Burden of migraine related to menses: results from the AMPP study

The AMPP Study was approved by the Albert Einstein College of Medicine Institutional Review Board. The AMPP Study was modeled on the methods of the American Migraine Studies I [17] and II [18], described in detail elsewhere [16] and briefly summarized herein. In 2004, a screening survey was mailed to a stratified random sample of 120,000 U.S. households encompassing 257,339 household members [16]. The questionnaire was completed by the head of the household, who reported the total number of household members and the number of household members experiencing at least occasional self-defined “severe headache”. Each household member with severe headaches was asked to complete a questionnaire that included questions the AMS/AMPP diagnostic module which allows for assignment of migraine based upon on modified ICHD-2 criteria. This module has been demonstrated to have a sensitivity of 100% and specificity of 82% for the diagnosis of migraine [19]. No significant changes occurred between ICHD-2 and ICHD-3beta that are related to the criteria used in this study.

A random sample of 24,000 of the adult (i.e., ≥18 years of age) respondents to the 2004 survey who self-reported active (i.e., past 12 months) “severe headache” were asked to participate in an annual longitudinal follow up study. They completed questionnaires annually from 2005-2009. We used the 2009 AMPP Study survey because complete data were available to describe subtypes of menstrual migraine and it included the HIT-6 (with paid permission for use) as well as the MIDAS.

In the 2009 survey, respondents answered questions about headache symptoms, frequency, severity, menstrual status and whether they had headache/migraine associated with menstruation, employment status (i.e., working for pay full- or part-time, unemployed, retired, a student, a homemaker, disabled, a volunteer, on medical or maternity leave, or “other”) and completed the MIDAS [20] and HIT-6 questionnaire [21]. 17,052 females were mailed the 2009 AMPP Study questionnaire and 71.4% (n = 12,180) were completed and returned (Figure 1).

Respondents were asked to indicate the number of days they had headache in the preceding three months and the number of days with their “most severe type of headache” over the preceding year. A total of 5,134 female respondents of the 2009 AMPP Study survey met criteria for episodic migraine and were considered active cases (i.e., defined as having at least one migraine in the previous 12 months and an average of <15 headache days per month over the preceding 3 months). Of these, 1,697 were eligible for this analysis which included the following: aged 18 to 60 years, had at least one menstrual cycle in the preceding two months, and responded to the questions used to determine menstrual migraine status.

To assess burden of migraine in the population, we compared three groups of women with migraine based on the self-reported association of their migraine attacks with menses using data from the AMPP Study. The majority of women reported some association of migraine with menses, though in most, migraine also occurred at other times of the month. Those with predominantly menstrually-related attacks (MM) had fewer headache-days but appeared to be more impaired by attacks as measured by impairment in ability to work and elevated HIT-6 scores. Women with MAM had overall highest burden, due to experiencing not only peri-menstrual migraines but additional migraines outside of the peri-menstrual window.

Women with MM had fewer headache-days per three months, as was expected given the case definition for MM. In contrast, the MAM group had the highest number of headache-days per three months. This pattern may be important when interpreting findings for the MIDAS LPT headache-days adjusted measure and the HIT-6 measure (Table 4). These measures reflect, in part, the frequency of headaches, as well as, the impact that headaches have on functioning. The adjusted odds ratios for MIDAS LPT were statistically significant and indicate that women with MM experience headaches that have a substantial impact on the work role that is more disabling than that of the other two subgroups. Moreover, as the threshold for work impact was increased (i.e., missed days of work or absenteeism), the difference between MM cases and other cases increased, a finding that is consistent with specialty clinic [9,10] and population studies [3,24]. The HIT-6 measures the global impact of headaches on the social role and other domains of functioning and includes a measure of pain. The elevated odds ratios for a “severe impact” HIT-6 score (≥56) is consistent with the above findings for MIDAS and suggests a more general impact on functioning from MM than the work role.

Previous diary studies compared all peri-menstrual headaches to headaches at other times in the cycle. The prior study from our group based on prospectively filled diaries from the general population [11] and one clinic study suggested that attacks of menstrual and nonmenstrual migraine have similar disability [25]. However, other studies primarily from specialty clinics, suggest that attacks of peri-menstrual migraine are more disabling than attacks of nonmenstrual migraine [8-10]. All these studies focused on comparisons of specific migraine attacks rather than migraine groups.

