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.

Human Milk Fortifiers Do Not Meet the Current Recommendation for Nutrients in Very Low Birth Weight Infants.

BACKGROUND: Use of multinutrient fortifiers is standard of care for small preterm infants fed exclusively human milk. However, adequacy of human milk fortifiers (HMFs) to meet the recommended intake for macronutrients and micronutrients is now known. MATERIALS AND METHODS: Nutrient content of human milk fortified according to manufacturer's recommendations was compared at isocaloric levels for 1 human milk-based (HMF-A), 2 bovine milk protein-based (HMF-B, HMF-C), and 2 preterm infant formulas (PTF-B, PTF-C). In addition, 4 multivitamin supplements were compared. RESULTS: At 130 kcal/kg, intake of macronutrients was similar to the recommendation, although deficient and excess intake of micronutrient occurred with all fortifiers. Four to 9 micronutrients were absent in HMF or PTF (biotin, choline, inositol, carnitine, taurine, molybdenum, iodine, selenium, or chromium). For the remainder, HMF resulted in deficient intake for 1-13 micronutrients, occurring most frequently with HMF-A. Excess micronutrients (3-15 at <50% and 1-3 at 109%-437%) occurred with all HMF and most frequently with HMF-B and HMF-C. At 150 kcal/kg, deficient intake improved but generally remained below recommendation, while excess intake became exaggerated. PTF and multivitamin formulations do not fully compensate for the deficiencies and can result in extremely high micronutrient intake. CONCLUSIONS: At the recommended energy intake for very low birth weight infants, many micronutrients are absent or are present in grossly inadequate amounts, and several micronutrients are in excess. Reformulation of HMF is urgently needed since PTF or multivitamin supplement only partially corrects some deficiencies while providing some nutrients in excess.

Lack of Effect of Graded Doses of Vitamin D on Bone Metabolism of Breastfed Infants.

OBJECTIVE: A range of doses of supplemental vitamin D has been shown to be effective in preventing rickets in breastfed infants, but the effect of different doses of vitamin D on bone metabolism and mineral content has not been delineated. METHODS: In a randomized trial, breastfed infants received from 2 to 9 months daily supplements of vitamin D in doses of 200 IU/d, 400 IU/d, 600 IU/d or 800 IU/d. Measures of bone metabolism (plasma) were determined periodically and bone mineral content (DXA) was determined at study entry and at the end of winter when infants were 5.5 to 9 months old. The main findings have been reported; here we report findings related to bone metabolism. RESULTS: There were no consistent meaningful effects of vitamin D dose on markers of bone metabolism. Some markers showed changes with age. Bone mineral content increased with age but showed no effect of vitamin D dose. CONCLUSION: Vitamin D in daily doses from 200 IU/d to 800 IU/d had no measurable effect on bone mineral content or bone metabolism of breastfed infants.

Posthospital discharge feeding for preterm infants: effects of standard compared with enriched milk formula on growth, bone mass, and body composition.

BACKGROUND: Despite the theoretical benefits of nutrient-enriched formula given to preterm infants after hospital discharge, its role in reversing growth deficits after hospital discharge remains poorly defined. OBJECTIVE: The aim was to determine the effect of different formulas on the growth, bone mass, and body composition of preterm infants after hospital discharge. DESIGN: This was a randomized, double blind comparison of a nutrient-enriched formula (EF) and a formula for term infants (TF) given for 1 y after hospital discharge. Compared with the TF, the EF had a higher energy density and higher contents of protein, calcium, and phosphorus (by 10%, 21%, 44%, and 11%, respectively) and higher contents of almost all other nutrients (by >or=10%). RESULTS: Birth weights of the infants were 630-1620 g (median: 1250 g) and gestational ages were 24-34 wk (median: 29 wk). TF resulted in significantly greater weight, length, head circumference measurements, and their respective z scores on the basis of age- and sex-specific norms. At the end of the study, the mean z scores for the corrected age of infants in the TF group were -0.37 for weight, 0.001 for length, and 0.50 for head circumference. The TF group also had significantly greater dual-energy X-ray absorptiometry measured bone and lean and fat mass than did the EF group (P < 0.05 for all comparisons). CONCLUSIONS: The use of EF for preterm infants after hospital discharge shows no advantage over TF in growth, bone mineralization, and body composition. More studies are needed to determine the optimal postdischarge nutrition support for preterm infants.

Palm olein in the fat blend of infant formulas: effect on the intestinal absorption of calcium and fat, and bone mineralization.

OBJECTIVE: To evaluate the published clinical data on the physiologic effects of using palm oil and its low melting fraction, palm olein (PO) as a dominant lipid source in the fat blend in infant formulas. DESIGN: A systematic search of Medline and the Cochrane Database of Systematic Reviews was performed to retrieve studies comparing infants who received infant formulas containing PO with those who received infant formulas without PO or which contained synthetic triacylglyceride as a source of palmitic acid. Outcomes of interest include intestinal fractional absorption of fat, palmitic acid and calcium; and bone mass. The effect size for each dependent variable in each published study was obtained by standardizing based on the difference in means between non-PO and PO group with respect to the standard deviation of the PO group. Trend analysis of the outcome of interest was performed when 3 or more between group comparisons were available. The comparison of effect size across different studies was based on all available data and includes results that showed no significant difference between infants fed PO or non-PO study formulas in the outcomes of interest. RESULTS: Nine publications were identified with non-PO and PO comparison groups. The gestational ages of infants in the published studies were between 28 to 42 weeks and postnatal ages were birth to 192 days at study onset. Within each published study, there was some variability in the effect size between non-PO and PO groups. The standardized results were consistently significantly (p < 0.05) positive in favor of the feeding with non-PO formulas with respect to increased intestinal fractional absorption of fat, palmitic acid and calcium. The latter two variables were significantly different by at least 0.6 SD. Bone mass measured as total body bone mineral content was significantly higher in the non-PO group by at least 0.3 SD. CONCLUSION: The use of PO in infant formulas to match the human milk content of palmitic acid has unintended physiological consequences including diminished intestinal absorption of fat, palmitic acid and calcium and lower bone mass. The avoidance of PO or its substitution with synthetic triacylglyceride in infant formulas can prevent this detrimental effect.

