Use of cell-free non-invasive prenatal testing in pregnancies affected by placental mosaicism.

OBJECTIVE: To evaluate cell-free non-invasive prenatal testing (cfNIPT) in pregnancies affected by mosaicism. METHOD: We assessed paired cfNIPT and chorionic villus sample (CVS) results from the same pregnancies in a case series of mosaicism detected in Central and North Denmark Regions from April 2014 to September 2018. Indications for the clinically obtained CVS, pregnancy markers and outcome were retrieved from The Danish Fetal Medicine Database. RESULTS: Mosaicisms in CVS involved common aneuploidy, n = 14; sex chromosomal aneuploidies, n = 14; rare autosomal trisomies (RATs), n = 16 and copy number variants (CNVs) >5Mb, n = 9. Overall, 24/53 (45.3%; CI 95%: 31.8%-59.4%) of cases with mosaicism were detected by cfNIPT; highest for RATs (56%) and lowest for CNVs (22%). CfNIPT more commonly detected high-level than low-level mosaic cases (p = 0.000). CfNIPT detected 7/16 (43.8%; CI 95%: 21%-69%) clinically significant mosaic cases, either true fetal mosaicism or confined placental mosaicisms with adverse pregnancy outcome. There was a trend toward a higher risk for adverse outcome in pregnancies where mosaicism was detected by cfNIPT compared to pregnancies where mosaicism was not detected by cfNIPT (p = 0.31). CONCLUSION: CfNIPT has a low detection rate of mosaicism, including pregnancies with clinically significant mosaicism. However, abnormal cfNIPT results may be a predictor of adverse pregnancy outcomes.

Patients' choices and opinions on chorionic villous sampling and non-invasive alternatives for prenatal testing following preimplantation genetic testing for hereditary disorders: A cross-sectional questionnaire study.

OBJECTIVE: The aim of this study was to investigate choices of and reasoning behind chorionic villous sampling and opinions on non-invasive prenatal testing among women and men achieving pregnancy following preimplantation genetic testing (PGT) for hereditary disorders. METHODS: A questionnaire was electronically submitted to patients who had achieved a clinical pregnancy following PGT at the Center for Preimplantation Genetic Testing, Aalborg University Hospital, Denmark, between 2017 and 2020. RESULTS: Chorionic villous sampling was declined by approximately half of the patients. The primary reason for declining was the perceived risk of miscarriage due to the procedure. Nine out of 10 patients responded that they would have opted for a non-invasive prenatal test if it had been offered. Some patients were not aware that the nuchal translucency scan offered to all pregnant women in the early second trimester only rarely provides information on the hereditary disorder for which PGT was performed. CONCLUSION: Improved counseling on the array of prenatal tests and screenings available might be required to assist patients in making better informed decisions regarding prenatal testing. Non-invasive prenatal testing is welcomed by the patients and will likely increase the number of patients opting for confirmatory prenatal testing following PGT for hereditary disorders.

Impact of simulation-based prenatal invasive procedure training on professional practice, a preliminary study.

INTRODUCTION: Amniocentesis and chorionic villus sampling remain the cornerstone of prenatal diagnosis. These procedures are associated with a risk of miscarriage estimated at approximately 0.5 %. Our team has developed a training model for performing simulation-based prenatal invasive procedures. Several simulation sessions are offered each year to obstetricians-gynecologists involved in fetal medicine in France and abroad. This simulation-based learning has already been conclusively evaluated according to levels I and II of the Kirkpatrick model. Here, we carried out a preliminary study according to level III: does participation in training in prenatal invasive procedures through simulation have an influence on professional practice? METHODS: An anonymous online survey was sent to 82 obstetricians-gynecologists who participated in the training in prenatal invasive procedures at the Antoine Béclère maternity hospital between January 1st, 2014 and December 31, 2018. This questionnaire, entitled "Evaluation of the professional impact of training in invasive procedures through simulation", included 20 quantitative and qualitative items. RESULTS: 48 (59 %) obstetricians-gynecologists responded to the questionnaire. 98 % of the participants considered that participation in the training had a significant impact on their professional practice. Half considered this impact to be major. 60 % of the former participants are now attached to a Multidisciplinary Center for Prenatal Diagnosis. CONCLUSION: Participation in training is considered by former participants to have a significant impact on their professional practice. In order to finalize the evaluation of this learning, a study of the benefits for patients and their pregnancy should be discussed.

