ETHICS/EDUCATION

Developmental origins of longitudinal studies of 25,000 UK men and women in which size
at birth was related to the occurrence of disease in middle age.

health and disease People who were small or disproportionate (thin or short) at
birth, or whose infant growth faltered, had high rates of coronary
heart disease, raised blood pressure and cholesterol levels, and
Sarah El-Heis
impaired glucose tolerance, particularly if their restricted fetal
Keith Godfrey and infant growth was followed by increased childhood weight
gain. There is also evidence linking impaired early growth with
later osteoporosis and obstructive airways disease including
Abstract asthma. The relations with size at birth cannot be explained by
Patterns of health, illness and disease are influenced at different stages of
confounding variables acting during adult life. There is now ev-
the lifecourse by a combination of genetic, epigenetic and environmental
idence that both premature birth and fetal growth restriction are
factors. Substantial research has demonstrated that during early develop-
associated with adverse long-term effects.
ment, responses to a range of stimuli are likely to ‘programme’ the risk of
Repeated replication of the UK findings has led to wide
metabolic and other non-communicable disorders, as articulated by the
acceptance that low rates of fetal growth are associated with
‘developmental origins’ or ‘Developmental Origins of Health and Disease
cardiovascular disease in later life. Associations with coronary
(DOHaD)’ concept. Subsequent environmental exposures during infancy,
heart disease have, for example, been shown in further studies
childhood and adult life may modify or condition this later risk of disease.
from the UK, Finland, India and the USA. A systematic review of
In animals the environment during early life induces altered phenotypes
48 publications relating birthweight to later glucose and insulin
in ways which are influenced or mediated by epigenetic mechanisms,
metabolism concluded that, generally, people who were light at
including DNA methylation, covalent modifications of histones and non-
birth have an adverse profile of later glucose and insulin meta-
coding RNAs. Experimental and human data indicate that efforts to
bolism. Moreover, it is widely accepted that birthweight is a
improve the nutrition of young women before and during pregnancy
crude proxy for developmental exposures, such as maternal diet
will be central to future preventive strategies.
and body composition, and will not ‘capture’ the full extent of
Keywords development; epigenetics; non-communicable disease; the effects of developmental exposures. Studies in children sug-
nutrition gest that, as in animals, impaired renal development and endo-
thelial dysfunction may be on the mechanistic pathways linking
Background developmental exposures with an increased risk of coronary
heart disease. Some studies with follow up into adolescence or
Non-communicable diseases (NCDs), including obesity, diabetes, early adulthood have concluded that greater infant weight gain
and cardiovascular, chronic lung, mental and neurological dis- increases levels of cardiovascular risk factors; however, longer
orders, affect all countries, and people of all ages and WHO has term follow up studies have all found that greater weight gain in
identified them as “the world’s biggest killers”. The 2011 High- infancy is associated with lower rates of cardiovascular disease
level Meeting of the United Nations General Assembly on the
and impaired glucose tolerance in adult life.
Prevention and Control of NCDs noted that maternal and child
The relations between smaller size at birth and an increased
health is inextricably linked with NCDs and their risk factors. It
risk of ill-health and adult disease extend across the normal
stressed the importance of taking a lifecourse approach to
range of infant size in a graded manner. Moreover, animal
addressing NCDs. Likewise, the Department of Health and other
studies and our epidemiological data have demonstrated that
agencies now advocate a lifecourse approach to disease preven-
while maternal thinness and unbalanced diet during pregnancy
tion “from pre-conception through pregnancy, infancy, early
may have modest effects on size at birth, they are nonetheless
years, childhood, adolescence and teenage years, and through to
associated with raised blood pressure and altered glucose-insulin
adulthood and preparing for older age”. metabolism and stress responsiveness in the adult offspring. The
associations do not simply reflect genetic influences; rather our
The developmental origins of health and disease findings indicate that interactions between the early life envi-
Evidence that coronary heart disease and associated disorders ronment and genetic influences determine disease susceptibility.
originate during early development initially came from These observations have led to the hypothesis that coronary
heart disease, type 2 diabetes, osteoporosis and obstructive air-
ways disease originate through developmental plastic responses
Sarah El-Heis MBBS MRCP is a Clinical Research Fellow at the MRC
made by the fetus and infant as part of a prediction of the sub-
Lifecourse Epidemiology Unit, University of Southampton, UK. Conflicts
sequent environment to which it anticipates that it will be
of interest: none declared.
exposed. Critical periods in development result in irreversible
Keith Godfrey BM FRCP PhD is Professor of Epidemiology and Human changes; if the environment in childhood and adult life differs
Development at the MRC Lifecourse Epidemiology Unit and NIHR from that predicted during fetal life and infancy, the develop-
Southampton Biomedical Research Centre, University of Southampton mental responses may increase the risk of adult disease. Evolu-
and University Hospital Southampton NHS Foundation Trust, UK. tionary considerations and experimental findings in animals
Conflicts of interest: KMG has received reimbursement for speaking at strongly support the existence of major developmental effects on
conferences sponsored by companies selling nutritional products, and health and disease in adulthood. The preservation of this “pro-
is part of an academic consortium that has received research funding gramming” phenomenon across species and within the normal
from Abbott Nutrition, Nestec and Danone.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:8 236 Ó 2015 Elsevier Ltd. All rights reserved.
 ETHICS/EDUCATION

