Dutch Famine Combined (3)

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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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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

0263-6352 & 1999 Lippincott Williams & Wilkins


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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


9/29

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


10/29

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.



11/29

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


12/29

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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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

GLYCEMIC INDEX AND LIVER STEATOSIS 323


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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).

GLYCEMIC INDEX AND LIVER STEATOSIS 325


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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

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