Aneuploidy in first trimester chorionic villi and spontaneous abortions: Windows into the origin and fate of aneuploidy through embryonic and fetal development.

OBJECTIVE: To review the mosaic autosomal trisomies in chorionic villi sample (CVS) trophoblasts, mesenchyme, and both cell lineages and to compare them with trisomies in spontaneous abortions. METHODS: Mosaic autosomal trisomies from 76 102 diagnostic CVS tests were classified as involving trophoblasts, involving mesenchyme, or present in both. Autosomal trisomies in products of conception were based on 18 published studies. We evaluated correlates between trisomy frequency with chromosome size or number of protein coding genes in the imbalance. RESULTS: Distinctly different patterns of trisomy were found in trophoblasts, mesenchyme, or both. In trisomic spontaneous abortions, there was a weak, borderline significant, inverse association between frequency and trisomic chromosome size and also with the number of protein coding genes involved (r = 0.43, P = 0.04 and r = 0.39, P = 0.07, respectively). These associations became stronger after excluding trisomy 16 (r = 0.52, P = 0.01 and r = 0.64, P = 0.001, respectively). Only CVS trisomies in both trophoblasts and mesenchyme resembled the trisomies found in spontaneous abortions and these were also associated with chromosome size and protein coding genes (r = 0.42, P = 0.05 and r = 0.57, P = 0.006, respectively). CONCLUSION: The abnormalities seen in CVS differ from those reported in early embryos. From conception through birth, there are lineage-specific, evolving spectrums of aneuploidy in trophoblasts, mesenchyme, and fetus.

Prenatal array comparative genomic hybridization in a well-defined cohort of high-risk pregnancies. A 3-year implementation results in a public tertiary academic referral hospital.

OBJECTIVE: To find out whether the diagnostic yield of prenatal array comparative genomic hybridization (aCGH) can be improved by targeting preselected high-risk pregnancies. METHOD: All the in-house arrays ordered by the Fetomaternal Medical Center from February 2016 until December 2018 were retrospectively analyzed. The indications for array analysis included fetal structural abnormalities, increased nuchal translucency ≥3.5 mm and a chromosomal abnormality in a parent or a sibling. Common aneuploidies were excluded. RESULTS: Diagnostic yield was 15.1% in the entire patient cohort and as high as 20% in fetuses with multiple structural anomalies. The diagnostic yield was lowest in the group with isolated growth retardation. A total of 76 copy number variants (CNVs) were reported from a total of 65 samples, including 16 CNVs associated with a well-described microdeletion/microduplication syndrome, six autosomal trisomies in mosaic form, and three pathogenic single-gene deletions with dominant inheritance and 12 CNVs known to be risk factors for eg developmental delay. CONCLUSION: The diagnostic yield of aCGH was higher than what has previously been reported in less defined patient cohorts. However, the number of CNVs with unclear correlation to the fetal ultrasound findings was still relatively high. The importance of adequate pre- and posttest counseling must therefore be emphasized.

Increased prenatal detection of 22q11.2 deletion and 22q11.2 duplication after introduction of nationwide prenatal screening for trisomy 21, trisomy 13, and trisomy 18.

OBJECTIVE: To evaluate time of diagnosis of 22q11.2 deletion and 22q11.2 duplication as well as trisomies 21, 13, and 18 before and after introduction of a prenatal screening program including combined first-trimester screening (cFTS) for the trisomies in Denmark in 2004. METHOD: Cross-sectional, population-based register study employing The Danish Cytogenetic Central Register. Proportions of cases diagnosed 1998-2004 and 2005-2017 were compared before 14+0 and 22+0 weeks and birth (prenatal cases) or up to 1 or 10 years of age (postnatal cases). RESULTS: In total, 4562 cases were included. From 1998-2004 to 2005-2017, the proportion of 22q11.2 deletion cases identified prenatally increased from 4.3% (95% CI: 0.9-12.0%) to 27.3% (21.2-34.0%), while for 22q11.2 duplication an increase from 0/6 to 26/87 (prenatal cases/all cases) was observed. Similarly, proportions of trisomies 21, 13, and 18 detected before birth increased. A greater proportion of the studied conditions was identified earlier in pregnancy, but not generally earlier in the postnatal course. CONCLUSION: Proportions of 22q11.2 deletion and 22q11.2 duplication identified prenatally increased after introduction of a prenatal screening program not aimed specifically to identify these conditions,. A greater proportion of all cases were detected earlier in pregnancy, but not earlier postnatally, following introduction of screening.

