EARLY NUTRITION AND ITS LATER
CONSEQUENCES: NEW OPPORTUNITIES
Perinatal Programming of Adult Health - EC Supported Research
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EARLY NUTRITION AND
ITS LATER CONSEQUENCES:
Perinatal Programming of Adult Health -
EC Supported Research
Dept. of Pediatrics, Dr. von Hauner Children’s Hospital,
Univ. of Munich, Germany
Dept. of Agricultural Science, Imperial College London, Wye Campus, UK
Dept. of Pediatrics, Children’s Hospital, Univ. of Helsinki, Finland
Ashwell Associates, Visiting Research Fellow, Oxford Brookes University, UK
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TABLE OF CONTENTS
Berthold Koletzko, Manuel Serrano Rios……………………… …xiii
WHAT IS THE EU INFANT NUTRITION CLUSTER?.......................xv
EARLY NUTRITION AND ITS LATER CONSEQUENCES: NEW
THE DEVELOPMENTAL ORIGINS OF ADULT HEALTH AND
Alan Lucas ....................................................................................13
LONG TERM EFFECTS OF BREASTFEEDING ON THE INFANT
Lene Schack-Nielsen, Anni
Larnkjær, Kim Fleischer
EFFECTS OF EARLY DIET
M.E. Symonds, H.Budge, T. Stephenson and D.S. Gardner.........24
EVIDENCE FOR LONG-TERM PROGRAMMING
CANDIDATE GENES FOR OBESITY – HOW MIGHT THEY
INTERACT WITH ENVIRONMENT AND DIET ?
I. Sadaf Farooqi.............................................................................33
RATE OF GROWTH IN EARLY LIFE: A PREDICTOR OF
Marie Françoise Rolland-Cachera………………………………..35
PROTECTIVE EFFECT OF BREAST-FEEDING AGAINST
OBESITY IN CHILDHOOD
Stephan Arenz and Rüdiger von Kries...............................................40
Hildegard Przyrembel, Jean Michel Antoine, O. Hernell, D. Turck,
E. Underwood and M.C. Secretin,......................................................49
FROM INNOVATION TO IMPLEMENTATION
CHALLENGES AND OPPORTUNITIES IN PAN-EUROPEAN
COLLABORATION FOR RESEARCHERS FROM CENTRAL
AND EASTERN EUROPE
vi Table of Contents
T. Decsi, N. Fidler Mis, S. Kolaček, I. Kon, J. Kopecky, I. Penas-
Jimenez, P. Socha and H. Szajewska................................................. 54
BEST PRACTICE IN COMMUNICATING THE RESULTS OF
EUROPEAN RESEARCH TO THE PUBLIC
Margaret Ashwell and Michel Claessens………………………...60
LONGTERM EFFECTS OF PRE- AND POSTNATAL EXPOSURE
TO LOW AND HIGH DIETARY PROTEIN LEVELS
Cornelia C. Metges .......................................................................64
PROTEIN INTAKE IN THE FIRST YEAR OF LIFE: A RISK
FACTOR FOR LATER OBESITY?
Berthold Koletzko, Daniel Brasseur, Ricardo Closa, Marcello
Giovannini and Jerzy Socha...............................................................69
THE ROLE OF LONG-CHAIN POLY-UNSATURATED FATTY
ACIDS (LCPUFA) IN GROWTH AND DEVELOPMENT
Mijna Hadders-Algra ....................................................................80
EXPERIMENTAL MODELS FOR STUDYING PERINATAL
E. Herrera, I. López-Soldado, M. Limones, E. Amusquivar and
SUPPLEMENTATION IN PREGNANCY: THE NUHEAL TRIAL
Tamás Decsi, Cristina Campoy and Berthold Koletzko ..............109
OF N-3 POLYUNSATURATED FATTY ACID
YOUNG RESEARCHERS’ WORKSHOP
I. Broekaert, E. Larque................................................................114
CONSUMER NEEDS REGARDING DIETETIC PRODUCTS FOR
PREGNANT AND LACTATING WOMEN AND FOR BABY FOODS
Monique Raats , Kaisa Poutanen and Maria Almeida................120
FOCUS GROUP: BREAKFAST MEETING: SMES AND THEIR
CO-OPERATION WITH ACADEMIA
Jean Michel Antoine and Mats Strömqvist..................................127
ETHICAL ISSUES IN PERINATAL NUTRITION RESEARCH
Irene Cetin, and Robin Gill,........................................................132
EARLY PROGRAMMING OF DIABETES RISK
Table of Contents vii
INSULIN LIKE GROWTH FACTOR REGULATION OF
BODY MASS IN BREASTFED AND MILK FORMULA FED
P. Socha, R. Janas, A. Dobrzañska, B. Koletzko, I. Broekaert, D.
Brasseur, A. Sengier, M. Giovannini, C. Agostoni, R. Closa
Monasterolo, G. Méndez, EU Childhood Obesity Study Team...159
INVERSE ASSOCIATION BETWEEN TRANS ISOMERIC
AND LONG-CHAIN POLYUNSATURATED FATTY ACIDS
IN ERYTHROCYTE MEMBRANE LIPIDS IN PREGNANT
A. Kovacs, C. Campoy, B. Koletzko, T. Marosvölgyi, E. Szabo,
M. Jimenez, H. Demmelmair, T. Decsi.......................................164
COMPARISON OF ESSENTIAL FATTY ACID STATUS
AMONG GERMAN, HUNGARIAN AND SPANISH WOMEN
T. Marosvölgyi, C. Campoy, B. Koletzko, V. Jakobik, V. Dolz,
H. Demmelmair, B. Veszpremi, T. Decsi................................166
TRANS ISOMERIC FATTY ACIDS AS CONFOUNDING
VARIABLES IN STUDIES ON PERINATAL LC-PUFA
AN EIGHT YEARS PROSPECTIVE STUDY OF IRON
DEFICIENCY ANAEMIA IN INFANCY
Antunes H, Gonçalves S, Santos C, Costa-Pereira A, Tojo-Sierra
R, Aguiar A..............................................................................170
EARLY NUTRITION AND LATER DIABETES RISK
Mikael Knip and Hans K. Åkerblom………………………… ..142
IS TYPE 1 DIABETES A DISEASE OF THE GUT IMMUNE
SYSTEM TRIGGERED BY COW’S MILK INSULIN?
GLUTEN-FREE DIET IN SUBJECTS AT RISK FOR TYPE 1
DIABETES: A TOOL FOR DELAYING PROGRESSION
TO CLINICAL DISEASE?
Emanuele Bosi, Matteo R Pastore, Laura Molteni, Elena
Bazzigaluppi, Ezio Bonifacio and Lorenzo Piemonti.......................157
viii Table of Contents
NEW INSIGHTS IN THE POTENTIAL MECHANISM OF
ACTION OF NUCLEOTIDES TO MODULATE IMMUNITY
M. Manzano, A. Gil, R. Rueda............................................172
IS THE CRYING BEHAVIOUR IN INFANTS UP TO THE
AGE OF 3 MONTHS INFLUENCED BY THE TYPE OF
Sonia Schiess, Doris Oberle, Ilse Broekaert, Anna Reith,
Sabine Verwied-Jorky. Berthold Koletzko..............................177
DIETARY GANGLIOSIDES: BENEFICIAL EFFECTS FOR
THE NEONATE AND POTENTIAL MECHANISM OF
E. Vázquez, A. Gil, R. Rueda..............................................179
LEPTIN IN BREAST-FED AND FORMULA-FED INFANTS
Francesco Savino, Maria Francesca Fissore, Erica Clara
Grassino, Giuliana Eva Nanni, Roberto Oggero, Gian
DIETARY FATTY ACIDS DURING PREGNANCY
DETERMINES MATERNAL FATTY ACID PROFILE DURING
LATE PREGNANCY AND THEIR AVAILABILITY TO THE
FETUS EVEN DURING FASTING CONDITIONS
I. López-Soldado, H. Ortega, E. Amusquivar and
THRIVING OF MALNOURISHED BREASTFED INFANTS
AFTER ADDITIONAL FORMULA MILK FEEDING
N. Fidler Mis, I. Hren, J. Brecelj, A. Širca Čampa, M. Sedmak,
C. Kržišnik, B. Koletzko..........................................................174
ROLE OF MAMMARY GLAND LIPOPROTEIN LIPASE IN
THE AVAILABILITY OF POLYUNSATURATED FATTY
ACIDS FOR MILK SYNTHESIS
E. Amusquivar, I. López-Soldado, H. Ortega, E. Herrera....176
EFFECT OF OIL-SUPPLEMENTED DIETS ON LIVER
EXPRESSION OF PPAR ALPHA-RELATED GENES IN
C. Bocos, M. Gonzalez, I. Lopez-Soldado, and E. Herrera.......185
CHANGES OF PLASMA FATTY ACID PROFILE AND
ANTIOXIDANT VITAMINS DURING NORMAL
E. Herrera, H. Ortega, G. Alvino, N. Giovannini,
E. Amusquivar, I. Cetin................................................................190
OPTIMAL DESIGN FOR THE RECRUITMENT OF
PARTICIPANTS AS A FACTOR FOR THE EFFECTIVE
IMPLEMENTATION OF A CLINICAL TRIAL
B. Aschemeier BHC, C. Bittner, K. Lüpke, O. Kordonouri, T.
THE EFFECT OF PONDERAL INDEX ON PLASMA
CONCENTRATION OF INSULIN-LIKE GROWTH FACTOR-1
(IGF-1) IN NEONATAL PIGS
J. C. Litten, K. S. Perkins, J. Laws, A. M. Corson and L.
EFFECT OF A NEW INFANT FORMULA ENRICHED
WITH PREBIOTICS, PROBIOTICS, NUCLEOTIDES AND LC-
PUFA ON RECOVERY AFTER INFECTION
M. Rivero, A. Roca, R. Chifré, M. Conde, M. Rodriguez, A.
Santamaria, Gemma Colomé...................................................186
DOES HABITUAL PROTEIN INTAKE IN EARLY
CHILDHOOD INFLUENCE AGE AND BODY MASS INDEX
AT ADIPOSITY REBOUND?
Anke L. B. Günther, Anette E. Byuken, Sebastian Hahn,
Mathilde Kersting, Anja Kroke...............................................188
DIETARY COMPLIANCE IN DIABETES PREVENTION
PROJECT IN FINLAND
Sonja Bärlund, Ulla Uusitalo, Päivi Kleemola, Mikael Knip,
K. Åkerblom, Suvi M. Virtanen....................................189
EFFECTS OF PRENATAL EXPOSURE TO LOW AND
HIGH DIETARY PROTEIN LEVELS ON MATERNAL AND
FETAL AMINO ACID METABOLISM IN RATS
Maren Daenzer, Jeanette Günther, Klaus J. Petzke, Cornelia C.
