Oral contraceptive use and its association with symptomatology in migraine patients

Abstract

Background:

Hormonal changes in natural menstrual cycles are known to modulate and even worsen headache symptoms in migraineurs; however, the impact of oral contraceptive pills (OCP), including combined oral contraceptive (COC) and progestogen-only pills on migraine symptomatology, is little investigated.

Method:

In this retrospective cohort study of 1758 migraine patients, data from 1032 female patients aged 15–45 years were accessed and their contraceptive methods, if any, were analyzed. Further comparisons were conducted between patients with OCP use and those without OCP use regarding the demographics, headache symptoms, and associated symptoms. Most OCP users in this study were assumed to have used COC, but information of individual hormone content of OCP was not collected. Patients with nonoral hormonal contraceptives were excluded for further comparison.

Results:

The use of OCP was common (47.8%) among the study cohort. Compared to those without OCP use (n = 410), patients with OCP use (n = 493) were younger (27.4 ± 7.0 vs. 32.8 ± 7.9, p < 0.001), had lower headache frequency (days per month, 11.1 ± 7.5 vs. 12.3 ± 8.8, p = 0.03), were less likely to have osmophobia (47.3 vs. 54.4%, p = 0.033) or cranial autonomic symptoms (44.8 vs. 53.2%, p = 0.013), and more commonly reported menstrually-related worsening of headache (52.3 vs. 42.4%, p = 0.012). The proportion of migraine with aura or other headache characteristics including severity, unilaterality, and pulsatile characteristic showed no differences between groups.

Conclusion:

Our data provide real-life information about contraceptive use among patients with migraine. The use of OCP is associated with differences in migraine symptomatology. Further studies are needed to determine whether this relationship is causal and any possible underlying mechanism.

Keywords

aura contraceptive cranial autonomic symptoms estrogen hormone migraine OCP sensitivity

Introduction

Clinical and epidemiological studies suggest an association between migraine and hormones: before puberty, the prevalence of migraine is comparable in both sexes.¹ An increased female prevalence starts after menarche, peaks around the age of 40, and gradually decreases after menopause.² In women with migraine during their reproductive years, 35–54% of them reported prominent menstrually-related worsening of headache.³ Hormonal fluctuation and withdrawal from estrogen is the most accepted theory behind the accumulation and worsening of attack in these patients during menstruation.^4,5 Animal models showed an increase of pain behavior induced in the trigeminal dermatome when estrogen levels were low, and the increased pain behavior was reversed with estrogen supplement.⁶ A recent study in humans showed a higher pain threshold during the luteal phase in a menstrual cycle and suspected an association with a higher estrogen level in the phase⁷; other evidence suggests that progesterone instead reduces the unpleasantness of pain during this phase.⁸ Taken together, hormonal changes may influence pain perception: a higher level of female hormone during the luteal phase increases pain thresholds and estrogen withdrawal (before menstruation) may trigger migraine attacks.

It is reasonable to assume that the migraine symptomatology may adjust to the altered hormonal level. Data from patients with menstrually-related migraine showed perimenstrual attacks, compared to nonmenstrual attacks, were longer in duration, more disabling, and less likely to respond to treatment.^9,10 The hormonal changes in a natural menstrual cycle are fundamentally altered with the use of hormone contraceptive methods,¹¹ but the impact of oral contraceptive pill (OCP), the most commonly used hormone contraceptive method, on migraine symptomatology remains under-investigated. Based on the composition, OCP can be divided into combined oral contraceptives (COC) and progestogen-only pills (POP). The conventional COC (usually with a regimen of 21 days on and 7 days off) remains the most widely used OCP.¹² Previously, POP,^13,14 extended regimen of COC,^15,16 or COC with additionally supplementation of estradiol during the off-period,^17,18 have been all used in smaller trials in migraine prevention with various effects. However, these studies were small in scale, retrospective, or nonrandomized; therefore, the quality of evidence remains low. Moreover, any modulating effect of the most widely used conventional regimen, that is 21/7, was rarely explored.¹⁹

Another issue that comes with the use of OCP is the risk of cardiovascular events.²⁰ Migraine, especially migraine with aura, is known to increase the risk of subsequent development of cardiovascular events in women.^21
–23 The risk is even higher among those who smoke and use OCP.²⁴ Therefore, COC is contraindicated in patients with migraine with aura according to the World Health Organization (WHO) guideline.²⁵ One would assume that migraine patients are less likely to use/be prescribed with COC; however, real-life data on COC use behavior among female migraineurs are scarce. We therefore investigated OCP use among migraine patients and its impact on migraine symptomatology.

