The Impact of Maternal Nutrition on the Offspring - Nestlé Nutrition Workshop Series Pediatric Program Volume 55
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Nestlé Nutrition Workshop Series Pediatric Program Volume 55 The Impact of Maternal Nutrition on the Offspring
Information for the medical profession only Printed in Switzerland art. 4391 GB
© 2004, Nestec Ltd., avenue Nestlé 55, CH-1800 Vevey, Switzerland.
Printed by Les Presses de la Venoge S.A., CH-1026 Denges, Switzerland.
All rights reserved. Unless special permission in writing is obtained, no
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The material contained in this issue was submitted as previously unpub-
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the source from which some of the illustrative material was derived.
Nestec Ltd. cannot be held responsible for errors or omissions, or for any
consequences arising from the use of the information contained herein.
© 2004, Nestec Ltd., Vevey, SwitzerlandNestlé Nutrition Workshop Series Pediatric Program Volume 55 The Impact of Maternal Nutrition on the Offspring Beijing, April 25–29, 2004 Editors G. Hornstra R. Uauy X. Yang
Contents
iv Foreword
1 Maternal Nutrition and Adverse Pregnancy Outcomes:
Lessons from Epidemiology
M.S. Kramer
2 Nutrients Effects upon Embryogenesis: Folate,
Vitamin A and Iodine
T.H. Rosenquist, J.G. van Waes, G.M. Shaw and R. Finnell
5 Energy Requirements during Pregnancy and Consequences
of Deviations from Requirement on Fetal Outcome
N.F. Butte
7 Essential Fatty Acids during Pregnancy: Impact on
Mother and Child
G. Hornstra
11 Dietary Essential Fatty Acids in Early Postnatal Life:
Long-Term Outcomes
R. Uauy, C. Rojas, A. Llanos and P. Mena
19 Nutrient-Induced Maternal Hyperinsulinemia and
Metabolic Programming in the Progeny
M.S. Patel, M. Srinivasan and S.G. Laychock
22 Maternal Malnutrition and the Risk of Infection
in Later Life
S.E. Moore, A.C. Collinson, P.T. N’Gom and A.M. Prentice
27 Size and Body Composition at Birth and Risk of Type-2
Diabetes: A Critical Evaluation of ‘Fetal Origins’
Hypothesis for Developing Countries
C.S. Yajnik
ii28 Cardiovascular Diseases in Survivors of the
Dutch Famine
O.P. Bleker, T.J. Roseboom, A.C.J. Ravelli,
G.A. van Montfrans, C. Osmond and D.J.P. Barker
30 The Relationship between Maternal Obesity and
Adverse Pregnancy Outcomes
D.K. Waller and T.E. Dawson
32 Special Problems of Nutrition in the Pregnancy of
Teenagers
P.B. Pencharz
33 Dietary Intervention during Pregnancy and Allergic
Disease in the Offspring
S. Salvatore, K. Keymolen, R.K. Chandra
and Y. Vandenplas
35 List of Speakers
iiiForeword
For this 55th Nestlé Pediatric Nutrition Workshop, which took
place in April 2004 in Beijing, the topic ‘The Impact of Maternal
Nutrition on the Offspring’ was chosen. We know a lot about the
appropriate nutrition of infants and children. When it comes to the
point whether the nutritional status of a pregnant mother has an
impact on the development of the fetus in the womb and subsequently
on that of her child, there are little data except some very fundamen-
tal ones; most knowledge derives from animal studies. The intention of
this workshop was to learn more about the effects of maternal nutri-
tion on fetal growth, metabolic programming, the requirements of
energy and various nutrients as well as the effects of under- and over-
nutrition during pregnancy. Finally, the question of whether a distinct
diet during pregnancy could reduce food allergy in the offspring was
addressed.
I would like to thank the three chairmen, Prof. Gerard Hornstra,
Prof. Ricardo Uauy and Prof. Xiaoguang Yang, who are recognized
experts in this field, for putting the program together and inviting the
opinion leaders in the field of maternal and infant nutrition as speak-
ers. Pediatricians from 18 countries contributed to the discussions that
are published in the book, which will be published after this booklet.
Mrs. Kelan Liu and her team from Nestlé China provided all the
logistic support, enabling the participants to enjoy the Chinese hospi-
tality. Dr. Philippe Steenhout from Nestlé’s Nutrition Strategic
Business Division in Lausanne, Switzerland, was responsible for the
scientific coordination. His cooperation with the chairpersons was
essential to the success of this workshop.
Prof. Wolf Endres, MD
Vice-President
Nestec Ltd., Lausanne, Switzerland
ivMaternal Nutrition and Adverse
Pregnancy Outcomes: Lessons
from Epidemiology
Michael S. Kramer
This chapter reviews the epidemiologic evidence concerning
the role of maternal nutrition in the etiology of adverse pregnancy
outcomes. Descriptive epidemiologic studies are used to summarize
geographic and temporal occurrence patterns in preterm birth,
intrauterine growth restriction (IUGR), mean birth weight, and fetal
and infant mortality. Rates of most adverse pregnancy outcomes are
falling in both developed and developing countries, but rates of preterm
birth and large-for-gestational-age (LGA) infants are on the rise.
Observational studies are reviewed to summarize the evidence con-
cerning the effects of maternal anthropometry (height, pre-pregnancy
body mass index, and gestational weight gain). All of these maternal
anthropometric factors are associated with fetal growth, with reduced
risks of IUGR but increased risks of LGA birth in mothers who are taller,
heavier, or have higher weight gains. Importantly, maternal obesity is
also strongly associated with an increased risk of stillbirth.
As revealed in observational studies of famine and controlled sup-
plementation trials, energy intake is clearly associated with fetal
growth. Energy supplementation may also reduce the risk of stillbirth
and neonatal death. Other than iodine for preventing cretinism in
iodine-deficient geographic regions and folic acid for preventing neural
defects, supplementation with micronutrients, either in isolation or
combination, has not been clearly demonstrated to be beneficial for
pregnancy outcomes. Calcium and fish oil supplementation, however,
show promise for reducing preterm birth and justify additional ran-
domized trials.
1Nutrients Effects upon
Embryogenesis: Folate,
Vitamin A and Iodine
T h o m a s H . R o s e n q u i s t , J a n e e G e l i n e a u v a n Wa e s ,
Gary M. Shaw and Richard Finnell
Deficiencies of folic acid, vitamin A, and iodine are widespread.
An insufficient supply of any of these nutrients during embryogenesis
may result in major developmental anomalies including neural tube
closure defects, orofacial defects, and conotruncal heart defects.
