Christine Durand, Paul Sagot, Maurice Giroud, Yannick Bejot and Jean Bernard Gouyon
Véronique Darmency-Stamboul, Corinne Chantegret, Cyril Ferdynus, Nathalie Mejean,
Antenatal Factors Associated With Perinatal Arterial Ischemic Stroke
Print ISSN: 0039-2499. Online ISSN: 1524-4628
Copyright © 2012 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
2012;43:2307-2312; originally published online June 26, 2012;
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Antenatal Factors Associated With Perinatal Arterial
Ve ´ronique Darmency-Stamboul, MD; Corinne Chantegret, MD; Cyril Ferdynus, PhD;
Nathalie Mejean, MD; Christine Durand, MD; Paul Sagot, MD, PhD; Maurice Giroud, MD, PhD;
Yannick Bejot, MD, PhD; Jean Bernard Gouyon, MD, PhD
Background and Purpose—Perinatal arterial ischemic stroke (PAIS) is a common cause of hemiplegic cerebral palsy in
children. The diagnosis of PAIS is based on cerebral imaging. The objective of our study was to determine prenatal risk
factors associated with PAIS.
Methods—A retrospective case–control study was nested in the whole population of Burgundy, France, from January 2000
to December 2007. Case patients were confirmed by review of brain imaging and medical records. Three control
subjects per case were randomly selected from the study population by sex, term, place, and year of birth.
Results—PAIS was confirmed in 32 patients and its incidence was one per 4400 live births. In comparison to control
subjects, clinical conditions significantly associated to cases were gestational diabetes (16.1% versus 4.2%; P?0.04),
fetal heart rate abnormalities (35.5% versus 10.9%; P?0.001), and meconium-stained liquor (40% versus 12%;
P?0.001). At the limit of statistical significance were found maternal smoking before (39.3% versus 22.9%; P?0.08)
and during pregnancy (32.1% versus 16.7%; P?0.07), cord abnormalities (29% versus 14.1%; P?0.06), and cesarean
delivery (28.1% versus 14.6%; P?0.08). In the multivariate analysis, maternal smoking during pregnancy (OR, 3.1;
95% CI, 1.1–8.8; P?0.04) was the only risk factor significantly associated with PAIS.
Conclusions—This study is the first to identify maternal smoking during pregnancy as an independent prenatal risk factor
of PAIS. Additional prospective studies are needed to confirm this result and to investigate the role of maternal smoking
in fetal and neonatal thrombogenesis. (Stroke. 2012;43:2307-2312.)
Key Words: antenatal risk factors ? maternal smoking ? perinatal arterial ischemic stroke
mated between one per 2500 and one per 4000 live births and
could increase because of a better diagnosis allowed by the
emergence of new prenatal and neonatal cerebral imaging
techniques. PAIS is also the main cause of hemiplegic
cerebral palsy in children and it has been recently shown to
induce cognitive impairment.1Several questions persist about
the risk factors of PAIS and its prevention. Recent studies
have suggested that maternal risk factors for PAIS include
primiparity, infertility, chorioamnionitis, prolonged rupture
of membranes, pre-eclampsia, and intrauterine growth retar-
dation.1,2Nevertheless, no risk factors for maternal thrombo-
sis have been investigated as potential risk factors for PAIS.3
A recent study of 248 neonates with PAIS concluded that
definitive causes for most PAIS have not been established,
and case–control studies are required.4
The aim of this study was to identify prenatal risk factors
associated with symptomatic PAIS at a regional level.
erinatal arterial ischemic stroke (PAIS) is the most
frequent type of pediatric stroke. Its incidence is esti-
Materials and Methods
The study included the 141 879 live births with gestational age ?28
weeks gestation recorded from January 1, 2000, to December 31, 2007,
in Burgundy, a French region with approximately 18 500 births annu-
I hospitals. Pediatric care was provided in 14 of these hospitals.
Hospitalizations for PAIS during the 2000 to 2007 period were
recorded in the French hospitalization database (Programme de Me ´di-
calisation des Syste `mes d’Information), which was made available by
the Hospital Information Agency. Each hospital stay was identified by
an Anonymous Discharge Summary, defined by an anonymous record
identified by the code of the International Classification of Diseases,
10thRevision: R568 (seizures), P90 (neonatal seizures), P910 (neonatal
cerebral infarct), G802 (congenital hemiplegia), P524 (neonatal hemor-
rhage intracerebral), and P526 (neonatal cerebellar hemorrhage). Anon-
ymous Discharge Summaries for which the main related or associated
diagnosis did not correspond to these codes were excluded.
