Perinatal Intracranial Hemorrhages Pathology

This article reviews intracranial hemorrhages (ICHs) that may occur in the perinatal period. An ICH is the pathologic accumulation of blood within the cranial vault. This condition can be categorized according to the site of origin of the hemorrhage, as follows:

• Epidural hemorrhage indicates blood between the skull and dura

• Subdural hemorrhage denotes blood between the dura and arachnoid

• Subarachnoid hemorrhage refers to blood between the arachnoid and pia

• Intraventricular hemorrhage (IVH) refers to blood within the ventricles

• Intraparenchymal hemorrhage refers to blood within the brain parenchyma

The true incidence of perinatal ICH is not known. Clinical series do not identify the group of infants who do not present with clinical events, and autopsy series are biased toward infants with the poorest outcomes. The larger autopsy-based studies report small subdural, subarachnoid, and intracerebral hemorrhages in 20-30% of live births. Larger intraventricular and posterior fossa hemorrhages were less common in these studies, representing 10-15% of live births. However, these studies represent older cohorts, and incidences have been declining.

Germinal matrix hemorrhage and IVH occur more frequently in preterm infants (< 32 weeks' gestational age) and in very low birth weight infants (< 1500 grams). In addition, the risk of IVH increases with decreasing gestational age and birth weight. The overall incidence of IVH has decreased over the last 4 decades. In the 1970s and 1980s, the incidence of IVH in premature infants was 40-50% and fell to 15-25% in the late 1980s to the present. ^[1] The incidence of IVH has declined due to administration of antenatal steroids, improved ventilation strategies, and improved obstetric practices. ^[2]

Symptomatic ICH in full-term neonates is much less common, in the range of 4 per 10,000 live births. ^[3] The incidence is higher, however, in instrumented births. ^[4] A magnetic resonance imaging (MRI) study of full-term neonates found an approximately 25% incidence of asymptomatic ICH after vaginal delivery. ^[5]

The etiology of intracranial hemorrhage (ICH) in infants varies according to the location of the hemorrhage and the gestational age of the infant. In many cases, hemorrhage may involve more than one compartment.

Preterm infants

The most common source of ICH in preterm infants younger than 32 weeks' gestational age is the germinal matrix. The germinal matrix is a highly cellular and richly vascular region of the developing brain that is the site of proliferating glial and neuronal precursors. Supratentorially, the germinal matrix is located beneath the ependymal lining of the fetal lateral ventricles. During gestation, the germinal matrix gradually regresses beginning around 23-24 weeks' gestation and is nearly involuted by 36 weeks' gestation. ^[1]  From 28 to 32 weeks, the germinal matrix is most prominent at the caudothalamic (thalamostriate) groove, which is the most common site for germinal matrix hemorrhage (GMH).

The mechanism of GMH is multifactorial and primarily ascribed to the intrinsic fragility of microvasculature within the germinal matrix and disturbances in cerebral homeostasis and cerebral blood flow. High levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 activate rapid angiogenesis within the germinal matrix. The abundance of these growth factors may be attributed to relative physiologic hypoxia in the germinal matrix, perhaps resulting from high metabolic demand and oxygen consumption of proliferating progenitor cells. ^[6] These angiogenic vessels have few supporting pericytes, immature basal lamina, and reduced glial fibrillary acidic protein (GFAP) expression within the ensheathing astrocyte endfeet. Together, these factors contribute to the inherent fragility of vessels within the germinal matrix. ^[6]

Cerebral autoregulation, the ability of cerebral blood vessels to maintain constant cerebral blood flow with fluctuations in systemic blood pressures, is impaired in sick preterm infants. These immature ill infants exhibit pressure-passive cerebral circulation in which cerebral blood flow changes with alterations in systemic blood pressure. Thus, these infants are vulnerable to hemodynamic changes and fluctuations in cerebral blood flow that can occur in the setting of systemic hypotension and perinatal hypoxia. ^[6]

Cerebellar hemorrhagic injury (CHI) also occurs in approximately 3% of preterm infants weighing less than 1500 g and in 8.7% of infants weighing less than 750 g. ^[7] Cerebellar hemorrhage include small petechial hemorrhages, cerebellar GMH in the subependymal and subpial external granule cell layer of the cerebellar cortex, primary intraparenchymal hemorrhages, and ischemic infarcts with hemorrhagic transformation. Cerebellar hemorrhage occurs concurrently with supratentorial GMH in up to 77% of cases. ^[8]

