Gestação em idade avançada e aconselhamento genético: um estudo em torno das concepções de risco / Advanced maternal age pregnancy and genetic counseling: a study on the concept of risk

Resumo As inovações científicas em torno do estudo de cromossomos humanos surgidas após a segunda metade do século XX consolidaram a inserção da genética na assistência em saúde, no que tange ao diagnóstico pré-natal. A associação entre idade materna e síndromes genéticas, proposta por pesquisadores da biomedicina, produziu determinações sobre risco, referidas a gestantes a partir de determinada idade. O artigo apresenta as concepções de risco em torno do que a biomedicina considera ser idade materna avançada de modo a configurar o que é classificado como gestação de risco. A análise documental em manuais médicos brasileiros e estrangeiros das especialidades obstetrícia e genética evidenciou diferentes concepções de risco em relação ao fator etário reprodutivo. A idade materna é um aspecto presente na obstetrícia enquanto fator de risco de doenças. Para a especialidade genética, a idade materna não é um fator central de risco reprodutivo. A pesquisa constatou que a classificação de uma idade materna ideal para gestar é relativa e suscetível a alterações, segundo o contexto sócio-histórico de cada sociedade.

Abstract Scientific innovations around the study of human chromosomes, which emerged after the mid 20th century, consolidated the incorporation of genetics in prenatal diagnosis. The link between maternal age and genetic syndromes, proposed by biomedical researchers, produced resolutions about risks to pregnant women of a certain age. The article presents biomedicine concepts for advanced maternal age classified as a risk pregnancy. The review of Brazilian and foreign medical manuals in obstetrics and genetics showed different conceptions of risk concerning the reproductive age factor. Maternal age is an aspect in obstetrics related to the risk of diseases. For genetic expertise, advanced maternal age is not a central factor of risk for reproduction. The research found that the classification of an ideal maternal age for pregnancy is relative and susceptible to changes according to the socio-historical context of each society.

A two-year prospective study assessing the performance of fetal chromosomal microarray analysis and next-generation sequencing in high-risk pregnancies.

BACKGROUND: Introduction of cell-free fetal DNA (cff-DNA) testing in maternal blood opened possibilities to improve the performance of combined first-trimester screening (cFTS) in terms of better detection of trisomies and lowering invasive testing rate. The use of new molecular methods, such as chromosomal microarray analysis (CMA) and next-generation sequencing (NGS), has shown benefits in prenatal diagnosis of chromosomal and genetic diseases, which are not detectable with cff-DNA screening, but require an invasive procedure. METHODS: The objective of this study was to evaluate prospectively during two years performance of CMA and NGS in high-risk pregnancies. Initially, we investigated 14,566 singleton pregnancies with cFTS. A total of 334 high-risk pregnancies were selected for CMA diagnostic performance evaluation and 28 cases of highly dysmorphic fetuses for NGS analysis. CMA study group was divided into two groups based on the indications for testing; group A patients with high-risk for trisomies after cFTS, but normal ultrasound and group B patients who met criteria for CMA as a first-tier diagnostic test. RESULTS: The diagnostic yield of CMA was overall 3.6% (1.6% in Group A and 6.0% in Group B). In NGS analysis group, we report diagnostic yield of 17.9%. CONCLUSION: The use of CMA in high-risk pregnancies is justified and provides relevant clinical information in 3.6% of the cases. NGS analysis in fetuses with multiple anomalies shows promising results, but more investigations are needed for a better understanding of practical applications of this molecular diagnosis method in prenatal settings.

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.

Clinical utility of expanded non-invasive prenatal screening and chromosomal microarray analysis in high-risk pregnancy.

