Polyunsaturated
fatty acids in infant nutrition
By
Morten Bryhn MD, Ph D., Director of Research and Development,
Pronova Biocare
Polyunsaturated
fatty acids in infant nutrition
Pregnancy, lactation and early childhood are specific periods
in life when essential nutrients are crucial. During these
periods the requirement for most nutrients are different
than at other stages in life. This is of course to compensate
for the rapid growth and development of central organs and
tissue in the fetus and neonate.
Pregnancy,
lactation and early childhood are specific periods in life
when essential nutrients are crucial. During these periods
the requirement for most nutrients are different than at
other stages in life. This is of course to compensate for
the rapid growth and development of central organs and tissue
in the fetus and neonate. Although the infant is dependent
on many nutrients to achieve an optimal growth and development,
much attention has the recent years been given to the long-chain
omega-3 fatty acids.
Since
Dyerberg and Bang in the mid seventies suggested that marine
oils rich in omega-3 fatty acids (EPA and DHA) could explain
the low incidence of cardiovascular diseases in Greenland
Eskimos, extensive research of the omega-3 fatty acids on
human health and physiology has been done. It is now well
accepted that linoleic acid (LA, 18:2n-6) and alfa- linolenic
(ALA, 18:3n-3) are essential fatty acids for the human species.
In healthy
and normal humans these fatty acids can be converted to
their longer metabolites arachidonic acid (AA, 20:4n-6)
and docosahexaenoic acid (DHA, 22:6n-3), respectively. However,
in diabetics, elderly people with Alzheimers disease, in
infants and particular in pre-term infants, there is limited
capacity to convert LA to AA and ALA to DHA. On this basis
it has been assumed that AA and DHA are essential nutrients
for the infant, and should be provided as such in the diet.
In a
well-balanced diet both long-chain PUFAs should be present,
but in modern diets the omega-6 fatty (mainly as LA) acids
have become the dominating ones. At the same time the intake
of omega-3 fatty acids from fish- or sea mammals have declined
– leaving a gap for the intake of EPA and DHA. This
shift in intake of essential fatty acids has a great impact
on the production of the very-long-chain omega-6 and omega-3
fatty acids. Too much of the omega-6 fatty acids encourages
the formation of AA, and inhibits the formation of EPA and
DHA. The human body though seems to be more dependent on
receiving pre-formulated DHA than AA, as the conversion
ratio of ALA to DHA in the presence of high amounts of LA
(in normal diets LA is usually superior to ALA) is most
limited.
Omega-3
and omega-6 PUFAs are major components of membranes, and
play important roles on membrane functions and cell organization.
Many studies have been conducted to investigate the optimal
role in infant nutrition of the omega-3 long-chain PUFAs
alone or in conjunction with long chain PUFAs of the omega-6
family. Of great interest the recent years is the role of
DHA in neural and brain development and function. Besides
outcome as growth, length, head circumference, visual and
mental tests (including memory, problem solving, learning,
verbal communication, and perception) have been assessed
in order to study the effects of DHA.
Dietary
omega-3 fatty acids appear to affect the retina (where DHA
accumulates in rhodopsin) and visual acuity by influencing
their rate of development. In most cases these effects disappear
when children are evaluated at a later age, but the long-term
effects of dietary LCPUFAs on a range of visual and cognitive
outcomes remains to be studied.
Accretion
of long-chain PUFAs
Docosahexaenoic acid (DHA; 22:6n-3) and Arachidonic acid
(AA; 20:4n-6) are the main long-chain polyunsaturated fatty
acids (PUFAs) accumulating in the fetal brain during the
last trimester of pregnancy. In utero, the placenta selectively
and substantially extracts AA and DHA from the mother and
enriches the fetal circulation. Studies indicate that there
is little placental conversion of the parent fatty acid
LA to AA and ALA to DHA. The maximal DHA accumulation is
at 36-38 weeks, but accretion proceeds until well past term.
Once accumulation is complete, the retinal need for DHA
decreases, but to compensate for the regular 10% fatty acid
turnover in the brain, there is a lifetime need for supply
of DHA (or its precursors ALA or EPA).
