FETAL RENAL ANOMALIES: diagnosis, management and outcome.

Transcription

1 FETAL RENAL ANOMALIES: diagnosis, management and outcome.

2 cover: Albert Damen sr. print Budde-Elinkwijk, Nieuwegein

3 FETAL RENAL ANOMALIES: diagnosis, management and outcome Afwijkingen aan nieren en urinewegen bij de foetus: diagnose, behandeling en uitkomst. (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de Rector Magnificus, Prof. dr. W.H. Gispen, ingevolge het besluit van het College voor Promoties in het openbaar te verdedigen op dinsdag 14 december 2004 des middags te uur door Henrica Antonia Maria Damen Elias geboren te Tegelen, 27 mei 1941

4 Promotor: Copromotores: Prof. dr. G.H.A. Visser Department of Perinatology and Gynaecology University Medical Centre Utrecht Dr. T.P.V.M. de Jong Department of Paediatric Urology University Medical Centre Utrecht Dr. P.H. Stoutenbeek Department of Perinatology and Gynaecology University Medical Centre Utrecht ISBN: CIP-DATA KONINKLIJKE BIBLIOTHEEK DEN HAAG Damen-Elias, Henrica Antonia Maria FETAL RENAL ANOMALIES: diagnosis, management and outcome Utrecht, Universiteit Utrecht, Faculteit Geneeskunde Thesis Universiteit Utrecht Financial support for the publication of the this thesis is gratefully acknowledged: Stichting Kindernierziekten Easote Pie Medical Toshiba Medical Systems Europe Nierstichting Nederland

5 What does wisdom benefits us, if we do not possess love.

6 Referents: Prof. dr. F. van Bel Department of Neonatology University Medical Centre Utrecht Prof. dr. J.L.H.R. Bosch Department of Urology University Medical Centre Utrecht Prof. dr. H.W. Bruinse Department of Perinatology and Gynaecology University Medical Centre Utrecht Prof. dr. J.M. Nijman Department of Urology University Medical Centre Groningen Prof. dr. J.W. Wladimiroff Department of Obstetrics and Gynaecology Erasmus Medical Centre Rotterdam Paranimfen: Drs. P.J. Damen Mevr. M.J. Korenromp

7 Table of contents 7 Chapter 1 Introduction and aims of the thesis Chapter 2 Intra- and interobserver variability of fetal kidney and adrenal gland measurements revised version resubmitted to Ultrasound in Obstetrics and Gynaecology Chapter 3 Growth and size charts of the fetal kidney and the renal pelvis revised version resubmitted to Ultrasound in Obstetrics and Gynaecology Chapter 4 Growth and size charts of the fetal adrenal gland revised version resubmitted to Ultrasound in Obstetrics and Gynaecology Chapter 5 Congenital renal tract anomalies: outcome and follow-up of 402 cases detected antenatally over a period of 15 years. in press: Ultrasound in Obstetrics and Gynaecology Chapter 6 Concomitant anomalies in 100 children with unilateral multicystic kidney in press: Ultrasound in Obstetrics and Gynaecology Chapter 7 Mild pyelectasis diagnosed by prenatal ultrasound is not a predictor of urinary tract morbidity in childhood in press: Ultrasound in Obstetrics and Gynaecology Chapter 8 Variability in dilatation of the fetal renal pelvis during a bladder filling cycle in press: Ultrasound in Obstetrics and Gynaecology Chapter 9 Summary, discussion and conclusion Nederlandse samenvatting Dankwoord Curriculum Vitae

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9 Chapter 1 Introduction, aims and outline of the thesis

10 10 Chapter 1 introduction Interest in fetal development has grown enormously in the past decades. Till then non-invasive methods were used to asses fetal health such as the feeling of movements by the pregnant woman, measuring growth by palpation of the fundal height and auscultation of the fetal heart tones with a wooden stethoscope. X-ray examination was used in search for fetal abnormalities and to diagnose multiple pregnancies but the questionable safety of such investigation in pregnancy made this method unsuitable for routine examinations. All changed when it became possible to observe the fetus in utero by ultrasound. As early as 1958, Donald et al 1 showed the outline of the fetal skull. The technical and methodological development of this technique made it possible to investigate the fetus directly and the consequence of this quickly expanding and improving new technique has been an increasing amount of information concerning fetal morphological and physiological development during pregnancy. Further improvement of the equipment with high-resolution real-time ultrasound has given the possibility to more detailed information of the fetus and later on transvaginal sonography has made it possible to obtain detailed information of early embryonic development. The introduction of routine prenatal ultrasound scanning since the early 1980 s in several countries in Europe has increased our knowledge on morphology and functional development of the fetus. Moreover it became possible to diagnose anomalies in utero. In population studies minor or major structural anomalies are detected in 2 to 3 % of cases 2-5. Abnormalities of the urinary tract account for 15-20% of these anomalies with a detection rate of approximately 90% 2, 4. The fetal kidneys can first be visualised by transabdominal ultrasound at 9 weeks gestational age and can be seen in all cases from 12 weeks onwards. In early pregnancy the echogenity of the fetal kidneys is high but this decreases in the course of gestation when they become hypoechoic 6. At about 28 weeks the renal pyramids can be detected and also the borders of the kidneys can be seen more clearly with progressing gestational age, since fat tissue is developing around the kidneys from that moment on.

11 introduction, aims and outline 11 The fetal bladder can be visualised from the onset of urine production, which occurs at about 10 weeks gestation 7. At 11 weeks of gestation the bladder can be visualised, both transvaginally and transabdominally, in 80% of fetuses and at 13 weeks almost in all fetuses 8, 9. It should always be possible to visualize the bladder when the crown-rump length is more than 67 mm (13 + weeks). The fetal adrenal glands are visible by ultrasonography as early as 9 weeks of gestation and in all cases from 12 weeks onwards. In the second trimester they appear as a disc-like structure in a transverse plane, cranially and medially to the kidney. Three layers can clearly be distinguished of which the outer layer is hypoechogenic and the central medulla hyperechoic. In the sagittal view they appear as heart-shaped figures of low echogenicity. During the last three decades numerous papers have dealed with the fetal renal system and its anomalies. Follow-up studies on (long term) outcome are, however, scarce and this hampers adequate counselling of parents and giving appropriate treatment advice. Moreover, up to date charts on normal fetal kidney size and growth are scarce. We therefore formulated the following aims of this thesis. aims of the thesis 1 To develop charts of size and growth of the fetal kidney, renal pelvis and adrenal gland. 2 To study long-term follow-up of a large cohort of infants with an antenatally diagnosed renal tract anomaly. 3 To answer the question whether mild pyelectasis (anteroposterior diameter of the fetal renal pelvis of 5 10 mm) as diagnosed around 18 to 20 weeks of gestation results in increased morbidity in childhood and therefore requires postnatal treatment. 4 To study the relationship between the size of the renal pelvis and the fetal bladder-filling cycle, to answer the question if fixed cut-off values regarding renal pelvis dilatation can be used or whether bladder filling has to be taken into account.

12 12 Chapter 1 outline of the thesis In Chapters 2 to 4 a prospective longitudinal study is described on size and growth of the fetal kidney, the fetal renal pelvis and the fetal adrenal gland in 111 fetuses from 16 weeks gestational age onwards till term. These studies were preceded by a study on intra- and inter-observer variation. In Chapter 5 we describe the findings and outcome of a large cohort of 402 fetuses in which urogenital anomalies were detected antenatally. We could use the database of the ultrasound unit of the department of obstetrics of the University Medical Centre, Utrecht, The Netherlands, which was established in At follow-up the youngest infant was 3 years and the oldest was 17 years (median 7 years 11 months). In Chapter 6 we present the outcome of 100 fetuses with an antenatally detected unilateral multicystic kidney. All additional urogenital and other anomalies are described. According to the advice of the Dutch Society of Paediatric Urology the non-functioning cystic kidney is removed at approximately 6 months of age to prevent life-time follow-up of these children because of an increased risk of hypertension 10, infection 11 or malignancy 12, 13. When the parents decided to do so, each child underwent a cystoscopy and girls also a colposopy prior to the operation. All these findings are included in the follow-up of these children (median 5 years and 4 months). For Chapter 7 we could use the data of the ultrasound department of the Amphia Hospital, Oosterhout, The Netherlands, which was established since Two hundred and eight children, who had had a mild pyelectasis of 5 10 mm at 18 to 20 weeks gestation, were compared with 416 matched controls regarding voiding and defecation patrons and urinary tract infections. A validated questionnaire, as used in the International Reflux Study in children, was used for this purpose. In Chapter 8 we describe a study in which 18 third trimester pregnant women are examined by ultrasound during several fetal bladder-filling cycles, to investigate if there is a correlation between the size of the renal pelvis and the extent of bladder filling. In Chapter 9 a summary and general discussion is described.

13 introduction, aims and outline 13 references 1 Donald I, Macvicar J, Brown TG. Investigation of abdominal masses by pulsed ultrasound. Lancet 1958;1(7032): Grandjean H, Larroque D, Levi S. Sensitivity of routine ultrasound screening of pregnancies in the Eurofetus database. The Eurofetus Team. Ann N Y Acad Sci 1998;847: Levi S. Ultrasound in prenatal diagnosis: polemics around routine ultrasound screening for second trimester fetal malformations. Prenat Diagn 2002;22(4): Levi S. Mass screening for fetal malformations: the Eurofetus study. Ultrasound Obstet Gynecol 2003;22(6): Stoll C, Clementi M. Prenatal diagnosis of dysmorphic syndromes by routine fetal ultrasound examination across Europe. Ultrasound Obstet Gynecol 2003;21(6): Green JJ, Hobbins JC. Abdominal ultrasound examination of the first-trimester fetus. Am J Obstet Gynecol 1988;159(1): McHugo J, Whittle M. Enlarged fetal bladders: aetiology, management and outcome.prenat Diagn 2001;21(11): Rosati P, Guariglia L. Transvaginal sonographic assessment of the fetal urinary tract in early pregnancy. Ultrasound Obstet Gynecol 1996;7(2): Braithwaite JM, Armstrong MA, Economides DL. Assessment of fetal anatomy at 12 to 13 weeks of gestation by transabdominal and transvaginal sonography. Br J Obstet Gynaecol 1996;103(1): Webb NJ, Lewis MA, Bruce J, Gough DC, Ladusans EJ, Thomson AP, et al. Unilateral multicystic dysplastic kidney: the case for nephrectomy. Arch Dis Child 1997;76(1): Wacksman J, Phipps L. Report of the Multicystic Kidney Registry: preliminary findings. J Urol 1993;150(6): Elder JS, Hladky D, Selzman AA. Outpatient nephrectomy for nonfunctioning kidneys. J Urol 1995;154(2 Pt 2):712-4; discussion LaSalle MD, Stock JA, Hanna MK. Insurability of children with congenital urological anomalies. J Urol 1997;158(3 Pt 2):

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15 Chapter 2 Intra- and interobserver variability of fetal kidney and adrenal gland measurements H.A.M. Damen - Elias a, G.H.A. Visser a, P. Westers b, L. Pistorius a a Department of Perinatology and Gynaecology, University Hospital Utrecht, The Netherlands b Centre for Biostatistics, Utrecht University, The Netherlands

16 16 Chapter 2 ABSTRACT Objectives: To assess the intra- and interobserver variability of fetal kidney and fetal adrenal gland measurement by ultrasound. Methods: Data were obtained prospectively by experienced ultrasonographers. Thirty fetuses were measured for the intraobserver analysis and 20 fetuses for the interobserver analysis. Length, anteroposterior and transverse diameter from both the right and left kidney and from the length of the right and left adrenal gland were measured 3 times. Statistical analysis was performed by SPSS. Results: The reproducibility of the measurements of the kidney and of the adrenal gland were good with an intraclass correlation above 0,80 for all measurements for both the intraobserver and interobserver analysis. Conclusions: The high degree of intra- and interobserver reproducibility indicates that the three dimensions of the kidney and adrenal gland length are technically feasible to measure.

17 Intra- and interobserver variability 17 INTRODUCTION Many reference curves of the fetal renal kidney have been published 1-7. Knowledge of the normal range of the measurements of the fetus is essential when during screening an anomaly is identified. No intraobserver and interobserver variation analysis was done prior to any of these studies. Only Bertagnoli 2 in 1983 reported on the differences in measurements between 3 operators who each used a different ultrasound machine. Some studies describe the design, the patient selection and the methods of analysis 8-10 but do not involve differences in intraobserver and interobserver measurements. The discriminatory ability of a diagnostic test is in large extent depending on the repeatability of the test. The aim of this study was to assess the intra- and interobserver reproducibility of the length, the anteroposterior and the transverse measurements of the fetal kidney and of the length of the adrenal gland by ultrasound. MATERIALS AND METHODS Thirty pregnant women were asked to participate in the study for the intraobserver variation analysis and another twenty for the interobserver variation analysis. All women consented to participate in the study There were no exclusion criteria. Two experienced ultrasonographers, (HDE, LP) examined the fetuses. Each observer attempted to obtain three measurements with different time intervals between each measurement. The sonographers were not allowed to see their own measurements or to watch each other performing the measurements to avoid any possible influence. In both investigations the length, the anteroposterior and transverse diameter of the kidney and the length of the adrenal gland were measured transabdominally with the multifrequency transducer PVM 375 AT of the Toshiba Power Vision 6000, type SSA 370 A (manufacturer Toshiba, Tokyo, Japan). In a sagittal plane when the full length of the kidney with the renal pelvis was visualised the length of the kidney was measured and in the same sectional plane the length of the combination of the kidney and the adrenal gland. Subsequently the length of the adrenal gland was determined by subtraction of the kidney length from the combined length. Perpendicular to this plane in the largest sectional plane, the anteroposterior and transverse diameter of both kidneys were measured. The data

18 18 Chapter 2 were recorded on a photograph and stored in a database. Statistical analysis was performed by using SPSS, version 10.1 (Statistical Product and Service Solutions, Chicago). The mean and standard deviation were calculated to determine if there was a good consistency between the measurements. In addition the range, the Cronbachs alpha (α) and the intra class correlation (ICC) were calculated. The range is the distance between the highest and lowest value. Cronbachs α is a statistical index for internal consistency between the measurements. The index ranges from 0 = bad to 1 = excellent. The ICC is the measure of concordance and is a statistic that describes the reproducibility of repeated measures in the same subject and indicates true variance as a fraction of the total variance. Landis and Koch 11 have indicated the meaning of the different values of the ICC and a value of has a good agreement and larger > 0.81 an excellent one. The value of ICC of 1 for repeated measurements indicates perfect reproducibility while a value of 0 is interpreted as no better or worse than that expected by chance. RESULTS intraobserver variation analysis The kidney length, kidney anteroposterior diameter, kidney transverse diameter and adrenal gland length could be measured 3 times in all 30 women. Intraobserver agreement is given in Table 1. Statistic analysis shows a high alpha above the 0,9 and also a high IC above 0,8 for all different measurements. Table 1 Intraobserver variation of length, anteroposterior and transverse diameter of the kidney and of length of the adrenal gland. variable mean ± std.dev alpha intra class correlation (95% CI) RiKiL 22,706 ± ( ) LeKiL 22,413 ± ( ) RiKiAP 15,217 ± ( ) LeKiAP 15,190 ± ( ) RiKiTr 15,172 ± ( ) LeKiTr 15,412 ± ( ) RiGL 5,316 ± ( ) LeGL 5,275 ± ( ) RiKiL = right kidney length, LeKiL = left kidney length, RiKiAP = right kidney anterior/ posterior diameter, LeKiAP = left kidney anterior/ posterior diameter, RiKiTr = right kidney transverse diameter, LeKiTr = left kidney transverse diameter, RiGL = right adrenal gland length, LeGL = left adrenal gland length.

19 Intra- and interobserver variability 19 interobserver variation analysis Both investigators could take all measurements 3 times in all 20 women. The interobserver analysis is given in Table 2. There was a high alpha above 0,9 for all measurements as well as a high IC above 0,8. There was a high level of agreement between the two observers. Table 2 - Interobserver variation of length, anteroposterior diameter and transverse diameter of the kidney and of length of the adrenal gland. variable mean ± st.dev range alpha intraclass correlation observer 1 observer 2. 95% CI) HDE* LP# HDE LP RiKiL ± ± ( ) LeKiL ± ± ( ) RiKiAP ± ± ( ) LeKiAP ± ± ( ) RiKiTr ± ± ( ) LeKiTR ± ± ( ) RiGL ± ± ( ) LeGL ± ± ( ) HDE* = observer 1, LP# = observer 2 RiKiL = right kidney length, LeKiL = left kidney length, RiKiAP = right kidney anterior/ posterior diameter, LeKiAP = left kidney anterior/ posterior diameter, RiKiTr = right kidney transverse diameter, LeKiTr = left kidney transverse diameter, RiGL = right adrenal gland length, LeGL = left adrenal gland length. DISCUSSION Measurements of the kidney are of importance when an anomaly is identified. Measurements of the adrenal gland may be of importance in high-risk pregnancies when intra uterine growth retardation is suspected 12-14, when mothers use glucocosteriods 15 for a prolonged period of time or in case of congenital adrenal hyperplasia 16, 17. A valuable screenings test should be both feasible and repeatable. An intra- and interobserver analysis should be evaluated and measurements should only be introduced in routine setting if a good sensitivity and specificity is demonstrated. It was technically feasible to take three measurements of the fetal kidney and the length of the adrenal gland. We used various indices and coefficients to assess intra- and interobserver variability and found a good agreement of both for the intraobserver analysis and for the interobserver analysis. Comparison of our results with those of others is not possible because there is no study in literature on intra- and interobserver analysis of fetal kidney and adrenal gland measurements.

20 20 Chapter 2 REFERENCES 1. Jeanty P, Dramaix-Wilmet M, Elkhazen N, Hubinont C, van Regemorter N. Measurements of fetal kidney growth on ultrasound. Radiology 1982;144(1): Bertagnoli L, Lalatta F, Gallicchio R, Fantuzzi M, Rusca M, Zorzoli A, et al. Quantitative characterization of the growth of the fetal kidney. J Clin Ultrasound 1983;11(7): Sagi J, Vagman I, David MP, Van Dongen LG, Goudie E, Butterworth A, et al. Fetal kidney size related to gestational age. Gynecol Obstet Invest 1987;23(1): Pruggmayer M, Terinde R. [Fetal kidney screening: growth curves and indices]. Geburtshilfe Frauenheilkd 1989;49(8): Cohen HL, Cooper J, Eisenberg P, Mandel FS, Gross BR, Goldman MA, et al. Normal length of fetal kidneys: sonographic study in 397 obstetric patients. AJR Am J Roentgenol 1991;157(3): Scott JE, Wright B, Wilson G, Pearson IA, Matthews JN, Rose PG. Measuring the fetal kidney with ultrasonography. Br J Urol 1995;76(6): Chitty LS, Altman DG. Charts of fetal size: kidney and renal pelvis measurements. Prenat Diagn 2003;23(11): Royston P, Wright EM. How to construct 'normal ranges' for fetal variables. Ultrasound Obstet Gynecol 1998;11(1): Altman DG, Chitty LS. Design and analysis of studies to derive charts of fetal size. Ultrasound Obstet Gynecol 1993;3(6): Altman DG, Chitty LS. Charts of fetal size: 1. Methodology. Br J Obstet Gynaecol 1994;101(1): Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33(1): Hata K, Hata T, Kitao M. Ultrasonographic identification and measurement of the human fetal adrenal gland in utero. Int J Gynaecol Obstet 1985;23(5): Hata K, Hata T, Kitao M. Ultrasonographic identification and measurement of the human fetal adrenal gland in utero: clinical application. Gynecol Obstet Invest 1988;25(1): Bronshtein M, Tzidony D, Dimant M, Hajos J, Jaeger M, Blumenfeld Z. Transvaginal ultrasonographic measurements of the fetal adrenal glands at 12 to 17 weeks of gestation. Am J Obstet Gynecol 1993;169(5):

21 Intra- and interobserver variability Esser T, Chaoui R. Enlarged adrenal glands as a prenatal marker of congenital adrenal hyperplasia: a report of two cases. Ultrasound Obstet Gynecol 2004;23(3): Saada J, Grebille AG, Aubry MC, Rafii A, Dumez Y, Benachi A. Sonography in prenatal diagnosis of congenital adrenal hyperplasia. Prenat Diagn 2004;24(8):

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23 Chapter 3 Growth and size charts of the fetal kidney and the renal pelvis. H.A.M. Damen - Elias a, R.H. Stigter a,c, P. Westers b, G.H.A. Visser a a Department of Perinatology and Gynaecology, University Hospital Utrecht, The Netherlands b Centre for Biostatistics, Utrecht University, The Netherlands c Department of Obstetrics and Gynaecology, Deventer Hospital, Deventer, The Netherlands

24 24 Chapter 3 ABSTRACT Objectives The aim of this study was to develop a reference curve for the size and growth of the fetal kidney and of the fetal renal pelvis. Methods Prospective longitudinal study including 111 fetuses. Ultrasound examinations were made every four weeks beginning in one half of the cases at 16 weeks and in the other half at 18 weeks. Length, anteroposterior and transverse diameter from both the right and left kidney and the anteroposterior diameter and transverse diameter from the right and left renal pelvis were measured. Statistical analysis was performed by multilevel analysis. Results Fitted 5 th, 50 th and 95 th centile charts are presented with the raw data. Comparisons were made with previously published data. Conclusions The new charts for size and growth are of use for the three dimensions and for the perimeter of the fetal kidney and for the size of the renal pelvis.

25 Charts of fetal kidney and renal pelvis 25 INTRODUCTION Knowledge of the normal range of the dimensions of the fetal kidney and renal pelvis is essential. Various papers on the intrauterine growth of the renal size have been published but many failed to validate gestational age by measuring crown-rump length 1-5, do not cover the whole of the second and third trimester of pregnancy 1, 2, 6-8, did not measure the kidney in three dimensions 1, 2, 4-6 or used only pre-term born children or post-mortem specimens Several studies used a mixture of crosssectional and longitudinal data 1, 3-6, 8, 11. Cross-sectional data obtained by measurements of each fetus on a single occasion give information on size, whereas longitudinal data obtained by measurements of fetuses on a series of occasions may be used for a reference curve for size and growth The difficulty of any longitudinal study to construct nomograms is that there are some missing data. This problem has been overcome by the approach of multilevel analysis, which is able to correct for this problem 16. This statistical technique allows for the dependency of measurements in hierarchically structured data, whereas traditional regression analysis presupposes the independence of observations. Another advantage of this technique is that it can separately examine the effects of variables of different levels (repeated measures) and can also be used when measurements have been made at different times (e.g. recordings at 16 weeks, at 16 2/7 weeks or 16 6/7 weeks of gestation). An intraobserver and interobserver variation analysis forms no part of any publication of reference curves of the fetal renal kidney. Only Bertagnoli 6 in 1983 performed an interobserver analysis between 3 operators who each used a different ultrasound machine. Some studies describe the design, the patient selection and the methods of analysis but do not report on intra- or interobserver error 12, 13, 15. The aim of this study was to estimate a reference curve for the size and growth of the fetal kidney and fetal renal pelvis.

26 26 Chapter 3 MATERIAL AND METHODS One hundred and twelve low risk women with 116 fetuses (4 twin pregnancies) were asked during an ultrasound scan for validating gestational age by measuring the crown-rump length, to participate in the study. After written informed consent the women were divided in two groups in order of registration. One half was examined at around and 40 weeks of gestational age and the other half at around and 42 weeks of gestational age. All examinations were made by one ultrasonographer (HDE), using the multifrequency, abdominal transducer PVM 375 AT of the Toshiba Power Vision 6000, type SSA 370 A with (manufacturer Toshiba, Tokyo, Japan). An intra- and interobserver variation analysis preceded the study resulting in a good consistency in measurements. Exclusion criteria were: mono-chorionic twin pregnancies, chromosomal or congenital defects of the fetus, small for gestational age at birth (SGA = weight at birth <2.3% (17) percentile for gestational age) and maternal disease which might effect fetal growth (diabetes mellitus, hypertension requiring treatment). The length of the kidney was measured when in a sagittal plane the full length with the renal pelvis was visualised. Perpendicular to this, in the largest sectional plane, the anteroposterior (AP) and transverse diameter of the kidney were measured by placing the callipers from outer to outer border. In the same sectional plane the AP and transverse diameters of the renal pelvis were measured by placing the callipers on the inner borders of the renal tissue. All measurements were obtained three times and the data were averaged and stored in a database. Statistical analysis was performed by multilevel analysis with the software program Mln (Multilevel Model Project, London, UK) 16 and SPSS, version 10.1 (Statistical Product and Service Solutions, Chicago) to construct nomograms (medians and the 5 th and 95 th centiles). RESULTS Five fetuses were excluded: small for gestational age (n=2), congenital anomalies (n=3; triploidy, clubfoot and hydronephrosis >10mm anteroposterior diameter of the renal pelvis). Of the remaining 107 woman and 111 fetuses all measurements could be obtained from both kidneys and both renal pelves with a total of 628 data for each separate measurement for length, anteroposterior diameter and transverse diameter

27 Charts of fetal kidney and renal pelvis 27 of both kidneys and for the anteroposterior and transverse diameter of both renal pelves. Statistical analysis was performed on all separate measurement from the right and left fetal kidney. The charts of length, anteroposterior and transverse diameter and perimeter of the left and right kidney were about identical with a high correlation coefficient between the measurements from the right and left side: R = for length, R = for AP-diameter, R = for transverse diameter and R = for perimeter. There was no asymmetry between the right and left renal pelvic measurements (Table 1: Kappa 0,459). The charts made of the anteroposterior and transverse diameter of the right and left renal pelvis were similar with correlation coefficients between measurements of the right and left side of: R = for the AP-diameter and R = for the transverse diameter. In only 16 of 628 comparisons between right and left pelvic size there was a difference of more than 2 millimetres between the measurements (Table 1). Table 1 Partition of the dimensions of the right and left renal pelvis. Kappa 0,459 left renal pelvis measurements (mm) right renal pelvis measurements (mm) 0 <2 mm 2 <4 mm 4 <6 mm 6 <8 mm 8 <10 mm total 0 < 2 mm < 4 mm* < 6 mm < 8 mm <10 mm total The data of all right and left kidney and renal pelvis measurements were averaged to obtain the reference charts. The account of the nomograms of the 5 th, 50 th and 95 th fitted centiles of length, anteroposterior and transverse diameter and of the perimeter from the kidney are shown in Table 2 with the corresponding charts (Figures 1 to 4).

28 28 Chapter kidney length (mm) gestational age in weeks Figure 1 Fitted 5 th, 50 th and 95 th centiles for the kidney length and the raw data kidney AP-diameter (mm) gestational age in weeks Figure 2 Fitted 5 th, 50 th and 95 th centiles for the anteroposterior kidney diameter and the raw data.

29 Charts of fetal kidney and renal pelvis kidney transverse diameter (mm) gestational age in weeks Figure 3 Fitted 5 th, 50 th and 95 th centiles of the transverse kidney diameter and the raw data kidney perimeter gestational age in weeks Figure 4 Fitted 5 th, 50 th and 95 th centiles of the perimeter of the kidney and the raw data.

