UAT is a vascular disease with thrombi in one or both UAs, which can directly or indirectly affect the maternal-fetal circulation and leads to adverse perinatal outcomes. Since it has been rarely reported, its exact incidence remains uncertain. Heifetz [6] reported the incidence of UC thrombosis in deliveries, perinatal autopsies and high-risk pregnancies were approximately 0.08%, 0.1% and 0.4%, respectively. In our retrospective study, one single UAT was diagnosed in only 11 of 13258 pregnancies (13607 fetuses) postnatally, bringing the prevalence of 0.08%. Compared to UV thrombosis, UAT occurred less frequently [6]. However, it was more inclined to lead to adverse perinatal outcomes and was responsible for 80% of the stillbirths [6]. Sato et al. [7] reviewed 11 fetuses with UAT retrospectively, 38% of them were related to severe FGR and 25% led to intrauterine demise. Shilling et al. [8] reported 7 fetuses with one single UAT. Among them, 3 suffered from FGR, 2 were stillborn [8]. All neonates had been through an abnormal process and hypoperfusion was shown in all placentas [8]. Even though the blood flow of the unobstructed UA, amniotic fluid volume and fetal growth parameters in the third trimester are in normal range, UAT is still a life threaten event and the fetus could die suddenly without being noticed [9]. Thus, it is necessary to identify UAT more effectively by prenatal ultrasound, so proper clinical management can follow up as soon as possible.
At present, the etiology and pathogenesis of UAT have not been completely clarified. Hypercoagulability, blood flow stasis and endothelial injury are supposed to be the main reasons for thrombosis formation. As for UAT, it may be the same. It is well known that pregnant women are in a physiologic hypercoagulable state that can result in thromboembolism more easily. Hypercoagulability may be related to maternal genetic or acquired factors, for example, the unstable level of blood glucose of diabetes disrupting the coagulation function by affecting the expression of endothelial factors [10]. Not only maternal gestational diabetes mellitus, but also smoking and other complications during pregnancy such as hypertensive disease and thrombophilia can induce the formation of clots in UA [1, 2, 11]. Abnormal UC anatomy, mechanical injury of the UC, and pathological state of fetus or pregnant woman may be the high-risk factors for thrombosis of UC [6]. Cord abnormalities such as anatomical dysplasia, abnormal length (too long or too short), reduction of diameter, unusual Wharton jelly morphology, anomalous placental insertion, twisting, tieing, true knot, excessive helix or compression may induce flow stasis and lead to thrombi of UA [2, 7, 11–13]. According to studies in recent years, UAT might be closely related to accidental injury of the artery via unpremeditated UV puncture when inserting the needle into the cord [14]. Coincidentally, in our series, 2 out of 11 cases had undergone UV puncture. Consequently, we speculate that UV puncture is also a thrombophilia-related inducer. And there were 9 cases with U-fetal neck pressure traces before or when UAT was diagnosed by ultrasound, which implied cord-around-neck might cause blood flow stasis relating to thrombus formation. Avagliano et al. [11] considered the intrauterine infection could damage the vascular endothelium and caused inflammation and thrombus of umbilical vessels. Additionally, it was believed that protein S deficiency of the fetus which influenced the state of anticoagulant material in the endothelium of blood vessels might play an important part in the thrombosis of UA [1]. In our study, 1 newborn (Case 7) suffered from NEC, which might be related to the formation of intestinal microthrombi. 2 fetuses (Case 2, 3) were complicated with cardiac malformation (VSD and cTGA, respectively). However, whether intestinal microthrombi and fetal heart diseases are associated with UAT or not needs to be analyzed in further studies with larger sample.
