Smell and taste of milk during tube feeding of preterm infants: neurodevelopmental follow-up of the randomized TASTE trial, study protocol

**Background:** Preterm birth is strongly associated with long-term neurodevelopmental challenges. Optimizing nutrition is a key focus because improved weight gain and head growth during initial hospitalization are linked to better long-term outcomes. Smell and taste sensations activate cephalic phase responses and "early nutritional learning," which may influence appetite, satiety, and weight gain during a critical period of brain development. The TASTE trial randomized 396 infants born <29 weeks postmenstrual age and/or <1250 g to receive smell and taste of milk with each tube feeding versus routine care. While the primary outcome (weight z-score at discharge) showed no between-group difference, prespecified secondary analyses found higher head circumference and length z-scores at 36 weeks postmenstrual age in the intervention group. Given that head growth is associated with neurodevelopment, this follow-up study was warranted.

**Methods:** This is a neurodevelopmental follow-up of the two-center, placebo-controlled randomized TASTE trial conducted at Mater Mothers' Hospital (Brisbane) and Royal Women's Hospital (Melbourne). Infants born <29 weeks postmenstrual age and/or <1250 g were randomized to smell and taste of milk with each tube feed or routine care. Of 396 randomized infants, 334 were discharged and eligible for follow-up. However, only 270 met Australian and New Zealand Neonatal Network criteria for routine clinical follow-up (<28 weeks and/or <1000 g). Assuming 90% follow-up, the study expected 243 participants. At 2 years corrected age, participants undergo standardized neurological assessment by a blinded examiner. Cerebral palsy is diagnosed using standard criteria with GMFCS classification. Bayley-III or Bayley-4 scales assess cognitive, language, and motor development. The primary outcome is survival free of moderate or severe neurodevelopmental impairment. Moderate disability includes Bayley scores < -2 to -3 SD or GMFCS II–III; severe disability includes scores < -3 SD, GMFCS IV–V, blindness, or deafness. Secondary outcomes include death, disability severity, cerebral palsy severity, Bayley centiles, anthropometrics (head circumference, weight, length z-scores), breastfeeding status at 3/6/12 months, respiratory support, and oral feeding status at 2 years. Statistical analysis uses intention-to-treat with logistic GEE models, accounting for clustering from multiples. Multiple imputation will address missing data under a MAR assumption, with sensitivity analyses for MNAR violations.

**Key Results:** This is a study protocol; no results are reported. The original TASTE trial found no difference in weight z-score at discharge (primary outcome) but did find higher head circumference and length z-scores at 36 weeks postmenstrual age in the intervention group (prespecified secondary analyses). The follow-up study has >80% power to detect a 13.7% difference in the primary outcome (87.7% vs 74%) at α=0.05, though this is larger than a minimum clinically significant effect. The COVID-19 pandemic impacted data collection, particularly at the Royal Women's Hospital in Melbourne where prolonged lockdowns prevented outpatient attendance. This will result in missing data and reduced statistical power.

**Clinical Implications:** For families of preterm infants, neurodevelopmental outcomes are of paramount importance and should be assessed after any neonatal intervention. Smell and taste of milk is an uncomplicated, cost-effective intervention with no known side effects that requires minimal extra time. If this follow-up demonstrates improved neurodevelopmental outcomes, it would provide strong evidence for implementing this simple intervention routinely in neonatal care. Even if the study is underpowered due to pandemic-related attrition, the data can contribute to future meta-analyses and inform trial design. The study also highlights the importance of embedding follow-up protocols into neonatal trials from the outset, as was done here with neurodevelopmental outcomes listed as secondary outcomes in the original TASTE protocol.