Noninvasive Prenatal Testing (NIPT) through analysis of cell free DNA (cfDNA) was first introduced in 2011 as a screening test for Down syndrome (trisomy 21). The list of conditions that cfDNA can screen for has grown to include trisomy 18, trisomy 13, sex chromosome conditions, and several microdeletion conditions. Several professional organizations have published practices guidelines and statements regarding cfDNA including:
|Group||First-tier test?||Sex chromosomes?||Microdeletions and microduplications?||Multiple gestations?|
|ACOG||No||If requested by patient||No||No|
|ACMG||Yes||Let patient know it’s available||Let patient know it’s available||Check with lab first|
|ISPD||Yes?||Should be offered||Yes||Yes|
The key points from all recommendations are summarized below.
To the point –In May of 2016, The American College of Obstetricians and Gynecologists partnered with the Society for Maternal-Fetal Medicine on Practice Bulletin number 163: Screening for Fetal Aneuploidy. In this guideline, ACOG and SMFM recommend that all women should be offered the option of screening tests for aneuploidy and cfDNA screening is one testing option. This document provides an excellent overview of some of the potential benefits, drawbacks and limitations of various screening technologies. In June of 2015, ACOG and SMFM published Committee Opinion #640, Committee Opinion #640 Cell-free DNA Screening for Fetal Aneuploidy . The Committee Opinion states that cfDNA should not be considered “routine” and advocate that careful pretest counseling including discussion of the test’s limitations, risks and alternatives is necessary. The statement advises against the use of this testing as a first-line test in the general obstetric population as well as in pregnancies with multiple gestations. Furthermore they advise against routine screening for microdeletion conditions and with cfDNA.Here are some of the key points form current ACOG/SMFM Guidelines:
All patients should be counseled as to the risks, benefits, and alternatives of various methods of prenatal screening and diagnostic testing, including the option of no testing, should be discussed with all patients. The decision about whether or not to undergo prenatal genetic testing should be a choice.
When comparing cfDNA screening to other methods, it is important to note that no one screening test is superior to other screening tests in all test characteristics. Each test has relative advantages and disadvantages.
Screens such as Integrated Screening for the general population may have advantages over cfDNA such as the ability to screen for a broader array of conditions that may affect the fetus
Disadvantages of cfDNA in the low risk population are a lower positive predictive value (PPV)
Routine cell-free DNA screening for microdeletion syndromes should NOT be performed.
Screening for these microdeletions has not been validated in clinical studies
cfDNA is NOT recommended for women with multiple gestations
More studies are needed, however ACOG/SMFM note that any screening that depends on maternal blood will not be able to distinguish between fetuses.
Parallel or simultaneous testing with multiple screening methodologies for aneuploidy should NOT be performed.
This practice is not cost-effective and may lead to conflicting results
Management decisions, including termination of the pregnancy, should NOT be based on the results of the cell-free DNA screening alone.
Diagnostic testing is needed to confirm positive cfDNA results
“No Call” results indicate a higher chance of a chromosome conditions and patients who receive these results should be offered further assessment:
When results are not reported, indeterminate, or uninterpretable, patients should be referred for genetic counseling and offered comprehensive ultrasound evaluation and diagnostic testing
cfDNA should not be performed solely for early sex identification of the fetus.
Patients should be counseled that this screening also assesses the risk of the chromosome conditions and if that information is not desired, the screening should not be performed.
To the point – SMFM has been active in releasing professional guidance regarding cfDNA, and have taken a strong position that cfDNA should only be used in pregnancies determined to be high-risk for aneuploidy. Furthermore, SMFM does not support routine inclusion of microdeletion conditions on cfDNA panels and advocates that all women who receive a positive test result or a failed result from cfDNA should receive follow-up counseling from a qualified medical professional as well as the option to undergo diagnostic testing if desired. See: Committee Opinion #640 Cell-free DNA Screening for Fetal Aneuploidy and SMFM Consult Series #36: Prenatal Aneuploidy Screening using Cell Free DNA
An ACOG/SMFM Committee Opinion #545, published in 2012 says that cfDNA can be considered as one screening option for certain chromosome conditions in women who are at increased risk (35 or older, high risk result on other aneuploidy screen, past pregnancy with a trisomy condition, parental Robertsonian translocation involving chromosome 21 or 13). The statement cautions that this test should not be considered “routine” and advocates that careful pretest counseling including discussion of the test’s limitations is necessary. The statement advises against testing in low-risk women as well as in pregnancies with multiple gestations. Women with a positive result should be offered genetic counseling for consideration of follow-up testing. Diagnostic testing should remain available for patients desiring a more definitive result.
