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 [CPVL], periventricular hemorrhagic infarction [PVHI]), 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.

 

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

 

Grade II

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

 

Grade III

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

 

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 that the alteration from autoregulation to a pressure-passive circulatory pattern appears to be an important step in the development of GM/IVH in a series of investigations.[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 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, the 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 care giving; 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 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.

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 mental retardation 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 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 outcome 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, nonhemorrhagic 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 mater 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,[10]  glial cells appear to play a role in the limitation of damage resulting from neuronal injury and the recovery of function after injury. The role of these functions in neonatal brain injury associated with germinal matrix destruction remains to be determined.

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,[11]  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.[12]

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.[13]

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.[14]  Follow-up studies performed in school-aged children using functional magnetic resonance imaging (MRI) suggest that cognitive differences exist between males treated with indomethacin prophylaxis and those treated with placebo,[15]  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.[16]

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.[17]

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.[13] More recent rates of approximately 20% must be interpreted with a recognition of the increased survival of the extremely preterm infant.

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.[14] However, this effect, although also recognized in follow-up analysis of another large prophylaxis trial, was interpreted to involve a possible detrimental effect on female infants.[16] 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 aboved, 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 hemorrhage.

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 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 sequellae increases with the grade of the hemorrhage, unilaterality versus bilaterality, and frontal-occipital extent. 

Neurodevelopmental sequellae are likely due to 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.

Loss of autoregulation of cerebral blood flow is a pathophysiologic feature of germinal matrix/intraventricular hemorrhage (GM/IVH). Prematurity itself results in derangements in cerebral autoregulation. In some patients, a history of additional events that result in loss of autoregulation can be obtained. Furthermore, events that can result in beat-to-beat variability of cerebral blood flow may be identified in some patients.

In the majority of patients, GM/IVH is asymptomatic and diagnosed by surveillance ultrasonography.

The parent's/caregiver's history of the patient can be entirely noncontributory; however, they might note nonspecific, subtle signs.

The physical examination is usually negative in germinal matrix/intraventricular hemorrhage (GM/IVH). Occasionally, severe GM/IVH may present with nonspecific systemic findings suggestive of cardiovascular collapse.

The presentation of GM/IVH widely varies. Most infants are asymptomatic or demonstrate subtle signs that are easily overlooked. GM/IVH is then subsequently found on surveillance sonography.

One subgroup of infants with GM/IVH presents with the following:

• A sudden unexplained drop in hematocrit levels

• Possible physical findings related to anemia (eg, pallor, poor perfusion) or hemorrhagic shock

Another subgroup of infants with GM/IVH presents with extreme signs, including the following:

• A sudden and significant clinical deterioration associated with anemia, metabolic acidosis, glucose instability, respiratory acidosis, apnea, hypotonia, and stupor is present.

• Physical findings related to these signs include poor perfusion, pallor or an ashen color, irregularities of respiratory pattern, signs of respiratory distress including retractions and tachypnea, hypotonia, and altered mental status (eg, decreased responsiveness, coma).

• Additional neurologic signs, such as fullness of the fontanelles, seizures, and posturing, may also be observed.

• Progression can be rapid and may result in shock and death.

• Between the two extremes of presentation, infants may demonstrate varying degrees of neurologic and systemic signs. Those with symptoms are more likely to have a more serious grade of GM/IVH.

Work-up and diagnosis

The diagnosis of germinal matrix/intraventricular hemorrhage (GM/IVH) is made by bedside cranial ultrasonography, including views of the cerebellum. Following the initial diagnosis of GM/IVH, continued surveillance is required to assess the progression and the development of posthemorrhagic hydrocephalus (PHH).

Serial daily measurements of frontal-occipital head circumference should be performed in infants with ultrasonographic evidence of PHH as an adjunct tool in monitoring the progression of PHH.

Grade III GM/IVH and periventricular hemorrhagic infarction (PVHI) have been associated with abnormally high (odds ratio [OR], 2.931 [1.825-4.707]) or, to a lesser degree, low (OR, 1.24 [1.036-1.484]) lymphocyte counts,[18]  based on reference ranges the authors defined. Although these are nondiagnostic for GM/IVH, abnormalities may lead to further evaluation.

