Intraventricular Hemorrhage in the Preterm Infant

Germinal matrix/intraventricular hemorrhage (GM/IVH) is complication of premature delivery that can result in life-long medical and developmental consequences. ^{[1, 2]} Although GM/IVH can occur in term infants, hemorrhage in this group of infants remains distinct from periventricular hemorrhage (PVH)/IVH of the preterm infant.

Families and caregivers of preterm infants and those threatened with preterm delivery must face two major unknowns regarding these newborns: Will this child survive? If the child survives, will long-term sequelae be present, especially developmental sequelae? These questions are of particular importance because the answers can influence subsequent medical decisions, such as aggressiveness of care.

Several acquired lesions of the central nervous system (CNS) specifically affect infants born prematurely and result in long-term disability, including GM/IVH, periventricular white matter injury (eg, cystic periventricular leukomalacia, periventricular hemorrhagic infarction), hemorrhage, and diffuse injury to the developing brain. This article reviews one of the important CNS lesions, GM/IVH, which involves the periventricular white matter (motor tracts) and is associated with long-term disability. Intraparenchymal hemorrhage is another type of brain injury that also occurs in this population and has similar risk factors and, possibly, pathophysiology to GM/IVH.

GM/IVH remains a significant cause of both morbidity and mortality in infants who are born prematurely. Sequelae of GM/IVH include short- and long-term complications and can result in life-long neurologic deficits, specifically cerebral palsy, developmental delay, and seizures. GM/IVH is diagnosed primarily through the use of brain imaging studies, usually cranial ultrasonography, as shown below. Because GM/IVH can occur without clinical signs, screening and serial examinations are necessary for the diagnosis.

Intraventricular Hemorrhage in the Preterm Infant. Intraventricular hemorrhage (IVH) with periventricular hemorrhagic infarction (PVHI).

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Although classified according to anatomic involvement by Papile, the clear differentiation of intraparenchymal hemorrhage from lower grade hemorrhage is useful from both a prognostic and pathophysiologic basis. GM/IVH remains a serious problem, despite relatively recent decreases in incidence, because of the increased survival of extremely low birth weight infants (ie, < 1000 g) as well as the severity of sequelae.

Site of origin

The site of origin of germinal matrix/intraventricular hemorrhage (GM/IVH) is the subependymal germinal matrix, a region of the developing brain that regresses by term gestation. During fetal development, the subependymal germinal matrix is a site of neuronal proliferation as neuroblasts divide and migrate into the cerebral parenchyma. By approximately 20 weeks' gestation, neuronal proliferation is completed; however, glial cell proliferation is still ongoing. The germinal matrix supports the division of glioblasts and differentiation of glial elements until approximately 32 weeks' gestation, at which time regression is nearly complete. Cells of the germinal matrix are rich in mitochondria and, therefore, are quite sensitive to ischemia.

Supplying this area of metabolically active differentiating cells is a primitive and fragile retelike capillary network. Arterial supply to the plexus is through the Heubner artery and the lateral striate arteries, which are within the distribution of the anterior and middle cerebral arteries, respectively. This fragile capillary network is the site at which GM/IVH hemorrhage occurs. Venous drainage is through the terminal vein, which empties into the internal cerebral vein; this in turn empties into the vein of Galen. At the site of confluence of the terminal vein and the internal cerebral vein, blood flow direction changes from a generally anterior direction to a posterior direction.

Anatomic classification

GM/IVH can be classified into four grades of severity. This classification, which is useful for prognostic reasons when counseling parents and caregivers, is described below. Note that this classification is based on a radiologic appearance rather than a pathophysiologic description of events leading to GM/IVH.

Grade I

Subependymal region and/or germinal matrix, as shown below

Intraventricular Hemorrhage in the Preterm Infant. Grade I hemorrhage minimal or grade I periventricular hemorrhage (PVH).

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Grade II

Subependymal hemorrhage with extension into the lateral ventricles without ventricular enlargement, as shown below

Intraventricular Hemorrhage in the Preterm Infant. Moderate or grade II hemorrhage (subependymal, with no or little ventricular enlargement).

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Grade III

Subependymal hemorrhage with extension into the lateral ventricles with ventricular enlargement, as shown below

Intraventricular Hemorrhage in the Preterm Infant. Severe or grade III hemorrhage (subependymal, with significant ventricular enlargement).

