Fetal megacystis: A systematic review

Accepted Manuscript Fetal megacystis: a systematic review Dr K. Taghavi, C. Sharpe, M.D. Stringer PII:

S1477-5131(16)30285-6

DOI:

10.1016/j.jpurol.2016.09.003

Reference:

JPUROL 2334

To appear in:

Journal of Pediatric Urology

Received Date: 12 June 2016 Accepted Date: 10 September 2016

Please cite this article as: Taghavi K, Sharpe C, Stringer MD, Fetal megacystis: a systematic review, Journal of Pediatric Urology (2016), doi: 10.1016/j.jpurol.2016.09.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Fetal megacystis: a systematic review

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K. Taghavi a,b,*, C. Sharpe c, M. D. Stringer a,b

Department of Paediatric Surgery, Wellington Children’s Hospital, Wellington, New

Zealand

Department of Paediatrics and Child Health, University of Otago, Wellington, New

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b

Zealand

School of Medicine, University of Otago, Wellington, New Zealand

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*Corresponding author. Department of Paediatric Surgery, Wellington Children’s Hospital, Riddiford Street, Newtown, Wellington, 6021. New Zealand. Tel.: +61 4 385 5999; fax: +61 4 385 5856.

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E-mail address: [email protected] (Dr Kiarash Taghavi)

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Summary

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Fetal megacystis is variably defined and understood. The literature on fetal megacystis was systematically reviewed, and focused on prenatal diagnosis, associations and outcomes. This yielded a total of 18 primary references and eight secondary references.

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Fetal megacystis has an estimated first-trimester prevalence of between 1:330 and 1:1670, with a male to female ratio of 8:1. In the first trimester, megacystis is most commonly defined as

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a longitudinal bladder dimension of ≥7 mm. Later in pregnancy, a sagittal dimension (mm) greater than gestational age (in weeks) + 12 is often accepted. Megacystis can be associated with a thickened bladder wall, which has been objectively defined as >3 mm. Oligohydramnios is present in approximately half of all cases.

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The most common underlying diagnosis is posterior urethral valve (57%), followed by urethral atresia/stenosis (7%), prune belly syndrome (4%), megacystis-microcolon-intestinalhypoperistalsis syndrome (MMIHS) (1%), and cloacal anomalies (0.7%). Karyotype anomalies

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are found in 15%, and include trisomy 18, trisomy 13 and trisomy 21. Ultrasound imaging alone is often insufficient to enable a definitive diagnosis, although it may indicate that a specific

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diagnosis is more likely.

Overall, about 50% of reported fetuses with megacystis are terminated, but this

proportion varies considerably between countries and over time. Prognostic stratification is evolving, with the most important factors being oligohydramnios, gestational age at diagnosis, degree of bladder enlargement, renal hyperechogenicity, karyotype, and sex.

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Conclusions: This review demonstrated some consensus on the ultrasound criteria for defining fetal megacystis, and illustrated the spectrum of pathologies and their relative frequencies that can cause this condition. It also underlined important associated karyotype anomalies. To

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progress understanding of the natural history of enlarged fetal bladders, more accurate

diagnostics are required, and risk stratification needs to be refined to facilitate prenatal

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counseling.

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Keywords: Fetal megacystis; Prenatal diagnosis; Urinary bladder

Introduction

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Fetal megacystis is relatively poorly defined and understood. An ‘enlarged’ bladder can be diagnosed sonographically after the fetus starts producing urine at about the tenth week of

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gestation [1]. This finding suggests mechanical or functional bladder outlet obstruction, either partial or complete, although in some instances the bladder is normal.

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At 10–14 weeks gestation, the estimated prevalence of fetal megacystis is approximately

1 in 1500 pregnancies [2], but this varies between reports [3]. Although individual outcomes vary greatly, it is recognized that megacystis often carries a poor prognosis [3-6], particularly when associated with oligohydramnios. Persistent oligohydramnios impairs lung development, as demonstrated in animal models [7], leading to pulmonary hypoplasia. Oligohydramnios and echogenic kidneys have been suggested as indicators of an obstructive etiology [8] and associated renal dysplasia [9]. Megacystis may be found in several conditions, including PUV, 2

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prune belly syndrome (PBS), urethral atresia or stenosis, cloacal abnormalities, and megacystismicrocolon-intestinal-hypoperistalsis syndrome (MMIHS) [10]. This systematic review

natural history and outcomes of fetal megacystis?

