Sooner Is Better: Early Human Milk Fortification for Hospitalized Preterm Infants <29 Weeks

Extremely preterm infants frequently experience growth impairment during the months-long NICU hospitalization. Clinicians have known for decades that “supply-side” interventions, such as milk fortification, improve short-term growth and reduce long-term consequences of undernutrition, but most prior large, randomized studies used now-outdated approaches, such as formula rather than human milk as the base diet, or powdered rather than concentrated liquid human milk fortifiers. With well-documented health benefits, human milk is the preferred diet for extremely preterm infants,¹  but nutrient deficits accumulate even with fortification. Perceived safety concerns of fortification may further limit adequate nutrient delivery, although not supported conclusively by evidence. In the early postnatal days, parenteral nutrition is the primary diet, but recent data suggest safety limitations to parenteral protein provision.²  Thus, a pressing priority is to identify more effective early enteral nutrition strategies that minimize cumulative deficits while ensuring safety.

In this issue of Pediatrics, Ariel Salas and team report on “Increased Milk Protein to Accrue Critical Tissue” (IMPACT), a randomized trial testing a currently relevant, common-sense approach to enteral nutrition: rather than the typical practice of feeding unfortified milk until the infant reaches full-volume or nearly full-volume feeding, start human milk fortification early on enteral feeding day 2.³  IMPACT included 150 infants born < 29 weeks’ gestation. Results indicated better growth with early milk fortification (median age at fortification, 3 days) compared with fortification at or above 120 mL/kg per day (median age, 15 days). Early fortification resulted in less weight z-score decline during the intervention (−0.8 vs −1.1 from birth to day 14), as well as faster linear growth (0.9 vs 0.8 cm per week), and less head circumference z-score decline (−0.9 vs −1.3) through 36 weeks’ postmenstrual age (PMA), suggesting better overall growth quality. Adverse events, including necrotizing enterocolitis, were infrequent and no different between groups despite a chance imbalance in small for gestational age infants that might have favored more adverse events in the intervention group. Design strengths included randomization of participants and masking of families and most staff. Conclusions are strengthened by the racial and ethnic diversity of the sample, enhancing generalizability. Overall, results demonstrate a sustained growth benefit of early human milk fortification and support its safety, although precise estimation of adverse events is limited by sample size.

A focus on growth quality was a notable feature of IMPACT. Extremely preterm infants typically leave the NICU with a deficit in fat-free mass and excess of body fat compared with healthy newborns of the same PMA. Ideally, NICU diet interventions promote lean tissue accretion similar to the healthy fetus, while limiting excess fat accumulation. IMPACT specified fat-free mass at 36 weeks’ PMA as the primary outcome. To date, few randomized neonatal nutrition trials have used body composition indicators as study outcomes; IMPACT illustrates strengths and limitations of this approach. Because fat-free mass correlates with brain size⁴  and predicts later brain function⁵  better than fat mass, it is a more specific indicator of growth quality than body weight. However, body composition analysis with air displacement plethysmography is infeasible for infants receiving respiratory support. Sixteen IMPACT participants were unable to undergo air displacement plethysmography for this reason and were therefore missing primary outcome data. A related limitation is a gap in baseline data, because virtually all extremely preterm infants require respiratory support after birth. Fat-free mass z-score at study endpoint was higher in the intervention group (−1.2 vs −1.4) but the difference was not statistically significant. Changes in fat-free mass may have differed between groups, especially given chance differences in small for gestational age status at birth, but without baseline body composition data, one cannot make this comparison.

IMPACT used a human-milk–based human milk fortifier (HMF) for early fortification, followed by high protein liquid bovine-based HMF as standard of care for both study arms. The rationale for using human rather than bovine HMF for early fortification was not stated; it is possible that early fortification with bovine HMF would also be well-tolerated and produce similar—or even superior—results at substantially lower cost. Rigorously designed and implemented studies are needed to directly compare early fortification with human versus bovine HMF in terms of effectiveness, safety, costs, and overall value to inform decision-making. For NICUs that already use human HMF, IMPACT offers a potential strategy to shorten the treatment duration and lessen costs by switching to bovine HMF at 120 mL/kg per day rather than continuing for longer.

Overall, IMPACT is a well-designed, well-executed study supporting early human milk fortification for extremely preterm infants based on improved growth outcomes. Results suggest higher quality growth with early fortification, indicated by improved gains in body length and head circumference. IMPACT takes a notable step toward addressing the major gap in contemporary, pragmatic trials of diet-based strategies for extremely preterm infants during a critical period. In follow-up studies, it will be important to evaluate the extent to which early growth benefits translate to meaningful improvements in long-term neurodevelopment and other health outcomes.

HMF

human milk fortifier

IMPACT

Increased Milk Protein to Accrue Critical Tissue

PMA

postmenstrual age