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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Federica Fontanella, The Netherlands, 2018 ISBN 978-94-034-1269-6
ISBN (PDF) 978-94-034-1268-9
Printed by Ridderprint BV, www.ridderprint.nl Layout by Jos Hendrix
Coverdesign and illustrations on page 17, 71, 101 by Laura Fontanella © 2018 F. Fontanella, Groningen, The Netherlands
The copyright of the articles that have been published has been transferred to the respective journals. No parts of this thesis may be reproduced or transmitted in any form by any means, without prior permission of the copyright owner.
PhD thesis
to obtain the degree of PhD at the University of Groningen
on the authority of the Rector Magnifi cus prof. E. Sterken
and in accordance with the decision by the College of Deans. This thesis will be defended in public on Wednesday 9 January 2019 at 14.30 hours
by
Federica Fontanella
born on 13 November 1989 in Rome, Italy
Prof. D. Oepkes
Assessment Committee
Prof. A.F. Bos Prof. J.M. Nijman Prof. M.D. Kilby
Chapter 1 General introduction 7
Part 1 Fetal Megacystis: definition and differential diagnosis 17 Chapter 2 Reference charts of fetal urinary bladder in the second 19
and third trimester of pregnancy
Submitted
Chapter 3 Fetal megacystis: a lot more than LUTO 35 Ultrasound Obstet Gynecol 2018, in press
Chapter 4 Fetal Megacystis: Prediction of spontaneous resolution 57 and outcome
Ultrasound Obstet Gynecol 2017;50:458-63
Part 2 antenatal diagnosis and management of LUtO 71 Chapter 5 Antenatal work-up of early megacystis and selection 73
of candidates for fetal therapy
Fetal Diagn Ther, 2018
Chapter 6 Prenatal diagnosis of LUTO: improving diagnostic accuracy 87 Ultrasound Obstet Gynecol, 2017; in press
Part 3 Prediction of prognosis and staging of LUtO 101 Chapter 7 Antenatal staging of congenital Lower Urinary Tract 103
Obstructions (LUTO)
Ultrasound Obstet Gynecol 2018; in press
Chapter 8 Prediction model of postnatal renal function in fetuses with 117 LUTO – development and internal validation
Submitted
Chapter 9 Final discussion and future perspectives 131
Chapter 10 Summary in English 151
Nederlandse samenvatting 153
Abbreviations 155
Acknowledgements 157
About the author 161
1
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
1
(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
1
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
1. Flake A, Harrison M, Adzick N, Laberge J, Warsof S. Fetal sacrococcygeal teratoma. J Pediatr Surg. 1986;21(7):563– 6.
2. Adzick N, Harrison M, Flake A, Howell L, Golbus M, Filly R. Fetal surgery for cystic adenomatoid malformation of the lung. J Pediatr Surg. 1993;28(6):806–12.
3. Adzick S, Thom E, Spong C, Brock J, Burrows P, Johnson M, Howell LJ, Farrell JA, Dabrowiak ME, Sutton LN, Gupta N, Tulipan NB, D’Alton ME, Farmer DL; MOMS Investigators. A Randomized Trial of Prenatal versus Postnatal Repair of Myelomeningocele. N Engl J Med. 2011;365:883–91.
4. Anumba DO, Scott JE, Plant ND, Robson SC. Diagnosis and outcome of fetal lower urinary tract obstruction in the northern region of England. Prenat Diagn. 2005;25(1):7–13.
5. Parkhouse HF, Barratt TM, Dillon MJ, Duffy PG, Fay J, Ransley PG, Woodhouse CR, Williams DI. Long-term outcome of boys with posterior urethral valves. Br J Urol [Internet]. 1988;62(1):59–62.
6. Morris RK, Kilby MD. Congenital urinary tract obstruction. Best Pract Res Clin Obstet Gynaecol. 2008;22(1):97– 122.
7. Chevalier R. Fetal urinary tract obstruction: pathophysiology. Fetal Therapy: Scientific Basis and Critical Appraisal of Clinical Benefits. Kilby, M.D. Oepkes, D. Johnson, A. Cambridge University Press; 2012. 238 p. 8. Vanderheyden T, Kumar S, Fisk NM. Fetal renal impairment. Semin Neonatol. 2003;8(4):279–89.
9. Khalek N JM. Fetal urinary tract obstruction: prenatal assessment and prognosis. In Fetal Therapy: Scientific Basis and Critical Appraisal of Clinical Benefits. Kilby D, O. Cambridge CU press:, editor.
10. Sebire NJ, Von Kaisenberg C, Rubio C, Snijders RJM, Nicolaides KH. Fetal megacystis at 10–14 weeks of gestation. Ultrasound Obstet Gynecol. 1996;8(6):387–90.
11. Bornes M, Spaggiari E, Schmitz T, Dreux S, Czerkiewicz I, Delezoide AL, El-Ghoneimi A, Oury JF, Muller F. Outcome and etiologies of fetal megacystis according to the gestational age at diagnosis. Prenat Diagn. 2013;33(12):1162–6.
12. Fievet L, Faure A, Coze S, Harper L, Panait N, Braunstein D, Carson J, Gorincour G, Chaumoitre K, Guys JM, Alessandrini P, D’Ercole C, Merrot T. Fetal megacystis: Etiologies, management, and outcome according to the trimester. Urology. 2014;84(1):185–90.
13. Matsui F, Shimada K, Matsumoto F, Obara T. Prenatal resolution of megacystis possibly caused by spontaneous rupture of posterior urethral valves. J Pediatr Surg. 2008;43(12):2285–7.
14. Liao AW, Sebire NJ, Geerts L, Cicero S, Nicolaides KH. Megacystis at 10-14 weeks of gestation: Chromosomal defects and outcome according to bladder length. Ultrasound Obstet Gynecol. 2003;21(4):338–41. 15. Taghavi K, Sharpe C, Stringer MD. Fetal megacystis: A systematic review. J Pediatr Urol. 2017;13(1):7–15. 16. Johnson MP, Danzer E, Koh J, Polzin W, Harman C, O ’shaughnessy R, Brown R, Zaretsky MV; North American
Fetal Therapy Network (NAFTNet). Natural History of Fetal Lower Urinary Tract Obstruction with Normal Amniotic Fluid Volume at Initial Diagnosis.
17. Freedman a L, Johnson MP, Gonzalez R. Fetal therapy for obstructive uropathy: past, present.future? Pediatr Nephrol [Internet]. 2000;14(2):167–76.
18. Harrison MR, Golbus MS, Filly RA, Callen PW, Katz M, de Lorimier AA, Rosen M., Jonsen AR. Fetal surgery for congenital hydronephrosis. N Engl J Med [Internet]. 1982;306(10):591–3.
