Maria Makrides

Are long-chain polyunsaturated fatty-acids essential nutrients in infancy?

We investigated whether the disparity in neural maturation between breastfed and formula-fed term infants could be corrected by the addition of fish oil, a source of docosahexaenoic acid (DHA, 22:6 omega 3), to infant formula. Healthy, term infants were randomised at birth to receive either a supplemented or placebo formula if their mothers had chosen to bottle feed. Breastfed term infants were enrolled as a reference group. Infant erythrocyte fatty acids and anthropometry were assessed on day 5 and at 6, 16, and 30 weeks of age. Visual evoked potential (VEP) acuity was determined at 16 and 30 weeks. VEP acuities of breastfed and supplemented-formula-fed infants were better than those of placebo-formula-fed infants at both 16 and 30 weeks of age (p < 0.001 and p < 0.01). Erythrocyte DHA in breastfed and supplemented-formula-fed infants was maintained near birth levels throughout the 30-week study period but fell in placebo-formula-fed infants (p < 0.001). Erythrocyte DHA was the only fatty acid that consistently correlated with VEP acuity in all infants at both ages tested. A continuous supply of DHA may be required to achieve optimum VEP acuity since infants breastfed for short periods (< 16 weeks) had slower development of VEP than infants receiving a continuous supply of DHA from either breastmilk or supplemented formula. Erythrocyte arachidonic acid (20:4 omega 6) in supplemented-formula-fed infants was reduced below that of infants fed breastmilk or placebo formula at 16 and 30 weeks (p < 0.001), although no adverse effects were noted, with growth of all infants being similar. DHA seems to be an essential nutrient for the optimum neural maturation of term infants as assessed by VEP acuity. Whether supplementation of formula-fed infants with DHA has long-term benefits remains to be elucidated.

The importance of early complementary feeding in the development of oral tolerance: concerns and controversies.

Rising rates of food allergies in early childhood reflect increasing failure of early immune tolerance mechanisms. There is mounting concern that the current recommended practice of delaying complementary foods until 6 months of age may increase, rather than decrease, the risk of immune disorders. Tolerance to food allergens appears to be driven by regular, early exposure to these proteins during a ‘critical early window’ of development. Although the timing of this window is not clear in humans, current evidence suggests that this is most likely to be between 4 and 6 months of life and that delayed exposure beyond this period may increase the risk of food allergy, coeliac disease and islet cell autoimmunity. There is also evidence that other factors such as favourable colonization and continued breastfeeding promote tolerance and have protective effects during this period when complementary feeding is initiated. This discussion paper explores the basis for concern over the current recommendation to delay complementary foods as an approach to preventing allergic disease. It will also examine the growing case for introducing complementary foods from around 4 months of age and maintaining breastfeeding during this early feeding period, for at least 6 months if possible.

Effect of increasing breast milk docosahexaenoic acid on plasma and erythrocyte phospholipid fatty acids and neural indices of exclusively breast fed infants

Objectives: To determine the effect of increasing docosahexaenoic acid (DHA, 22: 6 n-3) in breast milk on infant fatty acid profiles. A secondary aim was to examine aspects of neural development. Design and Setting Double blind, placebo controlled study of infants recruited from postnatal wards at Flinders Medical Centre. Subjects: Fifty-two healthy term infants who were breast fed for at least 12 weeks and were from middle class families. Intervention: Breast milk with DHA concentrations that ranged from 0.1–1.7% of total fatty acids. This was achieved by supplementation of the maternal diet for the first 12 weeks post partum. Results: Breast milk DHA was related to infant plasma (r=0.89, P<0.001) and erythrocyte (r=0.88, P<0.001) phospholipids in a saturable curvilinear manner so that breast milk DHA above 0.8% of total fatty acids resulted in little further increase in infant plasma or erythrocyte DHA levels. The rise in plasma and erythrocyte DHA was approximated by a fall in total n-6 polyunsaturated fatty acids. We could detect no relationship between visual evoked potential acuity (measured at 12 and 16 weeks) of infants by either the dietary grouping or the DHA status of individuals. A stepwise multiple regression showed that infant erythrocyte DHA at 12 weeks and home stimulation were the only independent factors associated with Bayleys MDI at 1 y (adjusted model r2=0.18, P<0.005); while at 2 y gender and social score of the spouse were the only significant predictors of Bayleys MDI (adjusted model r2=0.22, P<0.005). Conclusions: Increasing breast milk DHA levels caused a dose dependent saturable increase in infant plasma and erythrocyte phospholipid DHA. There were no long-term effects of infant DHA status on indices of neurodevelopment. Sponsorship: Financial support was provided by Martek Biosciences, MD, USA and the National Health and Medical Research Council, Australia.

Erythrocyte docosahexaenoic acid correlates with the visual response of healthy, term infants.

