Long term mortality after severe starvation during the siege of Leningrad: prospective cohort study
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《英国医生杂志》
1 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, 2 Centre for Health Equity Studies, CHESS, Stockholm University/Karolinska Institute, Stockholm, Sweden, 3 Institute of Experimental Medicine, Russian Academy of Medical Sciences, St Petersburg, Russia, 4 S?dert?rns h?gskola, University College, Huddinge, Sweden, 5 Unit of Clinical Epidemiology, Department of Medicine, Karolinska Hospital, Stockholm, Sweden
Correspondence to: P Sparén Par.Sparen@meb.ki.se
Abstract
Famine and food shortage have both short and long term consequences for health. Particular concern has arisen for later consequences of in utero starvation, a concern reinforced by much new research suggesting that impaired foetal growth is indeed linked to increased risk of heart disease, stroke, and diabetes in adult life. Studies of the Dutch hunger winter (1944-5) showed that the average birth weight for babies conceived or born during that winter was around 300 g lower.1 The siege of Leningrad (1941-4) was associated with an average fall in birth weight of 500-600 g (for term babies born in 1942). Of those born in the first half of 1942, half weighed less than 2500 g.2 On the basis of previous studies we estimate that a fall of 500-600 g in birth weight would correspond to an average increase in blood pressure of 1-2 mm Hg in adult life,3 a 15% increased risk of mortality from ischaemic heart disease,4 and a 35% increased risk of haemorrhagic stroke.5
Follow up of 549 children born in or near Leningrad before or during the siege, however, concluded that there was no effect of intrauterine malnutrition on blood pressure, glucose intolerance, or lipid concentrations in adult life.6 Studying the Dutch hunger winter Roseboom et al concluded that starvation in mid or late fetal period did not carry an increased risk of an atherogenic lipid profile7 or heart disease later in life,8 while exposure in early gestation did. Bygren et al reported no excess mortality (at age 40-70) among individuals starved during the whole fetal period.9 In contrast, those who starved during part of it (early or late) were more likely to die from stroke. Kannisto et al, studying Finnish birth cohorts born around the 1866-8 famine, concluded that starvation in utero, infancy, or early childhood was not linked to mortality in adult life (at age 17-80).10 Typically, groups who experienced starvation during (part of) fetal life were compared with groups starving in other parts of fetal or early life, on the assumption that only one specific fetal period programs vulnerability to a specific disease.
These inconsistencies call for a more precise understanding of how and when starvation affects health. Does starvation outside the fetal period, say maternal starvation before pregnancy or offspring's starvation after birth, also have long term effects? Recent work on self starvation among young girls cautions against narrowing the age interval of exposure in studies of malnutrition or starvation.11 Before the fetal origins hypothesis most research did use a broader exposure.12-14 Kermack et al suggested that "the important factor from the point of view of the health of the individual during his life is his environment up to age of say 15 years."12
We studied the long term health consequences of involuntary starvation in a population of men who were aged 6-28 years at the peak of the period of severe food shortage. German troops prevented supplies from reaching Leningrad from 8 September 1941 to 27 January 1944. Of a population of 2.9 million (including 0.5 million children), 630 000 died from hunger-related causes,15 most during the winter of 1941-2. We investigated whether experience of the siege did in fact lead to an increased risk of mortality, particularly from cardiovascular disease.
Methods
Table 1 shows intermediate outcomes before the start of the mortality follow up. There was a significant excess risk of high systolic and diastolic blood pressure in men who lived through the siege. Those who were around the age of puberty (9-15 years) at the peak of starvation (January 1942) were especially prone to high systolic blood pressure (odds ratio 1.56, 95% confidence interval 1.21 to 2.02) with a mean excess of 3.3 mm Hg (Wald test P = 0.03). Except for a tendency to have a greater skinfold thickness, all other indicators of cardiovascular risk were remarkably similar for exposed and non-exposed.
Table 1 Intermediate outcomes measured at recruitment of cohort in 1975-7. Probability measures are odds ratios for dichotomous outcomes (estimated with logistic regression models) and mean differences for continuous outcomes (estimated with linear regression models), both with 95% confidence intervals. All estimates adjusted for birth cohort
During follow up 2048 of the 3905 men died. Cardiovascular disease accounted for 1050 deaths (51%), 662 from ischaemic heart disease and 333 from stroke, 97 of which were haemorrhagic. The excess risk of dying (all causes) for those who experienced the siege was 21% (relative risk 1.21, 1.10 to 1.32) (data not shown).
