AMERICAN JOURNAL OF HUMAN BIOLOGY 26:111–116 (2014)
Review
Early Life Stress and Later Health Outcomes—Findings from the Helsinki Birth Cohort Study 1 2,4,5,6 € € MIA ERIKSSON,1,2,3 KATRI RAIKK ONEN, AND JOHAN G. ERIKSSON * 1 Department of Psychology, Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland 2 Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland 3 Texas Christian University, Forth Worth, Texas 4 Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland 5 Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland 6 Folkh€ alsan Research Center, Helsinki, Finland
Objectives: Severe early life stress (ELS) is a well-known risk factor for mental health disorders later in life. Not only mental health disorders are affected by ELS but early life stressors can also induce physical and biological changes increasing the risk for several noncommunicable diseases including type 2 diabetes and cardiovascular disease. Methods: This review focuses on the cohesive studies of individuals from the Helsinki Birth Cohort Study born 1934–1944 who were sent abroad from Finland during World War II as “war children.” Results: The review encompasses both epidemiological and clinical studies ranging from mental health disorders to type 2 diabetes and cardiovascular disease as well as potential underlying mechanisms explaining the association between ELS and later health. Conclusions: ELS is capable of causing changes that alter the normal physiological responses and thereby increase C 2013 Wiley Periodicals, Inc. V later disease risk, including cardiometabolic disorders. Am. J. Hum. Biol. 26:111–116, 2014. It is a commonly accepted theory that severe early life stress (ELS) is a risk factor for mental health disorders later in life. Abuse, neglect, and separation from either one or both parents during childhood have been shown to be associated with a greater risk of mental health disorders (Afifi et al., 2006, 2009; Danese et al., 2009; Green et al., 2010; Hjern et al., 2002; Johnson et al., 1999, 2006; M€ akikyr€o et al., 1998; Morgan et al., 2007; Pesonen et al., 2007; Rubino et al., 2009; Rusby and Tasker, 2009; Sharon et al., 2009; Thompson et al., 2008; Tieman et al., 2005; Veijola et al., 2004, 2008; Widom, 1999; Widom et al., 2007, 2009). Also parental separation during childhood has been shown to have detrimental psychological long-term consequences (Birtchnell and Kennard, 1984; Breier et al., 1988; Foster et al., 2003; Kendler et al., 1992, 2002; Pesonen et al., 2007; Tennant et al., 1982). ELS in the form of parental separation during childhood has been linked to higher prevalence of personality disorders (Byrne et al., 1990; Gibbon et al., 2009; Kantoj€ arvi et al., 2008; M€ akikyr€o et al., 1998; Pert et al., 2004; R€ aikk€onen et al., 2011). A few studies suggest that an uncertain childhood environment could cause individuals to reproduce at a younger age in order to ensure the existence of offspring (Belsky, 2008; Charnov, 1993; Draper and Harpending, 1982). Not only mental health is effected by ELS; these early stressors can also induce physical and biological changes. An association between abuse in childhood and both structural and functional hippocampal changes (Bremner, 1999) along with short-term memory deterioration in adulthood (Bremner et al., 1995) has been described. Evidence suggests that even an increased risk of cardiovascular disease can stem from ELS (Dong et al., 2004; Korkeila et al., 2010; O’Rand and Hamil-Luker, 2005; Sumanen et al., 2005). This review focuses on the cohesive studies of individuals from the Helsinki Birth Cohort Study (HBCS) that were sent abroad from Finland during World War II, as “war children” and after the war returned home. ELS is focused upon from the perspective of temporary separaC 2013 Wiley Periodicals, Inc. V
tion from parents during childhood. The review encompasses both epidemiological and clinical studies ranging from mental health disorders to reproduction, type 2 diabetes and cardiovascular disease as well as potential underlying mechanisms explaining the association between ELS and later health (Table 1). WAR EVACUATIONS AND HELSINKI BIRTH COHORT STUDY Finland fought two separate wars with the Soviet Union during World War II: the Winter War and the Continuation War. Children were evacuated to Sweden and Denmark in order to escape the dangers of war. These children were sent away unaccompanied by their parents, but the evacuations were completely voluntary (Kaven, 1985; Pesonen et al., 2007). The evacuations were organized by the government, but very little is known about the children’s living conditions while abroad. All together around 70,000 Finnish children were evacuated (Alastalo et al., 2012). The Finnish National Archives have full records of age of children at separation and length of separation (Pesonen et al., 2007, 2010). The epidemiological part of HBCS includes 6,370 women and 6,975 men born at Helsinki University Central Hospital or the Maternity Hospital in Helsinki between the years of 1934 and 1944. In order to be included in the study cohort the individuals had to have attended child welfare clinics in Helsinki besides being born at one of these hospitals, and they had to be alive and living in Finland in 1971 when all residents were
*Correspondence to: Johan G. Eriksson, Department of General Practice and Primary Health Care, University of Helsinki, PO Box 20, 00014 University of Helsinki, Finland. E-mail: [email protected] Received 18 August 2013; Revision received 14 December 2013; Accepted 15 December 2013 DOI: 10.1002/ajhb.22502 Published online 26 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
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TABLE 1. Health outcomes associated with ELS in HBSC as well as
factors influencing the outcomes Mental Health Socioeconomic background Gender Age at separation Depressive symptoms Duration of separation Cognitive function Duration of separation Physical and psychosocial functioning Socioeconomic background Gender Cardiovascular disease and type 2 diabetes Age at separation Duration of separation Blood pressure Duration of separation Gender Reproductive traits Gender
assigned an individual identification number. Documentation showed that 1,781 of the 13,345 subjects (13.4%) had been evacuated, hence having experienced temporary separation from both parents. This number is in reality a little higher because some children were evacuated through friends and family, which resulted in there not being official documentation. The separated subjects were between 0.2 and 10.6 years of age, with a mean age of 4.6 years (SD 2.4 years) at the time of separation. The duration of separation ranged between 0.05 and 8.1 years with the mean being 1.7 years (SD 1.6 years). In 2001–2004, 2003 randomly selected men and women from the original epidemiological study cohort participated in clinical substudies. Of these, 14.8% had been evacuated during WWII. The HBCS has been described in detail elsewhere (Barker et al., 2005; Eriksson, 2001; R€ aikk€ onen et al., 2011). Mental health This section focuses on the risk of mental health disorders contributing to or causing hospitalization during adult life. In general, men compared with women had a higher risk of any mental and substance use disorder, but the difference between the sexes was not significant. A higher risk was also seen among those with a lower childhood socioeconomic background. Sex and childhood socioeconomic background did not have an impact on the prevalence of mood, anxiety, psychotic, and personality disorders. When compared with the nonseparated, the separated individuals had a significantly higher risk of any mental health disorder, substance use disorders, and personality disorders (all P 0.05). However, this difference was only observed among men. Among those with a higher childhood socioeconomic background, the risk of any mental health (HR 2.12, 95% CI 1.41–3.20) or substance use disorder (HR 2.57, 95% CI 1.49–4.45) was higher in the separated group. In general, those individuals with a lower childhood socioeconomic background had a greater risk of mental health and substance use disorders regardless of being separated or not. Temporary separation in childhood is a risk factor for developing any severe mental health, substance use, and personality disorders. Interestingly, children from upper socioeconomic backgrounds seemed to react more strongly to ELS (R€ aikk€onen et al., 2011). American Journal of Human Biology
