What’s New in Prenatal Genetic Screening?

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Whats New in Prenatal Genetic Screening?

• Pamela M. Williams MD
• Dept of Family Medicine
• USUHS

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Genetics in Medicine

• Human Genome Project has brought inherited health
  factors to the forefront
• Genetic risk assessment, screening and testing
  are now part of primary care
• Are you ready?

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Objectives

• List the elements of prenatal genetic risk
  assessment
• Discuss the expanding role of ethnicity-based
  genetic screening
• Describe current options for screening for fetal
  chromosomal abnormalities

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Reproductive Genetic Risk Assessment

• May occur as part of preconception or prenatal
  care
• 4 key assessment areas
• Maternal age
• Family medical history
• Current pregnancy history
• Ethnic background

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Risk AssessmentMaternal Age

• Risk for chromosome abnormalities increases with
  maternal age
• Age establishes a priori risk

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EBM Recommendation 1

• Women at high risk for fetal aneuploidy (age gt 35
  at time of delivery or prior child/fetus with
  aneuploidy) should be offered genetic counseling
• Source DoD/VA Uncomplicated Pregnancy Guideline
• Strength of evidence B

Source National Guideline Clearinghouse
www.guideline.gov
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EBM Recommendation Update

• Screening invasive diagnostic testing for
  aneuploidy should be available to all women who
  present for prenatal care before 20 wks of
  gestation regardless of age
• Source ACOG Practice Bulletin 77 (1/07)
• Strength of evidence B

Source National Guideline Clearinghouse
www.guideline.gov
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Risk AssessmentFamily Medical History

• If a family history of a diagnosed genetic
  condition or birth defect is identified, referral
  for genetic counseling is appropriate
• Examples
• Prior child with spina bifida
• Niece with cystic fibrosis
• Nephew with Duchenne Muscular Dystorphy
• Brother with Fragile X syndrome

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Family Medical History

• For a non-specific, but concerning history,
  referral for counseling is also appropriate
• Examples
• Close family member with mental retardation of
  unknown etiology
• Multiple family members with kidney disease
• Previous child with seizure disorder and
  developmental delay

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Risk AssessmentPregnancy History

• During a pregnancy, any reported exposures or
  maternal condition may prompt genetic counseling
  referral

• Known / potential teratogens
• Accutane
• Seizure medications
• Lithium
• Coumadin
• Street drugs
• Other
• High fever
• Viral infections
• Maternal Diabetes

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Risk Assessment Ethnic background
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Ethnicity-Based Carrier Screening

• Purpose To detect couples at risk for
  prenatally diagnosable genetic disease
• Tests offered based on ethnic background
• Should be offered to patients
• Seeking preconception counseling or
• Seeking infertility care or
• In first or early second trimester of pregnancy

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Carrier Frequencies Based on Ethnic Origin
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Principles of Counseling

• Pre-screening, counseling should include
• Purpose, voluntary nature
• Range of symptoms/severity of each disease
• Risk of carrier status affect on offspring
• Meaning of positive and negative results
• Factors to consider in decision-making
• Further testing necessary for prenatal diagnosis

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Case Study CF Screening

• ACMG (American College of Medical Genetics)
• Published laboratory standards and guidelines for
  population-based CF screening

• ACOG ( American College of Obstetrics and
  Gynecology)
• Fall 2001, updated Dec 2005
• Recommended offering or making available CF
  screening to preconception or prenatal patients

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2005 ACOG Guidelines

• Information about screening should be made
  available to all couples
• Screening should be offered to
• Individuals with a family history of CF
• Reproductive partners of individuals with CF
• Couples in whom one or both are Caucasian and are
  planning pregnancy or seeking prenatal care
• Universal offering of screening is an option

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CF Carrier Screening

• Carrier frequency 1/25 to 1/29 in Caucasian
  Ashkenazi Jewish populations
• Screening by DNA mutation analysis
• Pan-ethnic panel including all mutations with an
  allele frequency of at least 0.1
• Current panel 23 mutations
• Sequential vs. concurrent screening

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Interpreting the Results

• Risk estimation
• Directly related to ancestry
• Sensitivity is a function of number of mutations
  searched for in the panel
• Negative screen does not mean no risk
• Remaining riskResidual risk

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Carrier Rates Pre/Post Testing
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Pitfalls in Screening

• All mutations are not tested
• Screening assumes properly identified paternity
• Residual risk estimates assume no family history
• Genotype-phenotype correlation cannot be assumed

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Dealing with Positive Results

• For the individual identified as a carrier
• Recommend testing of father of baby ASAP
• Consider offering genetic counseling
• For the couple who are both positive
• Chance of having an affected baby 1 in 4
• Prompt referral for genetic counseling with
  discussion of prenatal testing

