We report here the largest study performed on ID and seasonality of birth. When patients with different conditions were grouped together, a clear seasonal birth distribution was observed with a peak in April and a trough exactly six months later in October. The effect size of being born at the 'wrong time' appears very low, with the highest ORs being under 1.1. However, considering the increased risk of all ID in the rest of the year versus October-born individuals and the proportion of the population born in months other than October, the population proportional attributable risk per cent is 5.05%. This suggests that approximately 5% of ID cases could be prevented by ameliorating the risk factor responsible for the seasonal distribution of ID births. The season of birth effect was particularly clear in Scotland as compared with England, but no prominent differences between the two sites could be observed.
That the risk of MS varies by month of birth has already been shown in a number of regions, including Canada, Denmark, Sweden, Sardinia, Finland, England, Scotland and Australia [5, 30–34]. We further confirmed these findings by increasing the sample size of a previously analysed cohort of UK patients with MS . Based on the Cosinor test, RA, UC and SLE births also followed a clear seasonal distribution. Notably, all the predicted sinusoids peaked around the same period, with phases ranging from 2.69 to 4.12 (late winter-spring). In contrast to other ID, the distribution of CD births was not seasonal.
The presence of seasonality of births among patients with UC but not CD is interesting but difficult to interpret. Somehow similar is the observation that the season of birth effect in MS is present among patients with relapsing remitting but not primary progressive MS . It is therefore plausible to observe such differences between similar but distinct phenotypes. Furthermore, increasing evidence supports the presence of gene-environment interactions in disease aetiology [36, 37] and particular genetic variants could be involved and mediating the season of birth effect. Although many genetic variants influence the risk of both UC and CD, many others (including variants located within the major histocompatibility complex) appear to be disease specific and this could contribute to the observed difference between UC and CD births [20, 38–41].
A recent Australian study reported an inverse association between the risk of MS and UVB exposure during the first trimester of gestation . However, the sample size was relatively small (n = 1,524) and thus analysis had to be performed using bi-monthly periods. Furthermore, the seasonal variation of 25-OH-D levels was not investigated and no other studies have tried to answer the same question in ID other than MS. We found that the risk of ID was inversely associated with predicted second trimester UVB exposure and third trimester vitamin D status. These findings are interesting since several lines of evidence now support a role for vitamin D deficiency in the pathogenesis of ID [23, 24]. Notably, vitamin D production is strictly dependent on UVB radiation and vitamin D levels therefore follow a seasonal distribution . This is also the case among pregnant women, whose vitamin D status largely depends on season and follows the same distribution as the levels of the general population [28, 42, 43]. Furthermore, in utero vitamin D deficiency has a significant effect on the developing immune system and our group has recently shown that genes associated with MS, RA, CD, SLE and T1D are significantly enriched for vitamin D receptor binding sites [44–46]. In addition to its well-known immunological roles, this exceptionally pleiotropic hormone has been implicated in autophagy and mucosal barrier homeostasis, which are thought to play a pathogenic role in CD and UC [20, 47, 48]. It may be that in utero vitamin D deficiency, in conjunction with individual genetic variation and subsequent exposure to other environmental agents, may then lead to disease specificity. Notably, schizophrenia is also influenced by the season of birth and a recent study has shown that neonatal vitamin D levels are significantly associated with risk of schizophrenia later in life [49, 50]. Future studies should try to answer the same question in MS as well as in other ID.
This study has limitations. Information on sex and ethnicity was not available and this may have confounded our results. Furthermore, the data we gathered from the Scottish NHS and the English HES could not be restricted to UK born but only to UK resident individuals. However, the enormous sample size (115,172 ID cases), the relatively homogeneous Scottish population and the strong a priori evidence for a month of birth effect in MS make the risk of a spurious association improbable. Furthermore, it is striking that the ID analysed (apart from CD) show a similar seasonal risk distribution, which is also the one reported in patients with T1D [6, 7]. This makes the data unlikely to be a chance finding.
We were limited to using average UVB radiation and general population vitamin D measures, which may differ from the individual maternal exposures. It is important to note that our UVB and vitamin D correlation analysis does not prove causation and that, although the vitamin D hypothesis is supported by both epidemiological and functional observations, seasonality dominates many features of the global environment and other seasonal factors may play a role in determining the risk of ID. Climate, temperature, infectious disease and maternal nutrition are all characterised by seasonality and thus represent excellent candidate factors.