Does Delayed Cord Clamping Improve Long-Term (≥4 Months) Neurodevelopment in Term Babies? A Systematic Review and a Meta-Analysis of Randomized Clinical Trials

Abstract

Background: Recently, the literature suggested that placental transfusion facilitated by delayed cord clamping (DCC), besides having benefits on hematological parameters, might improve the infants' brain development. Objective: The present review primarily evaluates the Ages and Stages Questionnaire (ASQ) total score mean difference (MD) at long-term follow-up (≥4 months) comparing DCC (>90 or >180 s) to early cord clamping (ECC). Secondary aims consisted of evaluating the ASQ domains' MD and the results obtained from other methods adopted to evaluate the infants' neurodevelopment. Methods: MEDLINE, Scopus, Cochrane, and ClinicalTrials.gov databases were searched (up to 2nd November 2020) for systematic review and meta-analysis. All randomized controlled trials (RCTs) of term singleton gestations received DCC or ECC. Multiple pregnancies, pre-term delivery, non-randomized studies, and articles in languages other than English were excluded. The included studies were assessed for bias and quality. ASQ data were pooled stratified by time to follow up. Results: This meta-analysis of 4 articles from 3 RCTs includes 765 infants with four-month follow-up and 672 with 12 months follow-up. Primary aim (ASQ total score) pooled analysis was possible only for 12 months follow-up, and no differences were found between DCC and ECC (MD 1.1; CI 95: -5.1; 7.3). DCC approach significantly improves infants' communication domains (MD 0.6; CI 95: 0.1; 1.1) and personal-social assessed (MD 1.0; CI 95: 0.3; 1.6) through ASQ at 12 months follow-up. Surprisingly, the four-month ASQ personal social domain (MD -1.6; CI 95: -2.8; -0.4) seems to be significantly lower in the DCC group than in the ECC group. Conclusions: DCC, a simple, non-interventional, and cost-effective approach, might improve the long-term infants' neurological outcome. Single-blinding and limited studies number were the main limitations. Further research should be performed to confirm these observations, ideally with RCTs adopting standard methods to assess infants' neurodevelopment. Trial registration: NCT01245296, NCT01581489, NCT02222805, NCT01620008, IRCT201702066807N19, and NCT02727517.

Keywords: cord clamping time; delayed cord clamping; neurodevelopment; placental transfusion; third stage of labor.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Xodo, Xodo, Baccarini, Driul and Londero.

Figures

Figure 1

(A) The PRISMA flow diagram showing the literature search and selection. (B) Study quality summary, which includes our judgements about each risk-of-bias item for each included study [colors legend: green (+) as low risk of bias (high quality), yellow (?) as unclear, and red (–) as high risk of bias (low quality)]. (C) Methodological quality score summary shown as percentage of all included 6 trials (denominator) published in 8 articles.

Figure 2

(A) Forest plot showing mean difference of the Ages and Stages Questionnaire (ASQ) total score at 12 months follow up between delayed cord clamping (DCC) and early cord clamping (ECC) groups. (B) Forest plot showing mean difference of the ASQ communication domain score at 4 months follow up between DCC and ECC groups. (C) Forest plot showing mean difference of the ASQ communication domain score at 12 months follow up between DCC and ECC groups.

Figure 3

(A) Forest plot showing mean difference of the Ages and Stages Questionnaire (ASQ) gross motor domain score at 4 months follow up between delayed cord clamping (DCC) and early cord clamping (ECC) groups. (B) Forest plot showing mean difference of the ASQ gross motor domain score at 12 months follow up between DCC and ECC groups. (C) Forest plot showing mean difference of the ASQ fine motor domain score at 4 months follow up between DCC and ECC groups. (D) Forest plot showing mean difference of the ASQ fine motor domain score at 12 months follow up between DCC and ECC groups.

Figure 4

(A) Forest plot showing mean difference of the Ages and Stages Questionnaire (ASQ) problem solving domain score at 4 months follow up between delayed cord clamping (DCC) and early cord clamping (ECC) groups. (B) Forest plot showing mean difference of the ASQ problem solving domain score at 12 months follow up between DCC and ECC groups. (C) Forest plot showing mean difference of the ASQ personal-social domain score at 4 months follow up between DCC and ECC groups. (D) Forest plot showing mean difference of the ASQ personal-social domain score at 12 months follow up between DCC and ECC groups.