These are among the most common and devastating of developmental
anomalies, and each is the result of perturbed development of cells of
the embryonic neural crest and neural tube.
Folic Acid
Perinatal folic acid (folate) supplementation is especially effective
in reducing the rate of neural tube and neural crest abnormalities.
Folate is a cofactor in two metabolic processes that are vitally impor-
tant to normal embryonic development, DNA synthesis and gene
methylation. These processes may be impaired in embryos with a
folate deficit. If that deficit results from abnormal uptake of folate by
the embryo itself, perinatal folate supplementation my offer protection
to the embryo even when conventional tests may indicate that mater-
nal folate status is normal. Supplementary folic acid may also protect
embryos by reducing their exposure to homocysteine, which rises
inversely with folic acid, and has been shown by both epidemiological
and experimental evidence to induce abnormal development of the
neural crest and neural tube.
Vitamin A
Vitamin A is required for pattern formation during embryogenesis,
and it regulates key developmental processes: apoptosis, proliferation,
2Thymidylate DNA Mitosis
Folate Methylation
Homocysteine Gene
nm
regulation
Maternal
Vit A ret RA RXR/RAR
diet
Early brain
development
Trans-
thyretin RXR/TR
Iodine
Late brain
TR development
Fig. 1. Mechanisms for the regulation of developmental processes by
folate, vitamin A and iodine, and interactions among these key nutrients. This
figure highlights brain development during embryogenesis when neural tube
closure occurs (Early brain development) and after week 15 of gestation (Late
brain development) when neurogenesis, cell migration and synaptogenesis are
the dominant processes. Folate metabolism may impact upon retinoic acid
(RA) synthesis when elevated homocysteine interferes with the processing of
retinal. Elevated homocysteine also may provoke dysregulation of genes in
early development via its effect upon the calcium channel of the N-methyl-
D-aspartate type of glutamate receptor (nm) on neural crest or neural tube
cells. Vitamin A (Vit A) is transported in the serum bound by transthyretin in
common with thyroid hormone. In the cell nucleus, a retinoid X receptor/
triiodothyronine heterodimer (RXR/TR) may regulate gene expression related
to both early and late brain development. RAR Retinoic acid receptor.
differentiation, and migration. By a complex interactive set of receptors,
vitamin A as retinoic acid regulates the expression of early-acting genes
that are fundamental to normal development. These include the retinol-
binding proteins on the plasma membrane; the cytoplasmic retinol-
binding proteins and the cytoplasmic retinoic acid-binding proteins, and
in the nucleus, the retinoic receptors (RARs) and the retinoid X receptors
(RXRs). An RXR may form a heterodimer with another RXR, an RAR, a
nuclear thyroid receptor, or a nuclear vitamin D receptor; and these
heterodimers regulate the expression of early-expressed genes that are
the basis for normal development, especially the Hox family of genes.
The temporal and spatial distribution of these receptors during
embryogenesis determines the ultimate phenotype of the embryo,
3fetus and neonate. By altering their expression, both hypo- and hyper-
vitaminosis A can disrupt the elegant hierarchy that is required for
normal development, especially of the neural crest and neural tube:
hypo-vitaminosis A by failure to activate, and hyper-vitaminosis A by
inappropriately activating one or more of the key Hox or related genes.
Iodine
The only known biological function of iodine in humans is its role
in the synthesis of the thyroid hormones triiodo-L-thyronine (T3) and
tetraiodo-L-thyronine (T4), and all adverse developmental effects of
iodine deficiency are the result of hypothyroidism. The most well-
known of these adverse effects involve disordered brain development,
for example cretinism, and they arise principally during stages of
development that are later than embryogenesis. However, there is
growing evidence that an adequate supply of maternal hormone also
may be essential during embryogenesis. Embryos express thyroxin
receptors during early embryogenesis, and experimentally increased
or decreased exposure to thyroxin during embryogenesis can induce
major structural defects of neural tube derivatives. However, unlike
the case for folic acid or vitamin A, the mechanism by which maternal
thyroxin might contribute directly to the regulation of early develop-
mental events is not yet known.
In addition to their separate effects upon early development, folic
acid, vitamin A and thyroid hormone may interact in complex ways to
maintain normal developmental potentials in the early embryo; and
conversely, a reduction in the availability of one of these key nutrients
may produce an unexpected impact upon the availability or synthesis
of another. These relationships are outlined in figure 1.
4Energy Requirements during
Pregnancy and Consequences
of Deviations from Requirement
on Fetal Outcome
N a n c y F. B u t t e
Energy requirements of pregnancy are comprised of the energy
deposited in maternal and fetal tissues, and the rise in energy expen-
diture attributable to basal metabolism and physical activity. Because
of uncertainties regarding desirable gestational weight gain (GWG),
maternal fat deposition, putative reductions in physical activity and
energetic adaptations to pregnancy, controversy remains regarding the
energy requirements during pregnancy. The objectives of this chapter
are to review: (1) energy requirements during pregnancy; (2) energetic
adaptations to pregnancy, and (3) the consequences of deviations from
maternal energy requirement on fetal outcome.
Energy requirements during pregnancy in healthy, normal-weight
women were estimated factorially from the increment in basal meta-
bolic rate (BMR) and from the increment in total energy expenditure
(TEE), plus the energy deposition associated with a mean GWG of
13.8 kg. Energy deposition was determined from fat (4.3 kg) and protein
(686 g) accretion. BMR increased on average over pre-gravid values by
4, 10 and 24% in the first, second and third trimesters, respectively. Free-
living TEE increased on average by 1, 6 and 19% across pregnancy. The
incremental cost of pregnancy was 371 MJ, distributed as 430, 1,375 and
2,245 kJ/day for the first, second and third trimesters, respectively.
Incremental cost of pregnancy predicted for women with a mean GWG
of 12.0 kg, as found in the WHO Collaborative Study on Maternal
Anthropometry and Pregnancy Outcomes, was 323 MJ, distributed as
375, 1,200 and 1,950 kJ/day for the first, second and third trimesters,
respectively.
Energetic adaptations in basal metabolism, energetic efficiency
and physical activity can occur to meet the increased energy needs
of pregnancy. Suppression of BMR, increased energetic efficiency in
5weight-bearing activity, and declines in physical activity as pregnancy
progresses, all act to conserve energy. Although these adaptations may
protect the fetus from environmental and nutritional stresses, they
may not totally prevent adverse pregnancy outcomes.
