Risk Factors for Intracerebral Hemorrhage

in the General Population

A Systematic Review
M.J. Ariesen, MSc; S.P. Claus, MD; G.J.E. Rinkel, MD, FAHA; A. Algra, MD, FAHA
Background and PurposeAlthough data on some risk factors for intracerebral hemorrhage (ICH) already are beyond
doubt, for other factors, the evidence is less clear. We performed a systematic overview of case-control and cohort
studies on risk factors for ICH.
MethodsWe searched MEDLINE, LILACS, EXTRAMED, and Pascal from 1966 to 2001 to identify studies. Studies
were included if they met predefined methodological criteria. When possible, 22 tables were extracted and combined
with the Mantel-Haenszel method. Summary odds ratios (ORs) were calculated for case-control studies, and summary
relative risks (RRs) were found for cohort studies and for case-control and cohort studies combined.
ResultsFourteen case-control and 11 cohort studies were identified. We could not always combine the results of
case-control and cohort studies. In cohort studies, the crude RR for age (every 10-year increase) was 1.97 (95%
confidence interval [CI], 1.79 to 2.16). In case-control studies, the crude OR for high alcohol intake was 3.36 (95% CI,
2.21 to 5.12) and for hypertension was 3.68 (95% CI, 2.52 to 5.38). Two cohort studies showed an increasing risk of
ICH with increasing degree of hypertension. In cohort and case-control studies combined, the crude RR for sex (male
versus female) was 3.73 (95% CI, 3.28 to 4.25); for current smoking, 1.31 (95% CI, 1.09 to 1.58); and for diabetes, 1.30
(95% CI, 1.02 to 1.67).
ConclusionsRisk factors for ICH appeared to be age, male sex, hypertension, and high alcohol intake. High cholesterol
tends to be associated with a lower risk of ICH. We could not assess whether these risk factors are independent. (Stroke.
2003;34:2060-2066.)
Key Words: intracerebral hemorrhage meta-analysis risk factors

pontaneous intracerebral hemorrhage (ICH) is a serious disease despite progressing medical knowledge.
ICH appears suddenly without warning, unlike ischemic
strokes that are often preceded by a transient ischemic
attack. Outcome is determined by the initial severity of the
bleeding; mortality and morbidity of ICH are high.1 So far,
treatment regimens are limited. Therefore, prevention of
ICH is the most effective approach. Until now, limited
attempts have been made to search systematically for risk
factor profiles in these patients. Studies conducted to
evaluate risk factors for stroke focused mainly on ischemic
stroke or a combination of ICH and subarachnoid hemorrhage rather than on spontaneous ICH as a separate entity.
The studies that focus on spontaneous ICH often address 1
risk factor in particular and do not give an overview of
all important risk factors. Hence, we conducted a metaanalysis to evaluate risk factors for ICH in the general
population.

See Editorial Comment, page 2065

Methods
Literature Search
We searched MEDLINE from 1966 to 2001 and EMBASE from
1974 to 2001 for case-control and cohort studies on risk factors for
ICH. We also searched LILACS, EXTRAMED, and Pascal to
identify studies with non-English publications. The terms we used
were hemorrhage, cerebral; case control studies or cohort
studies; and adult, combined with risk factors and with potential risk factors cholesterol, alcohol, hypertension, oral contraceptives, body height, body weight, and race. OLDMEDLINE was not searched because it contains only studies published
before 1966; at that time, brain imaging was not yet available for the
diagnosis of ICH. Reference lists of all relevant publications were
checked for additional relevant articles. Publications had to be in
English, French, German, or Spanish.

Inclusion Criteria
Studies were included if they were conducted in the general
population. ICH needed to be recognized and analyzed as a separate

Received November 26, 2003; final revision received March 19, 2003; accepted March 28, 2003.
From the Julius Center for Health Sciences and Primary Care, University Medical Center (M.J.A., A.A.), and Department of Neurology, University
Medical Center Utrecht (S.P.C., G.J.E.R., A.A.), Utrecht, the Netherlands.
Correspondence to A. Algra, MD, Department of Neurology and Julius Center for Health Sciences and Primary Care, University Medical Center
Utrecht, D.01.335, PO Box 85500, 3508 GA Utrecht, Netherlands. E-mail A.Algra@neuro.azu.nl
2003 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

DOI: 10.1161/01.STR.0000080678.09344.8D

2060
Downloaded from http://stroke.ahajournals.org/
by guest on April 6, 2015

Ariesen et al
stroke entity and not to be combined with subarachnoid hemorrhage.
For case-control studies, the diagnosis of ICH needed to be confirmed in at least 70% of the cases by the presence of intracerebral
blood on a CT or MRI scan or by autopsy. Case and control subjects
had to be comparable. For longitudinal studies, the diagnosis had to
be based on a review of medical records and not only on International Classification of Diseases codes. The studies had to present
crude data to allow recalculations in our analyses. Studies in
postoperative patients were excluded, as were studies on patients
with ICH as result of a trauma.

