Protocol citation

Overview outcomes pre‐specified in protocol

Abiramalatha T, Thomas N, Gupta V, Viswanathan A, McGuire W. High versus standard volumes of enteral feeds for preterm or low birth weight infants (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 10.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcomes assessed after 12 months post term: neurological evaluations; developmental scores; and classifications of disability, including auditory and visual disability. We will define neurodevelopmental impairment as the presence of 1 or more of the following: non‐ambulant cerebral palsy; developmental quotient > 2 SD below the population mean; and blindness (VA less than 6/60) or deafness (any hearing impairment requiring — or unimproved by — amplification)

Amari S, Shahrook S, Ota E, Mori R. Branched‐chain amino acid supplementation for improving nutrition in term and preterm neonates (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 7.

Primary outcomes pre‐specified include:

1. Neurological development

   1. Major neurodevelopmental disability after 18 months' post‐term age

   2. Cerebral palsy (yes/no)

   3. Developmental delay (> 2 SD below the mean in a validated mental development test) or intellectual impairment (> 2 SD below the mean in a validated intelligence test) (yes/no)

   4. Blindness (vision < 6/60 in both eyes) (yes/no)

   5. Sensorineural deafness (requiring amplification) (yes/no)

Askie LM, Darlow BA, Davis PG, Finer N, Stenson B, Vento M, Whyte R. Effects of targeting higher versus lower arterial oxygen saturations on death or disability in preterm infants (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 7.

Primary outcomes pre‐specified include:

1. Composite outcome of death or major disability by 18 to 24 months' corrected age (gestational age plus chronological age)

Secondary outcomes pre‐specified include:

1. Major disability by 18 to 24 months' corrected age (gestational age plus chronological age)

2. Cerebral palsy with GMFCS level 2 or higher, or MACS level 2 or higher at 18 to 24 months' corrected age (gestational age plus chronological age)

Choo YM, Ahmad Kamar A, Tengku Kamalden TAF, Looi ML, Tan K, Lai NM. Lutein and zeaxanthin for reducing morbidity and mortality in preterm infants (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 5.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome assessed at 18 months to 28 months (Newman 2012). We will accept any of the following outcomes alone or in combination:cerebral palsy, mental retardation (BSID MDI < 70), and hearing deficit (aided or < 60 dB on audiometric testing) or assessment via use of a validated cognitive/language/behavioural/social interaction/adaptive test (Albers 2007)

Dawson JA, Davis PG, Foster JP. Routine oro/nasopharyngeal suction versus no suction in the delivery room (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 1.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome (rates ofcerebral palsy on physician assessment; developmental delay, i.e. DQ > 2 SD < the mean on validated assessment tools, e.g. BSID MDI)

Foster JP, Buckmaster A, Sinclair L, Lees S, Guaran R. Nasal continuous positive airway pressure (nCPAP) for term neonates with respiratory distress (Protocol). Cochrane Database of Systematic Reviews 2015, Issue 11.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental disability (after at least 18 months' postnatal age) defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay > 2 SD below population mean on a standardised test of development, blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification)

Foster JP, Taylor C, Bredemeyer SL. Topical anaesthesia for needle‐related pain in newborn infants (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 1.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental disability (after at least 18 months' postnatal age) defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay > 2 SD below population mean on a standardised test of development

Good M, Jones LJ, Osborn DA, Abdel‐Latif ME. Transfusion of fresh versus non‐fresh (older) red blood cell in neonates (Protocol). Cochrane Database of Systematic Reviews 2015, Issue 11.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental disability to at least 18 months' postnatal age (defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay > 2 SD below population mean on a standardised test of development, blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification) at any time after term corrected)

Gordon A, Greenhalgh M, McGuire W. Early planned removal versus expectant management of peripherally inserted central catheters to prevent infection in newborn infants (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcomes assessed after 12 months post term using validated tools: neurological evaluations; developmental scores; and classifications of disability, including auditory and visual disability. We will define neurodevelopmental impairment as the presence of 1 or more of the following: non‐ambulant cerebral palsy; DQ > 2 SD below the population mean; and blindness (VA < 6/60) or deafness (any hearing impairment requiring or unimproved by amplification)

2. Death or neurological impairment assessed after 12 months post term

Gordon A, Greenhalgh M, McGuire W. Early planned removal of umbilical venous catheters to prevent infection in newborn infants (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcomes assessed after 12 months post term using validated tools: neurological evaluations; developmental scores; and classifications of disability, including auditory and visual disability. We will define neurodevelopmental impairment as the presence of 1 or more of the following: non‐ambulant cerebral palsy; DQ > 2 SD below the population mean; and blindness (VA < 6/60) or deafness (any hearing impairment requiring or unimproved by amplification)

2. Death or neurological impairment assessed after 12 months post term

Green DS, Abdel‐Latif ME, Jones LJ, Osborn DA. Pharmacological interventions for prevention and treatment of upper gastrointestinal bleeding in newborn infants (Protocol). Cochrane Database of Systematic Reviews 2015, Issue 7.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental disability (defined as neurological abnormality including cerebral palsy on clinical examination or global developmental delay (2 or more SD below population mean on BSID or GMDS at any time after term corrected at 1 year, 18 months', 2 years', and 5 years' postnatal age)

Han S, Yu Z, Guo X, Dong X, Chen X, Soll R. Intratracheal instillation of corticosteroids using surfactant as a vehicle for the prevention of chronic lung disease in preterm infants with respiratory distress syndrome (Protocol). Cochrane Database of Systematic Reviews 2011, Issue 4

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome at a later time point (> 1 year post‐conceptional age). Neurodevelopmental impairment is defined as the presence of cerebral palsy and/or mental retardation (BSID MDI < 70) and/or legal blindness (< 20/200 VA) and or deafness (aided or < 60 dB on audiometric testing)

Hegarty JE, Harding JE, Crowther CA, Brown J, Alsweiler J. Oral dextrose gel for the prevention of hypoglycaemia in newborn infants (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 4.

Primary outcomes pre‐specified include:

1. Major neurological disability at 2 years of age or greater (any of legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, or developmental delay/intellectual impairment (defined as a DQ or IQ lower than 2 SD below the mean))

Secondary outcomes pre‐specified include:

1. Cerebral palsy and severity at 2 years of age or older

Hyttel‐Sorensen S, Støy Saem L, Greisen G, Als‐Nielsen B, Gluud C. Cerebral near‐infrared spectroscopy monitoring for prevention of brain injury in very preterm infants (Protocol). Cochrane Database of Systematic Reviews 2015, Issue 2.

Primary outcomes pre‐specified include:

1. Major neurodevelopmental disability:

   1. Cerebral palsy

   2. Developmental delay or intellectual impairment:

      1. BSID or GMDS assessment > 2 SD below the mean or intellectual impairment (IQ > 2 SD below mean)

      2. Neuromotor development (BSID ‐ PDI) assessed in survivors

      3. Mental development (BSID ‐ MDI) assessed in survivors

   3. Blindness (vision < 6/60 in both eyes)

Jauncey‐Cooke J, Bogossian F, Hough JL, Schibler A, Davies MW, Grant CA, Gibbons K, East CE. Lung recruitment manoeuvres for reducing respiratory morbidity in mechanically ventilated neonates (Protocol). Cochrane Database of Systematic Reviews 2012, Issue 7.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental impairment: cerebral palsy, sensorineural hearing loss, visual impairment or developmental delay (e.g. GMDS, BSID) assessed at 12 to 24 months' corrected age, 2 years, or 5 years

Kaempfen S, Neumann RP, Jost K, Schulzke SM. Beta‐blockers for prevention and treatment of retinopathy of prematurity in preterm infants (Protocol). Cochrane Database of Systematic Reviews 2015, Issue 9.

Secondary outcomes pre‐specified include:

1. Adverse neurodevelopmental outcomes at 18 to 24 months' corrected age

   1. Cerebral palsy

   2. Moderate to severe developmental delay as assessed by validated neurodevelopmental tests such as BSID

Kent A, Kecskes Z. Magnesium sulfate for term infants following perinatal asphyxia (Protocol). Cochrane Database of Systematic Reviews 2003, Issue 2.

Primary outcomes pre‐specified include:

1. Severe neurodevelopmental disability at or equal to 12 months of age or more. Severe neurodevelopmental disability is defined as cerebral palsy, developmental delay (DQ < 70), or blindness (VA < 6/60 in both eyes), or any combination of these disabilities

Kulasekaran K, Sargent PH, Flenady V. Milrinone for the treatment of cardiac dysfunction in neonates (Protocol). Cochrane Database of Systematic Reviews 2004, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome (neurodevelopmental outcome assessed by a standardised and validated assessment tool and/or a child developmental specialist) at any age reported (outcome data will be grouped at 12, 18, 24 months if available) ‐ cerebral palsy, developmental delay, blindness, sensorineural deafness

Lai NM, Ahmad Kamar A, Choo YM, Kong JY, Ngim CF. Fluid supplementation for neonatal unconjugated hyperbilirubinaemia (Protocol). Cochrane Database of Systematic Reviews 2015, Issue 9.

Primary outcomes pre‐specified include:

1. Proportion of infants with moderate or severe cerebral palsy, defined as a non‐progressive disorder with abnormal muscle tone in at least 1 arm or leg that was associated with abnormal control of movement or posture and a modified GMFCS score (Palisano 2008) ≥ 2 (Rosenbaum 2007), measured at predefined intervals, e.g. at 6, 12, 18, and 24 months

Secondary outcomes pre‐specified include:

1. Proportion of infants with motor impairment, as indicated by a score of 2 or higher in the modified GMFCS evaluation (Palisano 2008)

Lui K, Foster JP, Davis PG, Ching SK, Oei JL, Osborn DA. Higher versus lower oxygen concentrations titrated to target oxygen saturations during resuscitation of preterm infants at birth (Protocol). Cochrane Database of Systematic Reviews 2012, Issue 11.

Primary outcomes pre‐specified include:

1. Neurodevelopmental disability (after > 18 months' postnatal age):

   1. Neurological abnormality including cerebral palsy on clinical examination, developmental delay > 2 SD below population mean on any standard test of development

   2. Blindness (VA < 6/60)

   3. Deafness (any hearing impairment requiring amplification)

Malhotra A, Veldman A. Recombinant activated Factor VII for prevention and treatment of intraventricular haemorrhage in neonates (Protocol). Cochrane Database of Systematic Reviews 2011, Issue 3.

Primary outcomes pre‐specified include:

1. Severe neurodevelopmental disability as defined by cerebral palsy, low developmental scores (DQ < 2 SD or untestable), blindness, or any combination of these using validated assessment tools at 18 or 24 months: neurological examinations, developmental scores (BSID, etc.)

McCarthy LK, Davis PG, O'Donnell CPF. Nasal airways (single or double prong, long or short) for neonatal resuscitation (Protocol). Cochrane Database of Systematic Reviews 2011, Issue 5.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome (rates of cerebral palsy on physician assessment; developmental delay, i.e. DQ > 2 SD < the mean on validated assessment tools, e.g. BSID MDI)

Molloy EJ, McCallion N, O'Donnell CPF, Davis PG. Heliox for prevention of morbidity and mortality in ventilated newborn infants (Protocol). Cochrane Database of Systematic Reviews 2008, Issue 3.

Secondary outcomes pre‐specified include:

1. Death or long‐term (< 18 months) major neurodevelopmental disability (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)

Neary E, Ni Ainle F, El‐Khuffash A, Cotter M, Kirkham C, McCallion N. Plasma transfusion to prevent intraventricular haemorrhage in very preterm infants (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 9.

Primary outcomes pre‐specified include:

1. Neurodevelopmental disability at 2 years' postnatal age, defined as neurological abnormality on clinical examination, including cerebral palsy, developmental delay > 2 SD below the population mean on any standard test of development, blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification) at any time after 2 years' corrected age

O'Donnell CPF, Davis PG, Morley CJ. Endotracheal intubation versus face mask for newborns resuscitated with positive pressure ventilation at birth (Protocol). Cochrane Database of Systematic Reviews 2004, Issue 4.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome (rates ofcerebral palsy on physician assessment, developmental delay, i.e. IQ 2 SD < the mean on validated assessment tools, e.g. BSID MDI)

O'Donnell CPF, Davis PG, Morley CJ. Manual ventilation devices for neonatal resuscitation (Protocol). Cochrane Database of Systematic Reviews 2004, Issue 3.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome (rates of cerebral palsy on physician assessment, developmental delay, i.e. IQ 2 SD < the mean on validated assessment tools, e.g. BSID MDI)

Onland W, De Jaegere APMC, Offringa M, van Kaam A. Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 1.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental sequelae, assessed after at least 1 year corrected gestational age and before a corrected gestational age of 4 years, and at the latest reported time point, including cerebral palsy and BSID (MDI)

Onyango AB, Suresh G, Were F. Intermittent phototherapy versus continuous phototherapy for neonatal jaundice (Protocol). Cochrane Database of Systematic Reviews 2009, Issue 4.

