Perinatal Stroke in Fetuses, Preterm and Term

Infants
R. Srivastava,* J. Mailo,* and M. Dunbar†,z,x,║

Perinatal stroke is a well-defined heterogenous group of disorders involving a focal disrup-

tion of cerebral blood flow between 20 weeks gestation and 28 days of postnatal life. The
most focused lifetime risk for stroke occurs during the first week after birth. The morbidity
of perinatal stroke is high, as it is the most common cause of hemiparetic cerebral palsy
which results in lifelong disability that becomes more apparent throughout childhood. Peri-
natal strokes can be classified by the timing of diagnosis (acute or retrospective), vessel
involved (arterial or venous), and underlying cause (hemorrhagic or ischemic). Perinatal
stroke has primarily been reported as a disorder of term infants; however, the preterm brain
possesses different vulnerabilities that predispose an infant to stroke injury both in utero
and after birth. Accurate diagnosis of perinatal stroke syndromes has important implications
for investigations, management, and prognosis. The classification of perinatal stroke by age
at presentation (fetal, preterm neonatal, term neonatal, and infancy/childhood) is summa-
rized in this review, and includes detailed descriptions of risk factors, diagnosis, treatment,
outcomes, controversies, and resources for family support.
Semin Pediatr Neurol 43:100988 © 2022 Elsevier Inc. All rights reserved.

Introduction either arterial presumed perinatal ischemic stroke (APPIS),

presumed perinatal hemorrhagic stroke (PPHS), or as peri-

S troke that occurs in the perinatal period is distinct from

stroke that occurs at any other time in life due to its spe-
cific timing, risk factors, and outcomes. Perinatal stroke
occurs between the 20th week of gestation and the first
28 days after delivery.1 It is classified as arterial ischemic,
hemorrhagic, or venous and then further characterized by
timing of presentation. Neonatal arterial ischemic stroke
(NAIS), neonatal hemorrhagic stroke (NHS) and stroke due
to neonatal cerebral sinous venous thrombosis (NCSVT)
present acutely, typically with the symptoms of encephalopa-
thy and seizures. The remaining 3 types present beyond the
first month after delivery, usually with hemiparesis, and are
classified based on the characteristic imaging findings as
ventricular venous infarction (PVI) which is a presumed fetal
stroke (Fig. 1). Perinatal stroke affects approximately 1/1100
births,2 and it is a leading cause of hemiparetic cerebral palsy.
As an injury to the developing brain, perinatal stroke carries
life-long consequences, including motor, learning and behav-
ior challenges, and epilepsy.3 However, the plasticity of the
developing brain can be harnessed in infants, and outcomes
may be surprisingly good compared to similar lesions in
adults. This paper will review the classification of perinatal
stroke by age at presentation (fetal, preterm neonatal, term
neonatal, and infancy/childhood), including risk factors,
diagnosis, treatment, outcomes, current controversies, and
family support.

From the *Division of Pediatric Neurology, Department of Pediatrics, Uni-

versity of Albertam, AB, Canada.
y
Department of Pediatrics, University of Calgary, Calgary, AB, Canada.
z
Department of Community Health Sciences, University of Calgary, AB, Classification of Perinatal
x
Canada. Stroke: Acute Presentations in
Alberta Children’s Hospital Research Institute (ACHRI), Calgary, AB,
Canada. Term Infants (NAIS, NHS, CSVT)
║
Hotchkiss Brain Institute, Calgary, AB, Canada.
Address reprint requests to Dr. Mary Dunbar, Department of Pediatrics,
Perinatal strokes are most often diagnosed after an acute pre-
Alberta Children’s Hospital, 28 Oki Drive NW, Calgary, AB, Canada, sentation in neonates, and it is from this group that much of
T3B 6A8. E-mail: mjdunbar@ucalgary.ca the diagnostic criteria and risk factors have been derived.

https://doi.org/10.1016/j.spen.2022.100988 1
1071-9091/11/© 2022 Elsevier Inc. All rights reserved.
2 R. Srivastava et al.

Figure 1 Perinatal stroke types by vascular classification and timing of presentation.

Coronal illustrations of the vascular classification of stroke, purple = venous blood, red = arterial blood, grey = ischemia, black = cerebrospinal
fluid (CSF)
PVHI, periventricular hemorrhagic infarction; FAIS, fetal arterial ischemic stroke; FHS, fetal hemorrhagic stroke; CSVT, cerebral sinovenous
thrombosis, NAIS, neonatal arterial ischemic stroke; NHS, neonatal hemorrhagic stroke; PVI, periventricular infarction (chronic form of fetal
PVHI); APPIS, arterial presumed perinatal ischemic stroke (chronic form of NAIS/FAIS); PPHS, presumed perinatal hemorrhagic stroke
(chronic form of NHS/FHS) (Color version of figure is available online.)

