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Epidemiology and classification of perinatal stroke
Seminars in Fetal & Neonatal Medicine 14 (2009) 245–249
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Epidemiology and classification of perinatal stroke John Kylan Lynch* Division of Stroke Diagnostics and Therapeutics, National Institutes of Neurological Disorders and Stroke, 10 Center Drive, MSC 1447, Bethesda, MD 20892-1447, USA
s u m m a r y Keywords: Epidemiology Ischemic stroke Outcome Perinatal stroke Risk factors
Stroke is an important cause of mortality and chronic morbidity in infants and children. Case definitions for perinatal stroke have varied among studies by clinical and laboratory criteria. A recent US National Institutes of Health workshop on perinatal stroke provided consensus recommendations on the definition and classification of perinatal stroke. The incidence of perinatal stroke has been estimated at 1 in 1600 to 5000 births. The clinical presentation of perinatal stroke depends on the time of diagnosis, acute or delayed, but most will present with seizures. Risk factors for perinatal stroke have not been well studied. Several maternal and neonatal disorders have been reported in infants with perinatal stroke. Children who suffer perinatal stroke typically develop long-term disabilities including motor deficits, cognitive and behavioral disorders, and epilepsy. More than half will develop long-term motor or cognitive problems and the recurrence rate after perinatal stroke is very low. Ó 2009 Published by Elsevier Ltd.
1. Introduction Over the last several years, our knowledge of perinatal stroke has substantially improved, but much work remains. Recent epidemiological studies have provided important information on the incidence, risk factors, and outcome of stroke in neonates. Factors associated with stroke in the perinatal period include maternal disorders, blood disorders, cardiac disorders, infection, and other miscellaneous disorders. It is clear that stroke is an important cause of mortality and chronic morbidity in children. Of the infants who suffer a stroke each year, more than half will have permanent motor or cognitive disability. The recurrence rate after perinatal stroke is less than 3% and there are no established treatment or prevention strategies. This paper discusses the epidemiology of arterial ischemic stroke occurring in the perinatal and neonatal periods, including both cerebrovascular events that are diagnosed during the perinatal period and also those diagnosed retrospectively, when evidence of hemiparesis or postneonatal seizures leads to later evaluation and neuroimaging. 2. Definition and classification Perinatal stroke typically refers to neurologic signs and symptoms due to a vascular cause around the time of birth, with confirmatory evidence by neuroimaging or pathology. Case
* Tel.: þ1 301 896 7547; fax: þ1 301 896 4002. E-mail address: [email protected] 1744-165X/$ – see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.siny.2009.07.001
definitions for perinatal stroke studies have varied by age at diagnosis and by clinical and laboratory criteria. Perinatal stroke occurs most often in term or near-term infants, but is also reported in preterm infants.1,2 Diagnostic confirmation of perinatal stroke is typically based on neuroimaging findings, but autopsy criteria have been used in the past.3 The time at diagnosis is usually within the first few days of life, but some studies have included cases that were identified after the perinatal period. A diagnosis of presumed perinatal stroke is considered when post-perinatal neuroimaging reveals chronic changes suggestive of a stroke during an earlier period. Although the precise timing of this injury cannot be determined, the stroke is presumed to be perinatal in onset if the infant had been neurologically well since birth without any symptoms of acute stroke. It is unclear whether these remotely diagnosed cases should be included, as the underlying risk factors and outcome may differ. Why these strokes are not captured in the perinatal period is unclear, but is likely related to a case-finding strategy that requires clinical events and imaging studies. Some infants with stroke may not manifest symptoms to elicit imaging studies, or the studies that are performed are not sensitive enough to detect acute ischemic stroke. Ultrasound may be less sensitive for the detection of stroke than computed tomography or magnetic resonance imaging (MRI).4 Diagnostic criteria for stroke may be negative in cases where early imaging studies are normal.5,6 Studies of perinatal stroke have also differed in the inclusion of stroke subtypes: perinatal arterial ischemic stroke, cerebral sinovenous thrombosis, intracerebral hemorrhage, and periventricular venous infarction. In August 2006, the United States National Institutes of Health convened a workshop on perinatal stroke to develop consensus
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recommendations on the definition and classification of perinatal stroke. The participants proposed a working definition of perinatal stroke to include ‘a vascular event causing focal interruption of blood supply, occurring between 20 weeks of fetal life through 28th postnatal day, and confirmed by neuroimaging or neuropathology studies.’ The workshop panel also classified perinatal stroke according to two major subtypes, ischemic (including cerebral venous thrombosis) and hemorrhagic perinatal stroke. 7 3. Incidence The incidence of perinatal stroke has been estimated at 1 in 1600 to 5000 births.8–12 Incidence estimates have been difficult to interpret due to the variability in clinical and diagnostic criteria, number of cases, and underlying population. In most studies, cases were defined as infants with arterial ischemic stroke diagnosed in the neonatal period. More recent studies have included retrospectively diagnosed cases as well as hemorrhagic stroke. A population-based study of perinatal stroke in the USA that included acutely and retrospectively diagnosed cases found an overall incidence of 20 per 100 000 live births.10 A study in Estonia which included acute, delayed, and hemorrhage cases reported a much higher rate at 63 per 100 000 live births.12 In both of these studies, retrospectively diagnosed cases were more common than acute cases and suggest that the burden of perinatal stroke may be greater than in previous reports. 4. Clinical presentation The clinical presentation of perinatal stroke depends on the age at diagnosis. In infants who are diagnosed in the newborn period, most present with seizures. There may also be signs and symptoms of neonatal encephalopathy such as lethargy, hypotonia, feeding difficulties, or apnea. In infants with presumed perinatal stroke who are not diagnosed until months later, the presentation includes focal hand weakness, delayed milestones, and/or seizures. Whether an infant is diagnosed in the newborn period or several months later may depend on the size and location of the stroke and other clinical factors. It seems possible that infants with certain patterns of injury, such as those involving the basal ganglia that spare the cortex, may be more difficult to diagnose in the newborn period because these infants are less likely to exhibit neonatal seizures. In a large series by Golomb of presumed perinatal stroke cases, 40% of the strokes were restricted to small perforating arteries of the middle cerebral artery.13 A second study of latediagnosed cases revealed that only 40% had cortical involvement.12 At present, there are limited data on differences in underlying risk factors among acutely and retrospectively diagnosed cases that could account for time at diagnosis. Maternal and pregnancyrelated disorders including chorioamnionitis, placental disorders, and birth asphyxia seem to be more prevalent in acutely diagnosed cases.10,12 These findings suggest that the presence of specific clinical factors may predispose to seizures or symptoms that lead to a diagnosis of perinatal stroke in the newborn period. 5. Risk factors Risk factors for perinatal stroke have not been well studied. Most studies of perinatal stroke have been descriptive and have provided little information on quantitative risk estimates, environmental factors, and genetic and environmental interactions. There have been few controlled studies of factors specific to stroke risk in the perinatal period, such as maternal characteristics, placental disorders, and other complications of birth and pregnancy. Environmental factors related to the peripartum period
likely play a major role in the perinatal stroke as the recurrence rate is extremely low. Several maternal and neonatal disorders have been reported in infants with perinatal stroke (Table 1).
