Journal of Neurology

, Volume 265, Issue 6, pp 1295–1302 | Cite as

Sex ratio in multiple sclerosis mortality over 65 years; an age-period-cohort analysis in Norway

  • Ola Nakken
  • Jonas Christoffer Lindstrøm
  • Trygve Holmøy
Original Communication


Increasing female: male ratio in multiple sclerosis (MS) has been assigned to cohort effects, with females in more recent birth cohorts possibly being more exposed or vulnerable to environmental risk factors than males. We collected MS mortality data in Norway from 1951 to 2015 from The Norwegian Cause of Death registry. Age-Period-Cohort analysis was conducted using log-linear Poisson models, including sex interaction terms. MS was registered as the underlying, contributing or direct cause in 6060 deaths. MS associated mortality remained stable with a slight preponderance among males until after 1980, and have since increased preferentially among females. Throughout the study period the mean annual increase was 1.25% for females and 0.3% for males (p < 0.0001). Age-period-cohort analysis revealed limited evidence of cohort effects for the gender differences; the best fitting model only included gender-age and gender-period interaction terms. The period effect evened out for males in the last three decades but increased for females, especially among the oldest age-groups. In conclusion, the increased female: male mortality ratio in MS associated mortality is driven mainly by increased mortality among females in the three last decades, particularly in the older age groups. It is best explained by disproportional period effects, providing evidence of time-varying external factors including improved access to diagnosis among females.


Multiple sclerosis Sex ratio Neuro-epidemiology Mortality Age-period-cohort model 



We are grateful for data supplied by the Norwegian Cause of Death Registry.

Compliance with ethical standards

Conflicts of interest

On behalf of all authors, the corresponding author declares that there is no conflict of interest.

Ethical approval

The study was approved by the Regional Committee for Medical and Health Research Ethics (REC South East).

Research involving human and animal participants

The manuscript does not contain clinical studies or individual patient data.