Neonatal Arterial Ischemic Stroke (NAIS) in
Term Infants
NAIS is an ischemic stroke in one or more arterial territories
presenting in term neonates within the first 28 days after
delivery.1 NAIS is the most common type of perinatal stroke,
representing approximately 40%-80% of all perinatal stroke
cases, 60% of acutely presenting cases, and affecting 1/3000
births.4,5 The artery most often affected is the middle cerebral
artery (MCA), which supplies large areas of the frontal, tem-
poral, parietal lobes, and the basal ganglia. Though the classic
injury in NAIS is from a single large-artery occlusion, multi-
ple and/or bilateral cerebral arteries may be involved. In
70%-90% of NAIS cases, the neonates present with a focal
motor seizure between 12-72 hours after delivery.6-8 The
occurrence of seizures, with or without other signs of distress
or encephalopathy, prompts acute neuroimaging that subse-
quently reveals an arterial pattern of diffusion weighted imag-
ing (DWI) hyperintensity consistent with ischemia (Fig. 2A).
After 1-2 days T1 hypointensity and T2 hyperintensity con-
sistent with cytotoxic edema can be appreciated.9
NAIS is presumed to occur in-utero or around the time of
birth, invoking consideration of pregnancy, obstetrical, and
fetal-specific risk factors. A number of controlled studies
have attempted to correlate such risk factors to stroke
etiology10-15 but definitive mechanisms have not been deter-
mined. There are suggested associations with maternal and
pregnancy factors such as nulliparity, preeclampsia, and ges-
tational diabetes,14-16 intrapartum factors such as maternal
fever and chorioamnionitis14,16-18 and fetal/neonatal factors
such as fetal heart rate abnormalities, intrauterine growth
restriction, male sex12,13,19, and a unique inflammatory
profile.20 The etiology of NAIS may be clear in the presence
of complex congenital cardiac disease21 or bacterial meningi-
tis22, but these are rare. The most consistent risk factors in
NAIS are those associated with a difficult transition from fetal
to postnatal life,6 including prolonged second stage of labor,
emergency caesarean section, meconium staining, resuscita-
tion at birth, and an Apgar score of <7 at 5
minutes.11,13,16,19 There has long been controversy and spec-
ulation about the role of birth trauma as a mechanism for
NAIS,23 however definitive evidence is lacking. The placenta
as a gestational organ is a key player in the transition from
fetal to postnatal life, also providing a thromboembolic
source to the brain that is unique to the perinatal period.
Many placental conditions have been associated with perina-
tal stroke.24,25
Neonatal Hemorrhagic Stroke (NHS) in Term
Infants
NHS is a focal accumulation of blood within the brain paren-
chyma that presents in a term neonate. NHS includes pri-
mary hemorrhage, hemorrhagic transformation of ischemic
injury, and hemorrhagic venous infarct (below). With an
estimated incidence of approximately 1:6300 live births,6
primary NHS is less common than NAIS but may present
similarly with the focal seizures and/or encephalopathy.26
Large intraparenchymal hemorrhages may lead to non-focal
signs such as decreased level of consciousness and increased
intracranial pressure. Screening head ultrasound can detect
larger hemorrhages, though CT or MRI can make a more
Perinatal Stroke in Fetuses, Preterm and Term 3

Figure 2 Neonatal acute stroke in term infants.

Neonatal arterial ischemic stroke (NAIS, A): Axial DWI demonstrating restricted diffusion in the territory of the left middle cerebral artery
(MCA) in a 1 day old who presented with seizures. NAIS is defined by one or more areas of restricted diffusion within an arterial territory
(hyperintense on diffusion weighted imaging (DWI) and hypointense on apparent diffusion coefficient (ADC) in the acute phase (up to 7-
10 days postinjury), with T2 hyperintensity and T1 hypointensity becoming more apparent in the days after injury.
Neonatal Hemorrhagic Stroke (NHS, B): Axial T2 image demonstrating hypointensity in the left frontal lobe and extra-axial space in keeping
with hemorrhage, also hypointense on gradient echo (GRE) and SWI. NHS is defined by an area of GRE blooming within the parenchyma
which may cause displacement of adjacent neural tissue.
Cerebral sino-venous thrombosis (CSVT, C): Axial SWI demonstrating intraventricular and left thalamic hemorrhage consistent with occlu-
sion of the deep venous system (terminal vein). Diagnosis is confirmed by visualizing clot within the venous system on MRV, or probable in
the absence of confirmed clot but characteristic distribution of ischemia (DWI/ADC) or hemorrhage (SWI/GRE) in a venous pattern.

accurate diagnosis by identifying the specific type of hemor-
rhagic injury (Fig. 2B).
NHS is occasionally attributed to a known underlying
cause such as coagulopathy, vascular malformation, or trans-
formation of ischemic infarct.4 The most common presenta-
tion is as an isolated intraparenchymal hemorrhage with no
clear causal factor.27 NHS has been associated with a difficult
transition from fetal to postnatal life through non-specific
factors, but not with obstetrical factors such as induction,
instrumentation, or elective caesarean section.6,27,28 Impor-
tantly, no clear association with the physical trauma has been
found.27,28 The likely mechanism of NHS is a small vascular
anomaly that ruptured at transition to postnatal life and then
obliterated, preventing identification of such vascular anoma-
lies on follow-up imaging.27
the thalamus, often with secondary intraventricular hemor-
rhage (Fig. 2C).6,32 CSVT often presents in systemically ill
neonates and may be discovered incidentally in cases of dif-
fuse intracranial problems including HIE, meningitis, or
non-accidental injury.33 Clinical presentations of CSVT are
similar to NAIS, in addition to non-specific symptoms of irri-
tability, encephalopathy, or signs of increased intracranial
pressure.34
The 2 most common risk factors for CSVT include infec-
tion, particularly bacterial meningitis, and dehydration,
which often presents in a newborn with poor feeding. Other
associations include congenital cardiac disease, cardiac sur-
gery, coagulopathy, and mechanical compression of the
venous sinuses.34 In a term neonate with intraventricular
hemorrhage, deep CSVT is the presumed diagnosis until
proven otherwise. CSVT should always be ruled out as a
potentially treatable underlying cause of NHS.

