Lower incidence of necrotizing enterocolitis in infants fed a preterm formula with egg phospholipids.

Necrotizing enterocolitis (NEC) causes approximately 4000 deaths/y and significant morbidity among U.S.-born preterm infants alone. Various combinations of inadequate tissue oxygenation, bacterial overgrowth, and enteral feeding with immaturity may cause the initial damage to intestinal mucosa that culminates in necrosis. Presently, there is not a way to predict the onset of the disease or to prevent its occurrence. As part of risk-benefit assessment, we compared disease in hospitalized preterm infants fed a commercial (control) preterm formula or an experimental formula with egg phospholipids for a randomized, double-masked, clinical study of diet and infant neurodevelopment. Infants fed the experimental formula developed significantly less stage II and III NEC compared with infants fed the control formula (2.9 versus 17.6%, p < 0.05), but had similar rates of bronchopulmonary dysplasia (23.4 versus 23.5%), septicemia (26 versus 31%), and retinopathy of prematurity (38 versus 40%). Compared with the control formula, the experimental formula provided 7-fold more esterified choline, arachidonic acid (AA, 0.4% of total fatty acids), and docosahexaenoic acid (0.13%). Phospholipids are constituents of mucosal membranes and intestinal surfactant, and their components, AA and choline, are substrates for intestinal vasodilatory and cytoprotective eicosanoids (AA) and the vasodilatory neurotransmitter, acetylcholine (choline), respectively. One or more of these components of egg phospholipids may have enhanced one or more immature intestinal functions to lower the incidence of NEC in this study. Regardless of the potential mechanism, a larger randomized trial designed to test the effect of this egg phospholipid-containing formula on NEC seems warranted.

Effect of long-chain n-3 fatty acid supplementation on visual acuity and growth of preterm infants with and without bronchopulmonary dysplasia.

Healthy preterm infants fed formula with long-chain n-3 fatty acids (n-3 LCFAs) from marine oil have better early visual acuity but lower plasma phosphatidylcholine (PC) arachidonic acid (AA) and growth than infants fed formula containing linolenic acid (LLA) as the sole n-3 fatty acid. This randomized, double-blind trial was designed to study the effects of a different source of n-3 LCFAs and a shorter feeding interval on visual acuity (by Teller Acuity Card) and growth of preterm infants (n = 59; 747-1275 g birth wt), some of whom required long periods of supplemental oxygen and developed bronchopulmonary dysplasia (BPD). Infants were studied at 0, 2, 4, 6, 9, and 12 mo past term. Plasma PC AA, and normalized weight, length, and head circumference were not influenced by BPD or n-3 LCFAs except that n-3 LCFA-supplemented infants weighed less at 6 (P<0.05) and 9 (P<0.01) mo and had smaller head circumferences at 9 mo (P<0.05). Compared with control infants, however, those fed n-3 LCFAs had lower weight-for-length at 2, 6, 9, and 12 mo (P<0.0003, P<0.0114, P<0.0008, and P<0.006, respectively). n-3 LCFAs improved early (2-mo) but not later acuity among infants without BPD (P<0.02). Regardless of diet, infants with BPD had poorer grating acuity at 2 (P<0.0002) and 4 (P<0.04) mo but not thereafter.

Visual acuity and fatty acid status of term infants fed human milk and formulas with and without docosahexaenoate and arachidonate from egg yolk lecithin.