Methods

Study participants

The Headache Outpatient Department of the University Medical Center Hamburg-Eppendorf is one of the largest headache clinics in Germany. Upon the first visit at the clinic, the patient is required to answer a custom-built battery of questionnaires (AC-STB; http://www.akkaya.de/de/), which includes demographics and migraine symptomatology including associated symptoms such as migraine-associated symptoms and cranial autonomic symptoms (CAS). Regarding the social history, the patient is asked to check the following contraceptive methods if present, including pills, intrauterine device, vaginal ring, injectable hormone, hormone implant, or condom. A menstrually-related worsening was defined when the patient checks “menstruation” as a trigger or aggravating factor of the headache. To be more specific, the monthly bleed in patients with COC use is a “hormone withdrawal bleed,” instead of menstrual shedding of the lining of the womb that occurs with the natural menstrual cycle. This study was approved by the local ethics committee of the chamber of physicians of Hamburg, Germany (PV 3183), and patients gave written informed consent to having their anonymized data used for later researches.

Study design

We conducted a retrospective cohort study to identify migraine patients using our database between November 2008 and December 2017. During the first visit, patients were seen by a trained headache specialist (TPJ or AM). The migraine diagnosis and pertinent headache diagnoses were made per International Headache Society’s criteria. Of note, we intended to study the difference between migraine patients with and without oral contraceptive use; therefore, we evaluated exclusively female patients in the age range of 15–45 years, while it has been shown that most women who use OCP fall into this age range, with a peak among those aged 25–34 years.²⁶ Of note, even though OCP can be divided into COC and POP, the latter is rarely used (0.06% among all women in childbearing age) in Germany.²⁷ The top 40 most commonly used COCs are all conventional regimen, of which 37 are 21/7 regimen, two are 24/4 regimen, and the rest are 22/6 regimen. Off-license prescription or use (e.g. extended use) cannot be explored in the current study design.²⁸ Therefore, we assume that most COC users in the current study used the conventional regimen. Comparisons between those with and without OCP use were made regarding the demographics, headache, and associated symptoms.

Statistics

Statistical analysis was performed using SPSS for MAC, version 25.0 (IBM Corp., Armonk, New York, USA). Categorical variables were compared using χ ² test. Continuous variables with normal distribution were analyzed using student’s t-test; those without normal distribution were analyzed using Mann–Whitney U test. All p-values were two-tailed, and a p-value of <0.05 was defined as statistically significant.

Result

A total of 1758 migraine patients were identified with completed questionnaires during the enrollment period, of which 1439 (81.9%) were women and 1032 were between 15 and 45 years of age; among them, 83 patients refused to disclose their status of contraceptive use. A final study cohort of 949 female migraine patients was determined (response rate, 92.0%). Of the 949 patients, OCP remained the most commonly used method of contraception (493 of 949, 51.9%). Details of contraceptive use are shown in Figure 1.

Figure 1.

Current methods of contraception among female migraineurs aged 15–45 years (n = 1032). IUD: intrauterine device.

Among the 949 patients, none used hormonal implants, 37 patients used the combined hormone-releasing vaginal ring, and 9 patients used the hormonal injection for contraception. Those with hormonal injection were excluded from the final analysis due to longer-lasting systemic hormonal effects in comparison to the use of OCP; patients with vaginal rings were also excluded because the systemic estrogen effect was lower in vaginal ring user, and whether the systemic effect of vaginal ring is still comparable to COC remains inconclusive.²⁹ Subjects who used contraceptive methods without systemic hormonal effects (e.g. condom) (Figure 1) were initially compared with those who did not use any contraception. There were no significant demographic or symptomatic differences between those who used contraception without systemic hormonal effects and those who did not use contraception (data not shown). Therefore, both groups, those with contraception without systemic hormonal effects and those without contraception, were combined into the “without OCP use group” for further analysis. A final sample of 493 migraine patients with OCP use and 410 patients without OCP use were concluded.

Compared to patients without OCP use, patients with OCP use were younger (27.4 ± 7.0 vs. 32.8 ± 7.9, p < 0.001). The proportion of the patients diagnosed with migraine with aura did not differ between groups (31.4 vs. 33.9%, p = 0.432). Patients with OCP use were more likely to report menstrually-related worsening of headache (52.3 vs. 42.4%, p = 0.012) and showed a lower frequency of headache days (migrainous and nonmigrainous combined) per month (11.1 ± 7.5 vs. 12.3 ± 8.8, p = 0.03). Headache symptoms (e.g. duration, severity, and characteristics) showed no significant differences between groups. Regarding associated symptoms, patients with OCP use were less likely to have osmophobia (47.3 vs. 54.4%, p = 0.033) or CAS (44.8 vs. 53.2%, p = 0.013). There was a trend toward less phonophobia and skin sensitivity among patients with OCP use (0.05 < p < 0.1). Details of the between-group comparison are summarized in Table 1.