Supplementary material

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  1. 1.
    Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, Ebers GC (2006) Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 5(11):932–936. CrossRefPubMedGoogle Scholar
  2. 2.
    Alonso A, Hernan MA (2008) Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 71(2):129–135. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Debouverie M, Pittion-Vouyovitch S, Louis S, Roederer T, Guillemin F (2007) Increasing incidence of multiple sclerosis among women in Lorraine, Eastern France. Mult Scler (Houndmills, Basingstoke, England) 13(8):962–967. CrossRefGoogle Scholar
  4. 4.
    Westerlind H, Bostrom I, Stawiarz L, Landtblom AM, Almqvist C, Hillert J (2014) New data identify an increasing sex ratio of multiple sclerosis in Sweden. Mult Scler (Houndmills, Basingstoke, England) 20(12):1578–1583. CrossRefGoogle Scholar
  5. 5.
    Heydarpour P, Mohammad K, Yekaninejad MS, Elhami SR, Khoshkish S, Sahraian MA (2014) Multiple sclerosis in Tehran, Iran: a joinpoint trend analysis. Mult Scler (Houndmills, Basingstoke, England) 20(4):512. CrossRefGoogle Scholar
  6. 6.
    Celius EG, Smestad C (2009) Change in sex ratio, disease course and age at diagnosis in Oslo MS patients through seven decades. Acta Neurol Scand Suppl 189:27–29. CrossRefGoogle Scholar
  7. 7.
    Simpson S Jr, Pittas F, van der Mei I, Blizzard L, Ponsonby AL, Taylor B (2011) Trends in the epidemiology of multiple sclerosis in Greater Hobart, Tasmania: 1951–2009. J Neurol Neurosurg Psychiatry 82(2):180–187. CrossRefPubMedGoogle Scholar
  8. 8.
    Holford TR (1991) Understanding the effects of age, period, and cohort on incidence and mortality rates. Annu Rev Public Health 12:425–457. CrossRefPubMedGoogle Scholar
  9. 9.
    Carstensen B (2007) Age-period-cohort models for the Lexis diagram. Stat Med 26(15):3018–3045. CrossRefPubMedGoogle Scholar
  10. 10.
    Akaike H (1974) A new look at the statistical model identification. IEEE Trans Autom Control 19:716–723. CrossRefGoogle Scholar
  11. 11.
    Ajdacic-Gross V, Schmid M, Mutsch M, Steinemann N, von Wyl V, Bopp M (2017) The change in the sex ratio in multiple sclerosis is driven by birth cohort effects. Eur J Neurol 24(1):98–104. CrossRefPubMedGoogle Scholar
  12. 12.
    Ajdacic-Gross V, Tschopp A, Schmid M, Bopp M, Gutzwiller F (2013) Missed epidemics and missing links: international birth cohort trends in multiple sclerosis. Eur J Neurol 20(3):440–447. CrossRefPubMedGoogle Scholar
  13. 13.
    Koch-Henriksen N, Sorensen PS (2010) The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 9(5):520–532. CrossRefPubMedGoogle Scholar
  14. 14.
    Ascherio A (2013) Environmental factors in multiple sclerosis. Expert Rev Neurother 13(12 Suppl):3–9. CrossRefPubMedGoogle Scholar
  15. 15.
    Meyer HE, Tverdal A (2005) Development of body weight in the Norwegian population. Prostaglandins Leukot Essent Fatty Acids 73(1):3–7. CrossRefPubMedGoogle Scholar
  16. 16.
    Brundtland GH, Liestøl K, Walløe L (1980) Height, weight and menarcheal age of Oslo schoolchildren during the last 60 years. Ann Hum Biol 7(4):307–322. CrossRefPubMedGoogle Scholar
  17. 17.
    Ronneberg A, Lund KE, Hafstad A (1994) Lifetime smoking habits among Norwegian men and women born between 1890 and 1974. Int J Epidemiol 23(2):267–276CrossRefPubMedGoogle Scholar
  18. 18.
    Hedstrom AK, Hillert J, Olsson T, Alfredsson L (2013) Smoking and multiple sclerosis susceptibility. Eur J Epidemiol 28(11):867–874. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hedstrom AK, Olsson T, Alfredsson L (2016) Smoking is a major preventable risk factor for multiple sclerosis. Mult Scler (Houndmills, Basingstoke, England) 22(8):1021–1026. CrossRefGoogle Scholar
  20. 20.
    Rostgaard K, Vaeth M, Holst H, Madsen M, Lynge E (2001) Age-period-cohort modelling of breast cancer incidence in the Nordic countries. Stat Med 20(1):47–61CrossRefPubMedGoogle Scholar
  21. 21.
    Talley CL (2005) The emergence of multiple sclerosis, 1870–1950: a puzzle of historical epidemiology. Perspect Biol Med 48(3):383–395. CrossRefPubMedGoogle Scholar
  22. 22.
    Swank RL, Lerstad O, Strom A, Backer J (1952) Multiple sclerosis in rural Norway its geographic and occupational incidence in relation to nutrition. N Engl J Med 246(19):722–728CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Miller DH, Leary SM (2007) Primary-progressive multiple sclerosis. Lancet Neurol 6(10):903–912. CrossRefPubMedGoogle Scholar
