Background
PHH of prematurity
Maternal and neonatal risk and protective factors
Physiological risk factors
Pathophysiology of PHH
Current treatments for PHH of prematurity
Review of clinical trials
Interventions that alter risk of IVH
Drug(s) or intervention | Dosage | Mechanism | Data class | Degree of IVH reduction | Neurological outcome improvement | References |
---|---|---|---|---|---|---|
Antenatal betamethasone | Single 2-dose (12 mg each); 24 mg | May reduce endothelial proliferation, vascular density, and increase pericyte vascular coverage [270] | Class 2, Class 2, Class 2, Class 2, Class 1, Class 2, Class 1 | IVH reduction from 6 to 47 h, slowly increased 48 h ≥ 10 days); beneficial for women < 34 weeks GA; decreased IVH from 22–29 GA; decreased IVH even with incomplete course | Not significant, not examined in study; associated improved neurological outcome | |
Antenatal betamethasone/dexamethasone | Meta-study with unknown dosing | May reduce endothelial proliferation, vascular density, and increase pericyte vascular coverage | Class 2 | Beneficial for women peri-viable ages 23–26 weeks GA | Not examined | [274] |
Prophylactic indomethacin (oral or IV) | Oral 0.2 mg/kg daily for 3 days; 0.1 mg/kg IV for daily for 2 days | Inhibits cyclooxygenase-mediated production of prostaglandins, promotes germinal matrix vascular maturation | Class 2, Class 1, Class 1 | 50–80% reduction in IVH | Higher verbal scores in 3-8 yr old boys | |
Ibuprofen | Oral 5–10 mg/kg daily for 3 days | Inhibits cyclooxygenase-mediated production of prostaglandins | Class 2, Class 1 | Mixed results: 0–80% reduction in IVH | Not examined | |
Neonatal Ethamsylate | 12.5 mg/kg daily for 4 days | Inhibits cyclooxygenase-mediated production of prostaglandins; possibly increases platelet aggregation | Class 1, Class 1, Class 1 | Reduction in IVH | No decrease in mortality (possibly increased), no improvement in cognitive outcomes | |
Inhaled nitric oxide | Inhaled at 20 ppm | Mediates rapid vasodilation by stimulating guanylate cyclase, subsequent reduced phosphorylation of myosin, and relaxes smooth muscle cells | Class 1, Class 1 | No reduction in IVH | No significant neurological improvement | |
Phenobarbital | IV injections of 20–30 mg/kg loading dose, followed by 3–7 days of maintenance doses | Acts on GABA receptors and is thought to stabilize blood pressure and may protect against free radicals | Class 2, 3 | Mixed results from 12 clinical trials; overall does not appear to reduce severe IVH or ventricular dilatation | Did not seem to attenuate neurological impairments | [282] |
Prophylactic surfactant | Bolus or infusion delivery via endotracheal tube (e.g., 5 ml/kg) | Replenishes insufficient surfactant production in premature neonates in order to increase pulmonary compliance, increase alveolar gas exchange, and decrease hypoxia | Class 1, Class 1, Class 1 | No reduction in IVH (though there was decrease in neonatal morbidity) | Not examined | |
Postnatal corticosteroids (typically dexamethasone) | 0.12–0.5 mg/kg/day for several days | May reduce endothelial proliferation, vascular density, and increase pericyte vascular coverage | Class 1, Class 1 | Possible trend towards reduction of neonatal IVH | Unclear neurological improvement | |
Magnesium (magnesium sulfate) | 4–6 g IV MgSO4 loading dose, 2–4 g/h for 12–24 h | Tocolytic mechanisms include competition for calcium, prevent release of acetylcholine, and activation of myosin light chain kinase, which blocks myometrial contractions; neuroprotective effects may include stabilization of rapid blood pressure fluctuations, increased cerebral blood flow, and decreased neuroinflammation | Class 1, Class 1, Class 1, Class 2 | No effect on IVH reduction | Possible neurological protection | |
Cesarean delivery | 22–37 weeks gestational age planned delivery | Prevention of stresses associated with vaginal delivery | Class 2, Class 2 | 35% reduction in IVH in < 30 week preterm neonates | Not examined | |
Delayed cord clamping | Delayed clamping usually performed 60–75 s (compared with 30–45 s) | Proposed mechanisms include cardiovascular transition with ventilation, establishment of red blood cell volume, decreased need for blood transfusion | Class 1, Class 1, Class 3, Class 3 | Up to 50% reduction in preterm IVH; benefits unclear in term neonates | May improve fine motor and social domains at 4 years in low-risk children [293] |
Neonatal interventions to stop development of progressive PHH
Lessons from adult intracerebral and intraventricular hemorrhage clinical trials
Workshop recommendations: key areas for research and intervention
Early identification
Identifying genetic risk factors |
Identifying susceptibility/risk factors of IVH and PHH |
Identify diagnostic, prognostic, predictive, and monitoring biomarkers (e.g., molecular, cellular, imaging biomarkers) |
Developing a prognostic scale |
Prevention of hemorrhage
Determining the tolerance of the germinal matrix to respiratory and cardiac instability |
Understanding the development of the germinal matrix |
Understanding the physiology of the blood/ventricular barrier of the germinal matrix |
Determining how to modify the germinal matrix vasculature without altering corticogenesis |
Prevention of blood-induced injury
Identifying mechanisms of toxicity |
Elucidating the effects of IVH on ventricular ependymal and choroid plexus epithelium |
Developing targeted therapeutics |
Determining how to clear the blood clot rapidly and safely |
Prevention of secondary injury
Therapeutic modulation of neuroinflammation |
Preventing fibrosis |
Preventing ependymal damage |
Minimizing edema |
Targeting brain fluid dynamics
Understanding and targeting CSF fluid production |
Understanding and targeting alternative routes for CSF absorption |
Understanding and targeting CSF and brain interstitial fluid flow |
Understanding changes in barrier function after IVH |
Understanding and targeting ependymal cell–cell junctions |
Understanding brain development and long-term outcomes after IVH
Determining if PHH is associated with worse long-term neurodevelopmental, cognitive, and motor deficits compared to IVH and prematurity |
Determining how damage to motile and primary cilia affects brain development |
Understanding how cell proliferation from the ventricular and subventricular zones are altered after IVH |
Identifying and targeting the mechanisms responsible for changes in cell proliferation |
Linking neurodevelopmental and cognitive deficits to altered brain function |
Developing targeted rehabilitation strategies for preterm neonates with IVH and PHH. |
Determining mechanisms of tissue repair after PHH and how to enhance it |
Determining the benefits of stem cell therapies on long-term outcomes |
Determining impact of non-surgical interventions on long-term outcomes |
Developing optimal psychometric and imaging-based instruments |
Improving clinical management and clinical trials
Developing standardized management and treatment protocols |
Implementing standardized management and treatment protocols |
Collecting common classification data (e.g., gestational age at birth, birth weight) |
Using common study inclusion/exclusion criteria when possible |
Developing standardized diagnosis criteria/definitions |
Developing standardized treatment criteria/definitions |
Developing standardized outcome measures/definitions |