Before UAT occurs, UC usually develops normally. Two-dimensional ultrasound imaging shows that the transverse section of UC includes three circular structures, of which the larger one is UV while the two smaller ones are UAs (Figure 2A), and the longitudinal section of the cord is arranged in a spiral form, which shows all of the three vessels are unobstructed. Color doppler imaging shows two UAs on both sides of the bladder and the vessels in the cord are in "one red two blue" or "one blue two red" structure in which different color means the opposite directions of blood flow. As shown in the ultrasound images of the cases in our study, when thrombosis in one UA occurs, the structure of three vessels can still be seen in the transverse and longitudinal section of UC. One UA is normal and the other one becomes thinner with thrombus filling inside in a hypoechoic or hyperechoic way by two-dimensional ultrasound (Figure 2B, 2D, 3A, 4B-4C, 4E, 5A, 5D, 6F). Color Doppler imaging shows only one UA is displayed on either side of the bladder, while the blood flow of the other UA is obstructed by thrombus in the bladder level (Figure 1B, 4A, 6B, 6E) and in the free segment of UC (Figure 1C, 2C, 2E, 3B, 4D, 5B, 5E, 6C). Some cases were accompanied by excessive helix of UC (Figure 3A-B, 4B, 4D, 6C). Thrombus observed in the lumen of one UA can be used as a direct sign to diagnose UAT. It is worth noting that ultrasonographic appearance of thrombus may be different depending on the occurrence time and the range of thrombosis.
It is easy to misdiagnose one single UAT as SUA when only one UA is found on either side of the bladder by prenatal ultrasound in the third trimester. Persutte et al. [15] inferred that the main reasons for the occurrence of SUA might be congenital agenesis or dysplasia and gradual disappearance of one UA in the later development, even both probabilities might coexist. The incidence of SUA reported in literature was around 0.31% [16], which was significantly higher than that of UAT. Due to the fact that SUA is associated with the congenital dysplasia of UC, it is detectable as early as 12 weeks of gestation age by modern ultrasonography equipment [17], while UAT usually occurs during the third trimester. Thus, it becomes possible for making the prenatal diagnosis of UAT via comparing the patient’s initial ultrasound scans, in which two arteries could be clearly seen in the cord, with later ultrasound images in the third trimester, which shows the pathological manifestation of UAT. However, when it comes to the cases without any routine ultrasound examination data before, the differentiation can only rely on the sonographic manifestation in late pregnancy. Compared to one single UAT, two-dimensional ultrasound imaging of SUA shows only two vessels, one artery and one vein, in the cord through the whole pregnancy. Color Doppler flow imaging shows only one UA on either side of the fetal bladder and the umbilical vessels are in "one red and one Blue", which represents different directions of blood flow. Besides thrombi observed in the artery, which was recognized as the direct sign of UAT, a distinctive ultrasonic sign of UAT found by Klaritsch et al. [18] was that one clogged UA was in parallel with the other unobstructed one and surrounded by UV, like ‘an orange grabbed by a hand’ in the transverse section of the umbilical cord. Moreover, Tanaka et al. [19] regarded ‘Orange grabbed sign’ might stand for hyper-coiling of UC, meanwhile, it was suggested as a repeatable and innovative way of UAT diagnosis. In our series, ‘Orange grabbed sign’ could be observed in Case 7 (Figure 4E) and Case 9 (Figure 6F). Since this sign is totally different from the ultrasound manifestation of SUA in the transverse section, it can be used for the differentiation between UAT and SUA.
In our study, thrombi could not be found in 3 cases (27.27%) (Case 9-11) by prenatal ultrasound, and they were misdiagnosed as SUA. 1 case (Case 7) had been misdiagnosed as SUA and the diagnosis was corrected to UAT in later examination. The possible explanation for this might be as follows: (1) The examiners lacked fully understanding of the implications of the presence of one single UAT. Thus, the ultrasonic history in the second trimester was often ignored and they failed to spend enough time in examining the vasculature of cord to find out the thrombi. (2) There were some technical difficulties, such as the blockage by fetus in the third trimester and examiners’ lack of training of complete observation of UC and thrombi in the artery. (3) Excessively spiral cord might cause narrower vascular lumen of UA, which made small thrombi hard to be detected. (4) The clots had formed for a long time and were gradually absorbed, so that it was too tiny to be detected. Therefore, comprehending the different formation mechanisms and ultrasonic manifestations of one single UAT and SUA is conducive to differentiate them from each other and improve the diagnostic accuracy. For those suspected cases, even if no direct signs of thrombi are observed, the diagnosis of UAT cannot be denied.