Negative deviations from maternal energy requirement (dietary
energy deficiency) can perpetuate low maternal weights and inade-
quate weight gains during pregnancy. Failure of the materno-placental
supply to satisfy fetal energy and nutrient requirements can result in
intrauterine growth retardation, increased perinatal and neonatal mor-
bidity and mortality, and a range of adaptations and developmental
changes which may lead to permanent structural and metabolic alter-
ations which may influence metabolic diseases later in life. In the WHO
Collaborative Study on Maternal Anthropometry and Pregnancy
Outcomes, pre-pregnancy weight and attained weight at 36 weeks of
gestation were the most significant predictors of low-birth weight
infants.
Positive deviations from maternal energy requirement can result
in excessive GWG. High GWG is associated with high-birth weight,
which can secondarily lead to prolonged labor, cesarean delivery,
shoulder dystocia, birth trauma and asphyxia. Women who are over-
weight are much more likely to have gestational diabetes and glucose
intolerance, and in turn produce larger infants with a propensity to
childhood obesity and adolescent-onset of type-2 diabetes.
Although energetic-sparing adaptations can occur during preg-
nancy to protect the fetus from environmental and nutritional stresses,
they may not totally prevent adverse maternal and fetal outcomes.
Every effort should be made to provide pregnant women with suffi-
cient but not excessive food to meet the substantial energy demands
of pregnancy.
6Essential Fatty Acids during
Pregnancy: Impact on Mother
and Child
Gerard Hornstra
Essential fatty acids (EFAs) and their longer chain, more unsatu-
rated derivatives, the so-called LCPUFAs, are indispensable for human
development and health. Since these essential polyunsaturated fatty
acids (EPUFAs) cannot (EFAs) or hardly (LCPUFAs) be synthesized by
man, they need to be consumed with the diet. Consequently, the LCPUFA
status of the developing fetus depends on that of its mother, as is also
suggested from the positive relation observed between maternal EPUFA
consumption and neonatal EPUFA status.
Pregnancy is associated with increasing amounts of LCPUFAs in
maternal plasma phospholipids (PLs). However, a relatively stronger
increase in the amounts of EPUFA ‘shortage markers’ indicates that
the increased LCPUFA demand during pregnancy is not adequately
covered. In figure 1 this is shown for docosahexaenoic acid (DHA;
22:6n-3), the major LCPUFA in the central nervous system, and its
shortage marker Osbond acid (ObA; 22:5n-6). The ratio between DHA
and ObA (100) indicates the functional DHA status, which decreases
continuously during pregnancy.
A reduction in the maternal LCPUFA status during pregnancy is
also suggested by the decrease in the relative amounts of most mater-
nal LCPUFAs during pregnancy. For the most important LCPUFAs,
DHA and arachidonic acid (AA; 20:4n-6), this decrease is more pro-
nounced the higher the neonatal birth weight. Nonetheless, in term
neonates the DHA and AA contents of umbilical plasma PL are nega-
tively related to birth weight. This suggests that the maternal-to-fetal
fatty acid transfer is limited, as a result of which the neonatal essen-
tial PUFA status may not be optimal. This latter suggestion is sup-
ported by the high amounts of LCPUFA shortage markers in neonatal
blood and tissue and by the lower neonatal LCPUFA status after mul-
tiple as compared to single births. For most maternal EPUFA levels,
normalization after delivery is complete within 32 weeks. However,
7ObA
DHA
200 Ratio100
% of 10th pregnancy week
150
100
50
0 10 20 30 40
Weeks of pregnancy
Fig. 1. Plasma phospholipid amounts (mg/l) of DHA (䉱) and its func-
tional shortage marker Osbond acid (ObA; 䊏) during pregnancy in percent
of their values at week 10 of gestation. The ratio between both values
([DHA/ObA] 100) represents the functional DHA status (䊉) which reduces
steadily during pregnancy.
maternal DHA concentrations are lower with each following preg-
nancy, suggesting a long-lasting effect of pregnancy on LCPUFA
metabolism or mobilization. As a result, the amount of DHA in plasma
PL of first-born neonates is higher than that of their later born siblings.
Breast-feeding compromises normalization of the maternal LCPUFA
status after delivery and is associated with a lower maternal DHA
status than bottle-feeding.
Neonatal DHA levels and head circumference are negatively
related with maternal linoleic acid consumption during pregnancy.
This indicates that for an optimum perinatal DHA status, the EPUFA
balance of the maternal diet needs to be optimized.
Maternal supplementation with EPUFA during pregnancy miti-
gates the reduction of the maternal EPUFA status and increases the
neonatal LCPUFA status. Since both EPUFA families compete with
each other, an overall increase in the maternal and, consequently,
neonatal LCPUFA status requires an increased maternal consumption
of both LCPUFA families (fig. 2).
Maternal and neonatal LCPUFA status is thought to be associ-
ated with certain pregnancy complications and certain aspects of the
8Supplementation with linoleic acid Supplementation with fish oil
n-6 fatty acids n-6 fatty acids
35.0
25.0 Control
Control
% of fatty acids
% of fatty acids
LA Fish oil
30.0 22.5
20.0
25.0
17.5
20.0 15.0
Cord vein Cord arteries Cord vein Cord arteries
7.0 n-3 fatty acids 8.0 n-3 fatty acids
% of fatty acids
% of fatty acids
7.0
6.0
6.0
5.0
5.0
4.0 4.0
Cord vein Cord arteries Cord vein Cord arteries
Fig. 2. Maternal supplementation during pregnancy with linoleic acid
(LA) increases the fetal n-6 status at the expense of the n-3 status, whereas
supplementation with fish oil increases the fetal n-3 status at the expense of the
n-6 PUFA. Fatty acid concentrations (% of fatty acids) in cord venous and arte-
rial tissue phospholipids of neonates born to control or supplemented mothers.
pregnancy outcome, but data are not consistent. Evidence that a low
maternal DHA status is associated with a high risk of post partum
depression is becoming rather strong, however.
The growth spurt of the developing brain takes place during late
pregnancy and early extrauterine life. However, no significant associa-
tions were observed between the perinatal DHA or AA availability to
infants and their cognitive performance at 3.5 and 7 years of age. On
the other hand, movement quality (which is another marker of brain
maturity and has been shown to be a significant predictor of later
developmental problems like attention deficit hyperactivity disorder)
was significantly and positively related to DHA status at birth, as was
visual acuity and speed of visual information processing. None of
the functional outcome measures were significantly associated with
neonatal AA levels or with DHA or AA concentrations at follow-up.
