Ultrasound Obstet Gynecol 2006; 27: 452–461
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.2747
Ductus venosus shunting in the fetal venous circulation:
regulatory mechanisms, diagnostic methods and medical
importance
M. TCHIRIKOV*, H. J. SCHRÖDER† and K. HECHER*
*Departments of Obstetrics and Fetal Medicine and †Experimental Feto-Maternal Medicine, University Medical Center
Hamburg-Eppendorf, Germany
K E Y W O R D S: blood flow volume; ductus venosus; DV shunting; fetal growth regulation; liver perfusion
ABSTRACT
The fetal liver is located at the crossroads of the umbilical
venous circulation. Anatomically, the ductus venosus
(DV) and the intrahepatic branches of the portal vein
are arranged in parallel. The actual DV shunting rate,
i.e. the percentage of umbilical blood flow entering
the DV measured by Doppler velocimetry, seems to
be lower than that estimated using radioactively-labeled
microspheres. In human fetuses the DV shunting rate is
about 20–30%. Increases in the DV shunting rate are a
general adaptational mechanism to fetal distress. Hypoxia
results in a significant increase in the DV shunting rate,
most probably in order to ensure an adequate supply
of oxygen and glucose to vitally important organs such
as the brain and heart. The mechanism of blood flow
redistribution between the fetal liver and the DV is still a
matter of debate. The isthmic portion of the DV contains
less smooth muscle tissue than the intrahepatic branches
of the portal vein, which in vitro react more forcefully in
response to catecholamines than the DV.
In growth-restricted human fetuses DV shunting is
increased and the umbilical blood supply to the fetal liver
is reduced. The long-term reduction of the hepatic blood
supply may be involved in fetal growth restriction. The
occlusion of the DV leads to a significant increase in cell
proliferation in fetal skeletal muscle, heart, kidneys and
liver, and possibly to an increase in insulin-like growth
factor (IGF)-I and -II mRNA expression in the fetal liver.
These findings hint at the possible role of the perfusion of
the fetal liver in the control of the growth process.
The quantification of DV shunting by Doppler
velocimetry may improve the early recognition of fetal
compromise in prenatal medicine. In this Review we
summarize the published data on the anatomical structure
and histology of the DV, the mechanisms of regulation
of DV shunting, its role in fetal survival and growth and
the possible use of the measurement of DV shunting in
clinical practice. Copyright  2006 ISUOG. Published by
John Wiley & Sons, Ltd.
INTRODUCTION
The fetal liver is located at the crossroads of the
umbilical venous (UV) circulation. Anatomically, the
ductus venosus (DV) and the affluent hepatic veins – the
intrahepatic branches of the portal vein – are arranged in
parallel (Figure 1). This is important because the ratio of
flow through the DV and the liver will be inversely related
to the ratio of flow resistances, regardless of whether the
resistance values actually decrease or increase. In fetal
sheep, under normal conditions two-thirds of the UV
blood flow supplies the liver (equivalent to about 70% of
total hepatic blood flow)1,2 , with about one-third passing
through the DV3 – 7 (as measured by the radioactivelylabeled microsphere technique). The actual DV shunting
rate (i.e. the percentage of umbilical blood flow that enters
the DV) when measured with Doppler velocimetry seems
to be lower than that estimated with radioactively-labeled
microspheres8 – 12 . Hypoxia results in a significant increase
in the DV shunting rate, most probably in order to ensure
an adequate supply of oxygen and glucose to vitally
important organs such as the brain and heart5,7 – 9,13 . The
mechanism of redistribution of blood flow between the
fetal liver and the DV is still a matter of debate.
It is assumed that an increase in DV shunting rate
is important for fetal survival during stress situations.
In other words, an increase in DV/UV flow ratio is
an indicator that the fetus is compromised. The early
recognition of distressed fetuses is important in obstetrics.
Correspondence to: Dr M. Tchirikov, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf,
Martinistrasse 52, 20246 Hamburg, Germany (e-mail: [email protected])
Accepted: 1 January 2005
Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.
REVIEW
Ductus venosus shunting in the fetus
453
RHV
LHV
DV
LPV
RPV
UV
PV
IVC
cava (IVC)23 – 25 . As an organized vascular structure, the
DV is present in the fetuses of most mammalian species.
Amphibians and other lower-order vertebrates do not
have a DV26 . The DV has been described in fetuses
of mice27,28 , rats29 , dogs30 – 33 , cats34,35 and many other
mammals. However, guinea pig and horse fetuses do not
have a DV at term36 – 38 . In pig fetuses, the DV disappears
during intrauterine life39,40 , while in sheep fetuses the
DV increases in size up to birth as a short-circuit for
re-oxygenated blood returning from the placenta36 .
