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The EFSA Journal (2009) 1000, 1-13

 

© European Food Safety Authority, 2009



  

SCIENTIFIC OPINION 

DHA and ARA and brain development  

Scientific substantiation of a health claim related to docosahexaenoic acid 

(DHA) and arachidonic acid (ARA) and brain development pursuant to 

Article14 of Regulation (EC) No 1924/2006

1

 

Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies 

(Question No EFSA-Q-2008-212)  

Adopted on 13 March 2009 

P

ANEL 

M

EMBERS

 

Jean-Louis Bresson, Albert Flynn, Marina Heinonen, Karin Hulshof, Hannu Korhonen, Pagona 

Lagiou, Martinus Løvik, Rosangela Marchelli, Ambroise Martin, Bevan Moseley, Hildegard 

Przyrembel, Seppo Salminen, Sean (J.J.) Strain, Stephan Strobel, Inge Tetens, Henk van den 

Berg, Hendrik van Loveren and Hans Verhagen. 

S

UMMARY

 

Following an application from Mead Johnson & Company submitted pursuant to Article 14 of 

Regulation (EC) No 1924/2006 via the Competent Authority of France, the Panel on Dietetic 

Products, Nutrition and Allergies was asked to deliver an opinion on the scientific 

substantiation of a health claim related to docosahexaenoic acid and arachidonic acid and brain 

development. 

The scope of the application was proposed to fall under a health claim referring to children’s 

development and health. 

The food constituents that are the subject of the health claim are docosahexaenoic acid (DHA) 

and arachidonic acid (ARA), which are well characterised fatty acids that can be quantified in 

foods by established methods. The absorption of DHA and ARA is well documented. The Panel 

considers that the food constituents DHA and ARA are sufficiently characterised. 

The claimed effect is the contribution to the optimal brain development of infants and young 

children. The target population proposed by the applicant is infants and young children (from 

birth to three years of age). The Panel considers that contribution to the normal development of 

the brain is beneficial for infants’ and children’s development and health. 

The applicant identified a total 33 publications as being pertinent to the health claim for 

humans. A total of 13 full publications which report original data from RCTs on the effects of 

                                                 

1

  For citation purposes: Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies on a request from Mead 



Johnson & Company on DHA and ARA and brain development. The EFSA Journal (2009) 1000, 1-13 


DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 2-13 

DHA supplementation (with or without ARA) on brain development in physiologic conditions 

and in subjects born at term and have been presented, reporting the results from eight study 

designs. All these studies were conducted in term infant populations fed different formulas 

from birth through the first months of life up to 12 months at the maximum. 

In two RCTs, formulas with less than 0.2% DHA (in various combinations with ARA) from 

birth through six  or 12 months of age had no effect on neurodevelopmental indices measured 

with different methods as compared to standard, unsupplemented formulas. Two double-blind 

RCTs investigated the effects of formulas supplemented with DHA around 0.3% either alone or 

in combination with ARA at around the same level (ARA:DHA ratio = 1) form birth to 6-12 

months of life on Bayley’s Mental and Psychomotor Developmental Indices (MDI and PDI) at 

12 and 24 months or at 18 months of age as compared to unsupplemented formulas. No 

differences in MDI or PDI scores were observed among the formula-fed groups. In another 

double-blind RCT, term infants allocated at birth to consume a formula supplemented with 

0.15-0.25% DHA and 0.30-0.40% ARA (ARA:DHA ratio = 1.7:1 to 2:1) for four months had 

significantly more intentional solutions and higher intention scores at 10 months of age than 

infants who received the unsupplemented formula. 

In the remaining three study designs, formulas supplemented with either 0.3 % DHA alone or 

in combination with ARA in higher dosages (ARA:DHA ratio from 1.4:1 to 2:1) were used in 

the intervention groups. These doses of DHA and the DHA:ARA ratio are in the range of those 

recommended by the applicant to obtain the claimed effect.  

In the first study, term infants consuming a formula supplemented with 0.30% DHA and 0.44% 

ARA for four months scored significantly higher in the Brunet-Lézine test than infants in the 

control (unsupplemented) formula group at four months of age, but these differences were not 

sustained at 24 months of life. In the second study, healthy term infants consuming a formula 

supplemented with 0.3% DHA and 0.45% ARA (ARA:DHA ratio = 1.5) for two months had 

mildly abnormal GMs significantly less often than did infants receiving the unsupplemented 

formula. No differences between groups were found in clinical neurological condition, 

neurological optimality score, fluency score, or the Bayley’s MDI or PDI at 18 months of life. 

