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Molecular and Cellular Endocrinology 185 (2001) 9398
Effects of prenatal exposure to the Dutch famine on adult diseasein later life: an overview
Tessa J. Roseboom *, Jan H.P. van der Meulen, Anita C.J. Ravelli, Clive Osmond,David J.P. Barker, Otto P. Bleker
Department of Clinical Epidemiology, Academic Medical Centre, Amsterdam, The Netherlands
Abstract
Chronic diseases are the main public health problem in Western countries. There are indications that these diseases originat
in the womb. It is thought that undernutrition of the fetus during critical periods of development would lead to adaptations i
the structure and physiology of the fetal body, and thereby increase the risk of diseases in later life. The Dutch faminethough
a historical disasterprovides a unique opportunity to study effects of undernutrition during gestation in humans. This thesi
describes the effects of prenatal exposure to the Dutch famine on health in later life. We found indications that undernutrition
during gestation affects health in later life. The effects on undernutrition, however, depend upon its timing during gestation and
the organs and systems developing during that critical time window. Furthermore, our findings suggest that maternal malnutrition
during gestation may permanently affect adult health without affecting the size of the baby at birth. This may imply tha
adaptations that enable the fetus to continue to grow may nevertheless have adverse consequences of improved nutrition o
pregnant women will be underestimated if these are solely based on the size of the baby at birth. Little is known about what an
adequate diet for pregnant women might be. In general, women are especially receptive to advice about diet and lifestyle befor
and during a pregnancy. This should be exploited to improve the health of future generations. 2001 Elsevier Science Irelan
Ltd. All rights reserved.
Keywords: Undernutrition; Coronary heart disease; Fetal origins
www.elsevier.com/locate/mce
1. Introduction
Chronic degenerative diseases are the main public
health problem in most Western countries. Cardiovas-
cular disease, respiratory disease and cancer have be-
come the commonest causes of death and account for
three quarters of mortality at adult age (Murray and
Lopez, 1994). A growing body of evidence suggests that
these diseases originate in the womb. People who were
small at birth have been shown to have an increased
risk of CHD and chronic bronchitis in later life
(Barker, 1998). Cancer, however, has been linked to
increased birth weight (Michels et al., 1996). The link
between size at birth and health in later life is thought
to reflect programming. This term is used to describe
the process by which a stimulus or insult during critical
periods of growth and development has lasting effects
on the structure or function of tissues and body sys-
tems. Programming occurs because the tissues and sys-
tems of the body go through critical, often brief,
periods of growth and development during foetal life
and infancy (Winick and Noble, 1966). Failure of de-
velopment during these periods as a result of adverse
environmental influences changes the bodys structure
and function permanently.The associations between small size at birth and
CHD later in life have extensively been replicated in
studies in several European countries, but also in the
US and in India (Osmond et al., 1993; Lithell et al.,
1996; Stein et al., 1996; Rich-Edwards et al., 1997; Leon
et al., 1998; Eriksson et al., 1999; Forsen et al., 1999;
Huxley et al., 2000). They extend across the normal
range of size at birth and depend on small size for
gestational age rather than on prematurity (Osmond et
al., 1993; Leon et al., 1998; Eriksson et al., 1999). A
study in Finland showed that the path of growth in
childhood modifies the risk of CHD associated with* Corresponding author.
0303-7207/01/$ - see front matter 2001 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 0 3 7 2 0 7 ( 0 1 ) 0 0 7 2 1 3
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T.J. Roseboom et al. /Molecular and Cellular Endocrinology 185 (2001) 939894
small size at birth. Death rates from CHD were highest
among men who were thin at birth but had accelerated
weight gain in childhood (Eriksson et al., 1999). The
effect size, a more than 5-fold increase in mortality
among men who were thin at birth and overweight at
age 11 compared with men with a high ponderal index
at birth and lean in childhood, is among the largest
found in cardiovascular epidemiology.
These findings have led to the foetal origins hypothe-sis that proposes that the foetus adapts to a limited
supply of nutrients, and in doing so it permanently
alters its physiology and metabolism, which could in-
crease its risk of disease in later life (Barker, 1998). The
Dutch faminethough a historical disasterprovides
a unique opportunity to study effects of undernutrition
during gestation in humans. Famine has seldom, if ever,
struck where extensive, reliable and valid data allow the
long-term effects to be studied. Moreover, the famine
occurred in a previously well-nourished population, it
was sharply circumscribed in both time and place, and,
the type and degree of nutritional deprivation duringthe famine were known with a precision unequalled in
any large human population before or since. All these
characteristics enable that the Dutch famine can be
considered as a unique experiment of history to test
the foetal origins hypothesis. The foetus becomes un-
dernourished when its demand for nutrients, which
largely depends on its rate of growth, exceeds its sup-
ply. Nutrient supply to the foetus depends on maternal
nutritional state and the foetal supply line. The famine
affected maternal nutrition, but possible not the foetal
supply line. So the famine enables us to assess thecontribution of maternal dietary intake and to a lesser
extent, maternal body composition to foetal program-
ming of adult disease.
2. The Dutch famine 1944 1945
After weeks of heavy fighting following the invasion
of France on the 6th of June 1944, the Allied forces
finally broke through German lines. With lightning
speed, the Allied troops took possession of much of
France, Luxembourg and Belgium. By the 4th of Sep-tember 1944 the Allies had the strategic city of Antwerp
in their hands, and on the 14th they entered The
Netherlands. Everyone in The Netherlands expected
that the German occupation would soon be over. The
advance went so quickly that the commanders of the
Allied forces also thought it would be only a matter of
days before the Germans would surrender. But the
advance of the Allies to the north of The Netherlands
came to a halt when attempts to get control of the
bridge across the river Rhine at Arnhem (operation
Market Garden) failed.
In order to support the Allied offensive, the Dutch
government in exile had called for a strike of the Dutch
railways. As a reprisal, the Germans banned all food
transport. This embargo on food transport was lifted in
early November 1944, when food transport across wa-
ter was permitted again. By then, it had become impos-
sible to bring in food from the rural east to the urban
west of The Netherlands because most canals and wa-
terways were frozen due to the extremely severe winter
of 1944 1945, which had started unusually early. Con-sequently, food stocks in the urban west of The Nether-
lands ran out rapidly.
As a result, the official daily rations for the general
adult population which had decreased gradually from
about 1800 calories in December 1943 to 1400 calories
in October 1944fell abruptly to below 1000 calories
in late November 1944. At the height of the famine
from December 1944 to April 1945, the official daily
rations varied between 400 and 800 calories. Children
younger than 1 year were relatively protected, because
their official daily rations never fell below 1000 calories,
and the specific nutrient components were always above
the standards used by the Oxford Nutritional Survey
(Osmond et al., 1993; Burger et al., 1948). Pregnant and
lactating women were entitled to an extra amount of
food, but at the peak of the famine these extra supplies
could not be provided any more. In addition to the
official rations, food came from church organisations,
central kitchens, the black market and foraging trips to
the countryside (Trienekens, 1985). After the liberation
of the Netherlands in early May 1945, the food situa-
tion improved swiftly. In June 1945, the rations had
risen to more than 2000 calories (Burger et al., 1948).There was a serious shortage of fuel during the war
which caused a gradual decrease and finally a complete
shutting down of the production of gas and electricity,
and in several places even the water supply had to be
cut off, while the authorities were unable to provide
fuel for stoves and furnaces in homes. Throughout the
Winter of 1944 1945 the population had to live with-
out light, without gas, without heat, laundries ceased
operating, soap for personal use was unobtainable, and
adequate clothing and shoes were lacking in most
families. In hospitals, there was serious overcrowding aswell as lack of medicines. Above all, hunger dominated
all misery.
The famine had a profound effect on the general
health of the population. In Amsterdam, the mortality
rate in 1945 was more than doubled compared with
1939, and it is likely that most of this increase in
mortality was attributable to malnutrition (Banning
1946). But, even during this disastrous famine, women
conceived and gave birth to babies, and it is in these
babies that the effects of maternal malnutrition during
different periods of gestation on health in adult life can
be studied.