In humans, the development of the DV can be divided
into two stages41 . The first stage involves the establishment of the DV as a major vessel in the bilateral
symmetrical arrangement of the hepatic sinusoids. From
the yolk sac blood flows through the omphalo-mesenteric
veins and the liver to the sinus venosus, while blood from
the chorionic villi bypasses the liver and empties into the
sinus via the right and left UVs. In the second stage the
symmetry of the first stage is transformed into the asymmetric definitive condition, in which the DV connects the
left UV with the right hepato-cardiac vein, later destined
to become the inferior vena cava (IVC). In late embryonic
and fetal stages this general arrangement of the DV and
main venous vessels remains substantially unaltered41 .
In rhesus monkeys, the DV drains into a dilated
ampullary area – the collectus venosus – which is connected to the IVC (Figure 2)42 . This venous structure
also receives blood entering on the right side from the
Placenta
Figure 1 Principle of venous blood circulation in the fetal liver.
Blood flow directions in the liver are indicated by arrows. The
vessels/vascular bed resistances to blood flow involved in the
regulation of the ductus venosus shunting rate are marked by the
boxes. DV, ductus venosus; IVC, inferior vena cava; LHV, left
hepatic vein; LPV, left branch of the intrahepatic portal vein; PV,
portal vein; RHV, right hepatic vein; RPV, right branch of the
intrahepatic portal vein; UV, umbilical vein.
In growth-restricted human fetuses DV shunting is
increased and the umbilical blood supply to the fetal
liver is reduced8,12 . This may influence cell proliferation
in fetal organs because the liver synthesizes many growth
factors14 – 19 .
In clinical practice at present, analysis of the blood flow
velocity profile of the DV also serves as an indicator of
circulatory decompensation20,21 . Reversed blood flow in
the DV during atrial contraction is strongly associated
with poor fetal outcome21,22 .
In this review we summarize the published data on
the anatomical structure and histology of the DV, the
mechanisms of regulation of DV shunting, its role in
fetal survival and growth and the possible use of the
measurement of DV shunting in clinical practice.
ANATOMICAL STRUCTURE AND
H I S T O L O G Y OF T H E D U C T U S V E N O S U S
IN HUMANS AND ANIMALS
The ductus venosus Arantii is a venous shunt between
the intra-abdominal umbilical vein and the inferior vena
Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.
Figure 2 Frontal (anterior view) of the ductus venosus and central
venous system in a rhesus fetus at term. The foramen ovale is
marked by metal wire with a diameter of 2 mm. A, ductus venosus;
B, umbilical vein; C, abdominal and cardiac portions of the inferior
vena cava; D, left branch of the portal vein; E, collectus venosus.
(Reproduced from Tchirikov M, Schlabritz-Loutsevitch NE,
Hubbard GB, Schröder HJ, Tardif S, Nathanielsz PW. Structural
evidence for mechanisms to redistribute hepatic and ductus venosus
blood flows in non-human primate fetuses. Am J Obstet Gynecol
2005; 192: 1146–1152. Copyright  2005 Mosby, Inc.)
Ultrasound Obstet Gynecol 2006; 27: 452–461.
Tchirikov et al.
454
identify the sphincter of the DV in human fetuses at
13–17 weeks using scanning electron microscopy and
immunohistochemical methods48 . We found that in fetal
sheep the isthmic portion of the DV mainly contained
connective tissue and small amounts of smooth muscle
tissue but no completely circular layer of muscle cells49 .
In contrast, the media of hepatic affluent veins contained
well-organized muscle tissue49 .
In non-human primate fetuses a small layer of muscle
tissue was observed throughout the DV wall just below
the endothelium (Figure 3)42 . A non-completed circular
layer, 3 to 7 cells thick, formed a contractile element at
the DV inlet. This smooth muscle structure frequently
took the form of a lip or a ‘horseshoe’ protruding into
the lumen at the junction of the DV and UV. However,
this condensation of smooth muscle generally represented
a thin band of muscle fibers and did not constitute a
complete sphincter.
The diameter of the DV in marmoset fetuses at a
gestational age (GA) between 100 and 124 days (term,
144 days) is frequently about half the diameter of the
UV (mean diameters 0.7 ± 0.1 mm and 1.7 ± 0.4 mm,
abdominal vena cava and from effluent hepatic veins. The
DV courses to the posterior wall of the venosus collector.
