Conceived and designed the experiments: AHP JS ES. Performed the experiments: AHP. Analyzed the data: AHP. Contributed reagents/materials/analysis tools: ES CJ JB. Wrote the paper: AHP ES JB CJ SF JS. Supervised AHP perform the experiments and analyze the data: JS SF.
Since 1994, CJ has been a Consultant to the Danish National Board of Health in the area electromagnetic fields and health and received support from Sonofon and TeleDenmark Mobile for the establishment of the nationwide cohort in 1999. ES has received financial support for congress participation from Bayer Schering, Merck Serono, Biogen Idec, Sanofi Aventis and Novartis and unrestricted research grants from Bayer Schering, Merck Serono, and Biogen Idec. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors.
We investigated the risk of, prognosis of and symptoms of multiple sclerosis (MS) among all Danish residents who owned a mobile phone subscription before 1996. Using the Danish Multiple Sclerosis Registry and Civil Registration System, study subjects were followed up for MS through 2004. Poisson models were used to calculate incidence rate ratios (IRR, age range: 18–64 years) and mortality rate ratios (MRR, age range: 18+) and to compare presenting symptoms among subscribers and all non-subscribers. A total of 405 971 subscription holders accrued four million years of follow up, with men accounting for 86% of the observation time. Among subscription holding men, the IRR of MS was close to unity, overall as well as 13+ years after first subscription (IRR 1.02, 95% CI: 0.48–2.16). Among women, the IRR was 3.43 (95% CI: 0.86–13.72) 13+ years after first subscription, however, based on only two cases. Presenting symptoms of MS differed between subscribers and non-subscribers (p = 0.03), with slightly increased risk of diplopia in both genders (IRR: 1.38, 95% CI: 1.02–1.86), an increased risk of fatigue among women (IRR: 3.02, 95% CI: 1.45–6.28), and of optic neuritis among men (IRR: 1.38, 95% CI: 1.03–1.86). Overall the MRR was close to one (MRR: 0.91, 95%CI 0.70–1.19) among MS-patients with a subscription and although we observed some increased MRR estimates among women, these were based on small numbers. In conclusion, we found little evidence for a pronounced association between mobile phone use and risk of MS or mortality rate among MS patients. Symptoms of MS differed between subscribers and nonsubscribers for symptoms previously suggested to be associated with mobile phone use. This deserves further attention, as does the increased long-term risk of MS among female subscribers, although small numbers and lack of consistency between genders prevent causal interpretation.
Usage of mobile phones has changed dramatically in the last two decades, with steeply increasing number of users and decreasing age at first use. The radiofrequency electromagnetic fields (RF-EMF) emitted from mobile phones held to the head penetrates up to six cm into the brain
The study was approved by the Danish ethical committee system (KF 01–075/96), the Danish Data Protection Board (1996–1200–121, 2009–41–3886), and the Danish Ministry of Justice (Jnr. 1996–760–0219). In accordance with Danish law informed consent was not obtained as the study was entirely register-based and did not involve biological samples from, or contact with study participants.
We conducted this study within the population of Denmark during the period 1987–2004. All Danish citizens are assigned a unique personal identification number at birth by the Danish Central Population Registry (CPR), which keeps complete information about the date of birth, gender, vital status, migration and current and former addresses of all Danes
MS cases were identified from the Danish Multiple Sclerosis Registry
Records of all (723 421) mobile phone subscriptions in Denmark during the period 1982 (when this service was established) until the end of 1995 were obtained from the Danish network operatoros. Details of the cleaning process of these data has been reported previously
In analyses of risk of MS and presenting symptoms among mobile phone subscription holders, symptom free subjects entered the study population on 1 January 1987 or age 18 years, whichever occurred latest. Follow-up ended at date of MS diagnosis, age 65 years, death, emigration from Denmark or 31 December 2004, whichever came first. Exposed person time was further categorized based on duration of follow-up since date of first subscription (<1, 1–3, 4–6, 7–9, 10–12, 13+ years). In a subanalysis, we used July 1st in the year of the first recorded symptom(s) as endpoint. Due to the retrospective nature of debut data follow-up was, for this analysis, terminated on 31 December 2000 allowing four years until 2004 to identify patients with first symptoms in 2000 or earlier. In these analyses, we excluded 13 573 subscription holders who obtained their subscription after age 65 years, 30 with MS symptoms before age 18 years, 366 with symptoms before 1987 and 142 diagnosed with MS before getting a subscription, yielding a population of 405 971 mobile phone subscription holders.