Table 1.

Demographics and headache characteristics between female migraine patients aged 15–45 years with and without OCP.

	Migraineurs with OCP (n = 493)	Migraineurs without OCP (n = 410)	p-value
General
Age	27.4 ± 7.0	32.8 ± 7.9	<0.001
Migraine with aura diagnosis	155 (31.4%)	139 (33.9%)	0.432
Menstrually-related worsening of headache	258 (52.3%)	173 (42.4%)	0.012
Headache characteristics
Unilateral	373 (75.7%)	300 (73.2%)	0.393
Pulsatile	324 (65.7%)	265 (64.6%)	0.733
Exacerbated by physical activities	360 (73.0%)	281 (68.5%)	0.139
Moderate or severe pain intensity	444 (91.7%)	369 (91.8%)	0.976
Headache rating (0–10 scale)	6.6 ± 2.3	6.7 ± 2.3	0.101
Headache frequency (days per month)	11.1 ± 7.5	12.3 ± 8.8	0.030
Headache duration (hours)	8.9 ± 6.0	9.7 ± 7.4	0.266
Accompanied symptoms
Nausea	350 (71%)	298 (72.7%)	0.452
Vomiting	326 (66.1%)	250 (61.0%)	0.163
Photophobia	415 (84.2%)	328 (80.0%)	0.102
Phonophobia	396 (80.3%)	347 (84.6%)	0.091
Osmophobia	233 (47.3%)	233 (54.4%)	0.033
CAS	221 (44.8%)	218 (53.2%)	0.013
Hypersensitivity of skin/scalp	171 (34.7%)	166 (40.5%)	0.073
Difficulty in speech	108 (21.9%)	118 (28.8%)	0.031

OCP: oral contraceptives pills; CAS: cranial autonomic symptoms.

Even though in patients with hormonal intrauterine device (IUD), there is theoretically a predominantly paracrine effect into the uterus rather than a systemic effect. The serum hormone level in hormonal IUD was only 4–13% of the levels compared to oral pills.³⁰ Indeed, we could not exclude the possibility that such a level is already enough for milder systemic effects from the hormonal IUD. The information of hormonal IUD and nonhormonal IUD was not differentiated in the original questionnaire design. We therefore conducted a sensitivity analysis excluding all patients with any IUD use (n = 66) from the non-OCP groups. The subsequent comparison between the OCP use group (n = 493) versus non-OCP use group (n = 344) showed similar results (data not shown).

While the average age between both groups differs, we cannot exclude the possibility that the main findings in the current study are due to the confounding effect of age. Therefore, we conducted a sensitivity analysis focusing on the most prevalent age group of OCP use (20–30 years). Among this age subgroup, there were 299 patients with OCP use and 171 patients without OCP use. Compared to those without OCP use, patients with OCP use were comparable in age (25.2 vs. 25.9, p = 0.11), less likely to have CAS (32.5 vs. 53.8%, p = 0.035), and had less headache days per month (10.7 vs. 12.9, p < 0.001). The difference in menstrually-related worsening and osmophobia still showed a similar trend as those before the sensitivity analysis but did not reach statistical significance.

Discussion

Our data showed that the use of OCP is associated with symptomatology differences in migraine including more menstrually-related worsening of headache, lower headache frequency, lower proportion of CAS, and certain other migraine associated symptoms including osmophobia.

The use of OCP remains the most popular way of contraception in several European and American countries, among which Germany has one of the highest usage rates, up to 63%, among women in childbearing age in the general population.²⁹ Our data revealed that among migraine patients, nearly half of them use OCP, which is less compared to the general population in Germany. One could assume that this is due to fewer prescriptions in aura patients since migraine with aura is known to increase the risk of cardiovascular events, and the risk is even higher among those who use OCP.^21

–24 However, we found no differences in aura prevalence between both groups. It is worth mentioning that OCP are prescription drugs in Germany. That most OCPs are prescribed by gynecologists, the lack of association between migraine with aura and the use of OCP suggests: (i) the gynecologist might not be informed of the diagnosis of migraine with aura in some of our patients; (ii) aura patients in Germany use other methods than OCPs since WHO guidelines regarding risks for prescribing contraceptives relate to contraceptive use²⁵; (iii) OCPs might have been prescribed for other purposes than contraception (e.g. to reduce endometriosis-induced pain); (iv) POP, instead of COC, may be more favorably prescribed to patients with migraine with aura; and (v) the newer generation of COC usually has a lower dosage of estrogen (≤20–30 mcg ethinylestradiol/day) and the risk of cardiovascular events depends on the estrogen dosage.^31,32 In a data source in 2015, among the top 40 used COCs in Germany, a daily dosage of 30 mcg ethinylestradiol remained the most popular (23/40) regimen followed by a daily dosage of 20 mcg (15/40).²⁸ Unfortunately, we do not have the information in our questionnaire about the content of the OCP and whether it differs regarding the status of aura.

