Stroke and cerebrovascular disease in pregnancy: incidence, temporal trends, and risk factors Shiliang Liu MD, PhD,1 Wee-Shian Chan MD, MSc,2 Joel G. Ray MD, MSc,3 Michael S. Kramer MD,4 K.S. Joseph MD, PhD,5 for the Canadian Perinatal Surveillance System (Public Health Agency of Canada) 1 Maternal, Child and Youth Health Division, Centre for Surveillance and Applied Research, Public Health Agency of Canada, Ottawa, ON 2 Departments of Medicine, and of Obstetrics and Gynaecology, University of British Columbia and the Children’s and Women’s Hospital of British Columbia, Vancouver, BC 3 Departments of Medicine, Health Policy Management and Evaluation, and Obstetrics and Gynecology, St Michael’s Hospital, University of Toronto, Toronto, ON. 4 Departments of Pediatrics, and of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC 5 Department of Obstetrics and Gynaecology and the School of Population and Public Health, University of British Columbia and the Children’s and Women’s Hospital of British Columbia, Vancouver, BC, Canada KS Joseph is indexed as such in PubMed and other indices For posts: Drs. K.S. Joseph and Wee-Shian Chan Word counts Abstract 250; Text 2,789; Tables 5; Figures 0 Supplemental tables 3 Short title Risk of stroke in pregnancy Address for correspondence Dr. Shiliang Liu Maternal, Child and Youth Health Division Centre for Surveillance and Applied Research HPCDP Branch - Public Health Agency of Canada 785 Carling Ave. AL 6804A Ottawa, ON, Canada K1A 0K9 E-mail: shiliang.liu@canada.ca Tel: 613-355-0134 ABSTRACT Background and Purpose: Few studies have examined the epidemiology of stroke in pregnancy despite the high associated burden of death and disability. We aimed to quantify the incidence, temporal trends, risk factors and case fatality associated with stroke and cerebrovascular disease in pregnancy. Methods: All antepartum, peripartum and postpartum hospitalizations and readmissions within 42 days of delivery in Canada (except Quebec) were obtained from the Canadian Institute of Health Information for the years 2003 to 2016. We assessed temporal trends in stroke and quantified associated risk factors using logistic regression. Results: 524 stroke cases were identified among 3,907,262 deliveries (13.4 per 100,000). The majority of cases were hemorrhagic strokes (307 cases, 58.6%), and most occurred in the postpartum period (270 cases, 51.5%). The case fatality rate was 7.4%. Stroke incidence rose from 10.8 per 100,000 in 2003-04 to 16.6 per 100,000 deliveries in 2015-16 (P value 0.002). Risk factors for stroke included older maternal (age ≥40 years) [adjusted odds ratio (AOR) 1.7, 95% CI 1.1-2.6], pre-eclampsia (AOR 7.1, 95% CI 5.3-9.6), eclampsia (AOR 65.9, 95% CI 43.6-99.6), maternal congenital heart disease (AOR 38.1, 95% CI 22.1-65.8), connective tissue disorders (AOR 12.6, 95% CI 6.1-26.9), sepsis (AOR 7.6, 95% CI 3.6-16.2), severe postpartum hemorrhage (AOR 4.7, 95% CI 2.8-8.0), and thrombophilia (AOR 4.2, 95% CI 1.5-12.1). Conclusions: The rising incidence of stroke in pregnancy, especially during the postpartum period, and its strong association with hypertensive disorders of pregnancy (especially preeclampsia) suggest that follow-up of severe hypertensive patients is required after delivery. INTRODUCTION Stroke is a neurological emergency and a major cause of disability and death around the world.1 It is the third leading cause of death among Canadians,2 and the age-adjusted occurrence of stroke in Canada increased from 2.3% in 2003 to 2.6% in 2012.1,3 Stroke in pregnancy is of particular importance not just because it affects women of reproductive age, but because it is often a result of specific pregnancy-associated conditions and is potentially preventable.4-8 Pregnancy-associated strokes are also the most common cause of serious long-term disability after pregnancy.7,8 Risk factors for stroke include hypertensive disorders of pregnancy such as preeclampsia and eclampsia, and a pro-thrombotic state, which increases the risk of arterial and venous thrombosis.4-8 Canadian studies have reported an incidence of cerebrovascular diseases during hospitalization for childbirth of 4.8 per 100,000 deliveries in 2003-07;9,10 45% of affected women had a prolonged hospital stay, and the associated case fatality was 9.4%.10 A number of other studies have found an increased risk of stroke in pregnancy, especially in the puerperium.11-14 Jeng et al reported an incidence of stroke during pregnancy and puerperium among Chinese women in Taiwan of 