30 Table 2 Fitted centiles of fetal renal kidney length, anteroposterior diameter, transverse diameter and perimeter with the number of fetuses for exact weeks between 16 and 42 weeks of gestational age. weeks of gestation N fetuses fitted centiles kidney length fitted centiles kidney anteroposterior diameter fitted centiles kidney transverse diameter fitted centiles kidney perimeter 5 th 50 th 95 th SD 5 th 50 th 95 th SD 5 th 50 th 95 th SD 5 th 50 th 95 th SD ,9 14,3 15,7 0,70 7,4 8,6 9,8 0,60 7,3 8,6 9,9 0,66 23,5 27,0 30,6 1, ,3 15,7 17,2 0,74 8,2 9,5 10,7 0,64 8,3 9,7 11,1 0,70 26,2 29,9 33,7 1, ,6 17,1 18,7 0,79 9,0 10,4 11,7 0,68 9,3 10,8 12,2 0,74 29,2 33,2 37,2 2, ,9 18,5 20,2 0,84 9,8 11,2 12,6 0,71 10,3 11,8 13,2 0,78 31,8 36,0 40,2 2, ,2 19,9 21,6 0,88 10,6 12,1 13,5 0,75 11,2 12,8 14,4 0,82 34,6 39,1 43,5 2, ,0 21,8 23,7 0,94 11,3 12,8 14,4 0,79 12,1 13,9 15,4 0,86 37,9 42,3 46,9 2, ,7 22,6 24,5 0,96 12,0 13,6 15,3 0, ,8 16,5 0,90 39,8 44,6 49,5 2, ,0 24,0 25,9 1,00 12,7 14,4 16,1 0,86 13,9 15,7 17,6 0,94 42,3 47,3 52,4 2, ,2 25,3 27,3 1,05 13,4 15,1 16,9 0,90 14,7 16,6 18,6 0,99 44,6 49,9 55,2 2, ,5 26,6 28,7 1,10 14,0 15,8 17,7 0,95 15,5 17,5 19,5 1,03 46,8 52,4 57,8 2, ,6 27,9 30,1 1,14 14,6 16,5 18,4 0,98 16,3 18,4 20,5 1,07 49,1 54,8 60,6 2, ,8 29,0 31,3 1,19 15,2 17,2 19,2 1, ,3 21,4 1,10 50,9 57,2 62,8 3, ,0 30,4 32,8 1,23 15,7 17,8 19,9 1,05 17,8 20,1 22,3 1,15 53,3 59,5 65,7 3, ,2 31,7 34,2 1,27 16,3 18,4 20,6 1,10 18,5 20,8 23,2 1,19 55,3 61,7 68,1 3, ,3 32,9 35,5 1,31 16,8 19,0 21,2 1,13 19,2 21,6 24 1,23 57,2 63,8 70,5 3, ,5 34,2 36,8 1,35 17,3 19,6 21,8 1,17 19,9 22,4 24,9 1,27 59,0 65,9 72,7 3, ,6 35,3 38,1 1,40 17,7 20,1 22,5 1,20 20,5 23,1 25,7 1,31 60,8 67,9 74,9 3, ,3 36,5 40,1 1,43 18,4 20,6 23,4 1,23 21,2 23,7 26,5 1,35 63,1 69,5 77,5 3, ,0 37,7 40,8 1,49 18,6 21,1 23,6 1,28 21,8 24,5 27,2 1,40 64,1 71,6 79,1 3, ,0 38,9 41,9 1,52 19,0 21,6 24,1 1,31 22, ,9 1,43 65,7 73,4 81,2 3, ,0 40,0 43,1 1,57 19,3 22,0 24,7 1,35 22,9 25,8 28,7 1,48 67,1 75,0 83,0 4, ,9 41,0 44,2 1,61 19,7 22,4 25,1 1,39 23,5 26,4 29,5 1,52 68,5 76,7 84,8 4, ,8 42,0 45,2 1,66 20,0 22,8 25,6 1,43 23, ,56 69,8 78,2 86,6 4, ,6 42,9 46,2 1,71 20,3 23,2 26,0 1,47 24,4 27,5 30,7 1,60 71,0 79,6 88,3 4, ,4 43,8 47,1 1,75 20,6 23,5 26,5 1,50 24,8 28,1 31,3 1,64 72,2 81,0 89,9 4, ,1 44,8 48 1,79 20,8 23,8 26,8 1,54 25,2 28,5 31,8 1,68 73,3 82,3 91,4 4, ,8 45,6 48,8 1,81 21,1 24,1 27,2 1,57 25,6 28,9 32,2 1,72 74,4 83,6 92,9 4,68 total 111

31 Charts of fetal kidney and renal pelvis 31 The account of the nomograms of the 5 th, 50 th and 95 th fitted centiles of the anteroposterior and transverse diameter from the renal pelvis are given in Table 3 with the corresponding charts (Figures 5 and 6). Table 3 - Fitted centiles of the anteroposterior and transverse diameter of the fetal renal pelvis with the number of fetuses for exact weeks between 16 and 42 weeks of gestational age weeks of gestation N fetuses fitted centiles pelvis anteroposterior diameter fitted centiles pelvis transverse diameter 5 th 50 th 95 th SD 5 th 50 th 95 th SD ,2 1,1 1,9 0,4-0,8 1,4 3,6 1,1 17 0,5 1,3 2,2 0,5-0,6 1,7 4,0 1, ,7 1,6 2,5 0,5-0,1 2,3 4,7 1,2 19 0,9 1,8 2,8 0,5 0,1 2,6 5,1 1, ,2 2,1 3,1 0,5 0,5 3,1 5,6 1,3 21 1,3 2,3 3,3 0,5 0,9 3,4 6,0 1, ,6 2,6 3,6 0,5 1,0 3,7 6,5 1,4 23 1,7 2,7 3,8 0,5 1,2 4,0 6,8 1, ,9 3,0 4,0 0,5 1,4 4,3 7,2 1,5 25 2,0 3,1 4,2 0,6 1,6 4,5 7,5 1, ,2 3,3 4,4 0,6 1,7 4,8 7,9 1,6 27 2,3 3,4 4,6 0,6 1,9 5,0 8,2 1, ,4 3,6 4,7 0,6 2,0 5,2 8,5 1,7 29 2,5 3,7 4,9 0,6 2,0 5,4 8,8 1, ,5 3,8 5,0 0,6 2,1 5,5 9,0 1,8 31 2,6 3,8 5,1 0,6 2,1 5,7 9,2 1, ,6 3,9 5,2 0,7 2,1 5,8 9,4 1,9 33 2,7 4,0 5,3 0,7 2,1 5,8 9,6 1, ,7 4,0 5,4 0,7 2,0 5,9 9,7 2,0 35 2,6 4,0 5,4 0,7 2,0 5,9 9,8 2, ,6 4,0 5,5 0,7 1,9 6,0 10,0 2,1 37 2,6 4,0 5,5 0,7 1,8 5,9 10,0 2, ,5 4,0 5,5 0,8 1,6 5,9 10,1 2,2 39 2,5 4,0 5,5 0,8 1,5 5,8 10,1 2, ,4 4,0 5,5 0,8 1,3 5,7 10,1 2,3 41 2,3 3,9 5,4 0,8 1,1 5,6 10,1 2, ,3 3,9 5,4 0,8 1,0 5,5 10,0 2,3 total 111

32 32 Chapter pyelum AP-diameter (mm) gestational age in weeks Figure 5 Fitted 5 th, 50 th and 95 th centiles of the A-P diameter of the renal pelvis and the raw data transverse pyelum diameter (mm) gestational age in weeks Figure 6 Fitted 5 th, 50 th and 95 th centiles of the transverse diameter of the renal pelvis and the raw data.

33 Charts of fetal kidney and renal pelvis 33 The centile charts were compared with previously published charts from Chitty and Altman 18 for length, AP-diameter, transverse diameter and renal pelvis measurements and from Pruggmayer and Terinde 3 for length and transverse diameter. See figures 7, 8, 9 and kidney length (mm) gestational age in weeks Figure 7 Comparison of 5 th, 50 th and 95 th centiles for kidney length measurements obtained in this study (solid lines) and the 10 th, 50 th and 90 th centiles of Chitty (dashed lines ) and the 5 th, 50 th and 95 th centiles of Pruggmayer (dashed lines ). 35 kidney A-P diameter (mm) gestational age in weeks Figure 8 Comparison of 5 th, 50 th and 95 th centiles for kidney anteroposterior diameter obtained in this study (solid lines) and the 10 th, 50 th and 90 th centiles of Chitty (dashed lines ).

34 34 Chapter 3 kidney transverse diameter (mm) gestational age in weeks Figure 9 Comparison of 5 th, 50 th and 95 th centiles for kidney transverse diameter obtained in this study (solid lines) and the 10 th, 50 th and 90 th centiles of Chitty (dashed lines ) and the 5 th, 50 th and 95 th centiles of Pruggmayer (dashed lines ). renal pelvis (mm) gestational age in weeks Figure 10 Comparison of 5 th, 50 th and 95 th centiles for anteroposterior renal pelvis measurements obtained in this study (solid lines) and the 10 th, 50 th and 90 th centiles of Chitty (dashed lines). DISCUSSION Several charts of fetal kidney sizes have been published before, but some with shortcomings in data collection or with methodological weaknesses. Our charts of the fetal kidney and fetal renal pelvis were obtained from longitudinal data derived from prospective investigations that were done specifically for the development of the centile charts. The data were obtained from a large longitudinal sample and therefore the charts are suitable for size and growth measurements i.e. for comparing renal size at a known gestational age between 16 and 42 weeks of gestation and for

35 Charts of fetal kidney and renal pelvis 35 following the growth of the fetal kidney by comparing the measured data of the fetus between two separate occasions with the fitted data. Until now there had not been a chart published, which combines both possibilities, when taken into account methodological pitfalls and incorrect methods in design such as not validating gestational age 1-5, only partly covering the second and third trimester 1, 2, 6-8, measuring only one or two dimensions of the kidney 1, 2, 4-6 or averaging both crosssectional and longitudinal data 1, 3-6, 8, 11. Moreover this study has the added advantage that the statistical analysis used is able to correct for missing data. We were limited in comparing our findings with previously published charts of kidney size because several studies gave no raw data or when they did so they gave evidence of methodological weakness or did not cover the whole second and third trimester of pregnancy. None of the previous studies had carried out an intra- and interobserver variation analysis before data collecting, as we did. Chitty and Altman 18 obtained their data in a cross-sectional study, including approximately 15 to 20 cases per week. Measurements were only done once. They published the 3 rd, 10 th, 50 th, 90 th and 97 th centile. Pruggmayer and Terinde 3 also performed a cross-sectional study including 612 fetuses. They did not give data on the number of fetuses measured each week and excluded 18.6% of infants because they were either large or small for dates. The most obvious differences between our kidney charts and those of the other two groups relate to the smaller ranges that we found. The 50 th centile of measurements of Chitty and Altman was higher than ours at around 30 weeks of gestation, but almost the same near term. The 50 th centile for the transverse kidney diameter was about the same in the three studies, apart from term age, when our data were in between those of the two other groups. It is difficult to explain the differences between the findings of the three studies. The fact that we have repeated the measurements three times may have resulted in narrowed ranges. Regarding the fetal renal pelvic dimensions only two charts have been published before. Chitty et al 18 published a chart based on cross-sectional data from fetuses measured only once for the purpose of the study but examined only a low number of fetuses at each week of gestation (3 to 11: mean 7). Scott 5 published a chart with a mixture of cross-sectional and longitudinal data obtained during routine scanning and

36 36 Chapter 3 as a consequence some fetuses were only included once whereas others were included at many ages; the resulting scatter diagrams of kidney and pelvis sizes show many data at around weeks and at around weeks and a lack data beyond 36 weeks of gestational age. They did not publish the raw data. We therefore only compared our chart with the one published by Chitty and Altman. Their chart suggests a linear growth of the renal pelvis size, with a wide range, whereas ours shows a curved line, with no increase size from 32 weeks onwards, an a considerable narrower range (especially, when taken into account the fact that we gave the 5 th, 50 th and 95 th centile and Chitty and Altman the 10 th, 50 th and 90 th centiles) (Figure 8). Renal pathology often presents itself late in pregnancy. A chart for size and growth chart of the kidney may be useful in case of diagnostic problems. The same holds for renal pelvic dilatation, which is a common sonographic finding in pregnancy.

37 Charts of fetal kidney and renal pelvis 37 REFERENCES 1. Cohen HL, Cooper J, Eisenberg P, Mandel FS, Gross BR, Goldman MA, et al. Normal length of fetal kidneys: sonographic study in 397 obstetric patients. AJR Am J Roentgenol 1991;157(3): Gloor JM, Breckle RJ, Gehrking WC, Rosenquist RG, Mulholland TA, Bergstralh EJ, et al. Fetal renal growth evaluated by prenatal ultrasound examination. Mayo Clin Proc 1997;72(2): Pruggmayer M, Terinde R. [Fetal kidney screening: growth curves and indices]. Geburtshilfe Frauenheilkd 1989;49(8): Sagi J, Vagman I, David MP, Van Dongen LG, Goudie E, Butterworth A, et al. Fetal kidney size related to gestational age. Gynecol Obstet Invest 1987;23(1): Scott JE, Wright B, Wilson G, Pearson IA, Matthews JN, Rose PG. Measuring the fetal kidney with ultrasonography. Br J Urol 1995;76(6): Bertagnoli L, Lalatta F, Gallicchio R, Fantuzzi M, Rusca M, Zorzoli A, et al. Quantitative characterization of the growth of the fetal kidney. J Clin Ultrasound 1983;11(7): Bernaschek G, Kratochwil A. [Ultra-sound study on the growth of the fetal kidney in the second half of pregnancy (author's transl)]. Geburtshilfe Frauenheilkd 1980;40(12): Jeanty P, Dramaix-Wilmet M, Elkhazen N, Hubinont C, van Regemorter N. Measurements of fetal kidney growth on ultrasound. Radiology 1982;144(1): Chiara A, Chirico G, Barbarini M, De Vecchi E, Rondini G. Ultrasonic evaluation of kidney length in term and preterm infants. Eur J Pediatr 1989;149(2): Gonzales J. [Anatomical measurements during fetal growth of the kidney. Its value for the ultrasonographer and the anatomo-pathologist (author's transl)]. J Gynecol Obstet Biol Reprod (Paris) 1981;10(2): Vries de L, Levene MI. Measurement of renal size in preterm and term infants by real-time ultrasound. Arch Dis Child 1983;58(2): Altman DG, Chitty LS. Design and analysis of studies to derive charts of fetal size. Ultrasound Obstet Gynecol 1993;3(6): Altman DG, Chitty LS.Charts of fetal size: 1. Methodology. Br J Obstet Gynaecol 1994;101(1): Royston P, Altman DG. Design and analysis of longitudinal studies of fetal size. Ultrasound Obstet Gynecol 1995;6(5): Royston P, Wright EM. How to construct 'normal ranges' for fetal variables. Ultrasound Obstet Gynecol 1998;11(1): Goldstein H. Multilevel statistical models. 2nd ed. London: University of London. ed; Kloosterman GJ. On intrauterine growth. Int J Gynaecol Obstet 1970;8: Chitty LS, Altman DG. Charts of fetal size: kidney and renal pelvis measurements. Prenat Diagn 2003;23(11):891-7.

38

39 Chapter 4 Growth and size charts of the fetal adrenal gland H.A.M. Damen - Elias a, R.H. Stigter a,c, P. Westers b, G.H.A. Visser a a Department of Perinatology and Gynaecology, University Hospital Utrecht, The Netherlands b Centre for Biostatistics, Utrecht University, The Netherlands c Department of Obstetrics and Gynaecology, Deventer Hospital, Deventer, The Netherlands

40 40 Chapter 4 ABSTRACT Objectives It was the aim of this study was to develop a reference curve for size and growth of the length of the fetal adrenal gland. Methods Longitudinal prospective study of one hundred eleven fetuses that were scanned every four weeks. The ultrasound measurements started in one half of the cases at sixteen weeks of gestation and in the other half at eighteen weeks. Statistical analysis was performed by multilevel analysis. Results Fitted 5 th, 50 th and 95 th centile charts for the length of the adrenal gland are presented with the raw data. There was a high correlation between adrenal and kidney length (R = 0,932) with a ratio of 2 to 7. Conclusions The chart for size and growth is of use for measurements of the length and growth of the adrenal gland.

41 Charts of fetal adrenal gland 41 INTRODUCTION Knowledge of the normal range of the growth and size of the fetal adrenal gland is of importance for the identification of morphological changes once an anomaly is suspected. A number of reference values of adrenal gland measurements have been published 1-7, but none covers the whole second and third trimester of the pregnancy. Moreover in none of these studies data were used with an ultrasound validated gestational age and in some publications only post-mortem specimens were used 1, 2. All studies used cross-sectional data. Since 1990 there has been no study using abdominal investigations. In 1993 a study has been published using transvaginal ultrasound between 12 and 17 weeks of gestation. It was the aim of this prospective study to develop a reference curve for the size and growth of fetal adrenal gland length. MATERIAL AND METHODS Data of the length of the adrenal gland were collected in a longitudinal, prospective study. Measurements of the fetal kidney and fetal renal pelvis were collected simultaneously and will be published in a separate paper. One hundred and twelve low risk women with 116 fetuses (4 twin-pregnancies) were included after written informed consent had been obtained. They were divided in two groups who were scanned at four weeks interval starting at 16 weeks or at 18 weeks gestational age, respectively. All women had had a dating scan before 13 weeks of gestation. One experienced ultrasonographer (HDE) made all the examinations using the multifrequency transducer PVM 375 AT of the Toshiba Power Vision 6000, type SSA 370 A (manufacturer Toshiba, Tokyo, Japan). An intra- and interobserver variation analysis was performed before carrying out this study. The results of which will be published elsewhere. Women were excluded when they had a mono-chorionic twin pregnancy, a chromosomal or congenital defect of the fetus, a small for gestational age infant (SGA = birth weight according to growth charts <2.3% percentile 8 ) or a maternal disease which might effect fetal growth (diabetes mellitus, hypertension requiring treatment).

42 42 Chapter 4 The suprarenal adrenal glands are heart-shaped structures located cranially to the kidney like little helmets placed askew on top of the kidneys. They are imaged as relatively anechoic pyramidal structures but sometimes the echogenicity of the adrenal glands is similar to that of the adjacent kidney. In a transverse scan three layers can usually be distinguished; the cortex is hypoechoic and the central medulla hyperechoic. When visualising the full length of the kidney in a sagittal plane the length of the kidney was measured and in the same plane the length of the kidney including the adrenal gland was measured by placing the callipers from the outer to outer border. The adrenal gland length was determined by subtraction of the kidney length from the total length (Figure 1). Statistical analysis was performed by using SPSS, version 10.1 (Statistical Product and Service Solutions, Chicago) and by multilevel analysis using the software program Mln (Multilevel Model Project, London, UK 9 ) to construct nomograms (medians and the 5 th and 95 th centiles). The latter method is able to rectify the problem of missing data inherent to any study with longitudinal data. A adrenal gland B D kidney ureter C Figure 1 The length of the fetal adrenal gland is AC BC.

43 Charts of fetal adrenal gland 43 RESULTS Five fetuses were excluded, SGA (n=2), congenital anomalies (n=3; triploidy, clubfoot and hydronephrosis >10mm anteroposterior diameter of the renal pelvis), leaving data from 111 fetuses for analysis. At each gestational age all measurements could be obtained from both the right and the left adrenal gland with a total of 628 data for each side. Statistical analysis was performed on the separate measurements of the length of the right and left adrenal gland. The charts were virtually identical with a high correlation of R = (Figure 2) left adrenal gland length (mm) rigth adrenal gland length (mm) Figure 2 Scatter from the data of the right and left adrenal gland length with the fitted correlation line (correlation R = 0,979). The data of the length of right and left adrenal gland were averaged to construct the reference chart. The account of the nomograms of the 5 th, 50 th and 95 th fitted centiles are given in Table 1 with the corresponding chart in Figure 3.

44 44 Chapter 4 Table 1 Fitted centiles of the fetal adrenal gland with the number of fetuses for exact weeks between 16 and 42 weeks of gestational age. weeks of gestation fetuses N fitted centiles adrenal length 5 th 50 th 95 th SD total adrenal gland length (mm) gestational age in weeks Figure 3 Fitted 5 th, 50 th and 95 th centiles for the adrenal gland and the raw data.

45 Charts of fetal adrenal gland 45 The adrenal-to-kidney length correlation was calculated using the data of the kidney length chart (separate article) and those from the adrenal length. A strong linear correlation was found between kidney length and adrenal gland length: R = 0,932 (Figure 4). The length of the adrenal gland was on average 27% (range 25 to 29%) of that of the kidney (ratio 2 to 7) and this relation did not change with gestation/ kidney size kidney length in mm adrenal gland length in mm Figure 4 - Scatter from the data of the length of the kidney and the adrenal gland with the fitted correlation line (correlation R = 0,932). DISCUSSION Fetal adrenal glands are relatively large in comparison to early postnatal life. After delivery their size rapidly decreases and increases again at the end of the first year to attain their maximal weight and size by adulthood 10. The fetal adrenal gland has been the subject of only a few previous ultrasonographic investigations 1-7, 11 with the latest study published in the early 1990 s. Insufficient resolution of the equipment at that time resulted in an inability to obtain accurate data especially during the second trimester 3-5, 7. In the early 1980 s Rosenberg et al 7 could identify the adrenal glands in only 12% of cases before 26 weeks gestational age and in 90% beyond that age. In the same period, Jeanty et al 5 were, not able to detect the adrenal gland in 30% of cases before 25 weeks gestational age, decreasing to 6.5% in term fetuses.

46 46 Chapter 4 All previous charts have been made using cross-sectional data and several charts showed evidence of methodological weaknesses such as the use of post-mortem specimens 1, 2 or the measurement of only one adrenal gland 6. We calculated the correlation between adrenal and kidney length since that may be of significance in high-risk pregnancies. Naeye et al 12 found in post mortem examinations that fetal adrenal glands were relatively more reduced in weight than body weight, in case of intra-uterine growth retardation. Hata et al 3, 4 found a decrease in the calculated adrenal gland surface in growth retarded fetuses and others found small fetal adrenal glands when the mother was using glucocosteriods because of congenital adrenal hyperplasia 11. There are two case-reports on ultrasound diagnosis of congenital adrenal hyperplasia Our charts of the length of the fetal adrenal gland were obtained using longitudinal data derived from a large prospective investigation that was done especially for the development of a reference curve. The chart is suitable for size and growth of the adrenal gland i.e. first of all for comparing adrenal size at a known gestational age between 16 and 42 weeks of gestation and secondly for following the growth of the adrenal gland by comparing the measured data of the fetus between two separate occasions with the fitted data Until now there had not been a chart published, which combines both possibilities. Comparison of previously published charts with ours was not possible. Hata et al 3, 4 published two studies: in one study he gave no raw data and in the other study the data can not be used because he measured the length of the adrenal gland in another way than we did by placing the callipers at A and D (Figure 1). We have chosen for the distance A to B since this measure can be standardized better because the borders of the adrenal gland are better visible at these points. Jeanty at al 5 gave averaged data with a range for every 5 weeks from 20 weeks gestation onwards. Lewis et al 6 published data between 30 and 39 weeks gestation but they did only provide information on the length in comparison with kidney length and biparietal diameter.

47 Charts of fetal adrenal gland 47 Fetal adrenal gland measurements can be an important ultrasonographic parameter especially when a fetus is at risk for intra uterine growth retardation. The ratio of 2 to 7 between the adrenal gland and kidney length does not change with gestational age and that may also be helpful.

48 48 Chapter 4 REFERENCES 1. Aragao de AH, Mandarim-de-Lacerda CA. Allometric growth of the adrenal gland in Brazilian fetuses. Okajimas Folia Anat Jpn 1990;67(2-3): Gaillard DA, Lallemand AV, Moirot HH, Visseaux-Coletto BJ, Paradis PH. Fetal adrenal development during the second trimester of gestation. Pediatr Pathol 1990;10(3): Hata K, Hata T, Kitao M. Ultrasonographic identification and measurement of the human fetal adrenal gland in utero. Int J Gynaecol Obstet 1985;23(5): Hata K, Hata T, Kitao M. Ultrasonographic identification and measurement of the human fetal adrenal gland in utero: clinical application. Gynecol Obstet Invest 1988;25(1): Jeanty P, Chervenak F, Grannum P, Hobbins JC. Normal ultrasonic size and characteristics of the fetal adrenal glands. Prenat Diagn 1984;4(1): Lewis E, Kurtz AB, Dubbins PA, Wapner RJ, Goldberg BB. Real-time ultrasonographic evaluation of normal fetal adrenal glands. J Ultrasound Med 1982;1(7): Rosenberg ER, Bowie JD, Andreotti RF, Fields SI. Sonographic evaluation of fetal adrenal glands. AJR Am J Roentgenol 1982;139(6): Kloosterman GJ. [Intrauterine growth and intrauterine growth curves]. Ned Tijdschr Verloskd Gynaecol 1969;69(5): Goldstein H. Multilevel statistical models. 2nd ed. London: University of London. ed; Potter EL, Craig JM. Pathology of the fetus and infant. St.Louis: A.S. Patterson; Bronshtein M, Tzidony D, Dimant M, Hajos J, Jaeger M, Blumenfeld Z. Transvaginal ultrasonographic measurements of the fetal adrenal glands at 12 to 17 weeks of gestation. Am J Obstet Gynecol 1993;169(5): Naeye RL. Malnutrition: Probable Cause of Fetal Growth Retardation. Arch Pathol 1965;79: Esser T, Chaoui R. Enlarged adrenal glands as a prenatal marker of congenital adrenal hyperplasia: a report of two cases. Ultrasound Obstet Gynecol 2004;23(3): Saada J, Grebille AG, Aubry MC, Rafii A, Dumez Y, Benachi A. Sonography in prenatal diagnosis of congenital adrenal hyperplasia. Prenat Diagn 2004;24(8): Altman DG, Chitty LS. Design and analysis of studies to derive charts of fetal size. Ultrasound Obstet Gynecol 1993;3(6): Altman DG, Chitty LS. Charts of fetal size: 1. Methodology. Br J Obstet Gynaecol 1994;101(1): Royston P, Altman DG. Design and analysis of longitudinal studies of fetal size.ultrasound Obstet Gynecol 1995;6(5): Royston P, Wright EM. How to construct 'normal ranges' for fetal variables. Ultrasound Obstet Gynecol 1998;11(1):30-8.

49 Chapter 5 Congenital renal tract anomalies: outcome and follow-up of 402 cases detected antenatally over a period of 15 years. H.A.M. Damen - Elias a, T.P.V.M. de Jong b, R.H. Stigter a,c, G.H.A. Visser a, P.H. Stoutenbeek a a Department of Perinatology and Gynaecology, University Hospital Utrecht, The Netherlands b Department of Paediatric Urology, University Hospital Utrecht, The Netherlands c Department of Obstetrics and Gynaecology, Deventer Hospital, Deventer, The Netherlands

50 50 Chapter 5 ABSTRACT Objectives To determine the long-term prognosis of antenatally detected renal tract anomalies in order to optimise counselling of the parents. Methods Follow-up study of all renal tract abnormalities detected antenatally in a level three-ultrasound department between 1986 and Follow-up data (medium age 8 years) were retrieved from the records of the Paediatric Urology Department or the attending paediatrician. Results A urinary tract anomaly was detected in 408 fetuses. There were 4 false positive diagnoses. From 2 children follow-up data were incomplete, leaving 402 cases for analysis. A chromosomal abnormality was present in 7 of 81 fetuses that had karyotyping (8,6%). Termination of pregnancy occurred in 55 cases (13,7%) and a further 66 children (16,4%) died during the perinatal period and up to 1 year of age. In 106 of the 121 deceased children the cause of death was directly related to the renal tract anomaly (26,4%). In the 281 surviving children a total of 545 renal tract anomalies were diagnosed postnatally, requiring a total of 351 surgical interventions in 160 infants. Outcome in survivors was generally good, with impaired renal function in 9 infants and hypertension in 3 (4% of the survivors). Conclusions Congenital renal tract anomalies are associated with a high mortality rate, especially when they are structural developmental anomalies of the kidneys. Survivors require multiple operations, but outcome is generally favourable. Ultrasound diagnosis, especially when made early, of non-lethal urinary tract anomalies may prevent additional renal damage by timing of delivery and early postnatal treatment.