In June 2015 ACOG and SMFM released an updated joint statement, Committee Opinion #640 Cell-free DNA Screening for Fetal Aneuploidy. Here are the highlights:
In 2014, the SFMF released this statement, Maternal serum cell-free DNA screening in low risk women, reiterating their recommendation that cfDNA only be offered to women who are considered at increased risk for aneuploidy.
Cell Free DNA is not a Simple Blood Test In this piece, the SMFM highlights the dangers that may result from providers minimizing the limitations of the testing. .
In another statement by SMFM, Choosing Wisely: Five Things Physicians and Patients Should Question , they boldly state:
“Don’t offer noninvasive prenatal testing (NIPT) to low-risk patients or make irreversible decisions based on the results of this screening test.”
At the SMFM meeting in February 2015, Mary Norton, MD – President Elect of SMFM, presented data comparing cfDNA to conventional biochemical screening based on California state data and concluded that the detection rate of cfDNA is lower than that of sequential screening, when all chromosomal abnormalities are considered. She also notes that the sensitivity of cfDNA testing is not as robust in clinical studies as it is often reported given the high aneuploidy incidence in pregnancies that do not receive a cfDNA result (“no-call” results).
In March of 2015, SMFM released a paper as part of their Consult Series titled, Prenatal Aneuploidy Screening using Cell Free DNA.
To the point – The International Society for Prenatal Diagnosis (IPSD) released a report in April 2015, Position Statement from the Chromosome Abnormality Screening Committee on Behalf of the Board of the International Society for Prenatal Diagnosis. Unlike the previous statement by the ISPD in 2013, this document suggests that cfDNA may be used as a primary screening for all pregnant women as one of many possible approaches that may be considered by a screening program. The ISPD also supports biochemical & combined biochemical and ultrasound screening as primary testing options. They suggest cfDNA may be used as a secondary screen for intermediate or high-risk women as determined by other screening methods. and they emphasize that diagnostic testing is only possible through amniocentesis or CVS.
The ISPD recommends development of prenatal screening protocols that best meet the resources and needs of individual communities.
According to the ISPD, The following protocol options are currently considered appropriate for a screening program:
1. cfDNA screening as a primary test offered to all pregnant women.
2. cfDNA secondary to a high risk assessment based on serum and ultrasound screening protocols (options 4-9 below).
3. cfDNA contingently offered to a broader group of women ascertained as having high or intermediate risks by conventional screening. Contingent provision of cfDNA, could also include a protocol in which women with very high risks are offered invasive prenatal diagnosis while those with intermediate risk are offered cfDNA.
4. Ultrasound nuchal translucency at 11-13 completed weeks combined with serum markers at 9-13 weeks’ gestation.
5. Extending option (4) to include other first trimester serum or sonographic markers. Ultrasound performance needs to be prospectively validated by the center where the screening is performed.
6. A contingent test whereby women with borderline risks from option (4) have option (5) at a specialist center and risk is subsequently modified.
7. Four maternal serum markers (quadruple test) at 15-19 weeks, for women who first attend after 13 weeks 6 days gestation.
8. Combining options (4) and (7) in either a stepwise or contingent protocol – provided that all screening test data are included in the final risk assessment. Integrated screening can be offered when CVS is not available. A serum integrated test when NT measurement is unavailable.
9. Contingent second trimester ultrasound to modify risks for aneuploidy for women having options (4), (7) or (8). Ultrasound performance must be prospectively validated by the center where the screening is performed.
Except in exceptional circumstances, the ISPD recommends against:
The use of maternal age as a sole criterion for aneuploidy risk assessment.
First trimester measurement of NT with no additional tests
Conventional screening tests for chromosome abnormalities following successful and unambiguous cfDNA screening.
A summary of the Prior Position Statement published by the IPSD in April 2013 can be seen here:
Position Statement from the Aneuploidy Screening Committee on Behalf of the Board of International Society for Prenatal Diagnosis – April 2013
ISPD suggests that combining biochemical screening with first trimester ultrasound nuchal translucency is optimal for patients desiring aneuploidy screening. The ISPD states that cfDNA can be considered for women who are:
determined to be high risk through other screening
who did not receive other screening AND who are considered to be high risk based on
maternal age or
ultrasound makers suggestive of T21, T13 or T18.
Women interested in cfDNA should receive detailed counseling that explains the benefits and limitations of the tests, and patients should be made aware that these tests are still under clinical development
*Of note-many members of the committees in the author groups of these ISPD documents are employed as staff or consultants for companies offering cfDNA.
To the point – The NSGC currently supports the use of cfDNA as an option for patients who are considered to be at an increased risk for aneuploidy. NSGC advocates that cfDNA should only be offered in the context of informed consent, education, and counseling by a qualified provider, such as a certified genetic counselor. Patients whose cfDNA results are abnormal, or who have other factors suggestive of a chromosome abnormality, should receive genetic counseling and be given the option of standard confirmatory diagnostic testing. The NSGC has a white paper on the topic of cfDNA as well as fact sheets to assist providers in pre and posttest counseling regarding cfDNA results.
