Oral Contraceptives and Multiple Sclerosis/Clinically Isolated Syndrome Susceptibility
Oral Contraceptives and Multiple Sclerosis/ Clinically Isolated Syndrome Susceptibility
Kerstin Hellwig 0 1
Lie H. Chen 0 1
Frank Z. Stancyzk 0 1
Annette M. Langer-Gould 0 1
0 Editor: Jerome de Seze, Strasbourg university hospital , FRANCE
1 1 St. Josef University Hospital , Bochum , Neuroimmunological Ward and Outpatient Clinic , Bochum, Germany , 2 Kaiser Permanente Southern California, Department of Research & Evaluation, Pasadena, California, United States of America, 3 University of Southern California, Keck School of Medicine, Los Angeles, California, United States of America, 4 Kaiser Permanente, Southern California Los Angeles Medical Center, Neurology Department , Los Angeles, California , United States of America
Our findings should be interpreted cautiously. While the use of some combination oral
contraceptives may contribute to the rising incidence of MS in women, an unmeasured
Funding: This work was supported by Kaiser
Permanente Direct Community Benefit Funds and
National Institute of Neurological Disorders and
Stroke 1R01NS075308. The funders had no role in
study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing Interests: Dr. Hellwig has been
supported by the German Research Council
Deutsche Forschungsgemeinshaft and has received
speaker honoraria from Biogen Idec, Teva Sanofi
Aventis, Novartis, Bayer Healthcare and Merck
Serono. Dr. Langer-Gould is site principal investigator
for two industry-sponsored phase 3 clinical trials
(Biogen-Idec, Hoffman-LaRoche) and was site PI on
one industry-sponsored observation study
(BiogenIdec). She received grant support from the National
Institutes of Health, National Institute of Neurological
Disorders and Stroke, and the National Multiple
Sclerosis Society. Lie Chen, Christopher Schroeder
and Frank Stancyzk have declared that no competing
interests exist. These competing interests do not alter
the authors’ adherence to PLOS ONE policies on
sharing data and materials.
confounder associated with the modern woman’s lifestyle is a more likely explanation for
this weak association.
Whether oral contraceptives (OC) influence the risk of multiple sclerosis (MS) is unclear. The
most popular hypothesis is that OCs should protect against MS because pregnancy (a high
estrogen and progesterone state) ameliorates disease activity in humans as does exogenous
administration of high-dose estrogens in the animal model of MS. However, the recently
reported rising incidence of MS in women but not men[
] have led others to hypothesize that
OC use could be partially responsible[
], along with other factors that reflect the modern
The most commonly used forms of hormonal contraception today are combined oral
contraceptives (COCs) containing low doses of estrogen and one of a variety of progestins. The
effects of these low dose hormones either individually or in combination on animal models of
MS have not been carefully studied. Progestins are particularly interesting because they vary in
their affinity for androgen, progesterone and glucocorticoid receptors and could therefore have
theoretically diverse effects on MS susceptibility.
The sparse number of previous studies of COC use and MS risk hypothesized a protective
effect and concluded that COCs had either no effect[
] or a protective effect(5). However,
two of these studies reported a statistically non-significant trend toward a slight increase[
in MS risk. These studies had several limitations included long enrollment period, small
] and/or non-representative samples[
]. None examined whether the risk varies
by progestin content.
The purpose of this study was to determine whether use of contemporary COCs could be
influencing the risk of MS and whether this risk varies by progestin content.
This nested case-control study was based on a retrospective cohort of women of childbearing
age (14–48 years) who were members of Kaiser Permanente Southern California (KPSC) health
plan between Jan 1, 2008 and Dec 31, 2011.
The institutional review board (IRB) at Kaiser Permanente Southern California (KPSC)
approved this study. Informed consent by the IRB was waived as this was a chart review study
only without direct patient contact. Analyses were performed on a de-identified limited dataset.
KPSC is a large prepaid health maintenance organization with over 3.5 million members. It
provides comprehensive health care coverage to ~20% of the population in the geographic area
]. The KPSC membership is representative of the general population in Southern
California with respect to ethnicity, age, gender and socioeconomic status with the exception of
an under-representation of the lowest and highest ends of the socioeconomic spectrum[
cost of specialist consultations, hospitalizations, MRI scans, other diagnostic tests and
medications are almost fully covered with minimal co-pays. This study utilized data from the
electronic clinical databases including the pharmacological, clinical and administrative records.