OBJECTIVE: To evaluate the utility of expanded non-invasive prenatal screening (NIPS), compared with chromosomal microarray analysis (CMA), for the detection of chromosomal abnormalities in high-risk pregnancies. METHODS: This was a multicenter retrospective study of singleton pregnancies at high risk for chromosomal abnormality. Patients who underwent expanded NIPS and CMA sequentially during pregnancy from 2015 to 2019 were included in the analysis. Pregnancies with a positive result for sex chromosome aneuploidy were excluded as the full details could not be retrieved. The utility of expanded NIPS and CMA for detection of chromosomal abnormalities in this cohort was compared by assessing the concordance between the results. RESULTS: Of the 774 included high-risk pregnancies, 550 (71.1%) had a positive NIPS result, while a positive CMA result was detected in 308 (39.8%) cases. The rate of full or partial concordance between NIPS and CMA was 82.2%, 59.6% and 25.0% for trisomies 21, 18 and 13, respectively. For rare aneuploidies and segmental imbalances, NIPS and CMA results were fully or partially concordant in 7.5% and 33.3% of cases, respectively. Copy-number variants < 5 Mb were detected more often by CMA, with an incidence of 7.9% (61/774) compared with 3.1% (24/774) by NIPS. A genetic aberration was detected by CMA in 1 in 17 (5.8%) high-risk pregnancies that had a negative or non-reportable NIPS result. CONCLUSION: CMA allows for comprehensive detection of genome-wide chromosomal abnormalities in high-risk pregnancies. CMA should be offered instead of expanded NIPS for high-risk pregnancies. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Universal chromosomal microarray analysis reveals high proportion of copy-number variants in low-risk pregnancies.

OBJECTIVES: To evaluate the yield and utility of the routine use of chromosomal microarray analysis (CMA) for prenatal genetic diagnosis in a large cohort of pregnancies with normal ultrasound (US) at the time of genetic testing, compared with pregnancies with abnormal US findings. METHODS: We reviewed all prenatal CMA results in our center between November 2013 and December 2018. The prevalence of different CMA results in pregnancies with normal US at the time of genetic testing ('low-risk pregnancies'), was compared with that in pregnancies with abnormal US findings ('high-risk pregnancies'). Medical records were searched in order to evaluate subsequent US follow-up and the outcome of pregnancies with a clinically relevant copy-number variant (CNV), i.e. a pathogenic or likely pathogenic CNV or a susceptibility locus for disease with > 10% penetrance, related to early-onset disease in the low-risk group. RESULTS: In a cohort of 6431 low-risk pregnancies that underwent CMA, the prevalence of a clinically significant CNV related to early-onset disease was 1.1% (72/6431), which was significantly lower than the prevalence in high-risk pregnancies (4.9% (65/1326)). Of the low-risk pregnancies, 0.4% (27/6431) had a pathogenic or likely pathogenic CNV, and another 0.7% (45/6431) had a susceptibility locus with more than 10% penetrance. Follow-up of the low-risk pregnancies with a clinically significant early-onset CNV revealed that 31.9% (23/72) were terminated, while outcome data were missing in 26.4% (19/72). In 16.7% (12/72) of low-risk pregnancies, an US abnormality was discovered later on in gestation, after genetic testing had been performed. CONCLUSION: Although the background risk of identifying a clinically significant early-onset abnormal CMA result in pregnancies with a low a-priori risk is lower than that observed in high-risk pregnancies, the risk is substantial and should be conveyed to all pregnant women. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Fecundity is impaired in a mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by mutations in genes encoding type I collagen or proteins that process it. Women with OI have a small, but significant increase in risk of serious pregnancy complications including uterine rupture. Here, the OI mouse, Col1a2oim/oim , was used to examine the effects of collagen mutation on establishment and maintenance of pregnancy. Picrosirius birefringence was faint in Col1a2oim/oim uteri, indicating diminished collagen in the myometrium and endometrium. There was some evidence of increased uterine gland number (p = .055) and size (p = .12) in (p = .055) virgin uteri, though the they were not significantly different than controls. There were no differences in the number of corpora lutea, or the time from pairing to delivery of pups between Col1a2oim/oim and control dams, suggesting that ovulation and conception occur normally. However, when examined at Gestation Day 6.5 (postimplantation), gestation Day 10.5 (midpregnancy), and Postnatal Days 1-2, Col1a2oim/oim dams had significantly fewer viable pups than controls overall. In pairwise comparisons, the loss was only significant in the postnatal group, suggesting the gradual loss of pups over time. Overall, the Col1a2oim/oim mouse data suggest that OI impairs uterine function in pregnancy in a way that affects a small but significant number of fetuses.

