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Prenatal genetic screening: Minimize confusion, maximize counselling Dr. Jaime Schachar MD FRCSC Maternal Fetal Medicine University of Calgary

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Page 1: Prenatal genetic screening: Minimize confusion, maximize … · Test Performance •PPV for both high and low‐risk populations is higher for NIPT compared to other conventional

Prenatal genetic screening: Minimize confusion, maximize counsellingDr. Jaime Schachar MD FRCSCMaternal Fetal MedicineUniversity of Calgary

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Faculty/Presenter Disclosure• Faculty: 

• Relationships with financial sponsors:‐ Grants/Research support: N/A‐ Speakers Bureau/Honoraria: N/A‐ Consulting Fees: N/A‐ Patents: N/A‐ Other:  The Alberta College of Family Physicians has provided support in the form of a speaker fee and/or expenses.

‐ Locum for EFW Radiology in Calgary

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Learning Objectives:

• Review the basics of prenatal screening and diagnosis.

• Review key counselling points for all patients in early pregnancy.

• Review new advances, including cfDNA and CMA, and their applications in the prenatal setting. 

• To provide an overview of current screening paradigms in Canada (SOGC).  

geneticsupportfoundation.org

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Why Screen?

• Genetic testing and screening have become part of contemporary medicine and public health initiatives

• Women have the right to access information about the health of their fetus   

SOGC Statement on Access to Genetic Screening, 2007. 

All pregnant women in Canada, regardless of age, should be offered through an informed counseling process, the option of a prenatal screening test for the most common clinically significant fetal aneuploidies.                   

J Obstet Gynaecol Can 2011;33 (7):746‐750

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EXPECTATIONS

VS.

REALITY

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Key Counselling Issues

• Advantages, disadvantages, and limitations of the test

• Difference between a screening test and a diagnostic test

• Discussion of what patient would do in the event of a positive test• Diagnostic testing• Family preparation• Site of delivery

• Reproductive choice

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geneticseducation.ca

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Courtesy of Dr. J. Johnson

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First Trimester Combined Screening (FTS) in Calgary Zone

Early Risk Assessment (ERA)1. Screening for Aneuploidy2. Screening for pregnancy complications

• FTS introduced 2006• FMF certified NT sonographers• Program performance audited annually• Provides risk T21, 18, 13 and for low PAPP‐A• 85‐90% DR 5‐7% FPR

First Trimester Screen (FTS)• Maternal age• NT• Free‐bHCG• PAPP‐A

Courtesy of Dr. J. Johnson

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“Actually, we are only taking DNA samples.”

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Maternal Plasma Cell‐Free DNA Based NIPT• Highly effective screening test for the common fetal trisomies (21, 18, 13), performed after 10 weeks’ gestation 

• Based on genomic sequencing of maternal plasma cfDNA fragments using either “massively parallel” sequencing or targeted sequencing

• Superior performance for aneuploidy screening• Other indications: fetal sex determination, fetal Rh status, paternally derived autosomal genetic conditions

Placenta Maternal plasma Maternal blood cells

Lo et al, Lancet 1997

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cfDNA –Test Characteristics 

• Positive predictive value (PPV) and the residual risk must be included in the NIPT reports

• Results depend on maternal plasma DNA sample quality and adequacy of fetal fraction (%)

• False positive rate of 1%

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Test Performance

• PPV for both high and low‐risk populations is higher for NIPT compared to other conventional approaches. 

• Even for population with high a priori risks, approximately one in ten referrals will be a false‐positive. 

• Positive predictive values are lower for the other aneuploidies because the prevalences are lower and/or the test performance is lower.

Bellcross, 2015

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NIPT Challenges

• No call results due to low fetal fraction (FF)Affected by gestational age, maternal BMI, type of aneuploidy 

• TwinsEach fetus will have a different FF Increased no call rate , 10‐15% FF < 4%Increased false negative rate 

• TriploidyLower fetal fractionMissed by non‐SNP methods 

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False Positives

• Placental mosaicism 

• Vanishing twin 

• Maternal sex chromosome abnormality 

• Neoplasia – apoptosis of cancer cells, aneuploidy common 

Stgeorges.nhs.uk

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NIPT Counselling Points• Failed test, false negative or positive fetal result, and an unexpected fetal or maternal result all possible.

• Management decisions, including TOP, require diagnostic testing and should not be based on maternal plasma cfDNA results alone.

• If fetal structural abnormality is identified regardless of previous screening test results, the woman should undergo genetic counselling and be offered invasive diagnostic testing.

• Although cfDNA screening for aneuploidy in twin pregnancy is available, there is less validation data than for a singleton pregnancy and it should be undertaken with caution.

• Routine cfDNA screening for fetal microdeletions is not currently recommended (II‐2B).

• Sex chromosome abnormalities require counselling

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*SIPS, IPS, cFTS, Quad**Risk adjustment as per local resources

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• The NT measurement for aneuploidy risk estimation (combined with maternal serum) should not be performed if cell‐free DNA screening has been used. 

• Every effort should be made to improve access to high‐quality first trimester ultrasound for all Canadian women. 

• In areas where NT assessment is not available, a first trimester dating ultrasound improves the accuracy of maternal serum screening and the management of pregnancy.

First Trimester Ultrasound 

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Far beyond aneuploidy prediction alone….

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What about “soft markers”?

The presence of an isolated fetal soft marker in the second trimester, with the exception of increased nuchal fold, should not be used to adjust the a priori risk for fetal aneuploidy.

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Soft Markers

• In women with a low risk of aneuploidy following first trimester aneuploidy screening, the presence of specific ultrasound “soft markers” associated with fetal trisomy 21 are not clinically relevant due to poor predictive value and do not warrant further testing.

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Issues with Soft Markers

• Studies not done on women who had undergone first trimester screening

• Likelihood ratios markedly reduced after effective screening• Echogenic intracardiac focus and choroid plexus cysts are not relevant if used in isolation

• Should not be used at all if maternal cfDNA screening has been done

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Final Thoughts• All patients should have the opportunity to discuss options for prenatal genetic screening in early pregnancy

• Pre‐test counselling should include:• Tests available • Difference between screening and diagnostic test• Risks and benefits of testing• Possible actions (individual to the patient) in event of positive test

• First trimester offers significant benefit in addition to aneuploidy screening

• NIPT is a powerful screening test• Soft markers have minimal role

geneticsupportfoundation.org

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Questions/Comments

[email protected]