1. Delayed Cord Clamping
T. Flint Porter, MD, MPH

2. Disclosure I had an umbilical cord
I sometimes receive remuneration for clamping and cutting umbilical cords
I believe this is appropriate
Legal Department:
I’m kidding, this is a joke, I’m kidding.
Nothing to disclose

3. IMC Parking Lot

4. Background
Placental transfusion: blood volume transfused to baby after delivery
Umbilical Cord Blood Flow (UCBF)
Factors that influence transfusion
Delayed cord clamping (DCC)
Cord milking (MUC)
Gravity
Uterotonics
Blood in umbilical arteries thought to stop flowing within 25 – 45 s after delivery.

5. Mechanisms of DCC and Improved Outcome
Increased neonatal blood volume
Improved perfusion
Reduction in organ injury
Allow spontaneous breathing to begin
Smoother transition of cardiopulmonary and cerebral circulation
Reduce need for resuscitation
Increase iron stores, reduce anemia
Transfusion of blood enriched with stem cells and immunoglobulin

6. Potential Drawbacks Delayed resuscitation
Increase risk of neonatal hypothermia, polycythemia, hyperbilirubinemia
Increase risk for maternal hemorrhage
Interfere with cord blood collection

8. How long does umbilical cord blood flow continue?
Prospective observational trial of UCBF after delivery in 30 term infants
Protocol
Placed skin-to-skin by CNM
Doppler of straight portion until clamping
Cord clamped at CNM discretion (pulsation)
Pulse cessation determined by researcher
Measurements after 1st breath (30/30) and oxytocin (28/30)
Boere et al, Arch Dis Child Fet Neo Ed, 2014

9. UCBF After Delivery Venous Flow
No venous flow at initial exam
3/30 (10%)
Flow stopped 04:36 (03:03–08:22)
Cord clamped 06:02 (04:47–09:35)
17/30 (57%)
Flow still present when cord clamped 05:13 (02:56–09:15)
10/30 (33%)
Boere et al, Arch Dis Child Fet Neo Ed, 2014

10. UCBF After Delivery Venous Flow
Flow stopped during deep breaths
Breathing
Flow stopped
Flow reversed flow with “hard” crying
Crying

11. UCBF After Delivery Arterial Flow
No flow at initial exam
5/30 (17%)
Flow stopped 04:22 (02:29–07:17)
Cord clamped 06:15 (05:02–09:30)
12/30 (40%)
Flow still present when cord clamped 05:16 (03:32–10:10)
13/30 (43%)

12. UCBF After Delivery Time Differences
In 15 infants arterial and venous flow stopped simultaneously
Flow to baby
7 infants
Arterial stopped first 01:08 (00:51–03:03)
Net flow from baby!
8 infants
Venous stopped first 01:43 (00:51–02:45)

13. UCBF After Delivery Conclusions
UCBF longer than previously described
Complex process affected by
Breathing and crying
Differing arteriovenous flow cessation
Arterial flow toward the placenta
UCBF unrelated to pulsations… reconsider as a time point for cord clamping

14. Term Infants Cochrane 2013 15 RCTs of 3911 women > 37 weeks
Clamping Groups
< 60 seconds after delivery
> 60 seconds after delivery or pulse cessation
Primary outcomes
PP hemorrhage
maternal and neonatal mortality
Secondary outcomes
Maternal blood loss and related morbidity
Neonatal morbidity

15. NO DIFFERENCE Term Infants Cochrane 2013 Severe PPH or mortality
Maternal blood loss
Apgar scores
NICU admission
RDS
Polycythemia
NO DIFFERENCE

16. Term Infants Cochrane 2013 Hemoglobin (g/dL) Iron Deficiency
Newborn
-2.17 g/dL (-4.06 to -0.28)
24 – 48 hours
-1.49 g/dL (-1.78 to -1.21)
3 – 6 months
No difference
Iron Deficiency
(3-6 months)
2.7 (1.04 to 6.7)
Jaundice
Phototherapy
0.62 (0.41 to 0.96)
Clinical jaundice
0.84 (0.66 to 1.07) ND
Hemoglobin (g/dL)
Newborn
-2.17 g/dL (-4.06 to -0.28)
24 – 48 hours
-1.49 g/dL (-1.78 to -1.21)
3 – 6 months
No difference
Iron Deficiency
(3-6 months)
2.7 (1.04 to 6.7)
Jaundice
Phototherapy
0.62 (0.41 to 0.96)
Clinical jaundice
0.84 (0.66 to 1.07) ND

17. Term Infants Cochrane 2013 Authors’ Conclusion
“DCC in healthy term infants appears to be warranted… growing evidence that DCC increases early hemoglobin concentrations and iron stores...
… as long as access to treatment for jaundice requiring phototherapy is available.”

