BMJ  2005;330:120 (15 January), doi:10.1136/bmj.38301.686030.63 (published 7 December 2004)

Paper

Timing of birth and risk of multiple sclerosis: population based study

¹ Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA, ² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, ³ Department of Medical Genetics and Faculty of Medicine (Division of Neurology), University of British Columbia, Vancouver, BC, Canada V6T 2B5, ⁴ Department of Clinical Neurology, Radcliffe Infirmary, University of Oxford OX2 6HE, ⁵ Dalhousie University, Halifax, NS, Canada B3H 4R2

Abstract

Objectives To determine if risk of multiple sclerosis (MS) is associated with month of birth in countries in the northern hemisphere and if factors related to month of birth interact with genetic risk.

Design Population based study with population and family based controls and a retrospective cohort identified from death certificates. A post hoc pooled analysis was carried out for large northern datasets including Sweden and Denmark.

Setting 19 MS clinics in major cities across Canada (Canadian collaborative project on the genetic susceptibility to multiple sclerosis); incident cases of MS from a population based study in the Lothian and Border regions of Scotland; and death records from the UK Registrar General.

Populations 17 874 Canadian patients and 11 502 British patients with multiple sclerosis.

Main outcome measure Diagnosis of multiple sclerosis.

Results In Canada (n = 17 874) significantly fewer patients with MS were born in November compared with controls from the population census and unaffected siblings. These observations were confirmed in a dataset of British patients (n = 11 502), in which there was also an increase in the number of births in May. A pooled analysis of datasets from Canada, Great Britain, Denmark, and Sweden (n = 42 045) showed that significantly fewer (805%) people with MS were born in November and significantly more (9.1%) were born in May. For recent incident data, the effect of month of birth was most evident in Scotland, where MS prevalence is the highest.

Conclusions Month of birth and risk of MS are associated, more so in familial cases, implying interactions between genes and environment that are related to climate. Such interactions may act during gestation or shortly after birth in individuals born in the northern countries studied.

Introduction

Studies of twins, adoptees, half siblings, and families^1-4 have led to a widely accepted notion that multiple sclerosis (MS) is a complex trait in which susceptibility is determined by the interplay of genes and environmental factors. Environment seems to influence risk at a population level, but specific details remain unclear. The most striking clue to the role of environment has always been the gradient with latitude (see bmj.com).

Studies of month of birth and risk of MS have been carried out in several cohorts of people with MS, but sample sizes, ethnic groups, and statistical methods differed for each study and findings have been inconsistent.^5-9 Although significant differences in month of birth compared with population based controls have been reported, they have not been for the same months.

Methods

Data on month of birth, along with detailed information on demographics and clinical and family history, were collected as part of the population based longitudinal Canadian collaborative project on genetic susceptibility to multiple sclerosis¹⁰ in 17 874 patients with MS. The first control group comprised all the recorded births in Canada from 1926 to 1970 (Statistics Canada). A second control group comprised unaffected siblings of people with MS.

As Scandinavian studies have shown an increase of MS in people born in spring, we hypothesised a similar increase, but we analysed each month separately. We compared the births in a single month with the 11 other months for cases and controls (population or siblings). For months for which we found no previous evidence of association, we corrected the P value for the 12 comparisons using Bonferroni correction.

We obtained datasets of patients from England, Wales (n = 8702), and Scotland (n = 2356) from death certificates that mentioned "multiple sclerosis" and were registered in 1979-91. The controls for this sample were obtained from randomly selected death certificates of individuals born in the same year and country, with no mention of "multiple sclerosis." We also studied newly diagnosed cases from a population based study of the incidence of MS in the Lothian and Border regions of Scotland performed in 1992-5 inclusive (n = 444)¹¹ and used Scottish population birth records from 1940 to 1980 as controls (General Register Office Scotland).

