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ilation of the ductus venosus by stent implantationncreases placental blood perfusion in fetal sheepichael Tchirikov, MD, PhD

BJECTIVE: The reduction of resistance to flow in the ductus venousDV) and a decrease of blood supply to the liver serve for the survivalf the fetus during hypoxia. The present study investigated the influ-nce of the increased diameter of the DV on placental blood perfusion.

TUDY DESIGN: In 15 ewes with twin pregnancies at gestational agesf 117 � 4 days, a stent (4 or 5 mm) was placed into the DV of 1 twinDVstent group) under ultrasound guidance. Blood flow rates in the um-ilical vein (UV) and DV of both fetuses were measured using Dopplerltrasound. Eight pairs of twin fetuses were included for the finalnalysis.

ESULTS: The dilatation of the DV increased the blood flow volumeate passed through the DV from 136.61 � 41.07 to 398.93 � 86.62

obtained from the fetaoi: 10.1016/j.ajog.2007.06.066

38.e1 American Journal of Obstetrics & Gynecology JANUARY 2008

lood perfusion from 454.35 � 143.0 in control twin to 663.56 �67.36 in the DVstent group (P � .05, mL/min�1), respectively. TheV/UV ratio increased from 30.6 � 11.6% in the control group to 58.9

11.6% in DVstent gemini (P � .0001). The positive effect of DVilation on the placental blood perfusion was stable and could be ob-erved up to 3 weeks after the operation.

ONCLUSION: The dilatation of the DV by means of stent implantationn the DV increased the blood flow volume rate in the umbilical vein.etal surviving mechanism, the increase of DV shunting rate includingedistribution of the blood flow in the liver with a reduction of DVesistance to flow, could have a second effect: the improvement of re-uced placental blood perfusion during hypoxia.

mL/min , P � .0001) and also significantly increased placental Key words: ductus venosus, placental blood perfusion, stent

ite this article as: Tchirikov M. Dilation of the ductus venosus by stent implantation increases placental blood perfusion in fetal sheep. Am J Obstet Gynecol008;198:138.e1-138.e6.

he umbilical blood flow redistribu-tion in the fetal liver, the ductus ve-

osus shunting, is 1 of the main fetalechanisms to ensure the survival of the

etus during stress situations (eg, acuter chronic hypoxia).1-3 Usually severe fe-al hypoxia is associated with a reductionf placental blood perfusion.4 To protectital important fetal organs, such as the

brain and the heart, from hypoxic dam-age, umbilical blood centralization takesplace. Under this condition the ratio ofthe ductus venosus (DV) to the umbilicalvein (UV) blood flow increases to main-tain the oxygen supply to vital importantfetal organs.1-3,5-8 In normal conditionsin fetal sheep and primates, two thirds ofthe UV blood flow supplies the liver andabout one third passes through the DV(as measured by the radioactively labeledmicrosphere technique).1-3,5,9,10

Using Doppler ultrasound methodol-ogy, the actual DV shunting rate (ie, per-centage of umbilical blood flow that en-ters the DV) seems to be lower thanestimated with radioactively labeled mi-crospheres.6-8,11-13 During fetal hypoxiathe DV shunting rate increases becauseof the reduction of the liver blood supplyfrom the placenta. It should require a de-crease of resistance to flow in the DV andan increase of vascular resistance inbranches of the portal vein (afferent in-trahepatic veins) that receive blood fromthe UV.

In vitro investigation with vessel rings

that intrahepatic branches of the portalvein response was significantly strongerto catecholamines, compared with theDV.14 Other factors, such as reducedumbilical venous pressure and increasedhematocrit, could also reduce the umbil-ical blood supply of the fetal liver.15

Using ultrasound method Bellotti etal11,16 were able to demonstrate the in-crease of the DV diameter in growth-re-tarded human fetuses. Kiserud et al17

also demonstrated a substantial increasein the diameter of the DV during hypox-emia in fetal sheep, which is ordinarilyassociated with a catecholamine increasein fetal plasma.7 This phenomenon hasbeen discussed as an important part ofliver blood redistribution to maintainDV blood flow and also oxygen and glu-cose supply to vital important fetal or-gans during fetal stress situations.

