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HPV vaccination and risk of chronic fatigue syndrome/myalgic
encephalomyelitis: A nationwide register-based study from Norway
Berit Feiring
a,
⇑
, Ida Laake
a
, Inger Johanne Bakken
b
, Margrethe Greve-Isdahl
c
, Vegard Bruun Wyller
d
,
Siri E. Håberg
e
, Per Magnus
f
, Lill Trogstad
a
a
Department of Infectious Disease Epidemiology and Modelling, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway
b
Department of Child Health, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway
c
Department of Vaccine Preventable Diseases, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway
d
Department of Paediatrics and Adolescent Health, Akershus University Hospital, 1478 Lørenskog, Norway
e
Division of Physical and Mental Health, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway
f
Division of Health Data and Digitalisation, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway
article info
Article history:
Received 10 February 2017
Received in revised form 25 May 2017
Accepted 9 June 2017
Available online xxxx
Keywords:
Human papillomavirus vaccine
Chronic fatigue syndrome
Myalgic encephalomyelitis
Vaccine safety
Vaccine uptake
Medical history
abstract
Background: Vaccination has been suggested to be involved in the aetiology of chronic fatigue syndrome/
myalgic encephalomyelitis (CFS/ME). HPV vaccine was introduced in the Norwegian Childhood
Immunisation Programme and offered 12 year old girls from 2009. We studied the association between
HPV vaccination and risk of CFS/ME and also assessed medical history in relation to both risk of CFS/ME
and HPV vaccine uptake.
Methods: Individual data from national registries, including the Norwegian Population Registry, the
Norwegian Patient Registry and the Norwegian Immunisation Registry were linked using the unique per-
sonal identification number. Yearly incidence rates of CFS/ME for 2009–2014 were calculated among the
824,133 boys and girls, aged 10–17 living in Norway during these 6 years. A total of 176,453 girls born
1997–2002 were eligible for HPV vaccination and included in further analyses. Hazard ratios (HRs) of
CFS/ME were estimated using Cox regression. Risk differences (RDs) of vaccine uptake were estimated
with binomial regression.
Results: A similar yearly increase in incidence rate of CFS/ME was observed among girls and boys,
IRR = 1.15 (95% confidence interval (CI) 1.10–1.19) and 1.15 (95% CI 1.09–1.22), respectively. HPV vacci-
nation was not associated with CFS/ME, HR = 0.86 (95% CI 0.69–1.08) for the entire follow-up period and
0.96 (95% CI 0.64–1.43) for the first two years after vaccination. The risk of CFS/ME increased with
increasing number of previous hospital contacts, HR = 5.23 (95% CI 3.66–7.49) for 7 or more contacts
as compared to no contacts. Girls with 7 or more hospital contacts were less likely to be vaccinated than
girls with no previous hospital contacts, RD = 5.5% (95% CI 6.7% to 4.2%).
Conclusions: No indication of increased risk of CFS/ME following HPV vaccination was observed among
girls in the first 6 birth cohorts offered HPV vaccine through the national immunisation programme in
Norway.
Ó2017 The Authors. Published by Elsevier Ltd. This is an open access articleunder the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)
is a complex clinical condition characterized by persistent severe
and disabling unexplained fatigue [1]. The aetiology of CFS/ME is
unknown. There are no biomarkers for the disease and no validated
laboratory test for diagnosis. Altered cognitive function, autonomic
dysfunction, neuroendocrine abnormalities and alterations in the
immune system, including abnormal cytokine patterns, deficien-
cies in natural killer cell function and poorly responsive T cells,
are reported in CFS/ME patients [1–8]. Also, higher frequencies of
autoantibodies have been described, and autoimmune mecha-
nisms may be involved [2,9–11]. Autoimmunity might be triggered
by infections, and CFS/ME is often precipitated by a long-lasting
viral infection, such as glandular fever [1,11–13]. Recently, a slight
impairment of B cell differentiation and development combined
http://dx.doi.org/10.1016/j.vaccine.2017.06.031
0264-410X/Ó2017 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
⇑
Corresponding author.
E-mail addresses: berit.feiring@fhi.no (B. Feiring), ida.laake@fhi.no (I. Laake),
inger.johanne.bakken@fhi.no (I.J. Bakken), margrethe.greve-isdahl@fhi.no
(M. Greve-Isdahl), brwylle@online.no (V.B. Wyller), sirieldevik.haberg@fhi.no
(S.E. Håberg), per.magnus@fhi.no (P. Magnus), lill.trogstad@fhi.no (L. Trogstad).
Vaccine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Please cite this article in press as: Feiring B et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-
based study from Norway. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.031
with activation of anti-viral innate immunity was suggested from
gene expression studies, further suggesting a possible pathophysi-
ological role for viral infections [14].
Vaccines have also been suggested to play a role in the develop-
ment of CFS/ME, but no associations between vaccination and CFS/
ME have been found for the vaccines studied, including the biva-
lent HPV vaccine [12,15–18]. The risk of CFS/ME after vaccination
with the quadrivalent HPV vaccine has not been studied.
Concerns have been raised about a possible relationship between
HPV vaccination and two syndromes with symptoms that partly
overlap with CFS/ME, namely postural orthostatic tachycardia syn-
drome (POTS) and complex regional pain syndrome (CRPS) [19–26].
Moreover, clinical manifestations with CFS/ME-like symptoms
reported after HPV vaccination have been referred to as ‘HPV vaccina-
tion associated neuro immunopathic syndrome (HANS)’ and ‘human
papillomavirus vaccination syndrome’ [27,28].However,studies
comparing vaccinated and unvaccinated girls have not been per-
formed. Reviews performed by the European Medicines Agency
(EMA) and the WHO Global Advisory Committee on Vaccine Safety
(GACVS) foundno evidence to supporta causal link between HPV vac-
cination and development of CRPS or POTS [29,30]. However, the
body of evidence is limited, and the conclusion in EMA’s report has
been discussed [31–34]. Thus, further research is still warranted.
