Stroke

EDITORIAL

Higher Incidence of Ischemic Stroke in Young

Women Than in Young Men
Mind the Gap
Merel S. Ekker, MD; Frank-Erik de Leeuw , MD, PhD

T
here is more and more evidence of gender dispari- administrative data should be interpreted with care, as
ties in the occurrence, risk factors and causes, and acknowledged by the authors.
outcome of ischemic stroke.1,2 These differences First, selection bias may have played a role as it seems
are illustrated by European population-based stud- plausible that having health care insurance is related to
ies that showed a higher stroke incidence in young the risk of ischemic stroke which may differ from nonin-
women, with age varying from 15 to 44 years, than in sured people, and even gender inequalities might exist in
men.3–7 Although not all studies reported unequivocal terms of health care insurance. Second, misclassification
results, as illustrated by another European and Asian may have occurred as stroke mimics may not always have
study reporting a similar incidence between men and been recoded once a definite diagnosis has been made.
women in the younger age groups (18–35 and 20–40 A frequently occurring stroke mimic includes migraine
years) and an even higher incidence in men over 35 with aura, which is overrepresented among women,
or 40 years.8,9 which may easily be misclassified as ischemic stroke.11
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These methodological explanations may, at least in part,

explain a higher incidence of (presumed) ischemic stroke
See related article, p 3352 in young women. Another common limitation of using
administrative databases is the lack of phenotypic detail,
and this study is no exception with no information on risk
In this issue of Stroke, results of Leppert et al10 may factors and causes of stroke.
shed more light on these discrepancies by investigating However, based on cohort studies, there is some limited
a large number of young cases (n=5198) and by extend- evidence for women-specific risk factors that may provide
ing the results on the occurrence of ischemic stroke in a rationale for the findings by Leppert et al,10 that may also
young adults to a United States population. They found an serve as a starting point for research towards gender-tai-
incidence rate ratio of 0.7 for young (aged 25–44 years) lored management of ischemic stroke. Putaala et al6 found
men compared with young women, based on insurance an increased risk of ischemic stroke during pregnancy
claims data.10 This is an alarming finding of a disease with about 2.5% of all ischemic strokes in young women
that strikes at fertile age, at a time that young women explained by pregnancy. They also found a higher occur-
are preparing for a study, planning families, work or deci- rence of patent foramen ovale and atrial septum defects
sive career moves. This important finding suggests that in women.6 With a patent foramen ovale prevalence only
there are women-specific risk factors and causes that slightly higher in patients with stroke compared with stroke
lead to a higher incidence of ischemic stroke at young free population12,13 the causal relation with first-ever stroke
age in women then in men, although findings based on needs to be further investigated, especially since patent

Key Words: Editorials ◼ incidence ◼ migraine with aura ◼ risk factors ◼ selection bias ◼ young adult

 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Correspondence to: Frank-Erik de Leeuw, MD, PhD, Radboud University Medical Centre, Department of Neurology (935), PO Box 9101, 6500 HB Nijmegen, the
Netherlands. Email frankerik.deleeuw@radboudumc.nl
For Disclosures, see page 3196.
© 2020 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

Stroke. 2020;51:3195–3196. DOI: 10.1161/STROKEAHA.120.032062 November 2020   3195

 Ekker and de Leeuw Stroke Incidence Gap Between Young Men and Women

foramen ovale closure trials have reported a lower risk of 4. Putaala J, Yesilot N, Waje-Andreassen U, Pitkäniemi J, Vassilopoulou S,
Nardi K, Odier C, Hofgart G, Engelter S, Burow A, et al. Demographic and
recurrent ischemic stroke in patients who underwent pat- geographic vascular risk factor differences in European young adults with
ent foramen ovale closure versus those on optimal medical ischemic stroke: the 15 cities young stroke study. Stroke. 2012;43:2624–
Editorial

