To assess whether month of birth influences susceptibility to immune disorders, we initially compared the distribution of all patients with ID with that of the general population. Using the Cosinor test, the birth distribution of patients with ID was found to follow a seasonal distribution as compared with the general population (P = 5e-12, amplitude = 0.033, phase = 3.08, low point = 9.08). When monthly ORs were calculated, a statistically significant peak was found in April (OR = 1.045, 95%CI = 1.024 to 1.067, P < 0.0001) and a significant trough exactly six months later in October (OR = 0.945, 95%CI = 0.925 to 0.966, P < 0.0001). A smaller deficit was also detected in August (OR = 0.972, 95%CI = 0.951 to 0.9927, P = 0.008) (Figure ). The peak to trough ratio indicated the presence of a 6.5% increased risk for individuals born in April versus those born in October (OR = 1.065, 95%CI = 1.035 to 1.096, P < 0.0001).
Odds ratio distribution with 95% CI based on month of birth in all immune-mediated diseases (n = 115,172) versus general population. April peak and October trough of risk can be observed.
When the analysis was performed according to country, the seasonal effect appeared to be present in both England and Scotland (Scotland P = 5e-10, amplitude = 0.034, phase = 3.05, low point = 9.05; England P = 0.005, amplitude = 0.032, phase = 3.23, low point = 9.23). The highest and lowest monthly ORs were found in the Scottish population; however, 95%CIs were substantially overlapping (Figure ).
Odds ratio distribution based on month of birth in England and Scotland. The highest and lowest odds ratios are observed in Scotland but 95%CI substantially overlap.
The seasonality of birth detected by grouping all patients with ID could arise from a single disease such as MS, for which the presence of a month of birth effect has already been described. We therefore stratified the analysis by disease type. The Cosinor test indicated the presence of clear seasonality in all ID but CD: MS, P = 5e-06; amplitude = 0.041, phase = 4.12, low point = 10.12; RA, P = 5e-04, amplitude = 0.032, phase = 2.69, low point = 8.69; UC, P = 5e-04, amplitude = 0.04, phase = 2.74, low point = 8.74; SLE, P = 0.025, amplitude = 0.063, phase = 2.89, low point = 8.89; CD, P > 0.05. When calculating monthly ORs, a peak in spring and a deficit in autumn could be observed in each ID apart from CD, in which a January rather than spring peak was found. Birth percentages and monthly ORs with 95%CIs are presented in Table .
Birth percentages and monthly odds ratios with 95%CI for each and all immune-mediated diseases
We next investigated whether the monthly risk of ID inversely correlated with predicted gestational UVB exposure and vitamin D status during different trimesters of pregnancy. Based on the Nimbus 7 satellite, UVB radiation in the UK reaches the minimum and maximum levels during winter (December to January) and summer (June to July), respectively. The highest and lowest 25-OH-D levels were collected during September and February respectively [28
]. Figure shows the direct relation between UVB radiation and vitamin D status and the amount of time required for a change in UVB to impact on vitamin D metabolism. The peak and the trough of 25-OH-D levels are shifted approximately two to three months later than UVB radiation (two months lag: Spearman's rho = 0.91, P
; three months lag: Spearman's rho = 0.88, P
= 0.002). This is consistent with previous reports [29
Figure 3 Correlation between monthly ultraviolet B radiation from the NASA's Total Ozone Mapping Program and 25-hydroxyvitamin D levels from the general UK population. The seasonal distribution of 25-hydroxyvitamin D levels is shifted approximately two to three (more ...)
We found that the monthly risk of ID inversely correlated with predicted UVB exposure during the second trimester of pregnancy (Spearman's rho = -0.49, P = 0.00005). Similarly, predicted maternal 25-OH-D levels were also inversely associated with risk of ID but the negative correlation was shifted to the third trimester (Spearman's rho = -0.44, P = 0.0003) (Figure ).
Inverse correlation between risk of immune-mediated diseases and predicted second trimester ultraviolet B exposure (left panel) and third trimester vitamin D status (right panel).