Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial

Jacques Rigo, Jean-Michel Hascoët, Claude Billeaud, Jean-Charles Picaud, Fabio Mosca, Amandine Rubio, Elie Saliba, Michaël Radkë, Umberto Simeoni, Bernard Guillois, Virginie de Halleux, Jonathan Jaeger, Laurent Ameye, Nicholas P Hays, Johannes Spalinger, Jacques Rigo, Jean-Michel Hascoët, Claude Billeaud, Jean-Charles Picaud, Fabio Mosca, Amandine Rubio, Elie Saliba, Michaël Radkë, Umberto Simeoni, Bernard Guillois, Virginie de Halleux, Jonathan Jaeger, Laurent Ameye, Nicholas P Hays, Johannes Spalinger

Abstract

Objectives: The aim of this study was to assess growth and nutritional biomarkers of preterm infants fed human milk (HM) supplemented with a new powdered HM fortifier (nHMF) or a control HM fortifier (cHMF). The nHMF provides similar energy content, 16% more protein (partially hydrolyzed whey), and higher micronutrient levels than the cHMF, along with medium-chain triglycerides and docosahexaenoic acid.

Methods: In this controlled, multicenter, double-blind study, a sample of preterm infants ≤32 weeks or ≤1500 g were randomized to receive nHMF (n = 77) or cHMF (n = 76) for a minimum of 21 days. Weight gain was evaluated for noninferiority (margin = -1 g/day) and superiority (margin = 0 g/day). Nutritional status and gut inflammation were assessed by blood, urine, and fecal biochemistries. Adverse events were monitored.

Results: Adjusted mean weight gain (analysis of covariance) was 2.3 g/day greater in nHMF versus cHMF; the lower limit of the 95% CI (0.4 g/day) exceeded both noninferiority (P < 0.001) and superiority margins (P = 0.01). Weight gain rate (unadjusted) was 18.3 (nHMF) and 16.8 g · kg · day (cHMF) between study days 1 and 21 (D1-D21). Length and head circumference (HC) gains between D1 and D21 were not different. Adjusted weight-for-age z score at D21 and HC-for-age z score at week 40 corrected age were greater in nHMF versus cHMF (P = 0.013, P = 0.003 respectively). nHMF had higher serum blood urea nitrogen, pre-albumin, alkaline phosphatase, and calcium (all within normal ranges; all P ≤ 0.019) at D21 versus cHMF. Both HMFs were well tolerated with similar incidence of gastrointestinal adverse events.

Conclusions: nHMF providing more protein and fat compared to a control fortifier is safe, well-tolerated, and improves the weight gain of preterm infants.

Trial registration: ClinicalTrials.gov NCT01771588.

Figures

FIGURE 1
FIGURE 1
Study design. cHMF = control human milk fortifier; D1 = study day 1; D7 = study day 7; D10/11 = study day 10/11; D14 = study day 14; D21 = study day 21; DC = discharge (note that infants continued to receive their allocated study fortifier [or were transitioned to a routine/standard fortifier] until neonatal unit discharge or medical decision to stop fortification if length of stay was >21 days, and fortification was stopped after discharge) ; FSI1 = fortification strength increase day 1; HC = head circumference; HM = human milk; nHMF = new human milk fortifier; W40CA = week 40 corrected age.
FIGURE 2
FIGURE 2
Flow of study participants. AE = adverse event; cHMF = control human milk fortifier; D21 = study day 21; ITT = intent-to-treat; NEC = necrotizing enterocolitis; nHMF = new human milk fortifier; NICU = neonatal intensive care unit; PP = per-protocol; SAE = serious adverse event. ∗Although screening procedures were standardized across sites, some variability in prescreening procedures did occur. Based on the typical clinical characteristics of infants who were admitted to each NICU during the study interval, the total number of infants who would have been theoretically considered eligible for the study was higher than the number shown here.
FIGURE 3
FIGURE 3
Mean ± SD weight-for-age (panel A), length-for-age (panel B), and head circumference-for-age (panel C) z scores for the overall ITT population. Circle symbols/solid line represents nHMF. Triangle symbols/dashed line represents cHMF. FSI1 = fortification strength increase day 1; ITT = intent-to-treat; SD = standard deviation; W40CA = week 40 corrected age; z scores calculated using Fenton preterm growth chart (25). ∗P = 0.013 vs cHMF (by analysis of covariance, adjusting for value at D1, sex, and center); †P = 0.007 vs day 1 (by t test); ‡P = 0.041 vs day 1 (by t test); ∗∗P = 0.003 vs cHMF (by analysis of covariance, adjusting for value at D1, sex, and center).

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