Stroke in the Newborn

Vascular Abnormalities

Prenatal stroke has been increasingly identified in utero with advances in fetal imaging. Many of these disorders are related to vascular abnormalities (see Table 25.4 ). A particularly well-documented case of a prenatal focal parenchymal defect with porencephaly, secondary to vascular maldevelopment (see Table 25.4 ), involved the lenticulostriate branches of the middle cerebral artery and the anterior choroidal arteries. Of additional interest in this case was the occurrence of polymicrogyric cortex in the margins of the porencephalic defect, compatible with a destructive process in the sixth month of gestation. The similarity to the experiments involving second trimester carotid occlusion in fetal monkeys discussed earlier is interesting.

Intrauterine focal or multifocal ischemic injury secondary to vasculopathy (see Table 25.4 ) has been shown in several disorders. A multifocal vascular disorder in association with hydranencephaly in utero was observed in association with a proliferative vasculopathy. The likelihood of a genetic disorder was supported by the occurrence of multiple affected siblings in three families. In two cases, a mitochondrial disorder was suspected because of the finding of low levels of complexes III and IV of the electron transport chain. Microangiopathy related to a mutation in collagen IV A1 appeared to underlie another familial disorder with congenital porencephaly.

Genetic vasculopathies have been identified recently as causes of prenatal ischemic stroke. For example, the identification of a mutation in the FLVCR2 gene among infants with apparent intrauterine stroke due to vasculopathy and subsequent hydranencephaly increased the likelihood of a genetic disorder. Though most children do not survive beyond the neonatal period or early infancy, some have lived to the second and third decades, indicative of intrafamilial variability in this disorder. Cerebral arteriopathy associated with ACTA2 gene mutations occurs in newborns as part of a multisystem smooth muscle dysfunction syndrome due to deficient alpha-2 actin a central component in smooth muscle contractility. Heterozygous carriers of ACTA2 mutation can have a variety of vascular diseases, including early-onset coronary artery disease and premature ischemic strokes. The neuropathology of this disorder is characterized by fibrosis of the media and weakening of the arterial wall. Such cerebrovascular disease is accompanied by such other indications of smooth muscle dysfunction such as mydriasis, hypotonic bladder, gastrointestinal dysmotility, and, in some cases, intestinal malrotation. The cerebral arterial tree demonstrates dilation of proximal internal carotid arteries, stenoocclusive internal carotid termini, and a strikingly straight configuration of the intracranial arteries. Several newborn infants with this arteriopathy have been reported to present with cerebral infarction, white matter signal change, and the vascular features of this distinctive cerebral arteriopathy.

A second category of disorder, neonatal isoimmune thrombocytopenia , results in intrauterine multifocal cystic lesions and is generally considered to represent a sequela of intracerebral hemorrhage. However, the apparent relation to vascular territories suggests an ischemic lesion (perhaps with secondary hemorrhage). Endothelial injury and even thrombosis have been observed in other types of immune thrombocytopenia.

Vasospasm may underlie the focal cerebral infarctions observed with intrauterine exposure to cocaine (see Chapter 42 ). The vasospasm is postulated to occur secondary to transplacentally acquired cocaine as well as to the surge of catecholamines caused by the systemic and local cerebral effects of cocaine, as detailed in Chapter 42 .

Emboli

Sources of emboli (see Table 25.4 ) may include placental fragments or clots (e.g., with placental infarcts) or thrombi in fetal vessels. The placenta has been recognized increasingly as a potential source of emboli and cerebral infarction. The principal placental lesions have involved fetal vessels (fetal thrombotic vasculopathy or fetal vasculitis) and have been associated with intrauterine infection with chorioamnionitis and maternal and, perhaps, fetal coagulopathies. Inflammatory markers have been identified in analyses of neonatal blood in such cases. Related placental lesions could underlie in part the increased risk of perinatal stroke with preeclampsia, ovarian-hyperstimulating treatments in women with a history of infertility, and severe intrauterine growth retardation. Emboli from the fetal venous circulation could enter the arterial circulation by passage across the foramen ovale.