In some primate fetuses the DV terminates in the left
hepatic vein42 .
The presence of a ‘sphincter’ in the isthmic portion of
the DV is controversial. For the following discussion
it may be useful to make a distinction between a
‘morphological’ sphincter, and a ‘functional’ sphincter.
In 1942 Barron described the sphincter at the inlet of the
DV in his short report43 , while 2 years later Barclay et al.
identified, with cineangiography, a ridge located at the
inlet of the fetal lamb DV which projected slightly into
the DV lumen36 . In agreement with later investigators,
Barclay et al. postulated that this ridge functioned as
a sphincter mechanism36,41,44 . In 1984 Coceani et al.
also described in histological sections a smooth muscle
sphincter in fetal sheep45 . The development of the DV
sphincter in humans was described by Chacko and
Reynolds in 195346 . However, as described in their
1966 report Meyer and Lind were unable to identify
a muscular sphincter between the UV and the DV in
human fetuses47 , and Mavrides et al. in 2002 could not
I
II
III
(a)
(b)
Figure 3 Histological structure of (a) the ductus venosus (DV) and (b) the intrahepatic branch of the portal vein (BPV), in the baboon fetus.
(a) The DV. I: Hematoxylin eosin staining of the ductus venosus. A, the contractile element of the DV as an asymmetrical lip at the isthmic
portion of the shunt; B, the umbilical vein. II: Masson’s trichrome staining. The vessel wall of the isthmic portion of the DV consists of a
network of collagenous tissue in the subendothelial zone. A, the contractile element of the DV; B, the umbilical vein. III: Histological
structure of the isthmic portion of the DV using antibodies against α-smooth-muscle actin. A few muscle cells in the DV inlet are present
only in the lip portion. (b) Right intrahepatic BPV. I: Histological structure of the branches of the portal vein (hematoxylin eosin staining).
II: Masson’s trichrome staining. The media of the vessel wall is well seen. III: The same level stained to show α-smooth-muscle actin. Muscle
cells in the media of the BPV are more plentiful than in III (a). (Reproduced from Tchirikov M, Schlabritz-Loutsevitch NE, Hubbard GB,
Schröder HJ, Tardif S, Nathanielsz PW. Structural evidence for mechanisms to redistribute hepatic and ductus venosus blood flows in
non-human primate fetuses. Am J Obstet Gynecol 2005; 192: 1146–1152. Copyright  2005 Mosby, Inc.)
Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.
Ultrasound Obstet Gynecol 2006; 27: 452–461.
Ductus venosus shunting in the fetus
455
respectively). In baboon fetuses at a GA between 90 and
144 days (term, 185 days) the DV is 1.1 ± 0.2 mm and the
UV is 3.1 ± 0.5 mm. Abundant nerve bundles and nerve
fibers with small arteries could frequently be observed in
the region of the DV inlet42 .
Contractile capacities of the ductus venosus and central
venous vessels
The function of the DV depends largely on its contractile
abilities. In 1944 Barclay et al. postulated that the
sphincter of the DV could control the amount of blood
which traverses the liver sinusoids, but that its main
function was to occlude the ductus at birth36 , while in
1951 Reynolds considered that the function of the DV
was to maintain the pressure in the UV, thus preventing
collapse50 . He suggested that, in addition to keeping
the veins distended, the DV sphincter, by constriction or
relaxation, acts as a valve that evens out pressure changes.
Writing in 1956, Dickson was of the opinion that the main
function of the DV is to control the intravascular pressure
in the UV40 . In 1980 Edelstone postulated that when UV
flow and pressure fluctuated widely, the DV could react
passively, to ensure an adequate venous return to the fetal
heart13 .
The available information on the contractile capabilities
of the DV is controversial, which may, in part, be owing
to different experimental DV conditions, as well as the
methods applied. The response of the isthmic portion of
the DV depends in vitro and in vivo on specific conditions
detailed as follows9,44,48,51 – 56 .
In vitro, isolated DV rings contract in response to catecholamines and electrical stimulation45,57 . Prostaglandins
H2 and I2 lead to relaxation of the indomethacinconstricted DV and thromboxane A2 evokes DV
contraction58 .