The medical files of mothers and children with suspected PAIS in the
Programme de Me ´dicalisation des Syste `mes d’Information database
were reviewed by one of the authors (V.D.-S.) using a standardized
protocol. Gestational data were obtained from medical files of mothers.
Received October 20, 2011; final revision received May 15, 2012; accepted May 22, 2012.
From the Departments of Pediatrics (V.D.-S., C.C.), Radiology (N.M.), Obstetrics (P.S.), and Neurology (M.G., Y.B.), University Hospital, Dijon,
France; the Department of Biostatistics (C.F.) and the Department of Pediatrics (GHSR; J.B.G.), University Hospital, Reunion Island, France (C.F.); the
Dijon Stroke Registry, EA4184, Faculty of Medecine of Dijon, University of Burgundy, Burgundy, France (C.F., P.S., M.G., Y.B., J.B.G.); and the
Department of Radiology, Hospital of Beaune, Beaune, France (C.D.).
Correspondence to Ve ´ronique Darmency-Stamboul, MD, Service de Pe ´diatrie, Ho ˆpital d’Enfants, 10 Bd du Mare ´chal de Lattre de Tassigny, 21029
Dijon ce ´dex, France. E-mail email@example.com
© 2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.orgDOI: 10.1161/STROKEAHA.111.642181
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These files were filled in by obstetricians and midwives. Data from
maternal files could not be modified after delivery.
The diagnosis of perinatal stroke (acute or retrospective, arterial or
venous, ischemic, hemorrhagic) had to be ascertained by neuroim-
aging or by pathology. Therefore, newborns were excluded when
neuroimaging was not performed or the report of the neuroimaging
study did not reveal PAIS (particularly, patients with global ischemic
encephalopathy, subarachnoid hemorrhage, perinatal intraventricular
hemorrhage, and brain malformations).
Each case of PAIS was matched with 3 control subjects for sex,
gestational age, place, and year of birth. The control subjects were
selected using records contained in a regional perinatal database that
includes all live births in Burgundy since 2000.5
Finally, 711 children were selected from the Programme de
Me ´dicalisation des Syste `mes d’Information database and the corre-
sponding obstetric and neonatal files were reviewed. Forty-six of the
711 medical records were identified as potential perinatal strokes or
presumed perinatal strokes. The stroke was considered to be pre-
sumed perinatal if a child had been considered neurologically normal
before 1 month of age but was later diagnosed with a remote arterial
infarction. Then, 2 pediatric neuroradiologists (N.M. and C.D.)
independently reviewed the brain MRI and CT scan reports of the
46 infants. The reviewers disagreed for 3 patients, who were therefore
excluded. For more homogeneity, 2 hemorrhagic strokes without
ischemia and 3 border zone infarcts were also excluded to allow an
analysis strictly limited to PAIS. The Figure shows the selection
process of the 32 cases of PAIS included in the case–control study.
The medical records of cases and control subjects provided the
variables presented in Tables 1, 2, and 3. Maternal body mass index
was calculated from weight and height measurements according to
the formula: weight (kg)/height (cm)2. Intrauterine growth restriction
was defined as birth weight below the third percentile according to
the fetal growth curves of Burgundy.6Gestational diabetes was
defined as a serum glucose level at the beginning of pregnancy of
0.95 g/L and/or a positive O’Sullivan test. Oligohydramnios was
diagnosed by ultrasound examination and defined as a volume of
amniotic liquid ?250 mL from the 20th week of gestation. Seizures
were defined when a physician diagnosed clinical seizures.
Neurological outcome was assessed by each physician referent of
each infant and noted in the medical file. Then these data were
collected by one of the author (V.D.-S.).
Figure. Process of the study.
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The qualitative and quantitative variables were expressed as percent-
ages and means (SDs), respectively. Univariate analysis of quanti-
tative data were performed using one-way analysis of variance or, if
the normality assumption was violated, by the Kruskal-Wallis test.
The ?2test or Fisher exact test was used to compare the distributions
of categorical variables.
The multivariate analysis was performed using a conditional logistic
regression model with a backward selection method. Covariables
included in the initial model were those identified with a probability
value ?0.20 in the univariate analysis and also those considered as risk
factors in other studies.2Interactions were systematically tested and
removed from the final model if they did not reach statistical signifi-
cance. ORs and their 95% CIs were estimated.
All hypotheses were tested at the ? risk of 0.05. Statistical
analyses were performed using SAS 9.2 (SAS Institute Inc).