19. Chur E. Michael Harrison: Inventing Devices & a New Field. 2017. Available from: https://surgicalinnovations. ucsf.edu/spotlight/innovator-profiles/michael-harrison,-md.aspx
20. Ruano R. Fetal surgery for severe lower urinary tract obstruction. Vol. 31, Prenatal Diagnosis. 2011. p. 667–74. 21. Ruano R, Pimenta EJ, Duarte S, Zugaib M. Four-dimensional ultrasonographic imaging of fetal lower urinary
tract obstruction and guidance of percutaneous cystoscopy. Ultrasound Obstet Gynecol [Internet]. 2009 Feb 1 [cited 2018 Feb 1];33(2):250–2.
22. Ruano R, Sananes N, Sangi-Haghpeykar H, Hernandez-Ruano S, Moog R, Becmeur F,Zaloszyc A, Giron AM, Morin B, Favre R. Fetal intervention for severe lower urinary tract obstruction: A multicenter case-control study comparing fetal cystoscopy with vesicoamniotic shunting. Ultrasound Obstet Gynecol. 2015; 23. Ruano R, Yoshisaki CT, Salustiano EMA, Giron AM, Srougi M, Zugaib M. Early fetal cystoscopy for first-trimester
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24. Ruano R, Yoshizaki CT, Giron AM, Srougi M, Zugaib M. Cystoscopic placement of transurethral stent in a fetus with urethral stenosis. Ultrasound Obstet Gynecol. 2014 Aug 1;44(2):238–40.
25. Haeri S. Fetal Lower Urinary Tract Obstruction (LUTO): a practical review for providers. Matern Heal Neonatol Perinatol [Internet]. 2015;1:26.
26. Morris RK, Malin GL, Quinlan-Jones E, Middleton LJ, Hemming K, Burke D, Daniels JP, Khan KS, Deeks J, Kilby MD. Percutaneous vesicoamniotic shunting versus conservative management for fetal lower urinary tract obstruction (PLUTO): A randomised trial. Lancet. 2013;
27. Haeri S, Simon DH, Pillutla K. Serial amnioinfusions for fetal pulmonary palliation in fetuses with renal failure. J Matern Neonatal Med [Internet]. 2017;30(2):174–6.
28. Polzin WJ, Lim FY, Habli M, Van Hook J, Minges M, Jaekle R, Crombleholme TM. Use of an Amnioport to Maintain Amniotic Fluid Volume in Fetuses with Oligohydramnios Secondary to Lower Urinary Tract Obstruction or Fetal Renal Anomalies. Fetal Diagn Ther. 2017;41(1):51–7.
29. Van Mieghem T, Ryan G. The PLUTO trial: a missed opportunity. Lancet. 2013 Nov;382(9903):1471–3. 30. Ruano R, Sananes N, Sangi-Haghpeykar H, Hernandez-Ruano S, Moog R, Becmeur F,Zaloszyc A, Giron AM,
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32. Nassr AA, Shazly SAM, Abdelmagied AM, Araujo Júnior E, Tonni G, Kilby MD, Ruano R. Effectiveness of vesico-amniotic shunt in fetuses with congenital lower urinary tract obstruction: An updated systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2016 Jun.
Fetal Megacystis: definition
and differential diagnosis
2
bladder in the second and third
trimester of pregnancy
F. Fontanella, H. Groen, R. Smidt, L. Duin and C.M. Bilardo
abstract
Objective: To use 3D ultrasound images to construct reference values for fetal normal
urinary bladder size and volume between 15 and 35 weeks of gestation.
Methods: This was a prospective cross-sectional study carried out from 2016 to 2017 at the
University Medical Centre Groningen, the Netherlands. Singleton pregnancies in absence of fetal abnormalities were included in the study between 15 and 35 weeks’ gestation. All ultrasound examinations were performed by a trained sonographer. During each scan, lasting approximately 40-60 minutes, at least three 3D volumes of the urinary bladder were obtained for each fetus. Fetal bladder volume was calculated offline by the automatic volume calculation (AVC) tool and the manual virtual organ computer-aided analysis (VOCAL) technique, with 30° rotation angles. Postnatal data were reviewed, and only live-born children without congenital anomalies were kept in the study.
results: A 3D ultrasound sweep of the fetal bladder was obtained every 20 minutes in 225
pregnant women between 15 and 35 weeks of gestation. A total of 1238 measurements of urinary bladder volume (BV) and largest bladder diameter (LBD) were obtained. Urinary BV was successfully measured by the semi-automatic SonoAVC tool in 123 cases (55%) and by VOCAL method in all cases. There was no significant correlation between measurements obtained by SonoAVC and by VOCAL technique (r = 0.37). A linear relationship was observed between LBD and GA (r2: 0.78 for the largest LBD and 0.76 for the mean LBD), while a polynomial regression line was fitted for the BV according to GA. Gestational age based normal ranges for the largest and mean LBD and bladder volume (BV) were constructed.
Conclusions: This normative data will be useful to establish if a bladder is pathologically
2
Introduction
The function of the bladder is storing urine at low pressure and expelling it periodically via coordinated and sustained contractions (1). Neurogenic bladder dysfunctions, lower urinary tract obstruction (LUTO) or vesico-ureteral reflux can prejudice this function during fetal life and alter the physiological bladder filling and voiding process. When one of these conditions is suspected prenatally, it is crucial for the differential diagnosis and prognosis to objectively assess if the bladder size falls within normal ranges and to reproducibly triage an eventual pathological bladder enlargement (2)(3)(4).
Fetal bladder is standardly assessed at the first trimester scan, when the normal longitudinal bladder diameter measures less than 7 mm (5). However, beyond the 14th week of gestation, although the assessment of bladder filling is part of every standard ultrasound examination (6)(7), a clear cut-off for defining normal or enlarged bladder size is lacking. Since the 1970s, hourly fetal urine production throughout gestation has been studied by using both 2D and 3D US (8)(9)(10)(11)(12)(13)(14)(15), showing that urinary production and bladder capacity progressively increase during gestation (16). However, all these studies have failed to report reference ranges and growth charts for fetal urinary bladder size beyond 14 weeks’ gestation. This means that currently the diagnosis of an enlarged bladder is largely based on a subjective judgment, rather than on objective parameters defining a normal or pathological bladder distension.
Main objective of the study was therefore to fill this gap and to construct charts of fetal bladder volume (BV) and longitudinal bladder diameter (LBD) from 15to 35 weeks of pregnancy.