In our experiments the intrahepatic branches of
the portal vein developed more force in reaction to
14
12
catecholamines than vascular rings obtained from the
isthmic portion of the DV (Figure 4)49 . α-adrenergic
receptors were present in the structured media of the
intrahepatic branches of the portal vein, but were less
frequently observed in the wall of the DV49 . The same
situation was demonstrated in non-human primate fetuses
(Figure 3)42 . Because fetal hypoxia provokes a profound
rise in plasma catecholamine levels5,9,59 , it is conceivable
that the increase in the DV shunting rate is caused by the
more forceful response of the intrahepatic branches of the
portal vein to catecholamines when compared to the DV.
In vivo, the main DV reaction in response to hypoxic
situations seems to be vessel dilatation. Using ultrasonographic observations, Bellotti et al. – in 1998 and
2004 – were able to demonstrate an increase in the diameter of the DV in growth-restricted human fetuses12,54 ,
and Kiserud et al. in 2000 also demonstrated a substantial
increase in the diameter of the DV in response to induced
hypoxemia in fetal sheep; however, the α1 -adrenergic agonist phenylephrine did not have any effect on the diameter
of the DV in this experiment55 . The application of sodium
nitroprusside dilated the DV as expected. In 1944 Barclay et al. showed by cineangiography that vagal nerve
stimulation in neonatal lambs had no effect on the diameter of the DV36 , but Arstila et al. in 1965 were able to
demonstrate dilatation of the DV in lambs in response to
stimulation of the left and right vagal nerves60 . In 1964
Peltonen et al. dilated the DV by injecting acetylcholine,
epinephrine and norepinephrine into the umbilical or
jugular veins of newborn lambs61 . Prostaglandin E1 can
also open the DV in newborn lambs62 .
The dilatation of the DV during acute hypoxia in vivo
may reflect the passive reaction of the shunt to increased
pressure in the central venous system. We hypothesize
that changes in blood content of the liver may evoke
alterations to the vascular geometry of the DV, which
might also affect its resistance to flow.
In our opinion, the forceful contractional capabilities
of the intrahepatic branches of the portal vein, as opposed
to the isthmic portion of the DV, are mainly responsible
for the regulation of DV shunting.
Force (mN)
10
UMBILICAL BLOOD FLOW SHUNTING
THROUGH THE DUCTUS VENOSUS
8
6
4
∗
∗
∗
2
0
−2
KClmax
Norepinephrine
Epinephrine
Figure 4 Maximum tension of ductus venosus and intrahepatic
vein rings to potassium chloride (KCl), norepinephrine and
epinephrine. Cell depolarization of vessel rings was induced with
124 mM potassium chloride (KClmax , n = 12). The concentration
of norepinephrine was 100 µM (n = 9) and the concentration of
epinephrine was 42 µM (n = 12). Bars show means. Whiskers show
standard deviation. *P < 0.05; , ductus venosus; , branch of
portal vein.
Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.
Under normal conditions and during acute or chronic
hypoxia, hemorrhage and in response to vasoactive
substances
The blood flow in the UV was directly measured for the
first time by use of a ‘stromuhr’, placed in an umbilical
artery in fetal sheep63 . Direct measurement of the blood
flow volume in the DV is difficult because the DV is usually
located within the liver parenchyma. The four methods
most frequently used to determine quantitatively blood
flow rates in the DV and the UV and/or the DV/UV ratio
were: (1) cineangiography; (2) indicator dye-dilution;
(3) radioactively-labeled microspheres; and (4) blood flow
volume measurement using Doppler velocimetry. The
Ultrasound Obstet Gynecol 2006; 27: 452–461.
Tchirikov et al.
456
accuracy of these techniques in measuring flow ratios
or flow rates differs considerably. To our knowledge, no
experimental data on direct flow rate measurements of
both vessels with electromagnetic or Doppler velocimetry
probes were available.
Cineangiography was used to study fetuses, delivered by
Cesarean section, in which radio-opaque substances were
injected into the UV. Barclay et al. found that at least one
ninth (and probably more) of the umbilical blood passed
directly to the posterior caval vein via the DV36 .
The second method resulted in the occurrence of double
peaks of dye concentration in peripheral fetal arteries after
the injection of dye into a UV. The first peak represented
the umbilical venous blood through the DV, whereas the
second peak resulted from the slow passage of umbilical
blood through the hepatic vasculature. In 1975 Power and
Longo thus measured a DV shunting rate of 42.5 ± 5.2%
(mean ± SD), 36% after correction for the removal of dye
by liver parenchyma (Table 1)64 .