The role and mechanism of asymmetric dimethylarginine in fetal growth restriction via interference with endothelial function and angiogenesis.

PURPOSE: Fetal growth restriction (FGR) is a high-risk pregnancy, and placental dysfunction is the main cause of FGR. The upregulation of asymmetric dimethylarginine (ADMA) is linked to FGR pathology, but the mechanism needs to be investigated. METHODS: The levels of ADMA and other related molecules were measured in human biological samples. We further used human umbilical vein endothelial cells (HUVECs) to reveal the mechanism of ADMA-induced FGR in vitro. RESULTS: Compared with the control group, FGR patients had higher placental resistance, and ADMA levels were increased in the maternal blood, cord blood, and placenta; additionally, nitric oxide (NO) production decreased, accompanied by a decreased expression of endogenous NO synthase (eNOS). The expression of vascular growth factor (VEGF) and placental growth factor (PLGF) in the maternal blood during the third trimester and umbilical cord of the FGR group was lower than the control group. The PLGF levels in the placentas of the FGR group were also reduced, while the expression of soluble fms-like tyrosine kinase-1 (sFlt-1) increased. In in vitro cell experiments, NO production was obviously lower when the cells were exposed to 100 µM of ADMA, with no difference in eNOS expression. There was a dose-dependent decrease in PLGF expression with increasing doses of ADMA, and the levels of sFlt-1 increased. Moreover, we confirmed that tube formation in HUVECs was lower after ADMA treatment compared with the control group. CONCLUSION: The accumulation of ADMA during pregnancy has an adverse effect on fetal development via interference with placental endothelial function and angiogenesis.

High risk-What's next? A survey study on decisional conflict, regret, and satisfaction among high-risk pregnant women making choices about further prenatal testing for fetal aneuploidy.

OBJECTIVES: To investigate decision making among pregnant women when choosing between noninvasive prenatal testing, invasive testing, or no further testing. METHODS: Women with a high-risk result from the first trimester screening were invited to fill in two online questionnaires at gestational age 12 to 14 (Q1) and 24 weeks (Q2). The scales used were Decisional Conflict and Regret Scales, Satisfaction with genetic Counselling Scale, and Health-Relevant Personality Inventory. RESULTS: Three hundred thirty-nine women agreed to participate, and the response rates were 76% on Q1 and 88% on Q2. A percentage of 75.4% chose an invasive test, 23.8% chose noninvasive prenatal testing (NIPT), 0.4% chose no further testing, and 0.4% had both NIPT and invasive testing. Among all participants, 13.3% had a high level of decisional conflict. We found that choosing NIPT was associated with a high decisional conflict (p = 0.013), receiving genetic counselling the same day was associated with a high decisional conflict (p = 0.039), and a high satisfaction with the genetic counselling was associated with low decisional conflict (p < 0.001). Furthermore, the personality subtrait "alexithymia" was associated with low decisional conflict (p = 0.043). There was a significant association between high decisional conflict and later decisional regret (p = 0.008). CONCLUSION: We present evidence that satisfaction with and timing of counselling are important factors to limit decisional conflict. Interestingly, women choosing NIPT had more decisional conflict than women choosing invasive testing.

Molecular Analysis of HLA-G in Women with High-Risk Pregnancy and Their Partners with Regard to Possible Complications.