51 Congenital renal tract anomalies: 402 cases 51 INTRODUCTION High-resolution ultrasound equipment increasingly gives the opportunity to identify congenital anomalies antenatally. The prevalence of any detected congenital anomaly during pregnancy is approximately 1-2% 1-4. Abnormalities of the urinary tract account for 15-20% with a detection rate of approximately 89% 3,4. Evidence exists that the number of antenatally detected malformations of the urinary tract is increasing. This is attributed to the widespread use of ultrasound in pregnancy and not to epidemiological changes 5,6. Data on antenatal diagnosis and postnatal follow-up are important for assessing prognosis and counselling of the parents. They may be helpful in making difficult decisions as to whether or not to terminate a pregnancy before viability, in determining the need for further diagnostic procedures and on the best management before and after birth. Data on large cohorts are scarce 7 and most follow-up data are confined to specific urological anomalies, such as hydronephrosis or multicystic dysplastic kidneys The aim of this study was to determine the long-term prognosis of antenatally detected renal tract anomalies in order to optimise counselling of the parents. MATERIALS AND METHODS A cohort study was carried out by reviewing the database of the obstetric ultrasound unit of the University Medical Centre, Utrecht, The Netherlands. The unit is a tertiary referral centre and the database contains all cases from the population attending the antenatal clinic of the hospital including those referred from District General Hospitals. In the Netherlands tertiary centres only provide level 3 ultrasound facilities and examinations are performed for specific, well-defined indications without doing routine antenatal screening. The database was reviewed for urinary tract anomalies detected between January 1 st, 1986 and December 31 st, There were no exclusion criteria. The cut-off point used in dilated renal pelves was >5 mm for the anteroposterior diameter before 32 weeks in pregnancy and >10mm thereafter. The diagnosis of polycystic kidney disease was made when there was the typical in utero presentation of two enlarged hyperechogenic kidneys with loss of cortical differentiation and oligohydramnios 12,13. We defined kidneys as multicystic dysplastic when cysts of

52 52 Chapter 5 various size without connection between the cysts were located in the mostly bright echogenic parenchyma of a structurally abnormal kidney in which no renal pelvis could be demonstrated 13. The term dysplastic kidney was used when the kidney was echogenic in isolation, had no normal parenchyma and was structurally abnormal without large cysts 13,14. The diagnosis of an isolated megabladder was made antenatally, when the distended bladder reached the insertion of the umbilical vein independently of oligohydramnios. Prune Belly syndrome was diagnosed postnatally, when the triad of abnormalities 15,16 (abdominal wall deficient muscular tissue, dilated urinary tract and bilateral cryptorchidism) with proven absence of urethral obstruction was present, thus excluding female fetuses. Follow-up data were obtained by chart review of the department of Paediatric Urology and by contacting the paediatricians and general practitioners for information having obtained consent from the parents. Clinical findings and/ or autopsy reports were used to determine postnatal outcome. Prenatal diagnosis was confirmed by postnatal ultrasound scans, radiological investigations, biochemical data on kidney function and surgical records. During the 15-year study period 2070 fetuses were seen with confirmed congenital anomalies of which 408 cases (19,7%) were for urinary tract abnormalities. There were four infants in whom the urinary tract appeared normal at follow-up and two cases were lost to follow-up, due to relocation abroad, leaving 402 patients for further analysis. From all these cases follow-up data were available up to the age of between 3 and 17 years (median 7 years, 11 months). RESULTS diagnosis (n = 402) Table 1 shows the antenatal diagnosis in the 402 fetuses. 151/402 (37,6%) fetuses had a structural kidney anomaly, 247/402 (61,5%) had urinary tract dilatation, and 4/402 (1,0%) had anomalies of miscellaneous origin. The anomaly was bilateral in 206/402 (51,2%) fetuses and unilateral in 173/402 (43,1%) fetuses. 20/402 (4,9%) fetuses had an isolated megabladder, and 3/402 (0,8%) had postnatally confirmed Prune Belly syndrome. Forty-nine percent of the 173 unilateral anomalies were on the right (n=84) side and 51 percent were on the left side (n=89).

53 Table 1 A list of all children, alive or dead, with a structural developmental kidney anomaly, urinary tract dilatation or miscellaneous uropathy along with prenatal and postnatal diagnosis, details of abnormalities, surgery and renal function. prenatal diagnosis postnatal diagnosis all dead dead renal anomaly alive infants with surgery No. of operations renal function structural developmental anomaly n = 151 unilateral renal agenesis unilateral renal agenesis normal bilateral renal agenesis bilateral renal agenesis n.a. unilateral enlarged normal echogenic/ cystic kidney unilateral MCKD 1 mild failure unilateral dysplasia normal bilateral enlarged n.a. echogenic/ cystic kidneys bilateral MCKD bilateral dysplasia dialysis 1 mild failure PKD n.a. Meckel Gruber syndrome 5 5 n.a. Perlman syndrome 1 1 n.a. bilateral echogenic kidneys normal normal normal size total urinary tract dilatation n = 247 unilateral dilatation normal bilateral dilatation transplant 4 chronic failure 3 hypertension 109 normal unilateral megaureter normal bilateral megaureter normal isolated megabladder Prune Belly 3 3 megabladder normal total miscellaneous anomaly n = 4 pelvic kidney normal horseshoe kidney normal total total failure 3 hypertension MCKD = multicystic kidney disease, PKD = polycystic kidney disease, n.a. = not applicable

54 54 Chapter 5 The overall male to female ratio was 7 : 3. In the structural kidneys anomaly group this ratio was 5 : 3 and in the urinary tract dilatation group it was 9 : 3,4. The mortality rate was 30,1% (121/402). At the end of the follow-up 9 children of the 281 surviving infants had impaired renal function and 3 children had hypertension, 12/281 (4,3%). 7/281 (2,5%) children had one dysplastic and one normal kidney left but they had overall normal renal function. mortality (n = 121) In 106/402 (26,4%) deceased children the cause of death was directly related to the renal tract anomaly. Perinatal mortality (Table 1) was highest in the group with structural kidney anomalies, namely 87/150 (58%). Mortality in the group with urinary tract dilatation was 13,4% (33/247). Perinatal mortality included all cases with polycystic kidney disease, bilateral renal agenesis and bilateral multicystic kidney disease (MCKD) and these cases accounted for 61,2% (74/121) of total mortality. Moreover, mortality in case of an isolated megabladder was high (17 out of 20). Autopsy in 9 of these fetuses revealed 3 cases of urethral stenosis, 4 cases of urethral obstruction and 2 cases of urethral atresia. The parents of 8 fetuses refused autopsy: 5 times stillbirth occurred, 1 fetus had caudal regression syndrome, 1 a cloacal anomaly and another one no visible anomalies. Ten of 64 children (15,6%) with unilateral MCKD died because of contralateral renal anomalies: renal agenesis in 9 and renal dysplasia in one. In the miscellaneous group one child died with a unilateral pelvic kidney and Arnold Chiari syndrome. Table 2 lists all 121 deceased children with the main renal anomaly and additional renal and extrarenal anomalies. Autopsy was performed in 72/121 (59,5%) deceased fetuses, and in all but 1 of them the main antenatal diagnosis was confirmed. Fiftyfive pregnancies were terminated on parental request, 55/402 (13,7%), at a mean gestational age of 22,7 (range 15-35) weeks. In 54 of those cases there was a lethal anomaly and in one case a suspected poor quality of life especially of the newborn (Table 2). 12/402 (3,0%) fetuses were stillborn, and a further 50/402 (13,4%) children died during the first 28 days after birth, and 4 others during the first year of life: 1 due to the renal tract anomaly and 3 for other reasons, 4/402 (1,0%). Sixty-nine percent of all perinatal deaths were boys.

55 Table 2 - Overview of all children who died, classified according to the anomaly. Data on additional renal and extrarenal malformations are given as well as the time of death. renal anomaly total No. additional malformations renal agenesis bilateral renal additional malformations absent bladder 1 urethral stenosis 2 agenesis of the ureters MCKD bilateral cloacal malformation 1 multiple anomalies of the renal tract extrarenal additional malformations 1 hydrocephalus 1 diaphragmatic hernia 3 heart defects 1 anal/ oesophageal atresia 2 sirenomelia 3 heart defect TOP stillborn neonatal death < 28 days late infant death > 28 days total (27,3%) (18,2%) 1 anal/ oesophageal atresia MCKD unilateral agenesis contralateral 2 pulmonary hypoplasia (10,7%) 1 dysplasia contralateral 1 preterm labour PKD Meckel Gruber (15,7%) 1 Perlman s syndrome Prune Belly syndrome (2,5%) obstructive uropathy cloacal malformation* 1 omphalocele 10* (15,7%) = reason death 1 caudal regression obstructive uropathy (9,1%) reason death uropathy reason death trisomy 13 2 heart defects = Noonan 1 hypoperistaltis syndrome 1 intra-uterine infection 1 megabladder, cloacal anomaly and preterm labour 1 Arnold Chiari malformation 1 Dandy Walker malformation 1 obstructive uropathy + anal/ oesophageal atresia = VACTERL association 1 obstructive uropathy + anal atresia, genotype 46 xx, phenotype male = VACTERL association 1 obstructive uropathy + anal/ oesophageal atresia + VSD = VACTERL association pelvic kidney + Arnold Chiari malformation 1 1 (0,8%) total (45,5%) TOP = termination of pregnancy, all had a lethal anomaly except one*, PKD = polycystic kidney disease, VACTERL= vertebral defects (V), anal atresia (A), cardiac anomaly (C), tracheal-esophageal fistula with esophageal atresia (TE), renal defects (R), radial limb dysplasia (L), VSD = ventricle), septal defect 12 (9,9%) 50 (41,3%) 4 (3,3%) 121 (100%)

56 56 Chapter 5 survivors (n = 281) Altogether 281 infants survived the perinatal period (Table 1). In these infants a total of 545 anomalies was identified, resulting in 381 surgical interventions in 156 infants (55,5% of the 281 survivors). Indications for surgery were upper tract dilatation with split function on renal scan <40%, deteriorating function at follow-up renography or renal colics based on UPJ obstruction. Table 3 shows all diagnosed renal tract anomalies and all surgical interventions. Table 3 - Summary of all 545 renal tract anomalies diagnosed in the 281 survivors (most had more than one anomaly diagnosed) and details of the number and type of surgical procedures in 156 of these children. diagnosis of the renal tract surgery on the renal tract pyelo-ureteric junction obstruction 113 kidney transplant 1 vesico-ureteric junction obstruction 8 nephrectomy 51 multicystic kidney 51 hemi-nephrectomy 21 posterior urethral valves 45 reimplantation (mega-) ureter 53 narrowed urethra 15 ureterectomy 22 megaureter 129 pyeloplasty 36 vesico ureteric reflux 46 incision posterior urethral valves 64 megabladder 45 vesicostomy 6 agenesis kidney 8 pull through vagina (Mayer Rokitanski) 3 dysplastic kidney 4 reconstruction vagina (cloacal malformation) 2 duplex system 43 ureterocele excision /reconstruction lower tract 19 urinary ascites 3 diverticulectomy 3 unclear 35 drainage of the upper tract 43 VUR - endoscopic treatment 13 closure of bladder rupture 1 excision/ incision syringocele or utriculus cyst 22 miscellaneous small interventions 21 number of diagnosis 545 total number of surgical interventions 381 Most children had more than one renal tract anomaly diagnosed and approximately half of the survivors needed on average two to three surgical interventions.

57 Congenital renal tract anomalies: 402 cases 57 surviving infants with structural kidney anomaly (n=64) Most (51/64 (79,7%)) children in this group had unilateral MCKD, and 12/51 (23,5%) infants had contralateral renal anomalies: a dysplastic kidney in 3, pyelectasis in 6, a megaureter in 1 and vesicoureteral reflux (VUR) in 2 (one grade IV and one grade V). There was one fetus with bilateral echogenic kidneys of normal size and normal amniotic fluid at 24 weeks gestational age of which the echogenicity normalized during pregnancy. The child had normal function after birth. Surgery in the infants with a structural anomaly mainly consisted of unilateral nephrectomy (Table 1). In 43 of 45 cases with nephrectomy of the multicystic kidney there was no functioning at all on the renogram, whereas the other 2 had an overall function of less than 10%. At histology of the multicystic kidneys the diagnosis of MCKD was confirmed in all cases including the two cases with minimal function on the isotope scan. Of the 63 survivors 61 children have normal renal function at follow-up. The two cases with impaired outcome are: 1 - One child with bilateral echogenic, dysplastic kidneys due to bilateral obstructive uropathy based on ectopic ureter with ureterocele, contralateral megaureter and bilateral VUR. The girl had several operations and eventually developed end-stage renal failure at the age of 8 (2002) and started peritoneal dialysis. 2 - One girl with bilateral echogenic, dysplastic kidneys, who was finally diagnosed as having the hereditary branchio-oto-renal (BOR)-syndrome(17), which includes renal failure and impaired hearing (Creatinine 71 µmol/l at 7½ years).

58 58 Chapter 5 surviving infants with urinary tract dilatation (n = 214) Table 5 gives an overview of the age of diagnosis, size of the dilatation at diagnosis and outcome of the 118 surviving infants with a solitary uni- or bilateral renal pelvis dilatation. Forty-five infants needed a total of 88 interventions. One child has chronic renal failure and 1 hypertension; both children had bilateral dilated pelves. Another 96 infants had a uni- or bilateral urinary tract dilatation in combination with a uni- or bilateral megaureter and/ or megabladder. There was a high intervention rate of 227 interventions in 62 of these children, 62/96 (64,6%). Forty-five of these 96 children had posterior urethral valves (PUV) with an intervention rate of 100%, leaving 4 infants with impaired function and 1 infant with hypertension. In 14 of these infants labour had been induced (Table 7). Moreover the intervention rate was high (39/45 (86,6%)) in case of VUR. Outcome in all 39 children with a unilateral renal tract dilatation was favourable. Most of the 54 infants with a bilateral dilatation had a good outcome. There were six infants with chronic renal failure, one requiring kidney transplant (Table 4) and 2 with hypertension. Impaired outcome was not related to the time of diagnosis or to the size of dilatation at diagnosis. Table 4 - Children with obstructive uropathy and impaired renal function. Induced labour = No. corresponding with those in Table 7 2 Boy with bilateral pyelectasis = 5/ 5 mm, megaureter and megabladder in week 16 of gestational age. He had PUV and bilateral VUR (gr IV and IV). After two years of renal dialysis and multiple operations he had a kidney transplant at the age of five. He is 16 years of age and doing well. 7 Boy with unilateral megaureter and contralateral MCKD. He had MCKD nephrectomy and reimplantation of the ureter at the opposite side, excision of ureterocele and relief of urethral obstruction. He is now 9½ years old with creatinine levels of 81 µmol/l. 8 Boy with bilateral hydronephrosis =10/ 10 mm, megaureter and megabladder in week 27 of gestational age. He had PUV and extensive surgery with temporary diversion by vesicostomy and drainage of the upper tract. He is 9 years old with creatinine levels of 74 µmol/l. 9 Boy with bilateral hydronephrosis =10/ 13 mm, megaureter and megabladder in week 23 of gestational age. He had PUV and bilateral VUR (gr IV and V). He has dysplastic kidneys with immature parenchyma and underwent ample surgical reconstructions. At 10 years of age he has a preterminal renal failure (creatinine 179 µmol/l). 18 Boy with bilateral hydronephrosis= 25/ 25 mm, megaureter and megabladder in week 34 of gestational age. He had PUV. After multiple operations he has mild chronic renal failure (creatinine 80 µmol/l) and a renal urine concentration defect at 10 years of age. 19 Boy with bilateral hydronephrosis = 10/ 10 mm, megaureter and megabladder in week 34 of gestational age. He had bilateral VUR (gr III and IV). At 10 years and after multiple operations he has mild renal failure = reflux nephropathy (creatinine 74 µmol/l) and hypertension. No induced labour Boy with bilateral pyelectasis = 9/ 7 mm in week 29 of gestational age. He had bilateral VUR (gr V and V) and developed pyelonephritis in spite of antibiotic prophylaxis. He underwent bilateral reimplantation and recalibration of the ureter. He has a creatinine of 74 µmol/l at three years of age.

59 Table 5 - Children with solitary uni- or bilateral renal pelvis dilatation along with gestational age and size of dilatation at first diagnosis. Figures in parentheses indicate operated children. Total number of surgical interventions and renal failure after surgery are presented in the last columns mm unilateral 2 2 ( 1) ( 1 = 10 %) 2 bilateral ( 1) 1 18 ( 1 = 5,5 %) 5 1 chronic renal failure mm unilateral 2 ( 1) 1 ( 1) 3 ( 1) 5 ( 2) 3 ( 1) 14 ( 6 = 42,9 %) 11 bilateral 5 ( 1) 6 ( 2) ( 3 = 13,0 %) mm unilateral 1 ( 1) 4 ( 3) 6 ( 2) 11 ( 6 = 54,5 %) 7 bilateral ( 2) 3 ( 2) 9 ( 4 = 44,4 %) mm unilateral 1 ( 1) 2 ( 2) 2 5 ( 3 = 60 %) 5 bilateral 1 4 ( 1) 2 ( 2) 7 ( 3 = 42,9 %) 8 1 hypertension mm unilateral 2 ( 2) 1 ( 1) 1 4 ( 3 = 75 %) 10 bilateral 1 ( 1) 1 ( 1 = 100 %) mm unilateral 1 1 ( 1) 2 ( 1 = 50 %) 1 bilateral 1 ( 1) 1 1 ( 1) 3 ( 2 = 66,6 %) 3 > 35 mm unilateral 2 ( 2) 3 ( 3) 1 ( 1) 6 ( 6 =100 %) 8 bilateral 1 ( 1) 1 ( 1) 2 ( 2 =100 %) 5 solitaire unilateral 1 ( 1) 1 ( 1 =100 %) 2 megaureter bilateral 1 1 ( 1) 2 ( 1 = 50 %) 3 total ( 3) 16 ( 8) 26 (10) 30 (16) 22 ( 8) 118 (44 = 37,3 %) 84

60 60 Chapter 5 In 21 of the 119 cases (17,7%) with a bilateral dilatation labour was electively induced before 37 weeks of gestation (mean 34,9 weeks: range 29 37) because of the development of anhydramnios. Only one fetus had solitary bilateral hydronephrosis (Table 7). All 21 neonates (19 boys and 2 girls) had surgery within a few days after birth. Almost all children with impaired outcome can be found in this group (6 chronic renal failure, 1 hypertension). VUR was diagnosed in 45 of the 214 children (21,0%) with urinary tract dilatation after evaluation by voiding cystourethrography; 39 infants needed a total of 123 interventions, 39/45 (86,6%). The male : female ratio was 7 : 2. Table 6 gives an overview of all cases with uni- and bilateral VUR, surgical interventions and final renal function. Table 6- Summary of interventions and outcome in 45 infants with unilateral or bilateral VUR. urinary tract children with No. of final renal function anomaly with VUR surgery operations 13 = unilateral urinary tract anomaly with VUR unilateral reflux nephropathy 2 dysplasia in operated kidney 10 = bilateral urinary tract 10 13* 1 hypertension and mental delay anomaly with unilateral VUR 22 = bilateral urinary tract anomaly with bilateral VUR kidney transplant 1 peritoneal dialysis 1 hypertension, bilateral reflux nephropathy, unilateral hypoplasia 1 chronic renal failure 1 preterminal insufficient 1 hypertension 1 dysplasia in operated kidney *7 in reflux kidney, 6 in the contralateral hydronephrotic kidney. surviving infants with miscellaneous anomaly (n = 4) These four infants (Table 1) had a developmental kidney anomaly without consequences for renal function and were all normal at follow-up.

61 Table 7 - Cases in which labour was induced along with sex, gestational age, antenatal diagnosis, type of anomaly, surgery and renal function after surgery. (PUV = posterior urethral valves) induced labour n =21 No. sex inducing labour antenatal diagnosis postnatal anomaly - surgery renal function after surgery 1 xy 32 weeks bilateral hydronephrosis and megaureters PUV - excision urethral valves good 2 xy 36 weeks bilateral hydronephrosis, megaureter-megabladder PUV-bilateral VUR (gr IV + IV) -extensive surgery kidney transplant 3 xy 33 weeks bilateral hydronephrosis and megaureters PUV - extensive surgery good 4 xy 35 weeks bilateral hydronephrosis bilateral hydronephrosis - bilateral pyeloplasty good 5 xy 36 weeks bilateral hydronephrosis, megaureter-megabladder PUV - extensive surgery good (unilateral dysplasia) 6 xy 35 weeks bilateral hydronephrosis and urinary ascites PUV - extensive surgery good 7 xy 36 weeks unilateral megaureter and contralateral MCKD unilateral megaureter and contralateral MCKD ureter reimplantation and nephrectomy mild failure 8 xy 37 weeks bilateral hydronephrosis, megaureter-megabladder PUV - extensive surgery mild failure 9 xy 33 weeks bilateral hydronephrosis, megaureter-megabladder PUV-bilateral VUR (gr IV + V) - extensive surgery preterminal failure 10 xy 29 weeks bilateral hydronephrosis, megaureter-megabladder premature labour after amnion infusion - PUV - extensive surgery 11 xy 35 weeks megabladder and urinary ascites PUV and spontaneous bladder rupture - extensive surgery 12 xy 33 weeks bilateral hydronephrosis, megaureter-megabladder PUV - extensive surgery good 13 xy 37 weeks unilateral hydronephrosis,contralateral megaureter PUV - extensive surgery good - hypertension and utereocele 14 xy 36 weeks bilateral hydronephrosis, megabladder - urinary bilateral hydronephrosis died during heart surgery ascites 15 xy 36 weeks bilateral hydronephrosis, megabladder - urinary ascites 16 xy 37 weeks unilateral hydronephrosis with megaureter, contralateral MCKD PUV and bilateral VUR (gr III and IV) extensive surgery UVJ stenosis with unilateral MCKD, unilateral megaureter with VUR gr V- extensive surgery good good DORV, TGA good 17 xy 36 weeks bilateral hydronephrosis, megabladder PUV- excision urethral valves good 18 xy 34 weeks bilateral hydronephrosis, megaureter-megabladder PUV- extensive surgery mild failure 19 xy 37 weeks bilateral hydronephrosis, megaureter-megabladder bilateral VUR (gr III and IV) and megaureter bilateral ureteral reimplantation bilateral reflux nephropathy and hypertension 20 xx 34 weeks bilateral hydronephrosis and megaureters bilateral hydronephrosis - extensive surgery good 21 xx 37 weeks unilateral hydronephrosis with megaureter, contralateral MCKD DORV = double outlet of the right ventricle, TGA = transposition of the great arteries unilateral MCKD, contralateral VUR gr V - extensive surgery good good

62 62 Chapter 5 infants with chromosomal anomalies (n=7) Karyotyping was done antenatally in 77 fetuses (in 13 cases because of maternal age >36 years) and postnatally in another 4 children, in total 81/402 (20,2%). Seven children had a chromosomal anomaly, 7/81 (8,6%). (Table 8). In another three stillborn fetuses a chromosomal anomaly was suspected but parents refused karyotyping and autopsy. Four children had trisomy 21 and these 4 infants accounted for 1,8% of all 221 living children with uni- or bilateral renal tract dilatation. Table 8 - Overview of fetuses with a chromosomal anomaly. N o. urinary tract anomaly chromosomal anomaly extra renal anomaly postnatal management renal function 1 bilateral MCKD Klinefelter syndr. XXY none n.a. n.a. 2 bilateral pyelectasis, trisomy 13 multiple n.a. n.a. Ø 8 mm 3 bilateral hydronephrosis mosaicism none resection urethral valve normal >20 mm and megaureter chromosome 8 4 hydronephrosis >20mm, trisomy 21 none resection urethral valve normal megaureter,megabladder diverticulectomy 5 bilateral megaureter trisomy 21 hydrops foetalis prophylactic antibiotics normal polyhydramnios 6 bilateral hydronephrosis trisomy 21 VSD, stenosis closure VSD defect normal > 15 mm and megabladder of pulmonary artery, unilateral clubfoot clubfoot correction 7 bilateral hydronephrosis trisomy 21 VSD prophylactic antibiotics normal L > 30 mm, R > 6 mm n.a. = not applicable, VSD = ventricle septal defect false positive diagnosis (n=4) There were 4/402 (1,0%) infants in whom the urinary tract appeared to be normal at follow-up. The antenatal diagnoses in these four cases were: a) pelvic kidney (appeared to be normal position), b) extrarenal dilatation of the kidney (appeared to be adrenal gland haemorrhage), c) cyst of upper moiety of a duplex kidney (appeared to be extralobar sequestration of the lung), d) dysplastic kidneys with increased echogenicity (appeared to be normal).

63 Congenital renal tract anomalies: 402 cases 63 DISCUSSION The population in this study may not be representative of the overall obstetric population, since severe anomalies are likely to be referred more frequently to our tertiary centre, than minor ones. Nevertheless, our data may be helpful in assessing the prognosis of the various anomalies and be of help in counselling parents. Urinary tract anomalies accounted for 20% of all congenital anomalies, detected antenatally, with a very low false positive rate of 1,0% that never caused inappropriate treatment. Mortality due to the renal tract anomaly was high, approximately one quarter of all cases and was mainly restricted to the perinatal period (including TOP in half of these cases). The mortality rate, almost 60%, was especially high in infants with a structural kidney anomaly and relatively low, with 13,3% in the group with urinary tract dilatation. Approximately half of the survivors needed an average of two to three surgical interventions. Outcome in the surviving infants was generally good, with impaired renal function in 9 children and hypertension in 3 (12 out of 281 survivors = 4,3%). This favourable outcome applied both to infants with a structural anomaly and to these with a urinary tract dilatation. There were seven children with one dysplastic and one normal kidney left but they all have overall normal renal function at follow-up. We did not include data on the incidence of urine incontinence. One may rightly argue that the incidence of impaired outcome may increase with increasing age, but the median duration of follow up was already considerable (almost 8 years). Large bright kidneys in polycystic kidney disease are well documented 12 and the typical multicystic kidney usually does not present a diagnostic problem 7,13,18,19. Increased echogenicity of the renal parenchyma may represent significant disease with poor outcome especially when there is oligo- or anhydramnios but with normal amniotic fluid there may be normal function 14, 20. The degree of echogenicity had to be judged by comparing the kidneys to the echogenicity of the liver because normally they should appear with similar brightness. In our series structural anomalies represented approximately one third of anomalies. Postnatally most of the multicystic kidneys had a non-functioning parenchyma and they were removed to avoid the need for lifetime follow-up when the kidney is left in place, according to the guidelines of

64 64 Chapter 5 the Dutch Society for Paediatric Urology 21,22. Fetuses with a unilateral MCKD had 34% chance of having contralateral renal anomalies with a high mortality rate of 15,6%. Thus, the finding of a unilateral MCKD must lead to meticulous screening of the complete urinary tract, both pre- and postnatally. Agreement exists that in case of urinary tract dilatation different thresholds are used for measurements of the antero-posterior diameter of the renal pelvis in the second and third trimester of pregnancy but the size and gestational age at diagnosis vary because of the lack of diagnostic criteria Some authors suggest that the risk of surgery is minimal when the dilatation is <10 mm in late pregnancy 26,27 but Thomas 28 has stated that the size of the prenatal dilatation is not a sensitive predictor of pathology but that increasing dilatation is associated with morbidity and mortality. An antero-posterior diameter of > 10 mm is usually considered of significance 27,29 but the Great Ormond Street Experience 30 showed that there is a very low risk of clinically significant obstruction when the dilatation does not exceed 15 mm at any gestational age. However, in our series 11 out of 65 infants with an isolated uni- or bilateral mild dilatation (<15 mm) still required surgery. It is the policy in our clinic that in case of an early and mild pyelectasis (<10 mm) and after scanning for additional anomalies, patients are advised to have the ultrasound investigation repeated at around 32 weeks of gestation and when the dilatation is the same or less to refrain from further investigations before or after birth. (The two cases with a dilatation <10 mm and surgery postnatally had both a dilatation >10 mm at the 32 week ultrasound scan.) Low grade VUR may be missed, although in our series none of the infants with VUR had a dilatation less than 10 mm. We inform the parents that there may be an enhanced risk for urinary tract infection due to VUR and when their child feels listless or has fever of unknown origin a urinary tract infection must be ruled out. With such a policy unnecessary parental anxiety may be prevented as well as unnecessary costs of follow-up. Surgery can be needed in case of an isolated uni- or bilateral dilatation of the renal renal pelvis of >10 mm and in our study nearly half of these infants had surgery. Especially high was the intervention rate in the 45 boys with PUV (100%). Labour was induced in 14 of these infants and 6 have impaired renal function and 1

65 Congenital renal tract anomalies: 402 cases 65 hypertension. The overall conclusion for obstructive uropathy that can be drawn from this series is that, regardless of the presence of 1 or 2 kidneys and regardless of the degree of urinary tract dilatation, the prognosis for renal function is excellent when oligohydramnios is absent before birth and when proper urological care is given postnatally. Almost all renal failures were located in the group with progressive oligohydramnios in which labour was induced preterm (6 of 21 infants). Poor outcome of fetuses with bilateral urinary tract dilation combined with prolonged periods of oligohydramnios has been repeatedly described Intrauterine therapy still has a poor outcome with about 50% fetal loss and 40% end-stage renal disease in the survivors 34,35 but such a therapy is only a possible option when there is a megabladder at midgestation. Our policy of preterm induction of labour when oligohydramnios develops seems to result in a relatively favourable outcome although the timing of induction is still uncertain and the proof that we actually gave them better chances is non-existent. Isolated megabladder was diagnosed in 23 cases antenatally, of which 3 boys had Prune Belly syndrome diagnosed postnatally. In literature usually a high number of Prune Belly is given 15,16 without looking for urethral obstruction. Our number is low 15, 16 because of the definitions we use for the Prune Belly syndrome with proven patent ureter and excluding female fetuses. VUR accounted for approximately 21% of antenatally diagnosed urinary tract dilatations, which is slightly higher than the 15% described by others There was a high surgical intervention rate in 86,6% of the infants who needed approximately one third of all surgical interventions (Table 6). VUR predisposes to urinary tract infection and can lead to renal scarring and chronic renal failure but approximately 60% of kidneys with reflux already have an abnormal renogram even in the absence of urinary tract infection Therefore all children with an anteroposterior renal pelvis dilatation >10 mm around 32 weeks of gestation should be carefully managed postnatally (low-dosed antibiotics, voiding cystourethrography). We did antenatal karyotyping only when additional anomalies next to that of the urogenital tract were found and postnatally only when there was a suspicion of chromosomal abnormalities. Also at autopsy it is not routine in our unit to karyotype the child. Seventeen parents refused autopsy and/ or karyotyping. Seven of 81

66 66 Chapter 5 fetuses, which were karyotyped, had a chromosomal disorder, 8,6%. See Table 8. Others mentioned chromosomal disorders in 11-12% 1,43 and even 25% 44. However, these studies are not quite comparable with ours because Stoll et al 1 did not mention the percentage of cases in which karyotyping was carried out, Nicolaides et al 45 performed karyotyping at all children with the prenatal diagnosis of urogenital tract anomalies and Isaksen et al 44 described a selected group of deceased children. Fetuses with a pyelectasis have a higher chance of having chromosomal anomalies (mostly trisomy 21 followed by trisomy 13 and 18) 43,46,47. In our series all the 7 fetuses (3,2%) with a chromosomal defect had a uni- or bilateral pyelectasis which is in accordance with the 3,2 till 5,4% as reported in literature 43,46,47. However, it is the prevalent opinion that there is not an indication for fetal karyotyping in isolated pyelectasis 45. Autopsy was performed in 72 of the 121 deceased fetuses (59,5%). The main urological, prenatal diagnosis was confirmed in all but one of these fetuses (98,6%). A suspected bilateral MCKD was a unilateral one with a normal contralateral kidney. The child had also severe idiopathic pulmonary hypoplasia and anhydramnios and did not die as a result of the inappropriate diagnosis. In 18 fetuses additional autopsy findings, such as anal atresia in 5 fetuses, had not been found antenatally by ultrasonography mostly due to the anhydramnios. Isaksen et al found a slightly lower 91% agreement between prenatal diagnosis of severe urogenital tract anomalies and autopsy findings. CONCLUSIONS The overall value of antenatal diagnosis is that it indicates early termination of fetuses with fatal renal disease, prepares parents and medical staff for the likelihood of serious neonatal problems, and shows dangerous abnormalities of the urinary tract that may not easily be detected postnatally. The drawback of antenatal diagnosis is that the majority of detected mild dilatations has no therapeutic consequences at all but still causes unnecessary anxiety in many cases. This study was undertaken to ameliorate insight into which parents should have anxiety and which can be congratulated with the fact that they can expect a healthy child with, possibly, a minor problem without consequences for life or life expectancy. More studies about this will be needed in future.

