Nestlé Nutrition Workshop Series
Pediatric Program Volume 55
The Impact of
Maternal Nutrition
on the Offspring
Information for the medical profession only
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© 2004, Nestec Ltd., Vevey, Switzerland
Nestlé 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
ii
28
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
iii
Foreword
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 fundamental ones; most knowledge derives from animal studies. The intention of
this workshop was to learn more about the effects of maternal nutrition on fetal growth, metabolic programming, the requirements of
energy and various nutrients as well as the effects of under- and overnutrition 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 speakers. 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 hospitality. 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
iv
Maternal 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 concerning 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 supplementation 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 randomized trials.
1
Nutrients 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 important 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 maternal 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,
2
Thymidylate
Folate
DNA
Methylation
Homocysteine
Maternal
diet
Vit A
Mitosis
ret
RA
nm
Gene
regulation
RXR/RAR
Early brain
development
Transthyretin
Iodine
TR
RXR/TR
Late brain
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-methylD-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 retinolbinding proteins on the plasma membrane; the cytoplasmic retinolbinding 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,
3
fetus and neonate. By altering their expression, both hypo- and hypervitaminosis 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 wellknown 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 developmental 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.
4
Energy 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 expenditure 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 metabolic 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. Freeliving 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
5
weight-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 inadequate 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 morbidity and mortality, and a range of adaptations and developmental
changes which may lead to permanent structural and metabolic alterations 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 overweight 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 pregnancy 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 sufficient but not excessive food to meet the substantial energy demands
of pregnancy.
6
Essential Fatty Acids during
Pregnancy: Impact on Mother
and Child
Gerard Hornstra
Essential fatty acids (EFAs) and their longer chain, more unsaturated 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 maternal LCPUFAs during pregnancy. For the most important LCPUFAs,
DHA and arachidonic acid (AA; 20:4n-6), this decrease is more pronounced the higher the neonatal birth weight. Nonetheless, in term
neonates the DHA and AA contents of umbilical plasma PL are negatively related to birth weight. This suggests that the maternal-to-fetal
fatty acid transfer is limited, as a result of which the neonatal essential PUFA status may not be optimal. This latter suggestion is supported by the high amounts of LCPUFA shortage markers in neonatal
blood and tissue and by the lower neonatal LCPUFA status after multiple as compared to single births. For most maternal EPUFA levels,
normalization after delivery is complete within 32 weeks. However,
7
ObA
DHA
Ratio100
% of 10th pregnancy week
200
150
100
50
0
10
20
30
40
Weeks of pregnancy
Fig. 1. Plasma phospholipid amounts (mg/l) of DHA (䉱) and its functional 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 pregnancy, 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 mitigates 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 associated with certain pregnancy complications and certain aspects of the
8
Supplementation with linoleic acid
25.0
7.0
25.0
Control
Fish oil
22.5
20.0
17.5
15.0
Cord vein
Cord arteries
Cord vein
n-3 fatty acids
6.0
5.0
4.0
% of fatty acids
30.0
20.0
% of fatty acids
Control
LA
n-6 fatty acids
8.0
% of fatty acids
% of fatty acids
35.0
Supplementation with fish oil
n-6 fatty acids
Cord vein
Cord arteries
Cord arteries
n-3 fatty acids
7.0
6.0
5.0
4.0
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 arterial 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 associations 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
9
birth were negatively related to body fatness and plasma leptin concentrations at age 7 years. This suggests that a low intrauterine availability
of (D)GLA could be one of the factors predisposing individuals to obesity 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 reticulum 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, vasoconstriction and vasodilatation, blood pressure control, bronchial constriction, 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
11
length) derived from EFAs has only recently been established, based
on studies of preterm and term human infants. Animal tissues, especially the liver, can further elongate and desaturate the parent EFAs,
generating a family of compounds for the respective families. The competitive 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 docosahexaenoic 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 relatively 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 biochemical 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 metabolism 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 conducting detailed analytical work using isotopic tracers and gas chromatography-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 formula. Some studies have also revealed altered mental development
and cognitive function. Over recent years, the role of LCPs in modulating 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 shortand 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 shortand long-term effects of nutrients, in this case LCPs, on health
12
Early diet
Short-term
Neurosensory development
Growth muscle/bone
Body composition
Other
epigenetic
factors
Metabolic programming
CHO, lipids, proteins
Hormone, receptor, genes
Long-term
Cognitive capacity
& education
Immunity
Work capacity
Diabetes
Obesity
Cardiovascular
disease, stroke
Hypertension
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 affecting membrane thickness, by changing lipid phase properties, by specific 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 expression 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 regulation 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,
13
and 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) production 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 lipoxygenase, LCPs form eicosanoid products (prostaglandins, prostacyclins,
thromboxanes and leukotrienes) that play key roles in modulating
inflammation, cytokine release, immune response, platelet aggregation, 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, respectively. 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 controls, 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
14
content (0.2%) with a AA to DHA ratio of 2.4 to 3.1 revealing a relationship 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 content (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 statistically 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 analysis 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 correspond 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 chemotactic 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
15
the 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 studies have examined effect of LCPs on plasma and tissue lipid composition, 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 developmental outcomes. There may be transient effects that reflect the
acceleration or the slowing of a maturational process with a fully normal 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 prevention 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
16
HDL
OX-LDL
Macrophage
Arterial wall
Inflammation atherogenesis
PPAR /
LDL
lipase
FA
VLDL
VLDL
FA synthesis and oxidation
Lipoprotein synthesis
PPAR ()
Adipocyte differentiation
Lipogenesis and storage
PPAR FA oxidation
PPAR /
()
Fig. 2. Molecular effects (PPARs) of LCP supply on energy and lipid
metabolism.
