University of Groningen

Antenatal diagnosis and management of fetal megacystis and lower urinary tract obstructionFontanella, Federica

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Publication date:2019

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Citation for published version (APA):Fontanella, F. (2019). Antenatal diagnosis and management of fetal megacystis and lower urinary tractobstruction. [Groningen]: University of Groningen.

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Summary in EnglishNederlandse samenvattingAbbreviationsAcknowledgmentsAbout the authorList of publications

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Summary in Englis

English summary

The term LUTO refers to a heterogeneous group of anatomical anomalies characterized by an obstruction in the urethra and by an increased intraluminal pressure along the urinary tract. During fetal life, LUTO leads to the development of an enlarged urinary bladder (also known as megacystis), severe hydronephrosis and oligohydramnios with high risk of early renal damage and perinatal mortality. Over the last 20 years, fetal therapy, in the form of vesico-amniotic shunt or fetal cystoscopy, has been attempted on the assumption that by relieving the intrauterine pressure caused by the obstruction, mortality and renal damage could be possible prevented. However, to date, whether and when the in-utero treatment should be offered is still a matter of debate, and the eventual selection of candidates remains suboptimal owing to the disappointing diagnostic accuracy of fetal LUTO.

Aim of this thesis was to gather at a national level, clinical data that would elucidate the natural history from fetal megacystis to congenital LUTO and guide fetal specialists in the challenging counseling, diagnostic work-up and antenatal management. The thesis is divided in three main parts.

Part I includes chapter 2, chapter 3 and chapter 4, and focuses on the differential diagnosis and definition of fetal megacystis. In chapter 2, we report for the first time in the literature reference values for the dimension of a normal urinary bladder in the second and third trimester of pregnancy. Chapter 3 presents an overview of the structural anomalies and congenital disorders associated with fetal megacystis. From this chapter we also conclude that fetal megacystis does not only occur in fetuses with LUTO, but it can be observed also as corollary finding of miscellaneous genetic syndromes, developmental disorders and chromosomal abnormalities. In chapter 4 we investigates the natural history of megacystis and demonstrates that the longitudinal bladder diameter and the gestational age at resolution of megacystis are reliable predictors of spontaneous resolution and outcome, respectively.

In Part II, we develop two management algorithms for optimizing the antenatal diagnosis of isolated LUTO with the aim of more accurately selecting those fetuses theoretically eligible for in-utero treatment. In chapter 5, we propose an algorithm for identifying fetuses with early megacystis and isolated posterior urethral valves. The visualization of an umbilical cord cyst appears to be a strong marker of the more severe urethral atresia. In chapter 6, we propose a clinical score for the optimal antenatal diagnosis of LUTO in the second and third trimester of pregnancy, as alternative to the commonly used LUTO triad (megacystis, keyhole sign and hydronephrosis). This score can accurately discriminate fetuses with LUTO from those with non-obstructive megacystis, a group non eligible to in-utero treatment.

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Finally, Part III of this thesis aims at predicting antenatally the prognosis of LUTO cases, in terms of survival and postnatal renal function. In chapter 7, we propose a staging system for congenital LUTO capable of predicting the severity of the condition and its prognosis in terms of perinatal survival. 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).

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Nederlandse samenvatting

Nederlandse samenvatting

Bij een Lower Urinary Tract Obstruction (LUTO) is er sprake van een groep van anatomische afwijkingen gekenmerkt door een vernauwing of afsluiting van de plasbuis. Foetale LUTO leidt tot de ontwikkeling van een foetale megablaas met ernstige hydronefrose en oligohydramnion. Hierdoor is een LUTO geassocieerd met vroege nierbeschadiging en perinatale sterfte. In de afgelopen 20 jaar werd door middel van foetale therapie getracht om de obstructie in utero op te heffen door de plaatsing van een vesico-amniotische shunt of door foetale cystoscopie. Echter, op dit moment zijn de effectiviteit en de timing voor de in-utero therapie nog steeds niet duidelijk. Bovendien blijft de antenatale selectie van kandidaten nog steeds suboptimaal ten gevolge van de beperkte diagnostische nauwkeurigheid van foetale LUTO tijdens de zwangerschap.