5.1. Maternal coagulation disorders Pregnancy is a time of relative hypercoagulability during which several plasma proteins are affected and thrombin generation is increased. Venous thromboembolism is common during pregnancy with risk highest during the third trimester and puerperium,14 time periods when most perinatal strokes are likely to occur. The addition of a coagulation abnormality in the setting of pregnancy may lead to thrombosis. Maternal coagulation disorders are associated with an increased risk of thrombosis in pregnancy15 and perinatal stroke. Two recent studies found an increased rate of specific acquired and genetic coagulation abnormalities among mothers of children with perinatal stroke.16,17 In the first study, prothrombotic abnormalities were identified in 55% of mothers and 50% of infants with perinatal stroke.16 A second case–control study from Israel revealed similar findings with 68% of mothers and 64% of infants with a coagulation abnormality. In addition, this study found that the presence of factor V Leiden (FVL) or antiphospholipid
Table 1 Maternal and infant disorders reported with perinatal stroke. Maternal disorders Infertility Pre-eclampsia Chorioamnionitis Autoimmune disorders Coagulation disorders Twin to twin transfusion syndrome Cocaine use Placental disorders Placental thrombosis Placental abruption Placental infection Fetomaternal hemorrhage Placental chorioangioma Blood, homocysteine and lipid disorders Polycythemia Disseminated intravascular coagulopathy Factor V Leiden mutation Protein S deficiency Protein C deficiency Prothrombin 20210A mutation Homocysteine Elevated Lipoprotein a Factor VIII Antiphospholipid antibodies Cardiac disorders Congenital heart disease Patent ductus arteriosus Pulmonary valve atresia Cardiac surgery Infectious disorders Meningitis Systemic infection Miscellaneous disorders Vascular maldevelopment Arterial dissection Trauma Catheterization Dehydration Extracorporeal membrane oxygenation (ECMO)
J.K. Lynch / Seminars in Fetal & Neonatal Medicine 14 (2009) 245–249
antibodies in the mothers increased the risk of perinatal stroke severalfold.17 The results of these studies suggest that the presence of a coagulation disorder in the mother may increase the risk of perinatal stroke in the child. The pathway through which these disorders lead to perinatal stroke is undetermined, but may be due to thrombosis at the placenta, where maternal uterine spiral arteries profuse fetal villous vessels in an area of low pressure. Thrombus formation at the placenta could impede maternal–fetal circulation and potentially lead to pregnancy complications or embolization. Thrombosis on the maternal side may possibly lead to miscarriage, pre-eclampsia, and intrauterine growth restriction. While several placental and pregnancy-related disorders have been reported in association with mothers of infants with perinatal stroke, controlled studies of maternal thrombophilia and placentarelated pregnancy complications have been inconsistent and the risk is clearly not established.18–20 Thrombosis on the fetal side could provide a source of emboli that could bypass the hepatic and pulmonary circulation and embolize to the fetal brain. 5.2. Complications of pregnancy and delivery Complications of pregnancy and delivery are common among mother of infants with perinatal stroke.16,21–23 Case–control studies of perinatal stroke have found several obstetrical complications to be more frequent in mothers of infants with stroke than in control mothers. A nested case–control study by Wu of 38 children from the Kaiser population in Northern California found several pregnancy complications (pre-eclampsia, intrauterine growth restriction) and delivery complications (emergency cesarean section, 5 min Apgar <7, resuscitation at birth) to be associated with an increased risk of perinatal stroke.22 A follow-up study of the same population in Northern California of 40 children with perinatal stroke revealed an increased rate of pregnancy complications (infertility, pre-eclampsia, chorioamnionitis) and delivery complications (prolonged rupture of membranes) among cases compared to controls.10 A case–control study from the Netherlands of 31 preterm infants with perinatal stroke also found an increased rate of intrapartum complications.23 Early studies of perinatal stroke reported a history of birth asphyxia among several cases.8,24,25 At present, there is little evidence to support the association between perinatal stroke and birth asphyxia. Hemiplegic cerebral palsy, a common outcome of perinatal stroke, is not considered to be caused by perinatal hypoxic ischemia.26 In early studies of perinatal stroke, birth asphyxia was variably defined and these findings have not been confirmed in more recent studies. A recent study of full-term infants with stroke found no significant difference between cases and controls in abnormalities of intrauterine cardiac monitoring, umbilical artery pH, or Apgar score at 5 min.10 The analysis of obstetric factors associated with neonatal stroke is done in this seminar by Cowan and Choong (Chapter 3). 5.3. Cardiac disorders Cardiac disorders are a common risk factor for ischemic stroke in neonates and children. These disorders can lead to the development of intracardiac thrombi that can embolize to the brain. Several cardiac disorders and cardiac surgery complications have been reported in neonates and children with stroke.27–29 Neonates with congenital heart disease are at an increased risk of stroke before and after surgical repair.30 Neuroimaging studies performed preoperatively on infants scheduled for congenital heart disease surgery have revealed high rates of stroke.29,31 A recent study from the Hospital for Sick Children estimated that 1 out of 185 children with congenital heart disease who undergo surgery will develop