In our opinion, this reduction of DVresistance to flow in response to stresssituations could have a second effect; itcould also improve the reduced placentalblood perfusion during fetal hypoxia.Jaeggi et al18 even described a distinct in-

rom the University Clinic of Obstetricsnd Gynecology, Johannes Gutenbergniversity of Mainz, Mainz, Germany.

eceived Oct. 3, 2006; revised Feb. 14, 2007;ccepted June 28, 2007.

eprints: Univ-Prof Michael Tchirikov, MD,hD, Johannes Gutenberg University Mainz,niversity Medical Center, Department ofbstetrics and Gynecology,angenbeckstraße 1, 55101 Mainz, [email protected].

he work was supported by Grant Schr 165/4-1 from the Deutscheorschungsgemeinschaft as well as theeutsch-russische Akademie für Geburtshilfend Gynäkologie.

002-9378/$34.002008 Mosby, Inc. All rights reserved.

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78 � 42% in 8 human fetuses with ex-rahepatic umbilical vein connectionsnd congenital agenesis of the DV be-ause the flow to the atrium will have aower resistance.

The aim of this study was to investigatehe influence of increased diameter ofhe DV on placental blood perfusion.

ATERIALS AND METHODShe experimental procedures were ap-roved by the board on animal studies ofhe State Authority for Labor, Health,nd Social Issues of the State of Ham-urg, Germany. The experiments wereonducted in 2001-2003 on 15 ewes withwin pregnancies at gestational ages of17 � 4 days.

urgical procedurehe ewes were sedated with xylazine in-

ramuscularly (Rompun, 0.25 mg/kg).urthermore, animals were anesthetizedith thiopental-sodium intravenously

i.v.) (Trapanal, 1.0 g) and intubated byrtificially ventilation with 1.0% to 1.5%soflurane in O2/N2O (2:1). Ewes re-eived 5% glucose and lactated Ringerolutions at 500 mL/hour i.v. The uterusas exposed through a midline abdomi-al incision under aseptic conditions.hen the head and neck of 1 fetus waselivered through the hysterotomy. Aatheter (5F HNB-5.0-38-45-PW-NS-PA, Cook, USA) and guide wire wereassed through a catheter port (RCFW,ook), inserted into the right external

ugular vein of the fetus and advancedhrough the right atrium and the ductusenosus into the intrahepatic part of thembilical vein under ultrasound controlAcuson Aspen, Walpole, MA, orOGIQ 9, GE Technology, Waukesha,I).19,20

A coronary stent (10-15 mm lengthnd 4 mm diameter in inflated state,iotronik Tenax, Berlin, Germany, n �) or flexible stent (30 mm length and 5m diameter in inflated stage, JohnsonJohnson, New Brunswick, NJ, n � 6)

ith a balloon catheter was placed in thesthmic portion of the DV in 15 twins.fterward the balloon was inflated for 1inute and the stent was fixed in the

sthmic portion of the shunt (DVstent e

roup, Figure 1A). The inserted catheteras removed and replaced by a short

hronic venous catheter in 9 fetuses. Ad-itional catheters were placed in theight carotid artery in all fetuses and inhe amniotic cavity in 6 experiments.he fetal head was returned into theterine cavity and the uterus was closed.The head and neck of the sibling fetusere exposed through the second hyste-

otomy. The sham catheterization of theV was performed in 9 fetuses. Then

atheters were inserted into the right ex-ernal jugular vein (n � 9) and the ca-otid artery (n � 15) as described earlier.he fetal incisions were closed, the fetalead was returned, and the uterotomyas sutured. These siblings served as a

ontrol group. All catheters were led tohe left flank of the ewe and stored in aouch attached to the maternal skin (n

