![\"\"](\"https:\/\/obgconnect.com\/curbside\/wp-content\/uploads\/sites\/4\/2023\/04\/6784-NIPT-Illustration-V3.png\")
<\/figure>\n\n\n\nPrenatal Genetic Screening Basics <\/h3>\n\n\n\n\n- All pregnancies have a risk for genetic abnormalities, regardless of maternal age <\/li>\n\n\n\n
- 1 in 150 livebirths have a genetic abnormality<\/li>\n\n\n\n
- Genetic disorders can include
- Chromosomal disorders including aneuploidy: Deletions or duplications of either entire chromosomes or partial segments of chromosomes that can affect multiple genes<\/li><\/ul>\n
\n- Single gene disorders: Changes in DNA<\/span> sequence within a gene that can result in disease<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Since the early 1980s, maternal screening for fetal aneuploidy such as Down syndrome has been available as part of prenatal care<\/li>\n\n\n\n
- These screening tests are a key component of prenatal care but have important limitations\n
\n- Positive screening tests always need to be confirmed<\/li>\n\n\n\n
- cfDNA<\/span> assesses placental DNA<\/span> that does not always accurately reflect true fetal DNA<\/span><\/li>\n\n\n\n
- Negative screening tests always have associated residual risks<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- ACOG<\/span>, SMFM<\/span> and ACMG<\/span> all recommend offering all pregnant women the option of invasive diagnostic testing for aneuploidy regardless of maternal age or risk\n
\n- By definition, screening tests are less accurate than diagnostic testing such as amniocentesis or chorionic villus sampling (CVS)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
Current Guidelines<\/h3>\n\n\n\n
ACMG<\/span><\/em><\/p>\n\n\n\n\n- For both singleton and twin pregnancies, ACMG<\/span> recommends offering cfDNA<\/span> as first line fetal aneuploidy screening over standard screening (biomarkers and ultrasound) for\n
\n- Down syndrome: Trisomy 21 (T21)<\/li>\n\n\n\n
- Edward syndrome: Trisomy 18 (T18)<\/li>\n\n\n\n
- Patau syndrome: Trisomy 13 (T13)<\/li>\n\n\n\n
- Fetal sex chromosome aneuploidies (SCA) such as Turner syndrome (45,X), Triple X syndrome (XXX), Jacobs syndrome (XYY), and Klinefelter syndrome (47,XXY)<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- ACMG<\/span> Suggests offering prenatal cfDNA<\/span> screening for\n
\n- 22q11 deletion syndrome (DiGeorge syndrome)<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- ACMG<\/span> does not recommend against testing for additional CNVs and rare autosomal trisomies (i.e., not including 13, 18, 21, X and Y) but rather states “Insufficient Evidence to Recommend”<\/li>\n<\/ul>\n\n\n\n
ACOG<\/span>\/SMFM<\/span><\/em><\/p>\n\n\n\n\n- cfDNA<\/span> is recognized as “the most sensitive and specific screening test for the common fetal aneuploidies”<\/li>\n\n\n\n
- Options include
- Aneuploidy screening with cfDNA<\/span> or<\/strong><\/li><\/ul>
- First trimester serum screening with or without nuchal translucency<\/span><\/li><\/ul>\n
\n- ACOG<\/span> and SMFM<\/span> do not recommend screening for CNVs due to concerns regarding detection and false-positive rates<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
PRETEST COUNSELING – KEY POINTS <\/h2>\n\n\n\nOptions for Aneuploidy Screening in the First Trimester<\/h3>\n\n\n\n
First Trimester Screening (biomarkers and first trimester ultrasound)<\/em><\/p>\n\n\n\n\n- Benefits\n
\n- Simple blood test performed between 11 and 14 weeks using beta-human chorionic gonadotrophin (free or total hCG) and pregnancy-associated plasma protein A (PAPP-A) represents serum portion<\/li>\n\n\n\n
- First trimester ultrasound component with NT can detect structural and placental abnormalities as well as additional chromosome or single gene defects<\/li>\n\n\n\n
- Relatively high detection rate for T21 | Can also detect other common aneuploidies especially T18<\/li>\n\n\n\n
