1. Discussion on the pathogenesis of single umbilical artery combined with bladder exstrophy
1.1 Single umbilical artery may contribute to fetal malformations
The umbilical cord begins to form at about 28 days of gestation. At the embryonic stage of 10 weeks after fertilization, the extraembryonic body cavity disappears, and the pedicle of amniotic membrane inclusions, degenerated allantoic, yolk sac and allantoic blood vessels form a cord-like structure, which is the umbilical cord. The allantoic vessels in the extraembryonic mesoderm outside the allantoic wall are divided into two allantoic arteries and two allantoic veins. After that, the right allantoic vein will degenerate, and the left allantoic vein will finally evolve into an umbilical vein. Nevertheless, the umbilical artery is always preserved, so in a normal umbilical cord, there are two lateral umbilical arteries and a thicker umbilical vein which is in the middle, and the three blood vessels are surrounded by Wharton's jelly.
Single umbilical artery is the most common umbilical cord dysplasia. The mechanism of occurrence of single umbilical artery is not fully understood yet. There are generally three theories: one is that there is only one umbilical artery when the embryo begins to develop; the other theory is that there are two umbilical arteries when the embryo begins to develop, but one of them gradually shrinks or becomes atresia in later development; and the third one is the persistence of the primitive allantoic artery of the body stalk. However, some scholars have proposed another possible mechanism of single umbilical artery: the allantoin-derived umbilical artery stops developing, or becomes atrophy or atresia after forming a normal umbilical artery, or the degeneration of yolk-derived vasculature fails [14]. Moreover, some scholars believe that the occurrence of single umbilical artery is not caused by a single high-risk factor, but may be related to genetics, environment or other factors [15]. Single umbilical artery can lead to malformation of multiple organs and systems in the fetus, and Staribratova [2] found that it was associated with an increased incidence of hollow organ atresia, renal abnormalities, limb reduction defects, and spontaneous abortion. Friebe-Hoffmann [3] conducted a retrospective analysis of 1169 singleton pregnancies prenatally diagnosed as single umbilical artery from 1997 to 2014. They found that 989 (84.6%) fetuses showed a single umbilical artery without any combinations. And 180 cases (15.4%) fetuses not only had a single umbilical artery, these cases also had structural abnormalities or chromosomal abnormalities. The structural abnormalities were mainly: 9.0% cardiovascular abnormalities, 3.5% genitourinary abnormalities, 2.9% skeletal muscle abnormalities, 3.0% gastrointestinal abnormalities, 2.1% brain abnormalities, and 2.1% fetal chromosomal abnormalities.
The current mechanism of abnormal fetal development caused by single umbilical artery is mainly the theory of “vitelline vascular steal” [4] and “disturbance of embryo caudal development” [5].
The “vitelline vascular steal” theory holds that a thick malformed vessel is derived from the vitelline artery which originates from the high abdominal aorta and performs the function of the umbilical artery. This artery transports blood from the umbilical cord to the placenta, while the abdominal aorta is often small and has no branches. Thus, the thick and deformed blood vessels “steal” a large amount of blood from the abdominal aorta into the placenta, causing its origin to be far from the abdominal aorta which leads the blood to be significantly reduced, and it contributes a serious lack of blood supply to various structures of the fetus. These in turn may lead to severe deformities of spine, lower limbs, kidneys, lower gastrointestinal tract, urogenital tract, and reproductive organs. Another study found that a single umbilical artery has a clear and definite relationship with the occurrence of caudal defect syndrome (such as Sirenomelia which is also called the mermaid syndrome). This discovery supports the theory of “vitelline vascular steal” which leads to abnormal fetal development, and the degree of blood loss and the timing of the embryonic developmental process may determine the exact type of defect [4].
