Consensus on Science – Delayed Cord Clamping in Preterm Infants, including those receiving
resuscitation
Consensus on Science
For the critical outcomes of
• Infant death we identified moderate quality evidence from 11 RCTs enrolling 591 patients showing no benefit (OR 0.6, 95% CI
0.26,1.36) [Baenziger 2007/455, Hofmeyr 1988/104, Hofmeyr 1993/, Kinmond 1993/172, Kugelman 2007/307, McDonnell 1997/308,
Mercer 2003/466, Mercer 2006/1235, Oh 2011/S68, Rabe 2000/775, Strauss 2008/658]
• Severe IVH we identified moderate quality evidence from 5 RCTs enrolling 265 patients showing no benefit (OR 0.85, 95% CI 0.20,3.69)
[Hofmeyr 1988/104, Hofmeyr 1993/, Mercer 2003/466, Mercer 2006/1235]
• PVH/IVH we identified moderate quality evidence from 9 RCTs enrolling 499 patients showing benefit (OR 0.49, 95% CI 0.29, 0.82)
[Hofmeyr 1988/104, Hofmeyr 1993/, Kugelman 2007/307, McDonnell 1997/308, Mercer 2003/466, Mercer 2006/1235, Oh 2011/S68,
Rabe 2000/775, Strauss 2008/658]
• Cardiovascular stability
o Mean blood pressure at birth - we identified moderate quality evidence from 2 RCTs enrolling 97 patients showing benefit (MD
3.52, 95% CI 0.6, 6.45) [Kugelman 2007/307, Mercer 2003/466]
o Mean blood pressure at 4 hours after birth - we identified moderate quality evidence from 3RCTs enrolling 143 patients showing
benefit (MD 2.49, 95% CI 0.74, 4.24) [Baenziger 2007/455, Mercer 2003/466, Mercer 2006/1235]
o Blood volume - we identified low quality evidence from 2 RCTs enrolling 81 patients showing benefit (MD 8.25, 95% CI 4.39,
12.11) [Aladangady 2006/93, Strauss 2008/658]
o Transfusion – we identified moderate quality evidence from 7 RCTs enrolling 398 patients showing benefit (OR 0.44, 95% CI 0.26,
0.75) [Aladangady 2006/93, Kinmond 1993/172, Kugelman 2007/307, McDonnell 1997/308, Mercer 2006/1235, Rabe 2000/775,
Strauss 2008/658]
• Necrotizing enterocolitis we identified moderate quality evidence from 5 RCTs enrolling 241 patients showing benefit (OR 0.3, 95% CI
0.19, 0.8) [Kugelman 2007/307, Mercer 2003/466, Mercer 2006/1235, Oh 2011/S68, Rabe 2000/775]
• Temperature on admission we identified moderate quality evidence from 4 RCTs enrolling 208 patients showing no statistically
significant benefit (MD 0.1, 95% CI -0.04, 0.24) [Kugelman 2007/307, Mercer 2003/466, Mercer 2006/1235, Rabe 2000/775]
• We did not identify any evidence to address the critical outcome of long-term neurodevelopment.
For the important outcome of
• Hyperbilirubinemia
o Peak serum bilirubin (mmol/L) we identified moderate quality evidence from 6 RCTs enrolling 280 patients showing higher peak
bilirubin value (MD 16.15, 95% CI 6.13, 26.17) [Kugelman 2007/307, McDonnell 1997/308, Mercer 2003/466, Mercer 2006/1235,
Oh 2011/S68, Rabe 2000/658]
o Treated hyperbilirubinemia (phototherapy) we identified low quality evidence from 2 RCTs enrolling 143 patients showing no
statistically significant difference (RR 1.29, 95% CI 1.00, 1.67) [Rabe 2008/658, Strauss 2008/658]
Treatment Recommendation
We suggest delayed umbilical cord clamping over immediate cord clamping for preterm infants not receiving resuscitation after
birth.
(weak recommendation, moderate quality of evidence)
Grade 2B
There is insufficient evidence to recommend the approach to cord clamping for preterm infants who do receive resuscitation immediately after
birth.