 

 

The following imaging studies are indicated in patients at risk for periventricular hemorrhage/intraventricular hemorrhage (PVH/IVH) and those who have germinal matrix/IVH (GM/IVH).

Cranial ultrasonography

Ultrasonography is the diagnostic tool of choice for screening examination and follow-up of individuals with PVH/IVH. Current recommendations by the Quality Standards Subcommittee of the American Academy of Neurology suggest that all infants younger than 30 weeks' gestation be screened by cranial ultrasonography at 7-14 days of postnatal life and at 36-40 weeks of postmenstrual age.[19]

Ultrasonography is also the diagnostic tool of choice for the follow-up of individuals with PVH/IVH and posthemorrhagic hydrocephalus, as shown below. Serial ultrasonography is indicated weekly to follow for progression of the hemorrhage and the development of posthemorrhagic hydrocephalus.

 

Normal neonatal brain images are shown below.

Computed tomography (CT) scanning

Prior to the availability of ultrasonography, CT scanning was used for diagnosis and follow-up of IVH. CT scanning is no longer used for diagnosis and follow-up in view of the safety and cost effectiveness of ultrasonography.

Magnetic resonance imaging (MRI)

MRI of the brain is useful in determining the need and opimal intervention for posthemorrhagic hydrocephalus.

The use of MRI to diagnose associated white mater injury (periventricular leukomalacia [PVL]) is evolving.

Germinal matrix/intraventricular hemorrhage (GM/IVH) is graded according to the most extensive ultrasonographic appearance of the hemorrhage, as follows:

1. Grade I: Presence of hemorrhage in the germinal matrix
2. Grade II: Hemorrhage into the cerebral ventricles without ventricular dilatation
3. Grade III: Hemorrhage into the cerebral ventricles with ventricular dilatation
4. Periventricular hemorrhagic infarction (PVHI): Associated PVHI

In addition, laterality (unilateral vs bilateral) and extent (frontal to occipital extent) may be useful in prognosis. 

In a study of 58 infants with PVHI, standardized ultrasonographic findings, including bilaterality, midline shift, and extent of the PVHI lesion, were used to predict neurologic outcomes.[20]  In this scoring system, high scores were statistically associated with death, early seizures, and abnormal meuromotor examinations. Such information may be of use in determining prognosis as well as follow-up and the initiation of intervention programs.

General supportive care includes the correction of underlying medical disturbances that might be related to the development of germinal matrix/intraventricular hemorrhage (GM/VH), as well as cardiovascular, respiratory, and neurologic support. Such measures include the following:

• Correction of anemia, acidosis, and hypotension, as well as ventilatory support, might be required in those neonates who present with acute deterioration.

• Serial lumbar puncture is not indicated, although it was once used to prevent progressive hydrocephalus.

Mazzola et al published recommendations on the management of posthemorrhagic hydrocephalus in premature infants in 2014.[21]

Long-term monitoring includes neurologic and developmental follow-up. Developmental intervention programs are indicated in individuals with GM/IVH.

Consultations

Consult neurosurgery specialists in the event of rapidly progressive ventricular enlargement or prolonged (>4 wk) slowly progressive ventricular enlargement.

Neurology consultation may be of value in the event of intractable seizures in an individual with germinal matrix/intraventricular hemorrhage (GM/IVH).

A developmental interventionist might be of help with a patient with high-grade hemorrhages.

Surgical support for germinal matrix/intraventricular hemorrhage (GM/IVH) is limited to intervention for posthemorrhagic hydrocephalus (PHH). Because most patients with hydrocephalus following periventricular hemorrhage (PVH)-IVH demonstrate spontaneous resolution within weeks of onset, surgical intervention is usually unnecessary. Note the following:

• Serial lumbar punctures have been used to manage early hydrocephalus. However, because spontaneous resolution of hydrocephalus is usually observed, the use of this intervention has been questioned. A multicenter evaluation of serial lumbar punctures demonstrated no benefit when the individual with GM/IVH is aged 30 months. A more recent systematic analysis showed no evidence that repeated cerebrospinal fluid (CSF) removal via lumbar puncture, ventricular puncture, or from a ventricular reservoir has any benefit over conservative management in infants at risk for developing PHH with regard to reducing disability, mortality, or requirement for permanent shunt placement.[22] The role of serial lumbar punctures in the management of late or rapidly progressive hydrocephalus remains controversial.