Neonatal Cerebral Sinovenous Thrombosis

(CSVT) in Term Infants
CSVT is diagnosed when thrombosis is identified in the cere-
Classification of Perinatal
bral venous sinuses or veins within the first 28 days of post- Stroke: Acute Presentations in
natal life. The estimated incidence is 1-12/100, 000 live Preterm Infants (NAIS, NHS,
births with a slight male predominance.29,30 Though not a
stroke itself, CSVT often leads to cerebral venous congestion
PVHI, CSVT)
and edema and eventual venous infarction with or without Stroke also occurs in preterm infants before 37 weeks post-
hemorrhage.31 CSVT in the deep venous system may lead to menstrual age, either in-utero or after birth (Fig. 4). Most
bilateral infarction of deep gray matter structures, particularly studies of perinatal strokes do not include premature
4 R. Srivastava et al.

Figure 3 Neonatal acute stroke in preterm infants.

Neonatal arterial ischemic stroke (NAIS, A): coronal ultrasound over the anterior fontanelle on day one after delivery for an infant born at 31
weeks for baseline assessment demonstrating acute infarction in the left MCA territory. Follow up MRI months later demonstrated chronic
changes confirming MCA infarct. MRI is the preferred method for stroke diagnosis if the neonate’s clinical status allows for the transport to
MRI suite. Echogenicity on cranial ultrasound (cUS) related to ischemic infarct is apparent after several days.
Neonatal Hemorrhagic Stroke (NHS, B): coronal GRE image demonstrating cerebellar hemorrhage and intraventricular hemorrhage in a 36
week neonate with hypotonia.
Periventricular hemorrhagic infarction (PVHI, C): Ci: coronal ultrasound at 30 weeks of an infant born at 26 weeks gestational age demon-
strating intraventricular blood and hyperintensity in the periventricular white matter. Cii: Coronal T1 image at 35 weeks demonstrates evolu-
tion of porencephaly and T1 hyperintense blood products.
Cerebral sino-venous thrombosis (CSVT, D): Di: axial SWI demonstrating IVH secondary to deep venous infarction and secondary hemor-
rhage in a 10 day old infant born at 32 weeks. DII: MRV demonstrates absent flow in all major intracerebral veins, confirmed by doppler (not
shown).

