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Cognitive assessment of children at age 2½ years after maternal fish oil supplementation in pregnancy: a randomised controlled trial

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To assess the effects of antenatal omega 3 long-chain polyunsaturated fatty acid (n-3 LC PUFA) on cognitive development in a cohort of children whose mothers received high-dose fish oil in pregnancy. A double-blind randomised placebo-controlled trial. Perth, Western Australia, Australia. 98 pregnant women received the supplementation from 20 weeks' gestation until delivery. Their infants (n = 72) were assessed at age 2(1/2) years. Fish oil (2.2 g docosahexaenoic acid (DHA) and 1.1 g eicosapentaenoic acid (EPA)/day) or olive oil from 20 weeks' gestation until delivery. Effects on infant growth and developmental quotients (Griffiths Mental Development Scales), receptive language (Peabody Picture Vocabulary Test) and behaviour (Child Behaviour Checklist). Children in the fish oil-supplemented group (n = 33) attained a significantly higher score for eye and hand coordination (mean ((SD) score 114 (10.2)) than those in the placebo group (n = 39, mean score 108 (SD 11.3); p = 0.021, adjusted p = 0.008). Eye and hand coordination scores correlated with n-3 PUFA levels in cord blood erythrocytes (EPA: r = 0.320, p = 0.007; DHA: r = 0.308, p = 0.009) and inversely correlated with n-6 PUFA (arachidonic acid 20:4n-6: r = -0.331, p = 0.005). Growth measurements in the two groups were similar at age 2(1/2) years. Maternal fish oil supplementation during pregnancy is safe for the fetus and infant, and may have potentially beneficial effects on the child's eye and hand coordination. Further studies are needed to determine the significance of this finding.
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Cognitive assessment of children at age 2K years
after maternal fish oil supplementation in pregnancy:
a randomised controlled trial
J A Dunstan,
1
K Simmer,
1
G Dixon,
2
S L Prescott
1
1
School of Paediatrics and Child
Health, University of Western
Australia, Perth, Western
Australia, Australia;
2
Telethon
Institute for Child Health
Research, Centre for Child
Health Research, The University
of Western Australia, Western
Australia, Australia
Correspondence to:
A/Professor S L Prescott, School
of Paediatrics and Child Health,
University of Western Australia,
Princess Margaret Hospital, PO
Box D184, Perth, WA 6840,
Australia; susanp@ichr.uwa.
edu.au
Accepted 19 September 2006
ABSTRACT
Objective: To assess the effects of antenatal omega 3
long-chain polyunsaturated fatty acid (n-3 LC PUFA) on
cognitive development in a cohort of children whose
mothers received high-dose fish oil in pregnancy.
Design: A double-blind randomised placebo-controlled
trial.
Setting: Perth, Western Australia, Australia.
Patients: 98 pregnant women received the supplemen-
tation from 20 weeks’ gestation until delivery. Their
infants (n = 72) were assessed at age 2K years.
Interventions: Fish oil (2.2 g docosahexaenoic acid
(DHA) and 1.1 g eicosapentaenoic acid (EPA)/day) or
olive oil from 20 weeks’ gestation until delivery.
Outcome measures: Effects on infant growth and
developmental quotients (Griffiths Mental Development
Scales), receptive language (Peabody Picture Vocabulary
Test) and behaviour (Child Behaviour Checklist).
Results: Children in the fish oil-supplemented group
(n = 33) attained a significantly higher score for eye and
hand coordination (mean ((SD) score 114 (10.2)) than
those in the placebo group (n = 39, mean score 108 (SD
11.3); p = 0.021, adjusted p = 0.008). Eye and hand
coordination scores correlated with n-3 PUFA levels in
cord blood erythrocytes (EPA: r = 0.320, p = 0.007; DHA:
r = 0.308, p = 0.009) and inversely correlated with n-6
PUFA (arachidonic acid 20:4n-6: r = 20.331, p = 0.005).
Growth measurements in the two groups were similar at
age 2K years.
Conclusion: Maternal fish oil supplementation during
pregnancy is safe for the fetus and infant, and may have
potentially beneficial effects on the child’s eye and hand
coordination. Further studies are needed to determine the
significance of this finding.
During gestation, large amounts of docosahexae-
noic acid (DHA; 22:6n-3) and arachidonic acid
(20:4n-6) are deposited in the fetal retina and
brain,
1
and these fatty acids seem to be critical for
normal neuronal and visual development.
