Association of Umbilical Cord Management Strategies With Outcomes of Preterm Infants: A Systematic Review and Network Meta-analysis | Neonatology | JAMA Pediatrics | JAMA Network
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Figure 1.  Summary of Study Selection Process
Summary of Study Selection Process

RCT indicates randomized clinical trial.

Figure 2.  Network Plots for Mortality and Severe Intraventricular Hemorrhage Across Study Population and Subgroups
Network Plots for Mortality and Severe Intraventricular Hemorrhage Across Study Population and Subgroups

Each node indicates an umbilical cord management modality and is sized proportionally to the number of infants who received the modality. Each line connecting 2 nodes indicates a direct comparison between 2 modalities, and the thickness of each is proportional to the number of trials directly comparing the 2 modalities.

DCC indicates delayed umbilical cord clamping; ICC, immediate umbilical cord clamping; UCM, umbilical cord milking; UCM+DCC, combination of umbilical cord milking followed by delayed cord clamping.

Figure 3.  Treatment Effects on Outcomes of Predischarge Mortality, Intraventricular Hemorrhage, and Severe Intraventricular Hemorrhage (Preterm Infants <37 Weeks’ Gestation)
Treatment Effects on Outcomes of Predischarge Mortality, Intraventricular Hemorrhage, and Severe Intraventricular Hemorrhage (Preterm Infants <37 Weeks’ Gestation)

CrI indicates credible interval; DCC, delayed umbilical cord clamping; ICC, immediate umbilical cord clamping; NA, not available; OR, odds ratio; UCM, umbilical cord milking.

aActual values are 1.01 × 10−9 (1.21 × 10−29; 0.07).

bActual values are 3.6 × 10−11 (2.0 × 10−36; 0.11).

Figure 4.  Treatment Effects on Outcomes of Need for Packed Red Cell Transfusion, Late-Onset Sepsis, and Bronchopulmonary Dysplasia (Preterm Infants <37 Weeks’ Gestation)
Treatment Effects on Outcomes of Need for Packed Red Cell Transfusion, Late-Onset Sepsis, and Bronchopulmonary Dysplasia (Preterm Infants <37 Weeks’ Gestation)

CrI indicates credible interval; DCC, delayed umbilical cord clamping; ICC, immediate umbilical cord clamping; NA, not available; OR, odds ratio; UCM, umbilical cord milking.

aActual values are 2.4 × 10−9 (2.8 × 10−32; 0.10).

bActual values are 3.6 × 10−10 (7.1 × 10−28; 0.22).

Table.  Characteristics of Included Studies
Characteristics of Included Studies
Supplement.

eTable 1. Search Strategy

eTable 2. Transitivity Assumption and Effect Modifiers Across Included Studies

eTable 3. List of Excluded Studies

eFigure 1. Risk of Bias Assessment for Included Studies

eFigure 2. Network Plots for Primary and Secondary Outcomes: Preterm Infants <33 Weeks’ Gestation

eFigure 3. Network Plots for Primary and Pre-specified Secondary Outcomes: Preterm Infants <29 Weeks’ Gestation

eTable 4. Quality-of-Evidence Assessment by CINeMA: Primary and Secondary Outcomes (<37 Weeks’ , <33 Weeks’, <29 Weeks’ Gestation)

eFigure 4. Secondary Outcomes of Various Cord Management Strategies for Preterm Neonates <37 Weeks’ Gestation

eTable 5. Primary and Secondary Outcomes for Trials with Low Risk of Bias in Preterm Neonates <37 Weeks’ Gestation

eTable 6. Primary and Secondary Outcomes in Preterm Neonates <33 Weeks’ Gestation

eTable 7. Primary and Secondary Outcomes in Preterm Neonates <29 Weeks’ Gestation

eTable 8. Surface Under the Cumulative Ranking Curve (SUCRA) for Primary and Secondary Outcomes in Preterm Neonates <37 Weeks’, <33 Weeks’, <29 Weeks’ Gestation

eFigure 5. Ranking Probabilities for Primary and Secondary Outcomes in Preterm Neonates <37 Weeks’ Gestation