Concentrations in cord plasma PL of -linolenic acid (GLA; 18:3n-6)
and dihomo--linolenic acid (DGLA; 20:3n-6) were negatively related to
plasma triglyceride levels, fasting insulin concentrations, and calculated
insulin resistance at 7 years of age. In addition, GLA concentrations at
9birth were negatively related to body fatness and plasma leptin concen- trations at age 7 years. This suggests that a low intrauterine availability of (D)GLA could be one of the factors predisposing individuals to obe- sity and insulin resistance later in life. If confirmed, maternal (D)GLA supplementation during pregnancy to improve the fetal GLA status may present a simple and safe way to lower the risk of newborns for later insulin resistance and obesity. 10
Dietary Essential Fatty Acids in
Early Postnatal Life: Long-Term
Outcomes
R i c a r d o U a u y, C e c i l i a R o j a s , A d o l f o L l a n o s
and Patricia Mena
Introduction
The formation of long-chain polyunsaturated fatty acids (LCPs)
from the parent essential fatty acids (EFAs) in early life is limited, thus
infants are dependent on the exogenous provision of LCPs from human
milk or supplemented formula. LCPs are structural components of all
tissues, they are indispensable for cell membrane synthesis and for the
function of key organelles such as mitochondria, endoplasmic reticu-
lum and synaptic vesicles, and also for membrane receptors and signal
transduction systems. The brain, retina and other neural tissues are
particularly rich in LCPs; if diet is deficient in LCPs during early
life, neural structural development and function is affected. LCPs
also serve as specific precursors for 20-carbon eicosanoid production
(prostaglandins, prostacyclins, thromboxanes, and leukotrienes).
Recently docosanoids derived from 22-carbon LCPs have been identified
and their capacity to protect neural tissue from hypoxia-reperfusion
injury characterized. Eicosanoids and docosanoids act as autocrine
and paracrine mediators. They are powerful regulators of numerous
cell and tissue functions (e.g. thrombocyte aggregation, inflammatory
reactions and leukocyte functions, cytokine release and action, vaso-
constriction and vasodilatation, blood pressure control, bronchial con-
striction, uterine contraction).
Metabolism and Dietary Requirements
The need to include linoleic acid (LA), the parent n-6 EFA in the
early diet, has been recognized for over 50 years. Over the past decades
the need to provide -linolenic acid (LNA; 18:3n-3) as a source of the
n-3 EFAs has been recognized. A need for LCPs (18-carbon chain
11length) derived from EFAs has only recently been established, based
on studies of preterm and term human infants. Animal tissues, espe-
cially the liver, can further elongate and desaturate the parent EFAs,
generating a family of compounds for the respective families. The com-
petitive desaturation of the n-3 and n-6 series by 6-desaturase is of
major significance because this is the controlling step of the pathway
leading to the formation of arachidonic acid (AA; 20:4n-6) and docosa-
hexaenoic acid (DHA; 22:6n-3) from LA (18:2n-6) and LNA (18:3n-3)
respectively, further details can be found in recent reviews. The n-6
polyunsaturated fatty acids (PUFAs) are abundant in commonly used
vegetable oils (corn, sunflower, safflower), whereas n-3 PUFAs are rel-
atively low except in soy, canola and linseed oils. Presently, most infant
formulas are designed to provide a similar fatty acid (FA) composition
to that found in mature human milk from omnivorous women. The
EFA content of human milk, especially the LCP content, will change
according to the maternal diet. The evidence indicates that in early life
18n-3 precursors are not sufficiently converted to DHA to allow bio-
chemical and functional normalcy. Thus, not only LA and LNA but DHA
and AA are now considered necessary nutrients for normal eye and
brain development in the human. Up to a few years ago, the metabo-
lism of LCPs beyond the 20-carbon step leading to the formation of
DHA was considered to be an apparently simple reaction catalyzed by
a 4-desaturase forming DHA from 22: 5n-3. Sprecher’s group after con-
ducting detailed analytical work using isotopic tracers and gas chro-
matography-mass spectrometry found evidence that in fact what was
apparently a 4-desaturase was really a 3-step pathway.
Effect of LCP Deficiency
The evidence to date indicates that human infants who receive an
inadequate supply of LCPs have altered retinal rod function, delayed
maturation of the visual cortex, and poorer auditory discrimination as
compared to the infants fed human milk or LCP-supplemented for-
mula. Some studies have also revealed altered mental development
and cognitive function. Over recent years, the role of LCPs in modu-
lating signal transduction and regulating gene expression have been
described, emphasizing the complexity of FA effects on biological
systems. Dietary FAs, especially LCPs, have potentially significant
effects in the modulation of developmental processes affecting short-
and long-term health outcomes related to growth, body composition,
mental development, immune and allergic responses, and prevalence
of nutrition-related chronic disease. Figure 1 illustrates the short-
and long-term effects of nutrients, in this case LCPs, on health
12Early diet Short-term Long-term
Neurosensory development Cognitive capacity
& education
Growth muscle/bone Immunity
Body composition Work capacity
Diabetes
Metabolic programming Obesity
CHO, lipids, proteins Cardiovascular
Other Hormone, receptor, genes disease, stroke
epigenetic Hypertension
factors Cancer
Aging
Fig. 1. Short- and long-term effects of nutrients.
outcomes related to neurodevelopment, growth and body composition
and nutrition-related chronic diseases.
Mechanisms for Biological Effects
Changes in Lipid Membrane Properties
The FA composition of structural membrane lipids can affect
membrane function by modifying overall membrane fluidity, by affect-
ing membrane thickness, by changing lipid phase properties, by spe-
cific changes in the membrane microenvironment, or by interaction of
FAs with membrane proteins. Most dietary n-3 FA-induced membrane
changes are not reflected by an overall change in membrane fluidity
but rather result in selective changes in membrane micro-domains
affecting specific functions.
Gene Expression
Over the past decade the role of LCPs in regulating gene expres-
sion has been extensively studied given the potentially of dietary FAs
to affect several developmental and metabolic processes with relevant
short- and long-term health outcomes. The mechanism for the regula-
tion of gene expression by FAs involves members of the superfamily
of nuclear receptors that function as transcription factors. Two types of
transcription factors account for the main transcriptional effects
of PUFAs, namely the peroxisome proliferator-activated receptor (PPAR)
and the hepatic nuclear factor-4a. The superfamily of nuclear receptors
also includes steroid hormone receptors, the glucocorticoid receptor,
vitamin D receptor, the thyroxine receptor, the retinoic acid receptor,
13and the retinoid receptor. The effect of LCPs on gene expression may
have profound and long-lasting implications for human health. LCPs
affect the expression of genes that regulate cell differentiation and
growth; therefore, early diet may influence structural development
of organs, as well as neurologic and sensory functions. Specifically, a
possible role of DHA on retinal and neuronal differentiation has been
proposed.
