required and implementation considerations
Organization of care Feed advancement should be based on clinical judgement for all infants at home and in health-care facilities. In facilities, there can be fast advancement of feed volumes by up to 30 ml/kg per day.

# Infrastructure, equipment and supplies
National or local guidance on infrastructure, equipment and supplies for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring.

# Feasibility and equity
No specific evidence was located about the feasibility and equity of providing slow or fast feed advancement to preterm or LBW babies.

# Summary of judgements
- The GDG made strong recommendation in favour of exclusive breastfeeding (EBF) until 6 months of age despite the very-low-certainty evidence because they considered the potential harms of less than 6 months of EBF to outweigh the potential harms of having at least 6 months of EBF.
- In making the decision, the GDG also considered the results of a systematic review of 42 studies (89 638 infants) comparing mother's own milk with infant formula in babies aged 0-6 months (60). This review showed consistent harm from the use of infant formula on a critical outcome (morbidity: necrotizing enterocolitis) in the first 6 months after birth. It also reported no evidence of benefit from infant formula over the same period.
- The GDG also considered that EBF until 6 months of age is the standard of care for preterm and LBW infants across many high-, middle-and low-income countries and is the foundation of many national policies and programmes.
- The GDG also felt that mothers should be encouraged and supported before and after birth to provide their own breast-milk (including colostrum) for their infants.

# Background and definitions
WHO defines exclusive breastfeeding (EBF) as feeding no other foods or fluids (not even water) except breast-milk, medicines, vitamins and minerals (22). EBF until 6 months of age is recommended for full-term, normal-birth-weight infants (22). However, preterm and LBW infants are more vulnerable to nutritional deficiencies (13,56). The risks of contamination of complementary foods and early infant formula feeding are also well known (98). In 2011, WHO recommended EBF until 6 months of age for preterm and LBW babies (19), but new studies have been published since that time.

# Summary of the

# Other outcomes
There was a decrease in anaemia (haemoglobin level < 10.5 g/dl) (RR 0.10, 95% CI 0.01 to 0.77, 1 trial, 104 participants) but not in infants who received iron supplements (RR 1.07, 95% CI 0.22 to 5.28; 1 trial, 29 participants).

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14).
There are studies that report the difficulties in providing mother's own milk when the mother and baby return home, including difficulties balancing work commitments, maternity leave, night-time feeding and father/partner support (14). There are also studies that report family concerns with infant formula, including concerns about nutrient composition, water supply, contamination and cost (64,65). Studies also report families valuing having formula available if their circumstances demand it, such as work commitments, maternity leave, nighttime feeding, father and partner support (64,65). No specific evidence was located about whether families value EBF for up to 6 months of age for their preterm or LBW baby or whether they find the different durations of EBF more or less acceptable.

# Resources required and implementation considerations
Organization of care Promotion of exclusive breastfeeding for six months should be done at the community and facility level and be integrated within standard national programmes. This should occur throughout the antenatal and postnatal periods and up until the infant reaches 6 months of age.

# Infrastructure, equipment and supplies
National or local guidance for infrastructure, equipment and supplies for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can promote exclusive breastfeeding for six months. Standardized packages are needed for training, supervision and monitoring.

# Feasibility and equity
There was no specific evidence on the feasibility and equity of duration of EBF for preterm or LBW infants.

# Summary of judgements
- The GDG noted that there were limited data on dose, timing of initiation and duration of iron supplementation.
- Based on most trials included in the evidence review, the GDG suggests a daily dose of 2-4 mg/kg per day of elemental iron may be initiated when enteral feeds are well established, and may be continued until the infant receives iron from another source.

# Background and definitions
Iron deficiency is associated with poor growth and development outcomes in term and preterm babies (100,101). Human milk may not meet the nutritional requirements of preterm or LBW infants because of their low iron stores, red blood cell expansion, catch-up growth and iatrogenic blood loss. The most recent systematic reviews of RCTs and non-randomized studies reported that enteral iron supplementation may improve haematological outcomes in preterm and LBW babies but that there was insufficient evidence to assess effects on growth and neurodevelopmental outcomes (100,101). The optimal dose, optimal timing of initiation and the level and types of morbidity associated with iron supplementation were also unclear. In 2011, WHO recommended that VLBW infants fed mother's own milk or donor human milk should be given iron supplementation of 2-4 mg/kg per day starting at 2 weeks and continuing until 6 months of age (19).

# Summary of the

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). There was no specific evidence available about whether families value iron supplements for their preterm or LBW baby or whether they find them acceptable.

# Resources required and implementation considerations

# Organization of care
The supplements can be provided in the healthcare facility or at home. The family needs accurate information on the dose and how to administer the supplement. National or local guidance for healthcare facilities should be used.

# Infrastructure, equipment and supplies
Iron supplements are commonly provided to LBW and preterm infants as oral liquid solution. Infants are commonly prescribed 2-4 mg/kg of elemental iron per day for the prophylaxis of iron deficiency anaemia. Concentrations of 5 mg of elemental iron per millilitre of liquid are often used (e.g. 1 ml/day to a 2 kg baby will provide 2.5 mg of elemental iron per day). Droppers or syringes can be used to administer the supplement to the infant. Doses are different for the treatment of iron deficiency anaemia. National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring. Dispensing needs to be documented in clinical records.

# Feasibility and equity
There was no specific evidence available about the feasibility of providing iron supplements to preterm or LBW babies.

# Summary of judgements
- The GDG noted that the evidence on harms (decreased neurodevelopment) was uncertain due to verylow-certainty evidence and imprecision.
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The GDG noted that there were limited data on the dose, timing of initiation and duration of supplementation. Based on most trials included in the evidence review, the GDG suggests a daily dose of 1-3 mg/kg per day of elemental zinc. The GDG also suggests that zinc may be initiated when enteral feeds are well established, and may be continued until the infant receives zinc from another source.

# Background and definitions
Zinc is a trace element essential for physiological functions of the human body (103). Zinc deficiency is associated with dysfunction in epidermal, gastrointestinal, central nervous, immune, skeletal and reproductive systems (104,105). Human milk may not be able to meet the nutritional requirements of preterm or LBW infants because of their low zinc stores and catch-up growth (104)(105)(106). A recent (2021) Cochrane review of enteral zinc supplementation in hospitalized preterm infants fed any type of milk (i.e. infant formula or human milk) reported that zinc supplementation reduced all-cause mortality and was associated with a probable improvement in short-term weight gain and linear growth, but had little or no effect on common morbidities of prematurity (107). However, there have been no recent systematic reviews of zinc supplementation in babies born at home or in the hospital or on babies fed human milk only. The optimal dose and timing of initiation are also unclear.

# Summary of the

# Other outcomes
There was a decrease in hospitalization (at least one hospitalization) at latest follow-up (RR 0.70, 95% CI 0.24 to 2.00; 2 trials, 277 participants).

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome. For the dose of elemental zinc, no subgroup differences were seen for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). There was no specific evidence available about whether families value zinc supplements for their preterm or LBW baby or whether they find them acceptable.

# Resources required and implementation considerations

# Organization of care
The supplements can be provided in the healthcare facility or at home. The family needs accurate information on the dose and how to administer the supplement. National or local guidance for healthcare facilities should be used.

# Infrastructure, equipment and supplies
Zinc supplements are often provided as either 5 mg zinc capsules that are then opened and mixed with 5 ml of water (1 mg elemental zinc per ml) or zinccontaining multinutrient syrups (5 mg elemental zinc in 120 mls) (i.e. 42 g elemental zinc per ml). Babies are often prescribed 1-5 mls of these formulations daily. Droppers or syringes can be used to administer the supplement to the infant. National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring. Dispensing needs to be documented in clinical records.

# Feasibility and equity
There was no specific evidence available about the feasibility and equity of providing zinc supplements to preterm or LBW babies.

# Summary of judgements
- The GDG noted that the evidence on harms (increased mortality) was uncertain due to low-certainty evidence and imprecision.
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The GDG also noted improvements in vitamin D deficiency and alkaline phosphatase levels but there were no data on other markers of bone health such as osteopenia or rickets.
- The GDG noted that there were limited data on the dose, timing of initiation and duration of supplementation. Based on most trials included in the evidence review, the GDG suggests a daily dose of 400-800 IU may be initiated when enteral feeds are well established, and may be continued until the infant receives vitamin D from another source.

