Abstract
Objective:
As previous research has suggested that exposure to vitamin D insufficiency in utero may have relevance for the risk of multiple sclerosis (MS), we aimed to examine the direct association between level of neonatal vitamin D and risk of MS.
Methods:
We carried out a matched case-control study. Dried blood spots samples (DBSS) belonging to 521 patients with MS were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1–2 controls with the same sex and birth date were retrieved from the Biobank (n = 972). Level of 25-hydroxyvitamin D (25[OH]D) in the DBSS was measured using liquid chromatography tandem mass spectroscopy. The association between different levels of 25(OH)D and risk of MS was evaluated by odds ratios (OR) calculated in conditional logistic regression models.
Results:
We observed that lower levels of 25(OH)D in neonates were associated with an increased risk of MS. In the analysis by quintiles, MS risk was highest among individuals in the bottom quintile (<20.7 nmol/L) and lowest among those in the top quintile of 25(OH)D (≥48.9 nmol/L), with an OR for top vs bottom of 0.53 (95% confidence interval [CI] 0.36–0.78). In the analysis treating 25(OH)D as a continuous variable, a 25 nmol/L increase in neonatal 25(OH)D resulted in a 30% reduced risk of MS (OR 0.70, 95% CI 0.57–0.84).
Conclusion:
Low concentrations of neonatal vitamin D are associated with an increased risk of MS. In light of the high prevalence of vitamin D insufficiency among pregnant women, our observation may have importance for public health.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS affecting approximately 2.5 million individuals worldwide.1,2 The etiology and exact pathogenesis of MS is still unknown, but there is growing evidence that low vitamin D levels are associated with an increased risk of MS3,4 and that supplementary vitamin D intake may have a protective effect.5,6 The results of a recent mendelian randomization study strongly support the causality of an association between lower vitamin D levels and increased susceptibility to MS.7
Although some controversy exists, patients with MS from the Northern hemisphere seem to be more likely to be born in April or May,8–12 just after the very low winter levels of vitamin D,13 suggesting that in utero exposure to vitamin D insufficiency also is relevant for the risk of MS.14
In a Swedish case-control study,15 no association was found between levels of neonatal 25-hydroxyvitamin D (25[OH]D) measured in dried blood spots samples (DBSS) and later risk of MS, but the results may have been affected by degradation of 25(OH)D due to high storage temperatures.15,16 In contrast, in a recent study in the Finnish Maternity Cohort, maternal vitamin D deficiency (serum 25[OH]D levels <30 nmol/L) in early pregnancy was associated with a 90% increase in risk of MS in the offspring.17
Here, we examine the association between neonatal 25(OH)D status and risk of MS in a large population-based case-control study using data from the nationwide Danish MS registry and the Danish Newborn Screening Biobank (DNSB).
METHODS
Participants.
The study was based on a linkage between the Danish Multiple Sclerosis Registry,18 the Danish Civil Registration System,19 and DBSS from the DNSB.20 Residual DBSS have been systematically stored at −20°C for individuals born in Denmark since May 1, 1981. The biobank is considered close to complete for virtually all newborns in Denmark since 1982, corresponding to approximately 1.8 million samples. DBSS are taken by a heel prick 5–7 days after birth and analyzed for a number of inborn errors of metabolism at the Newborn Screening Laboratory, Statens Serum Institut, in Copenhagen.20,21 Using data from the nationwide Danish Multiple Sclerosis Registry (MS Registry), we identified all the individuals who were born since April 30, 1981, and had onset of MS before or in 2012. The Danish MS Registry, which was established in 1956, is the longest running nationwide MS registry and covers a period of more than 50 years.18 In the present study, we only included cases fulfilling the diagnostic criteria of Allison or Poser including possible MS (when other diseases are ruled out), and since 2005 the McDonald criteria and their updates, but not cases of clinically isolated syndrome or poorly documented cases. The linkage between the MS Registry and the DNSB was possible due to the unique personal ID number assigned to every Danish citizen by the Civil Registration System since April 1968.19 For every MS case with a DBSS in the DNSB, DBSS from 1 to 2 controls of same sex and exact birth date were selected. Controls had to be alive or living in Denmark on the date of MS diagnosis in the matched patient with MS.
