Peds 20200576
Peds 20200576
Peds 20200576
CONTEXT: The International Liaison Committee on Resuscitation prioritized scientific review of abstract
umbilical cord management strategies at preterm birth.
To determine the effects of umbilical cord management strategies (including timing
OBJECTIVE:
of cord clamping and cord milking) in preterm infants ,34 weeks’ gestation.
Cochrane Central Register of Controlled Trials, Medline, PubMed, Embase,
DATA SOURCES:
CINAHL, and trial registries were searched through July 2019 for randomized controlled trials
assessing timing of cord clamping and/or cord milking.
STUDY SELECTION: Two authors independently assessed trial eligibility, extracted data, appraised
risk of bias, and assessed evidence certainty (GRADE).
DATA EXTRACTION: We identified 42 randomized controlled trials (including 5772 infants)
investigating 4 different comparisons of cord management interventions.
RESULTS: Compared to early cord clamping, delayed cord clamping (DCC) and intact-cord
milking (ICM) may slightly improve survival; however, both are compatible with no effect
(DCC: risk ratio: 1.02, 95% confidence interval: 1.00 to 1.04, n = 2988 infants, moderate
certainty evidence; ICM: risk ratio: 1.02, 95% confidence interval: 0.98 to 1.06, n = 945
infants, moderate certainty evidence). DCC and ICM both probably improve hematologic
measures but may not affect major neonatal morbidities.
LIMITATIONS: For
many of the included comparisons and outcomes, certainty of evidence was low.
Our subgroup analyses were limited by few researchers reporting subgroup data.
CONCLUSIONS: DCC appears to be associated with some benefit for infants born ,34 weeks. Cord
milking needs further evidence to determine potential benefits or harms. The ideal cord
management strategy for preterm infants is still unknown, but early clamping may be harmful.
a
National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia; bCochrane Pregnancy and Childbirth Group, University of Liverpool, Liverpool,
United Kingdom; cAcademic Department of Paediatrics, Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom; dDepartamento de Neonatologia del Hospital de
Clínicas, Universidad de la Republica, Montevideo, Uruguay; eNottingham Clinical Trials Unit, University of Nottingham, Nottingham, United Kingdom; fDepartment of Pediatrics, University of
Alberta, Edmonton, Canada; gDepartment of Paediatrics, Universidade Federal de São Paulo, São Paulo, Brazil; hNewborn Research Centre, The Royal Women’s Hospital and The University of
Melbourne, Melbourne, Victoria, Australia; iDepartment of Pediatrics, The Robert Larner College of Medicine, The University of Vermont, Burlington, Vermont; and jDivision of Neonatology,
Department of Pediatrics, Medical University Graz, Graz, Austria
To cite: Seidler AL, Gyte GML, Rabe H, et al. Umbilical Cord Management for Newborns ,34 Weeks’ Gestation: A Meta-analysis. Pediatrics. 2021;147(3):e20200576
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Table 1. Prespecified subgroup Study and Participant risk of selection bias (62% low for
analyses, search strategy, study Characteristics of Included Studies random sequence generation, 71%
selection, data extraction, risk of bias Study characteristics and participant low for allocation concealment). All
evaluation, certainty of evidence characteristics for the included included studies were at high risk of
assessment, and data synthesis are studies are outlined for each performance bias, because it is
detailed in Appendix 1 in comparison in Tables 1a–1d in the difficult, if not impossible, to blind the
Supplemental Information. Supplemental Information and Tables clinicians managing the infant’s care.