In Denmark, girls and women reporting severe adverse events
following HPV vaccination, including POTS and other CFS/ME-like
symptoms, had been seeking healthcare more often in the two
years prior to vaccination than vaccinees not reporting adverse
events [35]. Underlying conditions that predispose for medical out-
comes suspected to be adverse vaccine reactions have been linked
to lower vaccine uptake [36]. This may result in healthy vaccinee
bias [37,38]. Thus, it is important to consider medical history when
studying adverse events following vaccination [35,36]. Whether
conditions associated with increased risk of CFS/ME-like symp-
toms are linked to lower uptake of HPV vaccine was not addressed
in the Danish study.
The HPV vaccine was included in the Norwegian Childhood
Immunisation Programme in the autumn of 2009. The quadrivalent
vaccine has been offered in a three-dose schedule to girls aged 12
through a school-based programme during 7th grade. The uptake
of at least one dose HPV vaccine has increased from 70% among
girls born in 1997, the first cohort eligible for vaccination, to 88%
among girls born in 2002 [39,40]. A catch-up programme for older
girls was first implemented in November 2016.
A Norwegian study found two distinct age peaks in the incidence
of CFS/ME, the first among adolescents aged 10–19 years, and a sec-
ond in the age group 30–39 years [41]. During the last decade, an
increase in referrals of children with fatigue has been reported in
Norway [42]. If this increase is related to the implementation of
the HPV vaccination programme, we would expect to observe a lar-
ger increase in CFS/ME incidence among girls than among boys.
The main aim was to study the association between HPV vacci-
nation and risk of CFS/ME among girls eligible for HPV vaccination
in the national immunisation programme in Norway. Also, we
wanted to describe and compare the incidence of CFS/ME among
adolescent girls and boys after introduction of the HPV vaccine in
2009. Finally, we wanted to study medical history in relation to
both risk of CFS/ME and uptake of HPV vaccine.
2. Material and methods
2.1. Data sources
Information on sex and dates of birth, immigration, emigration
and death on all residents in Norway, born 1992–2004 was
obtained from the Norwegian Central Population Registry.
The Norwegian Patient Registry (NPR) provided information on
hospital contacts. The NPR contains information on date and dis-
charge diagnosis of all in- and outpatient visits in specialist health-
care from 2008 onwards [43]. Hospital discharge diagnoses are
reported according to the International Classification of Diseases,
Version 10 (ICD-10) [44].
Information on vaccinations was extracted from the Norwegian
Immunisation Registry. Notification to the immunisation registry
is mandatory for all vaccinations within the national childhood
immunisation programme [45].
Statistics Norway provided information on parental countries of
birth, parental education levels (as of 31 December 2012) and
county of residence.
We used the unique personal identification number allocated to
all Norwegians to link information from the different national
registers.
The study was approved by the Regional Committee for Medical
and Health Research Ethics, South East Norway.
2.2. Study populations and follow-up
The study population included all individuals born 1992–2004
residing in Norway at any time before December 31, 2012,
n = 859,285. Follow-up started from the 10-year birthday, January
1, 2009 or start of residency in Norway, whichever came last. Indi-
viduals were followed until diagnosis of CFS/ME (see definition
below), death, emigration, their 18-year birthday (corresponding
to the age in 2015 of the first cohort offered the HPV vaccine), or
December 31, 2014, whichever came first. We excluded individuals
who did not reside in Norway during the follow-up period, i.e. indi-
viduals who emigrated (n = 25,150) or died (n = 4584) before start
of follow-up, and individuals who immigrated after end of follow-
up, i.e. after their 18-year birthday (n = 5162). Furthermore, 199
individuals diagnosed with CFS/ME before start of follow-up were
excluded. Finally, we excluded 55 individuals missing from the
Norwegian Central Population Registry as of December 31, 2014
and 2 emigrated individuals with missing date of emigration. Inci-
dence rates of CFS/ME were calculated among the remaining
824,133 individuals.
All other analyses were further restricted to the subset of girls
born 1997–2002 and thus eligible for HPV vaccination through
the national immunisation programme, n = 183,569. In analyses
of this subset, end of follow-up was defined as described above.
However, follow-up started later; September 1, the year the girls
turned 12 and were offered HPV vaccine. We excluded girls who
emigrated (n = 978), died (n = 31) or were diagnosed with CFS/
ME (n = 61) before the start of this new follow-up period. Further-
more, girls who immigrated later than January 1, the year they
turned 11 (n = 4291) were excluded to ensure complete informa-
tion on medical history. Finally, girls with missing information
on both parents’ country of birth (n = 49), both parents’ education
level (n = 1292), or county of residence (n = 414) were excluded.
Thus, 176,453 girls were included in the analyses. To study
whether associations were stronger during the first period after
exposure, we performed additional analyses where the girls were
censored after 2 years (two-year follow-up).
2.3. Study variables
CFS/ME was defined as an in-or outpatient hospital visit with a
discharge diagnosis coded as G93.3 in the NPR. The national guide-
lines on CFS/ME recommend using ICD-10 code G93.3 for CFS/ME,
regardless of suspected cause, and that children and adolescents
are diagnosed by a paediatrician in the specialized health care
[46]. Children and adolescents are usually diagnosed according to
guidelines from the Norwegian Paediatric Association [41,47],
2B. Feiring et al. / Vaccine xxx (2017) xxx–xxx
Please cite this article in press as: Feiring B et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-
based study from Norway. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.031
which refer both to the Fukuda criteria [48] and to a broader case
definition, requiring 3 months of unexplained, disabling, chronic
fatigue. A recent Norwegian study found that 73% of adolescents
diagnosed with CFS/ME, were diagnosed according to the Fukuda
criteria [49].