Primary outcomes pre‐specified include:

1. Kernicterus defined as either the pathological finding of deep‐yellow staining of neurons and neuronal necrosis of the basal ganglia and brainstem nuclei or acute or chronic neurological deficit including athetoid cerebral palsy, impaired upward gaze and deafness, isolated conditions like auditory neuropathy or dyssynchrony, and subtle bilirubin‐induced neurological dysfunction

Pierro M, Thébaud B, Soll R. Mesenchymal stem cells for the prevention and treatment of bronchopulmonary dysplasia in preterm infants (Protocol). Cochrane Database of Systematic Reviews 2015, Issue 11.

Secondary outcomes pre‐specified include:

1. Cerebral palsy at 18 to 24 months' corrected age

2. Neurodevelopmental outcome at approximately 2 years' corrected age (acceptable range 18 months to 28 months) including cerebral palsy, delayed neurodevelopment (BSID MDI < 70), legal blindness (< 20/200 VA), and hearing deficit (aided or < 60 dB on audiometric testing). We will define the composite outcome 'neurodevelopmental impairment' as having any 1 of the aforementioned deficits

Rivas‐Fernandez M, Roqué i Figuls M, Tobias A, Balaguer A. Different strains of probiotics for preventing morbidity and mortality in preterm infants: a network meta‐analysis (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 8.

Secondary outcomes pre‐specified include:

1. Neurodevelopment impairment (i.e. rates of cerebral palsy, cognitive delay, deafness, blindness or their composite reported at 18 months' corrected age or later)

Romantsik O, Calevo MG, Bruschettini M. Head midline position for preventing the occurrence or extension of germinal matrix‐intraventricular hemorrhage in preterm infants (Protocol). Cochrane Database of Systematic Reviews 2016, Issue 9.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcomes (yes/no): cerebral palsy on physician assessment, developmental delay (i.e. IQ 2 SD below the mean on validated assessment tools such as BSID MDI) (Bayley 1993; Bayley 2006)

2. Major neurodevelopmental disability: cerebral palsy, developmental delay (BSID MDI (Bayley 1993; Bayley 2006) or GMDS (Griffiths 1954) assessment > 2 SDs below the mean), intellectual impairment (IQ > 2 SDs below the mean), blindness (vision < 6/60 in both eyes), or sensorineural deafness requiring amplification (Jacobs 2013). We plan to evaluate each of these components as a separate outcome and to extract data on each long‐term outcome from studies that evaluated children after 18 months' chronological age. We will separately assess data on children 18 to 24 months of age and on those 3 to 5 years of age

Seliem W, Bhutta ZA, Soll R, McGuire W. Topical emollient therapy for preventing infection in preterm infants in low‐ or middle‐income countries (Protocol). Cochrane Database of Systematic Reviews 2007, Issue 3.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcomes at > 12 months post term (measured using validated assessment tools) and classifications of disability, including auditory and visual disability. The composite outcome "severe neurodevelopmental disability" will be defined as any 1 or combination of the following: non‐ambulant cerebral palsy, severe developmental delay, auditory and visual impairment

Shah D, Tracy M. Cutaneous antisepsis for prevention of intravascular catheter–associated infection in newborn infants (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 3.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome: neurodevelopmental outcome at approximately 2 years' corrected age (acceptable range 18 months to 28 months) including cerebral palsy, significant mental developmental delay (BSID MDI < 70), legal blindness (< 20/200 VA), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome "neurodevelopmental impairment" was defined as having any 1 of the aforementioned deficits

Sinn JKH, Kumar K, Osborn DA, Bolisetty S. Higher versus lower amino acid intake in parenteral nutrition for newborn infants (Protocol). Cochrane Database of Systematic Reviews 2006, Issue 2.

Primary outcomes pre‐specified include:

1. Neurodevelopmental disability at at least 18 months' postnatal age (defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay > 2 SD below population mean on a standardised test of development, blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification) at any time after term corrected)

Secondary outcomes pre‐specified include:

1. Individual components of neurodevelopment at at least 18 months' postnatal age:

   1. Cerebral palsy on clinical examination

   2. Developmental delay > 2 SD below population mean on a standardised test of development

   3. Blindness (VA < 6/60)

   4. Deafness (any hearing impairment requiring amplification) at any time after term corrected

Van Rostenberghe H, Ho JJ, Quah BS, Noraida R. The effects of thyroxine on end organ damage in asphyxiated neonates (Protocol). Cochrane Database of Systematic Reviews 2009, Issue 4.

Primary outcomes pre‐specified include:

1. Any neurodevelopmental disability assessed at 12 months or more of age:

   1. Presence of no/minor or major disabilities

   2. Presence ofcerebral palsy

   3. Any objective quantitative assessments of neurodevelopmental assessment that are internationally recognised

Xiong T, Chen H, Mu D. Effect of pre‐exchange albumin infusion on neonatal hyperbilirubinaemia and long‐term developmental outcomes (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 2.

Primary outcomes pre‐specified include:

1. Neurological deficits consistent with kernicterus at 2 years of age (including separate analysis of each component): athetoid cerebral palsy, impaired upward gaze and deafness, auditory neuropathy or dys‐synchrony (ABR abnormality), dental dysplasia, and subtle bilirubin‐induced neurological dysfunction

Xiong T, Li H, Zhao J, Dong W, Qu Y, Wu T, Mu D. Hyperbaric oxygen for term newborns with hypoxic ischemic encephalopathy (Protocol). Cochrane Database of Systematic Reviews 2011, Issue 8.

Primary outcomes pre‐specified include:

1. Long‐term (> 18 months) major neurodevelopmental disabilities among all participants or survivors (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)

Yu B, Li S, Zhou D, Davis PG. Subcutaneous reservoir drainage versus ventriculoperitoneal shunt for the treatment of posthemorrhagic hydrocephalus in preterm infants (Protocol). Cochrane Database of Systematic Reviews 2009, Issue 3.

Primary outcomes pre‐specified include:

1. The incidence rates of death or neurodevelopmental disability in infancy (> 12 months' postnatal age). Neurodevelopmental disability includes developmental delay (e.g. the score of BSID < 2 SD below the mean indicates developmental delay), cerebral palsy, blindness, deafness, and any other neurodevelopmental abnormalities

Yu Z, Guo X, Han S, Lu J, Sun Q. Erythropoietin for term and late preterm infants with hypoxic ischemic encephalopathy (Protocol). Cochrane Database of Systematic Reviews 2010, Issue 1.

Primary outcomes pre‐specified include:

1. The primary outcome measure will be either death or long‐term (1 year or 18 months) major neurodevelopmental disability (cerebral palsy, developmental delay (BDIS 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)

Secondary outcomes pre‐specified include:

1. Each component of the primary outcome:

   1. Cerebral palsy

   2. Developmental delay or intellectual impairment

   3. Blindness

   4. Sensorineural deafness requiring amplification patient

Yu Z, Sun Q, Han S, Lu J, Ohlsson A, Guo X. Erythropoietin for preterm infants with hypoxic ischaemic encephalopathy (Protocol). Cochrane Database of Systematic Reviews 2012, Issue 12.

Primary outcomes pre‐specified include:

1. Either death (at 28 days and at discharge) or long‐term (1 year or 24 months' corrected age) intellectual impairment (IQ > 2 SD below mean), blindness (vision < 6/60 in both eyes), sensorineural deafness requiring amplification

Secondary outcomes pre‐specified include:

1. Each component of the primary outcome:

   1. Death at 28 days and at discharge

   2. Cerebral palsy at > 1 year (the criterion for the diagnosis of cerebral palsy was a fixed motor deficit diagnosed by a neurologist)

   3. Developmental delay (BSID or GMDS > 2 SD below the mean) or intellectual impairment (IQ > 2 SD below mean) at 1 year or 24 months' corrected age

   4. Blindness (vision < 6/60 in both eyes) at 1 year or 24 months' corrected age

   5. Sensorineural deafness requiring amplification patient at 1 year or 24 months' corrected age

Review citation

Overview outcomes pre‐specified in review with no outcome data

Main conclusion(s) of review

Abdel‐Latif ME, Osborn DA. Intratracheal Clara cell secretory protein (CCSP) administration in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2011, Issue 5.

Primary outcomes pre‐specified include:

1. Neurodevelopmental disability ≥ 18 months' postnatal age (defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay > 2 SD below population mean on a standardised test of development, blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification) at any time after term corrected)

"There are insufficient data to determine the role of rhCC10 in clinical practice. Further studies are required to determine if rhCC10 reduces lung inflammation in infants at risk of CLD, and to determine dose and dosing strategy"

Abdel‐Latif ME, Osborn DA. Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2011, Issue 7.

Primary outcomes pre‐specified include:

1. Neurodevelopmental disability ≥ 18 months' postnatal age (defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay > 2 SD below population mean on a standardised test of development, blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification) at any time after term corrected)

"There is evidence from a single small trial that LMA surfactant administration in preterm infants ≥ 1200 g with established RDS may have a short term effect in reducing oxygen requirements although the study is underpowered to detect important clinical effects. Adequately powered trials are required to determine the effect of LMA surfactant administration for prevention or treatment of RDS in preterm infants. LMA surfactant administration should be limited to clinical trials"

Abdel‐Latif ME, Osborn DA. Pharyngeal instillation of surfactant before the first breath for prevention of morbidity and mortality in preterm infants at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2011, Issue 3.

Primary outcomes pre‐specified include:

1. Neurodevelopmental disability at ≥ 18 months' postnatal age, defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay of > 2 SD below the population mean on a standardised test of development, blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification) at any time after the age was term corrected

No included trials.

"There were no data from randomised controlled or quasi‐randomised trials that evaluated the effect of intrapartum instillation of pharyngeal surfactant before the first breath. Evidence from animal and observational human studies suggest that pharyngeal instillation of surfactant before the first breath is potentially safe, feasible and may be effective. Well designed trials are needed"

Abdel‐Latif ME, Osborn DA. Nebulised surfactant in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2012, Issue 10.

Primary outcomes pre‐specified include:

1. Neurodevelopmental disability assessed at 18 months' postnatal age or later defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay > 2 SD below population mean on a standardised test of development, blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification) at any time after term corrected

"There are insufficient data to support or refute the use of nebulised surfactant in clinical practice. Adequately powered trials are required to determine the effect of nebulised surfactant administration for prevention or early treatment of RDS in preterm infants. Nebulised surfactant administration should be limited to clinical trials"

Ainsworth S, McGuire W. Percutaneous central venous catheters versus peripheral cannulae for delivery of parenteral nutrition in neonates. Cochrane Database of Systematic Reviews 2015, Issue 10.

Primary outcomes pre‐specified include:

1. Neurodevelopmental outcomes during infancy and beyond, using validated assessment tools, such as BSID, and classifications of disability, including auditory and visual disability. Severe neurodevelopmental disability was defined as any one or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), or auditory and visual impairment

"Data from one small trial suggest that use of percutaneous central venous catheters to deliver parenteral nutrition increases nutrient input. The significance of this in relation to long‐term growth and developmental outcomes is unclear. Three trials suggest that use of percutaneous central venous catheters decreases the number of catheters/cannulae needed to deliver nutrition. No evidence suggests that percutaneous central venous catheter use increases risks of adverse events, particularly invasive infection, although none of the included trials was large enough to rule out an effect on uncommon severe adverse events such as pericardial effusion"

Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database of Systematic Reviews 2002, Issue 3.

Outcomes pre‐specified include:

1. Incidence ofcerebral palsy.

"Although the results show a significant reduction in the need for exchange transfusion in those treated with intravenous immunoglobulin, the applicability of the results is limited. The number of studies and infants included is small and none of the three included studies was of high quality. The protocols of two of the studies mandated the use of early exchange transfusion, limiting the generalizability of the results. Further well designed studies are needed before routine use of intravenous immunoglobulin can be recommended for the treatment of isoimmune haemolytic jaundice"

Anabrees J, AlFaleh K. Fluid restriction and prophylactic indomethacin versus prophylactic indomethacin alone for prevention of morbidity and mortality in extremely low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 7.

Secondary outcomes pre‐specified include:

1. Neurosensory impairment defined as rates of cerebral palsy, cognitive delay, deafness, blindness at 18 to 24 months' corrected age as per BSID score (Bayley 1993)

2. The composite of death or neurosensory impairment at 18 to 24 months' corrected age

No included trials

"We found no randomized controlled trials to investigate the possible interaction between fluid restriction and indomethacin prophylaxis versus indomethacin prophylaxis alone in ELBW infants. A well‐designed randomized trial is needed to address this question"

Austin N, Cleminson J, Darlow BA, McGuire W. Prophylactic oral/topical non‐absorbed antifungal agents to prevent invasive fungal infection in very low birth weight infants. Cochrane Database of Systematic Reviews 2015, Issue 10.

