Antenatal diagnosis and management of fetal megacystis and lower urinary tract obstruction
Fontanella, Federica
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Fontanella, F. (2019). Antenatal diagnosis and management of fetal megacystis and lower urinary tract obstruction. University of Groningen.
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Final discussion
and future perspectives
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Summary
Fetal megacystis and congenital LUTO are severe conditions with challenging diagnostic work-up and controversial antenatal management (1)(2)(3)(4). In the previous chapters, we have reported in detail the results of a retrospective multicenter national study and a cross-sectional prospective study, with the main aim of providing clinicians with robust data regarding the differential diagnosis and management of fetal megacystis and LUTO. In summary, we firstly focused on the definition and differential diagnosis of megacystis (part 1); secondly, we aimed at optimizing patient selection in cases with isolated LUTO, theoretically eligible for antenatal intervention (part 2); finally, we concentrated on the antenatal prediction of prognosis in LUTO, both in terms of survival and postnatal renal function (part 3). In this last chapter, we provide a general overview of our results and present three management algorithms (figure 1, 2 and 3), developed on the base of our findings. To conclude, future perspectives and limitations of this thesis will be discussed.
From fetal megacystis to LUtO
The suspicion of LUTO typically arises from the evidence of an enlarged fetal bladder, also known as megacystis (1)(2). However, whenever faced with either early (diagnosed before or at the 17th week of gestation) or late megacystis (diagnosed after the 17th week of
gestation), a number of underlying conditions and associated structural anomalies need to be considered and excluded (2)(6).
In chapter 3, the etiologies of megacystis were investigated and in 33% of cases an underlying chromosomal abnormality, genetic syndrome or developmental anomaly cases was found. Fetal medicine specialists should be aware that fetal megacystis may appear as a corollary finding of an underlying genetic disorder and that associated structural anomalies can be detected in 30-34% of cases (chapter 3)(2)(6)(7).
At the light of this evidence, as shown in figure 1 and 2, we recommend to perform a detailed ultrasound scan, with special attention for the spine, skeleton and hear. It is also crucial to verify fetal sex as early as possible, since female fetuses carry a much worse prognosis, due to the common involvement of other abnormally developed organs. Moreover, amniocentesis or chorionic villus sampling (CVS) with QF-PCR should be offered more liberally in view of the well-known association between megacystis and chromosomal abnormalities, of which trisomy18 is the most frequent. Furthermore, in case of negative QF-PCR result and depending on the detected structural anomalies, arrays CHG and even prenatal WES or fetal MRI may be considered.
Early megacystis
(≤17th weeks’ gestation)
Detailed ultrasound examination with full anatomic survey + karyotyping (QF-PCR with fetal sex)
Presence of associated
anomalies Absence of associated anomalies
Consider further investigations (array CHG, fetal MRI) for excluding:
ANM, cloacal anomalies VACTERL association OEIS and CRS
Measure LBD
LBD > 12 mm LBD ≤ 12 mm
Repeat weekly US scan (resolution in 70% of cases)
Resolution before
23 weeks Resolution after 23 weeks
Good prognosis Recheck postnatal
Consider:
- UA (in case of associated UCC) - PUV
- MMHIS
See next flowchart (figure 3)
Figure 1. Clinical algorithm to guide fetal specialists in the diagnostic work-up and management of
early megacystis.
NT, nuchal translucency; LBD longitudinal bladder diameter; MRI, magnetic resonance imaging; UA, urethral atresia; PUV, posterior urethral valves; MMIHS, megacystis microcolon intestinal hypoperistalsis syndrome.
