Antenatal diagnosis and management of fetal megacystis and lower urinary tract obstruction
Fontanella, Federica
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Publication date: 2019
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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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Background
During fetal life, a number of conditions can potentially disrupt the in-utero development and lead to short and long-term damaging effects for the fetus. For a minority of them, an intervention during pregnancy can limit the life-threatening consequences of the disease and potentially ameliorate the prognosis. In these cases, fetal specialists are not only expected to diagnose the condition, but also to inform parents on the available therapies and help them choose the best option for their unborn baby.
To date, the effectiveness of fetal surgery has been ascertained for some congenital conditions such as for sacrococcygeal teratoma (1), cystic pulmonary adenomatoid malformations (2) and myelomeningocele (3). For other disorders, the benefit of fetal therapy is still unclear and the lack of large studies and high-quality evidences limits the ability of counseling parents exhaustively and correctly on therapeutic options. This is the case for Lower Urinary Tract Obstruction (LUTO).
Lower Urinary tract Obstruction: etiology and physiopathology.
The term LUTO refers to a heterogeneous group of anatomical anomalies causing an obstruction in the urethra, such as urethral atresia, urethral stenosis or, most commonly, posterior urethral valves. The incidence of LUTO is reported between 1 in 5.000 to 1 in 25.000 pregnancies, without accounting for cases with elective termination, intrauterine fetal demise (IUFD), or cases with postnatal diagnosis (4).
Congenital obstructive uropathy accounts for the largest identifiable cause of kidney failure in infants and children (7). In fact, during fetal life LUTO can affect the renal (glomerular and tubular) function and lead to cystic renal dysplasia (6). In the second trimester, when fetal urine starts to constitute 90% of the amniotic fluid (8), severe forms of LUTO progressively cause oligohydramnios, with subsequent pulmonary hypoplasia and respiratory insufficiency at birth, being the primary cause of neonatal death in LUTO. For these reasons, congenital LUTO is associated with high perinatal mortality and postnatal morbidity owing to pulmonary hypoplasia and renal dysplasia (5).
From fetal megacystis to the antenatal diagnosis of LUtO
The suspicion of LUTO typically arises from the ultrasound (US) evidence of an enlarged fetal bladder, also called megacystis (10). However, fetal megacystis is not only associated with LUTO, but also with chromosomal abnormalities, anorectal malformations and other
miscellaneous syndromal associations (11). Moreover, the bladder enlargement can also spontaneously resolve during pregnancy (12)(13)(14).
In the first trimester of pregnancy, fetal megacystis has been defined by a longitudinal bladder diameter (LBD) greater than 7 mm. The LBD measurement is typically used also to guide the counseling and work-up: if this is between 7 and 15 mm, fetal karyotype is recommended, as the majority of chromosomal anomalies falls in this group and, if the karyotype is normal, a spontaneous resolution will occur in 90% of cases, while in cases with LBD > 15 mm, the prognosis is poor due to a high incidence LUTO and subsequent obstructive uropathy (14)(10)(14)(Table 1).
table 1. Prevalence of chromosomal defects and outcome of fetuses with megacystis according to
LBD from Liao et al (14). LBD: 7-15 mm n (%) LBD > 15 mmn (%) Abnormal Karyotype 26 (23.6%) 4 (11.4) Normal Karyotype 79 30 Spontaneous Resolution 71 (89.9%) 0 Obstructive uropathy 8 (10.1%) 30 (100%)
LBD, Longitudinal bladder diameter.
Beyond the 14th week, when the majority of cases with LUTO are identified, an objective
and unanimously accepted definition of megacystis and congenital LUTO has not yet been formulated (15). As consequence, an epidemiological study has in fact reported that 27% of cases prenatally suspected for LUTO had their diagnosis reclassified after pathological examination after birth (14).
The wide spectrum of etiologies and different outcomes of megacystis and the deceptive accuracy of US scan for detecting the progression to obstructive uropathy makes nowadays the counseling of megacystis extremely challenging.
Counseling on prognosis and management of LUtO
Once LUTO is suspected, parents should be informed on the therapeutic options and short- and long-term prognosis.
Perinatal mortality in LUTO is high, being around 45% (17). Among those who survive the neonatal period, 25-30% will develop end-stage chronic renal impairment and will necessitate renal transplantation and/or dialysis (5). However, in a minority of cases normal amniotic fluid amount and good renal function can be preserved throughout pregnancy
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(16). To sum up, natural history of LUTO is highly variable and fetal specialists can only rely on gestational age at onset of obstruction and sex of the baby to have a general idea of the outcome (9).
Since the beginning of the 1980s, the poor and irreversible prognosis of severe LUTO and the knowledge of the pathophysiology from animal models have paved the road for research aimed at developing an antenatal intervention to decompress the urinary tract. It is therefore not a case that in 1981 at the University of California, San Francisco (UCSF), the team of Mike Harrison performed the first open fetal surgery intervention in the history of medicine in a fetus with LUTO (Figure 1, 18).
Figure 1. First open fetal surgery at UCSF. The lower limbs and torso of the fetus are exteriorized in
order to surgically decompress the urinary tract.