Characteristics of PAIS
Within the birth cohort of 141 879 neonates, we identified 32
cases of PAIS. The incidence was therefore one case per 4400
live births. The majority of the 32 children with symptomatic
PAIS were delivered at term (87%), 59% were boys, and 75%
were diagnosed in the neonatal period. Median gestational
age was 40 weeks of gestation (range, 36–42 weeks). The 4
preterm infants were born at 36 weeks of gestation.
In the 24 cases with neonatal diagnosis, the median age at
presentation was 36 hours (range, 24–72 hours). The major
symptom in the neonatal period was seizure, which occurred
in 23 cases (96%). Seizures were focal in 20 cases (83%)
and/or generalized in 14 cases (58%). Other symptoms such
as hypotonia (41.9%) or apnea (25.8%) were also observed.
In the 8 cases with delayed diagnosis, the median age at
presentation was 8 months (range, 5–22 months). The major
symptom was hemiplegia, which occurred in 7 cases. Dysto-
nia was observed in 5 cases. Among these 8 cases, 6
presented no other neonatal diseases and did not require
hospitalization at birth. The 2 remaining cases were hospital-
ized during the neonatal period: the first with anal imperfo-
ration and the second with congenital diaphragmatic hernia.
The diagnosis of PAIS was made using transfontanellar
ultrasound (62%) and/or CT scan (69%) and/or MRI (94%;
Table 1). In these 32 patients with PAIS, stroke was limited
to the middle cerebral artery territory in 78% of cases.
Lesions were left-sided in 40.6%, right-sided in 43.7%, and
bilateral in 15.7%. Among the 32 strokes, 5 were initially
ischemic and then hemorrhagic. An electroencephalogram
was performed in 29 cases (91%) and was abnormal in 25
cases (86%) with slow waves or focal spikes.
In this cohort, 3 children died (9%) and 2 were lost to
follow-up (Table 2). Neurological outcome was assessed at a
median age of 19 months (range, 12–96) in the 27 other
children. A single infant was still unable to walk at the last
examination at 4 years. The average age of walking was 13.3
(?2.1) months. Four children developed epilepsy (one with
West syndrome, one with severe refractory focal epilepsy,
and 2 with well-controlled focal epilepsy). Hemiplegia was
found in 12 of 27 infants and dystonia in 37% of cases. Four
of the 19 children diagnosed with PAIS in the neonatal period
had hemiplegia (21%) with no clinical or radiological symp-
toms predictive of this symptom.
A thrombophilia workup was available for 15 patients and
4 of them (27%) had abnormalities: one deficit in antithrom-
bin III, protein C and S; one deficit in protein S and factor V
Leiden; one deficit in proteins C and S; and one deficit in
protein S. The thrombophilia workup was performed in the
neonatal period for 3 newborns and between 1 and 12 months
for 12 newborns. Infants with (n?15) and without (n?17)
thrombophilia workup had similar clinical characteristics
(data not shown).
Factors Associated With PAIS
In the univariate analysis comparing the 32 cases and their 96
control subjects, significant differences were observed for
gestational diabetes (16.1% versus 4.2%; P?0.04), fetal heart
Arterial Ischemic Stroke
Neuroimaging Features of 32 Cases of Perinatal
No. PercentNo. Percent
Side of the damage
Middle cerebral artery (MCA)
Anterior cerebral artery (ACA)
Posterior cerebral artery (PCA)
Three arteries (MCA and ACA
19 Mo of Median Age
Neurological Outcome of the 32 Cases of PAIS at
No. of Cases/
Total No. of Cases
No. of Cases/
Total No. of Cases
PAIS indicates perinatal arterial ischemic stroke.
Darmency-Stamboul et alPerinatal Arterial Ischemic Stroke
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rate abnormalities (35.5% versus 10.9%; P?0.001), and
meconium-stained amniotic fluid (40% versus 12%; P?0.001;
Table 3). Maternal cigarette smoking before pregnancy
(39.3% versus 22.9%; P?0.08) and during pregnancy (32.1%
versus 16.7%; P?0.07) were associated with a nonsignificant
increase in the likelihood of PAIS as were cord abnormalities
(29% versus 14.1%; P?0.06) and cesarean delivery (28.1%
versus 14.6%; P?0.08). Birth weights were similar in PAIS
(3.18?0.56 kilos) and control subjects (3.27?0.5 kilos;
In the final multivariate model, smoking during pregnancy
was significantly associated with an increase in the risk of PAIS
(OR, 3.1; 95% CI, 1.1–8.8; P?0.04). Moreover, 2 other inde-
pendent factors were found associated with a marginally non-
significant increase in the risk of PAIS and were kept in the final
model: diabetes (OR, 3.2; 95% CI, 0.8–13.5; P?0.10) and cord
abnormalities (OR, 2.9; 95% CI, 0.9–9.1; P?0.07).