2–4
The
composition of long-chain polyunsaturated fatty
acids (LC PUFAs) influences membrane stability,
fluidity and function of many cell types through its
effects on gene expression and tissue differentia-
tion.
4
Deficiencies in LC PUFAs could have
implications for wide-ranging effects on health
and development. Despite selective transplacental
transfer of LC PUFAs
5
with higher concentrations
in the neonatal circulation,
6–8
fatty acid status in
the fetus remains dependent on maternal fatty acid
status and dietary intake. The recent decline in
dietary DHA and other n-3 PUFAs with progressive
westernisation has raised concerns about its
potential effects on the developing fetus. The
implications are even greater for preterm infants
who are deprived of maternal supplies in the third
trimester. This has led to growing interest in the
role and indications for LC PUFA supplementation
in early life, both in pregnancy and in the early
postnatal period for preterm infants. With con-
cerns about methylmercury contamination in
certain types of fish, there is growing consumption
of pharmaceutical-grade fish oil supplements,
which have been shown to be safe.
So far, only three studies have assessed the
effects of LC PUFAs in term pregnancies on
cognitive function of children after maternal
supplementation with cod liver oil,
910
fish oil
11
and DHA-enriched eggs.
12
Although data are still
limited, these studies have shown associations
between DHA and several functional neurological
outcomes including improved attention up to age
2 years
12
and improved mental processing at age
4 years.
10
Other studies have assessed the effects of
supplementation on preterm infants during the
equivalent (third trimester) period ex utero, and
have shown some beneficial effects on neurodeve-
lopmental parameters.
13
Although any conclusive
long-term benefit of PUFA-supplemented formula
in preterm infants has yet to be proved,
14 15
a meta-
regression analysis of seven trials in term infants
showed that the DHA dose in milk formula was
positively related to visual acuity measurements at
age 4 months.
16
Although the benefits are unclear, theoretical
concerns remain about the potential detrimental
effects of selective n-3 PUFA supplementation,
which could lead to a reduction in n-6 arachidonic
acid status at high doses. Thus, although the
available literature suggests more beneficial rather
than harmful effects (if any) on development,
clearly, more studies are needed to confirm this.
We were able to deal with these issues in a
cohort of children whose mothers received n-3
PUFA fish oil in pregnancy. This cohort was part of
a randomised controlled trial designed to assess the
effects of n-3 PUFA supplementation during
pregnancy on neonatal immune responses, ulti-
mately with a view to reducing the risk of allergic
disease.
17
High doses of fish oil (4 g/day) resulted in
markedly higher levels of n-3 PUFA but consider-
ably lower levels of n-3 arachidonic acid in cell
membranes of the neonates from the intervention
group.
18
We used this opportunity to test the
hypothesis that exposure to high-dose fish oil in
utero would not have a deleterious effect on
subsequent growth and development (up to age
Original article
Arch Dis Child Fetal Neonatal Ed 2008;93:F45–F50. doi:10.1136/adc.2006.099085 F45
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2K years). These data were collected to provide further informa-
tion to assess the safety of (high-dose) fatty acid supplementation
in the preterm period (both in utero and ex utero).
PARTICIPANTS AND METHODS
Participants
Ninety eight pregnant Caucasian women with allergic disease
were recruited before 20 weeks of pregnancy between January
2000 and September 2001 to a randomised double-blind
controlled trial conducted in Perth, Western Australia,
Australia. Women were ineligible for the study if they smoked,
had medical problems, a complicated pregnancy, seafood
allergy, or if their normal dietary intake exceeded two meals
of fish per week. Children were excluded from the study if they
were born before 36 weeks’ gestation or with major disease (to
avoid the confounding effects on immune response) or if cord
blood was not collected. Anthropometric data were collected
from hospital records at the time of delivery. The sample size for
this study is small, as the study was designed to assess
immunological effects rather than neurodevelopmental out-
come and growth.
17
Assuming a level of 80% statistical power
and a significance level of 0.05, the sample size allowed us to
detect a difference in height of 3.3 cm and in weight of 1.4 kg at
age 2–3 years.
Study design and intervention
Women were block randomised according to parity, age, body
mass index before pregnancy and maternal allergy to minimise
the potential effects of these confounding factors. Women
received four (1 g) fish oil capsules (fish oil group, n = 52; Ocean
Nutrition, Halifax, Nova Scotia, Canada) providing 1.1 g
eicosapentaenoic acid (EPA; 20:5n-3) and 2.2 g DHA/day, or
four (1 g) capsules of olive oil per day (olive oil or placebo group,
n = 46; providing 2.7 g n-9 oleic acid per day; Pan Laboratories,
Moorebank, New South Wales, Australia) from 20 weeks’
gestation until birth. This dose was chosen as approximately
equivalent to one fatty fish meal per day.