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T.J. Roseboom et al. /Molecular and Cellular Endocrinology 185 (2001) 9398 95
3. The Dutch famine birth cohort study
We studied people who were born around the time of
the Dutch famine in a university hospital, in Amster-
dam, the Netherlands. All singletons born alive between
1 November 1943 and 28 February 1947 in the Wil-
helmina Gasthuis in Amsterdam, were candidates to be
included in the Dutch famine birth cohort. We excluded
babies whose main medical records were missing, andthose with a gestational age at birth of less than 259
days. In all, 2414 babies were included. The Bevolk-
ingsregister of Amsterdam traced 2155 (89%) of the
2414 babies. Of these, 265 had died, 199 had emigrated
from the Netherlands and 164 did not allow the popu-
lation registry to give us their address. We obtained the
current addresses of 1527 people and asked 1018 people
who lived in or close to Amsterdam to be interviewed,
912 of them agreed to be interviewed about their medi-
cal history and current health. Of these, 741 attended
the clinic to undergo more detailed measurements.
Mean birth weights among the 912 who were visited athome or the 741 who attended the clinic did not differ
from the rest of the 2414 babies (difference adjusted for
exposure to famine: 12 g, P=0.5; and 22 g, P=0.3,
respectively). We considered a baby to be exposed to
famine in utero if the average daily ration during any
13-week period of gestation was below 1000 calories.
We used three periods of 16 weeks to distinguish be-
tween babies exposed during late gestation (born be-
tween 7 January and 28 April 1945), mid gestation (29
April 18 August 1945) and early gestation (19 Au-
gust 8 December 1945). We compared the exposedbabies with babies born before or conceived after the
famine period, whom we grouped as unexposed.
4. Findings
Of the 2414 babies who were included, 307 were
exposed in late gestation, 297 exposed in mid gestation
and 217 in early gestation. People conceived after the
famine had the lowest mortality up to age 50 (7.2%).
Mortality was higher in those exposed to famine in
early gestation (11.5%) and mid gestation (11.2%).
Mortality was highest in those exposed to famine in lategestation (14.6%) and those born before the famine
(15.2%). The differences in mortality were caused by
effects of famine on mortality in the first year of life,
and these deaths were mainly related to nutrition and
infections (Stein et al., 1975). There were no differences
in either overall or cause-specific mortality in adulthood
between the exposure groups.
Women who were exposed to famine in late preg-
nancy were slightly older than women in the other
exposure groups and a higher proportion of them was
married (Tables 1 and 2). Women exposed to famine in
late pregnancy did not gain any weight in the thirdtrimester, whereas women exposed in mid and early
pregnancy gained more weight than non-exposed moth-
ers did due to the immediate provision of food after the
war. Consequently, women exposed in late pregnancy
weighed less at their last prenatal visit. Exposure to
famine during gestation had an effect on the sex ratio
of live born babies. The percentage of boys born alive
was lower, especially after exposure in late gestation.
Babies exposed to famine in late gestation were lighter,
shorter, and thinner with smaller heads and placentas
than unexposed babies. Babies exposed to famine inmid gestation were lighter, shorter, and had smaller
heads than non-exposed ones. Children who were ex-
Table 1
Maternal and infant characteristics according to timing of prenatal exposure to the Dutch famine (*geometric mean and S.D.)
nExposure to famine in
Conceived afterEarly gestationMid gestationLate gestationBorn before All (SD)
Proportion of men 44%42%47% 241450% 48%52%
Maternal characteristics
Weight last prenatal visit 61.8a
213366.6 (8.7)69.167.963.5a
66.7(kg)
4.35.7a4.9a0.0a3.2 16823.5 (3.2)Weight gain 3rd trimester
(kg)
38%Primiparous 241440% 30% 37% 39% 39%
28 28 28 (6.4) 241430Age (years) 2829
13.2 16.3 15.8 24149.8 20.2Not married 25.8
Infant characteristics
34703217a3133a 24143373Birth weight (g) 3346 (487)3413
50.5 50.5 50.3 (2.1) 238249.5a 49.8aBirth length (cm) 50.9
32.9 32.3a 32.1aHead circumference (cm) 32.8 33.2 32.8 (1.6) 2397
25.8 238226.2 (2.4)26.526.226.1 26.0Ponderal index (kg/m3)
285 283 285 287 286 285 (11)Gestational age (days) 2043
a PB0.05 compared with unexposed.
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T.J. Roseboom et al. /Molecular and Cellular Endocrinology 185 (2001) 939896
Table 2
Adult characteristics according to timing of prenatal exposure to the Dutch famine
nExposure to famine in
Late gestation Mid gestation Early gestation Conceived after All (S.D.)Born before
Adult characteristics
5.7 6.3a 6.1 6.1 5.9 6.0 (1.4) 702Plasma glucose 120 min*
(mmol/l)
160 200a
190Plasma insulin 120 min* 207 181 181 (2.4) 694(pmol/l)
15% 21% 14% 16% 15%IGT/NIDDM (WHO 16% 702
criteria)
5.83 5.80 6.13Total cholesterol (mmol/l) 6.006.06 5.97 (1.06) 704
1.35 1.32 1.37HDL cholesterol* 1.26a 1.32 1.33 (1.33) 704
(mmol/l)
3.87 3.81 4.26LDL cholesterol (mmol/l) 4.024.05 3.99 (1.01) 704
Triglycerides* (g/l) 1.15 1.08 1.10 1.10 1.16 1.13 (1.71) 704
2.82 2.69 3.26a2.91 2.94LDL/HDL cholesterol* 2.90 (1.53) 704
3.02Fibrinogen (g/l) 3.05 3.05 3.21 3.10 3.07 (0.6) 725
128Factor VII* 131 133 117a 133 129 (1.4) 725
(% of standard)
26.7 26.6 28.1BMI* (kg/m2) 27.226.7 27.0 (1.2) 741
CHD 3.8% 2.5% 0.9% 8.8%a
2.6% 3.3% 736126.0 127.4 124.8 123.4Systolic blood pressure 125.1 125.5 (15.5) 739
(mmHg)
86.2 86.4 84.4Diastolic blood pressure 84.8 85.2 85.6 (9.9) 739
(mmHg)
Obstructive airways 15.5% 15.0% 24.8%a 23.0% 17.3% 18.1% 733
disease
6.4 3.7 10.3a 5.3 5.5 912General health poor 4.5
*Geometric mean and S.D.a PB0.05 compared with unexposed.
posed to famine in early gestation were heavier andlonger at birth.
5. Adult disease
People who had been exposed to famine in late or
mid gestation had reduced glucose tolerance, shown by
increased 2 h plasma glucose concentrations (Ravelli et
al., 1998). We also found that those who were light at
birth had increased 2 h plasma glucose concentrations,
but the effects of exposure to famine on glucose toler-
ance were larger than could be explained by the smallfamine-related reduction in birth weight. We found that
people exposed to famine in early gestation had a more
atherogenic lipid profile (Roseboom et al., 2001a),
somewhat higher fibrinogen concentrations and re-
duced plasma concentrations of factor VII (Ravelli et
al., 1998), a higher BMI (Roseboom et al., 2000a,b) and
they appeared to have a higher risk of CHD (Ravelli et
al., 1999; Roseboom et al., 2000c). Though the latter
was based on small numbers, as could be expected from
the relatively young age of the cohort. Nevertheless,
this is the first evidence in humans that maternal under-
nutrition during gestation is linked with the risk of
CHD in later life. In addition, people who had beenexposed to famine in early gestation more often rated
their health as poor. This indicates that they are not
only less healthy in terms of objective measures of
health, but that they also feel less healthy. Since the
famine ended abruptly, the women who conceived dur-
ing the famine (and whose foetuses were thus under-
nourished in early gestation) were well nourished in
later pregnancy, which may have contributed to the
above average birth weight of their babies. The transi-
tion from nutritional deprivation in early gestation to
nutritional adequacy later on may have led to
metabolic conflicts resulting in disease in later life.Although we found that people who had been small
at birth had high blood pressures in later life, we could
not demonstrate an effect of prenatal exposure to
famine on blood pressure (Roseboom et al., 1999). A
more detailed analysis, however, revealed that blood
pressure of the offspring was inversely associated with
the protein/carbohydrate ratio of the average ration
during the third trimester of pregnancy, whereas it was
not associated with any absolute measure of intake
during pregnancy (Roseboom et al., 2001b). Children
whose mothers ate little protein in relation to carbohy-
drate during the third trimester of pregnancy had
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T.J. Roseboom et al. /Molecular and Cellular Endocrinology 185 (2001) 9398 97
higher blood pressures at adult age. This may imply
that blood pressure is not so much linked to absolute
amounts of nutrients but to variations in the balance of
macronutrients in the maternal diet during late
gestation.
