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

1

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

2


• 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

3

Who Discovered This ?

C 570 BC

4

Who is This ?

Late 1600s

5

Who is This ?

“Ars medica tota in

observationibus”

the medical art entirely consists of observations.

1787-1872

6

Ars medica tota in observationibus

Cord-clamping.com 7

http://cordclamping.files.wordpress.com/2011/09/cord-engorged-clamped.png



8

“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 9

Anatomy in utero

10

Transition at birth

11

Adult

Biochemical Control



12

Hydrodynamics

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

13

http://en.wikipedia.org/wiki/File:Roihuvuori_watertower3.png

Living Tissue

14

15

Living Tissue

From Szasz, T et al 2007 16

Phenotypic Heterogeneity of the Endothelium

William C. Aird Circ Res. 2007;100:158-173

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.

17

Prostaglandin H Synthase and Vascular Function

T. Davidge Circ. Res. 2001;89;650-660

aka PG Endoperoxide Synthase or Cyclooxygenase

• PGs and Thromboxane are Critical Modulators of Vascular Tone

18


T. Davidge Circ. Res. 2001;89;650-660 19



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

20



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 21



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

22



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

23

T Nakanishi, et al. Circ. Res. 1993;72;1218-1228

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

Mechanisms of oxygen-induced contraction of ductus arteriosus isolated from the fetal rabbit

25

T Nakanishi, et al Circ. Res. 1993;72;1218-1228

Mechanisms of oxygen-induced contraction of ductus arteriosus isolated from the fetal rabbit

_

Verapamil Diltiazem

Ductus Closure

26

KAJINO H, et al Pediatr Res 56: 586–590, 2004

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.

27


In Vivo rats - Controls

28


In Vivo rats - Indomethacin

In Vivo rats –Indomethacin and EP4- Agonist

29

KAJINO H, et al Pediatr Res 56: 586–590, 2004 30

KAJINO H, et al Pediatr Res 56: 586–590, 2004 BIRTH

In Utero In Ex PGE2 produced by Placenta EP4 + PGE2 Dilation Ex Utero EP4 Receptors down regulate Loss of PGE2 and High pO2 Constriction

31

Reactive Oxygen Species Metabolism

Fig 1 From Szasz, T et al Exp Biol Med 232:27–37, 2007 32

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

Sensor

O2 Incr ETC

Mitoch Hyperpolarization

Mediator

Increase ROS (H2O2)

Effector

Kv Channel Inhibition

DASMC Depolarization Ca Channel Activation

Incr Ca Influx

Fetus Low O2

Newborn High O2

O2 Sensing in the Human Ductus Arteriosus: Regulation of Voltage-Gated K+Channels in Smooth Muscle Cells by a Mitochondrial Redox Sensor

33

Constriction of Human Umbilical Arteries INTERACTION BETWEEN OXYGEN AND BRADYKININ

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

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

35



Results: [O2]

36



Results: [Vasoactive]

37



Results: [Bradykinin]

38



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

39

Mildenberger, E et al, Ped Res 55(2):267-272, 2004

“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

40

Mildenberger E, et al Am J Physiol Heart Circ Physiol 285: H1730–H1737, 2003

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

Nitric oxide and Endothelin in O2-dependent regulation of vascular tone of human Umb V.

41


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

42


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

43

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

44



46

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

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

Physiological Adaptation to the Placental Transfusion

47

20 ml/Kg

8 ml/Kg

Day 1 2 3

Placental Transfusion rate over Time


RBC Volume


48

ICC

DCC

60% Increase

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

Peripheral blood flow in ICC vs. DCC


Capillary Perfusion


49

PVR is a Compensatory

Mechanism

to SHUNT BLOOD to the Vital Organs

Yao, AC Moinian, M and Lind, J 1969 Lancet 7626:871–873

Distribution of blood between the infant and the placenta after birth.

0 28 30 40 50 55 55 75 ml

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.

52


• Study Results

• RBC Volume = Blood Volume x Wt in KG x Hct 53


• Study Results

• Note: True Delay group

54

Farrar, D. et al BJOG 118:70-75, 2011

• 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

55

Farrar, D. et al BJOG 118:70-75, 2011 56

Farrar, D. et al BJOG 118:70-75, 2011

• 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

1930, 1947, 1957

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58

Lung Expansion

Farber and Wilson 1933 at least 25 mm H2O Wilson, Torrey and Johnson 1937 18 mm Hg could not expand but caused injury Gruenwald 1947 10-21 cm H2O with Air 5-10 cm H2O with Saline Day et al 1952 SPEED of inflation matters 40 cm H2O for only 0.15 sec Goddard et al 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

Investigators Year Pressure to inflate Lungs

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Lung Expansion

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.