We have also examined whether any personality disorder and dramatic personality disorders are associated with ELS. Dramatic personality disorders include antisocial, borderline, narcissistic, and histrionic personality disorders. Children who had been separated had a 1.5fold risk of having any serious personality disorder in combination with any mental health disorder (P < 0.05). This was more prevalent among women. Men that had been separated had a greater risk of having dramatic personality disorders. These findings suggest that parental separation might have different effects on females and males. Length of separation did not affect the risk for any personality or dramatic personality disorders. Children separated after the age of 5 years had the same risk for any or dramatic personality disorders as the nonseparated individuals. This speaks to the fact that children who experienced separation at an age when attachment continuity is vital for development are more vulnerable to the long-term effects of separation than others (Lahti et al., 2012). Depressive symptoms In a longitudinal clinical study setting, we have been focusing upon whether separation in childhood is a risk factor for depressive symptoms later in life. The evacuated group suffered from 20% more severe depressive symptoms (95% CI 8.7–33.1). Among the separated and nonseparated 17.7% and 10.8%, respectively, had at least mild depressive symptoms. The separated group had a 1.7 times greater risk (95% CI 1.1–2.6, P 5 0.02) of the depressive symptoms remaining at least mild over time. When a group of children that were separated but stayed in Finland was focused upon, it was evident that location of separation did not matter. Both those separated abroad and those separated within the country had higher rates of depressive symptoms than the nonseparated. Duration of separation had a large effect on depressive symptoms. Those separated for the longest and for the shortest time had more severe depressive symptoms. The group separated for the longest period had an odds ratio of 4.4 (95% CI 1.8–10.8, P < 0.001) for depressive symptoms remaining at least mild over time. Children separated at school age, in toddlerhood or in infancy, also displayed more severe symptoms (Pesonen et al., 2007). Cognitive function Cognitive function or intellectual ability was assessed based on scores from the Finnish Defense Forces Basic Ability Test, which is administered to all new recruits in the military around the age of 20 years. Those who had been separated as children scored lower on verbal, visuospatial, and arithmetic ability as well as on the composite score of intellectual ability (all P 0.03). Even though the scores were lower for the separated ones, they were within one standard deviation from the scores of the nonseparated. This study showed that there is a threshold for length of separation and change in intellectual ability. Significantly lower scores on verbal, visuospatial, and composite ability were associated with a separation between 1 and 2 years in duration (P 0.05). Separations longer than this showed significant effects in lowering verbal, arithmetic, and composite scores. Children separated for less than a year scored similar to the nonseparated ones. The age
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when a child’s intellectual development is most vulnerable is after infancy but before school age. Separation during infancy, toddlerhood, or early childhood was associated with lower verbal ability. The largest effect on cognitive function was observed in those separated during toddlerhood. Separation during toddlerhood was also associated with lower visuospatial, arithmetic, and composite abilities. School-aged evacuees, on the other hand, were not affected. ELS affected verbal abilities the most, but longer duration of ELS was associated with worse intellectual abilities in general (Pesonen et al., 2011). Another study within HBCS focused upon intellectual ability and cognitive decline in men and was based upon the same tests as described above. The men were asked to repeat the test at the age of 70 years. It was analyzed whether or not the effects on intellectual ability caused by ELS persisted to old age and if differences in age-related changes could be observed. The ones separated in childhood scored lower on all tests, as described previously. The separated and nonseparated men had similar agerelated changes in the scores. One difference between the two groups was observed. A longer duration of separation was associated with a greater change in arithmetic ability. Those separated for a short time in fact increased their arithmetic ability, whereas those separated for over 2 years had a decline in arithmetic ability in comparison with the nonseparated group. ELS did not cause greater cognitive decline, but its effects seemed to persist into old age. This was the first study to show a connection between permanent cognitive impairment and ELS (Pesonen et al., 2013). Physical and psychosocial functioning Another clinical study focused upon the role of ELS on physical and psychosocial functioning later in life. The assessments were done using the SF-36 scale. In general, the ones that had been separated had lower socioeconomic status both in childhood as well as in adulthood when compared with the nonseparated group. The separated men scored significantly lower than the nonseparated men in physical functioning (all P < 0.03) and other general health subscales. Men had a greater risk of lowered physical functioning later in adulthood. For women, there was no difference between the separated and nonseparated groups. Separation in school age was associated with the highest risk for decreased physical functioning in men. Separation durations of over 2 years also correlated with lowered physical and psychosocial functioning in men. Individuals separated during childhood were at a significantly increased risk of impaired physical functioning and chronic disease later in life. This finding was stronger among men (Alastalo et al., 2013b). Cardiovascular disease and type 2 diabetes As expected, cardiovascular morbidity and mortality were inversely associated with childhood socioeconomic status. Those separated were 1.29 times more likely (95% CI 1.04–1.59, P 5 0.02) to take medication for coronary heart disease (CHD) than the nonseparated. However, they were not more likely to be hospitalized due to cardiac events than the nonseparated. Overall morbidity and mortality due to CHD was increased in the separated group (10.9% vs. 7.5%, P 5 0.04). Those separated in early childhood had a significantly higher CHD morbidity.
