C. Poon

OC15.04: Chromosomal abnormalities detected by cell‐free DNA testing as a contingent approach versus direct invasive prenatal diagnosis

Objectives: The uptake of cell-free DNA (cfDNA) testing has resulted in a decrease in invasive prenatal diagnosis (IPD), but atypical chromosomal abnormalities may be missed. We analyzed the chromosomal abnormalities detected by cfDNA as a contingent approach in a single public centre with universal Down syndrome screening (DSS). Methods: In this retrospective cohort study, we compared the types of chromosomal abnormalities detected by IPD using cytogenetic +/chromosomal microarray analysis (CMA) after a positive cfDNA testing as a contingent approach (group 1) versus a positive DSS (group 2) from August 2011 to July 2016 using descriptive analysis and Chi-square test. IPD was publicly funded while cfDNA was self-financed. Results: Of 2,132 women with a positive DSS, 721 chose cfDNA testing and 1,411 direct IPD. Of 721 cfDNA testing (group 1), two failed, one showed an inconclusive result and 29 (4.0%) abnormal results. Of the latter, 27 had known outcomes after IPD including 74.1% common Trisomies, 3.7% mosaicism, 14.8% sex chromosomal abnormalities (SCA), 3.7% atypical aneuploidy, and 3.7% confined placental mosacism. Of 1,411 direct IPD (group 2), 193 (13.7%) showed chromosomal abnormalities including 66.8% common Trisomies, 11.9% mosaicism, 7.8% SCA, 5.3% atypical aneuploidies including those by CMA and 8.3% balanced translocation. Compared to direct IPD (group 2), the proportion and types of chromosomal abnormalities detected by IPD after a positive cfDNA testing (group 1) was different (p < 0.001) with a low/no detection rate of mosacism, atypical aneuploidies and balanced translocations though comparable detection rate of common Trisomies and SCA. Conclusions: The detection rate of mosaicism, atypical aneuploidies, and balanced translocation after using cfDNA as contingent approach was low/no. This could be related to women’ characteristics or limitation of cfDNA. Women should be carefully assessed and adequately counselled on cfDNA vs. IPD after a positive DSS.

EP06.05: Did women's hepatitis B status affect their uptake of invasive prenatal diagnosis after a positive conventional aneuploidy screening?

Objectives: Congenital heart defect (CHD) is the one of the major causes for neonatal lethality. And ultrasound screening enables the early diagnosis of CHD in prenatal stage. Emerging studies by using chromosomal microarray analysis of prenatal samples show that pathogenic copy number variants (CNVs) are highly associated with CHD. Methods: Here, we collected DNA samples from 145 unrelated fetuses with CHD diagnosed by ultrasound screening and subjected them for CNV analysis by low-pass whole-genome sequencing. CNV classification was performed according to the guideline from the American College of Medical Genetics. Maternal ages are 27.6±3.73, while the gestational weeks are 24.4±5.2. Sixty-one samples out of them are intra-cardiac defects (42.1%) and the remaining samples are extra-cardiac abnormalities (57.9%).Subtype classification of two groups is different, in intracardiac defect, the top were TOF (21.3%), TGA(14.8%) and AVSD (11.8%), while, the other were VSD (21.4%), AVSD (16.7%) and PS (13.1%). Results: Aneuploidies were identified in 29 (20%) fetuses, 27 out of them were with extra-cardiac abnormalities. Pathogenic CNVs were detected in seven cases, including a heterozygous loss at 22q13 harbouring FBLN1 and a gain at 10q23.31q26.3 with SHOC2 and ANKRD1.There were 344 unknown clinical significance micro-duplication or micro-deletion found in 91 samples, the number of CNV per sample was more in extra-cardiac abnormalities group when compared to intra-cardiac defect (p-value = 0.1514). 7.53% of which were predicted to be pathogenic by DECIPHER and GeneReviews. Conclusions: Our study demonstrates the potential clinical diagnostic utility of genomic imbalance profiling in CHD patients.