We found that people who had been exposed to
famine in mid gestation had an increased prevalence of
obstructive airways disease (Lopuhaa et al., 2000).
These observations were not paralleled by reduced lungfunction or increased serum concentrations of IgE. This
suggests that the increased prevalence of symptoms and
disease may be attributable to increased bronchial reac-
tivity rather than to irreversible airflow obstruction or
atopic disease. Since the bronchial tree grows most
rapidly in mid gestation, our findings support the hy-
pothesis that foetal undernutrition permanently affects
the structure and physiology of the airways during
critical periods of development that coincide with
periods of rapid growth.
6. Methodologic issues
Our findings mimic a scientific experiment in that
they compare the health of people exposed to famine at
different times during their gestation. However, the
analogy with an experiment is violated to some extent
because the famine affected the mothers fertility and
the offsprings survival (Stein et al., 1975). Selective
fertility did not seem to explain our findings as adjust-
ments for maternal characteristics that might be proxies
for fertility (age, parity, maternal weight and socio-eco-nomic status) hardly altered the results. Nor did we find
indications that selective early mortality had caused
differences in adult health: there were no differences in
adult health between people who were born before the
famine and those who were conceived after the famine,
whereas early mortality differed most strongly between
these two groups.
Although the famine was characterised by extreme
shortage of food, the availability of food was not the
only aspect that varied with the famine. The famine
coincided with a very cold winter during which infec-
tions were widespread (Banning, 1946). Also, the stressexperienced by pregnant women during the famine due
to lack of food, the war, and the absence of their
spouses will have been more extreme than in those who
were pregnant before or after the famine. We can not
rule out effects of exposure to stress contributing to
long-term effects on the offsprings health. We do not,
however, consider stress to be a major cause of the
effects we found since we did not find differences in
health between people who were born before the famine
and those conceived after the famine, whereas one
would expect differences in the levels of exposure to
stress between these groups. Moreover, we observed
effects on health predominantly in the offspring of
women exposed to famine in early gestation. One
would expect at least the same or even higher levels of
stress in pregnant women exposed to famine in late or
mid gestation, yet, we did not find that offspring of
these women had a poorer health. Whatever the true
cause of the adaptations made by the foetus that re-
sulted in disease in later life, our findings indicate that
an adverse environment in utero can have permanenteffects on health.
7. Conclusion
Our findings broadly support the hypothesis that
chronic diseases originate through adaptations made by
the foetus in response to undernutrition. The long-term
effects of intrauterine undernutrition, however, depend
upon its timing during gestation and on the tissues and
systems undergoing critical periods of development at
that time. Our findings suggest that risk factors forCHD, such as impaired glucose tolerance, hypercholes-
terolaemia, raised blood pressure and obesity, which
often co-exist, have their origins in utero, but are
programmed at different times. Furthermore, our find-
ings suggest that maternal malnutrition during gesta-
tion may permanently affect adult health without
affecting the size of the baby at birth. This gives the
foetal origin hypothesis a new dimension. It may imply
that adaptations that enable the foetus to continue to
grow may nevertheless have adverse consequences for
health in later life. CHD may be viewed as the pricepaid for successful adaptations to an adverse intra-uter-
ine environment. It also implies that the long-term
consequences of improved nutrition of pregnant women
will be underestimated if these are solely based on the
size of the baby at birth.
We need to know more about what an adequate diet
for pregnant women might be. In general, women are
especially receptive to advice about diet and lifestyle
before and during a pregnancy. This should be ex-
ploited to improve the health of future generations.
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Blood pressure in adults after prenatal exposure to famineTessa J. Rosebooma, Jan H.P. van der Meulena, Anita C.J. Ravellia,Gert A. van Montfransb, Clive Osmondd, David J.P. Barkerd andOtto P. Blekerc
BackgroundMany studies have shown that low birth
weight is associated with high blood pressure. The
composition of the diet of pregnant women has also been
found to affect blood pressure in their children. We
assessed the effect of prenatal exposure to the Dutch
famine of 19441945, during which the caloric intake from
protein, fat and carbohydrate was proportionally reduced,
on blood pressures in adults now aged about 50 years.
Methods and results We measured blood pressures at
home and in the clinic among people born at term in onehospital in Amsterdam, The Netherlands, between
November 1 1943 and February 28 1947, for whom we had
detailed birth records. Blood pressures of people exposed
to famine during late (n 120), mid- (n 109) or early
gestation (n 68) were compared with those of people
born in the year before or conceived in the year after the
famine (unexposed subjects, n 442). No effect of
prenatal exposure on systolic and diastolic blood pressure
was observed. The mean systolic blood pressure taken in
the clinic in those exposed in late gestation, and adjusted
for sex and age, was 1.3 mmHg higher than in the
unexposed group (95% condence interval 1.9 to 4.4).
The mean systolic blood pressure differed by 0.6 mmHg(95% condence interval 3.9 to 2.7) for those exposed in
mid-gestation and 1.7 mmHg (95% condence interval
5.6 to 2.2) for those exposed in early gestation. People who
were small at birth had higher blood pressures. A 1 kg
increase in birth weight was associated with a decrease of
2.7 mmHg (95% condence interval 0.3 to 5.1) in systolic
blood pressure. Analyses of blood pressures measured at
home gave similar results.
Conclusion High blood pressure was not linked to
prenatal exposure to a balanced reduction of macro-
nutrients in the maternal diet. However, it was linked to
reduced fetal growth. We postulate that it might be the
composition rather than the quantity of a pregnant
woman's diet that affects her child's blood pressure in laterlife. J Hypertens 1999, 17:325330 & Lippincott Williams &Wilkins.
Journal of Hypertension 1999, 17:325330
Keywords: blood pressure, fetal origins, famine, pregnancy, birth weight
aDepartment of Clinical Epidemiology and Biostatistics, bDepartment of InternalMedicine, and cDepartment of Obstetrics and Gynaecology, Academic MedicalCentre, University of Amsterdam, The Netherlands and dMRC EnvironmentalEpidemiology Unit, University of Southampton, UK.
Sponsorship: This study was funded by the Medical Research Council, UK, theDiabetes Fonds Nederland, and Wellbeing, UK.
Correspondence and requests for reprints to Dr J.H.P. van der Meulen, MRCEnvironmental Epidemiology Unit, University of Southampton, SouthamptonSO16 6YD, UK.Tel: 44 1703 777 624; fax: 44 1703 704 021; e-mail [email protected]
Received 17 August 1998 Revised 30 November 1998Accepted 4 December 1998
IntroductionA systematic review of the published literature hasshown that low birth weight is associated with high
blood pressure both in children and adults [1]. Low
weight at birth is also associated with non-insulin
dependent diabetes [2,3], high levels of serum choles-terol [4] and brinogen [5], and higher mortality from
coronary heart disease [6,7]. All these associations are
the result of reduced fetal growth rather than prema-ture birth [5]. This has led to the hypothesis that an
adverse fetal environment is important in the develop-ment of coronary heart disease [5]. It has been
suggested that fetal under-nutrition during sensitive
periods of rapid growth induces permanent changes in
the structure and physiology of fetal organs [8].
The hypothesis regarding fetal origins is supported by
data from animal experiments. In rats, maternal malnu-
trition during pregnancy retards fetal growth and raisesblood pressure in the offspring [9]. So far, there have
only been two studies on the relation between the
maternal diet during pregnancy and blood pressure in
humans. One study [10] showed that the balancebetween protein and carbohydrate in the maternal diet
during late pregnancy was associated with the blood
pressure in the offspring 40 years later. This associationbetween maternal diet and blood pressure of the
offspring was independent of size at birth. Anotherstudy [11] showed that the blood pressures of 169
people exposed in utero to the Leningrad siege of
19411944 were only slightly increased compared with
those of 188 people born in the province of Leningradbut outside the city (134.7 versus 130.9 mmHg,
P 0.1).