2–5, respectively. Blinding of outcome assessment was
rated separately for delivery room
RESULTS All of the included studies were outcomes and outcomes assessed at
individual RCTs (unit of randomization a later stage. Although risk of bias
Literature Search and Study was either the mother or the infant). was high across all studies for
Selection Studies were undertaken in a range of delivery room outcomes (because of
Forty-two studies (reported in 102 countries (although most were high the nature of the intervention), it was
articles) including 5772 infants met income by World Bank country low for most studies (55%) for other
the inclusion criteria for the review, classifications22). Most studies excluded outcomes. Most studies were at low
of which 41 studies (including 5676 infants with complications such as major risk of attrition bias. There were some
infants) had data that could be malformations or congenital anomalies. concerns regarding selective outcome
included in the meta-analysis (Fig 1, reporting bias. Evidence profile tables
Appendix 3 in Supplemental Risk of Bias were collated for primary and key
Information: full list of included Risk of bias is summarized in Fig 2. secondary outcomes applying the
studies per comparison). The majority of studies were at low Grading of Recommendations
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TABLE 2 ILCOR Preterm Cord Management Comparison 1: DCC Versus ECC Participant Characteristics
Study Intervention (DCC) and Control (ECC) No. Infants Gestational Age (Mean 6 Birth Weight (Mean 6 Antenatal Steroid Cesarean
SD), wk SD), g Administration, Delivery,
% %
Aladangady et al51 DCC $30–90 s 23 NR NR NR 48
2006
ECC (immediate) 23 NR NR NR 39
Armanian et al52 DCC 30–45 s 32 31.9 6 1.58 1597 6 282 33 83
2017
ECC 5–10 s 31 31.0 6 2.09 1518 6 327 47 67
Backes et al532016 DCC 30–45 s 18 24.4 6 1.2 645 6 193 100 NR
ECC 5–10 s 22 24.6 6 1.1 634 6 160 100 NR
Baenziger et al54 DCC 60–90 s 15 30 3/7 6 2.3 1115 6 344 NR 73.3
2007
ECC ,20 s 24 29 5/7 6 2.4 1330 6 484 NR 66.7
Das et al55 2018 DCC 60 s 233 31.9 6 1.1 1540 6 374 89 42
ECC ,10 s 228 31.8 6 1.1 1550 6 336 86 38
Dipak et al56 2017 DCC 1.60 s 26 30.1 6 1.2 1316 6 163 NR 15.9
DCC 2.60 s 1 ergometrine 25 30.2 6 1.2 1298 6 178 NR 16
ECC ,10 s 27 29.9 6 1.4 1284 6 176 NR 14.8
Dong et al57 2016 DCC 45 s 46 NR NR NR NR
ECC ,10 s 44 NR NR NR NR
Duley et al58 2018 DCC .120 s 137 28.9a 1108 (880–1360)a 87 61
ECC ,20 s 139 29.2a 1180 (900–1418)a 94 67
Finn et al25 2019 DCC .60 s (with respiratory 14 28.0 (26.4–29.6)a 925 (630–1490)a NR NR
support if needed)
ECC ,20 s 12 28.5 (25.7–30.5)a 1080 (755–1613)a NR NR
59
Gokmen et al 2011 DCC 30–45 s 21 29.3 6 1.2 1360 6 413 95 NR
ECC 5–10 s 21 29.4 6 1.5 1323 6 358 86 NR
Hofmeyr et al60 1988 DCC .60 s 6 ergometrine 24 NR NR NR NR
ECC (immediate) 14 NR NR NR NR
Hofmeyr et al61 1993 DCC 60–120 s 40 31.9 6 0.33 (SE) 1761 6 65 (SE) NR 18
ECC (immediate) 46 32.1 6 0.36 (SE) 1734 6 75 (SE) NR 26
Kazemi et al27 2017 DCC 30–45 s 35 30.1 6 1.7 1261 6 213 NR 100
ECC ,10 s 35 29.8 6 1.8 1241 6 234 NR 100
Kinmond et al62 1993 DCC 30 s 17 30 (27–32)b 1500 (1010–2330)b NR 0
ECC (at attendant discretion) 19 30 (27–32)b 1600 (1070–2410)b NR 0
Kugelman et al63 DCC 30–45 s 30 32.0 6 2.5 1616 6 497 53 67
2007
ECC 5–10 s 35 31.9 6 2.5 1676 6 475 62 66
McDonnell et al64 DCC 30 s Total 30 (28–33)b 1350 (755–2290)b NR NR
1997 enrolled
ECC (immediate) 46 30 (26–33)b 1505 (865–2110)b NR NR
Mercer et al65 2003 DCC 30–45 s 16 28.0 6 2.0 1064 6 290 94 56
ECC 5–10 s 16 27.0 6 2.2 1005 6 260 94 37.5
Mercer et al66 2006 DCC 30–45 s 36 28.3 6 2.1 1175 6 346 42 43
ECC 5–10 s 36 28.2 6 2.4 1151 6 379 47 39
Oh et al67 2011 DCC 30–45 s 16 26.0 6 1.4 854 6 222 NR NR
ECC ,10 s 17 26.0 6 1.1 767 6 243 NR NR
Rabe et al68 2000 DCC 45 s 20 30.01 6 1.57 1185 6 394 NR 78.9
ECC 20 s 20 29.48 6 1.96 1080 6 340 NR 95
Rana et al69 2018 DCC 120 s 50 32.3 6 1.1 1818 6 282 NR 16
ECC ,30 s 50 32.4 6 1.0 1679 6 373 NR 18
Ruangkit et al31 2018 DCC 30–60 s 51 33.6 6 2.2 1895 6 431 NR 100
ECC 3–5 s 50 33.4 6 2.0 1916 6 402 NR 100
Tarnow-Mordi et al18 DCC $60 s 818 28 6 2 1018 6 281 NR 66.3
2017
ECC #10 s 816 28 6 2 1000 6 269 NR 65.1
NR, not reported.
a Median (interquartile range).
b Median (range).
reported on mothers’ views and 3.05), lower incidence of any blood immediately and within 20 seconds of
experiences.23,24 transfusion (RR: 0.83, 95% CI: 0.77 to birth, and in most studies (69%),
0.90), and a lower total number of clamping was immediately. For ICM,
Other outcomes are detailed in Table blood transfusions per infant (MD: the cord was milked between 2 and 4
7a in Supplemental Information. Few 20.63, 95% CI: 21.08 to 20.17) times, with most studies (54%)
differences were found except for during hospital course. reporting milking 3 times.
