Scolaris Content Display Scolaris Content Display

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Table 1. Characteristics of excluded reviews

Review ID and title

Reason for exclusion

Atherton 2012

Email for clinical communication between patients/caregivers and healthcare professionals

Wrong participants (not neonates):

  1. "We included all healthcare professionals, patients and caregivers regardless of age, gender and ethnicity. We considered participants originating the email communication, receiving the email communication and copied into the email communication"

Barlow 2015

Parent‐infant psychotherapy for improving parental and infant mental health

Wrong participants (not neonates):

  1. "We included studies involving parent‐infant dyads in which the parent was experiencing mental health problems, domestic abuse or substance dependency, with or without the infant showing signs of attachment or dysregulation problems, or both attachment and dysregulation problems. We included all infants irrespective of the presence of problems such as low birthweight, prematurity or disabilities. We included studies targeting infants and toddlers in which the mean age of the infant participants was 24 months or less at the point of referral. We included studies targeting all parents (i.e. including fathers, birth parents, adoptive and kinship parents, but not foster parents)"

Bredemeyer 2012

Body positioning for spontaneously breathing preterm infants with apnoea

Secondary outcomes pre‐specified include the following:

  1. Short‐term motor development up to about 12 months' corrected age, as measured by a validated assessment tool

  2. Longer‐term motor development up to about 2 years' corrected age, as measured by a validated assessment tool

  3. Neurodevelopment assessed at about 2 years' corrected age, as measured by a validated assessment tool

No outcome data for these outcomes

Brown 2016

C‐reactive protein for diagnosing late‐onset infection in newborn infants

Protocol for diagnostic test accuracy review

Carr 2003

G‐CSF and GM‐CSF for treating or preventing neonatal infections

Secondary outcomes pre‐specified include:

  1. Long‐term outcomes: death and disability at or > 1 year from birth

No outcome data for cerebral palsy (single study results reported "cognition, language and social developmental performance scores were within the normal range for age and motor deficits were 'typical of high‐risk, low birth weight neonates'. However there was no comparison made between G‐CSF and control infants"

Davis 2001

Intravenous dexamethasone for extubation of newborn infants

No pre‐specified outcome focused on development/disability at follow‐up

Ethawi 2016

High‐frequency jet ventilation vs high‐frequency oscillatory ventilation for pulmonary dysfunction in preterm infants

Secondary neonatal outcomes pre‐specified include:

  1. Neurodevelopmental outcomes including motor, mental, and sensory outcomes at 2 years of age (study author defined)

No outcome data for this outcome (no included trials)

Hancock 2013

Treatment of infantile spasms

Outcomes pre‐specified include:

  1. Long‐term psychomotor development

No outcome data for cerebral palsy (single‐study results reported related to BSID; VABS; 'cognitive development'; Japanese Tumor Scale; DDST)

Jones 2003

Antiviral therapy for symptomatic congenital cytomegalovirus infection in neonates and infants up to 3 months of age

Protocol

Primary outcomes pre‐specified include:

  1. Mortality at 1 year of life and the presence of cognitive, developmental, audiological, motor, or visual impairment upon completion of therapy, at follow‐up at 1 year of life, and in later childhood

Lewin 2010

Lay health workers in primary and community health care for maternal and child health and management of infectious diseases

No pre‐specified outcome focused on development/disability at follow‐up

Malviya 2013

Surgical vs medical treatment with cyclo‐oxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants

Secondary outcomes pre‐specified include:

  1. Neurodevelopmental outcome (neurodevelopmental outcome assessed by a standardised and validated assessment tool, a child developmental specialist, or both) at any age (outcome data will be grouped at 6, 9, 12, 18, 24 months, if available)

No outcome data for this outcome

Morag 2016

Cycled light in the intensive care unit for preterm and low birthweight infants

Secondary outcomes pre‐specified include:

  1. Long‐term outcomes: growth and neurodevelopment, including visual and auditory outcomes at any age as reported by study authors using standardised and validated tests

No outcome data for these outcomes

Okwundu 2014

Transcutaneous screening for hyperbilirubinaemia in neonates

Protocol

No pre‐specified outcome focused on development/disability at follow‐up

Pammi 2011

Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropaenia

Primary outcomes pre‐specified include:

  1. Neurological outcome at 1 year of age or later (neurodevelopmental outcome as assessed by any validated test)

No outcome data for this outcome

Pammi 2015

Molecular assays for diagnosis of sepsis in neonates

Protocol for diagnostic test accuracy review

Pammi 2015b

Pentoxifylline for treatment of sepsis and necrotising enterocolitis in neonates

Secondary outcomes pre‐specified include:

  1. Neurological outcome at 2 or more years of age (neurodevelopmental outcome as assessed by a validated test)

No outcome data for this outcome

Scholefield 2013

Hypothermia for neuroprotection in children after cardiopulmonary arrest

Primary outcomes pre‐specified include:

  1. Best neurological outcome at hospital discharge and within the first year as assessed by the Paediatric Cerebral Performance Category score and other validated outcome scores for use in children (e.g. VABS)

No outcome data for these outcomes (no included trials)

Shah 2012

Intraventricular antibiotics for bacterial meningitis in neonates

Secondary outcomes pre‐specified include:

  1. Neurodevelopmental outcome (neurodevelopmental outcome as assessed by a standardised and validated assessment tool or a child developmental specialist, or both) at any age (outcome data will be grouped at 12, 18, and 24 months, if available)

No outcome data for this outcome

Suresh 2003

Metalloporphyrins for treatment of unconjugated hyperbilirubinaemia in neonates

Outcomes pre‐specified include:

  1. Presence of neurodevelopmental sequelae (i.e. any sensory, motor, cognitive, psychological, or behavioural impairment reported on follow‐up any time after the neonatal period)

  2. Degree of such neurodevelopmental impairment (expressed as mean or median scores on tests of neurodevelopmental function performed any time after the neonatal period)

No outcome data for these outcomes

Thukral 2015

Periodic change of body position under phototherapy in term and late preterm neonates with hyperbilirubinaemia

Protocol

Secondary outcomes pre‐specified include:

  1. Incidence of BIND (proportion). BIND or subtle encephalopathy shall be defined as neurological, cognitive, learning, or movement disorders; isolated hearing loss; or auditory dysfunction in the presence of hyperbilirubinaemia (Bergman 1985; Hyman 1969; Johnson 1974; Rubin 1979; Scheldt 1977)

Upadhyay 2016

Short‐duration vs standard‐duration antibiotic regimens for treatment of neonatal bacterial infection

Protocol

Secondary outcomes pre‐specified include:

  1. Survival without major disability at 18 to 24 months' corrected age (proportion)

Ward 2003

Steroid therapy for meconium aspiration syndrome in newborn infants

Primary outcomes pre‐specified include:

  1. Long‐term growth and neurodevelopmental outcomes assessed at age 1, 2, and 5 years with validated assessment tools

No outcome data for this outcome

Whitelaw 2001

Diuretic therapy for newborn infants with post‐haemorrhagic ventricular dilatation

Outcomes pre‐specified include:

  1. Moderate to severe long‐term motor disability at 1 to 3 years of age

  2. Combined outcome: death or (moderate to severe) long‐term disability at 1 to 3 years of age

Data reported for these outcomes; no outcome data for cerebral palsy. "The larger trial showed that acetazolamide and furosemide treatment resulted in a borderline increase in the risk for motor impairment at one year (RR 1.27, 95% CI 1.02 ‐ 1.58; RD 0.16, 95% CI 0.02 ‐ 0.31), but did not significantly affect the risk for the combined outcome of delay, disability or motor impairment among survivors, or the risk of the combined outcome of death, delay, disability or impairment at one year"

Whitelaw 2001b

Repeated lumbar or ventricular punctures in newborns with intraventricular haemorrhage

Outcomes pre‐specified include:

  1. Surviving with major disability for 12 months or longer in survivors

  2. Surviving with multiple neurodevelopmental impairments

Data reported for these outcomes; no outcome data for cerebral palsy. "The tables and figures show that none of the trials found a significant effect of CSF tapping on a) need for shunt b) death c) major disability in survivors d) multiple disability in survivors e) death or disability. Similarly, meta‐analysis of the results of all included trials shows no significant effect of CSF tapping on any of these outcomes"

Woodgate 2001

Permissive hypercapnia for prevention of morbidity and mortality in mechanically ventilated newborn infants

Outcomes pre‐specified include:

  1. Neurodevelopmental outcome

No outcome data for this outcome

Abbreviations: BIND: bilirubin‐induced neurological dysfunction; BSID: Bayley Scales of Infant Development; CI: confidence interval; CSF: cerebrospinal fluid; DDST: Denver Developmental Screening Test; G‐CSF: granulocyte‐colony stimulating factor; GM‐CSF: granulocyte‐macrophage colony‐stimulating factor; RD: risk difference; RR: risk ratio; VABS: Vineland Adaptive Behavior Scales.

Figures and Tables -
Table 1. Characteristics of excluded reviews
Table 2. Characteristics of included reviews

Review ID and title

Date of search and date assessed as up‐to‐date

No. included trials (countries and publication years)

No. participants in included trials

Inclusion criteria for 'Types of participants'

Relevant comparison interventions (no. trials and participants)

Overview outcomes for which data were reported (no. trials and participants)

Neonatal care: asphyxia

Chaudhari 2012

Allopurinol for preventing mortality and morbidity in newborn infants with hypoxic‐ischaemic encephalopathy

Searches: March 2012

Up‐to‐date:
4 April 2012

3 RCTs

(Countries: Netherlands, Turkey;

Published: 1990s: 1 RCT; 2000s: 2 RCTs)

114 infants

Newborn infants (> 34 weeks' gestation) with hypoxic‐ischaemic encephalopathy defined as clinical evidence of cardiorespiratory or neurological depression (Apgar score < 7 at 5 minutes and beyond after birth) and/or evidence of severe metabolic acidosis in intrapartum foetal, umbilical arterial cord, or very early neonatal blood samples (pH < 7 or base deficit > 12 mmol/L), and/or clinical or electro‐encephalographic (multi‐channel or amplitude integrated) evidence of neonatal encephalopathy (MacLennan 1999)

Allopurinol vs control (3 RCTs, 114 neonates)

Severity of cerebral palsy ("Severe quadriplegia in surviving infants" (3 RCTs, 73 children); reported as a primary outcome)

Other composite outcome that includes cerebral palsy as a component ("Death or severe neurodevelopmental disability in survivors" (3 RCTs, 110 children); reported as a primary outcome)

Jacobs 2013

Cooling for newborns with hypoxic‐ischaemic encephalopathy

1 May 2012

11 RCTs

(Countries: China: 2 RCTs; New Zealand: 1 RCT; Turkey: 1 RCT; USA; 3 RCTs; international: 4 RCTs

Published: 1990s: 1 RCT; 2000s: 7 RCTs; 2010s: 3 RCTs)

1505 infants

1. Newborn infants of 35 weeks' gestation or greater

2. Evidence of peripartum asphyxia, with each enrolled infant satisfying at least 1 of the following criteria:

a. Apgar score of 5 or less at 10 minutes

b. Mechanical ventilation or resuscitation at 10 minutes

c. Cord pH < 7.1, or arterial pH < 7.1, or base deficit of 12 or more within 60 minutes of birth

3. Evidence of encephalopathy according to Sarnat staging (Finer 1981; Sarnat 1976):

a. Stage 1 (mild): hyperalertness, hyper‐reflexia, dilated pupils, tachycardia, absence of seizures

b. Stage 2 (moderate): lethargy, hyper‐reflexia, miosis, bradycardia, seizures, hypotonia with weak suck and Moro

c. Stage 3 (severe): stupor, flaccidity, small to mid position pupils that react poorly to light, decreased stretch reflexes, hypothermia, and absent Moro

No major congenital abnormalities recognisable at birth

Therapeutic hypothermia vs standard care (11 RCTs, 1505 neonates)

Cerebral palsy ("Cerebral palsy in survivors assessed" (7 RCTs, 881 children) and "Outcome at 6 to 7 years of age: Cerebral palsy" (1 RCT, 121 children); reported as secondary outcomes)

Other composite outcomes that include cerebral palsy as a component ("Death or major disability in survivors assessed" (8 RCTs, 1344 children); reported as a primary outcome) ("Major neurodevelopmental disability" (8 RCTs, 1344 children); "Major neurodevelopmental disability in survivors assessed" (8 RCTs, 917 children); "Outcome at 6 to 7 years of age: death or moderate‐to‐severe disability" (1 RCT, 190 children); "Outcome at 6 to 7 years of age: moderate‐to‐severe disability" (1 RCT, 119 children); reported as secondary outcomes)

Motor dysfunction ("Neuromotor delay (BSID PDI more than 2 SD below mean) in survivors assessed" (6 RCTs, 657 children); reported as a secondary outcome)

Young 2016

Prophylactic barbiturate use for the prevention of morbidity and mortality following perinatal asphyxia

30 November 2015

9 RCTs

(Countries: Finland: 1 RCT; India: 2 RCTs; Mexico: 1 RCT; Romania: 1 RCT; South Africa: 1 RCT; Spain: 1 RCT; USA: 2 RCTs;

Published: 1980s: 2 RCTs; 1990s: 2 RCTs; 2000s: 2 RCTs; 2010s: 3 RCTs)

456 infants

  1. Term infants (37 weeks or greater) and late preterm infants (34 to 36+6 weeks' gestation) 3 days of age or less with perinatal asphyxia

  2. Evidence of perinatal asphyxia, characterised by evidence of neonatal or foetal distress with each enrolled infant satisfying at least 1 of the following criteria:

    1. Cord gas or postnatal blood gas (within the first hour of life) with pH 7.0 or less or base deficit 12 mEq/L or greater

    2. Apgar score 5 or less at 10 minutes

    3. Need for mechanical ventilation or resuscitation at 10 minutes of life

  3. With or without evidence of encephalopathy (moderate or severe) according to Sarnat staging (Sarnat 1976)

  4. No evidence of seizures

  5. No major congenital abnormalities recognisable at birth

Barbiturates vs control (8 RCTs, 439 neonates)

Cerebral palsy ("Cerebral palsy" (2 RCTs, 69 children); reported as a secondary outcome)

Other composite outcomes that include cerebral palsy as a component ("Death or major neurodevelopmental disability" (1 RCT, 31 children); reported as a primary outcome) ("Major neurodevelopmental disability" (1 RCT, 31 children); reported as a secondary outcome)

Neonatal care: haemorrhage: periventricular/intraventricular

Hunt 2010

Ethamsylate for the prevention of morbidity and mortality in preterm or very low birth weight infants

Search: 24 August 2009

Up‐to‐date: 22 September 2009

7 RCTs

(Countries: France, Greece, UK: 1 RCT; India: 1 RCT; Switzerland: 1 RCT; Taiwan: 1 RCT; Turkey: 1 RCT; UK: 2 RCTs;

Published: 1980s: 3 RCTs; 1990s: 4 RCTs)

1410 infants

Preterm infants born before and including 34 weeks plus 6 days' completed gestation or with birthweight < 2000 g

Ethamsylate vs placebo (7 RCTs, 1410 neonates)

Cerebral palsy ("Cerebral palsy in surviving children available for follow‐up" (3 RCTs, 532 children); reported as a primary outcome)

Other composite outcomes that include cerebral palsy as a component ("Neurodevelopmental disability at 2 years of age in surviving children available for follow‐up" (3 RCTs, 532 children); "Death or any disability by 2 years of age in children with known outcome at any point in time" (7 RCTs, 1334 children); reported as primary outcomes)

Smit 2013

Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants

Search: 31 October 2012

Up‐to‐date: 17 December 2012

12 RCTs

(Countries: not reported;

Published: 1980s: 8 RCTs; 1990s: 1 RCT: 2000s: 3 RCTs)

982 infants

Newborn infants (less than 24 hours old) with gestational age < 34 weeks or birthweight < 1500 g. We included preterm infants with gestational age 33 to 36 weeks or birthweight up to 1750 g, if they were mechanically ventilated. We excluded infants with serious congenital malformations

Phenobarbital vs control (12 RCTs, 982 neonates)

Other composite outcomes that include cerebral palsy as a component ("Mild neurodevelopmental impairment" (1 RCT, 101 children); "Severe neurodevelopmental impairment" (1 RCT, 101 children); reported as secondary outcomes)

Neonatal care: hypotension

Osborn 2007b

The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow

19 May 2010

1 RCT

(Country: not reported;

Published: 2000s)

42 infants

Preterm infants (< 37 weeks' gestational age) with low SBF or organ blood flow in the neonatal period. Low SBF may be determined on the basis of echocardiographically measured ventricular outputs or surrogates for SBF such as SVC flow. Low organ blood flow may be determined on the basis of techniques including ultrasound Doppler, near infrared spectroscopy, or xenon clearance techniques when evidence in the literature suggests that measurement is associated with substantial clinical outcomes and/or actual organ blood flow. The review does not include studies that include surrogates of flow such as BP, ultrasound Doppler‐measured velocities, pulsatility, or resistive indices

Dobutamine vs dopamine in preterm infants with low superior vena cava flow (1 RCT, 42 neonates)

Cerebral palsy ("Cerebral palsy at 3 years in survivors assessed" (1 RCT, 13 children); reported as a primary outcome)

Other composite outcomes that include cerebral palsy as a component ("Disability at 3 years in survivors assessed" (1 RCT, 13 children); "Death or disability at 3 years" (1 RCT, 37 children); "Death or disability at latest follow‐up" (1 RCT, 41 children); reported as primary outcomes)

Neonatal care: fluid therapy

Osborn 2004

Early volume expansion for prevention of morbidity and mortality in very preterm infants

30 July 2008

8 RCTs

(Countries: not reported;

Published: 1970s: 1 RCT; 1980s: 1 RCT; 1990s: 4 RCTs; 2000s: 2 RCTs)

1185 infants

Very preterm infants born ≦ 32 weeks' gestation or ≦ 1500 g and enrolled and treated the first 72 hours after birth. Trials were eligible if they enrolled unselected preterm infants, preterm infants with clinically suspected poor perfusion (e.g. low BP, poor cutaneous perfusion, metabolic acidosis), or preterm infants with low blood flow (e.g. determined by Doppler ultrasound). Low BP may be defined as BP less than a specified percentile of a standard chart, mean BP ≦ 30 mmHg in any preterm infant, or mean BP ≦ 1 mmHg per week of gestation

Volume vs no treatment in very preterm infants (5 RCTs, 978 neonates)

Gelatin vs fresh frozen plasma in hypotensive infants (1 RCT, 519 neonates)

Cerebral palsy ("Cerebral palsy in survivors" (1 RCT, 604 children; and 1 RCT, 399 children); reported as a primary outcome)

Other composite outcomes that include cerebral palsy as a component ("Severe neurodevelopmental disability in survivors" (1 RCT, 604 children; and 1 RCT, 399 children); "Death or severe neurodevelopmental disability" (1 RCT, 776 children; and 1 RCT, 518 children); reported as primary outcomes)

Neonatal care: patent ductus arteriosus

Fowlie 2010

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants

Searches: April 2010

Up‐to‐date:
19 May 2010

19 RCTs

(Countries: North America: 13 RCTs; Latin America, Europe, Asia: 6 RCTs;

Published: 1980s: 11 RCTs; 1990s: 7 RCTs; 2000s; 1 RCT)

2872 infants

Preterm neonates (less than 37 weeks' completed gestation)

Prophylactic IV indomethacin vs placebo or no drug (19 RCTs, 2872 neonates)

Cerebral palsy ("Neurological assessments (18‐54 months: Cerebral palsy" (4 RCTs, 1372 children); "School age neurological assessments: Cerebral palsy aged 8 years" (1 RCT, 304 children); reported as primary outcomes)

Other composite outcome that includes cerebral palsy as a component ("Death or severe neurosensory impairment" (3 RCTs, 1491 children); reported as a primary outcome)

