Dutch Famine Combined

Molecular and Cellular Endocrinology 185 (2001) 93 98 www.elsevier.
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Effects of prenatal exposure to the Dutch famine on adult disease in 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 originate in the womb. It is thought that undernutrition of the fetus during critical periods of development would lead to adaptations in the structure and physiology of the fetal body, and thereby increase the risk of diseases in later life. The Dutch faminethough a historical disaster provides a unique opportunity to study effects of undernutrition during gestation in humans. This thesis 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 ndings suggest that maternal malnutrition during gestation may permanently affect adult health without affecting the size of the baby at birth. This may imply that adaptations that enable the fetus to continue to grow may nevertheless have adverse consequences of improved nutrition of 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 before and during a pregnancy. This should be exploited to improve the health of future generations. 2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Undernutrition; Coronary heart disease; Fetal origins
1. Introduction Chronic degenerative diseases are the main public health problem in most Western countries. Cardiovascular disease, respiratory disease and cancer have become 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 reect 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
* Corresponding author.
on the structure or function of tissues and body systems. Programming occurs because the tissues and systems of the body go through critical, often brief, periods of growth and development during foetal life and infancy (Winick and Noble, 1966). Failure of development during these periods as a result of adverse environmental inuences 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 modies the risk of CHD associated with
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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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 ndings have led to the foetal origins hypothesis 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 increase its risk of disease in later life (Barker, 1998). The Dutch faminethough a historical disaster provides 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 during the 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 undernourished when its demand for nutrients, which largely depends on its rate of growth, exceeds its supply. 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 the contribution of maternal dietary intake and to a lesser extent, maternal body composition to foetal programming of adult disease.
2. The Dutch famine 1944 1945 After weeks of heavy ghting following the invasion of France on the 6th of June 1944, the Allied forces nally broke through German lines. With lightning speed, the Allied troops took possession of much of France, Luxembourg and Belgium. By the 4th of September 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 water was permitted again. By then, it had become impossible to bring in food from the rural east to the urban west of The Netherlands because most canals and waterways were frozen due to the extremely severe winter of 19441945, which had started unusually early. Consequently, food stocks in the urban west of The Netherlands ran out rapidly. As a result, the ofcial daily rations for the general adult population which had decreased gradually from about 1800 calories in December 1943 to 1400 calories in October 1944 fell abruptly to below 1000 calories in late November 1944. At the height of the famine from December 1944 to April 1945, the ofcial daily rations varied between 400 and 800 calories. Children younger than 1 year were relatively protected, because their ofcial daily rations never fell below 1000 calories, and the specic 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 ofcial 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 situation 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 nally 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 19441945 the population had to live without 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 as well 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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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 Amsterdam, the Netherlands. All singletons born alive between 1 November 1943 and 28 February 1947 in the Wilhelmina Gasthuis in Amsterdam, were candidates to be included in the Dutch famine birth cohort. We excluded babies whose main medical records were missing, and those with a gestational age at birth of less than 259 days. In all, 2414 babies were included. The Bevolkingsregister 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 population 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 medical history and current health. Of these, 741 attended the clinic to undergo more detailed measurements. Mean birth weights among the 912 who were visited at home 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 between babies exposed during late gestation (born between 7 January and 28 April 1945), mid gestation (29 April18 August 1945) and early gestation (19 August 8 December 1945). We compared the exposed babies 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 late gestation (14.6%) and those born before the famine (15.2%). The differences in mortality were caused by effects of famine on mortality in the rst 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-specic mortality in adulthood between the exposure groups. Women who were exposed to famine in late pregnancy 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 third trimester, whereas women exposed in mid and early pregnancy gained more weight than non-exposed mothers 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 in mid 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.) Exposure to famine in Born before Proportion of men Maternal characteristics Weight last prenatal visit (kg) Weight gain 3rd trimester (kg) Primiparous Age (years) Not married Infant characteristics Birth weight (g) Birth length (cm) Head circumference (cm) Ponderal index (kg/m3) Gestational age (days)
a
n Mid gestation 42% 63.5a 4.9a 37% 28 20.2 3217a 49.8a 32.1a 26.0 285 Early gestation 44% 67.9 5.7a 39% 28 25.8 3470 50.9 32.8 26.2 287 Conceived after All (SD) 52% 69.1 4.3 39% 28 16.3 3413 50.5 33.2 26.5 286 48% 66.6 (8.7) 3.5 (3.2) 38% 28 (6.4) 15.8 3346 (487) 50.3 (2.1) 32.8 (1.6) 26.2 (2.4) 285 (11) 2414 2133 1682 2414 2414 2414 2414 2382 2397 2382 2043
Late gestation 47% 61.8a 0.0a 30% 30 9.8 3133a 49.5a 32.3a 25.8 283
50% 66.7 3.2 40% 29 13.2 3373 50.5 32.9 26.1 285
PB0.05 compared with unexposed.
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Table 2 Adult characteristics according to timing of prenatal exposure to the Dutch famine Exposure to famine in Born before Adult characteristics Plasma glucose 120 min* (mmol/l) Plasma insulin 120 min* (pmol/l) IGT/NIDDM (WHO criteria) Total cholesterol (mmol/l) HDL cholesterol* (mmol/l) LDL cholesterol (mmol/l) Triglycerides* (g/l) LDL/HDL cholesterol* Fibrinogen (g/l) Factor VII* (% of standard) BMI* (kg/m2) CHD Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Obstructive airways disease General health poor Late gestation Mid gestation Early gestation Conceived after All (S.D.) n
5.7 160 15% 6.06 1.35 4.05 1.15 2.91 3.02 128 26.7 3.8% 126.0 86.2 15.5% 4.5
6.3a 200a 21% 5.83 1.32 3.87 1.08 2.82 3.05 131 26.7 2.5% 127.4 86.4 15.0% 6.4
6.1 190 14% 5.80 1.37 3.81 1.10 2.69 3.05 133 26.6 0.9% 124.8 84.4 24.8%a 3.7
6.1 207 16% 6.13 1.26a 4.26 1.10 3.26a 3.21 117a 28.1 8.8%a 123.4 84.8 23.0% 10.3a
5.9 181 15% 6.00 1.32 4.02 1.16 2.94 3.10 133 27.2 2.6% 125.1 85.2 17.3% 5.3
6.0 (1.4) 181 (2.4) 16% 5.97 (1.06) 1.33 (1.33) 3.99 (1.01) 1.13 (1.71) 2.90 (1.53) 3.07 (0.6) 129 (1.4) 27.0 (1.2) 3.3% 125.5 (15.5) 85.6 (9.9) 18.1% 5.5
702 694 702 704 704 704 704 704 725 725 741 736 739 739 733 912
*Geometric mean and S.D. a PB0.05 compared with unexposed.
posed to famine in early gestation were heavier and longer 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 tolerance were larger than could be explained by the small famine-related reduction in birth weight. We found that people exposed to famine in early gestation had a more atherogenic lipid prole (Roseboom et al., 2001a), somewhat higher brinogen concentrations and reduced 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 rst evidence in humans that maternal undernutrition during gestation is linked with the risk of
CHD in later life. In addition, people who had been exposed 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 during the famine (and whose foetuses were thus undernourished in early gestation) were well nourished in later pregnancy, which may have contributed to the above average birth weight of their babies. The transition from nutritional deprivation in early gestation to nutritional adequacy later on may have led to metabolic conicts 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 carbohydrate during the third trimester of pregnancy had
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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 lung function or increased serum concentrations of IgE. This suggests that the increased prevalence of symptoms and disease may be attributable to increased bronchial reactivity rather than to irreversible airow obstruction or atopic disease. Since the bronchial tree grows most rapidly in mid gestation, our ndings support the hypothesis that foetal undernutrition permanently affects the structure and physiology of the airways during critical periods of development that coincide with periods of rapid growth.
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 nd that offspring of these women had a poorer health. Whatever the true cause of the adaptations made by the foetus that resulted in disease in later life, our ndings indicate that an adverse environment in utero can have permanent effects on health.
7. Conclusion Our ndings 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 ndings suggest that risk factors for CHD, such as impaired glucose tolerance, hypercholesterolaemia, raised blood pressure and obesity, which often co-exist, have their origins in utero, but are programmed at different times. Furthermore, our ndings suggest that maternal malnutrition during gestation 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 price paid for successful adaptations to an adverse intra-uterine 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 exploited to improve the health of future generations.
6. Methodologic issues Our ndings mimic a scientic 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 ndings as adjustments for maternal characteristics that might be proxies for fertility (age, parity, maternal weight and socio-economic status) hardly altered the results. Nor did we nd 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 infections were widespread (Banning, 1946). Also, the stress experienced 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 nd 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
References
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T.J. Roseboom et al. / Molecular and Cellular Endocrinology 185 (2001) 9398 Rich-Edwards, J.W., Stampfer, M.J., Manson, J.E., Rosner, B., Hankinson, S.E., Colditz, G.A., Willet, W.C., Hennekes, C.H., 1997. Birth weight and risk of cardiovascular disease in a cohort of men followed up since 1976. Br. Med. J. 315, 396 400. Roseboom, T.J., van der Meulen, J.H.P., Ravelli, A.C.J., van Montfrans, G.A., Osmond, C., Barker, D.J.P., Bleker, O.P., 1999. Blood pressure in adults after prenatal exposure to famine. J. Hypertens. 17, 325 330. Roseboom, T.J., van der Meulen, J.H.P., Osmond, C., Barker, D.J.P., Ravelli, A.C.J., Bleker, O.P., 2000a. Plasma lipid prole after prenatal exposure to the Dutch famine. Am. J. Clin. Nutr. 72, 1101 1106. Roseboom, T.J., van der Meulen, J.H.P., Ravelli, A.C.J., Osmond, C., Barker, D.J.P., Bleker, O.P., 2000b. Plasma brinogen and factor VII concentrations in adults after prenatal exposure to the Dutch famine. Br. J. Haematol. 111, 112 117. Roseboom, T.J., van der Meulen, J.H.P., Osmond, C., Barker, D.J.P., Ravelli, A.C.J., Schroeder-Tanka, J.M., van Montfrans, G.A., Michels, R.P.J., Bleker, O.P., 2000c. Coronary heart disease in adults after prenatal exposure to the Dutch famine. Heart 84, 595 598. Roseboom, T.J., van der Meulen, J.H.P., Osmond, C., Barker, D.J.P., Ravelli, A.C.J., Bleker, O.P., 2001a. Adult survival after prenatal exposure to the Dutch famine 1944 45. Pediatr. Perinatal Epidemiol. 15, 220 225. Roseboom, T.J., van der Meulen, J.H.P., van Montfrans, G.A., Ravelli, A.C.J., Osmond, C., Barker, D.J.P., Bleker, O.P., 2001. Maternal nutrition during gestation and adult blood pressure. Journal of Hypertension, 19, 29 34. Stein, Z.A., Susser, M., Saenger, G., Moraolla, F., 1975. Famine and Human Development: The Dutch Hunger Winter of 1944 1945. Oxford University Press, New York. Stein, C.E., Fall, C.H.D., Kumaran, K., Osmond, C., Cox, V., Barker, D.J.P., 1996. Fetal growth and coronary heart disease in South India. Lancet 348, 1269 1273. Trienekens, G. (Ed.), 1985. Tussen ons volk en de honger, rst ed. Matrijs, Utrecht. Winick, M., Noble, A., 1966. Cellular response in rats during malnutrition at various ages. J. Nutr. 89, 300 306.
Forsen, T., Eriksson, J.G., Tuomilehto, J., Osmond, C., Barker, D.J.P., 1999. Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study. Br. Med. J. 319, 1403 1407. Huxley, R.R., Shiell, A.W., Law, C.M., 2000. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J. Hypertens. 18, 815831. Leon, D.A., Lithell, H.O., Vagero, D., Koupilova, I., Mohsen, R., Berglund, L., Lithell, U.B., McKeigue, P.M., 1998. Reduced foetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915 1929. Br. Med. J. 317, 241 245. Lithell, H.O., McKeigue, P.M., Berglund, L., Mohsen, R., Lithell, U.B., Leon, D.A., 1996. Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50 60 years. Br. Med. J. 312, 406 410. Lopuhaa, C.E., Roseboom, T.J., Osmond, C., Barker, D.J.P., Ravelli, A.C.J., Bleker, O.P., van der Zee, J.S., van der Meulen, J.H.P., 2000. Atopy, lung function and obstructive airways disease in adults after prenatal exposure to the Dutch famine. Thorax 55, 555 561. Michels, K.B., Trichopoulos, D., Robins, J.M., Rosner, B.A., Manson, J.E., Hunter, D.J., et al., 1996. Birth weight as a risk factor for breast cancer. Lancet 348, 1542 1546. Murray, J.C.L., Lopez, A.D., 1994. Global and regional cause-ofdeath patterns in 1990. In: Murray, C.J.L., Lopez, A.D. (Eds.), Global Comparative Assessments in the Health Sector. Disease Burden, Expenditures, and Intervention Packages. World Health Organisation, Geneva, pp. 21 54. Osmond, C., Barker, D.J.P., Winter, P.D., Fall, C.H.D., Simmonds, S.J., 1993. Early growth and death from cardiovascular disease. Br. Med. J. 307, 1519 1524. Ravelli, A.C.J., van der Meulen, J.H.P., Michels, R.P.J., Osmond, C., Barker, D.J.P., Hales, C.N., Bleker, O.P., 1998. Glucose tolerance in adults after prenatal exposure to the Dutch famine. Lancet 351, 173177. Ravelli, A.C.J., van der Meulen, J.H.P., Osmond, C., Barker, D.J.P., Bleker, O.P., 1999. Obesity in adults after prenatal exposure to famine. Am. J. Clin. Nutr. 70, 811 816.
Original article 325
Tessa J. Rosebooma , Jan H.P. van der Meulena , Anita C.J. Ravellia , Gert A. van Montfransb , Clive Osmondd , David J.P. Barkerd and Otto P. Blekerc
Background Many 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 one hospital 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
Blood pressure in adults after prenatal exposure to famine
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 macronutrients 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 later life. J Hypertens 1999, 17:325330 & Lippincott Williams & Wilkins.
Journal of Hypertension 1999, 17:325330 Keywords: blood pressure, fetal origins, famine, pregnancy, birth weight
a Department of Clinical Epidemiology and Biostatistics, b Department of Internal Medicine, and c Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, The Netherlands and d MRC Environmental Epidemiology Unit, University of Southampton, UK.
Sponsorship: This study was funded by the Medical Research Council, UK, the Diabetes Fonds Nederland, and Wellbeing, UK. Correspondence and requests for reprints to Dr J.H.P. van der Meulen, MRC Environmental Epidemiology Unit, University of Southampton, Southampton SO16 6YD, UK. Tel: 44 1703 777 624; fax: 44 1703 704 021; e-mail jvdm@mrc.soton.ac.uk Received 17 August 1998 Revised 30 November 1998 Accepted 4 December 1998
Introduction
A systematic review of the published literature has shown 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 cholesterol [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 premature birth [5]. This has led to the hypothesis that an adverse fetal environment is important in the development 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
0263-6352 & 1999 Lippincott Williams & Wilkins
data from animal experiments. In rats, maternal malnutrition during pregnancy retards fetal growth and raises blood 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 balance between protein and carbohydrate in the maternal diet during late pregnancy was associated with the blood pressure in the offspring 40 years later. This association between maternal diet and blood pressure of the offspring was independent of size at birth. Another study [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 Leningrad but outside the city (134.7 versus 130.9 mmHg, P 0.1).
326 Journal of Hypertension 1999, Vol 17 No 3
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 course of 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 midgestation [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) with those exposed to famine during different periods of gestation (exposed subjects). We measured blood pressures at the homes of the subjects and during a visit to the clinic.
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, carbohydrate and fat was approximately proportionally reduced. The ofcial rations should be considered as a relative measure of the amount of food available. A person 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). The medical records of the mothers provided information 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 time interval between these weight measurements and multiplied 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 four times 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 overStudy parameters
Subjects and methods