Intervention

Risk of Old
None
chronic Age
NCDs
Late life
Adulthood intervention
can have
impact in
Child/adolescent
vulnerable
intervention benefits
next generation groups

Mother/infant
Mother/infa
f nt Early life
intervention can intervention
change trajectory improves
functional
Pre-conception capacity and
reproductive fitness responses to
new challenges

Life course

Plasticity & consequent

f unctional capacity Inadequate response
to new challenges

Figure 1 Lifecourse strategy for disease prevention.

range of fetal growth suggests a physiological rather than a been linked with childhood bone mineral content and muscle
pathological basis to the DOHaD phenomenon. function. Studies of health behaviours have shown that few
women prepare for pregnancy and that the diets of infants and
Underlying mechanisms and maternal influences toddlers are strongly associated with the mother’s diet before
pregnancy.
Although it has been proposed that the associations between fetal
The adverse effect of maternal undernutrition appears to
or infant growth and later adult disease represent the pleiotropic
extend beyond the first (F1) generation and may also include the
effects of genes transmitted from mother to child, maternally
following (F2 or grandchildren) or succeeding generations, at
mediated environmental modulation of gene expression in
least in animal models. The F2 generation of children whose
offspring and geneeenvironment interactions appears to be more
parents were exposed to undernutrition in utero are also at
important than purely heritable genetic risk. There is also
increased risk of developing hypertension and diabetes in adult
growing evidence that epigenetic mechanisms (DNA methyl-
life. Although the mechanisms behind this are unknown, it is
ation, histone modification and non-coding RNAs) are respon-
speculated to involve epigenetic changes to the F2 generation’s
sible for tissue-specific gene expression during growth and
parents’ gametes while exposed to poor nutrition in utero.
development and that these mechanisms underlie the processes
Experimental evidence is accruing that endocrine or nutri-
of developmental plasticity. We have shown that epigenetic gene
tional interventions during early postnatal life can reverse
promoter methylation at birth is associated with the child’s later
epigenetic and phenotypic changes induced, for example, by an
adiposity and measures of bone health, and that peroxisomal
unbalanced maternal diet during pregnancy. Elucidation of these
proliferator activated receptor-g-co-activator-1a promoter
epigenetic processes may permit perinatal identification of in-
methylation in blood at 5e7 years is stable across childhood and
dividuals at risk of later NCD and facilitate a new generation of
associated with adiposity from 9 to 14 years. Our recent studies
early intervention strategies to reduce such risk.
have shown that genetic differences alone best explain 25% of
Figure 1 shows the conceptual framework for ongoing
neonatal methylome variation, with the remaining 75%
research. The risk of NCDs increases across the lifecourse as a
explained by the interaction of genetic differences with the pre-
result of declining plasticity and accumulative effects of inade-
natal environment. Mechanistic studies have also identified fetal
quate responses to new challenges (orange triangles). The
liver blood flow adaptations that link maternal influences with
greatest increase occurs in adult life, but the trajectory is set
offspring body composition.
much earlier, being influenced by factors such as the mother’s
Studies of the UK Southampton Women’s Survey have shown
diet and body composition before and during pregnancy, and
that greater childhood adiposity is associated with higher
fetal, infant and childhood nutrition. In early life, timely in-
maternal adiposity, low maternal vitamin D status, excessive
terventions can have a large effect on disease risk later (purple
gestational weight gain, and short duration of breastfeeding;
area/arrow), while later intervention can remain impactful for
maternal dietary patterns in pregnancy and vitamin D status have
vulnerable groups (blue area/arrow). Intervention in childhood