Methods
A cross-sectional prospective study was carried out from May 2016 to October 2017 at the University Medical Center Groningen. Pregnant women with a viable singleton uncomplicated pregnancy and with an accurate gestational-age assessment were recruited from the 15th week of gestation age until 35 weeks’ gestation. Exclusion criteria were: multiple pregnancies, fetal congenital abnormalities -detected either before or after birth-, and the use of medications or maternal diseases that could potentially affect fetal growth or diuresis (diabetes mellitus, smoking, hypertensive disorders). Postnatal data were collected in order to exclude neonates with abnormalities of pathological conditions at birth.
A trans-abdominal US scan was performed only once for each patient by a trained operator (FF) using either a Voluson E8 or E10 system (GE Voluson TM Healthcare, Zipf, Austria). The scan lasted 40 minutes and serial 2D and 3D ultrasound images of the fetal
urinary bladder were collected.
For the measurement of the urinary bladder volume (BV), 3D sweeps of the lower fetal abdomen were taken, digitally stored and subsequently analyzed with the 4D View software (GE VolusonTM Healthcare, Zipf, Austria). The BV was calculated by using two methods: Sono automatic volume calculation (SonoAVC) and manual Virtual Organ Computer-aided Analysis (VOCAL), drawing the contours of the fluid filled area at every 30º of rotation (Figure 1). Additionally, the longitudinal bladder diameter (LBD) was measured manually on the multiplanar 3D image, corrected to the exact mid-sagittal plane, by placing one caliper on the inner border of the bladder wall at the upper pole (bladder dome) and the other on the inner border of the lower pole (bladder neck). A single trained operator measured manually the LBD and drew the contours of the bladder.For the study design, patient selection and statistical method, the guidelines from Altman and Chitty (1993) and by Ioannou et al (2011) were followed. The measurements were modeled against the gestational age and reference charts were constructed. Polynomial regression models were fitted to the mean and standard deviation (SD) of each measurement as functions of gestational age.
The study was authorized by the Medical Ethics Committee in Groningen (dossier number NL54636.042.15).
Figure 1. 3D sweeps of fetal pelvis with manual Virtual Organ Computer-aided Analysis of bladder contours.
2
results
A total of 225 pregnant women at different gestation age participated once into the study (Table 1). BV and LBD were measured at 20 minutes’ interval. In 56 cases, the scan lasted less than 40 minutes and the third US measurement was not performed. In total, 1238 measurements were obtained.
table 1. Gestational age distribution of the study population.
GA N % 15 12 5,3 16 11 4,9 17 13 5,8 18 9 4,0 19 10 4,4 20 15 6,7 21 17 7,6 22 15 6,7 23 19 8,4 24 16 7,1 25 12 5,3 26 13 5,8 27 7 3,1 28 14 6,2 29 9 4,0 30 9 4,0 31 6 2,7 32 5 2,2 33 5 2,2 34 4 1,8 35 4 1,8 Total 225 100
The BV was measured by using both the SonoAVC and the VOCAL method. The SonoAVC tool was successful in identifying and calculating the BV in 123 (55%). In the remaining 102 cases (45%) where the SonoAVC failed to semi-automatically identify and calculate the BV, this was only calculated by the Vocal method. In the 123 cases with volume measured by both SonoAVC or VOCAL, the bladder measurements differed by 3% (mean difference 6 cm3) and a significant correlation was not found (r = 0.37).
The three volumes, from the largest to the smallest were used to visually reconstruct bladder dynamics (fi gure 2). During a span of 40 minutes, fetal voiding was visually observed in all cases and the BV decreased of minimal one-third of its maximal volume within a mean period of 32 minutes (within 32.0, 29.5and 32.4 minutes in the gestational age windows between 15-21 week, 22-26 weeks, and 27-35 weeks, respectively).
Figure 2. Dynamics of fetal micturition between 28 and 35 weeks (red line), between 21 and 27 weeks (green line), and between 15 – 20 weeks (blue line): for each category, the mean of the maximal, medial and minimal bladder volume during the US examination has been calculated.
Gestational age based reference size and growth charts were reported for: mean BV (table 2a), largest BV (table 2b), mean LBD (table 2c) and largest LBD (table 2d). A linear relation was observed between LBD and GA (r2: 0.78 for the largest LBD and 0.76 for the mean LBD), while a polynomial regression line was fi tted for the BV according to GA (fi gures 3-5).
2
Figure 4. Largest fetal bladder volume (max BV, mm) and gestational age (weeks)
Figure 5. Mean longitudinal diameter (cm3)and gestational age (weeks).
Discussion
This study reports normograms for the longitudinal bladder diameter and bladder volume from 15throughout 35weeks of gestation. These are, to our knowledge, the first normative data enabling the definition of a normal bladder size during the second and third trimester of pregnancy.
Cut-offs of normal bladder size have long been known in the first trimester of pregnancy (2). However, LUTO, posterior urethral valves, VUR or neurogenic bladder dysfunctions are more frequently suspected later in pregnancy, when bladder size assessment has already proved valuable for predicting prognosis (2)(3)(17). So far, previous studies have reported the hourly urinary fetal production (HUFP) throughout gestation without reporting on the size of the urinary bladder(18)(12)(14).The lack of normative data on urinary bladder size has represented a major issue, in particular for the definition of megacystis in the second and third-trimester of pregnancy (19).
table 2. Fitted centiles of the largest longitudinal diameter (largest LBD, mm; 2d), mean longitudinal bladder diameter (mean LBD, mm; 2c), largest bladder volume (BV, cm3; 2b) and mean bladder volume
(BV, cm3; 2a) for exact gestational week between 15 and 35 weeks of gestational age (GA).
