Umbilical cord milking (UCM) appeared to be a safe alternative to delayed cord clamping in very premature infants, those born at 28 to 32 weeks’ gestation, according to a randomized controlled trial.
The worst outcomes — severe intraventricular hemorrhage (IVH) or death — were similarly uncommon among preemies randomized to the two approaches, Anup Katheria, MD, of Sharp Mary Birch Hospital for Women and Newborns in San Diego, and colleagues reported in Pediatrics.
Seven of 511 infants treated with UCM to squeeze the blood from the cord into the newborn’s abdomen developed severe IVH or died, compared with seven of 508 infants randomized to delayed cord clamping (DCC) as a more passive means of increasing infant blood volume, for a rate difference of just 0.01% (95% CI -1.4 to 1.4, P=0.99).
“Although the event rates for the primary outcome are both low and the same for the two groups, the 95% CI includes the 1% noninferiority margin and thus we cannot formally demonstrate noninferiority of UCM,” the researchers wrote.
Still, as the largest randomized controlled trial comparing the two cord management strategies in premature infants, Katheria told MedPage Today in an email that the study answered an important question raised by his group’s prior finding early in the trial enrollment that infants born at 23 to 27 weeks had excess IVH with UCM.
“However, there are many infants born prematurely greater than 27 weeks that may benefit from either UCM or DCC, and it was important to study the safety in infants 28 to 32 weeks’ gestational age,” she said.
The NIH, which provided support for the trial, argued in a press release that the new findings suggest that the concerns raised by the earlier findings of infants born before 28 weeks “do not apply to preterm infants born after 28 weeks.”
“The standard procedure, delaying cord clamping while blood naturally flows into the infant’s body, takes 30 to 180 seconds,” the NIH added. “However, cord milking, takes about 20 seconds, reducing delay for infants who need immediate assistance, such as respiratory support. Both procedures allow for umbilical cord blood to reach the infant’s body before clamping, reducing the risk of anemia and other complications seen among infants receiving immediate cord clamping and cutting.”
Even so, there are unanswered questions, Roger Soll, MD, of the University of Vermont in Burlington, suggested in a commentary accompanying the study.
“Certainly, Katheria and colleagues have shown that we can achieve effective placental transfusion in moderately preterm infants with umbilical cord milking, but other more subtle outcomes, such as parental/maternal attitudes and experience are missing from these analyses,” Soll wrote. “The authors of this study clearly understand the commitment to examining all the nuances of cord management and are committed to follow-up of the infants in this study as well as leading a variety of other studies evaluating different cord management.”
For their PREMOD2 trial, Katheria and colleagues screened 5,998 pregnancies to end up with 1,019 infants born premature at participating sites at 19 university and private medical centers in four countries from June 2017 to September 2022.
After the initial finding of risk among the younger neonates, the trial was restarted with enrollment of only infants born at 28 to 32 weeks. The primary outcome was also shifted to 2-year neurodevelopmental outcomes, which has not yet been reported; but the original primary endpoint — a composite of severe IVH (grade III or IV) or death following delivery — was deemed important to report in a timely fashion as well.
Average gestational age at enrollment was 31 weeks, and 44% of the infants were female. There were “no notable imbalances” in regards to maternal, infant, or delivery characteristics.
The mean time in seconds to umbilical cord clamping was higher in the DCC group than the UCM group (58.4 vs 24.5, P<0.001). And a greater number of newborns were breathing before the cord was clamped in those randomized to DCC (86% vs 75%, P<0.0001).
Ultimately, there were no significant differences in severe IVH, death, any-grade IVH, hemoglobin at 4 hours of life, or exploratory outcomes between infants randomized to the two cord management groups, Katheria and colleagues reported.
In a sensitivity analysis analyzing just the cohort born at 28 to 32 weeks after the trial was restarted, the composite primary outcome occurred in four of 367 infants randomized to UCM and three of 360 infants randomized to DCC (rate difference 0%, 95% CI -1 to 2).
In terms of limitations of the trial, Katheria and colleagues noted that when recruitment changed to exclude infants born at less than 28 weeks, the target sample size was not increased to account for a resulting lower event rate.
Overall, Katheria concluded, “Among preterm infants born at 28 to 32 weeks’ gestational age, UCM may be a safe and easily implemented alternative to DCC for premature infants who require resuscitation.”
Katheria reported receiving grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Co-authors reported no conflicts of interest.
Soll reported no conflicts of interest.
Source Reference: Katheria A, et al “Umbilical cord milking versus delayed cord clamping in infants 28 to 32 weeks: a randomized trial” Pediatrics 2023; DOI: 10.1542/peds.2023-063113.
Source Reference: Soll RF “Further insights into cord management” Pediatrics 2023; DOI: 10.1542/peds.2023-063505.