Data Extraction
Studies were assessed independently by 2 researchers (M.J.A. and
S.P.C.). We systematically extracted data by means of a predefined
data extraction form. Any discrepancies in the data extracted by the
2 researchers were resolved through discussion.

Data Analysis
Studies were included only once if there were multiple publications,
and there had to be at least 2 studies available on the same potential
risk factor. We used Poisson regression (allowing multivariate
adjustments) to combine the data of the cohort studies. If this was not
possible because of a lack of crude data, we combined the maximal
adjusted estimates (adjusted relative risk [RRadjusted]) with the general
variance-based method.2 For case-control studies, we reconstructed
22 tables and combined them with the Mantel-Haenszel method.
The boxes in the figures describe both the study size (the larger the
box, the larger the study) and the value of the point estimate of the
crude odds ratio (ORcrude). Overall estimates of the case-control and
cohort studies were combined with the general variance-based
method.
If there was statistically significant heterogeneity (P0.10)
among the results of the included studies, we used random-effects
models as opposed to fixed-effect models because they include both
within-study sampling error (variance) and between-study variation
in the assessment of the uncertainty (confidence interval [CI]) of the
results of a meta-analysis.3
We found data on age, sex, alcohol, cholesterol, smoking, diabetes, physical activity, and hypertension. To allow comparison of data
from different studies, we recategorized some factors. Alcohol was
recalculated in grams per day. Because not all studies distinguished
between never and former smokers, we performed separate analyses
for current smokers versus previous and nonsmokers and for ever
smokers versus never smokers. Physical activity was recategorized
as active versus inactive. For hypertension, hypercholesterolemic
and diabetic subjects were dichotomized according to the criteria
used in the separate studies. There was no information available on
duration of hypercholesterolemia, diabetes, and hypertension; diabetes could not be divided into type I or II.

Results
Of the 497 abstracts identified in the different searches with
both the general term risk factors and the separate risk
factors themselves, 118 were considered possibly relevant
after a quick screen of title and abstracts. Of these 118, 62
were considered potentially relevant after careful reading of
the abstract. These 62 articles were reviewed in detail, and
data were extracted. Finally, we included in the analysis 33
articles that met the inclusion criteria. These 33 articles
contained data on 14 different case-control studies and 11
different cohort studies; some studies had multiple publications. Details on the studies are given in the Table.
In the following sections, we report on the results of
case-control studies (Mantel-Haenszel method) and cohort
studies (age and sex, univariate Poisson regression; other
factors, general variance-based method). Because of the use

Risk Factors for ICH in the General Population

2061

of different cutoff points or the lack of crude data, it was not

always possible to combine the data.

Age and Sex

The investigators of 5 cohort studies reported on age and risk
of ICH; the crude RR (RRcrude) was 1.06. After recalculation
into 10-year increase, we found an RRcrude of 1.97 (95% CI,
1.79 to 2.16).4 9 Almost all case-control studies matched their
cases and controls on age; the 2 studies that did not match did
not show crude data, so it was not possible to evaluate this
association in the case-control studies.
The RRcrude for men compared with women was 4.64 (95%
CI, 4.02 to 5.40).4 7,9,10 From the 2 case-control studies
without matching for sex, we recalculated an overall ORcrude
of 1.35 (95% CI, 0.99 to 1.86).1113 Combining the cohort and
case-control studies resulted in an overall RRcrude of 3.73
(95% CI, 3.28 to 4.25).

Alcohol
The investigators of 8 case-control studies reported on alcohol intake and risk of ICH.12,14 20 Because the definitions of
high alcohol intake differed in the studies from 36 g/d to
100 g/d, we arranged the studies according to cutoff point
from low to high. The overall OR should be interpreted at an
approximate mean cutoff of 56 g/d, the weighted mean. The
ORcrude at this cutoff was 3.36 (95% CI, 2.21 to 5.12) (Figure
1). Figure 1 also indicates a possible trend of higher risks of
ICH with higher alcohol intake (ORcrude, 2.12 with the lowest
cutoff and 4.86 with the highest cutoff; value for heterogeneity, P0.014). To further evaluate a possible dose-response
effect, we dichotomized the studies into moderate intake
(56 g/d alcohol) and high intake (56 g/d). We found an
overall ORcrude of 2.05 (95% CI, 1.35 to 3.11) for moderate
intake and 4.11 (95% CI, 2.54 to 6.65) for high intake.
The investigators of 3 cohort studies4,9,21 reported on an
average alcohol intake of 36 g/d (compared with nondrinkers)
and found an overall RRadjusted of 1.12 (95% CI, 0.89 to 1.41).
Hirvonen et al22 compared the risk of ICH in subjects who
drank 1 glasses of wine a week with subjects who drank
less than that and found an RRadjusted of 1.01 (95% CI, 0.50 to
2.03).

