Premature Infants Receiving Milking or Delayed Cord Clamping: PREMOD2 (PREMOD2)

Premature Infants Receiving Milking or Delayed Cord Clamping: Randomized Controlled Multicenter Non-inferiority Trial

This study is being done to find out whether umbilical cord milking (UCM) is at least as good as or better than delayed cord clamping (DCC) to reduce bleeding in the brain or prevent death in premature newborns. The investigators will study short and long term outcomes of infants delivered before 32 weeks gestation that receive either UCM or DCC.

* The trial was stopped by the DSMB for safety in the small strata. They subsequently allowed for continuation of the trial in infants 29-32+6 wk GA.

Study Overview

• Status: Completed
• Conditions: Death; Neonatal; Intraventricular Haemorrhage Neonatal
• Intervention / Treatment: Procedure: Umbilical cord milking UCM; Procedure: Delayed cord clamping DCC

Detailed Description

Aim 1. Compare the incidence of severe intraventricular hemorrhage (IVH) and/or death in premature newborns <33 weeks gestational age (GA) delivered by C/S receiving UCM to those receiving DCC.

Hypothesis1: First demonstrate infants in the UCM group are not inferior to the DCC group (reject H10).

Hypothesis2: If H1 is true, demonstrate lower incidence of severe IVH and/or death in UCM infants compared to DCC.

Aim 2. Compare the safety and efficacy profiles of premature newborns <33 weeks GA delivered by C/S receiving UCM vs. DCC during their hospitalization.

Hypothesis3: UCM group will have a decreased need for resuscitation interventions with no differences in bilirubin or polycythemia compared to DCC.

Hypothesis4: UCM group will have improved blood pressures in the first 24 hours of life compared to DCC.

Aim 3 (exploratory). To compare the outcomes of premature newborns <33 weeks GA delivered by C/S (Cesarean section) (from Aims 1 and 2) with those born by V/D (vaginal delivery) receiving UCM or DCC.

• Study Type: Interventional
• Enrollment (Actual): 1201
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2R3
      • Governors of University of Alberta
• Germany
  • Baden-Wurttemberg
    • Ulm, Baden-Wurttemberg, Germany, 89075
      • University of Ulm
• Ireland
  • Cork, Ireland
    • Cork University Maternity Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0004
      • University of Alabama
  • California
    • Loma Linda, California, United States, 92350
      • Loma Linda Medical Center
    • Los Angeles, California, United States, 90033
      • LAC+USC Medical Center
    • Los Angeles, California, United States, 90033
      • PIH Health Good Samaritan Hospital
    • Orange, California, United States, 92868
      • University of California, Irvine Medical Center
    • San Diego, California, United States, 92123
      • Sharp Mary Birch Hospital for Women and Newborns
    • San Diego, California, United States, 91942
      • Sharp Grossmont Hospital
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Care
  • Illinois
    • Chicago, Illinois, United States, 60612
      • John H. Stroger, Jr. Hospital of Cook County
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • St. Louis University
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97225-6603
      • Providence St. Vincent Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee-Womens Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 7 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 23 to 32 +6 Gestational age (currently enrolling 29 to 32+6 weeks)
• Multiples without Twin-to-twin Transfusion Syndrome (TTTS)

Exclusion Criteria:

• Congenital anomalies
• Major cardiac defects
• Placental abruption or previa with hemorrhage
• Cord prolapse
• Hydrops
• Bleeding Accreta
• Monochorionic multiples with evidence of TTTS
• Fetal or maternal risk (i.e. compromise)
• Parents declined study
• Unlikely to return for 2 yr Follow Up