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Methods

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addressed the question: What is known about the prenatal diagnosis, associated abnormalities,

The search strategy is summarized in Fig. 1. Specific search terms were: ‘megacystis’; or

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‘fetal/foetal’ and ‘megabladder’, ‘large bladder’, ‘enlarged bladder’, ‘dilated bladder’, or ‘distended bladder’. The databases used were: Scopus, PubMed and MEDLINE, together with the first ten pages of Google Scholar (100 articles). The search was restricted to Englishlanguage articles and human studies, and no additional time limitations were placed. After

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removal of duplicates, 198 article abstracts were reviewed. Articles that did not qualify as original research, and studies reporting fewer than five cases, were excluded (152 articles excluded). Case reports were excluded to reduce bias and because they represent a level of

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evidence that is inferior to case series. Of the remaining 46 citations, 28 articles were excluded, as they did not mention any prenatal bladder dimension or criteria qualifying the diagnosis of

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megacystis. A single author performed the literature search, and all authors checked data extraction from the referenced articles. Data were extracted from these papers in a standardized manner and entered into a database; the focus was on prenatal diagnosis, associated anomalies, natural history, and outcomes. The 18 primary references that focused on the prenatal diagnosis of megacystis were supplemented by an additional eight articles identified from the bibliographies of the primary 3

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articles, yielding a total of 26 articles for analysis. Two of the authors reviewed bibliographies of

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primary references to gain secondary references.

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Results

Baseline data

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Of the 26 articles included in the systematic review, 21 were retrospective case series and five were prospective studies, which included two non-randomized interventional studies [11] and one randomized, controlled trial of fetal intervention [12]. No additional data were obtained from corresponding authors. Most studies did not report the exact ultrasound imaging method used, but some specified a particular technique: 2D transvaginal ultrasound [3], 2D transabdominal

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ultrasound [9, 13], 3D transabdominal ultrasound [14], or a combination of these with 3D transvaginal ultrasound [10]. Where the published data were ambiguous, corresponding authors

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were contacted via e-mail to supply missing information, specifically in relation to fetal bladder measurements at different gestational ages.

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Study samples were heterogeneous. Nineteen studies included all fetuses identified with megacystis during a specific time period, whereas others focused on specific diagnoses to define their sample: PBS [14], MMIHS [15], PUV [16] or ‘megacystis-megaureter association’ [17]. One report focused on urethral obstruction (mostly PUV but also urethral atresia) [18] and another on ‘lower urinary tract obstruction’ (including PUV, urethral atresia, and obstructing urethral syrinx) [12].

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The majority of reports were retrospective reviews from tertiary or quaternary referral centers; thus, the incidence of megacystis is likely to be overestimated, as well as potentially skewing the data towards more severe cases. In addition, there are inherent weaknesses

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introduced through publication bias. Accepting these limitations, Kagan et al. reported a 0.06% prevalence among 57,119 first-trimester singleton pregnancies from the UK and Germany [13], while Favre et al. found a 0.31% prevalence in a smaller cohort of 5240 first-trimester fetuses

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from France [3]. The former is similar to an earlier UK study that found a 0.06% prevalence amongst 24,492 pregnancies assessed at 10–14 weeks [2]. Differences in referral patterns as well

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as definitions of megacystis (a longitudinal bladder length of ≥7 mm in the UK/German series and >6 mm in the French series) may have contributed to the observed differences in prevalence. For those studies that reported the sex of the affected fetus, the male:female ratio was approximately 8:1 (1155 males:147 females). However, a female preponderance (9 females:5

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males) was reported in the single study focusing on MMIHS [15]. Four studies did not report sex distribution [5, 11, 13, 19], and sex was incompletely recorded in another five publications [2, 3,

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6, 14, 20].

