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Original Investigation
November 19, 2019

Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants

Author Affiliations
  • 1Neonatal Research Institute, Sharp Mary Birch Hospital for Women & Newborns, San Diego, California
  • 2Department of Obstetrics, University of Ulm, Ulm, Germany
  • 3Department of Pediatrics, University of Ulm, Ulm, Germany
  • 4Division of Neonatology, Department of Pediatrics, Sidra Medicine, Doha, Qatar
  • 5Department of Obstetrics, University of Alabama at Birmingham
  • 6Department of Pediatrics, University of Alabama at Birmingham
  • 7Department of Pediatrics, Loma Linda University, Loma Linda, California
  • 8Department of Obstetrics, Loma Linda University, Loma Linda, California
  • 9Department of Pediatrics, University of Alberta, Edmonton, Canada
  • 10Department of Obstetrics, University of Alberta, Edmonton, Canada
  • 11Women and Children’s Services, Providence St Vincent Medical Center, Portland, Oregon
  • 12Department of Pediatrics, Magee Women’s Hospital of UPMC, Pittsburgh, Pennsylvania
  • 13Department of Obstetrics, Magee Women’s Hospital of UPMC, Pittsburgh, Pennsylvania
  • 14Department of Paediatrics and Child Health, University College Cork, Cork, Ireland
  • 15INFANT Research Centre, University College Cork, Cork, Ireland
  • 16Department of Obstetrics, University College Cork, Cork, Ireland
  • 17Department of Pediatrics, Christiana Care Health System, Newark, Delaware
  • 18Department of Obstetrics, Christiana Care Health System, Newark, Delaware
  • 19Department of Radiology, Children’s Hospital Colorado, University of Colorado School of Medicine, Denver
  • 20Department of Radiology, Rady Children’s Hospital, San Diego, California
  • 21Department of Obstetrics and Gynecology, University of Utah, Salt Lake City
  • 22Department of Biostatistics, University of Alabama at Birmingham
JAMA. 2019;322(19):1877-1886. doi:10.1001/jama.2019.16004
Key Points

Question  Is there a difference in the rates of death or severe intraventricular hemorrhage among preterm infants who receive placental transfusion with umbilical cord milking vs delayed umbilical cord clamping?

Findings  In a randomized clinical trial that was terminated early, precluding the planned noninferiority analysis and requiring post hoc comparison, 474 of a planned 1500 infants born at less than 32 weeks’ gestation were enrolled. There was no significant difference in the composite primary outcome of death or severe intraventricular hemorrhage for the umbilical cord milking group vs the delayed umbilical cord clamping group (12% vs 8%, respectively), but umbilical cord milking was significantly associated with a higher rate of severe intraventricular hemorrhage (8% vs 3%).

Meaning  Among preterm infants born at less than 32 weeks’ gestation, there was no significant difference in the rates of the composite primary outcome of death or severe intraventricular hemorrhage with umbilical cord milking vs delayed umbilical cord clamping, but a significantly higher rate of severe intraventricular hemorrhage (a signal of harm) in the umbilical cord milking group led to early termination of the study. The early study termination and post hoc nature of the analyses preclude definitive conclusions.

Abstract

Importance  Umbilical cord milking as an alternative to delayed umbilical cord clamping may provide equivalent benefits to preterm infants, but without delaying resuscitation.

Objective  To determine whether the rates of death or severe intraventricular hemorrhage differ among preterm infants receiving placental transfusion with umbilical cord milking vs delayed umbilical cord clamping.

Design, Setting, and Participants  Noninferiority randomized clinical trial of preterm infants (born at 23-31 weeks’ gestation) from 9 university and private medical centers in 4 countries were recruited and enrolled between June 2017 and September 2018. Planned enrollment was 750 per group. However, a safety signal comprising an imbalance in the number of severe intraventricular hemorrhage events by study group was observed at the first interim analysis; enrollment was stopped based on recommendations from the data and safety monitoring board. The planned noninferiority analysis could not be conducted and a post hoc comparison was performed instead. Final date of follow-up was December 2018.

Interventions  Participants were randomized to umbilical cord milking (n = 236) or delayed umbilical cord clamping (n = 238).

Main Outcomes and Measures  The primary outcome was a composite of death or severe intraventricular hemorrhage to determine noninferiority of umbilical cord milking with a 1% noninferiority margin.

Results  Among 540 infants randomized, 474 (88%) were enrolled and completed the trial (mean gestational age of 28 weeks; 46% female). Twelve percent (29/236) of the umbilical cord milking group died or developed severe intraventricular hemorrhage compared with 8% (20/238) of the delayed umbilical cord clamping group (risk difference, 4% [95% CI, −2% to 9%]; P = .16). Although there was no statistically significant difference in death, severe intraventricular hemorrhage was statistically significantly higher in the umbilical cord milking group than in the delayed umbilical cord clamping group (8% [20/236] vs 3% [8/238], respectively; risk difference, 5% [95% CI, 1% to 9%]; P = .02). The test for interaction between gestational age strata and treatment group was significant for severe intraventricular hemorrhage only (P = .003); among infants born at 23 to 27 weeks’ gestation, severe intraventricular hemorrhage was statistically significantly higher with umbilical cord milking than with delayed umbilical cord clamping (22% [20/93] vs 6% [5/89], respectively; risk difference, 16% [95% CI, 6% to 26%]; P = .002).

Conclusions and Relevance  In this post hoc analysis of a prematurely terminated randomized clinical trial of umbilical cord milking vs delayed umbilical cord clamping among preterm infants born at less than 32 weeks’ gestation, there was no statistically significant difference in the rate of a composite outcome of death or severe intraventricular hemorrhage, but there was a statistically significantly higher rate of severe intraventricular hemorrhage in the umbilical cord milking group. The early study termination and resulting post hoc nature of the analyses preclude definitive conclusions.

Trial Registration  ClinicalTrials.gov Identifier: NCT03019367

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