hematologic outcomes. Compared
with infants in the ECC group, infants Comparison 2: ICM Compared to ECC Compared to ECC, ICM may make no
in the DCC group had less inotropic We identified 13 studies comparing difference, slightly decrease, or
support for hypotension during the ICM to ECC (Table 3). Studies in slightly improve survival to discharge
first 24 hours of life (RR: 0.36, 95% comparison 2 included 1170 infants, (RR: 1.02, 95% CI: 0.98 to 1.06; I2 =
CI: 0.17 to 0.75), a higher and all were single center. Two 24%, 10 studies, 945 infants;
measurement of lowest mean arterial studies (18%) included only preterm certainty of evidence moderate) (Fig
blood pressure in the first 12 hours of births ,30 weeks. Timing of ECC 4). This translates into an RR of 0.77
life (MD: 1.79 mm Hg, 95% CI: 0.53 to ranged between clamping (95% CI: 0.49 to 1.23) for the inverse
TABLE 4 ILCOR Preterm Cord Management Comparison 3: CCM Versus ECC, Participant Characteristics
Study Intervention (CCM) and No. Gestational Age (Mean 6 SD) Birth Weight (Mean 6 SD) Antenatal Steroid Cesarean
Control (ECC) Infants Administration, % Delivery, %
Ram Mohan et al78 2018 CCM 33 30 33 (27–36)a 1400 (945–3750)a 53 NR
ECC 30 33 (29–36)a 1516 (760–2370)a 50 NR
NR, not reported.
a Median and interquartile range.
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TABLE 5 ILCOR Preterm Cord Management Comparison 4: DCC Versus ICM, Participant Characteristics
Study Intervention No. Gestational Age (Mean 6 Birth Weight (Mean 6 Antenatal Steroid Cesarean
Infants SD) SD) Administration, Delivery, %
%
Finn et al25 2019 DCC .60 s (with respiratory support if 14 28 (26.4–29.6)a 925 (630–1490)a NR NR
needed)
ICM 19 28.4 (25.7–29.6)a 930 (700–1545)a NR NR
Katheria et al 79
DCC 45–60 s 99 28 6 2 1132 6 392 75 100
2015
ICM 34 98 28 6 2 1255 6 413 69 100
Katheria et al26 DCC .60 s 238 28.4 6 2.5 NR 88 67
2019
ICM 34 236 28.4 6 2.4 NR 89 76
Krueger et al80 DCC 30 s 32 28.3 6 2.3 1087 6 406 NR NR
2015
ICM 34 35 28.5 6 2.4 1111 6 363 NR NR
Pratesi et al30 2018 DCC 180 s 20 27.1 6 1.3 955 6 211 92.8 42.8
ICM 34 20 26.7 6 1.7 960 6 305 91.6 54.1
Rabe et al11 2011 DCC 30 s 31 29.2 6 2.3 1263 6 428 77 58
ICM 34 27 29.5 6 2.7 1235 6 468 52 78
Shirk et al32 2019 DCC 60 s 104 32.0 (29.2–34.0)a 1579 6 576 NR 49
ICM 34 100 32.1 (29.5–34.0)a 1620 6 587 NR 54
NR, not reported.
a Median and interquartile range.
outcome of mortality (post hoc were higher for ICM compared to ECC were no researchers assessing
analysis, Table 6 in Supplemental within 24 hours after birth (peak sensory outcomes in later infancy.
Information). hemoglobin: MD: 1.18 g/dL, 95% CI:
The evidence is uncertain about
0.65 to 1.71; peak hematocrit: MD:
We found no clear difference for maternal complications, including
3.04%, 95% CI: 1.28 to 4.80).
severe IVH (RR: 0.72, 95% CI: 0.44 to severe postpartum hemorrhage
Evidence was uncertain for peak
1.19), chronic lung disease (RR: 1.02, $1000 mL or blood transfusion, and
hematocrit and hemoglobin within 7
95% CI: 0.63 to 1.65), and NEC (RR: there were no researchers assessing
days after birth.
