Childhood stroke includes arterial ischemic stroke, cerebral sinus venous thrombosis, and intracranial hemorrhage.
Diagnosis of acute stroke in childhood is often delayed owing to failure to detect neurologic deficit in a child, low clinical suspicion of stroke, frequency of stroke mimics, and delays in diagnostic imaging.
Compared with adults, the causes of pediatric stroke are much more heterogeneous, and often risk factors, rather than definitive causes, are identified.
Supportive care in an ICU—with careful attention to optimizing cerebral perfusion and oxygenation, decreasing metabolic demands on the brain, and preventing early stroke recurrence—is critical.
The incidence of childhood stroke ranges from 2.3 to 13 per 100,000 children. , Following an episode of stroke, 10% of children die, approximately 10% to 20% will have another stroke, and most survivors will have long-term neurologic or neuropsychological deficits, including emerging deficits over time. Childhood stroke encompasses arterial ischemic stroke, hemorrhagic stroke, and cerebral sinus venous thrombosis (CSVT). Approximately half of childhood strokes are ischemic and half are hemorrhagic. The diverse etiologies, risk factors, presentations, treatments, and potential complications of acute stroke in childhood must be considered to minimize morbidity and mortality in the intensive care setting.
Arterial ischemic stroke
Acute arterial ischemic stroke (AIS) is defined as the acute onset of a neurologic deficit consistent with infarction in a vascular territory, with imaging or pathologic confirmation. Secondary hemorrhage due to tissue and vascular injury within the ischemic core can occur (hemorrhagic conversion); however, unlike hemorrhagic stroke, the initial event is ischemic.
Etiologies and risk factors
Approximately half of all children presenting with initial AIS have an underlying condition that increases the risk of stroke (symptomatic stroke) and the other half have cryptogenic stroke. After extensive evaluation, most children will have at least one risk factor for stroke identified. It is likely that most AISs in childhood are multifactorial.
Cerebral arteriopathy is well associated with primary and recurrent stroke. , In the Vascular Effects of Infection in Pediatric Stroke (VIPS) study, definite or possible arteriopathy was present on vascular imaging in 46% of all patients and in 55% of the subset of patients who were previously healthy, that is, had no previously known risk factors for stroke. In addition, cerebral arteriopathy has been found in children with acute AIS who have other stroke risk factors, such as congenital heart disease.
Focal cerebral arteriopathy (FCA) is a discrete intracranial arterial stenosis that accounts for approximately one-quarter of arteriopathies in childhood AIS. , FCA has been well associated with varicella zoster virus (VZV) infection. A subset of FCA is transient cerebral arteriopathy (TCA), which is defined as FCA that improves or shows no progression after 6 months.
Moyamoya is a progressive steno-occlusive disease of the distal internal carotid arteries and proximal middle cerebral arteries and, not infrequently, the anterior cerebral arteries, associated with collateral formation at the base of the brain, producing the moyamoya (Japanese for “puff of smoke”) configuration seen on catheter cerebral angiogram. Moyamoya usually presents with AIS in childhood, whereas adults frequently present with hemorrhagic stroke. Moyamoya may be idiopathic, termed moyamoya disease , or occur in association with predisposing syndromes, such as sickle cell disease, trisomy 21, or neurofibromatosis type 1, termed moyamoya syndrome ( Fig. 66.1 ). Moyamoya disease is likely a genetic disease, most probably polygenic, based on the high prevalence of moyamoya in Asia, as well as familial aggregation in 5% to 10% of cases. , The only effective treatment for moyamoya is surgical revascularization to decrease the risk of further transient ischemic attacks (TIAs), and ischemic and hemorrhagic stroke.
Cervicocephalic arterial dissection (CCAD) accounts for 7.5% to 20% of childhood AIS. , , Because children with CCAD are at risk for recurrent stroke, anticoagulant therapy is recommended, although antiplatelet therapy such as aspirin is also used, which is consistent with the recommendation of antiplatelet or anticoagulant treatment of CCAD in adults. Often, a history of trauma to the head or neck is obtained in children presenting with CCAD, such as can occur with sports injuries. However, CCAD can also present spontaneously. Dissection can also be complicated by subarachnoid hemorrhage due to aneurysmal dilation and recurrent dissection. Children with collagenopathies or elastinopathies—such as Ehlers-Danlos syndrome, Marfan syndrome, Loeys-Dietz syndrome, and arterial tortuosity syndrome—are at increased risk for initial and recurrent CCAD.