ABSTRACT: Recent studies have reported that formulafed preterm infants score lower on visual and developmental tests relative to breast-fed preterm infants. This phenomenon has been associated with the presence of docosahexaenoic acid (DHA), an omega-3 fatty acid, in breast milk and its absence from infant formula. To investigate the possibility that DHA status of healthy, term infants is also related to neuronal function of the visual pathway, we studied the erythrocyte fatty acid profiles of 16 infants at 22.3 ± 3.9 wk of age and related these to maturity of the visual pathway as assessed by visual-evoked potentials. Healthy, term infants fed breast milk had better visual-evoked potential acuity (p < 0.05) and higher DHA levels (p < 0.001) than infants who received infant formula as their major energy source. There was a positive correlation between erythrocyte DHA and visual-evoked potential acuity (p < 0.01). The data are preliminary and the long-term effects as yet unknown. However, our results suggest that there is an urgent need to evaluate the dietary fatty acid supply of formula-fed term infants.

A critical appraisal of the role of dietary long-chain polyunsaturated fatty acids on neural indices of term infants: a randomized, controlled trial.

Objective. To determine whether dietary long-chain polyunsaturated fatty acids (LCPUFA), such as docosahexaenoic acid (DHA) and arachidonic acid, affect visual evoked potential (VEP) acuity of formula-fed infants, relative to breastfed infants. A secondary objective was to assess the effect of LCPUFA on Bayleys mental developmental index (MDI) and psychomotor developmental index (PDI). Methods. Formula-fed infants were randomly allocated, in a double-blind manner, to either a placebo (no LCPUFA;n = 21), DHA supplemented (n = 23), or DHA+arachidonic acid supplemented formula (n = 24). Infants were fed their assigned formula from the first week of life until 1 year of age. A parallel reference group of breastfed infants was recruited and followed (n = 46). Infant VEP acuity was assessed at 16 and 34 weeks, and Bayleys MDI and PDI were assessed at 1 and 2 years of age. Results. There were no differences among the randomized formula groups for VEP acuity at either 16 or 34 weeks of age. Breastfed infants had better VEP acuity at 34 weeks of age, but not at 16 weeks, compared with all formula-fed infants. Bayleys MDI and PDI were similar in the 3 formula-fed groups at 1 and 2 years. Breastfed infants had higher MDI scores than formula-fed infants at 2 years of age even after adjusting for environmental variables. Conclusions. LCPUFA supplementation did not influence VEP acuity development in these well-nourished, formula-fed infants.

Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants’ allergies in first year of life: randomised controlled trial

Objective To determine whether dietary n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation of pregnant women with a fetus at high risk of allergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age. Design Follow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome (DOMInO) randomised controlled trial. Setting Adelaide, South Australia. Participants 706 infants at high hereditary risk of developing allergic disease whose mothers were participating in the DOMInO trial. Interventions The intervention group (n=368) was randomly allocated to receive fish oil capsules (providing 900 mg of n-3 LCPUFA daily) from 21 weeks’ gestation until birth; the control group (n=338) received matched vegetable oil capsules without n-3 LCPUFA. Main outcome measure Immunoglobulin E associated allergic disease (eczema or food allergy with sensitisation) at 1 year of age. Results No differences were seen in the overall percentage of infants with immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups (32/368 (9%) v 43/338 (13%); unadjusted relative risk 0.68, 95% confidence interval 0.43 to 1.05, P=0.08; adjusted relative risk 0.70, 0.45 to 1.09, P=0.12), although the percentage of infants diagnosed as having atopic eczema (that is, eczema with associated sensitisation) was lower in the n-3 LCPUFA group (26/368 (7%) v 39/338 (12%); unadjusted relative risk 0.61, 0.38 to 0.98, P=0.04; adjusted relative risk 0.64, 0.40 to 1.02, P=0.06). Fewer infants were sensitised to egg in the n-3 LCPUFA group (34/368 (9%) v 52/338 (15%); unadjusted relative risk 0.61, 0.40 to 0.91, P=0.02; adjusted relative risk 0.62, 0.41 to 0.93, P=0.02), but no difference between groups in immunoglobulin E associated food allergy was seen. Conclusion n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence of immunoglobulin E associated allergies in the first year of life, although atopic eczema and egg sensitisation were lower. Longer term follow-up is needed to determine if supplementation has an effect on respiratory allergic diseases and aeroallergen sensitisation in childhood. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606).

