Use of combined oral contraceptives among women with migraine and nonmigrainous headaches: a systematic review

Contraception 73 (2006) 189 – 194

Review article

Use of combined oral contraceptives among women with migraine and nonmigrainous headaches: a systematic review Kathryn M. Curtisa,T, Anshu P. Mohllajeea, Herbert B. Petersonb,c a

WHO Collaborating Center in Reproductive Health, Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA b Department of Maternal and Child Health, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA c Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Received 27 July 2005; accepted 11 August 2005

Abstract This systematic review examines evidence evaluating whether women with headaches who use combined oral contraceptives (COCs) have a greater risk of stroke than women with headaches who do not use COCs. We searched MEDLINE for articles published from 1966 through March 2005 relevant to headaches and COC use as risk factors for stroke. Of the 79 articles identified, nine met our selection criteria (eight reports of six observational studies plus one meta-analysis). All studies reported specifically on migraine headaches. Evidence from six case-control studies suggested that COC users with a history of migraine were two to four times as likely to have an ischemic stroke as nonusers with a history of migraine. The odds ratios for ischemic stroke ranged from 6 to almost 14 for COC users with migraine compared with nonusers without migraine. The three studies that provided evidence on hemorrhagic stroke reported low or no risk associated with migraine or with COC use. D 2006 Elsevier Inc. All rights reserved. Keywords: Combined oral contraceptives; Migraine; Headache; Stroke; Systematic review

1. Introduction Combined oral contraceptive (COC) use has been associated with an increased risk of stroke. Recent metaanalyses have reported statistically significant increased risks for COC use and ischemic stroke [pooled odds ratio (OR) 2.74, 95% CI 2.24– 3.35), but not for hemorrhagic stroke (pooled OR 1.30, 95% CI 0.99–1.71) for all COC formulations [1]. Relative risks (RR) associated with lowdose pills containing b 50 Ag ethinyl estradiol were somewhat lower (summary RR 2.08, 95% CI 1.55–2.80 for ischemic stroke) [2]. Studies that have been able to examine populations of COC users without risk factors for stroke generally have not found significantly increased relative risks of stroke [3–5]. Migraine has also been identified as a risk factor for stroke, with a recent meta-analysis reporting a pooled relative risk of 2.16 (95% CI 1.89–2.48) for the association between migraine and ischemic stroke [6]. Migraine with aura has a higher risk of stroke than migraine without aura T Corresponding reviewer. Tel.: +1 770 488 6397; fax: +1 770 488 6391. E-mail address: [email protected] (K.M. Curtis). 0010-7824/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2005.08.009

(pooled RR 2.88, 95% CI 1.89 – 4.39 for migraine with aura; pooled RR 1.56, 95% CI 1.03–2.36 for migraine without aura) [6]. Evidence from two case-control studies suggested that the association between migraine and stroke may be limited to women less than age 45 [7,8]. It has been estimated that the absolute annual risk of stroke in women below age 45 is 17 per 100,000 women with any migraine, increasing to 52 per 100,000 in women experiencing migraine with aura [9]. Nonmigrainous headaches have not been associated with an increased risk of stroke. We conducted this systematic review in preparation for an Expert Working Group of international family planning experts convened by the World Health Organization (WHO) in October 2003 to develop and revise medical eligibility criteria for contraceptive use. As both COC use and migraine may be independent risk factors for stroke, a woman with migraine who uses COCs may further increase her risk of stroke. In this report, we describe the evidence obtained through our systematic review regarding the joint effects of headache and COC use on the risk of stroke, as well as provide the WHO recommendations that were derived in part from this evidence. This review also includes evidence identified since the 2003 meeting through March 2005.