It is worthy to note that 33 women smoked before
pregnancy; 25 of these women (75.8%) continued smoking
during pregnancy until the end of gestation and 8 (24.2%)
stopped smoking either before getting pregnant or early in
pregnancy when pregnancy was diagnosed.
This population-based study has many similarities with pre-
vious studies for the incidence, clinical symptoms, neurolog-
Table 3. Maternal and Gestational Characteristics in 32 Cases With PAIS Versus 96 Control Subjects
(n?96) OR (95% CI)P Value
Maternal characteristics before pregnancy
Age, y, mean (SD)
Body mass index, kg/m2, mean (SD)
History of infertility
Smoking during pregnancy
Placenta praevia, abruption placenta
Prolonged rupture of membranes
Prolonged second stage of labor
Use of oxytocin
Fetal heart rate abnormalities
Meconium-stained amniotic fluid
Forceps, vacuum extractor
Gestational age (median) WG
. . .
. . .
. . .
. . .
. . .
. . .
. . .
. . .
PAIS indicates perinatal arterial ischemic stroke; HDP, hypertensive disease of pregnancy (eclampsia, pre-eclampsia, hypertension);
IUGR, intrauterine growth restriction; WG, weeks of gestation.
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ical imaging, and outcomes of PAIS. However, this study
identified for the first time the potential deleterious role of
maternal smoking as a promoter of symptomatic PAIS. This
adds a new adverse effect of tobacco smoking in young
women to the already long list.
The incidence of symptomatic PAIS in this study was one
per 4400 live births. The consensus of the National Institute
of Neurological Disorders and Stroke previously concluded
that this incidence ranges between one per 2300 and one per
5000 births.7Our study could have slightly underestimated
the incidence of symptomatic PAIS because home births,
children not diagnosed because neurological symptoms were
mild, and children only cared for in an ambulatory setting
were not recorded in the Programme de Me ´dicalisation des
Syste `mes d’Information database. However, the rarity of
births at home in Burgundy (40 annually) and the organiza-
tion of perinatal and pediatric care in France make these
biases more theoretical than reality.
The preponderance of boys (59%) in this cohort was also
found in other recent studies: 62% in a French study8and
57% in an International study.9Golomb et al9found that boys
with PAIS had a higher birth weight, and they hypothesized
that a traumatic and complicated delivery could be a cause of
PAIS. This assumption was not confirmed in our study
because no infant presented macrosomia at birth.
Epileptic seizures, among which 83% were focal, were the
leading neurological symptom, occurring in 96% of children
with symptomatic PAIS. Other frequent symptoms were
hypotonia (41.9%) and apnea (25.8%). This clinical picture
seems to be characteristic of PAIS according to previous
studies.2,8For instance, Chabrier et al8found seizures in 91%
of PAIS (74% of focal seizures), hypotonia in 46%, and apnea
in 7%. The diagnosis of PAIS in cases of hemiplegia was
delayed in 25% of cases at a median age of 8 months. A
delayed presentation after the age of 2 months was observed
in 40% to 65% of PAIS in previous studies.2,10,11
The radiological presentation of PAIS in this cohort
showed that most strokes (78%) were limited to the middle
cerebral artery territory (with classical late thalamic atro-
phy12). This finding is in keeping with other studies with
corresponding rates of 74% or 89%.2,8
The retrospective nature of this study precluded precise
information about the incidence of thrombophilia in symptom-
atic PAIS. Although the incidence of thrombophilic disorders
(27%) was higher than the 0.02% to 5% observed in the global
population without thrombosis,133 of the abnormal results were
obtained in the first week of life at a time when interpretation of
results was uncertain. It is worthy to note that Simchen et al14
reported thrombophilic abnormalities in 64% of PAIS and the
presence of either a factor V Leiden or antiphospholipid anti-
bodies appeared to be major pathogenetic risk factors of PAIS.
Currently, the need for a thrombophilia workup in PAIS is
controversial as is the age at which such tests should be done.15
Indeed, the standard values differ according to the measurement
method used. Monagle et al16demonstrated the need for labo-
ratories to develop age-related reference ranges specific to their
own analyzer systems.
To our knowledge, this is the first clinical report to identify
maternal smoking during pregnancy as an independent risk
factor for PAIS. Very few studies have provided a reliable
analysis of the impact of maternal smoking during pregnancy
because of insufficient data.2The case–control study con-
ducted by Chabrier et al8in French newborns found 16.0% of
maternal smoking during pregnancy in cases and 14.7% in
control subjects. Maternal smoking may have been underes-
timated in Chabrier et al’s study because the incidence
smoking in pregnant French women was measured at 25% in
a prospective study17and was 22% in our control group.