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We used the same methods as described in detail elsewhere[
] to identify individuals with
newly diagnosed MS or its potential precursor, clinically isolated syndrome (CIS). Briefly, we
searched electronic medical records for first mention of ICD-9 diagnostic codes for MS and
other acquired CNS demyelinating diseases January 1, 2008–December 31, 2011 including all
inpatient and outpatient encounters since enrollment into the health plan (N = 3556).
Diagnoses were confirmed, symptom onset date and additional clinical details were extracted through
full medical records abstraction including all inpatient and outpatient records, MRI scans,
and diagnostic test results by an MS specialist (ALG) according to revised McDonald criteria
for MS and the proposed consensus definitions for idiopathic transverse myelitis (TM)[
]. All patients with optic neuritis (ON) had been evaluated by ophthalmologists who
confirmed the diagnosis. Men and females less than 14 or older than 48 years old were excluded.
Cases with symptom onset prior to January 1, 2000, missing/imprecise symptom onset date or
those without 12 months of continuous KPSC membership prior to symptom onset were
For each incident case, a maximum of 10 control subjects from the KPSC population were
matched to the case on date of birth (within 1 year), sex, race/ethnicity and membership
characteristics including membership duration (within 1 year) at the time of the case’s symptom
onset date to avoid immortal time bias. The matched controls were assigned the same index
date as their matched case (symptom onset date) and were also required to have 12-month
continuous membership prior to the index date for study inclusion. With this algorithm 99%
of cases had 10 matched controls.
Hormonal Contraceptive Use
Pharmacy records within 10 years of index date were obtained from the complete electronic
health records (EHR). The search included product codes indicating prescriptions of
contraceptive use in pharmacy database, and current procedural terminology (CPT) procedure
codes relating to contraceptive use in clinical database. The pharmacy database includes the
inpatient and outpatient prescription medication dispensed at KP hospitals, medical centers
and medical offices. Ninety seven percent of members have a drug benefit with minimal
copays and fill their prescriptions at Kaiser Pharmacies located at each facility.
Combination oral contraceptive (COC) use was defined in the following forms: (1) ever vs.
never use, (2) current, former, and never use (3) duration or cumulative dose. Ever use was
defined as two and more consecutive COC prescriptions of any type covering at least 56 days
to avoid misclassifying women who did not continue COCs for at least 1 cycle. Current users
were defined as ever users who had at least one prescription period prior to and within 1
month of the index date. Former users were defined as ever users who had no dispense periods
prior to and within 1 month of the index date. Duration of use was calculated by dispense date,
and supply days. Duration of use was modeled as categorical variables based on the quintiles of
duration use in controls up to ten years prior to index date.
Covariates extracted from KPSC EHR and membership files included the most recent body
mass index (BMI) and smoking status recorded prior to the index date; and births and
miscarriages/abortions in the 10 years before the index date. 88 controls were excluded from analyses
due to missing BMI information.
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Conditional logistic regression was used to estimate the matched odds ratio (OR) and its
corresponding 95% confidence interval (CI) for the association between MS/CIS and HC and COC
use. The models were adjusted for BMI (under or normal weight 25.0 kg/m2,
over-weight2529.99 kg/m2, class I-III obesity class I 30–34.99 kg/m2; class II 35–39.99 kg/m2; class III 40.0
kg/m2), smoking (ever/never), live births (0, 1 or more) and abortions/miscarriages (yes/no).
Analyses of COC use were stratified by progestin family as follows norethindrone
(norethindrone, norethindrone acetate, ethynodiol diacetate); levonorgestrel (levonorgestrel,
norgestimate, norgestrel, desogestrel) and drospirenone. Women who used multiple types of COCs
with different progestin family contents were classified in two ways: the most recently or
longest used COC family during the study period. Sensitivity analyses of the primary and
secondary exposure (HC and COC use ever/never) restricted to 3 years prior to symptom onset or MS
cases only were conducted. Post-hoc analyses restricted to MS cases only were conducted.
The means and standard deviations of normally distributed continuous variables were
compared using two-sample t tests; Wilcoxon-Mann-Whitney test for non-normally distributed
continuous variables and for binary or categorical variables, Chi-square or Fisher exact test. All
analyses were conducted using SAS software v9.2 (Cary, NC).
