528761
research-article2014
MSJ0010.1177/1352458514528761Multiple Sclerosis JournalNM Nielsen, BV Pedersen
MULTIPLE SCLEROSIS MSJ JOURNAL
Research Paper
Stressful life-events in childhood and risk of multiple sclerosis: a Danish nationwide cohort study
Multiple Sclerosis Journal 2014, Vol. 20(12) 1609–1615 DOI: 10.1177/ 1352458514528761 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Nete Munk Nielsen, Bo V Pedersen, Egon Stenager, Nils Koch-Henriksen and Morten Frisch
Abstract Background: Current knowledge concerning the association between exposure to stressful life-events (SFLEs) in childhood and later risk of multiple sclerosis (MS) is sparse. Objectives: We studied the associations between SFLEs in childhood and subsequent risk of MS in a nationwide cohort of 2.9 million Danes born from 1968 to 2011. Methods: A SFLE in childhood was defined as exposure before age 18 years to parental divorce, parental death, or death of a sibling, using information from the Danish Civil Registration System. MS cases in the cohort were identified in the Danish Multiple Sclerosis Registry. Associations of SFLE with MS risk were evaluated by incidence rate ratios (RR) of MS obtained in log-linear Poisson regression models. Results: Persons exposed to any SFLE in childhood were at 11% elevated risk of MS (RR = 1.11; 95% confidence interval: 1.03–1.20), compared to non-exposed persons. Stratification by subtype of SFLE showed that parental death and death of a sibling were not associated with MS risk. However, persons exposed to parental divorce were at 13% increased risk of developing MS compared to non-exposed (RR = 1.13; 1.04–1.23). Conclusions: Associations of SFLEs in childhood with risk of MS are weak. However, parental divorce is somehow associated with modestly increased risk of MS.
Keywords: Multiple sclerosis, stressful life-events, childhood, epidemiology Date received: 7 November 2013; revised: 27 January 2014; accepted: 14 February 2014 Introduction Multiple sclerosis (MS) is the most frequent immune mediated disease of the central nervous system and the leading cause of non-traumatic disability in young adults in Western countries.1 The etiology of MS remains largely unknown, but genetic susceptibility in combination with exposure to different environmental factors is believed to play an important role.2 Exposure to stressful life-events (SFLEs) might be among such environmental factors. Several studies have linked exposure to SFLE to exacerbations of clinical symptoms in MS,3,4 and some have suggested that SFLEs may be etiologically involved in MS.5–7 Childhood maltreatment and other psychological trauma are considered to be among the most extreme forms of stress and may have long-lasting negative
consequences for both mental and physical health in adulthood.8 However, only few studies have addressed the possible association between SLFE in childhood and risk of MS. A recent case-control study based on 234 patients with MS and 885 controls from the general population found that persons who reported having been exposed to emotional or sexual abuse in childhood were at 2–3 times increased risk of MS.9 In contrast, a study nested in the Nurses’ Health Study showed no overall association between physical or sexual abuse in childhood and MS risk but noted an elevated, though not statistically significant, risk of MS in women with a history of repeated forced sexual activity in childhood.6 Both studies were, however, limited by the use of retrospectively collected data and self-reported information on childhood traumas, which render them susceptible to information bias. Further, only women
Correspondence to: Nete Munk Nielsen Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark. [email protected] Bo V Pedersen Department of Epidemiology Research, Statens Serum Institut, Denmark Egon Stenager The Danish MS Registry, the Danish MS Research Center, Rigshospitalet, Copenhagen/Institute of Regional Health Research/ Multiple Sclerosis Clinic of Southern Jutland (Sønderborg, Vejle, Esbjerg), Department of Neurology, Sønderborg, Denmark and National Institute of Public Health, University of Southern Denmark, Denmark Nils Koch-Henriksen The Danish MS Registry, the Danish MS Research Center, Rigshospitalet, Copenhagen, Denmark/ Clinical Institute, Department of Clinical Epidemiology, Aarhus University, Denmark Morten Frisch Department of Epidemiology Research, Statens Serum Institut, Denmark
http://msj.sagepub.com 1609