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Consider further investigations (array CHG, fetal MRI) for excluding: 22q11 deletion Overgrowth syndromes MMHIS Measure LBD LBD ≤ 22 mm LBD > 22 mm
Measure AFI, ureteral diameters, bladder volume and calculate LUTO score
Late megacystis (>17th weeks’ gestation) Good prognosis No Resolution before 23 weeks Score ≥ 9.5 .5 Score < 9.5
Consider isolated LUTO
Consider VUR and MMHIS See next flowchart (figure 3)
Check growth charts (Chapter 1) + Detailed fetal ultrasound + fetal echocardiography + karyotyping (QF-PCR with fetal sex)
Presence of associated
anomalies Absence of associated anomalies
Resolution before 23 weeks
Figure 2. Clinical algorithm to guide fetal specialists in the diagnostic work-up and management of
late megacystis.
LBD longitudinal bladder diameter; MRI, magnetic resonance imaging; VUR, vesicoureteral reflux; MMIHS, megacystis microcolon intestinal hypoperistalsis syndrome.
can in fact provide better imaging of fetal anatomy in case of severe oligo- or anhydramnios or suspicion of an anorectal malformation (8)(9). Array CHG should be in particular offered when heart defects are detected in order to exclude a 22q11 deletion syndrome (chapter 3)(10)(11).Other miscellaneous non-classic chromosomal abnormalities (e.g. duplication 19q13.33; deletion 5q.35.2; etc.) can be detected by array CGH in fetuses with isolated megacystis, however their clinical significance is uncertain for most of them (chapter 3).
Once complex megacystis and associated anomalies have been ruled out, the possibility of spontaneous resolution should be considered (12). From chapter 4, it can be inferred that the LBD measurement can reliably estimate the chance of resolution. In particular, the bladder enlargement will spontaneously regress in 70% of fetuses with early megacystis and LBD ≤12 mm (chapter 4), and cases of megacystis resolving before 23weeks’ gestation have generally a favorable outcome without major urological sequelae. The underlying cause for this transitory bladder enlargement may be sought, as previously suggested, in the immaturity of autonomic innervation and smooth muscle fibers in early gestation (12).
antenatal diagnosis of LUtO and eligibility for fetal therapy
In order to offer parents appropriate therapeutic options for LUTO and avoid meaningless interventions, only cases theoretically eligible for antenatal intervention should be selected (13). Although this concept may seem trivial and the diagnosis of LUTO may be considered straightforward, previous studies have highlighted that one third of all prenatally suspected LUTO are reclassified postnatally, with the majority of them reclassified to vesico-ureteral reflux (VUR)(14). Such cases would not benefit from in utero treatment and need to be identified prenatally (13).
In chapter 5, we investigated the best antenatal criteria for identifying, among fetuses with early megacystis, those with isolated posterior urethral valves (PUV), theoretically eligible for early fetal treatment. This approach demonstrated good accuracy with a sensitivity of 82% and a specificity of 68% (chapter 4). As shown in figure 1, we also found that the finding of an associated umbilical cord cyst (UCC) carried a high risk of urethral atresia (OR 15; p=0.3), which is an unfavorable form of LUTO, not eligible for early fetal cystoscopy (chapter 4). This finding confirms the hypothesis of Sepulveda et al., who speculated that an abnormally distended bladder may prevent the closure of the allantois in the first stages of life, when bladder is connected with the umbilical cord (15)(16), and may eventually lead to a cystic dilatation of the umbilical cord. This is more likely to occur in fetuses with an early and severe bladder enlargement, as it is the case in the setting of urethral atresia (17)(chapter 5). As shown in the second algorithm in figure 2, a standardized US approach with the assessment of bladder volume, ureters, amniotic fluid (AF) amount and fetal gender, should
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be carried out in fetuses with late megacystis. This recommendation originates from our findings in chapter 6, where the optimal combination of US parameters for diagnosing LUTO has been investigated (chapter 6). The assessment of these five antenatal parameters, and their combination in a clinical score, showed good discriminative capacity for predicting LUTO and reducing the number of false positive diagnoses (chapter 6). However, an external validation of these results is essential before endorsing this statement and supporting its clinical applicability.
