Abstract
Background. Early life experiences might have long-term effects on health.
Aim. To assess prevalence of cardiovascular disease and diabetes in later life among individuals exposed to traumatic separation in early childhood due to World War II.
Methods. Of the participants of the Helsinki Birth Cohort 1934–44 Study (n=2003), 320 had been evacuated abroad to temporary foster care in childhood. The remaining participants served as controls. The mean age at evacuation was 4.8 (SD=2.4) years and the mean duration of the evacuation was 1.7 (SD=1.0) years.
Results. Cardiovascular morbidity was higher among the former war evacuees (14.7% versus 7.9%; odds ratio (OR)=2.0, 95% confidence interval (95% CI) 1.4–2.9; P<0.001). A similar difference in prevalence of type 2 diabetes was observed (19.7% versus 14.8%; OR=1.4, 95% CI 1.1–1.9, P=0.025). The former war evacuees were also more likely to be hypertensive (P<0.05). The effects on morbidity were not explained by age at testing or socio-economic circumstances in childhood or adulthood.
Conclusion. Early life traumatic events may extend lifelong effects on health. This study is among the first to show that early life trauma predicts higher prevalence of cardiovascular disease and type 2 diabetes in late adulthood, in a longitudinal clinical study setting.
Introduction
During World War II approximately 70,000 Finnish children were evacuated unaccompanied by their parents to temporary foster families in Sweden and Denmark. The likelihood of a Finnish child being evacuated was associated with an unpredictable interplay between political and intrafamilial factors Citation1. The evacuations were voluntary and seen as a positive opportunity in families with various socio-economic backgrounds.
Separation of children from their parents is a severe stressor shown to have adverse long-term effects on psychological well-being Citation2–8. Yet, little is known about the effects of early life separation on physical well-being of an individual Citation9–13. Now, over 60 years later, we have examined the long-term consequences of the experiences of war-time evacuation occurring during childhood on cardiovascular health and type 2 diabetes, in a longitudinal clinical study setting.
Key messages
Early life traumatic events may extend lifelong effects on health and influence overall well-being.
Early life trauma predicts higher prevalence of cardiovascular disease and type 2 diabetes in late adulthood.
Early life traumatic experiences may alter body systems important in physiological stress regulation, like the hypothalamic-pituitary-adrenocortical (HPA) axis.
Materials and methods
Participants
The original epidemiological study cohort consists of 8760 people who were born at Helsinki University Central Hospital between 1934 and 1944 and who were alive and living in Finland in 1971 when a unique personal identification number was allocated to each member of the Finnish population. As previously described we used random number tables to select a subset of 2003 people within the cohort (928 men and 1075 women) Citation14. All participants signed an informed consent. The ethical committee at the National Public Health Institute in Helsinki approved the study protocol.
Evacuation
Information on evacuations was obtained from a register in the Finnish National Archives that gives full documentation of children sent aboard through the Ministry of Social Affairs and Health during 1939–46. We identified 252 former child evacuees from this register. In addition, there were children evacuated abroad both through personal contacts of the families and through civil organizations. We also obtained information on war-time separations in a self-report questionnaire in the years 2001–2004 clinical examination, which enabled us to identify an additional 68 former war evacuees who were not registered in the archived records. Altogether, of the 2003 participants in the clinical study, 320 (16.0%) had been evacuated in childhood to Sweden and Denmark due to war circumstances (49.7% men; n=159). The mean age at evacuation was 4.8 (SD=2.4) years, and the mean duration of the evacuation was 1.7 (SD = 1.0) years as indicated by the archival and self-reported information. Data on age at evacuation was available for 234 evacuated and on duration for 229 evacuated, respectively. Participants without evacuation experiences served as the non-separated control group (n=1683).
Health outcomes
The participants (n=2003) attended a clinical examination in the years 2001–2004. The examination took place in the morning after an overnight fast. A 2-hour 75-g oral glucose tolerance test was performed. Glucose was measured at base-line, and at 30 and 120 minutes. The World Health Organization criteria for disturbances in glucose regulation were applied, in order to assess type 2 diabetes Citation15. Serum total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride concentrations were measured using standard enzymatic methods. Apolipoprotein A and B and lipoprotein(a) were measured using standard immunoturbometric methods Citation16–18. Low-density lipoprotein (LDL) cholesterol concentrations were derived by the Freidewald formula Citation19. Height was measured to the nearest centimetre, and weight was measured to the nearest 0.1 kg in light indoor clothing. Body mass index (BMI) was calculated (kg/m2). Blood pressure was measured from the right arm in the sitting position. The result was recorded as the mean of two successive readings from a standard sphygmomanometer. Information about chronic diseases was obtained from a questionnaire that the participants filled in during the clinical visit. Use of medication for chronic, physician-diagnosed diseases (e.g. blood pressure, diabetes, coronary heart disease) was assessed during the clinical visit, and the medication used was recorded. Cardiovascular disease was defined as a self-reported physician-diagnosed coronary heart disease and/or stroke.