observations, that poor maternal dietary LCP supply could be responsible 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 reperfusion. 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 leukocyte infiltration, inflammatory gene expression and cytokine production 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
17
this 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 development, 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 longterm follow-up of controlled feeding studies is needed before this issue
can be resolved.
18
Nutrient-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 development 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 (overlapping 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 provide convincing evidence for this concept. In animal studies, the consequences 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 progeny 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 difference being a switch in the major source of calories to carbohydrate
in the HC milk formula compared to fat in rat milk. This caloric redistribution in the HC formula in the neonatal life of rats results in the
immediate onset of hyperinsulinemia, its persistence into adulthood
19
Hyperinsulinemia
Biochemical, molecular and cellular adaptations in islets
Lab chow
Birth
High CHO
Prenatal
a
0
Suckling
22 4
12
Increase in
weight gain
Obesity
Post-weaning
24
55
Postnatal age (days)
75
100
Hyperinsulinemia
Biochemical and molecular adaptations in islets
Birth
Increase in
weight gain
Lab chow
Obesity
Maternal HI
Prenatal
0
b
Suckling
22
12
Post-weaning
24 28
55
75
100
Postnatal age (days)
Fig. 1. a Summary of the metabolic responses (inclusive of both immediate 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 immediate 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 observation from studies on this model is that metabolic processes programmed in females during the period of dietary modulation are not
only expressed in the adulthood of the same generation but are transmitted 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 transmission of the HC phenotype to the progeny. Although the HC progeny
do not develop hyperinsulinemia during the suckling period, immediately 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
20
HC 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 epidemic of metabolic diseases encountered in the Western world in
recent times.
21
Maternal 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 debilitating annual ‘hungry’ (wet) season have an odds ratio of premature
adult mortality up to 10 times greater than those born during the ‘harvest’ (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 deprivation 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 susceptibility, following intrauterine growth retardation, to infections in childhood 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.
22
100
OR 10.3 (P 0.00002)
Survivors (%)
90
OR 3.7 (P 0.000013)
80
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 thymuses 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 community 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 maternal 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
23
Wet minus dry (% difference)
15
10
5
0
5
10
15
1
a
8
24
52
Postnatal age (weeks)
Wet minus dry (% difference)
5
0
5
10
15
b
1
8
24
52
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 suggest 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 elucidate 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
24
Table 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
Pneumococcal
vaccination
Rabies
vaccination
NS
NS
Increased response in
intervention children
(p 0.006)2
NS
NS
NS
Intestinal
permeability
Salivary
sIgA2 levels
NS
NS
NS
Increased
response
in hungry
season births
(p 0.0018)
Increased response
in control children
(1st dose p 0.024,
2nd dose p 0.005)2
NS
NS
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 lactation (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 system during fetal and early postnatal life.
References
1
2
3
4
Moore SE, Cole TJ, Poskitt EME, et al: Season of birth predicts mortality in
rural Gambia. Nature 1997;388:434.
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.
Winick M, Noble A: Cellular response in rats during malnutrition at various
ages. J Nutr 1966;89:300–306.
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.
25
5
6
7
8
9
10
11
12
26
Beach RS, Gershwin ME, Hurley LS: Gestational zinc deprivation in mice:
Persistence of immunodeficiency for three generations. Science 1982;218:
469–471.
