Effects of Delayed Cord Clamp and/or Indomethacin on Preterm Infant Brain Injury

Hong Huang

Status and phase: Completed; Phase 2; Phase 1

Conditions: Intraventricular Hemorrhage; Brain Injury; Periventricular Leukomalacia; Renal Injury

Treatments: Procedure: immediate cord clamp at birth; Procedure: delay in umbilical cord clamp at birth; Drug: placebo infusion; Drug: Indomethacin

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02221219

R01HD070792 (U.S. NIH Grant/Contract)

HD070792

Details and patient eligibility

About

Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) are brain lesions that commonly occur in preterm infants and are well-recognized major contributors to long-term brain injury and related disabilities later in life. Despite its prevalence, long term consequences, and enormous medical and social costs, mechanisms of IVH and optimal strategies to prevent or treat its occurrence are poorly defined, especially for extremely premature infants. Only one medical therapy, prophylactic indomethacin during the first 3 days of life, has been shown to prevent or decrease the severity of IVH in preterm infants, but its use is limited by toxic side effects and debatable effects on long-term outcomes. Several small studies and case reports suggest that delayed umbilical cord-clamping (DCC) may also decrease the incidence of IVH in premature infants, but thus far these trials have indomethacin treatment mixed within their cord clamping protocols. The investigators are conducting a randomized, blinded investigation of 4 treatment groups: 1) Control (no intervention); 2) DCC alone; 3) Prophylactic indomethacin alone; 4) Combination of DCC/indomethacin, with respect to survival, IVH or PVL incidence and severity, neurodevelopmental outcomes, and relevant mechanistic effects. With the steady rise in extreme prematurity births and clear links of IVH to long-term disabilities there is a need to improve care for these patients. This multi- disciplinary project addresses an important medical problem for an understudied patient population, where the current practice has clear limitations.

Full description

The investigators will compare efficacy and safety of prophylactic indomethacin, DCC, and their combination, in affecting the incidence and severity of IVH/PVL in infants <30wks gestational age (primary outcome measure of 'fraction of survivors with no severe IVH or PVL' among the 4 groups), and longer term neurocognitive function. Other secondary endpoints and investigations include mechanistic effects of prophylactic indomethacin, DCC, and their combination (blood volume/circulatory status, inflammatory stress, progenitor cells) as well as defining relationships between clinical outcomes and mechanistic measurements among treatment groups.

Enrollment: 256 patients

Sex: All

Ages: 24 to 30 weeks old

Volunteers: No Healthy Volunteers

Inclusion criteria

• pregnant women admitted >24weeks and <30weeks gestational age,
• in-hospital birth (allowing for cord clamp randomization)

Exclusion criteria

• preterm infant <24weeks or >30weeks at birth
• maternal risks identified by obstetrician
• fetal risks identified by obstetrician
• any congenital abnormality of newborn infant
• placental abruption/placental previa
• delivery less than 2hrs from consenting to study participation

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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256 participants in 4 patient groups, including a placebo group

immediate cord clamp & placebo IV solution

Placebo Comparator group

Description:

This Arm will receive immediate clamp of umbilical cord at birth, and an intravenous delivery of placebo drug solution (diluent for active drug, indomethacin) within the first 12hrs of life.

Treatment:

Drug: placebo infusion

Procedure: immediate cord clamp at birth

delay cord clamp & placebo IV solution

Experimental group

Description:

A delay in cord clamp for 45 seconds will be instituted in the delivery room. Placebo drug solution will be administered within 12hrs post-birth.

Treatment:

Drug: placebo infusion

Procedure: delay in umbilical cord clamp at birth

immediate cord clamp & indomethacin IV

Active Comparator group

Description:

Umbilical cord will be clamped immediately at birth. Indomethacin will be administered IV, starting within 12hrs of life (0.1mg/kg every 24 hrs for three total doses.This intervention is considered 'standard care' at many Neonatology medical facilities. The dose of indomethacin has been shown to be effective in reducing brain bleeds in preterm infants (although there are also data showing safety concerns).

Treatment:

Drug: Indomethacin

Procedure: immediate cord clamp at birth

indomethacin iv & delayed cord clamp

Experimental group

Description:

A delay in cord clamp of 45 seconds will be instituted in the delivery room. In addition, indomethacin will be administered iv (initiated within 12hrs of life), 0.1mg/kg every 24 hrs for three total doses.

Treatment:

Drug: Indomethacin

Procedure: delay in umbilical cord clamp at birth