A decade of change – lessons learned from prenatal diagnostics in Central Denmark region in 2008–2018

Abstract

IntroductionIn 2011, it was decided to implement chromosomal microarray in prenatal testing in the Central Denmark Region, mainly due to the expected higher diagnostic yield. Chromosomal microarray was introduced gradually for an increasing number of pregnancies and without a transition period where both karyotyping and chromosomal microarray were performed: first malformations (2011), then large nuchal translucency (2013), then high risk at combined first trimester risk screening (2016) and finally for all indications (2018). This retrospective study summarizes 11 years of using chromosomal microarray in invasive prenatal testing and presents the effect on diagnostic yield and turnaround time. Furthermore, the concerns when introducing chromosomal microarray are presented and discussed.Material and methodsRegistry data from the Danish Fetal Medicine Database, the regional fetal medicine database, the Danish Cytogenetic Central Register and the local laboratory database at Department of Clinical Genetics were all combined, and a cohort of 147 158 singleton pregnancies with at least one ultrasound examination was establishedResultsOf the 147 158 pregnancies, invasive sampling was performed (chorionic villi or amniocytes) in 8456, corresponding to an overall invasive rate of 5.8%. Between 2016 and 2018, 3.4% (95% confidence interval [CI] 2.8–4.2%; n = 86) of the invasive samples (n = 2533) had a disease causing copy number variant and 5.3% (95% CI 4.4–6.2%; n = 133) had trisomies and other aneuploidies. The turnaround time more than halved from 14 days to an average of 5.5 days for chorionic villus sampling.ConclusionsChromosomal microarray identified 5.3% trisomies and 3.4% copy number variants, thereby increased the diagnostic yield by more than 64% compared with karyotype only and it also more than halved the turnaround time. Some preliminary concerns proved real, eg prenatal counseling complexity, but these have been resolved over time in a clinical path with expert consultations.

Has the introduction of increased genetic prenatal testing affected rates of termination of pregnancy due to fetal abnormality?

“…CMA has now become the primary method for cytogenetic analysis in prenatal testing and has significantly enhanced diagnostic yield. 8,11,28 As expected we did observe an elevated identification of deletions, duplications, and single nucleotide variations as the indication for TOPFA, but without significantly affecting the overall number of pregnancy terminations. -285…”

“…Over the investigated time period, there was a small increase in the number of cases with genetic deletions, duplications and single nucleotide variations, which may reflect the more recent introductions of CMA, WES and WGS, whereas all other subgroups were stable. 11,28,29 The number of cases with genetic aberrations in the present study seems higher compared to other studies, but this may reflect increased access to genetic testing in Denmark compared to other countries. [30][31][32] It is surprising that the rates of TOPFA remained stable despite the improvement in diagnostic tools, which would logically lead to an expected increase in the identification of fetal abnormalities.…”

“…Over the years, diagnostic techniques have progressed, shifting from conventional chromosome analysis to CMA in 2015 and noninvasive prenatal testing test (NIPT) was introduced in 2016. 11 Since 2018, WES or WGS has been an option for specific cases, [11][12][13] and during these years, MRI has also become accessible for fetal malformations. The implementation of screening in 2004 led to an elevated detection rate for prenatally diagnosed malformations such as multiple congenital anomalies, heart malformations and lip and/or palate cleft.…”

“…For instance, replacing karyotyping with CMA led to a 64% rise in the diagnostic yield as a result of detecting disease-causing copy number variation (CNVs) like deletions and duplications. 11 The incorporation of MRI has enhanced the precision of central nervous system (CNS) diagnoses 6 and in a specific study, it was estimated to have provided additional information in 23% of investigated cases with CNS malformations. 20 With increased diagnostic precision, there is a probability of detecting a greater number of fetuses with abnormal findings of uncertain significance.…”