- Typically will return a result <\/li>\n\n\n\n
- Carries no procedure-related risk<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns
- Lower detection rate for common aneuploidies vs cfDNA<\/span><\/li><\/ul>
- PPV<\/span> is approximately 5% for T21 | Only 1 in 20 women with a positive result will actually have a fetus affected with T21 and therefore many women will experience unnecessary anxiety, emotional distress and invasive testing they may not have otherwise opted for<\/li><\/ul>
- Does not include sex chromosome aneuploidies<\/li><\/ul>
- NT measurement, unlike laboratory testing, requires proximity to an advanced ultrasound unit with training and expertise and should only be performed by NT certified sonographers | Potential equity issue<\/li><\/ul>\n
\n- Performance less robust in twin vs singleton pregnancies <\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
cfDNA<\/span><\/em><\/p>\n\n\n\n\n- Benefits
- ACMG<\/span> considers cfDNA<\/span> superior and the first line choice for prenatal aneuploidy screening | ACOG<\/span> recommends cfDNA<\/span> be offered to all women as an option for prenatal aneuploidy screening<\/li><\/ul>
- Performed as early as 9 weeks | Single visit | No ultrasound needed | Can do at any point in pregnancy<\/li><\/ul>
- cfDNA<\/span> consistently outperforms standard screening especially for T21 (ACMG<\/span>)
- Detection Rate: 98.8% vs 82%<\/li><\/ul>
- False Positive Rate: 0.04% vs 5.6%<\/li><\/ul><\/li><\/ul>
- Positive predictive value<\/span> (PPV<\/span>), indicating the chance a screen positive result will be confirmed as a true positive, is substantially higher for cfDNA<\/span> vs standard screening, especially for T21 regardless of maternal age
- cfDNA<\/span>: 91.8%<\/li><\/ul>
- Traditional Screening: 3.6%<\/li><\/ul><\/li><\/ul>\n
\n- Only screening test available that can identify
- Fetal sex and sex chromosome aneuploidies<\/li><\/ul>
- Microdeletion syndromes<\/li><\/ul>\n
\n- Genome wide changes including copy number and all aneuploidies <\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns
- Because the detection rate and PPV<\/span> are so high, it is easy for patients to get confused and consider cfDNA<\/span> a diagnostic test vs a screening test<\/li><\/ul>
- Unlike standard screening, a positive cfDNA<\/span> often represents a true positive but it is not 100% and confirmation is still required for a definitive diagnosis<\/li><\/ul>
- Negative predictive value<\/span> (NPV<\/span>) of a chromosome abnormality following a negative result is very low but not 0%<\/li><\/ul>
- A ‘no call’ is possible (approximately 1%) and is more likely in patients with
- High BMI | Exposure to LMWH | Fetal aneuploidy especially T13 and T18<\/li><\/ul><\/li><\/ul>\n
\n- Report may also return with “higher risk for maternal malignancy” due to multiple chromosomal aberration signals detected on cfDNA<\/span> or may be abnormal due to maternal mosaicism<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
WHAT DISORDERS ARE COVERED WITH cfDNA?<\/h2>\n\n\n\nBoth ACMG and ACOG\/SMFM Recommend<\/h3>\n\n\n\n
Common Aneuploidies<\/em><\/p>\n\n\n\n\n- T21: >99% detection rate for T21<\/li>\n\n\n\n
- 98% detection rate for T18<\/li>\n\n\n\n
- 99% detection rate for T13<\/li>\n\n\n\n
- Combined false positive rate of 0.13%<\/li>\n\n\n\n
- cfDNA<\/span> is the most sensitive and specific screen for T21, T18 and T13<\/li>\n<\/ul>\n\n\n\n
ACMG Also Recommends <\/h3>\n\n\n\n
Sex chromosome abnormalities<\/em><\/p>\n\n\n\n\n- Benefits
- Certain sex chromosome aneuploidies such as Turner syndrome may have higher rate of fetal malformation and warrant fetal echocardiogram<\/li><\/ul>\n
\n- Early treatment of Klinefelter syndrome in childhood may be advantageous<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns\n
