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Multiple sclerosis
RESEARCH PAPER
Major stressful life events in adulthood and risk of multiple sclerosis Nete Munk Nielsen,1 Peter Bager,1 Jacob Simonsen,1 Anders Hviid,1 Egon Stenager,2,3,4,5 Henrik Brønnum-Hansen,6 Nils Koch-Henriksen,2,7 Morten Frisch1 1
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark 2 The Danish Multiple Sclerosis Registry, Rigshospitalet, Copenhagen, Denmark 3 Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark 4 Multiple Sclerosis Clinic of Southern Jutland (Sønderborg, Vejle, Esbjerg), Department of Neurology, Sønderborg, Denmark 5 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark 6 Faculty of Health Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark 7 Department of Clinical Epidemiology, Clinical Institute, University of Aarhus, Aarhus, Denmark Correspondence to Dr Nete Munk Nielsen, Department of Epidemiology, Statens Serum Institut, Artillerivej 5, Copenhagen S 2300, Denmark; [email protected] Received 6 November 2013 Revised 9 January 2014 Accepted 4 February 2014 Published Online First 7 March 2014
To cite: Nielsen NM, Bager P, Simonsen J, et al. J Neurol Neurosurg Psychiatry 2014;85: 1103–1108.
ABSTRACT Objective It is unclear whether psychological stress is associated with increased risk of multiple sclerosis (MS). We studied the association between major stressful life events and MS in a nationwide cohort study using death of a child or a spouse or marital dissolution as indicators of severe stress. Methods We created two study cohorts based on all Danish men and women born 1950–1992. One cohort consisted of all persons who became parents between 1968 and 2010, and another cohort consisted of all persons who married between 1968 and 2010. Members of both cohorts were followed for MS between 1982 and 2010 using data from the National Multiple Sclerosis Registry. Associations between major stressful life events and risk of MS were evaluated by means of MS incidence rate ratios (RR) with 95% confidence interval (CI) obtained in Poisson regression analyses. Results During approximately 30 million person-years of follow-up, bereaved parents experienced no unusual risk of MS compared with parents who did not lose a child (RR=1.12 (95% CI 0.89 to 1.38)). Likewise, neither divorced (RR=0.98 (95% CI 0.89 to 1.06)) nor widowed (RR=0.98 (95% CI 0.71 to 1.32) persons were at any unusual risk of MS compared with married persons of the same sex. Conclusions Our national cohort study provides little evidence for a causal association between major stressful life events (as exemplified by divorce or the loss of a child or a spouse) and subsequent MS risk.
INTRODUCTION Multiple sclerosis (MS) is a chronic, often disabling, autoimmune disease of the central nervous system (CNS) that affects approximately 2.5 million people worldwide.1 The possible role of psychological stress in the aetiology and progression of MS has been debated for decades. It has been suggested that major stressful life events may somehow cause damage to the CNS or provoke dysfunction of the immune system, which could lead to the development of MS2–4 Also, it has been hypothesised that stress may induce a disruption of the blood–brain barrier, resulting in T cell entry into the CNS and development of MS.5 A large number of studies have reported a stressrelated aggravation of symptoms and disease activity in individuals with established MS.6–9 However, only a few studies have examined the possible association between stress and risk of developing MS,
Nielsen NM, et al. J Neurol Neurosurg Psychiatry 2014;85:1103–1108. doi:10.1136/jnnp-2013-307181
and results are conflicting. Two small case–control studies showed no significant difference in number of negative emotional events (ie, domestic quarrels)10 or stressful life events (ie, divorce or suicide of partner)11 among MS cases and controls groups. An analysis based on the Nurses’ Health study reported no association between exposure to physical or sexual abuse and subsequent risk of MS12 However, other case–control studies have reported significantly more severe life events (eg, marital conflicts) in MS patients compared with healthy controls13–15 or a greater prevalence of family problems and use of social support14 prior to onset of MS. Finally, a Danish study observed 28 cases of MS among 21 062 bereaved parents16 compared with 230 MS cases in a matched cohort of 293 745 parents who had not lost a child, corresponding to a 1.5-fold increased risk of MS among bereaved parents (HR=1.56 (1.05 to 2.31)). The interpretation and comparisons of the previous studies are however difficult due to heterogeneity in the usage of stress indicators and control groups (healthy or hospitalised neurological patients) and particularly potential recall and selection biases. Interviewers in many of the case–control studies appeared not to be blinded,10 11 13 14 age and gender distribution of cases and control differed,11 the recall period of interest prior to diagnosis of MS/index date was of different length for cases and controls and finally memory impairment for cases as well as for certain control groups (patients with organic diseases of the nervous system) may have influenced previous findings. Further epidemiological studies using reliable data on stressful life events, potential confounders and MS outcomes and well-described methodologies are therefore needed. In the present study, we analysed the risk of MS following exposure to well-defined indicators of severe stress induced by own divorce or loss of a close family member using nationwide register data on bereavement, divorce, socioeconomic confounders and MS.