In analyses of risk of death among MS patients using mobile phone, MS patients diagnosed between age 18 and 65 years in 1980 or later entered the study population at date of diagnosis or 1 January 1987, whichever came latest. Follow-up ended at date of death, emigration from Denmark or on 31 December 2004, whichever came first. A total of 7420 MS-patients met the inclusion criteria, of whom 717 were subscription holders. For these patients, exposed person-years were cumulated from date of diagnosis or date of subscribing, whichever came last, and subdivided into five categories (<1, 1–3, 4–6, 7–9, 10+ years).
To evaluate a potentially reverse association, we analysed MS as an explanatory factor for obtaining a subscription in the 5 050 MS patients with a first symptom between age 18 and 65 years in the period 1980 to 1995. Entry and exit criteria were as for the main analysis, except that subjects were censored at the date of subscription acquisition, or on 31 December 1995, and not at the time of the MS-diagnosis. Time after first MS-symptom was subdivided according to diagnostic status (1st symptom, diagnosis), and years since first symptom and since diagnosis (<1, 1–3, 4–6, 7–9, 10+ years).
Log-linear Poisson regression analysis was used to compute incidence and mortality rate ratios (IRRs or MRRs) for MS diagnosis, MS debut and risk of death in MS patients among mobile phone subscription holders compared to non-subscribers. The analyses were adjusted for gender, age (in incidence analyses: 18–29, 30–39, 40–49 and 50–65 years; in mortality analyses:18–29, 30–39, 40–49, 50–59, 60–69, 70–79 and 80+ years) and individual calendar year (1987 to 2004 by increments of 1 year). Subjects were allowed to change between categories of covariates and exposure variables over time. When analysing risk of death, years since diagnosis was included as a linear covariate.
The presenting symptoms of MS among subscribers and nonsubscribers were compared by analysing MS diagnoses with different initial symptoms as competing risks in a Poisson model as above with independent gender, age and period dependency for each symptom.
For date variables with missing day values, the 15th of the respective month was used and when the month was missing, July 1st was used. As only the year of first symptom was available, the date of first symptom was set to July 1st of the given year or the actual date of diagnosis, whichever came first. The statistical analyses were performed in SAS 9.1.
The gender and age profile of new subscription holders changed dramatically over the course of the exposure (mobile phone subscription) period (
Mobile phone subscription penetration in the Danish population by age in 1990 and 1995.
The 405 971 subscription holders accrued 4 063 040 years of follow up (mean 10.0 years; maximum 18.0 years). The overall risks of MS in subscription holding women and men were 1.02 (95% CI: 0.83–1.24) and 1.11 (95% CI: 0.98–1.26), respectively (
Women | Men | Total | ||||||||
Personyears | MS | IRR 95% CI | Personyears | MS | IRR 95% CI | Personyears | MS | IRR 95% CI | ||
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27 517 890 | 3 531 | Reference | 25 309 803 | 1 517 | Reference | 52 827 693 | 5 048 | Reference | |
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572 177 | 102 | 1.02 (0.83–1.24) | 3.490.862 | 304 | 1.11 (0.98–1.26) | 4 063 040 | 406 | 1.06 (0.96–1.18) | |
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<1 | 60 044 | 13 | 1.61 (0.93–2.79) | 344 413 | 18 | 0.91 (0.57–1.46) | 404 457 | 31 | 1.09 (0.76–1.56) | |
1–3 | 176 918 | 26 | 1.00 (0.68–1.48) | 1 012 944 | 70 | 1.12 (0.87–1.44) | 1 189 862 | 96 | 1.05 (0.85–1.29) | |
4–6 | 171 243 | 28 | 0.84 (0.58–1.22) | 975 610 | 100 | 1.21 (0.98–1.50) | 1 146 853 | 128 | 1.08 (0.90–1.29) | |