Postpartum
studies show that the fetus accretes 50-60mgLCPUFAs during
the last trimester, most of which is DHA. This fatty acid
along with other is transported from the placenta. To balance
this intake the maternal intake of omega-3 fatty acids is
estimated to about 100mg/day.
From
retrospective analysis it is shown that during the first
6 months of life DHA accumulates at about 10mg/day in the
whole body of breast-fed infants, and as much as 48% of
the DHA appears in the brain, mainly in the white cerebellum.
To achieve this rate of accumulation, not taken into account
that DHA can be synthesized from ALA, breast-fed infants
need to consume a daily amount of 20mg DHA. Virtually all
breast-milk provide at least 60mg DHA/day. Hence, in infants
who are breast-fed there is little concern as to the supply
of DHA provided that the mother has an optimal status of
the long-chain omega-3 fatty acids (EPA/DHA).
Term
infants are normally born with about 1050mg DHA in the body
fat. If they are fed formula providing ALA as the only source
of omega-3 fatty acid, typical level at 390mg/day, they
will during a 6 months period experience only 50% lower
accretion of DHA in the brain compared to breast-milk fed
infants. There are no studies given evidence that term infants
are able to convert the necessary amount of DHA from ALA.
Illustrating the need for DHA, and/or its precursor EPA,
to be included in the diet.
Supply
of long-chain PUFAs
The infant is dependent of the supply of fatty acids (as
for all other nutrients) from breast-milk. In cases where
breast-feeding is impossible or not preferred the infant
must rely on the nutrients provided by the formula. Infants
who do not receive adequate amounts of DHA from mother's
milk or from supplemented formulas are known to have decreased
level of brain DHA and along with this a sup-optimal development
of neural tissue as assessed by visual function and learning-memory
behavioral tasks.
The
major source of essential fatty acids (EFAs) for the brain,
retina, nerve and other developing tissues are in the plasma
lipoprotein fraction. These lipids are therefore regarded
as benchmark for adequate fatty acid nutrition.
There
is a high degree of inconsistency between different studies
on the effect of omega-3 fatty acids on visual function.
Much of this might be attributed to the use of different
methods to assess visual function, but differences in intake
of ALA, DHA or both also contribute to discrepant results.
The concentrations of DHA and AA in human milk vary due
to the time after birth and the maternal diet, and also
EPA is present at variable amounts. Hence, a golden standard
for these fatty acids to be present in the formulas might
be difficult to determine.
Low-birth
weight infants
Low-birth weight infants and pre-term infants are born with
a lack of long-chain omega-3 fatty acids. Such deficiency
might have great impact on their growth and development.
Deficiency of AA is associated with low prenatal and postnatal
growth in pre-term infants, whereas DHA deficiency has been
connected with visual and neural dysfunctions.
Several
studies have been conducted with low-birth weight and pre-term
infants fed formulas with different sources and amounts
of DHA. The general view is that visual acuity in these
infants is higher in the DHA supplemented group up to a
certain period, but not affected above 9 months of age.
The effects are not specific for any particular source of
DHA. What seems to be important is to balance the type of
omega-3 fatty acids and the omega-3 to omega-6 long chain
PUFAs.
Although
the fractional rate of endogenous synthesis of DHA is higher
(and the fractional rate of AA synthesis is lower) in infants
who receive higher ALA intakes, adequate versus inadequate
ALA intake appears to enhance visual development of the
pre-term infants. But studies show that they will not achieve
normal visual development unless also DHA is added in adequate
amounts.
Controlled randomized trials with pre-term infants indicate
that essentiality of omega-3 PUFAs and the need for inclusion
of DHA in formulas. There is a consensus for the inclusion
of both AA and DHA in pre-term and low-birth weight infant
formulas, at same levels as found in human milk. It appears
that supplementing pre-term formulas with AA/DHA in the
ratios of 1,4-2,0 (with AA ranging from 0,5-0,75% of total
fatty acids) results in plasma and erythrocyte phospholipid
contents of AA and DHA similar to those infants fed pre-term
human milk. There are some indications that if marine oil
is the omega-3 source in formulas, EPA should be the minor
omega-3 fatty acids as compared to DHA to avoid any negative
effects on growth. In some studies feeding studies with
such oils have shown little or no depression on AA and no
compromise on weight gain or head circumference in pre-term
infants. Other studies have not detected any negative effects
on growth even if EPA was present in higher amounts than
DHA in the formula, and to some extent depressed the AA
content in plasma.
