ABSTRACT
Arterial ischemic infarction occurring around the time of birth is an increasingly recognized cause of neurological disability in children. The rate of arterial infarction in neonates is as high as the annual incidence of large-vessel ischemic stroke in adults. Factors contributing to this increased risk of stroke among neonates include complications that occur before, during, and after delivery. Maternal conditions that have been associated with perinatal stroke in the fetus include prothrombotic disorders, cocaine abuse, and placental complications such as chorioamnionitis and placental vasculopathy. In many cases, the placenta is suspected to be the underlying embolic source for perinatal stroke, although data on placental pathology is often lacking. During the delivery process, an infant may develop a cervical arterial dissection that leads to stroke. Several conditions in the neonatal period predispose to perinatal stroke including prothrombotic disorders, congenital heart disease, meningitis, and systemic infection. Perinatal stroke may present with neonatal seizures during the first weeks of life or may be asymptomatic until months later when the infant is first noted to have pathological handedness. The outcome of perinatal stroke is variable and depends on severity, anatomic localization, and other factors not yet well characterized. As many as 50% of infants with documented stroke recognized in the newborn period do not develop a hemiparesis. The incidence, clinical presentation, pathogenesis, risk factors, and outcome of this increasingly recognized disorder are reviewed.
KEYWORDS
Perinatal arterial stroke - epidemiology - risk factors - outcome
REFERENCES
-
1
Schneider A T, Kissela B, Woo D et al..
Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites.
Stroke.
2004;
35
1552-1556
-
2
Fullerton H J, Wu Y W, Zhao S, Johnston S C.
Risk of stroke in children: ethnic and gender disparities.
Neurology.
2003;
61
189-194
-
3
Wu Y W, Escobar G J, Grether J K, Croen L A, Greene J D, Newman T B.
Chorioamnionitis and cerebral palsy in term and near-term infants.
JAMA.
2003;
290
2677-2684
-
4
Lynch J K, Nelson K B.
Neonatal stroke in the United States: results of the national hospital discharge survey, 1980-1998.
Neurology.
2001;
56
A10
-
5
Schmidt B, Zipursky A.
Thrombotic disease in newborn infants.
Clin Perinatol.
1984;
11
461-488
-
6
Manco-Johnson M J, Nuss R.
Thrombophilia in the infant and child.
Adv Pediatr.
2001;
48
363-384
-
7
Andrew M E, Monagle P, deVeber G, Chan A K.
Thromboembolic disease and antithrombotic therapy in newborns.
Hematology (Am Soc Hematol Educ Program).
2001;
358-374
-
8
Wu Y W, March W M, Croen L A, Grether J K, Escobar G J, Newman T B.
Perinatal stroke in children with motor impairment: a population-based study.
Pediatrics.
2004;
114
612-619
-
9
Lao T T, Yin J A, Yuen P M.
Coagulation and anticoagulation systems in newborns-correlation with their mothers at delivery: lower levels of anticoagulants and fibrinolytic activity in the newborn.
Gynecol Obstet Invest.
1990;
29
181-184
-
10
Estan J, Hope P.
Unilateral neonatal cerebral infarction in full term infants.
Arch Dis Child Fetal Neonatal Ed.
1997;
76
F88-F93
-
11
Perlman J M, Rollins N K, Evans D.
Neonatal stroke: clinical characteristics and cerebral blood flow velocity measurements.
Pediatr Neurol.
1994;
11
281-284
-
12
Mercuri E, Cowan F, Gupte G et al..
Prothrombotic disorders and abnormal neurodevelopmental outcome in infants with neonatal cerebral infarction.
Pediatrics.
2001;
107
1400-1404
-
13
Wang L W, Huang C C, Yeh T F.
Major brain lesions detected on sonographic screening of apparently normal term neonates.
Neuroradiology.
2004;
46
368-373
-
14
Lee J L, Croen L A, Lindan C .
Predictors of outcome in perinatal arterial stroke: a population-based study.
Ann Neurol.
2005;
58
303-308
-
15
Lynch J K, Nelson K B.