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Periventricular hemorrhagic infarction (PVHI)

Intraparenchymal hemorrhage (formerly referred to as grade IV IVH)

Pathogenesis

GM/IVH is thought to be caused by capillary bleeding. Two major factors that contribute to the development of GM/IVH are (1) loss of cerebral autoregulation and (2) abrupt alterations in cerebral blood flow and pressure. Healthy infants who were born prematurely have some ability to regulate cerebral blood flow through a process called autoregulation. However, autoregulation is lost under some circumstances and is frequently compromised in very premature infants with pulmonary disease. Perlman et al and Volpe demonstrated in a series of investigations that the alteration from autoregulation to a pressure-passive circulatory pattern appears to be an important step in the development of GM/IVH. ^{[3, 4, 5, 6, 7]} The underlying conclusion of these studies is that when a pressure-passive circulatory pattern is challenged with fluctuations of cerebral blood flow and pressure, hemorrhage can occur.

The autoregulatory abilities of neonates vary proportionally to the gestational age at the time of birth. The range of perfusion pressures over which a premature neonate can control regional cerebral blood flow is narrower and lower than that of infants born at term. In the absence of autoregulation, systemic blood pressure becomes the primary determinant of cerebral blood flow and pressure, a pressure-passive situation. In this state, any condition that affects systemic blood pressure and, specifically, rapid alterations in blood pressure, can result in PVH/IVH.

Multiple events can result in rapid changes in the cerebral circulation, potentially overwhelming the impaired autoregulatory mechanisms of the neonate. These events include asynchrony between spontaneous and mechanically delivered breaths; birth; noxious procedures of caregiving; instillation of mydriatics; tracheal suctioning; pneumothorax; rapid volume expansion (iso-osmotic or hyperosmotic as in sodium bicarbonate); rapid colloid infusion (eg, exchange transfusion); seizures; and changes in pH, PaCO₂ (partial pressure of carbon dioxide), and PaO₂ (partial pressure of oxygen). ^{[5, 7, 8]} Specific metabolic derangements (eg, hypocarbia, hypercarbia, hypoxemia, acidosis) also can disrupt the autoregulatory abilities in infants. Although it may be possible to avoid or minimize some of the aforementioned events (rapid volume expansion), some are unavoidable by nature (birth) and others are commonly encountered in the care of sick very low birth weight (VLBW) infants (mechanical ventilation, alterations in blood gases).

Impaired autoregulatory ability coupled with rapid alterations in cerebral blood flow and pressure can result in hemorrhage. The capillaries of the immature germinal matrix possess neither tight junctions between endothelial cells nor a strong basement membrane. Therefore, increased flow and pressure may rupture the delicate capillaries, leading to bleeding.

In a series of investigations, Perlman et al described the relationship between cerebral blood flow and respiratory pattern in preterm infants. ^[3] Their findings suggest that, when mechanical breaths are not synchronized with the efforts of the patient, beat-to-beat fluctuations in blood pressure occur, resulting in fluctuations in cerebral perfusion and subsequent GM/IVH. Interventions to reduce the fluctuations by suppressing the respiratory efforts of the infant by pharmacologic muscle blockade prevented hemorrhage. Patients without asynchrony between mechanical ventilation and patient efforts had stable blood pressures, stable cerebral perfusion, and a lower incidence of hemorrhage. Similar experimental models have demonstrated a relationship between rapid volume expansion following ischemia or hemorrhagic shock and GM/IVH.

Based on the above discussion, the development of GM/IVH appears to occur in two steps; the loss of cerebral autoregulation is followed by rapid changes in cerebral perfusion. Additionally, because the range of arterial pressures over which a prematurely born neonate can maintain autoregulation is narrow, abrupt large changes in blood pressures can overwhelm the ability of the neonate to protect the cerebral circulation and result in GM/IVH. Experimental models also describe this development. Host factors can modify the mechanisms of GM/IVH. Among others, such factors include coagulopathy, acid-base balance, hydration, and hypoxia-ischemia.

The aforementioned mechanisms account for grades I, II, and III GM/IVH. The pathogenesis of PVHI differs. Hemorrhages formerly referred to as grade IV hemorrhages appear to result from hemorrhagic venous infarctions surrounding the terminal vein and its feeder vessels, probably primarily related to the increased venous pressure following or associated with the development of lower-grade hemorrhages. Indeed, the use of the term "periventricular hemorrhagic infarction" is preferred over the term "grade IV hemorrhage." The use of this terminology stresses the current theory that PVHI is a complication of a lower grade hemorrhage rather than a more severe version of the same pathophysiologic events. See the images below.

Intraventricular Hemorrhage in the Preterm Infant. Periventricular hemorrhagic infarction (PVHI) with porencephalic cyst formation.

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Intraventricular Hemorrhage in the Preterm Infant. Periventricular hemorrhagic infarction (PVHI) on magnetic resonance imaging (MRI).

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Pathogenesis of sequelae

The major sequelae of GM/IVH relate to the destruction of the cerebral parenchyma and the development of posthemorrhagic hydrocephalus. Furthermore, the sequelae of ventricular-peritoneal shunt placement (primarily infection) can contribute to poor neurodevelopmental outcomes.