67 Congenital renal tract anomalies: 402 cases 67 REFERENCES 1. Stoll C, Clementi M. Prenatal diagnosis of dysmorphic syndromes by routine fetal ultrasound examination across Europe. Ultrasound Obstet Gynecol 2003;21(6): Levi S. Ultrasound in prenatal diagnosis: polemics around routine ultrasound screening for second trimester fetal malformations. Prenat Diagn 2002;22(4): Levi S. Mass screening for fetal malformations: the Eurofetus study. Ultrasound Obstet Gynecol 2003;22(6): Grandjean H, Larroque D, Levi S. Sensitivity of routine ultrasound screening of pregnancies in the Eurofetus database. The Eurofetus Team. Ann N Y Acad Sci 1998;847: Alladi A, Agarwala S, Gupta AK, Bal CS, Mitra DK, Bhatnagar V. Postnatal outcome and natural history of antenatally-detected hydronephrosis. Pediatr Surg Int 2000;16(8): Barker AP, Cave MM, Thomas DF, Lilford RJ, Irving HC, Arthur RJ, et al. Fetal pelvi-ureteric junction obstruction: predictors of outcome. Br J Urol 1995;76(5): Dillon E, Ryall A. A 10 year audit of antenatal ultrasound detection of renal disease. Br J Radiol 1998;71(845): Broadley P, McHugo J, Morgan I, Whittle MJ, Kilby MD. The 4 year outcome following the demonstration of bilateral renal pelvic dilatation on pre-natal renal ultrasound. Br J Radiol 1999;72(855): Feldman DM, DeCambre M, Kong E, Borgida A, Jamil M, McKenna P, et al. Evaluation and follow-up of fetal hydronephrosis. J Ultrasound Med 2001;20(10): Thomas DF, Madden NP, Irving HC, Arthur RJ, Smith SE. Mild dilatation of the fetal kidney: a follow-up study. Br J Urol 1994;74(2): Onen A, Jayanthi VR, Koff SA. Long-term followup of prenatally detected severe bilateral newborn hydronephrosis initially managed nonoperatively. J Urol 2002;168(3): Reuss A, Wladimiroff JW, Stewart PA, Niermeijer MF. Prenatal diagnosis by ultrasound in pregnancies at risk for autosomal recessive polycystic kidney disease. Ultrasound Med Biol 1990;16(4): Winyard P, Chitty L. Dysplastic and polycystic kidneys: diagnosis, associations and management Prenat Diagn 2001;21(11): Wellesley D, Howe DT. Fetal renal anomalies and genetic syndromes. Prenat Diagn 2001;21(11): Jennings RW. Prune belly syndrome. Semin Pediatr Surg 2000;9(3): Sutherland RS, Mevorach RA, Kogan BA. The prune-belly syndrome: current insights. Pediatr Nephrol 1995;9(6): Rodriguez Soriano J. Branchio-oto-renal syndrome. J Nephrol 2003;16(4): Aubertin G, Cripps S, Coleman G, McGillivray B, Yong SL, Van Allen M, et al. Prenatal diagnosis of apparently isolated unilateral multicystic kidney: implications for counselling and management. Prenat Diagn 2002;22(5): Lam BC, Wong SN, Yeung CY, Tang MH, Ghosh A. Outcome and management of babies with prenatal ultrasonographic renal abnormalities. Am J Perinatol 1993;10(4):263-8.

68 68 Chapter Estroff JA, Mandell J, Benacerraf BR. Increased renal parenchymal echogenicity in the fetus: importance and clinical outcome. Radiology 1991;181(1): Oliveira EA, Diniz JS, Vilasboas AS, Rabelo EA, Silva JM, Filgueiras MT. Multicystic dysplastic kidney detected by fetal sonography: conservative management and follow-up. Pediatr Surg Int 2001;17(1): Webb NJ, Lewis MA, Bruce J, Gough DC, Ladusans EJ, Thomson AP, et al.unilateral multicystic dysplastic kidney: the case for nephrectomy. Arch Dis Child 1997;76(1): Kent A, Cox D, Downey P, James SL. A study of mild fetal pyelectasia - outcome and proposed strategy of management. Prenat Diagn 2000;20(3): Langer B. Fetal pyelectasis. Ultrasound Obstet Gynecol. 2000;Jul;16(1): Ismaili K, Hall M, Donner C, Thomas D, Vermeylen D, Avni FE. Results of systematic screening for minor degrees of fetal renal pelvis dilatation in an unselected population. Am J Obstet Gynecol 2003;188(1): Sairam S, Al-Habib A, Sasson S, Thilaganathan B. Natural history of fetal hydronephrosis diagnosed on mid-trimester ultrasound. Ultrasound Obstet Gynecol 2001;17(3): Dremsek PA, Gindl K, Voitl P, Strobl R, Hafner E, Geissler W, et al. Renal Pyelectasis in fetuses and neonates: Diagnostic value of renal pelvis diameter in pre and postnatal sonographic screening. AJR Am J Roentgenol 1997(Apr;168(4)): Thomas DF. Prenatal diagnosis: does it alter outcome? Prenat Diagn 2001;21(11): Adra AM, Mejides AA, Dennaoui MS, Beydoun SN. Fetal pyelectasis: is it always 'physiologic'? Am J Obstet Gynecol 1995(Oct;173(4)): Dhillon HK. Prenatally diagnosed hydronephrosis: the Great Ormond Street experience. British Journal of Urology 1998(81,Suppl.2): Brumfield CG, Guinn D, Davis R, Owen J, Wenstrom K, Mize P. The significance of nonvisualization of the fetal bladder during an ultrasound examination to evaluate second-trimester oligohydramnios. Ultrasound Obstet Gynecol 1996;8(3): Eckoldt F, Woderich R, Gellermann J, Hammer H, Tennstedt C, Heling KS. Survival in second trimester oligohydramnios secondary to bilateral pelviureteral junction obstruction. Urology 2003;61(5): Winn HN, Chen M, Amon E, Leet TL, Shumway JB, Mostello D. Neonatal pulmonary hypoplasia and perinatal mortality in patients with midtrimester rupture of amniotic membranes--a critical analysis. Am J Obstet Gynecol 2000;182(6): Freedman AL, Johnson MP, Smith CA, Gonzalez R, Evans MI. Long-term outcome in children after antenatal intervention for obstructive uropathies. Lancet 1999;354(9176): Holmes N, Harrison MR, Baskin LS. Fetal surgery for posterior urethral valves: long-term postnatal outcomes. Pediatrics 2001;108(1):E Anderson NG, Abbott GD, Mogridge N, Allan RB, Maling TM, Wells JE. Vesicoureteric reflux in the newborn: relationship to fetal renal pelvic diameter. Pediatr Nephrol 1997;11(5): Arena F, Romeo C, Cruccetti A, Centonze A, Basile M, Arena S, et al. Fetal vesicoureteral reflux: neonatal findings and follow-up study. Pediatr Med Chir 2001;23(1):31-4.

69 Congenital renal tract anomalies: 402 cases Herndon CD, McKenna PH, Kolon TF, Gonzales ET, Baker LA, Docimo SG. A multicenter outcomes analysis of patients with neonatal reflux presenting with prenatal hydronephrosis. J Urol 1999;162(3 Pt 2): Shapiro E, Elder JS. The office management of recurrent urinary tract infection and vesicoureteral reflux in children. Urol Clin North Am 1998;25(4):725-34, x. 40. Anderson PA, Rickwood AM. Features of primary vesicoureteric reflux detected by prenatal sonography. Br J Urol 1991;67(3): Gordon AC, Thomas DF, Arthur RJ, Irving HC, Smith SE. Prenatally diagnosed reflux: a followup study. Br J Urol 1990;65(4): de Jong TP, van Gool JD, Van Wijk AA, Stoutenbeek P, Van Isselt HW. Antenatally diagnosed obstructive uropathy--kidney imaging vs kidney function. Acta Urol Belg 1989;57(2): Nicolaides KH, Cheng HH, Abbas A, Snijders RJ, Gosden C. Fetal renal defects: associated malformations and chromosomal defects. Fetal Diagn Ther 1992;7(1): Isaksen CV, Eik-Nes SH, Blaas HG, Torp SH. Fetuses and infants with congenital urinary system anomalies: correlation between prenatal ultrasound and postmortem findings. Ultrasound Obstet Gynecol 2000;15(3): Nicolaides KH. Screening for chromosomal defects. Ultrasound Obstet Gynecol 2003;21(4): Benacerraf BR, Mandell J, Estroff JA, Harlow BL, Frigoletto FDJ. Fetal pyelectasis: a possible association with Down syndrome. Obstet Gynecol 1990(Jul;76(1)): Corteville JE, Dicke JM, Crane JP. Fetal pyelectasis and Down syndrome: is genetic amniocentesis warranted? Obstet Gynecol 1992;79(5 ( Pt 1)):770-2.

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71 Chapter 6 Concomitant anomalies in 100 children with unilateral multicystic kidney Henny A.M. Damen - Elias a, Philip H. Stoutenbeek a, Gerard H.A. Visser a, Peter G.J. Nikkels b, Tom P.V.M. de Jong c. a Department of Perinatology and Gynaecology, University Hospital Utrecht, The Netherlands b Department of Pathology, University Medical Centre Utrecht, The Netherlands. c Department of Paediatric Urology, University Medical Centre Utrecht, The Netherlands.

72 72 Chapter 6 ABSTRACT Objectives To determine the incidence and type of associated urogenital anomalies in children with unilateral multicystic kidney disease and to assess the additional diagnostic value of cystoscopy and colposcopy (in girls) in children with nephrectomy. Methods Follow-up study of 100 children with antenatally detected unilateral multicystic kidney disease. After ultrasound confirmation of the diagnosis a voiding cystourethrography and isotope scan were done in each child to exclude vesico ureteral reflux and to establish renal function. Eighty-one children had a nephrectomy and prior to surgery all had a cystoscopy and girls also had a colposcopy. Results Seventy-five children had one or more additional urogenital anomalies: 39 infants of the contralateral kidney, 42 of the ipsilateral kidney and 28 one or more on the lower urogenital tract. With cystoscopy 54 anomalies of the genitourinary tract were detected in 48 children and with colposcopy 3 anomalies in 35 girls. Eighty-one children had a (hemi-) nephrectomy and 33 of them needed other urological interventions. Thirteen fetuses died (mostly on agenesis of the contralateral kidney) and 6 infants had no surgery at all. Conclusion Children with unilateral multicystic kidney disease have a considerable risk of having other urogenital anomalies. When cystoscopy and colposcopy are added to the routine investigations the rate of detected anomalies is 75%, twice as much as reported in literature.

73 Concomitant anomalies with unilateral multicystic kidney 73 INTRODUCTION MCKD gives only rarely diagnostic dilemmas on prenatal ultrasound 1 due to the typical manifestation with in general multiple non-communicating cysts that are randomly arranged with a size of less than 1 mm up to several centimetres in diameter. The multicystic kidney is frequently enlarged, misshapen and irregularly cystic with often a pyelo-calyceal occlusion and an atretic ureter and may go into involution, pre- or postnatally and may become a small non-functional solid mass with or without cystic lesions in the retroperitoneum 2. A multicystic dysplastic kidney is an aberrant developmental disturbance secondary to an early obstruction 3-8. They can be of any size ranging between kidneys with multiple large cysts, commonly termed as multicystic dysplastic kidneys (MCKD), to normal or small kidney remnants without cysts. A severe pyeloureteric junction obstruction with dilated calices and hardly visible parenchyma may mimic a multicystic kidney so in strictest terms renal dysplasia can only be diagnosed at histology 5. The multicystic kidney can be affected unilateral, bilateral or as segmental part of a duplex kidney. The incidence of unilateral MCKD is between 1 in live births 9. Rarely inheritance 10 has been reported but in that case it can be a feature of syndromes or chromosomal disorders 11. An abnormal karyotype has only been found in cases with associated non-urological anomalies 12, 13. The function of the affected kidney is absent or poor. Therefore, bilateral MCKD is invariably associated with a fatal outcome. The prognosis of unilateral MCKD is favourable and depends on the integrity of the contralateral kidney 14, 15. Contralateral ureteropelvic junction (UPJ) stenosis, vesico ureteral reflux (VUR) and renal agenesis have been reported in 15 50% of children 2, 16, 17 and extrarenal associated anomalies in 16-35% 1, 12. Removal of the multicystic kidney as standard procedure is still under debate. In some studies the affected kidney is removed because of fear for potential complications such as hypertension 18, infection 15 or malignancy 17, 19 and in others the children were examined periodically because their opinion is that the risk of developing a malignancy or hypertension is considered very low or even nonexisting 2, 15.

74 74 Chapter 6 It was the aim of our study to determine the incidence and type of associated urogenital anomalies when prenatally a unilateral MCKD was diagnosed and to assess the additional diagnostic value of cystoscopy and colposcopy (in girls) when a nephrectomy was performed. MATERIALS AND METHODS One hundred children with a prenatally diagnosed unilateral MCKD, between January 1986 and December 2001, were evaluated. Data were obtained by reviewing the database of the obstetric ultrasound department and of the paediatric urology department of the University Medical Centre Utrecht, The Netherlands. In all children postnatal ultrasound examination within a few days after birth confirmed the presence and location of the multicystic kidney. Within four weeks all infants had a voiding cystourethrography (VCUG) without anaesthesia to exclude reflux in the opposite kidney and a MAG3 renography or DMSA scan to measure function. In case of VUR antibiotic prophylaxis was given. All surviving children were offered a nephrectomy at the age of approximately six months, under general anaesthesia, combined with cystoscopy and the girls were also offered a colposcopy. RESULTS Unilateral MCKD was diagnosed in 100 fetuses between 15 and 42 weeks of gestation: 21% before 20 weeks gestation, 49% between 20 and 30 weeks gestation and 30% thereafter (mean 26.7 weeks). The left to right affected kidney ratio was 47 : 53. There were 58 boys, 41 girls and 1 fetus with unknown sex because of sirenomelia. Thirteen fetuses died in the perinatal period: 9 with an agenesis of the contralateral kidney, 1 with a contralateral dysplastic kidney, megabladder and arrhythmia, 1 with a contralateral dysplastic kidney, pulmonary hypoplasia and sirenomelia and 2 with idiopathic pulmonary hypoplasia. Autopsy was performed in 7 of these infants and the diagnoses were confirmed. The other 87 infants survived and were between 0-16 years (mean 5 years and 4 months) at follow-up. All living infants were morphologically normal. Four parents refused investigations after birth. In the remaining 83 an ultrasonography, a VCUG and an isotope scan were performed within a few weeks after birth. The multicystic kidney was non-functional in 80 children and had a function of 3% to 7% of total renal

75 Concomitant anomalies with unilateral multicystic kidney 75 function in the other three. Seventy-five of the 100 children had one or more additional anomalies. Thirty-nine of these infants had 52 renal anomalies of the contralateral kidney of which agenesis, hydronephrosis and pyelectasis as most occurring. Forty-two infants had 56 renal anomalies of the ipsilateral kidney so besides the multicystic kidney an ectopic or megaureter as most common and another 28 infants had altogether 32 anomalies of the lower urogenital tract with as most diagnosed an infravesical obstruction (Table 1). No differences were made between minor or major anomalies neither between primary or secondary developed abnormalities. Reflux was seen in 9 children, 7 boys and 2 girls. It was bilateral in 3 cases. Three children had a reimplantation of the ureter and 1 endoscopic treatment by subureteric injection of a bulking agent. Table infants with unilateral MCKD. Total number of minor and major anomalies of the contralateral kidney (39 infants), ipsilateral kidney (42 infants) and of the lower urogenital tract (27 infants), which were primary or secondary developed. contralateral kidney ipsilateral kidney lower urogenital tract kidney agenesis 9 kidney non-cystic dysplasia 5 duplex system 1 4 ectopic pelvic kidney 1 3 horseshoe kidney 1 spider kidney 1 hydronephrosis* 7 VUR 9 3 megaureter 5 10 ectopic ureter 32 partially doubled urethra 2 ureterocele 2 2 infravesical obstruction 18 megabladder 3 diverticulum of the bladder wall 3 urethral meatus stenosis 5 multicystic testicle 1 Mayer-Rokitansky syndrome 1 hymen imperforates 1 total anomalies * renal pelvis diameter >10mm anteroposterior, # renal pelvis diameter 5-10 mm anteroposterior, top of the bladder reached the umbilical height Two of the 5 infants with a contralateral kidney dysplasia died perinatally. The other three are 2, 4 and 10 years old and have creatinine levels of 94, 35 and 75 µmol/l., respectively. The two-year-old boy is mentally and motor retarded with syndromal

76 76 Chapter 6 anomalies without a specific diagnosis, the 4-year-old boy is idiopathic motor retarded and the 10-year-old boy is otherwise healthy. Nine infants had also extra renal anomalies (Table 2). One of the latter died neonatally and four are mentally and/ or motor retarded. Table 2 - Associated extrarenal anomalies in 9 cases with unilateral MCKD infant alive anomaly 1 anomaly 2 anomaly 3 structural anomalies male yes anus atresia partial sacral agenesis male yes multiple congenital spina bifida neurogenic bladder male yes pulmonary valve male* no cheilo-gnatho- - - functional anomalies male yes hypertension mental retardation motor retardation female yes dimorphism hypotonic motor retardation female yes dimorphism mental retardation motor retardation male yes panhypopituitarism male yes mental retardation motor retardation - * Fetus died; there was a contralateral kidney agenesis. In general, anomalies were divided equally between boys and girls except for predominance in males of contralateral kidney agenesis (8 out of 9), ectopic ureter (23 out of 32) and infravesical obstruction (18 out of 21). Eighty-one infants were operated: 79 had a nephrectomy and 2 a hemi-nephrectomy and thirty-seven of these 81 children needed 53 other interventions for urological anomalies (Table 3). At histology of the 81 multicystic kidneys the diagnosis of MCKD was confirmed in all cases including the three cases with minimal function on the isotope scan. Cartilage was found in 54 specimens (66,6%) and a nephrogenic rest lesion in 6 kidneys (7,4%). Table 3 - Interventions in 81 children with unilateral MCKD surgery No. nephrectomy 79 hemi-nephrectomy 2 reimplantation of a ureter 7 pyeloplasty 4 resection of urethral valves 18 meatotomy 5 excision ureterocele/ diverticulum 6 incision partial double urethra 1 excision multicystic testis 1 endoscopic treatment by subureteric injection of a bulking agent in VUR 1 orchidopexy 1 other small incisions/ excisions 9 total interventions 134

77 Concomitant anomalies with unilateral multicystic kidney 77 In two cases there was a bladder incision made to remove the distal segment of the ectopic ureter that ended in both cases in an ureterocele. In all other cases the ureter was removed as far as possible at the nephrectomy. Reimplantation of a ureter was performed in 7 cases: 3 times because of VUR (grade III, IV and V), twice the remaining ureter after heminephro-urethrectomy, once it was a solitary obstructive megaureter and once it was together with a pyeloplasty and ureteral obstruction. Directly before nephrectomy cystoscopy was performed. Thirty-six of the 81 infants (44,4%) had one or more anomalies: 18 had urethral obstruction, 5 meatal stenosis, 3 a secondary diverticulum of the bladder and 32 an ectopic ureter of which 1 ended in a utricular cyst and 2 in an ectopic ureterocele. In 10 of the 18 children with a urethral obstruction an excision of urethral valves was performed and in the other 8 an incision was done because of a narrow bladder neck or mid-urethral stenosis. In 2 of the 5 children with a meatal stenosis the meatus was obstructive for the cystoscope and in three other girls calibration of the meatus was narrow for age and the jet of urine was anomalous. In 35 girls colposcopy was performed. In 3 of them (8,6%) anomalies of the genital tract were found. One girl had Mayer-Rokitansky s syndrome (vaginal atresia, uterus duplex, abnormal pelvic blood vessels) and 1 child had an imperforate hymen. Another 4 girls had an ectopic ureter ending into a Gartner s duct of (in 1 case with an opening into the vagina, diagnosed at colposcopy). Six girls had no colposcopy: 3 had died perinatally and 3 had no surgery at all. The diagnosis of an ectopic ureter was made at the cystoscopy by seeing a hemitrigonum and an absent orifice. At nephrectomy 10 ureters could not be traced and the histology of the remaining 22 ectopic ureters showed that 2 had a double lumen, that 7 were atretic, that 1 was fibrotic, that 6 were mega dilated (2 ending in a ureterocele, 1 ending in a seminal vesicle), that 1 was totally obstructed, that 4 ended in the duct of Gartner and that 1 ended in a ureterocele. There was one boy with a scrotally located multicystic testicle removed from the same side as the multicystic kidney. Six children had no surgery at all because two parents refused surgery, two children have one moiety of a well functioning duplex system affected and 2 were under control elsewhere and conservative management was recommended by their paediatricians.

78 78 Chapter 6 DISCUSSION Children with unilateral MCKD have an increased risk of abnormalities of the contralateral kidney and the lower urogenital tract 9, 14, 15, 20. The finding of a unilateral MCKD must therefore lead to meticulous screening of the complete urinary tract, both pre- and postnatally, as most studies also recommend, which implies a full urologic investigation to verify the diagnosis, to assess renal functioning and to exclude or confirm additional anomalies, which may require additional urologic treatment. There is no uniformity of opinion on the role of nephrectomy in the management of MCKD. Most authors stated that indications for surgery include a large mass compromising respiration or feeding, pain or an enlarging mass. The increased incidence of hypertension warrants routine blood pressure monitoring by some authors and others stated that there is no increased risk 2, 8, 15, 21, 22. An every 3 to 6 months ultrasound scan is recommended by some authors because of a higher risk on malignant degeneration 18 while others claimed the opposite 2, 15. Webb et al 18 recommend nephrectomy because of a higher risk on hypertension and malignancy and Ranke et al 23 advices the same because of money saving on the long-term. Manzoni et al 8 describe indications for management but admitted that long-term follow-up is requested and because of poor parental compliance nephrectomy should strongly be considered. The view of the Dutch Society for Paediatric Urology is that nephrectomy done at the early age of approximately six months, because flank musculature is hardly used at that time because most of the children cannot yet sit, is as a minor operation with negligible morbidity. This allows for day-care nephrectomy or short stay due to limited need of post operation analgesia. There will be no need for the lifetime follow-up in case the kidney is left in place because this long-term follow-up will easily be neglected in the course of years. Furthermore parents need not to be anxious when their child has abdominal pain. Different to all referred sources we performed a cystoscopy and in girls a colposcopy prior to nephrectomy. With these examinations a high number of anomalies of the

79 Concomitant anomalies with unilateral multicystic kidney 79 urinary tract and of the internal genital organs was detected with ectopic ureters in 40% of the children, infravesical obstructions in 26% and - in girls - an ectopic ending ureter into the duct of Gartner in 11%, as most common findings. Some may argue that only 3 anomalies discovered by colposcopy can lead to the conclusion that this examination is superfluous. But an atresia of the vagina and hymen imperforates would not have been found at the standard investigation after birth (department of neonatology: personal communication) and probably not earlier than the beginning of the puberty. In our opinion colposcopy is a minor intervention in a child already under anaesthesia and every anomaly found is of importance for the child and for her parents. Moreover we found 4 ectopic ending ureters into a Gartner s duct, one with an opening into the vagina, which otherwise would not have been detected. Nephrectomy, preferably at the age of approximately six months was proposed to all parents according to the guidelines of the Dutch Society for Paediatric Urology. At histology cartilage was found in 66,6% of the removed multicystic kidneys which is thought to be a sign of dysplasia as a result of obstruction 11, 24. A nephrogenic rest lesion was found in 7,4% of the removed MCKD kidneys and is considered a risk factor for developing a Wilms tumor 25 later in life. A similar percentage (6,4%) was found by Dimmick et al 26. The differences in outcome for anomalies on the contralateral or ipsilateral kidney and the lower urogenital tract are remarkable when we compare our series with others. In our study 39 children had 41 anomalies of the contralateral kidney. We found agenesis of the kidney in 9% of cases comparable with Lazebnik et al 12 but higher than the 2,3 to 2,6% of others 14, 20. A hydronephrosis was seen in 18% of children higher than the 7,9 to 12 % of others 12. In approximately 11% of the children VUR was diagnosed hardly higher than the 8% of van Eijk et al 20 but lower than the 14 to 20% of others 20, Wacksman et al 15 mentioned even 43%. In our study 42 children had 56 abnormalities on the ipsilateral side with an ectopic ureter in 38,6% and a megaureter in 12,1% as most common. Those anomalies are mentioned sporadically or not at all in the literature in which VUR and UPJ stenosis

80 Table 4 An overview of concomitant anomalies in children with a unilateral multicystic kidney in seven studies. author total No. N (%) with anomaly additional renal contralateral ipsilateral lower tract extrarenal anomalies total No. agenesis dysplasia hydronephrosis VUR / pyelectasis Atiyeh = 51 % 39% 4% 12% 18% 6,1% 6,1% = 57 % 23,3% 2,3% 20% 13,3% Al-Khaldi 1994 Rudnik Schonebőrn 1998 Lazebnik 1999 Aubertin ? = 27 % 27% 14% = 23 % 32% 9% 9,8% 3,8% 3,8% 35% = 33 % 24,1% 5,5% 3,7% 16% Eijk van = 21 % 13% 2,6% 7,9% 8% 8% 5,3% present = 75 % 48,1% 9% 5% 18% 10,8% 48,3% 33% 10% study

81 Concomitant anomalies with unilateral multicystic kidney 81 were mostly mentioned 9, 20. We found ureteroceles in 4 cases (4,8%) comparable with Lazebnik et al 12 with an incidence of 3.8%. VUR was found in 9 children (10,8%) comparable with the 8% of van Eijk et al 20 but lower than the 14% till 43% mentioned by others 2, 9, 14, 15. A lower urinary tract anomaly was only mentioned by Atiyeh et al 9, 12 in 6% of cases. This study found 32 anomalies in 26 infants (31.3%): an infravesical obstruction in 21,7% (18 infants), a diverticulum in 3,6% (3 infants) and a stenosis of the urethral meatus in 6,0% (5 infants) as most common. Posterior urethral valve incision was done at the judgment of the paediatric urologist at the time of cystoscopy and we are aware that the incidence of infravesical obstruction and consequently incision of urethral valves is high compared to other studies. There was no urodynamic study done routinely before the valve incision to proof the obstruction and it was up to the, subjective, judgment of the surgeon whether or not to incise the folds. Associated extrarenal anomalies were found with an incidence of 10%, less than the 16% of Aubertin et al 1, 12 and the 35% as reported by Lazebnik et al 1, 12. Outcome, however, is not comparable because in most studies another target group was included e.g. both bilateral and unilateral MCKD or a different population limited to fetuses with chromosomal analysis. Only van Eijk et al 20 described a comparable population and reported an incidence of 5,3% of extrarenal anomalies. Mental and motor retardation in 4 cases was the most common extrarenal anomaly in our study followed by a cardiac abnormality in 2 children. Table 4 shows an overview of all additional anomalies found in our study in comparison with literature. The male to female ratio (58 : 41) showed a predominance of males similar to the literature. The left to right affected kidney ratio in our series was 47 : 53. This is in contrast with literature that reports more left-sided multicystic kidneys identical with the explanation that the left kidney is more often associated with primary obstruction (27, 28). We have no explanation for this difference and It is probably simply chance that our ratio is the opposite.