Twin-Twin Transfusion Syndrome

The most dramatic example of prenatal arterial ischemic stroke occurs as a component of the twin-twin transfusion syndrome. Twin gestation deserves special consideration as a cause of focal and multifocal ischemic brain injury, often related to thromboembolic phenomena (see Tables 25.4 and 25.5 ). As discussed later, generalized as well as focal disturbance of CBF is involved in the origin of the neuropathology. Most of the clinically significant brain injury observed with twin gestation occurs in monozygotic monochorionic (i.e., a single placenta) twin gestations. Approximately 65% of twin gestations are dizygotic, diamniotic, dichorionic, and generally not associated with brain injury (except for a modest risk related to prematurity or the rare occurrence of stroke). Approximately 35% of twin gestations are monozygotic. Of the latter, approximately 30% are diamniotic, dichorionic (if the zygote splits early before blastocyst formation). However, approximately 70% of monozygotic twin gestations are diamniotic but monochorionic (when the zygote splits after blastocyst formation). In the latter group, in which each fetus shares the single placenta, the risk of brain injury is considerable (see Table 25.5 ). In this context, placental vascular anastomoses occur, especially arteriovenous connections, in which placental tissue perfused by an artery from one fetus is drained by a vein from the other. These vascular connections involve one or more arteries or veins from one fetus inserting into a common placental cotyledon of the other fetus and, thereby, allow for potential abnormal volume distribution between the fetuses. In most situations, the anastomoses are balanced, but in 10% to 20%, they are unbalanced, and twin-twin transfusion syndrome (TTTS) results. TTTS is the setting for most of the brain injury associated with twin gestations. Although this brain injury may occur consequent to the fetal death of a cotwin, most such injury occurs without such fetal death. It has been noted that in monochorionic twin gestation in which spontaneous in utero fetal death occurs, 14% to 20% of surviving cotwins experience prenatal brain injury.

The neuropathology of brain injury associated with twin gestations relates particularly to the timing of the injury, as outlined in Table 25.5 . Disturbances in early brain development (e.g., anencephaly and encephalocele) occur only rarely, and such early lesions are considered to be caused by vascular insufficiency. Also of presumed vascular basis are the somewhat more common occurrences of microcephaly with multiple porencephalies and of polymicrogyria. The polymicrogyria may contain features both of a disorder of neuronal migration (nonlayered cortex, heterotopias) and of a postmigrational encephaloclastic process (cortical laminar necrosis). The most characteristic lesions are associated with insults in the second trimester and later and consist of the full range of focal, multifocal, and generalized ischemic lesions (i.e., isolated infarction, porencephaly, hydranencephaly, multicystic encephalomalacia, and periventricular leukomalacia). Concerning the most serious of the ischemic lesions (i.e., hydranencephaly and severe porencephaly), twin gestations accounted for 11% of all cases in one series. In most such cases, a deceased cotwin was identified. (The incidence of deceased cotwin in these most severe cases could be higher because the remnants of such a cotwin are easily missed without careful examination of the placenta. In addition, the prenatal mortality in twins is high; i.e., approximately 20% to 80% of twins detected in the first trimester of gestation were singletons by the time of birth. )

Arterial ischemic stroke occurs not uncommonly among survivors of monochorionic twin gestations in which fetal death has occurred (see later). Nearly 50% of survivors were found to have focal AIS often involving one or both middle cerebral artery territories. Other cerebral injuries included multicystic encephalomalacia, cortical necrosis, and periventricular leukomalacia. Definition of the occurrence of focal stroke as well as more generalized brain injury in the fetus has been facilitated by neuroimaging including ultrasonography but especially by recent application of MRI (see Chapter 9 ). The use of prenatal MRI for imaging of fetal brain in the survivor has resulted in documentation of prenatal focal infarction in the surviving twin.

