Perinatal Intracranial Hemorrhages Pathology

Updated: Dec 29, 2015
  • Author: Cynthia E Hawkins, MD, PhD, FRCPC; Chief Editor: Adekunle M Adesina, MD, PhD  more...
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Overview

Overview

This article will review intracranial hemorrhages that may occur in the perinatal period. An intracranial hemorrhage is the pathologic accumulation of blood within the cranial vault. This condition can be categorized according to the site of origin of the hemorrhage (in some cases, intracranial hemorrhage may involve multiple compartments), as follows:

  • Epidural hemorrhage indicates blood between the skull and outside of dura
  • Subdural hemorrhage denotes blood between the dura and the arachnoid mater
  • Subarachnoid hemorrhage refers to blood between the arachnoid and the pia mater
  • Intraventricular hemorrhage refers to blood within the ventricles
  • Intraparenchymal hemorrhage refers to blood within the brain itself

The true incidence of perinatal intracranial hemorrhage 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 worst 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.

More recent imaging-based studies show an inverse relationship between gestational age at birth and the incidence of intraventricular hemorrhage (IVH), ranging from 40-50% of neonates at less than 26 weeks' gestation to fewer than 5% of neonates at more than 32 weeks' gestation. A magnetic resonance imaging (MRI) study of full-term neonates found approximately a 25% incidence of asymptomatic intracranial hemorrhage after vaginal delivery. [1]

Symptomatic intracranial hemorrhage in full-term neonates is much less common, in the range of 4 per 10,000 live births. [2] The incidence is higher, however, in instrumented births. [3]

The following image is an example of a grade I germinal matrix hemorrhage.

Gross appearance of grade I germinal matrix hemorr Gross appearance of grade I germinal matrix hemorrhage (GMH).
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Etiology

The etiology of intracranial hemorrhage in infants varies according to the location of the hemorrhage and the gestational age of the infant. Furthermore, in many cases, more than one compartment may be involved.

Preterm infants

In preterm infants of less than 32 weeks' gestation, the most common source of intracranial hemorrhage is the germinal matrix. Supratentorially, the germinal matrix lines the lateral ventricles; thus, germinal matrix hemorrhage (GMH) may result in intraventricular hemorrhage (IVH), intraparenchymal hemorrhage, or both.

Risk factors

Studies have identified many risk factors for the development of intracranial hemorrhage in preterm infants, such as low gestational age (LGA) and birth weight, maternal chorioamnionitis and other infections or inflammation, lack of antenatal steroid exposure, hypotension, hypoxemia, hypercapnia, pneumothorax, respiratory distress syndrome, and many others. [4, 5, 6] In all cases, however, GMH results from a combination of the intrinsic fragility of the germinal matrix vasculature, disturbances in cerebral blood flow, and coagulation disorders.

The microvasculature of the germinal matrix is frail because of an abundance of neovascularization. These new vessels have few supporting pericytes, immature basal lamina, and deficient glial fibrillary acidic protein (GFAP) in the ensheathing astrocyte endfeet. [7] High vascular endothelial growth factor (VEGF) and angiopoietin-2 levels activate rapid angiogenesis in the germinal matrix.

The abundance of these growth factors may be ascribed to a relative hypoxia of the germinal matrix, perhaps resulting from high metabolic activity and oxygen consumption in the neural progenitor cells. [7] The structural frailty of the microvasculature is easily susceptible to the significant hemodynamic changes that occur in the setting of perinatal hypoxia and predispose to GMH.

Molecular/genetic factors

It is thought that some genetic factors may contribute to the development of GMHs, although the 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] Any underlying genetic coagulation disorder can also increase the risk of intracranial hemorrhage.

