Umbilical Cord Management at Term and Late Preterm Birth: A Meta-analysis

In this review, we followed methodology outlined in the Cochrane Handbook for Systematic Reviews of Interventions and adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines.^9,10  The protocol was registered prospectively with the International Prospective Register of Systematic Reviews (CRD42020155498). Methods are detailed in the Supplemental Information and summarized below.

We considered all randomized controlled trials (RCTs) comparing different policies and procedures regarding umbilical cord management in late preterm infants (34⁺⁰–36⁺⁶ weeks’ gestational age) and term infants (≥37⁺⁰ weeks’ gestational age). Multiple gestations were included.

Studies in which authors compare the following broad interventions were included (Supplemental Table 3):

1. early cord clamping (ECC), defined as clamping the umbilical cord <30 seconds after birth, without cord milking;

2. later or delayed cord clamping (DCC), defined as clamping the umbilical cord ≥30 seconds after birth or based on physiologic parameters (such as when cord pulsation has ceased or breathing has been initiated), without cord milking;

3. intact-cord milking (ICM) (also referred to as “intact-cord stripping”), defined as repeated compression of the cord from the placental side toward the infant with the connection to the placenta intact at any time point within the first few minutes after birth; and

4. cut-cord milking (CCM) (also referred to as “cut-cord stripping”), defined as drainage of the cord by compression from the cut end toward the infant after clamping and cutting a long segment.

The 8 specific comparisons of these various cord management techniques we attempted to assess are detailed in the Supplemental Information (Supplemental Table 3).

The review outcomes were selected in consultation with representatives from the World Health Organization (WHO) and ILCOR Neonatal Life Support Task Force. These outcomes were considered clinically relevant and therefore likely to influence clinical practice. Primary outcomes are survival without neurodisability, anemia in early infancy, and maternal PPH. Methods including outcome definitions, prespecified subgroup analyses, information sources, search strategy, study selection, data extraction, and evaluation of the risk of bias and certainty of evidence assessments are detailed in the Supplemental Information.

Overall, we identified 46 studies involving a total of 9159 women and their late preterm or term infants, of which 44 studies (including 8899 women and their late preterm or term infants) had data that could be included in the meta-analysis (Fig 1, Supplemental Information). In most studies, authors compared DCC ≥30 seconds with ECC (n = 33). In 7 studies, authors assessed different DCC times (≥60 vs <60 seconds); few or no studies were included in the remaining 6 prespecified comparisons (Fig 2).

Study and participant characteristics for included studies are outlined in Table 1 and Supplemental Table 4. The number of mother-infant pairs in the studies ranged from 30 (Backes et al¹¹ ) to 755 (Kc et al¹² ), with most (n = 32) performed in low- or middle-income countries.¹³  Thirty studies included only term infants and 2 studies included only late preterm infants (Salae et al¹⁴  and Ultee et al¹⁵ ). Most studies (n = 37) included singletons only.

The studies covered a variety of timings of cord clamping and positioning of the infant (Supplemental Table 4). Timing of DCC assessed in the included studies ranged between 30 and ≥120 seconds; most studies delayed by 30 to 45 seconds.

Overall, study-level risk of bias was mixed to high (Fig 3, Supplemental Table 5). Most studies had unclear allocation concealment, difficulties with adequate blinding of participants and personnel because of the nature of the intervention, and a high level of attrition. Most of the studies were also at high or unclear risk of selective reporting because of a lack of prospectively registered protocols and inadequate reporting. All outcomes selected for Grading of Recommendations Assessment, Development and Evaluations (GRADE) assessment were rated as very low or low-certainty evidence (Supplemental Tables 6–13). In addition to the design limitations outlined above, there was also considerable imprecision (usually because of low event rates for many outcomes and small numbers of studies per outcome). There was some inconsistency in findings between studies because of unclear or missing definitions of outcomes.

