Cytokine patterns in very low birth weight infants under different cord clamping strategies: preliminary EXPLAIN trial data

Delayed umbilical cord clamping (DCC) improves survival and hematologic outcomes in preterm infants. Strategies that provide initial respiratory support before cord clamping may prolong intact placental circulation beyond standard time-based DCC in very low birth weight (VLBW) infants. Whether prolonged intact placental circulation modifies neonatal cytokine patterns remains unclear.

This pre-specified secondary analysis of a single-center randomized controlled trial (Extrauterine Placental Transfusion in Resuscitation of VLBW Infants [EXPLAIN]) included preterm infants with a birth weight < 1500 g and gestational age > 23 6/7 weeks delivered by cesarean section between May 2019 and June 2021. Infants were randomized to either extrauterine placental perfusion (EPP group) with intact placental circulation or time-based DCC (DCC group). Samples were obtained from umbilical cord blood at cord clamping (d0) and venous blood on postnatal day 28 (d28). Twenty-seven cytokines were quantified using multiplex ELISAs.

Samples were available from 44 infants; 1 infant was excluded a priori because of neonatal sepsis, leaving 43 infants in the cytokine analysis set. Mean time until cord clamping was 469.6 s in the EPP group and 40.8 s in the DCC group (p < 0.001). At d0, significant relative differences between groups were observed for IL-1ra, IL-17, and IP-10. At d28, EPP was associated with lower IP-10 concentrations than DCC. No broad or consistent differences in cytokine profiles were observed between groups.

In this small exploratory secondary analysis, EPP was not associated with broad cytokine changes compared with DCC in VLBW infants, despite markedly prolonged placental circulation. These findings may support the biological feasibility of EPP and may indicate that prolonged placental perfusion is not associated with major systemic cytokine perturbation. Given the limited sample size, the results should be considered hypothesis-generating and require confirmation in larger studies.

Clinicaltrials.gov (NCT03916159, registered April 05, 2019).