Research & Strategy Brochure

Immediate vs.
Delayed Cord Clamping What is the Evidence

AAPLOG Feb 21 2014 Leonard Marotta MD MS FACOG Medical Director Normal Obstetrics Crouse Hospital Associate Professor SUNY Syracuse Medical University Syracuse, NY
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Timing of Cord Clamping

What is Science anyway? Transition Basic Science Vascular A&P Blood Volume Pulmonary Heart Kidney Brain History Studies to Assess ICC vs. DCC
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What is Science anyway? History Fetal to Newborn Cardiovascular Changes Basic Science Vascular A&P Studies to Assess ICC vs. DCC Neonatal Shock Brain Damage Mammals Protocols
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Who Discovered This ?
C 570 BC
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Who is This ?
Late 1600s
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Who is This ?
Ars medica tota in observationibus
the medical art entirely consists of observations.
1787-1872
Ars medica tota in observationibus
Cord-clamping.com

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The majority of English language textbooks do not provide an accurate description of physiological transition.
Hutchon, D.J.R. J of Obstetrics & Gynaecology 32:724-729, 2012
Anatomy in utero
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Adult
Transition at birth
Biochemical Control
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Hydrodynamics
How a water tower works: 1. Pump station 2. Reservoir 3. Water user
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Living Tissue
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Living Tissue
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16 From Szasz, T et al 2007
Phenotypic Heterogeneity of the Endothelium

Endothelial cells (ECs) are Highly Metabolically Active. Many physiological functions: The control of Vasomotor Tone Blood cell Trafficking, Hemostasis, Permeability, Proliferation, Survival, Innate and Adaptive Immunity.
William C. Aird Circ Res. 2007;100:158-173
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Prostaglandin H Synthase and Vascular Function

aka PG Endoperoxide Synthase or Cyclooxygenase
PGs and Thromboxane are
Critical Modulators of Vascular Tone
T. Davidge Circ. Res. 2001;89;650-660 18

Prostaglandin H Synthase Activity Auto inactivation occurs after 1300 molecules of AA
PGHS-1 is induced in Umbilical Vein endothelial cells by Shear Stress PGHS-2 can be induced by cytokines, Cholesterol, Lipoproteins, Hypoxia
PGHS is localized in Umbilical Vein
Endothelium and Smooth Muscle cells

Endothelial cell has 20 times more enzyme than the SMC

PGH-2 deficient mice
35% die within 48o of birth from Patent DA PGH-1 and 2 Deficient mice 100% die within 12o of birth from PDA

PGHS 20 times more in Endothelium than SMC
Subcellular localization of both PGH-1 and PGH-2 in Human Umbilical Vein Endothelial cells: -in equal proportions -Luminal surface of the Endoplasmic Reticulum -Inner & Outer membranes of the Nuclear Envelope

Prostacyclin is a potent vasodilator IL- 1b stimulation of Human Umbilical Vein Endoth cell - Increases PGH-2 production of PG E2, F2a, and D2 - Inactivates Prostacyclin Synthase Thromboxane is a potent Vasoconstrictor - Mainly produced by Platelets - Inducible in endothelium Isoprostanes affect the free radical environment
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Mechanisms of oxygen-induced contraction of ductus arteriosus isolated from the fetal rabbit
Biochemical study to elucidate mechanism of DA contraction: Results: DA Contraction is Dependent on pO2 rise Extracellular [Ca] , thus release from sarcolemma This [Ca] change is inhibited by Verapamil, Diltiazem, Ni Findings: Oxygen increase causes membrane depolarization which increases [Ca] via Calcium Channels
T Nakanishi, et al. Circ. Res. 1993;72;1218-1228
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Mechanisms of oxygen-induced contraction of ductus arteriosus isolated from the fetal rabbit
_
Ductus Closure
Verapamil Diltiazem
T Nakanishi, et al Circ. Res. 1993;72;1218-1228
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Four subtypes of PGE2 receptor have been identified: EP1, EP2, EP3, and EP4. EP4 the primary receptor subtype of PGE2 at fetal DA in several mammals and In the human neonatal DA Study: Test a selective EP4 agonist as a DA dilator during indomethacin tocolysis using near-term pregnant rats.
KAJINO H, et al Pediatr Res 56: 586590, 2004
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In Vivo rats - Controls
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In Vivo rats - Indomethacin
In Vivo rats Indomethacin and EP4- Agonist
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In
Ex
In Utero PGE2 produced by Placenta EP4 + PGE2 Dilation
Ex Utero EP4 Receptors down regulate Loss of PGE2 and High pO2 Constriction
BIRTH
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Reactive Oxygen Species Metabolism
Fig 1 From Szasz, T et al Exp Biol Med 232:2737, 2007
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O2 Sensing in the Human Ductus Arteriosus: Regulation of Voltage-Gated K+Channels in Smooth Muscle Cells by a Mitochondrial Redox Sensor
Fetus Newborn
Low O2
High O2
Sensor
O2 Incr ETC Mitoch Hyperpolarization
Mediator
Increase ROS (H2O2)
Effector
Kv Channel Inhibition DASMC Depolarization Ca Channel Activation Incr Ca Influx
Michelakis E D. et al Circ. Res. 2002;91;478-486
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Constriction of Human Umbilical Arteries INTERACTION BETWEEN OXYGEN AND BRADYKININ