Risk factors

Studies have identified many risk factors for the development of ICH in preterm infants, such as low gestational age and very low birth weight, maternal chorioamnionitis or other infections, lack of antenatal steroid therapy, hypotension, hypoxemia, hypercapnia, pneumothorax, respiratory distress syndrome, thrombocytopenia, and many others. ^{[9, 10, 11, 12]}

Molecular/genetic factors

It is thought that some genetic factors may contribute to the development of GMH, although associations are often inconsistent and unclear. It is possible that conditions such as thrombophilia may occlude some germinal vasculature, thereby leading to vessel rupture or infarction. Research has shown that the incidence of GMH is higher in carriers of factor V or prothrombin G20210A gene mutations. ^[8] Mutations in collagen type IV alpha1 (COL4A1) and alpha 2 (COL4A2) have been associated with prenatal ICH with porencephaly. ^{[13, 14]} Any underlying genetic coagulation disorder can also theoretically increase the risk of ICH.

Term infants

Subdural hemorrhages (SDHs) result from injury to the tentorium, falx, and/or bridging veins. They are more frequent in term neonates than in preterm infants, and they are frequently asymptomatic. In imaging studies, infratentorial SDH is the most common hemorrhage in asymptomatic term infants. ^[5]  This is most commonly a traumatic lesion and frequently occurs with unusual or rapid deforming stresses (eg compression, molding, stresses on extraction) on the infant head during labor. ^[15] SDH may also occur in the absence of trauma.

Primary subarachnoid hemorrhage (SAH) is the most common type in symptomatic term infants. ^[3] Although the pathogenesis of primary SAH is not completely understood, most cases of major primary SAH occur in the setting of trauma. Primary SAH is thought to originate from small, involuting anastomotic vascular channels within the leptomeninges.

Intraparenchymal hemorrhages are less common than SDH and SAH in term infants. These may result from birth-related trauma, in association with coagulopathy or from ischemia-reperfusion injury.

The rate of ICH is higher among infants requiring instrumented or cesarean delivery during labor than among infants delivered spontaneously. The rate of ICH among infants delivered by cesarean section before labor is not higher, which suggests that the common risk factor for hemorrhage is abnormal labor. ^[4]

The incidence of intraventricular hemorrhage (IVH) in term neonates is lower than in preterm infants. IVH in term neonates usually arises from the choroid plexus or extends from a thalamic hemorrhage. ^[3] GMH is rare in term infants, as the germinal matrix has mostly involuted by delivery. Only a minor fraction of IVHs arise from the small residual germinal matrix at the caudothalamic groove in term infants.

Epidural hemorrhage is relatively rare in newborns. The middle meningeal artery, which is the usual origin of epidural hemorrhage, is not yet encased within bone in this age group and moves freely away with displacements of the skull. However, epidural hemorrhage may occur in the absence of skull fracture if the dura detaches from the skull, as can occur with difficult forceps extraction. ^[3]

Risk factors

Neonatal factors such as thrombocytopenia; coagulopathies, including defects of coagulation factor(s); and increased cerebral venous pressure may also place an infant at high risk for bleeding. Thrombocytopenia is the most common congenital risk factor for intracranial bleeding in term neonates. Genetic, immunologic, drug-induced, or infectious factors; disseminated intravascular coagulation; and/or placental insufficiency may underlie its development. ^[3] ICHs may also be associated with extracorporeal membrane oxygenation (ECMO). Neuroimaging studies in infants on ECMO demonstrate that approximately 40% of identified intracranial abnormalities are purely hemorrhagic and 20% are hemorrhagic complications of ischemic lesions. ^[15]

Aside from perinatal risk factors, maternal risk factors (eg, drug use, pregnancy-induced hypertension, placental abruption, autoimmune disorders, and platelet alloimmunization) may contribute to the development of ICHs. ^[3]

The discussion of the clinical features and imaging of perinatal intracranial hemorrhages (ICHs) is divided into that for preterm infants and for term infants.

Preterm infants

Presentation

Germinal matrix hemorrhages (GMH) are usually clinically silent; they are diagnosed on routine cranial ultrasonographic (CUS) screening in up to 50% of cases. In premature infants, 50% of cases are diagnosed on the first day of life and up to 90% within the first 4 days of life. Symptomatic infants may clinically present slowly or very rapidly. Infants with very large hemorrhages may present with altered consciousness, cardiorespiratory abnormalities, metabolic derangements (eg, acidosis, blood glucose changes), bulging fontanelles, abnormal neurologic findings (eg, hypotonia, abnormal eye movements, altered pupillary responses), or seizures. ^[8]

Radiologic studies

The current imaging modality of choice for diagnosing and monitoring GMH is CUS because of its availability, portability, low cost, reliability, and high resolution for bleeding. The sensitivity and specificity for detecting ICH by CUS is 96% and 94%, respectively. ^[16] Doppler ultrasonography may be used to assess vascular flow; however, it is rarely used in a clinical setting, because its usefulness is unclear.