Term
infants
If the need for AA and DHA in pre-term infants is rather
clear, the evidence for a favorable effect of these fatty
acids in term infants is inconsistent.
A number
of controlled studies have been initiated to test the effect
of dietary long-chain PUFAs (omega-3 and omega-6 fatty acids)
on neural postnatal development and function in term infants.
These studies have mainly involved a comparison between
breast-feeding and formula with long-chain PUFAs added or
formula without these fatty acids. Adding DHA or DHA+AA
to formula has in most studies shown to improve the growth,
and beneficial effect the cognitive and mental development
in infants similar to that observed in infants on breast
milk. However, there are studies failing to show such effects.
It is
shown that breast-fed infants accumulate DHA in the brain
for the fist 40 weeks of life, whereas formula fed infants
who are denied of DHA, maintain their DHA level similar
to that at birth. In contrast, AA accumulation in term infants
seems to be unaffected of diet. This again illustrates the
difference in metabolism of the very-long chain fatty acids,
and reflects the higher conversion rate of LA to AA compared
to the conversion of ALA to DHA.
Much
of the uncertainty as to the need for DHA and AA in term
infants is related to the methods used for assessing the
cognitive and mental development as well as the impact of
the measured differences. Some researchers may therefore
conclude that it is still an open question as to the essentiality
and requirement for DHA and AA in full term infants.
However, taken into account that diets high in LA have been
shown to inhibit the incorporation of omega-3 fatty acids
in various cells and organs – both in animals and
humans, the problem is related to the competition between
LA and ALA, and AA and DHA. So if there is a high intake
of LA DHA should be provided as such or combined EPA/DHA
(not solely as ALA) to overcome the limiting delta 5-desaturatase
step.
In term
infants it has also been shown that despite normal intrauterine
accumulation of DHA and AA, infants fed formula with 2%
LA and 0,1% DHA had better visual acuity than those fed
formula with 2% LA (and no DHA).
Pregnancy
Since the fetus cannot, or hardly, synthesize long-chain
PUFAs, these fatty acids must be provided via the mother.
In several studies there have been found a positive correlation
between maternal PUFA consumption and the PUFA status of
the neonate. Although pregnancy is associated with increased
levels of total PUFAs in the maternal plasma phospholipids,
there is a relative decrease in the AA and DHA supply to
the fetus, and circulating levels of DHA seem to be lower
with each following pregnancy. The clinical impact of this
is that there may be situations where the supply of DHA
to the mother or to the fetus or both may be to little –
and critical outcomes may be observed.
Pre-term
delivery is found in 10% of the pregnancies and of about
every third women have given pre-term delivery has a risk
for pre-term delivery at the next pregnancy. The baby's
birth weight is one of the essential factors for survival.
Hence it is of great value to prevent pre-term delivery
and/or increase the intrauterine growth.
Epidemiological
studies from the Faroe Island have suggested that marine
diets increase birth weight. The mechanisms underlying this
effect may be a prolonged pregnancy, resulting form an altered
balance between the prostaglandins involved in the initiation
of labor. It is known that long-chain omega-3 fatty acids
may postpone parturation by a down regulation of PGE2 and
PGF2á formation, and an increased formation of PGI2
and PGI3. In addition an increased fetal growth rate resulting
from improved placental blood flow due to lowered thromboxane/prostacylin
ratio and blood viscosity may also be connected with an
increased birth weight.
It has
been hypothesized that marine oils lower risk of certain
complications of pregnancy, in particular pre-term delivery,
intrauterine growth retardations, pre-eclampsia, and pregnancy
induced hypertension. Even though there is an extensive
biological basis for the hypothesis that fish oil may reduce
the risk of pregnancy-induced hypertension, clinical trials
have failed to show this effect at significant levels.
