In 2010, many research gaps in the care of preterm and low birth weight (LBW) infants were identified.1  Important questions about the efficacy and effectiveness of interventions for preterm and LBW infants have been answered over the last 10 years,2  yet gaps in the global evidence base remain. A framework of care needed for preterm and LBW infants was developed at a World Health Organization (WHO) guideline development group expert meeting in December 2020.3  Thirty-eight interventions were identified (Tables 1 and 2). Thirty interventions had already been included in other WHO guidelines. Eight interventions with 24 research questions had not been addressed by other WHO guidelines (Table 3).

TABLE 1

Framework for Care of the Preterm or LBW Infant

ComponentsScope
Target population Preterm (<37 wk gestation) or LBW (<2.5kg) infants 
Setting Care of the infant in both the health facility and the home 
Focus is low- and middle-income country settings, but the guidelines can be used in all settings 
Intervention type Preventive and promotive care from birth, care for complications 
Emphasis on (1) the care that all infants need that may have a special impact on preterm and LBW infants and (2) the special care that only preterm and LBW infants need 
Intervention period From birth to 24 mo of life 
Outcome type Mortality, morbidity, growth, neurodevelopment 
Outcome period At latest follow-up and specific for intervention 
Important strata and subgroups <32 wk gestation, ≥32 wk gestation, <1.5kg birth wt, ≥1.5kg birth wt, and specific for intervention 
ComponentsScope
Target population Preterm (<37 wk gestation) or LBW (<2.5kg) infants 
Setting Care of the infant in both the health facility and the home 
Focus is low- and middle-income country settings, but the guidelines can be used in all settings 
Intervention type Preventive and promotive care from birth, care for complications 
Emphasis on (1) the care that all infants need that may have a special impact on preterm and LBW infants and (2) the special care that only preterm and LBW infants need 
Intervention period From birth to 24 mo of life 
Outcome type Mortality, morbidity, growth, neurodevelopment 
Outcome period At latest follow-up and specific for intervention 
Important strata and subgroups <32 wk gestation, ≥32 wk gestation, <1.5kg birth wt, ≥1.5kg birth wt, and specific for intervention 
TABLE 2

Interventions for Care of the Preterm or LBW Infant

DomainIntervention
Preventive and promotive care of the infant from birth  
 Delivery management Early identification of preterm and LBW infants 
  Cord clamping 
 Infection prevention Infection prevention 
  Vaccination 
 Thermal care Kangaroo mother care 
  Thermal care if kangaroo mother care cannot be done 
 Responsive care Responsive caregiving 
  Positioning during care 
  Sleep positioning 
 Prevention of injury and pain Injury prevention 
  Pain management 
 Nutrition Milk feeding 
  Micronutrients 
 Probiotics Probiotics 
 Skin, cord, eye care and bathing Emollients 
  Cord care 
  Eye care 
  Bathing 
 Congenital and metabolic screening Metabolic screening 
  Congenital abnormality screening 
 Discharge and postdischarge care Discharge preparedness 
 Hearing, vision, growth, neurodevelopment 
Management of respiratory complications  
 Respiratory distress and apnea Oxygen 
  Surfactant 
  Continuous positive airway pressure 
  Methylxanthines 
 Chronic lung disease Bronchopulmonary dysplasia 
Management of other preterm and LBW complications  
 Growth and neurodevelopment Growth failure 
  Encephalopathy 
  Neurodisability, hearing, vision, retinopathy 
 Gastrointestinal Necrotizing enterocolitis 
 Metabolic Hypoglycemia 
 Hyperbilirubinemia 
 Anemia 
 Polycythemia 
Management of other neonatal problems  
 Including sepsis, respiratory, diarrhea 
Family care  
 Family involvement 
 Family support 
DomainIntervention
Preventive and promotive care of the infant from birth  
 Delivery management Early identification of preterm and LBW infants 
  Cord clamping 
 Infection prevention Infection prevention 
  Vaccination 
 Thermal care Kangaroo mother care 
  Thermal care if kangaroo mother care cannot be done 
 Responsive care Responsive caregiving 
  Positioning during care 
  Sleep positioning 
 Prevention of injury and pain Injury prevention 
  Pain management 
 Nutrition Milk feeding 
  Micronutrients 
 Probiotics Probiotics 
 Skin, cord, eye care and bathing Emollients 
  Cord care 
  Eye care 
  Bathing 
 Congenital and metabolic screening Metabolic screening 
  Congenital abnormality screening 
 Discharge and postdischarge care Discharge preparedness 
 Hearing, vision, growth, neurodevelopment 
Management of respiratory complications  
 Respiratory distress and apnea Oxygen 
  Surfactant 
  Continuous positive airway pressure 
  Methylxanthines 
 Chronic lung disease Bronchopulmonary dysplasia 
Management of other preterm and LBW complications  
 Growth and neurodevelopment Growth failure 
  Encephalopathy 
  Neurodisability, hearing, vision, retinopathy 
 Gastrointestinal Necrotizing enterocolitis 
 Metabolic Hypoglycemia 
 Hyperbilirubinemia 
 Anemia 
 Polycythemia 
Management of other neonatal problems  
 Including sepsis, respiratory, diarrhea 
Family care  
 Family involvement 
 Family support 
TABLE 3