# Background and definitions
Vitamin D increases intestinal absorption of calcium and phosphorus, and enhances bone mineralization (42). Low vitamin D levels are associated with seizures, irritability, rickets (swollen, deformed, painful joints and bones), bone fractures, osteopenia (radiological evidence of thin bones) and metabolic bone disease (radiological evidence of widened or deformed bones) (109)(110)(111). Vitamin D deficiency has also been associated with increased risk of respiratory and diarrhoeal disease. Human milk may not be able to meet the nutritional requirements of preterm or LBW infants because of their low vitamin D stores and catch-up growth (56). Babies born to darker-skinned mothers are at higher risk of vitamin D deficiency, especially those born in higher latitudes and in the winter months (112). In 2011, WHO recommended that VLBW infants with birth weight below 1.5 kg should be given vitamin D supplements (400-1000 IU per day) until 6 months of age (19).
A systematic review published in 2020 reported improvements in vitamin D biomarkers (vitamin D levels, calcium levels, parathyroid hormone) after vitamin D supplementation was provided to all preterm infants (113).

# Summary of the

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials reporting on any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). There was no specific evidence available about whether families value vitamin D supplements for their preterm or LBW baby or whether they find them acceptable.

# Resources required and implementation considerations

# Organization of care
The supplements can be provided in the healthcare facility or at home. The family needs accurate information on the dose and how to administer the supplement. National or local guidance for healthcare facilities should be used.

# Infrastructure, equipment and supplies
Common methods of providing enteral vitamin D for preterm and LBW infants include infant multivitamin formulations (e.g. vitamins D, A, C, B group). Many formulations contain 400 IU vitamin D per 0.45-0.6 ml. Droppers or syringes can be used to administer the supplement to the infant. National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring. Dispensing needs to be documented in clinical records.

# Feasibility and equity
There was no specific evidence on the feasibility and equity of providing vitamin D supplements to preterm or LBW babies.

# Summary of judgements
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- There were no trials in infants born  32 weeks' gestation or  1.5 kg birth weight, so the GDG did not make a recommendation for those infants.
- The GDG noted that there were limited data on the dose, timing of initiation and duration of supplementation. Based on most trials included in the evidence review, the GDG suggests a daily dose of 1000-5000 IU may be initiated when enteral feeds are well established, and may be continued until the infant receives vitamin A from another source.

# Background and definitions
Vitamin A regulates cellular growth and helps to maintain the integrity of the mucosa and epithelium of the respiratory and gastrointestinal tracts (116,117).
Vitamin A may also boost immune function (118,119).
Preterm infants are born with low cord blood and liver storage of vitamin A (117). Supplementation with vitamin A has been reported to reduce bronchopulmonary dysplasia in studies of very preterm infants (born before 32 weeks' gestation) (116,120,121).

# Summary of the

# Effectiveness: Comparison -Vitamin A supplementation versus no vitamin A supplementation

# Sources and characteristics of the evidence
The effectiveness evidence was derived from a systematic review of RCTs of "low" daily dose (< 10 000 IU/day) enteral vitamin A supplementation for preterm and/or LBW infants, which included four trials and 800 participants from three countries (China, India and the United Kingdom) (122). All infants in the included trials had gestational age below 32 weeks or birth weight below 1.5 kg and most were born before 28 weeks' gestation (extremely preterm) or with birth weight below 1.0 kg (extremely LBW). Doses ranged from 1500 to 10 000 IU/day and initiation of supplementation was between 1 and 4 days of age in the trials. Two trials provided supplementation until 28 days after birth while the other two trials continued until 34-36 weeks PMA. n Growth: Low-certainty evidence from one trial with 188 participants suggests little to no effect on weight gain at latest follow-up (by hospital discharge or 16 weeks) (MD 0.02, 95% CI -0.2 to 0.24).

# Critical outcomes

# Other outcomes
There was a decrease in length of hospital stay (mean 6.3 weeks) (MD -8.76, 95% CI -32.1 to 14.58; 2 trials, 450 participants) and an increase in serum retinol concentration (measured in g/ml) at latest followup (mean 8 weeks) (MD 4.7, 95% CI 1.2 to 8.2; 1 trial, 36 participants).

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials reporting on any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). There was no specific evidence available about whether families value vitamin A supplements for their preterm or LBW baby or whether they find them acceptable.

# Resources required and implementation considerations

# Organization of care
The supplements can be provided in the healthcare facility or at home. The family needs accurate information on the dose and how to administer the supplement. National or local guidance for healthcare facilities should be used.

# Infrastructure, equipment and supplies
Common methods of providing enteral vitamin A for preterm and LBW infants include infant multivitamin formulations (e.g. vitamins D, A, C, B group) in 30-50 ml bottles. Many formulations contain 1000-5000 IU vitamin A per 0.45-0.6 ml. Droppers or syringes can be used to administer the supplement to the infant. National or local guidance for healthcare facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring. Dispensing needs to be documented in clinical records.

# Feasibility and equity
There was no specific evidence available about the feasibility and equity of providing vitamin A supplements to preterm or LBW babies.

# Summary of judgements
- The GDG decided not to make a recommendation on calcium or phosphorous supplementation as there was little evidence of benefits or harms on any critical outcome.

# Background and definitions
Preterm and LBW infants have low skeletal stores of calcium and phosphorus (123). Previous systematic reviews have reported that calcium and phosphorous supplements given to human-milk-fed preterm or LBW infants had no effect on growth (weight, length, head circumference) but improved bone biomarkers (serum alkaline phosphatase) (123,124). No effects have been reported on mortality, morbidity or neurodevelopment and no evidence was found on the optimal dose or timing of initiation.

# Summary of the

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials reporting on any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). There was no specific evidence available about whether families value calcium and phosphorous supplements for their preterm or LBW baby or whether they find them acceptable.

# Resources required and implementation considerations

# Organization of care
The supplements can be provided in the healthcare facility or at home. The family needs accurate information on the dose and how to administer the supplement. National or local guidance for healthcare facilities should be used.

# Infrastructure, equipment and supplies
Common methods of providing enteral calcium and phosphorous for preterm and LBW infants include a 5 ml suspension containing 125 mg of calcium, 55 mg of phosphorus and 200 IU of vitamin D, which is given three times a day at a dose of 2 ml/kg. Droppers or syringes can be used to administer the supplement to the infant. National or local guidance for health facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring. Dispensing needs to be documented in clinical records.

# Feasibility and equity
There was no specific evidence available about the feasibility and equity of providing calcium and phosphorous supplements to preterm or LBW babies.

# Summary of judgements
- The GDG decided not to make a recommendation on MMN supplementation as there was no evidence of benefits or harms on any critical outcome.

# Background and definitions
Many health workers advise families to give MMN supplements to human-milk-fed preterm and LBW infants (76,123). The supplements commonly include A, D, E, B group vitamins, and some contain iron, zinc, folate and magnesium (56). However, there has been no systematic review of the effect of MMN supplements on health and developmental outcomes in preterm and LBW infants. All of these neurodevelopment outcomes were measured using BSID-III.

# Summary of the

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials reporting on any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting nutrition, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14). There was no specific evidence available about whether families value MMN supplements for their preterm or LBW baby or find them acceptable.

# Resources required and implementation considerations

# Organization of care
The supplements can be provided in the healthcare facility or at home. The family needs accurate information on the dose and how to administer the supplement. National or local guidance for healthcare facilities should be used.

# Infrastructure, equipment and supplies
Common methods of providing enteral MMN supplements for preterm and LBW infants include infant multivitamin formulations (e.g. vitamins D, A, C, B group with added iron) in 30-50 ml bottles. Droppers or syringes can be used to administer the supplement to the infant. National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring. Dispensing needs to be documented in clinical records.

# Feasibility and equity
There was no specific evidence available about the feasibility and equity of providing MMN supplements to preterm or LBW babies.

# Summary of judgements
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The GDG noted that there are many infant probiotic formulations available in the public domain that have variable quality control and formulation (127,128).
- The GDG considered that only probiotics especially formulated for preterm or LBW infants that meet regulatory standards should be used, and clear instructions for safe use should be given to health workers.
- The GDG did not make a recommendation for infants born after 32 weeks' gestation because the data were insufficient.
- Only five trials (254 participants) included infants fed formula as the sole diet, so the GDG did not make a recommendation for these infants.
- The GDG was not able to make a recommendation on type (i.e. genera, species or strain), formulation (e.g. powder or drops), dose, timing or duration of probiotic administration as there was insufficient evidence. The GDG considered that type, formulation, dose, timing and duration should be based on clinical judgement.