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Diagnostic sonography

Bladder enlargement is the defining feature of fetal megacystis. Fetal bladder volume varies with gestational age, and bladder filling and emptying, which can be observed from about 18–20 weeks of gestation [21].

A historically important retrospective study determined that megacystis could be defined at 10–14 weeks gestation as a longitudinal bladder dimension of ≥8 mm compared with ≤6 mm

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in normal fetuses [2]. It is uncertain how the authors would have classified a 7 mm length fetal bladder. Bladder length was standardized to fetal size by calculating bladder length/crown-rump length; in normal fetuses, this consistently measured as <10%. Subsequent studies have reported

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similar thresholds for defining fetal megacystis in the first trimester. Thus, three studies

sonographically defined megacystis as a longitudinal bladder dimension of >7 mm [19, 22, 23], and another five studies as >6 mm [3, 9, 13, 24, 25]. Three further studies selected thresholds of

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10 mm [4], 12 mm [6], and 15 mm [11]; however, early second-trimester fetuses were included

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in these reports.

Based on measurements in 39 fetuses with normal bladders, Maizels et al. developed a formula to define the sagittal length (SL) of the normal fetal bladder, namely: the distance from fetal bladder dome to bladder neck in the midline sagittal plane. The results showed an exponential growth pattern, approximating to a linear relationship between 15 and 40 weeks

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gestation. This was expressed by the formula: normal SL (mm) = GA (wks) - 5 (95% CI ± 7) [5]. The authors went on to analyze 37 fetuses with an enlarged bladder defined as an SL greater than the upper limit of the 95% confidence interval expected for gestational age (GA). ‘Megacystis’

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was defined as a fetal bladder SL of >10 mm above the upper limit of the 95% confidence

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interval. Later studies have frequently used this formula to define megacystis [23, 26, 27]. Sonographic definitions of megacystis in the second and third trimester have been more

variable. In many reports, reference is made to an ‘enlarged bladder’, often qualified as showing no evidence of bladder emptying during a period of at least 45 minutes [9, 22, 23, 28]. Muller et al. used >99th percentile length for gestational age as the threshold for diagnosis, but did not reference a nomogram [15]. Ruano et al. defined persistent megacystis at 16 weeks as a longitudinal measurement of >10% of crown-rump length [11]. One early study used the 6

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criterion of the urinary bladder filling the true pelvis, and not emptying during the examination [18]. Several studies did not specify an objective definition of megacystis [8, 10, 14, 16, 17, 20, 29]; most of these studies were either from the 1990s or focused on specific postnatal diagnoses

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such as PUV [16] or PBS [14].

The most commonly reported measurement of bladder size was maximum longitudinal dimension (usually in the midline sagittal plane). Data from studies reporting this measurement

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in the first trimester are shown in Table 1 [2-4, 9, 10, 13, 14, 24, 25, 27]. Bladder longitudinal

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dimensions ranged from 7–49 mm. One study estimated fetal bladder volumes from maximum length, width and transverse dimensions [3].

Additional structural abnormalities reported in association with megacystis, including a thickened bladder wall [9, 10, 12, 18, 20, 24, 28, 29] and the ‘keyhole sign’ (Fig. 2) [6, 9, 10]. A

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thickened bladder wall was initially diagnosed by visualization of a finite thickness of the entire bladder wall [18]. Using high-resolution ultrasound, a more accurate definition has emerged, namely a bladder wall thickness of >3 mm [12]. Osborne et al. found bladder wall thickness

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difficult to assess and concluded that the only important discriminating feature between PUV and PBS is the ‘keyhole sign’ [10]. However, they also observed the keyhole sign in a few fetuses

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with PBS and MMIHS. Abbott et al. highlighted the difficulties of trying to reach an accurate prenatal sonographic diagnosis of PUV based on the following sonographic features: amniotic fluid volume; suspected male gender; bladder size, wall thickness, contour and shape; presence of urethral dilatation; and degree of hydronephrosis. Despite examining multiple variables, PUV was confirmed postnatally in eight of 19 fetuses (42%) in which it was suspected [20]. Similarly, the prenatal diagnosis was erroneous in two-thirds of cases in another series [9].

