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Physiology of Fetal Circulation

G. Ganesh Konduri, MD

Medical College of WIMilwaukee, WI

Disclosure

• Plagiarism = Copy material from one source

• Research = Copy material from multiple sources

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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

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Normal Fetus

Satyan

Fetal Circulation

4

Normal Fetal

CirculationPlacenta UA

UVIVC

Liver

SVCAorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

PFO

Placental Circulation

5

DV

PDA

PFO

Arrows indicate sites of arterio-venous shunts in the placenta

Vessel PO2

Maternal Uterine art 90-100Inter-villous space 50Umbilical artery 20Umbilical vein 30-35

Chorionic villus

Branch Villus

Intervillous space(Maternal blood)

(50)

(20)(35)

() PO2

(100)

Hb-O2 Dissociation Curve

Fetal Hb=70% Term Neo

P50= 20-HbF, 28-HbA

90%= 45-HbF. 60-HbA

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right shift left shift

temperature high low

DPG high low

p(CO2) high low

p(CO) low high

pH (Bohr effect) low (acidosis) high (alkalosis)

type of hemoglobin

adult hemoglobin

fetal hemoglobin

Hb-O2 Dissociation Curve

Normal Fetal

CirculationPlacenta UA

UVIVC

Liver

SVCAorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

PFO

8535

70

5065

65

55

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Oxygen Content of Blood at Different Levels of Oxygen Tension

PO2 (torr) SO2 (%) O2 Combined with Hb(ml/100ml)

O2 dissolved in plasma (ml/100ml)

Total O2content per 100ml of blood

25 (Hb=16) 65 13.95 0.075 14.01

90 (Hb=16)

90 (Hb=12)

100

100

21.4

16.08

0.3

0.3

21.74

16.38600 (Hb=16) 100 20.1 1.8 21.9

Modified from Cyanosis in the newborn infants – Joseph Kitterman, MD Pediatrics in Review Vol 4 (1) July 1982

Hb binds 1.34 ml O2/gmDissolved O2 = 0.3 ml/100 mmHg

Normal Fetal

CirculationPlacenta UA

UVIVC

Liver

SVCAorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

PFO

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Left LobeRight Lobe

3-9 mmHg10-20 cm/s

60-80 cm/s

30-50% of UV Blood across DV

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Normal Fetal

CirculationPlacenta UA

UVIVC

Liver

SVCAorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

PFO

Percent Combined Output20 Wks 30 Wks 38 Wks

Combined output

210 ml/min 960 ml/min 1900 ml/min

Left Ventr 47 43 40

Right Ventr 53 57 60

PFO 40 30 28

Lungs 5 10 12

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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

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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

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Normal Fetal

CirculationPlacenta UA

UVIVC

Liver

SVCAorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

PFO

Response to Physiologic Stimuli

Stimulus PDA Pulm Artery

Hypoxia Dilate Constrict

Acidosis Dilate Constrict

Alkalosis Constrict Dilate

Oxygen Constrict Dilate

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PGE2 Effects on PDA

Endothelial Cell

Smooth Muscle Cell

PGE2

cAMPPDE3

AMP

Relaxation

Low PO2 High luminal pressure

COX

Placental PGE2

EP2 EP3 EP4

K+ K+ATP

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Normal Fetal

CirculationPlacenta UA

UVIVC

Liver

SVCAorta

Lung

PA

PV

DA

Portal Vein

Iliac Arteries

FO

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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 CirculationSystemic Blood PressurePulmonary arterial pressure

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Low PO2

↓NO, PGI2↑ET-1, EET, TxA2

↓cGMP, cAMP↑Ca++

↓K+Ca, Kv

Pre-pro-ET-1 Big-ET1

ET-1

ECE

ET-A

↑Ca++Contr

ET-B

↑eNOS

NO↓Ca++Relax

Endothelin Effects on Vessel

(203 AA)(92 AA)

(21 AA)

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Vas

cula

r Res

ista

nce

Blo

od F

low

Arte

rial P

ress

ure

(mm

Hg/

ml/m

in/k

g)

(

ml/m

in/k

g)

(

mm

Hg)

50

40

30

20

10

0450

400

350

300

250

200

150

100

501.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0 95 136 Birth 1-3 6 days Age

80% decrease in 24 h

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Transition of Lung at Birth

20 >100

4020

Fetus Newborn

Transition in Pulm Flow

0100200

300400500

600700

800

BL Drain lq Dist Dist+O2

Left

pulm

flow

(ml/m

in)

