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Keywords:

  • Doppler;
  • ductus venosus agenesis;
  • fetus;
  • hydrops;
  • prenatal diagnosis;
  • sonography

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Objective

To evaluate the conditions associated with absent ductus venosus (ADV) diagnosed by prenatal ultrasonography.

Methods

Retrospective review of 23 cases with ADV diagnosed in two tertiary referral centers with a general screening policy concerning Doppler assessment of the ductus venosus. The results are discussed together with 63 cases from a review of the literature.

Results

In 19 fetuses the umbilical vein connected to the portal sinus, while the remaining four fetuses had extrahepatic umbilical venous drainage. Associated anomalies were present in 15 out of 23 fetuses: complex malformation syndromes (n = 6), chromosomal anomalies (n = 4), isolated cardiac defects (n = 4) and isolated extracardiac anomalies (n = 1). Eight fetuses had either no associated anomalies or minor anomalies. Hydropic changes were present in 12 of the 23 fetuses. In common with the reviewed cases, the presence of cardiac malformations, complex non-chromosomal malformation syndromes and hydrops was significantly associated with intrauterine or postnatal death while the type of umbilical venous drainage was not significantly different between survivors and non-survivors. However, among fetuses with no or minor associated anomalies the outcome was significantly better in the group without liver bypass.

Conclusions

ADV is significantly associated with fetal cardiac and extracardiac anomalies, aneuploidies and hydrops. Fetuses with liver bypass have an additional risk of developing congestive heart failure that significantly affects outcome, even if the fetal cardiovascular anatomy is otherwise normal. ADV without liver bypass seems to have a more favorable prognosis if it is not associated with other malformations. Copyright © 2006 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The fetal ductus venosus (DV) connects the intra-abdominal umbilical vein to the inferior vena cava at its inlet to the heart. The portocaval pressure gradient causes well oxygenated blood in the DV to accelerate towards the left lateral wall of the inferior vena cava enabling its preferential streaming through the foramen ovale and ultimately to the cephalic and coronary circulation1. It therefore plays a key role in the distribution of the umbilical venous return, even more so because the fraction of umbilical blood shunted through the DV increases significantly in hypoxemia and decreased placental return2, 3.

Absence of ductus venosus (ADV) in the fetus was reported in the nineteenth century4, but it was not until a decade ago that the first cases were detected in utero using modern ultrasound techniques5–8. Since these four initial reports, 63 additional cases have been reported in the English literature2, 6, 7, 9–22, which helped to define the frequent association with congestive heart failure, aneuploidies and cardiac as well as extracardiac malformations.

Two different routes for umbilical venous return have been described in fetuses with ADV:

  • 1
    Extrahepatic umbilical venous drainage bypassing the liver (the umbilical vein directly connects to the iliac vein, the inferior vena cava, the renal vein, the right atrium or, exceptionally, the left atrium or the coronary sinus14, 15, 19, 20).
  • 2
    Intrahepatic umbilical venous drainage without liver bypass (the umbilical vein connects to the portal sinus in its usual way without giving rise to the DV2, 10, 15, 16, 22).

While previous reports clearly demonstrated high incidences of congestive heart failure and agenesis of the portal venous system in ADV with extrahepatic umbilical venous drainage15, 19, 20, there is only scant information about the associated conditions of ADV with intrahepatic umbilical venous drainage, as only 10 cases have been previously diagnosed in utero2, 10, 15, 16, 22.

