Abstract
This cohort study examines the extent to which hypertensive disorders mediate the association between migraines and maternal stroke.
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).
Table 1. Maternal Demographics and Characteristics of Births Between 2007 and 2012 in California by Maternal Migraine Diagnosis During Pregnancy/Birth.
| Characteristic | Frequency (%) | |
|---|---|---|
| No migraines (n = 2 866 316) | One + migraine code (n = 26 440) | |
| Race/ethnicity | ||
| Non-Hispanic white | 742 853 (25.9) | 10 846 (41.0) |
| Hispanic | 1 402 210 (48.9) | 9161 (34.7) |
| Black | 152 619 (5.3) | 2331 (8.8) |
| Asian | 357 582 (12.5) | 1431 (5.4) |
| Other | 211 052 (7.4) | 2671 (10.1) |
| Born outside the US | 1 246 786 (43.5) | 5205 (19.7) |
| Age, y | ||
| <18 | 83 288 (2.9) | 309 (1.2) |
| 18-34 | 2 276 520 (79.4) | 21 366 (80.8) |
| >34 | 506 400 (17.7) | 4764 (18.0) |
| Payer source | ||
| Private | 1 324 763 (46.2) | 16 171 (61.2) |
| Public | 1 429 352 (49.9) | 9647 (36.5) |
| Other | 112 201 (3.9) | 622 (2.4) |
| Body mass index categorya | ||
| <25 | 1 450 888 (50.6) | 11 201 (48.6) |
| 25-29.9 | 680 512 (23.7) | 6684 (29.0) |
| ≥30.0 | 541 670 (18.9) | 7034 (30.5) |
| Unknown | 193 246 (6.7) | 1521 (6.6) |
| Diabetes | 262 398 (9.2) | 3150 (11.9) |
| Anxiety disorder | 36 226 (1.3) | 2508 (9.5) |
| Depression | 35 625 (1.2) | 2426 (9.2) |
| Bipolar disorder | 16 495 (0.6) | 1268 (4.8) |
| Smoking | 128 511 (4.5) | 2354 (8.9) |
| Drug use | 46 453 (1.6) | 1742 (6.6) |
| Alcohol use | 12 390 (0.4) | 406 (1.5) |
| Hypertensive disorders | 201 299 (7.0) | 3995 (15.1) |
| Hypertension without preeclampsia | 104 648 (3.6) | 2114 (8.0) |
| Preeclampsia | 96 651 (3.4) | 1881 (7.1) |
Calculated as weight in kilograms divided by height in meters squared.
Table 2. Adjusted Risk Ratios and Mediation Analysis for Any Migraines in Pregnancy.
| Diagnosis | No. (%) | aRR, (95% CI)a | Proportion mediated by hypertensive disorders, % | |
|---|---|---|---|---|
| No migraine codes (n = 2 866 316) | One + migraine codes (n = 26 440) | |||
| Gestational hypertensive disorders | 201 299 (7.0) | 3995 (15.1) | 1.6 (1.6-1.7) | NA |
| Maternal stroke (pregnancy or delivery)b | 362 (0.0) | 39 (0.2) | 6.8 (4.7-9.8) | 21 |
| Maternal stroke (post partum)b | 418 (0.0) | 13 (0.1) | 2.1 (1.2-3.7) | 27 |
Abbreviations: aRR, adjusted risk ratio; NA, not applicable.
Risk ratios adjusted for maternal age, body mass index (calculated as weight in kilograms divided by height in meters squared), race/ethnicity, payer source, anxiety, depression, bipolar disorder, smoking, drug use, alcohol use, maternal nativity, and diabetes.
A total of 843 stroke events: 11 women had strokes during pregnancy and at delivery and 29 women had strokes during pregnancy/delivery and the postpartum period.
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.
References
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