The third study included infants randomised at the age of five days to consume either a formula 

with DHA 0.35% alone, a formula with DHA 0.36% plus ARA 0.72%, or a control formula 

devoid of DHA and ARA for 17 weeks. Infants supplemented with DHA and ARA yielded 

significantly higher MDI scores at 18 months than infants in the control group. No significant 

differences between groups were observed among the three groups regarding the PDI or the 

Behaviour Rating Scale. Infants were tested at four years of age for Intelligence Quotient (IQ). 

Verbal IQ in the control and DHA-supplemented formula groups was significantly lower than 

in the DHA plus ARA group. No differences were observed among groups regarding the full 

scale IQ or the performance IQ. 

The Panel notes that none of the studies using formulas supplemented with doses of DHA and 

ARA lower than proposed in the conditions of use or 0.3% DHA and an ARA:DHA ratio of 

one show an effect of DHA and ARA supplementation on neurodevelopment indices infants as 

compared to unsupplemented formulas. The Panel also notes that the four studies using either 

slightly lower DHA doses or about 0.3% DHA and the ARA:DHA ratio proposed in the 

conditions of use (between 1.4:1 and 2:1) show a short-tem beneficial effect of DHA and ARA 

supplementation on different measures of neurodevelopment. However, the different testing 

ages and the use of different tests for assessment limit the comparability of the studies. Also, 

the predictive value of the neurodevelopment tests used is uncertain. Indeed, only two of the 

studies above show an effect beyond the supplementation period, and only one reports a 

sustained effect beyond the first year of life in a limited sample of subjects. In no case the 



DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 3-13 

breastfed reference group showed lower developmental indices when compared to any formula-

fed group.  

On the basis of the data presented, the Panel concludes that the data presented are insufficient 

to establish a cause an effect relationship between the intake of infant and follow-on formula 

supplemented with DHA at levels around 0.3% of the fatty acids and a ratio ARA:DHA 

between 1.4:1 and 2:1 and the contribution to normal brain development in infants and young 

children from birth to three years of age. 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Key words:    Docosahexaenoic acid, arachidonic acid, brain development, infants, children 


DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 4-13 

T

ABLE OF 

C

ONTENTS

 

Panel Members ............................................................................................................................................1

 

Summary .....................................................................................................................................................1



 

Table of Contents ........................................................................................................................................4

 

Background .................................................................................................................................................5



 

Terms of reference.......................................................................................................................................5

 

EFSA Disclaimer.........................................................................................................................................5



 

Acknowledgements .....................................................................................................................................6

 

1.

 



Information provided by the applicant ................................................................................................7

 

1.1.



 

Food/constituent as stated by the applicant ...............................................................................7

 

1.2.


 

Health relationship as claimed by the applicant.........................................................................7

 

1.3.


 

Wording of the health claim as proposed by the applicant ........................................................7

 

1.4.


 

Specific conditions of use as proposed by the applicant............................................................7

 

2.

 



Assessment ..........................................................................................................................................7

 

2.1.



 

Characterisation of the food/constituent ....................................................................................7

 

2.2.


 

Relevance of the claimed effect to human health ......................................................................7

 

2.3.


 

Scientific substantiation of the claimed effect ...........................................................................8

 

Conclusions ...............................................................................................................................................11



 

Documentation provided to EFSA ............................................................................................................12

 

References .................................................................................................................................................12



 

Glossary / Abbreviations ...........................................................................................................................13

 

 



DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 5-13 

B

ACKGROUND

 

Regulation (EC) No 1924/2006

2

 harmonises the provisions that relate to nutrition and health 



claims and establishes rules governing the Community authorisation of health claims made on 

foods. As a rule, health claims are prohibited unless they comply with the general and specific 

requirements of that Regulation and are authorised in accordance with this Regulation and 

included in the lists of authorised claims provided for in Articles 13 and 14 thereof. In 

particular, Articles 14 to 17 of that Regulation lay down provisions for the authorisation and 

subsequent inclusion of reduction of disease risk claims and claims referring to children’s 

development and health in a Community list of permitted claims. 