Primary outcomes pre‐specified include:

1. Neurodevelopmental outcomes assessed beyond infancy (neurological evaluations, developmental scores, and classifications of disability, including auditory and visual disability, non‐ambulant cerebral palsy, developmental delay); and cognitive and educational outcomes at 5 years or older (IQ and/or indices of educational achievement measured using a validated tool including school examination results)

"The finding of a reduction in risk of invasive fungal infection in very low birth weight infants treated with oral/topical non‐absorbed antifungal prophylaxis should be interpreted cautiously because of methodological weaknesses in the included trials. Further large randomised controlled trials in current neonatal practice settings are needed to resolve this uncertainty. These trials might compare oral/topical non‐absorbed antifungal agents with placebo, with each other, or with systemic antifungal agents and should include an assessment of effect on long‐term neurodevelopmental outcomes"

Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 2012, Issue 11.

Secondary outcomes pre‐specified include:

1. Cerebral palsy

2. Neurodevelopmental outcome at approximately 2 years' corrected age (acceptable range 18 months to 28 months) including cerebral palsy, mental retardation (BSID MDI < 70), legal blindness (< 20/200 VA), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome "neurodevelopmental impairment" will be defined as having any 1 of the aforementioned deficits

"Early selective surfactant administration given to infants with RDS requiring assisted ventilation leads to a decreased risk of acute pulmonary injury (decreased risk of pneumothorax and pulmonary interstitial emphysema) and a decreased risk of neonatal mortality and chronic lung disease compared to delaying treatment of such infants until they develop worsening RDS"

Rivas‐Fernandez M, Roqué i Figuls M, Diez‐Izquierdo A, Escribano J, Balaguer A. Infant position in neonates receiving mechanical ventilation. Cochrane Database of Systematic Reviews 2016, Issue 11.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcomes at age 2 years: rates of cerebral palsy as assessed by physician, developmental delay (i.e. IQ < 2 SD) on validated assessment tools (e.g. the S‐B Intelligence Scale or others), or sensory impairment

"This update of our last review in 2013 supports previous conclusions. Evidence of low to moderate quality favours the prone position for slightly improved oxygenation in neonates undergoing mechanical ventilation. However, we found no evidence to suggest that particular body positions during mechanical ventilation of the neonate are effective in producing sustained and clinically relevant improvement"

Balain M, Oddie SJ, McGuire W. Antimicrobial‐impregnated central venous catheters for prevention of catheter‐related bloodstream infection in newborn infants. Cochrane Database of Systematic Reviews 2015, Issue 9.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcomes assessed > 12 months' corrected age using validated tools: neurological evaluations; developmental scores; and classifications of disability, including auditory and visual disability. We will define neurodevelopmental impairment as the presence of 1 or more of the following: non‐ambulant cerebral palsy; DQ > 2 SD below the population mean; and blindness (VA < 6/60) or deafness (any hearing impairment requiring or unimproved by amplification)

2. Death or neurological impairment assessed > 12 months' corrected age

"Although the data from one small trial indicates that antimicrobial‐impregnated central venous catheters might prevent catheter‐related bloodstream infection in newborn infants, the available evidence is insufficient to guide clinical practice. A large, simple and pragmatic randomised controlled trial is needed to resolve on‐going uncertainty"

Bassler D, Kreutzer K, McNamara P, Kirpalani H. Milrinone for persistent pulmonary hypertension of the newborn. Cochrane Database of Systematic Reviews 2010, Issue 11.

Primary outcomes pre‐specified include:

1. Neurodevelopment (assessed by the presence of cerebral palsy, cognitive delay, blindness or deafness, and the BSID‐II) assessed > 18 months of life

"The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs. Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or, in well resourced countries, should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone"

Basuki F, Hadiati DR, Turner T, McDonald S, Hakimi M. Dilute versus full strength formula in exclusively formula‐fed preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2013, Issue 11.

Secondary outcomes pre‐specified include:

1. Neurodevelopment:

   1. Death or severe neurodevelopmental disability defined as any 1 or a combination of the following: non‐ambulant cerebral palsy; developmental delay (DQ < 70); auditory and visual impairment (each component will be analysed individually as well as part of the composite outcome)

   2. Neurodevelopmental scores in survivors aged ≥ 12 months of age measured using validated assessment tools

   3. Cognitive and educational outcomes in survivors aged > 5 years old

"There is evidence from three small, old trials at unclear risk of bias that use of dilute formula in preterm or low birth weight formula‐fed infants leads to an important reduction in the time taken for these infants to attain an adequate energy intake. There was no evidence of important differences in feeding intolerance. The impact on serious gastrointestinal problems, including necrotising enterocolitis, was not reported. Further randomised trials are needed to confirm these results"

Beveridge CJE, Wilkinson AR. Sodium bicarbonate infusion during resuscitation of infants at birth. Cochrane Database of Systematic Reviews 2006, Issue 1.

Secondary outcomes pre‐specified include:

1. Long‐term severe neurodevelopmental disability reported at any time during follow‐up. Defined as any of cerebral palsy, cognitive delay (score > 2 SD below mean for a recognised psychometric test e.g. BSID), blindness, and deafness

"There is insufficient evidence from randomised controlled trials to determine whether the infusion of sodium bicarbonate reduces mortality and morbidity in infants receiving resuscitation in the delivery room at birth"

Bhola K, Foster JP, Osborn DA. Chest shielding for prevention of a haemodynamically significant patent ductus arteriosus in preterm infants receiving phototherapy. Cochrane Database of Systematic Reviews 2015, Issue 11.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental disability (after at least 18 months' postnatal age) defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay > 2 SD below population mean on a standardised test of development, blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification at any time after term corrected age)

"The available evidence is very low quality and insufficient to assess the safety or efficacy of chest shield during phototherapy for prevention of PDA in preterm infants. Further trials of chest shielding are warranted, particularly in settings where infants are not receiving prophylactic or early echocardiographic targeted cyclo‐oxygenase inhibitors for PDA"

Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database of Systematic Reviews 2004, Issue 3.

Primary outcomes pre‐specified include:

1. Significant neurodevelopmental impairment (any 1 or combination of: cerebral palsy, developmental delay DQ > 2 SD, blindness) assessed at 1 to 2 years of age

2. Death or significant neurodevelopmental impairment (any 1 or combination of: cerebral palsy, developmental delay DQ > 2 SD, blindness) assessed at 1 to 2 years of age

"At present there is little evidence from randomised controlled trials to support the use of any of the anticonvulsants currently used in the neonatal period. In the literature, there remains a body of opinion that seizures should be treated because of the concern that seizures in themselves may be harmful, although this is only supported by relatively low grade evidence (Levene 2002; Massingale 1993). Development of safe and effective treatment strategies relies on future studies of high quality (randomised controlled trials with methodology that assures validity) and of sufficient size to have the power to detect clinically important reductions in mortality and severe neurodevelopmental disability in addition to any short term reduction in seizure burden"

Bottino M, Cowett RM, Sinclair JC. Interventions for treatment of neonatal hyperglycemia in very low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 10.

Primary outcomes pre‐specified include:

1. Neurodevelopmental impairment, defined as presence of 1 or more of the following: cerebral palsy, MDI or PDI < 70, blindness or deafness assessed between 18 and 24 months' postmenstrual age or with latest assessment up to 24 months' postmenstrual age

"Evidence from randomized trials in hyperglycemic VLBW neonates is insufficient to determine the effects of treatment on death or major morbidities. It remains uncertain whether the hyperglycemia per se is a cause of adverse clinical outcomes or how the hyperglycemia should be treated. Much larger randomized trials in hyperglycemic VLBW neonates that are powered on clinical outcomes are needed in order to determine whether, and how, the hyperglycemia should be treated"

Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 4.

Primary outcomes pre‐specified include:

1. Mortality, combined outcome at 18 months including mortality (mortality, bronchopulmonary dysplasia, blindness, mental retardation, or cerebral palsy), and combined outcome at 18 months excluding mortality (bronchopulmonary dysplasia, blindness, mental retardation, or cerebral palsy)

"Vitamin E supplementation in preterm infants reduced the risk of intracranial hemorrhage but increased the risk of sepsis. In very low birth weight infants, vitamin E increased the risk of sepsis, and reduced the risk of severe retinopathy and blindness among those examined. Evidence does not support the routine use of vitamin E supplementation by intravenous route at high doses or aiming at serum tocopherol levels greater than 3.5 mg/dl"

Brown JVE, Embleton ND, Harding JE, McGuire W. Multi‐nutrient fortification of human milk for preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 5.

Primary outcomes pre‐specified include:

1. Neurodevelopmental outcomes assessed after 12 months post term: neurological evaluations, developmental scores, and classifications of disability, including auditory and visual disability. We defined neurodevelopmental impairment as the presence of 1 or more of the following: non‐ambulantcerebral palsy, DQ > 2 SD below the population mean, and blindness (VA < 6/60) or deafness (any hearing impairment requiring or unimproved by amplification)

"Limited available data do not provide strong evidence that feeding preterm infants with multi‐nutrient fortified breast milk compared with unfortified breast milk affects important outcomes, except that it leads to slightly increased in‐hospital growth rates"

Brown JVE, Moe‐Byrne T, McGuire W. Glutamine supplementation for young infants with severe gastrointestinal disease. Cochrane Database of Systematic Reviews 2014, Issue 12.

Primary outcomes pre‐specified include:

1. Neurodevelopmental outcomes assessed beyond infancy (neurological evaluations, developmental scores, and classifications of disability including auditory and visual disability, non‐ambulant cerebral palsy, and developmental delay) and cognitive and educational outcomes (IQ and/or indices of educational achievement measured using a validated tool, including school examination results)

"The available data from randomised controlled trials do not suggest that glutamine supplementation has any important benefits for young infants with severe gastrointestinal disease"

Bruschettini M, Romantsik O, Zappettini S, Banzi R, Ramenghi LA, Calevo MG. Antithrombin for the prevention of intraventricular hemorrhage in very preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 3.

Secondary outcomes pre‐specified include:

1. Major neurodevelopmental disability assessed at age of 12 months or more (defined as cerebral palsy, developmental delay (BSID or GMDS assessment > 2 SD below the mean), intellectual impairment (IQ > 2 SD below mean), blindness (vision < 6/60 in both eyes), or sensorineural deafness requiring amplification)

"The administration of antithrombin seems not to reduce the incidence and severity of intraventricular hemorrhage in very preterm infants. Limited evidence is available on other clinically relevant outcomes. Given the imprecision of the estimate, the results of this systematic review are consistent with either a benefit or a detrimental effect of antithrombin and do not provide a definitive answer to the review question"

Bruschettini M, Zappettini S, Moja L, Calevo MG. Frequency of endotracheal suctioning for the prevention of respiratory morbidity in ventilated newborns. Cochrane Database of Systematic Reviews 2016, Issue 3.

Secondary outcomes pre‐specified include:

1. Major neurodevelopmental disability (cerebral palsy, developmental delay (BSID or GMDS assessment > 2 SD below the mean) or intellectual impairment (IQ > 2 SD below mean), blindness (vision less than 6/60 in both eyes), sensorineural deafness requiring amplification). We evaluated each component of major neurodevelopmental disability:

   1. Cerebral palsy on physician assessment (yes/no)

   2. Developmental delay or intellectual impairment: BSID or GMDS assessment > 2 SD below the mean or intellectual impairment (IQ > 2 SD below mean); neuromotor development (BSID PDI) assessed in survivors; mental development (BSID MDI) assessed in survivors

   3. Blindness vision (less than 6/60 in both eyes)

   4. Sensorineural deafness requiring amplification

"There was insufficient evidence to identify the ideal frequency of ETT suctioning in ventilated neonates. Future research should focus on the effects in the very preterm newborns, that is, the most vulnerable population as concerns the risk of both lung and brain damage. Assessment should include the cases of prolonged ventilation, when more abundant, dense secretions are common. Clinical trials might include comparisons between 'as‐scheduled' versus 'as‐needed' endotracheal suctioning, that is, based on specific indications, as well frequent versus less frequent suctioning schedules"

Bruschettini M, Romantsik O, Zappettini S, Banzi R, Ramenghi LA, Calevo MG. Heparin for the prevention of intraventricular haemorrhage in preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 5.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome (yes/no): cerebral palsy on physician assessment, developmental delay, i.e. IQ 2 SD below the mean on validated assessment tools, e.g. BSID MDI (Bayley 1993; Bayley 2006)

2. Major neurodevelopmental disability: cerebral palsy, developmental delay (BSID MDI (Bayley 1993; Bayley 2006) or GMDS assessment (Griffiths 1954) > 2 SD below the mean), intellectual impairment (IQ > 2 SD below mean), blindness (vision < 6/60 in both eyes), or sensorineural deafness requiring amplification (Jacobs 2013). We planned to evaluate each of these components as a separate outcome and to extract data on this long‐term outcome from studies that evaluated children after 18 months of chronological age. Data on children aged 18 to 24 months and those aged 3 to 5 years were to be assessed separately

"There is very limited data on the effect of prophylactic administration of heparin on the incidence and severity of IVH in very preterm neonates. Both the identified trials used heparin in the context of maintaining umbilical line patency and not specifically as an agent to prevent germinal matrix‐intraventricular haemorrhage. Given the imprecision of our estimates, the results of this systematic review are consistent with either a benefit or a detrimental effect of heparin and do not provide a definitive answer to the review question. Limited evidence is available on other clinically relevant outcomes"

Bruschettini M, Romantsik O, Zappettini S, Ramenghi LA, Calevo MG. Transcutaneous carbon dioxide monitoring for the prevention of neonatal morbidity and mortality. Cochrane Database of Systematic Reviews 2016, Issue 2.