HPV vaccination was defined as receipt of at least one dose of
HPV vaccine after the age of 9 and before the end of the study per-
iod, December 31, 2014. Due to the time lag between onset of
symptoms and CFS/ME diagnosis, estimating a dose response rela-
tionship was not feasible. Moreover, occurrence of CFS/ME-like
symptoms after the first or second dose could influence the deci-
sion to receive the next dose. In birth cohorts offered all three
doses, 95% of girls starting vaccination, completed the three-dose
schedule.
Medical history was defined according to hospital contacts reg-
istered in the NPR during the 20 months before HPV vaccine was
offered to each birth cohort, i.e. before September 1, the year the
girls turned 12. This period was chosen since data was only avail-
able from January 1, 2008, i.e. 20 months prior to vaccination of the
first birth cohort. The majority of hospital contacts, 89.7% were
outpatient visits, 2.9% were admissions for day time treatment,
and 7.4% were over-night admissions.The number of hospital con-
tacts ranged from 0 to 110 and was categorised as 0, 1, 2, 3–4, 5–6
and 7 or more. The main hospital discharge diagnoses were
categorised according to ICD-10 chapters: A00-B99, C00-D48,
D50-D89, E00-E99, F00-F99, G00-G99, H00-H59, H60-H95,
I00-I99, J00-J99, K00-K93, L00-L99, M00-M99, N00-N99,
Q00-Q99, R00-R99, S00-T98 and Z00-Z99.
Country background was defined as ‘Norwegian’ if both parents
were Norwegian-born, and otherwise ‘non-Norwegian’.
Parental education was categorised based on maternal educa-
tion: ‘compulsory education’, ‘secondary education (including ter-
tiary vocational education)’, ‘higher education, undergraduate
level’ and ‘higher education, graduate level’. If maternal education
was missing, paternal education was used.
Region of residence was defined as ‘Oslo’,’ Eastern-Norway,
except Oslo ‘, ‘Southern-‘, ‘Western-‘, ‘Mid-‘ and ‘Northern-
Norway’.
2.4. Statistical analyses
We calculated annual age-standardized incidence rates of
CFS/ME for 2009–2014. The person-time from 2010 to 2014, in
1-year age groups, was used as the standard. We calculated corre-
sponding rate ratios with 2009 as reference. To compare the rates
for girls and boys, we used a Poisson regression model with the fol-
lowing variables: sex, year, and age (1-year age groups). An inter-
action term between sex and year was included to investigate
whether the yearly changes differed by sex. A Wald test was used
to test for significance of the terms in the model.
We used Cox regression to study HPV vaccination and medical
history in relation to CFS/ME risk. Hazard ratios (HRs) and 95% con-
fidence intervals (CIs) were estimated separately for HPV vaccina-
tion, number of hospital contacts, and each discharge diagnosis
category. We used stratified Cox models with year of birth as strata
and age in days as the time variable. Vaccination was modelled as a
time-dependent variable. Subjects were classified as exposed from
90 days after receipt of the first dose of HPV vaccine until the end
of follow-up, since CFS/ME diagnosis require symptoms lasting for
at least 3 months. We performed sensitivity analyses using lag
times of 0, 30, and 180 days. All models were adjusted for parental
education, country background and region of residence. When HPV
vaccination was the exposure, adjustment was made also for total
number of hospital contacts. When discharge diagnosis was the
exposure, adjustment was made for hospital contacts with diag-
noses from other ICD-10 chapters.
The association between medical history and HPV vaccine
uptake, was evaluated with linear binomial regression. Risk differ-
ences (RDs) were estimated separately for number of hospital con-
tacts and each discharge diagnosis category. We adjusted for
parental education, country background, and region of residence.
When discharge diagnosis was the main exposure, adjustment
was made for hospital contacts with diagnoses from other ICD-10
chapters.
All tests were two sided, and p < 0.05 were considered statisti-
cally significant. The data were analysed with Stata/SE 14.0 (Stata-
Corp, College Station, Texas, USA).
3. Results
A total of 1392 adolescents aged 10–17 years were first regis-
tered with a diagnosis of CFS/ME in Norway during the period
2009–2014. The majority, 939 (67.5%), were female.
We observed an increase in the incidence rates of CFS/ME both
among girls and boys (Fig. 1). In girls, the age-standardized inci-
dence rate increased from 42.1 (95% CI 33.6–52.1) cases per
100,000 person-years in 2009 to 88.5 (95% CI 77.1–101.2) in
2014, whereas in boys it increased from 15.5 (95% CI 11.1–21.2)
to 38.0 (95% CI 30.8–46.4) in the same period (Table 1). The inci-
dence rate was significantly higher (p < 0.001) in girls than in boys,
IRR = 2.23 (95% CI 1.78–2.80). However, the increase per year was
similar in girls (IRR = 1.15, 95% CI 1.10–1.19) and boys (IRR = 1.15,
95% CI 1.09–1.22).
The characteristics of the 176,453 girls born 1997–2002 and
thus eligible for HPV vaccination, are shown in Table 2. Among
these girls, 145,195 (82.3%) had received at least one dose HPV vac-
cine. The mean age at first dose was 12.3 years. A total of 407 cases
of CFS/ME were identified during the entire follow-up. The mean
age at diagnosis was 14.5 years. During the two-year follow-up
period, 139 cases were identified.
HPV vaccination was not associated with increased risk of CFS/
ME, adjusted HR = 0.86 (95% CI 0.69–1.08) for the entire follow-up
and 0.96 (95% CI 0.64–1.43) for the two-year follow-up (Table 3).
We also observed estimates close to 1 in models where exposure
to HPV vaccine was lagged 0, 30, and 180 days, with adjusted
HR’s 0.79 (95% CI 0.64–0.99), 0.83 (95% CI 0.66–1.03) and 0.91
(95% CI 0.72–1.14), respectively, for the entire follow-up.
