Migraines During Pregnancy and the Risk of Maternal Stroke | Cerebrovascular Disease | JAMA Neurology | JAMA Network
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Table 1.  Maternal Demographics and Characteristics of Births Between 2007 and 2012 in California by Maternal Migraine Diagnosis During Pregnancy/Birth
Maternal Demographics and Characteristics of Births Between 2007 and 2012 in California by Maternal Migraine Diagnosis During Pregnancy/Birth
Table 2.  Adjusted Risk Ratios and Mediation Analysis for Any Migraines in Pregnancy
Adjusted Risk Ratios and Mediation Analysis for Any Migraines in Pregnancy
1.
Bushnell  CD, Jamison  M, James  AH.  Migraines during pregnancy linked to stroke and vascular diseases: US population based case-control study.   BMJ. 2009;338:b664. doi:10.1136/bmj.b664PubMedGoogle ScholarCrossref
2.
Wabnitz  A, Bushnell  C.  Migraine, cardiovascular disease, and stroke during pregnancy: systematic review of the literature.   Cephalalgia. 2015;35(2):132-139. doi:10.1177/0333102414554113PubMedGoogle ScholarCrossref
3.
Valeri  L, Vanderweele  TJ.  Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros.   Psychol Methods. 2013;18(2):137-150. doi:10.1037/a0031034PubMedGoogle ScholarCrossref
4.
Lee  MJ, Lee  C, Chung  C-S.  The migraine-stroke connection.   J Stroke. 2016;18(2):146-156. doi:10.5853/jos.2015.01683PubMedGoogle ScholarCrossref
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    Research Letter
    June 1, 2020

    Migraines During Pregnancy and the Risk of Maternal Stroke

    Author Affiliations
    • 1Department of Pediatrics, University of California, San Diego, La Jolla
    • 2Preterm Birth Initiative, University of California, San Francisco, La Jolla
    • 3Department of Neurology, University of California, San Francisco, La Jolla
    JAMA Neurol. 2020;77(9):1177-1179. doi:10.1001/jamaneurol.2020.1435

    Migraines have been associated with increased risk of maternal stroke in the perinatal period.1,2 Hypertensive disorders have been hypothesized to mediate the association; however, to our knowledge, this has not been formally quantified.2 The objective of this study was to determine the extent to which hypertensive disorders mediate the association between migraines and maternal stroke.

    Methods

    We queried a retrospective California birth cohort of 3 million singleton, live births between January 2007 to December 2012 created from linked birth certificates and hospital discharge summaries. Institutional review board approval was granted by the Committee for the Protection of Human Subjects for the State of California. Migraines were identified from International Classification of Diseases, Ninth Revision (ICD-9) codes (346) in emergency department or hospital discharge records during pregnancy or delivery. Stroke was identified from ICD-9 codes (ischemic stroke: 433, 434, 436; hemorrhagic stroke: 430, 431) and analyzed separately for occurrence during pregnancy/delivery or postpartum periods. Hypertensive disorders (including preeclampsia) were identified by ICD code 642. To estimate the association between migraine and stroke, we performed a multivariable log-linear regression, adjusting for age, body mass index (calculated as weight in kilograms divided by height in meters squared), race/ethnicity, nativity, payer source, mental illness, smoking, drug or alcohol use, and diabetes. A mediation analysis estimated the proportion of the total association of migraine with the risk of maternal stroke mediated by gestational hypertensive disorders.3 Analyses were conducted in SAS, version 9.4 (SAS Institute), and statistical significance was set at P < .05.