The understanding of the molecular and biochemical characteristics of the human leukocyte antigen-G (HLA-G) is important because of the diverse influence of this antigen's polymorphisms on the course of a pregnancy. The aim of our study was to assess how the variation of the HLA-G allele and the HLA-G 14-bp ins/del polymorphism influence predisposition to a complicated pregnancy. The clinical material consisted of parental pairs with complicated pregnancies (210 women; 190 men). The control group included parental pairs without complications during pregnancy (89 women; 86 men). The study involved isolation of genome DNA from peripheral blood leukocytes, sequencing, and analysis of the 14-bp ins/del polymorphism in the 3'-untranslated region (3'-UTR) of the HLA-G gene based on polymerase chain reaction (PCR). The most common HLA-G allele in the group of women with complicated pregnancies was the HLA-G 10101 allele. There were no statistically significant differences in the frequencies of the 14-bp ins/del polymorphism in the 3'UTR of the HLA-G gene between the groups. Our results suggest that the risk of complications in pregnancy is influenced by the HLA-G 10101, HLA-G 10108, and HLA-G 10106 alleles and is not influenced by the 14-bp ins/del polymorphism in the 3'UTR of the HLA-G gene.

Prevalence of chromosomal abnormalities identified by copy number variation sequencing in high-risk pregnancies, spontaneous abortions, and suspected genetic disorders.

OBJECTIVE: High-throughput sequencing based on copy number variation (CNV-seq) is commonly used to detect chromosomal abnormalities including aneuploidy. This study provides evidence for the prevalence of chromosomal abnormalities in target populations. METHODS: A total of 160 samples, including 83 high-risk pregnancies, 37 spontaneous abortions, and 40 suspected genetic disorders, were analyzed by CNV-seq. Relationships between the incidence of these chromosomal abnormalities and risk factors (e.g. advanced maternal age, abnormal pregnancy history, and family history of congenital disease) were further analyzed by subgroup. RESULTS: A total of 37 (44.6%) high-risk pregnancies, 25 (67.6%) spontaneous abortions, and 22 (55%) suspected genetic disorders had chromosomal abnormalities including aneuploidy and CNVs. There was an increased risk association between the prevalence of aneuploidy and pathogenic-relevant CNV in the fetus or abortive tissue and advanced maternal age. Moreover, a family history of congenital disease was also positively correlated with fetal chromosomal abnormalities in high-risk pregnancies. CONCLUSION: A relatively high prevalence of chromosomal abnormalities was detected in high-risk pregnancies, spontaneous abortions, and suspected genetic disorders, indicating the importance of CNV detection in such populations.

Gene polymorphism associated with endothelial nitric oxide synthase (4VNTR, G894T, C786T) and unexplained recurrent spontaneous abortion risk: A meta-analysis.

To evaluate the association between endothelial nitric oxide synthase gene polymorphisms (4VNTR A/B, G894T, C786T) and risk of URSA.Related case-control studies were collected by computers. A meta-analysis was conducted using Stata 12.0 software to assess the strength of association.Altogether 37 articles were examining the relationship between endothelial nitric oxide synthase gene polymorphisms and URSA, among which sixteen (16) studies were related to 4VNTR, twelve (12) to G894T, and nine (9) to C786T, the study suggested that 4VNTR A/B polymorphism was closely connected with URSA risk under all gene models except for recessive model (AA vs. BB + AB). The integrated result which indicated the association between G894T gene mutation and URSA risk had been shown under homozygote (TT vs. GG; OR 1.585, 95%CI 1.175-2.138) and recessive models (TT vs. TG + GG; OR 1.530, 95%CI 1.142-2.052). Considering heterogeneity in the remaining gene models, subgroup analysis was performed on ethnicity, and the results showed that it was the dominant (TT + TG vs. GG; OR 1.585, 95%CI 1.175-2.138) and additive models (T vs. G; OR 1.727, 95%CI 1.372-2.175) of G894T in Asians and the heterozygote model (TG vs. GG; OR 1.015, 95%CI 0.846-1.217) in Caucasians that were associated with URSA (P < .05). Besides C786T gene was significantly connected with URSA under all models except for additive model (T vs. C).It is of great guiding significance for screening out and preventing URSA among high-risk women via testing on 4VNTR A/B, G894T, C786T eNOS under gene models mentioned above which are closely associated with URSA.