Metges, Susanne Klaus............................................................195
Table of Contents
x Table of Contents
VISUAL EVOKED POTENTIALS IN INFANTS AFTER
DIETARY SUPPLY OF DOCOSAHEXAENOIC ACID AND 5-
METHYLTETRAHYDROFOLATE DURING PREGNANCY
I. Broekaert, C. Campoy, C. Iznaola, B. Hoffmann, W.
Müller-Felber, B. Koletzko......................................................201
ELECTRONIC DATA CAPTURE AND USE OF INTERNET
TECHNOLOGIES IN A DOUBLE-BLIND RANDOMISED
D. Oberle, H. Köhler, T. Richardsen, D. Brasseur,
COW'S MILK INTRODUCTION IN SPANISH INFANTS
Santamaria-Orleans A, Miranda-León MT, Rivero-Urgell M,
LONGER TERM EFFECTS OF EARLY CHOLESTEROL
INTAKE ON CHOLESTEROL BIOSYNTHESIS AND PLASMA
LIPIDS: A RANDOMIZED CLINICAL TRIAL
Théa A. Demmers, Peter J.H. Jones, Yanwen Wang, Susan
Krug, Vivian Creutzinger, James E. Heubi..............................197
PATTERNS OF GROWTH AND ENERGY UTILIZATION
OF THE DIET AFTER A PERIOD OF DIETARY
RESTRICTION DURING THE WEANING PERIOD
A.P.R. Battochio; A.G. Santos; C.A.R. Coelho...................198
INFANT FORMULA FEEDING PATTERN AND WEANING
INTRODUCTION IN SPANISH INFANTS
Santamaria-Orleans A, Miranda-León MT, Rivero-Urgell M,
NUTRITIONAL STATUS IN YOUNG ADULTS WITH
SCREEN-DETECTED SILENT/SUB-CLINICAL COELIAC
BREASTFEEDING AND BABY FRIENDLY HOSPITAL
INITIATIVE IN SLOVENIA
B. Bratanič, N. Fidler Mis, Z. Felc, P. Truden Dobrin........205
ANALYSIS OF DROP-OUTS IN A LONGITUDINAL
G. Méndez, V. Luque, F. Capdevila, J. Mariné, R. Closa, J.
RECRUITMENT STRATEGIES OF THE SPANISH GROUP
IN THE “EU CHILDHOOD OBESITY: PROGRAMMING BY
V. Luque, G. Méndez, F. Capdevila, J. Mariné, R. Closa, J.
M. Haapalahti, P. Kulmala, TJ. Karttunen, L. Paajanen,
K. Laurila, M. Mäki, H. Mykkänen, J. Kokkonen...................207
LIPOPROTEIN LIPASE (LPL) MRNA EXPRESSION IN
PLACENTAS FROM NORMAL AND IUGR (INTRAUTERINE
GROWTH RESTRICTED) PREGNANCIES BY REAL-TIME
S. Tabano, G. Alvino, P. Antonazzo, V. Cozzi, F. Grati, M.
Miozzo, I. Cetin.......................................................................208
MATERNAL FASTING EFFECT ON NEONATAL HEALTH
Kavehmanesh Z. Md............................................................210
THE QUALITY OF SCHOOLCHILDREN'S NUTRITION IN
Mirjana Pavlovic, Agnes Kadvan, Milija Vukotic..............212
TENDENCY TOWARDS OBESITY IN SYDNEY SCHOOL
Kaye Brock, Stephen Morrell, Richard Taylor...................214
MONITORING AND SUPERVISING A DIETARY
INTERVENTION TRIAL USING MODERN DATA
M. J. Koski, J. P. Krischer...................................................216
INFLUENCE OF TWO FORMS OF
CASEINOPHOSPHOPEPTIDE ON IRON BIO AVAILABILITY
DIET AND NUTRITIONAL RISK FACTORS IN
Mirjana Pavlovic, Agnes Kadvan, Draginja Rapic.............219
Table of Contents
Table of Contents
EXCESS FETAL ADIPOSITY IS ASSOCIATED WITH
PROGRAMMING OF PLACENTAL LIPID GENES
Tatjana Radaelli, Ali Varastehpour, Patrick Catalano, Sylvie
APPETITE CONTROL IN BREASTFED AND FORMULA
D. Gruszfeld; R. Janas; J. Socha; B. Koletzko; I. Broekaert; D.
Brasseur; A. Sengier; M. Giovannini; C. Agostoni; R. Closa
Monasterolo; V. Luque; EU Childhood Obesity Study Team......233
WHAT ARE THE DANONE INSTITUTES.............................235
I.B. Kibangou, S. Bouhallab, F. Bureau, P. Guerin, S. Allouche,
P. Arhan, D. Bouglé..................................................................221
MODEL OF CHILDHOOD OBESITY PRIMARY
PROBLEMS RELATED TO RECRUITMENT OF
PARTICIPANTS FOR THE TRIGER PROJECT
VITAMIN D STATUS AT BIRTH IN BRUSSELS-
F. Petry, L. Gianquinto, H. Cheblal, N. Hennebert, J. Vanderpas,
OBESITY AMONG YOUNG ADOLESCENT KUWAITIS
Abdulwahab Naser Al-Isa....................................................228
DYNAMIC CHANGES IN ADIPOSITY FROM FETAL TO
POSTNATAL LIFE ARE INVOLVED IN THE ADULT
METABOLIC SYNDROME ASSOCIATED WITH REDUCED
D. Jaquet MD, PhD, S. Deghmoun, D. Chevenne PhD, D. Collin
MD, P. Czernichow MD, C. Lévy-Marchal MD.....................229
Berthold Koletzko1, Manuel Serrano Rios2
1Divison Metabolic Diseases and Nutritional Medicine, Dr. von Hauner Children’s
Hospital, University of Munich, Lindwurmstr. 4, D-80337 München, Germany,
2University of Madrid and Danone Institute International, 126 rue Jules Guesde, 92302
Nutrition during pregnancy and infancy has powerful programming
effects on long-term development and health of the child, extending well
into adulthood and old age. Exploration and understanding of these
fascinating interrelationships offer new opportunities for improving
nutrition policy, public health, and nutritional products. Up-to-date
information on this exciting area of research is presented in this volume.
The contributions are based on presentations and discussions at a
European Commission supported Scientific Conference held on 2-3 July
2004 at Paris, France, that preceded the 2nd World Congress on Pediatric
Gastroenterology, Hepatology and Nutrition. The conference has been
supported by a grant of the European Commission’s Fifth Framework
Programme “Quality of Life and Management of Living Resources” as
an Accompanying Measure to the research project “Childhood Obesity –
Programming by Infant Nutrition?”, one of three large research projects
of the “EU Infant Nutrition Cluster”. The conference was organized by
the University of Munich, Germany, in close collaboration with the
Danone Institutes International, and was attended by some 430
participants from 57 countries, with backgrounds in research, public
health, governmental organizations, food and dietetic industry, and
health care. The plenary lectures, 86 poster presentations and focus
group sessions allowed for intensive exchange of information, fruitful
discussions, and the transfer of knowledge for new applications in
research, policy and practice.
We are very grateful indeed to the European Commission and
Danone Institute International for their generous financial support, and to
the International Association of Infant Food Manufacturers and the
University of Munich for ancillary funding. We also thank Prof. Hans
Akerblom, Dr. Peter Dodds, and the members of the Scientific Advisory
Committee for active help in developing the scientific programme; Prof.
Olivier Goulet, President of the 2nd World Congress on Pediatric
Gastroenterology, Hepatology and Nutrition for the integration of the
conference with the World Congress; Dr. Doris Oberle, Dr. Hans
Demmelmair, Agnes Martin and Sandrine Piredda for their untiring work
organizing the conference; Dr. Margaret Ashwell for her thoughtful and
vigilant input in preparing and disseminating the conference information,
and for editing these proceedings; Alkmini Katsada, Isabelle de
Froidmont-Goertz, and Achim Boenke from the EC Directorate General
Research for their sympathetic support; and the many other friends and
colleagues who helped to make this project a success.
May this volume be useful to its readers and stimulate further
progress in research and practice in the area of early nutrition.
Berthold Koletzko Manuel Serrano Rios
University of Munich University of Madrid
Berthold Koletzko, Manuel Serrano Rios
Danone Institute International
WHAT IS THE EU INFANT NUTRITION
The Infant Nutrition Cluster is an association of three research projects
funded by the EU; all are concerned with the effects of early nutrition on
the health and development of the newborn child.
These research projects all aim to assess the roles of early nutritional
influences on the current and future well-being of the child and its
mother as well as to determine the potential of nutritional interventions
during pregnancy and infancy to modify health and well-being.
1. CHILDHOOD OBESITY: PROGRAMMING
BY INFANT NUTRITION?
Childhood obesity is a major public health problem. Breastfed infants are
less likely to become obese children than infants fed formula. The higher
protein content of infant formulae, compared with breast milk, could be a
The EU Childhood Obesity Programme, includes a one year multicentre
intervention trial on new-born infants, to see whether feeding infant
formulae, which differ in their level of milk proteins, can influence the
risk of later childhood obesity.
The trial is taking place in five countries with different habitual total
protein intakes to test the ‘early protein hypothesis’, namely that early
protein intake predicts infant growth and later risk of childhood obesity.
Expected achievements include:
• Improved health and quality of life by preventing childhood obesity.
• Promotion of the benefits of breast-feeding.
• A better understanding of consumer (parental) attitudes to infant
• The potential for the development of new infant foods (formula and
• The provision of safety data for infant formula with adequate protein
• The provision of information for the training of health professionals to
make it easier for them to advise consumers about infant feeding.
Contract Number: QLK1-CT-2001-00389 www.childhood-obesity.org
Berthold Koletzko, Manuel Serrano Rios
2. INFLUENCE OF DIETARY FATTY ACIDS ON
THE PATHOPHYSIOLOGY OF
INTRAUTERINE FOETAL GROWTH AND
Nutrition during pregnancy and early life is known to affect the health
and development of the new-born child. A foetus that suffers intra-
uterine growth restriction (IUGR) is more likely to suffer from heart
problems or diabetes in later life.
PERILIP adopts a multidisciplinary approach to the study of lipids in
Six partners, from as many countries, combine expertise in obstetric
monitoring of foetal development, nutrition of premature infants,
nutritional studies using animal models and the structure and functioning
of the placenta as well as a range of lipid analytical techniques.
Expected achievements includes:
• An improved understanding of the roles of different fatty acids in the
diets of women at different stages of pregnancy and during lactation.
