Multiple sclerosis and birth order: a longitudinal cohort study

BACKGROUND: Genetic epidemiological studies suggest both genetic and environmental factors have a role in multiple sclerosis (MS). Environmental effects are strongly suggested from geographical gradients, migration data, and discordance rates in twins. In epidemiological studies, risk of MS in offspring of small families and in those with an early birth-order position has been reported and interpreted in the context of the hygiene hypothesis, which is that infections at an early age, introduced by older siblings, are protective. We aimed to study the effect of birth order on MS risk. METHODS: A longitudinal, population-based sample of individuals with MS and their healthy siblings were identified from the Canadian Collaborative Project on Genetic Susceptibility to MS. Data were grouped according to single (simplex) or multiple (multiplex) siblings with MS in a sibship. Separate analyses were done for each sibship size. FINDINGS: We studied 10 995 individuals with MS and 26 336 healthy siblings, and found no relation between MS risk and birth-order position. In simplex sibships of at least seven siblings, slightly more siblings who were born late in the birth order had MS; the same was found for the first-born sibling with MS in a multiplex sibship. Siblings with MS were slightly younger (p<0.0001) than those without MS, contrary to the expected age at onset bias. INTERPRETATION: These findings do not support the hygiene hypothesis and could be due to a cohort effect resulting from increasing MS incidence. Birth order has no effect on MS risk in most families, and there is no support for the hypothesis that having older siblings protects against MS.