Original article 325
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In the present study, we assessed the effect of exposure
to severe maternal malnutrition at different periods of
gestation on blood pressure. We studied people who
had been born around the time of the Dutch famine in
one hospital in Amsterdam, The Netherlands. The
birth records of these subjects are still available, and
provide detailed information on the mother, the courseof pregnancy and body size at birth. We have already
shown that the glucose tolerance of these people was
reduced after exposure to the famine in late and mid-
gestation [12]. The Dutch famine occurred in the
western part of The Netherlands at the end of World
War II, beginning suddenly in late November 1944 and
ending in early May 1945 after the liberation of the
Netherlands by the Allied forces. At its peak, in the
rst months of 1945, the ofcial rations available for the
general population varied between 400 and 800 calories
(16803360 kJ). We compared the blood pressures of
those born in the year before and those conceived in
the year after the famine (unexposed subjects) withthose exposed to famine during different periods of
gestation (exposed subjects). We measured blood pres-
sures at the homes of the subjects and during a visit to
the clinic.
Subjects and methodsSelection procedures
The selection procedures for the Dutch famine birth
cohort study have been described in detail elsewhere
[12]. All singletons born alive in the Wilhelmina
Gasthuis Hospital in Amsterdam between November 1
1943 and February 28 1947 after a pregnancy duration
of at least 259 days were candidates to be included.We retrieved the medical records of 1380 babies born
alive between November 1 1944 and February 28 1946
and the records of random samples of 650 singletons
born between November 1 1943 and October 31 1944
and 650 singletons born between March 1 1946 and
February 28 1947. Of these, 27 were excluded from
the study because their main medical records were
missing, and 239 were excluded because the gesta-
tional age at birth was less than 259 days. We thus
included 2414 babies born alive. The `Bevolkingsregis-
ter' (population registry) of Amsterdam traced 2155
(89%) of the 2414 included babies. Of these, 265 had
died, 199 had emigrated from The Netherlands, and164 did not allow the population registry to give us
their address. We visited 912 subjects, who lived in or
close to Amsterdam, at home and measured blood
pressure successfully in 905 of them. We also asked
them to attend the clinic, and 741 agreed to attend; we
successfully measured the blood pressures of 739 of
them. Birth weights according to prenatal exposure to
famine in this group of 739 subjects were not different
from the 1675 babies who were not included (differ-
ence in birth weight adjusted for exposure to famine
was 28 g, P 0.23).
Exposure to famine
We dened the famine period according to the daily
ofcial food rations for the general population older
than 21 years. The caloric intake from protein, carbo-
hydrate and fat was approximately proportionally re-
duced. The ofcial rations should be considered as a
relative measure of the amount of food available. Aperson was considered to be prenatally exposed if the
average daily ration for people older than 21 years
during any thirteen-week period of gestation contained
less than 1000 calories. The ofcial daily rations for
children younger than 1 year were always higher than
1000 calories [13]. Therefore, children born between 7
January 1945 and 8 December 1945 were exposed
prenatally. We dened periods of 16 weeks each to
differentiate between those who were exposed in late
gestation (born between 7 January 1945 and 28 April
1945), in mid-gestation (born between 29 April 1945
and 18 August 1945), and in early gestation (born
between 19 August 1945 and 8 December 1945).
Study parameters
The medical records of the mothers provided informa-
tion on maternal age, parity, date of last menstrual
period, mean systolic blood pressure during pregnancy
and weight at the beginning of the third trimester and
at the end of pregnancy (within 2 weeks of birth). They
also included records of the baby's sex, body measures
at birth, and length and width of the placenta, and gave
the occupation of the head of the family. Maternal
weight gain during the third trimester was calculated as
the difference between the weights at the beginning
and end of the third trimester divided by the timeinterval between these weight measurements and mul-
tiplied by the trimester duration (13 weeks). Ponderal
index (birth weight divided by the cube of length) and
head-to-birthweight ratio and placental area (length 3
width 3 /4) were calculated from the measures at
birth. Head circumference was estimated as 3
(biparietal diameter occipito-frontal diameter)/2. The
occupation of the head of the family was dichotomized
into manual and non-manual labour, and used as a
measure of socioeconomic status [14].
Blood pressures were measured four times at home
(twice before and twice after an interview), and fourtimes at the clinic (twice before and twice after a
physical examination). Blood pressure measurements
were made in the non-dominant arm using a validated
automated auscultatory device (Prolomat; Disetronic
Medical Systems AG, Burgdorf, Switzerland) [15]. All
blood pressures were measured after 5 min rest while
the participants were seated. The measurements were
performed between January 1995 and August 1996.
Unlike the blood pressure measurements taken at
home, those taken in the clinic were performed under
standardized conditions, in the morning after an over-
326 Journal of Hypertension 1999, Vol 17 No 3
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night fast, and with the participants having not smoked
or drunk coffee or tea. We analysed the blood pressures
measured at home and in the clinic separately. We also
measured height and weight (Seca scale) and we
recorded information on smoking, alcohol use and anti-
hypertensive medication. Current socioeconomic status
was coded using the ISEI-92 scale according to theoccupation of the participants or their partners, which-
ever had the highest value on the scale [16]. The ISEI
scale is a continuous measure which represents the
education needed for an occupation and the income
generated by it, with a scale ranging from 16 for the
lowest to 87 for the highest status.
Statistical methods
Body mass index (BMI) had a skewed distribution and
was therefore log-transformed before analysis. We cal-
culated the differences between the blood pressures of
unexposed subjects and those exposed in late, mid- or
early gestation separately. We used multiple linearregression analysis to adjust for sex and age at blood
pressure measurement, and in a second step also for
gestational age, maternal characteristics (age, parity,
weight at the end of pregnancy, weight gain, blood
pressure and socioeconomic status at birth), and adult
characteristics (BMI, smoking, alcohol use, anti-hyper-
tensive medication and current socioeconomic status).
Information on maternal weight at the end of preg-
nancy, weight gain or socioeconomic status at birth was
missing for a relatively large number of persons. There-
fore, when adjusting for these variables, we added a
separate group for missing information, after having
categorized weight and weight gain into four equally
sized groups. Parity, socioeconomic status at birth,
smoking and use of anti-hypertensive medication wereadjusted for by adding a dichotomous variable into the
linear regression model; the other variables were added
to the model as continuous variables.
ResultsCharacteristics of study population
Two-hundred and ninety-seven (40%) of the 739
subjects had been exposed to famine in utero (Table 1).
Because it was more difcult to contact men, fewer
men than women were included, especially in the
groups that had been exposed to famine in utero. The
mean systolic blood pressure measured in the clinic was
3.8 mmHg higher in men than in women [95% con-dence interval (CI) 1.5 6.0]. Mothers who were
exposed to famine during late pregnancy were older,
less often primiparous, lighter at the end of pregnancy
and they also gained less weight in the third trimester
than mothers of unexposed subjects. Socioeconomic
status at birth was similar across exposure groups. The
mean systolic blood pressure of the mother during
pregnancy was lower in all exposed groups. Babies
Table 1 Maternal characteristics, birth outcomes, adult characteristics and blood pressure according to timing of prenatal exposure tofamine
Exposure to famine
B orn before In l ate gestat ion In mid-gestat ion In ear ly gestation Concei ved after Al l Mi ssi ng(n 120) (n 120) (n 109) (n 68) (n 232) (n 739) observations
Men 50% 48% 40% 44% 51% 48% 0Maternal characteristics
Age (years) 29.1 30.9 28.8 27.2 28.7 29.0 6.5 0Primiparous 35% 24% 32% 38% 35% 33% 0Weight at end of pregnancy (kg) 66.4 62.9 63.5 67.5 68.6 66.2 8.6 93Weight gain in thirdtrimester (kg)
3.2 0.1 5.1 5.6 4.2 3.5 3.3 214
Systolic blood pressure (mmHg) 116.2 114.2 114.6 114.9 115.9 115.5 10.3 9Manual labour 79% 70% 72% 64% 62% 70% 182
Birth outcomesGestational age at birth (days) 285 286 285 286 286 286 12 96Birth weight (g) 3383 3166 3217 3450 3444 3349 470 0Body length (cm) 50.6 49.5 49.8 51.0 50.5 50.3 2.1 7Head circumference (cm) 32.9 32.4 32.2 33.0 33.1 32.8 1.5 8
Placental area (cm2
) 298 270 260 278 275 280 69 115Ponderal index (kg/m3) 26.1 26.0 25.9 26.0 26.6 26.2 2.3 7Head-to-birth weight ratio (cm/g) 9.9 10.4 10.1 9.7 9.8 10.0 1.2 8
Adult characteristicsAge at measurement (years) 51.4 50.8 50.5 50.3 49.8 50.4 0.9 0Body mass index (kg/m2) 26.7 26.7 26.6 28.1 27.2 27.0 1.2 0Height (cm) 171 171 169 171 171 171 9.0 0Socioeconomic status (ISEI) 46 50 48 48 47 47 14 0Current smoker 37% 34% 32% 41% 34% 35% 0Alcohol (units/week) 10 10 9 8 9 9 12 0Anti-hypertensive medication 8% 9% 13% 12% 9% 10% 0
Adult blood pressure in the clinicSystolic blood pressure (mmHg) 126.0 127.4 124.8 123.4 125.1 125.5 15.5 0Diastolic blood pressure (mmHg) 86.2 86.4 84.4 84.8 85.2 85.6 9.9 0
Data are expressed as means or mean SD except geometric mean and standard deviation.