Ohlsson 2015

Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants

7 May 2014

33 RCTs

(Countries: Albania: 1 RCT; Belgium: 2 RCTs; Czech Republic: 1 RCT; China: 1 RCT; Egypt: 1 RCT; India: 1 RCT; Iran: 3 RCTs; Israel: 1 RCT; Italy: 6 RCTs; Poland: 1 RCT; Qatar: 1 RCT; Spain: 2 RCTs; Taiwan: 2 RCTs; Thailand: 2 RCTs; Tunisia: 1 RCT; Turkey: 3 RCTs; UK: 2 RCTs; USA: 2 RCTs;

Published: 1990s: 4 RCTs; 2000s: 18 RCTs; 2010s: 11 RCTs)

2190 infants

Preterm infants less than 37 weeks' gestational age or LBW infants (less than 2500 g) with PDA diagnosed either clinically or by echocardiographically (ECHO) guided criteria in the neonatal period (less than 28 days)

Oral ibuprofen vs IV ibuprofen (data for maximum of 4 RCTs, 304 neonates)

Cerebral palsy ("Moderate/severe cerebral palsy at 18‐24 months" (1 RCT, 57 children); reported as a secondary outcome)

Neonatal care: blood disorders

Ohlsson 2014

Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants

1 July 2013

27 RCTs

(Countries: Austria: 2 RCTs; Bangladesh: 1 RCT; Chile: 1 RCT; China: 2 RCTs; Greece: 3 RCTs; Iran: 1 RCT; Italy: 2 RCTs; Mexico: 1 RCT; New Zealand: 1 RCT; Poland: 1 RCT; Singapore: 1 RCT; South Africa: 1 RCT; Switzerland: 1 RCT; Turkey: 1 RCT; USA: 5 RCTs; Europe: 3 RCTs;

Published 1990s: 12 RCTs; 2000s: 13 RCTs; 2010s: 2 RCTs)

2209 infants

Preterm (< 37 weeks) and/or LBW (< 2500 g) neonates less than 8 days of age

Erythropoietin vs placebo or no treatment (27 RCTs, 2209 neonates)

Darbepoetin alfa vs placebo or no treatment (1 RCT, 66 neonates)

Cerebral palsy ("Cerebral palsy at 18 ‐ 22 months' corrected age (in children examined)" (2 RCTs, 153 children; and 1 RCT, 51 children); reported as secondary outcomes)

Other composite outcome that includes cerebral palsy as a component ("Any neurodevelopmental impairment at 18‐22 months' corrected age (in children examined)" (1 RCT< 99 children); reported as a secondary outcome)

Motor dysfunction ("PDI < 70 at 18 ‐ 22 months' corrected age (in children examined)" (1 RCT, 90 children); reported as a secondary outcome)

Whyte 2011

Low versus high haemoglobin concentration threshold for blood transfusion for preventing morbidity and mortality in very low birth weight infants

Search: August 2011

Up‐to‐date: 1 September 2011

5 RCTs

(Countries: Canada: 1 RCT; International (Canada, USA, Australia): 1 RCT; Taiwan: 1 RCT; USA: 2 RCTs;

Published: 1980s: 1 RCT; 1990s: 1 RCT; 2000s: 3 RCTs)

670 infants

VLBW infants (i.e. of birthweight less than or equal to 1500 g, or less than 32 weeks' gestational age) admitted to NICU at less than 1 week of age. We aimed specifically to include studies of infants receiving all levels of intensive care

Transfusion at a low haemoglobin or haematocrit level (restrictive) vs transfusion at a high haemoglobin or haematocrit level (liberal) (4 RCTs, 614 neonates)

Cerebral palsy ("Neurosensory impairment at 18‐21 months' follow‐up among survivors: Cerebral palsy" (1 RCT, 335 children); reported as a secondary outcome)

Other composite outcomes that include cerebral palsy as a component ("Death or severe morbidity: at 18‐21 months' follow‐up with MDI < 70" (1 RCT, 421 children); "Death or severe morbidity: at 18‐21 months' follow‐up with MDI < 85" (1 RCT, 421 children); reported as primary outcomes) ("Neurosensory impairment at 18‐21 months' follow‐up among survivors: any neurosensory impairment" (1 RCT, 328 children); reported as a secondary outcome)

Neonatal care: pulmonary hypertension

More 2016

Endothelin receptor antagonists for persistent pulmonary hypertension in term and late preterm infants

28 December 2015

2 RCTs

(Countries: Saudi Arabia: 1 RCT; unclear (multi‐centre): 1 RCT;

Published: 2010s: 2 RCTs)

68 infants

Late preterm infants (born at 34+0 to 36+6 weeks), term infants (born at 37+0 to 41+6 weeks), and post‐term infants (i.e. born after 41+6 weeks' gestation) until post‐menstrual age (PMA) up to 44 weeks with PPHN were eligible for inclusion. The diagnosis of PPHN was clinical or was based on echocardiography. Clinical diagnosis of PPHN was considered when there was hypoxaemia refractory to oxygen therapy and mechanical ventilation (Roberts 1997). The echocardiographic diagnosis of PPHN was made by demonstrating the presence of extrapulmonary right‐to‐left shunting at the ductal or atrial level, near or suprasystemic pulmonary arterial pressures, and doppler evidence of tricuspid regurgitation (Dhillon 2012; Stayer 2010)

Endothelin receptor antagonists vs placebo (1 RCT, 47 neonates)

Cerebral palsy ("Cerebral palsy" (1 RCT, 37 children); reported as a secondary outcome)

Motor dysfunction ("Adverse neurodevelopmental outcome at 6 months" (1 RCT, 37 children); reported as a secondary outcome)

Neonatal care: resuscitation

Tan 2005

Air versus oxygen for resuscitation of infants at birth

Search: December 2003/January 2004

Up‐to‐date: 15 February 2005

5 RCTs

(Countries: India: 1 RCT; 6 countries: 1 RCT; not reported: 3 RCTs

Published: 1990s: 2 RCTs; 2000s: 3 RCTs)

1302 infants

Term or preterm neonates requiring IPPV at birth

Room air vs 100% oxygen (5 RCTs, 1302 neonates)

Cerebral palsy ("Long‐term neurodevelopmental outcome: cerebral palsy in those followed up at 18‐24 months" (1 RCT, 213 children); reported as a post hoc outcome)

Motor dysfunction ("Long‐term neurodevelopmental outcome: not walking in those followed up at 18‐24 months" (1 RCT, 213 children); reported as a post hoc outcome)

Neonatal care: nitric oxide

Barrington 2010

Inhaled nitric oxide for respiratory failure in preterm infants

Search: June 2010

Up‐to‐date: 12 October 2010

14 RCTs

(Countries: Europe: 3 RCTs; Taiwan: 1 RCT; USA: 1 RCT; not reported/unclear: 9 RCTs

Published: 1990s: 3 RCTs; 2000s: 11 RCTs)

3430 infants

Premature infants (less than 35 weeks' gestation) with respiratory failure after adequate treatment with surfactant

Inhaled NO compared with control; analyses conducted based on:

  1. Studies with entry before 3 days based on oxygenation (9 RCTs, 1006 neonates)

  2. Studies with entry after 3 days based on BPD risk (2 RCTs, 624 neonates)

  3. Studies of routine use in intubated preterm infants (3 RCTs, 1800 neonates)

Cerebral palsy ("Cerebral palsy"; reported as an outcome (2 RCTs, 209 children; 2 RCTs, 498 children; and 2 RCTs, 593 children) (not separated into primary/secondary))

Other composite outcome that includes cerebral palsy as a component ("Neurodevelopmental disability" (2 RCTs, 208 children; 2 RCTs, 498 children; and 2 RCTs, 593 children); reported as an outcome (not separated into primary/secondary))

Motor dysfunction ("Bayley MDI or PDI <‐2SD" (1 RCT, 138 children); reported as an outcome (not separated into primary/secondary))

Finer 2006

Nitric oxide for respiratory failure in infants born at or near term

Search: November 2005

Up‐to‐date:
30 May 2006

14 RCTs

(Countries: 33 French and Belgian Units: 1 RCT; not reported: 13 RCTs

Published: 1990s: 11 RCTs; 2000s: 3 RCTs)

1715 infants

Newborn infants (< 1 month of age) with hypoxaemia suspected to be due to lung disease, pulmonary hypertension with right‐to‐left shunting, or both

Only studies in term and near‐term infants (> 34 weeks' gestation) were included

Efforts were made in all studies to exclude infants with intracardiac shunting due to structural congenital heart disease

Infants with diaphragmatic hernia may respond differently from other near term infants (from preliminary data), and as far as possible results from infants with diaphragmatic hernias have been evaluated separately

Inhaled NO vs control (10 RCTs, 1068 infants)

Inhaled NO vs control in infants with diaphragmatic hernia (2 RCTs, 84 neonates)

Cerebral palsy ("Cerebral palsy among survivors" (2 RCTs, 299 children; and 1 RCT, 22 children); reported as an outcome (not separated into primary/secondary))

Other composite outcome that includes cerebral palsy as a component ("Neurodevelopmental disability at 18 to 24 months among survivors" (2 RCTs, 301 children); reported as an outcome (not separated into primary/secondary))

Motor dysfunction ("Bayley PDI more than 2 SD below the mean" (2 RCTs, 283 children); reported as an outcome (not separated into primary/secondary))

Neonatal care: apnoea

Henderson‐Smart 2010b

Methylxanthine treatment for apnoea in preterm infants

Search:
June 2010

Up‐to‐date:
4 July 2010

6 RCTs

(Countries: not reported

Published: 1980s: 3 RCTs; 1990s: 1 RCT; 2000s: 2 RCTs)

959 infants

Preterm infants with recurrent apnoea. There must have been an effort to exclude specific secondary causes of apnoea

Any methylxanthine vs control

(placebo or no drug therapy) (6 RCTs, 959 neonates)

Cerebral palsy ("Cerebral palsy" (1 RCT, 729 children); reported as a secondary outcome)

Other composite outcome that includes cerebral palsy as a component ("Death or major disability by late infancy" (1 RCT, 767 children); reported as a secondary outcome)

Henderson‐Smart 2010c

Prophylactic methylxanthine for prevention of apnoea in preterm infants

Search: August 2010

Up‐to‐date: 29 September 2010

3 RCTs

(Countries: not reported

Published: 1980s: 2 RCTs; 2000s: 1 RCT)

557 infants

Preterm infants, particularly those born at less than 34 weeks' gestation, who are at risk of developing recurrent apnoea, bradycardia, and hypoxic episodes

Prophylactic methylxanthine vs control (3 RCTs, 557 neonates)

Cerebral palsy ("Cerebral palsy" (1 RCT, 415 children); reported as a secondary outcome)

Other composite outcome that includes cerebral palsy as a component ("Death or major disability" (1 RCT, 423 children); reported as a secondary outcome)

Neonatal care: respiratory distress syndrome

Howlett 2015

Inositol in preterm infants at risk for or having respiratory distress syndrome

14 September 2014

4 RCTs

(Countries: Finland: 2 RCTs; USA: 2 RCTs

Published: 1980s: 1 RCT; 1990s: 2 RCTs; 2010s: 1 RCT)

429 infants

Preterm infants (< 37 weeks' post‐menstrual age) or LBW (< 2500 g) infants

Inositol supplementation (repeat doses) vs control (3 RCTs, 355 neonates)

Other composite outcomes that include cerebral palsy as a component ("Major neural developmental impairment at one year corrected age" (1 RCT, 169 children); reported as a secondary outcome)

Motor dysfunction ("Minor neural developmental impairment at one year corrected age" (1 RCT, 169 children); reported as a secondary outcome)

Seger 2009

Animal derived surfactant extract for treatment of respiratory distress syndrome

Search: December 2008

Up‐to‐date: 13 February 2009

13 RCTs

(Countries: not reported

Published: 1980s: 7 RCTs; 1990s: 6 RCTs)

1611 infants

Preterm infants (< 37 weeks' gestation) with clinical and/or radiological evidence of respiratory distress syndrome requiring assisted ventilation

Animal‐derived surfactant extract treatment of respiratory distress (all infants) (13 RCTs, 1611 neonates)

Cerebral palsy ("Cerebral palsy" (1 RCT, 73 children); reported as a secondary outcome)

Other composite outcome that includes cerebral palsy as a component ("Major neurodevelopmental disability in survivors" (1 RCT, 73 children); reported as a secondary outcome)

Soll 2000

Synthetic surfactant for respiratory distress syndrome in preterm infants

Search:
not reported

Up‐to‐date:
21 May 1998

6 RCTs

(Countries: not clearly reported; Canada/USA/both: 3 RCTs

Published; 1980s: 1 RCT; 1990s: 5 RCTs)

2358 infants

Neonates with clinical and radiological evidence of respiratory distress syndrome requiring assisted ventilation

Synthetic surfactant vs control (6 RCTs, 2358 neonates)

Cerebral palsy ("Cerebral palsy in survivors examined" (5 RCTs, 1557 children); reported as an outcome (not separated into primary/secondary))

Severity of cerebral palsy ("Moderate ‐ severe cerebral palsy in survivors examined" (5 RCTs, 1557 children); reported as an outcome (not separated into primary/secondary))

Soll 2010

Prophylactic protein free synthetic surfactant for preventing morbidity and mortality in preterm infants

Search: September 2009

Up‐to‐date: 27 October 2009

7 RCTs

(Countries: 1: UK; 6 RCTs: not reported

Published: 1980s: 3 RCTs; 1990s: 4 RCTs)

1583 infants

Premature infants with or without evidence of surfactant deficiency

Prophylactic synthetic surfactant vs control (7 RCTs, 1583 neonates)

Cerebral palsy ("Cerebral palsy, 1‐2 years" (4 RCTs, 670 children); reported as a secondary outcome)

Severity of cerebral palsy ("Cerebral palsy, moderate/severe" (4 RCTs, 670 children); reported as a secondary outcome)

Neonatal care: mechanical ventilation

Cools 2015

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants

30 November 2014

19 RCTs

(Countries: not reported

Published: 1980s: 1 RCT; 1990s: 6 RCTs; 2000s: 10 RCTs; 2010s: 2 RCTs)

4096 infants

Preterm or LBW infants with pulmonary dysfunction, mainly due to respiratory distress syndrome, who were considered to require IPPV

High‐frequency oscillatory ventilation vs conventional ventilation (19 RCTs, 4096 neonates)

Cerebral palsy (reported in text as a secondary outcome (3 RCTs))

Ho 2015

Continuous distending pressure for respiratory distress in preterm infants

30 April 2015

6 RCTs

(Countries: not reported

Published: 1970s: 4 RCTs; 1990s: 1 RCT; 2000s: 1 RCT)

355 infants

Preterm infants with respiratory failure

Continuous distending pressure vs standard care (6 RCTs, 355 neonates)

Cerebral palsy ("Cerebral palsy" (1 RCT, 36 children); reported as a secondary outcome)

Other composite outcomes that include cerebral palsy as a component ("Death or severe disability" (1 RCT, 38 children); "Severe disability" (1 RCT, 37 children); "Any disability" (1 RCT, 37 children); reported as secondary outcomes)

Henderson‐Smart 2010

Prophylactic methylxanthines for endotracheal extubation in preterm infants

Search:
July 2010

Up‐to‐date: 16 August 2010

7 RCTs

(Countries: not reported

Published: 1980s: 3 RCTs; 1990s: 3 RCTs; 2000s: 1 RCT)

916 infants

Preterm or LBW infants being weaned from IPPV

Methylxanthine vs control (7 RCTs, 914 neonates)

Cerebral palsy ("Cerebral palsy" (1 RCT, 644 children); reported as a secondary outcome)

Other composite outcome that includes cerebral palsy as a component ("Death or major disability by 18‐21 months" (1 RCT, 676 children); reported as a secondary outcome)

Kamlin 2003

Long versus short inspiratory times in neonates receiving mechanical ventilation

Search:
April 2004

Up‐to‐date:
22 June 2003

5 RCTs

(Countries: not reported

Published: 1980s: 3 RCTs; 19980s; 2 RCTs)

694 infants

Term and preterm infants at less than 28 days of age and requiring conventional mechanical ventilation. No restrictions on underlying pathophysiology were applied

Long vs short inspiratory times (5 RCTs, 694 neonates)

Cerebral palsy ("Cerebral palsy in survivors less than 33 weeks' gestation at birth" (1 RCT, 177 children); reported as a secondary outcome)

Wheeler 2010

Volume‐targeted versus pressure‐limited ventilation in the neonate

Search: January 2010 Up‐to‐date:
30 June 2010

12 RCTs

(Countries: not reported

Published: 1990s: 2 RCTs; 2000s: 10 RCTs)

693 infants

All intubated infants of less than 28 days' corrected age who were being mechanically ventilated with IPPV at the time of study entry. Infants of all gestational ages and both paralysed and non‐paralysed infants were eligible

Volume‐targeted vs pressure‐limited ventilation (12 RCTs, 693 neonates)

Other composite outcomes that include cerebral palsy as a component ("Severe disability (any definition)" (2 RCTs, 209 children); "Severe disability (any definition) or death" (1 RCT, 109 children; reported as outcomes from post hoc meta‐analyses)

Motor dysfunction ("Gross motor developmental issue (any definition)" (1 RCT, 128 children); reported as an outcome from a post hoc meta‐analysis)

Neonatal care: bronchopulmonary dysplasia

Doyle 2014b

Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

Search: August 2013

Up‐to‐date: 18 February 2014

29 RCTs

(Countries: not reported

Published: 1970s: 1 RCT; 1990s: 17 RCTs; 2000s: 10 RCTs; 2010s: 1 RCT)

3750 infants

Preterm infants at risk of developing chronic lung disease, including those who were ventilator dependent

Early (< 8 days) postnatal corticosteroids vs control (29 RCTs, 3750 neonates)

Cerebral palsy ("Cerebral palsy" (12 RCTs, 1452 children); "Cerebral palsy in survivors assessed" (12 RCTs, 959 children); reported as primary outcomes)

Cerebral palsy or death ("Death or cerebral palsy" (12 RCTs, 1452 children); reported as a primary outcome)

Other composite outcomes that include cerebral palsy as a component ("Major neurosensory disability (variable criteria ‐ see individual studies)" (7 RCTs, 1233 children); "Major neurosensory disability (variable criteria) in survivors examined" (7 RCTs, 799 children); "Death or major neurosensory disability (variable criteria)" (7 RCTs, 1233 children); reported as primary outcomes)

Motor dysfunction ("Bayley Psychomotor Developmental Index (PDI) <‐2SD" (3 RCTs, 842 children); "Bayley PDI <‐2SD in tested survivors" (3 RCTs, 528 children); reported as primary outcomes)

Halliday 2003

Moderately early (7‐14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

Search: October 2002

Up‐to‐date: 11 November 2008

7 RCTs

(Countries: not reported

Published: 1980s: 1 RCT; 1990s: 6 RCTs)

669 infants

Preterm babies developing chronic lung disease including those who were ventilator dependent

Moderately early (7‐14 days) postnatal corticosteroids vs control (7 RCTs, 659 neonates)

Cerebral palsy ("Cerebral palsy" (4 RCTs, 204 children); "Cerebral palsy in survivors assessed" (4 RCTs, 130 children); reported as review outcomes (not separated into primary and secondary))

Cerebral palsy or death ("Death or cerebral palsy" (4 RCTs, 204 children); reported as a review outcome)

Other composite outcomes that include cerebral palsy as a component ("Major neurosensory disability (variable criteria ‐ see individual studies)" (2 RCTs, 96 children); "Major neurosensory disability (variable criteria) in survivors assessed" (2 RCTs, 56 children); "Death or major neurosensory disability (variable criteria)" (2 RCTs, 96 children); reported as review outcomes)

Doyle 2014

Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants

Search:

August 2013

Up‐to‐date: 18 February 2014

21 RCTs

(Countries: Australia, Canada, New Zealand: 1 RCT; 6 countries: 1 RCT; not reported: 19 RCTs

Published: 1980s: 5 RCTs; 1990s: 12 RCTs; 2000s: 3 RCTs; 2010s: 1 RCT)

1424 infants

Preterm infants with evolving or established chronic lung disease, defined as oxygen‐dependent, ventilator‐dependent, or both, with or without radiographic changes of BPD