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a stroke. The study also found a number of variables to be associated with stroke, including older age at time of procedure, longer duration of bypass, and reoperation procedures.32 Infants with congenital heart disease who develop a perinatal stroke may have other coexisting genetic or acquired risk factors that predispose to thrombosis.16 5.4. Blood disorders Over the last 10 years, there has been an increased interest in the contribution of inherited coagulation and metabolic factors to the risk of stroke in infants and children. Whether genetic factors play a substantial role in perinatal stroke is uncertain. Several genetic and acquired prothrombotic abnormalities have been evaluated in infants with stroke, but there has been wide variability in the factors evaluated and the populations studied. Prothrombotic risk factors in the infant are discussed in this seminar by Cnossen et al. (Chapter 8). A study by Miller et al., which evaluated a large panel of single nucleotide polymorphisms associated with thrombosis, failed to show a difference between cases and controls.33 5.5. Infection, trauma and catheterization procedures Infection leads to a hypercoagulable state and is a risk factor for perinatal stroke.34 Cerebral arterial and venous thrombosis has been reported as a complication of meningitis, disseminated intravascular coagulation, and sepsis.35 During serious infection, there is a rapid destruction of protein C and antithrombin III, both of which normally inhibit coagulation. Infection produces endothelial injury and a release of inflammatory cytokines, which can lead to the downregulation of thrombomodulin. Meningitis has been reported in association with perinatal stroke in several large series. A study by Fitzgerald et al. revealed that meningitis was present in 2% of cases of ischemic stroke and 8% of cases of sinovenous thrombosis.35 Meningitis was reported among 5% of cases in a perinatal stroke study in California10 and in 7% of cases from a study in Canada.36 Certain acquired conditions, including dehydration, trauma, and catheterization procedures have been reported in association with neonatal arterial and venous thrombosis. Genetic risk factors may also predispose to the development of catheter-related thrombosis.37 6. Outcome Children who suffer perinatal stroke typically develop longterm disabilities including motor deficits, cognitive disorders, and epilepsy. The outcome after perinatal stroke has varied widely among studies due to differences in functional measures, stroke types, duration of follow-up, and cohorts studied. A summary review of studies of perinatal stroke over a 30 year period found that at follow-up 40% of infants were considered neurologically normal, 57% had motor and/or cognitive deficits, and 3% died from the stroke.38 Perinatal stroke is a common cause of congenital hemiplegia. Motor dysfunction, ranging from mild hand weakness to severe quadriplegia, has varied widely among case series. Among the largest series of perinatal stroke, the rates of motor disability and cerebral palsy have ranged from 50% to 60%.36,39–41 Despite these findings, most children with perinatal stroke will walk independently by 2 years of age.42 Neuroimaging and electroencephalography studies may be helpful in predicting long-term motor outcome. Advances in neuroimaging have allowed for enhancements in both the diagnosis and prognosis of perinatal stroke. Neuroimaging studies, including
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multimodal MRI, have improved our ability to predict long-term motor outcome. In general, lesion size and location are important predictors of long-term motor disability. A long-term follow-up study found that infants with involvement of the internal capsule are more likely to develop motor deficits.41 Infants with stroke involving the motor cortex, basal ganglia, and internal capsule are most likely to develop hemiparesis.43 Electroencephalography (EEG) in combination with MRI may also be helpful in predicting prognosis. A follow-up study of infants with perinatal stroke revealed an association between early EEG and MRI abnormalities and motor outcome after 15 months.44 Infants with an abnormal background on EEG in the first week were more likely to develop hemiplegia. While most neonates with stroke will present with seizures, the majority do not have epilepsy after the neonatal period. The incidence of recurrent seizures after perinatal stroke has ranged from 0% to 40%.11,13,40 The severity of early seizures and neurologic examination at discharge may also aid in prognosis.36 Cognitive and behavioral disorder estimates have been difficult to interpret due to the variability in outcome measures and the heterogeneity of the population studied. Cognitive and behavioral abnormalities have been identified in up to 55% of children with perinatal stroke.13 A large Canadian series of 46 children with neonatal stroke followed for a mean of 42 months found that 41% developed some cognitive abnormality.36 A population-based study from Northern California of 40 children with perinatal stroke identified language delay in 25% of cases.40 Despite these results, other studies have shown good outcomes. A study of 29 children with unilateral perinatal stroke revealed that all children aged >2 years had IQ scores in the normal range.39 A recent study from the UK including children with neonatal unilateral middle cerebral artery stroke found that the 78% had normal IQ at school age.45 While cognitive disorders are common, behavior abnormalities are relatively rare. A population-based study from Northern California of 40 children with perinatal stroke identified behavioral disorders in 18% of cases.40 A case–control study of 39 children with unilateral perinatal stroke found no significant difference between cases and controls in clinically significant behavioral or emotional problems.46 Case mortality rates for perinatal stroke have ranged as high as 22% among hospital-based series.24 A summary review of studies of perinatal stroke over a 30 year period found that 3% died from the stroke.38 In 2005, in the USA, the infant death rate due to cerebrovascular disorders was 3 per 100 000.47 The recurrence rate after perinatal stroke is very low. The largest prospective study of neonatal stroke which followed 215 children for a median of 3.5 years found that only 1.8% developed a recurrent stroke, and 3.3% of children developed a recurrent symptomatic thromboembolism.48 7. Summary and future recommendations Cerebrovascular disorders in neonates are an important cause of chronic morbidity in children, and are an emerging area for clinical research. The clinical presentation may be subtle, and recent population-based studies suggest that many go undiagnosed in the perinatal period. Several risk factors for perinatal stroke have been reported, but there are few controlled studies on environmental factors inherent to the perinatal period. Recent evidence suggests that these factors in combination with coagulation abnormalities probably contribute the most risk for perinatal stroke. Improvements in neuroimaging have improved our understanding of the underlying mechanisms of stroke in neonates and long-term outcome. Currently, there is a need for well-controlled studies which utilize a consensus perinatal stroke classification system and a standard diagnostic strategy and evaluation of risk factors and outcome.