According to Article 15 of that Regulation, an application for authorisation shall be submitted 

by the applicant to the national competent authority of a Member State, who will make the 

application and any supplementary information supplied by the applicant available to European 

Food Safety Authority (EFSA). 

Steps taken by EFSA

 



The application was received on 14/02/2008. 

 



The scope of the application was proposed to fall under a health claim referring to 

children’s development and health. 

 

During the check for completeness



3

 of the application, the applicant was requested to 

provide missing information on 21/03/2008 and on 23/09/2008. 

 



The applicant provided the missing information on 31/08/2008 and on 06/10/2008. 

 



The scientific evaluation procedure started on 15/10/2008. 

 



During the meeting on 13/03/2009, the NDA Panel, after having evaluated the overall 

data submitted, adopted an opinion on the scientific substantiation of a health claim 

related to docosahexaenoic acid and arachidonic acid and brain development. 

T

ERMS OF REFERENCE

 

EFSA is requested to evaluate the scientific data submitted by the applicant in accordance with 

Article 16 of Regulation (EC) No 1924/2006. On the basis of that evaluation, EFSA will issue 

an opinion on the scientific substantiation of a health claim related to: docosahexaenoic acid 

and arachidonic acid and brain development. 

EFSA

 

D

ISCLAIMER

 

The present opinion does not constitute, and cannot be construed as, an authorisation to the 

marketing of docosahexaenoic acid and arachidonic acid, a positive assessment of its safety, 

nor a decision on whether docosahexaenoic acid and arachidonic acid are, or are not, classified 

as a foodstuff. It should be noted that such an assessment is not foreseen in the framework of 

Regulation (EC) No 1924/2006. 

                                                 

2

  European Parliament and Council (2006). Regulation (EC) No 1924/2006 of the European Parliament and of the Council of 



20 December 2006 on nutrition and health claims made on foods. Official Journal of the European Union OJ L 404, 

30.12.2006. Corrigendum OJ L 12, 18.1.2007, p. 3–18. 

3

  In accordance with EFSA “Scientific and Technical guidance for the Preparation and Presentation of the Application for 



Authorisation of a Health Claim” 


DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 6-13 

It should also be highlighted that the scope, the proposed wording of the claim and the 

conditions of use as proposed by the applicant may be subject to changes, pending the outcome 

of the authorisation procedure foreseen in Article 17 of Regulation (EC) No 1924/2006. 



A

CKNOWLEDGEMENTS

 

The European Food Safety Authority wishes to thank Carlo Agostoni and the members of the 

Working Group for the preparation of this opinion: Jean-Louis Bresson, Albert Flynn, Marina 

Heinonen, Hannu Korhonen, Ambroise Martin, Andreu Palou, Hildegard Przyrembel, Seppo 

Salminen, Sean (J.J.) Strain, Inge Tetens, Henk van den Berg, Hendrik van Loveren and Hans 

Verhagen. 




DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 7-13 

1. 

Information provided by the applicant 

Applicant’s name and address: Mead Johnson & Company 3 rue Joseph Monier-BP 325, 

92506 Rueil-Malmaison Cedex, France.  

The application includes a request for the protection of proprietary data. 

1.1. Food/constituent 

as 

stated by the applicant 

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) 



1.2. Health 

relationship 

as claimed by the applicant 

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are important for brain 

development. 

1.3. 

Wording of the health claim as proposed by the applicant 

DHA and ARA contribute to the optimal brain development of infants and young children. 



1.4. 

Specific conditions of use as proposed by the applicant 

Condition of use for the claim: the formula contains at least 0.3% of the fatty acids as DHA and 

the ratio ARA: DHA is between 1.4:1 and 2.0:1. 

2. Assessment 

2.1. Characterisation 

of the food/constituent 

The food constituents that are the subject of the health claim are docosahexaenoic acid (DHA) 

and arachidonic acid (ARA) derived from single cell oils for which complete specifications, 

manufacturing process, bioavailability and stability information have been provided. DHA is 

derived from the alga Crypthecodinium cohnii and ARA from the fungus Mortierella alpina.