Central nervous system (CNS) vasculitis is an inflammatory cerebral arteriopathy that can be primary, idiopathic, or secondary to a systemic cause—most commonly, systemic rheumatologic disease or infection. In childhood primary angiitis of the CNS (cPACNS), inflammation involves only the arteries of the CNS. cPACNS can be divided into large-medium-vessel disease, in which arteriopathy can be detected on cerebral catheter angiogram, and small-vessel cPACNS, in which it is not visible on a catheter angiogram. Children with large-medium-vessel cPACNS typically present with hemiparesis or aphasia, and stuttering onset of symptoms is common. Systemic inflammatory markers are often unremarkable in large-medium-vessel cPACNS, and cerebrospinal fluid (CSF) pleocytosis or elevated protein is present in only one-third of children. Treatment of progressive large-medium-vessel cPACNS requires immunosuppression. The use of anticoagulation or antiplatelet treatment may decrease the risk of stroke.
In small-vessel cPACNS, patients often present with diffuse neurologic deficits and headache. Brain magnetic resonance imaging (MRI) is usually abnormal, but findings are nonspecific. Biomarkers—including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), leukocytosis, anemia, and thrombocytosis—are frequently, but not consistently, abnormal. Brain biopsy is necessary to diagnose small-vessel CNS vasculitis. However, it may yield a false-negative result in a significant number of patients.
Secondary CNS vasculitis is a common manifestation of underlying systemic inflammatory diseases such as Takayasu arteritis, polyarteritis nodosa, and systemic lupus erythematosus. Arteritis is also commonly seen with acute bacterial meningitis. Heparin and aspirin have been used to prevent recurrent stroke in childhood bacterial meningitis.
VZV infection, both primary infection and reactivation, is associated with vasculopathy and stroke in children and adults. , VZV vasculopathy is diagnosed by the detection of VZV deoxyribonucleic acid or anti-VZV immunoglobulin G (IgG) antibody in CSF, or both. Treatment of VZV vasculopathy with both acyclovir and corticosteroids is recommended.
Sickle cell disease
Stroke is a common complication of sickle cell disease (SCD). Without treatment, 11% of children will have a stroke by 20 years of age (see Chapter 88 ). The incidence of initial stroke is markedly decreased by regular red blood cell transfusions in children with elevated transcranial Doppler velocity in the middle cerebral artery. , Following initial stroke, the risk of a recurrent stroke is approximately 20% even with the use of chronic red blood cell transfusion. Many patients with SCD-associated stroke have an underlying cerebral arteriopathy, a risk factor for primary and recurrent stroke. In addition, patients with SCD are at risk for aneurysmal hemorrhage.
The possibility of stroke needs to be considered in any child with SCD with transient or persistent focal weakness or deficit in addition to a history of new seizures or severe headache regardless of presence of pain. Blood should be sent for type and to cross-match sickle-negative, antigen-selected, leuko-reduced (minor antigen-matched red blood cells if available) blood for exchange transfusion. Risk factors for stroke include increased blood pressure, lower hemoglobin concentrations, high leukocyte count, prior transient ischemic attacks, history of meningitis, presentation with seizure, surgery, priapism, acute anemia, recent acute chest syndrome and transfusion within the past 2 weeks, and a history of overt or silent stroke. , ,
An emergent head computed tomography (CT) scan without contrast can be used to assess for possible hemorrhage or other intracranial process. Head MRI and magnetic resonance angiography (MRA) with diffusion weighted imaging is the best way to assess for possible acute stroke in a child with SCD and clinical presentation of possible stroke. Current guidelines recommend urgent erythrocyte transfusion in neuroimaging-confirmed stroke. However, some recommend that transfusion not be delayed while awaiting confirmatory neuroimaging. There is a risk of ischemia due to increased viscosity if hemoglobin rises to greater than 13 g/dL following transfusion.
Oxygen supplementation is used to maintain oxygen saturation greater than 93% through the completion of the transfusion and through the following first night to minimize nocturnal hypoxemia. Cooling blankets should be avoided in patients with SCD. Cardiology consultation should be obtained prior to exchange transfusion if there is clinical suspicion of cardiac dysfunction, to assist with cardiac monitoring during exchange transfusion.
