Tianhua Huang

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

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 Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 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 Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 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, Stanford University School of Medicine, Stanford, CA, USA 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 & Redbridge University Hospitals, King George Hospital, Goodmayes, UK Genetics Program, North York General Hospital, Toronto, ON, Canada 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 This Statement replaces the January 2011 Statement (Prenatal Diagnosis 2011;31:519–522) and the Rapid Response Statement (Prenatal Diagnosis 2012;32:1–2).

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

Maternal serum screening in Ontario using the triple marker test

Objectives: To summarise the experience and evaluate the performance of the Ontario maternal serum screening (MSS) programme. Methods: This study used information collected in the Ontario MSS database, which contains data on each screened pregnancy. In the Ontario MSS programme, women are screened between 15 and 20 weeks of gestation. The risk cut-off for Downs syndrome was ≥1 in 385 at term and women with a serum alpha-fetoprotein ≥2.2 multiples of the unaffected population median were defined as screen-positive for open neural tube defects. Results: Between 1 October 1993 and 30 September 2000, 428,410 women residing in Ontario were screened for open neural tube defects, and 423,895 women were screened for Downs syndrome and trisomy 18. Approximately 48% of all pregnant women in the province had MSS. The uptake rate of amniocentesis following a positive Downs syndrome screening was 67%. Of 717 cases of Downs syndrome ascertained in the screened population, 531 were detected by MSS, giving a term detection rate (DR) of 70.6%, with a false-positive rate (FPR) of 7.2%. For neural tube defects, the DRwas 72.7%, with a FPR of 2.0%. The screen also detected 50% of cases of trisomy 18 at term, with a FPR of 0.2%. Coincidentally, 113 cases of chromosome aneuploidies other than Downs syndrome and trisomy 18 were detected Discussion: In the Ontario MSS programme, MSS performed as expected in the detection of Downs syndrome, open neural tube defects and trisomy 18. MSS is an effective and practical method for large- scale second ttrriimester screeni.ng for Downs syndrome, open neuraI tube defects and ttrriisomy 18, and the MSS database is an extremely useful tool in monitoring the performance of this screen.

Prediction of adverse pregnancy outcomes by combinations of first and second trimester biochemistry markers used in the routine prenatal screening of Down syndrome

To investigate the associations between four defined adverse pregnancy outcomes and levels of first and second trimester maternal serum markers focusing in particular on how well combinations of markers predict these adverse outcomes.

The price of performance: a cost and performance analysis of the implementation of cell‐free fetal DNA testing for Down syndrome in Ontario, Canada

To examine the cost and performance implications of introducing cell‐free fetal DNA (cffDNA) testing within modeled scenarios in a publicly funded Canadian provincial Down syndrome (DS) prenatal screening program.

The implications of a false positive second-trimester serum screen for Down syndrome.

OBJECTIVE To investigate the genetic and obstetric implications of false positive Down syndrome serum screening results. METHODS The study population comprised 162,774 women underwent triple marker screening in the Ontario Maternal Serum Screening program between October 1995 and September 1998, with outcomes obtained from the Canadian Institute of Health Information. The study compares the incidence of chromosomal abnormalities other than Down syndrome in screen positive women with background incidence from the literature. It also compares the risks of having a fetus with congenital abnormalities or of developing obstetric complications in 11,549 screen positive women with their matched controls. RESULTS A higher incidence of trisomy 13 (12.4 per 10,000) was seen in screen positive women; the incidence of other chromosomal abnormalities in screen positive women was not increased relative to the general population. The higher incidence of trisomy 13 may have been biased by the selective uptake of amniocentesis in women who had high risks for Down syndrome or abnormal ultrasound findings. Incidences of fetal congenital abnormality in screen positive and negative women were similar. Women who screened positive for Down syndrome had increased risk of spontaneous fetal loss (odds ratio 1.80; 95% confidence interval 1.54, 2.07) but no other obstetric complications. CONCLUSION Among women who screened positive for Down syndrome, we found a higher number of spontaneous fetal losses and a possibly higher risk of having a fetus with trisomy 13. We did not find an increased risk for other chromosomal abnormalities, congenital abnormalities, or other adverse obstetric outcomes.

Prospective experience with integrated prenatal screening and first trimester combined screening for trisomy 21 in a large Canadian urban center

To evaluate the performance of integrated prenatal screening (IPS) and first trimester combined screening (FTS) for trisomy 21 in a large Canadian urban center.

First trimester screening for Down syndrome using nuchal translucency, maternal serum pregnancy‐associated plasma protein A, free‐β human chorionic gonadotrophin, placental growth factor, and α‐fetoprotein

The aim of this study was to assess the screening performance for Down syndrome using first trimester combined screening (FTS) and two additional markers, serum placental growth factor (PlGF) and α‐fetoprotein (AFP).

The effect of differences in the distribution of maternal age in England and Wales on the performance of prenatal screening for Down's syndrome

We aimed to determine how differences in the age at which women had their pregnancies influenced the expected detection and false‐positive rates of serum screening for Downs syndrome (i) between 1970 and 1993 in England and Wales, and (ii) between regions and districts of England and Wales in 1991. We applied published estimates of Downs syndrome screening to regional and district data on the age distribution of maternities and changes in the age distribution over time in England and Wales obtained from the Office of Population Censuses and Surveys. From 1970 to 1993 women, on average, became pregnant at an older age; the percentage of maternities among women aged 35 or more increased from 7 to 9·2 per cent. This was not a great enough change to have had a material effect on the performance of Downs syndrome screening. In 1991, the percentage of maternities among women aged 35 or more varied from 5 to 20 per cent among Health Districts, a difference that would influence the performance of screening; for example, using the triple test and a risk cut‐off of 1 in 250, the detection rates would have varied from about 55 to 70 per cent and the false‐positive rates from 4·4 to 8·8 per cent across different districts. The tendency for women to have their pregnancies at an older age would have had a negligible impact on the performance of serum screening for Downs syndrome, but differences in the age when women had their pregnancies in different parts of the country would lead to twice as many women being referred for amniocentesis in some districts than in others when offered the same method of serum screening and at the same risk cut‐off level. The results will have important implications for the local purchasers of Downs syndrome screening services.

Reliability of statistics on Down's syndrome notifications

Objectives— To evaluate the completeness of notifications of Downs syndrome live births and terminations to the Office for National Statistics (ONS) using data from the National Down Syndrome Cytogenetic Register (NDSCR). To examine the agreement of observed birth prevalence of Downs syndrome with the expected birth prevalence derived from published maternal age specific rates. Methods— The number of live births (adjusted to allow for the estimated under-ascertainment) and the number of terminations due to fetal Downs syndrome from NDSCR were compared with those figures reported to the ONS. Subsequently, using the NDSCR figures, the live birth prevalence of Downs syndrome that would have occurred in the absence of antenatal diagnosis and selective termination was calculated in England and Wales in the years 1990–1993. These figures were compared with those derived by applying published age specific prevalences to the maternal age distribution in England and Wales. Results— It is estimated that only 48% and 46% respectively of Downs syndrome live births and terminations of pregnancy were notified to ONS between 1990 and 1993. The annual expected birth prevalences of Downs syndrome obtained by applying maternal age specific prevalences to the maternal age distribution were in close agreement with observed rates from NDSCR. Conclusions— There is considerable underreporting of Downs syndrome births and terminations to ONS. The NDSCR data are more complete and therefore the effects of screening should be monitored using data from this source, or using estimates derived from the age specific rates of Downs syndrome.