Hypercholesterolemia
The investigators of 4 case-control studies reported on hypercholesterolemia and the risk of ICH.16,17,20,23 The overall
ORcrude for high cholesterol was 1.22 (95% CI, 0.56 to 2.67)
(Figure 2).
The investigators of the following cohort studies reported
on hypercholesterolemia and ICH; all studied total serum
cholesterol levels. Leppl et al7 found an RRadjusted of 0.20
(95% CI, 0.10 to 0.42) for 7.0 mmol/L compared with
4.9 mmol/L. Iribarren et al4 found for each 1-SD increase in
serum cholesterol (1.45 mmol/L in men and 1.24 mmol/L in
women) an RRadjusted of 0.84 (95% CI, 0.69 to 1.02) in men
and 0.92 (95% CI, 0.79 to 1.08) in women. Suh et al9 found
for 4.31 mmol/L an RRadjusted of 1.22 (95% CI, 0.88 to 1.69)
compared with 5.69 mmol/L. Yano et al24 found an RRadjusted
of 0.64 (95% CI, 0.46 to 0.91) for 4.80 mmol/L compared
with 4.80 mmol/L.

Downloaded from http://stroke.ahajournals.org/ by guest on April 6, 2015

2062

Stroke

August 2003

Study Details
Current
Ever
HyperHyperPhysical
Age Sex Smoking Smoking Alcohol Diabetes tension cholesterolemia Activity

Year

Cases

Controls

Bell and Ambrose25

1982

103

103

Calandre et al15

1986

73

73

Inzitari et al

1990

116

155

Monforte et al18

1990

24

48

Case-control studies

13

Gill et al11,12

1989, 1991

91

573

Woo et al30

1992

79

79

Fogelholm and Murros

1993

155

155

Giroud et al16

1995

130

130

Juvela et al27

1995

156

332

Kubota et al17

1997

158

158

Caicoya et al14

1999

66

477

Zodpey et al20

2000

166

166

Saloheimo et al28

2001

98

206

19982001

331

331

26

Thrift et al19,23,29,36,37,38
Cohort studies

Cohort

28

107 137

1993

53

117 006

1996

386

61 756

Qureshi et al8

1997

33

3852

Nakayama et al10

1997

27

2302

Leppala et al

1999

112

28 519

Hirvonen et al22

2000

95

26 593

Hu et al32

2000

42

72 488

Iso et al5,6

19992001

74

85 764

Suh et al

2001

372

114 793

Yano et al24, Abbott et al33

1989/1994

Klatsky et al21

1989

Kawachi et al

Iribarren et al4

31

77/92 7850/7530

P indicates population based; H, hospital based.

, Information available.
, Information not available.
*Study was matched for this characteristic.
Study was conducted in men or women alone.
These studies evaluated recent heavy drinking and risk of ICH and were therefore not included in the analyses of alcohol intake and risk of ICH.

Smoking
In some case-control studies, the investigators did not specify
in detail whether smokers were current smokers, former
smokers, or both. We took these studies into account in the
analyses of both current and ever smoking.
The investigators of 10 case-control studies25 reported on
current smoking and ICH (Figure 3).11,15,17,18,26 30 The overall
ORcrude for current smoking was 1.25 (95% CI, 0.94 to 1.66).
The investigators of 3 cohort studies reported on current
smoking for an overall RRadjusted of 1.36 (95% CI, 1.07 to
1.73).4,9,31 Combining the case-control and cohort studies
resulted in an overall RR of 1.31 (95% CI, 1.09 to 1.58).
The investigators of 9 case-control studies reported on ever
smoking and ICH. The overall ORcrude was 1.01 (95% CI, 0.71
to 1.44).15,17,18,20,2529 The investigators of 3 cohort studies
reported on ever smoking for an overall RRadjusted of 1.07 (95%

CI, 0.88 to 1.31).4,9,31 Combining the case-control and cohort

studies resulted in an overall RR of 1.06 (95% CI, 0.89 to
1.26).