therapy.14 Other putative risk factors for ischemic stroke that 2630. doi: 10.1161/STROKEAHA.112.662866
5. Tibaek M, Dehlendorff C, Jorgensen HS, Forchhammer HB, Johnsen SP,
are overrepresented among young women include migraine Kammersgaard LP. Increasing incidence of hospitalization for stroke and
(with aura), auto-immune disorders, oral contraception, and transient ischemic attack in young adults: a registry-based study. J Am Heart
hormone replacement therapy.6,15,16 Still, these women-spe- Assoc. 2016;5:e003158. doi: 10.1161/JAHA.115.003158
6. Putaala J, Metso AJ, Metso TM, Konkola N, Kraemer Y, Haapaniemi E,
cific risk factors do not seem to explain the entire gap in Kaste M, Tatlisumak T. Analysis of 1008 consecutive patients aged 15 to 49
incidence of young stroke between men and women. with first-ever ischemic stroke: the Helsinki young stroke registry. Stroke.
The findings of Leppert et al10 are, therefore, encourag- 2009;40:1195–1203. doi: 10.1161/STROKEAHA.108.529883
7. Ekker MS, Verhoeven JI, Vaartjes I, van Nieuwenhuizen KM, Klijn CJM,
ing to search for additional explanations. As the incidence of de Leeuw FE. Stroke incidence in young adults according to age, sub-
ischemic stroke is especially higher in women in the youngest type, sex, and time trends. Neurology. 2019;92:e2444–e2454. doi:
age strata (<35 years), hormonal,1 lifestyle and cultural dif- 10.1212/WNL.0000000000007533
8. Díaz-Guzmán J, Egido JA, Gabriel-Sánchez R, Barberá-Comes G, Fuentes-
ferences are likely candidates for further research. The com- Gimeno B, Fernández-Pérez C; IBERICTUS Study Investigators of the
bination of the unexplained gender gap in ischemic stroke Stroke Project of the Spanish Cerebrovascular Diseases Study Group.
incidence and the large proportion of cryptogenic strokes Stroke and transient ischemic attack incidence rate in Spain: the IBERIC-
TUS study. Cerebrovasc Dis. 2012;34:272–281. doi: 10.1159/000342652
and strokes with uncertain or multiple possible causes6,17 9. Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, Wang L, Jiang Y, Li Y,
in young women calls for further research. Given the fact Wang Y, et al; NESS-China Investigators. Prevalence, incidence, and
that ischemic stroke among very young women (<30 years) mortality of stroke in China: results from a nationwide population-
based survey of 480 687 adults. Circulation. 2017;135:759–771. doi:
occurs rarely, studies should be large, preferably collabora- 10.1161/CIRCULATIONAHA.116.025250
tive with extensive phenotyping available with some of them 10. Leppert MH, Ho MP, Burke J, Madsen TE, Kleindorfer D, Silla S, Daugherty
already ongoing such as the SiPP study (Stroke in Preg- S, Bradly CJ, Poisson SN. Young women had more strokes than young men
in a large, United States claims sample. Stroke. 2020;51:3352–3355. doi:
nancy and Postpartum),18 SECRETO19 study (Searching for 10.1161/STROKEAHA.120.030803
Explanations for Cryptogenic Stroke in the Young: Revealing 11. Vetvik KG, MacGregor EA. Sex differences in the epidemiology, clinical fea-
the Triggers, Causes, and Outcome) and ODYSSEY20 study tures, and pathophysiology of migraine. Lancet Neurol. 2017;16:76–87. doi:
10.1016/S1474-4422(16)30293-9
(Observational Dutch Young Symptomatic Stroke Study). 12. Mazzucco S, Li L, Binney L, Rothwell PM; Oxford Vascular Study Pheno-
To conclude, highlighting the higher incidence of isch- typed Cohort. Prevalence of patent foramen ovale in cryptogenic transient
emic stroke at young age in women, Leppert et al10 take ischaemic attack and non-disabling stroke at older ages: a population-based
study, systematic review, and meta-analysis. Lancet Neurol. 2018;17:609–
a first important step in closing this gender gap. While
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617. doi: 10.1016/S1474-4422(18)30167-4

current treatment strategies are based on results of sec- 13. Koutroulou I, Tsivgoulis G, Tsalikakis D, Karacostas D, Grigoriadis N,
ondary prevention trials in which both women and young Karapanayiotides T. Epidemiology of patent foramen ovale in general popu-
lation and in stroke patients: a narrative review. Front Neurol. 2020;11:281.
adults were underrepresented, a better understanding of doi: 10.3389/fneur.2020.00281
the underlying etiological differences of ischemic stroke 14. Turc G, Calvet D, Guerin P, Sroussi M, Chatellier G, Mas JL; the CLOSE
between men and women will provide stepping stones Investigators. Closure, anticoagulation, or antiplatelet therapy for crypto-
genic stroke with patent foramen ovale: systematic review of randomized
for the development of personalized, sex-specific therapy. trials, sequential meta-analysis, and new insights from the CLOSE Study. J
Am Heart Assoc. 2018;7:e008356. doi: 10.1161/JAHA.117.008356
15. Ekker MS, Boot EM, Singhal AB, Tan KS, Debette S, Tuladhar AM,
ARTICLE INFORMATION de Leeuw FE. Epidemiology, aetiology, and management of isch-
aemic stroke in young adults. Lancet Neurol. 2018;17:790–801. doi:
Affiliation 10.1016/S1474-4422(18)30233-3
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, 16. Maaijwee NA, Rutten-Jacobs LC, Schaapsmeerders P, van Dijk EJ, de Leeuw
Radboud University Medical Centre, Nijmegen, the Netherlands. FE. Ischaemic stroke in young adults: risk factors and long-term conse-
quences. Nat Rev Neurol. 2014;10:315–325. doi: 10.1038/nrneurol.2014.72
Disclosures 17. Nakagawa E, Hoffmann M. Young women’s stroke etiology differs from
Dr de Leeuw is an associate editor of the International Journal of Stroke, and sup- that in young men: an analysis of 511 patients. Neurol Int. 2013;5:e12. doi:
ported by a clinical established investigator grant from the Dutch Heart Founda- 10.4081/ni.2013.e12
tion (2014 T060). The other author reports no conflicts. 18. Lorenzano S, Kremer C, Pavlovic A, Jovanovic DR, Sandset EC, Christensen
H, Bushnell C, Arsovska A, Sprigg N, Roffe C, et al; SiPP Trial Investiga-
tors and ESO-WISE Group. SiPP (Stroke in Pregnancy and Postpartum):
a prospective, observational, international, multicentre study on pathophysi-
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3196   November 2020 Stroke. 2020;51:3195–3196. DOI: 10.1161/STROKEAHA.120.032062