\n- Subject to false positive test results<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
Note: <\/strong>A result consistent with Turner syndrome may reflect the maternal chromosomal complement and not fetal | Any suspicion for preexisting maternal mosaic Turner syndrome should prompt referral to Maternal Fetal Medicine, Genetics and Cardiology services for further follow up<\/p>\n\n\n\nACMG Also Suggests Offering<\/h3>\n\n\n\n
22q11.2 Deletion Syndrome<\/em><\/p>\n\n\n\n\n- Benefits
- May occur in 1 in 990 to 1 in 2148 pregnancies | Higher prevalence<\/span> than T21 in pregnancies of younger women<\/li><\/ul>
- Cases can be missed at birth leading to diagnostic odyssey for parents<\/li><\/ul>
- PPV<\/span> reported to be as high as 52.6% (although may be lower in a truly low risk population without any structural abnormalities)<\/li><\/ul>\n
\n- Negative predictive value<\/span> (NPV<\/span>) is >99%<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns\n
\n- Similar to other disorders, positive screening result requires follow-up confirmation with definitive genetic testing<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
Other Chromosomal Abnormalities – CNVs<\/h3>\n\n\n\n
Targeted Microdeletions<\/em><\/p>\n\n\n\n\n- Benefits
- There are other microdeletion syndromes aside from 22q11.2 deletion syndrome that carry significant morbidity and mortality<\/li><\/ul>
- cfDNA<\/span> offers a noninvasive approach to detect some of these microdeletions associated with significant clinical outcomes<\/li><\/ul>\n
\n- Conditions screened that are severe may include\n
\n- Prader Willi\/Angelman Syndrome | Cri-du-chat | Wolf Hirshhorn syndrome<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns
- Not recommended by ACOG<\/span>\/SMFM<\/span> due to concerns regarding detection and false positive rates | Women who want information on microdeletions should be offered microarray from CVS or amnio specimen<\/li><\/ul>
- ACMG<\/span> notes that “there will be families for whom cfDNA<\/span> for CNVs could be offered based on the pregnancy or family history” and recommend consultation with a genetic service<\/li><\/ul>\n
\n- PPV<\/span> is lower due to lower prevalence<\/span> of disease<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
Genome-Wide Changes (not targeted)<\/em><\/p>\n\n\n\n\n- Benefits
- Analyzes chromosomal changes across the genome<\/li><\/ul>\n
\n- The rare autosomal aneuploidies have been associated with adverse pregnancy events though currently no way to predict precise pregnancy outcomes<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns
- Incidental findings are more likely to occur with genome-wide vs more targeted cfDNA<\/span><\/li><\/ul>
- Crucial to counsel patients that genome-wide cfDNA<\/span> may miss clinically significant findings detectable with invasive diagnostic testing using microarrays<\/li><\/ul>\n
\n- Generally genome-wide screening for additional CNVs and rare autosomal trisomies is not recommended by professional organizations for routine screening<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
POSTTEST COUNSELING – KEY POINTS<\/h2>\n\n\n\nPositive Screen Result<\/h3>\n\n\n\n
What is the Chance the Positive Report will Be a True Positive?<\/em><\/p>\n\n\n\n\n- PPV<\/span> is the critical performance characteristic for posttest counseling and refers to the likelihood that the patient’s positive cfDNA<\/span> report actually correlates with a definitive diagnosis
- T21: PPV<\/span> 91.8%<\/li><\/ul>
- T18: PPV<\/span> 65.8%<\/li><\/ul>
- T13: PPV<\/span> 37.2%<\/li><\/ul>\n
\n- Lower with T18 and T13 because of lower prevalence<\/span><\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Important to counsel regarding PPV<\/span> for particular aneuploidy where a report is screen positive
