Anti-reflux formula and metabolic acidosis in NICU infants: a retrospective cohort study

To determine the incidence, time course, and reversibility of metabolic acidosis associated with anti-reflux (AR) formula in NICU infants, and to identify associated clinical factors. Retrospective cohort study of 161 NICU infants receiving Novalac AR for ≥ 3 days with serial blood gas data (Level IV NICU, Seoul, 2021–2025). Pre-specified time-point analyses demonstrated significant acid–base deterioration at Day 3 (mean ΔBE − 2.14 mEq/L; p < 0.001; n = 110) and Day 7 (− 2.46 mEq/L; p < 0.001; n = 120). Nadir-based analysis showed mean base excess declining from 0.53 ± 3.02 to − 3.51 ± 3.18 mEq/L (mean ΔBE − 4.04 mEq/L; 95% CI − 4.54 to − 3.54; p < 0.001). New-onset metabolic acidosis occurred in 19/161 infants (11.8%) by primary definition (pH < 7.35, HCO₃⁻ <20 mmol/L, and BE < − 4 mEq/L) and 37/161 (23.0%) by broader definition (HCO₃⁻ <20 mmol/L and BE < − 4 mEq/L). Acid–base deterioration was detectable at a mean of 2.3 days after initiation and reached nadir at a median of 5.4 days (IQR 3.3–8.4); 37.3% of infants had their recorded nadir after day 7. Among 50 infants in whom AR formula was discontinued, base excess improved by a mean of + 2.78 mEq/L ( p < 0.001), with 77.8% showing improvement from nadir. Both infants who underwent rechallenge following confirmed metabolic acidosis developed recurrent metabolic acidosis. Lower postmenstrual age (PMA) at initiation was the only independent predictor of acidosis risk on multivariable analysis (adjusted OR 0.71 per 1-week increase; 95% CI 0.57–0.89; p = 0.003). AR formula use is temporally associated with acid–base changes consistent with a retrospective safety signal, meeting metabolic acidosis criteria in 11.8–23.0% of cases; these changes were reversible in most cases after discontinuation. Consideration of acid–base monitoring within the first week of initiation may be reasonable, pending prospective confirmation, with particular attention to infants at lower postmenstrual ages.