NEJM (New England Journal of Medicine)
October 27, 2005


By Matthew W. Gillman, M.D.

At first glance, it may seem implausible that your mother's exposure
to stress or toxins while she was pregnant with you, how she fed you
when you were an infant, or how fast you grew during childhood can
determine your risk for chronic disease as an adult. Mounting
evidence, however, indicates that events occurring in the earliest
stages of human development -- even before birth -- may influence the
occurrence of diabetes, cardiovascular disease, asthma, cancers,
osteoporosis, and neuropsychiatric disorders.

More than 40 years ago, Widdowson and McCance[1] discovered that rat
pups that were undernourished during the three weeks of lactation
gained weight more slowly over their lifetime than control pups did,
even though they had access to ad libitum diets after weaning. In
contrast, an identical duration of an energy deficit between 9 and 12
weeks of age had only a short-term effect on weight gain. These
experiments showed not only that an environmental insult in early life
could have long-term, irreversible consequences, but also that the
insult must occur during a critical period in development to have
maximal effect.

In the years since, investigators have induced such developmental
programming of adverse health outcomes in many animal species with the
use of diverse interventions, ranging from the modification of the
maternal (or even the grandmaternal) diet to the prenatal
administration of glucocorticoid hormones, ligation of the uterine
artery, experimentally produced anemia, and alteration of postnatal
growth.[2] These perturbations can result in the adverse development
of organs or organ systems directly or in adaptive responses that may
be beneficial in the short term but deleterious in the long run.
Because such experiments in animals involve environmental changes,
they do not address purely genetic influences, but epigenetic
processes may play a key role in the mechanisms underlying these

Although experiments in animals illustrate the principle that adult
health outcomes can trace some of their roots to early development,
the extent to which similar developmental processes explain variations
in human health outcomes remains unclear. The first generation of
epidemiologic studies found intriguing associations between birth
weight and disease outcomes decades later.[3] Researchers have found
consistent inverse associations between birth weight and a central
distribution of body fat, insulin resistance, the metabolic syndrome,
type 2 diabetes mellitus, and ischemic cardiovascular disease.[4]
Moreover, the phenotype of lower birth weight coupled with a higher
body-mass index in childhood or adulthood appears to be associated
with the highest risks of these outcomes. This pattern holds, for
example, for insulin resistance in children eight years of age in
India,[5] blood pressure among Filipino adolescents,[6] the metabolic
syndrome among white and Mexican-American adults,[7] and coronary
heart disease among Welsh men and among American women who are

In this issue of the Journal, Barker and colleagues,[10] taking
advantage of unusually extensive data from Finland on childhood growth
and adult outcomes, present a detailed analysis of this pattern. As
compared with members of the cohort in whom heart disease outcomes did
not develop, those who were hospitalized for or died from coronary
heart disease had relatively small body size during the first two
years of life, then grew more rapidly through 11 years of age. This
growth pattern also predicted elevations in biomarkers for insulin
resistance, which is a risk factor for coronary disease. Adjusting for
variables that represent social and economic circumstances in
adulthood did not appreciably change the results. Although some
differences appeared to be present between the affected boys and girls
in patterns of growth during infancy, the limited number of cardiac
events among women precludes strong inferences.

Together with published results from India showing that an increasing
body-mass index through adolescence confers an excess risk of impaired
glucose tolerance in early adulthood,[11] the findings of Barker et
al. provide evidence that for those with a relatively low birth
weight, excess weight gain during childhood and adolescence portends a
particularly poor prognosis for the development of coronary heart
disease in adulthood.

One issue that remains unresolved is the role of early postnatal
growth from birth to two years of age. In contrast to the findings of
Barker et al., recent observational studies of full-term infants and
randomized trials involving premature infants suggest that accelerated
weight gain during infancy, even during the first weeks of life, can
result in overweight, insulin resistance, and high leptin levels and
blood-pressure levels one to two decades later.[12,13] Some of the
discrepancies between the studies may have resulted from the
limitations of body-mass index to represent true fatness, variable
loss to follow-up, and differences in infant growth from one era to
another. Furthermore, published intervention trials are restricted to
premature infants. Getting the right answers, however, is more than an
academic issue. If rapid weight gain in infancy is indeed harmful to
adult health, then clinicians and public health professionals are
faced with many challenges, including those of overcoming cultural
stereotypes suggesting that "a big baby is a healthy baby,"
considering whether growth charts based largely on formula-fed infants
are still appropriate, questioning whether to continue using energy-
enriched formulas for premature infants, and devising more effective
strategies to promote the duration and exclusivity of breast-feeding.