Although SCD did not increase the risk of intravenous tissue plasminogen activator (t-PA) for acute stroke in adults, there is no data with which to guide the use of t-PA for stroke in children with SCD. In addition, the pathophysiology of stroke in children with SCD may not be particularly responsive to thrombolysis.
Congenital and acquired heart disease
Cardioembolic stroke secondary to congenital and acquired cardiac disease accounts for almost one-third of AIS in children, with children with complex congenital heart disease (CHD) and right-to-left shunts at highest risk. Among children with heart disease and stroke, one-quarter of strokes occurred in the setting of cardiac surgery or catheterization. Not infrequently, the child with cardiac disease and stroke is acutely ill and sedated, and the stroke is not discovered until sedation or paralytics are weaned. Prothrombotic factors increase the risk of both initial and recurrent stroke in the setting of CHD. The risk of recurrent stroke in children with CHD is 27% at 10 years, with the highest risk immediately following the initial stroke.
A prothrombotic state is identified in 13% of children with AIS, and the risk of AIS is increased when multiple thrombophilias are present or when combined with other risk factors such as CHD. Protein S deficiency, protein C deficiency, factor V Leiden mutation, antithrombin III deficiency, elevated lipoprotein(a), homocystinuria, and antiphospholipid antibodies have been associated with AIS in childhood ( Box 66.1 ). ,
Cervicocephalic arterial dissection
Focal cerebral arteriopathy
Primary central nervous system vasculitis
Sickle cell disease
Iron deficiency anemia
Congenital heart disease
Acquired heart disease
Protein C deficiency
Protein S deficiency
Elevated lipoprotein A
Varicella zoster virus
Illicit drugs (cocaine, methamphetamine)
Systemic lupus erythematosus
Vasculitis (as above)
Ischemic stroke occurs when blood supply to an area of the brain is not adequate for metabolic needs. This may occur due to occlusion of flow caused by thrombus or embolus or due to critical stenosis. Decreased cerebral blood flow (CBF) below a critical threshold results in neuronal injury and, potentially, neuronal death. The central region with absence of CBF (“no flow”) is the ischemic core, which will not survive. The surrounding area of ischemic penumbra is not irreversibly injured and potentially viable but will not survive without prompt restoration of blood flow (see Chapter 65 ). The goal of reperfusion using intravenous t-PA or acute endovascular intervention is to “rescue” the penumbra by restoring adequate perfusion to prevent cell death. The size of an infarct is determined by the extent and duration of ischemia, cerebral perfusion pressure, and extent of collateral circulation. Fever may increase infarct size due to increased metabolic demands. Therefore, strategies to minimize injury include ensuring adequate cerebral perfusion pressure and aggressively treating fever.
As energy failure at the cellular level results in neuronal hyperexcitability, seizures—including status epilepticus—can occur following acute stroke. Although prophylactic antiepileptic medication is not recommended, close monitoring for seizures, including the use of electroencephalography monitoring for subclinical seizures, is recommended. Seizures can be refractory in the immediate poststroke period.
Recognition of stroke in childhood is challenging. Identifying neurologic deficits in children, particularly young children, is difficult; stroke is often not considered in the child presenting with acute neurologic deficit. In addition, mimics of childhood stroke are common, and the differential diagnosis is broad, including other conditions requiring urgent diagnosis and treatment, such as brain tumors, hypertensive encephalopathy, demyelinating disorders, infection, postictal hemiparesis, and metabolic disorders. , Signs and symptoms of anterior circulation stroke in childhood include hemiparesis, hemisensory loss, aphasia, visual field cuts with gaze preference, and neglect. Posterior circulation strokes can present with ataxia, vomiting, vertigo, dysarthria, diplopia, and dysmetria. Diagnosis of cerebellar stroke is particularly challenging, as cerebellar stroke often presents with nonspecific symptoms such as headache and vomiting, or with ataxia, which mimics acute cerebellar ataxia. From 10% to 20% of childhood AISs are heralded by seizures. New neurologic deficit following a seizure in a child with acute stroke may be mistaken for postictal paresis.
