Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) I-Cognitive Function and Metabolic Risk.

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) II: Growth.

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials registers from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m2: adjusted mean difference (aMD) -0.11[95% CI -0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed (p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.

Individualized target fortification of breast milk with protein, carbohydrates, and fat for preterm infants: A double-blind randomized controlled trial.

BACKGROUND & AIMS: In preterm infants, natural variation of breast milk composition makes it difficult to achieve recommended macronutrient intakes with standard fortification. Evidence suggests that nutritional deficiency induces poor postnatal growth. This study investigates impacts of target fortification on preterm growth and metabolism by adjusting breast milk macronutrients. METHODS: This study was conducted as a single-centre, double-blind, randomized controlled trial for infants <30 gestational weeks. The control group received standard fortification and the intervention group received standard plus target fortification adding modular protein, lipids, and carbohydrates. Breast milk content was measured 3x/week using a validated near-infrared bedside spectrometer (NIRS). Modulars were added to achieve recommended values. To assess total nutrient intake, all 2810 native breast milk samples were analyzed - protein and fat using bedside-NIRS, lactose using tandem mass spectrometry (UPLC-MS/MS). Body composition was measured using air displacement plethysmography. Primary outcome was weight gain during the first 21 days of intervention. RESULTS: Baseline characteristics, morbidities, and total fluid intake were not different between groups (intervention n = 52, control n = 51). The intervention group infants had higher macronutrient intakes, weight gain (21.2 ± 2.5 vs 19.3 ± 2.4 g/kg/d, mean difference: 1.9 g/kg/d, 95% CI: 0.9 - 2.9), and body weight. Infants in the intervention group from mothers with below-average breast milk protein content showed greatest impact on weight at 36 weeks (2580 ± 280 g vs 2210 ± 300 g), length, head circumference, fat, and fat-free mass. Also, feeding intolerance was less frequent, blood urea was higher, and triglycerides were lower. CONCLUSIONS: This study provides evidence that target fortification of breast milk with low macronutrient content enhances the quality of nutrition and growth and is feasible in clinical routine.

Source and Quality of Enteral Nutrition Influences Oxidative Stress in Preterm Infants: A Prospective Cohort Study.

BACKGROUND: Preterm infants are at risk of oxidative stress from neonatal intensive care interventions. 8-Oxo-2'-deoxyguanosine (8-oxodG), generated by oxygen radical attack on DNA, is a potential marker of oxidative stress. The aim of the present study was to investigate the impact of quality and source of enteral nutrition (EN) on renal excretion of 8-oxodG in preterm infants. METHODS: Spontaneous urine samples were collected on postnatal days 26-31 in 33 preterm infants. Infants were fed either breast milk (BM), formula (FM), or BM/FM mixtures. Daily iron (Fe) supplementation was started day 28 ± 1 postnatally. 8-oxodG was determined by highperformance liquid chromatography-electrochemical detection (HPLC-EC). RESULTS: The 8-oxodG/creatinine ratio was significantly higher in infants fed FM vs FM/BM (38.7 ± 28.7 vs 16.7 ± 12.2 nmol 8-oxodG/mmol creatinine, P < 0.0001) or BM (11.6 ± 10.4 nmol 8-oxodG/mmol creatinine, P < 0.0001). There was no significant effect of Fe supplementation (P = 0.547). 8-OxodG excretion showed significant interindividual variation but was similar within pairs of twins. CONCLUSION: Quality and source of EN seem to influence oxidative stress in preterm infants. The underlying pathophysiological mechanism is unclear and needs further investigation. It may be speculated that other mechanisms than Fe supplementation contribute to oxidative stress, such as cow's milk protein-mediated up-regulation of the intestinal inflammatory cascade.

Target Fortification of Breast Milk: Predicting the Final Osmolality of the Feeds.

