日本医学会：医療における遺伝学的検査・診断に関するガイドライン （2022年3月改訂）．2022.
厚生科学審議会先端医療技術評価部会・出生前診断に関する専門委員会編：母体血清マーカー検査に関する見解. 1999.
Dungan JS, Klugman S, Darilek S, Malinowski J, Akkari YMN, Monaghan KG, Erwin A, Best RG; ACMG Board of Directors.
Noninvasive prenatal screening (NIPS) for fetal chromosome abnormalities in a general-risk population: An evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG).
Genet Med. 2023 Aug;25(8):100874. doi: 10.1016/j.gim.2023.100874. Epub 2023 Jun 27.
Abstract/Text
日本産科婦人科学会倫理委員会、母体血を用いた出生前遺伝学的検査に関する検討委員会編：母体血を用いた出生前遺伝学的検査(NIPT)に関する指針 (2020)、2020.
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Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders.
Obstet Gynecol. 2016 May;127(5):e108-e122. doi: 10.1097/AOG.0000000000001405.
Abstract/Text
Prenatal genetic diagnostic testing is intended to determine, with as much certainty as possible, whether a specific genetic disorder or condition is present in the fetus. In contrast, prenatal genetic screening is designed to assess whether a patient is at increased risk of having a fetus affected by a genetic disorder. Originally, prenatal genetic testing focused primarily on Down syndrome (trisomy 21), but now it is able to detect a broad range of genetic disorders. Although it is necessary to perform amniocentesis or chorionic villus sampling (CVS) to definitively diagnose most genetic disorders, in some circumstances, fetal imaging with ultrasonography, echocardiography, or magnetic resonance imaging may be diagnostic of a particular structural fetal abnormality that is suggestive of an underlying genetic condition.The objective of prenatal genetic testing is to detect health problems that could affect the woman, fetus, or newborn and provide the patient and her obstetrician-gynecologist or other obstetric care provider with enough information to allow a fully informed decision about pregnancy management. Prenatal genetic testing cannot identify all abnormalities or problems in a fetus, and any testing should be focused on the individual patient's risks, reproductive goals, and preferences. It is important that patients understand the benefits and limitations of all prenatal screening and diagnostic testing, including the conditions for which tests are available and the conditions that will not be detected by testing. It also is important that patients realize that there is a broad range of clinical presentations, or phenotypes, for many genetic disorders and that results of genetic testing cannot predict all outcomes. Prenatal genetic testing has many benefits, including reassuring patients when results are normal, identifying disorders for which prenatal treatment may provide benefit, optimizing neonatal outcomes by ensuring the appropriate location for delivery and the necessary personnel to care for affected infants, and allowing the opportunity for pregnancy termination.The purpose of this Practice Bulletin is to review the current status of prenatal genetic diagnostic testing and the evidence supporting its use. For information regarding screening for fetal aneuploidy, refer to Practice Bulletin No. 163, Screening for Fetal Aneuploidy.
Committee on Genetics and the Society for Maternal-Fetal Medicine.
Committee Opinion No.682: Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology.
Obstet Gynecol. 2016 Dec;128(6):e262-e268. doi: 10.1097/AOG.0000000000001817.
Abstract/Text
Genetic technology has advanced dramatically in the past few decades, and its applications and use in caring for and counseling pregnant women has been transformational in the realm of prenatal diagnosis. Two of the newer genetic technologies in the prenatal setting are chromosomal microarray and whole-exome sequencing. Chromosomal microarray analysis is a method of measuring gains and losses of DNA throughout the human genome. It can identify chromosomal aneuploidy and other large changes in the structure of chromosomes as well as submicroscopic abnormalities that are too small to be detected by traditional modalities. Prenatal chromosomal microarray analysis is recommended for a patient with a fetus with one or more major structural abnormalities identified on ultrasonographic examination and who is undergoing invasive prenatal diagnosis. Whole-genome sequencing analyzes the entire genome, including noncoding regions (introns) and coding regions (exons). However, because the introns are typically of little clinical relevance, there has been a focus instead on whole-exome sequencing, which examines the coding regions (exons) of the genome. The exons generally have greater clinical relevance and applicability to patient care. However, the routine use of whole-genome or whole-exome sequencing for prenatal diagnosis is not recommended outside of the context of clinical trials.
日本産科婦人科学会：出生前に行われる遺伝学的検査に関する見解. 日本産科婦人科学会誌 75．2023.
ACOG Committee on Practice Bulletins.
ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities.
Obstet Gynecol. 2007 Jan;109(1):217-27. doi: 10.1097/00006250-200701000-00054.
Abstract/Text
In the last decade, numerous markers and strategies for Down syndrome screening have been developed. Algorithms that combine ultrasound and serum markers in the first and second trimesters have been evaluated. Furthermore, the practice of using age cutoffs to determine whether women should be offered screening or invasive diagnostic testing has been challenged. The purpose of this document is to 1) present and evaluate the best available evidence for the use of ultrasonographic and serum markers for selected aneuploidy screening in pregnancy and 2) offer practical recommendations for implementing Down syndrome screening in practice.
佐藤 卓,末岡 浩ほか編：羊水検査、産婦人科の実際 産婦人科におけるリスクマネジメント、金原出版、2017；66(6)：721-727.
Bombard AT, Powers JF, Carter S, Schwartz A, Nitowsky HM.
Procedure-related fetal losses in transplacental versus nontransplacental genetic amniocentesis.
Am J Obstet Gynecol. 1995 Mar;172(3):868-72. doi: 10.1016/0002-9378(95)90013-6.
Abstract/Text
OBJECTIVE: We hypothesize that loss rates after amniocentesis do not differ in transplacental and nontransplacental taps performed by experienced operators.
STUDY DESIGN: Subjects were 1000 women undergoing second-trimester amniocentesis: 745 were referred for maternal age; 132 for positive maternal serum alpha-fetoprotein screens, 41 indicating a risk for fetal neural tube defect, 91 indicating a risk for fetal chromosome abnormality; and 123 were referred for other reasons. All procedures were videotaped. The placenta was anterior in 518 cases; in 306 of these the needle went through the placenta. All pregnancies were prospectively evaluated through delivery.
RESULTS: There were 13 losses among the 1000 procedures (1.3%). The transplacental losses occurred from 4 to 71 days after procedure, median 26.5 days; the nontransplacental losses from 12 days after procedure to term, median 25 days. The loss rate was essentially similar in the two categories: six transplacental (1.96%) and seven nontransplacental (1%) (relative risk 1.52 [95% confidence limits 0.84 to 2.75], p = 0.23). If the three patients with elevated maternal serum alpha-fetoprotein values were excluded from data analysis, the loss rates in the two groups were virtually identical (relative risk 0.98 [95% confidence limits 0.38 to 2.54], p = 1.0000).
CONCLUSION: Transplacental amniocentesis does not appear to increase the fetal loss rate in the hands of experienced surgeons. Moreover, in view of the time span between amniocentesis and loss in both groups, a procedural cause seems questionable.
Mujezinovic F, Alfirevic Z.
Analgesia for amniocentesis or chorionic villus sampling.
Cochrane Database Syst Rev. 2011 Nov 9;(11):CD008580. doi: 10.1002/14651858.CD008580.pub2. Epub 2011 Nov 9.