Dit proefschrift richt zich op de differentiële diagnose, counseling en management van een foetale megablaas en LUTO. Het doel van dit proefschrift was om het pathofysiologische verloop van de foetale megablaas te presenteren op basis van landelijke data, en specialisten te begeleiden in de uitdagende counseling en prenatale behandeling van de foetale megablaas en LUTO.

Deel I van dit proefschrift richt zich op de differentiële diagnose en definitie van een foetale megablaas. In hoofdstuk 2 worden prospectieve referentiewaarden voor de dimensie van een normale urineblaas in het tweede en derde trimester van de zwangerschap gepresenteerd. Hoofdstuk 3 beschrijft de structurele anomalieën en aangeboren aandoeningen die geassocieerd zijn met een megablaas. Er kan geconcludeerd worden dat de foetale megablaas niet alleen een marker is voor LUTO maar ook is geassocieerd met een breed spectrum aan genetische syndromen, structurele en chromosomale afwijkingen. Hoofdstuk 4 richt zich op het fysiologische verloop van een foetale megablaas tijdens de zwangerschap. Waarbij de zwangerschapsduur bij de eventueel spontane resolutie van megablaas en de longitudinale blaasdiameter betrouwbare voorspellers zijn van respectievelijk de uitkomst en van de kans op resolutie van een megablaas.

Het doel van deel II van dit proefschrift was om de nauwkeurigheid van de prenatale diagnose van een geïsoleerde LUTO te optimaliseren. In hoofdstuk 5 hebben wij de antenatale criteria voor de optimale selectie van foetussen met een vroege megablaas en urethrakleppen die in theorie in aanmerking voor in-utero interventie komen, onderzocht. Tevens is aangetoond dat een navelstreng cyste in combinatie met een vroege megablaas een sterke marker is voor een urethrale atresie. Hoofdstuk 6 definieert een klinische echografische score om de nauwkeurigheid van de prenatale diagnostiek voor LUTO in het tweede en derde trimester te verbeteren.

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Deel III van dit proefschrift richt zich op prenatale voorspellers voor de postnatale en perinatale prognose. In hoofdstuk 7 presenteren we een echografisch stadiëringssysteem om de ernst van LUTO en het risico op perinatale sterfte te voorspellen. Hoofdstuk 8 gaat in op prenatale echografische voorspellers voor de postnatale nierfunctie.

Het proefschrift eindigt met een algemene discussie over de implicaties van onze bevindingen en toekomstperspectief (hoofdstuk 9).

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Abbreviation

abbreviations

LUTO lower urinary tract obstructions LBD longitudinal bladder diameterUS ultrasoundVAS vesico-amniotic shuntPUV posterior urethral valvesRCT randomized controlled trial3D US three-dimensional ultrasoundSonoAVC Automated Volume CalculationsVOCAL Virtual Organ Computer-aided AnaLysisBV bladder volumeGE General electricsSD standard deviationGA gestational ageHUFP hourly urinary fetal productionAUC area under the curveUCC umbilical cord cystANM anorectal malformationsMCA multiple congenital anomaliesNT nucal translucency OR odds ratiocfDNA cell-free DNAPPV positive predictive valueNPV negative predictive valueROC-curve receiver operating characteristic curve AF amniotic fluideGFR estimated glomerular filtration rate TOTAL trial tracheal occlusion to accelerate lung growth trialPLUTO trial Percutaneous vesico-amniotic shunting versus conservative management for fetal lower urinary tract obstruction

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Acknowledgments

acknowledgments

My first meeting with Prof. Bilardo took place in Groningen during my last year of Medical School. We met with the idea of carrying out a very short research project for my master’s thesis. This project did not start with the intention of publishing seven papers and writing a PhD thesis. Our idea was simply retrieving data on fetal megacystis between Groningen and Amsterdam. The situation got a bit out of hand; email by email Catia managed to involve all the academic centers in the Netherlands, months by months we managed to finish our prospective study, and so we ended up here. Dear Catia, it has been a beautiful adventure. Thank you for having firmly invested in this project and in me from that first meeting onwards, thank you for all the learning moments and for your constant and sincere support. The mutual affection of two human beings can be measured by the number of words they exchange, says M. Kundera, and I feel lucky for the amount of words exchanged with you, in the form of manuscripts, drafts, revisions, calls and meetings every time I needed. Grazie!

