CORRELATION BETWEEN THE SONOGRAPHIC MEASUREMENT OF THE FETAL ILIAC ANGLE AND USUAL FETAL ANEUPLOIDIES. Ph.D. THESIS

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1 CORRELATION BETWEEN THE SONOGRAPHIC MEASUREMENT OF THE FETAL ILIAC ANGLE AND USUAL FETAL ANEUPLOIDIES Ph.D. THESIS Fetal and neonatal medicine Ph.D. programme Author: Zorán Belics, M.D. Supervisor: Zoltán Papp, M.D., Ph.D., D.Sc. Program director: Zoltán Papp, M.D., Ph.D., D.Sc. Semmelweis University I. Department of Obstetrics and Gynecology Budapest, 2005

2 INTRODUCTION There are several methods used in prenatal screening for fetal aneuploidy and a number of factors are taken into account to determine which method should be used. Different sonographic markers for trisomy 21, 18 and 13 have been described. With the using of these sonographic markers, there is a real opportunity to decrease the prevalence of neonates born with chromosomal aberration, but the prenatal screening of fetal aneuploidies is still unresolved. Accordingly, the quests for new facilities are important. The aim of present dissertation was to determine whether sonographic measurement of the fetal iliac angle can be useful in the prenatal detection of trisomy 21, 18 and 13 during the first and second trimester of pregnancy. AIMS 1. To review experiences with the sonographical measurement of the fetal iliac angle in fetuses with trisomy 21, 18 and 13: a) Process of the measurement b) Method of the ultrasound examination 2. To investigate reliability of the screening method in prenatal ultrasound screening of the a) trisomy 21, b) trisomy 18 and c) trisomy 13. 1

3 3. To determine the value of the fetal iliac angle which shows the best results in the antenatal sonographic screening of the fetal aneuploidy 4. To examine the values of the iliac angle measured fetuses of different gestational age 5. To determine the earliest gestational time when the measurement of the iliac angle is possible 6. To examine the values of the iliac angle measured in female and male fetuses 7. To define the reproducibility of the examination 8. To determine the optimal level of the fetal pelvis where the measurement can be performed 9. To review the actual limitations of the method MATERIAL AND METHODS Fetal iliac angle measurements were performed in 1928 first and second trimester fetuses at the Semmelweis University, I. Department of Obstetrics and Gynecology, between 1999 and The measurement was taken from a transverse section of the fetal pelvis, which was photo documented during each examination. Between 1999 and 2002 in the printed photos with elongation of the iliac bone, the iliac wing angles were measured with a protractor. Between 2002 and 2004, recent internal measurement packages have made this measurement possible during a real time scan of the pelvis. On the prospective investigation the results of the measurements, the gestational- and maternal age were compared among fetuses with trisomy 21, 18 and 13 and euploid fetuses. 2

4 I determined the specificity, sensitivity, and positive and negative predictive values for 70 o, 75 o, 80 o, 85 o, 90 o, 95 o, 100 o, 105 o and 110 o thresholds and a ROC curve was obtained. Statistical analysis included descriptive statistics and Student s t-test, as apropriate. Statistical results were considered significant when p< In 43 cases the iliac angle was measured independently by two examiners (included the examiner). The interobserver reproducibility was determined by statistical analysis, included variations of coefficient, Bland-Altman test and the Student s t-test. The Student s t-test was used to compare the mean iliac angle between female and male healthy fetuses (n=75). Similarly Bland-Altman test and Student s t-test was used to compare the mean iliac angle between 44 euploid fetuses in different gestational age (first versus second trimester). Statistical results were considered significant when p< RESULTS Of the 1928 fetuses 1836 (95.23%) fetuses had adequate images of the pelvic bones for satisfactory measurements of the iliac wing angle. 92 (4.77%) control fetuses were excluded from the investigation. Of the 1836 fetuses 1754 (95.53%) were healthy and 82 (4.47%) had chromosome aberrations: trisomy 21 (n=50), trisomy 18 (n=16), trisomy 13 (n=11), or other chromosomal aberrations (n=5). Of the fetuses with chromosomal aberrations, only the fetuses with trisomy 21, 18 and 13 were included in the investigation. 3

5 The mean maternal age was years (range: 15-46; ±SD 7.07) in cases with trisomy 21 fetuses, 44 years (range: 26-45, ±SD 6.80) in cases with trisomy 18, 33.9 years (range: 27-44; ±SD 6.49) in cases with trisomy 13, and years (range: 15-49; ±SD 5.27) in the control group. The mean gestational age at the time of sonographic examination was: - healthy fetuses: weeks (range: ; ±SD 3.17), - trisomy 21: weeks (range ; ±SD 2.51), - trisomy 18: weeks (range: 14-23; ±SD 2.29) - trisomy 13: weeks (range: ; ±SD 2.12). In the normal fetuses the mean iliac wing angle was o (range: o ; ±SD 14.25). The mean iliac wing angle in the fetuses with trisomy 21 was o ( o ; ±SD 14.50). The mean iliac angle in fetuses with trisomy 18 and 13 was o ( o ; ±SD 25.11) and o ( o ; ±SD 16.56). Values detected in fetuses with trisomy 21 were significantly higher than those seen in normal fetuses (p<0.001). Values observed in fetuses with trisomy 18 and 13 were not significant different than those seen in normal fetuses (p = and p = 0.043). I compared the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of 70 o, 75 o, 80 o, 85 o, 90 o, 95 o, 100 o, 105 o and 110 o thresholds for fetuses with trisomy 21, trisomy 18 and trisomy 13 (table 1). 4