In order to shed some light on the associated conditions of ADV as well as the distribution of the two distinct routes of umbilical venous drainage we reviewed our databases for cases of ADV since the inclusion of Doppler assessment of the DV in all sonographic examinations in our two centers. We present the largest series of cases of ADV published so far, including 19 cases with intrahepatic umbilical venous drainage. The associated conditions are discussed together with 63 cases retrieved from a review of the literature.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Fetuses with a diagnosis of ADV were identified in the perinatal databases of two tertiary referral centers for prenatal medicine and fetal echocardiography (Lübeck, Germany, 1999–2002 and Bonn, Germany, 1999–2004). During the study period, the anatomical survey and fetal echocardiography were performed in a standardized fashion23, 24 including the assessment of the DV by color and spectral Doppler in all second-trimester and late first-trimester sonograms. In our institutions, where the referral base comprises high-risk pregnancies and/or fetal anomalies, the screening policy concerning anomalies of the DV was introduced by analogy with other markers of embryopathy that require more attention during the morphological examination, e.g. single umbilical artery25 or left persistent superior vena cava26. Furthermore, spectral Doppler assessment of the DV offers further insights into cardiac function27 over echocardiographic examination alone and is therefore routinely performed in our centers.

5.0–7.5-MHz curved array probes were used for all ultrasound examinations (Logic 9 and Voluson 730 Expert Pro, GE Healthcare, Solingen, Germany; Aspen, Acuson, Mountain View, CA, USA; ATL HDI 5000, Philips, Solingen, Germany).

The diagnosis of ADV was established by color Doppler demonstration of the absence of a connection between the portal veins and the inferior vena cava in optimal scanning planes for the visualization of ductal blood flow, using high, medium and low pulse repetition frequencies during several examinations10, 15. The DV was diagnosed as being absent, notwithstanding that the underlying pathophysiology may include primary agenesis as well as functional or structural closure.

Postnatal follow-up was available for all surviving patients of the study population, with a minimum follow-up of 6 months. Seven of the 12 non-survivors underwent autopsy by a specialist in fetal pathology and the diagnosis of ADV was confirmed in all of them.

Sixty-three additional cases were retrieved from a review of the English literature2, 6, 7, 9–22. Only cases from the past 10 years were included, as in cases prior to this period descriptions of the fetal anatomy were partly incomplete, rendering a comparison with our cohort difficult.

Statistical analysis of the incidence of the associated conditions and the outcome was performed using the χ2 and Fisher's exact test. P < 0.05 was considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Over the study period 23 fetuses were diagnosed with ADV. The reasons for referral were hydrops (n = 5), increased nuchal translucency (n = 4), complex malformation syndrome (n = 4), cardiac defect (n = 2), aneuploidy (n = 2), oligohydramnios (n = 1) and growth restriction (n = 1). The remaining four cases were diagnosed during routine scans in high-risk patients.

In 19 fetuses the umbilical vein connected to the portal sinus without giving rise to the DV (Figures 1 and 2; Table 1). In the remaining four fetuses the hepatic circulation was bypassed, the umbilical vein being connected to the abdominal part of the inferior vena cava in three cases (Figure 3) and directly to the right atrium in the fourth case (Figure 4; Table 2). In all four cases with liver bypass, a triphasic flow profile similar to that usually seen in the DV could be demonstrated in the umbilical vein. In contrast, fetuses without liver bypass had markedly dilated portal veins and a triphasic flow profile with unusually high peak velocities as well as antegrade flow throughout the cardiac cycle in the hepatic veins.

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Figure 1. Color flow map of the fetal portal circulation in a median sagittal plane at 22 weeks' gestation in a fetus with absent ductus venosus and intrahepatic umbilical venous drainage (Case 17). No connection between the umbilical vein and the inferior vena cava could be demonstrated in various planes using high, medium and low pulse repetition frequencies during several examinations. HV, hepatic vein; IVC, inferior vena cava; UV, umbilical vein.

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thumbnail image

Figure 2. Color flow map of the fetal portal circulation in a transverse plane at 33 weeks' gestation in a fetus with absent ductus venosus and intrahepatic umbilical venous drainage (Case 4). No connection between the umbilical vein and the inferior vena cava could be demonstrated in various planes. DAO, descending aorta; IVC, inferior vena cava; RPV, right portal vein; UV, umbilical vein.

