Presentation on theme: "Genetic Testing in Pregnancy"— Presentation transcript:
1 Genetic Testing in Pregnancy Johanna Warren, MDOAFP Women’s Health Winter ConferenceJanuary 19, 2014
2 What genetic screening test do you routinely offer your patients? Quad/Penta screenIntegrated ScreeningNuchal Translucency (NT) onlyStepwise Sequential ScreenNIPT (cffDNA)none
3 Learning ObjectivesUse the concepts of pre-test probability, positive and negative predictive values as they apply to testing for fetal aneuploidy.Outline advantages and disadvantages of various approaches to first-trimester and second-trimester screening as well as invasive diagnostic testing for Down syndrome.Discuss emerging cell-free fetal DNA (cffDNA) technology and review indications for use in screening.Summarize the current recommendations for cystic fibrosis screening.
4 Statistics Pre-test probability Positive predictive value (PPV) Prevalence of the diseasePost-test probability after one or more preceding testsRough clinical estimationPositive predictive value (PPV)the likelihood that an individual with a positive test result truly is affected/has the genetic conditioninherently dependent upon the prevalenceNegative predictive value (NPV)the likelihood that an individual with a negative test result is truly unaffected/does NOT have the genetic conditionmeasure of test accuracyPPV- The likelihood that an individual with a positive test result truly has the particular gene and/or disease in question.The probability that an individual is affected with the condition when a positive test result is observed. Predictive values should only be calculated from cohort studies or studies that legitimately reflect the number of people in the population who have the condition of interest at that time since predictive values are inherently dependent upon the prevalence.NPVThe probability that an individual is not affected with the condition when a negative test result is observed. This measure of accuracy should only be used if the data on the prevalence of condition of interest in given population is available. NPVDT can be determined by calculating: number of true negative results divided by the sum of true negative results plus number of false negative results.The likelihood that an individual with a negative test result is truly unaffected and/or does not have the particular gene mutation in question.
5 What Makes a Good Screening Test? The condition should be an important health problem.There should be an acceptable test for the condition.High sensitivity to detect not yet clinically detectable conditionHigh specificity to minimize false positivesThe test should be available to the population.The test should be affordable.There should be acceptable treatment for the condition.There should be a “latent stage” of the disease, allowing for detection/testing before a critical point, during which treatment would be optimal.
6 What is the purpose of antenatal genetic testing? Assess risk for chromosome abnormalitiesparticularly Down syndrome & Trisomy 18Determine which pregnancies should be offered invasive prenatal diagnosis
7 Who Should Be Screened? ACOG Practice Bulletin (2007) All pregnant women, regardless of their age, should be offered screening and diagnostic testing for aneuploidy.Women should be counseled regarding the differences between screening and invasive diagnostic testing.Ideally, patients seen early in pregnancy should be offered screening that combines 1st and 2nd trimester testingScreening test chosen will depend on availability of NT US as well as CVS
8 Testing for Fetal Aneuploidy – Focus on Down Syndrome (trisomy 21) Explosion of available screening testsDetection of Down Syndrome 90+% with non-invasive screening testsConfirmation diagnosis still requires invasive testingAmniocentesisChorionic villus sampling
9 Quick ReviewSeveral methods for combining first- and second-trimester screening reach higher detection rates for Trisomy 21 than either first- or second-trimester screening alone.Common options:Ultrasound: Nuchal TranslucencyIntegrated ScreeningsQuadruple/Penta Marker ScreeningsStepwise Sequential Screening
10 First Trimester - Ultrasound Nuchal Translucency (NT)Normal: 1-3mmIncreased NT is an indication of a chromosomal abnormality, single gene defect, or birth defects (commonly cardiac defects)Nasal BoneAbsent/hypoplastic in 70% T21Ductus Venosus – reversed a-wave flowDetection rate 75%, FPR 5%Tricuspid RegurgitationDetection rate 67.3% in T21, FPR 5.2%
11 Integrated Screenings Ultrasound for Nuchal Translucency (NT) + serum PAPP-A/hCG analysis between wks GA; results of these tests are HELDSerum quad screen test between wks GAAt that time, the results of all the studies, combined with risk assessment due to the patient's age, are used to present a single-risk figureSerum Integrated Screeningfirst-trimester serum PAPP-A/hCG test result is combined with a second-trimester quad screen test to provide a single-risk figure (no NT US)
12 Quadruple Marker Screening Measure raw values of:AFP (alpha fetoprotein)ue3 (unconjugated estriol)hCG (human chorionic gonadotropin)DIA (dimeric inhibin A)Compare to median value for the appropriate gestational age (MoM)Valid between weeks GA (optimal wks); risk of NTD not provided for samples collected prior to 15 weeks.Quad Screen - Detection rate for Down Syndrome 79%, FPR 5%Penta Screen adds hyperglycosylated hcg (h-hcg)Penta Screen – Detection rate for Down Syndrome 83%, FPR 5%
13 Stepwise Sequential Screening First TrimesterNT US + serum PAPP-A analysis between wks GAResults combined with the patient's age-associated risk,Patient is given a risk assessment for aneuploidymay choose at this time to undergo invasive testing (e.g., amnio or CVS), or add quad screen test at wks GASecond TrimesterQuad screen test at wks GAa new risk is assessed based on the results of patient’s age and both the first- and second-trimester screening test results
14 Sequential ScreeningHow do you decide when to proceed with invasive testing?Risk of miscarriage (approximate; operator-specific)chorionic villus sampling (CVS) ~ 0.5-1/100amniocentesis ~1/1000After 1st trimester results return:If risk is greater than ~1 in 50, offer CVSIf risk is less than ~1 in 1,000, advise no further testing is necessary.If risk is between these two (arbitrary) cutoffs, offer quad screen test after 15 wks GA, and determine a new risk assessment
15 FASTER Trial Data Screening Test Best Detection Rate for Down Syndrome NT alone70%Quad screen alone (2nd trimester)81%First Screen (with NT)87%Serum Integrated (1st tri PAPP-A/hcg + 2nd tri quad)88%Sequential Screen (1st tri PAPP-A + NT + 2nd tri quad)94%Integrated Screen (1st tri PAPP-A/hcg + NT + 2nd tri quad); patient does not receive results until 2nd trimester testing complete96%
16 What do you do with…Normal UltrasoundsOther Abnormal Serum Studies
17 Normal UltrasoundsNormal ultrasound: % decrease in risk for chromosome abnormalitiesRemember that at least 30% of fetuses with Down syndrome have NO abnormal ultrasound findings!