Following parenchymal hemorrhages, necrotic areas form cysts that can become contiguous with the ventricles (porencephalic cysts). Cerebral palsy is the primary neurologic disorder observed after GM/IVH, although intellectual disability and seizures can ensue as well.

The occurrence of cerebral palsy is related to the anatomic structure of the periventricular region of the brain. The cortical spinal motor tracts run in this region. The white matter is arranged such that the tracts innervating the lower extremities are nearest to the ventricles, followed by those innervating the trunk, the arm, and, finally, the face. This anatomic arrangement accounts for the greater degree of motor dysfunction of the extremities as compared to the face (spastic hemiplegia in unilateral lesions and spastic diplegia or quadriplegia in bilateral lesions). In addition to the destruction of periventricular motor tracts, destruction of the germinal matrix itself can occur. The long-term effects of the loss of glial cell precursors are unknown.

The second mechanism by which long-term neurologic outcomes can be altered is through the development of posthemorrhagic hydrocephalus. The mechanisms by which hydrocephalus develop include (1) decreased absorption of cerebral spinal fluid (CSF) secondary to obstruction of the arachnoid villi by blood and debris or the development of obliterative arachnoiditis (ie, communicating hydrocephalus) and (2) obstruction to CSF circulation (ie, obstructive hydrocephalus).

It should be noted that, because the development of GM/IVH is related to alterations in cerebral blood flow, injury to other portions of the brain must be considered. Two disorders that may occur with GM/IVH are global hypoxic-ischemic injury and periventricular leukomalacia (PVL). PVL is a disorder of the periventricular white matter, similar to PVHI. However, the mechanism of PVL, non-hemorrhagic ischemic necrosis, differs substantially from that of all grades of PVH/IVH, including PVHI. Both PVL and global hypoxic-ischemic injury can significantly affect the neurologic outcome in infants affected with these disorders.

Although the destruction of periventricular white matter can be directly associated with the subsequent development of motor abnormalities (cerebral palsy), the loss of glial cell precursors may also be of significance. The importance of glial cells in the structural development and support of the central nervous system has long been recognized. Roles in metabolic support and a response to injury have emerged. ^[9] For example, in rat models, glial cells appear to play a role in the limitation of damage resulting from neuronal injury and the recovery of function after injury. ^[10] The role of these functions in neonatal brain injury associated with germinal matrix destruction remains to be determined. ^[11]

The significance of alterations in cerebral blood flow is perhaps of greater importance than previously recognized, not only in the generation of hemorrhage but in more diffuse brain injury as well. For example, studies have demonstrated alterations in cerebral blood flow during rapid infusions of indomethacin, ^[12] raising the concern that prophylactic use may decrease the risk of GM/IVH while increasing the risk of PVL. Fortunately, this has not been shown to be true. Indeed, in a large follow-up study of patients receiving indomethacin prophylaxis, Ment et al demonstrated that although indomethacin prophylaxis did not result in improved motor outcomes, cognitive and verbal outcomes were improved with prophylaxis. ^[13]

The pathophysiology described above may appear inconsistent with that observation; however, poorly understood alterations in cerebral blood flow distribution and cellular energy use may be beneficially affected by indomethacin. That these findings are not consistent with earlier results is concerning. ^[14]

The selection of patients most likely to benefit from prophylaxis may partially explain these results. For example, a follow-up analysis of the data reported above suggested that male infants may be more likely to benefit from indomethacin prophylaxis than female infants. ^[15] Follow-up studies performed in school-aged children using functional MRI suggest that cognitive differences exist between males treated with indomethacin prophylaxis and those treated with placebo, ^[16] however, the matter is still unresolved. In an analysis of another cohort of infants, Ohlsson et al found differences in the effect of indomethacin in males and females, but this may be due, in part, to a detrimental effect on female infants. ^[17]

Thus, based on the conflicting results of the large multicenter trials discussed above, the long-term benefit of indomethacin prophylaxis for IVH in preterm infants remains in debate. Indeed, in a meta-analysis updated in 2010, Fowlie et al concluded that given the lack of support for an impact on long-term outcomes, the decision to use indomethacin prophylaxis would depend on the importance of short-term outcomes (reduced incidence of symptomatic patent ductus arteriosus) rather than improved long-term outcomes. ^[18]

Prematurity is the most important risk factor for germinal matrix/intraventricular hemorrhage (GM/IVH). However, other factors have been associated with the development of hemorrhage, including the following:

• Rapid volume expansion (eg, the correction of hypotension with volume infusions)

• Asynchrony between mechanically delivered and spontaneous breaths in infants on ventilation

• Hypertension or beat-to-beat variability of blood pressure

• Coagulopathy

• Hypoxic-ischemic insults

• Respiratory disturbances (eg, hypercarbia, hypocarbia pneumothorax, hypoxemia, rapid alterations in blood gasses)