Table 2 (restricted sample) shows the excess risk of dying from ischaemic heart disease (1.28, 1.08 to 1.51). Among those aged 9-15 at the peak of starvation this estimate was 1.39 (1.07 to 1.79). The effects of starvation around puberty were stronger still for stroke (1.67, 1.15 to 2.43), including haemorrhagic stroke (1.71, 0.90 to 3.22). For stroke, but not for other mortality, the siege effect was significantly stronger for those who experienced it around puberty than at other ages (Wald test P = 0.02).
Table 2 Cardiovascular mortality 1975-99 for restricted sample* by age at siege exposure. Relative risks and 95% confidence intervals as estimated with Poisson regression models
Adjustment for occupation, education, marital status, smoking, or alcohol consumption had no impact on risk estimates, although all these variables were themselves strongly correlated with mortality. Among those aged 9-15 years adjustment for systolic and diastolic blood pressure changed risk estimates downwards from 1.39 to 1.29 for ischaemic heart disease, from 1.67 to 1.49 for stroke, and from 1.71 to 1.51 for haemorrhagic stroke. Addition of other intermediate outcomes rendered small changes.
Throughout the follow up period there was a pattern of higher cardiovascular mortality for those who experienced the siege (figure). This was particularly pronounced in 1987-91, when those who did not experience the siege seemed to have a reduced risk. The period specific relative risk was 1.79, based on the main effect and a highly significant interaction (P = 0.004) effect (1.55, 1.16 to 2.08) (data not shown).
Cardiovascular mortality over time by exposure to Leningrad siege (mortality estimated from Poisson regression model)
Discussion
Stein Z, Susser M, Saengler G, Marolla F. Famine and human development. The Dutch hunger winter of 1944-1945. London: Oxford University Press, 1975.
Antonov AN. Children born during the siege of Leningrad in 1942. J Pediatr 1947: 250-9.
Leon D, Koupilová I. Birth weight, blood pressure and hypertension. Epidemiological studies. In: Barker DJ, editor. Fetal origins of cardiovascular and lung disease. New York and Basel: Marcel Dekker, 2001.
Leon DA, Lithell HO, Vagero D, Koupilova I, Mohsen R, Berglund L, et al. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915-29. BMJ 1998;317: 241-5.
Hypp?nen E, Leon DA, Kenward MG, Lithell H. Prenatal growth and risk of occlusive and haemorrhagic stroke in Swedish men and women born 1915-29: historical cohort study. BMJ 2001;323: 1033-4.
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: 1342-8.
Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, 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 JH, Osmond C, Barker DJ, Ravelli AC, Schroeder-Tanka JM, et al. Coronary heart disease after prenatal exposure to the Dutch famine, 1944-45. Heart 2000;84: 595-8.
Bygren LO, Edvinsson S, Brostrom G. Change in food availability during pregnancy: Is it related to adult sudden death from cerebro- and cardiovascular disease in offspring? Am J Human Biol 2000;12: 447-53.
Kannisto V, Christensen K, Vaupel JW. No increased mortality in later life for cohorts born during famine. Am J Epidemiol 1997;145: 987-94.
Cooke RA, Chambers JB. Anorexia nervosa and the heart. Br J Hosp Med 1995;54: 313-7.
Kermack W, McKendrick A, McKinley P. Death rates in Great Britain and Sweden. Some general regularities and their significance. Lancet 1934;i: 698-703.
Forsdahl A. Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease? Br J Prev Soc Med 1977;31: 91-5.
Peck AM, V?ger? D. Adult body height, self perceived health and mortality in the Swedish population. J Epidemiol Community Health 1989;43: 380-4.
Pavlov D. Leningrad 1941: the blockade. Chicago: University of Chicago Press, 1965.
Abernathy JR, Thorn MD, Ekelund LG, Holme I, Stinnett SS, Shestov DB, et al. Correlates of systolic and diastolic blood pressure in men 40 to 59 years of age sampled from United States of America and Union of Soviet Socialist Republics Lipid Research Clinics populations. Am J Cardiol 1988;61: 1071-5.
Breslow NE, Day NE. Statistical methods in cancer research. Vol II: The design and analysis of cohort studies. Lyons: International Agency for Research on Cancer, 1987.
Agresti A. Categorical data analysis. New York: John Wiley, 1990.