Diabetes Mellitus
The investigators of 8 case-control studies reported on diabetes
mellitus.13,16,17,20,23,26,28,30 The overall ORcrude was 1.27 (95% CI,
0.98 to 1.65) (Figure 4). Leppl et al7 reported on diabetes and
risk of ICH; the RRadjusted was 1.64 (95% CI, 0.77 to 3.51).
Combining the case-control studies and the finding of Leppl
resulted in an overall RR of 1.30 (95% CI, 1.02 to 1.67).

Physical Activity
The investigators of 2 cohort studies reported on physical
activity and ICH; overall RRcrude was 0.76 (95% CI, 0.48 to
1.20) (active versus inactive).32,33

Downloaded from http://stroke.ahajournals.org/ by guest on April 6, 2015

Ariesen et al

Figure 1. Alcohol. Note that studies were sorted by increasing

alcohol intake level. Value for heterogeneity was P0.014. Alcohol cutoff used per study was as follows: (a) 36, (b) 43, (c)
57, (d) 60, (e) 70, (f) 80, (g) 80, and (h) 100 g/d.

Risk Factors for ICH in the General Population

2063

Figure 3. Current smoking. Value for heterogeneity was

P0.006. Definition of current smoking per study was as follows: (a, e through j) current smoking versus ex-smoking and
nonsmoking, (b, c) smoking yes versus no, and (d) current
smoking yes versus no.

Hypertension
The investigators of 11 case-control studies reported on
hypertension and risk of ICH.13,1518,20,23,26 28,30 All studies
showed a positive association between hypertension and ICH.
The overall ORcrude was 3.68 (95% CI, 2.52 to 5.38) (Figure 5).
Three cohort studies evaluated this association. Suh et al9
found an RRadjusted of 2.2 (95% CI, 1.5 to 3.2) for high-normal,
5.3 (95% CI, 3.9 to 7.4) for stage 1 hypertension, 10.4 (95%
CI, 7.1 to 15.3) for stage 2 hypertension, and 33 (95% CI, 23
to 49) for stage 3 hypertension. Iribarren et al4 found for each
1-SD increase (18 mm Hg in men; 19 mm Hg in women) an
RRadjusted of 1.14 (95% CI, 0.96 to 1.36) in men and 1.17 (95%
CI, 0.98 to 1.39) in women. Leppl et al7 found an RRadjusted
of 2.20 (95% CI, 1.34 to 3.61) for 140 to 159 mm Hg and 3.78
(95% CI, 2.28 to 6.25) for 160 mm Hg compared with
139 mm Hg.

Discussion
In our systematic review, we identified 4 risk factors for ICH:
male sex, age, hypertension, and alcohol intake. Suh et al9
and Leppl et al7 found an increasing risk of ICH with

Figure 2. Hypercholesterolemia. Value for heterogeneity was

P0.001. Definition of hypercholesterolemia per study was as
follows: (a) history of hyperlipidemia (5.18 mmol/L), (b) history
of hyperlipidemia, (c) serum total cholesterol 5.72 mmol/L, and
(d) history of high cholesterol.

increasing blood pressure. Current smoking and diabetes

mellitus are weak risk factors, if at all. Data are inconclusive
for physical activity. Ever smoking was no risk factor. Data
for hypercholesterolemia were conflicting. Thrift et al34 found
a negative association; Giroud et al16 found no association;
and Zodpey et al20 and Kubota et al17 found a positive
association for hypercholesterolemia. The difference might
be explained by the use of different definitions of hypercholesterolemia. The cohort studies, however, show a clear
association: a decreasing risk with an increasing serum
cholesterol level. Therefore, we interpret that the cumulative
data on cholesterol may be summarized as follows: There
tends to be a lower risk of ICH with higher cholesterol levels.
One of the strengths of this meta-analysis is that the
literature was collected systematically from several different
databases. Publication bias is less of a problem in our
meta-analysis than in meta-analyses of randomized clinical
trials because it is just as interesting whether there is no
association between a potential risk factor and the risk of ICH

Figure 4. Diabetes mellitus. Value for heterogeneity was

P0.368. Definition of diabetes mellitus per study was as follows: (a) previous diagnosis or previous or intercurrent treatment, (b, c, d, g) past medical history, (e) glycemia 1.20 g/L,
(f) previous clinical diagnosis, (h) hospital records, and (i) diagnosis by medical practitioner.

Downloaded from http://stroke.ahajournals.org/ by guest on April 6, 2015

2064

Stroke

August 2003

Figure 5. Hypertension. Value for heterogeneity was P0.000.