25(OH)D assessment.
We measured 25-hydroxyvitamin D3 (25[OH]D3), which is the main circulating form of vitamin D,22 and the related ergosterol-derived form 25-hydroxyvitamin D2 (25[OH]D2), which can be obtained from certain dietary sources, e.g., mushrooms, fortified foods, and vitamin supplements.21 For each individual, one 3.2-mm disc of DBSS was used. The assay was performed at the Statens Serum Institut, Copenhagen, and is a modified version of the method by Eyles et al.23 The assay method is highly sensitive and uses minimal sample cleanup to reduce sample loss during extraction, chemical derivatization to enhance 25(OH)D2 and 25(OH)D3 ionization, and liquid chromatography tandem mass spectroscopy coupled with multiple reaction monitoring. It has previously been shown that the assay can reliably detect seasonal (within year) fluctuations, is strongly correlated with neonatal cord blood (r = 0.85),13 and that appropriate 25(OH)D3 concentrations can be detected after prolonged storage time (e.g., greater than 20 years).23 Neonatal DBSS are routinely collected from capillary blood. The protein-bound 25(OH)D is excluded from erythrocytes, thus, concentrations in whole blood are lower than in serum. We therefore multiplied the total 25(OH)D concentrations measured in capillary blood by 2.56 (1/[1–0.61]) to estimate serum levels13,23; all 25(OH)D values reported below correspond to estimated serum levels.
Potential confounders.
Perinatal factors such as gestational age, birthweight, maternal age at birth, Apgar score, and parental ethnicity have been shown to be associated with neonatal vitamin D status or maternal D vitamin deficiency,24,25 whereas the association with MS is less clear.26–28 Data on birthweight (<3,000, 3,000–3,249, 3,250–3,499, 3,500–3,749, 3,750–3,999, 4,000–4,249, ≥4,250 g), Apgar score 5 minutes after birth (0–9, 10), and gestational age (≤37, 38, 39, 40, ≥41 weeks) were obtained from the Danish Medical Birth Register.29 Information on parents' age at child's birth (<20, 20–24, 25–29, 30–34, 35–39, ≥40 years) and place of birth (both parents Danish born, both born abroad or one born abroad and one unknown/with missing information, one Danish and one born abroad, one Danish born and one unknown/missing information) was obtained from the civil registration system.19 Greenland was considered a foreign country. Parental place of birth was used as a proxy measure of ethnicity. Parental history of MS was determined using information from the MS Registry.
Statistics.
Odds ratios (ORs) of MS according to neonatal levels of 25(OH)D were estimated using conditional logistic regression. Due to the matching scheme, all analyses were controlled for sex, age, and exact date of birth. To explore a dose-response relationship with MS, we modeled neonatal 25(OH)D levels in 5 groups according to quintiles of 25(OH)D in controls. Individuals were furthermore classified into predefined categories of 25(OH)D levels, i.e., individuals with neonatal 25(OH)D serum levels <30 nmol/L, 30–<50 nmol/L, and ≥50 nmol/L were considered to have been born with deficient, insufficient, and sufficient levels, respectively, of 25(OH)D.22,25 Under an assumption of linearity between levels of 25(OH)D and MS risk, we finally modeled 25(OH)D as a continuous variable.
We a priori included gestational age, birthweight, and parental ethnicity in the multivariable conditional logistic regression analysis. Other covariates (mother's age, father's age, Apgar score, and parental MS) were only retained in the model if they changed at least one of the quintile-specific ORs estimated in the above multivariable model by ≥10%. In the multivariable analysis, we excluded cases and controls having missing values.
Standard protocol approvals, registrations, and patient consents.