Marshall W, Tanner J. Puberty. In: Falkner F, Tanner JM, editors. Human Growth. A comprehensive treatise. Part 2. Postnatal growth neurobiology. New York: Plenum Press, 1986: 171-209.
de Simone G, Scalfi L, Galderisi M, Celentano A, Di Biase G, Tammaro P, et al. Cardiac abnormalities in young women with anorexia nervosa. Br Heart J 1994;71: 287-92.
Swenne I. Heart risk associated with weight loss in anorexia nervosa and eating disorders: electrocardiographic changes during the early phase of refeeding. Acta Paediatr 2000;89: 447-52.
Garnett ES, Barnard DL, Ford J, Goodbody RA, Woodehouse MA. Gross fragmentation of cardiac myofibrils after therapeutic starvation for obesity. Lancet 1969;i: 914-6.
St?ving RK, Hangaard J, Hansen-Nord M, Hagen C. A review of endocrine changes in anorexia nervosa. J Psychiatr Res 1999;33: 139-52.
Holdaway IM, Rajasoorya C. Epidemiology of acromegaly. Pituitary 1999;2: 29-41.
Bohlooly YM, Carlson L, Olsson B, Gustafsson H, Andersson IJ, Tornell J, et al. Vascular function and blood pressure in GH transgenic mice. Endocrinology 2001;142: 3317-23.
Nelson MJ, Ragland DR, Syme SL. Longitudinal prediction of adult blood pressure from juvenile blood pressure levels. Am J Epidemiol 1992;136: 633-45.
Zicha J, Kunes J. Ontogenetic aspects of hypertension development: analysis in the rat. Physiol Rev 1999;79: 1227-82.
Kreipe RE, Harris JP. Myocardial impairment resulting from eating disorders. Pediatr Ann 1992;21: 760-8.
Brozek J, Chapman C, Keys A. Drastic food restriction: effect on cardiovascular dynamics in normotensive and hypertensive conditions. J Am Med Assoc 1948: 1569-74.
Keys A, Brozek J, Henschel A, Mickelsen O, Taylor HL. The biology of human starvation. Minneapolis: University of Minnesota Press, 1950.
Beevor A. Stalingrad. London: Viking, 1998.
Melamed S, Ugarten U, Shirom A, Kahana L, Lerman Y, Froom P. Chronic burnout, somatic arousal and elevated salivary cortisol levels. J Psychosom Res 1999;46: 591-8.
Rosmond R, Bjorntorp P. The hypothalamic-pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke. J Intern Med 2000;247: 188-97.(P?r Sparén, senior resear)
Correspondence to: P Sparén Par.Sparen@meb.ki.se
Abstract
Famine and food shortage have both short and long term consequences for health. Particular concern has arisen for later consequences of in utero starvation, a concern reinforced by much new research suggesting that impaired foetal growth is indeed linked to increased risk of heart disease, stroke, and diabetes in adult life. Studies of the Dutch hunger winter (1944-5) showed that the average birth weight for babies conceived or born during that winter was around 300 g lower.1 The siege of Leningrad (1941-4) was associated with an average fall in birth weight of 500-600 g (for term babies born in 1942). Of those born in the first half of 1942, half weighed less than 2500 g.2 On the basis of previous studies we estimate that a fall of 500-600 g in birth weight would correspond to an average increase in blood pressure of 1-2 mm Hg in adult life,3 a 15% increased risk of mortality from ischaemic heart disease,4 and a 35% increased risk of haemorrhagic stroke.5
Follow up of 549 children born in or near Leningrad before or during the siege, however, concluded that there was no effect of intrauterine malnutrition on blood pressure, glucose intolerance, or lipid concentrations in adult life.6 Studying the Dutch hunger winter Roseboom et al concluded that starvation in mid or late fetal period did not carry an increased risk of an atherogenic lipid profile7 or heart disease later in life,8 while exposure in early gestation did. Bygren et al reported no excess mortality (at age 40-70) among individuals starved during the whole fetal period.9 In contrast, those who starved during part of it (early or late) were more likely to die from stroke. Kannisto et al, studying Finnish birth cohorts born around the 1866-8 famine, concluded that starvation in utero, infancy, or early childhood was not linked to mortality in adult life (at age 17-80).10 Typically, groups who experienced starvation during (part of) fetal life were compared with groups starving in other parts of fetal or early life, on the assumption that only one specific fetal period programs vulnerability to a specific disease.
