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Abstract

Background

Data on the effectiveness of preventive treatments on menstrually-related migraine (MRM) is scarce. Our objective was to analyze the efficacy of anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs) and onabotulinumtoxinA (BTX-A) in the reduction of perimenstrual headache days (PHD) and perimenstrual migraine days (PMD) compared to non-perimenstrual headache days (non-PHD) and non-perimenstrual migraine days (non-PMD) per month in women with MRM.

Methods

A retrospective study was conducted including females with menstruation and headache records, treated with either anti-CGRP mAbs or BTX-A. Patients completed e-Diary one month before and three months after preventive treatment. We collected clinical data and analyzed PHD/PMD and non-PHD/non-PMD before and after treatment. Additional analyses included PHD/PMD and non-PHD/non-PMD comparisons grouped by aura, episodic/chronic migraine, treatment and contraceptive intake.

Results

We analyzed data from 113 females with a median (range) age of 39.0 (33.0–45.0) years. When combining patients treated with anti-CGRP mAbs or BTX-A, a median (range) of 2.0 (2.0–3.0) PHD/month (corresponding to 13.6% baseline monthly headache days (MHD)) and 13.0 (9.0–17.0) non-PHD/month pre-treatment was observed. From these, 2.0 (1.0–3.0) were PMD/month, and 7.0 (4.0–11.0) were non-PMD/month. After treatment, the median PHD/month was 2.0 (1.0–3.0) (corresponding to 16.67% of MHD) (p = 0.085), and 8.0 (5.0–13.0) were non-PHD/month (p < 0.001); from these, 1.0 (0.0–3.0) were PMD/month (proportion difference, p = 0.035) and 4.0 (2.0–7.0) were non-PMD (proportion difference, p < 0.001). When analyzing grouped by treatment, only patients treated with anti-CGRP experienced a reduction in PMD. No statistically significant differences in clinical factors (aura, migraine diagnosis, contraceptive intake) between PHD/non-PHD or PMD/non-PMD, either pre- or post-treatment. A higher probability risk of headache and migraine during the perimenstrual window was observed independently of the treatment received (odds ratio = 1.637, 95% confidence interval = 1.356–1.984, p < 0.001).

Conclusions

Three-month treatment with anti-CGRP mAbs or BTX-A effectively reduced non-PHD and non-PMD but had limited effect on PHD/PMD because headache probability risk was higher during the perimenstrual window after treatment.

Graphical abstract

This is a visual representation of the abstract.

Keywords

Anti-calcitonin related-peptide CGRP contraceptive menstrually-related migraine menstrual migraine preventive treatment sex hormones treatment

Introduction

Menstrual migraine (MM) affects 4.0–8.0% of women in the general population, being more prevalent among females with migraine, with MM without aura affecting 18.0–25.0% and MM with aura affecting 1.7–8.1% of these (1). MM is classified in the appendix of the International Classification of Headache Disorders, 3rd edition (ICHD-3) (2) as either pure menstrual migraine (PMM) when attacks occur exclusively on day 1 ± 2 of menstruation (perimenstrual window) in at least two out of three menstrual cycles, or menstrually-related migraine (MRM), when attacks mainly occur in the perimenstrual window, but also at other times in the cycle.

Migraine attacks during the perimenstrual window (perimenstrual headache day (PHD) and perimenstrual migraine day (PMD)) are mostly without aura (3) and tend to be more severe, longer-lasting and harder to treat than those outside the window (non-perimenstrual headache days and non-perimenstrual migraine days, non-PHD and non-PMD) (4 –8). PHD/PMD are also more likely to recur and are frequently associated migraine-related and non-neurological symptoms, leading to reduced quality of life and greater functional impairment (4,5,7,8).

The pathophysiology of MM is complex and not yet fully understood, with fluctuations in sex hormones during the menstrual cycle playing a key role. The “estrogen withdrawal hypothesis” is considered a primary mechanism (9). Evidence suggests interactions between sex hormones and migraine-related neuropeptides, such as CGRP and PACAP-38 (10,11). Other hormones, including oxytocin and prolactin, may also play a significant role (12). Genetics and epigenetic modulation by sex hormones are also considered to be involved (13,14).

Different treatment approaches have been proposed for MM. Regarding acute treatment, non-steroidal anti-inflammatory drugs (NSAIDs) are a first-line option. If ineffective, triptans can be considered, which have shown to be superior to placebo in randomized controlled trials (RCTs) for 2-hour and 24-hour pain relief. In a recent meta-analysis, sumatriptan 100 mg emerged as the most effective for both time-points. The combination of sumatriptan 85 mg with naproxen 550 mg has shown mixed results. Other less supported strategies include combinations of acetaminophen, aspirin and caffein, or rizatriptan 10 mg with dexamethasone 4 mg, although the latter carries a high risk of adverse events (15). Lasmiditan and ubrogepant have also shown efficacy for acute MRM treatment, though further evidence is needed (16,17).

For patients with regular menstruations, frequent and disabling attacks during perimenstrual periods, 5–7-day short-term prevention with naproxen (550 mg twice daily) and rofecoxib (25 or 50 mg daily) has been shown to reduce headache days. Frovatriptan (2.5 mg twice daily), followed by zolmitriptan (2.5 mg three times daily) and naratriptan (2.5 mg twice daily) (15), has also proven effective. However, short-term strategy may increase the risk of chronification, induce or worsen a medication overuse (17) in individuals with high-frequency episodic (EM) or chronic migraine (CM); therefore, long-term prevention should be considered.

Long-term prevention strategies include topiramate (18), anti-calcitonin gene related monoclonal antibodies (anti-CGRP mAbs), hormonal treatments and non-pharmacological approaches. Studies suggest that galcanezumab (19 –21), erenumab (19,22 –24) and fremanezumab (19,23) reduce headache frequency and improve characteristics in MRM, although evidence remains limited. The impact of onabotulinumtoxinA (BTX-A) in MRM has not yet been assessed. However, because most affected women are of childbearing potential, highly effective contraception during these treatments should be recommended, as topiramate and anti-CGRP mAbs, are contraindicated during pregnancy.

Hence, the present study aims to analyze the efficacy of anti-CGRP mAbs and BTX-A in reducing perimenstrual headache and perimenstrual migraine days compared to non-perimenstrual headache and migraine days in women with MRM. Secondary objectives include assessing the effects of contraceptives, aura, and migraine diagnosis on PHD characteristics.

Methods

Study design

This retrospective cohort study analyzed prospectively collected headache and menstruation data from women diagnosed with migraine by a headache-specialist neurologist and treated with anti-CGRP mAbs or BTX-A, between January 2020 to December 2023. Participants completed e-Diaries for one month before starting treatment (baseline) and continued up to four months throughout treatment. Women with coexisting headache disorders, pregnancy or breastfeeding were excluded.

The selection of women receiving anti-CGRP mAbs and BTX-A was based on several factors. First, unlike those on oral preventive treatments alone, patients undergoing these therapies are required to maintain a headache diary for reimbursement purposes, ensuring detailed and consistent data collection. Additionally, patients who achieve good control with oral preventive treatments are typically managed by general practitioners or general neurologists rather than being followed up in specialized Headache Clinics. This naturally led to a focus on patients receiving anti-CGRP mAbs and BTX-A because they represent the population most frequently monitored in our setting. None of the included women were undergoing short-term preventive treatment.

Data collection

The pre-treatment period took the last menstruation cycle before M0, consisting of 28 completed calendar days with menstruation period in the middle. Headache characteristics were recorded in the e-Diary, and days were classified either as migraine days (as defined by ICHD-3) or headache days (those not meeting migraine criteria). For clarity and a more comprehensive overview, in the present study, headache days encompass both migraine and non-migraine headache days, whereas migraine days specifically refer to those meeting the established migraine criteria.

We identified the perimenstrual window (days 1 ± 2 of menstruation), and accordingly, the PHD and PMD. Several scenarios could occur (see supplemental material, Figure S1):

Case 1: No menstruation cycle before M0 existed.

Case 2: Last cycle before M0 was incomplete and there was no other complete cycle before.

Case 3: Last cycle was incomplete, as well as the previous cycle.

Case 4: Last cycle was incomplete, but the previous one was complete.

Case 5: No existing complete menstruation cycle before M0, the available cycle overlaps with M0. The latest day a menstrual cycle could start was 4 days before M0, to ensure that the treatment had no effect.

Case 6: Last cycle was complete.

Post-treatment period took the last complete menstruation cycle in the period between one month before M3, and a month and a half after it. As in the pre-treatment cycle, the aim was to find 28 completed calendar days with the perimenstrual window in the middle. Likewise, in the pre-treatment period, different scenarios could occur (see supplemental material, Figure S2).

In women with overlapping BTX-A and anti-CGRP treatments, only the treatment with most completed e-Diary entries for pre- and post-treatment was selected. Cases 1, 2 or 3 in pre- and/or post-treatment periods were considered incomplete, whereas cases 4, 5 or 6 in pre- and post-treatment periods were considered complete. For individuals with two consecutive treatments, a value of “0” was given if none had e-Diary data, “1” if just one treatment had entries and “2” if both treatments had entries. Females with no entries were excluded. Females with one treatment with complete e-Diary data were directly included, and the missing treatment removed. Females where both treatments had complete e-Diary data, the compliance had to be equal or higher than 75.0%, and given that both treatments had the same compliance, BTX-A treatment was selected because the number of individuals per group was lower. In women with a single treatment, the completeness and compliance were checked and included accordingly.

At this point, all females had just one treatment kept for the study, either anti-CGRP or BTX-A, pre- and post-treatment periods complete, and a compliance higher than 75.0% per both periods (see supplemental material, Figure S3).

Statistical analysis

All statistical analysis were conducted in R, version 4.3.1. P-values for multiple comparisons were adjusted using the false discovery rate (FDR).

Nominal variables such as medical history (hypertension, obesity, anxiety, depression, cardiovascular and neurovascular disease), aura, allodynia, type of pain (unilateral any side, right or left or bilateral), failed preventive treatment (beta blockers, neuromodulators, antidepressants, calcium chain blockers, angiotensin receptor blockers, BTX-A and anti-CGRP mAbs), number of failed preventive treatments, oral treatment, contraceptives, current treatment administered (erenumab, galcanezumab, fremanezumab and BTX-A) and side effects were reported as frequencies (percentages), whereas the median and interquartile range (IQR) were reported for quantitative variables including age, evolution (number of years since migraine started), chronification (number of years since patient had more than eight headache days per month), monthly headache days (MHD) (the sum of PHD and non-PHD), monthly migraine days (MMD) (the sum of PMD and non-PMD), acute medication days/month (AMDM), anxiety scale (Beck Anxiety Inventory, BAI), depression scale (Beck Depression Inventory, BDI-II), Migraine Disability Assessment Test (MIDAS), headache impact test (HIT-6) and migraine specific quality of life questionnaire (MSQ).

Headache e-Diary variables aimed to describe each day of the menstrual cycle and were factorized for easier interpretation. Individuals had to write down whether they had headache and menstruation each day. Given that the patient had headache, several variables had to be completed including intensity (scale from 1 = lowest- to 3 = highest), start time (scale with 1 = waking up with headache; 2 = waking up at midnight due to headache; and 3 = headache appeared during the night), symptomology (aura, nausea, light sensitivity, noise sensitivity and dizziness), medication (triptans, NSAIDs, simple analgesics, opioids and combined medication) and effectivity of medication (scale with 1 = not effective; 2 = lower intensity but not disappeared; 3 = better but pain left in more than 2 h; and 4 = pain disappeared in less than two hours).

Women with a naturally occurring menstrual cycle and those using contraception (hormonal, hormone-free interval and non-hormonal) were included in the study. Contraceptive data including its use and type of contraceptive (contraceptive pills, patch or vaginal ring, injections, intrauterine devices and surgery) was required for every patient. However, because the number of females taking contraceptives was low, we grouped all contraceptive types.

Headache and migraine days falling in the perimenstrual window (headache days 1 ± 2 of menstruation) were labelled as PHD or PMD; otherwise, they were considered non-PHD/non-PMD. In this study, only patients with MRM were considered.

Beforehand, we attempted to identify existing correlations between some demographic variables, including evolution and scales, and PHD/PMD and non-PHD/non-PMD using Spearman's correlation test.

The primary outcome of the study was to analyze the effectiveness of preventive treatment in the reduction of PHD and PMD/month compared to non-PHD and non-PMD/month before and after treatment, for which paired t-tests and two-sample tests for equality of proportions with continuity correction were used. The change in number of PHD or PMD/month and non-PHD or non-PMD/month was studied in females grouped by treatment using paired t-tests. Likewise, differences in the amount of PHD pre-treatment were compared segregating by aura, contraceptives intake and type of treatment using logistic mixed models. Fisher’s exact test was used in binary categorical variables with small group sizes, a chi-squared test was used for categorical variables with larger group sizes and the Mann–Whitney U-test for ordinal variables.

As secondary objectives, we compared PHD/PMD and non-PHD/non-PMD clinical characteristics pre-treatment, using Fisher's test, a chi-squared test or the Mann–Whitney U-test accordingly. The same was carried out for post-treatment comparisons. Besides, grouped comparisons between PHD/PMD and non-PHD/non-PMD were analyzed meeting requirements based on EM/CM, anti-CGRP mAbs/BTX-A treatment, with/without aura and taking/not taking contraceptives, at baseline and post-treatment.

Additionally, we wanted to observe the tendencies of headache, both PHD/PMD and non-PHD/non-PMD, together in the menstrual cycle. We plotted the percentage of individuals with an attack each day of the menstrual cycle. Based on that, we studied the probability risk of a headache attack per four-day window, using a binomial regression model.

In search of the effect of contraceptives on headache, we segregated by females taking and not taking contraceptives and plotted independently the percentage individuals with a headache/migraine attack per day on the menstrual cycle pre- and post-treatment. We fragmented the menstrual cycle before and after the perimenstrual window and checked whether there were statistical differences in the distribution of headache/migraine based on contraceptives intake. We tried to fit the best distribution explaining the data using generalized linear mixed models (GLMM), finally fitting gaussian distributions in all cases.

Results

Cohort description

Data was collected from 113 females, with a median age of 39.0 (IQR = 33.0–45.0) years. Of the total participants, 35.4% (40/113) had EM, 64.6% (73/113) CM and 21.2% (24/113) aura. Some 72.6% (82/113) received anti-CGRP mAbs and 27.4% (31/113) received BTX-A. The median (range) baseline headache frequency was 16.5 (12.8–21.0) days/month, with median (range) AMDM of 11.0 (7.0–14.0). At baseline, PHD and non-PHD were found to be significantly correlated, using Spearman, to BDI II (r = 0.207, p = 0.045 and r = 0.204, p = 0.049). Additional pre-treatment data can be found in Table 1 , as well as the supplemental material, Table S1.

Table 1.

Demographics, comorbidities and headache characteristics of participants at baseline.

Variables	n = 113
Demographics
Age (years), median (IQR)	39.0 (33.0–45.0)
Migraine characteristics
Episodic migraine, n (%)	40 (35.4%)
Chronic migraine, n (%)	73 (64.6%)
Evolution (years), median (IQR)	15.0 (10.0–21.0)
Chronification (years), median (IQR)	36.0 (29.0–41.0)
Allodynia, n (%)	46 (46.9%)
Aura, n (%)	24 (21.2%)
Headache eDiary days, median (IQR)
Headache days per month	15.0 (11.0–19.0)
Perimenstrual headache days	2.0 (2.0–3.0)
Non-perimenstrual headache days	13.0 (9.0–17.0)
Migraine days per month
Perimenstrual migraine days	2.0 (1.0–3.0)
Non-perimenstrual migraine days	7.0 (4.0–11.0)
Treatment, median (IQR)
Acute medication days per month	11.0 (7.0–14.0)
NSAIDs	7.0 (2.0–11.5)
Triptans	6.0 (3.0–11.0)
Failed preventive treatments, n (%)
Betablockers	48 (42.5%)
Neuromodulators	63 (55.8%)
Antidepressants	75 (66.4%)
Calcium channel blockers	29 (25.7%)
Angiotensin receptor blockers	11 (9.7%)
BTX-A	19 (16.8%)
Anti-CGRP mAbs	3 (2.7%)
Contraceptives, n (%)	25 (28.1%)
Current treatment, n (%)
Anti-CGRP mAbs
Erenumab	50 (44.2%)
Galcanezumab	13 (11.5%)
Fremanezumab	19 (16.8%)
BTX-A	31 (27.4%)
Adverse events, n (%)	0 (0.0%)
Comorbidities, median (IQR)
BAI	16.0 (8.0–28.0)
BDI II	11.5 (5.0–21.0)
Migraine-related clinical burden, median (IQR)
MIDAS	49.0 (30.0–93.0)
HIT6	65.0 (62.0–68.0)
MSQ total	42.3 (21.8–56.8)

AMDM = acute medication days per month; anti-CGRP mAbs = anti calcitonin-gene related peptide monoclonal antibodies; BAI = Beck Anxiety Inventory; BDI-II = Beck Depression Inventory; BTX-A = onabotulinumtoxinA; HIT-6 = Headache Impact Test; IQR = interquartile range; MIDAS = migraine disability assessment test; MSQ total = Minnesota Satisfaction Questionnaire; NSAIDs = non-steroidal anti-inflammatory drugs.

Perimenstrual and non-perimenstrual headache days reduction

At baseline, the median (range) number of PHD was 2.0 (2.0–3.0) days/month (corresponding to 13.6% of baseline MHD) and 13.0 (9.0–17.0) days/month were non-PHD. From these, 2.0 (1.0–3.0) days/month were PMD and 7.0 (4.0–11.0) days/month were non-PMD. At 3-month treatment, the median PHD was 2.0 (1.0–3.0) days/month (corresponding to 16.7% of MHD) (proportion difference, p = 0.085) and 8.0 (5.0–13.0) days/month were non-PHD (proportion difference, p < 0.001). From this, 1.0 (0.0–3.0) days/month were PMD (proportion difference, p = 0.035) and 4.0 (2.0–7.0) days/month were non-PMD (proportion difference, p < 0.001).

When analyzing PHD and non-PHD grouped by treatment, we observed a reduction in non-PHD from 13.0 (9.0–17.0) at baseline to 7.5 (5.0–13.0) after treatment (p < 0.001), whereas PHD changed from 2.0 (1.0–3.0) to 2.0 (1.0–3.0) (p = 0.145) in patients with anti-CGRP mAbs. Patients with BTX-A showed a reduction in non-PHD from 13.0 (8.5–16.5) to 9.0 (4.5–13.0) (p < 0.001) and in PHD from 2.0 (2.0–3.0) to 2.0 (1.0–3.0) (p = 0.355). Regarding PMD and non-PMD, females with anti-CGRP mAbs showed a reduction in non-PMD from 7.0 (4.0–10.0) at baseline to 4.0 (2.0–7.0) after treatment (p < 0.001), whereas PMD changed from 2.0 (1.0–3.0) to 1.0 (0.0–2.0) (p < 0.001). In patients with BTX-A, non-PMD changed from 8.0 (4.5–12.0) to 5.0 (2.0–7.5) (p = 0.004), whereas PMD changed from 2.0 (1.0–3.0) to 3.0 (1.0–3.0) (p = 0.460).

We conducted three complementary studies and found no statistically significant differences in the baseline PHD proportions, or the change in PHD proportion before and after treatment among individuals stratified by aura (odds ratio (OR) = 1.007, 95% confidence interval (CI) = 0.323–3.137, p = 0.942; OR = 1.002, 95% CI = 0.982–1.022, p = 0.711), contraceptives use (OR = 0.934, 95% CI = 0.289–3.019, p = 0.871; OR = 1.010, 95% CI = 0.991–1.030, p = 0.648) or treatment type (OR = 1.035, 95% CI = 0.370–2.897, p = 0.903; OR = 1.004, 95% CI = 0.986–1.023, p = 0.567). When inspecting PMD and change in PMD proportions before and after treatment, we found no statistically significant differences grouped by aura (OR = 0.749, 95% CI = 0.289–1.942, p = 0.552; OR = 0.993, 95% CI = 0.855–1.154, p = 0.926), contraceptives use (OR = 1.050, 95% CI = 0.389–2.828, p = 0.924; OR = 1.076, 95% CI = 0.922–1.255, p = 0.352) or treatment type (OR = 1.148, 95% CI = 0.472–2.792, p = 0.762; OR = 1.099, 95% CI = 0.960–1.259, p = 0.171).

Headache e-Diary variables comparison

Baseline headache e-Diary characteristics, including symptomatology, headache intensity, acute medication use and treatment effectiveness were collected and compared between PHD and non-PHD, showing no statistically significant differences (see supplemental material, Table S2). Similarly, a grouped analysis based on aura, contraceptive use, treatment type and migraine diagnosis (EM/CM) also showed no significant differences.

Later, PHD characteristics at baseline and post-treatment were compared, finding no statistically significant differences after FDR p-value adjustments (Table 2). However, a sensitivity analysis of PHD characteristics before and after treatment showed that individuals receiving anti-CGRP mAbs experienced a reduction in headache pain intensity, with the distribution shifting from 31.6% mild, 36.7% moderate and 31.7% severe pain to 47.8%, 34.2% and 18.0%, respectively (p = 0.019). Additionally, nausea decreased from 31.0% to 17.0% (p = 0.019). Individuals with aura had a reduction in the aura frequency (p = 0.027) and those taking contraceptives reported a decrease in dizziness (p = 0.027).

Table 2.

Perimenstrual headache clinical characteristics comparison before and after 3-month treatment with anti-CGRP mAbs or BTX-A.

Characteristics	Perimenstrual headache days at baseline (days = 244)	Perimenstrual headache days after treatment (days = 223)	p-value	Adjustedp-value
Intensity			0.162	0.576
Mild	76 (31.3%)	86 (38.6%)
Moderate	97 (39.9%)	87 (39.0%)
Severe	70 (28.8%)	50 (22.4%)
Start time			0.784	0.998
At wake-up	49 (38.9%)	37 (39.8%)
Midnight	19 (15.1%)	11 (11.8%)
During the day	58 (46.0%)	45 (48.4%)
Symptoms
Aura	58 (25.7%)	39 (18.0%)	0.052	0.363
Nausea and/or vomiting	71 (31.4%)	47 (21.7%)	0.024	0.335
Light sensitivity	157 (69.5%)	152 (70.0%)	0.918	>0.999
Noise sensitivity	149 (65.9%)	143 (65.9%)	>0.999	>0.999
Dizziness	73 (32.3%)	54 (24.9%)	0.093	0.434
Medication
Triptans	109 (44.7%)	93 (41.7%)	0.575	0.805
NSAIDS	125 (51.2%)	104 (46.6%)	0.354	0.642
Simple analgesics	47 (19.3%)	43 (19.3%)	>0.999	>0.999
Opioids	1 (0.4%)	3 (1.3%)	0.352	0.642
Combined medication	8 (3.3%)	3 (1.3%)	0.226	0.633
Effectivity of acute medication			0.373	0.642
Same pain	33 (19.1%)	21 (13.5%)
Less pain but not disappeared	60 (34.7%)	65 (41.7%)
Pain disappeared in +2 hours	27 (15.6%)	20 (12.8%)
Pain disappeared in −2 hours	53 (30.6%)	50 (32.1%)

anti-CGRP mAbs = anti calcitonin-gene related peptide monoclonal antibodies; BTX-A = onabotulinumtoxinA; NSAIDs = non-steroidal anti-inflammatory drugs. In bold: significant variables (p < 0.05).

Post-treatment comparisons of headache-related characteristics between PHD and non-PHD showed no significant differences (Table 3). However, headache pain intensity was significantly higher on PHD compared to non-PHD in individuals who underwent BTX-A treatment. On PHD, the pain intensity was 14.5% (9/62) mild, 51.6% (32/62) moderate and 33.9% (21/62) severe. By contrast, on non-PHD, 39.4% (122/310) were mild, 35.2% (109/310) moderate and 25.5% (79/310) severe (p = 0.013). No significant statistical differences were observed in pre- and post-treatment comparisons between groups stratified by migraine diagnosis, treatment type, aura or contraceptive use.

Table 3.

Perimenstrual and non-perimenstrual headache days comparison of clinical characteristics after three months of preventive treatment with anti-CGRP mAbs or BTX-A.

Characteristics	Perimenstrual headache days after treatment (days = 223)	Non-perimenstrual headache days after treatment (days = 1095)	p-value	Adjustedp-value
Intensity			0.723	>0.999
Mild	86 (38.6%)	453 (41.4%)
Moderate	87 (39.0%)	412 (37.6%)
Severe	50 (22.4%)	230 (21.0%)
Start time			0.984	>0.999
At wake-up	37 (39.8%)	189 (39.9%)
Midnight	11 (11.8%)	59 (12.4%)
During the day	45 (48.4%)	226 (47.7%)
Symptoms
Aura	39 (18.0%)	191 (18.3%)	>0.999	>0.999
Nausea and/or vomiting	47 (21.7%)	276 (26.4%)	0.171	0.399
Light sensitivity	152 (70.0%)	688 (65.8%)	0.237	0.474
Noise sensitivity	143 (65.9%)	656 (62.7%)	0.396	0.693
Dizziness	54 (24.9%)	313 (29.9%)	0.140	0.392
Medication
Triptans	93 (41.7%)	394 (36.0%)	0.110	0.385
NSAIDs	104 (46.6%)	487 (44.5%)	0.605	0.941
Simple analgesics	43 (19.3%)	149 (13.6%)	0.037	0.177
Opioids	3 (1.3%)	2 (0.2%)	0.037	0.177
Combined medication	3 (1.3%)	16 (1.5%)	>0.999	>0.999
Effectivity of acute medication			0.825	>0.999
Same pain	21 (13.5%)	96 (13.2%)
Less pain but not disappeared	65 (41.7%)	331 (45.6%)
Pain disappeared in +2 hours	20 (12.8%)	85 (11.7%)
Pain disappeared in −2 hours	50 (32.1%)	214 (29.5%)

anti-CGRP mAbs = anti calcitonin-gene related peptide monoclonal antibodies; BTX-A = onabotulinumtoxinA; NSAIDs = non-steroidal anti-inflammatory drugs. In bold: significant variables (p < 0.05).

Headache risk during the menstrual cycle and contraceptive use

Trends in headache occurrence throughout the menstrual cycle were studied before and after treatment (Figure 1). Although the overall MHD and MMD was significantly decreased post-treatment, reducing PHD and PMD proved challenging. To investigate further, headache risk probabilities (Figure 1(a)) were calculated for four-day windows within the menstrual cycle, identifying statistically significant higher risks during specific periods: from day −14 to −11 corresponding to ovulation (OR = 1.356, 95% CI = 1.124–1.639, p = 0.002); from day −2 to +2 corresponding to the perimenstrual window (OR = 1.637, 95% CI = 1.356–1.984, p < 0.001); from day +3 to +6 corresponding to menstruation (OR = 1.557, 95% CI = 1.290–1.884, p < 0.001); and from day +7 to +10 corresponding to post-menstruation (OR = 1.520, 95% CI = 1.256–1.844, p < 0.001). When inspecting migraine risk probabilities (Figure 1(b); see also supplemental material, Figure S4), we found the highest risk during the perimenstrual window. Given that, windows from −14 until −3 had lower odds than the reference group (window “−2 to +2”) (OR = 0.717, 95% CI = 0.534–0.960, p = 0.026; OR = 0.458, 95% CI = 0.332–0.626, p < 0.001; OR = 0.585, 95% CI = 0.432–0.790, p = 0.001). The window “+3 to +6”, including one day of the perimenstrual window, showed similar odds to the reference (OR = 1.074, 95% CI = 0.812–1.422, p = 0.617), differences were not significant. The windows from +7 until +14 also shows lower OR than the reference (OR = 0.702, 95% CI = 0.522–0.941, p = 0.018; OR = 0.683, 95% CI = 0.507–0.919, p = 0.012).

Figure 1.

Percentage of females with headache and migraine each day on a menstrual cycle. The menstrual cycle is centered around the perimenstrual window, which spans from day −2 to day +3 and is marked by dashed lines. (a) The yellow line represents the percentage of females experiencing a headache per day at baseline, whereas the blue line shows the percentage after treatment. (b) The yellow line represents the percentage of females experiencing a migraine per day at baseline, whereas the blue line shows the percentage after treatment. In both (a) and (b), the perimenstrual window is associated with a higher likelihood of headache and migraine occurrence.

Furthermore, the risk of headache for the “−14 to −11”, “−2 to +2”, and “+3 to +6” windows was higher in individuals taking contraceptives, whereas the risk during “+7 to +10” was higher in those not using contraceptives (Figure 2). Besides, a trend of higher probability of migraine per day was also observed from females using contraceptives, 36.0% (29.0–46.0%) compared to 30.0% (18.0–46.0%) at baseline, but, again, these differences were not statistically significant (OR = 1.072, 95% CI = 0.970–1.186, p = 0.173).

Figure 2.

Predicted risk of headache per 4-day window with and without contraceptive use. Females using contraceptives (n = 25) are represented in blue; females not using contraceptives (n = 64) are shown in green. The black dashed vertical lines represent the start and end of the perimenstrual window, spanning from day −2 until day +3. Each dot represents the median risk of headache, whereas the vertical colored (blue or green) line includes the first and third quantiles. False discovery rate adjusted p-values for statistically significant differences in the predicted risk of headache, among patients with and without contraceptives, are shown in black at the top. False discovery rate adjusted p-values for statistically significant risk of headache, per combination of group (contraceptive use or no contraceptive use) and window, are shown in respective colors, blue or green. A higher predicted risk of headache per day was observed from “−14 to −11”, “−2 to +2” and “+3 to +6” windows in individuals taking contraceptives.

To further determine whether there were statistically significant differences in headache probability based on contraceptives use, we divided individuals into: 64 females not using and 25 females using contraceptives. We created separate plots to visually inspect the data (see supplemental material, Figure S5), revealing a trend toward a higher probability of headache per day in the menstrual cycle for females using contraceptives, 61.0% (44.0–68.0%) compared to 50.0% (36.0–70.0%) at baseline, although this difference was not statistically significant (OR = 1.049, 95% CI = 0.941–1.169, p = 0.389).

We conducted two additional analyses: one focusing on the period prior to the perimenstrual window, from day −14 to −3, and the other on the period after perimenstrual window, from day +4 to +14. After fitting the best distribution for the GLMM, we found no statistical differences between females using and not using contraceptives (OR = 1.057, 95% CI = 0.938–1.191, p = 0.362) and (OR = 1.017, 95% CI = 0.886–1.167, p = 0.811), respectively. Similarly, when we studied the difference in probability of migraine before or after the perimenstrual window among females taking and not taking contraceptives, we found no statistical differences (OR = 1.098, 95% CI = 0.994–1.213, p = 0.065; OR = 1.063, 95% CI = 0.930–1.214, p = 0.370).

Discussion

The main results of the present study include four concepts: (i) three-month treatment with anti-CGRP mAbs and BTX-A reduces the overall headache and migraine days but appears to have limited impact on PHD and PMD; (ii) PHD intensity and nausea decrease with anti-CGRP mAbs; (iii) the perimenstrual window is associated with a higher risk of headache attack, independently of the treatment used; and (iv) females with migraine on contraceptives seem to have a higher probability of headache and migraine per day.

Our findings revealed a reduction of five headache days/month, from a median of 15 PHD at baseline to 10 at M3 (p < 0.001). However, significant reductions were only observed in non-PHD (median of 13 days reduced to 8, p < 0.01), with no significant changes in PHD. When only considering MDM, an overall reduction from a median of nine migraine days/month to five migraine days/month at M3 was observed, with a reduction of one PMD day/month (proportion difference, p < 0.001) and three non-PMD/month (proportion difference, p < 0.001).

A post-hoc analysis (22) from the STRIVE RCT demonstrated erenumab's efficacy versus placebo (PBO) in reducing MMD and AMDM in women with self-reported MM (n = 232/814; 28.5%), with similar results in those using contraceptives. However, the analysis did not differentiate between PMD and non-PMD, and the self-reported data was not cross-referenced with e-Diaries. In 2023, a post-hoc analysis (23) from a single-arm study on the efficacy of women treated with erenumab and fremanezumab in a real-world setting showed similar relative reductions in MMD between PMD and non-PMD (28.4% versus 32.1% from baseline to six-month follow-up). Furthermore, a post-hoc analysis from the EVOLVE-1 and EVOLVE-2 RCT of galcanezumab versus PBO in individuals with EM (21) demonstrated that those treated with galcanezumab experienced greater reductions in PMD per cycle in five of seven explored cycles, although differences were not as pronounced as those seen when examining the total number of MHD. Galcanezumab has also been tested in Japanese individuals with EM in a secondary analysis of a phase 2 RCT (20), showing that galcanezumab was associated with a decrease in the proportion of MMD (mean of −3.6% in the 120 mg and −5.5% in the 240 mg group compared to −1.5% in the PBO group).

Although our study found a statistically significant reduction in PMD following aCGRP treatment (potentially as a result of decreased headache intensity and nausea/vomiting symptoms), no significant differences were observed in the overall reduction of PHD. This, along with the consistently higher probability of headache and migraine during the perimenstrual window regardless of treatment, suggests that CGRP may not play a dominant role in this phase. Instead, hormonal influences might be the primary factor driving headache and migraine patterns during the perimenstrual window.

Some of the differences between our study compared to previous studies may likely stem from variation in methodology, such as including self-reported data instead of using headache e-Diaries, comparing women undergoing treatment with a PBO group rather than comparing the same individuals before/after treatment, not differentiating between PHD/PMD and non-PHD/non-PMD, and excluding/including patients with CM, studies with small sample sizes or a different duration. Nevertheless, all studies suggest anti-CGRP treatment reduces overall cycle MHD, with the most significant reduction occurring outside the perimenstrual window. We expect that ongoing and upcoming RCTs evaluating anti-CGRP therapies for the prevention of MRM attacks will provide further insights into the current evidence. These include studies with fremanezumab (NCT06659120, NCT06173661), rimegepant (NCT06641466), atogepant (NCT06806293) and ubrogepant (NCT06417775).

Neither RCTs, nor observational studies have assessed the impact of BTX-A on PHD. A subgroup analysis from the PROMPT study (18) found that topiramate reduces both perimenstrual (45.9%) and non-perimenstrual headaches (46.1%); however, moderate-certainty evidence indicates tolerability issues resulting in discontinuation. No other studies have evaluated oral migraine prophylaxis.

Moreover, adverse events in individuals undergoing anti-CGRP mAbs have been reported in terms of abnormal hormone level, menstrual disorder, irregular menstruation and oligomenorrhoea, suggesting that blocking CGRP could induce changes in menstruation (25).

Regarding the clinical presentation of PHD/PMD compared to non-PHD/PMD, we did not find statistically significant differences in terms of the headache-related characteristics before the preventive treatment. However, before treatment a trend toward a presence of more intense attacks, more accompanying symptoms, increased use of acute pain medications and greater pain duration after its use, was observed in PHD compared to non-PHD. This aligns with diary-based studies suggesting that females with MRM present higher headache/migraine frequency (26), longer duration (4,5), greater severity (5,26 –28), more accompanying symptoms (4,5,7,29 –31), higher use of acute medications (26) and higher recurrence rate of attacks after treatment (27), resulting in greater burden (5,7,8). However, studies focused on the clinical differences are limited and mostly of low or very-low quality evidence (31), suggesting the need for further prospective studies to draw definite conclusions.

Besides, as mentioned before, we observed a 1.6-fold increased risk of headache attack during the perimenstrual window, consistent with previous studies showing variable risk levels but indicating up to a 2.5-fold increased risk (26,27). Interestingly, we observed that the highest probability of a headache attack occurred 48 hours after the first bleeding day. This result might partially explain the higher recurrence rates previously described after triptan intake (4,5). It could be a result of the potential ineffectiveness depending on the timing of the last triptan dose, or because headache during this period could be more hormonal-driven than CGRP-dependent (32).

Regarding hormonal contraception, we observed a higher risk of headache attacks in individuals taking contraceptives during the ovulation and perimenstrual period. By contrast, those patients not using contraceptives experienced a higher risk during the menstruation or post-menstruation periods. Moreover, a higher trend of headache and migraine attacks during the whole cycle was observed on females with contraceptive use compared with individuals not undergoing contraception, despite being not statistically significant. The difference in risk periods for individuals undergoing contraceptives may partially be explained by the interaction sex hormones and CGRP. A recent study (10) showed that during menstruation, female participants with EM had higher interictal CGRP concentrations in plasma and tear fluid, which was not observed in participants with combined oral contraceptives and during post-menopausal.

The strengths of our study include the use of validated headache e-Diaries with menstrual cycle tracking, allowing accurate identification of the PHD/PMD and non-PHD/non-PMD, and the collection of contraceptive data. However, low proportion of contraceptive users (25/89; 22.1%) and migraine with aura (24/113; 21.2%) cases may have limited statistical power. Nevertheless, these proportions likely reflect inherent disease characteristics, with contraceptive use possibly reduced among migraine sufferers because of patient preferences to minimize medication intake and perceived exacerbation of migraine symptoms with contraceptives. Another limitation of our study is the absence of sensitivity analyses for missing clinical headache data. However, as an exploratory study, it serves as a solid basis for future research. In our next study, we plan to address this limitation by conducting a prospective cohort study with systematically collected data. Importantly, the main outcome, namely whether a headache or migraine occurred, was already recorded in our current analysis. Additionally, although previous research has shown that the efficacy of anti-CGRP mAbs and BTX-A can be observed within the first three months (33 –36), supporting our evaluation at three months being reliable, a longer follow-up period might have revealed more pronounced differences. Importantly, this is the first study evaluating the effect of BTX-A on MRM.

Conclusions

A three-month treatment with anti-CGRP mAbs and BTX-A effectively reduces non-PHD and non-PMD but appears to have limited impact on PHD and PMD, with the probability of headache and migraine risk remaining higher during the perimenstrual window. Females using contraceptives appear to exhibit a higher trend of headache and migraine attacks, suggesting a different pathophysiology in MRM. RCTs are needed to evaluate the long-term effectiveness of migraine preventive treatments on MRM, as well as research focused on hormone-related migraine mechanisms aiming to improve our understanding of the impact of sex hormones in migraine.

Clinical implications

Preventive treatment with anti-CGRP mAbs and BTX-A effectively reduces non-perimenstrual headache and non-perimenstrual migraine days but appears to have limited efficacy in perimenstrual headache and migraine days.

The perimenstrual window represents the period with the highest risk of headache and migraine attacks during the menstrual cycle.

Women using contraceptive treatments seem to have an increased daily likelihood of experiencing headache and migraine attacks.

Supplemental Material

sj-docx-1-cep-10.1177_03331024251332519 - Supplemental material for Effectiveness of anti-CGRP monoclonal antibodies and onabotulinumtoxinA in menstrually-related migraine: The unmet need of perimenstrual headache days

Supplemental material, sj-docx-1-cep-10.1177_03331024251332519 for Effectiveness of anti-CGRP monoclonal antibodies and onabotulinumtoxinA in menstrually-related migraine: The unmet need of perimenstrual headache days by Rut Mas-de-les-Valls, Laura Gómez-Dabó, Edoardo Caronna, Victor J Gallardo, Alicia Alpuente, Marta Torres-Ferrus and Patricia Pozo-Rosich in Cephalalgia

Footnotes

Author contributions

RM-d-l-V, LGD and PPR made substantial contributions to conception and study design. LGD, EC, AA, MT-F and PP-R were responsible for acquisition of data. RM-d-l-V and VJG performed all the data mining. RM-d-l-V, LGD, VJG and PPR contributed to analysis and interpretation of data. RM-d-l-V and LG-D wrote first draft. EC, VJG, AA, MT-F and PP-R critically revised and approved the final version of the manuscript submitted for publication. All authors fully comply with and approve the version to be published.

Data availability

All data are available, and anonymized data will be shared upon reasonable request from any qualified investigator.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: RM-d-l-V reports no disclosures; LG-D salary has been partialy funded by Río Hortega grant Acción Estratégica en Salud 2021–2023 from Instituto de Salud Carlos III (CM24/00072); EC has received honoraria from Novartis, Chiesi, Lundbeck, MedScape, Lilly, Teva and Dr. Reddy’s; his salary has been partially funded by Río Hortega grant Acción Estratégica en Salud 2017–2020 from Instituto de Salud Carlos III (CM20/00217) and Juan Rodés fellowship, Subprograma Estatal de Incorporación de la Acción Estratégica en Salud 2023 (JR23/00065). He is a junior editor for Cephalalgia. VJG reports no disclosures. AA has received honoraria from Allergan-AbbVie, Novartis, Chiesi. MT-F has received honoraria from Allergan-AbbVie, Novartis, Chiesi and Teva. PP-R has received, in the last three years, honoraria as a consultant and speaker for: AbbVie, Dr. Reddy’s, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer, Organon and Teva. Her research group has received research grants from AbbVie, Novartis and Teva; as well as, Instituto Salud Carlos III, EraNet Neuron, European Regional Development Fund (001-P-001682) under the framework of the FEDER Operative Programme for Catalunya 2014–2020 - RIS3CAT; has received funding for clinical trials from AbbVie, Amgen, Biohaven, Eli Lilly, Novartis, Teva. She is the Honorary Secretary of the International Headache Society. She is in the editorial board of Revista de Neurologia. She is an associate editor for Cephalalgia, Headache and Neurologia. She is a member of the Clinical Trials Guidelines Committee of the International Headache Society. She has edited the Guidelines for the Diagnosis and Treatment of Headache of the Spanish Neurological Society. She is the founder of . PPR does not own stocks from any pharmaceutical company.

Ethical statement

The study was approved by the Vall d’Hebron Ethics Committee (PR(AG)53/2017). All patients gave an informed consent for the analysis of patients’ data. All patients consented to publication of anonymous individual data.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

ORCID iDs

Rut Mas-de-les-Valls

Laura Gómez-Dabó

Marta Torres-Ferrus

Edoardo Caronna

Victor J Gallardo

Alicia Alpuente

Patricia Pozo-Rosich

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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