p u b l i c h e a l t h 1 2 6 ( 2 0 1 2 ) 1 8 5 e1 8 9

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Public Health

journal homepage: www.elsevier.com/puhe

Sir Richard Doll Lecture

Developmental origins of chronic disease

D.J.P. Barker a,b,*

a
Medical School, University of Southampton, Southampton, UK
b
Heart Research Center, Oregon Health & Science University, Portland, OR, USA

article info summary

Article history: Coronary heart disease, type 2 diabetes, breast cancer and many other chronic diseases are
Available online 10 February 2012 unnecessary. Their occurrence is not mandated by genes passed down to us through
thousands of years of evolution. Chronic diseases are not the inevitable lot of humankind.
They are the result of the changing pattern of human development. We could readily
Keywords: prevent them, had we the will to do so. Prevention of chronic disease, and an increase in
Fetal programming healthy ageing require improvement in the nutrition of girls and young women. Many
Chronic disease babies in the womb in the Western world today are receiving unbalanced and inadequate
Maternal nutrition diets. Many babies in the developing world are malnourished because their mothers are
Placenta chronically malnourished. Protecting the nutrition and health of girls and young women
should be the cornerstone of public health. Not only will this prevent chronic disease, but it
will produce new generations who have better health and well-being through their lives.
2011 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Introduction
The search for the causes of chronic adult diseases, and the
way to prevent them, has largely failed. For example, there
will soon be 250 million people around the world with type 2
diabetes. Hitherto, the search has been guided by a destructive
model in which the causes to be identified are adverse envi-
ronmental influences that act in adult life, and accelerate
processes associated with normal ageing, such as hardening
of the arteries and rising blood pressure. This model of
causation is based on infectious disease, and presupposes that
each different disease has a separate cause. It has had limited
success. Cigarette smoking and psychosocial stress have been
implicated, but these only go a small way to explaining why
one person lives a short life and another lives to old age. Genes
offer another possibility, but the search for these has been
expensive and largely fruitless. Genes are unlikely to explain
why coronary heart disease, which was rare 100 years ago, is
now the worlds most common cause of death.
There is now clear evidence that people who develop
cardiovascular disease or type 2 diabetes grew differently to
other people in their early life. They tended to grow slowly in
utero, so that their birthweights were toward the lower end of
the normal range. In addition, they tended to remain small for
the first 2 years after birth1,2 and throughout infancy. After
that, they gained weight and body mass index rapidly.3 These
are large effects. If each individual in the Helsinki Birth Cohort
had been in the highest third for birthweight and had
decreased their standard deviation score for body mass index
between 3 and 11 years of age, the incidence of type 2 diabetes
would have been halved.4 Fig. 1, based on the original obser-
vations in Hertfordshire, UK, shows that the relationship
between birthweight and later disease is graded.5 These
findings have been replicated extensively.6e9 They have led to