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thumbnail image

Figure 3. Ultrasound image in the transabdominal plane at 20 weeks' gestation in a fetus with absent ductus venosus and extrahepatic umbilical venous drainage to the intra-abdominal part of the inferior vena cava (Case 20). The unusual winding course of the intra-abdominal umbilical vein is demonstrated. DAO, descending aorta; ICV, inferior vena cava; IUV, intra-abdominal umbilical vein.

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thumbnail image

Figure 4. Color flow map of the fetal abdomen in a median sagittal plane at 35 weeks' gestation in a fetus with absent ductus venosus and extrahepatic umbilical venous drainage to the right atrium (Case 22). RA, right atrium; UV, umbilical vein.

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Table 1. Associated anomalies, sonographic findings and outcome in 19 fetuses with absence of ductus venosus and umbilical venous drainage in the portal sinus (no liver bypass)
CaseAssociated anomaliesGA (weeks)Hydropic changesAdditional sonographic findingsKaryotypeOutcome
  1. CMV, cytomegalovirus; CoA, coarctation; DORV, double outlet right ventricle; GA, gestational age; IUFD, intrauterine fetal death; IUGR, intrauterine growth restriction; LPSVC, left persistent superior vena cava; PRUV, persistent right umbilical vein; PPROM, preterm premature rupture of membranes; SUA, single umbilical artery; TOP, termination of pregnancy; UV, umbilical vein; VSD, ventricular septal defect.

1Isolated extracardiac12 + 5Nuchal edemaExtrophy of bladder46,XYTOP, no autopsy
2Chromosomal25 + 3Bilateral hydrothoraces, cranial skin edemaAgenesis of corpus callosum46,XY, del 13p-TOP, autopsy
3Chromosomal12 + 4Cystic hygroma, generalized skin edema, ascitesNone45,X0IUFD at 16 weeks, CoA suspected at autopsy
4Chromosomal32 + 3NoneWolf–Hirschhom syndrome; IUGR, retrognathia, CoA, SUA46,XY, del 4p-Delivery at term, died on the second postnatal day, no autopsy
5Malformation syndrome19 + 3Hygroma colli, generalized skin edemaMuscular VSD, pectus excavatum46,XYTOP, autopsy
6Malformation syndrome26 + 3NoneVACTERL-association; bilateral fibula aplasia, bilateral renal agenesis, umbilical vein varix, SUA, biventricular myocardial hypertrophy46,XYTOP, esophageal and anal atresia detected at autopsy
7Malformation syndrome31 + 2Generalized skin edema, ascitesDandy–Walker malformation, horseshoe kidney left, DORV, cleft palate46,XYDelivery at 34 weeks, unexplained death at age of 9 months, no autopsy
8Malformation syndrome24 + 6NoneSmith-Lemli–Opitz syndrome; CoA, muscular VSD, LPSVC, hypospadia, PRUV, anal atresia, hypertelorismNot assessedDelivery at term, lives disabled, follow-up 1 year
9Isolated cardiac16 + 3Hygroma colli, generalized skin edema, left hydrothorax, placentomegalyDORV46,XYIUFD at 20 weeks, autopsy
10Isolated cardiac26 + 2NoneIUGR, tricuspid atresia with VSD, LPSVC46,XXIUFD at 38 weeks, autopsy
11Isolated cardiac19 + 4NoneIUGR, perimembranous VSD46,XX (placental trisomy 22)Elective preterm delivery at 32 weeks, alive and well without treatment, follow-up 1 year
12Isolated cardiac28 + 0Ascites, polyhydramnios, placentomegalyPulmonary atresia with VSD, supraventricular tachycardia, cardiomegalyNot assessedIntrauterine treatment with flecainide, hydrops resolved after cardioversion, alive and well after initial palliation, follow-up 6 months
13None/minor17 + 6Hygroma colli, ascites, bilateral hydrothoracesSingle umbilical artery46,XXTOP, autopsy
14None/minor32 + 6NoneUV varix46,XXDelivery at term, alive and well, follow-up 2 years
15None/minor21 + 6NoneLPSVCNot assessedDelivery at term, alive and well, follow-up 1 month
16None/minor33 + 1AscitesCardiomegaly46,XXDelivery at term, periportal fibrosis, congenital CMV infection, periventricular leukomalacia, alive and well with mild motor delay, follow-up 8 years
17None/minor15 + 6Hygroma colliNone46,XXDelivery at term, alive and well with mild hygroma, follow-up 3 years
18None/minor28 + 1NoneNone46,XXDelivery at 28 weeks due to PPROM, alive and well, follow-up 1 year
19None/minor36 + 1NoneNoneNot assessedDelivery at term, alive and well, follow-up 11 years
Table 2. Associated anomalies, sonographic findings and outcome in four fetuses with absence of ductus venosus and extrahepatic umbilical venous drainage (liver bypass)
CaseAssociated anomaliesGA (weeks)Venous connectionHydropic changesAdditional sonographic findingsKaryotypeOutcome
  1. CoA, coarctation; DORV, double outlet right ventricle; GA, gestational age; IVC, inferior vena cava; LPSVC, left persistent superior vena cava; RA, right atrium; SUA, single umbilical artery; Th, thoracic spine; TOP, termination of pregnancy; UV, umbilical vein.