 

DHA and ARA from single cell oils are intended to be added to food for particular nutritional 

uses for infants and young children from birth to 3 years of age according to

 

Directive 



89/398/EEC at the concentration of at least 0.3% of the fatty acids as DHA and a ratio 

ARA:DHA between 1.4:1 and 2:1. This evaluation will apply to DHA and ARA from all 

sources with appropriate bioavailability in the specified amounts. 

DHA and ARA are well characterised fatty acids the absorption of which is well documented 

and can be quantified in foods by established methods. 

The Panel considers that the food constituents DHA and ARA are sufficiently characterised.  



2.2. 

Relevance of the claimed effect to human health 

The claimed effect is the contribution to the optimal brain development of infants and young 

children. The target population proposed by the applicant is infants and young children (from 

birth to three years of age). 

The Panel considers that contribution to the normal development of the brain is beneficial for 

infants’ and children’s development and health.

 

 



DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 8-13 

2.3.

 

Scientific substantiation of the claimed effect 

The applicant performed a literature search in PubMed and Scopus to identify randomised 

controlled trials (RCTs) on the effects of formulae intended for infants and young children 

(from birth to 36 months) containing DHA and ARA on brain and cognitive development (as 

primary or secondary outcome) with the following search terms: DHA, ARA, infant, brain, 

cognitive, mental, long-chain polyunsaturated fatty acids, fatty acids, omega 3, omega 6, 

toddler milk and all combinations of terms. The snow ball method (search for additional 

references in the papers identified through the search) was used for hand searching.  

The applicant identified a total 33 publications as being pertinent to the health claim for 

humans (13 RCTs, one meta-analysis of RCTs, one observational cohort study, three 

postmortem studies, six reviews, seven expert recommendations and two abstracts containing 

unpublished data).   

The Panel considers that publications/reports presented in summary form only and/or 

investigating the effects of DHA and ARA in pre-term infants and/or addressing clinical 

outcomes other than brain development in physiologic conditions are not suitable sources of 

data to support the claimed effect. The Panel also considers that the results of the meta-analysis 

presented assessing the effects of long-chain polyunsaturated fatty acid supplementation on 

developmental outcomes in term infants cannot be directly extrapolated for the substantiation 

of the claimed effect as the inclusion criteria used for trial selection do not match the conditions 

of use proposed by the applicant in the present application (Simmer et al., 2008). 

A total of 13 full publications (Agostoni et al, 1995; Agostoni et al. 1997; Auestad et al., 2001; 

Auestad et al., 2003; Ben et al., 2004; Birch et al., 2000, proprietary data; Birch et al., 2007, 

proprietary data; Bouwstra et al., 2003; Bouwstra et al., 2005; Lucas et al., 1999 ; Makrides et 

al., 2000; Willatts et al. 1998a and 1998b) which report original data from RCTs on the effects 

of DHA supplementation (with or without ARA) on brain development in physiologic 

conditions and in subjects born at term and have been presented by the applicant.  

The 13 publications above include long term observations on subjects supplemented in the first 

months of life (Agostoni et al., 1997; Auestad et al., 2003; Bouwstra et al., 2005; Birch et al., 

2007) while one publication reports complementary observations on neurodevelopmental 

outcomes (Willatts et al., 1998b). Therefore, the results from eight original study designs are 

available. All these studies were conducted in term infant populations fed different formulas 

from birth through the first months of life up to 12 months at the maximum (Agostoni et al., 

1995; Auestad et al., 2001; Ben et al., 2004; Birch et al., 2000; Bouwstra et al., 2003; Lucas et 

al., 1999; Makrides et al., 2000; Willatts et al., 1998a).  

In two RCTs (Auestad et al, 2001; Ben et al, 2004), formulas with less than 0.2% DHA (in 

various combinations with ARA) from birth through six (Ben et al., 2004) or 12 months of age 

(Auestad et al., 2001; Auestad et al., 2003, follow-up) had no effect on neurodevelopmental 

indices measured with different methods as compared to standard, unsupplemented formulas. 

Only in one study the power calculations were reported (Auestad et al., 2001). The Panel notes 

that the doses of DHA (and ARA) used in these studies were lower than those proposed by the 

applicant to obtain the claimed effect. 

