Summary
Evidence Report/Technology Assessment: Number 118
Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
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Introduction / Key Questions / Methods / Results / Discussion / Availability of Full Report / References
Authors: Lewin GA, Schachter HM, Yuen D, Merchant P, Mamaladze V, Tsertsvadze A, et al.
Introduction
The purpose of this study was to conduct a
systematic review of the scientific-medical
literature to identify, appraise, and synthesize the
human evidence for the effects of omega-3 fatty
acids on child and maternal health. The review
was requested and funded by the Office of
Dietary Supplements, National Institutes of
Health. It was undertaken as part of a
consortium involving three Evidence-based
Practice Centers (EPCs), which investigated the
value of omega-3 fatty acid supplementation
across eleven health/disease areas.
The three
EPCs are:
- Southern California-RAND.
- Tufts-New England Medical Center.
- The University of Ottawa.
To ensure consistency of approach, the
three EPCs collaborated on selected methodologic
elements, including literature search strategies,
rating of evidence, and data table design.
It has been posited that the accretion of
omega-3 fatty acids within the maternal biological
system has the potential to influence both
maternal health during pregnancy and fetal
health. Likewise, it has been hypothesized that
their accumulation within the post-delivery child's
biological system can affect its development and
health. Birth weight is the most important factor
affecting neonatal morbidity and mortality, and is
thus an outcome worth monitoring.1 Moreover,
premature infants are at risk of injury to every
organ system in the newborn period. Of greatest
concern for infants who survive are the risks of
developing permanent neurocognitive deficits that
impact their lifelong health and functional
capacity.2-5
Results of studies conducted on residents of the
Faroe Islands6,7 suggest that marine diets, which
contain omega-3 fatty acids, increase birth weight
either by prolonging pregnancy8 or by increasing
the fetal growth rate.9,10 Additionally, it has been
hypothesized that marine oils may lower risks of
certain complications of pregnancy, in particular
preterm delivery, intrauterine growth retardation,
preeclampsia, and gestational hypertension,11
given that some of omega-3 fatty acids' presumed
mechanisms of action overlap with those of
aspirin.12-14
Docosahexaenoic acid (DHA) and arachidonic
acid (AA) have been identified as important
structural components of the highly specialized
membrane lipids of the human central nervous
system, with phospholipids of brain gray matter
containing high proportions of DHA.15-17 DHA
has also been observed to be the major long-chain
polyunsaturated fatty acid (LC PUFA) in the
outer segments of the retina's rods and cones.15
Based on observational studies, it has been
shown that human milk fed infants have
improved neurocognitive development compared
to formula fed infants; it was hypothesized that
one of the contributing factors may be the
availability of long-chain derivatives of linoleic
acid (LA) and alpha-linolenic acid (ALA) that is
present only in human milk.18,19 This difference
in fatty acids intake is reflected in lower
erythrocyte membrane phospholipid DHA in infants fed formula.18 Until the recent availability of infant
formula with added omega-3 LC PUFAs, standard infant
formula was devoid of these fatty acids.
The likely significance of omega-3 fatty acids for child health
is therefore suggested by the observations that:
- The human brain and retina each contain considerable amounts of omega-3 fatty acids.
- The children delivered at term receive an important supply of omega-3 fatty acids, especially in the third trimester of pregnancy.
- Due to a shortened gestational period, a child delivered prematurely receives less exposure to omega-3 fatty acids content than does the term child.
Not
surprisingly, the observation concerning preterm infants has
afforded considerable empirical study of the impact of omega-3
fatty acids on the health of such infants.
Return to Contents
Key Questions
The questions are organized by type of population (i.e.,
maternal/pregnancy versus child) and type of outcome data
(i.e., clinical/pregnancy versus clinical/child-developmental).
Maternal population, pregnancy outcomes/biomarkers
associations:
- What is the evidence that intake of omega-3 fatty acids influences:
- Duration of gestation?
- Incidence of preeclampsia, eclampsia or gestational hypertension?
- Incidence of births of human infants small for gestational age (SGA)?
Child population, growth patterns, neurological, visual or
cognitive developmental outcomes/biomarkers
associations:
- What is the evidence that maternal intake of omega-3 fatty acids
- During pregnancy influences any of the clinical outcomes in term or preterm human infants?
- Within maternal breast milk, infant formula, both and/or other sources (i.e., diet) influences any of the clinical outcomes in term or preterm human infants?
