Pränataldiagnostik zur Detektion chromosomaler Aberrationen: Wandel in der Anwendung invasiver und nicht-invasiver Methoden
Prenatal diagnostics for detection chromosomal aberrations: changes in the use of invasive and non-invasive methods
by Veronika Franziska Bach
Date of Examination:2022-05-18
Date of issue:2022-05-12
Advisor:Prof. Dr. Dr. Birgit Zirn
Referee:PD Dr. Gerd-Johannes Bauerschmitz
Referee:Prof. Dr. Margarete Schön
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EnglishIntroduction: Prenatal diagnostics includes, among other things, risk assessment for chromosomal disorders, especially for monosomy X, trisomy 13, trisomy 18, trisomy 21, triploidy and a large number of structural rearrangements. In addition to non-invasive methods (biochemical screening, prenatal ultrasound, non-invasive prenatal tests), which only determine an individual risk, invasive methods (chorionic villus biopsy 10th - 14th week of pregnancy, amniocentesis from the 15th week of pregnancy) can achieve a high level of diagnostic certainty. The aim of the study was to present the data and changes in the invasive testing over time. Methods: Fetal karyotypes obtained at the genetikum Neu-Ulm following 2396 chorionic villus biopsies and 34182 amniocentesis between 2001 and 2015 were retrospectively reviewed. The examination included the patient characteristics (age, week of pregnancy, indication for invasive testing), the number of invasive procedures and the aneuploidy rates in the total cohort and over time. Furthermore, the detected sonographic abnormalities and the pregnancy outcome in fetuses with monosomy X, trisomy 13, trisomy 18, trisomy 21 and triploidy were evaluated and the aneuploidy rate and detected chromosomal disorders of the frequent ultrasound abnormalities. Results: 54.8% and 70.5% of patients in whom a chorionic villus or amniotic fluid examination was performed were ≥ 35 years. Among clinical indications, isolated advanced maternal age was found in 23.5% or 57.2%, abnormal ultrasound in 50.8% or 9.4%, abnormal first trimester aneuploidy screening in 16.8% or 7.5%, anxiety in 5.0% or 15.8% and a positive family history in 6.8% or 1.1%. The aneuploidy rate in the chorionic villi was 25.3% (606 cases, trisomy 21 - 38.4%, trisomy 18 - 19.0%, monosomy X - 15.0%, structural chromosomal disorders - 8.6%, trisomy 13 - 6.1%, triploidy - 4.0%) and in the amniotic fluid in 3.8% (1298 cases, trisomy 21 - 36.7%, structural chromosomal disorders - 27.1%, trisomy 18 - 12.9 %, trisomy 13 – 4.7%, monosomy X – 4.6%, triploid – 3.3%). A monosomy X mosaic was found in 6.6% at the time of chorionic villus sampling and in 28.3% at amniocentesis. An increased aneuploidy rate with advanced maternal age could be detected mainly due to the increase in autosomal trisomies, an inverse age effect was found in monosomy X, triploidy, tetraploidy and structural chromosomal disorders. The aneuploidy rate was also dependent on the referral reason, with the highest rate in the case of a known chromosomal disorder in one of the parents (64.9% and 38.3%), followed by an abnormal ultrasound (43.7% and 20.0%) and an abnormal first trimester aneuploidy screening (30.5% and 7.2%), with isolated advanced maternal age, a chromosomal aberration was found in only 3.4% and 1.9%. After an inauspicious diagnosis, 92.8% and 86.0% of the patients opted for termination of pregnancy, whereas with monosomy X there was a clear discrepancy (89.2% and 61.1%). Overall, sonographic malformations or soft markers were found in 100% or 86.0%, in 100% or 88.1%, in 100% or 86.7%, in 93.5% or 54.0% and in 100% or 100% of fetuses with monosomy X, trisomy 13, trisomy 18, trisomy 21 or triploidy. The most common sonographic feature of fetuses