Values and Preferences
Overall quality of evidence for the question was moderate. Despite drawing evidence from well-conducted randomized controlled trials,
the small sample size in most trials and the imprecision associated limited the quality of evidence for many outcomes. Although two larger
observational trials were considered, the effects were not sufficiently large or strong to influence the conclusions. The quality of evidence for
necrotizing enterocolitis and hyperbilirubinemia was limited by inconsistent definitions of the outcomes measured and inconsistent thresholds
for treatment with phototherapy across studies.
Balance of consequences favors delayed cord clamping, as desirable consequences probably outweigh undesirable consequences in most
settings. The results of randomized controlled trials and non-randomized observational studies with comparison groups were generally
consistent. However, small and sick infants who received immediate resuscitation were generally excluded from randomized controlled trials,
so data are very limited on this group at highest risk for physiologic instability, complications of prematurity, and mortality who may also
realize highest benefit or harm from the intervention.
Preference (Babies’ or Parents’) favors delayed clamping, which has received strong popular support through social media and internet
sites. The advantages of delayed cord clamping assume heightened importance in resource-limited settings where specialty care for preterm
neonates may be limited. Improving initial cardiovascular stability with maintenance of temperature and lower risk of morbidities such as
necrotizing enterocolitis and severe intracranial haemorrhage may offer significant survival advantages where neonatal intensive care is not
available. In areas where maternal anemia is prevalent and severe, iron supplementation limited, and a safe blood supply often unavailable,
the reduction in need for transfusion and improved blood volume at birth have increased significance and help eliminate disparities in health
care.
Acceptability to staff at delivery is high when delayed cord clamping is introduced in the context of a quality improvement process.
Delayed cord clamping requires increased coordination between obstetrical and neonatal providers. The intervention is dependent upon realtime assessment of conditions at delivery (intrapartum haemorrhage, need for neonatal resuscitation). The approach to infants whose
condition calls for immediate resuscitation (bradycardia or prolonged apnea) requires very different preparation from routine if ventilation is
to be provided with the umbilical cord intact. For this pragmatic reason, as well as uncertainty about the physiologic consequences,
insufficient information is currently available to make a general recommendation on umbilical cord clamping for all preterm infants.
Cost of delayed cord clamping is negligible and mainly related to the investment in changing behavior. Some reconfiguration of resuscitation
equipment is necessary if the initial steps of resuscitation or positive-pressure ventilation are provided with the umbilical cord intact. The
long-term savings through reduction of morbidities may more than outweigh the initial investment.
Knowledge Gaps
•
•
•
Results of ongoing large randomized controlled trials (UK, Australia)
Other specific systematic reviews:
o Comparison of delayed vs. immediate cord clamping among preterm infant who receive resuscitation with positive-pressure
ventilation at birth
o Comparison of delayed cord clamping and cord milking
Outcome data of high importance
o Need for resuscitative intervention at delivery
o Long-term neurodevelopment
o Hyperbilirubinemia among high-risk populations
Reviewer Final Comments
For preterm neonates, there is evidence of a benefit to delaying cord clamping for a minimum time ranging from 30 seconds to 3 minutes
following delivery. Although there was no clear difference between groups in the risk of death, severe IVH, temperature on admission, those
who experienced delayed clamping had higher blood pressures during stabilization, a lower incidence of necrotizing enterocolitis and
intracranial hemorrhage of all grades, as well as fewer blood transfusions. Their serum bilirubin peak was higher and there was a trend
toward greater use of phototherapy. There are limited data on the hazards or benefits of delayed cord clamping in the preterm infants who
required resuscitation and no trial reported the neurodevelopmental outcome at two or three years.
The benefits of delayed cord clamping outweigh the risks for both term and preterm infants who do not require resuscitation at birth.
Additional research should focus on understanding the physiology and outcomes of delayed cord clamping in the groups of infants who do
require immediate resuscitative intervention – asphyxiated term infants and preterm infants who fail to establish spontaneous respirations or
who have experienced asphyxial events prior to birth. Additional research should also build upon experimental animal physiology to explore
the optimal time for delay and better define the obstetrical and fetal contraindications to delayed cord clamping.