6 Table 1. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of different thresholds for fetuses with A) trisomy 21, B) trisomy 18 and C) trisomy 13. FPR: false positive rate. 1/A Trisomy Sensitivity Specificity PPV NPV FPR /B Trisomy Sensitivity Specificity PPV NPV /C Trisomy Sensitivity Specificity PPV NPV Consequently, I found that the optimum threshold for detection of trisomy 21 is an iliac wing angle of 90 o, but an angle of 85 o also showed good results. 5

7 On the corresponding ROC curve, using a cutoff iliac angle above 90, 60% of trisomy 21 fetuses were detected (sensitivity 60%), with a false-positive rate (FPR) of 2.85% (specificity 97.15%), and a PPV of 37.50%, and a NPV of 98.84%. The interobserver variability was small, no statistically significant difference in iliac angle measurement was found between two examiners. No statistically significant difference in iliac angle measurement was found between female and male fetuses with normal karyotype. There was no statistically significant relationship between gestational age and iliac angle measurement results in healthy fetuses. CONCLUSIONS 1/a. I concluded that the measurement of the iliac angle can be performed only on the transverse section of the fetal pelvis 1/b. The examination can be performed through transvaginal and transabdominal sonography 2/a. Iliac angle in fetuses with trisomy 21 is significantly wider than in euploid fetuses 2/b. Using the present results, the sonographic measurement of the fetal iliac angle can not be used as a marker for trisomy 18. There was no significant difference between the iliac angle measured in fetuses with trisomy 18 and healthy fetuses 2/c. There was no significant difference between the iliac angle measured in fetuses with trisomy 13 and healthy fetuses. Using the present results, the sonographic measurement of the fetal iliac angle can not be used as a marker for trisomy 13 6

8 3. The specificity and sensitivity of the cut-off level of 90 degrees is 60.00% and 97.15% respectively, however in case of using 85 degrees as a cut-off angle the specificity and sensitivity is 72.00% and 92.36% respectively 4. There was no significant difference between angle values measured in euploid fetuses in different gestational age (first vs. second trimester) 5. Iliac angle measurement can be performed at the 11 th week of gestation at the earliest 6. No significant difference could be observed between angle values measured in female and male euploid fetuses 7. The interobserver variability was 9.1 and there was not significant difference between results measured by different examiners 8. The iliac wing angle measurement results are different in different levels of the fetal pelvis. A prospective study measuring angles at different iliac levels is needed to identify the most efficacious level on the fetal bony pelvis to obtain the iliac wing angle measurement. The advisable level, in my judgment, is the mild transverse level of the fetal bony pelvis 9. The sonographical measurement of the fetal iliac angle has the following limitations:? The sensitivity and specificity depends on the level of the fetal pelvis? The phenomenon of virtual deformation of the fetal bony pelvis influences the results? The measurement of the iliac angle is not always possible, especially when the fetuses are in poorly accessible positions, or the fetus is in oligohydramnios, or the mother have crass fatty abdominal wall 7

9 Peer reviewed articles in the topic 1. Belics Z., Csabay L., Szabó I., Barakonyi E., Német J., Papp Z. (2000) Sonographic measurement of the fetal iliac angle as a marker for trisomy 21. Fetal Diagn Ther 15, Belics Z., Csabay L., Szabó I., Barakonyi E., Német J., Siposné Radványi Zs., Pászkányné Jenei K., Hozsdora A. (2000) A medencecsontok (os ilii) által bezárt szög mérésének jelentosége a Down syndroma szurésében. Magy Noorv L 63, Belics Z. (2003) Sonographic measurement of the fetal iliac angle and fetal nasal bone length: markers for trisomy 21 in the second trimester. Ultrasound Rev Obstet Gynecol 3, Belics Z., Beke A., Csabay L., Szabó I., Papp Z. (2003) Mesure de l angle iliaque foetal pour les trisomies 21, trisomies 18 et trisomies 13. Journal Mensuel D Echographie 7/8, Be lics Z., Beke A., Csabay L., Szabó I., Papp Z. (2003) Sonographic measurement of the fetal iliac angle in trisomy 21, 18 and 13. Fetal Diagn Ther 18, Belics Z., Csabay L., Beke A., Szabó I., Fekete T., Papp Z. (2003) Az ossa ilii által bezárt szög mérésével szerzett tapasztalataink a 18- as trisomia ultrahag-szurésében. Magy Noorv L 66, Belics Z., Csabay L., Szabó I., Beke A., Fekete T., Halmos A., Papp Z. (2004) Prenatal sonographic measurement of the fetal iliac angle during the second trimester of the pregnancy. In Papp Z., Rodeck C. (ed.) Recent advances in prenatal genetic diagnosis. Medimond International Proseedings,