Two publications report the results of double-blind RCTs investigating the effects of formulas 

supplemented with DHA around 0.3% either alone or in combination with ARA at around the 

same level (ARA:DHA ratio = 1) form birth to 6-12 months of life as compared to 

unsupplemented formulas (Lucas et al., 1999; Makrides et al., 2000). In the study by Lucas et 

al. (1999), 309 healthy term infants were randomly allocated at birth to receive either a DHA 

and ARA supplemented formula (n = 154) or a control (unsupplemented) formula (n = 155) for 



DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 9-13 

six months. Breastfed infants for at least six weeks served as reference group (n = 138). Sample 

sizes were based on power calculations considering the Bayley’s Mental and Psychomotor 

Developmental Indices (MDI, PDI) of infant development as primary outcomes. A total of 125, 

125, and 104 infants in the intervention, control and reference groups were evaluated at 18 

months for Bayley’s MDI and PDI. No significant differences were observed at 18 months 

between the intervention and the control group, or between the formula-fed vs the breastfed 

groups, on either cognitive or motor development after adjustment for confunders. In the study 

by Makrides et al. (2000), 83 healthy full-term infants were randomly allocated at the age of 

one week to receive one of three formulae (placebo formula, formula with 0.35 % of total fatty 

acids as DHA or formula with both DHA 0.34 % and ARA 0.34 %) to be consumed throughout 

the first year of life. A total of 61 infants could be investigated at 1 and 2 years of age. From a 

control group of 63 breast-fed infants, 46 completed the trial until two years of age. Sample 

sizes were based on power calculations considering sweep VEP acuity (and not Bayley’s MDI 

and/or PDI scales) as primary outcome. No differences were observed between the three 

formula-fed groups at one or two years of age on Bayley’s MDI or PDI. Breastfed infants had 

higher MDI scores than formula-fed infants at two years of age even after adjusting for 

environmental variables. The Panel notes that doses of DHA in these studies (but not the 

DHA:ARA ratio) are in the range of those recommended by the applicant to obtain the claimed 

effect. 


In the double-blind RCT by Willatts et al. (1998a), 44 term infants were randomly allocated at 

birth to consume either a formula supplemented with 0.15-0.25% DHA and 0.30-0.40% ARA 

(ARA:DHA ratio = 1.7:1 to 2:1, n = 21) or a standard (control, n = 23) unsupplemented 

formula for four months in order to investigate the effects of DHA and ARA supplementation 

on infant cognitive behaviour at 10 months of age by a means-end problem-solving test. A 

sample size of 24 subjects per group was calculated as being required to detect a difference of 

one intentional solution on the entire three-step problem with a power of 90% at P=0.05. 

Infants who received the DHA and ARA supplemented formula had significantly more 

intentional solutions and higher intention scores than infants who received the unsupplemented 

formula. The means-end problem-solving test is currently used to explore the function of 

specific associative areas in the prefrontal lobes, which are particularly rich in DHA. 

Significantly higher DHA content in these brain areas has been observed in breastfed infants vs 

(unsupplemented) formula-fed infants at four months of life in autoptic studies (“cot” death) 

presented by the applicant in the section of biological plausibility (Farquharson et al., 1993;  

Makrides et al., 1994). In anoher publication on the same infant population (Willatts et al., 

1998b), a post-hoc analysis comparing infants with evidence of reduced growth parameters at 

birth and impaired attention control as manifested by a late peak fixation during infant 

habituation assessment at three months versus infants with early peak fixation within the 

supplemented (n = 11 vs n = 9, respectively) and the unsupplemented (n = 10   n = 10, 

respectively) formula groups showed that the number of solutions in the means-end problem-

solving ability at nine months was significantly reduced in the late peak-fixation infants 

receiving the unsupplemented formula as compared to the other three groups. The Panel notes 

the small sample size on each of the groups and that the hypothesis tested in this post-hoc 

analysis falls beyond the primary outcome (number of solutions at the means-end problem 

solving test) for which the sample size required was initially identified (Willatts et al., 1998a). 

The Panel also notes that doses of DHA (but not the DHA:ARA ratio) reported in these studies 

were lower than those recommended by the applicant to obtain the claimed effect. 

In the remaining three study designs (Agostoni et al, 1995; Bouwstra et al., 2003; Birch et al., 

2000) formulas supplemented with either 0.3 % DHA alone or in combination with ARA in 

higher dosages (ARA:DHA ratio from 1.4:1 to 2:1) were used in the intervention groups. The 




DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 10-13 

Panel also notes these doses of DHA and the DHA:ARA ratio are in the range of those 

recommended by the applicant to obtain the claimed effect. 