- PPV<\/span> will change based on maternal age and a priori risk based on presence or absence of ultrasound findings<\/li><\/ul>\n
\n- PPV<\/span> should be available on reports <\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
What Can Cause a False Positive?<\/em><\/p>\n\n\n\n\n- Less likely for T21 but can occur | More common with T18 and T13<\/li>\n\n\n\n
- Biological causes include
- Mosaicism (mixture of abnormal and normal cell lines) | Confined placental mosaicism can lead to false positive result since cfDNA<\/span> analyzes DNA<\/span> fragments from placenta<\/li><\/ul>
- Vanishing twin | More likely to be aneuploid and residual abnormal cells may be retained in the placenta<\/li><\/ul>
- Chromosomal disorders including aneuploidy: Deletions or duplications of either entire chromosomes or partial segments of chromosomes that can affect multiple genes<\/li><\/ul>\n
- \n
- Single gene disorders: Changes in DNA<\/span> sequence within a gene that can result in disease<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Since the early 1980s, maternal screening for fetal aneuploidy such as Down syndrome has been available as part of prenatal care<\/li>\n\n\n\n
- These screening tests are a key component of prenatal care but have important limitations\n
- \n
- Positive screening tests always need to be confirmed<\/li>\n\n\n\n
- cfDNA<\/span> assesses placental DNA<\/span> that does not always accurately reflect true fetal DNA<\/span><\/li>\n\n\n\n
- Negative screening tests always have associated residual risks<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- ACOG<\/span>, SMFM<\/span> and ACMG<\/span> all recommend offering all pregnant women the option of invasive diagnostic testing for aneuploidy regardless of maternal age or risk\n
- \n
- By definition, screening tests are less accurate than diagnostic testing such as amniocentesis or chorionic villus sampling (CVS)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
Current Guidelines<\/h3>\n\n\n\n
ACMG<\/span><\/em><\/p>\n\n\n\n
- \n
- For both singleton and twin pregnancies, ACMG<\/span> recommends offering cfDNA<\/span> as first line fetal aneuploidy screening over standard screening (biomarkers and ultrasound) for\n
- \n
- Down syndrome: Trisomy 21 (T21)<\/li>\n\n\n\n
- Edward syndrome: Trisomy 18 (T18)<\/li>\n\n\n\n
- Patau syndrome: Trisomy 13 (T13)<\/li>\n\n\n\n
- Fetal sex chromosome aneuploidies (SCA) such as Turner syndrome (45,X), Triple X syndrome (XXX), Jacobs syndrome (XYY), and Klinefelter syndrome (47,XXY)<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- ACMG<\/span> Suggests offering prenatal cfDNA<\/span> screening for\n
- \n
- 22q11 deletion syndrome (DiGeorge syndrome)<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- ACMG<\/span> does not recommend against testing for additional CNVs and rare autosomal trisomies (i.e., not including 13, 18, 21, X and Y) but rather states “Insufficient Evidence to Recommend”<\/li>\n<\/ul>\n\n\n\n
ACOG<\/span>\/SMFM<\/span><\/em><\/p>\n\n\n\n
- \n
- cfDNA<\/span> is recognized as “the most sensitive and specific screening test for the common fetal aneuploidies”<\/li>\n\n\n\n
- Options include
- Aneuploidy screening with cfDNA<\/span> or<\/strong><\/li><\/ul>
- First trimester serum screening with or without nuchal translucency<\/span><\/li><\/ul>\n
- \n
- ACOG<\/span> and SMFM<\/span> do not recommend screening for CNVs due to concerns regarding detection and false-positive rates<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
PRETEST COUNSELING – KEY POINTS <\/h2>\n\n\n\n
Options for Aneuploidy Screening in the First Trimester<\/h3>\n\n\n\n
First Trimester Screening (biomarkers and first trimester ultrasound)<\/em><\/p>\n\n\n\n
- \n
- Benefits\n
- \n
- Simple blood test performed between 11 and 14 weeks using beta-human chorionic gonadotrophin (free or total hCG) and pregnancy-associated plasma protein A (PAPP-A) represents serum portion<\/li>\n\n\n\n