- What is the evidence that term or preterm human infants' clinical outcomes are associated with the omega-3 or omega-6/omega-3 fatty acids content of:
- Maternal or fetal biomarkers during pregnancy?
- Child biomarkers?
Adverse effects:
- What is the evidence for the risk, in pregnant or
breastfeeding women, term or preterm human infants, of
short- and long-term adverse events related to their intake
of omega-3 fatty acids during pregnancy or after birth?
Return to Contents
Methods
A Technical Expert Panel (TEP) consisting of six members
was convened to provide advisory support to the project,
including refining the questions and highlighting key variables
requiring consideration in the evidence synthesis.
Study Identification
Several electronic databases were searched: MEDLINE®,
PreMEDLINE®, EMBASE, the Cochrane Library including
the Cochrane Central Register of Controlled Trials, and CAB
Health. Searches were not restricted by language of publication,
publication type, or study design, except with respect to the
MeSH term "dietary fats," which was limited by study design
to increase its specificity. Search elements included scientific
terms, with acronyms, as well as generic and trade names
relating to the exposure and its sources (e.g., eicosapentaenoic
acid [EPA], omega-3 fatty acids, infant formula) and relevant
population terms (e.g., gestational hypertension).
Reference
lists of included studies, book chapters, and narrative or
systematic reviews retrieved after having passed the first level of
relevance screening were manually searched to identify
additional unique references. Through contact with content
experts, attempts were made to identify both published and
unpublished studies. A final set of 2,049 unique references was
identified and posted to an internet-based software system for
review.
Studies were considered relevant if they described live,
otherwise "healthy" human populations of any age. The
generic term "child" was used to refer to infants (less than 12
months of age), toddlers, and children up to 18 years old.
Excluded were studies whose biomarker data were solely
obtained from aborted fetuses and which did not distinguish
between data obtained from term and preterm births.
Interventional/exposure studies had to specifically investigate
foods or supplements known to contain omega-3 fatty acids of
any type, from any source, any serving size or dose, delivered in
any fashion and for any length of time. No restrictions were
placed on the types or doses of pre- or on-study
cointerventions. While omega-6 fatty acids appear to play a key
role in health and development, and their possible co-influence
on outcomes is thus assessed in our review, studies exclusively
investigating their impact on health outcomes were excluded.
If at least two randomized controlled trials (RCTs) were
identified, no other types of design were required. Yet, if
insufficient numbers of RCTs were retrieved, non-RCT (i.e.,
controlled clinical trials, without random allocation) and observational studies (i.e., cohort, case-control, or cross-sectional
studies) were included. Descriptive study designs
were also excluded.
Any and all child developmental outcomes reflecting the
four categories of the developmental arc were considered
relevant. As markers of omega-3 fatty acids metabolism, the
following fatty acids compositions or concentrations, from any
source (e.g., red blood cell [RBC] membranes, plasma
phospholipids) were considered relevant: EPA, DHA, AA/EPA,
AA/DHA, AA/EPA+DHA.
Two initial levels of screening for relevance, and two
reviewers per level, were employed (directed at bibliographic
records, then full articles). A screening identified and excluded
uncontrolled studies. Calibration exercises preceded each step
of the screening process. The reasons for the unsuitability of
excluded studies were noted according to a modified
QUOROM format.20 Disagreements were resolved by
consensus and, when necessary, third-party intervention.
Data Abstraction
Following a calibration exercise involving two studies, eleven
reviewers independently abstracted the contents of included
studies using an electronic data abstraction form. A second
reviewer then verified these data. Data abstracted included:
- The characteristics of the report (e.g., publication status).
- Study (e.g., sample size).
- Population (e.g., preterm versus term status).
- Intervention/exposure (e.g., omega-3 fatty acids types).
- Comparator(s), cointerventions (e.g., omega-6 fatty acids use).
- Withdrawals and dropouts, including reasons, clinical outcomes, fatty acids content of biomarkers, and adverse events.