In this study women with any of the menstrually-related migraine disorders reported on all of their headaches, rather than separately reporting on the impact of menstrually-related and menstrually-unrelated migraine. If menstrually-related migraine attacks are more disabling, then our data will underestimate impact of these headaches. The extent to which impact is underestimated will depend on the ratio of the number of menstrually-related migraine to the number of migraine occurring at other times in the cycle. This “dilution” effect is likely to be less significant for MM cases. The overall self-assessment by MM cases may largely represent experience with peri-menstrual headaches in contrast to the MAM and MUM groups who are largely reporting on non-peri-menstrual headaches. It is of interest that one third of our MM cases also endorsed that they have headaches outside of their menstruation (-2 to +3 days from start on menstruation window), further diluting the MM subgroup and the likely burden of migraine in those who have only menstrual migraines. As clinical experience suggests these are likely women who do not meet ICHD diagnostic criteria for pure MM, but likely experience the majority of their attacks during the menstrual window and only rare attacks at other times. As both clinic and population diary studies have been limited to three months, it is uncertain whether women who fulfill diagnostic criteria for pure MM in these studies actually occasionally experience attacks outside of their menstrual window. Clinical experience suggests so, but further longitudinal studies are needed to clarify this. Furthermore, if peri-menstrual attacks are truly more severe and burdensome as evidence suggests, there would be a bias in reporting of these events compared to non-menstruation related events. As such, the findings from this study cannot be used to determine if peri-menstrual headaches among women with MM, MAM or MUM are more disabling than headaches that occur at other times in the cycle. However, there is a clear trend of overall greater burden in the MM group than in MAM and both have greater burden than the MUM.

This study has several strengths. First, the study population was population-based and was not subject to the potential selection bias that is a concern with clinic-based samples. That is, our study population was less likely to be prone to selection bias that can occur if women are more likely to seek care because they have migraine headaches associated with menses that are not responsive to treatment. Second, the study population (N = 1,697) was large and representative of the demographics of the U.S. population. Finally, we used well validated instruments to assign migraine diagnosis and asses our primary variables of headache-impact and migraine-related disability.

The primary limitation in this study is that our operational criteria for assigning women to different subgroups differed from the ICHD recommended definitions. Diary data over several months would have been the ideal means of classifying women. Since these data were not available, we relied on self-reported, retrospective data. Our data likely mirror the information that patients will provide to healthcare professionals in clinical practice unless the patient or healthcare professional gather three months of prospective daily diary data. Nonetheless, we assume that self-identification of menstrual migraine status resulted in some misclassification and we acknowledge that we are not approximating the ICHD criteria for menstrual migraine. Rather, this is a descriptive study of women in the US population describing their perception of the relationship between their migraine attacks and their menstrual cycle. Notably, almost a third of MM cases reported seven or more headache-days in the past three months. It is likely that a number of these women did not have pure MM according to ICHD, although it is possible if their headaches last three days or if they also have non-migraine headaches. Furthermore, misclassification of MAM to MM cases is likely to have occurred as outlined above and this would diminish the strength of observed associations (i.e. biased the odds ratio toward the null) because data from MAM would have been falsely mixed in with the MM data. In contrast, misclassification of MM cases as MAM or MUM is likely to have had a negligible effect on assessing differences in disability due to the small size of the group in comparison to other groups.

Furthermore, our definition for MAM (“I am more likely to get headaches with my period but they also occur at other times of the month”) was broad and did not require that migraine occur only two days prior or three days after the start of menstruation as is required by ICHD criteria. Individuals could have responded yes to having a “menstrually-associated migraine” even if their migraine occurred on the final three days of their period, which does not match menstrual migraine criteria. It will be useful in the future to determine if peri-menstrual headaches in the MAM group are more disabling than headaches that occur at other times in the cycle. We also did not limit our EM group to those without aura, as is listed in ICHD criteria. Finally, menstrually related migraine has the benefit of being relatively predictable which allows for the preemptive use of therapy or short-term prophylaxis for migraine prevention. While short-term prophylaxis or preemptive use of triptans is not FDA approved, it is a strategy that is used in clinical practice for patients with menstrual related migraine [8,26,27]. In the current study we did not report or control for short-term prophylaxis; therefore it is possible that some percentage of the MM group may be well controlled on this therapeutic strategy. Therefore, the disability seen among that group may be reduced due, in some part, to short-term prophylaxis.

In this large population study representative of the US population, we have shown that most women self-report migraine attacks associated with menstruation and those attacks are associated with impairment including impact on occupational, academic and household responsibilities. When these women are divided into subgroups, those with predominantly peri-menstrual migraines experience the greatest burden. While suggestions for treatment strategies may help, more research will be required to better understand these subgroups given that they account for a significant majority of women with migraine and to determine the best course of treatment for MM and MAM cases and as a result, reduce the burden of migraine associated with menstruation.