The risk of CFS/ME increased with increasing number of previ-
ous hospital contacts. For the entire follow-up, adjusted HR for
seven or more contacts was 5.23 (95% CI 3.66–7.49) as compared
to no contacts (Table 4). According to ICD-10 diagnoses, the highest
risk of CFS/ME was found among girls with diagnoses in chapters
I00-I99 (Diseases of the circulatory system), adjusted HR = 4.42
(95% CI 2.27–8.63), A00-B99 (Certain infectious and parasitic dis-
eases), adjusted HR = 3.69 (95% CI 1.89–7.20) and R00-R99 (Symp-
toms, signs and abnormal clinical and laboratory findings, not
elsewhere classified), adjusted HR = 3.41 (95% CI 2.55–4.56). The
associations with CFS/ME became even stronger when restricting
follow-up to two years.
Girls with seven or more hospital contacts prior to vaccination
had lower HPV vaccine uptake than girls with no previous hospital
contacts, adjusted RDs = 5.5% (95% CI 6.7% to 4.2%) (Table 5).
Among girls with up to six previous hospital contacts, no associa-
tion or slightly increased vaccine uptake was observed. Having
diagnoses in some ICD-chapters was associated with lower vaccine
uptake. This was most prominent for girls with diagnoses in chap-
ters F00-F99 (mental and behavioural disorders), D50-D98 (dis-
eases of the blood and blood-forming organs) or G00-G99
(disease of the nervous system, excluding CFS/ME), adjusted
RDs = 7.8% (95% CI 10.1% to 5.4%), 7.2% (95% CI 13.1% to
1.2%), and 6.6% (95% CI 8.3% to 4.9%), respectively. The
B. Feiring et al. / Vaccine xxx (2017) xxx–xxx 3
Please cite this article in press as: Feiring B et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-
based study from Norway. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.031
uptake of HPV vaccine among girls diagnosed with CFS/ME prior to
start of follow-up (n = 61) was only 39.4%.
4. Discussion
In this large, population-based study, we observed an increase
in the incidence of CFS/ME among adolescents aged 10–17 in Nor-
way, during 2009–2014. The increase was similar among girls and
boys. No increased risk of CFS/ME after HPV vaccination was
observed among the first six birth cohorts of girls eligible for
HPV vaccination through the national immunisation programme.
Medical history was associated with both increased risk of CFS/
ME and lower uptake of HPV vaccine. Our findings add to the cur-
rent knowledge on the safety of the HPV vaccine [18,50–58] and
support the conclusions made by EMA and WHO [29,30].
A major strength of the current study is the inclusion of com-
plete birth cohorts and the use of nationwide registries with indi-
vidual level data for the total population, thereby reducing the risk
of selection bias. Information on HPV vaccination is electronically
transferred from patient records to the immunisation registry
[45]. Thus, notification to the registry is considered almost com-
plete. Norway has a public healthcare system with universal access
to healthcare, and with few exceptions, public hospitals only.
According to national guidelines, children and adolescents with
suspected CFS/ME should be examined by a paediatrician [46].
Specialized paediatric care is primarily available at hospitals, and
suspected cases are routinely referred for diagnostic work up.
The reporting of hospital discharge diagnoses to the NPR is linked
to the national reimbursement system and believed to be nearly
complete. Furthermore, information in the NPR is collected inde-
pendently of the vaccination information, which minimizes risk
of bias from differential reporting. The suspected association
between HPV vaccination and CFS/ME-like conditions was not sub-
ject to any media attention in Norway during the study period. The
first report in the media that received some attention was an arti-
cle in one of the largest newspapers in June 2015 [59], shortly
before EMA started their investigation in July 2015. Thus, we do
not believe that vaccinated girl with CFS/ME-like symptoms were
more likely to be diagnosed with CFS/ME than unvaccinated girls
with similar symptoms.
The major limitation of this study is the lack of validation of the
diagnoses. We did not have access to patient records for verifica-
tion of the CFS/ME diagnoses retrieved from the NPR. Diagnosing
CFS/ME may be challenging since there are no biomarkers for the
disease, and the diagnosis is based on reported symptoms and
0
20
40
60
80
100
Cases per 100,000 person years
2009
2010
2011
2012
2013
2014
Year
Girls
Boys
Fig. 1. Incidence rates of chronic fatigue syndrome/myalgic encephalomyelitis among Norwegian adolescents aged 10–17, 2009–2014, N = 824,133.
Table 1
Incidence rates of CFS/ME
a
(cases per 100,000 person-years) among Norwegian adolescents aged 10–17 years in the period 2009–2014, N = 824,133.
Sex Year No. of cases Person-years Incidence rate
b
(95% CI) Ratio of standardized rates (95% CI)
Girls 2009 91 230,254 42.1 (33.6–52.1) 1.00 (ref)
2010 118 245,997 48.3 (40.0–57.8) 1.15 (0.87–1.52)
2011 172 246,125 70.0 (59.9–81.2) 1.66 (1.28–2.16)
2012 169 246,074 68.5 (58.6–79.6) 1.63 (1.25–2.11)
2013 175 243,377 71.7 (61.4–83.1) 1.70 (1.31–2.21)
2014 214 241,161 88.5 (77.1–101.2) 2.10 (1.63–2.71)
Boys 2009 40 243,584 15.5 (11.1–21.2) 1.00 (ref)
2010 64 260,382 24.5 (18.9–31.3) 1.58 (1.07–2.35)
2011 83 260,271 31.9 (25.4–39.6) 2.06 (1.41–3.00)
2012 63 259,451 24.3 (18.6–31.0) 1.57 (1.05–2.33)
2013 107 256,075 41.7 (34.2–50.4) 2.69 (1.87–3.87)
2014 96 252,951 38.0 (30.8–46.4) 2.45 (1.70–3.55)
a
CFS/ME, Chronic fatigue syndrome/myalgic encephalomyelitis.
b
Age-standardized with person-time from 2010 to 2014 as the standard.