2a 2b
GA fitted centiles mean BV fitted centiles largest BV
5th 50th 95th SD 5th 50th 95th SD 15 0,00 0,69 1,99 0,66 0,00 0,85 2,10 0,64 16 0,00 0,55 1,46 0,46 0,00 0,69 1,66 0,50 17 0,00 0,45 1,06 0,31 0,00 0,57 1,33 0,39 18 0,00 0,39 0,79 0,21 0,00 0,53 1,13 0,31 19 0,10 0,39 0,68 0,15 0,03 0,55 1,08 0,27 20 0,18 0,46 0,73 0,14 0,14 0,67 1,20 0,27 21 0,24 0,60 0,96 0,18 0,27 0,89 1,52 0,32 22 0,29 0,82 1,36 0,27 0,41 1,23 2,05 0,42 23 0,34 1,15 1,95 0,41 0,57 1,70 2,83 0,58 24 0,40 1,58 2,75 0,60 0,76 2,32 3,87 0,79 25 0,49 2,13 3,77 0,84 0,98 3,09 5,21 1,08 26 0,62 2,81 5,01 1,12 1,24 4,05 6,85 1,43 27 0,79 3,64 6,49 1,45 1,55 5,20 8,84 1,86 28 1,02 4,62 8,22 1,84 1,91 6,55 11,19 2,37 29 1,33 5,77 10,21 2,27 2,34 8,14 13,93 2,96 30 1,72 7,10 12,48 2,74 2,83 9,96 17,09 3,64
2
GA fitted centiles mean BV fitted centiles largest BV5th 50th 95th SD 5th 50th 95th SD 31 2,21 8,62 15,04 3,27 3,40 12,05 20,69 4,41 32 2,81 10,35 17,90 3,85 4,06 14,41 24,76 5,28 33 3,53 12,30 21,07 4,47 4,81 17,07 29,32 6,25 34 4,40 14,49 24,58 5,15 5,67 20,04 34,41 7,33 35 5,41 16,92 28,42 5,87 6,63 23,34 40,04 8,52 2c 2d
GA fitted centiles mean LBD fitted centiles largest LBD
5th 50th 95th SD 5th 50th 95th SD 15 0,00 5,05 11,47 3,90 3,99 6,08 8,17 1,27 16 0,00 6,53 13,32 4,13 5,43 7,79 10,15 1,43 17 0,85 8,01 15,17 4,36 6,84 9,50 12,16 1,62 18 1,95 9,49 17,03 4,58 8,21 11,21 14,21 1,83 19 3,06 10,97 18,88 4,81 9,53 12,92 16,31 2,06 20 4,17 12,45 20,73 5,03 10,82 14,63 18,44 2,32 21 5,28 13,93 22,58 5,26 12,06 16,34 20,62 2,60 22 6,38 15,41 24,44 5,49 13,25 18,05 22,85 2,92 23 7,49 16,89 26,29 5,71 14,40 19,76 25,12 3,26 24 8,60 18,37 28,14 5,94 15,49 21,47 27,45 3,64 25 9,70 19,85 30,00 6,17 16,53 23,18 29,83 4,04 26 10,81 21,33 31,85 6,39 17,51 24,89 32,27 4,49 27 11,92 22,81 33,70 6,62 18,44 26,60 34,76 4,96 28 13,03 24,29 35,55 6,85 19,30 28,31 37,32 5,48 29 14,13 25,77 37,41 7,07 20,10 30,02 39,94 6,03 30 15,24 27,25 39,26 7,30 20,84 31,73 42,62 6,62 31 16,35 28,73 41,11 7,53 21,51 33,44 45,37 7,25 32 17,46 30,21 42,96 7,75 22,11 35,15 48,19 7,93 33 18,56 31,69 44,82 7,98 22,64 36,86 51,08 8,64 34 19,67 33,17 46,67 8,21 23,10 38,57 54,04 9,41 35 20,78 34,65 48,52 8,43 23,48 40,28 57,08 10,22 table 2. Continued 2a 2b
Thus far, the definition of megacystis beyond the first trimester has been heterogeneous including: a longitudinal bladder measurement above the 99th centile without referring to any normative data (20); a fetal bladder reaching the umbilical cord insertion, or most commonly, a bladder failing to empty within 45 minutes (21). All these definitions lack an objective cut-off to define a physiological and pathological bladder distension and to allow reproducibility and consistency among the studies. Maizels et al. were the first in the literature to propose a mathematical formula to calculate the LBD according to GA, but only based on 39 normal bladders measurements between 15 and 40 weeks’ gestation (22). The study reported a linear relationship between GA and largest LBD and the calculated formula was LBD = GA – 5. We also found a linear relationship between LBD and GA, but with the following formula defining the mean physiological LBD: LBD = 1.48 * GA - 17.15.
The bladder volume can be assessed either by applying a mathematical formula for the three bladder diameters (longitudinal, antero-posterior and transverse) obtained by 2D US, or by directly calculating the volume on 3D pictures taking into account the true shape of the fetal bladder. Two major limitations can be envisaged with the first approach: first, the fact that the volume is calculated on an arbitrarily selected image, assumed to represent the maximal bladder size and (8) second, the difficulty of choosing an appropriate formula to calculate the BV from the bladder diameters. In fact, throughout the filling phase, the bladder shape changes from an ellipsoid to a super-ellipsoid, a virtually more cylindrical shape(8). Therefore, the use of a unique formula for estimating the bladder volume at different filling phases and GA it is not appropriate (23)(8). Both these limitations can be overcome by the use of a 3D US technique enabling accurate volume estimation, even in irregularly shaped or asymmetrical organs (24)(25)(26). Three D technique is at present the most accurate method (27) for calculating the BV and we therefore report charts and centiles for the 3D-measured fetal bladder volume.
After acquisition of a 3D image, different methods can be used to measure the volume of an organ, such as the rotational Virtual Organ Computer-aided AnaLysis ((VOCAL); GE Medical Systems, Zipf, Austria) or the automated segmentation tool for fluid-filled spaces Sono-AVC (GE Medical Systems). The Sono-AVC tool semi-automatically recognizes, traces and measures the fluid-filled structures in the 3D volume. This tool represents the easiest and quickest method in daily practice, however the volumes obtained on the same image with either SonoAVC and VOCAL setting in our cohort were not strictly correlated (r=0.037), and the SonoAVC method failed in recognizing the right structure in 45% of our cases. The VOCAL method has been previously used for measuring the BV by Peixoto-Filho et al. (27). The authors also investigated the inter- and intra-observer reliability by using 15 and 30° rotation steps calculation. Since an excellent correlation between the two measurements was found, the authors suggested to use 30° of rotation as this is significantly faster. This is why we adopted 30° rotational angle.
2
As 3D technique is not universally available, we also propose reference ranges for LBD, based on 2D Images and therefore more easily applicable in daily practice.
In the present study, the 40-minutes period for the US examination resulted in the observation of a complete bladder cycle of filling and voiding in all fetuses. This confirms the results of Hata et al., which reported that the time needed for observing the bladder empty was approximately 30 minutes at 28 weeks, and 40 minutes at 35 weeks’ gestation (28). These and our results (figure 1), confirm that the capacity of the fetal bladder to store urine and empty changes and matures with advancing gestation, with a progressively increasing capacity and more complete emptying with advancing gestation (1).As we examined the fetuses for 40 minutes, the HUFP could not be calculated. However, the HUFP has been already reported in details by other studies, and recently by using 3D US scans (11)(29).
A strength of this study is its prospective and cross sectional design, in accordance to the best practice for constructing fetal reference charts (30)(31). Moreover, the US examinations were performed by the same operator (F.F.), and the contours of the urinary bladder and the LBD were all measured by another operator (R.S.) This should have limited any inter-operator bias.
In conclusion, we provide normograms for fetal bladder size during the second and third trimester of pregnancy. Future research is needed to validate these results and define an objective threshold for second and third-trimester megacystis.
appendix 1. Micturition dynamics between 15 – 20 weeks.
appendix 2. Micturition dynamics between 21 and 27 weeks
appendix 3. Micturition dynamics between 28 and 35 weeks.