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None of the studies in this systematic review documented fetal bladder wall trabeculation, although this has been mentioned in isolated case reports [30] and seen on fetal cystoscopy [31]. Two studies briefly referred to a bladder diverticulum, but the frequency or significance of this is

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unclear.

Amniotic fluid volume

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Amniotic fluid volumes were recorded in 16 studies (Table 2) [3, 4, 6, 9-12, 14, 15, 17, 18, 20,

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23, 27, 28, 32]. After excluding studies focusing on specific diagnoses, a mean of 45% (13–83%) of fetuses with megacystis had reduced liquor volumes. The presence of oligohydramnios appears to confer a poor prognosis [27]. However, it is not restricted to fetuses with megacystis secondary to lower urinary tract obstruction; 62% of fetuses with PBS were also found to have oligohydramnios in one study [14]. One report of 11 cases with ‘megacystis-megaureter

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association’ found no abnormalities in amniotic fluid volume [17]. Polyhydramnios was recorded in three studies and was observed in half of all fetuses with MMIHS at 24–32 weeks gestation; excess amniotic fluid in such cases is related to impaired gut function [15]. Variable definitions

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of oligohydramnios, different gestational ages at assessment, and incomplete data limit the

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conclusions that can be drawn from amniotic fluid volumes associated with megacystis.

Composition of fetal urine and amniotic fluid Vesicocentesis and analysis of fetal urine were used by some centers in an attempt to gauge renal function [11, 19, 27]. In some instances, this was with a view to selecting fetuses for interventional therapy such as vesicoamniotic shunting [3, 4, 23]. Three studies investigated the

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utility of digestive enzyme assays in fetal urine or amniotic fluid as a marker of a co-existing

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anorectal malformation [3, 4] or MMIHS [15].

Abnormal karyotype

Numerous studies reported karyotype analysis in fetuses with megacystis. Table 3 shows the

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results from studies that did not focus on a specific diagnosis [2-4, 6, 9, 13, 19, 20, 22-27]. The

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commonest associated chromosomal anomalies were trisomy 18, trisomy 13 and trisomy 21.

Definitive diagnosis and pregnancy outcome

Postnatal diagnoses in fetuses with megacystis were at least partially reported in 19 studies [3-5, 9-11, 14-16, 18, 20, 22-24, 26-29, 32]. Reports of series with fetal megacystis that did not

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concentrate on a single pathology only are summarized in Table 4. The pathology was PUV in over half of all reported cases (57%). Other diagnoses included urethral stenosis or atresia (7.4%), PBS (3.8%), MMIHS (1.1%), and cloacal anomalies (0.7%). The rare omphalocele-exstrophy-

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imperforate anus-spinal defect (OEIS) complex was noted in two cases [22, 23]. Because some series did not define a diagnosis for all subjects, these totals will underestimate the true incidence

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(36.5% cases did not carry a definitive diagnosis). Megacystis is frequently associated with a poor prognosis. After multi-disciplinary

review and antenatal counseling, the pregnancy may be terminated. Reported termination rates vary from 4–96%, with huge variations between countries and over time (Table 5). The high termination rate in one series is likely to be explained by the one-child policy that was active at the time of the study [14]. 9

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Megacystis carries a substantial risk of fetal or perinatal mortality [16, 18, 27]. Lee et al. reported a 46% survival in pregnancies that were not terminated (a more favorable prognostic group) [27]. Prenatal identification of particularly poor prognostic groups (e.g. those with

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urethral stenosis or atresia [9]) would facilitate prenatal counseling. Thus far, prenatal

sonographic imaging has failed to accurately identify such cases, and the role of fetal cystoscopy is under investigation [9, 11]. In one study, postnatal survival to 28 days was 39% (12/31), and

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those that survived to 2 years of age had considerable morbidity, with eight of ten cases having impaired renal function [12]. A few studies reported instances of pulmonary hypoplasia or