4B. Feiring et al. / Vaccine xxx (2017) xxx–xxx
Please cite this article in press as: Feiring B et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-
based study from Norway. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.031
exclusion of other illnesses [8,46,60]. Also, different criteria for the
CFS/ME diagnosis may be used [46,47]. Furthermore, since several
conditions have symptoms partly overlapping with CFS/ME, e.g.
ICD-10 codes F48.0 (neurasthenia) and R53 (malaise and fatigue),
some misclassification may occur. The ICD-10 code F48.0 is pri-
marily used in mental healthcare. According to national guidelines,
CFS/ME patients are diagnosed and treated in somatic healthcare,
where the ICD-10 code G93.3 is used. The use of the ICD-10 codes
F48.0 and R53 both exclude the G93.3 code, according to ICD-10
guidelines [44]. Since 2007, national guidelines have recom-
mended the use of ICD-10 code G93.3 for CFS/ME, regardless of
suspected cause [46]. According to guidelines, children and adoles-
cents should have experienced symptoms for at least three months
prior to diagnosis. A recently published Norwegian study found
that many children were diagnosed with weakness and general
tiredness in primary healthcare one year or more before CFS/ME
diagnosis in specialist care [13]. We have no information on exact
date of disease onset. To account for time of referral and diagnostic
work up, we used different time lags, but results were basically
unchanged.
While the incidence of fatigue syndromes remained unchanged
the three first years after introduction of HPV vaccine in the UK
[18], we observed an increase in CFS/ME during 2009–2014. The
increase was similar in girls and boys. Analysing individual data,
we found no evidence of an increased risk of developing CFS/ME
after vaccination with quadrivalent HPV vaccine in Norway. This
is in accordance with the UK results for the bivalent vaccine [18].
While the UK study applied a self-control case series approach
among 187 vaccinated girls with fatigue syndromes to estimate
risk after HPV vaccination, our study included six complete birth
cohorts comprising 176,453 girls, among them 407 cases of CFS/
ME - both vaccinated and unvaccinated.
Table 2
Characteristics of girls born 1997–2002 eligible for HPV vaccination through the Norwegian childhood immunisation programme in the period 2009–2014, N = 176,453.
Received HPV vaccine
a
Not received HPV vaccine
n%n%
Girls eligible for HPV vaccination 145,195 100 31,258 100
Year of birth
1997 21,592 14.9 8261 26.4
1998 23,811 16.4 5587 17.9
1999 24,816 17.1 4977 15.9
2000 25,279 17.4 4631 14.8
2001 25,106 17.3 3860 12.3
2002 24,591 16.9 3942 12.6
Age at first vaccine dose, mean, y (SD) 12.3 (0.42) – – –
Parental education level
Compulsory 26,631 18.3 5926 19.0
Secondary 54,769 37.7 11,668 37.3
Higher, undergraduate level 51,770 35.7 10,988 35.2
Higher, graduate level 12,025 8.3 2676 8.6
Country background
Norwegian 130,776 90.1 27,997 89.6
Non-Norwegian 14,419 9.9 3261 10.4
Region of residence
Oslo 12,817 8.8 2942 9.4
Eastern-Norway 37,412 25.8 7605 24.3
Southern-Norway 28,462 19.6 6256 20.0
Western-Norway 32,299 22.2 6756 21.6
Mid-Norway 20,152 13.9 4720 15.1
Northern-Norway 14,053 9.7 2979 9.5
Total number of hospital contacts
b
0 103,010 70.9 22,238 71.1
1 17,798 12.3 3619 11.6
2 8532 5.9 1810 5.8
3–4 9210 6.3 1846 5.9
5–6 3254 2.2 712 2.3
7 or more 3391 2.3 1033 3.3
a
At least one dose HPV vaccine by the end of 2014.
b
Registered in the NPR during 20 months prior to September 1, the year the girls turned 12 (i.e. at the start of 7th grade).
Table 3
Hazard ratios (HRs) and 95% confidence intervals (CIs) of CFS/ME
a
according to HPV vaccination among girls born 1997–2002 eligible for HPV vaccination through the Norwegian
childhood immunisation programme in the period 2009–2014, N = 176,453.
Two-year follow up period
b
Entire follow-up period
HPV
vaccination
No of
cases
Person-years
at risk
Crude HR
(95% CI)
Adjusted
b
HR
(95% CI)
No of
cases
Person-years
at risk
Crude HR
(95% CI)
Adjusted
c
HR
(95% CI)
No 45 107,114 1.0 (ref) 1.0 (ref) 117 156,475 1.0 (ref) 1.0 (ref)
Yes 94 178,893 0.94 (0.63–1.40) 0.96 (0.64–1.43) 290 346,717 0.85 (0.68–1.07) 0.86 (0.69–1.08)
a
CFS/ME, Chronic fatigue syndrome/myalgic encephalomyelitis.
b
CFS/ME cases diagnosed in the two-year period from September 1 in 7th grade (start of HPV vaccination) to September 1 in 9th grade.
c
Adjusted for parental education level, country background, region of residence, and number of previous hospital contacts.
B. Feiring et al. / Vaccine xxx (2017) xxx–xxx 5
Please cite this article in press as: Feiring B et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-
based study from Norway. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.031
Table 4
Hazard ratios (HRs) and 95% confidence intervals (CIs) of CFS/ME
a
according to medical history
b
among girls born 1997–2002 eligible for HPV vaccination through the Norwegian childhood immunisation programme in the period 2009–
2014, N = 176,453.
