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
IVC
UV
Placenta
Normal
Fetal
Circulation
Iliac Arteries
UA
Placental Circulation
4
Chorionic villus
PDA
(100)
Branch Villus
PFO
(35)
(20)
Vessel
PO2
Maternal Uterine art
DV
(50)
Arrows indicate
sites of space
Intervillous
arterio-venous
shunts
in blood)
(Maternal
the placenta
()
90-100
Inter-villous space
50
Umbilical artery
20
Umbilical vein
30-35
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
pH (Bohr effect) low (acidosis)
high
(alkalosis)
type of
hemoglobin
fetal
hemoglobin
adult
hemoglobin
DA
SVC
Aorta
PA
65
Lung
PV
PFO
70
65
50
Liver
55
Portal Vein
IVC 35
UV
85
Placenta
Normal
Fetal
Circulation
Iliac Arteries
UA
6
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 O2
content per
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
IVC
UV
Placenta
Normal
Fetal
Circulation
Iliac Arteries
UA
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
IVC
UV
Normal
Fetal
Circulation
Iliac Arteries
UA
Placenta
Percent Combined Output
20 Wks
Combined
output
Left Ventr
30 Wks
38 Wks
210 ml/min 960 ml/min 1900
ml/min
47
43
40
Right Ventr 53
57
60
PFO
40
30
28
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
IVC
UV
Normal
Fetal
Circulation
Iliac Arteries
UA
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
COX
PGE2
EP2
K+
K+ATP
EP3
cAMP
Placental PGE2
Endothelial Cell
EP4
AMP
PDE3
Relaxation
Smooth Muscle Cell
13
DA
Aorta
SVC
PA
Lung
PV
FO
Liver
Portal Vein
IVC
UV
Placenta
Normal
Fetal
Circulation
Iliac Arteries
UA
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
↓NO, PGI2
↑ET-1, EET, TxA2
↑Ca++
↓cGMP, cAMP
↓K+Ca, Kv
Endothelin Effects on Vessel
Pre-pro-ET-1
(203 AA)
Big-ET1 (92 AA)
ECE
↑eNOS
ET-B
(21 AA) ET-1
ET-A
↑Ca++
Contr
↓Ca++
Relax
NO
16
Arterial Pressure
(mmHg)
50
40
30
20
10
0
450
400
Blood Flow
(ml/min/kg)
350
300
250
200
150
100
50
Vascular Resistance
(mmHg/ml/min/kg)
1.4
1.2
1.0
0.8
80% decrease in 24 h
0.6
0.4
0.2
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
Left pulm flow (ml/min)
800
*
700
600
500
*
400
300
*
200
100
0
BL
Drain lq
Dist
Dist+O2
18
Hyperbar O2
3 Atm
Oxygen
Left pulm flow (ml/min)
Oxygen & Pulmonary Flow
800
700
600
500
400
300
200
100
0
BL
Fetal PO2 22
Norm O2
Hyperbar O2
27
47
19
Oxygen & Pulmonary Flow
800
700
600
500
Control
N-LA
400
300
200
100
0
BL
Fetal PO2 22
Norm O2
27
Hyperbar O2
47
20
Oxygen
Alveolus
ADP
AMP
Aden
ATP
Pulmonary
artery
Fetal RBC
NO
Plasma ATP level (µM)
PG
Left Pulmonary Flow (ml/min)
ATP
ATP
*
9
8
7
6
5
4
3
2
1
0
ADP
1400
*
1200
1000
*
*
*
*
800
AMP
* *
*
*
*
600
*
400
*
*
200
Bl
10%
21%
FiO2
100%
8
4
2
1
0.5
0.25
0
0
ATP conc. µM
21
Pulmonary
Artery
ATP, VEGF
Oxygen, Distension
Ligand
Receptor
L-arginine
eNOS
AA
L-citrulline
COX PGIS
NO
PGI2
Adenylate
Cyclase
sGC
GTP
cGMP
GMP
ATP
cAMP
PDE3 AMP
PDE5
Pulm flow as % cardiac output
Pulmonary flow and Maturation of
NOS & COX
120
120
100
100
80
80
60
60
40
40
20
20
0
NOS
COX-1
0
0.4
0.8
birth
0.4
0.8
Birth
22
Akt
Serine 1177 -P
e-e
NADPH
e-
CaveolinCaveolin-1
FAD
e-
FMN
e-
O2
.
O2CaM
HemeFe3+
NH2
II
ThrThr-497 P
BH4
C
Hsp90
I
L-Arg
NO
O =C
I
L-Citr
Reactive Oxygen Species
NOX, NOS
_•
O2
eNOS
NO
SOD
H2O2
H2O + O2
Peroxynitrite
Constriction
cGMP
Vasodilation
23
Estrogen, Steroids, Shear stress
Endo
↑eNOS ↑COX ↑SOD
↑ NO
↑ PGI2
↑cGMP
_•
↓O2
↑cAMP
Smooth
muscle
Regulation of cGMP
ANP
BNP
Endo
CNP
NOS
pGC
NO
CO
sGC
↑cGMP
Smooth
muscle
Relaxation
24
AIR
CO
NO
ANP
BNP
O2
Air
O2
PGI2
K+v
Postnatal Circulation
25
Summary
• Fetal circulation uniquely adapted to the
intra-uterine life- Low PO2 and nonrespiring 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
Atrium
Left
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
Low PO2
Lumen pressure
eNOS
NO
Cox1,2
PGE2
↑cAMP
CO
↑cGMP
Hox 1,2
Oxygen
↓Pressure
↑cGMP
ET-1
Cyp 450
↑Ca++
↓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 substancesPGE2, NO, ATP, K+ channel blockers etc
similar to pulmonary vessels
30
Breath NO Levels - Infants
Nasal NO
Ex NO-Vent
Parts per billion
140
120
100
80
60
40
20
0
Preterm
Term
Williams et al Ear Hum Dev ’03
Leipala et al Eur J Ped ‘04
Right Lobe
Left Lobe
Po
rta
lV
ei
n
DV
31
Fetal Pulmonary Artery
↑Ca++
↑Lip Oxy
Low PO2
↑Lumen pressure
TxA2
TxB2
↓eNOS
↓cGMP
↓Cox1,2
↓cAMP
↓Hox 1,2
↑ET-1
ETA
↑Cyp 450 EET
↓cGMP
↑Ca++
↓Kv
Lumen
EC
VSM
↓Ca++
Estrogen
Steroids
Shear Stress
↑eNOS
↑GC
↑Cox1,2
↑AC
SOD-1,2
↓SMC growth
↑Kv
Lumen
EC
VSM
Maturation of vasodilator system during gestation
32
Basal ATP levels in fetus
Blood ATP
0
800
PA
PA Sat 59%
LA
LA Sat 81%
*
PA
LA
*
0
Plasma ATP
5
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+
O2
NOS NO
Dist
COX PGI2
NOS
GCGC-cGMP
ACAC-cAMP
34