2/4/2016 DELAYED CORD CLAMPING An old idea revisited 211 YEARS AGO - - PDF document

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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

• nly repeatedly breathed but till all

pulsation in the cord ceases. As

• therwise 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 transfusion but 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 Grade IV 1(3%) 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%) 1 (8%) NEC 3 (16%) 1 (6%) 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 REALLY PRETERM 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