82 82 Chapter 6 We agree that the benefice for the child is not demonstrated with our invasive management. The problem is that a large randomised controlled study is needed to prove whether a nephrectomy or an expectant policy has the preference. In addition follow-up will be needed during several decades because hypertension or malignancy can develop later in life. CONCLUSIONS Children with unilateral MCKD have a considerable chance of having other congenital anomalies of the urinary tract and therefore they need to be precisely screened pre- and postnatally. We recommend that a routine postnatal examination consist of an ultrasound examination, an isotope scan and a VCUG and when a nephrectomy is done also a cystoscopy and a colposcopy to detect possibly hidden anomalies of the genitourinary tract.

83 Concomitant anomalies with unilateral multicystic kidney 83 REFERENCES 1. Aubertin G, Cripps S, Coleman G, McGillivray B, Yong SL, Van Allen M, et al. Prenatal diagnosis of apparently isolated unilateral multicystic kidney: implications for counselling and management. Prenat Diagn 2002;22(5): Rudnik-Schoneborn S, John U, Deget F, Ehrich JH, Misselwitz J, Zerres K. Clinical features of unilateral multicystic renal dysplasia in children. Eur J Pediatr 1998;157(8): Beck AD. The effect of intra-uterine urinary obstruction upon the development of the fetal kidney. J Urol 1971;105(6): Peters CA. Animal models of fetal renal disease. Prenat Diagn 2001;21(11): Winyard P, Chitty L. Dysplastic and polycystic kidneys: diagnosis, associations and management. Prenat Diagn 2001;21(11): Felson B, Cussen LJ. The hydronephrotic type of unilateral congenital multicystic disease of the kidney. Semin Roentgenol 1975;10(2): Peters CA, Carr MC, Lais A, Retik AB, Mandell J. The response of the fetal kidney to obstruction. J Urol 1992;148(2 Pt 2): Manzoni GM, Caldamone AA. Pediatric Surgery and Urology: Long Term Outcome. London: W.B. Saunders; Atiyeh B, Husmann D, Baum M. Contralateral renal abnormalities in multicystic-dysplastic kidney disease. J Pediatr 1992;121(1): Srivastava T, Garola RE, Hellerstein S. Autosomal dominant inheritance of multicystic dysplastic kidney. Pediatr Nephrol 1999;13(6): Zerres K, Volpel MC, Weiss H. Cystic kidneys. Genetics, pathologic anatomy, clinical picture, and prenatal diagnosis. Hum Genet 1984;68(2): Lazebnik N, Bellinger MF, Ferguson JE, 2nd, Hogge JS, Hogge WA. Insights into the pathogenesis and natural history of fetuses with multicystic dysplastic kidney disease. Prenat Diagn 1999;19(5): Nicolaides KH, Cheng HH, Abbas A, Snijders RJ, Gosden C. Fetal renal defects: associated malformations and chromosomal defects. Fetal Diagn Ther 1992;7(1): Al-Khaldi N, Watson AR, Zuccollo J, Twining P, Rose DH. Outcome of antenatally detected cystic dysplastic kidney disease. Arch Dis Child 1994;70(6): Wacksman J, Phipps L. Report of the Multicystic Kidney Registry: preliminary findings. J Urol 1993;150(6): Lippert MC. Renal Cystic Disease. In: (eds) LWW, editor. Adult and Pediatric Urology. Philadelphia; p Elder JS, Hladky D, Selzman AA. Outpatient nephrectomy for nonfunctioning kidneys. J Urol 1995;154(2 Pt 2):712-4; discussion Webb NJ, Lewis MA, Bruce J, Gough DC, Ladusans EJ, Thomson AP, et al. Unilateral multicystic dysplastic kidney: the case for nephrectomy. Arch Dis Child 1997;76(1): LaSalle MD, Stock JA, Hanna MK. Insurability of children with congenital urological anomalies. J Urol 1997;158(3 Pt 2):

84 84 Chapter Eijk van L, Cohen-Overbeek TE, den Hollander NS, Nijman JM, Wladimiroff JW. Unilateral multicystic dysplastic kidney: a combined pre- and postnatal assessment. Ultrasound Obstet Gynecol 2002;19(2): Sukthankar S, Watson AR. Unilateral multicystic dysplastic kidney disease: defining the natural history. Anglia Paediatric Nephrourology Group. Acta Paediatr 2000;89(7): Oliveira EA, Diniz JS, Vilasboas AS, Rabelo EA, Silva JM, Filgueiras MT. Multicystic dysplastic kidney detected by fetal sonography: conservative management and follow-up. Pediatr Surg Int 2001;17(1): Ranke A, Schmitt M, Didier F, Droulle P. Antenatal diagnosis of Multicystic Renal Dysplasia. Eur J Pediatr Surg 2001;11(4): Glassberg KI, Stephens FD, Lebowitz RL, Braren V, Duckett JW, Jacobs EC, et al. Renal dysgenesis and cystic disease of the kidney: a report of the Committee on Terminology, Nomenclature and Classification, Section on Urology, American Academy of Pediatrics. J Urol 1987;138(4 Pt 2): Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am J Med Genet 1998;79(4): Dimmick JE, Johnson HW, Coleman GU, Carter M. Wilms tumorlet, nodular renal blastema and multicystic renal dysplasia. J Urol 1989;142(2 Pt 2):484-5; discussion Glassberg KI. Dilated ureter. Classification and approach. Urology 1977;9(1): Johnston JH, Evans JP, Glassberg KI, Shapiro SR. Pelvic hydronephrosis in children: a review of 219 personal cases. J Urol 1977;117(1):

85 Chapter 7 Mild pyelectasis diagnosed by prenatal ultrasound is not a predictor of urinary tract morbidity in childhood H.A. Damen Elias a, S.E. Luijnenburg a, G.H.A. Visser a, P.H. Stoutenbeek a, T. P.V.M. de Jong b a Department of Perinatology and Gynaecology, University Hospital Utrecht, The Netherlands b Department of Paediatric Urology, University Hospital Utrecht, The Netherlands

86 86 Chapter 7 ABSTRACT Objectives To determine children whether with an antenatally diagnosed mild pyelectasis have more urinary tract morbidity during childhood than children without this finding. Methods Case-control study in children with pyelectasis (anteroposterior diameter of the fetal renal pelvis of 5-10 mm) detected at about 20 weeks of gestational age by ultrasound. A validated questionnaire, regarding voiding and defecation habits and urinary tract infections (UTI), was send to the parents of 208 cases and 416 matched controls. Results The questionnaire was returned by 146 cases and 250 controls. There was a male predominance in the case group as compared to the controls (p=<0,000). There were neither differences in voiding habits nor in incidence of UTI. The incidence of infections was high in both groups: 11,6% in cases and 10,0% in controls. The only difference between the groups was a higher incidence of constipation (stools frequency of 2 times a week or less) in the case group (p=0,003). Postnatally forty-one children had an ultrasound examination and 16 were referred to a paediatrician or urologist: 3 had persisting pyelectasis, 3 had a recurrent urinary tract infection (one girl also VUR grade I) and 1 required surgery (a pyeloplasty). Four of the controls were referred to a paediatrician or urologist: 3 had recurrent UTI and 1 was urinary incontinent. Conclusion Children with a mild fetal pyelectasis do not have more urinary tract morbidity during childhood than children without this finding. Therefore, there seems to be no need for additional investigation after birth.

87 Mild pyelectasis 87 INTRODUCTION Mild uni- or bilateral fetal pyelectasis is a frequent finding at prenatal ultrasound examination, with a considerable variation in the reported incidence, from 0,6% to 5,5% 1-4. This wide variation is likely to be due to differences in criteria as to the definition of pyelectasis, in particular regarding size and gestational age at diagnosis. The clinical significance of mild fetal pyelectasis is still unclear; it may resolve, stabilize or be the first indicator of significant urinary tract pathology. The anteroposterior diameter of the renal pelvis above which further investigation during or after pregnancy is required is still controversial 3, 5-7. Some investigators consider an anteroposterior diameter of the renal pelvis <10 mm as physiological, since this will resolve or improve within a couple of years after birth Others recommend a full postnatal investigation for all fetuses with mild pyelectasis 1, In their opinion a significant percentage of these infants will have vesico ureteral reflux (VUR) or need postnatal surgery, when the pyelectasis persists at a follow-up scan around 32 weeks of gestation. Evidence exists that pyelectasis may result in clinical complications such as obstructive uropathy or VUR. A single observation of a pyelectasis puts the fetus at risk for VUR but a normal scan does not exclude the possibility of VUR 13, 15. So far no correlation has been found between antenatal and postnatal dilatation and the severity of VUR 13. There is a suggestion of a between-pregnancy consistency in fetal pyelectasis in subsequent pregnancies and this emphasizes the possibility that genetic and/or environmental factors play a role in its development Counselling the parents is difficult due to our limited understanding of the natural history of pyelectasis. False positive diagnosis of fetal pyelectasis may lead to unwarranted anxiety, as well as unnecessary and expensive diagnostic investigations after delivery. Pyelectasis is still a controversial problem since renal pelvis measurements are not well standardized and since there are no consistent guidelines in relating the severity of pyelectasis to appropriate perinatal and postnatal management. Because of the lack of data on possible long-term morbidity in late childhood in infants who had been antenatally diagnosed as having mild pyelectasis, it was the aim of this study to investigate the occurrence of urinary tract morbidity in childhood in these infants in

88 88 Chapter 7 comparison to a control group, to assess if there is an indication for postnatal follow-up of these children. METHODS In the Netherlands standard screening for fetal anomalies has not yet been introduced, in spite of an extensive debate. Nonetheless, in the Amphia hospital (a District General Hospital, location Oosterhout, The Netherlands), the anomaly scan has been introduced for all pregnant women in the early 1980 s. Two midwives ultrasonographer examined all women at weeks gestational age using the same ultrasound machine. Data were recorded in a standardized way. When a pyelectasis was noticed, defined as an anteroposterior diameter (A-P diameter) of the renal pelvis of 5 10 mm, the anteroposterior diameter of the renal pelvis was measured when in a sagittal plane the full length with the renal pelvis was visualised and perpendicular to this, in the largest sectional plane, the anteroposterior diameter of the pelvis by placing the callipers on the inner borders of the renal tissue. No dilatation of the calices was noticed unless the pyelectasis exceeded 10 mm. All examinations were carried out during daytime. Maternal fluid intake was not specified because it is questionable whether maternal hydration influences fetal pyelectasis When a mild pyelectasis was found, it was customary to re-exam the women at approximately 32 weeks of gestation. When the A-P diameter exceeded 10 mm, the child was referred to a paediatrician or urologist for urological follow-up during the first weeks of life. When the mild pyelectasis had stabilized or resolved, the parents were advised to refrain from further investigations before or after birth and were told that their child might have an increased risk for urinary tract infection (UTI) due to VUR and that, in case of feeling listless or fever of unknown origin, UTI should be ruled out. This advice corresponds to the current opinion about pyelectasis in the Netherlands. The archives of the obstetric ultrasound department were reviewed over the period January 1 st, 1994 till December 31 st, All accounts of fetuses with an isolated mild uni- or bilateral pyelectasis were extracted, in common with the notes of controls (two per case) seen on the same day, in which no anomaly had been found.

89 Mild pyelectasis 89 The local ethical review board and the board of the University Medical Centre Utrecht, The Netherlands, authorized the study. After written informed consent was obtained, the parents of the cases and controls were asked, to fill out a standardized questionnaire (Appendix 1) regarding voiding and defecation patrons and urinary tract infections. The questionnaire, we used, was based on the validated questionnaire used in the International Reflux Study in Children (23). Simultaneously they answered questions about day and night potty training of the child and consultations of the general practitioner or other doctors (Appendix 2). We choose the study period because for answering the questionnaires the children had to be potty-trained. Statistical analyses were performed using Statistical Product and Service Solutions package 10.1 (SPSS R ) 24. For the calculations the t-test, the chi-square test or the Fisher s exact test (we appropriate) were used, with p<0.05 considered significant. RESULTS During the 5-year study period the weeks anomaly scan was performed in 4532 pregnant women. Uni- or bilateral pyelectasis was diagnosed in 208 fetuses, giving an incidence of 4,6 %. In 164 fetuses (78,8%) there was a bilateral pyelectasis and in 44 (21,2%) a unilateral pyelectasis. The ratio of bilateral to unilateral affected kidneys was 4 : 1 and in the group with a unilateral pyelectasis the ratio of the right to left kidney was 1 : 1. One hundred and seventy-nine fetuses with pyelectasis, 179/208 (86,1%), were rescanned at approximately 32 weeks (range 28 till 38 weeks). The pyelectasis was resolved in 67 fetuses (37,4%) was stable in 96 fetuses (53,6%) and had progressed to >10 mm in 16 fetuses (8,9%). These 16 cases were excluded from the present study since these children were referred for urological follow-up during the first week of life. In 20 fetuses (11,2%) the pyelectasis had changed from bilateral to unilateral and in 4 children (2,2%) from unilateral to bilateral. The response rate was 146 out of 192 cases ( excluded cases) and 250 out of 416 controls. Five cases and 4 controls could not be traced and were lost to follow-up, giving corrected response rates of 76,0% (146/192) and 60,7% (250/412), respectively. In the case group another 17 fetuses were excluded because no repeat

90 90 Chapter 7 scan had been made at 32 weeks gestation and we therefore lacked information about dilatation of the renal pelvis during the third trimester. So, finally the calculations were made on 129 cases and 250 controls. There were no significant differences between responders and non-responders except for maternal age at the first ultrasound examination (p=0,005; see Table 1). Table 1 - Comparison between patient characteristics of responders and non-responders in the casegroup. variable responders n = 146 non-responders n = 57 significant difference? mean maternal age at time of the first 30 years, years, 11 p =0,005 * gestational ultrasound examination months months mean age (wks) of detection of pyelectasis 21,6 22,1 p = 0,449 mean number of antenatal ultrasound 2,5 2,7 p = 0,221 examinations mean number of previous deliveries of the 0,77 0,75 p = 0,939 mother unilateral pyelectasis at time of detection p = 0,977 bilateral pyelectasis at time of detection p = 0,977 no follow-up ultrasound examination p = 0,085 ± 32 weeks pyelectasis resolved (<5mm) during p = 0,933 pregnancy pyelectasis stabilized (5-10mm) during p = 0,109 pregnancy pyelectasis progressed (>10mm) during 10 6 p = 1,000 pregnancy pyelectasis changed from bilateral to 11 8 p = 0,153 unilateral pyelectasis changed from unilateral to 4 0 p = 0,578 bilateral * significant difference The responders in the case and control group were comparable on the most important items (Table 2). Table 2 - Comparison between patients characteristics of the responders in the case and control group. variable case-group n = 146 control-group n = 250 significant difference? mean maternal age at time of delivery 31 years, 2 30 years, 5 p = 0,057 months months mean number of pregnancies 1,98 1,84 p = 0,207 mean number of previous deliveries 0,77 0,63 p = 0,094 mean current age of the children 6 years, 1month 5 years, 9 p = 0,314 months mean number of antenatal ultrasound 2,52 1,63 p = <0,000* examinations * significant difference

91 Mild pyelectasis 91 As expected, the only variable that showed a significant difference was the number of antenatal ultrasound examinations (p=<0,000) because of the repeated ultrasound scan in the third trimester of pregnancy in the case group; median of number of examinations in the case group 2,52 and in the control group 1,63. Data on voiding and defecation habits and urinary tract infections are shown in Table 3. On three items there were significant differences: a) the male to female ratio in the case group was 2,17:1 and in the control group 1:1,02 (p=<0,000), b) children in the case-group were more often constipated, when constipation was defined as a stool frequency of 2 times a week or less (p=0,003), c) children in the case group were potty trained during daytime at a slightly higher age (p=0,026). Table 3 - Voiding and defecation habits and urinary tract infections in the case and control group. variable case-group n = 129 control-group n = 250 significant difference? number of males number of females Male : Female ratio 2,17 : 1 1 : 1,02 p = <0,000* daytime urinary incontinence 22 = 17,1% 34 = 13,6% p = 0,476 nocturnal enuresis 30 = 23,3% 49 = 19,6% p = 0,794 urinary tract infection 17 = 11,6 % 25 = 10 % p = 0,601 soiling 17 = 11,6 % 45 = 18,0% p = 0,095 constipation A = stool frequency of <2 times a 9 = 7,0% 2 = 0,8% p = 0,003* week constipation B = hard stools 9 = 7,0% 14 = 5,6% p = 0,811 constipation C = stool frequency of <2 times a 1 = 0,8% 0 p = 0,368 week and hard stools constipation treatment 4 = 3,1% 2 = 0,8% p = 0,195 mean number of months in which the children 3 years, 2 years, p = 0,026* were trained in voiding during daytime 1 month 10 months mean number of months in which the children 3 years, 3 years, p = 0,128 were trained in voiding during nighttime 4 months 2 months mean number of months in which the children 3 years, 2 years, p = 0,108 were trained in stools 0 months 11 months * significant difference

92 92 Chapter 7 In Table 4 data are presented separately for males and females. There were no significant differences between the boys and girls except for a higher incidence of constipation A in the females in the case group (p=0,005). The incidence of UTI was not different in boys and girls of case and control groups: 17 cases, 17/129 (13,2%): 6 males and 11 females and in 25 controls, 25/250 (10,0%): 6 males and 19 females. Table 4 - Voiding and defecation habits and urinary tract infections (in numbers or mean age in years and months) in males and females from the case and control group. variable males n = 212 females n = 167 case control p-value case control p-value n = 88 n = 124 n = 41 n = 126 daytime urinary incontinence p=0, p = 0,873 nocturnal enuresis p=0, p = 0,737 urinary tract infection 6 6 p=0, p = 0,177 soiling p=0, p = 0,198 constipation A = stool frequency 3 0 p=0, p =0,005* of <2 times a week constipation B = hard stools 5 6 p=1, p = 1,000 constipation C = stool frequency p = 0,267 of <2 times a week or less and hard stools constipation treatment 3 1 p=0, p = 1,000 mean age (n of years/ months) of potty-training during daytime 3 years, 1 month mean age (n of years/ months) of 3 years, potty-training during nighttime 5 months mean age (n of years/ months) at 3 years, which the children were trained in 1 month stools * significant difference 3 years, 0 months p=0,420 3 years, 4 months 2 years, 9 months p = 0,245 3 years, p=0,256 3 years, 3 years, p = 0,915 4 months 0 months 0 months 3 years, p=0,543 2 years, 2 years, p = 0,464 0 months 10 months 9 months In spite of our advice to refrain from any investigation postnatally, 41 children, 41/129 (31,8%), in the case-group received a postnatal ultrasound examination of the urinary tract. Sixteen of them were subsequently referred to a paediatrician or urologist. Nine of these infants received prophylactic antibiotics, 9/129 (7,0%). The dilatation resolved spontaneously in 7 of the 16 referred children; in 3 infants the dilatation persisted but no further treatment was necessary; 3 infants had recurrent UTI (with a

93 Mild pyelectasis 93 VUR grade I in one female); 1 child had a dilatation of an extrarenal pelvis; 1 child had transient haematuria but normal anatomy of the urinary tract and 1 infant required surgery. This child, a boy, showed a unilateral pyelectasis at 20 weeks gestational age of 8mm, which had stabilized (9 mm) at the 31 weeks ultrasound scan. The boy required surgery 36 months after birth because of progressive pelvicalyceal dilatation and deterioration of the renal function. In the control group 4 children were referred to a paediatrician or urologist: 3 had recurrent UTI and 1 had problems with urinary incontinence. All infants in the case and control group are doing well and have normal renal function. Thirty children of the remaining 88 children (129-41) in the case group consulted a general practitioner 48 times, mindful of our advice to have the urine checked because of lethargy or fever of unknown origin and 5 were treated with antibiotics because of a proven UTI. DISCUSSION Little is known about urinary tract morbidity during childhood in children who had a mild prenatal pyelectasis. Fetuses with a mild fetal pyelectasis are frequently encountered during ultrasound examination, but the aetiology and clinical significance are unclear. Distinguishing cases in which the pyelectasis has no clinical consequences from those with underlying renal pathology is not yet possible and consistent guidelines about antenatal and postnatal follow up are absent. Questionnaires, which are a good method of studying large groups or to study a population, were used to interview the children. A drawback is that the physical examination and other tests are lacking and that the parents or guardians have to fill in the test, which implies the possibility of subjective opinion. But an advantage is that the information can be gathered without too much bother for the children and their parents. Questionnaires can be used to screen on health, on the prevalence of diseases or to investigate the quality of life 25, 26. They should be tested before for reproducibility and should be validated 23. Studies on antenatal detection of pyelectasis show considerable differences in outcome 3, 15, Percentages for resolving of the pyelectasis range from 5 to 51%, for remaining stable from 21 to 39% and for worsening from 9 till 27% (Table 5). These wide variations are understandable given the different criteria for pyelectasis.

94 94 Chapter 7 Some authors have stated that the size of the prenatal dilatation is not a sensitive predictor of pathology but that an increasing size during pregnancy is associated with morbidity and mortality 32. An A-P diameter of >10 mm is usually considered of significance 9, 15, but the Great Ormond Street Experience 33 showed that there is a very low risk of clinically significant obstruction when the dilatation does not exceed 15 mm at any gestational age. We found hardly any (significant) differences in morbidity between children with or without mild prenatal pyelectasis. There was a male predominance in the case group, which is in concordance with findings of others (Table 5). Table 5 - An overview of studies about mild fetal pyelectasis: definitions, course during pregnancy, sex ratio and advice given. No. of cut-off points resolution stable progression : advice fetuses pyelectasis ratio Adra mm <33wks 7mm 10mm at 33wks 31%?? 2 : 1 repeat scan 28 wks gestation; full post natal investigation in case >8mm Feldman 347 4mm 7mm 51% 39% 10%?? 2001 at 21wks 5mm 8mm at >20wks Harding <10mm 30,4 21,4 19,6 2,2 : 1 repeat scan 34wks gestation ultrasound week 1 and 6 after birth Morin mm 10mm at < 20wks 29% 25% 9%? ultrasound after >72 hours after birth 5mm 10mm at 20wks Persutte mm 10mm 4,7%? 27,1% 2,3 : 1 antibiotic prophylaxis - ultrasound < 1 month after birth + voiding cystourethrography present study 208 5mm 10mm 37,4% 53,6% 8,9% 2,2 : 1 repeat scan 32wks gestation - after birth: urine check in case of lethargy or fever of unknown origin

95 Mild pyelectasis 95 Furthermore we found in the case group a low stool frequency and a higher age at toilet training. There are no reports published in literature suggesting a correlation between mild fetal pyelectasis and constipation during childhood. There was no statistical significant difference in UTI between both groups, although the incidence of 11,6% in cases and 10,0% in controls is higher than the 3,3% - 8,6% 9, 34 found by others and also higher than Dutch figures obtained from general practitioners practices. Accordingly to those data the incidence of UTI s in the Netherlands is 2,9% ( 0,5%, 2,4%) in infants of 0 4 years of age and 3,2% ( 0,4%, 2,8%)(35) in children of 5-9 years of age. It might be that the higher incidence of UTI s that we found in this study is due to the very detailed questions on voiding and defecation habits in the questionnaire. De Kort et al 36 have used the same questionnaire in a study of hypermobility of joints in children of the same age as in our study and found an incidence of UTI 15,7% in cases and 7,8% in controls. Another reason for the high incidence of UTI at least in the case group might be that general practitioners in this area are more focused on a UTI because of the advice given to the parents to have the urine checked if their child is lethargic or develops a fever of unknown origin. Earlier studies have reported that UTI s are underdiagnosed in children and concluded that a greater awareness of the importance of investigation and management of UTI in children is needed because as already known infections may lead to renal scarring Shaw et al 40 reported that even the presence of another potential source of fever, such as otitis media or respiratory infection, does not reliably exclude UTI. In spite of our advice, corresponding to the current opinion about pyelectasis in the Netherlands, that in case of a mild fetal pyelectasis no further investigations were needed after birth, 41 infants of these infants still had an ultrasound examination at request of the general practitioner or gynaecologist. Sixteen children were referred to a paediatrician or urologist (12,4%). Finally 1 child underwent surgery at the age of 3 years, because of an UPJ-obstruction. This resulted in a surgical intervention rate of 2,5% (1/41), or may be 0,8% (1/129), although we cannot completely exclude renal pathology requiring surgery in the other infants. Anyhow the intervention rate seems much lower than reported by others (3,6%-24,3%) 1, 3, 27.

96 96 Chapter 7 CONCLUSIONS The finding of fetal pyelectasis often generates considerable parental anxiety 32, 34. At birth the affected infants seem healthy and outwardly normal, but parental relief is short-lived if their asymptomatic infant is then required to undergo intensive and invasive investigations. Our study demonstrated similar incidence UTI s. Therefore, there seems to be no need for postnatal investigations. In case of a mild renal pyelectasis at 20 weeks of gestation we suggest a single follow-up scan in the third trimester to determine if the pyelectasis has resolved, stabilized or progressed. The child should only be referred for postnatal examination if there is progression >10mm. With this policy there is only a very small chance of missing an occasional case of VUR or potential obstruction. On the other hand, however, this policy may reduce parental anxiety and minimizes the burden of unnecessary invasive investigations in healthy infants as well as unnecessary costs. Parents should be advised to visit their general practitioner if their child is lethargic or has fever of unknown origin to have urine tested to rule out UTI or treat infection effectively in order to prevent renal damage.