Once we focused on the natural history of fetal megacystis, many questions related to the antenatal management and treatment of LUTO easily came out. For this purpose, the collaboration and the expertise of the LUMC has been essential and I would like to sincerely thank Prof. Oepkes for his expertise and scientific contribution to this thesis, and Phebe Adama van Scheltema for having me helped from the beginning of this project with the data collection.

I would also like to sincerely thank Leonie Duin, who has guided me since day one of my arrival in Groningen: from the first short explanation about Astraia, to the first 3D ultrasound, to each practical help and encouragements for the clinical practice. Thanks a lot for your support!

My sincere gratitude goes to the reading committee and all the committee members for their time in reviewing this thesis, and thanks to Prof. Mark Kilby for his scientific contribution and availability in traveling twice from Birmingham up to Groningen.

-Science is the name but collaboration is the game- To Eva Pajkrt, Titia Cohen-Overbeek, Christine Willekes, Mireille Bekker and Caroline Bax goes my sincere acknowledgment for their collaboration during these years that made possible to conduct this research.

Thanks also to dr. Suresh Seshadri who allowed me to spend the last period of my PhD life in India. Thanks for the inspiring experience and for your warm hospitality at Mediscan!

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I would like to express my gratitude to Prof. Scherjon for his help and support in arranging my PhD trajectory.

To Henk Groen, thanks for your time, answers and supervision to all my questions in statistics.

To Valentina Gracchi, thanks for having always gladly shared your expertise in this field.

A sincere acknowledgment also goes to all the patients who agreed to participate to the FEBLA study and to Rixt and Sofia for their collaboration on working on the 3D images.

A special thanks also goes to my mentors from Rome, Prof. Di Iorio and dr. Margherita Pace for having me helped in arranging the first exchange period to Groningen.

To all the PND staff of UMCG, what a great team! Thanks for everything you taught me about antenatal ultrasound, for your help with the administration behind the FEBLA study, and thanks for your patience with my very first shy and reticent words in Dutch!! To Merel, thanks for your time in correcting the most difficult texts in Dutch and thanks for your precious reliability as colleague, friend and belayer!

Years can pass very fast when they are cheered by nice colleagues around you. Thanks Jan, Tom, Nastaran, Eva, Rikst Nynke, Violeta and whoever has worked on room Y4.228 even just for a while. Thanks for that atmosphere of caring and sharing both our failures and achievements. Thanks Laura and Luana for bringing to Groningen your spontaneity, enthusiasm and the best of our beautiful country. My deep gratitude goes to my colleague, friend and lovely paranymph Francesca. Thanks for having provided with a daily amount of jokes and uncontrollable laughter during these years, for all your help in organizing this day and still more thanks for being supportive every time I needed it.

From Groningen to Delft, I have been lucky to come across many new friends without whom my daily life would have been bleak. Thanks to Gabbia di Matti! A very heterogeneous group of people which has seen a number of people passing by Groningen as well a number of kingdoms succeeding year by year: from the vibrant authentic era of Queen Kappi the First, to the extravagant years of Queen Storm, until our current era guided by Queen Giuls the Lion and characterized by a huge amount of political debates on WhatsApp (sorry for the spam!). During these years, two things have never changed: our bond with this amazing city and our mayor doc Gabri. To Gabri goes my thanks for mentoring me during my first steps in Groningen until my first clinical stage at UMCG. To my sweet Pinkies goes my sincere love and gratitude for the warm and spontaneous pinky-atmosphere of sharing, caring

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Acknowledgments

and laughing out loud, to Ciccio for our genuine friendship and for my favorite idiotic and brilliant moments in Groningen, and to Prof. Giuma thanks for our inspiring mid-afternoon lunches and calls. Thanks to all the people who felt part of this group for even just a short period: I have learned something from each of you!

From Groningen to Delft, I have also found good friends who supported me 24/7, even when a mouse comes to visit your bedside table in the middle of the night, or when suddenly your window collapses: one of the most surreal beer moments ever, with you there Giulia! thanks to both Alessandri, Elly, Giulia and Joe! To my friends, big family, colleagues, and to the Magnifici Dieci spread across Europe, thanks for every plane, train ticket, message and call aimed at let growing and strengthening our long-distance friendships. A special thanks goes to my Miks for the lifelong and silent emotional support and to Antonietta for making me feel at home every time I came back.