  24. 24.
    Compston A, Coles A (2002) Multiple sclerosis. Lancet 359(9313):1221–1231. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Presthus J (1960) Report on the multiple sclerosis investigations in West-Norway. Acta Psychiatr Scand Suppl 35(147):88–92CrossRefPubMedGoogle Scholar
  26. 26.
    Oftedal SI (1966) Multiple sclerosis in Vestfold, Norway. Acta Neurol Scand 42(Suppl 19):19–26PubMedGoogle Scholar
  27. 27.
    Statistics Norway (1994) Historical statistics. Accessed Dec 1st 2017
  28. 28.
    Trojano M (2011) Multiple sclerosis: the evolving diagnostic criteria for multiple sclerosis. Nat Rev Neurol 7(5):251–252. CrossRefPubMedGoogle Scholar
  29. 29.
    Midgard R, Riise T, Svanes C, Kvale G, Nyland H (1996) Incidence of multiple sclerosis in More and Romsdal, Norway from 1950 to 1991,An age-period-cohort analysis. Brain 119(Pt 1):203–211CrossRefPubMedGoogle Scholar
  30. 30.
    Kampman MT, Aarseth JH, Grytten N, Benjaminsen E, Celius EG, Dahl OP, Holmoy T, Loken-Amsrud K, Midgard R, Myhr KM, Risberg G, Vatne A, Torkildsen O (2013) Sex ratio of multiple sclerosis in persons born from 1930 to 1979 and its relation to latitude in Norway. J Neurol 260(6):1481–1488. CrossRefPubMedGoogle Scholar
  31. 31.
    Trojano M, Lucchese G, Graziano G, Taylor BV, Simpson S Jr, Lepore V, Grand’maison F, Duquette P, Izquierdo G, Grammond P, Amato MP, Bergamaschi R, Giuliani G, Boz C, Hupperts R, Van Pesch V, Lechner-Scott J, Cristiano E, Fiol M, Oreja-Guevara C, Saladino ML, Verheul F, Slee M, Paolicelli D, Tortorella C, D’Onghia M, Iaffaldano P, Direnzo V, Butzkueven H (2012) Geographical variations in sex ratio trends over time in multiple sclerosis. PLoS ONE 7(10):e48078. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lunde HMB, Assmus J, Myhr KM, Bo L, Grytten N (2017) Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study. J Neurol Neurosurg Psychiatry 88(8):621–625. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Franconi F, Campesi I (2014) Sex and gender influences on pharmacological response: an overview. Expert Rev Clin Pharmacol 7(4):469–485. CrossRefPubMedGoogle Scholar
  34. 34.
    Li R, Sun X, Shu Y, Mao Z, Xiao L, Qiu W, Lu Z, Hu X (2017) Sex differences in outcomes of disease-modifying treatments for multiple sclerosis: a systematic review. Mult Scler relat Disord 12:23–28. CrossRefPubMedGoogle Scholar
  35. 35.
    Bassetti C (2009) History of the Swiss Neurological Society in the context of the national and international development of neurology. vol 160. Schweizer Archiv für Neurologie und Psychiatrie 160(2):52–65CrossRefGoogle Scholar
  36. 36.
    Nakken O, Lindstrom JC, Tysnes OB, Holmoy T (2016) Mortality trends of amyotrophic lateral sclerosis in Norway 1951–2014: an age-period-cohort study. J Neurol 263(12):2378–2385. CrossRefPubMedGoogle Scholar
  37. 37.
    Midgard R, Albrektsen G, Riise T, Kvale G, Nyland H (1995) Prognostic factors for survival in multiple sclerosis: a longitudinal, population based study in More and Romsdal, Norway. J Neurol Neurosurg Psychiatry 58(4):417–421CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Bostrom I, Stawiarz L, Landtblom AM (2013) Sex ratio of multiple sclerosis in the National Swedish MS Register (SMSreg). Mult Scler (Houndmills, Basingstoke, England) 19(1):46–52. CrossRefGoogle Scholar
  39. 39.
    Trojano M (2014) The use of multiple population-based data sources for estimating MS sex ratio trends over time. Mult Scler (Houndmills, Basingstoke, England) 20(12):1551–1552. CrossRefGoogle Scholar
  40. 40.
    Midgard R (2012) Incidence and prevalence of multiple sclerosis in Norway. Acta Neurol Scand Suppl 195:36–42. CrossRefGoogle Scholar
  41. 41.
    Berg-Hansen P, Moen S, Harbo H, Celius E (2014) High prevalence and no latitude gradient of multiple sclerosis in Norway. Mult Scler (Houndmills, Basingstoke, England) 20(13):1780–1782. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Clinical MedicineUniversity of OsloOsloNorway
  2. 2.Department of NeurologyAkershus University HospitalLørenskogNorway
  3. 3.Health Services Research UnitAkershus University HospitalLørenskogNorway

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