Perinatal ischemic stroke – a review of current knowledge

Summary

Perinatal stroke is a significant brain injury occurring between the 20^th week of gestation and the 28^th day of life. The most common form is arterial ischemic stroke, with a significantly higher incidence in premature newborns. The etiology of perinatal arterial ischemic stroke (PAIS) in the neonatal period is multifactorial. Immaturity of the brain, immaturity of the coagulation system and the presence of risk factors increase the incidence. Thromboembolisation from the placenta and congenital heart defects are common causes, along with genetic factors, coagulopathies, maternal and other neonatal risk factors. Data on the incidence of perinatal stroke in the Czech Republic are lacking, but abroad it is estimated at 1 : 1,600 to 1 : 2,300 live births. Neonatal ischemic stroke often manifests itself with focal epileptic seizures, while in premature children it may be asymptomatic. Diagnosis involves various methods, including cranial ultrasonography, MRI, and laboratory tests. Therapeutic procedures in the acute phase include also supportive care, treatment of potential complications, and in some cases anticoagulant therapy. Early and long-term rehabilitation with a multidisciplinary approach, focused on motor and cognitive development, is important. The prognosis is variable, although most affected children suffer from neurological deficits and psychomotor developmental delays. Further research and improved availability of diagnostic methods may contribute to a better understanding of this complex issue and improve the prognosis of patients.

Keywords:

Prognosis – risk factors – neonate – perinatal stroke

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

Introduction, Definition

Perinatal stroke is a vascular brain injury occurring between the 20th week of gestation and the 28th day of life [1]. The most common form is arterial ischemic injury [1,2]. Due to the immaturity of the brain, the immaturity of the coagulation system, and the possible presence of numerous risk factors during this period, perinatal stroke (in general) has a high incidence compared to other age periods in childhood [2–6]. It occurs more frequently in preterm newborns. Currently, the incidence of these events is increasing due to the use of neuroimaging methods.

 

Classification

Based on the type of involvement, we distinguish between arterial ischemic stroke (70%), hemorrhagic stroke (20%), and cerebral venous thrombosis (10%) [1,2,6]. Based on age at the time of diagnosis, we distinguish between fetal, neonatal, and presumed fetal/neonatal stroke [2,3].

The following section of this article will focus on ischemic perinatal strokes (Table 1).

 

Perinatal Arterial Ischemic Stroke (PAIS)

Etiology, Risk Factors

The neonatal period is the period lasting from birth through the 28th day of life. During this period, the incidence of ischemic strokes (IS) is nearly 6 times higher compared to other periods of childhood [1–3]. A possible explanation for this higher incidence is the presence of numerous peculiarities and physiological changes characteristic of this period. In newborns, the compensatory mechanisms for maintaining cerebral perfusion are immature, the blood-brain barrier exhibits higher permeability than in adults, and the vascular endothelium is functionally immature [1,4,6]. Characteristics of the perinatal period that influence coagulation status include the presence of fetal hemoglobin, fetal proteins, a high hematocrit, and high blood viscosity. Concentrations of procoagulant and anticoagulant proteins vary depending on gestational and postnatal age, with activation of coagulation processes in both the fetal and maternal circulations during the perinatal period [2,7,8]. Pregnancy itself constitutes a hypercoagulable state, and there are also many risk factors associated with childbirth that may play a role in the development of perinatal IS [4].

Perinatal IS likely has a multifactorial etiology, and the risk of its development is higher in the presence of multiple risk factors [8,9]. The etiology is often undetermined, but there are also clear clinical diagnoses in which the risk of IS is elevated [10].

The most likely cause of perinatal IS is thromboembolism originating from the placenta. Various placental pathologies have been described (retroplacental hematoma, acute umbilical cord occlusion, chorionic vascular thrombosis, acute chorioamniotitis, chronic inflammation of the chorionic villi, multiple placental infarcts, and others) have been described; in these conditions, placental thrombosis may occur, leading to embolization of the thrombus into the fetal circulation, where it passes through the foramen ovale into the fetal cerebral arteries [4,10,11].

Another source of thromboemboli may be congenital heart defects, such as transposition of the great arteries, hypoplastic left heart syndrome, and congenital pulmonary valve stenosis [8,10]. In these conditions, a thrombus may form in the heart and embolize into the cerebral arteries [8,10]. Both pre -⁠ and post-cardiac surgery defects are also associated with an increased risk of IS [8].

The following coagulopathies are associated with a higher risk of developing PAIS: the presence of antiphospholipid antibodies, the Leiden mutation, mutations in the methylene tetrahydrofolate reductase (MTHFR) gene with proven hyperhomocysteinemia, protein S and C deficiencies, antithrombin deficiency, and elevated lipoprotein (a) [7,12].