Length of separation also seemed to play a role. Children separated for 1–2 years or over 3 years had an increased risk of CHD. These findings show that ELS may predispose to CHD later in life (Alastalo et al., 2012). Another clinical study showed that ELS increased the risk of CVD and type 2 diabetes later in life. Evacuees had an increased risk of CVD the OR being 2.0 (95% CI 1.4– 2.9, P < 0.001). The prevalence for type 2 diabetes was pointing in the same direction (OR 1.4, 95% CI 1.1–1.9, P 5 0.025). Duration of evacuation showed a positive correlation with CVD prevalence. There were no significant differences between the groups in traditional cardiovascular risk factors like cholesterol and triglyceride concentrations. There was, however, significantly higher lipoprotein(a) levels among the separated individuals. We believe that this study was the first to evaluate the effects of separation on cardiovascular health and type 2 diabetes. The group of separated individuals was two times more likely to develop CVD when compared with the nonseparated group. This study presented evidence that ELS can have life-long effects on later cardiometabolic health (Alastalo et al., 2009). Blood pressure One clinical sub-study examined the long-term impacts of ELS on blood pressure in nonobese individuals. One main finding was that the systolic blood pressure of the separated individuals was significantly higher (148.6 vs. 142.2 mm Hg, P < 0.0001). This group also used hypertensive medication more frequently, but the difference was significant only for women. When compared with the nonseparated group, those separated in early childhood had both higher systolic and diastolic blood pressure. For women, this was not statistically significant. The highest systolic blood pressures were associated with separations of durations less than 1 year (151.7 vs. 142.2 mm Hg (nonseparated), P < 0.05). This finding was strongest for women. When focusing upon diastolic blood pressure, we found that the highest levels are among women separated for less than 1 year and for men separated for over 2 years. In other words, a strong connection between separation status and blood pressure levels in adulthood was observed. Both age and duration of ELS seem to influence later blood pressure levels (Alastalo et al., 2013a). Reproductive traits The long-term effects of ELS on reproductive and marital status, especially on menarche, menopause, duration of fertility, timing, and number of children have been studied in HBCS. Those separated in childhood reported less caring by their parents until the age of 16 years. Children born toward the end of the war formed the majority of the nonseparated group. These individuals had fewer children and became more educated. An earlier onset of menarche was reported among women who had been evacuated. The length or timing of the evacuation did not influence the onset. The separated women gave birth to a higher number of children. Especially those separated for 2–3 years or less than 1 year had a significantly higher number of children. Among men, the separated men had children earlier and with shorter intervals. When focusing upon marital traits, it was seen that the separated individuals had a 1.4-fold chance of not divorcing. Those American Journal of Human Biology
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separated in early childhood were most likely to remain married (Pesonen et al., 2008). DISCUSSION Based on animal work and human studies, we know that early life adversities can alter physiological responses and predispose the organism to various chronic diseases in adult life. Findings from HBCS confirm these findings and we have been able to show that ELS is increasing the risk of mental health disorders, cardiovascular disease, and type 2 diabetes in later life. Separated men had a higher risk for hospitalization due to any mental health, substance use, and personality disorders. Our findings are similar to findings of naturally occurring ELS in the Christmas Seal Home Study. The children studied here were separated at birth from their families due to tuberculosis within the family, and included all social classes in Finland during the 1930s. Children that had been separated from their families had a greater risk for depressive disorders (Veijola et al., 2004), criminal behavior (M€ aki et al., 2003), and hospital treated substance abuse (Veijola et al., 2008). Later risk for depression was also elevated within the HBCS. In general, there is a vast literature supporting the association between ELS and later mental health outcomes. A study of children surviving the Holocaust has shown that these children scored higher for posttraumatic stress disorders (PTSDs) symptoms and depression. Furthermore, anxiety, somatization, and anger-hostility scores were also higher. The scores reflecting quality of life, on the other hand, were lower (Amir and Lev-Wiesel, 2001, 2003). One Holocaust study of children and adolescent showed a connection between the survivors and greater risk of anxiety disorders, emotional distress, and sleep disturbances (Sharon et al., 2009). Another study focusing on elderly survivors showed a decline in accuracy of age-related memory (Yehuda et al., 2006). During the Second World War, children from the UK were sent to stay in safer places away from their families. This enabled the study of child-parent separation. One of these studies reported lower psychological well-being and insecure attachment styles (Foster et al., 2003) along with heightened risk of depression and anxiety (Rusby and Tasker, 2009). Other studies found no change in depression, anxiety, or mental health (Birtchnell and Kennard, 1984; Tennant et al., 1982). We have shown that ELS is also affecting cognitive function later in life. Similar findings have been reported from animal studies showing that ELS can permanently alter cognitive abilities. Also human studies based on the Dutch Hunger Winter Study support our findings. Associations between maternal malnutrition during pregnancy and negative effects on cognitive function of the child later in life have been reported (De Rooij et al., 2010). Famine during early gestation can also lead to lowered performance on selective attention tasks. One explanation for the lowered attention might be increased vascular damage (Roseboom et al., 2000; Van Abeelen et al., 2012). In humans, ELS has traditionally been linked to anxiety, depression, and other mental health outcomes in adult life. The Adverse Childhood Experiences Study showed that long-term effects including CHD, chronic lung disease, cancer, and liver disease in adulthood can result from psychological, physical, or sexual abuse as American Journal of Human Biology
well as a dysfunctional home setting (Dong et al., 2004; Felitti et al., 1998). Findings in HBCS support these results showing that ELS is associated with an increased risk of cardiovascular disease and type 2 diabetes as well as elevated cardiovascular risk factors. Similar findings have been reported in other studies (Van Abeelen et al., 2012). As shown, the effects of ELS have a wide range and the stressors can themselves also vary greatly. The underlying mechanisms explaining the long-term effects of ELS have been the topic of several studies, but no definite proof has been found. Several studies suggest that changes in the HPA-axis could explain the association between ELS and later health outcomes (Gallagher et al., 2009). Studies in rats have shown that those separated from their mothers during childhood exhibit a 2- to 3-fold greater stress response of the HPA axis as adults (Boyce and Ellis, 2005; Ellis et al., 2005; Gunnar and Quevedo, 2007; Gunnar et al., 2006; Levine, 2005; Luecken, 1998). Other studies have shown that the HPA functioning and the expression of glucocorticoid receptors in the hippocampus of humans are influenced by maternal care or lack there of (McGowan et al., 2009). ELS has also been linked to changes in the hippocampus due to epigenetic alterations of promoters (Labonte et al., 2012). We have shown that the HPA-axis seems to be reprogrammed due to ELS and this is still evident in later life. The separated individuals in HBCS have increased salivary cortisol and plasma ACTH concentrations compared with those who had not been separated. Separated women compared with nonseparated women had significantly higher baseline concentrations of plasma cortisol and ACTH along with decreased increments and AUC increments. Separated men had increased salivary cortisol, peaks in plasma ACTH along with AUC increments and increased