eTable 9. Meta-Regression on Covariate ‘Mode of Birth’ for Preterm Infants <37 Weeks’ Gestation for Outcomes of Mortality and Intraventricular Hemorrhage

eTable 10. Sensitivity Analysis Post Exclusion of UCM+DCC Trials for Selected Outcomes in Preterm Neonates <37 Weeks’, <33 Weeks’ Gestation

eTable 11. Heterogeneity of Network (Assessed by I-square and Tau-square)

eFigure 6. Funnel Plot for Assessment of Publication Bias

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Fogarty  M, Osborn  DA, Askie  L,  et al.  Delayed vs early umbilical cord clamping for preterm infants: a systematic review and meta-analysis.   Am J Obstet Gynecol. 2018;218(1):1-18. doi:10.1016/j.ajog.2017.10.231PubMedGoogle ScholarCrossref
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Rabe  H, Gyte  GM, Díaz-Rossello  JL, Duley  L.  Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.   Cochrane Database Syst Rev. 2019;9(9):CD003248. doi:10.1002/14651858.CD003248.pub4PubMedGoogle Scholar
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Balasubramanian  H, Ananthan  A, Jain  V, Rao  SC, Kabra  N.  Umbilical cord milking in preterm infants: a systematic review and meta-analysis.   Arch Dis Child Fetal Neonatal Ed. 2020;105(6):572-580. doi:10.1136/archdischild-2019-318627PubMedGoogle ScholarCrossref
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    Original Investigation
    March 8, 2021

    Association of Umbilical Cord Management Strategies With Outcomes of Preterm Infants: A Systematic Review and Network Meta-analysis

    Author Affiliations
    • 1Department of Neonatology, Hospital for Sick Children, Toronto, Ontario, Canada
    • 2Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
    • 3Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada
    • 4Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada
    JAMA Pediatr. 2021;175(4):e210102. doi:10.1001/jamapediatrics.2021.0102
    Key Points

    Question  Which umbilical cord management strategy is associated with reducing mortality and morbidities in preterm infants?

    Findings  In this network meta-analysis of 56 trials including 6852 preterm infants, compared with immediate umbilical cord clamping, delayed umbilical cord clamping was associated with lower odds of mortality and intraventricular hemorrhage, and umbilical cord milking was associated with lower odds of intraventricular hemorrhage. There was no significant difference between delayed umbilical cord clamping and umbilical cord milking for any outcome.

    Meaning  Delayed umbilical cord clamping should be the preferred strategy for preterm infants; however, larger trials directly comparing delayed umbilical cord clamping and umbilical cord milking are needed.

    Abstract

    Importance  It is unclear which umbilical cord management strategy is the best for preventing mortality and morbidities in preterm infants.

    Objective  To systematically review and conduct a network meta-analysis comparing 4 umbilical cord management strategies for preterm infants: immediate umbilical cord clamping (ICC), delayed umbilical cord clamping (DCC), umbilical cord milking (UCM), and UCM and DCC.

    Data Sources  PubMed, Embase, CINAHL, and Cochrane CENTRAL databases were searched from inception until September 11, 2020.

    Study Selection  Randomized clinical trials comparing different umbilical cord management strategies for preterm infants were included.

    Data Extraction and Synthesis  Data were extracted for bayesian random-effects meta-analysis to estimate the relative treatment effects (odds ratios [OR] and 95% credible intervals [CrI]) and surface under the cumulative ranking curve values.

    Main Outcomes and Measures  The primary outcome was predischarge mortality. The secondary outcomes were intraventricular hemorrhage, severe intraventricular hemorrhage, need for packed red blood cell transfusion, and other neonatal morbidities. Confidence in network meta-analysis software was used to assess the quality of evidence and grade outcomes.