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Multiple Sclerosis Journal 20(12) were involved in the Nurses’ Health Study and, given the demanding nature of the nursing profession, traumatized individuals may deselect becoming a nurse, which may limit generalizability of findings in that study. We aimed to address the possible association of SFLE in childhood with subsequent risk of MS in a large, nationwide cohort using parental divorce and death of a close family member as objective measurements of severe stress. Material and methods The study cohort and exposure The Danish Civil Registration System (CRS) was established on 1 April 1968, and since then all Danish citizens have been assigned at 10-digit personal identification number. The CRS contains continuously updated information on place of birth, family relations, marital status, and vital status for every Danish resident. Restricting the study cohort to persons born between 1968 and 2011 with known parents,10 the CRS enables us to identify a divorce between their parents as well as the death of a parent or sibling before the person’s 18th birthday. Siblings were operationally defined as persons sharing the same mother. MS outcomes MS cases in the study cohort were identified in the nationwide Danish Multiple Sclerosis Registry (DMSR), which was established in 1956. All MS cases have been reclassified by neurologists at the DMSR, and we included in the present study all cases fulfilling the diagnostic criteria of Allison or Poser including possible MS (when other diseases are ruled out), and later the McDonald criteria and their updates, but not cases of clinically isolated syndrome (CIS) or poorly documented cases. In the DMSR first symptoms and diagnosis of MS are only recorded by calendar year. Consequently, in all the analyses we defined the date of first symptoms and the date of diagnosis as 1 July in the recorded year of first symptoms and diagnosis, respectively. If the MS patient died or emigrated in the same year he or she was diagnosed with MS, date of diagnosis was defined as the date in the middle of the period from 1 January of that year to the date of death or emigration.11 Statistical analyses The cohort members contributed person-years at risk from birth until date of MS diagnosis, death,
emigration, or 31 December 2011, whichever came first. Persons diagnosed with MS before parental divorce or before the loss of a parent or a sibling, were included in the study, but censored on the date of MS diagnosis, i.e. did no longer contribute person-years at risk. The statistical analysis of the resulting table of stratum-specific MS incidence rates was carried out as a log-linear Poisson regression analysis, yielding incidence rate ratios (RRs) of MS according to history of childhood SFLE with likelihood-based 95% confidence intervals (CI) and homogeneity tests. RRs were calculated for any SFLE and for each of the three different SFLEs (parental divorce, parental death, death of sibling). In the analyses defining exposure as parental divorce, death of a parent or death of a sibling, respectively, unexposed persons were defined as persons who had not experienced the SFLE in question before the age of 18 years. All estimates were adjusted for sex, age. and calendar. Adjustment for age and calendar period were performed using cubic splines restricted to be linear in the tails.12 Analysis strategy In the primary analyses we included all persons born between 1968 and 2011 with known parents. Subsequent robustness analyses examined the stability of associations observed in the primary analyses. Familial co-occurrence of MS is well-established and the risk of divorce appears to be elevated for couples affected by MS.13 Accordingly in the first robustness analysis we repeated the primary analysis concerning the impact of parental divorce on the risk of MS, censoring follow-up on the date of diagnosis of parental MS and restricted the study cohort to persons born in Denmark to Danish-born parents in order to obtain complete information on family relations, and parental divorce. Secondly, to address any possible influence from the delay between first symptoms and clinical MS diagnosis, we repeated the primary analyses and the first robustness analysis, this time using first symptoms of MS as the outcome measure. The DMSR is considered to be complete through 2008, whereas the Danish National Patient Register (DNPR), in which the diagnostic validity for MS compared against the DMSR is slightly lower (95%),14 is continuously updated. Accordingly, in a third robustness analysis we repeated the primary analysis and the first robustness analysis defining the cohort of MS patients according to the DNPR using the International Classification of Diseases (ICD), 8th revision code 340 from 1977 to 1993 and its 10th revision code G35 for the period 1994 to 2011.