7–9 | 139 559 | 26 | 0.91 (0.61–1.34) | 840 374 | 91 | 1.11 (0.89–1.39) | 979 932 | 117 | 1.04 (0.86–1.26) | |
10–12 | 20 847 | 7 | 1.87 (0.89–3.94) | 234 295 | 18 | 0.88 (0.55–1.41) | 255 142 | 25 | 1.04 (0.70–1.54) | |
13+ | 3 567 | 2 | 3.43 (0.86–13.72) | 83 227 | 7 | 1.02 (0.48–2.16) | 86 794 | 9 | 1.26 (0.65–2.43) | |
10+ | 24 414 | 9 | 2.08 (1.08–4.01) | 317 522 | 25 | 0.92 (0.61–1.37) | 341 936 | 34 | 1.09 (0.77–1.53) | |
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21 929 622 | 3 336 | Reference | 20 599 730 | 1 485 | Reference | 42.529.353 | 4 821 | Reference | |
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351 972 | 57 | 0.94 (0.72–1.23) | 2 261 285 | 195 | 1.10 (0.94–1.28) | 2 613 258 | 252 | 1.05 (0.92–1.19) | |
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<1 | 60 012 | 7 | 0.70 (0.33–1.48) | 344 332 | 33 | 1.33 (0.94–1.90) | 404 344 | 40 | 1.11 (0.81–1.52) | |
1–3 | 176 836 | 30 | 0.98 (0.69–1.41) | 1 012 638 | 84 | 1.06 (0.84–1.33) | 1 189 474 | 114 | 1.02 (0.84–1.24) | |
4–6 | 104 217 | 17 | 0.93 (0.58–1.51) | 705 980 | 65 | 1.09 (0.84–1.41) | 810 197 | 82 | 1.06 (0.84–1.32) | |
7–9 | 8 703 | 1 | 0.73 (0.10–5.16) | 138 245 | 11 | 1.06 (0.59–1.93) | 146 948 | 12 | 1.05 (0.60–1.86) | |
10+ | 2 204 | 2 | 6.75 (1.69–27.05) | 60 091 | 2 | 0.50 (0.13–2.02) | 62 295 | 4 | 0.99 (0.37–2.65) |
Analysing until year of first symptom yielded similar results when comparing ever versus never subscribing. However, among men we observed a 33% increased risk of having the first symptom within one year of obtaining a subscription. In subsequent years there was little deviation from unity, except in the strata of 10+ years of usage where the risk was reduced by half but based on only two cases (IRR: 0.50, 95%CI 0.13–2.02). Among women, there was a 30% decreased risk in the first year after subscribing and the only estimate above one was for 10+ years of subscribing where there was a more than six fold increased risk, however based on only two cases.
Presenting symptoms of MS differed significantly between subscribers and non-subscribers (
Women | Men | Total | |||||||
Unexposedcases | Exposedcases | IRR 95% CI | Unexposedcases | Exposedcases | IRR 95% CI | Unexposedcases | Exposedcases | IRR 95% CI | |
Person years | 27 517 890 | 572 177 | 25 309 803 | 3 490 862 | 52 827 693 | 4 063 040 | |||
Cerebellar symptoms | 326 | 4 | 0.40 (0.15–1.08) | 138 | 21 | 0.81 (0.51–1.30) | 464 | 25 | 0.67 (0.44–1.01) |
Diplopia | 300 | 14 | 1.59 (0.92–2.72) | 157 | 40 | 1.32 (0.92–1.89) | 457 | 54 | 1.38 (1.02–1.86) |
Optic neuritis | 694 | 23 | 1.08 (0.71–1.64) | 217 | 58 | 1.38 (1.03–1.86) | 911 | 81 | 1.24 (0.97–1.57) |
Pyramidal dysfunction | 837 | 17 | 0.71 (0.44–1.15) | 452 | 80 | 1.00 (0.78–1.27) | 1 289 | 97 | 0.90 (0.73–1.12) |
Sensory symptoms | 1 836 | 50 | 0.92 (0.69–1.22) | 653 | 130 | 1.02 (0.84–1.24) | 2 489 | 180 | 0.98 (0.84–1.15) |
Sphincter control | 116 | 1 | 0.27 (0.04–1.97) | 63 | 15 | 1.20 (0.68–2.14) | 179 | 16 | 0.95 (0.56–1.61) |
Vertigo | 226 | 8 | 0.95 (0.47–1.92) | 61 | 12 | 0.79 (0.43–1.47) | 287 | 20 | 0.85 (0.53–1.35) |
Fatigue | 74 | 8 | 3.02 (1.45–6.28) | 40 | 11 | 1.09 (0.56–2.12) | 114 | 19 | 1.61 (0.96–2.69) |
Other/Unstated symptoms | 355 | 8 | 1.28 (0.63–2.59) | 145 | 23 | 1.30 (0.82–2.06) | 500 | 31 | 1.30 (0.89–1.89) |
The 717 subscription holding MS-patients accrued 4 934 years of exposed follow-up from 1987 onwards (mean: 6.9 years; maximum 18.0 years). The overall MRRs of death were 1.27 (95% CI: 0.77–2.09) and 0.79 (95% CI: 0.58–1.09) among female and male MS-patients, respectively, with a subscription (
Women | Men | Total | |||||||
Person years | Deaths | MRR 95% CI | Person years | Deaths | MRR 95% CI | Person years | Deaths | MRR 95% CI | |
