Prenatal diagnosis of persistent right umbilical vein – Incidence and clinical impact. A prospective study

Background Persistent right umbilical vein (PRUV) is usually an isolated finding but it may be accompanied by other fetal malformations. Aims We aimed to determine the incidence of prenatally diagnosed PRUV in a referral population, assess the neonatal outcome and discuss the findings together with those from previous publications. Materials and methods A total of 2360 women with low‐risk singleton pregnancies were examined in the second and third trimesters. A transabdominal convex volume transducer was used. B‐mode was applied in each patient. Scanning of the venous system included imaging of the target vessels with two‐dimensional colour Doppler mapping. The diagnosis of PRUV was made in a transverse section of the fetal abdomen. Three‐dimensional ultrasounds were performed as necessary, when anomalous cases were encountered. Results The incidence of PRUV in our population was 12/2360 = 0.5%, and it was higher than in other retrospective studies. In 75% (n = 9), PRUV was an isolated finding where delivery was uneventful and the postnatal outcome was favourable. In two cases PRUV was accompanied by omphalocele, and in one case by tetralogy of Fallot and single umbilical artery. Conclusions PRUV is an uncommon prenatal finding. Screening for this anomaly can be easily performed in all pregnant patients. A diagnosis of PRUV should be followed by a thorough fetal morphology scan in order to exclude any other malformations, especially those of the cardiovascular system.


INTRODUCTION
The anomalies of the umbilical veins may involve the persistence of embryological structures, abnormal insertion, course and supernumerary vessels. The majority of the anomalies of the venous system appear infrequently, and some of them may be completely asymptomatic. In early development, both umbilical veins (UVs) are connected to the sinus venosus. Obliteration of the right UV begins at four weeks gestation and at seven weeks it disappears. 1,2 The left one, which is connected to the left DOI: 10.1111/ajo.12791 portal vein (PV) in the fetal liver, then transports all the blood. When the right UV remains open it carries oxygenated blood to the heart. It may coexist with the left UV as an intrahepatic supernumerary structure. 3 Persistent right umbilical vein (PRUV) is an altered embryonic development, in which the left umbilical vein regresses and the right vein remains open. The precise incidence of this lesion has never been established; however, recent studies have demonstrated that PRUV is more common than previously thought, and occurs in 1/250-1/1250 pregnancies. [4][5][6] The exact incidence of PRUV might be higher, but the abnormality can be easily overlooked during standard ultrasound for abdominal circumference measurement. Better ultrasound techniques and colour Doppler and three-dimensional ultrasounds (3D US) may help in the diagnosis. [7][8][9] The cause of PRUV remains unknown. Thrombus obstruction, teratogens or folic acid deficiency are possible etiologies. 5,10,11 More recent retrospective studies have proven that fetuses with isolated PRUV (76.3-98.6%) have a good prognosis. 4,12,13 However, PRUV may be associated with the congenital absence of the ductus venosus (DV) and other severe fetal malformations. 7,10,14 In isolated cases when the DV is normally connected and the portal system has all its branches, the haemodynamics are supposed to be normal. However, a close follow-up is necessary to detect early signs of haemodynamic decompensation in the absence of DV. 4,15 The purpose of this prospective study was to determine the incidence of prenatally diagnosed PRUV in a referral population, assess the neonatal outcome and discuss the findings together with those from previous publications.
According to the available databases of worldwide literature, this is the first prospective study in Europe and only the fourth worldwide. 4,16,17

MATERIALS AND METHODS
Women with low-risk singleton pregnancies presenting for targeted organ scanning in the second and third trimesters were ex- US were performed as necessary when anomalous cases were encountered (Fig. 4). The imaging of the umbilical vein was similar to that described in other studies. 14,15 During the 3D data acquisition the women were asked to hold their breath. A medium wall filter and a gain of 50% were used. The volume angle was set at 55°.
In the cases of PRUV the diagnosis was confirmed by the second sonographer. Detailed fetal US and echocardiography were then performed to detect any other anomalies. In all cases of detected anomalies, a fetal karyotyping was offered. After birth, the infants were evaluated by paediatricians for any additional abnormalities.  In Poland, no written permission is needed to use or evaluate any data obtained during diagnostic examinations or standard therapeutic procedures for any scientific analysis. Any data provided the patients' name, religion, sexuality, ethnicity and so on, are not given in the final report.

