Fetal origins of adult disease: the Barker
hypothesis revisited—2004
Sue Y.S. Kimm
Purpose of review
The Barker hypothesis implicates the fetal in-utero environment
as a significant determinant of risk for major chronic diseases,
such as cardiovascular disease, stroke, hypertension, type 2
diabetes, and obesity later in life. Although the Barker
hypothesis has gained increasing recognition since it was first
introduced 20 years ago, it is still being met with skepticism
because of the largely observational and cross-sectional
nature of the studies on which it is primarily based. The
purpose of this review is to re-examine the Barker hypothesis
in the context of new information with a focus on prospective
studies in humans and experimental observations made in
laboratory animal models.
Recent findings
The debate on the Barker hypothesis continues, in part fueled
by conflicting findings from different studies. While one study
from the U.S. found no significant correlation between birth
weights and blood pressure at ages 11 to 14 years, another
large study of Filipino children found that the highest levels of
blood pressure were present among those who were relatively
thin at birth but who were later relatively heavy as adolescents.
Two relatively recent review papers on the relationship
between birth weights and blood pressure levels later in life
also drew opposite conclusions. Even animal studies are not
free of controversy. A study linking maternal malnutrition during
the pre-implantation period of rat development to abnormalities
in blastocyst formation was openly faulted for methodologic
flaws in its statistical analysis. There is increasing evidence
that birth weight per se cannot be viewed as a major culprit for
this increased risk. Although the study of Filipino adolescents
had methodologic weaknesses readily acknowledged by the
authors, their findings still suggests that the postnatal
condition of heavier body habitus during adolescence also
played a significant role in blood pressure levels as well as
smaller birth weights. A study of birth weight and later risk for
type 2 diabetes found a higher prevalence of lower birth
weight among those with type 2 diabetes, but in the same
study, they found that the prevalence of diabetes was also
higher among those with larger birth weight and high BMI in
childhood. A recent review of the literature found no strong
evidence to link birth weight to blood lipid levels later in life.
Summary
At present, the Barker hypothesis is in need of further scientific
insight and stronger supporting evidence. The most recent
publications on this subject are review papers and a book
rather than original research that presents novel findings. Thus
far, there is no information that provides any mechanistic
192
insight into the relationship between the intra uterine milieu
and adverse post-natal consequences. There are no unifying
theories which link low birth weights to a variety of different
outcomes later in life. Hence, there are regrettably more
questions remaining than there are answers regarding the
Barker hypothesis. It is timely to perhaps, apply some of the
generally accepted principles for assessing causality to the
available information on the fetal origins hypothesis. The next
step might be to conduct studies that test this notion as an a
priori hypothesis rather than as post hoc examination of
cross-sectional data. The time has also come to further refine
the hypothesis to encompass more than mere correlation
between birth weight and risk for chronic disease later in life.
Surely, life-long exposures to environmental factors such as
dietary patterns, physical activity, and stress levels have to play
either independent or effect modifying roles in the causal web
of chronic disease. It is, therefore, timely to further refine the
Barker hypothesis to a testable proposition, Barker
Hypothesis-Version 2004.
Keywords
Barker hypothesis, fetal origins, chronic disease
Curr Opin Endocrinol Diabetes 11:192–196. © 2004 Lippincott Williams &
Wilkins.
Department of Internal Medicine, Epidemiology, 1 University of New Mexico,
Albuquerque, New Mexico, USA
Correspondence to Sue Y.S. Kimm, MD, Department of Internal Medicine,
Epidemiology, 1 University of New Mexico, MSC 10 5550, Albuquerque, NM
87131, USA
E-mail: skimm@salud.unm.edu
Current Opinion in Endocrinology & Diabetes 2004, 11:192–196
© 2004 Lippincott Williams & Wilkins
1068-3097
The notion that adult-onset chronic diseases have their
biologic and psychosocial roots in childhood is no longer
novel with cholesterol and blood pressure screening hav-
ing become a part of routine pediatric care currently. A
question still remains, however, as to how early in child-
hood the genesis of this process occurs. According to a
proposition set forth by David Barker, the in-utero envi-
ronment may be a significant determinant of the risk for
cardiovascular disease, stroke, obesity, and type 2 diabe-
tes during adulthood.

