Pregnancy-related stroke is a rare, but potentially devastating event. Not only do an estimated 8% to 15% of pregnancy-related stroke victims die1,2 but also survivors may suffer profound, permanent disability.3,4 Because stroke is rare in this population, the ability to estimate incidence, identify risk factors, or report meaningful outcomes, such as mortality or disability, requires large, population-based studies. In the United States, 3 population-based studies of stroke have been published, but there are limitations to each of these analyses. One used data abstracted from medical records of young patients with strokes in the Baltimore-Washington area, but was limited by small numbers.5 One used data from the National Hospital Discharge Survey from 1979–1991,6 and the other used data from the Nationwide Inpatient Sample from 1993–1994.2 Although these analyses included very large numbers of pregnancy discharges, only the code for pregnancy-related cerebrovascular events, 674.0, was used, and other non–pregnancy-related stroke codes were not considered.
Only the analysis from the 1993–1994 Nationwide Inpatient Sample provided an estimate of mortality and disability. Approximately 15% of women with pregnancy-related stroke died and 10% of survivors were discharged to a facility other than home.2 The most recent update from the Pregnancy Mortality Surveillance System for 1999 estimated that pregnancy-related stroke accounted for 5.0% of all maternal mortalities, or 0.66 per 100,000 live births.7
Previously recognized risk factors for pregnancy-related stroke include hypertension, preeclampsia, infection, delivery, the puerperium, nonwhite race and age older than 35.2 Because the majority of medical conditions and complications of pregnancy and delivery are coded in the hospital discharge data captured by the Nationwide Inpatient Sample, it allows for the investigation of risk factors for pregnancy-related stroke. The objective of this study was to estimate, with as complete an ascertainment as possible, the incidence, risk factors, disability and mortality from pregnancy-related stroke in the United States.
MATERIALS AND METHODS
The Nationwide Inpatient Sample, from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality contains data from 5 to 8 million hospital stays from approximately 1,000 hospitals and is the largest all-payer inpatient care database in the United States.8,9 The Nationwide Inpatient Sample is a 20% stratified sample of all discharges and allows for national estimates.8,9 Included in the sample are general hospitals and academic medical centers.8,9 Rehabilitation hospitals, long-term hospitals, psychiatric hospitals, and alcoholism or chemical dependency treatment facilities are excluded.8,9 The hospitals are divided into strata based on ownership, bed size, teaching status, urban compared with rural location, and region. Sampling probabilities are proportional to the number of hospitals in each stratum. The sampling frame comprises 90% of all U.S. hospital discharges.8,9 Information included in the Nationwide Inpatient Sample is similar to that in a typical discharge abstract, with safeguards to protect the privacy of individual patients, physicians, and hospitals.8,9 Data are available for the purposes of aggregate statistical reporting, analysis, and research. Although the nature of the data is limited to discharge diagnoses and demographic information, the Nationwide Inpatient Sample allows for the study of relatively rare conditions such as pregnancy-related stroke.8,9
Records were identified in the Nationwide Inpatient Sample using International Classification of Diseases, Ninth Revision (ICD-9) for all pregnancy-related discharge codes for the years 2000 to 2001 (the latest data available at the inception of the study). The pregnancy-related discharge records included in the sample from that period were classified as to whether they were an antepartum admission, an admission at the time of delivery, or a postpartum admission. An antepartum admission was defined as any discharge record with a pregnancy-related code (ICD-9 codes 630–648) that did not also include a delivery code. An admission for delivery was defined as any discharge record that included a delivery code (ICD-9 codes 74 for cesarean delivery and 72, 73, 75, v27, or 650–659 for vaginal delivery). A postpartum admission was defined as any discharge record that included a postpartum diagnosis (ICD-9 codes 660–677) and did not also include a delivery code.
Strokes were classified as hemorrhagic (ICD-9 code 431), ischemic (ICD-9 codes 434 and 436), cerebral vein thrombosis (ICD-9 code 325) or pregnancy-related cerebrovascular event (ICD-9 code 674). The pregnancy-related code for “thrombosis not otherwise specified” (ICD-9 code 671.5), which includes not only cerebral vein thrombosis, but a number of other possibilities, was not queried due to its lack of specificity.10
For comorbidities, both the ICD-9 code for a particular condition in pregnancy and the general ICD-9 code for that condition were used. If the pregnancy-related code was not specific, it was not used.