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reduced lung volumes, either on prenatal scans [24] or at post-mortem [9, 12, 15, 23]. In the second trimester, reduced lung volume has been associated with a worse prognosis [24]. In the PLUTO study, all neonatal deaths were due to pulmonary hypoplasia [12]. Of crucial importance is the observation that mild megacystis in early gestation may

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resolve spontaneously. For example, Sebire et al. reported that mild megacystis (8–12 mm) at 10–14 weeks gestation subsequently resolved in seven of eight cases. In contrast, fetuses with a bladder length >17 mm had a consistently poor prognosis [2]. In another series, spontaneous

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resolution of mild first-trimester megacystis (longitudinal bladder measurement of 7–15 mm)

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was seen in 90% of fetuses with a normal karyotype [25]. Kagan et al. similarly reported spontaneous resolution in 90% of euploid first-trimester fetuses with a bladder length of ≤15 mm [13].

Some reports have suggested that when megacystis is first diagnosed in the second

trimester (as opposed to the first trimester), it is more likely to result in a live birth [24]. According to Bornes et al. this difference in mortality is not accounted for by differences in

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karyotype or associated abnormalities between the groups, although an increased rate of termination in the first-trimester group is a factor [22].

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Emerging data suggest that megacystis can be divided into two or more categories based on: the degree of fetal bladder enlargement [5, 11, 25] and the presence of oligohydramnios [9,

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27] and hyperechogenic kidneys [9].

Fetal intervention

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Various interventions have been trialed to treat fetal megacystis in an effort to mitigate renal parenchymal damage and the adverse effects of chronic oligohydramnios on pulmonary development; these include amnioinfusion, vesicoamniotic shunting and vesicocentesis. The utility of these interventions is largely uncertain because the natural history of fetal megacystis is

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variable [13]. One prospective, non-blinded, controlled trial involving 31 fetuses with megacystis attributed to lower urinary tract obstruction randomized them to vesicoamniotic shunting or conservative treatment. Overall survival to 28 days was 8/16 in the shunted group compared with

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4/15 in the conservative group; only two babies (both shunted) survived to 2 years with normal renal function [12]. The study was underpowered by recruitment of only 20% of its planned

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target sample [33]. Further randomized, controlled trials are planned to determine the role of fetal cystoscopy and vesicoamniotic shunting in the management of fetal megacystis [34, 35]. However, it is likely that disease severity is the most powerful determinant of perinatal survival, regardless of intervention [36].

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Discussion Prenatal detection of megacystis suggests several possible underlying diagnoses, the most

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common being PUV in boys. Although there may be pointers to a specific diagnosis such as the ‘keyhole sign’, the precise diagnosis is often uncertain until after birth [3, 9, 17]. The overall prognosis for a fetus with persistent megacystis is poor [3-6], and termination of pregnancy is

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frequently advised. About 15% of affected fetuses will have aneuploidy. Fetuses with

particularly large bladders and those with associated oligohydramnios are particularly likely to

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develop pulmonary hypoplasia and have a perinatal mortality of >50% [27]. Oligohydramnios appears to be an independent adverse prognostic factor [18, 27, 28].

In contrast to fetuses with persistent and/or severe megacystis, bladder volume may normalize in up to 90% of first-trimester fetuses with mild megacystis (7–15 mm longitudinal

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dimension) and a normal karyotype [2, 13, 25]. These fetuses presumably have transient partial bladder outflow obstruction [13, 19, 25], possibly related to reduced bladder contractility in early gestation [13, 37]. However, mild megacystis in early gestation is not uniformly associated with

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a better prognosis, as some fetuses have a serious underlying pathology [16, 22, 24]. Indeed, the distribution of potential pathologies underlying fetal megacystis varies between the first and

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second trimester [23].

Poor prognostic factors are gradually being defined. They include oligohydramnios,

chromosomal abnormality, and a markedly dilated bladder. However, discrepancies in bladder measurement techniques at different gestational ages indicate the need for a more standardized approach to the diagnosis of megacystis. Only one study reported associated prenatal lung

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volumes [24]. Assessment of this parameter, as well as other prognostic and diagnostic factors, may be improved through the use of fetal MRI [38].

