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2/4/2016
1
An old idea revisited
DELAYED CORD CLAMPING
Another thing very injurious to the
child is the tying and cutting of the
naval string too soon, which should
always be left till the child has not
only repeatedly breathed but till all
pulsation in the cord ceases. As
otherwise the child is much weaker
than it ought to be, a part of the
blood being left in the placenta
which ought to have been in the
child and at the same time the
placenta does not so naturally
collapse and withdraw itself from the
sides of the uterus, and is not
therefore removed with so much
safety and certainty.
211 YEARS AGO………………
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During my time at the Maternité in Paris, my chief…..recommended me not to tie and not to cut the umbilical cord as soon as the child
was born. When one hurries too much in performing this operation…one finds the placenta full of blood, and one risks….
depriving the child of a certain quantity of blood, which….would have returned to his
circulatory system.
Pierre Budin 1875
“A Quel Moment Doit-On Pratiquer La Ligature du Cordon Ombilical”
137 YEARS AGO…………………
• “Early” clamping was about 1 minute
after birth
• “Late” clamping was after 5 minutes
EARLY 1900S
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Two veterinarians at a race track in England in 1959
• Foals delivered in captivity had immediate cord clamping and often developed cough and fatal respiratory distress after birth with pulmonary hyaline membranes noted on autopsy—similar to RDS.
• These foals had high amounts of residual blood volume in placenta.
• Wild-born foals had no cord clamping and low residual placental blood and did not develop fatal respiratory distress with hyaline membranes.
• Bound et al (1962), Usher et al (1975) linked placental transfusion to incidence and severity of RDS, Linderkamp (1978) RBC mass lower in those w/RDS
• Considerable research in 1960s and 70s into delayed cord clamping showed increased blood volume by about 10 to 15%, lower residual placenta blood volumes, and higher RBC masses by 20 to 60%.
BARKER FOAL SYNDROME
• The flow of blood from the placenta to the baby after birth
• Influenced by
Intrauterine asphyxia (causes antenatal placental transfusion)
Onset of respirations prior to clamping umbilical cord
Boston City Hospital Study (1965, Lancet)
Diabetic mothers (1965, Lancet), Edinburgh (1973)
and for C-sections in Honolulu (1977)
Timing of clamping of cord—50 to 60% of transfusion in 1st min
Gravity/Position of baby—lower increases amount of transfusionbut infants held above mother can still receive positive flow
Uterine contractions—increase venous pressure in placental circuit
PLACENTAL TRANSFUSION
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Post Partum Hemorrhage
Botha (1968) found that unclamped cord allowed placenta to drain
Decreased duration of 3rd stage of labor from 10.5±4 min in ECC to
3.5±2 min when cord is left unclamped
Decreased maternal blood loss from 236±135 ml to 100±83 ml
Magnitude of post-delivery placenta-maternal hemorrhage decreased by
leaving cord unclamped but not by delaying clamping (Dunn, 1966).
Nevertheless, “active management” of third stage of labor necessitates early
cord clamping and is used to decrease post partum hemorrhage.
MATERNAL EFFECTS OF TIMING
OF CORD CLAMING
Early cord clamping soon after delivery due to ……
• Fear of polycythemia and significant
hyperbilirubinemia
• Presence of resuscitation team awaiting infant
• Need to obtain cord blood gases
• Desire for Skin-to-skin contact and early breast
feeding
• Promote active management of 3rd stage of labor to
decrease post partum hemorrhages
CURRENT PRACTICE
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• Hutton and Hassan (2007) JAMA Meta-analysis of 15 controlled trials
totalling 1912 term newborns (ICC v DCC at 2 min)
• Signficant differences in:
HCT at 24 to 48 hr and at 5 days (Figure 1)
Blood viscosity (figure 2) and polycythemia (Fig 7)
Improved mean ferritin concentrations at 2 to 3 mo (Fig 4)
Less Anemia at 2 to 3 mo (Fig 5)
• No differences in mean Hgb at 2-3mo (Fig 1 bottom), mean bilirubin (Fig
3), clinical jaundice or need for phototherapy (Fig 6), or resp distress (Fig
8)