Primary outcomes pre‐specified include:

1. Major neurodevelopmental disability (cerebral palsy, developmental delay (BSID or GMDS > 2 SD below the mean) or intellectual impairment (IQ > 2 SD below mean), blindness (vision < 6/60 in both eyes), sensorineural deafness requiring amplification) (Jacobs 2013)

Secondary outcomes pre‐specified include:

1. Each component of major neurodevelopmental disability: (a)cerebral palsy on physician assessment (yes/no); (b) developmental delay or intellectual impairment: BSID or GMDS assessment > 2 SD below the mean or intellectual impairment (IQ > 2 SD below mean); neuromotor development (BSID PDI) assessed in survivors; mental development (BSID MDI) assessed in survivors; (c) blindness vision (< 6/60 in both eyes); (d) sensorineural deafness requiring amplification. We will report these components of this long‐term outcome for all trials that have evaluated children after 18 months' chronological age. We will perform separate analyses for children aged 18 months to 24 months and those aged 3 years to 5 years

No included trials

"There was no evidence to recommend or refute the use of transcutaneous CO2 monitoring in neonates. Well‐designed, adequately powered randomized controlled studies are necessary to address efficacy and safety of transcutaneous CO2 monitoring in neonates"

Cleminson J, McGuire W. Topical emollient for preventing infection in preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 1.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcomes assessed at > 12 months post term (measured using validated assessment tools) and classifications of disability, including auditory and visual disability. A composite outcome "severe neurodevelopmental disability" was defined as any 1 or combination of the following: non‐ambulant cerebral palsy, severe developmental delay, auditory impairment, and visual impairment

"The available data do not provide evidence that the use of emollient therapy prevents invasive infection or death in preterm infants in high‐, middle‐ or low‐income settings. Some evidence of an effect of topical vegetable oils on neonatal growth exists but this should be interpreted with caution because lack of blinding may have introduced caregiver or assessment biases. Since these interventions are low cost, readily accessible, and generally acceptable, further randomised controlled trials, particularly in both community‐ and health care facility‐based settings in low‐income countries, may be justified"

Clerihew L, McGuire W. Antifungal therapy for newborn infants with invasive fungal infection. Cochrane Database of Systematic Reviews 2012, Issue 6.

Primary outcomes pre‐specified include:

1. Neurodevelopmental outcomes assessed beyond infancy (neurological evaluations, developmental scores, and classifications of disability, including auditory and visual disability, non‐ambulant cerebral palsy, developmental delay) and cognitive and educational outcomes (IQ and/or indices of educational achievement measured using a validated tool including school examination results)

"There are insufficient data to inform practice. Large randomised controlled trials are required to compare antifungal drugs, drug preparations or drug combinations for treating newborn infants with invasive fungal infection"

Cooke L, Steer PA, Woodgate PG. Indomethacin for asymptomatic patent ductus arteriosus in preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 1.

Outcomes pre‐specified include:

1. Neurodevelopmental outcome (cerebral palsy, sensorineural hearing loss, visual impairment, developmental delay)

"This review demonstrates a significant decrease in the incidence of symptomatic PDA following treatment of an asymptomatic PDA with indomethacin. There is also a small but statistically significant decrease in the duration of requirement for supplemental oxygen. There are no reported long term outcomes in the included trials, and so it is not possible to comment on possible long term effects. Further studies are required to determine the long term benefits or harms of closing a PDA prior to the onset of symptoms"

Davies MW, Kimble RM, Woodgate PG. Ward reduction without general anaesthesia versus reduction and repair under general anaesthesia for gastroschisis in newborn infants. Cochrane Database of Systematic Reviews 2002, Issue 3.

Outcomes pre‐specified include:

1. Neurodevelopmental outcome (cerebral palsy, sensorineural hearing loss, visual impairment, and/or developmental delay)

No included trials

"There is no evidence from RCTs to support or refute the practice of ward reduction for the immediate management of gastroschisis. There is an urgent need for RCTs to compare ward reduction versus reduction under general anaesthesia in infants with gastroschisis. Initial trials would best be limited to those infants with uncomplicated gastroschisis (using pre‐defined selection criteria excluding infants that are unstable, have gut perforation, necrosis or atresia, have other organs requiring reduction besides bowel, or are considered to need a silo prior to any reduction). Trials should use adequate pain relief and specify a pre‐defined time period after which manual reduction is abandoned"

Davies MW, Woodgate PG. Tracheal gas insufflation for the prevention of morbidity and mortality in mechanically ventilated newborn infants. Cochrane Database of Systematic Reviews 2002, Issue 2.

Outcomes pre‐specified include:

1. Neurodevelopmental outcome (cerebral palsy, sensorineural hearing loss, visual impairment, and/or developmental delay) at 1, 2, 3, 5, or 7 years

"There is evidence from a single RCT that TGI may reduce the duration of mechanical ventilation in preterm infants ‐ although the data from this small study do not give sufficient evidence to support the introduction of TGI into clinical practice. The technical requirements for performing TGI (as performed in the single included study) are great. There is no statistically significant reduction in the total duration of respiratory support or hospital stay. TGI cannot be recommended for general use at this time"

De Paoli AG, Davis PG, Faber B, Morley CJ. Devices and pressure sources for administration of nasal continuous positive airway pressure (NCPAP) in preterm neonates. Cochrane Database of Systematic Reviews 2008, Issue 1.

Secondary outcomes pre‐specified include:

1. Long‐term neurosensory outcomes at 2 years' corrected age or older as defined by the incidence of:

   1. Cerebral palsy

   2. Moderate to severe developmental delay

   3. Blindness

   4. Deafness

"Short binasal prong devices are more effective than single prongs in reducing the rate of re‐intubation. Although the Infant Flow Driver appears more effective than Medicorp prongs the most effective short binasal prong device remains to be determined. The improvement in respiratory parameters with short binasal prongs suggests they are more effective than nasopharyngeal CPAP in the treatment of early RDS. Further studies incorporating longer‐term outcomes are required. Studies are also needed to determine the optimal pressure source for the delivery of NCPAP"

Dimmick SJ, Badawi N, Randell T. Thyroid hormone supplementation for the prevention of morbidity and mortality in infants undergoing cardiac surgery. Cochrane Database of Systematic Reviews 2004, Issue 3.

Outcomes pre‐specified include:

1. Development: neurological abnormality (cerebral palsy) or developmental delay on standardised tests in the first year 5

"At present, there is a lack of evidence concerning the effects of triiodothyronine supplementation in infants undergoing cardiac surgery. Further randomised controlled trials which include sufficiently large subject numbers in a variety of different age strata (neonates, infants and older children) need to be undertaken"

Foster JP, Psaila K, Patterson T. Non‐nutritive sucking for increasing physiologic stability and nutrition in preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 10.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcomes at 12 months or more of age (corrected for preterm birth) measured using validated assessment tools such as BSID and classifications of disability, including auditory and visual disability. Severe neurodevelopmental disability will be defined as any one or combination of the following: non‐ambulant cerebral palsy, developmental delay (developmental quotient < 70), auditory and visual impairment

"Meta‐analysis demonstrated a significant effect of NNS on the transition from gavage to full oral feeding, transition from start of oral feeding to full oral feeding, and length of hospital stay. None of the trials reported any adverse effects. Well‐designed, adequately powered studies using reliable methods of randomisation, concealment of treatment allocation and blinding of the intervention and outcome assessors are needed. In order to facilitate meta‐analysis of these data, future research should involve outcome measures consistent with those used in previous studies"

Görk AS, Ehrenkranz RA, Bracken MB. Continuous infusion versus intermittent bolus doses of indomethacin for patent ductus arteriosus closure in symptomatic preterm infants. Cochrane Database of Systematic Reviews 2008, Issue 1.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome (sensorineural hearing loss, visual impairment, cerebral palsy, developmental delay at 24 months' corrected age assessed by a standardised and validated assessment tool and/or a child developmental specialist)

"The available data is insufficient to draw conclusions regarding the efficacy of continuous indomethacin infusion vs. bolus injections for the treatment of PDA. Although continuous indomethacin seems to cause less alterations in cerebral, renal and mesenteric circulations, the clinical meaning of this effect is unclear. Definitive recommendations about the preferred method of indomethacin administration in premature infants cannot be made based on the current findings of this review"

Henderson G, Anthony MY, McGuire W. Formula milk versus maternal breast milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2007, Issue 4.

Primary outcomes pre‐specified include:

1. Development:

   1. Neurodevelopmental outcomes at ≥ 12 months of age (corrected for preterm birth) measured using validated assessment tools

   2. Severe neurodevelopmental disability defined as any 1 or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70 or > 2 SD below the mean), severe auditory impairment (sensorineural deafness requiring (or too severe to (benefit from) hearing aids), or visual impairment (legal blindness). We plan to analyse each component individually as well as part of the composite outcome

   3. Cognitive and educational outcomes at age > 5 years: IQ and/or indices of educational achievement measured using a validated assessment tool (including school examination results)

No included trials

"There are no data from randomised trials of formula milk versus maternal breast milk for feeding preterm or low birth weight infants. This may relate to a perceived difficulty of allocating an alternative feed to an infant whose mother wishes to feed with her own breast milk. Maternal breast milk remains the default choice of enteral nutrition because observational studies, and meta‐analyses of trials comparing feeding with formula milk versus donor breast milk, suggest that feeding with breast milk has major non‐nutrient advantages for preterm or low birth weight infants"

Henderson G, Fahey T, McGuire W. Nutrient‐enriched formula milk versus human breast milk for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2007, Issue 4.

Primary outcomes pre‐specified include:

1. Neurodevelopmental outcomes at ≥ 12 months of age (corrected for preterm birth) measured using validated assessment tools such as BSID and classifications of disability, including auditory and visual disability. Severe neurodevelopmental disability will be defined as any 1 or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment

No included trials

"There are no data from randomised controlled trials to determine whether feeding preterm infants following hospital discharge with nutrient‐enriched formula milk versus human breast milk affects growth and development. Mothers who wish to breast feed, and their health care advisors, would require very clear evidence that feeding with a nutrient‐enriched formula milk had major advantages for their infants before electing not to feed (or to reduce feeding) with maternal breast milk. If evidence from trials that compared feeding preterm infants following hospital discharge with nutrient‐enriched versus standard formula milk demonstrated an effect on growth or development, then this might strengthen the case for undertaking trials of nutrient‐enriched formula milk versus human breast milk"

Henderson‐Smart DJ, Wilkinson AR, Raynes‐Greenow CH. Mechanical ventilation for newborn infants with respiratory failure due to pulmonary disease. Cochrane Database of Systematic Reviews 2002, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental abnormalities in childhood (developmental delay, cerebral palsy)

"When MV was introduced in the 1960s to treat infants with severe respiratory failure due to pulmonary disease, trials showed an overall reduction in mortality which was most marked in infants born with a birthweight of more than 2 kg. This review does not provide information to evaluate the relative benefits or harms of MV in the setting of modern perinatal care"

Ho JJ, Henderson‐Smart DJ, Davis PG. Early versus delayed initiation of continuous distending pressure for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 2002, Issue 2.

Secondary outcomes pre‐specified include:

1. Long‐term growth and neurodevelopmental outcome (cerebral palsy and abnormal mental development < 2 SD below the mean on a standardised score)

"Early application of CDP has a clinical benefit in the treatment of RDS in that it reduces subsequent use of IPPV and thus may be useful in preventing the adverse effects of this treatment. However, many of the trials were done in the 1970s and 1980s and re‐evaluation of the strategy of early CDP in the era of antenatal steroid use and early surfactant administration is indicated focusing on administration methods"

Ho JJ, Rasa G. Magnesium sulfate for persistent pulmonary hypertension of the newborn. Cochrane Database of Systematic Reviews 2007, Issue 3.

Secondary outcomes pre‐specified include:

1. Cerebral palsy on physician assessment

No included trials

"On the basis of the current lack of evidence, the use of magnesium sulphate cannot be recommended in the treatment of PPHN. Randomised controlled trials are recommended"

Hunt R, Osborn DA. Dopamine for prevention of morbidity and mortality in term newborn infants with suspected perinatal asphyxia. Cochrane Database of Systematic Reviews 2002, Issue 3.