In the double-blind RCT by Agostoni et al. (1995), healthy term infants were randomised at 

birth to consume either a formula supplemented with 0.30% DHA and 0.44% ARA 

(ARA:DHA ratio = 1.4:1, n = 29) or a control (unsupplemented) formula (n = 31) for four 

months. An exclusively breastfed group (n = 31) served as reference. Global 

neurodevelopmental performance was assessed by means of the Brunet-Lézine test as 

Developmental Quotient (DQ) at 4 months. A sample size of 24 subjects per group was 

calculated as being required to detect a clinically significant difference on DQ (10%) between 

groups with a power of 90% at P=0.05. Infants in the supplemented formula and in the 

breastfed groups scored significantly higher in the Brunet-Lézine test than infants in the control 

group at four months of age. No differences were observed between the supplemented formula 

and the breastfed groups. Differences between the formula-fed groups were not sustained when 

infants were re-evaluated with the Brunet-Lézine test at 24 months of life (Agostoni et al., 

1997). The Panel notes that the Brunet-Lézine test (as well as the Griffith’s scale and the 

Bayley’s indices) ultimately derives from the Gesell’s developmental schedules published in 

1947 (Gesell and Amatruda, 1947), which were originary developed for the definition of mental 

handicap and not for the scoring of attitudes generally indicated as “intelligence” within the 

“normal” population of infants and children, in which their predictive value is doubtful.  

In the double-blind RCT by Bouwstra et al. (2003), healthy term infants were randomised at 

birth to consume either a formula supplemented with 0.3% DHA and 0.45% ARA (ARA:DHA 

ratio = 1.5:1, n = 119) or a control (unsupplemented) formula (n = 131) for two months. A 

breastfed group (n = 147), of which 73 infants stopped breasfeeding before the 2-month 

intervention and were subsequently assigned to the supplemented formula, served as reference. 

The quality of general movements (GMs) based on the observations of videotapes recording the 

infants’ movements was assessed 3 months of age. The quality of GMs was classified as 

normal-optimal, normal-suboptimal and midly abnormal. This test appears to have a predictive 

value for the neurological development (not intelligence) later in life. No power calculations 

are reported. Infants in the control group had mildly abnormal GMs significantly more often 

than did infants in the supplemented formula and breastfed groups (31% compared with 19% 

and 20%, respectively). Infants in the breastfed group had normal-optimal GMs more 

frequently than did infants in the supplemented formula and control groups (34% compared 

with 18% and 21%, respectively). No differences between the supplemented formula, the 

control formula and the breastfeed groups were found in clinical neurological condition, 

neurological optimality score, fluency score, or the Bayley’s MDI or PDI when the infants were 

re-tested at 18 months of life (Bouwstra et al., 2005).   

The double-blind RCT by Birch et al. (2000) included 112 infants randomised at the age of five 

days to consume either a formula with DHA 0.35% alone, a formula with DHA 0.36% plus 

ARA 0.72%, or a control formula devoid of DHA and ARA for 17 weeks. An additional group 

of term infants (n = 29) exclusively breastfed for at least the first 17 weeks of life served as 

non-randomised control group. A sample size of 16 subjects per group was calculated as being 

required to detect mean differences in the MDI of the Bayley scales of 1SD or greater at 18 

months between groups. At that age, 20 subjects in the control formula group, 17 in the DHA-

supplemented formula group and 19 in the DHA plus ARA formula groups were tested with the 

Bayley scales of infant development. Infants supplemented with DHA and ARA yielded 

significantly higher MDI scores (mean = 7 points) than infants in the control group. Both the 

cognitive and motor subscales of the MDI showed a significant developmental age advantage 

for the groups supplemented with DHA and with DHA plus ARA as compared to controls. No 

significant differences between groups were observed among the three groups regarding the 

PDI or the Behaviour Rating Scale. Significant correlations were observed between DHA 



DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 11-13 

concentrations in red blood cells (but not between ARA, linoleic acid, 

α-linolenic acid or 

eicosapentaenoic acid) at four months (but not at 12 months) and the MDI scores at 18 months 

of age. Infants in the formula-fed and breastfed groups were tested at four years of age for 

Intelligence Quotient (IQ). Verbal IQ in the control and DHA-supplemented formula groups 

was significantly lower than in the DHA plus ARA and the breastfed groups. No differences 

were observed among all four groups regarding the full scale IQ or the performance IQ (Birch 

et al., 2007).  

