Enteral Feeding Progression Trajectories in the First Two Postnatal Weeks Are Associated with Motor Neurodevelopment at 24 Months in Preterm Infants: A Multicenter Cohort Study

Background/Objectives: Preterm infants are at substantial risk of neurodevelopmental impairment. Current guidelines recommend gradual advancement of enteral feeds during the first postnatal weeks, but the rate that is optimal for the individual infant remains uncertain. We modeled the day-by-day balance between enteral and parenteral nutrition during the first two postnatal weeks as longitudinal trajectory phenotypes and examined their association with neurodevelopment at 24 months of corrected age. Methods: Retrospective multi-center observational cohort of preterm infants (gestational age < 32 completed weeks or birth weight < 1500 g) from two centers managed under closely aligned nutritional protocols. The daily enteral-to-total-energy ratio on postnatal days 0–7 and 14 was clustered by K-means (K = 3) into parenteral-dominant (C0), moderate-progression (C1) and rapid-progression (C2) phenotypes. The primary outcome was the Bayley-III Motor composite at 24 months; Cognitive and Language composites at 24 months and the Motor composite at 12–18 months were additional outcomes. Linear mixed-effects models were adjusted for gestational age, birth-weight z-score and sex, with a random intercept for center. Results: Among 260 infants, three trajectory phenotypes were identified. At 24 months, the moderate-progression cluster had a higher Motor composite than the parenteral-dominant cluster (adjusted mean difference + 4.96 points; 95% CI, +1.51 to +8.41; p = 0.005; n = 194). In exploratory analyses of the other two domains, the unadjusted differences favoring the moderate cluster (cognitive + 7.1 points, p = 0.022; language + 6.9 points, p = 0.009) were abolished by adjustment for maturity (cognitive + 0.17 points, p = 0.94; language + 1.80 points, p = 0.45), whereas the motor difference remained statistically significant; the confidence intervals for these two domains do not exclude clinically relevant differences. The rapid-progression cluster did not differ significantly from either the parenteral-dominant or the moderate cluster, yielding a non-monotonic pattern. The motor association remained statistically significant after adjustment for baseline illness severity and was attenuated only marginally by downstream morbidities or the proportion of human milk. Conclusions: A moderate-progression enteral trajectory during the first two postnatal weeks was associated with better motor neurodevelopment at 24 months, whereas rapid advancement did not differ from parenteral dominance, so that the association was confined to a graded progression rather than to either extreme. The moderate-progression association was homogeneous across gestational-age strata (cluster × gestational age interaction, p = 0.23). These real-world findings are compatible with previously divergent evidence within a single non-monotonic dose–response framework.