| Canadian Guideline |
| Society of Obstetricians and Gynaecologists of Canada, Canadian College of Medical Geneticists, 201737
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A discussion of the risks, benefits, and alternatives of the various prenatal diagnoses and screening options, including the option of no testing, should be undertaken with all patients prior to any prenatal screening. Following this counselling, patients should be offered (1) no aneuploidy screening, (2) standard prenatal screening based on locally offered paradigms, (3) ultrasound-guided invasive testing when appropriate indications are present, or (4) maternal plasma cell-free DNA screening where available, with the understanding that it may not be provincially funded [Quality of evidence: II-2, Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group. Classification of recommendation: B, There is fair evidence to recommend the clinical preventive action] Regardless of aneuploidy screening choice, all women should be offered a fetal ultrasound (optimally between 11 and 14 weeks) to confirm viability, gestational age, number of fetuses, chorionicity in multiples, early anatomic assessment, and nuchal translucency (NT) evaluation where available. 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 [Quality of evidence: II-1, Evidence from well-designed controlled trials without randomization. Classification of recommendation: A, There is good evidence to recommend the clinical preventive action]
Women who are considering undergoing maternal plasma cell-free DNA (cfDNA) screening should be informed that:
It is a highly effective screening test for the common fetal trisomies (21, 18, 13), performed after 10 weeks’ gestation. [Quality of evidence assessment, II-1, Evidence from well-designed controlled trials without randomization. Classification of recommendations: A, There is good evidence to recommend the clinical preventive action] There is a possibility of a failed test (no result available), false-negative or positive fetal result, and an unexpected fetal or maternal result. [Quality of evidence assessment, II-1, Evidence from well-designed controlled trials without randomization. Classification of recommendations: A, There is good evidence to recommend the clinical preventive action] All positive cfDNA screening results should be confirmed with invasive fetal diagnostic testing prior to any irrevocable decision (II-1B). Classification of recommendation: B, There is fair evidence to recommend the clinical preventive action] Management decisions, including termination of pregnancy, require diagnostic testing and should not be based on maternal plasma cfDNA results alone, because it is not a diagnostic test [Quality of evidence: II-2, Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group. Classification of recommendation: B, There is fair evidence to recommend the clinical preventive action] If a fetal structural abnormality is identified in a woman, regardless of previous screening test results, the woman should undergo genetic counselling and be offered invasive diagnostic testing with rapid aneuploidy detection and reflex to microarray analysis if rapid aneuploidy detection is normal or inconclusive. [Quality of evidence: II-2, Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group. Classification of recommendation: B, There is fair evidence to recommend the clinical preventive action] 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. [Quality of evidence: II-2, Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group. Classification of recommendation: C, The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making] Routine cfDNA screening for fetal microdeletions is not currently recommended. [Quality of evidence: II-2, Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group. Classification of recommendation: B, There is fair evidence to recommend the clinical preventive action]
|
| International Guidelines |
| American College of Medical Genetics and Genomics, 2016132
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For implementation of NIPS into practice, ACMG recommends:
Providing up-to-date, balanced, and accurate information early in gestation to optimize patient decision-making, independent of the screening approach used Laboratories work with public health officials, policymakers, and private payers to make NIPS, including the pre- and post-test education and counseling, accessible to all pregnant women Allowing patients to select diagnostic or screening approaches for the detection of fetal aneuploidy and/or genomic changes that are consistent with their personal goals and preferences Informing all pregnant women that diagnostic testing (CVS or amniocentesis) is an option for the detection of chromosome abnormalities and clinically significant CNVs
For average- and low-risk women, ACMG recommends:
Informing all pregnant women that NIPS is the most sensitive screening option for traditionally screened aneuploidies (i.e., Patau, Edwards, and Down syndromes) Referring patients to a trained genetics professional when an increased risk of aneuploidy is reported after NIPS Offering diagnostic testing when a positive screening test result is reported after NIPS Providing accurate, balanced, up-to-date information, at an appropriate literacy level when a fetus is diagnosed with a chromosomal or genomic variation in an effort to educate prospective parents about the condition of concern. These materials should reflect the medical and psychosocial implications of the diagnosis Laboratories should provide readily visible and clearly stated DR, SPEC, PPV, and NPV for conditions being screened, in pretest marketing materials, and when reporting laboratory results to assist patients and providers in making decisions and interpreting results Laboratories should not offer screening for Patau, Edwards, and Down syndromes if they cannot report DR, SPEC, and PPV for these conditions
For autosomal aneuploidies other than Patau, Edwards, and Down syndrome, ACMG does not recommend:
For sex chromosome aneuploidies, ACMG recommends:
Informing all pregnant women, as part of pretest counseling for NIPS, of the availability of the expanded use of screening for sex chromosome aneuploidies Providers should make efforts to deter patients from selecting sex chromosome aneuploidy screening for the sole purpose of biologic sex identification in the absence of a clinical indication for this information Informing patients about the causes and increased possibilities of false-positive results for sex chromosome aneuploidies as part of pretest counseling and screening for these conditions. Patients should also be informed of the potential for results of conditions that, once confirmed, may have a variable prognosis (e.g., Turner syndrome) before consenting to screening for sex chromosome aneuploidies Referring patients to a trained genetics professional when an increased risk of sex chromosome aneuploidy is reported after NIPS Offering diagnostic testing when a positive screening test result is reported after screening for sex chromosome aneuploidies Providing accurate, balanced, up-to-date information and materials at an appropriate literacy level when a fetus is diagnosed with a sex chromosome aneuploidy in an effort to educate prospective parents about the specific condition. These materials should reflect medical and psychosocial implications for the diagnosis Laboratories include easily recognizable and highly visible DR, SPEC, PPV, and NPV for each sex chromosome aneuploidy when reporting results to assist patients and providers in making decisions and interpreting results Laboratories should not offer screening for sex chromosome aneuploidies if they cannot report DR, SPEC, PPV, and NPV for these conditions
For CNV, ACMG recommends:
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Informing all pregnant women of the availability of the expanded use of NIPS to screen for clinically relevant CNVs when the following conditions can also be met:
○ Obstetric care providers should discuss with their patients the desire for prenatal screening as opposed to diagnostic testing (i.e., CVS or amniocentesis) ○ Obstetric care providers should discuss with their patients the desire for maximum fetal genomic information through prenatal screening ○ Obstetric care providers should inform their patients of the higher likelihood of false-positive and false-negative results for these conditions as compared to results obtained when NIPS is limited to common aneuploidy screening ○ Obstetric care providers should inform their patients of the potential for results of conditions that, once confirmed, may have an uncertain prognosis
Referring patients to a trained genetics professional when NIPS identifies a CNV Offering diagnostic testing (CVS or amniocentesis) with chromosomal microarray when NIPS identifies a CNV Providing accurate, balanced, up-to-date information at an appropriate literacy level when a fetus is diagnosed with a CNV in an effort to educate prospective parents about the condition of concern. These materials should reflect the medical and psychosocial implications of the diagnosis Laboratory requisitions and pretest counseling information should specify the DR, SPEC, PPV, and NPV of each CNV screened. This material should state whether PPV and NPV are modeled or derived from clinical utility studies (natural population or sample with known prevalence) Laboratories include easily recognizable and highly visible DR, SPEC, PPV, and NPV for each CNV screened when reporting laboratory results to assist patients and providers in making decisions and interpreting results. Reports should state whether PPV and NPV are modelled or derived from clinical utility studies (natural population or sample with known prevalence). When laboratories cannot report specific DR, SPEC, PPV, and NPV, screening for those CNVs should not be performed by that laboratory
For CNV, ACMG does not recommend:
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| American College of Obstetricians and Gynecologists, Society for Maternal–Fetal Medicine, 2016133
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The following recommendations and conclusions are based on good and consistent scientific evidence (Level A):