6). In 9 ewes the catheters were at-ached to a port (Bard Access systems,alt Lake City, UT), which was fixed un-er maternal skin on the left flank to re-uce the risk of infection.Catheters were flushed daily (n � 6) or

FIGURE 1Blood flow profiles

uctus venosus flow in a DVstent fetus

he blood flow profiles in the DV after the stent in the DVstent, the diameter of the stent was usen the fetuses after the stent implantation (A). Dblique section (B). Inner diameters were determ

he calipers at right angles to the vessel axind-diastolic blood flow velocity; HR, heart rate;S, maximum blood flow velocity; RI, resistanceelocity; VF Diam, vessel diameter; VolFlow, blchirikov. Dilatation of the ductus venosus increases placenta

very 4 days (n � 9) with heparinized i

JANUARY 2008 America

aline (1000 U/mL). Antibiotic (cefazo-in-sodium, 1 g/day i.v. and 1 g/day intohe amniotic fluid in 6 animals) was usedo protect fetuses from infection. In 9 ex-eriments the antibiotic was given onlyerioperatively by using port systems.lood gases were determined every 4ays from carotid arterial blood samplesRadiometer Copenhagen ABL 710,openhagen, Denmark).

ltrasound Doppler blood flowolume measurementslood flow rates in the umbilical veinnd DV of both fetuses were measuredsing Doppler ultrasound (Acuson As-en [n � 6] or LOGIQ 9, GE Technologyn � 9]) with a 7 MHz convex ultra-ound transducer.

In most cases the Doppler evaluationsere done without any sedation of the

we.7

Both the time-averaged mean velocityTAV) and vessel diameter were deter-ined using a longitudinal section of the

mbilical vein in real-time mode follow-

Ductus venosus flow in a control twin

antation A, in the DV and B, in the control twin.r the calculation of the blood flow volume rateiameter of the control fetuses was measured ind to the nearest tenth of a millimeter by placingn frozen B-mode image (without color). ED,, mean blood flow velocity; PI, pulsatility index;ex; TAMAX, time averaged maximum blood flow

flow volume rate.od perfusion. Am J Obstet Gynecol 2008.

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ludes the measurement of maximal ves-el diameter and maximal TAV.21 Thengle of insonation was determined us-ng the maximum length of the intraab-ominal part of umbilical vein. DV di-meters were measured in obliqueection (Figure 1, A and B). Inner diam-ters were determined to the nearestenth of a millimeter by placing the cali-ers at right angles to the vessel axis on

rozen B-mode image (without color).

FIGURE 2Correct position of a stent in the D

orrect position of a stent (4 mm diameter andection of the stent (3 mm) is placed in the Rechirikov. Dilatation of the ductus venosus increases placenta

TABLE 1Blood gas parameters and weightin the DVstent gemini and the cont

Mean � SDParameter DVstent twins (n � 11)

pH 7.35 � 0.07...................................................................................................................

pO2 (mm Hg) 17.84 � 3.05...................................................................................................................

pCO2 (mm Hg) 53.75 � 4.51...................................................................................................................

BE 3.15 � 4.51...................................................................................................................

Weight (kg) 2.5 � 0.6...................................................................................................................

The blood gases were determined from carotid arterial blooDenmark). n.s., not significant.

Tchirikov. Dilatation of the ductus venosus increases placental

38.e3 American Journal of Obstetrics & Gynecol

V and UV blood volume flow ratesere calculated from the diameter (D)

nd TAV as milliliters per minute (flowate � TAV * � * [D/2]2).

In the DVstent group, the inner diame-er of the stent (4 or 5 mm) was acceptedor a DV diameter (Figure 1A). If neces-ary, flow measurements were repeatedincluding determination of diameters)o improve quality. The pulsatility indexf the umbilical arteries of twin fetuses

mm length) in the DV at autopsy. The smallcessus. An arrow points the stent.od perfusion. Am J Obstet Gynecol 2008.

deliverysiblings

Mean � SDControl siblings (n � 11) P value

7.36 � 0.03 n.s...................................................................................................................