Primary outcomes pre‐specified include:

1. Neurodevelopmental disability (neurological abnormality including cerebral palsy, developmental delay > 2 SD below population mean, or sensory impairment)

(Review reports on 'neurodevelopmental disability' for 1 RCT (14 infants), which did not include cerebral palsy)

"There is currently insufficient evidence from randomised controlled trials that the use of dopamine in term infants with suspected perinatal asphyxia improves mortality or long‐term neurodevelopmental outcome. The question of whether dopamine improves outcome for term infants with suspected perinatal asphyxia has not been answered. Further research is required to determine whether or not the use of dopamine improves mortality and long‐term morbidity for these infants and if so, issues such as which infants, at what dose and with what co‐interventions should be addressed"

Hunt R, Davis PG, Inder TE. Replacement of estrogens and progestins to prevent morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 4.

Primary outcomes pre‐specified include:

1. Neurodevelopmental disability defined as neurological abnormality includingcerebral palsy on clinical examination > 12 months' postnatal age, developmental delay > 2 SD below population mean on any standard test of development, blindness (VA < 6/60), or deafness (any hearing impairment requiring amplification) at any time after term corrected

"The one small randomised controlled trial demonstrated neither evidence of benefit or harm related to the replacement of estradiol and progesterone in preterm infants less than 30 weeks' gestation. A properly powered randomised controlled trial is required to determine whether or not administration of estradiol or progesterone, either alone or in combination, and at varying doses, confers any clinically significant benefits, or poses any risk, to the preterm infant"

Ibrahim H, Sinha IP, Subhedar NV. Corticosteroids for treating hypotension in preterm infants. Cochrane Database of Systematic Reviews 2011, Issue 12.

Primary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome (cerebral palsy, developmental delay, sensorineural impairment, abnormal neurological examination)

"Hydrocortisone may be as effective as dopamine when used as a primary treatment for hypotension. But the long term safety data on the use of hydrocortisone in this manner is unknown. Steroids are effective in treatment of refractory hypotension in preterm infants without an increase in short term adverse consequences. However, long term safety or benefit data is lacking. With long term benefit or safety data lacking steroids cannot be recommended routinely for the treatment of hypotension in preterm infants"

Ibrahim MDH, Sinn JKH, McGuire W. Iodine supplementation for the prevention of mortality and adverse neurodevelopmental outcomes in preterm infants. Cochrane Database of Systematic Reviews 2006, Issue 2.

Primary outcomes pre‐specified include:

1. Neurodevelopmental outcomes at ≥ 12 months of age (corrected for preterm birth) measured using validated assessment tools such as BSID

2. Severe neurodevelopmental disability defined as any 1 or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment. We planned to analyse each component individually as well as part of the composite outcome

"There are insufficient data at present to determine whether providing preterm infants with supplemental iodine (to match fetal accretion rates) prevents morbidity and mortality in preterm infants. Future randomised controlled trials of iodine supplementation should focus on extremely preterm and extremely low birth weight infants, the group at greatest risk of transient hypothyroxinaemia. These trials should aim to assess the effect of iodine supplementation on clinically important outcomes including respiratory morbidity and longer term neurodevelopment"

Inglis GDT, Davies MW. Prophylactic antibiotics to reduce morbidity and mortality in neonates with umbilical venous catheters. Cochrane Database of Systematic Reviews 2005, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome (cerebral palsy, sensorineural hearing loss, visual impairment and/or developmental delay will be considered as separate components ‐ at 1 year, 18 months, 2 years, or 5 years)

"There is insufficient evidence from randomised trials to support or refute the use of prophylactic antibiotics when UVCs are inserted in newborn infants. There is no evidence to support or refute continuing antibiotics once initial cultures rule out infection in newborn infants with UVCs"

Inglis GDT, Jardine LA, Davies MW. Prophylactic antibiotics to reduce morbidity and mortality in ventilated newborn infants. Cochrane Database of Systematic Reviews 2007, Issue 3.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome (cerebral palsy, sensorineural hearing loss, visual impairment and/or developmental delay at 1 year, 18 months, 2 years, or 5 years)

"There is insufficient evidence from randomised trials to support or refute the use of prophylactic antibiotics when starting mechanical ventilation in newborn infants, or to support or refute continuing antibiotics once initial cultures have ruled out infection in mechanically ventilated newborn infants"

Inglis GDT, Jardine LA, Davies MW. Prophylactic antibiotics to reduce morbidity and mortality in neonates with umbilical artery catheters. Cochrane Database of Systematic Reviews 2007, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome (cerebral palsy, sensorineural hearing loss, visual impairment and/or developmental delay ‐ at 1 year, 18 months, 2 years, or 5 years)

"There is insufficient evidence from randomised trials to support or refute the use of prophylactic antibiotics when umbilical artery catheters are inserted in newborn infants, and no evidence to support or refute continuing antibiotics once initial cultures rule out infection in newborn infants with umbilical artery catheters"

Jardine LA, Inglis GDT, Davies MW. Prophylactic systemic antibiotics to reduce morbidity and mortality in neonates with central venous catheters. Cochrane Database of Systematic Reviews 2008, Issue 1.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome (cerebral palsy, sensorineural hearing loss, visual impairment, and/or developmental delay ‐ at 1 year, 18 months, 2 years, or 5 years)

"Prophylactic systemic antibiotics in neonates with a central venous catheter reduces the rate of proven or suspected septicaemia. However, this may not be clinically important in the face of no significant difference in overall mortality and the lack of data on long‐term neurodevelopmental outcome. Furthermore, there is a lack of data pertaining to the potentially significant disadvantages of this approach such as the selection of resistant organisms. The routine use of prophylactic antibiotics in infants with central venous catheters in neonatal units cannot currently be recommended"

Jardine LA, Inglis GDT, Davies MW. Strategies for the withdrawal of nasal continuous positive airway pressure (NCPAP) in preterm infants. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD006979. DOI: 10.1002/14651858.CD006979.pub2.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome (cerebral palsy, sensorineural hearing loss, visual impairment, and/or developmental delay ‐ at 1 year, 18 months, 2 years, or 5 years)

"Infants who have their NCPAP pressure weaned to a predefined level and then stop NCPAP completely have less total time on NCPAP and shorter durations of oxygen therapy and hospital stay compared with those that have NCPAP removed for a predetermined number of hours each day. Future trials of withdrawing NCPAP should compare proposed strategies with weaning NCPAP pressure to a predefined level and then stopping NCPAP completely. Clear criteria need to be established for the definition of stability prior to attempting to withdraw NCPAP"

Kaushal A, McDonnell CG, Davies MW. Partial liquid ventilation for the prevention of mortality and morbidity in paediatric acute lung injury and acute respiratory distress syndrome. Cochrane Database of Systematic Reviews 2013, Issue 2.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopment (cerebral palsy, sensorineural hearing loss, visual impairment, developmental delay)

2. Long‐term disability

"There is no evidence from RCTs to support or refute the use of partial liquid ventilation in children with acute lung injury or acute respiratory distress syndrome. Adequately powered, high quality RCTs are still needed to assess its efficacy. Clinically relevant outcome measures should be assessed (mortality at discharge and later, duration of both respiratory support and hospital stay, and long‐term neurodevelopmental outcomes). The studies should be published in full"

Kecskes Z, Healy G, Jensen A. Fluid restriction for term infants with hypoxic‐ischaemic encephalopathy following perinatal asphyxia. Cochrane Database of Systematic Reviews 2005, Issue 3.

Primary outcomes pre‐specified include:

1. Severe neurodevelopmental disability at or equal to 12 months of age or more. Severe neurodevelopmental disability was defined as cerebral palsy, developmental delay (DQ < 70) or blindness (VA < 6/60 in both eyes), or any combination of these disabilities

No included trials

"Given that fluid restriction for the treatment of hypoxic ischaemic encephalopathy following perinatal asphyxia is recommended in standard textbooks, there is a need for randomised, controlled trials to establish if this practice affects mortality and morbidity. As it may not be ethical to include neonates with acute renal failure in a randomised trial, these babies will have to be excluded from the trial. These studies should investigate the effects of fluid management on outcomes such as mortality, seizure activity, evidence of cerebral damage on histology, and effects on renal function and electrolytes"

Keir AK, Wilkinson D, Andersen C, Stark MJ. Washed versus unwashed red blood cells for transfusion for the prevention of morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 1.

Primary outcomes pre‐specified include:

1. Cerebral palsy by physician assessment

Secondary outcomes pre‐specified include:

1. Composite outcome of mortality or severe adverse neurosensory outcome (or its complement, survival without serious adverse neurosensory outcome) at a defined period of follow‐up at age 18 to 24 months' adjusted gestational age or older, where adverse neurosensory outcome is defined as:

   1. Cerebral palsy by physician assessment

   2. DQ (> 2 SD below the mean on validated assessment tool of cognitive function (e.g. BSID))

   3. Blindness (VA < 20/200 in best eye)

   4. Deafness (hearing loss requiring amplification or cochlear implantation)

"We identified a single small study. The results from this study show a high level of uncertainty, as the confidence intervals are consistent with both a large improvement or a serious harm caused by the intervention. Consequently, there is insufficient evidence to support or refute the use of washed RBCs to prevent the development of significant neonatal morbidities or mortality. Further clinical trials are required to assess the potential effects of pre‐transfusion washing of RBCs for preterm or very low birth weight infants, or both, on short‐ and long‐term outcomes"

Kylat RI, Ohlsson A. Recombinant human activated protein C for severe sepsis in neonates. Cochrane Database of Systematic Reviews 2012, Issue 4.

Secondary outcomes pre‐specified include:

1. Severe disability, defined as any of blindness, deafness,cerebral palsy or cognitive delay (score > 2 SD below the mean for a recognised psychometric test for neurodevelopmental outcome assessed by a validated test, e.g. BSID), or adverse neurological outcome, at 18 months of age or later. These outcomes will be reported both as a composite outcome and individually

2. Cerebral palsy

"Despite the scientific rationale for its use, there is insufficient data to use rhAPC for the management of severe sepsis in newborn infants. Due to the results among adults with lack of efficacy, an increase in bleeding and resulting withdrawal of rhAPC from the market, neonates should not be treated with rhAPC and further trials should not be conducted"

Lai NM, Foong SC, Foong WC, Tan K. Co‐bedding in neonatal nursery for promoting growth and neurodevelopment in stable preterm twins. Cochrane Database of Systematic Reviews 2016, Issue 4.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopment, measured by validated scales such as BSID (Washington 1998), whereby average scores between twin pairs would be taken if data were available. Clinically diagnosed non‐ambulatory cerebral palsy or significant auditory and visual impairment would be accepted if data were available

"Evidence on the benefits and harms of co‐bedding for stable preterm twins was insufficient to permit recommendations for practice. Future studies must be adequately powered to detect clinically important differences in growth and neurodevelopment. Researchers should assess harms such as infection, along with medication errors and caregiver satisfaction"

Lai NM, Rajadurai SV, Tan K. Increased energy intake for preterm infants with (or developing) bronchopulmonary dysplasia/chronic lung disease. Cochrane Database of Systematic Reviews 2006, Issue 3.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental disabilities at or after 12 months' corrected age, assessed using validated tools like BSID, including diagnosed cerebral palsy, blindness, or deafness

2. Mortality or neurodevelopmental disabilities

No included trials

"To date, no randomised controlled trials are available that examine the effects of increased versus standard energy intake for preterm infants with (or developing) CLD/BPD. Research should be directed at evaluating the effects of various levels of energy intake on this group of infants on clinically important outcomes like mortality, respiratory status, growth and neurodevelopment. The benefits and harms of various ways of increasing energy intake, including higher energy density of milk feed and/or fluid volume (clinically realistic target volume should be set), parenteral nutrition, and the use of various constituents of energy like carbohydrate, protein and fat for this purpose also need to be assessed"

Lai NM, Taylor JE, Tan K, Choo YM, Ahmad Kamar A, Muhamad NA. Antimicrobial dressings for the prevention of catheter‐related infections in newborn infants with central venous catheters. Cochrane Database of Systematic Reviews 2016, Issue 3.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcomes, measured using validated scales such as the BSID (Washington 1998) at 12, 18, or 24 months of age. Data on clinically diagnosed non‐ambulatory cerebral palsy or significant auditory and visual impairment would be accepted if available

"Based on moderate‐quality evidence, chlorhexidine dressing/alcohol skin cleansing reduced catheter colonisation, but made no significant difference in major outcomes like sepsis and CRBSI compared to polyurethane dressing/povidone‐iodine cleansing. Chlorhexidine dressing/alcohol cleansing posed a substantial risk of contact dermatitis in preterm infants, although it was unclear whether this was contributed mainly by the dressing material or the cleansing agent. While silver‐alginate patch appeared safe, evidence is still insufficient for a recommendation in practice. Future research that evaluates antimicrobial dressing should ensure blinding of caregivers and outcome assessors and ensure that all participants receive the same co‐interventions, such as the skin cleansing agent. Major outcomes like sepsis, CRBSI and mortality should be assessed in infants of different gestation and birth weight"

Lai M, Inglis GDT, Hose K, Jardine LA, Davies MW. Methods for securing endotracheal tubes in newborn infants. Cochrane Database of Systematic Reviews 2014, Issue 7.