# Background and definitions
Probiotics are formulations given by the enteral route that contain bacteria (e.g. Bifidobacterium spp. or Lactobacillus spp.) or fungi (e.g. Saccharomyces spp.) (129,130). A range of probiotic supplements are available commercially. Probiotics colonize the mucosal surface of the human gastrointestinal tract, modulate the intestinal microbiome and promote mucosal barrier functions (129,130). Probiotics have been used to prevent and treat infectious or inflammatory gastrointestinal conditions primarily in adults, with only low-certainty evidence of any benefit for most conditions (131)(132)(133). There have also been many trials of probiotics in preterm and LBW infants in the last 10 years showing varying effects, including reductions in sepsis and necrotizing enterocolitis (134)(135)(136)(137), but also increases in bacteraemia and fungaemia (134,138,139).

# Summary of the evidence

# Other outcomes
There was a decrease in length of hospital stay (in days) (MD -1.93, 95% CI -3.78 to -0.08; 22 trials, 5458 infants).

# Subgroup analyses
Subgroup differences for growth and neurodevelopment could not be assessed as there were insufficient studies. No difference was found for mortality, necrotizing enterocolitis or sepsis for any of the subgroups: gestational age and birth weight, probiotic species or type of enteral feed.

# Other studies

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, and want to take an active role in deciding what interventions are given to infants, including what and how they are fed (14).
A study from the United Kingdom reported that families are willing to consider use of probiotics for their preterm or LBW infants if there is evidence of benefit and safety (140). There was no other specific evidence available about whether families value probiotic supplements for their preterm or LBW baby or find them acceptable.

# Resources required and implementation considerations
Organization of care Probiotics can be provided in the health-care facility or at home. The family needs accurate information on the dose and how to administer the supplement. National or local guidance for health-care facilities should be used.

# Infrastructure, equipment and supplies
Common probiotic preparations are either singlegenus or multi-genus probiotic combinations (including Bifidobacterium spp. plus Lactobacillus spp). Dosing, amounts, frequency and duration vary.
Probiotics can be provided as powder or liquids in bottles or mixed with infant milk or sterile water. National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring. Dispensing needs to be documented in clinical records.

# Feasibility and equity
There was no specific evidence available about the feasibility and equity of providing probiotics to preterm or LBW babies.

# Summary of judgements
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The GDG noted that there were limited data on the type, dose, timing of initiation and duration of oil use. Based on most of the trials included in the evidence review, the GDG suggested that sunflower or coconut oils may be used and that initiation and duration of use may be based on clinical judgement. The GDG also felt that application of oils should be done gently to avoid disrupting skin integrity.
- The GDG decided not to make a recommendation on the use of ointments or creams due to little or no effect on mortality and morbidity (invasive infection, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity) and no evidence on other critical outcomes.

# Background and definitions
Emollients are moisturizing treatments applied topically, i.e. directly to the skin. They include ointments (water-in-oil suspensions), creams (oilin-water suspensions) and natural vegetable or plant topical oils (e.g. sunflower and coconut oils). The skin of preterm infants is developmentally immature (141,142) and can be easily abraded, which can allow entry of pathogenic organisms (143). Topical emollients can improve skin integrity and barrier (protective) functions but they can also disrupt skin integrity, remove normal flora and microorganisms and increase colonization with other microorganisms (142). Emollients also contain fatty acids and other fluids that can be absorbed through the skin (141). However, there have been no recent systematic reviews of the effectiveness of topical ointments, creams or oils in preterm and LBW infants.

# Summary of the

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Other studies
One additional trial also reported a decrease in infection-specific mortality by 28 days of age (adjusted odds ratio 0. Very-low-certainty evidence from one trial with 952 participants suggests little or no effect on retinopathy of prematurity by hospital discharge (RR 0.99, 95% CI 0.77 to 1.28).

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, and want to take an active role in deciding what interventions are given to infants, including what and how they receive skin care (14). There was no specific evidence available about whether families value emollients for their preterm or LBW baby or find them more or less acceptable.

# Resources required and implementation considerations

# Organization of care
Emollients can be provided in the health-care facility or at home. They can be spread gently over the infant's abdomen, back and limbs. The family needs accurate information on how to apply the emollients gently. National or local guidance for health-care facilities should be used.

# Infrastructure, equipment and supplies
Emollient preparations include sunflower and coconut oils. National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring. Dispensing needs to be documented in clinical records.

# Feasibility and equity
There was no specific evidence available about the feasibility and equity of topical emollient application for preterm or LBW babies.

# Summary of judgements
- The GDG noted that the evidence on harms (increased pneumothorax) was of uncertain clinical significance and the overall certainty of the body of evidence was low due to imprecision and indirectness.
- The GDG noted that there were limited data on the timing of initiation and duration of CPAP. Based on most of the trials included in the evidence review, the GDG suggests that CPAP may be considered as soon as the diagnosis of respiratory distress syndrome (RDS) is clinically suspected, and that duration should be based on clinical judgement.
- The GDG also noted that CPAP implementation must be done with skilled staff, quality equipment and quality consumables (including humidified blended oxygen-air and monitors).
- The GDG decided not to make a separate recommendation on the timing of CPAP for infants with RDS.

# Background and definitions
Respiratory distress syndrome (RDS) is a major cause of morbidity and mortality in preterm infants (146). RDS commonly develops in the first hours after birth and develops or "becomes established" over the first few days after birth (146)(147)(148). Until the 1970s, initial therapy for RDS was traditionally oxygen given through a head box or nasal prongs, and infants with severe disease received mechanical ventilation.
Continuous positive airway pressure (CPAP) involves connecting a nasal "interface" (prongs, face mask or head box) via tubing to a pressure source with an air-oxygen mix (149,150). CPAP provides distending pressure into the upper and lower airways preventing collapse, especially during expiration. CPAP devices were adapted for use in preterm babies in the 1970s and CPAP is now routinely used for preterm babies with RDS in many health-care facilities globally. Effectiveness: Comparison -Any CPAP versus supplemental oxygen

# Sources and characteristics of the evidence
The effectiveness evidence for this comparison was derived from a Cochrane systematic review of five RCTs conducted in the 1970s and 1980s reporting on a total of 322 preterm infants (151). An updated search conducted on 1 October 2021 located no new trials.
Four studies were conducted in high-income settings (Australia, the United Kingdom and the USA) and one in a low-resource setting (the United Republic of Tanzania). Infants were included if they had RDS (defined as an infant needing FiO 2  > 0.30). All trials used traditional CPAP as the intervention, none used "bubble" or newer types of CPAP. The comparator in all the trials was supplemental oxygen. No infants received mechanical ventilation in the control group. The mean age at study entry ranged from 10 to 150 hours postbirth. The mean birth weight of infants was 1.7-2.0 kg, with two trials excluding infants weighing less than 1.0 kg at birth.

# Critical outcomes
For any CPAP compared with supplemental oxygen for RDS, five trials reported all-cause mortality outcomes, five trials reported morbidity (

# Other outcomes
One trial reported a decrease in the composite outcome of death or abnormal blood gases by hospital discharge (RR 0.53, 95% CI 0.32 to 0.90; 1 trial, 24 infants). One trial reported a decrease in the outcome of "transfer to an NICU" by hospital discharge (RR 0.49, 95% CI 0.30 to 0.78; 1 trial, 24 infants). One trial reported a decrease in the duration of oxygen therapy by hospital discharge (MD 0.20 days, 95% CI -2.47 to 2.87; 1 trial, 24 infants).

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Effectiveness: Comparison 2 -Early versus delayed CPAP

# Sources and characteristics of the evidence
The effectiveness evidence for this comparison was derived from a systematic review of four trials (2 RCTs and 2 quasi-RCTs) that recruited 119 preterm infants with RDS (mean birth weight 1.5-2.1 kg, mean gestational age 31-34 weeks) conducted in the United Kingdom and the USA in the 1970s or the early 1980s (152). An updated search conducted on 1 October 2021 located no new trials. Infants were eligible for inclusion if they were given a diagnosis of RDS (based on clinical and radiological criteria) and were breathing spontaneously. Infants were randomized to receive CPAP immediately as soon as the diagnosis of RDS was made ("early group") or for treatment to be delayed until deterioration as defined by the study ("delayed group"). The early CPAP group received CPAP at a mean age of 7-18 hours post-birth and required FiO 2 0.30 to 0.60. The delayed CPAP group required FiO 2 from 0.60 to 1.0 but the mean age of receipt of CPAP was not stated in any trial.