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2. Materials and methods We searched the MEDLINE database for all relevant articles published from 1966 through March 2005 using the following search terms: (bHeadacheQ[MeSH] OR bHeadache DisordersQ[MeSH] OR bCluster HeadacheQ[MeSH] OR bTension HeadacheQ[MeSH] OR bMigraineQ[MeSH] OR bVascular HeadachesQ[MeSH] OR bClassic MigraineQ[MeSH] OR migraine[tw] OR headache[tw]) AND (bCerebrovascular AccidentQ[MeSH] OR stroke[tw]) AND (bContraceptives, OralQ[MeSH] OR bContraceptives, Oral, SequentialQ[MeSH] OR bContraceptives, Oral, CombinedQ[MeSH] OR bContraceptives, Oral, HormonalQ[MeSH] or oral contracept*[tw]) NOT review [pt]. Articles in all languages were accepted. We also searched reference lists of identified articles and relevant review articles for additional citations of interest. We did not consider abstracts of conference presentations, dissertations, unpublished studies, nor did we contact the authors of individual articles. 2.1. Study selection We selected primary research articles or meta-analyses describing observational studies examining the risk of stroke associated with COC use and headaches. All of the studies identified reported specifically on migraine headaches. Studies had to have reported relative risks or odds ratios for stroke either for COC and migraine separately or for the joint effects of COC use and migraine. Of the 79 articles identified by the search strategy, nine met our selection criteria —eight reports of six observational studies plus one meta-analysis [2,4,10 –16]. One of these studies included primarily users of high-dose COCs ( z 50 Ag

ethinyl estradiol) [10], one study included only users of low-dose pills ( b50 Ag ethinyl estradiol) [4] and the rest included a range of different doses [2,11–18]. Most of the studies restricted their outcome to ischemic stroke or cerebral thromboembolic attack (CTA), although three studies also examined risk of hemorrhagic stroke [4,10,15]. 2.2. Study quality assessment and data synthesis We summarized and systematically assessed the evidence through the use of standard abstract forms [19]. The quality of each individual piece of evidence was assessed using a preliminary draft of a grading system developed by members of the Grades of Recommendation Assessment, Development and Evaluation (GRADE) Working Group (Appendix A) [20]. We assessed heterogeneity among the studies by examining the characteristics of the participants included in this review. Although the studies were too heterogeneous to calculate summary statistics, a summary graph of relative risks is included in this review (Fig. 1). We also constructed evidence tables which summarize key elements and results from the studies included in this review (Table 1). 3. Results The first study to examine COC use and migraine together as risk factors for stroke identified 598 women with stroke, ages 15 to 44 years of age, from 91 hospitals in 12 cities in the United States, along with a hospital and a neighborhood control for each case [10]. Most of the COC users reported use of either a 100-Ag mestranol or a 50-Ag

Fig. 1. What is the difference in stroke risk between COC users with migraine and non-COC users with migraine?

Table 1 Evidence from case-control studies regarding COC use, migraine and risk of stroke Author, year, funding source

Study population

Collaborative Group for the Study of Stroke in Young Women, 1975 [10] Supported by the US National Institutes of Health

598 women, ages 15– 44 years, with stroke from 91 hospitals in 12 US cities One hospital and neighbor control for each case, 1969–1971 High-dose pills

Lidegaard, 1993, 1995, 1996 [11–13] Supported by The Helse Foundation, The Danish Heart Foundation and the National Health Research Council Tzourio et al., 1995 [14] Supported by GLAXO France

320 women ages 15–44 with cerebral thromboembolic attack and 1197 controls, Denmark, 1985–1989

Schwartz et al., 1998 [4]

Pooled analysis, 175 women, ages 18 – 44, with ischemic stroke and 1191 controls from the same health plan or county as cases, US, 1991–1995 291 women ages 20–44 years with ischemic stroke and 736 hospital-based controls, five European centers, June 1990–January 1993 (January 1994 for one center)

Nightingale and Farmer, 2004 [16]

a

Limitations

Grade

Lack of standard criteria for migraine diagnosis Lack of validation of stroke diagnosis and type of stroke Lack of control for potential confounders Self-report of COC use

Low

Lack of standard criteria for migraine diagnosis Odds ratios for all relevant groups not reported Self-report of COC use

Low

Self-report of COC use

Intermediate

Lack of standard criteria for migraine diagnosis Self-report of COC use

Low

Self-report of COC use

Intermediate

Lack of standard criteria for migraine diagnosis Did not report joint effects of COC use and migraine on risk of ischemic stroke

Low

Do COCs increase risk of stroke in women with migraine?