Investigators Year Pressure in Pulmonary Capillaries

60

S. JAYKKA Acta Pediatrica, 43:399, Sept 1954

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

NEONATAL LUNGS Increased Blood Flow to the Capillary bed distends the air sacs

62

Lung Expansion

“ 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.”

Jaykka 1954 Mechanical Changes

63



66

Walsh S Z British Heart J 1969,31:122

ICC (within 4 sec) vs. DCC (3-5 minutes) Shorter Intervals P duration, P-R segment, P-R, QRS, Q-Tc Longer Intervals Lower Amplitude deflections in PII, QV6, RV6. SV6 Higher Amplitude Earlier Inversions T wave in V1 Delayed Inversions 67

Higher Pulmonary Arterial Pressure

Effect on the Heart

Immediate Cord Clamp

RV Filling pressure K 50% RV Output K 50% LV Afterload J LV Diameter at End Diast J

Cardiac Output K

Tonse Clinics in Perinatology 2012 68

J. Mercer et al Medical Hypotheses 72 (2009) 458–463

•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 •Severe Hypotension at delivery FULL Resuscitation Intubation/epi/dopamine/Fluid bolus/bicarb/etc •Cord gas immediately after delivery

69

Case 2 pH 7.11 BD -9.6

NORMAL

J. Mercer et al Medical Hypotheses 72 (2009) 458–463

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

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71

• 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 72

• 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 73



74

Van Os et al. Pediatr Res 59: 221–226, 2006

Methods - Near term lambs 35-36 week equivalent - Bled out to 30% of normotension for 2.5 hr

- Brain biopsy stain for Microtubule Assoc’d 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

75

Van Os et al. Pediatr Res 59: 221–226, 2006

Results -Brain biopsy stain for MAP2

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Van Os et al. Pediatr Res 59: 221–226, 2006 77

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).

Mercer J S et al Pediatrics Vol 117, No.4 April 2006, pg 1235-1242

Method - < 32 weeks VLBW - ICC defined as < 10 sec n=36 DCC defined as 30-45 sec 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

78

Mercer J S et al Pediatrics Vol 117, No.4 April 2006, pg 1235-1242

Results - Multivariate Analyses indicated Odds Ratios of

> 3 fold more IVH in the ICC group > 10 fold more Sepsis in the ICC group

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Near Infrared Spectroscopy

80

• 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 81

• 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 82

Wolfgang J. Streit , Toxicol Pathol 2000 28(1): 28-30

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.”

Function- Neurotoxic Immune effector cells vs. Neurotrophic repair cells

83

Role of Microglia in CNS Infections

R. Bryan Rock et al CLINICAL MICROBIOLOGY REVIEWS, Oct. 2004, Vol 17 (4): 942–964

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

84

Microglia in the developing brain: a potential target with lifetime

effects • 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): 191–206. 85

Spastic Paresis After Perinatal Brain Damage in Rats Is Reduced by Human Cord Blood Mononuclear Cells

Meier, C et al PEDIATRIC RESEARCH Vol. 59, No. 2, 2006

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

86

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).

87



Green = Microglial Activation i.e. Inflammation Red = Apoptosis i.e. Cell Death Contralateral Hemisphere shown in (C) is normal

88



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 Lesion Group Treated

severe cerebral damage contralateral spastic paresis Toe Distance Step length

No difference in gross Morphology spastic paresis was largely alleviated, resulting in a normal walking behavior.

Control H-I H-I + Transf 90

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.

91

Human Umbilical Cord Blood Cells Protect Against Hypothalamic Apoptosis and Systemic Inflammation Response During Heatstroke in Rats

Won-Shiung Liu et al Pediatr Neonatol 2009;50(5):208−216

43 O C 109.4 O F for 68 minutes to induce Heat stroke Control Gp Serum free Lymphocytes Study Gp HUCBC

92

Human Umbilical Cord Blood Cells Protect Against Hypothalamic Apoptosis and Systemic Inflammation Response During Heatstroke in Rats

Control HUCBC

Hyperthermia

Hypotension MAP K i

Bradycardia P K g

Hypothalamic Neuronal Apoptosis

60% cell death 30% cell death

Systemic Inflammatory Response: TNF-a, sIAM-1, E-selectin

J

2-20 x i

IL-10 h 5 x h

Survival in Minutes 22 214 p<0.05 93

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 they are Liable. London: Edward and Charles Dilly; 1773.