Background variables
Information on childhood socio-economic status, based on the father's occupation, was available from birth records, child welfare clinic, and school health care records and categorized into three groups (lower, middle, upper). Own attained level of education, categorized into four groups (elementary school, vocational school, senior high school, college/university degree), was assessed in conjunction with the clinical examination.
Statistical analyses
Tests for differences in health between the evacuated and non-separated were based on multivariate linear and logistic regression analyses. The group differences were adjusted for sex, age at testing, father's occupational status in childhood, and own attained level of education in adulthood. We also tested if, among the evacuated, age at evacuation and duration of evacuation have bearing on health by using linear and logistic regression analyses. Because the effects of age and duration are not necessarily linear Citation8, non-linearity was tested by entering squared terms of age at evacuation and duration of evacuation into regression equation together with the linear terms. SPSS (Statistical Package for Social Sciences) version 15.0 was used for the analyses.
Results
shows characteristics of the war evacuees and non-separated controls. Men and women were equally likely to have been evacuated. The former war evacuees were older at testing and in adulthood had attained somewhat lower levels of education. No significant differences in socio-economic status in childhood between the groups were observed.
Table I. Characteristics of the sample.
Prevalence of cardiovascular disease and type 2 diabetes
Former war evacuees were more likely to have been diagnosed with cardiovascular disease (Odds Ratio (OR) = 2.0, 95% CI 1.4–2.9, P<0.001; P=0.012 for the adjusted model). They were also more likely to have type 2 diabetes (OR = 1.4, 95% CI, 1.1–1.9, P = 0.025; P = 0.029 for the adjusted model) (). Age at evacuation did not exert significant linear or non-linear effects on prevalence of cardiovascular disease or type 2 diabetes (P-values >0.11 for the adjusted models). Duration of evacuation exerted a significant, non-linear, J-shaped association on the prevalence of cardiovascular disease (P=0.02 for the adjusted model), such that in those who had been evacuated the longest the prevalence of cardiovascular disease was the highest (19.6%, 10.0%, 5.7%, and 32.1% for those evacuated for less than 1, 1–2, 2–3, and over 3 years, respectively).
Figure 1. Prevalence of cardiovascular disease and type 2 diabetes in war evacuees and non-separated controls. AOR refers to an adjusted odds ratio and 95% CI to a 95% confidence interval in a model adjusting for sex, age at testing, father's occupational status in childhood and own attained level of education in adulthood. Error bars represent 95% confidence intervals.
Blood pressure
shows that the former war evacuees were more likely to be hypertensive. The groups differed in systolic, but not in diastolic blood pressure (). Age at evacuation did not exert linear or non-linear effects on blood pressure (P-values >0.25), but duration of evacuation exerted a linear effect on physician-diagnosed hypertension (P=0.04 for the adjusted model). In those evacuated for the longest period, the prevalence of hypertension was the highest (26.8%, 43.6%, 31.4%, and 51.7% for those evacuated for less than 1, 1–2, 2–3, and over 3 years, respectively).
Table II. Differences (95% confidence intervals (95% CI)) in blood pressure levels, lipids, obesity, and in risk of elevated blood pressure and hypertension between war evacuees and non-separated controls.
Lipids and obesity
There were no differences in total cholesterol, HDL, LDL-cholesterol, and triglyceride concentrations between the groups or in concentrations of apolipoprotein A and B (). Lipoprotein(a) was significantly higher among the former war evacuees (). The war evacuees and non-separated controls did not differ significantly in BMI or in waist circumference (). Age at evacuation and duration of evacuation were not significantly associated with lipids or obesity (P-values >0.53).
Finally, we tested if the differences in the health outcomes between the evacuated and non-separated differed by sex. There were no such differences (P-values >0.47 for evacuation status by sex interaction).
Discussion
War evacuation in childhood is a severe traumatic stressor that is beyond the control of the child and therefore poses a severe challenge to the child's adaptation. The normal attachment bonding process of the evacuated child is disrupted twice: first when separated from the child's own biological parent(s) and then again when separated from the temporary foster parents. Previously, war evacuation in childhood has been shown to be associated with less optimal psychological well-being and psychiatric morbidity in adult life Citation2, Citation3, Citation7, Citation8. Our study was the first one to explore the long-term consequences on cardiovascular health and type 2 diabetes of the experiences of war-time evacuation.
