Evaluation of Fetuses Diagnosed with Megacystis During Prenatal Period

STUDY DESIGN: The data of cases who were prenatally diagnosed with megacystis between 1 January 2017 and 31 December 2019 were analyzed. Ultrasonography findings and antenatal interventions were withdrawn from the computerized database. Information about postpartum status was also received. The data were analyzed in terms of diagnostic methods, fetal interventions (vesicosynthesis, vesicoamniotic shunt), potential prognostic markers and short/long-term outcomes.


Introduction
Fetal urine production begins at approximately 10 th weeks of gestation. The fetal bladder can easily be visualized as a round or oval structure without echogenicity between two umbilical arteries in the pelvis by routine ultrasonography (1). Although urogenital anomalies are common, megacystis (MC) is very rare and its incidence is reported to be 0.06% (2,3). It has been reported that several genetic, environmental and teratogens may be responsible for urinary tract abnormalities (4). However, etiological factors directly related to MC has not been clarified yet.
The longitudinal diameter of the normal bladder in the first trimester is usually <6mm (2). The diagnosis of early-onset MC is made when the bladder is detected more than 7mm in the first-trimester ultrasonography. In the second and third trimesters, there is not a definitive cut-off value for the MC diagnosis, but the diagnosis is commonly made by the persistence of at dilated bladder visualization (1). MC is 8 times more frequent in male fetuses compared to female fetuses (4). MC pathogenesis is divided into two subgroups as obstructive and non-obstructive. Main non-obstructive causes are Prune Belly syndrome (PBS), Megacystis Microcolon Intestinal Hypoperistaltism Syndrome (MMIHS), chromosomal anomalies (especially trisomy 13 and 18), primary mega urethra, vesicoureteral reflux (VUR) and neurogenic megacystis. On the other hand, obstructive causes are more common and posterior urethral valve (PUV), urethral atresia and urethral stricture are the main causes in this group (5).
When the reasons of MC were examined one by one, the most common cause is shown to be lower urinary tract obstruction secondary to PUV (57%) (6). PUV is seen in 1/8 000 -1/25 000 births and is responsible for %4 of perinatal deaths. The presence of classical keyhole and thickened bladder wall may be detected in PUV related MC with an antenatal ultrasound examination (4). MC may be associated with a chromosomal abnormality in %15 of cases, especially in the nonobstructive group. An increase in nuchal translucency (NT) may be detected in patients with concurrent chromosomal abnormalities (6).
Gestational week at diagnosis, severity and type of obstruction effect postnatal prognosis. The prognosis varies according to the underlying pathology. Isolated obstructive MC can be treated in the prenatal period with several interventions. Methods such as vesicoamniotic shunt (VAS), valve resection and urinary stent are used for treatment in the literature (6,7) We evaluated the characteristics, follow-up processes, postnatal course and clinical management of fetuses who were diagnosed with MC in our perinatology clinic.

Material and Method
This study was designed retrospectively. The study protocol was approved by the Local Committee of Ethics in our hospital (90057706-799) and conducted according to the Declaration of Helsinki. Signed informed consent could not be obtained for the present study because of the retrospective design. Patients who were admitted to Ankara Etlik Zubeyde Hanim Woman's Health Care, Training and Research Hospital and diagnosed with megacystis between 1 January 2017 and 31 December 2019 were included in the study. Fetal bladder longitudinal diameter was measured between the bladder dome and the bladder neck in a sagittal plane, and the longest distance was used to diagnose MC. Diagnosis of fetal MC was made if the bladder size was >7mm in the first trimester. If the bladder was dilated in two sonographic evaluations within 45 minutes in the second and third trimester, fetuses were accepted to have MC. Patients diagnosed with MC were evaluated in perinatology council and detailed fetal ultrasonographic examination was performed for each case. Then, the appropriate invasive procedure was offered to determine both karyotype analysis and renal functions. The renal function was evaluated by using the laboratory findings of beta 2-microglobulin, osmolality, sodium, chlorine, calcium and total protein in the fetal urine sample.
Concurrent pelviectasis, echogenicity in the kidneys, urinary tract abnormalities and oligo/anhydramnios were noted. Cases without additional anomalies except urinary system anomalies were accepted as isolated MC. Patients were informed about prognosis and intrauterine treatment options after the detailed evaluation. Vesicosynthesis was performed to evaluate the renal function as a first step approach. VAS was recommended only for patients considered as isolated lower urinary tract obstruction with oligohydramnios and renal functions favoring a good prognosis. Postnatal genetic testing was recommended for patients who didn't accept prenatal karyotype examination. Informed consent was obtained for invasive procedures and archived in patient files. All prenatal diagnoses were confirmed by postnatal examination of the fetuses and postnatal images were also recorded.
All necessary data was withdrawn from the hospital registry system retrospectively. Information about the final health status of cases who did not continue to follow up was obtained by phone call.
Statistical analyses were performed using SPSS version 22 (Statistical Package for the Social Sciences, Chicago). Data were expressed as mean ± standard deviation, median (range) and percentage.