And here comes to the acknowledgements for my beautiful and strong family, who still support me whenever and from wherever. Thank you, mum, for your eternal example. Thanks for passing like clouds in the sky, for whispering to me how strong I can still be, and for reminding me that our love, kindness and knowledge is the best thing we can leave to this world. Dear Papa and Ala, your quiet presence during these years have preciously accompanied me step by step, from the first move to Groningen to the last moving out, thank you for staying silently always on my side and for being such a precious source of encouragements. Thanks, Papi for your support in taking that first plane and for your message once I landed, thanks for always desiring the best for me, and even at the cost of your own convenience. To my sister Laura: a tough woman, brilliant researcher, talented artist (thanks for your patience in painting cover and illustration of this thesis) and wonderful mother. You never stopped exceling in doing what you love and I am looking forward to seeing you shining again and again! And thanks to Giulio and Chow-Nadia for making me feel home even in Cachan.

Last but not least, thanks to Dems, my paranymph, best friend and favorite human being in this world. Sharing my days with you means genuinely enjoying life beyond any pre-packaged form of happiness, and seeking a balance in the midst of that dissatisfaction feeling that long drove us - always eager and never set -. Thanks for your endless and unconditional support, love and presence. Thank you for being my sourest critic and my most hardcore fan, for bringing out the best of me and for encouraging me to climb the most challenging routes together. Thanks, because no matter how far you can be, the first call is always for you.

Thank you, all folks!

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About the author

about the author

Federica was born on the 13th of November, 1989 in Rome, Italy. She grew up in Rome with her parents Teresa and Giampietro and her elder sister Laura. In 2008, she graduated from the scientific Liceum Malpighi and she was admitted to the Medical School in La Sapienza, University of Rome. During her third year of University, Federica started to attend the department of gynecology and obstetrics at San Peter Hospital, in Rome under the supervision of Prof. Di Iorio and in 2012 she obtained an Erasmus scholarship to study six months at the Medical University of Innsbruck. There, Federica had the possibility to observe for the first time in her life a procedure of fetal therapy in a twin pregnancy with twin-to-twin transfusion syndrome and her interest in gynecology and prenatal diagnosis grew further. Just after her return from Innsbruck, she obtained a scholarship that took her abroad once again, this time to write her Master’s thesis at the university of Groningen under the supervision of Prof. Bilardo. In 2014, she graduated in Medicine at the La Sapienza University with the highest marks and decided to come back to Groningen for a PhD trajectory. From 2015 to 2018, she collected data from the Netherlands to India, independently performed more than 300 three-dimensional ultrasounds for her research project, and managed to write this PhD thesis.

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List of publications

Publications

Fetal Megacystis: Prediction of spontaneous resolution and outcome. Fontanella F, Duin L, Adama van Scheltema PN, Cohen-Overbeek TE, Pajkrt E, Bekker M, Willekes C, Bax CJ, Bilardo CM. Ultrasound in Obstetr and Gynecol 2017.

Yield of a 12-13-week scan for the early diagnosis of fetal congenital anomalies in the cell-free DNA era. Kenkhuis MJ, Bakker M, Bardi F, Fontanella F, Bakker MK, Fleurke-Rozema H, Bilardo CM. Ultrasound in Obstetr and Gynecol 2017.

Prenatal Evidence of Persistent Notochord and Absent Sacrum Caused by a Mutation in the T (Brachyury) Gene. Fontanella F, van Maarle MC, Robles de Medina P, Oostra RJ, van Rijn RR,Pajkrt E, Bilardo CM. Report in Obstetrics and Gynecology 2016.

Prenatal diagnosis of LUTO: how to improve diagnostic accuracy. Fontanella F, Duin L, Adama van Scheltema PN, Cohen-Overbeek TE, Pajkrt E, Bekker M, Willekes C, Bax CJ, V. Gracchi, D. Oepkes and Bilardo CM. Ultrasound in Obstetr and Gynecol 2017.