Examination time (40 minutes)
Bladder volume 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4
Examination time (40 minutes)
Bladder volume 0 10 20 30 40 50
Examination time (40 minutes)
Bladder volume 0.0 0.5 1.0 1.5 2.0 2.5
2
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12. Takeuchi H, Koyanagi T, Yoshizato T, Takashima T, Satoh S, Nakano H. Fetal urine production at different gestational ages: correlation to various compromised fetuses in utero. Early Hum Dev. 1994 Dec 16 [cited 2017 May 12];40(1):1–11.
13. Lee SM, Park SK, Shim SS, Jun JK, Park JS, Syn HC. Measurement of fetal urine production by three-dimensional ultrasonography in normal pregnancy. Ultrasound Obstet Gynecol. John Wiley & Sons, Ltd.; 2007 Sep 1 [cited 2017 Nov 28];30(3):281–6.
14. Rabinowitz R, Peters MT, Vyas S, Campbell S, Nicolaides KH. Measurement of fetal urine production in normal pregnancy by real-time ultrasonography. Am J Obstet Gynecol. 1989;161(5):1264–6.
15. Stigter RH, Schelven LJ. van, Bruinse HW, Mulder EJH, Gemert MJC. van. On the measurement of fetal bladder volume and urine production: methodological considerations. Prenat neonatal Med. 2000;5:169–76. 16. Baskin L, Meaney D, Landsman A, Zderic SA, Macarak E. Bovine Bladder Compliance Increases with Normal
Fetal Development. J Urol [Internet]. Elsevier; 1994 Aug 1 [cited 2018 Mar 20];152(2):692–5.
17. Fontanella F, Duin LK, Adama van Scheltema PN, Cohen-Overbeek TE, Pajkrt E, Bekker M,Willekes C, Bax CJ, Gracchi V, Oepkes D, Bilardo CM. Prenatal diagnosis of LUTO: how to improve diagnostic accuracy. Ultrasound Obstet Gynecol. 2017.
18. Nicolaides KH, Peters MT, Vyas S, Rabinowitz R, Rosen DJD, Campbell S. Relation of rate of urine production to oxygen tension in small-for-gestational-age fetuses. Am J Obstet Gynecol. 1990;162(2):387–91.
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Lespinard C, Perrotin F, Poulain P, Sarramon MF; Study Group of the French Fetal Medicine Society. Prenatal diagnosis of megacystis-microcolon-intestinal hypoperistalsis syndrome: Contribution of amniotic fluid digestive enzyme assay and fetal urinalysis. Prenat Diagn. 2005;25(3):203–9.
21. Bornes M, Spaggiari E, Schmitz T, Dreux S, Czerkiewicz I, Delezoide AL, El-Ghoneimi A, Oury JF, Muller F. Outcome and etiologies of fetal megacystis according to the gestational age at diagnosis. Prenat Diagn. 2013;33(12):1162–6.
22. Maizels M, Alpert SA, Houston JTB, Sabbagha RE, Parilla B V., MacGregor SN. Fetal bladder sagittal length: A simple monitor to assess normal and enlarged fetal bladder size, and forecast clinical outcome. J Urol. 2004;172(5 I):1995–9.
23. Hedriana HL, Moore TR. Accuracy limits of ultrasonograhic estimation of human fetal urinary flow rate. Am J Obstet Gynecol. Mosby; 1994 Oct 1;171(4):989–92.
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25. Riccabona M, Nelson TR, Pretorius DH, Davidson TE. In vivo three-dimensional sonographic measurement of organ volume: Validation in the urinary bladder. J Ultrasound Med. 1996;15(9):627–32.
26. Rousian M, Koning AHJ, Van Oppenraaij RHF, Hop WC, Verwoerd-Dikkeboom CM, Van Der Spek PJ, Exalto N, Steegers EA. An innovative virtual reality technique for automated human embryonic volume measurements. Hum Reprod. 2010;25(9):2210–6.
27. Peixoto-Filho FM, Sá RAM, Lopes LM, Velarde LGC, Marchiori E, Ville Y. Three-dimensional ultrasound fetal
urinary bladder volume measurement: Reliability of rotational (VOCALTM) technique using different steps of
rotation. Arch Gynecol Obstet. 2007;276(4):345–9.
28. Hata T, Dater RL. A review of fetal organ measurements obtained with ultrasound: normal growth. J Clin Ultrasound. 1992;Mar-Apr;20.
29. Lee SM, Park SK, Shim SS, Jun JK, Park JS, Syn HC. Measurement of fetal urine production by three-dimensional ultrasonography in normal pregnancy. Ultrasound Obstet Gynecol. 2007;30(3):281–6.
30. Ioannou C, Talbot K, Ohuma E, Sarris I, Villar J, Conde-Agudelo A, Papageorghiou AT. Systematic review of methodology used in ultrasound studies aimed at creating charts of fetal size. BJOG An Int J Obstet Gynaecol. 2012;119(12):1425–39.
31. Altman DG, Chitty LS. Design and analysis of studies to derive charts of fetal size. Ultrasound in Obstetrics and Gynecology. 1993;3(6):378–84.
3
a lot more than LUTO
F. Fontanella, L. Maggio, J.B.G.M. Verheij, L.K. Duin,
P.N. Adama van Scheltema, T.E. Cohen – Overbeek,
E. Pajkrt, M. Bekker, C. Willekes, C.J. Bax, V. Gracchi,
D. Oepkes and C.M. Bilardo
abstract
aim: Megacystis represents a challenge in terms of counseling and management due to its
various etiology and evolution. The aim of this study is to present a comprehensive overview of the underlying etiologies and structural anomalies associated with fetal megacystis.
Methods: This was a retrospective multicenter study carried out at the Fetal Medicine Units
(FMUs) of the eight Academic Hospitals in the Netherlands. For each case referred to one of these centers due to fetal megacystis, data and measurements of fetal urinary tract and associated structural anomalies were collected. All available postmortem examinations and postnatal investigations were reviewed in order to establish the final diagnosis. In the first trimester, fetal megacystis was defined as a bladder with a longitudinal diameter (LBD) ≥ 7 mm, and in the 2nd and 3rd trimester as an enlarged bladder failing to empty during an extended US examination lasting at least 40 minutes.
results: Out of 541 megacystis, megacystis was isolated (or merely accompanied by other
signs of LUTO) in 360 cases (66%); and associated with other abnormal ultrasound findings in 181 cases (34%). The most common associated anomaly was an increased nuchal translucency (NT, 22%), followed by SUA and cardiac defects (10%). A final diagnosis was established in 418 cases, including 222 cases with isolated LUTO (53%) and 60 infants (14%) with normal micturition or isolated urological anomalies. In the remaining 136 cases (33%), a genetic syndrome, developmental or chromosomal abnormality was diagnosed.
