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International Journal of Epidemiology 2002;31:294–299

The relatively new research field of the fetal origins of adult

disease has matured greatly in the past decade. Recent sys-

tematic overviews provide strong evidence that robust inverse

epidemiological associations exist between birthweight and later blood pressure/hypertension1 and glucose intolerance/type 2

diabetes.2 Consistent associations are also evident for the in-

verse associations of birthweight with coronary heart disease

incidence and mortality.3,4 Studies with high follow-up rates

and adjustment for social and economic variables have to a large

extent mitigated earlier criticisms that observed associations

were highly subject to confounding and selection bias.5 Many

questions remain, however, about the contributing roles of

postnatal growth and development, underlying biological mech-

anisms, and the importance of the epidemiological findings to

public health. This review outlines current challenges—stated

in the form of propositions—that epidemiologists in this field

currently face.

1. The Lifecourse Approach Helps PutFetal Influences into Perspective

The lifecourse approach to chronic disease posits that fetal life

is one important period of development, but not the only one,

in determining susceptibility to adult chronic disease.6 Many

studies have now shown that associations of birth size with later

cardiovascular outcomes are modified by body mass index in

adulthood or, indeed, in childhood.7,8 The highest risk is typic-

ally among adults who were born small and become overweight

during childhood or adulthood. Examples of outcomes that fit

this profile include insulin resistance in Indian 8-year-old boys

and girls,9 blood pressure levels among 50-year-old Swedish

men,10 and incidence of coronary heart disease among middle

to older age Welsh men.4 In another example, body mass index

at age 11 appeared to modify the association of ponderal index

at birth with adult coronary disease risk in Finnish males.7

From this observed phenomenon some have inferred that

that postnatal ‘catch up growth’ modifies intrauterine influences.

There are two problems with this inference. First, most studies

to date include only two weight points—one at birth and one

later in life. Without a third, intermediate, point, it is difficult to

distinguish whether the findings represent an interaction

between fetal and postnatal exposures or merely some facets ofpostnatal growth itself.11 Some recent studies, however, have

had multiple postnatal measures of height and weight. Overall

they have suggested that both intrauterine and postnatal

growth are important, but it is not clear exactly which periods

are important or even whether increased or decreased postnatal

growth is harmful. For example, in a Finnish cohort, adult

hypertension was associated with both lower birthweight and

accelerated growth in the first 7 years of life.12 In contrast, in a

small group of Chinese adults, both lower ponderal index

at birth and a decrease in ponderal index from 6 to 18 months of

life were related to increased systolic blood pressure level at age

30 years.13 Moreover, in two recently reported studies from the

UK, catch up growth in the first 6 months of life was not clearly

related to young adult blood pressure at all, although birth-

weight was.14,15 In another study, growth patterns exemplified

by lower birthweight followed by reduced growth until age 1

seemed to confer the highest risk for ischaemic heart disease

later in life, but the analysis was confined to men.16 These dis-

parate results call for additional serial growth data to determine

which periods of growth contribute most to the observed inter-

actions between fetal and postnatal size in determining health

outcomes.

A second issue is that catch up growth traditionally refers to

the first 6–12 months after birth, not later growth. The standard

interpretation is that catch up growth represents realignment of

one’s genetic growth potential after intrauterine growth restric-

tion. One advantage of this interpretation is that it allows for

fetal growth restriction at any birthweight—even large fetuses

can be growth restricted relative to their genetic potential—thus

obviating the need for arbitrary definitions such as ‘small for

gestational age’. This distinction is important in the fetal origins

of adult disease, since observed associations of birthweight with

later outcomes generally span the entire birthweight spectrum,

not just at the ‘low birthweight’ end. The major problems,

however, are in the measurement of catch up growth. Some

investigators resort to a post hoc , empirical definition, using the

observed infant growth patterns relative to birthweight.17 A

second possibility is that mid-parental height gives a good

REVIEWS

Epidemiological challenges in studying the

fetal origins of adult chronic diseaseMatthew W Gillman

Keywords Fetal origins of adult disease, lifecourse, socioeconomic status, fetal growth, gene-

environment interaction, nutrition, epidemiological study design, fetal programming

Accepted 23 October 2001

Department of Ambulatory Care and Prevention, Harvard Medical School and

Harvard Pilgrim Health Care, and the Department of Nutrition, Harvard

School of Public Health, Boston, MA, USA.