18 Low 1st Trimester PAPP-A Pregnancies with PAPP-A of ≤ 5%tile (0.4MoM) are at increased risk for:Spontaneous fetal loss < 24 wks GALow birth weightPreeclampsiaGestational HTNPreterm birth and stillbirthPreterm premature rupture of membranesPlacental abruption
21 Cell-free Fetal DNA (cffDNA) Screening or Diagnosis?Known as “Noninvasive Prenatal Testing” or “NIPT”Technology uses circulating cell free fetal DNA found in the maternal plasmaThought to be derived primarily from placentaNew recognition of limitations of screening with pregnancies with placental mosacismsUnclear data for egg donor pregnanciesAvailable as early as 10th week of pregnancyCleared from maternal blood almost immediately after childbirth
22 Cell-free Fetal DNA (cffDNA) 2012 publications (Sparks et al., Ashoor et al., Bianchi et al.)targeted (chromosome-selective) sequencing of chromosomes 18 and 21highly accuratepotentially more cost-effectiveTechnology can be expected to identify 98% of cases of T21 with a false-positive rate of < 0.5%.Multiple different labsMaterniT21plus by SequenomVerifi by VerinataHarmony by Ariosa
23 Cell-free Fetal DNA (cffDNA) Labs MaterniT21plus by Sequenom>99% detection for T21, T18~90% detection for T13<1% false positive rateCost: $Verifi by Verinata~80% detection for T13>90% detection for 45,XCost: $Harmony by AriosaCost: up to $795
24 Cell-free Fetal DNA (cffDNA) ACOG Committee Opinion, Dec – “Noninvasive Prenatal Testing for Fetal Aneuploidy”cffDNA testing should be an informed patient choice after counseling and should not be part of routine prenatal laboratory assessment.cffDNA testing should not be offered to low-risk women or women with multiple gestations (has not been studied).A negative cffDNA test result does not ensure an unaffected pregnancy.A patient with a positive test result should be referred for genetic counseling and should be offered invasive prenatal diagnosis for confirmation of test results.
25 Indications for Considering Use of cffDNA for Screening Maternal Age ≥ 35 years at deliveryFetal ultrasound findings indicating increased risk of aneuploidyCPCs?IEF?Clinodactyly?Absent/hypoplastic nasal bone?History of a prior pregnancy with a trisomyPositive test result for aneuploidy (any serum test)Parental balanced translocation with increased risk of fetal trisomy 13 or 21.
27 ConsiderationsPrimary insurers are generally reimbursing for first-trimester screenings, including NT ultrasounds as well as NIPT.Are there referral sites available to your patients for appropriate genetic counseling and NT US measurements? What about for CVS and/or amniocentesis?What testing strategy makes the most sense for your patients?How do you see it evolving in the next 1-2 years?
28 Testing for Cystic Fibrosis (CF) Site of genetic defect = CF Transmembrane Regulator (CFTR) gene, a chloride channel protein~ 1700 mutations of CFTR gene have been describedDisease incidence: 1 in 2500 in the non-Hispanic white populationCarrier frequencies:1/24-25 Caucasians of European descent or Ashkenazi Jews1/58 Hispanic American1/61 African American1/94 Asian American
29 CF Genetic TestingDifficult to assign a single ethnicity to individualsACOG 2011 Recommendation – offer CF carrier screening to all women of reproductive ageNeed to be screened only once
30 CF Parental Genetic Testing Sequential testingTest mother for carrier stateIf positive, test fatherConcurrent testingTest mother and father simultaneouslyAdvantage: can be done prior to conceptionLimitation: depends on accurate ID of fatherIf both parents are unaffected but family hx of CF exists:Genetic counselingIdentify if CFTR mutation analysis in affected family member is available
31 Positive CF Testing If both parents are carriers… and prior to conceptionoffer ART options for diagnosis of embryoand currently pregnantoffer CVS or amnio to confirm status of fetusNo in-utero treatments existVariable clinical scenarios, with median survival for patients 37yrs
32 “Residual Risk”Potential risk of having an affected child with CF after testing is completed and is negativeVaries by race and current testing panel for gene abnormalitiesWill vary over time and by laboratoryNewborn screening panels that include CF screening do not replace maternal carrier testing
33 Summary Recommendations Genetic screening in pregnancy (and pre-conception!) is rapidly getting more complex.OHSU Online Course (FREE!)0.5 CME credits availableUnderstand your patient population and your local capabilities, specifically as they relate to genetic counseling, ultrasound expertise, and diagnostic testing.Develop practice workflows that allow women to access early genetic screening should they desire.3 recommendations to take back to your practice; “write down 1 you will commit to” (with strong recommendations of a single listed item)