JOURN

EES CHEVREUL 2011 LIPIDS AND BRAIN

The role of omega-3 fatty acids in child development*

Saskia JM OSENDARP Abstract: Omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) are important
constituents of the maturing brain and therefore considered crucial for brain
Unilever R&D Vlaardingen,
development in utero and in early infancy. However, it is uncertain whether n-3
The Netherlands & Division of Human
LCPUFA supplementation during pregnancy and lactation can have beneficial,
Nutrition, sustainable effects on visual or cognitive development. Beneficial effects on child
Wageningen University, cognitive function after supplementation with EPA and DHA during pregnancy and
The Netherlands lactation were observed at 4 years of age, but not at 3, 6 months or 7 years. In term
<saskia.osendarp@unilever.com> infants LCPUFA when given in relative high dosages, seems to improve visual acuity, but
not cognitive function. Evidence for an effect of LCPUFA supplementation of preterm
infants remains inconclusive. In children older than 2 years of age, epidemiological
evidence suggests an association between psychiatric or neurodevelopmental disorders
and omega-3 fatty acid deficiencies. However, the evidence from randomized controlled
trials exploring the impact of omega-3 fatty acids on cognitive performance or brain
function in school-aged children is not conclusive. In conclusion, n-3 LCPUFA are highly
present in the maturing brain and are important for normal brain functioning and
development. When provided in relative high dosages, n-3 LCPUFA may improve visual
acuity in term infants. However, it remains unclear whether supplementation with n-3
LCPUFA during pregnancy, early infancy, and childhood can improve cognitive function.
Key words: child development, omega-3 fatty acids, neurodevelopmental disorders
psychiatric disorders

There is considerable interest in the role of brane fluidity, membrane activity-bound developmental outcomes of the off-
certain long chain polyunsaturated fatty enzymes, number and affinity of recep- spring (> 2 years) were reported from
acids (LCPUFA), in visual and cognitive tors, function of neuronal membrane both observational studies and rando-
development throughout childhood. The ionic channels, and production of neuro- mized controlled trials (RCTs) (figure 1).
n-3 fatty acid docosahexaenoic acid transmitters and brain peptides (Yehuda,
2003). Although DHA and AA are the Three RCTs from high-income countries
(DHA) and the n-6 fatty acid arachidonic supplemented with n-3 fatty acids during
acid (AA) are the major LCPUFA in the major structural components of the
central nervous system, there is currently pregnancy. Two of these trials reported
brain (Martinez, 1992). DHA and AA are improvements in problem solving at
rapidly incorporated in the nervous tissue no consensus whether dietary supple-
mentation of LCPUFA has benefits for 9 months of age (Judge et al., 2007) or
of retina and brain during the brain’s hand-eye coordination at 30 months of
growth spurt, which mainly takes place visual and cognitive development of
infants. age (Dunstan et al., 2008). However, as a
from the last trimester of pregnancy up to lot of outcome measures were tested in
2 years of age (Dobbing and Sands, 1973; these RCTs without adjusting p-values
Clandinin et al., 1980; Martinez, 1992). accordingly, positive findings may have
Beyond development of the central Evidence from pregnant been due to chance. In contrast, one
nervous system, n-3 and n-6 fatty acids
may influence brain function throughout
and lactating mothers recent large study with high-DHA fishoil
in Australia did not observe benefits
life by modifications of neuronal mem- There is suggestive evidence for a in cognitive and language scores at
beneficial effect of early exposure to 18 months of age after maternal
n-3 fatty acids on children’s cognitive supplementation during pregnancy
*
Lecture from the symposium ‘‘Lipids and development. Repeatedly, positive fin- (Makrides et al., 2010).
dings on a beneficial effect of n-3 fatty
doi: 10.1684/ocl.2011.0417

Brain II’’ held by The French Society for the

Study of Lipids (Sfel) - Paris 28-30 March acid supplementation or fish intake Two intervention trials on prenatal
2011, cf. OCL 18-4 and 18-5. during pregnancy and/or lactation on supplementation with n-3 LCPUFA have

To cite this article: Osendarp SJM. The role of omega-3 fatty acids in child development. OCL 2011 ; 18(6) : 307-313. doi : 10.1684/
ocl.2011.0417

OCL VOL. 18 N8 6 novembre-décembre 2011 307

Article disponible sur le site http://www.ocl-journal.org ou http://dx.doi.org/10.1051/ocl.2011.0417

 intake during pregnancy and/or lacta-
tion on developmental outcomes of the
offspring up to 14 years were reported
from observational studies. The small
number of RCTs, however, reported
only few positive findings on single
Human brain development outcome measures, which may have
been due to chance. Overall, there is no
consistency in the benefits observed,

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with improvements being reported for

