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A
proportion of all human foetuses fail to grow and develop
normally in utero. These foetuses are characterised
by low birth weight (for their gestational age) and, sometimes,
asymmetric proportions indicating poor development during
specific periods of gestation. Such babies are referred to
as “intra-uterine growth restricted” (IUGR). Because
the definition of IUGR varies between individual centres,
it is difficult to estimate the prevalence of IUGR; however,
figures of around 3-7% of all pregnancies in EC countries
are widely accepted. IUGR can be classified into three groups
representing progressive degrees of severity according to
biophysical and biochemical measurements made in utero
[2].
In
the short term, IUGR babies suffer increased neonatal mortality
and morbidity [3, 4]. In the long term, the “Barker Hypothesis”
predicts that humans, subjected to insufficient intra-uterine
nutrition, grow abnormally leading to permanent effects on
the body’s structure, physiology and metabolism. These
effects are referred to as “foetal programming”
and include susceptibility to hypertension, cardiovascular
disease, respiratory disease and diabetes in adult life [5-9].
IUGR
can have many different aetiologies, a common factor of which
is inadequate nutrition of the foetus. This can arise from
problems with placental structure and function, maternal control
of circulating substrates and nutrition of the mother. At
present, no intrauterine therapy for IUGR is available but
much interest is centred on the possibility of modifying neonatal
outcomes by altering the composition of the maternal diet.
The proposed project will investigate the roles of dietary
fatty acids in the nutrition of the pregnant mother, their
foetus and the neonate, and the potential for improving the
prognosis of IUGR.
Requirements
for fatty acids in infant growth and foetal development Long-chain
polyunsaturated fatty acids (LC-PUFA) are essential to normal
growth and development. Docosahexaenoic acid (DHA, 22:6, n-3)
and arachidonic acid (AA, 20:4, n-6) are essential components
of membrane phospholipids, and are deposited in the central
nervous system during brain growth especially during the last
trimester of pregnancy and first months of postnatal life
[10-12], when a suboptimal supply can cause adverse effects
or irrevocable damage [13, 14]. DHA constitutes a large proportion
of the phospholipid fatty acids in cerebral cortex and retina
[15, 16]; AA is the precursor of eicosanoids [17] and is also
essential for neonatal growth and development [18]. Non-essential,
saturated and monounsaturated (n-9) fatty acids also have
important roles in neonatal nutrition as a source of structural
components (e.g. for the lung alveolae), of energy and of
adipose energy stores. Intrauterine growth of the human foetus
is accompanied by a large deposition of fat tissue during
the third trimester [19] that is frequently compromised in
IUGR.
DHA
and AA are members of the n-3 and n-6 families of fatty acids,
respectively. Humans, like other animals, do not possess desaturase
enzymes capable of inserting either the n-3 or the n-6 double
bonds; consequently, both can only be obtained in the diet
and are regarded as essential. Dietary linoleic acid (18:2,
n-6) from plant sources is the usual precursor of AA whereas
DHA may be derived directly from dietary fish oils or via
the precursor a-linolenic acid (18:3, n-3).
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All
of the n-3 and n-6 fatty acids required by the foetus, either
as preformed LC-PUFA or as precursor essential fatty acids,
have to cross the placenta. Placental transport of fatty acids,
and selective transport of LC-PUFA in particular [20, 21],
is critical for proper foetal growth [22]. The biggest determinant
of fatty acid delivery to the foetus is the composition of
lipids in the maternal circulation. However, the human placenta
is able to modify the fatty acid composition reaching the
foetal circulation by further desaturation and elongation
of maternal 18-carbon n-3 and n-6 fatty acids [23] and by
selective transport. Fatty acids are delivered to the placenta
mostly in the form of lipoprotein triacylglycerols from which
they must be hydrolysed by lipoprotein lipase before entering
the trophoblast cells [24-26]. Little is known about how placental
transport of fatty acids is affected in IUGR.
During
the first half of pregnancy, maternal adipose tissue behaves
in an anabolic manner as a result of hyperinsulinaemia and
normal insulin sensitivity [27-29], conditions which enhance
adipose tissue lipogenesis [30] and lipoprotein lipase (LPL)
activity [31]. During this period, fat derived from dietary
substrates accumulates. In late gestation, adipose tissue
becomes catabolic, lipolytic activity increases [32, 33],
insulin sensitivity decreases [34-36] and LPL activity is
lost [37, 38]. Mammary gland becomes insulin sensitive [39]
and gains significant LPL activity [40]. These changes result
in fatty acids becoming available (as VLDL-triacylglycerol)
to the placenta in the final trimester of pregnancy and to
the mammary gland for lactation [41].