Neonatal stroke in the United States: results of the National Hospital Discharge Survey, 1980-1998.
Neurology.
2001;
56(suppl 3)
A10
-
16
Lee J, Croen L A, Backstrand K H et al..
Maternal and infant characteristics associated with perinatal arterial stroke in the newborn.
JAMA.
2005;
293
723-729
-
17
Govaert P, Matthys E, Zecic A, Roelens F, Oostra A, Vanzieleghem B.
Perinatal cortical infarction within middle cerebral artery trunks.
Arch Dis Child Fetal Neonatal Ed.
2000;
82
F59-F63
-
18
Cowan F, Rutherford M, Groenendaal F et al..
Origin and timing of brain lesions in term infants with neonatal encephalopathy.
Lancet.
2003;
361
736-742
-
19
Miller V.
Neonatal cerebral infarction.
Semin Pediatr Neurol.
2000;
7
278-288
-
20
Mercuri E, Cowan F.
Cerebral infarction in the newborn infant: review of the literature and personal experience.
Eur J Paediatr Neurol.
1999;
3
255-263
-
21
Ment L R, Duncan C C, Ehrenkranz R A.
Perinatal cerebral infarction.
Ann Neurol.
1984;
16
559-568
-
22
Ramaswamy V, Miller S P, Barkovich A J, Partridge J C, Ferriero D M.
Perinatal stroke in term infants with neonatal encephalopathy.
Neurology.
2004;
62
2088-2091
-
23
Nelson K B, Ellenberg J H.
Neonatal signs as predictors of cerebral palsy.
Pediatrics.
1979;
64
225-232
-
24
Guzzetta A, Mercuri E, Rapisardi G et al..
General movements detect early signs of hemiplegia in term infants with neonatal cerebral infarction.
Neuropediatrics.
2003;
34
61-66
-
25
Al-Sulaiman A, Bademosi O, Ismail H, Magboll G.
Stroke in Saudi children.
J Child Neurol.
1999;
14
295-298
-
26
Suarez C R, Walenga J, Mangogna L C, Fareed J.
Neonatal and maternal fibrinolysis: activation at time of birth.
Am J Hematol.
1985;
19
365-372
-
27
Kraus F T, Acheen V I.
Fetal thrombotic vasculopathy in the placenta: cerebral thrombi and infarcts, coagulopathies, and cerebral palsy.
Hum Pathol.
1999;
30
759-769
-
28
Kraus F T.
Cerebral palsy and thrombi in placental vessels of the fetus: insights from litigation.
Hum Pathol.
1997;
28
246-248
-
29
Nelson K B, Lynch J K.
Stroke in newborn infants.
Lancet Neurol.
2004;
3
150-158
-
30
Lequin M H, Peeters E A, Holscher H C, de Krijger R, Govaert P.
Arterial infarction caused by carotid artery dissection in the neonate.
Eur J Paediatr Neurol.
2004;
8
155-160
-
31
Sreenan C, Bhargava R, Robertson C M.
Cerebral infarction in the term newborn: clinical presentation and long-term outcome.
J Pediatr.
2000;
137
351-355
-
32
Barmada M A, Moossy J, Shuman R M.
Cerebral infarcts with arterial occlusion in neonates.
Ann Neurol.
1979;
6
495-502
-
33
de Vries L S, Groenendaal F, Eken P, van Haastert I C, Rademaker K J, Meiners L C.
Infarcts in the vascular distribution of the middle cerebral artery in preterm and fullterm infants.
Neuropediatrics.
1997;
28
88-96
-
34
Stromberg B, Dahlquist G, Ericson A, Finnstrom O, Koster M, Stjernqvist K.
Neurological sequelae in children born after in-vitro fertilisation: a population-based study.
Lancet.
2002;
359
461-465
-
35
Ericson A, Nygren K G, Olausson P O, Kallen B.
Hospital care utilization of infants born after IVF.
Hum Reprod.
2002;
17
929-932
-
36
Badawi N, Kurinczuk J J, Keogh J M et al..
Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study.
BMJ.
1998;
317
1549-1553
-
37
Mannino F L, Trauner D A.