Two year follow-up period
c
Entire follow-up period
Person-years at risk No of cases Crude HR (95% CI) Adjusted
d
HR (95% CI) Person-years at risk No of cases Crude HR (95% CI) Adjusted
d
HR(95% CI)
Total number of hospital contacts
b
0 203,862 60 1.0 (ref) 1.0 (ref) 360,336 212 1.0 (ref) 1.0 (ref)
1 34,335 20 1.98 (1.19–3.28) 2.02 (1.21–3.34) 60,014 57 1.63 (1.21–2.18) 1.64 (1.22–2.19)
2 16,714 17 3.44 (2.01–5.90) 3.54 (2.07–6.07) 29,027 37 2.19 (1.54–3.10) 2.22 (1.57–3.15)
3–4 17,739 14 2.68 (1.50–4.79) 2.79 (1.56–5.00) 30,730 41 2.30 (1.65–3.21) 2.35 (1.68–3.28)
5–6 6319 11 5.87 (3.09–11.17) 6.15 (3.23–11.71) 11,039 25 3.87 (2.56–5.86) 3.96 (2.62–6.00)
7 or more 7038 17 8.17 (4.76–13.99) 8.78 (5.12–15.07) 12,048 35 5.04 (3.52–7.21) 5.23 (3.66–7.49)
At least one hospital visit with discharge diagnosis within the following ICD-10 chapter
b
A00 – B99 Certain infectious and parasitic diseases
No 284,765 135 1.0 (ref) 1.0 (ref) 500,937 398 1.0 (ref) 1.0 (ref)
Yes 1241 4 6.94 (2.57–18.76) 4.32 (1.57–11.88) 2255 9 4.97 (2.57–9.62) 3.69 (1.89 –7.20)
C00 – D48 Neoplasms
No 284,126 135 1.0 (ref) 1.0 (ref) 499,913 402 1.0 (ref) 1.0 (ref)
Yes 1881 4 4.44 (1.64–12.0) 2.92 (1.07–7.94) 5479 5 1.90 (0.79–4.59) 1.38 (0.57–3.34)
D50 – D98 Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism
No 285,665 138 1.0 (ref) 1.0 (ref) 502,603 405 1 (ref) 1.0 (ref)
Yes 342 1 6.19 (0.87–44.28) 3.41 (0.47–24.63) 590 2 4.34 (1.08–17.41) 2.79 (0.69–11.28)
E00 – E9 Endocrine, nutritional and metabolic diseases
No 281,396 133 1.0 (ref) 1.0 (ref) 495,013 393 1.0 (ref) 1.0 (ref)
Yes 4611 6 2.73 (1.21–6.19) 1.88 (0.82–4.29) 8179 14 2.14 (1.25–3.64) 1.63 (0.95–2.79)
F00 – F99 Mental and behavioural disorders
No 283,718 136 1.0 (ref) 1.0 (ref) 499,155 401 1.0 (ref) 1.0 (ref)
Yes 2288 3 2.79 (0.89–8.75) 1.42 (0.45–4.53) 4037 6 1.86 (0.83–4.17) 1.07 (0.47–2.42)
G00 – G99 Diseases of the nervous system (excluding G93.3, CFS/ME)
No 281,793 129 1.0 (ref) 1.0 (ref) 495,787 388 1.0 (ref) 1.0 (ref)
Yes 4214 10 5.15 (2.71–9.80) 2.74 (1.41–5.31) 7406 19 3.28 (2.07–5.20) 2.04 (1.28–3.27)
H00 – H59 Diseases of the eye and adnexa
No 280,955 134 1.0 (ref) 1.0 (ref) 494,266 395 1.0 (ref) 1.0 (ref)
Yes 5052 5 2.11 (0.87–5.16) 1.46 (0.59–3.62) 8927 12 1.69 (0.95–2.99) 1.21 (0.67–2.16)
H60 – H95 Diseases of the ear and mastoid process
No 282,425 133 1.0 (ref) 1.0 (ref) 496,916 395 1.0 (ref) 1.0 (ref)
Yes 3582 6 3.56 (1.57–8.06) 2.12 (0.92–4.86) 6277 12 2.41 (1.36–4.28) 1.67 (0.93–2.98)
I00 – I99 Diseases of the circulatory system
No 285,033 135 1.0 (ref) 1.0 (ref) 501,513 398 1.0 (ref) 1.0 (ref)
Yes 974 4 8.78 (3.25–23.75) 5.10 (1.87–13.96) 1680 9 6.84 (3.53–13.24) 4.42 (2.27–8.63)
J00 – J99 Diseases of the respiratory system
No 279,459 129 1.0 (ref) 1.0 (ref) 491,738 382 1.0 (ref) 1.0 (ref)
Yes 6548 10 3.34 (1.75–6.35) 2.29 (1.19–4.40) 11 454 25 2.84 (1.89–4.25) 2.15 (1.43–3.25)
K00 – K93 Diseases of the digestive system
No 279,632 128 1.0 (ref) 1.0 (ref) 492,156 384 1.0 (ref) 1.0 (ref)
Yes 6375 11 3.76 (2.03–6.96) 2.40 (1.28–4.50) 11 036 23 2.70 (1.77–4.12) 1.89 (1.23–2.90)
L00-L99 Diseases of the skin and subcutaneous tissue
No 282,944 135 1.0 (ref) 1.0 (ref) 497,895 401 1.0 (ref) 1.0 (ref)
Yes 3063 4 2.74 (1.01–7.41) 2.04 (0.75–5.54) 5298 6 1.42 (0.64–3.19) 1.17 (0.52–2.62)
M00 – M99 Diseases of the musculoskeletal system and connective tissue
No 278,698 134 1.0 (ref) 1.0 (ref) 490,695 390 1.0 (ref) 1.0 (ref)
Yes 7309 5 1.41 (0.58–3.44) 0.88 (0.36–2.16) 12,497 17 1.74 (1.07–2.83) 1.22 (0.74–1.99)
6B. Feiring et al. / Vaccine xxx (2017) xxx–xxx
Please cite this article in press as: Feiring B et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-
based study from Norway. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.031
Table 4 (continued)
Two year follow-up period
c
Entire follow-up period
Person-years at risk No of cases Crude HR (95% CI) Adjusted
d
HR (95% CI) Person-years at risk No of cases Crude HR (95% CI) Adjusted
d
HR(95% CI)
N00 – N99 Diseases of the genitourinary system
No 284,308 137 1.0 (ref) 1.0 (ref) 500,251 403 1.0 (ref) 1.0 (ref)
Yes 1699 2 2.46 (0.61–9.95) 1.60 (0.39–6.51) 2941 4 1.72 (0.64–4.60) 1.26 (0.47–3.39)
Q00 – Q99 Congenital malformations, deformations and chromosomal abnormalities
No 280,793 136 1.0 (ref) 1.0 (ref) 494,222 399 1.0 (ref) 1.0 (ref)
Yes 5214 3 1.19 (0.38–3.73) 0.69 (0.22–2.18) 8971 8 1.12 (0.56–2.25) 0.75 (0.37–1.51)
