Combining Phenobarbital and Indomethacin to Improve Early Neonatal Outcomes in the Extremely Low Birth Weight Infant

Felix A. Okah; David C. Mundy; Ikechukwu I. Ekekezie

doi:10.1055/s-2004-837741

American Journal of Perinatology, Table of Contents

Am J Perinatol 2005; 22(1): 11-17
DOI: 10.1055/s-2004-837741

Combining Phenobarbital and Indomethacin to Improve Early Neonatal Outcomes in the Extremely Low Birth Weight Infant

Felix A. Okah¹ ^, ² ^, ³ , David C. Mundy² ^, ³ , Ikechukwu I. Ekekezie¹ ^, ² ^, ³

¹Children's Mercy Hospital and Clinics, Kansas City, Missouri
²Truman Medical Center, Kansas City, Missouri
³University of Missouri Kansas City School of Medicine, Kansas City, Missouri

Abstract

ABSTRACT

In this retrospective study, we tested the following hypotheses: rates of severe intraventricular hemorrhage (SIVH) and early neonatal survival are similar among extremely low birth weight (ELBW) infants treated with combination prophylaxis of phenobarbital and indomethacin compared with phenobarbital alone or no prophylaxis; and rates of patent ductus arteriosus (PDA) and necrotizing enterocolitis (NEC) are similar among indomethacin-exposed and nonexposed ELBW infants. Data were abstracted on 265 ELBW infants admitted into a level 3 neonatal intensive care unit from 1994 through 2002. Combination prophylaxis neither reduced the odds ratio (OR) of SIVH (OR = 1.53; 95% confidence interval [CI], 0.43 to 1.16) versus phenobarbital (OR = 2.91; 95% CI, 0.91 to 9.27 versus none (OR = 1; 95% CI, reference) nor increased the odds of early neonatal survival (OR = 0.72; 95% CI, 0.17 to 3.09 for combination prophylaxis versus OR = 0.66; 95% CI, 0.16 to 2.67 for phenobarbital versus OR = 1; 95% CI, reference for none). Indomethacin exposure reduced the odds of PDA (OR = 0.35; 95% CI, 0.17 to 0.75) without increasing the risk of NEC (OR = 1.37; 95% CI, 0.60 to 3.12). In conclusion, combination prophylaxis does not improve SIVH and early neonatal survival outcomes. Early exposure to indomethacin offers some benefits without any added risks.

