Birth Asphyxia
Conditions
Keywords
Umbilical Cord Milking, Immediate Cord Clamping, Resuscitation
Brief summary
The investigators will conduct a study of non-vigorous term infants to determine if umbilical cord milking (UCM) results in a lower rate of NICU admissions than early clamping and cutting of the umbilical cord at birth for infants who need resuscitation.
Detailed description
At birth, it is critical that an infant begins breathing quickly. The infant has to switch from relying on the placenta for oxygen to using its lungs for the first time. The currently recommended practice for infants who need resuscitation is to immediately clamp the umbilical cord. Animal studies show that clamping the cord before the baby breathes can cause the heart beat to slow and can decrease the amount of blood being pumped out of the heart each minute. This study will test whether infants will benefit from UCM. The cord will be quickly milked four times before cutting and will not delay the resuscitation procedures. This study is important because when there is need for resuscitation, neither UCM or delayed cord clamping, are recommended by national and international organizations due to lack of evidence. Yet, several large studies from around the world have identified that infants needing resuscitation are more likely to develop conditions such as cerebral palsy, autism and other developmental problems. The trial is a cluster crossover design in which each hospital will be randomly assigned to use either early cord clamping or UCM for any infant needing resuscitation over a period of 12 months. Then sites will change to the other method for an additional 12 months.
Interventions
PROCEDUREUmbilical Cord Milking
At delivery, the umbilical cord is grasped, and blood is pushed toward the infant 4 times before the cord is clamped. This procedure infuses a placental transfusion of blood into the infant and can be done in 15-20 seconds.
PROCEDUREEarly Cord Clamping
The umbilical cord is clamped within 60 seconds of delivery.
Sponsors
Sharp Mary Birch Hospital for Women & Newborns
Sharp Grossmont Hospital
University of Utah
University of Alberta
Poznan University of Medical Sciences
IWK Health Centre
University of California, Davis
Loma Linda University
George Washington University
Providence Hospital
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sharp HealthCare
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Cluster Randomized Crossover
Eligibility
Sex/Gender
ALL
Age
35 Weeks to 42 Weeks
Healthy volunteers
No
Inclusion criteria
* Non-vigorous newborns born between 35-42 weeks gestation
Exclusion criteria
* Known major congenital or chromosomal anomalies of newborn * Known cardiac defects other than small ASD, VSD and PDA * Complete placental abruption/cutting through the placenta at time of delivery * Monochorionic multiples * Cord anomaly (i.e. cord avulsion, true knot) * Presence of non-reducible nuchal cord * Perinatal providers unaware of the protocol * Incomplete delivery data * Infants born in extremis, for whom additional treatment will not be offered
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Neonatal Participants Admitted to the NICU for Predefined Criteria | Birth to first 48 hours of life. | Number of neonatal participants admitted to the neonatal intensive care unit for study-specific predefined criteria including respiratory distress, oxygen desaturation, hypoglycemia, hypotonia, apnea, lethargy or difficulty arousing, hypertonia or irritability, temperature instability, bradycardia or tachycardia, seizures or seizure-like activity, poor feeding or emesis, hyperbilirubinemia, death before NICU admission. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Neonates Treated With Therapeutic Hypothermia (Cooling) | Birth to 78 hours of life. | Number of neonates that were treated with therapeutic hypothermia (Cooling to 33.5 degrees Celsius) for 72 hours and initiated within the first 6 hours of life. |
| Number of Neonates Treated With Normal Saline Bolus in the First 24 Hours of Life | Birth through 24 hours of life | Number of neonates treated with normal saline bolus in the first 24 hours of life to support blood pressure. |
| Median Peak Total Serum Bilirubin in Neonates | First week of life | Highest single measurement of total serum bilirubin obtained as part of standard care to assess hyperbilirubinemia in neonate. |
| Median Transcutaneous Bilirubin in Neonates | birth to 7 days of life | Highest single measurement of transcutaneous bilirubin obtained as part of standard care to assess hyperbilirubinemia in each neonate. |
| Number of Neonatal Deaths | Birth to discharge, assessed up to 180 days of life. | Number of neonatal deaths prior to discharge |