Effective treatment and prevention strategies can only be developed when the causes of stroke in infants are understood and populations at greatest risk are identified. International collaborations are currently ongoing to collect information on the risk factors, treatment and outcome of perinatal stroke, and to establish a network of investigators for future prevention and treatment studies. Conflict of interest None declared. Funding sources Dr. Lynch is supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. References 1. Benders MJ, Groenendaal F, Uiterwaal CS, de Vries LS. Perinatal arterial stroke in the preterm infant. Semin Perinatol 2008;32:344–9. 2. Golomb MR, Garg BP, Edwards-Brown M, Williams LS. Very early arterial ischemic stroke in premature infants. Pediatr Neurol 2008;38:329–34. 3. Aso K, Scher MS, Barmada MA. Cerebral infarcts and seizures in the neonate. J Child Neurol 1990;5:224–8. 4. Golomb MR, Dick PT, MacGregor DL, Armstrong DC, DeVeber GA. Cranial ultrasonography has a low sensitivity for detecting arterial ischemic stroke in term neonates. J Child Neurol 2003;18:98–103. 5. Mercuri E, Cowan F, Rutherford M, Acolet D, Pennock J, Dubowitz L. Ischaemic and haemorrhagic brain lesions in newborns with seizures and normal apgar scores. Arch Dis Child Fetal Neonatal Ed 1995;73:F67–74. 6. Krishnamoorthy KS, Soman TB, Takeoka M, Schaefer PW. Diffusion-weighted imaging in neonatal cerebral infarction: clinical utility and follow-up. J Child Neurol 2000;15:592–602. 7. Raju TN, Nelson KB, Ferriero D, Lynch JK. Ischemic perinatal stroke: summary of a workshop sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Pediatrics 2007;120:609–16. 8. Perlman JM, Rollins NK, Evans D. Neonatal stroke: clinical characteristics and cerebral blood flow velocity measurements. Pediatr Neurol 1994;11:281–4. 9. Schulzke S, Weber P, Luetschg J, Fahnenstich H. Incidence and diagnosis of unilateral arterial cerebral infarction in newborn infants. J Perinat Med 2005;33:170–5. 10. Lee L, Croen LA, Backstrand KH, et al. Maternal and infant characteristics associated with perinatal arterial stroke in the newborn. J Am Med Assoc 2005;293:723–9. 11. Estan J, Hope P. Unilateral neonatal cerebral infarction in full term infants. Arch Dis Child Fetal Neonatal Ed 1997;76:F88–93. 12. Laugesaar R, Kolk A, Tomberg T, et al. Acutely and retrospectively diagnosed perinatal stroke: a population-based study. Stroke 2007;38:2234–40. 13. Golomb MR, MacGregor DL, Domi T, et al. Presumed pre- or perinatal arterial ischemic stroke: risk factors and outcomes. Ann Neurol 2001;50:163–8. 14. Martinelli I. Thromboembolism in women. Semin Thromb Hemost 2006;32: 709–15. 15. Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008;6:632–7. 16. Curry CJ, Bhullar S, Holmes J, Delozier CD, Roeder ER, Hutchison HT. Risk factors for perinatal arterial stroke: a study of 60 mother–child pairs. Pediatr Neurol 2007;37:99–107. 17. Simchen MJ, Goldstein G, Lubetsky A, et al. Leiden and antiphospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke. Stroke 2009;40:65–70. 18. Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med 2002;347:19–25. 19. Rodger MA, Paidas M, McLintock C, et al. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol 2008;112:320–4. 20. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003;361:901–8. 21. Lee DK, Kim JS, Kwon SU, Yoo SH, Kang DW. Lesion patterns and stroke mechanism in atherosclerotic middle cerebral artery disease: early diffusionweighted imaging study. Stroke 2005;36:2583–8. 22. Wu YW, March WM, Croen LA, Grether JK, Escobar GJ, Newman TB. Perinatal stroke in children with motor impairment: a population-based study. Pediatrics 2004;114:612–9. 23. Benders MJ, Groenendaal F, Uiterwaal CS, et al. Maternal and infant characteristics associated with perinatal arterial stroke in the preterm infant. Stroke 2007;38:1759–65. 24. Ment LR, Duncan CC, Ehrenkranz RA. Perinatal cerebral infarction. Ann Neurol 1984;16:559–68.
J.K. Lynch / Seminars in Fetal & Neonatal Medicine 14 (2009) 245–249 25. Mannino FL, Trauner DA. Stroke in neonates. J Pediatr 1983;102:605–10. 26. Rennie JM, Hagmann CF, Robertson NJ. Outcome after intrapartum hypoxic ischaemia at term. Semin Fetal Neonatal Med 2007;12:398–407. 27. Pellicer A, Cabanas F, Garcia-Alix A, Perez-Higueras A, Quero J. Stroke in neonates with cardiac right-to-left shunt. Brain Dev 1992;14:381–5. 28. Kirkham FJ. Recognition and prevention of neurological complications in pediatric cardiac surgery. Pediatr Cardiol 1998;19:331–45. 29. McQuillen PS, Barkovich AJ, Hamrick SE, et al. Temporal and anatomic risk profile of brain injury with neonatal repair of congenital heart defects. Stroke 2007;38:736–41. 30. Miller SP, McQuillen PS, Hamrick S, et al. Abnormal brain development in newborns with congenital heart disease. N Engl J Med 2007;357:1928–38. 31. Mahle WT, Tavani F, Zimmerman RA, et al. An MRI study of neurological injury before and after congenital heart surgery. Circulation 2002;106:I109–14. 32. Domi T, Edgell DS, McCrindle BW, et al. Frequency, predictors, and neurologic outcomes of vaso-occlusive strokes associated with cardiac surgery in children. Pediatrics 2008;122:1292–8. 33. Miller SP, Wu YW, Lee J, et al. Candidate gene polymorphisms do not differ between newborns with stroke and normal controls. Stroke 2006;37:2678–83. 34. Ment LR, Ehrenkranz RA, Duncan CC. Bacterial meningitis as an etiology of perinatal cerebral infarction. Pediatr Neurol 1986;2:276–9. 35. Fitzgerald KC, Golomb MR. Neonatal arterial ischemic stroke and sinovenous thrombosis associated with meningitis. J Child Neurol 2007;22:818–22. 36. Sreenan C, Bhargava R, Robertson CM. Cerebral infarction in the term newborn: clinical presentation and long-term outcome. J Pediatr 2000;137:351–5. 37. Nowak-Gottl U, Dubbers A, Kececioglu D, et al. Factor V Leiden, protein C, and lipoprotein (a) in catheter-related thrombosis in childhood: a prospective study. J Pediatr 1997;131:608–12.