The analysis accounted for the cluster sampling used by the Nationwide Inpatient Sample. Data were weighted by the strata’s primary sampling units (hospitals) and sampling weights based on the Nationwide Inpatient Sample sampling design. STATA 8.0 (Stata Corp LP, College Station, TX) and the SVY (survey data) commands using these weights were used for both descriptive and inferential analyses. Two-way χ2 analyses yielded cell frequencies and their confidence intervals. Rates were computed from cell frequencies by dividing sample numbers. Logistic regression modeling was used to generate relative risk estimates for age and race. The protocol was reviewed and approved by the Duke University Medical Center Institutional Review Board.
During the period from 2000 to 2001, there were 8,322,799 deliveries among 9,135,755 pregnancy-related discharges. Among the pregnancy-related discharges, 2,850 cases of stroke were identified. Of these cases, 301 (11%) were antepartum, 1,172 (41%) were at the time of delivery, and 1,377 (48%) were postpartum. As summarized in Table 1, among the cases of stroke, 766 (27%) were ischemic, 707 (25%) were hemorrhagic, 50 (2%) were due to cerebral venous thrombosis, and 1,325 (46%) were pregnancy-related cerebrovascular events. The overall risk of pregnancy-related stroke was 34.2 (95% confidence interval [CI] 33.3–35.1) per 100,000 deliveries. There were 117 stroke-related deaths, for a case fatality rate of 4.1% and a mortality rate of 1.4 (95% CI 1.1–1.7) per 100,000 deliveries. Compared with only 3% of all pregnancy-related discharges, 22% of stroke survivors were discharged to another facility rather than home (P < .01).
The risk of stroke generally increased with age (Table 2), but the risk of stroke was higher among women aged younger than 20 years (30.3 per 100,000 deliveries) than it was among women aged 20 to 34 years (26.3 per 100,000 deliveries). The risk increased dramatically among women aged 35 to 39 years (58.1 per 100,000 deliveries) and was highest among women aged 40 years and older (90.5 per 100,000 deliveries).
The risk of stroke also differed by race or ethnicity (Table 2). African-American women had the highest risk of stroke (52.5 per 100,000 deliveries) compared with Hispanic women (26.1 per 100,000 deliveries) or white women (31.7 per 100,000 deliveries, P < .01). Within all 3 racial or ethnic groups, women aged 35 years and older had a higher risk of stroke (59.9, 63.2, and 41.8 per 100,000 deliveries for white, African-American, and Hispanic women, respectively). When controlled for age and race, white women aged 35 and older were twice as likely (odds ratio [OR] 2.2) to have a stroke than their younger counterparts, but the highest risk of stroke was among African-American women aged 35 years and older (OR 4.5, Table 2).
Table 3 presents the odds ratios for the univariate analysis of various medical conditions associated with risk for pregnancy-related stroke. With the exception of obesity, all of the medical conditions queried were significantly associated with pregnancy-related stroke. The strongest associations for stroke were migraine headaches (OR 16.9), thrombophilia (OR 16.0), lupus (OR 15.2), heart disease (OR 13.2), sickle cell disease (OR 9.1), hypertension (OR 6.1), and thrombocytopenia (OR 6.0). Other significant risk factors were diabetes (OR 2.5), substance abuse (OR 2.3), smoking (OR 1.9), and anemia (OR 1.9).
Table 4 presents the odds ratios for the univariate analysis of various complications of pregnancy and delivery. Complications significantly associated with pregnancy-related stroke were postpartum hemorrhage (OR 1.8), preeclampsia and gestational hypertension (OR 4.4), fluid and electrolyte imbalance (OR 7.2), transfusion (OR 10.3), and the highest, pregnancy-related infection (OR 25.0).