| Median Neonatal Hemoglobin Between 12 to 48 Hours of Life | 12-48 hours of life | Single hemoglobin measurement for the neonate which was obtained between 12 to 48 hours of life collected with written consent or as part of standard care. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Median Neonatal Admission Blood Pressure | Birth to 48 hours of life. | First single neonatal blood pressure measurement by cuff or arterial line obtained on admission to the neonatal intensive care unit and by 48 hours of life. |
| Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Birth to first hour of life. | Neonates were assessed for poor tone, poor color (pale, dusky, cyanotic) and poor breathing effort by obstetric provider as part of standard care. Resuscitation assessment and interventions were conducted by neonatal intensive care clinical team. Recorded resuscitation interventions included: use of supplemental oxygen, continuous positive airway pressure respiratory support, positive pressure ventilation respiratory support, endotracheal intubation, chest compressions, epinephrine, normal saline bolus and other cardiorespiratory support medications. Resuscitation interventions including cardiorespiratory support were determined by individual site's clinical standards. |
| Median Length of Neonate's Hospitalization in Days Among Participants Discharged Alive | birth to discharge, up to 120 days of life. | Number of days neonate was admitted to the neonatal intensive care unit from birth to discharge home. |
| Number of Neonates Diagnosed With Mild, Moderate or Severe Hypoxic Ischemic Encephalopathy | Birth to discharge, up to 120 days of life. | Number of neonates with a diagnosis of mild, moderate or severe hypoxic ischemic encephalopathy during neonatal intensive care unit admission. |
Countries
Canada, Poland, United States
Participant flow
Recruitment details
10 sites were randomized to perform umbilical cord milking or early cord clamping for eligible neonate-mother dyads. Research staff at each sites approached eligible neonate-mother dyads after delivery for written informed consent for additional data collection. Hospital recruited neonate-mother dyads in the initial period from January 2019 to January 2020 and from February 2020 and May 2021 for the crossover period. Neonate-mother dyads participated in a single period of the study.
Pre-assignment details
Prior to the initiation of recruitment each participating hospital was assigned to perform umbilical cord milking or early cord clamping on non-vigorous neonates-mother dyads delivered during the recruitment period. Prior to the start of recruitment in the crossover study period (Study Period 2) a 1-2-month washout period was specified by the protocol for the purpose of site hospital staff retraining and to assess adherence to the new assigned intervention.
Participants by arm
| Arm | Count |
|---|---|
| Umbilical Cord Milking - Neonate All neonates who received umbilical cord milking intervention at the time of birth.
Umbilical Cord Milking: At delivery, the umbilical cord is grasped, and blood is pushed toward the infant 4 times before the cord is clamped. | 872 |
| Early Cord Clamping - Neonate All neonates who received early cord clamping at the time of birth. Early Cord Clamping: The umbilical cord is clamped as soon as possible and within 60 seconds of delivery. | 858 |
| Total | 1,730 |
Baseline characteristics
| Characteristic | Umbilical Cord Milking - Neonate | Early Cord Clamping - Neonate | Total |
|---|---|---|---|
| Age, Continuous Infants gestational age at birth | 39.3 weeks | 39.4 weeks | 39.3 weeks |
| Age, Continuous Maternal age at time of delivery | 31 years | 30 years | 31 years |
| Ethnicity (NIH/OMB) Neonatal Ethnicity Hispanic or Latino | 113 Participants | 152 Participants | 265 Participants |
| Ethnicity (NIH/OMB) Neonatal Ethnicity Not Hispanic or Latino | 460 Participants | 379 Participants | 839 Participants |
| Ethnicity (NIH/OMB) Neonatal Ethnicity Unknown or Not Reported | 299 Participants | 327 Participants | 626 Participants |
| Maternal age | 31 years | 30 years | 31 years |
| Maternal diabetes | 106 Participants | 92 Participants | 198 Participants |
| Maternal general anesthesia | 41 Participants | 41 Participants | 82 Participants |
| Maternal group B streptococcus infection | 164 Participants | 139 Participants | 303 Participants |
| Maternal hypertension | 154 Participants | 118 Participants | 272 Participants |
| Maternal intrauterine inflammation or infection | 84 Participants | 96 Participants | 180 Participants |
| Maternal level of education: some college education | 404 Participants | 384 Participants | 788 Participants |
| Maternal narcotic or central nervous system depressant medication ≤ 2 hours before delivery | 63 Participants | 66 Participants | 129 Participants |
| Mode of delivery Cesarean | 362 Participants | 321 Participants | 683 Participants |
| Mode of delivery Unknown | 115 Participants | 140 Participants | 255 Participants |
| Mode of delivery Vaginal | 395 Participants | 397 Participants | 792 Participants |