neonates, and the studies describing preterm brain injuries
usually focus on white matter injury or germinal matrix hem-
orrhage-intraventricular hemorrhage (GMH-IVH). An impor-
tant complication of GMH-IVH is periventricular
hemorrhagic infarction (PVHI), a venous stroke.35 A recent
systematic review reported PVHI to be most common type of
stroke in preterm infants, followed by perinatal arterial ische-
mic stroke (PAIS) and CSVT36 (Fig 1).
Neonatal Arterial Ischemic Stroke (NAIS) in
Preterm Infants
Incidence of arterial stroke in preterm infants is rarely
reported, although estimated to be around 7/1000 preterm
births, higher than in term infants.10,37,38 In a single-center
study, almost half of NAIS cases occurred in infants born
before 36 weeks of gestational age.39 Systemic illnesses, pro-
cedures, and indwelling catheters are common in preterm
infants, increasing the risk. Several studies suggest a higher
number of risk factors compared to term infants with stroke
including twin-twin-transfusion syndrome, fetal heart rate
anomalies, and hypoglycemia.10,36,37 Preterm infants are
more likely to be asymptomatic (Fig. 3A) or have subtle
symptoms including ictal apnea, therefore the diagnosis may
be delayed.10 Imaging changes on MRI are as described for
term infants. Many preterm infants may first be evaluated by
cranial ultrasound using the anterior fontanelle, which can
demonstrate a focal increase in echogenicity in an arterial dis-
tribution, however sensitivity is reduced (72%-87% com-
pared to MRI) by the difficulty in fully visualizing the
territory of the MCA.40
An interesting phenomenon is the changing involvement
of MCA branches with increasing gestational age. Lenticulos-
triate infarcts are more common before 32 weeks of gesta-
tional age, while main branch MCA is involved after 32
weeks gestation. This differential pattern of cortical injury
after MCA stroke in preterm compared to term newborns
has been referred to as cortical sparing.41 Complete sparing
was only observed in neonates under 32 weeks of gestation
and appeared to correlate with embryological vascular
changes throughout gestation including regression of lepto-
meningeal arteries.41 Preterm cerebellar ischemic stroke has
been described in a single retrospective study of 32 very pre-
mature infants, all born before 28 weeks of gestation with
birthweight under 1000g.42
Neonatal Hemorrhagic Stroke (NHS) in
Preterm Infants
Cerebellar Hemorrhage (CBH)
Advances in imaging have resulted in improved diagnosis
and better characterization of cerebellar hemorrhage (CBH),
the most recognized focal cerebellar injury occurring in
10%-30% of preterm infants.43 The severity of CBH varies
from one or more punctate lesions to unilateral or bilateral
hemorrhages frequently involving the vermis (Fig. 3B). While
large hemorrhage can be diagnosed by cranial ultrasound,
smaller punctate hemorrhages (<4 mm in diameter) are only
detectable on MRI.35
The timing, risk factors, and pathogenic mechanisms seem
to overlap with GMH-IVH, which may occur in 80% of
infants with CBH.43 Risk factors appear to be the same for
small and large CBH. The presence of highly vascularized, fri-
able germinal matrix in the fourth ventricle and vulnerable
granular layer covering the cerebellum increase bleeding
risk.44 Circulatory risk factors including need for inotropic
support and arterial blood pressure fluctuations have been
associated with more severe CBH.45 The overall risk for CBH
is likely multifactorial and significantly increased by decreas-
ing gestational age.43 Complications of CBH include focal
Perinatal Stroke in Fetuses, Preterm and Term
destruction of cerebellar parenchyma and contralateral cere-
bral growth impairment,46 as well as obstructive
hydrocephalus.47
Periventricular Hemorrhagic Infarction in
Preterm Infants (PVHI)
PVHI is a parenchymal hemorrhage in preterm infants, typi-
cally unilateral, and occurring adjacent to the lateral ventricle
(Fig. 3C). PVHI is caused by obstruction of the medullary
veins, classically as a complication of moderate to large
GMH-IVH leading to impaired drainage and subsequent
venous infarction of the white matter,48 though medullary
CSVT can present identically (Fig. 1). PVHI complicates 3%-
15% of all GMH-IVH.4951 PVHI typically occurs prior to 32
weeks gestational age, before the germinal matrix involutes,
resulting in discrete parenchymal lesions, porencephalic
cysts, and porencephalic ex-vacuo dilation of the ventricle on
the injured side35 (Fig. 3C). Unilateral lesions distinguish
PVHI from cystic periventricular leukomalacia (PVL) which
is usually bilateral and not associated with large IVH.48 In
very preterm neonates, parietal PVHI is more common than
frontal or temporal location.36,52
Common risk factors include multiple intubation attempts
and resuscitation with CPR, although causation remains
unclear.48 The only risk factors found consistently in infants
with PVHI were low gestational age and low birth weight.53
Early onset sepsis has been associated with PVHI infants
born before 28 weeks of gestation.54 The immature hemosta-
sis and coagulation cascade in preterm infants could also
play a role, although the relationship is likely more complex
since prophylactic transfusion of fresh frozen plasma or coag-
ulation factors have not reduce the incidence.48 In neonates
with atypical PVHI presentation (before 6 or after 96 hours
after delivery) Factor V Leiden testing is recommended as
heterozygosity potentially contributing to hemorrhagic injury
has been reported.36,55,56
Cerebral Sinovenous Thrombosis (CSVT) in
Preterm Infants
CSVT should be considered in any preterm infant with late
onset IVH or white matter injury. Symptoms of preterm
CSVT are often absent, resulting in delayed diagnosis com-
pared to term infants10 and missed opportunities for thera-
peutic intervention.53 Presenting symptoms are non-specific,
but seizures and apnea have been described.36 Dehydration
and sepsis have been reported as risk factors.53 True inci-
dence in preterm newborns is unknown since most studies
do not distinguish between preterm and term CSVT. Exten-
sive white matter injury is common in preterm infants with
CSVT, often followed by the development of extensive cysts
(Fig. 3D). The risks and benefits of treatment with anticoagu-
lation in preterm infants at risk for IVH remains unclear,
though a recent small study suggested it is safe,57 requiring
larger studies to assess the mortality and long-term outcome.
5
Classification of Perinatal
Stroke: Diagnosis in the fetus
(FAIS, FHS, PVHI)
Antenatal diagnosis of perinatal stroke remains uncommon
but is increasing due to widespread availability of fetal MRI.
There is no known birth-prevalence for fetal stroke as routine
assessment of fetuses does not occur in many countries after
20 weeks gestation. The preterm brain is uniquely vulnerable
to disruptions of the normal maturation sequences resulting
in malformations such as schizencephaly and porencephaly
as a consequence of stroke.58 Fetal stroke can be subdivided
into arterial ischemic, hemorrhagic, and venous thrombotic,
with the same diagnostic criteria as described above (Fig. 5).
We propose the terms Fetal Arterial Ischemic Stroke (FAIS)
and Fetal Hemorrhagic Stroke (FHS) in addition to the exist-
ing PVHI to most accurately describe when these strokes are
diagnosed in utero (Fig. 1).
Fetal Arterial Ischemic Stroke (FAIS)
Focal ischemia in an arterial distribution is the least com-
monly appreciated stroke type in fetuses, perhaps due to a
proclivity for hemorrhagic transformation, and may only be
suspected due to classic arterial distribution.59 The mecha-
nism by which FAIS occurs is unclear and has been docu-
mented in the setting of twin-to-twin transfusion (Fig. 4A),
where proposed mechanisms include hypotension, anemia,
vasospasm, or thromboembolism.58 Case reports have identi-
fied possible MCA occlusion after cocaine exposure60 and
placental thromboembolism to the fetus in the setting of
maternal illness or inflammation.61 The role of thrombo-
philia is unclear.62
Fetal Hemorrhagic Stroke (FHS)
Parenchymal hemorrhage is frequently identified in fetal
stroke, affecting both the cerebral and cerebellar hemispheres
and often accompanied by hemorrhage in the ventricles (dis-
cussed below) and extra-axial space.62 The discussion here
will be limited to intraparenchymal hemorrhage. In the MER-
IDAN study of 570 fetuses with brain abnormalities, 3.5%
had stroke, 70% of which were hemorrhagic.63 Maternal
conditions possibility associated with hemorrhage include
trauma, substance abuse, diabetes, and medication such as
anticoagulants. Pregnancy related disorders include hyper-
tension, pre-eclampsia/eclampsia, twin-to-twin transfusion
syndrome, and placental dysfunction.54 Fetal factors include
alloimmune thrombocytopenia, infections (TORCH; Toxo-
plasmosis, Other (syphilis, varicella-zoster, parovirus B19,
and zika), Rubella, Cytomegalovirus, Herpes), pyruvate
decarboxylase deficiency, pyruvate dehydrogenase defi-
ciency, and protein-C deficiency62,64(Fig. 4B). COL4A1 and
COL4A2 disorders may present with hemorrhage but often
with a mixed ischemic/hemorrhagic phenotype53 frequently
accompanied by polymicrogyria, schizencephaly, and poren-
cephaly.65 COL4A1/2 gene mutations should be considered
6 R. Srivastava et al.