Women who have a negative screening test result should not be offered additional screening tests for aneuploidy because this will increase their potential for a false-positive test result Because cell-free DNA is a screening test with the potential for false-positive and false-negative results, such testing should not be used as a substitute for diagnostic testing All women with a positive cell-free DNA test result should have a diagnostic procedure before any irreversible action, such as pregnancy termination, is taken Women whose cell-free DNA screening test results are not reported, are indeterminate, or are uninterpretable (a no call test result) should receive further genetic counselling and be offered comprehensive ultrasound evaluation and diagnostic testing because of an increased risk of aneuploidy Women with a positive screening test result for fetal aneuploidy should be offered further detailed counselling and testing
The following recommendations and conclusions are based on limited or inconsistent scientific evidence (Level B):
Cell-free DNA screening tests for microdeletions have not been validated clinically and are not recommended at this time Patients who conceive after preimplantation genetic screening for aneuploidy should be offered aneuploidy screening and diagnosis during their pregnancy No method of aneuploidy screening is as accurate in twin gestations as it is in singleton pregnancies. Because data generally are unavailable for higher-order multifetal gestations, analyte screening for fetal aneuploidy should be limited to singleton and twin pregnancies
The following recommendations and conclusions are based primarily on consensus and expert opinion (Level C):
Screening for aneuploidy should be an informed patient choice, with an underlying foundation of shared decision-making that fits the patient's clinical circumstances, values, interests, and goals Aneuploidy screening or diagnostic testing should be discussed and offered to all women early in pregnancy, ideally at the first prenatal visit All women should be offered the option of aneuploidy screening or diagnostic testing for fetal genetic disorders, regardless of maternal age If an isolated ultrasonographic marker for aneuploidy is detected, the patient should be offered aneuploidy screening if it was not offered previously Some women who receive a positive test result from traditional screening may prefer to have cell-free DNA screening rather than undergo definitive testing. This approach may delay definitive diagnosis and management and may fail to identify some fetuses with aneuploidy Parallel or simultaneous testing with multiple screening methodologies for aneuploidy is not cost-effective and should not be performed In multifetal gestations, if fetal demise or an anomaly is identified in one fetus, serum-based aneuploidy screening should be discouraged. There is a significant risk of an inaccurate test result in these circumstances
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| American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, 2015134
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Given the performance of conventional screening methods, the limitations of cell-free DNA screening performance, and the limited data on cost-effectiveness in the low-risk obstetric population, conventional screening methods remain the most appropriate choice for first-line screening for most women in the general obstetric population Although any patient may choose cell-free DNA analysis as a screening strategy for common aneuploidies regardless of their risk status, the patient choosing this testing should understand the limitations and benefits of this screening paradigm in the context of alternative screening and diagnostic options Given the potential for inaccurate results and to understand the type of trisomy for recurrence-risk counselling, a diagnostic test should be recommended for a patient who has a positive cell-free DNA test result Parallel or simultaneous testing with multiple screening methodologies for aneuploidy is not cost-effective and should not be performed Management decisions, including termination of the pregnancy, should not be based on the results of the cell-free DNA screening alone Women whose results are not reported, indeterminate, or uninterpretable (a “no call” test result) from cell-free DNA screening should receive further genetic counselling and be offered comprehensive ultrasound evaluation and diagnostic testing because of an increased risk of aneuploidy Routine cell-free DNA screening for microdeletion syndromes should not be performed Cell-free DNA screening is not recommended for women with multiple gestations Patients should be counselled that a negative cell-free DNA test results does not ensure an unaffected pregnancy Cell-free DNA screening does not assess risk of fetal anomalies such as neural tube defects or ventral wall defects; patients who are undergoing cell-free DNA screening should be offered maternal serum alpha-fetoprotein screening or ultrasound evaluation for risk assessment Patients may decline all screening or diagnostic testing for aneuploidy |
| Society for Maternal–Fetal Medicine, 2015135
|
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Optimal candidates for routine cfDNA aneuploidy screening are women with [Level 1B recommendation: strong recommendation, moderate quality of evidence]:
○ Maternal age ≥ 35 years at delivery ○ Fetal ultrasound finding that indicates an increased risk of aneuploidy, specifically for trisomies 13, 18, or 21 ○ History of previous pregnancy with a trisomy detectable by cfDNA screening (trisomies 13, 18, or 21) ○ Positive screening results for aneuploidy that include a first-trimester, sequential, integrated, or quadruple screen ○ Parental balanced Robertsonian translocation with increased risk of fetal trisomy 13 or 21
Routine screening for microdeletions with cfDNA is not recommended [Level 1B recommendation: strong recommendation, moderate quality of evidence] For women who desire comprehensive testing for chromosomal disorders, diagnostic testing should be offered [Level 1B recommendation: strong recommendation, moderate quality of evidence] For women who undergo cfDNA aneuploidy screening, maternal serum alpha-fetoprotein, and/or second-trimester anatomy ultrasound scan should also be performed [Best practice recommendation] Formal genetic counseling by maternal–fetal medicine subspecialist, geneticist, or genetic counselor after a positive cfDNA test is recommended [Best practice recommendation] Chorionic villous sampling or amniocentesis should be offered after a positive cfDNA screen to confirm the diagnosis [Best practice recommendation] Traditional aneuploidy screening and cfDNA aneuploidy screening should not be performed at the same time [Best practice recommendation]
After a failed cfDNA test, genetic counseling should be performed that includes offering diagnostic testing (chorionic villous sampling or amniocentesis) and repeat cfDNA screening [Best practice recommendation] |
| Society for Maternal–Fetal Medicine, 2017136
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In women who have already received a negative cfDNA screen, ultrasound at 11–14 weeks of gestation solely for the purpose of NT measurement is not recommended (GRADE 1B: strong recommendation, moderate-quality evidence) Diagnostic testing should not be recommended to patients solely for the indication of an isolated soft marker in the setting of a negative cfDNA screen (GRADE 1B: strong recommendation, moderate-quality evidence) In women with an isolated soft marker that has no other clinical implications (i.e., choroid plexus cyst or echogenic intracardiac focus) and a negative cfDNA screen, we recommend describing the finding as not clinically significant or as a normal variant (GRADE 2B: weak recommendation, moderate-quality evidence) In women with an isolated soft marker without other clinical implications (i.e., choroid plexus cyst or echogenic intracardiac focus) and a negative first- or second-trimester screening result, we recommend describing the finding as not clinically significant or as a normal variant (GRADE 2B: weak recommendation, moderate-quality evidence) We recommend that all women in whom a structural abnormality is identified by ultrasound be offered diagnostic testing with chromosomal microarray (GRADE 1A: strong recommendation, high-quality evidence) Routine screening for microdeletions with cfDNA is not recommended (GRADE 1B: strong recommendation, moderate-quality evidence) |
| National Society of Genetic Counselors, 2013137
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NSGC recognizes NIPT as an option for aneuploidy assessment in pregnancy: Peer-reviewed data currently supports NIPT only as a screening tool for select populations. While NIPT has proven effective in detecting fetuses with aneuploidy, in light of potential false-positive results, NIPT results should not be considered diagnostic, and any abnormal results should be confirmed through a conventional prenatal diagnostic procedure, such as chorionic villus sampling or amniocentesis NSGC does not currently support NIPT as a routine, first-tier aneuploidy screening test in low-risk populations: To date, these technologies have been validated primarily in pregnancies considered to be at an increased risk for fetal aneuploidy, based on maternal age, family history, or positive serum and/or sonographic screening tests or in pregnancies in which invasive testing is being performed, which is not truly representative of an average-risk population Although one study has suggested that NIPT in screening for trisomy 21 and trisomy 18 in an average-risk population would be effective, further studies are needed before NIPT can replace current aneuploidy screening programs Clinical studies show that MPS effectively detects fetal trisomy 21, trisomy 13, trisomy 18, and monosomy X and that DANSR effectively detects trisomy 21, trisomy 18, and trisomy 13. NIPT has not yet been proven efficacious in detecting other chromosomal abnormalities or single-gene disorders. NSGC recommends that pretest counselling for NIPT include information about the disorders that it may detect, its limitations in detecting these conditions, and its unproven role in detecting other conditions Pre- and post-NIPT genetic counselling: As with any prenatal testing, patients must have accurate, up-to-date information regarding the test, the possible results, and the available follow-up in order to make an informed choice when considering NIPT. Given NIPT's vastly superior sensitivity and specificity compared to other available aneuploidy screening—such as, first-trimester nuchal translucency and/or biochemical screening and second-trimester quad screening—it is imperative that patients understand