Rudolph and Heymann made the first quantitative measurements of DV blood flow rates, in 1967, by using the
radioactively-labeled microsphere technique on acutelycatheterized fetal sheep (0.7–0.9 of gestation)1 . The DV
shunting ratio varied considerably (Table 1). In 1979
Edelstone and Rudolph were also able to demonstrate
that DV-derived blood was preferentially distributed to
upper body organs, including the brain and heart3 .
Using the radioactively-labeled microsphere technique,
DV shunting in fetal Macaca mulatta was determined
to be 53 ± 14.3% of 208 ± 20 mL/min/kg UV blood
flow65 , and in 1973 Paton et al. described a similar DV
shunting ratio in anesthetized near-term baboon fetuses
(Papio spp.), using the antipyrine equilibration technique
together with the radioactively-labeled microsphere
technique66 . Rudolph et al. estimated DV shunting in
heavily compromised exteriorized human fetuses (0.3–0.5
of gestation, Table 1)2 .
The most frequent experimental condition to provoke
changes in the DV shunting rate was induced maternal
hypoxia, which was followed by fetal hypoxia. This
maneuver usually resulted in a significant increase in the
DV shunting rate (Table 1). Other techniques (cord and
aortic occlusion, fetal hemorrhage, reduction of uterine
blood flow), besides their respective circulatory effects,
will also influnce the state of fetal oxygenation.
Reduction of blood pressure and flow in the UV, by
partially occluding the descending aorta in fetal sheep,
resulted in a significant increase in DV shunting13 . The
authors postulated that at each reduction of UV pressure
there must have been a relatively high resistance to blood
flow through the liver as compared to flow through
the DV. This would explain why the proportion of
DV shunting increased with corresponding decreases in
blood pressure. In 1987 Itskovitz et al. investigated the
Table 1 The proportion of umbilical blood shunting through the ductus venosus in control fetuses and in fetuses under distress conditions
Authors
Rudolph and Heymann (1967)1
Behrman et al. (1970)65
Rudolph et al. (1971)2
Paton et al. (1973)66
Power and Longo (1975)64
Edelstone et al. (1980)4
Reuss and Rudolph (1980)7
Itskovitz et al. (1982)68
Itskovitz et al. (1987)67
Paulick et al. (1990)5
Paulick et al. (1991)6
Control
(%, mean ± SD
or range)
Jensen et al. (1991)59
Tchirikov et al. (1998)8
Tchirikov et al. (1998)9
Kiserud et al. (2000)10
Bellotti et al. (2000)11
Kiserud et al. (2000)55
Tchirikov et al. (2001)56
34–91
53 ± 14.3
51.6 (8–92)
55.4 ± 16.4
36 (10–73)
44.9 ± 8.3
57 ± 12
57.7 ± 4.8
43.9
50.5 ± 8
60.8 ± 6.8
62 ± 7.5
69.8 ± 8.8
66.8 ± 8.8
44.6 ± 18.6
43 ± 9
36 ± 5
32 and 18
40 and 15
17 ± 9
22 (13–41)
Haugen et al. (2004)16
Bellotti et al. (2004)12
Tchirikov et al. (2005)73
Tchirikov et al. (2005)73
25 (13–47)†
29 (21–35)‡
41 ± 18 (18–76)
28 ± 8 (17–42)
Distress group
(%, mean ± SD
or range)
90 ± 9
Distress situation
Hypoxia
49.5 ± 10.6
65 ± 12
67.2 ± 5.3
71.8
62.4 ± 10
73.5 ± 6.6
75.4 ± 7.9
62.9 ± 7
77 ± 14.5
53 ± 19.8
62 ± 8
53 ± 6
Hypoxia
Hypoxia
Hemorrhage
Cord compression
Hypoxia
Norepinephrine (1 µg/kg/min)
Epinephrine (2 µg/kg/min)
Vasopressin (4 mU/kg/min)
Angiotensin (100 ng/kg/min)
Reduction of uterine blood flow
IUGR
Hypoxia
SGA
29 ± 5
56 (17–97)
Hypoxia
Fetoscopic coagulation of one
umbilical artery
90 (59–117)‡
IUGR
Method
Sheep (RM)
Macaque (RM)
Human (RM)
Baboon (RM)
Sheep (DD)
Sheep (RM)
Sheep (RM)
Sheep (RM)
Sheep (RM)
Sheep (RM)
Sheep (RM)
Sheep (RM)
Human (Doppler)
Sheep (Doppler)
Human* (Doppler)
Human* (Doppler)
Sheep (Doppler)
Sheep (Doppler)
Human (Doppler)
Human (Doppler)
Marmoset (Doppler)
Baboon (Doppler)
*DV shunting in early and late pregnancy. †Median, 10th and 90th centiles. ‡Median, 25th and 75th centiles. DD, indicator dye-dilution
method; Doppler, blood flow volume measurement using the Doppler ultrasound technique; IUGR, intrauterine growth restriction; RM,
radioactively-labeled microsphere technique; SGA, small for gestational age.
Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.
Ultrasound Obstet Gynecol 2006; 27: 452–461.
Ductus venosus shunting in the fetus
distribution of blood flow in response to cord compression
in fetal sheep67 . Hepatic blood flow decreased after cord
compression and the proportion of DV shunting and
O2 delivery from the DV blood to upper body organs
increased67 . In 1991 Jensen et al. found no reduction in
umbilical blood flow in response to a graded reduction
in uterine blood flow after the constriction of the
common uterine artery59 . However, the brain and heart
obtained significantly more blood derived from the DV.
The proportion of UV return that bypassed the liver
through the DV significantly increased following fetal
hemorrhage, resulting in maintenance of the DV blood
flow, despite a marked decrease in the UV return68 . The
combined cardiac output and the umbilical blood flow
were distinctly reduced. The DV blood flow remained
constant, implying a significant decrease in umbilical
blood supply to the liver.
The DV shunting rate may also depend on blood
viscosity. In 1997 Kiserud et al. investigated the flow
distribution in isolated livers of fetal sheep, which were
perfused with blood with different levels of hematocrit69 .
The authors found that reduced UV pressure and increased
hematocrit favor an increase in the fraction of blood flow
through the DV (red boxes, Figure 1).
In 1980 Reuss and Rudolph demonstrated that, despite
a 40% reduction in total available oxygen in the umbilical
blood of fetal sheep during hypoxia, oxygen delivery to the
myocardium was significantly increased and maintained
to the placenta and the brain7 . Paulick et al., in 1990,
also found an elevated DV shunting during hypoxemia,
which was associated with an increase in the plasma
norepinephrine (11-fold) and epinephrine (55-fold), as
compared with controls5 . The authors discussed the role
of catecholamines in umbilical blood flow distribution.
One year later, the same group published results of a study
in which infusion of catecholamines increased the vascular
resistance of the UV and the intrahepatic branches of the
portal vein, resulting in an increase in DV blood flow
(Table 1)6 . Catecholamines may be responsible for an
increase in DV shunting during fetal hypoxia which is in
agreement with our in vitro results (red boxes, Figure 1)49 .
The idea of preferential UV blood flow through the DV
and foramen ovale to the left side of the heart and the brain
was well documented by Dawes et al. in 195470 , while
Cross et al. (1959)71 studied O2 saturation in anesthetized
fetal sheep.
The radioactively-labeled microsphere technique is
considered to be more accurate than the other methods
discussed above13 . However, this technique is invasive
and requires preparation of the fetal or placental vessels
for injection of the microspheres. In our opinion, the
fetus, after the surgical preparation of the fetal vessels in
acutely or chronically catheterized fetal sheep, cannot be
regarded as being completely under normal physiological
conditions. The DV shunting ratios measured by the
microsphere technique thus may be influenced by the
short- or long-term effects of surgical stress and of the
implanted catheters, which will undoubtedly block parts
of the fetal circulation.
Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.
457
Non-invasive, transcutaneous Doppler velocimetry
measurements in the UV and DV have been performed
in humans, as well as in experimental animals. The DV
shunting rate has been estimated in human fetuses under
normal conditions, in fetuses with intrauterine growth
restriction and in multifetal pregnancies8 . Absolute blood
flow volume through the DV increased with gestational
age, whereas blood flow normalized for estimated fetal
body weight (ultrasound morphometry), decreased with
gestational age8 . The proportion of UV return passing
through the DV was significantly increased in growthrestricted fetuses8,12 as well as in multifetal pregnancies
when compared with the control group. Accordingly,
the calculated umbilical blood supply to the liver
was significantly decreased in growth-restricted fetuses
and in multifetal pregnancies8 . As a consequence of
these findings, estimation of the proportion of DV
shunting may serve as an indicator of early fetal
distress in a clinical setting. The finding was confirmed
by other research groups using Doppler velocimetry
(Table 1)10 – 12,16,69,72,73 .