Critical initial data to be collected in a child presenting with possible stroke include history of predisposing factors, time since the child was last seen well, recent trauma or infection, and medications. A baseline neurologic assessment, such as the pediatric version of the National Institutes of Health Stroke Scale (PedNIHSS) should be performed.
The potential for acute treatment and intervention will determine the urgency of neuroimaging studies (see Chapter 61 ). Head CT is usually the imaging modality used for a child presenting with acute neurologic symptoms or signs because of speed and availability, along with sensitivity for acute intracranial hemorrhage (ICH), cerebral edema, and impending herniation. Head CT is the first-line imaging study for the child with suspected ICH, trauma, or if MR is contraindicated. However, it is much less sensitive for early ischemic stroke than MRI using diffusion-weighted imaging (DWI).
Although head CT and brain MRI will both evaluate for acute hemorrhage in children, the need to confirm AIS and rule out stroke mimics and desire to limit radiation exposure results in MRI as the optimal first-line study in most cases. A rapid stroke MR protocol that can be done in 20 to 30 minutes may be used. Sequences should include DWI/apparent diffusion coefficient (ADC), which is very sensitive for early ischemia although not specific, and T1- and T2-weighted (or T2 FLAIR [fluid attenuation inverse recovery]) sequences, and MRA of the head and neck ( Fig. 66.2 ). FLAIR is less useful in children under 2 years of age owing to immature cerebral myelination. Susceptibility-weighted imaging or gradient echo will increase the sensitivity for detection of hemorrhage. Young children and those unable to cooperate will need sedation for acquired neuroimaging, which will require maintenance of blood pressure to optimize brain perfusion, particularly in the setting of flow-limiting arteriopathy .
MRA will reveal arteriopathy, including stenosis and dissection, in half to three-quarters of children with acute stroke , , , ; however, MRA cannot detect lesions in smaller arteries. Related imaging of the cerebral venous system is indicated if there are concerns about cerebral venous thrombosis. Vessel wall imaging is increasingly used in adults to evaluate the arterial wall itself, including for the presence of inflammation, rather than just the lumen, as seen with MRA, CT angiography (CTA) and catheter angiograms, and is being used more often in children as well.
CTA of the head and neck can diagnose arteriopathy but requires sedation in the younger child and entails significant radiation exposure. For the latter reason, if head MRA can be obtained, CTA may be avoided in some instances. If cerebral arteriopathy is strongly suspected despite a normal MRA, cerebral catheter angiography may be preferable to CTA due to greater sensitivity in diagnosing cerebral arteriopathy, particularly medium- and small-vessel arteriopathy. It requires radiation and anesthesia; however, periprocedural complications are rare with experienced angiographers. A cerebral catheter angiogram can be used for diagnosis of arteriopathy as well as for mechanical thrombectomy, treatment of aneurysm, and other neurointerventions.
Even when hyperacute treatment is not being considered, diagnosis of underlying etiologies such as CCAD, cardiac embolus, and CSVT will modify immediate treatment. Cerebral arteriopathy is an important predictor for primary and recurrent arterial ischemic stroke in childhood; depending on etiology, treatment with antithrombotic medications, immunosuppressive agents, and antiviral medication may be indicated.
Initial laboratory studies include complete blood count (CBC), electrolytes, blood urea nitrogen (BUN), creatinine, glucose, prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR), ESR, blood gas and type, and screen or cross-match if ICH is suspected, the child has SCD, or thrombolysis or thrombectomy is being considered ( Box 66.2 ).
Complete blood count
Coagulation studies: PT, PTT, INR
For child on anticoagulation:
LMWH activity and anti-Xa for LMWH
PT/INR for warfarin
Renal and liver function studies
If clinically indicated:
Urine or serum toxicology
Fibrinogen, if intravenous t-PA being considered
Type and screen or cross if intracranial hemorrhage is suspected, the child has sickle cell disease, or thrombolysis or thrombectomy is being considered
Initial laboratory studies in child with possible acute stroke
If the child is on anticoagulation, studies to assess therapeutic range include low-molecular-weight heparin (LMWH) activity and anti-Xa for LMWH, PTT for unfractionated heparin (UH), and PT/INR for warfarin.