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general IQ, memory, verbal, motor

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Neuralisation

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proliferation te
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migration
Myelination pre-term infants
-8 -6 -4 -2 0 2 4 6 8 10 12 2 4 6 8 10 12 14 16 18 20
Evidence on the effects of LCPUFA during
Conception

Months Years
infancy have been well-documented and
TRENDS in Cognitive Sciences summarised in recent meta-analysis.
Overall, there is no good evidence for a
Birth beneficial effect of LCPUFA supplemen-
tation on mental development in infants
(< 2 yr). A recent meta-analysis on the
Figure 1. Brain development in childhood. Adapted from Thompson, RA, Nelson CA. Develop- effects of LCPUFA supplementation of
ment. Am Psychol 2001; 56: 5-15. Animation: Gogtay et al., 2007 pre-term infants on neurodevelopment
up to 18 months of age reported that
four out of seven studies did not show a
benefit; the three trials which showed
been conducted in low-income coun- feeding mothers for improving child improvements on cognitive develop-
tries: in Bangladesh and Mexico. Both growth and development conducted a ment scores all used the newer version
studies did not observe differences pooled analysis of outcomes on five of the Bayles Scales of Infant Develop-
between infants from treated and control clustered areas of neurodevelopment, ment, suggesting that the effects may
mothers in development scores at 10 or i.e. language development, intelligence/ have been too subtle to be detected with
18 months of age were observed (Tofail problem solving ability, psychomotor other methods (Schulzke et al., 2011).
et al., 2006; Ramakrishan et al., 2010). development, motor development and No beneficial effects of LCPUFA supple-
child attention. Overall, no significant mentation on visual development were
One study reported on the effects of
effects were found, except for attention seen either (Schulzke et al., 2011). A
maternal supplementation with 803 mg
at 5 years which was due to one single meta-analysis on the effects of LCPUFA
EPA and 1183 mg DHA from 18 weeks
study (Jensen et al., 2010). It was supplementation in term infants did not
gestation until 3 months postpartum.
concluded that based on the limited show an effect on either mental or
Beneficial effects were observed on
evidence, LCPUFA supplementation dur- psychomotor development (Simmer
mental processing index at 4 years
ing the lactation period did not appear to et al., 2008). Outcomes on visual acuity
(Helland et al., 2003; Helland et al.,
improve children’s neurodevelopment. were inconsistent, with six out of nine
2008) but not any more at 7 years of
age. Infant, maternal or cord blood DHA Six (Lederman et al., 2008; Oken et al., studies not showing a beneficial effect.
status was repeatedly found to be 2008; Mendez et al., 2008; Gale et al., Beneficial effects on visual acuity in term
positively correlated to cognitive out- 2008; Budtz-Jorgensen et al., 2007; infants were seen with higher doses of
comes (Helland 2003 et al.;, Helland et Hibbeln et al., 2007) out of seven DHA (0.35% or 0.36% in formula) and
al., 2008; Dunstan et al., 2008). (Strain et al., 2008) observational studies when measured by electrophysiological
report a significant beneficial association tests.
Overall, there is no consistency with
regard to the areas of mental develop- of maternal fish intake during pregnancy
ment that might benefit from maternal and children’s development up to 14
n-3 fatty acid supplementation; impro- years of age on one or more sub-scales Evidence from healthy
vements were reported for general IQ, (PDI/motor abilities; hyperactivity & children
memory, verbal, motor performance, social behaviour; verbal und full IQ) in
attention, hyperactivity and social beha- combination with non-significant trends Studies in healthy children (> 2 yr) do
viour. for other outcome measures suggesting not show consistent beneficial effects of
beneficial effects of fish intake. a DHA or EPA supplementation. In total,
A recent Cochrane review (Delgado- seven out of ten randomised controlled
Noguera et al., 2010) on the effects of In summary, repeatedly, positive fin- intervention studies in 4-14 year old
supplementation with LCPUFA to breast- dings on a beneficial effect of n-3 or fish children did not find a beneficial effect