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Umbilical cord milking UCM; Milking the umbilical cord 4 times towards the infant at a speed of 20cm/2seconds.	Procedure: Umbilical cord milking UCM; At delivery, the umbilical cord is grasped, and blood is pushed toward the infant 4 times before it is clamped. This procedure infuses a placental transfusion of blood into the preterm neonate and can be done in 15-20 seconds.
ACTIVE_COMPARATOR: Delayed cord clamping DCC; Delayed clamping of the umbilical cord for at least 60 seconds.	Procedure: Delayed cord clamping DCC; At delivery, delayed cord clamping will be performed by having the delivering obstetrician delay clamping of the umbilical cord for at least 60 seconds.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of severe IVH or death	Severe intraventricular hemorrhage of grade 3 or 4 or death	Through study completion at death or discharge, up to 6 months corrected gestational age (CGA)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All Grade IVH	Any intraventricular hemorrhage (grades 1-4)	Through study completion at discharge, up to 6 months corrected gestational age (CGA)
Severe IVH (Grade 3 or 4)	Severe intraventricular hemorrhage (bleeding in the brain parenchyma and/or ventricular dilation)	Through study completion at discharge, up to 6 months corrected gestational age (CGA)
Hemoglobin/Hematocrit at 4 hours	hemoglobin/hematocrit	4 +/- 2 hours of life
Incidence of Severe IVH or death in infants <28 weeks gestation	Severe intraventricular hemorrhage (grade 3 or 4) in infants born under 28 weeks gestational age	Through study completion at discharge, up to 6 months corrected gestational age (CGA)
Delivery room interventions	Resuscitation interventions including positive pressure ventilation, continuous positive airway pressure, intubation, chest compressions and medications	In the first 10 minutes of life
Blood pressures in the first 24 hours of life	Blood pressure on admission, 6, 12, 18 and 24 hours of life	In the first 24 hours of life

Collaborators and Investigators

• Sponsor: Sharp HealthCare
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); University of Alabama at Birmingham; University of Pittsburgh; University of Alberta; Christiana Care Health Services; University of California, Irvine; Children's Hospital Medical Center, Cincinnati; University of Utah; Loma Linda University; University of Ulm; University College Cork; University of Mississippi Medical Center; St. Louis University; LAC+USC Medical Center; John H. Stroger Hospital; Providence Hospital; Sharp Mary Birch Hospital for Women & Newborns; Sharp Grossmont Hospital; PIH Health Good Samaritan Hospital

Publications and helpful links

General Publications

• Katheria AC, Allman P, Szychowski JM, Essers J, Carlo WA, Schmolzer GM, Dempsey E, Yanowitz T, Kaempf J, Vora F, Bhat S, Arnell K, Rich W, Varner M. Perinatal Outcomes of Subjects Enrolled in a Multicenter Trial with a Waiver of Antenatal Consent. Am J Perinatol. 2022 Jun;39(8):904-908. doi: 10.1055/s-0040-1719184. Epub 2020 Nov 3.
• Katheria A, Reister F, Essers J, Mendler M, Hummler H, Subramaniam A, Carlo W, Tita A, Truong G, Davis-Nelson S, Schmolzer G, Chari R, Kaempf J, Tomlinson M, Yanowitz T, Beck S, Simhan H, Dempsey E, O'Donoghue K, Bhat S, Hoffman M, Faksh A, Arnell K, Rich W, Finer N, Vaucher Y, Khanna P, Meyers M, Varner M, Allman P, Szychowski J, Cutter G. Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants. JAMA. 2019 Nov 19;322(19):1877-1886. doi: 10.1001/jama.2019.16004.

Helpful Links

• Website for trial
• NIRS Sub-study PREMOD2
• Followup Study-PREMOD2

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 6, 2017
• Primary Completion (ACTUAL): September 16, 2022
• Study Completion (ACTUAL): September 16, 2022

Study Registration Dates

• First Submitted: November 21, 2016
• First Submitted That Met QC Criteria: January 10, 2017
• First Posted (ESTIMATE): January 12, 2017

Study Record Updates

• Last Update Posted (ACTUAL): November 23, 2022
• Last Update Submitted That Met QC Criteria: November 22, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Premature infants; Death; Delayed cord clamping; Intraventricular Hemorrhage; Umbilical cord milking
• Additional Relevant MeSH Terms: Pathologic Processes; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Hemorrhage; Premature Birth
• Other Study ID Numbers: PREMOD2; 1R01HD088646-01A1 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be made available per NICHD requirements (National Institute of Child Health and Human Development).
• IPD Sharing Time Frame: 2 years after primary publication
• IPD Sharing Access Criteria: An archived dataset with documentation will be made available for additional uses by outside investigators, in collaboration with the study investigators. We will work with NICHD program staff to develop a broad data sharing plan over time.
• IPD Sharing Supporting Information Type: SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No