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38. Lynch JK, Nelson KB. Epidemiology of perinatal stroke. Curr Opin Pediatr 2001;13:499–505. 39. Trauner DA, Chase C, Walker P, Wulfeck B. Neurologic profiles of infants and children after perinatal stroke. Pediatr Neurol 1993;9:383–6. 40. Lee J, Croen LA, Lindan C, et al. Predictors of outcome in perinatal arterial stroke: a population-based study. Ann Neurol 2005;58:303–8. 41. Mercuri E, Barnett A, Rutherford M, et al. Neonatal cerebral infarction and neuromotor outcome at school age. Pediatrics 2004;113:95–100. 42. Golomb MR, deVeber GA, MacGregor DL, et al. Independent walking after neonatal arterial ischemic stroke and sinovenous thrombosis. J Child Neurol 2003;18:530–6. 43. Boardman JP, Ganesan V, Rutherford MA, Saunders DE, Mercuri E, Cowan F. Magnetic resonance image correlates of hemiparesis after neonatal and childhood middle cerebral artery stroke. Pediatrics 2005;115:321–6. 44. Mercuri E, Rutherford M, Cowan F, et al. Early prognostic indicators of outcome in infants with neonatal cerebral infarction: a clinical, electroencephalogram, and magnetic resonance imaging study. Pediatrics 1999;103:39–46. 45. Ricci D, Mercuri E, Barnett A, et al. Cognitive outcome at early school age in term-born children with perinatally acquired middle cerebral artery territory infarction. Stroke 2008;39:403–10. 46. Trauner DA, Nass R, Ballantyne A. Behavioural profiles of children and adolescents after pre- or perinatal unilateral brain damage. Brain 2001;124:995–1002. 47. Kung HC, Hoyert DL, Xu J, Murphy SL. Deaths: final data for 2005. Natl Vital Stat Rep 2008;56:37. 48. Kurnik K, Kosch A, Strater R, Schobess R, Heller C, Nowak-Gottl U. Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke: a prospective follow-up study. Stroke 2003;34: 2887–92.
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Epidemiology and classification of perinatal stroke John Kylan Lynch* Division of Stroke Diagnostics and Therapeutics, National Institutes of Neurological Disorders and Stroke, 10 Center Drive, MSC 1447, Bethesda, MD 20892-1447, USA
s u m m a r y Keywords: Epidemiology Ischemic stroke Outcome Perinatal stroke Risk factors
Stroke is an important cause of mortality and chronic morbidity in infants and children. Case definitions for perinatal stroke have varied among studies by clinical and laboratory criteria. A recent US National Institutes of Health workshop on perinatal stroke provided consensus recommendations on the definition and classification of perinatal stroke. The incidence of perinatal stroke has been estimated at 1 in 1600 to 5000 births. The clinical presentation of perinatal stroke depends on the time of diagnosis, acute or delayed, but most will present with seizures. Risk factors for perinatal stroke have not been well studied. Several maternal and neonatal disorders have been reported in infants with perinatal stroke. Children who suffer perinatal stroke typically develop long-term disabilities including motor deficits, cognitive and behavioral disorders, and epilepsy. More than half will develop long-term motor or cognitive problems and the recurrence rate after perinatal stroke is very low. Ó 2009 Published by Elsevier Ltd.
1. Introduction Over the last several years, our knowledge of perinatal stroke has substantially improved, but much work remains. Recent epidemiological studies have provided important information on the incidence, risk factors, and outcome of stroke in neonates. Factors associated with stroke in the perinatal period include maternal disorders, blood disorders, cardiac disorders, infection, and other miscellaneous disorders. It is clear that stroke is an important cause of mortality and chronic morbidity in children. Of the infants who suffer a stroke each year, more than half will have permanent motor or cognitive disability. The recurrence rate after perinatal stroke is less than 3% and there are no established treatment or prevention strategies. This paper discusses the epidemiology of arterial ischemic stroke occurring in the perinatal and neonatal periods, including both cerebrovascular events that are diagnosed during the perinatal period and also those diagnosed retrospectively, when evidence of hemiparesis or postneonatal seizures leads to later evaluation and neuroimaging. 2. Definition and classification Perinatal stroke typically refers to neurologic signs and symptoms due to a vascular cause around the time of birth, with confirmatory evidence by neuroimaging or pathology. Case
* Tel.: þ1 301 896 7547; fax: þ1 301 896 4002. E-mail address: [email protected] 1744-165X/$ – see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.siny.2009.07.001
definitions for perinatal stroke studies have varied by age at diagnosis and by clinical and laboratory criteria. Perinatal stroke occurs most often in term or near-term infants, but is also reported in preterm infants.1,2 Diagnostic confirmation of perinatal stroke is typically based on neuroimaging findings, but autopsy criteria have been used in the past.3 The time at diagnosis is usually within the first few days of life, but some studies have included cases that were identified after the perinatal period. A diagnosis of presumed perinatal stroke is considered when post-perinatal neuroimaging reveals chronic changes suggestive of a stroke during an earlier period. Although the precise timing of this injury cannot be determined, the stroke is presumed to be perinatal in onset if the infant had been neurologically well since birth without any symptoms of acute stroke. It is unclear whether these remotely diagnosed cases should be included, as the underlying risk factors and outcome may differ. Why these strokes are not captured in the perinatal period is unclear, but is likely related to a case-finding strategy that requires clinical events and imaging studies. Some infants with stroke may not manifest symptoms to elicit imaging studies, or the studies that are performed are not sensitive enough to detect acute ischemic stroke. Ultrasound may be less sensitive for the detection of stroke than computed tomography or magnetic resonance imaging (MRI).4 Diagnostic criteria for stroke may be negative in cases where early imaging studies are normal.5,6 Studies of perinatal stroke have also differed in the inclusion of stroke subtypes: perinatal arterial ischemic stroke, cerebral sinovenous thrombosis, intracerebral hemorrhage, and periventricular venous infarction. In August 2006, the United States National Institutes of Health convened a workshop on perinatal stroke to develop consensus