Blood pressure after prenatal exposure to famine Roseboom et al. 327
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exposed to famine in late or mid-gestation were lighter
and shorter, and had smaller heads and smaller placen-
tas than those not exposed. They also had higher head-
to-birthweight ratios, which suggests `brain sparing'.
Babies exposed to famine in early gestation seemed to
be somewhat heavier and longer, especially taking
account of the smaller number of men in this group.Adult BMI was also higher in those exposed to famine
in early gestation. Systolic blood pressure measured in
the clinic increased by 1.1 mmHg (95% CI 0.91.3) per
unit (kg/m2) increase in BMI. Adult height, smoking,
alcohol consumption, socioeconomic status and use of
anti-hypertensive medication were similar in the expo-
sure groups.
Blood pressure measured in the clinic
After adjustment for sex and age, we found that the
mean systolic blood pressure of those exposed to
famine in late gestation was 1.3 mmHg higher (95% CI
1.9 to 4.4) and the diastolic blood pressure was0.4 mmHg higher (95% CI 1.6 to 2.5) than in those
who were not exposed (born before or conceived after).
The corresponding differences for those exposed in
mid-gestation were 0.6 mmHg (95% CI 3.8 to 2.7)
in systolic and 1.2 mmHg (95% CI 3.3 to 0.9) in
diastolic blood pressure, and for those exposed in early
gestation there were mean decreases of 1.7 mmHg
(95% CI 5.6 to 2.2) in systolic and 0.7 mmHg (95%
CI 3.2 to 1.9) in diastolic blood pressure.
The maternal characteristics (age, parity, weight at the
end of pregnancy, weight gain in the third trimester,
mean systolic blood pressure and socioeconomic statusat birth) were not associated with the systolic blood
pressure of the offspring (P always > 0.4). Birth weight,
body length, head circumference and ponderal index
were all inversely related to systolic blood pressure.
After adjustment for sex, we found that an increase of
1 kg in birth weight was associated with a decrease of
2.7 mmHg (95% CI 0.35.1) in systolic blood pressure,
an increase of 1 cm in length with a decrease of
0.4 mmHg (95% CI 0.1 to 0.9), an increase of 1 cm in
head circumference with a decrease of 0.9 mmHg (95%
CI 0.1 1.6), and an increase of 1 kg/m3 in ponderal
index with a decrease of 0.4 mmHg (95% CI 0.00.9).
Head-to-birthweight ratio was positively associated with
blood pressure, and an increase of 1 cm/g was asso-ciated with an increase in systolic blood pressure of
0.9 mmHg (95% CI 0.01.8). Blood pressure was not
associated with placental area (P 0.6).
The effect of prenatal exposure to famine on systolic
blood pressure in late or early gestation was affected
little by adjustment for maternal characteristics includ-
ing maternal weight at the end of pregnancy and
weight gain in the third trimester (Table 2). We also
found that adjustments for adult characteristics includ-
ing BMI and socioeconomic status did not alter the
results. Adjustment for size at birth changed the
differences in blood pressure between those exposed tofamine and those not exposed, to the same extent as
could be expected from the famine-related changes in
size at birth. When we simultaneously adjusted for
maternal characteristics (weight at the end of pregnancy
and weight gain), characteristics at birth (gestational
age, birth weight and socioeconomic status), and adult
characteristics (BMI, socioeconomic status and use of
anti-hypertensive medication), we found that systolic
blood pressure differed by 1.5 mmHg (95% CI 1.9 to
4.8) among those exposed in late gestation, by
0.9 mmHg (95% CI 4.2 to 2.4) among those exposed
in mid-gestation, and by 3.6 mmHg (95% CI 7.5 to
0.4) among those exposed in early gestation. Simultane-ous adjustment for all these potential confounders had
also only small effects on the differences in diastolic
blood pressure. Adjustment for gestational age at birth,
maternal and adult characteristics did not change the
observed associations between size at birth and blood
pressure appreciably. For instance, after adjustment for
all these characteristics we found that an increase of
Table 2 Differences in systolic blood pressure (mmHg) measured in the clinic according tothe timing of prenatal exposure to famine, compared with non-exposed participants(those born before or conceived after the famine)
Exposure to famine
In late gestation In mid- gestation In early gestation
Adjusted for:Sex and age 1.3 (1.9 to 4.4) 0.6 (3.8 to 2.7) 1.7 (5.6 to 2.2)Sex, age and maternal weight 1.5 (1.7 to 4.7) 0.4 (3.6 to 2.9) 1.9 (5.8 to 2.0)Sex, age and maternal weight gain# 1.8 (1.6 to 5.1) 0.9 (4.2 to 2.4) 2.2 (6.2 to 1.7)Sex, age and birth weight 0.8 (2.4 to 3.9) 1.0 (4.2 to 2.3) 1.6 (5.6 to 2.3)Sex, age and BMI 1.6 (1.4 to 4.5) 0.1 (3.2 to 2.9) 3.1 (6.7 to 0.6)Sex, age and socioeconomicstatus (at birth and current)
1.3 (1.9 to 4.4) 0.5 (3.8 to 2.7) 1.8 (5.8 to 2.1)
Data are expressed as mean differences (with negative values denoting a decrease and positive values anincrease) and 95% condence intervals. Maternal weight at the end of pregnancy; #weight gain during thirdtrimester. BMI, body mass index.
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1 kg in birth weight was associated with a 3.9 mmHg
(95% CI 1.26.6) decrease in systolic blood pressure.
Blood pressure measured at home
After adjustment for sex and age, the mean systolic
blood pressure of those exposed to famine in late
gestation was 0.7 mmHg lower (95% CI 2.3 to 3.7)and the diastolic blood pressure was 0.4 mmHg lower
(95% CI 1.6 to 2.3) than in those who were not
exposed. The corresponding differences for those ex-
posed in mid-gestation were 1.3 mmHg (95% CI 4.3
to 1.7) in systolic and 1.7 mmHg (95% CI 3.6 to 0.2)
in diastolic blood pressure; for those exposed in early
gestation, 1.4 mmHg (95% CI 5.1 to 2.2) in systolic
and 0.9 mmHg (95% CI 3.2 to 1.4) in diastolic blood
pressure. The associations between size at birth and
blood pressures measured at home, however, were
similar to those based on blood pressure measurements
taken in the clinic. We found that an increase of 1 kg
in birth weight was associated with a decrease of3.3 mmHg (95% CI 0.66.0) in systolic blood pressure
after adjustment for sex.
DiscussionWe could not demonstrate an effect of prenatal expos-
ure to famine during which caloric intake from
protein, fat and carbohydrate was approximately propor-
tionally reduced on systolic and diastolic blood
pressure measured either in the clinic or at home.
However, we found, as many other studies have done,
that small size at birth (low birth weight, short body
length, thinness or small head size) was associated with
higher blood pressure in later life [1]. The associationbetween size at birth and blood pressure was only
slightly altered by adjustment for circumstances in early
(gestational age at birth, maternal weight, weight gain,
socioeconomic status at birth) or later life (BMI, smok-
ing, alcohol use, present socioeconomic status).
The conditions during the Dutch famine closely
matched the experimental set-up of animal studies on
the effects of low-energy diets during pregnancy. The
famine had a sudden beginning and end, and struck
the entire population, almost irrespective of social class.