Other risk factors for PAIS include: signs of fetal distress (abnormal heart rate and meconium-stained amniotic fluid), an Apgar score < 7 at 5 minutes, decreased umbilical arterial blood pH, postnatal resuscitation, global hypoxia, vacuum extraction, infections (neonatal meningitis, neonatal sepsis, intrauterine infections—TORCH), hypoglycemia, male sex, polycythemia, extracorporeal membrane oxygenation (ECMO), disseminated intravascular coagulation (DIC), and the presence of catheters [1,8,13,14].

A rare cause of perinatal cerebral infarction is carotid artery dissection, which can occur during traumatic delivery, instrumental delivery, or an emergency cesarean section [2,3,13,15]. Lequin et al. [16] also described a case of spontaneous dissection. The internal carotid artery is most commonly affected, thereby becoming a source of thromboembolism to the cerebral arteries [15,16]. Obstetric traumas such as subdural hematoma or subarachnoid hemorrhage can lead to vasospasm and, through uncal herniation of the edematous brain, to compression of the posterior cerebral artery [6,16,17].

Maternal risk factors include thrombophilia, nulliparity, a history of infertility, arterial hypertension, preeclampsia, eclampsia, oligohydramnios, gestational diabetes mellitus, substance abuse during pregnancy (smoking, cocaine, amphetamines), acute cesarean section, fever during labor, prolonged second stage of labor, prolonged rupture of membranes, placental abruption, and chorioamnionitis (Table 2) [8,13,17]. Prevention of IS in the perinatal period involves early detection of hypercoagulable states in pregnant women and prophylactic administration of low-molecular-weight heparin. Risk factors for perinatal IS in preterm infants include twin-to-twin transfusion syndrome, heart rate abnormalities, decreased fetal movement, and neonatal hypoglycemia (Tables 3 and 4) [7,8,18].

Epidemiology

Data on the incidence of perinatal CMP and IS in the Czech Republic are not available. The following data are based exclusively on foreign studies.

The estimated incidence of perinatal CMP (in general) is 1 in 1,600 to 1 in 2,300 live-born infants, while the incidence in the older pediatric population is significantly lower—estimated at 2.5 to 13 per 100,000 children per year [1,2,19]. Of the total number of perinatal CMP cases, the incidence of IS (compared to other types of CMP) is the highest at 1 : 3,500 [18,20]. In children older than 28 days, the incidence of IS is estimated at 1.72 per 100,000 children per year [20]. The incidence of IS in the neonatal period is nearly 6 times higher than in the rest of the pediatric population [20].

The incidence of perinatal IS in preterm infants with a gestational age of 34 weeks or less is higher, reaching up to 7 per 1,000 [18,20,21]. This higher incidence is due not only to a greater number of risk factors but also to the frequent routine use of cranial ultrasonography in intensive care units. This group of patients is the only one that undergoes imaging even in the absence of neurological symptoms [20,21]. The overall prevalence of CMP in preterm newborns varies across different publications and is estimated to range from 1 : 1,600 to 1 : 8,000 [20,21].

 

Clinical Manifestation

Neonatal IS manifests as focal symptomatic epileptic seizures in 70–90% of cases within 12–72 hours after birth [4,5,22]. This time window is crucial for differential diagnosis, as earlier neonatal seizures are more likely to be associated with hypoxic-ischemic encephalopathy or another etiology [2]. According to a study by Glass et al. [22], IS is the second most common cause of neonatal seizures, accounting for 18% of these seizures. Between seizures, the patient may be alert and asymptomatic or may exhibit nonspecific symptoms such as irritability or lethargy, abnormalities in muscle tone, or feeding difficulties [2,5]. Other symptoms include apneic pauses, tremors, a pulsating fontanelle, and abnormalities in neonatal reflexes [16].

IS in preterm infants constitutes a separate group. It is often clinically asymptomatic, though it may sometimes present with seizures or apnea [2,16]. The diagnosis is usually made incidentally based on routine cranial ultrasonography [10].

Presumed perinatal IS does not present with acute symptoms and does not manifest until 28 days after birth. It usually manifests as hemiparesis, such as asymmetric use of the limbs or head preference, delayed motor development milestones, focal seizures, or infantile spasms [6,23]. More rarely, it manifests in preschool -⁠ to school-age children as cognitive impairment, visual impairment, learning disabilities, or epileptic seizures [22,24].