Figure 4 Fetal acute stroke.

Fetal arterial stroke (FAIS, A): Ai: Coronal T2 fetal MRI demonstrating encephalomalacia in the bilateral MCA and ACA territories in a 30
week fetus with demise of their twin one month prior. Aii: Axial T2 fetal MRI demonstrating encephalomalacia in the ACA and MCA territories.
Fetal hemorrhagic stroke (FHS, B): Bi: coronal T2 MRI demonstrating periventricular fan-shaped hypointense signal consistent with venous
hemorrhage in a 34-week fetus diagnosed postnatally with protein C deficiency. Bii: Sagittal T2 MRI demonstrating focal areas of periventricu-
lar hypointense signal predominantly affecting the white matter
Fetal Periventricular hemorrhagic infarction (PVHI, C): Coronal T2 fetal MRI demonstrating porencephaly of the right lateral ventricle with
areas of hypointensity consistent with blood products in the caudothalamic groove.

in any case of severe, multifocal hemorrhagic or ischemic- the child may present to the pediatrician before any neuroim-
hemorrhagic cerebral lesions, particularly if there is associ- aging has been completed.
ated schizencephaly or porencephaly.

Arterial Presumed Perinatal Ischemic Stroke

Periventricular Hemorrhagic Infarction (PVHI)
in the fetus
Periventricular hemorrhagic infarction (PVHI) after germinal
matrix hemorrhage and intraventricular hemorrhage (GMH-
IVH) of any grade is a well-known consequence of premature
birth (see preterm PVHI above). Intraventricular hemorrhage
due to GMH is the most common type of fetal intracranial
hemorrhage, accounting for up to 67%, with half compli-
cated by PVHI66 (Fig. 4C). The causes of fetal GMH-IVH and
PVHI are not well understood. A recent systematic review of
105 cases of antenatally diagnosed PVHI found 40%
occurred in an uncomplicated pregnancy. The remainder
were complicated by twin gestation (11%), congenital anom-
alies (13%), intrauterine growth restriction (10%), abnormal-
ities of amniotic fluid volume (8%) and a variety of other
conditions including fetal bleeding diathesis, pre-eclampsia,
maternal illness, maternal trauma, and COL4A1 mutation.2
Classification of Perinatal
Stroke: Chronic Presentations
Beyond 28 Days (APPIS, PPHS,
PVI)
Perinatal stroke may present later in infancy or in early child-
hood (Figs. 1 and 5). Birth history is often unremarkable in
children with these remote, presumed perinatal strokes,
commonly presenting with the motor asymmetries or early
hand preference around 4-6 months.67,68 A clinical diagnosis
of cerebral palsy may precede a perinatal stroke diagnosis, as
(APPIS)
Arterial presumed perinatal ischemic stroke (APPIS) is
thought to represent the chronic presentation of NAIS,55 and
affects approximately 1/8000 births.2 These term-born chil-
dren most often present with asymmetry of motor develop-
ment in the first year of life, but may also present with focal
seizures outside the neonatal period or infantile spasms.69
Diagnosis is made when neuroimaging identifies chronic
arterial infarction appearing as cystic encephalomalacia (Fig.
5A), with most lesions affecting the MCA territory including
the corticospinal tracts.70
Presumed Perinatal Hemorrhagic Stroke
(PPHS)
Presumed perinatal hemorrhagic stroke (PPHS) has been
documented in only a few cases.27 It is considered a chronic
presentation of NHS; however, asymptomatic hemorrhage
outside the neonatal period cannot be excluded. PPHS in
term birth appears to be rare and, in the absence of history of
neonatal infection, may be related an underlying genetic syn-
drome associated with hemorrhagic events such as hemo-
philia27 (Fig. 5B). Remote hemorrhage can be seen on
imaging in cases of childhood epilepsy or developmental
delays. Increased recognition may help to identify and under-
stand mechanisms behind PPHS.
Periventricular Venous Infarction (PVI)
Periventricular venous infarction (PVI) affects 1/6000 births2
and is the second-most common form of perinatal stroke
(after NAIS). It is presumed to be the chronic presentation of
Perinatal Stroke in Fetuses, Preterm and Term 7