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This systematic review highlights the lack of consensus on the sonographic definition of megacystis. Associated structural features such as bladder wall thickness, trabeculation, or the presence of a ‘keyhole sign’ are inconsistently reported and defined. Some studies have

suggested that the presence of a bladder diverticulum/a may be protective by providing a pop-off

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mechanism for urinary obstruction [32, 39], but this has not yet been substantiated. The review

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also demonstrates that the current literature is beset by heterogeneity in the definition of megacystis, the timing of diagnosis, and the inclusion of different diagnoses, thereby markedly limiting the conclusions that can be drawn. Further research is needed to: (1) progress understanding of the natural history of enlarged fetal bladders; (2) establish a more standardized

counseling.

Conclusions

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approach to fetal bladder evaluation; and (3) refine risk stratification to facilitate prenatal

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Fetal megacystis is most often detected in males, in whom PUV accounts for 57% of cases. An

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enlarged or dilated fetal bladder is variably defined by sonographic imaging, but in the first trimester, a longitudinal dimension of ≥7 mm is most commonly used in diagnosis. The ‘keyhole sign’ is generally, but not exclusively, associated with PUV. Oligohydramnios is seen in 45% of cases, and together with severe bladder enlargement denotes a worse prognosis. Major karyotype anomalies are found in 15% of affected fetuses. Termination rates vary greatly, underlining the importance of advancing understanding about the natural history of this finding and the need to develop improved prognostic guidelines. 13

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Conflict of Interest There are no conflicts of interest to declare.

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Acknowledgements

This work was supported by a research grant provided by the Surgical Research Trust,

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Wellington.

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[31] Chitty L, Whitten S. Prenatal Diagnosis of Fetal Renal Abnormalities. 2010. [32] Kaefer M, Michael A, Adams MC, Rink RC. Posterior urethral valves, pressure pop-offs and bladder function. J Urol 1995;154:708-11. [33] Van Mieghem T, Ryan G. The PLUTO trial: a missed opportunity. Lancet 2013;382:1471-3.

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[34] Ruano R, Sananes N, Sangi‐Haghpeykar H, Hernandez‐Ruano S, Moog R, Becmeur F, et al. Fetal intervention for severe lower urinary tract obstruction: a multicenter case–control study comparing fetal cystoscopy with vesicoamniotic shunting. Ultrasound Obstet Gynecol

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2015;45:452-8.

[35] Nassr AA, Shazly SA, Abdelmagied AM, Araujo Junior E, Tonni G, Kilby MD, et al.

Effectiveness of vesico-amniotic shunt in fetuses with congenital lower urinary tract obstruction:

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An updated systematic review and meta-analysis. Ultrasound Obstet Gynecol 2016.

[36] Smith-Harrison LI, Hougen HY, Timberlake MD, Corbett ST. Current applications of in

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utero intervention for lower urinary tract obstruction. J Pediatr Urol 2015;11:341-7. [37] Gilpin SA, Gosling JA. Smooth muscle in the wall of the developing human urinary bladder and urethra. J Anat 1983;137:503.

[38] Calvo-Garcia MA. Imaging Evaluation of Fetal Megacystis: How Can Magnetic Resonance

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Imaging Help? Semin Ultrasound CT MR: Elsevier; 2015. p. 537-49. [39] Rittenberg M, Hulbert W, Snyder 3rd H, Duckett J. Protective factors in posterior urethral

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valves. J Urol 1988;140:993-6.

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2014, Fievet et al. France

n

Range (mm)

10–14

≥8

15

SC

11–15

>6

10–14

≥7

12–19

>10

12–24

LD 8–32

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Gestational age (weeks)

Mean (mm)

20

145

LD 7–49

10

19

LD 11–35

21 (median)

≥7 (1st trimester)

24

SL 19–91

48

11–13

≥7

35

13–22

Not stated

6

Not stated

20

LD 7–15 (n=31) >15 (n=4) Longest axis 49–109 26–67 (axis not recorded) SL Not stated

11–39

11–13

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LD 8–46

10–28

≥7 (1st trimester)

61

>6

26

SL 10–39

Mean calculated bladder volume, ml (range)

13.3

16

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1996, Sebire et al. UK 1999, Favre et al. France 2003, Liao et al. UK 2003, Jouannic et al. London & Brussels 2005, Robyr et al. France 2010, Kagan et al. London & Tuebingen 2010, Chen et al. China 2011, Osborne et al. Multicentre 2011, Lee et al. Australia

Definition of megacystis (mm)

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Year, author

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Table 1. Fetal bladder measurements.