Stroke in neonates.
J Pediatr.
1983;
102
605-610
-
38
Roberts J M, Cooper D W.
Pathogenesis and genetics of pre-eclampsia.
Lancet.
2001;
357
53-56
-
39
Shah D M.
Perinatal implications of maternal hypertension.
Semin Pediatr Neurol.
2001;
8
108-119
-
40
Kupferminc M J, Eldor A, Steinman N et al..
Increased frequency of genetic thrombophilia in women with complications of pregnancy.
N Engl J Med.
1999;
340
9-13
-
41
Salafia C M, Pezzullo J C, Lopez-Zeno J A, Simmens S, Minior V K, Vintzileos A M.
Placental pathologic features of preterm preeclampsia.
Am J Obstet Gynecol.
1995;
173
1097-1105
-
42
Pabinger I, Grafenhofer H, Kaider A et al..
Preeclampsia and fetal loss in women with a history of venous thromboembolism.
Arterioscler Thromb Vasc Biol.
2001;
21
874-879
-
43
Hunt R W, Badawi N, Laing S, Lam A.
Pre-eclampsia: a predisposing factor for neonatal venous sinus thrombosis?.
Pediatr Neurol.
2001;
25
242-246
-
44
Bremme K A.
Haemostatic changes in pregnancy.
Best Pract Res Clin Haematol.
2003;
16
153-168
-
45
Malm J, Laurell M, Dahlback B.
Changes in the plasma levels of vitamin K-dependent proteins C and S and of C4b-binding protein during pregnancy and oral contraception.
Br J Haematol.
1988;
68
437-443
-
46
Silver R K, MacGregor S N, Pasternak J F, Neely S E.
Fetal stroke associated with elevated maternal anticardiolipin antibodies.
Obstet Gynecol.
1992;
80
497-499
-
47
Akanli L F, Trasi S S, Thuraisamy K et al..
Neonatal middle cerebral artery infarction: association with elevated maternal anticardiolipin antibodies.
Am J Perinatol.
1998;
15
399-402
-
48
Tabbutt S, Griswold W R, Ogino M T, Mendoza A E, Allen J B, Reznik V M.
Multiple thromboses in a premature infant associated with maternal phospholipid antibody syndrome.
J Perinatol.
1994;
14
66-70
-
49
de Klerk O L, de Vries T W, Sinnige L G.
An unusual cause of neonatal seizures in a newborn infant.
Pediatrics.
1997;
100
E8
-
50
Chow G, Mellor D.
Neonatal cerebral ischaemia with elevated maternal and infant anticardiolipin antibodies.
Dev Med Child Neurol.
2000;
42
412-413
-
51
De Carolis C, Greco E, Guarino M D et al..
Anti-thyroid antibodies and antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy outcome in recurrent spontaneous aborters.
Am J Reprod Immunol.
2004;
52
263-266
-
52
Chasnoff I J, Bussey M E, Savich R, Stack C M.
Perinatal cerebral infarction and maternal cocaine use.
J Pediatr.
1986;
108
456-459
-
53
Dominguez R, Aguirre V, Slopis J M, Bohan T P.
Brain and ocular abnormalities in infants with in utero exposure to cocaine and other street drugs.
Am J Dis Child.
1991;
145
688-695
-
54
Heier L A, Carpanzano C R, Mast J, Brill P W, Winchester P, Deck M D.
Maternal cocaine abuse: the spectrum of radiologic abnormalities in the neonatal CNS.
AJNR Am J Neuroradiol.
1991;
12
951-956
-
55
Lanir N, Aharon A, Brenner B.
Haemostatic mechanisms in human placenta.
Best Pract Res Clin Haematol.
2003;
16
183-195
-
56
Arias F, Romero R, Joist H, Kraus F T.
Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta.
J Matern Fetal Med.
1998;
7
277-286
-
57
Facchinetti F, Marozio L, Grandone E, Pizzi C, Volpe A, Benedetto C.
Thrombophilic mutations are a main risk factor for placental abruption.
Haematologica.
2003;
88
785-788
-
58
Weiner Z, Younis J S, Blumenfeld Z, Shalev E.
