**Comparison of the Effect of Two Human Milk Fortifiers on Clinical Outcomes in Premature Infants**

**Melissa Thoene 1 , Corrine Hanson 2 , Elizabeth Lyden 3 , Laura Dugick 1 , Leslie Ruybal 4 and Ann Anderson-Berry 4,\*** 


*Received: 26 October 2013; in revised form: 17 December 2013 / Accepted: 20 December 2013 / Published: 3 January 2014* 

**Abstract:** The use of human milk fortifiers (HMF) helps to meet the high nutritional requirements of the human milk-fed premature infant. Previously available powdered products have not met the protein requirements of the preterm infant population and many neonatologists add powder protein modulars to help meet protein needs. The use of powdered products is discouraged in neonatal intensive care units (NICU) due to concern for invasive infection. The use of a commercially available acidified liquid product with higher protein content was implemented to address these two concerns. During the course of this implementation, poor growth and clinically significant acidosis of infants on Acidified Liquid HMF (ALHMF) was observed. The purpose of this study was to quantify those observations by comparing infant outcomes between groups receiving the ALHMF *vs*. infants receiving powdered HMF (PHMF). A retrospective chart review compared outcomes of human milk-fed premature infants <2000 g receiving the ALHMF (*n* = 23) and the PHMF (*n* = 46). Infant growth, enteral feeding tolerance and provision, and incidence of necrotizing enterocolitis (NEC), metabolic acidosis, and diaper dermatitis were compared between the two groups. No infants were excluded from this study based on acuity. Use of ALHMF resulted in a higher incidence of metabolic acidosis (*p* = 0.002). Growth while on HMF as measured in both g/kg/day (10.59 *vs*. 15.37, *p* < 0.0001) and in g/day (23.66 *vs*. 31.27, *p* = 0.0001) was slower in the ALHMF group, on increased mean cal/kg/day (128.7 *vs*. 117.3, *p* = 0.13) with nearly twice as many infants on the ALHMF requiring increased fortification of enteral feedings beyond 24 cal/ounce to promote adequate growth (48% *vs*. 26%, *p* = 0.10). Although we were not powered to study NEC as a primary outcome, NEC was significantly increased in the ALHMF group. (13% *vs*. 0%, *p* = 0.03). Use of a LHMF in an unrestricted NICU population resulted in an increase in clinical complications within a high-acuity NICU, including metabolic acidosis and poor growth. Although further research is needed to assess outcomes among infants with a variety of clinical acuities, gestational ages, and weights to confirm these findings, based on this experience, caution is urged to avoid potential risks.

**Keywords:** prematurity; human milk; fortifier; infant feeding; growth; acidosis

#### **1***.* **Introduction**

Infants born prematurely have increased nutrient needs compared to those born at term [1–3]. Nutrition-related goals for premature infants aim to mimic fetal nutrient accretion and growth *in utero* [4], yet many develop extrauterine growth restriction (EUGR) [5].

Despite the availability of customized, nutrient-dense enteral formulas, the American Academy of Pediatrics strongly supports the use of human milk for premature infants [6]. However, unfortified human milk remains inadequate to meet the high nutrient requirements of premature infants [1,4,7]. Provision of unfortified human milk has subsequently been linked to suboptimal growth (development of EUGR or growth < 15 g/kg/day), reduced bone density leading to osteopenia of prematurity and a clinical diagnosis of rickets, and the secondary consequences of each [1,4].

The use of commercial human milk fortifiers (HMF) allows for a more optimal provision of essential nutrients to meet premature infant requirements [1,4,7]. Macronutrient recommendations for low birth weight premature infants vary, but consensus goal ranges suggest enteral intake of 110–120 cal/kg/day and 3.4–4.4 g protein/kg/day [1]. Protein is specifically emphasized, as early and higher provisions promote more desirable growth and clinical outcomes [8,9]. The use of HMF has been shown to be both safe and effective in improving growth and nutrition status of premature infants compared to unfortified human milk [7,10,11]. In recent years the use of HMF with additional powdered protein modular has been presented as a method of supplying the preterm infant with the recommended amount of enteral protein to provide improved linear growth and neurodevelopmental outcomes [12,13].

Human milk fortifiers have primarily been available in powder form, although the United States Food and Drug Administration discourages the use of powdered forms in the neonatal intensive care units (NICU) secondary to contamination risk [14]. They additionally advise that "alternatives to powdered forms should be chosen when possible" [14]. To comply with this recommendation and achieve improved protein intake, The Nebraska Medical Center (TNMC) NICU changed standard human milk fortification practices with a powdered product when an acidified liquid HMF (ALHMF) with improved protein delivery became available. However, in the four months following our initial use of the ALHMF, clinical observations of infants receiving the ALHMF suggested an increased feeding intolerance, increased incidence of metabolic acidosis, poor growth, and a need for higher caloric densities of enteral feedings to promote adequate growth. Due to our concern for patient outcomes, use of the ALHMF was discontinued. The purpose of this study is to objectively quantify these clinical observations by comparing outcomes of infants receiving the ALHMF to those receiving the originally-used PHMF. Our study also looked to identify potential risk factors for the development of the observed clinical complications, as previous research evaluating the ALHMF also documented changes in pH and CO2 when compared to a powder HMF (PHMF) [15].

#### **2. Patients and Methods**

### *2.1. Participants and Study Design*

The institutional review board at the University of Nebraska Medical Center (Omaha, NE, USA) approved this study. Data was retrospectively collected from inpatient electronic medical records of all infants admitted to the NICU, between October 2009 and July 2011, if they met the following inclusion criteria: birth weight (BW) < 2000 g, received enteral feedings as fortified maternal breast milk during NICU stay, and remained in the NICU 14 days. Exclusion criteria included infants with congenital abnormalities or conditions that significantly inhibited growth, such as Trisomy 13. No infants were excluded based on clinical acuity. After extensive chart review, 69 infants were eligible for the study.