Selection 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 gestational age at birth was less than 259 days. We thus included 2414 babies born alive. The `Bevolkingsregister' (population registry) of Amsterdam traced 2155 (89%) of the 2414 included babies. Of these, 265 had died, 199 had emigrated from The Netherlands, and 164 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 (difference in birth weight adjusted for exposure to famine was 28 g, P 0.23).
Blood pressure after prenatal exposure to famine Roseboom et al. 327
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 antihypertensive medication. Current socioeconomic status was coded using the ISEI-92 scale according to the occupation of the participants or their partners, whichever 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
nancy, weight gain or socioeconomic status at birth was missing for a relatively large number of persons. Therefore, 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 were adjusted for by adding a dichotomous variable into the linear regression model; the other variables were added to the model as continuous variables.
Results
Characteristics of study population
Body mass index (BMI) had a skewed distribution and was therefore log-transformed before analysis. We calculated the differences between the blood pressures of unexposed subjects and those exposed in late, mid- or early gestation separately. We used multiple linear regression 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-hypertensive medication and current socioeconomic status). Information on maternal weight at the end of pregTable 1
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% condence interval (CI) 1.56.0]. 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
famine
Maternal characteristics, birth outcomes, adult characteristics and blood pressure according to timing of prenatal exposure to
Exposure to famine Born before (n 120) In late gestation (n 120) 48% 30.9 24% 62.9 0.1 114.2 70% 286 3166 49.5 32.4 270 26.0 10.4 50.8 26.7 171 50 34% 10 9% 127.4 86.4 In mid-gestation (n 109) 40% 28.8 32% 63.5 5.1 114.6 72% 285 3217 49.8 32.2 260 25.9 10.1 50.5 26.6 169 48 32% 9 13% 124.8 84.4 In early gestation (n 68) 44% 27.2 38% 67.5 5.6 114.9 64% 286 3450 51.0 33.0 278 26.0 9.7 50.3 28.1 171 48 41% 8 12% 123.4 84.8 Conceived after (n 232) 51% 28.7 35% 68.6 4.2 115.9 62% 286 3444 50.5 33.1 275 26.6 9.8 49.8 27.2 171 47 34% 9 9% 125.1 85.2 All (n 739) 48% 29.0 6.5 33% 66.2 8.6 3.5 3.3 115.5 10.3 70% 286 12 3349 470 50.3 2.1 32.8 1.5 280 69 26.2 2.3 10.0 1.2 50.4 0.9 27.0 1.2 171 9.0 47 14 35% 9 12 10% 125.5 15.5 85.6 9.9 Missing observations 0 0 0 93 214 9 182 96 0 7 8 115 7 8 0 0 0 0 0 0 0 0 0
Men Maternal characteristics Age (years) Primiparous Weight at end of pregnancy (kg) Weight gain in third trimester (kg) Systolic blood pressure (mmHg) Manual labour Birth outcomes Gestational age at birth (days) Birth weight (g) Body length (cm) Head circumference (cm) Placental area (cm2 ) Ponderal index (kg/m3 ) Head-to-birth weight ratio (cm/g) Adult characteristics Age at measurement (years) Body mass index (kg/m2 ) Height (cm) Socioeconomic status (ISEI) Current smoker Alcohol (units/week) Anti-hypertensive medication Adult blood pressure in the clinic Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
50% 29.1 35% 66.4 3.2 116.2 79% 285 3383 50.6 32.9 298 26.1 9.9 51.4 26.7 171 46 37% 10 8% 126.0 86.2
Data are expressed as means or mean SD except geometric mean and standard deviation.
exposed to famine in late or mid-gestation were lighter and shorter, and had smaller heads and smaller placentas than those not exposed. They also had higher headto-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 exposure groups. 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 was 0.4 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 status at 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,
Blood pressure measured in the clinic
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 0.11.6), 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 associated 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 including maternal weight at the end of pregnancy and weight gain in the third trimester (Table 2). We also found that adjustments for adult characteristics including BMI and socioeconomic status did not alter the results. Adjustment for size at birth changed the differences in blood pressure between those exposed to famine 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. Simultaneous 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 to the 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 Adjusted for: Sex and age Sex, age and maternal weight Sex, age and maternal weight gain# Sex, age and birth weight Sex, age and BMI Sex, age and socioeconomic status (at birth and current) 1.3 (1.9 to 4.4) 1.5 (1.7 to 4.7) 1.8 (1.6 to 5.1) 0.8 (2.4 to 3.9) 1.6 (1.4 to 4.5) 1.3 (1.9 to 4.4) In mid- gestation 0.6 (3.8 to 2.7) 0.4 (3.6 to 2.9) 0.9 (4.2 to 2.4) 1.0 (4.2 to 2.3) 0.1 (3.2 to 2.9) 0.5 (3.8 to 2.7) In early gestation 1.7 (5.6 to 2.2) 1.9 (5.8 to 2.0) 2.2 (6.2 to 1.7) 1.6 (5.6 to 2.3) 3.1 (6.7 to 0.6) 1.8 (5.8 to 2.1)
Data are expressed as mean differences (with negative values denoting a decrease and positive values an increase) and 95% condence intervals. Maternal weight at the end of pregnancy; #weight gain during third trimester. BMI, body mass index.
Blood pressure after prenatal exposure to famine Roseboom et al. 329
1 kg in birth weight was associated with a 3.9 mmHg (95% CI 1.26.6) decrease in systolic blood pressure. 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 exposed 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 of 3.3 mmHg (95% CI 0.66.0) in systolic blood pressure after adjustment for sex.
Blood pressure measured at home
In those subjects exposed in utero to the Leningrad siege of 19411944, blood pressure was increased by about 4 mmHg (P = 0.1) compared with those born in the same period but outside the famine area. Unfortunately, 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 of The 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 eats during 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 and throughout 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, carbohydrate 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 in Aberdeen 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
Discussion
We could not demonstrate an effect of prenatal exposure to famine during which caloric intake from protein, fat and carbohydrate was approximately proportionally 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 association between 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, smoking, 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 conceptions at the peak of the famine and consequently also to exposure during early gestation was about 50% lower than that corresponding to pre-famine conceptions [14]. This famine-induced reduction in fertility 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 adjustments for maternal characteristics, which might be determinants of fertility (maternal age, parity, weight and socioeconomic status), did not alter the results.
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.
9 10 11
Conclusions
12 13 14 15
Our 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 undernutrition 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 the effect on fetal growth was small. This suggests that glucose metabolism and blood pressure are programmed in fetal life through different maternal inuences.
16 17 18 19 20 21 22
Acknowledgements
We 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 for tracing 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.
Langley-Evans SC. Intrauterine programming of hypertension in the rat: nutrient interactions. Comp Biochem Physiol 1996; 114:327333. Campbell DM, Hall MH, Barker DJP, Cross J, Shiell AW, Godfrey KM. Diet in pregnancy and the offspring's blood pressure 40 years later. Br J Obstet Gynaecol 1996; 103:273280. Stanner SA, Bulmer K, Andres C, Lantseva OE, Borodina V, Poteen VV, et al. Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study. BMJ 1997; 315:13421349. Ravelli ACJ, van der Meulen JHP, Michels RPJ, Osmond C, Barker DJP, Hales CN, et al. Glucose tolerance in adults after prenatal exposure to the Dutch famine. Lancet 1998; 351:173177. Burger GCE, Drummond JC, Sandstead HR (editors). Malnutrition and starvation in western Netherlands: September 1944July 1945. The Hague: General State Printing Ofce; 1948. Stein Z, Susser M. Fertility, fecundity, famine: food relations in the Dutch Famine 1944/1945 have a causal relation to fertility and probably to fecundity. Human Biology 1975; 47:131154. O'Brien E, Mee F, Atkins N, O'Malley K. Accuracy of the Prolomat ambulatory blood pressure measuring system determined by the British Hypertension Society Protocol [Short report]. J Hypertens 1992; 10:1285 1286. Bakker B, Sieben I. Measures of prestige, socio-economic status and social class for the standard occupation classication 1992 [in German]. Sociale Wetenschappen 1997; 40:122. Leon DA, Chenet L, Shkolnikow VM, Zakharov S, Shapiro J, Rakhmanova G, et al. Huge variation in Russian mortality rates 19841994: artefact, alcohol, or what? Lancet 1997; 350:383388. Godfrey KM, Forrester T, Barker DJP, Jackson AA, Landman JP, Hall J, et al. Maternal nutritional status in pregnancy and blood pressure in childhood. Br J Obstet Gynaecol 1994; 101:398403. Clark PM, Atton C, Law CM, Shiell A, Godfrey K, Barker DJP. Weight gain in pregnancy, triceps skinfold thickness, and blood pressure in offspring. Obstet Gyneacol 1998; 91:103107. Langley-Evans SC. Intrauterine programming of hypertension by glucocorticoids. Life Sci 1997; 60:12131221. Woodall SM, Johnston BM, Breier BH, Gluckman PD. Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure in the offspring. Pediatr Res 1996; 40:438443. Gerber RT, Holemans K, Van Assche FA, Opston L. Female offspring from undernourished Wistar rats have normal blood pressure but altered vascular reactivity. Fetal physiology and development meeting Cambridge, 2529 June 1997.
References
1 2 3 4 5 6 7 8 Law CL, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens 1996; 14:935941. Hales CN, Barker DJP, Clark PMS, Cox LJ, Fall C, Osmond C, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991; 303:10191022. Phipps K, Barker DJP, Hales CN, Fall CHD, Osmond C, Clark PMS. Fetal growth and impaired glucose tolerance in men and women. Diabetologia 1993; 36:225228. Fall CHD, Barker DJP, Osmond C, Winter PD, Clark PMS, Hales CN. Relation of infant feeding to adult serum cholesterol concentration and death from ischaemic heart disease. Br J Obstet Gynaecol 1992; 304:801805. Barker DJP. Mother, babies and disease in later life. 2nd edition. Edinburgh: Churchill Livingstone; 1997. Barker DJP, Winter PD, Osmond C, Margetts B. Weight in infancy and death from ischaemic heart disease. Lancet 1989; 9:577580. Osmond C, Barker DJP, Winter PD, Fall CHD, Simmonds SJ. Early growth and death from cardiovascular disease in women. Br J Obstet Gynaecol 1993; 307:15191524. Lucas A. Programming by early nutrition in man. In: Bock RJ, Whelan J (editors): Ciba Foundation Symposium 156. The childhood environment and adult disease. 1st edition. London: Wiley; 1991. pp. 3855.