the significant implications of a positive result prior to undergoing NIPT. NSGC recognizes that, due to limited resources, it may not be feasible for all women seeking NIPT to receive pretest counselling from a genetic counsellor. But a qualified healthcare provider should provide nondirective pretest counselling for all women considering NIPT. NSGC recommends that any patient with abnormal NIPT results should receive genetic counselling with a certified genetic counsellor and be given the option of conventional confirmatory diagnostic testing NSGC recommends that patients who have other factors suggestive of a chromosome abnormality should receive genetic counselling and have the option of conventional confirmatory diagnostic testing, regardless of NIPT results: Because NIPT does not screen for all chromosomal or genetic conditions, it does not replace standard risk assessment and prenatal diagnosis. Indications for genetic counselling, regardless of NIPT results, include the presence of ultrasound abnormalities, family or personal history of a chromosome anomaly, and a history of recurrent pregnancy loss. Patients who are of advanced maternal age and/or have had a positive screening test may also benefit from detailed genetic counselling, regardless of NIPT results. In addition, patients who have an increased risk for genetic conditions that are beyond NIPT's scope should receive genetic counselling to discuss appropriate testing options Future considerations: NIPT's landscape is rapidly changing. Additional companies are currently administering studies to validate their laboratory-developed tests for NIPT, and are expected to launch competing tests in the near future. NIPT will likely expand to include additional chromosomal abnormalities and/or microarray analysis as future studies support the clinical validity of such results. Studies to assess clinical validity in the general population (e.g. average-risk women) are currently underway. As the sensitivity and specificity in the general population are better established, NIPT has the potential to function with the sensitivity and specificity similar to currently available diagnostic tests. Single-gene testing will also be possible, as this is an area of ongoing research. As this technology evolves, NSGC will reassess its recommendations to reflect these changes |
| Human Genetics Society of Australia, Royal Australian and New Zealand College of Obstetricians and Gynaecologists, 2016138
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Accurate dating, confirmation of viability and determination of the number of embryos by ultrasound is recommended prior to cfDNA testing (Consensus-based recommendation) cfDNA based screening for fetal aneuploidy is not diagnostic. The chance of having an affected fetus following a cfDNA result reported as high-risk (i.e., the positive predictive value, PPV) may be < 50%, depending on the specific chromosome involved and the background risk of the woman. Confirmatory diagnostic testing is strongly recommended after an abnormal cfDNA result (Consensus-based recommendation) If a woman has received a cfDNA reported as normal/low-risk, an additional calculation for aneuploidy (e.g. by combined first-trimester or second-trimester serum screening) is not recommended as this will increase the false-positive rate without substantially improving the detection rate (Consensus-based recommendation) The presence of a fetal structural anomaly remains an important indication for invasive prenatal testing, even in the presence of a prior cfDNA result reported as normal/low risk (Consensus-based recommendation) Pretest counselling should include informed decision-making regarding testing for fetal sex and sex chromosome aneuploidy. Women should be given the choice to opt out of receiving this information (Consensus-based recommendation) |
| European Society of Human Genetics, American Society of Human Genetics, 2015139
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NIPT offers improved accuracy when testing for common autosomal aneuploidies compared with existing tests such as cFTS. However, a positive NIPT result should not be regarded as a final diagnosis: false positives occur for a variety of reasons (including that the DNA sequenced is both maternal and fetal in origin, and that the fetal fraction derives from the placenta as well as the developing fetus). Thus women should be advised to have a positive result confirmed through diagnostic testing, preferably by amniocentesis, if they are considering a possible termination of pregnancy The better test performance, including lower invasive testing rate of NIPT-based screening should not lead to lower standards for pretest information and counselling. This is especially important in the light of the aim of providing pregnant women with meaningful options for reproductive choice. There should be specific attention paid to the information needs of women from other linguistic and cultural backgrounds or who are less health literate If NIPT is offered for a specific set of conditions (e.g., trisomies 21, 18 and 13), it may not be reasonably possible to avoid additional findings, such as other chromosomal anomalies or large scale insertions or deletions. As part of pretest information, women