Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial—statistical analysis plan for a multicenter randomized controlled trial

Sten P. Willemsen; Ronny Knol; Emma Brouwer; Thomas van den Akker; Philip L.J. DeKoninck; Enrico Lopriore; Wes Onland; Willem P. de Boode; Anton H. van Kaam; Debbie H. Nuytemans; Irwin K.M. Reiss; G. Jeroen Hutten; Sandra A. Prins; Estelle E.M. Mulder; Christian V. Hulzebos; Sam J. van Sambeeck; Mayke E. van der Putten; Inge A. Zonnenberg; Arjan B. te Pas; Marijn J. Vermeulen

doi:10.1186/s13063-024-08014-y

Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial—statistical analysis plan for a multicenter randomized controlled trial

Sten P. Willemsen, Ronny Knol^*, Emma Brouwer, Thomas van den Akker, Philip L.J. DeKoninck, Enrico Lopriore, Wes Onland, Willem P. de Boode, Anton H. van Kaam, Debbie H. Nuytemans, Irwin K.M. Reiss, G. Jeroen Hutten, Sandra A. Prins, Estelle E.M. Mulder, Christian V. Hulzebos, Sam J. van Sambeeck, Mayke E. van der Putten, Inge A. Zonnenberg, Arjan B. te Pas, Marijn J. Vermeulen

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC. Methods: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data. Discussion: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth. Trial registration: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019.

Original language	English
Article number	164
Pages (from-to)	1-9
Number of pages	9
Journal	Trials
Volume	25
Early online date	4 Mar 2024
DOIs	https://doi.org/10.1186/s13063-024-08014-y
Publication status	Published - 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

The trial is funded by The Netherlands Organisation for Health Research and Development (project number 852001902). AtP is a recipient of an NWO innovational research incentives scheme (VIDI 91716428). RK received a grant from the Sophia Children’s Hospital Foundation (Rotterdam, S17-14). This project was sponsored by the Gisela Thier Fund (Leiden).

Funders	Funder number
ZONMW	852001902
Children’s Hospital Foundation	S17-14

Keywords

Cord clamping
Physiological-based cord clamping
Preterm infants
Randomized clinical trial
Statistical Analysis Plan

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Willemsen, S. P., Knol, R., Brouwer, E., van den Akker, T., DeKoninck, P. L. J., Lopriore, E., Onland, W., de Boode, W. P., van Kaam, A. H., Nuytemans, D. H., Reiss, I. K. M., Hutten, G. J., Prins, S. A., Mulder, E. E. M., Hulzebos, C. V., van Sambeeck, S. J., van der Putten, M. E., Zonnenberg, I. A., te Pas, A. B., & Vermeulen, M. J. (2024). Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial—statistical analysis plan for a multicenter randomized controlled trial. Trials, 25, 1-9. Article 164. https://doi.org/10.1186/s13063-024-08014-y

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title = "Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial—statistical analysis plan for a multicenter randomized controlled trial",

abstract = "Background: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC. Methods: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data. Discussion: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth. Trial registration: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019.",

keywords = "Cord clamping, Physiological-based cord clamping, Preterm infants, Randomized clinical trial, Statistical Analysis Plan",

author = "Willemsen, {Sten P.} and Ronny Knol and Emma Brouwer and {van den Akker}, Thomas and DeKoninck, {Philip L.J.} and Enrico Lopriore and Wes Onland and {de Boode}, {Willem P.} and {van Kaam}, {Anton H.} and Nuytemans, {Debbie H.} and Reiss, {Irwin K.M.} and Hutten, {G. Jeroen} and Prins, {Sandra A.} and Mulder, {Estelle E.M.} and Hulzebos, {Christian V.} and {van Sambeeck}, {Sam J.} and {van der Putten}, {Mayke E.} and Zonnenberg, {Inge A.} and {te Pas}, {Arjan B.} and Vermeulen, {Marijn J.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1186/s13063-024-08014-y",

language = "English",

volume = "25",

pages = "1--9",

journal = "Trials",

issn = "1745-6215",

publisher = "BioMed Central",

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Willemsen, SP, Knol, R, Brouwer, E, van den Akker, T, DeKoninck, PLJ, Lopriore, E, Onland, W, de Boode, WP, van Kaam, AH, Nuytemans, DH, Reiss, IKM, Hutten, GJ, Prins, SA, Mulder, EEM, Hulzebos, CV, van Sambeeck, SJ, van der Putten, ME, Zonnenberg, IA, te Pas, AB & Vermeulen, MJ 2024, 'Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial—statistical analysis plan for a multicenter randomized controlled trial', Trials, vol. 25, 164, pp. 1-9. https://doi.org/10.1186/s13063-024-08014-y

TY - JOUR

T1 - Physiological-based cord clamping in very preterm infants

T2 - the Aeration, Breathing, Clamping 3 (ABC3) trial—statistical analysis plan for a multicenter randomized controlled trial

AU - Willemsen, Sten P.

AU - Knol, Ronny

AU - Brouwer, Emma

AU - van den Akker, Thomas

AU - DeKoninck, Philip L.J.

AU - Lopriore, Enrico

AU - Onland, Wes

AU - de Boode, Willem P.

AU - van Kaam, Anton H.

AU - Nuytemans, Debbie H.

AU - Reiss, Irwin K.M.

AU - Hutten, G. Jeroen

AU - Prins, Sandra A.

AU - Mulder, Estelle E.M.

AU - Hulzebos, Christian V.

AU - van Sambeeck, Sam J.

AU - van der Putten, Mayke E.

AU - Zonnenberg, Inge A.

AU - te Pas, Arjan B.

AU - Vermeulen, Marijn J.

PY - 2024

Y1 - 2024

N2 - Background: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC. Methods: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data. Discussion: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth. Trial registration: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019.

AB - Background: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC. Methods: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data. Discussion: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth. Trial registration: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019.

KW - Cord clamping

KW - Physiological-based cord clamping

KW - Preterm infants

KW - Randomized clinical trial

KW - Statistical Analysis Plan

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U2 - 10.1186/s13063-024-08014-y

DO - 10.1186/s13063-024-08014-y

M3 - Article

C2 - 38439024

AN - SCOPUS:85186841143

SN - 1745-6215

VL - 25

SP - 1

EP - 9

JO - Trials

JF - Trials

M1 - 164

ER -

Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial—statistical analysis plan for a multicenter randomized controlled trial

Abstract

Bibliographical note

Funding

Keywords

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