Method: 87 Human Umbilical Arteries removed within 3 hours of birth Artery cannulated Artery bathed in and perfused with a physiologic Krebs solution Vascular Pressures measured continuously Evaluated the effect of Vasoconstriction related to [O2] Evaluated effect of vasoactive substances Bradykinin Epinephrine Serotonin Isoproterenol Phentolamine Propranolol
L. G. Eltherington et al. Circ. Res. 1968;22;747-752
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Results: [O2]
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Results: [Vasoactive]
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Results: [Bradykinin]
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Conclusion:
Extent of UA Constriction is Directly related to [O2]
Bradykinin was the most potent vasoconstrictor (over epinephrine and serotonin)
Neither phentolamine, propranolol nor isoproterenol altered the Bradykinin response
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We demonstrated that human umbilical vein was far from being a passive conduit but was able to adjust its vascular tone in response to changes in local pO2 Increasing pO2 resulted in constriction of human UV vascular strips Hypoxia led to vasodilation.
Adrenergic Nerve fibers in the adventitial smooth muscle Mildenberger, E et al, Ped Res 55(2):267-272, 2004
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Nitric oxide and Endothelin in O2-dependent regulation of vascular tone of human Umb V.
Background: Umbilical Vein Vascular tone was once thought to be negligible as a contributor to umbilical blood flow. Once thought that the UV worked at Max Dilatation 1999 same authors found UV to respond to endothelium-dependent factors in response to low pO2 yielding vasodilatation. Known local regulators of vascular tone include: Prostinoids, Endothelial NO and Endothelin.
There is a Continuous release of endothelial NO in the vasculature which, when stimulated to increase NO production, leads to endothelium-dependent vasodilatation
Mildenberger E, et al Am J Physiol Heart Circ Physiol 285: H1730H1737, 2003
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Nitric oxide and Endothelin in O2-dependent regulation of vascular tone of Human Umb V.
There is a Continuous release of endothelin (ET) in the vasculature
Production and Secretion of ET is dependent on many factors including - pO2 - ETA and ETB2 Receptors on Vascular Smooth Muscle - ETB1 Receptors on Endothelium
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Nitric oxide and Endothelin in O2-dependent regulation of vascular tone of human Umb V.
Endothelium of the UV has substances that control vasodilatation Prostanoids function to control UV tone at HIGH pO2 Ex NO and Endothelin play a major role in UV vasodilatation at LOW pO2 In
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Summary - Biochemistry
PGHS is localized in the Endothelium and the Smooth Muscle of Umbilical Vein Endothelial cell has 20 times > the SMC EP4 receptors with PG Vasodilate High pO2 Vasoconstrict Ca++ channels Voltage dependent K+ channels Norepinephrine Bradykinin Nitric oxide Endothelin Reactive Oxygen Species
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I 131-tagged Human Albumin Dilution technique for total blood volume

Physiological Adaptation to the Placental Transfusion
20
ml/Kg
8
ml/Kg
Day 1
2 3
Lind, J. Canad. Med. Ass. J. 93:1091-1100, 1965
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Placental Transfusion rate over Time

RBC Volume
DCC
60% Increase
ICC
This volume shift, Translated to a 60 kg adult, is equivalent to 1600 cc

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Peripheral blood flow in ICC vs. DCC

Capillary Perfusion
PVR is a Compensatory Mechanism

to SHUNT BLOOD to the Vital Organs
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Distribution of blood between the infant and the placenta after birth.
0 28 30 40 50 55 55 75 ml
Yao, AC Moinian, M and Lind, J
1969 Lancet 7626:871873
Problem: Studies using Hct do not take into count RBC mass the effect of changing Plasma volume on Hct
Study: Use Biotinylated RBCs to measure Total RBC Volume in newborns, ICC vs. DCC
Straus, R.G. et al TRANSFUSION 43:1168-1172, 2003
Study Design 24 months RCT 2 arms of Study : N ICC 2-5 s (must be <15 s) 24 DCC 30-36 wks 60 s Held at/or below Plac. 11 <30 wks ICC, Collect CB, Spin down, Transfuse Autologous All given Biotinylated Blood 1 ml/Kg for calc.
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Study Results
RBC Volume = Blood Volume x Wt in KG x Hct

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Study Results
Note: True Delay group
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Study Design 13 Vaginal
13 Cesarean
Immediately upon birth, baby is placed on Scale Continuous weight recorded for 5 min Calculate placental transfusion 1 ml Blood weighs 1.05 g
Farrar, D. et al BJOG 118:70-75, 2011
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1930, 1947, 1957
Study Results 13 Vaginal 13 Cesarean 1 ml Blood weighs 1.05 g Mean difference blood transfer 116 g 116 g = 100 mL Whole blood 24-32 mL/kg blood volume 30-40% of total blood volume at birth No difference Vag/Cesarean Timing difference: some faster than others
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Lung Expansion
Investigators Year Pressure to inflate Lungs
Farber and Wilson 1933 Wilson, Torrey and Johnson 1937

Gruenwald Day et al Goddard et al
at least 25 mm H2O 18 mm Hg could not expand but caused injury 1947 10-21 cm H2O with Air 5-10 cm H2O with Saline 1952 SPEED of inflation matters 40 cm H2O for only 0.15 sec 1955 <20 cm H2O does not expand 20-60 cm expands uniformly >60 cm over expands/rupture Premie Inspiration 0.3-0.6 s Term Inspiration 0.5-0.6 s
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Lung Expansion
Investigators Year Pressure in Pulmonary Capillaries
Hensley
1872
Hypothesis blood propelled through the lung capillaries straightens them out like the petals on an unopened flower bud Potter 1950s
Newborn lungs expand even in cases of bronchial obstruction and Diaphragmatic hernia. Thus something other than aeration must exist to expand the lungs.
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Capillary Erection and the Structural Appearance of Fetal and Neonatal Lungs
FETAL LUNGS Atelactatic Folded Capillary tubes are Non-patent within the collapsed air sac walls Increased Blood Flow to the Capillary bed distends the air sacs
S. JAYKKA Acta Pediatrica, 43:399, Sept 1954
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NEONATAL LUNGS
Lung Expansion
Jaykka 1954 Mechanical Changes
The capillary system of the lung can be readily erected by means of liquid being introduced under pressure.
The resulting microscopic picture resembles that of a normal aerated lung.
The capillary system rendered rigid by liquid forms a framework that supports the respiratory part of the lung.
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Mary I. Townsley* Compr Physiol 2011. DOI: 10.1002/ cphy. c100081 Copyright 2011 American Physiological Society
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ICC (within 4 sec)