We identified 33 studies comparing DCC at ≥30 seconds to ECC in 5263 mothers and their late preterm or term infants (Supplemental Information).

The main outcomes are addressed in Table 2, with priority (GRADE-assessed) outcomes reported in the text below. All outcomes were assessed as very low certainty, except for PPH, which was low certainty.

Compared to ECC, it is uncertain whether DCC impacts on neonatal mortality (risk ratio [RR] 2.54 [95% confidence interval (CI) 0.50 to 12.74]; risk difference [RD] 0.01 [95% CI −0.01 to 0.03]; 4 studies, 537 infants), the need for resuscitation (RR 5.08 [95% CI 0.25 to 103.58]; RD 0.01 [95% CI −0.02 to 0.04]; 3 studies, 329 infants), or admission to the NICU (RR 1.16 [95% CI 0.69 to 1.95]; RD 0.00 [95% CI −0.01 to 0.02]; 10 studies, 1968 infants) (Fig 4). The use of phototherapy to treat hyperbilirubinemia was possibly higher for DCC ≥30 seconds compared to ECC (RR 1.28 [95% CI 0.90 to 1.82]; RD 0.01 [95% CI −0.00 to 0.03]; 15 studies, 2814 infants) perhaps more so in term infants (RR 1.54 [95% CI 1.01 to 2.34]; RD 0.01 [95% CI 0.00 to 0.03]; 13 studies, 2691 infants) (Fig 5). Hypoxic ischemic encephalopathy and respiratory support were not reported by any studies.

Compared to ECC, DCC ≥30 seconds may improve hematologic measures, including hemoglobin within 24 hours after birth (mean difference [MD] 1.17 g/dL [95% CI 0.48 to 1.86]; random effects; 9 studies, 1352 infants) (Fig 6) and 7 days after birth (MD 1.11 g/dL [95% CI 0.40 to 1.82]; random effects; 3 studies, 695 infants) as well as hematocrit concentrations at 24 hours after birth (MD 3.38% [95% CI 2.08 to 4.67]; random effects; 12 studies, 2183 infants) (Fig 7). There was little to no difference in the number of infants with anemia 4 to 6 months after birth (RR 1.01 [95% CI 0.75 to 1.37]; RD 0.00 [95% CI −0.04 to 0.04]; 4 studies, 937 infants).

In the included studies, none of the authors assessed our primary infant outcome of survival without moderate to severe neurodevelopmental impairment in early childhood (up to and including 4 years). One study did not reveal evidence of differences in neurodevelopment between DCC ≥30 seconds and ECC at 4 years, including Ages and Stages Questionnaire, Third Edition (ASQ-3) total scores (MD 3.40 points [95% CI −2.86 to 9.66]; 245 children).¹⁶ 

Compared to ECC, DCC ≥30 seconds may make little or no difference to maternal complications including PPH ≥500 mL (RR 0.89 [95% CI 0.70 to 1.13]; RD −0.01 [95% CI −0.03 to 0.01]; 10 studies, 2675 women). In no studies did authors report on maternal deaths (up to 1 year after delivery) or severe morbidity.

Other outcomes for this comparison are detailed in Supplemental Table 14.

We identified 1 study of 24 infants evaluating ICM compared to ECC.¹⁷ 

Few clinical outcomes were reported. No effect of ICM was seen on admission to the NICU or special care nursery (RR not estimable; RD 0.00 [95% CI −0.15 to 0.15]), clinical jaundice (RR 1.19 [95% CI 0.89 to 1.59]; RD 0.17 [95% CI −0.07 to 0.41]), or exchange transfusion (RR not estimable; RD 0.00 [95% CI −0.15 to 0.15]).

Compared to ECC, ICM may improve hematologic measures including hemoglobin concentrations (grams per deciliter) within the first 7 days after birth (MD 2.20 [95% CI 0.48 to 3.92]) and hematocrit (percentage) within the first 7 days after birth (MD 7.50 [95% CI 2.30 to 12.70]).