- First trimester ultrasound component with NT can detect structural and placental abnormalities as well as additional chromosome or single gene defects<\/li>\n\n\n\n
- Relatively high detection rate for T21 | Can also detect other common aneuploidies especially T18<\/li>\n\n\n\n
- Typically will return a result <\/li>\n\n\n\n
- Carries no procedure-related risk<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns
- Lower detection rate for common aneuploidies vs cfDNA<\/span><\/li><\/ul>
- PPV<\/span> is approximately 5% for T21 | Only 1 in 20 women with a positive result will actually have a fetus affected with T21 and therefore many women will experience unnecessary anxiety, emotional distress and invasive testing they may not have otherwise opted for<\/li><\/ul>
- Does not include sex chromosome aneuploidies<\/li><\/ul>
- NT measurement, unlike laboratory testing, requires proximity to an advanced ultrasound unit with training and expertise and should only be performed by NT certified sonographers | Potential equity issue<\/li><\/ul>\n
- \n
- Performance less robust in twin vs singleton pregnancies <\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
cfDNA<\/span><\/em><\/p>\n\n\n\n
- \n
- Benefits
- ACMG<\/span> considers cfDNA<\/span> superior and the first line choice for prenatal aneuploidy screening | ACOG<\/span> recommends cfDNA<\/span> be offered to all women as an option for prenatal aneuploidy screening<\/li><\/ul>
- Performed as early as 9 weeks | Single visit | No ultrasound needed | Can do at any point in pregnancy<\/li><\/ul>
- cfDNA<\/span> consistently outperforms standard screening especially for T21 (ACMG<\/span>)
- Detection Rate: 98.8% vs 82%<\/li><\/ul>
- False Positive Rate: 0.04% vs 5.6%<\/li><\/ul><\/li><\/ul>
- Positive predictive value<\/span> (PPV<\/span>), indicating the chance a screen positive result will be confirmed as a true positive, is substantially higher for cfDNA<\/span> vs standard screening, especially for T21 regardless of maternal age
- cfDNA<\/span>: 91.8%<\/li><\/ul>
- Traditional Screening: 3.6%<\/li><\/ul><\/li><\/ul>\n
- \n
- Only screening test available that can identify
- Fetal sex and sex chromosome aneuploidies<\/li><\/ul>
- Microdeletion syndromes<\/li><\/ul>\n
- \n
- Genome wide changes including copy number and all aneuploidies <\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns
- Because the detection rate and PPV<\/span> are so high, it is easy for patients to get confused and consider cfDNA<\/span> a diagnostic test vs a screening test<\/li><\/ul>
- Unlike standard screening, a positive cfDNA<\/span> often represents a true positive but it is not 100% and confirmation is still required for a definitive diagnosis<\/li><\/ul>
- Negative predictive value<\/span> (NPV<\/span>) of a chromosome abnormality following a negative result is very low but not 0%<\/li><\/ul>
- A ‘no call’ is possible (approximately 1%) and is more likely in patients with
- High BMI | Exposure to LMWH | Fetal aneuploidy especially T13 and T18<\/li><\/ul><\/li><\/ul>\n
- \n
- Report may also return with “higher risk for maternal malignancy” due to multiple chromosomal aberration signals detected on cfDNA<\/span> or may be abnormal due to maternal mosaicism<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
WHAT DISORDERS ARE COVERED WITH cfDNA?<\/h2>\n\n\n\n
Both ACMG and ACOG\/SMFM Recommend<\/h3>\n\n\n\n
Common Aneuploidies<\/em><\/p>\n\n\n\n
- \n
- T21: >99% detection rate for T21<\/li>\n\n\n\n
- 98% detection rate for T18<\/li>\n\n\n\n
- 99% detection rate for T13<\/li>\n\n\n\n
- Combined false positive rate of 0.13%<\/li>\n\n\n\n
- cfDNA<\/span> is the most sensitive and specific screen for T21, T18 and T13<\/li>\n<\/ul>\n\n\n\n