Shorter Intervals Lower Amplitude Earlier Inversions
vs.
DCC (3-5 minutes)

Longer Intervals Higher Amplitude Delayed Inversions
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P duration, P-R segment, P-R, QRS, Q-Tc deflections in PII, QV6, RV6. SV6 T wave in V1
Higher Pulmonary Arterial Pressure
Walsh S Z British Heart J 1969,31:122
Effect on the Heart
Immediate Cord Clamp

RV Filling pressure K 50% RV Output K 50% LV Afterload J LV Diameter at End Diast Cardiac Output K
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Tonse Clinics in Perinatology 2012
2 cases are presented Severe shoulder dystocia ICC Apgars 0 0 0 SZ Death Severe shoulder dystocia CC prior to delivery Apgars 0 0 0 SZ CP Continuous EFM prior to delivery NORMAL
Severe Hypotension at delivery FULL Resuscitation Intubation/epi/dopamine/Fluid bolus/bicarb/etc Cord gas immediately after delivery Case 2 pH 7.11 BD -9.6
J. Mercer et al Medical Hypotheses 72 (2009) 458463
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The Hypothesis Compression on the Body and Cord prohibits blood return from the placenta ICC prohibits volume resuscitation Establishing breathing changes Cardiac Output from 8% in-utero to 50% after birth Severe hypovolemia leads to inadequate organ perfusion Cardiac Asystole Hypoxia, Hypovolemia, Anemia HIE in survivors
J. Mercer et al Medical Hypotheses 72 (2009) 458463
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Study Design 24 months RCT

Exclusion : Anomalies, Multiples, Hydrops Inclusion : 24-28 weeks gestation
2 arms of Study : ICC vs. DCC with Milking Held at/or below Plac. 30 cm of cord 10 cm/s for 2-3 times All Babies admitted to Level III nursery
S Hosono, et al Arch Dis Child Fetal Neonatal Ed 94:F328-331, 2009
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Study Findings Outcome ICC DCC/Milk p Hgb 14.1 16.5 <0.01 BP Higher Vol Expand/Inotropes Less UOP Higher 5 days were required for the ICC group to equalize these parameters with the Milking group
S Hosono, et al Arch Dis Child Fetal Neonatal Ed 94:F328-331, 2009
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Methods
- Near term lambs 35-36 week equivalent - Bled out to 30% of normotension for 2.5 hr
- Brain biopsy stain for Microtubule Assocd Protein MAP2 Loss of these proteins has been shown to be associated with Neuronal damage after brain injury and a trigger of Neuronal Apoptosis - Electrocortical Brain Activity ECBA
Van Os et al. Pediatr Res 59: 221226, 2006
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Results
-Brain biopsy stain for MAP2
Van Os et al. Pediatr Res 59: 221226, 2006
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Figure 1. The relationship between no (n 6), minor (n 4), and extensive (n 4) cerebral cortical tissue damage and cerebral O2 supply (p 0.05). Extreme values are represented by D.
Figure 3. The relationship between no (n 6), minor (n 4), and extensive (n 4) cerebral cortical tissue damage and brain cell function (p 0.05). Van Os et al. Pediatr Res 59: 221226, 2006
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Method - < 32 weeks VLBW - ICC defined as < 10 sec DCC defined as 30-45 sec
n=36 n=36
- Vaginal Delivery Baby held 20-25 cm below introitus Cesarean Delivery -- Baby held below the level of incision
- Evaluated rate of BPD Bronchopulmonary Dysplasia SNEC Suspected NEC LOS Late-onset Sepsis IVH Intraventricular Hemorrhage
Mercer J S et al Pediatrics Vol 117, No.4 April 2006, pg 1235-1242
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Results - Multivariate Analyses indicated Odds Ratios of
> 3 fold more IVH in the ICC group > 10 fold more Sepsis in the ICC group
Mercer J S et al Pediatrics Vol 117, No.4 April 2006, pg 1235-1242
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Near Infrared Spectroscopy
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Study design 39 neonates avg 30 weeks gestation Control Group n= 24 Experimental Group n= 15 Control Group delivered conventionally Experimental Group Immediate pp Pitocin 15 cm below placental ht DCC for 60-90 sec
Baenziger, O. et al PEDIATRICS 199 (3); 455-459, 2007
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Study Results At 4, 24 and 72 hrs of life tested Hb and StO2
DCC
vs.
ICC
Higher Hb Higher StO2 69.8 vs 63.3 at 4 hr

71.3 vs 67.0 at 24 hr
Similar results in 2 studies Neonates post Transf

Baenziger, O. et al PEDIATRICS 199 (3); 455-459, 2007
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Microglial Response to Brain Injury: A Brief Synopsis

Historically- Pio del Rio-Hortega 1932 became The father of Microglia Biology - Ignored till the mid 1980s when staining techniques improved - Now they are considered, perhaps the single most important cellular entity for understanding disease processes that afflict the CNS.
FunctionNeurotoxic Immune effector cells vs. Neurotrophic repair cells
Wolfgang J. Streit , Toxicol Pathol 2000 28(1): 28-30
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Role of Microglia in CNS Infections