Clinical heterogeneity and underlying pathophysiology of LUtO
In fetuses highly suspected for isolated LUTO, antenatal counseling and management should be individualized on the base of the expected outcome. This is made problematic by the highly variable natural history and outcome of LUTO. In fact, severe forms of LUTO can lead to early and massive bladder distention, renal dysplasia, oligohydramnios, and eventual soft tissue deformities (Potter sequence) (18)(19). Conversely, fetuses with milder forms of LUTO can even preserve normal AF amount throughout pregnancy and favorable renal function after birth (20). This heterogeneity in the clinical presentation of LUTO can be partially explained by two factors: the type of obstruction, and the reaction to the obstructive insult, with the occasional occurrence of a pressure ‘pop-off’ mechanism.The term LUTO refers to a heterogeneous group of anatomical defects, that includes urethral atresia, urethral valves and urethral stenosis. Urethral atresia (UA), defined as complete infravesical obstruction that obliterates the distalmost portion of the prostatic urethra, represents the most severe form of LUTO with very poor prognosis (21). Urethral stenosis constitutes a less common and less severe variant of UA and presents with narrowing of the urethral lumen. Urethral valves can be distinguished in anterior urethral valves (AUV), caused by a mucosal fold arising from the floor of the urethra (22)(23), and posterior urethral valves (PUV), that constitute the most common cause of LUTO with a birth prevalence of 1 to 2 per 10,000 live male births (24)(25). Three types of PUV have been described by Hugh Hampton Young (26)(27). Type I valves are the most frequent and appear as leaflets originating from verumontanum and extending in an inferior and anterior direction. Type II valves are not obstructive and represent mucosal folds extending superiorly from the verumontanum to the bladder neck. Type III valves appear as an annular ring or membrane in the posterior urethra (26).
Irrespective of obstruction type, LUTO can progress differently case per case: with megacystis or bladder wall fibrosis, with unilateral or bilateral hydronephrosis, with renal dysplasia or severe vesicoureteral reflux (28). This clinical heterogeneity can be partially explained also by the occurrence of a number of “pop-off” mechanisms, developed as
response to the increased intraluminal pressure within the urinary tract. Pop-off mechanisms could protect the urinary system from the deleterious effects of elevated bladder pressure by allowing urine to extravasate: into the peritoneal cavity (urinary ascites), within the perirenal space or retroperitoneum (urinomas) or in the umbilical cord (umbilical cord cyst and patent urachus). Another pop-off mechanisms is represented by the cystic dilatation of the ureter (ureterocele), that in some cases can expand into the bladder and obstruct the urine outflow, thus constituting a non-classic and infrequent cause of LUTO (obstructive ureterocele) (26). The development of bladder diverticula or unilateral vesico-ureteral reflux have been also defined as pop-off mechanisms (29)(30).
To date, antenatal pop-off mechanisms of LUTO have been little studied and their role in terms of perinatal and long-term outcome has not been yet elucidated. It still not clear whether they could protect the urinary system from the deleterious effects of an elevated vesical pressure or they could rather indicate the presence of a severe insult that will anyway entail bladder and urinary dysfunctions later in life (30). Hereby in Table1, we report on the incidence of some of these pop-off mechanisms in our retrospective cohort.
table 1. Incidence and GA at diagnosis in fetuses developing or not a pop-off mechanism.
Incidence GA at diagnosis of megacystis
Urinary Ascites 41 (8%) 20 ±6
UCC 41 (8%) 16 ±6*
Urinomas/ureterocele 27 (5%) 24 ±7
Rest of the population 432 (80%) 21 ±8
UCC, umbilical cord cyst; GA, gestational age; ANM, anorectal malformations; TOP, terminations of pregnancy; IUFD, intrauterine fetal death; eGFR, estimated glomerular filtration rate.
Staging of LUtO
The type of obstruction and the occasional development of pop-off mechanisms can partially account for the erratic variability in the clinical presentation of LUTO, that leads to a different timing and severity of urinary distension, oligohydramnios and renal impairment. Although the anatomical details of the urinary obstruction cannot be established during fetal life, their effects in term of urinary distension and progression to oligohydramnios can be more easily assessed.
