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Early life child exposure and the risk of multiple sclerosis: A population based study
Journal of the Neurological Sciences 307 (2011) 162–163
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Early life child exposure and the risk of multiple sclerosis: A population based study Sreeram V. Ramagopalan a,b, Colleen Guimond c, David A. Dyment a,b, Irene M. Yee c, George C. Ebers a,b, A. Dessa Sadovnick c,d,⁎ a
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK Department of Clinical Neurology, University of Oxford, Oxford, UK Department of Medical Genetics, University of British Columbia, Vancouver, Canada d Faculty of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada b c
a r t i c l e
i n f o
Article history: Received 25 January 2011 Received in revised form 6 April 2011 Accepted 20 April 2011 Available online 23 May 2011 Keywords: Multiple sclerosis Epidemiology Infections Infant exposure Hygiene
a b s t r a c t The precise aetiology of multiple sclerosis (MS) is yet to be conclusively determined, but both genes and environment and interactions thereof are important. It has been suggested that early life child exposure influences MS susceptibility. Here, in a population-based cohort, we investigated whether infant day care attendance influences the subsequent risk to develop MS. We identified 379 MS index cases and 101 spousal controls, all of whom were a single child (i.e. they had no biological sibs, half-sibs, step-sibs, adopted sibs) from the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). Frequency of infant day care attendance was compared for index cases and controls and the results were not statistically significant. Exposure to other infants during early childhood thus does not appear to be a risk factor for MS. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterised by myelin loss, varying degrees of axonal pathology, and progressive neurological dysfunction [1]. In developed countries, strong evidence of steady rises in incidence of allergic and some autoimmune diseases parallels a decreasing incidence of childhood infections [2]. Antibiotics, vaccination, and/or improved hygiene and better socioeconomic conditions have been credited [2]. This “hygiene hypothesis” proposes that early life infections down-regulate allergic and autoimmune disorders [2]. Support for this hypothesis comes from animal models. For example, the incidence of spontaneous autoimmune disease is directly correlated with the sanitary conditions of the animal facilities. For non-obese diabetic (NOD) mouse, it has been clearly shown that the lower the infectious burden (i.e. sanitary conditions), the higher the NOD incidence [2]. A protective role for early life infection in the development of MS is coherent with several features of MS. These include the recent increase in MS incidence coupled with a temporal decline in childhood infection rates [3], the relative rarity of MS in less developed countries compared
⁎ Corresponding author at: S-113, Koerner Pavilion, VCHA-UBC Hospital, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5. Tel.: + 1 604 827 3111; fax: + 1 604 822 7362. E-mail address: sadovnik@infinet.net (A.D. Sadovnick). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.04.014
to more developed ones [4] and the increase of MS upon migration from less developed to more developed geographic regions [5], even at ages past puberty [6]. The present study focused on “only child” families. Sibships with 2 or more children may increase the rate of exposure to early life infections. For example, siblings born late in a sibship birth order position are thought to be exposed to infection at an earlier age resulting in greater immune stimulation than those born early in a birth order [2]. The hypothesis was first proposed by Strachan, who observed an inverse correlation between hay fever and the number of older siblings when following more than 17,000 British children born in 1958 [7]. However, investigations of large numbers of families in Canada [8] and Denmark [9] were unable to find any skewing of birth order in MS patients, even controlling for sibship size. A recent study suggested that MS risk is not influenced by birth order but rather by the amount of exposure to other infants up to age 6 years [10]. The Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) has collected information, including data on childhood day care attendance, on a cohort of more than 30,000 families in which at least one member has MS. The same data were obtained on spouse controls. Children attending day care are known to have more frequent infections than those who remain at home [11]. This report attempts to identify whether infant contact through preschool day care attendance is associated with MS risk in a study of MS index cases and spousal controls who were only children and never cohabitated with siblings (full, adopted, half or step siblings).