19
Both active and placebo
capsules contained 3–4 mg/g oil a-tocopherol (vitamin E) as an
antioxidant. Randomisation and allocation of capsules was carried
out in a blinded manner, and capsules in the two groups were
image matched. Mothers and research staff remained blinded until
completion of the cognitive testing. Compliance was confirmed by
measuring fatty acid levels in erythrocytes in the mothers at 30
and 37 weeks’ gestation and 6 weeks postnatally.
18
Follow-up of children at age 2
1
/
2
years
All eligible children whose mothers completed supplementation
(n = 83) were invited to attend follow-up visits. Height, weight
and head circumference were measured. As secondary outcome
measures, children were assessed for development (Griffiths
Mental Development Scales (GMDS)),
20
receptive language
(Peabody Picture Vocabulary Test) (PPVT)) IIIA
21
and behaviour
(Child Behavior Checklist (CBCL) 1K–5 years).
22
These tests
were chosen because they have valid and reliable psychometric
properties for assessing children aged 2K years. The GMDS
comprise six subscales of development (locomotor, personal
social, speech and hearing, eye and hand coordination,
performance, and practical reasoning). One quotient was
calculated for each subscale, as well as a general quotient that
was derived as the mean of the subscale quotients. The GMDS
20
version used has been updated since the commencement of the
study; however, the original version still provides robust
comparative data. The PPVT
21
is a test of listening comprehension
to measure receptive vocabulary attainment for standard English.
A standard score in the PPVT IIIA is calculated from the raw score.
The average range for receptive language is defined as a mean
standard score of 100 (standard deviation (SD) 15). The CBCL
1K–5 years is an instrument designed to measure parental
perception of child competencies and behaviours in children aged
1K–5 years, and includes a language development survey based on
length of phrases and number of words in the child’s vocabulary.
Raw scores for the CBCL are used to calculate internalising,
externalising and total problem behaviour T scores. A T score of
>64 is in the clinical range for behaviour problems.
Fatty acid analyses
Phospholipid fatty acid analyses were carried out as described
previously.
18
The fatty acids were quantified as a percentage of
the weight of the total fatty acids measured. The results were
expressed as the total sum of n-3 PUFAs (20:5n-3, 22:5n-3 and
22:6n-3) and n-6 PUFAs (18:2n-6, 20:3n-6, 20:4n-6, 22:3n-6 and
22:4n-6), and the ratio of n-3 to n-6 fatty acids.
Statistical analyses
The independent samples t test using SPSS V.11.5 was used to
compare the equality of means (equal variances not assumed)
between the fish oil-supplemented group and the control group.
Differences between the groups for dichotomous data were
determined by the x
2
test. The groups were also combined to
determine associations between individual fatty acid propor-
tions and subscales of development in the GMDS using
Pearson’s correlation.
Potential confounding factors including length of gestation,
maternal age and education, parity, sex of the infant and breast
feeding were determined by Pearson’s correlation. A linear
regression (single-step) model was used to examine relationships
between continuous variables, after adjusting for confounding
factors; p,0.05 was considered significant for all analyses.
Owing to the exploratory nature of this study, we did not wish
to exclude any important relationships by using stringent
correction factors for multiple analyses, and we recognised the
potential for a type 1 error.
The ethics committees of St John of God Hospital, Subiaco,
Australia, and Princess Margaret Hospital, Perth, Australia,
approved the study, and all women gave written consent.
RESULTS
Study demographics
Figure 1 shows the flow of participants through the trial. In all, 83
women and their healthy babies completed the study at birth (40
in the fish oil group and 43 in the placebo group) as reported
previously.
23
Seven children were lost to follow-up and 33 children
were assessed at age 2K years (mean age 34.0 (SD 5.3) months) in
the fish oil group. In the olive oil group, four children were lost to
follow-up and 39 were assessed at age 2K years (mean age 34.7
(SD 5.7) months, p = 0.599). Although mothers in the fish oil
group were slightly younger than those in the olive oil group, we
found no other differences between the mothers and children who
completed the follow-up at 2.5 years (table 1).
Fatty acid composition at birth
The content of n-3 PUFAs (EPA and DHA) in the phospholipid
fraction of erythrocyte membranes in the umbilical cord blood
was significantly increased and that of the n-6 PUFA,
arachidonic acid, was significantly decreased in infants from
the fish oil group compared with controls (p,0.001; table 2).
