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Stroke and Cerebrovascular Disease in Pregnancy

Incidence, Temporal Trends, and Risk Factors


Shiliang Liu, MD, PhD; Wee-Shian Chan, MD, MSc; Joel G. Ray, MD, MSc;
Michael S. Kramer, MD; K.S. Joseph, MD, PhD;
for the Canadian Perinatal Surveillance System (Public Health Agency of Canada)*

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—Five hundred twenty-four 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 to 2004 to 16.6 per 100 000 deliveries
in 2015 to 2016 (P=0.002). Risk factors for stroke included older maternal (age ≥40 years; adjusted odds ratio [AOR],
1.7; 95% CI, 1.1–2.6), preeclampsia (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.   (Stroke. 2019;50:13-20. DOI: 10.1161/STROKEAHA.118.023118.)
Key Words: epidemiology ◼ hypertension ◼ incidence ◼ pregnancy ◼ stroke
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S troke is a neurological emergency and a major cause of


disability and death around the world.1 It is the third lead-
ing cause of death among Canadians,2 and the age-adjusted
100 000 deliveries in 2003 to 20079,10; 45% of affected women
had a prolonged hospital stay, and the associated case fatality
was 9.4%.10 Many other studies have found an increased risk
occurrence of stroke in Canada increased from 2.3% in 2003 of stroke in pregnancy, especially in the puerperium.11–14 Jeng
to 2.6% in 2012.1,3 Stroke in pregnancy is of particular impor- et al11 reported an incidence of stroke during pregnancy and
tance not just because it affects women of reproductive age, puerperium among Chinese women in Taiwan of 46.2 per
but because it is often a result of specific pregnancy-associ- 100 000 pregnancies. A more recent study by Ban et al12 from
ated conditions and is potentially preventable.4–8 Pregnancy- United Kingdom reported a 9-fold increased risk of ischemic
associated strokes are also the most common cause of serious or hemorrhagic stroke during the peripartum period and a
long-term disability after pregnancy.7,8 Risk factors for stroke 3-fold increased risk during the early postpartum period. In
include hypertensive disorders of pregnancy, such as pree- the United States, the rate of stroke (including subarachnoid
clampsia and eclampsia, and a prothrombotic state, which hemorrhage, intracerebral hemorrhage, ischemic stroke, tran-
increases the risk of arterial and venous thrombosis.4–8 sient ischemic attack, cerebral venous thrombosis, or unspeci-
Canadian studies have reported an incidence of cerebrovas- fied stroke) among antepartum hospitalizations increased from
cular diseases during hospitalization for childbirth of 4.8 per 15 to 22 per 100 000 deliveries from 1994 to 1995 to 2006 to

Received August 2, 2018; final revision received September 28, 2018; accepted October 8, 2018.
From the Maternal, Child and Youth Health Division, Centre for Surveillance and Applied Research, Public Health Agency of Canada, Ottawa, ON
(S.L.); Departments of Medicine and Obstetrics and Gynaecology, University of British Columbia, the Children’s and Women’s Hospital of British
Columbia, Vancouver, BC (W.-S.C.); Departments of Medicine, Health Policy Management and Evaluation and Obstetrics and Gynecology, St Michael’s
Hospital, University of Toronto, ON (J.G.R.); Departments of Pediatrics and of Epidemiology, Biostatistics and Occupational Health, McGill University,
Montreal, QC (M.S.K.); and Department of Obstetrics and Gynaecology, 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 (K.S.J.).
*A list of all Canadian Perinatal Surveillance System (Public Health Agency of Canada) study participants is given in the Appendix.
The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.118.023118.
Correspondence to Shiliang Liu, MD, PhD, 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 K1A 0K9, Canada. Email shiliang.liu@canada.ca
© 2018 American Heart Association, Inc.
Stroke is available at https://www.ahajournals.org/journal/str DOI: 10.1161/STROKEAHA.118.023118