 

Differential Diagnosis

Perinatal IS often presents with nonspecific symptoms. For this reason, we must distinguish it from so-called “stroke mimics,” i.e., conditions that can mimic IS [2,25]. Since hypoxic-ischemic encephalopathy—as mentioned earlier—is the leading cause of neonatal seizures, it must also be taken into account [25]. Perinatal intraventricular hemorrhage may mimic IS in its clinical course [25]. In cases of subsequent ventricular system dilatation, in addition to drainage procedures (external ventricular drainage, a series of subgaleal ventricular reservoir punctures, and a series of lumbar punctures), neuroendoscopic lavage (NEL) is performed to reduce the incidence of shunt-dependent hydrocephalus and infectious complications [26–28]. Furthermore, it is necessary to differentiate between conditions such as arterial hypotension, perinatal asphyxia, kernicterus, bacterial and viral encephalitis, mitochondrial disorders, posterior reversible encephalopathy syndrome (PRES), and tumors [2,29]. Unlike post-hypoglycemic cerebral infarction, neonatal hypoglycemic brain damage is bilateral and symmetrical [2].

 

Diagnosis

Imaging methods play a key role in diagnosis (Table 5). The most accessible and rapid method is trans-fontanelle cranial ultrasonography [2,4]. It is the method of first choice; however, it has its drawbacks, as it may fail to detect lesions located peripherally [2,4,13]. The optimal diagnostic imaging method is diffusion-weighted MRI (MR DWI), which allows for the visualization of ischemic tissue with high sensitivity within the first two days after symptom onset [2,4,6]. However, 5 days after the first symptoms, its sensitivity decreases, and ischemic tissue is better visualized on T1 -⁠ and T2-weighted MR images [4,6]. MR angiography allows for the identification and localization of cerebral artery occlusion [2,4,13]. An alternative method when MR is unavailable is a CT scan of the brain [2,6]. Given the radiation exposure and the occurrence of stroke mimics, MRI is clearly preferred [2,25].

Several methods are used as part of the etiological investigation and search for the cause of IS. Transthoracic echocardiography (TTE) is used to diagnose congenital heart defects [8,23]. EEG is used to diagnose clinical and subclinical seizures [22,30]. Routine laboratory tests include basic biochemical blood tests, a complete blood count, a differential white blood cell count, basic coagulation tests, and measurements of protein C and S, fibrinogen, and antithrombin levels [7,23,31]. In indicated cases, testing for inherited metabolic disorders, lipoprotein (a) levels, anticardiolipin antibodies, and lupus anticoagulant, as well as lumbar puncture, is performed [2,7,12,25,29].

 

Therapeutic Approaches and Rehabilitation

The cornerstone of therapy during the acute phase of perinatal IS is symptomatic treatment, which includes monitoring vital signs, ensuring optimal oxygenation, supporting circulation, maintaining adequate blood glucose levels and body temperature, hydration, correction of anemia/polycythemia, acidosis, and electrolyte imbalances, and administration of anticonvulsant medication [4,22,32]. The indication for anticoagulant therapy (unfractionated heparin or low-molecular-weight heparin) is proven cardioembolization [33,34]. In cases of risk for recurrent IS (thrombophilia or cardiac disease), administration of acetylsalicylic acid or anticoagulant therapy (unfractionated heparin or low-molecular-weight heparin) is recommended, depending on the etiology [23,25]. Thrombolytic therapy and mechanical thrombectomy are not recommended in this age group due to limited experience, a lack of data, and the immaturity of the newborn’s hemostatic system [23,31].

A history of perinatal IS is not an indication for long-term prophylactic anticonvulsant therapy, as the risk of seizure recurrence in the first years of life is low [22]. The current 2023 guidelines from the International League Against Epilepsy (ILAE) recommend considering discontinuation of treatment even before hospital discharge if the child has been seizure-free for 24–72 hours, is clinically stable, and the EEG shows no ongoing epileptiform activity [30].

Since perinatal IS can affect the development of motor, speech, and cognitive functions, early and long-term rehabilitation is important. Rehabilitation methods used to support a child’s motor development include, among others, passive stretching, splinting, the Vojta method, the Bobath method, and the use of positioning aids. A pharmacological approach is used to treat spasticity, for example, with baclofen or botulinum toxin A [35–37]. Most studies on the rehabilitation of pediatric patients following a stroke focus on the rehabilitation of motor functions, and there is little information regarding the effectiveness of speech-language or cognitive therapy [24]. The issue of perinatal IS requires a multidisciplinary approach. Psychological interventions and support for the child’s caregivers also play an important role in the rehabilitation process.