For this reason, in the last part of the thesis, we focused on a series of US parameters to predict perinatal mortality and postnatal renal function of LUTO (chapter 7 and 8). Figure 3 summarizes our results in the form of a management algorithm, specifically formulated for male fetuses at high risk of LUTO, selected by following the two previous algorithms
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(figure 1 and 2). However, it is probably essential to specify that female fetuses with LUTO are generally anyway excluded from fetal therapeutic interventions, since they almost invariably have a poor prognosis and extensive anomalies in the genitourinary region, including bowel, uterus and pelvic floor.
In chapter 6, we have shown that the risk of perinatal mortality can be estimated by considering gestational age at first evidence of oligo- or anhydramnios, and the bladder volume at diagnosis. According to these two criteria, the severity of LUTO can be classified as severe, moderate of mild, entailing a perinatal mortality of 55%, 26% or 9%, respectively (chapter 7).
Antenatal determination of renal injury in obstructive uropathy has been so far considered problematic (31). Previous observational studies reported that the accuracy of prenatal ultrasound for predicting renal function has low sensitivity and specificity (31)(32). In chapter 5, we tried to elaborate a model based on prenatal US examination to predict postnatal renal function. We found that evidence of keyhole sign, hyperechogenicity of the renal cortex and abnormal amniotic fluid volume at diagnosis were associated with poor postnatal renal function (chapter 8).
On the basis of the proposed staging system and the predicted postnatal renal function, the parents can be extensively counseled on the management options. In the majority of cases, parents will opt for terminating the pregnancy or for an expectative management (33)(4)(34). In a minority of cases, fetal intervention can be attempted.
Management of LUtO
As discussed in the introduction of the thesis, the first antenatal therapeutically attempt for LUTO consisted in a bilateral utererostomies performed in open fetal surgery (35). This technique was promptly abandoned in favor of percutaneous vesico-amniotic shunting (VAS), that currently represents the most commonly used method to relieve the obstruction (36)(37). VAS has been widely used for at least 25 years and more than 300 cases of shunt-treatment have been reported in the literature (37). During these years, different types of shunts have been developed, and a number of complications, such as shunt displacement, shunt blockage, preterm labor, chorio-amnionitis, iatrogenic gastroschisis and urinary ascites, have been reported (13).
Few studies have analyzed the pro and con of each shunt, therefore hereby, in table 2, we report an overview of their main characteristics.
Weekly US for bladder and AF measurement + estimate the prognosis
Severe LUTO:
Bladder volume >5.4 cm3
and/or oligohydramnios before 20 weeks Perinatal mortality: 55% Poor renal function: 44%
Moderate LUTO:
Bladder volume <5.4 cm3
and/or normal AF at 20 weeks
Perinatal mortality: 26% Poor renal function: 31%
Mild LUTO:
Normal AF at 26 weeks Perinatal mortality: 9% Poor renal function: 11%
Counsel on management options
Expectant management
Fetal intervention
Estimate postnatal renal function by US scan + vesicocentesis and urine biochemistry + karyotype (if not already performed)
Good renal function Poor renal function Early and late megacystis in male fetuses
at risk of isolated LUTO
Weekly US scan and consider amnioinfusions as experimental option
Termination of pregnancy
Deliver at a tertiary care facility
Figure 3. Clinical algorithm to guide fetal specialists in the diagnostic work-up and management of
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table 2. Characteristics of different catheter types used for VAS (38).