Abstract/Text
BACKGROUND: Besides risks of miscarriage, pregnant women undergoing amniocentesis or chorionic villus sampling (CVS) are also concerned about pain associated with these procedures. Currently, approaches to analgesia can be categorised in two broad categories - non-pharmacological and pharmacological agents.
OBJECTIVES: To evaluate whether different methods of analgesia have any impact on pain reduction during amniocentesis or chorionic villus sampling (CVS).
SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2011).
SELECTION CRITERIA: All randomised trials comparing different method of analgesia for amniocentesis or CVS. We also include trials with quasi-randomised designs, but analyse and report their results separately.
DATA COLLECTION AND ANALYSIS: Both review authors assessed eligibility and trial quality and performed data extraction.
MAIN RESULTS: We included a total of five randomised studies (involving 805 women) evaluating different methods of analgesia for amniocentesis; there were no studies in women undergoing CVS.One RCT (N = 203) and one quasi-randomised study (N = 220) compared infiltrative local anaesthesia with no anaesthesia and found no statistical difference in experienced pain on the visual analogue scale (VAS) (mean differences (MD) -2.50 and 1.20; 95% confidence interval (CI) -6.98 to 1.98 and -2.67 to 5.07).One study (N = 200) compared light leg rubbing versus no intervention during amniocentesis and found no change in experienced anxiety (MD 0.2; 95% CI -0.63 to 1.03) or VAS pain score (MD 0.3; 95% CI -0.35 to 0.95) during amniocentesis.Another study with 62 patients did not find any benefit of using subfreezing temperature needle during amniocentesis in terms of decreased VAS pain score (MD -0.8; 95% CI -1.8 to 0.2). In addition, there was no difference between anticipated and actual pain (MD 0.4; 95% CI -0.82 to 1.62) (before/after comparison).There was also no difference in VAS pain scores in the study with 120 participants comparing lidocaine-prilocaine analgesic cream to placebo cream before amniocentesis (MD -0.6; 95% CI -1.44 to 0.24).
AUTHORS' CONCLUSIONS: In general, women who undergo amniocentesis could be informed that pain during procedure is minor and that there is currently insufficient evidence to support the use of local anaesthetics, leg rubbing or subfreezing the needle for pain reduction during procedure.
Gordon MC, Ventura-Braswell A, Higby K, Ward JA.
Does local anesthesia decrease pain perception in women undergoing amniocentesis?
Am J Obstet Gynecol. 2007 Jan;196(1):55.e1-4. doi: 10.1016/j.ajog.2006.08.025.
Abstract/Text
OBJECTIVE: The null hypothesis is that local anesthesia does not decrease pain perception during amniocentesis.
STUDY DESIGN: We performed a prospective randomized study comparing local anesthesia (1% lidocaine) with no anesthesia before amniocentesis in a racially diverse population. Immediately after the procedure, subjects were asked to assess their pain using both a Visual Analogue Scale and a 101-point Numerical Rating Scale.
RESULTS: Two hundred four women were enrolled; 101 women received local, 102 women received no local, and 1 woman declined the amniocentesis after randomization. There was no difference in pain perception between the 2 groups as measured by either the visual analogue scale or the numeric rating scale (P = .28 and .18 respectively). The correlation coefficient between the 2 pain scales was strong with 0.86 for the local group and 0.92 for the no local group, (P < .001).
CONCLUSION: Administration of local anesthesia before amniocentesis does not decrease maternal pain perception.
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Midtrimester amniocentesis for prenatal diagnosis. Safety and accuracy.
JAMA. 1976 Sep 27;236(13):1471-6. doi: 10.1001/jama.1976.03270140023016.
Abstract/Text
This prospective study of the safety and accuracy of midtrimester amniocentesis involved 1,040 subjects and 992 controls. Immediate complications of amniocentesis (vaginal bleeding or amniotic fluid leakage) occurred in approximately 2% of the women. There was no statistically significant difference between the two groups in rate of fetal loss (3.5% for the subjects, 3.2% for the controls) or incidence of complications of pregnancy of delivery. Newborn examination indicated no significant differences between the two groups in incidence of congenital anomalies and no evidence of physical injury resulting from amniocentesis. The two groups did not differ significantly in physical, neurological, or developmental status at one year of age. Diagnostic accuracy was 99.4%. Midtrimester amniocentesis is a highly accurate and safe procedure that does not significantly increase the risk of fetal loss or injury.
Eddleman KA, Malone FD, Sullivan L, Dukes K, Berkowitz RL, Kharbutli Y, Porter TF, Luthy DA, Comstock CH, Saade GR, Klugman S, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, D'Alton ME.
Pregnancy loss rates after midtrimester amniocentesis.
Obstet Gynecol. 2006 Nov;108(5):1067-72. doi: 10.1097/01.AOG.0000240135.13594.07.
Abstract/Text
OBJECTIVE: The purpose of this study was to quantify the contemporary procedure-related loss rate after midtrimester amniocentesis using a database generated from patients who were recruited to the First And Second Trimester Evaluation of Risk for Aneuploidy trial.
METHODS: A total of 35,003 unselected patients from the general population with viable singleton pregnancies were enrolled in the First And Second Trimester Evaluation of Risk for Aneuploidy trial between 10 3/7 and 13 6/7 weeks gestation and followed up prospectively for complete pregnancy outcome information. Patients who either did (study group, n=3,096) or did not (control group, n=31,907) undergo midtrimester amniocentesis were identified from the database. The rate of fetal loss less than 24 weeks of gestation was compared between the two groups, and multiple logistic regression analysis was used to adjust for potential confounders.
RESULTS: The spontaneous fetal loss rate less than 24 weeks of gestation in the study group was 1.0% and was not statistically different from the background 0.94% rate seen in the control group (P=.74, 95% confidence interval -0.26%, 0.49%). The procedure-related loss rate after amniocentesis was 0.06% (1.0% minus the background rate of 0.94%). Women undergoing amniocentesis were 1.1 times more likely to have a spontaneous loss (95% confidence interval 0.7-1.5).
CONCLUSION: The procedure-related fetal loss rate after midtrimester amniocentesis performed on patients in a contemporary prospective clinical trial was 0.06%. There was no significant difference in loss rates between those undergoing amniocentesis and those not undergoing amniocentesis.
LEVEL OF EVIDENCE: II-2.
Mennuti MT.
Risks of second-trimester amniocentesis: why all the fuss 30 years later?
Obstet Gynecol. 2008 Mar;111(3):586-8. doi: 10.1097/AOG.0b013e318166eae6.
Abstract/Text
ACOG Committee Opinion No. 446: Array Comparative Genomic Hybridization in Prenatal Diagnosis. Obstet Gynecol [Internet]. 2009 Nov [cited 2019 May 17];114(5):1161–1163. Available from: http://insights.ovid.com/crossref?an=00006250-200911000-00039
Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L.
Chromosomal microarray versus karyotyping for prenatal diagnosis.
N Engl J Med. 2012 Dec 6;367(23):2175-84. doi: 10.1056/NEJMoa1203382.
Abstract/Text
BACKGROUND: Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental yield of chromosomal microarray analysis as compared with karyotyping for routine prenatal diagnosis.