* MRC Lifecourse Epidemiology Unit, Mailpoint 95, Southampton General Hospital, Southampton SO16 6YD, UK.
E-mail address: djpbarker@gmail.com.
0033-3506/$ e see front matter 2011 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.puhe.2011.11.014
186 p u b l i c h e a l t h 1 2 6 ( 2 0 1 2 ) 1 8 5 e1 8 9
Fig. 1 e Mortality from coronary heart disease in 15,726 men and women in Hertfordshire.
a new developmental model for chronic disease in which the
causes to be identified are linked to normal variations in
fetoplacental and infant development.
Programming
Like other living creatures, humans are plastic during their
development, and adverse influences can permanently
change body structure and function; a phenomenon known
as programming.10 In animals, it is surprisingly easy to
produce lifelong changes in the physiology and metabolism
of the offspring by minor modifications to the diet of the
mother before and during pregnancy.11,12 Malnutrition and
other adverse influences during development permanently
alter gene expression. They also lead to slowing of growth,
which is why chronic disease is associated with low
birthweight.
During development, there are critical periods during
which a system or organ has to mature. These periods are
brief, they occur at different times for different systems, and
they occur in utero for most systems. After birth, only the
brain; liver and immune system remain plastic. Much of
human development is completed during the first 1000 days
after conception (i.e. during intra-uterine life and infancy).
There are three reasons why people who were small at birth
and during infancy are more vulnerable to chronic disease.
First, they have reduced function in key organs, such as the
kidney.13 Second, they have altered settings in their metabo-
lism and hormonal feedback.14 Third, they are more vulner-
able to adverse environmental influences in later life.15
The human baby is challenged and does not have sufficient
resources to perfect every aspect of its body.16 It has a hier-
archy of priorities. Brain growth is at the top of this hierarchy,
and the development of organs such as the kidney and lungs,
which do not function in the womb, are at the bottom. The
development of low-priority organs is traded off to protect
more important organs.
Compensatory growth
If the growth of a fetus, infant or child falters because of
malnutrition or other adversity, it has the ability, once the
adversity has discontinued, to return to its growth trajectory
by accelerated growth. The ability to mount rapid compen-
satory growth following growth faltering is common in
animals and familiar to farmers.17 If energy is allocated to
rapid growth, the allocation to some other developmental
activity must be reduced. In animals, compensatory growth
has a wide range of physiological and metabolic costs that
include premature death. The costs of compensatory growth
are illustrated by its effect on lifespan. In the Helsinki Birth
Cohort, boys who were tall when they entered school lived
longer lives.18 However, there was a group of boys among
whom being tall was associated with a 6-year reduction in
lifespan. These boys were tall because they had undergone
rapid compensatory growth.
Fetal nutrition
Size at birth is the product of the fetuss trajectory of growth,
which is set at an early stage in development, and the
maternoplacental capacity to supply sufficient nutrients to
maintain this trajectory. A rapid trajectory of growth
increases the fetuss demand for nutrients.19 This demand is
greatest late in pregnancy, but the trajectory is thought to be
primarily determined by genetic and environmental effects in
early gestation. Experiments in animals have shown that
alterations in maternal diet around the time of conception can
change the fetal growth trajectory.20 The sensitivity of the
human embryo to its environment is being increasingly
recognized with the development of assisted reproductive
technology.21 The trajectory of fetal growth is thought to
increase with improvements in periconceptional nutrition,
and is faster in male fetuses. The consequent greater vulner-
ability of male fetuses to undernutrition may contribute to the
shorter lives of men.22
 p u b l i c h e a l t h 1 2 6 ( 2 0 1 2 ) 1 8 5 e1 8 9
100 years of nutritional flow
Grandmother Mother
Made grandchilds Released egg
egg Provided nutrients
Donated genes Influenced
placenta
Delivered baby
Fed baby
Stimulated baby
Fed child
Father
Donated genes
1000 days of development
Fig. 2 e The transgenerational roots of chronic disease.
Maternal nutrition
The graded relationship between birthweight and later
disease (Fig. 1) implies that variations in the supply of food
from normal healthy mothers to normal healthy babies have
major implications for the long-term health of the babies.23 A
baby does not depend on the mothers diet during pregnancy:
that would be too dangerous a strategy. Rather, it lives off her
stored nutrients and the turnover of protein and fat in her
tissues.24 These are related to her body composition and
therefore reflect her lifetime nutrition. A girl is born with all
the eggs she will ever have, and the quality of these therefore
reflects her mothers nutritional state. Fig. 2 shows how the
critical 1000 days of development, that determine health for
life, reflect 100 years of nutritional flow.
Studies in Europe and India have shown that high maternal
weight and adiposity are associated with the development of
insulin deficiency, type 2 diabetes and coronary heart disease
in the offspring.25e27 Gestational diabetes is known to be
associated with adverse long-term outcomes in the