Double-Pigtail Double-Basket
Characteristic Rocket Harrison Hakko
Diameter of device (F) 6.5 5 4.5
Diameter of coils-opened basket (mm) 18 NA 10
Length between both coils-baskets (mm) 3 1.5–3.5 2-3
Amniotic portion Double coil Double coil Basket
Intravesical portion 1.5 coil Single coil Basket
Double-pigtails catheters represent the classic choice. Two different types of double-pigtails catheters are available: Harrison type (Cook Medical, Bloomington, IN) and Rocket KCH one (Rocket Medical plc, Watford, England). The risk of shunt dislocations seems to be higher for the Harrison fetal bladder stent compared to the Rocket KCH fetal bladder catheter (78%
vs 30%). Due to its smaller diameter, some clinicians prefer the Harrison catheter before 18
weeks’ gestation (39)(40). A double-basket catheter has been more recently developed. This is a shunt with smaller diameter, therefore less invasive and with a lower risk of premature rupture of membranes (38). Despite the small diameter, the risk of occlusion seems comparable to that of the double-pigtail catheter, while the risk of dislocation seems to be higher (38).
Fetal cystoscopy represents to date a promising alternative to VAS, although several technical difficulties still limit its use (13). In fact, in order to get a good visualization of the bladder neck, the scope would need to have a significant curve. Moreover, inserting the device in the dome of the bladder and manipulating it to enter the posterior urethra leads to leakage of urine into the abdominal cavity with subsequent loss of pressure in the bladder. For this reason, continuous fluid infusion and rapid performance of the procedure is needed. If the procedure fails to open the urethra, a shunt may be inserted through the cystoscope’s trocar, however the position of the shunt in the dome of the bladder is not ideal. Fetal cystoscopy allows to perforate the urethral valves by using hydroablation, guide-wire or laser fulguration and thus to restore the physiologic micturition (41)(42). Complications related to fetal cystoscopy are urethro-cutaneous or urethro-rectal fistulas, reported in 10% of treated fetuses (43).
In our cohort, all fetuses were treated with VAS, with the use of the Rocket shunt, and only in one fetuses, after the second VAS dislodgement, fetal cystoscopy was experimentally attempted.
Limitations and strength of this thesis.
A number of potential limitations of this thesis needs to be acknowledged. Firstly, our results, except those from chapter 1, have been based on a retrospective study. The retrospective study design nature has limited the possibility to obtain specific measurements (such as urinary biochemistry, serial measurements, 3D bladder volume, echogenicity of renal parenchyma) in all cases. Despite this major limitation, the nationwide setting of this project constitutes a major strength of the thesis, and makes of this study the largest thus far published datasets on this topic.
In this thesis, the bladder volume showed to have a central role for the diagnostic and prognostic assessment of megacystis and LUTO. Based on our results, we strongly recommended to incorporate the bladder measurement in the standard assessment of fetal megacystis and congenital LUTO. In the study the bladder volume was mathematically calculated from the three bladder diameters, rather than directly measured by the 3D US. This implied a bias due to the inaccuracy of the available formulas for measuring the fetal bladder (45)(46). We speculate that the bladder volume, measured by using 3D US, could have an even stronger prognostic and diagnostic value and future studies in this direction are needed. Moreover, for defining second and third trimester megacystis, we did not used a specific cut-off for the bladder enlargement but rather the most commonly used definition of a bladder failing to empty within 40 minutes. In fact, when our retrospective data collection was started, no reference range for defining an abnormally enlarged bladder was available. For this reason, we started to construct prospectively fetal bladder growth charts in Chapter 1.
Another crucial limitation of this study is the lack of an external validation for our proposed prediction models (chapter 5, 6 and 7). External validation is of paramount importance to judge the applicability of a prognostic model in a population outside the scope where the data have been derived from.
Future perspectives and challenges
Improvements in diagnostic accuracy of LUTO: Fetal MRI, grey-scale histogram, urine analysis and combined approaches.
In this thesis we relied upon clinical data from antenatal US investigations. However, further attention to other additional diagnostic tools should be paid.
For instance, MRI, a technique increasingly used in fetal imaging (9)(8), may be explored for its value in assessing more accurately renal cortex integrity and lung development, as suggested by Craig Peters in a panel discussion at the Society of Fetal Urology (47).
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Alternatively to the MRI, the use of grey-scale histogram may be tested for a more objective evaluation of the echogenicity of fetal renal parenchyma, which has proven to be, among all the other US parameters, the most reliable to predict postnatal renal function (32)(chapter 8).