METHODS: Samples from women undergoing prenatal diagnosis at 29 centers were sent to a central karyotyping laboratory. Each sample was split in two; standard karyotyping was performed on one portion and the other was sent to one of four laboratories for chromosomal microarray.
RESULTS: We enrolled a total of 4406 women. Indications for prenatal diagnosis were advanced maternal age (46.6%), abnormal result on Down's syndrome screening (18.8%), structural anomalies on ultrasonography (25.2%), and other indications (9.4%). In 4340 (98.8%) of the fetal samples, microarray analysis was successful; 87.9% of samples could be used without tissue culture. Microarray analysis of the 4282 nonmosaic samples identified all the aneuploidies and unbalanced rearrangements identified on karyotyping but did not identify balanced translocations and fetal triploidy. In samples with a normal karyotype, microarray analysis revealed clinically relevant deletions or duplications in 6.0% with a structural anomaly and in 1.7% of those whose indications were advanced maternal age or positive screening results.
CONCLUSIONS: In the context of prenatal diagnostic testing, chromosomal microarray analysis identified additional, clinically significant cytogenetic information as compared with karyotyping and was equally efficacious in identifying aneuploidies and unbalanced rearrangements but did not identify balanced translocations and triploidies. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT01279733.).
Muys J, Blaumeiser B, Jacquemyn Y, Bandelier C, Brison N, Bulk S, Chiarappa P, Courtens W, De Leener A, De Rademaeker M, Désir J, Destrée A, Devriendt K, Dheedene A, Fieuw A, Fransen E, Gatot JS, Holmgren P, Jamar M, Janssens S, Keymolen K, Lederer D, Menten B, Meuwissen M, Parmentier B, Pichon B, Rombout S, Sznajer Y, Van Den Bogaert A, Van Den Bogaert K, Vanakker O, Vermeesch J, Janssens K.
The Belgian MicroArray Prenatal (BEMAPRE) database: A systematic nationwide repository of fetal genomic aberrations.
Prenat Diagn. 2018 Dec;38(13):1120-1128. doi: 10.1002/pd.5373. Epub 2018 Nov 14.
Abstract/Text
OBJECTIVE: With the replacement of karyotyping by chromosomal microarray (CMA) in invasive prenatal diagnosis, new challenges have arisen. By building a national database, we standardize the classification and reporting of prenatally detected copy number variants (CNVs) across Belgian genetic centers. This database, which will link genetic and ultrasound findings with postnatal development, forms a unique resource to investigate the pathogenicity of variants of uncertain significance and to refine the phenotypic spectrum of pathogenic and susceptibility CNVs.
METHODS: The Belgian MicroArray Prenatal (BEMAPRE) consortium is a collaboration of all genetic centers in Belgium. We collected data from all invasive prenatal procedures performed between May 2013 and July 2016.
RESULTS: In this three-year period, 13 266 prenatal CMAs were performed. By national agreement, a limited number of susceptibility CNVs and no variants of uncertain significance were reported. Added values for using CMA versus conventional karyotyping were 1.8% in the general invasive population and 2.7% in cases with an ultrasound anomaly. Of the reported CNVs, 31.5% would have remained undetected with non-invasive prenatal test as the first-tier test.
CONCLUSION: The establishment of a national database for prenatal CNV data allows for a uniform reporting policy and the investigation of the prenatal and postnatal genotype-phenotype correlation.
© 2018 John Wiley & Sons, Ltd.
Patterson J, Wellesley D, Morgan S, Cilliers D, Allen S, Gardiner CA; Fetal Genomics Steering Group; UK Clinical Genetics Lead Clinician Group; UK Heads of Genetics Laboratory Group.
Prenatal chromosome microarray: 'The UK experience'. A survey of reporting practices in UK genetic services (2012-2019).
Prenat Diagn. 2021 May;41(6):661-667. doi: 10.1002/pd.5944. Epub 2021 Apr 13.
Abstract/Text
BACKGROUND: The value of chromosome microarray (CMA) in the prenatal detection of significant chromosome anomalies is well-established. To guide the introduction of this technique in routine clinical practice, the Joint Committee on Genomics in Medicine developed national UK guidelines for reporting prenatal CMA in 2015.
OBJECTIVE: To evaluate the UK experience of utilising prenatal CMA.
METHOD: A 36-item survey was distributed to all UK clinical genetics services (n = 23) in March 2019 requesting information pertaining to experience since diagnostic testing commenced and current practice (March 2018 to March 2019).
RESULTS: Eighteen UK genetics services currently offer prenatal CMA. A total of 14,554 tests had been performed. A pathogenic copy number variant was identified in 7.8% of tests overall, though the diagnostic rate increased to 8.4% in the final year of the survey. Variants of uncertain significance (VUS) were reported in 0.7% of tests, and 'actionable' incidental findings in 0.12%.
CONCLUSION: Diagnostic rate has improved over time, while reporting of VUS has decreased. Reviewing survey responses at a national level highlights variation in testing experience and practice, raising considerations both for future guideline development and implementation of other novel techniques including prenatal whole exome sequencing.
© 2021 John Wiley & Sons Ltd.
Li S, Shi Y, Han X, Chen Y, Shen Y, Hu W, Zhao X, Wang Y.
Prenatal Diagnosis of Chromosomal Mosaicism in Over 18,000 Pregnancies: A Five-Year Single-Tertiary-Center Retrospective Analysis.
Front Genet. 2022;13:876887. doi: 10.3389/fgene.2022.876887. Epub 2022 May 16.
Abstract/Text
Background: Chromosomal mosaicism (CM) is a common biological phenomenon observed in humans. It is one of the main challenges in prenatal diagnosis due to uncertain outcomes, especially when fetal ultrasonographic features appear normal. This study aimed to assess the phenotypic features of CM detected during prenatal diagnosis and the risk factors affecting parents' pregnancy decisions. Materials and methods: A retrospective cohort study involving 18,374 consecutive pregnancies that underwent prenatal diagnosis by karyotyping, fluorescence in situ hybridization (FISH), or chromosome microarray analysis (CMA) was conducted. The association of risk factors with malformations detected by ultrasound and pregnancy outcomes was assessed using the chi-square test and binary logistic regression. Discordant results between the different methods were identified and further analyzed. Results: During this five-year period, 118 (0.6%) patients were diagnosed with CM. The incidences of CM in the chorionic villus, amniotic fluid, and umbilical cord blood were 3.2, 0.5, and 0.7%, respectively. The frequency of ultrasound malformations in individuals with a high fraction of autosomal CM was significantly higher than that in other groups (62.5% vs. 21.4-33.3%, all p <0.05). Inconsistent results between karyotyping and CMA/FISH were observed in 23 cases (19.5%). The risk of pregnancy termination in cases with ultrasound malformations, consistent results, autosomal CM, or a high CM fraction increased with an odds ratio of 3.09, 8.35, 2.30, and 7.62 (all p <0.05). Multiple regression analysis revealed that all four factors were independent risk factors for the termination of pregnancy. Conclusion: Patients with a high fraction of autosomal CM are more likely to have ultrasound malformations. Inconsistent results between different methods in CM are not rare. Ultrasound malformations, consistent results between different methods, autosomal CM, and a high CM fraction were independent risk factors for the choice to terminate pregnancies.