Figure 5 Chronic presentations of perinatal stroke.

Arterial presumed perinatal ischemic stroke (APPIS, A): axial T1 weighted MRI demonstrating encephalomalacia in the right middle/posterior
MCA territory of a 1 year presenting with hemiparesis, thought to represent the chronic form of NAIS/FAIS.
Presumed perinatal hemorrhagic stroke (PPHS, B): axial GRE weighted MRI demonstrating an area of hemosiderin in the right cingulate gyrus
consistent with remote hemorrhage in a 6 year old with a family history of hereditary hemorrhagic telangiectasia. Thought to represent the
chronic form of FHS/NHS.
Periventricular venous infarction (PVI, C): Ci: Coronal T1 weighted MRI demonstrating left porencephaly and Wallerian degeneration of the
thalamus secondary to presumed GMH-IVH and PVHI. Cii: axial T2 weighted MRI demonstrating hypointense blood products in the caudo-
thalamic groove consistent with prior GMH-IVH in a term-born two-year-old with early hand preference and focal seizures. Thought to repre-
sent the chronic form of fetal PVHI.

fetal PVHI (see above). PVI lesions often disrupt the descend-
ing corticospinal tracts (Fig. 5C), leading to contralateral
hemiparesis that presents with early hand preference or
asymmetric gait. In keeping with previous small case
series,6,67 a large controlled analysis of 141 PVI cases found
no relationship to peripartum factors but possible associa-
tions with primiparity, maternal age, gestational diabetes,
and small for gestational age,71 similar to those found in
antenatally diagnosed PVHI.
Pathways for Investigations and
Management
Investigations
There are no strong evidence-based protocols for the diagno-
sis, investigations, and management of perinatal stroke (Fig.
6); however, examples of possible approaches to acute stroke
management in a term newborn have been previously
published.72,73 Timely neuroimaging with MRI is required to
differentiate NAIS or NHS from HIE, as such conditions may
present similarly but require different treatments.4,74 EEG
background asymmetry is suggestive of stroke.75 Diffusion-
weighted imaging (DWI) sequences are the gold standard for
diagnosing NAIS acutely, and can delineate stroke injury dis-
tribution to help differentiate between focal arterial, venous,
and watershed patterns.1 MR arteriogram/venogram (MRA/
MRV) should be performed acutely, if available, particularly
when thrombosis is suspected.4 Cranial ultrasound or CT
head can be considered in an unstable or unwell neonate,
particularly if NHS is suspected. Placental examination is
encouraged in cases of acute stroke to better clarify risk fac-
tors, though is notoriously difficult to obtain.
While preliminary investigations often include a septic
work-up and echocardiogram, perinatal stroke is more often
idiopathic and occurs in otherwise well term babies. The
extremely low recurrence rate of perinatal stroke argues
against underlying thrombophilia and, in a large controlled
series of children with perinatal stroke, no consistent associa-
tions with known prothrombotic conditions were found
when tested during the childhood.55 This does not exclude
disordered coagulation at the time of stroke, and investiga-
tions may be indicated in cases of unusual systemic thrombo-
sis or strong family history for both NAIS and CSVT.
Hematological investigations may be required for NHS, based
on recognizing specific patterns such as multifocal intracere-
bral hemorrhage. Single gene diseases have rarely been linked
to perinatal stroke, with COL4A1 being the most established
example.76 While these investigations often do not change
management of the child with the perinatal stroke, they may
help to counsel families.
Management
Currently, no evidence exists for hyperacute stroke treat-
ments such as tPA or endovascular thrombectomy in acute
perinatal stroke syndromes (NAIS, NHS, and CSVT),4
though there are trials ongoing in childhood stroke.77,78
While therapeutic hypothermia is the standard of care for
term neonates with moderate-severe HIE,79 there is inade-
quate evidence to support cooling after a stroke given the
uncertain time of onset.80
Antiplatelet or anticoagulation therapy is not routinely
indicated in NAIS, except in rare cases with an increased
recurrence risk such as known severe thrombophilia or com-
plex congenital heart disease.4,81 Expert consensus guidelines
suggest that aspirin or heparin may be considered in
8 R. Srivastava et al.

