Susan E. Carlson

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 prodedures 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.

A RANDOMIZED TRIAL OF VISUAL ATTENTION OF PRETERM INFANTS FED DOCOSAHEXAENOIC ACID UNTIL NINE 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.

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 ≥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.

Long chain polyunsaturated fatty acids (LC-PUFA) and perinatal development

This paper reports on the conclusions of a workshop on the role of long chain polyunsaturated fatty acids (LC‐PUFA) in maternal and child health The attending investigators involved in the majority of randomized trials examining LC‐PUFA status and functional outcomes summarize the current knowledge in the field and make recommendations for dietary practice. Only studies published in full or in abstract form were used as our working knowledge base.

A Randomized Trial of Docosahexaenoic Acid Supplementation During the Third Trimester of Pregnancy

OBJECTIVE To hypothesize that higher intake of docosahexaenoic acid, an n-3 long chain polyunsaturated fatty acid, would increase duration of gestation and birth weight in US women. METHODS This was a randomized, double-blind, controlled, clinical trial. Subjects were enrolled in an ambulatory clinic where they received prenatal care. This was a population-based sample. Most subjects received government assistance for medical care and most were black (73%). Subjects were enrolled between the 24th and 28th week of pregnancy and consumed docosahexaenoic acid (33 or 133 mg) from eggs until parturition. Gestational age and birth weight were the main study outcomes. Infant length and head circumference, preterm birth, and low birth weight were secondary outcomes. RESULTS Eighty-three percent of subjects completed the study (291 of 350 enrolled). No subject was discontinued for an adverse event. After controlling for important predefined risk factors and confounding variables, gestation increased by 6.0 ± 2.3 days (P = .009) in the higher docosahexaenoic acid group. Birth weight, length, and head circumference increased, but did not reach statistical significance (P = .06–.18), although the increases could be clinically important indications of enhanced intrauterine growth. No safety concerns were raised by the study. CONCLUSION Duration of gestation increased significantly when docosahexaenoic acid intake was increased during the last trimester of pregnancy. The increase in gestation was similar to that reported for interventions with much larger amounts of n-3 long chain polyunsaturated fatty acids

Polyunsaturated fatty acid status and neurodevelopment: A summary and critical analysis of the literature

The rationale for randomized trials designed to measure the effects of variable docosahexaenoic acid (DHA) status on neurodevelopment in human infants came from earlier studies of neurodevelopment in animals that were deficient in DHA owing to diets low in α-linolenic acid. The session on neurodevelopment looked at the results of these animal studies and discussed outcomes that appear to be analogous in human infants with variable DHA status. Presentations focused mainly on measures of development that may be attributed to more specific developmental domains (e.g., visual attention, recognition memory, problem-solving), some of which have been shown to be affected by long-chain polyunsaturated fatty acid (LCPUFA) status. This paper derives from discussions that took place during the session and reviews subsequent developments in this area. Although more difficult to interpret, global measures of infant development (e.g., the Bayley Scales of Infant Development, and Brunet-Lezine) can only suggest a relationship to specific developmental domains, but they have been applied in some randomized trials of LCPUFA and infant development. Those results are also summarized here.

The DIAMOND (DHA Intake And Measurement Of Neural Development) Study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid

BACKGROUND The range of human milk docosahexaenoic acid (DHA) concentrations worldwide is much broader than the range explored in randomized clinical trials to date. OBJECTIVE The primary objective was to determine the effect of 4 amounts of DHA supplementation on the visual acuity of formula-fed infants at 12 mo of age. Secondary objectives were to evaluate visual acuity maturation, red blood cell fatty acids, tolerance, anthropometric measures, and adverse events. DESIGN This double-masked, randomized trial was conducted at 2 sites (Dallas and Kansas City). Three hundred forty-three healthy, term, formula-fed infants were enrolled at 1-9 d of age and were randomly assigned to be fed 1 of the following 4 infant formulas containing equivalent nutrient amounts, except for long-chain polyunsaturated fatty acids: control (0% DHA), 0.32% DHA, 0.64% DHA, or 0.96% DHA; DHA-supplemented formulas also provided 0.64% arachidonic acid. Visual acuity was measured by visual evoked potentials in 244 infants who completed the 12-mo primary outcome examination. RESULTS Infants fed control formula had significantly poorer visual evoked potential visual acuity at 12 mo of age than did infants who received any of the DHA-supplemented formulas (P < 0.001). There were no significant differences in visual evoked potential visual acuity between the 3 amounts of DHA supplementation for either site at any age tested. CONCLUSIONS DHA supplementation of infant formula at 0.32% of total fatty acids improves visual acuity. Higher amounts of DHA supplementation were not associated with additional improvement of visual acuity. This trial was registered at clinicaltrials.gov as NCT00753818.