Early regular egg exposure in infants with eczema: A randomized controlled trial

BACKGROUND Observational studies suggest that early regular ingestion of allergenic foods might reduce the risk of food allergy. OBJECTIVE We sought to determine whether early regular oral egg exposure will reduce subsequent IgE-mediated egg allergy in infants with moderate-to-severe eczema. METHODS In a double-blind, randomized controlled trial infants were allocated to 1 teaspoon of pasteurized raw whole egg powder (n = 49) or rice powder (n = 37) daily from 4 to 8 months of age. Cooked egg was introduced to both groups after an observed feed at 8 months. The primary outcome was IgE-mediated egg allergy at 12 months, as defined based on the results of an observed pasteurized raw egg challenge and skin prick tests. RESULTS A high proportion (31% [15/49]) of infants randomized to receive egg had an allergic reaction to the egg powder and did not continue powder ingestion. At 4 months of age, before any known egg ingestion, 36% (24/67) of infants already had egg-specific IgE levels of greater than 0.35 kilounits of antibody (kUA)/L. At 12 months, a lower (but not significant) proportion of infants in the egg group (33%) were given a diagnosis of IgE-mediated egg allergy compared with the control group (51%; relative risk, 0.65; 95% CI, 0.38-1.11; P = .11). Egg-specific IgG4 levels were significantly (P < .001) greater in the egg group at both 8 and 12 months. CONCLUSION Induction of immune tolerance pathways and reduction in egg allergy incidence can be achieved by early regular oral egg exposure in infants with eczema. Caution needs to be taken when these high-risk infants are first exposed to egg because many have sensitization already by 4 months of age.

Conversion of linoleic acid and alpha-linolenic acid to long-chain polyunsaturated fatty acids (LCPUFAs), with a focus on pregnancy, lactation and the first 2 years of life

Over the past two decades, there has been a marked shift in the fatty acid composition of the diets of industrialized nations towards increased intake of the n-6 fatty acid linoleic acid (LA, 18:2n-6), largely as a result of the replacement of saturated fats with plant-based polyunsaturated fatty acid (PUFA). While health agencies internationally continue to advocate for high n-6 PUFA intake combined with increased intakes of preformed n-3 long-chain PUFAs (LCPUFA) docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3) to reduce the incidence of cardiovascular disease (CVD), there are questions as to whether this is the best approach. LA competes with alpha-linolenic acid (18:3n-3) for endogenous conversion to the LC derivatives EPA and DHA, and LA also inhibits incorporation of DHA and EPA into tissues. Thus, high-LA levels in the diet generally result in low n-3 LCPUFA status. Pregnancy and infancy are developmental periods during which the fatty acid supply is particularly critical. The importance of an adequate supply of n-3 LCPUFA for ensuring optimal development of infant brain and visual systems is well established, and there is now evidence that the supply of n-3 LCPUFA also influences a range of growth, metabolic and immune outcomes in childhood. This review will re-evaluate the health benefits of modern Western diets and pose the question of whether the introduction of similar diets to nations with emerging economies is the most prudent public health strategy for improving health in these populations.

Determination of the optimal ratio of linoleic acid to α-linolenic acid in infant formulas

The fatty acid composition of erythrocyte total lipids taken from a group of term infants 10 weeks after being fed a commercial infant formula with a high ratio of linoleic acid (18:2n-6) (LA) to α -linolenic acid (18:3n-3) (ALA) (19:1; LA, 14%; ALA, 0.7%; group A, n=10) was compared with the fatty acid composition of erythrocytes from infants fed formulas that contained LA/ALA ratios reduced by either increasing ALA (4:1; LA, 13%; ALA, 3.3%; group B, n=11) or decreasing LA (3:1; LA, 3.5%; ALA, 1.1%; group C, n=8). Results were compared with those in an age-controlled group (n=9) of breast-fed infants. Decreasing the LA/ALA ratio increased n-3 C20 and C22 fatty acid incorporation (formula B=8.98%±0.65%; formula C=9.30%±0.95%) relative to formula A (5.97%±0.76%; p p p p

The effect of maternal omega-3 (n-3) LCPUFA supplementation during pregnancy on early childhood cognitive and visual development: a systematic review and meta-analysis of randomized controlled trials

BACKGROUND Maternal fish consumption during pregnancy has been positively associated with cognitive and visual abilities in the offspring, leading to the hypothesis that maternal omega-3 (n-3) long-chain PUFA (LCPUFA) supplementation improves childrens neurologic and visual development. OBJECTIVE The objective was to evaluate the effect of maternal omega-3 LCPUFA supplementation in pregnancy on neurologic and visual development in the offspring. DESIGN Five electronic databases were searched. Human randomized controlled trials that supplemented the maternal diet with omega-3 LCPUFAs during pregnancy, or pregnancy and lactation, and that assessed either neurologic or visual development of the offspring were included. Trial quality was assessed, and the results of eligible trials were compared in meta-analyses. RESULTS Eleven RCTs involving 5272 participants were included in the review. Most trials had methodologic limitations. No differences in standardized psychometric test scores for cognitive, language, or motor development were observed between the LCPUFA-supplemented and control groups, except for cognitive scores in 2-5-y-old children, in whom supplementation resulted in higher Developmental Standard Scores (mean difference: 3.92; 95% CI: 0.77, 7.08; n = 156; P = 0.01). However, this effect was from 2 trials with a high risk of bias. Because of the variety of visual assessments and age ranges, it was not possible to combine studies with visual outcomes in a meta-analysis, although 6 of the 8 assessments in 5 trials reported no difference between the supplemented and control groups. CONCLUSION The evidence does not conclusively support or refute that omega-3 LCPUFA supplementation in pregnancy improves cognitive or visual development.