| Multiple gestation birth | 21 Participants | 29 Participants | 50 Participants |
| Neonatal birth weight | 3355 grams | 3395 grams | 3370 grams |
| Number of hours membranes were ruptured before delivery of neonate | 7 hours | 6 hours | 6 hours |
| Race/Ethnicity, Customized Hispanic Mother | 97 Participants | 136 Participants | 233 Participants |
| Race/Ethnicity, Customized Maternal ethnicity/race not stated or unknown | 297 Participants | 274 Participants | 571 Participants |
| Race/Ethnicity, Customized Non-Hispanic Asian Mother | 49 Participants | 56 Participants | 105 Participants |
| Race/Ethnicity, Customized Non-Hispanic Black Mother | 55 Participants | 53 Participants | 108 Participants |
| Race/Ethnicity, Customized Non-Hispanic Multiracial Mother | 16 Participants | 22 Participants | 38 Participants |
| Race/Ethnicity, Customized Non-Hispanic Native American Mother | 14 Participants | 5 Participants | 19 Participants |
| Race/Ethnicity, Customized Non-Hispanic Pacific Islander Mother | 6 Participants | 9 Participants | 15 Participants |
| Race/Ethnicity, Customized Non-Hispanic White Mother | 338 Participants | 303 Participants | 641 Participants |
| Race (NIH/OMB) Neonatal Race American Indian or Alaska Native | 9 Participants | 5 Participants | 14 Participants |
| Race (NIH/OMB) Neonatal Race Asian | 39 Participants | 45 Participants | 84 Participants |
| Race (NIH/OMB) Neonatal Race Black or African American | 50 Participants | 47 Participants | 97 Participants |
| Race (NIH/OMB) Neonatal Race More than one race | 102 Participants | 107 Participants | 209 Participants |
| Race (NIH/OMB) Neonatal Race Native Hawaiian or Other Pacific Islander | 2 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) Neonatal Race Unknown or Not Reported | 337 Participants | 327 Participants | 664 Participants |
| Race (NIH/OMB) Neonatal Race White | 333 Participants | 320 Participants | 653 Participants |
| Region of Enrollment Canada | 227 neonate participants | 228 neonate participants | 455 neonate participants |
| Region of Enrollment Poland | 20 neonate participants | 28 neonate participants | 48 neonate participants |
| Region of Enrollment United States | 625 neonate participants | 602 neonate participants | 1227 neonate participants |
| Sex: Female, Male Neonatal Sex Female | 375 Participants | 355 Participants | 730 Participants |
| Sex: Female, Male Neonatal Sex Male | 460 Participants | 455 Participants | 915 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 872 | 4 / 858 |
| other Total, other adverse events | 4 / 872 | 2 / 858 |
| serious Total, serious adverse events | 1 / 872 | 2 / 858 |
Outcome results
Primary
Number of Neonatal Participants Admitted to the NICU for Predefined Criteria
Number of neonatal participants admitted to the neonatal intensive care unit for study-specific predefined criteria including respiratory distress, oxygen desaturation, hypoglycemia, hypotonia, apnea, lethargy or difficulty arousing, hypertonia or irritability, temperature instability, bradycardia or tachycardia, seizures or seizure-like activity, poor feeding or emesis, hyperbilirubinemia, death before NICU admission.
Time frame: Birth to first 48 hours of life.
Population: Neonates with admission disposition status
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Umbilical Cord Milking - Neonate | Number of Neonatal Participants Admitted to the NICU for Predefined Criteria | Total number of neonates admitted to the neonatal intensive care unit for predefined criteria | 199 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonatal Participants Admitted to the NICU for Predefined Criteria | Total number of neonates admitted to neonatal intensive care unit for other criteria | 53 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonatal Participants Admitted to the NICU for Predefined Criteria | Total number of neonates without a neonatal intensive care unit admission | 620 Participants |
| Early Cord Clamping - Neonate | Number of Neonatal Participants Admitted to the NICU for Predefined Criteria | Total number of neonates admitted to the neonatal intensive care unit for predefined criteria | 239 Participants |
| Early Cord Clamping - Neonate | Number of Neonatal Participants Admitted to the NICU for Predefined Criteria | Total number of neonates admitted to neonatal intensive care unit for other criteria | 52 Participants |
| Early Cord Clamping - Neonate | Number of Neonatal Participants Admitted to the NICU for Predefined Criteria | Total number of neonates without a neonatal intensive care unit admission | 567 Participants |
p-value: 0.8795% CI: [-6.36, 5.37]Hierarchical generalized linear mixed mo
Secondary
Median Neonatal Hemoglobin Between 12 to 48 Hours of Life
Single hemoglobin measurement for the neonate which was obtained between 12 to 48 hours of life collected with written consent or as part of standard care.