A Nucleic Acid Quality Control Strategy for Frozen Tissues from a Biobank of High-Risk Pregnancy.

BACKGROUND: The preservation of placental and fetal tissues will contribute to studying the pathogenesis of high-risk pregnancy diseases. However, few studies have focused on the effects of different preservation methods and cold ischemia time (CIT) on the quality of nucleic acids. An available quality control (QC) strategy will be beneficial to evaluate these effects for high-risk pregnancy biobanks. METHODS: We established an evaluation strategy of nucleic acid QC by analyzing total RNA and genomic DNA (gDNA). Through this strategy, the effects of CIT, cryoprotectants (CPAs), and freeze/thaw cycles on the yield and integrity of placental RNA were analyzed. In addition, the effects of CIT on the yield and integrity of fetal DNA were determined. RESULTS: For placental samples, there was no significant difference in RNA integrity (CIT <2 hours). After several freeze/thaw cycles, the RNA quality number values of placental samples in the CPA-free group and in the RNasin (TRIzol) group were decreased. For fetal samples, the DNA integrity of different organs (CIT <24 hours) was completely satisfactory, but it declined with the extension of CIT. Furthermore, different organs had different tolerances to cold ischemia, and the rank was as follows: skin, heart, liver, and placenta. In addition, the content of medium-length (600 bp) and long (1310 bp) fragments of gDNA were mainly reduced with the extension of CIT. CONCLUSION: The RNA integrity of placental tissue was affected by CIT significantly. It is recommended that placenta should be cryopreserved within 2 hours (4°C) from isolation. To ensure DNA quality of fetal tissues, the samples are suggested to be frozen within 24 hours (4°C) from isolation. On the contrary, if samples have a long CIT, skin is superior to other organs in the aspect of biobanking donor's genetic information.

[Screening for hotspot mutations associated with genetic hearing impairment in pregnant women and subsequent prenatal diagnosis in high risk pregnancies].

Objective: To screen for hotspot gene mutations associated with genetic deafness in Chinese pregnant women, and to perform risk assessment and prenatal diagnosis in high-risk families. Methods: Between November 2012 and October 2017, 26 117 pregnant women were screened by molecular hybridization microarray for 9 hot-spot mutations in 4 hereditary deafness related genes (GJB2 c. 35 del G, c. 176_191 del 16 bp, c. 235 del G, c. 299_300 del AT, GJB3 c. 538 C>T, SLC26A4 c. 2168 A>G, IVS 7-2 A>G, mitochondrial DNA 12S rRNA m. 1494 C>T, m. 1555 A>G). Genotype analysis was carried out in husbands of women carrying mutations, and prenatal diagnosis was carried out in the fetuses with high risk of deafness. Results: Among all women tested, 1 208(4.63%) were carriers of genetic deafness mutations, 7 with hearing impairment were affected by homozygous or compound heterozygous mutations, 51 were mitochondrial gene mutation carriers, 103 were carriers of GJB3 c. 538 C>T heterozygous mutation, 1 026 were carriers of GJB2 or SLC26A4 heterozygous mutations, and 21 carried heterozygous mutations in two genes simultaneously. In 394 families, the husbands accepted gene sequence testing, and 27 in which were determined as carriers of mutations in identical genes as their wives. Among which, 18 families received prenatal diagnosis, and 5 fetuses were diagnosed as hereditary deafness. In 9 families who did not receive prenatal diagnosis, 1 neonate was diagnosed as compound heterozygote after delivery. Conclusion: In order to prevent birth defects with congenital hearing problems, it is effective to provide screening for hotspot mutations in pregnant women and to perform prenatal diagnosis on high risk pregnancies.

