Investigating the effect of caffeine to improve neurodevelopmental outcomes in babies born late preterm: a randomised controlled trial

INTERVENTION: Phase III trial Caffeine citrate, as an oral cherry flavoured syrup, 20 mg/kg once daily from Day 3 after birth until term corrected age. Dose can be reduced to 10 mg/kg if the baby is tachycardic (heart rate greater than 180 beats per min at rest 1 week after randomisation) or if the parents or clinicians believe the infant is having side effects. Adherence will be assessed by a research nurse measuring the remaining syrup in the bottle after 3 weeks of intervention. CONDITION: Late preterm birth;Neurodevelopmental impairment; ; Late preterm birth ; Neurodevelopmental impairment Neurological ‐ Other neurological disorders Reproductive Health and Childbirth ‐ Complications of newborn PRIMARY OUTCOME: Bayley Scale of Infant Development 4th Edition (BSID IV) cognitive score[Two and a half years corrected age] INCLUSION CRITERIA: Babies born between 34+0 and 36+6 weeks’ gestational age without contra‐indication to caffeine treatment. SECONDARY OUTCOME: Asthma/wheeze defined as wheeze or whistling in the chest in the past 12 months or doctor diagnosed asthma (yes to PARC #1/International Study of Asthma and Allergies in Childhood (ISAAC) #3 or ISAAC #7‐8 questions) by parental questionnaire[2.5 years corrected age] body mass inde X(BMI) z scores using data from secondary outcomes 9 and 23[two and half years corrected age] BSID IV language score (continuous)[Two and a half years corrected age] BSID IV motor score (continuous)[Two and a half years corrected age] Cognitive impairment, (BSID IV cognitive score more than one standard deviation (SD) below the test mean (<85, categorical))[Two and a half years corrected age] Death [assessed continuously from birth up to 2.5 years’ corrected age] Developmental delay (BSID IV cognitive or language score more than one SD below the test mean, <85, categorical)[2.5 years corrected age] Fully breastfeeding (the baby has taken breast milk only, no other liquids or solids except a minimal amount of water or prescribed medicines, in the past 48 hours) as reported by telephone follow up with parents. [ Term corrected age (40+0 weeks’ gestational age).] Head circumference z score assessed using tape measure[Two and half years corrected age] Healthcare utilisation after primary hospital discharge from ministry of health records of hospitalization, outpatient visits and emergency department visits[Assessed continuously from primary hospital discharge until 2.5 years corrected age] height z score assessed using stadiometer[two and half years corrected age] Infant and Toddler quality of life score[Two and a half years corrected age] Language delay (BSID IV language score more than one SD below the test mean, <85, categorical)[2.5 years corrected age] Length of stay in hospital, by review of medical records[From birth until discharge from primary neonatal admission] Moderate‐Severe cognitive impairment (BSID IV cognitive score more than two SD below the test mean, <70, categorical)[2.5 years corrected age] Moderate‐Severe language delay (BSID IV language score more than two SD below the test mean, <70, categorical)[2.5 years corrected age] Moderate‐Severe motor delay (BSID IV motor score more than two SD below the test mean, <70, categorical)[2.5 years corrected age] Motor delay (BSID IV motor score more than one SD below the mean, <85, categorical)[2.5 years corrected age] Predicating Asthma Risk in Childhood (PARC) score greater than or equal to 5 (high risk of school‐age asthma)[Two and a half years corrected age] Social‐emotional/behavioural delay (BSID IV Social‐Emotional score or BSID IV Adaptive Behaviour score more than one SD below the mean, <85, categorical)[2.5 years corrected age] Study drug dose discontinued due to side effects or poor tolerance from follow up phone‐call with parents[term corrected age (40+0 weeks’ gestational age)] Study drug dose reduced due to side effects or poor tolerance from follow up phone‐call with parents[Prior to term corrected age] Weight reported by parents during telephone follow up[term corrected age (40+0 weeks’ gestational age)] Weight z score assessed using digital scales, ; [Two and a half years corrected age] Weight z score based on weight reported by parents during telephone follow up[Term corrected age (40+0 weeks’ gestational age)]