    Results  Fifty-six studies enrolled 6852 preterm infants. Compared with ICC, DCC was associated with lower odds of mortality (22 trials, 3083 participants; 7.6% vs 5.0%; OR, 0.64; 95% CrI, 0.39-0.99), intraventricular hemorrhage (25 trials, 3316 participants; 17.8% vs 15.4%; OR, 0.73; 95% CrI, 0.54-0.97), and need for packed red blood cell transfusion (18 trials, 2904 participants; 46.9% vs 38.3%; OR, 0.48; 95% CrI, 0.32-0.66). Compared with ICC, UCM was associated with lower odds of intraventricular hemorrhage (10 trials, 645 participants; 22.5% vs 16.2%; OR, 0.58; 95% CrI, 0.38-0.84) and need for packed red blood cell transfusion (9 trials, 688 participants; 47.3% vs 32.3%; OR, 0.36; 95% CrI, 0.23-0.53), with no significant differences for other secondary outcomes. There was no significant difference between UCM and DCC for any outcome.

    Conclusions and Relevance  Compared with ICC, DCC was associated with the lower odds of mortality in preterm infants. Compared with ICC, DCC and UCM were associated with reductions in intraventricular hemorrhage and need for packed red cell transfusion. There was no significant difference between UCM and DCC for any outcome. Further studies directly comparing DCC and UCM are needed.

    Introduction

    Umbilical cord/placental transfusion refers to the transfer of blood to a baby from the time of birth to the time of umbilical cord clamping. The additional blood volume may be relevant for preterm infants because a larger amount of blood is sequestered in the placenta compared with term infants.1 Delayed umbilical cord clamping (DCC; ≥30 seconds) is endorsed for practice by several bodies for term and preterm infants.2,3 The exceptions for DCC in preterm infants include those who need immediate resuscitation after birth. For such circumstances, an alternative technique has been in practice, umbilical cord milking (UCM), which consists of gently grasping the umbilical cord and squeezing the cord from the placenta toward the infant 2 to 4 times. Three or 4 repetitions of milking the intact cord deliver approximately 14 mL/kg of blood,4 a volume similar to that delivered in a 2-minute DCC in term infants.5 However, data from preterm lambs identified fluctuations in carotid artery pressure and flow with UCM, which may place extremely preterm infants at risk of intraventricular hemorrhage.6 Conversely, none of the preterm lambs received antenatal steroids, and all were anesthetized and instrumented prior to delivery, which makes extrapolation to preterm human infants challenging. A few trials7-9 have evaluated the combination of UCM and DCC (UCM+DCC) in comparison with DCC or immediate umbilical cord clamping (ICC) and reported varying results. Therefore, the objective of our systematic review and network meta-analysis (NMA) was to evaluate the effectiveness and safety of various umbilical cord management strategies in preterm infants: DCC, UCM, UCM+DCC, and ICC.

    Methods

    This study complied with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analysis extension statement for reporting NMA of health care interventions.10 The protocol was registered in PROSPERO (CRD42019118241).11

    Inclusion Criteria

    Randomized clinical trials of preterm infants born at younger than 37 weeks’ gestation or low-birth-weight infants (<2500 g) who received DCC, UCM (intact or cut cord), UCM+DCC, or ICC (<30 seconds) were included. Quasirandomized trials were excluded. Only fully published articles (from 1988-2020) were included. Abstracts presented at conferences were read but not included unless full studies were published. Observational studies, narrative reviews, systematic reviews, case reports, letters, editorials, and commentaries were excluded but were read to identify potential studies.

    Interventions

    Immediate CC was defined as clamping the umbilical cord immediately (<30 seconds) after birth of the infant. Delayed CC was defined as clamping the umbilical cord at least 30 seconds after birth. Umbilical cord milking consisted of grasping the intact or cut umbilical cord and squeezing the cord from the placenta 2 to 4 times toward the infant. Finally, UCM+DCC was defined as squeezing the intact cord from the placenta toward the infant immediately after birth and then clamping the cord at least 30 seconds after birth.

    Outcomes

    The primary outcome was predischarge mortality. Secondary outcomes were intraventricular hemorrhage, severe intraventricular hemorrhage (grade 3 or 4),12 receipt of packed red blood cell transfusion, late-onset sepsis, bronchopulmonary dysplasia defined as oxygen use at 36 weeks’ postmenstrual age,13 necrotizing enterocolitis (≥stage II per modified Bell staging),14 retinopathy of prematurity requiring treatment, and neurodevelopmental impairment at approximately 2 years of corrected age.