308 OCL VOL. 18 N8 6 novembre-décembre 2011

LCPUFA on cognitive outcomes (Kirby 2009). The positive effects found cannot relationship between n-3 FA or fish
et al., 2010; Kennedy et al., 2009; for sure be contributed to EPA & DHA as intake and cognitive outcomes.
Muthayya et al., 2009; Ryan et al., the fish flour also contains vitamins and
2008; Osendarp et al., 2007; de Jong minerals which might have had an effect. Five cross-sectional studies assessing 4-
et al., 2010). The dosages used in this trial An fMRI study in 33 UK boys found 16 yr old children found a significant
varied significantly and ranged from 100- significantly increased cortical activation positive association between fish, n-3, or
1,200 mg DHA/EPA per day. In addition, during a sustained attention task upon total PUFA intake and at least some
all of these RCTs had some quality eight weeks of supplementation with cognitive outcomes (Kirby et al., 2010,
limitations, like a low intervention dose, 400 or 1200 mg/d DHA (McNamara Theodore et al., 2009; Kim et al., 2009;
a too short intervention period, use of et al., 2010), but no differences between Zhang et al., 2005, Freire et al., 2010).
non-validated tests, tests in non-native groups in behavioural test outcomes. Two other studies did not find any
language, ceiling effect, multiple asses- Another study in UK children found significant associations (Mendez et al.,
sors, inappropriate control product, a significant effects of a three month 2008, Eilander et al., 2010).
small sample size, which might explain intervention with EPA (558 mg/d),
Five longitudinal studies, followed chil-
the lack of positive findings. DHA (174 mg/d) and GLA (60 mg/d)
dren form birth to childhood (Bakker
on reading age and working memory but
Three RCTs did find some beneficial et al., 2003, 2009; Ghys et al., 2002; Gale
not on behaviour. However, this study
effects (Dalton et al., 2009; McNamara et al., 2010) or throughout childhood
had some quality limitations and is still
et al., 2010; Portwood, 2011). One RCT (Rask-Nissila et al., 2002; Aberg et al.,
not published in a peer-reviewed paper
in South African children of low SES with 2009); two studies showed significant
(Portwood, 2011).
a habitual low fish intake found signi- beneficial effects of DHA fortified formula
ficant effects of a spread fortified with Observational (cross-sectional and lon- during the first 6 months (Gale et al.,
fish flour on verbal recognition, discri- gitudinal) studies in healthy children 2010) and fish intake during adolescence
mination and spelling (Dalton et al., suggest that there might be a positive (Aberg et al., 2009) on children’s overall

Socio-cultural Psycho-social
factors risk factors

Sensori-
motor
Brain
development
Social- Cognitive-
and function
emotional language

Biological
Poverty risk factors Mental development
(Nutrition)

Figure 2. Conceptual framework on role of nutrition in mental development. Adapted from Walker et al., Lancet 2007

