Prenatal Testing for Down Syndrome: Where Do We Stand Today? David B. Fox, MD Riverside Methodist Hospital

Down Syndrome Phenotype abnormalities Mental retardation Cardiac defects LeukemiaAlzheimer's Visual/hearing impairment Intestinal malformations Shortened life span

Why is Prenatal Testing Important? Peace of mind Education Emotional preparation Neonatal issues Termination

Increased Risk of Fetal Aneuploidy Previous fetus or child with autosomal trisomy or sex chromosome abnormality Previous fetus or child with autosomal trisomy or sex chromosome abnormality One major or two minor fetal structural defects on ultrasound One major or two minor fetal structural defects on ultrasound Either parent with chromosomal translocation or inversion Either parent with chromosomal translocation or inversion Parental aneuploidy Parental aneuploidy

Is Prenatal Testing for Everyone?

Prenatal Testing Screening versus Diagnosis First trimester versus Second trimester Serum and/or Ultrasound Low-risk versus High-risk Women

Diagnostic Tests First trimester CVS TC10 0/ /7 wks TA10 0/7 - Term (if anterior placenta) Second trimester Amniocentesis 15 0/7 - Delivery

Procedure-related Risks Amniocentesis Pregnancy loss 1:300-1:500 Pregnancy loss 1:300-1:500 Spotting or leakage Spotting or leakage 1-2% 1-2% Needle injury - rare Needle injury - rare Infection - rare Infection - rare CVS Pregnancy loss - similar to amniocentesis (TA=TC) Spotting - up to 32% (TC) Leakage or infection - less than 0.5%

Screening Second trimester Maternal age Triple screen (AFP, HCG, estriol) Quad (Triple + inhibin) Ultrasound

Gestational Age (wk) Maternal Age (y) Adapted from Nicolaides, AJOG, 2004

“Age-Based” Screening Old story 5% of pregnant women > 35 yo 80% DS babies born to younger women New story 14% of pregnant women > 35 yo 70% DS born to younger women

Second Trimester MSAFP Merkatz, 1984 Case report: Serendipitous discovery of low MSAFP in case of T18 led to discovery of low MSAFP associated with fetal trisomy Sensitivity 20% for DS Age + MSAFP = 40% DS detection

Second Trimester Triple Screen MSAFP + HCG + Estriol Sensitivity 65% 5%

Second Trimester Quad Screen Triple screen + inhibin 75 –80% DS detection 5% false positive rate

Second Trimester Ultrasound Markers weeks Thickened nuchal fold Pyelectasis Echogenic bowel Short long bones Congenital anomaly Hypoplastic 5 th digit Ear length Echogenic intracardiac focus

2 nd Trimester Nasal Bone Screening Absent NB 7 studies: 37% prevalence in T21, 0.9% in euploid Short NB 6 studies: 48.2% prevalence in T21, 2.4% in euploid Short or Absent NB 6 studies: 60% prevalence in T21, 1.4% in euploid

Second Trimester Ultrasound Up to 75% of DS fetus will have a marker Therefore, 25% will have a normal ultrasound

Problems with Second Trimester Ultrasound Poor specificity Poor specificity Subjective Subjective Technical limitations Technical limitations Variability of gestational age Variability of gestational age

DefectAneuploidy Risk Most Common Aneuploidies Cystic hygroma 60-75%45X,21 Hydrops30-80%13,21,18 Cardiac defect 5-30%13,18 AV canal defect 40-70%21 Duodenal atresia 20-30%21 Aneuploidy Risk for Major Anomalies ADAPTED FROM SLIPP AND BENACERRAF (1990)

First trimester Screening Nuchal translucency Free beta HCG PAPP-A Combined NT and Serum

Increased Nuchal Thickness

Thickened NT with Normal Karyotype

First-Trimester or Second-Trimester Screening, or Both, for Down’s Syndrome (FASTER Trial) Malone et al, NEJM, U.S. Centers 38,167 women with singletons enrolled 117 cases of DS CRL 36-79mm (10 3/7 – 13 6/7 wks) NT + free beta HCG + PAPP-A (1:150) wks Quad screen (1:300)

FASTER Trial First trimester with 5% FP 11/12/13 (wks) 11/12/13 (wks) NT70/68/64 Free beta HCG/PAPP-A 70/67/65 Combined87/85/82* *similar to Quad screen at 13 wks *similar to Quad screen at 13 wks

First and Second Trimester Sequential independent Sequential step-wise Serum integrated Fully integrated Sequential contingent

Faster Trial Sequential independent 11/12/13 (wks) 1 st : Combined NT/Serum87%/85%/82% 2 nd : Triple/Quad 69%/81% detection rates Calculate separately Not recommended because (1) high false positive rate and (2) a priori risk not re-adjusted

Faster Trial Sequential Step-wise Fully Integrated First trimester NT/serum PLUS Second trimester Quad Blind patient to initial result until completion of Quad. Then give single risk. Exclude those with cystic hygoma. 11/12/13 (wks) 11/12/13 (wks) Detection rate (%):96/95/94

Fully Integrated “Potential” problems Both parts required Loss of follow-up (potential litigation) Physician/patient reluctance to withhold information Precludes early termination

Contingent First-trimester Screen High Risk Offer CVS Intermediate Risk Quad Screen Offer Amino if HR Low Risk No Further Testing

1 st Trimester “Absent” Nasal Bone Usefulness controversial Usefulness controversial 3 European studies: 3 European studies: Down Syndrome sensitivity: % in women ( % FP rate) Down Syndrome sensitivity: % in high-risk women ( % FP rate) Some studies show poor performance in general population

Issues with Nasal Bone Screening Correct technique Correct technique Significance of ethnicity Significance of ethnicity Absent NB seen in 2.8% Caucasians, 6.8% Asians, 10.4% Afro-Carribeans Optimal population (HR vs. LR) Optimal population (HR vs. LR) Optimal gestational age Optimal gestational age

Nasal bone present Sonek, 2006

Nasal bone absent Sonek, 2006

First-Trimester Screening Pros Pros Higher detection rate Higher detection rate Earlier detection Earlier detection Safer termination Safer termination NT identifies HR fetuses NT identifies HR fetuses Less bonding Less bonding More privacy More privacy Cons Cost ($600 – 700) Unnecessary termination Unwanted information

NTD Lab US: CRL45 – 84 mm (11 1/ /7 wks) Blood: 9 0/7 – 13 6/7 wks Instant Risk Assessment (IRA) Cost is $165 blood work/$513 Ultrasound DS 1:301 (90%) T18/13 1:150 (95%)

“Invasive diagnostic testing for aneuploidy should be available to all women regardless of maternal age” ACOG, December 2007