Ameoboid - active during development till 18 weeks gest Ramified Resting Reactive- in response to a variety of insults such as infection, traumatic injury, or ischemia, reactivate and move to the site of injury
R. Bryan Rock et al CLINICAL MICROBIOLOGY REVIEWS, Oct. 2004, Vol 17 (4): 942964
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Microglia can serve in a neuroprotective role with the production of multiple regulatory factors including neurotrophins such as neuronal growth factor (NGF) brain derived neurotrophic factor (BDNF) neurotrophin-3 (NT3) glial derived neurotrophic factor (GDNF) and cytokines with neurotrophic activity Macrophage CSF acts as a neurotrophic factor supporting neuronal survival and neurite outgrowth indirectly through microglia
Harry, G.J. and Kraft A.D. Neurotoxicology. 2012 March ; 33(2): 191206.
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Microglia in the developing brain: a potential target with lifetime effects
Spastic Paresis After Perinatal Brain Damage in Rats Is Reduced by Human Cord Blood Mononuclear Cells
Study Design: Induce Cerebral Hypoxic-Ischemic Damage in Neonatal Rats Postnatal day 7 Left Carotid Artery Ligation 8% O2 inhalation for 80 minutes Control Group No LESION Lesion Group No Treatment Lesion Group With Treatment Postnatal day 8 Intraperitoneal transplantation of Human Umbilical Cord cells Histological and Immunohistochemical analysis Postnatal day 21
Meier, C et al PEDIATRIC RESEARCH Vol. 59, No. 2, 2006
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Spastic Paresis After Perinatal Brain Damage Human Cord Blood Cells
The lesion affects the hippocampus (hc) parietal and temporal cortex (cx) periventricular areas(pv) and results in an enlarged lateral ventricle (v).
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Green = Microglial Activation i.e. Inflammation
Red = Apoptosis i.e. Cell Death

Contralateral Hemisphere shown in (C) is normal
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B. Hypoxic-Ischemic site Trans-peritoneal Human Umbilical Cord Blood Mononuclear cells MIGRATE to the regions of brain damage to Activated Microglia
Red = Astrocyte network Green = Human Cord Cells

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Lesion Group Not Treated severe cerebral damage contralateral spastic paresis Toe Distance Step length Lesion Group Treated No difference in gross Morphology spastic paresis was largely alleviated, resulting in a normal walking behavior.
Control
H-I H-I + Transf 90 Meier, C et al PEDIATRIC RESEARCH Vol. 59, No. 2, 2006
Spastic Paresis After Perinatal Brain Damage in Rats Is Reduced by Human Cord Blood Mononuclear Cells
Study Conclusion: Induced Cerebral Hypoxic-Ischemic Damage in Neonatal Rats Treated with Human Umbilical Cord Mononuclear Cells yields: a) migration of cells from the peritoneal cavity to the CNS b) incorporation of cells around the cerebral lesion (homing) c) an alleviation of spastic paresis.
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Human Umbilical Cord Blood Cells Protect Against Hypothalamic Apoptosis and Systemic Inflammation Response During Heatstroke in Rats
43 O C 109.4 O F for 68 minutes to induce Heat stroke Control Gp Study Gp Serum free Lymphocytes HUCBC
Won-Shiung Liu et al Pediatr Neonatol 2009;50(5):208216
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Human Umbilical Cord Blood Cells Protect Against Hypothalamic Apoptosis and Systemic Inflammation Response During Heatstroke in Rats
Control Hyperthermia HUCBC
Hypotension
Bradycardia
MAP
P
Hypothalamic Neuronal Apoptosis
K K 60% cell death

J h 22
i g 30% cell death

2-20 x i 5xh 214 p<0.05
Systemic Inflammatory Response: TNF-a, sIAM-1, E-selectin

IL-10
Survival in Minutes
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Summary - Physiology
BLOOD VOLUME I131 30% higher Blood Vol. >72 Hr RBC Mass 60% higher in 5 min CAPILLARY REFILL 20 C / 3.6 0 F 72 Hr PULMONARY Capillary Erection Opens the Alveoli CARDIAC Change in EKG Change in Preload and Afterload thus C.O. RENAL - UOP CNS - Premies >3 fold IVH >10 fold Sepsis NIRS Significantly Higher StO2 72 Hr Microglia Neuroprotection/Apoptosis Spastic Hemiparesis Heat Stroke 94
"The common method of tying and cutting the navel string in the instant the child is born, is likewise one of those errors in practice that has nothing to plead in its favour but custom. Can it possibly be supposed that this important event, this great change which takes place in the lungs, the heart, and the liver, from the state of a foetus, kept alive by the umbilical cord, to that state when life cannot be carried on without respiration, whereby the lungs must be fully expanded with air, and the whole mass of blood instead of one fourth part be circulated through them, the ductus venosus, foramen ovale, ductus arteriosus, and the umbilical arteries and vein must all be closed, and the mode of circulation in the principal vessels entirely altered - Is it possible that this wonderful alteration in the human machine should be properly brought about in one instant of time, and at the will of a by-stander?" p 45
White C. A Treatise on the Management of Pregnant and Lying-in Women, and the Means of Curing, but more Especially of Preventing the Principal Disorders to which 95 they are Liable. London: Edward and Charles Dilly; 1773.
Case study
20 yo MWF G1, uncomplicated pregnancy 35 6/7 weeks gestation Preterm Labor Community Hospital in rural setting Near term
Outcome: Live Male infant 5# 11 oz APGARS 9/10 pH 7.37 Home PPD 2 on Breast
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Why Immediate Cord Clamping Must Cease in Routine Obstetric delivery
Without doubt, ICC is not physiological

Hutchon, D.J.R. FRCOG The Obstetrician & Gynaecologist 10:112-116, 2008
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ICC Is an Intervention thus requires Informed Consent Immediately stops the return of O2-ated Blood and results in increased asphyxia and a degree of hypovolemia in the neonate Unethical
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ICC Should have been rigorously evaluated decades ago before it became normal clinical practice. Bedside Assessment, Stabilization and Initial Cardiopulmonary Support (BASIC) Trolley developed in UK.
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Historical View of Cord Clamping

