Physiology of Fetal Circulation

G. Ganesh Konduri, MD

Medical College of WI Milwaukee, WI

Disclosure

• Plagiarism = Copy material from one source

• Research = Copy material from multiple sources

1 Outline

• Arrangement of fetal circulation • Different segments of fetal circulation -Placenta – pulmonary circulation • Developmental changes • Transition at birth

Function of Circulatory System

• Provide oxygen and nutrient supply to the tissues • Adjust the oxygen supply to the metabolic needs of the tissues

• Return deoxygenated blood and CO2 to the organ of gas exchange

2 Normal Fetus

Satyan

Fetal Circulation

3 DA Aorta SVC PA

Lung PV PFO

Liver Portal Vein Normal IVC UV Iliac Arteries Fetal

UA Circulation Placenta

Placental Circulation

4 Chorionic villus PDA (100)

Branch Villus

PFO (35) Vessel PO2 (20) Maternal Uterine art 90-100 DV Inter-villous space 50 (50) Umbilical artery 20 Umbilical vein 30-35 Arrows indicateIntervillous sites of space arterio-venous(Maternal shunts in blood) the placenta

() PO2

Hb-O2 Dissociation Curve

Fetal Hb=70% Term Neo P50= 20-HbF, 28-HbA 90%= 45-HbF. 60-HbA

5 Hb-O2 Dissociation Curve

right shift left shift temperature high low DPG high low

p(CO2) high low p(CO) low high high pH (Bohr effect) low (acidosis) (alkalosis) type of adult fetal hemoglobin hemoglobin hemoglobin

DA Aorta SVC 65 PA Lung PFO PV 70 65 50

Liver 55 Portal Vein Normal IVC35 UV Iliac Arteries 85 Fetal

UA Circulation Placenta

6 Oxygen Content of Blood at Different Levels of Oxygen Tension

PO2 (torr) SO2 (%) O2 Combined O2 dissolved Total O2 with Hb in plasma content per (ml/100ml) (ml/100ml) 100ml of blood

25 (Hb=16) 65 13.95 0.075 14.01 90 (Hb=16) 100 21.4 0.3 21.74

90 (Hb=12) 100 16.08 0.3 16.38 600 (Hb=16) 100 20.1 1.8 21.9

Hb binds 1.34 ml O2/gm Dissolved O2 = 0.3 ml/100 mmHg Modified from Cyanosis in the newborn infants – Joseph Kitterman, MD Pediatrics in Review Vol 4 (1) July 1982

DA Aorta SVC PA

Lung PV PFO

Liver Portal Vein Normal IVC UV Iliac Arteries Fetal

UA Circulation Placenta

7 Right Lobe Left Lobe

30-50% of UV Blood across DV

60-80 cm/s 10-20 cm/s 3-9 mmHg

8 DA Aorta SVC PA

Lung PV PFO

Liver Portal Vein Normal IVC UV Iliac Arteries Fetal

UA Circulation Placenta

Percent Combined Output 20 Wks 30 Wks 38 Wks

Combined 210 ml/min 960 ml/min 1900 output ml/min Left Ventr 47 43 40

Right Ventr 53 57 60

PFO403028

Lungs 5 10 12

9 Developmental Limitations

• 30% of fetal (premature) myocardial cell consists of myofibrils (60% of adult myocyte) • Myofibrils less Ca++ sensitive • Mitochondrial size & complexity less in fetus • More dependent on carbohydrate for energy

Fetal/neonatal myocardial physiology

Fetus/ Neonate Adult Cardiac output HR dependent SV & HR Starling response limited normal Compliance less normal Afterload compensation limited effective Ventricular high relatively low interdependence

10 Changes at birth

• SVR increases suddenly • Pulmonary flow increases by 10-fold • Left ventricle-increases in pre-load & after-load • Increased oxygen supply- improved left ventricular performance

11 DA Aorta SVC PA

Lung PV PFO

Liver Portal Vein Normal IVC UV Iliac Arteries Fetal

UA Circulation Placenta

Response to Physiologic Stimuli

Stimulus PDA Pulm Artery

Hypoxia Dilate Constrict

Acidosis Dilate Constrict

Alkalosis Constrict Dilate

Oxygen Constrict Dilate

12 PGE2 Effects on PDA

Low PO2 High luminal pressure Placental PGE2

COX PGE2 Endothelial Cell

EP2 EP3 EP4

cAMP AMP K+ K+ PDE3 ATP Smooth Muscle Cell Relaxation

13 DA Aorta SVC PA

Lung PV FO

Liver Portal Vein Normal IVC UV Iliac Arteries Fetal

UA Circulation Placenta

14 20 weeks 28 weeks 36 weeks

• 40-Fold increase in # small blood vessels in 3 trimester • Increase in smooth muscle layer around small PA • Increase in responsiveness of PA to stimuli

Fetal Pulmonary Circulation

Pulmonary arterial pressure Systemic Blood Pressure

15 Low PO2

↑ET-1, EET, TxA2 ↓NO, PGI2

↑Ca++ ↓cGMP, cAMP

↓K+Ca, Kv

Endothelin Effects on Vessel

Pre-pro-ET-1 Big-ET1 (92 AA) (203 AA) ↑eNOS ECE (21 AA) ET-1 ET-B

ET-A

↑Ca++ Contr ↓Ca++ NO Relax

16 50 40 30 20 10

4500 400 350 300 250 200 150 100 501.4 1.2 1.0 0.8 0.6 80% decrease in 24 h 0.4 0.2 Vascular ResistanceVascular (mmHg/ml/min/kg) (ml/min/kg) (mmHg) Flow Blood Pressure Arterial 0.0 95 136 Birth 1-3 6 days Age

