Cord Clamping Among Neonates With Congenital Heart Disease

Study Overview
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Brief Summary
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The goal of this clinical trial is to compare 2 different timepoints for clamping the umbilical cord at birth for term-born infants with a prenatal diagnosis of congenital heart disease (CHD). The main questions it aims to answer are: Does Delayed Cord Clamping at 120 seconds (DCC-120) or Delayed Cord Clamping at 30 seconds (DCC-30) after birth lead to better health outcomes? Does DCC-120 seconds or DCC-30 seconds after birth lead to better neuromotor outcomes at 22-26 months of infant age (postnatal)? Participants will be asked to do the following: Participate in either DCC-120 or DCC-30 at birth (randomized assignment). Complete General Movements Assessment (GMA) at 3-4 months of infant age (postnatal), complete questionnaires / surveys at this time. Complete questionnaires / surveys at 9-12 months of infant age (postnatal). Complete Hammersmith Infant Neurological Examination (HINE), Developmental Assessment of Young Children 2 Edition (DAYC-2), and questionnaires / surveys at 22-26 months of infant age (postnatal). Permit data collection from electronic medical records for both the mother and infant study participants. Investigators will compare DCC-120 vs. DCC-30 to see which approach is more beneficial to both the mother and baby with CHD.

Detailed Description
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AIM 1: Test the hypothesis that, among neonates with critical congenital heart disease, DCC-120 results in lower (better) post-cardiac surgery or catheterization global rank score (GRS), based on a higher win odds, than with DCC-30. AIM 2: Test the hypothesis that, among neonates with critical congenital heart disease, DCC-120 will result in better neuromotor outcomes at 22-26 months postnatal, based on a join test of bivariate outcome (Developmental Assessment of Young Children 2nd Ed. motor score [DAYC-2] and Hammersmith Infant Neurological Exam [HINE]) than with DCC-30. As a secondary objective, investigators will test the hypothesis that, among neonates with critical congenital heart disease, improved neuromotor profiles (General Movement Assessment [GMA]) at 3-4 months mediate improved neuromotor outcome at 22-26 months. Investigators will complement functional assessments with parent perception of their child's health, engaging parent stakeholders in the design of a questionnaire to be administered at 22-26 months. AIM 3: Estimate the difference in risk of maternal postpartum hemorrhage between DCC-120 and DCC-30 to evaluate safety among mothers who give birth to neonates with critical congenital heart disease.

Official Title
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CORD-CHD: Clamp OR Delay Among Neonates With Congenital Heart Disease

Conditions
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Congenital Heart Disease (CHD)

Intervention / Treatment
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* Procedure: Umbilical Cord Clamping at  30 seconds
* Procedure: Umbilical Cord Clamping at  120 seconds
* Procedure: Umbilical Cord Milking