OB Texts ACOG
500 BC
1800
1900
2000
102
Frequently the child appears to be born dead, when it is feeble and when, before the tying of the cord, a flux of blood occurs into the cord adjacent parts. Some nurses who have already acquired skill squeeze (the blood) back out of the cord (into the childs body) and at once the baby, who had previously been as if drained of blood, comes to life again.
Aristotle. History of Animals. Tr. Cresswell R. London: Henry G Bohn;1862.
103
Erasmus Darwin
Another thing very injurious to the child, is the tying and cutting of the navel 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 portion of the blood being left in the placenta, which ought to have been in the child.
Erasmus Darwin, Charles Darwins grandfather: 1801
104
1841105
Regarding clamping a cord around the neck I have known an accoucheurs capability called harshly into question upon this very point of practice. I have never felt it necessary to do it but once. The cord should not be cut until the pulsations Charles Delucena Meigs have ceased.
Meigs 1842
106
If the child be healthy, and not have suffered from pressure, etc. it will cry as soon as it is born, and when respiration is established, it may be separated from its mother
Churchill 1850 107
The umbilical arteries continued to beat strongly as long as the membranes were unruptured; but they fell into inertia as soon as the lungs and chest, upon coming into contact with the air, attempted to perform some respiratory movements. And do we not every day see the blood flow or stop spontaneously in the same child, according as the respiration is free or embarrassed?
Arch Dis Child Fetal Neonatal Ed 2005;90:F184F186
108
A strong healthy child, as soon as it is born, will begin to breathe freely, and in most cases cry vigorously. As soon as it has thus given satisfactory proof of its respiratory power, you may at once proceed to separate it from its mother by tying and dividing the umbilical cord.
Swayne
1856 109
Eileen Nicole Simon
1800s
Hypothesis, Clamping the Umbilical cord may be Unsafe

"The cord should not be tied until the child has breathed vigorously a few times. When there is no occasion for haste, it is safer to wait until the pulsations of the cord have ceased altogether." Lusk 1882
In cases of suspended animation, the cord should not be tied until it has ceased to pulsate, as there is a possibility in such circumstances, of a certain amount of placental respiration" Leishman 1888
"Q: When an infant is born what is the proper treatment to adopt to severing the umbilical cord? A: You must first assure yourself that the child is alive and breathing " Corney 1899
110
The British Medical Journal May 16, 1908
111
When respiration is established, let the infant rest on the bed between the thighs of the mother, preferably on its right side or back, avoiding contact with the discharges, while the navel string is attended to. No haste is necessary in tying and cutting the cord, unless relaxation of the uterus, flooding, or some other condition of the mother, requires immediate attention from the physician.
Dr. Albert Freeman Africanus King

112
Eileen Nicole Simon
1900s

As soon as the child is born, its eyes are wiped, any mucus in the air passages is removed, and it is placed in a convenient position between the patient's legs. The cord is tied as soon as it has stopped pulsating, and the infant is then removed." Jellett 1910 "Normally the cord should not be ligated until it has ceased to pulsate" Williams 1917
" A compromise is usually adopted, in that the cord is not tied immediately after birth, nor does one wait till the expression of the placenta, but only until the cessation of pulsation in the cord, an average of five to ten minutes." vonReuss 1921
"After waiting until the pulsation in the exposed umbilical cord has perceptibly weakened or disappeared, the child is severed from its mother." DeLee 1930 "In most clinics the cord is not tied until pulsation has ceased." Curtis 1933 "If the infant has cried and has respired well for about five minutes, there is no advantage in leaving at attached any longer to the placenta." FitzGibbon 1937
John Whitridge Williams
Whenever possible, clamping or ligating the umbilical cord should be deferred until its pulsations wane or, at least, for one or two minutes.
Williams Obstetrics 1950
114
Eileen Nicole Simon
1900s

"As soon as respiration is well established, lay the child on the bed on its side. Wait for a few minutes until the cord shows signs of ceasing to pulsate" Johnstone 1949
"After waiting until the pulsation in the exposed umbilical cord has ceased, the child is severed from its mother." Greenhill 1951 " The cord is cut after about three minutes or after it collapses." Greenhill 1955 "After pulsation in the exposed cord has ceased, using dull scissors, the child is separated from its mother." Greenhill 1965
"The cord is clamped and divided as soon as pulsations have ceased." Garrey et al. 1974 "The umbilical cord should be tied up after its vessels stop pulsating, which occurs in 2-3 min following the delivery of the infant." Bodyazhina 1983 "Q: What is the significance of continued pulsation of the arteries in the umbilical cord at birth? A: It means that respiration has not commenced. The physiological stimulus causing closure of umbilical arteries (and ductus arteriosus) is an increase in oxygen saturation of the blood which occurs when the lungs expand with air." Beischer et al. 1986

OB Texts
vonReuss 1921 Corney 1899 DeLee 1930 Leishman 1888 Curtis 1933 Meigs 1842 Edward Rigby 1841 500 BC 1800 1900 BMJ 1908 Jellett 1910 King 1914 Williams Obstetrics 4th Ed. 1950 FitzGibbon 1937 Johnstone 1949 Jaykka 1954 2000
Aristotle C White 1773 Erasmus Darwin 1801
Churchill 1850 Velpeau c1850
Beischer 1986 Bodyazhina 1983 Garrey 1974 Greenhill 1951-65

116
Swayne 1856 Lusk 1882
Williams 1917

OB Texts ACOG
vonReuss 1921 Corney 1899 DeLee 1930 Leishman 1888 Curtis 1933 Meigs 1842 Edward Rigby 1841 500 BC 1800 1900 BMJ 1908 Jellett 1910 King 1914 Williams Obstetrics 4th Ed. 1950 ACOG 1991-2012
FitzGibbon 1937 Johnstone 1949 Jaykka 1954 2000
Aristotle C White 1773 Erasmus Darwin 1801
Churchill 1850 Velpeau c1850
Beischer 1986 Bodyazhina 1983 Garrey 1974 Greenhill 1951-65