However, the number of births corresponding to con-
ceptions at the peak of the famine and consequentlyalso to exposure during early gestation was about
50% lower than that corresponding to pre-famine con-
ceptions [14]. This famine-induced reduction in fertil-
ity invalidates the similarity between our study and
experimental studies to some extent, but by using the
well-kept birth records we were able to take potentially
confounding factors into account. Selective fertility
does not seem to explain our ndings, since adjust-
ments for maternal characteristics, which might be
determinants of fertility (maternal age, parity, weight
and socioeconomic status), did not alter the results.
In those subjects exposed in utero to the Leningrad
siege of 1941 1944, blood pressure was increased by
about 4 mmHg (P = 0.1) compared with those born in
the same period but outside the famine area. Unfortu-
nately, it is difcult to compare the results of that study
with ours because the conditions before and after the
famine period in Leningrad and in the western part ofThe Netherlands were essentially different. First, the
Dutch famine had a shorter duration than the famine in
Leningrad (5 months versus more than 2 years in
Leningrad), and it was preceded and followed by more
or less adequate nutrition. Second, the Dutch people
who were born around the time of the famine grew up
in a period of rapidly increasing afuence, whereas the
standard of living in Russia remained relatively poor
and may have even deteriorated in the past 10 years
[17].
The ability of a mother to supply the fetus with
nutrients is not only determined by what she eatsduring pregnancy, but also by her own growth and
physical development over the years. The effects of
malnutrition during a short period of gestation on fetal
growth may therefore have been buffered by nutritional
reserves built up in the mother's body. After chronic
malnutrition, these reserves might be small or absent,
and the effects of malnutrition during gestation might
be more severe. This notion is in agreement with the
results of studies performed in Jamaica and the UK
[18,19], in which women with low triceps skinfold
thickness, which suggests chronic malnutrition, were
shown to have children with higher blood pressures. In
experiments with rats, under-nutrition before andthroughout pregnancy increased blood pressure more
strongly than under-nutrition over short periods, also
suggesting that the effect of maternal malnutrition
depends on its duration [20].
The ofcial record of rations during the Dutch famine
indicated that the caloric content of the diet decreased
strongly, but that the balance between protein, carbo-
hydrate and fat remained approximately the same. We
could not demonstrate that prenatal exposure to such a
balanced reduction of macro-nutrients had an effect on
blood pressure. Recently, it was found, however, that
the blood pressures of 40-year-old men and women inAberdeen were related to the balance of carbohydrate
and protein in their mothers' diet during pregnancy
[10]. At either extreme of this balance, their blood
pressures were raised, even if their growth in utero was
hardly affected [10]. These ndings are in agreement
with results of animal studies [9,21,22], which showed
that the effects of protein restriction in the diet of
pregnant rats on the blood pressure of their offspring
are stronger than the effects of caloric restriction with a
balanced reduction of all macro-nutrients. Moreover,
the effects seem to depend not only on the composition
Blood pressure after prenatal exposure to famine Roseboom et al. 329
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of the diet with respect to macro-nutrients in general,
but also with respect to particular fatty acids [9] or
amino acids (Langley-Evans, personal communication,
1997). All this suggests that the blood pressure of
offspring depends not so much on how much the
mother eats during pregnancy as on what she eats.
ConclusionsOur study showed that a short period of a proportionate
reduction in nutrients has only a small effect on fetal
growth and little if any effect on the blood pressure of
the offspring. We conrmed, however, that reduced
fetal growth is related to raised blood pressure. We
consider it likely that more prolonged periods of under-
nutrition or deviations in the balance of macro-nutrients
in the maternal diet have an appreciable effect on
blood pressure. These ndings contrast with ndings of
the glucose tolerance in the same group of people [12].
We found that prenatal exposure to famine in late and
mid-gestation reduced glucose tolerance even if theeffect on fetal growth was small. This suggests that
glucose metabolism and blood pressure are pro-
grammed in fetal life through different maternal inu-
ences.
AcknowledgementsWe thank all men and women of the Dutch Famine
Birth Cohort who participated in the study. We thank
Marjan Loep, Mieneke Vaas, Lydia Stolwijk, Yvonne
Graafsma, Jokelies Knopper and Maartje De Ley for
collecting the data, and Professor J.G. Koppe, Dr L.H.
Lumey and Dr C.H.D. Fall for their help. Furthermore,
we thank the Gemeentearchief of Amsterdam fortracing the birth records, the Bevolkingsregister of
Amsterdam for tracing the subjects, and the nurses at
the Special Research Unit of the Academic Medical
Centre, University of Amsterdam, for their support with
the blood pressure measurements.
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20 Langley-Evans SC. Intrauterine programming of hypertension by glucocorti-coids. Life Sci 1997; 60:12131221.
21 Woodall SM, Johnston BM, Breier BH, Gluckman PD. Chronic maternalundernutrition in the rat leads to delayed postnatal growth and elevatedblood pressure in the offspring. Pediatr Res 1996; 40:438443.
22 Gerber RT, Holemans K, Van Assche FA, Opston L. Female offspring fromundernourished Wistar rats have normal blood pressure but altered vascularreactivity. Fetal physiology and development meeting Cambridge, 2529June 1997.
330 Journal of Hypertension 1999, Vol 17 No 3
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See corresponding editorial on page 271.
See corresponding CME exam on page 466.
Early onset of coronary artery disease after prenatal exposure to theDutch famine13
Rebecca C Painter, Susanne R de Rooij, Patrick M Bossuyt, Timothy A Simmers, Clive Osmond, David J Barker,Otto P Bleker, and Tessa J Roseboom
ABSTRACT
Background: Limited evidence suggests that maternal undernutri-
tion at the time of conception is associated with increased cardio-
vascular disease risk in adult offspring.
Objective: We investigated whether persons conceived during the
Dutch famine of World War II had an early onset of coronary artery
disease (CAD).Design: We compared the age at onset and cumulative incidence of
CAD between persons born as term singletons who were exposed to
the 1944 1945 Dutch famine during late(n 160), mid- (n 138),
or early (n 87) gestation and 590 unexposed subjects at age 50 or
58 y. Age at CAD onset was defined as the age at which angina
pectoris was identified (according to the Rose questionnaire), Q
waves were observed on an electrocardiogram (Minnesota codes
11 or 12), or coronary revascularization was performed (by an-
gioplasty or bypass surgery).
Results: Of the 83 CAD cases identified, persons conceived during
the famine were 3 y younger than the unexposed persons at the time
of CAD diagnosis (47 y compared with 50 y) and had a higher
cumulative incidence of CAD [13%; hazard ratio (HR) adjusted forsex: 1.9; 95% CI: 1.0, 3.8] than did the unexposed persons. The HR
changed little after adjustment for smoking (HR: 1.8), social class
(HR: 2.0), or size at birth (HR: 2.0).
Conclusions: We found an earlier onset of CAD among persons
conceived during the famine, which suggests that maternal nutrition
in early gestation may play a role in the onset of CAD. This finding
agrees with evidence from animal experimentsthat identify pericon-
ceptional maternal diet as important in the offsprings adult
health. Am J Clin Nutr 2006;84:3227.
KEY WORDS Coronary artery disease, age at onset, maternal
nutrition, maternal starvation, pregnancy, cardiovascular program-
ming
INTRODUCTION
Restricted intrauterine growth has been proposed as an impor-
tant contributor to later coronary artery disease (CAD) and its
biological risk factors (1). Developing organ systems respond
negatively to the reduced availability of nutrients, particularly
during periods of rapid developmentso-called critical peri-
ods (2).
Most studies in humans have access only to indirect measures
of intrauterine nutrition, such as birth weight. Substantial
changes in cardiovascular function can result from maternal or
fetal undernutrition without affecting birth weight (3). To gain
more insight into the mechanisms of disease in later life in hu-
mans after restricted prenatal nutrition, the sequelae of restricted
maternal nutritionduring gestation have been studied in theLen-
ingradSiege Study (4)and the DutchFamine Birth CohortStudy.
The Dutch famine was a 5-mo period of extreme food shortage
duringthe winterof 1944 1945 in World WarII. The Leningrad
Study reported no effect of maternal malnutrition on the adult
offsprings CAD prevalence. The Dutch famine, however, was
relatively shortcompared with the Leningrad Siege Study, which
allowed the effects to be studied by trimester of prenatal famine
exposure. The previous findings from the Dutch Famine Birth
Cohort Study support the hypothesis that the timing of the nu-
tritional insult is important in determining its effect in later life;
exposure to the Dutch famine in late gestation was associated
with decreased glucose tolerance (5), whereas more microalbu-
minuria (6) was present among subjects exposed during mid-
gestation. The most marked effects were described in the group
of subjects conceived during the famine and include a moreatherogenic lipid profile (7), altered clotting (8), more obesity
(9), and a tripling of CAD prevalence at age 50 y (10).