72 women ages 18– 44 with ischemic stroke and 173 hospital-based controls, France, January 1990–December 1993

190 women, ages 15–49, with ischemic stroke and 1129 controls, matched for age and general practitioner, 1992–1998; from the United Kingdom General Practice Research Database

Thrombotic stroke — hospital controls No migraine Migraine No OCs 1.0 1.2 (0.8–2.0) All OCs 4.4 (2.5–7.8) 4.6 (2.2–9.6) Thrombotic stroke — neighbor controls No migraine Migraine No OCs 1.0 2.0 (1.2–3.3) All OCs 4.9 (2.9–8.3) 5.9 (2.9–12.2) Similar findings for hemorrhagic stroke, but of lesser magnitude Women with 30– 40 Ag COC use: adjusted OR 1.8 (1.1–2.9) without migraine (or other predisposing factors) COC use and migraine were bindependent exposuresQ Estimate of women with COC use and migraine is 5.0

No migraine Migraine No OCs 1.0 3.7 (1.5–9.1) All OCs 3.5 (1.5–8.3) 13.9 (5.5–35.1) No interaction: among OC users, women with migraine had a fourfold risk of stroke (as in non-OC users) All OCs Low-dose COCs vs. no COCs Women with migraine Women without migraine 2.08 (1.19 – 3.65) 0.88 (0.44 – 1.76)

Ischemic stroke No COCs All COCs Low-dose COCs Hemorrhagic stroke No COCs All COCs Low-dose COCs Current COC use History of migraine No significant interaction

No migraine 1.0 2.76 (1.01–7.55) 1.19 (0.33– 4.29) No migraine 1.0 1.10 (0.55–2.19) 0.76 (0.32–1.81) 2.30 (1.15– 4.59) 2.33 (1.04–5.21)

Migraine 2.27 (0.69–7.47) 16.9 (2.72–106)a 6.59 (0.79–54.8)a Migraine 1.13 (0.60–2.12) 1.10 (0.40–2.97) 0.52 (0.13–2.01)a

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Chang et al., 1999 [15] Supported by the World Health Organization and the US National Institutes of Health

Results

No significant interaction.

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ethinyl estradiol formulation. When compared with neighborhood controls who did not use COCs and did not report a history of migraine, COC users without migraine had almost five times the risk of ischemic stroke (RR 4.9, 95% CI 2.9–8.3), women with migraine who did not use COCs had two times the risk (RR 2.0, 95% 1.2–3.3) and COC users with migraine had almost six times the risk (RR 5.9, 2.9–12.2). Relative risks for hemorrhagic stroke were also elevated among COC users without migraine (RR 2.2, 95% CI 1.3–3.6), nonusers with migraine (RR 1.8, 95% CI 1.2–2.7) and COC users with migraine (RR 2.6, 95% CI 1.2–5.5), again compared with neighborhood controls who did not use COCs and did not report a history of migraine. The relative risks for ischemic and hemorrhagic stroke using hospital controls were slightly lower than with neighborhood controls, but followed a similar pattern. An analysis from a case-control study in Denmark examined 320 cases of CTA and 1197 population-based controls. After excluding women with predisposing factors for CTA including migraine, the odds ratio for CTA among women using 30- to 40-Ag COCs was 1.8 (95% CI 1.1–2.9) and for women using 50-Ag pills was 2.9 (95% CI 1.6–5.4) compared with nonusers [11]. In a separate analysis of the same study population, the odds ratio for the association between migraine and CTA was 2.8 (pb .01; confidence intervals not reported) among 497 cases and 1370 controls [12]. The authors stated that these two odds ratios for COC use and for migraine were independent of each other — that is, there was no interaction between COC use and migraine on risk of CTA—suggesting that low-dose COC users with migraine had 1.8 times the risk of stroke as nonusers with migraine (i.e., the same as that for low-dose COC users overall) [13]. Therefore, the odds ratio for stroke for women with both risk factors—COC use and migraine — compared with women with neither factor would be approximately 5.0 [the odds ratio associated with COC use (1.8) times the odds ratio associated with migraine (2.8)] [13]. In a case-control study that evaluated 72 cases of ischemic stroke in women of reproductive age and 173 hospital controls, there was an increased risk of ischemic stroke risk for women with migraine and no COC use (OR 3.7, 95% CI 1.5–9.1), for women with COC use and no history of migraine (OR 3.5, 95% CI 1.5–8.3) and for women with migraine and COC use (OR 13.9, 95% CI 5.5–35.1), compared with women who had no history of migraine and who did not use COCs [14]. Therefore, COC users with migraine had about four times the risk of ischemic stroke as women with migraine who did not use COCs. These estimates do not suggest an interaction between COC use and migraine, but rather independent effects of the two factors on the risk of ischemic stroke. Data from two US population-based case-control studies of low-dose COC use and stroke were pooled to evaluate the effects of COC use and migraine on risk of stroke [4]. The pooled data showed no increased risk of ischemic stroke (OR 1.09, 95% CI 0.54 –2.21) or hemorrhagic stroke (OR