Pathogeneses of the brain injuries in monochorionic twin gestations are best divided into those associated with a dead cotwin and those associated with severe TTTS but not necessarily fetal demise. Pathogenesis in cases with death of a cotwin includes the following: (1) now considered most common, fetal exsanguination from the surviving to the dead fetus through placental anastomoses, resulting in severe hypotension and cerebral ischemia; (2) thrombosis caused primarily by transfer of thromboplastin material from the dead twin, with disseminated intravascular coagulation resulting; and (3) embolus from the placenta or the dead fetus through the fetal vascular anastomoses (see Table 25.5 ). Benirschke and Kim, and others postulated an induction of disseminated intravascular coagulation in the surviving twin and consequent ischemic tissue injury due to thromboplastin transferred from the dead twin via placental vascular anastomoses in monochorionic twin gestations. The resulting disseminated intravascular coagulation was postulated to cause arteriolar obstruction and end organ tissue ischemia, including the brain. An alternative hypothesis for brain injury relates to an embolus from the placenta or from the dead fetus conveyed through the vascular anastomoses to the survivor and ramification in the cerebral arterial circulation. Finally, the most common and affecting mechanism proposed is that of exsanguination from the twin survivor to the deceased twin resulting in cerebral injury in the surviving twin. As a result of comparatively low systemic pressure in the deceased twin, the survivor transfers its blood volume through the monochorionic placenta with resulting anemia, hypotension, and end organ hypoperfusion, which leads to tissue hypoxia and injury in the surviving twin’s brain. The presence of placental superficial, rather then deeper, arterioarterial or venovenous anastomoses in monochorionic twin gestations appears to allow greater shunting of blood volume from the surviving cotwin to the dead twin and is associated with greater cerebral injury demonstrable by cranial ultrasound in the surviving twin.

Pathogenesis in the more common situation of severe TTTS relates principally to the cerebral hemodynamic consequences of TTTS (see Table 25.5 ). In most situations, the anastomoses are balanced, but in up to 20% they are unbalanced, and TTTS results. TTTS is the setting for most of the brain injury associated with twin gestations (see later). Although this brain injury may occur consequent to the fetal death of a cotwin, most such injury occurs without such fetal death . Through aforementioned arteriovenous placental anastomoses, blood volume is shunted unidirectionally from one twin (the donor; often the more diminutive in size) to the other twin (the recipient; often, the larger twin). Left uncorrected, the recipient can become hyperperfused, hypervolemic, and polyhydramniotic with development of pulmonary hypertension. The donor can become correspondingly hypoperfused, hypovolemic, and oligohydramniotic (e.g., disturbances by compression or distortion of umbilical blood flow or of placental flow, with risk of thrombosis; see Table 25.5 ).

Therapy has been directed toward the pregnancies complicated by severe TTTS ( Table 25.6 ). Two fundamental approaches (i.e., serial amnioreduction and fetoscopic laser occlusion of the vascular anastomoses) have been used. Diagnosis of severe TTTS in the second trimester of gestation and institution of therapy shortly thereafter have comprised the usual protocol. The benefit of laser therapy relates to the reduction of the vascular anastomoses (a single amnioreduction to reduce polyhydramnios is carried out at the time of the laser surgery) (see Table 25.6 ). In 2004 after the publication of the Eurofetus randomized control trial, laser therapy became the treatment of choice and, indeed, standard of care for this condition. The Eurofetus randomized control trial and subsequent prospective study have established that laser therapy constitutes the treatment of choice for this condition. Without treatment, mortality can be substantial, as high as 90%. Combining subsequent published series, perinatal survival of at least one twin after laser therapy was reported in 81% to 88% of pregnancies and survival of both twins in 52% to 54%. Recently, a meta-analysis of 13 studies with an aggregate 1573 cases of antenatally diagnosed TTTS treated with laser ablative therapy captured the frequency of antenatally detected brain injury in these fetuses. Scanned with MRI and ultrasonography, 88 fetuses demonstrated cerebral injury (2.2%), 30.4% of these ischemic injury. Among these, injury included cerebral infarction, porencephaly, and cystic encephalomalacia. Most recently, management of TTTS has involved refinement in the prediction of the disease, clarification of the optimum frequency of surveillance, technique of laser ablation, prediction of adverse outcome after treatment, and development of other vascular ablative techniques. Improvements in intrauterine monitoring, including fetal echocardiography and advanced Doppler studies, have guided earlier treatment, which now includes more advanced methods of selective fetoscopic laser photocoagulation with laser photocoagulation of the surface of the placenta, most notably the Solomon technique. In a recent follow-up study that compared standard fetoscopic laser surgery to the Solomon technique of more extensive placental equatorial laser photocoagulation, no differences were observed in fetal deaths (16%–18%), neonatal deaths (4%), and survival with neurodevelopmental impairment (9%–11%). The Solomon technique is now favored because of the reduction in short-term complications; that is, twin anemia–polycythemia sequence or recurrent TTTS.