Another theory of “disturbance of embryo caudal development” suggests that the umbilical artery is the largest caudal branch to the embryonic dorsal artery. If the primordium of the umbilical artery is not formed, the development of the dorsal caudal artery of the embryo will be abnormal. In addition, the development of embryos supplied by the caudal artery will be affected, resulting in deformities of the corresponding organ structures, which can lead to developmental deformities in three aspects: (1) the blood supply of the lower part of the early embryo is affected, resulting in abnormalities in the cloaca, urogenital tract, stomach and other organs or resulting in developmental malformations of the gut, central nervous system, and lower extremities; (2) there may be disturbances in the formation of the anterior abdominal wall below the umbilical cord; (3) embryonic hemodynamics is altered, resulting in cardiovascular malformations and possible development of defects toward the embryonic head [5].
1.2 Possible mechanism of occurrence of bladder exstrophy
BE is effectively short for bladder exstrophy-epispadias compound deformity, which is mainly characterized by the exposure to bladder mucosa. It is a rare and complex congenital malformation of the urogenital system. Main features of this condition include the absence of anterior bladder wall by different sizes, eversion of the posterior bladder mucosa, exposure to ureter and urethra and direct fusion of the posterior bladder wall with the lower abdominal wall skin [6]. The morbidity rate of BE is roughly 1/10000-1/50000, and the incidence ratio is proximately 1.5/1–5/1 as male to female on the basis of biological gender [7–8]. Presently, the exact pathogenesis of bladder exstrophy is unclear. The mainstream view is that mesenchymal cells fail to migrate between the ectoderm of the abdomen and the cloaca during the fourth week of gestation, resulting to a series of abnormalities such as eversion of bladder on the abdominal surface, inferiorly displaced umbilicus, divergence of pubis, and abnormal external genitalia [9–10]. Another hypothesis proposed by Satish is that pubic symphysis diastasis triggers a hammock status of levator ani muscles which forces the pelvic organs to move forward, resulting in the stretching, thinning and rupture of bladder and anterior abdominal wall. This aforementioned process is related to the formation of BE [16]. The etiology of bladder exstrophy is unknown but may be related to genetic, environmental and other factors. Most patients have normal chromosomal phenotypes, but Catharina et al. pointed out that rare genetic copy number variations may trigger BE [17].
1.3 Discussion on the relationship of bladder exstrophy and cloacal exstrophy
The bladder is part of the urinary tract, which is derived from the cloaca. The cloaca is the enlarged part of the terminal part of the rectum, which is connected to the allantoic ventrally and is the exit of the intestinal tract, urinary tract and reproductive tract. And the ventral caudal is closed by the cloacal membrane. In addition, the cloaca is divided into the primitive rectum and the urogenital sinus by the urorectal septum. The former differentiates into the rectum and upper anal canal, and the latter forms the bladder and urethra.
Typically, the cloacal membrane ruptures by the end of the 8th week of pregnancy. If it ruptures prematurely, it may cause cloacal exstrophy, bladder exstrophy, and other developmental abnormalities in the fetus. Cloacal exstrophy is commonly manifested as a combination of omphalocele, bladder exstrophy, imperforate anus, and spinal deformities. In 1978, scholar Carey named the four deformities of cloacal exstrophy in the form of acronyms and called them the OEIS syndrome.
At present, some scholars believe that bladder exstrophy and cloacal exstrophy should be regarded as a disease spectrum for clinical purpose. These scholars believe that both cloacal exstrophy and bladder exstrophy are abnormalities of early embryonic development, and they both belong to the abnormal development of the cloaca. Therefore, these two diseases should be included in the same disease spectrum to increase the cases of affected individuals and highlight their overlapping features, so as to better to explore their pathogenesis. They suggest that damage that occurs early in embryonic development leads to cloacal exstrophy. “Hits” occurs later in embryogenesis, the period after the urogenital septum has reached the cloacal membrane, leading to bladder exstrophy [11–13]. These malformations may also result from environmental or genetic abnormalities that impede the formation of the last somites of caudal, thereby preventing normal urorectal septum and allantoic development [19].