Preterm infants fed formulas with docosahexaenoic acid (DHA, 22:6n-3) during the interval equivalent to the last intrauterine trimester and beyond have higher circulating DHA and transiently higher visual acuity compared with infants fed formulas containing linolenic acid. In term infants several nonrandomized studies of infants receiving DHA from human milk suggest a relationship between DHA status and acuity, but the evidence for a cause-and-effect relationship is mixed. In the present study, term infants were randomly assigned to a standard term formula (n = 20) or the same formula with egg yolk lecithin to provide DHA (0.1%) and arachidonic acid (AA, 20:4n-6, 0.43%) (n = 19) at levels reported in milk of American women. A third group of infants was breast fed for > or = 3 mo (n = 19). Grating visual acuity (Teller Acuity Card procedure) and plasma and red blood cell (RBC) phosphatidylcholine (PC) and phosphatidylethanolamine (PE) DHA and AA were determined at corrected ages of 2, 4, 6, 9 (acuity only), and 12 mo past term = 40 wk postmenstrual age (PMA). At 2 mo breast-fed infants and infants fed the supplemented formula had higher grating acuity than term infants fed standard formula. As in preterm infants, the increase was transient. Plasma PC DHA and AA and RBC PE AA increased by 2 mo in supplemented infants, but RBC PE DHA in supplemented infants was not higher than in controls until 4 mo and beyond. Despite normal intrauterine accumulation of DHA and AA, infants fed formula with 2% linolenic acid and 0.1% DHA had better 2-mo visual acuity than infants fed formula with 2% linolenic acid.

A randomized trial of visual attention of preterm infants fed docosahexaenoic acid until two months.

This was a randomized, double-blind trial to determine if a nutrient-enriched (preterm) formula supplemented with 0.2% docosahexaenoic acid (DHA, 22:6n-3) from a low eicosapentaenoic acid (0.06%) source of marine oil would enhance visual novelty preference and attention of preterm infants. Both the standard and experimental formulas contained 3% of total fatty acids as linolenic acid (18:3n-3) and were fed from approximately three days of age to two months past term. After two months, both diet groups were fed a commercially-available term formula with linolenic acid as the only source of n-3 fatty acid. At 12 mo visual recognition memory (novelty preference) and visual attention (number and duration of discrete looks) were determined with the Fagan Test of Infant Intelligence. The DHA-supplemented group compared with the control group had more and shorter duration looks in comparisons of familiar and novel stimuli, confirming earlier evidence that DHA can increase information processing speed of preterm infants who otherwise are receiving good intakes of linolenic acid. Because supplementation was stopped at two months and the effects seen at 12 mon, this study demonstrates for the first time that a relatively short period of DHA supplementation can produce significant effects on later visual attention.

A randomized trial of visual attention of preterm infants fed docosahexaenoic acid until nine months.

This randomized, double-blind trial tested the hypothesis that the addition of 0.2% docosahexaenoic acid (DHA, 22:6n-3) from marine oil to commercially-available preterm and term formulas with > or = 3% linolenic acid (18:3n-3) would enhance novelty preference and visual attention of preterm infants. Among preterm infants cared for in our center, study infants were a select group considered to be at lower risk for developmental delay. Study infants received their assigned diet (control, DHA-supplemented) from a mean postnatal age of 25 d until 9 mon past term. At 6.5, 9, and 12 mon past term, they were tested for visual recognition memory (novelty preference) and attention with the Fagan Test of Infant Intelligence. The effects of DHA supplementation were analyzed by repeated measures analysis of variance. In paired comparisons of novel and familiar stimuli, DHA-supplemented and control infants had the same novelty preference, but supplemented infants had more discrete looks to both novel (P < 0.03) and familiar (P < 0.02) stimuli and a shorter overall look duration (P < 0.03). These data are analogous to those from n-3-deficient and n-3-fed monkeys in that the group with better DHA status had shorter overall look duration. Because shorter look duration has been associated with more rapid information processing, preterm infants fed formulas with only linolenic acid may have had slower information processing than those fed DHA.

Long-chain fatty acids and early visual and cognitive development of preterm infants.

Preterm infants fed formula supplemented with DHA were shown in two randomized, clinical trials to have improved visual acuity in the first half of infancy. In the second clinical trial, infants simultaneously supplemented with DHA and provided with a nutrient-enriched preterm formula had a higher Bayley MDI score at 12 months than controls fed preterm formula. These data are the first evidence that DHA alone can also improve performance on early tests of mental development. Because visual and behavioural development are improved by providing this single dietary compound, DHA appears to be conditionally essential for preterm infants. Nevertheless, we would like to insert a few words of caution. More information about long chain n-3 and n-6 fatty acid requirements and balance for developing human infants is needed. As formulas are designed to meet n-3 and n-6 fatty acid needs, controlled studies of biochemistry and function should continue.