# Critical outcomes
For early compared with delayed CPAP for RDS, four trials reported all-cause mortality, four trials reported morbidity (4 reported the use of mechanical ventilation, 3 pneumothorax, 1 bronchopulmonary dysplasia

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Other studies
Two studies assessing the effect of continuous negative pressure (153,154) were included in the previous Cochrane review (155) but not in the updated Cochrane review (152), due to a change in the PICO intervention from negative pressure to continuous positive airway pressure (CPAP). The Cochrane review also excluded two RCTs (156,157) because they provided very early CPAP at 5 minutes of age, which was considered to be earlier that RDS could be established in the babies. These two

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that carers want assistance in interacting with their babies, especially when they are undergoing therapies that make it difficult to have physical contact (14). They want to learn about the health-care setting where they need to stay and care for their baby. They want to understand what medical equipment is being used and why. Studies report that families can find mechanical ventilation and CPAP intimidating and frightening and that these therapies can accentuate their feelings of inadequacy and lack of control over their baby's health care (147,159). Families also worry about the pain and discomfort their baby is experiencing in NICUs (14). No other specific evidence was located about whether families value CPAP rather than supplemental oxygen for their preterm or LBW baby or whether they find CPAP more or less acceptable than other supplemental oxygen.

# Resources required and implementation considerations
Organization of care CPAP for preterm or LBW infants should be done in special or intensive care units (level 2 or 3 facilities).
Infrastructure, equipment and supplies CPAP devices include a pressure source with an air-oxygen mix. CPAP devices include "bubble" (underwater, water-seal) CPAP, ventilator CPAP and "Infant Flow Driver" CPAP. CPAP also requires an "interface", which is commonly a mask or nasal prongs. Disposable tubes and suction catheters are also needed. National or local guidance for healthcare facilities should be used.

# Workforce, training, supervision and monitoring
Health workers who are qualified to work in level 2 (special newborn care units, special care nurseries) and level 3 (intensive care) facilities can support the provision of CPAP. Standardized packages are needed for training, supervision and monitoring.

# Feasibility and equity
There was no specific evidence on the feasibility and equity of providing CPAP for preterm or LBW infants.

# Summary of judgements
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The GDG noted that duration of CPAP (i.e. when to stop CPAP) should be based on clinical judgement.
- The GDG also noted that skilled staff and quality equipment (including humidified blended oxygen-air) are needed for the administration of CPAP to preterm and LBW infants.

# Background and definitions
The benefits of CPAP for RDS in preterm infants are well established (151,155). However, it can be difficult to ascertain respiratory status in preterm babies soon after birth and to accurately predict the prognosis.
Preterm babies with respiratory failure may not show signs of respiratory distress in the first hours after birth and babies with early respiratory distress may improve (147). Thus, health workers in NICUs sometimes administer CPAP immediately after birth to all babies at risk, regardless of respiratory status (sometimes called immediate CPAP), rather than assessing for RDS. Benefits and harms of this practice have been unclear (147,148,150). However, recent trials have assessed the effectiveness of immediate CPAP compared with both supplemental oxygen and mechanical ventilation.

# Other outcomes
Three trials reported a decrease in surfactant use by hospital discharge (RR 0.75, 95% CI 0.58 to 0.96; 3 trials, 683 participants).

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Effectiveness: Comparison 2 -Immediate CPAP versus mechanical ventilation
Sources and characteristics of the evidence For this comparison, the effectiveness evidence was derived from the same Cochrane systematic review (158). Three trials were included, which enrolled a total of 2364 very preterm infants (< 32 weeks' gestation) from 17 countries (Argentina, Australia, Belgium, Brazil, Canada, Chile, France, Germany, Greece, Italy, the Islamic Republic of Iran, New Zealand, Norway, Paraguay, Peru, Uruguay and the USA). An updated search conducted on 1 October 2021 located no new trials. The review included the same two types of trials as described above.

# Critical outcomes

# Other outcomes
There was decrease in surfactant use (RR 0.60, 95% CI 0.57 to 0.63; 3 trials, 2354 infants).

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that carers want assistance in interacting with their babies, especially when they are undergoing therapies that make it difficult to have physical contact (14). They want to learn about the health-care setting where they need to stay and care for their baby. They want to understand what medical equipment is being used and why. Studies report that families can find mechanical ventilation and CPAP intimidating and frightening and that these therapies can accentuate their feelings of inadequacy and lack of control over their baby's health care (147,159).
Families also worry about the pain and discomfort their baby is experiencing in NICUs (14). No other specific evidence was located about whether families value immediate CPAP for their preterm or LBW baby or whether they find it more or less acceptable than supplemental oxygen.

# Resources required and implementation considerations
Please refer to the information on this topic in section B.1.

# Feasibility and equity
As described in section B.1, there was no specific evidence on the feasibility and equity of providing CPAP for preterm or LBW infants.

# Summary of judgements
Comparison 1. CPAP immediately after birth for very preterm infants vs supplemental oxygen (B2.a)

# Comparison 2. CPAP immediately after birth for very preterm infants vs mechanical ventilation (B2.a) Justification
In trials where most participants are very preterm (< 32 weeks' gestation):
- Evidence of small benefits: decreased "failed treatment" (defined as recurrent apnoea, hypoxia, hypercarbia, increasing oxygen requirement or the need for mechanical ventilation), decreased bronchopulmonary dysplasia (moderatecertainty evidence) and decreased pneumothorax (low-certainty evidence)
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- Evidence was derived from trials that compared underwater (water-seal) "bubble" CPAP with mechanical ventilator CPAP or Infant Flow Driver (IFD) CPAP. All trials used commercially available devices and all used humidified blended oxygen-air.
- The GDG noted that the evidence on harms (increased nasal injury) was of uncertain clinical significance and the certainty of the body of evidence was low due to bias and imprecision.
- The GDG suggested that the nasal interfaces (i.e. prongs and cannulas) used with bubble CPAP machines should be carefully selected and that skilled nursing care is needed for the prongs and cannulas.
- The GDG also considered that careful selection, maintenance and monitoring of bubble CPAP devices is needed. Only commercially available bubble CPAP devices should be used; locally-manufactured or locally-adapted bubble CPAP devices should not be used.

# Background and definitions
There are many different types of CPAP machines and pressure generation for ventilatory support of preterm infants. There is also considerable variation in practice and differing reports of benefits and harms (150,160,161). The older-style CPAP pressure sources were mechanical ventilators; newer types include Infant Flow Driver (IFD) and bubble CPAP. Bubble CPAP uses an underwater water-seal method and is commonly used for providing CPAP to babies in LMICs (150,160,161).

# Sources and characteristics of the evidence
The effectiveness evidence was derived from a systematic review of 15 RCTs including a total of 1437 preterm infants (162). Most trials were small (median number of participants 88 [IQR. They were conducted over the past 25 years in neonatal centres in seven countries (Albania, Armenia, Brazil, India, the Islamic Republic of Iran, Italy and the United Kingdom). The inclusion criteria were infants who required primary treatment for RDS after birth or following a period of mechanical ventilation (postextubation). Most infants were born before 32 weeks' gestation (very preterm). Thirteen trials included both RDS and post-extubation infants, two trials included infants with RDS only and no trials included post-extubation infants only. All trials compared bubble CPAP with ventilator or IFD CPAP devices.
The devices were all commercially manufactured; no locally manufactured or locally adapted devices were used. The interfaces in all trials were short nasal prongs. All infants received standard supportive care (i.e. supplemental oxygen).

# Critical outcomes
For bubble CPAP compared with ventilator or IFD nasal CPAP, 10 trials reported all-cause mortality, 14 reported morbidity (13 reported "treatment failure", 14 pneumothorax, 7 bronchopulmonary dysplasia and 8 nasal injury

# Other outcomes
There was a decrease in length of hospital stay (in days) (MD -3.27, 95% CI -4.99 to -1.56 days; 5 trials, 591 participants).