Definition of hypertension per study was as follows: (a) history
of hypertension, both treated and untreated; (b) history of hypertension, 160 mm Hg systolic or 95 mm Hg diastolic; (c) previous diagnosis or intercurrent treatment; (d) past medical history; (e) medical history of hypertension and use of
antihypertensive medication; (f) 160 mm Hg systolic or
95 mm Hg diastolic; (g) 160/100 mm Hg; (h) previous clinical
diagnosis; (i) 140/90 mm Hg; (j) 160/95 mm Hg or use of
antihypertensive medication; and (k) diagnosis by medical
practitioner.

as when there is an association. With regard to the statistical

analyses, we attempted to integrate as much of the available
information as possible.
Because this study is a meta-analysis, we were able to
study only risk factors on which much research was already
done; therefore, the risk factors that we have identified
probably do not represent all risk factors. Because we
included only articles in English, German, French, or Spanish, whites are probably over represented in our results, so our
results may be invalid for people of other races.
Another limitation of this meta-analysis is that we were not
able to study the risk factors identified in this study simultaneously. Poisson regression that would have allowed adjustment for other potentially confounding ICH risk factors
appeared not feasible because often crude data were not
reported. Such an analysis could, for example, have shed
more light on the different propensity for ICH between men
and women: Is it truly a sex difference, or do other ICH risk
factors such as a high alcohol intake contribute to this
difference. This problem of confounding could also be solved
in a project in which raw nondichotomized individual patient
data are brought together for a pooled analysis. Within the
constraints of the present study, this was not feasible.
Compared with a previous review of the epidemiology of
ICH,35 ours is more extensive because it includes studies
published until 2001 and uses an explicit and very elaborate
search strategy. Additionally, our data analysis strategies
were more extensive because we combined case-control
studies separately, cohort studies separately, and these 2 types
of studies together.
With regard to alcohol and ICH, a stronger association was
found in the case-control studies than in the cohort studies.
An explanation for the difference in strength of the association might be that the alcohol intake in the cohort studies was
lower (36 g/d) than in the case-control studies (average,

56 g/d). We were unable to study binge drinking as a risk

factor of ICH because of limited studies.
When we compare the risk factors identified for ICH with
those for ischemic stroke, we see that current smoking and
diabetes mellitus are risk factors for ischemic stroke but not
obvious risk factors for ICH. Furthermore, hypercholesterolemia seems to lower the risk of ICH but clearly increases the
risk of ischemic stroke.36 These differences in risk factors
suggest different underlying mechanisms. If smoking, diabetes mellitus, and hypercholesterolemia are not risk factors for
ICH, apparently atherosclerosis is not the prevailing pathophysiological mechanism in ICH. Because hypertension is a
risk factor for ICH, increased fragility seems a plausible
explanation. This fragility may be caused by microaneurysms, amyloid, vascular malformations, or other as-yetunknown factors.
Because this study shows that age is a risk factor for ICH,
one might expect an increasing incidence of ICH as our
society ages. Therefore, prevention of ICH is highly important. More attention should be given to modifiable risk factors
such as alcohol intake and hypertension to reduce the risk of
ICH in the elderly. In further research, it might be interesting
to pool individual patient data to evaluate whether these risk
factors are independent.

Acknowledgments
This research was supported by the Health Research and Development Counsel of the Netherlands (ZONMw, project number 904
61190). Dr Rinkel is a clinical established investigator of the
Netherlands Heart Foundation (grant D98.014). We wish to thank
Chris Zielinski from EXTRAMED for his help in searching the
EXTRAMED database.

References
1. Gebel JM, Broderick JP. Intracerebral hemorrhage. Neurol Clin. 2000;
18:419 438.
2. Petitti DB. Meta-Analysis, Decision Analysis, and Cost-Effectiveness
Analysis. New York, NY: Oxford University Press; 1994.
3. Scholten RJ, Assendelft WJ, Kostense PJ, Bouter LM. [The practice of
systematic reviews, V: heterogeneity between studies and subgroup analysis]. Ned Tijdschr Geneeskd. 1999;143:843 848.
4. Iribarren C, Jacobs DR, Sadler M, Claxton AJ, Sidney S. Low total serum
cholesterol and intracerebral hemorrhagic stroke: is the association
confined to elderly men? The Kaiser Permanente Medical Care Program.
Stroke. 1996;27:19931998.
5. Iso H, Stampfer MJ, Manson JE, Rexrode K, Hennekens CH, Colditz GA,
Speizer FE, Willett WC. Prospective study of calcium, potassium, and
magnesium intake and risk of stroke in women. Stroke. 1999;30:
17721779.
6. Iso H, Stampfer MJ, Manson JE, Rexrode K, Hu F, Hennekens CH,
Colditz GA, Speizer FE, Willett WC. Prospective study of fat and protein
intake and risk of intraparenchymal hemorrhage in women. Circulation.
2001;103:856 863.
7. Leppl JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP. Different risk factors for different stroke subtypes: association of blood
pressure, cholesterol, and antioxidants. Stroke. 1999;30:25352540.
8. Qureshi AI, Giles WH, Croft JB, Stern BJ. Number of pregnancies and
risk for stroke and stroke subtypes. Arch Neurol. 1997;54:203206.
9. Suh I, Jee SH, Kim HC, Nam CM, Kim IS, Appel LJ. Low serum
cholesterol and haemorrhagic stroke in men: Korea Medical Insurance
Corporation Study. Lancet. 2001;357:922925.
10. Nakayama T, Date C, Yokoyama T, Yoshiike N, Yamaguchi M, Tanaka
H. A 15.5-year follow-up study of stroke in a Japanese provincial city: the
Shibata Study. Stroke. 1997;28:4552.
11. Gill JS, Shipley MJ, Tsementzis SA, Hornby R, Gill SK, Hitchcock ER,
Beevers DG. Cigarette smoking: a risk factor for hemorrhagic and nonhemorrhagic stroke. Arch Intern Med. 1989;149:20532057.

