Download PDF
Am J Perinatol 2005; 22(1): 11-17
DOI: 10.1055/s-2004-837741
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

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
Further Information

Publication History

Publication Date:
11 January 2005 (online)

Also available at
    Permissions and Reprints

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

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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    Google Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 19 Schmidt B, Davis P, Moddemann D et al.. Trial of indomethacin prophylaxis in preterms investigators.  N Engl J Med. 2001;  344 1966-1972
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 24 Lacayo A, Mitra N. Report of a case of phenobarbital-induced dystonia.  Clin Pediatr. 1992;  31 252
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 27 Whitelaw A. Postnatal phenobarbitone for the prevention of intraventricular hemorrhage in preterm infants.  Cochrane Database Syst Rev. 2001;  1 CD001691
    PubMedGoogle Scholar
  • 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
    Google Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 36 Silverman W A. Disclosing the “inclusion benefit”.  J Perinatol. 2002;  22 261-262
    CrossrefPubMedGoogle Scholar
  • 37 Okah F A. The autopsy: experience of a regional neonatal intensive care unit.  Paediatr Perinat Epidemiol. 2002;  16 350-354
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 39 Rennie J M, Doyle J, Cooke R W. Early administration of indomethacin to preterm infants.  Arch Dis Childh. 1986;  61 233-238
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 41 Perlman J M, Volpe J J. Intraventricular hemorrhage in extremely small premature infants.  Am J Dis Child. 1986;  140 1122-1124
    PubMedGoogle Scholar

Felix A OkahM.D. 

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

2401 Gillham Road, Kansas City, MO 64108