Beyond reproducing the observation that lower birth weight is
associated with heart-disease outcomes, Barker et al. do not address
the area of research most readers will associate with Professor
Barker's name -- the prenatal origins of adult disease. Birth weight is
easily measured and is available from historical records, but if the
truth be told, it is a dreadful marker of prenatal etiologic
pathways.[14] Fortunately, a new generation of epidemiologic studies
directly examine the effects of prenatal determinants on postnatal
health outcomes, irrespective of birth weight. Investigators have
recognized that the initially invoked concept of maternal
undernutrition is a simplistic model of prenatal influences. They now
consider perturbations anywhere along the entire fetal-supply line,
which includes not only maternal diet but also uteroplacental blood
flow, placental function, and fetal metabolism.

Recent studies of maternal diet during pregnancy indicate, for
example, that the higher a mother's intake of fish, if the fish is low
in mercury content, the higher the child's score will be on a test of
cognition,[15] and the higher the mother's calcium intake, the lower
the child's blood-pressure level will be.[16] Despite the known
relationship between smoking and reduced fetal growth, maternal
smoking during pregnancy is associated with an increased risk of
obesity in the offspring.[17] Experiments in animals show that reduced
activity of the placental enzyme 11-hydroxysteroid dehydrogenase type
2 programs hypertension and hyperglycemia in the offspring, as a
result of excess fetal exposure to glucocorticoids.[18] Gestational
diabetes (which is associated with higher birth weight) leads to fetal
hyperinsulinemia and is associated with obesity and impaired glucose
tolerance in the growing child.[19] The treatment of gestational
diabetes is effective in reducing adverse perinatal outcomes,[20] but
its long-term effectiveness in reducing obesity-related consequences
in the offspring is not known, and evidence with regard to strategies
to prevent gestational diabetes is scarce. Indeed, for most of the
epidemiologic associations described to date, the extent to which
interventions that are intended to modify risk can improve long-term
health is not yet clear.

In populations of the world that are undergoing the nutritional and
epidemiologic transition to Western styles of diet, sedentary
behavior, obesity, and chronic diseases, the ominous pattern that
Barker et al. identify -- lower birth weight followed by excess weight
gain in childhood -- is both common and liable to persist for the
foreseeable future. It is therefore imperative that, along with
vigorous efforts to optimize childhood growth, researchers and
policymakers identify, quantify, and evaluate strategies to modify
prenatal and perinatal determinants of adverse adult health outcomes.
These are the goals of the field of inquiry known as the developmental
origins of health and disease, which is now represented by a learned
society, the International Society for Developmental Origins of Health
and Disease, and by yearly interdisciplinary congresses that are
devoted to catalyzing a rapid expansion of research and policy
initiatives. Slowly but surely, investigators in this field are
learning ways by which ensuring the well-being of women of
reproductive age and their newborn children can have substantial
health-promoting effects in the next generation.

* From the Department of Ambulatory Care and Prevention, Harvard
Medical School and Harvard Pilgrim Health Care, and the Department of
Nutrition, Harvard School of Public Health -- all in Boston.


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undernutrition at different ages on the composition and subsequent
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[3] Barker DJP. Mothers, babies, and disease in later life. 2nd ed.
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[4] Oken E, Gillman MW. Fetal origins of obesity. Obes Res

[5] Bavdekar A, Yajnik CS, Fall CHD, et al. Insulin resistance
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[6] Adair LS, Cole TJ. Rapid child growth raises blood pressure in
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[7] Valdez R, Athens MA, Thompson GH, Bradshaw BS, Stern MP.
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[8] Frankel S, Elwood P, Sweetnam P, Yarnell J, Smith GD. Birthweight,
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[9] Rich-Edwards JW, Kleinman K, Michels KB, et al. Longitudinal study
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[10] Barker DJP, Osmond C, Forsen TJ, Kajantie E, Eriksson JG.
Trajectories of growth among children who have coronary events as
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[11] Bhargava SK, Sachdev HS, Fall CH, et al. Relation of serial
changes in childhood body-mass index to impaired glucose tolerance in
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[12] Stettler N, Stallings VA, Troxel AB, et al. Weight gain in the
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[13] Singhal A, Lucas A. Early origins of cardiovascular disease: is
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[14] Gillman MW. Epidemiological challenges in studying the fetal
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[15] Oken E, Wright RO, Kleinman K, et al. Maternal fish consumption,
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[16] Gillman MW, Rifas-Shiman SL, Kleinman KP, Rich-Edwards JW,
Lipshultz SE. Maternal calcium intake and offspring blood pressure.
Circulation 2004;110:1990-1995.

[17] Toschke AM, Montgomery SM, Pfeiffer U, von Kries R. Early
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[18] Seckl JR. Glucocorticoid programming of the fetus: adult
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[19] Gillman MW, Rifas-Shiman SL, Berkey CS, Field AE, Colditz GA.
Maternal gestational diabetes, birth weight, and adolescent obesity.
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[20] Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson
JS. Effect of treatment of gestational diabetes mellitus on pregnancy
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Copyright 2005 Massachusetts Medical Society