Term infants

Epidural hemorrhage is relatively rare in newborns, because the middle meningeal artery, the tearing of which is the usual cause of epidural hemorrhage, moves freely away from displacements of the skull in this age group. Subdural hemorrhages are more common and occur when vertical molding of the skull during labor causes tearing of the tentorial blood vessels. Subarachnoid hemorrhages are the most common type in term neonates and result from tearing of bridging blood vessels or dural sinuses during labor.

The rate of intracranial hemorrhage is higher among infants requiring instrumented delivery or cesarean section during labor than among infants delivered spontaneously. The rate among infants delivered by cesarean section before labor is not higher, which suggests that the common risk factor for hemorrhage is abnormal labor. [3]

In term infants, IVH is quite rare, partially because of the maturity of the central nervous system (CNS). The germinal matrix, a richly vascularized collection of neuronal-glial precursor cells found in the developing brain, has mostly regressed in full-term infants; therefore, only a minor fraction of hemorrhages arise from the small residual germinal matrix area near the caudate nucleus. IVH usually arises from the choroid plexus or extends from a thalamic hemorrhage. [2]

Intraparenchymal hemorrhage is also relatively uncommon and may result from birth-related trauma, in association with a coagulopathy (see below) or from ischemia-reperfusion injury.

In the cerebellum, precursor cells are found in the outer layer of the cerebellar cortex. Thus, preterm cerebellar hemorrhages are more superficial.

Risk factors

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 intracranial hemorrhages.

Congenital factors, such as thrombocytopenia, coagulopathies, 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 may underlie its development. In many cases, the etiology of the hemorrhage is unknown. [2]

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Clinical Features and Imaging

Below, discussion of the clinical features and imaging of perinatal intracranial hemorrhages are divided into that for preterm infants and that for term infants.

Preterm infants

Most preterm neonates are diagnosed in the first day of life, and about 90% are diagnosed in the first 4 days.

Presentation

Germinal matrix hemorrhage (GMH) is usually asymptomatic and is diagnosed on routine screening. Some cases present slowly, others very rapidly. The rapidly presenting cases involve very large hemorrhages, and the affected infants have altered consciousness, cardiorespiratory abnormalities, metabolic abnormalities (eg, acidosis and blood glucose changes), bulging fontanelle, abnormal findings on neurologic examination (eg, hypotonia, abnormal eye movements, and altered pupillary responses), or seizures. [8]

Radiologic studies

The traditional imaging modality for diagnosing GMH has been cranial ultrasonography because of its availability, low cost, and high resolution for bleeding. Doppler ultrasonography may be used to assess vascular flow; however, it is rarely used in a clinical setting, because its usefulness is unclear.

Computed tomography (CT) scans are discouraged, because the effect of radiation on the immature central nervous system (CNS) is not known. Magnetic resonance imaging (MRI) can often detect petechial hemorrhages and smaller lesions; however, its use is limited by high cost, transportation issues, and concerns over sedation of the infant.

In recent years, 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 preterm GMH

GMH is graded according to severity, as shown in Table 1, below.

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

Grade Characteristics Radiographic findings
I Subependymal hemorrhage Confined to germinal matrix where it originated
II Intraventricular hemorrhage without ventricular dilatation Hemorrhage in nondistended ventricle (blood fills < 50% of ventricular diameter)
III Intraventricular hemorrhage with ventricular dilatation Lateral ventricle is distended by blood (blood fills >50% of ventricular diameter)
IV Intraventricular hemorrhage with parenchymal hemorrhage Hemorrhage into surrounding parenchyma
Source: Bassan H. Intracranial hemorrhage in the preterm infant: understanding it, preventing it. Clin Perinatol. Dec 2009;36(4):737-62, v. [8]

Full-term infants

The majority of neonates with intracranial hemorrhage have no clinical symptoms, including some with moderate to severe hemorrhages. [1] Neonates who are clinically symptomatic may present with any of a number of neurologic symptoms, singly or in combination, including decreased level of consciousness, generalized hypotonia, and seizures. [2] However, these manifestations are not specific to intracranial hemorrhage.