• An improved understanding of the roles played by antioxidant status in
the perinatal nutrition.
Potential applications are:
• The refinement of dietary recommendations for specific times during
pregnancy and lactation.
What is The EU Infant Nutrition Cluster?
• Improvement of formulations for intravenous feeding of premature
• Protocols to reduce neonatal mortality in piglets, a common welfare
and economic problem in the pig industry.
Acronym : Perilip
Contract Number : QLK1-CT-2001-00138
3. TRIAL TO REDUCE IDDM IN THE
GENETICALLY AT RISK (NUTRITIONAL
PRIMARY PREVENTION OF TYPE 1
Type 1 diabetes in children is a major health problem in Europe, and the
incidence of the disease is increasing. The disease develops in
genetically susceptible individuals, if one or several environmental
factors (of which cow milk proteins are one of the main candidates) lead
to autoimmune destruction of the pancreatic beta-cells.
The objective of TRIGR is to determine whether denial of nutritional
cow milk proteins for at least the first 6 m of life reduces the incidence
of Type 1 diabetes in children with increased genetic risk of developing
the disease and/or the appearance of diabetes associated auto-antibodies
by the age of 6 and 10 years.
Expected Achievements are to find an answer to the important question
of the incidence of Type 1 diabetes in children by dietary intervention in
infancy in subjects with increased genetic risk.
Application is the potential to use modified formula after exclusive
breastfeeding to decrease the risk of Type 1 diabetes in subjects with
increased genetic risk.
Acronym: TRIGR or DIABETES PREVENTION
Contract Number: QLK1-CT-2002-00372
EARLY NUTRITION AND ITS LATER
CONSEQUENCES: NEW OPPORTUNITIES
Perinatal nutrition programmes adult health
Divison Metabolic Diseases and Nutritional Medicine, Dr. von Hauner Children’s
Hospital, University of Munich, Lindwurmstr. 4, D-80337 München, Germany, Fax +49
89 5160 7742
Abstract: Some 30 years ago Dörner proposed that disease risk and body functions
in human adults are programmed during critical early periods of
development by hormones and metabolites. Indeed, dietary factors in
pregnant and lactating women and in their children were shown to
modulate growth and functional development of the organism and to exert
life-long programming effects on health, disease and mortality risks in
adulthood, neural function and behaviour, and the quality of life. Much of
the available evidence on nutritional programming in humans has come
from historical observational studies that cannot examine the association
with diet directly, establish whether associations are causal, and identify
appropriate dietary recommendations for pregnant women and infants.
Also, open questions exist on the critical pre- and postnatal time periods
during which nutritional exposures programme later health. Therefore, a
new approach is required to study early programming of adult health that
integrates evidence from randomised controlled trials in humans,
prospective observational studies and animal experiments. Considering
the far-reaching consequences for public health, policy and product
development, major investments in research on early nutritional
programming are justified.
Key words: metabolic programming, metabolic imprinting, developmental origins of
adult disease risk, accelerated early growth, infant feeding
1. SCIENTIFIC EXPLORATION OF THE ROLE OF
EARLY NUTRITION FOR LONG TERM
Evidence accumulates that food supply and the metabolism of food
ingredients in women during pregnancy and lactation and in their
children have marked implications on child development and long-term
health. Epidemiological evidence and intervention studies performed in
pregnant women and in infants have highlighted the fact that maternal
and intrauterine influences are of special importance during the
development of the infant and child. Early nutrition modulates growth
and functional development of the organism and appears to exert life-
long programming effects that modulate health, disease and mortality
risks in adulthood, neural function and behaviour, and quality of life. The
scientific exploration of these relationships and their underlying
mechanisms offer new windows of opportunity for preventive health
concepts, the provision of sound nutritional advice, and the development
of improved food products for mothers and children.
The latest knowledge on long-term programming effects of early
nutrition, future trends and the potential for application was discussed by
some 450 scientists at a European Commission supported Scientific
Workshop held at Paris, France, in July 2004, as a satellite meeting to the
2nd World Congress on Paediatric Gastroenterology, Hepatology and
Nutrition. This volume summarises the data and concepts discussed at
this workshop. The meeting was organised on behalf of the “EU Infant
Nutrition Cluster”, a collaboration of three large research projects
supported by the European Commission’s Fifth Framework Programme
that all investigate long-term consequences of nutrition and metabolism
in early life:
? Childhood Obesity – Early Programming by Infant Nutrition
Prof. Berthold Koletzko, University of Munich, Germany)
? Influence of Dietary Fatty Acids on the Pathophysiology of
Intrauterine Foetal Growth
(www.wye.ie.ac.uk; QLRT – 2001 –00138; Coordinator Dr. Peter
Dodds, Imperial College, Wye, UK)
? Nutritional Primary Prevention
(www.trigr.org; QLRT – 2001 – 00372; Coordinator Prof. Hans
Akerblom, Univ. of Helsinki, Finland)
and Neonatal Development
of Type 1 Diabetes
EARLY NUTRITION AND ITS LATER CONSEQUENCES
The main goals of this scientific workshop on long-term effects of
early nutrition were a) to provide a platform for a critical review of
current knowledge on early nutritional programming of adult health and
well-being, b) to discuss new results and open questions, c) to explore
evolving opportunities for research, public health, policy and product
development, d) to strengthen networking and involvement of young
researchers, scientists from Central & Eastern Europe, outside Europe,
industry and small and medium size enterprises, and e) to publish the
lectures and workshop summaries to inform EU policy makers,
researchers and the public. The workshop has been organised by the Div.
of Metabolic Diseases and Nutrition at the Dr von Hauner Children‘s
Hospital, University of Munich, Germany, in collaboration with the
International Danone Institutes.
2. THE 30TH ANNIVERSARY OF METABOLIC
PROGRAMMING OF ADULT HEALTH
The workshop commemorated the 30th anniversary of the
introduction of the term “Programming” into the scientific literature in
1974 by Professor Günter Dörner, former head of the Institute of
Experimental Endocrinology at the Charité Hospital, Humboldt
University at Berlin, Germany (1). In a visionary article reviewing a
series of clinical and experimental data, Dörner concluded that the
concentrations of hormones, metabolites and neurotransmitters during
critical early periods of development are capable of pre-programming
brain development, functional disturbances, diseases as well as
syndromes of reproduction and metabolism in human adulthood. Dörner
also proposed an interaction between the genetic material of the
individual and environmental influences during early development to
determine later function in adult life, a concept that only recently has
been confirmed by experimental data (2,3). Over many more years,
Dörner and coworkers continued to study programming effects of
perinatal metabolic and endocrine factors on later risk of diabetes,
obesity and cardiovascular risk in a series of systematic studies (4,5).
Even though the thoughts of Dörner were revolutionary at that time,
developmental plasticity and thus long term imprinting effects of early
events are widely known in biology. For example, gametic imprinting
through epigenetic modification during gonadal passage with parent-
specific gene expression causes serious diseases, including the Silver-
Russel-syndrome, the Beckwith-Wiedemann-syndrome, the Prader-
Willi-syndrome and the Angelman-syndrome (6). Intrauterine exposure
to sex hormones during sensitive time windows of development
programmes gender identity and gender specific cerebral lateralization
(7,8). A critical dependency on the timing of exposure during sensitive
time windows of early development is also known for teratogenic effects
of radiation, infectious agents, drugs such as thalidomide and intrauterine
metabolic insults such as hyperphenylalanemia due to maternal
Programming effects of early nutrition were first studied by
Widdowson and McCance in the 1960ies. Limited periods of
undernutrition in rats during the early postnatal period led to permanent
alterations of adult body weight and body composition in spite of free
access to food after the intervention period (11). In contrast, later
undernutrition had no lasting effects. Widdowson summarized their
observations as follows: “The size that animals undernourished at
different stages of development can be expected to attain when they are
rehabilitated depends on the stage of development that they were at when
they were undernourished.”
In spite of this experimental support, Dörner’s hypothesis of early
programming of human adult health only received wider recognition
when Alan Lucas from Cambridge, UK, rediscovered the concept and
the term programming (12). Lucas and co-workers introduced systematic
long-term follow-up first of preterm, then also of term infants fed
different diets during early life, which allowed them to test the
programming hypothesis. Wide popularity for the programming concept
was achieved when David Barker and co-workers provided strong
epidemiological evidence for a link between anthropometric measures at
birth and later morbidity and mortality in adult life (13). Indeed, the
concept that early nutrition and growth programmes adult disease risk is
often called the “Barker hypothesis” (14,15), even though the hypothesis
was created almost 20 years prior to Barker’s insightful studies and thus
might rather deserve the name “Dörner hypothesis” (1).
EARLY NUTRITION AND ITS LATER CONSEQUENCES
3. FETAL OR POSTNATAL ORIGINS OF ADULT
The observation that body weight at birth and at age 1 year,
respectively, is inversely related to the risk of hypertension, diabetes and
coronary heart disease in adulthood lead Barker to suspect that maternal
malnutrition during pregnancy would lead both to foetal growth
restriction and increased risk of later disease, the foetal origins of adult
disease hypothesis (13). However, this interpretation has recently been
challenged based on the observation that low birth weight is associated
with catch-up growth after birth, and accelerated weight gain by itself
might be a risk factor for later disease (16).
Cole substantiated the latter concept by multiple-regression analysis
of blood pressure outcomes on weights at different ages. Data from
cohort studies from Brazil and the Philippines relating blood pressure in
adolescence to weight through childhood showed small inverse weight
effects in infancy, but early weight proved to be less important than
weight and weight gain during adolescence (16). Furthermore, Tu and
co-workers raised the possibility that evidence for the foetal origins of
adult disease hypothesis might be a statistical artefact, due in part to
inappropriate statistical adjustment for variables on the causal pathway
such as early weight gain and current body size, which may create an
artefactual statistical effect known as the "reversal paradox" (17). They
performed computer simulations for three hypothetical relations between
birth weight and adult blood pressure. The effect of statistically adjusting
for different correlations between current weight and birth weight and
between current weight and adult blood pressure was examined to assess
their impact on associations between birth weight and blood pressure.
When there was no genuine relation between birth weight and blood
pressure, adjustment for current weight created an inverse association
whose size depended on the magnitude of the positive correlations
between current weight and birth weight and between current weight and
blood pressure. When there was a genuine inverse relation between birth
weight and blood pressure, the association was exaggerated following
adjustment for current weight, whereas a positive relation between birth
weight and blood pressure could be reversed after adjusting for current
weight. Thus, researchers must consider the reversal paradox when
adjusting for variables that lie within causal pathways.