    Results

    There were 26 440 women with a diagnosis of migraine (914/100 000 deliveries). Strokes occurred in 843 women (29/100 000 deliveries); ischemic strokes were 58% of all stroke events. Women with migraines were more likely to be non-Hispanic white, have private insurance, have obesity, have diabetes (preexisting or gestational), have a mental health disorder, use tobacco, and use drugs or alcohol (Table 1). Women with migraines during pregnancy were more likely to have a hypertensive disorder (15.1% vs 7.0%; adjusted risk ratio [aRR], 1.6; 95% CI, 1.6-1.7), a stroke during pregnancy or delivery (0.15% vs 0.01%; aRR, 6.8; 95% CI, 4.7-9.8), or a stroke post partum (0.05% vs 0.01%; aRR, 2.1; 95% CI, 1.2-3.7) (Table 2). Although the numbers were small, the effects were twice as strong in models for ischemic stroke compared with hemorrhagic stroke (results not shown). In a mediation analysis adjusted for the same potential confounders, hypertensive disorders mediated 21% of the risk of stroke during pregnancy/delivery and 27% of the risk of postpartum stroke. In stratified analyses, preeclampsia appeared to contribute most of the excess risk associated with hypertensive disorders (results not shown).

    Discussion

    Similar to previous work both in pregnant and nonpregnant women,1,2,4 we found an elevated risk of stroke among women with migraines. Approximately one-fourth of the excess cases of maternal stroke associated with migraine were attributable to hypertensive disorders. This suggests that other pathways exist between migraine and stroke during the perinatal period, potentially through pathophysiologic changes, such as increased blood volume and cerebral circulation.2

    The limitations of this study include the uncertain temporality of migraine, hypertension, and stroke in prenatal models. As severe headache can accompany strokes or preeclampsia, migraine may be coded as a sequela of either condition, the timing of which would not be distinguishable on discharge summaries. Mediation assumes that the exposure (migraine) causes the mediator (hypertension), which in turn causes the outcome, and deviations to this temporal sequence or framework would affect findings and interpretation. Also, it is likely that only severe and active migraines are recorded in discharge summaries, which could lead to stronger risk ratios that are not generalizable to less severe migraines. Finally, we did not have any data on treatment of migraine and all models are vulnerable to unmeasured confounding.

    In conclusion, approximately 25% of the excess risk of maternal stroke associated with migraine was mediated through hypertensive disorders. Although strokes are rare events, the associated morbidity and mortality warrants focus on identifying modifiable intervention targets.

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    Article Information

    Corresponding Author: Gretchen Bandoli, PhD, Department of Pediatrics, University of California, San Diego, 9500 Gilman Dr, MC 0828, La Jolla, CA 92093 (gbandoli@ucsd.edu).

    Published Online: June 1, 2020. doi:10.1001/jamaneurol.2020.1435

    Author Contributions: Dr Bandoli had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Concept and design: Baer, Jelliffe, Chambers.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Bandoli, Jelliffe, Chambers.

    Critical revision of the manuscript for important intellectual content: Baer, Gano, Jelliffe, Chambers.

    Statistical analysis: Bandoli, Jelliffe.

    Obtained funding: Jelliffe.

    Administrative, technical, or material support: Baer, Gano, Jelliffe, Chambers.

    Supervision: Jelliffe.

    Conflict of Interest Disclosures: Dr Bandoli reported grants from the Benioff Preterm Birth Initiative at University of California, San Francisco during the conduct of the study and from National Institutes of Health outside the submitted work. No other disclosures were reported.

    Funding/Support: This work was funded as part of the California Preterm Birth Initiative at the University of California San Francisco. Dr Bandoli is funded by the National Institutes on Alcohol Abuse and Alcoholism (grant 1 K01 AA027811-01).

    Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    References
    1.
    Bushnell  CD, Jamison  M, James  AH.  Migraines during pregnancy linked to stroke and vascular diseases: US population based case-control study.   BMJ. 2009;338:b664. doi:10.1136/bmj.b664PubMedGoogle ScholarCrossref
    2.
    Wabnitz  A, Bushnell  C.  Migraine, cardiovascular disease, and stroke during pregnancy: systematic review of the literature.   Cephalalgia. 2015;35(2):132-139. doi:10.1177/0333102414554113PubMedGoogle ScholarCrossref
    3.
    Valeri  L, Vanderweele  TJ.  Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros.   Psychol Methods. 2013;18(2):137-150. doi:10.1037/a0031034PubMedGoogle ScholarCrossref
    4.
    Lee  MJ, Lee  C, Chung  C-S.  The migraine-stroke connection.   J Stroke. 2016;18(2):146-156. doi:10.5853/jos.2015.01683PubMedGoogle ScholarCrossref
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