Pharmacokinetic Basis for Antenatal Dosing of Phenobarbital for the Prevention of Neonatal Intracerebral Hemorrhage

Abstract

The transplacental and elimination pharmacokinetics of phenobarbital administered antenatally was analyzed in both mothers and infants as part of a study evaluating the efficacy of antenatally administered phenobarbital in the prevention of neonatal intracerebral hemorrhage. Twenty-five pregnant women in labor less than 35 weeks’ gestation received 500 mg phenobarbital administered intravenously. The maternal serum phenobarbital level at delivery was 8.76 ± 1.99 μg/ml and cord serum phénobarbital level was 9.0 ± 1.75 μg/ml (all values are mean ± SD). There was no correlation between the time from phénobarbital administration to delivery (5.6 ± 4.6 h) and the cord:maternal serum phénobarbital ratio (1.05 ± 0.21) (r = -0.03; p > 0.05). The mean apparent half-life of phenobarbital estimated in 11 infants was 175.5 ± 45.6 h. The present study documents the ability to predict serum levels in the fetus and neonate from the serum concentrations achieved in the mother.

Pathogenesis and Prevention of Intraventricular Hemorrhage

“…Initial studies showed some protective effect of phenobarbital, however, subsequent clinical trials failed to confirm the protective effect of phenobarbital in preventing IVH. 89–93 Maternal treatment of vitamin K or magnesium sulfate to prevent IVH did not demonstrate any benefit either. 64, 94–96 …”

Clinical Pharmacology of the Perinatal Period and Early Infancy

“…These effects have been documented for phenytoin, phenobarbitone, diazepam, lignocaine, amylobarbitone, phenylbutazone, pethidine (meperidine), salicylates, indomethacin, valproic acid, mepivacaine, clonazepam, metronidazole, tolazoline (Andre et al 1986;Bianchetti et al 1980;Boreus et al 1975;Dvorchik et al 1986;Hall et al 1985;Krauer et al 1973;Leff et al 1986;Loughnan et al 1977;Mandelli et al 1975;Meffin et al 1973;Mihaly et al 1978;Monin et al 1987b;Moore et al 1978;Morgan et al 1977;Morselli & Rovei 1980;Nau et al 1982;Painter et al 1978;Rubenson & Rosetzsky 1986;Sakuma et al 1985;Shankaran et al 1986). …”

Antenatal Phenobarbital in Preventing Intraventricular Hemorrhage in Premature Newborns

“…Phénobarbital administered postnatally to premature new borns is reported to decrease the incidence and the severity of IVH [7,8], Later studies showed a tendency to milder grades of bleed ing or no effect at all in infants treated with phénobarbital [3,9,10]. However, since IVH develops in the early postnatal hours and phénobarbital crosses the placenta [11], it was suggested to treat premature newborns antenatally to cover the period of highest risk for IVH. Two randomized studies were performed to evaluate this form of pre vention, which appears to be effective [12,13],…”