In total, 40 chromosomal abnormalities were diagnosed, including: Trisomy 18 (n = 24), Trisomy 21 (n = 5), Turner syndrome (n = 5), Trisomy 13 (n = 3) and deletion 22q11 (n = 3). Thirty-two cases presented with Ano-Rectal Malformations involving anus, rectum and urogenital tract. In cases with confirmed urethral and anal atresia, megacystis occurred early in pregnancy and the bladder appeared severely distended (the longitudinal diameter was equal or greater than twice the gestational age). Fetal macrosomia was detected in 6 cases and an overgrowth syndrome was detected in other 4 cases: 2 infants with Beckwith–Wiedemann and 2 infants with Sotos syndrome. Megacystis-microcolon-intestinal hypoperistalsis syndrome was diagnosed in five cases (1%) and prenatally suspected only in one case.
Conclusions: Although the main cause of megacystis is LUTO, an enlarged fetal bladder can
also be present as corollary finding of miscellaneous genetic syndromes, developmental disturbances and chromosomal abnormalities. This study provides an overview of the structural anomalies and congenital disorders associated with megacystis and proposes a flowchart for the differential diagnosis of genetic syndromes, chromosomal and developmental abnormalities, focusing on the morphological examination of the fetus.
3
Introduction
Fetal urine production begins at about 10 weeks’ gestation, when the urinary bladder can be identified as an anechoic structure within the fetal pelvis, surrounded by the two umbilical arteries1. The evidence of a distended urinary bladder, also known as megacystis, is an ultrasound finding as easily identifiable as hardly manageable, due to its various etiology and uncertain evolution. In the first-trimester, fetal megacystis is defined by a longitudinal bladder diameter (LBD) greater than 7 mm and is reported in 0.06% of pregnancies (2). Beyond the first trimester, prevalence of megacystis remains unclear and its definition is still ambiguous (3).
The main cause of fetal megacystis, diagnosed at any trimester in pregnancy, is bladder outlet obstruction, also known as Lower Urinary Tract Obstructions (LUTO) (4,5,6). In cases with severe early megacystis, parents often choose for termination of pregnancy. In less severe cases with early megacystis (with LBD ≤12 mm) and negative work-up, a spontaneous resolution often occurs4,6,7. In fetuses surviving the second half of pregnancy LUTO commonly leads to hydronephrosis, renal dysplasia and severe oligohydramnios with a known poor prognosis. However, besides isolated LUTO, the differential diagnosis of fetal megacystis should also include chromosomal abnormalities, genetic syndromes and developmental anomalies. The wide spectrum of etiologies and prognoses makes the counseling and management of this condition particularly challenging (8). Given the low prevalence of megacystis (9,10) and the main focus on LUTO as etiology, the other causes of enlarged bladder have been thus far poorly investigated.
The main aim of this study is to present a comprehensive overview of the underlying etiologies and structural anomalies associated with fetal megacystis and to identify patterns of anomalies and US features related to specific complex anomalies and syndromes, beyond LUTO.
Methods
This study is part of a large retrospective multicenter study carried out at the Fetal Medicine Units (FMUs) of all eight Academic Hospitals in the Netherlands, acting as referral centers for fetal anomalies detected at ultrasound examination. Cases with fetal megacystis were retrieved from local databases according to when registration in the databases had started (from year 2000 to 2014 at Erasmus Medical Center, Academic Medical Center, Amsterdam and at the University Medical Center, Maastricht; between 2004 and 2015 at the University Medical Center Groningen and at the Radboud University Medical Center, Nijmegen; between 2007 and 2014 in the remaining centers). In the first trimester fetal megacystis
was defined as a bladder with longitudinal diameter (LBD) ≥ 7 mm (2), and in the 2nd and 3rd trimester as an enlarged bladder failing to empty during an extended US examination lasting at least 40 minutes (11).
In the Netherlands, all cases suspected for megacystis are referred to one of the eight FMUs for confirmation of diagnosis and further investigations. Cases were referred after either a dating scan, first-trimester scan, 20-week anomaly scan or after a scan performed on other indications later in pregnancy. All cases had undergone a detailed anomaly scan, except for those pregnancies that had not reached the 18th week of gestation (n = 142, including 115 pregnancies terminated and 27 miscarriages). Parents were counseled about the prognosis and informed about the possibility of in-utero treatment. The vesico-amniotic shunt placement was only offered to chromosomally normal male fetuses with isolated signs of LUTO and with concomitant oligohydramnios.
For each case, the following prenatal data were collected: gestational age at diagnosis (GA), longitudinal bladder diameter (LBD) and associated US findings. The LBD was obtained from a mid-sagittal view of the fetus, by measuring the distance from fetal bladder dome to bladder neck. The US findings typically associated with LUTO, such as hydronephrosis, abnormal renal cortical appearance, keyhole sign and oligohydramnios (with eventual compression deformities), were not regarded as associated US anomalies. The nuchal translucency was considered increased if greater than the 95th percentile according to the GA12. We considered the NT measured at referral for cases referred in the first trimester of pregnancy while, in fetuses referred later in pregnancy, we retrospectively collected the NT measurement.
All available postmortem examinations and postnatal investigations were reviewed in order to establish a final diagnosis. LUTO was defined as a bladder outlet obstruction caused by urethral valves, urethral stenosis or urethral atresia. With the term Ano-Rectal Malformation (ARM) reference is made to a group of complex congenital anomalies characterized by an abnormal development of the urorectal septum, therefore resulting in congenital abnormalities of the distal anus, rectum and genitourinary tract13. Among this group, cloacal dysgenesis or cloacal malformations were characterized by the absence of anal, genital and urinary orifices14. VACTERL association was diagnosed if three of the following criteria were met: Vertebral defects, Anal atresia/imperforate anus, Cardiovascular anomalies, Tracheo-esophageal fistula or Esophageal atresia, Renal anomalies and Limb defects (including radial anomalies) in at least two of the three regions involved (thorax, pelvis/lower abdomen and limb)15. Caudal regression spectrum (CRS) was defined by the occurrence of abnormalities at the level of caudal spinal segments, ranging from minor sacrococcygeal malformations to complete absence of sacrum and lumbar spine16. OEIS complex was diagnosed in case of Omphalocele associated with bladder Exstrophy, Imperforate anus and Spinal defect17. Infants without LUTO or other severe congenital
3
abnormalities or congenital syndromes were included in the group with normal urinary tract or isolated urological anomaly, such as vesico-ureteral reflux (VUR) or duplex collecting system. In case of isolated LUTO, the postnatal renal function was evaluated by considering the estimated glomerulaater filtration rate (eGFR): this was calculated using the Schwartz formula and by taking into account the infant’s length and the creatinine nadir in the first year of diagnosis18.
results
During the study period, 541 pregnancies (25 twin and 516 singleton pregnancies) were referred to one of the eight Fetal Medicine Unit in the Netherlands owing to the finding of fetal megacystis. Out of 541 cases, 233 pregnancies (43%) were referred before the 18th week of gestation (early megacystis), and 308 cases (57%) at or after the 18th week of gestation (late megacystis; figure 1). This study has dealt with structural anomalies, genetic syndromes, and developmental or chromosomal abnormalities associated with megacystis. Other outcome measures relative to this cohort have been reported on different studies (4,5,6).