18.77 � 3.91 n.s...................................................................................................................

52.82 � 3.72 n.s...................................................................................................................

3.50 � 2.33 n.s...................................................................................................................

2.4 � 0.6 n.s...................................................................................................................

mples (Radiometer Copenhagen ABL 710, Copenhagen,

fblood perfusion. Am J Obstet Gynecol 2008.

ogy JANUARY 2008

as also measured. Doppler resultseemed acceptable were documented onideo prints, stored on hard disc by using

LOGIQ 9 ultrasound machine (GEechnology), and also recorded on vid-otape. Each case was evaluated later us-ng information on prints and videos.

ermination of experimentshe experiments were terminated by in-

ection of a proprietary euthanasia solu-ion T61 (Hoechst/Aventis, Berlin, Ger-

any). Autopsies were performed onoth fetuses in parallel, and stent posi-ion was documented.

tatisticsata are presented as mean � SD andere compared between both gemini in

ach ultrasound Doppler examinationsing a Student t test for dependent sam-les. Calculations were carried out usingtatistica software (Statsoft, Tulsa, OK).� .05 was considered to be statistically

ignificant.

ESULTSn 11 fetuses the stent was found in theorrect position during autopsy (Figure). In 3 fetuses the stent was placed in-orrectly in the Rex recessus before isth-ic portion of the ductus venosus (dataere not included for the analysis). In 1

etus the 5 mm diameter stent was lost inhe DV on the fourth day after operation.t was identified by ultrasound and latern autopsy in the right atrium. One fetusied because of perforation of the righttrium during the catheterization. Twoetuses (1 DVstent fetus and 1 control fe-us) died before autopsy, so only 8 pairsf gemini were included for finalnalysis.

Data of blood gas examination areresented in Table 1. We did not find anyifferences between the DVstent groupnd the control siblings. The fetal weightas also not different between bothroups.The dilatation of DV by means of stent

mplantation from 2.7 � 0.3 mm in con-rol twins to 4 or 5 mm in the DVstent

roup significantly increased the bloodow volume passed through the DV

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roup to 398.93 � 86.62 in the DVstent

win (milliliters per minute�1, P �0001; Table 2 and Figure 3), respec-ively. The reduced DV resistance in theVstent fetuses was associated with a sig-ificant increase of placental blood per-

usion from 454.35 � 143.0 to 663.56 �67.36 (milliliters per minute �1; Table 2nd Figure 4). The proportion of umbil-cal blood passed through the DVDV/UV ratio) was also significantly in-reased in fetuses after stent implanta-ion, compared with sibling fetuses (Ta-

FIGURE 3Blood flow volume rate in theductus venosus (DV) in DVstentgemini and in the controlsiblings

1st 4 th 8 th 12 th

days post OP

0

100

200

300

400

500

600

700

DV

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ars show SD. Boxes represent the SEM. Meansre indicated by squares inside boxes. Dottedines connect fetuses from each twin pregnancy.pen circles represent the fetuses with the stent

n the DV. Control sibling fetuses are indicatedy closed circles. * P � .05; ** P � .0001.chirikov. Dilatation of the ductus venosus increaseslacental blood perfusion. Am J Obstet Gynecol 2008.

TABLE 2Blood flow volume rate in the UV,and the umbilical blood supply ofin the DVstent twin and the control

Mean � SDParameter DVstent twins (n �

UV (ml/min�1) 663.56 � 167.36...................................................................................................................

DV (ml/min�1) 398.93 � 86.62...................................................................................................................

DV/UV flow ratio (%) 58.9 � 11.6...................................................................................................................

LV (ml/min�1) 296.24 � 133.43...................................................................................................................

PI UA 0.39 � 0.22...................................................................................................................

