Antoni Borrell

Prenatal Detection of Down Syndrome using Massively Parallel Sequencing (MPS): a rapid response statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, 24 October 2011

Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT, USA Prenatal Diagnosis Unit, Institute of Gynecology, Obstetrics and Neonatology, Hospital Clinic, Maternitat Campus, University of Barcelona Medical School, Catalonia, Spain Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, New York, NY, USA Department of Obstetrics and Gynecology, University of Calgary, Calgary, AB, Canada Department of Obstetrics and Gynecology, Assaf Harofe Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Obstetrics and Gynecology, Washington University in St Louis, St Louis, MO, USA Laboratory for Infectious Diseases and Perinatal Screening, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Prenatal Screening Unit, Clinical Biochemistry Department, Barking Havering and Redbridge University Hospital, King George Hospital, Goodmayes, UK Department of Mathematics and Statistics, University of Plymouth, Plymouth, UK Prenatal Diagnosis Unit, Genetic Institute, Sourasky Medical Center, Tel Aviv, Israel *Correspondence to: Peter Benn. E-mail: benn@nso1.uchc.edu

Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis

President President-Elect Past President Secretary Treasurer Lucas Otano MD, PhD (Argentina) Ignatia B. Van den Veyver MD (USA) Jan M.M. van Lith MD, PhD (Netherlands) Louise Wilkins-Haug MD (USA) Antoni Borrell MD, PhD (Spain) Directors Peter Benn PhD, DSc (USA) Lyn Chitty PhD (UK) Rossa Chiu (Hong Kong) Roland Devlieger MD, PhD (Belgium) Sylvie Langlois MD, CCMG (Canada) Anthony O. Odibo MD, MSCE (USA) R. Doug Wilson MD, Msc, FRCSC (Canada) Yuval Yaron MD (Israel) Diana W. Bianchi MD, ex officio (USA) Position Statement from the Chromosome Abnormality Screening Committee on Behalf of the Board of the International Society for Prenatal Diagnosis

Cytogenetic study of spontaneous abortions using semi‐direct analysis of chorionic villi samples detects the broadest spectrum of chromosome abnormalities

Conventional tissue culturing and karyotyping of spontaneous abortions has limitations such as culture failure, external contamination and selective growth of maternal cells. Molecular cytogenetic techniques such as FISH, QF‐PCR, and CGH allow diagnosis on uncultured cells but are also limited as to the spectrum of cytogenetic abnormalities detected. We describe the cytogenetic findings in a series of 116 first trimester arrested pregnancies, obtained through chorionic villi sampling (CVS) and semi‐direct analysis that avoids some of the long‐culture pitfalls such as maternal contamination, and compare our results with those that would have been obtained theoretically using molecular cytogenetic techniques. Samples were obtained by transcervical CVS from women with a diagnosis of missed abortion, most of them referred for cytogenetic prenatal diagnosis. Cytogenetic analysis was performed using semi‐direct technique. A karyotype was obtained in 103 cases. Eighty‐two abnormal karyotypes were found (80%), including 12 triploidies, 10 monosomies, 61 trisomies, and 9 structural abnormalities; a double abnormality being present in 10 cases. Between 10% and 50% of our abnormal results would have been missed using the most common molecular cytogenetic techniques. Semi‐direct analysis of CVS may still be considered as a comprehensive, reasonably rapid, cost‐effective and reliable method for detecting the broadest spectrum of chromosome abnormalities in missed abortions.

Genomic microarray in fetuses with increased nuchal translucency and normal karyotype: a systematic review and meta‐analysis

To estimate the incremental yield of detecting copy number variants (CNVs) by genomic microarray over karyotyping in fetuses with increased nuchal translucency (NT) diagnosed by first‐trimester ultrasound.

Array comparative genomic hybridization and fetal congenital heart defects: a systematic review and meta‐analysis

Array comparative genomic hybridization (aCGH) is a molecular cytogenetic technique that is able to detect the presence of copy number variants (CNVs) within the genome. The detection rate of imbalances by aCGH compared to standard karyotyping and 22q11 microdeletion analysis by fluorescence in‐situ hybridization (FISH), in the setting of prenatally‐diagnosed cardiac malformations, has been reported in several studies. The objective of our study was to perform a systematic literature review and meta‐analysis to document the additional diagnostic gain of using aCGH in cases of congenital heart disease (CHD) diagnosed by prenatal ultrasound examination, with the aim of assisting clinicians to determine whether aCGH analysis is warranted when an ultrasonographic diagnosis of CHD is made, and to guide counseling in this setting.