Magnetic resonance imaging (MRI) may detect petechial hemorrhages and smaller lesions; however, its use is limited by high cost, transportation issues, and concerns over sedation of the infant. MRI is more frequently used to monitor GMH evolution and may be useful in identifying cerebellar hemorrhages and white matter injury. ^[8] Computed tomography (CT) scanning is discouraged, because the effect of radiation on the immature central nervous system (CNS) is not known.

Near-infrared spectroscopy (NIRS) has become increasingly popular for monitoring CNS blood flow and oxygen perfusion because of its bedside availability, reduced invasiveness, and low cost. ^[8]

Grading of GMH

Papile et al formed an early classification system that is still commonly used in clinical practice with any form of neuroimaging. It divides GMH into four grades based on severity as assessed by CT (see Table 1, below). ^[17] Volpe later adapted this grading system, classifying GMH into three grades based on the amount of blood within the ventricle as detected on CUS (parasagittal view). ^[18] In Volpe's classification, intraparenchymal hemorrhage in the setting of a germinal matrix hemorrhage (GMH) is regarded as periventricular hemorrhagic infarction (PVHI), rather than a distinct grade of GMH. PVHIs are secondary venous infarctions that result from compression of the terminal vein by the IVH and impaired venous drainage of the medullary veins, rather than direct intraparenchymal extension of an IVH. ^[8] Note that GMHs can be unilateral or bilateral, and symmetric or asymmetric.

Table 1. Grading of Germinal Matrix Hemorrhage in Preterm Neonates (Open Table in a new window)

Full-term infants

Presentation

The majority of neonates with ICH have no clinical symptoms, including some with moderate to severe hemorrhages. ^[5] Neonates who are clinically symptomatic may present with apnea, bradycardia, decreased level of consciousness, generalized hypotonia, and seizures. ^{[3, 19]} However, these manifestations are not specific to ICH.

The symptomatic presentation also varies according to the site and compartment of hemorrhage, and it may be difficult to distinguish clinically from encephalopathies or other brain lesions. Therefore, obtaining an accurate and detailed history is crucial for assessing risk factors and deciding on appropriate interventions. ^[3]

Radiologic studies

In full-term infants, CUS is widely used for diagnosis of ICH. It can be used to visualize ischemic and hemorrhagic lesions, as well as ventricular enlargement and choroid plexus abnormalities. CT scans have better resolution and may help in the diagnosis of SAHs, widespread intraparenchymal injuries, and small IVHs. MRI is also used to clinically diagnose slowly progressing hemorrhages, as well as extracerebral or infratentorial hemorrhages. ^[3]

Grading of ICHs in term infants

ICHs in full-term neonates are graded on the basis of severity, as summarized in Table 2, below.

Table 2. Grading of Intracranial Hemorrhages in Full-Term Neonates (Open Table in a new window)

Differential diagnosis

Among the conditions considered in the differential diagnosis of perinatal ICHs are CNS infections, including herpes simplex virus infection, hypoxic-ischemic encephalopathy, and sinus venous thrombosis.

Gross features

In terms of gross appearance, epidural, subdural, and subarachnoid hemorrhages in infants are similar to those in older children and adults. The main caveat is that epidural hemorrhages (and skull fractures) may be missed in infants if the dura is not stripped from the skull.

Intraventricular hemorrhage may originate from a germinal matrix hemorrhage (GMH) (more frequently seen in preterm infants) or from a choroid plexus hemorrhage (more commonly encountered in term infants).

The gross appearance of GMH in preterm infants varies according to the severity (grade) of the hemorrhage. The hemorrhage may be confined to the germinal matrix (grade I) (see the first image below), or it may extend to the lateral ventricles (grade II or III) (see the second image below). The most common location of a GMH is at the caudothalamic groove.