10 8. Belics Z., Papp Z. (2005) Ultrasound markers of aneuploidy int he first trimester. In Kurjak A., Arenas J.B. (ed.) Donald School Textbook of Transvaginal Sonography. Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, Peer reviewed articles not related to the topic 1. Inovay J., Sztanyik L., Dévényi N., Hidvégi J., Szendei Gy., Belics Z. (1996) Polycystás ovarium syndroma laparoszkópos kezelése. Kezdeti eredményeink és tapasztalataink. Magy Noorv L 59, Belics Z., Csabay L., Szabó I., Joó J. (1997) Köldökzsinórcysta a terhesség elso trimeszterében. Lege Aartis Medicinae 7, Inovay J., Ádám Zs., Belics Z., Papp Z. (1997) Myoma-enucleatio szerepe az infertilitás kezelésében. Magy Noorv L 60, Hajdú J., Marton T., Tóth-Pál E., Cesko I., Hruby E., Belics Z., Papp Z. (1998) Súlyos bal szívfél fejlodési rendellenesség és súlyos magzati arrhythmia egyazon családban - véletlen társulás? Orv Hetil 139, Belics Z. (2001) A magazat thoraco-abdominalis rendellenességei. In Tóth Z., Papp Z. (szerk.) Szülészet-nogyógyászati ultrahangdiagnosztika. White Golden Book, Budapest, Szabó I., Csabay L., Belics Z., Fekete T., Papp Z. (2002) A méh vérkeringésének transvaginalis színes Doppler-ultrahangvizsgálata méhen kívüli terhességben. Magy Noorv L 65, Belics Z., Csapó Zs., Szabó I., Pápay J., Szabó J., Papp Z. (2003) Large gastrointestinal stromal tumor presenting as an ovarian tumor. J Reprod Med 48,

11 8. Szabó I., Csabay L., Belics Z., Fekete T., Papp Z. (2003) Assessment of uterine circulation in ectopic pregnancy by transvaginal color Doppler. Eur J Obstet Gyn Reprod Biol 106, Belics Z., Papp Z. (2003) Ovariumtumor klinikai képét utánozó, a colon transversumból kiinduló gastrointestinalis stromatumor. Szende B., Schaff Zs., Zalatnai A. (szerk.) Klinikopatológiai esettanulmányok Medicina, Budapest, Joó J.G., Tóth Z., Beke A., Papp Cs., Tóth-Pál E., Belics Z., Szigeti Zs., Papp Z. (2004) A ventriculomegalia/hydrocephalus kóreredete 230 prenatalisan diagnosztizált eset kapcsán I. Magy Noorv L 67, Joó J.G., Tóth Z., Beke A., Papp Cs., Tóth-Pál E., Belics Z., Szigeti Zs., Papp Z. (2004) A ventriculomegalia/hydrocephalus kóreredete 230 prenatalisan diagnosztizált eset kapcsán II. Magy Noorv L 67, Beke A., Joó J.G., Csaba Á., Papp Cs., Tóth-Pál E., Bán Z., Belics Z., Fekete T., Barakonyi E., Papp Z. (2004) Ultrasound minor and major anomalies detected in fetus with aneuploidies in second trimester. In Papp Z., Rodeck C. (ed.) Recent advances in prenatal genetic diagnosis. Medimond International Proseedings, Belics Z. (2005) A magzatvíz körfolgalmának zavarai. Rigó J. Jr., Papp Z. (szerk.) A várandós no gondozása. Medicina, Budapest, Abstracts it the topic I. Belics Z., Csabay L., Beke A., Szabó I., Papp Z. (2002) Sonographic measurement of the fetal iliac angle: a new marker for the prenatal detection of trisomy 21? Fetal Diagn Ther 17S,

12 II. Belics Z., Csabay L., Beke A., Szabó I., Papp Z. (2002) Felhasználható-e az ossa ilii által bezárt szög mérése a 21-es trisomia ultrahangszurésében? Nogyógyászati és Szülészeti Továbbképzo Szemle 4S, III. Belics Z., Beke A., Fekete T., Csabay L., Szabó I., Papp Z. (2003) Prenatal sonographic measurement of the fetal iliac angle in trisomy 21, 18 and 13 Ultrasound Obstet Gynecol 22S, Abstracts not related in the topic I. Kohalmi B., Kulka J., Kiss I., Belics Z., Demeter A., Görbe É., Jeager J (2002) Cystic duplication in the intestinal tract of the newborn infant Fetal Diagn Ther 17S, II. Kohalmi B., Kulka J., Kiss I., Belics Z., Demeter A., Görbe É., Jeager J (2002) Újszülöttkori cysticus bélduplicatio. Nogyógyászati és Szülészeti Továbbképzo Szemle 4S, III. Csabay L., Jenei K., Hargitai B., Fekete T., Belics Z., Halmos A., Szabó I., Barakonyi E., Sipos Zs., Lázár L., Bán Z., Papp Z. (2004) Case of exomphalos complicated with umbilical cord teratoma. Ultrasound Obstet Gynecol 24S,