Clinical outcomes
| Description | Time frame | |
| Primary clinical outcome | ||
| Composite of necrotising enterocolitis (NEC), culture-proven sepsis and mortality | Requires any of these three diagnoses to fulfil the criterion | A |
| Secondary clinical outcomes | ||
| Feeding intolerance and growth | ||
| Time to reach full enteral feeds | The day of life the infant has received at least 150 mL/kg enteral feeds | A |
| Feeding interruption | Number 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 breast | A |
| Parenteral nutrition | Number of days of parental amino acid and/or lipid infusion; only days when the enteral feed <150 mL/kg/day should be included | A |
| Gastric aspirates | ≥100% of prefeed volume (2 hours volume if continuous); lower limit of 2 mL/kg | A |
| Stool frequency | Number of stools per day | A |
| Time to regain birth weight | First day of three success days when the infant weight is greater than birth weight | A |
| Weight, height and head circumference | SD score will be used for the calculations | B |
| Clinical variables for morbidity | ||
| Infancy | ||
| Mortality | A | |
| NEC | Bell'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 investigators | A |
| Culture-proven sepsis | Positive 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 sepsis | Requires any of these two diagnoses to fulfil the criterion | A |
| Mortality and morbidity index | Composite 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 perforation | Intestinal perforation without signs of intramural and/or portal gas and no signs of inflammation at surgery | A |
| Abdominal surgery | A | |
| Suspected sepsis, not culture-proven | Clinical deterioration and laboratory inflammatory response but negative blood culture | A |
| Pneumonia | Pathological X-ray confirmed by a radiologist, need of increased respiratory support/oxygen and laboratory inflammatory response | A |
| Bronchopulmonary dysplasia (BPD) | Need of extra oxygen, high flow nasal cannula, CPAP or ventilator at w36+040 | C |
| 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+0 | D |
| Intraventricular haemorrhage | Assessed with ultrasound; classified into grade I–IV42 | A |
| Periventricular leukomalacia | Assessed with ultrasound and MRI; criteria according to de Vries43 | A |
| Number of days with intensive care | Need of respirator or CPAP | A |
| Length of stay at the hospital | GW and day at discharge | A |
| Length of need of feeding tube | GW and day when the infant does not need it anymore | A |
| 2-year follow-up | ||
| Neurocognitive development | Bayleys III,44 Parent Report of Children’s Abilities–Revised (PARCA-R), and Ages and Stages Questionnaires (ASQ-3) tested by psychologist | E |
| Cerebral palsy | Tested by an experienced paediatrician and/or physiotherapist | E |
| Epilepsy | E | |
| Strabismus and/or impaired vision | E | |
| Impaired hearing | E | |
| Respiratory support | Need of extra oxygen and/or ventilatory support | F |
| Wheeze and/or asthma | G | |
| Severe infections | H | |
| Mortality | Including cause of death | H |
| Need of feeding tube | H | |
| Extra nutritional support | H | |
| Level of education of the parents | E | |
| Family status | E | |
| Day-care | E | |
| 5.5-year follow-up | ||
| Neurocognitive development | Wechsler Preschool and Primary Scale of Intelligence IV tested by a psychologist and Movement ABC-2 tested by a physiotherapist | I |
| Cerebral palsy | Tested by an experienced paediatrician and/or physiotherapist | I |
| Epilepsy | I | |
| Strabismus and/or impaired vision | I | |
| Impaired hearing | I | |
| Wheeze and/or asthma | I | |
| Mortality | Including cause of death | J |
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.