Vascular Distortion

Vascular distortion is a potential cause of intrauterine stroke (see Table 25.4 ). We raise this possibility because extremes of neck extension or rotation have the potential to produce impairment of blood flow in the vertebrobasilar system or in the carotid system, respectively. Precedent for such occurrences in older patients is available. The vertebro-basilar system may be particularly vulnerable in the fetus and newborn because of poorly developed ligamentous structures of the upper cervical spine that allow sliding and slipping movements between the atlanto-occipital and atlanto-axial articulations. Hyperextension of the head may cause inversion of the atlas through the foramen magnum and impair flow coursing through the vertebral arteries. In a careful postmortem study, cerebral artery compression was shown in three of five infants with neck extension and in three of nine cases of neck rotation.

Intrauterine Trauma

Intrauterine trauma , secondary to blunt trauma to the maternal abdomen, has resulted in prenatal stroke (see Table 25.4 ). MRI of infants of mothers who sustained abdominal trauma during pregnancy has revealed evidence of chronic cerebral infarction. In addition, prenatal cerebral injury and cerebral palsy have been associated with maternal abdominal trauma during pregnancy. The mechanism of this effect is not clear.

Thrombus, Embolus

Arterial occlusion by embolus or thrombus (see Table 25.4 ) is a well-documented neonatal cause of focal and multifocal parenchymal defects. Often it has been difficult by clinical imaging or even pathological criteria to distinguish between a thrombotic and embolic process. As noted earlier, the lesions have been observed principally in the regions of the middle (and sometimes anterior) cerebral arteries (see Figs. 25.1 and 25.3 ).

Emboli

Sources of emboli (see Table 25.4 ) may be similar to those in some cases of prenatal stroke (see earlier) and include placental fragments or clots—for example, with placental infarcts—thrombi in involuting fetal vessels—for example, umbilical vein, portal vein, or ductus arteriosus—and thrombi or air in punctured or catheterized vessels. As noted earlier, the placenta has been increasingly recognized as a potential source of emboli and occurrence of cerebral infarction (see earlier). Emboli from the fetal or neonatal venous circulation could enter the arterial circulation by passage across the foramen ovale. In 50% to 90% of normal newborns at rest, interatrial left to right shunting is documented readily, and in approximately 60% of healthy newborns studied at 24 hours of age, right-to-left blood flow could be demonstrated across the foramen ovale.

Other sources of emboli include thrombi in the internal carotid artery, portal vein, central venous catheter (thrombus or air), and heart. Cardiac sources of emboli are relatively uncommon in the newborn period, although infants with congenital heart disease, especially with right to left shunts , may exhibit thromboembolic phenomena of cerebral arteries. The newborn with congenital heart disease, particularly if critically ill, can have cardioembolic events through right-to-left shunts, intracardiac thrombogenesis, or cardiac instrumentation. Stroke with congenital heart disease can occur in the preoperative, intraoperative, or postoperative periods. Cerebral injury including stroke has been associated with placental pathology particularly thrombosis in infants with congenital heart disease. The characteristics of the cardiac lesion and the management thereof are important determinants for stroke, with strongest associations with an intracardiac right-to-left shunt, preoperative balloon atrial septostomy, transposition of the great arteries, or single ventricle physiology. In addition, operative features such as duration of bypass, age at surgical correction, and need for reoperation increase the likelihood of occurrence of stroke with congenital heart disease. Diagnostic procedures, including cardiac catheterization and the more recent use of ventricular assist devices as a bridge from extracorporeal membrane oxygenation (ECMO) to transplant have been associated with AIS. Rarer causes of cardiac emboli include single cases of atrial myxoma and rhabdomyoma (infant with tuberous sclerosis) that we have seen.

