Families and caregivers of preterm infants and those threatened with preterm delivery must face 2 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 CNS specifically affect infants born prematurely and result in long-term disability, including periventricular hemorrhage–intraventricular hemorrhage (PVH-IVH), periventricular white matter injury (including cystic periventricular leukomalacia and grade IV PVH-IVH), hemorrhage, and diffuse injury to the developing brain. This article reviews one of the important CNS lesions, PVH-IVH, which involves the periventricular white matter (motor tracts) and is associated with long-term disability. Another type of brain injury also occurs in this population (ie, intraparenchymal hemorrhage) and has similar risk factors and, possibly, pathophysiology to PVH-IVH.
PVH-IVH remains a significant cause of both morbidity and mortality in infants who are born prematurely. Sequelae of PVH-IVH include short- and long-term complications and can result in life-long neurological deficits, specifically cerebral palsy, developmental delay, and seizures. PVH-IVH is diagnosed primarily through the use of brain imaging studies, usually cranial ultrasonography, as shown below. Because PVH-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 pathophysiological basis. PVH-IVH remains a serious problem, despite recent decreases in incidence, because of increased survival of extremely low birthweight infants (ie, < 1000 g) as well as severity of sequelae.
Site of origin
The site of origin of PVH-IVH is the subependymal germinal matrix, a region of the developing brain that regresses by term. 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 PVH-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.
PVH-IVH can be classified into 4 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 radiological appearance rather than a pathophysiological description of events leading to PVH-IVH.
Grade I - Subependymal region and/or germinal matrix, as shown belowGrade I hemorrhage minimal or grade I periventricular hemorrhage (PVH).
Grade II - Subependymal hemorrhage with extension into lateral ventricles without ventricular enlargement, as shown belowModerate or grade II hemorrhage (subependymal with no or little ventricular enlargement).
Grade III - Subependymal hemorrhage with extension into lateral ventricles with ventricular enlargement, as shown belowSevere or grade III hemorrhage (subependymal with significant ventricular enlargement).
Grade IV - Intraparenchymal hemorrhage
PVH-IVH hemorrhage is now thought to be caused by capillary bleeding. Two major factors that contribute to the development of PVH-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 have demonstrated that the alteration from autoregulation to a pressure-passive circulatory pattern appears to be an important step in the development of PVH-IVH in a series of investigations. [1, 2, 3, 4, 5] 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 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 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, and PaO2. [6, 3, 5] Specific metabolic derangements (eg, hypocarbia, hypercarbia, hypoxemia, acidosis) also can disrupt the autoregulatory abilities in infants. As can be seen, while it might be possible to avoid or minimize some of the aforementioned events (rapid volume expansion), some are unavoidable (birth) by nature 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.  Their findings suggest that, when mechanical breaths are not synchronized with efforts of the patient, beat-to-beat fluctuations in blood pressure occur, resulting in fluctuations in cerebral perfusion and subsequent PVH-IVH. Interventions to reduce the fluctuations by suppressing the respiratory efforts of the infant by pharmacological 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 PVH-IVH.
Based on the above discussion, the development of PVH-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 PVH-IVH. Experimental models also describe this development. Host factors can modify mechanisms of PVH-IVH. Among others, such factors include coagulopathy, acid-base balance, hydration, and hypoxia-ischemia.
The above mechanisms account for grades I, II, and III PVH-IVH. The pathogenesis of grade IV hemorrhages differs. Grade IV hemorrhages appear to result from hemorrhagic venous infarctions surrounding the terminal vein and its feeders, probably primarily related to increased venous pressure following or associated with the development of lower-grade hemorrhages. Indeed, the use of the term "periventricular hemorrhagic infarction" has been suggested rather than using the term grade IV hemorrhage. The use of this terminology stresses the current theory that periventricular hemorrhagic infarction (rather than grade IV PVH-IVH) is a complication of 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 PVH-IVH relate to the destruction of 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 neurological disorder observed after PVH-IVH, although mental retardation and seizures can ensue as well.
The occurrence of cerebral palsy is related to the anatomical structure of the periventricular region of the brain. The cortical spinal motor tracts run in this region. The white matter is arranged such that tracts innervating the lower extremities are nearest to the ventricles, followed by those innervating the trunk, the arm, and, finally, the face. This anatomical 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 neurological 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 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 PVH-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 PVH-IVH are global hypoxic-ischemic injury and periventricular leukomalacia (PVL). PVL is a disorder of the periventricular white matter, similar to periventricular hemorrhagic infarction. However, the mechanism of PVL, nonhemorrhagic ischemic necrosis, differs substantially from that of all grades of PVH-IVH, including periventricular hemorrhagic infarction. Both PVL and global hypoxic-ischemic injury can significantly affect the neurologic outcome in infants affected with these disorders.
While 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 might also be of significance. The importance of glial cells in the structural development and support of the CNS has long been recognized. Roles in metabolic support and a response to injury are now emerging.  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. 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,  raising concern that prophylactic use might decrease the risk of PVH-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. 
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. 
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.  Follow-up studies performed in school-aged children using functional MRI suggest cognitive differences between males treated with indomethacin prophylaxis and those treated with placebo;  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. 
At present, based on conflicting results of large multicenter trials discussed above, the long-term benefit of indomethacin prophylaxis for IVH in preterm infants is still debatable. 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 PDA) rather than improved long-term outcomes.
Incidence of PVH-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 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.  Current rates of approximately 20% must be interpreted with a recognition of the increased survival of the extremely preterm infant.
Because the incidence of PVH-IVH is inversely proportional to gestational age, and because resource availability appears to influence aggressiveness of intervention and survival, international incidences of PVH-IVH are likely dramatically different from US incidence. However, no evidence suggests that international rates of PVH-IVH differ from those reported above, provided similar resources are available.
Mortality from severe (high-grade) PVH-IVH is 27-50%. An inverse relationship between extent of hemorrhage and survival is observed. Mortality from low-grade hemorrhage is significantly lower (5%).
Post-hoc analysis of patients enrolled in a multicenter trial investigating indomethacin prophylaxis for PVH-IVH suggests a possible link between sex and effectiveness of prophylaxis.  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.  Therefore, the data remain inconclusive.
Although all infants who are born prematurely should be considered at risk for PVH-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. Risk of developing PVH-IVH is inversely proportional to gestational age.
Postnatally, most hemorrhages 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. PVH-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, 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 PVH-IVH in infants who are premature.
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