A Spontaneous Pregnancy in a Patient with Turner Syndrome with 45,X/47,XXX Mosaicism: A Case Report and Review of the Literature.

BACKGROUND: Turner syndrome is a chromosomal abnormality, due to a total or partial loss of 1 of the X chromosomes and is mostly characterized clinically by short stature and primary ovarian insufficiency. Spontaneous pregnancies are rare (5%) and of relatively high risk. This is 1 of few reported cases of spontaneous conception and favorable prognosis in a patient with Turner syndrome and a 45,X/47,XXX karyotype. CASE: A 21-year-old woman with Turner mosaicism (45,X/47,XXX) who had a full-term, uncomplicated pregnancy after spontaneous conception, gave birth to a healthy female (46,XX) infant. SUMMARY AND CONCLUSION: Spontaneous pregnancies in women with Turner syndrome are a rarity. Fertility preservation methods are being discussed. Due to the high reported incidence of neonatal, obstetric, maternal, and especially cardiovascular complications in those pregnancies, close monitoring is essential.

Overall evaluation of the clinical value of prenatal screening for fetal-free DNA in maternal blood.

OBJECTIVE: To explore the clinical value of prenatal screening for fetal-free DNA in maternal blood. METHODS: A total of 10,275 maternal blood samples were collected from October 2012 to May 2016 at the prenatal diagnosis center of Changzhou Woman and Children Health Hospital. RESULTS: Among 10,275 pregnant women accepted noninvasive prenatal testing (NIPT), 9 cases could not get the results after collected the blood second times. The rate of NIPT failure was 0.09%. Seventy-two cases got the NIPT positive results of trisomy 21/trisomy 18/trisomy 13, and the detection rate, specificity, positive predictive value (PPV), and false positive rate were 98.59%, 99.99%, 97.22%, and 0.02%. The top-3 indications of the study were advanced age women (34.90%), high risk (25.22%), and intermediate risk (19.56%). They all had the satisfactory results of NIPT. Fifty-seven pregnant women had the high risk of fetal sex chromosomal aneuploidies (SCA). After informed consent, 33 cases accepted prenatal diagnosis. Eighteen cases were confirmed as sex chromosome aneuploidies. The PPV was 54.54%. Compared with other SCA, the PPV of Turner syndrome was lower. One case was false negative after followed up. CONCLUSIONS: NIPT showed a broad application prospects for prenatal screening and diagnosis of fetal chromosomal diseases. We should deepen mining and analyzing the clinical data, and explore the use of NIPT more reasonably from the perspective of evidence-based medicine.

A Systematic Review of DNA Methylation and Preterm Birth in African American Women.

BACKGROUND: The causes of many cases of preterm birth (PTB) remain enigmatic. Increased understanding of how epigenetic factors are associated with health outcomes has resulted in studies examining DNA methylation (DNAm) as a contributing factor to PTB. However, few studies on PTB and DNAm have included African American women, the group with the highest rate of PTB. METHODS: The objective of this review was to systematically analyze the existing studies on DNAm and PTB among African American women. RESULTS: Studies ( N = 10) were limited by small sample size, cross-sectional study designs, inconsistent methodologies for epigenomic analysis, and evaluation of different tissue types across studies. African Americans comprised less than half of the sample in 50% of the studies reviewed. Despite these limitations, there is evidence for an association between DNAm patterns and PTB. CONCLUSIONS: Future research on DNAm patterns and PTB should use longitudinal study designs, repeated DNAm testing, and a clinically relevant definition of PTB and should include large samples of high-risk African American women to better understand the mechanisms for PTB in this population.