The mechanisms by which smoking during pregnancy
could increase the risk of stroke in the fetus or the newborn
are unknown and can only be a matter of speculation.
Maternal exposure to drugs and toxins has been investigated
and may cause neonatal arterial ischemic strokes. For in-
stance, Dominguez et al18,19identified the consumption of
cocaine as a risk factor of PAIS probably due to cerebral
artery vasoconstriction in the fetus.
It can be also assumed that maternal smoking may promote
thrombosis and inflammation of the placenta, a condition that
could favor PAIS in the fetus, who presents besides a
physiological state of hypercoagulability.
During pregnancy, the levels of protein S and of protein C are
low, whereas the levels of factors VIII, V, and I are in-
creased.20,21Therefore, pregnancy promotes maternal hyperco-
agulability and contributes to maternal thrombosis. High mater-
nal age, obesity, lupus, infection, inflammatory conditions,
diabetes, and also smoking have been reported as risk factors of
maternal thrombosis.22Cigarette smoking predisposes the indi-
vidual to atherosclerosis and increases the relative risk of
ischemic stroke by approximately 2-fold.23Toxicity is higher
among female smokers, especially when they have several risk
factors such as pregnancy. Cigarette smoking could promote
vasomotor dysfunction (with decreased availability of nitric
oxide), atherogenesis (by free radical-mediated oxidative stress),
and inflammation (with an increase in C-reactive protein and
This study also showed that gestational maternal diabetes
is associated with an increase in the odd of PAIS. Curry et al24
reported 3 mothers with gestational diabetes and 2 with
pre-existing insulin-dependent diabetes among 60 cases of
PAIS. It was claimed that diabetes could increase the risk of
PAIS by increasing the hemoglobin concentration in blood
and the size of the fetus, a condition favoring a difficult birth.
In this cohort, the children born to mothers with diabetes were
no heavier than those born to mothers without diabetes (data
not shown) and this series provided no evidence to support
the traumatic birth hypothesis.
Fetal heart rate abnormalities, meconium-stained amniotic
fluid, and cesarean delivery, all of which are recognized
markers of perinatal asphyxia, were more common in cases
than in control subjects. Complications during labor were also
more frequent in cases than in control subjects in other
studies.1,2,25,26It is worthy of note that the focal character
distinguishes PAIS from hypoxic–ischemic encephalopathy,
although these 2 pathological conditions share many risk
factors and can coexist in the same patient.26
Cord abnormalities (mainly tight umbilical cord) were
associated with a nonsignificant increase in the likelihood of
PAIS in this study. Lee et al2also reported a significant
Darmency-Stamboul et al Perinatal Arterial Ischemic Stroke
by guest on September 19, 2013http://stroke.ahajournals.org/ Downloaded from
difference between PAIS and control subjects for cord abnor- Download full-text
malities (22% versus 6%). According to Cheong et al,27a
tight umbilical cord could contribute to a decrease in cerebral
blood flow that favors arterial thrombosis in the fetus.
Other maternal risk factors of PAIS previously reported
were not found in this study, that is, pre-eclampsia or
infertility, chorioamnionitis, and prolonged rupture of mem-
branes.2,8,11,24,28–33This is not a surprising finding because
risk factors of PAIS, with complex multifactorial relation-
ship, were no systematically found in the literature. Evidence
for true causation of perinatal stroke was lacking for most
cases, even in large multinational studies.4
Finally, this study was subject to a number of limitations
related to a relatively small sample of final cases. However, the
case–control design of the study partially overcame this limit
and allowed the identification of maternal smoking as an
important risk factor of PAIS. The retrospective character of this
study also precluded any identification of radiological factors
associated with development of hemiplegia in patients with
PAIS. For instance, 4 of the 19 children diagnosed with PAIS in
the neonatal period and who developed hemiplegia did not have
diffusion-weighted imaging in the neonatal period.
To our knowledge, this study is the first to identify maternal
smoking during pregnancy as an independent prenatal risk
factor of PAIS. Our results emphasize the major role of
prevention in pregnant women exposed to cigarette smoke.
Additional prospective studies are needed to confirm this
result and investigate the role of maternal smoking in fetal
and neonatal thrombogenesis.
We thank the perinatal staffs of the Clinique de St Marthe, the Clinique
de Cheno ˆve, and public hospitals of Chalon-sur-Sao ˆne, Sens, Nevers,
Auxerre, Macon, Semur-en-Auxois, Beaune, Paray Monial, Le Creusot,
Montceau-les-mines, Decize, Autun, Cosnes/Loire, and Clamecy.
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