18. Iron and Neuro. Status at 1 Year Andersson, JAMA Ped 2014
Randomized controlled trial of DCC in full term infants
Groups
Delayed: >180 secs after delivery
Early: < 10 secs after delivery
Outcomes
Ferritin levels at 12 months
Neurodevelopment at 12 months assessed by ASQ (Ages and Stages Questionnaire)

19. Iron and Neuro. Status at 1 Year Andersson, JAMA Ped 2014
Cord Clamping
Measure
DCC (174)
ECC (163) P Hb
11.8
12.0 NS
Hematocrit 35
Ferritin
35.4
33.6
Proportion with Iron Status Outside Norm (%)
Anemia
16.1
11.6
Iron deficiency
3.4
5.4
NO DIFFERENCE

20. Iron and Neuro. Status at 1 Year Andersson, JAMA Ped 2014
Proportion of infants with low ASQ Scores (%)
Cord Clamping
ASQ Measure
DCC (174)
ECC (163) P
Communication
3.5
3.6 NS
Gross Motor
5.9
4.8
Fine Motor
6.5
4.2
Problem Solving
4.1
2.4
Personal-Social
NO DIFFERENCE

21. DCC in Term Infants, F/U at Age 4 Anderson et al, JAMA Ped 2015
Iron deficiency associated with poor neurodevelopmental outcome
Follow up study at 4 years
Outcomes
“Full scale” IQ (Primary Outcome)
Fine motor testing (Movement ABC)
Ages and Development (ASQ)
Behavior (SDQ)

22. DCC in Term Infants, F/U at Age 4 Anderson et al, JAMA Ped 2015
Primary Outcome
Full scale IQ scores: No difference
Low IQ (<85): No difference
No difference in verbal, performance, processing speed, or general language

23. DCC in Term Infants, F/U at Age 4 Anderson et al, JAMA Ped 2015
Secondary Outcomes
Movement ABC – Proportion with low test scores
Delayed (%)
Early (%)
P Value
Manual dexterity 18 26 NS
Coins in box 30 35
Bead threading 16 20
Drawing bike trail 4 13
0.02

24. DCC in Term Infants, F/U at Age 4 Anderson et al, JAMA Ped 2015
ASQ – Proportion with low test scores
Delayed (%)
Early (%)
P Value
Communication
8.3
4.3 NS
Gross Motor
5.2
6.7
Fine motor
3.7
11.0
0.03
Problem solving
8.5
Personal/Social
3.0
8.4
0.006
Pencil Grip
13.2
25.6
0.01

25. DCC in Term Infants, F/U at Age 4 Anderson et al, JAMA Ped 2015
Gender Differences

26. DCC in Term Infants, F/U at Age 4 Anderson et al, JAMA Ped 2015
Reduction in children with low scores in fine motor and social domains
Boys have the most improved results
Fine motor skills
Optimizing the time to cord clamping may effect neurodevelopment in a low risk population of children born in high income countries.

27. Editorial Comment JAMA Ped 2015
“The potential benefit of improving maternal and neonatal care by a simple no-cost intervention of delayed CC should be championed by the international community beginning now and leading into the next decade.”

28. DCC in Term Infants Conclusions Iron deficiency
Long term effects, possible
Doesn’t matter if you keep the baby below the placenta…
How long to wait? For the cord to stop pulsating?

