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

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

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

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.

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.

It is not possible to blind the delivering obstetrician, however all other caregivers will be blinded. The procedure will be documented as "placental transfusion" in the delivery summary or admission-progress notes and all study assessments whether primary (head US) or secondary (neurodevelopmental exams) will be performed by blinded team members.

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.

At delivery, delayed cord clamping will be performed by having the delivering obstetrician delay clamping of the umbilical cord for at least 60 seconds.

Resuscitation interventions including positive pressure ventilation, continuous positive airway pressure, intubation, chest compressions and medications

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

Data will be made available per NICHD requirements (National Institute of Child Health and Human Development).

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.

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.