Chorionic villus sampling: 10 years of experience in a University referral center.

OBJECTIVES: The purpose of this study was to estimate our center-specific CVS-related miscarriage rate. METHODS: This is an observational retrospective study of women submitted to a CVS in our hospital, between January 1st, 2007 and December 31st, 2016. Maternal and pregnancy characteristics, procedure details, genetic results and pregnancy outcomes of all patients were collected. The FMF miscarriage risk algorithm was used to estimate our population expected risk of miscarriage. To establish the procedure-related risk of miscarriage, we compared the observed with the expected miscarriage rate. RESULTS: We had a total number of 1523 women with a singleton pregnancy who did a CVS over the 10-year period. The mean maternal age was 34 years old; the majority of the women was Caucasian, multiparous and had a spontaneous pregnancy. The most common indication for CVS was a high-risk result in the 1st trimester combined screening test. The karyotype was normal in 72,7% of cases, 11,1% were T21 and 7,2% were T13 or T18. In the study group, 33 women were diagnosed with a fetal demise, 435 had a TOP and there were 4 intrauterine deaths and 34 miscarriages. The rate of miscarriage in our population was 3,2% and the expected patient specific risk for miscarriage was 3,0%. There was no statistical significance between the two miscarriage rates p = 0,705. CONCLUSION: In our study the risk of miscarriage in the CVS group was not significantly different from that the expected patient specific risk (3.2 % vs 3%, p = 0.7). The procedure-related risk of miscarriage was 0,2%, similar to the rates describe in the literature. An accurate risk of pregnancy loss should be used when counseling women for CVS to allow an informed decision.

Genetic abnormalities seen on CVS in early pregnancy failure.

Objective: To determine the frequency and distribution of chromosome abnormalities in women with early pregnancy failure (EPF) detected by cytogenetic testing on chorionic villus sampling.Method: Retrospective observational cohort study of chromosomal analysis from transvaginal chorionic villus sampling (CVS) or reflex products of conception (POC) karyotype. CVS was offered as a training tool for Maternal Fetal Medicine fellows prior to manual vacuum aspiration for EPF 9-week gestation. POC were analyzed for cytogenetics if no results were obtained on CVS.Results: One hundred thirty samples were collected from December 2011 to April 2015. 33 (27.3%) cases had a normal karyotype and 88 (73.0%) cases had an abnormal karyotype. The most common group of abnormalities were trisomy, (n = 50, 41.3%), triploidy/tetraploidy, (n = 17, 14.0%), monosomy (n = 15, 12.4%), and structural rearrangements (n = 6, 5.0%). Nine (6.9%) samples were maternal decidua only. Abnormal karyotype in EPF was significantly increased in women by age group (p < .01) but not in women with a history of prior miscarriage (p = .5).Conclusion: Our cohort had a high detection rate of aneuploidy. The most common chromosomal abnormalities in EPF were: trisomy, followed by triploidy/tetraploidy, monosomy, and structural rearrangements. Maternal age had the strongest correlation with EPF associated with aneuploidy.

Obstetrical outcomes after first-trimester chorionic villus sampling in twin pregnancies: A retrospective case-control study.