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recommendations on the definition and classification of perinatal stroke. The participants proposed a working definition of perinatal stroke to include ‘a vascular event causing focal interruption of blood supply, occurring between 20 weeks of fetal life through 28th postnatal day, and confirmed by neuroimaging or neuropathology studies.’ The workshop panel also classified perinatal stroke according to two major subtypes, ischemic (including cerebral venous thrombosis) and hemorrhagic perinatal stroke. 7 3. Incidence The incidence of perinatal stroke has been estimated at 1 in 1600 to 5000 births.8–12 Incidence estimates have been difficult to interpret due to the variability in clinical and diagnostic criteria, number of cases, and underlying population. In most studies, cases were defined as infants with arterial ischemic stroke diagnosed in the neonatal period. More recent studies have included retrospectively diagnosed cases as well as hemorrhagic stroke. A population-based study of perinatal stroke in the USA that included acutely and retrospectively diagnosed cases found an overall incidence of 20 per 100 000 live births.10 A study in Estonia which included acute, delayed, and hemorrhage cases reported a much higher rate at 63 per 100 000 live births.12 In both of these studies, retrospectively diagnosed cases were more common than acute cases and suggest that the burden of perinatal stroke may be greater than in previous reports. 4. Clinical presentation The clinical presentation of perinatal stroke depends on the age at diagnosis. In infants who are diagnosed in the newborn period, most present with seizures. There may also be signs and symptoms of neonatal encephalopathy such as lethargy, hypotonia, feeding difficulties, or apnea. In infants with presumed perinatal stroke who are not diagnosed until months later, the presentation includes focal hand weakness, delayed milestones, and/or seizures. Whether an infant is diagnosed in the newborn period or several months later may depend on the size and location of the stroke and other clinical factors. It seems possible that infants with certain patterns of injury, such as those involving the basal ganglia that spare the cortex, may be more difficult to diagnose in the newborn period because these infants are less likely to exhibit neonatal seizures. In a large series by Golomb of presumed perinatal stroke cases, 40% of the strokes were restricted to small perforating arteries of the middle cerebral artery.13 A second study of latediagnosed cases revealed that only 40% had cortical involvement.12 At present, there are limited data on differences in underlying risk factors among acutely and retrospectively diagnosed cases that could account for time at diagnosis. Maternal and pregnancyrelated disorders including chorioamnionitis, placental disorders, and birth asphyxia seem to be more prevalent in acutely diagnosed cases.10,12 These findings suggest that the presence of specific clinical factors may predispose to seizures or symptoms that lead to a diagnosis of perinatal stroke in the newborn period. 5. Risk factors Risk factors for perinatal stroke have not been well studied. Most studies of perinatal stroke have been descriptive and have provided little information on quantitative risk estimates, environmental factors, and genetic and environmental interactions. There have been few controlled studies of factors specific to stroke risk in the perinatal period, such as maternal characteristics, placental disorders, and other complications of birth and pregnancy. Environmental factors related to the peripartum period
likely play a major role in the perinatal stroke as the recurrence rate is extremely low. Several maternal and neonatal disorders have been reported in infants with perinatal stroke (Table 1).
5.1. Maternal coagulation disorders Pregnancy is a time of relative hypercoagulability during which several plasma proteins are affected and thrombin generation is increased. Venous thromboembolism is common during pregnancy with risk highest during the third trimester and puerperium,14 time periods when most perinatal strokes are likely to occur. The addition of a coagulation abnormality in the setting of pregnancy may lead to thrombosis. Maternal coagulation disorders are associated with an increased risk of thrombosis in pregnancy15 and perinatal stroke. Two recent studies found an increased rate of specific acquired and genetic coagulation abnormalities among mothers of children with perinatal stroke.16,17 In the first study, prothrombotic abnormalities were identified in 55% of mothers and 50% of infants with perinatal stroke.16 A second case–control study from Israel revealed similar findings with 68% of mothers and 64% of infants with a coagulation abnormality. In addition, this study found that the presence of factor V Leiden (FVL) or antiphospholipid
Table 1 Maternal and infant disorders reported with perinatal stroke. Maternal disorders Infertility Pre-eclampsia Chorioamnionitis Autoimmune disorders Coagulation disorders Twin to twin transfusion syndrome Cocaine use Placental disorders Placental thrombosis Placental abruption Placental infection Fetomaternal hemorrhage Placental chorioangioma Blood, homocysteine and lipid disorders Polycythemia Disseminated intravascular coagulopathy Factor V Leiden mutation Protein S deficiency Protein C deficiency Prothrombin 20210A mutation Homocysteine Elevated Lipoprotein a Factor VIII Antiphospholipid antibodies Cardiac disorders Congenital heart disease Patent ductus arteriosus Pulmonary valve atresia Cardiac surgery Infectious disorders Meningitis Systemic infection Miscellaneous disorders Vascular maldevelopment Arterial dissection Trauma Catheterization Dehydration Extracorporeal membrane oxygenation (ECMO)
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antibodies in the mothers increased the risk of perinatal stroke severalfold.17 The results of these studies suggest that the presence of a coagulation disorder in the mother may increase the risk of perinatal stroke in the child. The pathway through which these disorders lead to perinatal stroke is undetermined, but may be due to thrombosis at the placenta, where maternal uterine spiral arteries profuse fetal villous vessels in an area of low pressure. Thrombus formation at the placenta could impede maternal–fetal circulation and potentially lead to pregnancy complications or embolization. Thrombosis on the maternal side may possibly lead to miscarriage, pre-eclampsia, and intrauterine growth restriction. While several placental and pregnancy-related disorders have been reported in association with mothers of infants with perinatal stroke, controlled studies of maternal thrombophilia and placentarelated pregnancy complications have been inconsistent and the risk is clearly not established.18–20 Thrombosis on the fetal side could provide a source of emboli that could bypass the hepatic and pulmonary circulation and embolize to the fetal brain. 