83 40 10–14 weeks: 33 15–26 weeks: 46 27–39 weeks: 57

Comment

LD in 300 controls ≤6 mm 7.4 (0.2–43)

Specifically Prune Belly Syndrome

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LD, longitudinal dimension: SL, sagittal length

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Table 2. Amniotic fluid volumes associated with fetal megacystis.

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* 2/22 (9.1%) *

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1/40 (2.5%)

Normal liquor volume n (%) 11/40 (27.5%) 11/11 (100.0%) * 10/22 (45.5%) * 14/16 (87.5%) 12/19 (63.2%) 5/14 (36%) * * * 8/15 (53.3%) 7/20 (35%) 15/31 (48.4%) 12/31 (38.7%) *

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21/40 (52.5%) 0/11 (0%) 8/15 (53.3%) 10/22 (45.5%) 9/21 (42.9%) 2/16 (12.5%) 7/19 (36.8%) 2/14 (14%) 20/24 (83.3%) 2/10 (20.0%) 3/6 (50.0%) 7/15 (46.7%) 13/20 (65%) 16/31 (51.6%) 19/31 (61.3%) 19/54 (35.2%)

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7/14 (50%) * * *

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1985, Mahony et al. 1992, Mandell et al. 1997, Kaefer et al. 1998, Abbott et al. 1998, Montemarano et al. 1999, Favre et al. 2003, Jouannic et al. 2005, Muller et al. 2005, Robyr et al. 2005, Maymon et al. 2009, Chen et al. 2011, Ruano et al. 2011, Osborne et al. 2011, Lee et al. 2013, Morris et al. 2014, Müller Brochut et al. Total (excludes reports of specific diagnoses)

Polyhydramnios n (%)

*

Specific case-mix?

Y – ‘urethral obstruction’ only Y – ‘megacystis-megaureter association’ only

Y – MMIHS only

Y – PBS only

Y – ‘lower urinary tract obstruction’ only

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Study date, author

Oligohydramnios n (%)

113/247 (45.7%)

*The remaining cases were not stated as having increased or normal liquor in these studies The other seven cases in this series were stated to have ‘low normal or borderline decreased amniotic fluid volume’.

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Table 3. Associated chromosomal abnormalities in reports of megacystis.

Trisomy 18

1996, Sebire et al. 1/9 1/15

Trisomy 21

Other

1/14

1/14

1/14 - unbalanced translocation (chromosome 14 & 20)

2/15

1/15

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1997, Wisser et al. 1999, Favre et al.

Trisomy 13

7/145

1/145 - triploidy 1/145 - trisomy 4 1/145 - mosaic trisomy 15 1/145 - unbalanced translocation (chromosome 14 & 20)

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2003, Jouannic et al.

2003, Liao et al.

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Study

17/145

2/145

2005, Robyr et al.

1/10

2011, Lee et al. 2012, Shettikeri et al. 2012, Al-Hazmi et al. 2013, Bornes et al. 2014, Fievet et al.

4/61 9/113 7/84 1/26

2014, Müller Brochut et al.

1/54

Total

5.7% (35/616)

6/35

1/35

1/113 2/84 2/26

4.9% (31/616)

Tot t

11/14

1/15

1

8/9 11/15

1/16

1

12/12

7/19

1

115/145

14

24/24

2

9/10

1

24/35

3

6 1 11 8 2

1/14 8/113

1/14 - trisomy 16 1/113 - Turner syndrome 2/84 – ‘complex chromosomal defects’

57/61 12/14 94/113 73/84 23/26

1/54

1/54 - Klinefelter’s

51/54

5

2.6% (16/616)

1.6% (10/616)

84.9% (523/616)

61

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4/35

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2010, Kagan et al.