Time frame: 12-48 hours of life
Population: Neonates with a hemoglobin measurement obtained between 12 to 48 hours of life either by standard or care of with parental consent.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Umbilical Cord Milking - Neonate | Median Neonatal Hemoglobin Between 12 to 48 Hours of Life | 18.0 g/dL |
| Early Cord Clamping - Neonate | Median Neonatal Hemoglobin Between 12 to 48 Hours of Life | 17.3 g/dL |
Secondary
Median Peak Total Serum Bilirubin in Neonates
Highest single measurement of total serum bilirubin obtained as part of standard care to assess hyperbilirubinemia in neonate.
Time frame: First week of life
Population: All neonates with a total serum bilirubin result from a blood test obtained as part of standard care.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Umbilical Cord Milking - Neonate | Median Peak Total Serum Bilirubin in Neonates | 8.4 mg/dL |
| Early Cord Clamping - Neonate | Median Peak Total Serum Bilirubin in Neonates | 7 mg/dL |
Secondary
Median Transcutaneous Bilirubin in Neonates
Highest single measurement of transcutaneous bilirubin obtained as part of standard care to assess hyperbilirubinemia in each neonate.
Time frame: birth to 7 days of life
Population: All neonates with a transcutaneous bilirubin measurement in the first week of life as part of standard care.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Umbilical Cord Milking - Neonate | Median Transcutaneous Bilirubin in Neonates | 7.1 mg/dL |
| Early Cord Clamping - Neonate | Median Transcutaneous Bilirubin in Neonates | 6.5 mg/dL |
Secondary
Number of Neonatal Deaths
Number of neonatal deaths prior to discharge
Time frame: Birth to discharge, assessed up to 180 days of life.
Population: Neonates with discharge status available
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Umbilical Cord Milking - Neonate | Number of Neonatal Deaths | 0 Participants |
| Early Cord Clamping - Neonate | Number of Neonatal Deaths | 4 Participants |
Secondary
Number of Neonates Treated With Normal Saline Bolus in the First 24 Hours of Life
Number of neonates treated with normal saline bolus in the first 24 hours of life to support blood pressure.
Time frame: Birth through 24 hours of life
Population: Neonates with admission disposition status
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Umbilical Cord Milking - Neonate | Number of Neonates Treated With Normal Saline Bolus in the First 24 Hours of Life | 58 Participants |
| Early Cord Clamping - Neonate | Number of Neonates Treated With Normal Saline Bolus in the First 24 Hours of Life | 56 Participants |
Secondary
Number of Neonates Treated With Therapeutic Hypothermia (Cooling)
Number of neonates that were treated with therapeutic hypothermia (Cooling to 33.5 degrees Celsius) for 72 hours and initiated within the first 6 hours of life.
Time frame: Birth to 78 hours of life.
Population: Neonates with admission disposition status
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Umbilical Cord Milking - Neonate | Number of Neonates Treated With Therapeutic Hypothermia (Cooling) | 21 Participants |
| Early Cord Clamping - Neonate | Number of Neonates Treated With Therapeutic Hypothermia (Cooling) | 35 Participants |
Other Pre-specified
Median Length of Neonate's Hospitalization in Days Among Participants Discharged Alive
Number of days neonate was admitted to the neonatal intensive care unit from birth to discharge home.
Time frame: birth to discharge, up to 120 days of life.
Population: Neonates with discharge status
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Umbilical Cord Milking - Neonate | Median Length of Neonate's Hospitalization in Days Among Participants Discharged Alive | 3 days |
| Early Cord Clamping - Neonate | Median Length of Neonate's Hospitalization in Days Among Participants Discharged Alive | 3 days |
Other Pre-specified
Median Neonatal Admission Blood Pressure
First single neonatal blood pressure measurement by cuff or arterial line obtained on admission to the neonatal intensive care unit and by 48 hours of life.
Time frame: Birth to 48 hours of life.