Figure 6 Presentation, diagnosis, care, investigations, treatment and follow up of perinatal stroke types.
FAIS and FHS not included as the data is too limited, it would be expected that many may be asymptomatic or present similar to APPIS or
PPHS respectively. ACT, anticoagulation therapy; cUS, cranial ultrasound (Color version of figure is available online.)

neonates with increased risk of recurrent stroke,4 but these Treatment Controversies
treatments are generally not considered after a first stroke in
Given the lifelong burden of perinatal stroke, there may be a
a neonate without any known underlying cause.
desire to attempt hyperacute stroke interventions such as
Neuroprotection and supportive care are the foundation of
thrombectomy in this population97; however, this is not sup-
acute perinatal stroke management.
ported by evidence. Hyperacute interventional therapies are
Seizures are the most common presenting symptom and
limited by the inability to know exactly when the stroke
often require treatment in the acute symptomatic period.
occurred. Thromboembolism from placental conditions may
Seizures usually resolve within several days and have a low
be present for days or weeks prior to delivery, with resulting
recurrence rate in infancy, suggesting maintenance anti-sei-
fetal/neonatal large vessel occlusion occurring anytime within
zure medication is not required,82,83 nor it is protective
that period. Additionally, neonates have small arteries that
against the development of epilepsy.84 Acute surgical inter-
may be more susceptible to secondary dissection and/or
vention is rarely needed but may be considered in cases of
hemorrhage with endovascular procedures.
large NHS with progressive hydrocephalus,4 as an important
Although use is variable, the best evidence for anticoagula-
treatment in those who develop refractory focal epilepsy or
tion is in neonatal CSVT where anticoagulation with heparin
epileptic encephalopathy.85 In preterm neonates with PVHI
has been shown to be safe and well-tolerated.4,98 In cases of
and CBH, acute management also includes early detection of
neonatal CSVT where clinical observation is preferred, repeat
complications including development of obstructive hydro-
imaging at 5-7 days is advised to assess clot propagation.4,98
cephalus.
This is particularly important to consider in cases of IVH or
Active neuroprotection therapies do not yet exist, but
thalamic infarcts in a term baby, where CSVT portends high
there is currently a phase 2 clinical trial of Darbepoietin (Dar-
risk to crucial areas of the brain if propagation were to
bepoetin for Ischemic Neonatal Stroke to Augment Regenera-
occur.99
tion; DINOSAUR, NCT03171818) underway to assess
Another potential indication for anticoagulation or anti-
changes in tissue loss when administered acutely in NAIS,
platelet therapy is neonatal bacterial meningitis, associated
with implications for improved motor function and
with stroke through neuroinflammation and hypercoagula-
cognition.86,87 Stem cell therapy for perinatal stroke is also
bility. A randomized placebo-controlled trial of dexametha-
being considered,86,88 with recent encouraging safety data.89
sone in neonatal meningitis has suggested some mortality
With limited options for prevention and protection, neu-
benefit100; however, steroids in meningitis are typically only
rorehabilitation is the focus for improved outcomes. Early
used in cases of haemophilus influenza.101 Though not
physical therapy90 such as constraint induced movement
widely implemented, anti-inflammatory and antithrombotic
therapy (CIMT),91 and non-invasive modulation92 in infants
medications are readily available and likely safe in neonatal
and children with perinatal stroke have also been shown to
meningitis.102,103
be feasible and effective.93-96

Table 1 Outcomes in Perinatal Stroke
Stroke type Motor
NAIS & APPIS -Predominantly motor deficits, most
(PAIS) commonly spastic hemiplegic
cerebral palsy107-109
- severity is variable across individ-
uals due to the developmental
plasticity of the motor system fol-
lowing early unilateral injury94 and
stroke site: large MCA branch
stroke usually result in hemipare-
sis
-early Wallerian degeneration can
help predict the likelihood of motor
impairment110
- Most children with APPIS develop
cerebral palsy, as this is usually
also the presenting sign.
PVHI Preterm neonates with atypical
PVHI (<6h or >96h after delivery)
are more likely to develop CP
- A PVHI severity grading system
was developed to improve predic-
tion of neurodevelopmental out-
come at 2 years of age123, based
on lesion size, presence of the
contralateral parenchymal lesion
and presence of midline shift.
-Terminal veins involvement
increases risk of CP due to
involvement of the corticospinal
tract, while involvement of veins of
caudate or temporal lobe is asso-
ciated with favorable outcome124
-Diffusion-tension imaging
Cognitive, behavior, language
- about 25% of children with unilat-
eral PAIS have cognitive
impairment109,111
- early aEEG and NIRS abnormali-
ties may be associated with early
neurocognitive development after
correction for the size of the
lesion112
- impairments in complex neuropsy-
chological functions may become
apparent once child reaches
school-age.
-Language impairment is rare
regardless of the side of the
lesion109,113
-Children with perinatal stroke and
abnormal language development
or regression, particularly in their
preschool years, should have a
sleep EEG to exclude epileptic
encephalopathy114
-In preterm NAIS, cortical sparing
does not lead to better neurodeve-
lopmental outcome
-Most have favorable cognitive and
neurodevelopmental outcomes70
-In Fetal PVHI developmental delay
were seen in 55% when outcomes
were reported at least one year of
age2
Epilepsy
- Can usually be discharged without
seizure medication
-development of epilepsy is com-
mon, and it has been associated
with poor neurodevelopmental
outcome115,116
-Epilepsy can become refractory in
approximately 25% of PAIS
survivors117,118, many of whom
could potentially be good surgical
candidates85,119, and consider-
ation for epilepsy surgery should
occur early in their course
-Epilepsy is seen in approximately
25%2,53
Perinatal Stroke in Fetuses, Preterm and Term
Other
-Approximately one third of children
with PAIS will have normal
outcome107,108
-Severe disabilities are rare120 and
usually restricted to bilateral
lesions115
-Visual deficits vary based on loca-
tion and extent of the stroke, most
often associated with MCA or pos-
terior cerebral arteries
(PCA)121,122
-Complications associated with fetal
PVHI include hydrocephalus, and
motor impairment in 75%, regard-
less of whether they were born at
term or preterm2
-Fetal outcomes are remarkably
similar to those occurring in deliv-
ered preterm infants with PVHI53
9
 10
Table 1 (Continued )
Stroke type Motor Cognitive, behavior, language Epilepsy Other