LATE VS EARLY CLAMPING OF THE UMBILICAL CORD FOR TERM
INFANTS
• 400 Term infants born after low risk pregnancy (no cigs, no DM, no drugs, etc)
• Randomized to DCC at 180 sec or ICC at < 10 sec
• At 4 mo post partum:
No difference is Hgb concentrations
45% higher ferritin in DCC group ( P < 0.001)
ECC had significantly more iron deficiency (5.7% v 0.6%, P 0.01)
ECC had significantly lower total body iron (P < 0.001)
Iron indices significantly better in DCC group (iron concentration,
transferrin levels, transferrin receptors, transferrin saturation)
• No difference in mean bilirubin levels, bilirubin > 15 mg/dL, or phototherapy
BMJ 2011: EFFECT OF DELAYED VS EARLY UMBILICAL CORD CLAMPING ON
NEONATAL OUTCOMES AND IRON STATUS AT 4 MONTHS: A RANDOMIZED
CONTROLLED TRIAL
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After initial interest in 1960s to 1970s as a way to ameliorate RDS research
tapered off for about 15 to 20 years
1990s to early 2000s—multiple small studies examining DCC
Led to Cochrane review in 2004
7 studies included (297 infants < 37 wk) and 9 studies excluded
Actual gestational ages 24 to 33 wk
Inconsistent interventions, controls, variation in outcomes measured
Cord clamp time 30 to 120 seconds
DELAYED CORD CLAMPING IN PREMATURE INFANTS
• Transfusions for anemia: Higher among infants with ICC
29/55 in ICC vs 14/55 in DCC RR 2.01 95% CI 1.24 to 3.27
• Transfusions for low BP: Fewer in infants with DCC
2 trials with 58 total infants, RR 2.58 95% CI 1.17 to 5.67
• IVH: DCC had a protective effect for overall risk for IVH
5 trials with 225 infants, RR 1.74 95% CI 1.08 to 2.81
Caveat to this is that S African studies had high rates of IVH
• Severe IVH: too little data
• Peak Bili: higher in DCC infants (WMD 1.26 mg/dL) 95% CI 2.22-0.29)
• Treatment for jaundice: too little data for conclusions
• Exchange transfusions: not reported
• Hematocrit at 1 and 4 hours: no differences.
2004 COCHRANE REVIEW RESULTS
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• DCC in Very Preterm Infants Reduces the Incidence of IVH and Late
Onset Sepsis: A Randomized, Controlled Trial at Univ. Rhode Island
• Goal was to examine DCC with primary outcomes of BPD and NEC
• Secondary outcomes: LOS, IVH, ROP < 32 wk
• Method: RCC, unmasked, < 32 wk, DCC at 30 to 45 sec vs ICC
• 72 Babies
2006 MERCER, OH, ET AL PEDIATRICS
ICC (n=36) DCC (n=36) P value OR 95%CI
All IVH 13 (36%) 5 (14%) 0.03 3.5 1.1-11
Grade I 4 (11%) 3 (8%)
Grade II 8 (22%) 2 (6%)
Grade III 0 0
Grade IV 1(3%) 0
LOS 8 (22%) 1 (3%) 0.03
MERCER, OH, ET AL 2006 RESULTS
Mean time to clamping was shorter in those with IVH (13 v 22 sec, p = 0.03)
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ICC
Boys (n=19)
ICC
Girls (n=18)
DCC
Boys(n=23)
DCC
Girls (n=13)
All IVH 8 (42%) 5 (29%) 2 (9%) 3 (23%)
Sepsis 6 (32%) 2 (12%) 0 1 (8%)
NEC 3 (16%) 1 (6%) 0 2 (15)
PROTECTIVE EFFECT WAS IN BOYS
Differences for boys between DCC and ICC were significant (p<0.05) by Fisher’s
Exact test
IVH prophylaxis, gest age distribuion was similar between DCC and ICC
Analysis based on Intent to Treat and one boy in DCC w/IVH actually had ICC
• Obj: compare infant blood volume after ICC v DCC of 30 to 90 sec
• Hold infant as low as possible and administer oxytocin
• Resuscitation commenced with infant attached to cord
• 46 infants 24 to 32 6/7 wk
23 in DCC, 23 ICC
Delivered by CS: 11/23 in DCC, 9/23 in ICC
• Measure blood volume
In those needing transfusion, measure dilution of fetal by adult Hgb
Those not needing transfusion, infuse biotin labeled autologous RBC
PREMIE BLOOD VOLUME WITH DCC V
ICC (ALADANGADY, ET AL 2006)
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Mean BV for DCC deliveries: 74.4 ml/kg (range 45 to 103 ml/kg)
Mean BV for ICC deliveries: 62.7 ml/kg (range 47 to 77 ml/kg) p < 0.001
Vaginal DCC delivery estimated BV: 80.5 ml/kg
Vaginal ICC delivery estimated BV: 61.3 ml/kg p < 0.001
C Section DCC estimated BV: mean 70.4 ml/kg (range 45 to 83 ml/kg)
C Section ICC esteimated BV: mean 64 ml/kg (range 48 to 77ml/kg) p =0.1*but 3 infants in the C-section DCC group actually underwent ICC due to short cords. Excluding them produced statistical significance (DCC 72.8 ml/kg, ICC 63.6 ml/kg p = 0.01 95% CI 2 to 16.4)
Mean HCt for DCC = 0.53, Mean for ICC = 0.49 p = 0.1.