Copyright © 2022 Li, Shi, Han, Chen, Shen, Hu, Zhao and Wang.
Firth H.
Chorion villus sampling and limb deficiency--cause or coincidence?
Prenat Diagn. 1997 Dec;17(13):1313-30.
Abstract/Text
Chorion villus sampling (CVS) is a widely used technique in first trimester prenatal diagnosis. In the early 1990s, two clusters of babies with limb defects following CVS were reported, raising the possibility of a causal association between early CVS and transverse limb deficiency. The evidence for this association is reviewed and shows a diminishing risk for transverse limb deficiency with advancing gestation. The risk of limb deficiency extends through the period of limb morphogenesis and slightly beyond; falling from levels 10-20-fold above background at nine weeks and below, to levels approaching (or only a few-fold above) background at 11 weeks and beyond.
Akolekar R, Beta J, Picciarelli G, Ogilvie C, D'Antonio F.
Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis.
Ultrasound Obstet Gynecol. 2015 Jan;45(1):16-26. doi: 10.1002/uog.14636.
Abstract/Text
OBJECTIVES: To estimate procedure-related risks of miscarriage following amniocentesis and chorionic villus sampling (CVS) based on a systematic review of the literature and a meta-analysis.
METHODS: A search of MEDLINE, EMBASE, CINHAL and The Cochrane Library (2000-2014) was performed to review relevant citations reporting procedure-related complications of amniocentesis and CVS. Only studies reporting data on more than 1000 procedures were included in this review to minimize the effect of bias from smaller studies. Heterogeneity between studies was estimated using Cochran's Q, the I(2) statistic and Egger bias. Meta-analysis of proportions was used to derive weighted pooled estimates for the risk of miscarriage before 24 weeks' gestation. Incidence-rate difference meta-analysis was used to estimate pooled procedure-related risks.
RESULTS: The weighted pooled risks of miscarriage following invasive procedures were estimated from analysis of controlled studies including 324 losses in 42 716 women who underwent amniocentesis and 207 losses in 8899 women who underwent CVS. The risk of miscarriage prior to 24 weeks in women who underwent amniocentesis and CVS was 0.81% (95% CI, 0.58-1.08%) and 2.18% (95% CI, 1.61-2.82%), respectively. The background rates of miscarriage in women from the control group that did not undergo any procedures were 0.67% (95% CI, 0.46-0.91%) for amniocentesis and 1.79% (95% CI, 0.61-3.58%) for CVS. The weighted pooled procedure-related risks of miscarriage for amniocentesis and CVS were 0.11% (95% CI, -0.04 to 0.26%) and 0.22% (95% CI, -0.71 to 1.16%), respectively.
CONCLUSION: The procedure-related risks of miscarriage following amniocentesis and CVS are much lower than are currently quoted.
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
Mardy AH, Norton ME.
Diagnostic testing after positive results on cell free DNA screening: CVS or Amnio?
Prenat Diagn. 2021 Sep;41(10):1249-1254. doi: 10.1002/pd.6021. Epub 2021 Aug 25.
Abstract/Text
OBJECTIVE: The positive predictive values of cell free DNA (cfDNA) and rates of confined placental mosaicism (CPM), imprinting and other factors vary by chromosome.
METHODS: We sought to review the literature for each of these features for each chromosome and provide recommendations on chorionic villus sampling (CVS) versus amniocentesis after an abnormal cfDNA result.
RESULTS: For chromosomes with high rates of CPM (trisomy 13, monosomy X and rare autosomal trisomies [RATs]), an amniocentesis should be considered if the first trimester ultrasound is normal. For monosomy X on cfDNA with an unaffected fetus, maternal karyotyping should be considered after normal fetal diagnostic testing. In cfDNA cases with a trisomy involving a chromosome with imprinted genes (6, 7, 11, 14, 15 and 20), CVS should be considered, followed by amniocentesis if abnormal. If the fetus is unaffected, methylation studies should be considered given the risk of uniparental disomy. A third trimester growth ultrasound should be considered for patients with a positive cfDNA screen for a RAT and an unaffected fetus, especially in the case of trisomy 16. For patients with multiple aneuploidy results on cfDNA, a work-up for maternal malignancy should be considered.
CONCLUSIONS: Clinicians should consider rates of CPM, imprinting, ultrasound findings and maternal factors when considering whether to recommend amniocentesis or CVS after an abnormal cfDNA result.
© 2021 John Wiley & Sons Ltd.
Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, Wainscoat JS.
Presence of fetal DNA in maternal plasma and serum.
Lancet. 1997 Aug 16;350(9076):485-7. doi: 10.1016/S0140-6736(97)02174-0.
Abstract/Text
BACKGROUND: The potential use of plasma and serum for molecular diagnosis has generated interest. Tumour DNA has been found in 'the plasma and serum of cancer patients, and molecular analysis has been done on this material. We investigated the equivalent condition in pregnancy-that is, whether fetal DNA is present in maternal plasma and serum.
METHODS: We used a rapid-boiling method to extract DNA from plasma and serum. DNA from plasma, serum, and nucleated blood cells from 43 pregnant women underwent a sensitive Y-PCR assay to detect circulating male fetal DNA from women bearing male fetuses.
FINDINGS: Fetus-derived Y sequences were detected in 24 (80%) of the 30 maternal plasma samples, and in 21 (70%) of the 30 maternal serum samples, from women bearing male fetuses. These results were obtained with only 10 microL of the samples. When DNA from nucleated blood cells extracted from a similar volume of blood was used, only five (17%) of the 30 samples gave a positive Y signal. None of the 13 women bearing female fetuses, and none of the ten non-pregnant control women, had positive results for plasma, serum or nucleated blood cells.
INTERPRETATION: Our finding of circulating fetal DNA in maternal plasma may have implications for non-invasive prenatal diagnosis, and for improving our understanding of the fetomaternal relationship.
Chiu RW, Chan KC, Gao Y, Lau VY, Zheng W, Leung TY, Foo CH, Xie B, Tsui NB, Lun FM, Zee BC, Lau TK, Cantor CR, Lo YM.
Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma.
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20458-63. doi: 10.1073/pnas.0810641105. Epub 2008 Dec 10.
Abstract/Text
Chromosomal aneuploidy is the major reason why couples opt for prenatal diagnosis. Current methods for definitive diagnosis rely on invasive procedures, such as chorionic villus sampling and amniocentesis, and are associated with a risk of fetal miscarriage. Fetal DNA has been found in maternal plasma but exists as a minor fraction among a high background of maternal DNA. Hence, quantitative perturbations caused by an aneuploid chromosome in the fetal genome to the overall representation of sequences from that chromosome in maternal plasma would be small. Even with highly precise single molecule counting methods such as digital PCR, a large number of DNA molecules and hence maternal plasma volume would need to be analyzed to achieve the necessary analytical precision. Here we reasoned that instead of using approaches that target specific gene loci, the use of a locus-independent method would greatly increase the number of target molecules from the aneuploid chromosome that could be analyzed within the same fixed volume of plasma. Hence, we used massively parallel genomic sequencing to quantify maternal plasma DNA sequences for the noninvasive prenatal detection of fetal trisomy 21. Twenty-eight first and second trimester maternal plasma samples were tested. All 14 trisomy 21 fetuses and 14 euploid fetuses were correctly identified. Massively parallel plasma DNA sequencing represents a new approach that is potentially applicable to all pregnancies for the noninvasive prenatal diagnosis of fetal chromosomal aneuploidies.