Los defectos congénitos en la práctica pediátrica / Birth defects in pediatric practice

Los defectos congénitos (DC) son anomalías estructurales o funcionales, presentes desde el momento del nacimiento originadas por mutaciones genéticas (genómicas, cromosómicas o génicas), por factores ambientales, o por interacción de ambos. Son causa importante de mortalidad en menores de cinco años, y generalmente provocan discapacidades duraderas, con consecuencias negativas para los afectados, sus familias y la sociedad en general. En el 2014 en nuestro país su prevalencia fue de 11,3 por cada 1 000 nacidos vivos, y constituyó la segunda causa de muerte en los menores de un año, con una tasa de 0,9 por cada 1 000 nacidos vivos.1 Se estima que del 12 al 25 por ciento de los ingresos en los hospitales pediátricos se relacionan con DC...

Clinical evaluation of the IONA test: a non-invasive prenatal screening test for trisomies 21, 18 and 13.

OBJECTIVE: To evaluate the clinical accuracy of the IONA® test for aneuploidy screening. METHODS: This was a multicenter blinded study in which plasma samples from pregnant women at increased risk of trisomy 21 underwent cell-free DNA analysis utilizing the IONA test. For each sample, the IONA software generated a likelihood ratio and a maternal age-adjusted probability risk score for trisomies 21, 18 and 13. All results from the IONA test were compared against accepted diagnostic karyotyping. RESULTS: A total of 442 maternal samples were obtained, of which 437 had test results available for analysis and assessment of clinical accuracy. The IONA test had a detection rate of 100% for trisomies 21 (n = 43; 95% CI, 87.98-100%), 18 (n = 10; 95% CI, 58.72-100%) and 13 (n = 5; 95% CI, 35.88-100%) with cut-offs applied to likelihood ratio (cut-off > 1 considered high risk for trisomy) and probability risk score incorporating adjustment for maternal age (cut-off ≥ 1/150 considered high risk for trisomy). The false-positive rate (FPR) was 0% for trisomies 18 and 13 with both analysis outputs. For trisomy 21, a FPR of 0.3% was observed for the likelihood ratio, but became 0% with adjustment for maternal age. CONCLUSION: This study indicates that the IONA test is suitable for trisomy screening in a high-risk screening population. The result-interpretation feature of the IONA software should facilitate wider implementation, particularly in local laboratories, and should be a useful addition to the current screening methods for trisomies 21, 18 and 13.

Clinical experience with single-nucleotide polymorphism-based non-invasive prenatal screening for 22q11.2 deletion syndrome.

OBJECTIVES: To evaluate the performance of a single-nucleotide polymorphism (SNP)-based non-invasive prenatal test (NIPT) for the detection of fetal 22q11.2 deletion syndrome in clinical practice, assess clinical follow-up and review patient choices for women with high-risk results. METHODS: In this study, 21 948 samples were submitted for screening for 22q11.2 deletion syndrome using a SNP-based NIPT and subsequently evaluated. Follow-up was conducted for all cases with a high-risk result. RESULTS: Ninety-five cases were reported as high risk for fetal 22q11.2 deletion. Diagnostic testing results were available for 61 (64.2%) cases, which confirmed 11 (18.0%) true positives and identified 50 (82.0%) false positives, resulting in a positive predictive value (PPV) of 18.0%. Information regarding invasive testing was available for 84 (88.4%) high-risk cases: 57.1% (48/84) had invasive testing and 42.9% (36/84) did not. Ultrasound anomalies were present in 81.8% of true-positive and 18.0% of false-positive cases. Two additional cases were high risk for a maternal 22q11.2 deletion; one was confirmed by diagnostic testing and one had a positive family history. There were three pregnancy terminations related to screening results of 22q11.2 deletion, two of which were confirmed as true positive by invasive testing. CONCLUSIONS: Clinical experience with this SNP-based non-invasive screening test for 22q11.2 deletion syndrome indicates that these deletions have a frequency of approximately 1 in 1000 in the referral population with most identifiable through this test. Use of this screening method requires the availability of counseling and other management resources for high-risk pregnancies.