KEYWORDS

Hemorrhage - survival - neonate

Full Text

References

REFERENCES

1 Krishnamoorthy K S, Shannon D C, DeLong G R, Todres I D, David K R. Neurological sequelae in the survivors of neonatal intraventricular hemorrhage. Pediatrics. 1979; 64 233-237
2 McMenamin J B, Shackelford G D, Volpe J J. Outcome of neonatal intraventricular hemorrhage with periventricular echodense lesions. Ann Neurol. 1984; 15 285-290
3 Williamson W D, Desmond M M, Wilson G S, Murphy M A, Rozelle J, Garcia-Prats J A. Survival of low birth weight infants with intraventricular hemorrhage. Outcome in the preschool years. Am J Dis Child. 1983; 137 1181-1184
4 Ment L R, Duncan C C, Ehrenkranz R A et al.. Randomized indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight infants. J Pediatr. 1985; 107 937-943
5 Hanigan W C, Kennedy G, Roemisch F, Anderson R, Cusack T, Powers W. Administration of indomethacin for the prevention of periventricular-intraventricular hemorrhage in high-risk neonates. J Pediatr. 1988; 112 941-947
6 Couser R J, Ferrara T B, Wright G B et al.. Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room. J Pediatr. 1996; 128 631-637
7 Bandstra E S, Montalvo B M, Goldberg R N et al.. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics. 1988; 82 533-542
8 National Institute of Health Consensus Development Conference on the effect of corticosteroids for fetal maturation on perinatal outcomes .Consensus Development Conference Statement. Bethesda, MD; National Institute of Health 1994: pp. 1-21
9 Ment L R, Oh W, Ehrenkranz R A, Philip A G, Duncan C C, Makuch R W. Antenatal steroids, delivery mode, and intraventricular hemorrhage in preterm infants. Am J Obstet Gynecol. 1995; 172 795-800
10 Bottoms S F, Paul R H, Iams J D et al.. Obstetric determinants of neonatal survival: influence of willingness to perform caesarian delivery on survival of extremely low-birthweight infants. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol. 1997; 176 960-966
11 Donn S M, Roloff D W, Goldstein G W. Prevention of intraventricular hemorrhage in preterm infants by phenobarbitone. A controlled trial. Lancet. 1981; 2 215-217
12 Hope P L, Stewart A L, Thorburn R J, Whitehead M D, Reynolds E OR, Lowe D. Failure of phenobarbitone to prevent intraventricular hemorrhage in small preterm infants. Lancet. 1982; 1 444-445
13 Morgan M EI, Massey R F, Cooke R WI. Does phenobarbitone prevent periventricular hemorrhage in very low birth weight babies? A controlled trial. Pediatrics. 1982; 70 186-189
14 Bedard M P, Shankaran S, Slovis T L, Pantoja A, Dayal B, Poland R L. Effect of prophylactic phenobarbital on intraventricular hemorrhage in high-risk infants. Pediatrics. 1984; 73 435-439
15 Ment L R, Duncan C C, Ehrenkranz R A et al.. Randomized low-dose indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates. J Pediatr. 1988; 112 948-955
16 Ment L R, Oh W, Ehrenkranz R A et al.. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics. 1994; 93 543-550
17 Bada H S, Green R S, Poucyrous M et al.. Indomethacin reduces the risks of severe intraventricular hemorrhage. J Pediatr. 1989; 115 631-637
18 Yeh T F, Goldbarg H R, Henek T, Thalji A, Pildes R S. Intravenous indomethacin therapy in premature infants with patent ductus arteriosus. Causes of death and one-year follow-up. Am J Dis Child. 1982; 136 803-807
19 Schmidt B, Davis P, Moddemann D et al.. Trial of indomethacin prophylaxis in preterms investigators. N Engl J Med. 2001; 344 1966-1972
20 Krueger E, Mellander M, Bratton D, Cotton R. Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin. J Pediatr. 1987; 111 749-754
21 Ment L R, Oh W, Ehrenkranz R A et al.. Low-dose indomethacin therapy and extension of intraventricular hemorrhage: a multicenter randomized trial. J Pediatr. 1994; 124 951-955
22 Ment L R, Vohr B, Allan W et al.. Outcome of children in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics. 2000; 105 485-491
23 Sulzbacher S, Farwell J R, Temkin N, Lu A S, Hirtz D G. Late cognitive effects of early treatment with phenobarbital. Clin Pediatr. 1999; 38 387-394
24 Lacayo A, Mitra N. Report of a case of phenobarbital-induced dystonia. Clin Pediatr. 1992; 31 252
25 Brent D A, Crumrine P K, Varma R R, Allan M, Allman C. Phenobarbital treatment and major depressive disorders in children with epilepsy. Pediatrics. 1987; 80 909-917
26 Vining E P, Mellitis E D, Dorsen M M et al.. Psychologic and behavioral effects of antiepileptic drugs in children: a double-blind comparison between phenobarbital and valproic acid. Pediatrics. 1987; 80 165-174
27 Whitelaw A. Postnatal phenobarbitone for the prevention of intraventricular hemorrhage in preterm infants. Cochrane Database Syst Rev. 2001; 1 CD001691
28 Fujii A M, Brown E, Mirochnick M, O'Brien S, Kaufman G. Neonatal necrotizing enterocolitis with intestinal perforation in extremely premature infants receiving early indomethacin treatment for patent ductus arteriosus. J Perinatol. 2002; 22 535-540
29 Grosfeld J L, Chaet M, Molinari F et al.. Increased risk of necrotizing enterocolitis in premature infants with patent ductus arterious treated with indomethacin. Ann Surg. 1996; 224 350-355
30 Horbar J D, Badger G J, Carpenter J H et al.. Trends in mortality and morbidity for very low birth weight infants, 1991-1999. Pediatrics. 2002; 110 143-151
31 Papile L, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978; 92 529-534
32 Fowlie P W, Davis P G. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2002; 3 CD0000174
33 Ment L R, Stewart W B, Scott D T, Duncan C C. Beagle puppy model of intraventricular hemorrhage: randomized indomethacin prevention trial. Neurology. 1983; 33 179-184
34 Mahony L, Caldwell R L, Girod D A et al.. Indomethacin therapy on the first day of life in infants with very low birth weight. J Pediatr. 1985; 106 801-805
35 Schmidt B, Gillie P, Caco C, Roberts J, Roberts R. Do sick newborn infants benefit from participation in a randomized clinical trial?. J Pediatr. 1999; 134 151-155
36 Silverman W A. Disclosing the “inclusion benefit”. J Perinatol. 2002; 22 261-262
37 Okah F A. The autopsy: experience of a regional neonatal intensive care unit. Paediatr Perinat Epidemiol. 2002; 16 350-354
38 Mellander M, Leheup B, Lindstrom D P et al.. Recurrence of symptomatic patent ductus arteriosus in extremely premature infants, treated with indomethacin. J Pediatr. 1984; 105 138-143
39 Rennie J M, Doyle J, Cooke R W. Early administration of indomethacin to preterm infants. Arch Dis Childh. 1986; 61 233-238
40 Meidell R, Marinelli P, Pettett G. Perinatal factors associated with early-onset intracranial hemorrhage in premature infants. A prospective study. Am J Dis Child. 1985; 139 160-163
41 Perlman J M, Volpe J J. Intraventricular hemorrhage in extremely small premature infants. Am J Dis Child. 1986; 140 1122-1124

Felix A OkahM.D.

Children's Mercy Hospital and Clinics, Section of Neonatal-Perinatal Medicine

2401 Gillham Road, Kansas City, MO 64108