Individualized Target Fortification of Breast Milk with Protein, Carbohydrates, and Fat for Preterm Infants: Effect on Neurodevelopment

Abstract

Background/Objectives: Preterm infants are at high risk of extrauterine growth restriction and suboptimal neurological development due to cumulative nutrient deficits. Standard fortification (SF) of human milk does not account for individual macronutrient variability, potentially leading to inadequate intake. Target fortification (TFO) adjusts supplementation based on the measured macronutrient content, aimed at providing macronutrient intake aligned with ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) recommendations and optimize growth and development. This study aims to evaluate the effects of TFO compared to SF on growth, body composition, and neurological outcomes at 18 months corrected age. Methods: In this double-blind, randomized controlled trial, preterm infants (<30 weeks gestation) received either SF or TFO for at least three weeks. Macronutrient levels in breast milk were analyzed three times per week, with modular adjustments in the TFO group. Growth parameters, body composition at 36 weeks postmenstrual age, and Bayley Scales of Infant and Toddler Development III (BSID-III) scores at 18 months corrected age were assessed (n = 69). Results: TFO significantly increased protein, fat, and carbohydrate intake compared to SF, leading to higher weight gain (2514 ± 289 g vs. 2283 ± 332 g, p < 0.01) and growth velocity (21.7 ± 2.3 g/kg/d vs. 19.2 ± 2.2 g/kg/d, p < 0.001). In infants whose mother's milk had low protein levels, fat-free mass was significantly higher with TFO compared to SF. BSID-III scores were higher in the TFO group across cognitive, language, and motor domains, with significant improvements in expressive language scores in infants whose mother's milk had high protein levels (p < 0.05). The number of preterm infants with a motor BSID-III score of ≤70 was significantly lower in the TFO group compared to the SF group (0 vs. 3, p < 0.05). Conclusions: TFO enhanced growth and body composition and may support better neurological outcomes in preterm infants. While most BSID-III differences were not statistically significant, the data suggest that TFO may reduce the risk of developmental delays. Larger, multicenter trials are needed to confirm these findings.

Keywords: body composition; carbohydrates; fat; growth; human milk; milk analysis; neurodevelopment; preterm infants; protein; target fortification.

Figure 1

Calculation of TFO. Template used by dietetic staff to determine the required amounts of modular protein, carbohydrate, and fat supplements to achieve ESPGHAN-recommended targets when added to standard-fortified breast milk. TFO—target fortification.

Figure 2

CONSORT flow diagram of the recruitment process. BM—breast milk; BSID-III—Bayley Scales of Infant and Toddler Development III; IVH—intraventricular hemorrhage; NEC—necrotizing enterocolitis.

Figure 3

Protein and energy intakes after fortification of human milk. Protein intake in g/kg/d and energy intake in kcal/kg/d had been calculated for every infant daily. Values were plotted against each other and are shown for (a) the control group (n = 1151) and (b) the intervention group (n = 1163). Blue ellipse marks the 95% confidence interval. A smaller 95% confidence interval represents smaller variability in protein and/or energy intake. Red dashed lines – median, n—number of measurements; SF—standard fortification; TFO—target fortification.

Figure 4

BSID-III scores for individual preterm infants. BSID-III scores were assessed on (a) the cognitive scale, (b) the language scale, and (c) the motor scale in the control and intervention groups. Values are presented as median and each point representing the BSID-III score of a single preterm infant. BSID-III—Bayley Scales of Infant and Toddler Development III.

Figure 5

Comparison of the effect size of short- vs. long-term outcome. Effect size of (a) the short-term outcome weight at 36 weeks is compared to (b) the long-term outcome Bayley cognitive (COG) score at 18 months, displayed for the low-protein (red) and high-protein (green) subgroups within the control and intervention groups. The difference (blue) between intervention and control group is attributed to TFO. Delta1 and Delta2 can be explained by differences in the protein content of native human milk during the intervention; Delta3 is attributable to variations in the protein content of native human milk before the start of TFO and after discharge from the NICU. COG—cognitive, TFO—target fortification.

Figure 6

Measured protein and energy content of nutrition before fortification, after SF, and after TFO, as well as the expected protein and energy content of breast milk after discharge. The target values during the NICU stay align with the ESPGHAN guidelines, set at 3.0 g of protein per 100 mL and 90 kcal of energy per 100 mL, assuming a fluid intake of 150 mL/kg/d [12]. The post-discharge target values follow World Health Organization recommendations for newborns aged 0 to 3 months, with 12.5 g/d of protein and 545 kcal/d for male newborns and 515 kcal/d for female newborns [58]. BM—breast milk; SF—standard fortification; TFO—target fortification.