Long-Term Feeding of Formulas High in Linolenic Acid and Marine Oil to Very Low Birth Weight Infants: Phospholipid Fatty Acids

ABSTRACT: 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% α-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/100g) and plasma AA (g/100 g; mg/L plasma) decreased progressively until late infancy and were depressed further by marine oil. We conclude that 1) AA and DHA decline in RBC and plasma phospholipids of preterm infants when only their n-6 and n-3 fatty acid precursors are consumed; and 2) marine oil can maintain cord concentrations of RBC phosphatidylethanolamine DHA but further reduces AA.

DHA supplementation and pregnancy outcomes

BACKGROUND Observational studies associate higher intakes of n-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) during pregnancy with higher gestation duration and birth size. The results of randomized supplementation trials using various n-3 LCPUFA sources and amounts are mixed. OBJECTIVE We tested the hypothesis that 600 mg/d of the n-3 LCPUFA docosahexaenoic acid (DHA) can increase maternal and newborn DHA status, gestation duration, birth weight, and length. Safety was assessed. DESIGN This phase III, double-blind, randomized controlled trial was conducted between January 2006 and October 2011. Women (n = 350) consumed capsules (placebo, DHA) from <20 wk of gestation to birth. Blood (enrollment, birth, and cord) was analyzed for red blood cell (RBC) phospholipid DHA. The statistical analysis was intent-to-treat. RESULTS Most of the capsules were consumed (76% placebo; 78% DHA); the mean DHA intake for the treated group was 469 mg/d. In comparison with placebo, DHA supplementation resulted in higher maternal and cord RBC-phospholipid-DHA (2.6%; P < 0.001), longer gestation duration (2.9 d; P = 0.041), and greater birth weight (172 g; P = 0.004), length (0.7 cm; P = 0.022), and head circumference (0.5 cm; P = 0.012). In addition, the DHA group had fewer infants born at <34 wk of gestation (P = 0.025) and shorter hospital stays for infants born preterm (40.8 compared with 8.9 d; P = 0.026) than did the placebo group. No safety concerns were identified. CONCLUSIONS A supplement of 600 mg DHA/d in the last half of gestation resulted in overall greater gestation duration and infant size. A reduction in early preterm and very-low birth weight could be important clinical and public health outcomes of DHA supplementation. This trial was registered at clinicaltrials.gov as NCT00266825.

n−3 Fatty acids and cognitive and visual acuity development: methodologic and conceptual considerations

Several randomized clinical studies in infants born preterm and at term have explored the effects on visual acuity development of postnatal supplementation with various sources of docosahexaenoic acid (DHA). Higher visual acuity after DHA supplementation is a consistent finding in infants born preterm. For infants born at term, the results are less consistent and are better explained by differences in sensitivity of the visual acuity test (electrophysiologic tests being more sensitive than subjective tests) or by differences in the amount of DHA included in the experimental formula. Differences in the sensitivity of the test may also be relevant in discussions of whether the effects of DHA on visual acuity are transient or persistent. A smaller number of studies have attempted to study the effects of DHA on cognitive development. The major focus of this article is to review the types of methods that have been used to evaluate the effects of DHA on cognition and to provide the rationale for measures that are a better conceptual fit. Research is needed (1) to probe the effects of variable DHA exposure on infant and child development, (2) to measure outcomes that better relate to preschool and school-age cognitive function, and (3) to reinforce, and in some cases demonstrate, links between specific infant and preschool measures of cognitive development. We strongly encourage collaborations with developmental cognitive neuroscientists to facilitate these research goals.