These inconsistencies call for a more precise understanding of how and when starvation affects health. Does starvation outside the fetal period, say maternal starvation before pregnancy or offspring's starvation after birth, also have long term effects? Recent work on self starvation among young girls cautions against narrowing the age interval of exposure in studies of malnutrition or starvation.11 Before the fetal origins hypothesis most research did use a broader exposure.12-14 Kermack et al suggested that "the important factor from the point of view of the health of the individual during his life is his environment up to age of say 15 years."12
We studied the long term health consequences of involuntary starvation in a population of men who were aged 6-28 years at the peak of the period of severe food shortage. German troops prevented supplies from reaching Leningrad from 8 September 1941 to 27 January 1944. Of a population of 2.9 million (including 0.5 million children), 630 000 died from hunger-related causes,15 most during the winter of 1941-2. We investigated whether experience of the siege did in fact lead to an increased risk of mortality, particularly from cardiovascular disease.
Methods
Table 1 shows intermediate outcomes before the start of the mortality follow up. There was a significant excess risk of high systolic and diastolic blood pressure in men who lived through the siege. Those who were around the age of puberty (9-15 years) at the peak of starvation (January 1942) were especially prone to high systolic blood pressure (odds ratio 1.56, 95% confidence interval 1.21 to 2.02) with a mean excess of 3.3 mm Hg (Wald test P = 0.03). Except for a tendency to have a greater skinfold thickness, all other indicators of cardiovascular risk were remarkably similar for exposed and non-exposed.
Table 1 Intermediate outcomes measured at recruitment of cohort in 1975-7. Probability measures are odds ratios for dichotomous outcomes (estimated with logistic regression models) and mean differences for continuous outcomes (estimated with linear regression models), both with 95% confidence intervals. All estimates adjusted for birth cohort
During follow up 2048 of the 3905 men died. Cardiovascular disease accounted for 1050 deaths (51%), 662 from ischaemic heart disease and 333 from stroke, 97 of which were haemorrhagic. The excess risk of dying (all causes) for those who experienced the siege was 21% (relative risk 1.21, 1.10 to 1.32) (data not shown).
Table 2 (restricted sample) shows the excess risk of dying from ischaemic heart disease (1.28, 1.08 to 1.51). Among those aged 9-15 at the peak of starvation this estimate was 1.39 (1.07 to 1.79). The effects of starvation around puberty were stronger still for stroke (1.67, 1.15 to 2.43), including haemorrhagic stroke (1.71, 0.90 to 3.22). For stroke, but not for other mortality, the siege effect was significantly stronger for those who experienced it around puberty than at other ages (Wald test P = 0.02).
Table 2 Cardiovascular mortality 1975-99 for restricted sample* by age at siege exposure. Relative risks and 95% confidence intervals as estimated with Poisson regression models
Adjustment for occupation, education, marital status, smoking, or alcohol consumption had no impact on risk estimates, although all these variables were themselves strongly correlated with mortality. Among those aged 9-15 years adjustment for systolic and diastolic blood pressure changed risk estimates downwards from 1.39 to 1.29 for ischaemic heart disease, from 1.67 to 1.49 for stroke, and from 1.71 to 1.51 for haemorrhagic stroke. Addition of other intermediate outcomes rendered small changes.
Throughout the follow up period there was a pattern of higher cardiovascular mortality for those who experienced the siege (figure). This was particularly pronounced in 1987-91, when those who did not experience the siege seemed to have a reduced risk. The period specific relative risk was 1.79, based on the main effect and a highly significant interaction (P = 0.004) effect (1.55, 1.16 to 2.08) (data not shown).
Cardiovascular mortality over time by exposure to Leningrad siege (mortality estimated from Poisson regression model)
Discussion
Stein Z, Susser M, Saengler G, Marolla F. Famine and human development. The Dutch hunger winter of 1944-1945. London: Oxford University Press, 1975.
Antonov AN. Children born during the siege of Leningrad in 1942. J Pediatr 1947: 250-9.
Leon D, Koupilová I. Birth weight, blood pressure and hypertension. Epidemiological studies. In: Barker DJ, editor. Fetal origins of cardiovascular and lung disease. New York and Basel: Marcel Dekker, 2001.
Leon DA, Lithell HO, Vagero D, Koupilova I, Mohsen R, Berglund L, et al. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915-29. BMJ 1998;317: 241-5.
Hypp?nen E, Leon DA, Kenward MG, Lithell H. Prenatal growth and risk of occlusive and haemorrhagic stroke in Swedish men and women born 1915-29: historical cohort study. BMJ 2001;323: 1033-4.