The Barker hypothesis of “fetal origins” or “fetal pro-
gramming” advocates that the origins of chronic diseases
of adult life lie in fetal responses to the intrauterine en-
vironment. Specifically, it suggests that the genesis of
adult-onset chronic diseases originates through fetal ad-
aptations to undernourishment. This thesis was initially
based largely on observational studies. The first clue
came from a positive correlation between the geographic
distribution of neonatal mortality and death rates from
cardiovascular disease in England and Wales [1]. Be-
cause neonatal mortality can be viewed as an indication
of poor fetal growth, it was hypothesized that there may
be a linkage between fetal malnutrition and cardiovas-
cular mortality. Since the initial report of this relatively
crude ecological observation, several other studies have
found similar associations [2–4].
Skeptics of the Barker hypothesis generally decry the
relatively crude nature of the association and the lack of
adjustment for potential confounders. What would be
the most plausible confounder in these ecological corre-
lations? Fetal malnutrition assumes maternal malnutri-
tion. It can be assumed then that maternal malnutrition
is more likely to occur among women from lower socio-
economic (SES) status. Coronary heart disease was gen-
erally viewed as a disease of the middle class and white
collar professionals in England and Wales until the mid-
1960s when there was a crossover in these associations so
that more recently, socioeconomic status is inversely as-
sociated with coronary heart disease risk. Barker’s first
report linking low birth weight and ischemic heart dis-
ease was based on cardiovascular mortality after the
crossover to an inverse association with SES had taken
place in England. Therefore, it is entirely plausible that
socioeconomic status may be a confounding variable,
since lower SES would be more likely associated with
higher neonatal mortality and also with higher ischemic
heart disease mortality in England and Wales since the
mid-1960s. On the other hand, reports from Sweden and
the US also found a significant association between low
birth weights and ischemic heart disease even after ad-
justing for SES in their analyses, although the effect size
became slightly attenuated with adjustment [3,4]. How-
ever, these two populations (ie, Swedish cohorts born at
the Upsala Academic Hospital and the US Nurse’s Study
cohort) were likely to be more homogeneous across SES
classes and hence, may have lacked adequate statistical
power to detect any effect with variation in SES.
If there were a true linkage between fetal malnutrition
and coronary heart disease, one would have expected to
see a parallel downward secular trend between neonatal
mortality and coronary heart disease before the mid-20th
century. Although neonatal mortality declined, coronary
heart disease continued to rise and peaked in the US in
the late 1960s and since then, there has been a dramatic
Fetal origins of adult disease Kimm 193
drop. Hence, this secular trend runs counter to the
Barker hypothesis.
Another entity that has been implicated in the Barker
hypothesis is obesity. There has been a rather steep rise
in the prevalence of obesity and overweight in the US [5]
in recent decades. The rate of increase in children has
been especially dramatic [6]. One may then ask if this
young obese population might have been a cohort that
was subject to intrauterine malnutrition. To the contrary,
there could be no such cohort effect since there has been
a steady decline in infant and neonatal mortality in the
US during this time. Further, both white and minority
children are experiencing this rise in obesity prevalence.
Therefore, the secular trend in declining neonatal mor-
tality occurring in parallel with the trend of rising obesity
provides information that runs counter to the thesis ad-
vocated by Barker.
The Barker hypothesis has remained a plausible hypoth-
esis in part because there were more studies that tended
to confirm the link between lower birth weight and
higher adult chronic disease mortality than studies that
contradicted it, even though almost all evidence comes
from observational studies. Leon and Koupilova con-
cluded from their review of studies of the relation be-
tween birth weight and later blood pressure levels that
there is substantial and consistent evidence for a nega-
tive association between birth weight and systolic blood
pressure from childhood through the eighth decade of
life [7]. Based on 27 independent studies, the authors
estimated a change (ie, a decrease) of 1.7 mm Hg per 1 kg
increase in birth weight. They also concluded that the
strength of this inverse relation increases with age when
assessed using estimates from cross-sectional studies.