Fetal megacystis: a lot more than LUTO. Fontanella F, L. Maggio, J. B. G. M. Verheij, Duin L,Adama van Scheltema PN, Cohen-Overbeek TE, Pajkrt E, Bekker M, Willekes C, Bax CJ, D. Oepkes, Bilardo CM. Ultrasound in Obstetr and Gynecol. 2018

Antenatal work-up of early megacystis and selection of candidates for fetal therapy Fontanella F, L. Maggio, J. B. G. M. Verheij, Duin L, Adama van Scheltema PN, Cohen-Overbeek TE, Pajkrt E, Bekker M, Willekes C, Bax CJ, D. Oepkes, Bilardo CM. Fetal Diagnosis and Therapy 2018

Prediction model of postnatal renal function in fetuses with Lower Urinary Tract Obstruction: development and internal validation. Duin L, Fontanella F, Groen H, Adama van Scheltema PN, Cohen-Overbeek TE, Pajkrt E, Bekker M, Willekes C, Bax CJ, V. Gracchi, D. Oepkes and Bilardo CM. Submitted

Prediction of perinatal mortality and disease severity in congenital LUTO. Fontanella F, P. N. Adama van Scheltema, L. Duin, T. E. Cohen-Overbeek, E. Pajkrt, M. Bekker, C. Willekes, C. J. Bax, D. Oepkes and C.M. Bilardo. Ultrasound in Obstetr and Gynecol 2018

Reference curves for fetal urinary bladder in the second and third trimester of pregnancy. Fontanella F, H. Groen, Duin L, Bilardo CM. Submitted

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Oral communications at international conferencesMegacystis: risk stratification. F. Fontanella, L. Duin, Bilardo C. 16th World Conference in Fetal Medicine

Maggio, L., Elvan, A., Fontanella, F., & Bilardo, C. M. Grading the fetal echogenic bowel (EB): correlation between quantitative computerissed gray-scale analysis and subjective qualitative evaluation. 27th ISUOG World Conference

Fetal Megacystis: a lot more than LUTO, F. Fontanella, P. Adama Van Scheltema, V. Gracchi, T.E. Cohen-Overbeek, C. Willekes, M.N. Bekker, E. Pajkrt, D. Oepkes and C.M. Bilardo. 15th World Conference in Fetal Medicine

Vesico-amniotic shunting versus conservative management in fetal lower urinary tract obstruction: a 10-year registry, F. Fontanella, P. Adama Van Scheltema, V. Gracchi, T.E. Cohen-Overbeek, C. Willekes, M.N. Bekker, E. Pajkrt, D. Oepkes and C.M. Bilardo. 26th ISUOG World Conference

Spontaneous resolution of fetal megacystis: when and why? F. Fontanella, L. Duin, T.E. Cohen-Overbeek, M.N. Bekker, P. Adama Van Scheltema, C. Willekes, E. Pajkrt, C. Bax and C.M. Bilardo. 26th ISUOG World Conference

Prognostic value of umbilical cord cysts in fetal megacystisF. Fontanella, L. Duin, T.E. Cohen-Overbeek, M.N. Bekker, P. Adama Van Scheltema, C. Willekes, E. Pajkrt, C. Bax and C.M. Bilardo. 26th ISUOG World Conference

Antenatal Ultrasound prediction of postnatal renal function in congenital lower urinary tract obstruction F. Fontanella, P. Adama Van Scheltema, V. Gracchi, T.E. Cohen-Overbeek, C. Willekes, M.N. Bekker, E. Pajkrt, D. Oepkes and C.M. Bilardo. 24th ISUOG World Conference

Prices and grantsTop Publication Award 2018, SHARE institute - Rijksuniversiteit Groningen Top Publication Award 2017, SHARE institute - Rijksuniversiteit GroningenBest Oral Communication Award, ISUOG 24th World CongressShortlisted for Young Investigator Award, ISUOG 24th World CongressUniversity Scholarship for International Research Projects, La Sapienza UniversityUniversity Fellowship for International Research Projects, La Sapienza University

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Research Institute SHARE

research Institute SHarE

This thesis is published within the Research Institute SHARE (Science in Healthy Ageing and healthcaRE) of the University Medical Center Groningen / University of Groningen.Further information regarding the institute and its research can be obtained from our internet site: http://www.share.umcg.nl/

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