0.80, 95% CI: 0.55 to 1.18), and there other maternal complications such as
was little or no difference for Limited data are available regarding postpartum hemorrhage $500 mL
hyperbilirubinemia treated by outcomes in later infancy. Certainty of (Table 7).
phototherapy (RR: 1.04, 95% CI: 0.94 evidence was very low for moderate
to severe neurodevelopmental Other outcomes are detailed in Table
to 1.16). 7b in Supplemental Information. In
impairment in early childhood (RR:
ICM probably improves hematologic 0.75, 95% CI: 0.21 to 2.71) and infants, few differences were found,
measures within 24 hours after birth. cerebral palsy in early childhood (RR: with the exception of less inotropic
Peak hemoglobin and hematocrit (%) 2.65, 95% CI: 0.88 to 7.97). There support for hypotension during the
first 24 hours of life (RR: 0.61, 0.44 to
0.84) and fewer infants receiving $1
blood transfusion (RR: 0.73, 95% CI:
0.56 to 0.94) in the ICM group.
decision.
b CI includes null effect, or clinically important outcome of 36 more survivals per 1000. Downgrade by 1 for imprecision. This is a borderline decision.
c Largest study (.50% wt) unblinded for outcome assessment. Severe IVH assessment can be subjective. Downgrade by 1 for risk of bias.
d CI includes clinically important increase and clinically important decrease. Downgrade by 1 for imprecision.
e CI includes clinically important decrease and no effect. Downgrade by 1 for imprecision.
f Substantial heterogeneity. Direction of effect the same across all studies. Downgrade by 1 for inconsistency.
g Only one 100-ppt single-center study impairs generalizability. Downgrade by 1 for indirectness.
h Unable to assess inconsistency (only 1 study). No downgrade.
i All studies unblinded for intervention and outcome assessment. Subjective outcome; may have been influenced by lack of blinding. Downgrade by 1 for risk of bias.
j Moderate heterogeneity. Downgrade by 1 for inconsistency.
k Unable to assess inconsistency (only 1 study). No downgrade.
l Very large CI and low event rates. Downgrade by 2 for imprecision.
m Some concerns due to lack of participant and personnel blinding. No downgrade for risk of bias because outcome unlikely to be influenced by this. This is a borderline decision.
n Only 1 study, large CI, low event rates. Downgrade by 2 for imprecision. (Borderline decision whether to downgrade by 1 or 2).
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FIGURE 3
Forest plot: comparison 1. DCC versus ECC (based on timing of delaying clamping); outcome: survival to discharge from hospital. df, degrees of freedom;
M-H, Mantel-Haenszel.
15.26), and NEC (RR: 0.50, 95% CI: Other outcomes are detailed in Table between 30 and 180 seconds, and
0.05 to 5.22). CCM may increase peak 7c in Supplemental Information. most studies (71%) reported delay of
hematocrit concentrations within 24 30 to 60 seconds. For ICM, the cord
hours after birth (MD: 3.34%, 95% Comparison 4: DCC Compared to ICM was milked between 3 and 4 times,
CI: 0.60 to 6.08). The authors of the We identified 7 studies including with most studies (71%) reporting
study did not report other 1073 infants comparing DCC to ICM. milking 4 times.
hematologic measures and did not The studies were published between
assess any of the included early 2011 and 2019, and most were single Compared to ICM, DCC may make no
childhood or maternal outcomes. center (71%). Timing of DCC ranged difference, slightly decrease, or
slightly improve survival to discharge delay in early childhood (RR: 14.06, studies with 5722 infants comparing
(RR: 0.99, 95% CI: 0.95 to 1.02; I2 = 95% CI: 0.83 to 237.84). Researchers cord management interventions.
14%; 5 studies, 1000 infants, of 1 study assessed legal blindness Compared to early clamping, delayed
certainty of evidence moderate) (Fig and reported no events, and no clamping may slightly improve infant
5, Table 9). This translates into an RR researchers assessed hearing deficits. survival but may make no difference
of 1.21 (95% CI: 0.76 to 1.94) for the (moderate quality evidence). We
No researchers reported the included
inverse outcome of mortality (post found moderate- to high-quality
maternal outcomes. Other outcomes
hoc analysis, Table 6 in Supplemental evidence that delayed clamping does
are detailed in Table 7d in
Information). not reduce or increase major neonatal
Supplemental Information. Few
differences were found between ICM morbidities, but it probably improves
There were no clear differences for key
and DCC. hematologic measures and may
neonatal morbidities of severe IVH (RR:
reduce the use of inotropes and blood
0.60, 95% CI: 0.32 to 1.12), chronic
Comparisons 5 to 8 transfusions in infants.
lung disease (RR: 0.91, 95% CI: 0.67 to
1.25), NEC (RR: 1.57, 95% CI: 0.83 to No studies were identified for any of
Compared to early clamping, intact
2.97), and hyperbilirubinemia treated these comparisons (DCC versus CCM,
milking may result in increased
phototherapy (RR: 1.05, 95% CI: 0.90 ICM versus CCM, DCC ,60 seconds
survival, slightly reduced survival, or
to 1.24). versus DCC $60 seconds, time-based
DCC versus physiologic DCC). make no difference. We found low to
There were also no clear differences moderate quality evidence indicating
between DCC and ICM for hematologic Subgroup Analyses no clear difference in major neonatal
measures within 24 hours (peak morbidities such as chronic lung
No patterns were identified in the
hemoglobin concentrations [g/dL]: MD: subgroup analyses (Table 8 in disease, IVH, and NEC. Intact milking
20.02, 95% CI: 20.56 to 0.53, peak Supplemental Information). The probably improves hematologic
hematocrit concentrations [%] MD: number of prespecified subgroup measures.