Results

In the Canadian dataset (n = 17 874), 8.5% fewer people with MS were born in November; this was significant even after we corrected for the 12 monthly comparisons (1257 observed v 1373 expected, P = 0.013) (table 1). The peak birth month for people with MS was offset six months, in May, though this was not significant (P = 0.15). We found no difference within Canadian patients by sex, site of ascertainment, or decade of birth. Population control results, weighted to match patients with MS for year of birth, were similar to non-weighted controls (not shown). Among 67 Canadian patients born in the southern hemisphere, eight were born in November and two in May, suggesting a reversal of the pattern in northern countries.

View this table: [in this window] [in a new window]   Observed number of people in Canada with multiple sclerosis (MS) compared with expected number, according to month of birth

 

When we compared the dataset of British patients with MS, ascertained through death certificates and from incident cases (n = 11 502), with controls obtained via similar methods we found significantly fewer people with MS had been born in November (10.0%, P < 0.0001) and significantly more had been born in May (16.3%, P = 0.0003) (see bmj.com). The number born in December was also significantly lower (P = 0.028), but this was not significant when we corrected for multiple comparisons. We combined the data and the confidence intervals of the odds ratios for May and November in each group substantially overlapped (odds ratio 1.30, 95% confidence interval 1.17 to 1.44, for cases from England and Wales; 1.17, 0.94 to 1.47, for Scottish death certificate cases; and 1.89, 1.09 to 3.28, for Scottish incident cases).

In a post hoc analysis we added Danish⁵ (n = 6276) and Swedish⁶ (n = 6393) samples to our Canadian (n = 17 874) and British samples (n = 11 502; total n = 42 045). In this combined sample significantly more people with MS were born in May (9.1%) and significantly fewer were born in November (8.5%) (P values for May and November were all < 0.0001) (fig 1). This represents a 19% (odds ratio 1.19, 95% confidence interval 1.14 to 1.25) decreased risk of MS for those born in November compared with those born in May.

View larger version (28K): [in this window] [in a new window]   Fig 1 Pooled analysis of observed/expected births in people with multiple sclerosis in Canadian, British, Danish, and Swedish studies (n=42 045) with 95% confidence intervals

 

In the Canadian dataset, we used a second control group of matched unaffected siblings. We had complete data on 9248 unaffected siblings from 7450 patients with MS. Index cases were matched with one non-twin sibling, which resulted in a dataset of 4232 affected-unaffected sibling pairs. We compared affected siblings with their matched unaffected siblings furthest in age for November birth and observed 273 pairs in which the affected member of the pair was born in November and 343 where the unaffected sibling was born in November (P = 0.0048).

We tested whether the environmental component related to month of birth might contribute to familial risk, perhaps by interacting with susceptibility genes predictably enriched in families with multiple cases of MS.¹⁰ Among affected people with a family history of MS we found 16.2% fewer were born in November relative to population controls compared with 3.0% fewer among those with no family history of MS (² = 3.92, P = 0.050).

We also compared the odds ratio for increased risk of MS for people born in May compared with November. The highest odds ratio for May/November risk was in Scotland, followed by Denmark, Sweden, and Canada (fig 2).

View larger version (24K): [in this window] [in a new window]   Fig 2 Odds ratios for people with multiple sclerosis being born in May/November among incident cases in northern hemisphere countries

 

Discussion

We have conclusively shown the association between month of birth and risk of MS in northern countries. The sample size, internal replications, and selection of appropriate controls indicate that this is unlikely to be an artefact. Our pooled data show that being born in May is associated with increased risk, and the Canadian and British datasets clearly show that people born in November have the lowest risk. Correlation of specific years of increased risk related to season with features such as ultraviolet radiation, temperature, or weather patterns may help to elucidate this effect further.

Although the birth month results in MS now seem clear, the interpretation is not. May and November show significance in the pooled analysis and the peaks of altered risk are exactly six months apart. Although the reduced risk for November seems to also exist for December births in some datasets, the changes in risk are remarkably discrete. The abrupt change in risk by month suggests a threshold effect for both increased and decreased risk, something that is not easily explained.

Possible explanations of association
The risk factor(s) responsible for the effect of timing of birth must vary seasonally and probably interact with development of the central nervous system or immune systems, or both. Among candidate factors are maternal folate,¹² correlates of infant birth weight and virus infection, and factors also implicated in the effect of season of birth on schizophrenia.¹³ Undoubtedly other cyclic interactions remain to be identified.