offspring.28 There is also an increasing body of evidence
showing that low maternal weight, body mass index and
skinfold thickness are associated with insulin resistance and
raised blood pressure in the offspring.29e35 One of the meta-
bolic links between maternal body composition and birth size
is amino acid synthesis. Women with a greater lean body
mass have higher rates of synthesis in pregnancy.36
Although a mothers diet during pregnancy is not closely
linked to the birthweight of her baby, it can programme the
baby. Follow-up studies of people who were in utero during the
war-time famine in Holland have shown that, although the
babies birthweights were little affected, severe maternal
caloric restriction at different stages of pregnancy was vari-
ously associated with obesity, dyslipidaemia, insulin resis-
tance and coronary heart disease in the offspring.29 In the
Dutch studies, maternal rations with a low protein density
were associated with raised blood pressure in the adult
offspring.37 This adds to the findings of studies in Aberdeen
and Motherwell, UK, which showed that maternal diets with
either a low or a high ratio of animal protein to carbohydrate
187
Placenta Fetus Infant/child
Transported Made placenta Ate food
nutrients Took nutrients Grew
Produced hormones Made organs
Exported wastes Grew body
Vulnerability to
chronic
disease, cancer
and infections
were associated with raised blood pressure in the offspring
during adult life.30,38 While it may seem counterintuitive that
a high-protein diet should have adverse effects, these findings
are consistent with the results of controlled trials of protein
supplementation in pregnancy, which show that high protein
intakes are associated with reduced birthweight.39 One
possibility is that these adverse effects are a consequence of
the metabolic stress imposed on the mother by an unbalanced
diet in which high intakes of essential amino acids are not
accompanied by the micronutrients required to utilize them.
The placenta
A babys birthweight depends not only on the mothers
nutrition but also on the placentas ability to transport nutri-
ents to the fetus from its mother. The placenta seems to act as
a nutrient sensor regulating the transfer of nutrients to the
fetus according to the mothers ability to deliver them, and the
demands of the fetus for them.40 The weight of the placenta,
and the size and shape of its surface, reflect its ability to
transfer nutrients. The shape and size of the placental surface
at birth has become a new marker for chronic disease in later
life.41 The predictions of later disease depend on combina-
tions of the size and shape of the surface and the mothers
body size. Particular combinations have been shown to
predict coronary heart disease,42 hypertension,43 chronic
heart failure44 and certain forms of cancer.45 Variations in
placental size and shape reflect variations in the normal
processes of placental development, including implantation,
growth and compensatory expansion.41 These variations are
accompanied by variations in nutrient delivery to the fetus.
Conclusion
Under the new developmental model for the origins of chronic
disease, the causes to be identified are linked to normal vari-
ations in the processes of development, that lead to variations
in the supply of nutrients to the baby. These variations
188 p u b l i c h e a l t h 1 2 6 ( 2 0 1 2 ) 1 8 5 e1 8 9
programme the function of a few key systems that are linked to
chronic disease: the immune system, anti-oxidant defences,
inflammation,neuro-endocrine settings and the number and
quality of stem cells. There is not a separate cause for each different
disease. Rather, as cigarette smoking has shown, one cause can
have many different disease manifestations. Which chronic
disease originates during development may depend on timing.
Exploration of the developmental model will illuminate
peoples differing responses to the environment through their
lives. As Rene Dubos wrote long ago, The effects of the physical
and social environments cannot be understood without knowl-
edge of individual history.46 The model will also illuminate
geographical and secular trends in disease. As the human body
has changed over the past 200 years, so different chronic diseases
have risen and then fallen to be replaced by other diseases.47,48
Coronary heart disease, type 2 diabetes, breast cancer and
many other chronic diseases are unnecessary. Their occur-
rence is not mandated by genes passed down to us through
thousands of years of evolution. Chronic diseases are not the
inevitable lot of humankind. They are the result of the changing
pattern of human development. We could readily prevent
them, had we the will to do so. An increase in healthy ageing
and the prevention of chronic disease require improvement in
the nutrition of girls and young women. Many babies in the
womb in the Western world today are receiving unbalanced
and inadequate diets. Many babies in the developing world are
malnourished because their mothers are chronically
malnourished. Protecting the nutrition and health of girls and
young women should be the cornerstone of public health. Not
only will this prevent chronic disease, but it will produce new
generations who have better health and well-being through
their lives.
Acknowledgements
The writing of this lecture was greatly helped by discussions with
Professors Kent Thornburg (Oregon Health & Science University)
and Michelle Lampl (Emory University), and colleagues in the
MRC Lifecourse Epidemiology Unit, University of Southampton.
Ethical approval
None declared.
Funding
None declared.
Competing interest
None declared.
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