Growth, tolerance and biochemical measures in healthy infants fed a partially hydrolyzed rice protein-based formula: a randomized, blinded, prospective trial.

OBJECTIVE: To evaluate growth, tolerance and plasma biochemistries in infants fed an experimental rice protein-based infant formula. DESIGN: Randomized, blinded, 16 week parallel feeding trial of 65 healthy infants fed either an experimental partially hydrolyzed rice protein-based infant formula fortified with lysine and threonine (RPF, n = 32), or a standard intact cow's milk protein-based formula (CMF, n = 33) as a control. Assessments occurred at enrollment (average 2 days), 2, 4, 8, and 16 weeks of age. RESULTS: Growth as indicated by weight, length, and head circumference was not different between the 2 formula groups. All plasma biochemistries for both groups were within reference normal range. However, RPF group had lower phosphorus and urea nitrogen, lower essential amino acids except threonine, which was higher, and lower ratio of essential (including semi-essential) to non-essential amino acids. Differences in the concentrations and ratios of amino acids became less as feeding progressed with age. Plasma total protein, albumin, prealbumin, calcium, magnesium, and alkaline phosphatase were not different between groups. CONCLUSION: Healthy infants fed an experimental partially hydrolyzed rice protein-based formula had normal growth, tolerance, and plasma biochemistry comparable to those of infants fed a standard intact milk protein-based formula, despite some differences in amino acid profiles.

Calcium and bone health in infants.

Osteopenia, rickets, and fractures from nutrient deficiencies can occur during infancy, particularly in preterm infants. Bone mass accretion during the first year of life is equal to or greater than that achieved at any other stage of life, including adolescence. Optimizing calcium and bone status during infancy can have immediate benefits in maintaining calcium homeostasis and preventing disturbances in bone mineralization and can provide long-term benefits by helping infants to later reach their maximum genetic potential for peak bone mass, a prerequisite for the prevention of osteoporosis and its complications. Dietary calcium requirements during infancy generally reflect the need to achieve normal growth and bone mineralization because 99 percent of total body calcium is present in the skeleton. Knowledge of physiologic factors that determine infant calcium requirements and the bioavailability of calcium from various dietary sources is important to ensuring bone health during infancy. Also key are the practical issues related to optimizing calcium nutriture in infants born at term and prematurely.

Reduced bone mineralization in infants fed palm olein-containing formula: a randomized, double-blinded, prospective trial.

OBJECTIVE: Palm and palm olein (PO) oils are used in some infant formula fat blends to match the fatty acid profile of human milk, but their presence has been shown to lower calcium and fat absorption. We aimed to determine if the reported differences in calcium absorption could affect skeletal development by comparing bone mineral accretion in healthy term infants fed a milk-based formula with (PMF) or without PO. METHODS: Whole body bone mineralization was evaluated in healthy term infants fed 1 of 2 coded, commercially available, ready-to-feed infant formulas in a randomized, double-blind, parallel study. Subjects were fed either 1). PMF formula (Enfamil with iron; Mead Johnson Division of Bristol Myers, Evansville, IN; N = 63) containing PO/coconut/soy/high-oleic sunflower oils (45/20/20/15% oil); or 2). milk-based formula without PO (Similac with iron; Ross Products Division Abbott Laboratories, Columbus, OH; N = 65), containing high-oleic safflower/coconut/soy oils (40/30/30% oil) from enrollment by 2 weeks after birth until 6 months. Anthropometrics and formula intake were determined monthly; total body bone mineral content (BMC) and bone mineral density (BMD) were measured at baseline, 3, and 6 months of age using dual energy x-ray absorptiometry. RESULTS: Intent-to-treat analyses indicated no significant differences between feeding groups in weight, length, head circumference, or formula intake throughout the study. BMC and BMD were not different at baseline but repeated measures analyses show that infants fed PMF had significantly lower BMC and BMD at 3 and 6 months. CONCLUSIONS: Healthy term infants fed a formula containing PO as the predominant oil in the fat blend had significantly lower BMC and BMD than those fed a formula without PO. The inclusion of PO in infant formula at levels needed to provide a fatty acid profile similar to that of human milk leads to lower bone mineralization.

Efficacy and safety of docosahexaenoic acid and arachidonic acid addition to infant formulas: can one buy better vision and intelligence?

Long chain polyunsaturated fatty acids (LCPUFA) namely arachidonic acid (ARA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3) are highly concentrated in the phospholipid bilayer of biologically active brain and retinal neural membranes and are important in phototransduction and neuronal function. The rationale for adding these LCPUFA to infant formula (IF) was primarily because of their presence in large quantities in the retina and brain and in human milk. In addition, infants fed IF containing LCPUFA and breastfed infants have comparable ARA and DHA levels in red cell and plasma, in contrast to the lower ARA and DHA levels in those fed IF containing only the essential fatty acids: linoleic (LA, 18:2n-6) and linolenic (LNA, 18:3n-3), the precursors to ARA and DHA, respectively. However, functional benefits in particular visual or neural development from IF containing LCPUFA remains controversial. Potential for excessive and/or imbalanced intake of n-6 and n-3 fatty acids exists with increasing fortification of LCPUFA to infant foods other than IF.