Results
There was a total of 15 MC cases during the study period. The characteristics, prenatal and postnatal findings of the cases are shown in table I. One of the fetuses was female and the remaining cases were all male. The median maternal age was 27 years (range between 19-33). The median diameter of the fetal bladder was found to be 19.35 mm (min. 10 mm / max. 61 mm). The median gestational week at the time of MC diagnosis was 13 weeks (range between 11-33). The gestational week at the diagnosis was under 18 weeks in 13 cases; thus early-onset MC rate was found to be 86.6%.
There was one twin pregnancy in which co-twin was healthy and reaming 14 were singletons. Ten of the patients were isolated (66.6%), however, 5 were associated with other system abnormalities (33.4%). The most common concurrent anomalies were; single umbilical artery (SUA), ascites, increased intestinal echogenicity, choroid plexus cyst, extremity anomalies and increased NT. Polyhydramnios was detected in one pregnancy which was thought to be secondary to skeletal dysplasia. In remaining cases, the amniotic fluid was normal or decreased. Ten patients underwent antenatal invasive testing (66%) and 1 patient had trisomy 18, while other karyotype results were all normal. Four of the patients did not continue their antenatal followup (26.6%), and we had sufficient postnatal information about only one of them. Four pregnancies with early-onset anhydramnios or hydrops fetalis were terminated (26%). In two patients (one co-twin), intrauterine demise occurred (13%) at 16 th and 35 th gestational weeks. Two of the 6 alive born fetuses died during the postpartum period. There were 4 fetuses alive at the time of study among 12 cases; thus survival rate was 33.3%.

Discussion
Hydronephrosis, dysplastic kidney, and oligohydramnios may complicate ongoing pregnancies with fetal MC due to lower urinary tract obstruction. Voiding disorders, renal failure, growth retardation or infertility are the other important complications in surviving fetuses (5). In these cases, bladder decompression before 20 weeks of gestation is thought to reduce perinatal mortality and morbidity (6). However, it should be kept in mind that procedures such as VS and VAS are temporary solutions. Fetal cystoscopic laser ablation is also a permanent alternative to PUV treatment but it has more serious complications (ascites, fetal death) and not a widely used method yet (7). To prevent fetal mortality, it is recommended to regulate the amount of amniotic fluid before the canalicular phase is completed during lung development phases (8). Beside the intrauterine treatment modalities, families may refuse these options. In this study; only 4 of 15 (26.7%) cases underwent VS, but no VAS was performed due to the family decision.
As shown in the present study, lower urinary tract obstructions are the leading cause of MC. This problem may be a component of different genetic or syndromic disorders. However, it may also be an isolated fetal abnormality without any associated findings. Antenatal invasive procedures may be useful to evaluate the chromosomal structure and renal function of the fetus in some cases. VAS should be considered in selected cases with normal karyotype after obtaining good prognostic test results by VS (9).
Despite all these diagnostic awareness, the etiology of megacystis may not be clearly identified in some fetuses with prenatal interventions. For this reason, postnatal evaluation is also important to have more detailed information about this issue and to provide adequate information to families.
According to a systemic review, the most common abnormalities associated with fetal megacystis was reported to be increased NT, followed by SUA and cardiac anomalies (10). Increased intestinal echogenicity, echogenic kidneys, and pelvicaliectasis were the most common findings in our series. Due to the lack of information, first trimester NT measurements could not be obtained for all cases in our study. Among 5 cases with first-trimester ultrasonography reports, 1 had an increased NT.
If keyhole sign, bladder wall thickening, and echogenicity are detected with ultrasonography, PUV should be considered as the potential cause of MC. However, it should be noted that these findings are not specific. In a series of 54 infants with obstructive uropathy, 90% of infants with PUV had a dilated, thick-walled bladder on prenatal US examination, but a keyhole sign had been noted only in 45% (11). Providing urinary drainage in patients with PUV is the main treatment option (12). Obstructive urethral atresia should also be considered in cases with concurrent umbilical cord cysts. Associated congenital anomalies are more common in these fetuses compared to PUV cases. Antenatal treatment methods may not be useful in such cases because the postnatal prognosis is already very poor (13).
All fetuses should be evaluated carefully in terms of potential associated chromosomal and structural abnormalities. To understand the postnatal prognosis, necessary tests for genetic syndromes should be performed after detailed ultrasonography. Presence of additional concomitant anomalies, chromosomal anomalies, early detection and anhydramnios in early gestational weeks are generally related to poor prognosis. Also, laboratory findings are the other important prognostic markers which show the renal function (10). Termination of pregnancy is an acceptable intervention if any bad prognostic criteria are obtained after careful evaluation. In the present study, we have shown that additional chromosomal anomalies, hydrops fetalis and early onset anhydramnios are the main indications for pregnancy termination.
Muller et al. evaluated 68 MC cases and reported that 35 cases were isolated with a rate of 57.3%. There were 3 fetuses with a chromosomal abnormality (2). Our findings are in concordance with these findings. We have shown that an additional abnormality rate was 33.3% among MC cases.
There are some limitations in our study. Firstly, renal functions could not be fully evaluated in all cases because some families refused a postnatal autopsy and some babies lost during follow-up. The difficulties of reaching the information of the patients and the fact that the obtained information is mostly taken from the families verbally, the reliability of the postpartum data is controversial. Because of the insufficient number of patients, it is not possible to reach guiding conclusions about the evaluation of MC cases. In conclusion, ultrasound is a very important tool in the diagnosis of fetal megacystis. The presence of associated anomalies may increase the rate of chromosomal abnormalities. Therefore prenatal invasive diagnostic methods should be kept in mind to clarify the etiology. VAS should be considered in cases of isolated obstructive megacystis in order to ensure urinary drainage after evaluation of renal functions. Since the prognosis varies considerably according to the underlying cause, fetal megacystis cases should be evaluated by a multidisciplinary approach in a tertiary center which has pediatric urology, genetic and neonatal intensive care units.