Population: Neonates admitted to the neonatal intensive care unit with a blood pressure measurement in the first 48 hours of life.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Umbilical Cord Milking - Neonate | Median Neonatal Admission Blood Pressure | 48 mm Hg |
| Early Cord Clamping - Neonate | Median Neonatal Admission Blood Pressure | 46 mm Hg |
Other Pre-specified
Number of Neonates Diagnosed With Mild, Moderate or Severe Hypoxic Ischemic Encephalopathy
Number of neonates with a diagnosis of mild, moderate or severe hypoxic ischemic encephalopathy during neonatal intensive care unit admission.
Time frame: Birth to discharge, up to 120 days of life.
Population: Neonates with admission disposition status
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Umbilical Cord Milking - Neonate | Number of Neonates Diagnosed With Mild, Moderate or Severe Hypoxic Ischemic Encephalopathy | Neonates with a diagnosis of moderate hypoxic ischemic encephalopathy | 8 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonates Diagnosed With Mild, Moderate or Severe Hypoxic Ischemic Encephalopathy | Neonates with a diagnosis of mild hypoxic ischemic encephalopathy | 15 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonates Diagnosed With Mild, Moderate or Severe Hypoxic Ischemic Encephalopathy | Neonates with a diagnosis of severe hypoxic ischemic encephalopathy | 4 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonates Diagnosed With Mild, Moderate or Severe Hypoxic Ischemic Encephalopathy | Neonates with no hypoxic ischemic encephalopathy diagnosis | 801 Participants |
| Early Cord Clamping - Neonate | Number of Neonates Diagnosed With Mild, Moderate or Severe Hypoxic Ischemic Encephalopathy | Neonates with no hypoxic ischemic encephalopathy diagnosis | 768 Participants |
| Early Cord Clamping - Neonate | Number of Neonates Diagnosed With Mild, Moderate or Severe Hypoxic Ischemic Encephalopathy | Neonates with a diagnosis of mild hypoxic ischemic encephalopathy | 14 Participants |
| Early Cord Clamping - Neonate | Number of Neonates Diagnosed With Mild, Moderate or Severe Hypoxic Ischemic Encephalopathy | Neonates with a diagnosis of moderate hypoxic ischemic encephalopathy | 19 Participants |
| Early Cord Clamping - Neonate | Number of Neonates Diagnosed With Mild, Moderate or Severe Hypoxic Ischemic Encephalopathy | Neonates with a diagnosis of severe hypoxic ischemic encephalopathy | 5 Participants |
Other Pre-specified
Number of Neonates With Any Cardiorespiratory Support Intervention at Birth
Neonates were assessed for poor tone, poor color (pale, dusky, cyanotic) and poor breathing effort by obstetric provider as part of standard care. Resuscitation assessment and interventions were conducted by neonatal intensive care clinical team. Recorded resuscitation interventions included: use of supplemental oxygen, continuous positive airway pressure respiratory support, positive pressure ventilation respiratory support, endotracheal intubation, chest compressions, epinephrine, normal saline bolus and other cardiorespiratory support medications. Resuscitation interventions including cardiorespiratory support were determined by individual site's clinical standards.
Time frame: Birth to first hour of life.
Population: Neonates with resuscitation intervention data collected at the time of birth.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Umbilical Cord Milking - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates who received supplemental oxygen support in the delivery room | 267 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates who received chest compressions in the delivery room | 9 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates who received positive pressure ventilation support in the delivery room | 313 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates administered epinephrine, fluid bolus or other medication in the delivery room | 2 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates who received continuous positive airway pressure support in the delivery room | 295 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates with no cardiorespiratory support in the delivery room | 298 Participants |
| Umbilical Cord Milking - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates who received endotracheal intubation in the delivery room | 26 Participants |
| Early Cord Clamping - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates with no cardiorespiratory support in the delivery room | 216 Participants |
| Early Cord Clamping - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates who received continuous positive airway pressure support in the delivery room | 305 Participants |
| Early Cord Clamping - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates who received positive pressure ventilation support in the delivery room | 377 Participants |
| Early Cord Clamping - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates who received endotracheal intubation in the delivery room | 35 Participants |
| Early Cord Clamping - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates who received chest compressions in the delivery room | 7 Participants |
| Early Cord Clamping - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates administered epinephrine, fluid bolus or other medication in the delivery room | 3 Participants |
| Early Cord Clamping - Neonate | Number of Neonates With Any Cardiorespiratory Support Intervention at Birth | Number of neonates who received supplemental oxygen support in the delivery room | 337 Participants |