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (Table 1.1) reported that carers want assistance in interacting with their babies, especially when they are undergoing therapies that make it difficult to have physical contact (14). They want to learn about the health-care setting where they need to stay and care for their baby. They want to understand what medical equipment is being used and why. Studies report that families can find mechanical ventilation and CPAP intimidating and frightening and that these therapies can accentuate their feelings of inadequacy and lack of control over their baby's health care (147,159). Families also worry about the pain and discomfort their baby is experiencing in NICUs (14).
Studies from LMICs indicate that bubble CPAP is both valued and acceptable to families and health workers (163,164). No other specific evidence was located about whether families value bubble CPAP rather than other types of CPAP for their preterm or LBW baby or whether they find bubble CPAP more or less acceptable.

# Resources required and implementation considerations
Please refer to the information on this topic in section B.1.

# Feasibility and equity
Studies from LMICs (165)(166)(167)(168) report the low cost and feasibility of establishing bubble CPAP services. There was no other specific evidence on the feasibility and equity of providing CPAP for preterm or LBW infants.

# B.4 METHYLXANTHINES FOR TREATMENT OF APNOEA Recommendation and remarks RECOMMENDATION B.4 (NEW)
Caffeine is recommended for the treatment of apnoea in preterm infants. (Strong recommendation, moderate-certainty evidence)
- The GDG noted that evidence was available for all preterm infants, so caffeine (or other methylxanthines) is recommended for treatment of apnoea in preterm infants.
- The GDG noted that there were limited data on the dose, timing of initiation and duration of administration. Based on the largest trial (169) included in the evidence review, the GDG suggested a 20 mg/kg loading dose and a 5 mg/kg per day maintenance dose for six weeks. The duration of caffeine administration should be based on clinical judgement.
- If caffeine is not available, other methylxanthines (aminophylline or theophylline) may be considered.

# Background and definitions
Apnoea (temporary cessation of breathing) is common in preterm infants (170,171). The frequency of apnoea is inversely related to gestational age, and it occurs in almost all infants born before 28 weeks' gestation (extremely preterm) (170,171). Episodes of apnoea can result in hypoxaemia and bradycardia requiring mechanical ventilation. Intermittent hypoxic episodes in the first two months after birth are associated with increased risk of chronic conditions, such as retinopathy of prematurity, and adverse neurodevelopmental outcomes (172,173).
Since the 1970s, methylxanthine medicines such as theophylline, aminophylline and caffeine have been used to manage apnoea. More recently, large pragmatic studies have included methylxanthine treatment for a variety of indications, including the treatment and prevention of apnoea (174). Studies have also assessed the use of methylxanthines to prevent apnoea before and after extubation (169,175).

# Sources and characteristics of the evidence
The effectiveness evidence for this comparison was derived from a Cochrane review of 18 RCTs enrolling a total of 2705 preterm infants who received methylxanthines for any indication (174).
For the indication relevant to this comparison (for treatment of apnoea), the inclusion criteria for infants were gestational age at birth below 37 weeks and evidence of apnoea. Six RCTs were included, enrolling a total of 959 preterm infants from six countries (Australia, Canada, France, India, the United Kingdom and the USA). The largest study, the Caffeine for Apnoea of Prematurity (CAP) trial (169), enrolled 767 participants (birth weight 0.5-1.2 kg) from nine countries who received methylxanthines for treatment of apnoea and conducted follow-up after five years. The other five trials were small, with fewer than 100 infants in each trial. This composite outcome was defined as death or survival to 5 years with one or more of the following: motor impairment (defined as a gross motor function classification system level of 3-5), cognitive impairment (defined as a full-scale IQ < 70), behaviour problems, poor general health, deafness and/or blindness, all measured using validated tests.

# Critical outcomes

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported (within a theme on the healthcare environment) that carers want mechanisms and initiatives to help them to interact with their babies, especially when they are undergoing therapies that make it difficult to have physical contact with the infant (14). They also want to learn about the healthcare setting (including the equipment in use) where they need to stay and care for the infant. No other specific evidence was located about whether families value methylxanthines for their preterm or LBW baby or whether they find them more or less acceptable than other medicines or no treatment.

# Resources required and implementation considerations
Organization of care Methylxanthines (caffeine, theophylline and aminophylline) must be dispensed by a health worker. They can be provided in the health-care facility or at home. Caffeine is given once a day and theophylline and aminophylline are given three times a day.

# Infrastructure, equipment and supplies
Methylxanthines are available as intravenous and oral formulations. Caffeine citrate is available as 20 mg/ml and 10 mg/ml for intravenous and oral use, respectively. Oral caffeine comes as a ready-to-use formulation that needs no mixing. Theophylline is available as 50-60 mg/5 ml liquid. Aminophylline is available as 25 mg/ml ampoules.

# Workforce, training, supervision and monitoring
Health workers at all levels can support mothers and families. Standardized packages are needed for training, supervision and monitoring. Dispensing needs to be documented in clinical records.

# Feasibility and equity
Studies report that availability and cost are barriers for the use of caffeine citrate formulations in LMICs (176). Theophylline and aminophylline are more widely available than caffeine in LMICs (31,176).
There was no specific evidence on the feasibility and equity of providing methylxanthines for preterm or LBW infants.

# Summary of judgements
- The GDG noted that evidence was available only for preterm infants born before 34 weeks' gestation, but suggests that caffeine (or other methylxanthines) may also be considered for extubation of preterm infants born at or after 34 weeks and before 37 weeks, depending on clinical judgement.
- The GDG noted that there were limited data on the timing of initiation and duration of administration.
Based on the largest trials (169,175) included in the evidence review, the GDG suggested starting caffeine 24 hours before a planned extubation. If the extubation is unplanned, the infant should receive the caffeine as soon as possible after the extubation and within 6 hours, and should continue to receive it for six days.
- The GDG noted that there were limited data on the dosage. Based on the largest trials (169,175) included in the evidence review, the GDG suggested a 20 mg/kg loading dose and 5 mg/kg per day maintenance dose for six days.
- If caffeine is not available, other methylxanthines (aminophylline or theophylline) may be considered.

# Background and definitions
Please refer to the information in section B.4.

# Effectiveness: Comparison -Methylxanthine for extubation versus placebo or no methylxanthine treatment

# Sources and characteristics of the evidence
The effectiveness evidence for this comparison was derived from the same Cochrane review of preterm infants who received methylxanthines for any indication (174). For the indication relevant to this comparison (for extubation), the inclusion criteria for infants were gestational age at birth below 34 weeks and planned extubation. Seven RCTs enrolling a total of 870 preterm infants were included from five countries (Australia, Canada, Spain, the United Kingdom and the USA). The largest study was also the CAP trial (169), which followed up 676 participants who received methylxanthines for extubation. The other six trials were small, with fewer than 100 infants in each trial.

# Critical outcomes

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.
Values and acceptability, resources, feasibility and equity
Please refer to the information on these topics in section B.4.

# Summary of judgements
- The GDG noted that the evidence on increased mortality came from three small trials totalling 129 infants (177)(178)(179) and was uncertain due to very low quality, and imprecision. Also, data on "death alone" were not available from a large trial of 423 infants (169), which reported no effect on a combined outcome of death and neurodevelopmental disability. The GDG also noted that the evidence on harms from increased use of mechanical ventilation was uncertain due to very low quality, and imprecision.
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The GDG noted that evidence was available only for preterm infants born before 34 weeks' gestation, but suggests that caffeine (or other methylxanthines) may also be considered for prevention of apnoea in preterm infants born at or after 34 weeks and before 37 weeks if there is clinical indication.
- The GDG noted that there were limited data on the dose, timing of initiation and duration of administration. Based on the largest trial (169) included in the evidence review, the GDG suggested a 20 mg/kg loading dose and a 5 mg/kg per day maintenance dose for six weeks. The duration of caffeine administration should be based on clinical judgement.
- If caffeine is not available, other methylxanthines (aminophylline or theophylline) may be considered.