13
14  Stroke  January 2019

2007, whereas rates of stroke were stable at 27 per 100 000 superficial thrombophlebitis, and deep venous thrombosis but these
deliveries among delivery hospitalizations and increased from were not retained in the final analysis because of small numbers of
associated stroke cases. Supplementary analyses were also performed
12 in 1994 to 1995 to 22 per 100 000 deliveries in 2006 to 2007
on a subset of the data including hospital admissions between 2009
among postpartum hospitalizations.14 In addition, previous and 2016 to examine associations between thrombophilia and stroke
studies suggest that Asians have an increased risk of hemor- and between use of assisted reproductive technology and stroke
rhagic stroke compared with whites and blacks.11,13,14 (because these conditions were only coded in the DAD from 2009
Risk factors for cerebrovascular disease and stroke, such onwards).
Hospital length of stay was calculated as the number of days be-
as older maternal age and hypertension, have increased sig-
tween admission and discharge. Health insurance numbers (scram-
nificantly in high-income countries in recent years.15–17 We bled by a systematic algorithm) were used to link antenatal, delivery,
performed a study to quantify the incidence, temporal trends, and postpartum admissions for the same woman using deterministic
regional variations, risk factors, and case fatality associated record linkage (ie, delivery records were linked to any preceding an-
with cerebrovascular disease and stroke in pregnancy in tenatal admission and subsequent postpartum readmissions).
Canada.
Statistical Analysis
Methods Incidence rates of stroke by 2-year period and province of delivery
The data used for this study are available from the Canadian Institute hospitalization were calculated, with rates expressed per 100 000
for Health Information. deliveries. The Cochran-Armitage test for trend in proportions was
used to examine biennial trends in the occurrence of stroke. The
burden of illness because of cerebrovascular disease and stroke was
Study Population, Case Ascertainment, estimated by calculating average length of hospital stay, proportion
and Stroke Subtypes of women with prolonged length of stay (ie, >7 days of hospitaliza-
This retrospective population-based cohort study included all ante- tion), and case fatality rates. Multivariate logistic regression analysis
natal admissions, delivery hospitalizations, and postpartum hospital was used to estimate adjusted odds ratios (AOR) and corresponding
readmissions within 42 days of delivery in Canada (except Quebec) 95% CIs for the association between maternal risk factors and stroke
for the fiscal years 2003 to 2004 to 2016 to 2017. Information on and cerebrovascular diseases. We also estimated the proportion
pregnant women was obtained from the Canadian Institute for Health of stroke cases that would be eliminated if a particular risk factor
Information’s Discharge Abstract Database (DAD), which contained (assumed to be causally associated with stroke) were removed from
the abstracted and collated information from medical records of all the population using the adjusted effect measure in the following
hospitalizations in Canada. Data from Quebec are not available in equation: Pe(RR-1)/Pe(RR-1)+1 where Pe=proportion of the popu-
the DAD. lation exposed to the risk factor and RR=relative risk (OR given rare
Hospitalization data were extracted by trained medical archivists disease) associated with the risk factor.24 This study was performed
in each hospital and coded according to a standardized protocol18 by the Canadian Perinatal Surveillance System of the Public Health
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and included demographic and residence information, date of ad- Agency of Canada under its health surveillance and applied research
mission, date and status at discharge, principal diagnosis, and up mandate using publicly accessible anonymized data, hence, ethics re-
to 25 secondary diagnoses (coded using the International Statistical view board approval was not required. Statistical analyses were car-
Classification of Diseases and Related Health Problems, Tenth ried out using SAS version 9.2 (SAS Institute, Cary, NC).
Revision, Canadian version). Validation and data quality studies have
shown this information to be complete and accurate,19,20 and informa-
tion on pregnancy conditions and obstetric complications in the DAD
Results
is routinely used for perinatal research.19–23 A total of 524 stroke cases were identified among 3 907 262
First-ever cases of stroke and cerebrovascular disease in preg- hospital deliveries, yielding an overall incidence of 13.4 cases
nancy during the index delivery were identified using International per 100 000 deliveries from 2003 to 2016. More than half
Statistical Classification of Diseases and Related Health Problems, (51.7%) of the recorded strokes occurred postpartum, and
Tenth Revision, Canadian version diagnostic codes and categorized
as follows: (1) hemorrhagic stroke (I60-I62); (2) ischemic stroke the overall case fatality rate was 7.4%. Hemorrhagic stroke
(I63 except I63.6); (3) cerebral venous thrombosis (I63.6, I67.6); accounted for almost 60% of all strokes, while ischemic
(4) stroke not specified (I64); (5) any stroke (including hemorrhagic stroke constituted nearly 30% of strokes (Table 1). The rate of
stroke, ischemic stroke, cerebral venous thrombosis, and stroke un- occlusion, stenosis of precerebral or cerebral arteries, or TIAs
specified); (6) occlusion or stenosis of precerebral or cerebral arter-
or other vascular syndromes not resulting in stroke was 3.5
ies, transient cerebral ischemic attack (TIA) and related syndromes,
and vascular syndromes of the brain not resulting in stroke (I65, I66, per 100 000 deliveries, while the frequency of other cerebro-
G45, and G46); and (7) other cerebrovascular diseases not result- vascular diseases not resulting in stroke was 6.4 per 100 000
ing in stroke (I67 except I67.6). However, we were unable to verify deliveries (Table 1).
whether the identified strokes were first-time events or complications Despite substantial fluctuation, the rate of stroke during
of a condition that preceded the index pregnancy/delivery. Nor were
we able to follow-up the women with recorded strokes. pregnancy increased significantly from 10.8 cases per 100 000
deliveries in 2003 to 2004, to 13.8 in 2009 to 2010, and 16.6
per 100 000 deliveries in 2015 to 2016 (P=0.002 for increas-
Maternal Characteristics and Conditions
ing linear trend; Table I in the online-only Data Supplement).
Maternal characteristics such as age, parity, gestational age at de-
livery, and province of occurrence were obtained from all delivery This temporal increase remained significant after adjustment
hospitalizations with a gestational age ≥20 weeks, as was informa- for maternal age (P=0.005). Women with nonfatal stroke re-
tion on multifetal gestation, chronic hypertension, gestational hyper- quired longer hospital stays compared with women without
tension, preeclampsia or eclampsia, preexisting diabetes mellitus, stroke (mean 11.6 versus 2.5 days, respectively; Table 2). The
connective tissue disorders, sepsis, HIV infection/disease, migraine,
anemia, obesity, congenital heart disease, postpartum hemorrhage,
proportion of women with a nonfatal stroke whose hospital
and blood transfusion. Other clinical conditions explored as potential stay exceeded 7 days was 43.7%, compared with 1.7% among
risk factors included renal failure (acute, chronic, and unspecified), women without stroke. The frequency of stroke by gestational
Liu et al   Risk of Stroke in Pregnancy   15

