Plant-Derived Amino Acid-Based vs. Bovine-Derived Protein Human Milk Fortifiers in Preterm Infants at <34 Weeks' Gestation: An Open-Label Pilot Randomized Controlled Trial.

Background: Bovine milk protein-based human milk fortifiers (HMFs) are routinely used in preterm infants in low- and middle-income countries (LMICs) but are associated with potential adverse effects. Plant-derived amino acid-based HMFs are a promising alternative, but comparative data from randomized controlled trials (RCTs) are lacking. This pilot RCT aimed to evaluate the feasibility, safety, and growth outcomes of a novel plant-derived amino acid-based HMF compared to a bovine-derived whole-protein-based HMF in preterm infants at <34 weeks' gestation. Methods: In this open-label, parallel pilot RCT, preterm infants at <34 weeks' gestation were randomized to a plant-derived amino acid-based HMF (n = 66) or a bovine-derived whole-protein-based HMF (n = 70). Primary outcomes were time to reach 180 mL/kg/d enteral feeds and growth velocities to discharge and 40 weeks' postmenstrual age (PMA). Feasibility and safety were also assessed. The analysis followed an intention-to-treat approach. The trial was registered (CTRI/2025/06/089133). Results: Baseline characteristics were comparable between groups. Times to reach enteral feeds of 180 mL/kg/d did not differ (adjusted Hazard Ratio 0.93, 95% CI 0.65, 1.33; p = 0.70). In-hospital weight gain was significantly higher in the plant-derived HMF group (adjusted mean difference (aMD) 3.20 g/kg/d, 95% CI 0.46, 5.95; p = 0.02). This benefit was most evident in subgroup analyses of infants with birth weight ≥1500 g (aMD 4.47 g/kg/d, 95% CI 0.09, 8.84; p = 0.04). Length, head circumference growth, and all safety outcomes were similar between groups. Conclusions: The plant-derived amino acid-based HMF demonstrated clinical feasibility and was well-tolerated. While it was associated with better in-hospital weight gain, differences in overall macronutrient density between the formulations may account for this finding. These results are hypothesis-generating and warrant future adequately powered trials.