# Background and definitions
Please refer to the information in section B.4.

# Summary of the

# Sources and characteristics of the evidence
The effectiveness evidence for this comparison was derived the same Cochrane review of preterm infants who received methylxanthines for any indication (174). For the indication relevant to this comparison (for prevention of apnoea), the inclusion criteria for infants were gestational age at birth below 34 weeks and no evidence of apnoea. Seven RCTs enrolling a total of 706 preterm infants were included from six countries (Australia, Canada, the Islamic Republic of Iran, Switzerland, the United Kingdom and the USA). The largest study was also the CAP trial, which followed up 423 participants who received methylxanthines for prevention of apnoea (169).
The other six trials were small, with fewer than 100 infants in each.  24). Data on death alone and neurodevelopmental disability alone were not available for this trial.

# Critical outcomes

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Values and acceptability, resources, feasibility and equity
Please refer to the information on these topics in section B.4.

# Summary of judgements
- The trials in the systematic review varied widely in intervention content, intensity and effect but all showed consistent and similar effects.
- The GDG noted that the resources needed for and the feasibility of implementing family involvement strategies vary according to setting but that simple family involvement interventions such as the delivery of direct bedside care and involvement in medical decision-making could be implemented in all settings.
Other components that can be provided include chairs near the infant's cot, even in busy and crowded hospital wards.
- The GDG also noted that family involvement strategies reduced the length of hospital stay, improved breastfeeding and reduced parental anxiety and stress.

# Background and definitions
Preterm and LBW infants commonly require specialized care, close monitoring and medical interventions (2,180). In some health-care facilities, families are not allowed any physical access to their infants and receive only intermittent verbal updates from health workers (181)(182)(183)(184). Family involvement is often defined as the participation of mothers, fathers/ partners and other family members in routine care of the newborn while the baby is in the health-care facility (180,185,186). It may include promotion of direct bedside care from the family (e.g. feeding and administration of medicines), inclusion of the family in medical decision-making, infrastructure changes (e.g. beds and chairs near the baby's cot, family rooms), health-care facility culture change and health worker behaviour change. Strategies to increase family involvement have typically focused on packages of one or more of these interventions with the overall aims of increasing the amount of direct hands-on care that parents provide for their infant and empowering families to collaborate in health-care decision-making. Well known packages that are implemented in high-, middle-and lowincome countries include family-centred care, family-participatory care and family-integrated care (180,185,186). Effectiveness: Comparison -Family involvement in routine care versus usual hospital care

# Summary of the evidence

# Sources and characteristics of the evidence
The effectiveness evidence was derived from a systematic review of 15 RCTs enrolling a total of 5240 preterm or LBW infants from nine countries (Australia, Canada, China, India, the Islamic Republic of Iran, New Zealand, the Republic of Korea, Sweden and the USA) (187). Most infants were born before 32 weeks' gestation or had birth weight below 1.5 kg, and most trials excluded infants with major congenital anomalies. All trials were conducted in NICUs.
All trials evaluated the effect of family-centred models or packages for the hospital care of preterm or LBW infants on infant and parental outcomes.
No studies of infrastructure or behaviour change interventions were located. The family-centred packages were heterogeneous, but their common core content was the involvement of family members in the provision of direct bedside care. Skin-to-skin care or kangaroo mother care (KMC) was included in nine trials, though frequency and duration were not described. Other common components included neurodevelopmental care (8 trials), preparation for transition to home (6 trials) and the involvement of parents in medical decision-making (4 trials).

# Critical outcomes

# Subgroup analyses
For gestational age and birth weight, differences for weight gain and neurodevelopment could not be assessed as there were insufficient studies. For the other outcomes there was no evidence of a subgroup difference.
For the intensity of intervention, differences for intraventricular haemorrhage, weight gain and neurodevelopment could not be assessed as there were insufficient studies.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, and want to take an active role in deciding what interventions are given to infants, in the routine care of the newborn, in direct bedside care, including feeding their baby and in medical decision-making, and that they value hospital infrastructure changes (e.g. beds and chairs near the baby's cot, family rooms) (14). No other specific evidence was located.

# Resources required and implementation considerations
Organization of care Family involvement strategies can be implemented at all levels of newborn care (primary, secondary and tertiary). Health-care facilities should ensure that families have access to beds, food, bathing and toilet facilities throughout the infant's hospital stay.

# Infrastructure, equipment and supplies
No special infrastructure, equipment or supplies are needed to support family involvement in the care of their preterm or LBW infants. However, many arrangements can make the infant and mother more comfortable, e.g. reclining beds and chairs. More structured packages may include infrastructure changes such as beds and chairs near the infant's cot, and family rooms.
If couplet care or maternal-newborn intensive care units (M-NICUs) are used, they should have all the infrastructure, equipment and supplies that NICUs have for small or sick babies and that maternity wards have for mothers. For infants, this includes CPAP machines, pulse oximeters, and radiant warmers or incubators if the infant is not in KMC. For mothers, this includes adult beds and an examination area where she can receive the health care she needs.

# Workforce, training, supervision and monitoring
Health workers at all levels can support family involvement in the routine care of their preterm or LBW infant. Standardized packages can be used for training, supervision and monitoring. This can include the promotion of direct bedside care from the family (e.g. feeding and administration of medicines), inclusion of the family in medical decision-making, health-care facility culture change, health worker behaviour change and infrastructure change.

# Feasibility and equity
There was no specific evidence on the feasibility and equity of promoting family involvement for preterm or LBW infants.

# Summary of judgements
- The recommendation is conditional on shared decision-making with parents; this includes informing parents about the benefits and risks and the need for further research.
- The GDG noted that education and counselling also had important effects in improving parent-to-infant interaction, improving breastfeeding and decreasing parental anxiety, stress and depression, though these were not critical outcomes. - The GDG noted that there were limited data on frequency, duration and intensity of education and counselling.
- The GDG noted that discharge preparation also had important effects in improving parent-to-infant interaction, improving breastfeeding and decreasing parental anxiety, stress and depression, though these were not critical outcomes. - The GDG noted that there were limited data on the frequency, duration and intensity of discharge preparation. - Preterm and LBW infants often require care from multiple health workers so the GDG also noted that careful coordination of care is needed post-discharge.
- The GDG made a conditional recommendation on peer support, although there were no data on critical outcomes; this was because of the effects on maternal anxiety and the importance of the intervention. - The GDG noted that there were limited data on frequency, duration and intensity of peer support.
- The GDG decided not to make a recommendation on digital information systems as there was no evidence of benefits or harms on any critical outcome.

# Background and definitions
Supporting families to care for their sick, vulnerable, preterm or LBW infant is a basic and integral component of any health system. However, many families still feel ill-equipped to care for their preterm or LBW newborn infant at home (188,189). Families need support at all stages, starting from before conception, and including at the identification of a high-risk pregnancy, at the birth of the baby, in the health-care facility, at discharge and when the baby reaches home. Much of the support that families need to care for their preterm and LBW infants is provided through social services in high-, middle-and low-income countries. However, "what the health system can do" and the "health system building blocks" they can use (i.e. service delivery, workforce, digital information systems, medical products and technologies, financing, leadership and governance) (190) are often overlooked. Two systematic reviews have recently assessed the effectiveness of communication and peer-support interventions for families of preterm infants (191,192). However, there have been no recent systematic reviews of the effects of other health system "building blocks" on infant mortality, morbidity, growth and neurodevelopmental outcomes.
Overall, the effectiveness evidence was derived from a systematic review of 37 trials (

# Sources and characteristics of the evidence
For comparison 2, the effectiveness evidence was derived from the systematic review, which included two trials enrolling a total of 118 preterm or LBW infants (193). The peer supporters were all women who had cared for a preterm or LBW infant in a similar environment and were willing to use their experiences to support others. The interventions all commenced in the facility and took place either following agreement from the parent or were initiated by the parent. Content included well-being strategies and newborn-care practices.

# Critical outcomes

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Effectiveness: Comparison 3 -Discharge preparation versus usual care
Sources and characteristics of the evidence For comparison 3, the effectiveness evidence was derived from the systematic review, which included one trial enrolling 173 preterm or LBW infants (193). The interventions were delivered by health workers in the days just prior to hospital discharge and focused specifically on preparing parents for the discharge of their infant. The content included well-being strategies and newborn-care practices, but also "anticipatory guidance" (i.e. what to expect), financial and social support information, and referral pathways.

# Critical outcomes

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Effectiveness: Comparison 4 -Digital information systems versus usual care
Sources and characteristics of the evidence For comparison 4, the effectiveness evidence was derived from the systematic review, which included four trials enrolling a total of 902 preterm or LBW infants (193)

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting all newborn-care practices, and want to take an active role in deciding what interventions are given to infants, including what newborn-care practices they receive and how they are implemented (14).
No specific evidence was located about the kinds of support families of preterm or LBW babies value or find acceptable.