For preterm infants, it is common practice to add human milk fortifiers to native breast milk to enhance protein and calorie supply because the growth rates and nutritional requirements of preterm infants are considerably higher than those of term infants. However, macronutrient intake may still be inadequate because the composition of native breast milk has individual inter- and intra-sample variation. Target fortification (TFO) of breast milk is a new nutritional regime aiming to reduce such variations by individually measuring and adding deficient macronutrients. Added TFO components contribute to the final osmolality of milk feeds. It is important to predict the final osmolality of TFO breast milk to ensure current osmolality recommendations are followed to minimize feeding intolerance and necrotizing enterocolitis. This study aims to develop and validate equations to predict the osmolality of TFO milk batches. To establish prediction models, the osmolalities of either native or supplemented breast milk with known amounts of fat, protein, and carbohydrates were analyzed. To validate prediction models, the osmolalities of each macronutrient and combinations of macronutrients were measured in an independent sample set. Additionally, osmolality was measured in TFO milk samples obtained from a previous clinical study and compared with predicted osmolality using the prediction equations. Following the addition of 1 g of carbohydrates (glucose polymer), 1 g of hydrolyzed protein, or 1 g of whey protein per 100 mL breast milk, the average increase in osmolality was 20, 38, and 4 mOsm/kg respectively. Adding fat decreased osmolality only marginally due to dilution effect. Measured and predicted osmolality of combinations of macronutrients as well as single macronutrient (R2 = 0.93) were highly correlated. Using clinical data (n = 696), the average difference between the measured and predicted osmolality was 3 ± 11 mOsm/kg and was not statistically significant. In conclusion, the prediction model can be utilized to estimate osmolality values after fortification.

Challenges in breast milk fortification for preterm infants.

PURPOSE OF REVIEW: To outline new evidence published from 2013 to 2014 about breast milk fortification in preterm infants. RECENT FINDINGS: Breast milk is the feeding choice for preterm infants because of its immunoprotective properties. However, breast milk's nutrient content is not sufficient for preterm infants, and interindividual variation is high. The variation challenges standard fortification, which assumes a standard breast milk composition. Two new fortification strategies (adjustable fortification and target fortification) optimize macronutrient intake and improve growth. Adjustable fortification uses blood urea nitrogen levels to adjust fortifier strength. Target fortification analyzes breast milk and fortifies macronutrients individually to achieve targeted intake. Its feasibility is shown in clinical routine. Current breast milk analyzers used for target fortification achieve acceptable precision for protein and fat but not for lactose and energy. Evidence of benefits for postdischarge breast milk fortification is lacking. Eliminating cow's milk products and feeding exclusively breast milk may decrease the occurrence of feeding intolerance and necrotizing enterocolitis. To facilitate exclusively breast milk diets, a collaboration of prenatal, nutrition and lactation stakeholders is key. Fortification increases osmolality; however, safety cutoffs to prevent necrotizing enterocolitis are unclear. There is also new evidence that composition and structure of various macronutrients and micronutrients affect growth and development, and might play a role in future fortification concepts. SUMMARY: Recent research focuses on the variability of breast milk composition, its impact on postnatal growth patterns and the usefulness of target fortification. As well, diets exclusively composed of human milk are a promising approach to improve feeding tolerance. For safe fortification, osmolality cutoff levels are needed.

Fortification of breast milk in VLBW infants: metabolic acidosis is linked to the composition of fortifiers and alters weight gain and bone mineralization.

BACKGROUND & AIMS: Study objectives were to test (a) whether increased incidence of metabolic acidosis (MA) was caused by introduction of a new commercially available fortifier for breast milk, (b) if so, whether its modification would decrease the incidence of MA and (c) to analyze the impact of MA on growth. METHODS: Double-blind randomized design. Healthy breast-fed infants (≤34 gestational weeks). Primary outcome measure was incidence of MA (BE < -6.0 mmol/L). Secondary outcome measures were growth, bone mineral content (BMC), vital signs, treatment with sodium hydrogen carbonate and Ca and laboratory parameters (pH, pCO2, HCO3⁻, electrolytes). RESULTS: Part 1 (comparison of standard (SF) and new fortifier (NF)): Interim analysis showed MA in 1 out of 7 (SF) and 7 out of 8 (NF) infants, p = 0.01; therefore the study was interrupted; subsequently the fortifier was adapted by modifying mineral components. Part 2 (comparison of SF and reformulated fortifier (RF)): MA occurred in 3 out of 15 (SF) and 6 out of 19 (RF), p = 0.7. When data of all infants studied, those with MA had lower mean weight gain (median: 9 vs. 21 g/kg/d, p < 0.01) and lower BMC (1.6% vs. 1.9% BMC/lean, p = 0.04) at discharge. CONCLUSIONS: When fed fortified breast milk, mild MA spontaneously may develop in 20-30% of VLBW infants. A fortifier with an inappropriate composition may increase the severity and frequency of MA. Our data show that weight gain and BMC seem to be related to acid-base homeostasis. It may be speculated that inadequate growth of fully fed preterm infants is triggered more often by imbalances of acid-base status than previously expected.