    Information Sources and Search Methods

    The electronic databases PubMed, Embase, CINAHL, and Cochrane CENTRAL, and the Chinese Academic Journal database were searched from inception until September 11, 2020, without language restrictions. Trials were searched using the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. Unpublished and gray literature were searched through ProQuest, OpenGrey, and Google Scholar. Searches were conducted by an information specialist, and supplemental hand searches were conducted by the reviewers. The reference lists of eligible studies and review articles were searched. Attempts were made to contact the authors of published studies, abstracts, and ongoing trials for additional data on methods and results from any of the studies, but we received no responses. Only published data were used for those studies, where available. A detailed search strategy is provided in eTable 1 in the Supplement.

    Study Selection and Data Extraction

    Three authors (B.J., R.T., and S.S.) independently reviewed abstracts, selected trials, and extracted data. Disagreements were resolved through discussion or by involving a third reviewer (P.S.). Multiple publications of the same study were identified, and duplication of the data was avoided. Variables such as population, inclusion and exclusion criteria, intervention, control, and primary and secondary outcomes were recorded from each included study.

    Risk-of-Bias Assessment

    Three authors (B.J., R.T., and S.S.) independently used the Cochrane risk of bias tool15 to evaluate the quality of included trials across 7 domains (random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias). The possible judgments for these domains were “high risk,” “low risk,” or “unclear risk” of bias. Considering that blinding of participants and personnel is not feasible with these interventions, we excluded that domain before making a final judgment for each study as follows: “low risk,” if all domains were judged to be of low risk or when a maximum of 1 domain was judged “unclear risk”; “moderate risk,” if at least 2 domains were judged to be of unclear risk and no domains were judged “high risk”; and “high risk” if any domain was judged to be of high risk.

    Quality-of-Evidence Assessment

    Two review authors (B.J. and R.T.) used the Confidence in Network Meta-analysis (CINeMA) Web application (University of Bern) to judge the confidence in the NMA results considering 6 domains: within-study bias (judged according to majority risk of bias in included trials), indirectness (judged as low/moderate or high based on relevance of study to the research question), imprecision (by assessing credible interval), heterogeneity, and incoherence. Each domain was judged as having no concerns, some concerns, or major concerns. The latter would downgrade the level of evidence by 1 level. An overall confidence rating of either high, moderate, low, or very low confidence was given to each outcome comparison.16

    Data Synthesis and Analyses

    The available direct comparisons between the umbilical cord management strategies were presented using a network diagram. The node size represented number of patients and the line thickness represented number of trials for the respective comparison. For each outcome, NMA were conducted using a random-effects model with bayesian approach17 for the direct and indirect cord management strategies comparisons under the transitivity assumption. Transitivity was subjectively evaluated by comparing study population; assessing variability in intervention; and evaluating distribution of effect modifiers (gestational age at birth, timing of delayed cord clamping, mode of delivery, and location of trial) in included studies (eTable 2 in the Supplement). Because inclusion criteria for gestational age differed between included studies, we preplanned subgroup analyses for infants of fewer than 33 weeks’ gestation and fewer than 29 weeks’ gestation. Apart from gestational age, other modifiers were similarly distributed and did not violate the assumption of transitivity. Post hoc sensitivity analyses were conducted including only studies with low risk of bias. For comparisons of outcomes between strategies, group-based analyses were applied to estimate the management strategies’ effects, the odds ratios (ORs) of the outcomes, and the 95% credible intervals (95% CrIs). We also estimated the relative rankings of the umbilical cord management strategies for each outcome using the distribution of the ranking probabilities and used the surface under the cumulative ranking curve (SUCRA)18 to assess the overall rankings of the management strategies for each outcome. Heterogeneity was assessed using the I2 values for direct comparisons. Between-studies heterogeneity was evaluated using tau2 values for NMA. Incoherence was assessed by comparing direct and indirect estimates using the node-splitting method. When incoherence was identified, sensitivity analyses were conducted excluding the strategy for which incoherence was identified.