The authors admitted, however, that only a small num-
ber of studies included socioeconomic status as an ad-
justment variable. Additionally, the authors also injected
a cautionary note about the existing studies, which were
mostly cross-sectional.
On the other hand, in a recent review of the same subject
of the linkage between birth weight and blood pressure
levels, the authors concluded that the available evidence
does not support the relevance of birth weight to blood
pressure levels later in life [8]. Their critical review in-
dicated that despite the inverse associations in 52 of 55
studies included in reviews, when the studies are or-
dered according to their statistical size, there was a clear
trend towards weaker associations in the larger studies.
Because of the tendency towards publication bias, one
would assume that the information reported in published
studies on the whole would tend to be supportive of the
hypothesis.
There are two recent reports from longitudinal studies
that examine the relation between birth weight and ado-
194 Obesity and nutrition
lescent blood pressure. A large longitudinal study of Fili-
pino adolescent males showed that the highest odds of
elevated blood pressure occurred among those who were
relatively thin at birth but relatively heavy as adolescents
[9]. Among males, after controlling for birth length and
current BMI, age, and height, the odds for high blood
pressure were significantly decreased with a change in
odds ratio of 0.53 (0.29–0.94, 95% confidence interval)
for each kilogram increase in birth weight. One potential
problem with this study, as the authors noted, is catego-
rization of high blood pressure based on a triplicate mea-
surement of blood pressure, but only on a single occa-
sion. Another question arising from this study is why this
observation of linkage to low birth weight was primarily
confined to boys and not to girls as well.
The second longitudinal study of 250 adolescents who
were examined at birth and prospectively re-examined at
11 to 14 years of age reported nonsignificant correlation
coefficients between birth weight and all blood pressure
measurements [10]. This cohort included a significant
number of low-birth-weight babies (36%) yet it failed to
show an association between birth weight and later blood
pressure. One may argue that the observation period
needs to be extended to adulthood rather than only
through early adolescence. However, it is accepted that
blood pressure levels tend to track, particularly of those
whose levels are in the higher end of the distribution.
Because of the prospective nature of this study, one
would assume that there would be greater internal va-
lidity than in cross-sectional ecological studies.
Based on available information thus far, birth weight
alone may not to be an ideal index of the exposure of the
fetus to an environment that leads to persistent cardio-
vascular alterations. Sanders et al. induced experimental
intrauterine stress in pregnant rats with bilateral ligation
of the uterine arteries and a sham operation as a control
procedure [10b]. This intrauterine stress was associated
with a regionally selective alteration of arterial adrenergic
function at 3 weeks after birth. Not all arteries were
affected such as the femoral and saphenous arteries, but
renal arteries displayed selective pharmacologic alter-
ation. However, these changes in vasculature were not
linked to small birth weights as the pups were matched
on birthweight.
As crude as observational studies generally are, they can
nevertheless be useful in providing clues for hypothesis
generation for identifying potential causal associations.
An example is the observation made by Ochsner and
DeBakey more than half a century ago when they noted
parallel trends in increasing automobile production, in-
creasing cigarette smoking, and increasing lung cancer
mortality in the US [11]. As helpful as such ecologic
observations may be, they provide only limited informa-
tion for hypothesis formulation. However, if there is bio-
logic plausibility of a hypothesis, a hypothesized causal
association such as that between fetal malnutrition and
risk of chronic diseases would be strengthened. Animal
model studies can offer potentially important mechanis-
tic insights. Are there animal data that support the fetal
programming concept? A study by Kwong et al. [12]
linked maternal undernutrition during the pre-implan-
tation period of rat development to abnormalities in blas-
tocyst formation. This study, however, was criticized for
statistical flaws. Because Kwong’s paper was based on
data analysis that pooled “between rat” and “within rat”
variation, Edwards suggested the findings reported in
this study be withdrawn and rigorous statistical evalua-
tion be carried out to provide a proper assessment of the
data [13].