*

*

*

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Oxygen

Hyperbar O2

3 Atm

Oxygen & Pulmonary Flow

0100

200300400

500600700

800

BL Norm O2 Hyperbar O2

Fetal PO2 22 27 47

Left

pulm

flow

(ml/m

in)

20

Oxygen & Pulmonary Flow

0100

200300400

500600700

800

BL Norm O2 Hyperbar O2

ControlN-LA

Fetal PO2 22 27 47

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ATP AMPAden

NO PG

Oxygen

ADPPulmonaryartery Fetal RBC

Alveolus

0123456789

Bl 10% 21% 100%

ATP

0

200400

600

800

10001200

1400

0

0.25 0.5 1 2 4 8

ATP ADP AMP

Plasma ATP level (µM) Left Pulmonary Flow (ml/min)

*

*

*

** * *

**

**

***

ATP conc. µMFiO2

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ATP, VEGF

Ligand

Receptor

Oxygen, Distension

eNOSL-arginine L-citrulline

NO

COX PGISAA

PGI2

AdenylateCyclase

PDE3PDE5

sGCGTP

cGMPGMP

ATP

AMP

cAMP

Pulmonary Artery

Pulmonary flow and Maturation of Pulmonary flow and Maturation of NOS & COXNOS & COX

0.4 0.8 birth0

20

40

60

80

100

120

Pul

m fl

ow a

s %

car

diac

out

put

0.4 0.8 Birth0

20

40

60

80

100

120

NOSCOX-1

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BH4BH4

Serine 1177 Serine 1177 --PP

ThrThr--497 497 PP

NADPHNADPH HemeFe3+

OO22

OO22--..

CaveolinCaveolin--11

ee--ee-- ee--

LL--ArgArg

NHNH22IIIICCII

NONO O =CO =CII

LL--CitrCitr

Hsp90Hsp90

ee--ee--FMNFAD CaM

Akt

Reactive Oxygen Species

O2_• NO

eNOS

H2O2

H2O + O2

Peroxynitrite

Constriction

SOD

cGMP

Vasodilation

NOX, NOS

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↑eNOS ↑COX ↑SOD

↑ NO ↑ PGI2

↑cGMP ↑cAMP

Endo

Smoothmuscle

Estrogen, Steroids, Shear stress

↓O2_•

Regulation of cGMP

NOS

↑↑cGMPcGMP

sGCsGCpGCpGC

NOANPBNP CO

Relaxation

CNP

Endo

Smoothmuscle

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AIR

O2 O2

AirCONOANPBNPPGI2K+v

Postnatal Circulation

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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

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Normal Post natalCirculation

Normal TransitionSystemic Blood Pressure

Pulmonary arterial pressure

Left Atrium

Right Atrium

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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

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PDA - Compensatory Mechanism?

EC SMLumen

Low PO2Lumen pressure

eNOS

Cox1,2

Hox 1,2

Oxygen↓Pressure

ET-1

Cyp 450

NO ↑cGMP

PGE2 ↑cAMP

CO ↑cGMP

↑Ca++

↓Kv

↑Kv

PDA Physiology

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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

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Breath NO Levels Breath NO Levels -- InfantsInfants

0

20

40

60

80

100

120

140

Preterm Term

Nasal NO Ex NO-VentPa

rts p

er b

illio

n

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

Right Lobe Left Lobe

DV

Portal

Vein

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EC VSMLumen

Low PO2↑Lumen pressure

↓eNOS

↓Cox1,2

↓Hox 1,2

↑ET-1↑Cyp 450

↓cGMP

↓cAMP

↓cGMP

↑Ca++

↓Kv

↑Ca++

ETA

EET

↑Lip OxyTxA2TxB2

Fetal Pulmonary Artery

EC VSMLumen

EstrogenSteroidsShear Stress

↑eNOS

↑Cox1,2

SOD-1,2

↑GC

↑AC

↓SMC growth

↑Kv

↓Ca++

Maturation of vasodilator system during gestation

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Basal ATP levels in fetus

0 800

PA PA Sat 59%

LA LA Sat 81%

0 5

PA

LA

Blood ATP

Plasma ATP

*

*

Advantages of sheep model

Gest age 140 daysCarry single or twinsFetus large enough for instrumentationUterus is quiescent

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Superoxide Dismutases

NOSOO22

GCGC--cGMPcGMPKK++

NONONOSNOS

EndoEndo SMCSMC

COXCOX PGI2PGI2 ACAC--cAMPcAMPDistDist