Data Synthesis
A summary table provided a question-specific overview of
included studies' relevant data, which is presented in greater
detail in evidence tables. A question-specific summary matrix
described each study in terms of its quality and applicability
ratings. Question-specific qualitative syntheses of the evidence
were derived. Meta-analysis was performed if the following
criteria were met: at least two RCTs, same population
characteristics (mean age, health status, gender), same cointerventions,
same intervention based on the type of omega-3
fatty acids supplemented (DHA+AA vs. DHA vs. DHA+EPA,
etc.) regardless of the daily dose in the child population, same
comparator based on source of placebo (e.g., olive oil,
unsupplemented formula), outcomes relevant to respond to the
key-questions: percentage (n) of premature deliveries, incidence
of gestational hypertension (GHT), pre-eclampsia or eclampsia,
incidence of IUGR or SGA infants, weight, length, and head
circumference of infants (means), neurological and cognitive
development measured by validated scales (e.g., Bayley's
Developmental Scale score), and visual acuity or visual function
of infants measured by appropriate tests (Teller's Card test,
etc.).
Return to Contents
Results
Literature Search
Of the 2,049 records entered into the initial screening for
relevance, 1,579 were excluded. Of the 191 reports that made
it to this level of screening, 74 were excluded. Hence, in total,
117 reports, describing 89 unique studies, were deemed
relevant for the systematic review, with 20 studies each
described by more than one report and three reports describing
more than one unique study. There were 63 randomized
controlled trials (RCTs) and 26 observational studies across all
the key questions. Only one study required translation from
German to English.21
No studies were identified across all the
child outcomes (i.e., growth patterns, neurocognitive
development, and visual function) regarding the influence of
the intake of omega-3 fatty acids from sources other than
human milk, or infant formula, as well as the association
between omega-3 or omega-6/omega-3 fatty acids content of
fetal biomarkers and any of the clinical outcomes.
Synopses of
evidence are presented according to the clinical outcomes by
population.
Safety Issues
Overall, omega-3 fatty acids supplementation in pregnant
women, breastfeeding mothers, and preterm and term infants,
was very well tolerated and did not generate any serious adverse
events across the included RCTs. The safety data was reported
in 21 RCTs. In pregnant women, the adverse events related to
the omega-3 fatty acids intake were mild and transient, with
nausea and gastrointestinal discomfort being the most
commonly reported.22,23 For both term and preterm
populations, change in number of stools and flatulence were
the most common adverse events related to the omega-3
supplemented formulas. However, most of the serious harms
were related to the fact that the infants were premature with
low birth weights, which increases the occurrence of necrotizing
enterocolitis (NEC), bleeding problems, infections and
respiratory failure, among others in the case of preterm
infants.24-43 None of the withdrawals were due to the
interventional formula.
Pregnancy Outcomes
Duration of Gestation-intake During Pregnancy
Fifteen
poor quality RCTs addressed this question.11,44-51,59 Seven trials
included otherwise healthy pregnant women,52-58 the remaining
eight studies included a high-risk population of pregnant women. Ten studies did not find a significant difference
between intervention groups in the duration of gestation
measured as mean of gestational age at delivery.22,23,53-58 Four
poor quality studies observed that the omega-3 fatty acids
group had a significantly greater duration of gestation after
treatment compared with the unsupplemented group.22,52
Omega-3 fatty acids did not have a significant effect on the
proportion of premature deliveries in ten studies.11,23,52,55,59 Fish
consumption in the background diet was used as a covariate in
only one trial.52 Other covariates used to control the results
were: the compliance with the intervention,52 current smoking
status,23,55 maternal BMI, and number of prior pregnancies.55
The only variable that had an impact on the results was the
smoking status in Smuts, et al's study.55 The duration of
gestation was significantly longer in the high-DHA group in
the nonsmokers.55
Meta-analysis of the incidence of premature deliveries was
performed from eight RCTs that used capsules containing
DHA+EPA (OR: 0.88 [95% CI: 0.62-1.25]),11,44,49 and two
trials using high DHA eggs (OR: 0.53 [95% CI: 0.13-2.29])47,50
or control group. There is inconsistent evidence of the use of
omega-3 fatty acids supplements during the second or third
trimester of pregnancy to reduce the incidence of premature
pregnancies in high- and low-risk populations. Nevertheless,
the overall effect does not show a significant difference between
study arms.