See corresponding editorial on page 271. See corresponding CME exam on page 466.
Early onset of coronary artery disease after prenatal exposure to the Dutch 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
Downloaded from www.ajcn.org at UNIVERSITY OF WISCONSIN MADISON on October 6, 2011
ABSTRACT Background: Limited evidence suggests that maternal undernutrition at the time of conception is associated with increased cardiovascular 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 angioplasty 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 for sex: 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 experiments that identify periconceptional 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 programming
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 humans after restricted prenatal nutrition, the sequelae of restricted maternal nutrition during gestation have been studied in the Leningrad Siege Study (4) and the Dutch Famine Birth Cohort Study. The Dutch famine was a 5-mo period of extreme food shortage during the winter of 1944 1945 in World War II. The Leningrad Study reported no effect of maternal malnutrition on the adult offsprings CAD prevalence. The Dutch famine, however, was relatively short compared 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 nutritional 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 microalbuminuria (6) was present among subjects exposed during midgestation. The most marked effects were described in the group of subjects conceived during the famine and include a more atherogenic 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 periconceptional maternal nutrition in programming cardiovascular disease 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
From the Departments of Clinical Epidemiology and 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 number 2001B087), Wellbeing (United Kingdom), the Medical Research Council (United Kingdom), and the Academic Medical Centre (Netherlands). 3 Address reprint requests to RC Painter, PO Box 22660, 1100 DD, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail: r.c.painter@amc.uva.nl. Received November 28, 2005. Accepted for publication February 24, 2006.
1
INTRODUCTION
Restricted intrauterine growth has been proposed as an important 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 periods (2). Most studies in humans have access only to indirect measures of intrauterine nutrition, such as birth weight. Substantial
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findings of a study conducted at age 50 y and included information 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 loss to 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. All eligible subjects were asked to participate at ages 50 and 58 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 Committee approved the study. The study conformed to the Declaration 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 kitchens, 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 average 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 December 1945 and 28 February 1947 (conceived after the famine) 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 and 18 August 1945), and early gestation (born between 19 August and 8 December 1945), in correspondence with previous publications on this cohort (5, 10). Persons exposed 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 average caloric intake in June 1945 was 2000 kcal. Data collection Medical birth records provided information about the mother, the course of gestation, and the size of the infant and the placenta 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 measured 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
mass index was calculated by dividing weight in kilograms by the square of height in meters. Blood pressure was measured twice on 2 occasions (morning and afternoon) with an automated device: 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 electrocardiograms (ECGs) were used for all participants. Trained technicians blinded to the clinical data scored the ECGs according to the Minnesota criteria. Nondiabetic participants underwent standard 75-g oral glucose tolerance testing. Blood was drawn for the 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 formula. Participants were interviewed to obtain information about their medical history, including operations, lifestyle, and use of medication. We defined current SES according to the participants or their partners occupation, whichever was highest, using the ISEI-92 (18). The ISEI-92 scale ranges from 16 (minimum score; lowest status) to 87 (maximum score; highest status). 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 revascularization (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 associations between the progression of CAD and the timing of famine exposure during gestation and size at birth, we used the Cox regression model of the cumulative incidence and age of manifestation of CAD and calculated hazard ratios (HRs) and 95% CIs for subjects exposed in late, mid-, and early gestation and compared them with unexposed subjects. We constructed a KaplanMeier 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 questionnaire. 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 characteristics of persons with and without CAD. Because of the left skewed distribution of age at first occurrence of CAD, this variable is reported in means after we applied a quadratic transformation. Body mass index, SES, the ratio of LDL to HDL, and glucose were log transformed because of their skewed distributions. These variables are reported as geometric means SDs; all
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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 Time of exposure to famine Born before famine General No. of subjects Men (%) Maternal characteristics Maternal age (y) Weight at the end of gestation (kg) Weight gain in the last trimester (kg) Occupation of head of family, manual (%) Primiparous (%) Birth characteristics Birth weight (g) Head circumference (cm) Ponderal index (kg/m3) Coronary artery disease No. of cases Cumulative incidence (%) Age at onset (y)5
1 2
Late gestation 160 44 311 621 0.01 71 241 31833 32.43 26.03 12 8 50
Midgestation 138 39 29 631 5.01 70 34 31953 32.13 25.73 11 8 50
Early gestation 87 44 271 68 5.51 621 39 3437 32.8 26.0 11 134 474
Conceived after famine 301 53 28 69 4.3 69 39 3449 33.2 26.7 25 8 49
All subjects 47 29 66 3.4 73 34 3353 32.8 26.2 467 1.6 2.4 62 8.7 3.2
Total n 975 975 975 854 682 809 975 Downloaded from www.ajcn.org at UNIVERSITY OF WISCONSIN MADISON on October 6, 2011 975 965 966 975 81
289 48 29 67 3.2 83 35 3396 32.8 26.2 24 8 51
83 9 49 (4556)
Significantly different from those born before or conceived after the famine, P 0.05 (linear or logistic regression). x 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.
other variables are reported as means SDs. All statistical analyses were performed by using SPPS 12.0.2 (SPSS Inc, Chicago, IL). We considered differences to be statistically significant if P values were 0.05.
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 participated in this study. At age 50 y (range: 48 53 y), 736 persons participated, of whom 491 participated again at age 58 y. At age 58 y (range: 56 61 y), 732 persons participated in the 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 did not 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 incidence of CAD of 9% in men and 8% in women. Persons exposed to famine in early gestation had the highest cumulative incidence of CAD (13%; sex-adjusted HR compared with unexposed persons: 1.9; 95%
CI: 1.0, 3.8) (Table 1). The cumulative incidence of CAD in 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 not differ significantly from that of those unexposed to famine (8% after exposure in mid- and late gestation compared with 8% in unexposed persons). On average, CAD manifested 3 y earlier 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: 4557 y) (Figure 1). Men and women with CAD were lighter (3275 compared with 3360 g) and thinner (25.9 compared with 26.3 kg/m3) at birth and 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 factors The distribution of cardiovascular disease risk factors according 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 glucose 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 for the 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.
325
FIGURE 1. Kaplan-Meier curve of the cumulative incidence of coronary artery disease (CAD) in persons born before the famine (n 24); exposed to famine in late (n 12), mid- (n 11), or early (n 11) gestation; or conceived after the famine (n 25). The cumulative incidence of CAD was significantly greater in persons exposed to famine in early gestation than in those born before or conceived after the famine, P 0.05 (Cox regression).
Maternal constitution and fertility There were no significant differences 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 gestation and CAD was little changed (multivariable-adjusted HR: 1.8; 95% CI: 0.9, 3.6).
DISCUSSION
We found that the risk of CAD before the age of 61 y in persons conceived during the Dutch famine was double that of unexposed persons. This association was independent of size at birth and of smoking and low SES. Of the 83 persons with CAD, those who were conceived during the famine 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 gestation. Women were less fertile during the famine (19). Those who did conceive may have been 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 seriously affected persons may have led to an underestimation of 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 excess all cause or CAD mortality among people conceived in the famine (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 factors, including hypertension (21), impaired glucose tolerance
TABLE 2 Characteristics of men and women who participated in the Dutch Famine Birth Cohort Study at age 58 y1 Time of exposure to famine Born before famine Glucose at 120 min (mmol/L) Insulin at 120 min (pmol/L) Triacylglycerol (g/L) LDL:HDL BMI (kg/m2) Ever smoked (%) SES3
1
Late gestation 6.0 247 1.3 2.52 28.1 62 502
Midgestation 6.1 251 1.3 2.3 27.9 66 49
Early gestation 6.2 264 1.3 2.62 28.0 762 45
Conceived after famine 5.8 236 1.3 2.4 28.6 59 48
All subjects 5.9 245 1.3 2.4 28.3 63 48 14 2.4 294 1.0 1.0 4.8
Total n 632 627 724 720 726 727 721
5.8 243 1.2 2.3 28.4 64 46