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2005, Maymon et al.

Normal karyotype Not known

6/20 1/114

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Table 4. Definitive diagnoses in fetuses with megacystis.

PUV

1985, Mahony et al. 1997, Kaefer et al. 1997, Wisser et al. 1998, Abbott et al. 1998, Montemarano et al. 1999, Favre et al. 2003, Jouannic et al. 2004, Maizels et al. 2005, Robyr et al. 2011, Ruano et al. 2011, Osborne et al. 2011, Lee et al. 2012, Al-Hazmi et al. 2013, Bornes et al. 2014, Fievet et al. 2014, Muller Brochϋt et al. Total

40 15 9 22 21 16 19 37 24 15 20 61 561 84 69 54 1067

28/40 8/15

Urethral atresia/stenosis 3/40

PBS

MMIHS

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n

Cloacal abnormality

1/15 1/9 1/22

8/22 10/21

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4/21 3/16

3/19 14/37 9/24 7/15 10/20 17/61 369/561 25/84

2/37

2/37 2/15 1/20 2/61

1/15

4/84 1/69

3/84

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14/24 5/15 1/20 11/61 27/561 10/84 23/69*

1/54 74/998 (7%)

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16/54 568/998 (57%)

1/16

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Year, author

8/20 13/61

1/84 7/69 2/54 41/1067 (4%)

12/1067 (1%)

1/61

1/54 7/1067 (0.7%)

Undefined 9/40 6/15 8/9 13/22 7/21 12/16 16/19 19/37 1/24 3/15 0/20 17/61 165/561 41/84 38/69 34/54 389/1067 (36.5%)

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*Not included in totals for PUV and urethral atresia/stenosis because the diagnosis was not specified.

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Table 5a. Pregnancy termination rates of fetuses with megacystis. Year

Country

Reported TOP rate

% TOP

Sebire et al. Wisser et al. Montemarano et al. Favre et al. Liao et al. Jouannic et al. Maizels et al. Robyr et al. Kagan et al. Ruano et al. Osborne et al. Lee et al. Shettikeri et al. Al-Hazmi et al. Bornes et al. Morris et al. Fievet et al. Müller Brochut et al. Total

1996 1997 1998 1999 2003 2003 2004 2005 2010 2011 2011 2011 2012 2012 2013 2013 2014 2014

England Switzerland USA France England London USA France UK, Germany Brazil Panama, Spain, Brazil, USA Australia India France, Saudi Arabia France England France Switzerland

5/15 3/9 4/21 13/16 61/145 11/19 3/76 23/24 6/35 6/15 5/20 30/61 17/20 307/561 44/84 5/31 23/69 16/54 636/1274

33 33 19 81 42 58 4 96 17 40 25 49 85 55 52 16 33 30 50%

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Table 5b. Pregnancy termination rates of fetuses with a specific diagnosis. Year

Country

Diagnosis

Reported TOP rate

Abbott et al.

1998

USA

PUV

7/22

32

Muller et al.

2005

France

MMIHS

3/14

21

Chen et al.

2010

China

PBS

6/6

100

Morris et al.

2013

England

Lower urinary tract obstruction

5/31

16

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Study

% TOP

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Search terms:

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(megacystis) OR ((foetal OR fetal) AND (megabladder OR ‘large bladder’ OR ‘enlarged bladder’ OR ‘dilated bladder’ OR ‘distended bladder’))

Inclusion criteria: - English language - Human studies 198 citations after removal of duplicates

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Exclusion criteria: - Non-original research - Reports of <5 cases -

46 citations reviewed

Inclusion criteria: - Prenatal ultrasound evaluation of megacystis -

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18 primary and 8 secondary articles selected and analysed

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POSTERIOR URETHRA

Fig. 2. Keyhole sign with megacystis and a dilated posterior urethra, as seen on sagittal 2D ultrasound imaging. The scan shows a bladder measuring 31 mm transverse and 47 mm sagittal length in an 18 week-old male fetus that subsequently had an amnioinfusion and Harrison’s vesicoamniotic shunt placed.