In sheep fetuses, we found a significant increase
of DV shunting during late hypoxemia induced by
maternal hypoxia9 . The DV blood flow volume rate
was not significantly increased (88 ± 29.6 mL/min to
101.7 ± 30.1 mL/min); however, the placental perfusion
was decreased from 238.7 ± 47.3 mL/min to 194.4 ±
58.4 mL/min, while umbilical blood supply to the liver
was reduced by 39%. In these experiments, fetal plasma
catecholamine levels were elevated9 .
We investigated the influence of reduced placental
perfusion, after coagulation of one umbilical artery, on
DV shunting using fetoscopy in acutely anesthetized fetal
sheep56 . The blood flow volume rate through the DV
remained constant (94 and 92 mL/min/kg) during the
reduction of placental flow from 408 to 173 mL/min/kg.
The DV shunting rate increased from 22% to 56% and
the estimated umbilical blood supply to the liver was
reduced by 70%56 .
Recently, Bellotti et al. found a dilated DV in growthrestricted human fetuses that also increased the DV
shunting rate12,54 . We investigated the influence of DV
dilatation on the placental and hepatic circulations in fetal
sheep15 . The DV diameter was increased up to 5 mm by
implantation of a stent. DV dilatation was associated with
a significant increase in DV shunting from 30.1% (range,
23.8–36.4%) to 59.2% (range, 49.3–69.0%)15 .
In conclusion, the increase in the proportion of
umbilical blood that bypasses the liver tissue through
the DV following or during fetal distress may facilitate
fetal adaptation by preferentially supplying important
fetal organs, such as the brain and heart, with oxygen
and nutrients. It requires changes of resistance to flow in
the DV and/or in those parts of the hepatic vascular
bed. Regardless of which vessel or group of vessels
is involved, the ratio of DV resistance to intrahepatic
venous resistance must decrease to allow blood to flow
preferentially through the DV (Figure 1). Umbilical flow
will also depend, of course, on the arteriovenous pressure
Ultrasound Obstet Gynecol 2006; 27: 452–461.
Tchirikov et al.
458
difference and placental vascular resistance (yellow box,
Figure 1). The diagnosis of increased DV shunting using
non-invasive Doppler velocimetry may improve the early
recognition of fetal compromise.
Methodology of the Doppler measurement of the DV
shunting
For UV blood volume flow measurement, a straight
segment of the intra-abdominal part of the UV upstream
of any hepatic branches should be selected, with the
Doppler gate positioned so as to completely cover the
vessel’s diameter. The UV flow volume can also be
measured in the umbilical cord. We suggest measuring
blood flow volume following the ‘maximum principle’,
which aims to determine the maximum diameter of the
vessel, the maximum intensity weighted mean velocity
(or time-averaged mean velocity, TAV) at the maximum
vessel length in a straight longitudinal section74 . The
inner vessel diameter is determined to the nearest tenth of
a millimeter by placing the calipers at right angles to the
vessel axis on a frozen B-mode image (without color). This
is followed by the TAV measurement at the same vessel
portion with a small angle of insonation (less than 30◦ ).
The blood volume flow rate is calculated from diameter
(D) and TAV as flow rate = TAV × π × (D/2)2 mL/min.
We recommend repeating flow measurements at least
three times (including the determination of diameters) to
improve precision. Doppler evaluations must be carried
out in the absence of fetal breathing and body movements.
Doppler velocimetry is increasingly being used in
prenatal medicine to estimate blood flow volume
rates12,16 . However, the precision of the method is still a
matter of debate, with accurate measurement of the vessel
diameter being regarded as a major problem. For example,
our first measurements, 9 years ago, of the DV shunting
rate in humans seem to have been higher when compared
to later investigations owing to the large diameter of
the DV isthmic portion measured with the ultrasound
equipment available at the time8 . Flow measurements and
thus calculation of the DV shunt rate should be regarded
with caution, especially when determined in small fetuses.
The requirements to measure precisely the true vascular
diameters and TAMXVs are difficult to fulfill; however,
no alternative non-invasive measurement technique is
currently available. The progressive development of
functional nuclear magnetic resonance and positron
emission tomography imaging, and three-dimensional
ultrasound techniques may improve the quality of blood
flow measurements in the near future.
Liver blood perfusion and DV umbilical blood shunting
in the regulation of fetal growth
The liver is privileged amongst fetal organs in that
it receives well-oxygenated, nutrient-rich blood directly
from the placenta. The anatomical position of the liver
also determines its role in controlling the distribution
of nutrients to other fetal organs. The liver produces
Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.
proteins, lipids and carbohydrates and is involved in
their metabolism75,76 . In addition, the liver synthesizes
insulin-like growth factors (IGFs), IGF binding proteins
(IGF-BPs), and other growth factors, which may influence
cell proliferation in fetal organs17 – 19 .