• Acidosis

• Infusions of hypertonic solutions (eg, sodium bicarbonate)

• Anemia

• Vacuum-assisted delivery

• Frequent handling

• Tracheal suctioning

United States data

The incidence of germinal matrix/intraventricular hemorrhage (GM/IVH) in infants of very low birth weight (< 1500 g) or infants of less than 35 weeks' gestation has been reported to be as high as 50%. This incidence appears to have fallen in relatively recent years. Although no firm estimates of incidence can be made at this point, a multicenter study conducted by Ment et al in 1994 reported rates of 12% with indomethacin prophylaxis and 18% without indomethacin prophylaxis. ^[14] More recent rates of approximately 20% must be interpreted with a recognition of the increased survival of the extremely preterm infant. Recent data from a study by Gillam-Krakhauer et al has demonstrated both the efficacy of single-dose indomethacin to close the PDA and is associated with increased survival and decreased incidence of cerebral palsy. ^[19]

International data

Because the incidence of GM/IVH is inversely proportional to gestational age, and because resource availability appears to influence the aggressiveness of intervention and survival, international incidences of GM/IVH are likely dramatically different from the US incidence. However, no evidence suggests that international rates of GM/IVH differ from those reported above, provided similar resources are available.

Sex- and age-related demographics

Post-hoc analysis of patients enrolled in a multicenter trial investigating indomethacin prophylaxis for GM/IVH suggests a possible link between the infant's sex and the effectiveness of prophylaxis. ^[15] However, this effect, although also recognized in the follow-up analysis of another large prophylaxis trial, was interpreted to involve a possible detrimental effect on female infants. ^[17] Therefore, the data remain inconclusive.

Although all infants who are born prematurely should be considered at risk for GM/IVH, neonates delivered at less than 32 weeks' gestation are at significant risk. Beyond approximately 32 weeks' gestation, the germinal matrix has regressed to the point that hemorrhage is significantly less likely. As noted above, the risk of developing GM/IVH is inversely proportional to gestational age.

Postnatally, most IVHs occur when the neonate is younger than 72 hours, with 50% of hemorrhages occurring on the first day of life. The extent of hemorrhage is greatest when the neonate is aged approximately 5 days. GM/IVH can occur when the individual is older than 3 days, especially if a significant life-threatening illness arises. This forms the basis for screening programs and recommendations for screening at age 7 days.

Although IVH is uncommon in infants who are born at term, the disorder has been reported in this group, especially in association with trauma and asphyxia. The site of hemorrhage in term infants is usually the choroid plexus, a difference from the site of GM/IVH in infants who are premature.

Grade I and grade II hemorrhage

The neurodevelopmental prognosis is excellent (ie, perhaps slightly worse than infants of similar gestational ages without germinal matrix/intraventricular hemorrhage (GM/IVH) in those with grade I or II hemorrhages.

Grade III hemorrhage without white matter disease

Mortality is less than 10% in infants with grade III hemorrhage without white matter disease. Of these patients, 30%-40% have subsequent cognitive or motor disorders.

Periventricular hemorrhagic infarction (PVHI) and/or periventricular leukomalacia (PVL)

Mortality approaches 80% in infants with PVHI and/or PVL. A 90% incidence of severe neurologic sequelae including cognitive and motor disturbances is noted.

Morbidity/mortality

Mortality from severe (high-grade) GM/IVH ranges from 27% to 50%. An inverse relationship between the extent of hemorrhage and survival is observed. Mortality from low-grade hemorrhage is significantly lower (5%).

Complications

Complications of GM/IVH include the following:

• Obstructive hydrocephalus

• Nonobstructive hydrocephalus

• Posthemorrhagic hydrocephalus

• Developmental impairment

• Cerebral palsy

• Seizures

Short-term complications of GM/IVH include expansion of hemorrhage and transient ventricular enlargement. Serial cranial ultrasonography should be performed until the extent of the hemorrhage and ventricular dilatation have stabilized.

Long-term complications include the development of posthemorrhagic hydrocephalus and neurodevelopmental sequelae such as motor and cognitive developmental delays, as well as seizures (which occur beyond the immediate neonatal period). The incidence of significant neurodevelopmental sequalae increases with the grade of the hemorrhage, unilaterality versus bilaterality, and frontal-occipital extent. ^[20]

Neurodevelopmental sequalae are likely due to the destruction of the periventricular long motor tracks, loss of glial precursors in the periventricular germinal matrix, and complications of ventriculoperitoneal shunt placement.

During the prenatal period, discuss with the parents the specific risks of the relevant gestational age and potential sequelae of germinal matrix/intraventricular hemorrhage (GM/IVH).

Provide postnatal education (if not provided previously) or reinforce prenatal education, as well as provide results of ultrasonography and the expectations for short-term and long-term care.