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Benefits of DHA Supplementations in Infants: Results From The DIAMOND Trial
By - Dr. S. Giridhar
MD (Pediatrics), DM (Neonatology), Associate Professor of Neonatology Chettinad Hospital and Research Institute, Kelambakkam, Chief Consultant Neonatologist, Neolife Children’s Hospital, Madipakkam, Chennai

Infants, both term and preterm, require long-chain polyunsaturated fatty acids like Docosahexaenoic acid (DHA) and Arachidonic acid (ARA),prominent nutrients required for brain, vision and cognition development. Previous studies on the benefits of DHA supplementation had conflicting results on the optimal dosage and neurodevelopmental outcomes.1.

The DIAMOND (DHA Intake and Measurement of Neural Development) trial represents one of the few studies on the long-term dose-response effects of DHA supplementation. This article discusses the results of the trial and the importance of minimum 0.32% DHA supplementation in infants for optimal cognitive development.

Benefits of DHA and ARA and the need for supplementation

DHA and ARA are long chain polyunsaturated fatty acids (LCPUFA), important in signal transduction of nervous system. DHA and ARA are precursors to vital physiologically important metabolites and modulators of central and enteric nervous systems. DHA is anti-inflammatory, important for vision, growth and neurological development in infants. Whereas, ARA is a proinflammatory fatty acid that supports neuronal firing and long-term potentiation in brain. 2

DHA is assimilated in the fetus in the last 5 weeks of gestation. Following delivery, the infants rely on enteral sources for their DHA requirements. The DHA content of breast milk is directly associated with maternal intake of DHA. However, gestational age and stage of lactation bear an effect on the amount of DHA in breast milk. Studies have observed a decrease in DHA in breast milk over the first months of lactation in both term and preterm human milk samples. To avoid this, it may be essential to regulate either the maternal DHA intake or ensure other sources of DHA supplementation for the infant.3

The long-term neurodevelopmental advantage of breastmilk has been attributed to the presence of LCPUFA’s and this initiated the addition of DHA to infant feed by various regulatory bodies across the world, including India.The benefits of LCPUFA supplementation on visual and cognitive maturation of term and preterm infants have been studied in many randomized clinical trials but with conflicting results. This could be attributed to the variation in DHA concentrations used, as also the duration of feeding and outcome measures between the studies.1

To address this paucity of information, , the DIAMOND trial was designed to carry out a dose-response study of DHA supplementation of infant feed.4

About the DIAMOND Trial

DIAMOND study (DHA Intake and Measurement of Neural Development) is a double-masked, randomized, controlled, parallel-group trial. A total of 343 healthy, term, singleton-birth infants born in hospitals from two different locations, were included in the study. These infants received infant feed from birth up to 12 months of age and it was the only source of nutrition until 4 months of age. From 1-9 days of age, the infants were randomly assigned to four groups that were administered different cow-milk based feeds with same nutrient amounts and ingredients except LCPUFA’s. The variation maintained in the feeds regarding LCPUFA is as listed-

  • Control feed with no DHA or ARA but containing Linoleic and Alpha Linolenic acid
  • Experimental feed:
    1. 0.32% DHA and 0.64% ARA (1:2 ratio of DHA:ARA)
    2. 0.64% DHA and 0.64% ARA (1:1 ratio of DHA:ARA)
    3. 0.96% DHA and 0.64% ARA (1.5:1 ratio of DHA:ARA)

This study examined the effect of these different levels of DHA and ARA supplementation on visual acuity maturation of infants at the age of 12 months, time period corresponding to the maximum cumulative consumption of assigned feed. This effect was also assessed at different stages of growth viz. 1.5, 4 and 9 months of age. Also, the cognitive outcome up to 6 years of age was measured.

1. Data on Maturation of Visual Acuity

Tests Performed

Targeted tests were performed to determine the effect of DHA and ARA supplementation on visual and cognitive development in infants, focusing on the differences in cytoarchitecture of the developing brain.

  • Using sophisticated hardware and software, the visual evoked potential (VEP) for visual acuity (a measure of cognitive development) was measured for every participant infant.
  • RBC Fatty Acids concentration was evaluated. This data was merged with VEP visual acuity.
  • The anthropometric parameters of birth weight, length and head circumference measurements of the infants were collected from their birth records.
  • Infant feed consumption and tolerance data were accumulated from the parents using 24-hour diet and tolerance recalls.

Results


Figure 1- Graph depicting mean (+/- SE) sweep visual evoked potential (VEP) visual acuity (logMAR, log of the minimum angle of resolution) for each diet group as a function of age. Lower visual acuity indicates better acuity.(Adapted from: Birch, et.al., 2010)

Analysis of the data revealed that infants receiving the control feed without DHA supplementation showed significantly poor visual acuity than the groups who received DHA fortified infant feeds. It was evident that the 0.32% DHA supplementation improved VEP visual acuity maturation in comparison to control feed (with 0% DHA).The higher amount of DHA upto 0.96%, did not confer any additional benefit for VEP visual acuity maturation.