20.18, 95% CI: 21.90 to 1.54). No analyses was large, and P values were
study authors reported data on peak For the 1 study in which researchers
not adjusted for multiple
hemoglobin or peak hematocrit compared ECC to CCM, the evidence
comparisons. Researchers of only 2
concentration within 7 days after birth. was uncertain for infant survival and
studies reported data by subgroup,
major morbidities. CCM may increase
limiting the ability to perform
Limited data were available regarding peak hematocrit within 24 hours
subgroup analyses.
outcomes in later infancy. Certainty of after birth.
evidence was low for moderate to
severe neurodevelopmental DISCUSSION Compared to ICM, delayed clamping
impairment (RR: 0.22, 95% CI: 0.01 probably results in little to no
to 4.40), cerebral palsy in early Summary of Main Findings difference in survival, major neonatal
childhood (RR: 0.36, 95% CI: 0.01 to In this systematic review and meta- morbidities, and hematologic
8.65), and significant developmental analysis, we identified 42 eligible measures.
10 SEIDLER et al
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TABLE 7 Key Outcomes for Comparison 2: ICM Versus ECC
Outcomes No. Participants Certainty of the Evidence Relative Effect (95% CI) RD/MD (95% CI) I2, %
(Studies) Follow-up
Neonatal outcomes
Survival to discharge from hospital 945 (10 RCTs) ÅÅÅ⊝ Moderatea,b,c RR: 1.02 (0.98 to 1.06) RD: 0.02 (20.01 to 0.05) 24
Severe IVH: ultrasound diagnosis grades III, IV 889 (10 RCTs) ÅÅ⊝⊝ Lowd,e RR: 0.72 (0.44 to 1.19) RD: 20.02 (20.05 to 0.01) 0
CLD: oxygen at 36 wk PMA 685 (7 RCTs) ÅÅ⊝⊝ Lowf,g RR: 1.02 (0.63 to 1.65) RD: 20.02 (20.12 to 0.08) 60
NEC (Bell’s stage $II or any grade47; requiring surgery) 843 (9 RCTs) ÅÅÅ⊝ Moderatea,h RR: 0.80 (0.55 to 1.18) RD: (20.06 to 0.02) 0
Peak Hb concentrations within the first 24 h after birth 914 (10 RCTs) ÅÅÅ⊝ Moderatei,j Continuous outcome MD: 1.18 (0.65 to 1.71) 71
Peak Hct within the first 24 h after birth 774 (7 RCTs) ÅÅÅ⊝ Moderatei,j Continuous outcome MD: 3.04 (1.28 to 4.80) 69
Peak Hb concentrations within 7 d after birth 54 (1 RCT) ÅÅ⊝⊝ Lowa,k,l,m Continuous outcome MD: 0.60 (20.57 to 1.77) Not estimable
Peak Hct within 7 d after birth 54 (1 RCT) ÅÅ⊝⊝ Lowa,k,l,m Continuous outcome MD: 1.00 (22.32 to 4.32) Not estimable
Hyperbilirubinemia (treated by phototherapy) 480 (5 RCTs) ÅÅÅÅ Higha RR: 1.04 (0.94 to 1.16) RD: 0.03 (20.04 to 0.10) 10
is a borderline decision.
b Some inconsistency, but not sufficient to downgrade. I2 = 24%.
c Effect ranges from clinically important reduction to clinically important increase of survival. Downgrade by 1 for imprecision.
e Effect ranges from clinically important reduction to clinically important increase. Low events and low participants. Downgrade by 2 for imprecision.
d No downgrade despite concerns because of blinding of intervention and selective outcome reporting bias. Blinding less likely to affect this outcome. Biggest and majority of studies were blinded for outcome assessment. Selective outcome
reporting bias less likely to affect this estimate because this is a null result. This is a borderline decision.
f Effect ranges from clinically important reduction to clinically important increase. Downgrade by 1 for imprecision.
g Moderate heterogeneity downgrade by 1 for inconsistency.
h Wide CI and relatively low event rates. Downgrade by 1 for imprecision.
i No downgrade despite concerns due to blinding of intervention and selective outcome reporting bias. Blinding less likely to affect this outcome. This is a borderline decision.
j Substantial heterogeneity, all but one effect estimates point in the same direction. Downgrade by 1 for inconsistency.
k Unable to assess inconsistency (only 1 study). No downgrade.
l Only 1 small study, wide CI. Downgrade by 1 for imprecision.
m Only 1 single-center study impairs generalizability. Downgrade by 1 for indirectness.
n No downgrade despite concerns due to blinding of intervention and selective outcome reporting bias. Blinding less likely to affect this outcome. Selective outcome reporting bias less likely to affect this estimate because this is a null result. This
is a borderline decision.
o Unable to assess inconsistency (only 1 study). No downgrade.
p Only 1 small study, low event numbers, very wide CI. Downgrade by 2 for imprecision.
q Only 1 single-center study impairs generalizability. Downgrade by 1 for indirectness.
r Very wide CI, only 1 event. Downgrade by 2 for imprecision.