Secondary outcomes pre‐specified include:

1. Incidence of an adverse neurodevelopmental outcome (e.g. cerebral palsy, sensorineural hearing loss, visual impairment, developmental delay) whenever measured in the primary studies

"This review highlighted the need for further well designed and completed studies to be conducted for this common neonatal procedure. Evidence is lacking to determine the most effective and safe method to stabilise the endotracheal tube in the ventilated neonate"

Lawn CJ, Weir FJ, McGuire W. Base administration or fluid bolus for preventing morbidity and mortality in preterm infants with metabolic acidosis. Cochrane Database of Systematic Reviews 2005, Issue 2.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcomes at ≥ 12 months of age (corrected for preterm birth) measured using validated assessment tools such as BSID and classifications of disability, including (a) auditory and (b) visual disability. The composite outcome of "severe neurodevelopmental disability" is defined as any 1 or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment

"There is insufficient evidence from randomised controlled trials to determine whether infusion of base or fluid bolus reduces morbidity and mortality in preterm infants with metabolic acidosis. Further large randomised trials are needed"

Malwade US, Jardine LA. Home‐ versus hospital‐based phototherapy for the treatment of non‐haemolytic jaundice in infants at more than 37 weeks' gestation. Cochrane Database of Systematic Reviews 2014, Issue 6.

Primary outcomes pre‐specified include:

1. Incidence (percentage) of chronic bilirubin encephalopathy or kernicterus, defined by a tetrad of choreoathetoid cerebral palsy, high‐frequency sensorineural hearing loss, palsy of vertical gaze, and dental enamel hypoplasia

No included trials

"No high‐quality evidence is currently available to support or refute the practice of home‐based phototherapy for non‐haemolytic jaundice in infants at more than 37 weeks' gestation"

McGuire W, Fowlie PW, Evans DJ. Naloxone for preventing morbidity and mortality in newborn infants of greater than 34 weeks' gestation with suspected perinatal asphyxia. Cochrane Database of Systematic Reviews 2004, Issue 1.

Primary outcomes pre‐specified include:

1. Severe neurodevelopmental disability assessed at ≥ 12 months of age. Severe neurodevelopmental disability will be defined as any 1 or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment. Development should have been assessed by means of a previously validated tool, such as BSID PDI and MDI

"There are insufficient data available to evaluate the safety and effectiveness of the routine use of naloxone for newborn infants of greater than 34 weeks' gestation with suspected perinatal asphyxia. A further randomised controlled trial is needed to determine if naloxone benefits newborn infants with suspected perinatal asphyxia. Such a trial should assess clinically important outcomes such as mortality, and adverse short and long term neurological outcomes"

Morgan J, Bombell S, McGuire W. Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants. Cochrane Database of Systematic Reviews 2013, Issue 3.

Secondary outcomes pre‐specified include:

1. Neurodevelopment: death or severe neurodevelopmental disability defined as any 1 or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment. Each component will be analysed individually as well as part of the composite outcome

"The available trial data do not provide evidence of important beneficial or harmful effects of early trophic feeding for very preterm or very low birth weight infants. The applicability of these findings to extremely preterm, extremely low birth weight or growth restricted infants is limited. Further randomised controlled trials would be needed to determine how trophic feeding compared with enteral fasting affects important outcomes in this population"

Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2015, Issue 10.

Secondary outcomes pre‐specified include:

1. Neurodevelopment:

   1. Death or severe neurodevelopmental disability defined as any 1 or a combination of the following: non‐ambulatory cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment. Each component was to be analysed individually as well as part of the composite outcome

   2. Neurodevelopmental scores in survivors aged 12 months or greater measured using validated assessment tools

   3. Cognitive and educational outcomes in survivors aged > 5 years

"The available trial data suggest that advancing enteral feed volumes at daily increments of 30 to 40 mL/kg (compared to 15 to 24 mL/kg) does not increase the risk of NEC or death in VLBW infants. Advancing the volume of enteral feeds at slow rates results in several days of delay in establishing full enteral feeds and increases the risk of invasive infection. The applicability of these findings to extremely preterm, extremely low birth weight, or growth‐restricted infants is limited. Further randomised controlled trials in these populations may be warranted to resolve this uncertainty"

Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2014, Issue 12.

Secondary outcomes pre‐specified include:

1. Neurodevelopment:

   1. Death or severe neurodevelopmental disability defined as any 1 or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment. Each component was analysed individually as well as part of the composite outcome

   2. Neurodevelopmental scores in survivors aged 12 months or greater measured using validated assessment tools

   3. Cognitive and educational outcomes in survivors aged > 5 years

"The evidence available from randomised controlled trials suggested that delaying the introduction of progressive enteral feeds beyond four days after birth did not reduce the risk of developing NEC in very preterm or VLBW infants, including growth‐restricted infants. Delaying the introduction of progressive enteral feeds resulted in a few days' delay in establishing full enteral feeds but the clinical importance of this effect was unclear. The applicability of these findings to extremely preterm or extremely low birth weight was uncertain. Further randomised controlled trials in this population may be warranted"

Mosalli R, AlFaleh K. Prophylactic surgical ligation of patent ductus arteriosus for prevention of mortality and morbidity in extremely low birth weight infants. Cochrane Database of Systematic Reviews 2008, Issue 1.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental impairment (i.e. rates of cerebral palsy, cognitive delay defined as a MDI score < 70 (2 SD below the mean of 100) on the BSID II (Bayley 1993), deafness, blindness, or composite reported at 18 months' corrected age or later)

"Prophylactic surgical ligation of the PDA did not decrease mortality or BPD in ELBW infants. A significant reduction of stage II or III NEC was noted. Based on the current evidence, the high rate of spontaneous closure, availability of effective safe medical therapies, and the potential short and long‐term complications of surgical ligation, the use such prophylactic surgical therapy is not indicated in the management of the preterm infants"

O'Donnell CPF, Bruschettini M, Davis PG, Morley CJ, Moja L, Calevo MG, Zappettini S. Sustained versus standard inflations during neonatal resuscitation to prevent mortality and improve respiratory outcomes. Cochrane Database of Systematic Reviews 2015, Issue 7.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome (rates of cerebral palsy on physician assessment, developmental delay, i.e. IQ 2 SD < mean on validated assessment tools, e.g. BSID MDI)

"At present there is insufficient evidence from clinical trials to determine the efficacy and safety of initial sustained lung inflation for newborn infants resuscitated with PPV. RCTs comparing PPV with and without sustained inflations at neonatal resuscitation are warranted"

Ogunlesi TA, Odigwe CC, Oladapo OT. Adjuvant corticosteroids for reducing death in neonatal bacterial meningitis. Cochrane Database of Systematic Reviews 2015, Issue 11.

Secondary outcomes pre‐specified include:

1. Presence of severe neurological deficits or developmental delay between 1 and 2 years of age (a neurological deficit was defined as a functional abnormality of a body area that is observed as the result of an abnormality in function of the brain, spinal cord, muscles, or nerves; developmental delay was defined as any significant lag in a child's physical or motor, cognitive, behavioural, emotional, or social development, in comparison with other children of the same age and sex within similar environments; formal evaluation tools were used to assess neurological deficits and developmental delay). Examples of neurological deficits include mental retardation, cerebral palsy, epilepsy, blindness, and behavioural disorders. We considered evaluation tools such as BSID or GMDS (for neurodevelopmental deficits), the GMFCS or the Movement ABC (forcerebral palsy), the Sonken‐Silver VA test (for blindness), distraction tests (for behavioural disorders), and electroencephalography (for epilepsy) ‐ all applied between 1 and 2 years of age. We also accepted other measures used by individual trialists to evaluate and document neurological deficits in their respective trials

"Very low‐quality data from two randomised controlled trials suggest that some reduction in death and hearing loss may result from use of adjunctive steroids alongside standard antibiotic therapy for treatment of patients with neonatal meningitis. Benefit is not yet seen with regards to reduction in neurological sequelae. Researchers who wish to clarify these findings must conduct more robustly designed trials with greater numbers of participants, evaluating more relevant outcomes and providing adequate follow‐up"

Onland W, Offringa M, van Kaam A. Late (≥ 7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants. Cochrane Database of Systematic Reviews 2012, Issue 4.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental sequelae, assessed after at least 1 year CGA and before a CGA of 4 years includingcerebral palsy and BSID (MDI)

"Based on the results of the currently available evidence, inhalation corticosteroids initiated at ≥ 7 days of life for preterm infants at high risk of developing BPD cannot be recommended at this point in time. More and larger randomised, placebo‐controlled trials are needed to establish the efficacy and safety of inhalation corticosteroids"

Osborn DA, Evans NJ. Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 2.

Primary outcomes pre‐specified include:

1. Neurodevelopmental disability (neurological abnormality includingcerebral palsy, developmental delay, or sensory impairment)

"Dopamine was more successful than albumin at correcting low BP in hypotensive preterm infants, many of whom had already received volume. Neither intervention has been shown to be superior at improving blood flow or in improving mortality and morbidity in preterm infants. The trials do not allow any firm conclusions to be made as to whether or when volume or dopamine should be used in preterm infants"

Osborn DA, Hunt R. Postnatal thyroid hormones for preterm infants with transient hypothyroxinaemia. Cochrane Database of Systematic Reviews 2007, Issue 1.

Primary outcomes pre‐specified include:

1. Neurodevelopmental status at follow‐up. Neurodevelopmental outcome was categorised as:

   1. Abnormal mental developmental > 12 months' corrected age (a development or IQ > 2 SD below the mean of a standardised test)

   2. Abnormal neurological outcome (infants with abnormal mental development or definite cerebral palsy)

   3. Motor deficits

   4. Sensorineural impairments including hearing deficit requiring aids; VA < 6/60

"There is insufficient evidence to determine whether use of thyroid hormones for treatment of preterm infants with transient hypothyroxinaemia results in changes in neonatal morbidity and mortality, or reductions in neurodevelopmental impairments. Further research is required"

Osborn DA, Hunt R. Postnatal thyroid hormones for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 2007, Issue 1.

Primary outcomes pre‐specified include:

1. Abnormal neurodevelopmental outcome:

   1. Abnormal mental development > 12 months' corrected age (a validated development or IQ > 2 SD below the mean of a standardised test)

   2. Abnormal neurological outcome (infants with abnormal mental development or definite cerebral palsy)

   3. Motor deficits

   4. Sensorineural impairments (hearing deficit requiring aids or VA < 6/60)

"There is no evidence from controlled clinical trials that postnatal thyroid hormone treatment reduces the severity of respiratory distress syndrome, neonatal morbidity or mortality in preterm infants with respiratory distress syndrome"

Özek E, Soll R, Schimmel MS. Partial exchange transfusion to prevent neurodevelopmental disability in infants with polycythemia. Cochrane Database of Systematic Reviews 2010, Issue 1.

Primary outcomes pre‐specified include:

1. Neurodevelopmental status at 2 years of age, neurodevelopmental status at school age. This will include both combined and separate analyses of the components of severe neurodevelopmental delay defined as an MDI < 70, cerebral palsy, vision loss, and hearing loss

"There are no proven clinically significant short or long‐term benefits of PET in polycythemic newborn infants who are clinically well or who have minor symptoms related to hyperviscosity. PET may lead to an increase in the risk of NEC. The data regarding developmental follow‐up are extremely imprecise due to the large number of surviving infants who were not assessed and, therefore, the true risks and benefits of PET are unclear"

Paradisis M, Osborn DA. Adrenaline for prevention of morbidity and mortality in preterm infants with cardiovascular compromise. Cochrane Database of Systematic Reviews 2004, Issue 1.

Primary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome: cerebral palsy and standardised assessment of developmental delay or sensorineural impairment

"There are insufficient data on the use of adrenaline infusions in preterm infants with cardiovascular compromise to make recommendations for practice. There is a need for larger trials to determine whether adrenaline is effective in reducing morbidity and mortality in preterm infants with cardiovascular compromise"

Pfister RH, Soll R, Wiswell TE. Protein‐containing synthetic surfactant versus protein‐free synthetic surfactant for the prevention and treatment of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2009, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome at approximately 2 years' corrected age (acceptable range 18 months to 28 months) including cerebral palsy, mental delay (BSID MDI < 70), legal blindness (< 20/200 VA), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome "neurodevelopmental impairment" was defined as having any 1 of the aforementioned deficits

"In the one trial comparing protein containing synthetic surfactants compared to protein free synthetic surfactant for the prevention of RDS, no statistically different clinical differences in death and chronic lung disease were noted. Clinical outcomes between the two groups were generally similar although the group receiving protein containing synthetic surfactants did have decreased incidence of respiratory distress syndrome. Further well designed studies comparing protein containing synthetic surfactant to the more widely used animal derived surfactant extracts are indicated"

Pfister RH, Soll R, Wiswell TE. Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2007, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome at approximately 2 years' corrected age (range 18 months to 28 months) including cerebral palsy, mental retardation (BSID MDI < 70), legal blindness (< 20/200 VA), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome "neurodevelopmental impairment" was defined as having any 1 of the aforementioned deficits

"In two trials of protein containing synthetic surfactants compared to animal derived surfactant extract, no statistically different clinical differences in death and chronic lung disease were noted. In general, clinical outcomes between the two groups were similar. Further well designed studies of adequate size and power will help confirm and refine these findings"

Pilley E, McGuire W. Pre‐discharge "car seat challenge" for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2006, Issue 1.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcomes at > 12 months post term measured using validated assessment tools such as BSID and classifications of disability, including auditory and visual disability. The composite outcome "severe neurodevelopmental disability" will be defined as any 1 or combination of the following: non‐ambulantcerebral palsy, developmental delay (DQ < 70), auditory and visual impairment

No included trials

"It is unclear whether undertaking a pre‐discharge car seat challenge is beneficial or harmful to preterm infants. Further studies are needed to determine whether the car seat challenge accurately predicts the risk of clinically significant adverse events in preterm infants travelling in car seats. If this is shown to be the case then a large randomised controlled trial is needed to provide an unbiased assessment of its utility in pre‐discharge assessment"

Quigley M, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2014, Issue 4.