# Resources required and implementation considerations
Organization of care Families may need education, counselling, discharge preparation and peer support at all levels of health facility care. Education, counselling and peer support may be needed at home. Support and planning should be started in the antenatal period where possible. Services should follow national and local guidance for health-care facilities.

# Infrastructure, equipment and supplies
National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can provide family support. Standardized packages can be used for training, supervision and monitoring.

# Feasibility and equity
There was no specific evidence on the feasibility and equity of providing family support for preterm or LBW infants.

# Summary of judgements
- Trained health workers can include nurses, midwives, doctors and community health workers.
- The GDG noted that there were limited data on the content, frequency, duration and intensity of home visits for preterm and LBW infants. Based on the trials included in the evidence review, the GDG recommended that extra home visits (i.e. additional to the routine scheduled postnatal contacts for all infants should be made, and that their content, frequency, duration and intensity should be based on clinical judgement.
- The GDG noted that home visits also increased exclusive breastfeeding, immunization visits and parental-infant attachment and decreased parental stress, though these were not critical outcomes.

# Background and definitions
Families need support at all stages, from before conception, and including at the identification of a high-risk pregnancy, at the birth of the baby, in the health-care facility, at discharge, and especially when the baby reaches home (189,194). Studies over the last 10 years in high-, middle-and low-income countries have shown that home visiting during the antenatal and postnatal periods can improve both the demand for and the use of antenatal, delivery and postnatal services and reduce maternal and newborn mortality (22,195). However, there is limited information on the effects of home visiting for preterm and LBW infants. There was an increase in EBF at 6 months (RR 4.48, 95% CI 0.28 to 72.9; 3 trials, 7221 participants) and an increase in immunization visits in the first year (MD 1.21, 95% CI 0.93 to 1.49; 1 trial, 970 participants).

# Subgroup analyses
The effect of gestational age and birth weight could not be assessed as there were insufficient trials for any critical outcome.

# Values and acceptability
The systematic review about what matters to families about the care of the preterm or LBW infant (see Table 1.1) reported that families want to be involved in delivering care to infants, including supporting all newborn-care practices, and want to take an active role in deciding what interventions are given to infants, including what newborn-care practices they receive and how they are implemented (14). No specific evidence was located about whether families value home visiting for their preterm or LBW baby or whether they find it more or less acceptable than other care.

# Resources required and implementation considerations
Organization of care A minimum of four postnatal care contacts is recommended for all infants (22). Extra home visits (i.e. additional to the routine scheduled postnatal contacts for all infants) are needed for preterm and LBW babies. Their content, frequency, duration and intensity should follow national and local guidance for health-care facilities and should be based on clinical judgement.

# Infrastructure, equipment and supplies
National or local guidance for health-care facilities should be used.

# Workforce, training, supervision and monitoring
Health workers at all levels can provide home visits. However, standardized packages are needed for training, supervision and monitoring. Further guidance on follow-up care is being developed and will be published separately.

# C.4 PARENTAL LEAVE AND ENTITLEMENTS

# Good practice statement and remarks GOOD PRACTICE STATEMENT C.4 (NEW)
Parental leave and entitlements should address the special needs of mothers, fathers and other primary caregivers of preterm or low-birth-weight infants.
- The GDG made this good practice statement in recognition of the costs and burdens to parents and families of implementing preterm and LBW infant care.
- Based on the studies in the review, the GDG considered that parental leave and entitlements should include additional days of leave from work and additional financial payments. However, there was insufficient information available to enable the GDG to make recommendations about the number of days of leave parents should be given or what type of financial entitlements they should receive.
- The GDG also noted that the special needs of mothers and fathers/partners of preterm and LBW infants vary according to individual preferences and setting. They include: support for long hospital stays, multiple medical appointments, transport and equipment; support to help manage stress and anxiety about the infant; and support for caring for other children and family members.
- The GDG noted that parental leave and entitlements are in place in some countries but recommended that they should be expanded globally across high-, middle-and low-income countries.

# Background and definitions
Families of preterm and LBW infants are well known to have increased risks of financial impoverishment, stress, anxiety and depression (188,195,196). Leave from work is needed to help families care for the infant. Families may also need financial support for transport and equipment as well as for the costs of the hospitalization and caring for other children or family members (189,191,197). Government and regulatory policies and entitlements are important ways to ensure families receive the financial and workplace support they need. However, there have been few reviews of policies for parental leave and entitlements for families of preterm or LBW infants across high-, middle-and low-income countries.
The recommendations should be adapted to the needs of different countries, local contexts, and individual families and infants. The Guideline Development Group proposed implementation considerations for each recommendation and also reflected on adoption, adaptation and implementation to ensure availability, accessibility, acceptability and quality of care, in accordance with a human rights-based approach. Providers of services for the preterm or low-birth-weight (LBW) infant must consider the needs of, and provide equal care to, all individuals and their newborns.
Health policy considerations for the adoption and scale-up of recommended interventions for the care of the preterm or LBW infant: n A firm government commitment to scale-up and increased coverage of these interventions is needed, irrespective of social, economic, ethnic, racial or other factors. National support must be secured for all recommendations, not just for specific components. n To set the policy agenda, to secure broad anchoring and to ensure progress in policy formulation and decision-making, representatives of training facilities and the relevant medical specialties and professional societies should be included in participatory processes at all stages, including prior to an actual policy decision, to secure broad support for scaling up. n To facilitate negotiations and planning, situationspecific information on the expected impact of the implementation of the recommendations on service users, health workers and costs should be compiled and disseminated.
Health system or organization-level considerations for implementation: n Derivative tools should be updated, such as Integrated management of childhood illness: management of the sick and young infant aged up to 2 months (201), Pocket book of hospital care for children and Guidelines for the management of common childhood illnesses (202), and global and national essential medicines lists. n National and subnational subgroups may be established to adapt and implement these recommendations, including the development or revision of existing national or subnational guidelines or protocols. n Long-term planning is needed for resource generation and budget allocation to address the shortage of health workers and trained community health workers, to improve facility infrastructure and referral pathways, and to strengthen and sustain high-quality small and sick newborn care services. n Implementation of the recommendations should involve pre-service training institutions and professional bodies, so that training curricula for small and sick newborn care services can be updated as quickly and smoothly as possible. n In-service training and supervisory courses will need to be developed according to health workers' professional requirements, considering the content and duration of the courses and the procedures for the selection of health workers for training. These courses can also be explicitly designed to address staff turnover, particularly in low-resource settings. n Standardized tools will need to be developed for supervision, ensuring that supervisors are able to support and enable health workers to deliver integrated, comprehensive small and sick newborn care services. n A strategy to optimize the use of human resources. n Tools or "job aids" for implementation at the different levels of health-care facility and in communities will need to be developed or updated with all the key information. n Strategies will need to be devised to improve supply chain management according to local requirements, such as developing protocols for the procedures of obtaining and maintaining the stock of supplies, encouraging health workers to collect and monitor data on the stock levels and strengthening the provider-level coordination and follow-up of medicines and health-care supplies required for implementation. n Development or revision of national guidelines and/or health-care facility-based protocols is needed. n Good-quality supervision, communication and transport links between community, primary-and higher-level facilities need to be established to ensure that referral pathways are efficient.
n Successful implementation strategies should be documented and shared as examples of best practice for other implementers.
User-level considerations for implementation: n Community-sensitizing activities should be undertaken to disseminate information about the importance of each component of care, and infants' rights to receive care for their health and well-being. This information should provide details about the timing and content of the recommended contacts, and about the expected user fees.
Considerations for humanitarian emergencies: n The adaptation of the recommendations should consider their integration and alignment with other response strategies. Additional considerations should be made for the unique needs of families and infants in emergency settings, including their values and preferences. Context-specific tools may be needed in addition to standard tools to support the implementation by stakeholders of the recommendations in humanitarian emergencies.