Periventricular hemorrhagic infarctions (PVHIs) (grade IV GMH) are areas of hemorrhagic necrosis within the periventricular white matter, dorsal and lateral to the outer corner of the lateral ventricle (see the image below). In some cases, massive PVHIs can extend from the frontal to the occipital lobes. PVHIs are usually asymmetric, with 67% of cases occurring unilaterally. The majority of cases are associated with large ipsilateral intraventricular hemorrhages. ^[1]

In the setting of a choroid plexus hemorrhage, the choroid plexus is engulfed with blood and the GMH is intact without evidence of hemorrhage. Determining whether an intraventricular hemorrhage originates from the choroid plexus or germinal matrix can occasionally be difficult or impossible on gross examination.

Blood within the lateral ventricles, regardless of the source of the hemorrhage, may spread through the ventricular system. Blood can extend into the third and fourth ventricles and through the foramina of Megendie and Luschka, leading to hemorrhage within the subarachnoid space of the cerebellum, brainstem, and/or spinal cord.

Cerebellar hemorrhages may be unilateral or bilateral, and they frequently involve the ventral surface of the posterior lobe of the cerebellum. ^[7] GMH may be present in the subependymal regions of the fourth ventricular and/or subpial regions in the cerebellar cortex. Cerebellar hemorrhagic injury (CHI) is frequently associated with supratentorial GMH.

Microscopic features

Microscopic examination of the hemorrhage may help with dating, particularly in cases of subdural hemorrhage. Evidence of remote hemorrhage can be elicited with the help of iron stains, which may highlight hemosiderin-laden macrophages.

Acute hemorrhage within the germinal matrix may or may not disrupt the overlying ependyma. Some small GMHs that were missed on gross examination may be identified microscopically.

The resolving hematoma of a GMH is frequently replaced by a cystic lesion containing hemosiderin-laden macrophages and surrounded by reactive gliosis. Destruction of the germinal matrix associated with hemorrhage leads to loss of precursor cells in the germinal matrix, which may lead to dysmaturation in the cerebral cortex, thalamus, and white matter with reduced myelination. The cerebellum may be also be underdeveloped, possibly related to the presence of associated extraaxial blood. ^[1]

When the source of intraventricular hemorrhage is from a ruptured vessel in the choroid plexus, the choroid plexus is engulfed in blood, severely congested, and has acute hemorrhage within its stroma. In addition, the germinal matrix is intact without hemorrhage.

Cerebellar hemorrhages may originate from the germinal matrix of the ventricular zone in the roof of the fourth ventricle or of the external granular layer of the cerebellar cortex. CHI is frequently associated with neuronal loss and gliosis in the cerebellar cortex. CHI may be also associated with periventricular leukomalacia, pontosubicular necrosis, and neuronal loss and gliosis in the inferior olivary nuclei and dentate nuclei. ^[7]

 

The prognosis of germinal matrix hemorrhage (GMH) in the preterm infant is dependent on the extent of parenchymal involvement. Periventricular hemorrhagic infarction (PVHI), periventricular leukomalacia (PVL), posthemorrhagic hydrocephalus (PHH), cerebellar hemorrhagic injury (CHI), brainstem or hippocampal hypoxic-ischemic injury, and/or decreased brain volumes point(s) to a poorer prognosis. Seizure activity may also affect outcome by altering central nervous system (CNS) activity and may even lead to long-term neurologic deficits. ^[8]

Although any grade of GMH may be associated with neurodevelopmental outcomes, morbidity and mortality are proportional to the severity of the hemorrhage. Infants with grade I and II hemorrhages generally recover well, but they are at baseline risk for major neurologic issues (relative to infants without hemorrhages). Mortality increases exponentially with increasing grades of GMH, with up to 40% of preterm infants with PVHI (grade IV GMH) dying during their first hospital stay. ^{[20, 21]} Higher-grade GMHs are strongly associated with poor neurologic outcomes.

Preterm infants with GMH complicated by PVHI may suffer from spastic cerebral palsy, developmental delay, visual field defects, or epilepsy. ^{[20, 22]} Infants with GMH complicated by PHH may develop profound developmental delay and/or quadriplegic cerebral palsy. CHI may lead to motor deficits, as well as social and cognitive functional impairments. ^[8]

As with preterm infants, the extent, severity, and duration of the hemorrhage all affect long-term outcomes. ^{[23, 24]}

Conservative treatment generally yields excellent results in full-term infants. Adequate ventilation, control of metabolic processes (eg, acidosis), and control of seizure activity with phenobarbital is recommended. Neurosurgical interventions are rarely required. Epilepsy, developmental delay, motor deficits, and other conditions may result. ^[3]