MPA | Pharmacy News

by Sarah Hoerner, Pharm.D. PGY-1 resident, Spectrum Health, and Carissa Jacobs, Pharm.D. PGY-2 pediatric pharmacy resident, Helen DeVos Children’s Hopital 

One of the numerous complications that may occur in a premature neonatal patient is intraventricular hemorrhage (IVH), which is intracranial bleeding confined to the ventricles. Premature neonates are at risk for developing IVH due to the fragility of their germinal matrix vasculature, fluctuation in their cerebral blood flow and underlying coagulopathies.1 The patients at highest risk for developing IVH are those born at less than 32 weeks gestation or at a very low birth weight (VLBW) of less than 1500 grams.2 IVH typically occurs within the first week of life, and the degree of IVH can vary with grade four being the most severe.3 The prevalence of IVH is roughly 50 percent in patients born at extremely low birth weights of less than 1000 grams and approximately 20 percent in VLBW patients.2,3 Overall, about 12,000 neonates develop IVH annually.1 Of those that survive, at least 50 percent of the patients develop any or all of the following sequelae: cerebral palsy, mental retardation and hydrocephalus.1 Due to this high incidence of morbidity associated with IVH, a preventive measure may positively impact society.

Prophylaxis for IVH started evolving as the treatment of patent ductus arteriosus (PDA) was medically managed with nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin or ibuprofen. Indomethacin was the first NSAID available and had been the medication of choice for decades before ibuprofen was approved. Indomethacin has shown to reduce cerebral blood flow and affect cerebral oxygenation making it potentially useful in the prevention of high-grade IVH.4 One of the larger multicenter trials studying indomethacin’s use for IVH prophylaxis was conducted by Ment et al6. This study specifically compared intravenous indomethacin to placebo for decreasing the incidence and severity of IVH in neonates that weighed between 600 to 1,250 grams at birth. The study was able to demonstrate a statistically significant reduction in the number of IVH diagnoses (12% treatment group vs. 18% placebo group, P=0.03) and the severity of IVH.  Only one neonate in the treatment group versus ten in the placebo group develop grade four IVH (P=0.01).5  However, there was a follow-up trial with the same population that demonstrated there were no clinically significant improvements of neurological outcomes associated with indomethacin-treated children at 18 and 36 months when compared to the control group.6

After indomethacin demonstrated potential efficacy, ibuprofen became available warranting additional research from this class of medication. Both indomethacin and ibuprofen are nonselective cyclooxygenase (COX) inhibitors warranting many adverse effects including spontaneous intestinal perforation, necrotizing enterocolitis, increased serum creatinine, oliguria and hyperbilirubinemia. Ibuprofen is structurally different than indomethacin, resulting in different pharmacologic and kinetic properties. Ibuprofen has not shown the same vasoconstrictive effects in the brain as indomethacin, but has demonstrated efficacy at closing PDAs, therefore, research was warranted to determine if this medication may prevent IVH.4 Two multicenter, placebo-controlled, randomized trials that occurred in the early 2000s demonstrated that ibuprofen did not prevent IVH in premature neonates.7,8 In 2004, Van Overmeire et al. enrolled 415 premature (<30 week gestation age) neonates, who were randomized to receive either placebo or intravenous ibuprofen (210 patients, 205 patients, respectively). The incidence of grade three or four IVH was similar between both groups (8% treatment vs. 9% placebo, RR 0.97, CI 0.51-1.82).7 One year later, Dani et al. analyzed the prophylactic effects of intravenous ibuprofen on grade two through four IVH. Similar results to the 2004 study were achieved; there was not a statistically significant difference in the development of grade two through four IVH between the treatment and the placebo groups (21% treatment vs 17% placebo, P=0.652).8

NSAIDs have been a mainstay in the pharmacologic treatment of symptomatic PDAs, but have been used controversially for the prevention of IVH. Indomethacin has demonstrated statistical differences in decreasing the incidence and severity of IVH in the premature neonates; however, long term clinical benefits have not been proven. More recently, ibuprofen has not shown clinical or statistical benefit when utilized for IVH prophylaxis. 

1.       Ballabh P. Pathogenesis and prevention of intraventricular hemorrhage. Clin Perinatol. 2014 Mar;41(1):47-67.

2.       Wilson-Costello D, et al. Improved survival rates with increased neurodevelopmental disability for extremely low birth weight infants in the 1990s. Pediatrics. 2005 Apr;115(4):997-1003.

3.       Luque MJ, et al. A risk prediction model for severe intraventricular hemorrhage in very low birth weight infants and the effect of prophylactic indomethacin. J Perinatol. 2014 Jan;34(1):43-48.

4.       Johnston PG, et al. Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unit. Clin Perinatol. 2012 Mar;39(1):111-136.

5.       Ment LR, et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics. 1994 Apr;93(4):543-550.

6.       Ment LR, et al. Neurodevelopmental outcome at 36 months' corrected age of preterm infants in the Multicenter Indomethacin Intraventricular Hemorrhage Prevention Trial. Pediatrics. 1996 Oct;98(4 Pt 1):714-718.

7.       Van Overmeire B, et al. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2004 Nov 27-Dec 3;364(9449):1945-1949.

8.       Dani C, et al. Prophylactic ibuprofen for the prevention of intraventricular hemorrhage among preterm infants: a multicenter, randomized study. Pediatrics. 2005 Jun;115(6):1529-1535.

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