MATERIALS AND METHODS Exposures Information on death of a child less than 18 years of age, divorce and loss of a spouse was obtained from the nationwide Danish Civil Registration System (CRS). 1103
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Multiple sclerosis The CRS was established on 1st of April 1968 and has since assigned all Danes a 10-digit unique personal identification number, which enables identity-secure linkages between registers.17 Apart from continuously updated information on addresses, marital status and vital status for all Danish residents alive or born after the 1st of April 1968, the CRS contains complete parental links for all Danish-born children, born since 1968.17 Operationally, therefore, we restricted the study cohort to persons born in Denmark between 1950 and 1992 and identified all those who married or who had their first Danish live born child in or after 1968. By restricting the cohorts to persons born 1950–1992, we will have close to complete information about all live born children and the possible loss of a live born child, marriage, divorce and widowhood in the study period ending 2010.
MS outcomes MS cases in the study cohort were identified in the Danish Multiple Sclerosis Registry (DMSR), which was established in 1956, in continuation of a nationwide MS prevalence study carried out a few years earlier.18 All cases have been reclassified by neurologists at the DMSR according to the criteria of Allison and Millar for those with onset before 1994 and according to the criteria of Poser et al for those with onset after 1993. Since 2005 MacDonald’s criteria have been used. In this study, we included all cases fulfilling the diagnostic criteria including possible MS (when other diseases are ruled out), but not cases of clinically isolated syndrome (CIS) or poorly documented cases. Appearance of first symptoms of MS and date of diagnosis of MS are only recorded by calendar year. Consequently, in all analyses we defined the date of first symptoms and the date of diagnosis as the first of 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 day before death or emigration.