S.V. Ramagopalan et al. / Journal of the Neurological Sciences 307 (2011) 162–163
2. Subjects and methods The CCPGSMS is a unique, longitudinal, population-based MS study and the methodology has been previously described [12,13]. Briefly, MS clinics across Canada used standardised, personally administered questionnaires to screen individuals with MS and to collect data about themselves, their families and spouses. Data were collected between 1997 and 2008. Specific to this study, with appropriate consent, preschool day care attendance information (for infants younger than age 5 years) was collected by telephone interview from mothers of both MS index cases and spouse controls (the term “spouse” is used generically to refer to legal spouse, common law partner, or same-sex partner). We analysed data on MS index cases and spouse controls who did not have any siblings (full, adopted, half or step siblings) to control for infant exposure at home.
There are limitations to this study. Maternal recall of day care attendance many years later may not be as accurate as data from school records, etc. We only had information on day care attendance, and not the frequency or length of time of attendance or the type of day care attended, which can vary in terms of the number of other children. We therefore may have missed relevant effects. Data were available for only 101 spousal controls which may be underpowered to detect effects, but the study was of comparable size to the Tasmanian investigation. Additionally, we did not observe any temporal differences in the likelihood of daycare attendance, but this is likely to change following implementation of new maternal leave legislation in 2001, and thus future studies may be warranted. In conclusion, our results do not lend support to the hypothesis that early life child exposure is associated with the risk of MS. Disclosure of sources of funding This work was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation.
2.1. Statistical analyses The chi squared test was used to assess significance when comparing frequency of day care attendance in index cases and controls. The effect of attending day care and sex on the risk of MS was assessed by logistic regression using the R statistical package.
Disclosure of conflicts of interest The authors declare no conflicts of interest. Acknowledgments
3. Results When limited for cases and controls with no siblings, complete information on infant day care attendance was available for 379 index cases and 101 spousal controls. The clinical and demographic details of the index cases and controls are shown in Table 1. The proportion of index cases and controls attending preschool day care was compared. Fifty-four (14.2%; females 14.2% and males 14.4%) index cases attended day care compared to 14 (13.9%; females 15.2% and males 13.2%) controls. This difference was not significant (p = 0.92). This was confirmed by logistic regression analysis, which showed an effect of sex on the risk of MS (p b 0.0001) but no effect of infant day care attendance (p = 0.88). 4. Discussion MS is believed to be an immunological disorder caused by both genetic and environmental factors [14]. In particular, several epidemiologic observations lend support to the hypothesis that MS could result from an aberrant immune response, possibly triggered by an infection [14]. In a case-control study of 136 MS patients in Tasmania, Australia, it was reported that MS risk was reduced with greater exposure to other children in the first 6 years of life [10]. Using day care attendance as a proxy measure for exposure to other children for infants who did not have siblings, we did not reproduce this result. We observed that MS patients and spousal controls were equally as likely to have attended day care as an infant. This is in line with epidemiological data from thousands of MS patients showing no skewing of birth order [8,9].
Table 1 Clinical and demographic details of MS index cases and controls.
n Mean age in years (SD) n (females) n (males) Sex ratio (f:m) % Relapsing–remitting MS
163
MS index cases
Spousal controls
379 51.8 (10.7) 268 111 2.4:1 84.5
101 54.2 (12.2) 33 68 0.5:1 /
SD = standard deviation, (f:m) = female to male sex ratio.