    Meta-regression

    Network meta-regression was conducted to examine the possible effect of the birth mode on the associations between the strategies and predischarge mortality and intraventricular hemorrhage. Publication bias was assessed by the comparison adjusted funnel plot using the Egger test.19 All analyses were performed in a bayesian framework using the GeMTC package in R, version 4.0.0 (The R Foundation).20

    Results
    Study Selection and Study Characteristics

    The process of identification and selection of studies is summarized in Figure 1. Fifty-six randomized clinical trials enrolling 6852 infants were included. The characteristics of the included studies are summarized in the Table.7-9,21-76 Eight studies were published in the Chinese language.28,47,50-52,74-76 Twenty-five studies were excluded after full review. Of these excluded studies, 10 studies were of mixed populations (term and preterm infants), 5 studies were nonrandomized clinical trials, and 10 studies had methods (inclusion criteria and population) not relevant to this review (eTable 3 in the Supplement).

    Summary of Included Studies

    Thirty-one studies21-52 compared DCC with ICC, of which 1 study reported neurodevelopmental outcomes.30 Among these studies, the duration of DCC ranged from at least 30 seconds to more than 180 seconds. Thirteen studies compared UCM with ICC,53-65 including 2 studies58,62 in which the umbilical cord was cut and 11 studies in which the cord was intact during UCM. The milking was done at or below the level of the placenta, depending on the mode of delivery. The distance of milking varied from 20 to 30 cm, and the umbilical cords were milked 2 to 4 times at rates of 5 to 10 cm/s in included studies. Five studies compared UCM with DCC,66-72 of which 2 studies reported long-term neurodevelopmental outcomes.68,71 Two studies compared UCM+DCC vs ICC,7,8 of which 1 study reported neurodevelopmental outcomes,8 and 1 study compared UCM+DCC vs DCC.9 Four studies were multiple-arm studies.73-76

    Risk of Bias Assessment

    The risk of bias assessment of included studies is shown in eFigure 1 in the Supplement. All included studies had high risk of bias in the domain of blinding of participants and personnel owing to the nature of the intervention (conducted on preterm infants). Twenty-two studies (39%) had overall low risk of bias.

    Network Plots

    The network plots for head-to-head comparisons between the different cord management strategies for primary and secondary outcomes are presented in Figure 2. The network plots for gestational age subgroups are presented in eFigures 2 and 3 in the Supplement.

    Primary Outcome

    A total of 42 trials including 5851 infants reported the primary outcome of predischarge mortality. The overall mortality was 6.2% (364 of 5851). Compared with ICC, DCC was associated with lower odds of mortality (22 trials, 3083 participants; 7.6% vs 5.0%; OR, 0.64; 95% CrI, 0.39-0.99; I2 = 0%; confidence rating: moderate) (Figure 3; eTable 4 in the Supplement). None of the other comparisons were associated with significant differences in mortality, including the comparison between UCM and DCC (Figure 3).

    Secondary Outcomes

    A total of 41 trials, including 5519 infants reported intraventricular hemorrhage, 29 trials including 4388 infants reported severe intraventricular hemorrhage, and 30 trials including 4319 infants reported need for packed red blood cell transfusion. Compared with ICC, DCC was associated with significantly lower odds of intraventricular hemorrhage (25 trials; 3316 participants; 17.8% vs 15.4%; OR, 0.73; 95% CrI, 0.54-0.97; I2 = 13%; confidence rating: high) and need for packed red blood cell transfusion (18 trials, 2904 participants; 37% vs 46%; OR, 0.48; 95% CrI, 0.32-0.66; I2 = 45%; confidence rating: high) (Figure 3 and Figure 4; eTable 4 and eFigure 4 in the Supplement). Compared with ICC, UCM was associated with significantly lower odds of intraventricular hemorrhage (10 trials, 645 participants; 22.5% vs 16.2%; OR, 0.58; 95% CrI, 0.38-0.84; I2 = 0%; confidence rating: high) and need for packed red blood cell transfusion (9 trials, 688 participants; 47.3% vs 32.3%; OR, 0.36; 95% CrI, 0.23-0.53; I2 = 0%; confidence rating: high) (Figures 3 and 4; eTable 4 and eFigure 4 in the Supplement). There were no significant differences among the different cord management strategies with regards to other prespecified secondary outcomes. There were no significant differences between UCM and DCC for any prespecified secondary outcomes (Figures 3 and 4; eTable 4 and eFigure 4 in the Supplement). Sensitivity analyses of only low risk of bias studies revealed that results of all outcomes did not differ (wider confidence interval) between strategies; however, the directions of effects were similar to those in the overall comparison (eTable 5 in the Supplement).