Participation Criteria
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Eligibility Criteria
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Inclusion criteria are listed below and will be confirmed prior to randomization: Fetal diagnosis of congenital heart disease (CHD) by prenatal ultrasound / echocardiography from local fetal ECHO, conducted between 18 - 36 weeks of gestation. The study fetal diagnosis of CHD must be rated as 3 - 6 on the Fetal Cardiovascular Disease Severity Score (FCDSS), as determined by independent evaluators at the CORD-CHD trial ECHO Core at the Children's Hospital of Philadelphia (to determine final eligibility for randomization). For each potential participant that has provided consent, the most relevant diagnostic prenatal ultrasound will be uploaded (shared) between 32 and 36 weeks of gestation for review by the ECHO Core. The ECHO Core will make the final FCDSS determination for eligibility status and stratification assignment.] [NOTE: A fetal diagnosis of CHD rated as 3 - 6 FCDSS per local review, including borderline cases, will be used to determine preliminary eligibility for consent. Among borderline cases, eligible patients will be included if there is a reasonable expectation of the need for surgery or cardiac catheterization during the birth hospitalization or within the first year of life.] Singleton gestation. Gestational age at labor and delivery admission (randomization) between 37 0/7 - 41 6/7 weeks of gestation inclusive based on clinical information and evaluation of the earliest ultrasound determined using criteria proposed by the American Congress of Obstetricians and Gynecologists (ACOG), the American Institute of Ultrasound in Medicine and the Society for Maternal-Fetal Medicine and is denoted as projected gestational age. [NOTE: Pregnant individuals who were admitted to the delivery hospital prior to 37 0/7 weeks of gestation remain eligible, provided they deliver within the 37 0/7 and 41 6/7 weeks eligibility window.] Informed consent to participate for both the pregnant individual and their infant Exclusion criteria are listed below and will be confirmed prior to randomization: Exclusion Criteria for Pregnant Individuals: Pregnant individual is a gestational carrier or surrogate. Compromise of the pregnant individual (e.g., vasa previa, placental accreta with hypotension), as determined by local care team [NOTE: There is no limitation on pregnant individual's age] Fetal Exclusion Criteria: Fetal demise or planned termination of pregnancy prior to randomization Tachyarrhythmia requiring transplacental therapy Fetal hydrops Autoimmune myocardial disease Planned fetal surgery Diaphragmatic hernia, omphalocele, gastroschisis, intestinal atresia Major chromosomal defects (e.g., Trisomy 13, 18) identified prenatally; Trisomy 21 is allowed Neuromuscular disorders (e.g., holoprosencephaly) Parents choosing to limit treatment Pregnancy Exclusion Criteria: Delivery planned at an institution not affiliated with or does not refer to a CORD-CHD participating site Participation in another prenatal interventional study that influences cord clamping or perinatal morbidity or mortality