1610 http://msj.sagepub.com
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NM Nielsen, BV Pedersen et al. To account for any possible confounding effect of socio-economic status,15 we carried out a fourth set of robustness analyses, in which we adjusted RRs for maternal and paternal educational level and income as well as for own education and income. Income level was expressed as percent of the average personal income for persons of the same sex and birth year (
research-article2014
MSJ0010.1177/1352458514528761Multiple Sclerosis JournalNM Nielsen, BV Pedersen
MULTIPLE SCLEROSIS MSJ JOURNAL
Research Paper
Stressful life-events in childhood and risk of multiple sclerosis: a Danish nationwide cohort study
Multiple Sclerosis Journal 2014, Vol. 20(12) 1609–1615 DOI: 10.1177/ 1352458514528761 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Nete Munk Nielsen, Bo V Pedersen, Egon Stenager, Nils Koch-Henriksen and Morten Frisch
Abstract Background: Current knowledge concerning the association between exposure to stressful life-events (SFLEs) in childhood and later risk of multiple sclerosis (MS) is sparse. Objectives: We studied the associations between SFLEs in childhood and subsequent risk of MS in a nationwide cohort of 2.9 million Danes born from 1968 to 2011. Methods: A SFLE in childhood was defined as exposure before age 18 years to parental divorce, parental death, or death of a sibling, using information from the Danish Civil Registration System. MS cases in the cohort were identified in the Danish Multiple Sclerosis Registry. Associations of SFLE with MS risk were evaluated by incidence rate ratios (RR) of MS obtained in log-linear Poisson regression models. Results: Persons exposed to any SFLE in childhood were at 11% elevated risk of MS (RR = 1.11; 95% confidence interval: 1.03–1.20), compared to non-exposed persons. Stratification by subtype of SFLE showed that parental death and death of a sibling were not associated with MS risk. However, persons exposed to parental divorce were at 13% increased risk of developing MS compared to non-exposed (RR = 1.13; 1.04–1.23). Conclusions: Associations of SFLEs in childhood with risk of MS are weak. However, parental divorce is somehow associated with modestly increased risk of MS.
Keywords: Multiple sclerosis, stressful life-events, childhood, epidemiology Date received: 7 November 2013; revised: 27 January 2014; accepted: 14 February 2014 Introduction Multiple sclerosis (MS) is the most frequent immune mediated disease of the central nervous system and the leading cause of non-traumatic disability in young adults in Western countries.1 The etiology of MS remains largely unknown, but genetic susceptibility in combination with exposure to different environmental factors is believed to play an important role.2 Exposure to stressful life-events (SFLEs) might be among such environmental factors. Several studies have linked exposure to SFLE to exacerbations of clinical symptoms in MS,3,4 and some have suggested that SFLEs may be etiologically involved in MS.5–7 Childhood maltreatment and other psychological trauma are considered to be among the most extreme forms of stress and may have long-lasting negative
consequences for both mental and physical health in adulthood.8 However, only few studies have addressed the possible association between SLFE in childhood and risk of MS. A recent case-control study based on 234 patients with MS and 885 controls from the general population found that persons who reported having been exposed to emotional or sexual abuse in childhood were at 2–3 times increased risk of MS.9 In contrast, a study nested in the Nurses’ Health Study showed no overall association between physical or sexual abuse in childhood and MS risk but noted an elevated, though not statistically significant, risk of MS in women with a history of repeated forced sexual activity in childhood.6 Both studies were, however, limited by the use of retrospectively collected data and self-reported information on childhood traumas, which render them susceptible to information bias. Further, only women
Correspondence to: Nete Munk Nielsen Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark. [email protected] Bo V Pedersen Department of Epidemiology Research, Statens Serum Institut, Denmark Egon Stenager The Danish MS Registry, the Danish MS Research Center, Rigshospitalet, Copenhagen/Institute of Regional Health Research/ Multiple Sclerosis Clinic of Southern Jutland (Sønderborg, Vejle, Esbjerg), Department of Neurology, Sønderborg, Denmark and National Institute of Public Health, University of Southern Denmark, Denmark Nils Koch-Henriksen The Danish MS Registry, the Danish MS Research Center, Rigshospitalet, Copenhagen, Denmark/ Clinical Institute, Department of Clinical Epidemiology, Aarhus University, Denmark Morten Frisch Department of Epidemiology Research, Statens Serum Institut, Denmark
http://msj.sagepub.com 1609
Downloaded from msj.sagepub.com at Gebze Yuksek Teknoloji Enstitu on December 25, 2014