46.2 per 100,000 pregnancies.11 A more recent study by Ban et al from UK reported a nine-fold increased risk of ischemic or hemorrhagic stroke during the peripartum period and a three-fold increased risk during the early postpartum period.12 In the United States, the rate of stroke (including subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, transient ischemic attack, cerebral venous thrombosis, or unspecified stroke) among antepartum hospitalizations increased from 15 to 22 per 100,000 deliveries from 1994-95 to 2006-07, while rates of stroke were stable at 27 per 100,000 deliveries among delivery hospitalizations and increased from 12 in 1994-95 to 22 per 100,000 deliveries in 2006-07 among postpartum hospitalizations.14 In addition, previous studies suggest that Asians have an increased risk of hemorrhagic stroke compared with Caucasians and African-Americans.11,13,14 Risk factors for cerebrovascular disease and stroke such as older maternal age and hypertension have increased significantly in high-income countries in recent years.15-17 We carried out a study to quantify the incidence, temporal trends, regional variations, risk factors and case fatality associated with cerebrovascular disease and stroke in pregnancy in Canada. METHODS The data used for this study are available from the Canadian Institute for Health Information. Study population, case ascertainment and stroke subtypes This retrospective population-based cohort study included all antenatal admissions, delivery hospitalizations and postpartum hospital readmissions within 42 days of delivery in Canada (except Quebec) for the fiscal years 2003-04 to 2016-17. Information on pregnant women was obtained from the Canadian Institute for Health Information’s (CIHI) Discharge Abstract Database (DAD), which contained the abstracted and collated information from medical records of all hospitalizations in Canada. Data from Quebec are not available in the DAD. Hospitalization data were extracted by trained medical archivists in each hospital and coded according to a standardized protocol18 and included demographic and residence information, date of admission, date and status at discharge, principal diagnosis and up to 25 secondary diagnoses (coded using the International Statistical Classification of Diseases and Related Health Problems, 10th revision, Canadian version; ICD-10CA). Validation and data quality studies have shown this information to be complete and accurate19,20 and information on pregnancy conditions and obstetrical complications in the DAD is routinely used for perinatal research.19-23 First-ever cases of stroke and cerebrovascular disease in pregnancy during the index delivery were identified using ICD-10CA diagnostic codes and categorized as follows: (1) hemorrhagic stroke (I60-I62); (2) ischemic stroke (I63 except I63.6); (3) cerebral venous thrombosis (I63.6, I67.6); (4) stroke, not specified (I64); (5) any stroke (including hemorrhagic stroke, ischemic stroke, cerebral venous thrombosis and stroke unspecified); (6) occlusion or stenosis of pre-cerebral or cerebral arteries, transient cerebral ischemic attack (TIA) and related syndromes, and vascular syndromes of the brain not resulting in stroke (I65, I66, G45 and G46); and (7) other cerebrovascular diseases not resulting in stroke (I67 except I67.6). However, we were unable to verify whether the identified strokes were first-time events or complications of a condition that preceded the index pregnancy/delivery. Nor were we able to follow up the women with recorded strokes. Maternal characteristics and conditions Maternal characteristics such as age, parity, gestational age at delivery, and province of occurrence were obtained from all delivery hospitalizations with a gestational age ≥20 weeks, as was information on multi-fetal gestation, chronic hypertension, gestational hypertension, pre-eclampsia or eclampsia, pre-existing diabetes mellitus, connective tissue disorders, sepsis, HIV infection/disease, migraine, anemia, obesity, congenital heart disease, postpartum hemorrhage and blood transfusion. Other clinical conditions explored as potential risk factors included renal failure (acute, chronic and unspecified), superficial thrombophlebitis and deep venous thrombosis but these were not retained in the final analysis because of very small numbers of associated stroke cases. Supplementary analyses were also carried out on a subset of the data including hospital admissions between 2009 and 2016 in order to examine associations