    Subgroup Analyses

    For preterm infants of less than 33 weeks’ gestation, compared with ICC, DCC was associated with significantly lower odds of mortality (12 trials, 2291 participants; 9.4% vs 5.8%; OR, 0.58; 95% CrI, 0.30-0.96; I2 = 22%; confidence rating: moderate) and need for packed red blood cell transfusion (10 trials, 2234 participants; 56.7% vs 45.9%; OR, 0.42; 95% CrI, 0.23-0.66; I2 = 74%; confidence rating: moderate). Similarly, compared with ICC, UCM was associated with significantly lower odds of intraventricular hemorrhage (7 trials, 433 participants; 24.5% vs 18.4%; OR, 0.64; 95% CrI, 0.38-0.96; confidence rating: moderate) and need for packed red blood cell transfusion (5 trials, 243 participants; 82.5% vs 61.7%; OR, 0.34; 95% CrI, 0.17-0.64; confidence rating: high) (eTables 4 and 6 in the Supplement).

    For preterm infants of less than 29 weeks’ gestation, compared with ICC, DCC was associated with significantly lower odds of severe intraventricular hemorrhage (1 trial, 37 participants; 20% vs 5.9%; OR, 0.18; 95% CrI, 0.03-0.99; confidence rating: moderate), and UCM was associated with significantly lower odds of need for packed red blood cell transfusion (2 trials, 115 participants; 88% vs 66%; OR, 0.17; 95% CrI, 0.03-0.91) (eTables 4 and 7 in the Supplement).

    Ranking Probability

    For the outcome of mortality, UCM+DCC had the highest probability of being the best umbilical cord management strategy in preterm infants, with a SUCRA value of 0.84; however, there was incoherence between direct and indirect comparison and imprecision in estimates (eTable 8 and eFigure 5 in the Supplement). The second-best strategy for mortality was DCC (SUCRA, 0.62); this result was statistically significant, coherent, and precise. For prespecified secondary outcomes, DCC was the best strategy for severe intraventricular hemorrhage (SUCRA, 0.64) and late-onset sepsis (SUCRA, 0.72), whereas UCM was the best strategy for intraventricular hemorrhage (SUCRA, 0.93), bronchopulmonary dysplasia (SUCRA, 0.71), retinopathy of prematurity requiring treatment (SUCRA, 0.93), and need for packed red blood cell transfusion (SUCRA 0.96) (eTable 8 and eFigure 5 in the Supplement). For primary outcome and prespecified secondary outcomes in subgroups, SUCRA values are shown in eTable 8 in the Supplement.

    Statistical Heterogeneity and Meta-regression

    Statistical heterogeneity in direct comparison was identified to be none or minimal (I2 values <50%), except for the outcomes of intraventricular hemorrhage (UCM+DCC vs ICC for <37 weeks’ gestation and DCC vs UCM for <33 weeks’ gestation): sepsis (DCC vs ICC for <37 weeks’ gestation and <33 weeks’ gestation), packed red blood cell transfusion (DCC vs ICC for <33 weeks’ gestation), necrotizing enterocolitis (DCC vs UCM for <33 weeks’ gestation), and bronchopulmonary dysplasia (DCC vs UCM for <29 weeks’ gestation). Network meta-regression analysis using the mode of birth as an independent variable revealed no significant effect of mode of birth on any outcome. However, compared with ICC, the point estimates for OR for mortality and intraventricular hemorrhage increased with increasing proportions of cesarean births. This implies potential differential effects of interventions based on mode of birth (eTable 9 in the Supplement), and further studies are warranted. Incoherence was infrequent when it was feasible to address. We identified incoherence in the domains of mortality and bronchopulmonary dysplasia for the comparisons between UCM+DCC vs ICC and UCM+DCC vs DCC. This was likely owing to small study effect, especially for the UCM+DCC group. Post hoc subgroup analyses excluding the UCM+DCC arm (owing to incoherence) revealed similar findings (eTable 10 in the Supplement). Between-studies heterogeneity assessment revealed no significant P values for tau2, except for the outcome of bronchopulmonary dysplasia (eTable 11 in the Supplement). There was no evidence of publication bias for the outcome of mortality (P = .77 via the Egger test; eFigure 6 in the Supplement).