1.4 Single umbilical artery may cause bladder exstrophy
Several cases of single umbilical artery combined with cloacal exstrophy have been reported previously [19–21]. Therefore, if BE and CE are regarded as the same disease spectrum, then we can speculate that the single umbilical artery should have the probability of being accompanied by BE at the same time. The rationale is as follows: BE and CE are both abnormal development of the cloaca, and the association between single umbilical artery and CE has been confirmed, so there should be a certain probability that single umbilical artery will be accompanied by BE. However, previous cases have only reported that single umbilical artery and CE can be accompanied simultaneously, and so far, there is no report of single umbilical artery combined with BE in singleton pregnancy. Martínez-Frías, Bermejo, Rodríguez-Pinilla and Frías [18] investigated 1,601,860 live births and discovered that 8 cases had cloacal exstrophy, and about 37.5% of them were associated with single umbilical artery. However, no single umbilical artery was found to be associated with BE before. Therefore, our case which BE is accompanied by single umbilical artery strengthens the evidence that CE and BE are the same disease spectrum, and enriches the disease spectrum of single umbilical artery. The theory of “vitelline vascular steal” [4] and “disturbance of embryo caudal development”[5] discuss the mechanism of abnormal fetal development caused by single umbilical artery from different perspectives, and our case provides a new clinical evidence for the above theory, hoping to provide a new perspective for related theories.
2. How to diagnose single umbilical artery combined with bladder exstrophy
When the fetus has a single umbilical artery, two-dimensional ultrasound will show that it is in the shape of two parallel circles, and the long-axis section will show that the spiral is sparse. In addition, color Doppler ultrasonography will show that the umbilical artery and umbilical vein are running in parallel, and in the transverse section at the level of the fetal bladder, only the umbilical artery blood flow signal will be seen on the bladder side (Fig. 1).
When the fetus is associated with BE, the ultrasound findings are as follows: (1) no bladder can be seen in the pelvic cavity of the fetus; (2) there is a protruding mass in the abdominal wall of the lower abdomen; (3) the kidneys are normal and the amniotic fluid volume is normal; (4) the sex of the fetus is difficult to determine. Details are as follows:
Absence of bladder indication on prenatal ultrasonography is the first clue to the diagnosis of bladder exstrophy [22]. Normally, the fetal bladder can be fully displayed on ultrasound at 14 weeks of gestation, and the bladder is filled and emptied every 30 to 40 minutes. However, the posterior wall of the bladder with diagnosis of BE is directly adjoined with the abdominal wall, and the ureter on the bladder wall is exposed. Urine is drained directly into the amniotic cavity, and there is no urine filling in the bladder [23]. Bladder exstrophy can be diagnosed if urine is directly jetted into the amniotic cavity during fetal examination. This approach can shorten examination time and avoid waiting for possible bladder filling or multiple targeted ultrasounds to confirm the diagnosis. The dynamic observation of the fetal bladder is quite important during the second trimester structural screening. Especially when there is no obvious abnormality in both kidneys of the fetus and the amniotic fluid volume is normal, the disease should be highly suspected when the bladder between the bilateral umbilical arteries is not filled continuously for 30–60 minutes [24]. However, the bladder can have an alternating indication of filling and emptying, especially in fetuses with normal kidneys and normal amniotic fluid volume, sonographers tend to misidentify absence of bladder as bladder emptying, thus bladder exploration is easy to be ignored in sonography examination. Prenatal ultrasound of fetal bladder exstrophy often shows that the bladder between the two umbilical arteries in the lower abdomen is not continuously visible. Therefore, several studies suggest measuring the bilateral umbilical arteries when the bladder is not visualized [25]. However, in some rare cases as our case here, there is only one umbilical artery making it nearly impossible to assist diagnosis by measuring the umbilical artery. In addition, the urachal cyst in the lower abdomen and the umbilical cords on both sides are similar to the normal bladder, and the true bladder exstrophy is easy to be missed in some rare cases [16]. Prenatal diagnosis of bladder exstrophy becomes more difficult when the bladder is not visible which is also accompanied by bilateral renal malformations and oligohydramnios. Fetal structural malformation screening is usually performed near the 24th week of gestation. When diagnosed as bladder exstrophy, the gestation often reaches the later stage. In some special cases, fetal karyotypes are even required. It is often in the third trimester when the results of fetal karyotypes are received. Because of the late stage of gestation and related legal issues, the best time to terminate the pregnancy has passed. Therefore, methods for early diagnosis of this disease are urgently needed. Fishel-Bartal [22] discovered that the umbilical cord insertion–to–genital tubercle length of fetuses with bladder exstrophy was below the fifth percentile of the general population. This measurement can be used as a complementary objective ultrasound parameter in prenatal assessment and used for the diagnosis of suspected cases in early pregnancy. Under normal circumstances, an equilateral triangle consisting of the aorta, umbilical artery, and umbilical vein can be seen under color Doppler ultrasound, and Kavita Aneja [26] discovered that when the fetal bladder is everted, this equilateral triangle can deform. Thus, it is a finding that helps detect BE in early pregnancy.