salivary cortisol AUC in comparison with nonseparated men. Children separated between the ages of 2 and 7 years had higher peaks of salivary cortisol in response to a stress test than those who were younger or older at time of separation. We have also shown a correlation between ELS and a change in the HPA axis function, not caused by depressive symptoms. The reactivity of the HPA axis is higher 60 years after the stressor, indicating that the effects of ELS can last over the life course (Pesonen et al., 2010). One possible explanation for the correlation between health risks later in life and the changes in the HPA axis is that the reprogramming of the HPA axis and the changes in cortisol secretion might in fact be the cause of these later health issues, but our longitudinal study design does not allow us to draw conclusions on causality. Genetic factors could certainly modify the associations between ELS and later health. Especially, the FKBP5 gene has been focused upon in relation to PTSDs, depression, and anxiety. If carriers of the risk allele FKBP5 are exposed to early trauma they are at a significantly increased risk of lifetime PTSD. This association is believed to be due to epigenetic changes and carriers of the risk allele who have suffered from ELS show a large decrease in DNA methylation. The demethylation affects the sensitivity of the glucocorticoid receptors, indicating a receptor resistance in the trauma-exposed allele carriers. They also exhibit morphological changes in the brain. This is one of the potential epigenetic mechanisms explaining the effects of ELS on later health. If these
EARLY LIFE STRESS AND LATER HEALTH OUTCOMES
epigenetic changes take place during critical periods of development, they will remain stable over the course of life. Enhanced responsiveness of the FKBP5 allele can lead to Neural circuit alterations such as changes in the hippocampus and changes in the immune system, which in turn can lead to psychiatric, immune, and metabolic disorders in adults when combined with childhood ELS exposure (Klengel et al., 2013). In summary, we have evidence supporting the theory that severe ELS is a risk factor for a variety of health related factors later in life. ELS is capable of causing changes that alter the normal physiological responses and thereby increase later disease risk. We have been able to show that it is most likely mediated by reprogramming of the HPA-axis. LITERATURE CITED Afifi TO, Boman J, Fleisher W, Sareen J. 2009. The relationship between child abuse, parental divorce, and lifetime mental disorders and suicidality in a nationally representative adult sample. Child Abuse Neglect 33:139–147. Afifi TO, Brownridge DA, Cox BJ, Sareen J. 2006. Physical punishment, childhood abuse and psychiatric disorders. Child Abuse Neglect 30: 1093–1103. Alastalo H, R€ aikk€onen K, Pesonen A-K, Osmond C, Barker DJP, Heinonen K, Kajantie E, Eriksson JG. 2012. Cardiovascular morbidity and mortality in Finnish men and women separated temporarily from their parents in childhood–a life course study. Psychosom Med 74:583–587. Alastalo H, R€ aikk€onen K, Pesonen A-K, Osmond C, Barker DJP, Heinonen K, Kajantie E, Eriksson JG. 2013a. Early life stress and blood pressure levels in late adulthood. J Hum Hypertens 27:90–94. Alastalo H, Raikkonen K, Pesonen A-K, Osmond C, Barker DJP, Kajantie E, Heinonen K, Forsen TJ, Eriksson JG. 2009. Cardiovascular health of Finnish war evacuees 60 years later. Ann Med 41:66–72. Alastalo H, von Bonsdorff MB, R€ aikk€ onen K, Pesonen A-K, Osmond C, Barker DJP, Heinonen K, Kajantie E, Eriksson JG. 2013b. Early life stress and physical and psychosocial functioning in late adulthood. PLoS One 8:e69011. Amir M, Lev-Wiesel R. 2001. Does everyone have a name? Psychological distress and quality of life among child holocaust survivors with lost identity. J Trauma Stress 14:859–869. Amir M, Lev-Wiesel R. 2003. Time does not heal all wounds: quality of life and psychological distress of people who survived the holocaust as children 55 years later. J Trauma Stress 16:295–299. Barker DJP, Osmond C, Fors en TJ, Kajantie E, Eriksson JG. 2005. Trajectories of growth among children who have coronary events as adults. N Engl J Med 353:1802–1809. Belsky J. 2008. War, trauma and children’s development: observations from a modern evolutionary perspective. Int J Behav Dev 32:260–271. Birtchnell J, Kennard J. 1984. How do the experiences of the early separated and the early bereaved differ and to what extent do such differences affect outcome? Soc Psychiatry 19:163–171. Boyce WT, Ellis BJ. 2005. Biological sensitivity to context: I. An evolutionary-developmental theory of the origins and functions of stress reactivity. Dev Psychopathol 17:271–301. Breier A, Kelsoe JR Jr, Kirwin PD, Beller SA, Wolkowitz OM, Pickar D. 1988. Early parental loss and development of adult psychopathology. Arch Gen Psychiatry 45:987–993. Bremner JD. 1999. Does stress damage the brain? Biol Psychiatry 45: 797–805. Bremner JD, Randall P, Scott TM, Capelli S, Delaney R, McCarthy G, Charney DS. 1995. Deficits in short-term memory in adult survivors of childhood abuse. Psychiatry Res 59:97–107. Byrne CP, Velamoor VR, Cernovsky ZZ, Cortese L, Losztyn S. 1990. A comparison of borderline and schizophrenic patients for childhood life events and parent-child relationships. Can J Psychiatry Rev Can Psychiatr 35: 590–595. Charnov EL. 1993. Life history invariants: some explorations of symmetry in evolutionary ecology, Oxford series in ecology and evolution. Oxford [England]: Oxford University Press. Danese A, Moffitt TE, Harrington H, Milne BJ, Polanczyk G, Pariante CM, Poulton R, Caspi A. 2009. Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. Arch Pediatr Adolesc Med 163:1135– 1143.
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follow-up of the Finnish Christmas Seal Home Children. Schizophr Res 60:13–19. M€ akikyr€o T, Sauvola A, Moring J, Veijola J, Nieminen P, J€ arvelin MR, Isohanni M. 1998. Hospital-treated psychiatric disorders in adults with a single-parent and two-parent family background: a 28-year follow-up of the 1966 Northern Finland Birth Cohort. Fam Process 37:335–344. McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labont e B, Szyf M, Turecki G, Meaney MJ. 2009. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12:342–348. Morgan C, Kirkbride J, Leff J, Craig T, Hutchinson G, McKenzie K, Morgan K, Dazzan P, Doody GA, Jones P, Murray R, Fearon P. 2007. Parental separation, loss and psychosis in different ethnic groups: a case-control study. Psychol Med 37:495–503. O’Rand AM, Hamil-Luker J. 2005. Processes of cumulative adversity: childhood disadvantage and increased risk of heart attack across the life course. J Gerontol B Psychol Sci Soc Sci 60 Spec No 2:117–124. Pert L, Ferriter M, Saul C. 2004. Parental loss before the age of 16 years: a comparative study of patients with personality disorder and patients with schizophrenia in a high secure hospital’s population. Psychol Psychother 77:403–407. Pesonen A-K, R€ aikk€onen K, Heinonen K, Kajantie E, Fors en T, Eriksson JG. 2007. Depressive symptoms in adults separated from their parents as children: a natural experiment during World War II. Am J Epidemiol 166:1126–1133. Pesonen A-K, R€ aikk€onen K, Heinonen K, Kajantie E, Fors en T, Eriksson JG. 2008. Reproductive traits following a parent-child separation trauma during childhood: a natural experiment during World War II. Am J Hum Biol 20:345–351. Pesonen A-K, R€ aikk€onen K, Feldt K, Heinonen K, Osmond C, Phillips DIW, Barker DJP, Eriksson JG, Kajantie E. 2010. Childhood separation experience predicts HPA axis hormonal responses in late adulthood: a natural experiment of World War II. Psychoneuroendocrinology 35:758– 767. Pesonen A-K, R€ aikk€onen K, Kajantie E, Heinonen K, Henriksson M, Leskinen J, Osmond C, Fors en T, Barker DJP, Eriksson JG. 2011. Intellectual ability in young men separated temporarily from their parents in childhood. Intelligence 39:335–341. Pesonen A-K, Eriksson JG, Heinonen K, Kajantie E, Tuovinen S, Alastalo H, Henriksson M, Leskinen J, Osmond C, Barker DJP, R€ aikk€ onen K. 2013. Cognitive ability and decline after early life stress exposure. Neurobiol Aging 34:1674–1679. R€ aikk€onen K, Lahti M, Heinonen K, Pesonen A-K, Wahlbeck K, Kajantie E, Osmond C, Barker DJP, Eriksson JG. 2011. Risk of severe mental disorders in adults separated temporarily from their parents in childhood: the Helsinki birth cohort study. J Psychiatr Res 45:332–338. Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Schroeder-Tanka JM, van Montfrans GA, Michels RP, Bleker OP. 2000.