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39 575 | 400 | Reference | 18 333 | 306 | Reference | 57 908 | 706 | Reference |
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1 339 | 16 | 1.27 (0.77–2.09) | 3 595 | 45 | 0.79 (0.58–1.09) | 4 934 | 61 | 0.91 (0.70–1.19) |
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<1 | 190 | 2 | 1.35 (0.33–5.45) | 509 | 2 | 0.40 (0.10–1.64) | 700 | 4 | 0.59 (0.22–1.59) |
1–3 | 487 | 4 | 1.06 (0.39–2.85) | 1 305 | 7 | 0.47 (0.22–1.00) | 1 792 | 11 | 0.58 (0.32–1.06) |
4–6 | 382 | 2 | 0.57 (0.14–2.00) | 934 | 14 | 0.91 (0.53–1.57) | 1 317 | 16 | 0.90 (0.54–1.48) |
7–9 | 246 | 8 | 2.44 (1.20–4.98) | 645 | 16 | 1.06 (0.63–1.78) | 891 | 24 | 1.41 (0.93–2.15) |
10+ | 33 | 0 | – | 202 | 6 | 0 93 (0.41–2.12) | 235 | 6 | 0.95 (0.42–2.15) |
The 5 050 MS patients accrued 29 993 person years from 1987 to 1995 (mean, 5.9 years; maximum 9.0 years). Among women, there was no increased likelihood of obtaining a subscription after first symptoms or in the first year after being diagnosed with MS (
Women | Men | Total | ||||||||
Personyears | Subscrpt | IRR 95% CI | Person years | Subscrpt | IRR 95% CI | Person years | Subscrpt | IRR 95% CI | ||
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14 376 975 | 60 019 | Reference | 14 188 947 | 338 243 | Reference | 28 565 922 | 398 262 | Reference | |
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Symptoms | 8 604 | 41 | 1.00 (0.73–1.35) | 3 857 | 97 | 1.04 (0.85–1.27) | 12 461 | 138 | 1.04 (0.88–1.22) | |
Diagnosis | 11 172 | 86 | 1.22 (0.99–1.51) | 6 360 | 193 | 1.00 (0.87–1.15) | 17 532 | 279 | 1.07 (0.95–1.21) | |
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<1 | 1 581 | 7 | 1.00 (0.48–2.10) | 742 | 21 | 1.24 (0.81–1.90) | 2 323 | 28 | 1.17 (0.81–1.69) | |
1–3 | 3 168 | 8 | 0.61 (0.31–1.23) | 1 512 | 40 | 1.25 (0.92–1.71) | 4 680 | 48 | 1.07 (0.80–1.42) | |
4–6 | 2 052 | 12 | 1.31 (0.74–2.30) | 874 | 17 | 0.85 (0.53–1.36) | 2 926 | 29 | 1.00 (0.69–1.43) | |
7–9 | 1 190 | 6 | 0.96 (0.43–2.14) | 501 | 11 | 0.78 (0.43–1.40) | 1 692 | 17 | 0.84 (0.52–1.35) | |
10+ | 612 | 8 | 1.41 (0.70–2.81) | 228 | 8 | 0.82 (0.41–1.64) | 840 | 16 | 1.07 (0.65–1.74) | |
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<1 | 1 629 | 6 | 0.67 (0.30–1.50) | 865 | 24 | 1.02 (0.69–1.52) | 2 494 | 30 | 0.93 (0.65–1.33) | |
1–3 | 4 068 | 31 | 1.31 (0.92–1.87) | 2 252 | 72 | 1.22 (0.97–1.54) | 6 320 | 103 | 1.26 (1.04–1.53) | |
4–6 | 2 849 | 23 | 1.44 (0.96–2.17) | 1 735 | 48 | 0.96 (0.72–1.28) | 4 584 | 71 | 1.08 (0.86–1.37) | |
7–9 | 1 735 | 14 | 1.18 (0.70–2.00) | 1 010 | 32 | 0.94 (0.67–1.33) | 2 745 | 46 | 1.02 (0.76–1.36) | |
10+ | 891 | 12 | 1.20 (0.68–2.11) | 498 | 17 | 0.64 (0.40–1.04) | 1 389 | 29 | 0.81 (0.56–1.17) |
In our population-based cohort study of mobile phone subscription holders, we found no overall increased risk of MS among subscription holders, irrespective of whether analyzed until clinical MS diagnosis or until first recorded symptom. Neither did we find any overall increased risk of death among subscription holding MS-patients. Among subgroups of women, we did observe some risk increases of MS, MS-symptoms and death after long-term subscription, however, the numbers were small in these analyses and may have been chance findings. Among men, we found a tendency towards increased risks of MS-symptoms, in the first year after mobile phone subscription, and of MS in the period 1–9 years after first subscription. Among male MS patients, the risk of death appeared to be decreased in the first years of mobile phone exposure, approaching unity after 4 years. The first symptoms of MS were different among mobile phone users compared to non-subscribers, with subscription holders having more frequent fatigue among women, increased optic neuritis among men, and diplopia in both sexes.