Our suspicion has been that emboli may be a more common cause of NAIS than currently recognized. It is noteworthy that cerebral emboli at later ages more commonly affect the left hemisphere (perhaps because of the direct route from the aorta of the left common carotid artery), and the left hemisphere predominance in neonatal middle cerebral artery stroke is striking (see Table 25.2 ). Additionally, transient right-to-left shunting through the ductus arteriosus also might favor the occurrence of left hemispheral emboli. Further support for a relative frequency of embolic infarction in NAIS is the finding by serial Doppler studies of four infants with focal middle cerebral artery strokes of an ipsilateral decrease in cerebral blood flow velocity at the time of diagnosis of the infarct and a reemergence of blood flow in the ensuing days, consistent with embolic occlusion with subsequent fragmentation and distal migration of embolic fragments.

Thrombi

Thrombosis may involve arteries or veins (see Table 25.4 ). The most common cause of NAIS related to an abnormality of the artery or vein per se is the vasculitis associated with bacterial meningitis (see Chapter 39 ). Cases of apparent occlusion caused by extremes of neck movement or cranial trauma may relate to vascular injury and resulting thrombosis (see earlier discussion of vascular distortion regarding prenatal AIS). Neonatal stroke has also been described in relation to carotid artery dissection and to fibromuscular dysplasia affecting multiple intracranial vessels.

ECMO may lead to focal cerebral infarction by several mechanisms, including thrombus (see Table 25.4 and see Chapter 26 ). In one series of 180 infants subjected to serial brain imaging studies, 16 exhibited a major brain lesion (9%); 6 of the 16 infants exhibited focal ischemic lesions, and 10 exhibited hemorrhagic lesions. Of the six ischemic lesions, five were in the right hemisphere; that is, ipsilateral to the carotid artery ligation. Of the 10 hemorrhagic lesions, seven were in the left hemisphere and only three were in the right hemisphere; the origin of the hemorrhages in the infants treated with ECMO is discussed in Chapter 26 . A preponderance of right hemispheric ischemic phenomena has been observed by others. The mechanisms for the right hemispheral infarcts include the following: (1) prior ischemic injury, secondary to persistent pulmonary hypertension and the associated systemic hypotension and impaired cerebrovascular autoregulation (secondary to hypoxemia or hypercarbia or both), partially compensated by cerebral vasodilation prior to institution of carotid ligation and ECMO; (2) ischemia caused by the carotid artery ligation because of insufficient collateral circulation through the circle of Willis; (3) ischemia caused by impaired cerebrovascular autoregulation during ECMO with disproportionate decrease in cerebral blood flow with hypotension in the right hemisphere because of the ligated carotid artery; and (4) thrombosis propagated into the anterior cerebral circulation from the ligated carotid. The occurrence of ischemic lesions in the left hemisphere could relate to emboli emanating from the ECMO circuit or to a steal phenomenon caused by the strong collateral flow from the left cerebral circulation to the right.

In a large series that studied ECMO use in 677 newborn infants, the great majority of whom were treated with venoarterial ECMO and canulated on the right side, 94 had stroke (13.9%). Though the majority had hemorrhagic stroke (the origin of the hemorrhages in the infants treated with ECMO is discussed in Chapter 26 ), fully 30 had ischemic stroke (4.4%), 19 of which occurred in the left hemisphere and 2 of which were bilateral. As noted earlier, the pathophysiologic basis for stroke in patients treated with ECMO is likely multifactorial and relates to pre-ECMO comorbidity, an inflammatory response engendered by ECMO placement, ECMO-related disruption of hemostasis, and ECMO-related disturbance of autoregulation and cerebral perfusion.