The present study was approved by the Danish Ethical Committee of the Capital Region, Copenhagen, and The Danish Data Protection Agency.
RESULTS
According to the MS Registry, 796 individuals born on or after April 30, 1981, had developed MS. One hundred seventy-seven patients with MS, 68% of whom were born before 1986, were not identified in DNSB. Restricting to singletons and excluding individuals who did not have sufficient DBSS to measure 25(OH)D, the number of cases and controls was reduced to 534 and 1,001. Twenty of the controls died or had emigrated from Denmark before MS diagnosis in the corresponding case. Finally, we excluded 13 cases without a matched control, and 9 controls without a case, thus limiting the dataset to 521 cases and 972 controls (figure 1).
Figure 1. Study flowchart.
Flowchart shows the identification of patients with multiple sclerosis (MS) and controls.
Characteristics of patients with MS and controls participating in the study are described in table 1. Mean values of serum 25(OH)D were 33.0 nmol/L (SD 16.9, minimum 1.3 nmol/L, maximum 101.4 nmol/L) among patients with MS and 35.9 nmol (SD 17.5, minimum 4.9, maximum 114.7) among controls (p < 0.01) (figure e-1 at Neurology.org). Importantly, 25(OH)D levels measured in DBSS from persons born in the period 1981 to 2000 showed no evidence of 25(OH)D degradation by year for cases or controls (figure 2). Figure 3 shows mean 25(OH)D levels according to month of birth among cases and controls. As expected, a clear seasonal variation was seen for cases as well as for controls, with the lowest levels of 25(OH)D in the winter and early spring.
Table 1.
Characteristics of multiple sclerosis (MS) cases (n = 521) and controls (n = 972)
Figure 2. Mean levels of 25-hydroxyvitamin D (25[OH]D) according to year of birth.
Mean levels of 25(OH)D by year of birth among patients with multiple sclerosis (MS) and controls. Ninety-five percent confidence intervals are shown on the figure. *Based on very few cases: in 1994, 7 cases and 13 controls; in 1995, 4 cases and 8 controls; in 1996, 6 cases and 13 controls; and in 1997, 3 cases and 6 controls. One case and 2 controls were born in 2000 (not shown).
Figure 3. Mean levels of 25-hydroxyvitamin D (25[OH]D) according to month of birth.
Mean levels of 25(OH)D by month of birth among patients with multiple sclerosis (MS) and controls. Ninety-five percent confidence intervals are shown on the figure.
We observed that lower levels of neonatal 25(OH)D were associated with an increased risk of MS. In the analyses by quintiles, MS risk decreased monotonically with increasing 25(OH)D (OR for the highest compared to lowest quintile 0.53, 95% confidence interval [CI] 0.36–0.78; p for trend 0.001, table 2). A similar pattern was seen using predefined categories of 25(OH)D, although no statistically significant difference was observed between sufficient and insufficient levels of 25(OH)D (table 2). Finally, for every 25 nmol/L increase in neonatal 25(OH)D level, the risk of MS was reduced by 30% (OR 0.70, 95% CI 0.57–0.84) (table 2).
Table 2.
Risk of multiple sclerosis according to neonatal levels of 25-hydroxyvitamin D (25[OH]D)
In the multivariable analyses, we ended up adjusting only for parental ethnicity, birthweight, and gestational age, and results were practically unchanged (table 2).
DISCUSSION
In this large population-based case-control study, we found an inverse association between neonatal levels of 25(OH)D and risk of MS. Especially children born with 25(OH)D levels less than 30 nmol/L were at an increased risk of MS, whereas the additional benefit of higher levels of 25(OH)D were less strong. Our results support previous studies suggesting a protective role of vitamin D in the development of MS, but also suggests that vitamin D insufficiency in utero may be of relevance for the risk of MS.