Effect of vitamin A supplementation of intravenous lipids on early vitamin A intake and status of premature infants.

Preterm infants were randomly assigned to receive routine vitamin A supplementation (Regular A) or additional vitamin A in intravenous lipids (High A). Because infants with bronchopulmonary dysplasia (BPD) have poorer vitamin A status than infants who do not develop BPD, High A and Regular A infants were divided by BPD (no or yes) before determining the effects of treatment on intake and plasma concentration of retinol in the first month. Compared with infants without BPD, those with BPD received less retinol (RE.kg-1.d-1) if assigned to Regular A and more if assigned to High A (BPD by vitamin A interaction, P < 0.002). High A-BPD infants compared with Regular A-BPD infants had significantly higher plasma retinol concentrations in the first month. Retinyl palmitate appears to be an effective adjunct to routine vitamin A administration. Infants most likely to benefit from receiving vitamin A in intravenous lipids are those advanced more slowly to full enteral feeding.

Visual-acuity development in healthy preterm infants: effect of marine-oil supplementation.

Docosahexaenoic acid (DHA; 22:6n-3) is important for normal visual development. We hypothesized that preterm infants fed formulas with marine oil as a source of DHA would have better visual acuity than infants fed formulas without marine oil, as measured by the Teller Acuity Card procedure. Marine oil (P < 0.001) and age (P < 0.0001) influenced visual acuity, by repeated-measures analysis of variance (ANOVA) corrected for the effect of subject. Marine-oil-supplemented infants had better visual acuity than those fed standard formulas at 2 and 4 mo of age, by Fishers' least-squares difference (LSD). Acuity of both dietary groups improved through 6.5 mo of age, then plateaued. Through 4 mo of age, acuity was inversely related to oxygen supplementation (log10 h) and positively related to DHA status, by general-linear-models (GLM) analysis. After 4 mo of age, birth weight and gestational age were the only variables consistently related to visual acuity by GLM. We conclude that marine-oil-supplemented formula improved visual acuity of preterm infants through 4 mo of age by improving DHA status.

Arachidonic acid status correlates with first year growth in preterm infants.

Diets deficient in the omega-6 fatty acid linoleic acid reduce arachidonic acid (Ach) concentrations and retard growth of developing animals and humans. Nevertheless, plasma phosphatidylcholine Ach concentrations declined from 84 +/- 23 mg/liter at birth to a nadir of 38 +/- 11 mg/liter at 4 mo of age in preterm infants fed commercial formulas with linoleic acid, and weight normalized to that of term infants fell progressively beginning at 2 mo of age. The nadir of plasma phosphatidylcholine Ach (31 +/- 7 mg/liter) and growth were further reduced by formula containing marine oil compared with the commercial formulas. Ach status (defined as the mean plasma phosphatidylcholine Ach concentration at 2, 4, and 6.5 mo) correlated with one or more measures of normalized growth through 12 mo. Ach status and maternal height accounted for as much as 59% of the weight variance and 68% of the length variance in infants fed standard formulas. Better Ach status was not from higher energy intakes. A conditional Ach deficiency in preterm infants may contribute to growth over the first year of life. On the strength of the relationship between Ach status and growth, we hypothesize that dietary Ach could improve first year growth of preterm infants.

First year growth of preterm infants fed standard compared to marine oil n-3 supplemented formula.

Very low birth weight (VLBW) infants (748-1390 g, n = 65) were randomly assigned to receive control or marine oil-supplemented formula when they achieved intakes > 454 kJ (110 kcal)/kg/d of a formula designed for VLBW infants. Study formulas with or without marine oil were provided until 79 wk of postconceptional age (PCA), first in a formula designed for preterm infants followed by a formula designed for term infants. Infants were studied at regular intervals through 92 wk PCA. Weight, length, and head circumference were determined by standardized procedures and normalized to the National Center for Health Statistics figures for growth of infants born at term of the same age and gender. Mean normalized weight, weight-to-length, and head circumference were greatest at 48 wk and decreased thereafter. The decline in normalized weight was greater in infants fed the marine oil-supplemented formula. Beginning at 40 wk, marine oil-supplemented infants compared to controls had significantly poorer Z-scores for weight, length and head circumference. In addition, birth order (negatively) and maternal height (positively) influenced weight and length achievement in infancy as shown previously in infants born at term.