The Panel notes that none of the studies using formulas supplemented with doses of DHA and 

ARA lower than proposed in the conditions of use or 0.3% DHA and an ARA:DHA ratio of 

one show an effect of DHA and ARA supplementation on neurodevelopment indices infants as 

compared to unsupplemented formulas (Auestad et al., 2001; Auestad et al., 2003; Ben et al., 

2004; Lucas et al., 1999; Makrides et al., 2000). The Panel also notes that the four studies using 

either slightly lower DHA doses (Willatts et al., 1998a) or about 0.3% DHA (Agostoni et al, 

1995; Birch et al, 2000; Bouwstra et al., 2003) and the ARA:DHA ratio proposed in the 

conditions of use (between 1.4:1 and 2:1) show a short-tem beneficial effect of DHA and ARA 

supplementation on different measures of neurodevelopment. However, the different testing 

ages and the use of different tests for assessment limit the comparability of the studies. Also, 

the predictive value of the neurodevelopment tests used is uncertain. Indeed, only two of the 

studies above show an effect beyond the supplementation period (Willatts et al., 1998a; Birch 

et al., 2007), and only one reports a sustained effect beyond the first year of life in a limited 

sample of subjects (Birch et al., 2007). In no case the breastfed reference group showed lower 

developmental indices when compared to any formula-fed group.  

Although the Panel acknowledges that there is some evidence supporting a short-tem effect of 

DHA and ARA supplementation starting at birth on brain development in non-breastfed infants, 

the Panel considers that the data available is inconsistent and does not support an effect beyond 

the supplementation period or beyond the first year of life.  

The Panel concludes that the data presented are insufficient to establish a cause an effect 

relationship between the intake of infant and follow-on formula supplemented with DHA at 

levels around 0.3% of the fatty acids and a ratio ARA:DHA between 1.4:1 and 2:1 and the 

contribution to normal brain development in infants and young children from birth to three 

years of age. 

C

ONCLUSIONS 

 

On the basis of the data presented, the Panel concludes the following: 

 

The food constituents DHA and ARA are sufficiently characterised. 



 

The claimed effects is the contribution to the optimal brain development of infants and 



young children.

 

The target population proposed by the applicant is infants and young 



children (from birth to three years of age). Contribution to the normal development of 

the brain is beneficial for infants’ and children’s development and health. 

 

The data presented are insufficient to establish a cause an effect relationship between 



the intake of infant and follow-on formula supplemented with DHA at levels around 

0.3% of the fatty acids and a ratio ARA:DHA between 1.4:1 and 2:1 and the 

contribution to normal brain development in infants and young children (from birth to 

three years of age). 




DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 12-13 

D

OCUMENTATION PROVIDED TO 

EFSA 

Health claim application on DHA and ARA and brain development pursuant to Article 14 of 

Regulation (EC) No 1924/2006 (Claim serial No:0131a-FR). October 2008. Submitted by 

Mead Johnson & Company. 



R

EFERENCES

 

Agostoni C, Trojan S, Bellu R, Riva E, Giovannini M, 1995. Neurodevelopmental quotient of 

healthy term infants at 4 months and feeding practise: the role of long-chain polyunsaturated 

fatty acids. Pediatr. Res. 38, 262-266.  

Agostoni C, Trojan S, Bellu R, Riva E, Bruzzese MG, Giovannini M, 1997. Developmental 

quotient at 24 month and fatty acid composition of diet in early infancy: a follow up study. 



Arch. Dis. Child. 76, 421-424. 

Auestad N, Halter R, Hall RT, Blatter M, Bogle ML, Burks W, Erickson JR, Fitzgerald KM, 

Dobson V, Innis SM, Singer LT, Montalto MB, Jacobs JR, Qiu W, Bornstein MH, 2001. 

Growth and development in term infants fed long-chain polyunsaturated fatty acids: a 

double-masked, randomized, parallel, prospective, multivariate study. Pediatrics, 108, 372-

381.  