5.2. Complications of pregnancy and delivery Complications of pregnancy and delivery are common among mother of infants with perinatal stroke.16,21–23 Case–control studies of perinatal stroke have found several obstetrical complications to be more frequent in mothers of infants with stroke than in control mothers. A nested case–control study by Wu of 38 children from the Kaiser population in Northern California found several pregnancy complications (pre-eclampsia, intrauterine growth restriction) and delivery complications (emergency cesarean section, 5 min Apgar <7, resuscitation at birth) to be associated with an increased risk of perinatal stroke.22 A follow-up study of the same population in Northern California of 40 children with perinatal stroke revealed an increased rate of pregnancy complications (infertility, pre-eclampsia, chorioamnionitis) and delivery complications (prolonged rupture of membranes) among cases compared to controls.10 A case–control study from the Netherlands of 31 preterm infants with perinatal stroke also found an increased rate of intrapartum complications.23 Early studies of perinatal stroke reported a history of birth asphyxia among several cases.8,24,25 At present, there is little evidence to support the association between perinatal stroke and birth asphyxia. Hemiplegic cerebral palsy, a common outcome of perinatal stroke, is not considered to be caused by perinatal hypoxic ischemia.26 In early studies of perinatal stroke, birth asphyxia was variably defined and these findings have not been confirmed in more recent studies. A recent study of full-term infants with stroke found no significant difference between cases and controls in abnormalities of intrauterine cardiac monitoring, umbilical artery pH, or Apgar score at 5 min.10 The analysis of obstetric factors associated with neonatal stroke is done in this seminar by Cowan and Choong (Chapter 3). 5.3. Cardiac disorders Cardiac disorders are a common risk factor for ischemic stroke in neonates and children. These disorders can lead to the development of intracardiac thrombi that can embolize to the brain. Several cardiac disorders and cardiac surgery complications have been reported in neonates and children with stroke.27–29 Neonates with congenital heart disease are at an increased risk of stroke before and after surgical repair.30 Neuroimaging studies performed preoperatively on infants scheduled for congenital heart disease surgery have revealed high rates of stroke.29,31 A recent study from the Hospital for Sick Children estimated that 1 out of 185 children with congenital heart disease who undergo surgery will develop
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a stroke. The study also found a number of variables to be associated with stroke, including older age at time of procedure, longer duration of bypass, and reoperation procedures.32 Infants with congenital heart disease who develop a perinatal stroke may have other coexisting genetic or acquired risk factors that predispose to thrombosis.16 5.4. Blood disorders Over the last 10 years, there has been an increased interest in the contribution of inherited coagulation and metabolic factors to the risk of stroke in infants and children. Whether genetic factors play a substantial role in perinatal stroke is uncertain. Several genetic and acquired prothrombotic abnormalities have been evaluated in infants with stroke, but there has been wide variability in the factors evaluated and the populations studied. Prothrombotic risk factors in the infant are discussed in this seminar by Cnossen et al. (Chapter 8). A study by Miller et al., which evaluated a large panel of single nucleotide polymorphisms associated with thrombosis, failed to show a difference between cases and controls.33 5.5. Infection, trauma and catheterization procedures Infection leads to a hypercoagulable state and is a risk factor for perinatal stroke.34 Cerebral arterial and venous thrombosis has been reported as a complication of meningitis, disseminated intravascular coagulation, and sepsis.35 During serious infection, there is a rapid destruction of protein C and antithrombin III, both of which normally inhibit coagulation. Infection produces endothelial injury and a release of inflammatory cytokines, which can lead to the downregulation of thrombomodulin. Meningitis has been reported in association with perinatal stroke in several large series. A study by Fitzgerald et al. revealed that meningitis was present in 2% of cases of ischemic stroke and 8% of cases of sinovenous thrombosis.35 Meningitis was reported among 5% of cases in a perinatal stroke study in California10 and in 7% of cases from a study in Canada.36 Certain acquired conditions, including dehydration, trauma, and catheterization procedures have been reported in association with neonatal arterial and venous thrombosis. Genetic risk factors may also predispose to the development of catheter-related thrombosis.37 6. Outcome Children who suffer perinatal stroke typically develop longterm disabilities including motor deficits, cognitive disorders, and epilepsy. The outcome after perinatal stroke has varied widely among studies due to differences in functional measures, stroke types, duration of follow-up, and cohorts studied. A summary review of studies of perinatal stroke over a 30 year period found that at follow-up 40% of infants were considered neurologically normal, 57% had motor and/or cognitive deficits, and 3% died from the stroke.38 Perinatal stroke is a common cause of congenital hemiplegia. Motor dysfunction, ranging from mild hand weakness to severe quadriplegia, has varied widely among case series. Among the largest series of perinatal stroke, the rates of motor disability and cerebral palsy have ranged from 50% to 60%.36,39–41 Despite these findings, most children with perinatal stroke will walk independently by 2 years of age.42 Neuroimaging and electroencephalography studies may be helpful in predicting long-term motor outcome. Advances in neuroimaging have allowed for enhancements in both the diagnosis and prognosis of perinatal stroke. Neuroimaging studies, including
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multimodal MRI, have improved our ability to predict long-term motor outcome. In general, lesion size and location are important predictors of long-term motor disability. A long-term follow-up study found that infants with involvement of the internal capsule are more likely to develop motor deficits.41 Infants with stroke involving the motor cortex, basal ganglia, and internal capsule are most likely to develop hemiparesis.43 Electroencephalography (EEG) in combination with MRI may also be helpful in predicting prognosis. A follow-up study of infants with perinatal stroke revealed an association between early EEG and MRI abnormalities and motor outcome after 15 months.44 Infants with an abnormal background on EEG in the first week were more likely to develop hemiplegia. While most neonates with stroke will present with seizures, the majority do not have epilepsy after the neonatal period. The incidence of recurrent seizures after perinatal stroke has ranged from 0% to 40%.11,13,40 The severity