Further evidence accumulates that high early weight gain is
associated with greater disease risk at later ages. We studied early
predictors of overweight at school age in a large cohort of 4235 children
in Bavaria, Southern Germany (18). Weight, length, body mass index,
and ponderal index differences between birth, 6 months, 12 months, and
24 months of age were compared by receiver operating characteristic
curves and predictive values for later overweight. For all variables, the
largest area under the receiver operating characteristic curve was
observed for weight gain between birth and age 2 years (0.76 [95%
confidence interval, 0.74-0.79]). Thus, high weight gain from birth to 24
months predisposes for later overweight. This relationship might be at
least one of the reasons why infants breast fed after birth have a lower
risk of overweight and obesity in later life than previously formula fed
individuals (19-21), since breast feeding is associated with lesser weight
gain in the first year of life than formula feeding (22). Rapid early
growth has also been associated with higher later risks for dyslipidemia,
markers of insulin resistance,
cardiovascular diseases (23). Thus, further research needs to elucidate
the critical time periods during which nutritional exposures may
programme later disease risk.
endothelial dysfunction, and
4. EXPLORING LONG TERM EFFECTS OF
NUTRITIONAL PROGRAMMING AND
UTILISING THE PREVENTIVE POTENTIAL
The available data from epidemiological studies, and to some extent
also from prospective intervention studies, provide evidence for lasting
effects of early nutrition during the pre- and postnatal period on later
cardiovascular health, obesity, neural and brain function, immune
function and allergy risk, diabetes type I and bone health. These data
indicate the enormous potential for health prevention, improved
performance and well-being by appropriate perinatal nutrition. However,
the available evidence of nutritional programming in humans has, until
recently, come largely from historical observational studies that have
shown associations between small size in early life and adult disease
risk. These cohorts have been constructed from available maternal or
child health records and have necessarily relied on indirect measures of
maternal and infant nutrition (rather than direct measures of maternal or
infant diet) and have lacked detailed data on potential confounding
variables. Many of these cohorts were born before the Second World
EARLY NUTRITION AND ITS LATER CONSEQUENCES
War and it is possible that the nature and size of the associations is
different in contemporary European populations. While these studies
have generated considerable interest they have been unable to:
examine the association with diet directly,
establish whether associations are causal (because of the
observational nature of the data), and
identify appropriate dietary recommendations for pregnant women,
small babies and small infants
Therefore, a new approach is now required to study early
programming of adult health that integrates evidence from randomised
controlled trials in humans (RCTs), prospective observational studies
and animal experiments. In the EU 6th Framework Programme, the
project “Early Nutrition Programming of Adult Health - Long term
follow up of efficacy and safety trials and integrated epidemiological,
genetic, animal, consumer and economic research (EARNEST) will bring
together a unique group of partners from 13 countries and of resources
into just such an integrated programme of research (www.metabolic-
programming.org). The project is planned to extend
The EARNEST project will
integrate human, animal,
molecular and cell studies
to develop and test new
from 2005 to 2010 with an allocated grant support by the European
Commission of 13.4 million € and a total budget of approximately 20
million €. The scientific objectives of EARNEST will be achieved
through the follow-up of informative randomized controlled trials in
humans (conducted both in pregnant women and infants), through
analyses of large contemporary prospective observational studies that
have collected data on diet in pregnancy and in the first years of life,
together with clearly defined animal studies aimed at defining the
underlying mechanisms, including gene regulation and the integration
and synthesis of knowledge from these three approaches. The expected
achievements of this approach include:
• provision of a fully integrated approach to work on programming in
• demonstration of causal associations in humans,
• establishment of the long-term safety as well as efficacy of early
• exploration of fundamental mechanisms to guide future intervention
• estimation of the biological, social and economic importance of
early nutritional programming,
• formulation of evidence-based policy and practice, and
• development of appropriate products and creation of wealth in
The scientific strategy of the EARNEST project
The approach taken by the EARNEST project is to use the best
methodology and technology available to investigate the hypothesis and
its implications. This consortium has assembled a majority of the key
Plus Diet at critical periods
EARLY NUTRITION AND ITS LATER CONSEQUENCES
relevant intervention trials conducted in infancy and pregnancy in this
field for exploitation. Many of these trials were targeted at the outset to
explore long-term health outcomes. Others were set up to examine
shorter-term effects but the cohorts can now be exploited for long-term
follow up. This emphasis on randomized trials and prospective
observational trials means that the conclusions will be based on a sound
scientific footing. In addition they will be of a sufficient quality to
provide the level of detail required to quantify the size of the effects and
thus their relative importance, economic impact and detect adverse
The proposed strategy of utilizing existing trials and cohorts has (i)
the economic benefit of exploiting vast prior expenditure on randomizing
and maintaining these cohorts, and (ii) the scientific benefit of allowing
us to study cohorts, randomly assigned to early nutrition, that have now
reached an age when outcomes are relevant to adult health and
morbidity. We recognize that in using randomized trials it is impractical
to study some late adult endpoints such as stroke. However some
outcomes have predictive value even from childhood (e.g. IQ).
Moreover, changes in cardiovascular risk factors such as blood pressure
and LDL cholesterol, which we shall measure in adults, have published
predictive value for subsequent endpoint events. Indeed, demonstration
in a randomized trial of a clear causal effect of an early nutritional
intervention in reducing adult diastolic blood pressure (given the known
association between each mm change in blood pressure and later risk of
cardiovascular death), would be of much greater value in underpinning
practice than the speculated causal significance of an observed
relationship between birth weight and later ischaemic heart disease.
5. RELEVANCE OF PROGRAMMING FOR PUBLIC
The general concept that early nutrition might programme long-term
health has potentially far-reaching consequences. Recently published
data give insight into the large potential effects sizes of early nutritional
intervention and long-term health. The reported effect of early feeding
with human milk or with formula providing long-chain polyunsaturated
fatty acids, respectively, on lowering later mean or diastolic blood
pressure by around 3-4mm Hg (24,25) is greater than all other non-
pharmacological means of reducing blood pressure such as weight loss,
salt restriction, or exercise. These data must be viewed against the
finding that lowering population-wide diastolic blood pressure by only 2
mm Hg would be expected to reduce the prevalence of hypertension by
17%, the risk of coronary heart disease by 6% and the risk of
stroke/transient ischaemic attacks by 15% (23). Similarly, the 10%
lowering of cholesterol shown in a recent randomised trial of early
nutrition compares favourably with the effects of dietary interventions in
adults, which lower cholesterol by only 3-6%. Such an effect on
cholesterol concentration would be expected to reduce the incidence of
cardiovascular disease by approximately 25% and mortality by 13-14%.
These examples indicate that early nutrition may be one the most
important influences on long term health that can be manipulated by
public health practice and emphasises the immense importance of this
field. Thus, further high quality research is needed to provide the critical
data on the impact of a range of early nutritional interventions (whole
diets and individual nutrients) in both healthy and high risk populations,
and covering a range of programmed outcomes that include most of the
main areas of adult morbidity in the West (hypertension, obesity,
diabetes, vascular health, bone health, immune health and cancer). Such
data should provide a strong scientific basis for the intelligent promotion
of health in European populations.
Supported by the European Commission (Grant QLK1-CT-2002-
30582) and the University of Munich, with additional unconditional
grant support by the International Danone Institutes and the International
Association of Infant Food Manufacturers. The author is indebted to the
steering group members of the EARNEST consortium for insightful
discussions and stimulating thoughts.
1. Dörner G. Perinatal hormone levels and brain organization. In: Stumpf WE, Grant LD
(eds) Anatomical neuroendocrinology. Basel, Karger 1975:245-52
EARLY NUTRITION AND ITS LATER CONSEQUENCES
2. Schmidt I., Schoelch C., Ziska T., Schneider D., Simon E., Plagemann A.. Interaction
of genetic and environmental programming of the leptin system and of obesity
disposition. Am J Physiol Physiol Genomics 2000;3:113-120.
3. Ozanne SE, Fernandez-Twinn D, Hales CN. Fetal growth and adult diseases. Semin
Perinatol. 2004 Feb;28(1):81-7.
4. Dörner G, Plagemann A. Perinatal hyperinsulinism as possible predisposing factor for
diabetes mellitus, obesity and enhanced cardiovascular risk in later life. Horm Metab
5. Plagemann A. ‘Fetal programming‘ and ‘functional teratogenesis‘: on epigenetic
mechanisms and prevention of perinatally acquired lasting health risks. J Perinat Med
6. Jiang YH, Bressler J, Beaudet AL. Epigenetics and human disease. Annu Rev
Genomics Hum Genet. 2004;5:479-510
7. MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med.
2004 Jan 22;350(4):367-78.
8. Cohen-Bendahan CC, Buitelaar JK, van Goozen SH, Cohen-Kettenis PT.Prenatal
exposure to testosterone and functional cerebral lateralization: a study in same-sex and
opposite-sex twin girls. Psychoneuroendocrinology. 2004 Aug;29(7):911-6.
9. Brent RL, Beckman DA. The contribution of environmental teratogens to embryonic
and fetal loss. Clin Obstet Gynecol. 1994 Sep;37(3):646-70
10. Koch R, Hanley W, Levy H, Matalon K, Matalon R, Rouse B, Trefz F, Guttler F,
Azen C, Platt L, Waisbren S, Widaman K, Ning J, Friedman EG, de la Cruz F. The
Maternal Phenylketonuria International Study: 1984-2002. Pediatrics. 2003 Dec;112(6
11. Widdowson EM, McCance RA, The effect of finite periods of undernutrition at
different ages on the composition and subsequent development of the rat. Proc. Roy.
Soc., Lon. 158, 329-342 (1963).
12. Lucas A. Programming by early nutrition in man: In: Bock GR, Whelan J Eds. The
childhood environment and adult disease. (CIBA Foundation Symposium 156). Whiley,
Chichester, UK. 1991: 38-55.
13. Barker D. Mothers, babies and diseases in later life. London, BMJ Publishing Group
14. Khan IY, Lakasing L, Poston L, Nicolaides KH. Fetal programming for adult disease:
where next? J Matern Fetal Neonatal Med. 2003 May;13(5):292-9.
15. Ellison PT. Evolutionary perspectives on the fetal origins hypothesis. Am J Hum
Biol. 2005 Jan-Feb;17(1):113-8.
16. Cole TJ. Modeling postnatal exposures and their interactions with birth size. J Nutr.
17. Tu YK, West R, Ellison GT, Gilthorpe MS. Why Evidence for the Fetal Origins of
Adult Disease Might Be a Statistical Artifact: The "Reversal Paradox" for the Relation
between Birth Weight and Blood Pressure in Later Life. Am J Epidemiol. 2005 Jan
18. Toschke AM, Grote V, Koletzko B, von Kries R. Identifying children at high risk for
overweight at school entry by weight gain during the first 2 years. Arch Pediatr Adolesc
Med. 2004 May;158(5):449-52.