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Coronary heart disease after prenatal exposure to the Dutch famine, 1944-45. Heart 84:595–598. Rubino IA, Nanni RC, Pozzi DM, Siracusano A. 2009. Early adverse experiences in schizophrenia and unipolar depression. J Nerv Ment Dis 197: 65–68. Rusby JSM, Tasker F. 2009. Long-term effects of the British evacuation of children during World War 2 on their adult mental health. Aging Ment Health 13:391–404. Sharon A, Levav I, Brodsky J, Shemesh AA, Kohn R. 2009. Psychiatric disorders and other health dimensions among Holocaust survivors 6 decades later. Br J Psychiatry J Ment Sci 195:331–335. Sumanen M, Koskenvuo M, Sillanm€ aki L, Mattila K. 2005. Childhood adversities experienced by working-aged coronary heart disease patients. J Psychosom Res 59:331–335. Tennant C, Hurry J, Bebbington P. 1982. The relation of childhood separation experiences to adult depressive and anxiety states. Br J Psychiatry J Ment Sci 141:475–482. Thompson RG Jr, Lizardi D, Keyes KM, Hasin DS. 2008. Childhood or adolescent parental divorce/separation, parental history of alcohol problems, and offspring lifetime alcohol dependence. Drug Alcohol Depend 98:264–269. Tieman W, van der Ende J, Verhulst FC. 2005. Psychiatric disorders in young adult intercountry adoptees: an epidemiological study. Am J Psychiatry 162:592–598. Van Abeelen AFM, Elias SG, Bossuyt PMM, Grobbee DE, van der Schouw YT, Roseboom TJ, Uiterwaal CSPM. 2012. Cardiovascular consequences of famine in the young. Eur Heart J 33:538–545. €r€ Veijola J, L€ aa a E, Joukamaa M, Isohanni M, Hakko H, Haapea M, aki P. 2008. Temporary parental separation at birth and Pirkola S, M€ substance use disorder in adulthood. A long-term follow-up of the Finnish Christmas Seal Home Children. Soc Psychiatry Psychiatr Epidemiol 43:11–17. €r€ Veijola J, M€ aki P, Joukamaa M, L€ aa a E, Hakko H, Isohanni M. 2004. Parental separation at birth and depression in adulthood: a long-term follow-up of the Finnish Christmas Seal Home Children. Psychol Med 34:357–362. Widom CS. 1999. Posttraumatic stress disorder in abused and neglected children grown up. Am J Psychiatry 156:1223–1229. Widom CS, Czaja SJ, Paris J. 2009. A prospective investigation of borderline personality disorder in abused and neglected children followed up into adulthood. J Pers Disord 23:433–446. Widom CS, DuMont K, Czaja SJ. 2007. A prospective investigation of major depressive disorder and comorbidity in abused and neglected children grown up. Arch Gen Psychiatry 64:49–56. Yehuda R, Tischler L, Golier JA, Grossman R, Brand SR, Kaufman S, Harvey PD. 2006. Longitudinal assessment of cognitive performance in Holocaust survivors with and without PTSD. Biol Psychiatry 60: 714–721.
Review
Early Life Stress and Later Health Outcomes—Findings from the Helsinki Birth Cohort Study 1 2,4,5,6 € € MIA ERIKSSON,1,2,3 KATRI RAIKK ONEN, AND JOHAN G. ERIKSSON * 1 Department of Psychology, Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland 2 Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland 3 Texas Christian University, Forth Worth, Texas 4 Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland 5 Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland 6 Folkh€ alsan Research Center, Helsinki, Finland
Objectives: Severe early life stress (ELS) is a well-known risk factor for mental health disorders later in life. Not only mental health disorders are affected by ELS but early life stressors can also induce physical and biological changes increasing the risk for several noncommunicable diseases including type 2 diabetes and cardiovascular disease. Methods: This review focuses on the cohesive studies of individuals from the Helsinki Birth Cohort Study born 1934–1944 who were sent abroad from Finland during World War II as “war children.” Results: The review encompasses both epidemiological and clinical studies ranging from mental health disorders to type 2 diabetes and cardiovascular disease as well as potential underlying mechanisms explaining the association between ELS and later health. Conclusions: ELS is capable of causing changes that alter the normal physiological responses and thereby increase C 2013 Wiley Periodicals, Inc. V later disease risk, including cardiometabolic disorders. Am. J. Hum. Biol. 26:111–116, 2014. It is a commonly accepted theory that severe early life stress (ELS) is a risk factor for mental health disorders later in life. Abuse, neglect, and separation from either one or both parents during childhood have been shown to be associated with a greater risk of mental health disorders (Afifi et al., 2006, 2009; Danese et al., 2009; Green et al., 2010; Hjern et al., 2002; Johnson et al., 1999, 2006; M€ akikyr€o et al., 1998; Morgan et al., 2007; Pesonen et al., 2007; Rubino et al., 2009; Rusby and Tasker, 2009; Sharon et al., 2009; Thompson et al., 2008; Tieman et al., 2005; Veijola et al., 2004, 2008; Widom, 1999; Widom et al., 2007, 2009). Also parental separation during childhood has been shown to have detrimental psychological long-term consequences (Birtchnell and Kennard, 1984; Breier et al., 1988; Foster et al., 2003; Kendler et al., 1992, 2002; Pesonen et al., 2007; Tennant et al., 1982). ELS in the form of parental separation during childhood has been linked to higher prevalence of personality disorders (Byrne et al., 1990; Gibbon et al., 2009; Kantoj€ arvi et al., 2008; M€ akikyr€o et al., 1998; Pert et al., 2004; R€ aikk€onen et al., 2011). A few studies suggest that an uncertain childhood environment could cause individuals to reproduce at a younger age in order to ensure the existence of offspring (Belsky, 2008; Charnov, 1993; Draper and Harpending, 1982). Not only mental health is effected by ELS; these early stressors can also induce physical and biological changes. An association between abuse in childhood and both structural and functional hippocampal changes (Bremner, 1999) along with short-term memory deterioration in adulthood (Bremner et al., 1995) has been described. Evidence suggests that even an increased risk of cardiovascular disease can stem from ELS (Dong et al., 2004; Korkeila et al., 2010; O’Rand and Hamil-Luker, 2005; Sumanen et al., 2005). This review focuses on the cohesive studies of individuals from the Helsinki Birth Cohort Study (HBCS) that were sent abroad from Finland during World War II, as “war children” and after the war returned home. ELS is focused upon from the perspective of temporary separaC 2013 Wiley Periodicals, Inc. V
tion from parents during childhood. The review encompasses both epidemiological and clinical studies ranging from mental health disorders to reproduction, type 2 diabetes and cardiovascular disease as well as potential underlying mechanisms explaining the association between ELS and later health (Table 1). WAR EVACUATIONS AND HELSINKI BIRTH COHORT STUDY Finland fought two separate wars with the Soviet Union during World War II: the Winter War and the Continuation War. Children were evacuated to Sweden and Denmark in order to escape the dangers of war. These children were sent away unaccompanied by their parents, but the evacuations were completely voluntary (Kaven, 1985; Pesonen et al., 2007). The evacuations were organized by the government, but very little is known about the children’s living conditions while abroad. All together around 70,000 Finnish children were evacuated (Alastalo et al., 2012). The Finnish National Archives have full records of age of children at separation and length of separation (Pesonen et al., 2007, 2010). The epidemiological part of HBCS includes 6,370 women and 6,975 men born at Helsinki University Central Hospital or the Maternity Hospital in Helsinki between the years of 1934 and 1944. In order to be included in the study cohort the individuals had to have attended child welfare clinics in Helsinki besides being born at one of these hospitals, and they had to be alive and living in Finland in 1971 when all residents were
*Correspondence to: Johan G. Eriksson, Department of General Practice and Primary Health Care, University of Helsinki, PO Box 20, 00014 University of Helsinki, Finland. E-mail: [email protected] Received 18 August 2013; Revision received 14 December 2013; Accepted 15 December 2013 DOI: 10.1002/ajhb.22502 Published online 26 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
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TABLE 1. Health outcomes associated with ELS in HBSC as well as
factors influencing the outcomes Mental Health Socioeconomic background Gender Age at separation Depressive symptoms Duration of separation Cognitive function Duration of separation Physical and psychosocial functioning Socioeconomic background Gender Cardiovascular disease and type 2 diabetes Age at separation Duration of separation Blood pressure Duration of separation Gender Reproductive traits Gender