Other tests of hypercoagulability ( eTable 66.1 )
Laboratory tests considered in childhood AIS do not need to be sent urgently when maintaining an optimal hematocrit is critical, and not all patients require exhaustive testing. Urgent evaluations may include screen for systemic inflammatory disease (ESR, CRP, antinuclear antibodies [ANAs]), and lupus inhibitor screen, antiphospholipid panel, and pregnancy test. Lumbar puncture may be indicated if there are concerns about infection. However, it may need to be delayed until risk of intracranial hypertension has passed. If a cardioembolic etiology is suspected, urgent echocardiogram is indicated.
|Hemoglobin S percentage||If child with known or suspected sickle cell disease|
|Iron and total iron binding capacity||Severe iron deficiency anemia is a risk factor for stroke|
|Antinuclear antibodies a||If clinical concern about underlying rheumatologic disease|
|Rheumatoid factor a||If clinical concern about underlying rheumatologic disease|
|Antiphospholipid antibody studies||Includes anticardiolipin antibody IgM, IgG, and IgA; anti-β 2 glycoprotein IgM, IgG, IgA; and lupus anticoagulant|
|FVL mutation||Most common cause of activated protein C resistance; 3%–8% of people with European ancestry carry one copy of the mutation|
|Prothrombin gene mutation (Factor II/G20210A) a||More common in white population|
|Protein C activity and antigen||Can be lowered by warfarin, vitamin K deficiency, liver disease, DIC|
|Protein S activity and free antigen||Can be lowered by warfarin, vitamin K deficiency, liver disease, DIC, pregnancy. Only the free protein S is functional as a cofactor for protein C.|
|APCR a||Rarely indicated, as FVL accounts for most cases of APCR|
|5,10-methylenetetrahydrofolate reductase a||Needs to be sent only if homocysteine is elevated|
|PT, aPTT, and INR||PT and INR measure extrinsic pathway of coagulation. PTT measures intrinsic pathway of coagulation.|
|AT III activity||Heparin and direct thrombin inhibitors can affect results. AT III should be checked if a patient is requiring higher heparin doses than expected, as anti-Xa activity is dependent on patient’s AT III level.|
|D-Dimer||May reflect clot burden|
|C reactive protein||Acute phase reactant to inflammation|
|Erythrocyte sedimentation rate||Nonspecific measure of inflammation|
|Homocysteine a||Fasting sample preferred|
|β-human chorionic gonadotropin (pregnancy test)||Strongly consider in any female of childbearing age|
|Toxicology screen||Cocaine, methamphetamine, other vasoactive drugs, and cannabis associated with stroke|
|Lipoprotein (A) a||Does not need to be a fasting sample|
Initial management includes optimizing cerebral perfusion and preventing hypoxemia, rescuing and minimizing expansion of the penumbra, and preventing complications. Children with acute stroke should be admitted to the pediatric intensive care unit (PICU) for a minimum of 48 hours for neurologic and medical monitoring and aggressive management of complications. Neurologic status should be followed by the bedside nurse (hourly pediatric Glasgow Coma Scale and pupils until stable) as well as by medical staff. Ideally, the pediatric NIHSS should be used to serially assess the patient. Urgent neuroimaging should be obtained for any neurologic deterioration.
For the most part, therapy for childhood stroke is based on extrapolation from adult-based guidelines. Endotracheal intubation and mechanical ventilation are indicated for children with inadequate oxygenation and/or respiratory drive or inability to protect their airway and may be needed to facilitate diagnostic or therapeutic procedures. Keeping the head of the bed flat may optimize cerebral perfusion. Blood pressure should be maintained, with careful attention to adequate blood volume to avoid hypotension. Many children have transient hypertension following stroke, possibly representing a compensatory mechanism to maintain CBF, and permissive hypertension is usually recommended. If hypertension requires treatment, blood pressure should be lowered cautiously, with close attention to worsening of neurologic status. Clinical and electrographic seizures should be treated, but there are no data to support seizure prophylaxis with antiepileptic medications. Fever should be treated aggressively to decrease metabolic demands on the brain. Cooling blankets should not be used in patients with sickle cell anemia.
There is minimal data on the use of recanalization therapies in acute childhood stroke; currently the American Heart Association (AHA) notes that “hyperacute therapies for AIS remain controversial.” Due to the challenge of determining time of stroke onset and limitations of extrapolation from adult data to very young children, t-PA for AIS should be used with great caution in children younger than 2 years and avoided in neonates. For older children and adolescents, data on safety and efficacy is limited, but t-PA could be considered in selected patients. Published consensus-based guidelines and safety monitoring recommendations exist. The risk of symptomatic intracranial hemorrhage following intravenous t-PA for appropriately selected children with AIS appears to be low.
