Umbilical cord milking in non-vigorous infants: A cluster-randomized crossover trial

BACKGROUND: Delayed cord clamping (DCC) and umbilical cord milking (UCM) provide placental transfusion to vigorous newborns. Delayed cord clamping in non-vigorous newborns may not be provided due to perceived need for immediate resuscitation. UCM is an alternative since it can be performed more quickly than DCC and may confer similar benefits. OBJECTIVE: We hypothesized that UCM would reduce admission to the neonatal intensive care unit (NICU) compared with early cord clamping (ECC) in non-vigorous newborns born between 35-42 weeks\u27 gestation. STUDY DESIGN: A pragmatic cluster-randomized crossover trial of infants born at 35-42 weeks\u27 gestation from 10 medical centers in 3 countries between January 2019 and May 2021. Centers were randomized to UCM or ECC for approximately one year and then crossed over for an additional year or until the required number of consented subjects was reached. Waiver of consent as obtained in all centers to implement the intervention. Infants were eligible if non-vigorous at birth (poor tone, pale color, or lack of breathing in the first 15 seconds after birth) and were assigned to UCM or ECC according to their birth hospital randomization assignment. Baseline characteristics and outcomes were collected following deferred informed consent. The primary outcome was admission to the NICU for predefined criteria. The main safety outcome was hypoxic-ischemic encephalopathy (HIE). Data were analyzed by intention to treat. RESULTS: Among 16,234 screened newborns, 1780 were eligible (905 UCM, 875 ECC) and 1730 had primary outcome data for analysis (97% of eligible; 872 UCM, 858 ECC) via either informed consent (606 UCM, 601 ECC) or waiver of informed consent (266 UCM, 257 ECC). The difference in the frequency of NICU admission using predefined criteria between the UCM (23%) and ECC (28%) groups did not reach statistical significance (modeled OR 0.69, 95% CI 0.41-1.14). UCM was associated with predefined secondary outcomes including a higher hemoglobin (modeled mean difference between UCM and ECC groups 0.68 g/dL, 95% CI 0.31-1.05), lower odds of abnormal 1-minute Apgar scores (Apgar ≤3, 30% vs 34%, crude OR 0.72, 95%CI 0.56-0.92); cardiorespiratory support at delivery (61% vs 71%, modeled OR 0.57, 95% CI 0.33-0.99) and therapeutic hypothermia (3% vs 4%, crude OR 0.57, 95% CI 0.33-0.99). Moderate-severe HIE was significantly less common with UCM (1% vs 3%, crude OR 0.48, 95% CI 0.24-0.96). No significant difference was observed for normal saline bolus, phototherapy, abnormal 5-minute Apgar scores (Apgar ≤6, 15.7% vs 18.8%, crude OR 0.81, 95% CI 0.62-1.06), or a serious adverse event composite of death before discharge. CONCLUSIONS: Among non-vigorous infants born at 35-42 weeks\u27 gestation, UCM did not reduce NICU admission for predefined criteria. However, infants in the UCM arm had higher hemoglobin, received less delivery room cardiorespiratory support, had a lower incidence of moderate to severe HIE and received less therapeutic hypothermia. These data may provide the first randomized controlled trial evidence that UCM in non-vigorous infants is feasible, safe and superior to ECC