Original article
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Growth measurements
We found no significant differences between the fish oil group
(n = 28) and the olive oil group (n = 36). The mean age for both
groups was 30 months; the mean (SD) height was 93.8 (3.8) cm
for the fish oil group v 93.3 (4.6) cm for the olive oil group
(p = 0.642); the mean (SD) weight was 14.5 (2.0) v 14.1 (2.0) kg,
respectively (p = 0.456); and the head circumference was 49.4
(1.6) v 49.8 (1.7) cm, respectively (p = 0.304).
GMDS results
Table 3 gives the results of the Griffiths assessments. Children
from the fish oil group attained a significantly higher score for
eye and hand coordination (p = 0.021). When tested in a linear
regression model with eye and hand coordination as the
dependent variable and potential confounding factors (maternal
age, maternal education and duration of breast feeding) as
independent variables, the effect of supplementation remained
significant (b = 27.213, p = 0.008). We found no significant
difference between the groups for the mean general quotient or
for mean quotients for other subscales of development (table 3).
Receptive language results
Results from the PPVT indicate no significant difference
(p = 0.110) between the mean (SD) standard score obtained in
the fish oil group (n = 31; 101.3 (9.9)) and in the olive oil group
(n = 39; 97.4 (9.7)).
CBCL results
Results from the CBCL 1K–5 years indicated no significant
differences between the mean (SD) T scores of the fish oil and
Table 1 Characteristics of the two study populations
Characteristics
Fish oil
(n = 33)
Control
(n = 39) p Value
Mean (SD) maternal age, years 30.9 (3.7) 32.6 (3.6
0.047
Maternal disease, n (%)
Asthma 12 (36.4) 15 (38.5)
0.855
Allergic rhinitis 21 (63.6) 24 (61.5)
Maternal education (years), n (%)
10–12 10(30.3) 9 (23.1)
0.488
.12 23 (69.7) 30 (76.9)
Parity >1, n (%) 15 (45.5) 21 (53.8)
0.478
Mean (SD) gestation period, days 276 (8) 274.5 (8
0.429
Infant sex, n (%)
Male 13 (39.4) 20 (51.3)
0.819
Female 20 (60.6) 19 (48.7)
Mean (SD) birth weight, g 3508 (353) 3434 (377)
0.397
Mean (SD) birth length, cm 50.5 (1.9) 49.7 (1.9)
0.066
Ever breast fed, n (%) 30 (91) 37 (95)
0.655
Duration of breast feeding, months 8.8 (4.3) 7.5 (4.5
0.253
p,0.05 was considered to be a significant difference between the groups.
Figure 1 Progress of participants through the trial. *Fish oil or placebo received from 20 weeks’ gestation to delivery.
Original article
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olive oil groups for internalising (44 (8.7) v 45 (9.2); p = 0.576),
externalising (49 (9) v 48 (9); p = 0.706) and total problem
behaviour scales (35 (5.2) v 36 (5.2); p = 0.548). We found no
significant difference between the groups for mean length of
phrases (mean (SD) centile score 73.2 (15.8) v 67.8 (20.2),
respectively; p = 0.300) and vocabulary centile score (mean (SD)
57.6 (16.9) v 55.3 (20.2), respectively; p = 0.650).
Relationship between LC PUFA levels in erythrocyte membranes
at birth and neurodevelopmental outcomes in children at age
34 months
These relationships were examined for the study population as
a whole (table 4). We found a significant positive correlation
between the eye and hand coordination score at age 34 months
and n-3 PUFA composition of cord blood erythrocytes (EPA,
p = 0.007; DHA, p = 0.009). Conversely, the eye and hand
coordination and performance scores were inversely correlated
with arachidonic acid (p = 0.005 and 0.044, respectively). The
significant associations were independent of potential con-
founding factors including maternal education and the duration
of breast feeding. We found no other significant associations of
LC PUFA levels in cell membranes at birth with developmental,
language or behaviour outcomes at age 2K–3 years.
DISCUSSION
We found that cord erythrocyte phospholipid n-3 LC PUFA
levels positively correlated and n-6 levels negatively correlated
with eye and hand coordination, a finding that, to the best of
our knowledge, has not been reported previously.
Our finding of enhanced eye and hand coordination with fish
oil supplementation is plausible and consistent with previously
reported benefits on visual function after postnatal n-3 PUFA
supplementation in both preterm
14 24
and term
15 25
infants.
Although the underlying mechanism is not understood, DHA
is known to facilitate rapid phototransduction in the retinal
membrane,
26
and deficiencies are associated with reduced retinal
function in infant primates.
