This study is to our knowledge the first to report an association of lower levels of 25-OH D during pregnancy with a higher risk of type 1 diabetes in the offspring. Our population-based study is nested within a cohort of ~30,000 pregnant women, and selection bias is likely to be a smaller problem than in studies where control subjects are selected from other sources than the case subjects. Nevertheless, we observed a higher than expected proportion of girls among the case subjects and a lower than expected proportion of girls among control subjects. Because the case subjects were identified by linkage to the nearly complete nationwide registry and control subjects were selected by computer-generated random sampling, we do not have any explanation for this other than random chance. At any rate, statistical adjustment for sex did not influence our main results.
As a result of the long follow-up time, we were able to identify almost all children of the original maternal cohort who developed type 1 diabetes during childhood. The long follow-up gives an equivalent long storage time for the serum samples, but 25-OH D seems to be stable over a long period of time.[17,18] Even in the event that some degradation has occurred, this is not likely to differ according to whether the unborn child later develops type 1 diabetes. Furthermore, the expected seasonal pattern is supportive of valid 25-OH D measurements. In a few instances, we could not obtain a 25-OH D measurement, partly because the serum sample had been used in other studies and partly because the serum sample had dried up and was unsuitable for analyses.
Previous studies have been based on the reported intake of vitamin D via food or supplements during pregnancy, which is subject to recall bias and other measurement errors, including the fact that contributions to vitamin D status from sun exposure are not accounted for. Our findings are consistent with small cohort studies in which maternal reported intake of vitamin D via food or dietary supplements during pregnancy was associated with a decreased risk of diabetes-related autoantibodies in offspring.[7,8] Another larger study did not find any association between reported dietary intake of vitamin D by pregnant women and the risk of islet autoimmunity or early clinical diabetes in children. These previous studies are not directly comparable with ours, because we have not only measured maternal 25-OH D but also followed the children until they were 15 years of age, with respect to the onset of clinical type 1 diabetes. Intake of vitamin D and levels of 25-OH D during childhood were measured in a newly published study from the Diabetes Autoimmunity Study in the Young (DAISY), and they did not find any relationship to the risk of islet autoimmunity or progression to type 1 diabetes. This study has no information on fetal or maternal levels of 25-OH D.
We did not have separate information on the intake of vitamin D from food or supplements or on sun exposure, but measuring the serum levels of 25-OH D should be superior to questionnaires in that they reflect the integrated vitamin D status of an individual. Blood sampling in our study was not standardized for season, because this would not be possible in practice, but we adjusted for this in the statistical analysis. Previous literature suggests that the serum levels of 25-OH D vary little over gestational age, and our data (not shown) suggested that the season of the blood collection contributed more to between-sample variation than did gestational age.
We did not have access to DNA for genotyping of the participants in our study, but previous studies have not indicated that associations between measures of vitamin D and type 1 diabetes differed by HLA type.[8,21] Recent studies have identified weak associations between polymorphisms in genes related to vitamin D metabolism and type 1 diabetes,[22,23] but it is not likely that these polymorphisms in the mother or offspring would materially influence the association between maternal 25-OH D status and the risk of type 1 diabetes in the children. Despite some initial indications of a potential association between vitamin D receptor polymorphisms and the risk of type 1 diabetes, a systematic review concluded that there was no evidence to support such an association for any of the studied polymorphisms.
The exact mechanisms by which vitamin D acts in a potential protective manner against type 1 diabetes are not known, but many steps in the immune process may be altered under the influence of 1α,25(OH)2D in the direction of better tolerance, which is of general importance in preventing autoimmune processes.[3,25,26] For instance, maturation of dendritic cells has been shown to be inhibited, and the cytokine production from T-helper cells shifted toward an anti-inflammatory pattern.
In conclusion, our results indicate an association between lower maternal serum concentrations of 25-OH D during pregnancy and increased risk of type 1 diabetes development in childhood. Given future replication in independent cohorts, this could provide support for the initiation of a randomized intervention trial to prevent type 1 diabetes in children by enhancing maternal 25-OH D status during pregnancy.
This study was supported by grants from the South-East Regional Health Authority of Norway, the Research Unit at the Women and Child's Division at Oslo University Hospital Ullevål, and the Oslo Diabetes Research Centre.
No potential conflicts of interest relevant to this article were reported.
I.M.S. wrote the manuscript. I.M.S. and L.C.S. contributed to the data analysis. G.J., A.E., and L.C.S. contributed to the conception and planning. P.A.J. contributed to organizing the original cohort study. P.A.T. was responsible for the 25-OH D assay. L.C.S. is the guarantor for this article. All authors commented on the manuscript.
Parts of this study were presented in abstract form at the 46th Annual Meeting of the European Association for the Study of Diabetes, Stockholm, Sweden, 20–24 September 2010 and at the 36th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes, Miami, Florida, 19–22 October 2011.
The authors thank Anikken Kristiansen at the Hormone Laboratory, Oslo University Hospital, for the 25-OH D measurements.
Diabetes. 2012;61(1):175-178. © 2012 American Diabetes Association, Inc.