between thrombophilia and stroke, and between use of assisted reproductive technology and stroke (since these conditions were only coded in the DAD from 2009 onwards). Hospital length of stay was calculated as the number of days between admission and discharge. Health insurance numbers (scrambled by a systematic algorithm) were used to link antenatal, delivery and postpartum admissions for the same woman using deterministic record linkage (i.e., delivery records were linked to any preceding antenatal admission and/or subsequent postpartum readmissions). Statistical analysis Incidence rates of stroke by 2-year period and province of delivery hospitalization were calculated, with rates expressed per 100,000 deliveries. The Cochran-Armitage test for trend in proportions was used to examine biennial trends in the occurrence of stroke. The burden of illness due to cerebrovascular disease and stroke was estimated by calculating average length of hospital stay, proportion of women with prolonged length of stay (i.e., >7 days of hospitalization) and case fatality rates. Multivariate logistic regression analysis was used to estimate adjusted odds ratios (AOR) and corresponding 95% confidence intervals (CI) for the association between maternal risk factors and stroke and cerebrovascular diseases. We also estimated the proportion of stroke cases that would be eliminated if a particular risk factor (assumed to be causally associated with stroke) were removed from the population using the adjusted effect measure in the following equation: Pe(RR-1)/Pe(RR-1)+1 where Pe=proportion of the population exposed to the risk factor and RR=relative risk (OR given rare disease) associated with the risk factor.24 This study was carried out by the Canadian Perinatal Surveillance System of the Public Health Agency of Canada under its health surveillance and applied research mandate using publicly accessible anonymized data, hence ethics review board approval was not required. Statistical analyses were carried out using SAS version 9.2 (SAS Institute, Cary, NC). RESULTS A total of 524 stroke cases were identified among 3,907,262 hospital deliveries, yielding an overall incidence of 13.4 cases per 100,000 deliveries from 2003 to 2016. More than half (51.7%) of the recorded strokes occurred postpartum, and the overall case fatality rate was 7.4%. Hemorrhagic stroke accounted for almost 60% of all strokes, while ischemic stroke constituted nearly 30% of strokes (Table 1). The rate of occlusion, stenosis of pre-cerebral or cerebral arteries, or TIAs or other vascular syndromes not resulting in stroke was 3.5 per 100,000 deliveries, while the frequency of other cerebrovascular diseases not resulting in stroke was 6.4 per 100,000 deliveries (Table 1). Despite substantial fluctuation, the rate of stroke during pregnancy increased significantly from 10.8 cases per 100,000 deliveries in 2003-04, to 13.8 in 2009-10, and 16.6 per 100,000 deliveries in 2015-16 (P value 0.002 for increasing linear trend, supplemental Table I). This temporal increase remained significant after adjustment for maternal age (P value 0.005). Women with non-fatal stroke required longer hospital stays compared with women without stroke (mean 11.6 versus 2.5 days, respectively, Table 2). The proportion of women with a non-fatal stroke whose hospital stay exceeded 7 days was 43.7%, compared with 1.7% among women without stroke. The frequency of stroke by gestational duration at delivery increased with advancing gestation (supplemental Table II). Mothers aged 35-39 and ≥40 years had a significantly higher risk of any stroke than younger mothers (i.e., women 20-29 years) with an AOR of 1.6, 95% CI 1.2–2.0, and 1.7, 95% CI 1.1–2.6, respectively (Table 3). Gestational hypertension was associated with a 60% higher risk of stroke, while the AOR for stroke associated with chronic hypertension was 2.5 (95% CI 1.3-4.7). Preeclampsia (AOR 7.1), eclampsia (AOR 65.9), connective tissue disorders (AOR 12.6), sepsis (AOR 7.6), postpartum hemorrhage with blood transfusion (AOR 4.7), and congenital heart disease (AOR 38.1) were all very strongly associated with stroke. Approximately 7.9% and 3.8% of the stroke cases could be attributed to preeclampsia and eclampsia, respectively. Overall, 20.3% of stroke cases could be prevented if any of hypertensive disorders were eliminated from the pregnant women (Table 3). Table 4 shows the associations between maternal risk factors for hemorrhagic and ischemic stroke. Older maternal age was significantly