20Chromosomal19 + 6UV–IVCNoneCardiomegaly47,XX + 21Delivery at term, alive, disabled owing to Down syndrome, follow-up 5 years
21Malformation syndrome21 + 6UV–IVCNoneDextrocardia, DORV, LPSVC, cardiomegaly, juxtaposition of IVC/aorta, aplasia of right lung, SUA, female phenotype46,XYTOP, gonadal dysgenesis, arteria lusoria, situs solitus of the atria, microphthalmia, malrotation and hypoplasia of cerebellar vermis diagnosed at autopsy
22Malformation syndrome16 + 2UV–RALeft hydrothorax, polyhydramniosVACTERL-association; esophageal atresia, horseshoe kidney, CoA, hemivertebrae Th 4–9, SUA46,XYDelivery at term, alive and well after surgical correction of defects, follow-up 3 years
23None/minor11 + 3UV–IVCHygroma colli, bilateral hydrothoracesCardiomegaly46,XXTOP, autopsy

Associated anomalies in our cohort were complex malformation syndromes (n = 6), chromosomal anomalies (n = 4), isolated cardiac defects (n = 4) and isolated extracardiac anomalies (n = 1). The remaining eight fetuses had either no associated anomalies (n = 5) or minor anomalies (one umbilical vein varix, one single umbilical artery and one persistent left superior vena cava). Cardiac defects were present in 11 out of 23 fetuses and therefore represent the most common associated anomaly in our series.

Hydropic changes were present in 12 of the 23 fetuses, six of them in combination with hygroma colli and six with hydrothorax. Cardiomegaly was diagnosed in six cases. While hydrops was equally distributed among the different types of umbilical venous drainage, cardiomegaly was significantly associated with the presence of a liver bypass (P < 0.05).

Seven couples elected to terminate the pregnancy. Three fetuses died in utero, one in the neonatal period and one in infancy. Among these latter five fetuses with continued pregnancies that subsequently died (one Wolf–Hirschhom syndrome (4p-), one monosomy X, one unclassified complex malformation syndrome and two isolated cardiac malformations), only two cases with intrauterine demise were attributable to ADV rather than to the associated conditions alone. Both had isolated cardiac defects (double outlet right ventricle and tricuspid atresia) that are generally not associated with intrauterine congestive heart failure and fetal demise and both had intrahepatic umbilical venous drainage. At the latest follow-up, 11 children were alive. Two of the survivors had ascites in the prenatal period that was probably not related to the venous anomaly (one had a congenital cytomegalovirus infection and one had supraventricular tachycardia that was successfully treated in utero with flecainide).