We found that such an early life traumatic experience extends substantial lifelong effects on cardiovascular disease, its risk factors, and type 2 diabetes. Children who were evacuated to temporary foster care in childhood compared to those who were not separated from their parents were twice as likely to have been diagnosed with cardiovascular disease and 1.4-fold more likely to have been diagnosed with type 2 diabetes than those who were not separated from their parents. In addition, we found that the evacuated children were more likely to be hypertensive as well as display elevated systolic blood pressure and lipoprotein(a) levels. High plasma lipoprotein(a) levels have been associated with an increased risk for coronary heart disease. Age at evacuation did not matter for the health outcomes, but duration of evacuation did: those evacuated for the longest (>3 years) exhibited the highest prevalence rates of cardiovascular disease and hypertension (self-reported physician-diagnosed) These associations were not explained by sex, age at testing, or socio-economic circumstances in childhood and in adulthood.
Among the potential mechanisms that may underlie these associations, the most likely points to alterations in physiological stress regulation that may render an individual vulnerable to adverse physical health consequences later in life Citation20–22. Maternal separation is among the most severe of the experimental stressors also in animals as it deprives the pups of maternal care and disrupts normal attachment behaviour causing extreme strain in the offspring. As adults, the mother-separated rat pups compared to control and/or handled pups exhibit 2- to 3-fold greater hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to stress. As previously shown the link between early life traumatic stressors and HPA axis responsiveness is not restricted to animals Citation23–28. There is also evidence that individuals who had lost their parent in childhood exhibit higher blood pressure responses to psychosocial stress challenges Citation28.
HPA axis function can modulate inflammation processes. Both animal and human studies have shown that inflammation is involved in the pathophysiology of cardiovascular disease and type 2 diabetes. Early life stress may influence inflammation processes in adulthood and, thus, the risk for cardiovascular disease and type 2 diabetes Citation29, Citation30.
The effect of early life stress on HPA axis and inflammation is probably mediated by epigenetic modification. These epigenetic changes could modify HPA axis function as well as cause chronic inflammation resulting in a greater cardiovascular and diabetes risk. Epigenetic changes alter gene expression and they can be either silencing or activating the genes. Data suggest that epigenetic processes underlie relationships between early life events and later metabolic status Citation31–33. DNA methylation has been implicated as an early step in the development of atherosclerosis as well as in the development of type 2 diabetes Citation34. The data available to us do not, however, allow testing of whether these mechanisms may account for the associations we found.
The present study agrees with and adds to the mounting literature that shows that early life adversity is linked with a number of health problems in adult life Citation9–13. For instance, the Adverse Childhood Experiences Study has demonstrated that exposure to childhood psychological, physical, or sexual abuse, and household dysfunction (substance abuse, mental illness, violent/criminal behaviour by a household member) during childhood are associated with the presence of coronary heart disease (CHD), cancer, chronic lung disease, skeletal fractures, and liver disease, and those with accumulating childhood adversities display multiple disorders in adulthood Citation10, Citation11. An obvious limitation of the previous studies is, however, that they mostly rely on retrospective reports of the events precluding causal inferences of the associations. A major strength of this study thus lies in the definition of the early life trauma more objectively and reliably, mostly based on data extracted from national archives. The findings are highly consistent and show that separation experience during childhood predicts adverse physical health consequences decades later.
While the clinical longitudinal study setting is a major study strength, some limitations should also be addressed. First, we have studied people who were born in the Helsinki University Central Hospital. The people in our study may therefore be unrepresentative of all people born in Helsinki. However, we know that, at that time in Helsinki, approximately 60% of men worked as labourers, which is similar to the percentage of fathers in our study who belonged to this social class. We cannot rule out either the possibility that the selection of the children for evacuation was not truly random Citation1. Other potential limitations include stressful life events in adulthood which we have not been able to control for.
To conclude, this study showed that the effects of early life traumatic events on an individual's health may extend across the life-course. The former child evacuees had higher prevalence of cardiovascular disease and type 2 diabetes at the age of 60. Since early life traumatic experience may alter systems important in physiological stress regulation, we speculate a role for these systems in explaining the findings.