The cluster of cardiovascular disease risk factors previously
described in persons conceived in famine is in line with studies
in animals, which have highlighted the importance of pericon-
ceptional maternal nutrition in programming cardiovascular dis-
ease risk (1114). The effects of maternal periconceptional diet
on the course of adult disease have not been investigated. We
hypothesized that CAD manifests at an earlier age in persons
exposed to famine during early gestation. We reexamined the
1 From theDepartments of Clinical Epidemiologyand Biostatistics (RCP,
SRdR, PMB, and TJR), Cardiology (TAS), and Obstetrics and Gynecology(OPB), Academic Medical Center, University of Amsterdam, Amsterdam,
Netherlands, and the MRC Epidemiology Resource Centre (CO) and the
Developmental Origins of Adult Disease Centre (DJB), University of
Southampton, Southampton, United Kingdom.2 The Dutch Famine Birth Cohort Study is funded by the Diabetes Fonds
(Netherlands), the Netherlands Heart Foundation (grant number2001B087),
Wellbeing (United Kingdom), the Medical Research Council (United King-
dom), and the Academic Medical Centre (Netherlands).3 Address reprint requests to RC Painter, PO Box22660, 1100 DD,Meiberg-
dreef 9, 1105 AZ Amsterdam, Netherlands. E-mail: [email protected] November 28, 2005.
Accepted for publication February 24, 2006.
322 Am J Clin Nutr 2006;84:3227. Printed in USA. 2006 American Society for Nutrition
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findings of a study conducted at age 50 y and included informa-
tion from a subsequent study 8 y later.
SUBJECTS AND METHODS
Selection procedure
The Dutch Famine Birth Cohort consists of 2414 live-born
term singletons born in the Wilhelmina Gasthuis in Amsterdam,Netherlands. All infants were born between 1 November 1943
and 28 February 1947. The selection procedure for the study
conducted at age 50 y was described in detail elsewhere (5), as
was lossto follow-up because of mortality, emigration, and other
reasons (15, 16). In short, cohort members were eligible for
participation if they were living in the Netherlands at the start of
the study (January 1995 and September 2002), and their address
was known to the Dutch Famine Birth Cohort Study researchers.
Alleligible subjects were asked to participateat ages 50 and58 y.
Council registries helped trace people who had had a change of
address since they were last traced at age 50 y. All participants
provided written informed consent. The local Medical Ethics
Committeeapprovedthe study.The study conformed to theDec-laration of Helsinki.
Exposure to famine
We defined famine exposure according to the daily official
food rations for adults. In addition to the official rations, food
from other sources, such as church organizations, central kitch-
ens, and the black market, was also available and the people
may have had access to up to double the rationed amount at the
peak of the famine. The rations do, however, adequately reflect
the fluctuation of food availability during the famine (17). A
person was considered prenatally exposed to famine if the aver-
age daily rations for adults during any 13-wk period of gestation
were 1000 kcal. Therefore, persons born between 7 January
1945 and 8 December 1945 were considered exposed prenatally
to famine. Cohort members born between 1 November 1943 and
6 January 1945 (born before the famine) and between 9 Decem-
ber1945and 28 February1947 (conceived after thefamine)were
unexposed to famine. We defined periods of 16 wk each to
differentiate between those who were exposed in late gestation
(born between 7 January and 28 April 1945), midgestation (born
between 29 April and18 August1945), andearlygestation (born
between 19 August and 8 December 1945), in correspondence
with previous publications on this cohort (5, 10). Persons ex-
posed in early gestation were conceived during the famine. The
famine ended in May 1945, with the advance of the allied armies
into Holland. Food supplies were rapidly restored, and the aver-
age caloric intake in June 1945 was 2000 kcal.
Data collection
Medical birth records provided information about the mother,
thecourse of gestation, and the size of theinfant and theplacenta
at birth (5). Socioeconomic status (SES) at birth was defined
according to the occupation of the head of the family and was
classified as either manual or nonmanual on the basis of the
information provided by the birth records.
Consenting cohort members came to the hospital. We mea-
sured height using a fixed or a portable stadiometer, weight with
Seca scales (Hamburg, Germany) or Tefal portable scales
(Groupe SEB Nederland BV, Veenendaal, Netherlands). Body
massindex was calculated by dividingweightin kilograms by the
square of height in meters. Blood pressure was measured twice
on 2 occasions (morning and afternoon) with an automated de-
vice: a Profilomat (Disentronic Medical Systems AG, Burgdorf,
Switzerland) at age 50 y and an Omron 705CP/IT (Omron
Healthcare United Kingdom, West Sussex, United Kingdom) at
age 58 y. Mean blood pressure was calculated from both the
morning and afternoon measurements. Standard 12-lead electro-
cardiograms (ECGs) were used for all participants. Trained tech-nicians blinded to the clinical data scored the ECGs according to
the Minnesota criteria. Nondiabetic participants underwent stan-
dard 75-g oral glucose tolerance testing.Bloodwas drawn forthe
measurement of LDL, HDL, and triacylglycerol concentrations.
Total cholesterol, HDL, and triacylglycerol concentrations were
measured with the use of an enzymatic colorimetric reagent
(Roche Diagnostics, Switzerland) on a P-800 Modular (Roche,
Switzerland). LDL was calculated by using the Friedewald for-
mula.
Participants were interviewed to obtain information about
their medical history, including operations, lifestyle, and use of
medication. We defined current SES according to the partici-
pants or their partners occupation, whichever was highest, us-ing the ISEI-92 (18). The ISEI-92 scale ranges from 16 (mini-
mumscore; lowest status) to 87 (maximumscore;higheststatus).
Trained nurses carried out all measurements and interviews.
The presence of CAD was defined as the presence of one or
more of the following: angina pectoris according to the Rose/
World Health Organization questionnaire, Q waves on the ECG
(Minnesota codes 11 or 12), or history of coronary revascu-
larization (angioplasty or bypass surgery).
Statistical methods
For the investigation of age at onset of CAD, all subjects that
had participated at age 50 or 58 y were included. To study asso-
ciations between the progression of CAD and the timing of fam-ine exposure during gestation and size at birth, we used the Cox
regression model of the cumulative incidence and age of mani-
festation of CAD and calculated hazard ratios (HRs)and 95% CIs
for subjects exposed in late, mid-, and early gestation and com-
pared them with unexposed subjects. We constructed a Kaplan-
Meier curve showing the cumulative incidence of CAD as a
function of age per famine exposure group.
The time of event was defined as the age at onset of angina
pectoris according to the Rose/World Health Organization ques-
tionnaire. If no age at onset of angina pectoris was stated, the age
at the time of the first coronary revascularization procedure was
used, and, in cases where both ages were missing, the age at the
time of registration of Q waves on the ECG was used. Subjects
who had only participated at age 50 y were censored at the age at
that visit. When adjusting for covariates in the Cox model, we
used the most recently collected available measurement before
the event. If the event had occurred between the time points of
participation, an estimation of the covariate at the time of the
event was made with the use of linear interpolation.
We used logistic regression analysis to compare the charac-
teristics of persons with and without CAD. Because of the left
skewed distribution of age at first occurrence of CAD, this vari-
able is reported in means after we applied a quadratic transfor-
mation. Body mass index, SES, the ratio of LDL to HDL, and
glucose were log transformed because of their skewed distribu-
tions. These variables arereportedas geometric meansSDs;all
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other variables are reported as means SDs. All statistical anal-
yses were performed by using SPPS 12.0.2 (SPSS Inc, Chicago,
IL). We considered differences to be statistically significant ifP
values were0.05.
RESULTS
Study population
The cohort contained 2414 members. Loss to follow-up was
described previously (15, 16). At age 50 y, 1527 (63%) persons
were eligible for participation. At age 58 y, 1423 (59%) persons
were eligible for participation. A total of 975 subjects partici-
pated in this study. At age 50 y (range: 4853 y), 736 persons
participated, of whom 491 participated again at age 58 y. At age
58 y (range: 56 61 y), 732 persons participated inthe study, 239
of whom had not participated at age 50 y. The participation rates
among those exposed to famine (49%) and among those not
exposed to famine (40%) in utero didnot differ significantly (P
0.7). The birth weights of persons included in the study (3353 g)did not differ significantly from the birth weights of those not
included in the study (3341 g; P 0.6).