Duration of Gestation-maternal Biomarkers
Nothing
conclusive can be drawn from four studies that assessed this
association.55,60-62
Incidence of Gestational Hypertension (GHT),
Preeclampsia, or Eclampsia-intake During Pregnancy
Of
eight RCTs with a quality score approaching good internal
validity,22,23,52,63,64 six trials compared the use of fish oil
supplements containing DHA and EPA with placebo. The
population included healthy or high-risk pregnant women (i.e.,
twin pregnancy).22,23,63,64 The incidence of GHT in these
populations, after the use of omega-3 fatty acids or placebo did
not differ in six studies.22,23,52,59,63 Regarding the incidence of
preeclampsia (hypertension, edema, and proteinuria), six
studies showed that compared with placebo, supplementation
with omega-3 fatty acids did not have a significant
effect.22,23,55,59,63
Meta-analysis of the incidence of gestational
hypertension from two studies revealed a nonsignificant
difference between groups (OR: 1.07, CI 95%: 0.75; 1.51).22,23
These findings were not adjusted for the potential covariates or
confounders, such as background diet, grade of risk for GHT
or preeclampsia in the current pregnancy, smoking status, and
age.
Incidence of Preeclampsia-eclampsia or Gestational
Hypertension-maternal Biomarkers
Five observational studies
were identified,
21,65-68 of which four selected preeclamptic
women and normal pregnant women as controls.
21,66-68 The
results are very inconsistent across the studies.
Incidence of SGA Infants-intake During Pregnancy
Fourteen poor quality score RCTs showed that in the majority
of the studies, the mean birth weight was not influenced by the
intervention. None of the trials adjusted their results for the
maternal background diet, which can be an important effect
modifier.
Meta-analysis of the birth weight (mean) was combined in
two studies that were comparable in terms of type of
intervention and population (weight mean difference: -61.51,
CI 95%: -256.21; 133.18) showing a nonsignificantly
difference between groups.23 The incidence of infants with
IUGR showed a nonsignificant effect (OR: 1.14, CI 95%:
0.79; 1.64)22,23,59 of supplementation during pregnancy.
Incidence of SGA Infants-maternal Biomarker
Six
studies addressed this question.58,60,61,69-71 de Groot, et al.'s RCT
found a significantly positive correlation between the maternal
plasma and RBC DHA content and birth weight; however, this
relationship was nonsignificant when measured at delivery.58
Two observational studies found that the women with IUGR
fetuses had a significantly lower content of LA (omega-6) in the
plasma.69,71 The content of DHA, EPA, AA, total omega-3 and
omega-6 fatty acids, however, did not show a constant pattern
across the studies. Two observational studies did not observe a
correlation between maternal plasma biomarkers and birth
weight,61,69 consistent with the result in the RCT.58
Growth Pattern Outcomes
Maternal Intake During Pregnancy
One good quality
RCT addressed this question,54 showing no statistical difference
between infants (n=590 enrolled, 341 completers) from
mothers that were taking the supplementation with omega-3
and omega-6, or omega-6 fatty acids predominantly, on the
weight, length, and head circumference (HC) from birth to 12
months of age.54
Maternal Breast Milk
One good quality RCT evaluating
omega-3 supplementation in Norwegian mothers,54 one poor
quality RCT,72 and two observational studies were identified.73,74
Both RCTs showed no apparent effects of breast milk, with
maternal intake of omega-3 (DHA) or omega-6 fatty acids
(AA), on the growth patterns at any time point.54,72 The single
prospective cohort of Swedish mother/term infant pairs
showed a positive correlation between the maternal mother's
breast milk content of AA/DHA and the infant's rate of
increase of HC at 1 and 3 months of age.74 A cross-sectional study from Africa showed that the differences in weight-for-age
and weight-for-height z-scores and weight gain (g) were
significantly lower in infants from Ouagadougou (low omega-3
fatty acids intake) compared with infants from Brazzaville (high
omega-3 intake).73
Formula Intake, Preterm Infants
Twenty RCTs of poor
quality were identified,25-32,34,75-85 of which eighteen failed to find
an effect of the omega-3 supplementation in preterm formulas
on the growth parameters at any time point.25-30,32,34,75-84 The
outcomes measured were the mean (SD) and gain in weight,
length, and HC and the normalized z-score of weight. Two
trials found that the omega-3 fatty acids supplemented group
had a significantly lower weight from 6 to 18 months.31,85
The
results of the meta-analysis performed on the mean weight and
length measured at 4 months, from studies that compared the
use of formula supplemented with DHA+AA with control,
showed that the overall effect was nonstatistically significant
(weight: WMD: 0.04, CI 95%: -0.30; 0.38; length: WMD:
0.09, CI 95%: -0.62; 0.80).28,29
Formula Intake, Term Infants
Eighteen good quality
RCTs were identified.35-43,86-93 The effects on the growth
outcomes were nonstatistically different between study arms.