In our study, UA-S/D values were less than the 25th percentile and UA-PI values less than the 5th percentile. It was reported by Sepulveda et al. [20] that there was a compensatory increase of UA diameter in SUA since the entire blood flow was transported through only one UA. The patho-physiological changes might the same in UAT. We speculate that when one of the UAs is embolized, the other one will dilate in compensation to maintain the blood flow from the fetus to the placenta. Thus, the velocity of diastolic flow in the dilated UA increases in the whole cardiac cycle and the values of UA-S/D and UA-PI decrease relatively. Besides, our result showed an increase of ventricular diastolic velocity and a decrease of PI value of MCA (MCA-PI) in the spectrum Doppler. Due to the fact that the PI values of the unobstructed UAs are decreased, CPR (MCA-PI/UA-PI) tends to be normal. These changes might be related to fetal brain-sparing effect when one UA was obstructed. When intrauterine hypoxia occurs, fetal brain-sparing effect will be activated, with the cerebral arteries dilating and vascular resistance in ventricular diastole reducing, so that the cerebral perfusion can be maintained [21]. Hershkovitz et al. [22] found the resistance index of MCA in fetuses with SUA were similar to that in fetuses with a normal UC including two arteries. Currently, the vascular resistance indices of UA and MCA are being used to judge if there is intrauterine hypoxia. Whether they can also be used to differentiate UAT from SUA remains to be further confirmed.
SUA is associated with the high incidence of fetal anomaly. It was reported by Murphy-Kaulbeck et al. [23] that the fetuses and neonates with SUA had greater risks of congenital malformations and chromosomal abnormalities, 6.77 and 15.35 times respectively. Trisomy 18 and 21 were the most common chromosomal abnormalities [17]. Therefore, the prenatal identification of SUA by ultrasound may be helpful in the antenatal detection of congenital anomalies and aneuploidy. Xu et al. [24] implied that isolated SUA dramatically raised the risk for fetus of small for gestational age. Thus, when SUA fetuses are found by prenatal ultrasound, it needs not only to find out structural abnormalities of the fetuses, but also to assess their growth and development. Prenatal diagnosis for chromosomal anomalies and genetic counseling should be suggested. For the cases with the coexistence of only one UA displayed in the third trimester and fetal structural abnormalities, SUA should be suspected, which may be helpful in the differentiation between UAT and SUA.
According to the existing data, the standard of ultrasound scan and EFM frequency after the prenatal UAT diagnosis and the timing of pregnancy termination are absent. In Zhu’s opinion [25], when the signs of fetal intrauterine distress (reduction of fetal movement, abnormal EFM) appeared, the occurrence of UC thrombosis should be vigilant of, and ultrasound scan should be conducted seriously as well. For term pregnancy, emergency cesarean section should be performed without hesitation in order to avoid serious fetomaternal conditions [25]. For preterm cases, the duration of expectant management remained uncertain, and the timing to terminate pregnancy depended on the supportive capacity of NICU for premature neonates [25]. Dussaux et al. [26] reported a case of UV thrombosis diagnosed at 32 weeks of gestation with a slightly increased resistance index of UA found by Doppler ultrasound, in which close follow-up (daily EFM and weekly ultrasound scans) was suggested instead of emergency cesarean section after the diagnosis. Although the fetus died in utero 3 days later, the authors still insisted on expectant management and intensive fetal monitoring for the UC thrombosis cases before 37 weeks of gestational age on the basis of risk-benefit balance [26]. Luckily, in our study, the incidence of perinatal complications was not as high as reported in the literature, with only one fetus (9.09%) suffering from FGR. All fetuses were born alive, and their prognosis was good. The main reason might be most of the thrombosis were found by ultrasound prenatally, so that fetuses could benefit from the immediate clinical managements by obstetricians. Even if 3 cases (Case 9-11) were misdiagnosed as SUA, whose pregnancies were lucky to last without close surveillance until spontaneous delivery or elective cesarean section at term, and 1 case (Case 8) was given expectant management until full-term, we still recommended that emergency cesarean section should be performed once thrombus was found by ultrasound scan during term pregnancy. Fetal demise may happen all of a sudden without any warning. For preterm cases, even though EFM and ultrasound indices are normal during expectant management, the pregnancy should also be terminated by cesarean section once the gestational age exceeding 32 weeks, after the promotion of fetal lung maturation by corticosteroid therapy.