Ages Eligible for Study
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Minimum Age: 37 Weeks
Maximum Age: 42 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Delayed Cord Clamping at 30 Seconds (DCC-30)<br>The umbilical cord will be clamped between 1 - <60 seconds following delivery, with a goal of around 30 seconds. | Procedure: Umbilical Cord Clamping at  30 seconds<br>* Care team will wait to clamp the umbilical between 1-<60 seconds after birth. 30 seconds is the ideal time of clamping.<br>* Other names: Randomized to DCC-30 Group;|
| Active Comparator: Delayed Cord Clamping at 120 Seconds (DCC-120)<br>The umbilical cord will be clamped at 60 - 180- seconds following delivery, with a goal of around 120 seconds. If there is concern for pregnant individual or baby and their doctor is not able to wait 120 seconds, the doctor may do cord milking, which is four gentle squeezes of the umbilical cord pushing blood from the placenta to baby. | Procedure: Umbilical Cord Clamping at  120 seconds<br>* Care team will wait to clamp the umbilical cord between 60-180 seconds after birth.120 seconds is the ideal time of clamping<br>* Other names: Randomized to DCC-120 Group;Procedure: Umbilical Cord Milking<br>* For infants who need their cord clamped before the target in the DCC-120 group. Care team may milk the umbilical cord towards the infant four times.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global Rank Score (Infant participant) | GRS elements include: Mortality=97; Heart transplant=96; Complication preventing cardiac intervention=95; Post-intervention neurologic complication=95; Tracheostomy post-intervention=95; Renal failure, permanent dialysis=95; Unplanned cardiac surgery after initial cardiac intervention=94; Cardiac arrest=94; Post-intervention multisystem organ failure=94; Mechanical circulatory support=94; Pre-intervention polycythemia requiring exchange transfusion / hemodilution=93; Unplanned cardiac catheterization after initial cardiac intervention=93; Pre-intervention mechanical ventilation=93; Pre-intervention necrotizing enterocolitis=93; Pre-intervention shock=93; Post-intervention bleeding reoperation=93; Delayed sternal closure=93; Pre-intervention renal failure, temporary dialysis=93; Post-intervention renal failure, temporary dialysis=92; Post-intervention mechanical ventilation >7 days=92; Hospital length of stay >90 days=91 if >90 days; 1-90 if <= 90 days | Up to 30 days post-discharge following congenital heart disease intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuromotor Outcomes at 3-4 months of age (Infant participant) | General Movements Assessment (GMA): The General Movements Assessment is used to identify absent or abnormal general movements in infants. General movements are spontaneous movements exhibited during fetal development and through the first 6 months of life after birth. Trained investigators will evaluate the infants general movements as: 1) Fidgety present; 2) Fidgety abnormal; and 3) Absent fidgety where Fidgety present is considered normal, and the other two outcomes are considered abnormal. | 3-4 months after birth | 
| Impact of infant's congenital heart disease (Parents / Caregivers) | Questionnaire/Survey on the impact of infant's congenital heart disease upon the family dynamic; Impact on Family Scale - Revised: The Impact on Family Scale - Revised is a questionnaire for parents / caregivers used to evaluate perceptions of the impact of an infant's chronic medical condition (e.g., congenital heart disease) upon the family. The IFS-R uses a 4-point Likert-type scale (strongly agree to strongly disagree) for responses. High scores correlate with parental / caregiver stressors and psychiatric symptoms, poor infant health, and increased pediatric hospitalizations and/or health maintenance requirement, representing worse outcomes. | 3-4 months after birth | 
| Impact of infant's congenital heart disease (Parents / Caregivers) | Questionnaire/Survey on the impact of infant's congenital heart disease upon the family dynamic; Functional Status II - Revised, Short Form: The Functional Status II - Revised, Short Form will be used to evaluate the functional status of infants that have been diagnosed with and undergone treatment for congenital heart disease. This survey, completed by parents / caregivers, is used to evaluate a core of 14 items using a 3-point Likert scale. The respondent (parent / caregiver) first rates the extent of difficulty with specific behaviors that the infant experiences, and then rates for those behaviors with difficulty, the extent to which the difficulty is due to the infants chronic illness. Higher scores generally indicate a reduced burden of chronic heart disease impacting the family, and therefore, a better outcome. | 3-4 months after birth | 
| Impact of infant's congenital heart disease (Parents / Caregivers) | Questionnaire/Survey on the impact of infant's congenital heart disease upon the family dynamic; Impact on Family Scale - Revised: The Impact on Family Scale - Revised is a questionnaire for parents / caregivers used to evaluate perceptions of the impact of an infant's chronic medical condition (e.g., congenital heart disease) upon the family. The IFS-R uses a 4-point Likert-type scale (strongly agree to strongly disagree) for responses. High scores correlate with parental / caregiver stressors and psychiatric symptoms, poor infant health, and increased pediatric hospitalizations and/or health maintenance requirement, representing worse outcomes. | 9-12 months after birth | 
| Impact of infant's congenital heart disease (Parents / Caregivers) | Questionnaire/Survey on the impact of infant's congenital heart disease upon the family dynamic; Functional Status II - Revised, Short Form: The Functional Status II - Revised, Short Form will be used to evaluate the functional status of infants that have been diagnosed with and undergone treatment for congenital heart disease. This survey, completed by parents / caregivers, is used to evaluate a core of 14 items using a 3-point Likert scale. The respondent (parent) first rates the extent of difficulty with specific behaviors that the infant experiences, and then rates for those behaviors with difficulty, the extent to which the difficulty is due to the infants chronic illness. Higher scores generally indicate a reduced burden of chronic heart disease impacting the family, and therefore, a better outcome. | 9-12 months after birth | 