Yet, some inconsistent differences were found across five trials
at certain timepoints and subgroup of patients.94-98 Meta-analysis
demonstrated a nonstatistically significant overall effect
of formulas containing DHA+AA compared with control
formula at 4 or 12 months of age for the growth parameters:
- 4 months: weight: WMD: -0.06, CI 95%: -0.45; 0.34; length: WMD: -0.33, CI 95%: -1.07; 0.40.
- 12 months: weight: WMD: -0.33, CI 95%: -0.87; 0.21; length: WMD: -0.37, CI 95%: -1.26; 0.51; HC: WMD: 0.14, CI 95%: -0.83; 1.12.
Or DHA:
- 4 months: weight: WMD: -0.12, CI 95%: -0.44; 0.20; length: WMD: -0.43, CI 95%: -1.20; 0.34; HC: WMD: 0.04, CI 95%: -0.37; 0.46.
- 12 months: weight: WMD: -0.33, CI 95%: -0.87; 0.21; length: WMD: -0.71, CI 95%: -2.18; 0.76; HC: WMD: -0.04, CI 95%: -0.45; 0.38.36,39
Only four trials
adjusted the results for potential confounders, such as gender,
maternal education, parental socioeconomic status and center,
failing to find any change in the results.39,41,43,88
Child Biomarkers
Five were RCTs in preterm
infants,25,28,29,76,85 and five RCTs39,43,87,88,99 and a prospective single
cohort100 in term infants.
There is a negative correlation between weight and the
plasma or RBC content of DHA, and a positive correlation
between weight and the content of AA in plasma or RBC.
However, not all of the studies found this association. The
content of omega-6 fatty acids (AA) as a biomarker may be
related to weight gain in infants. The content of DHA seems
to be inversely related to weight gain, yet no significant clinical
outcomes were detected.
Neurological Development Outcomes
Maternal Intake During Pregnancy
Helland, et al. failed
to find a significant difference between groups in maturity as
evaluated from the EEGs, neither at day 1 of life nor at 3
months of age.54
Maternal Breast Milk
Two studies, one RCT101 and one
single prospective cohort design102 showed that maternal breast
milk may not have an influence on the neurological outcome,
measured with the PDI scale of the Bayley's Index.
Formula Intake, Preterm Infants
Six good quality RCTs
were identified.28,30,31,34,82,103 For the Bayley's PDI scale, two trials
did not observe a significant difference between the
supplemented and the control formula.31,34 Meta-analysis was
not possible for this outcome. Only Fewtrell, et al. found that
there was no difference between groups in the neurological
impairment assessment at 9 and 18 months of corrected age
(CA), and in the Knobloch, Passamanick, and Sherrards'
Developmental Screening Inventory score.34 There is not
consistent evidence to suggest that the omega-3 fatty acids
supplementation of infant formula, with or without breast
milk, influences the neurological development in preterm
infants.
Formula Intake, Term Infants
Eight good-quality RCTs,36-39,42,43,104 of which seven failed to find a statistically significant
difference between diet groups at different followups (6 to 24
months of age) in the Bayley's PDI scale.36-39,42,43 One trial
showed a significantly better Brunet-Lézine test result in the LC
PUFAs supplemented group compared with control at 4
months of age (after exclusive formula intake) but not at 24
months.104 Meta-analysis of Bayley's PDI score showed a
nonstatistically significant difference between groups using
formula supplemented with DHA+AA and control (WMD: -2.80, CI 95%: -7.43; 1.82) at 12 months.36,39,42
Maternal Biomarkers
One cross-sectional study showed
that maternal DHA was negatively associated with active sleep
(AS), AS:QS (quiet sleep) and sleep-wake transition, and
positively associated with wakefulness (postpartum day 2).105
The ratio of n-6:n-3 in maternal plasma was positively
associated with AS, AS:QS and sleep-wake transition, and
negatively associated with wakefulness (day 2), suggesting a
greater CNS maturity.