Among the 11 survivors (one Smith-Lemli–Opitz syndrome, one VACTERL-association, one trisomy 21, two isolated cardiac malformations and six with no or minor associated anomalies) none had sequelae attributable to ADV. All newborns had a liver sonogram performed prior to discharge that showed no abnormalities. There was no case of portal vein agenesis in our cohort. All six cases with isolated ADV are alive and are doing well.

A review of the literature of the past 10 years revealed a total of 63 prenatally diagnosed cases with ADV2, 6, 7, 9–22. Combining our series with the cases previously reported, a significant correlation could be demonstrated between extrahepatic umbilical venous drainage, portal vein agenesis and cardiomegaly (P < 0.05), while the associated anomalies were equally distributed among the different types of umbilical venous drainage. After exclusion of terminated cases the presence of cardiac malformations, complex non-chromosomal malformation syndromes and hydrops was significantly associated with intrauterine or postnatal death (P < 0.05) (Table 3), while the type of umbilical venous drainage was not significantly different between survivors and non-survivors. However, among fetuses with no or minor associated anomalies the outcome was significantly better in the group without liver bypass (P < 0.05): none of the 13 fetuses without liver bypass subsequently died, while in the group with liver bypass only 20 out of 29 survived (Table 4).

Table 3. Associated conditions and outcome of fetuses with absent ductus venosus in 23 cases from the current series and 63 cases retrieved from a review of the literature over the past 10 years2, 6, 7, 9–22
 Associated conditionsAlive at latest follow-up; total n (%)
Present study, n (%)Reviewed cases, n (%)Total, n (%)
  • *

    Significantly associated with intrauterine or postpartum death; P < 0.05 (terminated cases excluded).

Associated conditions23 (100)63 (100)86 (100)51 (59)
 Isolated extracardiac malformations1 (4)7 (11)8 (9)6 (7)
 Isolated cardiac malformations4 (17)5 (8)9 (10)6 (7)
 Complex malformation syndromes6 (26)5 (8)*11 (13)*2 (2)
 Chromosomal anomalies4 (17)7 (11)11 (13)4 (5)
 None or minor anomalies8 (35)39 (62)47 (55)33 (38)
Cardiac malformations11 (48)*14 (22)*25 (29)*8 (9)
Cardiomegaly6 (26)43 (68)49 (57)31 (36)
Hydrops10 (43)12 (19)*22 (26)*7 (8)
Portal vein agenesis15 (24)15 (17)12 (14)
Extrahepatic umbilical venous drainage4 (17)53 (84)57 (66)34 (40)
 Cardiomegaly4 (17)42 (67)46 (53)28 (33)
 Hydrops2 (9)12 (19)*14 (16)*4 (5)
 Portal vein agenesis14 (22)14 (16)11 (13)
Intrahepatic umbilical venous drainage19 (83)9 (14)28 (33)16 (19)
 Cardiomegaly2 (9)1 (1.6)3 (3)3 (3)
 Hydrops10 (43)10 (12)3 (3)
 Portal vein agenesis1 (1.6)1 (1)1 (1)
Table 4. Different types of umbilical venous drainage, their associated conditions and outcome in 42 fetuses with continued pregnancies and no or minor associated anomalies (eight cases from the current series and 34 cases retrieved from a review of the literature over the past 10 years2, 6, 7, 9–22)
 Associated conditions, nAlive at latest follow up, n
  • *

    Significantly associated with intrauterine or postpartum death; P < 0.05.

Extrahepatic umbilical venous drainage29*20
 Cardiomegaly2416
 Hydrops7*2
 Portal vein agenesis109
Intrahepatic umbilical venous drainage1313
 Cardiomegaly22
 Hydrops22
 Portal vein agenesis11