and couples should be made aware of the possibility of such additional findings and the range of their implications. There should be a clear policy for dealing with such findings, as much as possible also taking account of pregnant women's wishes with regard to receiving or not receiving specific information Expanding NIPT-based prenatal screening to also report on sex-chromosomal abnormalities and microdeletions not only raises ethical concerns related to information and counseling challenges but also risks reversing the important reduction in invasive testing achieved with implementation of NIPT for aneuploidy, and is therefore currently not recommended Emerging opportunities for combining prenatal screening for fetal abnormalities with screening aimed at prevention may undermine adequate counseling by sending mixed messages. The objective of any prenatal screening activity should be made explicit and, as far as possible, forms of prenatal screening with different aims should be presented separately. If not physically possible, this separation should at least be made conceptually when providing the relevant information In countries where prenatal screening for fetal abnormalities is offered as a public health program, governments and public health authorities should adopt an active role to ensure the responsible introduction of NIPT as a second or first-tier screening test for Down syndrome and other common autosomal aneuploidies. This entails ensuring quality control also extending to the non-laboratory aspects of NIPT-based prenatal screening (information, counseling), education of professionals, systematic evaluation of all aspects of the screening program, as well as promoting equity of access for all pregnant women within the confines of the available budget, and setting up a governance structure for responsible further innovation in prenatal screening Different scenarios for NIPT-based screening for common autosomal aneuploidies are possible, including NIPT as an alternative first-tier option. The inevitable trade-offs underlying those scenarios should not just be regarded as a matter of screening technology and health economics; the question is also how these trade-offs enable or impede meaningful reproductive choices and how they affect both the balance of benefits and burdens for pregnant women and their partners, and the screening goals and values acceptable to society In order to adequately evaluate prenatal screening practices, there is a need to further develop and validate measures of informed choice as well as interventions aimed at enabling informed choices. The transition to NIPT-based prenatal screening presents an opportunity to fill this gap in knowledge In the light of sequencing technologies becoming better and cheaper, there is an acute need for a proactive professional and societal debate about what the future scope of prenatal screening for fetal abnormalities should be. As argued in this document, there are strong ethical reasons for not expanding the scope of prenatal screening beyond serious congenital and childhood disorders The scenario in which prenatal screening would open up possibilities for fetal therapy in addition to autonomous reproductive choice raises fundamental questions about the relation between reproductive autonomy and parental responsibility that require an in-depth proactive ethical analysis |
Schmid et al, 2015140
(Supported by: Austrian Society of Obstetrics and Gynecology, Austrian Society of Ultrasound in Medicine, Austrian Society of Pre- and Perinatal Medicine, Austrian Society of Human Genetics, German Society of Ultrasound in Medicine, Fetal Medicine Foundation of Germany, Swiss Society of Ultrasound in Medicine) |
cfDNA testing should be offered only after, or in conjunction with, a qualified ultrasound and following appropriate counseling about the nature, scope and significance of the test cfDNA tests are screening tests. A high-risk cfDNA testing result should always be confirmed by an invasive diagnostic test (chorionic villous sampling, amniocentesis), before a clinical consequence is drawn from the findings cfDNA testing can be used as secondary screening test for trisomy 21 (Down syndrome) for the reduction of invasive procedures after a high or intermediate-risk result from first trimester combined test (1 in 1,000 or > 1: 500 [FMF-D]). It should be noted that, even when cfDNA testing is used as a secondary screening, invasive diagnostic testing (chorionic villous sampling, amniocentesis) is still the method of choice when the adjusted risk for trisomy 21 after the combined test is > 1:10 or the fetal nuchal translucency thickness is > 3.5mm or a fetal malformation is present cfDNA tests can also be used as a primary screening method for fetal trisomy 21 in pregnant women of every age and risk group In general, it should be noted that the performance of cfDNA screening for trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome) is lower than that for trisomy 21 Based on the available evidence the use of cfDNA tests to screen for aneuploidy of sex chromosomes and microdeletion syndromes can currently not be recommended without reservation |
| Polish Gynecological Society, Polish Human Genetics Society, 2017141