Child Biomarkers
Three RCTs37,39,43 and a prospective
cohort study100 evaluated the association between the infant's
plasma and RBC DHA content and the Bayley's psychomotor
developmental index (PDI) score in healthy term infants. Two
RCTs found a significant positive correlation between the plasma DHA and the PDI score.39,43 Two other studies
(including the observational study), did not find a significant
correlation between the PDI and the infant content of PUfatty
acids in plasma or RBC.37,100
Visual Function Outcomes
Maternal Intake During Pregnancy
One RCT failed to
find a significant effect of DHA supplementation during
pregnancy on the retinal sensitivity (ERG) measured at birth in
term infants.51 One cross-sectional study failed to find a
statistically significant difference in mean visual function values
between the exclusively breastfed group and the infants who
were also receiving formula.106
Maternal Breast Milk
Five studies found that the
correlation between the DHA content in breast milk and visual
function was not consistent with the clinical outcomes
measured in breastfed term infants of mothers who were or
were not taking supplements containing high DHA.72,101,106-108
Formula Intake, Preterm Infants
Nine RCTs with a
quality score approaching good internal validity were
identified.25,26,28,29,76,77,82,85,103 Of five studies that measured visual
evoked potentials (VEP), two did not find a statistical
difference between feeding groups at any time point (from 1 to
12 months).82,103 Three studies found that compared with the
unsupplemented group, infants fed with LC PUFAs-supplemented
formula had a better or faster maturation of
visual function, in terms of significantly shorter waves in the
VEP.25,28,77 Two studies found a significant difference between
groups in the Teller's Acuity Card test.85
Meta-analysis of the
relevant visual outcomes comparing the studies by the type of
omega-3 fatty acids used in the supplemented formula (DHA
or DHA+AA) and control formula, and by the type of outcome
(VEP and Teller's test of visual acuity) was done. For the VEP
visual acuity outcomes, only two studies were combined.25,28
O'Connor, et al. found that the use of formulas with DHA+AA
resulted in a better VEP measurements compared with control
formula at 6 months of age yet not at 4 months.25,28
No significant effect of DHA-supplementation at 2, 4, 6, or
9 months of CA,29,76 or DHA+AA supplementation at 2, 3, 4,
or 6 months of CA was found in the visual acuity measured
with the Teller's Card test.25,28,29,85,103
Formula Intake, Term Infants
Thirteen RCTs, of average
good quality (Jadad: 3.61/5) were identified,36,37,39,41-43,88,89,91,93,109,110
of which five trials did not find a significant difference between
groups in the VEP at any age.36,39,41,43,89 Four trials found a
significantly better VEP in the LC PUFAs-supplemented group
compared with the control group at a number of time points,
from 1.5 to 13 months of age.37,87,91,93
The meta-analysis
performed on this outcome, by LC PUFAs content of DHA
alone (or with the addition of AA), versus control, showed that
the studies that compared DHA supplemented formula with
control formula did not have an overall significant effect at any
age.36,37,39 Conversely, in seven studies that compared the use of
DHA+AA formula with placebo, there was no difference
between groups at any age,36,37,39,87,89,91,93 with the exception of
four studies that found a significant difference at 12 months of
age.36,37,91,93
One trial that evaluated behavioral visual acuity with the
Teller's test,110 found a significantly better acuity in the LC
PUFAs formula group compared with the control group at 2
months of age, yet not at 4, 6, 9, or 12 months. The
remaining four trials did not observe a significant difference
between groups in this outcome, at any time point.36,42,88 The
meta-analysis performed on this outcome showed that, in
studies comparing the use of DHA+AA with a control
intervention, acuity was only significantly better in the
DHA+AA group at 2 months of age,36,37,110 but not at 4, 6, 9, or
12 months of age.
Maternal Biomarkers
One study measured the association
between the maternal content of biomarkers at 2 months
postpartum and the visual acuity (Teller's Card Test) in term
infants at 2 months of age that failed to find a significant
correlation.106
Child Biomarkers
Twenty-one studies assessed this
association. Of five studies in the preterm group, three were
RCTs,25,76,77 and two were cross-sectional studies.111,112 Of the 16
term infant studies, nine were RCTs,37,43,72,87-89,91,93,101 and seven
were observational studies.100,106,107,111,113-115 There was no pattern
of correlation between the infant's biomarkers in blood and the
visual function outcomes across 21 studies that addressed this
issue.