None of our priority maternal outcomes were reported for this comparison.

Other outcomes for this comparison are detailed in Supplemental Table 15.

We identified 1 study of 200 infants evaluating CCM compared to ECC in which authors reported on priority (GRADE-assessed) outcomes¹⁸  (Supplemental Table 3 in Supplemental Information).

No impact of CCM was seen on admission to the NICU or special care nursery (RR not estimable; RD 0.00 [95% CI −0.02 to 0.02]), neonatal mortality (RR 0.20 [95% CI 0.01 to 4.11]; RD −0.02 [95% CI −0.05 to 0.01]), or hyperbilirubinemia requiring phototherapy (RR not estimable; RD [0.00 95% CI −0.02 to 0.02]).

Compared to ECC, CCM may improve hematologic measures at 24 and 72 hours of life including hemoglobin concentrations (grams per deciliter) within the first 24 hours after birth (MD 1.60 [95% CI 0.96 to 2.24]), hematocrit (percentage) within the first 24 hours after birth (MD 4.30 [95% CI 2.36 to 6.24]), hemoglobin concentrations (grams per deciliter) within first 7 days after birth (MD 1.10 [95% CI 0.74 to 1.46]), and hematocrit (percentage) within the first 7 days after birth (MD 4.00 [95% CI 2.29 to 5.71]).

None of our priority maternal outcomes were reported for this comparison.

Other outcomes for this comparison are detailed in Supplemental Table 16.

We identified 1 study of 250 infants evaluating this comparison in which authors reported outcomes identified as critical or important.¹⁹ 

Other outcomes for this comparison are detailed in Supplemental Table 17.

We identified 3 studies of 740 infants evaluating DCC compared to CCM.^20–22 

Compared to CCM, DCC does not reveal differences in neonatal mortality (RR 1.00 [95% CI 0.09 to 10.90]; RD 0.00 [95% CI −0.02 to 0.02]; 1 study, 300 infants), admission to the NICU or special care nursery (RR 1.83 [95% CI 0.71 to 4.77]; RD 0.05 [95% CI −0.03 to 0.13]; 1 study, 200 infants), or phototherapy for the treatment of hyperbilirubinemia (RR 1.36 [95% CI 0.66 to 2.81]; RD 0.02 [95% CI −0.02 to 0.06]; 2 studies, 500 infants).

Lower hemoglobin and hematocrit values at 24 hours and 7 days of life were seen in infants receiving DCC compared to CCM, including hemoglobin concentrations (grams per deciliter) within the first 24 hours after birth (MD −0.56 [95% CI −0.92 to −0.21]; 2 studies, 500 infants), hematocrit (percentage) within the first 24 hours after birth (MD −1.60 [95% CI −3.11 to −0.09]; 2 studies, 500 infants), hemoglobin concentrations (grams per deciliter) within first 7 days after birth (MD −0.47 [95% CI −0.81 to −0.13]; 2 studies, 500 infants), and hematocrit (percentage) within first 7 days after birth (MD −1.11 [95% CI −2.12 to −0.09]; 2 studies, 500 infants).

None of our priority maternal outcomes were reported for this comparison.

Other outcomes for this comparison are detailed in Supplemental Table 18.

We identified no studies in which authors compared ICM to CCM.

We identified 7 studies including 2745 mothers and their infants for inclusion (Table 1). In 1 study, authors recruited only infants who required resuscitation.²³  Few clinically important measures were available for analysis.