Effect of vegetable and marine oils in preterm infant formulas on blood arachidonic and docosahexaenoic acids.

Adding docosahexaenoic acid (DHA) (22:6n-3) to formulas is more effective than increasing formula alpha-linolenic acid (18:3n-3) in maintaining blood phospholipid DHA levels similar to those in breast-fed infants. However, in long-term trials supplementary DHA given as marine oil reduces blood phospholipid arachidonic acid (AA) in preterm infants. This effect is not seen in short-term trials unless the total n-3 intake from marine oil exceeds 0.5% of the total fatty acids. In addition, there is considerable variability among individual preterm infants in blood phospholipid AA and DHA levels that is not dependent on diet. Within dietary treatments, a significant positive correlation between AA and DHA concentrations suggests that factor(s) other than marine oil supplementation affect both AA and DHA status. Docosahexaenoic acid and AA concentrations in plasma phospholipids are significantly correlated with DHA and AA concentrations in red blood cell phospholipids, suggesting that the observed individual differences in DHA and AA within groups represent true differences in fatty acid status. Preterm infants appear to be vulnerable to a poor status of both DHA and AA; further feeding trials are needed to identify the optimal balance of fatty acids for feeding these infants.

Long-term feeding of formulas high in linolenic acid and marine oil to very low birth weight infants: phospholipid fatty acids.

Red blood cell (RBC) phospholipids of infants fed human milk compared with formula have more arachidonic acid (AA) and docosahexanoic acid (DHA). The addition of low levels of marine oil to infant formula with 0.6 to 2.0% alpha-linolenic acid (LLA, 18:3n-3) prevented declines in DHA in formula-fed infants; however, the feeding trials were short (4 to 6 wk), LLA concentrations were low compared with current formulas (3.0 to 5.0% LLA), and the formulas were unstable. Trials with stable formulas were necessary to determine if dietary DHA could maintain phospholipid DHA after discharge from the hospital and, in fact, if it was necessary with higher intakes of LLA. The results of acute (4 wk) and extended (to 79 wk postconception) feeding of such formulas on RBC and plasma phospholipid AA and DHA are reported here. Control formulas were identical to commercially available formulas. Experimental formulas differed only in the addition of small amounts of marine oil. DHA in RBC and plasma phosphatidylethanolamine (PE) declined during four weeks of feeding but not if marine oil provided DHA (0.2% or 0.4%) and plasma phospholipid AA (g/100 g) decreased with time and marine oil feeding. Extended feeding with marine oil accounted for half the DHA in RBC and plasma phosphatidylethanolamine at equilibrium; however, RBC (g/100 g) and plasma AA (g/100 g; mg/L plasma) decreased progressively until late infancy and were depressed further by marine oil.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin A status of preterm infants during infancy.

Plasma retinol and retinol-binding protein (RBP) were measured in 67 enterally fed preterm infants (750-1398 g) at 33 +/- 2 wk postconceptional age (PCA), and at regular intervals during infancy. Retinol and RBP declined by 35 +/- 2 wk PCA and remained low at 38 wk after discharge, with the infants fed a term-infant formula. At 38 +/- 2 wk PCA, 48% (32 of 67) of these infants had plasma retinol concentrations less than 0.35 mumol/L. Mean retinol and RBP rose over the next 7 mo, but large numbers of infants (26 of 59 at 48 wk, 10 of 61 at 57 wk) had hyporetinolemia (0.35-0.67 mumol/L). Plasma RBP leveled off at 57 +/- 2 wk PCA and remained low (less than 0.95 mumol/L) in many infants throughout the first year of life. Lower plasma retinol and RBP concentrations at 33 and 38 wk correlated with longer periods of intravenous nutrition. At 57 and 69 wk, lower retinol and RBP correlated with higher birth order. Suboptimal vitamin A status may occur for many months after preterm infants are discharged from the hospital.