Chandra RK: Fetal malnutrition and postnatal immunocompetence. Am J Dis
Child 1975;129:450–454.
Ferguson AC, Lawlor GJ, Neuman GG, et al: Decreased rosette forming lymphocytes in malnutrition and intra-uterine growth retardation. J Pediatr 1974;
85:717–723.
Victora CG, Smith PG, Vaughan JP: Influence of birth weight on mortality from
infectious diseases: A case control study. Pediatrics 1988;81:807–811.
Ashworth A: Effects of intrauterine growth retardation on mortality and morbidity in infants and young children. Eur J Clin Nutr 1998;52:S34–S42.
Collinson AC, Moore SE, Cole TJ, Prentice AM: Birth season and environmental influences on patterns of thymic growth in rural Gambian infants. Acta
Paediatr 2003;92:1014–1020.
N’Gom PT, Collinson AC, Pido-Lopez J, et al: Improved thymic function in exclusively breast-fed babies is associated with higher breast milk IL-7. Am J Clin
Nutr 2004; in press.
Moore SE, Jalil F, Ashraf R, et al: Birth weight predicts response to vaccination in adults born in an urban slum in Lahore, Pakistan. Am J Clin Nutr 2004;
in press.
Size 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 diabetes. 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 circulating 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.
27
Cardiovascular 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 previously 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 malnutrition 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 prevalence 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 interval 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
28
women 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 relations 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 throughout 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 normal 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 special 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 interventions 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.
29
The Relationship between Maternal
Obesity and Adverse Pregnancy
Outcomes
D . K i m Wa l l e r a n d Tr a c y E . D a w s o n
The increase in obesity over the last three decades is of great concern because obesity is associated with an elevated risk of many types
of diseases. This chapter reviews epidemiologic studies on the effect of
maternal obesity on reproductive function, pregnancy complications,
and pregnancy outcomes.
Obese women are more likely to have irregular menstrual cycles
and to have difficulty becoming pregnant. This may be explained by the
large increase in the risk of developing polycystic ovarian syndrome
among them.
Obesity is associated with an increased risk of several pregnancy
complications. Obese women are more likely to develop gestational
diabetes compared with women who are not obese. They also have an
increased risk of having a macrosomic infant (birth weight 4,000 g).
Macrosomia is of concern because there is a risk of shoulder dystocia,
dysfunctional labor and cesarean birth among these infants. Obese
women also have an increased risk of having hypertension and
preeclampsia during their pregnancies, and increased rates of blood
loss and postoperative infection following cesarean deliveries.
Finally, maternal obesity impacts pregnancy outcome. Studies are
consistent in reporting that obese women have a 2- to 3-fold increase
in the risk of late fetal death. This may be due to the increased risk of
diabetes, hypertension and preeclampsia among obese women. In contrast, obese women and overweight women are about half as likely to
have a small-for-gestational age infant, compared with thin or underweight women. This association has been found to be independent of
weight gain during pregnancy, suggesting that caloric intake at the time
of conception and during the first trimester may play an important role
in the determining the overall growth of the fetus.
Studies of the association between maternal obesity and preterm
birth are inconsistent. More recent studies suggest that obese women
30
have no increase in the risk of preterm birth after adjusting for confounding variables such as maternal age, race and income.
Seven case-control studies and two cohort studies have found that
obese women have a 2-fold increase in the risk of having an infant with
a neural tube defect. In addition, evidence is accumulating to support
an association between maternal obesity and other birth defects; however, further research is needed. Obese women are more likely to have
high serum insulin levels and altered response to glucose tolerance
tests. Alterations in glucose tolerance have been shown to be teratogenic in women who have insulin-dependent diabetes mellitus.
Therefore, it has been proposed that the mechanism that causes the
excess of birth defects among infants of obese women is similar to the
mechanism that causes the well-established excess of major birth
defects among infants of diabetic mothers.
Studies conducted in Western countries have observed that obesity
is associated with a number of adverse reproductive outcomes. As obesity has wide-ranging metabolic effects, it seems likely – although not
proven – that obesity will also prove to be associated with adverse
reproductive outcomes among Asian populations. Currently, China has
much lower rates of obesity than the United States and other Western
countries. Thus, China should encourage programs to prevent children
and adolescents from becoming obese. Such programs may be particularly effective in China and other Asian countries because the problem
of obesity is not yet fully entrenched in these countries.