All values, except for ever smoking, are geometric x or 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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in adults after prenatal exposure to the Dutch famine. J Am Soc Nephrol 2005;16:189 94. Roseboom TJ, van der Meulen JHP, Osmond C, Barker DJP, Ravelli ACJ, Bleker OP. Plasma lipid profiles in adults after prenatal exposure to the Dutch famine. Am J Clin Nutr 2000;72:1101 6. Roseboom TJ, van der Meulen JHP, Ravelli ACJ, Osmond C, Barker DJP, Bleker OP. Plasma fibrinogen and factor VII concentrations in adults after prenatal exposure to famine. Br J Haematol 2000;111:1127. Ravelli ACJ, van der Meulen JHP, Osmond C, Barker DJP, Bleker OP. Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 1999;70:811 6. Roseboom TJ, van der Meulen JHP, Osmond C, et al. Coronary heart disease after prenatal exposure to the Dutch famine, 1944 45. Heart 2000;84:595 8. Gardner DS, Pearce S, Dandrea J, et al. Peri-implantation undernutrition programs blunted angiotensin II evoked baroreflex responses in young adult sheep. Hypertension 2004;43:1290 6. Gopalakrishnan GS, Gardner DS, Rhind SM et al. Programming of adult cardiovascular function after early maternal undernutrition in sheep. Am J Physiol Regul Integr Comp Physiol 2004;287:R1220. Fleming TP, Kwong WY, Porter R, et al. The embryo and its future. Biol Reprod 2004;71:1046 54. Edwards LJ, McMillen IC. Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep. Am J Physiol Regul Integr Comp Physiol 2002;283:R669 79. Roseboom TJ, van der Meulen JHP, Osmond C, Barker DJP, Ravelli ACJ, Bleker OP. Adult survival after prenatal exposure to the Dutch famine 1944 45. Paediatr Perinat Epidemiol 2001;15:220 5. Painter RC, Roseboom TJ, Bossuyt PM, Osmond C, Barker DJ, Bleker OP. Adult mortality at age 57 after prenatal exposure to the Dutch famine. Eur J Epidemiol 2005;20:673 6. Trienekens G. Tussen ons volk en de honger. (Between our people and the famine.) Utrecht, Netherlands: Matrijs, 1985(in Dutch). Bakker B, Sieben I. Maten voor prestige, sociaal-economische status en sociale klasse voor de standaard beroepenclassificatie 1992. (Measures of prestige, socio-economic status and social class for the standard classification of occupations. ) Sociale Wetenschappen 1997;40:122(in Dutch). Stein Z, Susser M, Saenger G, Morolla F. Famine and human development. The Dutch Hunger Winter of 1944-45. New York, NY: Oxford University Press, 1975. Barker DJP, Osmond C, Forsen TJ, Kajantie E, Eriksson JG. Trajectories of growth among children who have coronary events as adults. N Engl J Med 2005;353:18029. Law C, Shiell A, Newsome C, et al. Fetal, infant, and childhood growth and adult blood pressure: a longitudinal study from birth to 22 years of age. Circulation 2002;105:1088 92. Lithell HO, McKeigue PM, Berglund L, Mohsen R, Lithell UB, Leon DA. Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50 60 years. BMJ 1996;312:406 10. Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ. Birth weight and adult hypertension, diabetes mellitus and obesity in US men. Circulation 1996;94:3246 50. Barker DJP, Martyn CN, Osmond C, Hales CN, Fall CHD. Growth in utero and serum cholesterol concentrations in adult life. BMJ 1993;307: 1524 7. Bloomfield FH, Oliver MH, Giannoulias CD, Gluckman PD, Harding JE, Challis JRG. Brief undernutrition in late-gestation sheep programs the hypothalamic-pituitary-adrenal axis in adult offspring. Endocrinology 2003;144:2933 40. Phillips D, Walker B, Reynolds R, et al. Low birth weight predicts elevated plasma cortisol concentrations in adults from 3 populations. Hypertension 2000;35:1301 6. Ward AM, Moore VM, Steptoe A, Cockington RA, Robinson JS, Phillips DI. Size at birth and cardiovascular responses to psychological stressors: evidence for prenatal programming in women. J Hypertens 2004;22:2295301. Vonnahme KA, Hess BW, Hansen TR, et al. Maternal undernutrition from early- to mid-gestation leads to growth retardation, cardiac ventricular hypertrophy, and increased liver weight in the fetal sheep. Biol Reprod 2003;69:133 40. Goodfellow J, Bellamy MF, Gorman ST, et al. Endothelial function is
(22, 23), and lipid metabolism (24). Consistent with our previous study of the Dutch Famine Birth Cohort, persons conceived during the famine had higher plasma glucose concentration at 120 min and higher ratios of LDL to HDL cholesterol than did persons 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 of disease. Moreover, many of the subjects were being treated for type 2 diabetes or hypercholesterolemia. There are many possible processes by which persons conceived in famine could have increased rates of CAD. Slow intrauterine growth has been shown to be associated with hormonal axis programming (25, 26), alterations in cardiovascular control mechanisms (11, 12, 27), altered myocardial structure (28), endothelial dysfunction (29), and accelerated atherogenesis (30). In future studies we hope to elucidate the role of these factors in the pathophysiology of coronary artery disease after prenatal famine exposure. Persons conceived in famine not only had a higher cumulative incidence of CAD, but the disease occurred at an earlier age. Models in which animals were prenatally nutrient restricted had premature aging (31) and more rapid age-related progression of the biological risk factors of CAD (32, 33). There is some evidence of an association between low birth weight and increased aging rates in human studies too (34, 35). Although little research has been carried out elucidating the underlying mechanisms, Jennings et al (36) suggest that telomere shortening induced by prenatal undernutrition may be responsible for the premature senescence of tissues such as the liver and kidney. These studies also pointed out that catch-up growth, such as that which may have occurred in fetuses conceived during famine but exposed to adequate nutrition during the remainder of gestation, could result in further telomere shortening. In summary, our findings suggest that maternal nutrition in early gestation may play an important role in the course of CAD. This suggestion is in line with evidence from animal experiments that identified preconceptional and preimplantation maternal diet as important for the offsprings adult health (1114).
We are grateful for the willing cooperation of all participants. OPB, TJR, PMB, DJB, and CO conceived of and planned the study. RCP, TJR, SRdR, and TAS carried out the study. RCP, CO, and DJB performed the statistical analyses. All authors critically discussed the results. None of the authors had a conflict of interest.
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impaired in fit young adults of low birth weight. Cardiovasc Res 1998; 40:600 6. Martyn CN, Gale CR, Jespersen S, Sherrif SB. Impaired fetal growth and atherosclerosis of carotid and peripheral arteries. Lancet 1998;352:173 8. Ozanne SE, Hales CN. Lifespan: catch-up growth and obesity in male mice. Nature 2004;427:4112. Petry CJ, Dorling MW, Pawlak DB, Ozanne SE, Hales CN. Diabetes in old male offspring of rat dams fed a reduced protein diet. Int J Exp Diabetes Res 2001;2:139 43. Nwagwu MO, Cook A, Langley-Evans SC. Evidence of progressive
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deterioration of renal function in rats exposed to a maternal low-protein diet in utero. Br J Nutr 2000;83:79 85. 34. Law CM, Swiet de M, Osmond C, et al. Initiation of hypertension in utero and its amplification throughout life. Br J Obstet Gynaecol 1993;306: 24 7. 35. Aihie Sayer A, Cooper C, Evans J, et al. Are rates of ageing determined in utero? Age Ageing 1998;27:579 83. 36. Jennings BJ, Ozanne SE, Dorling MW, Hales CN. Early growth determines longevity in male rats and may be related to telomere shortening in the kidney. FEBS Lett 1999;448:4 8.
AMERICAN JOURNAL OF HUMAN BIOLOGY 18:853856 (2006)
Short Report
A Possible Link Between Prenatal Exposure to Famine and Breast Cancer: A Preliminary Study
R.C. PAINTER,1* S.R. DE ROOIJ,1 P.M.M. BOSSUYT,1 C. OSMOND,2 D.J.P. BARKER,3 O.P. BLEKER,4 AND T.J. ROSEBOOM1 1 Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands 2 MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK 3 Developmental Origins of Adult Disease Centre, University of Southampton, Princess Anne Hospital, Southampton SO16 5YA, UK 4 Department of Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands
ABSTRACT In a study of 475 women born around the 19441945 Dutch famine, women exposed to prenatal famine more often reported a history of breast cancer than nonexposed women (hazard ratio, 2.6; 95% condence interval, 0.97.7). They also had alterations in reproductive risk factors. Prenatal famine may increase breast cancer incidence. Am. J. Hum. Biol. 18:853 856, 2006. ' 2006 Wiley-Liss, Inc.
Maternal diet during gestation can affect the risk of breast cancer in offspring in animal models (Hilakivi-Clarke et al., 1997, 1999). Whether and to what extent maternal caloric restriction during gestation might be involved in the early origins of breast cancer in humans is unclear. The Dutch famine was a 5-month period of severe food shortage during the last year of World War II. In this paper, we investigate the role of maternal undernutrition during gestation on cumulative breast-cancer incidence up to age 61 years. SUBJECTS AND METHODS The Dutch Famine Birth Cohort consists of 2,414 live-born term singletons, of whom 1,174 were females, born in the Wilhelmina Gasthuis in Amsterdam, The Netherlands, between November 1, 1943February 28, 1947. The selection and tracing procedures and losses to follow-up were described in detail elsewhere (Painter et al., 2005; Roseboom et al., 2001; Ravelli et al., 1998). The local Medical Ethics Committee approved the study. A person was considered prenatally exposed to famine if the average daily ration for adults during any 13-week period of gestation was less than 1,000 calories. Using this denition, all cohort members born between January 7, 1945December 8, 1945 had been exposed pre-
natally. We dened periods of 16 weeks each to differentiate between those who were exposed in late gestation (born between January 7April 28, 1945), midgestation (born between April 29August 18, 1945), and early gestation (born between August 19December 8, 1945). All eligible women in the cohort were invited to visit the hospital. Three hundred ninety-one women visited the hospital, 50 women were visited at home, and 34 women were interviewed by telephone. Women were asked whether they had ever been diagnosed with cancer, and if so, what type of cancer and at what age. Spontaneous menopause was dened as the cessation of menstrual periods, not due to surgery of the
Grant sponsor: Netherlands Heart Foundation; Grant numbers: 2001B087, 2003B165; Grant sponsor: Medical Research Council, UK; Grant sponsor: Academic Medical Centre. An abstract based on this work was presented at the Third International Congress on the Developmental Origins of Health and Disease, November 2005, Toronto, Canada, and was published by R.C. Painter et al. in Pediatric Research 58:1048, 2005. *Correspondence to: Rebecca Painter, M.D., M.Sc., PO Box 22660, 1100 DD Amsterdam, The Netherlands. E-mail: r.c.painter@amc.uva.nl Received 16 May 2006; Revision received 26 June 2006; Accepted 27 June 2006 Published online in Wiley InterScience (www.interscience. wiley.com). DOI 10.1002/ajhb.20564
C V 2006
Wiley-Liss, Inc.
854
R.C. PAINTER ET AL. TABLE 1. Breast cancer cumulative incidence and maternal, birth, and adult characteristics for
women who participated in Dutch Famine Birth Cohort1