Effects Mediated by Eicosanoid and Docosanoid Production
The effect of LCPs in the early diet can modulate eicosanoid
(derived from 20-carbon FAs, AA and eicosapentaenoic acid (EPA))
and possibly docosanoid (derived from 22-carbon FAs, DHA) produc-
tion affecting multiple physiologic functions that may explain both
acute and long-term health effects. Membrane phospholipases liberate,
depending on the nature of the dietary supply, AA and/or EPA from
phospholipids. Thus, through the action of cycloxygenase or lipoxyge-
nase, LCPs form eicosanoid products (prostaglandins, prostacyclins,
thromboxanes and leukotrienes) that play key roles in modulating
inflammation, cytokine release, immune response, platelet aggrega-
tion, vascular reactivity, thrombosis, and allergic phenomenon. The
balance between AA (n-6) and EPA (n-3) in biological membranes
is regulated based on dietary supply and tissue-specific factors. The
n-6/n-3 ratio in phospholipids modulates the balance between
prostanoids of the 2 and 3 series derived from AA and EPA, respec-
tively. The n-3/n-6 balance affects health outcomes modifying the
severity, progression and recovery from diseases that are mediated by
prostanoids.
Growth and Body Composition
The classic LA deficit is accompanied by growth failure. In fact,
recent studies suggest that if the LA:LNA ratio is very low, LA may be
insufficient to support normal growth. Observational studies from
malnourished populations are not conclusive of EFA deficiency as
evidenced by plasma and red blood cell FA composition. Studies in
Sudan compared EFA blood levels in normal children under 4 years of
age to those suffering from marasmic protein energy malnutrition or
Kwashiorkor. The n-6 EFAs, including LA and AA, were significantly
lower in plasma phospholipids and cholesterol esters. Relative to con-
trols, there was a corresponding increase in the non-EFAs such as oleic
(18:1n-9) in the malnourished. No differences were found for the n-3
series EFAs. Studies from rural China, where soy oil is consumed and
diets are low in total protein and energy, human milk has a low DHA
14content (0.2%) with a AA to DHA ratio of 2.4 to 3.1 revealing a rela-
tionship between growth and the EFA content of human milk. At 3
months of age weight gain was significantly related to the AA content
of human milk (r 0.46) while linear growth was related to DHA con-
tent (r 0.80). This issue has recently been addressed by conducting
a meta-analysis of all available studies in both term and preterm
infants. Randomized trials involving 1,680 term infants and 1,647
preterm infants met criteria for inclusion in the meta-analysis. Term
infants allocated to any type of LCP supplementation were not statis-
tically different at 4 or 12 months of age. A subgroup analysis of infants
allocated to an n-3 LCP alone group (no AA) also showed no effect of
supplementation on any growth parameter at either 4 or 12 months of
age. Preterm trials provided raw data for 1,624 preterm infants; the
growth of preterm infants was explored through the generation of
growth curves of infants in control, n-3 LCP AA treatment and n-3
LCP alone treatment. No difference in the pattern of growth for weight,
length or head circumference was noted. A multiple regression analy-
sis to assess the determinants of growth in these infants at 40, 57 and
92 weeks post-menstrual age found a significant effect of size at birth,
gender and the actual age of assessment. The overall influence of
LCPUFA supplementation accounted for less than 3% of the variance
in growth.
Allergic and Inflammatory Responses
Asthma is considered a good example of allergic disease. The
main features of obstructive airway disease are related to alterations
in the airway and air trapping in the lung. Airway obstruction due to
bronchoconstriction and increased mucous production leads to air
trapping and loss of gas exchange. Virtually all these features corre-
spond to the known actions of AA metabolites, prostanoids and
leukotrienes C4, D4, E4. Moreover, leukotrienes have been postulated
to amplify oxygen radical-mediated lung injury by inducing chemotac-
tic mediators, which attract polymorphonuclear cells and increase
vascular permeability. These findings indicate an important role for
inflammatory mediators in the pathophysiology of this disease.
Neurologic and Sensory Development
The effect of LCPs on brain development was the topic of a recent
meeting published as a supplement to the Journal of Pediatrics
(October 2003), thus we will only discuss selected aspects. Preterm
Infants are considered particularly vulnerable to EFA deficiency given
15the virtual absence of adipose tissue at birth, the possible immaturity of
the FA elongation/desaturation pathways and the inadequate LNA and
DHA intake provided by formula. Over the past decades, several stud-
ies have examined effect of LCPs on plasma and tissue lipid composi-
tion, retinal electrophysiological function, on the maturation of the
visual cortex as measured by pattern reversal visual evoked potentials
and behaviorally by the forced-choice preferential looking visual acuity
response. The largest collaborative multicenter study of a large group
of preterm infants included 450 preterm infants fed LCPUFA formula
supplemented with different AA and DHA sources: fish oil and egg
phospholipids or fungal oil. Significant differences were found in sweep
visual evoked potentials at 6 months favoring the LCP-supplemented
formula group as compared to the control formula group.
Term Infants
The question of whether healthy full-term infants need LCPUFAs
in their formula has received great attention over the past decade. The
finding of lower plasma DHA concentrations in infants fed formula
compared to that of breast-fed infants suggests that formulas provide
insufficient LNA or that chain elongation-desaturation enzymes are not
sufficiently active during early life to support optimal tissue accretion
of DHA. Full-term infants also appear to be dependent on dietary DHA
for optimal functional maturation of the retina and visual cortex.
Several studies have demonstrated significant effects of dietary
LCPUFAs on visual maturation in the first 4 months of life but in most
cases the delayed response becomes normal at 6 months or at most by
1 year of age. The duration and reversibility of diet-induced effects are
important considerations in evaluating diet-induced changes in devel-
opmental outcomes. There may be transient effects that reflect the
acceleration or the slowing of a maturational process with a fully nor-
mal final outcome. This is of special relevance during the first few
months of life when visual maturation is progressing rapidly.