Late (> 7 days) postnatal corticosteroids vs control (21 RCTs, 1424 neonates)

Cerebral palsy ("Cerebral palsy: at 1 to 3 years" (14 RCTs, 876 children); "Cerebral palsy: at latest reported age" (15 RCTs, 855 children); "Cerebral palsy in survivors assessed: at 1 to 3 years" (14 RCTs, 631 children); "Cerebral palsy in survivors assessed: at latest reported age" (15 RCTs, 591 children); reported as primary outcomes)

Cerebral palsy or death ("Death or cerebral palsy: at 1 to 3 years" (14 RCTs, 876 children); "Death or cerebral palsy: at latest reported age" (15 RCTs, 855 children); reported as primary outcomes)

Other composite outcomes that include cerebral palsy as a component ("Major neurosensory disability (variable criteria ‐ see individual studies)" (8 RCTs, 655 children); "Major neurosensory disability (variable criteria) in survivors assessed" (8 RCTs, 480 children); "Death or major neurosensory disability (variable criteria)" (8 RCTs, 655 children); reported as primary outcomes)

Motor dysfunction ("Bayley Psychomotor Developmental Index (PDI) < ‐2 SD" (1 RCT, 118 children); "Bayley PDI < ‐2 SD in survivors tested" (1 RCT, 90 children); reported as primary outcomes)

Shah 2012

Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates

29 July 2011

7 RCTs

(Countries: Canada: 1 RCT; China: 1 RCT; Germany: 1 RCT; UK: 1 RCT; USA: 1 RCT; not reported: 2 RCTs

Published: 1990s: 5 RCTs; 2000s: 2 RCTs)

495 infants

Ventilator‐dependent preterm neonates with birthweight ≤ 1500 g and postnatal age < 2 weeks

Early inhaled steroids (< 2 weeks) vs placebo (7 RCTs, 495 neonates)

Cerebral palsy ("Cerebral palsy" (1 RCT, 56 children); reported as a secondary outcome)

Motor dysfunction ("Mean developmental index on BSID‐II < 2 SD of the mean" (1 RCT, 56 children); reported as a secondary outcome)

Darlow 2016

Vitamin A supplementation to prevent mortality and short‐ and long‐term morbidity in very low birth weight infants

1 May 2016

11 RCTs

(Countries: Greece: 1 RCT; South Africa: 1 RCT; Thailand: 1 RCT; UK: 2 RCTs; USA: 6 RCTs

Published: 1980s: 2 RCTs; 1990s: 4 RCTs; 2000s: 3 RCTs: 2010s: 2 RCTs)

1580 infants

VLBW infants (defined as birthweight ≤ 1500 g or at less than 32 weeks' gestation)

Supplemental vitamin A vs no supplementation (10 RCTs, 1460 neonates)

Other composite outcomes that include cerebral palsy as a component ("Neurodevelopmental impairment at 18 to 22 months" (1 RCT, 538 children); "Death or neurodevelopmental impairment at 18 to 22 months" (1 RCT, 687 children); reported as secondary outcomes)

Neonatal care: infections: necrotising enterocolitis

AlFaleh 2014

Probiotics for prevention of necrotising enterocolitis in preterm infants

1 October 2013

24 RCTs

(Countries: Australia and New Zealand: 1 RCT; Brazil: 1 RCT; Colombia: 1 RCT; France: 1 RCT; Germany: 2 RCTs; Greece: 2 RCTs; India: 1 RCT; Israel: 1 RCT; Italy: 4 RCTs; Japan: 2 RCTs; Taiwan: 2 RCTs; Turkey: 1 RCT; UK: 1 RCT; USA: 1 RCT; not reported; 3 RCTs

Published: 1980s: 1 RCT; 1990s: 2 RCTs; 2000s: 12 RCTs; 2010s: 9 RCTs)

5529 infants (20 RCTs with reported outcomes)

Preterm infants at < 37 weeks and birthweight < 2500 g, or both

Probiotics vs control (20 RCTs, 5529 neonates)

Other composite outcome that includes cerebral palsy as a component ("Mental retardation and cerebral palsy" (1 RCT, 85 children); reported as a secondary outcome)

Shah 2007

Arginine supplementation for prevention of necrotising enterocolitis in preterm infants

Search: August 2010

Up‐to‐date: 28 November 2010

1 RCT

(Country: not reported

Published; 2000s)

152 infants

Preterm infants less than 37 weeks' gestation at birth

Arginine supplementation vs placebo (1 RCT, 152 neonates)

Cerebral palsy ("Cerebral palsy" (1 RCT, 135 children); reported as a post hoc secondary outcome)

Other composite outcome that includes cerebral palsy as a component ("Major neurodevelopmental disability" (1 RCT, 132 children); reported as a post hoc secondary outcome)

Neonatal care: infections: fungal infections

Cleminson 2015

Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants

Search: August 2015

Up‐to‐date: 1 September 2015

15 RCTs

(Countries: India: 2 RCTs; Italy: 2 RCTs; Korea: 1 RCT; Saudi Arabia: 1 RCT; Turkey: 2 RCTs; USA: 7 RCTs

Published: 2000s: 7 RCTs; 2010s: 8 RCTs)

1690 infants

Very preterm or VLBW infants with or without evidence of fungal colonisation but without evidence of invasive fungal infection at study entry

Systemic antifungal agent vs placebo or no drug (10 RCTs, 1371 neonates)

Cerebral palsy ("Cerebral palsy" (1 RCT, 219 children); reported as a primary outcome)

Other composite outcome that includes cerebral palsy as a component ("Neurodevelopmental impairment (composite)" (1 RCT, 171 children); reported as a primary outcome)

Neonatal care: infections: herpes simplex

Jones 2009

Antiviral agents for treatment of herpes simplex virus infection in neonates

Search: November 2008

Up‐to‐date: 14 March 2009

2 RCTs

(Countries: USA: 2 RCTs

Published: 1980s: 1 RCT; 1990s: 1 RCT)

273 infants

Hospitalised newborn infants less than 1 month of age with virologically confirmed HSV infection

Vidarabine vs placebo (1 RCT, 56 neonates)

Aciclovir vs vidarabine (1 RCT, 202 neonates)

Cerebral palsy ("Cerebral palsy in CNS HSV neonatal infection up to three years by HSV serotype: HSV‐1" (1 RCT, 9 children); "Cerebral palsy in CNS HSV neonatal infection up to three years by HSV serotype: HSV‐2" (1 RCT, 14 children); reported as primary outcomes)

Other composite outcomes that include cerebral palsy as a component ("Abnormal neurodevelopment at one year" (1 RCT, 56 children; and 1 RCT, 202 children); "Abnormal neurodevelopment or death at approximately one year of age" (1 RCT, 56 children; and 1 RCT, 202 children); reported as primary outcomes)

Neonatal care: jaundice

Okwundu 2012

Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants

31 March 2011

9 RCTs

(Countries: USA: 6 RCTs; Brazil: 1 RCT; Canada: 1 RCT; India: 1 RCT

Published: 1960s: 2 RCTs; 1970s: 1 RCT; 1980s: 2 RCTs; 2000s: 4 RCTs)

3449 infants

  1. Preterm infants (< 37 weeks' gestation)

  2. LBW infants (< 2500 g), within first 36 hours of birth

Originally (in the protocol), the focus of the review was narrower (to include VLBW infants; < 1500 g birthweight); however, so as not to lose valuable information, we made a post hoc decision to include any study that involved LBW (< 2500 g birthweight) or preterm infants

We excluded studies of infants with a known cause that can lead to significant hyperbilirubinaemia, such as ABO incompatibility, Rh incompatibility, minor blood group incompatibility, or G‐6PD deficiency

Prophylactic phototherapy vs control (9 RCTs, 3449 neonates)

Cerebral palsy ("Cerebral palsy" (2 RCTs, 756 children); reported as a primary outcome)

Other composite outcomes that include cerebral palsy as a component ("Neurodevelopmental impairment" (1 RCT, 1804 children); reported as a primary outcome)

Neonatal care: hypoglycaemia

Weston 2016

Oral dextrose gel for the treatment of hypoglycaemia in newborn infants

29 February 2016

2 RCTs

(Countries: Ireland: 1 RCT; New Zealand: 1 RCT;

Published: 2000s: 1 RCT; 2010s: 1 RCT)

317 infants

We included newborn infants from birth to discharge home who were hypoglycaemic (blood glucose concentrations below the normal range, investigator defined) for any reason. We excluded infants who had received prior IV treatment for maintenance of glucose control at the time of hypoglycaemia

Dextrose gel vs control (2 RCTs, 317 neonates)

Cerebral palsy ("Cerebral palsy and severity at age 2 years or older" (1 RCT, 183 children); reported as a secondary outcome)

Other composite outcomes that include cerebral palsy as a component ("Major neurosensory disability (2‐year follow‐up)" (1 RCT, 184 children); reported as a primary outcome) ("Developmental disability at age 2 years or older" (1 RCT, 184 children); reported as a secondary outcome)

Neonatal care: parenteral feeding

Moe‐Byrne 2016

Glutamine supplementation to prevent morbidity and mortality in preterm infants

18 December 2015

12 RCTs

(Countries: China; 1 RCT; Greece: 1 RCT; Malaysia:
1 RCT; Netherlands: 1 RCT; Turkey: 1 RCT; UK: 1 RCT; USA: 4 RCTs; not reported;
2 RCTs;

Published: 1990s: 2 RCTs; 2000s: 6 RCTs; 2010s: 4 RCTs)

2877 infants

We included preterm infants (gestational age < 37 weeks) admitted to neonatal intensive or special care units or comparable settings after birth. When participants in a trial included both term and preterm infants, we sought subgroup data from the report or from trial authors

Glutamine supplementation vs no supplementation (12 RCTs, 2877 neonates)

Other composite outcome that includes cerebral palsy as a component ("Neurodevelopmental impairment" (1 RCT, 72 children); reported as a primary outcome)

Neonatal care: other

Osborn 2001

Thyroid hormones for preventing neurodevelopmental impairment in preterm infants

Search:
June 2001

Up‐to‐date: 1 February 2009

5 RCTs

(Countries: not reported;

Published: 1980s: 2 RCTs; 1990s: 2 RCTs; 2000s; 1 RCT)

362 infants

Studies that enrolled and treated preterm infants in the neonatal period

Thyroid hormones vs control (5 RCTs, 362 neonates)

Cerebral palsy ("Cerebral palsy in survivors" (1 RCT, 156 children); reported as a primary outcome)

Cerebral palsy or death ("Death or cerebral palsy" (1 RCT, 200 children); reported as a primary outcome)

Osborn 2007

Prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants

Search:
March 2006

Up‐to‐date: 12 October 2006

4 RCTs

(Countries: not reported;

Published: 1990s: 2 RCTs; 2000s: 2 RCTs)

318 infants

Studies that enrolled preterm infants (born < 37 completed weeks' gestation) in the neonatal period. Trials that enrolled infants on the basis of results of abnormal thyroid function tests (known congenital hypothyroidism or transient hypothyroxinaemia), or with only respiratory distress syndrome, were excluded

Prophylactic thyroid hormones vs no thyroid hormones (4 RCTs, 318 neonates)

Cerebral palsy ("Cerebral palsy in survivors" (1 RCT, 156 children); reported as a primary outcome)

Cerebral palsy or death ("Death or cerebral palsy" (1 RCT, 200 children); reported as a primary outcome)

Almadhoob 2015

Sound reduction management in the neonatal intensive care unit for preterm or very low birth weight infants

18 December 2014

1 RCT

(Country: USA;

Published: 2009)

34 infants

Preterm infants (< 32 weeks' post‐menstrual age or < 1500 g birthweight) cared for in the resuscitation area, during transport, or once admitted to an NICU or a stepdown unit

Silicone earplugs vs no earplugs (1 RCT, 34 infants)

Cerebral palsy ("Cerebral palsy at 18 to 22 months' corrected age" (1 RCT, 14 children); reported as a primary outcome)

Conde‐Agudelo 2016

Kangaroo mother care to reduce morbidity and mortality in low birthweight infants

30 June 2016

21 RCTs

(Countries: 13 RCTs in low‐ or middle‐income countries: Colombia: 1 RCT; Ecuador:
1 RCT; Ethiopia: 1 RCT; Indonesia, Mexico, Ethiopia: 1 RCT; Indonesia: 1 RCT; India: 8 RCTs; Madagascar: 1 RCT; Malaysia: 1 RCT; Nepal: 1 RCT; 5 RCTs in high‐income countries: Australia: 1 RCT; United Kingdom: 1 RCT; United States: 3 RCTs; Published: 1990s: 5 RCTs; 2000s: 10 RCTs; 2010s: 6 RCTs)

3042 infants

LBW infants (defined as birthweight < 2500 g) regardless of gestational age

Kangaroo mother care vs conventional neonatal care (20 RCTs, 2969 neonates)

Cerebral palsy ("Cerebral palsy at 12 months' corrected age" (1 RCT, 588 children); reported as a primary outcome)

Spittle 2015

Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants

15 August 2015

25 RCTs

(Countries: not reported;

Published: 1970s: 1 RCT; 1980s: 5 RCTs; 1990s:
3 RCTs; 2000s: 13 RCTs; 2010s: 3 RCTs)

3615 infants

Preterm infants born at < 37 weeks' gestational age (according to best obstetrical estimate at the time of delivery). We excluded studies that did not report outcomes for preterm infants separately from those for infants born at term

Early developmental intervention vs standard follow‐up (25 RCTs, 3615 neonates)

Cerebral palsy ("Rate of cerebral palsy" (7 RCTs, 985 children); reported as a secondary outcome)

Motor dysfunction ("Motor outcome at school age (low score on Movement ABC)" (2 RCTs, 333 children); reported as a secondary outcome)

Abbreviations: BP: blood pressure; BPD: bronchopulmonary dysplasia; BSID: Bayley Scales of Infant Development; CNS: central nervous system; ECHO: echocardiogram; g: grams; G‐6PD: glucose‐6‐phosphate dehydrogenase; HSV: herpes simplex virus; IPPV: intermittent positive‐pressure ventilation; IV: intravenous; LBW: low birthweight; MDI: Mental Development Index; Movement‐ABC: Movement Assessment Battery for Children; NICU: neonatal intensive care unit; NO: nitric oxide; PDA: patent ductus arteriosus; PDI: Psychomotor Development Index; PMA: post‐menstrual age; PPHN: persistent pulmonary hypertension of the newborn; RCT: randomised controlled trial; Rh: Rhesus; SBF: systemic blood flow; SD: standard deviation; SVC: superior vena cava; VLBW: very low birthweight.

Figures and Tables -
Table 2. Characteristics of included reviews
Table 3. Risk of bias assessments from included reviews

Review ID and title

Summary of trial limitations (risk of bias)*

Neonatal care: asphyxia

Chaudhari 2012

Allopurinol for preventing mortality and morbidity in newborn infants with hypoxic‐ischaemic encephalopathy

Random sequence generation: 2 RCTs low risk; 1 RCT unclear risk

Allocation concealment: 3 RCTs low risk

Blinding: 2 RCTs low risk; 1 RCT high risk

Incomplete outcome data: 3 RCTs low risk

Overall: "Although small, the trials were generally of good methodological quality"

Jacobs 2013

Cooling for newborns with hypoxic‐ischaemic encephalopathy

Random sequence generation: 9 RCTs low risk; 1 RCT unclear risk; 1 RCT high risk

Allocation concealment: 8 RCTs low risk; 2 RCTs unclear risk; 1 RCT high risk

Blinding (participants and personnel): 11 RCTs high risk

Blinding (outcome assessors): 10 RCTs low risk; 1 RCT unclear risk

Incomplete outcome data: 6 RCTs low risk; 1 RCT unclear risk; 4 RCTs high risk

Selective reporting: 11 RCTs low risk

Overall: "Several limitations of the available evidence should be noted"

Young 2016

Prophylactic barbiturate use for the prevention of morbidity and mortality following perinatal asphyxia

Random sequence generation: 7 RCTs low risk; 2 RCTs unclear risk

Allocation concealment: 4 RCTs low risk; 4 RCTs unclear risk; 1 RCT high risk

Blinding: 4 RCTs unclear risk; 5 RCTs high risk

Incomplete outcome data: 6 RCTs low risk; 2 RCTs unclear risk; 1 RCT high risk

Selective reporting: 9 RCTs low risk

Neonatal care: haemorrhage: periventricular/intraventricular

Hunt 2010

Ethamsylate for the prevention of morbidity and mortality in preterm or very low birth weight infants

Adequate sequence generation: 4 RCTs yes; 2 RCTs unclear; 1 RCT no

Allocation concealment: 3 RCTs yes; 2 RCT unclear; 2 RCTs no

Blinding: 4 RCTs yes; 3 RCTs unclear

Incomplete outcome data addressed: 5 RCTs yes; 1 RCT unclear; 1 RCT no

Free of selective reporting: 7 RCTs yes

Free of other bias: 7 RCTs yes

Smit 2013

Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants

Random sequence generation: 5 RCTs low risk; 6 RCTs unclear risk; 1 RCT high risk

Allocation concealment: 4 RCTs low risk; 7 RCTs unclear risk; 1 RCT high risk

Blinding (participants and personnel): 2 RCTs low risk; 10 RCTs high risk

Blinding (outcome assessors): 6 RCTs low risk; 6 RCTs unclear risk

Incomplete outcome data: 8 RCTs low risk; 4 RCTs unclear risk

Selective reporting: 2 RCTs low risk; 10 RCTs unclear risk

Neonatal care: hypotension

Osborn 2007b

The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow

Adequate sequence generation: 1 RCT yes

Allocation concealment: 1 RCT yes

Blinding (outcomes): 1 RCT yes

Blinding (intervention): 1 RCT yes

Incomplete outcome data addressed: 1 RCT yes

Free of selective reporting: 1 RCT yes

Free of other bias: 1 RCT yes

Overall: "The study was of adequate methodology"

Neonatal care: fluid therapy

Osborn 2004

Early volume expansion for prevention of morbidity and mortality in very preterm infants

Adequate randomisation: 7 RCTs yes; 1 RCT unclear

Allocation concealment: 7 RCTs yes; 1 RCT unclear

Blinding of intervention: 1 RCT yes; 7 RCTs no

Blinding of measurement: 3 RCTs yes; 1 RCT unclear; 4 RCTs no

Losses to follow‐up: 5 RCTs none; 1 RCT unclear; 2 RCTs yes

Neonatal care: patent ductus arteriosus

Fowlie 2010

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants

Blinding of randomisation: 12 RCTs yes; 7 RCTs can't tell

Blinding of intervention: 16 RCTs yes; 2 RCTs can't tell; 1 RCT no

Blinding of outcome assessment: 16 RCTs yes; 2 RCTs can't tell; 1 RCT no

Complete follow‐up (short‐term outcomes): 18 RCTs yes; 1 RCT no

Overall: "Overall, the quality of the trials was good"

Ohlsson 2015

Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants

Random sequence generation: 9 RCTs low risk; 24 RCTs unclear risk

Allocation concealment: 18 RCTs low risk; 14 RCTs unclear risk; 1 RCT high risk

Blinding: 6 RCTs low risk; 7 RCTs unclear risk; 20 RCTs high risk

Incomplete outcome data: 28 RCTs low risk; 3 RCTs unclear risk; 2 RCTs high risk

Selective reporting: 5 RCTs low risk; 28 RCTs unclear risk

Other: 29 RCTs low risk; 4 RCTs unclear risk

Overall: "Study quality was variable…we identified concerns about bias in most individual studies and therefore for the group of studies included as well"

Neonatal care: blood disorders

Ohlsson 2014

Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants

Random sequence generation: 8 RCTs low: risk; 19 RCTs unclear risk

Allocation concealment: 13 RCTs low risk; 14 RCTs unclear risk

Blinding: 12 RCTs low risk; 3 RCTs unclear risk; 12 RCTs high risk

Incomplete outcome data: 23 RCTs low risk; 2 RCTs unclear risk; 2 RCTs high risk

Selective reporting: 1 RCT low risk; 26 RCTs unclear risk

Other: 26 RCTs low risk; 1 RCT unclear risk

Whyte 2011

Low versus high haemoglobin concentration threshold for blood transfusion for preventing morbidity and mortality in very low birth weight infants