In all, 400 women ages 14–48 years with newly diagnosed MS or CIS were included in the
study after exclusion of 5 individuals (1%) because their symptom onset could not be precisely
determined and 126 (23.7%) because they had less than 12 months of KPSC membership prior
to symptom onset. Of these, 239 (60%) met diagnostic criteria for MS and 113 (70%) of the 161
CIS cases had abnormal brain MRI scans at the time of symptom onset indicating a high
lifetime risk of MS. Most cases (n = 363, 91%) had onset of symptoms between 2007 and 2011.
The baseline demographic and clinical characteristics of cases and controls are presented in
Women with MS/CIS were more likely to be obese and have smoked but less likely to have
given birth or had a miscarriage/abortion. Matching factors including age, race/ethnicity and
membership duration was similar among cases and controls. Women classified as never COC
users had a shorter duration of membership than ever users but this did not vary by
case/control status (Table 1).
Combined oral contraceptives were the most commonly used type of hormonal
contraceptive. Very few women used progestin-only oral contraceptives (13 cases and 140 controls),
non-oral agents (patch 14 cases and 140 controls; vaginal ring 16 cases and 128 controls) or
high dose estrogen (50μg) COCs (2 cases and 18 controls) precluding further analysis
The use of COCs was independently associated with a slight increased risk of MS/CIS
regardless of whether it was current or former use (Fig 1). Analyses restricted to those women
with MS yielded similar results (adjusted OR = 1.51, 95%CI 1.12–2.03; p = 0.007, ever use;
Table 3). Analyses restricted to women with at least 3 years of continuous membership prior to
symptom onset (n = 305) also yielded similar results (adjusted OR = 1.35, 95%CI 1.01–1.80;
p = 0.04 ever use).
The cumulative duration of use of COCs up to 10 years prior to symptom onset/index date
ranged from 1 to 114 months (Table 2). There was no clear trend in MS risk with increasing
duration of use when comparing increasing quintiles of duration of COC use to never users
(reference category; Fig 1). Being nulliparous up to ten years prior to symptom onset and
obesity were independent risk factors for MS/CIS although the latter did not reach statistical
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significance (Table 4). When analyses were restricted to only those women with MS, parity and
smoking but not obesity were independently associated with MS (Table 3).
Many women (48%) used COC preparations that varied in progestin family content. The
most common progestins used were norethindrone (NE) and levonorgestrol (LNG; 56.9% and
44.6% of COC users, respectively). Both NE family and LNG family-containing COCs were
associated with a modest increased MS/CIS risk although this risk was more pronounced
among LNG users regardless if women were classified by which type they used most recently
or the longest (Table 5). Interestingly, using drospirenone-containing COCs was not associated
In this contemporary cohort, women who developed MS/CIS appear to live a more modern
lifestyle than controls. The women who developed MS/CIS were more likely to be current or
former smokers and use hormonal contraception. They were less likely to get pregnant, have a
baby, or miscarriages/abortions. The use of COCs was independently associated with a slight
increased risk of MS/CIS that persisted even after adjusting for known confounders. However,
the risk of MS/CIS did not change with increasing duration of COC use, a strong indicator of a
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non-casual association. While it is possible that the use of some COCs may be contributing at
least a small part to the rising incidence of MS in women, unmeasured factors related to the
modern woman’s lifestyle, residual confounding or reverse causality are more likely
Fig 1. Association between combined oral contraceptive use and multiple sclerosis/clinically isolated syndrome. Ever using COCs, regardless
whether current or former, was associated with a slight increased risk of MS/CIS (p<0.001; p = 0.02; and p = 0.001 respectively). Longer duration of use
(1stshortest -5thlongest quintiles) did not result in any change in risk. OR are adjusted for parity, miscarriage/abortions, smoking and obesity.
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a. Adjusted for parity, miscarriage, smoking, obesity
a. Adjusted for parity, miscarriage, smoking, obesity
b. Norethindrone family includes norethindrone and ethynodiol diacetate; levenorgestrol family includes levonorgestrol, norgestimate, and norgestrel;
drospirenone family includes drospirenone
Abbreviations: CI = confidence interval; COC = combined oral contraceptives; MS = multiple sclerosis; CIS = clinically isolated syndrome
Previous studies examining the association between COC and MS have conflicting results.