Prioritized Interventions (n = 8) and PICO Questions (n = 24) for Care of the Preterm or LBW Infant

InterventionsPICO
Thermal care  
 Kangaroo mother care In preterm or LBW infants (P), what is the effect of KMC (I) compared with conventional neonatal care (C) on critical outcomes (O)? If KMC is effective, then what is the effect of early‐onset KMC (I) compared with late‐onset KMC (C) on critical outcomes (O)? What is the effect of short (I) compared with longer (C) durations of KMC on critical outcomes (O)? 
Milk feeding  
 Mother’s own milk In preterm or LBW infants (P), what is the effect of feeding mother's own milk (I) compared with feeding infant formula (C) on critical outcomes (O)? 
 Donor human milk In preterm or LBW infants who cannot be fed mother's own milk (P), what is the effect of feeding donor human milk (I) compared with feeding infant formula (C) on critical outcomes (O)? 
 Fortification In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of multicomponent fortification of milk (I) compared with no fortification (C) on critical outcomes (O)? 
 Infant formula In preterm or LBW infants who cannot be fed mother's own milk or donor human milk (P), what is the effect of feeding nutrient enriched (“preterm”) infant formula (I) compared with feeding standard infant (“term”) formula (C) on critical outcomes (O)? 
 Initiation of enteral feeding In preterm or LBW infants (P), what is the effect of early initiation of enteral feeding (I) compared with delayed feeding (C) on critical outcomes (O)? If early, then when should feeding be initiated? Does this effect differ in infants given full enteral feeding compared with infants given restricted volumes, including minimal enteral feeding? 
 Responsive feeding In preterm or LBW infants who receive any enteral feeding (P), what is the effect of responsive feeding based on infants’ cues (I) compared with scheduled feeding (C) on critical outcomes (O)? 
 Volume advancement In preterm or LBW infants who receive any enteral feeding (P), what is the effect of fast advancement of enteral feeds (I) versus slower rates of feed advancement (C) on critical outcomes (O)? 
 Duration of exclusive breastfeeding In preterm or LBW infants (P), what is the effect of exclusive breastfeeding for <6 mo (I) compared with exclusive breastfeeding for 6 mo (C) on critical outcomes (O)? If <6 mo, then what is the optimal duration? 
Micronutrients  
 Iron In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral iron supplementation (I) compared with no iron supplementation (C) on critical outcomes (O)? 
 Zinc In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral zinc supplementation (I) compared with no zinc supplementation (C) on critical outcomes (O)? 
 Vitamin D In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral vitamin D supplementation (I) compared with no vitamin D supplementation (C) on critical outcomes (O)? 
 Vitamin A In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral vitamin A supplementation (I) compared with no vitamin A supplementation (C) on critical outcomes (O)? 
 Calcium and phosphorous In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral calcium and phosphorous supplementation (I) compared with no supplementation (C) on critical outcomes (O)? 
 Multiple micronutrient supplements In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral multiple micronutrient supplements (I) compared with no enteral multiple micronutrient supplements (C) on critical outcomes (O)? 
Probiotics In preterm or LBW infants who receive any enteral feeding (P), what is the effect of probiotics (I) versus no probiotics (C) on critical outcomes (O)? 
Skin care  
 Emolients In preterm or LBW infants (P) what is the effect of topical ointment, cream or oil applied to the skin (I) compared with routine skin care (C) on critical outcomes (O)? 
CPAP respiratory support  
 CPAP for respiratory distress In preterm infants with respiratory distress syndrome (P), what is the effect of any CPAP therapy (I) versus supportive care with oxygen therapy by head box, face mask, or nasal cannula (C) on critical outcomes (O)? 
 Early CPAP In preterm infants with respiratory distress syndrome (P), what is the effect of early CPAP (I) versus late CPAP(C) on critical outcomes (O)? 
 CPAP prophylaxis In preterm infants <32 wks, regardless of respiratory status (P), what is the effect of CPAP started immediately after birth (I) compared with supportive care with oxygen therapy by head box, face mask, or nasal cannula (C) on critical outcomes (O)? What is the effect of CPAP started immediately after birth (I) compared with mechanical ventilation (C) on critical outcomes (O)? 
 CPAP pressure source In preterm infants with respiratory distress syndrome, what is the effect of bubble (I) compared with other forms of CPAP (C) on critical outcomes (O)? 
Methylxanthine respiratory management In preterm infants, what is the effect of any methylxanthine compared with no methylxanthine on critical outcomes? What is the effect by indication (any, prevention, treatment), by type of methylxanthine (eg, caffeine, theophylline) and by gestational age or birth wt? 
Family care  
 Family involvement In hospitalized preterm or LBW infants (P), do interventions to involve families in the infant’s routine health care (family involvement strategies) (I) compared with standard hospital or NICU care (C) improve critical outcomes (O)? 
 Family support In preterm or LBW infants (P), do interventions to support the family to care for the infant in the home (I) compared with no or different interventions (C) improve critical outcomes (O)? 