R00 – R99 Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified
No 275,798 109 1.0 (ref) 1.0 (ref) 485,378 349 1.0 (ref) 1.0 (ref)
Yes 10 209 30 7.45 (4.98–11.17) 5.26 (3.43–8.07) 17 815 58 4.56 (3.45–6.02) 3.41 (2.55–4.56)
S00 – T98 Injury, poisoning and certain other consequences of external causes
No 247,943 116 1.0 (ref) 1.0 (ref) 437,847 323 1.0 (ref) 1.0 (ref)
Yes 38 063 23 1.28 (0.82–2.00) 0.87 (0.55–1.37) 65 345 84 1.77 (1.39–2.25) 1.39 (1.09–1.79)
Z00 – Z99 Factors influencing health status and contact with health services
No 264,666 106 1.0 (ref) 1.0 (ref) 465,939 336 1.0 (ref) 1.0 (ref)
Yes 21 341 33 3.86 (2.61–5.71) 2.20 (1.40–3.45) 37 254 71 2.66 (2.06–3.43) 1.62 (1.21–2.17)
a
CFS/ME, Chronic fatigue syndrome/myalgic encephalomyelitis.
b
Registered in the NPR during the 20 months prior to September 1, the year the girls turned 12 (i.e. at the start of 7th grade).
c
CFS/ME cases diagnosed during the two-year period between September 1 in 7th grade and September 1 in 9th grade.
d
Adjusted for parental education, country background, and region of residence. Estimates according to ICD-10 chapters also adjusted for number of hospital contacts with diagnosis from other ICD-10 chapters.
Table 5
Risk differences (RDs) and 95% confidence intervals (CIs) of HPV vaccination according to medical history
a
among girls born 1997–2002 eligible for HPV vaccination through the Norwegian childhood immunisation programme in the
period 2009–2014, N = 176,453.
Received HPV vaccine
b
Uptake of HPV vaccine Crude RD (95% CI) Adjusted
c
RD (95% CI)
No Yes
nn % % %
Total number of hospital contacts
a
0 22,238 103,010 82.2 0 (ref) 0 (ref)
1 3619 17,798 83.1 0.9 (0.3, 1.4) 0.9 (0.3, 1.4)
2 1810 8532 82.5 0.3 (0.5, 1.0) 0.3 (0.5, 1.0)
3–4 1846 9210 83.3 1.1 (0.3, 1.8) 1.1 (0.4, 1.9)
5–6 712 3254 82.0 0.2 (1.4, 1.0) 0.1 (1.3, 1.1)
7 or more 1033 3391 76.7 5.6 (6.9, 4.3) 5.5 (6.7, 4.2)
At least one hospital visit with discharge diagnosis within the following ICD-10 chapter
a
A00 – B99 Certain infectious and parasitic diseases
No 31,102 144,606 82.3 0 (ref) 0 (ref)
Yes 156 589 79.1 3.2 (6.2, 0.3) 2.3 (5.2, 0.7)
C00 – D48 Neoplasms
No 31,034 144,243 82.3 0 (ref) 0 (ref)
Yes 224 952 81.0 1.3 (3.6, 0.9) 0.7 (3.0, 1.5)
D50 – D98 Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism
No 31,204 145,041 82.3 0 (ref) 0 (ref)
Yes 54 154 74.0 8.3 (14.2, 2.3) 7.2 (13.1, 1.2)
(continued on next page)
B. Feiring et al. / Vaccine xxx (2017) xxx–xxx 7
Please cite this article in press as: Feiring B et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-
based study from Norway. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.031
Table 5 (continued)
Received HPV vaccine
b
Uptake of HPV vaccine Crude RD (95% CI) Adjusted
c
RD (95% CI)
No Yes
nn % % %
E00 – E9 Endocrine, nutritional and metabolic diseases
No 30,737 142,887 82.3 0 (ref) 0 (ref)
Yes 521 2308 81.6 0.7 (2.2, 0.7) 0.3 (1.8, 1.1)
F00 – F99 Mental and behavioural disorders
No 30,894 144,170 82.4 0 (ref) 0 (ref)
Yes 364 1025 73.8 8.6 (10.9, 6.2) 7.8 (10.1, 5.4)
G00 – G99 Diseases of the nervous system (excluding G93.3, CFS/ME)
No 30,616 143,226 82.4 0 (ref) 0 (ref)
Yes 642 1969 75.4 7.0 (8.6, 5.3) 6.6 (8.3, 4.9)
H00 – H59 Diseases of the eye and adnexa
No 30,624 142,678 82.3 0 (ref) 0 (ref)
Yes 634 2517 79.9 2.4 (3.9, 1.0) 1.6 (3.0, 0.2)
H60 – H95 Diseases of the ear and mastoid process
No 30,829 143,411 82.3 0 (ref) 0 (ref)
Yes 429 1784 80.6 1,7 (3.3, 0.0) 1.2 (2.8, 0.5)
I00 – I99 Diseases of the circulatory system
No 31,140 144,715 82.3 0 (ref) 0 (ref)
Yes 118 480 80.3 2.0 (5.2, 1.2) 1.5 (4.7, 1.7)
J00 – J99 Diseases of the respiratory system
No 30,530 141,980 82.3 0 (ref) 0 (ref)
Yes 728 3215 81.5 0.8 (2.0, 0.5) 0.4 (1.6, 0.8)
K00 – K93 Diseases of the digestive system
No 30,450 141,994 82.3 0 (ref) 0 (ref)
Yes 808 3201 79.8 2.5 (3.8, 1.2) 2.1 (3.4, 0.9)
L00-L99 Diseases of the skin and subcutaneous tissue
No 30,906 143,648 82.3 0 (ref) 0 (ref)
Yes 352 1547 81.5 0.8 (2.6, 0.9) 0.3 (2.1, 1.4)
M00 – M99 Diseases of the musculoskeletal system and connective tissue
No 30,347 141,411 82.3 0 (ref) 0 (ref)
Yes 911 3784 80.6 1.7 (2.9, 0.6) 1.3 (2.4, 0.1)
N00 – N99 Diseases of the genitourinary system
No 31,065 144,340 82.3 0 (ref) 0 (ref)
Yes 193 855 81.6 0.7 (3.1, 1.6) 0.2 (2.5, 2.2)
Q00 – Q99 Congenital malformations, deformations and chromosomal abnormalities
No 30,558 142,627 82.3 0 (ref) 0 (ref)