Impaired placental 11␤-hydroxysteroid dehydrogenase
(11␤-HSD2) has been associated with intrauterine
growth restriction and with programming of hyperten-
sion in adulthood [14]. There are two distinct isozymes
of (11␤-HSD) that catalyze the interconversion of hor-
monally active cortisol and inactive cortisone. Type 2
enzyme (11␤-HSD2) is widely expressed in fetal tissues,
including placental syncytiotrophoblasts. Glucocorticoid
excess in utero decreases fetal growth, and the high levels
of placental 11␤-HSD2 activity may protect the fetus
from maternal glucocorticoid excess. Quinkler and Stew-
ard [15] in their review of hypertension and the cortisol-
cortisone shuttle, hypothesized a theoretical pathway for
the linkage between intrauterine malnutrition and later
development of hypertension. About 30 years ago, the
syndrome of apparent mineralocorticoid excess (AME) in
children with features of mineralocorticoid hypertension
(low-renin, hypokalemia) but with low levels of aldoste-
rone and deoxycorticosterone was identified in children
with low birth weight, failure to thrive, and severe hy-
pertension with hypokalemic alkalosis. The poor growth
rate seen in children with AME has been assumed to be
due to glucocorticoid excess in utero due to absent or
impaired 11␤-HSD2 activity.
The currently available evidence that links early life
situations to later development of insulin resistance also
suggests that birth weight alone may not be the sole
determinant of later onset chronic disease such as type 2
diabetes. In a study of 290 subjects with type 2 diabetes,
most (192 of 290) had birthweights ⱕ 3.5 kg [16]. The
findings of this study indicate that in people with birth
weights > 3.5 kg, high childhood BMI had a greater im-
pact on the incidence of type 2 diabetes than it did
among people with birth weight < 3.5 kg. Another recent
study on the link between pre-term birth and later insu-
lin resistance indicated that relative undernutrition early
in life associated with slower growth in children born
pre-term may actually have beneficial effects on insulin
resistance in adolescence [17]. In a chapter on non-
independent diabetes and obesity in a book on fetal ori-

gins of cardiovascular and lung disease, Phillips specu-
lates on a potential pathway for fetal malnutrition to type
2 diabetes [18]. Poor maternal diet and reduced placental
transfer lead to fetal undernutrition, which triggers hor-
monal and metabolic adaptations in utero, which in turn
leads to lifelong metabolic thrift, thus rendering a fetus
more susceptible to adult obesity and insulin resistance.
If this were the case, one could convert this into a test-
able hypothesis. “Metabolic thrift” can be assumed to
involve thermogenesis. In this case, those infants or sub-
jects would most likely display lower resting energy ex-
penditure after adjusting for all other factors that might
impact on it.
One recent paper examined the relation between birth
weight and carotid intima-media thickness in young
adults in the Netherlands [19]. They found that overall,
birth weight per se was not related to common carotid
artery intima-media thickness. However, the intimal
thickness in young adulthood was significantly associ-
ated with low birth weight only in those who experi-
enced severe intrauterine growth retardation and in
those who showed exaggerated postnatal growth. Also,
those with very small birth weights and short birth length
had greater carotid intima thickness as young adults.
After performing a comprehensive review of the litera-
ture between 1966 to 2003, Lauren et al. [20] reported
that the evidence did not strongly support a link be-
tween birth weight and blood lipid levels later in life.
Lauren et al. went on to caution that research in this area
is limited and noted that longitudinal studies with suffi-
cient statistical power would be needed to properly ex-
amine its relation. Barker in his commentary on this re-
view paper disagreed with the notion of an estimated
effect from all published studies since one should not
search for “an effect” but rather one should search for a
number of effects, “depending on what, in a particular
individual, preceded low birth weight, and what fol-
lowed” [21]. This view of Barker is counter to one of the
attributes of a causal association, which is consistency
among observations. Although absence of consistency
does not negate sine qua non a causal relation, its presence
helps to strengthen it.
At this midpoint in 2004, the Barker hypothesis is in
need of further insight and stronger supporting evidence.
Within the past 2 years, there have been more review
papers and a book rather than original study findings. In
reviewing the available evidence, one needs to be cog-
nizant of the general tendency for publication bias. Sev-
eral questions remain still. Is there a plausible biologic
pathway that would unify various reported disparate ob-
servations? How is fetal programming linked to the ini-
tially observed outcome measure of ischemic heart dis-
ease? Is this via the separate effects of fetal programming
on individual risk factors for cardiovascular disease, such
Fetal origins of adult disease Kimm 195
as hypertension, hyperlipidemia, obesity, and insulin re-
sistance? How does fetal programming affect these dis-
parate biologic processes? What is the nidus of the trigger
for fetal programming as a consequence of intrauterine
malnutrition? If intrauterine malnutrition were the trig-
ger, one would expect to see cohorts with increased car-
diovascular disease, such as people born during the sub-
Sahel famine or during the Khmer Rouge era in
Cambodia, if they survived into adulthood. How does
one explain the paradoxical secular trends in the US of a
rising prevalence of obesity and type 2 diabetes in the
face of declining neonatal and cardiovascular disease
mortality?
As Khan in a recent review of the Barker hypothesis
observed, future research in the field of fetal program-
ming needs to move towards hypothesis-driven investi-
gation of potential mechanisms underlying the observa-
tions both in humans and animal models [22]. Additional
cross-sectional observations will continue to fuel the de-
bate since some findings will be confirmatory and some
most likely will also be contradictory. Such approaches
will not help make inroads to further understanding the
biologic mechanisms underlying the ecological correla-
tions.
Thus, the Barker hypothesis remains an intriguing idea
regarding the genesis of adult chronic disease. However,
even after its introduction two decades ago, it still re-
mains speculative and has not even reached the status of
a tenable scientific “hypothesis” since by its very nature,
it cannot be tested by traditional scientific methods. In
human populations, the only experimental method avail-
able for testing the hypothesis would be a randomized
clinical trial. Clearly, allocation of subjects to an intra-
uterine malnutrition “exposure” is not feasible. The
next available step is to employ more indirect approaches
for gathering evidence to evaluate the possibly causal
nature of the association between fetal malnutrition and
adult chronic disease. The Barker hypothesis is based on
evidence from ecological associations. To advance this
concept, we need to transcend beyond this relatively
primordial level of epidemiology. Thus far, even at this
level, there is still a lack of consistency among all the
reported observations. The issue of confounding with
socioeconomic and behavioral factors has not yet been
adequately addressed.
If intrauterine malnutrition were the trigger for the pro-
cess that leads to adult chronic disease, there needs to be
a clear-cut time sequence. Yet, most of the ecological
observations were based on the concurrent rates of neo-
natal mortality and cardiovascular disease. It would be
nice to see a well-conducted cohort study of exposure to
small birth weights and later development of chronic
disease or to truncate the observation period, at least for
196 Obesity and nutrition
risk factors such as hyperlipidemia or elevated blood
pressure.
Since the introduction of the Barker hypothesis, there
has been tremendous progress in biomedical research.
Yet, there is a disappointing paucity of laboratory find-
ings that unequivocally support a link between fetal mal-
nutrition and hypertension, type 2 diabetes, or hyperlip-
idemia. Laboratory evidence would help shed light on
the biologic mechanism by which fetal malnutrition
serves as the trigger for fetal programming. The presence
of some biologic plausibility would further strengthen
the association between fetal malnutrition and later de-
velopment of chronic disease/risk factors.
Another fundamental attribute of a causal association is
the strength of the association. We still lack a pooled
estimate of the strength of the association even between
neonatal mortality and ischemic heart disease. It may be
timely to conduct a careful meta-analysis of pooled in-
formation from the available studies. Because neonatal
mortality is impacted by many factors other than fetal
malnutrition, the strength of the relation between neo-
natal mortality and ischemic heart disease needs to be
particularly robust since other confounders such as socio-
economic status, prenatal care, maternal age, and neona-
tal care can all impact the outcome. If the unadjusted
association is not particularly strong, the Barker hypoth-
esis cannot be advanced beyond where it is at present.
As more questions than answers remain today, the
Barker hypothesis has not advanced our fundamental un-
derstanding of the fetal origins of adult chronic disease.
Nevertheless, it has served as an important impetus for
removing the traditional dichotomization of the human
lifespan into childhood and adulthood. For primary pre-
vention, it is essential to understand the earliest origins
of those chronic disease processes that ultimately result
in the major causes of morbidity and mortality in most of
the world today.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
• Of special interest
•• Of outstanding interest
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