19. von Kries R, Koletzko B, Sauerwald T, von Mutius E, Barnert D, Grunert V, von
Voss H. Breastfeeding and obesity: cross sectional study. Brit Med J 1999;319:147-150
20. Toschke AM, Vignerova J, Lhotska L, Osancova K, Koletzko B, von Kries R.
Overweight and obesity in 6- to 14- year-old Czech children in 1991: protective effect
of breastfeeding. J Pediatrics 2002;141:764-769
21. Arenz S, Rückerl R, Koletzko B, von Kries R. Breast-feeding and childhood obesity.
A systematic review. Int J Obesity 2004;28:1247-1256
22. Kramer MS, Guo T, Platt RW, Vanilovich I, Sevkovskaya Z, Dzikovich I,
Michaelsen KF, Dewey K; Promotion of Breastfeeding Intervention Trials Study
Group. Feeding effects on growth during infancy. J Pediatr. 2004 Nov;145(5):600-5.
23. Singhal A, Lucas A. Early origins of cardiovascular disease: is there a unifying
hypothesis? Lancet. 2004 May 15;363(9421):1642-5.
24. Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later blood
pressure: two cohorts after randomised trials. Lancet. 2001 Feb 10;357(9254):413-9.
25.Forsyth JS, Willatts P, Agostoni C, Bissenden J, Casaer P, Boehm G. Long chain
polyunsaturated fatty acid supplementation in infant formula and blood pressure in later
childhood: follow up of a randomised controlled trial. BMJ. 2003 May
THE DEVELOPMENTAL ORIGINS OF ADULT
HEALTH AND WELL-BEING
Medical Research Council-Institute of Child Health, London, UK
1. THE CONCEPT OF PROGRAMMING
Previously, nutritional scientists focused on meeting nutritional needs
and preventing deficiencies. This focus has changed radically. Current
interest lies in the biological effects that nutrition has on health, notably
That nutrition has lifetime effects raises a broader concept concerning
the general importance of early life events. In this context, I popularised
the term “programming” - the idea that “a stimulus or insult during a
critical or sensitive period of development, can have long-term or life-
time effects on the organism”. Many short-lived internal ‘signals’ or
environmental experiences, operating during brief critical periods, have
2. EVIDENCE FROM ANIMALS
Evidence that early nutrition has such ‘programming’ effects in
animals is overwhelming. Adult outcomes programmed by infant
nutrition include lipid metabolism, blood pressure, obesity, diabetes,
arteriosclerosis, behaviour and longevity. Such programming occurs in
diverse species, including primates.
In humans, observational studies link adult disease with size or mode
of nutrition in early life. Yet, it is difficult to use observational
associations to prove causation, and hence underpin health policy.
However, over 20 years ago we used the pharmaceutical intervention
trial model to test prospectively long term effects of early diet, randomly
assigned, on health and neurodevelopmental outcomes. Given the need
for long-term follow up to detect emergence of programmed effects, the
major impact of early nutrition has only recently emerged.
3. STUDIES ON PREMATURE BABIES
The longest-term experimental evidence for programming is based on
studies of premature babies. We showed only 2-4 weeks of randomised
dietary manipulation in neonates programmes in adolescence and
beyond: (1) key components of the metabolic syndrome - blood pressure,
tendency to obesity and diabetes and blood lipids, (ii) the first stages of
the atherosclerotic process (determined by ultrasound), (iii) brain
structure and function (iv) bone health, possibly relevant to degenerative
bone disease, (v) atopy. Effect sizes are large. Thus early diet has a
greater effect on later cardiovascular risk factors than lifestyle
modification in adulthood.
4. STUDIES ON FULL TERM INFANTS
However, programming also occurs in healthy full-term infants,
through effects of specific nutrients
polyunsaturated fatty acids) or whole diets (e.g. breast milk).
Importantly for some outcomes, early nutrition may operate by
influencing postnatal growth. Early growth acceleration in invertebrates
and vertebrates carries long term health costs. Our new experimental
evidence shows in humans faster postnatal growth is a major adverse
influence on later cardiovascular risk.
(e.g. iron, long-chain
THE DEVELOPMENTAL ORIGINS OF ADULT HEALTH
5. POSTNATAL GROWTH ACCELERATION
Relative effects of fetal versus postnatal growth need reappraisal. We
suggest the postnatal period is particularly important and the risk for the
small fetus may relate to deleterious postnatal growth acceleration
(‘catch-up’) seen in this population. Thus the ‘fetal origins hypothesis’
may be largely explained in terms of the broader ‘growth acceleration
6. A BALANCE OF RISKS
Designing optimal early nutritional policies requires balance of risks.
In premature babies, a high plane of nutrition benefits later brain
development but adversely programmes cardiovascular health. Defining
the corresponding balance of risks in healthy full-term infants is a critical
In summary, 40 years of animal and human studies show early
nutrition is a key factor for health with major biological and social
LONG TERM EFFECTS OF BREASTFEEDING
ON THE INFANT AND MOTHER
Lene Schack-Nielsen, Anni Larnkjær, Kim Fleischer Michaelsen
Department of Human Nutrition, The Royal Veterinary and Agric University, Denmark
Abstract: There is increasing evidence that breastfeeding has long term beneficial
effects on the infant. The most important are improved cognitive
development, reduced incidence of immune related diseases (e.g. Type-1
diabetes and inflammatory bowel disease), and childhood cancers. A
reduced risk of breast cancer in the mother is another important benefit.
Key words: Breastfeeding;
cardiovascular effects; immune system; allergy; maternal effects.
long-term effects; cognitive function, growth;
Breastfeeding (BF) has numerous advantages for the child and affects
several physiological mechanisms/systems. Not only short-term effects,
but also effects in later life have been reported. Many of these health
benefits exhibit dose-response relationships; i.e. longer duration of BF is
associated with greater degrees of benefit. The WHO recommended
optimal duration of exclusive BF is 6 months (WHO, 2002). This is
based on a systematic review of studies from developed and -developing
countries comparing growth, development, morbidity, and mortality of
infants with different durations of BF (Kramer and Kakuma, 2002). The
aim of this paper is to briefly review the effects of BF on infant and
maternal health with emphasis on long term effects. The effect of BF on
childhood obesity is covered in another chapter.
LONG TERM EFFECTS OF BREASTFEEDING ON THE INFANT 17
2. METHODOLOGICAL CONSIDERATIONS
Studies examining the effects of BF are mainly based on
observational studies, as it is unethical to randomise newborn infants to
BF or formula. This presents methodological challenges due to possible
sources of errors such as confounding, reverse causality and selection
bias, e.g. social status and maternal education are strong predictors of the
duration of BF and some of the outcomes studied. The quality of
observational studies has, however, improved over the last 15 years
through improved designs and better control for relevant confounders.
3. COGNITIVE DEVELOPMENT
Many studies have found an association between BF and cognitive
development. A meta-analysis including studies of children between 6
months and 15 years reported an overall effect of 3.2 IQ points after
controlling for potential confounders (Anderson et al., 1999). The effect
was stronger in preterm infants. There was a significant dose-response
relationship with the duration of BF and the effects seemed to be
independent of the age at which the outcome was measured. One study
has suggested that this effect persists into later life since a positive
association between duration of BF and intelligence in a group of men
(mean age 18.7) and in another group of both women and men (mean age
27.2) was found (Mortensen et al., 2002). Different IQ tests were, used
for the two groups.
The most plausible explanation for the positive effects of BF on
mental function is the higher level of long chain poly-unsaturated fatty
acids (LCPUFA) especially the n-3 fatty acid docosahexaenoic acid
(DHA.) in breast milk compared to infant formula, DHA accumulates in
neural membranes during infancy (Lauritzen et al., 2001; Michaelsen et
al., 2003; SanGiovanni, 2000). Preterm infants have a lower LCPUFA
status which supports this mechanism. Although the effect on cognitive
function is not large in the individual it can have an important impact at
the population level.
Lene Schack-Nielsen, Anni Larnkjær, Kim Fleischer Michaelsen
Breast-fed infants generally exhibit a different growth pattern to that
of formula-fed infants. The weight gain of breastfed infant is lower and,
in some studies, the length gain is also affected. Furthermore, breast-fed
infants are generally leaner then formula-fed infants by 12 months of age
(Michaelsen et al., 1994; Dewey, 1998). There are no known adverse
consequences related to the slower growth in breast-fed infants.
5. IMMUNE SYSTEM AND ITS DISORDERS
Breast milk contains many immune factors, which give the infant
passive protection against infections. The most important immune
related factors are leucocytes including B and T lymphocytes,
macrophages, neutrophiles, secretory immunoglobulin A (SIgA),
cytokines, bifidus factor, lyzosyme, oligosaccharides, and lactoferrin
(Heinig & Dewey, 1996; Hanson et al., 2003). BF also stimulates the
infant’s own immune system: the thymic gland is larger in breast-fed
infants (Hasselbalch et al., 1996), SIgA concentration in urine is higher
in BF infants (Goldblum et al., 1996) who also respond with higher
levels of antibodies after certain vaccines (Hahn-Zoric et al., 1990). It
seems that this stimulation has long-term effects.
The incidence of infections is lower in breast-fed infants compared to
formula-fed infants. BF provides the most significant protection against
gastrointestinal infections but also the incidence of respiratory infections
is reduced (Howie et al., 2002; Oddy et al., 2003). Protection against
urinary tract infections and otitis media up to 3 years has also been
reported (Heinig & Dewey, 1996; Léon-Cava et al., 2002).
The effect of BF on the development of allergy is commonly
regarded as one of its most significant advantages. BF protects against
cow’s milk allergy (Halken, 2004), but the effect against other allergic
diseases as atopic dermatitis and asthma is less conclusive. In a
systematic review with meta-analysis of prospective studies of BF and
the risk of bronchial asthma, BF was reported to reduce the incidence of
wheezing and asthma by 30%. In case of family history for allergy the
LONG TERM EFFECTS OF BREASTFEEDING ON THE INFANT 19
effect was stronger (Gdalevich et al., 2001). In a recent review it was
concluded that there seemed to be a positive effect of BF on atopic
diseases and that the effect was stronger in families with atopic disease
(van Odijk et al., 2003). However, two other studies report no overall
effect of BF. If the children were stratified by family history of allergy, a
protective effect was observed in children with parents with allergy,
whereas there was a slightly increased risk of atopic dermatitis in
children with parents without allergy (Laubereau et al., 2004; Stabell et
Coeliac disease, or permanent gluten-sensitive enteropathy, is an
immunologic disease dependent on exposure to gluten. BF reduces the
risk of coeliac disease if gluten-containing foods are introduced
gradually into the diet of infants while they are still being breast-fed
(Ivarsson et al., 2002).