Allocation concealment: 4 RCTs low risk; 1 RCT unclear risk

Blinding: 1 RCT unclear risk; 4 RCTs high risk

Incomplete outcome data: 3 RCTs low risk; 1 RCT unclear risk; 1 RCT high risk

Selective reporting: 1 RCT low risk; 3 RCTs unclear risk; 1 RCT high risk

Overall: "This review consists of five randomised controlled trials in which there appears to be no allocation bias; the overall level of evidence is high"

Neonatal care: pulmonary hypertension

More 2016

Endothelin receptor antagonists for persistent pulmonary hypertension in term and late preterm infants

Random sequence generation: 1 RCT low risk; 1 RCT unclear risk

Allocation concealment: 2 RCT unclear risk

Blinding (participants and personnel): 2 RCTs low risk

Blinding (outcome assessors): 2 RCTs low risk

Incomplete outcome data: 1 RCT low risk; 1 RCT high risk

Selective reporting: 1 RCT low risk; 1 RCT unclear risk

Other: 2 RCTs low risk

Overall: "the quality of evidence was considered low because of the very small sample size and methodological issues in the included studies"

Neonatal care: resuscitation

Tan 2005

Air versus oxygen for resuscitation of infants at birth

Concealment of allocation: 2 RCTs yes; 3 RCTs no

Blinding of intervention: 2 RCTs yes; 3 RCTs no

Blinding of outcome assessment: 2 RCTs yes; 3 RCTs no

Completeness of follow‐up (short‐term): 4 RCTs yes; 1 RCT no

Completeness of follow‐up (long‐term): 3 RCTs no; 2 RCTs unclear

Neonatal care: nitric oxide

Barrington 2010

Inhaled nitric oxide for respiratory failure in preterm infants

Allocation concealment: 12 RCTs low risk; 2 RCTs unclear risk

Blinding: 7 RCTs low risk; 7 RCTs high risk

Incomplete outcome data: 14 RCTs low risk

Selective reporting: 8 RCTs low risk; 6 RCTs not reported

Other: 3 RCTs low risk; 4 RCTs high risk; 7 RCTs not reported

Finer 2006

Nitric oxide for respiratory failure in infants born at or near term

Masking of allocation: 10 RCTs yes; 4 RCTs cannot tell

Masking of intervention: 6 RCTs yes; 8 RCTs no

Masking of outcome assessment: 6 RCTs yes; 1 RCT can’t tell; 7 RCTs no

Completeness of follow‐up: 13 RCTs yes; 1 RCT can't tell

Overall: "The overall quality of these studies is quite variable"

Neonatal care: apnoea

Henderson‐Smart 2010b

Methylxanthine treatment for apnoea in preterm infants

Random sequence generation: 1 RCT high risk; 5 RCTs not reported

Allocation concealment: 2 RCTs low risk; 2 RCTs unclear risk; 2 RCTs high risk

Blinding: 4 RCTs low risk; 2 RCTs high risk

Incomplete outcome data: 3 RCTs low risk; 1 RCT unclear risk; 2 RCTs high risk

Selective reporting: 2 RCTs low risk; 1 RCT unclear risk; 2 RCTs high risk; 1 RCT not reported

Overall: "There was variation in trial design"

Henderson‐Smart 2010c

Prophylactic methylxanthine for prevention of apnoea in preterm infants

Allocation concealment: 3 RCTs low risk

Blinding: 3 RCTs low risk

Incomplete outcome data: 3 RCTs low risk

Selective reporting: 2 RCTs low risk; 1 RCT not reported

Overall: "Three studies are generally of high quality"

Neonatal care: respiratory distress syndrome

Howlett 2015

Inositol in preterm infants at risk for or having respiratory distress syndrome

Random sequence generation: 1 RCT low risk; 3 RCTs unclear risk

Allocation concealment: 2 RCTs low risk; 2 RCTs unclear risk

Blinding: 2 RCTs low risk; 2 RCTs unclear risk

Incomplete outcome data: 4 RCTs low risk

Selective reporting: 3 RCTs low risk; 1 RCT unclear risk

Other: 3 RCTs high risk; 1 RCT low risk

Overall: "Study quality varied and interim analyses had occurred in all trials"

Seger 2009

Animal derived surfactant extract for treatment of respiratory distress syndrome

Blinding of randomisation: 10 RCTs yes; 3 RCTs not described

Blinding of intervention: 8 RCTs yes; 1 RCT not described; 4 RCTs no

Blinding of outcome measurement: 6 RCTs yes; 4 RCTs not described; 2 RCTs no; 1 RCT not reported

Complete follow‐up (short‐term): 13 RCTs yes

Complete follow‐up (long‐term): 4 RCTs yes; 9 RCTs no

Overall: "studies are of high methodological quality"

Soll 2000

Synthetic surfactant for respiratory distress syndrome in preterm infants

Blinding of randomisation: 6 RCTs yes

Blinding of intervention: 5 RCTs yes; 1 RCT no

Blinding of outcome measurement: 5 RCTs yes; 1 RCT no

Complete follow‐up (short term): 6 RCTs yes

Complete follow‐up (long term): 80 to 100%

Soll 2010

Prophylactic protein free synthetic surfactant for preventing morbidity and mortality in preterm infants

Adequate sequence generation: 6 RCTs unclear: 1 RCT not reported

Allocation concealment: 7 RCTs yes

Blinding of intervention: 5 RCTs yes; 1 RCT unclear; 1 RCT no

Blinding of outcome measurement: 6 RCTs yes; 1 RCT no

Incomplete outcome data addressed: 5 RCTs yes; 2 RCTs unclear

Free of selective reporting: 7 RCTs yes

Free of other bias: 7 RCTs yes

Neonatal care: mechanical ventilation

Cools 2015

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants

Random sequence generation: 11 RCTs low risk; 8 RCTs unclear risk

Allocation concealment: 7 RCTs low risk; 12 RCTs unclear risk

Blinding of participants and personnel: 19 RCTs high risk

Blinding of outcome assessment: 7 RCTs low risk; 12 RCTs unclear risk

Incomplete outcome data: 19 RCTs low risk

Overall: "The quality of the studies was generally high"

Ho 2015

Continuous distending pressure for respiratory distress in preterm infants

Random sequence generation: 2 RCTs low risk; 3 RCTs unclear risk; 1 RCT high risk

Allocation concealment: 4 RCTs low risk; 1 RCT unclear risk; 1 RCT high risk

Blinding (intervention): 6 RCTs high risk

Blinding (short term outcomes): 6 RCTs high risk (1 RCT low risk for long term outcomes)

Incomplete outcome data (short term outcomes): 3 RCTs low risk; 3 RCTs unclear risk (1 RCT low risk for long‐term outcomes)

Selective reporting: 2 RCTs low risk; 4 RCTs unclear risk

Other: 6 RCTs unclear risk

Overall: "These data should be interpreted with caution as in the studies reviewed, the numbers of infants were small, blinding of treatment was not possible and blinding of the outcome assessment was reported in only one study for the outcomes in childhood, thus possibly introducing bias"

Henderson‐Smart 2010

Prophylactic methylxanthines for endotracheal extubation in preterm infants

Sequence generation: 1 RCT low risk; 6 RCTs not reported

Allocation concealment: 6 RCTs low risk; 1 RCT unclear risk

Blinding: 6 RCTs low risk; 1 RCT high risk

Incomplete outcome data: 3 RCTs low risk; 3 RCTs high risk; 1 RCT not reported

Selective reporting: 4 RCTs low risk; 2 RCTs high risk; 1 RCT not reported

Other: 1 RCT low risk; 6 RCTs not reported

Kamlin 2003

Long versus short inspiratory times in neonates receiving mechanical ventilation

Concealment of allocation: 1 RCT yes; 1 RCT cannot tell; 3 RCTs no

Blinding of intervention: 5 RCTs no

Blinding of outcome measurement: 3 RCTs no; 2 RCTs some

Completeness of follow‐up (short term outcomes): 5 RCTs yes

Wheeler 2010

Volume‐targeted versus pressure‐limited ventilation in the neonate

Sequence generation: 6 RCTs low risk; 6 RCTs unclear risk

Allocation concealment: 11 RCTs low risk; 1 RCT unclear risk

Blinding: 12 RCTs high risk

Incomplete outcome data: 12 RCTs low risk

Selective reporting: 10 RCTs low risk; 1 RCT unclear risk; 1 RCT high risk

Other: 5 RCTs low risk; 5 RCTs unclear risk; 2 RCTs high risk

Overall: "There are no major concerns about the methodology used in the twelve trials included in this review"

Neonatal care: bronchopulmonary dysplasia

Doyle 2014b

Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

Random sequence generation: 15 RCTs low risk; 14 RCTs unclear risk

Allocation concealment: 27 RCTs low risk; 2 RCTs unclear risk

Blinding of participants and personnel: 23 RCTs low risk; 2 RCTs unclear risk; 4 RCTs high risk

Blinding of outcome assessment: 23 RCTs low risk; 2 RCTs unclear risk; 4 RCTs high risk

Incomplete outcome data: 28 RCTs low risk; 1 RCT unclear risk

Overall: "Overall the risk of bias was low for most studies"

Halliday 2003

Moderately early (7‐14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

Blinding of randomisation/allocation concealment: 7 RCTs yes/low risk

Blinding of intervention: 5 RCTs yes; 2 RCTs no

Blinding of outcome measurement: 5 RCTs yes; 1 RCT some; 1 RCT cannot tell

Complete follow‐up: 6 RCTs yes/almost; 1 RCT no

Overall: "the methodological quality of the studies to determine long‐term outcome is limited in some cases"

Doyle 2014

Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants

Random sequence generation: 12 RCTs low risk; 9 RCTs unclear risk

Allocation concealment: 17 RCTs low risk; 4 RCTs unclear risk

Blinding of participants and personnel: 15 RCTs low risk; 4 RCTs unclear risk; 2 RCTs high risk

Blinding of outcome assessment: 16 RCTs low risk; 4 RCTs unclear risk; 1 RCT high risk

Incomplete outcome data: 20 RCTs low risk; 1 RCT unclear risk

Overall: "Overall the risk of bias was low for most studies"

Shah 2012

Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates

Random sequence generation: 7 RCTs unclear risk

Allocation concealment: 7 RCTs low risk

Blinding of participants and personnel: 7 RCTs low risk

Blinding of outcome assessment: 1 RCT low risk; 6 RCTs unclear risk

Incomplete outcome data: 6 RCTs low risk; 1 RCT unclear risk

Overall: "Overall, the studies included for this review were of high methodological quality"

Darlow 2016

Vitamin A supplementation to prevent mortality and short‐ and long‐term morbidity in very low birth weight infants

Random sequence generation: 9 RCTs low risk; 2 RCTs unclear risk

Allocation concealment: 8 RCTs low risk; 3 RCTs unclear risk

Blinding: 6 RCTs low risk; 2 RCTs unclear risk; 3 RCTs high risk

Incomplete outcome data: 9 RCTs low risk; 1 RCT unclear risk; 1 RCT high risk

Selective reporting: 8 RCTs low risk; 2 RCTs unclear risk; 1 RCT high risk

Other: 2 RCTs low risk; 6 RCTs unclear risk; 2 RCTs high risk; 1 RCT not reported

Neonatal care: infections: necrotising enterocolitis

AlFaleh 2014

Probiotics for prevention of necrotising enterocolitis in preterm infants

Random sequence generation: 15 RCTs low risk; 8 RCTs unclear risk; 1 RCT high risk

Allocation concealment: 11 RCTs low risk; 12 RCTs unclear risk; 1 RCT high risk

Blinding: 15 RCTs low risk; 9 RCTs unclear risk

Incomplete outcome data: 21 RCTs low risk; 2 RCTs unclear risk; 1 RCT high risk

Selective reporting: 17 RCTs low risk; 6 RCTs high risk; 1 RCT not reported

Other: 14 RCTs low risk; 10 RCTs not reported

Overall: "Eleven of our included trials were classified as high quality trials"

Shah 2007

Arginine supplementation for prevention of necrotising enterocolitis in preterm infants

Masking of randomisation: 1 RCT yes

Masking of intervention: 1 RCT yes

Masking of outcome assessment: 1 RCT yes

Completeness of follow‐up: 1 RCT yes

Overall: "The methodological quality of the included study was good"

Neonatal care: infections: fungal infections

Cleminson 2015

Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants

Allocation concealment: 12 RCTs low risk; 3 RCTs unclear risk

Blinding of participants and personnel: 10 RCTs low risk; 3 RCTs unclear risk; 2 RCTs high risk

Blinding of outcome assessment: 10 RCTs low risk; 3 RCTs unclear risk; 2 RCTs high risk

Incomplete outcome data: 15 RCTs low risk

Overall: "The included trials were generally of good methodological quality"

Neonatal care: infections: herpes simplex

Jones 2009

Antiviral agents for treatment of herpes simplex virus infection in neonates

Allocation concealment: 1 RCT unclear; 1 RCT inadequate

Overall: "The two trials... have a number of methodological flaws"

Neonatal care: jaundice

Okwundu 2012

Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants

Random sequence generation: 4 RCTs low risk; 3 RCTs unclear risk; 2 RCTs high risk

Allocation concealment: 3 RCTs low risk; 4 RCTs unclear risk; 2 RCTs high risk

Blinding: 1 RCT low risk; 2 RCTs unclear risk; 6 RCTs high risk

Incomplete outcome data: 8 RCTs low risk; 1 RCT high risk

Selective reporting: 2 RCTs low risk; 7 RCTs unclear risk

Other: 7 RCTs low risk

Overall: "In general, the overall methodological quality of the included studies was acceptable"

Neonatal care: hypoglycaemia

Weston 2016

Oral dextrose gel for the treatment of hypoglycaemia in newborn infants

Random sequence generation: 1 RCT low risk; 1 RCT unclear risk

Allocation concealment: 1 RCT low risk; 1 RCT unclear risk

Blinding of participants and personnel: 1 RCT low risk; 1 RCT unclear risk

Blinding of outcome assessors: 1 RCT low risk; 1 RCT unclear risk

Incomplete outcome data: 1 RCT low risk; 1 RCT high risk

Selective reporting: 1 RCT low risk; 1 RCT unclear risk

Other: 1 RCT low risk; 1 RCT unclear risk

Neonatal care: parenteral feeding

Moe‐Byrne 2016

Glutamine supplementation to prevent morbidity and mortality in preterm infants

Random sequence generation: 8 RCTs low risk; 3 RCTs unclear risk; 1 RCT high risk

Allocation concealment: 8 RCTs low risk; 2 RCTs unclear risk; 2 RCTs high risk

Blinding: 10 RCTs low risk; 2 RCTs unclear risk

Incomplete outcome data: 8 RCTs low risk; 2 RCTs unclear risk; 2 RCTs high risk

Overall: "in general the trials were of good quality"

Neonatal care: other

Osborn 2001

Thyroid hormones for preventing neurodevelopmental impairment in preterm infants

Blinding of randomisation/allocation concealment: 4 RCTs yes; 1 RCT no

Blinding of intervention: 4 RCTs yes; 1 RCT no

Blinding of outcome assessment: 4 RCTs yes; 1 RCT not stated

Complete follow‐up: 2 RCTs yes; 3 RCTs no

Overall: "four studies... were of good methodology"

Osborn 2007

Prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants

Allocation concealment: 4 RCTs low risk

Blinding of intervention: 4 RCTs yes

Blinding of outcome assessment: 3 RCTs yes; 1 RCT probably

Complete follow‐up: 3 RCTs yes; 1 RCT no

Overall: "All studies... were of adequate methodology"

Almadhoob 2015

Sound reduction management in the neonatal intensive care unit for preterm or very low birth weight infants

Random sequence generation: 1 RCT low risk

Allocation concealment: 1 RCT low risk

Blinding of participants and personnel: 1 RCT high risk

Blinding of outcome assessment: 1 RCT low risk

Incomplete outcome data: 1 RCT low risk

Selective reporting: 1 RCT low risk

Other: 1 RCT low risk

Overall: "We considered the overall risk of bias to be low"

Conde‐Agudelo 2016

Kangaroo mother care to reduce morbidity and mortality in low birthweight infants

Random sequence generation: 21 RCTs low risk

Allocation concealment: 10 RCTs low risk; 11 RCTs unclear risk

Blinding of participants and personnel: 21 RCTs high risk

Blinding of outcome assessment: 2 RCTs low risk; 15 RCTs unclear risk; 4 RCTs high risk

Incomplete outcome data: 14 RCTs low risk; 3 RCTs unclear risk; 4 RCTs high risk

Selective reporting: 16 RCTs low risk; 3 RCTs unclear risk; 2 RCTs high risk

Other: 15 RCTs low risk; 3 RCTs unclear risk; 3 RCTs high risk

Overall: "The methodological quality of the included trials was mixed"

Spittle 2015

Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants

Random sequence generation: 11 RCTs low risk; 8 RCTs unclear risk; 5 RCTs high risk; 1 RCT not reported

Allocation concealment: 11 RCTs low risk; 9 RCTs unclear risk; 5 RCTs high risk

Blinding of participants and personnel: 2 RCTs low risk; 4 RCTs unclear risk; 19 RCTs high risk

Blinding of outcome assessment: 21 RCTs low risk; 3 RCTs unclear risk; 1 RCT high risk

Incomplete outcome data: 12 RCTs low risk; 4 RCTs unclear risk; 9 RCT high risk

Selective reporting: 3 RCTs unclear risk; 6 RCT high risk; 16 RCTs not reported

Overall: "The methodological quality of included studies was variable"

Abbreviations: RCT: randomised controlled trial.
*We have reported only the risk of bias components assessed and reported in the included reviews.

Figures and Tables -
Table 3. Risk of bias assessments from included reviews
Table 4. AMSTAR assessments for included reviews

Review ID

AMSTAR criteria

TOTAL SCORE

'A priori' design

Duplicate selection and extraction

Comprehensive search

Grey literature considered

Included and excluded studies lists

Characteristics of included studies

Quality assessed and documented

Quality considered for conclusions

Methods for combining studies appropriate

Publication bias considered or assessed

Conflicts stated

Neonatal care: asphyxia

Chaudhari 2012

10/11

HIGH QUALITY

Jacobs 2013

10/11

HIGH QUALITY

Young 2016

10/11

HIGH QUALITY

Neonatal care: haemorrhage: periventricular/intraventricular

Hunt 2010

9/11

HIGH QUALITY

Smit 2013

10/11

HIGH QUALITY

Neonatal care: hypotension

Osborn 2007b

N/A

9/10

HIGH QUALITY

Neonatal care: fluid therapy

Osborn 2004

9/11

HIGH QUALITY

Neonatal care: patent ductus arteriosus

Fowlie 2010

9/11

HIGH QUALITY

Ohlsson 2015

10/11

HIGH QUALITY

Neonatal care: blood disorders

Ohlsson 2014

10/11

HIGH QUALITY

Whyte 2011

10/11

HIGH QUALITY

Neonatal care: pulmonary hypertension

More 2016

N/A

9/10

HIGH QUALITY

Neonatal care: resuscitation

Tan 2005

9/11

HIGH QUALITY

Neonatal care: nitric oxide

Barrington 2010

?

8/11

HIGH QUALITY

Finer 2006

8/11

HIGH QUALITY

Neonatal care: apnoea

Henderson‐Smart 2010b

9/11

HIGH QUALITY

Henderson‐Smart 2010c

9/11

HIGH QUALITY

Neonatal care: respiratory distress syndrome

Howlett 2015

10/11

HIGH QUALITY

Seger 2009

?

8/11

HIGH QUALITY

Soll 2000

?

?

?