31
Special Problems of Nutrition in
the Pregnancy of Teenagers
Paul B. Pencharz
It is well established that the average birth weight of babies resulting from teenage pregnancy is lower than in those from adult women;
and the proportion which have a low birth weight (2,500 g) is greater.
These adverse pregnancy outcomes in adolescents may be due in part
to the fact that the diet must supply enough to permit maternal growth
as well as fetal growth. Clearly this matter is more of a concern in adolescents who are still capable of growth (usually those 16 years). All
of this at a time in the life cycle where maternal diet habits are less than
optimal. Adolescents may restrict their total food intake in order to
limit weight gain and thereby make their pregnant state less obvious.
In addition to concerns about macronutrients (protein and energy),
attention needs to be focussed on micronutrients and those of major
importance are folate and iron. Folate deficiency has been associated
with fetal wastage and with neural tube defects. Iron deficiency can
result in anemia and weakness.
It is now well accepted that suboptimal fetal growth is associated
with higher fetal mortality and neonatal morbidity and mortality.
Further that suitable nutrition-based interventions can substantially
improve the health of mothers and their infants. Most of the studies
to date have been conducted in adult mothers. However, there are
clear data that adolescent pregnancies especially in mothers 16 years
are at increased risk. Recognition of these issues has resulted in programs specifically designed to meet the nutritional needs of the pregnant teenager. These programs have managed to get the adolescent
mothers to take more energy and protein as well as taking micronutrient supplements and have shown a clear improvement in infant
birth weight and a reduction in low birth weight prevalence. Many
questions remain such as what is an optimal nutritional intervention
for a teenage mother. Secondly how to motivate the adolescent
mother to take the additional food to ‘both feed herself and her
unborn baby’.
32
Dietary Intervention during
Pregnancy and Allergic Disease
in the Offspring
S. Salvatore, K. Keymolen, R.K. Chandra,
a n d Y. Va n d e n p l a s
Because of its high incidence, allergic disease has become a
worldwide problem of health care. Because of the impact of allergic
disease on health care cost, interest is more focused on prevention
than on therapy, although the etiology of allergic disease and atopy is
not yet fully understood. The avoidance of contact with allergens postpones the development of allergic disease, but does not result in the
development of tolerance, which is the ultimate goal. Many studies
have focused on how to intervene in the infant to ensure the development of tolerance and to decrease the development of allergy. It has
been clearly demonstrated that some postnatal dietary, environmental
and drug interventions beyond doubt result in a decrease in some
aspects of allergic disease in at-risk groups of infants and children.
However, it is also obvious that the hoped for impact of postnatal intervention studies could have been larger.
The bottom line of consensus is limited. Agreement exists on the
fact that the etiology of allergic disease is multifactorial, with many
variables contributing to the final (absence of) clinical expression of
atopic disease. Three breeding grounds are needed to develop allergic
disease: the appropriate genetic background; contact with the allergen(s), and environmental factors. Timing and dosing of the contact
with the allergen(s) are of major importance. Contact with allergens
occurs not only during postnatal life, but also perinatally and prenatally. To date, little attention has been given to sensitization during prenatal life, although it is obvious that the fetus is in contact with
multiple allergens, such as respiratory and dietary allergens. Fetal contact with various agents such as metabolites of medications, alcohol,
tobacco smoke, and viral infections have made it obvious that fetal
development is (at least partially) determined by maternal factors.
33
Dietary antigens are possibly another interfering factor. A critical
review of published evidence regarding the impact of dietary antigens
ingested by the mother during pregnancy on later development of allergic disease in the offspring can only result in the conclusion that more
research is urgently needed. It can be speculated that contact with
multiple dietary allergens should in general be of benefit to the fetus
since tolerance is likely to develop. However, it may well be that in a
subset of fetuses with a (yet unknown) specific genetic background,
the development of allergic disease is enhanced via contact with
dietary antigens during pregnancy. As a consequence, avoidance of
dietary antigens during pregnancy may become recommended in the
future in pregnant woman or fetuses with a specific genetic background. If parental history is insufficient to determine the fetal risk,
then determination of the genetic background may in practice not be
feasible. In the latter, preventive measurements would be advisable for
all fetuses.
Today’s knowledge suggests that pregnant women should have a
normal diversified diet, avoiding toxic agents such as tobacco and
alcohol. Since peanuts are strong allergens and they are rather consumed as a dietary habit rather than being an important nutrient, their
consumption during pregnancy should be avoided, although it has not
been demonstrated that regular ingestion of peanuts during pregnancy
results in the development of tolerance in the offspring. The role of
polyunsaturated fatty acids ingested by pregnant women on the development of atopy in the infants needs to be further evaluated.