• Acetazolamide may be used to diminish CSF production and limit late or rapidly progressive hydrocephalus. Its use in the treatment of early ventricular dilatation is probably limited.

• Ventriculostomy placement may be required for the management of significant hydrocephalus while awaiting definitive surgical drainage.

• Ventriculoperitoneal and ventriculosubgaleal shunting remain the definitive treatments for PHH requiring surgical intervention.

In a retrospective study that evaluated early surgical management and long-term surgical outcome for IVH-related PHH in ventriculoperitoneal shunt (VPS)-treated premature infants, investigators noted low gestational age and higher-order IVH in these patients had no significant impact on time to first shunt revision (revision-free shunt survival), but there were marked differences in mean revision rates at 5-year follow-up.[23] They concluded that use of a ventricular access device as a temporizing measure is a reasonable measure to gain time and decision guidance before insertion of a permanent VPS in preterm infants with PHH.

Antenatal steroids and the prevention of prematurity are important elements in the prevention of periventricular hemorrhage/intraventricular hemorrhage (PVH/IVH).

Prevention of germinal matrix/IVH (GM/IVH) begins with avoidance of conditions that do the following:

• Interfere with autoregulation (eg, hypocarbia, hypercarbia, hypoxia, acidosis)

• Overwhelm autoregulatory abilities (eg, hypertension)

• Contribute to rapid fluctuations of cerebral blood flow (eg, ventilatory asynchrony, rapid volume expansion, noxious stimuli, frequent handling)

Perform correction of host factors (eg, coagulopathy, acid-base balance, hydration, hypoxia-ischemia).

Pharmacologic prophylaxis can be accomplished through the use of indomethacin. Although the mechanism of action is currently unknown, indomethacin has been shown to reduce the incidence of GM/IVH and, specifically, high-grade hemorrhages.[13]  Follow-up of patients enrolled in a multicenter prophylaxis study conducted by Ment et al was less convincing,[12]  although sex-related differences favoring treatment in male infants have been postulated. Another large multicenter trial yielded contradictory evidence.[24]  With such contradictory evidence regarding benefit, a lack of a definitive demonstration of improvement in developmental outcomes, and a concern for complications, this therapy is not universally accepted and remains controversial.

In addition to effects on pulmonary development, prenatal treatment with glucocorticoids has a protective effect with regard to PVH/IVH.

The use of other pharmacologic modalities to prevent GM/IVH has been proposed; however, this use is not widely accepted. The other pharmacologic modalities include prenatal treatment with vitamin K and phenobarbital and postnatal treatment with ethamsylate, phenobarbital, and vitamin E. Although positive reports concerning the efficacy of these agents are noted, further investigation is required to prove conclusive evidence of benefit.

Pharmacologic intervention in the prevention and treatment of germinal matrix/intraventricular hemorrhage (GM/IVH) and posthemorrhagic hydrocephalus remains controversial.

Class Summary

Prostaglandin inhibitors are postulated to perform prostaglandin synthesis inhibition. They inhibit free radical formation and accelerate maturation of germinal matrix vasculature. Indomethacin has been shown to decrease the risk of high-grade PVH-IVH. However, developmental outcomes have not been shown to be improved with the use of indomethacin prophylaxis. For this reason, the role of indomethacin in the prevention of IVH remains uncertain. Analysis of patients enrolled in a multicenter trial of indomethacin prophylaxis suggests that prophylaxis is effective in male infants but not in female infants. This remains to be confirmed through prospective evaluations.

Other members of this class of drugs have not been demonstrated to be of value in reducing the incidence of PVH-IVH.

Indomethacin (Indocin)

Indomethacin use is controversial but possibly indicated in patients at risk for GM/IVH, including those younger than 32 weeks' gestation or those who weigh less than 1250 g at birth. Among its actions, indomethacin inhibits the formation of prostaglandins by decreasing the activity of cyclooxygenase. Additionally, through poorly understood mechanisms, indomethacin causes maturation of the germinal matrix microvasculature. It is also associated with decreased cerebral blood flow, cerebral blood flow velocity, and cerebral blood volume, especially when administered rapidly. Alterations of oxidative metabolism are also suggested. Unfortunately, there are conflicting data regarding long-term improvement in outcomes.