Workup of Neonatal Stroke
DIAGNOSIS/INDICATION
Definition of Neonatal Stroke
A stroke, in general, is defined as an event that leads to poor blood flow to a localized area of the brain. One of the difficulties in studying strokes in the neonate is that, until recently, there has not been full agreement on the definition of neonatal stroke. Recently, however, the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke provided a consensus definition of neonatal stroke as “a group of heterogeneous conditions in which there is a focal disruption of cerebral blood flow secondary to arterial or cerebral venous thrombosis or embolization between 20 weeks of fetal life through 28th post-natal day, and confirmed by neuroimaging or neuropathological studies.” Neuroimaging was defined as T2-weighted magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), or diffusion-weighted imaging, as head ultrasounds can miss anterior and posterior lesions and computed tomography (CT) may not detect small or early lesions.1 However, ultrasounds and CT scans remain commonly used techniques in the evaluation of neonatal stroke. Neuropathological studies included autopsy and detailed evaluation of the placenta. Thus, the definition of neonatal stroke is currently defined by neuroimaging or neuropathologic findings, is either venous or arterial, and is either thrombotic or hemorrhagic. The location and type of stroke, as well as the neonate’s clinical status, help guide the workup.
Neonatal stroke is a common clinical event; with an estimated incidence between 1/2300 and 1/5000 live births.1 The incidence in this age category is second only to the incidence seen in elderly adults. The majority of neonatal strokes are caused by thrombosis of the arteries (70%), with a lower rate of hemorrhagic strokes (20%) and sinus venous thrombosis (10%). There is a slightly increased frequency in males compared to females and in African American infants when compared with Caucasian babies. A majority of these events occur in term infants because of their physiological hypercoagulable state near the time of delivery. As neuroimaging techniques become more sophisticated and the technology becomes more available, neonatal stroke may be more easily diagnosed, and this reported incidence may begin to rise.
Maternal Risk Factors
1. Thrombotic Stroke
a. Pregnancy results in a relative hypercoagulable state with several plasma proteins affected and increased thrombin generation, putting both mother and baby at increased risk of thrombus.2 Several publications reported that about half (50%) of mothers of infants diagnosed with a thrombotic stroke were found to have prothrombotic abnormalities.
b. Chorioamnionitis has also been shown to be associated with increased risk of thrombotic strokes in neonates. A multivariate analysis of a retrospective case control study involving a total of 208 infants found that maternal fever, even in the absence of an identified infection, had a statistically significant association with perinatal arterial ischemia.3
Maternal autoimmune disorders, in particular lupus, can lead to neonatal stroke. The maternally derived autoantibodies can cross the placenta and cause myriad clinical findings in the neonate. In particular, these antibodies can also cause a vasculitis in the neonate, leading to cerebral arterial or venous thrombosis.
c. Other maternal factors that compromise the placenta, including the use of cocaine, increase the risk of stroke in the prenatal or perinatal periods.
2. Hemorrhagic Stroke
a. Quantitative platelet disorders can lead to hemorrhagic neonatal stroke and may be related to the mother. The main maternal risk factor for hemorrhagic stroke is a maternal-paternal platelet antigen mismatch leading to neonatal alloimmune thrombocytopenia (NAIT). Because of the risk of subsequent neonatal hemorrhagic stroke in future infants, this is an important diagnosis to make correctly. Prophylactic measures, such as maternal intravenous immune globulin (IVIG) administration, may be effective in preventing thrombocytopenia, and thereby stroke, caused by NAIT.
The mother may also have maternal immune-mediated thrombocytopenia (ITP), which carries less risk than NAIT. In this scenario, the mother’s autoantibodies, which are directed at antigens on her own platelets, cross the placenta and then increase the clearance of the infant’s platelets, leading to thrombocytopenia and the potential for increased hemorrhagic stroke. Thus, obtaining the mother’s platelet count, if available, is often helpful in guiding the workup in neonatal hemorrhagic stroke caused by neonatal thrombocytopenia.
Infant Risk Factors
1. Thrombotic Strokes
a. The physiology of newborns places them at increased risk for thrombotic strokes. Their physiologically elevated hematocrit, which can be made worse in the setting of twin-twin transfusion, increases the risk of thrombosis. Neonates also have a relatively decreased rate of cerebral blood flow. The patent foramen ovale, always present at birth with variable rate of closure, allows a thrombus entering the right side of the heart to pass to the brain.
b. Congenital cardiac abnormalities are at risk for developing intracardiac thrombi, and these may embolize to the central nervous system (CNS), leading to arterial stroke. Testing for congenital thrombophilic disorders remains controversial in neonates. Testing for congenital thrombophilias, such as factor V Leiden, prothrombin mutations, hyperhomocysteinemia, and protein C/S and antithrombin deficiencies is often performed, but the utility for screening for these disorders in the neonate with thrombotic strokes, both arterial and sinus venous thrombosis, is controversial. Testing may not influence treatment or ultimate length of treatment. Thus, with the limitations of blood available for diagnostic testing, the clinician should be judicious in ordering these tests and when to begin testing. One recommended test in infants is to look for antiphospholipid antibodies, which may be placentally transferred from the mother, possibly contributing to development of thrombotic stroke.
c. Any foreign bodies, such as arterial or venous catheters, particularly in the setting of extracorporeal membrane oxygenation (ECMO), increase turbidity of the blood and therefore increase the risk of thrombosis.
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