P09.02: Risk of prenatal diagnostic invasive procedures in hepatitis B surface antigen‐positive women

results from a prospective study of high-risk singleton pregnancies undergoing such a screening between 2002 and 2009 in Bulgaria. Methods: Bilateral UA Doppler analysis was performed between 18 and 24 w.g. Mean RI and PI indices were calculated. Presence of notching was also recorded. Logistic regression analysis was performed. 169 pregnant women were enrolled in the study. 37 patients developed PE and 11 of those delivered < 34 w.g. There was no difference in the mean maternal age, parity and gestational age between the groups at inclusion. The 90th centile RI had a better sensitivity for PE than the 95th centile with a FPR < 10%. Results: The high mean PI raised the relative risk /RR/ for development of PE 4.8 times (71% sensitivity and 5.3% FPR, P = 0.034). The mean RI > 90th centile was associated with a significant increase of the RR for development of PE and early PE – 3.8 and 8.5 times, respectively (95% CI 1.34–10.9). The best predictor for development of PE and PE < 34 w.g. was the combination of RI > 90th centile and the presence of bilateral notching – 65 times increased RR for development of early PE, with 81% sensitivity and 1.2% FPR (95% CI 6–699). Conclusions: UA Doppler analysis is a non-invasive screening modality for assessment of patients at risk for development of PE, in particular those requiring delivery < 34 w.g. RI and PI evaluation, combined with presence of notching, is the best predictor in identifying high-risk pregnancies.

P07.02: Can we predict who will choose invasive testing after a positive first trimester combined screening for Down syndrome?

given a ruler indicating different risk levels from which risk level for Down Syndrome they would demand an invasive procedure, considering its 1% risk of miscarriage. Results: In this prospective cohort of 720 women (median age 32 years), the mean gestational age was 12.57 weeks. While the combined risk screening showed a median risk of 1/4439, the median risk level chosen by patients for having an invasive test was of 1/500. 0.9% (n = 6) of the patients demanded an amniocentesis regardless of the screening results. 4.6% of these patients had an invasive procedure for karyotype testing with no miscarriage. Had we followed their risk perception, a supplementary 12.6% would have had an invasive procedure (P = 0.0001) with a theoretical increased miscarriage rate. Conclusions: The median risk level for Down Syndrome spontaneously accepted by the patients is of 1/500. Considering this threshold would imply a substantial increase in invasive procedures (4.6% to 17.2%) and a subsequent increased in costs, detection and miscarriage rates. The consequences of such change in screening policies should be further evaluated.

OP02.07: Trend in uptakes of prenatal testing for Down syndrome

Objectives: To describe any trends in the uptake of prenatal testing for Down syndrome in a public hospital after the introduction of massively parallel sequencing (MPS) in private and the characteristics of women who underwent the latter. Methods: The uptake of prenatal diagnostic invasive testing after a positive screening test for Down syndrome in one public hospital in 2011 was analysed. With the use of descriptive statistics and the Mann-Whitney test, the uptake rates were compared before and after the introduction of MPS in private in August 2011. The women who underwent the latter were invited to complete a questionnaire. Results: A total of 4842 Down syndrome screening test was performed in 2011. Compared to the first seven months in 2011, there was a significant increase in the total number of screening test (375.3 vs. 443.0; P = 0.013) and first trimester combined screening test (325 vs. 409; P = 0.001) performed per month in the subsequent five months. The percentages of a diagnostic invasive test after a positive screening test was decreased significantly from 93.7% to 79.4% (P = 0.018) while that of ‘doing nothing’remained similar (6.3% vs. 10.1%; P = 0.639). About 9.6% of screen positive women went to the private for a MPS. Of 25 women who underwent the MPS, 60.0% aged 35 or above, 68.0% were nulliparous, 64.0% received University or Tertiary education, and 80.0% were working women, and 88.0% regarded themselves knew MPS, mainly from their private obstetrician and web. They answered correctly in 76.8% of the five questions (based on the position statement on MPS released by the ISPD in 2011). In their future pregnancies, 36.0% and 84.0% of them would opt for MPS directly and after a positive screening test respectively. Conclusions: The percentages of a diagnostic invasive test after a positive screening test was decreased mildly in a public hospital recently, probably related to the uptake of MPS in private by a small proportion of women who were willing to pay to reduce an invasive test.