associated with hemorrhagic stroke (AOR 2.0, 95% CI 1.4-2.8 for women 35-39 years) but not ischemic stroke (AOR 1.3, 95% CI 0.8-2.0 for women 35-39 years). Similarly, gestational hypertension was significantly associated with hemorrhagic stroke but not ischemic stroke. On the other hand, the AOR for multifetal gestation and hemorrhagic stroke (0.7, 95% CI 0.3-1.7) was significantly lower than the AOR for ischemic stroke (3.7, 95% CI 1.9-7.1). AORs were also different between parity and hemorrhagic stroke versus ischemic stroke. Other risk factors, such as pre-eclampsia, eclampsia, connective tissue disorders, sepsis, postpartum hemorrhage with blood transfusion and congenital heart disease showed strong associations with both hemorrhagic and ischemic stroke. HIV infection and migraine were strongly associated with ischemic stroke (Table 4). Table 5 shows associations between maternal risk factors for occlusion, stenosis of pre-cerebral or cerebral arteries, or TIAs or vascular syndromes not resulting in stroke. Most associations were similar to those observed with hemorrhagic and ischemic stroke, except for a strong association with pre-existing diabetes mellitus (AOR 5.5, 95% CI 2.5-12.3) and a non-significant association with pre-eclampsia (AOR 1.8, 95% CI 0.6-4.8). Table 5 also shows associations between maternal risk factors and other cerebrovascular diseases not resulting in stroke. These associations were generally similar to those with hemorrhagic and ischemic stroke. Supplementary analyses based on hospital admissions between 2009 and 2016 showed that thrombophilia was strongly associated with stroke (AOR 4.2, 95% CI 1.5-12.1). The crude association between assisted reproductive technology and stroke was not statistically significant (AOR 0.5, 95% CI 0.2-1.3), although the adjusted association showed use of assisted reproductive technologies was associated with a significantly lower rate of stroke (AOR 0.3, 95% CI 0.1-0.7; supplemental Table III). DISCUSSION We observed a temporal rise in the age-adjusted incidence of stroke during pregnancy in Canada over the past 14 years. Strokes occurring in the postpartum period and resulting in re-hospitalization accounted for the majority of cases. The case-fatality rate following stroke was substantial, with 7.4% of women dying during hospitalization. Risk factors for stroke included older maternal age, hypertensive disorders, especially pre-eclampsia and eclampsia, connective tissue disorders, sepsis, severe postpartum hemorrhage and congenital heart disease. Risk factors for the subtypes of stroke were generally similar to those for occlusion, stenosis of pre-cerebral or cerebral arteries, and TIAs, vascular syndromes or other cerebrovascular diseases not resulting in stroke. Exceptions included pre-existing diabetes mellitus, which was not a risk factor for stroke in pregnancy but was strongly associated with occlusion, stenosis of pre-cerebral and cerebral arteries, TIAs, and vascular syndromes not resulting in stroke. Rates of stroke observed in our study differed from those reported elsewhere. The rate of stroke reported in the United States was considerably higher (22 per 100,000 during antepartum hospitalizations, 27 per 100,000 during childbirth hospitalizations and 22 per 100,000 during postpartum hospitalizations in 2006-07) than the 13.4 per 100,000 deliveries observed in our study for the entire pregnancy and postpartum period. The higher rate reported in the U.S. may be explained by differences in coding systems used (ICD-9CM in the U.S. vs ICD-10CA in this study) and differences in the conditions included in the stroke definition (e.g., TIAs were included in the U.S. study). Population differences in maternal age distributions and race (the U.S. has a much larger proportion of African-American women, who are at high risk for stroke) may also have contributed to the reported differences.25 A different U.S. study also reported a pregnancy-related stroke incidence of 34.2 per 100,000 deliveries but acknowledged that the incidence may have been overestimated.26 The higher risk of stroke we observed in the postpartum period 8 and the temporal age-adjusted increase in incidence have both been reported previously.10, 25 Previous studies have attributed the temporal increase to a rise in prevalence of hypertensive disorders and heart disease in pregnancy.8,14,26 A recent study reported an increased risk of stroke during pregnancy among younger women (compared with their non-pregnant contemporaries), but not