assigned an individual identification number. Documentation showed that 1,781 of the 13,345 subjects (13.4%) had been evacuated, hence having experienced temporary separation from both parents. This number is in reality a little higher because some children were evacuated through friends and family, which resulted in there not being official documentation. The separated subjects were between 0.2 and 10.6 years of age, with a mean age of 4.6 years (SD 2.4 years) at the time of separation. The duration of separation ranged between 0.05 and 8.1 years with the mean being 1.7 years (SD 1.6 years). In 2001–2004, 2003 randomly selected men and women from the original epidemiological study cohort participated in clinical substudies. Of these, 14.8% had been evacuated during WWII. The HBCS has been described in detail elsewhere (Barker et al., 2005; Eriksson, 2001; R€ aikk€ onen et al., 2011). Mental health This section focuses on the risk of mental health disorders contributing to or causing hospitalization during adult life. In general, men compared with women had a higher risk of any mental and substance use disorder, but the difference between the sexes was not significant. A higher risk was also seen among those with a lower childhood socioeconomic background. Sex and childhood socioeconomic background did not have an impact on the prevalence of mood, anxiety, psychotic, and personality disorders. When compared with the nonseparated, the separated individuals had a significantly higher risk of any mental health disorder, substance use disorders, and personality disorders (all P 0.05). However, this difference was only observed among men. Among those with a higher childhood socioeconomic background, the risk of any mental health (HR 2.12, 95% CI 1.41–3.20) or substance use disorder (HR 2.57, 95% CI 1.49–4.45) was higher in the separated group. In general, those individuals with a lower childhood socioeconomic background had a greater risk of mental health and substance use disorders regardless of being separated or not. Temporary separation in childhood is a risk factor for developing any severe mental health, substance use, and personality disorders. Interestingly, children from upper socioeconomic backgrounds seemed to react more strongly to ELS (R€ aikk€onen et al., 2011). American Journal of Human Biology
We have also examined whether any personality disorder and dramatic personality disorders are associated with ELS. Dramatic personality disorders include antisocial, borderline, narcissistic, and histrionic personality disorders. Children who had been separated had a 1.5fold risk of having any serious personality disorder in combination with any mental health disorder (P < 0.05). This was more prevalent among women. Men that had been separated had a greater risk of having dramatic personality disorders. These findings suggest that parental separation might have different effects on females and males. Length of separation did not affect the risk for any personality or dramatic personality disorders. Children separated after the age of 5 years had the same risk for any or dramatic personality disorders as the nonseparated individuals. This speaks to the fact that children who experienced separation at an age when attachment continuity is vital for development are more vulnerable to the long-term effects of separation than others (Lahti et al., 2012). Depressive symptoms In a longitudinal clinical study setting, we have been focusing upon whether separation in childhood is a risk factor for depressive symptoms later in life. The evacuated group suffered from 20% more severe depressive symptoms (95% CI 8.7–33.1). Among the separated and nonseparated 17.7% and 10.8%, respectively, had at least mild depressive symptoms. The separated group had a 1.7 times greater risk (95% CI 1.1–2.6, P 5 0.02) of the depressive symptoms remaining at least mild over time. When a group of children that were separated but stayed in Finland was focused upon, it was evident that location of separation did not matter. Both those separated abroad and those separated within the country had higher rates of depressive symptoms than the nonseparated. Duration of separation had a large effect on depressive symptoms. Those separated for the longest and for the shortest time had more severe depressive symptoms. The group separated for the longest period had an odds ratio of 4.4 (95% CI 1.8–10.8, P < 0.001) for depressive symptoms remaining at least mild over time. Children separated at school age, in toddlerhood or in infancy, also displayed more severe symptoms (Pesonen et al., 2007). Cognitive function Cognitive function or intellectual ability was assessed based on scores from the Finnish Defense Forces Basic Ability Test, which is administered to all new recruits in the military around the age of 20 years. Those who had been separated as children scored lower on verbal, visuospatial, and arithmetic ability as well as on the composite score of intellectual ability (all P 0.03). Even though the scores were lower for the separated ones, they were within one standard deviation from the scores of the nonseparated. This study showed that there is a threshold for length of separation and change in intellectual ability. Significantly lower scores on verbal, visuospatial, and composite ability were associated with a separation between 1 and 2 years in duration (P 0.05). Separations longer than this showed significant effects in lowering verbal, arithmetic, and composite scores. Children separated for less than a year scored similar to the nonseparated ones. The age
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when a child’s intellectual development is most vulnerable is after infancy but before school age. Separation during infancy, toddlerhood, or early childhood was associated with lower verbal ability. The largest effect on cognitive function was observed in those separated during toddlerhood. Separation during toddlerhood was also associated with lower visuospatial, arithmetic, and composite abilities. School-aged evacuees, on the other hand, were not affected. ELS affected verbal abilities the most, but longer duration of ELS was associated with worse intellectual abilities in general (Pesonen et al., 2011). Another study within HBCS focused upon intellectual ability and cognitive decline in men and was based upon the same tests as described above. The men were asked to repeat the test at the age of 70 years. It was analyzed whether or not the effects on intellectual ability caused by ELS persisted to old age and if differences in age-related changes could be observed. The ones separated in childhood scored lower on all tests, as described previously. The separated and nonseparated men had similar agerelated changes in the scores. One difference between the two groups was observed. A longer duration of separation was associated with a greater change in arithmetic ability. Those separated for a short time in fact increased their arithmetic ability, whereas those separated for over 2 years had a decline in arithmetic ability in comparison with the nonseparated group. ELS did not cause greater cognitive decline, but its effects seemed to persist into old age. This was the first study to show a connection between permanent cognitive impairment and ELS (Pesonen et al., 2013). Physical and psychosocial functioning Another clinical study focused upon the role of ELS on physical and psychosocial functioning later in life. The assessments were done using the SF-36 scale. In general, the ones that had been separated had lower socioeconomic status both in childhood as well as in adulthood when compared with the nonseparated group. The separated men scored significantly lower than the nonseparated men in physical functioning (all P < 0.03) and other general health subscales. Men had a greater risk of lowered physical functioning later in adulthood. For women, there was no difference between the separated and nonseparated groups. Separation in school age was associated with the highest risk for decreased physical functioning in men. Separation durations of over 2 years also correlated with lowered physical and psychosocial functioning in men. Individuals separated during childhood were at a significantly increased risk of impaired physical functioning and chronic disease later in life. This finding was stronger among men (Alastalo et al., 2013b). Cardiovascular disease and type 2 diabetes As expected, cardiovascular morbidity and mortality were inversely associated with childhood socioeconomic status. Those separated were 1.29 times more likely (95% CI 1.04–1.59, P 5 0.02) to take medication for coronary heart disease (CHD) than the nonseparated. However, they were not more likely to be hospitalized due to cardiac events than the nonseparated. Overall morbidity and mortality due to CHD was increased in the separated group (10.9% vs. 7.5%, P 5 0.04). Those separated in early childhood had a significantly higher CHD morbidity.