| Impact of infant's congenital heart disease (Parents / Caregivers) | Questionnaire/Survey on the impact of infant's congenital heart disease upon the family dynamic; Impact on Family Scale - Revised: The Impact on Family Scale - Revised is a questionnaire for parents / caregivers used to evaluate perceptions of the impact of an infant's chronic medical condition (e.g., congenital heart disease) upon the family. The IFS-R uses a 4-point Likert-type scale (strongly agree to strongly disagree) for responses. High scores correlate with parental / caregiver stressors and psychiatric symptoms, poor infant health, and increased pediatric hospitalizations and/or health maintenance requirement, representing worse outcomes. | 22-26 months after birth | 
| Impact of infant's congenital heart disease (Parents / Caregivers) | Questionnaire/Survey on the impact of infant's congenital heart disease upon the family dynamic; Functional Status II - Revised, Short Form: The Functional Status II - Revised, Short Form will be used to evaluate the functional status of infants that have been diagnosed with and undergone treatment for congenital heart disease. This survey, completed by parents / caregivers, is used to evaluate a core of 14 items using a 3-point Likert scale. The respondent (parent) first rates the extent of difficulty with specific behaviors that the infant experiences, and then rates for those behaviors with difficulty, the extent to which the difficulty is due to the infants chronic illness. Higher scores generally indicate a reduced burden of chronic heart disease impacting the family, and therefore, a better outcome. | 22-26 months after birth | 
| Neurodevelopmental Outcomes at 22-26 months (Infant participant) | Hammersmith Infant Neurological Exam (HINE): The Hammersmith Infant Neurological Examination (HINE) consists of 26 items that assess different aspects of infant neurological function. The maximal global (total) score is 78, divided among the following domains: cranial nerve function (maximum score 15); posture (maximum score 18); movements (maximum score 6); muscle tone (maximum score 24) and reflexes and reactions (maximum score 15). Higher scores indicate better expected outcomes. | 22-26 months after birth | 
| Neurodevelopmental Outcomes at 22-26 months (Infant participant) | Developmental Assessment of Young Children, 2nd Edition (DAYC-2): The Developmental Assessment of Young Children, Second Edition (DAYC-2) is used to evaluate infants and children over 5 domains: cognition; communication; social-emotional development; physical development; and adaptive behavior. The DAYC-2 uses a norm-referenced sample to establish standardized scores in each domain, allowing investigators to compare the results to infants of similar age. Percentile ranks, and age equivalents are provided for each domain. Elements are graded on a simple Yes or No scale, with Yes being 1 point and No being 0 points. In general, higher scores reflect better expected outcomes. | 22-26 months after birth | 
| Parental perspectives of outcomes (Parents / Caregivers) | Survey of parent / caregiver opinions of expectations and outcomes as it relates to their infant with congenital heart disease. This questionnaire will examine parental perspectives with regards to health and neurodevelopmental outcomes, as compared to those commonly used in pediatric medicine. For example, parents / caregivers may place greater emphasis upon their child being able to conduct physical activity as compared to how well they perform tasks (fine and gross neuromotor function). Additionally, parents may express concern for their infant being able to eat without requiring a feeding tube, or breathing without the need for assistance or additional oxygen support. The survey will also seek to determine areas in which parents / caregivers feel there is room for improvement as it applies to their infant. There is no formal scale for this survey, as responses are primarily open-ended, requiring descriptive content analysis. | 22-26 months after birth | 
| Delivery Complications and Outcomes (Pregnant individual participant) | Incidence of postpartum hemorrhage (defined as blood loss >1L within 24 hours post-delivery) | Through hospital discharge (up to 1 month) | 
| Delivery Complications and Outcomes (Pregnant individual participant) | Incidence of prolonged 3rd stage of labor (defined as retention of placenta for >30 minutes postpartum) | Through hospital discharge (up to 1 month) | 
| Delivery Complications and Outcomes (Pregnant individual participant) | Incidence of use of medications for postpartum hemorrhage management other than oxytocin (e.g., methergine, tranexamic acid, hemabate, misoprostol) | Through hospital discharge (up to 1 month) | 
| Delivery Complications and Outcomes (Pregnant individual participant) | Incidence of requirement for uterine balloon tamponade or other surgical intervention to treat postpartum hemorrhage | Through hospital discharge (up to 1 month) | 
| Delivery Complications and Outcomes (Pregnant individual participant) | Incidence of requirements for manual placental removal | Through hospital discharge (up to 1 month) | 
| Delivery Complications and Outcomes (Pregnant individual participant) | Incidence of requirement for transfusion, post-partum | Through hospital discharge (up to 1 month) | 
| Delivery Complications and Outcomes (Pregnant individual participant) | Volume of transfusion required, if applicable | Through hospital discharge (up to 1 month) | 
| Delivery Complications and Outcomes (Pregnant individual participant) | Type of transfusion required (e.g., whole blood, red blood cells, platelets, etc.), if applicable | Through hospital discharge (up to 1 month) | 
| Delivery Complications and Outcomes (Pregnant individual participant) | Incidence of postpartum endometritis | Through hospital discharge (up to 1 month) | 
| Delivery Complications and Outcomes (Pregnant individual participant) | Incidence of mortality | Through hospital discharge (up to 1 month) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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congenital heart disease (CHD), CORD-CHD, cord clamping, echocardiography (ECHO)