97 Mild pyelectasis 97 APPENDIX 1 Questionnaire for children with voiding dysfunction and/or urinary tract infection, translated from Dutch. A2 Age.. years A3 Gender boy girl A4 Date of filling out questionnaire..... B Daytime incontinence B1 Does your child wet his pants yes no >> go to question B2 B1a If yes, at what age started the wetting B1b If yes, how often does it happen < 3 times a week 3-4 times a week > 4 times a week B1c If yes, are the pants damp soaking variable don t know B1d If yes, wet pants all day in the afternoon variable with physical activity don t know B1e If yes, only in certain situations (playing) yes no don t know B1f If yes, does your child ignore the wet pants yes no don t know Continue with question C1 B2 When dry at daytime, at what age did your child achieve continence.. years and.. months

98 98 Chapter 7 C Voiding habits yes no don t know C1 Is there normal early morning voiding C2 Do you have to send your child to the bathroom C3 Does your child void hasty and sloppy C4 Does your child strain during voiding C5 Is the stream interrupted or staccato C7 Is voiding painful C8 For girls: does she wet the toilet seat C9 For girls: is the meatus irritated C6 How often does your child void during day time < >7 D Urge and reaction on urge never sometimes always don t know D1 Does your child have difficult to suppress urgency D2 If yes, does your child take an urge position, like squatting, crossing the legs, hand to the genitals D3 Is there adequate reaction to urge (timely voiding) D4 Does your child postpone voiding E Bedwetting E1 Does your child wet the bed or diaper yes >> go to question E1b no E2 If no, at what age was your child continent at night.. years and.. months E1b If yes, how many times a week.. times E1c Are the sheets/diapers damp soaking E1d If yes, has your child been dry for > ½ year yes no >> E2 E1da If yes, at what age started the bedwetting.. years and.. months yes no sometimes don t know E2 Are there family members who wet their beds E3 Does your child wake up by itself to void E4 Is it hard to wake up your child to void

99 Mild pyelectasis 99 F Urinary tract infection F1 Has your child ever been treated by medication yes for urinary tract infection no >> go to question G F1a If yes, how often < > 10 F1b Since when. (year) F1c If yes, when was the last infection.. (month). (year) F1d Does your child have low dose antibiotics yes At the moment to prevent new infections no F1da If yes, what kind of medication nitrofurantoin norfloxacin trimethoprim other G Defecation G1 Frequency of defecation/stools once a day or more often every 2 days 1-2 a week less than once a week yes no sometimes don t know G2 Is defecation painful G3 Does your child feel urge to defecate G4 Form of stools soft but molded firm and dry very soft, not molded otherwise, explain G5 Does your child have abdominal pain yes no G6 Is there fecal soiling yes no >> go to question G8 G6a If yes, how often a week < 3 times a week 3-4 times a week > 4 times a week G6b If yes, at what age started the soiling.. years and.. months G7 Does your child ever defecate in its pants yes no

100 100 Chapter 7 G8 Is your child being treated for constipation yes no >> go to question G10 G8a If yes, in what way high fiber diet lactulose suppository enema bowel lavage otherwise G10 At what age did your child achieve fecal continence.. years and.. months G11 How many cups does your child drink a day.. cups a day Thank you for filling out the questionnaire.

101 Mild pyelectasis 101 APPENDIX 2 Does a mild dilatation of the urinary tract give morbidity in childhood? Last name mother: Date of birth mother: Ultrasound investigation: date year Code-number: Name child (forename + family name) boy / girl Address: Zip code/ residence: Phone number: Date of birth child: Is your child healthy? Yes O No O Don t know O Is your child toilet trained? by day Yes O No O at night Yes O No O At what age your child was toilet trained? by day year months at night year months Had your child a little bit liquid in one or both kidneys?? Yes O No O Go further on the next page. If, yes, this was the right kidney O left kidney O both kidneys O You became the advice that if your child was lethargic to go to your general practitioner to have the urine checked. Was did ever necessary? Yes O No O If so, how often? 1 time O 2 times O 3 till 5 times O more than 5 times O Has your child been to a doctor to have his kidneys checked? Yes O No O If so, did you become an advice? Yes O No O If so, which advice? Became your child medication? Yes O No O Is your child still under control? Yes O No O If so, do you agree that we asked for information? Yes O No O If so, put your signature please? What is the name of the doctor? In which hospital? Thank you for filling out the questionnaire.

102 102 Chapter 7 REFERENCES 1. Kent A, Cox D, Downey P, James SL. A study of mild fetal pyelectasia - outcome and proposed strategy of management. Prenat Diagn 2000;20(3): Langer B, Simeoni U, Montoya Y, Casanova R, Schlaeder G. Antenatal diagnosis of upper urinary tract dilation by ultrasonography. Fetal Diagn Ther 1996;11(3): Persutte WH, Koyle M, Lenke RR, Klas J, Ryan C, Hobbins JC. Mild pyelectasis ascertained with prenatal ultrasonography is pediatrically significant. Ultrasound Obstet Gynecol 1997;10(1): Scott JE, Renwick M. Antenatal renal pelvic measurements: what do they mean? BJU Int 2001;87(4): Ismaili K, Hall M, Donner C, Thomas D, Vermeylen D, Avni FE. Results of systematic screening for minor degrees of fetal renal pelvis dilatation in an unselected population. Am J Obstet Gynecol 2003;188(1): Langer B. Fetal pyelectasis. Ultrasound Obstet Gynecol 2000;16(1): Ouzounian JG, Castro MA, Fresquez M, al-sulyman OM, Kovacs BW. Prognostic significance of antenatally detected fetal pyelectasis. Ultrasound Obstet Gynecol 1996;7(6): Broadley P, McHugo J, Morgan I, Whittle MJ, Kilby MD. The 4 year outcome following the demonstration of bilateral renal pelvic dilatation on pre-natal renal ultrasound. Br J Radiol 1999;72(855): Dremsek PA, Gindl K, Voitl P, Strobl R, Hafner E, Geissler W, et al. Renal Pyelectasis in fetuses and neonates: Diagnostic value of renal pelvis diameter in pre and postnatal sonographic screening. AJR Am J Roentgenol 1997(Apr;168(4)): Grignon A, Filion R, Filiatrault D, Robitaille P, Homsy Y, Boutin H, et al. Urinary tract dilatation in utero: classification and clinical applications. Mild dilatation of the fetal kidney: a follow-up study. Radiology 1986;160(3): Thomas DF, Madden NP, Irving HC, Arthur RJ, Smith SE. Mild dilatation of the fetal kidney: a follow-up study. Br J Urol 1994;74(2): Corteville JE, Gray DL, Crane JP. Congenital hydronephrosis: correlation of fetal ultrasonographic findings with infant outcome. Am J Obstet Gynecol 1991;165(2): Jaswon MS, Dibble L, Puri S, Davis J, Young J, Dave R, et al. Prospective study of outcome in antenatally diagnosed renal pelvis dilatation. Arch Dis Child Fetal Neonatal Ed 1999;80(2):F Wilson RD, Lynch S, Lessoway VA. Fetal pyelectasis: comparison of postnatal renal pathology with unilateral and bilateral pyelectasis. Prenat Diagn 1997;17(5): Adra AM, Mejides AA, Dennaoui MS, Beydoun SN. Fetal pyelectasis: is it always "physiologic"? Am J Obstet Gynecol 1995;173(4): Chertin B, Puri P. Familial vesicoureteral reflux. J Urol 2003;169(5): Degani S, Leibovitz Z, Shapiro I, Gonen R, Ohel G. Fetal pyelectasis in consecutive pregnancies: a possible genetic predisposition. Ultrasound Obstet Gynecol 1997;10(1): Hollowell JG, Greenfield SP. Screening siblings for vesicoureteral reflux. J Urol 2002;168(5):

103 Mild pyelectasis Scott JE, Swallow V, Coulthard MG, Lambert HJ, Lee RE. Screening of newborn babies for familial ureteric reflux. Lancet 1997;350(9075): Allen KS, Arger PH, Mennuti M, Coleman BG, Mintz MC, Fishman M. Effects of maternal hydration on fetal renal pyelectasis. Radiology 1987;163(3): Babcook CJ, Silvera M, Drake C, Levine D. Effect of maternal hydration on mild fetal pyelectasis. J Ultrasound Med 1998;17(9):539-44; quiz Robinson JN, Tice K, Kolm P, Abuhamad AZ. Effect of maternal hydration on fetal renal pyelectasis. Obstet Gynecol 1998;92(1): Gool van JD, Hjalmas K, Tamminen-Mobius T, Olbing H. Historical clues to the complex of dysfunctional voiding, urinary tract infection and vesicoureteral reflux. The International Reflux Study in Children. J Urol 1992;148(5 Pt 2): SPSS Inc. Chicago Hellstrom AL, Hanson E, Hansson S, Hjalmas K, Jodal U. Micturition habits and incontinence in 7-year-old Swedish school entrants. Eur J Pediatr 1990;149(6): Jones MA, Breckman B, Hendry WF. Life with an ileal conduit: results of questionnaire surveys of patients and urological surgeons. Br J Urol 1980;52(1): Dudley JA, Haworth JM, McGraw ME, Frank JD, Tizard EJ. Clinical relevance and implications of antenatal hydronephrosis. Arch Dis Child Fetal Neonatal Ed 1997;76(1):F Feldman DM, DeCambre M, Kong E, Borgida A, Jamil M, McKenna P, et al. Evaluation and follow-up of fetal hydronephrosis. J Ultrasound Med 2001;20(10): Harding LJ, Malone PSJ, Wellesley DG. Antenatal minimal hydronephrosis: is its follow-up an unnecessary cause of concern? Prenat Diagn 1999(19): Mandell J, Blyth BR, Peters CA, Retik AB, Estroff JA, Benacerraf BR. Structural genitourinary defects detected in utero. Radiology 1991;178(1): Morin L, Cendron M, Crombleholme TM, Garmel SH, Klauber GT, D'Alton ME. Minimal hydronephrosis in the fetus: clinical significance and implications for management. J Urol 1996;155(6): Thomas DF. Prenatal diagnosis: does it alter outcome? Prenat Diagn 2001;21(11): Dhillon HK. Prenatally diagnosed hydronephrosis: the Great Ormond Street experience. British Journal of Urology 1998(81,Suppl.2): Harding LJ, Malone PS, Wellesley DG. Antenatal minimal hydronephrosis: is its follow-up an unnecessary cause of concern? Prenat Diagn 1999;19(8): Wolfhagen MJ, Weezenlanden HM. Incidentie en sterfte naar leeftijd en geslacht in: Volksgezondheid. Toekomst Verkenning, Nationaal Kompas Volksgezondheid, Bilthoven, RIVM, Gezondheidstoestand/ Ziekten en aandoeningen/ Urinewegen en de geslachtsorganen/ acute urineweginfecties, 2001(24 sept.2001). 36. de Kort LM, Verhulst JA, Engelbert RH, Uiterwaal CS, de Jong TP. Lower urinary tract dysfunction in children with generalized hypermobility of joints. J Urol 2003;170(5): Jadresic L, Cartwright K, Cowie N, Witcombe B, Stevens D. Investigation of urinary tract infection in childhood. Bmj 1993;307(6907):761-4.

104 104 Chapter van der Voort J, Edwards A, Roberts R, Verrier Jones K. The struggle to diagnose UTI in children under two in primary care. Fam Pract 1997;14(1): Van Der Voort JH, Edwards AG, Roberts R, Newcombe RG, Jones KV. Unexplained extra visits to general practitioners before the diagnosis of first urinary tract infection: a case-control study. Arch Dis Child 2002;87(6): Shaw KN, Gorelick M, McGowan KL, Yakscoe NM, Schwartz JS. Prevalence of urinary tract infection in febrile young children in the emergency department. Pediatrics 1998;102(2):e16.

105 Chapter 8 Variability in dilatation of the fetal renal pelvis during a bladder filling cycle H.A.M. Damen - Elias a, R.H. Stigter b, T. P.V.M. de Jong c, G.H.A. Visser a. a Department of Perinatology and Gynaecology, University Hospital Utrecht, The Netherlands b Department of Obstetrics and Gynaecology, Deventer Hospital, Deventer, The Netherlands c Department of Paediatric Urology, University Hospital Utrecht, The Netherlands

106 106 Chapter 8 ABSTRACT Objective To investigate the variation of the dimensions of the fetal renal pelvis in relation to the degree of bladder filling in fetuses with mild pyelectasis. Methods Eighteen third trimester pregnant women with mild uni- or bilateral fetal pyelectasis, defined as an anteroposterior diameter of the renal pelvis between 5-10 mm, were recruited for the study. The women were examined for 2 3 hours by ultrasound. The anteroposterior and transverse dilatation of the renal pelvis and the bladder dimensions (to calculate fetal bladder volume) were measured at 2 to 3 minutes intervals. Results In 6 of the 18 fetuses a consistent relationship between size of the renal pelvis and bladder filling was found, with a mean difference in renal pelvis diameter between before and after voiding of 6,7mm and a largest observed difference of 14,3mm. In the other two third of infants no such relationship was found. Postnatally all children had an ultrasonography and 5 infants were referred to the paediatric urologist. The investigations in these 5 children could not confirm the hypothesis that variation in renal pelvis size in relation to bladder size may predict prenatal vesicoureteral reflux. Conclusions In case of mild pyelectasis, the size of the renal pelvis is highly variable in one third of cases. The association with bladder volume and micturition suggests evidence of vesicoureteral reflux, but this could not be proven. If cut-off values are used to differentiate between normal and abnormal renal pelvis size than not only gestational age but also the degree of bladder filling at the time of measurement should be taken in account. Caution should be expressed when the diagnosis of a possible urological anomaly is based on one single measurement during only one investigation.

107 Variability in dilatation of the fetal renal pelvis 107 INTRODUCTION A mild uni- or bilateral fetal pyelectasis is a frequent finding with a considerable variation in the reported incidence of 0,6-5,5% 1-4 due to different criteria being used to define pyelectasis, in particular regarding size and gestational age at diagnosis. Evidence exists that the antenatal detection of pyelectasis can predict postnatal complications such as obstructive uropathy or vesico ureteral reflux (VUR) and is related to an increased risk of aneuploidy (1.6 tot 3.9%) 5-8. During routine examinations we have often noted that the size of the renal pelvis varies considerably over time. This variation may be relevant, since a diagnosis of abnormal dilatation of the urinary system is usually based on fixed cut-off values. So far two studies had addressed the relationship between dimensions of the renal pelvis in relation to the degree of bladder filling 9,10. In one study such a relationship was found and in the other one not. It was the aim of the present study to investigate systematically the variation in the dimensions of the fetal renal pelvis in relation to the degree of bladder filling in fetuses with a mild pyelectasis.

108 108 Chapter 8 METHODS Eighteen women participated in the study. Measuring crown-rump length by ultrasound validated gestational age. None of the women used any medication and all had an uncomplicated, singleton pregnancy. No congenital anomaly was present except a uni- or bilateral pyelectasis at the week anomaly scan. Pyelectasis was defined as an anteroposterior diameter (A-P diameter) of the fetal renal pelvis of 5-10 mm. All women were rescanned at approximately 32 weeks gestational age and were included in the study, only, when the A-P diameter of the renal pelvis did not exceed 10mm. (In the institution this is the cut-off point where the child was referred for urological follow-up during the first weeks of life.) The parents were advised to refrain from further investigations before or after birth and were told that their child might have an increased risk for urinary tract infection (UTI) due to VUR and that, in case of feeling listless or fever of unknown origin, UTI should be ruled out. This advice is in accordance with the policy in our institution. All investigations were done between 36 and 38 weeks gestational age since it has been shown that fetuses at that age have prolonged cycles of bladder filling/ emptying, related to fetal behavioural states 11,12. All examinations were carried out between 8 and 12 a.m. after a normal breakfast. Maternal fluid intake was not specified because it is questionable whether maternal hydration influences fetal pyelectasy Every scan was made by one midwife-ultrasonographer (HDE), using the abdominal multifrequency transducer PVM 375 AT of the Toshiba Power Vision 6000, type SSA 370, Toshiba Medical Systems Europe, Zoetermeer, The Netherlands. As part of another study the same investigator carried out an intra-observer study before the data of this study were collected (Article in preparation). After obtaining informed consent, measurements of the renal pelvis and the bladder were taken during a 2 to 3 hour period with 2 to 3 minutes intervals. After identification of the fetal spine or the aorta and perpendicular on this plane with both kidneys in the largest sectional plane, the diameters of the renal pelvis were obtained by placing the callipers on the inner borders of the renal pelvis. In every fetus the right and left renal pelvis was measured in A-P and transverse diameter. The area of the bladder was measured,

109 Variability in dilatation of the fetal renal pelvis 109 by hand tracing, in a longitudinal plane with the largest outline to calculate the volume of the bladder as previously described by Stigter et al 16. Data from all measurements were plotted in a graph separately for every bladder filling cycle. The A-P and transverse diameter of the right and left renal pelvis and the perimeter derived from these measurements (mathematical formula for an ellipse = (.(½a+½b), where a = the long axis and b= the short axis), together with the calculated bladder volumes were all marked against time and standardized according to the moment of fetal voiding. All graphs were printed and visually judged by a gynaecologist who did not participate in the study, to assess if there was relationship between the various measurements obtained from the renal pelvis and the degree of bladder filling, especially around the moment of bladder emptying. Statistical analyses were performed using Statistical Product and Service Solutions version 10.1 (SPSS R ). Postnatally, all children were investigated by ultrasound within 3 or 4 months after birth by the same investigator (HDE). Parents were asked to take care of a large fluid intake by their child so that the examination could be done both before and after voiding comparatively the same investigation as the investigations at approximately 37 weeks gestational age.

110 Table 1 - Overview of all antenatal measurements and postnatal findings of the 18 children. Patient number and sex Dilatation Dilatation right kidney* left kidney* ±20 ±32 pn ±20 ±32 pn No. of filling cycles No. of measurements Right renal pelvis positive correlation Left renal pelvis positive correlation Postnatally ultrasonographic investigation۲ Right 8>6 mm, left 7>6 mm referred because of restlessness crying, VUR L=gr I R=gr II = 1 year antibiotic prophylaxis both cycles + both cycles Right 10>6 mm and left 20>8 mm Urine concentration problem just like his older brother and mother both cycles + both cycles No dilatation of renal pelves, nl bladder wall < 5 mm dilatation of the renal pelves, nl bladder wall No dilatation of renal pelves, nl bladder wall < 5 mm dilatation of the renal pelves, nl bladder wall Right 8>4 mm, left no dilatation of renal pelvis, residue after voiding, renogram: high pressure voiding, incision urethral valve Right < 5 mm dilatation, left 10>8 mm, nl bladder wall both cycles < 5 mm dilatation of the renal pelves, nl bladder wall No dilatation of renal pelves, nl bladder wall Right 3>9 mm, left no dilatation, nl bladder wall three cycles < 5 mm dilatation of the renal pelves, nl bladder wall < 5 mm dilatation of the renal pelves, nl bladder wall three cycles < 5 mm dilatation of the renal pelves, nl bladder wall No dilatation of renal pelves, nl bladder wall Right < 5 mm dilatation, left 22>18 mm, no high pressure, under control < 5 mm dilatation of the renal pelves, nl bladder wall three cycles Right 16>15 mm, left 29>28 mm with dilated calices, residue after voiding, no VUR, nl renogram, resection urethral valve Total = 3 girls 15 boys cycles = 3 kidneys 12 cycles = 5 kidneys *Measured at 20 and 32 weeks and postnatally ۲numbers correspond to the anteroposterior diameter of the renal pelvis befiore and after voiding

111 Variability in dilatation of the fetal renal pelvis 111 RESULTS In the 18 patients 40 bladder filling/emptying cycles (range 1 4) could be evaluated. In 4 patients it was not possible to record more than one filling cycle because of a maternal supine hypotension syndrome. All measurements were obtained from all 18 fetuses with a total of 945 measurements of the right as well as of the left kidney (Table 1). The mean interval between first and last measurement in one cycle was 33 minutes (range 11-64) with an average of 17 renal pelves and bladder volume measurements per cycle (range 7-33). Assessed visually, in 6 of the 18 fetuses (33,3%) there were concomitant volume changes of the renal pelvis in association with those of the bladder (data: Table 2). Twice this concerned both kidneys (Number 2 and 3, Table 1) and in four fetuses one kidney (Number 9, 12, 14, 18, Table 1). In these fetuses these associations occurred during all the observed bladder cycles and this concerned for the A-P diameter, for the transverse diameter and for the perimeter of the renal pelvis as well, each separately, by comparison with the bladder volume. Figure 1 (a) gives an example of such a correlation between fetal renal pelvis dimensions and bladder volumes and figure 1 (b) shows the same measurements in a fetus in whom no such correlations were present. (a) (b) pyelum L anteroposterior w idth L pyelum pyelum R anteroposterior w idth R pyelum perimeter L pyelum volume bladder perimeter re pyelum volume bladder mm/ cm/ cm mm/ cm/ cm time time Figure 1 a = Example of a case in which there is a concomitant variation in renal pelvis size and fetal bladder filling/ emptying. Figure 1 b = Example in which no such association was found. The x-axis is the time in minutes to the time of fetal micturition (point 0). The y-axis shows the size of the anterior/ posterior pelvis diameter and of the width of the pelvis, in millimetres. As to the perimeter of the pelvis in cm and bladder volume in cubic mm, respectively.

112 112 Chapter 8 Figure 2 (a) shows the measurements of decreasing and increasing size of renal pelves, in relation to bladder filling and micturition (figure 2 b) of the 19 cycles in the 6 children in whom changes in renal pelvis dilatation were related to the bladder filling/emptying cycle. It concerned 7 times the right kidney and 12 times the left kidney (Table 1) in 6 fetuses. (a) (b) 25 pyelum 25 volume bladder volume bladder millimetres centimetres time time Figure 2 a = Diameter of the pelvis in relation to the time of fetal micturition (0 minutes; 19 observations) Figure 2 b = The corresponding lines of bladder volume in these cases. The x-axis is the time in minutes to the time of fetal micturition (point 0). The y-axis shows the size of the anterior/ posterior pelvis diameter and of the width of the pelvis, in millimetres. As to the perimeter of the pelvis in cm and bladder volume in cubic mm, respectively. The mean difference between renal pelvis diameter 4 minutes before voiding and directly after voiding was 6,7 millimetre, range 2,9 to 14,3. In five of these cases the diameter was more than 15 mm before voiding, 16,8/ 18,1/ 18,0/ 18,9/ 19,8 mm, respectively and 9,1/ 3,8/ 10,6/ 8,9 and 10,8 mm, respectively, thereafter. The maximal renal pelvis diameter 4 minutes before voiding was related to the maximal bladder volume (r=0,95) and the minimal renal pelvis diameter after voiding was related to the minimal bladder volume (r=0,91). Postnatally all children had an ultrasound scan at the age of approximately 3 or 4 months to measure renal pelvis size once again before and after voiding (Table 1). None of the children were reported to have had urinary tract problems and all were clinically well. Only one child had visited a paediatrician because of excessive crying and restlessness at night but no conclusive diagnosis had been made.

113 Variability in dilatation of the fetal renal pelvis 113 Five of the eighteen investigated infants (27,7%) were referred to the paediatric urologist because of dilated renal pelves and/or hydronephrosis (n=3), residual bladder volume after voiding (n=1) or restlessness and excessive crying (n=1). Table 1. Antenatally, two of these children (No. 2 and 18) had shown a clear correlation between the dilatation of the renal pelvis and bladder volume during a filling cycle in contrast to the three others (No 1, 7 and 16). The referred children were: - No. 1, a boy, referred because of restlessness and crying at night, to exclude an underlying renal cause. A voiding cystourethrography (VCUG) showed grade I VUR on the left and grade II on the right side. The child was put on antibiotic prophylaxis for one year. - No. 2, a boy, referred because of visible reduction of the dilated renal pelves (before and after voiding, left 20 mm>5mm, right 10>6mm) and excessive drinking. The child drank 2 litres per day and even 500 ml by night. Further information from the mother, led to the diagnosis of a renal concentration disorder that also affected her other son and also herself. No VUR was demonstrable during VCUG in this infant. - No. 7, a boy referred because of residual urine after voiding. An urodynamic study notified suspicion on a urethral obstruction and high pressure at voiding. No VUR was noted at VCUG. Posterior urethral valves were resected during a subsequent cystoscopy. - No. 16, a boy referred because of a unilateral hydronephrosis with a renal pelvis of >20mm and dilated calices. An ultrasound showed a kidney with a plump collecting system and no evidence for high pressure. The child will be followed up at 3 months intervals. - No. 18, a boy referred with bilateral hydronephrosis (right 17 and left 30 mm) with dilated calices. A renogram showed normal function and no important obstruction. A VCUG showed no VUR but a megabladder with significant residual urine after voiding and a suspicion for obstruction of the bladder neck. At cystoscopy no obstruction was found and the child will be followed up at 3 months intervals.

114 Table 2 The distribution of measurements, 10 minutes before till 10 minutes after voiding, of the fetuses with a correlation between the pelvis of the right and/ or left kidney and bladder volume plotted against the time in minutes. patiënt cycle time min. renal pelvis dilatation right left bladder volume patiënt cycle time min. renal pelvis dilatation right left bladder volume patiënt cycle time min. renal pelvis dilatation right left bladder volume patiënt cycle time min. renal pelvis dilatation right left 2 / ,9 12,2 10,65 9 / ,7 25,07 12 / ,9 17,32 18 / ,8 12, ,3 12,1 10,22-8 9,1 26, ,3 15, ,1 13, ,1 11,3 9,34-6 9,9 26, ,6 13, ,4 13,13-4 9,3 11,8 7, ,2 28, ,9 12, ,88-2 8,8 12,2 7, ,6 16, ,8 11, ,5 14,12 0 5,7 7,7 1,61 0 3,4 5,74 0 9,1 2, ,6 6,31 2 6,4 7,7 2,57 2 6,9 8, ,2 3, ,1 7,17 4 6,8 9,5 3,34 4 7,4 10, ,1 5, ,81 6 6,7 9,2 4,51 6 8,8 10, ,6 6, ,1 8,13 8 8,2 9,7 6, ,2 14, ,2 9, ,2 8, ,9 10,0 6, ,1 14, ,1 10, ,8 9,81 2 / ,5 10,5 9,04 9 / ,8 14,62 14 / ,7 9,91 18 / ,11-8 9,4 11,3 9, ,2 14,99-8 7,8 10, ,9 12, ,4 11,4 9, ,1 15,97-6 9,1 11, ,9 13, ,2 10,6 10, ,4 18, ,6 12, ,3 13, ,5 10,6 11, ,6 17, ,3 12, ,9 14,12 0 7,6 5,8 2,01 0 6,2 2,51 0 6,4 2,56 0 8,9 2,09 2 8,2 6,4 3,42 2 7,4 3,46 2 7,1 3,79 2 9,8 2,75 4 8,9 7,6 4,10 4 8,8 4,15 4 7,8 4, ,8 3,16 6 8,7 8,1 5,00 6 9,2 4,65 6 8,7 6, ,4 3,79 8 9,9 8,6 5,38 8 9,4 4,92 8 9,4 7, ,1 5, ,6 10,1 5, ,8 5, ,6 7, ,2 5,29 3 / ,5 9,5 10,10 12 / ,9 13,48 14 / ,9 10,19 18 / ,6 14,12-8 7,8 10,7 10, , ,8 11, ,1 13,39-6 8, , ,3 9, ,6 17, ,8 13,51-4 9,4 11,6 11, , ,8 20, ,3 14,37-2 9,4 11,5 7, ,6 6, ,1 21, ,8 14,37 0 5,7 8,1 1,80 0 7,4 4,42 0 3,8 2, ,8 4,47 2 6,4 8,8 2,82 2 8,9 6,12 2 4,5 3, ,6 6,31 4 6,9 9 3, ,2 7,49 4 6,2 4, ,6 7,19 6 7,7 9,6 4, ,6 8,93 6 6,9 4, ,3 8,29 8 7,9 9,5 4, ,3 10,21 8 7,1 5, ,4 8, ,9 6, ,6 12, ,2 6, ,9 10,99 3 / ,7 10,8 9,22 12 / ,6 12,54 14 / ,3 7,17-8 7,8 10,9 9, ,3 12,14-8 8,9 7,97-6 9, , ,6 10,21-6 9,1 9, ,6 11,2 12, ,93-4 9,9 10, ,3 11,8 12, ,7 7,49-2 9,9 11,85 0 6,4 7,9 2,56 0 4,6 2,29 0 5,6 4,19 2 7,1 8,6 3,79 2 6,7 2, ,98 4 7,8 9,5 4,05 4 7,5 3,66 4 9,7 10,13 6 8,7 10,2 6, ,4 5, ,4 13,76 8 9,4 10,8 7, , ,9 14, ,6 11,4 7, ,3 6, ,8 16,58 bladder volume / / / /

115 Variability in dilatation of the fetal renal pelvis 115 DISCUSSION This study shows that in approximately one-third of term fetuses with a mild pyelectasis the diameter of the renal pelvis varies according to bladder volume, with a mean difference in renal pelvis diameter before and after voiding of 6,7 mm and a largest observed difference of 14,3 mm. So the volume of the bladder should be considered when fetal hydronephrosis is suspected. In the other two-third of fetuses with a mild pyelectasis no changes in dilatation of the renal pelvis in relationship to voiding were observed. Petrikosky et al 10 studied the overall relationship between renal pelvis diameter and bladder volume in 43 fetuses with hydronephrosis between 18 and 24 weeks gestational age. No criteria of the definition of hydronephrosis were given. The anterior posterior diameter of the fetal renal pelvis diminished from 6,8 to 4,5 mm when the bladder was emptied and the size of the fetal renal pelvis was correlated to the bladder area (r=0,55). They only studied the overall effect in the total group and did not distinguish between fetuses in which a relationship with bladder volume was present or not. This explains the low correlation coefficient between pelvic size and bladder volume as compared to our data but they also concluded that the volume of the bladder should be considered when fetal hydronephrosis is diagnosed. In contrast, Persutte et al 9 found no relationship between bladder size and pyelectasis (A-P diameter >4 mm and <10mm), but they took their measurements every 15 minutes and therefore may have missed the changes in diameter, which occur specifically around fetal micturition. However, they did find a highly variable size of the fetal renal collecting system. These studies are not quite comparable with ours because of the differences in intervals of the measurements and the use of the data of all the fetuses for the calculations instead of a selected part of the total group were the diameter of the renal pelvis varies according to bladder volume, as we did. One of the reasons of the variations in dilatation has been suggested to be an association between maternal hydration and fetal renal pyelectasis 14,15 although another study has claimed the opposite 13. Another possible reason for the association between renal pelvis size and bladder filling, might be the presence of

116 116 Chapter 8 VUR, a renal tract anomaly that can be diagnosed antenatally only by the invasive procedure of adding cystourethrography to a diagnostic puncture of the fetal bladder 17. Pyelectasis, hydronephrosis or a dilated ureter suggests the need for postnatal investigations to rule out VUR. However, thus far no correlation has been found between antenatal and postnatal dilatation and the severity of VUR 18. Even postnatal ultrasound is falsely negative in 18 to 30% of the infants with VUR and until now the golden standard for the diagnosis of VUR is a VCUG. We had not the possibility to offer all 18 children a VCUG and so we could not confirm the hypothesis that cyclic variation in bladder and renal pelvis size are diagnostic regarding VUR. After the postnatal ultrasound investigation only 5 children in our study group showed abnormal dilatation of the renal pelvis and had subsequent investigations. Two of these children (No 2 and 18; Table1) showed a correlation between the size of the renal pelvis dilatation and the bladder volume but a VCUG did not confirm the diagnosis of VUR. In another fetus (No 1) no correlation between bladder and renal pelvis fluctuations had been found and nevertheless the child appeared to have bilateral VUR. We suggest another study in a greater cohort of third trimester pregnant woman with measurements of the fetal renal pelves every 2 or 3 minutes from 15 minutes before till 15 minutes after fetal voiding occurs and, if concomitant changes in size of the renal pelvis in relation to that of the fetal bladder volume occur a postnatal VCUG.

