First and Second Trimester Genetic Screening. Objectives. Genetic (chromosome) Testing

Transcription

1 First and Second Trimester Genetic Screening Patricia O Day, MD Maternal-Fetal Medicine Essential Health Duluth Objectives Review the difference between genetic diagnosis and screening Review the history and evolution of genetic screening in pregnancy Explain the different options available for first and second trimester genetic screening Effectively counsel patients as to the options available and the associated detection rates Genetic (chromosome) Testing Diagnosis vs. screening Hard concepts for some patients to understand Validity of screening depends on prevalence in the population 1

2 Genetic diagnosis CVS Amniocentesis Fetal blood Genetic diagnosis All methods of prenatal diagnosis are invasive CVS gives earliest diagnosis (10-13 wks) if pts would consider TOP, this affords earlier and safer procedures Amniocentesis is 15 weeks and beyond 1 st Trimester Invasive Testing Early complications ROM bleeding fetal loss wk 2.9% 1.9% 2.2% wk 0.2% 0.2% 0.2% No difference in late complications Brumfield et al, Obstet Gynecol, 1996; 88(1):

3 1 st Trimester Invasive Testing CEMAT Losses between amnio and 20 wks: Early amnio: 53/1916 (2.8%) Mid amnio: 9/1775 (0.5%) Also with early amnio More failed procedures, multiple sticks, fluid leakage, failed cultures, and talipes equinovares Johnson et al, Prenat Diagn, 1999; 19(8): st Trimester Invasive Testing NICHD EATA Trial Randomized trial comparing amnio to transabdominal CVS at 11+0 to 14+6 wks over 90% done after 13 wks Spontaneous losses and procedure related terminations 1.5% with amnio, 0.9% with CVS (RR = 1.74) 4-fold increase in rate of talipes equinovares after amniocentesis Philip et al, Obstet Gynecol 2004; 103(6): Invasive Testing More recent studies demonstrate midtrimester amnio complication rate of 1:400 to 1:600 Early amnio is not a reasonable alternative Increased complications, talipes CVS carries a slightly higher risk than amnio 3

4 Genetic screening Age Triple screen Quad screen First trimester screening Ultrasound Genetic screening Age Standard of care for prenatal screening until 20 years ago was age and family history Screen positive were pts age 35 20% detection rate, 5% false positive rate Genetic Screening 2nd Trimester First advance was the triple screen Combined -hcg, ue 3, FP with age in women under 35, age only screening over age 35 65% detection rate, 10% false positive rate All women over 35 were screen positive, 3-5% under 35 were screen positive 4

5 Genetic screening 2 nd Trimester Quad screen was then offered in some labs Inhibin is added to other three serum markers This increases detection to ~80%, with a 5% FP rate First Trimester Screening Next interest was in moving screening to the first trimester Motivated by desire to give earlier results Both ultrasound and serum markers were investigated First Trimester Serum Screening Rates of detection of trisomy 21 for serum markers: 17% for FP, 4% for estriol, 29% for hcg, 42% for PAPP-A Combination of PAPP-A, hcg and maternal age: detection rate was 63% Haddow, N Engl J Med 1998;338:

6 First Trimester Nuchal Measurements Assessment of risk by a combination of maternal age and fetal nuchal-translucency, over 96,000 subjects Measured by ultrasound at weeks of gestation Abnormal nuchal in: 8.3% of normal pregnancies 82% with trisomy 21 78% with other chromosome defects Snijders RJ et al; Lancet

7 First Trimester Screening (BUN Study) Maternal serum assayed for free beta-hcg and PAPP-A, ultrasound measurement of nuchal translucency 78.7% detection rate for trisomy 21, FP rate of 5% Identified 90.9% of trisomy 18 with a 2% FP rate Wapner et al NEJM Vol 349: : 2003 First Trimester Screening (BUN Study) Measurements of nuchal translucency were assessed according to the standards of the Fetal Medicine Foundation of London Sonographers underwent training and certification before participating in the study 1 st and 2 nd Trimester Comparisons SURUSS Trial Prospective study 47,053 singleton pregnancies 101 with trisomy 21 Nuchal translucency measurements Serum and urine samples in 1 st and 2 nd trimester 1 st trimester results not disclosed to patient Wald et al, J Med Screen 2003; 10:

8 1 st and 2 nd Trimester Comparisons SURUSS Trial For an 85% Trisomy 21 detection rate: 1 st trimester screen (NT, hcg, PAPP-A) 4.3% false positive rate Quad screen ( FP, ue 3, hcg, inhibin-a) 6.2% false positive rate Integrated screen (NT,PAPP-A + quad) 0.9% false positive rate 1 st and 2 nd Trimester Comparisons FASTER Trial Prospective trial 38,167 patients, 117 w/ trisomy 21 1 st trimester combined screen NT, PAPP-A, free hcg 2 nd trimester quad screen FP, total hcg, ue 3, inhibin-a 1 st trimester results not disclosed Malone et al, NEJM; 2005; 353(19): st and 2 nd Trimester Comparisons FASTER Trial Trisomy 21 detection rate (5% FP): 1 st tri combined screen: 85-87% (11-12 wks) 2 nd tri quad screen: 81% Stepwise sequential screening: 95% Fully integrated screening: 96% 8

9 Step-wise Sequential Screening FASTER Trial 1 st trimester combined screen Positive results offer CVS Negative results quad screen at 15 wks New risk estimate provided that combines results of 1 st and 2 nd trimester markers Offer amnio if this new result is positive Must send all tests to the same lab Fully Integrated Screening FASTER Trial 1 st trimester NT and PAPP-A Results not disclosed 2 nd trimester quad screen Assessment of risk then calculated Amnio offered if screen positive 1 st Trimester Genetic Screening Details of Testing CRL between mm Corresponds approximately to wks Normal nuchal measurement directly proportional to CRL Risk assessment based on MoM for NT, hcg, PAPP-A and maternal age Report will give numeric risk (1:230) Report as normal if risk is less than that of a 35 y/o 9

10 Important Reminder 1 st trimester screening does not evaluate for open NTDs or abdominal wall defects All patients who choose 1 st trimester testing must be offered a MS FP Do the MS FP at ~16-20 wks Order MS FP only (not the quad screen) 10

11 Abnormal Nuchal Measurement 29,154 pregnancies; 1822 had abnormal nuchal All had normal chromosomes 50 cases with heart defects 28 (56%) had abnormal nuchal Abnormal nuchal measurement identifies many fetuses with heart defects Hyett et al BMJ 1999;318:

12 Septated Cystic Hygroma Incidence of 1 in 285 screened patients 51% of fetuses had chromosome abnormality Trisomy 18 or 21 or Turner syndrome in 85% 34% had major structural abnormality Cardiac or skeletal 8% fetal demise 17% survival with normal pediatric outcome Malone et al, Obstet Gynecol 2005; 106: First Trimester Screening ACOG Opinion First-trimester screening using nuchal translucency, free ß-hCG, and PAPP-A has comparable detection rates and positive screening rates for Down syndrome as second-trimester screening using 4 serum markers ACOG committee opinion; July

13 First Trimester Nuchal Measurements ACOG bulletin wording about reliability*: The ability to measure nuchal translucency reliably is dependent on the operator, ultrasound equipment, proper magnification and contrast, fetal position, correct placement of the calipers, and maternal body habitus Ultrasonographer training and ongoing quality assurance are essential At present, labs will not process specimens sent from non-certified sonographers Certification is through the SMFM or London based Fetal- Medicine Foundation *ACOG committee opinion; July 2004 First Trimester Screening ACOG Statement First trimester screening for Down syndrome and trisomy 18 should be offered only if the following criteria can be met: Appropriate ultrasound training and ongoing quality monitoring programs are in place Sufficient information and resources to provide counseling regarding the different screening options Access to an appropriate diagnostic test when screening test results are positive First Trimester Diagnosis Where Are We Going Goal is definitive noninvasive diagnosis Direct assessment of karyotype Not deductions from ultrasound or blood Intact fetal cells in maternal blood Cell-free DNA in maternal blood Fetal trophoblasts from maternal cervix 13