    Quality-of-Evidence Assessment

    The quality-of-evidence assessments for primary and secondary outcomes are shown in eTable 4 in the Supplement. The confidence ratings assessed by CINeMA ranged from low to high confidence in the results of the NMA. The most common reasons for downgrading the evidence quality were within-study bias, heterogeneity, and imprecision of results.

    Discussion

    In this systematic review and NMA of 56 randomized clinical trials of umbilical cord management strategies for preterm infants, compared with ICC, DCC had lower odds of mortality. In addition, DCC+UCM had lower odds of intraventricular hemorrhage and need for packed red blood cell transfusion compared with ICC. There were no significant differences between any of the strategies for any other prespecified outcomes.

    Previous Systematic Reviews and Important Differences From Our Study

    Fogarty et al77 compared DCC with ICC in 2834 preterm infants enrolled in 18 randomized controlled trials.77 The infants allocated to DCC had significantly lower risk of all-cause mortality prior to discharge in the whole group and among infants of 28 weeks’ gestation or less (3 randomized controlled trials; 996 infants), with a reported high quality of evidence. The 2019 Cochrane review78 compared DCC with ICC in 3100 preterm infants enrolled in 25 randomized controlled trials and showed that infants in the DCC group had significant reductions in all-cause mortality and any grade intraventricular hemorrhage, with no reductions in any other neonatal morbidities.78 Both these reviews suggested DCC as the standard-of-care umbilical cord management strategy in vigorous preterm infants. Our NMA results are also suggestive of similar findings.

    Controversy exists regarding the applicability of DCC in nonvigorous preterm infants and those delivered via cesarean section, where it might be ineffective owing to the lack of tonic uterine contractions.21,67 Umbilical cord management has been suggested as an alternative to DCC. In a systematic review comparing UCM with DCC or ICC, Balasubramanian et al79 reported that, compared with DCC, UCM significantly increased the risk of severe intraventricular hemorrhage in preterm infants (4 randomized controlled trials; 718 infants; number needed to harm: 29; grade: low); but compared with ICC, UCM significantly reduced the need for packed red blood cell transfusion. The increase in rates of severe intraventricular hemorrhage stemmed from the results of the “premature infants receiving cord milking or DCC trial.”69 This multicenter noninferiority trial of UCM or DCC (474 neonates of <32 weeks’ gestation) was prematurely terminated because the first interim analysis revealed a significantly increased risk of severe intraventricular hemorrhage with UCM (22% vs 6%; P = .002) among infants born at 23 to 27 (+6 days) weeks’ gestation (182 neonates). This risk was not evident in the 27 to 31 (+6 days) weeks’ gestation subgroup or in the overall analysis of the 23 to 31 (+6 days) weeks’ gestation group, and there were no differences in mortality between the UCM and DCC groups. In our NMA, UCM was not associated with reduction in mortality; however, it was associated with reduction in intraventricular hemorrhage.

    None of the previous reviews cited here have compared the various umbilical cord management strategies simultaneously. There were no significant differences among all strategies with regards to severe intraventricular hemorrhage. This is in contrast to previous traditional meta-analyses. The reasons for this could include higher sample size in our NMA, the use of a random-effects rather than a fixed-effects model for the meta-analysis, and the exclusion of randomized infants delivered by vaginal delivery from the trial by Katheria et al67 in a previous meta-analysis.79 In subgroup analyses, infants who received DCC had significant reductions in mortality (<33 weeks’ gestation subgroup) or severe intraventricular hemorrhage (<29 weeks’ gestation subgroup). These findings may be supportive of DCC as a preferred strategy vs UCM; however, we did not identify any specific outcome differences between DCC and UCM in network comparison.