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Screening for Fetal Chromosomal Abnormalities
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Screening Option Explosion

• First trimester
• Second Trimester
• Integrative
• Sequential

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First Trimester

• NT (Nuchal translucency)
• PAPP-A (pregnancy associated plasma protein-A)
• hCG (human chorionic gonadotropin)

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Nuchal Translucency

• Timing 11-14 wks EGA
• NT measurement gt 3. 5 mm associated with
  increased risk of
• Chromosomal abnormalities
• Structural anomalies
• SAB, SGA, stillbirth
• Down syndrome detection rate 64-70

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1st Trimester Serum Screening

• Timing EGA 9 to 136 wks
• Analytes used (with maternal age)
• hCG or Free b-hCG
• PAPP-A
• Detection rates with 5 screen positive rate
• Trisomy 21 68
• Trisomy 18 90

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Combined 1st Trimester Serum NT

• Timing 11-14 wks gestation
• NT best visualized _at_ CRL 45-84 mm
• NT maternal serum analytes
• Detection rates w/ 5 screen positive rate

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1st Trimester Serum NT Screen

• Pros
• Fingerstick dry blood is easy to collect
• Results available earlier in gestation
• Higher detection rates than 2nd trimester
• More accurate for multiple gestations

• Cons
• Requires certified ultrasonographer
• Does not screen for NTDs

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Second Trimester Options

• Triple screen
• Quadruple screen
• Genetic sonogram
• Extended sonogram serum ultrasound markers

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Quad Screen

• Analytes used (with maternal age)
• Alpha-fetoprotein (AFP)
• Unconjugated estriol (uE3)
• Beta-human chorionic gonadotropin (b-HCG)
• Dimeric inhibin-A
• Detection rates w/ 5 screen positive rate
• Trisomy 21 75-80 (vs 60-70 with triple
  screen)
• Trisomy 18 60
• NTD 75-80

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Genetic Ultrasound

• Fetal anatomy screen
• Timing 18-20 wks
• Evaluate for major structural anomalies and minor
  markers for aneuploidy
• Conflicting views surround use as independent or
  adjunct screening test

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Integrative TestingNondisclosure of
1st-trimester results

• Options
• Integrated (NT, PAPP-A, quad screen)
• Serum integrated (PAPP-A, quad screen)
• Down syndrome detection rates
• Integrated 94-96
• Serum integrated 85-88

Faster Trial NEJM 2005 353 2001-11.
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Sequential TestingDisclosure of 1st-trimester
results

• Independent
• Step-wisefirst-trimester test
• Positive diagnostic testing offered
• Negative second trimester offered, then final
  combined risk determined
• Contingent..first-trimester test
• Positive diagnostic test offered
• Negative no further testing
• Intermediate second trimester offered combined
  risk determined

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Sequential Testing Detection Rates

• Independent 94-98
• False positive rates higher! (11-17)
• Not recommended.
• Step-wise sequential 95
• Contingent 88-94

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ACOG 2007Practice Bulletin 77
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Reminder!

• Screening invasive diagnostic testing for
  aneuploidy should be available to all women who
  present for prenatal care before 20 wks of
  gestation regardless of age. Women should be
  counseled regarding the differences between
  screening and invasive diagnostic testing.

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Updated ACOG Recommendations (Level A)

• Combined 1st trimester screening is an effective
  screening test, better than NT alone
• Women with positive first trimester screens
  should be offered counseling and an option of CVS
  or 2nd trimester amniocentesis
• Training/standardization need for NT
• Neural tube screening should be offered to all
  women who elect first trimester aneuploidy
  screening

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Updated ACOG Recommendations (Level B )

• Integrated 1st 2nd screening is more sensitive
  than first trimester screening alone
• Serum integrated (1st) screening is a viable
  option if NT is unavailable
• Abnormal second trimester U/S warrants counseling
  offer of diagnostic procedure
• Patients with gt NT but negative aneuploidy screen
  should be offered targeted U/S and fetal
  echocardiogram

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Factors Impacting Choice

• Gestational age at first visit
• Number of fetuses
• Prior obstetric history
• Family history
• Availability of NT
• Test sensitivity

• Test limitations
• Risk of invasive procedures
• Desire for early test results
• Options for earlier termination

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Practical Application

• Identify tests available in your area
• NT
• CVS
• Identify which tests will meet the needs of your
  patients
• Obtain materials to allow patients to make an
  informed decision
• Learn how to interpret and counsel risk assessment

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Take Home Points

• Screening protocols are complex and evolving
  rapidly
• The best test may differ from patient to
  patient
• Education is keyboth for patients and providers

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Questions?