Statistical analyses Analyses were carried out as two separate cohort studies: the first study addressed the association between MS and loss of a child; the second study addressed the association between MS and divorce/widowhood. In the first analysis, only persons born in Denmark 1950–1992, who had given birth to a live born child in Denmark, were included, thus constituting the cohort of parents. The cohort members contributed person-years at risk from birth of their first live born child or the 1st of January 1982 (information concerning education and income is not available from Statistic Denmark before 1981 and 1980, respectively), whichever came later until MS diagnosis, date of death, emigration, or the 31st of December 2010, whichever came first. Persons diagnosed with MS before loss of a child were censored at the date of MS diagnosis. Family type,19 parental socioeconomic factors,19 20 urbanisation21 and reproductive factors such as age at first child birth and number of children22 have previously been found to be associated with child death. Although the relationship between the above factors and MS23–25 is less certain, we decided to adjust for age at first child birth (2000), marital status (unmarried, married, widowed, divorced) and number of children (1, 2, 3, 4+), information obtained from CRS and income level (expressed as percentage of the average personal income for persons of the same sex and birth year:
Multiple sclerosis
RESEARCH PAPER
Major stressful life events in adulthood and risk of multiple sclerosis Nete Munk Nielsen,1 Peter Bager,1 Jacob Simonsen,1 Anders Hviid,1 Egon Stenager,2,3,4,5 Henrik Brønnum-Hansen,6 Nils Koch-Henriksen,2,7 Morten Frisch1 1
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark 2 The Danish Multiple Sclerosis Registry, Rigshospitalet, Copenhagen, Denmark 3 Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark 4 Multiple Sclerosis Clinic of Southern Jutland (Sønderborg, Vejle, Esbjerg), Department of Neurology, Sønderborg, Denmark 5 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark 6 Faculty of Health Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark 7 Department of Clinical Epidemiology, Clinical Institute, University of Aarhus, Aarhus, Denmark Correspondence to Dr Nete Munk Nielsen, Department of Epidemiology, Statens Serum Institut, Artillerivej 5, Copenhagen S 2300, Denmark; [email protected] Received 6 November 2013 Revised 9 January 2014 Accepted 4 February 2014 Published Online First 7 March 2014
To cite: Nielsen NM, Bager P, Simonsen J, et al. J Neurol Neurosurg Psychiatry 2014;85: 1103–1108.
ABSTRACT Objective It is unclear whether psychological stress is associated with increased risk of multiple sclerosis (MS). We studied the association between major stressful life events and MS in a nationwide cohort study using death of a child or a spouse or marital dissolution as indicators of severe stress. Methods We created two study cohorts based on all Danish men and women born 1950–1992. One cohort consisted of all persons who became parents between 1968 and 2010, and another cohort consisted of all persons who married between 1968 and 2010. Members of both cohorts were followed for MS between 1982 and 2010 using data from the National Multiple Sclerosis Registry. Associations between major stressful life events and risk of MS were evaluated by means of MS incidence rate ratios (RR) with 95% confidence interval (CI) obtained in Poisson regression analyses. Results During approximately 30 million person-years of follow-up, bereaved parents experienced no unusual risk of MS compared with parents who did not lose a child (RR=1.12 (95% CI 0.89 to 1.38)). Likewise, neither divorced (RR=0.98 (95% CI 0.89 to 1.06)) nor widowed (RR=0.98 (95% CI 0.71 to 1.32) persons were at any unusual risk of MS compared with married persons of the same sex. Conclusions Our national cohort study provides little evidence for a causal association between major stressful life events (as exemplified by divorce or the loss of a child or a spouse) and subsequent MS risk.
INTRODUCTION Multiple sclerosis (MS) is a chronic, often disabling, autoimmune disease of the central nervous system (CNS) that affects approximately 2.5 million people worldwide.1 The possible role of psychological stress in the aetiology and progression of MS has been debated for decades. It has been suggested that major stressful life events may somehow cause damage to the CNS or provoke dysfunction of the immune system, which could lead to the development of MS2–4 Also, it has been hypothesised that stress may induce a disruption of the blood–brain barrier, resulting in T cell entry into the CNS and development of MS.5 A large number of studies have reported a stressrelated aggravation of symptoms and disease activity in individuals with established MS.6–9 However, only a few studies have examined the possible association between stress and risk of developing MS,
Nielsen NM, et al. J Neurol Neurosurg Psychiatry 2014;85:1103–1108. doi:10.1136/jnnp-2013-307181
and results are conflicting. Two small case–control studies showed no significant difference in number of negative emotional events (ie, domestic quarrels)10 or stressful life events (ie, divorce or suicide of partner)11 among MS cases and controls groups. An analysis based on the Nurses’ Health study reported no association between exposure to physical or sexual abuse and subsequent risk of MS12 However, other case–control studies have reported significantly more severe life events (eg, marital conflicts) in MS patients compared with healthy controls13–15 or a greater prevalence of family problems and use of social support14 prior to onset of MS. Finally, a Danish study observed 28 cases of MS among 21 062 bereaved parents16 compared with 230 MS cases in a matched cohort of 293 745 parents who had not lost a child, corresponding to a 1.5-fold increased risk of MS among bereaved parents (HR=1.56 (1.05 to 2.31)). The interpretation and comparisons of the previous studies are however difficult due to heterogeneity in the usage of stress indicators and control groups (healthy or hospitalised neurological patients) and particularly potential recall and selection biases. Interviewers in many of the case–control studies appeared not to be blinded,10 11 13 14 age and gender distribution of cases and control differed,11 the recall period of interest prior to diagnosis of MS/index date was of different length for cases and controls and finally memory impairment for cases as well as for certain control groups (patients with organic diseases of the nervous system) may have influenced previous findings. Further epidemiological studies using reliable data on stressful life events, potential confounders and MS outcomes and well-described methodologies are therefore needed. In the present study, we analysed the risk of MS following exposure to well-defined indicators of severe stress induced by own divorce or loss of a close family member using nationwide register data on bereavement, divorce, socioeconomic confounders and MS.