Aneuploidy screening: a position statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, January 2011

Definitive prenatal diagnosis of Down syndrome and certain other fetal aneuploidies through chromosome analysis of amniocytes or chorionic villus samples (CVS) is an accepted part of prenatal care. But these procedures carry some degree of risk for miscarriage or other pregnancy complications (Tabor and Alfirevic, 2010). Therefore, in most developed countries it is now a routine practice to provide a woman’s personal risk for aneuploidy (screening) and to offer definitive diagnosis through amniocentesis or CVS if the risk exceeds a fixed cut-off. However, in the United States it has been recommended that amniocentesis and CVS should be available to all women whether or not they have screening (American College of Obstetricians and Gynecologists, 2007a), although it is recognized that screening can be helpful to women before they decide whether to accept or reject amniocentesis or CVS (American College of Obstetricians and Gynecologists, 2007b). Fetal aneuploidy risk can be evaluated on the basis of a combination of maternal age, prior family history, maternal serum biochemical tests and fetal ultrasound markers (Cuckle and Benn, 2010). Risk evaluation provides an opportunity to re-assure most women that their fetus is unlikely to be affected by a chromosomal disorder and also to reduce the number of unnecessary invasive procedures performed. Those women who are identified as being at high risk can receive genetic counseling, additional testing and appropriate follow-up obstetric care. Because Down syndrome is the most common significant aneuploidy, prenatal screening has emphasized the detection of this disorder. However, it is recognized that many of the screening tests have a variable potential to detect other aneuploidies, some other genetic disorders, specific fetal anatomic abnormalities and pregnancy complications such as preeclampsia.

CRITERIA FOR FETAL NUCHAL THICKNESS CUT-OFF: A RE-EVALUATION

An attempt has been made to establish a more effective cut‐off criterion for nuchal thickness (NT) and to assess the optimal gestational period for the prediction of trisomies 21 and 18. Reference intervals were established for NT from the tenth to the 18th week, using either gestation‐specific centiles or the parametric method. The measurements in 47 consecutive trisomy 21 and 18 trisomy 18 cases were plotted against these intervals. Assaying different cut‐off criteria for both the centile and the parametric methods, sensitivities and false‐positive rates for each gestational week were calculated and then compared with the commonly applied ‘two‐stepped’ cut‐off method (3 mm early, 6 mm later). The parametric method, based on a progressive rise, with +2·5 SD for the corresponding gestational week as a cut‐off value, showed the best performance (likelihood ratio 38) in the prediction for trisomy 21. The optimal gestational age was the 12–18 week period, with an overall sensitivity of 62 per cent (23/37) for an average false‐positive rate of 0·7 per cent. For trisomy 18, the most effective cut‐off was also +2·5 SD, and 10–13 gestational weeks as the optimal period, achieving 86 per cent (6/7) sensitivity for a 1·9 per cent false‐positive rate.

Natural evolution of Nuchal thickness in trisomy-21 fetuses

Objective To assess the natural evolution of nuchal thickness in trisomy-21 fetuses. Methods Serial measurements of nuchal thickness were performed over a 1- to 6-week period in 45 consecutive fetuses with trisomy 21, between the 10th and the 23rd weeks of pregnancy. To avoid a gestational age confounding effect, nuchal thickness also was expressed in standard deviations (SDs) for the corresponding gestational week. In addition, the changes were assessed in terms of the presence of clinical positive thickening, considered as such when the measurement was above 2.5 SD. Results A mean increase of 1.8 mm (95% confidence interval [CI] 1.3,2.3) for nuchal thickness was observed for a mean period of 21 days. When corrected by gestational age, the mean increase of 0.3 SD (95% CI −0.2, 0.9) was found to be not significant. No clinically relevant nuchal thickening changes were recorded (51% versus 69%) at re-examination. Conclusion Nuchal thickening at re-examination is observed in a similar proportion of trisomy-21 fetuses as when first observed.

First‐trimester biochemical markers for Down syndrome

The value of maternal serum pregnancy‐associated protein A (PAPP‐A), free and total β human chorionic gonadotrophin (fβhCG, βhCG) and α‐fetoprotein (AFP) in screening for Down syndrome (DS) in early pregnancy has been assessed. To evaluate the different biochemical markers, 32 DS pregnancies and 267 controls were used for AFP, βhCG and PAPP‐A. A subgroup of those (17 DS and 136 controls) were used to evaluate fβhCG. All analytes were determined in fresh serum samples. Our results give support to the feasibility of maternal serum levels of PAPP‐A as the best biochemical marker for DS in the first trimester, and either βhCG or fβhCG as the second marker. No differences were found between βhCG and fβhCG distribution levels as expressed as MoMs in normal and DS pregnancies in this study. Copyright

Combining nuchal translucency with umbilical Doppler velocimetry for detecting fetal trisomies in the first trimester of pregnancy

Objective The aim of our study was to evaluate whether the combined use of umbilical artery pulsatility index (UAPI) and nuchal translucency (NT) measurements would be useful in the prediction of fetal chromosomal abnormalities at 10 to 13 weeks of gestation.