ACMG Also Recommends <\/h3>\n\n\n\n
Sex chromosome abnormalities<\/em><\/p>\n\n\n\n
- \n
- Benefits
- Certain sex chromosome aneuploidies such as Turner syndrome may have higher rate of fetal malformation and warrant fetal echocardiogram<\/li><\/ul>\n
- \n
- Early treatment of Klinefelter syndrome in childhood may be advantageous<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns\n
- \n
- Subject to false positive test results<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
Note: <\/strong>A result consistent with Turner syndrome may reflect the maternal chromosomal complement and not fetal | Any suspicion for preexisting maternal mosaic Turner syndrome should prompt referral to Maternal Fetal Medicine, Genetics and Cardiology services for further follow up<\/p>\n\n\n\n
ACMG Also Suggests Offering<\/h3>\n\n\n\n
22q11.2 Deletion Syndrome<\/em><\/p>\n\n\n\n
- \n
- Benefits
- May occur in 1 in 990 to 1 in 2148 pregnancies | Higher prevalence<\/span> than T21 in pregnancies of younger women<\/li><\/ul>
- Cases can be missed at birth leading to diagnostic odyssey for parents<\/li><\/ul>
- PPV<\/span> reported to be as high as 52.6% (although may be lower in a truly low risk population without any structural abnormalities)<\/li><\/ul>\n
- \n
- Negative predictive value<\/span> (NPV<\/span>) is >99%<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns\n
- \n
- Similar to other disorders, positive screening result requires follow-up confirmation with definitive genetic testing<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
Other Chromosomal Abnormalities – CNVs<\/h3>\n\n\n\n
Targeted Microdeletions<\/em><\/p>\n\n\n\n
- \n
- Benefits
- There are other microdeletion syndromes aside from 22q11.2 deletion syndrome that carry significant morbidity and mortality<\/li><\/ul>
- cfDNA<\/span> offers a noninvasive approach to detect some of these microdeletions associated with significant clinical outcomes<\/li><\/ul>\n
- \n
- Conditions screened that are severe may include\n
- \n
- Prader Willi\/Angelman Syndrome | Cri-du-chat | Wolf Hirshhorn syndrome<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns
- Not recommended by ACOG<\/span>\/SMFM<\/span> due to concerns regarding detection and false positive rates | Women who want information on microdeletions should be offered microarray from CVS or amnio specimen<\/li><\/ul>
- ACMG<\/span> notes that “there will be families for whom cfDNA<\/span> for CNVs could be offered based on the pregnancy or family history” and recommend consultation with a genetic service<\/li><\/ul>\n
- \n
- PPV<\/span> is lower due to lower prevalence<\/span> of disease<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
Genome-Wide Changes (not targeted)<\/em><\/p>\n\n\n\n
- \n
- Benefits
- Analyzes chromosomal changes across the genome<\/li><\/ul>\n
- \n
- The rare autosomal aneuploidies have been associated with adverse pregnancy events though currently no way to predict precise pregnancy outcomes<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Concerns
- Incidental findings are more likely to occur with genome-wide vs more targeted cfDNA<\/span><\/li><\/ul>
- Crucial to counsel patients that genome-wide cfDNA<\/span> may miss clinically significant findings detectable with invasive diagnostic testing using microarrays<\/li><\/ul>\n
- \n
- Generally genome-wide screening for additional CNVs and rare autosomal trisomies is not recommended by professional organizations for routine screening<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
POSTTEST COUNSELING – KEY POINTS<\/h2>\n\n\n\n
Positive Screen Result<\/h3>\n\n\n\n
What is the Chance the Positive Report will Be a True Positive?<\/em><\/p>\n\n\n\n
- \n
- PPV<\/span> is the critical performance characteristic for posttest counseling and refers to the likelihood that the patient’s positive cfDNA<\/span> report actually correlates with a definitive diagnosis