Infants born after exposure to famine in late and midgestation
were lighter and smaller than the unexposed infants, and their
mothers weighed less at the end of gestation (Table 1).
Age at onset of coronary artery disease
A total of 83 subjects had developed CAD by the end of
follow-up. We found an overall cumulative incidenceof CAD of
9%in men and 8%in women. Persons exposed tofamine inearly
gestation had the highest cumulative incidence of CAD (13%;
sex-adjusted HR compared with unexposed persons: 1.9; 95%
CI:1.0,3.8) (Table1). Thecumulativeincidenceof CADin those
exposed to famine in late gestation (sex-adjusted HR: 0.8; 95%
CI 0.4 to 1.6) and midgestation (sex-adjusted HR: 1.1; 95% CI:
0.6, 2.1) did notdiffer significantly from that of those unexposed
to famine(8% after exposure inmid- andlategestation compared
with 8%in unexposedpersons). On average, CADmanifested3 yearlier in those exposed to famine in early gestation (mean age:
47 y; interquartile range: 4551 y) than in those unexposed to
famine(mean age: 50 y; interquartile range:4557y) (Figure1).
Menand women with CAD were lighter (3275 compared with
3360 g) andthinner (25.9 compared with 26.3 kg/m3)atbirthand
had a smaller head circumference (32.5 compared with 32.8 cm)
at birth, although none of these differences was significant. After
size at birth was adjusted for, the association between famine
exposure in early gestation and CAD was not attenuated (HR:
2.0; 95% CI: 1.0, 3.8).
Coronary artery disease risk factorsThe distribution of cardiovascular disease risk factors accord-
ing to famine exposure during various stages of gestation among
subjects at age 58 y is shown in Table 2.
In addition to the results shown in Table 2, famine exposure
during any period of gestation was associated with elevated glu-
cose concentrations at 120 min (P 0.04; adjusted for sex and
body mass index) and an elevated ratio of LDL to HDL (P
0.03; adjusted for sex). Adjustment forthe 2 social risk factors in
Table 2, smoking (adjusted HR: 1.8; 95% CI: 0.9, 3.5) and low
SES (adjusted HR: 2.0; 95% CI: 1.0, 3.8), had little effect on the
association between famine exposure in early gestation and
CAD.
TABLE 1
Maternal, birth, and coronary artery disease characteristics of men and women who participated in the Dutch Famine Birth Cohort Study at age 50 or 58 y
Born
before
famine
Time of exposure to famine
Conceived
after
famine Al l subjects
Total
n
Late
gestation Midgestation
Early
gestation
General
No. of subjects 289 160 138 87 301 975
Men (%) 48 44 39 44 53 47 975
Maternal characteristics
Maternal age (y) 29 311 29 271 28 29 62 975
Weight at the end of gestation (kg) 67 621 631 68 69 66 8.7 854
Weight gain in the last trimester (kg) 3.2 0.01 5.01 5.51 4.3 3.4 3.2 682
Occupation of head of family, manual (%) 83 71 70 621 69 73 809
Primiparous (%) 35 241 34 39 39 34 975
Birth characteristics
Birth weight (g) 3396 31833 31953 3437 3449 3353 467 975
Head circumference (cm) 32.8 32.43 32.13 32.8 33.2 32.8 1.6 965
Ponderal index (kg/m3) 26.2 26.03 25.73 26.0 26.7 26.2 2.4 966
Coronary artery disease
No. of cases 24 12 11 11 25 83
Cumulative incidence (%) 8 8 8 134 8 9 975
Age at onset (y)5
51 50 50 474
49 49 (4556) 811 Significantly different from those born before or conceived after the famine, P 0.05 (linear or logistic regression).2x SD (all such values).3,4 Significantly different from those born before or conceived after the famine after adjustment for sex: 3 P 0.05 (linear or logistic regression), 4 P
0.05 (Cox regression).5 Mean after quadratic transformation; interquartile range in parentheses.
324 VALTUENA ET AL
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Maternal constitution and fertility
There were no significantdifferences in maternal weight, age,
parity, or SES at birth between persons with or without CAD.
When these variables were entered into a multivariable Cox
model, the association between exposure to famine in early ges-
tation and CAD was little changed (multivariable-adjusted HR:
1.8; 95% CI: 0.9, 3.6).
DISCUSSION
Wefoundthat the riskof CAD beforetheageof 61y inpersons
conceived during the Dutch famine was double thatof unexposed
persons. This association was independent of size at birth and ofsmoking and low SES. Of the 83 persons with CAD, those who
were conceivedduring thefamine were 3 y younger at diagnosis.
Ours was the first study to describe the course of CAD in the
offspring of mothers nutritionally deprived during early gesta-
tion.
Women were less fertile during the famine (19). Those who
did conceive may havebeen of a different constitution. However,
the correction for markers of maternal constitution or fertility,
including maternal weight, age, parity, and SES, did not change
the association of prenatal famine exposure with CAD.
Selective participation of persons who were fit enough to
attend the clinic and prior excess mortality among the most
seriouslyaffectedpersons may have ledto an underestimationof
the effect of prenatal famine on subsequent CAD progression.
However, we believe that the estimate reported in this article is
relatively accurate, because analyses of the prevalence of angina
pectoris and history of coronary revascularization surgery
among persons who were not able to visit the clinic, but who
agreed to a home or telephone interview, yielded results in the
same direction (RC Painter, SR de Rooij, and TJ Roseboom,
unpublished observations, 2005). Moreover, there was no excessall cause or CAD mortality among people conceived in the fam-
ine (16).
Although not statistically significant, persons with CAD were
also lighter at birth than were persons without CAD. This finding
agreed with results from other studies (1, 20).
Suboptimal intrauterine growth has been described to have
programming effects on many cardiovascular disease risk fac-
tors, including hypertension (21), impaired glucose tolerance
FIGURE 1. Kaplan-Meiercurveof thecumulative incidence ofcoronaryartery disease(CAD) in persons born beforethe famine(n 24); exposed to famineinlate (n 12), mid-(n 11), orearly (n 11)gestation; or conceived after the famine (n 25). The cumulativeincidence of CADwas significantly greaterin persons exposed to famine in early gestation than in those born before or conceived after the famine, P 0.05 (Cox regression).
TABLE 2
Characteristics of men and women who participated in the Dutch Famine Birth Cohort Study at age 58 y1
Born
before
famine
Time of exposure to famine Conceived
after
famine All subjects Total n
Late
gestation Midgestation
Early
gestation
Glucose at 120 min (mmol/L) 5.8 6.0 6.1 6.2 5.8 5.9 2.4 632
Insulin at 120 min (pmol/L) 243 247 251 264 236 245 294 627
Triacylglycerol (g/L) 1.2 1.3 1.3 1.3 1.3 1.3 1.0 724
LDL:HDL 2.3 2.52 2.3 2.62 2.4 2.4 1.0 720
BMI (kg/m2) 28.4 28.1 27.9 28.0 28.6 28.3 4.8 726
Ever smoked (%) 64 62 66 762 59 63 727
SES3 46 502 49 45 48 48 14 721
1 All values, except for ever smoking, are geometric xor geometric x SD.2 Significantly different from those born before or conceived after the famine after adjustment for sex, P 0.05 (linear or logistic regression).3 Socioeconomic status, determined by using the ISEI-92 (18).
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(22, 23), and lipid metabolism (24). Consistent with our previous
study of the Dutch Famine Birth Cohort, persons conceived dur-
ing the famine had higher plasma glucose concentration at 120
min and higher ratios of LDL to HDL cholesterol than did per-
sons who had not been exposed to famine in utero. It is possible
that the effects of famine on CAD are mediated through these 2
biological risk factors. It was not possible for us to explore the
effect of these risk factors on CAD incidence because, for many
subjects, we did not have measurements from before the onset ofdisease. Moreover, many of the subjects were being treated for
type 2 diabetes or hypercholesterolemia.
There are many possible processes by which persons con-
ceived in famine could have increased rates of CAD. Slow in-
trauterine growth has beenshown to be associated withhormonal
axis programming (25, 26), alterations in cardiovascular control
mechanis