The majority of previous studies have examined the relevance of vitamin D intake, UV radiation, or serum 25(OH)D levels in adolescence or adulthood4,6,16,30–32; few studies have examined the possible association between in utero vitamin D levels and risk of MS, and findings are conflicting.3,14,15,17 Furthermore, direct measurements of in utero levels of D vitamin are not possible, meaning that the above association has only been addressed using different markers of fetal vitamin D levels, including maternal intake of vitamin D14 during pregnancy, maternal serum levels of 25(OH)D during pregnancy,3,17 or neonatal levels of vitamin D.15
A study among US nurses found a lower MS risk in the offspring of women with higher vitamin D intake during pregnancy.14 Results should, however, be interpreted with caution because food intake during pregnancy relied on self-reported data collected several decades after the pregnancy at a point when many patients with MS already had been diagnosed among the offspring, which increases the risk of recall bias.
Two prospective, nested case-control studies have been conducted measuring maternal serum 25(OH)D in pregnancy (primarily 1st trimester) and risk of MS in the offspring. In the first of these studies, conducted in Sweden and including 37 patients with MS and 185 matched controls, there was no significant association between serum 25(OH)D levels in pregnancy and MS risk among the offspring.3 This analysis was, however, limited by the small sample size and by insufficient matching on date of birth. More recently, a larger study was conducted in the Finnish Maternity Cohort. In this study, which included 176 patients with MS and 326 matched controls, maternal vitamin D deficiency during pregnancy (25[OH]D < 30 nmol/L) was associated with a 90% increased risk of MS in the offspring.17
Finally, in a Swedish case-control study, neonatal levels of 25(OH)D were measured in DBSS stored in the Swedish Phenylketonuria Biobank since 1975. In this study, similar in design to ours and including 459 cases and 663 controls, levels of neonatal 25(OH)D were not associated with MS risk.15 Several limitations of the study may have contributed to the null findings, including low participation among controls (∼44%) as compared to cases (∼88%), so that the representativeness of the controls is uncertain.16 In addition, Ueda and colleagues15 reported a substantial degradation of 25(OH)D in older DBSS, which is likely to be due to storage conditions. DBSS in the Swedish Phenylketonuria Biobank were stored at room temperature from 1975 to August 1981, and since then at 4°C. Approximately 50% of the DBSS were collected between 1975 and 1981 and thus exposed to room temperature. In our study, there was no evidence of 25(OH)D degradation, likely due to storage of the DBSS at −20°C.20 Degradation is expected to be similar among cases and controls, and is likely to result in nondifferential misclassification,16 which could also explain the null finding in the Swedish study. Ueda and colleagues15 did repeat the analyses stratifying on 5-year interval of birth year, and interestingly, they observed a tendency towards a lower risk of MS the higher the level of neonatal 25(OH)D levels for individuals born between 1980 and 1984. Thus, for every 10 nmol/L increase in neonatal 25(OH)D level, the risk of MS was reduced by 10% (OR 0.9 [0.78–1.01]), which is consistent with our findings.
A potential limitation of our study is that only 534 of the 796 patients with MS born since the establishment of the DNSB were included in the 25(OH)D analysis, mainly due to lack of DBSS material or due to less completeness of the DNSB in the first years after establishment. However, inadequate material is unlikely to be related to 25(OH)D levels or future MS risk and thus inconsequential for the results of the study. Further, 25(OH)D levels in the present study were low, with more than 40% of the children born with deficient levels of 25(OH)D (<30 nmol/L). Nevertheless, our measured levels of neonatal 25(OH)D are compatible with neonatal values measured in a previous study by Eyles et al.13 Another important issue is how well neonatal 25(OH)D levels measured in DBSS represent 25(OH)D status during pregnancy. 25(OH)D levels in DBSS are highly correlated with levels in umbilical cord blood,13 but probably only moderately correlated with maternal levels at midgestation.25 Thus in a recent longitudinal study in the Netherlands, the correlation between maternal serum levels of 25(OH)D at midgestation and levels of 25(OH)D in the offspring's umbilical cord was 0.57 and levels of 25(OH)D in umbilical cord were about 20 nmol/L lower than maternal serum levels at midgestation.25
Data concerning sun exposure, including outdoor physical activity, body mass index, diet, and intake of vitamin D supplements in adolescence and adult life were not available for cases and controls in our study, which could have influenced our results.25,33 However, in previous studies14,15 adjustment for these covariates did not change the results.