among older pregnant women.14,26,27 On the other hand, some of the temporal increase in stroke may be the product of improved ascertainment. Thus, the very high odds ratio associated with eclampsia (vs the high odds ratio associated with preeclampsia) may be partly attributable to the imaging and other testing routinely used for women with eclampsia in recent years.28 In addition to hypertensive and connective tissue disorders,7,29,30 congenital heart disease has been reported as a significant risk factor for pregnancy-related stroke.25,31 With advances in cardiac surgery and improved survival among affected children over the last few decades, a growing population of women with congenital heart disease is choosing to experience pregnancy. In this study, we examined congenital heart disease as a single entity and observed a 40-fold higher risk of pregnancy-associated stroke among such women. Whether this association results from decreased cardiac output from inadequate hemodynamic adaption to pregnancy, intra-cardiac shunts, or thrombi formation, requires further study.31,32 Women with congenital heart diseases are also at increased risk of a number of adverse pregnancy outcomes,31,33 including maternal placental syndrome.34 We also observed a higher risk of both hemorrhagic and ischemic stroke associated with postpartum haemorrhage requiring blood transfusion. We speculate that massive transfusion for postpartum haemorrhage, which has been linked to a higher rate of maternal morbidity,35 may also be responsible for increasing stroke risk. Use of assisted reproductive technologies for conception was not associated with an increased risk of stroke after adjusting for other potential confounding factors such as age, and hypertensive disorders. Limitations of our study include use of a large perinatal database that likely included transcription and other errors.18,19 However, data in the DAD have been validated in several studies,19-21 and the information is considered accurate, especially for highly morbid conditions such as stroke and eclampsia. Stroke events in the antepartum and postpartum periods were identified after linking childbirth and other hospitalizations using scrambled health insurance numbers, which could have introduced some errors. Additionally, information on some important confounders such as maternal smoking, body mass index, ethnicity, and socio-economic status was not available in the database used for our analysis. Finally, the data source did not include home deliveries, although the latter constitute a small fraction of deliveries in Canada (approximately 2%).18 Our study details the changing epidemiology of stroke and cerebrovascular disease in pregnancy in Canada. Age-adjusted incidence has increased over the last 14 years, and the case fatality from stroke and cerebrovascular disease remains high, even relative to other subtypes of severe morbidity.9,10,36 Risk factors for stroke and cerebrovascular disease include older maternal age, hypertensive disorders, connective tissue disorders, severe postpartum hemorrhage, HIV infection, sepsis, thrombophilia and congenital heart disease. The higher risk of stroke in the postpartum period and strong association between hypertensive disorders of pregnancy (especially preeclampsia) and stroke suggest that follow-up of severe hypertensive patients is required after delivery. The high case fatality rate associated with the development of stroke and cerebrovascular disease in pregnancy emphasizes the need for clinical vigilance, prompt diagnosis, and management of the factors leading to the development of this maternal complication. Acknowledgments We thank the Canadian Institute for Health Information for providing access to the Discharge Abstract Database (DAD). We thank Susie Dzakpasu, Emily Hollink, Wei Luo, Howard Morrison, Anne-Marie Ugnat (all with the Public Health Agency of Canada) for their review of the previous version of manuscript. Appendix Canadian Perinatal Surveillance System External Advisory Committee Members: Laura Arbour (University of British Columbia, Vancouver), Nathalie Auger (University of Montreal, Montreal), Liz Darling (Midwifery Group of Ottawa, Ottawa), Jane Evans (University of Manitoba, Winnipeg), K.S. Joseph (University of British Columbia, Vancouver), Julian Little (University of Ottawa, Ottawa), Michael S. Kramer (McGill University, Montreal), Lily Lee (Perinatal Services BC, Vancouver), Sarah McDonald (McMaster University, Hamilton), Aideen Moore (The Hospital for Sick Children, Toronto), Phil Murphy (Perinatal Program of Newfoundland and Labrador, St. John’s), Joel G. Ray (St. Michael’s Hospital, Toronto), Reginald Sauve (University of Calgary), Heather Scott (Dalhousie University, Halifax), Prakesh Shah (University of Toronto, Toronto), Mike Van den Hof (Dalhousie University, Halifax). Funding Sources: This study was carried out by the Public Health Agency of Canada. Disclosures: None REFRENCES 1. GBD 2015 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life expectancy [HALE], 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016; 388:1603-1658. 