Length of separation also seemed to play a role. Children separated for 1–2 years or over 3 years had an increased risk of CHD. These findings show that ELS may predispose to CHD later in life (Alastalo et al., 2012). Another clinical study showed that ELS increased the risk of CVD and type 2 diabetes later in life. Evacuees had an increased risk of CVD the OR being 2.0 (95% CI 1.4– 2.9, P < 0.001). The prevalence for type 2 diabetes was pointing in the same direction (OR 1.4, 95% CI 1.1–1.9, P 5 0.025). Duration of evacuation showed a positive correlation with CVD prevalence. There were no significant differences between the groups in traditional cardiovascular risk factors like cholesterol and triglyceride concentrations. There was, however, significantly higher lipoprotein(a) levels among the separated individuals. We believe that this study was the first to evaluate the effects of separation on cardiovascular health and type 2 diabetes. The group of separated individuals was two times more likely to develop CVD when compared with the nonseparated group. This study presented evidence that ELS can have life-long effects on later cardiometabolic health (Alastalo et al., 2009). Blood pressure One clinical sub-study examined the long-term impacts of ELS on blood pressure in nonobese individuals. One main finding was that the systolic blood pressure of the separated individuals was significantly higher (148.6 vs. 142.2 mm Hg, P < 0.0001). This group also used hypertensive medication more frequently, but the difference was significant only for women. When compared with the nonseparated group, those separated in early childhood had both higher systolic and diastolic blood pressure. For women, this was not statistically significant. The highest systolic blood pressures were associated with separations of durations less than 1 year (151.7 vs. 142.2 mm Hg (nonseparated), P < 0.05). This finding was strongest for women. When focusing upon diastolic blood pressure, we found that the highest levels are among women separated for less than 1 year and for men separated for over 2 years. In other words, a strong connection between separation status and blood pressure levels in adulthood was observed. Both age and duration of ELS seem to influence later blood pressure levels (Alastalo et al., 2013a). Reproductive traits The long-term effects of ELS on reproductive and marital status, especially on menarche, menopause, duration of fertility, timing, and number of children have been studied in HBCS. Those separated in childhood reported less caring by their parents until the age of 16 years. Children born toward the end of the war formed the majority of the nonseparated group. These individuals had fewer children and became more educated. An earlier onset of menarche was reported among women who had been evacuated. The length or timing of the evacuation did not influence the onset. The separated women gave birth to a higher number of children. Especially those separated for 2–3 years or less than 1 year had a significantly higher number of children. Among men, the separated men had children earlier and with shorter intervals. When focusing upon marital traits, it was seen that the separated individuals had a 1.4-fold chance of not divorcing. Those American Journal of Human Biology
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separated in early childhood were most likely to remain married (Pesonen et al., 2008). DISCUSSION Based on animal work and human studies, we know that early life adversities can alter physiological responses and predispose the organism to various chronic diseases in adult life. Findings from HBCS confirm these findings and we have been able to show that ELS is increasing the risk of mental health disorders, cardiovascular disease, and type 2 diabetes in later life. Separated men had a higher risk for hospitalization due to any mental health, substance use, and personality disorders. Our findings are similar to findings of naturally occurring ELS in the Christmas Seal Home Study. The children studied here were separated at birth from their families due to tuberculosis within the family, and included all social classes in Finland during the 1930s. Children that had been separated from their families had a greater risk for depressive disorders (Veijola et al., 2004), criminal behavior (M€ aki et al., 2003), and hospital treated substance abuse (Veijola et al., 2008). Later risk for depression was also elevated within the HBCS. In general, there is a vast literature supporting the association between ELS and later mental health outcomes. A study of children surviving the Holocaust has shown that these children scored higher for posttraumatic stress disorders (PTSDs) symptoms and depression. Furthermore, anxiety, somatization, and anger-hostility scores were also higher. The scores reflecting quality of life, on the other hand, were lower (Amir and Lev-Wiesel, 2001, 2003). One Holocaust study of children and adolescent showed a connection between the survivors and greater risk of anxiety disorders, emotional distress, and sleep disturbances (Sharon et al., 2009). Another study focusing on elderly survivors showed a decline in accuracy of age-related memory (Yehuda et al., 2006). During the Second World War, children from the UK were sent to stay in safer places away from their families. This enabled the study of child-parent separation. One of these studies reported lower psychological well-being and insecure attachment styles (Foster et al., 2003) along with heightened risk of depression and anxiety (Rusby and Tasker, 2009). Other studies found no change in depression, anxiety, or mental health (Birtchnell and Kennard, 1984; Tennant et al., 1982). We have shown that ELS is also affecting cognitive function later in life. Similar findings have been reported from animal studies showing that ELS can permanently alter cognitive abilities. Also human studies based on the Dutch Hunger Winter Study support our findings. Associations between maternal malnutrition during pregnancy and negative effects on cognitive function of the child later in life have been reported (De Rooij et al., 2010). Famine during early gestation can also lead to lowered performance on selective attention tasks. One explanation for the lowered attention might be increased vascular damage (Roseboom et al., 2000; Van Abeelen et al., 2012). In humans, ELS has traditionally been linked to anxiety, depression, and other mental health outcomes in adult life. The Adverse Childhood Experiences Study showed that long-term effects including CHD, chronic lung disease, cancer, and liver disease in adulthood can result from psychological, physical, or sexual abuse as American Journal of Human Biology