A low-set umbilicus is another unique characteristic of bladder exstrophy, but currently neither ultrasound nor MRI has an objective reference point for evaluating the location of the fetal umbilical cord entry [27]. The judgment of the location of the umbilical cord mainly depends on the experience of the sonographer. Gilboa [28] suggested that the umbilical cord insertion-to-genital tubercle length of the fetus at 12 to 18 weeks of gestation was below the 5th percentile of the normal range, indicating a diagnosis of bladder exstrophy. Howbeit, it is difficult to obtain this section in fetuses over 17 weeks, which reduces the application value of this method in the diagnosis of BE.
A lower abdominal mass is another sign of BE, this mass is the bulging back wall of the bladder and bowel, mostly located below the entrance of the umbilical cord. Unfortunately, due to the occlusion of the umbilical cord set, the low intra-abdominal pressure, the non-protrusion of the everted bladder and the fetal position, the detection rate of the sub umbilical bulge mass is merely 28–47% [29]. In recent years, some scholars have also suggested that MRI is better at examining a lower abdominal mass than ultrasound does. When prenatal ultrasonography suspects BE but does not detect a lower abdominal mass, it is recommended to perform fetal MRI to assist the diagnosis. MRI can effectively identify ureteral and bladder wall abnormalities without possible interference by maternal body habitus, amniotic fluid volume and fetal position [30].
Frequently, BE is also accompanied by widened pubic rami. Prenatal ultrasound can determine the degree of pubic symphysis separation by measuring the distance of the fetal symphysis. Antomarchi [27] measured the pubic symphysis distance in 868 fetuses and found that this method was feasible in 71% of cases before 27 weeks of gestation. He then proposed that it can be used to distinguish almost any normal and pubic separation cases of age when the cut-off value is 1 cm, however, it is inapplicable in 60% of fetuses above 32 weeks of gestation.
BE is often associated with abnormal external genitalia, and the prognosis of male infants is worse than that of female infants. Prenatal ultrasound examination of fetal external genitalia can provide an important basis for the diagnosis of BE [31]. However, there are plenty types of external genital abnormalities. Thus, when prenatal ultrasound and MRI examinations are difficult to identify fetal gender, fetal chromosome examination can be recommended. In our case, the external genitalia were not clearly displayed on color Doppler ultrasound, and the sex of the fetus is highly related to the prognosis. Therefore, we arranged fetal MRI for her, but the external genitalia were still not clearly displayed (Fig. 2). The fetus also had a ventricular septum and a single umbilical artery, so the patient underwent amniocentesis for fetal chromosome examination. The chromosome result showed that it was male, and no other abnormal results were found. The patient and her family eventually chose to induce fetal demise because they were worried about problems related to the prognosis of the newborn, such as sexual life.