ArticlesEfficacy and safety of long-chain polyunsaturated fatty acid supplementation of infant-formula milk: a randomised trial
Introduction
Whether long-chain polyunsaturated fatty acids (LCPUFA) should be added to infant formula is one of the most debated issues in infant nutrition. The debate concerns two families of non-interconvertible fatty acids of the n-3 and n-6 series.1 The 18-carbon parent fatty acids—respectively α-linolenic (LNA) and linoleic acids—are converted by a series of elongation and desaturation steps to LCPUFAs. Of these, arachidonic acid (AA [20:4n-6]) of the n-6 series, and docosahexaenoic acid (DHA [22:6n-3]) of the n-3 series have received most attention as major membrane constituents of the central nervous system of importance to normal neural function.2, 3 AA and DHA are present in breast milk,2 but there is uncertainty whether they should be added to infant-formula milk. The key question has been whether formula-fed infants can adequately synthesise AA and DHA given a sufficient supply of 18-carbon precursors in formula milk.
Several lines of evidence bear on this question. Rats and monkeys4, 5 made profoundly n-3-deficient develop disturbances of learning and vision, but these do not occur if there is adequate supply of the parent fatty acid LNA. Thus, no absolute dietary requirements for DHA itself in these species has been shown. However, studies in human babies are essential. Formula-fed human infants develop lower concentrations of AA and DHA in plasma or red cells than those fed breast milk,6, 7, 8, 9, 10 but blood AA and DHA concentrations have not been found to be a reliable indicator of function6 and are not necessarily an indicator of essentiality.10 Biochemical analyses of brains of human infants who died of various causes show those fed formula rather than breast milk had lower DHA in the cerebral cortex.11, 12 However, the functional significance of this finding is unknown because the range of cortical DHA content associated with normal function has not been defined. That breast milk contains AA and DHA does not in itself prove a dietary requirement because not all breast-milk constituents are essential. Nonetheless, many studies show higher cognitive scores or visual development in breastfed infants versus formula-fed infants.13, 14, 15 However, this finding has not been consistent,16 and such non-randomised comparisons are potentially highly confounded by demographic differences between these dietary groups. In preterm infants, a role of breast milk in promoting neurodevelopment is more compelling,17, 18 but clear attribution of such a finding, even if causal, to the LCPUFA content of breast milk is precluded, because human milk contains many other substances not present in formula (eg, hormones)19 that may promote neurodevelopment.
The foregoing evidence, therefore, does not prove that LCPUFAs are essential in the diet of infants; a stronger approach is to study the development of infants fed formula with or without LCPUFA supplementation in randomised trials.7, 8, 10, 20, 21, 22, 23, 24, 25 Most trials of this type, however, have insufficient sample size and inadequate follow-up.10 Some trials, both on full-term infants and preterm infants, show early or transient acceleration in visual or retinal development in those receiving LCPUFA, but the longer-term significance of these promising findings is not yet known.10 Effects on cognitive function, however, have been inconsistent—some studies show lower scores whereas others show higher scores with LCPUFA supplements.8, 10, 22, 25, 26 Early studies on preterm infants fed formula containing fish oil (providing DHA but not AA as now recommended) showed suppression of growth, including head growth, beyond the period of dietary assignment compared with unsupplemented formula.20, 23, 26
Because of these uncertainties over efficacy and safety neither an expert panel for the US Food and Drug Administration (FDA) nor a working group for the Canadian authorities27 recommend that LCPUFAs should be added to infant formula. The FDA expert panel plans to revisit this field in 5 years when more data from larger studies are available.10 Against this background we present the results of a large randomised trial on AA plus DHA supplemented formula, with adequate size to explore efficacy and safety outcomes.
Section snippets
Study population
Women giving birth to healthy singletons of appropriate size for gestational age and of at least 37 weeks' gestation were approached to enter the study. Those with congenital abnormalities known to affect development were ineligible. Individuals were recruited from four hospitals in Nottingham and Leicester, UK, during the period 1993–1995 and follow-up to 18 months was completed in 1997. Informed written consent was always obtained, following approval from the ethics committees of the
Results
309 babies were randomised to standard or supplemented formula and 138 breastfed babies were recruited as a reference group. The trial design and number of individuals at each stage is shown in the figure. Individuals in the supplemented and control groups were well balanced at baseline (table 2). More than 97% of visits at 6 weeks, 12 weeks, and 6 months took place within 2 weeks of schedule, more than 90% of visits at 9 months took place within 3 weeks of schedule, and more than 85% of visits
Discussion
To our knowledge, this is the largest randomised controlled trial to date to investigate the effect of supplementation with LCPUFAs on subsequent child development. Despite having sufficient power to detect plausible, clinically significant differences we found no effect on cognitive, social, or motor development at 9 months or 18 months. At the 18-month follow-up we used the most widely employed test of global cognitive and motor performance in this age group—the Bayley scales of infant
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A Review of Studies on the Growth of Infants Fed Infant Formula
2019, Current Developments in NutritionOmega-3 polyunsaturated fatty acid supplementation during the pre and post-natal period: A meta-analysis and systematic review of randomized and semi-randomized controlled trials
2016, Journal of Nutrition and Intermediary MetabolismCitation Excerpt :One study was excluded because it did not have a randomized or blinded process [38]. This resulted in a total of 32 infant formula [26–28,30,31,34,39–64] and 37 breastmilk publications [25,65–100] evaluating 2443 infants on n-3 PUFA enriched formula and 4553 infants that were fed from mothers that were supplemented with n-3 PUFA during gestation and/or lactation. All the trials included used a randomized or semi-randomized clinical trial design from both high and low-income countries (Table S25) with the experimental interventions summarized (Table S26) and a reference list of pooled studies (Table S27).
A comprehensive review on in vitro digestion of infant formula
2015, Food Research InternationalCitation Excerpt :However, Neumann et al. (2000) observed that infants fed on formulas supplemented with DHA and AA did not lead to any expected influence on visual evoked potential, mental development, and psychomotor development, while their breastfed counterparts had significantly higher corresponding indexes. A report by Lucas et al. (1999) advocated that there was no significant difference in cognitive development between infants feeding with or without enriched LCPUFAs. In contrast, Willatts, Forsyth, DiModugno, Varma, and Colvin (1998) concluded that LCPUFAs could increase the intelligence of babies who received LCPUFA elevated formula.