出生前検査認証制度等運営委員会，日本医学会：NIPT 等の出生前検査に関する情報提供及び施設（医療機関・検査分析機関）認証の指針. 2022. Available from: https://www.mhlw.go.jp/content/11908000/000901425.pdf
Ravi H, McNeill G, Goel S, Meltzer SD, Hunkapiller N, Ryan A, Levy B, Demko ZP.
Validation of a SNP-based non-invasive prenatal test to detect the fetal 22q11.2 deletion in maternal plasma samples.
PLoS One. 2018;13(2):e0193476. doi: 10.1371/journal.pone.0193476. Epub 2018 Feb 23.
Abstract/Text
INTRODUCTION: Non-invasive prenatal testing (NIPT) for aneuploidy using cell-free DNA in maternal plasma has been widely adopted. Recently, NIPT coverage has expanded to detect subchromosomal abnormalities including the 22q11.2 deletion. Validation of a SNP-based NIPT for detection of 22q11.2 deletions demonstrating a high sensitivity (97.8%) and specificity (99.75%) has been reported. We sought to further demonstrate the performance of a revised version of the test in a larger set of pregnancy plasma samples.
METHODS: Blood samples from pregnant women (10 with 22q11.2-deletion‒affected fetuses and 390 negative controls) were successfully analyzed using a revised SNP-based NIPT for the 22q11.2 deletion. The sensitivity and specificity of the assay were measured.
RESULTS: Sensitivity of the assay was 90% (9/10), and specificity of the assay was 99.74% (389/390), with a corresponding false positive-rate of 0.26%.
DISCUSSION: The data presented in this study add to the growing body of evidence demonstrating the ability of the SNP-based NIPT to detect 22q11.2 deletions with high sensitivity and specificity.
Palomaki GE, Deciu C, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Grody WW, Nelson SF, Canick JA.
DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study.
Genet Med. 2012 Mar;14(3):296-305. doi: 10.1038/gim.2011.73. Epub 2012 Feb 2.
Abstract/Text
PURPOSE: To determine whether maternal plasma cell-free DNA sequencing can effectively identify trisomy 18 and 13.
METHODS: Sixty-two pregnancies with trisomy 18 and 12 with trisomy 13 were selected from a cohort of 4,664 pregnancies along with matched euploid controls (including 212 additional Down syndrome and matched controls already reported), and their samples tested using a laboratory-developed, next-generation sequencing test. Interpretation of the results for chromosome 18 and 13 included adjustment for CG content bias.
RESULTS: Among the 99.1% of samples interpreted (1,971/1,988), observed trisomy 18 and 13 detection rates were 100% (59/59) and 91.7% (11/12) at false-positive rates of 0.28% and 0.97%, respectively. Among the 17 samples without an interpretation, three were trisomy 18. If z-score cutoffs for trisomy 18 and 13 were raised slightly, the overall false-positive rates for the three aneuploidies could be as low as 0.1% (2/1,688) at an overall detection rate of 98.9% (280/283) for common aneuploidies. An independent academic laboratory confirmed performance in a subset.
CONCLUSION: Among high-risk pregnancies, sequencing circulating cell-free DNA detects nearly all cases of Down syndrome, trisomy 18, and trisomy 13, at a low false-positive rate. This can potentially reduce invasive diagnostic procedures and related fetal losses by 95%. Evidence supports clinical testing for these aneuploidies.
Nicolaides KH, Syngelaki A, Gil M, Atanasova V, Markova D.
Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y.
Prenat Diagn. 2013 Jun;33(6):575-9. doi: 10.1002/pd.4103. Epub 2013 Apr 24.
Abstract/Text
OBJECTIVE: To assess the performance of cell-free DNA (cfDNA) testing in maternal blood for detection of fetal aneuploidy of chromosomes 13, 18, 21, X, and Y using targeted sequencing of single-nucleotide polymorphisms.
METHODS: Prospective study in 242 singleton pregnancies undergoing chorionic villus sampling at 11 to 13 weeks. Maternal blood was collected before chorionic villus sampling and sent to Natera (San Carlos, CA, USA). cfDNA was isolated from maternal plasma, and targeted multiplex PCR amplification followed by sequencing of 19 488 polymorphic loci covering chromosomes 13, 18, 21, X, and Y was performed. Sequencing data were analyzed using the NATUS algorithm that determines the copy number and calculates a sample-specific accuracy for each of the five chromosomes tested. Laboratory personnel were blinded to fetal karyotype.
RESULTS: Results were provided for 229 (94.6%) of the 242 cases. Thirty-two cases were correctly identified as aneuploid, including trisomy 21 [n = 25; sensitivity = 100% (CI: 86.3-100%), specificity = 100% (CI: 98.2-100%)], trisomy 18 (n = 3), trisomy 13 (n = 1), Turner syndrome (n = 2), and triploidy (n = 1), with no false positive or false negative results. Median accuracy was 99.9% (range: 96.0-100%).
CONCLUSIONS: cfDNA testing in maternal blood using targeted sequencing of polymorphic loci at chromosomes 13, 18, 21, X, and Y holds promise for accurate detection of fetal autosomal trisomies, sex chromosome aneuploidies, and triploidy.
© 2013 John Wiley & Sons, Ltd.
Norwitz ER, McNeill G, Kalyan A, Rivers E, Ahmed E, Meng L, Vu P, Egbert M, Shapira M, Kobara K, Parmar S, Goel S, Prins SA, Aruh I, Persico N, Robins JC, Kirshon B, Demko ZP, Ryan A, Billings PR, Rabinowitz M, Benn P, Martin KA, Hedriana HL.
Validation of a Single-Nucleotide Polymorphism-Based Non-Invasive Prenatal Test in Twin Gestations: Determination of Zygosity, Individual Fetal Sex, and Fetal Aneuploidy.
J Clin Med. 2019 Jun 28;8(7). doi: 10.3390/jcm8070937. Epub 2019 Jun 28.
Abstract/Text
We analyzed maternal plasma cell-free DNA samples from twin pregnancies in a prospective blinded study to validate a single-nucleotide polymorphism (SNP)-based non-invasive prenatal test (NIPT) for zygosity, fetal sex, and aneuploidy. Zygosity was evaluated by looking for either one or two fetal genome complements, fetal sex was evaluated by evaluating Y-chromosome loci, and aneuploidy was assessed through SNP ratios. Zygosity was correctly predicted in 100% of cases (93/93; 95% confidence interval (CI) 96.1%-100%). Individual fetal sex for both twins was also called with 100% accuracy (102/102; 95% weighted CI 95.2%-100%). All cases with copy number truth were also correctly identified. The dizygotic aneuploidy sensitivity was 100% (10/10; 95% CI 69.2%-100%), and overall specificity was 100% (96/96; 95% weighted CI, 94.8%-100%). The mean fetal fraction (FF) of monozygotic twins (n = 43) was 13.0% (standard deviation (SD), 4.5%); for dizygotic twins (n = 79), the mean lower FF was 6.5% (SD, 3.1%) and the mean higher FF was 8.1% (SD, 3.5%). We conclude SNP-based NIPT for zygosity is of value when chorionicity is uncertain or anomalies are identified. Zygosity, fetal sex, and aneuploidy are complementary evaluations that can be carried out on the same specimen as early as 9 weeks' gestation.