We developed a method in a fetal sheep model,
with twin pregnancies, in which the DV was either
occluded with an embolization coil14,77 or dilatated with
a wide-bore coronary stent15 . A catheter with a guide
wire was inserted into the right external jugular vein
of the fetus and advanced under ultrasound guidance
through the right atrium and the IVC to the DV77 .
The embolization coil was then placed in the DV to
occlude the vessel in one twin. The sibling fetuses served
as controls. The fetuses survived the DV occlusion for
up to 3 weeks14,15 . A wide-bore coronary stent was
used, instead of the embolization coil, to increase the
diameter of the DV using the same method of DV
catheterization15 .
Occlusion of the DV led to a significant increase in
relative liver weight from 3.4 ± 0.8% to 4.3 ± 0.8%14 . In
fetal skeletal muscles, heart and kidneys, the elevated
umbilical blood supply to the liver led to a 2- to
3-fold increase in cell proliferation (pKi−67), with a
corresponding 6-fold increase in cell proliferation in
the fetal liver. The index of proliferate cell activity in
the placenta was not different between groups. The
occlusion of the DV was associated with an apparent
increase in mRNA for IGF-I and IGF-II in the fetal
liver14 . However, we could not determine any significant
differences between twins in either body weight, or
in the concentration of amino acids, free fatty acids,
catecholamines and IGFs in the fetal plasma15 . It is likely
that the supply and consumption of amino acids and
free fatty acids in fetuses with an increased blood supply
to the liver were well-balanced owing to the placenta
not being affected. On the other hand, other growth
factors and parameters, such as IGF-BPs, insulin, leptin,
the epidermal growth factor and interleukins may be
involved in the regulation of fetal growth.
Stent implantation in the DV significantly decreased
umbilical blood supply to the liver by around half, from
499 ± 371 to 278 ± 219 mL/min, occasionally inducing
reversed blood flow in the hepatic veins with pulsations
in the UV. Reduced hepatic blood supply in the stent
group appeared to be associated with a 50% decrease
in cell proliferation in the liver and in the heart and
skeletal muscle. However, in some cases DV dilatation
increased total placental blood perfusion; thus, in spite
of a distinctly increased DV shunting rate, hepatic blood
supply was not diminished (unpublished observation). It
seems possible that the combined resistances to flow of
the DV and the hepatic vasculature may also influence
placental perfusion.
CONCLUSIONS
The present review summarizes the results of clinical and
experimental research on the DV in the fetal circulation.
Ultrasound Obstet Gynecol 2006; 27: 452–461.
Ductus venosus shunting in the fetus
The isthmic portion of the DV contains less smooth
muscle tissue than the intrahepatic branches of the portal
vein, which in vitro react more forcefully in response
to catecholamines than the DV. More α-adrenoreceptors
were found in the vessel wall of affluent hepatic veins than
in the DV, which may also contribute to the functional
difference. In humans, about three-quarters of the UV
blood supplies the fetal liver in late gestation, with the
remainder passing through the DV. The DV shunting rate
increases under fetal stress situations, in particular with
acute hypoxia of varying origin. This implies a decrease
in the umbilical blood supply to the fetal liver, provided
that total umbilical blood flow does not increase. The
increase in DV shunting rate is a general adaptational
mechanism to fetal distress and is observed in growthretricted human fetuses as well as twin pregnancies. The
late-gestational increase in the proportion of umbilical
blood that supplies the liver, as deduced from the decrease
in the DV shunting rate, may indicate that fetal maturation
in late gestation leads to an increasing demand for hepatic
metabolism. The relatively low non-stress shunt rates may
also allow a wide margin of DV shunt increases when
necessary in a temporary stress situation. The Doppler
velocimetric quantification of DV shunting may improve
the early recognition of fetal compromise in prenatal
medicine.
A long-term reduction in hepatic blood supply may be
involved in fetal growth restriction. The occlusion of the
DV leads to a significant increase in cell proliferation in
fetal skeletal muscles in the heart, kidneys and liver and
possibly to an increase in mRNA for IGF-I and IGF-II in
the fetal liver. These findings hint at the possible role of
the perfusion of the fetal liver in the control of the growth
process.
ACKNOWLEDGMENTS
We would like to thank Prof. Dr Torvid Kiserud,
University of Bergen, Department of Clinical Medicine,
Bergen, Norway, for his editorial help in creating Figure 1.
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