Compared to DCC <60 seconds, DCC ≥ 60 seconds may make little or no difference to neonatal mortality (RR 0.10 [95% CI 0.01 to 1.98]; RD 0.01 [95% CI −0.01 to 0.03]; 1 trial, 231 infants), resuscitation (RR 0.40 [95% CI 0.08 to 1.90]; RD −0.10 [95% CI −0.26 to 0.06]; 1 trial, 60 infants), admission to the NICU (RR 0.73 [95% CI 0.40 to 1.35]; RD −0.04 [95% CI −0.12 to 0.04]; fixed effects; 2 studies, 291 infants), moderate to severe hypoxic ischemic encephalopathy (no events; 1 study, 60 infants), or respiratory support (RR 0.53 [95% CI 0.27 to 1.07]; RD −0.23 [95% CI −0.47 to 0.01]; 1 trial, 60 infants). The need for hyperbilirubinemia to be treated with phototherapy was possibly higher for DCC ≥60 seconds (RR 1.93 [95% CI 1.00 to 3.72]; RD 0.09 [95% CI −0.08 to 0.25]; random effects; 2 studies, 906 infants).

Compared to DCC <60 seconds, hemoglobin concentrations at 24 hours after birth were higher with clamping delayed ≥60 seconds (MD 1.30 g/dL [95% CI 0.14 to 2.46]; 1 trial, 60 infants). Hematocrit in the first 24 hours was not reported.

In a single study of 540 children, moderate to severe neurodevelopmental impairment in early childhood was reduced with later clamping, with generally better scores in the delayed ≥60 seconds group than in the <60 seconds group. Anemia and ferritin concentrations in infancy were not reported.

None of our priority maternal outcomes were reported for this comparison.

Other outcomes for this comparison can be found in Supplemental Table 19. No indication of differences between the groups was seen for the few outcomes reported.

We identified 3 studies involving 1113 mother-infant pairs in which authors evaluated this comparison.^24–26 

No differences between DCC based on timing versus physiologic parameters were seen in clinical outcomes, including neonatal mortality (RR 5.00 [95% CI 0.24 to 103.37]; RD 0.01 [95% CI −0.01 to 0.03]; 1 study, 338 infants), admission to the NICU (RR 2.58 [95% CI 0.04 to 163.65]; RD 0.02 [95% CI −0.04 to 0.09]; 2 studies, 878 infants), or hyperbilirubinemia requiring phototherapy (RR 0.88 [95% CI 0.53 to 1.44]; RD −0.01 [95% CI −0.05 to 0.03]; 3 studies, 932 infants).

DCC based on timing may be less effective than the physiologic approach on hematocrit (percentage) within the first 24 hours after birth (MD −1.40 [95% CI −2.79 to −0.01]; 1 study, 540 infants), hemoglobin concentrations (grams per deciliter) within the first 7 days after birth (MD −1.70 [95% CI −1.97 to −1.43]; 1 study, 338 infants), hematocrit (percentage) within the first 7 days after birth (MD −6.50 [95% CI −7.64 to −5.36]; 1 study, 338 infants).

None of our priority maternal outcomes were reported for this comparison.

Other outcomes for this comparison are detailed in Supplemental Table 20.

The subgroup analyses revealed no clear subgroup differences for any of the selected clinically important outcomes except for hematocrit (percentage) 24 hours after birth, which suggested a favorable effect for DCC ≥30 seconds compared to ECC that was greater in studies performed in high-income countries than in low- or middle-income countries (Supplemental Table 21).

We identified 46 studies comparing cord management interventions. In most (33), the authors compared DCC ≥30 seconds after birth to ECC (clamping <30 seconds after birth). In none of these studies did authors report our primary outcome of survival without moderate to severe neurodevelopmental impairment. Evidence was evaluated as either very low or low certainty.