InterventionsPICO
Thermal care  
 Kangaroo mother care In preterm or LBW infants (P), what is the effect of KMC (I) compared with conventional neonatal care (C) on critical outcomes (O)? If KMC is effective, then what is the effect of early‐onset KMC (I) compared with late‐onset KMC (C) on critical outcomes (O)? What is the effect of short (I) compared with longer (C) durations of KMC on critical outcomes (O)? 
Milk feeding  
 Mother’s own milk In preterm or LBW infants (P), what is the effect of feeding mother's own milk (I) compared with feeding infant formula (C) on critical outcomes (O)? 
 Donor human milk In preterm or LBW infants who cannot be fed mother's own milk (P), what is the effect of feeding donor human milk (I) compared with feeding infant formula (C) on critical outcomes (O)? 
 Fortification In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of multicomponent fortification of milk (I) compared with no fortification (C) on critical outcomes (O)? 
 Infant formula In preterm or LBW infants who cannot be fed mother's own milk or donor human milk (P), what is the effect of feeding nutrient enriched (“preterm”) infant formula (I) compared with feeding standard infant (“term”) formula (C) on critical outcomes (O)? 
 Initiation of enteral feeding In preterm or LBW infants (P), what is the effect of early initiation of enteral feeding (I) compared with delayed feeding (C) on critical outcomes (O)? If early, then when should feeding be initiated? Does this effect differ in infants given full enteral feeding compared with infants given restricted volumes, including minimal enteral feeding? 
 Responsive feeding In preterm or LBW infants who receive any enteral feeding (P), what is the effect of responsive feeding based on infants’ cues (I) compared with scheduled feeding (C) on critical outcomes (O)? 
 Volume advancement In preterm or LBW infants who receive any enteral feeding (P), what is the effect of fast advancement of enteral feeds (I) versus slower rates of feed advancement (C) on critical outcomes (O)? 
 Duration of exclusive breastfeeding In preterm or LBW infants (P), what is the effect of exclusive breastfeeding for <6 mo (I) compared with exclusive breastfeeding for 6 mo (C) on critical outcomes (O)? If <6 mo, then what is the optimal duration? 
Micronutrients  
 Iron In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral iron supplementation (I) compared with no iron supplementation (C) on critical outcomes (O)? 
 Zinc In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral zinc supplementation (I) compared with no zinc supplementation (C) on critical outcomes (O)? 
 Vitamin D In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral vitamin D supplementation (I) compared with no vitamin D supplementation (C) on critical outcomes (O)? 
 Vitamin A In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral vitamin A supplementation (I) compared with no vitamin A supplementation (C) on critical outcomes (O)? 
 Calcium and phosphorous In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral calcium and phosphorous supplementation (I) compared with no supplementation (C) on critical outcomes (O)? 
 Multiple micronutrient supplements In preterm or LBW infants who are fed mother's own milk or donor human milk (P), what is the effect of enteral multiple micronutrient supplements (I) compared with no enteral multiple micronutrient supplements (C) on critical outcomes (O)? 
Probiotics In preterm or LBW infants who receive any enteral feeding (P), what is the effect of probiotics (I) versus no probiotics (C) on critical outcomes (O)? 
Skin care  
 Emolients In preterm or LBW infants (P) what is the effect of topical ointment, cream or oil applied to the skin (I) compared with routine skin care (C) on critical outcomes (O)? 
CPAP respiratory support  
 CPAP for respiratory distress In preterm infants with respiratory distress syndrome (P), what is the effect of any CPAP therapy (I) versus supportive care with oxygen therapy by head box, face mask, or nasal cannula (C) on critical outcomes (O)? 
 Early CPAP In preterm infants with respiratory distress syndrome (P), what is the effect of early CPAP (I) versus late CPAP(C) on critical outcomes (O)? 
 CPAP prophylaxis In preterm infants <32 wks, regardless of respiratory status (P), what is the effect of CPAP started immediately after birth (I) compared with supportive care with oxygen therapy by head box, face mask, or nasal cannula (C) on critical outcomes (O)? What is the effect of CPAP started immediately after birth (I) compared with mechanical ventilation (C) on critical outcomes (O)? 
 CPAP pressure source In preterm infants with respiratory distress syndrome, what is the effect of bubble (I) compared with other forms of CPAP (C) on critical outcomes (O)? 
Methylxanthine respiratory management In preterm infants, what is the effect of any methylxanthine compared with no methylxanthine on critical outcomes? What is the effect by indication (any, prevention, treatment), by type of methylxanthine (eg, caffeine, theophylline) and by gestational age or birth wt? 
Family care  
 Family involvement In hospitalized preterm or LBW infants (P), do interventions to involve families in the infant’s routine health care (family involvement strategies) (I) compared with standard hospital or NICU care (C) improve critical outcomes (O)? 
 Family support In preterm or LBW infants (P), do interventions to support the family to care for the infant in the home (I) compared with no or different interventions (C) improve critical outcomes (O)? 