Exposure to famine Born before Late 82 3.7 3 71 27 4.9 3,140* 58.5 28.1 46 13 1.9 12.7 23.6 49.3 Mid 77 3.9 3 69 33 3.9 3,144* 58.3 28.1 50* 5* 2.0** 12.9 23.5*** 52.1*** Early 46 8.7*** 4 54* 50* 2.2 3,448 58.1 26.9* 45 4 2.0** 12.9 22.9*** 48.7
Conceived after 126 0.8 1 68 37 5.6 3,354 57.5 29.1 49 12 1.7 12.7 24.2 49.3
All (SD) 3.2 15 72 40 4.2 3,293 (450) 58.4 (0.9) 28.2 (5.2) 47 (15) 12 1.8 (1.0) 12.9 (1.7) 23.3 (3.8) 50.1 (5.0)
N 475 475 475 381 475 473 475 475 440 465 472 472 470 416 325
Number Breast cancer (%) Breast cancer (n) Maternal characteristics Maternal socio-economic status low (manual labor) Primiparous (%) Maternal breast cancer (%) Birth characteristics Birth weight (g) Adult characteristics Age at interview (years) Body mass index (kg/m2)2 Socio-economic status (ISEI-92)2,3 Nulliparous (%) Number of children Age at menarche (years) Age at rst child (years)4 Age at spontaneous menopause (years)
1 2 3
144 2.8 4 86 31 3.5 3,356 59.2 27.8 44 16 1.7 13.2 23.2 50.7
Means and standard deviations (SD), except where given as percentages. Geometric mean. Socioeconomic status scale according to International Socio-Economic Index-92 ranges from 1687. 4 Median age. *P < 0.05 compared to unexposed (logistic or linear regression). **P < 0.05 compared to unexposed (Mann-Whitney test). ***P < 0.05 compared to unexposed (Cox regression).
ovaries or uterus, for a period of longer than 12 months. We assessed maternal breast cancer history by asking all participants whether their mothers had any health problems, and scoring all mentions of breast malignancies. Information on whether or not women had a history of hormone replacement therapy use was not collected. We used the Cox proportional hazards model to calculate hazard ratios (HR) to compare the incidence of breast cancer in women who were exposed to famine in early, mid-, or late gestation with that in unexposed women (born before or conceived after). We added covariates to the Cox model to adjust for potential confounders. Due to the small number of cases, we limited multivariable models to one added covariate.
RESULTS Of the 1,174 women in the cohort, 141 women had died before the start of the study, 114 had emigrated, and 60 women refused permission for their addresses to be included in the study database. The municipalities were unable to trace a further 96 women to a correct
address. Seven hundred and sixty-three women were eligible for the current study, of whom 475 (62%) participated in the study. Participation rates did not differ between women who had (65%) and had not (60%, P 0.2) been exposed to famine. Birth weights of women included in the study (mean weight 3,293 g) did not differ signicantly from birth weights of eligible women not included (mean weight 3,286 g, P 0.9). Table 1 describes the maternal, birth, and adult characteristics as well as breast cancer prevalence among the women in the study, according to the timing of exposure to famine in utero. The breast cancer incidences within the control group (born before or conceived after the famine) did not differ signicantly (P 0.3). Table 2 shows the unadjusted HRs and HRs adjusted for maternal, birth, and adult risk factors for breast cancer among women exposed to famine in utero compared to unexposed women. Women exposed to famine in utero more frequently reported a history of breast cancer than unexposed women (unadjusted HR, 2.6; 95% condence interval, 0.97.7). The birth weights of women with breast cancer (mean, 3,191 g) did not differ signicantly
American Journal of Human Biology DOI 10.1002/ajhb
BREAST CANCER AND PRENATAL EXPOSURE TO FAMINE TABLE 2. Hazard ratios (with 95% condence intervals) for breast cancer among women exposed
855
to famine in utero compared to unexposed women, unadjusted and adjusted for risk factors
Exposure to famine during gestation Late Unadjusted Adjusted for: Maternal socio-economic status low (manual labor) Maternal parity Maternal breast cancer status Birth weight Body mass index Socioeconomic status Nulliparity Age at rst child 2.0 (0.58.3) 2.2 (0.59.3) 1.9 (0.48.0) 2.0 (0.58.2) 1.8 (0.47.5) 2.9 (0.615.6) 2.0 (0.58.3) 2.0 (0.58.3) 0.6 (0.15.6) Mid 2.1 (0.58.7) 2.3 (0.59.6) 2.1 (0.58.6) 2.1 (0.58.8) 1.9 (0.47.9) 3.3 (0.78.4) 2.0 (0.58.4) 2.2 (0.59.2) 1.9 (0.47.8) Early 4.8 (1.217.8) 5.8 (1.521.7) 5.1 (1.419.4) 4.8 (1.318.1) 5.0 (1.318.9) 7.1 (1.632.0) 5.0 (1.318.7) 5.0 (1.318.8) 4.4 (1.216.6) All exposed 2.6 (0.97.7) 3.0 (1.08.7) 2.6 (0.97.7) 2.6 (0.97.7) 2.5 (0.87.4) 4.0 (1.114.5) 2.6 (0.97.7) 2.7 (0.97.9) 2.0 (0.66.0)
from those of women without breast cancer (mean, 3,296 g, P 0.4). DISCUSSION Women who had been exposed to famine in utero had a higher incidence of breast cancer compared to unexposed women, although the effect failed to reach statistical signicance. The effect was largest, and statistically signicant, among women who were conceived during the famine. The effect of maternal starvation during gestation on breast cancer incidence in offspring was not explained by differences in known risk factors for breast cancer, including parity and body mass index. The number of cases in this study is small, and the reported effect may be spurious or associated with selective participation. However, this study may present the rst direct evidence that maternal undernutrition during gestation may be linked to breast cancer risk in offspring. Due to the small size of the cohort and relatively young ages at time of data collection, this study did not have sufcient power to detect modest effects of undernutrition during gestation on subsequent breast cancer at a statistically signicant level. Sixty-two percent of eligible women participated in this study. Selective participation may therefore present a source of bias. However, birth weights did not differ between participants and nonparticipants, and participation rates were similar among famine-exposed and unexposed women. Women were less likely to conceive during the famine, and those who did conceive may have been of a different constitution, they may have had enhanced reproduction or more efcient metabolism. The effect of prenatal expo-
sure to famine on adult breast cancer incidence was, however, not limited to daughters of mothers who conceived during the famine. We found no indication for more breast cancer among the mothers of study participants exposed to famine during gestation. This suggests that selective fertility among women more prone to develop breast cancer (making their daughters more susceptible by familial inheritance) is unlikely to be wholly responsible for the effect of prenatal famine exposure on subsequent breast cancer. A previous study of adult mortality in the same cohort suggested higher cancer mortality among women exposed in early gestation (Painter et al., 2005). This nding may reect the fact that higher breast cancer morbidity after famine exposure in utero is followed by higher cancer mortality. Higher cancer mortality may have led to an underestimation of the effect of famine exposure, because only women who were alive at age 58 could participate in the study. In a different study, childhood famine exposure was linked to breast cancer (Elias et al., 2004). In accordance with these ndings, women born before the famine who were exposed as infants had more breast cancer than those conceived after. Although this difference was not statistically signicant, and the records show that young infants received adequate rations during the famine (Burger et al., 1948), the fact that we adhered to the pooled controlgroup model (Ravelli et al., 1998) may have led to an underestimation of the effect of prenatal famine exposure on breast cancer incidence. Little is known about the pathophysiology of the association between prenatal factors and subsequent cancer risk. High birth weight was associated with an excess of cancer, and partic-
856
R.C. PAINTER ET AL. Burger GCE, Sandstead HR, Drummond JC. 1948. Malnutrition and starvation in western Netherlands, September 1944 to July 1945. Parts I and II. The Hague: General State Printing Ofce. Ekbom A, Hsieh CC, Lipworth L, Adami HQ, Trichopoulos D. 1997. Intrauterine environment and breast cancer risk in women: a population-based study. JNCI 89:7176. Elias SG, Peeters PH, Grobbee DE, van Noord PA. 2004. Breast cancer risk after caloric restriction during the 19441945 Dutch famine. JNCI 96:539546. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. 1998. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351:13931396. Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E, Lippman M. 1997. A maternal diet high in n-6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring. Proc Natl Acad Sci USA 94:93729377. Hilakivi-Clarke L, Clarke R, Lippman M. 1999. The inuence of maternal diet on breast cancer risk among female offspring. Nutrition 15:392401. Hilakivi-Clarke L, Forsen T, Eriksson JG, Luoto R, Tuomilehto J, Osmond C, Barker DJ. 2001. Tallness and overweight during childhood have opposing effects on breast cancer risk. Br J Cancer 85:16801684. Holt RI. 2002. Fetal programming of the growth hormoneinsulin-like growth factor axis. Trends Endocrinol Metab 13:392397. Leonhardt M, Lesage J, Croix D, Dutriez-Casteloot I, Beauvillain JC, Dupouy JP. 2003. Effects of perinatal maternal food restriction on pituitary-gonadal axis and plasma leptin level in rat pup at birth and weaning and on timing of puberty. Biol Reprod 68:390400. McCormack V, dos Santos Silva I, De Stavola B, Mohsen R, Leon D, Lithell HO. 2003. Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort. Br Med J [Clin Res] 326:248251. Painter RC, Roseboom TJ, Bossuyt PM, Osmond C, Barker DJ, Bleker OP. 2005. Adult mortality at age 57 after prenatal exposure to the Dutch famine. Eur J Epidemiol 20: 673676. Ravelli ACJ, van der Meulen JHP, Michels RPJ, Osmond C, Barker DJP, Hales CN, Bleker OP. 1998. Glucose tolerance in adults after prenatal exposure to famine. Lancet 351:173177. Roseboom TJ, van der Meulen JHP, Osmond C, Barker DJP, Ravelli ACJ, Bleker OP. 2001. Adult survival after prenatal exposure to the Dutch famine 194445. Paediatr Perinat Epidemiol 15:220225. van Noord PA. 2004. Breast cancer and the brain: a neurodevelopmental hypothesis to explain the opposing effects of caloric deprivation during the Dutch famine of 1944 1945 on breast cancer and its risk factors. J Nutr 134: 33993406.
ularly breast cancer (McCormack et al., 2003; Ahlgren et al., 2003), although other studies (Ekbom et al., 1997; Hilakivi-Clarke et al., 2001), including our own, could not conrm this association. Rapid postnatal growth following fetal growth restriction is associated with permanently raised levels of growth factors (Holt, 2002), possibly propagating premalignant cell growth (Hankinson et al., 1998). The restoration of an adequate diet after a period of relative growth restriction due to maternal malnutrition, as in women exposed to famine during gestation, could also be associated with increased levels of growth factors, though this is speculative. Alternatively, hormonal axis programming may be involved in programming subsequent breast cancer (van Noord, 2004). In rats, maternal starvation has a programming effect on the fetal hypothalamic pituitary gonadal (HPG) axis (Leonhardt et al., 2003), possibly with lasting repercussions for breast tissue. There is circumstantial evidence for HPG programming in our data. Women exposed to famine during gestation had more children and were less likely to be childless; women exposed in mid- or early gestation had children at a younger age; menopause was delayed in women exposed in midgestation. The increase in breast cancer among women who were in utero during famine reported here is based on very small numbers. In the future, we hope to be able to link this unique birth cohort to the national hospital admissions database, in order to objectify our nding that prenatal famine exposure is associated with increased breast cancer prevalence.
LITERATURE CITED
Ahlgren M, Sorensen T, Wohlfahrt J, Haidadottir A, Holst C, Melbye M. 2003. Birth weight and risk of breast cancer in a cohort of 106,504 women. Int J Cancer 107: 9971000.
Diabetologia (2006) 49: 637643 DOI 10.1007/s00125-005-0136-9
ARTICLE
S. R. de Rooij . R. C. Painter . T. J. Roseboom . D. I. W. Phillips . C. Osmond . D. J. P. Barker . M. W. Tanck . R. P. J. Michels . P. M. M. Bossuyt . O. P. Bleker
Glucose tolerance at age 58 and the decline of glucose tolerance in comparison with age 50 in people prenatally exposed to the Dutch famine
Received: 29 August 2005 / Accepted: 10 November 2005 / Published online: 10 February 2006 # Springer-Verlag 2006
Abstract Aims/hypothesis: People who were small at birth have an increased risk of type 2 diabetes in later life. People who were in utero during the Dutch famine had decreased glucose tolerance and raised insulin concentrations at age 50. We aimed to evaluate whether prenatal famine exposure leads to more rapid progression of impaired glucose/insulin homeostasis with increasing age. Methods: We performed an OGTT in 702 men and women at age 50 and in 699 men and women at age 58, all born as term singletons immediately before, during or after the 19441945 Dutch famine. Results: People who had been exposed to famine in utero had significantly
S. R. de Rooij (*) . R. C. Painter . T. J. Roseboom . M. W. Tanck . P. M. M. Bossuyt Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Room nr J1B-210-1, Meibergdreef 9, P.O. Box 22660, 1100 DD, Amsterdam, the Netherlands e-mail: s.r.derooij@amc.uva.nl Tel.: +31-205668975 Fax: +31-206912683 D. I. W. Phillips . C. Osmond MRC Epidemiology Resource Centre at the University of Southampton, Southampton, UK D. J. P. Barker Developmental Origins of Adult Disease Centre, University of Southampton, Southampton, UK R. P. J. Michels Department of Internal Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands O. P. Bleker Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
higher 120-min glucose concentrations at age 58 compared with people who had not been exposed to famine (difference=0.4 mmol/l, 95% CI 0.1 to 0.7, adjusted for sex and BMI). Glucose tolerance deteriorated between the age of 50 and 58. The unadjusted 120-min glucose concentrations rose by 0.2 mmol/l (95% CI 0.0 to 0.4), while 120-min insulin concentrations had increased by 64 pmol/l (95% CI 48 to 82). There were no differences in the rates of glucose and insulin level increase between the famine-exposed group and the unexposed group (p=0.28 for the difference in increase in glucose concentrations and p=0.09 for insulin concentrations). Conclusions/interpretation: Although we confirmed that undernutrition during gestation is linked to decreased glucose tolerance, the effect does not seem to become more pronounced at age 58 as compared with age 50. Keywords Glucose tolerance . Progression . Prenatal famine Abbreviation HPA: hypothalamic-pituitary-adrenal
Introduction
People who were small at birth have an increased risk of type 2 diabetes in later life [17]. One interpretation of this association is that an adverse intrauterine environment permanently impairs glucose homeostasis, primarily by inducing insulin resistance [8, 9]. This interpretation is strongly supported by animal studies, which have consistently shown that experimental undernutrition during gestation leads to impaired glucose homeostasis [10]. The Dutch famine was a period of extreme food shortage in the west of the Netherlands that occurred during the last 5 6 months of World War II. The famine offers a unique opportunity to study the effects of prenatal undernutrition on health in later life. In 1998, we found the first direct evidence in humans that exposure to undernutrition during gestation reduced glucose tolerance in later life [11].
638
The prevalence of type 2 diabetes and IGT increases with age, mainly as a result of the increase in BMI, insulin resistance and a fall in insulin secretion [1214]. It is not yet known whether the age-related decline in glucose tolerance is increased in people who experienced an adverse intrauterine environment. In animal experiments the effects of prenatal undernutrition on glucose tolerance have been shown to increase with age. Rats that were undernourished during gestation showed a decrease in glucose tolerance between 3 and both 12 and 15 months of age [15, 16]. In humans the prenatal influences on blood pressure have been shown to increase with age [17, 18]. The present study was designed to assess glucose tolerance in the famine cohort at age 58 and to evaluate whether the previously demonstrated effect of prenatal famine exposure on glucose tolerance in the Dutch famine birth cohort progresses with ageing.
been described in detail elsewhere [11]. Of the cohort, 1,423 (59%) were still living in the Netherlands and their current address was known. A total of 810 people (57%) agreed to participate and underwent medical examination and a standardised interview. Two-thirds of this group (538 people, 66%) had also participated in the previous study at age 50. People who agreed to participate had mean birthweights similar to those of eligible people who did not participate (3,357 vs. 3,349 g, p=0.78). Informed consent was obtained from all participants. The local Medical Ethics Committee had approved the study. The study was carried out in accordance with the Declaration of Helsinki. Exposure to famine We defined the famine period based on the official daily rations for the general population older than 21 years. These rations were about 7,560 kJ/day in December 1943 and gradually decreased to about 5,880 kJ in October 1944. On 26 November 1944 the rations fell below 4,200 kJ and after 12 May 1945 they rose above 4,200 kJ again. In June 1945 rations were over 8,400 kJ. The rations during the famine did not apply to children younger than 1 year, who were relatively protected. Their official daily rations were always higher than 4,200 kJ, which is adequate according to The Oxford Nutrition Survey [19]. We considered
Age 58
Subjects and methods