117 Variability in dilatation of the fetal renal pelvis 117 REFERENCES 1. Kent A, Cox D, Downey P and James SL: A study of mild fetal pyelectasis - outcome andproposed strategy of management. Prenat Diagn. 20: 206-9, Langer B, Simeoni U, Montoya Y, Casanova R and Schlaeder G: Antenatal diagnosis of upper urinary tract dilation by ultrasonography. Fetal Diagn Ther. 11: 191-8, Persutte WH, Koyle M, Lenke RR, Klas J, Ryan C and Hobbins JC: Mild pyelectasis ascertained with prenatal ultrasonography is pediatrically significant. Ultrasound Obstet Gynecol. 10: 12-8, Scott JE and Renwick M: Antenatal renal pelvic measurements: what do they mean? BJU Int. 87: , Aviram R, Pomeranz A, Sharony R, Beyth Y, Rathaus V, Tepper R and Pomeran A: The increase of renal pelvis dilatation in the fetus and its significance. Ultrasound Obstet Gynecol. 16: 60-2, Chudleigh PM, Chitty LS, Pembrey M and Campbell S: The association of aneuploidy and mild fetal pyelectasis in an unselected population: the results of a multicenter study. Ultrasound Obstet Gynecol. 17: , Corteville JE, Dicke JM and Crane JP: Fetal pyelectasis and Down syndrome: is genetic amniocentesis warranted? Obstet Gynecol. 79: 770-2, Nicolaides KH, Cheng HH, Abbas A, Snijders RJ and Gosden C: Fetal renal defects: associated malformations and chromosomal defects. Fetal Diagn Ther. 7: 1-11, Persutte WH, Hussey M, Chyu J and Hobbins JC: Striking findings concerning the variability in the measurement of the fetal renal collecting system. Ultrasound Obstet Gynecol. 15: , Petrikovsky BM, Cuomo MI, Schneider EP, Wyse LJ, Cohen HL and Lesser M: Isolated fetal hydronephrosis: beware the effect of bladder filling. Prenat Diagn. 15: 827-9, Visser GH, Goodman JD, Levine DH and Dawes GS: Micturition and the heart period cycle in the human fetus. Br J Obstet Gynaecol. 88: 803-5, Stigter RH, Mulder EJ and Visser GH: Hourly fetal urine production rate in the near-term fetusis it really increased during fetal quiet sleep? Early Hum Dev. 50: , Allen KS, Arger PH, Mennuti M, Coleman BG, Mintz MC and Fishman M: Effects of maternal hydration on fetal renal pyelectasis. Radiology. 163: 807-9, Babcook CJ, Silvera M, Drake C and Levine D: Effect of maternal hydration on mild fetal pyelectasis. J Ultrasound Med. 17: ; quiz 545-6, Robinson JN, Tice K, Kolm P and Abuhamad AZ: Effect of maternal hydration on fetal renal pyelectasis. Obstet Gynecol. 92: , Stigter RH, Schelven van LJ, Bruinse HW, Mulder EJH, Gemert van MJC. On the measurement of fetal bladder volume and urine production: methodological consideration. Prenat Neonat Med 2000; 5: Stoutenbeek P, de Jong TP, van Gool JD and Drogtrop AP: Intra-uterine cystography for evaluation of prenatal obstructive uropathy. Pediatr Radiol. 19: 247-9, Jaswon MS, Dibble L, Puri S, Davis J, Young J, Dave R and Morgan H: Prospective study of outcome in antenatally diagnosed renal pelvis dilatation. Arch Dis Child Fetal Neonatal Ed. 80: F135-8, Najmaldin A, Burge DM and Atwell JD: Fetal vesicoureteric reflux. Br J Urol. 65: 403-6, 1990

118 118 Chapter Tibballs JM and De Bruyn R: Primary vesicoureteric reflux--how useful is postnatal ultrasound? Arch Dis Child. 75: 444-7, Zerin JM, Ritchey ML and Chang AC: Incidental vesicoureteral reflux in neonates with antenatally detected hydronephrosis and other renal abnormalities. Radiology. 187: , 1993.

119 Chapter 9 Summary and discussion Nederlandse samenvatting Dankwoord Curriculum Vitae

120 120 Chapter 9 SUMMARY, DISCUSSION AND CONCLUSION introduction In two to three percent of fetuses structural anomalies can be found with prenatal ultrasound investigation 1-4. Anomalies of the urinary tract account for 15 to 20% of these anomalies with a detection rate of approximately of 90% 3, 4. During the latest decades numerous papers have been published on the fetal renal system and its anomalies. However, follow-up studies on long-term outcome are still scarce and this hampers adequate counselling of parents and of giving adequate treatment advises. Moreover, up-to-date charts on normal fetal kidney and adrenal gland development are scarce. We therefore formulated the following aims of this thesis (Chapter 1): 1 To develop charts of size and growth of the fetal kidney, renal pelvis and adrenal gland. 2 To study long-term follow-up of a large cohort of infants with a prenatally diagnosed renal tract anomaly. 3 To answer the question whether mild pyelectasis (anteroposterior diameter of the fetal renal pelvis of 5 10 mm) as diagnosed around 18 to 20 weeks of gestation results in increased morbidity in childhood and therefore requires postnatal treatment. 4 To study the relationship between the size of the renal pelvis and the fetal bladder-filling cycle, to answer the question if fixed cut-off values regarding renal pelvis dilatation can be used or whether bladder filling has to be taken into account. charts for size and growth of kidney, renal pelvis and adrenal gland A reference curve for size and growth of fetal kidney, renal pelvis and adrenal gland is of importance to judge the growth of these organs during pregnancy, especially when during an ultrasound investigation an anomaly is suspected. Several charts of fetal kidney sizes have been published, but mostly with shortcomings in data collection or with methodological weaknesses i.e. not validating gestational age 5-9, not covering the whole of the second and third trimester of pregnancy 5, 6, 10-12, not measuring the kidney in three dimensions 5, 6, 8-10 or using data from infants born preterm or from post-mortem specimens Moreover several studies averaged both cross-sectional and longitudinal data 5, 7-10, 12, 15. In none of these publications an intraobserver and interobserver variation analysis had preceded the study.

121 Summary, discussion and conclusion 121 We performed an intraobserver and interobserver variation analysis for the measurements of length, anteroposterior diameter and transverse diameter of the kidney and for length of the adrenal gland (Chapter 2). Data regarding an intraobserver variation were obtained from 30 fetuses and by comparing three measurements with different time intervals between each measurement. Statistical analysis showed that there was a high intraobserver agreement with Cronbach s alpha (α) above 0.9 and the intra class correlation (IC) above 0.8. Interobeserver agreement was studied in 20 fetuses by two experienced ultrasonographers. Also these data were satisfactory (α above 0.9, IC above 0.8). All measurements could be taken in each fetus both in the intra- and interobserver study. In a prospective longitudinal study in 111 low risk fetuses we measured length, anteroposterior diameter and transverse diameter of both kidneys, anteroposterior and transverse diameter of both renal pelves and the length of both adrenal glands (Chapter 3 and 4). Data were obtained every 4 weeks from 16 weeks onwards. Data obtained in a longitudinal study by measurements of a considerable cohort of fetuses on a series of occasions may be used for a reference curve for size and growth. Cross-sectional data obtained by measurements of each fetus on a single occasion give only information on size Statistical analysis was performed by multilevel analysis a recently developed new technique that can be used when some data are missing and when measurements have been made at variable times 16. It allows for the dependency in hierarchically structured data in contrast to multiple regression analysis that presupposes the independency of observations. Repeated measurements in the same individual with investigations at different gestational ages belong to a low level. Computed means of an individual measurement (e.g. kidney length) belong to a higher level. There was hardly any difference between the curves of the right and left kidney, the right and left renal pelvis and the right and left adrenal gland. Definitive charts were made after averaging the data from both sides. It was difficult to compare our charts with those of others because several studies did not cover the whole second and third trimester of pregnancy or gave no raw data or when they did so they gave evidence of methodological weakness. We compared our

122 122 Chapter 9 charts with those of Chitty and Altman 7, 17 and of Pruggmayer and Terinde 7. Both studies used cross-sectional data and measured every fetus only once. Chitty et al measured every week approximately 15 to 20 fetuses while Pruggmayer et al gave no data on numbers/ week and excluded nearly 20% of infants because they were either large or small for dates. Our charts differ from theirs in having smaller ranges. This may be due to the fact that we did each measurement three times whereafter we averaged the data. A strong linear correlation was found between adrenal gland length and kidney length with a ratio 2 to 7 and this relation did not change with gestation/ kidney size. Comparing our chart of the length of the adrenal gland with others was not possible because another measure of the adrenal was measured 18 or data were published only for every 5 weeks 19 or were compared with biparietal diameter and kidney length and not with weeks of gestation 20. structural anomalies of the fetal renal tract The prevalence of any congenital anomaly that can be detected by ultrasound during pregnancy is approximately 1 to 2% 1-4. Urinary tract abnormalities account for 15 to 20% of these anomalies with a detection rate of approximately 90% 3, 4. Data on antenatal diagnosis and postnatal follow-up are important for assessing prognosis of the individual fetus with a diagnosed anomaly and for subsequent counselling of the parents. Such data may also be helpful in making difficult decisions as to whether or not to terminate a pregnancy before viability and in determining the need for further diagnostic procedures and best management before and after birth. In Chapter 5 we describe the ultrasound findings and outcome of a large cohort of 402 fetuses with a prenatally diagnosed urinary tract anomaly. We could use the database of the ultrasound unit of the department of obstetrics of the University Medical Centre, Utrecht, and The Netherlands, which was established in At follow-up the youngest infant was 3 years and the oldest was 17 years (median 7 years 11 months).

123 Summary, discussion and conclusion 123 We made a distinction between a structural kidney anomaly and urinary tract dilatation to gain insight into the prognosis and outcome of these two district groups of anomalies. A structural anomaly exists when in the very beginning aberrant development or defects in maturation have taken place in the embryologic urinary tract. Dilatation of the urinary tract may result from slow maturation and canalisation of the excretory system 25. One hundred and twenty-one of the 402 fetuses died before or after birth in 106 cases the reason of death was directly related to the renal tract anomaly (26,4%). Eighty-four of these fetuses had a structural anomaly and died mostly due to bilateral renal agenesis (33 fetuses), bilateral multicystic kidneys (22 fetuses) or bilateral polycystic kidneys (19 fetuses). Another 22 fetuses had a urinary tract dilatation and they died mainly due to an isolated megabladder (17 fetuses). Two hundred and eighty-one fetuses survived of which 64 had a structural anomaly and 213 had a urinary tract dilatation. The structural anomaly was in approximately 80% a unilateral multicystic kidney and 12 of these infants had a contralateral anomaly. Surgery consisted mainly of nephrectomy of the multicystic kidney. Only two children, both with bilateral echogenic dysplastic kidneys, had impaired function at follow-up (one with peritoneal dialysis, one with an increased creatinine level of 71 µmol/l at 7½ years of age). The dilatation in the 213 fetuses was approximately equally divided in uni- or bilaterally. One hundred and eighteen fetuses had a solitary uni- or bilateral dilatation of the renal pelvis while the 95 others had a combination with a uni- or bilateral megaureter and/ or megabladder. Approximately 50% of these children had surgery with a total of 315 interventions. Especially high was the intervention rate in 45 children with posterior urethral valves (100%) as in the 45 cases of vesico ureteral reflux (86,6%). In 21 cases with a bilateral dilatation labour was electively induced before 37 weeks of gestation (mean 34,9 weeks: range 29 37) because of the development of anhydramnios. Almost all children with impaired outcome can be found in this group (6 chronic renal failure, 1 hypertension). The overall conclusion for obstructive uropathy that can be drawn from this series is that, regardless of the presence of 1 or 2 kidneys and regardless of the degree of urinary tract dilatation, the

124 124 Chapter 9 prognosis for renal function is excellent when oligohydramnios is absent before birth and when proper urological care is given postnatally. All in all, at follow-up 9 of the 281 surviving infants had impaired renal function and 3 children had hypertension, 12/281 (4,3%). So, overall outcome in the children was generally good. In Chapter 6 a large cohort of 100 fetuses with unilateral multicystic kidney disease (MCKD), prenatally diagnosed between 15 and 42 weeks of gestation (mean 26.7 weeks), is described. Data were obtained by reviewing the databases of the obstetric ultrasound department and of the paediatric urology department of the University Medical Centre Utrecht, The Netherlands. The children were at follow-up 0-16 years of age (mean 5 years and 4 months). MCKD only gives rarely diagnostic dilemmas on prenatal ultrasound (26) due to its typical manifestation with (in general) multiple non-communicating cysts. The function of the affected kidney is absent or poor. Therefore, bilateral MCKD is invariably associated with a fatal outcome. The prognosis of unilateral MCKD is 27, 28 favourable and depends on the integrity of the contralateral kidney It is known from literature that children with unilateral MCKD have an increased risk of abnormalities of the contralateral kidney and of the lower urogenital tract The finding of a unilateral MCKD must therefore lead to meticulous screening of the complete urinary tract, both pre- and postnatally, as most studies also recommend. There is no unanimous opinion as to whether the multicystic kidney should be removed. In some studies the children are examined periodically 28, 31 after birth while others remove the affected kidney because of possible higher risks of hypertension, infection or malignancy 28, It is the view of the Dutch Society for Paediatric Urology to remove the non-functioning cystic kidney to prevent lifetime follow-up of these children, which could easily be neglected in the course of years. Furthermore parents need not to be anxious when their child has abdominal pain. In our population nephrectomy has been performed in 93% of surviving children and this operation was combined with cystoscopy and in the girls also with colposcopy.

125 Summary, discussion and conclusion 125 Comparing our results with others is difficult because in some studies another target group was included e.g. both the uni- and bilateral MCKD 27 or a different population limited to fetuses with a chromosomal anomaly 35. We found an additional anomaly in 26, 27, 75% of the fetuses. This is much higher than the 21 to 57% as found by others 29-31, 35. There were anomalies in the contralateral kidney in 48% of cases, as compared to 13 to 39% in literature, in the ipsilateral kidney in 48% of cases (4 to 14% in literature) and in the lower urogenital tract in 33% as compared to 4 to 6% in literature. We have no real explanation for the higher incidence of anomalies that we found in the contralateral kidney and in the lower urogenital tract. The higher incidence of anomalies of the ipsilateral kidney is probably the result of the cystoscopy and the colposcopy in girls and concerned mainly an ectopic ureter or a megaureter. Other studies only mentions an ureteral reflux or an ureteropelvic junction stenosis 27, 29, 30. Once a multicystic kidney is diagnosed we advice a thorough screening both preand postnatally since the chance of having other congenital anomalies of the urinary tract appears high. Moreover we recommend a routine postnatal examination consisting of an ultrasound examination, an isotope scan and a VCUG and when a nephrectomy is done also cystoscopy and colposcopy to detect possibly hidden anomalies of the genitourinary tract. pyelectasis In Chapter 7 a study is described that was done to investigate urinary tract morbidity in late childhood in infants with a prenatally diagnosed mild pyelectasis. We defined pyelectasis as an anteroposterior diameter of the fetal renal pelvis of 5-10 mm without a specified gestational age at diagnosis. In literature there is no consensus as to the cut-off points to use before birth to diagnose pyelectasis Mild uni- or bilateral fetal pyelectasis is a frequent finding at prenatal ultrasound examination, with a considerable variation in the reported incidence, from 0,6% to 5,5% (36-39), due to differences in criteria of the definition of pyelectasis, in particular regarding size and gestational age at diagnosis. Guidelines relating the severity of pyelectasis to perinatal and postnatal management are not well standardized. The clinical significance of mild fetal pyelectasis is still unclear; it may resolve, stabilize or

126 126 Chapter 9 be the first indicator of significant urinary tract pathology. Evidence exists that pyelectasis may result in clinical complications such as obstructive uropathy or vesico ureteric reflux. Because of the lack of data on possible long-term morbidity we investigated the occurrence of urinary tract morbidity in childhood. We could use the data of the Amphia hospital (a District General Hospital, location Oosterhout, The Netherlands). All women in that region have an anomaly scan at weeks gestation. It was customary to reexam the women at approximately 32 weeks of gestation when at the first ultrasound scan a uni- or bilateral pyelectasis was found. When the dilatation had progressed to > 10 millimetres the child was referred to a paediatrician or urologist for urological follow-up during the first weeks of life. When the dilatation was stable or disappeared parents were advised to refrain from follow-up before and after birth and were told that their child might have an increased risk for urinary tract infection due to vesico ureteral reflux and that, in case of feeling listless or of fever of unknown origin, urinary tract infection should be ruled out. A large group of 208 cases and 416 matched controls were examined by a validated questionnaire, developed by a group of The International Reflux Study in Children (40), containing questions about urinary tract infections, incontinence, voiding and bowel patrons. No significant differences in morbidity between children with or without mild prenatal pyelectasis were found. Of interest is the higher incidence of urinary tract infections in both the cases and controls as compared to literature 41, 42. This high incidence of infections was also found in another study of our group 43. The surgical intervention rate in our case-group was only 0,8% much lower than reported by others (3,6%-24,3%) 36, 38, 44. Based on these findings we advocate in case of a mild renal pyelectasis at about 20 weeks of gestation a single follow-up scan in the third trimester to determine if the pyelectasis has resolved, stabilized or progressed. The child should only be referred for postnatal examination if there is progression of the pyelectasis to >10mm. With this policy there seems to be only a very low chance of missing an occasional case of VUR or potential obstruction. Parents should be advised to visit the general practitioner in case their child is lethargic or has fever of unknown origin to have the

127 Summary, discussion and conclusion 127 child s urine tested to rule out urinary tract infection or treat infection effectively in order to prevent renal damage. In Chapter 8 a study is described on the variation of the dimensions of the fetal renal pelvis in relation to the degree of bladder filling in fetuses with mild pyelectasis. Pyelectasis, defined as an anteroposterior diameter of the fetal renal pelvis of 5-10 mm, might predict postnatal complications such as obstructive uropathy or vesico ureteral reflux. Until now two studies have been published on the variation over time of the fetal renal pelvis in relation to bladder filling 45, 46. In one study such a relationship had been found, in the other not. This existence or not of a variation in pelvic size in relation to bladder filling is relevant since the diagnosis of abnormal dilatation of the upper tract is usually based on fixed cut-off values. We investigated 18 pregnant women who had fetus with a uni- or bilateral pyelectasis at the weeks anomaly scan, which did not exceed 10 mm at the repeat scan at approximately 32 weeks of gestation. Investigations were made in the late third trimester since it has been shown that fetuses at that age have prolonged cycles of bladder filling/ emptying, related to fetal behavioural states 47, 48. We found in one third of the fetuses that the dilatation of the renal pelvis varied according to bladder volume with a mean difference of 6,7 mm and a largest observed difference of 14,3 mm. So the filling state of the bladder should be taken into account when fetal hydronephrosis is suspected. CONCLUSION The mortality rate in fetuses is high once a renal anomaly is identified. The prognosis for the surviving children is relatively good and these infants have only a little chance on lifelong damage, if during pregnancy the right diagnosis has been made and if these children have had good urological care after birth. It is important that paediatricians and urologists are acquainted with the advices, which were given when antenatally anomalies at the urinary tract are diagnosed, because they will be consulted often about these anomalies after birth.

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129 Summary, discussion and conclusion Lewis E, Kurtz AB, Dubbins PA, Wapner RJ, Goldberg BB. Real-time ultrasonographic evaluation of normal fetal adrenal glands. J Ultrasound Med 1982;1(7): Altman DG, Chitty LS. Design and analysis of studies to derive charts of fetal size. Ultrasound Obstet Gynecol 1993;3(6): Altman DG, Chitty LS. Charts of fetal size: 1. Methodology. Br J Obstet Gynaecol 1994;101(1): Royston P, Altman DG. Design and analysis of longitudinal studies of fetal size. Ultrasound Obstet Gynecol 1995;6(5): Royston P, Wright EM. How to construct 'normal ranges' for fetal variables. Ultrasound Obstet Gynecol 1998;11(1): Cuckow PM, Nyirady P, Winyard PJ. Normal and abnormal development of the urogenital tract. Prenat Diagn 2001;21(11): Aubertin G, Cripps S, Coleman G, McGillivray B, Yong SL, Van Allen M, et al. Prenatal diagnosis of apparently isolated unilateral multicystic kidney: implications for counselling and management. Prenat Diagn 2002;22(5): Al-Khaldi N, Watson AR, Zuccollo J, Twining P, Rose DH. Outcome of antenatally detected cystic dysplastic kidney disease. Arch Dis Child 1994;70(6): Wacksman J, Phipps L. Report of the Multicystic Kidney Registry: preliminary findings. J Urol 1993;150(6): Atiyeh B, Husmann D, Baum M. Contralateral renal abnormalities in multicystic-dysplastic kidney disease. J Pediatr 1992;121(1): Eijk van L, Cohen-Overbeek TE, den Hollander NS, Nijman JM, Wladimiroff JW. Unilateral multicystic dysplastic kidney: a combined pre- and postnatal assessment. Ultrasound Obstet Gynecol 2002;19(2): Rudnik-Schoneborn S, John U, Deget F, Ehrich JH, Misselwitz J, Zerres K. Clinical features of unilateral multicystic renal dysplasia in children. Eur J Pediatr 1998;157(8): Elder JS, Hladky D, Selzman AA. Outpatient nephrectomy for nonfunctioning kidneys. J Urol 1995;154(2 Pt 2):712-4; discussion LaSalle MD, Stock JA, Hanna MK. Insurability of children with congenital urological anomalies. J Urol 1997;158(3 Pt 2): Webb NJ, Lewis MA, Bruce J, Gough DC, Ladusans EJ, Thomson AP, et al. Unilateral multicystic dysplastic kidney: the case for nephrectomy. Arch Dis Child 1997;76(1): Lazebnik N, Bellinger MF, Ferguson JE, 2nd, Hogge JS, Hogge WA. Insights into the pathogenesis and natural history of fetuses with multicystic dysplastic kidney disease. Prenat Diagn 1999;19(5): Kent A, Cox D, Downey P, James SL. A study of mild fetal pyelectasia - outcome and proposed strategy of management. Prenat Diagn 2000;20(3): Langer B, Simeoni U, Montoya Y, Casanova R, Schlaeder G. Antenatal diagnosis of upper urinary tract dilation by ultrasonography. Fetal Diagn Ther 1996;11(3): Persutte WH, Koyle M, Lenke RR, Klas J, Ryan C, Hobbins JC. Mild pyelectasis ascertained with prenatal ultrasonography is pediatrically significant. Ultrasound Obstet Gynecol 1997;10(1):12-8.

130 130 Chapter Scott JE, Renwick M. Antenatal renal pelvic measurements: what do they mean? BJU Int 2001;87(4): Gool van JD, Hjalmas K, Tamminen-Mobius T, Olbing H. Historical clues to the complex of dysfunctional voiding, urinary tract infection and vesicoureteral reflux. The International Reflux Study in Children. J Urol 1992;148(5 Pt 2): Dremsek PA, Gindl K, Voitl P, Strobl R, Hafner E, Geissler W, et al. Renal Pyelectasis in fetuses and neonates: Diagnostic value of renal pelvis diameter in pre and postnatal sonographic screening. AJR Am J Roentgenol 1997(Apr;168(4)): Harding LJ, Malone PS, Wellesley DG. Antenatal minimal hydronephrosis: is its follow-up an unnecessary cause of concern? Prenat Diagn 1999;19(8): Kort de LM, Verhulst JA, Engelbert RH, Uiterwaal CS, de Jong TP. Lower urinary tract dysfunction in children with generalized hypermobility of joints. J Urol 2003;170(5): Dudley JA, Haworth JM, McGraw ME, Frank JD, Tizard EJ. Clinical relevance and implications of antenatal hydronephrosis. Arch Dis Child Fetal Neonatal Ed 1997;76(1):F Petrikovsky BM, Cuomo MI, Schneider EP, Wyse LJ, Cohen HL, Lesser M. Isolated fetal hydronephrosis: beware the effect of bladder filling. Prenat Diagn 1995;15(9): Persutte WH, Hussey M, Chyu J, Hobbins JC. Striking findings concerning the variability in the measurement of the fetal renal collecting system. Ultrasound Obstet Gynecol 2000;15(3): Visser GH, Goodman JD, Levine DH, Dawes GS. Micturition and the heart period cycle in the human fetus. Br J Obstet Gynaecol 1981;88(8): Stigter RH, Mulder EJ, Visser GH. Hourly fetal urine production rate in the near-term fetus: is it really increased during fetal quiet sleep? Early Hum Dev 1998;50(3):

131 Nederlandse samenvatting 131 NEDERLANDSE SAMENVATTING Sinds in 1950 Ian Donald e.a. voor het eerst ultrageluid toepasten voor onderzoek van de ongeborene, heeft deze techniek een enorme invloed gehad op de dagelijkse praktijk in de verloskunde. Tot dan toe was uitwendig onderzoek van de zwangere buik de enige manier om foetale groei te bepalen. Informatie over de foetale conditie werd verkregen door het voelen van kindsbewegingen door de zwangere en het beluisteren van de foetale harttonen met behulp van een houten stethoscoop. Aanvankelijk werd echoscopie alleen gebruikt om de zwangerschapsduur vast te stellen, de ligging van het kind en de placenta te bepalen, of om een tweelingzwangerschap vast te stellen. Door het voortdurend verbeteren van de apparatuur werden het oplossend vermogen en de beeldkwaliteit steeds beter. Hierdoor nam de kennis over ontwikkeling en groei van foetale organen snel toe en werden toenemend foetale afwijkingen ontdekt. Heden ten dage is het opsporen van aangeboren afwijkingen een van de meest belangrijke redenen voor echoscopisch onderzoek in de zwangerschap. Bij 1 tot 2% van alle foetussen kan met behulp van echoscopie een ernstige of minder ernstige afwijking worden vastgesteld. Hiervan hebben 15 tot 20% betrekking op de urinewegen. In het begin van de jaren tachtig werd ongeveer 15% van alle nierafwijkingen tijdens de zwangerschap opgespoord, momenteel is dit ruim 90%. Dit percentage is zo hoog, omdat afwijkingen aan de urinewegen veelal gepaard gaan met vochtophoping in de nieren en vocht is met echoscopie goed te zien. Hierdoor kunnen afwijkingen, die meestal symptoomloos zijn in de zwangerschap, worden ontdekt zodat een behandelbeleid voor na de geboorte tijdig kan worden vastgesteld en nierschade zo veel mogelijk kan worden voorkomen. Bovendien hebben de ouders, in voorkomende gevallen, de mogelijkheid om de zwangerschap te laten afbreken, indien een niet met het leven verenigbare afwijking is aangetoond of afwijkingen die zo ernstig zijn dat zij de kwaliteit van leven ernstig aantasten. Hierbij moet men bijvoorbeeld denken aan het beiderzijds ontbreken van de nieren of aan beiderzijds multicysteuze nieren waarbij door een zeer vroege afsluiting een vochtophoping in beide nieren ontstaat waardoor het aanvankelijk gezonde nierweefsel te gronde gaat.