No differences between DCC ≥30 seconds and ECC (33 studies) were seen in neonatal mortality, need for resuscitation or admission to NICU, although there was a possible increase in phototherapy treatment in the delayed group. Although hemoglobin and hematocrit concentrations were higher 24 hours and 7 days after birth in the delayed group, there was little or no difference seen in anemia at 4 to 6 months after birth. Although the 24-hour and 7-day results were statistically significant, these results are of uncertain clinical significance. Child neurodevelopment and maternal outcomes did not reveal clear differences between DCC ≥30 seconds and early clamping. For delayed clamping ≥60 vs <60 seconds (7 studies), no differences were apparent for neonatal mortality, need for resuscitation, or admission to neonatal intensive care, although (as above) there was a possible increase in the need for phototherapy to treat hyperbilirubinemia in the group delayed ≥60 seconds. Hemoglobin concentrations at birth were higher in the group delayed ≥60 seconds, and no studies reported later hematologic measures. In 1 study, authors reported better early childhood neurodevelopment scores in the group delayed ≥60 seconds compared to <60 seconds clamping.

The most recent Cochrane systematic review considering timing of umbilical cord clamping in term infants (McDonald et al²⁷ ) included 15 studies (involving 3911 women and infant pairs). McDonald et al²⁷  did not show differences in neonatal mortality or morbidity between later (generally at least 180 seconds) and early clamping (usually 15 seconds). They showed that hemoglobin concentration in infants at 24 hours after birth was higher in the later cord clamping group, and fewer infants in the ECC group received phototherapy to treat hyperbilirubinemia.²⁷  These findings are broadly consistent with those of our updated review, which now includes data from more than twice as many studies and participants.

The 2013 review included only term infants.²⁷  Our review includes “late preterm” as well as term infants. Although late preterm infants have a higher risk than term infants for admission to the NICU and poor developmental outcomes, they do not have the same degree of serious morbidities experienced by less mature preterm infants.²⁸  In general, care and outcomes, in the absence of additional risk factors for illness such as infection, congenital anomalies, or birth injury, tend to be more similar to term rather than to very preterm infants, prompting our grouping these categories together. The effects of cord management at birth for preterm infants before 34 weeks’ gestation²⁹  and all preterm infants³⁰  are considered in 2 separate systematic reviews.

Whereas McDonald et al²⁷  specified neonatal mortality as the primary infant outcome, in this review, we specified survival without evidence of moderate or severe neurodevelopmental impairment as the primary outcome, as per ILCOR consensus. The incorporation of data from new studies (through July 2019) and of studies including late preterm infants, however, has not provided additional evidence of the effect of cord management strategies on childhood neurodevelopmental outcomes. Perhaps reflecting logistic and financial challenges in long-term follow-up assessment of study cohorts, in only 1 study did authors report outcomes in early childhood for later clamping compared to early clamping (≥30 vs <30 seconds).³¹  In the study, the authors assessed neurodevelopment using parental responses to the ASQ-3. There were no between-group differences in the overall scores for the tested domains (communication, gross and fine motor, problem solving, personal-social) at 4 months, 12 months, and 4 years of age. The total number of tested children was small, with only 245 participants assessed up to 4 years (61% of randomly assigned children).

For the most commonly studied comparisons of delayed versus early clamping (≥30 vs <30 seconds) and later clamping at ≥60 vs <60 seconds, there is low-certainty evidence of improved hemoglobin and hematocrit status in the neonatal period and improved iron status in infancy without sufficient evidence of reducing iron deficiency anemia or improving survival and/or neurodevelopmental outcomes in early childhood. The increased rates of phototherapy-treated hyperbilirubinemia warrant attention when practicing DCC in term infants.

Currently, there is insufficient evidence for recommending cord milking and physiologic approaches to improve infant outcomes.

In this review, we identified low-certainty evidence that DCC ≥30 seconds versus ECC <30 seconds did not affect the risk of PPH (>500 mL) or the risk of severe PPH (>1000 mL), downgraded for risk of bias in the included studies and imprecision of the effect estimate. No studies reporting priority maternal outcomes were identified among those assessing clamping after ≥60 seconds versus <60 seconds or any of the other cord management strategies.

In no studies have authors evaluated the effects of different cord management strategies on maternal mortality or other severe morbidity.

