Early high-dose phenobarbital treatment for prevention of hypoxic-ischemic brain damage in very low birth weight infants. Antenatal phenobarbital for the prevention of periventricular and intraventricular hemorrhage: a double-blind, randomized, placebo-controlled, multihospital trial. Administration of indomethacin for the prevention of periventricular-intraventricular hemorrhage in high-risk neonates. Antenatal phenobarbital and bilirubin metabolism in the very low birth weight infant. Effect of phenobarbital on motor activity and intraventricular hemorrhage in preterm infants with respiratory disease weighing less than 1500 grams. [Prevention of brain hemorrhage in infants with low and extremely low birth weight and infants treated with surfactants. Late observation]. Antenatal phenobarbital for the prevention of neonatal intracerebral hemorrhage. Prevention of intraventricular hemorrhage in very low birth weight infants by maternally administered phenobarbital.
In a randomized prospective trial, we studied the effect of early high-dose phenobarbital treatment on the early (intraventricular hemorrhage) and late (neurodevelopmental abnormalities) manifestations of hypoxic-ischemic encephalopathy in preterm infants weighing 1500 g or less at birth. The first intravenous dose of 15 mg/kg was given at a mean age of 110 minutes, followed by 15 mg/kg after 4 hours and then by 5 mg/kg at 24-hour intervals for 5 days. The overall incidence of intraventricular hemorrhage was 32% in treated and 46% in control infants, a nonsignificant difference. An ultrasound brain scan at 9 months old revealed no significant difference in the incidence of ventricular dilatation between treated (19%) and control (29%) infants. At 27 months, a similar incidence of mild (10%) and severe (10%) neurodevelopmental handicaps was found in both treated and control groups. Since beneficial effects could not be documented by any of the criteria used, we conclude that routine administration of phenobarbital to low birth weight infants is not justified. To determine whether the neuroprotective properties of phenobarbital would alter the incidence and severity of intracranial hemorrhage in premature infants, we randomly assigned 110 women at less than 31 weeks of gestation to receive 10 mg/kg phenobarbital or placebo in a blinded fashion before delivery. Infants were examined postnatally with real-time ultrasonography for evidence of intracranial hemorrhage. Maternal demographics, pregnancy complications, antenatal management, and route of delivery did not differ between the phenobarbital group (n = 50) and the placebo group (n = 60). The total incidence of periventricular-intraventricular hemorrhage did not differ between the phenobarbital-treated (n = 54) and the placebo-treated (n = 67) infants. However, the frequency of grade 3 and grade 4 hemorrhages was 15% (10 infants) in the placebo group and 3.7% (2 infants) in the phenobarbital group (p less than 0.05). There were no differences in the severity of associated conditions in the babies to explain the difference in the incidence of severe hemorrhage between the study groups. We conclude that antenatal administration of phenobarbital appears to be effective in decreasing the severity of periventricular-intraventricular hemorrhage in infants delivered at less than 31 weeks of gestation. One hundred twenty-two preterm infants were enrolled in a placebo-controlled, double-blind trial using intravenous indomethacin for the prevention of periventricular-intraventricular hemorrhage (PVH-IVH). Before random assignment, data on the infants were stratified according to low-weight (500 to 999 g) or high-weight (1000 to 1500 g) subgroups. Cranial sonography was used to document the absence of PVH-IVH before enrollment and the occurrence of PVH-IVH during the 7-day protocol. Indomethacin, 0.1 mg/kg, or placebo was administered before 12 hours of age and at 24, 48, and 72 hours of age. Five patients receiving indomethacin and six receiving placebo were withdrawn before completion of the study. In the remaining 111 patients, the indomethacin and placebo groups were comparable with respect to gestational ages, maternal complications, Apgar scores, ventilatory requirements, complications of prematurity, and mortality rate. PVH-IVH developed in six of 56 infants who received indomethacin and 11 of 55 infants who received placebo (P = 0.174). Analysis of the individual strata showed that the indomethacin-treated infants in the low-weight subgroup sustained a higher mortality rate (11/17 vs 3/16; P = 0.008) without a reduction in the incidence of PVH-IVH. Infants in the indomethacin-treated high-weight subgroup demonstrated a significantly lower incidence of PVH-IVH (2/39 vs 8/39; P = 0.04), but the frequency of high-grade hemorrhages was comparable for both indomethacin- and placebo-treated groups. In summary, the prophylactic administration of intravenous indomethacin for the prevention of PVH-IVH cannot be recommended for infants less than 1000 g. In preterm infants between 1000 and 1500 g birth weight, indomethacin significantly reduced the incidence of PVH-IVH. Prior studies in term infants have suggested that in utero phenobarbital exposure may accelerate bilirubin metabolism by stimulating hepatocyte glucuronyl transferase activity. This report reviews our experience with maternal phenobarbital therapy and fetal bilirubin conjugation in the very premature fetus. Mothers with arrested premature labor between 26 and 33 