Jiménez-Coll V, El Kaaoui El Band J, Llorente S, González-López R, Fernández-González M, Martínez-Banaclocha H, Galián JA, Botella C, Moya-Quiles MR, Minguela A, Legaz I, Muro M.
All That Glitters in cfDNA Analysis Is Not Gold or Its Utility Is Completely Established Due to Graft Damage: A Critical Review in the Field of Transplantation.
Diagnostics (Basel). 2023 Jun 6;13(12). doi: 10.3390/diagnostics13121982. Epub 2023 Jun 6.
Abstract/Text
In kidney transplantation, a biopsy is currently the gold standard for monitoring the transplanted organ. However, this is far from an ideal screening method given its invasive nature and the discomfort it can cause the patient. Large-scale studies in renal transplantation show that approximately 1% of biopsies generate major complications, with a risk of macroscopic hematuria greater than 3.5%. It would not be until 2011 that a method to detect donor-derived cell-free DNA (dd-cfDNA) employing digital PCR was devised based on analyzing the differences in SNPs between the donor and recipient. In addition, since the initial validation studies were carried out at the specific moments in which rejection was suspected, there is still not a good understanding of how dd-cfDNA levels naturally evolve post-transplant. In addition, various factors, both in the recipient and the donor, can influence dd-cfDNA levels and cause increases in the levels of dd-cfDNA themselves without suspicion of rejection. All that glitters in this technology is not gold; therefore, in this article, we discuss the current state of clinical studies, the benefits, and disadvantages.
出生前検査認証制度等運営委員会：NIPT(非侵襲性出生前遺伝学的検査). Available from: https://jams-prenatal.jp/testing/nipt/follow-up-survey/
Dar P, Curnow KJ, Gross SJ, Hall MP, Stosic M, Demko Z, Zimmermann B, Hill M, Sigurjonsson S, Ryan A, Banjevic M, Kolacki PL, Koch SW, Strom CM, Rabinowitz M, Benn P.
Clinical experience and follow-up with large scale single-nucleotide polymorphism-based noninvasive prenatal aneuploidy testing.
Am J Obstet Gynecol. 2014 Nov;211(5):527.e1-527.e17. doi: 10.1016/j.ajog.2014.08.006. Epub 2014 Aug 8.
Abstract/Text
OBJECTIVE: We sought to report on laboratory and clinical experience following 6 months of clinical implementation of a single-nucleotide polymorphism-based noninvasive prenatal aneuploidy test in high- and low-risk women.
STUDY DESIGN: All samples received from March through September 2013 and drawn ≥9 weeks' gestation were included. Samples that passed quality control were analyzed for trisomy 21, trisomy 18, trisomy 13, and monosomy X. Results were reported as high or low risk for fetal aneuploidy for each interrogated chromosome. Relationships between fetal fraction and gestational age and maternal weight were analyzed. Follow-up on outcome was sought for a subset of high-risk cases. False-negative results were reported voluntarily by providers. Positive predictive value (PPV) was calculated from cases with an available prenatal or postnatal karyotype or clinical evaluation at birth.
RESULTS: Samples were received from 31,030 patients, 30,705 met study criteria, and 28,739 passed quality-control metrics and received a report detailing aneuploidy risk. Fetal fraction correlated positively with gestational age, and negatively with maternal weight. In all, 507 patients received a high-risk result for any of the 4 tested conditions (324 trisomy 21, 82 trisomy 18, 41 trisomy 13, 61 monosomy X; including 1 double aneuploidy case). Within the 17,885 cases included in follow-up analysis, 356 were high risk, and outcome information revealed 184 (51.7%) true positives, 38 (10.7%) false positives, 19 (5.3%) with ultrasound findings suggestive of aneuploidy, 36 (10.1%) spontaneous abortions without karyotype confirmation, 22 (6.2%) terminations without karyotype confirmation, and 57 (16.0%) lost to follow-up. This yielded an 82.9% PPV for all aneuploidies, and a 90.9% PPV for trisomy 21. The overall PPV for women aged ≥35 years was similar to the PPV for women aged <35 years. Two patients were reported as false negatives.
CONCLUSION: The data from this large-scale report on clinical application of a commercially available noninvasive prenatal test suggest that the clinical performance of this single-nucleotide polymorphism-based noninvasive prenatal test in a mixed high- and low-risk population is consistent with performance in validation studies.
Copyright © 2014 Elsevier Inc. All rights reserved.
Grati FR, Malvestiti F, Ferreira JC, Bajaj K, Gaetani E, Agrati C, Grimi B, Dulcetti F, Ruggeri AM, De Toffol S, Maggi F, Wapner R, Gross S, Simoni G.
Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results.
Genet Med. 2014 Aug;16(8):620-4. doi: 10.1038/gim.2014.3. Epub 2014 Feb 13.
Abstract/Text
PURPOSE: Noninvasive prenatal screening for fetal aneuploidy analyzes cell-free fetal DNA circulating in the maternal plasma. Because cell-free fetal DNA is mainly of placental trophoblast origin, false-positive and false-negative findings may result from placental mosaicism. The aim of this study was to calculate the potential contribution of placental mosaicism in discordant results of noninvasive prenatal screening.
METHODS: We performed a retrospective audit of 52,673 chorionic villus samples in which cytogenetic analysis of the cytotrophoblast (direct) and villus mesenchyme (culture) was performed, which was followed by confirmatory amniocentesis in chorionic villi mosaic cases. Using cases in which cytogenetic discordance between cytotrophoblast and amniotic fluid samples was identified, we calculated the potential contribution of cell line-specific mosaicism to false-positive and false-negative results of noninvasive prenatal screening.
RESULTS: The false-positive rate, secondary to the presence of abnormal cell line with common trisomies in cytotrophoblast and normal amniotic fluid, ranged from 1/1,065 to 1/3,931 at 10% and 100% mosaicism, respectively; the false-negative rate was calculated from cases of true fetal mosaicism, in which a mosaic cell line was absent in cytotrophoblast and present in the fetus; this occurred in 1/107 cases.
CONCLUSION: Despite exciting advances, underlying biologic mechanisms will never allow 100% sensitivity or specificity.
Yaron Y.
The implications of non-invasive prenatal testing failures: a review of an under-discussed phenomenon.
Prenat Diagn. 2016 May;36(5):391-6. doi: 10.1002/pd.4804. Epub 2016 Apr 2.
Abstract/Text
INTRODUCTION: Non-invasive prenatal testing (NIPT) using cell-free DNA in maternal blood is a relatively new screening modality for the common trisomies of chromosomes 21, 18 and 13 and sex chromosome aneuploidies. For some patients, however, results are not reported because of laboratory technical issues such as low fetal fraction and sequencing failures. In this review, the clinical implications of NIPT test failures are discussed.
METHODS: A Medline search was performed for all studies on NIPT that include >1000 samples. The failure rates were assessed by technology.
RESULTS: Methods based on massive parallel sequencing have been found to have the lowest failure rate (1.58%), while tests based on single-nucleotide polymorphism analysis have the highest failure rate (6.39%).