6/11

MODERATE QUALITY

Soll 2010

9/11

HIGH QUALITY

Neonatal care: mechanical ventilation

Cools 2015

9/11

HIGH QUALITY

Ho 2015

9/11

HIGH QUALITY

Henderson‐Smart 2010

8/11

HIGH QUALITY

Kamlin 2003

9/11

HIGH QUALITY

Wheeler 2010

9/11

HIGH QUALITY

Neonatal care: bronchopulmonary dysplasia

Doyle 2014b

10/11

HIGH QUALITY

Halliday 2003

?

?

7/11

MODERATE QUALITY

Doyle 2014

10/11

HIGH QUALITY

Shah 2012

10/11

HIGH QUALITY

Darlow 2016

10/11

HIGH QUALITY

Neonatal care: infections: necrotising enterocolitis

AlFaleh 2014

9/11

HIGH QUALITY

Shah 2007

?

N/A

7/10

HIGH QUALITY

Neonatal infections: fungal infections

Cleminson 2015

10/11

HIGH QUALITY

Neonatal infections: herpes simplex

Jones 2009

N/A

8/10

HIGH QUALITY

Neonatal care: jaundice

Okwundu 2012

?

8/11

HIGH QUALITY

Neonatal care: hypoglycaemia

Weston 2016

11/11

HIGH QUALITY

Neonatal care: parenteral feeding

Moe‐Byrne 2016

10/11

HIGH QUALITY

Neonatal care: other

Osborn 2001

?

8/11

HIGH QUALITY

Osborn 2007

9/11

HIGH QUALITY

Almadhoob 2015

N/A

9/10

HIGH QUALITY

Conde‐Agudelo 2016

10/11

HIGH QUALITY

Spittle 2015

9/11

HIGH QUALITY

Figures and Tables -
Table 4. AMSTAR assessments for included reviews
Table 5. ROBIS assessments for included reviews

Review ID

ROBIS domains

OVERALL RISK OF BIAS

Study eligibility criteria

Identification and selection of studies

Data collection and study appraisal

Synthesis and findings

Neonatal care: asphyxia

Chaudhari 2012

Low risk

Low risk

Low risk

Low risk

LOW RISK

Jacobs 2013

Low risk

Low risk

Low risk

Low risk

LOW RISK

Young 2016

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: haemorrhage: periventricular/intraventricular

Hunt 2010

Low risk

Low risk

Low risk

Low risk

LOW RISK

Smit 2013

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: hypotension

Osborn 2007b

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: fluid therapy

Osborn 2004

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: patent ductus arteriosus

Fowlie 2010

Low risk

Low risk

Low risk

Low risk

LOW RISK

Ohlsson 2015

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: blood disorders

Ohlsson 2014

Low risk

Low risk

Low risk

Low risk

LOW RISK

Whyte 2011

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: pulmonary hypertension

More 2016

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: resuscitation

Tan 2005

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: nitric oxide

Barrington 2010

Low risk

Low risk

Low risk

Low risk

LOW RISK

Finer 2006

Low risk

Unclear risk

Low risk

Low risk

UNCLEAR RISK

Neonatal care: apnoea

Henderson‐Smart 2010b

Low risk

Low risk

Low risk

Low risk

LOW RISK

Henderson‐Smart 2010c

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: respiratory distress syndrome

Howlett 2015

Low risk

Low risk

Low risk

Low risk

LOW RISK

Seger 2009

Unclear risk

Low risk

Low risk

Low risk

LOW RISK

Soll 2000

Unclear risk

Unclear risk

Unclear risk

Unclear risk

UNCLEAR RISK

Soll 2010

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: mechanical ventilation

Cools 2015

Low risk

Low risk

Low risk

Low risk

LOW RISK

Ho 2015

Low risk

Low risk

Low risk

Low risk

LOW RISK

Henderson‐Smart 2010

Low risk

Low risk

Low risk

Low risk

LOW RISK

Kamlin 2003

Low risk

Low risk

Low risk

Low risk

LOW RISK

Wheeler 2010

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: bronchopulmonary dysplasia

Doyle 2014b

Low risk

Low risk

Low risk

Low risk

LOW RISK

Halliday 2003

Low risk

Unclear risk

Unclear risk

Unclear risk

LOW RISK

Doyle 2014

Low risk

Low risk

Low risk

Low risk

LOW RISK

Shah 2012

Low risk

Low risk

Low risk

Low risk

LOW RISK

Darlow 2016

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal infections: necrotising enterocolitis

AlFaleh 2014

Low risk

Low risk

Low risk

Low risk

LOW RISK

Shah 2007

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal infections: fungal infections

Cleminson 2015

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal infections: herpes simplex

Jones 2009

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: jaundice

Okwundu 2012

Low risk

Low risk

Low risk

Unclear risk

LOW RISK

Neonatal care: hypoglycaemia

Weston 2016

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: parenteral feeding

Moe‐Byrne 2016

Low risk

Low risk

Low risk

Low risk

LOW RISK

Neonatal care: other

Osborn 2001

Low risk

Unclear risk

Unclear risk

Low risk

UNCLEAR RISK

Osborn 2007

Low risk

Low risk

Low risk

Low risk

LOW RISK

Almadhoob 2015

Unclear risk

Low risk

Low risk

Low risk

LOW RISK

Conde‐Agudelo 2016

Low risk

Low risk

Low risk

Low risk

LOW RISK

Spittle 2015

Low risk

Low risk

Low risk

Low risk

LOW RISK

Figures and Tables -
Table 5. ROBIS assessments for included reviews
Table 6. Cerebral palsy

Intervention and comparison

Outcome

Assumed risk with comparator

Corresponding risk with intervention

Relative effect (95% CI)

Number of participants (trials)

Quality of the evidence (GRADE)

Comments

Neonatal care: asphyxia

Therapeutic hypothermia vs standard care for newborns with hypoxic‐ischaemic encephalopathy (Jacobs 2013)

Cerebral palsy in survivors assessed at 18 to 24 months

352 per 1000

(143/406)

232 per 1000 (190 to 289)

RR 0.66 (0.54 to 0.82)

881 (7 RCTs)

HIGH

Not downgraded

Cerebral palsy at 6 to 7 years

288 per 1000

(15/52)

173 per 1000 (89 to 340)

RR 0.60 (0.31 to 1.18)

121 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with small sample size

Barbiturates (phenobarbital) vs conventional therapy for prevention of morbidity and mortality following perinatal asphyxia (Young 2016)

Cerebral palsy at 3 to 6 years

242 per 1000

(8/33)

141 per 1000 (46 to 412)

RR 0.58 (0.19 to 1.70)

69 (2 RCTs)

VERY LOW

Study limitations (‐1): unblinded studies; concern regarding performance bias and detection bias

Imprecision (‐1): 95% CIs were wide and imprecise

Inconsistency (‐1): clinically important heterogeneity noted

(GRADED by review authors themselves)

Neonatal care: haemorrhage: periventricular/intraventricular

Ethamsylate vs placebo for prevention of morbidity and mortality in preterm or very low birthweight infants (Hunt 2010)

Cerebral palsy in surviving children available for follow‐up at 2 years up to 3.5 to 4.2 years (only cerebral palsy significant enough to cause moderate or severe impairment was included)

78 per 1000

(21/270)

88 per 1000 (50 to 156)

RR 1.13 (0.64 to 2.00)

532 (3 RCTs)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Neonatal care: hypotension

Dobutamine vs dopamine in preterm infants with low superior vena cava flow (Osborn 2007b)

Cerebral palsy at 3 years in survivors assessed

429 per 1000

(3/7)

69 per 1000 (4 to 1131)

RR 0.16 (0.01 to 2.64)

13 (1 RCT)

VERY LOW

Study limitations (‐1): 5/18 surviving infants were not assessed at 3 years of age

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with very small sample size

Neonatal care: fluid therapy

Volume vs no treatment for prevention of morbidity and mortality in very preterm infants (Osborn 2004)

Cerebral palsy in survivors at 2 years

132 per 1000

(27/205)

100 per 1000 (63 to 158)

RR 0.76 (0.48 to 1.20)

604 (1 RCT)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Gelatin vs fresh frozen plasma for prevention of morbidity and mortality in very preterm infants (Osborn 2004)

103 per 1000

(21/203)

97 per 1000 (54 to 175)

RR 0.94 (0.52 to 1.69)

399 (1 RCT)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Neonatal care: patent ductus arteriosus

Prophylactic indomethacin vs placebo for preventing mortality and morbidity in preterm infants (Fowlie 2010)

Cerebral palsy at 18 to 54 months

111 per 1000

(77/694)

115 per 1000 (85 to 155)

RR 1.04 (0.77 to 1.40)

1372 (4 RCTs)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Cerebral palsy at 8 years

76 per 1000

(11/145)

94 per 1000 (45 to 199)

RR 1.24 (0.59 to 2.62)

304 (1 RCT)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Oral ibuprofen vs intravenous ibuprofen for treatment of patent ductus arteriosus in preterm or low birthweight (or both) infants (Ohlsson 2015)

Moderate or severe cerebral palsy at 18 to 24 months

74 per 1000

(2/27)

100 per 1000 (18 to 554)

RR 1.35 (0.24 to 7.48)

57 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at unclear risk of selection and reporting bias; high risk of performance, detection, and attrition bias

Imprecision (‐2): wide CI crossing line of no effect; small sample size and few events

Neonatal care: blood disorders

Erythropoietin vs placebo for preventing red blood cell transfusion in preterm and/or low birthweight infants (Ohlsson 2014)

Cerebral palsy at 18 to 22 months' corrected age (in children examined)

187 per 1000

(14/75)

123 per 1000 (58 to 256)

RR 0.66 (0.31 to 1.37)

153 (2 RCTs)

VERY LOW

Study limitations (‐1): 1 RCT at unclear risk of selection bias and high risk of attrition bias (˜73% follow‐up)

Inconsistency (‐1): I² = 72%

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes

Darbepoetin alfa vs placebo for preventing red blood cell transfusion in preterm and/or low birthweight infants (Ohlsson 2014)

208 per 1000

(5/24)

17 per 1000 (0 to 292)

RR 0.08 (0.00 to 1.40)

51 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with small sample size and few events

Transfusion at a restrictive vs a liberal haemoglobin threshold for preventing morbidity and mortality in very low birthweight infants (Whyte 2011)

Cerebral palsy at 18 to 21 months' follow‐up among survivors

52 per 1000

(9/172)

68 per 1000 (29 to 159)

RR 1.29 (0.55 to 3.03)

335 (1 RCT)

LOW

Study limitations (‐1): 1 RCT at high risk of performance bias and unclear risk of reporting bias

Imprecision (‐1): wide CI crossing line of no effect

Neonatal care: pulmonary hypertension

Endothelin receptor antagonists vs placebo for persistent pulmonary hypertension in term and late preterm infants (More 2016)

Cerebral palsy at 6 months (delayed motor development and spasticity)

214 per 1000

(3/14)

19 per 1000 (0 to 345)

RR 0.09 (0.00 to 1.61)

37 (1 RCT)

LOW

Study limitation (‐1): 8/23 infants in the placebo group were excluded from analysis

Imprecision (‐1): 1 RCT; small sample size

(GRADED by review authors themselves)

Neonatal care: resuscitation

Room air vs 100% oxygen for resuscitation of infants at birth (Tan 2005)

Cerebral palsy in those followed up at 18 to 24 months

74 per 1000

(9/122)

99 per 1000 (41 to 239)

RR 1.34 (0.55 to 3.24)

213 (1 RCT)

VERY LOW

Study limitations (‐2): 1 qRCT with no blinding and < 70% follow‐up

Imprecision (‐1): wide CI crossing line of no effect

Neonatal care: nitric oxide

Inhaled NO vs placebo for respiratory failure in preterm infants (entry before 3 days based on oxygenation) (Barrington 2010)

Cerebral palsy at 18 to 22 months (moderate/severe or disabling)

100 per 1000

(11/110)

185 per 1000 (93 to 371)

RR 1.85 (0.93 to 3.71)

209 (2 RCTs)

LOW

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes

Inhaled NO vs placebo or no treatment for respiratory failure in preterm infants (entry after 3 days based on BPD risk) (Barrington 2010)

Cerebral palsy at 2 years' corrected age or 30 months (1 RCT all severities; 1 RCT moderate/severe or disabling)

56 per 1000

(14/248)

62 per 1000 (30 to 126)

RR 1.10 (0.54 to 2.23)

498 (2 RCTs)

LOW

Study limitations (‐1): 1 RCT with no blinding of intervention or outcome measurement

Imprecision (‐1): wide CI crossing line of no effect; small sample sizes

Inhaled NO vs placebo for respiratory failure in preterm infants (studies of routine use in intubated preterm infants) (Barrington 2010)

Cerebral palsy at 1 or 2 years' corrected age (1 RCT all severities; 1 RCT moderate/severe or disabling)

70 per 1000

(20/286)

66 per 1000 (36 to 119)

RR 0.94 (0.51 to 1.70)

593 (2 RCTs)

LOW

Study limitations (‐1): 2 RCTs with 74%‐82% follow‐up

Imprecision (‐1): wide CI crossing line of no effect

Inhaled nitric oxide vs placebo for respiratory failure in infants born at or near term (Finer 2006)

Cerebral palsy among survivors at 13 or 18 to 24 months

89 per 1000

(16/179)

91 per 1000 (44 to 191)

RR 1.02 (0.49 to 2.14)

299 (2 RCTs)

LOW

Study limitations (‐1): 1 RCT masking of allocation, masking of outcomes. and completeness of follow‐up

Imprecision (‐1): wide CI crossing line of no effect

"This group has now published follow up data, including neurodevelopmental outcomes, which were obtained by telephone interview of 60 of the 83 survivors of the original trial. The interview was conducted between one and four years of age... Although cerebral palsy [was] reported it is unclear how [it] was defined... It is not, therefore, possible to add any of these data to the meta‐analysis, but they do appear to show no evidence of neurodevelopmental impairment due to inhaled nitric oxide therapy"

NOT GRADED

Inhaled nitric oxide vs placebo for respiratory failure in infants with diaphragmatic hernias born at or near term (Finer 2006)

Cerebral palsy among survivors at 18 to 24 months

(0/14)

(2/8)

RR 8.33 (0.45 to 154.78)

22 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with 76% follow‐up of survivors

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: apnoea

Caffeine vs placebo for treatment of apnoea in preterm infants (Henderson‐Smart 2010b)

Cerebral palsy at 18 to 21 months' corrected age

50 per 1000

(18/361)

30 per 1000 (14 to 62)

RR 0.60 (0.29 to 1.25)

729 (1 RCT)

LOW

Study limitations (‐1): results based on 1 RCT subgroup from post hoc subgroup analyses (randomisation not stratified according to indication for inclusion)

Imprecision (‐1): wide CI crossing line of no effect

Caffeine vs placebo for prevention of apnoea in preterm infants (Henderson‐Smart 2010c)

Cerebral palsy at 18 to 21 months' corrected age

45 per 1000

(9/200)

46 per 1000 (19 to 112)

RR 1.03 (0.43 to 2.49)

415 (1 RCT)

LOW

Study limitations (‐1): results based on 1 RCT subgroup from post hoc subgroup analyses (randomisation not stratified according to indication for inclusion)

Imprecision (‐1): wide CI crossing line of no effect

Neonatal care: respiratory distress syndrome

Animal‐derived surfactant extract vs no treatment for treatment of respiratory distress syndrome (Seger 2009)

Cerebral palsy at 1 and 2 years' corrected age

207 per 1000

(6/29)

182 per 1000 (70 to 470)

RR 0.88 (0.34 to 2.27)

73 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with no blinding of intervention; and blinding of outcome measurement not reported

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Synthetic surfactant vs placebo for respiratory distress syndrome in preterm infants (Soll 2000)

Cerebral palsy in survivors examined at 1 year (in 4 of the 5 RCTs)

96 per 1000

(74/767)

73 per 1000 (53 to 101)

RR 0.76 (0.55 to 1.05)

1557 (5 RCTs)

MODERATE

Imprecision (‐1): wide CI crossing the line of no effect

Prophylactic protein‐free synthetic surfactant vs placebo for preventing morbidity and mortality in preterm infants (Soll 2010)

Cerebral palsy at 1 or 2 years

153 per 1000

(49/320)

142 per 1000 (52 to 204)

RR 0.93 (0.64 to 1.33)

670 (4 RCTs)

LOW

Study limitations (‐1): "Somewhat fewer infants who received surfactant failed to return for follow‐up evaluation (typical relative risk 0.63, 95% CI 0.48, 0.82; typical risk difference ‐0.10, 95% CI ‐0.15, ‐0.04)"

Imprecision (‐1): wide CI crossing the line of no effect

Neonatal care: mechanical ventilation

Elective high‐frequency oscillatory ventilation vs conventional ventilation for acute pulmonary dysfunction in preterm infants (Cools 2015)

Cerebral palsy

  1. "Neurodevelopmental status was assessed at 16 to 24 months corrected age in 77% of survivors of the HIFI 1989 study (185 HFOV & 201 CV) using Bayley psychometric tests and central nervous system examinations... The rate of cerebral palsy was 11% in both groups"

  2. "Moriette 2001 assessed neuromotor outcome at the corrected age of two years in 192 of 212 survivors (90%) using a physician questionnaire... the risk of spastic cerebral palsy was significantly lower for infants ventilated with HFOV (4% versus 17%; OR 0.87, 95% CI 0.79 to 0.96), even after adjustment for multiple factors. Survival without cerebral palsy was significantly more likely in the HFOV group than in the CV group (OR 1.89, 95% CI 1.04 to 3.44)"

  3. "Sun 2014 assessed neurodevelopmental outcomes at 18 months of corrected age in 145 infants of the HFOV group (84% of survivors) and in 143 infants of the CV group (86% of survivors). Cerebral palsy occurred significantly less in the HFOV group (3% versus 10% in the CV group, P = 0.03)"

NOT GRADED

"The age and methods of assessment varied between studies so the results were presented in the text and not included in a meta‐analysis"

Continuous distending pressure vs standard care for respiratory distress in preterm infants (Ho 2015)

Cerebral palsy at 9 to 15 years

(0/18)

(2/18)

RR 5.0 (0.26 to 97.37)

36 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at unclear risk of selection and attrition bias and high risk of performance bias

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Prophylactic methylxanthines (caffeine) vs placebo for endotracheal extubation in preterm infants (Henderson‐Smart 2010)

Cerebral palsy at 18 to 21 months' corrected age

115 per 1000

(39/339)

62 per 1000 (37 to 106)

RR 0.54 (0.32 to 0.92)

644 (1 RCT)

MODERATE

Study limitations (‐1): results based on 1 RCT subgroup from post hoc subgroup analyses (randomisation not stratified according to indication for inclusion)

Long vs short inspiratory times in neonates receiving mechanical ventilation (Kamlin 2003)

Cerebral palsy in survivors less than 33 weeks' gestation at birth at 18 months

133 per 1000

(12/90)

387 per 1000 (129 to 1153)

RR 2.9 (0.97 to 8.65)

177 ( 1 RCT)

VERY LOW

Study limitations: 1 RCT at high risk of performance bias; follow‐up of subset (< 33 weeks only)

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: bronchopulmonary dysplasia

Early (< 8 days) postnatal corticosteroids vs placebo or no treatment for preventing chronic lung disease in preterm infants (Doyle 2014b)

Cerebral palsy at 11 months to 7 to 9 years

88 per 1000

(63/715)

128 per 1000 (93 to 174)

RR 1.45 (1.06 to 1.98)

1452 (12 RCTs)

MODERATE

Study limitations (‐1): 4 RCTs at unclear risk of selection bias; 2 RCTs at high risk of performance and detection bias; 2 RCTs had 13%‐53% follow‐up overall

Cerebral palsy in survivors assessed at 11 months to 7 to 9 years

134 per 1000

(63/470)

201 per 1000 (151 to 268)

RR 1.50 (1.13 to 2.00)

959 (12 RCTs)

MODERATE

Study limitations (‐1): 4 RCTs at unclear risk of selection bias; 2 RCTs at high risk of performance and detection bias; 2 RCTs had 13%‐53% follow‐up overall

Moderately early (7‐14 days) postnatal corticosteroids vs placebo or no treatment for preventing chronic lung disease in preterm infants (Halliday 2003)

