Bleeding in the Brain, Intraventricular Hemorrhage (IVH), Prematurity, Very Low Birth Weight Infants
Conditions
Keywords
intraventricular hemorrhage (IVH), bleeding in the brain, indomethacin, prematurity, very low birth weight infants
Brief summary
The purpose of this multicenter trial is to determine if indomethacin prevents bleeding in the brain of very low birth weight preterm infants.
Detailed description
Intraventricular hemorrhage (IVH) or bleeding in the brain remains a major problem of preterm infants. This randomized, placebo-controlled multicenter trial enrolled 505 infants of 600 to 1250g birth weight to determine if indomethacin lowers the incidence of IVH, and 125 term infant controls. During this longitudinal trial, follow-up assessments have been performed at the ages of 3, 4 1/2, 6, 8, 12 and 16 years. The initial results at age 3 years revealed no advantages to the indomethacin group over and above the decreases in IVH, however, the results did show a significant increase in ventriculomegaly in the placebo group. Results at 4 1/2, 6 and 8 years of age showed beneficial effects of indomethacin on cognitive and behavioral outcomes over and above the effects on preventing IVH but not at later ages. At 12 and 16 years, no significant influence of indomethacin on cognitive outcome was noted. Age, gender and zip-code matched control subjects were added when the preterm subjects were 8 years. Throughout all subsequent testing, term controls have higher IQ and Peabody Picture Vocabulary Scores. Additional longitudinal volumetric, functional and diffusion tensor MR imaging studies showed differences between preterm and term control subjects at 8, 12 and 16 years of age. These were consistent with utilization of the right hemisphere and left cerebellum for language in the preterm group compared to term controls. No effects of indomethacin were seen. The study closed on 31 March 2012.
Interventions
DRUGindomethacin
an anti-inflammatory drug
DRUGplacebo
saline
Sponsors
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Hours
Healthy volunteers
Yes
Inclusion criteria
* Preterm infants \< 1250 g birth weight * Admitted to participating institution \< 6 hrs of age * No evidence for congenital malformations * Cranial US at 6 postnatal hours without evidence of Grades III - IV intraventricular hemorrhage
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| IVH at 5 Postnatal Days | at 5 days | Cranial ultrasounds were performed daily for the first 5 postnatal days; the main outcome measure was intraaventricular hemorrhage (IVH) at 5 days of age |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Language Outcome | at 8 years | Peabody Picture Vocabulary Test (PPVT) This is a semantic language test. The mean value is 100; standard deviation is 16 points. A higher score means better language; a lower score means poorer language. There are no subscales to the PPVT. The measurement unit is points on a scale. A score \< 70 indicates severely abnormal language function. |
Countries
United States
Participant flow
Recruitment details
Preterm neonates of 600 - 1250 g birth weight were enrolled between 6 and 12 postnatal hours at Yale New Haven Hospital (New Haven, CT), Maine Medical Center (Portland, ME) and Women and Infants' Hospital (Providence, RI).
Pre-assignment details
Cranial ultrasounds were performed on all study participants between 6 - 12 hours of age for group assignment. Subjects with major congenital cerebral malformations were excluded.
Participants by arm
| Arm | Count |
|---|---|
| Indomethacin subjects randomized to early low dose indomethacin | 209 |
| Placebo Group randomized to an equal volume of placebo | 222 |
| Total | 431 |
Baseline characteristics
| Characteristic | Indomethacin | Placebo | Total |
|---|---|---|---|
| Age Continuous | 7.8 hours STANDARD_DEVIATION 2.3 | 7.9 hours STANDARD_DEVIATION 2.4 | 7.8 hours STANDARD_DEVIATION 2.3 |
| Region of Enrollment United States | 209 participants | 222 participants | 431 participants |
| Sex: Female, Male Female | 93 Participants | 103 Participants | 196 Participants |
| Sex: Female, Male Male | 116 Participants | 119 Participants | 235 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 209 | 12 / 222 |
| serious Total, serious adverse events | 0 / 208 | 0 / 222 |
Outcome results
Primary
IVH at 5 Postnatal Days
Cranial ultrasounds were performed daily for the first 5 postnatal days; the main outcome measure was intraaventricular hemorrhage (IVH) at 5 days of age
Time frame: at 5 days
Population: All subjects had negative cranial ultrasounds with no evidence for IVH at 6 - 12 postnatal hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Indomethacin | IVH at 5 Postnatal Days | 25 IVH |
| Placebo | IVH at 5 Postnatal Days | 40 IVH |
Secondary
Language Outcome
Peabody Picture Vocabulary Test (PPVT) This is a semantic language test. The mean value is 100; standard deviation is 16 points. A higher score means better language; a lower score means poorer language. There are no subscales to the PPVT. The measurement unit is points on a scale. A score \< 70 indicates severely abnormal language function.
Time frame: at 8 years
Population: Three hundred twenty eight subjects were available at age 8 years. They were tested with the PPVT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Indomethacin | Language Outcome | 12 participants with PPVT score < 70 |
| Placebo | Language Outcome | 5 participants with PPVT score < 70 |
| Placebo - no IVH | Language Outcome | 24 participants with PPVT score < 70 |
| Placebo - IVH | Language Outcome | 7 participants with PPVT score < 70 |