Individuals participating in the present study were young (the majority born after 1981), and many had not yet reached the age of peak MS incidence by the time of the study (2012). Thus our findings largely reflect the association between neonatal vitamin D levels and MS diagnosis up to age 30, and may not necessary be applicable to MS onset in older individuals.
A key question is whether the lower MS risk among children born with higher 25(OH)D levels reflects a direct protective effect of higher 25(OH)D levels in utero, or rather if it is mediated by higher vitamin D status during childhood and early adulthood. The association between 25(OH)D levels at birth and later in life is most likely to occur because of a combination of behavioral (similarity between mother and child in vitamin D intake and sunlight exposure) and genetic factors. Although genetic variations in 25(OH)D levels are modest34 and by themselves insufficient to explain the strong association found in this study, the impact of behavioral factors is more difficult to quantify, and we cannot therefore exclude the possibility that 25(OH)D levels in childhood and adolescence account for the apparent protective effects of in utero 25(OH)D.
Nevertheless, our results support previous suggestions of a protective role for vitamin D in the development of MS.16,32 Although the exact mechanism of a vitamin D effect is incompletely understood, it is likely to involve an attenuation of the T-cell response to autoantigens and suppression of the production of proinflammatory cytokines such as interferon-γ and Th17-interleukin 17.35 By modifying and regulating the production and release of neurotrophic factors, vitamin D may also have a neuroprotective effect.36 Animal studies have furthermore suggested that prenatal exposure to vitamin D deficiency may lead to alteration in mitochondrial, cytoskeletal, and synaptic functions of the brain.37,38
We observed an inverse association between neonatal levels of 25(OH)D and risk of MS, thus the higher the level of 25(OH)D among neonates the lower their risk of MS in later life. However, we cannot exclude the possibility that this apparent beneficial effect is mediated by a correlation between 25(OH)D levels at birth and levels later in life, in which case maternal vitamin D supplementation would not reduce MS risk in the offspring. This uncertainty notwithstanding, the high global prevalence of hypovitaminosis D among pregnant women25,39 and the fact that increasing maternal vitamin D levels is likely to reduce the mother's risk of MS as well as her offspring's provides a rationale for universal vitamin D supplementation in pregnancy.
Supplementary Material
GLOSSARY
- 25(OH)D
25-hydroxyvitamin D
- 25(OH)D2
25-hydroxyvitamin D2
- 25(OH)D3
25-hydroxyvitamin D3
- CI
confidence interval
- DBSS
dried blood spots samples
- DNSB
Danish Newborn Screening Biobank
- MS
multiple sclerosis
- OR
odds ratio
Footnotes
Supplemental data at Neurology.org
Editorial, page 13
AUTHOR CONTRIBUTIONS
All the authors contributed to the conception and design of the study. A.A., K.L.M., N.M.N., N.K.-H., M.M., E.S., D.M.H., A.C., and M.L. contributed to the acquisition of data. A.A., K.L.M., J.S., and N.M.N. performed the statistical analyses; D.M.H., A.C., and M.L. carried out the vitamin D analyses. All the authors contributed to drafting a significant portion of the manuscript and the figures.
STUDY FUNDING
The study was supported by the Danish Society of Multiple Sclerosis and the Aase & Ejnar Danielsen's Foundation. Drs. Ascherio and Munger are supported by research grants from the US NIH (NIH R01NS073633 and R01NS046635) and National Multiple Sclerosis Society for the investigation of the role of vitamin D and other risk factors in MS.
DISCLOSURE
The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
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