132 132 Chapter 9 In de voorbije decennia zijn vele onderzoeken verschenen over nierafwijkingen bij ongeborenen. Studies waarin langdurige vervolgonderzoek van deze kinderen worden beschreven zijn echter schaars. Hierdoor is het moeilijk om de ouders juist voor te lichten over wat er met hun kind aan de hand is en over de eventuele gevolgen met betrekking tot het verdere leven. Ook advisering omtrent de juiste behandeling na de geboorte wordt hierdoor bemoeilijkt. In het kader van dit proefschrift werden daarom de volgende studies gedaan: 1 Het vaststellen van grootte en groei van de foetale nier, het nierbekken en de bijnier in het verloop van de zwangerschap. 2 Het verzamelen van de lange termijn follow-up gegevens van een grote groep kinderen bij wie vóór de geboorte nierafwijkingen waren vastgesteld. 3 Onderzoek naar bijkomende afwijkingen bij kinderen bij wie vóór de geboorte een enkelzijdige multicysteuze nier is vastgesteld. 4 Het beantwoorden van de vraag of kinderen bij wie rond 20 weken zwangerschapsduur met echoscopie een lichte verwijding van het nierbekken (tussen de 5 en 10 mm) werd gezien, meer kans hebben op problemen aan de urinewegen op de kinderleeftijd, dan kinderen bij wie dit niet was waargenomen. 5 Het bestuderen van de relatie tussen de mate van verwijding van het nierbekken en de vulling van de foetale blaas. groeicurven van foetale nier, nierbekken en bijnier Groeicurven van foetale organen zijn van belang als een afwijking wordt vermoed. Eerdere groeicurven van foetale nieren vertoonden veelal beperkingen zoals: het niet nauwkeurig bepalen van de duur van de zwangerschap met een vroege echoscopie, alleen curven voor het tweede en derde trimester van de zwangerschap, bepaling van uitsluitend de lengte van de nier, of ontwikkeling van de groeicurven op basis van metingen gedaan bij te vroeg geboren kinderen of met de nieren van overleden kinderen. In hoofdstuk 2 wordt een zogeheten intra- en interobserver variantie analyse beschreven, die is uitgevoerd om vast te stellen of herhaalde metingen gedaan door één persoon tot dezelfde resultaten leiden èn of er een goede overeenkomst is tussen de metingen gedaan door twee echoscopisten. De afmetingen van nier en

133 Nederlandse samenvatting 133 bijnier blijken door één persoon consistent gemeten te worden en de overeenkomst tussen de metingen van twee onderzoekers was groot. Hoofdstuk 3 en 4 beschrijven de longitudinale onderzoeken waarbij de grootte en groei van lengte, voorachterwaartse diameter en dwarse diameter van de foetale nier en van de voorachterwaartse en dwarse diameter van het nierbekken en de lengte van de bijnier zijn bepaald. Bij 111 zwangeren werden deze afmetingen iedere vier weken gemeten waarbij alle metingen drie maal achterelkaar werden gedaan. Bij de ene helft van de zwangeren startte dit onderzoek bij 16 weken en bij de andere helft bij 18 weken zwangerschapsduur. Omdat de verzamelde gegevens een groot aantal foetussen betreffen, die herhaaldelijk in de zwangerschap werden gemeten, kunnen de verkregen curven gebruikt worden om de groei van de organen te meten maar ook om tijdens de zwangerschap te beoordelen of de grootte overeenkomt met de zwangerschapsduur. De statische berekeningen werden gedaan met behulp van de multilevel analysis. Dit is een recent ontwikkelde methode die corrigeert voor ontbrekende data èn berekeningen kan doen met gegevens die van elkaar afhankelijk zijn. De curven voor linker en rechter nier, linker en rechter nierbekken en linker en rechter bijnier bleken nagenoeg identiek. De uiteindelijke curven werden dan ook gemaakt op basis van de gemiddelde gegevens van links en rechts. Het vergelijken van onze niercurven met eerdere studies was moeilijk vanwege de genoemde gebreken in de opzet van die studies. Daar waar vergeleken kon worden bleken onze curven een aanzienlijk geringere spreiding te hebben ten opzichte van de 50 ste percentiel-lijn. De reden hiervan is vermoedelijk het grote aantal door ons geïncludeerde foetussen en het feit dat wij gemiddelde waarden gebruikten van drie achtereenvolgende metingen. Voor de bijniercurve was er geen mogelijkheid om deze te vergelijken met eerdere studies. Er werd een lineair verband gevonden tussen de lengte van de bijnier en de nier met een verhouding van 2 tot 7. Deze bevinding kan gebruikt worden bij het vermoeden op vergrote nieren ten gevolge van een afwijking, of bij aandoeningen waarbij de bijnier te groot of te klein is.

134 134 Chapter 9 afwijkingen aan urinewegen In hoofdstuk 5 beschrijven we de bevindingen en follow-up van 402 foetussen bij wie prenataal afwijkingen aan de urinewegen waren vastgesteld. Er werd gebruik gemaakt van de database van de afdeling obstetrische echoscopie van het Universitair Medisch Centrum in Utrecht. Tijdens het na-onderzoek was de gemiddelde leeftijd van deze kinderen bijna 8 jaar (spreiding 3 tot 17 jaar). Er werd onderscheid gemaakt tussen structurele afwijkingen en afwijkingen tengevolge van uitzetting van de nieren en urinewegen omdat deze afwijkingen een verschillende ontstaanswijze kennen. De bedoeling was om inzicht te krijgen in de prognose voor en de uiteindelijke uitkomst van deze kinderen. Van de 402 foetussen hadden 151 een structurele afwijking, 247 een uitzetting van nieren en/ of urinewegen en 4 een afwijking zonder invloed op de functie van de nier. In totaal overleden ruim 25% van de foetussen als gevolg van de afwijking aan de urinewegen. Van de overlevende kinderen met een structurele afwijking had ongeveer 80% een enkelzijdige multicysteuze nier, waarvan een kwart een bijkomende afwijking had aan de andere nier. De Nederlandse kinderurologen adviseren de aangedane nier te verwijderen. Dit betreft een relatief kleine ingreep die meestal verricht wordt rondom de leeftijd van 6 maanden en veelal slechts één dag opname vereist. Tot verwijdering van de nier wordt overgegaan nadat met een renogram is aangetoond dat er inderdaad geen functie meer is in de aangedane nier. Een renogram is een functieonderzoek van de nieren met radioactieve isotopen waarbij door de uitscheiding van deze isotopen de functie van de nier kan worden bepaald. Het voordeel van een dergelijke ingreep is dat geen levenslange follow-up meer noodzakelijk is om de bloeddruk te meten vanwege een kans op verhoogde bloeddruk en om het nierrestant te onderzoeken op een mogelijke eventuele kwaadaardige ontwikkeling. Tot de onderzoekspopulatie met een structurele afwijking behoorden verder twee kinderen, die beiderzijds dysplastische nieren hadden. Dysplasie is een ontwikkelingsstoornis van het nierweefsel waardoor dit slecht functioneert. Het ene kind krijgt buikdialyse en het andere heeft een gestoorde nierfunctie. Bij de kinderen met een verwijding van de nieren en urineleiders kwam deze afwijking ongeveer even vaak een- als tweezijdig voor. Ruim de helft van de kinderen

135 Nederlandse samenvatting 135 had een enkel- of dubbelzijdige verwijding van het nierbekken terwijl de overigen ook afwijkingen hadden aan de urineleiders en/ of blaas. Bijna de helft van de kinderen (n=107) werd geopereerd en bij hen werden in totaal 315 ingrepen verricht. Alle kinderen met afsluitende kleppen in de plasbuis werden geopereerd evenals 87% van de kinderen met reflux (terugstroom van urine vanuit de blaas naar het nierbekken tijdens het plassen). Bij 21 kinderen werd de bevalling vóór 37 weken zwangerschapsduur ingeleid, omdat er naast een toenemende uitzetting van het nierbekken een sterke afname van de hoeveelheid vruchtwater plaatsvond. Afname van de hoeveelheid vruchtwater bij deze kinderen wijst meestal op afname van de foetale mictie (hoeveelheid urine in het vruchtwater geloosd) en daarmee op een afname van de nierfunctie. Al deze kinderen werden binnen enkele dagen na de geboorte geopereerd. Zes van hen hebben een verminderde nierfunctie en één kind heeft een hoge bloeddruk. Tijdens de follow-up van alle 402 kinderen met een prenataal gediagnosticeerde nierafwijking, bleek dat 9 van de 281 levende kinderen een gestoorde nierfunctie hadden, waaronder één jongen een niertransplantatie heeft ondergaan en één meisje wordt behandeld met buikdialyse. Drie kinderen hebben een verhoogde bloeddruk. Geconcludeerd kan worden dat, kinderen met een vóór de geboorte vastgestelde nierafwijking, 25% kans hebben om voor of na de geboorte te overlijden. Als aan de overlevende kinderen na de geboorte goede zorg gegeven wordt is de prognose, ongeacht of een of beide nieren zijn aangedaan en ongeacht de ernst van de eventuele verwijding van de urinewegen, goed. Uitzondering vormt de groep met een sterke afname van de hoeveelheid vruchtwater. In hoofdstuk 6 wordt een groep van 100 kinderen besproken die allen een prenataal vastgestelde enkelzijdige multicysteuze nier hadden. De gegevens werden verkregen van de afdeling obstetrische echoscopie en van de afdeling kinderurologie van het Wilhelmina Kinderziekenhuis te Utrecht. Uit de literatuur is bekend dat deze kinderen vaak bijkomende afwijkingen hebben aan de overige urinewegen; reden waarom het gehele kind tijdens het echoscopisch onderzoek goed nagekeken dient te worden als een multicysteuze nier wordt gediagnostiseerd.

136 136 Chapter 9 Wij vonden bij 75% van deze kinderen een bijkomende afwijking. Dit is veel hoger dan de 21 tot 57% die in de literatuur wordt vermeld. Achtenveertig procent had een afwijking aan de andere nier (literatuur: 13 tot 39%). Aan de primair aangedane nier werd in 48% van de kinderen nog een bijkomende afwijking gevonden (literatuur: 4 tot 14%) en aan het lagere urogenitale stelsel in 33% van de gevallen (literatuur: 4 tot 6%). Een gedeeltelijke verklaring voor deze door ons gevonden hoge incidenties in vergelijking met de literatuur, vormt de in ons onderzoek routinematig uitgevoerde cystoscopie (onderzoek van de blaas en plasbuis) bij alle kinderen en daarnaast nog een colposcopie (onderzoek van de vagina en baarmoedermond) bij meisjes voorafgaand aan de operatie waarbij de nier werd verwijderd. Deze onderzoeken zijn eenvoudig uitvoerbaar en weinig belastend bij het kind dat al onder narcose is. Bij cystoscopie werden 54 afwijkingen gevonden bij 48 kinderen. Hierbij betrof het meestal een ectope ureter (een niet in de blaas eindigende urineleider) of een vernauwing van de plasbuis. Bij de colposcopie bij de meisjes werden 3 afwijkingen gevonden: eenmaal meerdere afwijkingen aan de inwendige geslachtsorganen waaronder een afwezige vagina, eenmaal een afgesloten maagdenvlies en eenmaal een ectope ureter die in de vagina uitmondde waardoor het meisje grote kans had onophoudelijk nat te zijn als deze afwijking niet gevonden was. pyelectasie = milde verwijding van het nierbekken In hoofdstuk 7 wordt een onderzoek beschreven naar het voorkomen van urinewegproblemen op kinderleeftijd bij kinderen, bij wie tijdens een echoscopisch onderzoek bij ongeveer 20 weken zwangerschapsduur een pyelectasie, een milde verwijding tussen de 5 en 10 mm, gevonden was van één of beide nierbekkens. Er werd gebruik gemaakt van de echoscopieverslagen van het Amphia ziekenhuis in Oosterhout. Aldaar is gebruikelijk om patiënten, bij wie tijdens de 20-weken echoscopie een pyelectasie wordt gezien, een herhaling van dit onderzoek te adviseren bij ongeveer 32 weken zwangerschapsduur. Als de verwijding groter is dan 10 mm wordt de zwangere verwezen naar een tertiair centrum voor nader onderzoek. Aldaar krijgt zij tevens een advies voor onderzoek en/ of behandeling van het kind na de geboorte. De andere patiënten krijgen het advies geen verder onderzoek te laten doen in de zwangerschap en na de geboorte, onafhankelijk van het feit of de pyelectasie bij 32 weken nog wel of niet meer aanwezig was. Hen wordt

137 Nederlandse samenvatting 137 uitgelegd dat kinderen bij wie een pyelectasie is gezien mogelijk een hoger risico hebben op reflux en dat als hun kind lusteloos of koortsig is zonder duidelijk aanwijsbare reden zij de huisarts moeten vragen de urine na te kijken om een eventuele urineweginfectie te kunnen behandelen. Deze studie toonde aan dat 4,6% van de ruim 4500 onderzochte kinderen een enkelof dubbelzijdige milde pyelectasie had bij 20 weken zwangerschapsduur (literatuur: 0,6 tot 5,5%). De spreiding in de literatuur is het gevolg van het gebruik van verschillende definities met betrekking tot verwijding van het nierbekken en van het meten op verschillende tijdstippen in de zwangerschap. Over de klinische betekenis van milde pyelectasie heerst nog veel onduidelijkheid. Er is overeenstemming dat pyelectasie kan verergeren tot obstructie van het nierbekken of een uiting kan zijn van reflux. Het is echter ook mogelijk dat de pyelectasie restloos verdwijnt. Sommige onderzoekers adviseren om al deze kinderen na de geboorte laaggedoseerde antibiotica te geven en hen te onderzoeken met een mictiecystogram (onderzoek met contrastvloeistof in de blaas onder röntgendoorlichting) om reflux uit te sluiten, terwijl andere een verwijding tot 10 mm als fysiologisch beschouwen. Wij vergeleken twee groepen kinderen, één groep van 208 kinderen met een een- of tweezijdige pyelectasie van 5 tot 10 mm tijdens de echoscopie rondom 20 weken zwangerschap en een groep van 416 controle kinderen zonder deze afwijking. De kinderen die werden geselecteerd waren tussen 4 en 9 jaar oud omdat zij zindelijk moesten zijn om de vragen van de vragenlijsten te kunnen beantwoorden. De ouders kregen een gestandaardiseerde vragenlijst toegezonden waarin gevraagd werd naar plasgedrag, urine incontinentie, urineweginfecties, bedplassen en ontlastingspatroon van het kind. Ruim 70% van de ouders van de kinderen met pyelectasie en 60% van de controlegroep stuurden de vragenlijsten terug. Het bleek dat jongens significant vaker vóór de geboorte een pyelectasie hadden dan de meisjes. Er was geen verschil in de incidentie van urineweginfecties en plasgedrag. Wel werd in beide groepen een hoger percentage urineweginfecties gevonden dan beschreven is in de literatuur en in een onderzoek van het RIVM onder huisartsenpraktijken. Dit hogere percentage is ook gevonden in een andere studie van onze onderzoeksgroep en wordt mogelijk verklaard door het feit dat de vragenlijsten zeer gedetailleerd naar plasgedrag en stoelgang vragen. Een andere mogelijkheid is misschien dat huisartsen in de onderzoeksregio sneller urine onderzoeken op een infectie, omdat

138 138 Chapter 9 zij daar expliciet om gevraagd worden zulks te doen conform het advies dat aan de ouders is gegeven en daardoor misschien ook eerder de urine nakijken bij kinderen vanuit de controle groep als die met onbegrepen klachten op het spreekuur komen.. Ondanks het advies het kind na de geboorte niet te laten onderzoeken werd dit bij ruim 30% van de kinderen toch gedaan. Meestal betrof het vrouwen die in het ziekenhuis bevallen waren en waarvan het kind door de kinderarts gecontroleerd was waarbij melding werd gemaakt van de bevinding van pyelectasie in de zwangerschap. Van al deze kinderen maakten slechts drie een urineweginfectie door. Eén kind werd geopereerd op de leeftijd van drie jaar omdat het nierbekken verder verwijdde en de nierfunctie verslechterde. Slechts één kind vertoonde een geringe reflux die spontaan verdween. Op grond van dit onderzoek kan geconcludeerd worden dat als een enkel- of dubbelzijdige pyelectasie wordt gezien tijdens de echoscopie bij 20 weken zwangerschapsduur het onderzoek herhaald dient te worden rondom de 32 e week. Alleen als de pyelectasie meer dan 10 mm bedraagt dient de zwangere verwezen te worden (in dit onderzoek bij 9% van de vrouwen; deze groep maakte overigens geen deel van het huidige onderzoek uit). De andere ouders dient geadviseerd te worden dat, indien hun kind hangerig of koortsig is zonder duidelijk aanwijsbare reden, zij de huisarts moeten vragen urine van het kind na te kijken om een eventuele urineweginfectie te kunnen diagnosticeren en zonodig te behandelen om nierschade te voorkomen. In hoofdstuk 8 werd onderzocht of er een relatie bestond tussen een verwijding van het nierbekken en de vulling van de blaas. Bij het doen van echoscopisch onderzoek was het regelmatig opgevallen dat de uitzetting van het nierbekken gedurende het onderzoek wisselde. Omdat vervolgonderzoek in de zwangerschap of na de geboorte meestal is gebaseerd op één enkele meting van het nierbekken is het van belang of deze relatie inderdaad aanwezig is. Achttien zwangeren werden onderzocht bij wie bij het echoscopisch onderzoek rondom 20 weken zwangerschapsduur een enkel- of dubbelzijdige foetale pyelectasie werd gezien. Bij de herhalingsechoscopie bij 32 weken was de verwijding niet tot meer dan 10 mm

139 Nederlandse samenvatting 139 toegenomen. Tijdens het onderzoek waren de patiënten 37 à 38 weken zwanger omdat aan het einde van de zwangerschap foetussen een lange blaasvullings/ ledigingscyclus hebben, die gerelateerd is aan foetale gedragstoestanden. Bij eenderde van de onderzochte foetussen werd een relatie gevonden tussen de mate van verwijding van het nierbekken en de vulling van de blaas. Bij deze subgroep was het gemiddelde verschil in de verwijding van het nierbekken bij volle of lege blaas 6,7 mm, en bedroeg het grootste gemeten verschil 14,3 mm. Uit dit onderzoek concluderen wij dat in geval van foetale milde pyelectasie, niet volstaan kan worden met één enkel meetmoment, maar dat tijdens het onderzoek meerdere keren gemeten dient te worden, bij voorkeur binnen een kwartier voor en na leegplassen. Anderzijds houdt dit onderzoek in dat een eenmalige normale bevinding een milde pyelectasie (een half uur later) niet uitsluit. conclusie Afwijkingen aan de foetale urinewegen kennen een hoge mortaliteit. Overlevende kinderen hebben echter slechts een geringe kans op blijvende schade indien de juiste diagnose in de zwangerschap wordt gesteld en indien deze kinderen na de geboorte goede urologische opvang hebben. Het is van belang dat kinderartsen en urologen bekend zijn met de adviezen die gegeven worden indien prenataal afwijkingen aan de urinewegen worden vastgesteld, omdat zij na de geboorte hieromtrent vaak geconsulteerd zullen worden.

140 140 Chapter 9 Dankwoord Ik wil graag al diegenen bedanken zonder wie dit proefschrift niet tot stand was gekomen. Hun inzet en steun waren van onschatbare waarde. Allereerst gaat heel veel dank naar alle 1316 zwangeren, bij wie tijdens 3091 consulten metingen werden verricht ten behoeve van alle onderzoeken die beschreven zijn in dit proefschrift. Deze vrouwen deden geheel belangeloos mee, soms moeizaam liggend, gedurende vaak urenlange onderzoeken maar tegelijkertijd veel interesse tonend in het onderzoek en blij dat zij mee konden doen ten behoeve van andere toekomstige moeders en kinderen. Dr. G. H.A. Visser Gerard, ik ben je onbenoembaar dankbaar dat je mij de gelegenheid hebt geboden onderzoek te gaan doen. Je zei erbij Als het een beetje goed gaat, mag je van mij promoveren. Ik was perplex. Jouw stimulans, opbouwende kritiek en waardevolle adviezen hebben me enorm gestimuleerd vooral als ik het eens niet zag zitten. Je straalde het uit en ging er ook van uit dat ik het een en ander tot een goed einde zou brengen. En ziedaar het proefschrift is klaar. Dank voor je vertrouwen in me. Dr. P.H. Stoutenbeek Philip, jouw database, opgestart in een fase van de IT dat dit nog niet zo gewoon was, vormt een belangrijk deel van dit proefschrift. Dank dat ik van al die gegevens gebruik mocht maken. Je kritische beoordeling en suggesties waren een waardevolle en welkome aanvulling van het manuscript. Ik denk met plezier terug aan al de jaren dat ik bij jou op de echokamer werkte. Dr. T.P.V.M. de Jong Tom, jij was degene die de basis hebt gelegd voor wat betreft mijn kennis van de foetale nieren. Altijd gaf je uitgebreid uitleg en was je behulpzaam met adviezen als ik weer eens vragen had met betrekking tot patiënten uit Oosterhout. Onbewust, heb jij daardoor aan het begin van dit proefschrift gestaan. Tom, jouw aanmoediging, het vaak even langs komen, hoe gaat het ermee? zijn voor mij een grote steun en stimulans geweest. Nooit was je iets teveel, je las manuscripten razendsnel en had altijd opbouwend kritiek hetgeen me grote steun gaf. Dank je wel.

141 Dankwoord 141 Dr. R.H. Stigter Rob, veel dank ben ik jou verschuldigd. Allereerst dat je me uitnodigde op jouw kamer om aan dit proefschrift te gaan werken. Ik heb dat enorm gewaardeerd. Van jou heb ik geleerd wetenschappelijk te gaan denken, vaak via losse opmerkingen van je die me tot denken aanzetten en op het goede spoor brachten. Maar vooral ben ik je dank verschuldigd door je kritische beoordeling van de diverse artikelen en natuurlijk je onmisbare hulp bij de correctie tot wetenschappelijk en leesbaar engels. Met groot genoegen denk ik terug aan onze gezamenlijke jaren op de echokamer en prenatale prik spreekuren. Drs. L.R. Pistorius Lou, sinds een klein jaar zijn we kamergenoten en hebben heel wat afgekletst. Ik dank je voor deze gezellige tijd. Het was heerlijk een native speaker naast me te hebben voor een lastig engels woord of uitdrukking. Samen hebben we de metingen voor de interobserver variatie in een sneltreinvaart afgerond. Je deed het naast je normale werk en ik kon je altijd bellen als een zwangere was gestrikt om mee te doen aan het onderzoek. Veel dank hiervoor. Dr. P. Westers Paul, jij was mijn steun en toeverlaat bij de statistische berekeningen. Voor mij vaak een abracadabra waarmee jij me vertrouwd hebt gemaakt en geholpen. Je beantwoordde altijd razendsnel per mail de vragen die ik op je afvuurde, hetgeen bijzonder aangenaam was als ik weer eens vastzat. Je hebt een humor die de vaak droge statistiek verteerbaar maakt. Dank voor alles.. Mevrouw M.J. Korenromp Marijke, ik ben heel blij dat je mijn paranimf wilt zijn. We kennen elkaar van de opleiding en waren dit jaar 40 jaar vroedvrouw! In al die jaren hebben we samen veel meegemaakt. Je was altijd een enorme steun voor me in moeilijke tijden en ik ben blij dat jij mijn vriendin bent. Drs. P.J. Damen, Pieter Jan, het geeft een bijzonder en trots gevoel dat jij tijdens de promotie naast me staat. Mijn jongste zoon die ook het medische vak is ingegaan en mijn paranimf wil zijn. Dank je wel.

142 142 Chapter 9 Verder dank ik alle familieleden en vrienden voor de interesse die zij getoond hebben de afgelopen jaren. Sommigen hoofdschuddend: Dat je dat leuk vindt! Waar begin je aan? Ga met de VUT! Anderen ook met bewondering : echt iets voor Hen! Maar van iedereen was er steun en aandacht. Dank jullie wel. En natuurlijk gaat heel, heel veel dank naar het thuisfront. Naar mijn man, Albert, die ik dank voor zijn onvoorwaardelijke geduld en steun. Ik kon altijd mijn verhaal kwijt van dit voor hem vaak onbegrijpelijke onderzoek. Ik hoop dat we nog vele jaren samen mogen delen. Veel te danken heb ik aan mijn kinderen, Annette, Albert jr. en Pieter Jan, die indien nodig altijd klaar staan om te helpen en steunen waar maar nodig is. Ik ben trots op jullie. En jullie kunnen me niet meer plagen want de enige HBO-er in het gezin verslaat jullie nu in één klap! Verder dank ik jullie partners, die wat meer vanaf de zijlijn toezien maar door hun aandacht en interesse veel steun gaven. En last but not least mijn twee kleinzonen, Joost en Ties. Oma is blij met jullie en nu kunnen jullie nog vaker komen logeren.

143 Curriculum vitae 143 Geboren 27 mei 1941, te Tegelen HBS-b, 1961, Sint Bonifacius Lyceum, Utrecht opleiding van Verloskundigen, , Vroedvrouwenschool, Heerlen Verloskundige, , Privé-kliniek: Dr.Bohler te Luxemburg, Luxemburg Verloskundige, , Sint Joseph ziekenhuis, Eindhoven. Aanvankelijk werkzaam op de verloskamers en polikliniek, later speciaal belast met het maken van een jaarverslag van de afdeling, verloskunde, gynaecologie en fertiliteit. Verloskundige echoscopiste, , Pasteur Ziekenhuis, Oosterhout N-Br. Verloskundige echoscopiste, 1989 nov. 1999, UMCU, Utrecht Verloskundige onderzoeker, nov , UMCU, Utrecht , Lid Commissie Ultrageluid, Koninklijke Nederlandse Organisatie van Verloskundigen (KNOV) 1985 heden, bestuurslid Werkgroep Foetale Echoscopie van de Nederlandse Vereniging voor Obstetrie en Gynaecologie! , lid van het hoofdbestuur van de KNOV , voorzitter van de afdeling Noord Brabant van de KNOV , gedelegeerde Stuurgroep Toekomst Scenario s Gezondheidszorg namens de KNOV , lid Subwerkgroep Echoscopisch Onderzoek van het Verloskundig Overleg bij de Ziekenfondsraad namens de KNOV ten behoeve van het Verloskundig Vademecum, uitgave 1 en heden, initiator en cursusmanager van de Cursus Echoscopie voor verloskundigen werkzaam in de eerste lijn.