Downloaded from http://stroke.ahajournals.org/ by guest on April 6, 2015

Ariesen et al
12. Gill JS, Shipley MJ, Tsementzis SA, Hornby RS, Gill SK, Hitchcock
ER, Beevers DG. Alcohol consumption: a risk factor for hemorrhagic
and non-hemorrhagic stroke. Am J Med. 1991;90:489 497.
13. Inzitari D, Giordano GP, Ancona AL, Pracucci G, Mascalchi M,
Amaducci L. Leukoariosis, intracerebral hemorrhage, and arterial hypertension. Stroke. 1990;21:1419 1423.
14. Caicoya M, Rodriguez T, Corrales C, Cuello R, Lasheras C. Alcohol and
stroke: a community case-control study in Asturias, Spain. J Clin Epidemiol. 1999;52:677 684.
15. Calandre L, Arnal C, Ortega JF, Bermejo F, Felgeroso B, del Ser T,
Vallejo A. Risk factors for spontaneous cerebral hematomas: casecontrol study. Stroke. 1986;17:1126 1128.
16. Giroud M, Creisson E, Fayolle H, Andre N, Becker F, Martin D, Dumas R.
Risk factors for primary cerebral hemorrhage: a population-based study: the
Stroke Registry of Dijon. Neuroepidemiology. 1995;14:2026.
17. Kubota M, Yamaura A, Ono J, Itani T, Tachi N, Ueda K, Nagata I,
Sugimoto S. Is family history an independent risk factor for stroke?
J Neurol Neurosurg Psychiatry. 1997;62:66 70.
18. Monforte R, Estruch R, Graus F, Nicolas JM, Urbano-Marquez A. High
ethanol consumption as risk factor for intracerebral hemorrhage in
young and middle-aged people. Stroke. 1990;21:1529 1532.
19. Thrift AG, Donnan GA, McNeil JJ. Heavy drinking, but not moderate or
intermediate drinking, increases the risk of intracerebral hemorrhage.
Epidemiology. 1999;10:307312.
20. Zodpey SP, Tiwari RR, Kulkarni HR. Risk factors for hemorrhagic
stroke: a case-control study. Public Health. 2000;114:177182.
21. Klatsky AL, Armstrong MA, Friedman GD. Alcohol use and subsequent
cerebrovascular disease hospitalizations. Stroke. 1989;20:741746.
22. Hirvonen T, Virtamo J, Korhonen P, Albanes D, Pietinen P. Intake of
flavonoids, carotenoids, vitamins C and E, and risk of stroke in male
smokers. Stroke. 2000;31:23012306.
23. Thrift AG, McNeil JJ, Forbes A, Donnan GA. Risk factors for cerebral
hemorrhage in the era of well-controlled hypertension: Melbourne Risk
Factor Study (MERFS) Group. Stroke. 1996;27:2020 2025.
24. Yano K, Reed DM, MacLean CJ. Serum cholesterol and hemorrhagic
stroke in the Honolulu Heart Program. Stroke. 1989;20:1460 1465.
25. Bell BA, Ambrose J. Smoking and the risk of a stroke. Acta Neurochir
(Wien). 1982;64:17.