 

Prognosis

Normal psychomotor development is observed in approximately 20–40% of children following perinatal IS [6,9]. The remaining children suffer from lifelong neurological deficits; in 75% of cases, these involve multiple impairments [9,24]. Motor impairment is present in 30–60% of children and manifests as hemiparetic cerebral palsy and other motor deficits, primarily affecting the upper extremities [9,10,36]. The prevalence of epilepsy in children with perinatal CMP is reported in various studies to range from 16–54% [22,38]. Delayed speech development is also common, as are cognitive deficits manifesting at a later age (in 20–25%), intellectual deficits, and behavioral disorders [24,39]. The recurrence rate of stroke is low (1–3%) [9,23]. The overall mortality rate for perinatal stroke is estimated at 3% [9,23,39].

 

Conclusion

Perinatal CMP is a serious neurological disorder that occurs between the 20th week of gestation and the 28th day of life. It most commonly presents as arterial IS, and the perinatal period is associated with the highest incidence of CMP in childhood. Diagnosis is based on modern neuroimaging methods, particularly cranial ultrasound and MRI. Early recognition of the disease and a multidisciplinary approach are essential for optimizing treatment, prognosis, and the long-term quality of life of affected children.

 

Conflict of Interest

The authors declare that they have no conflict of interest regarding the subject of this study.

 

Perinatal stroke
	Fetal	Neonatal	Estimated perinatal (fetal/neonatal)
time of diagnosis	in utero, before birth	from birth through the 28th day of life	after the 28th day of life, with onset presumed to have occurred between the 20th week of gestation and the 28th day of life

 

Table 1. Perinatal stroke by age at the time of diagnosis, adapted from [2,3].

 

Maternal risk factors	Intrapartum risk factors
maternal nulliparity	emergency cesarean section
history of infertility in the mother	vacuum extraction
preeclampsia, eclampsia in the mother	birth asphyxia
gestational diabetes mellitus	Heart rate abnormalities
maternal substance abuse (smoking, cocaine, amphetamines)	Meconium-stained amniotic fluid
oligohydramnios	prolonged rupture of membranes
maternal thrombophilia	prolonged second stage of labor
	maternal fever during labor

Table 2. Maternal and intrapartum risk factors for perinatal ischemic stroke, adapted from [8,13,17].

 

Neonatal risk factors

Apgar score < 7 at 5 minutes

Decreased pH of umbilical cord arterial blood

Polycythemia

Global hypoxia

hypoglycemia

DIC

coagulopathy

congenital heart defects

ECMO

postpartum resuscitation

male

presence of catheters

infections: -⁠ intrauterine (TORCH) -⁠ neonatal sepsis: -⁠ bacterial: Group B streptococcus, Escherichia coli, Haemophilus influenzae, Listeria monocytogenes, other Gram-negative intestinal bacteria, Staphylococcus aureus Streptococcus pyogenes, Neisseria meningitidis, Ureaplasma spp., other   -yeast: Candida spp   -viral: herpes simplex virus, enteroviruses   -⁠ neonatal meningitis: -⁠ bacterial: Group B streptococcus, Escherichia coli, Listeria monocytogenes, coagulase-negative staphylococci, enterococci   -⁠ yeast: Candida spp

Table 3. Neonatal risk factors for perinatal ischemic stroke, adapted from [6,15–19].

DIC –⁠ disseminated intravascular coagulation; ECMO –⁠ extracorporeal membrane oxygenation;

Coagulopathies in newborns associated with an increased risk of ischemic stroke

antiphospholipid antibodies

Leiden mutation

MTHFR (methylenetetrahydrofolate reductase) gene mutation

protein S deficiency

protein C deficiency

antithrombin deficiency

elevated lipoprotein(a)

Table 4. Coagulopathies in newborns associated with an increased risk of ischemic stroke, adapted from [11,12].

 

Diagnostic methods used in the diagnosis of ischemic stroke
For every newborn with suspected ischemic stroke:	In indicated cases:
-⁠ Brain MRI -⁠ Brain ultrasound -⁠ EEG -⁠ ECG -⁠ TTE -⁠ Complete blood count + differential -⁠ Coagulation tests -⁠ antithrombin III, protein C, protein S, fibrinogen, factor V -⁠ D-dimers -⁠ CRP, electrolyte panel, liver function tests, urea, creatinine, blood glucose -⁠ TORCH	-⁠ Inherited metabolic disorders -⁠ lipoprotein(a) -⁠ Anticardiolipin antibodies -⁠ lupus anticoagulant

Table 5. Diagnostic methods used in the diagnosis of ischemic stroke, adapted from [2,4,6,23].

CRP –⁠ C-reactive protein; ECG –⁠ electrocardiography; TTE –⁠ transthoracic echocardiography