Recently
it has been shown that omega-3 concentrate (EPA/DHA 2,7g/day
from week 20 until delivery) delayed spontaneous delivery
and reduced recurrence risk of pre-term delivery by 50%
in women having experienced preterm-delivery in earlier
pregnancy. The omega-3 supplementation, however, did not
affect recurrence risks for intrauterine growth retardation
or pregnancy induced hypertension, nor did it reduce preterm
risk in twin pregnancies.
The
levels of essential fatty acids (EFA) in cord blood samples
have been associated with attained weight at birth, primarily
in pre-term infants. In term infants both DHA, and AA has
been found to negatively correlate to weight. In mothers
having the heaviest babies a larger decrease in AA, DHA,
omega-3 long-chain PUFAs and omega-6 long-chain PUFAs were
observed, suggesting a larger EFA demand in heavier infants.
To prevent
a sub-optimal supply of long-chain PUFAs to the fetus, suggestions
are made on a general basis to improve the neonatal PUFA
status by maternal supplementation of PUFAs during pregnancy.
A high maternal LA intake may though have a lowering effect
on the maternal as well as on the neonatal omega-3 fatty
acids status. This suggests that either should a better
balance between the parent omega-6 and omega-3 fatty acids,
LA and ALA, be achieved, or pre-formed EPA/DHA given.
Lactation
The fatty acids of human milk are either synthesized by
the mammary gland, derived form the diet, or released form
the adipose tissue. Typically is found that about 60% of
the long chain PUFAs in the milk comes from the adipose
tissue. An optimal deposition of essential fatty acids in
the maternal adipose tissue is therefore, along with the
dietary fat, of significance for providing the newborn with
adequate amounts of long-chain essential fatty acids.
It is generally believed that breast milk contains all the
nutrients needed by the infant, including DHA and AA, and
hence, the breast milk is regarded as the best and only
proven source of fat and essential fatty acids in the infant
diet.
The
benefit of breast-feeding vs. formula feeding on cognitive
development at 6 months and up to 15 years of age was addressed
in a recent meta-analysis, and assumptions as to the content
of DHA in the milk was made, but not proven.
From
various studies it is clear that the composition of fatty
acids in human milk varies. The amount of DHA and EPA is
highly variable (0,13-1,4%, 0,05-1,10%, respectively), whereas
the amount of AA is less variable (0,09-0,82%). It is found
that DHA and EPA levels in milk from American women are
among the lowest in the world (DHA 0,13, EPA 0,06, AA 0,56%
of total fatty acids), and the highest levels are found
in milk from women where fish/seafood is a regular meal
(milk from the Canadian Inuits: DHA 1,4, EPA 1,1 and AA
0,6% of total fatty acids). In countries with medium fish
intake (like in Denmark) the DHA, EPA and AA are found in
the levels of 0,38, 0,11 and 0,40%, respectively of total
fatty acids.
In milk
form the "fish eating mothers" there is little
or no concern as to the DHA supplied to the infant. But
of particular concern with respect to DHA intake is the
pregnant vegetarian woman (there is little or no DHA in
vegetarian products), pregnant and adolescent females with
odd dietary habits, and all those avoiding fish and seafood.
In such conditions and in occasions when the dietary intake
of fish or seafood is generally low a relevant dose of marine
oil with EPA and DHA may improve the DHA levels of the maternal
milk to clinical significant levels in the infant.
After
delivery there is a decline in the long-chain PUFAs in maternal
plasma PL, especially during the early postpartum period.
The decline in DHA in maternal plasma is independent of
lactation, but may be normalized by dietary supplementation
in the range of 200-400mg DHA/day. During lactation the
mother looses about 70-80mg DHA per day to the milk. This
loss can be balanced by an intake of 60-70mg DHA per day,
whereas only the remaining 10-20mg may be converted from
ALA.
Although
EPA is present in rather variable amounts in the human milk
– reflected by the dietary habits of the mother, EPA
has not been reported to have any negative implications
either on mother, fetus or child. On the contrary, recent
studies indicate a relation between depression during lactation
and low levels of EPA. Hence, an adequate intake of EPA
and DHA may be healthy both for mother and child, although
in different physiological means and outcomes.