2. Statistics Canada. Table 102-0561 – Leading causes of death, total population, by age group and sex, Canada. CANSIM (death database). Ottawa (Ontario): Statistics Canada; 2017 March 8. http://www5.statcan.gc.ca/cansim/a26?lang=eng&id=1020561. Accessed September 18, 2018. 3. Public Health Agency of Canada. Stroke in Canada: Highlights from the Canadian Chronic Disease Surveillance System 2017. Cat: HP35-88/2017E-PDF. 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Anesth Analg. 2017; 124:890-897. doi: 10.1213/ANE.0000000000001877. 23. Mehrabadi A, Liu S, Bartholomew S, Hutcheon JA, Magee LA, Kramer MS, et al. Hypertensive disorders of pregnancy and the recent rise in obstetric acute renal failure: A population-based retrospective cohort study. BMJ. 2014;348:g4731 doi10.1136/bmj.g4371. 24. Rockhill B, Newman B, Weinberg C. Use and misuse of population attributable fractions. Am J Public Health.1998; 88:15-19. 25. Kittner SJ, Stern BJ, Feeser BR, Hebel JR, Nagey DA, Buchholz DW, et al. Pregnancy and the risk of stroke. N Engl J Med. 1996; 335:768-774. 26. James AH, Bushnell CD, Jamison MG, Myers ER. Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol. 2005; 106:509-516. 27. Miller EC, Gatollari HJ, Too G, et al. Risk of pregnancy-associated stroke across age groups in New York State. JAMA Neurol. 2016; 73; 1461-1467. 28. O’Goman N, Nicolaides KH, Poon LCY. The use of ultrasound and other markers for early detection of preeclampsia. Women’s Health (Lond) 2016; 12:199-207. 29. Lanska DJ, Kryscio RJ. Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis. Stroke. 2000; 31:1274-1282. 30. Branch DW, Khamasha MA. Antiphospholipid syndrome: obstetric diagnosis, management, and controversies. Obstet Gynecol. 2003; 101:1333-1344. 31. Greutnann M, Pieper PG. Pregnancy in women with congenital heart disease. Eur Heart J. 2015; 36:2491-2499. 32. Cornette J, Ruys TP, Rossi A, Rizopoulos D, Takkenberg JJ, Karamermer Y, et al. Hemodynamic adaptation to pregnancy in women with structural heart disease. Int J Cardiol. 2013; 168:825-831. 33. Cauldwell M, Dos Santos F, Steer PJ, Swan L, Gatzoulis M, Johnson MR. Pregnancy in women with congenital heart disease. BMJ. 2018; 360:k478 doi:10.1136/bmj.k478. 34. Ray GJ, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet. 2005; 366:1797-1803. 35. Green L, Knight M, Seeney FM, Hopkinson C, Collins PW, Collis RE, et al. The epidemiology and outcomes of women with postpartum haemorrhage requiring massive transfusion with eight or more units of red cells: a national cross-sectional study. BJOG. 2016;123:2164-2170. doi:10.1111/1471-0528.13831. 36. Liu S, Joseph KS, Liston RM., Bartholomew S, Walker M, Leon JA, et al; for the Maternal Health Study Group of the Canadian Perinatal Surveillance System. A population-based cohort study of eclampsia: Incidence, risk factors and associated complications. Obstet Gynecol. 2011; 118:987-994. 11 Table 1. Number and rate of stroke subtypes and related conditions by period of the pregnancy, Canada (excluding Quebec), 2003 to 2016. Stroke subtypes and other related conditions ICD-10CA diagnostic codes No. of cerebrovascular events by timing of occurrence in pregnancy or postpartum periods Total strokes Number (%) Rate per 100,000 deliveries Case fatality Number (%) Antenatal (n=377,370) Index delivery hospitalization (n=3,907,262) Postpartum readmission (n=67,438) Hemorrhagic stroke I60, I61, I62 12 131 164 307 (58.6) 7.9 25 (8.1) Ischemic stroke I63 (except I63.6) 15 52 82 149 (28.4) 3.8 11 (7.4) Cerebral venous thrombosis I63.6, I67.6 1 6 15 22 (4.2) 0.6 2 (9.1) Stroke, not specified I64 2 38 10 50 (9.4) 1.3 1 (2.3) Any stroke‡ I60-I64, I67.6 29 224 271 524 (100.0) 13.4 39 (7.4) Occlusion, stenosis of pre- cerebral and cerebral arteries, TIAs, vascular syndromes (not resulting in stroke) I65, I66, G45,G46 2 97 30 137 3.5 0 (0.0) Other cerebrovascular diseases (not resulting in stroke) I67 (except I67.6) 