2. Data for Cognitive Functions

The infants were assessed again at the age of 18 months to estimate the optimal DHA and ARA concentration in infant feed required to support the cognitive development of the infant. It was the first study to evaluate the cognitive outcomes in infants with different DHA concentrations ranging from 0% to 0.96%.

Tests Performed

  • Using the Bayley scales of infant development, cognitive development was evaluated. This includes the Mental Development Index (MDI), the Psychomotor Development Index (PDI). Also,behavioral assessment was done using the Behavior Rating Scale (BRS).

Results

Analysis of the data revealed that for the MDI scale, the score of the control group was slightly lower than the normalized score. Whereas, the scores of the supplemented group were higher than this normalized score. There were no significant differences in the PDI scores as well as BRS scores of control and supplemented groups. However, on the language facet, the DHA supplemented group scored significantly higher than the control group. The combined results suggested that the DHA supplementation of 0.32% was sufficient to improve cognitive function at 18 months of age, concurring with the results from the previous DIAMOND trial.4,5

The researchers postulate that the superior visual acuity in the DHA supplemented groups, indicates changes in the cytoarchitecture of the brain in the developing stage, which extends into the areas regulating cognitive function.5

DHA and ARA Balance in Neurodevelopment

Figure 2- Chart to depict the WPPSI Subscale and Full-Scale (Composite) scores at 72 months of age in the four groups of infant feed with varying proportions of DHA/ARA.(Adapted from: Colombo, et.al., Jun 2017)

  • While DHA and ARA in the feed from birth up to 12 months provided benefits in visual function and cognition, these benefits consistently reduced with higher doses of DHA and the highest ratio of DHA/ARA. Therefore, further analysis of the data from the DIAMOND trial was undertaken to determine the ongoing role of DHA and ARA supplementation on neuro-cognition.Beginning at 36 months of age, executive function and problem solving was assessed using Dimensional Change Card Sort Test. This test involves teaching the child certain rules for sorting pictures and then observing the child’s response when the rules are reversed.
  • At 60 months of age, children were assessed with Peabody Picture Vocabulary Test to estimate the verbal IQ, while Wechsler Preschool and Primary Scale of Intelligence (WPPSI) was used to determine verbal IQ, performance, and processing speed.

Assessment of cognitive parameters at later ages also showed that the DHA supplemented groups performed better in tests for attention, executive function and problem solving, compared to the unsupplemented control group (Figure 2). However, there was no significant differences in test results, between the 3 different DHA doses. Similar results were also obtained in the tests for verbal and composite IQ These results prove that DHA supplementation in infancy, provides improvement in later cognitive outcomes. Thus, the effects of DHA supplementation persist long after even DHA supplementation is stopped, due to probable developmental programming. Lack of better efficacy with higher doses of DHA (higher ratios of DHA:ARA) suggests that availability of DHA of atleast 0.32% in infancy, is essential for optimal cognitive and physiological development, an effect seen in the DIAMOND trial upto 6 years of age. 6

Conclusion

Thus, the DIAMOND trial has been pivotal in establishing the importance of DHA supplementation in infants from birth up to 12 months of age for an appropriate brain and vision development. The trials further established that the optimal DHA dose of at least 0.32% is essential and enough for optimal development of infants.

What is your opinion about the results of the DIAMOND trial and what are your recommendations for DHA intake in infants?

References:
  1. Jasani B, Simmer K, Patole SK, Rao SC. Long chain polyunsaturated fatty acid supplementation in infants born at term. Cochrane Neonatal Group, editor. Cochrane Database Syst Rev. 2017 Mar 10.
  2. Carlson SE, Colombo J. Docosahexaenoic Acid and Arachidonic Acid Nutrition in Early Development. Adv Pediatr. 2016 Aug;63(1):453–71.
  3. Smith SL, Rouse CA. Docosahexaenoic acid and the preterm infant. Matern Health Neonatol Perinatol. 2017 Dec;3(1).
  4. Birch EE, Carlson SE, Hoffman DR, Fitzgerald-Gustafson KM, Fu VL, Drover JR, et al. 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. Am J Clin Nutr. 2010 Apr 1;91(4):848–59.
  5. Drover JR, Hoffman DR, Castañeda YS, Morale SE, Garfield S, Wheaton DH, et al. Cognitive function in 18-month-old term infants of the DIAMOND study: A randomized, controlled clinical trial with multiple dietary levels of docosahexaenoic acid. Early Hum Dev. 2011 Mar;87(3):223–30.
  6. Colombo J, Jill Shaddy D, Kerling EH, Gustafson KM, Carlson SE. Docosahexaenoic acid (DHA) and arachidonic acid (ARA) balance in developmental outcomes. Prostaglandins Leukot Essent Fatty Acids. 2017 Jun;121:52–6.