including fractional anisotropy

measurement can potentially
assist with motor outcome
prediction.
NHS (includ- - physical impairments are present -Survivors of large CBH are at high -Seizures may be more persistent in Perinatal hemorrhagic stroke is
ing CBH) in only 10-20%. risk of adverse neurodevelopmen- cerebral hemorrhagic compared to associated with higher early mor-
-Large CBH is associated with tal outcome, especially if vermis is seizures in NAIS, may be dis- tality, but recurrence is
hypotonia125 involved43 charged on medication rare26,27,126
-in large CBH, impaired language -Large CBH carry high risk of
development, and long-term cog- mortality45
nitive, learning and behavioral dis-
abilities have been described125
-Infants with small CBH were shown
to have normal intelligence at
5 years of age even in the pres-
ence of mild motor impairment43
CSVT Outcomes in children with CVST vary significantly. The extent of infarction and presence of acute seizures have been associated with poor outcome in neona-
tal CSVT30. In survivors of preterm stroke, the outcome assessment is complicated by the comorbidities of prematurity, but overall, the outcomes seem to be
similar to term infants with CSVT. Thalamic hemorrhage is associated with increased risk of electrographic status epilepticus in sleep (ESES) 127

R. Srivastava et al.
Perinatal Stroke in Fetuses, Preterm and Term
Table 2 Example Pediatric Stroke Organizations With Resources for Family Support
International alliance for pediatric stroke128 https://iapediatricstroke.org/family-resources/
Pediatric stroke warriors129 https://www.pediatricstrokewarriors.org/family-supportresources.html
Canadian heart and stroke foundation130 https://www.heartandstroke.ca/stroke/what-is-stroke/stroke-in-children
Perinatal Stroke and
Neurodevelopment Outcomes
Most perinatal stroke survivors incur lifelong morbidity.
Some important outcome information is summarized in
Table 1 and covered in the subsequent issue of Seminars in
Pediatric Neurology (REF). A key message is that in children
with unilateral perinatal stroke, not complicated by meningi-
tis, the vast majority will walk and talk. If they do not, addi-
tional investigations such as EEG to assess for continuous
spike wave in sleep should be expedited.
Perinatal Stroke Family Support
For most parents, receiving a diagnosis of perinatal stroke in
their child is alarming and unexpected. While the child may
grow up with therapy and rehabilitation supports, parents
are often left with the psychological trauma that may go
unaddressed. The uncertainty of perinatal stroke etiology
leaves many parents with guilt and anger. Misplaced mater-
nal guilt is highly associated with the adverse mental health
outcomes affecting the entire family.104 A family-oriented,
online whiteboard video through the University of Calgary is
freely available to emphasize these issues as a routine part of
patient counselling.105
Education and family support groups, either in-person
and virtually, may help to alleviate misplaced feelings of guilt
and anger. Many pediatric stroke organizations provide
guides for families as well as local and international resources
(Table 2). Parent wellbeing has a positive influence on the
health and psychosocial functioning of children with cerebral
palsy104,106 and is an important consideration in family-cen-
tered perinatal stroke care.
Conclusions
Perinatal stroke is a common injury to the developing brain
in a uniquely vulnerable time. Risk factors are related to spe-
cific developmental windows, such as the presence of the
germinal matrix, as well as to the placenta, and transition for
uterine to extra-uterine life, making the recurrence rate of
perinatal stroke exceptionally low. The outcomes are specific
to the developing brain, including incredible plasticity such
that many children with perinatal stroke may walk and talk
when similarly affected adults would not. The correct classifi-
cation of perinatal stroke has far-reaching implications for the
management, investigations, and prognosis for the patient
and their family.
11
Declaration of interests
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
The authors wish to thank Dr. Adam Kirton for his mentor-
ship, expertise, and image resources. We are grateful to our
patients and their families for providing the inspiration and
motivation for our work.
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