The incidence of severe IVH remains substantial in those infants who have the smallest birth weights of the VLBW population. Thus, approximately 26% of infants of birth weight between 501 and 750 g and 12% weighing between 751 and 1,000 g still develop the most severe forms of hemorrhage. The primary lesion is bleeding from small vessels in the subependymal germinal matrix (GM), a transitional gelatinous region providing limited support for the luxurious but very immature capillary bed that courses through it. The genesis of capillary
bleeding from within the GM is complex, likely multifactorial, and influenced in part by intravascular, vascular, and extravascular factors. Experimental studies and clinical observations in the sick newborn infant suggest a pressure-passive cerebral circulation relative to systemic vascular changes, a state that increases cerebral vulnerability during episodes of systemic hypo- and/or hypertension. Indeed, experimental and clinical associations have been demonstrated between fluctuations, increases, and/or decreases in systemic blood pressure as well as elevations in venous pressure, that parallel simultaneous changes in the cerebral circulation and subsequent IVH. The bleeding into white matter is invariably related to an ipsilateral GM hemorrhage. This association may reflect an extension of bleeding from the GM into uninjured white matter, or it may represent secondary hemorrhage into an area of already ischemic white matter (i.e., reperfusion injury). Understanding the mechanism(s) contributing to WMI is crucial to preventing this important lesion. Thus, if WMI is directly related to PV-IVH, then prevention of hemorrhage should reduce the occurrence of WMI. However, if PV-IVH and WMI were to occur simultaneously, as a result of a primary ischemic event, with hemorrhage occurring as a secondary phenomenon, then prevention of the IVH is unlikely to effect the primary ischemic process and thus outcome. Indeed indomethacin treatment to prevent IVH in the neonatal period is supportive of this latter concern. Thus, although the incidence of severe IVH is reduced with indomethacin treatment, at 18-month follow-up, neurodevelopmental outcome, including cerebral palsy, remains comparable in treated infants as compared with controls.

Prevention continues to focus on both perinatal and postnatal approaches. Regarding perinatal strategies, the antenatal administration of a single short course of glucocorticoids to augment pulmonary maturation has had the positive, unanticipated benefit of a significant reduction in the incidence of severe IVH. Thus, the unadjusted odds ratio for severe IVH reduction following any antenatal glucocorticoid exposure has ranged from 0.49 to 0.79. A maternal medical condition associated with a lower incidence of IVH is pregnancy-induced hypertension (PIH), an effect that appears to be independent of the administration of magnesium sulfate, a medication often used to treat the condition.

The role of route of delivery and subsequent IVH remains controversial. However, recent data point to an important role of placental inflammation, and in particular fetal vasculitis, in the genesis of severe IVH, which may supersede the influence of route of delivery.

The focus of postnatal strategies should be directed toward the tiniest VLBW infants, that is, those of less than 1,000 g, and in particular those intubated because of respiratory distress syndrome. Postnatal medications evaluated to reduce severe IVH have included phenobarbital, vitamin E, ethamsylate, and indomethacin. Currently, indomethacin appears to hold the most promise, with a significant reduction in the incidence of grade IV IVH observed in infants who received the drug versus controls.

The infant with grade IV IVH is at high risk for delayed neurodevelopment. In particular, when the lesion is large (greater than 1 cm in diameter on head ultrasound scan), the outcome is invariably poor, resulting in both major motor and cognitive deficits. With a smaller lesion (less than 1 cm in diameter), the outcome is less precise, and a small percentage (approximately 20%) may even have a normal outcome.