Table 1.  Number and Rate of Stroke Subtypes and Related Conditions by Period of the Pregnancy, Canada (Excluding Quebec), 2003 to 2016

No. of Cerebrovascular Events by Timing of


Occurrence in Pregnancy or Postpartum Periods
Index Delivery Postpartum Rate per
Stroke Subtypes and Other Related ICD-10CA Diagnostic Antenatal Hospitalization Readmission Total Strokes, 100 000 Case Fatality,
Conditions Codes (n=377 370) (n=3 907 262) (n=67 438) Number (%) Deliveries Number (%)
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 precerebral I65, I66, G45,G46 2 97 30 137 3.5 0 (0.0)
and cerebral arteries, TIAs, vascular
syndromes (not resulting in stroke)
Other cerebrovascular diseases (not I67 (except I67.6) 6 78 53 252 6.4 2 (0.8)
resulting in stroke)
Puerperal readmission refers to admission within 42 days after termination of pregnancy. ICD-10 indicates International Classification of Diseases and Related Health
Problems; and TIA, transient ischemic attack.
*More than one stroke subtype may be coded.

duration at delivery increased with advancing gestation (Table was significantly associated with hemorrhagic stroke (AOR,
II in the online-only Data Supplement). 2.0; 95% CI, 1.4–2.8 for women 35–39 years) but not is-
Mothers aged 35 to 39 and ≥40 years had a significantly chemic stroke (AOR, 1.3; 95% CI, 0.8–2.0 for women 35–39
higher risk of any stroke than younger mothers (ie, women years). Similarly, gestational hypertension was significantly
20–29 years) with an AOR of 1.6; 95% CI, 1.2–2.0 and 1.7; associated with hemorrhagic stroke but not ischemic stroke.
95% CI, 1.1–2.6, respectively (Table 3). Gestational hyperten- However, the AOR for multifetal gestation and hemorrhagic
sion was associated with a 60% higher risk of stroke, while stroke (0.7; 95% CI, 0.3–1.7) was significantly lower than the
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the AOR for stroke associated with chronic hypertension was AOR for ischemic stroke (3.7; 95% CI, 1.9–7.1). AORs were
2.5 (95% CI, 1.3–4.7). Preeclampsia (AOR 7.1), eclampsia also different between parity and hemorrhagic stroke versus
(AOR 65.9), connective tissue disorders (AOR 12.6), sepsis ischemic stroke. Other risk factors, such as preeclampsia,
(AOR 7.6), postpartum hemorrhage with blood transfusion eclampsia, connective tissue disorders, sepsis, postpartum
(AOR 4.7), and congenital heart disease (AOR 38.1) were hemorrhage with blood transfusion, and congenital heart di-
all strongly associated with stroke. Approximately 7.9% and sease, showed strong associations with both hemorrhagic and
3.8% of the stroke cases could be attributed to preeclampsia ischemic stroke. HIV infection and migraine were strongly as-
and eclampsia, respectively. Overall, 20.3% of stroke cases sociated with ischemic stroke (Table 4).
could be prevented if any of hypertensive disorders were elim- Table 5 shows associations between maternal risk fac-
inated from the pregnant women (Table 3). tors for occlusion, stenosis of precerebral or cerebral arteries,
Table 4 shows the associations between maternal risk fac- or TIAs or vascular syndromes not resulting in stroke. Most
tors for hemorrhagic and ischemic stroke. Older maternal age associations were similar to those observed with hemorrhagic