Among other immune related diseases, BF has been reported to
reduce the risk of Crohn’s disease and colitis ulcerosa, but it is not know
if BF is of major importance for development of these diseases (Davis,
2001; Klement et al., 2004). Also protection against development of
multiple sclerosis, rheumatoid arthritis by BF has been reported (Hanson
et al., 2001). The use of donor human milk versus formulas seems to
reduce the risk of necrotising enterocolitis in preterm infants (McGuire
& Anthony, 2003).
6. TYPE 1-DIABETES MELLITUS
Type 1-diabetes mellitus (DM) is caused by both genetic and
environmental factors. A number of studies have shown a protective
effect of BF, whereas introduction of formula milk and complementary
food seems to increase the risk (Davis, 2001). In addition, increased
early growth is also associated with type 1 diabetes risk and is
independent of the other risk factor, early introduction to formula milk
(Hyppönen et al., 1999, EURODIAB Group, 2002). In a multi centre
study, BF was reported to reduce the risk of DM by 40% relative to
children never being BF after adjusting for growth pattern (EURODIAB
Group, 2002). It has been suggested that LCPUFA present in breast milk
improves the resistance of the β-cells (Das, 2003).
Lene Schack-Nielsen, Anni Larnkjær, Kim Fleischer Michaelsen
7. CARDIOVASCULAR DISEASE
The serum cholesterol concentration is higher in breast-fed infants
than in formula-fed infants since breast milk contains cholesterol but this
is not seen once BF finishes. Serum cholesterol level is lower in adults
who had been breast fed (Owen et al., 2002). In accordance with this a
meta-analysis reported that BF was associated with lower systolic blood
pressure in later life. However, the overall difference was only 1.1 mm
Hg, which is of limited clinical importance (Owen et al., 2003). An
adverse effect has also been reported in a single study, where BF was
associated with reduced arterial distensibility (Leeson et al., 2001). In
addition, two new studies find no conclusive evidence that BF influences
the risk of developing cardiovascular disease mortality (Martin et al.,
2004; Rich-Edwards et al., 2004)
Two meta-analyses suggest that BF is associated with a small
decrease in the risk for childhood leukaemia (Kwan et al., 2004) and
other childhood cancer forms (UK CCS Investigators, 2001). The
protective effect of BF seems similar for all cancer forms why a non-
specific effect of BF or a systematic bias shared by most of the included
studies cannot be excluded.
9. MATERNAL EFFECTS
Protection against breast cancer is the most significant effect of BF
on maternal health. A meta-analysis showed that the relative risk of
breast cancer decreased by 4.3% for every 12 month of BF, in addition to
a decrease of 7% for each birth (Collaborative Group, 2002).
LONG TERM EFFECTS OF BREASTFEEDING ON THE INFANT 21
Anderson, J.W., Johnstone, B.M., and Remley, D.T., 1999, Breast-feeding and cognitive
development: a meta-analysis, Am J Clin. Nutr. 70:525-535.
Collaborative Group on Hormonal Factors in Breast Cancer, 2002, Breast cancer and
breast feeding: collaborative reanalysis of individual data from 47 epidemiological
studies in 30 countries, including 50302 women with breast cancer and 96973 women
without the disease, Lancet, 360:187-95
Das, U.N., 2003, Can perinatal supplementation of long-chain polyunsaturated fatty acids
prevent diabetes mellitus? Eur J Clin Nutr. 57:218-26.
Davis, M.K., 2001, Breastfeeding and chronic disease in childhood and adolescence.
Pediatr Clin North Am, 48:125-41, ix.
Dewey, K.G., 1998, Growth characteristics of breast-fed compared to formula-fed
infants. Biol Neonate, 74:94-105.
EURODIAB Substudy 2 Study Group, 2002, Rapid early growth is associated with
increased risk of childhood type 1 diabetes in various European populations. Diabetes
Gdalevich, M., Mimouni, D., and Mimouni, M., 2001, Breast-feeding and the risk of
bronchial asthma in childhood: a systematic review with meta-analysis of prospective
studies. J Pediatr, 139:261-6.
Goldblum, R., Hanson, L., and Brandtzaeg, P., 1996, The mucosal defence system. In
Immunological Disorders in Infants and Children. 3rd edit. E. Stiehm, Ed.: 159-199.
Saunders. Philadelphia, PA.
Hahn-Zoric, M., Fulconis, F., Minoli, I., Moro, G., Carlsson, B., Bottiger, M., Raiha, N.,
and Hanson, L.A., 1990, Antibody responses to parenteral and oral vaccines are
impaired by conventional and low protein formulas as compared to breast-feeding.
Acta Paediatr Scand., 79 (12):1137-42
Halken S, 2004, Prevention of allergic disease in childhood: clinical and epidemiological
aspects of primary and secondary allergy prevention. Pediatr Allergy Immunol. 16:4-
Hanson, L., Silfverdal, S.A., and Stromback, L., 2001, The immunological role of breast
feeding. Pediatr Allergy Immunol; 12 Suppl 14:15-9.
Hanson, L.A., Korotkova, M., Lundin, S., 2003, The transfer of immunity from mother to
child. Ann N Y Acad Sci, 987:199-206.
Hasselbalch, H., Jeppesen, D.L., Engelmann, M.D., Michaelsen, K.F., and Nielsen, M.B.,
1996, Decreased thymus size in formula-fed infants compared with breastfed infants.
Acta Paediatr, 85:1029-32.
Heinig, M.J., and Dewey, K.G., 1996, The advantages of breast feeding infants: a critical
review. Nutrition Research Reviews, 9:89-110.
Howie, P.W., 2002, Protective effect of breastfeeding against infection in the first and
second six months of life, Adv Exp Med Biol 503 141-147
Hyppönen, E., Kenward, M.G., and Virtanen, S. M., 1999, Infant feeding, early weight
gain, and risk of type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group.
Diabetes Care, 22:1961-5.
Ivarsson, A., Hernell, O., Stenlund, H., and Persson, L.A., 2002, Breast-feeding protects
against celiac disease. Am J Clin Nutr 75:914-21.
Klement, E., Cohen, R.V., Boxman J., Joseph, A., and Reif S., 2004, Breastfeeding and
risk of inflammatory bowel disease: a systematic review with meta-analysis. Am J
Clin Nutr 80: 1342-52
Kramer, M.S., and Kakuma R., 2002, The optimal duration of exclusive breast feeding. A
Laubereau, B., Brockow, I., and Zirngibl, A., 2004, Effect of breast-feeding on the
development of atopic dermatitis during the first 3 years of life--results from the
GINI-birth cohort study. J Pediatr, 144:602-7.
Kwan M.L., Buffler P.A., Abrams B., and Kiley V.A., 2004, Breastfeeding and the risk
of childhood leukaemia: A meta-analysis. Public Health Rep. 119:521-535
Lauritzen, L., Hansen, H. S., Jorgensen, M.H., and Michaelsen, K. F., 2001, The
essentiality of long chain n-3 fatty acids in relation to development and function of the
brain and retina. Prog. Lipid Res. 40, 1-94.
Leeson, C.P., Kattenhorn, M., Deanfield, J.E., and Lucas, A., 2001, Duration of breast
feeding and arterial distensibility in early adult life: population based study. BMJ,
León-Cava, N., Lutter, C., Ross, J., and Martin, L., 2002, Quantifying the benefits of
breast feeding: a summary of the evidence,
Martin, R.M., Davey, S.G., Mangtani, P., Tilling, K., Frankel, S., and Gunnell, D., 2004,
Breastfeeding and cardiovascular mortality: the Boyd Orr cohort and a systematic
review with meta-analysis. Eur Heart J 25:778-86.
McGuire, W., and Anthony, M.Y., 2003, Donor human milk versus formula for
preventing necrotising enterocolitis in preterm infants: systematic review. Arch Dis
Child Fetal Neonatal Ed, 88:F11-F14.
Michaelsen K.F., Petersen S., Greisen G., and Thomsen B.L., 1994, Weight, length, head
circumference and growth velocity in a longitudinal study of Danish infants. Dan Med
Michaelsen K.F., Lauritzen, L., Jørgensen, M.H., and Mortensen, E.L., 2003, Breast-
feeding and brain development, Scand. J. Nutr,. 47:147-151.
Mortensen, E.L., Michaelsen, K.F., Sanders, S.A., and Reinisch, J.M., 2002, The
association between duration of breastfeeding and adult intelligence. JAMA,
Oddy, W.H., Sly, P.D., and de Klerk, N.H., 2003, Breast feeding and respiratory
morbidity in infancy: a birth cohort study. Arch Dis Child 88 :224-8.
Owen, C.G., Whincup, P.H., Gilg, J.A., and Cook, D.G., 2003, Effect of breast feeding in
infancy on blood pressure in later life: systematic review and meta-analysis. BMJ,
Owen, C.G., Whincup, P.H., Odoki, K., Gilg, J.A., and Cook, D.G., 2002, Infant feeding
and blood cholesterol: a study in adolescents and a systematic review. Pediatrics,
Rich-Edwards, J.W., Stampfer, M.J., and Manson, J.E., 2004, Breastfeeding during
infancy and the risk of cardiovascular disease in adulthood. Epidemiology, 15:550-6.
Lene Schack-Nielsen, Anni Larnkjær, Kim Fleischer Michaelsen
LONG TERM EFFECTS OF BREASTFEEDING ON THE INFANT 23
SanGiovanni, J.P., Berkey, C.S., Dwyer, J.T., and Colditz, G.A., 2000, Dietary essential
fatty acids, long-chain polyunsaturated fatty acids, and visual resolution acuity in
healthy full term infants: a systematic review. Early Hum Dev, 57:165-88.
Stabell, B.C., Wohlfahrt. J., and Aaby, P., 2004, Breastfeeding and risk of atopic
dermatitis, by parental history of allergy, during the first 18 months of life. Am J
UK Childhood Cancer Study Investigators, 2001, Breastfeeding and childhood cancer, Br
J Cancer, 85
van Odijk, J., Kull, I., and Borres, M.P., 2003, Breastfeeding and allergic disease: a
multidisciplinary review of the literature (1966-2001) on the mode of early feeding in
infancy and its impact on later atopic manifestations. Allergy, 58:833-43.
WHO, 2002, The optimal duration of exclusive breastfeeding. Report of an expert
EXPERIMENTAL EVIDENCE FOR LONG-
TERM PROGRAMMING EFFECTS OF EARLY
M.E. Symonds, H. Budge, T. Stephenson and D.S. Gardner
Centre for Reproduction and Early Life, Institute of Clinical Research, University
Hospital, Nottingham, NG7 2UH, United Kingdom.