Auestad N, Scott DT, Janowsky JS, Jacobsen C, Carroll RE, Montalto MB, Halter R, Qiu W, 

Jacobs JR, Connor WE, Connor SL, Taylor JA, Neuringer M, Fitzgerald KM, Hall RT, 

2003. Visual, cognitive, and language assessments at 39 months: a follow-up study of 

children fed formulae containing long-chain polyunsaturated fatty acids to 1 year of age. 



Pediatrics 112, e177-e183. 

Ben X, Zhou XY, Zhao WH, Yu WL, Pan W, Zhang WL, Wu SM, Beusekom CM Van, 

Schaafsma A, 2004. Growth and development of term infants fed with milk with long-chain 

polyunsaturated fatty acid supplementation. Chin. Med. J. (Beijing) 117, 1268-1270. 

Birch EE, Garfield S, Hoffman DR, Uauy R, Birch DG, 2000. A randomised controlled trial of 

early dietary supply of LCPUFA and mental development in term infants. Develop. Med. 



Child. Neurol. 42, 174-181. 

Birch EE, Garfield S, Castaneda Y, Birch DG, Uauy R, Hoffman DR, 2007. Visual acuity and 

cognitive outcomes at 4 years of age in a double-blind, randomized trial of long-chain 

polyunsaturated fatty acid-supplemented infant formula. Early Human Dev. 83, 279-284. 

Bouwstra H, Dijck-Brouwer DAJ, Wildeman JAL, Tjoonk HM, Van der Heide JC, Boersma 

ER, Muskiet FAJ, Hadders-Algra M, 2003. Long-chain polyunsaturated fatty acids have a 

positive effect on the quality of general movements of healthy term infants. Am. J. Clin. 

Nutr. 78, 313-8. 

Bouwstra H, Dijck-Brouwer DAJ, Boehm G, Boersma ER, Muskiet FAJ, Hadders-Algra M, 

2005. Long-chain polyunsaturated fatty acids and neurological developmental outcome at 18 

months in healthy term infants. Acta Pædiatrica 94, 26–32. 

Farquharson J, Cockburn F, Patrick WA, Jamieson EC, Logan RW, 1992. Infant cerebral cortex 

phospholipid fatty-acid composition and diet. Lancet 340, 810–813.  

Gesell A and Amatruda C, 1947. Developmental diagnosis. Harper & Brothers: New York. 

Lucas A, Stafford M, Morley R, Abbott R, Stephenson T, MacFadyen U, Elias-Jones A, 

Clements H, 1999. Efficacy of safety of long-chain polyunsaturated fatty acid 

supplementation in infant-formula milk: a randomised trial. Lancet 354, 1948-1954.  




DHA and ARA and brain development

 

 

The EFSA Journal (2009) 1000, 13-13 

Makrides M, Neumann MA, Byard RW, Simmer K, Gibson RA, 1994. Fatty acid composition 

of brain, retina, and erythrocytes in breast- and formula-fed infants. Am. J. Clin. Nutr. 60, 

189-194. 

Makrides M, Neumann MA, Simmer K, Gibson RA, 2000. A critical appraisal of the role of 

long-chain polyunsaturated fatty acids on neural indices of term infants: a randomised 

controlled trial. Pediatrics 2000; 105:32-38.  

Simmer K, Patole SK, Rao SC, 2008. Longchain polyunsaturated fatty acid supplementation in 

infants born at term. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: 

CD000376. DOI: 10.1002/14651858.CD000376.pub2 

Willatts, Forsyth JS, DiModugno MK, VarmaS, Colvin M, 1998a. Effect of long-chain 

polyunsaturated fatty acids in infant formula on problem solving at 10 month of age. Lancet 

352, 688-691. 

Willatts, Forsyth JS, DiModugno MK, VarmaS, Colvin M, 1998b. Influence of long-chain 

polyunsaturated fatty acids on infant cognitive function. Lipids 33, 973-980. 

G

LOSSARY 

/

 

A

BBREVIATIONS

 

ARA Arachidonic 

acid 

DHA Docosahexaenoic 



acid 

GMs General 

movements 

DQ Developmental 

Quotient 

IQ Intelligence 

Quotient 

MDI Mental 

Developmental 

Index 


PDI Psychomotor 

Developmental Index 



RCTs 

Randomised controlled trials 



 

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