In the current study, patients with OCP use were more likely to report headache worsening during their menstruation, that is, during their hormone-withdrawal bleed. This is consistent with previous studies that COC use may worsen headache during the perimenstrual period.^33,34 However, the late luteal phase decline of estradiol in a natural cycle is equivalent to the cessation of a daily dosage of 20 mcg ethinylestradiol.¹⁷ It has been postulated that both the magnitude³⁵ and the speed³⁶ of estrogen drop during the luteal phase contributes to the development of headache during the perimenstrual period synergistically. Of note, these patients may also fit into the diagnostic criteria of estrogen withdrawal migraine in ICHD-3.³⁷

The lower headache frequency in the OCP group is an unexpected finding. One can argue that the use of OCP decreases headache frequency. Continuous low-dose estrogen has been shown to decrease migraine attack.³⁸ Our clinical experience is that such patients have higher attack frequency but with lower intensity when stopping COC. Therefore, we hypothesize the stable estrogen level during the 21 days of “on” phase might be beneficial to migraine prevention and thus decreased the number of migraine attacks, specifically during the “on” phase. Another possibility is that the baseline headache frequency influences the OCP use behavior subsequently. Women who have a higher headache frequency may favorably choose nonhormonal contraceptive methods. Nevertheless, these speculations need further verification.

Even though the headache features are comparable between patients with and without OCP, patients with OCP use were less likely to experience osmophobia and CAS and showed a trend to less phonophobia and skin sensitivity during migraine attacks. In other words, in the current study, patients with OCP use have fewer “hypersensitivity” symptoms. Animal models suggest that estrogen may decrease the activity of dorsal root or even the trigeminal ganglion,^39,40 which could possibly explain the decrease in skin sensitivity and autonomic symptoms. However, clinical data showed inconsistent results: patients undergoing in vitro fertilization, when a high dosage of estrogen was given, showed no obvious changes in pain sensitivity measured by quantitative sensory tests.⁴¹ Additionally, patients with OCP use showed a higher tolerance and less unpleasantness toward painful stimuli.⁴² The modulatory effect of estrogen in the brain may be rather complex, depending on the concentration, speed of the fluctuation, and the duration of its exposure.⁴³

Despite the high number of patients, one could raise limitations in our study: (i) this is a retrospective study design and we could have underestimated the effects of OCP due to recall bias. (ii) It is not surprising that the age is different between the two groups—women who use OCP are younger. Even though previous studies, in both pediatric and adult cohorts, showed no influence of age on sensitivity or CAS in patients with migraine,^44,45 the difference in age is a possible confounding factor. We tried to minimize the age confounding using a sensitivity analysis on age and the results remain mostly unaltered. (iii) The composition and dosage of OCP are also critical. An older formula of daily dosage of ethinylestradiol of 30–50 mcg is known to increase menstrually-related worsening³³; whereas a lower dose of ethinylestradiol of 20 mcg daily on the 21-day “on” phase followed by a minimal dosage of 0.9 mg conjugated equine estrogens daily on the 7-day “off” phase may decrease menstrually-related worsening up to 50%.¹⁷ Unfortunately, such information was not provided in detail in our database. (iv) The changes in OCP use (starting, switching, and stopping) might have an impact on migraine symptomatology. Additionally, migraine patients with menstrually-related worsening may use COC with a different regimen, for example, extended duration. Our study design cannot answer these questions. (v) Patients without COC use might already have had contraindications to COC, which might affect the migraine symptomatology. This cannot be answered in the current study design.

Conclusion

Our data provide real-life OCP use behavior among migraine patients and add evidence to the hypothesis that use of OCP is associated with certain differences in symptoms of migraine. Future studies should focus on the type of hormone/s, dose and regimens, and their respective impact on the migraine symptoms and sensitivity changes.

Clinical implications

Use of oral contraceptive pills (OCP) is very common (up to 50%) among women with migraine between 15 and 45 years of age.

Combined oral contraceptive withdrawal bleeds, compared to menstruation in natural menstrual cycle, are at least in some women, more commonly associated with worsening of headache.

Use of OCP is associated with lower headache frequency, less osmophobia, and less cranial autonomic symptoms.

Status of aura does not alter the prevalence of OCP prescription in Germany.

Footnotes

Authors’ note

K-PP received a research grant from the International Headache Society; AM is the editor of Cephalalgia.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Kuan-Po Peng

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