MATERIALS AND METHODS Exposures Information on death of a child less than 18 years of age, divorce and loss of a spouse was obtained from the nationwide Danish Civil Registration System (CRS). 1103
Downloaded from jnnp.bmj.com on October 11, 2014 - Published by group.bmj.com
Multiple sclerosis The CRS was established on 1st of April 1968 and has since assigned all Danes a 10-digit unique personal identification number, which enables identity-secure linkages between registers.17 Apart from continuously updated information on addresses, marital status and vital status for all Danish residents alive or born after the 1st of April 1968, the CRS contains complete parental links for all Danish-born children, born since 1968.17 Operationally, therefore, we restricted the study cohort to persons born in Denmark between 1950 and 1992 and identified all those who married or who had their first Danish live born child in or after 1968. By restricting the cohorts to persons born 1950–1992, we will have close to complete information about all live born children and the possible loss of a live born child, marriage, divorce and widowhood in the study period ending 2010.
MS outcomes MS cases in the study cohort were identified in the Danish Multiple Sclerosis Registry (DMSR), which was established in 1956, in continuation of a nationwide MS prevalence study carried out a few years earlier.18 All cases have been reclassified by neurologists at the DMSR according to the criteria of Allison and Millar for those with onset before 1994 and according to the criteria of Poser et al for those with onset after 1993. Since 2005 MacDonald’s criteria have been used. In this study, we included all cases fulfilling the diagnostic criteria including possible MS (when other diseases are ruled out), but not cases of clinically isolated syndrome (CIS) or poorly documented cases. Appearance of first symptoms of MS and date of diagnosis of MS are only recorded by calendar year. Consequently, in all analyses we defined the date of first symptoms and the date of diagnosis as the first of 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 day before death or emigration.
Statistical analyses Analyses were carried out as two separate cohort studies: the first study addressed the association between MS and loss of a child; the second study addressed the association between MS and divorce/widowhood. In the first analysis, only persons born in Denmark 1950–1992, who had given birth to a live born child in Denmark, were included, thus constituting the cohort of parents. The cohort members contributed person-years at risk from birth of their first live born child or the 1st of January 1982 (information concerning education and income is not available from Statistic Denmark before 1981 and 1980, respectively), whichever came later until MS diagnosis, date of death, emigration, or the 31st of December 2010, whichever came first. Persons diagnosed with MS before loss of a child were censored at the date of MS diagnosis. Family type,19 parental socioeconomic factors,19 20 urbanisation21 and reproductive factors such as age at first child birth and number of children22 have previously been found to be associated with child death. Although the relationship between the above factors and MS23–25 is less certain, we decided to adjust for age at first child birth (2000), marital status (unmarried, married, widowed, divorced) and number of children (1, 2, 3, 4+), information obtained from CRS and income level (expressed as percentage of the average personal income for persons of the same sex and birth year:
