Endometriosis, Raynaud's Syndrome, and Migraine: A Retrospective Study of 12 Million Women

We performed a cross-sectional study using the Healthcare Cost and Utilization Project (HCUP) databases between the years 2007 and 2014. The study population comprised adult women who attended one of the hospitals participating in the HCUP during the study period. The HCUP database is a comprehensive source of inpatient care data, consisting of surgery and emergency department visits. Each year, information from over one thousand hospitals located in USA is collected. Also, patients are followed only in one hospital to prevent duplication of data. We used the International Classification of Disease, ninth revision (ICD-9), for collecting data of endometriosis, Raynaud’s syndrome, migraine, and other variables used in our study. We applied (617X) for endometriosis, (346X) for migraine, (4430) for Raynaud’s syndrome, (338.2, 338.4, 338.29) for chronic pain, (305.1) for smoking, (642.0–642.4, 642.10–642.14, 642.20–642.24, 401.0, 401.1, 201.9) for chronic hypertension, (278.00, 278.01, 278.02, 278.03, 278, 278.0) for obesity, (710X) for autoimmune connective tissue disorders, (296.2x, 296.3x, 300.4x, 311x) for depression, and (300.0x, 300.2x, 300.3x, 309.8x) for anxiety disorders. Since Raynaud’s syndrome and migraine might share a similar vascular phenomenon, we created an aggregate group by combining the two conditions. We used SPSS version 26.0 in Windows 11 and evaluated the prevalence of endometriosis, migraine, and Raynaud’s syndrome. Chi-square test was used for comparing the percentages of patients’ characteristics. We analyzed the association between endometriosis and aggregate group of migraine and Raynaud’s syndrome, and adjusted for potential confounders, including age, race, income, type of medical insurance, smoking, obesity, hypertension, anxiety, and depression. In addition, we applied logistic regression to calculate the odds ratios (OR) and the 95% confidence intervals (CIs). p value <0.05 was considered significant.

Of a total 12,468,167 hospitalized women included in our study, 91,219 had endometriosis, 14,714 presented with Raynaud’s syndrome, 328,022 had migraine, and 1,385 had a composite of Raynaud’s syndrome and migraine (online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000545204 ). Raynaud’s syndrome and migraine had an upward trend in their prevalence during the study period. The prevalence of Raynaud’s syndrome increased from 9 in 2007 to 13 in 2014 per 10,000 women (0.09 to 0.13%, respectively) ( Fig. 1a). Similarly, the prevalence of migraine in 2007 was 2.1% and in 2014 was 2.9% among hospitalized women ( Fig. 1 b). On the other hand, the prevalence of endometriosis declined from 86 in 2007 to 54 in 2014 per 10,000 hospitalized women (0.86 to 0.54%, respectively) ( Fig. 1 c). a Prevalence of hospitalized patients with Raynaud’s syndrome in the USA, 2007–2014. X: years, Y: prevalence of Raynaud’s syndrome. b Prevalence of hospitalized patients with migraine in the USA, 2007–2014. X: years, Y: prevalence of migraine. c Prevalence of hospitalized patients with endometriosis in the USA, 2007–2014. X: years, Y: prevalence of endometriosis. Orange line indicates chart area. The demography and characteristics of women with Raynaud’s syndrome, migraine, and combined Raynaud’s syndrome and migraine are shown in Tables 1 – 3 ; white race, 3rd and 4th quartiles of income, Medicare or private insurance type, and comorbidities including smoking, hypertension, anxiety, and depression were predominant. The prevalence of endometriosis was increased in patients with Raynaud’s syndrome, migraine, or both. Migraine showed a strong relationship with Raynaud’s syndrome ( Tables 1 – 3 ). The group positive for endometriosis, Raynaud’s syndrome, and migraine had a similar trend. Hospitalized women (age 18–55 years) with and without Raynaud’s syndrome a Medicare is US federal health insurance for people 65+ and some with disabilities. Medicaid is a federal-state program for low-income individuals. Distributions of hospitalized women (age 18–55 years) with and without migraine a Medicare is US federal health insurance for people 65+ and some with disabilities. Medicaid is a federal-state program for low-income individuals. Distributions of hospitalized women (age 18–55 years) by composite Raynaud’s syndrome and migraine a Medicare is US federal health insurance for people 65+ and some with disabilities. Medicaid is a federal-state program for low-income individuals. Unadjusted logistic regression analysis revealed a strong association between endometriosis, anxiety, depression, and combined Raynaud’s syndrome and migraine. This association was stronger in patients with anxiety (OR = 4.084, 95% CI: 3.591–4.646). Adjusted analysis for age, race, income, type of insurance, and hypertension showed a similar pattern; anxiety still had the most significant association (OR = 2.709, 95% CI: 2.344–3.130). Endometriosis had an OR of 2.491 (CI: 1.677–3.699) for unadjusted analysis and OR of 1.779 (CI: 1.166–2.716) for adjusted analysis ( Table 4 ). Unadjusted and adjusted associations between the composite of Raynaud’s syndrome and migraine with endometriosis and psychiatric comorbidities a Adjusted for age, race, insurance, smoking, obesity, chronic hypertension, anxiety, and depression. Online supplementary Table 1 outlines the unadjusted and adjusted analyses of associations between endometriosis, Raynaud’s syndrome, and migraine across two age groups: 18–35 and 18–49 years. Among younger patients (18–35 years) with endometriosis, stronger associations were observed with Raynaud’s syndrome (unadjusted OR = 2.26, 95% CI = 1.73–2.95; adjusted OR = 1.61, 95% CI = 1.20–2.16) and migraine (unadjusted OR = 3.62, 95% CI = 3.47–3.78; adjusted OR = 2.59, 95% CI = 2.47–2.72). For patients aged 18–49, the associations were weaker but remained significant for Raynaud’s syndrome (adjusted OR = 1.19, 95% CI = 1.02–1.40) and migraine (adjusted OR = 1.64, 95% CI = 1.58–1.69).

Our study suggests an association between endometriosis, Raynaud’s syndrome, and migraine. It is possible that those conditions share a similar mechanism, possibly vascular reaction and endothelial dysfunction related to chronic inflammation. Physicians should be encouraged to assess comorbidities in patients presenting with these conditions and consider screening for anxiety disorders to provide comprehensive patient care.

We found an increasing prevalence of migraine and Raynaud’s syndrome and a decreasing prevalence of inpatient endometriosis among patients registered in the HCUP database between 2007 and 2014. There was an association between endometriosis, anxiety and depression, and migraine and Raynaud’s syndrome. Finally, migraine had a higher fraction in patients with Raynaud’s syndrome. Those two conditions are often found together, might reflect similar vascular reaction, and could be associated with vascular endothelial cell dysfunction [ 13 , 14 ]. The prevalence of migraine in 2007 in our dataset for hospitalized women was 2.2%. A mail survey published in 2007 showed that 17.1% of female participants suffered from migraine [ 15 ]. It is possible that the severity of migraine among hospitalized patients is more than in those in the general population. Similarly, the prevalence of endometriosis and Raynaud’s syndrome was reported to be five [ 16 ] and ten [ 17 ] percent, compared to 0.9% and 0.1% in our study, respectively. The apparent declining prevalence of endometriosis in our study might be due to the increasing number of patients treated in the nonhospital setting. Previous studies have shown that migraine tends to occur among people aged 18 to 40 years [ 18 ]. This is in agreement with our findings (mean age: 36.4 ± 8.3 years). White ethnicity was the predominant race in our study, in contrast to native Americans (Alaskan native or American Indians) in Burch et al. [ 19 ] study. The lower prevalence in the low-income families in this study, however, is in agreement with a previous report [ 19 ]. Depression and anxiety were the two most frequent comorbidities associated with migraine. In agreement with our findings, in a meta-analysis of 139 studies involving 4.19 million patients, the most common coexisting conditions were depression, hypertension, and anxiety disorders [ 20 ]. The average age of patients with Raynaud’s syndrome in study was 38 ± 8.3 years. Previous studies suggest that primary Raynaud’s syndrome tends to occur in patients younger than 30, and secondary Raynaud’s syndrome usually appears after the age of 40 [ 16 , 21 ]. The database in our study does not distinguish between primary and secondary Raynaud’s syndrome. As previously shown [ 22 ], we also found that patients with low BMI had a higher percentage of Raynaud’s syndrome. Smoking is associated with the occurrence of Raynaud’s syndrome [ 22 ]. In our study, black race had a lower prevalence of Raynaud’s syndrome. It is possible that this condition was often not reported. Shigesi et al. [ 23 ] in a systemic review and meta-analysis studied 26 population-based articles and investigated the association between endometriosis and autoimmune disease. They found that endometriosis had a correlation with a wide variety of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroid disease, chronic liver disease, multiple sclerosis, inflammatory bowel disease, and Addison’s disease. However, the quality of most studies included was low or very low. To the best of our knowledge, there has been no comprehensive study evaluating the association between endometriosis and Raynaud’s syndrome. Although we found the association between the two conditions, we cannot determine whether it is a direct association or related to comorbidities associated with both endometriosis and Raynaud’s syndrome. Yet, it is known that endometriosis is a chronic inflammatory condition and has been associated with cardiovascular diseases and preeclampsia [ 5 , 6 ]. One of the manifestations of those conditions is endothelial dysfunction [ 24 ]. It appears that prevalence of migraine among patients with endometriosis is more than in the general population. In a meta-analysis, Jenabi and Khazaei [ 25 ] evaluated 802 articles involving 287,174 participants and concluded that there was a significant correlation between endometriosis and migraine. Adewuyi et al. [ 26 ] employed genome-wide association study (GWAS) data that confirmed a noncausal relationship between the two illnesses. In our study, unadjusted analysis revealed that endometriosis was associated with migraine. This association became stronger when migraine and Raynaud’s syndrome coexisted. Adjusting the analysis for age, race, income, type of medical insurance, smoking, and hypertension revealed a similar result. Our finding reiterates the association between endometriosis and migraine. It also suggests a possible relationship between endometriosis and Raynaud’s syndrome. Given these associations, it is important to increase awareness among healthcare providers about the potential co-occurrence of endometriosis, Raynaud’s syndrome, and migraine. Physicians should consider evaluating patients with migraine and Raynaud’s syndrome for endometriosis. Furthermore, given the high OR observed with anxiety, it may be beneficial to administer the Generalized Anxiety Disorder 7-item (GAD-7) scale to patients with endometriosis, migraine, or Raynaud’s syndrome to facilitate early identification and management of anxiety. Developing comprehensive guidelines covering these coexisting conditions could further improve patient outcomes. The HCUP database is cross-sectional in nature, and hence, we could not establish the temporal relationship between endometriosis, Raynaud’s syndrome, and migraine. Moreover, data on the severity of endometriosis and the treatment received by the patients were not available in the HCUP database, and it prevented us from investigating the role of potential confounding factors. Yet, examining a large population with multiple million patients and independent entry of patients’ data reduces selection bias. Also, even though we adjusted our analysis for important variables that could influence the results, there might still be some confounding effects that we could not completely eliminate.

Endometriosis is one of the most common conditions among reproductive-age women. It is estimated about one in ten women in these age groups suffers from it. Endometriosis is defined as the presence of endometrial-like tissue outside the uterus that causes a chronic inflammatory reaction. Endometriosis might reduce the quality of life of the patients and could have a negative impact on the economy [ 1 ]. In addition to physical symptoms, endometriosis can cause mental disorders including depression and anxiety [ 2 , 3 ]. Moreover, it has been shown to have a negative effect on social and sexual performance of patients [ 2 ]. Hormonal, neurological, and immunological factors have been implicated in the symptom-developing process [ 4 ]. Endometriosis has been associated with cardiovascular diseases and infertility [ 5 , 6 ]. Raynaud’s syndrome, also known as Raynaud’s phenomenon, is a condition caused by the spasm of small arteries and, consequently, decrease in blood flow to end arteries. Fingers are commonly involved, although toes, nose, ears, and lips can also be affected [ 7 ]. A wide variety of diseases including connective tissue disorders, obstructive disorder, eating disorders have been associated with Raynaud’s syndrome [ 7 ]. Neurogenic, inflammatory, and immune responses were postulated to be the main changes in Raynaud’s syndrome mechanism. Migraine is a common form of headache that typically affects one side of the head. It is usually pulsatile and could last a few hours to a few days. It is estimated that migraine affects about one billion individuals, mostly young adults and females, annually [ 8 ]. Although the pathophysiology of migraine is still unclear, many believe that it is related to neurovascular disorder [ 9 ]. It appears that migraine is commonly reported among women with endometriosis [ 10 , 11 ]. A few studies have suggested an association between migraine and Raynaud’s syndrome [ 12 , 13 ]. However, to date, there is a paucity of information on any possible association between endometriosis, Raynaud’s syndrome, and migraine. The purpose of our study was to evaluate a possible relationship between endometriosis, Raynaud’s syndrome, and migraine.

The authors report no conflict of interest.

Access to HCUP dataset and E.S. were supported by the Academic Enrichment Fund of the Department of Obstetrics and Gynecology of the McGill University Health Centre.

In accordance with the Tri-Council Policy statement (2014), our study was exempt from Institutional Review Board approval as it was based solely on anonymous publicly available data.

E.S., T.T., and H.N.K. designed the study. H.N.K. extracted and managed data from the HCUP dataset, performed statistical analysis under the supervision of E.S., and drafted the manuscript. T.C.M., E.S., T.T., and M.J. provided input for the study design and analysis, and critically reviewed the manuscript and analysis.