Recent
studies show that a dietary increase in DHA from 100mg to
1000mg resulted in a 2,5- fold increase in maternal plasma
PL and a 5-fold increase in breast-milk DHA. Maternal supplementation
with DHA during lactation shows a dose–dependent increase
in both plasma and milk. Based on studies with Inuits, a
high EPA intake is reflected in the milk, however there
are no reports on negatively influence of EPA on the growth
or development of these infants. From other studies with
marine oils supplementation to lactating women, different
intake of EPA and DHA did not affect the AA levels in the
milk. Supplementation of marine oils (containing both EPA
and DHA) to lactating mothers might therefore the best way
to supply the infant with adequate amounts of DHA.
Confounders
The current inconsistency of data on omega-3 and omega-6
fatty acids on infant, particular on term infant neural
development and function may be related to confounders.
Most of the earlier studies conducted in this area did not
control for confounders, hence, the conclusions draw are
not necessarily correct. Confounders shown to negatively
affect visual evoked potential in term infants are: male
gender, plasma level of 22:5n-6 at day 5, red blood cell
content of 20:3n-9 at day 5, and the number of smokers in
the family. The use of alcohol and social class may also
be confounders of significance. Combination of perinatal
factors could accumulate to either mask or enhance effects
of dietary components on VEP acuity.
Safety
Several investigators have evaluated the safety aspects
of long-chain PUFAs as EPA/DHA. Gastric emptying, gastric
transit time, peroxidation of erythrocyte membrane lipids,
and levels of vitamin E and A in blood have been measured
in infants. There is no data supporting any concern regarding
supplementation of healthy infants with marine oils rich
in EPA/DHA.
There
is no evidence of harm as to the supplementation of omega-3
long-chain PUFAs during either pregnancy or lactation. In
the study by Olsen, including a total of 1657 pregnant women
on moderate to high dose of EPA/DHA or olive oil during
several weeks, no side effects as to nausea, vomiting, diarrhoea,
constipation, nose bleeding or vaginal bleeding differed
between the groups.
Conclusion
* Maternal intake of PUFas should be both adequate (4-8%
of total dietary energy) and balanced in order to ensure
a normal brain and nerve development of the infant. A minimum
of 5:1 – 1:1 of n-6: n-3 fatty acids should be kept
from conception to age 2 years.
* There
is consistent evidence of the beneficial effects of dietary
long-chain fatty acids in preterm infants. Recent studies
suggest that pre-term formula should contain 0,49% AA and
0,35% DHA to reached lipoprotein levels of these fatty acids
similar to that found be feeding human milk.
* From
term-infant studies is concluded that variations in dietary
EPA/DHA do not influence growth of healthy term infants
to any clinically significant degree, whereas depressed
levels of AA in pre-term infants are associated with deceased
growth if EPA is present in higher amounts than DHA. Thus
preterm infants appear to be vulnerable to a poor status
of both DHA and AA.
* Formula-fed
infants are unable to match the omega-3 and omega-6 long-chain
fatty acids status of breast fed infants until at least
two months after birth.
* The
scepticism towards EPA in the formula to preterm infants
is relevant, but studies show that in the lactation and
term feeding situation this fatty acid does not have any
negative impact on the growth, development or function of
the infant.
* To
make sure an equal accretion of DHA in brain as in breast-milk
fed infants, DHA should be provided during the first 6 months
of life – also in term infants. The risk here is possible
benefits as to the visual development and mental scores
later in life.
* Supplementation
of EPA/DHA (from marine sources) to pregnant and lactating
women is of safe and significant value as to the supply
of EPA to the mother and DHA to the fetus and infant, respectively.
Although
there is sort of controversy among experts on the requirements
for long-chain PUFAs, the positive relation between DHA
and neurological and visual effects has been addressed by
several groups. WHO has in 1993 recommended that full-term
infants receive 20mg DHA per kilo body weight per day, and
preterm infants receive 40mg DHA per kg body weight per
day. This has been implemented in some formulas, but not
yet in all. Besides this the current knowledge on fatty
acid in infancy also addresses the need for inclusion of
AA at levels normally found in human milk.
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