Cerebral palsy at 12 months' corrected age up to 90 months

105 per 1000

(10/95)

108 per 1000 (49 to 236)

RR 1.03 (0.47 to 2.24)

204 (4 RCTs)

VERY LOW

Study limitations (‐1): 2 RCTs with 68%‐70% follow‐up; 1 RCT with unclear blinding of outcome assessment

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes

Cerebral palsy in survivors assessed at 12 months' corrected age up to 90 months

175 per 1000

(10/57)

146 per 1000 (68 to 305)

RR 0.83 (0.39 to 1.74)

130 (4 RCTs)

VERY LOW

Study limitations (‐1): 2 RCTs with 68%‐70% follow‐up; 1 RCT with unclear blinding of outcome assessment

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes

Late (> 7 days) postnatal corticosteroids vs placebo or no treatment for chronic lung disease in preterm infants (Doyle 2014)

Cerebral palsy at 1 to 3 years

127 per 1000

(55/433)

135 per 1000 (97 to 191)

RR 1.06 (0.76 to 1.50)

876 (14 RCTs)

LOW

Study limitations (‐1): 5 RCTs unclear risk of selection bias; 5 RCTs with follow‐up from 32% to 78%

Imprecision (‐1): wide CI crossing line of no effect

Cerebral palsy at 1 to 3 years in survivors assessed

172 per 1000

(53/309)

180 per 1000 (129 to 252)

RR 1.05 (0.75 to 1.47)

631 (14 RCTs)

LOW

Study limitations (‐1): 5 RCTs unclear risk of selection bias; 5 RCTs with follow‐up between 32% and 78%

Imprecision (‐1): wide CI crossing line of no effect

Cerebral palsy at latest reported age (from 1 year up to 17 years)

121 per 1000

(51/423)

135 per 1000 (95 to 193)

RR 1.12 (0.79 to 1.60)

855 (15 RCTs)

LOW

Study limitations (‐1): 5 RCTs unclear risk of selection bias; 7 RCTs with follow‐up between 32% and 78%

Imprecision (‐1): wide CI crossing line of no effect

Cerebral palsy at latest reported age in survivors assessed (from 1 year up to 17 years)

170 per 1000

(49/289)

190 per 1000 (134 to 268)

RR 1.12 (0.79 to 1.58)

591 (15 RCTs)

LOW

Study limitations (‐1): 5 RCTs unclear risk of selection bias; 7 RCTs with follow‐up between 32% and 78%

Imprecision (‐1): wide CI crossing line of no effect

Early inhaled corticosteroids vs placebo for preventing chronic lung disease in ventilated very low birthweight preterm neonates (Shah 2012)

Cerebral palsy (age not reported in review; from trial manuscript: 3 years)

107 per 1000

(3/28)

143 per 1000 (35 to 581)

RR 1.33 (0.33 to 5.42)

56 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at unclear risk of selection bias and detection bias

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: necrotising enterocolitis

Arginine supplementation vs placebo for prevention of necrotising enterocolitis in preterm infants (Shah 2007)

Cerebral palsy at 36 months' post‐menstrual age

55 per 1000

(4/73)

48 per 1000 (12 to 208)

RR 0.88 (0.21 to 3.80)

135 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: fungal infections

Systemic antifungal agent vs placebo to prevent mortality and morbidity in very low birthweight infants (Cleminson 2015)

Cerebral palsy at 18 to 22 months post term

112 per 1000

(12/107)

108 per 1000 (50 to 228)

RR 0.96 (0.45 to 2.03)

219 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: herpes simplex

Aciclovir vs vidarabine for treatment of herpes simplex virus infection in neonates (Jones 2009)

Cerebral palsy in CNS HSV neonatal infection up to 3 years by HSV serotype: HSV‐1

(0/4)

(0/5)

Not estimable

9 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with design limitations (inadequate allocation concealment)

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Cerebral palsy in CNS HSV neonatal infection up to 3 years by HSV serotype: HSV‐2

625 per 1000

(5/8)

669 per 1000 (306 to 1456)

(4/6)

RR 1.07 (0.49 to 2.33)

14 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with design limitations (inadequate allocation concealment)

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: jaundice

Prophylactic phototherapy vs standard care for preventing jaundice in preterm or low birthweight infants (Okwundu 2012)

Cerebral palsy in all infants (birthweight < 2500 g) at 1 year or 18 months

Medium risk population: 84 per 1000

(18/394)

Medium risk population:

81 per 1000 (42 to 155)

RR 0.96 (0.50 to 1.85)

756 (2 RCTs)

MODERATE

Study limitations (‐1): "There was no mention of blinding of the outcome assessors in two of the studies"

(GRADED by review authors themselves)

Cerebral palsy in all infants (birthweight < 1000 g) at 18 months

250 per 1000

(4/16)

72 per 1000 (10 to 568)

RR 0.29 (0.04 to 2.27)

30 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with no blinding

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Cerebral palsy at 6 years

"Secondary reports emanating from Brown 1985 at six‐year follow‐up also showed that there was no significant difference in the rate of cerebral palsy between the phototherapy and control group"

NOT GRADED

Neonatal care: hypoglycaemia

Dextrose gel vs placebo for treatment of hypoglycaemia in newborn infants (Weston 2016)

Cerebral palsy at age 2 years

(0/93)

(2/90)

RR 5.16 (0.25 to 106.12)

183 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with 78% follow‐up

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: parenteral feeding

Glutamine supplementation vs placebo to prevent morbidity and mortality in preterm infants (Moe‐Byrne 2016)

Cerebral palsy at 2 years

"van den Berg 2005 reported neurodevelopmental outcomes for infants aged two years post term. Outcomes assessed included... incidence of cerebral palsy... No significant differences between the glutamine and the control groups were reported for any of these individual outcomes"

NOT GRADED

Neonatal care: other

Thyroid hormones vs placebo for preventing neurodevelopmental impairment in preterm infants (Osborn 2001)

Cerebral palsy at 5.7 years

120 per 1000

(9/75)

86 per 1000 (34 to 221)

RR 0.72 (0.28 to 1.84)

156 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Prophylactic thyroid hormones vs placebo for prevention of morbidity and mortality in preterm infants (Osborn 2007)

Silicone earplugs vs no earplugs in the neonatal intensive care unit for preterm or very low birthweight infants (Almadhoob 2015)

Cerebral palsy at 18 to 22 months' corrected age

(0/7)

(1/7)

RR 3.0 (0.14 to 63.15)

14 (1 RCT)

VERY LOW

Study limitations (‐1): "Because of funding restraints only the ELBW infants could be followed at 18 to 22 months corrected age" (14/24 survivors)

Imprecision (‐1): wide CI crossing line of no effect; 1 small RCT

Kangaroo mother care vs conventional neonatal care to reduce morbidity and mortality in low birthweight infants (Conde‐Agudelo 2016)

Cerebral palsy at 12 months' corrected age

25 per 1000

(7/280)

16 per 1000 (5 to 51)

RR 0.65 (0.21 to 2.02)

588 (1 RCT)

LOW

Study limitation (‐1): 1 RCT with unclear risk of selection bias; high risk of performance and detection bias

Imprecision (‐1): wide CI crossing line of no effect

Early developmental intervention vs standard follow‐up post hospital discharge to prevent motor and cognitive impairment in preterm infants (Spittle 2015)

Cerebral palsy at 18 months to 6 years

79 per 1000

(32/405)

65 per 1000 (41 to 100)

RR 0.82 (0.52 to 1.27)

985 (7 RCTs)

LOW

Study limitations (‐1): 7 RCTs at unclear/high risk of performance bias; 2 RCTs at unclear/high risk of selection bias and unclear/high risk of attrition bias; 1 RCT at unclear risk of detection bias

Imprecision (‐1): wide CI crossing line of no effect

Abbreviations: BPD: bronchopulmonary dysplasia; CI: confidence interval; CNS: central nervous system; CV: conventional ventilation; ELBW: extremely low birthweight; g: grams; GRADE: Grades of Recommendation, Assessment, Development and Evaluation; HFOV: high‐frequency oscillatory ventilation; HSV: herpes simplex virus; NO: nitric oxide; OR: odds ratio; P: P value; qRCT: quasi‐randomised controlled trial; RCT: randomised controlled trial; RR: risk ratio.

Figures and Tables -
Table 6. Cerebral palsy
Table 7. Cerebral palsy: subgroup or sensitivity analyses

Intervention and comparison

Outcome

Subgroup or sensitivity analysis

Assumed risk with comparator

Corresponding risk with intervention

Relative effect (95% CI)

Number of participants (trials)

Test for subgroup differences

Neonatal care: asphyxia

Therapeutic hypothermia vs standard care for newborns with hypoxic‐ischaemic encephalopathy (Jacobs 2013)

Cerebral palsy in survivors assessed at 18 to 24 months

Method of cooling

Selective head cooling with mild hypothermia

338 per 1000

(49/145)

220 per 1000 (155 to 318)

RR 0.65 (0.46 to 0.94)

312 (3 RCTs)

Chi² = 0.01, df = 1 (P = 0.93), I² = 0.0%

Whole body cooling

360 per 1000

(94/261)

241 per 1000 (187 to 310)

RR 0.67 (0.52 to 0.86)

569 (4 RCTs)

Neonatal care: haemorrhage: periventricular/intraventricular

Ethamsylate vs placebo for prevention of morbidity and mortality in preterm or very low birthweight infants (Hunt 2010)

Cerebral palsy in surviving children available for follow‐up at 3 years up to 3.5 to 4.2 years

Infants < 31 completed weeks or < 1500 g

84 per 1000

(14/167)

69 per 1000 (32 to 147)

RR 0.82 (0.38 to 1.75)

328 (2 RCTs)

Not applicable

Neonatal care: fluid therapy

Volume vs no treatment for prevention of morbidity and mortality in very preterm infants (Osborn 2004)

Cerebral palsy in survivors at 2 years

Type of volume used

Fresh frozen plasma

132 per 1000

(27/205)

104 per 1000 (61 to 177)

RR 0.79 (0.46 to 1.34)

408 (1 RCT)

Not performed (as conducted as separate comparison)

Gelatin

132 per 1000

(27/205)

97 per 1000 (53 to 169)

RR 0.74 (0.42 to 1.28)

401 (1 RCT)

Timing of treatment

Early treatment (< 24 hours age)

132 per 1000

(27/205)

100 per 1000 (63 to 158)

RR 0.76 (0.48 to 1.20)

604 (1 RCT)

Not applicable

Types of infant enrolled

Unselected preterm infants (not selected on the basis of cardiovascular compromise)

Methodological quality

Complete follow‐up for neurodevelopmental outcomes

Neonatal care: respiratory distress syndrome

Animal‐derived surfactant extract vs no treatment for treatment of respiratory distress syndrome (Seger 2009)

Cerebral palsy at 1 and 2 years' corrected age

Surfactant product

Porcine surfactant extract

207 per 1000

(6/29)

182 per 1000 (70 to 470)

RR 0.88 (0.34 to 2.27)

73 (1 RCT)

Not applicable

Prophylactic protein‐free synthetic surfactant vs placebo for preventing morbidity and mortality in preterm infants (Soll 2010)

Cerebral palsy at 1 or 2 years

Surfactant product

Exosurf Neonatal

158 per 1000

(44/279)

144 per 1000 (98 to 211)

RR 0.91 (0.62 to 1.34)

591 (3 RCTs)

Not applied in review

DPPC/HDL

122 per 1000

(5/41)

132 per 1000 (41 to 420)

RR 1.08 (0.34 to 3.44)

79 (1 RCT)

Neonatal care: mechanical ventilation

Continuous distending pressure vs standard care for respiratory distress in preterm infants (Ho 2015)

Cerebral palsy at 9 to 15 years

Type of continuous distending pressure

Continuous negative pressure

(0/18)

(2/18)

RR 5.0 (0.26 to 97.37)

36 (1 RCT)

Not applicable

Neonatal care: bronchopulmonary dysplasia

Early (< 8 days) postnatal corticosteroids vs placebo or no treatment for preventing chronic lung disease in preterm infants (Doyle 2014b)

Cerebral palsy at 11 months to 7 to 9 years

Type of corticosteroid used

Dexamethasone

89 per 1000

(40/449)

156 per 1000 (107 to 227)

RR 1.75 (1.20 to 2.55)

921 (7 RCTs)

Chi² = 2.96, df = 1 (P = 0.09), I² = 66%

Hydrocortisone

86 per 1000

(23/266)

84 per 1000 (48 to 146)

RR 0.97 (0.55 to 1.69)

531 (5 RCTs)

Cerebral palsy in survivors assessed at 11 months to 7 to 9 years

Type of corticosteroid used

Dexamethasone

139 per 1000

(40/288)

253 per 100 (179 to 357)

RR 1.82 (1.29 to 2.57)

586 (7 RCTs)

Chi² = 3.99, df = 1 (P = 0.05), I² = 75%

Hydrocortisone

126 per 1000

(23/182)

120 per 1000 (71 to 206)

RR 0.95 (0.56 to 1.63)

373 (5 RCTs)

Neonatal care: other

Prophylactic thyroid hormones vs placebo for prevention of morbidity and mortality in preterm infants (Osborn 2007)

Cerebral palsy at 5.7 years

Dosing strategy

T4 8 mcg/kg/d, day 1 to 42

120 per 1000

(9/75)

86 per 1000 (34 to 221)

RR 0.72 (0.28 to 1.84)

156 (1 RCT)

Not applicable

Timing

Commenced < 48 hours

Methodological quality

Studies with adequate methods

Early developmental intervention vs standard follow‐up post hospital discharge to prevent motor and cognitive impairment in preterm infants (Spittle 2015)

Cerebral palsy at 18 months to 6 years

Commencement of intervention

Inpatient

79 per 1000

(12/152)

74 per 1000 (36 to 152)

RR 0.94 (0.46 to 1.93)

354 (3 RCTs)

Not applied in review

Post hospital discharge

79 per 1000

(20/253)

59 per 1000 (34 to 105)

RR 0.75 (0.43 to 1.33)

631 (4 RCTs)

Focus of intervention

Parent‐infant relationship and Infant development

77 per 1000

(21/272)

52 per 1000 (29 to 90)

RR 0.67 (0.38 to 1.17)

716 (4 RCTs)

Not applied in review

Infant development

83 per 1000

(11/133)

97 per 1000 (46 to 203)

RR 1.17 (0.56 to 2.46)

269 (3 RCTs)

Quality of studies

Higher‐quality studies

82 per 1000

(25/304)

72 per 1000 (44 to 116)

RR 0.87 (0.53 to 1.41)

776 (5 RCTs)

Not applied in review

Lower‐quality studies

69 per 1000

(7/101)

43 per 1000 (14 to 130)

RR 0.62 (0.20 to 1.87)

209 (2 RCTs)

Abbreviations: CI: confidence interval; DPPC/HDL: dipalmitoylphosphatidylcholine/high‐density lipoprotein; g: grams; P: P value; RCT: randomised controlled trial; RR: risk ratio; T4: thyroxine.

Figures and Tables -
Table 7. Cerebral palsy: subgroup or sensitivity analyses
Table 8. Cerebral palsy or death

Intervention and comparison

Outcome

Assumed risk with comparator

Corresponding risk with intervention

Relative effect (95% CI)

Number of participants (trials)

Quality of the evidence (GRADE)

Comments

Neonatal care: bronchopulmonary dysplasia

Early (< 8 days) postnatal corticosteroids vs placebo or no treatment for preventing chronic lung disease in preterm infants (Doyle 2014b)

Cerebral palsy or death at 11 months to 7 to 9 years

352 per 1000

(252/715)

384 per 1000 (334 to 441)

RR 1.09 (0.95 to 1.25)

1452 (12 RCTs)

MODERATE

Study limitations (‐1): 4 RCTs at unclear risk of selection bias; 2 RCTs at high risk of performance and detection bias; 2 RCTs had 13% to 53% follow‐up overall

Moderately early (7‐14 days) postnatal corticosteroids vs placebo or no treatment for preventing chronic lung disease in preterm infants (Halliday 2003)

Cerebral palsy or death at 12 months' corrected age up to 90 months

316 per 1000

(30/95)

262 per 1000 (174 to 388)

RR 0.83 (0.55 to 1.23)

204 (4 RCTs)

VERY LOW

Study limitations (‐1): 2 RCTs with 68% to 70% follow‐up; 1 RCT with unclear blinding of outcome assessment

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes

Late (> 7 days) postnatal corticosteroids vs placebo or no treatment for chronic lung disease in preterm infants (Doyle 2014)

Cerebral palsy or death at 1 to 3 years

328 per 1000

(142/433)

302 per 1000 (249 to 367)

RR 0.92 (0.76 to 1.12)

876 (14 RCTs)

LOW

Study limitations (‐1): 5 RCTs unclear risk of selection bias; 5 RCTs with follow‐up between 32% and 78%

Imprecision (‐1): wide CI crossing line of no effect

Cerebral palsy or death at latest reported age (from 1 year up to 17 years)

312 per 1000

(132/423)

296 per 1000 (240 to 362)

RR 0.95 (0.77 to 1.16)

855 (15 RCTs)

LOW

Study limitations (‐1): 5 RCTs unclear risk of selection bias; 7 RCTs with follow‐up between 32% and 78%

Imprecision (‐1): wide CI crossing line of no effect

Neonatal care: other

Thyroid hormones vs placebo for preventing neurodevelopmental impairment in preterm infants (Osborn 2001)

Cerebral palsy or death at 5.7 years

300 per 1000

(30/100)

210 per 1000 (129 to 342)

RR 0.70 (0.43 to 1.14)

200 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Prophylactic thyroid hormones vs placebo for prevention of morbidity and mortality in preterm infants (Osborn 2007)

Abbreviations: CI: confidence interval; GRADE: Grades of Recommendation, Assessment, Development and Evaluation; RCT: randomised controlled trial; RR: risk ratio.

Figures and Tables -
Table 8. Cerebral palsy or death
Table 9. Severity of cerebral palsy

Intervention and comparison

Outcome

Assumed risk with comparator

Corresponding risk with intervention

Relative effect (95% CI)

Number of participants (trials)

Quality of the evidence (GRADE)

Comments

Neonatal care: asphyxia

Allopurinol vs placebo or no drug for preventing mortality and morbidity in newborn infants with hypoxic‐ischaemic encephalopathy (Chaudhari 2012)

Severe quadriplegia in surviving infants (18 months and 4 to 8 years)

343 per 1000

(12/35)

202 per 1000 (96 to 435)

RR 0.59 (0.28 to 1.27)

73 (3 RCTs)

VERY LOW

Study limitations (‐1): 1 RCT with unclear risk of selection bias and high risk of performance/detection bias

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes with few events

Neonatal care: respiratory distress syndrome

Synthetic surfactant vs placebo for respiratory distress syndrome in preterm infants (Soll 2000)

Moderate to severe cerebral palsy in survivors examined at 1 year (in 4 of the 5 RCTs)

55 per 1000

(42/767)

41 per 1000 (26 to 64)

RR 0.75 (0.48 to 1.16)

1557 (5 RCTs)

MODERATE

Imprecision (‐1): wide CI crossing the line of no effect

Prophylactic protein‐free synthetic surfactant vs placebo for preventing morbidity and mortality in preterm infants (Soll 2010)

Moderate/severe cerebral palsy at 1 or 2 years

75 per 1000

(24/320)

69 per 1000 (40 to 119)

RR 0.92 (0.53 to 1.59)

670 (4 RCTs)

LOW

Study limitations (‐1): "Somewhat fewer infants who received surfactant failed to return for follow‐up evaluation (typical relative risk 0.63, 95% CI 0.48, 0.82; typical risk difference ‐0.10, 95% CI ‐0.15, ‐0.04)"

Imprecision (‐1): wide CI crossing the line of no effect

Abbreviations: CI: confidence interval; GRADE: Grades of Recommendation, Assessment, Development and Evaluation; RCT: randomised controlled trial; RR: risk ratio.

