今日の臨床サポート

妊娠初期の染色体・遺伝子検査

著者: 末岡浩 慶應義塾大学病院 産婦人科

著者: 佐藤卓 慶應義塾大学病院 産婦人科

監修: 金山尚裕 静岡医療科学専門大学校

著者校正/監修レビュー済:2020/01/24
参考ガイドライン:
  1. 日本医学会編:医療における遺伝学的検査・診断に関するガイドライン.2011.
  1. 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.
  1. 公益社団法人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(NIPT)に関する指針. 2019.
  1. 米国産科婦人科学会(ACOG):American College of Obstetricians and Gynecologists’Committee on Practice Bulletins—Obstetrics; Committee on Genetics; Society for Maternal–Fetal Medicine. Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders.2016.
  1. 日本産科婦人科学会編:出生前に行われる検査および診断に関する見解. 2011.

概要・推奨   

  1. 出生前遺伝学的検査の実施に先立って, 利用可能な選択肢の提示とそれぞれの意義と特徴に関する遺伝カウンセリングを行う[1]。実施には文書による同意が必要である(推奨度1)。
  1. 母体血清マーカー検査の実施にあたっては、非確定検査であること・高い陰性的中率(99%程度)を有する一方で、 陽性的中率がやや低いこと(1%程度であること)等を説明し、その性質に関して十分な理解を得る必要がある。検査陽性の事例にも、胎児がダウン症候群に必ずしも罹患していないこと・診断には羊水検査等の実施が必要であることを十分に説明する必要がある[2](推奨度1)。
  1. NT(nuchal translucency)を含む妊娠初期の超音波スクリーニング検査は、正確な計測のための十分な時間や機会が確保出来ない妊婦健診においてルーティンに実施されるべきではない。わが国における検査の標準化は依然として立ち後れているのだが、欧米における計測のためのライセンス精度に則り、一部の医療施設において検査の適正な提供が試みられている現状がある(推奨なし)。
  1. 母体血を用いた非侵襲的出生前遺伝学的検査(Non-invasive prenatal testing/screening: NIPT/NIPS)は、2013年の導入以来、わが国においては依然として臨床研究としての位置づけで実施されており、日本医学会による実施施設の審査・登録が義務づけられている。検査の高い精度(感度および特異度)に対して、ダウン症候群に対する陽性的中率が90%程度に留まること・検査陽性例では羊水検査による確定診断を実施することについて、実施に先立って理解を得ることが望ましい[3](推奨度1)。
  1. 羊水染色体検査の実施時期は、検査の安全性の観点からは妊娠15週以降の実施が望ましい。解析法には、従来のG分染法に加えて、マイクロアレイ法による解析が利用可能である。マイクロアレイ解析の不用意な実施により、臨床的意義の明らかでない染色体コピー数変化(variant of unknown significance: VUS)や、浸透率の低い/表現型に差異のある染色体コピー数変化(susceptibility copy number variants or CNVs)が検出される事があり、胎児の表現型の解釈に難渋する事例が存在する。したがって、現時点では妊娠初期の超音波検査にて胎児構造異常が指摘されている事例や、原因不明の胎児死亡の事例が良い適応となる[4][5] (推奨度1)。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
末岡浩 : 特に申告事項無し[2021年]
佐藤卓 : 特に申告事項無し[2021年]
監修:金山尚裕 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、特に母体血を用いた非侵襲的出生前遺伝学的検査の臨床研究について加筆・修正を行った。

病態・疫学・診察

まとめ  
  1. 出生前遺伝学的検査は、妊娠中の比較的早い時期に胎児の情報を知ることで、その状態を把握し、分娩後の胎児の最もよい成育環境を整備することを目的として行う[6]
  1. 検査の一般な適応としては、高齢妊娠・両親のいずれかが染色体異常の保因者・染色体異常児の妊娠・出産の既往・妊婦が新生児期もしくは小児期に発症する重篤なX連鎖遺伝病のヘテロ接合体の場合・夫婦の両者が新生児期もしくは小児期に発症する重篤な常染色体劣性遺伝病のヘテロ接合体の場合・夫婦の一方もしくは両者が新生児期もしくは小児期に発症する重篤な常染色体優性遺伝病のヘテロ接合体の場合・胎児が重篤な疾患に罹患する可能性のある場合とされる[6]
  1. 検査の実施に先立って、十分な専門知識を持った医師などで構成される、適正な遺伝カウンセリング体制が必要である[6]。検査を希望する夫婦に対し、あらかじめそれぞれの検査の意義・実施方法・検査の限界と危険性・かかる費用などについて、所定の説明要領に基づいて十分な説明を行い、文書に基づく同意を得る必要があるアルゴリズム
 