Participants The participants were selected from the Dutch famine birth cohort (see Fig. 1). This cohort consists of 2,414 men and women born as term singletons between 1 November 1943 and 28 February 1947 in the Wilhelmina Gasthuis in Amsterdam. The selection procedures of the cohort have
Fig. 1 Participants selected from the Dutch famine birth cohort
Age 50
Cohort=2,414
Cohort=2,414
Eligible people= 1,527

Participants at age 50 and age 58
Eligible people= 1,423
Clinic visits=741
n=538
Clinic visits/visits at home=810
32 people with pre-existent diabetes 7 people nonfasting/ venepuncture failed
70 people with pre-existent diabetes 41 people nonfasting/ venepuncture failed
OGTT=702
n=446
OGTT=699
639
foetuses to be exposed to famine if the average daily rations of the mother during any 13-week period of gestation were below 4,200 kJ. Babies born between 7 January 1945 and 8 December 1945 were thus exposed. We defined periods of 16 weeks each to differentiate between those who had been exposed in late gestation (born between 7 January and 28 April 1945), in mid-gestation (born between 29 April and 18 August 1945) and in early gestation (born between 19 August and 8 December 1945). Babies born before 7 January 1945 and babies conceived and born after 8 December 1945 were considered as unexposed to famine in utero and acted as a control group. Study parameters Birth measurements and information about the health and status of the mother were taken from the medical birth records [11]. Trained nurses carried out the medical examinations and the interview. Methods for OGTT and anthropometry at age 50 have been described in detail elsewhere [11]. At age 58, a standard 75-g OGTT was performed after an overnight fast. People with pre-existent diabetes, defined as taking oral or injected glucose-lowering medication, were excluded from the test. Plasma glucose concentrations were measured by a standardised enzymatic photometric assay on a Modular P Analyzer (Roche, Basel, Switzerland) and plasma insulin concentrations by an immunoluminometric assay on an Immulite 2000 Analyzer (Diagnostic Product Corporation, Los Angeles, CA, USA). We measured height with a fixed or portable stadiometer, weight with SECA and portable Tefal scales and waist and hip circumferences with a flexible tape measure. We interviewed all participants and asked them about their socio-economic status, their medical history, lifestyle and use of medication, using standardised questions. Current socio-economic status was coded according to ISEI-92, which is based on the persons, or their partners occupation, whichever status was highest. Statistical methods In order to make the results comparable with those of our previous study, we defined IGT as a 120-min glucose concentration of 7.811.0 mmol/l and type 2 diabetes as a 120-min glucose concentration of >11.0 mmol/l. Logarithmic transformations were applied to glucose, insulin and BMI values, because they had skewed distributions. We used linear regression analysis to determine the effect of prenatal exposure to famine at different stages of gestation on glucose tolerance at age 58. To detect a possible agerelated deterioration in glucose tolerance, we only included data of subjects participating at age 50 as well as at age 58, using repeated-measures analysis. We first calculated differences between the exposed and unexposed groups.
Then differences were calculated between unexposed subjects and subjects prenatally exposed to famine in late, mid- or early gestation. We adjusted for maternal and birth characteristics, sex, BMI, smoking and socioeconomic status. For the last three variables, measurements at age 50 and age 58 were both included in the repeatedmeasures analysis.
Results
Study group characteristics We were able to perform a standard OGTT on 699 of the 810 people (86%) asked to participate in the study at age 58. Seventy of the 810 people had to be excluded from the OGTT, because they had pre-existing diabetes (see Table 1 for distribution over study groups). The test was not performed on another 41 people because they had not adhered to fasting instructions (n=7) or because of difficulties in venepuncture (n=34). For 446 of these 699 people, data on 120-min glucose and insulin values at age 50 were available. Of the 699 participants, 291 (42%) had been exposed to famine in utero. The response rates were similar in the famine-exposed and control groups. Table 1 shows that mothers exposed in late and mid-gestation weighed significantly less at the last prenatal visit than mothers who were unexposed to famine. Mothers exposed during late gestation gained almost no weight in the last trimester of pregnancy. Babies exposed to famine in late and mid-gestation were lighter and shorter than unexposed babies. They also had smaller heads and placentas. Famine exposure and plasma glucose and insulin concentrations at age 58 People who had been exposed to famine in utero had significantly higher plasma glucose concentrations 120 min after administration of the standard oral glucose load than unexposed people (Table 2). After adjusting for sex and BMI, 120-min glucose concentrations were 0.4 mmol/l (95% CI 0.1 to 0.7) higher among the exposed people than among unexposed people. For people exposed during late gestation the difference compared with unexposed people was 0.3 mmol/l (95% CI 0.1 to 0.8), for people exposed during mid-gestation 0.4 mmol/l (95% CI 0.0 to 0.9) and for people exposed during early gestation 0.4 mmol/l (95% CI 0.1 to 1.0). After adjustment for sex and BMI, 120-min insulin concentrations were 27 pmol/l (95% CI 0 to 58) higher among exposed than among unexposed people. The difference for people exposed during late gestation compared with unexposed people was 25 pmol/l (95% CI 12 to 68). The difference for people exposed during mid-gestation was 22 pmol/l (95% CI 18 to 68) and for people exposed during early gestation 37 pmol/l (95% CI 12 to 97).
640 Table 1 Maternal, birth and adult characteristics according to timing of prenatal exposure to the Dutch famine Exposure to famine Born before In late gestation In mid-gestation In early gestation Conceived after General Number Proportion of men Maternal characteristics Age at delivery (years) Proportion of primiparous women Proportion doing manual labour Weight gain 3rd trimester (kg) Weight at last antenatal visit (kg) Birth outcomes Gestational age (days) Birth weight (g) Birth length (cm) Head circumference (cm) Ponderal index (kg/m3) Placental area (cm2) Adult characteristics BMI (kg/m2)a Current smoker (%) Current SES (ISEI-92) Proportion of diabetic patients excluded from OGTT
a b
All (SD)
215 0.48 29 0.37 0.82 2.8 66.4 284 3387 50.5 32.8 26.2 297 27.6 22 46 0.10
122 0.43 31b 0.21b 0.71 0.1b 62.8b 283 3206b 49.6b 32.5b 26.1 269b 27.8 25 50b 0.09
104 0.39 29 0.32 0.71 4.4b 63.6b 286 3181b 49.6b 32.2b 26.0 269 27.5 26 50b 0.10
65 0.40 27 0.43 0.61b 5.0b 69.2 288 3470 50.8 32.9 26.4 276 27.3 32 45 0.08
193 0.51 29 0.35 0.70 3.5 69.2 286 3497 50.8 33.3 26.7 275 28.5 24 47 0.07
699 0.46 29 (6) 0.33 0.73 2.9 (2.9) 66.4 (8.7) 285 (11) 3363 (474) 50.3 (2.1) 32.8 (1.6) 26.3 (2.4) 280 (68) 27.9 (1.2) 25 47 (1) 0.09
699 699 699 566 486 613 598 699 691 690 691 594 698 696 689 810
Geometric means and SD p<0.05 for difference from people who were not prenatally exposed to famine SES Socio-economic status
Effects of mothers weight and birthweight The weight of the mother at the last prenatal visit, birthweight, birth length and head circumference were all inversely related to 120-min glucose and insulin concentrations. Adjusted for sex and BMI the 120-min glucose concentrations increased by 0.8% (95% CI 0.5 to 1.1) per
kilogram decrease in mothers last weight, 13.2% (95% CI 7.4 to 19.2) with each kilogram decrease in birthweight, 2.6% (95% CI 1.4 to 3.9) with each centimetre decrease in birth length and 1.9% (95% CI 0.3 to 3.7) with each centimetre decrease in head circumference, all adjusted for sex and adult BMI. The 120-min insulin concentrations increased by 17 pmol/l (95% CI 10 to 23) per kilogram
Table 2 Means of plasma glucose and insulin concentrations and prevalences of IGT and type 2 diabetes according to timing of prenatal exposure to the Dutch famine Exposure to famine Born before In late gestation In mid-gestation In early gestation Conceived after Fasting Glucose (mmol/l)a Insulin (pmol/l)a HbA1c (%)a 120-min Glucose (mmol/l)a Insulin (pmol/l)a Prevalence of diabetes based on OGTT (%) Prevalence of IGT based on OGTT (%)
a
All (SD)
5.6 57 5.5 5.8 242 5 16
5.5 59 5.5 6.2 263 5 16
5.5 55 5.6 6.2 254 5 15
5.6 58 5.6 6.2 269 6 14
5.6 57 5.6 5.9 240 4 14
5.6 (1.1) 57 (1.8) 5.6 (1.1) 6.0 (1.4) 249 (2.1) 5 15
697 692 692 678 672 678 678
0.99 0.21 0.81 0.02 0.06 0.43 0.76
Geometric means and SD p values are for differences between exposed and non-exposed groups adjusted for sex and BMI
641