CONCLUSIONS: Recent publications suggest that patients who receive a 'no call' result are at increased risk of aneuploidy. Some professional societies have therefore recommended that these patients undergo genetic counseling and be offered invasive diagnostic testing. NIPT technology that has a high failure rate may increase the false positive rates, decrease the positive predictive value, and increase the procedure-related pregnancy loss. © 2016 John Wiley & Sons, Ltd.
© 2016 John Wiley & Sons, Ltd.
Suzumori N, Sekizawa A, Takeda E, Samura O, Sasaki A, Akaishi R, Wada S, Hamanoue H, Hirahara F, Kuriki H, Sawai H, Nakamura H, Yamada T, Miura K, Masuzaki H, Yamashita T, Kamei Y, Namba A, Murotsuki J, Tanemoto T, Fukushima A, Haino K, Tairaku S, Matsubara K, Maeda K, Kaji T, Ogawa M, Osada H, Nishizawa H, Okamoto Y, Kanagawa T, Kakigano A, Endo M, Kitagawa M, Ogawa M, Izumi S, Katagiri Y, Takeshita N, Kasai Y, Naruse K, Neki R, Masuyama H, Hyodo M, Kawano Y, Ohba T, Ichizuka K, Nagamatsu T, Watanabe A, Nishikawa N, Hamajima N, Shirato N, Yotsumoto J, Nishiyama M, Koide K, Hirose T, Sago H.
Classification of factors involved in nonreportable results of noninvasive prenatal testing (NIPT) and prediction of success rate of second NIPT.
Prenat Diagn. 2019 Jan;39(2):100-106. doi: 10.1002/pd.5408. Epub 2019 Jan 10.
Abstract/Text
OBJECTIVE: To evaluate the reasons for nonreportable cell-free DNA (cfDNA) results in noninvasive prenatal testing (NIPT), we retrospectively studied maternal characteristics and other details associated with the results.
METHODS: A multicenter retrospective cohort study in pregnant women undergoing NIPT by massively parallel sequencing (MPS) with failed cfDNA tests was performed between April 2013 and March 2017. The women's data and MPS results were analyzed in terms of maternal characteristics, test performance, fetal fraction (FF), z scores, anticoagulation therapy, and other details of the nonreportable cases.
RESULTS: Overall, 110 (0.32%) of 34 626 pregnant women had nonreportable cfDNA test results after an initial blood sampling; 22 (20.0%) cases had a low FF (<4%), and 18 (16.4%) cases including those with a maternal malignancy, were found to have altered genomic profile. Approximately half of the cases with nonreportable results had borderline z score. Among the women with nonreportable results because of altered genomic profile, the success rate of retesting using a second blood sampling was relatively low (25.0%-33.3%). Thirteen (11.8%) of the women with nonreportable results had required hypodermic heparin injection.
CONCLUSIONS: The classification of nonreportable results using cfDNA analysis is important to provide women with precise information and to reduce anxiety during pregnancy.
© 2018 John Wiley & Sons, Ltd.
Hui L.
Noninvasive prenatal testing for aneuploidy using cell-free DNA - New implications for maternal health.
Obstet Med. 2016 Dec;9(4):148-152. doi: 10.1177/1753495X16652007. Epub 2016 Jun 7.
Abstract/Text
The rapid global uptake of noninvasive prenatal testing for Down syndrome based on maternal plasma cell-free DNA has provided new data on the interrelationship between cell-free DNA and maternal health. Specific maternal conditions that can affect the performance of noninvasive prenatal testing include obesity, active autoimmune disease and low molecular weight heparin treatment. There is also a growing appreciation of the implications of discordant noninvasive prenatal testing results for maternal health, including unexpected diagnoses of maternal chromosomal conditions, or rarely, occult cancer. The interrelatedness of noninvasive prenatal testing and maternal health mean that the longstanding principles underpinning prenatal screening - voluntary testing, informed decision making, availability of specialist genetic counselling and well-defined clinical pathways - are more important than ever before.
日本産科婦人科学会：産婦人科診療ガイドライン-産科編（2023）．CQ106-3 nuchal translucency（NT）値の計測については？．2023．91-93.
Chan RW, Jiang P, Peng X, Tam LS, Liao GJ, Li EK, Wong PC, Sun H, Chan KC, Chiu RW, Lo YM.
Plasma DNA aberrations in systemic lupus erythematosus revealed by genomic and methylomic sequencing.
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):E5302-11. doi: 10.1073/pnas.1421126111. Epub 2014 Nov 26.
Abstract/Text
We performed a high-resolution analysis of the biological characteristics of plasma DNA in systemic lupus erythematosus (SLE) patients using massively parallel genomic and methylomic sequencing. A number of plasma DNA abnormalities were found. First, aberrations in measured genomic representations (MGRs) were identified in the plasma DNA of SLE patients. The extent of the aberrations in MGRs correlated with anti-double-stranded DNA (anti-dsDNA) antibody level. Second, the plasma DNA of active SLE patients exhibited skewed molecular size-distribution profiles with a significantly increased proportion of short DNA fragments. The extent of plasma DNA shortening in SLE patients correlated with the SLE disease activity index (SLEDAI) and anti-dsDNA antibody level. Third, the plasma DNA of active SLE patients showed decreased methylation densities. The extent of hypomethylation correlated with SLEDAI and anti-dsDNA antibody level. To explore the impact of anti-dsDNA antibody on plasma DNA in SLE, a column-based protein G capture approach was used to fractionate the IgG-bound and non-IgG-bound DNA in plasma. Compared with healthy individuals, SLE patients had higher concentrations of IgG-bound DNA in plasma. More IgG binding occurs at genomic locations showing increased MGRs. Furthermore, the IgG-bound plasma DNA was shorter in size and more hypomethylated than the non-IgG-bound plasma DNA. These observations have enhanced our understanding of the spectrum of plasma DNA aberrations in SLE and may provide new molecular markers for SLE. Our results also suggest that caution should be exercised when interpreting plasma DNA-based noninvasive prenatal testing and cancer testing conducted for SLE patients.
Norton ME, Jacobsson B, Swamy GK, Laurent LC, Ranzini AC, Brar H, Tomlinson MW, Pereira L, Spitz JL, Hollemon D, Cuckle H, Musci TJ, Wapner RJ.
Cell-free DNA analysis for noninvasive examination of trisomy.
N Engl J Med. 2015 Apr 23;372(17):1589-97. doi: 10.1056/NEJMoa1407349. Epub 2015 Apr 1.
Abstract/Text
BACKGROUND: Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first trimester in routine prenatal populations.
METHODS: In this prospective, multicenter, blinded study conducted at 35 international centers, we assigned pregnant women presenting for aneuploidy screening at 10 to 14 weeks of gestation to undergo both standard screening (with measurement of nuchal translucency and biochemical analytes) and cfDNA testing. Participants received the results of standard screening; the results of cfDNA testing were blinded. Determination of the birth outcome was based on diagnostic genetic testing or newborn examination. The primary outcome was the area under the receiver-operating-characteristic curve (AUC) for trisomy 21 (Down's syndrome) with cfDNA testing versus standard screening. We also evaluated cfDNA testing and standard screening to assess the risk of trisomies 18 and 13.