Venovenous ECMO, with its single lumen intracardiac catheter, has been compared with right carotid artery–jugular vein–based venoarterial ECMO for safety and protection from brain injury. The venovenous procedure has demonstrated better protection from focal neurological complication, especially stroke.

Abnormalities of blood volume and coagulability account for most of the remaining cases of thrombosis in NAIS. Hypernatremia-dehydration , which leads to thrombosis probably by a combination of vascular and hypovolemic causes, is among the unusual causes of neonatal thrombosis, affecting either arteries or veins, most commonly veins (see Table 25.4 ). Disseminated intravascular coagulation in association with sepsis is among the most commonly documented causes for thrombosis in many neuropathological series . For example, in the study of 29 newborns with cerebral infarcts and arterial occlusions by Barmada and coworkers, disseminated intravascular coagulation, usually with sepsis, was present in approximately two-thirds. Polycythemia rarely has been associated with neonatal ischemic lesions, often complicated by hemorrhage. Polycythemia may lead to arterial or venous thrombosis, and the nature of the pathology in neonatal cases is rarely clear. Impaired cognitive outcome, possibly related to ischemic cerebral phenomena, has been documented in infants with polycythemia and hyperviscosity. Increased cerebrovascular resistance and diminished cerebral blood flow velocity, determined by Doppler studies, have also been observed in polycythemic infants with hyperviscosity, and decreased CBF and oxygen delivery have been shown directly by studies of neonatal piglets with hyperviscosity produced by infusion of cryoprecipitate. The hemodynamic factors are probably important in genesis of the overt ischemic lesions associated with polycythemia, but it is necessary to recognize that such lesions are very unusual, even among polycythemic infants with neurological symptoms.

Prothrombotic/hypercoagulable endogenous factors and other genetic factors are recognized to be of importance in the genesis of perinatal NAIS (see Tables 25.4 , and 25.8 ). Similarly, these factors are frequent contributing factors in sinovenous thrombosis in newborns (see later). The most commonly implicated factors in NAIS have been the factor V Leiden mutation, prothrombin mutation, methylene tetrahydrofolate reductase deficiency (with resulting hyperhomocysteinemia), protein C deficiency, antithrombin III deficiency, and elevated lipoprotein(a). Although present in 30% to 70% of cases of neonatal stroke, these factors are usually combined with other pathogenetic factors that favor thrombosis or embolus; that is, preeclampsia, placental vasculopathy, chorioamnionitis, signs of “perinatal asphyxia,” sepsis, and congenital heart disease (see later). In addition, several of these factors are low in the newborn as part of their developmental trajectory of increasing concentration with age. Indeed, although we classify these disorders here under thrombosis, the likely mechanism of cerebral stroke in these disorders may relate less to thrombosis in situ in cerebral vessels but rather to embolus from thrombi in other sites, such as placenta, involuting fetal vessels, or the heart. Notably, a recent prospective study of the occurrence of thrombophilic factors in neonates with stroke, including NAIS, compared with controls indicated minimal association between the two. Further, the identification of a thrombophilic factor in a newborn with NAIS was not found to predict recurrence of stroke unless a family history of genetic thrombophilia existed. A recent scientific statement from the American Heart Association concluded that “routine” thrombophilia testing is not indicated in newborns with AIS.