Primary outcomes pre‐specified include:

1. Death or severe neurodevelopmental disability defined as any 1 or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment. We analysed each component individually as well as part of the composite outcome

"In preterm and low birth weight infants, feeding with formula compared with donor breast milk results in a higher rate of short‐term growth but also a higher risk of developing necrotising enterocolitis. Limited data on the comparison of feeding with formula versus nutrient‐fortified donor breast milk are available. This limits the applicability of the findings of this review as nutrient fortification of breast milk is now a common practice in neonatal care. Future trials may compare growth, development and adverse outcomes in infants who receive formula milk versus nutrient‐fortified donor breast milk given as a supplement to maternal expressed breast milk or as a sole diet"

Qureshi MJ, Kumar M. D‐Penicillamine for preventing retinopathy of prematurity in preterm infants. Cochrane Database of Systematic Reviews 2013, Issue 9.

Secondary outcomes pre‐specified include:

1. Abnormal neurodevelopment defined as abnormal neurological examination, epilepsy,cerebral palsy, or DQ < 70 diagnosed at 1 year of corrected age or older

"Administration of prophylactic D‐penicillamine in preterm infants does not prevent acute or severe ROP, death or neurodevelopmental delay. D‐penicillamine cannot be recommended for the prevention of ROP based on the available evidence"

Rojas‐Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2012, Issue 3.

Secondary outcomes pre‐specified include:

1. Cerebral palsy.

2. Neurodevelopmental outcome at approximately 2 years' corrected age (acceptable range 18 months to 28 months) including cerebral palsy, significant mental developmental delay (BSID < 70), legal blindness (< 20/200 VA), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome "neurodevelopmental impairment" was defined as having any one of the aforementioned deficits

(Review notes that 2 RCTs have reported on cerebral palsy, but not in the 'acceptable range' pre‐specified; therefore no results were reported:

"Neurodevelopmental outcome: For this outcome, we considered any trial reporting at approximately 2 years' corrected age (acceptable range 18 months to 28 months) any of the following entities cerebral palsy, intellectual disability or developmental delay (Bayley Scales of Infant Development Mental Developmental Index < 70), legal blindness (< 20/200 visual acuity), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome "neurodevelopmental impairment" would be defined as having any one of the aforementioned deficits. Two trials Sinkin 1998; Vaucher 1993 performed a follow‐up study including infants recruited in the Kendig 1991 and Merritt 1991 trials respectively. Sinkin 1998 reported cerebral palsy but in 148 children at school age, no data were available from ages between 18 and 28 months. Vaucher 1993 reported on cerebral palsy and developmental delay in 145 survivors at 12 months' corrected age. No one study reporting neurodevelopmental outcomes at 24 months' corrected age was found")

"Although the early trials of prophylactic surfactant administration to infants judged to be at risk of developing RDS compared with selective use of surfactant in infants with established RDS demonstrated a decreased risk of air leak and mortality, recent large trials that reflect current practice (including greater utilization of maternal steroids and routine post delivery stabilization on CPAP) do not support these differences and demonstrate less risk of chronic lung disease or death when using early stabilization on CPAP with selective surfactant administration to infants requiring intubation"

Rojas‐Reyes MX, Orrego‐Rojas PA. Rescue high‐frequency jet ventilation versus conventional ventilation for severe pulmonary dysfunction in preterm infants. Cochrane Database of Systematic Reviews 2015, Issue 10.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome (measured at approximately 2 years' corrected age; acceptable range 18 months to 28 months) including cerebral palsy, delayed neurodevelopment (BSID MDI < 70), legal blindness (< 20/200 VA), and hearing deficit (aided or < 60 dB on audiometric testing); impairment defined as including any of the aforementioned deficits

"Study authors reported no significant differences in overall mortality between rescue high‐frequency jet ventilation and conventional ventilation and presented highly imprecise results for important adverse effects such as intraventricular haemorrhage, new air leaks, airway obstruction and necrotising tracheobronchitis. The overall quality of evidence is affected by limitations in trial design and by imprecision due to the small number of infants in the included study. Existing evidence does not support the use of high‐frequency jet ventilation as rescue therapy in preterm infants. Studies that target populations at greatest risk and that have sufficient power to assess important outcomes are needed. These trials should incorporate long‐term pulmonary and neurodevelopmental outcomes"

Romantsik O, Bruschettini M, Zappettini S, Ramenghi LA, Calevo MG. Heparin for the treatment of thrombosis in neonates. Cochrane Database of Systematic Reviews 2016, Issue 11.

Secondary outcomes pre‐specified include:

1. Major neurodevelopmental disability, that is, (1) cerebral palsy on physician assessment (yes/no); (2) developmental delay or intellectual impairment: BSID or GMDS assessment > 2 SD below the mean, or intellectual impairment (IQ > 2 SD below the mean); neuromotor development (BSID PDI) assessed in survivors; mental development (BSID MDI) assessed in survivors; (3) blindness vision (< 6/60 in both eyes); or (4) sensorineural deafness requiring amplification. We will report these components of this long‐term outcome for all trials that have assessed children after 18 months' chronological age. We will perform separate analyses for children aged 18 to 24 months and for those aged 3 to 5 years

"We found no studies that met our inclusion criteria and no evidence from randomized controlled trials to recommend or refute the use of heparin for treatment of neonates with thrombosis"

Sankar MJ, Sankar J, Mehta M, Bhat V, Srinivasan R. Anti‐vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database of Systematic Reviews 2016, Issue 2.

Secondary outcomes pre‐specified include:

1. Adverse neurodevelopmental outcomes at 18 months to 24 months' corrected age:

   1. Cerebral palsy and/or

   2. Moderate to severe developmental delay as assessed on performance in formal neurodevelopmental testing such as the BSID scale

"Implications for practice: Intravitreal bevacizumab reduces the risk of refractive errors during childhood when used as monotherapy while intravitreal pegaptanib reduces the risk of retinal detachment when used in conjunction with laser therapy in infants with type 1 ROP. Quality of evidence was, however, low for both the outcomes because of the risk of detection and other biases. Effect on other critical outcomes and, more importantly, the long‐term systemic adverse effects of the drugs are not known. The insufficient data precludes strong conclusions favouring routine use of intravitreal anti‐VEGF agents in preterm infants with type 1 ROP. Implications for research: Further studies are needed to evaluate the effect of anti‐VEGF agents on structural and functional outcomes in childhood and delayed systemic adverse effects such as myocardial dysfunction and adverse neurodevelopmental outcomes"

Schulzke SM, Kaempfen S, Trachsel D, Patole SK. Physical activity programs for promoting bone mineralization and growth in preterm infants. Cochrane Database of Systematic Reviews 2014, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental abnormalities at 18 to 24 months' corrected age or later:

   1. Cerebral palsy

   2. Developmental delay (assessed by standardised and validated test, e.g. GMDS or BSID test, with abnormality defined as > 2 SD below the mean)

   3. Intellectual impairment (IQ > 2 SD below the mean as assessed by a standardised and validated test)

   4. Blindness (vision < 6/60 in both eyes)

   5. Sensorineural deafness requiring amplification

"Some evidence suggests that physical activity programs might promote short‐term weight gain and bone mineralization in preterm infants. Data are inadequate to allow assessment of harm or long‐term effects. Current evidence does not support the routine use of physical activity programs in preterm infants. Further trials incorporating infants with a high baseline risk of osteopenia are required. These trials should address adverse events, long‐term outcomes, and the effects of nutritional intake (calories, protein, calcium, phosphorus)"

Shah PS, Ohlsson A. Alpha‐1 proteinase inhibitor (a1PI) for preventing chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 3.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome (frequency of cerebral palsy and/or mental retardation, legal blindness, and /or deafness)

(Review reports on 'Developmental delay amongst infants assessed' for 1 RCT (83 infants); however it was not clear whether this included cerebral palsy (in review or RCT (published as abstract only))

"Prophylactic administration of a1PI did not reduce the risk of CLD at 36 weeks or long term adverse developmental outcomes in preterm neonates"

Shah PS, Kaufman DA. Antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants. Cochrane Database of Systematic Reviews 2009, Issue 2.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental disability at 18 to 24 months (includingcerebral palsy, cognitive impairment, deafness, and blindness)

"Antistaphylococcal immunoglobulins (INH A‐21 and Altastaph) are not recommended for prevention of staphylococcal infections in preterm or VLBW neonates. Further research to investigate the efficacy of other products such as Pagibaximab is needed"

Shah SS, Ohlsson A, Halliday HL, Shah VS. Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates. Cochrane Database of Systematic Reviews 2012, Issue 5.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome: Neurodevelopmental impairment was defined as presence of cerebral palsy and/or mental retardation (BSID MDI < 70) and/or legal blindness (< 20/200 VA) and/or deafness (aided or < 60 dB on audiometric testing) assessed at 18 to 24 months

"This review found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator dependent preterm infants. Neither inhaled steroids nor systemic steroids can be recommended as a part of standard practice for ventilated preterm infants. Because they might have fewer adverse effects than systemic steroids, further randomised controlled trials of inhaled steroids are needed that address risk/benefit ratio of different delivery techniques, dosing schedules and long‐term effects, with particular attention to neurodevelopmental outcome"

Shah SS, Ohlsson A, Halliday HL, Shah VS. Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants. Cochrane Database of Systematic Reviews 2012, Issue 5.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome: Neurodevelopmental impairment is defined as presence of cerebral palsy and/or mental retardation (BSID MDI < 70) and/or legal blindness (< 20/200 VA) and/or deafness (aided or < 60 dB on audiometric testing) assessed at 18 to 24 months

"This review found no evidence that inhaled corticosteroids confer net advantages over systemic corticosteroids in the management of ventilator dependent preterm infants. Neither inhaled steroids nor systemic steroids can be recommended as standard treatment for ventilated preterm infants. There was no evidence of difference in effectiveness or side‐effect profiles for inhaled versus systemic steroids. A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing side‐effects. To resolve this issue, studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. The long‐term effects of inhaled steroids, with particular attention to neurodevelopmental outcome, should be addressed in future studies"

Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database of Systematic Reviews 2011, Issue 8.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental disability at 18 to 24 months (including cerebral palsy, cognitive impairment, deafness, and blindness)

"Sildenafil in the treatment of PPHN has significant potential especially in resource limited settings. However, a large scale randomised trial comparing sildenafil with the currently used vasodilator, inhaled nitric oxide, is needed to assess efficacy and safety"

Sinclair JC, Bottino M, Cowett RM. Interventions for prevention of neonatal hyperglycemia in very low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 10.

Primary outcomes pre‐specified include:

1. Neurodevelopmental impairment defined as presence of 1 or more of the following: cerebral palsy, MDI or PDI < 70, blindness or deafness assessed between 18 and 24 months' post‐menstrual age or at latest assessment up to 24 months' corrected age

"Glucose infusion rate: There is insufficient evidence from trials comparing lower with higher glucose infusion rates to inform clinical practice. Large randomized trials are needed, powered on clinical outcomes including death, major morbidities and adverse neurodevelopment. Insulin infusion: The evidence reviewed does not support the routine use of insulin infusions to prevent hyperglycemia in VLBW neonates. Further randomized trials of insulin infusion may be justified. They should enrol extremely low birth weight neonates at very high risk for hyperglycemia and neonatal death. They might use real time glucose monitors if these are validated for clinical use. Refinement of algorithms to guide insulin infusion is needed to enable tight control of glucose concentrations within the target range"

Singh N, Halliday HL, Stevens TP, Suresh G, Soll R, Rojas‐Reyes MX. Comparison of animal‐derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 2015, Issue 12.

