Physiological versus time based cord clamping in very preterm infants (ABC3): a parallel-group, multicentre, randomised, controlled superiority trial

Abstract

Background: Physiological-based cord clamping (PBCC) in preterm infants is beneficial for cardiovascular transition at birth and may optimize placental transfusion. Whether PBCC can improve clinical outcomes is unknown. The aim of the Aeration, Breathing, Clamping (ABC3) trial was to test whether PBCC results in improved intact survival in very preterm infants.

Methods: The ABC3 trial was a parallel-group, multicentre, randomised, controlled superiority clinical trial conducted in all Dutch tertiary referral centers for perinatal care involving infants born before 30 weeks of gestation. Infants were randomised to either PBCC or time-based delayed cord clamping (TBCC), stratified by gestational age and treatment center. Infants receiving PBCC were stabilised with umbilical cord intact, which was clamped after reaching cardiorespiratory stability (heart rate >100 bpm and SpO2 >85% while supplemental oxygen <40%). In TBCC the cord was clamped after 30-60 s. The primary outcome was survival without major cerebral injury and/or necrotizing enterocolitis. The primary and key secondary analyses were done in both the intention-to-treat and per-protocol populations. The trial was registered with ClinicalTrials.gov (NCT03808051).

Findings: From January 25, 2019, through October 2, 2022, 669 infants were randomised (median gestational age 27⁺⁵ weeks (IQR 26⁺²-28⁺⁶)) and included in the intention-to-treat population. Intact survival occurred in 241 of 339 infants (71.1%) after PBCC, compared with 223 of 330 (67.6%) after TBCC (odds ratio 1.18, 95% CI 0.84-1.66; absolute risk difference 3.1 %points, 95% CI -11.0 to 15.8, p = 0.33). Pre-specified subgroup analysis showed 69.9% intact survival in male infants after PBCC, compared with 61.8% after TBCC (odds ratio 2.32, 95% CI 1.42-3.78, p for interaction 0.026). 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.

Interpretation: PBCC in very preterm infants did not increase survival without major cerebral injury or necrotizing enterocolitis compared to TBCC in the entire cohort. A possible beneficial effect in male infants requires confirmation from other trials. PBCC was safe to perform and parents reported more contentment and less anxiety.

Funding: The Netherlands Organization for Health Research and Development.

Keywords: Cord clamping; Newborn resuscitation; Preterm infants.

Fig. 1

Flow chart of assessment for Eligibility, Consent, Randomization, and Inclusion in the Analysis. TTS = twin transfusion syndrome. TAPS = twin anemia polycythemia syndrome. MCMA = mono-chorionic mono-amniotic twin. CS = caesarean section. COVID19 = Coronavirus disease 2019. GA = gestational age. IUFD = intra uterine fetal demise. TBCC = time-based cord clamping. PBCC = physiological-based cord clamping.

Fig. 2

Parental perception and appreciation of the approach during birth and stabilization (Intention-to-Treat Analysis).

Fig. 3

Learning curve: graph showing the estimated effect of the number of previously performed PBCC procedures in a center on the odds ratio (with 95% confidence interval) of intact survival of the intervention (p = 0.010). For each additional procedure the odds of PBCC increases with a factor 1.007 (95% CI 1.002–1.012).