Assessment of uterine placental circulation in thrombophilic women.
Semin Thromb Hemost.
2003;
29
213-218
-
59
Lockshin M D, Druzin M L, Goei S et al..
Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus.
N Engl J Med.
1985;
313
152-156
-
60 Curry C J, Holmes J, Roeder E, Storm A, Wall J. Thrombophilia in neonatal stroke. American Pediatric Society Meeting 2001: 5-1
-
61
Burke C J, Tannenberg A E.
Prenatal brain damage and placental infarction: an autopsy study.
Dev Med Child Neurol.
1995;
37
555-562
-
62
Burke C J, Tannenberg A E, Payton D J.
Ischaemic cerebral injury, intrauterine growth retardation, and placental infarction.
Dev Med Child Neurol.
1997;
39
726-730
-
63
Kraus F T.
Cerebral palsy and thrombi in placental vessels of the fetus: insights from litigation.
Hum Pathol.
1997;
28
246-248
-
64
Redline R W, Wilson-Costello D, Hack M.
Placental and other perinatal risk factors for chronic lung disease in very low birth weight infants.
Pediatr Res.
2002;
52
713-719
-
65
Golomb M R, Dick P T, MacGregor D L, Armstrong D C, deVeber G A.
Cranial ultrasonography has a low sensitivity for detecting arterial ischemic stroke in term neonates.
J Child Neurol.
2003;
18
98-103
-
66
Lanska D J, Kryscio R J.
Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis.
Stroke.
2000;
31
1274-1282
-
67
Kumar M, Avdic S, Paes B.
Contralateral cerebral infarction following vacuum extraction.
Am J Perinatol.
2004;
21
15-17
-
68
Amit M, Camfield P R.
Neonatal polycythemia causing multiple cerebral infarcts.
Arch Neurol.
1980;
37
109-110
-
69
Gunther G, Junker R, Strater R et al..
Symptomatic ischemic stroke in full-term neonates: role of acquired and genetic prothrombotic risk factors.
Stroke.
2000;
31
2437-2441
-
70
Thorarensen O, Ryan S, Hunter J, Younkin D P.
Factor V Leiden mutation: an unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis.
Ann Neurol.
1997;
42
372-375
-
71
Bertina R M.
Factor V Leiden and other coagulation factor mutations affecting thrombotic risk.
Clin Chem.
1997;
43
1678-1683
-
72
Kenet G, Sadetzki S, Murad H et al..
Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in children.
Stroke.
2000;
31
1283-1288
-
73
McColl M D, Chalmers E A, Thomas A et al..
Factor V Leiden, prothrombin 20210G→A and the MTHFR C677T mutations in childhood stroke.
Thromb Haemost.
1999;
81
690-694
-
74
Zenz W, Bodo Z, Plotho J et al..
Factor V Leiden and prothrombin gene G 20210 A variant in children with ischemic stroke.
Thromb Haemost.
1998;
80
763-766
-
75
Lynch J K, Nelson K B, Curry C J, Grether J K.
Cerebrovascular disorders in children with the factor V Leiden mutation.
J Child Neurol.
2001;
16
735-744
-
76
Nowak-Gottl U, Strater R, Heinecke A et al..
Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood.
Blood.
1999;
94
3678-3682
-
77
Prengler M, Sturt N, Krywawych S, Surtees R, Liesner R, Kirkham F.
Homozygous thermolabile variant of the methylenetetrahydrofolate reductase gene: a potential risk factor for hyperhomocysteinaemia, CVD, and stroke in childhood.
Dev Med Child Neurol.
2001;
43
220-225
-
78
Pellicer A, Cabañas F, García-Alix A, Pérez-Higueras A, Quero J.
Stroke in neonates with cardiac right-to-left shunt.
Brain Dev.
1992;
14
381-385
-
79
Pollack E S.
The epidemiology of cancer and the delivery of medical care services.
Public Health Rep.
1984;
99
476-483
-
80
Kirkham F J.
Recognition and prevention of neurological complications in pediatric cardiac surgery.
Pediatr Cardiol.