Our observation of an increased risk of MS among men 1–9 years after first subscription could be due to reverse causation, particularly since men were somewhat more likely to obtain a subscription in the years immediately after being recorded with their first symptoms. However, as a large proportion of MS cases were diagnosed within the first few years after their first symptom, we would have expected to also see a risk increase in the first year after first subscription. We did observe slightly increased risk of first symptoms of MS within the first year after first subscription. This could be a triggering/promoting effect, but such effects would likely also affect women, contrary to our findings, and it therefore seems more likely a chance finding or detection bias related to use of the mobile phone. In addition, there is also the possibility of reverse causation, since only the year of first recorded symptom and not the actual date of first symptom experienced was available for most subjects, therefore the temporal resolution does not allow exact sequencing of events within the year of first symptom. This interpretation is supported by the fact that we observed both an increased chance of obtaining a subscription in the year of the first symptom and an increased risk of having a first symptom of future MS within the first year after first subscription. Among female mobile phone users, we observed a doubling in risk of MS 10 or more years after first subscription, however, this finding was based on very few cases, and the limited statistical precision in combination with lack of dose response and disagreement with the results in men suggests chance as a more likely explanation. The fact that the risk was also present when analysing until first symptom and that the risk was even more pronounced when the follow-up period was restricted to 13+ years may, however, merit further attention. It should also be kept in mind that the first female users who were the most likely long term exposed subjects were a select subgroup of presumably affluent women, and therefore confounding may also have influenced the results.
Fatigue was more frequent among female mobile phone subscribers, but not among men. Although tiredness/fatigue is among the more common complaints in mobile users
We did not observe an increased risk of death in MS cases following mobile subscription, rather, among men, there was a tendency for a decreased risk of death in the first years after obtaining a subscription. These estimates were, however, based on small numbers, and the risk decrease among men is likely attributable to chance. It is, however, conceivable that there is a healthy subscriber bias at the time of mobile phone acquisition as its use requires the physical and cognitive capabilities to operate the mobile phone as well as spending enough time away from a landline phone to justify the extra expense. The numbers of deaths among female MS patients with mobile phone subscription were too small to allow any conclusions.
It is a general epidemiological concern that early symptoms of the outcome of interest may have a reverse effect on the likelihood of exposure and thereby make it difficult to discern cause and effect. For instance, migraine-like symptoms are more common in MS-patients
Our study was a nationwide cohort study based on objective and prospectively registered exposure data with validated and carefully evaluated outcome data from a nationwide high quality register
A limitation of the study was the lack of exposure details and potential exposure misclassification
We found little evidence for an association between mobile phone use and risk of MS or of death in MS patients in this nationwide study of mobile phone subscribers in Denmark. We did, however, observe an increased risk of both MS symptoms and diagnosis among long-term female subscribers, although this was based on small numbers. The presenting symptoms of MS differed between subscribers and nonsubscribers with elevated risks for symptoms previously suggested to be associated with mobile phone use (visual disturbances and fatigue) observed among the mobile phone users. These observations merit further attention in more detailed studies, such as the ongoing prospective COSMOS study