well as a dysfunctional home setting (Dong et al., 2004; Felitti et al., 1998). Findings in HBCS support these results showing that ELS is associated with an increased risk of cardiovascular disease and type 2 diabetes as well as elevated cardiovascular risk factors. Similar findings have been reported in other studies (Van Abeelen et al., 2012). As shown, the effects of ELS have a wide range and the stressors can themselves also vary greatly. The underlying mechanisms explaining the long-term effects of ELS have been the topic of several studies, but no definite proof has been found. Several studies suggest that changes in the HPA-axis could explain the association between ELS and later health outcomes (Gallagher et al., 2009). Studies in rats have shown that those separated from their mothers during childhood exhibit a 2- to 3-fold greater stress response of the HPA axis as adults (Boyce and Ellis, 2005; Ellis et al., 2005; Gunnar and Quevedo, 2007; Gunnar et al., 2006; Levine, 2005; Luecken, 1998). Other studies have shown that the HPA functioning and the expression of glucocorticoid receptors in the hippocampus of humans are influenced by maternal care or lack there of (McGowan et al., 2009). ELS has also been linked to changes in the hippocampus due to epigenetic alterations of promoters (Labonte et al., 2012). We have shown that the HPA-axis seems to be reprogrammed due to ELS and this is still evident in later life. The separated individuals in HBCS have increased salivary cortisol and plasma ACTH concentrations compared with those who had not been separated. Separated women compared with nonseparated women had significantly higher baseline concentrations of plasma cortisol and ACTH along with decreased increments and AUC increments. Separated men had increased salivary cortisol, peaks in plasma ACTH along with AUC increments and increased salivary cortisol AUC in comparison with nonseparated men. Children separated between the ages of 2 and 7 years had higher peaks of salivary cortisol in response to a stress test than those who were younger or older at time of separation. We have also shown a correlation between ELS and a change in the HPA axis function, not caused by depressive symptoms. The reactivity of the HPA axis is higher 60 years after the stressor, indicating that the effects of ELS can last over the life course (Pesonen et al., 2010). One possible explanation for the correlation between health risks later in life and the changes in the HPA axis is that the reprogramming of the HPA axis and the changes in cortisol secretion might in fact be the cause of these later health issues, but our longitudinal study design does not allow us to draw conclusions on causality. Genetic factors could certainly modify the associations between ELS and later health. Especially, the FKBP5 gene has been focused upon in relation to PTSDs, depression, and anxiety. If carriers of the risk allele FKBP5 are exposed to early trauma they are at a significantly increased risk of lifetime PTSD. This association is believed to be due to epigenetic changes and carriers of the risk allele who have suffered from ELS show a large decrease in DNA methylation. The demethylation affects the sensitivity of the glucocorticoid receptors, indicating a receptor resistance in the trauma-exposed allele carriers. They also exhibit morphological changes in the brain. This is one of the potential epigenetic mechanisms explaining the effects of ELS on later health. If these
EARLY LIFE STRESS AND LATER HEALTH OUTCOMES
epigenetic changes take place during critical periods of development, they will remain stable over the course of life. Enhanced responsiveness of the FKBP5 allele can lead to Neural circuit alterations such as changes in the hippocampus and changes in the immune system, which in turn can lead to psychiatric, immune, and metabolic disorders in adults when combined with childhood ELS exposure (Klengel et al., 2013). In summary, we have evidence supporting the theory that severe ELS is a risk factor for a variety of health related factors later in life. ELS is capable of causing changes that alter the normal physiological responses and thereby increase later disease risk. We have been able to show that it is most likely mediated by reprogramming of the HPA-axis. LITERATURE CITED Afifi TO, Boman J, Fleisher W, Sareen J. 2009. The relationship between child abuse, parental divorce, and lifetime mental disorders and suicidality in a nationally representative adult sample. Child Abuse Neglect 33:139–147. Afifi TO, Brownridge DA, Cox BJ, Sareen J. 2006. Physical punishment, childhood abuse and psychiatric disorders. Child Abuse Neglect 30: 1093–1103. Alastalo H, R€ aikk€onen K, Pesonen A-K, Osmond C, Barker DJP, Heinonen K, Kajantie E, Eriksson JG. 2012. Cardiovascular morbidity and mortality in Finnish men and women separated temporarily from their parents in childhood–a life course study. Psychosom Med 74:583–587. Alastalo H, R€ aikk€onen K, Pesonen A-K, Osmond C, Barker DJP, Heinonen K, Kajantie E, Eriksson JG. 2013a. Early life stress and blood pressure levels in late adulthood. J Hum Hypertens 27:90–94. Alastalo H, Raikkonen K, Pesonen A-K, Osmond C, Barker DJP, Kajantie E, Heinonen K, Forsen TJ, Eriksson JG. 2009. Cardiovascular health of Finnish war evacuees 60 years later. Ann Med 41:66–72. Alastalo H, von Bonsdorff MB, R€ aikk€ onen K, Pesonen A-K, Osmond C, Barker DJP, Heinonen K, Kajantie E, Eriksson JG. 2013b. Early life stress and physical and psychosocial functioning in late adulthood. PLoS One 8:e69011. Amir M, Lev-Wiesel R. 2001. Does everyone have a name? Psychological distress and quality of life among child holocaust survivors with lost identity. J Trauma Stress 14:859–869. Amir M, Lev-Wiesel R. 2003. Time does not heal all wounds: quality of life and psychological distress of people who survived the holocaust as children 55 years later. J Trauma Stress 16:295–299. Barker DJP, Osmond C, Fors en TJ, Kajantie E, Eriksson JG. 2005. Trajectories of growth among children who have coronary events as adults. N Engl J Med 353:1802–1809. Belsky J. 2008. War, trauma and children’s development: observations from a modern evolutionary perspective. Int J Behav Dev 32:260–271. Birtchnell J, Kennard J. 1984. How do the experiences of the early separated and the early bereaved differ and to what extent do such differences affect outcome? Soc Psychiatry 19:163–171. Boyce WT, Ellis BJ. 2005. Biological sensitivity to context: I. An evolutionary-developmental theory of the origins and functions of stress reactivity. Dev Psychopathol 17:271–301. Breier A, Kelsoe JR Jr, Kirwin PD, Beller SA, Wolkowitz OM, Pickar D. 1988. Early parental loss and development of adult psychopathology. Arch Gen Psychiatry 45:987–993. Bremner JD. 1999. Does stress damage the brain? Biol Psychiatry 45: 797–805. Bremner JD, Randall P, Scott TM, Capelli S, Delaney R, McCarthy G, Charney DS. 1995. Deficits in short-term memory in adult survivors of childhood abuse. Psychiatry Res 59:97–107. Byrne CP, Velamoor VR, Cernovsky ZZ, Cortese L, Losztyn S. 1990. A comparison of borderline and schizophrenic patients for childhood life events and parent-child relationships. Can J Psychiatry Rev Can Psychiatr 35: 590–595. Charnov EL. 1993. Life history invariants: some explorations of symmetry in evolutionary ecology, Oxford series in ecology and evolution. Oxford [England]: Oxford University Press. Danese A, Moffitt TE, Harrington H, Milne BJ, Polanczyk G, Pariante CM, Poulton R, Caspi A. 2009. Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. Arch Pediatr Adolesc Med 163:1135– 1143.
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