Delayed Cord Clamping T. Flint Porter, MD, MPH

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

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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.

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

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

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

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

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

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%)

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)

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

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

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

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

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.”

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)

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

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

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)

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

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

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

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

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.

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.”

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?

Preterm Infants

Preterm Infants Cochrane 2012 15 studies, 738 infants, < 37 weeks Study Groups Immediate Placental transfusion strategies: Delayed (≥ 30 - 120 seconds) Cord milking Outcomes Death, severe IVH, PVL, neurodevelopment

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

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)

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

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

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)

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

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

DCC in Preterm Neonate Elimian et al, OG 2014 RCT of DCC for neonates 24-34 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

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

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

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

MUC in ELGANs Patel et al, AJOG 2014

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

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

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

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

Summary from AAP/AHA Neonatal Resuscitation Program (NRP®) Current evidence suggests that cord clamping should be delayed for at least 30-60 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.

© 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

“…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.”

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

What do I think?

“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

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

Gravity Vain et al, Lancet, 2014 Introitus (197) Abdomen (194) Mean Weight Change Difference P 56 53 3 (–5.8-12.8) NS NO DIFFERENCE It doesn’t matter where you hold the baby.

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 (?)

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

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