Clinical Outcomes were not recorded other than “no complications”
ALADANGADY RESULTS 2006
BLOOD VOLUME AS A FUNCTION
OF TIME TO CORD CLAMPING
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Authors report that their findings were similar to those of others:
Yao 1969----Term infants using I125-labeled serum albumin DCC at ≥1 min
83.7±2.7 versus ICC 70.3±2.3 ml/kg
Saigal (1972) preterm infants 28 to 36 wk ICC 79.7 ml/kg v 89.6 ml/kg with 1
min DCC
Albumin method can overestimate due to leakage of albumin from vessels in
sick patients.
BLOOD VOLUME DISCUSSION
• 2007 Baenziger et al. The Influence of the Timing of Cord Clamping on
Postnatal Cerebral Oxygenation in Preterm Neonates: A Randomized
Controlled Trial
• 39 infants mean GA of 30.4 wk. 15 underwent DCC, 24 ICC.
Subset of patients from larger RCT on DCC so uneven randomization
• ICC v DCC at 60 to 90 sec with infant 15 cm below placenta, oxytocin
infusion.
• At 4 and 24 hr, use NIRS to measure cerebral Hgb, Cerebral BV, regional
tissue oxygenation
CEREBRAL OXYGENATION AND
DCC
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HR lower in DCC group at 4, 24, 72 hr, and 36 wk GA (but not statistically significant)
4 hr BP higher in DCC group (38.9 SD 9.34 v 33.56 SD 6.53) p< 0.05
24hr, 72 hr, 36 wk BP not statistically different
HCT significantly higher at 4 hr, 24h, 72 hr, but not 36 wk.
4 hr: 55.56 v 50.2*
24 hr: 55.93 v 49.7*
72 hr: 55.17 v 48.14*
36 wk: 31.9 v 31.7
Mean regional tissue oxygenation was higher in DCC group
4 hr: 69.9% v 65.5%
24 hr: 71.5% v 68%
DCC AND NIRS RESULTS
• A RCT Comparing ICC v DCC at 1 min in preterm infants
• Originally planned for 24 to 36 wk infants
• Reported data for 30 to 36 wk infants (n=105, 60 in ICC, 45 in DCC)
• Baby 10 to 12 inches below introitus for VD & clamped 3 to 5 cm from baby
• For C-section, placed infant alongside mother’s thigh
• Results: Statistically significant improvement in serial HCt and higher
circulating RBC mass
• No difference in:
IVH
Tranfusions
Mechanical ventilation
Apgar scores
2008 STRASS, MOCK, JOHNSON ET
AL. IN TRANSFUSION
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ICC DCC P value
Baseline HCt 53±1.1 56±1.3 0.188
Wk 1 47±0.9 52±1.0 0.005
Wk 2 41±0.07 46±0.8 <0.00001
Wk 3 36±0.7 41±0.9 <0.00001
Wk 4 31±0.6 35±0.8 <0.00001
STRASS AND MOCK DATA
• Ultee, van der Deure, Swar, et al. Arch Dis Child Fetal Neonatal Ed 2008
• Small study (n=37) examining early cord clamping (at 30 sec) v DCC at 3 min
• Examine:
glucose
hgb at 1 hr an 10 wk
Ferritin at 10 wk
Polycythemia
Jaundice
Need for phototherapy
• Non-Caucasians were not invited to participate due to perceived language barriers
DCC IN PRETERM INFANTS AT 34-
36 WK: A RCT
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• Glucose: No difference between CC at 30 sec and 3 min
• Jaundice (level not defined)—no difference
• Polycythemia—no difference (ECC: 0/19, DCC 1/18)
Infant with DCC had asymptomatic HCT > 70
• Phototherapy—no difference
• HCT: 1hr: ECC mean 50 DCC mean 59 (p< 0.05)
10 wk: ECC mean 27 DCC mean 31 (p< 0.05)
• Ferritin ECC 143 mcg/l DCC 162 mcg/l (NS—but interesting)
ULTEE ET AL RESULTS
2010: 7 month Dev Outcomes of VLBW Infants Enrolled in a RCT of DCC
v ICC. J Perinatol. Mercer, Oh, et al.
DCC at 30 to 45 sec for 24 to 31 6/7 wk infants
Result: No difference in BSID between groups.
Regression model of effects of DCC on motor scores controlling for gestational age, IVH, BPD,
sepsis, and male gender suggested protective effect of DCC for boys.
DEVELOPMENTAL OUTCOMES:
ESSENTIALLY NO DATA
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J Perinatol. Effects of DCC in VLBWs.