2
Furthermore, effects on visual
evoked potential could indicate that DHA may also have an
effect on the development of the visual cortex.
27
Finally, improved
stereoacuity in infants has been associated with LC PUFA formula
supplementation
28
and fish intake of lactating mothers.
29
To our knowledge, only one other study has assessed the
effects of supplementation with high-dose fish oil in pregnancy
on cognitive development of the offspring. A randomised
Table 2 Phospholipid fatty acids from erythrocytes in cord blood of
neonates who completed the cognitive studies
Fatty acids
Fish oil
(n = 32)
Control
(n = 39) p Value
18:1n-9 12.4 (1.2) 12.3 (0.8) 0.899
18:2n-6 3.8 (0.5) 3.6 (0.3) 0.023
20:3n-6 2.8 (0.4) 3.1 (0.5) 0.005
20:4n-6 14.9 (1.4) 17.6 (1.0) ,0.001
20:5n-3 1.3 (0.5) 0.4 (0.3) ,0.001
22:3n-6 2.8 (0.5) 3.9 (0.5) ,0.001
22:4n-6 0.8 (0.2) 1.5 (0.3) ,0.001
22:5n-3 6.3 (0.8) 6.0 (0.5) 0.037
22:6n-3 10.3 (1.1) 7.4 (0.9) ,0.001
Total n-6 PUFAs* 25.0 (1.8) 29.6 (1.1) ,0.001
Total n-3 PUFAs{ 17.9 (1.9) 13.7 (1.3) ,0.001
Total n-3 to n-6{ 0.8 (0.1) 0.5 (0.1) ,0.001
PUFA, polyunsaturated fatty acid.
Values for fatty acids are expressed as a percentage of total fatty acids (mean (SD)).
*Sum 18:2, 20:3, 20:4, 22:3, 22:4.
{Sum 20:5, 22:5, 22:6.
{Ratio [Sum 20:5, 22:5, 22:6] to [Sum 18:2, 20:3, 20:4, 22:3, 22:4].
Table 3 Mean subscales quotients and general quotient scores of
Griffiths assessments for both the study populations
GMDS subscales
Fish oil
(n = 33)
Control
(n = 39) p Value
Locomotor 112.5 (12.2) 107.9 (12.6)
0.125
Personal social 112.4 (11.9) 109.4 (11.5)
0.283
Speech and hearing 112.0 (15.0) 109.6 (14.9)
0.498
Eye and hand coordination 114.0 (10.2) 108.0 (11.3)
0.021*
Performance 120.9 (12.7) 115.8 (13.7)
0.108
Practical reasoning* 114.3 (14.5) 113.6 (15.0)
0.845
General quotient score 114.2 (9.8) 110.5 (10.6)
0.130
GMDS, Griffiths Mental Development Scales.
Values are mean (SD).
*Scores calculated for children aged .30 months (fish oil group, n = 31; olive oil
group, n = 37).
*p,0.05 was considered to be the significant difference between the groups.
Table 4 Association between cognitive outcomes and fatty acids in cord blood erythrocyte membranes
Test Cognitive outcomes
Fatty acids in cord blood erythrocytes
20:4n-6 20:5n-3 22:6n-3 Ratio n-3:n-6{
GMDS Locomotor (n = 71)
20.123 0.228 0.233 0.201
Social (n = 71)
20.017 0.137 0.148 0.103
Speech and hearing (n = 71)
20.118 0.139 0.143 0.136
Eye and hand coordination (n = 71)
20.331** 0.320** 0.308** 0.325**
Performance (n = 71)
20.240* 0.182 0.183 0.212
Practical reasoning (n = 67)
20.004 0.034 0.030 0.014
General quotient (n = 71)
20.170 0.209 0.215 0.202
PPVT IIIA Mean standard score (n = 71)
20.084 0.171 0.105 0.102
CBCL Internalising (n = 71)
0.067 20.064 20.131 20.114
Externalising (n = 71)
0.030 20.052 20.022 20.038
Total problems (n = 71)
0.024 0.001 20.022 20.014
LDS Average length of phrase (n = 49)
20.101 0.235 0.078 0.122
Vocabulary score (n = 57)
20.048 0.077 0.127 0.093
CBCL, Child Behavior Checklist; GMDS, Griffiths Mental Development Scales; LDS, language development survey; PPVT, Peabody
Picture Vocabulary Test.
*Pearson’s correlation is significant at the 0.05 level.