Mechanical thrombectomy is the standard of care in appropriately selected adults within 6 hours of AIS due to proximal large-vessel occlusion (LVO), with the treatment window for mechanical thrombectomy in anterior circulation LVO in acute AIS with salvageable penumbra on perfusion imaging extended to 24 hours. Mechanical thrombectomy is increasingly performed in children, with literature reports of good outcome, but no controlled studies. Recently published AHA guidelines note that it would be reasonable to limit mechanical thrombectomy to children with LVO and disabling deficit in larger children by an experienced team but do not address the time window for treatment or the role of perfusion-based imaging in childhood.
If the child was last seen at baseline within 6 hours and MRA or CTA shows occlusion in the internal carotid or M1 segment of the middle cerebral artery or the vertebral and basilar artery, the possibility of thrombectomy should at least be discussed, particularly for an older adolescent. An extended time window may be indicated, particularly for basilar artery occlusion. However, this procedure should be approached with caution, including full disclosure of the lack of data in children, and should be performed only by neurointerventionalists or interventional radiologists with pediatric experience.
Urgent neurosurgical consultation for possible decompressive hemicraniectomy should be obtained promptly in children with malignant middle cerebral artery infarct ( Fig. 66.3 ). Suboccipital craniectomy with dural expansion should be considered in patients with neurologic deterioration due to edema from cerebellar infarct. In malignant infarction, monitoring of intracranial pressure (ICP) has not been shown to be helpful and may delay surgical treatment in these patients.
A full review of the use of antithrombotic therapies in children is available in the Chest guidelines. Anticoagulation is typically used in children with acute AIS without hemorrhage pending complete workup of potential etiologies to prevent recurrent stroke, which can occur early, particularly in the setting of dissection or cardioembolic stroke. Anticoagulation is usually initially achieved with continuous intravenous heparin, which can be reversed if necessary by protamine or fresh frozen plasma, with transition to LMWH when the child is stable. LMWH has more predictable pharmacokinetics and reduces the risk of heparin-induced thrombocytopenia, a serious antibody-mediated complication of heparin. However, LMWH cannot be reversed rapidly and has renal clearance, necessitating dosage adjustment in the setting of impaired renal function. For long-term anticoagulation, LMWH or warfarin is used. Warfarin has difficult-to-manage pharmacokinetics; thus, LMWH often is the anticoagulant of choice, despite the need for subcutaneous injection. Newer anticoagulants are currently being studied in adult stroke but have not been used widely in pediatric stroke. Anticoagulation is usually continued in children with presumed cardioembolic stroke and significant thrombophilic, states such as antiphospholipid syndrome. , Chest guidelines recommend anticoagulation for cervical artery dissection, while AHA guidelines consider this to be controversial. ,
Aspirin inhibits platelet activity by irreversibly inhibiting cyclooxygenase-1 and is used based on consensus for stroke prevention in children not felt to require anticoagulation. A dose of 3 to 5 mg/kg per day is recommended after contraindications such as ICH have been excluded. Aspirin is often continued for long-term stroke prophylaxis in children. However, optimal duration is unknown. The doses used for stroke prophylaxis are less than those associated with Reye syndrome ( Table 66.2 ).
|Indication||ACCP guidelines, 2012||American Heart Association Guidelines for Management of Stroke in Infants and Children, 2019|
|Initial treatment||UH or LMWH or aspirin 1–5 mg/day until cardiac etiology or arterial dissection ruled out||UH or LMWH until etiology determined. Aspirin 3–5 mg/kg/day for children without known risk of recurrent embolism or severe hypercoagulable disorder|
|Cardiac embolism with risk of recurrence (excluding native valve endocarditis)||LMWH||UH or LMWH|
|Extracranial cervicocephalic arterial dissection||LMWH||Anticoagulation considered controversial|
|Sickle cell disease||Exchange transfusion with goal HbS <30%||Simple or exchange blood transfusion, depending on baseline hemoglobin|
|Intravenous t-PA||Not recommended for children outside of research protocol||No recommendations provided|