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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Indomethacin and Delayed Umbilical Cord Clamp for Preterm Infant IVH

Conditions
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Intraventricular Hemorrhage, Periventricular Leukomalacia, Brain Injury, Renal Injury

Intervention / Treatment
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* Drug: Indomethacin
* Procedure: delay in umbilical cord clamp at birth
* Drug: placebo infusion
* Procedure: immediate cord clamp at birth


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 24 Weeks
Maximum Age: 30 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: immediate cord clamp & placebo IV solution<br>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. | Drug: placebo infusion<br>* saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)<br>Procedure: immediate cord clamp at birth<br>* no delay in umbilical cord clamp; <10sec (recorded in delivery note)<br>|
| Experimental: delay cord clamp & placebo IV solution<br>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. | Procedure: delay in umbilical cord clamp at birth<br>* provision of a  45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)<br>Drug: placebo infusion<br>* saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)<br>|
| Active Comparator: immediate cord clamp & indomethacin IV<br>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). | Drug: Indomethacin<br>* indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants<br>* Other names: indocin;Procedure: immediate cord clamp at birth<br>* no delay in umbilical cord clamp; <10sec (recorded in delivery note)<br>|
| Experimental: indomethacin iv & delayed cord clamp<br>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. | Drug: Indomethacin<br>* indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants<br>* Other names: indocin;Procedure: delay in umbilical cord clamp at birth<br>* provision of a  45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Acute Kidney Injury | 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). | first 60 days of life | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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infant, brain injury, renal, indomethacin