29. Preterm Infants

30. Preterm Infants Cochrane 2012
15 studies, 738 infants, < 37 weeks
Study Groups
Immediate
Placental transfusion strategies:
Delayed (≥ seconds)
Cord milking
Outcomes
Death, severe IVH, PVL, neurodevelopment

31. Preterm Infants Cochrane 2012
Neonatal death
Severe IVH
PVL
Neurodevelopmental outcome
NO DIFFERENCE

32. Preterm Infants Cochrane 2012
Secondary Outcomes
RR (95% CI)
Inotropic support
0.42, (0.23 to 0.77)
NEC
0.62, (0.43 to 0.90)
Transfusion
0.61 (0.46 to 0.81)
Phototherapy
1.21 (0.94 to 1.55)
Secondary Outcomes
RR (95% CI)
Inotropic support
0.42, (0.23 to 0.77)
NEC
0.62, (0.43 to 0.90)
Transfusion
0.61 (0.46 to 0.81)
Phototherapy
1.21 (0.94 to 1.55)

33. Preterm Infants Cochrane 2012
Authors’ Conclusion
Less need for transfusion
Better circulatory stability
Less IVH (all grades)
Lower NEC
Insufficient data for reliable conclusions about any of the primary outcomes

34. Placental Transfusion in VPN Backes et al, OG 2014
Systematic review and meta-analysis of DCC and MUC < 32 week neonates (28 wks)
RCTs with the following interventions
Early clamping: < 15 seconds
DCC: at least 20 seconds
MUC: milking at least 3 times
Outcomes
Maternal and obstetric
Safety
Hematological status
Neonatal Outcomes

35. Placental Transfusion in VPN Backes et al, OG 2014
Safety Variables
RCT #
MD (95% CI) P
BP (4 hours) 4
3.24 (1.76, 4.72)
<.01
Apgar5
-0.07 (-.48, 0.33) NS
Temp 3
0.02 (-.18, 0.22)
Safety Variables
RCT #
MD (95% CI) P
BP (4 hours) 4
3.24 (1.76, 4.72)
<.01
Apgar5
-0.07 (-.48, 0.33) NS
Temp 3
0.02 (-.18, 0.22)

36. Placental Transfusion in VPN Backes et al, OG 2014
Hematologic Outcomes
RCT #
RR (95% CI) P
Transfusion 6
0.75 (0.63, 0.90)
<.01
MD (95% CI)
Transfusion (#)
-1.14 (-2.01, 0.27)
Hematocrit (1st) 10
4.49 (2.48, 6.5)
Bilirubin 8
0.53 (-0.01, 1.07)
0.05
Hematologic Outcomes
RCT #
RR (95% CI) P
Transfusion 6
0.75 (0.63, 0.90)
<.01
MD (95% CI)
Transfusion (#)
-1.14 (-2.01, 0.27)
Hematocrit (1st) 10
4.49 (2.48, 6.5)
Bilirubin 8
0.53 (-0.01, 1.07)
0.05

37. Placental Transfusion in VPN Backes et al, OG 2014
Neonatal Outcomes
RCT #
Risk Ratio (95% CI) P
Total IVH 9
0.62 (0.43,0.91)
<.01
Severe IVH 6
0.64 (0.34, 1.21) NS
NEC 4
0.55 (0.23, 1.31)
Sepsis 5
0.73 (0.44, 1.20)
Mortality 8
0.42 (0.19, 0.95)
.04
Neonatal Outcomes
RCT #
Risk Ratio (95% CI) P
Total IVH 9
0.62 (0.43,0.91)
<.01
Severe IVH 6
0.64 (0.34, 1.21) NS
NEC 4
0.55 (0.23, 1.31)
Sepsis 5
0.73 (0.44, 1.20)
Mortality 8
0.42 (0.19, 0.95)
.04

38. DCC in Preterm Neonate Elimian et al, OG 2014
RCT of DCC for neonates weeks
Groups
< 5 seconds
> 30 seconds (3-4 passes of milking allowed)
Intention to treat
Primary outcome
Need for transfusion (hb < 10 or symptomatic)
Secondary outcomes
Hematocrit and IVH

39. DCC in Preterm Neonate Elimian et al, OG 2014
Clamping
Outcome
Delayed (99)
Immediate (101) P
Transfusion
25 (25.3)
24 (23.7)
.80
Anemia
36 (36.4)
48 (47.5)
.11
Phototherapy
55 (55.6)
55 (54.5)
.89
IVH (grade III)
3 (3.0)
1.0
NO DIFFERENCE

40. Cord Milking in ELGANs Patel et al, AJOG 2014
MUC provides benefits of placental transfusion but avoids delay in resuscitation
Cohort study of outcomes < 30 weeks
MUC from 9/2011 – 8/2013
Historical EGLANs from 1/2010-8/2011
Composite outcome
IVH, NEC, death before discharge
Improvement in markers of hemodynamic stability