The 21-week-old fetus was treated with bilateral utererostomies, no maternal complications were reported and the fetus continued to grow after surgery. However, as the renal and pulmonary damage was already too extensive at the time of surgery, the infant died within a day of delivery (18). The team of the UCSF did not get discouraged and, just one year after, inserted the first vesico-amniotic shunt (VAS). This time the fetal patient survived and is now a healthy adult: the first to be born after surviving fetal surgery (19).
Nowadays, vesico-amniotic shunting consists of the percutaneous placement of a double pig-tailed catheter into the fetal bladder and represents the most used method to
relieve the urinary obstruction during fetal life (Figure 2)(6).
An alternative intervention for LUTO is fetal cystoscopy. This allows the direct visualization of the obstruction and ablation of the PUV using hydro-ablation, guide-wire or laser fulguration (20)(21)(22)(23)(24). Fetal cystoscopy is technically complicated and not therapeutic in fetuses with urethral atresia, but has the advantage to restore the physiological bladder dynamic and to not require amnioinfusions (25).
Despite these developments, most of the parents currently choose for terminating the pregnancy or opt for a conservative management (4)(26). This last option includes regular US scans for monitoring the bladder distension, amniotic fluid amount and fetal kidneys (6). Main goal is the surveillance of fetal well-being until an estimated weight of 2-2.5 kg is achieved in order to allow peritoneal dialysis catheter placement candidacy (25). Another recently proposed option consists in performing serial amnioinfusions until the 28th-30th week of
gestation in order to protect from oligohydramnios. This approach should be still considered experimental as further studies are needed to assess its safety and benefits (27)(28)(25).
PLUtO trial, open questions and rational of this thesis
In the last decade, the above mentioned management options have been further investigated. In 2006, the first randomized, multicenter control trial (PLUTO trial) to assess the effectiveness of vesico-amniotic shunting compared to conservative management has been started and in 2010 prematurely ended because of poor recruitment. The PLUTO trial showed a higher survival to 28 days, 1 year, and 2 years in fetuses treated with VAS. However, due to the small numbers of participants recruited (only 20% of the planned 150 pregnancies were randomized), the benefit of VAS was not conclusively proven. The PLUTO trail also reported that irrespective of whether or not vesico-amniotic shunting was done, the overall postnatal outlook was very poor (26).
With the premature conclusion of the PLUTO trial, the fetal medicine community has missed an important opportunity of high-quality evidence for clarifying the role of VAS and the appropriate antenatal management for LUTO (29). Since then, a second RCT comparing fetal cystoscopy and VAS has been started (Clinicaltrials.gov, identifier NCT01552824) (30) and new observational studies have been conducted (30)(31)(32).
In summary, the literature suggests a beneficial role of both VAS and cystoscopy in terms of perinatal survival in fetuses with severe LUTO. However, concerning the postnatal renal function, the role of VAS is still unclear, while fetal cystoscopy has been suggested as beneficial selectively in fetuses with PUV (30). To date, the role, best candidates and best timing for these antenatal interventions is still unclear and a new RCTs would represent the gold standard for further evaluating treatment effectiveness. However, in order to clarify
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these points, a more standardized and accurate diagnostic evaluation, staging approach and prognostic assessment of LUTO is first needed. For this purpose, multicenter co-operations and large-scale registries can firstly help set up the groundwork needed before moving towards the design of a new RCT.
aim and outline of the thesis
In this thesis we gathered information at a national level and collected prenatal and post-natal information on fetuses diagnosed with megacystis. The final aim was to investigate the above-mentioned open questions and be able to guide fetal specialists in the difficult counseling and diagnostic work-up, from fetal megacystis to congenital LUTO.
Part 1 - Fetal Megacystis: definition and counseling
In the first part of the thesis, the definition and differential diagnosis of fetal megacystis is discussed. In chapter 2, reference values for the definition of a normal fetal urinary bladder during second and third-trimester megacystis are provided for the first time in the literature. In chapter 3, we propose a flowchart for guiding the differential diagnosis of megacystis and ruling out genetic syndromes, developmental and chromosomal abnormalities. Chapter 4 focuses on prediction of spontaneous resolution of megacystis and postnatal outcome after resolution.
Part 2 - Prenatal diagnosis and management of LUTO
The second part of the thesis aims at improving the accuracy of US scan examination in the diagnosis of LUTO and its underlying cause (PUV or urethral atresia). Chapter 5 focuses on early megacystis and on the optimal criteria for selecting cases with PUV, thus eligible for fetal therapy early in pregnancy. In chapter 6, we propose a new scoring system for fine-tuning the prenatal diagnosis of LUTO in cases with late megacystis, diagnosed after the 17th week of gestation.
Part 3 - Prediction of prognosis and staging of LUTO
In the last part of the thesis, the focus is on predicting the prognosis of LUTO, in terms of perinatal survival and postnatal renal function. Chapter 7 aims at predicting of the risk of perinatal death and proposing of a new staging system for LUTO, while in chapter 8, a prediction model for postnatal renal function is presented.
The thesis ends with a general discussion of the implications of our findings and future perspective (chapter 9).
references
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