BMJ  2004;328:11 (3 January), doi:10.1136/bmj.37942.603970.9A (published 5 December 2003)

Paper

Long term mortality after severe starvation during the siege of Leningrad: prospective cohort study

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 Södertörns högskola, University College, Huddinge, Sweden, ⁵ Unit of Clinical Epidemiology, Department of Medicine, Karolinska Hospital, Stockholm, Sweden

Abstract

Objective To determine whether starvation during periods of increased growth after birth has long term health consequences.

Design Analysis of cardiovascular risk factors and mortality in a longitudinal follow up after the 1941-4 siege of Leningrad. Mortality measured from 1975 to the end of 1999.

Setting St Petersburg, Russia (formerly Leningrad).

Participants 5000 men born 1916-35 who lived in Leningrad, randomly selected to take part in health examinations in 1975-7. Of the 3905 men who participated, a third had experienced the siege.

Main outcome measures Relative risk of ischaemic heart disease and mortality from stroke by siege exposure. Odds ratios and means for several cardiovascular risk factors.

Results Three to six decades after the siege, in men who experienced the siege around the age of puberty blood pressure was raised (mean difference in systolic 3.3 mm Hg, in diastolic 1.3 mm Hg) as was mortality from ischaemic heart disease (relative risk 1.39, 95% confidence interval 1.07 to 1.79) and stroke (1.67, 1.15 to 2.43), including haemorrhagic stroke (1.71, 0.90 to 3.22). The effect on mortality was partly mediated via blood pressure but not by any other measured biological, behavioural, or social factor.

Conclusions Starvation, or accompanying chronic stress, particularly at the onset of or during puberty, may increase vulnerability to later cardiovascular disease.

Introduction

Famine and food shortage have both short and long term consequences for health. Results of studies on the effect of starvation are, however, inconsistent.^1-7 The focus on fetal malnutrition may have been too narrow. 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. During the second world war 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,⁸ 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

Study base and data collection
As part of the 1973 US-Soviet collaborative programme, data were collected for the lipid research clinics programme.⁹ A baseline survey was undertaken in Leningrad 1975-7, in which 5000 men born in 1916-35 were randomly selected from voting lists in the socially mixed Petrogradsky district; 3905 men (78%) participated. Data were collected on socioeconomic factors (education, occupation, and marital status), behaviour (smoking and alcohol consumption), anthropometric measures (weight, height, and skinfold thickness), and other biological measurements (blood pressure, cholesterol concentration, and a Rose questionnaire interview about cardiovascular dysfunction). Nearly a third (n = 1406) had lived in Leningrad during the siege, which normally meant that they spent the whole siege period there as most people were unable to leave.

We followed mortality from the time of the interview to 31 December 1999.

Food shortage
From 20 November 1941 bread rations in Leningrad were at their lowest: 250 g daily for manual workers and 125 g for other civilians. Children below the age of 12 belonged to the latter category, but children over 12 years received even less—for example, only 200 g of fat, 800 g of sugar, and 600 g of carbohydrate a month. If rations were received in full, which was not always the case, this amounted to about 460 calories a day.⁸ The average daily ration was around 300 calories, containing virtually no protein.³ This is extremely low, even compared with rations during the Dutch hunger winter.¹⁰

Statistical analyses
We used Poisson regression to calculate relative risks. Residence in Leningrad during the siege (yes/no) and age at siege ( 8, 9-15, 16-26 years v not in siege) were introduced into successive regression models with other explanatory factors. We always controlled for birth year and attained age. We examined whether there was any difference in risk of mortality between those living in Leningrad during the siege and those who were not; whether any effect was modified by age at exposure; and whether any effect was of similar magnitude during the whole follow up period.

To assess socioeconomic confounding we adjusted risk estimates for marital status, education, and occupational class at baseline (interview). We also adjusted for smoking and alcohol consumption.

Intermediate outcomes—namely, adult body mass index, adult height, skinfold thickness measured at the arm, diastolic and systolic blood pressure, and the ratio of low to high density lipoprotein cholesterol—were considered as potential mediators between starvation and later cardiovascular disease. We used biological risk indicators as dichotomised outcome variables in logistic regression models¹¹ to estimate odds ratios by siege experience. They were also treated as continuous outcome variables in linear regression models to estimate mean differences.

Results

We analysed intermediate outcomes, measured 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.

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). The excess risk of dying from ischaemic heart disease was 28% (1.28, 1.08 to 1.51) (table). 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).

View this table: [in this window] [in a new window]   Systolic and diastolic blood pressure measured at recruitment of cohort in 1975-7, and cardiovascular mortality 1975-99 for restricted sample* by age at siege exposure.

 

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).

View larger version (28K): [in this window] [in a new window]   Cardiovascular mortality over time by exposure to Leningrad siege (mortality estimated from Poisson regression model)

 

Discussion

Men who experienced the Leningrad siege have higher systolic and diastolic blood pressure and excess mortality from ischaemic heart disease and stroke. Blood pressure mediated part of the siege effect on mortality, while other biological risk markers (such as body mass index and cholesterol concentrations) did so to a lesser extent. Lifestyle and socioeconomic circumstances did not confound the association between cardiovascular mortality and siege exposure.