with aneuploidy in the first trimester was increased nuchal translucency, with 67.1%, 69.4%, 63.1%, 75.0%, and 21.7%, respectively. In the second trimester, cardiac malformations or abnormalities were found most frequently in 18.6%, 40.7%, 37.6%, 25.3% and 40.5%, respectively, malformations of the central nervous system in 9.3%, 49 .2%, 27.9%, 6.4% and 47.6%, growth retardation in 9.3%, 18.6%, 30.9%, 1.3% and 78.6% and malformations of the extremities in 2.3%, 20.3%, 32.7%, 5.1% and 31.0%, respectively. Fetuses with monosomy X showed a hygroma colli in 38.8% or 46.5% and a hydrops fetalis in 82.4% or 58.1%, fetuses with trisomy 13 abnormalities of the cerebellum in 5.6% or 15.3%, a holoprosencephaly in 13.9% or 16.9%, an omphalocele in 30.6% or 13.6%, a polydactyly in 25.0% or 13.6% and a cleft lip and palate in 25.0% or 30.5%, fetuses with trisomy 18 plexus choroideus cysts in 0.9% or 16.4%, an omphalocele in 29.7% or 17.6%, a singular umbilical artery in 11.7% or 10.9%, abnormal hands in 12.6% or 17.6% and abnormal feet in 7.2% or 13.9%, fetuses with trisomy 21 an atrioventricular canal in 12.9% or 9.1% and fetuses with triploidy ventriculomegaly in 8.7% or 26.2%, a singular umbilical artery in 17.4% or 11.9%, abnormal hands in 13.0% or 23.8%, a singular umbilical artery in 17.4% or 11.9%, abnormal hands in 13.0% or 23.8% as well as an oligohydramnios in 17.4% or 19.0%. Isolated ultrasound abnormalities with a high aneuploidy rate were the atrioventricular canal (61.5%), omphalocele (23.3%), increased nuchal translucency (29.6%), nuchal hygroma (38.8%), hydrops fetalis (66.0%) and growth retardation (32.1%). Monosomy X was found most frequently in fetuses with neck hygroma and hydrops fetalis in the first trimester, trisomy 13 in fetuses with holoprosencephaly, echodense kidneys, polydactyly and cleft lip and palate, trisomy 18 in fetuses with spina bifida, ventricular septal defects, megacystis, omphalocele, diaphragmatic hernia, singular umbilical artery, abnormal Doppler, flexed overlapping fingers, radial aplasia, clubfeet and rocker-bottom feet, trisomy 21 in fetuses with white spot, atrioventricular canal, tricuspid insufficiency, pyelectasis, hyperechoic bowel, duodenal atresia, shortened femur, abnormal nasal bone, increased nuchal translucency/neck edema, as well as hygroma colli and hydrops fetalis in the second trimester. From 2000 onwards there was a continuous decline in the number of amniocentesis, the number of chorionic villus biopsies initially increased until 2012 and decreased afterwards. The aneuploidy rate increased over time, the indications showed a decrease in advanced maternal age an anxiety and an increase for sonographic abnormalities and abnormal first trimester aneuploidy screening. The age distribution showed no changes for chorionic villi biopsy, while the patients with amniocentesis became progressively older. Discussion: The aneuploidy rates and the detected chromosomal abnormalities depend on the gestational age, the indication and the maternal age. Sonographic abnormalities can be seen in the majority of fetuses with monosomy X, trisomy 13, trisomy 18 and triploidy, whereas structural malformations are rarely observed in fetuses with trisomy 21. Some ultrasound abnormalities are relatively specific to certain chromosomal disorders, whereas many abnormalities occur in various chromosomal disorders and in chromosomally normal fetuses. The change in prenatal diagnostics in favor of non-invasive methods consequently leads to a reduced detection rate, which immediately requires increasing individual counseling of pregnant women.
Keywords: prenatal diagnostics; chromosomal aberrations; invasive prenatal testing; amniocentesis; chorionic villus sampling