Multiple Sclerosis Journal 20(12) were involved in the Nurses’ Health Study and, given the demanding nature of the nursing profession, traumatized individuals may deselect becoming a nurse, which may limit generalizability of findings in that study. We aimed to address the possible association of SFLE in childhood with subsequent risk of MS in a large, nationwide cohort using parental divorce and death of a close family member as objective measurements of severe stress. Material and methods The study cohort and exposure The Danish Civil Registration System (CRS) was established on 1 April 1968, and since then all Danish citizens have been assigned at 10-digit personal identification number. The CRS contains continuously updated information on place of birth, family relations, marital status, and vital status for every Danish resident. Restricting the study cohort to persons born between 1968 and 2011 with known parents,10 the CRS enables us to identify a divorce between their parents as well as the death of a parent or sibling before the person’s 18th birthday. Siblings were operationally defined as persons sharing the same mother. MS outcomes MS cases in the study cohort were identified in the nationwide Danish Multiple Sclerosis Registry (DMSR), which was established in 1956. All MS cases have been reclassified by neurologists at the DMSR, and we included in the present study all cases fulfilling the diagnostic criteria of Allison or Poser including possible MS (when other diseases are ruled out), and later the McDonald criteria and their updates, but not cases of clinically isolated syndrome (CIS) or poorly documented cases. In the DMSR first symptoms and diagnosis of MS are only recorded by calendar year. Consequently, in all the analyses we defined the date of first symptoms and the date of diagnosis as 1 July in the recorded year of first symptoms and diagnosis, respectively. If the MS patient died or emigrated in the same year he or she was diagnosed with MS, date of diagnosis was defined as the date in the middle of the period from 1 January of that year to the date of death or emigration.11 Statistical analyses The cohort members contributed person-years at risk from birth until date of MS diagnosis, death,
emigration, or 31 December 2011, whichever came first. Persons diagnosed with MS before parental divorce or before the loss of a parent or a sibling, were included in the study, but censored on the date of MS diagnosis, i.e. did no longer contribute person-years at risk. The statistical analysis of the resulting table of stratum-specific MS incidence rates was carried out as a log-linear Poisson regression analysis, yielding incidence rate ratios (RRs) of MS according to history of childhood SFLE with likelihood-based 95% confidence intervals (CI) and homogeneity tests. RRs were calculated for any SFLE and for each of the three different SFLEs (parental divorce, parental death, death of sibling). In the analyses defining exposure as parental divorce, death of a parent or death of a sibling, respectively, unexposed persons were defined as persons who had not experienced the SFLE in question before the age of 18 years. All estimates were adjusted for sex, age. and calendar. Adjustment for age and calendar period were performed using cubic splines restricted to be linear in the tails.12 Analysis strategy In the primary analyses we included all persons born between 1968 and 2011 with known parents. Subsequent robustness analyses examined the stability of associations observed in the primary analyses. Familial co-occurrence of MS is well-established and the risk of divorce appears to be elevated for couples affected by MS.13 Accordingly in the first robustness analysis we repeated the primary analysis concerning the impact of parental divorce on the risk of MS, censoring follow-up on the date of diagnosis of parental MS and restricted the study cohort to persons born in Denmark to Danish-born parents in order to obtain complete information on family relations, and parental divorce. Secondly, to address any possible influence from the delay between first symptoms and clinical MS diagnosis, we repeated the primary analyses and the first robustness analysis, this time using first symptoms of MS as the outcome measure. The DMSR is considered to be complete through 2008, whereas the Danish National Patient Register (DNPR), in which the diagnostic validity for MS compared against the DMSR is slightly lower (95%),14 is continuously updated. Accordingly, in a third robustness analysis we repeated the primary analysis and the first robustness analysis defining the cohort of MS patients according to the DNPR using the International Classification of Diseases (ICD), 8th revision code 340 from 1977 to 1993 and its 10th revision code G35 for the period 1994 to 2011.
1610 http://msj.sagepub.com
Downloaded from msj.sagepub.com at Gebze Yuksek Teknoloji Enstitu on December 25, 2014
NM Nielsen, BV Pedersen et al. To account for any possible confounding effect of socio-economic status,15 we carried out a fourth set of robustness analyses, in which we adjusted RRs for maternal and paternal educational level and income as well as for own education and income. Income level was expressed as percent of the average personal income for persons of the same sex and birth year (