PICO, population, intervention, comparator, outcome; KMC, kangaroo mother care.

An overview of the systematic reviews process was conducted (as outlined in paper 1 of this supplement),4  to understand which systematic reviews, if any, had addressed the 24 research questions in the last 3 years. Eight had already been addressed by published systematic reviews (donor human milk, multicomponent fortifier, formula milk, probiotics, emollients, use of continuous positive airways pressure [CPAP] in infants with respiratory distress syndrome, early initiation of CPAP, and prophylactic CPAP). Sixteen required new systematic reviews (kangaroo mother care, mother’s own milk, early initiation, responsive feeding, advancement of feeding, duration of exclusive breastfeeding, iron, zinc, vitamin A, vitamin D, calcium and phosphorous, multiple micronutrients, methylxanthines, family involvement, and family support).

The sixteen systematic reviews were subsequently completed. Four have been published elsewhere (kangaroo mother care, CPAP pressure source, methylxanthines, family support).58  Twelve are presented in this supplement. These reviews fill a much-needed gap in the evidence base. They can be used by the global public health community to (1) understand the impact, research priorities, and implementation considerations and (2) assist in the development of policies and programs to improve the care of these most vulnerable preterm and LBW infants.

Dr Edmond conceptualized and designed the study, drafted the initial manuscript, and approved the final manuscript as submitted.

FUNDING: No external funding.

CONFLICT OF INTEREST DISCLOSURES: The author has indicated they have no potential conflicts of interest relevant to this article to disclose.

     
  • CPAP

    continuous positive airways pressure

  •  
  • LBW

    low birth weight

  •  
  • WHO

    World Health Organization

1
Bahl
R
,
Martines
J
,
Bhandari
N
, et al
.
Setting research priorities to reduce global mortality from preterm birth and low birth weight by 2015
.
J Glob Health
.
2012
;
2
(
1
):
010403
2
Ashorn
P
,
Black
RE
,
Lawn
JE
, et al
.
The Lancet small vulnerable newborn series: science for a healthy start
.
Lancet
.
2020
;
396
(
10253
):
743
745
3
World Health Organization
.
Guideline Development Group meeting on updating WHO Recommendations on care of preterm or low birth weight infants
.
4
Edmond
K
,
Strobel
N
,
Gupta
S
,
Rao
S
,
Bahl
R
.
Evidence for global health care interventions for preterm and LBW infants; an overview of systematic reviews
.
Pediatrics
.
2022
;
150
(
suppl 1
):
e2022057092C
5
Prakash
R
,
De Paoli
AG
,
Davis
PG
,
Oddie
SJ
,
McGuire
W
.
Bubble devices versus other pressure sources for nasal continuous positive airway pressure in preterm infants
.
Cochrane Database of Syst Rev
.
CD015130
,
In press
6
Marques
K
,
Roehr
CC
,
Bruschettini
M
, %
Davis
PG
,
Soll
R
.
Methylxanthine for the prevention and treatment of apnea in preterm infants
.
Cochrane Database Syst Rev
.
2021
;(
1
):
CD015130
7
Bedwell
C
,
Lavender
T
,
Tate
N
,
Actis Danna
V
;
National Institute for Health Research
.
Interventions to support parents, families and carers in caring for premature or low birth weight (LBW) infants in the home: a systematic review
.
8
National Institute for Health Research
.
Kangaroo mother care for low-birth-weight infants
.
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