Brain Injury (Ischemia and Hemorrhage)
Hypoxic and hemorrhagic insults to the neonatal brain are not
infrequent, especially in preterm infants. Most ischemic injury occurs
prior to or at birth; intraventricular hemorrhage is detected mostly in
the first hours of life. Thus, it is difficult to propose a nutritional pre-
vention of these conditions, unless the intervention is given to the
mother. Whether maternal dietary LCP supply could play a role in
defining the occurrence and severity of brain hemorrhagic injury is not
known. Crawford has speculated, based on limited data from animal
16HDL
OX-LDL
Arterial wall
Macrophage
Inflammation atherogenesis
LDL
PPAR /
lipase
FA
VLDL
VLDL Adipocyte differentiation
Lipogenesis and storage
PPAR
FA synthesis and oxidation
Lipoprotein synthesis
FA oxidation
PPAR ()
PPAR / ()
Fig. 2. Molecular effects (PPARs) of LCP supply on energy and lipid
metabolism.
observations, that poor maternal dietary LCP supply could be respon-
sible for the high prevalence of hemorrhagic injury observed in small
preterm neonates. In addition the possibility of dietary modulation of
cytokine release should be considered, since cytokines mediate much
of the vascular and tissue damage observed during and after reperfu-
sion. Evidence of a specific role of inflammation and cytokine release
in periventricular leukomalacia has been proposed. Selected
docosanoids derived from DHA, such as 10,17S-docosatriene, exert a
potent anti-inflammatory role. These DHA derivatives inhibit leuko-
cyte infiltration, inflammatory gene expression and cytokine produc-
tion in hypoxia-reperfussion injury, decreasing by half the damage
induced by arterial occlusion if 10,17S-docosatriene is infused during
the recovery from hypoxia. The effect of early lipid supply on brain
injury deserves further research.
Nutrition-Related Chronic Disease (Obesity,
Diabetes, Hypertension and Dyslipidemias)
LCPs affect the expression of genes subject to transcriptional
activation by PPARs, and thus may contribute to the regulation of fuel
oxidation, lipid and glucose metabolism, fuel partitioning, adipocyte
growth and maturation. The long-term effects of LCP supply on
nutrition-related chronic diseases, in addition to their effects on gene
expression with direct bearings on glucose and lipid metabolism, and
on adipose tissue growth and maturation are depicted in figure 2. The
increased risk for nutrition-related chronic diseases in infants born
with intrauterine growth restriction is presently being recognized, and
17this is likely due to the increased risk of metabolic syndrome (insulin
resistance, hypertension, visceral obesity and cardiovascular disease)
in later life.
Conclusions
The data from animal studies and the preliminary data from
human studies presented in this review suggest that the supply of
essential lipids in early life may condition not only the short-term
effects related to growth, neurosensory maturation and mental devel-
opment, but could also contribute in determining the susceptibility to
allergic disease and immune responses, condition the severity of
inflammatory responses, and possibly modify the risk for diet-related
chronic disease linked to the metabolic syndrome (hypertension,
insulin resistance, obesity, and cardiovascular disease). The long-term
clinical significance of the experimental findings discussed is hard to
determine from the existing data, additional information from long-
term follow-up of controlled feeding studies is needed before this issue
can be resolved.
18Nutrient-Induced Maternal
Hyperinsulinemia and Metabolic
Programming in the Progeny
Mulchand S. Patel, Malathi Srinivasan and
Suzanne G. Laychock
Altered early life nutritional experiences, both during fetal devel-
opment and in the immediate postnatal period, are now recognized to
play an important role in the onset of adult-onset degenerative diseases
via the process of metabolic programming. Metabolic programming is
the phenomenon whereby an altered nutritional experience (overlap-
ping with the critical window of organogenesis during early periods in
life) by permanently modifying metabolic processes in the organism
predisposes it for the onset of diseases later in life. Data from several
epidemiological studies and results from various animal models pro-
vide convincing evidence for this concept. In animal studies, the con-
sequences of maternal protein restriction, total caloric restriction and
diabetes during pregnancy have been extensively investigated in the
progeny. Fetal development under such conditions programs the prog-
eny for adult-onset diseases via metabolic adaptations in islets and
hypothalamus with subsequent modulations at the level of peripheral
tissues, favoring the progression of metabolic diseases.
Studies from our laboratory have demonstrated that, in addition
to the effect of over- or undernutrition during early periods in life, the
immediate postnatal period is also vulnerable to changes in the quality
of nutrition via caloric redistribution without a change in the total
caloric availability. In our high-carbohydrate (HC) rat model, neonates
are artificially reared on a HC milk formula for a period of 3 weeks
from day 4 to 24 and then weaned onto laboratory chow. The HC milk
formula is isocaloric and isonitrogenous to rat milk, with the only dif-
ference being a switch in the major source of calories to carbohydrate
in the HC milk formula compared to fat in rat milk. This caloric redis-
tribution in the HC formula in the neonatal life of rats results in the
immediate onset of hyperinsulinemia, its persistence into adulthood
19Hyperinsulinemia
Biochemical, molecular and cellular adaptations in islets
Lab chow
Increase in Obesity
Birth weight gain
High CHO
Prenatal Suckling Post-weaning
0 22 4 12 24 55 75 100
a Postnatal age (days)
Hyperinsulinemia
Biochemical and molecular adaptations in islets
Birth
Increase in Obesity
Lab chow weight gain
Maternal HI
Prenatal Suckling Post-weaning
0 22 12 24 28 55 75 100
b Postnatal age (days)
Fig. 1. a Summary of the metabolic responses (inclusive of both immedi-
ate and long-term adaptations) in rats artificially reared on a high-carbohydrate
(HC) milk formula from postnatal day 4 to 24. High CHO High-carbohydrate
milk formula. b Summary of the metabolic responses observed in the immedi-
ate post-weaning as well as in adulthood of the HC progeny, acquired and
expressed due to fetal development in the HC female (female rats raised on the
HC formula up to postnatal day 24). Maternal HI Maternal hyperinsulinemia.
and the onset of obesity later in life (fig. 1a). An interesting observa-
tion from studies on this model is that metabolic processes pro-
grammed in females during the period of dietary modulation are not
only expressed in the adulthood of the same generation but are trans-
mitted to the next generation without the progeny having to undergo
an altered dietary experience in their immediate postnatal period. We
thus have a unique model for maternal programming of the progeny,
wherein the HC dietary experience in the female in its neonatal life
provides an altered intrauterine environment for fetal development
(characterized by chronic hyperinsulinemia and obesity without
changes in plasma glucose levels) to set up a vicious cycle of trans-
mission of the HC phenotype to the progeny. Although the HC progeny
do not develop hyperinsulinemia during the suckling period, immedi-
ately upon weaning to laboratory chow there is an increase in their
plasma insulin levels and subsequently chronic hyperinsulinemia
ensues (fig. 1b). There is no difference in the body weight gain in the
20HC progeny up to postnatal day 55, but thereafter there is an increase
in their body weights and they are distinctly obese by postnatal day
100. In several aspects the metabolic processes programmed and the
mechanisms supporting this phenomenon are similar between the HC
mothers and their progeny.
The results from our studies demonstrate that a change in the
quality of nutrition via caloric redistribution in neonatal life can prime
the organism not only for the onset of metabolic diseases in its own
adulthood, but via the female can set up a cycle of transmission of this
potential to the progeny. Based on these observations one wonders if
altered dietary practices in infants may, in part, contribute to the epi-
demic of metabolic diseases encountered in the Western world in
recent times.