One of the most frequently cited of the prothrombotic factors is the factor V Leiden mutation or so-called resistance to activated protein C . In this disorder, there is a defect in factor V, a procoagulant molecule, such that the factor cannot be inactivated by activated protein C. This so-called factor V Leiden mutation thus causes a “resistance” to the normal inactivating property of activated protein C. The result is an excess of the procoagulant factor V. The newborn may have a particular propensity for thrombosis with the factor V Leiden mutation because, unlike the relatively low levels of protein C in the newborn, factor V levels are similar to adult values. Therefore the capacity of protein C to inactivate the factor V, even without the Leiden mutation, is diminished. This defect has been described in association with neonatal cerebral infarction in many infants. Careful examination of the placenta has led to detection of placental thromboses , a finding suggesting that one mechanism of stroke in this setting is an embolus originating in the placenta and reaching the fetal cerebral circulation via the foramen ovale . (Approximately 60% of fetal cardiac output enters brain from this right-to-left shunt.) In approximately 50% of cases, other risk factors—for example, perinatal complications, infection, cardiac disease, or presence of another endogenous prothrombotic factor—were present. As noted earlier, available evidence does not warrant routine testing for thrombophilia in NAIS.

Generalized Systemic Circulatory Insufficiency

An apparently generalized disturbance of systemic circulation with impaired perfusion of brain in the past has been considered to account for a considerable proportion of ischemic cerebral lesions, occurring especially in the peripartum period (see Table 25.4 ). Indeed, the frequent occurrence of “prolonged second stage of labor,” “fetal heart rate abnormalities,” “signs of perinatal asphyxia,” placental and cord “complications,” and related features have suggested that a generalized circulatory insufficiency could contribute to the pathogenesis of neonatal stroke. Ramaswamy et al. reported 6 term neonates (5%) of 124 in their cohort who were born with neonatal encephalopathy and who were proved by MRI to have focal ischemic stroke. Each presented with seizure. Almost all involved the middle cerebral artery and, of these, in each less than two-thirds of the arterial territory. Two of these children also had bilateral anterior watershed injury. The co-occurrence of watershed injury may provide insight into the pathogenesis of focal ischemic injury in this setting. Intrapartum hypotension with autoregulatory impairment may lead to shunting of blood from peripheral branches in the anterior and posterior cerebrovascular trees in order to maintain perfusion in deep central structures such as basal ganglia and brainstem. In this regard, a meta-analysis of data from 550 newborns with arterial stroke found that fetal heart rate abnormality, low Apgar score, and need for neonatal resuscitation correlated with perinatal hypoxia and suggested some role for peripartum fetal hemodynamic instability. It remains unclear how a unilateral injury, in a discrete vascular territory, could occur in the presence of an apparently generalized disturbance of perfusion. This phenomenon has been observed in fetal and neonatal mammalian animal models. Notably, the vessels of the anterior circulation have a dense sympathetic innervation. Consequently, asphyxia, a potent sympathetic stimulator, may induce vasoconstriction in the arterial trees of the anterior circulation and thereby favor focal cerebral ischemic events within those vascular distributions compared with the vertebrobasilar circulation. A speculation would be that this innervation may exhibit asymmetries during development and that this developmental feature might explain some of the unilateral lesions seen with this apparently generalized insult. A second possibility involves the potential of placental emboli traveling to and ramifying in the cerebral circulation. In fetal sheep rendered hypoxic, the ductus venosus dilates and leads to a marked increase in flow through this vessel which bypasses the liver and provides a direct pathway from the placenta to the heart and thereon to the brain via the foramen ovale. Thus, both possible explanations linking a generalized hypoxic insult to focal vascular ischemia involve abnormalities in placental function or structure or both.

Importance of Multiple Risk Factors

The importance of multiple risk factors and the nature of these factors in the genesis of perinatal arterial stroke is illustrated by the data shown earlier in Table 25.9 . In this careful study of 37 cases, although data on endogenous prothrombotic factors were not available, the importance of factors such as preeclampsia, chorioamnionitis, prolonged rupture of membranes, and cord abnormality (tight nuchal cord, umbilical cord knot, body cord) was shown (see Table 25.9 ). Moreover, the markedly increased risk related to multiple rather than single risk factors was apparent. The data further illustrate that the pathogenesis of perinatal arterial stroke may often be multifactorial in origin.