1. Genetic Testing in Pregnancy Lisbeth M. Lazaron, MD March 2013

2. Genetic Screening Options  Genetic Counseling  Carrier screening for cystic fibrosis, SMA, MD, hemoglobinopathy, Tay-Sachs, Fragile X  1 st Trimester Aneuploidy and nuchal translucency screening (10 4/7-13 6/7 weeks)  CVS (>9 weeks)  MaterniT21 aneuploidy screening (>10 weeks)  Amniocentesis (14-20 weeks)  Quad screen (16-21 6/7 weeks)  AFP alone (>14 weeks)  Level 2 ultrasound screening for markers for aneuploidies

3. Genetic Counseling  Often the most cost effective option. Can refer patients to Genetic counselors at UC or Children’s Hospital EACH carrier test you obtain is $300-600; so a $200 consult to help you narrow the options is a good investment Can be done pre-conception

4. Carrier screening  Can be done preconception on both males and females, or at any time in pregnancy o Hemoglobinopathy or Sickle screen o Cystic Fibrosis carrier screen o Tay-Sachs o Fragile X o SMA (Spinal Muscular Atrophy) o MD (Muscular Dystrophy) o Many more Only needs to be tested ONCE in a life-time, not each pregnancy !!

5. Cystic Fibrosis screening  There are 1700 known mutations of the CFTR gene, screening only the 25 most common mutations The incidence of CF in 1/2500 and is autosomal recessive 98% of males with CF will have primary infertility due to agenesis of the vas deferens Females with CF have no infertility, but do have high risk pregnancies Carrier risk varies by race White 1/25 Hispanic 1/58 Black 1/61 Asian 1/94 Cost not covered by OB Special program-counsel before ordering!

6. 1 st Trimester Aneuploidy Screen “Ultrascreen”  Tests for Trisomy 13,18, 21 by a combination of fetal Nuchal Translucency ultrasound and blood tests for free Beta-HCG and PAPP-A (Pregnancy Associated Plasma Protein-A) Timing specific to 10 4/7-13 6/7 weeks Nuchal translucency needs to be done by perinatology with experience, not available in all centers Does NOT include testing for ONTD, will still need AFP later Can do NT alone at 12-13 weeks with 76% PPV Costs $600, covered by most insurances Cost not covered by OB Special program-counsel before ordering!

7. MaterniT21-aneuploidy screening Measures circulating free fetal DNA in maternal blood sample Tests for Trisomy 13,18, 21 (Down) Can be done at 10 weeks Validated on high risk pregnancies only (AMA, abnormal Quad, prior affected child, U/S finding with possible aneuploidy) Not valid on twins Currently FREE if getting perinatal consult or level 2 U/S at Christ Will still need AFP at 15-20 weeks for ONTD 98% specific; 0.5% false +

8. CVS-Chorionic Villi Sampling  CVS 9-14 weeks (1 week for results). Recommended for women with AMA or high risk for genetic abnormalities, or after abnormal Ultrascreen or MaterniT21 testing Chromosome testing so broad genetic array available Maternal tissue sampling errors in inexperienced hands (1% risk of mosaicism) Trans-cervical or trans-vaginal approach 1/300 or 1/500 procedure related pregnancy losses in EXPERIENCED hands 10X increase in limb reduction defects if done before 9 weeks, so early test NO LONGER RECOMMENDED Will still need AFP at 15-20 weeks for ONTD

9. Maternal Age-related Genetic Risks AGE Risk of Down Risk of ALL Gene 30 1:940 1:384 35 1:353 1:178 40 1:85 1:62 45 1:35 1:18 Risk of pregnancy loss with CVS/amnio 1:400

10. Amniocentesis  Amniocentesis 14-20 weeks (2 weeks for results) Recommended for women with AMA or high risk genetic issues, or after abnormal QUAD screen Chromosome testing so broad genetic array available takes longer for fetal cells to grow in culture, but fewer maternal sampling errors (0.25% risk of mosaicism) 1/300 to 1/500 procedure related pregnancy losses Early amniocentesis (11-13 weeks) 1/40 losses and more culture failures—NO LONGER RECOMMENDED Will still need AFP at 15-20 weeks for ONTD

11. Quad Screen  Measures AFP, hCG, estriol and Inhibin-A Screens for trisomy 21 (Down), trisomy 18 and ONTD (spina bifida) Accurate when done at 16-21 6/7 weeks, may need to have lab re-calculate values if dating changes after test is done Most commonly offered test but sensitivity is low (67% true +) Costs $150 dollars This test is covered on OB Special program  Doing both an Ultrascreen & Quad screen and integrating the statistical results significantly improves the specificity

12. AFP for ONTD  MSAFP Maternal Serum Alpha Feto Protein Tests for ONTD only Done at 15-20 weeks Circulating levels vary based on weeks gestation and number of fetuses so most common cause for abnormal is dating errors or multiple gestation Follow an abnormal with a level 2 anatomy scan for confirmation of ONTD

13. Level 2 U/S for aneuploidy markers First trimester  Nuchal translucency alone for triploidies 13,18,21 optimal timing is 12-13 weeks 76% true + 4% false +  Absent Nasal bone Only in experienced ultrasonographers (more common in UK) timing 11-14 weeks Diagnostic for trisomy 13, 18, 21 & Turners 67-80% true+, 0.2-1.4% false + Wide ethnic variances in euploid fetus with absent nasal bones, from 2.8% in Caucasians to 10.4% in Afro-Carribean

14. Level 2 U/S for aneuploidy markers Second Trimester  Significant Markers Thickened nuchal fold (NOT the same as nuchal translucency) Cardiac defects  “Soft” Markers Pyelectasis Shortened femur or humerus Echogenic bowel Intracardiac echogenic focus 21.9% false positive rate, but a normal test reduces a priori risk by 88%

15. Sensitivities & Specificities Test False + True +  Quad screen 5% 69%  NT, HCG, Papp-A 5% 82-86%  NT alone 4% 76%  Integrated 5% 95%  CVS & Amnio 0% 99%  MaterniT21 0.5% 98%  U/S for aneuploidy 21.9% 67-80%

16. What to do?  Options for testing depend on when the patient presents for prenatal care, their risk factors and their preferences and tolerance for risks & costs of procedures  Talk to the patient FIRST (or offer genetic counseling)  Order tests AFTER