    This review has several strengths. In particular, the use of bayesian NMA enabled comparisons among currently used umbilical cord management strategies in preterm infants while increasing statistical power by taking advantage of indirect network pathways. This systematic review used robust methods guided by the Cochrane handbook15 and the CiNEMA approach for appraising quality of evidence.16 The bayesian statistical methods provided ranking probabilities and allowed comparison of all strategies simultaneously. The subgroup analysis assessed the robustness of the findings.

    Limitations

    Out study has a number of limitations. First, although this systematic review is, to our knowledge, the largest yet performed, the overall small sample sizes for most included studies (except 2 trials21,69), especially in infants of less than 29 weeks’ gestation, limit the generalizability of our findings to this fragile and high-risk population. Second, the direct comparisons between UCM and DCC had smaller sample sizes than the optimal information sizes. Third, there were some differences in the baseline characteristics of included trials: mainly in the domains of gestational age; birth weight; variation in the technique for UCM (location, distance, number, speed, and allowance of refill); and variation in the timing of DCC. This prompted us to use a random-effects instead of a fixed-effects model for the meta-analysis as well as to conduct prespecified subgroup analyses. Fourth, only 4 studies across 4 interventions out of a total 56 trials reported long-term neurodevelopmental outcomes, providing very limited evidence.

    Implications for Clinicians and Researchers

    Based on the best available evidence, this systematic review and NMA identified the cord management strategies of DCC and UCM are significantly better than ICC for preventing certain morbidities. Delayed umbilical cord clamping is associated with significantly reduced mortality. We have categorically identified the utility of these strategies (DCC and UCM) for reducing the need for packed red cell transfusion in preterm infants. We identified no differences in any of the outcomes between DCC and UCM; however, considering concerns over the safety of UCM for extremely preterm infants in one study,69 further well-designed, multicenter trials with adequate power comparing UCM and DCC are warranted. Until more evidence is available, DCC should be performed when it is feasible, and when it is not feasible owing to an immediate need for resuscitation, UCM may be considered as an alternative. The mortality advantage identified in this study for DCC could have significant implications worldwide, considering the simplicity of the intervention.

    Conclusions

    Compared with ICC, DCC was associated with the lower odds of mortality in preterm infants. Compared with ICC, DCC and UCM were associated with reductions in intraventricular hemorrhage and need for packed red cell transfusion. There was no significant difference between UCM and DCC for any outcome. Further studies directly comparing DCC and UCM are needed.

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    Article Information

    Corresponding Author: Prakesh S. Shah, MD, Department of Pediatrics, 19-231, Mount Sinai Hospital, 600 University Ave, Toronto, ON M5G 1X5, Canada (prakeshkumar.shah@sinaihealth.ca).

    Accepted for Publication: December 11, 2020.

    Published Online: March 8, 2021. doi:10.1001/jamapediatrics.2021.0102

    Author Contributions: Dr Shah had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: All authors.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: All authors.

    Critical revision of the manuscript for important intellectual content: Jasani, Torgalkar, Ye, Shah.

    Statistical analysis: Jasani, Torgalkar, Ye, Shah.

    Administrative, technical, or material support: Shah.

    Supervision: Jasani, Shah.

    Conflict of Interest Disclosures: Dr Shah holds an Applied Research Chair in Reproductive and Child Health Services and Policy Research from the Canadian Institutes of Health Research (CIHR). Dr Shah also has received funding from the CIHR for the Canadian Preterm Birth Network. No other disclosures were reported.

    Additional Contributions: We thank Heather McDonald Kinkaid, PhD, from the Maternal-infant Care Research Centre (MiCare) at Mount Sinai Hospital in Toronto, Ontario, Canada, for editorial assistance preparing this manuscript. Dr Kinkaid is an employee of our research center and is paid a salary from our global center fund. We thank Chris Walsh, BA, MA, MI, an Information Specialist at Mount Sinai Hospital, for his help in developing and executing the search strategy for this review. We thank Qi Zhou, MD, from Mount Sinai Hospital, Toronto, for her help in translating and evaluating studies published in the Chinese language. Mr Walsh and Dr Zhou did not receive any compensation for their roles.

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