Background Observational data suggest that slowly advancing enteral feeds in preterm infants may reduce necrotising enterocolitis but increase late-onset sepsis. The Speed of Increasing milk Feeds Trial (SIFT) compared two rates of feed advancement. Objective To determine if faster (30 ml/kg/day) or slower (18 ml/kg/day) daily feed increments improve survival without moderate or severe disability and other morbidities in very preterm or very low-birthweight infants. Design This was a multicentre, two-arm, parallel-group, randomised controlled trial. Randomisation was via a web-hosted minimisation algorithm. It was not possible to safely and completely blind caregivers and parents. Setting The setting was 55 UK neonatal units, from May 2013 to June 2015. Participants The participants were infants born at < 32 weeks’ gestation or a weight of < 1500 g, who were receiving < 30 ml/kg/day of milk at trial enrolment. Interventions When clinicians were ready to start advancing feed volumes, the infant was randomised to receive daily feed increments of either 30 ml/kg/day or 18 ml/kg/day. In total, 1400 infants were allocated to fast feeds and 1404 infants were allocated to slow feeds. Main outcome measures The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for gestational age. The secondary outcomes were mortality; moderate or severe neurodevelopmental disability at 24 months corrected for gestational age; death before discharge home; microbiologically confirmed or clinically suspected late-onset sepsis; necrotising enterocolitis (Bell’s stage 2 or 3); time taken to reach full milk feeds (tolerating 150 ml/kg/day for 3 consecutive days); growth from birth to discharge; duration of parenteral feeding; time in intensive care; duration of hospital stay; diagnosis of cerebral palsy by a doctor or other health professional; and individual components of the definition of moderate or severe neurodevelopmental disability. Results The results showed that survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 out of 1224 (65.5%) infants allocated to faster increments and 848 out of 1246 (68.1%) infants allocated to slower increments (adjusted risk ratio 0.96, 95% confidence interval 0.92 to 1.01). There was no significant difference between groups in the risk of the individual components of the primary outcome or in the important hospital outcomes: late-onset sepsis (adjusted risk ratio 0.96, 95% confidence interval 0.86 to 1.07) or necrotising enterocolitis (adjusted risk ratio 0.88, 95% confidence interval 0.68 to 1.16). Cost–consequence analysis showed that the faster feed increment rate was less costly but also less effective than the slower rate in terms of achieving the primary outcome, so was therefore found to not be cost-effective. Four unexpected serious adverse events were reported, two in each group. None was assessed as being causally related to the intervention. Limitations The study could not be blinded, so care may have been affected by knowledge of allocation. Although well powered for comparisons of all infants, subgroup comparisons were underpowered. Conclusions No clear advantage was identified for the important outcomes in very preterm or very low-birthweight infants when milk feeds were advanced in daily volume increments of 30 ml/kg/day or 18 ml/kg/day. In terms of future work, the interaction of different milk types with increments merits further examination, as may different increments in infants at the extremes of gestation or birthweight. Trial registration Current Controlled Trials ISRCTN76463425. Funding This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 18. See the NIHR Journals Library website for further project information.

Background Loss to follow-up resulting in missing outcomes compromises the validity of trial results by reducing statistical power, negatively affecting generalisability and undermining assumptions made at analysis, leading to potentially biased and misleading results. Evidence that incentives are effective at improving response rates exists, but there is little evidence regarding the best approach, especially in the field of perinatal medicine. The NIHR-funded SIFT trial follow-up of infants at 2 years of age provided an ideal opportunity to address this remaining uncertainty. Methods Participants: parents of infants from participating neonatal units in the UK and Ireland followed up for SIFT (multicentre RCT investigating two speeds of feeding in babies with gestational age at birth < 32 weeks and/or birthweight < 1500 g). Interventions: parents were randomly allocated to receive incentives (£15 gift voucher) before or after questionnaire return. The objective was to establish whether offering an unconditional incentive in advance or promising an incentive on completion of a questionnaire (conditional) improved the response rate in parents of premature babies. The primary outcome was questionnaire response rate. Permuted block randomisation was performed (variable size blocks), stratified by SIFT allocation (slower/faster feeds) and single/multiple birth. Multiple births were given the same incentives allocation. Parents were unaware that they were in an incentives SWAT; SIFT office staff were not blinded to allocation. Results Parents of 923 infants were randomised: 459 infants allocated to receive incentive before, 464 infants allocated to receive incentive after; analysis was by intention to treat. Allocation to the incentive before completion led to a significantly higher response rate, 83.0% (381/459) compared to the after-completion group, 76.1% (353/464); adjusted absolute difference of 6.8% (95% confidence interval 1.6% to 12.0%). Giving an incentive in advance is the more costly approach, but the mean difference of ~£3 per infant is small given the higher return. Conclusions An unconditional incentive in advance led to a significantly higher response rate compared to the promise of an incentive on completion. Against a backdrop of falling response rates to questionnaires, incentives can be an effective way to increase returns. Trial registration SIFT (ISRCTN76463425). Registered on March 5, 2013.; SWAT registration (SWAT 69 available from http://www.qub.ac.uk/sites/TheNorthernIrelandNetworkforTrialsMethodologyResearch/FileStore/Filetoupload,864297,en.pdf). Registered on June 27, 2016.

ConclusionIn our analysis, we noted that paracetamol was preferred to ibuprofen due to our success in treating (86% vs 43%) and safety profile (Nil vs 29%) in preterm babies. We analyzed the safety profile of paracetamol with regular levels and liver function and only two (9%) babies did not require dose changes to maintain the therapeutic levels emphasizing the importance of checking levels.