In June 2013, the NSGC published a white paper on the topic of cfDNA, Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors, and has since published resource sheets to assist the primary obstetrical care provider in providing pretest counseling and posttest counseling to patients regarding cfDNA.
To the point – The European Society of Human Genetics (ESHG) and the American Society of Human Genetics (ASHG)released a joint statement on cfDNA in March 2015. Similar to other organizations the ESHG/ASHG statement emphasizes the cfDNA is a screening test and the importance of pretest information and counseling is highlighted. Many ethical issues of the expanding role of cfDNA to include condition such as microdeletions and sex chromosome conditions are discussed in detail and ultimately the statement advises against the use of cfDNA for conditions apart from Trisomy 21, Trisomy 18 and Trisomy 13.
The ESHG/ASHG joint policy statement on cfDNA, Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening, published online in the European Journal of Human Genetics March 2015 provides an excellent review of the ethical issues inherent in this new technology. Here are the main points from this publication:
cfDNA offers improved accuracy when testing for Trisomy 21, Trisomy 18 and Trisomy 13 as compared to compared other screening tests, however cfDNA is still a SCREENING test False positives occur for a variety of reasons and women should be advised to have a positive result confirmed through diagnostic testing, (they recommend amniocentesis specifically), if they are considering a possible termination of pregnancy.
Although this test may be a more accurate screen for some conditions in pregnancy the importance of patient education, counseling and informed consent should be short changed. The ESHG/ASHG identifies a goal of prenatal screening programs to provide women and couples with the opportunity for informed reproductive choices and as such, counseling and education to allow for informed choices about cfDNA is an essential component.
The ESHG/ASHG recognizes that it may be impossible to avoid unexpected, incidental findings through cfDNA. Pretest counseling should involve discussion of this possibility and the wishes of the patient/couple should be respected regarding whether to receive or not receive information regarding incidental findings.
The ESHG/ASHG recommends AGAINST using cfDNA to screen for sex chromosomal abnormalities and microdeletions given the associated ethnical concerns, counseling challenges and potential that expanding into rare conditions with higher likelihood of false positive results may reverse the reduction in invasive testing achieved with implementation of cfDNA for aneuploidy.
Currently the ESHG and ASHG do not recommend that cfDNA be used for any conditions outside of what may be considered ‘serious congenital and childhood onset disorders’.
In countries where cfDNA is offered as a public health program, governments and public health authorities should adopt an active role to ensure the responsible use of this technology that ensures not only laboratory quality control but also to include oversight of the quality of counseling and educational provided to patients as well as equity of access.
Different scenarios for cfDNA-based screening for common autosomal aneuploidies are possible, including cfDNA as an alternative first-tier option and all of the possible benefits, risks and limitations of each pathway should be carefully evaluated when developing a screening program.
More tools to enable informed choices regarding prenatal screening as are measures to evaluate these tools are needed.
A proactive professional and societal debate about what the future scope of prenatal screening for fetal abnormalities should be is needed.
The American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine (SMFM), Committee Opinion 640, Cell-free DNA Screening for Fetal Aneuploidy (2015)
The American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine (SMFM), Committee Opinion 545, Noninvasive Prenatal testing for Fetal Aneuploidy (2012)
The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin #77 (2007), Screening for Fetal Chromosomal Abnormalities
The Society for Maternal and Fetal Medicine (SMFM) SMFM Consult Series #36: Prenatal Aneuploidy Screening using Cell Free DNA (2015)
The Society for Maternal and Fetal Medicine (SMFM) Cell Free DNA is not a Simple Blood Test (2014)
The Society of Maternal and Fetal Medicine (SMFM) Maternal serum cell-free DNA screening in low risk women (2014)
The International Society of Prenatal Diagnosis (IPSD) Position Statement from the Aneuploidy Screening Committee on Behalf of the Board of International Society for Prenatal Diagnosis (2013)
The International Society of Prenatal Diagnosis (IPSD) Position Statement from the Chromosome Abnormality Screening Committee on Behalf of the Board of the International Society for Prenatal Diagnosis (2015)
The National Society of Genetic Counselors (NSGC) Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors (2013)
The National Society of Genetic Counselors Noninvasive Prenatal Testing: Q & A for Providers (2015)
The National Society of Genetic Counselors Abnormal NIPT results: What do the mean? A Fact Sheet for Providers (2015)
The European Society of Human Genetics (ESHG) and the American Society of Human Genetics (ASHG) joint policy statement Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening (2015)