117
Swayne 1856 Lusk 1882
Williams 1917
Meier, C 2006 Spastic Paresis in Newborn lungs expand even The capillary system Rats reversed with HUCS in cases of bronchial rendered rigid by Mercer J S 2006 >3 IVH and > 10 LOS in VPTD obstruction and liquid forms a Van Os 2006 Brain Damage, Hypotension Diaphragmatic hernia. Thus framework that William C. Aird 2007 Endothelium something other than supports the Farrar, D. 2011 aeration must exist to respiratory part of Mildenberger, E 2004 Weighing neonate expand the lungs. the lung. Oxygen and Norepi on UV for Total Placental Transfusion Potter 1950s Jaykka 1954 Mildenberger E 2003 NO , Endothelin , Oxygen on UV 17-1800 1950 1970 2000 2010 2014
Historical View of Cord Clamping Baenziger, O. 2007 NIRS, Hypoxia
Yao AC 1969 75 cc Placental Transfusion C White Lind, J. 1965 T. Davidge, 2001 1773 I-131 RBCs Total Walsh S Z 1969 PGHS 1 and 2 on Umbilical Hensley 1872 Blood Volume and Deleterious EKG Vein Endothelium and SMC Hypothesis blood propelled Won-Shiung Liu 2009 Capillary Perfusion changes Strauss, R.G. 2003 through the lung capillaries L. G. Eltherington 1968 Heat stroke and HUCS Biotinylated RBCs for straightens them out like the O and Bradykinin 2 Total RBC volume petals on an unopened flower on UAs bud
ACOG
Committee Opinion
2012
Currently, insufficient evidence exists to support or to refute the benefits from delayed umbilical cord clamping for term infants that are born in settings with rich resources.
Potter 1950s 17-1800 C White 1773 Hensley 1872 1950
Jaykka 1954 1970 Lind, J. 1965 Yao AC 1969
Baenziger, O. 2007 William C. Aird 2007 Meier, C 2006 Mercer J S 2006 Van Os 2006 2000 2010 2014
T. Davidge, 2001 Won-Shiung Liu 2009 Walsh S Z 1969 Strauss, R.G. 2003 Mildenberger E 2003 Farrar, D. 2011
L. G. Eltherington 1968 Mildenberger, E 2004
ACOG
Committee Opinion
Number 91, February 1991
Utility of Umbilical Cord Blood Acid-Base Assessment

Technique
Immediately after the delivery of the neonate, a segment of umbilical cord should be doubly clamped, divided, and placed on the delivery table pending assignment of the 5-minute Apgar score.
1991
120
ACOG
Committee Opinion
Number 138, April 1994 (Replaces #91, February 1991)
Utility of Umbilical Cord Blood Acid-Base Assessment

Technique
Immediately after the delivery of the neonate, a segment of umbilical cord should be doubly clamped, divided, and placed on the delivery table pending assignment of the 5-minute Apgar score.
1994
121
ACOG
Committee Opinion
Number 183, April 1997
Routine Storage of Umbilical Cord Blood For Potential Future Transplantation

Large volumes of cord blood are now being wasted as discarded human material that could theoretically be easily collected, typed, screened for infections, and banked cryogenically for transplantation.
1997
122
ACOG Task Force on Neonatal Encephalopathy and CP

Asphyxia:
a clinical situation of damaging acidemia, hypoxia, and metabolic acidosis. This definition, although traditional, is not specific to cause. A more complete definition of birth asphyxia includes a requirement for a recognizable sentinel event capable of interrupting oxygen supply to the fetus or infant
2003
123
ACOG
Committee Opinion
Number 348, November 2006
Umbilical Cord Blood Gas And Acid-Base Analysis

Technique for Obtaining Cord Blood Samples
Immediately after the delivery of the neonate, a segment of umbilical cord should be double-clamped, divided, and placed on the delivery table pending assignment of the 5-minute Apgar score.
2006
124
ACOG
Committee Opinion
Number 399, February 2008 replaces No. 183 1997
Umbilical Cord Blood Banking

Once considered a waste product that was discarded with the placenta, umbilical cord blood is now known to contain potentially life-saving hematopoietic stem cells. When used in hematopoietic stem cell transplantation, umbilical cord blood offers several distinct advantages over bone marrow or peripheral stem cells.
2008
125
ACOG
Committee Opinion
Number 543, December 2012
Timing of Umbilical Cord Clamping After Birth

Currently, insufficient evidence exists to support or to refute the benefits from delayed umbilical cord clamping for term infants that are born in settings with rich resources.
2012
126

127
The Effect of Timing of Cord Clamping on Neonatal Venous Hematocrit Values and Clinical Outcome at Term: A Randomized, Controlled Trial
Study Group 1 n=93 2 n=91
Timing of cord clamp 15 s 60 s ICC DCC
Anemia 6 hrs 8.9% 1.1%
Anemia 24 -48hrs 16.9% 2.3%
Polycythemia 6 hrs 4.4% 5.6%
Polycythemia 24-48 hrs 2.3% 3.4%
3 n=92
180 s
DCC
3.3%
14.1%
7.8%
Def: Anemia Hct < 45% Polycythemia Hct > 65% Follow up at 7, 14, and 28 days
Jos M. Ceriani Cernadas et al. Pediatrics 2006;117;e779-e786 128
The Effect of Timing of Cord Clamping on Neonatal Venous Hematocrit Values and Clinical Outcome at Term: A Randomized, Controlled Trial
No harmful effects of Polycythemia No respiratory harm No hyperbilirubinemia
Def: Anemia Hct < 45% Polycythemia Hct > 65% Follow up at 7, 14, and 28 days
Jos M. Ceriani Cernadas et al. Pediatrics 2006;117;e779-e786 129
Searched through 6 electronic Databases from their beginning to Nov 2006 37 English language studies identified 8 Randomized Controlled Trials 7 Non randomized Controlled trials 22 studies excluded - 12 exclusively Preterm infants 4 LBW only 2 No control group 1 included previously reported data 2 Did not report Gest age 1 Did not report on any outcomes of interest
Hutton, E K and Hassan E S JAMA, March 21, 2007 297(11): 1241-1252
130
Perinatal Mortality Rates in the countries studied

Low <10/1000 total births Canada Germany United Kingdom Sweden United States Moderate 10-20/1000 total births Argentina Libya High >20/1000 total births Egypt Guatemala India Mexico 8 Studies
2 Studies
5 Studies
131
Definitions of Timing of Cord Clamping