decrease in the mothers last weight. Additional adjusting for birthweight showed that the effect of prenatal exposure to famine on 120-min glucose concentrations was larger than could be explained by the famine-related differences in birthweight. After adjustment for sex, BMI and birthweight, 120-min glucose concentrations were 0.2 mmol/l (95% CI 0.1 to 0.6) higher among the exposed than among unexposed people. Adjusting for other possible confounding variables including maternal age at delivery, current smoking status, current socio-economic status or alcohol consumption had little effect on the association between famine exposure and 120-min glucose concentrations. The prevalence of IGT and type 2 diabetes based on the OGTT did not differ significantly between the exposed and the unexposed people. Effects of age Table 3 shows the effects of age on progression of 120-min glucose and insulin concentrations in people who participated at age 50 as well as at age 58. Mean glucose concentrations after 120 min had increased by 0.2 mmol/l (95% CI 0.0 to 0.4). Mean insulin concentrations after 120 min had increased by 64 pmol/l (95% CI 48 to 82). A large part of the increase in 120-min glucose and insulin concentrations could be attributed to an increase in BMI. Mean BMI had increased by 1.1 units (95% CI 0.9 to 1.3). Adjusted for sex and BMI at both ages, the 120-min glucose concentrations between age 50 and 58 had increased non-significantly by 0.1 mmol/l (95% CI 0.1 to 0.2), while the adjusted 120-min insulin concentrations had increased by 51 pmol/l (95% CI 38 to 64). Exposure to famine in utero was not associated with an excess in agerelated glucose tolerance deterioration (0.0 vs. 0.1 mmol/l for exposed vs. unexposed, p=0.28), nor with an excess of age-related rise in insulin (39 vs. 58 pmol/l for exposed vs. unexposed, p=0.09), nor an excess of age-related rise in BMI (1.0 vs. 1.2 unit for exposed vs. unexposed, p=0.48)
(all adjusted for sex and BMI). Table 3 shows that the relatively largest increases in plasma glucose and insulin concentrations occurred among people who were born before the famine compared with people conceived after the famine. The mean plasma glucose was 0.4 mmol/l higher (p=0.04) and the mean plasma insulin was 24 pmol/l higher (p=0.08). There was a small effect of birthweight on the increase in 120-min glucose concentrations between the age of 50 and 58. For each kilogram decrease in birthweight, there was a 6% (95% CI 0 to 12) larger increase in 120-min glucose concentrations, adjusted for sex and BMI at both ages. Birthweight did not affect the increase in 120-min insulin concentrations.
Discussion
In this unique cohort study of subjects born before, during and after the Dutch famine, we found that undernutrition during gestation was associated with reduced glucose tolerance and raised insulin concentrations at age 58. This confirms our previous findings at age 50 [11]. We found that both 120-min glucose and insulin concentrations were higher in people exposed to famine at any stage of foetal development than in unexposed people. Importantly, this effect was larger than could be explained by the lower birthweight of babies born during the famine and by the low weight gain of their mothers. As with our previous study, this association was independent of peoples current BMI [11]. This is a population-based study of men and women recruited from the original famine cohort and still living in the Netherlands. At this age a significant number of individuals have overt type 2 diabetes and related diseases, especially cardiovascular disease. Selective participation of the more healthy subjects in our cohort could have influenced our results. Although we maximised response rates by visiting and studying subjects in their homes if necessary, people with type 2 diabetes, cardiovascular
Table 3 Progression of 120-min glucose and insulin levels and BMI between age 50 and age 58, according to timing of prenatal exposure to the Dutch famine Exposure to famine Born before In late gestation In mid-gestation In early gestation Conceived after All (CI)c (CI)c (CI)c (CI)c (CI)c (CI)c n 135 Proportion of men (%) 52 120-min glucose (mmol/l)a 0.3 (0.0 to 0.6) 120-min insulin (pmol/l)a 71 (48 to 92) BMI (kg/m2)b 1.1 (0.5 to 1.6)
a b
80 47 0.1 (0.6 to 0.2) 35 (1 to 66) 0.8 (3.0 to 4.1)
67 42 0.1 (0.5 to 0.3) 33 (9 to 7) 1.3 (0.3 to 2.8)
43 43 0.2 (0.4 to 0.8) 54 (2 to 98) 0.9 (0.5 to 2.6)
121 49 0.1 (0.4 to 0.3) 47 (21 to 70) 1.3 (0.7 to 1.9)
446 48 0.1 (0.1 to 0.2) 51 (38 to 64) 1.1 (0.9 to 1.3)
446 446 0.28 446 0.09 446 0.48
Estimated marginal means (adjusted for sex and BMI) for differences Estimated marginal means (adjusted for sex) for differences c 95% CIs of estimated marginal means for differences p values are for differences between exposed and unexposed groups adjusted for sex and BMI
642
disease, high cholesterol levels and high blood pressure were less likely to attend the survey clinic (data not shown). However, there was no evidence of a difference in response rates between those who were famine-exposed or nonexposed. Consequently, we do not think that selective participation has affected the relative differences in glucose and insulin levels among the exposed and the unexposed groups. It could, however, have affected our power to detect effects of famine on type 2 diabetes. Glucose tolerance deteriorated between the age of 50 and 58. A large part of this decline could be attributed to an increase in BMI. The decline in glucose tolerance was not more marked in the famine-exposed groups than in the control groups (Table 3). People who were born before the famine had the relatively largest increase in 120-min glucose and insulin concentrations. A possible explanation is that these people experienced the famine during their first year of life, which may have affected their postnatal growth pattern. Reduced early growth has been shown to be associated with later IGT and type 2 diabetes [20, 21]. Although infants were relatively protected during the famine, their official daily rations always being higher than 4,200 kJ, we do not know whether the famine affected their growth [19]. Early mortality rates were highest for people born before the famine and the deaths were mainly related to undernutrition or infections, indicating that growth was probably also affected [22]. We found that people with low birthweight had a greater age-related progression of glucose intolerance. A larger age-related progression of raised blood pressure has already been demonstrated for people with low birthweight, but to the best of our knowledge this is the first direct evidence of an age-related amplification of the effect of reduced foetal growth on glucose tolerance in humans [17, 18]. The effect of prenatal exposure to famine on glucose tolerance could be mediated through a number of mechanisms. Animal experiments indicate that undernutrition during gestation affects the development of the pancreas, which leads to an impaired function of the beta cell and consequently insulin deficiency [23]. In contrast, most human evidence points to the importance of insulin resistance. People who were thin at birth or had low birthweights were shown to be more insulin resistant than adults [24, 25]. The raised insulin concentrations that we found in famine-exposed individuals (Table 2) are consistent with insulin resistance acting as a mediator of the effect of famine exposure on glucose tolerance. Increasing evidence suggests that skeletal muscle is a key site for programming of insulin resistance. Muscle is a major site of glucose uptake and associations between a low ponderal index and altered metabolism of adult skeletal muscle have been found [26, 27]. Recently, an association between low birthweight and specific changes in muscle insulin-signalling protein expression was found [28]. Another mechanism that could explain the association between prenatal exposure to famine and later glucose intolerance involves the hypothalamic-pituitary-adrenal
(HPA) axis. Maternal sheep and guinea pigs that were undernourished in late gestation gave birth to offspring in which HPA function was altered in adult life [29, 30]. In humans, low birthweight is associated with elevated basal plasma cortisol concentrations and increased adrenocortical responsiveness to adrenocorticotrophin at adult age [31, 32]. It has been hypothesised that undernutrition during gestation alters the setpoint of the HPA axis resulting in an increased activity and consequently an increased secretion of glucocorticoids, which is associated with glucose intolerance and insulin resistance [33, 34]. In summary, although we confirmed that poor nutrition in utero is related to decreased glucose tolerance in later life, the effect of prenatal exposure to the Dutch famine does not seem to become more pronounced at age 58 as compared with age 50. Progression of glucose intolerance was found to be related to famine exposure during the first year of life and to low birthweight. This suggests that prenatal famine exposure, famine exposure during the first year of life and low birthweight may contribute to glucose intolerance by different mediating mechanisms.
Acknowledgements This study was funded by the Netherlands Heart Foundation (Grant Number 2001B087), the Academic Medical Centre (Amsterdam, the Netherlands) and the Medical Research Council (UK). We thank the participants for their willing cooperation.
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Molecular and Cellular Endocrinology 185 (2001) 93 98 www.elsevier.