出生前診断における非確定検査と確定検査

検査時期
A.非確定的検査(非侵襲的検査):
  1. 母体血清マーカー
  a) トリプルマーカー:AFP、hCG、uE3(15週0日~18週6日)またはクアトロテスト:AFP、hCG、uE3、inhibin(15週0日~18週6日)
  b) NT計測など超音波検査に加えて、母体血清中のPAPP-Aおよびfree ß-hCG測定の組合わせによるスクリーニング検査を提供する施設もある(11週0日~13週6日)
 
B.確定的検査(侵襲的検査):
1.胎児染色体検査
  a)絨毛検査(10週0日~14週6日)
  b)羊水検査(15週0日以降)

出典

img1:  著者提供
 
 
 
  1. 検査の実施時期や検体採取の方法と解析法との組み合わせ等に基づき、様々な選択肢が利用可能である。大別すると、非確定的検査である非侵襲的検査および確定診断のための侵襲的検査に分類可能である。非侵襲的検査には、母体血清マーカー検査・胎児後頸部透亮像(nuchal translucency: NT)等を測定する妊娠初期胎児超音波検査および母体血を用いた非侵襲的出生前遺伝学的検査等が含まれ、検査結果に基づき胎児がなんらかの疾患に罹患している可能性の高いハイリスク群を抽出し、確定診断のための検査へ導く役割も果たすアルゴリズム。侵襲的検査には羊水検査・絨毛検査が含まれる。
  1. 結果の開示にあたっては、特に胎児に陽性所見を認めるとされた際には、最新の医学的知見と生命倫理に基づく慎重な検査後カウンセリングを行い、夫婦の意思を最大限に尊重した上で、その自己決定がなされるように支援することが大切である。

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文献 

著者: American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics, Committee on Genetics, Society for Maternal–Fetal Medicine
雑誌名: Obstet Gynecol. 2016 May;127(5):e108-22. 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.

PMID 26938573  Obstet Gynecol. 2016 May;127(5):e108-22. doi: 10.1097/A・・・
著者: Committee on Genetics and the Society for Maternal-Fetal Medicine
雑誌名: 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.

PMID 27875474  Obstet Gynecol. 2016 Dec;128(6):e262-e268. doi: 10.1097・・・
著者: ACOG Committee on Practice Bulletins
雑誌名: Obstet Gynecol. 2007 Jan;109(1):217-27.
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.

PMID 17197615  Obstet Gynecol. 2007 Jan;109(1):217-27.
著者:
雑誌名: Obstet Gynecol. 2009 Nov;114(5):1161-3. doi: 10.1097/AOG.0b013e3181c33cad.
Abstract/Text The widespread use of array comparative genomic hybridization (CGH)for the diagnosis of genomic rearrangements in children with idiopathic mental retardation,developmental delay, and multiple congenital anomalies has spurred interest in applying array CGH technology to prenatal diagnosis. The use of array CGH technology in prenatal diagnosis is currently limited by several factors, including the inability to detect balanced chromosomal rearrangements, the detection of copy number variations of uncertain clinical significance, and significantly higher costs than conventional karyotype analysis. Although array CGH has distinct advantages over classic cytogenetics in certain applications, the technology is not currently a replacement for classic cytogenetics in prenatal diagnosis.

PMID 20168129  Obstet Gynecol. 2009 Nov;114(5):1161-3. doi: 10.1097/AO・・・
著者: Ronald J Wapner, Christa Lese Martin, Brynn Levy, Blake C Ballif, Christine M Eng, Julia M Zachary, Melissa Savage, Lawrence D Platt, Daniel Saltzman, William A Grobman, Susan Klugman, Thomas Scholl, Joe Leigh Simpson, Kimberly McCall, Vimla S Aggarwal, Brian Bunke, Odelia Nahum, Ankita Patel, Allen N Lamb, Elizabeth A Thom, Arthur L Beaudet, David H Ledbetter, Lisa G Shaffer, Laird Jackson
雑誌名: 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.).