The symptomatic presentation also varies according to the type of hemorrhage affecting the brain, which 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. [2]

Radiologic studies

In full-term infants, as in preterm infants, cranial ultrasonography is widely used for diagnosis of intracranial hemorrhage. 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 subarachnoid hemorrhages, widespread parenchymal injuries, and small intraventricular hemorrhages. MRI is also used clinically to diagnose slowly progressing hemorrhages, as well as extracerebral or infratentorial hemorrhages. [2]

Grading of term intracranial hemorrhages

Intracranial hemorrhages 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)

Grade Characteristics
Mild Only 1 compartment or 1 lobe is involved; midline shift is less than 0.5 cm; or



intraventricular hemorrhage in only 1 ventricle without hydrocephalus



Moderate Only 1 compartment or 1 lobe is involved with midline shift; or



intraventricular hemorrhage of more than 1 ventricle without hydrocephalus



Severe More than 1 lobe and more than 1 compartment is involved; or



intraventricular hemorrhage with hydrocephalus



Source: Gupta SN, Kechli AM, Kanamalla US. Intracranial hemorrhage in term newborns: management and outcomes. Pediatr Neurol. Jan 2009;40(1):1-12. [2]

Differential diagnosis

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

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Gross and Microscopic 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.

The gross appearance of germinal matrix hemorrhage (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 ventricles (grade II or III) (see the second image below) or the white matter (grade IV).

Gross appearance of grade I germinal matrix hemorr Gross appearance of grade I germinal matrix hemorrhage (GMH).
Gross appearance of grade III germinal matrix hemo Gross appearance of grade III germinal matrix hemorrhage (GMH). Blood can be seen distending the lateral and third ventricles.

In grade IV periventricular hemorrhagic infarctions, a large unilateral area of hemorrhagic necrosis can be seen dorsolateral to the lateral ventricle. In some cases, these are massive hemorrhages extending from frontal to occipital lobes. In these cases, the etiology is thought to be secondary venous infarction due to obstruction of terminal veins by the large intraventricular hemorrhage rather than direct extension of the GMH.

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 help highlight hemosiderin-laden macrophages.

In some cases, small grade I GMHs (see the first image below) or cerebellar external granular layer hemorrhages (see the second image below) may be seen microscopically that were missed on gross examination. Furthermore, evidence of old GMHs may be found in the form of germinal matrix cysts lining the lateral ventricles (see the third image below).

Microscopic appearance of grade I germinal matrix Microscopic appearance of grade I germinal matrix hemorrhage (GMH).
Microscopic appearance of cerebellar external gran Microscopic appearance of cerebellar external granular cell layer hemorrhages in preterm infant.
Microscopic appearance of germinal matrix cysts li Microscopic appearance of germinal matrix cysts lining lateral ventricles. These findings are consistent with previous underlying germinal matrix hemorrhage (GMH).
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Prognosis

The prognosis of germinal matrix hemorrhage (GMH) is dependent on parenchymal involvement. The presence of periventricular hemorrhagic infarction (PVHI), periventricular leukomalacia (PVL), cerebellar hemorrhage, brainstem or hippocampal lesions, or decreased brain volumes points 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]

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). However, higher-grade bleeds are strongly associated with poor neurologic outcomes.

After a GMH that is complicated by PVHI, many infants suffer from spastic cerebral palsy, epilepsy, visual field defects, or developmental delay. Complications of GMH accompanied by posthemorrhagic hydrocephalus include profound developmental delay with quadriplegic cerebral palsy. Cerebellar hemorrhagic complications lead to motor deficits, as well as social and cognitive functional impairments. [8]

Conservative treatment generally yields excellent results for 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. As with preterm infants, the extent, severity, and duration of the hemorrhage all affect the long-term outcome. Epilepsy, developmental delay, motor deficits, and other conditions may be a result of damage to tissues and may persist for many years in the patient. [2]

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