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:8 237 Ó 2015 Elsevier Ltd. All rights reserved.
 ETHICS/EDUCATION

and adolescence increases biological capital, and may have an combined impact and potential for prevention. Am J Clin Nutr 2015;
important impact on the next generation. A 101: 368e75.
Teh AL, Pan H, Chen L, et al. The effect of genotype and in utero envi-
ronment on interindividual variation in neonate DNA methylomes.
FURTHER READING
Genome Res 2014; 24: 1064e74.
Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG. Trajectories of
growth among children who have coronary events as adults. N Engl J
Med 2005; 353: 1802e9.
Bateson P, Barker D, Clutton-Brock T, et al. Developmental plasticity and Practice points
human health. Nature 2004; 430: 419e21.
Clarke-Harris R, Wilkin TJ, Hosking J, et al. PGC1a promoter methylation in C Adult coronary heart disease, type 2 diabetes, hypertension and
blood at 5e7 years predicts adiposity from 9 to 14 years (EarlyBird other non-communicable disorders originate in developmental
50). Diabetes 2014; 63: 2528e37. plasticity, in response to an adverse environment during fetal life
Godfrey KM. The “Developmental origins” hypothesis: epidemiology. In: & infancy.
Hanson MA, Gluckman PD, eds. Developmental origins of health and C The preservation of this phenomenon across species and within
disease e A biomedical perspective. Cambridge University Press, the normal range of fetal growth suggests a physiological rather
2006; 6e32. than a pathological basis to the DOHaD phenomenon. It is
Godfrey KM, Gluckman PD, Hanson MA. Developmental origins of meta- underpinned by epigenetic processes.
bolic disease: life course and intergenerational perspectives. Trends C A new vision of optimal growth & development needs to
Endocrin Met 2010; 21: 199e205.
 take account of both short and long term outcomes
Godfrey KM, Haugen G, Kiserud T, et al. Fetal liver blood flow distribution:
 acknowledge that size per se is too crude an outcome measure
role in human developmental strategy to prioritize fat deposition
 recognise interactions between the pre and postnatal
versus brain development. PLoS One 2012; 7: e41759.
environments.
Godfrey KM, Sheppard A, Gluckman PD, et al. Epigenetic gene promoter
methylation at birth is associated with child’s later adiposity. Diabetes C Many infants are at increased risk of adult disease because of
2011; 60: 1528e34. impaired fetal development and maternal thinness, overweight,
Harvey NC, Sheppard A, Godfrey KM, et al. Childhood bone mineral dietary imbalance and micronutrient insufficiency, but at present
content is associated with methylation status of the RXRA promoter at there is only a limited basis for changing dietary advice.
birth. J Bone Miner Res 2014; 29: 600e7.
Robinson SM, Crozier SR, Harvey NC, et al. Modifiable early life risk fac-
tors for childhood adiposity and overweight: an analysis of their

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:8 238 Ó 2015 Elsevier Ltd. All rights reserved.