21Maternal Malnutrition and
the Risk of Infection in
Later Life
Sophie E. Moore, Andrew C. Collinson,
P a Ta m b a N ’ G o m a n d A n d r e w M . P r e n t i c e
In rural Gambia, individuals born during the nutritionally debili-
tating annual ‘hungry’ (wet) season have an odds ratio of premature
adult mortality up to 10 times greater than those born during the ‘har-
vest’ (dry) season (fig 1) [1]. Since the majority of these premature
adult deaths are from infections or infection-related diseases, it has
been hypothesized that an insult occurring in early life and linked to
the season of birth is disrupting immune development and resulting in
impaired immune function, increased susceptibility to infections, and
premature mortality later in life.
This hypothesis is supported by several pieces of evidence from
the literature. The principle components of the human immune system
develop in fetal life [2], and it is plausible that fetal nutrient depri-
vation could lead to a more permanent immunological insult than
a similar degree of undernutrition experienced in postnatal life.
Furthermore, maternal malnutrition has been observed to have
greater effects on thymic and lymphoid tissue development than on
other organs [3, 4], and such deficits in organ growth and development
occurring in utero appear more serious and long-lasting than those
caused by later malnutrition [5]. Some evidence exists to suggest that
low birth weight babies may have sustained impairment of immune
competence as infants and children [6–8], and increased susceptibil-
ity, following intrauterine growth retardation, to infections in child-
hood is also well known [9]. However, despite this evidence,
mechanisms to explain any of these observations are not described.
We are therefore attempting to define the biological mechanisms
underlying the early-life programming of immune function through a
series of ongoing studies, and some preliminary findings from these
studies are detailed below.
22100
OR 10.3 (P 0.00002)
90
OR 3.7 (P 0.000013)
80
Survivors (%)
70
Harvest
60
Hungry
50
40
0 10 20 30 40 50
Age (years)
Fig. 1. Kaplan-Meier survival plots by season of birth. n 3,162 (2,059 alive
and 1,103 dead). OR Odds ratio. Adapted from Ferguson et al. [7].
In The Gambia, a prospective birth-cohort study of neonatal
immune function and development has demonstrated seasonal effects
on thymic size (measured by ultrasonography), with the smallest thy-
muses found in infants both born and measured in the hungry season,
regardless of infant weight (fig. 2) [10]. This difference in thymic size
is greatest at 8 weeks of age, an age at which infants in this commu-
nity are exclusively breast-fed, have good weight, and have minimal
incidence of active infections. This finding could suggest that breast
milk has a specific trophic effect on the thymus. Indeed, further work
in this cohort has demonstrated that levels of the cytokine IL-7 were
significantly lower in samples of breast milk collected in the hungry
season compared to samples from the harvest season (79 vs.
100 pg/ml, p 0.02) [11]. This finding suggests that improved mater-
nal nutrition during the harvest season could influence certain factors
in breast milk, with the consequent improvement in thymic size and
function.
We have also investigated the association between size at birth
and response to vaccination (purified Vi surface polysaccharide
extracted from Salmonella typhi and rabies vaccines) in a cohort of
257 adults (mean age 29.4 years; 146 males) born in an urban slum in
Lahore, Pakistan during 1964–1978 [12]. Vaccine responses were not
consistently associated with contemporary variables (month of study,
gender, current age, indicators of wealth). The response to typhoid
vaccination was positively related to birth weight (anti-Vi IgG
2315
Wet minus dry (% difference)
10
5
0
5
10
15
1 8 24 52
a Postnatal age (weeks)
5
Wet minus dry (% difference)
0
5
10
15
1 8 24 52
b Postnatal age (weeks)
Fig. 2. Percentage (standard error) difference in mean thymic index
between hungry and harvest season births (a), and hungry and harvest season
measurements (b), adjusted for gender, gestation and current weight. Adapted
from Collinson et al. [Acta Paediatr 2003;92:1014–1020].
p 0.031; anti-Vi IgM p 0.034). The response to the rabies vaccine,
however, was not associated with birth weight. The contrasting effects
on typhoid and rabies responses observed in this study seem to sug-
gest that the antibody generation to polysaccharide antigens, which
has greater B-cell involvement, has been compromised by fetal growth
retardation. Ongoing research in this and other cohorts aims to eluci-
date the mechanisms involved.
All the key studies within this area of research have so far focused
on a limited number of cohorts from specific countries where infectious
diseases still prevail as the leading cause of mortality. However, if true,
then this hypothesis clearly has relevance for many more sectors of
24Table 1. Immune function in relation to birth weight, season of birth and
maternal supplementation status in 6- to 10-year-old Gambian children
Measure Birth weight Season of birth Supplementation
status1
CMI2 NS NS Increased response in
intervention children
(p 0.006)2
Pneumococcal NS NS NS
vaccination
Rabies NS NS Increased response
vaccination in control children
(1st dose p 0.024,
2nd dose p 0.005)2
Intestinal NS NS NS
permeability
Salivary NS Increased NS
sIgA2 levels response
in hungry
season births
(p 0.0018)
CMI Cell-mediated immune response; SIgA secretory immunoglobulin A.
Table adapted from Moore et al. [Am J Clin Nutr 2001;74:840–847].
1
Maternal dietary supplement during pregnancy (intervention) or during lacta-
tion (control).
2
Significantly different after adjustment for age, sex, month of study, and current
weight-for-age z-score.
society, and demonstrates the necessity for continued research into the
key factors that impact on the development of the human immune sys-
tem during fetal and early postnatal life.
References
1 Moore SE, Cole TJ, Poskitt EME, et al: Season of birth predicts mortality in
rural Gambia. Nature 1997;388:434.
2 Hayward AR: Development of immune responsiveness; in Falkner F, Tanner JM
(eds): Human Growth. 1. Principles and Prenatal Growth. New York, Plenum
Press, 1978, pp 593–607.
3 Winick M, Noble A: Cellular response in rats during malnutrition at various
ages. J Nutr 1966;89:300–306.
4 Owens JA, Owens PC: Experimental fetal growth retardation: Metabolic
and endocrine aspects; in Gluckman PD, Johnston BM, Nathanielsz PW (eds):
Advances in Fetal Physiology. Ithaca, Perinatology Press, 1989, pp 263–286.
255 Beach RS, Gershwin ME, Hurley LS: Gestational zinc deprivation in mice:
Persistence of immunodeficiency for three generations. Science 1982;218:
469–471.
6 Chandra RK: Fetal malnutrition and postnatal immunocompetence. Am J Dis
Child 1975;129:450–454.