The data were compared between both gemini in each ultrasouLV, calculated umbilical blood supply of the liver (LV�UV-Dsignificant.

Tchirikov. Dilatation of the ductus venosus increases place

c

le 2 and Figure 5). However, liver blooderfusion remained unaffected aftertent implantation in the DV because ofncreased placental blood perfusion (Ta-le 2).The stent implantation in the DV did

ot change the pulsatility index in thembilical artery (Table 2).The positive effect of DV dilatation on

he placental blood perfusion was stableFigure 4) and could be observed up to 3eeks after the operation (n � 1, dataot shown).

OMMENThe present study was performed inhronically instrumented fetal sheepith twin pregnancy 1 month before

erm. The dilatation of the DV by meansf coronary stent implantation in the DVlearly demonstrated the increase of pla-ental blood perfusion in fetal sheep. Theeduction of resistance to blood flow inhe DV after stent implantation in 1 ofach twin fetuses was associated with 146

37% higher blood flow volume rate inhe umbilical vein, compared with theibling fetuses.

This increase of placental perfusion asreaction to the DV dilatation using

tent implantation is important for un-erstanding the main fetal survivingechanisms, which include umbilical

lood flow redistribution in the fetaliver with an increase of DV shuntinguring stress situations. It must be ac-nowledged that the changes of the pla-

e DV, DV/UV flow ratio,fetal liver

blingsMean � SDControl siblings (n � 11) P value

454.35 � 143.00 .0017..................................................................................................................

136.61 � 41.07 � .0001..................................................................................................................

30.6 � 11.6 � .0001..................................................................................................................

307.24 � 155.05 n.s...................................................................................................................

0.56 � 0.21 n.s...................................................................................................................

oppler examination using a t test for dependent samples.PI UA, pulsatility index of the umbilical artery; n.s., not

blood perfusion. Am J Obstet Gynecol 2008.

ental blood perfusion during the hy- d


oxic situations may not be the same asn our twin model without hypoxia.

Associated with a raise of cat-cholamines, hypoxia decreased the re-istance in the DV and also caused an in-rease of inlet diameter of the DV in fetalheep, probably to ensure the oxygennd glucose supply through the DV toital important organs, such as brain andeart.7,9,15,22 Bellotti et al11,16 were ableo demonstrate the increase of DV diam-ter in growth-retarded human fetusessing ultrasound method. In the reviewrticle, Edelstone2 already discussed pas-ive reaction of the DV to alterations inystemic circulation (ie, pressure and re-istance differences across the liver). TheV could also react with a dilatation in

esponse to prostaglandin E1 to sodiumitroprusside and, probably, to in-reased central venous pressure duringypoxia.15,23,24

Hypoxia resulted in significant in-rease of umbilical venous blood flowhat bypassed the liver through theV.5,9,25 The afferent intrahepatic veins

trongly responded to catecholamineshan the DV that can obviously increaseesistance to flow in the hepatic venousirculation during hypoxia.14 In vitro in-estigation has shown on perfused liver

FIGURE 4Blood flow volume rate in theUV in DVstent gemini and thecontrol sibling group

1st 4 th 8 th 12 th

days post OP

0

100

200

300

400

500

600

700

800

900

1000

1100

UV

blo

od fl

ow v

olum

e ra

te (

ml -1

min

-1)

* Stent fetusesControl siblings

*

ars show SD. Boxes represent the standardEM. Means are indicated by squares insideoxes. Dotted lines connect gemini. Open cir-les represent the fetuses with the stent in theV. Control sibling fetuses are indicated bylosed circles. * P � .05.chirikov. Dilatation of the ductus venosus increaseslacental blood perfusion. Am J Obstet Gynecol 2008.

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mbilical venous pressure as well as in-reased hematocrit also increased theraction of flow through the DV.17 Thencreased placental circulation in our

odel could also be a result of an adap-ive response initiated in the liver thatas a reduction in its blood supply in ab-ence of hypoxia.