**Pearson’s correlation is significant at the 0.01 level.
{Ratio (Sum 20:5n-3, 22:6n-3) to 20:4n-6.
Original article
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clinical trial by Helland et al
9
involved 590 pregnant women
who received fish oil at half the dose we used in this study, from
18 weeks’ gestation until 3 months post partum. No differences
in development were observed in the 269 infants tested at 6 and
9 months; however, fish oil supplementation was associated
with increased mental processing in children at age 4 years.
Additionally, mental processing scores were significantly
correlated with maternal intake of DHA in pregnancy after
adjusting for potential confounding factors
10
; this is consistent
with observed correlations of DHA (and EPA) intake with eye
and hand coordination in this study.
Other studies have found positive relationships between n-3
PUFAs at birth (principally DHA) and aspects of visual and
neurological development, in either observational studies
30–32
or
intervention studies using much lower levels of supplementa-
tion.
11 12 33
Our findings suggest that detection of the potentially
beneficial effects of DHA in pregnancy may require larger doses.
Further, although it is difficult to directly extrapolate the
pregnancy dosage to supplementation of the preterm infant, the
doses in our study resulted in similar increases in cord blood
levels of DHA to those achieved with the higher doses trialled in
preterm infants.
34
The small size of the sample is a limitation of our study.
Although we cannot exclude a chance finding, there seem to be
no adverse effects on measures of development, receptive
language, behaviour and growth. Children who received
prenatal fish oil supplementation tended to perform better in
all subscales of development and had higher scores for receptive
language, average phrase length and vocabulary scores when
assessed at an average age of 34 months. Both the control group
and the fish oil group scored higher than the mean (100) in all
GMDS subscales, with the fish oil group scoring higher than the
control group in each subscale. However, in eye and hand
coordination on the GMDS, the difference was statistically
significant when the fish oil group was compared with controls.
We acknowledge the potential for a type 1 error due to multiple
comparisons; however, the significance was strengthened when
we used a multi-regression model to adjust for potential
confounding factors. We are confident in these results as we
have robust comparative data from a population-based sample
of Western Australian infants assessed at a similar age, with the
GMDS yielding similar mean subscale and general quotient
scores.
35
These preliminary data indicate that supplementation with a
relatively high-dose fish oil during the last 20 weeks of
pregnancy is not only safe but also seems to have potential
beneficial effects that need to be explored further. Given the
scarcity of data to support the efficacy of fish oil supplementa-
tion during pregnancy, our data have a potentially important
role in informing on the effects of fish oil supplementation on
early postnatal infant development. In conclusion, our findings
are important in tackling concerns that a relatively selective
supplementation (with n-3 PUFA but not n-6 PUFA) could have
detrimental effects by displacing other essential fatty acids.
Acknowledgements: We thank the staff and patients who helped in this study. We
particularly thank Dr Trevor Mori and Dr Ann Barden, who were responsible for the
fatty acid analyses.
Funding: This study was funded by a grant from the Raine Medical Research
Foundation of Western Australia and a grant from the National Health and Medical
Research Foundation of Australia. Dr Janet Dunstan is supported by the Child Health
Research Foundation of Western Australia.
Competing interests: None.
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n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4years of
age. Pediatrics 2003;111:e39–44.
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supplementation during pregnancy and visual evoked potential development in term
infants: a double blind, prospective, randomised trial. Arch Dis Child Fetal Neonatal Ed
2003;88:F383–90.
12. Colombo J, Kannass KN, Shaddy DJ, et al. Maternal DHA and the development of
attention in infancy and toddlerhood. Child Dev 2004;75:1254–67.
13. O’Connor DL, Hall R, Adamkin D, et al. Growth and development in preterm infants
fed long-chain polyunsaturated fatty acids: a prospective, randomized controlled trial.
Pediatrics 2001;108:359–71.
14. Simmer K, Patole S. Longchain polyunsaturated fatty acid supplementation in
preterm infants. Cochrane Database Syst Rev 2004;1:CD000375.
15. Gibson RA, Chen W, Makrides M. Randomized trials with polyunsaturated fatty acid
interventions in preterm and term infants: functional and clinical outcomes. Lipids
2001;36:873–83.
16. Uauy R, Hoffman DR, Mena P, et al. Term infant studies of DHA and ARA
supplementation on neurodevelopment: results of randomized controlled trials.
J Pediatr 2003;143:S17–25.
17. Dunstan J, Mori TA, Barden A, et al. Fish oil supplementation in pregnancy modifies
neonatal allergen-specific immune responses and clinical outcomes in infants at high
risk of atopy: a randomised controlled trial. J Allergy Clin Immunol 2003;112:1178–
84.
