MANUSCRIPT CITATION

Knol R, Brouwer E, van den Akker T, DeKoninck PLJ, Onland W, Vermeulen MJ, de Boode WP, van Kaam AH, Lopriore E, Reiss IKM, Hutten GJ, Prins SA, Mulder EEM, d’Haens EJ, Hulzebos CV, Bouma HA, van Sambeeck SJ, Niemarkt HJ, van der Putten ME, Lebon T, Zonnenberg IA, Nuytemans DH, Willemsen SP, Polglase GR, Steggerda SJ, Hooper SB, Te Pas AB. Physiological versus time based cord clamping in very preterm infants (ABC3): a parallel-group, multicentre, randomised, controlled superiority trial. Lancet Reg Health Eur. 2024 Dec 4;48:101146. doi: 10.1016/j.lanepe.2024.101146. PMID: 39717227; PMCID: PMC11664066..

REVIEWED BY

Anup C. Katheria, MD and Henry C. Lee, MD
Sharp Mary Birch Hospital for Women and Newborns and University of CA, San Diego
Email: anup.katheria@sharp.com henrylee@ucsd.edu

TYPE OF INVESTIGATION

Randomized controlled trial.

QUESTION

In (P) premature infants born<30 weeks, does (I) physiological based cord clamping (PBCC) compared to (c) time-based cord clamping (TBCC) improve survival without major cerebral injury and/or necrotizing enterocolitis (NEC)

METHODS

• Design: Individual patient randomization that included all 9 Dutch medical centers from January 25, 2019 though October 2, 2022)
• Allocation: A computer-generated allocation sequence was used to randomize
• Blinding: Due to the nature of the interventions, personnel providing clinical care at delivery were not blinded. Assessors of the primary outcome were blinded as to treatment allocation.
• Follow-up period: Through primary NICU hospitalization
• Setting: 9 Centers in the Netherlands
• Inclusion criteria:
Preterm infants born before 30 weeks of gestation.
Antenatal parental informed consent was necessary for all participants in the trial. Exclusion criteria:
Congenital malformations
signs of acute placental abruption
placenta previa or invasive placentation (accreta/percreta)
birth by emergency caesarean section
monochorionic twin gestation with signs of twin-to-twin transfusion syndrome or twin anemia polycythemia syndrome
multiple pregnancy >2 (triplets or higher order)
intended palliative care delivery.
Maternal general anesthesia was an exclusion criterium at the start of the trial, but inclusion was allowed after amendment of the protocol and approval by the IRB.

During the COVID19-pandemic, inclusion was temporarily halted in some participating centers following hospital regulations.

• Intervention: A specifically designed trolley (Concord Neonatal B.V., Leiden, The Netherlands) was used to perform PBCC in this trial. The trolley contains similar equipment as a regular resuscitation table. Immediately after birth, the infant was placed on the trolley, respiratory support was commenced applying continuous positive airway pressure and assisted ventilation when necessary via facemask, and temperature was managed using a plastic wrap and radiant heater. The umbilical cord was clamped when the infant was stabilised, defined as having a heart rate >100 bpm and SpO2 >85% while using <40% supplemental oxygen. The minimum time of cord clampnig was 3 min and maximum time 10 minutes.

• Primary Outcomes: The primary outcome was the dichotomous outcome of intact survival at Neonatal Intensive Care Unit (NICU) discharge, defined as survival without major cerebral injury (intraventricular hemorrhage ≥ grade 2 and/or periventricular venous infarction and/or Periventricular leukomalacia ≥ grade 2) and/or NEC ≥ stage 2.

• Secondary outcomes:
Respiratory Distress Syndrome
Pneumothorax
Number of oxygen days
Bronchopulmonary Dysplasia
Early onset sepsis
Late onset sepsis
Meningitis
Focal intestinal perforationPost hemorrhagic ventricular dilatation
Retinopathy of prematurity

• Analysis and Sample Size: The sample size was determined to detect an increase of intact survival of 10% (from 72% to 82%) with 80% power and test size (alpha) of 5%. The required sample size was 330 randomised participants in each arm.

To compare the difference in primary outcome between the two arms, a logistic regression model was estimated using generalized estimating equations with an exchangeable working correlation matrix and non-robust standard errors, to account for the potential correlation in the outcome between siblings and infants within the same center. The response of this model was intact survival at NICU discharge and the covariates were the treatment arm and gestational age. The marginal absolute risk difference (ARD) and bootstrapped confidence intervals were calculated using marginal standardization. A significance level of 5% was used for all tests. No multiplicity adjustment was used.

Secondary outcomes similarly were analyzed using generalized estimating equations. The analyses for the parental reported outcomes were measured on a five-point scale and considered to be continuous. Preplanned subgroup analysis was done based on gestational age (<27+0 weeks and ≥27+0 weeks), mode of birth and sex of the infant.
• Patient followup: 2 year neurodevelopment followup planned but not included in the analysis.