weeks' gestation were randomly assigned to receive oral phenobarbital (90 mg daily) or not. Infants in the two groups were similar in race, birth weight, and gestational age. Conjugated bilirubin levels at birth were significantly higher for infants receiving several days of phenobarbital in utero than no therapy (0.31 +/- 0.03 vs 0.16 +/- 0.01 mg dl, p less than 0.01). A smaller portion of infants exposed to phenobarbital in utero required phototherapy (10/23, 43% vs 24/29, 83%, p less than 0.01), which was also more likely to be delayed beyond 48 hours after delivery. Antenatal phenobarbital enhances bilirubin conjugation before delivery of a very low birth weight infant. The use of prophylactic phenobarbital to reduce motor activity and intraventricular hemorrhage was investigated in a controlled exploratory trial with 19 low birthweight premature infants with respiratory disease. Although phenobarbital significantly suppressed movement, it was associated with an increased incidence of intraventricular hemorrhage (IVH). Phenobarbital-treated infants were over eight times more likely to experience IVH than were untreated infants. These data indicate that inhibition of motor activity by phenobarbital may not alleviate the key pathogenetic factors in IVH. Prematurely born infants with intraventricular haemorrhage (IVH) suffer significant morbidity and mortality, particularly those infants with high grade haemorrhage. The more premature infants have a higher incidence, experiencing more severe IVH. The etiology of IVH is clearly multifactorial. Prevention, both prenatal and postnatal. These include efforts to prevent preterm delivery. Postnatally, the importance of optimal resuscitation and neonatal care practices is stressed, particularly those which minimize cerebral blood flow fluctuation. 130 premature infants of less than 32 weeks gestation with a very low birth weight (VLBW) and extremely low birth weight (ELBW) were studied. They were divided in four groups: group I (n=35) received Indocid; group II (n=42) received Indocid and Phenobarbital; group III (n=53) received Indocid and Phenobarbital; surfactant. These three groups were compare to a reference group (n=45). Newborns from the main group were given Indocid 0.1 mg/kg from 6-12 h of life and during next three days, Phenobarbital 5 mg/kg first five days after delivery and surfactant in the first 4 hours of life according to the protocol provided with the specific surfactant replacement product. Cerebral netrasaund in 24 hours, day 3, 5 and 10 of life and follow up till one year age were performed. We found that IVH/PVH percentage is lowest in newborns from group III, followed by newborns from group II and group I. Forty-six pregnant women less than 35 weeks of gestation were enrolled in a prospective randomized controlled study evaluating the effects of antenatal phenobarbital on neonatal intracerebral hemorrhage. The women were randomly assigned to control (n = 22) or treatment (n = 24) groups; the treatment group received 500 mg of phenobarbital intravenously. The time interval between the dose of phenobarbital and delivery was 5.5 +/- 4.8 hours (mean +/- SD). The infants in the control group (n = 23) and those in the phenobarbital-treated group (n = 25) were comparable regarding birth weight, gestational age, and other obstetric and neonatal risk factors associated with intracerebral hemorrhage. The incidence of intracerebral hemorrhage was 56.5% (13 of 23 infants) in the control group and 32% (eight of 25 infants) in the phenobarbital-treated group (p = 0.08). Moderate or severe hemorrhage was diagnosed in six of 13 control infants and in none of the phenobarbital-treated infants (p less than 0.01). The mortality rate was significantly lower in the phenobarbital-treated group (two of 25 infants) than in the control group (eight of 23 infants; p less than 0.05). Our study suggests that antenatal phenobarbital administration results in a decrease in mortality and in the severity of intracerebral hemorrhage in the preterm neonate. One hundred fifty pregnant women destined to deliver infants less than 32 weeks were randomly assigned to two groups. One group received phenobarbital in doses sufficient to achieve blood levels of 15 to 40 micrograms/mL, and this level was maintained in the neonate after birth. The second group received no antenatal treatment, but the infants were treated with phenobarbital after birth for at least four days. The infants were followed with ultrasound examinations of the head on postnatal days 1, 4, and 10 to assess the grade and progression of intraventricular hemorrhage. Intraventricular hemorrhage was significantly less frequent in the experimental group, 16 of 75 (21%) versus 35 of 75 (47%), P less than .01. Similarly, the experimental group had significantly fewer cases of severe intraventricular hemorrhage (grades III and IV), four of 75 (5%) versus 15 of 75 (20%), P less than .05 and mortality three of 75 (4%) versus ten of 75 (13%), P less than .05. Maternally administered phenobarbital appears to be effective in reducing the incidence of intraventricular hemorrhage and lessening its severity.
The evidence in this review does not support the use of prophylactic maternal phenobarbital administration to prevent PVH in preterm infants or to protect them from neurological disability in childhood. Phenobarbital administration may lead to maternal sedation. If any future trials are carried out, they should measure neurodevelopmental status at follow up.