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

Phase 1

Completed

Conditions: Periventricular Leukomalacia
Brain Injury
Renal Injury
Intraventricular Hemorrhage

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

Registration Number: NCT02221219

Lead Sponsor: Hong Huang

Brief Summary: 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.

Detailed 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 256

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
immediate cord clamp & placebo IV solution	placebo infusion	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.
immediate cord clamp & placebo IV solution	immediate cord clamp at birth	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.
delay cord clamp & placebo IV solution	delay in umbilical cord clamp at birth	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.
delay cord clamp & placebo IV solution	placebo infusion	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.
immediate cord clamp & indomethacin IV	immediate cord clamp at birth	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).
indomethacin iv & delayed cord clamp	delay in umbilical cord clamp at birth	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.
immediate cord clamp & indomethacin IV	Indomethacin	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).
indomethacin iv & delayed cord clamp	Indomethacin	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.

Primary Outcome Measures

Name	Time	Method
Percent of Survivors With no Severe IVH (Grades 3 or 4) or PVL	within first 60 days of life	determined by head ultrasound in Neonatal Intensive Care Unit (NICU) and single head MRI at 38weeks corrected gestational age

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Acute Kidney Injury	first 60 days of life	measures of serum creatinine and urine output during Neonatal Intensive Care Unit (NICU) stay. General measures of renal injury (which is a common risk of indomethacin treatment in this patient population).