RESULTS
There were 2360 women included in the study group. Their demographic characteristics are summarised in Table 1. PRUV was diagnosed in 12 women (0.5%). The median gestational age at diagnosis was 21 + 6 ± 2.5 weeks. The median maternal age in PRUV cases was 31 ± 4.39 years. In all cases, an intrahepatic type of PRUV (see discussion here) with present DV was observed. In nine cases (75%), PRUV was an isolated finding. In this group, seven healthy babies were delivered at term, and teo prematurely between 35-37 gestational weeks. The delivery was uneventful and the postnatal outcome was favourable in all cases of isolated PRUV ( Table 2).
In one fetus with normal karyotype, PRUV was accompanied by omphalocele. In another case of PRUV coexisting with omphalocele we lacked sufficient data on the fetal karyotype and time or mode of delivery. In one case, triploidy was diagnosed in a female fetus with PRUV accompanied by tetralogy of Fallot (TOF), and single umbilical artery (SUA). In this particular case, the gestation finished in a stillbirth and spontaneous delivery at 34 gestational weeks ( Table 2). Two variants of PRUV are described. 10 Type 1 -the intrahepatic PRUV (PRUV-I) -is the most prevalent, reported in 95% of cases. 1,12 In PRUV-I, the UV passes lateral to the right side of the gallbladder, connects to the right PV, and then bends toward the stomach. The DV is usually present and there is a little interference in haemodynamics. This type of PRUV has a good prognosis. All our cases were of the intrahepatic type, and DV was detected in all of them. Type 2 is the extrahepatic PRUV (PRUV-E), where the UV connects directly to the right atrium or the IVC. 1,12 PRUV-E is associated  other sonographic abnormalities but among them only one anomaly (1.4%) was clinically significant. 6 The extrahepatic types of PRUV are more frequently associated with these anomalies. 6 According to the analysis by Weichert et al., additional anomalies were present in all extrahepatic PRUV cases (n = 16). 5 The prognosis is thus worse than that of PRUV-I. 15 Aneuploidy testing showed no chromosomal abnormalities in any of the analysed PRUV-I cases in the study by Sun et al. 23 In the systemic review by Lide et al., 13 76.3%

DISCUSSION
of 240 cases of PRUV-I were isolated anomalies, but the rest were accompanied by heart abnormalities (7.9%), placental or umbilical cord anomalies (7%), genitourinary malformations (6.3%) or central nervous system malformations (3.8%). Genetic disorders were diagnosed in 1.3% of fetuses. Cardiovascular malformations also seem to be the leading coexisting anomaly in other reports. 15,23 The studies by Weichert et al. and Wolman et al., reported 74.4% and 76.4% respectively of isolated PRUV that had no associated anomalies, which is similar to Lide et al. 4,5,13 In our study, PRUV-I cases were isolated in 75%, which is consistent with the literature. 4,5,13 Out of 12 PRUV cases, three (25%) had different malformations. Two of the diagnosed fetuses had omphalocele, and in one case there were multiple abnormalities (TOF, SUA, PRUV).
Only two isolated and two non-isolated PRUV patients from our study group underwent fetal karyotyping. Aneuploidy was found only in the fetus with multiple abnormalities. The authors of the other reports suggest that invasive prenatal diagnosis should be limited to the usual obstetric indications because of the low prevalence of genetic abnormalities in isolated PRUV-I, but may be reasonable in the presence of additional abnormalities. 5,13,15 According to the databases of the worldwide literature, most of the investigations into PRUV have been either of a retrospective or review nature, and not prospective. They suggest that the incidence of PRUV amounts to 0.08-0.4% of all pregnancies. 5,6,13,15 In the most recent systematic review of the literature covering 166 548 women, the prevalence of PRUV was found to be 0.13%. 13 Our own data show a much higher incidence of PRUV than was traditionally considered and which is higher than in other European studies. 5,15 This higher incidence may be the result of the methodology as our study is prospective unlike the other retrospective and review investigations. The first prospective study in an Israeli cohort of 1810 low-risk women. 16,17 These differences may result from the size of the population under study.
In conclusion, PRUV is an uncommon prenatal finding but its incidence may be higher than traditionally thought. The most frequent form of PRUV is intrahepatic type without any coexisting malformations and this may be the reason why the anomaly can be overlooked on screening US. Prenatal screening for PRUV can be easily performed in all pregnant patients. The combination of 2D with multiplanar reconstruction allows the precise identification of the location of intra-abdominal UV, its shape and direction.
A diagnosis of anomalous venous anatomy or improper function