Use of prenatal phenobarbital in the prevention of subependymal/intraventricular hemorrhage in premature infants. Antenatal phenobarbital for the prevention of periventricular and intraventricular hemorrhage: a double-blind, randomized, placebo-controlled, multihospital trial. Effect of phenobarbital on motor activity and intraventricular hemorrhage in preterm infants with respiratory disease weighing less than 1500 grams. Role of ethamsylate in preventing periventricular-intraventricular hemorrhage in premature infants below 34 weeks of gestation. Effect of prophylactic phenobarbital on intraventricular hemorrhage in high-risk infants. Prevention of intraventricular hemorrhage in very low birth weight infants by maternally administered phenobarbital. Antiepileptic medication in pregnancy: late effects on the children's central nervous system development. Antenatal phenobarbital in preventing intraventricular hemorrhage in premature newborns. Antenatal phenobarbital for the prevention of neonatal intracerebral hemorrhage.
Subependymal/intraventricular hemorrhage (SE/IVH) is a frequent cause of disability and mortality.
                This is a prospective, randomized, double-blind study which included 100 pregnant Mexican women who need to interrupt their pregnancy within 28-32 weeks of gestation. One group was given a single dose of intravenous (IV) phenobarbital 10 micrograms/kg (phenobarbital group, n = 50), and the other was provided with diluted distilled water (control group). Measurements of phenobarbital serum concentrations were taken by both mother and newborn, and head sonograms were applied during the first 24 hours, at the 3rd and 7th days of life.
                The sample was made up of 42 newborns in the phenobarbital group, and 46 in the control group; the newborns had phenobarbital levels of 11.5 5.7 g/microliter at birth, and of 9.5 +/- 5.9 g/microliter 24 hours later. SE/IVH was found in 12 patients from the phenobarbital group and in 29 from the control group (p < 0.005), the first group were 11 mild SE/IVH (2 grade I, and 9 grade II), and 26 in the control group (4 grade I, and 22 grade II), p < 0.005. Severe hemorrhages were similar between groups. A larger frequency of SE/IVH was found in the newborn group which received mechanical ventilation (p = 0.0008).
                Prenatal phenobarbital can reduce the SE/IVH frequency in premature infants younger than 32 weeks at birth. Its main effect could be shown in patients with mechanical ventilation. 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. 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. To determine the role of ethamsylate in prevention of PVH-IVH in premature infants <34 weeks gestational age.
                Prospective, randomized, controlled study.
                Infants less than 34 weeks gestational age were included in the trial. Neonates with congenital malformations, family history of bleeding disorders and with Apgar scores <5 at 5 minutes were excluded. Subjects were randomized into two groups--Group A infants received intravenous ethamsylate (12.5 mg/kg) six hourly for four days and Group B infants served as a control group. Regular cranial ultrasounds to detect the presence of PVH-IVH were done between days 3-5, 10-14 and 28-30 of post natal age, and before hospital discharge in all infants and weekly in infants detected to have PVH-IVH on earlier scans. Various antenatal and postnatal factors known to affect the incidence of PVH-IVH were recorded.
                A total of 192 infants underwent the trial, 93 in Group A and 99 in Group B. Antenatal corticosteroids (1 or 2 doses) were administered to 32 ( 34.4%) and 36 (36.3%) women in Group A and Group B, respectively. None of the mothers received phenobarbitone, vitamin K or indomethacin antenatally and none of the infants received phenobarbitone, vitamin E or indomethacin postnatally during the study period. PVH-IVH was seen in 26 infants in Group A, of which Grade I IVH occurred in 9, Grade II in 14, Grade III in 2 and Grade IV in one infant. Twenty-nine infants had PVH-IVH in Group B of which 11 had Grade I, 15 Grade II and 3 Grade III. None of the differences were statistically significant.
                Postnatal administration of ethamsylate did not decrease the incidence of PVH-IVH in the study infants. Forty-two premature infants less than 24 hours of age, with normal admission echoencephalograms, were randomly assigned to control or phenobarbital treatment groups. Infants in the treated group received two loading doses of 10 mg/kg of phenobarbital 12 hours apart, followed by a maintenance dose of 2.5 mg/kg every 12 hours for 6 days. Serial echoencephalograms were obtained in both groups. The groups were comparable with regard to birth weight, gestational age, and potential risk factors for subependymal-intraventricular hemorrhage. Ten infants (48%) in each group developed hemorrhage. The hemorrhages in the phenobarbital-treated group were significantly less severe than those in the control group. The phenobarbital-treated infants who bled, however, were also significantly larger and more mature than control infants who bled. The results of this study indicate no effect of phenobarbital on the incidence of subependymal-intraventricular hemorrhage, but a possible beneficial effect on the severity of hemorrhage. 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. In a follow-up study long-term effects of antenatal exposure to two anticonvulsant drugs, phenobarbital and carbamazepine on central nervous system development were evaluated. Children aged 6 to 13 years of epileptic mothers who used phenobarbital (n = 13), carbamazepine (n = 12), phenobarbital plus carbamazepine (n = 12), or no medication (n = 24) during pregnancy were studied. None of the mothers had seizures during pregnancy. A control group carefully matched for confounding variables was selected of children of nonepileptic mothers (n = 61). Minor and major congenital anomalies appeared to be more related to mother's epilepsy than to maternal medication. There were no neurologic differences between the groups. Exposure to phenobarbital was associated with smaller head circumference. An accompanying negative effect of phenobarbital on cognitive development was suggested. Further research on this intriguing phenomenon seems warranted. In a randomized prospective study, we investigated the effect of antenatal phenobarbital on neonatal intraventricular hemorrhage in 39 women destined to deliver babies of less than 32 weeks of gestation. The treatment group received an intravenous loading dose of 700 mg of phenobarbital, followed by a daily maintenance dose until delivery. The newborns were treated with phenobarbital for the first 96 h. Ultrasound examinations of the infants' heads were performed. Intraventricular hemorrhage was significantly less frequent in the treated group: 2 of 21 (9.5%) versus 9 of 18 (50%; p less than 0.006). Moreover no severe hemorrhage (grade 3-4) occurred in the treated babies: 0 of 21 versus 5 of 18 (27.7%; p less than 0.01). 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.
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.