18. Dunstan JA, Mori TA, Barden A, et al. Effects of n-3 polyunsaturated fatty acid
supplementation in pregnancy on maternal and fetal erythrocyte fatty acid
composition. Eur J Clin Nutr 2004;58:429–37.
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and their effects on platelet function in men at risk of cardiovascular disease.
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What is already known on this topic
c Long-chain fatty acids are essential for normal neuronal and
visual development.
c Fetal fatty acid status is dependent on maternal fatty acid
status and dietary intake.
c Previous data are limited, but indicate potential benefits of
relatively low-dose n-3 polyunsaturated fatty acid (PUFA)
supplementation in pregnancy on functional neurological
outcomes. However, no data are available for the effect of
high-dose n-3 PUFA supplementation in pregnancy on
neurodevelopment.
What this study adds
c Children of mothers supplemented with 3.7 g n-3 long-chain
polyunsaturated fatty acid (LC PUFA) in pregnancy had
improved hand and eye coordination at age 2K years.
c High-dose n-3 LC PUFA taken in the second half of pregnancy
does not seem to have any deleterious effects on
neurodevelopment or growth.
Original article
Arch Dis Child Fetal Neonatal Ed 2008;93:F45–F50. doi:10.1136/adc.2006.099085 F49
group.bmj.com on May 6, 2014 - Published by fn.bmj.comDownloaded from
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23. Dunstan JA, Mori TA, Barden A, et al. Maternal fish oil supplementation in
pregnancy reduces interleukin-13 levels in cord blood of infants at high risk of atopy.
Clin Exp Allergy 2003;33:442–8.
24. SanGiovanni JP, Parra-Cabrera S, Colditz GA, et al. Meta-analysis of dietary
essential fatty acids and long-chain polyunsaturated fatty acids as they relate
to visual resolution acuity in healthy preterm infants. Pediatrics 2000;105:
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term. Cochrane Database Syst Rev 2001;4:CD000376.
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27. Morale SE, Hoffman DR, Castaneda YS, et al. Duration of long-chain
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2005;81:197–203.
28. Birch EE, Hoffman DR, Castaneda YS, et al. A randomized controlled trial of long-
chain polyunsaturated fatty acid supplementation of formula in term infants after
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29. Williams C, Birch EE, Emmett PM, et al. Stereoacuity at age 3.5 y in children born
full-term is associated with prenatal and postnatal dietary factors: a report from a
population-based cohort study. Am J Clin Nutr 2001;73:316–22.
30. Cheruku SR, Montgomery-Downs HE, Farkas SL, et al. Higher maternal plasma
docosahexaenoic acid during pregnancy is associated with more mature neonatal
sleep-state patterning. Am J Clin Nutr 2002;76:608–13.
31. Bakker EC, Ghys AJ, Kester AD, et al. Long-chain polyunsaturated fatty acids at
birth and cognitive function at 7 y of age. Eur J Clin Nutr 2003;57:89–95.
32. Ghys A, Bakker E, Hornstra G, et al. Red blood cell and plasma phospholipid
arachidonic and docosahexaenoic acid levels at birth and cognitive development at
4years of age. Early Hum Dev 2002;69:83–90.
33. Malcolm CA, Hamilton R, McCulloch DL, et al. Scotopic electroretinogram in term
infants born of mothers supplemented with docosahexaenoic acid during pregnancy.
Invest Ophthalmol Vis Sci 2003;44:3685–91.
34. Clandinin MT, Van Aerde JE, Parrott A, et al. Assessment of the efficacious dose of
arachidonic and docosahexaenoic acids in preterm infant formulas: fatty acid
composition of erythrocyte membrane lipids. Pediatr Res 1997;42:819–25.
35. Dixon G, Badawi N, Kurinczuk JJ, et al. Early developmental outcomes after
newborn encephalopathy. Pediatrics 2002;109:26–33.