Figure 1. Study population (TOP: 188, IUFD: 50, neonatal death: 68).
TOP, termination of pregnancy; IUFD intrauterine fetal death; NA, not available; MCA, multiple congenital anomalies. 541 Fetal megacystis
233 Early Megacystis (<18th week) 308 Late Megacystis (≥18th week)
188 TOP 50 IUFD 68 Neonatal death 235 Children 418 Final diagnosis Postmortem examinations (n=139)
Prenatal evidence of MCA or abnormal karyotype (n=50) Postnatal examinations (n=229)
Lost to follow-up (n=6)
Fetal megacystis was isolated (or merely associated with other signs of LUTO) in 360 cases (66%), and associated with other abnormal US findings in 181 cases (34%). In 70 cases, more than a single associated anomaly was found and in a total of 293 associated US findings were observed (Table 1). Overall, the most common associated US anomaly was an increased NT (22%), followed by a SUA and cardiac defects (10%).
table 1. Severe anomalies and ultrasound markers associated with fetal megacystis.
Abnormal ultrasound findings
(n = 293) n (%)
NT ≥ 95 centille 64 (22%)
Single umbilical artery 30 (10%)
Cardiac defects 30 (10%)
Ventricular Septal Defect 3 (1%)
Umbilical cord cyst 27 (9%)
Spine or skeletal anomalies 19 (6%)
Sacrococcygealteratoma 1 (0.3%)
Abdominal wall defects 18 (6%)
Urogenital anomalies 15 (5%)
Intrauterine growth restriction 7 (2%)
Macrosomia 6 (2%)
Macroglossia 1 (0.3%)
Central Nervous System 5 (2%)
Cleft lip/palate 3 (1%)
Fetal Hydrops 8 (3%)
Diaphragmatic hernia 3 (1%)
Plexus choroideus cyst 15 (5%)
Echogenic bowel 11 (4%)
Short long bones 6 (2%)
Ventriculomegaly 2 (0.7%)
Echogenic intracardiac focus 2 (0.7%)
Miscellaneous syndromal markers 16 (5%)
*Miscellaneous syndromal marker included: hypertelorism, strawberry skull, micrognathia, club foot.
Overall 88 pregnancies (35%) were terminated, 50 (9%) resulted in intra-uterine deaths (9%), 68 (13%) in neonatal deaths, and 235 (43%) children were live-born. Of the terminated pregnancies, parents did not consent to postmortem examination in 117 (62,2%) cases. Six cases were lost to follow-up (Figure 1). A final causal diagnosis was thus possible in 418 cases (77%), including 222 cases (53%) with isolated LUTO, 60 infants (14%) with another
3
minor isolated urological anomaly or normal urinary tract anomaly at birth and 136 (33%) ‘syndromic’ cases with miscellaneous chromosomal abnormalities, genetic syndromes or developmental anomalies (Table 2). This last group consisted of four categories: 1) major chromosomal abnormalities (n = 40), 2) ARM (n = 32), 3) fetuses with macrosomia or overgrowth genetic syndromes (n = 10) and 4) other cases with multiple congenital abnormalities (MCA) or other miscellaneous genetic syndromes (n = 54). Table 3 summarizes GA at referral, LBD, fetal gender, amniotic fluid (AF) volume, pregnancy outcome and findings at postnatal or postmortem investigations in the syndromic cases. In table 4, we report outcome and postnatal renal function of cases with isolated LUTO.
In total, 40 chromosomal abnormalities were diagnosed (table 2 and 3), with a predominance of trisomy 18 (24 cases, including 22 with trisomy 18, and 2 with trisomy 18 mosaicisms), followed by trisomy 21 (5 cases), Turner syndrome (5 cases: 1 with Turner syndrome and 4 with Turner mosaicisms), trisomy 13 (3 cases) and deletion 22q11 (3 cases). In the chromosomally abnormal fetuses megacystis was diagnosed at a mean GA of 17 weeks and was associated with increased NT or other severe structural anomalies. AF volume was normal in 30% of cases. In addition, 5 fetuses presented with miscellaneous chromosomal abnormalities of unclear clinical significance and likely unrelated to the observed phenotypes.
table 2. Final diagnosis and GA at diagnosis of 418 fetal megacystis (TOP: 188, IUFD: 50, neonatal death: 68).
Final diagnosis n (%) GA at diagnosis (wks)
mean (SD)
LUTO 222 (53%) 22.6 (±7)
Normal micturition at birth or other isolated urological anomaly 60 (14%) 21.7 (±10)
Miscellaneous congenital syndromes 136 (33%) 18.8 (±7)
- Chromosomalabnormalities 40 (10%) 15.3 (±4)
- Anorectal Malformations 32 (8%) 15.9 (±5)
- Fetal Macrosomia or Overgrowth syndrome 10 (2%) 22.7 (±8)
- MCA and other syndromes 54 (13%) 20 (±7)
TOP, termination of pregnancy; IUFD intrauterine fetal death; MCA, multiple congenital anomalies.
Thirty-two cases presented with a wide spectrum of developmental abnormalities involving anus, rectum and urogenital tract, and classified as ARM. This group included: 13 VACTERL associations, 6 cloacal malformations, 7 OEIS complex, 2 Fraser syndrome and 4 CRS. In fetuses with ARM, megacystis was detected already early in pregnancy (mean GA at referral: 16 weeks). In all cases with urethral and anal atresia, fetal bladder was severely distended with LBD equal or greater than twice the GA, while in case of moderate bladder
distension, with LBD lower than GA x 2 mm, a spinal or vertebral anomaly was found either at the antenatal scan or at the postmortem examination. In this group, the AF volume was reduced in 66% of cases.
Fetal macrosomia was detected in 6 cases and an overgrowth syndrome in other 4 cases: 2 infants with Beckwith–Wiedemann (BWS) and 2 infants with Sotos syndrome.