7 Ferguson AC, Lawlor GJ, Neuman GG, et al: Decreased rosette forming lym-
phocytes in malnutrition and intra-uterine growth retardation. J Pediatr 1974;
85:717–723.
8 Victora CG, Smith PG, Vaughan JP: Influence of birth weight on mortality from
infectious diseases: A case control study. Pediatrics 1988;81:807–811.
9 Ashworth A: Effects of intrauterine growth retardation on mortality and mor-
bidity in infants and young children. Eur J Clin Nutr 1998;52:S34–S42.
10 Collinson AC, Moore SE, Cole TJ, Prentice AM: Birth season and environ-
mental influences on patterns of thymic growth in rural Gambian infants. Acta
Paediatr 2003;92:1014–1020.
11 N’Gom PT, Collinson AC, Pido-Lopez J, et al: Improved thymic function in exclu-
sively breast-fed babies is associated with higher breast milk IL-7. Am J Clin
Nutr 2004; in press.
12 Moore SE, Jalil F, Ashraf R, et al: Birth weight predicts response to vaccina-
tion in adults born in an urban slum in Lahore, Pakistan. Am J Clin Nutr 2004;
in press.
26Size and Body Composition
at Birth and Risk of Type-2
Diabetes: A Critical Evaluation
of ‘Fetal Origins’ Hypothesis
for Developing Countries
C . S . Ya j n i k
There is a rapidly increasing epidemic of type-2 diabetes in India and
other developing countries. In addition to genetic susceptibility,
intrauterine nutrition may have an etiological role in this epidemic. The
‘thrifty phenotype’ hypothesis was based on the demonstration of an
inverse relation between birth weight and type-2 diabetes in elderly
Europid populations. People in the Indian subcontinent have faced
undernutrition for many generations, and Indian babies are among the
smallest in the world. However, the epidemic is of recent origin, and
more common in urban than in rural people despite higher birth weight.
The relationship between birth weight and type-2 diabetes may be
U-shaped and dependent on the body composition of the fetus. Adiposity
of the neonate may be the most relevant risk factor for risk of type-2 dia-
betes. For a given size, Indian neonates, children and adults have a higher
body fat percent (adiposity) and higher visceral fat compared to other
populations. In Mysore, South India, there was no relation between birth
weight and later diabetes but a higher ponderal index was predictive.
This is contrary to the findings in the Europid populations.
Neonatal size and body composition are influenced by parental
size, maternal food intake, physical activity and concentrations of cir-
culating nutrients and metabolites. Maternal insulin resistance and
hyperglycemia have a substantial influence on the adiposity of the
fetus. As yet there are no prospective human studies to demonstrate
an association between maternal nutrition in pregnancy and offspring
risk of type-2 diabetes. The Pune Maternal Nutrition Study will provide
some of this information for the first time. Preliminary findings in
6-year-old children suggest that the relationship may be different than
expected from retrospective studies in Europid populations.
27Cardiovascular Diseases in
Survivors of the Dutch Famine
O t t o P. B l e k e r, Te s s a J . R o s e b o o m , A n i t a C . J .
Ravelli, Gert A. van Montfrans, Clive Osmond,
a n d D a v i d J . P. B a r k e r
The Dutch famine was a 5- to 6-month period of extreme shortage
of food that affected all people in the west of the Netherlands, a previ-
ously well-nourished population. The official daily rations for an adult
in Amsterdam – which had gradually decreased from about 1,800 cal in
December 1943 to 1,400 cal in October 1944 – fell abruptly to below
1,000 cal in late November 1944. During the peak of the famine from
December 1944 to April 1945, the rations varied between 400 and
800 cal. After the liberation in early May, the rations improved rapidly
to over 2,000 calories in June 1945.
To assess the effect that prenatal exposure to maternal malnutri-
tion has on coronary heart disease (CHD) in people born around the
time of the Dutch famine, we studied the prevalence of CHD (defined
as the presence of angina pectoris according to the Rose questionnaire,
Q waves on the ECG, or a history of coronary revascularization)
among singletons born alive between November 1943 and February
1947 for whom we had detailed birth records. We compared the preva-
lence of CHD in those exposed to famine in late gestation (n 120), in
mid gestation (n 108), or in early gestation (n 68) with those born
in the year before the famine or those conceived in the year after the
famine (non-exposed subjects, n 440). The CHD prevalence was
higher in those exposed in early gestation than in non-exposed people
(8.8 versus 3.2%, odds ratio adjusted for sex 3.0, 95% confidence inter-
val 1.1–8.1). The CHD prevalence was not increased in those exposed
in mid gestation (0.9%) or late gestation (2.5%). The CHD effect of
exposure to famine in early gestation was independent of birth weight
(adjusted odds ratio 3.2, 95% confidence interval 1.2–8.8).
Previously, we have found that people exposed to famine in late
gestation had a reduced glucose tolerance at age 50, whereas exposure
to famine in early gestation was linked to higher levels of obesity in
28women and more atherogenic lipid profiles in both men and women.
Blood pressure was not affected by exposure to famine although it was
strongly negatively associated with size at birth. These distinct rela-
tions between prenatal exposure to famine and fetal growth on the one
hand and CHD and its risk factors on the other, suggest that an adverse
fetal environment contributes to several aspects of cardiovascular risk
in adult life, but that the effects very much depend on its timing during
gestation.
We would like to conclude that maternal conditions before and
during pregnancy are of main importance with respect to the adult
health of their offspring. If poor maternal conditions proceed through-
out pregnancy, lower birth weights are observed and will be found to
be related to impaired adult health. If poor maternal conditions only
exist around conception and in early pregnancy, especially CHD is
found at adult age. If poor conditions are especially present in late
pregnancy, effects on blood pressure and glucose tolerance are found.
However, if lower birth weights occur in healthy mothers with a nor-
mal nutritional status, due to limitations set by the placenta in special
cases like twins, adult health is not impaired at all. Obviously, in these
twin newborns the early organ development and the tuning of
endocrine and other systems essential for adult health are normal and
the placental limitations met in the second half of pregnancy do not
affect these essential developmental systems. Therefore, the observed
difference with respect to adult disease found in the children exposed
late to the Dutch famine and not found in twin children is of very spe-
cial interest and does not oppose the fetal origins hypothesis. Very
likely maternal malnutrition at conception and during early gestation
contributes to the occurrence of CHD in the offspring. Useful inter-
ventions to prevent disease in adulthood should not only aim at the
nutritional condition of pregnant women, but also at the nutritional
condition before pregnancy and at the very start of pregnancy, which
are much more meaningful for the nutritional status in childhood and
in young adults.
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