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s All studies unblinded for intervention and outcome assessment. Subjective outcome, may have been influenced by lack of blinding. Downgrade by 1 for risk of bias.
t No downgrade despite concerns due to blinding of intervention and selective outcome reporting bias. Blinding less likely to affect this outcome. Selective outcome reporting bias less likely to affect this estimate because this is a null result. This is
a borderline decision.
u Only 1 single-center study, this impairs generalizability. Downgrade by 1 for indirectness.
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TABLE 8 Key Outcomes for Comparison 3: CCM Versus ECC
Outcomes No. Participants Certainty of the Evidence Relative Effect (95% CI) RD/MD (95% CI) I2
(Studies) Follow-up
Neonatal outcomes
Survival to discharge from hospital 60 (1 RCT) Å⊝⊝⊝ Very lowa,b,c,d RR: 1.00 (0.94 to 1.07) RD: 0.00 (20.06 to 0.06) Not estimable
Severe IVH: ultrasound diagnosis grades III, IV 60 (1 RCT) Å⊝⊝⊝ Very lowa,c,d,e RR: 0.33 (0.01 to 7.87) RD: 20.03 (20.12 to 0.05) Not estimable
CLD: oxygen at 36 wk PMA 60 (1 RCT) Å⊝⊝⊝ Very lowf RR: 1.00 (0.07 to 15.26) RD: 0.00 (20.09 to 0.09) Not estimable
NEC (Bell’s stage $II or any grade47; requiring surgery) 60 (1 RCT) Å⊝⊝⊝ Very lowa,c,d,f RR: 0.50 (0.05 to 5.22) RD: 20.03 (20.14 to 0.08) Not estimable
Peak Hb concentrations within the first 24 h after birth 0 (0 studies) — — Not estimable Not estimable
Peak Hct within the first 24 h after birth 60 (1 RCT) ÅÅ⊝⊝ Lowa,c,d,g Continuous outcome MD: 3.34 (0.60 to 6.08) Not estimable
Peak Hb concentrations within 7 d after birth 0 (0 studies) — — Not estimable Not estimable
Peak Hct within 7 d after birth 0 (0 studies) — — Not estimable Not estimable
Hyperbilirubinemia (treated by phototherapy) 0 (0 studies) — Not estimable Not estimable Not estimable
Infant outcome
Moderate to severe neurodevelopmental impairment in early childhood 0 (0 studies) — Not estimable Not estimable Not estimable
Cerebral palsy in early childhood 0 (0 studies) — Not estimable Not estimable Not estimable
Significant mental developmental delay in early childhood 0 (0 studies) — Not estimable Not estimable Not estimable
Legal blindness in early childhood (,20/200 visual acuity) 0 (0 studies) — Not estimable Not estimable Not estimable
Hearing deficit in early childhood (aided or ,60 dB on audiometric testing) 0 (0 studies) — Not estimable Not estimable Not estimable
Maternal outcomes
PPH (clinically estimated blood loss of $500 mL) 0 (0 studies) — Not estimable Not estimable Not estimable
Maternal death or severe morbidity 0 (0 studies) — Not estimable Not estimable Not estimable
Severe PPH (blood loss $1000 mL) 0 (0 studies) — Not estimable Not estimable Not estimable
Use of therapeutic uterotonic agents 0 (0 studies) — Not estimable Not estimable Not estimable
Blood transfusion (maternal) 0 (0 studies) — Not estimable Not estimable Not estimable
SEIDLER et al
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TABLE 9 Key Outcomes for Comparison 4: DCC Versus ICM
Outcomes No. Participants Certainty of the Evidence Relative Effect (95% CI) Risk Difference/MD (95% I2, %
(Studies) (GRADE) CI)
Neonatal outcomes
Survival to discharge from hospital 1000 (5 RCTs) ÅÅÅ⊝ Moderatea,b RR: 0.99 (0.95 to 1.02) 20.01 (20.04 to 0.02) 14
Severe IVH: ultrasound diagnosis grades III, IV 761 (4 RCTs) ÅÅÅ⊝ Moderatec,d RR: 0.60 (0.32 to 1.12) 20.03 (20.06 to 0.00) 23
CLD: oxygen at 36 wk PMA 734 (4 RCTs) ÅÅÅ⊝ Moderatea,d RR: 0.91 (0.67 to 1.25) 20.02 (20.07 to 0.04) 0
NEC (Bell’s stage $II or any grade47; requiring surgery) 922 (5 RCTs) ÅÅÅ⊝ Moderatea,d RR: 1.57 (0.83 to 2.97) 0.02 (20.01 to 0.04) 0
Peak Hb concentrations within the first 24 h after birth 941 (6 RCTs) ÅÅÅ⊝ Moderatea,e Continuous outcome MD: 20.02 (20.56 to 0.53) 52
Peak Hct within the first 24 h after birth 841 (5 RCTs) ÅÅÅ⊝ Moderatea,f Continuous outcome MD: 20.18 (21.90 to 1.54) 51
Peak Hb concentrations within 7 d after birth 0 (0 studies) — — Not estimable Not estimable
Peak Hct within 7 d after birth 0 (0 studies) — — Not estimable Not estimable
Hyperbilirubinemia (treated by phototherapy) 236 (2 RCTs) ÅÅÅ⊝ Moderatea,g RR: 1.02 (0.92 to 1.13) 0.06 (20.10 to 0.22) 43
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FIGURE 5
Forest plot: comparison 4. DCC compared to ICM (based on timing of delaying clamping); outcome: survival to discharge from hospital. df, degrees of
freedom; M-H, Mantel-Haenszel.