OCL VOL. 18 N8 6 novembre-décembre 2011 309

cognitive outcome measures. Other lopmental disorders. Evidence from The question whether additional dietary
studies did not show an association studies in children with ADHD show supply of DHA, is required for cognitive
between DHA status at birth or intake some positive findings on self-reported functioning after the age of 2 years,
during the first six months with cognitive behaviour. Four (Richardson and Puri, remains therefore unanswered.
performance at 4 or 7 yr of age (Bakker 2002; Stevens et al., 2003; Sinn, 2007;
Rapoport et al. (2007) studied the
et al., 2003; Ghys et al., 2002), but a Johnson et al., 2009) out of five (Raz et al.,
turnover of DHA in the human brain
positive relationship with improved 2009) randomized controlled trials sup-
by measuring the daily incorporation of
motor performance at 5 (Rask-Nissila plementing a mix of n-3 fatty acids (120-
radio-labelled DHA into the brain. He
et al., 2002) and 7 years of age (Bakker 730 mg/d) and n-6 fatty acids (60 to
stated that the incorporation rate of
et al., 2009) (figure 2). 135 mg/d) showed improvements on
DHA equal the rate of loss because DHA
In summary, there is suggestive evidence self-reported ADHD symptoms. Six more
cannot be synthesized de novo in the
– from observational studies – of a positive studies of varying quality, two of them
brain, neither does its precursor (ALA)
relationship between n-3 FA status at were open-label studies, supplemented
contribute significantly (<1%) to brain
birth or fish intake during childhood and n-3 fatty acids alone (Voigt et al., 2001;
DHA. He found that the adult brain uses
developmental outcomes in healthy chil- Hiramaya et al., 2004; Joshi et al., 2006;
and replaces 4.6 mg of DHA per day.
dren up to the age of 18 years. Yet the Sorgi et al., 2007; Vaisman et al., 2008;
This suggests that DHA in the brain
results might be confounded by other Gustafsson et al., 2010). Only the open-
might need to be replenished to main-
influencing factors and don’t prove a label studies showed a significant effect
tain certain levels. However, in a rat
cause-effect relationship. The potential of ALA (400 mg/d) or very high doses of
study Rapoport et al. also showed that
beneficial effects are not confirmed in EPA/DHA (16 g/d) on behavioural out-
the rate of liver synthesis of DHA from
intervention trials. The majority (i.e. 7 out comes (Joshi et al., 2006; Sorgi et al.,
ALA was more than sufficient to main-
of 10) of randomized controlled inter- 2007). Three of the four randomized
tain brain DHA (Rapoport et al., 2007).
vention trials in healthy children does not controlled trials supplementing DHA
(+EPA) point into the same direction As several studies in specific patient
show an effect of n-3 fatty acid sup-
(Voigt et al., 2001; Vaisman et al., 2008; groups (ADHD, PKU) showed that EPA/
plementation on cognitive outcomes.
Gustafsson et al., 2010) (figure 2). DHA supplementation had a beneficial
effect on functional cognitive outcomes
(primarily behaviour related) one can
hypothesise that dietary fatty acids do
Evidence from diseased Discussion and arrive at the target organ and that they
populations conclusion are indeed used in their role in cognitive
functioning. However, this would still
There is some evidence from studies in LCPUFA and DHA in particular are need to be confirmed.
children with phenylkenonuria (PKU) on abundantly present in the human deve-
the role of n-3 fatty acids in neurotrans- loping brain. However, the evidence Because the conversion of ALA to DHA is
mission and behavioural outcomes. Chil- base for a beneficial effect of dietary very limited, many health authorities
dren with PKU have very low natural LCPUFA on child’s development is thin currently advice to ensure a minimum
intakes of EPA and DHA due to dietary and has inconsistent findings. Supportive intake of DHA and EPA from the diet,
restrictions (but a good supply of ALA). evidence for a beneficial role of n-3 fatty despite the fact that in principle the
Two studies (one of them an open label acids in cognitive functioning is mainly body should be able to make these fatty
study) in treated PKU children showed coming from studies in specific patient acids. EPA and DHA are for that reason
that these children had prolonged visual groups (PKU) or children with develop- considered ‘‘conditionally essential’’
evoked potentials compared to healthy mental disorders (ADHD, neurophysiolo- (Uauy and Dangour, 2009).
controls. After supplementation with gic diseases, n-3 deficiency). It is Recommendations for the intake of EPA
DHA, EPA (+ALA and AA) wave latency questionable however, how far this evi- and DHA for adults are mainly based on
of visual evoked potentials decreased in dence can be extrapolated to the general primary and secondary prevention of
both studies, indicating more rapid cen- population. cardiovascular disease (CVD; 250-
tral nervous system information process- It is unfortunate that most of the 500 mg/d EPA+DHA or 1-2 portions of
ing (Beblo et al., 2001). The open-label intervention studies reported to date fatty fish per week). For children from 2-
study also showed significant improve- suffer from methodological limitations. 10 years the FAO recently set recom-
ments of EPA+DHA supplementation on a Failure to find positive effects of LCPUFA mendations for an adequate EPA and
test of motor function and coordination on child development might have been DHA intake, i.e. 100 to 250 mg (depend-
(Beblo et al., 2007). When the subjects of due to intervention dosages which were ing on the age) (FAO, 2010) in line with
the controlled trial were assessed again too low, too short interventions, limita- adults aiming at the early prevention of
three years later after the end of the tions related to the use of psychological chronic disease (Koletzko et al., 2010). In
treatment to see whether improvements tests, inappropriate control products and children and adults, PUFA intakes are
had lasted in the longer term, initial small sample sizes. On the other hand, generally below the recommendations.
improvements had returned to baseline trials which did demonstrate positive Also EPA and DHA intakes are lower than
(Agostini et al., 2003). effects, may in fact have reported false- recommended; however, data are very
In addition, there is some evidence from positive findings particularly due to a limited (Harika et al., 2011). Despite the
EPA/DHA intervention studies on cogni- high number of test outcomes included on-going debate on the exact role of
tive functioning in children with deve- and the possibility of chance findings. LCPUFA in cognitive, efforts to increase

310 OCL VOL. 18 N8 6 novembre-décembre 2011

 www.medscape.com

DHA accumulates in the brain

beginning In utero through toddlerhood

12000
DHA accumulation in the brain,

10000
8000
mmol/forebrain

Third
trimester
6000

4000

2000

-2000
20 40 60 80 100 120 140 160
Postmenstrual age, weeks

Martinez M. J Pediatr. 1992 : 120 : S129-S138.

Figure 3. Brain DHA during gestation and early childhood. Adapted from Martinez M. J Pediatr 1992, 120: S129-s138

consumption of these fatty acids in supplementation improves visual evoked Delgado-Noguera MF, Calvache JA, Bonfill
children should therefore be supported potentials in children with phenylketonuria. Cosp X. Supplementation with long chain
(figure 3). Neurology 2001; 57: 1488-91. polyunsaturated fatty acids (LCPUFA) to
breastfeeding mothers for improving child
Beblo S, Reinhardt H, Demmelmair H, Muntau
growth and development. Cochrane Data-
AC, Koletzko B. Effect of fish oil supplementa-
base Syst Rev 2010; (12): CD007901.
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