Factors
affecting supply of fatty acid One of the most important factors
in IUGR is faulty placentation with inadequate conversion
of spiral arteries into uteroplacental blood vessels and a
consequent restraint upon the ability of the mother to supply
the foetus with nutrients (e.g. [42-44]) and O2.
It has been postulated that inadequate placentation is the
result of an abnormal maternal-trophoblastic interaction or
of alterations of the cytotrophoblasts’ invasive capacity
[45-48] mediated by maternally derived factors. Placentas
in IUGR may have delayed villus maturation characterised by
a disproportionate number of cytotrophoblasts. The number
of cytotrophoblasts in the placenta is the result of the balance
between their proliferation, apoptosis and differentiation
into syncytiotrophoblast (by fusion with pre-existing syncytiotrophoblast),
a balance which may be upset in IUGR [47].
IUGR pregnancies are associated with alterations in the general
and phospholipid fatty acid composition in the maternal circulation,
the placenta and the trophoblast membrane [49-52]. Membrane
fluidity, as controlled by its fatty acid composition, affects
the abilities of membranes to fuse [53] and, consequently,
the potential for trophoblast differentiation. Fatty acid
effects on the cell-cycle may also influence the balance between
proliferation and apoptosis [54]. We propose that cytotrophoblast
invasion may depend on membrane lipid composition, as has
been observed with tumour invasion [55, 56]. The significance
of modifying dietary fatty acid composition on placental structure
and function has not yet been investigated.
The
partitioning of nutrients between the maternal tissues and
the foetus, and subsequently the lactating mammary gland depends
upon a number of hormonal factors which themselves may be
influenced by the dietary composition. Unresolved questions
concern the roles of placental and maternal leptin in controlling
the energy balance and the mechanism in late-pregnancy of
the switch in insulin sensitivity from adipose tissue to mammary
gland [57]. It is, for instance, of interest that high foetal
leptin concentrations are associated with more severe signs
of foetal distress, an effect that may be related to corticosteroids
[58].
Fatty
acid composition of adipose tissue lipids reflects the fatty
acid composition of the dietary fat [59], while the tissue
is anabolic as in early gestation. During late gestation,
stored fatty acids are released into the circulation contributing
to hepatic synthesis of VLDL and maternal hypertriacylglycerolaemia,
the fatty acids of which are available to the foetus after
the action of placental lipases [26, 60, 61]. We propose that
the fatty acids available to the foetus in late gestation
are a reflection of both the current diet and the diet during
the first half of pregnancy when they were stored, temporarily,
in adipose tissue.
Dietary
supplementation with fish oil [62], as a source of DHA, is
still controversial. Several studies have shown desired improvements,
as a result of supplementation, in biochemical (fatty acid
composition) neurochemical, developmental, behavioural and
learning parameters of the foetus or the newborn infant [63-68].
However, other studies have shown that this supplementation
can lead to impaired growth (reviewed in [69]), an effect
related to the lower AA concentrations [70-72] resulting from
the inhibitory effect of DHA on the enzyme D6-desaturase [73]
which controls the conversion of 18:2 to AA. Furthermore,
detrimental effects of a fish oil-rich diet (compared to olive
oil) during lactation on the development of rat pups was related
to decreased milk yield and decreased AA concentrations [72].
In
some circumstances, IUGR is associated with an increased production
of free radicals [74]. Oxygen free radicals react most readily
with membrane lipids rich in LC-PUFA, excess intake of which
enhances lipid peroxidation [75], thus reducing antioxidant
capacity [76], and increasing oxidative damage [77]. Therefore,
the observed detrimental effect of high dietary fish oil intake
could also result from decreased concentrations of antioxidants.
Dietary n-9 monounsaturated acids (in olive oil) appear to
protect the LC-PUFAs from oxidation [78], to have no effect
on AA concentration [79-81] and to be resistant to lipid peroxidation
[75, 82, 83], thereby sparing vitamin E. Their presence could
be of benefit to the foetus, to the neonate and to low birth
weight, preterm infants fed by TPN.
The
energy requirements of the newborn are met in part by the
fat content of the milk. An inadequate supply can cause increased
morbidity and poorer recovery (catch-up growth) from IUGR.
In pigs, high neonatal mortality is related to poor nutrition
before weaning [84], and the fat content of the milk [85].
In humans, nutritional insufficiency pre-weaning is treated
with supplementary feeds but the optimum lipid composition
of the formulae is controversial. Similarly, preterm infants,
whether they are IUGR or AGA, are given TPN which contains
intravenous fat emulsions at between 1-3g/kg per day. The
composition of the fats used is restricted by the limited
range of commercially available emulsions.
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