Cognitive Development Outcomes
Maternal Intake During Pregnancy
One RCT addressed
this question.54 There were no differences between groups in
the novelty preference (Fagan Test of Infant Intelligence) at 6
and 9 months of age.54
Maternal Breast Milk
Two RCTs54,101 and one prospective
cohort102 were identified. The study by Helland, et al. was an
RCT described above,54 and Gibson, et al. included mother of
term infants who intended to breastfeed.101 They were
randomized to receive five increasing doses of DHA (algal oil)
during the first 3 months postpartum. The mean Bayley's
Mental Developmental Index (MDI) score did not differ
between groups at 1 or 2 years of age (underpowered).101
Formula Intake, Preterm Infants
Six good quality (Jadad:
4.4/5) RCTs were identified.28,30,31,34,76,103 Four of the five trials did not find an effect on the Bayley's MDI score from 3 to 24
months of age.28,31,34,116 Two studies found a significant
difference between the omega-3 fatty acids group and the
control group in the Fagan Test of Infant Intelligence.28,76
O'Connor, et al. found that there was no significant differences
between groups in the Infant version of the MacArthur
Communicative Development Inventories at 9 months CA and
14 months CA.28
Meta-analysis was not possible given the
heterogeneity across the studies for each of the different
outcomes due to the intervention characteristics (meaning dose,
source of omega-3 fatty acids, duration of intervention),
cointerventions, different assessment tools, and timing of the
outcomes measures.
Formula Intake, Term Infants
Six (of eight) good quality
RCTs36-39,42,43,92 did not find a significant difference between
groups (supplemented vs. control) in the Bayley's MDI score
from 6 to 18 months of age.36-39,42,43 Birch, et al. observed that
the DHA+AA group had a significantly higher score compared
with the control group at 18 months of age.37
The Knobloch, Passamanik, and Sherrards Development
Screening Inventory test (9 months),117 and the Fagan Test of
Infant Intelligence (6 and 9 months)98 did not differ between
groups. The IQ (Stanford-Binet), Receptive Vocabulary (PPVTR),
Expressive Vocabulary, and Visual-Motor Index scores, as
well as the Problem-Solving scores, did not differ between
groups in two studies.36,92
A meta-analysis using the Bayley's MDI score at 12 months
of age showed a nonstatistical difference between groups
(DHA+AA vs. control) from three trials (WMD: -0.80, CI
95%: -3.24; 1.63).36,39,42
Child Biomarkers
Four good quality RCTs and two single
prospective cohort studies100,118 showed inconsistent results.
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Discussion
Studies investigating the influence of omega-3 fatty acids on
child and maternal health revealed the absence of a notable
safety profile (i.e., moderate-to-severe adverse events).
Pregnancy outcomes were either unaffected by omega-3 fatty
acids supplementation, or the results were inconclusive. Results
suggested the absence of effects with respect to the impact of
supplementation on the incidence of GHT, preeclampsia or
eclampsia, as well as on infants being born SGA. However,
regarding evaluations of the duration of gestation, some
discrepancies were observed, although most of the studies failed
to detect a statistically significant effect. Biomarker data failed
to clarify patterns in pregnancy outcome data.
Results concerning the impact of the intake of omega-3 fatty
acids on the development of infants are primarily, although not
uniformly, inconclusive. The inconsistencies in study results
may be attributable to numerous factors.
In addition, making clear sense of the absolute or relative
effects of individual omega-3 fatty acids, or even omega-3 fatty
acids combinations, on child outcomes is complicated or
precluded by the following problem. Studies typically
employed interventions that involved various cointerventional
or background constituents (e.g., omega-6 fatty acids), yet
whose metabolic interactions with the omega-3 fatty acids were
not taken into account in interpreting the results. The
dynamic interplay among these fatty acid contents (e.g.,
competition for enzymes), and how this interplay may
influence outcomes, may differ in important ways depending
on whether DHA or olive oil is added to this combination of
cointerventional or background constituents, particularly in the
maternal population. This strategy prevented the isolation of
the exact effects relating to the omega-3 fatty acids content. It
is thus very difficult to reliably ascribe definite child outcome-related
benefits, or the absence thereof, to specific omega-3
fatty acids. Biomarker data failed to clarify patterns in child
outcome data.
Future research should likely consider investigating the
impact of specific omega-6/omega-3 fatty acids intake ratios, in
no small part to control for the possible metabolic interactions
involving these types of fatty acids. To produce results that are
applicable to the North American population, populations
consuming high omega-6/omega-3 fatty acids intake ratios
should likely be randomized into trials also exhibiting better
control of confounding variables than was observed, especially
in the present collection of studies of child outcomes.
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