AIM: Prenatal diagnostic testing by chorionic villus sampling (CVS) is sometimes recommended for women with twin pregnancies. However, few studies have compared the outcomes between twins with CVS and control twins without intervention. This study aimed to compare the obstetrical outcomes of CVS in twin pregnancies and those in non-intervention twin pregnancies. METHODS: First-trimester transabdominal CVS was performed on dichorionic-diamniotic twins (n = 54; Group 1) between December 2006 and January 2017 at the Department of Obstetrics and Gynecology at our hospital, and the data were retrospectively analyzed. CVS risks were evaluated by comparing obstetrical outcomes with those of a control population of 155 dichorionic-diamniotic twins without intervention (Group 2). RESULTS: The difference in the overall fetal loss rate (Group 1, 7.4% vs Group 2, 3.9%; P = 0.287) between the two groups was not statistically significant. The miscarriage rate, defined as delivery at <24 gestational weeks, and early preterm delivery, defined as delivery at <34 gestational weeks, were not significant between the groups (miscarriage: Group 1, 5.6% vs Group 2, 3.2%; P = 0.428; early preterm delivery: Group 1, 11.1% vs Group 2, 9.0%; P = 0.788). The mean gestational age at delivery, birth weights and neonatal intensive care unit admission rate were not statistically significant between the groups. Thus, the overall fetal loss rate and obstetrical outcomes of Group 1 were comparable with those of Group 2. CONCLUSION: In conclusion, the overall obstetrical outcomes were not significantly different between twins with CVS and control twins with the advantage of enabling early decision-making about selective feticide in twins with CVS.

Impact of introduction of noninvasive prenatal testing on uptake of genetic testing in fetuses with central nervous system anomalies.

OBJECTIVE: To evaluate the impact of introduction of noninvasive prenatal testing (NIPT) on the uptake of invasive testing in pregnancies complicated by fetal central nervous system (CNS) anomalies. METHODS: Retrospective review of all singleton pregnancies complicated by fetal CNS anomalies seen at a single tertiary center between 2010 and 2017. Cases who had undergone invasive testing or NIPT prior to the diagnosis of the CNS anomaly were excluded. Cases were segregated according to whether they were seen prior to introduction of NIPT (group A, 2010-2013) or thereafter (group B, 2014-2017). We examined the rate of invasive and noninvasive genetic testing in each group. RESULTS: We retrieved 500 cases: 308 (62%) were isolated CNS anomalies, and 192 (38%) had additional structural anomalies. In the total cohort, 165 women (33%) underwent expectant management with no further prenatal genetic testing, 166 (33%) had invasive testing, 52 (10%) had NIPT, and 117 pregnancies (23%) were terminated without further prenatal investigations. The introduction of NIPT significantly decreased the number of pregnancies having no testing (44% group A vs 22% in group B, p < .0001), particularly in the group presenting with isolated ventriculomegaly, but did not affect the uptake of invasive testing (34% vs 32%, respectively; p = .61). NIPT would have missed 4% of pathogenic copy number variants (CNVs) in the group of cases with isolated brain anomalies and 11% of CNVs in cases with complex anomalies. CONCLUSIONS: Uptake of invasive prenatal testing in fetuses with brain anomalies was not affected by NIPT. However, the incidence of no genetic testing was significantly reduced. NIPT was a suboptimal testing strategy in this population as it missed a significant number of subchromosomal genetic anomalies.

A survey of current clinical practice of chorionic villus sampling.

OBJECTIVE: The number of invasive procedures (chorionic villus sampling (CVS) or amniocentesis) for fetal testing is decreasing because of the availability of non-invasive prenatal test (NIPT) leading to a centralisation of prenatal diagnostic services to accredited fetal medicine centres. A new survey was conducted 10 years after the previous one to update the current clinical practice among clinicians who regularly perform CVS. METHOD: Consultants from 32 centres in the United Kingdom were invited to take part in an online survey evaluating: The total number of CVS procedures carried out in the unit in a typical week, the preferred route (transabdominal [TA] vs transcervical [TC]), technique (use of local anaesthetic [LA] and needle technique). RESULTS: Response rate was 96.9%; TA was the preferred route (96.8%) in all centres except one. Single-needle technique is used exclusively in half the centres (51.6%). LA is used by most operators (90.3%) before the procedure. Three centres did not routinely use LA for CVS. CONCLUSIONS: Operators across the United Kingdom almost exclusively use the TA route for CVS with single-needle technique in 51.6% of cases. The use of LA prior to CVS is a very common practice in the United Kingdom.

Risk of preeclampsia in of women who underwent chorionic villus sampling.