Early Cord Clamping Clamping within the first 10 seconds of birth Immediate clamping Up to 60 seconds Intermediate Clamping Clamping at 1 minute
# of Studies
8 6 1
Late Cord Clamping After cessation of cord pulsations or 3 minutes

132
Conclusions Improved H/H and Iron status over the first few months
No adverse impact on Bilirubin or viscosity Need to treat jaundice Phototherapy, or NICU admissions None of the infants with polycythemia had symptoms needing treatment
Long term benefits at 2-3 months 47% less Anemia 33% less cases of low Fe stores
133
Method
- 34 w 0 d to 36 w 6 d - Inclusion: Vag Del, Cauc - Exclusion: IDDM, GDM, PIH, Twins, Cong Anomalies - Randomized to ICC within 30 sec n= 20 DCC after 3 min n= 21 -Stop Watch by a trained Registrar -Evaluated Neonatal Glucose and Hgb 10 week Hgb and Ferritin
Ultee C A et al Arch Dis Child Fetal Neonatal Ed 2008;93:F20F23
134
Results
Glucose at 1 and 3 hours ICC DCC ns ns Hgb /Hct At 1 hr 11.1 / 50 13.4 / 59 p<0.05 Hgb/Hct At 10 wk 6.0 / 27 6.7 / 31 p<0.05
No treatment for polycythemia No diff in Ferritin levels

Ultee C A et al Arch Dis Child Fetal Neonatal Ed 2008;93:F20F23
135
Double blind Randomized Controlled Study 38-42 weeks gest Unmedicated deliveries Exclusion Criteria: APGAR < 7 at 1 or 5 min Congenital Anomalies SGA or LGA Cord Blood Hct < 40 or > 65 Method: ICC (30 sec) DCC (3 min) n= 30 n= 34
Jahazi, A et al. Journal of Perinatology (2008) 28, 523525
136
Outcomes measured: Hct at 2 hr and 18 hr of life Estimated Neonatal Blood Volume calculated Placental Residual Blood Volume measured
ICC Hct % 2 hr 61 DCC 61.6 Significance NS
Hct % 18 hr
ENBV cc PRBV cc
56.9
97.9 53.8
56.2
104.5 34.5
NS
P<o.oo1 P<o.oo1
137
Jahazi, A et al. Journal of Perinatology (2008) 28, 523525
Design:
< 36 week neonates ICC defined as < 15 sec from birth DCC defined as clamped exactly at 60 sec (time of Apgar) Autologous blood was biotinated and injected at a dose of 1 ml/Kg after 20 min capillary blood obtained RBC mass calculated Outcomes: Apgar scores SNAP scores for the first 8 days of life Weight and length at birth and changes relative to birth on Days 7, 14, 21, and 28 138 IVH, Death Strauss R G et al TRANSFUSION 2008;48:658-665
Findings: For Neonates 30-36 weeks DCC yielded 15% Higher RBC Mass No difference Hct for the first days of life Higher Hct from Day 7 and through Day 28 No difference Apgar scores No difference Intraventricular Hemorrhage
Strauss R G et al TRANSFUSION 2008;48:658-665
139
Method - > 35 weeks - Inclusion: Vag Del n=50 C-section n=50 - Exclusion: Preeclampsia, Eclampsia, Severe maternal Cardiac or Renal disease, Hgb > 10 gm/dL Severe antepartum Hemorrhage, History of > 5 prior deliveries Twins, Cong Anomalies, Asphyxia, Icterus within 24 hrs, HMD, RDS, Sepsis, Birth Weight < 2000 gm, EGA < 35 weeks - Evaluated Hgb, Hct, Ferritin at 48 hrs in re: ICC vs. DCC
Shirvani F et al. Archives of Iranian Medicine, Volume 13, Number 5, September 2010; 420-425
140
Method - ICC defined as < 15 sec (10-15 s) - DCC defined as > 15 sec (16-50 s)
n=30 n=70
Results - Sign. Higher Hgb/Hct at 48 hrs in the DCC group - No sign. difference in Ferritin levels at 48 hrs Conclusion - DCC for up to 3 min as reported by others is completely logical
Shirvani F et al. Archives of Iranian Medicine, Volume 13, Number 5, September 2010; 420-425
141
Early versus delayed umbilical cord clamping in preterm infants (Review) 2010 Rabe H, Reynolds GJ, Diaz-Rosello JL
142
Study Criteria
7 Randomized Controlled trials 297 Preterm infants born before 37 completed wks Interventions: delayed 30 sec or more prior to clamp immediate Confounders: With or WithoutOxytocin Position of baby relative to placenta Milking of cord
Early versus delayed umbilical cord clamping in preterm infants (Review) 2010
143
Outcome Measures
Overall: 1. Requirement for resuscitation 2. Apgar scores 3. Hypothermia during the first hour 4. Death
144
Neonatal Outcome Measures

Respiratory: 1. RDS during first 36 hours of life 2. use of exogenous surfactant 3. days of O2 dependency 4. O2 dependency at 28 days after birth 5. O2 dependency at equivalent of 36 completed weeks gestational age 6. chronic lung disease (Northway Stage 2-4).
145

Cardiovascular 1. Volume (colloid, NaCl 0.9 %, blood transfusion) administration for hypotension during the first 24 hours of life; 2. inotropic support for hypotension during the first 24 hours of life; 3. treatment for patent ductus arteriosus.
146

Haematological 1. Anaemia, number or volume of blood transfusions 2. treatment for hyperbilirubinaemia with phototherapy 3. treatment for hyperbilirubinaemia with blood exchange transfusion 4. blood counts at 6 and 12 months of age.
147

Central nervous system 1. Intraventricular haemorrhage (IVH) all grades; 2. IVH grades three and four; 3. periventricular leukomalacia. Gastrointestinal 1. Necrotizing enterocolitis.
148
Maternal Outcome Measures