- T21: PPV<\/span> 91.8%<\/li><\/ul>
- T18: PPV<\/span> 65.8%<\/li><\/ul>
- T13: PPV<\/span> 37.2%<\/li><\/ul>\n
- \n
- Lower with T18 and T13 because of lower prevalence<\/span><\/li>\n<\/ul>\n<\/li>\n\n\n\n
- Important to counsel regarding PPV<\/span> for particular aneuploidy where a report is screen positive
- PPV<\/span> will change based on maternal age and a priori risk based on presence or absence of ultrasound findings<\/li><\/ul>\n
- \n
- PPV<\/span> should be available on reports <\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
What Can Cause a False Positive?<\/em><\/p>\n\n\n\n
- \n
- Less likely for T21 but can occur | More common with T18 and T13<\/li>\n\n\n\n
- Biological causes include
- Mosaicism (mixture of abnormal and normal cell lines) | Confined placental mosaicism can lead to false positive result since cfDNA<\/span> analyzes DNA<\/span> fragments from placenta<\/li><\/ul>
- Vanishing twin | More likely to be aneuploid and residual abnormal cells may be retained in the placenta<\/li><\/ul>
- Vanishing twin | More likely to be aneuploid and residual abnormal cells may be retained in the placenta<\/li><\/ul>
- Mosaicism (mixture of abnormal and normal cell lines) | Confined placental mosaicism can lead to false positive result since cfDNA<\/span> analyzes DNA<\/span> fragments from placenta<\/li><\/ul>
- PPV<\/span> should be available on reports <\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
- Important to counsel regarding PPV<\/span> for particular aneuploidy where a report is screen positive
- Lower with T18 and T13 because of lower prevalence<\/span><\/li>\n<\/ul>\n<\/li>\n\n\n\n
- T13: PPV<\/span> 37.2%<\/li><\/ul>\n
- T18: PPV<\/span> 65.8%<\/li><\/ul>
- T21: PPV<\/span> 91.8%<\/li><\/ul>
- PPV<\/span> is the critical performance characteristic for posttest counseling and refers to the likelihood that the patient’s positive cfDNA<\/span> report actually correlates with a definitive diagnosis
- Generally genome-wide screening for additional CNVs and rare autosomal trisomies is not recommended by professional organizations for routine screening<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
- Crucial to counsel patients that genome-wide cfDNA<\/span> may miss clinically significant findings detectable with invasive diagnostic testing using microarrays<\/li><\/ul>\n
- Incidental findings are more likely to occur with genome-wide vs more targeted cfDNA<\/span><\/li><\/ul>
- Analyzes chromosomal changes across the genome<\/li><\/ul>\n
- Benefits
- PPV<\/span> is lower due to lower prevalence<\/span> of disease<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
- ACMG<\/span> notes that “there will be families for whom cfDNA<\/span> for CNVs could be offered based on the pregnancy or family history” and recommend consultation with a genetic service<\/li><\/ul>\n
- Not recommended by ACOG<\/span>\/SMFM<\/span> due to concerns regarding detection and false positive rates | Women who want information on microdeletions should be offered microarray from CVS or amnio specimen<\/li><\/ul>
- Conditions screened that are severe may include\n
- cfDNA<\/span> offers a noninvasive approach to detect some of these microdeletions associated with significant clinical outcomes<\/li><\/ul>\n
- There are other microdeletion syndromes aside from 22q11.2 deletion syndrome that carry significant morbidity and mortality<\/li><\/ul>
- Benefits
- Concerns\n
- Negative predictive value<\/span> (NPV<\/span>) is >99%<\/li>\n<\/ul>\n<\/li>\n\n\n\n
- PPV<\/span> reported to be as high as 52.6% (although may be lower in a truly low risk population without any structural abnormalities)<\/li><\/ul>\n
- Cases can be missed at birth leading to diagnostic odyssey for parents<\/li><\/ul>