Objective: To assess the risk of preeclampsia in women who underwent chorionic villus sampling (CVS). Study design: This is a retrospective, single-center, cohort study. All consecutive singleton gestations who underwent chorionic villus sampling from January 2014 to January 2016 were included in the study. The primary outcome was the incidence of preeclampsia. Subgroup analysis in women with beta thalassemic trait was performed. Logistic regression, presented as adjusted odds ratio (aOR) with the 95% of confidence interval (CI), was performed. Results: Five hundred forty-seven women who underwent CVS, and 1532 women who did not were analyzed. Women who underwent CVS had a significantly lower risk of preeclampsia (4.4 versus 8.0%; aOR 0.53, 95%CI 0.34-0.83), and late-onset preeclampsia (3.3 versus 6.1%; aOR 0.52, 95%CI 0.31-0.87). No statistically significant differences were found in preeclampsia with severe features, early-onset preeclampsia, and preterm birth (PTB). Women who underwent CVS due to thalassemic trait had a lower incidence of preeclampsia compare to those women who did not undergo CVS (3.3 versus 8.0%; aOR 0.39, 95%CI 0.14-0.87), while no differences were found comparing women who underwent CVS due to thalassemic trait with women who underwent CVS due to other reasons. Conclusions: Women who underwent first trimester CVS had a lower risk of preeclampsia compared to those who did not.

Prenatal diagnosis of chromosomal polymorphisms: most commonly observed polymorphism on Chromosome 9 have associations with low PAPP-A values.

INTRODUCTION: To identify the prevalence and types of fetal chromosomal polymorphisms in pregnant women and to examine possible associations with screening test parameters. MATERIALS AND METHODS: Fetal chromosomal polymorphism rate was investigated in pregnant women who had been implemented for invasive prenatal test in a tertiary reference center in Thrace Region of Turkey. Fetal chromosomal polymorphisms were determined and their effects on screening tests' parameters were investigated. Possible differences in the first and second-trimester screening test parameters between women; with fetal chromosomal polymorphism who had screening test results (Group 1) and those with a normal karyotype (Group 2) were evaluated. RESULTS: Fetal chromosomal polymorphism prevalence was 5.3% (n = 101). The most common polymorphisms were identified on chromosome 9, 1, and 16 [54.5% (n = 55); 8.9% (n = 9), and 6.9% (n = 7), respectively]. The most common polymorphic variant was 9qh+ (n = 23; 22.8%). Among the screening test parameters, significantly lower pregnancy-associated plasma protein-A (PAPP-A) (p = .028) and higher unconjugated estriol (uE3) (p = .019) values were found in Group 1. In patients having fetuses with polymorphic variants on chromosome 9, a significantly lower PAPP-A values were observed compared to women with other fetal polymorphic variants (p = .048) or women having fetuses with normal karyotype (p = .007). CONCLUSIONS: Lower PAPP-A and higher uE3 levels were observed in women having fetuses with chromosomal polymorphisms, which might affect screening test results. Lower PAPP-A levels were apparent in women having fetuses with polymorphism on chromosome 9.

Population-based trends in invasive prenatal diagnosis for ultrasound-based indications: two decades of change from 1994 to 2016.