MAIN RESULTS

669 infants were randomized with a median gestational age 27+5 weeks (IQR 26+2–28+6))
Results of the primary outcome and its components are shown below
PBCC (n=339) TBCC (n=330) Odds ratio (95% CI) ARD (95% CI) P value
Composite outcome
Survival without major cerebral injury and/or necrotizing enterocolitis 241(71.1%) 223(67.6%) 1.18(0.84–1.66) 3.1(−11.0to15.8) 0.33
Components of primary outcome
Infant death 46(13.6%) 46(13.9%) 0.99(0.53–1.84) −0.2(−8.8to14.1) 0.96
Major cerebral injury 57(16.8%) 55(16.7%) 1.03(0.88–1.21) −0.4(−6.0to10.9) 0.69
Necrotizing enterocolitis 25(7.4%) 29(8.8%) 0.83(0.53–1.32) −0.6(−6.0to16.1) 0.43

Secondary outcomes showed fewer red blood cell transfusions after PBCC (rate ratio 0.83, 95% CI 0.75–0.92, p = 0.0003), lower incidence of late-onset sepsis (27.4% versus 33.3%, odds ratio 0.77, 95% CI 0.62–0.95, p = 0.013) and lower admission temperature (36.3 ◦C versus 36.7 ◦C, mean difference −0.5, 95% CI −0.8 to −0.3, p < 0.0001). Parents were less anxious (Likert scale 1.52 (SD 0.97) versus 2.23 (SD 1.35); p < 0.001) and more content (Likert scale 4.74 (SD 0.75) versus 4.49 (SD 0.97); p < 0.001) after PBCC.

CONCLUSION PBCC in very preterm infants did not increase survival without major cerebral injury or necrotizing enterocolitis compared to TBCC in the entire cohort.

COMMENTARY

Intact cord resuscitation has been described since the early 14th century where the umbilical cord would not be clamped until the lungs were aerated. (1) Since then, observational cohort studies suggested benefit of maintaining placental circulation during initial breathing steps. Subsequently, randomized controlled trials comparing intact cord resuscitation to either immediate cord clamping or shorter durations of delayed cord clamping have been conducted. The ABC3 trial is the largest randomized controlled trial to date comparing intact cord resuscitation to a shorter unsupported time-based cord clamping approach. The ABC3 trial attempted to use a patient centered approach to cord clamping whereby infants had their cord clamped once they reached a peripheral oxygen saturation of 85 percent while requiring less than 40 percent supplemental oxygen and had a heart rate of >100 beats per minute. However, the minimum time was at least 3 minutes, and the maximum time was 10 minutes before cord clamping occurred. If there was excessive maternal blood loss, the cord was clamped earlier as well. The mean time of cord clamping was just under 6 minutes in the intervention group.

 

In 2024, the International Liaison Committee on Resuscitation (ILCOR) published a consensus on Science with treamtent recommendations for preterm infants. (2) The current ILCOR recommendations are summarized here: “While it is reasonable to consider [deferral of cord clamping for 120 seconds or more (long DCC)], the task force cannot recommend the long deferral for all infants based on this evidence. Instead, the long deferral could be considered only if there is no contraindication and if appropriate newborn stabilization can be provided on the intact cord (skilled team, proper training, appropriate equipment, enough space and ability to provide thermal management). More evidence is needed before recommending long DCC. Practicality, feasibility, cost-effectiveness, and equity issues need to be addressed.”

 

The group of infants who had longer DCC and resuscitation initiated on the cord had lower average initial temperatures. It was noted that there was a positive impact of improved effect for outcomes based on experience of the team in providing the intervention. As with other aspects of neonatal resuscitation that require coordination amongst team members, practice, experience, and training in behavioral skills are likely to advance care with newer approaches of cord management.

 

In this study, the authors have studied the effect of long DCC and promoting lung aeration compared to shorter durations of DCC. While there were no statistically significant differences in their primary outcome, there were a number of secondary benefits such as fewer red blood cell transfusions, less late onset sepsis. In additional family centered outcomes such as less anxiety from parents were noted. The authors mention that infants in this study are being followed for long term outcomes. It will be interesting to see the impact of PBCC on the neurodevelopment of these infants that had improved hemoglobin and less blood transfusions. Andersson et al demonstrated improved 4-year outcomes in term infants receiving 3 minutes of DCC compared to early cord clamping. (3) It is possible that preterm infants may have even greater benefits given their high risk of neurodevelopmental impairment.

REFERENCES

1. Hutchon D. Evolution of neonatal resuscitation with intact placental circulation. INFANT 2014; 10:58.
2. Greif R, Bray JE, Djärv T, Drennan IR, Liley HG, Ng K-C, et al. 2024 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Pediatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Aid Task Forces. Circulation 2024; 150 24:e580-e687.
3. Andersson O, Lindquist B, Lindgren M, Stjernqvist K, Domellof M, Hellstrom-Westas L. Effect of Delayed Cord Clamping on Neurodevelopment at 4 Years of Age: A Randomized Clinical Trial. JAMA pediatrics 2015; 169 7:631-8.