PMID 23215555  N Engl J Med. 2012 Dec 6;367(23):2175-84. doi: 10.1056/・・・
著者: Christine M Armour, Shelley Danielle Dougan, Jo-Ann Brock, Radha Chari, Bernie N Chodirker, Isabelle DeBie, Jane A Evans, William T Gibson, Elena Kolomietz, Tanya N Nelson, Frédérique Tihy, Mary Ann Thomas, Dimitri J Stavropoulos, On-Behalf-Of the Canadian College of Medical Geneticists
雑誌名: J Med Genet. 2018 Apr;55(4):215-221. doi: 10.1136/jmedgenet-2017-105013. Epub 2018 Mar 1.
Abstract/Text BACKGROUND: The aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update.
METHODS: A multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the CCMG membership-at-large for feedback and, following incorporation of feedback, was approved by the CCMG Board of Directors on 5 June 2017 and the SOGC Board of Directors on 19 June 2017.
RESULTS AND CONCLUSIONS: Recommendations include but are not limited to: (1) CMA should be offered following a normal rapid aneuploidy screen when multiple fetal malformations are detected (II-1A) or for nuchal translucency (NT) ≥3.5 mm (II-2B) (recommendation 1); (2) a professional with expertise in prenatal chromosomal microarray analysis should provide genetic counselling to obtain informed consent, discuss the limitations of the methodology, obtain the parental decisions for return of incidental findings (II-2A) (recommendation 4) and provide post-test counselling for reporting of test results (III-A) (recommendation 9); (3) the resolution of chromosomal microarray analysis should be similar to postnatal microarray platforms to ensure small pathogenic variants are detected. To minimise the reporting of uncertain findings, it is recommended that variants of unknown significance (VOUS) smaller than 500 Kb deletion or 1 Mb duplication not be routinely reported in the prenatal context. Additionally, VOUS above these cut-offs should only be reported if there is significant supporting evidence that deletion or duplication of the region may be pathogenic (III-B) (recommendation 5); (4) secondary findings associated with a medically actionable disorder with childhood onset should be reported, whereas variants associated with adult-onset conditions should not be reported unless requested by the parents or disclosure can prevent serious harm to family members (III-A) (recommendation 8).The working group recognises that there is variability across Canada in delivery of prenatal testing, and these recommendations were developed to promote consistency and provide a minimum standard for all provinces and territories across the country (recommendation 9).

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 29496978  J Med Genet. 2018 Apr;55(4):215-221. doi: 10.1136/jmedg・・・
著者: Gabriella L Morley, Ian D Wacogne
雑誌名: Arch Dis Child Educ Pract Ed. 2017 Aug 9;. doi: 10.1136/archdischild-2016-311557. Epub 2017 Aug 9.
Abstract/Text
PMID 28794004  Arch Dis Child Educ Pract Ed. 2017 Aug 9;. doi: 10.1136・・・
著者: Joke Muys, Bettina Blaumeiser, Yves Jacquemyn, Claude Bandelier, Nathalie Brison, Saskia Bulk, Patrizia Chiarappa, Winnie Courtens, Anne De Leener, Marjan De Rademaeker, Julie Désir, Anne Destrée, Koenraad Devriendt, Annelies Dheedene, Annelies Fieuw, Erik Fransen, Jean-Stéphane Gatot, Philip Holmgren, Mauricette Jamar, Sandra Janssens, Kathelijn Keymolen, Damien Lederer, Björn Menten, Marije Meuwissen, Benoit Parmentier, Bruno Pichon, Sonia Rombout, Yves Sznajer, Ann Van Den Bogaert, Kris Van Den Bogaert, Olivier Vanakker, Joris Vermeesch, Katrien Janssens
雑誌名: 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.
PMID 30334587  Prenat Diagn. 2018 Dec;38(13):1120-1128. doi: 10.1002/p・・・
著者: Michael C Gordon, Ada Ventura-Braswell, Kenneth Higby, John A Ward
雑誌名: 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.

PMID 17240233  Am J Obstet Gynecol. 2007 Jan;196(1):55.e1-4. doi: 10.1・・・
著者: Faris Mujezinovic, Zarko Alfirevic
雑誌名: 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.