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Diagnosis of ADV with intrahepatic umbilical venous drainage has rarely been reported2, 10, 15, 16, 22. Autopsy studies suggest a significant association with complex fetal malformation syndromes, cardiac defects and hydrothorax8, 28. In addition, overperfusion of the liver sinusoids was suspected to induce portal congestion and even fetal hydrops8, 10, 28. Indeed, 12 out of 19 cases without liver bypass in our cohort were associated with additional fetal anomalies or aneuploidies. Ten out of 19 cases had hydropic changes that frequently included hydrothorax and hygroma colli, suggesting an underlying defect of the lymphatic drainage. However, the prognosis of isolated ADV seems to be more favorable in the presence of intrahepatic umbilical venous drainage. Together with the reviewed cases a total of 13 fetuses with isolated ADV without liver bypass have been reported so far (four associated with hydrops and/or cardiomegaly, one of them attributable to a cytomegalovirus infection and another to supraventricular tachycardia); all of them survived and none had long-term sequelae attributable to the ADV.

In previous prenatal studies, ADV with extrahepatic umbilical venous drainage was associated with fetal malformations, aneuploidies and high-output cardiac failure due to chronic volume overload of the central venous system and the cardiac chambers15, 19, 20, 22. This is confirmed in our current series as well as in the reviewed cases.

A further problem that potentially affects the long-term outcome in fetuses with ADV and liver bypass is the significant association with agenesis of the portal venous system, which may be compatible with undisturbed postnatal development29, 30 but has also been linked to a long list of severe postnatal complications including congestive heart failure, pulmonary edema31, focal nodular hyperplasia and hepatic tumors32–34. Among the reviewed cases 24% of fetuses with liver bypass were associated with absence of the portal venous system. However, the limited follow-up in most studies prevents any conclusions being drawn concerning the long-term outcome of this rare anomaly. In our own series all four fetuses with liver bypass had a patent portal venous system.

In the absence of additional fetal anomalies the prognosis of ADV with extrahepatic umbilical venous drainage seems to depend mainly on the presence and extent of fetal congestive heart failure19, 20. Our review of the literature supports this concept. Twenty-nine fetuses with isolated ADV and liver bypass were identified, ten of which subsequently died (seven intrauterine deaths with cardiomegaly and/or hydrops, two perinatal deaths of fetuses with congestive heart failure that were prematurely delivered, one sudden infant death). No long-term sequelae attributable to the ADV with liver bypass could be demonstrated in the survivors so far.

The most striking difference between the present study and the previously published series is the high proportion of intrahepatic umbilical venous drainage. The most plausible explanation for this discrepancy is that in our institutions Doppler assessment of the DV is an integral part of every ultrasound examination from the late first trimester onward. While ADV with extrahepatic umbilical venous drainage can be detected by the aberrant course of the intra-abdominal umbilical vein on gray-scale sonography, ADV without liver bypass is only reliably diagnosed by meticulous color flow mapping of the portal circulation in various planes.

The higher proportion of otherwise normal anatomy in the previously reported cases contrasts with a higher rate of complex malformation syndromes in our series, and might also be due to the above mentioned difficulties in diagnosing ADV with intrahepatic umbilical venous drainage. Our results suggest that (despite the growing body of literature) ADV with extrahepatic umbilical venous drainage is a rare finding that is more reliably diagnosed, while ADV with intrahepatic umbilical venous drainage occurs more frequently, but often escapes diagnosis even in the presence of other fetal anomalies.

However, it has to be kept in mind that our collection may not represent the full spectrum of associated conditions of ADV as it is biased by our referral base. Most of the cases were referred for suspected fetal anomalies, and the four isolated cases were detected during routine scans in a high-risk population. In their low-risk cohort Kiserud et al.2 found one case of ADV among 203 fetuses, but the study population was too small to reveal the true incidence of the different types of ADV and their associated conditions. Therefore further prospective studies in large and unselected populations are warranted.

In summary, ADV itself is significantly associated with fetal cardiac and extracardiac anomalies, aneuploidies and hydrops, independent of the type of umbilical venous drainage. Fetuses with liver bypass have an additional risk of developing congestive heart failure that significantly affects the outcome even in those with otherwise normal fetal anatomy. ADV without liver bypass seems to have a more favorable prognosis if it is not associated with other malformations.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References