Starvation around puberty (ages 9-15) was more strongly associated with high systolic blood pressure and stroke in adult life than was starvation at other ages. This casts new light on the effect of severe malnutrition in early life. We used the age limit of 9 years on the basis of work by Marshall and Tanner, who considered "the fat spurt" to be the earliest manifestation, or trigger, of puberty that is visible before age 10.¹²

Literature on anorexia nervosa details several cardiovascular abnormalities in patients, including reduction of ventricular mass, valvular dysfunctions,¹³ and electrocardiographic abnormalities.¹⁴ Damage of the myocardial fibres has been documented in obese patients on very low calorie diets.¹⁵ Furthermore, endocrine changes accompany self starvation around puberty.¹⁶ At least two of these changes—increased circulating concentrations of growth hormone and cortisol—profoundly influence regulation of blood pressure. Increased secretion of growth hormone is linked with hypertension.^{17 18} Critical stages in the process of regulating blood pressure may therefore occur during puberty,^{19 20} and starvation may cause a permanent disruption of blood pressure regulation.

An early study of the siege concluded that the immediate effect of starvation was a lowering of blood pressure. However, overcompensation occurred on refeeding. In people who have to do hard physical work blood pressure may rise as a consequence of refeeding after starvation.^{21 22} Limited food supplies reached Leningrad from the spring of 1942 across Lake Ladoga. Keys et al refers to the subsequent "refeeding after starvation" in 1943.²³ A sample of 10 000 healthy people in Leningrad examined in April 1943 showed that the distribution of blood pressure had shifted radically upwards compared with that in 1940. The prevalence of hypertension had increased fourfold among those under age 39 and twofold among those aged 40 years. This "Leningrad blockade hypertension epidemic" remains visible in our data over three decades after the blockade.

Possible biases
We considered several methodological problems to rule out any potential bias.

Selection—The death toll during the 1941-4 siege was extreme. Death rates of survivors in 1944-75 may also have been increased. Siege survivors examined in 1975-7 constituted a group of individuals selected for better genetic, constitutional, and social resources for health than other study participants. This selection should bias our estimates of the mortality effects of starvation downwards.

Narrow exposure contrast—Food shortage was common all over Russia during the war, especially in areas occupied by the Germans. Livestock and harvests were appropriated for German needs, and not distributing food to the Russian population was part of the German war strategy.²⁴ Therefore we are comparing boys and men exposed to protracted starvation with those who experienced less severe food shortage, including episodes of starvation, which results in conservative risk estimates.

Residual confounding—We assessed potential confounding factors at only one point in time (1975-7). Although all of them were strongly associated with mortality, they had little confounding effect. Residual confounding is therefore likely to be small.

Differential ascertainment of death—The researchers who traced the movements of cohort members and collected death certificates did not know the siege status of participants. After the last date of contact we excluded from the study individuals who moved from Leningrad. A bias could occur if this follow up was imperfect and if men who had not experienced the siege were more likely to leave Leningrad for some reason. We found no such evidence.

Conclusions
On balance, our estimates of risks caused by siege exposure are probably conservative, perhaps very much so. It is difficult to suggest pathways, other than raised blood pressure, by which starvation causes cardiovascular mortality. Other potential mediating factors (for example, endocrine changes^{25 26}) were not measured at all, and thus remain hypothetical. The nutritional component of starvation is also entangled with the trauma of the siege.

Work predating the fetal origins hypothesis had a broader focus, which included childhood exposures. Our study indicates that puberty may also be a highly vulnerable period. Starvation in puberty today may have implications for future cardiovascular disease in many developing countries. War is still a leading cause of starvation and this may have consequences for circulatory disease decades later.

What is already known on this topic Impaired growth in utero is linked to raised blood pressure and increased risk of ischaemic heart disease and stroke Results of previous studies on the effect of severe starvation in utero, infancy, or childhood on cardiovascular outcomes are inconsistent, and few studies have assessed the long term effects of starvation at later ages Anorexia in young people is thought to affect cardiovascular health What this study adds Starvation during the Leningrad siege, with its accompanying stress and trauma, resulted in raised systolic and diastolic blood pressure, which was evident even three decades after the event In a further follow up to 25 years, men who had experienced the siege had increased mortality from ischaemic heart disease and stroke Puberty may be a highly vulnerable period for the development of later cardiovascular disease

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This is the abridged version of an article that was posted on bmj.com on 5 December 2003: http://bmj.com/cgi/doi/10.1136/bmj.37942.603970.9A

We are grateful to Ilona Koupil for comments on an early draft. We benefited greatly from discussion with participants in three seminars at the Monica-Centre in Novosibirsk, the London School of Hygiene and Tropical Medicine, and the Institute for Contemporary History at Södertörns högskola, University College, Huddinge.

Contributors: See bmj.com

Funding: Swedish Baltic Sea Foundation; Swedish Council for Social Research.

Competing interests: None declared.

Ethical approval: Not required.

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(Accepted 14 October 2003)

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