PMID 22071854  Cochrane Database Syst Rev. 2011 Nov 9;(11):CD008580. d・・・
著者:
雑誌名: JAMA. 1976 Sep 27;236(13):1471-6.
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.

PMID 989112  JAMA. 1976 Sep 27;236(13):1471-6.
著者: Keith A Eddleman, Fergal D Malone, Lisa Sullivan, Kim Dukes, Richard L Berkowitz, Yara Kharbutli, T Flint Porter, David A Luthy, Christine H Comstock, George R Saade, Susan Klugman, Lorraine Dugoff, Sabrina D Craigo, Ilan E Timor-Tritsch, Stephen R Carr, Honor M Wolfe, Mary E D'Alton
雑誌名: 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.

PMID 17077226  Obstet Gynecol. 2006 Nov;108(5):1067-72. doi: 10.1097/0・・・
著者: Michael T Mennuti
雑誌名: Obstet Gynecol. 2008 Mar;111(3):586-8. doi: 10.1097/AOG.0b013e318166eae6.
Abstract/Text
PMID 18310359  Obstet Gynecol. 2008 Mar;111(3):586-8. doi: 10.1097/AOG・・・
著者: Z Alfirevic, K Sundberg, S Brigham
雑誌名: Cochrane Database Syst Rev. 2003;(3):CD003252. doi: 10.1002/14651858.CD003252.
Abstract/Text BACKGROUND: A major disadvantage of second trimester amniocentesis is that the result is usually available only after 18 weeks' gestation. Chorionic villus sampling (CVS) and early amniocentesis can be done between 9 and 14 weeks and offer an earlier alternative.
OBJECTIVES: The objective was to assess comparative safety and accuracy of second trimester amniocentesis, early amniocentesis, transcervical and transabdominal CVS.
SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (March 2003) and the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2002).
SELECTION CRITERIA: All randomised trials comparing amniocentesis and CVS.
DATA COLLECTION AND ANALYSIS: Two reviewers assessed eligibility and trial quality and performed data extraction. We analysed the data using RevMan software.
MAIN RESULTS: A total of 14 randomised studies have been included. In a low risk population with a background pregnancy loss of around 2%, a second trimester amniocentesis will increase this risk by another 1%. This difference did not reach statistical significance, but the increase in spontaneous miscarriages following second trimester amniocentesis compared with controls (no amniocentesis) did (2.1% versus 1.3%; relative risk (RR) 1.02 to 2.52). Early amniocentesis is not a safe early alternative to second trimester amniocentesis because of increased pregnancy loss (7.6% versus 5.9%; RR 1.29, 95% CI 1.03 to 1.61) and higher incidence of talipes compared to CVS (1.8% versus 0.2%; RR 6.43, 95% CI 1.68 to 24.64).Compared with second trimester amniocentesis, transcervical CVS carries a significantly higher risk of pregnancy loss (14.5% versus 11%; RR 1.40, 95% CI 1.09 to 1.81) and spontaneous miscarriage (12.9% versus 9.4%; RR 1.50, 95% CI 1.07 to 2.11). One study compared transabdominal CVS with second trimester amniocentesis and found no significant difference in the total pregnancy loss between the two procedures (6.3% versus 7%). Transcervical CVS is more technically demanding than transabdominal CVS with more failures to obtain sample and more multiple insertions.
REVIEWER'S CONCLUSIONS: Second trimester amniocentesis is safer than transcervical CVS and early amniocentesis. If earlier diagnosis is required, transabdominal CVS is preferable to early amniocentesis or transcervical CVS. In circumstances where transabdominal CVS may be technically difficult the preferred options are transcervical CVS in the first trimester or second trimester amniocentesis.