Risk Factors for ICH in the General Population

2065

26. Fogelholm R, Murros K. Cigarette smoking and risk of primary intracerebral haemorrhage: a population-based case-control study. Acta
Neurol Scand. 1993;87:367370.
27. Juvela S, Hillbom M, Palomaki H. Risk factors for spontaneous intracerebral hemorrhage. Stroke. 1995;26:1558 1564.
28. Saloheimo P, Juvela S, Hillbom M. Use of aspirin, epistaxis, and
untreated hypertension as risk factors for primary intracerebral hemorrhage in middle-aged and elderly people. Stroke. 2001;32:399 404.
29. Thrift AG, McNeil JJ, Donnan GA. The risk of intracerebral hemorrhage
with smoking: the Melbourne Risk Factor Study Group. Cerebrovasc
Dis. 1999;9:34 39.
30. Woo J, Lau E, Kay R. Elderly subjects aged 70 years and above have
different risk factors for ischemic and hemorrhagic strokes compared to
younger subjects. J Am Geriatr Soc. 1992;40:124 129.
31. Kawachi I, Colditz GA, Stampfer MJ, Willett WC, Manson JE, Rosner
B, Speizer FE, Hennekens CH. Smoking cessation and decreased risk of
stroke in women. JAMA. 1993;269:232236.
32. Hu FB, Stampfer MJ, Colditz GA, Ascherio A, Rexrode KM, Willett
WC, Manson JE. Physical activity and risk of stroke in women. JAMA.
2000;283:29612967.
33. Abbott RD, Rodriguez BL, Burchfiel CM, Curb JD. Physical activity in
older middle-aged men and reduced risk of stroke: the Honolulu Heart
Program. Am J Epidemiol. 1994;139:881 893.
34. Thrift AG, McNeil JJ, Forbes A, Donnan GA. Three important subgroups of hypertensive persons at greater risk of intracerebral hemorrhage: Melbourne Risk Factor Study Group. Hypertension. 1998;31:
12231229.
35. Thrift AG, Donnan GA, McNeil JJ. Epidemiology of intracerebral hemorrhage. Epidemiol Rev. 1995;17:361381.
36. Goldstein LB, Adams R, Becker K, Furberg CD, Gorelick PB,
Hademenos G, Hill M, Howard G, Howard VJ, Jacobs B, et al. Primary
prevention of ischemic stroke: a statement for healthcare professionals
from the Stroke Council of the Am Heart Association. Stroke. 2001;32:
280 299.
37. Thrift AG, McNeil JJ, Forbes A, Donnan GA. Risk of primary intracerebral haemorrhage associated with aspirin and non-steroidal antiinflammatory drugs: case-control study. BMJ. 1999;318:759 764.
38. Thrift AG, Dewey HM, Macdonell RA, McNeil JJ, Donnan GA.
Incidence of the major stroke subtypes: initial findings from the North
East Melbourne Stroke Incidence Study (NEMESIS). Stroke.
2001;32:17321738.

Editorial Comment
Minor Risk Factors for Intracerebral Hemorrhage: The Jury Is Still Out
Prevention of intracerebral hemorrhage (ICH) is still the most
effective method for reducing the impact of this devastating
disease. To facilitate better development of prevention programs, we need precise estimates of risk and elucidation of
minor risk factors.
In the past, there have been some major difficulties
surrounding the identification of risk factors for ICH. The
first is that ICH is a relatively uncommon disease, making up
between 10% and 15% of all strokes in Western countries.1
Consequently, to ensure adequate cases of ICH, cohort
studies must be very large, and patients must be accrued over
many years. Alternatively, case-control methodology could
be used and, if carefully conducted to reduce bias, may
provide accurate results. Moreover, it is only since the CT era
that ICH could be studied as a separate entity with diagnostic
accuracy. Inclusion of cases with other types of stroke that
have differing etiologies would result in a weakening of any
associations identified.

To address some of the limitations of small data sets and

diversity of risk factors studied, Ariesen and colleagues2 have
conducted a meta-analysis of previous work in this area. This
is a timely analysis, given the number of publications in
recent years. Apart from age and sex, they have confirmed
that the most important risk factor for ICH is hypertension.35
Despite different definitions of hypertension in these studies,
the relationship between hypertension and ICH is clear. They
have also confirmed an association between heavy alcohol
consumption and ICH.4,6,7 Further support for alcohol consumption as a risk factor is provided by their summary
showing increasing odds ratios with increasing level of
alcohol consumption. The summary odds ratios are substantial, with an approximate doubling in the odds ratio of ICH
with each decade of life, whereas among men, heavy drinkers, and hypertensive people, the risk of ICH approximately
triples.
Although the associations between these 4 factors and ICH
are impressive, the summary odds ratios for the case-control

Downloaded from http://stroke.ahajournals.org/ by guest on April 6, 2015

2066

Stroke

August 2003

studies are subject to some imprecision for 2 main reasons.