Overall 1. Death; 2. postpartum haemorrhage; 3. complications with delivery of placenta; 4. effects on rhesus-isoimmunization; 5. psychological well-being; 6. bonding to the infant; 7. anxieties; 8. mothers views.
149
Paternal Outcome Measures

Overall 1. Psychological well-being; 2. bonding to the infant; 3. anxieties; 4. fathers views.
150
Outcome Measures
No two studies are similar in their outcome objectives Studies show a wide and varied definition of the type of outcome measures Manner of reporting outcomes varies Studies are not powered to answer questions of management
151

Respiratory: Even Taken Together, trials were too Small for any conclusion 1. RDS 2. use of exogenous surfactant 3. days of O2 dependency 4. O2 dependency at 28 days after birth 5. O2 dependency at equivalent of 36 completed weeks gestational age 6. chronic lung disease (Northway Stage 2-4).
152

Cardiovascular 1. Volume (colloid, NaCl 0.9 %, blood transfusion) administration for hypotension during the first 24 hours of life; DCC Needed Less RR 2.75-5.67 2. inotropic support for hypotension during the first 24 hours of life; Insufficient Evidence 3. treatment for patent ductus arteriosus. Insufficient Evidence
153

Haematological 1. Anaemia, number or volume of blood transfusions DCC fewer by RR 2.01 2. treatment for hyperbilirubinaemia with phototherapy 3. treatment for hyperbilirubinaemia with blood exchange transfusion 4. blood counts at 6 and 12 months of age.
Otherwise, Insufficient Data

154

Central nervous system 1. Intraventricular haemorrhage (IVH) all grades ICC increased RR 1.74 2. IVH grades three and four 3. periventricular leukomalacia Insufficient Data Gastrointestinal 1. Necrotizing enterocolitis Insufficient Data
155
Maternal Outcome Measures

Overall None of the Trials reported this data
156
Early versus delayed umbilical cord clamping in preterm infants (Review) 2010 Rabe H, Reynolds GJ, Diaz-Rosello JL
Feedback from this Review
157
Definition of Terms
Study McDonnell 1970 Rabe 2000 Hofmeyr 1988 Hofmeyr 1993 3 studies ICC 5 seconds 20 s DCC Mean 31 s 45 s 60-120 s 60-120 s Exact Time not given
158
What Now?
Cord Blood Banking for Stem Cells
159
International Perspectives: Cord Clamping for Stem Cell Donation: Medical Facts and Ethics
Uterine contractions in the 3rd stage of labor aid in the transfer of blood to the baby Expanding the Pulmonary vasculature after birth requires a volume load. ICC deprives the newborn of at least 25% of its circulating volume load therefore delaying transition
Diaz-Rossello, J.L. NeoReviews 2006;7;e557-e563
160
International Perspectives: Cord Clamping for Stem Cell Donation: Medical Facts and Ethics
Sound advice to parents is to allow natural placental and cord blood redistribution for the best interest of their child. All the evidence shows that the best bank for that blood is the baby.
Diaz-Rossello, J.L. NeoReviews 2006;7;e557-e563
161
What Now?
Transitional Delay Bilirubin clearance Late preterm delivery Neurologic injury Cord Blood Gasses
162
What Now?
Education of Healthcare workers Education of Lawyers Demand the Application of Science (EBM vs. Science Based Medicine) Before Making a Change in Practice Patterns
163

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Immediate vs.

Delayed Cord Clamping What is the Evidence

Timing of Cord Clamping

Timing of Cord Clamping

Who Discovered This ?

Ars medica tota in observationibus

Timing of Cord Clamping

Hutchon, D.J.R. J of Obstetrics & Gynaecology 32:724-729, 2012

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How a water tower works: 1. Pump station 2. Reservoir 3. Water user

16 From Szasz, T et al 2007

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Prostaglandin H Synthase and Vascular Function

PGHS is localized in Umbilical Vein

Endothelium and Smooth Muscle cells

Endothelial cell has 20 times more enzyme than the SMC

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Prostaglandin H Synthase and Vascular Function

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Prostaglandin H Synthase and Vascular Function

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KAJINO H, et al Pediatr Res 56: 586590, 2004

In Vivo rats - Controls

KAJINO H, et al Pediatr Res 56: 586590, 2004

In Vivo rats - Indomethacin

In Vivo rats Indomethacin and EP4- Agonist

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KAJINO H, et al Pediatr Res 56: 586590, 2004

In Utero PGE2 produced by Placenta EP4 + PGE2 Dilation

KAJINO H, et al Pediatr Res 56: 586590, 2004

Reactive Oxygen Species Metabolism

Fig 1 From Szasz, T et al Exp Biol Med 232:2737, 2007

Michelakis E D. et al Circ. Res. 2002;91;478-486

Constriction of Human Umbilical Arteries INTERACTION BETWEEN OXYGEN AND BRADYKININ

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L. G. Eltherington et al. Circ. Res. 1968;22;747-752

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L. G. Eltherington et al. Circ. Res. 1968;22;747-752

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L. G. Eltherington et al. Circ. Res. 1968;22;747-752

Constriction of Human Umbilical Arteries INTERACTION BETWEEN OXYGEN AND BRADYKININ

L. G. Eltherington et al. Circ. Res. 1968;22;747-752

Mildenberger E, et al Am J Physiol Heart Circ Physiol 285: H1730H1737, 2003

Mildenberger E, et al Am J Physiol Heart Circ Physiol 285: H1730H1737, 2003

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Timing of Cord Clamping

I 131-tagged Human Albumin Dilution technique for total blood volume

Lind, J. Canad. Med. Ass. J. 93:1091-1100, 1965

Placental Transfusion rate over Time

This volume shift, Translated to a 60 kg adult, is equivalent to 1600 cc

Peripheral blood flow in ICC vs. DCC

PVR is a Compensatory Mechanism

Yao, AC Moinian, M and Lind, J

1969 Lancet 7626:871873

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RBC Volume = Blood Volume x Wt in KG x Hct

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