95

96

Case study

20 yo MWF G1, uncomplicated pregnancy

35 6/7 weeks gestation “Near term”

Preterm Labor

Community Hospital in rural setting

Outcome: Live Male infant

5# 11 oz

APGARS 9/10 pH 7.37

Home PPD 2 on Breast

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 98

• 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


• 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.




101

Historical View of Cord Clamping

• OB Texts

• ACOG

500 BC 1900 2000 1800

102

Aristotle. History of Animals. Tr. Cresswell R. London: Henry G Bohn;1862.

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

child’s body) and at once the

baby, who had previously

been as if drained of blood,

comes to life again. 103

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 Darwin’s grandfather: 1801

Erasmus Darwin

104

1841 105

Regarding clamping a cord around the neck … “I have known an accoucheur’s 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 have ceased.

Meigs 1842

Charles Delucena Meigs

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

Arch Dis Child Fetal Neonatal Ed 2005;90:F184–F186

“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?”

108

1856

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 109

"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

Eileen Nicole Simon Hypothesis, Clamping the Umbilical cord may be Unsafe

1800s

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

“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


1900s

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

John Whitridge Williams

114

"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


1900s


• OB Texts

500 BC

Aristotle

1900 2000 1800

C White 1773

Erasmus Darwin 1801

Edward Rigby 1841

Meigs 1842

Churchill 1850

Velpeau c1850

Swayne 1856 Lusk 1882

Leishman 1888

Corney 1899

BMJ 1908

Jellett 1910 King 1914

Williams 1917

vonReuss 1921

FitzGibbon 1937

Curtis 1933

DeLee 1930

Johnstone 1949

Williams Obstetrics 4th Ed. 1950

Greenhill 1951-65

Garrey 1974

Bodyazhina 1983 Beischer 1986

Jaykka 1954

116


• OB Texts

• ACOG

500 BC

Aristotle

1900 2000 1800

C White 1773

Erasmus Darwin 1801

Edward Rigby 1841

Meigs 1842

Churchill 1850

Velpeau c1850

Swayne 1856 Lusk 1882

Leishman 1888

Corney 1899

BMJ 1908

Jellett 1910 King 1914

Williams 1917

vonReuss 1921

FitzGibbon 1937

Curtis 1933

DeLee 1930

Johnstone 1949

Williams Obstetrics 4th Ed. 1950

Greenhill 1951-65

Garrey 1974

Bodyazhina 1983 Beischer 1986

ACOG 1991-2012

Jaykka 1954

117


17-1800 1970 2014 1950

C White 1773

Jaykka 1954

William C. Aird 2007

T. Davidge, 2001

L. G. Eltherington 1968

Mildenberger, E 2004

Mildenberger E 2003

Hensley 1872

Potter 1950s

Deleterious EKG changes

Lind, J. 1965

Strauss, R.G. 2003

Farrar, D. 2011

2000 2010

Newborn lungs expand even in cases of bronchial obstruction and Diaphragmatic hernia. Thus something other than aeration must exist to expand the lungs.

Hypothesis – “blood propelled through the lung capillaries straightens them out like the petals on an unopened flower bud”

I-131 RBCs Total Blood Volume and Capillary Perfusion

The capillary system rendered rigid by liquid forms a framework that supports the respiratory part of the lung.”

O2 and Bradykinin on UAs

PGHS – 1 and 2 on Umbilical Vein Endothelium and SMC

Biotinylated RBCs for Total RBC volume

NO , Endothelin , Oxygen on UV

Oxygen and Norepi on UV

Endothelium

Weighing neonate for Total Placental Transfusion

Spastic Paresis in Rats reversed with HUCS

Heat stroke and HUCS

>3 IVH and > 10 LOS in VPTD Brain Damage, Hypotension

NIRS, Hypoxia

75 cc Placental Transfusion

Walsh S Z 1969

Yao AC 1969

Won-Shiung Liu 2009

Van Os 2006 Mercer J S 2006

Meier, C 2006 Baenziger, O. 2007

17-1800 1970 2014 1950

C White 1773

Jaykka 1954

William C. Aird 2007

T. Davidge, 2001

L. G. Eltherington 1968

Mildenberger, E 2004

Mildenberger E 2003 Hensley 1872

Potter 1950s

Lind, J. 1965

Strauss, R.G. 2003 Farrar, D. 2011

2000 2010

Walsh S Z 1969

Yao AC 1969 Won-Shiung Liu 2009

Van Os 2006 Mercer J S 2006 Meier, C 2006

Baenziger, O. 2007

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.