Additional trials assessing cord management strategies in late preterm and term infants are warranted. These could be used to assess the various techniques used in practice, including cord milking, or delay >60 seconds, or a physiologic approach to cord clamping (typically defined as cessation of cord pulsation). Trials should be informed by prospectively registered protocols with core outcome sets to minimize protocol deviations. Longer-term follow-up, particularly for anemia during infancy and neurodevelopment, is required to inform policy and practice. Large-scale RCTs or population-based studies are needed because most outcomes occur infrequently. Effects of different cord clamping management strategies should be assessed and reported for important population subgroups including infants requiring resuscitation.

Strengths of this review include rigorous methods, such as using a prospectively registered protocol and comprehensive search strategy, 2 reviewers independently completing each step of the review process, and using GRADE to determine certainty of evidence.³²  The author team is a multidisciplinary collaboration of experts in systematic reviews, neonatology, and obstetrics from the ILCOR Neonatal Life Support Task Force, Cochrane Neonatal, and Cochrane Pregnancy and Childbirth.

The overall incompleteness and uncertainty of findings from available RCTs limits the applicability of this review. For many reported comparisons and outcomes, certainty of evidence was low or very low mainly because of risk of bias and imprecision and in some cases because of inconsistency; alternatively, no studies were available. In this review, pairwise comparisons were undertaken. We did not conduct analyses comparing all available comparisons simultaneously (network meta-analysis). Our subgroup analyses were limited by most studies not reporting outcomes separately by subgroup, indicating a possible role for individual participant data meta-analyses to address these questions.

Additionally, definitions for early and delayed clamping and milking varied across studies. Delayed clamping ranged from 30 seconds to >3 minutes, and early clamping ranged from within 5 seconds to within 30 seconds. Thus, in some instances, early and delayed clamping groups overlapped and may have received similar interventions.

Compared to ECC, DCC (at ≥30 seconds) and cord milking led to increased hemoglobin and hematocrit immediately after birth in infants ≥34 weeks’ gestational age. Longer-term benefits on anemia at 4 to 6 months or on neurodevelopmental status were not seen. The effects of later clamping or use of cord milking in term and late preterm infants on survival without neurodisability, anemia in early infancy, or maternal PPH (and most other outcomes reported) are uncertain, inhibiting the usefulness of currently available evidence for informing and influencing policy and practice.

We thank Carol Friesen (Cochrane Neonatal) for developing and conducting literature searches. We thank the following members of the ILCOR Scientific Advisory Committee and Neonatal Life Support Task Force for their input and assistance in developing the protocol and offering feedback on the review: Myra H. Wyckoff, MD, chair; Jonathan Wyllie, MBChB, BSC, vice chair; Khalid Aziz, MBBS, BA, MA, Med(IT); Maria Fernanda de Almeida, MD; Jorge W. Fabres, MD; Joe Fawke, MD; Ruth Guinsburg, MD, PhD; Shigeharu Hosono, MD, PhD; Tetsuya Isayama, MD, MSc, PhD; Vishal S. Kapadia, MD, MSCS; Han-Suk Kim, MD, PhD; Helen G. Liley, MBChB; Chris JD McKinlay, MBChB, PhD; Lindsay Mildenhall, MBChB; Jeffrey M. Perlman, MBChB; Yacov Rabi, MD; Charles C. Roehr, MD, PhD; Edgardo Szyld, MD, MSc; Daniele Trevisanuto, MD; Sithembiso Velaphi, MBChB, FC Ped, PhD; and Gary Weiner, MD.

ASQ-3

Ages and Stages Questionnaire, Third Edition

CCM

cut-cord milking

CI

confidence interval

DCC

delayed cord clamping

ECC

early cord clamping

GRADE

Grading of Recommendations Assessment, Development and Evaluations

ICM

intact-cord milking

ILCOR

International Liaison Committee on Resuscitation

MD

mean difference

PPH

postpartum hemorrhage

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT

randomized controlled trial

RD

risk difference

RR

risk ratio

WHO

World Health Organization