Our findings are consistent with 2 previous prospective cohort studies. A pooled analysis of the
Harvard Nurses’ Health Study (HNHS) reported a trend toward an increased risk of MS
(relative rate 1.2, 95% CI 0.9–1.5) in ever versus never OC users[
]. Similarly the Royal College of
General Practitioners’ Oral Contraception Study reported a trend toward increased risk of MS
in former and current users (rate ratio 1.3 95% CI 0.9–2.0; 1.2 95% CI 0.7–2.0, respectively)[
These findings did not reach statistical significance in either study which may be due the
number of cases included in the analyses (n = 316(2) and n = 114[
], respectively). It should be
noted that the authors of these studies had hypothesized a protective effect of OC use and
interpreted these findings as evidence of no association between OC use and MS risk. Another
] study found no association (relative rate = 0.7, 95%CI 0.4–1.1) but was
underpowered to detect a difference due to the small number of women who developed MS
(n = 63).
Our findings are not consistent with a matched nested case-control study from the General
Practice Research Database (GPRD)[
]. This small study (n = 106 MS cases) reported a
statistically non-significant decreased risk of MS in women who had used COCs within 3 years of
symptom onset compared with those that had not used COCs in this time frame (OR = 0.6,
]. Misclassifying women who used COCs more than 3 years ago as never
users may explain these findings.
The most popular hypothesis is that exogenous estrogens like COCs should decrease the
risk of MS based on the observation that pregnancy ameliorates disease activity in women with
MS and that high dose estrogens ameliorate the animal model of MS (experimental allergic
encephalomyelitis; EAE) and have other anti-inflammatory properties. However, this line of
reasoning is problematic because contemporary COCs (like those used by the women in our
study) contain low doses of estrogen in combination with one of a variety of progestins. The
effects of low dose estrogen or progestins, particularly in combination, on EAE or even normal
immune responses have not been carefully studied. The relationship between sex hormones
and autoimmunity is undoubtedly complex and likely varies based on the doses and
combinations of hormones used and the underlying disease.
8 / 12
That COCs could increase the risk of MS/CIS or other autoimmune diseases is biologically
plausible. There is some evidence to suggest that low dose estrogen states and COCs could be
proinflammatory and enhance autoimmunity. Most autoimmune diseases including MS are
more common in women and the onset of disease coincides with the estrous cycle in humans
and animals. Women of childbearing age produce a more vigorous immunologic response to
vaccinations and infections then men[
]. In vitro studies of proteolipid protein-specific T cell
clones from MS patients showed that low doses of estradiol stimulated the proinflammatory
cytokines IFNγ and TNFα secretion while high doses stimulated IL-10 secretion[
Finally, COC use has been associated with a modest increase in risk of inflammatory bowel
]. This is particularly interesting because IBD is the only autoimmune disease
with a strong co-morbid association with MS.
It is also biologically plausible that the progestins in COC preparations may have different
effects on the risk of autoimmunity. Progestins vary in their androgen, progesterone,
mineralcorticoid and glucocorticoid receptor affinity and binding properties and could therefore have
theoretically diverse effects on MS susceptibility. Levonorgestrol (LNG) is the most androgenic
of the progestins contained in modern COCs; norethindrone (NE) has very low androgenic
actions and is converted to small amount of ethinyl estradiol; whereas the newest and most
unique progestin -drospirenone is a spironolactone-like compound with anti-androgenic
effects. No previous studies have examined whether the risk of MS/CIS could vary by progestin
content. Interestingly, we found an association with LNG- and NE-containing COCs that was
more pronounced among LNG users but no association between drospirenone use and the
development of MS/CIS. We speculate that this may be due to the differences in androgenicity
of these compounds. However, we had only a small number of cases that used drospirenone so
a spurious finding cannot be excluded. This hypothesis should be explored in future studies.
We favor the possibility of unmeasured factors related to a modern woman’s lifestyle (and
thereby COC use) as an explanation for our findings. If COC use has a causal relationship to
MS and its potential precursor CIS, then it would be expected that the longer the use the higher
the risk of MS/CIS. We, like previous studies[
], were unable to demonstrate such a duration
of use effect. One potential explanation could be that COCs increase the risk of MS/CIS
primarily in the first year after starting analogous to the relationship between COC use and risk of
thrombosis. However, we think this type of first-start effect is an unlikely explanation as
then the risk of MS/CIS should have decreased with longer duration of use.
Aside from COC use, many other aspects of the modern woman’s lifestyle have changed
some of which have also been linked to an increased risk of MS or CIS. These include increased
prevalence of smoking[
] and obesity[
] and decreased number of offspring[
]. The aspects
of a modern woman’s lifestyle that we could measure were indeed more common in the
women who went on to develop their first symptoms of MS/CIS and associated with risk in the
Another possible explanation is reverse causality- specifically that indications for COC use
other than birth control may be more common in women in the prodromal phase of MS. Aside
from preventing undesired pregnancies, other indications for COC use include acne and
indicators of fertility issues including dysmenorrhea and polycystic ovarian syndrome. A recent
Swedish MS case-control study found that both men and women with MS had fewer babies within
the 5 but not 10 years prior to diagnosis compared to controls implying that fertility may be
impaired during the prodromal phase of MS[
]. Neither we, nor any of the previous studies
that also showed a trend towards increased risk of MS with COC use[
] addressed this issue.