PB0.05 compared with unexposed.

*Geometric mean and S.D. a PB0.05 compared with unexposed.

posed to famine in early gestation were heavier and longer at birth.

Original article 325

Blood pressure in adults after prenatal exposure to famine

326 Journal of Hypertension 1999, Vol 17 No 3

Subjects and methods

Blood pressure after prenatal exposure to famine Roseboom et al. 327

Characteristics of study population

328 Journal of Hypertension 1999, Vol 17 No 3

Blood pressure after prenatal exposure to famine Roseboom et al. 329

330 Journal of Hypertension 1999, Vol 17 No 3

GLYCEMIC INDEX AND LIVER STEATOSIS

Downloaded from www.ajcn.org at UNIVERSITY OF WISCONSIN MADISON on October 6, 2011

Midgestation 138 39 29 631 5.01 70 34 31953 32.13 25.73 11 8 50

Conceived after famine 301 53 28 69 4.3 69 39 3449 33.2 26.7 25 8 49

289 48 29 67 3.2 83 35 3396 32.8 26.2 24 8 51

GLYCEMIC INDEX AND LIVER STEATOSIS

Downloaded from www.ajcn.org at UNIVERSITY OF WISCONSIN MADISON on October 6, 2011

Late gestation 6.0 247 1.3 2.52 28.1 62 502

Midgestation 6.1 251 1.3 2.3 27.9 66 49

Early gestation 6.2 264 1.3 2.62 28.0 762 45

Conceived after famine 5.8 236 1.3 2.4 28.6 59 48

Total n 632 627 724 720 726 727 721

5.8 243 1.2 2.3 28.4 64 46

Downloaded from www.ajcn.org at UNIVERSITY OF WISCONSIN MADISON on October 6, 2011

GLYCEMIC INDEX AND LIVER STEATOSIS

30. 31. 32. 33.

Downloaded from www.ajcn.org at UNIVERSITY OF WISCONSIN MADISON on October 6, 2011

AMERICAN JOURNAL OF HUMAN BIOLOGY 18:853856 (2006)

women who participated in Dutch Famine Birth Cohort1

American Journal of Human Biology DOI 10.1002/ajhb

American Journal of Human Biology DOI 10.1002/ajhb

American Journal of Human Biology DOI 10.1002/ajhb

Diabetologia (2006) 49: 637643 DOI 10.1007/s00125-005-0136-9

Subjects and methods

Eligible people= 1,527

Eligible people= 1,423

Clinic visits/visits at home=810

32 people with pre-existent diabetes 7 people nonfasting/ venepuncture failed

70 people with pre-existent diabetes 41 people nonfasting/ venepuncture failed

5.6 57 5.5 5.8 242 5 16

5.5 59 5.5 6.2 263 5 16

5.5 55 5.6 6.2 254 5 15

5.6 58 5.6 6.2 269 6 14

5.6 57 5.6 5.9 240 4 14

5.6 (1.1) 57 (1.8) 5.6 (1.1) 6.0 (1.4) 249 (2.1) 5 15

697 692 692 678 672 678 678

0.99 0.21 0.81 0.02 0.06 0.43 0.76

80 47 0.1 (0.6 to 0.2) 35 (1 to 66) 0.8 (3.0 to 4.1)

67 42 0.1 (0.5 to 0.3) 33 (9 to 7) 1.3 (0.3 to 2.8)

43 43 0.2 (0.4 to 0.8) 54 (2 to 98) 0.9 (0.5 to 2.6)

121 49 0.1 (0.4 to 0.3) 47 (21 to 70) 1.3 (0.7 to 1.9)

446 48 0.1 (0.1 to 0.2) 51 (38 to 64) 1.1 (0.9 to 1.3)

446 446 0.28 446 0.09 446 0.48

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