Figures and Tables -
Table 9. Severity of cerebral palsy
Table 10. Other composite outcomes that include cerebral palsy as a component

Intervention and comparison

Outcome

Assumed risk with comparator

Corresponding risk with intervention

Relative effect (95% CI)

Number of participants (trials)

Quality of the evidence (GRADE)

Comments

Neonatal care: asphyxia

Allopurinol vs placebo or no drug for preventing mortality and morbidity in newborn infants with hypoxic‐ischaemic encephalopathy (Chaudhari 2012)

Death or severe neurodevelopmental disability in survivors (18 months and 4 to 8 years) (defined as any 1 or combination of the following: non‐ambulant cerebral palsy, severe developmental delay assessed via validated tools, auditory and visual impairment)

611 per 1000

(33/54)

477 per 1000 (342 to 660)

RR 0.78 (0.56 to 1.08)

110 (3 RCTs)

VERY LOW

Study limitations (‐1): 1 RCT with unclear risk of selection bias and high risk of performance/detection bias

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes

Therapeutic hypothermia vs standard care for newborns with hypoxic‐ischaemic encephalopathy (Jacobs 2013)

Death or major disability in survivors assessed at 18 to 24 months (defined as cerebral palsy, developmental delay (BSID or GMDS assessment > 2 SD below the mean) or intellectual impairment (IQ > 2 SD below mean), blindness (vision < 6/60 in both eyes), sensorineural deafness requiring amplification)

614 per 1000

(409/666)

461 per 1000 (418 to 510)

RR 0.75 (0.68 to 0.83)

1344 (8 RCTs)

HIGH

Not downgraded

Major neurodevelopmental disability at 18 to 24 months (defined as cerebral palsy, developmental delay (BSID or GMDS assessment > 2 SD below the mean) or intellectual impairment (IQ > 2 SD below mean), blindness (vision < 6/60 in both eyes), sensorineural deafness requiring amplification)

249 per 1000

(166/666)

192 per 1000 (157 to 234)

RR 0.77 (0.63 to 0.94)

1344 (8 RCTs)

HIGH

Not downgraded

Major neurodevelopmental disability in survivors assessed at 18 to 24 months (defined as cerebral palsy, developmental delay (BSID or GMDS assessment > 2 SD below the mean) or intellectual impairment (IQ > 2 SD below mean), blindness (vision < 6/60 in both eyes), sensorineural deafness requiring amplification)

393 per 1000

(166/422)

264 per 1000 (216 to 315)

RR 0.67 (0.55 to 0.80)

917 (8 RCTs)

HIGH

Not downgraded

Death or moderate to severe disability at 6 to 7 years (defined as IQ ≥ 2 SD below the mean, a GMF level of 3 or greater, bilateral deafness (with or without amplification), bilateral blindness, or refractory epilepsy)

645 per 1000

(60/93)

523 per 1000 (413 to 671)

RR 0.81 (0.64 to 1.04)

190 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with small sample size

Moderate‐to‐severe disability at 6 to 7 years (defined as IQ ≥ 2 SD below the mean, a GMF level of 3 or greater, bilateral deafness (with or without amplification), bilateral blindness or refractory epilepsy)

380 per 1000

(19/50)

350 per 1000 (217 to 562)

RR 0.92 (0.57 to 1.48)

119 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with small sample size

Barbiturates (phenobarbital) vs conventional therapy for prevention of morbidity and mortality following perinatal asphyxia (Young 2016)

Death or major neurodevelopmental disability follow‐up: > 12 months (3 years) (defined as cerebral palsy, developmental delay (BSID or GMDS assessment > 2 SD below the mean) or intellectual impairment (IQ > 2 SD below mean), blindness (vision < 6/60 in both eyes), or sensorineural deafness requiring amplification)

813 per 1000

(13/16)

268 per 1000 (114 to 634)

RR 0.33
(0.14 to 0.78)

31 (1 RCT)

VERY LOW

Study limitations (‐1): unblinded study; concern regarding performance bias, detection bias, and incomplete follow‐up

Imprecision (‐2): 95% CIs were wide and imprecise

(graded by review authors themselves)

Major neurodevelopmental disability follow‐up: > 12 months (3 years) (defined as cerebral palsy, developmental delay (BSID or GMDS assessment > 2 SD below the mean) or intellectual impairment (IQ > 2 SD below mean), blindness (vision < 6/60 in both eyes), or sensorineural deafness requiring amplification)

563 per 1000

(9/16)

135 per 1000 (34 to 518)

RR 0.24
(0.06 to 0.92)

31 (1 RCT)

VERY LOW

Study limitations (‐1): unblinded study; concern regarding performance bias, detection bias, and incomplete follow‐up

Imprecision (‐2): 95% CIs were wide and imprecise

(graded by review authors themselves)

Neonatal care: haemorrhage: periventricular/intraventricular

Ethamsylate vs placebo for prevention of morbidity and mortality in preterm or very low birthweight infants (Hunt 2010)

Neurodevelopmental disability at 2 years of age in surviving children available for follow‐up (defined as cerebral palsy on clinical examination, developmental delay > 2 SD below population mean on any standard test of development, or blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification) at any time after 2 years' corrected age)

170 per 1000

(46/270)

135 per 1000 (90 to 199)

RR 0.79 (0.53 to 1.17)

532 (3 RCTs)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Death or any disability by 2 years of age in children with known outcome at any point in time (not defined in review)

338 per 1000

(233/690)

324 per 1000 (277 to 375)

RR 0.96 (0.82 to 1.11)

1334 (7 RCTs)

LOW

Study limitations (‐1): 4 RCTs at unclear risk of selection bias; 3 RCTs at unclear risk of bias due to lack of blinding

Imprecision (‐1): wide CIs crossing line of no effect

Phenobarbital vs no treatment for prevention of intraventricular haemorrhage in preterm infants (Smit 2013)

Severe neurodevelopmental impairment at 27 months (defined as clinical cerebral palsy or DQ below the range that can be measured)

74 per 1000

(4/54)

107 per 1000 (30 to 373)

RR 1.44 (0.41 to 5.04)

101 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at high risk of performance bias) and unclear risk of other bias

Imprecision (‐2): wide CI crossing line of no effect; small sample size, low event rate

Mild neurodevelopmental impairment at 27 months (defined as DQ < 80 or motor abnormality on examination)

111 per 1000 (6/54)

63 per 1000 (17 to 241)

RR 0.57 (0.15 to, 2.17)

101 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at high risk of performance bias) and unclear risk of other bias

Imprecision (‐2): wide CI crossing line of no effect; small sample size, low event rate

Neonatal care: hypotension

Dobutamine vs dopamine in preterm infants with low superior vena cava flow (Osborn 2007b)

Disability at 3 years in survivors (defined as GMDS quotient ≤ 70, cerebral palsy, blind (VA < 6/60) or deaf (hearing aids))

714 per 1000

(5/7)

71 per 1000 (7 to 1114)

RR 0.10 (0.01 to 1.56)

13 (1 RCT)

VERY LOW

Study limitations (‐1): 5/18 surviving infants were not assessed at 3 years

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with very small sample size

Death or disability at 3 years (defined as GMDS quotient ≤ 70, cerebral palsy, blind (VA < 6/60) or deaf (hearing aids))

882 per 1000

(15/17)

697 per 1000 (503 to 979)

RR 0.79 (0.57 to 1.11)

37 (1 RCT)

VERY LOW

Study limitations (‐1): 5/18 surviving infants were not assessed at 3 years

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with very small sample size

Death or disability at latest follow‐up (1 to 3 years) (defined as GMDS quotient ≤ 70, cerebral palsy, blind (VA < 6/60) or deaf (hearing aids))

750 per 1000

(15/20)

713 per 1000 (495 to 1035)

RR 0.95 (0.66 to 1.38)

41 (1 RCT)

VERY LOW

Study limitations (‐1): 5/18 surviving infants were not assessed at 3 years

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with very small sample size

Neonatal care: fluid therapy

Volume vs no treatment for prevention of morbidity and mortality in very preterm infants (Osborn 2004)

Severe neurodevelopmental disability in survivors at 2 years (defined as blind, dead, unable to walk, DQ > 3 SD below the mean, or another severe disability)

141 per 1000

(29/205)

113 per 1000 (74 to 174)

RR 0.80 (0.52 to 1.23)

604 (1 RCT)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Gelatin vs fresh frozen plasma for prevention of morbidity and mortality in very preterm infants (Osborn 2004)

113 per 1000

(23/203)

112 per 1000 (65 to 195)

RR 0.99 (0.57 to 1.72)

399 (1 RCT)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Volume vs no treatment for prevention of morbidity and mortality in very preterm infants (Osborn 2004)

Death or severe neurodevelopmental disability in survivors at 2 years (defined as blind, dead, unable to walk, DQ > 3 SD below the mean, or another severe disability)

318 per 1000

(82/258)

318 per 1000 (254 to 394)

RR 1.00 (0.80 to 1.24)

776 (1 RCT)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Gelatin vs fresh frozen plasma for prevention of morbidity and mortality in very preterm infants (Osborn 2004)

300 per 1000

(77/257)

333 per 1000 (258 to 428)

RR 1.11 (0.86 to 1.43)

518 (1 RCT)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Neonatal care: patent ductus arteriosus

Prophylactic indomethacin vs placebo for preventing mortality and morbidity in preterm infants (Fowlie 2010)

Death or severe neurodevelopmental disability at 18 to 36 months (defined as any 1 or a combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment)

400 per 1000

(299/748)

407 per 1000 (360 to 460)

RR 1.02 (0.90 to 1.15)

1491 (3 RCTs)

MODERATE

Study limitations (‐1): 2 RCTs at unclear risk of attrition bias (> 25% loss to follow‐up)

Neonatal care: blood disorders

Erythropoietin vs placebo for preventing red blood cell transfusion in preterm and/or low birthweight infants (Ohlsson 2014)

Any neurodevelopmental impairment at 18 to 22 months' corrected age (in children examined) (not defined in review; definition from trial manuscript: 1 of the following: MDI < 70, PDI < 70, moderate or severe cerebral palsy, blindness, or deafness)

451 per 1000

(23/51)

437 per 1000 (280 to 681)

RR 0.97 (0.62 to 1.51)

99 (1 RCT)

VERY LOW

Study limitations: 1 RCT at unclear risk of selection bias and high risk of attrition bias (˜73% follow‐up)

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with small sample size

Transfusion at a restrictive vs a liberal haemoglobin threshold for preventing morbidity and mortality in very low birthweight infants (Whyte 2011)

Any neurosensory impairment at 18 to 21 months' follow‐up among survivors (defined as cognitive delay (MDI < 70), cerebral palsy, severe visual impairment, severe hearing impairment)

220 per 1000

(37/168)

289 per 1000 (198 to 418)

RR 1.31 (0.90 to 1.90)

328 (1 RCT)

LOW

Study limitations (‐1): 1 RCT at high risk of performance bias and unclear risk of reporting bias

Imprecision (‐1): wide CI crossing line of no effect

Death or severe morbidity at 18 to 21 months' follow‐up (defined as cognitive delay (MDI < 70), cerebral palsy, severe visual impairment, severe hearing impairment)

385 per 1000

(82/213)

450 per 1000 (362 to 566)

RR 1.17 (0.94 to 1.47)

421 (1 RCT)

LOW

Study limitations (‐1): 1 RCT at high risk of performance bias and unclear risk of reporting bias

Imprecision (‐1): wide CI crossing line of no effect

Death or severe morbidity at 18 to 21 months' follow‐up (defined as cognitive delay (MDI < 85), cerebral palsy, severe visual impairment, severe hearing impairment)

498 per 1000

(106/213)

602 per 1000 (503 to 717)

RR 1.21 (1.01 to 1.44)

421 (1 RCT)

MODERATE

Study limitations (‐1): 1 RCT at high risk of performance bias and unclear risk of reporting bias

Neonatal care: nitric oxide

Inhaled NO vs placebo for respiratory failure in preterm infants (entry before 3 days based on oxygenation) (Barrington 2010)

Neurodevelopmental disability at 18 to 22 months (defined as moderate or severe cerebral palsy, blind, deaf, BSID MDI < 70, or PDI < 70)

455 per 1000

(50/110)

477 per 1000 (355 to 636)

RR 1.05 (0.78 to 1.40)

208 (2 RCTs)

LOW

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes

Inhaled NO vs placebo or no treatment for respiratory failure in preterm infants (entry after 3 days based on BPD risk) (Barrington 2010)

Neurodevelopmental disability at 2 years' corrected age or 30 months (defined as 1 RCT: moderate or severe cerebral palsy, blind, deaf, BSID MDI < 70, or PDI < 70; 1 RCT: cerebral palsy, BSID MDI or PDI < 71, or sensorineural impairment)

480 per 1000

(119/248)

432 per 1000 (355 to 523)

RR 0.90 (0.74 to 1.09)

498 (2 RCTs)

LOW

Study limitations (‐1): 1 RCT with no blinding of intervention or outcome measurement

Imprecision (‐1): wide CI crossing line of no effect; small sample sizes

Inhaled NO vs placebo for respiratory failure in preterm infants (studies of routine use in intubated preterm infants) (Barrington 2010)

Neurodevelopmental disability at 1 or 2 years' corrected age (defined as 1 RCT: cerebral palsy, blind, severe hearing loss, BSID MDI < 70, or PDI < 70; 1 RCT: cerebral palsy, bilateral blindness, bilateral hearing loss, or BSID score > 2 SD below the mean)

364 per 100

(104/286)

327 per 1000 (262 to 411)

RR 0.90 (0.72 to 1.13)

593 (2 RCT)

VERY LOW

Study limitations (‐1): 2 RCTs with 74% to 82% follow‐up

Imprecision (‐1): wide CI crossing line of no effect

Inconsistency (‐1): substantial heterogeneity I² = 83%

Inhaled nitric oxide vs control for respiratory failure in infants born at or near term (Finer 2006)

Neurodevelopmental disability among survivors at 13 or 18 to 24 months (defined as 1 RCT: cerebral palsy, BSID MDI or PDI < 2 SD below the mean, blind or hearing impaired; or 1 RCT: cerebral palsy, > 2 mild (mild neurological abnormalities; mild reductions in BSID scores 1 to 2 SD below the mean), or at least 1 severe impairment)

265 per 1000

(48/181)

257 per 1000 (175 to 382)

RR 0.97 (0.66 to 1.44)

301 (2 RCTs)

LOW

Study limitations (‐1): 1 RCT masking of allocation, masking of outcomes, and completeness of follow‐up 'can't tell'

Imprecision (‐1): wide CI crossing line of no effect

Neonatal care: apnoea

Caffeine vs placebo for apnoea in preterm infants (Henderson‐Smart 2010b)

Death or major disability at 18 to 21 months' corrected age (defined as cognitive delay, cerebral palsy, deafness, or blindness)

417 per 1000

(153/367)

354 per 1000 (296 to 421)

RR 0.85 (0.71 to 1.01)

767 (1 RCT)

LOW

Study limitations (‐1): results based on 1 RCT subgroup from post hoc subgroup analyses (randomisation not stratified according to indication for inclusion)

Imprecision (‐1): wide CI crossing line of no effect

Caffeine vs placebo for prevention of apnoea in preterm infants (Henderson‐Smart 2010c)

Death or major disability at 18 to 21 months' corrected age (not defined in review; definition from trial manuscript: cerebral palsy, cognitive delay, severe hearing loss, or bilateral blindness)

431 per 1000

(88/204)

431 per 1000 (345 to 535)

RR 1.00 (0.80 to 1.24)

423 (1 RCT)

LOW

Study limitations (‐1): results based on 1 RCT subgroup from post hoc subgroup analyses (randomisation not stratified according to indication for inclusion)

Imprecision (‐1): wide CI crossing line of no effect

Neonatal care: respiratory distress syndrome

Inositol supplementation (repeat doses) vs placebo in preterm infants at risk for or having respiratory distress syndrome (Howlett 2015)

Major neural developmental impairment at 1 year corrected age (defined as sensory deficit, cerebral palsy, developmental delay, severe hypotonia)

178 per 1000

(13/73)

94 per 1000 (43 to 207)

RR 0.53 (0.24 to 1.16)

169 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at unclear risk of selection, performance, detection, and reporting bias, and at high risk of other bias

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with small sample size

Animal‐derived surfactant extract vs no treatment for treatment of respiratory distress syndrome (Seger 2009)

Major developmental disability in survivors at 1 and 2 years' corrected age (defined as severe forms of cerebral palsy, blindness, deafness requiring hearing aids, or GMDS DQ < 70)

34 per 1000

(1/29)

114 per 1000 (5 to 923)

RR 3.30 (0.14 to 26.78)

73 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with no blinding of intervention; and blinding of outcome measurement not reported

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: mechanical ventilation

Continuous distending pressure vs standard care for respiratory distress in preterm infants (Ho 2015)

Death or severe disability at 9 to 15 years (not defined in review; severe disability as defined below)

158 per 1000

(3/19)

210 per 1000 (54 to 816)

RR 1.33 (0.34 to 5.17)

38 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at unclear risk of selection and attrition bias and high risk of performance bias

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Severe disability at 9 to 15 years (not defined in review; definition from trial manuscript: unable to undertake activity without aids or assistance most of the time, or completely dependent on carer: WASI ≤ 69; GMF level 4 to 5, arms: needs assistance to feed and dress; VA < 6/60, gross movement/light and dark only or worse; hearing loss not corrected with age; parent and teacher overall difficulties (Q26), "Yes" and impact score 6 to 10 parent and 3 to 6 teacher; or other condition needs supervision/aid constantly ‐ includes continuous home oxygen; communication severely limited)

158 per 1000

(3/19)

167 per 1000 (38 to 722)

RR 1.06 (0.24 to 4.57)

37 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at unclear risk of selection and attrition bias and high risk of performance bias

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Any disability at 9 to 15 years (not defined in review; definition from trial manuscript: mild: some loss of function but able to function independently; moderate: aids or assistance needed for some tasks. Moderate difficulty in doing some activities; severe: unable to undertake activity without aids or assistance most of the time, or completely dependent on carer; includes neuromotor components includes GMF levels 1 to 5)

632 per 1000

(12/19)

392 per 1000 (196 to 764)

RR 0.62 (0.31 to 1.21)

37 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at unclear risk of selection and attrition bias and high risk of performance bias

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Prophylactic methylxanthines (caffeine) vs placebo for endotracheal extubation in preterm infants (Henderson‐Smart 2010)

Death or major disability at 18 to 21 months' corrected age (defined as cognitive delay, cerebral palsy, deafness, or blindness)

525 per 1000

(189/360)

446 per 1000 (383 to 520)

RR 0.85 (0.73 to 0.99)

676 (1 RCT)

MODERATE

Study limitations (‐1): results based on 1 RCT subgroup from post hoc subgroup analyses (randomisation not stratified according to indication for inclusion)

Volume‐targeted vs pressure‐limited ventilation in the neonate (Wheeler 2010)

Severe disability (any definition) at 6 to 18 months and 22 months (definitions not reported in review; definitions from trial manuscripts: 1 RCT: abnormal neurological evaluation (gross or fine motor delay) or BSID MDI < 70; 1 RCT: cerebral palsy severe enough to hamper gross motor activity, deafness needing hearing aids, registered blind or partially sighted)

176 per 1000

(18/102)

152 per 1000 (83 to 281)

RR 0.86 (0.47 to 1.59)

209 (2 RCTs)

LOW

Indirectness (‐1): post hoc analysis including 2 RCTs with varied definitions

Imprecision (‐1): wide CI crossing line of no effect

(post hoc analysis in review)

Severe disability (any definition) at 22 months or death (definition not reported in review; definition from trial manuscript: cerebral palsy severe enough to hamper gross motor activity, deafness needing hearing aids, registered blind or partially sighted)

327 per 1000

(17/52)

177 per 1000 (88 to 347)

RR 0.54 (0.27 to 1.06)

109 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

(post hoc analysis in review)

Neonatal care: bronchopulmonary dysplasia

Early (< 8 days) postnatal corticosteroids vs placebo or no treatment for preventing chronic lung disease in preterm infants (Doyle 2014b)

