Safety of Cow’s Milk-Derived Fortifiers Used with an All-Human Milk Base Diet in Very Low Birthweight Preterm Infants

Abstract

Background: Very low birthweight (VLBW) preterm infants fed mothers own milk (MOM) need nutritional supplementation, traditionally achieved with cow’s milk derived fortifier (CMDF) and preterm formula (PTF) if MOM is insufficient. CM products have been associated with diverse major morbidities. The current recommendation is to preferentially replace PTF with donor milk (DM) to produce a 100% human milk (HM) base diet, usually fortified with CMDF. Objective: To identify whether CMDF, even when fed with a 100% HM base diet, is related to an increased risk of major morbidities. Methods: We identified a randomized trial with an all-HM base diet, comparing CMDF with a fortifier derived from human milk (HMDF), and two additional studies of this design were generated from raw data as subgroup analyses of a randomized controlled trial and a quasi-experimental study. Using these studies, we calculated the impact of CMDF on major morbidities of death, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), sepsis, bronchopulmonary dysplasia (BPD) and patent ductus arteriosus (PDA). Results: Each study individually provided support for an increase in major morbidities with CMDF. Meta-analyses of pooled data showed that compared to HMDF, the CMDF group had large in- creases in NEC (RR = 3.3; P = .001), ROP (RR = 2.2; P = .007), PDA (RR = 1.6; P = .009), interruption of feeding (RR = 3.4; P = .001) and a positive mortality/morbidity index based on one or more of death, NEC, sepsis, ROP and BPD (RR = 1.4; P = .006). Conclusions: Despite the increased use of HM in modern neonatal care as a base diet, we found a greater risk of critical morbidities with CMDF compared with HMDF. This burden of morbidity provides evidence that the benefits of an HM base diet, might be, in part, counteracted by multiple adverse outcomes relating to the use of CMDF.