Previous findings of associations between higher latitudes and risk of MS (Sardinians and Sami being notable exceptions) have suggested that exposure to the sun may account for the geographical variation of MS.¹⁴ Most biologically active vitamin D is generated in the skin with exposure to ultraviolet radiation¹⁵ and an increased risk of MS related to month of birth could reflect well documented seasonal deficiency in maternal concentrations of vitamin D.¹⁶ Vitamin D treatment reduces severity of symptoms and progression in experimental autoimmune encephalomyelitis (EAE), which is a mouse model of MS.¹⁷ Furthermore, exposure to sun during childhood is associated with a reduced risk of multiple sclerosis,¹⁸ and this may also extend to timing of birth. If the excess of MS in those born in May is related to maternal vitamin D deficiency, studies on blood concentrations suggest that the end of the second or the third trimester are the crucial time points.¹⁶ Vitamin D receptors are present in the brain, and gestational vitamin D deficiency has striking effects on brain development in experimental animals.¹⁹

What is already known on this topic Susceptibility to multiple sclerosis (MS) is influenced by genetic and environmental factors An association with latitude in early life has been shown in migrants from regions of differing risk A maternal parent of origin effect shown in half siblings with MS from Canada suggested that environment acts in gestation or the neonatal period to determine risk for this adult onset disease What this study adds In northern countries the risk of MS is greater for people born in May and lower for those born in November This effect is greater in Scotland, where the population prevalence of this disease is highest These findings support suggestions from studies in twins and half siblings that the gestational or neonatal environment, or both, influence the risk of MS later in life

The observed May/November birth ratio in living incident cases from Scotland (1.89), Denmark (1.22),⁵ Sweden (1.18),⁶ and Canada (1.13) decreases in order of population prevalence (fig 2). This suggests that the seasonal birth effect may be connected with environmental factors determining prevalence rates. These are powerful, seem to act at a broad population level,^1-3 and may hold the key to disease prevention. The "parent of origin" effect, recently reported in MS,²⁰ may suggest that, at least in part, environmental effects are maternally mediated and influence development in the nervous or immune system, or both.

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This is the abridged version of an article that was posted on bmj.com on 7 December 2004: http://bmj.com/cgi/doi/10.1136/bmj.38301.686030.63

We thank Irene Yee, Maria Criscuoli, Randy Holmes, Kevin Atkins, and Don Templer (at Alliant International University) for their help with this study and James Gowans, Rodney Phillips, Iain Chalmers, Anne Spurkland, Pierre Duquette, Ed Burton, Stacey Cherny, and Michael Boehnke for help with the manuscript. We also thank the participants of the vitamin D workshop held in Toronto in April 2002 for valuable insight, discussion, and advice and Nina Jablonski and George Chaplin for sharing their expertise. The Canadian Collaborative Study Group includes D W Paty, S A Hashimoto, V Devonshire, J Hooge, J Oger, L Kastrukoff, and T Traboulsee (Vancouver); L Metz (Calgary); S Warren (Edmonton); W Hader (Saskatoon); R Nelson and M Freedman (Ottawa); D Brunet (Kingston); J Paulseth (Hamilton); G Rice and M Kremenchutzky (London); P O'Connor, T Gray, and M Hohol (Toronto); P Duquette and Y Lapierre (Montreal); J-P Bouchard (Quebec City); V Bhan and C Maxner (Halifax); and W Pryse-Phillips and M Stefanelli (St Johns).

Contributors: See bmj.com

Funding: This work was part of a larger project funded by the MS Society of Canada Scientific Research Foundation. CJW and DAD were supported by studentships from the MS Society of Canada, during the time this study was mainly completed. ADS is a Michael Smith Distinguished Scholar.

Competing interests: None declared.

Ethical approval: The study was approved by the University of Western Ontario and the University of British Columbia, which were the two main sites of data collection. Each Canadian MS clinic obtained ethical approval from their local review board.

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(Accepted 3 November 2004)

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