Table 2.  Length of Hospital Stay Among Pregnant Women With and Without Nonfatal Stroke, Canada (excluding Quebec), 2003 to 2016

Mean (SD) Length of No. (%, 95% CI) With a


Stroke Subtypes and Other Related Conditions Number Stay in d* Mean (SD) Length of Stay >7 d
Hemorrhagic stroke 282 12.1 (13.2) 124 (44.0, 38.1–50.0)
Ischemic 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 137 5.3 (6.2) 23 (16.8, 11.0–24.1)
resulting in stroke
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 4 350 706 2.5 (2.2) 73 917 (1.70, 1.69–1.71)
cerebrovascular conditions
*Mean length of stay (LOS) was calculated as 42 d for women with a LOS >42 d.
16  Stroke  January 2019

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

Population Rate of Stroke per Rate of Stroke per Odds Ratio (95% CI) Population
Frequency 100 000 When Factor 100 000 When Factor Attributable
Characteristic (n=3 907 262) % Is Present Is Absent Crude Adjusted† Fraction, %
Maternal age, y <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) …
Multifetal 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
Preeclampsia 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
Preexisting diabetes mellitus 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
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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 mellitus 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
ICD-10 indicates International Classification of Diseases and Related Health Problems; and PPH, postpartum hemorrhage.
*Any stroke includes hemorrhagic stroke, ischemic stroke, cerebral venous thrombosis, and stroke not specified.
†All the variables listed in the first column are included in the adjusted modeling.
‡Defined using ICD-10 code O13 which included mild preeclampsia.
§Hypertensive disorders during pregnancy include chronic hypertension, gestational hypertension, preeclampsia, and eclampsia.

and ischemic stroke, except for a strong association with pre- significantly lower rate of stroke (AOR, 0.3; 95% CI, 0.1–0.7;
existing diabetes mellitus (AOR, 5.5; 95% CI, 2.5–12.3) and Table III in the online-only Data Supplement).
a nonsignificant association with preeclampsia (AOR, 1.8;
95% CI, 0.6–4.8). Table 5 also shows associations between Discussion
maternal risk factors and other cerebrovascular diseases not We observed a temporal rise in the age-adjusted incidence
resulting in stroke. These associations were generally similar of stroke during pregnancy in Canada over the past 14 years.
to those with hemorrhagic and ischemic stroke. Strokes occurring in the postpartum period and resulting in
Supplementary analyses based on hospital admissions be- rehospitalization accounted for the majority of cases. The
tween 2009 and 2016 showed that thrombophilia was strongly case fatality rate following stroke was substantial, with 7.4%
associated with stroke (AOR, 4.2; 95% CI, 1.5–12.1). The of women dying during hospitalization. Risk factors for stroke
crude association between assisted reproductive technology included older maternal age, hypertensive disorders, especially
and stroke was not statistically significant (AOR, 0.5; 95% preeclampsia and eclampsia, connective tissue disorders,
CI, 0.2–1.3), although the adjusted association showed use sepsis, severe postpartum hemorrhage, and congenital heart
of assisted reproductive technologies was associated with a disease. Risk factors for the subtypes of stroke were generally
Liu et al   Risk of Stroke in Pregnancy   17

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

Hemorrhagic Stroke (n=250) Ischemic Stroke (n=132)