OBJECTIVE: To assess trends in ultrasound-indicated prenatal diagnostic testing performed over the past two decades in the Australian state of Victoria, in the context of rapidly changing practices in aneuploidy screening and chromosome analysis. METHODS: This was a retrospective analysis of all ultrasound-indicated prenatal diagnostic testing (amniocentesis and chorionic villus sampling) performed in the state of Victoria between 1994 and 2016. Ultrasound indications for testing included: fetal structural abnormality, fetal death, fetal growth restriction, abnormal amniotic fluid volume, genetic 'soft marker' and unspecified ultrasound abnormality. Maternal age, indication for testing, type of diagnostic procedure, gestational age, type of chromosome analysis (G-banded karyotyping or chromosomal microarray (CMA)) and test results were obtained. Diagnostic yield (i.e. percentage of tests yielding a major abnormality) was analyzed by year, maternal age and gestational age. Statistical analysis was performed using the χ2 tests for trend or difference in proportions, as appropriate. RESULTS: During the 23-year study period, 1 533 317 births were recorded and 16 152 diagnostic procedures were performed for the primary indication of ultrasound abnormality. In recent years, ultrasound abnormality became the most common indication for prenatal invasive testing (29.4% of diagnostic tests between 2013 and 2016) due to a steep decline in testing for other indications such as positive result on combined first-trimester screening or advanced maternal age alone. In 2016, over 95% of ultrasound-indicated procedures were performed with CMA; among these, pathogenic copy number variant (CNV) was the most common (3.5%) abnormality detected, followed by trisomy 21 (2.8%). The diagnostic yield of ultrasound-indicated tests performed < 16 weeks was significantly higher than that of tests performed after 20 weeks (31.5% vs 9.0%). CONCLUSIONS: Ultrasound-indicated invasive testing is contributing to prenatal diagnosis in new ways in the genomic era. A pathogenic CNV is now the most likely diagnosis after ultrasound-indicated testing, rather than trisomy 21 or other whole-chromosome aneuploidy. Despite steady improvements in first-trimester screening for aneuploidy, the diagnostic yield of ultrasound-indicated tests > 20 weeks has remained stable due to increased utilization of CMA. Procedures performed for structural abnormalities < 16 weeks continue to have the highest diagnostic yield, supporting the benefits of early fetal structural assessment at 11-13 weeks. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Gestational Outcomes of Pregnant Women Who Have Had Invasive Prenatal Testing for the Prenatal Diagnosis of Duchenne Muscular Dystrophy.

AIM: To show the importance of prenatal diagnosis of Duchenne Muscular Dystrophy (DMD) and to demonstrate the effect of DMD gene mutations on gestational outcomes. MATERIALS AND METHODS: We retrospectively evaluated 89 pregnancies in 81 individuals who were referred to Hacettepe University for prenatal diagnosis of DMD between January 2000 and December 2015. Prenatal diagnostic methods (chorionic villus sampling (CVS): 66, amniocentesis (AC): 23) were compared for test results, demographic features, and obstetric outcomes of pregnancies. The female fetuses were divided into two groups according to the DMD status (healthy or carrier) to understand the effect of DMD gene mutations on obstetric outcomes. RESULTS: Eight prenatally diagnosed disease-positive fetuses were terminated. There was no statistically significant difference between the CVS and AC groups in terms of study variables. There were 46 male fetuses (51.6%) and 43 female fetuses (48.4%). Fifteen of the female fetuses were carriers (34.8%). Median birthweight values were statistically insignificantly lower in the carrier group. CONCLUSION: Pregnancies at risk for DMD should be prenatally tested to prevent the effect of disease on families and DMD carrier fetuses had obstetric outcomes similar to DMD negative female fetuses.

Early prenatal diagnosis of lysosomal storage disorders by enzymatic and molecular analysis.

OBJECTIVE: To report the 4-year experience of early prenatal diagnosis of lysosomal storage disorders (LSDs) at a center in mainland China. METHOD: Forty-seven pregnancies affected with LSDs were assed using enzymes and/or molecular studies. Prenatal studies were performed on 43 uncultured chorionic villi (CV) samples, two amniotic fluid samples, and two umbilical cord blood samples. RESULTS: Of the 47 fetuses, 23 (48.9%) were determined to normal, 13 (27.7%) to be carriers, and 11 (23.4%) diagnosed as affected. In this cohort, mucopolysaccharidoses (MPS) type II was the most common LSD, followed by Pompe disease and then metachromatic leucodystrophy. In the 17 MPS II cases, the four affected fetuses showed MPS II enzyme activity expression levels of 1.4% to 6.7%, while the enzyme activity levels of the 13 normal fetuses ranged from 72% to 240.4%. In the seven Pompe cases, three fetuses were normal with Pompe enzyme activity expression levels of 20%, 38.8%, and 77.3%, while four carrier pregnancies showed enzyme activity levels of 17.5%, 17.5%, 33.4%, and 13.8%, respectively. CONCLUSION: Based on different enzyme properties in uncultured CV, different prenatal diagnostic strategies should be adopted for MPS II and Pompe disease. Combining enzyme assay and molecular studies in uncultured CV improves the reliability of prenatal diagnosis of LSDs.