1.11, 95% CI 0.61–2.01) for women currently using lowdose COCs compared with women not using COCs. Among women reporting a history of migraine, COC users had a greater risk of ischemic stroke than nonusers (OR 2.08, 95% CI 1.19–3.65); the odds ratio was similar for hemorrhagic stroke when comparing COC users with nonusers, but it was not statistically significant (OR 2.15, 95% CI 0.85–5.45). Among women with no history of migraine, COC users did not have an increased risk of either ischemic or hemorrhagic stroke compared with nonusers (OR 0.88, 95% CI 0.44–1.76; OR 1.00, 95% CI 0.46–2.19 for ischemic and hemorrhagic stroke, respectively). Data from 291 women with stroke and 736 age- and hospital-matched controls from five European centers participating in the WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception were examined with regard to use of low-dose COCs, history of migraine and risk of ischemic or hemorrhagic stroke [15]. Compared with non-COC users without a history of migraine, COC users without migraine had an OR of 1.19 (95% CI 0.33– 4.29) for ischemic stroke, women with migraine who did not use COCs had an OR of 2.27 (95% CI 0.69–7.47) and COC users with migraine had an OR of 6.59 (95% CI 0.79–54.8). Therefore, COC users with migraine had about three times the risk of ischemic stroke as women with migraine who did not use COCs. No such increases were seen for hemorrhagic stroke. No association was found between COC use and change in frequency or type of migraine; more than 80% of women with migraine and using COCs had not experienced any change in migraine, a percentage comparable to that among women not using COCs. A nested case-control study of women of reproductive age in the United Kingdom that examined 190 cases of ischemic stroke and 1129 controls reported significantly increased risks of ischemic stroke with current COC use (OR 2.30, 95% CI 1.15– 4.59) and history of migraine (OR 2.33, 95% CI 1.04 –5.21) [16]. These risks were independent of each other, and the authors did not present estimates of the joint effects for risk of ischemic stroke. Finally, a published meta-analysis of 16 studies examined the association between COC use and ischemic stroke [2]. Of the 16 studies, four included information on migraine. Among women with a history of migraine, COC users had an increased risk of ischemic stroke in comparison with nonusers (summary RR 3.22, 95% CI 1.45–7.16). Among women without a history of migraine, the risk of ischemic stroke for COC use compared with nonuse was somewhat lower and not statistically significant (summary RR 2.30, 95% CI 0.74–7.1), although confidence intervals overlapped with the migraine estimates. 4. Discussion In this review, we found no studies that examined the association between nonmigrainous headaches and the risk