294

© International Epidemiological Association 2002 Printed in Great Britain


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CHALLENGES RELATING TO FETAL PROGRAMMING 295

estimate of the child’s growth potential, but usually for height,

not relative weight, and the estimation is better after 2 years of

age than in infancy. Third, while needing confirmation, recent

data raise the possibility that levels of maternal insulin-like

growth factor I during pregnancy may reflect fetal growth restric-

tion.18 A final issue with measuring catch up growth is that even

in the first 6 months of life, postnatal environmental factors can

also influence growth. For example, while having been breastfedseems to protect against obesity later in childhood,19 breastfed

infants in developed countries generally exhibit higher body mass

during the first year of life that formula-fed infants.20

In sum, there are three possible general inferences from

observations that the highest risk for cardiovascular outcomes

lies among individuals both born small and achieving high body

size later in life. The first is that fast postnatal growth itself

increases risk. The second is that factors related to fetal growth

restriction increase risk and the third involves an interaction

between the two. Thus studies of the fetal origins of adult

disease will benefit from having multiple measures of height

and weight through the lifecourse, to distinguish prenatal influ-

ences from influences occurring at various points in infancy,

childhood, and later. They will also benefit from a clear definitionof catch up growth and a non-circular method of measuring it.

In the meantime, authors should clarify what periods of life

their measurements cover, preferably reserving the term catch

up growth for its traditional meaning of realignment to genetic

potential during infancy.

2. Adjustment for Achieved Body MassIndex, Despite Being Controversial,Is Often Helpful

While the points above concern effect modification by achieved

body size, this section addresses adjustment for it. Some epi-

demiological associations, for example the inverse relationship

of birthweight with blood pressure, appear stronger—or in some

studies, appear only—after statistical adjustment for adult (or

childhood) body mass index.21,22 How, or even whether, to

make such adjustments is controversial. Some of the contro-

versy seems to emanate from the fact that epidemiologists from

a variety of fields—perinatal, cardiovascular, paediatric—with

different lexicons, are converging on the same research topics.

Also, perinatal epidemiologists have traditionally been concerned

with avoiding ‘low birthweight’. In fact, increasing birthweight

at this end of the spectrum, primarily by avoiding preterm

births,23 would reduce neonatal and infant adverse outcomes.

From this perspective, birthweight is an entity in and of itself,

with aetiological significance. In contrast, in the field of fetal

origins of adult disease, birthweight is not a monolith. Not all

determinants of birthweight are salient, so increasing birth-

weight is not necessarily helpful. Further, this new paradigm is

concerned with the entire spectrum of birthweight, rather than

just the lower parts of the distribution. Adjusting for later body

size is therefore appropriate; it can elucidate underlying aetio-

logical pathways.

Figure 1 demonstrates this argument, using the example of

blood pressure as an outcome. If it is true that (1) birthweight is

positively related to later body mass index,24 (2) birthweight

is inversely related to later blood pressure—the association of

primary interest, and (3) body mass index is positively relatedto contemporaneous blood pressure (a well-known relation-

ship), then the prenatal factors explaining pathways #1 and #2

(labelled Factors A and Factors B, respectively) are almost

surely different. Adjusting for body mass index could elucidate

some of the factors underlying the inverse birthweight-blood

pressure association, and is thus potentially useful.

One empirical example that serves to illustrate this point is

the relationship between birthweight and development of type

2 diabetes. Unadjusted for attained body mass index, the shape

of the relationship is a ‘U’ or reverse ‘J’, with increased risk at

both ends of the birthweight spectrum.25 But this observation

obscures the fact that there are probably two underlying mech-

anisms. At high birthweights, maternal gestational diabetes is

causing obesity and excess diabetes risk in the offspring. Adjust-

ment for attained body mass, however, reveals an inverse and

linear association across the birthweight spectrum, reflecting

a second pathway with reduced risk at higher birthweights,

a pattern sometimes attributed to the influence of a ‘thrifty

phenotype’.26

3. Social and Economic Factors Are NotJust Confounders

Many decades span the time from birth until cardiovascular

diseases declare themselves. Most of these diseases are related

to both lower birthweight and poorer socioeconomic circum-

stances in adulthood. Thus controlling for these circumstances

seems necessary to isolate prenatal influences. On the other

hand, for some social class is stable across generations. Under

these conditions, the same socioeconomic factors that affect

postnatal life may affect prenatal life as well, and could thus

determine the putative exposures under study. In this view, the

social and economic factors are part of the causal pathway, both

before and after birth.