Secondary outcomes pre‐specified include:

1. Cerebral palsy at approximately 2 years' corrected age (as defined by the study authors)

2. Neurodevelopmental outcome at approximately 2 years' corrected age (acceptable range 18 months to 28 months) including cerebral palsy, delayed neurodevelopment (BSID MDI < 70), legal blindness (< 20/200 VA), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome 'neurodevelopmental impairment' was defined as having any 1 of the aforementioned deficits

"Significant differences in clinical outcome were noted in the comparison trials of modified minced lung surfactant extract (beractant) compared with porcine minced lung surfactant extract (poractant alfa) including a significant increase in the risk of mortality prior to discharge, death or oxygen requirement at 36 weeks' postmenstrual age, PDA requiring treatment and "receiving > 1 dose of surfactant" in infants treated with modified bovine minced lung surfactant extract compared with porcine minced lung surfactant extract. The difference in these outcomes was limited to studies using a higher initial dose of porcine minced lung surfactant extract. It is uncertain whether the observed differences are from differences in dose or from source of extraction (porcine vs. bovine) because of the lack of dose‐equivalent comparison groups with appropriate sample size. No differences in clinical outcomes were observed in comparative trials between bovine lung lavage surfactant and modified bovine minced lung surfactants"

Soll R, Özek E. Prophylactic animal derived surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 1997, Issue 4.

Secondary outcomes pre‐specified include:

1. Cerebral palsy

2. Neurodevelopmental outcome at approximately 2 years' corrected age (acceptable range 18 months to 28 months) including cerebral palsy, mental retardation (BSID MDI < 70), legal blindness (< 20/200 VA), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome "neurodevelopmental impairment" will be defined as having any 1 of the aforementioned deficits

"Prophylactic intratracheal administration of animal derived surfactant extract to infants judged to be at risk of developing respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants who receive prophylactic animal derived surfactant extract have a decreased risk of pneumothorax, a decreased risk of PIE, a decreased risk of mortality, and a decreased risk of BPD or death"

Stevens TP, Blennow M, Myers EH, Soll R. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database of Systematic Reviews 2007, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome at hospital discharge and at a later time point (> 1 year post‐conceptional age). Neurodevelopmental impairment is defined as the presence of cerebral palsy and/or mental retardation (BSID MDI < 70) and/or legal blindness (< 20/200 VA) and/or deafness (aided or < 60 dB on audiometric testing)

"Early surfactant replacement therapy with extubation to NCPAP compared with later selective surfactant replacement and continued mechanical ventilation with extubation from low ventilator support is associated with less need mechanical ventilation, lower incidence of BPD and fewer air leak syndromes. A lower treatment threshold (FIO2 < 0.45) confers greater advantage in reducing the incidences of airleak syndromes and BPD; moreover a higher treatment threshold (FIO2 at study > 0.45) was associated with increased risk of PDA. These data suggest that treatment with surfactant by transient intubation using a low treatment threshold (FIO2 < 0.45) is preferable to later, selective surfactant therapy by transient intubation using a higher threshold for study entry (FIO2 > 0.45) or at the time of respiratory failure and initiation of mechanical ventilation"

Stewart A, Inglis GDT, Jardine LA, Koorts P, Davies MW. Prophylactic antibiotics to reduce morbidity and mortality in newborn infants with intercostal catheters. Cochrane Database of Systematic Reviews 2012, Issue 4.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome (cerebral palsy, sensorineural hearing loss, visual impairment, or developmental delay) at 1 year, 18 months, 2 years, or 5 years

No included trials

"There are no data from randomised trials to either support or refute the use of antibiotic prophylaxis for intercostal catheter insertion in neonates. Any randomised controlled trials of antibiotic prophylaxis would need to account for the fact that neonates who require insertion of an intercostal catheter may already be receiving antibiotics for other indications"

Subramaniam P, Ho JJ, Davis PG. Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 6.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental status at follow‐up: neurodevelopment measured on a validated scale that measures cognitive, motor, behavioural function, or blindness, deafness, or cerebral palsy at about 2 years of age

"There is insufficient evidence to evaluate prophylactic CPAP compared to oxygen therapy and other supportive care. However when compared to mechanical ventilation prophylactic nasal CPAP in very preterm infants reduces the need for mechanical ventilation and surfactant and also reduces the incidence of BPD and death or BPD"

Tan K, Lai NM, Sharma A. Surfactant for bacterial pneumonia in late preterm and term infants. Cochrane Database of Systematic Reviews 2012, Issue 2.

Secondary outcomes pre‐specified include:

1. Long‐term neurological outcomes (cerebral palsy, development measured by BSID or GMDS, intellectual function measured by IQ score, and presence of visual or hearing impairments) at 18 months of age or greater

No included trials

"There is no evidence from randomised controlled trials (RCTs) to support or refute the efficacy of surfactant in near‐term and term infants with proven or suspected bacterial pneumonia. RCTs are still required to answer this question"

Thayyil S, Milligan D. Single versus double volume exchange transfusion in jaundiced newborn infants. Cochrane Database of Systematic Reviews 2006, Issue 4.

Primary outcomes pre‐specified include:

1. Neurological deficits consistent with kernicterus at 2 years of age including athetoidcerebral palsy, impaired upward gaze and deafness, AN/AD, and subtle BIND (Shapiro 2005)

Secondary outcomes pre‐specified include:

1. Neurological deficits or neurodisabilty defined as any of deafness, cerebral palsy, or cognitive delay (score > 2 SD below the mean for any recognised test for neurodevelopment, e.g. BSID)

"There was insufficient evidence to support or refute the use of single volume exchange transfusion as opposed to double volume exchange transfusion in jaundiced newborns. A change from the current practice of double volume exchange transfusions for severe jaundice in newborns infant, cannot be recommended on current evidence"

Vasudevan C, Oddie SJ, McGuire W. Early removal versus expectant management of central venous catheters in neonates with bloodstream infection. Cochrane Database of Systematic Reviews 2016, Issue 4.

Primary outcomes pre‐specified include:

1. Neurodevelopmental outcomes assessed after 12 months' post‐menstrual age using validated tools: neurological evaluations, developmental scores, and classifications of disability, including auditory and visual disability. We will define neurodevelopmental impairment as the presence of 1 or more of the following: non‐ambulant cerebral palsy, developmental delay (DQ > 2 SD below population mean), blindness (VA < 6/60), or deafness (any hearing impairment requiring or unimproved by amplification)

No included trials

"There are no trial data to guide practice regarding early removal versus expectant management of central venous catheters in newborn infants with bloodstream infections. A simple and pragmatic randomised controlled trial is needed to resolve the uncertainty about optimal management in this common and important clinical scenario"

Verner AM, McGuire W, Craig JS. Effect of taurine supplementation on growth and development in preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2007, Issue 4.

Secondary outcomes pre‐specified include:

1. Development

   1. Neurodevelopmental outcomes at ≥ 12 months of age (corrected for preterm birth) measured using validated assessment tools

   2. Severe neurodevelopmental disability defined as any 1 or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment

   3. Cognitive and educational outcomes at > 5 years old: IQ and/or indices of educational achievement measured using a validated assessment tool (including school examination results)

"Despite that lack of evidence of benefit from randomised controlled trials, it is likely that taurine will continue to be added to formula milks and parenteral nutrition solutions used for feeding preterm and low birth weight infants given the putative association of taurine deficiency with various adverse outcomes. Further randomised controlled trials of taurine supplementation versus no supplementation in preterm or low birth weight infants are unlikely to be viewed as a research priority, but there may be issues related to dose or duration of supplementation in specific subgroups of infants that merit further research"

Watson J, McGuire W. Responsive versus scheduled feeding for preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 8.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcomes at > 12 months' corrected age measured using validated assessment tools such as BSID and classifications of disability including auditory and visual disability. We defined the composite outcome 'severe neurodevelopmental disability' as any 1 or combination of the following: non‐ambulant cerebral palsy, developmental delay (DQ < 70), auditory and visual impairment

"Overall, the data do not provide strong or consistent evidence that responsive feeding affects important outcomes for preterm infants or their families. Some (low quality) evidence exists that preterm infants fed in response to feeding and satiation cues achieve full oral feeding earlier than infants fed prescribed volumes at scheduled intervals. This finding should be interpreted cautiously because of methodological weaknesses in the included trials. A large RCT would be needed to confirm this finding and to determine if responsive feeding of preterm infants affects other important outcomes"

Wilkinson D, Andersen C, O'Donnell CPF, De Paoli AG, Manley BJ. High flow nasal cannula for respiratory support in preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 2.

Secondary outcomes pre‐specified include:

1. Long‐term neurodevelopmental outcome (rates of cerebral palsy on physician assessment, developmental delay, i.e. IQ 2 SD < mean on validated assessment tools such as BSID MDI), blindness, hearing impairment requiring amplification

"HFNC has similar rates of efficacy to other forms of non‐invasive respiratory support in preterm infants for preventing treatment failure, death and CLD. Most evidence is available for the use of HFNC as post‐extubation support. Following extubation, HFNC is associated with less nasal trauma, and may be associated with reduced pneumothorax compared with nasal CPAP. Further adequately powered randomised controlled trials should be undertaken in preterm infants comparing HFNC with other forms of primary non‐invasive support after birth and for weaning from non‐invasive support. Further evidence is also required for evaluating the safety and efficacy of HFNC in extremely preterm and mildly preterm subgroups, and for comparing different HFNC devices"

Wong V, Cheuk DKL, Chu V. Acupuncture for hypoxic ischemic encephalopathy in neonates. Cochrane Database of Systematic Reviews 2013, Issue 1.

Primary outcomes pre‐specified include:

1. Long‐term (> 12 months) major neurodevelopmental disability such 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, or any combination of these disabilities

No included trials

"The rationale for acupuncture in neonates with HIE is unclear and the evidence from randomized controlled trial is lacking. Therefore, we do not recommend acupuncture for the treatment of HIE in neonates. High quality randomized controlled trials on acupuncture for HIE in neonates are needed"

Woodgate PG, Flenady V, Steer PA. Intramuscular penicillin for the prevention of early onset group B streptococcal infection in newborn infants. Cochrane Database of Systematic Reviews 2004, Issue 2.

Secondary outcomes pre‐specified include:

1. Neurodevelopmental outcome (cerebral palsy, sensorineural hearing loss, visual impairment, developmental delay)

"This review does not support the routine use of intramuscular penicillin to prevent EOGBSD in newborn infants. There is a discrepancy between this finding and the results of a number of larger non‐randomised trials. Explanations for this are proposed. There is a need for this intervention to be tested as a component of the existing prevention strategies in widespread use"

Young L, Embleton ND, McCormick FM, McGuire W. Multinutrient fortification of human breast milk for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2013, Issue 2.

Primary outcomes pre‐specified include:

1. Development:

   1. Neurodevelopmental outcomes assessed using validated tools at > 12 months' corrected age and classifications of disability, including non‐ambulant cerebral palsy, developmental delay, auditory and visual impairment

   2. Cognitive and educational outcomes at > 5 years: IQ and/or indices of educational achievement measured using a validated tool (including school examination results)

"The limited available data do not provide convincing evidence that feeding preterm infants with multinutrient fortified breast milk compared with unfortified breast milk following hospital discharge affects important outcomes including growth rates during infancy. There are no data on long‐term growth. Since fortifying breast milk for infants fed directly from the breast is logistically difficult and has the potential to interfere with breast feeding, it is important to determine if mothers would support further trials of this intervention"

Young L, Morgan J, McCormick FM, McGuire W. Nutrient‐enriched formula versus standard term formula for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2012, Issue 3.

Primary outcomes pre‐specified include:

1. Development:

   1. Neurodevelopmental outcomes assessed using validated tools at > 12 months' corrected age and classifications of disability, including non‐ambulantcerebral palsy, developmental delay, auditory and visual impairment

   2. Cognitive and educational outcomes at > 5 years: IQ and/or indices of educational achievement measured using a validated tool (including school examination results)

"Current recommendations to prescribe "post‐discharge formula" for preterm infants following hospital discharge are not supported by the available evidence. Some limited evidence exists that feeding preterm infants following hospital discharge with "preterm formula" (which is generally only available for in‐hospital use) may increase growth rates up to 18 months corrected age"

Ziino AJA, Davies MW, Davis PG. Epinephrine for the resuscitation of apparently stillborn or extremely bradycardic newborn infants. Cochrane Database of Systematic Reviews 2002, Issue 3.

Primary outcomes pre‐specified include:

1. Severe disability at follow‐up at 12 months, 24 months, and 5 years on, defined as any of blindness, deafness, cerebral palsy, or cognitive delay (score > 2 SD below the mean for a recognised psychometric test, e.g. BSID)

Secondary outcomes pre‐specified include:

1. Cerebral palsy at 12 and 24 months, and at 5 years

No included trials

"No randomised, controlled trials evaluating the administration of epinephrine to the apparently stillborn or extremely bradycardic newborn infant were found. Similarly, no randomised, controlled trials that addressed the issues of optimum dosage and route of administration of epinephrine were found. Current recommendations for the use of epinephrine in newborn infants are based only on evidence derived from animal models and the human adult literature. Randomised trials in neonates are urgently required to determine the role of epinephrine in this population"