# Applicability issues
A number of factors may hinder the effective implementation and scale-up of the recommendations in this guideline. These barriers may be related to the behaviours of families or health workers and to the organization of care or health service delivery. As part of efforts to implement these recommendations, health system stakeholders may wish to consider the following potential barriers: n difficult access to health services and health workers for families and newborns, including lack of transport, geographical conditions and financial barriers; n lack of human resources with the necessary expertise and skills to implement, supervise and support recommended practices, including client counselling; n lack of infrastructure to support interventions (e.g. lack of electricity for refrigeration, lack of access to clean water and sanitation, lack of access to digital interventions and devices, lack of physical space to conduct individual care and counselling); n lack of time or understanding of the value of newly recommended interventions among health workers and health system administrators;
n lack of physical resources (such as equipment, supplies, medicines and nutritional supplements); n lack of opportunities for continuing education and professional development for health workers; n resistance of health workers to change from non-evidence-based to evidence-based practices (such as providing home visits or ensuring family involvement); n lack of effective referral mechanisms and care pathways for families and newborns identified as needing additional care (e.g. continuous positive airway pressure or methylxanthines); n lack of health management information systems designed to document and monitor recommended practices (e.g. patient records and registers).
Given these potential barriers, a phased approach to the adoption, adaptation and implementation of the recommendations in this guideline may be helpful.
Various strategies for addressing these barriers and facilitating implementation are provided in each chapter.

# Research implications
The Guideline Development Group (GDG) identified important knowledge gaps that need to be addressed through primary research. The research questions were prioritized by the GDG based on consideration of whether they would: (i) contribute to improvements in care and outcomes for preterm or low-birth-weight (LBW) infants; (ii) be likely to result in significant public health impacts; (iii) be answerable; (iv) inform a new recommendation or change an existing recommendation; (v) result in findings that would be feasible to implement; and (vi) be likely to promote equity. The full list of research gaps can be found in Web Annex B, but the prioritized research questions are listed below.

# A.3 Donor human milk
n What is the effectiveness, safety and feasibility of human milk banks in low-and middle-income countries?

# A.11 Probiotics
n What is the effectiveness and safety of probiotics in human-milk-fed infants? n What is the effect of probiotics on immune function and gut microbiome in preterm or LBW infants? n What are the most optimal probiotic compositions for preterm or LBW infants -that is, the optimal combination of genera, species and strains? n What is the optimal probiotics regimen (dosage and duration) for preterm or LBW infants? n What is the effectiveness of probiotics alone compared with a combination of probiotics and prebiotics for preterm or LBW infants? n What is the role of probiotics in the prevention and management of postnatal growth restriction in preterm infants?

# A.12 Emollients
n What is the effect of emollients on mortality, invasive infection, sepsis, growth and longer-term neurodevelopment in preterm or LBW infants in high-, middle-and low-income countries, especially in Africa? n What is the effect of emollients on thermoprotection and the microbiome in preterm or LBW infants? n Which emollients (which oils, which composition) are most effective and safe for preterm or LBW infants? n What is the optimal regime (dose, frequency, duration) and mode of application (e.g. nontouch applications) for very or extremely preterm infants?

# B.1 Continuous positive airway pressure (CPAP) for respiratory distress syndrome
n What is the effectiveness of CPAP compared with humidified high-flow nasal cannulae and other forms of non-invasive ventilation in preterm or LBW infants with respiratory distress syndrome?

# C.1 Family involvement
n What strategies can be used to increase family participation in the care of their preterm or LBW infants in intensive and special care units, and in settings without dedicated newborn units?

# C.2 Family support
n What is the most effective type of family support (including education, counselling, discharge preparation, peer support) for families of preterm or LBW infants?

# C.3 Home visits
n What is the effectiveness of standard in-person home visits compared with digital home visits (e.g. online video, mobile application mHealth) for post-discharge follow-up of preterm or LBW infants? n What is the feasibility of digital home visits in low-, middle-and high-income countries?
The recommendations will be disseminated through WHO regional and country offices, ministries of health, professional associations, WHO collaborating centres, other United Nations agencies and nongovernmental organizations. The recommendations will be available on the WHO website and also as a printed publication. Online versions will be available via the websites of the relevant WHO departments. Technical meetings will be held between WHO and stakeholders to share the recommendations and derivative products.
Evidence briefs for policy-makers, programme managers and health workers will be developed. They will focus on selected recommendations and context-specific issues, and will be developed and disseminated in collaboration with United Nations agencies and partners.
The executive summary and recommendations from this publication will be translated into the six United Nations languages for dissemination through the WHO regional and country offices, and web versions will be available via the websites of the WHO departments, as above.
In addition, a number of articles presenting the recommendations and key implementation considerations will be published, in compliance with WHO's open access and copyright policies. Relevant WHO clusters, departments and partnerships, such as the Partnership for Maternal, Newborn and Child Health (PMNCH), will also be part of the dissemination process.
WHO, in collaboration with other partners, will support national and subnational working groups to adopt, adapt and implement the guideline. This will include the development or revision of existing national policies, guidelines or protocols in line with the WHO recommendations, and tools to support the adaptation and implementation processes. This also includes technical support for local guideline implementers in the development of training materials and quality indicators.

# Monitoring and evaluating the impact of the recommendations
The implementation and impact of these recommendations will be monitored at the health service, subnational and national levels, based on clearly defined criteria and indicators that are associated with locally agreed targets. In collaboration with the monitoring and evaluation teams of the WHO Departments of Maternal, Newborn, Child and Adolescent Health and Ageing, and Sexual and Reproductive Health and Research, the data on country-and regional-level adoption of the recommendations will be collected and evaluated in the short to medium term across individual WHO Member States, through the WHO sexual, reproductive, maternal, newborn, child and adolescent health (SRMNCAH) policy survey (198).
A full monitoring framework will be developed. In the meantime, the Guideline Development Group for this guideline suggests the consideration of the following indicators, which have been adapted from current global recommended indicators (53,203), including the Every Newborn Action Plan (ENAP) indicators for mortality and coverage of postnatal care.
n Neonatal mortality -the proportion of preterm or low-birth-weight (LBW) infants dying in the first 28 days after birth. n Early breastfeeding -the proportion of preterm or LBW infants put to the breast within the first 24 hours after birth. n Early postnatal care for infants within two days of birth -the proportion of preterm or LBW infants who had postnatal contact with a health worker within two days of delivery. n Kangaroo mother care (KMC) -the proportion of preterm infants who receive KMC.
These indicators should be considered preliminary and will undergo further review. New indicators will be added, including those for the measurement of coverage and quality of care.

# Updating of the guideline
In accordance with the process for updating WHO guidelines, the "living guidelines" approach will be used (204). This is a systematic and continual process of identifying and bridging evidence gaps, at least every six months following guideline publication and dissemination. A Guideline Steering Group for maternal and newborn health recommendations will convene regularly to review WHO's current portfolio of relevant recommendations, and to prioritize new and existing questions for recommendation development and updating. The focus will be on recommendations supported by very-low-or lowcertainty evidence and where new recommendations or a change in the published recommendations may be needed. When new evidence that could potentially impact the current evidence base for any of the recommendations is identified, the recommendation will be updated. If no new reports or information are identified for a particular recommendation, the recommendation will be revalidated.
Any concern about the validity of any recommendation should be promptly communicated by email to the WHO Department of Maternal, Newborn, Child and Adolescent Health and Ageing (mncah@who.int). All communications will be reviewed and plans will be made to update the recommendation as needed.
WHO welcomes suggestions regarding additional questions for inclusion in future updates of this guideline; suggestions can be addressed by email to the same department (mncah@who.int).
Delayed cord clamping recommendations: 1 n In term or preterm newborns who do not require positive-pressure ventilation, the cord should not be clamped earlier than one minute after birth. n When term or preterm newborns require positivepressure ventilation, the cord should be clamped and cut to allow effective ventilation to be performed.
Thermal care recommendations: 2 n During stabilization and transfer of preterm newborns to specialized neonatal care wards, wrapping in plastic bags or wraps may be considered as an alternative to prevent hypothermia.
Immunization recommendations: 3 n Newborn immunization should be promoted in accordance with the latest existing WHO recommendations for routine immunization.

# Surfactant recommendations: 2
n Surfactant replacement therapy is recommended for intubated and ventilated newborns with respiratory distress syndrome. n Either animal-derived or protein-containing synthetic surfactants can be used for surfactant replacement therapy in ventilated preterm newborns with respiratory distress syndrome. n Administration of surfactant before the onset of respiratory distress syndrome (prophylactic administration) in preterm newborns is not recommended. n 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.
Oxygen recommendations: 2 n 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. n 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.