ACOG Committee Opinion

2012

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 seg-

ment 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

José M. Ceriani Cernadas et al. Pediatrics 2006;117;e779-e786

Study Group

Timing of cord clamp

Anemia 6 hrs

Anemia 24 -48hrs

Polycythemia 6 hrs

Polycythemia 24-48 hrs

1 n=93 15 s ICC 8.9% 16.9% 4.4% 2.3%

2 n=91 60 s DCC 1.1% 2.3% 5.6% 3.4%

3 n=92 180 s DCC 0 3.3% 14.1% 7.8%

Def: Anemia Hct < 45% Polycythemia Hct > 65% Follow up at 7, 14, and 28 days

128

The Effect of Timing of Cord Clamping on Neonatal Venous Hematocrit Values and Clinical Outcome at

Term: A Randomized, Controlled Trial

José M. Ceriani Cernadas et al. Pediatrics 2006;117;e779-e786

Def: Anemia Hct < 45% Polycythemia Hct > 65% Follow up at 7, 14, and 28 days

No harmful effects of Polycythemia No respiratory harm No hyperbilirubinemia

129

Hutton, E K and Hassan E S JAMA, March 21, 2007 297(11): 1241-1252

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

130


Perinatal Mortality Rates in the countries studied Low <10/1000 total births 8 Studies Canada Germany United Kingdom Sweden United States Moderate 10-20/1000 total births 2 Studies Argentina Libya High >20/1000 total births 5 Studies Egypt Guatemala India Mexico

131


Definitions of Timing of Cord Clamping # of Studies Early Cord Clamping – Clamping within the first 10 seconds of birth 8 “Immediate clamping” 6 Up to 60 seconds 1 Intermediate Clamping – Clamping at 1 minute 2 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

Ultee C A et al Arch Dis Child Fetal Neonatal Ed 2008;93:F20–F23

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

134

Ultee C A et al Arch Dis Child Fetal Neonatal Ed 2008;93:F20–F23

Results No treatment for polycythemia No diff in Ferritin levels

Glucose at 1 and 3 hours

Hgb /Hct At 1 hr

Hgb/Hct At 10 wk

ICC ns 11.1 / 50 6.0 / 27

DCC ns 13.4 / 59 p<0.05

6.7 / 31 p<0.05

135

Jahazi, A et al. Journal of Perinatology (2008) 28, 523–525

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

136

Jahazi, A et al. Journal of Perinatology (2008) 28, 523–525

Outcomes measured: Hct at 2 hr and 18 hr of life Estimated Neonatal Blood Volume calculated Placental Residual Blood Volume measured

ICC DCC Significance

Hct % 2 hr 61 61.6 NS

Hct % 18 hr 56.9 56.2 NS

ENBV cc 97.9 104.5 P<o.oo1

PRBV cc 53.8 34.5 P<o.oo1

137

Strauss R G et al TRANSFUSION 2008;48:658-665

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 IVH, Death 138

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

139

Shirvani F et al. Archives of Iranian Medicine, Volume 13, Number 5, September 2010; 420-425

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

140

Shirvani F et al. Archives of Iranian Medicine, Volume 13, Number 5, September 2010; 420-425

Method - ICC defined as < 15 sec (10-15 s) n=30 - DCC defined as > 15 sec (16-50 s) 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”

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 Without- Oxytocin 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


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).



• 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.



• 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.



• Central nervous system

1. Intraventricular haemorrhage (IVH) all grades;

2. IVH grades three and four;

3. periventricular leukomalacia.

• Gastrointestinal

1. Necrotizing enterocolitis.


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. mother’s views.


Paternal Outcome Measures

• Overall

1. Psychological well-being;

2. bonding to the infant;

3. anxieties;

4. father’s views.


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



• 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).



• 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



• 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



• 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


Maternal Outcome Measures

• Overall

None of the Trials reported this data


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 ICC DCC

McDonnell 1970

5 seconds Mean 31 s

Rabe 2000 20 s 45 s

Hofmeyr 1988

60-120 s

Hofmeyr 1993

60-120 s

3 studies Exact Time not given


What Now?

• Cord Blood Banking for Stem Cells

159

Diaz-Rossello, J.L. NeoReviews 2006;7;e557-e563

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

160

Diaz-Rossello, J.L. NeoReviews 2006;7;e557-e563

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.

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

research & strategy brochure

Documents

vascular function

pg endoperoxide synthase

umbilical vein endothelium

endothelial cells ecs

delayed cord

history fetal

o of birth

hypoxia pghs