Future studies should collect information on reason for COC use and fertility histories.
Although we strongly favor a non-causal association, assuming COC use is contributing to
the rise in MS incidence we would not recommend a change in COC use policy as over 25,000
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women per year would need to be using COCs for 1 additional woman to develop MS/CIS over
this period. In addition, several recent studies have reported an association between COC use
and a less severe MS disease course[
], milder MS symptoms and older age at onset of
first MS symptoms[
]. It should also be noted whether COC use influences the risk of
progressive-onset MS (PPMS) is unknown[
] as only one study distinguished between the risk of
relapsing and progressive-onset forms and the results were inconclusive as only 9 cases of
PPMS were included[
Variation in membership duration (and there by COC use information) was an anticipated
limitation of this study thus one of the matching criteria for controls was membership
duration. We compared the membership duration between ever and never COC users stratified by
case/control status to assess for potential differential misclassification. While we did find that
those cases and controls classified as never users had a significantly shorter duration of KP
membership than ever users this did not vary by case/control status. Thus it does not appear
that this bias explains our findings and would be expected to result in an underestimation of
the true magnitude of effect. However, we cannot exclude the possibility that COC use prior to
KP membership may have been more common among controls than cases. We are currently
conducting a study that includes lifetime COC use which will be able to address this issue.
The main limitation of this study is the lack of lifetime COC use and confounder
information potentially leading to misclassification of true COC users as never users and multi- as
null-parous women. Other limitations include the potential for misclassification of former
smokers as non-smokers; restricted range of ethinyl estradiol doses used precluding
comparison of true high and low-dose estrogen content; and the frequency of switching between COCs.
Strengths of this study included the biological classification of progestin content; the
prospectively collected complete clinical and pharmacy information while members of KPSC; the
ability to identify and include CIS cases and matched controls; a cohort that is largely
representative of the population from which it is drawn, and the relatively large number of incident
CIS/MS cases identified in a short timeframe.
Combined oral contraceptive use was associated with a modestly increased risk of
developing MS/CIS and this risk varied by progestin content. However, given the lack of a duration of
use effect and the limitations of this and previous studies, this association should be interpreted
cautiously as it is most likely due to an unmeasured confounder. Future studies with lifetime
COC use, fertility measures and other potential confounders that stratify analyses by progestin
content are needed to resolve this question. Our findings do not warrant any change in COC
S1 Appendix. Baseline demographic and clinical characteristics, MS only cases and
Role of the Sponsor
The funding sources had no role in the design and conduct of the study; collection,
management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript;
and decision to submit the manuscript for publication.
10 / 12
This research was supported by the Kaiser Permanente Direct Community Benefit Funds and
the National Institute of Neurological Disorders and Stroke (NINDS, 1R01NS075308 PI:
Dr. Hellwig has been supported by the German Research Council Deutsche
Forschungsgemeinschaft and has received speaker honoraria from Biogen Idec, Teva Sanofi Aventis,
Novartis, Bayer Healthcare and Merck Serono.
Dr. Chen reports no disclosures.
Dr. Stancyzk reports no disclosures.
Dr. Langer-Gould is site principal investigator for two industry-sponsored phase 3 clinical
trials (Biogen Idec; Hoffman-LaRoche) and was site PI one industry-sponsored observation
study (Biogen Idec). She receives grant support from the National Institutes of Health, NINDS
and the National MS Society.
We thank Wendy Gilmore, PhD, Division Chief, MS Comprehensive Care Center and
Research Group, Keck School of Medicine, University of Southern California for helpful
discussions; Corinna Koebnick, PhD, Kaiser Permanente Southern California, Department of
Research & Evaluation for preparing the figure and Ms. Pauline Field, Kaiser Permanente
Southern California for help preparing the manuscript.
Conceived and designed the experiments: KH ALG. Performed the experiments: KH ALG.
Analyzed the data: KH LC FS ALG. Contributed reagents/materials/analysis tools: KH LC FS
ALG. Wrote the paper: KH LC FS ALG.
11 / 12
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