6 78 53 252 6.4 2 (0.8) ICD-10 denotes International Classification of Diseases and Related Health Problems and TIA denotes transient ischemic attack. Puerperal readmission refers to admission within 42 days after termination of pregnancy. ‡More than one stroke subtype may be coded. A. Table 2. Length of hospital stay among pregnant women with and without non-fatal stroke, Canada (excluding Quebec), 2003 to 2016. Stroke subtypes and other related conditions No. Mean (SD) length of stay in days* Mean (SD) No. (%, 95% CI) with a length of stay > 7 days Hemorrhagic stroke 282 12.1 (13.2) 124 (44.0, 38.1 - 50.0) Ischaemic stroke 138 12.9 (12.5) 70 (50.7, 42.1 - 59.3) Cerebral venous thrombosis 20 9.6 (11.3) 8 (40.0, 19.1 - 63.9) Stroke, not specified 48 4.9 (6.8) 7 (14.6, 6.1 - 27.8) Any stroke 485 11.6 (12.7) 212 (43.7, 39.2 - 48.3) Occlusion, stenosis, TIAs, and vascular syndromes not resulting in stroke 137 5.3 (6.2) 23 (16.8, 11.0 - 24.1) Other cerebrovascular diseases not resulting in stroke 250 5.7 (6.3) 50 (20.0, 15.2 - 25.5) Hospitalizations excluding those with stroke and other cerebrovascular conditions 4,350,706 2.5 (2.2) 73,917 (1.70, 1.69 - 1.71) *Mean length of stay (LOS) was calculated as 42 days for women with a LOS > 42 days. Table 3. Rates of stroke and crude and adjusted odds ratios showing associations between maternal characteristics and conditions and any stroke* during pregnancy, childbirth and the postpartum period, Canada (excluding Quebec), 2003 to 2016. Characteristic Population frequency (n=3,907,262) % Rate of stroke per 100,000 when factor is present Rate of stroke per 100,000 when factor is absent Odds Ratio (95% CI) Population attributable fraction (PAF, %) Crude Adjusted§ Maternal age (years) <20 4.1 16.4 13.3 1.4 (0.9 - 2.3) 1.3 (0.9 - 2.1) 1.2 20-29 43.9 12.4 13.9 1.0 (reference) 1.0 (reference) -- 30-34 32.6 18.7 12.4 1.1 (0.9 - 1.4) 1.1 (0.9 - 1.4) 3.2 35-39 16.0 22.1 13.1 1.7 (1.3 - 2.1) 1.6 (1.2 - 2.0) 8.8 ≥40 3.4 51.2 13.2 2.0 (1.3 - 3.0) 1.7 (1.1 - 2.6) 2.3 Parity 0 34.8 8.4 16.1 1.3 (0.9 - 1.8) 1.1 (0.8 - 1.6) 3.4 1 27.0 5.4 5.8 1.0 (reference) 1.0 (reference) -- 2 14.3 5.5 5.4 1.0 (0.7 - 1.6) 1.0 (0.6 - 1.5) -- ≥3 2.6 9.1 5.2 1.7 (0.9 - 3.4) 1.4 (0.7 - 2.9) -- Unknown 21.3 30.2 6.2 5.5 (4.1 - 7.3) 5.1 (3.8 - 6.8) -- Multi-fetal gestation 1.5 35.0 13.1 2.7 (1.6 - 4.3) 1.5 (0.9 - 2.4) 0.7 Chronic hypertension 0.6 51.2 13.2 3.8 (2.0 - 7.1) 2.5 (1.3 - 4.7) 0.4 Gestational hypertension‡ 4.1 20.5 13.1 1.6 (1.1 - 2.3) 1.6 (1.1 - 2.3) 2.4 Pre-eclampsia 1.4 133.1 117.8 11.4 (8.7 - 14.9) 7.1 (5.3 - 9.6) 7.9 Eclampsia 0.06 1313.2 12.6 105.2 (71.5 - 154.3) 65.9 (43.6 - 99.6) 3.8 Pre-existing diabetes 0.7 7.7 13.2 0.7 (0.2 - 2.6) 0.4 (0.1 - 1.6) 0 Connective tissue disorders 0.08 278.8 13.2 22.1 (11.0 - 44.5) 12.6 (6.1 - 26.9) 0.9 Sepsis 0.11 21.9 13.2 17.4 (8.6 - 35.0) 7.6 (3.6 - 16.2) 0.7 HIV infection 0.05 50.2 13.4 4.4 (0.6 - 31.3) 4.3 (0.6 - 30.6) 0.2 PPH + blood transfusion 0.5 113.7 12.9 8.8 (8.5 - 14.2) 4.7 (2.8 - 8.0) 1.8 Migraine 0.03 81.4 13.4 7.2 (1.01 - 50.9) 3.6 (0.5 - 26.8) 0.1 Congenital heart disease 0.1 520.8 13.0 41.3 (24.2 - 70.4) 38.1 (22.1 - 65.8) 3.6 Gestational diabetes 5.6 21.5 12.9 1.7 (1.2 - 2.3) 1.2 (0.8 - 1.6) 1.1 Anemia 2.2 42.6 12.8 3.4 (2.3 - 4.9) 1.3 (0.9 - 2.0) 0.7 Obesity 1.3 21.9 13.3 1.6 (0.8 - 3.1) 1.3 (0.7 - 2.6) 0.4 Any of hypotensive disorders† 6.1 58.0 10.5 5.5 (4.5 - 6.8) 5.2 (4.2 - 6.4) 20.3 * Any stroke includes hemorrhagic stroke, ischemic stroke, cerebral venous thrombosis and stroke not specified. ‡ Defined using ICD-10 code O13 which included mild pre-eclampsia. HIV denotes human immunodeficiency virus and PPH denotes postpartum hemorrhage. †Hypertensive disorders during pregnancy include chronic hypertension, gestational hypertension, preeclampsia and eclampsia. § All the variables listed in the first column are included in the adjusted modeling. Table 4. Crude and adjusted odds ratios showing associations between maternal characteristics and conditions and hemorrhagic and ischemic subtypes of stroke during pregnancy, childbirth and the postpartum period, Canada (excluding Quebec), 2003 to 2016. Characteristic/condition Hemorrhagic stroke (n=250) Ischemic stroke (n=132) Crude odds ratio (95% CI) Adjusted odds ratio (95% CI)§ Crude odds ratio (95% CI) Adjusted odds ratio (95% CI)§ Maternal age (yrs) < 20 1.5 (0.8 - 2.8) 1.3 (0.7 - 2.5) 1.5 (0.7 - 3.3) 1.7 (0.8 - 3.7) 20-29 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 30-34 1.2 (0.9 - 1.6) 1.2 (0.9 - 1.7) 1.1 (0.7 - 1.6) 1.0 (0.6 - 1.5) 35-39 2.0 (1.4 - 2.7) 2.0 (1.4 - 2.8) 1.6 (0.9 - 2.5) 1.3 (0.8 - 2.0) ≥ 40 2.8 (1.7 - 4.6) 2.6 (1.5 - 4.3) 1.5 (0.7 - 3.6) 1.1 (0.5 - 2.6) Parity 0 1.3 (0.8 - 1.9) 1.1 (0.7 - 1.7) 0.7 (0.3 - 1.5) 0.6 (0.3 - 1.3) 1 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 2 0.6 (0.3 - 1.1) 0.5 (0.3 - 1.0) 2.0 (1.0 - 4.2) 2.0 (1.0 - 4.2) ≥ 3 0.9 (0.3 – 2.9) 0.7 (0.2 - 2.3) 4.6 (1.8 - 12.0) 4.2 (1.6 – 11.0) Unknown 5.0 (3.5 - 7.2) 4.6 (3.2 - 6.7) 7.6 (4.3 - 13.4) 7.0 (3.9 - 12.3) Multifetal gestation 1.4 (0.6 - 3.4) 0.7 (0.3 - 1.7) 6.1 (3.3 - 11.4) 3.7 (1.9 - 7.1) Chronic hypertension 2.7 (1.1 - 7.2) 1.9 (0.7 - 5.2) 5.2 (1.9 - 14.0) 2.8 (0.9 - 7.9) Gestational hypertension* 1.7 (1.1 - 2.8) 1.7 (1.1 - 2.9) 1.1 (0.5 - 2.5) 1.1 (0.5 - 2.5) Pre-eclampsia 14.0 (10.0 - 19.6) 9.2 (6.4 - 13.2) 9.4 (5.5 - 16.1) 5.1 (2.8 - 9.1) Eclampsia 128.8 (80.5 - 205.9) 74.8 (45.1 - 124.0) 61.3 (25.1 - 149.9) 38.0 (14.8 - 97.3) Pre-existing diabetes 0.6 (0.1 - 4.1) 0.3 (0.1 - 2.4) 1.1 (0.2 - 7.8) 0.7 (0.1 - 4.7) Connective tissue disorders 9.8 (2.4 - 39.3) 5.0 (1.2 - 20.4) 37.8 (14.0 - 102.4) 21.2 (7.3 - 61.5) Sepsis 11.6 (3.7 - 36.1) 4.6 (1.4 - 15.2) 37.5 (15.3 - 91.6) 15.3 (5.9 - 40.0) HIV infection - - 14.9 (2.1 - 107.1) 11.8 (1.6 - 85.7) PPH and blood transfusion 8.8 (4.7 - 16.5) 5.4 (2.7 - 10.7) 11.8 (5.5 - 25.3) 5.2 (2.2 - 12.2) Migraine - - 24.3 (3.4 - 174.1) 10.1 (1.3 - 77.3) Congenital heart disease 26.0 (10.7 - 63.0) 25.4 (10.4 - 62.2) 50.1 (20.5 - 122.6) 43.2 (17.1 - 109.3) Gestational diabetes 1.8 (1.2 - 2.7) 1.2 (0.8 - 1.9) 1.5 (0.8 - 2.9) 1.1 (0.6 - 2.0) Anemia 2.7 (1.6 - 4.6) 1.1 (0.6 - 1.9) 5.4 (3.1 - 9.3) 1.8 (0.9 - 3.4) Obesity 1.4 (0.5 - 3.4) 1.0 (0.4 - 2.9) 2.4 (0.9 - 6.5) 2.1 (0.8 - 5.9) * Defined using ICD-10 code O13 which included mild pre-eclampsia. HIV denotes human immunodeficiency virus and PPH denotes postpartum hemorrhage. § All variables listed in the first column are included in the adjusted modeling. Table 5. Crude and adjusted odds ratios showing associations between maternal characteristics and conditions and cerebrovascular disease subtypes during pregnancy, childbirth and the postpartum period, Canada (excluding Quebec), 2003 to 2016 Characteristic/condition Occlusion, stenosis of pre-cerebral and cerebral arteries, TIAs and vascular syndromes (n=129) Other cerebrovascular diseases not resulting in stroke (n=238) Crude OR Adjusted OR§ Crude OR Adjusted OR§ Maternal age (years) < 20 0.5 (0.3 - 0.9) 0.5 (0.3 - 1.01) 1.2 (0.6 - 2.3) 1.0 (0.5 - 1.9) 20-29 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 30-34 0.7 (0.5 - 1.2) 0.7 (0.5 - 1.2) 1.1 (0.8 - 1.5) 1.2 (0.9 - 1.6) 35-39 1.2 (0.7 - 1.9) 1.1 (0.7 - 1.8) 1.2 (0.8 - 1.8) 1.3 (0.9 - 1.9) ≥ 40 2.1 (1.0 - 4.1) 1.8 (0.8 - 3.6) 2.7 (1.7 - 4.4) 2.5 (1.5 - 4.1) Parity 0 1.0 (0.6 - 1.6) 0.9 (0.6 - 1.6) 1.8 (1.2 - 2.5) 1.5 (1.1 - 2.2) 1 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 2 1.4 (0.8 - 2.5) 1.3 (0.8 - 2.3) 0.8 (0.5 - 1.4) 0.8 (0.5 - 1.3) ≥ 3 1.5 (0.5 – 4.4) 1.3 (0.4 - 3.7) 1.8 (0.8 - 3.9) 1.4 (0.6 - 3.1) Unknown 1.9 (1.2 - 3.0) 1.8 (1.1 - 3.0) 2.1 (1.5 - 3.1) 2.0 (1.4 - 2.9) Multifetal gestation 0.5 (0.1 - 3.8) 0.3 (0.1 - 2.4) 2.3 (1.2 - 4.8) 1.4 (0.7 - 3.0) Chronic hypertension 6.7 (2.7 - 16.3) 3.4 (1.3 - 8.7) 7.3 (3.9 - 13.7) 4.2 (2.2 - 8.3) Gestational hypertension* 2.6 (1.5 - 4.6) 2.5 (1.4 - 4.4) 2.5 (1.6 - 3.8) 2.2 (1.4 - 3.4) Pre-eclampsia 2.3 (0.9 - 6.3) 1.8 (0.6 - 4.8) 7.4 (4.8 - 11.6) 4.1 (2.6 - 6.5) Eclampsia 24.5 (6.1 - 99.0) 19.1 (4.6 - 79.8) 159.7 (102.8 - 248.1) 103.8 (65.1 - 165.5) Pre-existing diabetes mellitus 8.2 (3.8 - 17.6) 5.5 (2.5 - 12.3) 3.7 (1.6 - 8.3) 1.8 (0.8 - 4.2) Connective tissue disorders 9.5 (1.3 - 67.6) 3.2 (0.4 - 25.3) 20.7 (7.7 - 55.6) 9.7 (3.4 - 27.4) Sepsis 15.0 (3.7 - 60.5) 10.0 (2.4 - 41.6) 4.0 (0.6 - 28.6) 1.8 (0.2 - 13.0) PPH and blood transfusion 5.0 (1.6 - 15.8) 2.8 (0.8 - 9.5) 5.5 (2.4 - 12.3) 2.4 (0.9 - 5.7) Migraine 102.2 (37.7 - 277.0) 55.4 (19.3 - 158.8) 13.4 (1.9 - 95.9) 6.6 (0.9 - 48.3) Congenital heart disease 107.2 (56.2 - 204.5) 94.6 (48.6 - 184.0) 32.9 (14.6 - 74.1) 25.7 (11.2 - 58.9) Gestational diabetes mellitus 0.8 (0.4 - 1.9) 0.6 (0.3 - 1.5) 1.3 (0.8 - 2.1) 1.0 (0.6 - 1.6) Anemia 3.0 (1.5 - 6.1) 1.8 (0.8 - 3.9) 3.5 (2.1 - 5.7) 1.9 (1.1 - 3.3) Obesity 1.2 (0.3 - 4.9) 0.7 (0.2 - 2.9) 4.1 (2.3 - 7.3) 2.8 (1.5 - 5.0) * Defined using ICD-10 code O13 which includes mild pre-eclampsia. § All variables listed in the first column are included in the adjusted modeling. OR denotes odds ratio and TIA denotes transient ischemic attacks. 24