PMID 12917956  Cochrane Database Syst Rev. 2003;(3):CD003252. doi: 10.・・・
著者: Committee on Practice Bulletins—Obstetrics, Committee on Genetics, and the Society for Maternal-Fetal Medicine
雑誌名: Obstet Gynecol. 2016 May;127(5):e123-37. doi: 10.1097/AOG.0000000000001406.
Abstract/Text Prenatal genetic screening is designed to assess whether a patient is at increased risk of having a fetus affected by a genetic disorder. In contrast, 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. The purpose of prenatal screening for aneuploidy is to provide an assessment of the woman's risk of carrying a fetus with one of the more common fetal aneuploidies. This is in contrast to prenatal diagnostic testing for genetic disorders, in which the fetal chromosomes are evaluated for the presence or absence of abnormalities in chromosome number, deletions, and duplications, or the fetal DNA is evaluated for specific genetic disorders. The wide variety of screening test options, each offering varying levels of information and accuracy, has resulted in the need for complex counseling by the health care provider and complex decision making by the patient. No one screening test is superior to other screening tests in all test characteristics. Each test has relative advantages and disadvantages. It is important that obstetrician-gynecologists and other obstetric care providers be prepared to discuss not only the risk of aneuploidy but also the benefits, risks, and limitations of available screening tests. Screening for aneuploidy should be an informed patient choice, with an underlying foundation of shared decision making that fits the patient's clinical circumstances, values, interests, and goals.The purpose of this Practice Bulletin is to provide current information regarding the available screening test options for fetal aneuploidy and to review their benefits, accuracy, and limitations. For information regarding prenatal diagnostic testing for genetic disorders, refer to Practice Bulletin No. 162, Prenatal Diagnostic Testing for Genetic Disorders.

PMID 26938574  Obstet Gynecol. 2016 May;127(5):e123-37. doi: 10.1097/A・・・
著者: Y M Lo, N Corbetta, P F Chamberlain, V Rai, I L Sargent, C W Redman, J S Wainscoat
雑誌名: 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.

PMID 9274585  Lancet. 1997 Aug 16;350(9076):485-7. doi: 10.1016/S0140・・・
著者: Glenn E Palomaki, Cosmin Deciu, Edward M Kloza, Geralyn M Lambert-Messerlian, James E Haddow, Louis M Neveux, Mathias Ehrich, Dirk van den Boom, Allan T Bombard, Wayne W Grody, Stanley F Nelson, Jacob A Canick
雑誌名: 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.

PMID 22281937  Genet Med. 2012 Mar;14(3):296-305. doi: 10.1038/gim.201・・・
著者: K H Nicolaides, A Syngelaki, M Gil, V Atanasova, D Markova
雑誌名: 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.
PMID 23613152  Prenat Diagn. 2013 Jun;33(6):575-9. doi: 10.1002/pd.410・・・
著者: Pe'er Dar, Kirsten J Curnow, Susan J Gross, Megan P Hall, Melissa Stosic, Zachary Demko, Bernhard Zimmermann, Matthew Hill, Styrmir Sigurjonsson, Allison Ryan, Milena Banjevic, Paula L Kolacki, Susan W Koch, Charles M Strom, Matthew Rabinowitz, Peter Benn
雑誌名: 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.
PMID 25111587  Am J Obstet Gynecol. 2014 Nov;211(5):527.e1-527.e17. do・・・
著者: Francesca R Grati, Francesca Malvestiti, Jose C P B Ferreira, Komal Bajaj, Elisa Gaetani, Cristina Agrati, Beatrice Grimi, Francesca Dulcetti, Anna M Ruggeri, Simona De Toffol, Federico Maggi, Ronald Wapner, Susan Gross, Giuseppe Simoni
雑誌名: 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.

PMID 24525917  Genet Med. 2014 Aug;16(8):620-4. doi: 10.1038/gim.2014.・・・
著者: Harini Ravi, Gabriel McNeill, Shruti Goel, Steven D Meltzer, Nathan Hunkapiller, Allison Ryan, Brynn Levy, Zachary P Demko
雑誌名: 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.

PMID 29474437  PLoS One. 2018;13(2):e0193476. doi: 10.1371/journal.pon・・・
著者: Lawrence D Platt, Naomi Greene, Anthony Johnson, Julia Zachary, Elizabeth Thom, David Krantz, Joe Leigh Simpson, Richard K Silver, Rosalinde J M Snijders, Laura Goetzl, Eugene Pergament, Karen Filkins, Maurice J Mahoney, W Allen Hogge, R Douglas Wilson, Patrick Mohide, Douglas Hershey, Scott MacGregor, Ray Bahado-Singh, Laird G Jackson, Ronald Wapner, First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study Group
雑誌名: 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

PMID 15458882  Obstet Gynecol. 2004 Oct;104(4):661-6. doi: 10.1097/01.・・・

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