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: 1342-8.
Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, 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 JH, Osmond C, Barker DJ, Ravelli AC, Schroeder-Tanka JM, et al. Coronary heart disease after prenatal exposure to the Dutch famine, 1944-45. Heart 2000;84: 595-8.
Bygren LO, Edvinsson S, Brostrom G. Change in food availability during pregnancy: Is it related to adult sudden death from cerebro- and cardiovascular disease in offspring? Am J Human Biol 2000;12: 447-53.
Kannisto V, Christensen K, Vaupel JW. No increased mortality in later life for cohorts born during famine. Am J Epidemiol 1997;145: 987-94.
Cooke RA, Chambers JB. Anorexia nervosa and the heart. Br J Hosp Med 1995;54: 313-7.
Kermack W, McKendrick A, McKinley P. Death rates in Great Britain and Sweden. Some general regularities and their significance. Lancet 1934;i: 698-703.
Forsdahl A. Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease? Br J Prev Soc Med 1977;31: 91-5.
Peck AM, V?ger? D. Adult body height, self perceived health and mortality in the Swedish population. J Epidemiol Community Health 1989;43: 380-4.
Pavlov D. Leningrad 1941: the blockade. Chicago: University of Chicago Press, 1965.
Abernathy JR, Thorn MD, Ekelund LG, Holme I, Stinnett SS, Shestov DB, et al. Correlates of systolic and diastolic blood pressure in men 40 to 59 years of age sampled from United States of America and Union of Soviet Socialist Republics Lipid Research Clinics populations. Am J Cardiol 1988;61: 1071-5.
Breslow NE, Day NE. Statistical methods in cancer research. Vol II: The design and analysis of cohort studies. Lyons: International Agency for Research on Cancer, 1987.
Agresti A. Categorical data analysis. New York: John Wiley, 1990.
Marshall W, Tanner J. Puberty. In: Falkner F, Tanner JM, editors. Human Growth. A comprehensive treatise. Part 2. Postnatal growth neurobiology. New York: Plenum Press, 1986: 171-209.
de Simone G, Scalfi L, Galderisi M, Celentano A, Di Biase G, Tammaro P, et al. Cardiac abnormalities in young women with anorexia nervosa. Br Heart J 1994;71: 287-92.
Swenne I. Heart risk associated with weight loss in anorexia nervosa and eating disorders: electrocardiographic changes during the early phase of refeeding. Acta Paediatr 2000;89: 447-52.
Garnett ES, Barnard DL, Ford J, Goodbody RA, Woodehouse MA. Gross fragmentation of cardiac myofibrils after therapeutic starvation for obesity. Lancet 1969;i: 914-6.
St?ving RK, Hangaard J, Hansen-Nord M, Hagen C. A review of endocrine changes in anorexia nervosa. J Psychiatr Res 1999;33: 139-52.
Holdaway IM, Rajasoorya C. Epidemiology of acromegaly. Pituitary 1999;2: 29-41.
Bohlooly YM, Carlson L, Olsson B, Gustafsson H, Andersson IJ, Tornell J, et al. Vascular function and blood pressure in GH transgenic mice. Endocrinology 2001;142: 3317-23.
Nelson MJ, Ragland DR, Syme SL. Longitudinal prediction of adult blood pressure from juvenile blood pressure levels. Am J Epidemiol 1992;136: 633-45.
Zicha J, Kunes J. Ontogenetic aspects of hypertension development: analysis in the rat. Physiol Rev 1999;79: 1227-82.
Kreipe RE, Harris JP. Myocardial impairment resulting from eating disorders. Pediatr Ann 1992;21: 760-8.
Brozek J, Chapman C, Keys A. Drastic food restriction: effect on cardiovascular dynamics in normotensive and hypertensive conditions. J Am Med Assoc 1948: 1569-74.
Keys A, Brozek J, Henschel A, Mickelsen O, Taylor HL. The biology of human starvation. Minneapolis: University of Minnesota Press, 1950.
Beevor A. Stalingrad. London: Viking, 1998.
Melamed S, Ugarten U, Shirom A, Kahana L, Lerman Y, Froom P. Chronic burnout, somatic arousal and elevated salivary cortisol levels. J Psychosom Res 1999;46: 591-8.
Rosmond R, Bjorntorp P. The hypothalamic-pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke. J Intern Med 2000;247: 188-97.(P?r Sparén, senior resear)