Across all comparisons, many of the reduction in severe IVH. There was compared with term infants, they do
infants could not be classified into the insufficient evidence to derive not have the same serious morbidities
correct subgroup categories, and conclusions for cord milking. With experienced by less mature preterm
thus, meaningful subgroup our review, we add new information, infants.36 Therefore, 18 studies
differences are not possible to detect because we identified and included included in the Cochrane review were
with the current data. 11 additional recently published excluded from the current review,
trials.25–35 leading to a slightly smaller total
Agreement and Disagreement With number of infants (188 less), despite
Previous Research Although previous reviews included the 11 additional trials.
The latest comprehensive review in preterm infants born at less than 37
this area was a Cochrane review with weeks’ gestational age,4,8 our review Previous reviews included infant
searches conducted in November is limited to infants born at less than mortality as a primary outcome,
2017.8 Authors of that review found 34 weeks’. Although late preterm whereas in this review, we assess the
a reduction in infant death for infants have increased risk for inverse of mortality, survival, because
delayed compared to early clamping, admission to neonatal intensive care this is the standard ILCOR approach.
a slight reduction in any IVH, but no and poor developmental outcome This changes the relative effect
14 SEIDLER et al
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measures, as shown in our post hoc In this review, we find improved outcome at 2 years of age for children
sensitivity analysis comparing RRs for hematologic measures and reduced born ,32 weeks, but confirmation in
survival and mortality using the same use of inotropes for delayed clamping, larger studies is needed.
data (Table 6 in Supplemental and intact and cut milking compared
Information). The reason for this is to early clamping, in accordance with
that relative risk depends on the previous reviews.4,8,13 This supports Implications for Practice and
incidence of an event, which is higher the proposed mechanism of placental Research
for survival than mortality. Thus, the transfusion (ie, increased net transfer Cord management at preterm birth is
same absolute number of deaths can of blood from the placenta to the an active research field, evidenced by
translate into different relative risk infant) through delayed clamping or the number of additional studies
estimates for survival or mortality. milking.10,37 Our findings did not included in this review compared to
For instance, in comparison 1, in the suggest a difference between delayed previous reviews. The searches for
delayed clamping group, 1383 (93%) clamping and milking with respect to the latest Cochrane update were
infants survived and 107 (7%) died. hematologic measures. conducted in November 2017.8 In ,2
In the early clamping group, 1364 years (search to July 2019), we
Although authors of previous reviews
(91%) infants survived and 134 (9%) identified 11 new studies. Still, more
report differences in IVH rates for
died. This equals a 2% absolute evidence is being generated; a search
different cord management
difference for both survival (93% to in February 2019 identified an
strategies,8 we did not find evidence
91% = 2%) and mortality (9% to 7% additional 62 ongoing trials
for this in the current review. Animal
= 2%). However, because survival evaluating cord management
models have been used to
was more common than mortality, the strategies in preterm infants.40
demonstrate that during umbilical
relative risk indicates a small 2%
cord milking, there was an increase in Ultimately, we want to answer the
increase in survival (RR: 0.93/0.91 = carotid blood flow and pressure.26 In
1.02) but a much larger 20% relative question: “which cord management
addition, a recent trial comparing strategy is the best and for whom?”
risk reduction for mortality (RR: delayed clamping to milking was
0.07/0.09 = 0.80). With the current study, we take a step
stopped early in the subgroup of very toward answering this question by
preterm infants (,28 weeks’ looking at different comparisons
For comparison 1 (early versus
gestation), because of a higher analyzed in pairwise meta-analyses.