We found a higher incidence of pregnancy-related stroke (34.2 compared with 24.7 per 100,000 deliveries), a higher proportion of women discharged to other facilities (22 compared with 15%) and a lower case fatality rate (4.1 compared with 14.7%) compared with a previous analysis using data from the Nationwide Inpatient Sample.2 Our estimate of incidence is likely higher than the previous analysis because, in addition to the pregnancy-related stroke code (674), we included specific stroke codes (430,431,434,436). Although it is higher than the previous Nationwide Inpatient Sample estimate, our estimate is in the broad range of those previously reported (4.3 to 210 strokes per 100,000 deliveries).2,5,11–13
There are several limitations to our analysis. As is also true of previous analyses of large public databases,2,6 our data are limited to information derived from discharge record abstractions. Consequently, detailed and precise information on diagnosis and treatment are not available to validate stroke and the other comorbidities. For instance, reversible syndromes associated with preeclampsia such as reversible posterior leukoencephalopathy syndrome,14,15 may have been coded as stroke. For that reason, our reported incidence of pregnancy-related stroke may be an overestimate. Nonetheless, although hospital discharge diagnoses may contain errors due to mistakes in abstraction or coding, the broad category of stroke is considered reliable.16 In addition, we excluded ICD-9 code 433, which also includes the diagnoses of carotid, vertebral, and basilar artery stenosis with or without infarction, and used codes 434 and 436, which are more sensitive and specific for ischemic stroke.16 Another limitation is that discharge abstracts do not allow for attribution of the timing of different diagnoses. It is possible that some of the conditions associated with pregnancy-related stroke occurred after the stroke and not before.
The mortality from pregnancy-related stroke, 1.4 per 100,000 deliveries, is more than twice the ratio estimate of 0.66 per 100,000 live births from the Center for Disease Control and Prevention’s Pregnancy Mortality Surveillance System. The Pregnancy Mortality Surveillance System is limited to data received from individual state health departments, maternal mortality review committees, the media, and individual providers,7 and it is recognized that pregnancy-related deaths are underreported.17–19 Although the Pregnancy Mortality Surveillance System used the most thorough reporting possible,7 by using hospital discharge data, our ascertainment may have been more complete. Another possibility that would account for the lower ratio reported by the Pregnancy Mortality Surveillance System is that stroke deaths were ascribed to another cause, particularly preeclampsia or eclampsia. Among 790 deaths from complications of preeclampsia or eclampsia reported to the Pregnancy Mortality Surveillance System, the actual cause of death in 38.7% was a cerebrovascular event.20
The case fatality rate for pregnancy-related stroke was estimated to be 4.1%. This figure is not only lower than the average case-fatality rate for stroke of 24%,21 but is at the low end of the 4.5 to 24% range published for young adults.3,22–30 Therefore, the low case-fatality rate in the current analysis is not completely explained by the fact that pregnant women are generally young and healthy. A possible explanation is that the case-fatality rate in other studies, typically calculated a month or even a year after stroke, captured deaths after hospital discharge whereas ours did not. Our rate, however, is also lower than the previous Nationwide Inpatient Sample analysis.2 This may reflect our inclusion of different diagnostic codes, but may also reflect, as has been observed,31 a declining case-fatality rate over time. Because access to care may influence outcome of stroke,32 another possibility is that a higher proportion of pregnancy-related strokes occur in the hospital setting where care is more readily available.