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Original article
F50 Arch Dis Child Fetal Neonatal Ed 2008;93:F45–F50. doi:10.1136/adc.2006.099085
group.bmj.com on May 6, 2014 - Published by fn.bmj.comDownloaded from
doi: 10.1136/adc.2006.099085
online December 21, 2006
2008 93: F45-F50 originally publishedArch Dis Child Fetal Neonatal Ed
J A Dunstan, K Simmer, G Dixon, et al.
randomised controlled trial
supplementation in pregnancy: a
years after maternal fish oil
Cognitive assessment of children at age 2½
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... Studies in animals and in human infants have shown that lower brain DHA is accompanied by an increase in brain 22:4ω-6 and 22:5ω-6 (8)(9)(10)(11), which, in animals, is associated with deficits in neural function (8,(11)(12)(13)(14)(15). In humans, several observational and intervention studies of DHA in maternal gestation alone or including gestation and the first few weeks after birth have reported no effect (16)(17)(18) or positive effects on neural and visual function of infants and children (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). However, the DHA intake or blood lipid status of children has also been shown to be associated with central nervous system (CNS) function, including learning ability, language, and nonverbal intelligence, with some studies showing a benefit of DHA supplementation (30)(31)(32)(33)(34)(35)(36)(37)(38). ...
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Newborn ecephalopathy is a clinically defined condition of abnormal neurological behaviours in the newborn period. Though most cases have their origin in the preconceptional and antepartum period, newborn encephalopathy represents a crucial link between intrapartum events and permanent neurological problems in the child. The birth prevalence of newborn encephalopathy ranges from 1.8 to 7.7 per 1000 term live births according to the definition used and the population to which it is applied. Few studies have investigated the outcomes of newborn encephalopathy other than for cases solely attributed to intrapartum hypoxia. These adverse outcomes range from death to cerebral palsy, intellectual disability, and less severe neurological disabilities such as learning and behavioural problems. Outcomes following newborn encephalopathy may vary from country to country with 9.1% of affected babies dying in the newborn period in Western Australia and 10.1% manifesting cerebral palsy by the age of two. These compare to a case fatality of 30.5% in Kathmandu and a cerebral palsy rate of 14.5% by one year of age. The study by Robertsonet al which followed children with hypoxic ischaemic encephalopathy found an incidence of impairment of 16% among survivors assessed at 8 years with 42% requiring school resource room help or special classes. This review emphasises the great need for comprehensive clinical and educational assessment as these infants approach school entry to enable appropriate educational provisions to be made.
Article
purpose. To test the hypothesis that the supplementation of the diets of pregnant women with a fish oil rich in docosahexaenoic acid (DHA) enhances retinal development in their healthy term infants, as measured during the early postnatal period by the electroretinogram (ERG). methods. One hundred pregnant women were randomized to receive either a fish oil (n = 50) or a placebo oleic acid dietary supplement (n = 50) from 15 weeks of pregnancy until delivery. Total fatty acids in red blood cells (RBCs) and plasma were measured in mothers at 15 and 28 weeks of pregnancy and at delivery and in their infants in umbilical cord blood. Infant retinal development was assessed within the first week of life with full-field ERGs that included a scotopic blue intensity series (n = 41) and a bright white flash (2.0 log cd-s/m²; n = 44). results. Infants born of mothers who received supplements did not differ at birth in weight, gestational age, or any other standard variable. Infant DHA status at birth, as measured from umbilical cord blood, did not differ significantly between maternal supplementation groups. ERG implicit times, amplitudes, and parameters of the stimulus–response function did not differ significantly between infants in the maternal supplemented and placebo groups. There was, however, a relationship between infant DHA status and maturity of the retina at birth, regardless of maternal supplementation group. A measure of retinal sensitivity (log σ) correlated significantly (P < 0.005) with DHA status (as a percentage of total fatty acid; TFA) in infant cord blood. Infants in the highest quartile for cord blood DHA had higher retinal sensitivity compared with infants in the lowest quartile. Infants in the highest quartile for plasma DHA, both as a percentage of TFA and concentration, were born at a significantly later gestational age than were infants in the lower quartiles. conclusions. These findings demonstrate an association between the DHA status of term infants and retinal sensitivity, suggesting an essential role of this long-chain polyunsaturated fatty acid (LCPUFA) in the development and function of the retina. However, maternal DHA status was not significantly associated with infant retinal sensitivity and no direct effect of maternal supplementation was observed.
Article
Infants were followed longitudinally to document the relationship between docosahexaenoic acid (DHA) levels and the development of attention. Erythrocyte (red-blood cell; RBC) phospholipid DHA (percentage of total fatty acids) was measured from infants and mothers at delivery. Infants were assessed in infant-control habituation at 4, 6, and 8 months augmented with psychophysiological measures, and on free-play attention and distractibility paradigms at 12 and 18 months. Infants whose mothers had high DHA at birth showed an accelerated decline in looking over the 1st year and increases in examining during single-object exploration and less distractibility in the 2nd year. These findings are consistent with evidence suggesting a link between DHA and cognitive development in infancy.