RESULTS: Of 18,955 women who were enrolled, results from 15,841 were available for analysis. The mean maternal age was 30.7 years, and the mean gestational age at testing was 12.5 weeks. The AUC for trisomy 21 was 0.999 for cfDNA testing and 0.958 for standard screening (P=0.001). Trisomy 21 was detected in 38 of 38 women (100%; 95% confidence interval [CI], 90.7 to 100) in the cfDNA-testing group, as compared with 30 of 38 women (78.9%; 95% CI, 62.7 to 90.4) in the standard-screening group (P=0.008). False positive rates were 0.06% (95% CI, 0.03 to 0.11) in the cfDNA group and 5.4% (95% CI, 5.1 to 5.8) in the standard-screening group (P<0.001). The positive predictive value for cfDNA testing was 80.9% (95% CI, 66.7 to 90.9), as compared with 3.4% (95% CI, 2.3 to 4.8) for standard screening (P<0.001).
CONCLUSIONS: In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes. (Funded by Ariosa Diagnostics and Perinatal Quality Foundation; NEXT ClinicalTrials.gov number, NCT01511458.).
American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics; Committee on Genetics; Society for Maternal-Fetal Medicine.
Screening for Fetal Chromosomal Abnormalities: ACOG Practice Bulletin, Number 226.
Obstet Gynecol. 2020 Oct;136(4):e48-e69. doi: 10.1097/AOG.0000000000004084.
Abstract/Text
Prenatal testing for chromosomal abnormalities is designed to provide an accurate assessment of a patient's risk of carrying a fetus with a chromosomal disorder. A wide variety of prenatal screening and diagnostic tests are available; each offers varying levels of information and performance, and each has relative advantages and limitations. When considering screening test characteristics, no one test is superior in all circumstances, which results in the need for nuanced, patient-centered counseling from the obstetric care professional and complex decision making by the patient. Each patient should be counseled in each pregnancy about options for testing for fetal chromosomal abnormalities. It is important that obstetric care professionals be prepared to discuss not only the risk of fetal chromosomal abnormalities but also the relative benefits and limitations of the available screening and diagnostic tests. Testing for chromosomal abnormalities should be an informed patient choice based on provision of adequate and accurate information, the patient's clinical context, accessible health care resources, values, interests, and goals. All patients should be offered both screening and diagnostic tests, and all patients have the right to accept or decline testing after counseling.The purpose of this Practice Bulletin is to provide current information regarding the available screening test options available for fetal chromosomal abnormalities and to review their benefits, performance characteristics, and limitations. For information regarding prenatal diagnostic testing for genetic disorders, refer to Practice Bulletin No. 162, Prenatal Diagnostic Testing for Genetic Disorders. For additional information regarding counseling about genetic testing and communicating test results, refer to Committee Opinion No. 693, Counseling About Genetic Testing and Communication of Genetic Test Results. For information regarding carrier screening for genetic conditions, refer to Committee Opinion No. 690, Carrier Screening in the Age of Genomic Medicine and Committee Opinion No. 691, Carrier Screening for Genetic Conditions. This Practice Bulletin has been revised to further clarify methods of screening for fetal chromosomal abnormalities, including expanded information regarding the use of cell-free DNA in all patients regardless of maternal age or baseline risk, and to add guidance related to patient counseling.
Fleddermann L, Hashmi SS, Stevens B, Murphy L, Rodriguez-Buritica D, Friel LA, Singletary C.
Current genetic counseling practice in the United States following positive non-invasive prenatal testing for sex chromosome abnormalities.
J Genet Couns. 2019 Aug;28(4):802-811. doi: 10.1002/jgc4.1122. Epub 2019 Apr 4.
Abstract/Text
The purpose of this study was to describe current genetic counseling practice in the United States following a non-invasive prenatal testing (NIPT) result positive for a sex chromosome abnormality (SCA). Screening for SCAs can be confounded by confined placental mosaicism, natural loss of the X chromosome from maternal cells during aging, and undiagnosed maternal SCA or copy number variant (CNV). Furthermore, with the exception of 45,X, individuals with SCAs usually have no ultrasound or postnatal findings. This makes follow-up for unresolved positive NIPT necessary; however, there are currently no clinical guidelines. This study used a cross-sectional design with an anonymous questionnaire to survey 176 genetic counselors. The majority of prenatal respondents always offered diagnostic testing (>88%) and anatomy ultrasound (~90%), but the percent consistently offering maternal karyotype (22%-52%) and postnatal evaluation (28%-87%) varied. Maternal karyotype was offered more often when NIPT was positive for 45,X or 47,XXX and patients had normal prenatal diagnostic testing (p < 0.02) or declined testing (p < 0.02). Offer of postnatal evaluation was more likely when diagnostic testing was declined (p < 0.001). The majority of pediatric providers always offered a postnatal karyotype for the newborn (>72%) but the percent offering maternal karyotype (6%-46%) varied widely. With the current inconsistencies, many newborns with undiagnosed SCAs who could benefit from growth hormone therapy, early intervention, and/or targeted surveillance may be missed. Therefore, there is a need for professional guidelines to help improve the consistency of clinical care for patients with NIPT results positive for SCAs.
© 2019 National Society of Genetic Counselors.
Platt LD, Greene N, Johnson A, Zachary J, Thom E, Krantz D, Simpson JL, Silver RK, Snijders RJ, Goetzl L, Pergament E, Filkins K, Mahoney MJ, Hogge WA, Wilson RD, Mohide P, Hershey D, MacGregor S, Bahado-Singh R, Jackson LG, Wapner R; First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study Group.
Sequential pathways of testing after first-trimester screening for trisomy 21.
Obstet Gynecol. 2004 Oct;104(4):661-6. doi: 10.1097/01.AOG.0000139832.79658.b9.
Abstract/Text
OBJECTIVE: To evaluate the performance and use of second-trimester multiple-marker maternal serum screening for trisomy 21 by women who had previously undergone first-trimester combined screening (nuchal translucency, pregnancy-associated plasma protein A, and free beta-hCG), with disclosure of risk estimates.
METHODS: In a multicenter, first-trimester screening study sponsored by the National Institute of Child Health and Human Development, multiple-marker maternal serum screening with alpha-fetoprotein, unconjugated estriol, and total hCG was performed in 4,145 (7 with trisomy 21) of 7,392 (9 with trisomy 21) women who were first-trimester screen-negative and 180 (7 with trisomy 21) of 813 (52 with trisomy 21) who were first-trimester screen-positive. Second-trimester risks were calculated using multiples of the median and a standardized risk algorithm with a cutoff risk of 1:270.
RESULTS: Among the first-trimester screen-negative cohort, 6 of 7 (86%) trisomy 21 cases were detected by second-trimester multiple-marker maternal serum screening with a false-positive rate of 8.9%. Among the first-trimester screen-positive cohort, all 7 trisomy 21 cases were also detected in the second trimester, albeit with a 38.7% false-positive rate.
CONCLUSION: Our data demonstrate that a sequential screening program that provides patients with first-trimester results and offers the option for early invasive testing or additional serum screening in the second trimester can detect 98% of trisomy 21-affected pregnancies. However, such an approach will result in 17% of patients being considered at risk and, hence, potentially having an invasive test.
LEVEL OF EVIDENCE: II-2