The authors would like to thank all patients who generously participated in this study and physicians participating in the CCPGSMS: Vancouver, BC (A Traboulsee, V Devonshire, S A Hashimoto, J Hooge, L Kastrukoff, JJF Oger); Calgary, AB (L Metz); Edmonton, AB (S Warren); Saskatoon, SK (W Hader, K Knox); Winnipeg (R.A. Marrie), London, ON (M Kremenchutzky); Ottawa, ON (M Freedman); Kingston, ON (D Brunet); Toronto, ON (P O'Connor, T Gray, M Hohol); Montreal, QC (P Duquette, Y Lapierre); Halifax, NS (TJ Murray, V Bhan, C Maxner); and St John's, NL (M Stefanelli). References [1] Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000 Sep 28;343(13):938–52. [2] Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002 Sep 19;347(12):911–20. [3] Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006 Nov;5(11):932–6. [4] Koch-Henriksen N, Sorensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010 May;9(5):520–32. [5] Dean G, Elian M. Age at immigration to England of Asian and Caribbean immigrants and the risk of developing multiple sclerosis. J Neurol Neurosurg Psychiatry 1997 Nov;63(5):565–8. [6] Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain 2000 May;123(Pt 5):968–74. [7] Strachan DP. Hay fever, hygiene, and household size. BMJ 1989 Nov 18;299(6710): 1259–60. [8] Sadovnick AD, Yee IM, Ebers GC. Multiple sclerosis and birth order: a longitudinal cohort study. Lancet Neurol 2005 Oct;4(10):611–7. [9] Bager P, Nielsen NM, Bihrmann K, Frisch M, Wohlfart J, Koch-Henriksen N, et al. Sibship characteristics and risk of multiple sclerosis: a nationwide cohort study in Denmark. Am J Epidemiol 2006 Jun 15;163(12):1112–7. [10] Ponsonby AL, van der Mei I, Dwyer T, Blizzard L, Taylor B, Kemp A, et al. Exposure to infant siblings during early life and risk of multiple sclerosis. JAMA 2005 Jan 26;293(4):463–9. [11] Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, Wright AL. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000 Aug 24;343(8):538–43. [12] Sadovnick AD, Risch NJ, Ebers GC. Canadian collaborative project on genetic susceptibility to MS, phase 2: rationale and method Canadian Collaborative Study Group. Can J Neurol Sci 1998 Aug;25(3):216–21. [13] Ramagopalan SV, Dyment DA, Valdar W, Herrera BM, Criscuoli M, Yee IM, et al. Autoimmune disease in families with multiple sclerosis: a population-based study. Lancet Neurol 2007 Jul;6(7):604–10. [14] Handel AE, Giovannoni G, Ebers GC, Ramagopalan SV. Environmental factors and their timing in adult-onset multiple sclerosis. Nat Rev Neurol 2010 Mar;6(3): 156–66.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Early life child exposure and the risk of multiple sclerosis: A population based study Sreeram V. Ramagopalan a,b, Colleen Guimond c, David A. Dyment a,b, Irene M. Yee c, George C. Ebers a,b, A. Dessa Sadovnick c,d,⁎ a
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK Department of Clinical Neurology, University of Oxford, Oxford, UK Department of Medical Genetics, University of British Columbia, Vancouver, Canada d Faculty of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada b c
a r t i c l e
i n f o
Article history: Received 25 January 2011 Received in revised form 6 April 2011 Accepted 20 April 2011 Available online 23 May 2011 Keywords: Multiple sclerosis Epidemiology Infections Infant exposure Hygiene
a b s t r a c t The precise aetiology of multiple sclerosis (MS) is yet to be conclusively determined, but both genes and environment and interactions thereof are important. It has been suggested that early life child exposure influences MS susceptibility. Here, in a population-based cohort, we investigated whether infant day care attendance influences the subsequent risk to develop MS. We identified 379 MS index cases and 101 spousal controls, all of whom were a single child (i.e. they had no biological sibs, half-sibs, step-sibs, adopted sibs) from the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). Frequency of infant day care attendance was compared for index cases and controls and the results were not statistically significant. Exposure to other infants during early childhood thus does not appear to be a risk factor for MS. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterised by myelin loss, varying degrees of axonal pathology, and progressive neurological dysfunction [1]. In developed countries, strong evidence of steady rises in incidence of allergic and some autoimmune diseases parallels a decreasing incidence of childhood infections [2]. Antibiotics, vaccination, and/or improved hygiene and better socioeconomic conditions have been credited [2]. This “hygiene hypothesis” proposes that early life infections down-regulate allergic and autoimmune disorders [2]. Support for this hypothesis comes from animal models. For example, the incidence of spontaneous autoimmune disease is directly correlated with the sanitary conditions of the animal facilities. For non-obese diabetic (NOD) mouse, it has been clearly shown that the lower the infectious burden (i.e. sanitary conditions), the higher the NOD incidence [2]. A protective role for early life infection in the development of MS is coherent with several features of MS. These include the recent increase in MS incidence coupled with a temporal decline in childhood infection rates [3], the relative rarity of MS in less developed countries compared