delayed clamping), the relative risk
incidence of severe IVH in the milking
for mortality (indicating a 20% Yet, there is insufficient evidence,
group.26 Thus, there may be different
reduction) is similar to that reported when using aggregate data, to derive
IVH risks related to cord management
in previous reviews (eg, 27% relative a definite answer, particularly when
strategies depending on gestational
risk reduction in the Cochrane assessing differences for key infant
age. Further evidence is required to
review).8 Although for previous subgroups. Once ongoing trials are
resolve this question. In addition, not
reviews, this finding was statistically completed, a network meta-analysis
all studies in the current review were
significant, in the current review, the will be possible, which allows
blinded for assessment of IVH, which
CI touches the line of no effect. This comparing and ranking of multiple
is problematic because ultrasound
may be due to different eligibility interventions simultaneously.41 For
diagnosis of IVH can be rater-
criteria for gestational age (as assessing differential treatment
dependent.38 Consequently, we
outlined above) or to the more-recent effects across subgroups, the use of
downgraded certainty of evidence for
studies included in the current individual participant data can
this outcome.
review. We did not find a difference in increase statistical power and reduce
survival between ICM and delayed Few researchers reported the risk of ecological bias.42 The
clamping (comparison 4). Point developmental outcomes in early individual participant data on Cord
estimates for survival with intact childhood, and the evidence was Management at Preterm Birth
milking compared to early clamping uncertain for all comparisons. One (iCOMP) Collaboration is collating
(comparison 2) are similar to point study published outcomes in early individual participant data from
estimates for delayed compared to childhood for early clamping ongoing and completed trials to
early clamping (comparison 1), but compared to delayed clamping perform network meta-analysis and
CIs are wider in comparison 2 (comparison 1) shortly after our subgroup analyses to resolve
because of fewer included studies. search date and was therefore not remaining questions.40 Investigators
This suggests that intact milking may included in the analysis.39 Authors of planning future trials in this area
be comparable to delayed clamping this study found that delayed should follow a prospective meta-
for the outcome of survival, but more clamping may reduce the risk of analysis framework in collaboration
evidence is needed to confirm this. death or adverse neurodevelopmental with the iCOMP Collaboration to
Ms Seidler conceptualized the protocol, designed the data collection forms, selected studies for inclusion, extracted data, assessed risk of bias and certainty of
evidence, conducted the analyses, drafted the initial manuscript, and reviewed and revised the manuscript; Ms Gyte conceptualized the protocol, designed the data
collection forms, selected studies for inclusion, extracted data, assessed risk of bias and certainty of evidence, conducted the analyses and reviewed the
manuscript; Ms Ovelman assisted with protocol development and study selection, checked data extractions, risk of bias assessments, conducted subgroup analyses
and reviewed and prepared the manuscript; Dr Soll conceptualized the protocol, supervised study selection, data extraction, risk of bias and certainty of evidence
assessments, and data analyses, and drafted, reviewed and revised the manuscript; Drs Rabe, Díaz-Rossello, Duley, Aziz, Testoni Costa-Nobre, Davis, Schmölzer, and
Askie conceptualized the protocol and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as
submitted and agree to be accountable for all aspects of the work.
This protocol has been registered with the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/prospero/) (identifier
CRD42019155475).
DOI: https://doi.org/10.1542/peds.2020-0576
16 SEIDLER et al
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by guest
Accepted for publication Aug 25, 2020
Address correspondence to Anna Lene Seidler, MSc, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Locked Bag 77,
Camperdown, NSW 1450, Australia. E-mail: lene.seidler@ctc.usyd.edu.au
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2021 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The following authors received payment from the American Heart Association, on behalf of the International Liaison Committee on
Resuscitation to complete this systematic review: Ms Gyte, Prof Rabe, and Drs Díaz-Rossello and Duley received honorariums as expert systematic reviewers for the
Knowledge Synthesis Unit; Ms Seidler received payment as research associate with the Knowledge Synthesis Unit; Ms Ovelman and Dr Soll are employees of the
Vermont Oxford Network; the other authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Funded by the American Heart Association, on behalf of the International Liaison Committee on Resuscitation for article submission to the editor. This
review has also been supported in part by the Vermont Oxford Network. Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: Ms Seidler is the chair of the individual participant data on Cord Management at Preterm Birth (iCOMP) Collaboration, a meta-
analysis on cord clamping management using individual participant data. Dr Duley was chief investigator for the Cord Pilot Trial, collaborator for Australian
Placental Transfusion Study, and a member of the secretariat for individual participant data on Cord Management at Preterm Birth. She was awarded a National
Institute for Health Research grant for applied research for a program of work on care at very preterm birth, which included the Cord Pilot Trial. Ms Gyte was an
investigator for the Cord Pilot Trial. Prof Rabe is the main author for 2 included studies in this review. In the event that an author of this review was also an author
on an included study, that author did not assess eligibility, extract data, or assess risk of bias for the study on which he or she was an author. Dr Soll and Ms
Ovelman work in the editorial office for Cochrane Neonatal, which received a contract from the American Heart Association as a Knowledge Synthesis Unit to
undertake this systematic review for International Liaison Committee on Resuscitation. Dr Soll was a collaborator for the Australian Placental Transfusion Study;
the other authors have indicated they have no potential conflicts of interest to disclose.
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