Crude Odds Ratio Adjusted Odds Ratio Crude Odds Ratio Adjusted Odds Ratio
Characteristic/Condition (95% CI) (95% CI)* (95% CI) (95% CI)*
Maternal age, y <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)
Preeclampsia 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)
Preexisting diabetes mellitus 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)
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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 mellitus 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)
ICD-10 indicates International Classification of Diseases and Related Health Problems; and PPH, postpartum hemorrhage.
*All variables listed in the first column are included in the adjusted modeling.
†Defined using ICD-10 code O13 which included mild preeclampsia.

similar to those for occlusion, stenosis of precerebral or cere- Ninth Revision, Clinical Modification [ICD-9-CM] in the
bral arteries, and TIAs, vascular syndromes or other cerebro- US versus International Statistical Classification of Diseases
vascular diseases not resulting in stroke. Exceptions included and Related Health Problems, Tenth Revision, Canadian ver-
preexisting diabetes mellitus, which was not a risk factor for sion in this study) and differences in the conditions included
stroke in pregnancy but was strongly associated with occlu- in the stroke definition (eg, TIAs were included in the US
sion, stenosis of precerebral and cerebral arteries, TIAs, and study). Population differences in maternal age distributions
vascular syndromes not resulting in stroke. and race (the United States has a much larger proportion of
Rates of stroke observed in our study differed from black women, who are at high risk for stroke) may also have
those reported elsewhere. The rate of stroke reported in the contributed to the reported differences.25 A different US study
United States was considerably higher (22 per 100 000 dur- also reported a pregnancy-related stroke incidence of 34.2 per
ing antepartum hospitalizations, 27 per 100  000 during 100 000 deliveries but acknowledged that the incidence may
childbirth hospitalizations, and 22 per 100 000 during post- have been overestimated.26
partum hospitalizations in 2006–2007) than the 13.4 per The higher risk of stroke we observed in the postpartum
100 000 deliveries observed in our study for the entire preg- period8 and the temporal age-adjusted increase in incidence
nancy and postpartum period. The higher rate reported in have both been reported previously.10,25 Previous studies have
the United States may be explained by differences in cod- attributed the temporal increase to a rise in prevalence of hyper-
ing systems used (International Classification of Diseases, tensive disorders and heart disease in pregnancy.8,14,26 A recent
18  Stroke  January 2019

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

Occlusion, Stenosis of Precerebral and


Cerebral Arteries, TIAs and Vascular Other Cerebrovascular Diseases Not Resulting
Syndromes (n=129) in Stroke (n=238)
Characteristic/Condition Crude OR Adjusted OR* Crude OR Adjusted OR*
Maternal age, y <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)
Preeclampsia 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)
Preexisting 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)
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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)
ICD-10 indicates International Classification of Diseases and Related Health Problems; and PPH, postpartum hemorrhage.
*All variables listed in the first column are included in the adjusted modeling. OR denotes odds ratio and TIA denotes transient
ischemic attacks.
†Defined using ICD-10 code O13 which includes mild preeclampsia.

study reported an increased risk of stroke during pregnancy a 40-fold higher risk of pregnancy-associated stroke
among younger women (compared with their nonpregnant among such women. Whether this association results from
contemporaries) but not among older pregnant women.14,26,27 decreased cardiac output from inadequate hemodynamic
However, some of the temporal increase in stroke may be the adaption to pregnancy, intracardiac shunts, or thrombi for-
product of improved ascertainment. Thus, the very high OR mation, requires further study.31,32 Women with congenital
associated with eclampsia (versus the high OR associated heart diseases are also at increased risk of a number of ad-
with preeclampsia) may be partly attributable to the imaging verse pregnancy outcomes,31,33 including maternal placental
and other testing routinely used for women with eclampsia in syndrome.34
recent years.28 We also observed a higher risk of both hemorrhagic and
In addition to hypertensive and connective tissue disor- ischemic stroke associated with postpartum hemorrhage
ders,7,29,30 congenital heart disease has been reported as a requiring blood transfusion. We speculate that massive trans-
significant risk factor for pregnancy-related stroke.25,31 With fusion for postpartum hemorrhage, which has been linked to
advances in cardiac surgery and improved survival among a higher rate of maternal morbidity,35 may also be responsible
affected children over the past few decades, a growing pop- for increasing stroke risk. Use of assisted reproductive tech-
ulation of women with congenital heart disease is choos- nologies for conception was not associated with an increased
ing to experience pregnancy. In this study, we examined risk of stroke after adjusting for other potential confounding
congenital heart disease as a single entity and observed factors, such as age and hypertensive disorders.
Liu et al   Risk of Stroke in Pregnancy   19

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