Antenatal Phenobarbital to Prevent Neonatal Intracranial Hemorrhage

Sponsor

NICHD Neonatal Research Network (Other)

Overall Status

Completed

CT.gov ID

NCT00009620

Collaborator

National Center for Research Resources (NCRR) (NIH)

610

Enrollment

Locations

Arms

Duration (Months)

55.5

Patients Per Site

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This large randomized trial tested whether phenobarbital given to a pregnant woman about to deliver a premature infant would prevent brain injuries in their newborns. Women with 24 to 32 week fetuses who were in preterm labor and were expected to deliver within 24 hrs were randomized to phenobarbital or usual care. They were treated until they deliver or the fetus reaches 33 wks gestation. Babies were followed until discharge and evaluated at 18-22 mos corrected age for neurodevelopmental outcome.

Condition or Disease	Intervention/Treatment	Phase
Infant, Newborn Infant, Low Birth Weight Infant, Small for Gestational Age Infant, Premature Intracranial Hemorrhages	Drug: Phenobarbital Drug: Saline	Phase 3

Detailed Description

The administration of phenobarbital to pregnant women before delivery has been thought to decrease the frequency of intracranial hemorrhage in preterm infants. To evaluate this potential neuroprotective therapy further, we determined the effect of antenatal administration of phenobarbital on the frequency of neonatal intracranial hemorrhage and early death. Women who were 24 to 33 weeks pregnant and who were expected to deliver their infants within 24 hours were randomly assigned to receive either intravenous phenobarbital (10 mg/kg body weight) or placebo, followed by maintenance doses until delivery or 34 wks gestation. Infants less than 34 wks at birth underwent serial cranial ultrasonography to detect the presence of intracranial hemorrhage. The sample size of 1038 pregnancies was based on an intracranial hemorrhage rate of 20 percent in the placebo and less than 12 percent in the phenobarbital group; 90 percent power; a 5 percent two-tailed type 1 error; and an 8 percent noncompliance rate. The twin with the highest grade of intracranial hemorrhage was included.

Degree of maternal sedation was evaluated after administration of study drug. Neonatal ultrasound exams were performed at 3-5 days, 10-14 days, and 38-42 wks postmenstrual age; neonatal medications were recorded during the first week of life; treatments, and outcomes were recorded through death, discharge, or 120 days, whichever occurred first. Neurodevelopmental outcome was evaluated at 18-22 months corrected age by certified examiners masked to treatment status.

Study Design

Study Type:

Interventional

Actual Enrollment :

610 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double

Primary Purpose:

Prevention

Official Title:

Randomized Clinical Trial of Antenatal Phenobarbital in the Prevention of Neonatal Intracranial Hemorrhage

Study Start Date :

Feb 1, 1993

Actual Primary Completion Date :

Feb 1, 1995

Actual Study Completion Date :

Feb 1, 1997

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phenobarbital	Drug: Phenobarbital 10 mg of phenobarbital per kilogram of body weight intravenously over a period of 20 to 40 minutes (maximal dose, 1000 mg)
Placebo Comparator: Placebo	Drug: Saline Infusion of normal sal

Arm

Intervention/Treatment

Experimental: Phenobarbital

Drug: Phenobarbital

10 mg of phenobarbital per kilogram of body weight intravenously over a period of 20 to 40 minutes (maximal dose, 1000 mg)

Placebo Comparator: Placebo

Drug: Saline

Infusion of normal sal

Outcome Measures

Primary Outcome Measures

Neonatal intracranial hemorrhage or death [72 hours of life]

Secondary Outcome Measures

Intracranial hemorrhage (grade I, II, III, or IV) [72 hours of life]
Periventricular leukomalacia [72 hours of life]
Neurodevelopmental impairment [18 to 22 months of corrected age]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Admission to a high risk perinatal unit or labor and delivery unit;
24 to 32 completed weeks gestation;
Expected delivery within 24 hrs;
Preterm labor or no labor with planned delivery for maternal-fetal indications;

Exclusion Criteria:

Anticipated delivery within two hours
Multiple congenital or chromosomal abnormalities in the fetus
Multiple gestation with more than two fetuses
Administration of phenobarbital during the pregnancy
Administration of indomethacin within one week before admission
Maternal platelet count of less than 100,000 per cubic millimeter

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University	Palo Alto	California	United States	94304
2	Yale University	New Haven	Connecticut	United States	06504
3	George Washington University	Washington	District of Columbia	United States	20052
4	Emory University	Atlanta	Georgia	United States	30303
5	Indiana University	Indianapolis	Indiana	United States	46202
6	Wayne State University	Detroit	Michigan	United States	48201
7	University of New Mexico	Albuquerque	New Mexico	United States	87131
8	Cincinnati Children's Medical Center	Cincinnati	Ohio	United States	45267
9	Case Western Reserve University, Rainbow Babies and Children's Hospital	Cleveland	Ohio	United States	44106
10	Brown University, Women & Infants Hospital of Rhode Island	Providence	Rhode Island	United States	02905
11	University of Tennessee	Memphis	Tennessee	United States	38163

Sponsors and Collaborators

NICHD Neonatal Research Network
National Center for Research Resources (NCRR)

Investigators

Study Director: Seetha Shankaran, MD, Wayne State University
Principal Investigator: Lu-Ann Papile, MD, University of New Mexico
Principal Investigator: Richard A. Ehrenkranz, MD, Yale University
Principal Investigator: Raymond Bain, PhD, George Washington University
Principal Investigator: James A. Lemons, MD, Indiana University
Principal Investigator: Sheldon B. Korones, MD, University of Tennessee at Memphis
Principal Investigator: David K. Stevenson, MD, Stanford University
Principal Investigator: Edward F. Donovan, MD, Children's Hospital Medical Center, Cincinnati
Principal Investigator: Barbara J. Stoll, MD, Emory University
Principal Investigator: Avroy A. Fanaroff, MD, Case Western Reserve University
Principal Investigator: William Oh, MD, Brown University, Women and Infants Hospital