Under control condition in anesthe-ized fetal sheep, it has been shown thathe blood pressure decreased from 6.0 �.7 mm Hg in the veins draining cotyle-ons to 2.1 � 0.3 mm Hg in the inferioraval vein.26 In these acute experiments,esistance of fetal liver and umbilicalein can be calculated to be about 8%ith a mean central arterial pressure of0 � 2 mm Hg. The main pressure dropsf 55% occurred across the placenta. Inelation to these results, it could be ex-ected that dilatation of the DV byeans of stent implantation in the DV in

ur experiments could reduce the resis-ance to flow to a maximum 8% of wholeetal vascular resistance followed by anncrease of placental blood perfusionnly to a small degree.We found that a 2-fold increase of di-

meter of DV with stent that was associ-ted with a 3 times propagate of thelood flow through the DV increased thelacental blood perfusion to 146 � 37%,

FIGURE 5DV/UV ratio in DVstent geminiand the control sibling group

1st 4 th 8 th 12 th

days post OP

0.0

0.2

0.4

0.6

0.8

1.0

DV

/UV

flow

vol

ume

ratio

* *

Stent fetusesControl siblings

* *

ars show SD. Boxes represent the SEM. Meansre indicated by squares inside boxes. Dottedines connect twin fetuses. Open circles repre-ent the DV stent group, and closed circles in-icate the control sibling fetuses. * P � .05; **� .0001.

chirikov. Dilatation of the ductus venosus increaseslacental blood perfusion. Am J Obstet Gynecol 2008.

ompared with sibling fetuses. Obvi- t

38.e5 American Journal of Obstetrics & Gynecol

usly the dilatation of the DV involvedther adaptation mechanisms such as an

ncrease of the combined cardiac outputaused by volume overload and, proba-ly, a reduction in vascular resistance oflacental circulation. So Jensen et al27

emonstrated the increase of DV shunt-ng rate in response to reduced uterinelood flow with maintenance of placen-al blood perfusion. Jaeggi et al18 wereble to demonstrate an increase of com-ined cardiac output to 178 � 42% in 8uman fetuses with the umbilical veinrained either directly into the righttrium, inferior caval vein, or iliac veinith an agenesis of the DV. Aberrantmbilical vein was distended because of

ncreased venous return from thelacenta.We did not find any change of the pul-

atility index in the umbilical artery inVstent fetuses. However, the increased

ombined cardiac output could also takelace after the stent implantation in theV in our experiments. The cardiac out-ut was not carried out in our study,hich obviously limits the interpreta-

ions of the results. The used Doppler ul-rasound technique for the measure-

ent of the blood flow volume rate inhe vessels also has its limitations, but us-ng an ultrasound machine with a veryigh resolution combined with a longxperience in the flow volume measure-ent may help to reduce the intraob-

erver variability and to increase of qual-ty of the measurements.25

Edelstone and Rudolph1 were able toemonstrate that DV-derived blood wasreferentially distributed to upper-bodyrgans including fetal brain and heart.he venous redistribution under stress

ituations including increased propor-ion of the DV shunting and reducediver blood perfusion was assumed for aong time as a main fetal mechanism torotect vital important fetal organs, suchs brain and heart, from hypoxic dam-ge.1-4,25 In our opinion, the increase ofhe DV diameter leads to a normaliza-ion of the venous blood flow in spite ofncreased resistance to flow in the fetaliver during hypoxia, likely to ensure thedequate placental blood perfusion ando maintain the blood pressure in the in-
ravillous placental space. We assume b
ogy JANUARY 2008

hat this effect could be the main goal ofhe evolution to rescue the fetuses fromeath under hypoxic situations. The rel-tively good blood perfusion of therain, compared with the strong reduc-ion of the liver perfusion, also takes par-llel place in the fetuses underypoxia.5,27