A retrospective exploratory study of fetal genetic invasive procedures at a University Hospital.

This is a retrospective analysis of the patient demographics and cytogenetic results of patients who underwent prenatal invasive testing for genetic analysis at the Foetal Medicine Division of the Department of Obstetrics and Gynecology, Sri Ramachandra Medical College and Research Institute. The main objective of this study was to characterise the changing trends in indications of pregnant women for foetal karyotyping in a 7-year period. A total of 257 procedures were performed in this period, and there was a significant change in the trend of indications for invasive prenatal diagnosis from an advanced maternal age in 2009 to a positive screen test by 2014. Chromosome abnormalities were observed in 9.8% of the cases, with trisomy 21 being the most frequent finding. The findings demonstrate the changing trends in screening and diagnostic testing in the tertiary care centre, with an acceptance of the first and second trimester maternal serum screening tests as a determinant for high-risk pregnancies. Impact statement What is already known on this subject? Despite the fact that India has one of the world's highest birth rates, there is still no public health care policy for the application of cytogenetic prenatal diagnosis. Nevertheless, we have been offering this test in our university teaching hospital since 2008, allowing us to characterise the changing trends in indications of pregnant women who sought invasive diagnostic procedures for foetal genetic studies. What do the results of this study add? The results of our study show that there were major changes in the common indications for prenatal diagnosis during the study period. In 2009, the main indication was an advanced maternal age, referred to in 31% of the cases, which declined steadily to 5% by 2014. In 2014, 51% of cases opted for a prenatal diagnosis because of a first trimester screen positive result, increasing from 12% in 2009. What are the implications of these findings for clinical practice and/or further research? This data is relevant as it would encourage other tertiary hospitals in developing countries like India to consider extending first trimester screening for all women, regardless of age and educate them on the options of prenatal genetic diagnosis for reassurance.

Chromosomal microarray as primary diagnostic genomic tool for pregnancies at increased risk within a population-based combined first-trimester screening program.

OBJECTIVE: To evaluate the performance of high-resolution chromosomal microarray (CMA) as the standard diagnostic approach for genomic imbalances in pregnancies with increased risk based on combined first-trimester screening (cFTS). METHODS: This was a retrospective study of genomic findings in a cohort of 575 consecutive pregnancies undergoing invasive testing because of a cFTS risk ≥ 1:300 on a publicly funded population-based screening program in the Central and Northern Regions of Denmark, between September 2015 and September 2016. Women with fetal nuchal translucency thickness ≥ 3.5 mm or opting for non-invasive prenatal testing (NIPT) were excluded. Comparative genomic hybridization was performed using a 180-K oligonucleotide array on DNA extracted directly from chorionic villus/amniocentesis samples. Genomic outcomes were reported in relation to cFTS findings. RESULTS: Of the 575 pregnancies that underwent invasive testing, CMA detected 22 (3.8% (95% CI, 2.5-5.7%)) cases of trisomies 21, 18 and 13, 14 (2.4% (95% CI, 1.4-4.0%)) cases of other types of aneuploidy and 15 (2.6% (95% CI, 1.5-4.3%)) cases with a pathogenic or probably pathogenic copy number variant (CNV). Of the 15 CNVs, three were > 10 Mb and would probably have been detected by chromosomal analysis, but the other 12 would most probably not have been detected using conventional cytogenetic techniques; therefore, the overall detection rate of CMA (8.9% (95% CI, 6.8-11.5%)) was significantly higher than that estimated for conventional cytogenetic analysis (6.8% (95% CI, 5.0-9.1%)) (P = 0.0049). Reducing the cFTS risk threshold for invasive diagnostic testing to 1 in 100 or 1 in 50 would have led, respectively, to 60% or 100% of the pathogenic CNVs being missed. CONCLUSIONS: CMA is a valuable diagnostic technique that can identify an increased number of genomic aberrations in pregnancies at increased risk on cFTS. Limiting diagnostic testing to pregnancies with a risk above 1 in 100 or 1 in 50, as proposed in contingent NIPT/invasive testing models, would lead to a significant proportion of pathogenic CNVs being missed at first-trimester screening. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.