Other studies have reported an increased risk of stroke among women who are pregnant compared with nonpregnant women. Wiebers et al33 found a 13-fold increase. Kittner et al5 examined cerebral infarction and cerebral hemorrhage separately and found no increased risk of ischemic stroke during pregnancy, but an 8.7-fold increased risk postpartum. They found a 2.5-fold increased risk of intracerebral hemorrhage during pregnancy and a 23.8-fold increased risk postpartum. We did not compute the incidence of stroke for women who were not pregnant, but Kittner’s cohort was the same age and racial composition as the pregnant women in this study. Petitti et al,34 however, reported an incidence of stroke of 10.7 per 100,000 women-years among women aged 15 to 44 years in a large health maintenance organization. Using these data for comparison, the incidence of stroke in our cohort is increased approximately 3-fold in pregnancy. This is not surprising, since estrogen (in the form of oral contraceptives) increases the risk of stroke 2-fold,35 and pregnancy is associated, not only with elevated levels of estrogen, but with increased blood volume and altered hemodynamics.36
Hypertension,2 heart disease,2 and smoking37 have previously been reported in population surveys as significant risk factors for pregnancy-related stroke. Other medical conditions that have been reported in case series or case reports include sickle cell disease,38 thrombophilia,11,39–45 and substance abuse, particularly cocaine.4,6,12,46,47 A Swedish population-based cohort study found the relative risk of pregnancy-related stroke to be 1.7 for diabetes,37 but this was not statistically significant (CI 0.7–3.7). We found a significant 2.5-fold increased risk among women with diabetes. Obesity, identified as a risk factor for stroke among nonpregnant women of reproductive age,34 was not a significant risk factor for stroke in this study. Obesity, however, was based on a diagnostic code rather than a calculated body mass index and was likely underreported. Although the presence of the lupus anticoagulant is a well-recognized risk factor for thromboembolic events in pregnancy,48 lupus per se has not previously been reported to be a significant risk factor for pregnancy-related stroke. However, we found a 15.2-fold increased risk among women with lupus. The highest odds ratio for a medical condition was for migraine headaches (OR 16.9). Although migraine headaches have been reported as a risk factor for stroke,49–53 they have not previously been reported as a risk factor for pregnancy-related stroke. While it is possible that migraine headaches are merely associated with pregnancy-related stroke or preeclampsia as a symptom of an impending stroke or as the consequence of one, this strong association requires further investigation.
We also found that anemia was a significant risk factor for pregnancy-related stroke. Anemia may result from blood loss that results in cerebral hypoperfusion, or there may be other explanations for this association between anemia and stroke, such as sickle cell disease, postpartum hemorrhage treated with methylergonovine, or hemolysis due to severe preeclampsia and the hemolysis, elevated liver enzymes, low platelets syndrome. Thrombocytopenia was a significant risk factor and could reflect the presence of the hemolysis, elevated liver enzymes, low platelets syndrome, which in 2 cases has been reported as a cause of pregnancy-related stroke.54,55
Similar to previous studies, we found that complications of pregnancy such as severe preeclampsia, eclampsia, infection, hyperemesis, and fluid and electrolyte imbalance were significant risk factors for pregnancy-related stroke.2,14,20,37 Other possible causes reported in case series or case reports included the use of 2 ergot derivatives, bromocriptine mesylate, previously prescribed for lactation suppression,56 and methylergonovine maleate, which is used to treat postpartum hemorrhage caused by uterine atony.12 Although the use of methylergonovine is not included in discharge records, we observed that postpartum hemorrhage was a significant risk factor for pregnancy-related stroke.
Transfusion increased the risk of stroke more than 10-fold. Although the need for transfusion is increased in conditions that place a woman at an increased risk of stroke, such as severe preeclampsia, postpartum hemorrhage, and sickle cell anemia, transfusion itself may be a risk factor for stroke. Storage and preservation of red blood cells increases their aggregability,13 possibly increasing the risk of thrombosis.
We found that age greater than 35 years and African-American race were significant risk factors for pregnancy-related stroke. Because the risk of stroke increases with age2,57,58 and is higher among African-Americans,2,58,59 the increased risk of pregnancy-related stroke among African-American women and women aged 35 years and older is not surprising. The magnitude of the risk, however, (over 2-fold for age greater than 35 years and almost 2-fold for African-American race), has not been previously appreciated.
Efforts to reduce pregnancy-related thromboembolic disease have focused on venous rather than arterial disease.60 Although venous thromboembolic disease is an important complication during pregnancy and the postpartum period, the risk of mortality is 30% higher for stroke than for venous thromboembolism (1.4 compared with 1.1 per 100,000 deliveries).61 Compared with women who survive venous thromboembolic disease, stroke survivors suffer significant disability, with serious consequences for themselves and their families. Little has been published about specific strategies to prevent pregnancy-related stroke, but efforts similar to those used to prevent and treat venous thromboembolism may be required to reduce the incidence and devastation of pregnancy-related stroke. Understanding the cause of pregnancy-related stroke and identification of women at risk are the first steps.
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