Small multicenter trial of 33 infants comparing ICC to DCC at 30 to 45 sec
Hypothesis: DCC in 24 to 28 wk will result in higher 4 hr HCT
Results:
• 4 hr HCT significantly higher in DCC group (45±8 vs 40±5, p <0.05)
• No difference in hourly mean BP during first 12 hr
• Trend toward improved HCT at 2, 4, and 6 wk and less transfusion volume
• (NSS)
• No difference in LOS, NEC, IVH, ROP, PDA
2011 OH, FANAROFF, CARLO ET AL
Sommers, Stonestreet, Oh, Yanowitz, Raker, Mercer. 2012 Pediatrics
Prospective study of a subset of infants in trial of DCC (n=25) v ICC (n=26)
among infants 24 to 31 6/7 wk.
Serial Doppler studies at 6±2, 24±4, 48±6, 108±12 hr of
SVC flow
RV output
MCA blood flow velocity
Superior mesenteric artery blood flow velocity
LV shortening fraction
PDA presence
Gest Age, BW, male gender were similar
HEMODYNAMIC EFFECTS OF DCC IN PREMATURE INFANTS
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DCC AND SVC BLOOD FLOW
DCC results in:
• higher SVC flow for 4+ days
• Greater RV output at 48h
• Greater RV stroke volumes at 48h.
No difference in PDA or other
measurements
Importance lies in the previously demonstrated association between decreased SVC flow and
IVH (Kluckow M, et al. 2000) and the demonstrated decrease in overall IVH rates by prior
studies of premature infants with DCC.
Concern for delay in resuscitation in apneic, bradycardic preterm infant
Why don’t we just quickly milk the cord????
Likely safe
UMBILICAL CORD MILKING
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2012 COCHRANE REVIEW
• RCC of DCC (could include “milking”) in infants < 37 wk
• 15 Studies were included (738 infants)
• 10 studies excluded for variety of reasons
• 24 to 36 weeks
• CS or VD
• Maximum DCC was 180 seconds (Ultee trial 2008)
• DCC: fewer infants need transfusions, fewer transfusions given, less NEC,
less overall IVH
2012 COCHRANE PRIMARY
OUTCOMES
Death of Baby: 13 studies, 668 infants. No difference(10/319 in DCC, 17 347 ICC)
Death or Neuro disability at 2 to 3 years: No trial reported this outcome.
Severe IVH (Gr 3-4): 6 trials reported outcome
5/154 in DCC versus 7/151. Not significant difference
PVL: only 2 studies (71 total infants) reported, too few to draw conclusion
Post partum hemorrhage: not reported at all
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SECONDARY OUTCOMES:
COCHRANE 2012
Apgar scores: no difference.
Hypothermia: No reports from DR, 3 studies of 143 total infants reported no
difference.
RDS: limited data, no clear difference
Surfactant: limited data, no clear difference.
CLD (O2 at 28 days or 36 wk): no difference
Treatment for PDA: no difference (5 trials reported with 223 total infants).
SECONDARY OUTCOMES:
COCHRANE 2012
Inotropes for Low BP: Mean BP higher at birth, 4 hr, and lower need for inotropes w/DCC (RR 0.42 CI 0.23-0.77).
IVH (all grades): 10 trials with 539 infants
DCC RR 0.59 95% CI: 0.41-0.85
NEC (unspecified grade): 5 trials w/241 infants
DCC RR 0.62 95% CI: 0.43 to 0.90
Anemia requiring tranfusion: 7 studies/392 infants
24% (44/186) with DCC
36% (75/206) w/ICC
RR 0.61 95% CI: 0.46 to 0.81
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SECONDARY OUTCOMES:
COCHRANE 2012
Overall Number of Transfusion: significantly lower in DCC
Hyperbilirubinemia: Peak bili sig. higher in DCC (7 trials 320 infants, mean
difference 0.88 mg/dL).
Treated Hyperbilirubinemia: no difference
No data given on exchange transfusions
Backes CH, Huang H, et al. Journal of Perinatology, 2015
RCT of 22-27 6/7 wk preterm infants
ICC versus DCC at 30 seconds (not really very long compared to some)
20 Babies in each arm
Improved:
Hematocrit at < 72 hr
Improved blood pressure
Less IVH in DCC group (but not significant, likely due to small n)
HOW ABOUT THE REALLYPRETERM BABIES???
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MEAN BP DCC V ICC
BACKES, HUANG, ET AL
Term infants: improved iron stores during first few months (less anemia, improved neurodevelopment).
Preterm infants: improvements in IVH and NEC, fewer tranfusions
Evidence of hypovolemia among some preterm infants with ICC
Better cerebral oxygenation and higher SVC flows at time of greatest IVH risk
Each institution needs to develop a site-specific protocol and determine who is not a candidate for delayed cord clamping.
SUMMARY