It is likely that both an immunological and a genetic profile adequately predict the risk for atopy, and that contact with allergens may
result in tolerance or allergic sensitization depending on the genetic
profile in combination with the immunological balance. The interaction between genetic predisposition and environmental factors, such
as the first gastrointestinal colonization, exists during a restricted window of time. It can be speculated that the impact of dietary intervention during pregnancy will only have a borderline effect if not followed
by adequate perinatal and postnatal intervention.
34
List of Speakers
Prof. Otto Pieter Bleker
Department of Obstetrics and
Gynecology, Academic Medical
Center, University of Amsterdam
Room H4-210, Postbox 22700
NL–1100 DE Amsterdam
The Netherlands
Tel. 31 20 5663658
Fax 31 20 6971651
E-Mail [email protected]
Dr. Nancy Butte
Department of Pediatrics
Children’s Nutrition Research
Center, Baylor College of
Medicine, 1100 Bates Street
Houston, TX 77030
USA
Tel. 1 713 798 7179
Fax 1 713 798 7187
E-Mail [email protected]
Prof. Gian Carlo Di Renzo
Centre of Perinatal and
Reproductive Medicine
Department of Gynecologic
Obstetric and Pediatric Sciences
University Hospital Monteluce
Via Brunamonti 51
I–06121 Perugia
Italy
Tel. 39 7 55720563/74
Fax 39 7 55729271
E-Mail [email protected]
Prof. Gerard Hornstra
Healthy Lipids Research and
Consultancy
Maastricht University
Brikkenoven 14
NL–6247 BG Gronsveld
The Netherlands
Tel. 31 43 3560537
Fax 31 43 3560535
E-Mail g.hornstra@
nutrim.unimaas.nl
Prof. Michael S. Kramer
Department of Pediatrics
Montreal Children’s Hospital
2300 Tupper Street
Room F-265
Montreal, Que. H3H 1P3
Canada
Tel. 1 514 412 4400/22687
Fax 1 514 412 4253
E-Mail michael.kramer@
mcgill.ca
Dr. Sophie Moore
MRC International Nutrition Unit
Public Health Nutrition Unit
London School of Hygiene and
Tropical Medicine, 49–51 Bedford
Square, London WC1B 3DP
UK
Tel. 44 207 299 4667
Fax 44 207 299 4666
E-Mail [email protected]
35
Prof. Mulchand Patel
Department of Biochemistry
School of Medicine and
Biomedical Sciences, State
University of New York at
Buffalo, 140 Farber Hall
3435 Main Street Buffalo
NY 14214
USA
Tel. 1 716 829 3074
Fax 1 716 829 2725
E-Mail [email protected]
Dr. Paul Pencharz
Hospital for Sick Children
Division of Gastroenterology and
Nutrition, 555 University Avenue
Toronto, Ont. M5G 1X8
Canada
Tel. 1 416 813 7733
Fax 1 416 813 4972
E-Mail paul.pencharz@
sickkids.ca
Dr. Thomas H. Rosenquist
University of Nebraska Medical
Center, 987878 Medical Center,
Omaha, NE 68198-7878
USA
Tel. 1 402 559 4032
Fax 1 402 559 3990
E-Mail [email protected]
Prof. Ricardo Uauy
INTA University of Chile, Macul
5540, Casilla 138-11, Santiago 11
Chile
Tel. 562 2 2214105
Fax 562 2 2214030
E-Mail [email protected]
36
Prof. Yvan Vandenplas
AZ-VUB, Laarbeeklaan 101
BE–1090 Brussels
Belgium
Tel. 32 2 477 5780/1
Fax 32 2 4775783
E-Mail yvan.vandenplas@
az.vub.ac.be
Prof. Kim Waller
School of Public Health
University of Texas, 1200 Herman
Pressler Drive, Suite W-210
Houston, TX 77030
USA
Tel. 1 713 500 9155
Fax 1 713 500 9149
E-Mail [email protected]
Dr. Chittaranjan Yajnik
King Edward Memorial Hospital
Diabetes Unit, Sardar Moodliar
Road, Rasta Peth, Pune 411 011
India
Tel. 91 22 6111958
Fax 91 22 6125603
E-Mail [email protected]
Prof. Xiaoguang Yang
Chinese Center for Disease
Control and Prevention, 27 Nan
Wei Road, Beijing 100050
China
Tel. 86 10 63012327
E-Mail [email protected]