Acknowledgements
This work was supported by the British Heart Foundation, the Academy of Finland, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, the Finnish Foundation for Cardiovascular Research, and the Juho Vainio Foundation.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Pesonen AK, Räikkönen K, Heinonen K, Kajantie E, Forsén T, Eriksson JG, et al. Pesonen et al. Respond to “The Life Course Epidemiology of Depression”. Am J Epidemiology. 2007; 166: 1138–1139
- Tennant C, Hurry J, Bebbington P. The relation of childhood separation experiences to adult depressive and anxiety states. Br J Psychiatry. 1982; 141: 475–82
- Birtchnell J, Kennard J. How do the experiences of the early separated and the early bereaved differ and to what extent do such differences affect outcome?. Soc Psychiatry. 1984; 19: 163–71
- Breier A, Kelsoe JR, Jr, Kirwin PD, Beller SA, Wolkowitz OM, Pickar D. Early parental loss and development of adult psychopathology. Arch Gen Psychiatry. 1988; 45: 987–93
- Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Childhood parental loss and adult psychopathology in women. A twin study perspective. Arch Gen Psychiatry. 1992; 49: 109–16
- Kendler KS, Sheth K, Gardner CO, Prescott CA. Childhood parental loss and risk for first-onset of major depression and alcohol dependence: the time-decay of risk and sex differences. Psychol Med. 2002; 32: 1187–94
- Foster D, Davies S, Steele H. The evacuation of British children during World War II: a preliminary investigation into the long-term psychological effects. Aging Ment Health. 2003; 7: 398–408
- Pesonen AK, Räikkönen K, Heinonen K, Kajantie E, Forsén T, Eriksson JG. Depressive symptoms in adults separated from their parents as children: A natural experiment during World War II. Am J Epidemiol. 2007; 50: 2433–8
- Maier EH, Lachman ME. Consequences of early parental loss and separation for health and well-being in midlife. Int J Behav Dev. 2000; 24: 183–9
- Felletti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. Am J Prev Med. 1998; 14: 245–58
- Dong M, Giles WH, Felletti VJ, Dube SR, Williams JE, Chapman DP, et al. Insights into causal pathways for ischemic heart disease. Circulation. 2004; 110: 1761–6
- Dube SR, Felletti VJ, Dong M, Giles WH, Anda RF. The impact of adverse childhood experiences on health problems: evidence from four birth cohorts dating back to 1900. Prev Med. 2003; 37: 268–77
- Batten SV, Aslan M, Maciejewski PK, Mazure CM. Childhood maltreatment as a risk factor for adult cardiovascular disease and depression. J Clin Psychiatr. 2004; 65: 249–54
- Barker DJP, Osmond C, Forsen TJ, Kajantie E, Eriksson JG. Trajectories of growth among children who have coronary events as adults. N Eng J Med. 2005; 353: 1802–9
- Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998; 15: 539–53
- Lie RF, Schmitz JM, Pierre KJ, Gochman N. Cholesterol oxidase-based determination, by continuous-flow analysis, of total and free cholesterol in serum. Clin Chem. 1976; 22: 1627–30
- Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem. 1982; 28: 2077–80
- Sugiuchi H, Uji Y, Okabe H, Irie T, Uekama K, Kayahara N, et al. Direct measurement of high-density lipoprotein cholesterol in serum with polyethylene glycol-modified enzymes and sulfated alpha-cyclodextrin. Clin Chem. 1995; 41: 717–23
- Friedewald WT, Levi RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma without the use of preparative ultracentrifuge. Clin Chem. 1972; 18: 499–502
- Sanchez MM, Ladd CO, Plotsky PM. Early adverse experience as a developmental risk factor for later psychopathology: evidence from rodent and primate models. Dev Psychopathol. 2001; 13: 419–49
- Cirulli F, Berry A, Alleva E. Early disruption of the mother-infant relationship: effects on brain plasticity and implications for psychopathology. Neurosci Biobehav Rev. 2003; 27: 73–82
- Bremner JD, Vermetten E. Stress and development: Behavioral and biological consequences. Dev Psychopathol. 2001; 13: 473–89
- Boyce WT, Ellis BJ. Biological sensitivity to context: I. An evolutionary-developmental theory of the origins and functions of stress reactivity. Dev Psychopathol. 2005; 17: 271–301
- Ellis BJ, Essex MJ, Boyce WT. Biological sensitivity to context: II. Empirical explorations of an evolutionary-developmental theory. Dev Psychopathol. 2005; 17: 303–28
- Levine S. Developmental determinants of sensitivity and resistance to stress. Psychoneuroendocrinology. 2005; 30: 939–46
- Gunnar MR, Fisher PA. Bringing basic research on early experience and stress neurobiology to bear on preventive interventions for neglected and maltreated children. Dev Psychopathol. 2006; 18: 651–77
- Gunnar M, Quevedo K. The neurobiology of stress and development. Annu Rev Psychol. 2007; 58: 145–73
- Luecken LJ. Childhood attachment and loss experiences affect adult cardiovascular and cortisol function. Psychosom Med. 1998; 60: 765–72
- Avitsur R, Hunzeker J, Sheridan JF. Role of early stress in the individual differences in host response to viral infection. Brain Behav Immun. 2006; 20: 339–48
- Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A. 2007; 104: 1319–24
- Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, et al. Epigenetic programming by maternal behaviour. Nat Neurosci. 2004; 7: 847–54
- Meaney MJ, Szyf M. Environmental programming of stress responses through DNA Methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci. 2005; 7: 103–23
- Gluckman PD, Lillycrop KA, Vickers MH, Pleasants AB, Phillips ES, Beedle AS, et al. Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci U S A. 2007; 31: 12796–800
- Waterland RA, Michels KB. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr. 2007; 27: 363–88