Yes 700 2568 78.6 3.8 (5.2, 2.4) 3.3 (4.6, 1.8)
R00 – R99 Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified
No 30,077 140,029 82.4 0 (ref) 0 (ref)
Yes 1181 5166 81.4 0.9 (1.9, 0.0) 0.5 (1.5, 0.5)
S00 – T98 Injury, poisoning and certain other consequences of external causes
No 27,289 125,279 82.1 0 (ref) 0 (ref)
Yes 3969 19,916 83.4 1.3 (0.8, 1.8) 1.5 (1.0, 2.0)
Z00 – Z99 Factors influencing health status and contact with health services
No 28,696 134,210 82.4 0 (ref) 0 (ref)
Yes 2562 10,985 81.1 1.3 (2.0, 0.6) 0.9 (1.7, 0.2)
a
Registered in the NPR during the 20 months prior to September 1, the year the girls turned 12 (i.e. at the start of 7th grade, when HPV vaccination started).
b
At least one dose HPV vaccine by the end of 2014.
c
Adjusted for parental education, country background, and region of residence. Estimates according to ICD-10 chapters also adjusted for number of hospital contacts with diagnosis from other ICD-10 chapters.
8B. Feiring et al. / Vaccine xxx (2017) xxx–xxx
Please cite this article in press as: Feiring B et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-
based study from Norway. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.031
The reasons for the increase in CFS/ME in Norway are unknown.
Based on the current analyses, the increase is unlikely to have
resulted from the introduction of HPV vaccine. During the last
10–15 years, there has been an increasing awareness of the CFS/
ME diagnosis. In particular, a discussion in the mid 2000’s on a pos-
sible increased risk of CFS/ME after vaccination with a Norwegian
produced meningococcal B vaccine alerted both the medical soci-
ety and the general public, although no association was found
[12]. National guidelines on the diagnosis and treatment of CFS/
ME were issued in 2007, and have later been revised [46]. In Nor-
way, it is likely that girls with symptoms similar to the POTS cases
reported from Denmark would be given the diagnosis CFS/ME.
Also, it has been suggested both by the Danish researchers and
EMA’s Pharmacovigilance Risk Assessment Committee (PRAC), that
CFS/ME may be a more appropriate diagnosis for most of the
patients diagnosed with POTS in Denmark [29,61].
In accordance with Danish findings, we observed an association
between medical history and risk of CFS/ME [35]. The risk
increased with increasing number of hospital contacts. Further-
more, the risk was increased in girls with diagnoses from specific
ICD chapters. However, a number of conditions have symptoms
overlapping with CFS/ME [60,62]. Some girls may also have
received CFS/ME-related diagnoses prior to CFS/ME diagnosis, for
instances diagnoses in ICD-10 chapter R. In addition, some patients
may fulfil criteria for more than one condition [62,63]. Thus, dis-
criminating comorbid conditions from CFS/ME is challenging.
In contrast to the Danish study [35], we included both vacci-
nated and unvaccinated girls, and observed an association also
between medical history and vaccine uptake. In line with our find-
ings, hospitalizations have previously been associated with low-
ered HPV vaccine uptake [64]. Higher HPV vaccine uptake have
been reported among both frequent and recent primary healthcare
users, possibly reflecting increased health awareness or physician’s
recommendation, rather than serious or prolonged disease [64–
67]. Adjustment for number of previous hospital contacts was
included in the analyses, aiming to minimize potential healthy vac-
cinee bias. However, the adjustment had little impact on the
estimates.
5. Conclusion
In this large, nationwide study including the first six birth
cohorts of girls offered quadrivalent HPV vaccine through the
national immunisation programme in Norway, no association
between HPV vaccination and risk of CFS/ME was observed. Medi-
cal history was associated with both increased risk of CFS/ME and
lower uptake of HPV vaccine. The current findings support the
favourable safety profile of quadrivalent HPV vaccine reported
from other pre- and post-licensure studies.
Conflicts of interest
None.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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10 B. Feiring et al. / Vaccine xxx (2017) xxx–xxx
Please cite this article in press as: Feiring B et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-
based study from Norway. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.031