- May occur in 1 in 990 to 1 in 2148 pregnancies | Higher prevalence<\/span> than T21 in pregnancies of younger women<\/li><\/ul>
- Benefits
- Subject to false positive test results<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
- Certain sex chromosome aneuploidies such as Turner syndrome may have higher rate of fetal malformation and warrant fetal echocardiogram<\/li><\/ul>\n
- Benefits
- Report may also return with “higher risk for maternal malignancy” due to multiple chromosomal aberration signals detected on cfDNA<\/span> or may be abnormal due to maternal mosaicism<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
- High BMI | Exposure to LMWH | Fetal aneuploidy especially T13 and T18<\/li><\/ul><\/li><\/ul>\n
- A ‘no call’ is possible (approximately 1%) and is more likely in patients with
- Negative predictive value<\/span> (NPV<\/span>) of a chromosome abnormality following a negative result is very low but not 0%<\/li><\/ul>
- Unlike standard screening, a positive cfDNA<\/span> often represents a true positive but it is not 100% and confirmation is still required for a definitive diagnosis<\/li><\/ul>
- Because the detection rate and PPV<\/span> are so high, it is easy for patients to get confused and consider cfDNA<\/span> a diagnostic test vs a screening test<\/li><\/ul>
- Microdeletion syndromes<\/li><\/ul>\n
- Fetal sex and sex chromosome aneuploidies<\/li><\/ul>
- Only screening test available that can identify
- Traditional Screening: 3.6%<\/li><\/ul><\/li><\/ul>\n
- cfDNA<\/span>: 91.8%<\/li><\/ul>
- Positive predictive value<\/span> (PPV<\/span>), indicating the chance a screen positive result will be confirmed as a true positive, is substantially higher for cfDNA<\/span> vs standard screening, especially for T21 regardless of maternal age
- False Positive Rate: 0.04% vs 5.6%<\/li><\/ul><\/li><\/ul>
- Detection Rate: 98.8% vs 82%<\/li><\/ul>
- cfDNA<\/span> consistently outperforms standard screening especially for T21 (ACMG<\/span>)
- Performed as early as 9 weeks | Single visit | No ultrasound needed | Can do at any point in pregnancy<\/li><\/ul>
- ACMG<\/span> considers cfDNA<\/span> superior and the first line choice for prenatal aneuploidy screening | ACOG<\/span> recommends cfDNA<\/span> be offered to all women as an option for prenatal aneuploidy screening<\/li><\/ul>
- Benefits
- Performance less robust in twin vs singleton pregnancies <\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
- NT measurement, unlike laboratory testing, requires proximity to an advanced ultrasound unit with training and expertise and should only be performed by NT certified sonographers | Potential equity issue<\/li><\/ul>\n
- Does not include sex chromosome aneuploidies<\/li><\/ul>
- PPV<\/span> is approximately 5% for T21 | Only 1 in 20 women with a positive result will actually have a fetus affected with T21 and therefore many women will experience unnecessary anxiety, emotional distress and invasive testing they may not have otherwise opted for<\/li><\/ul>
- Lower detection rate for common aneuploidies vs cfDNA<\/span><\/li><\/ul>
- Benefits\n
- ACOG<\/span> and SMFM<\/span> do not recommend screening for CNVs due to concerns regarding detection and false-positive rates<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n\n\n\n
- First trimester serum screening with or without nuchal translucency<\/span><\/li><\/ul>\n
- Options include
- cfDNA<\/span> is recognized as “the most sensitive and specific screening test for the common fetal aneuploidies”<\/li>\n\n\n\n
- For both singleton and twin pregnancies, ACMG<\/span> recommends offering cfDNA<\/span> as first line fetal aneuploidy screening over standard screening (biomarkers and ultrasound) for\n
- Single gene disorders: Changes in DNA<\/span> sequence within a gene that can result in disease<\/li>\n<\/ul>\n<\/li>\n\n\n\n