⁎ Corresponding author at: S-113, Koerner Pavilion, VCHA-UBC Hospital, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5. Tel.: + 1 604 827 3111; fax: + 1 604 822 7362. E-mail address: sadovnik@infinet.net (A.D. Sadovnick). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.04.014
to more developed ones [4] and the increase of MS upon migration from less developed to more developed geographic regions [5], even at ages past puberty [6]. The present study focused on “only child” families. Sibships with 2 or more children may increase the rate of exposure to early life infections. For example, siblings born late in a sibship birth order position are thought to be exposed to infection at an earlier age resulting in greater immune stimulation than those born early in a birth order [2]. The hypothesis was first proposed by Strachan, who observed an inverse correlation between hay fever and the number of older siblings when following more than 17,000 British children born in 1958 [7]. However, investigations of large numbers of families in Canada [8] and Denmark [9] were unable to find any skewing of birth order in MS patients, even controlling for sibship size. A recent study suggested that MS risk is not influenced by birth order but rather by the amount of exposure to other infants up to age 6 years [10]. The Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) has collected information, including data on childhood day care attendance, on a cohort of more than 30,000 families in which at least one member has MS. The same data were obtained on spouse controls. Children attending day care are known to have more frequent infections than those who remain at home [11]. This report attempts to identify whether infant contact through preschool day care attendance is associated with MS risk in a study of MS index cases and spousal controls who were only children and never cohabitated with siblings (full, adopted, half or step siblings).
S.V. Ramagopalan et al. / Journal of the Neurological Sciences 307 (2011) 162–163
2. Subjects and methods The CCPGSMS is a unique, longitudinal, population-based MS study and the methodology has been previously described [12,13]. Briefly, MS clinics across Canada used standardised, personally administered questionnaires to screen individuals with MS and to collect data about themselves, their families and spouses. Data were collected between 1997 and 2008. Specific to this study, with appropriate consent, preschool day care attendance information (for infants younger than age 5 years) was collected by telephone interview from mothers of both MS index cases and spouse controls (the term “spouse” is used generically to refer to legal spouse, common law partner, or same-sex partner). We analysed data on MS index cases and spouse controls who did not have any siblings (full, adopted, half or step siblings) to control for infant exposure at home.
There are limitations to this study. Maternal recall of day care attendance many years later may not be as accurate as data from school records, etc. We only had information on day care attendance, and not the frequency or length of time of attendance or the type of day care attended, which can vary in terms of the number of other children. We therefore may have missed relevant effects. Data were available for only 101 spousal controls which may be underpowered to detect effects, but the study was of comparable size to the Tasmanian investigation. Additionally, we did not observe any temporal differences in the likelihood of daycare attendance, but this is likely to change following implementation of new maternal leave legislation in 2001, and thus future studies may be warranted. In conclusion, our results do not lend support to the hypothesis that early life child exposure is associated with the risk of MS. Disclosure of sources of funding This work was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation.
2.1. Statistical analyses The chi squared test was used to assess significance when comparing frequency of day care attendance in index cases and controls. The effect of attending day care and sex on the risk of MS was assessed by logistic regression using the R statistical package.