41. MUC in ELGANs Patel et al, AJOG 2014
MUC Procedure
Neonate held 10 cm below placenta
Twisting and nuchal cords released
Milking technique
Pinched close to the placenta
Milked over 2-3 seconds X 3
Pause for 2-3 seconds between milking
Total procedure < 30 seconds

42. MUC in ELGANs Patel et al, AJOG 2014

43. MUC in ELGANs Patel et al, AJOG 2014
Effect of MUC on Mean BP First Day of Life
P < 0.01
P < 0.01
P < 0.01

44. DCC with and without MUC Krueger, AJOG 2015
RCT
DCC: 30 second delay in cord clamping
DCC + MUC (4 times, 4-5 sec. between)
24 – 31 6/7 weeks
Stratified results by gestational age
Primary outcome: hematocrit
Secondary outcomes
Mortality, days on ventilator, LOS, peak bilirubin, days of phototherapy, “neonatal complications

45. DCC with and without MUC Krueger, AJOG 2015
No difference in primary outcome
Hematocrit
No difference in secondary outcomes
Bilirubin
Phototherapy
Days on ventilator
Length of stay
Other neonatal morbidities
MUC added nothing to DCC

46. Placental Transfusion Strategies Conclusions for Preterm Babies
Seems to improve short term outcomes
Longer term?
Better for < 30 weeks
Inconsistent findings among latest round of trials
Different protocols
MUC as good as DCC?
May be easier in high risk settings

47. Summary from AAP/AHA Neonatal Resuscitation Program (NRP®)
Current evidence suggests that cord clamping should be delayed for at least seconds for most vigorous term and preterm newborns.
There is insufficient evidence to recommend an approach to cord clamping for newborns who require resuscitation at birth.

48. © World Health Organization Delayed umbilical cord clamping for improved maternal and infant health and nutrition outcomes (2014)
“The cord should not be clamped earlier than 1 min after birth.”
Regardless of route of delivery
Regardless of gestational age
Stimulation before cord clamping

49. “…the cord is not clamped in the first 60 seconds…
The cord should be clamped before 5 minutes, although women should be supported if they wish this to be delayed further.”

50. ACOG Committee Opinion Number 543, 2012 (reaffirmed 2014)
“Currently, insufficient evidence exists to support or to refute the benefits from DCC for term infants that are born in settings with rich resources.”
“Evidence supports DCC in preterm infants.”
Under Revision

51. What do I think?

52. “Perinatal medicine is replete with examples of promising interventions the short-term benefits of which did not translate into long-term benefits, including some that caused harm.”
Tarnow-Mordi et al, AJOG 2014

54. Gravity Vain et al, Lancet, 2014
RCT in Argentina
All had DCC for 2 mins after NSVD
Introitus vs. Abdomen
Primary outcome was weight
Proxy for volume of placental transfusion
Procedure
Weighed < 15 secs of delivery
Weighed again at 2 mins after

55. Gravity Vain et al, Lancet, 2014
Introitus (197)
Abdomen (194)
Mean Weight Change
Difference P 56 53
3 (– ) NS
NO DIFFERENCE
It doesn’t matter where you hold the baby.

56. Purported Advantages Preterm infants Term infants Decreased RDS
Decrease need for transfusion
(60-80% of < 32 weeks get transfusion)
Less IVH
Term infants
Less iron deficiency
Long term outcomes improved (?)

57. MUC in ELGANs Patel et al, AJOG 2014
Resuscitation Characteristics
Variable
Historical (160)
MUC (158) P
Gestation
27.1
27.4
0.10
Birthweight
880
960
0.009
Temp on admit
36.3
36.5 NS
Max resuscitation*
20 (13%)
34 (22%)
Chest compress.
8 (5%)
10 (6%)
Intubation (mins) 5 6
Surfactant (mins) 29 38
*blow by oxygen, positive airway pressure, positive pressure

58. MUC in ELGANs Patel et al, AJOG 2014
Neonatal Outcomes < 30 Weeks
Variable
Control (160)
MUC (158) P
Hematocrit
45.1 ± 7.4
49.9 ± 5.5
<.01
PRBC
127 (79)
90 (57)
<.01
Dopamine <72
51 (32)
28 (18)
<.01
NEC*
32 (20)
18 (11
<.05
Severe IVH
27 (17)
15 (10)
<.05
Death or IVH
40 (25)
22 (14)
<.05
Composite
63 (39)
34 (22)
<.01