Abstract: Nutritional manipulation targeted at specific periods of embryo or
placental development can result in substantial changes in fetal organ
development despite no effects on fetal weight. In particular, kidney and
fat mass are greater in nutrient restricted offspring in conjunction with
higher mRNA abundance for leptin, insulin-like growth factors I/II and
glucocorticoid receptors. As young adults, nutrient restricted offspring
exhibit a blunting of the cardiovascular baroreflex. They also
demonstrate increased plasma leptin following sympathetic stimulation,
not observed in controls, indicating resetting of adipocyte sensitivity to
stress. In conclusion, global nutrient restriction confined to periods of
early development programmes adult physiology in a manner that may
predispose to later disease given the appropriate environmental stimuli.
Key words: fetal development; mRNA; leptin; embryo, stress; kidney; fat
1. DEVELOPMENTAL PROGRAMMING OF
Hypertension and obesity are major risk factors for coronary heart
disease and represents a common cause of death in the population over
the age of 50 years1. Wide ranging epidemiological evidence from
different populations worldwide indicate that targeted changes in the
nutritional and hormonal environment encountered by the fetus are
strong determinants of later cardiovascular disease2,3. Epidemiological
and animal studies both indicate that the timing of maternal nutritional
manipulation is a key determinant of later outcomes4-6. Critically, these
effects can occur in the absence of any change in birth weight. Indeed, it
is striking that across a very wide range of caloric intakes there is very
little change in birth weight7. The long term consequences of maternal
EXPERIMENTAL EVIDENCE FOR LONG-TERM PROGRAMMING 25
nutrient restriction in utero appear to be dependent on, or amplified by,
the timing, magnitude and duration of nutritional rehabilitation8,9. Later,
nutritional intake becomes increasingly important, particularly after birth
when nutrient availability and physical constraints to growth are
“unlimited” and an individual’s full growth potential can be met. In the
current review we will focus on the experimental evidence that kidney
and fat development are programmed in utero given the strong link that
compromised kidney function and excess fat mass have with adult
2. ANIMAL MODELS OF FETAL PROGRAMMING
Studies from both small and large animal models have shown that
maternal dietary manipulations, either throughout gestation or targeted to
defined periods of pregnancy, can have long term health
consequences6,11. The magnitude of response varies greatly between
animal models which is likely to reflect the very different metabolic
constraints imposed on the mother by the growing fetus. Rats appear to
be particularly vulnerable to any nutritional imbalance during gestation,
perhaps because they are litter bearing, have a short gestation and there
is rapid growth of both the placenta and fetus over the final few days of
pregnancy. The products of conception in the rat exhibit an exceptional
rate of protein accretion during prenatal development (estimated at 23-
fold that of the sheep and human fetus12) and have a large total weight
relative to maternal weight at term (25-35% vs. 7-10% in the sheep and
3-5% in humans). Sheep, on the other hand, are similar to humans in that
a rapid phase of placental growth precedes that of the fetus13. Depending
on the breed of sheep, they are like humans and normally produce single
offspring, of a similar body weight after a long gestation, with a mature
hypothalamic-pituitary axis at birth.
3. NUTRITIONAL MANIPULATION AND FETAL
The full extent to which a deficiency or imbalance of macro or
micronutrients directly act to adversely influence fetal development
remains an area of debate. To date, the current consensus from
epidemiological and observational studies in the human support a
primary role for macronutrients4,14. One of the best characterised animal
models of fetal programming is the rat in which the effects of both a high
and low protein diet have been examined11,15. These studies have
repeatably shown that maternal consumption of a low protein diet either
throughout gestation11, or at specific time periods, results in offspring
with raised blood pressure16. The magnitude of effect is partly dependent
on the timing of exposure and in some16, but not all, studies is gender
specific. It is notable that a low protein diet does not have any initial
stimulatory effects on fat deposition17 which contrasts with the effects of
a high protein diet15. However, any programming effects of high or low
protein exposure in utero on later fat deposition appear to be dependent
on the postnatal diet. Offspring of rats fed a high protein diet during fetal
development only become obese when fed a standard diet after birth15.
Whilst in mice, consumption of excess nutrition after birth, following
exposure to a low protein diet is reported to result in obesity and reduce
life span by almost one-third18. The extent to which these responses are
the consequence of specific changes within the adipocyte, or related to
centrally mediated effects on appetite regulation, are unclear.
M.E. Symonds, H. Budge, T. Stephenson and D.S. Gardner
4. TISSUE SPECIFIC RESPONSES TO
NUTRITIONAL MANIPULATION THROUGH
Offspring of pregnant rats that were globally nutrient restricted so as
to cause intrauterine growth retardation in all offspring, become obese
but only after puberty. In this model, the resulting offspring exhibit a
range of adult complications including sedentary behaviour19,
hyperinsulinemia and hyperleptinemia20,21. Obesity is associated with
hyperphagia but is observed on both a standard as well as a hypercaloric
diet20. These rats are also hypertensive and the effects can be reversed by
treatment with growth hormone22. No adverse responses in the kidney
have been reported to date in this model.
In rats, the programming of higher blood pressure appears to be
greatly amplified compared with human epidemiological and large
animal studies. A 20-40 mmHg increase in systolic blood pressure
occurs not only with low protein diet11 but also with iron deficiency23
and excess fat intake24 through pregnancy. Impaired kidney development
EXPERIMENTAL EVIDENCE FOR LONG-TERM PROGRAMMING 27
with a low protein diet or iron deficiency is likely to cause this higher
blood pressure23,25. The later outcomes in kidney function after feeding
the mothers a high fat diet have not been reported, but an increase in
offspring blood pressure was confined to the females despite plasma
cortisone being raised in males and females24. Interestingly in this model,
abnormalities of vascular endothelial function i.e. endothelium-
dependent dilation were not gender specific and do not suggest this
mechanism is involved in the progression of hypertension.
Adverse long term outcomes of consuming a low protein diet are not
confined to blood pressure control but include abnormal pancreatic
development, as β-cell mass and islet vascularisation are both reduced26.
This defect can be overcome by taurine supplementation which has a
number of beneficial effects including restoration of the normal volume
and numerical density of blood vessels in fetal islets27. Taurine also
prevented under expression of both vascular endothelial growth factor
and its receptor fetal liver-kinase-1. It is not known if taurine similarly
rectifies the adverse cardiovascular outcomes. Moreover, conversely,
although pancreatic function is impaired, offspring born to taurine
deficient dams do not develop obesity.
5. MECHANISMS OF FETAL PROGRAMMING
AND LATER DISEASE
The kidney - is a primary organ implicated in fetal programming. In
large animals, such as sheep, early kidney development is highly
sensitive to excess corticosteroid exposure28. A key stage of fetal kidney
maturation is the period in which the pronephros develops and then
degenerates29, coincident with the time of implantation/uterine
attachment. Exposure to very high levels of glucocorticoids over this
period has no effect on glucocorticoid receptor number but may have
direct consequences for kidney function as assessed by a decline in the
osmolality, sodium and chloride content of allantoic fluid together with a
rise in potassium concentration30. These adaptations have been
interpreted to be a consequence of the premature up-regulation of Na,K-
ATPase activity within the mesonephroi which is similarly increased in
offspring born to mothers fed a low protein diet31. Fetuses exposed to
dexamethasone early in gestation exhibit increased urinary flow rate
following three days of angiotensin II infusion in late gestation32,
confirming persistent changes in kidney function. The offspring go on to
have higher resting, but not stimulated, blood pressure28.
In rat offspring, the higher blood pressure after low protein exposure
in utero is likely to be a result of a reduction in kidney nephron
number33, possibly due to excess glucocorticoid exposure in utero34
suppressing development of the renin-angiotensin system35. These
findings are partly in accord with the effect of targeted global caloric
restriction between early to mid gestation in sheep for which the
offspring have kidneys with a greater mRNA abundance of
glucocorticoid receptor and glucocorticoid responsive genes such as the
angiotensinogen 2 type I receptor36. Nephron number is decreased in the
offspring as is activity of the enzyme 11β-hydroxysteroid dehydrogenase
(HSD) type 237,38, thereby potentially leading to increased sensitivity to
subsequent stress. Interestingly, as a function of total body mass, the
difference in kidney weight between nutrient restricted and control
offspring reduces with age (Figure 1). At the same time blood pressure
of nutrient restricted offspring switches from being lower than that of
controls, to being higher. The transition to high blood pressure following
in utero nutrient restriction thus appears to be an age dependent process.
A prominent component of this adaptation resides in a resetting of the
cardiovascular baroreflex that is essential in maintaining central pressure
during ambulatory changes in blood pressure: if this is inadequate, then
the risk of later hypertension is increased39. Sheep born to nutrient
restricted mothers show a blunted baroreflex sensitivity during
angiotensin II infusion, whereas the tachycardia following a reduction in
central blood pressure is potentiated, relative to controls39,40. An increase
in regional angiotensin II activity in the area postrema and nucleus
tractus solitarius during this critical early phase of development is a
likely candidate mechanism.
Fat - In sheep, fetal fat growth is under tight nutritional regulation
and is highly sensitive to alterations in maternal nutrition through
pregnancy6. Fetal fat deposition is, thus, enhanced by nutrient restriction
commencing early in pregnancy but is reduced by maternal
undernutrition in late gestation41. Fat mass is raised in the offspring of
previously nutrient restricted mothers and remains so for as long as the
offspring have been studied (Figure 1). At term, the increased adiposity
is accompanied by higher mRNA abundance for leptin, plus insulin-like
growth factors I/II and glucocorticoid receptors36,37. These adaptations
M.E. Symonds, H. Budge, T. Stephenson and D.S. Gardner
EXPERIMENTAL EVIDENCE FOR LONG-TERM PROGRAMMING 29
occur in conjunction with reduced maternal plasma cortisol, thyroid
hormones and leptin concentrations over the period of nutrient
restriction36,42. Then, as young adults, nutrient restricted offspring
demonstrate increased plasma leptin following sympathetic stimulation,
which is not observed in controls, indicating resetting of adipocyte
sensitivity to stress40. It remains to be established whether increasing
nutrient availability at specific stages in later life could exacerbate these
symptoms, for example during lactation, when fat is the fastest growing
organ of the body43.
In conclusion, nutrient restriction, confined to the periods of
embryonic and placental development,
physiologyogy39. This is predicted to enhance the offspring’s
predisposition to later disease given the appropriate environmental
stimuli experienced as an adult.
The authors wish to acknowledge the financial support of the British
Heart Foundation, BBSRC and The Nutricia Foundation.