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) was diagnosed in 5 fetuses, 4 of which had normal AF volume during pregnancy. Moreover, a similar phenotype with intestinal hypoperistalsis and detrusor hypotonia was observed in one infant with Ochoa syndrome. Other miscellaneous genetic and structural anomalies observed are reported in Table 3.
Based on the antenatal findings and final diagnosis, a flowchart was designed to guide the differential diagnosis of fetal megacystis and rule out major genetic syndromes and developmental abnormalities (Figure 2).
In our study population, 360 fetuses had isolated megacystis (megacystis without other associated US abnormality or merely with associated signs of LUTO). This subgroup of fetuses showed a better outcome as reported on Figure 3. Their GA at onset of oligo or anhydramnios was related to fetal outcome. This was 17 weeks in the pregnancies that were terminated (n = 116), 20 weeks in pregnancies that ended in a IUFD (n = 19), 24 weeks in those that resulted in a neonatal death (n = 28) and 30 weeks in children that survived (n = 197). Among the 197 alive children, LUTO was confirmed in 129 cases, while in the remaining 70 a normal micturition or an isolated urological anomaly (including vesico-ureteral reflux or duplex collecting system) was diagnosed. A severely impaired renal function within the first year of life (< 30 mL/min/1.73m2) was observed in sixteen children with confirmed LUTO and in only one child without LUTO, but with severe vesico-ureteral reflux.
3
Fe ta l M ega cy st is Ea rly M eg ac ys tis Karyo ty pe - 22 q11 d ele tio n sy nd ro m e (C H D (co no tr un ca l), cle ft (l ip ) p al at e, ab se nt /h yp op la st ic t hy m us , la rg e ca vu m se pt um p el lu ci du m ) - LUT O + CHD - V AC TERL (r en al , s pi na l, li m bs or ca rd ia c an om al ie s, n o g as tr ic b ub bl e, a bs en t pe ria na l m us cu la r co m pl ex , U CC , S U A) - Ov erg ro w th sy nd ro m e - M M H IS ( th in b la dd er w all, dilated st om ach a nd b ow el lo op s ) Late M eg ac ys tis - V AC TERL a ss oc iati on (r en al, sp in al, lim bs o r ca rd ia c an om alie s, no ga st ric bu bb le , d ila te d co lo n, S U A, U CC ) - C RS (in cr ea se d N T, CRL s ho rt er th an ex pe cte d, sa cr al a ge ne si s) - LUT O - M M IHS ( th in b la dd er w all, dilated st om ach a nd b ow el lo op s ) - V AC TERL a ss oc iati on (r en al, sp in al, lim bs o r ca rd ia c an om alies , n o ga st ric bu bb le , d ila te d co lo n, S U A, U CC ) Om ph al oc ele An eu plo id y OEI S co m ple x (in cr ea se d N T, sp in al de fe ct an d SU A) ab no rm al ye s LB D > G A x 2 m m Clo ac al m alf orm atio n (U CC ) Sp in e an d Sk ele to n Ab no rm al Is olate d M eg ac ys tis - M M H IS ( th in b la dd er w all, dilated st om ach a nd b ow el lo op s ) ye s Card iac D ef ec t M ac ro so m ia or po ly hy dra m nio n no rm al no ye s no ye s ye s no no no Figur e 2. Flo w char t f or the diff er ential diag nosis of fetal megac ystis (genetic syndr omes , de velopmental disor ders and chr omosomal abnor malities).table 3. Ant enatal details and postnatal or postmor tem findings in megac yst ys cases with genetic syndr omes , de velopmental or chr omosomal abnor malities . Chr omosomal A bnormalities M
ean GA referr
al
(95%CI) (weeks)
M
ean LBD (mm)
Cases with LUTO sig
ns n (%) Oligo - or anh ydr amnios n (%) Se x (male%) O ut come (T OP ; IUFD
or neonatal deaths; aliv
e) A ssocia ted A nomalies at an tena tal US scan Findings a t postmor tem/ postna tal e xamina tion Tr isom y 18 or mosaicism (24) 17 (15-20) 25 21 (88%) 7 (29%) 88% 15;9;0 Incr eased NT ; CHD; UC C; omphalocele; sk eletal/ spine def ec ts CHD
, agenesis of the cer
ebellar ver mis , omphalocele , clubf oot Tr isom y 21 (5) 16 (12-21) 26 3 (60%) 3 (60%) 100% 4;1;0 Incr eased NT ; sk eletalanomalies NA Tur ner syndr ome or mosaicism (5) 15 (10-21) 15 2 (40%) 1 (20%) 40% 3;1;1 UC C, incr eased NT Imper forat e anus , facial dysmor phisms , CHD Tr isom y 13 (3) 12 (10-15) 9 3 (100%) 0 100% 3;0;0 CHD , labiopalat oschisis , SU A, poly dac tyly NA D eletion 22q11 syndr ome (3) 25 31 3 (100%) 1 (33%) 100% 1;0;2 CHD Unilat eral r enal agenesis , CHD , VUR Total (40) 17 (15-18) 23 32 (80%) 12 (30%) 82% 26;11;3 Common f eatur es: incr easedNT Common f eatur es: CHD
3
A
dditional chr
omosomal abnormalities with doubtful clinical sig
nificanc e (n = 5) Se x GA ref err al (w eeks) LBD (mm) Oligo - or anh ydr amnios n (%) LUT O sig ns O ut come A ssocia ted anomalies at an tena tal US scan Findings a t postmor tem/ postna tal e xamina tion 46,XY , 1.9 Mb duplication, 19q13.33 de no vo (1) M NA NA N N Aliv e UC C D ela yed mot or de velopment; muscular h ypot onia; gastr oesophageal r eflux; ec topic testis;epiph
yseal dysplasia, shor
t statur e 46,XY , 22q11.2 micr oduplication + 14q31 duplication (1) M 37 NA Y Y (K ; H; O) Aliv e N PUV + se ver e VUR (III-IV g rade) 46,X X, deletion 5q .35.2 (1) F 19 NA Y Y ( AR C; O) Aliv e N Thether ed cor d + neur ogenic bladder + VUR + multidysplastic kidne ys + psy chomot or ial disabilities 46,X, der ( X) t ( X; Y ) (p22.33;p11.31) (1) M 21 13 Y Y (K ; H; O) Aliv e N VUR + bilat eral r
enal displasia and
renal insufficienc y 46, X X, male 46, XY , t (14;16) ( q24.3; q24.1) pat (1) NA 22 NA Y Y (K ; AR C; H; O) TOP Unilat eral r enal agenesis (lef t) + r enal dyplasia (r ight) Unilat eral r
enal agenesis (lef
t +
renal dyplasia (r
ight)
table 3.