GRADE Grid
Problem
Criteria
Is there a problem
priority?
Benefits & harms of the options
What is the overall
certainty of this evidence?
Judgements
○ No
○ Probably no
○ Uncertain
○ Probably yes
x○ Yes
○ Varies
○ No included studies
○ Very low
X○ Low
x○ Moderate
○ High
○ Important
uncertainty or
variability
○ Possibly important
Is there important
uncertainty about how
much people value the
main outcomes?
Research evidence
uncertainty or
variability
○ Probably no
important uncertainty of
variability
x○ No important
uncertainty of variability
○ No known
undesirable
The overall certainty of evidence is limited by the
relatively small number of subjects, the heterogeneity
of patient populations, and the relatively long timespan
during which studies have been conducted (during
which time many practices in neonatology have
changed). Evidence on cardiovascular stability comes
from relatively few studies, but these studies show
consistent results. Evidence on intracranial
haemorrhage is more heterogenous and the number of
studies reporting the longer-term outcome of
necrotizing enterocolitis is small. Criteria for diagnosis
of necrotizing enterocolitis also varied considerably
among studies, and 3 of the 5 studies reported were
performed at the same center (Mercer 2003/466,
Mercer 2006/1235, Oh 2011/S68).
The main outcomes of death, long-term
neurodevelopmental outcome, and intracranial
haemorrhage are highly and universally valued.
Initial cardiovascular stability plays an important role in
the need for neonatal intensive care. Decreased need
for transfusion is desirable in any setting, but
especially valued in resource-limited environments
where a safe blood supply may not be available.
Additional considerations
Criteria
Are the desirable
anticipated effects large?
Are the undesirable
anticipated effects small?
Are the desirable effects
large relative to
undesirable effects?
Judgements
○ No
○ Probably no
x○ Uncertain
○ Probably yes
○ Yes
○ Varies
○ No
○ Probably no
○ Uncertain
○ Probably yes
x○ Yes
○ Varies
○ No
○ Probably no
○ Uncertain
○ Probably yes
x○ Yes
○ Varies
Research evidence
At present, the magnitude of observed effects
(benefits) is small to moderate.
Most studies have shown no significant difference in
temperature on admission to a newborn area between
infants with immediate or delayed cord clamping.
Although peak serum bilirubin levels trend higher
among infants with delayed cord clamping, these data
are strongly influenced by the high proportion of
preterm infants who receive phototherapy, regardless
of the timing of umbilical cord clamping.
The desirable effects occur in important outcomes
which influence survival and long-term quality of life
and thus are large compared to the potential
undesirable effects.
Additional considerations
Criteria
Resource use
Are the resources required
small?
Equity
Is the incremental cost
small relative to the net
benefits?
What would be the impact
on health inequities?
Judgements
○ No
○ Probably no
○ Uncertain
○ Probably yes
x○ Yes
○ Varies
○ No
○ Probably no
○ Uncertain
○ Probably yes
x○ Yes
○ Varies
○ Increased
○ Probably increased
○ Uncertain
○ Probably reduced
x○ Reduced
○ Varies
Research evidence
Additional considerations
Feasibility
Acceptability
Criteria
Is the option acceptable to
key stakeholders?
Is the option feasible to
implement?
Judgements
○ No
○ Probably no
○ Uncertain
x○ Probably yes
○ Yes
○ Varies
○ No
○ Probably no
○ Uncertain
○ Probably yes
x○ Yes
○ Varies
Research evidence
Additional considerations
Recommendation
Balance of
consequences
Undesirable consequences
clearly outweigh desirable
consequences in most
settings
Undesirable consequences
probably outweigh desirable
consequences in most
settings
The balance between desirable
and undesirable consequences
is closely balanced or uncertain
Desirable consequences
probably outweigh
undesirable consequences in
most settings
Desirable consequences
clearly outweigh undesirable
consequences in most
settings
○
○
○
x○
○
Type of recommendation
Recommendation
Justification
Subgroup considerations
Implementation
considerations
Monitoring and evaluation
Research possibilities
We recommend against offering this
option
We suggest not offering this
option
We suggest offering this
option
We recommend offering this
option
○
○
x○
○