Major neurosensory disability at 18 to 22 months to 53 months (variable criteria reported in review: 1 RCT: non‐ambulant cerebral palsy, global retardation (not specified), blindness, or deafness; 1 RCT: moderate or severe cerebral palsy, blindness, deafness, or BSID MDI or PDI < ‐2 SD; 1 RCT: cerebral palsy, BSID MDI or PDI < 71, blindness or deafness; 1 RCT: severe motor dysfunction (child non‐ambulant), or BSID MDI or PDI <‐2 SD; 2 RCTs: cerebral palsy, blindness, deafness, or developmental delay (BSID MDI < 70 (< ‐2 SD) or GMDS DQ < 70); 1 RCT: cerebral palsy, functional blindness, functional deafness, developmental delay (BSID MDI < 70 (<‐2 SD)), or motor delay (BSID PDI < 70 (<‐2 SD))

199 per 1000

(121/607)

231 per 1000 (187 to 285)

RR 1.16 (0.94 to 1.43)

1233 (7 RCTs)

LOW

Study limitations (‐1): 2 RCTs at unclear risk of selection bias; 1 RCT at high risk of performance and detection bias

Imprecision (‐1): wide CI crossing line of no effect

Major neurosensory disability in survivors examined at 18 to 22 months to 53 months (variable criteria as above)

307 per 1000

(121/394)

350 per 1000 (289 to 424)

RR 1.14 (0.94 to 1.38)

799 (7 RCTs)

LOW

Study limitations (‐1): 2 RCTs at unclear risk of selection bias; 1 RCT at high risk of performance and detection bias

Imprecision (‐1): wide CI crossing line of no effect

Death or major neurosensory disability at 18 to 22 months to 53 months (variable criteria as above)

466 per 1000

(283/607)

490 per 1000 (434 to 545)

RR 1.05 (0.93 to 1.17)

1233 (7 RCTs)

MODERATE

Study limitations (‐1): 2 RCTs at unclear risk of selection bias; 1 RCT at high risk of performance and detection bias

Moderately early (7‐14 days) postnatal corticosteroids vs placebo for preventing chronic lung disease in preterm infants (Halliday 2003)

Major neurosensory disability at 15 months' corrected age up to 90 months (variable criteria reported in review: 1 RCT: any of cerebral palsy or a BSID MDI or PDI < ‐ 1 SD; 1 RCT: not specified)

98 per 1000

(4/41)

123 per 1000 (44 to 340)

RR 1.26 (0.45 to 3.49)

96 (2 RCTs)

VERY LOW

Study limitations (‐1): 1 RCT with 70% follow‐up and unclear blinding of outcome assessment

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes

Major neurosensory disability in survivors assessed at 15 months' corrected age up to 90 months (variable criteria reported in review as above)

174 per 1000

(4/23)

155 per 1000 (66 to 365)

RR 0.89 (0.38 to 2.10)

56 (2 RCTs)

VERY LOW

Study limitations (‐1): 1 RCT with 70% follow‐up and unclear blinding of outcome assessment

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes

Death or major neurosensory disability at 15 months' corrected age up to 90 months (variable criteria reported in review as above)

366 per 1000

(15/41)

373 per 1000 (241 to 571)

RR 1.02 (0.66 to 1.56)

96 (2 RCTs)

VERY LOW

Study limitations (‐1): 1 RCT with 70% follow‐up and unclear blinding of outcome assessment

Imprecision (‐2): wide CI crossing line of no effect; small sample sizes

Late (> 7 days) postnatal corticosteroids vs placebo or no treatment for chronic lung disease in preterm infants (Doyle 2014)

Major neurosensory disability at 1 year corrected age up to 11 years (variable criteria reported in review: 1 RCT: non‐ambulant cerebral palsy, < 50% of age level on the Minnesota CDI, or predicted special schooling for sensory or other impairment; 1 RCT: abnormal neurological examination (i.e. cerebral palsy), cognitive delay (IQ < 71) or not in a regular classroom; 1 RCT: severe disability ‐ bilateral blindness, cerebral palsy with the child unlikely ever to walk or BSID MDI < 55 (< ‐3 SD)) or moderate disability ‐ deafness, cerebral palsy in children not walking at 2 years but expected to walk, or MDI from 55 to < 70 (‐3 SD to < ‐2 SD); 1 RCT: cerebral palsy, blindness, deafness requiring hearing aids or worse, or developmental delay (defined as BSID MDI < 70); 1 RCT: more than mild cerebral palsy, blindness, deafness, or needing extra help with schooling; 1 RCT: blindness, cerebral palsy or a BSID MDI < 70 OR cerebral palsy or mental retardation (IQ < 70 on either the DAS or the WISC‐III and a VABS composite score < 70); 1 RCT: not specified; 1 RCT moderate or severe cerebral palsy, bilateral blindness, deafness or an MDI < 2 SD

169 per 1000

(54/320)

197 per 1000 (143 to 270)

RR 1.17 (0.85 to 1.60)

655 (8 RCTs)

LOW

Study limitations (‐1): 3 RCTs with unclear risk of selection bias; 3 RCTs with follow‐up rates 60% to 78%

Imprecision (‐1): wide CI crossing line of no effect

Major neurosensory disability in survivors assessed at 1 year corrected age up to 11 years (variable criteria reported in review as above)

231 per 1000

(54/234)

254 per 1000 (187 to 346)

RR 1.10 (0.81 to 1.50)

480 (8 RCTs)

LOW

Study limitations (‐1): 3 RCTs with unclear risk of selection bias; 3 RCTs with follow‐up rates 60% to 78%

Imprecision (‐1): wide CI crossing line of no effect

Death or major neurosensory disability at 1 year corrected age up to 11 years (variable criteria reported in review as above)

375 per 1000

(120/320)

390 per 1000 (323 to 473)

RR 1.04 (0.86 to 1.26)

655 (8 RCTs)

LOW

Study limitations (‐1): 3 RCTs with unclear risk of selection bias; 3 RCTs with follow‐up rates 60% to 78%

Imprecision (‐1): wide CI crossing line of no effect

Supplemental vitamin A vs a sham injection to prevent mortality and short‐ and long‐term morbidity in very low birthweight infants (Darlow 2016)

Neurodevelopmental impairment at 18 to 24 months (defined as BSID‐II MDI < 70, PDI < 70, any cerebral palsy, blind in both eyes, or bilateral hearing aids )

481 per 1000

(128/266)

428 per 1000 (356 to 520)

RR 0.89 (0.74 to 1.08)

538 (1 RCT)

LOW

Imprecision (‐2): "Concerning imprecision: does not met the optimal information size criteria"

(graded by review authors themselves)

Death or neurodevelopmental impairment at 18 to 24 months (defined as BSID‐II MDI < 70, PDI < 70, any cerebral palsy, blind in both eyes, or bilateral hearing aids)

596 per 1000

(204/342)

549 per 1000 (483 to 626)

RR 0.92 (0.81 to 1.05)

687 (1 RCT)

MODERATE

Imprecision (‐1): wide CIs crossing line of no effect

Neonatal care: necrotising enterocolitis

Probiotics vs control (distilled water) for prevention of necrotising enterocolitis in preterm infants (AlFaleh 2014)

Mental retardation and cerebral palsy at 6 years

47 per 1000

(2/43)

47 per 1000 (7 to 323)

RR 1.02 (0.15 to 6.94)

85 (1 RCT)

VERY LOW

Study limitation (‐1): 1 RCT at unclear risk for selection, performance, and detection bias; and high risk of attrition and reporting bias

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Arginine supplementation vs placebo for prevention of necrotising enterocolitis in preterm infants (Shah 2007)

Major neurodevelopmental disability at 36 months' post‐menstrual age (definition not reported in review; definition from trial manuscript: presence of 1 or more of cerebral palsy, cognitive delay (index < 70), bilateral blindness, bilateral hearing loss requiring aids)

127 per 1000

(9/71)

82 per 1000 (29 to 232)

RR 0.65 (0.23 to 1.83)

132 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: fungal infections

Systemic antifungal agent vs placebo to prevent mortality and morbidity in very low birthweight infants (Cleminson 2015)

Neurodevelopmental impairment (composite) at 18 to 22 months (defined as at least 1 of (i) BSID‐III cognition composite score < 70, (ii) cerebral palsy, (iii) deafness or, (iv) blindness)

274 per 1000

(23/84)

309 per 1000 (194 to 496)

RR 1.13 (0.71 to 1.81)

171 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: herpes simplex

Vidarabine vs placebo for treatment of herpes simplex virus infection in neonates (Jones 2009)

Abnormal neurodevelopment at approximately 1 year of age (not defined in review; definition from trial manuscript: spasticity or hemiparesis only; or combinations of microcephaly, paresis, spasticity, seizures, blindness, or deafness)

214 per 1000

(6/28)

321 per 1000 (133 to 782)

RR 1.50 (0.62 to 3.65)

56 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with design limitations (method of randomisation not stated)

Imprecision (‐2): wide CIs crossing line of no effect; 1 small RCT

Abnormal neurodevelopment or death at approximately 1 year of age (not defined in review; definition from trial manuscript as above)

750 per 1000

(21/28)

645 per 1000 (450 to 915)

RR 0.86 (0.60 to 1.22)

56 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with design limitations (method of randomisation not stated)

Imprecision (‐2): wide CIs crossing line of no effect; 1 small RCT

Aciclovir vs vidarabine for treatment of herpes simplex virus infection in neonates (Jones 2009)

Abnormal neurodevelopment at approximately 1 year of age (not defined in review; definition from trial manuscript: mild impairment: only occular sequelae; moderate neurological impairment: hemiparesis or a persistent seizure disorder and no more than a 3‐month developmental delay; severe neurological sequelae: microcephaly, spastic quadriplegia, chorioretinitis or blindness, and a serious developmental delay of > 3 months according to the DDST)

263 per 1000

(25/95)

216 per 1000 (132 to 353)

RR 0.82 (0.50 to 1.34)

202 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with design limitations (inadequate allocation concealment)

Imprecision (‐2): wide CIs crossing line of no effect; 1 small RCT

Abnormal neurodevelopment or death at approximately 1 year of age (not defined in review definition from trial manuscript as above)

463 per 1000

(44/95)

366 per 1000 (264 to 509)

RR 0.79 (0.57 to 1.10)

202 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with design limitations (inadequate allocation concealment)

Imprecision (‐2): wide CIs crossing line of no effect; 1 small RCT

Neonatal care: jaundice

Prophylactic phototherapy vs standard care for preventing jaundice in preterm or low birthweight infants (Okwundu 2012)

Neurodevelopmental impairment at 18 to 22 months (defined as blindness, severe hearing loss, and moderate or severe cerebral palsy)

305 per 1000

(275/902)

259 per 1000 (226 to 302)

RR 0.85 (0.74 to 0.99)

1804 (1 RCT)

MODERATE

Study limitations (‐1): 1 RCT with high risk of attrition bias

Neonatal care: hypoglycaemia

Dextrose gel vs placebo for treatment of hypoglycaemia in newborn infants (Weston 2016)

Major neurosensory disability at 2 years (defined as any of the following: legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, developmental delay/intellectual impairment (defined as DQ < 2 SD below the mean))

11 per 1000

(1/94)

67 per 1000 (8 to 543)

RR 6.27 (0.77 to 51.03)

184 (1 RCT)

VERY LOW

Study limitations (‐1): "Evidence is based on a single trial"

Imprecision (‐2):"Wide confidence intervals, low event rates and small sample sizes are suggestive of imprecision:

(graded by review authors themselves)

Developmental disability at 2 years (defined as cognitive, language, or motor score below ‐1 SD, or cerebral palsy, blindness, or deafness)

32/94

34/90

RR 1.11 (0.75 to 1.63)

184 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT with 78% follow‐up

Imprecision: wide CI crossing line of no effect; 1 small RCT

Neonatal care: parenteral feeding

Glutamine supplementation vs placebo to prevent morbidity and mortality in preterm infants (Moe‐Byrne 2016)

Neurodevelopmental impairment at 2 years post term (defined as BSID‐II MDI ≤ 85, PDI ≤ 85, cerebral palsy, blindness in 1 or both eyes, or hearing loss requiring amplification)

375 per 1000

(12/32)

401 per 1000
(221 to 720)

RR 1.07 (0.59 to 1.92)

72 (1 RCT)

LOW

Imprecision (‐2): "Total sample size = 72"

(graded by review authors themselves)

Abbreviations: BSID: Bayley Scales of Infant Development; CDI: Child Development Inventory; CI: confidence interval; DAS: Differential Ability Scales; DDST: Denver Developmental Screening Test; DQ: development quotient; GMDS: Griffiths Mental Development Scales; GMF: gross motor function; GRADE: Grades of Recommendation, Assessment, Development and Evaluation; IQ: intelligence quotient; MDI: Mental Development Index; PDI: Psychomotor Development Index; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation; VA: visual acuity; VABS: Vineland Adaptive Behaviour Scales; WASI: Wechsler Abbreviated Scale of Intelligence; WISC: Wechsler Intelligence Scale for Children.

Figures and Tables -
Table 10. Other composite outcomes that include cerebral palsy as a component
Table 11. Motor dysfunction

Intervention and comparison

Outcome

Assumed risk with comparator

Corresponding risk with intervention

Relative effect (95% CI)

Number of participants (trials)

Quality of the evidence (GRADE)

Comments

Neonatal care: asphyxia

Therapeutic hypothermia vs standard care for newborns with hypoxic‐ischaemic encephalopathy (Jacobs 2013)

Neuromotor delay (BSID PDI > 2 SD below mean) in survivors assessed at 18 to 24 months

349 per 1000

(104/298)

262 per 1000 (206 to 328)

RR 0.75 (0.59 to 0.94)

657 (6 RCTs)

HIGH

Not downgraded

Neonatal care: blood disorders

Erythropoietin vs placebo for preventing red blood cell transfusion in preterm and/or low birthweight infants (Ohlsson 2014)

PDI < 70 at 18 to 22 months' corrected age (in children examined)

133 per 1000

(6/45)

311 per 1000 (131 to 737)

RR 2.33 (0.98 to 5.53)

90 (1 RCT)

VERY LOW

Study limitations: 1 RCT at unclear risk of selection bias and high risk of attrition bias (˜73% follow‐up)

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with small sample size

Neonatal care: pulmonary hypertension

Endothelin receptor antagonists vs placebo for persistent pulmonary hypertension in term and late preterm infants (More 2016)

Adverse neurological outcomes at 6 months (defined as clinical or electrographically proven seizures, abnormal muscle tone, abnormal deep tendon reflexes, delayed motor milestones, or abnormal auditory brainstem response)

286 per 1000

(4/14)

20 per 1000 (0 to 343)

RR 0.07 (0.00 to 1.20)

37 (1 RCT)

LOW

Study limitation (‐1): 8/23 infants in the placebo group were excluded from analysis

Imprecision (‐1): single RCT, small sample size

(graded by review authors themselves)

Neonatal care: resuscitation

Room air vs 100% oxygen for resuscitation of infants at birth (Tan 2005)

Not walking in those followed up at 18 to 24 months

107 per 1000

(13/122)

110 per 1000 (4 to 240)

RR 1.03 (0.04 to 2.25)

213 (1 RCT)

VERY LOW

Study limitations (‐2): 1 qRCT with no blinding, and < 70% follow‐up

Imprecision (‐1): wide CI crossing line of no effect

Neonatal care: nitric oxide

Inhaled NO vs placebo for respiratory failure in preterm infants (studies of routine use in intubated preterm infants) (Barrington 2010)

BSID MDI or PDI < ‐ 2 SD at 2 years' corrected age

412 per 1000

(28/68)

231 per 1000 (136 to 383)

RR 0.56 (0.33 to 0.93)

138 (1 RCT)

MODERATE

Study limitations (‐1): 1 small RCT with 82% follow‐up

Inhaled nitric oxide vs control for respiratory failure in infants born at or near term (Finer 2006)

BSID PDI > 2 SD below the mean at 13 or 18 to 24 months

148 per 1000

(25/169)

161 per 1000 (86 to 300)

RR 1.09 (0.58 to 2.03)

283 (2 RCTs)

LOW

Study limitations (‐1): 1 RCT masking of allocation, masking of outcomes, and completeness of follow‐up 'can't tell'

Inconsistency (‐1): substantial heterogeneity (I² = 77%)

Note: error in review for Ninos 1996 data; intervention and control group data switched; this has been rectified in this analysis

Neonatal care: respiratory distress syndrome

Inositol supplementation (repeat doses) vs placebo in preterm infants at risk for or having respiratory distress syndrome (Howlett 2015)

Minor neural developmental impairment at 1 year corrected age (defined as sensorimotor abnormality and/or developmental delay)

137 per 1000

(10/73)

115 per 1000 (52 to 255)

RR 0.84 (0.38 to 1.86)

169 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at unclear risk of selection, performance, detection, and reporting bias, and at high risk of other bias

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with small sample size

Neonatal care: mechanical ventilation

Volume‐targeted vs pressure‐limited ventilation in the neonate (Wheeler 2010)

Gross Motor Developmental Issue (any definition) at 6 to 18 months (defined as gross motor delay)

172 per 1000

(11/64)

172 per 1000 (81 to 368)

RR 1.00 (0.47 to 2.14)

128 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

(post hoc analysis in review)

Neonatal care: bronchopulmonary dysplasia

Early (< 8 days) postnatal corticosteroids vs placebo for preventing chronic lung disease in preterm infants (Doyle 2014b)

BSID PDI < ‐ 2 SD at 18 to 22 months or 25 months

146 per 1000

(61/419)

170 per 1000 (124 to 233)

RR 1.17 (0.85 to 1.60)

842 (3 RCTs)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

BSID PDI < ‐ 2 SD in tested survivors at 18 to 22 months or 25 months

232 per 1000

(61/263)

271 per 1000 (202 to 364)

RR 1.17 (0.87 to 1.57)

528 (3 RCTs)

MODERATE

Imprecision (‐1): wide CI crossing line of no effect

Late (> 7 days) postnatal corticosteroids vs placebo or no treatment for chronic lung disease in preterm infants (Doyle 2014)

BSID PDI < ‐ 2 SD at 1 year corrected age

180 per 1000

(11/61)

141 per 1000 (61 to 325)

RR 0.78 (0.34 to 1.80)

118 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with small sample size

BSID PDI < ‐ 2 SD in survivors assessed at 1 year corrected age

256 per 1000

(11/43)

171 per 1000 (77 to 384)

RR 0.67 (0.30 to 1.50)

90 (1 RCT)

LOW

Imprecision (‐2): wide CI crossing line of no effect; 1 RCT with small sample size

Early inhaled corticosteroids vs placebo for preventing chronic lung disease in ventilated very low birthweight preterm neonates (Shah 2012)

Mean developmental index on BSID‐II < 2 SD of the mean (age not reported in review;from trial manuscript: 3 years)

143 per 1000

(4/28)

179 per 1000 (53 to 596)

RR 1.25 (0.37 to 4.17)

56 (1 RCT)

VERY LOW

Study limitations (‐1): 1 RCT at unclear risk of selection bias and detection bias

Imprecision (‐2): wide CI crossing line of no effect; 1 small RCT

Neonatal care: other

Early developmental intervention vs standard follow‐up post hospital discharge to prevent motor and cognitive impairment in preterm infants (Spittle 2015)

Motor outcome at school age (5 years) (defined as low score on Movement ABC)

378 per 1000

(51/135)

423 per 1000 (329 to 544)

RR 1.12 (0.87 to 1.44)

333 (2 RCTs)

LOW

Study limitations (‐1): 2 RCTs at high risk of attrition bias and unclear risk of performance bias

Imprecision (‐1): wide CI crossing line of no effect

Abbreviations: BSID: Bayley Scales of Infant Development; CI: confidence interval; GRADE: Grades of Recommendation, Assessment, Development and Evaluation; MDI: Mental Development Index; Movement ABC: Movement Assessment Battery for Children; PDI: Psychomotor Development Index; qRCT: quasi‐randomised controlled trial; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation

Figures and Tables -
Table 11. Motor dysfunction