of early seizures and neurologic examination at discharge may also aid in prognosis.36 Cognitive and behavioral disorder estimates have been difficult to interpret due to the variability in outcome measures and the heterogeneity of the population studied. Cognitive and behavioral abnormalities have been identified in up to 55% of children with perinatal stroke.13 A large Canadian series of 46 children with neonatal stroke followed for a mean of 42 months found that 41% developed some cognitive abnormality.36 A population-based study from Northern California of 40 children with perinatal stroke identified language delay in 25% of cases.40 Despite these results, other studies have shown good outcomes. A study of 29 children with unilateral perinatal stroke revealed that all children aged >2 years had IQ scores in the normal range.39 A recent study from the UK including children with neonatal unilateral middle cerebral artery stroke found that the 78% had normal IQ at school age.45 While cognitive disorders are common, behavior abnormalities are relatively rare. A population-based study from Northern California of 40 children with perinatal stroke identified behavioral disorders in 18% of cases.40 A case–control study of 39 children with unilateral perinatal stroke found no significant difference between cases and controls in clinically significant behavioral or emotional problems.46 Case mortality rates for perinatal stroke have ranged as high as 22% among hospital-based series.24 A summary review of studies of perinatal stroke over a 30 year period found that 3% died from the stroke.38 In 2005, in the USA, the infant death rate due to cerebrovascular disorders was 3 per 100 000.47 The recurrence rate after perinatal stroke is very low. The largest prospective study of neonatal stroke which followed 215 children for a median of 3.5 years found that only 1.8% developed a recurrent stroke, and 3.3% of children developed a recurrent symptomatic thromboembolism.48 7. Summary and future recommendations Cerebrovascular disorders in neonates are an important cause of chronic morbidity in children, and are an emerging area for clinical research. The clinical presentation may be subtle, and recent population-based studies suggest that many go undiagnosed in the perinatal period. Several risk factors for perinatal stroke have been reported, but there are few controlled studies on environmental factors inherent to the perinatal period. Recent evidence suggests that these factors in combination with coagulation abnormalities probably contribute the most risk for perinatal stroke. Improvements in neuroimaging have improved our understanding of the underlying mechanisms of stroke in neonates and long-term outcome. Currently, there is a need for well-controlled studies which utilize a consensus perinatal stroke classification system and a standard diagnostic strategy and evaluation of risk factors and outcome.
Effective treatment and prevention strategies can only be developed when the causes of stroke in infants are understood and populations at greatest risk are identified. International collaborations are currently ongoing to collect information on the risk factors, treatment and outcome of perinatal stroke, and to establish a network of investigators for future prevention and treatment studies. Conflict of interest None declared. Funding sources Dr. Lynch is supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. References 1. Benders MJ, Groenendaal F, Uiterwaal CS, de Vries LS. Perinatal arterial stroke in the preterm infant. Semin Perinatol 2008;32:344–9. 2. Golomb MR, Garg BP, Edwards-Brown M, Williams LS. Very early arterial ischemic stroke in premature infants. Pediatr Neurol 2008;38:329–34. 3. Aso K, Scher MS, Barmada MA. Cerebral infarcts and seizures in the neonate. J Child Neurol 1990;5:224–8. 4. Golomb MR, Dick PT, MacGregor DL, Armstrong DC, DeVeber GA. Cranial ultrasonography has a low sensitivity for detecting arterial ischemic stroke in term neonates. J Child Neurol 2003;18:98–103. 5. Mercuri E, Cowan F, Rutherford M, Acolet D, Pennock J, Dubowitz L. Ischaemic and haemorrhagic brain lesions in newborns with seizures and normal apgar scores. Arch Dis Child Fetal Neonatal Ed 1995;73:F67–74. 6. Krishnamoorthy KS, Soman TB, Takeoka M, Schaefer PW. Diffusion-weighted imaging in neonatal cerebral infarction: clinical utility and follow-up. J Child Neurol 2000;15:592–602. 7. Raju TN, Nelson KB, Ferriero D, Lynch JK. Ischemic perinatal stroke: summary of a workshop sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Pediatrics 2007;120:609–16. 8. Perlman JM, Rollins NK, Evans D. Neonatal stroke: clinical characteristics and cerebral blood flow velocity measurements. Pediatr Neurol 1994;11:281–4. 9. Schulzke S, Weber P, Luetschg J, Fahnenstich H. Incidence and diagnosis of unilateral arterial cerebral infarction in newborn infants. J Perinat Med 2005;33:170–5. 10. Lee L, Croen LA, Backstrand KH, et al. Maternal and infant characteristics associated with perinatal arterial stroke in the newborn. J Am Med Assoc 2005;293:723–9. 11. Estan J, Hope P. Unilateral neonatal cerebral infarction in full term infants. Arch Dis Child Fetal Neonatal Ed 1997;76:F88–93. 12. Laugesaar R, Kolk A, Tomberg T, et al. Acutely and retrospectively diagnosed perinatal stroke: a population-based study. Stroke 2007;38:2234–40. 13. Golomb MR, MacGregor DL, Domi T, et al. Presumed pre- or perinatal arterial ischemic stroke: risk factors and outcomes. Ann Neurol 2001;50:163–8. 14. Martinelli I. Thromboembolism in women. Semin Thromb Hemost 2006;32: 709–15. 15. Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008;6:632–7. 16. Curry CJ, Bhullar S, Holmes J, Delozier CD, Roeder ER, Hutchison HT. Risk factors for perinatal arterial stroke: a study of 60 mother–child pairs. Pediatr Neurol 2007;37:99–107. 17. Simchen MJ, Goldstein G, Lubetsky A, et al. Leiden and antiphospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke. Stroke 2009;40:65–70. 18. Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med 2002;347:19–25. 19. Rodger MA, Paidas M, McLintock C, et al. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol 2008;112:320–4. 20. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003;361:901–8. 21. Lee DK, Kim JS, Kwon SU, Yoo SH, Kang DW. Lesion patterns and stroke mechanism in atherosclerotic middle cerebral artery disease: early diffusionweighted imaging study. Stroke 2005;36:2583–8. 22. Wu YW, March WM, Croen LA, Grether JK, Escobar GJ, Newman TB. Perinatal stroke in children with motor impairment: a population-based study. Pediatrics 2004;114:612–9. 23. Benders MJ, Groenendaal F, Uiterwaal CS, et al. Maternal and infant characteristics associated with perinatal arterial stroke in the preterm infant. Stroke 2007;38:1759–65. 24. Ment LR, Duncan CC, Ehrenkranz RA. Perinatal cerebral infarction. Ann Neurol 1984;16:559–68.
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