Disclosure of conflicts of interest The authors declare no conflicts of interest. Acknowledgments
3. Results When limited for cases and controls with no siblings, complete information on infant day care attendance was available for 379 index cases and 101 spousal controls. The clinical and demographic details of the index cases and controls are shown in Table 1. The proportion of index cases and controls attending preschool day care was compared. Fifty-four (14.2%; females 14.2% and males 14.4%) index cases attended day care compared to 14 (13.9%; females 15.2% and males 13.2%) controls. This difference was not significant (p = 0.92). This was confirmed by logistic regression analysis, which showed an effect of sex on the risk of MS (p b 0.0001) but no effect of infant day care attendance (p = 0.88). 4. Discussion MS is believed to be an immunological disorder caused by both genetic and environmental factors [14]. In particular, several epidemiologic observations lend support to the hypothesis that MS could result from an aberrant immune response, possibly triggered by an infection [14]. In a case-control study of 136 MS patients in Tasmania, Australia, it was reported that MS risk was reduced with greater exposure to other children in the first 6 years of life [10]. Using day care attendance as a proxy measure for exposure to other children for infants who did not have siblings, we did not reproduce this result. We observed that MS patients and spousal controls were equally as likely to have attended day care as an infant. This is in line with epidemiological data from thousands of MS patients showing no skewing of birth order [8,9].
Table 1 Clinical and demographic details of MS index cases and controls.
n Mean age in years (SD) n (females) n (males) Sex ratio (f:m) % Relapsing–remitting MS
163
MS index cases
Spousal controls
379 51.8 (10.7) 268 111 2.4:1 84.5
101 54.2 (12.2) 33 68 0.5:1 /
SD = standard deviation, (f:m) = female to male sex ratio.
The authors would like to thank all patients who generously participated in this study and physicians participating in the CCPGSMS: Vancouver, BC (A Traboulsee, V Devonshire, S A Hashimoto, J Hooge, L Kastrukoff, JJF Oger); Calgary, AB (L Metz); Edmonton, AB (S Warren); Saskatoon, SK (W Hader, K Knox); Winnipeg (R.A. Marrie), London, ON (M Kremenchutzky); Ottawa, ON (M Freedman); Kingston, ON (D Brunet); Toronto, ON (P O'Connor, T Gray, M Hohol); Montreal, QC (P Duquette, Y Lapierre); Halifax, NS (TJ Murray, V Bhan, C Maxner); and St John's, NL (M Stefanelli). References [1] Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000 Sep 28;343(13):938–52. [2] Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002 Sep 19;347(12):911–20. [3] Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006 Nov;5(11):932–6. [4] Koch-Henriksen N, Sorensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010 May;9(5):520–32. [5] Dean G, Elian M. Age at immigration to England of Asian and Caribbean immigrants and the risk of developing multiple sclerosis. J Neurol Neurosurg Psychiatry 1997 Nov;63(5):565–8. [6] Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain 2000 May;123(Pt 5):968–74. [7] Strachan DP. Hay fever, hygiene, and household size. BMJ 1989 Nov 18;299(6710): 1259–60. [8] Sadovnick AD, Yee IM, Ebers GC. Multiple sclerosis and birth order: a longitudinal cohort study. Lancet Neurol 2005 Oct;4(10):611–7. [9] Bager P, Nielsen NM, Bihrmann K, Frisch M, Wohlfart J, Koch-Henriksen N, et al. Sibship characteristics and risk of multiple sclerosis: a nationwide cohort study in Denmark. Am J Epidemiol 2006 Jun 15;163(12):1112–7. [10] Ponsonby AL, van der Mei I, Dwyer T, Blizzard L, Taylor B, Kemp A, et al. Exposure to infant siblings during early life and risk of multiple sclerosis. JAMA 2005 Jan 26;293(4):463–9. [11] Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, Wright AL. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000 Aug 24;343(8):538–43. [12] Sadovnick AD, Risch NJ, Ebers GC. Canadian collaborative project on genetic susceptibility to MS, phase 2: rationale and method Canadian Collaborative Study Group. Can J Neurol Sci 1998 Aug;25(3):216–21. [13] Ramagopalan SV, Dyment DA, Valdar W, Herrera BM, Criscuoli M, Yee IM, et al. Autoimmune disease in families with multiple sclerosis: a population-based study. Lancet Neurol 2007 Jul;6(7):604–10. [14] Handel AE, Giovannoni G, Ebers GC, Ramagopalan SV. Environmental factors and their timing in adult-onset multiple sclerosis. Nat Rev Neurol 2010 Mar;6(3): 156–66.