For others, social circumstances change over time. Depending

on the disorder, the place, and the era, societal factors can have

impact in different points in the lifespan. In the UK in the

Figure 1 Why adjustment for attained body mass index is warranted.

See text (‘Challenge No. 2‘) for explanation. BMI = body mass index;

BP = blood pressure; + indicates direct association; – indicates inverse

association


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late 20th century, for example, low childhood social class is

more strongly associated with risk of stroke than is adult social

class. For coronary heart disease, however, childhood and adult-

hood social factors appear to play equal roles.27

The challenges for future analyses are to consider the explan-

atory as well as confounding effects of social and economic

factors; and to take into account changes in these factors across

the lifespan. As these effects are being clarified, it will beimportant to assess how such societal factors affect physiological

mechanisms underlying the epidemiological phenomena. Some

factors may operate through their associations with behavioural

factors. For example, maternal diet may differ by social class.

In contrast, other societal factors may directly affect biological

responses; for example, accumulated stress may influence the

hypothalamic-pituitary-adrenal axis independent of lifestyle

choices. Alternatively, the two kinds of pathways may actually

work in concert with each other. In rodent models, stress during

gestation causes reduced levels of maternal licking/grooming of

her offspring, which are in turn related to levels of offspring

stress reactivity through effects on systems that regulate activity

of corticotropin-releasing hormone.28

4. Fetal Growth and Size at Birth Are NotSynonymous

In studies that can separate length of gestation from overall

birthweight, most observed associations between birthweight

and later cardiovascular outcomes are not due to length of

gestation.29 Epidemiologists have called the remaining factor in

birthweight ‘fetal growth’. However, fetal size at birth, adjusted

for length of gestation, is only a snapshot of the trajectory of

fetal growth throughout gestation.

Some, but clearly not all, epidemiological studies have found

stronger associations with later outcomes for thinness or short-

ness at birth, or even abdominal or other body circumferences,

rather than birthweight itself. Authors have hypothesized

trimester-specific perturbations of growth of the fetus or

particular organs to explain these phenomena.30 Whether such

hypotheses have merit cannot be fully addressed with crude

measures of fetal size at birth, considering not only the meas-

urement error inherent in length and circumference measures,

but also the non-specificity of even accurate measures at birth

for determining fetal growth trajectories.31,32

Ongoing animal studies of fetal growth will continue to in-

form the epidemiology. In addition, one way studies of humans

can be refined is to take advantage of serial ultrasound measures

to measure fetal growth parameters throughout pregnancy. For

example, preliminary data from one study suggested that femur

length at 24 weeks was more strongly inversely associated

with blood pressure at age 6 years than were either head or

abdominal circumferences.33 In that study, however, changes in

ultrasound measurements from 18 to 38 weeks were not clearly

related to the outcome.

In addition, the dearth of data linking reduced gestational

age at birth with adult health outcomes is chiefly a function of

the historical data available to date, not necessarily because the

link is absent. When most of the participants in the currently

published long-term studies were born, relatively few preterm

infants survived. To what extent gestational age predicts adult

outcomes is an unresolved question, but an important one. In

general, determinants of preterm birth and fetal growth are not

the same.34

5. Some Determinants of Fetal GrowthWill Be Red Herrings

While the observed epidemiological associations appear to im-

plicate fetal growth as a major factor, overall fetal size at birth is

an amalgam of many determinants. Some of these determinants

may be related to susceptibility to adult disease, and others may

not. Conversely, some prenatal determinants of adult outcomes

may not be related to fetal growth. While investigations of

fetal growth are likely to reveal some underlying processes, the

need exists to investigate more directly prenatal determinants of

postnatal outcomes, irrespective of effects on birthweight.

One example of size at birth potentially being a good proxy

for an underlying causal pathway derives from the hypothesis

that a congenital nephron deficit underlies predisposition to

hypertension in adult life.35 A recent study shows that kidney

volume is smaller in adults who were thinner at birth, even

after adjustment for current body size.36 In contrast, a potential

example of a prenatal exposure causing postnatal disease with-

out effects on birthweight is the newly described association of

paracetamol use by mothers in late pregnancy and risk of asthma

in their preschool age offspring.37 Maternal smoking during

pregnancy is a good example of a prenatal exposure whose

deleterious effect on fetal growth is well-known but whose

influence on long-term offspring health is uncertain. Perhaps

investigation of the seemingly paradoxical protective effect of

smoking against the development of pre-eclampsia38 will offer

insights.

6. Both Genes and Environment Are

Important. Even Distinction Betweenthe Two Is Difficult

Many critics of the ‘fetal origins hypothesis’ have taken to task

the epidemiological studies for not accounting for possible genetic

explanations. Although rare genetic mutations do not explain

the findings of population-based studies, they may provide a

paradigm for understanding. For example, a rare mutation in

the glucokinase gene causes drastically reduced birthweight and

offspring insulin resistance.39 No analogous common allelic

variation has yet been discovered, but it is possible that some

exist to help explain the observed phenomena.

In addition, maternal, paternal, and fetal genes may all play

roles. While inherited fetal gene expression can underlie sus-

ceptibility to disease, it is also likely that the maternal genome

codes for substances that affect the fetal environment. As such,

what is genetic for the mother is environmental for the fetus.

One example of this principle is that it appears that the

maternal thermolabile variant of methylenetetrahydrofolate

reductase may be associated with the risk of neural tube defects

in the offspring, even in the face of a normal fetal genotype.40

This consideration also highlights the close relationship

between genes and environment and the need to examine inter-

actions between them. Not only can maternal gene expression

alter the fetal environment, but it is also possible that the

maternal gestational environment can affect fetal gene expression.

296 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY


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For example, in a mouse model, feeding the mother foods with

different quantities of methyl donors can alter offspring coat

colour through modification of gene expression.41,42 More

substantial progress in humans will occur when investigators

can assess interactions among environmental factors and

candidate genes as their identities become available. Ultimately,

there will be probably be less distinction between genes and

environment than most researchers currently consider.

7. Maternal Nutrition Does Not EqualFetal Nutrition

Scientists and the public have been confused by statements

about ‘undernutrition’ explaining the observed epidemiological

phenomena. Except at the extremes of intake, maternal energy

and macronutrient intake have relatively little impact on

birthweight. In addition, little or no firm evidence suggests that

maternal intake of total energy or macronutrients during preg-

nancy, or maternal body composition, have substantial impact

on offspring risk of chronic disease. In fact, some empirical

results seem diametrically opposed to each other. For example,

results of one abstract presented at the 2001 World Congress onthe fetal origins of adult disease suggested that a high dietary

protein/carbohydrate ratio in the third trimester was associated

with lower offspring blood pressure, whereas the authors of the

next presentation observed higher blood pressures among

offspring of mothers consuming a relatively high protein, low

carbohydrate diet in late pregnancy.43,44

In contrast, what is often termed ‘fetal nutrition’ is likely to

be vital. The oxygen and nutrients that support fetal growth and

development rely on the entire nutrient supply line, beginning

with maternal consumption and body size, but extending to

uterine perfusion, placental function, and fetal metabolism.

Interruptions of the supply line at any point could result in pro-

gramming the fetus for future risk of cardiovascular disease.31

Some of the confusion arises because a common animal model

for interrupting the supply line is to alter maternal gestational

intake.45 Interrupting the supply line at other points, say by

underperfusing the placenta, can have analogous effects. One

should use the animal experimental data only as models, as

they are intended.

The placenta is likely to be a key to understanding associations

of fetal growth with adult health, owing to its inherent endo-

crine function as well as its metabolic and transfer capacities.31

The lack of good animal models for placentation has hampered

understanding of the pathways by which the fetus receives

nutrients and oxygen from the mother, and what processes alter

these pathways. Possible ways to study placental function

in population-based studies include placental morphological

pathology, as well as using specimens of placenta, maternal

prenatal blood or other biological specimens, and umbilical cord

blood to measure markers of altered blood flow, endocrine and

transport characteristics, or activity of specific enzymes. These

biological specimens can also be used to investigate other mech-

anisms underlying the observed epidemiological findings, includ-

ing maternal and fetal endocrine pathways,46 inflammatory

and immune function,47 and changes in the central and peri-

pheral nervous system,48,49 among others.

Still, researchers should not dismiss the possibility that

maternal dietary intake could be an important supply line

component in humans. In investigating maternal dietary

impact, investigators should concentrate on pathways that could

involve specific foods and micronutrients in addition to energy

and macronutrient intake, which appear to be relatively

unimportant on their own. For example, recent data from 27

pregnant women suggest that while overall gestational protein

intake is unimportant, relative partitioning from protein

oxidation to deposition, perhaps related to micronutrientfactors, is associated with birthweight.50 Relevant examples

from perinatal epidemiology include that fatty acids of the

n-3 family prolong gestation and reduce the incidence of pre-

term birth, and inadequate folic acid intake causes neural

tube defects.51,52 Future research may reveal that fatty acids,

folate, or other nutrients may also be involved in programming

of chronic disease risk.

8. New Epidemiological Study DesignsWill Help

Many of the extant epidemiological findings have emanated from

historical cohort studies, taking great advantage of serendipitous

clinically recorded perinatal variables. The next generation of

studies, however, should overcome the limitations of the earlier

studies. These limitations include lack of research quality meas-

ures, limited information on covarying factors, and absence of

biological specimens. Although no one study can address all

methodological issues, three types of studies will be especially

valuable in the coming years:

1. New prospective studies of pregnant women (including ones

that even start pre-conceptionally) that follow their offspring

over time, collecting biological samples to explore mechanisms,

as well as research quality epidemiological data.53 These have

the advantage of collecting detailed prospective data and exam-

ining childhood cardiovascular risk factors and diseases such asasthma, but must wait decades for adult disease outcomes to

occur.

2. Follow-up of adult cohorts in which biological samples and

prospectively collected epidemiological data are available from

the past.54 These have the advantage of research quality data

and emerging disease outcomes, but may lack important expos-

ure or covariate information, such as maternal diet during

pregnancy.

3. Follow-up into childhood or adulthood of randomized con-

trolled trials conducted during pregnancy.55 These have the

advantage of isolating an environmental ‘insult’ during preg-

nancy and so can come close to proving that programming

occurs. However, this type of study is limited to examining a

single or limited number of exposures.

9. To Make Policy RecommendationsNow Regarding Fetal Programming IsDangerous

Strong evidence exists for programming in humans. First is the

robust epidemiological findings of associations between size

at birth and later health outcomes. Second is the experimental

animal evidence that in utero environmental insults produce

lifelong alterations in metabolism, physiology, and pathology,



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298 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

whether or not the exact perturbations have analogy in human

systems.

One area of great importance is implications for developing

countries undergoing the epidemiological transition from infec-

tious disease to chronic disease, chiefly cardiovascular disease,

as well as the ‘nutrition’ transition from an active, low-calorie

lifestyle to a sedentary, high-calorie lifestyle.56 Available data

indicate that a lower birthweight combined with higher attained body mass confers the highest risk for cardiovascular disease.

Successive generations of individuals in developing countries

are likely to have ever larger proportions with that high-risk

profile. Efforts to prevent development of obesity in areas

undergoing the epidemiological and nutritional transitions are

paramount.

It is premature to make policy recommendations regarding

fetal programming. Since birthweight is only a marker for under-

lying aetiological pathways, the true aetiological factors are

unknown. Until they are identified, it is impossible to calculate

attributable risks or design interventions to modify them. Inter-

ventions to increase birthweight per se would be at best ineffi-

cient, probably ineffective, and potentially harmful. Ultimately,

the promise of the fetal origins paradigm is that attending to thehealth of women of reproductive age will have profound impact

on the well-being of their progeny.

Acknowledgements

Many of the ideas expressed here grew out of a Harvard Medical

School conference, Fetal Origins of Adult Cardiovascular

Disease: New Directions, which I chaired in November 1999.

The contributions of the 48 attendees of that conference, which

included epidemiologists, biomedical scientists, and health policy

researchers, were instrumental in the genesis of this paper. The

list of attendees and the conference agenda are available upon

request. I also acknowledge the helpful comments of Janet

Rich-Edwards, conference co-chair, on a draft of this manu-

script. Conference funding was supplied by Maternal and Child

Health Bureau of Health Resources and Services Administration

(6-MCJ-000102–45–1), Department of Ambulatory Care and

Prevention at Harvard Medical School/Harvard Pilgrim Health

Care, SmithKline Beecham Consumer Healthcare, Harvard Center

for Children’s Health, Department of Nutrition at Harvard School

of Public Health, Council on Epidemiology and Prevention of

the American Heart Association, Mead Johnson Nutritionals,

The Procter and Gamble Co. This work was also supported by

grants from the US National Institutes of Health (HD 34568,

HL 64925, HL 68041) and by Harvard Medical School and the

Harvard Pilgrim Health Care Foundation.

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