1. C. M. Law and A. W. Shiell, Is blood pressure inversely related to birth weight? The
strength of evidence from a systematic review of the literature. 14, 935-941 (1996).
2. D. J. P. Barker, In utero programming of chronic disease. Clin Sci 95, 115-128 (1998).
3. G. C. Curhan, W. C. Willett, E. B. Rimm, D. Spiegelman, A. L. Ascherio and M. J.
Stampfer, Birth weight and adult hypertension, diabetes mellitus, and obesity in US
men. Circulation 94, 3246-3250 (1996).
4. T. J. Roseboom, J. H. P. van der Meulen, C. Osmond, D. J. P. Barker, A. C. J. Ravelli
and O. P. Blecker, Plasma lipid profile in adults after perinatal exposure to famine.
Am J Clin Nutr 72, 1101-11106 (2000).
5. T. J. Roseboom, J. H. P. van der Meulen, C. Osmond, D. J. P. Barker, A. C. J. Ravelli,
S.-T. von Montfrans, G.A., R. P. J. Michels and O. P. Blecker, Coronary heart disease
in adults after perinatal exposure to famine. Heart 84, 595-598 (2000).
6. M. E. Symonds, S. Pearce, J. Bispham, D. S. Gardner and T. Stephenson, Timing of
nutrient restriction and programming of fetal adipose tissue development. Proc Nutr
Soc 63, (In press) (2004).
7. M. E. Symonds, D. S. Gardner, S. Pearce and T. Stephenson, in Fetal Nutrition and
Adult Disease - Programming of chronic disease through fetal exposure to
undernutrition ed. S. C. Langley-Evans 353-380 CAB International, Oxford, (2004).
8. J. Dandrea, V. Wilson, G. Gopalakrishnan, L. Heasman, H. Budge, T. Stephenson and
M. E. Symonds, Maternal nutritional manipulation of placental growth and glucose
transporter-1 abundance in sheep. Reprod 122, 793-800 (2001).
9. M. E. Symonds, H. Budge, T. Stephenson and I. C. McMillen, Fetal endocrinology
and development - manipulation and adaptation to long term nutritional and
environmental challenges. Reprod 121, 853-862 (2001).
10. J. E. Hall, The kidney, hypertension, and obesity. 41, 625-633 (2003).
11. S. C. Langley-Evans, Fetal programming of cardiovascular function through exposure
to maternal undernutrition. Proc Nutr Soc 60, 505-513 (2001).
13. L. Heasman, L. Clarke, J. Dandrea, T. Stephenson and M. E. Symonds, Correlation of
fetal number with placental mass in sheep. Cont Rev Obs Gynecol 10, 275-280
14. K. Godfrey, S. Robinson, D. J. P. Barker, C. Osmond and V. Cox, Maternal nutrition
in early and late pregnancy in relation to placental and fetal growth. BMJ 312, 410-
15. M. Daenzer, S. Ortmann, S. Klaus and C. C. Metges, Prenatal high protein exposure
decreases energy expenditure and increases adiposity in young rats. 132, 142-144
16. W. Y. Kwong, A. E. Wild, P. Roberts, A. C. Willis and T. P. Fleming, Maternal
undernutrition during the preimplantation period of rat development causes blastocyst
abnormalities and programming of postnatal hypertension. Development 127, 4195-
17. S. E. Ozanne, B. T. Nave, C. L. Wang, P. R. Shepherd, J. Prins and G. D. Smith, Poor
fetal growth causes long-term changes in expression of insulin signalling components
in adipocytes. Am J Physiol 273, E46-E51 (1997).
18. S. E. Ozanne and C. N. Hales, Lifespan: Catch-up growth and obesity in male mice.
427, 411-412 (2004).
19. M. H. Vickers, B. H. Breier, D. McCarthy and P. D. Gluckman, Sedentary behavior
during postnatal life is determined by the prenatal environment and exacerbated by
postnatal hypercaloric nutrition 285, R271-3 (2003).
20. M. H. Vickers, B. H. Breier, W. S. Cutfield, P. L. Hofman and P. D. Gluckman, Fetal
origins of hyperphagia, obesity, and hypertension and postnatal amplification by
hypercaloric nutrition 279, E83-7 (2000).
21. M. H. Vickers, S. Reddy, I. B.A. and B. H. Breier, Dysregulation of the adipoinsular
axis – a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes
induced by fetal programming. J. Endocrinol. 170, 323-332 (2001).
22. M. H. Vickers, B. A. Ikenasio and B. H. Breier, Adult growth hormone treatment
reduces hypertension and obesity induced by an adverse prenatal environment 175,
23. L. Gambling, S. Dunford, D. I. Wallace, G. Zuur, N. Solanky, K. S. Srai and H. J.
McArdle, Iron deficiency during pregnancy affects postnatal blood pressure in the rat.
552.2, 603-610 (2003).
M.E. Symonds, H. Budge, T. Stephenson and D.S. Gardner
EXPERIMENTAL EVIDENCE FOR LONG-TERM PROGRAMMING 31
24. I. Y. Khan, P. D. Taylor, V. Dekou, P. Seed, L. Lakasing, D. Graham, A. F.
Dominiczak, M. A. Hanson and L. Poston, Gender-linked hypertension in offspring of
lard fed pregnant rats. 188, 454-460 (2003).
25. M. O. Nwagwu, A. Cook and S. C. Langley-Evans, Evidence of progressive
deterioration of renal function in rats exposed to a maternal low-protein diet in utero.
Brit J Nutr 83, 79-85 (2000).
26. A. Snoeck, C. Remacle, B. Reusens and J. J. Hoet, Effect of low protein diet during
pregnancy on the fetal rat endocrine pancreas. 57, 107-118 (1990).
27. S. Boujendar, E. Arany, D. Hill, C. Remacle and Reusens. B, Taurine
supplementation of a low protein diet fed to rat dams normalizes the vascularization
of the fetal endocrine pancreas. 133, 2820-2825 (2003).
28. M. Dodic, V. Hantzis, J. Duncan, S. Rees, I. Koukoulas, K. Johnson, E. M. Wintour
and K. Moritz, Programming effects of short prenatal exposure to cortisol. FASEB J
16, 1017-1026 (2002).
29. E. M. Wintour, D. Alcorn, A. Butkus, M. Congiu, L. Earnest, S. Pompolo and S. J.
Potocnik, Ontogeny of hormonal and excretory function of the meso- and
metanephros in the ovine fetus Kidney Int. 50, 1624-1633 (1996).
30. A. Peers, V. Hantzis, M. Dodic, I. Koukoulas, A. Gibson, R. Baird, R. Salemi and E.
M. Wintour, Functional glucocorticoid recetpors in the mesonephros of the ovine
fetus. Kidney Int 59, 425-433 (2001).
31. C. E. Bertram, A. R. Trowern, N. Copin, A. A. Jackson and C. B. Whorwood, The
maternal diet during pregnancy programs altered expression of the glucocorticoid
receptor and type 2 11β-hydroxysteroid dehydrogenase: Potential molecular
mechanisms underlying the programming of hypertension in utero. Endocrinology
142, 2841-2853 (2001).
32. K. Moritz, K. Johnson, R. Douglas-Denton, E. M. Wintour and M. Dodic, Maternal
glucocorticoid treatment programs alterations in the renin-angiotensin system ovine
fetal kidney. Endocrinology 143, 4455-4463 (2002).
33. S. McMullen, D. S. Gardner and S. C. Langley-Evans, Prenatal programming of
angiotensinogen type II receptor expression in the rat. 91, 133-140 (2004).
34. S. C. Langley-Evans, G. J. Phillips, R. Benediktsson, D. S. Gardner, C. R. W.
Edwards, A. A. Jackson and J. R. Seckl, Protein intake in pregnancy, placental
glucocorticoid metabolism and the programming of hypertension. Placenta 17, 169-
35. L. L. Woods, J. R. Ingelfinger, J. R. Nyengaard and R. Rasch, Maternal protein
restriction suppresses the newborn renin-angiotensin system and programs adult
hypertension in rats. 49, 460-467 (2001).
36. J. Bispham, G. S. Gopalakrishnan, J. Dandrea, V. Wilson, H. Budge, D. H. Keisler, F.
Broughton Pipkin, T. Stephenson and M. E. Symonds, Maternal endocrine adaptation
throughout pregnancy to nutritional manipulation: consequences for maternal plasma
leptin and cortisol and the programming of fetal adipose tissue development
Endocrinology 144, 3575-3585 (2003).
37. C. B. Whorwood, K. M. Firth, H. Budge and M. E. Symonds, Maternal
undernutrition during early- to mid-gestation programmes tissue-specific alterations in
the expression of the glucocorticoid receptor, 11β-hydroxysteroid dehydrogenase
M.E. Symonds, H. Budge, T. Stephenson and D.S. Gardner
isoforms and type 1 angiotensin II receptor in neonatal sheep. Endocrinology 142,
38. L. Passingham, L. O. Kurlak, G. Gopalakrishnan, H. Budge, S. M. Rhind, M. T. Rae,
C. E. Kyle, T. Stephenson and M. E. Symonds, The effect of maternal nutrient
restriction during early to mid-gestation on the enzyme activity of 11 beta
hydroxysteroid dehydrogenase type 2 in sheep kidneys of 3 year old offspring. Early
Hum Dev, (In press) (2004).
39. D. S. Gardner, S. Pearce, J. Dandrea, R. M. Walker, M. M. Ramsey, T. Stephenson
and M. E. Symonds, Peri-implantation undernutrition programs blunted angiotensin II
evoked baroreflex responses in young adult sheep. 43, 1-7 (2004).
40. G. Gopalakrishnan, D. S. Gardner, S. M. Rhind, M. T. Rae, C. E. Kyle, A. N. Brooks,
R. M. Walker, M. M. Ramsay, D. H. Keisler, T. Stephenson and M. E. Symonds,
Programming of adult cardiovascular function after early maternal undernutrition in
sheep. 287, R12-20 (2004).
41. H. Budge, L. J. Edwards, I. C. Mcmillen, A. Bryce, K. Warnes, S. Pearce, T.
Stephenson and M. E. Symonds, Nutritional manipulation of fetal adipose tissue
deposition and uncoupling protein 1 abundance in the fetal sheep; differential effects
of timing and duration. Biol Reprod, (In press) (2004).
42. L. Clarke, L. Heasman, D. T. Juniper and M. E. Symonds, Maternal nutrition in
early-mid gestation and placental size in sheep. Brit J Nutr 79, 359-364 (1998).
43. L. Clarke, D. S. Buss, D. S. Juniper, M. A. Lomax and M. E. Symonds, Adipose
tissue development during early postnatal life in ewe-reared lambs. Exp Physiol 82,