To date, fetal urine analysis following serial vesicocentesis is standardly performed to estimate renal function before proceeding with any further intervention. Commonly, sodium, chloride, calcium, osmolarity and β2-microglobulin are evaluated, however data on their diagnostic ability are still conflicting (48)(49) and a systematic review reported that none of those analytes yields sufficient clinical accuracy for predicting renal function (48). Moreover, age-based reference ranges are to date available only for sodium and calcium (29), while the current established thresholds for the other analytes are only intended for fetuses undergoing fetal therapy (29). There has been an increasing interest in investigating a number of biochemical marker, such as α1-microglobulin, retinal binding protein, transforming growth factor-β, epidermal growth factor (29)(50), and more recently, the cystatine C and matrix metalloproteinase (MMP-9), independent predictors of severity of renal fibrosis. However, their clinical application has never been validated (31).
Future studies are recommended to combine measurement of the above mentioned analytes with a more standardized US evaluation of LUTO.
Improvements in for future RCT: patient selection, data sharing and technical advancements.
At this moment to be able to identify the best candidates and timing for fetal therapy is of pivotal importance to improve clinical outcome in LUTO. The logic continuation of the studies published in this thesis will be to select cases by using our diagnostic and prognostic criteria and, according to the baseline LUTO severity, ascertain when fetal therapy would be more successful. We deliberately did not evaluate the success of fetal therapy in our cohort, due to the small sample of treated fetuses (n = 24). However, future investigations in this direction are recommended, preferably in the setting of an adequately powered randomized controlled trial.
For this purpose, it must borne in mind that the low prevalence of LUTO and the high rate of terminations of pregnancy is likely to limit again the recruitment process, as it happened in the PLUTO trial (51). Therefore, more attention should also be paid on building large collaboration worldwide among the principal fetal surgery centers and on creating a more systematic approach to data sharing and frank disclosure of treatment failures.
Besides the refinements of the diagnostic criteria and patient selection of LUTO, more effort should be aimed at improving in the technical aspects of the procedures, in terms of minimizing the risks of shunt migration and blockage in VAS and develop new cystoscopes capable of making easier the visualization and entrance into the posterior urethra (13).
9.8.3 Change of perspectives in fetal surgery.
Classically, fetal surgery has been reserved to those fetuses with life-threatening conditions and few chances of survival (52). With technical advancements, antenatal surgery has been offered not only as ultimate attempt to rescue cases with otherwise fatal prognosis, but also to improve long-term outcome in fetuses with non-life-threatening conditions. This approach is now already used in the antenatal management of myelomeningocele. In fact, prenatal surgical repair of this non-lethal condition aims at improving the neurological outcome compared to the post-natal repair (53)(54). Similarly, also the TOTAL trial offers tracheal occlusion more liberally to diaphragmatic hernia cases at the less severe end of the spectrum in the attempt to improve long-term outcome (55).
Concerning LUTO, fetal specialists still tend to treat cases with markedly reduced amniotic fluid and severe forms of LUTO. However, the severe deterioration of renal reserve among the severest phenotypes of LUTO may prevent an appropriate ‘rescue’ by fetal therapy. Conversely, the milder phenotypes may benefit more from fetal intervention (33). Timing is the central overarching theme in congenital LUTO and the best timing of in-utero therapy for preserving fetal renal function has not been yet clarified (26).
Concluding remarks
We hope that the results of this thesis, with the proposed stepwise management algorithms, will contribute to refine the diagnostic work-up and the prognostic assessment of fetuses suspected with LUTO. We also hope that this may encourage a new trial where fetal surgery, in the form of refined shunts or cystoscopy, may be offered also to fetuses with good chances of survival but high risk of postnatal morbidity and renal insufficiency. This change in perspective is probably the necessary step in order to make an impact on the overall outcome of fetuses prenatally diagnosed with LUTO.
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