1998;
19
331-345
-
81
Day R W, Boyer R S, Tait V F, Ruttenberg H D.
Factors associated with stroke following the Fontan procedure.
Pediatr Cardiol.
1995;
16
270-275
-
82
Miller G, Mamourian A C, Tesman J R, Baylen B G, Myers J L.
Long-term MRI changes in brain after pediatric open heart surgery.
J Child Neurol.
1994;
9
390-397
-
83
Ment L R, Ehrenkranz R A, Duncan C C.
Bacterial meningitis as an etiology of perinatal cerebral infarction.
Pediatr Neurol.
1986;
2
276-279
-
84
Corrigan J J, Jordan C M, Bennett B B.
Disseminated intravascular coagulation in septic shock: report of three cases not treated with heparin.
Am J Dis Child.
1973;
126
629-632
-
85
Prian G W, Wright G B, Rumack C M, O'Meara O P.
Apparent cerebral embolization after temporal artery catheterization.
J Pediatr.
1978;
93
115-118
-
86
Ruff R L, Shaw C M, Beckwith J B, Iozzo R V.
Cerebral infarction complicating umbilical vein catheterization.
Ann Neurol.
1979;
6
85
-
87
Roessmann U, Miller R T.
Thrombosis of the middle cerebral artery associated with birth trauma.
Neurology.
1980;
30
889-892
-
88
Bull M J, Schreiner R L, Garg B P, Hutton N M, Lemons J A, Gresham E L.
Neurologic complications following temporal artery catheterization.
J Pediatr.
1980;
96
1071-1073
-
89
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
608-612
-
90 de Vries L S, Levene M I. Cerebral ischemic lesions. In Levene MI, Lilford RJ Fetal and Neonatal Neurology and Neurosurgery. Edinburgh; Churchill Livingstone 1995: 379-382
-
91
Lynch J K, Nelson K B.
Epidemiology of perinatal stroke.
Curr Opin Pediatr.
2001;
13
499-505
-
92
Golomb M R, Garg B P, Williams L S.
Measuring gross motor recovery in young children with early brain injury.
Pediatr Neurol.
2004;
31
311-317
-
93
Trauner D A, Chase C, Walker P, Wulfeck B.
Neurologic profiles of infants and children after perinatal stroke.
Pediatr Neurol.
1993;
9
383-386
-
94
Mercuri E, Barnett A, Rutherford M et al..
Neonatal cerebral infarction and neuromotor outcome at school age.
Pediatrics.
2004;
113
95-100
-
95
Domi T, MacGregor D, Curtis R et al..
Neurological outcomes in survivors of neonatal arterial ischemic stroke and cerebral sinovenous thrombosis: a prospective longitudinal study.
Ann Neurol.
2003;
54(suppl 7)
S138
-
96
Golomb M R, MacGregor D L, Domi T et al..
Presumed pre- or perinatal arterial ischemic stroke: risk factors and outcomes.
Ann Neurol.
2001;
50
163-168
-
97
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
-
98
Golomb M R, deVeber G A, MacGregor D L et al..
Independent walking after neonatal arterial ischemic stroke and sinovenous thrombosis.
J Child Neurol.
2003;
18
530-536
-
99
Trauner D A, Nass R, Ballantyne A.
Behavioural profiles of children and adolescents after pre- or perinatal unilateral brain damage.
Brain.
2001;
124
995-1002
-
100
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
2887-2892
-
101
Battin M R, Penrice J, Gunn T R, Gunn A J.
Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia.
Pediatrics.
2003;
111
244-251
-
102
Balduini W, Carloni S, Mazzoni E, Cimino M.
New therapeutic strategies in perinatal stroke.
Curr Drug Targets CNS Neurol Disord.
2004;
3
315-323
-
103
Griffin J H, Fernandez J A, Liu D, Cheng T, Guo H, Zlokovic B V.
Activated protein C and ischemic stroke.
Crit Care Med.
2004;
32
S247-S253
Yvonne WuM.D. M.P.H.
UCSF Child Neurology, 350 Parnassus Avenue, Suite 609, San Francisco, CA 94117
