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. 2017 Jun;49(6):721-728.
doi: 10.1002/uog.17228.

Clinical Utility of Non-Invasive Prenatal Testing in Pregnancies With Ultrasound Anomalies

Free PMC article

Clinical Utility of Non-Invasive Prenatal Testing in Pregnancies With Ultrasound Anomalies

L Beulen et al. Ultrasound Obstet Gynecol. .
Free PMC article


Objective: To evaluate the application of non-invasive prenatal testing (NIPT) as an alternative to invasive diagnostic prenatal testing in pregnancies with abnormal ultrasound findings.

Methods: This was a retrospective analysis of 251 singleton and multiple pregnancies at high risk for fetal chromosomal abnormality based on findings at sonographic examination, in which NIPT was performed as a first-tier genetic test. NIPT was performed by massively parallel sequencing of cell-free DNA in maternal plasma, allowing genome-wide detection of whole-chromosome, as well as partial, autosomal aneuploidy. Sex chromosomes were not analyzed, according to the current protocol in Dutch laboratories.

Results: NIPT was performed at a median gestational age of 20 weeks, indicated by the presence of multiple congenital anomalies (n = 13), isolated structural anomalies (n = 57), increased nuchal translucency ≥ 3.5 mm (n = 58), soft markers (n = 73), growth restriction (n = 40) and other anomalies (n = 10). NIPT results were normal in 224 (89.2%) pregnancies, inconclusive in one (0.4%) and abnormal in 26 (10.4%). Most genetic aberrations detected by NIPT were common whole-chromosome aneuploidies: trisomy 21 (n = 13), trisomy 18 (n = 6) and trisomy 13 (n = 3). Four further NIPT results were abnormal; one was suspected of being confined placental mosaicism and one was of maternal origin. In those with normal NIPT results, sonographic follow-up or examination of the newborn indicated the need for diagnostic genetic testing in 33/224 (14.7%) pregnancies. Clinically relevant genetic aberrations were revealed in 7/224 (3.1%) cases, two of which were whole-chromosome aneuploidies: trisomy 13 and monosomy X. As sex chromosomal aberrations are not included in NIPT analysis, the latter cannot be considered a false-negative result. Other discordant findings were subchromosomal aberrations (< 20 megabases, n = 2) and monogenic aberrations (n = 3).

Conclusions: NIPT should not be recommended for genetic evaluation of the etiology of ultrasound anomalies, as both resolution and sensitivity, or negative predictive value, are inferior to those of conventional karyotyping and microarray analysis. Nonetheless, some pregnant women consider NIPT to be an acceptable alternative to invasive diagnostic testing. © 2016 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Keywords: clinical utility; cohort study; etiology; genetic testing; non-invasive prenatal testing; prenatal diagnostic testing; ultrasound anomalies.


Figure 1
Figure 1
Flowchart of results of non‐invasive prenatal testing (NIPT) in 251 pregnancies with ultrasound anomaly. NIPT was by massively parallel sequencing of cell‐free DNA in maternal plasma. Diagnostic genetic testing was by quantitative fluorescent polymerase chain reaction, karyotyping, microarray analysis or targeted DNA testing of fetal or maternal tissue. Case 1: genetic testing indicated by polyhydramnios, NIPT did not meet quality criteria, however, visual inspection of plots repeatedly showed suspect chromosome 22 profile. Mother had mild intellectual disability, shortened palate, mild hearing impairment, common variable immunodeficiency. Maternal array was 22q11.21(18,970,562‐21,465,660)×1, ∼2.5 megabases (Mb). No further genetic testing. Resulted in live birth with no congenital anomaly. Postnatal microarray of newborn revealed 22q11.21(18,648,867‐21,798,908)×1 mat, ∼2.8 Mb. Case 2: multiple pregnancy, genetic testing indicated by multiple structural anomalies (intrauterine growth restriction, holoprosencephaly, omphalocele, megacystis with bilateral hydro‐nephrosis) in one fetus. No structural anomaly was observed in other fetus. NIPT showed T21. Follow‐up ultrasound at 17 weeks' gestation revealed atrioventricular septal defect and absent nasal bone in fetus without previously detected anomalies. Amniocentesis and genetic testing showed 47,XY + 21 and 47,XY + 13. Pregnancy was terminated. Cases 3–13 summarized in Tables 2 and 3. CNV, copy number variant; del, deletion; dup, duplication; kb, kilobases; MOPD1, microcephaly osteodysplastic primordial dwarfism Type I; T13, trisomy 13 (Patau syndrome); T16, trisomy 16; T18, trisomy 18 (Edwards syndrome); T21, trisomy 21 (Down syndrome); UPD(16)mat, maternal uniparental disomy of chromosome 16.

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