17 Transition of Lung at Birth

20 >100

20 40

Fetus Newborn

Transition in Pulm Flow

800 * 700 600 500 400 * 300 * 200 100 Left pulmLeft flow (ml/min) 0 BL Drain lq Dist Dist+O2

18 Hyperbar O2

3 Atm

Oxygen

Oxygen & Pulmonary Flow

800 700 600 500 400 300 200 100 Left pulmLeft flow (ml/min) 0 BL Norm O2 Hyperbar O2

Fetal PO2 22 27 47

19 Oxygen & Pulmonary Flow

800 700 600 500 400 Control 300 N-LA 200 100 0 BL Norm O2 Hyperbar O2 Fetal PO2 22 27 47

20 Oxygen

Alveolus

ADP Pulmonary ATP AMP artery Fetal RBC Aden NO PG

Plasma ATP level (µM) Left Pulmonary Flow (ml/min) ATP ATP ADP AMP 9 * ** 1400 * 8 * 7 1200 6 1000 * * * 5 * 800 * 4 600 * * 3 400 * 2 200 * 1 0

0 0 1 2 4 8 0.5 Bl 10% 21% 100% 0.25 FiO2 ATP conc. µM

21 Pulmonary Artery ATP, VEGF Oxygen, Distension Ligand

Receptor eNOS L-arginine L-citrulline AA COX PGIS

NO PGI2

Adenylate sGC Cyclase GTP ATP cGMP cAMP GMP PDE3 AMP PDE5

Pulmonary flowflow andand Maturation ofof NOSNOS & COX

120 120

100 100 NOS COX-1 80 80

60 60

40 40

Pulm flow as % cardiac output 20 20

0 0 0.4 0.8 birth 0.4 0.8 Birth

22 Akt Caveolin-1 Serine 1177 -P

O2 BH4 .. - O2 - - - - e- e e e 3+ e- NADPH FAD FMN CaM HemeFe

NH2 II Hsp90 Thr-497 P C I L-Arg

NO O =C I L-Citr

Reactive Oxygen Species

NOX, NOS eNOS

_• NO O2

SOD

Peroxynitrite cGMP H2O2

Constriction Vasodilation H2O + O2

23 Estrogen, Steroids, Shear stress

↑eNOS ↑COX ↑SOD Endo

_• ↑ NO ↑ PGI2 ↓O2

↑cGMP ↑cAMP Smooth muscle

Regulation of cGMP

Endo ANP BNP CNP NO CO

pGCNOS sGC

↑cGMP Smooth muscle

Relaxation

24 AIR Air CO O NO 2 O2 ANP BNP PGI2 K+v

Postnatal Circulation

25 Summary

• Fetal circulation uniquely adapted to the

intra-uterine life- Low PO2 and non- respiring lungs • Preparation for post-natal adaptation occurs throughout fetal life • Understanding these adaptations essential to management of infants in NICU

26 Normal Post natal Circulation

Normal Transition

Systemic Blood Pressure

Pulmonary arterial pressure

Right Left Atrium Atrium

27 O2 Saturations in Fetal Circulation

Ductus Venosus Shunt

• 30-50% of umbilical venous blood shunted thru DV • Percent shunted declines with gestation • Rest of umbilical venous blood-left and right lobes of liver • Left hepatic vein (65% Sat)-across PFO • Portal venous blood (40% Sat) mostly to right lobe of liver

28 PDA - Compensatory Mechanism?

PDA Physiology

↑Kv

eNOS NO ↑cGMP

Low PO2 Cox1,2 PGE2 ↑cAMP Lumen pressure Hox 1,2 CO ↑cGMP

ET-1 Oxygen ↑Ca++ ↓Pressure Cyp 450

↓Kv

Lumen EC SM

29 Flow Across PDA

• Regulated by PVR in the fetus • Response to blood gas changes- opposite to pulmonary circulation • Response to vasoactive substances- PGE2, NO, ATP, K+ channel blockers etc similar to pulmonary vessels

30 Breath NO Levels - Infants

Nasal NO Ex NO-Vent

140 120 100 80 60

Parts per billion Parts per 40 20 0 Preterm Term

Williams et al Ear Hum Dev ’03 Leipala et al Eur J Ped ‘04

Right Lobe Left Lobe

in e V l a rt o P

31 Fetal Pulmonary Artery

↑Ca++

TxA2 ↑Lip Oxy TxB2

↓eNOS ↓cGMP

Low PO2 ↓cAMP ↑Lumen pressure ↓Cox1,2

↓Hox 1,2 ↓cGMP

↑ET-1 ETA ↑Ca++ ↑Cyp 450 EET ↓Kv

Lumen EC VSM

↓Ca++

↑eNOS ↑GC Estrogen ↑AC Steroids ↑Cox1,2 Shear Stress SOD-1,2 ↓SMC growth

↑Kv

Lumen EC VSM

Maturation of vasodilator system during gestation

32 Basal ATP levels in fetus

0Blood ATP 800 PA PA Sat 59%

LA LA Sat 81% *

LA *

05Plasma ATP

Advantages of sheep model

Gest age 140 days Carry single or twins Fetus large enough for instrumentation Uterus is quiescent

33 Superoxide Dismutases

Endo SMC

K+ NO GC-cGMP O2 NOS NOS Dist COX PGI2 AC-cAMP