First, as acknowledged by the authors, only univariate odds
ratios were summarized. The use of multivariate analyses
would have enabled the isolation of the exposure (eg, hypertension) from the effects of any imbalance in the distribution
of potentially confounding factors between cases and controls
and would show whether the association is truly independent.
Without this adjustment, the odds ratio can be altered in either
direction; ie, it can be overestimated or underestimated.8
Second, some of the studies included in the meta-analyses
were based on matched samples. Matching eliminates substantial imbalance and therefore controls for confounding on
the matched variables. Because the matching was not retained
in the analyses of these matched studies, there is a tendency
for the odds ratio to be biased toward unity.8 Alternative
analytic techniques incorporating the use of odds ratios and
standard errors (or confidence intervals)9 would enable the
production of summary odds ratios based on both adjusted
and, when appropriate, matched analyses, as well as enabling
inclusion of studies without published raw data.3,6
Because of the likely imprecision in the odds ratios,
particular caution must be taken in interpreting the results of
the lesser potential risk factors, ie, smoking, hypercholesterolemia, and diabetes. Because the reported odds ratios are
small (in the order of 1.2 to 1.3) and because there has been
no adjustment for potentially confounding factors, these
findings may be spurious.
In support of their findings, Ariesen et al also summarized
relative risks from cohort studies (some were adjusted and
others were not). These results were both in agreement with
those of the case-control summary odds ratios (hypertension,
smoking, and diabetes) and in disagreement with them
(alcohol consumption and hypercholesterolemia). The disparate findings for alcohol consumption can be explained by the
fact that alcohol consumption was not subcategorized according to level of consumption for the cohort studies. The
findings for hypercholesterolemia were not in agreement
between the cohort and case-control studies, making interpretation difficult.

In summary, Ariesen and colleagues have made an

important contribution to our understanding of risk factors
for ICH. Hypertension and heavy alcohol consumption are
important and preventable risk factors for ICH. Treatment
and management of hypertension remain the most effective
prevention strategy for ICH, given both the relatively high
prevalence of hypertension within the community and the
strong association between hypertension and ICH. In
regard to the other potential risk factors (hypercholesterolemia, smoking, and diabetes), the most important message is that if these factors increase the risk of ICH, this
risk is modest. At present, there still remains insufficient
evidence that these factors are important contributors to
the development of ICH.
Amanda G. Thrift, BSc(Hons), PhD, Guest Editor
Epidemiology Division
National Stroke Research Institute
West Heidelberg, Victoria, Australia

References
1. Sudlow CLM, Warlow CP. Comparable studies of the incidence of stroke
and its pathological types: results from an international collaboration.
Stroke. 1997;28:491 499.
2. Ariesen MJ, Claus SP, Rinkel GJE, Algra A. Risk factors for intracerebral
hemorrhage in the general population: a systematic review. Stroke. 2003;
34:2060 2066.
3. Brott T, Thalinger K, Hertzberg V. Hypertension as a risk factor for
spontaneous intracerebral hemorrhage. Stroke. 1986;17:1078 1083.
4. Juvela S, Hillbom M, Palomki H. Risk factors for spontaneous intracerebral hemorrhage. Stroke. 1995;26:1558 1564.
5. Thrift AG, McNeil JJ, Forbes A, Donnan GA. Three important subgroups
of hypertensive persons at greater risk of intracerebral hemorrhage.
Hypertension. 1998;31:12231229.
6. Jamrozik K, Broadhurst RJ, Anderson CS, Stewart-Wynne EG. The role
of lifestyle factors in the etiology of stroke: a population-based casecontrol study in Perth, Western Australia. Stroke. 1994;25:5159.
7. Thrift AG, McNeil JJ, Donnan G. Heavy drinking, but not moderate or
intermediate drinking, increases the risk of intracerebral hemorrhage.
Epidemiology. 1999;10:307312.
8. Breslow NE, Day NE. General considerations for the analysis of casecontrol studies. In: Davis W, ed. Statistical Methods in Cancer Research:
The Analysis of Case-Control Studies. Lyon, France: IARC Scientific
Publications; 1980:84 119.
9. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987;9:130.

Downloaded from http://stroke.ahajournals.org/ by guest on April 6, 2015

Risk Factors for Intracerebral Hemorrhage in the General Population: A Systematic

Review
M.J. Ariesen, S.P. Claus, G.J.E. Rinkel and A. Algra
Stroke. 2003;34:2060-2065; originally published online July 3, 2003;
doi: 10.1161/01.STR.0000080678.09344.8D
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2003 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/34/8/2060

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Stroke is online at:
http://stroke.ahajournals.org//subscriptions/

Downloaded from http://stroke.ahajournals.org/ by guest on April 6, 2015