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of stroke among COC users, but such headaches by themselves have not been associated with increased risk of stroke. In contrast, we found evidence from six case-control studies that suggested that women with a history of migraine who use COCs are two to four times as likely to have an ischemic stroke as nonusers with history of migraine [4,10– 16]. It is unclear whether this increase in relative risk is solely due to the independent effects of COC use and history of migraine, or whether COC use has a greater effect in women with migraine than in women without migraine. Three of these studies estimated that the relative risks of COC use were about the same in women with and without migraine [10,13,14], while two studies found higher relative risks associated with COC use among women with migraine than among women with no history of migraine [4,15]. However, the confidence intervals for these estimates overlapped, and there was no evidence of statistical interaction. From the studies that reported on joint effects, the odds ratios for ischemic stroke ranged from 6 to almost 14 for COC users with migraine compared with nonusers without migraine [10,14,15]. The three studies that provided evidence on hemorrhagic stroke reported low or no risk associated with migraine or COC use [4,10,15]. Overall, the quality of these six observational studies ranged from intermediate to low (Table 1). Migraine can be difficult to diagnose, especially in studies that rely on selfreport of medical history, potentially leading to misclassification. Only two of the studies used standard criteria from the International Headache Society to classify migraine [14,15]. In addition, recall bias with regard to COC use may have occurred; the study from the General Practice Research Database in the UK was the only study to have medical record confirmation of COC prescription and formulation [16]. All but one [10] of the studies included some validation of the stroke diagnosis. Several of these studies did not report on the joint effects of COC use and migraine on the risk of stroke; while these studies generally reported that both COC use and migraine were independent risk factors for stroke, estimation of the joint effects from the data would have been useful in assessing interaction and the overall relative risk of stroke among women with both migraine and COC use. No studies have had enough power to examine the risk of stroke by COC use and type of migraine (with or without aura) simultaneously. Given the small absolute risk of stroke in women of reproductive age, it will be difficult to acquire this information. Women with aura generally have a higher risk of stroke than those without aura, although estimates of the difference vary widely. Regardless, it has been estimated that at age 20, women with migraine who are also taking COCs have an absolute risk of stroke of 10 per 100,000, with eight of these events being due to migraine and COC use [21]. By age 40, the absolute risk rises to 100 per 100,000, with an attributable risk of 80 per 100,000. In 2003, WHO convened an Expert Working Group to review medical eligibility criteria for contraceptive

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use [22]. After reviewing the evidence provided above (with the exception of the study by Nightingale and Farmer [16], which was published after the 2003 meeting), the group determined that women with nonmigrainous headaches can use COCs (WHO Category 1), women having migraine without aura who are less than age 35 can generally use COCs (WHO Category 2), women having migraine without aura who are 35 years or older generally should not use COCs (WHO Category 3) and women having migraine with aura, at any age, should not use COCs (WHO Category 4). In addition, WHO made recommendations regarding continued use of COCs among women with headaches and noted that any new headaches or marked changes in headaches while using COCs should be evaluated. If nonmigrainous headaches develop while taking COCs, the woman can generally continue COC use (WHO Category 2); if a woman develops migraine without aura while she is taking COCs and she is less than 35 years, she should generally not continue to use COCs (WHO Category 3); and if she develops migraine without aura at age 35 years or older or if she develops migraine with aura at any age while taking COCs, she should not continue to use COCs (WHO Category 4). Acknowledgments This review was supported by resources from WHO, the US Centers for Disease Control and Prevention (CDC), US Agency for International Development (USAID) and the US National Institute of Child Health and Human Development (NICHD). We would also like to acknowledge the assistance of William Thomas, MLIS, Technical Information Specialist at CDC, in developing the literature search strategies. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the funding agencies. Appendix A. Study quality assessment A.1. Individual study Each study was given a rating of very low, low, intermediate or high based on the interval validity of the study. If the study was indirect, the quality of the individual study was lowered by one level. If the study was direct, the quality of evidence was kept the same. Similarly, if there was sparseness of the data, the quality of the individual study was lowered by one level. A.2. Body of evidence The quality of the body of evidence was the highest rating given to an individual study. If the results were inconsistent, the quality of the body of the evidence was lowered by one level. If results were consistent, then the quality of the body of the evidence was left at the original level. Similarly, if there was reporting bias (publication

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bias), then the quality of the body of evidence would be lowered by one level.

[6]

Quality of evidence across studies for each main outcome RCT

Quality of the evidence

Observational studies

No serious flaws in study quality

High

Extremely strong association and no threats to validity Strong, consistent association and no plausible confounders

Serious flaws in Intermediate design or execution or quasi-experimental design Very serious flaws Low No serious flaws in design or in study quality execution Very serious flaws Very low Serious flaws in and at least one design and other serious execution threat to validity Additional factors that lower study quality are as follows: important inconsistency of results; some uncertainty about directness; high probability of reporting bias; and sparseness of data. Major uncertainty about directness can lower the quality by two levels Additional factors that may increase the quality of observational studies are as follows: all plausible residual confounding, if present, would reduce the observed effect, and evidence of a dose–response gradient. Adapted from: Judging Confidence: Guidelines for Grading Evidence and Recommendations. Grades of Recommendation Assessment, Development, and Evaluation (GRADE) Working Group. Draft, January 2003.

[7] [8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

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