Control mechanisms of resistance toow in the DV are largely unknown. Theresence of anatomical sphincter in theV is not clear until now. Chacko andeynolds28 described the anatomical

phincter in human DV. However, usinglectron microscopy, Mavrides et al29

ere able to show the lack of an anatom-cal smooth muscle sphincter at the DVnlet in human fetuses between 13 and 17eeks of gestation.In fetal sheep Coceani et al30 also de-

cribed a smooth muscle sphincter at theV inlet. We did not find well-organized

mooth muscle media at the DV inlet inetal sheep at gestational ages between 88nd 136 days as well as in nonhuman pri-ate fetuses in late gestation.14,31,32 Ob-

iously the amount of smooth muscleissue in the DV increased with gesta-ional age.14

The contraction abilities of isthmicortion of the DV in vitro and in vivoonditions are also controversial. Vesselings obtained from the isthmic portionf DV in fetal sheep contracted in vitro inesponse to catecholamines.14 On thether hand, in chronically instrumentedetal sheep, catecholamines infused intohe descending aorta decreased resis-ance to flow in the DV.10 Using ultra-ound methodology, Kiserud et al15

emonstrated in fetal sheep the lack ofontractile effect of �1 adrenergic ago-ist phenylephrine on the diameter of

sthmic portion of the DV.In conclusion, the dilatation of the DV

y means of stent implantation in theV increased the placental blood perfu-

ion. The fetal surviving mechanism, thencrease of DV shunting rate includingedistribution of the blood flow in theiver with a reduction of DV resistance toow, serves to not only protect vital im-ortant fetal organs, such as brain andeart, but also could have a second effect:he improvement of reduced placental
lood perfusion during hypoxia. The in-

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estigation of the placental perfusion ofrowth-retarded sheep fetuses in re-ponse to the stent implantation coulde useful for the understanding of mech-nisms of fetal survival. f

CKNOWLEDGMENTSthank Professor Dr Peter Nathanielsz (Depart-ent of Obstetrics and Gynecology, Center foromen’s Health Research, New York Univer-

ity School of Medicine, New York, NY) for hisditorial help. This study would not have beenossible without support of Professor Hobe J.chröder (University Medical Centre Hamburg-ppendorf, Hamburg, Germany).

EFERENCES. Edelstone DI, Rudolph AM. Preferentialtreaming of ductus venosus blood to brain andeart in fetal lambs. Am J Physiol979;237:724-9.. Edelstone DI. Regulation of blood flowhrough the ductus venosus. J Dev Physiol980; 2:219-38.. Rudolph AM. Hepatic and ductus venosuslood flows during fetal life. Hepatology983;3:254-8.. Block BS, Schlafer DH, Wentworth RA, Kre-

tzer LA, Nathanielsz PW. Intrauterine asphyxiand the breakdown of physiologic circulatoryompensation in fetal sheep. Am J Obstet Gy-ecol 1990;162:1325-31.. Reuss ML, Rudolph AM. Distribution and re-irculation of umbilical and systemic venouslood flow in fetal lambs during hypoxia. J Devhysiol 1980;2:71-84.. Tchirikov M, Rybakowski C, Hüneke B,chröder H.J. Blood flow through the ductusenosus in singleton and multifetal pregnan-ies, and in fetuses with intrauterine growth re-ardation. Am J Obstet Gynecol 1998;178:43-9.. Tchirikov M, Eisermann K, Rybakowski C,chröder HJ. Doppler ultrasound evaluation ofuctus venosus blood flow during acute hypox-mia in fetal lambs. Ultrasound Obstet Gynecol998;11:426-31.. Tchirikov M, Hecher K, Deprest J, Zirkulng L,evlieger R, Schröder HJ. Doppler ultrasoundeasurements in the central circulation of anes-

hetized fetal sheep during obstruction of um-ilical-placental blood flow. Ultrasound Obstet
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Dilation of the ductus venosus by stent implantation increases placental blood perfusion in fetal sheep