Table 1

Clinical outcomes

DescriptionTime frame
Primary clinical outcome
Composite of necrotising enterocolitis (NEC), culture-proven sepsis and mortalityRequires any of these three diagnoses to fulfil the criterionA
Secondary clinical outcomes
Feeding intolerance and growth
 Time to reach full enteral feedsThe day of life the infant has received at least 150 mL/kg enteral feedsA
 Feeding interruptionNumber of days feedings held for ≥12 hours or feeds reduced by >50% (mL/kg/day) not due to a clinical procedure or transitioning to the breastA
 Parenteral nutritionNumber of days of parental amino acid and/or lipid infusion; only days when the enteral feed <150 mL/kg/day should be includedA
 Gastric aspirates≥100% of prefeed volume (2 hours volume if continuous); lower limit of 2 mL/kgA
 Stool frequencyNumber of stools per dayA
 Time to regain birth weightFirst day of three success days when the infant weight is greater than birth weightA
 Weight, height and head circumferenceSD score will be used for the calculationsB
Clinical variables for morbidity
  NECBell's stage II–III;33 radiological assessment will be made blinded by an independent radiologist; the final decision will be confirmed by a blinded consensus panel review consisting of the investigatorsA
  Culture-proven sepsisPositive blood- and/or urine- and/or CSF culture, clinical deterioration and laboratory inflammatory response;34 further classified into early (<72 hours postpartum) or late (>72 hours postpartum) onset.A
  Composite of NEC and culture-proven sepsisRequires any of these two diagnoses to fulfil the criterionA
  Mortality and morbidity indexComposite measure requiring any of the following: death, NEC stage II–III, culture-proven sepsis, moderate to severe BPD or ROP stage III–V
  Spontaneous intestinal perforationIntestinal perforation without signs of intramural and/or portal gas and no signs of inflammation at surgeryA
  Abdominal surgeryA
  Suspected sepsis, not culture-provenClinical deterioration and laboratory inflammatory response but negative blood cultureA
  PneumoniaPathological X-ray confirmed by a radiologist, need of increased respiratory support/oxygen and laboratory inflammatory responseA
  Bronchopulmonary dysplasia (BPD)Need of extra oxygen, high flow nasal cannula, CPAP or ventilator at w36+040C
  Retinopathy of prematurity (ROP)Diagnosed by an independent ophthalmologist according to international classification; classified into stage I–V;41 the diagnosis is set after w42+0D
  Intraventricular haemorrhageAssessed with ultrasound; classified into grade I–IV42A
  Periventricular leukomalaciaAssessed with ultrasound and MRI; criteria according to de Vries43A
  Number of days with intensive careNeed of respirator or CPAPA
  Length of stay at the hospitalGW and day at dischargeA
  Length of need of feeding tubeGW and day when the infant does not need it anymoreA
 2-year follow-up
  Neurocognitive developmentBayleys III,44 Parent Report of Children’s Abilities–Revised (PARCA-R), and Ages and Stages Questionnaires (ASQ-3) tested by psychologistE
  Cerebral palsyTested by an experienced paediatrician and/or physiotherapistE
  Strabismus and/or impaired visionE
  Impaired hearingE
  Respiratory supportNeed of extra oxygen and/or ventilatory supportF
  Wheeze and/or asthmaG
  Severe infectionsH
  MortalityIncluding cause of deathH
  Need of feeding tubeH
  Extra nutritional supportH
  Level of education of the parentsE
  Family statusE
 5.5-year follow-up
  Neurocognitive developmentWechsler Preschool and Primary Scale of Intelligence IV tested by a psychologist and Movement ABC-2 tested by a physiotherapistI
  Cerebral palsyTested by an experienced paediatrician and/or physiotherapistI
  Strabismus and/or impaired visionI
  Impaired hearingI
  Wheeze and/or asthmaI
  MortalityIncluding cause of deathJ
  • Timeframe A, from birth until discharge (no longer than w44+0); B, at 7, 14, 21 and 28 days, end of intervention (≤ w34+0), w36+0, discharge (no longer than w44+0), and 2 years of age (corrected) and 5.5 years of age (uncorrected); C, at w36+0; D, from birth until w42+0; E, at 2 years of age (corrected); F, from w44+0 until 2 years of age; G, from birth until 2 years of age; H, from discharge or w44+0 (whether comes first) until 2 years of age; I, at 5.5 years of age (uncorrected); J, from 2 years until 5 years of age. Week (w) refers to postmenstrual week.

  • CPAP, continuous positive airway pressure; CSF, cerebrospinal fluid.