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

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Alan Lucas MD FMedSci, Maushumi Assad MD, MPH, Jan Sherman PhD, John Boscardin PhD, Steven Abrams MD

Abstract:

Background: Very low birthweight (VLBW) preterm infants fed mothers own milk (MOM) need nutritional supplementation, traditionally achieved with cow’s milk (CM) 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 fortif ied 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 increases in NEC (RR=3.3; P=0.001), ROP (RR=2.2; P=0.007), PDA (RR=1.6; P=0.009), interruption of feeding (RR=3.4; P=0.001) and a positive mortality/morbidity index based on one or more of death, NEC, sepsis, ROP and BPD (RR=1.4; P=0.006).

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.

Key Words: preterm infant feeding, cow’s milk-derived fortifiers, human milk-derived fortifiers, neonatal morbidity, donor milk

Abbreviations: MOM: Mothers own milk, CM: Cow’s milk, CMDF: Cow’s milk-derived fortifier, PTF: Preterm fortifier, HMDF: human milk-derived fortifier, NEC: Necrotizing enterocolitis, ROP: Retinopathy of prematurity, PDA: Patent ductus arteriosis, BPD: bronchopulmonary dysplasia, NICU: Neonatal intensive care unit

Introduction:

MOM is strongly recommended for very low birth weight (VLBW) preterm infants, but does not fully meet their nutritional needs, traditionally met by adding a CMDF to MOM, and when MOM is insufficient, by using a PTF. CM-based products have an important role in current neonatal practice in promoting growth, but evidence indicates that VLBW infants fed partly or wholly on CM products may have a greater risk of adverse outcomes relating to NEC14, late-onset sepsis (LOS) (5-8), mortality (7,8), ROP (7,9-11), BPD,(10,12) , brain development (13,14), cardiovascular risk (1517), bone health (18), atopic disease (19) and structural development of the heart, lungs and great vessels (20). It is unknown if these adverse outcomes relate to CM exposure, displacement of HM exposure, or both.

With increasing focus on using human milk in the NICU, official bodies (21,22) recommend using DM rather than PTF when MOM is insufficient, thus increasing HM exposure. Most units would then use a CMDF as the sole source of CM. Given the international emergence of this practice, testing the safety of CMDF, as used in this common practice, is critical. The ideal safety study is one where the base diet is 100% HM, and where it is possible to compare a CMDF versus an HMDF for a range of morbidities. However, remarkably few such studies have been undertaken. We identified only three studies of this design; the OptiMoM trial (9) together with two subgroup analyses of existing studies (1,10).

Our hypothesis, based on historical evidence of adverse outcomes seen with CM products (cited above), is that even when the base diet is 100% HM, CMDF is associated with major morbidity. A large, well-powered, hypothesis-testing trial has not been done to test this comprehensively. However, since feeding an all HM diet with a CMDF is so prevalent, we considered that the combined analysis of morbid outcomes and mortality from the three studies identified, providing 453 subjects, should be evaluated as this is the largest dataset of its type and may help to guide practice and research.

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