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NIPT should not replace first-trimester screening based on fetal ultrasound scan and biochemical testing of maternal blood. NIPT should be ordered by a physician who has experience in obstetrics, perinatology or clinical genetics NIPT should be performed between the 10th and 15th week of pregnancy NIPT is not recommended for low-risk pregnancies with a risk less than 1:1000 as indicated by integrated tests (ultrasound + biochemical testing of maternal blood) NIPT should be offered to pregnant women with a risk of fetal chromosomal aberration from 1:100 to 1:1000 If the risk is higher than 1:100, invasive prenatal diagnosis should be offered When fetal congenital anomalies are diagnosed based on ultrasound but the NIPT results are correct, the patient must be referred to a genetics specialist for further diagnostics and genetic counselling NIPT is not recommended for multiple pregnancies (triplets and higher) Before NIPT ultrasound scan should be performed to assess the number of fetuses and the gestational age NIPT should not replace fetal ultrasound examination. Ultrasound scan has to be performed following the guidelines of the Ultrasound Section of the Polish Gynaecological Society When NIPT results could not be obtained (up to 5%) the NIPT test may be repeated or invasive diagnostics has to be offered NIPT and invasive diagnostics should not be performed at the same time When NIPT shows high risk of chromosomal aberration amniocentesis is indicated as a method of invasive diagnostics When NIPT estimates high risk of fetal chromosomal aberration the patient has to be consulted by clinical geneticist or specialist in perinatology Pregnancy cannot be terminated based only on NIPT result NIPT results should be signed by a specialist in medical laboratory diagnostics |
| International Society for Prenatal Diagnosis, 2015142
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High sensitivities and specificities are potentially achievable with cfDNA screening for some fetal aneuploidies, notably trisomy 21 Definitive diagnosis of Down syndrome and other fetal chromosome abnormalities can only be achieved through testing on cells obtained by amniocentesis or CVS The use of maternal age alone to assess fetal Down syndrome risk in pregnant women is not recommended A combination of ultrasound NT measurement and maternal serum markers in the first trimester should be available to women who want an early risk assessment and for whom cfDNA screening cannot be provided A four-marker serum test should be available to women who first attend for their prenatal care after 13 weeks 6 days of pregnancy and where cfDNA screening cannot be provided Protocols that combine first-trimester and second-trimester conventional markers are valid Second-trimester ultrasound can be a useful adjunct to conventional aneuploidy screening protocols When cfDNA screening is extended to microdeletion and microduplication syndromes or rare trisomies, the testing should be limited to clinically significant disorders or well-defined severe conditions. There should be defined estimates for the DRs, FPRs, and information about the clinical significance of a positive test for each disorder being screened |
| International Society of Ultrasound in Obstetrics and Gynecology, 2017143
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All women should be offered a first-trimester ultrasound scan according to ISUOG guidelines, regardless of their intention to undergo cfDNA testing
○ If the woman has had a negative cfDNA test result, nuchal translucency (NT) thickness should still be measured and reported as a raw value and centile. The management of increased NT with a normal cfDNA test result is currently based on local guidelines. However, it is not necessary to compute first-trimester risk estimates for trisomies 21, 18 and 13 based on NT measurements and maternal biochemistry in a woman known to have a normal cfDNA result. Accordingly, soft markers for trisomy 21 should not be assessed in women with a normal cfDNA test result due to their high false-positive rate and poor positive predictive value -
○ If the woman has not had a cfDNA test, pretest counseling is essential. Various options regarding screening or testing for trisomy 21 and, to a lesser extent, trisomies 18 and 13 should be explained clearly, including information on the expected test performance, potential adverse effects, and pros and cons of each option. Following a normal first-trimester scan, as defined by ISUOG guidelines, three options might be considered for women who wish to have further risk assessment:
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1.
Screening strategies based on individual risk calculated from maternal age and NT measurement and/or maternal serum markers and/or other ultrasound markers in the first trimester (defined by the conventional crown–rump length range of 45–84 mm). Following such screening, women can be offered a choice, according to their calculated individual risk, of having no further testing, cfDNA testing or invasive testing. Cutoffs, defining two (low/high-risk) or three (low/intermediate/high risk) groups, should be defined on a local/national basis and will be affected by public health priorities and available resources. Offering cfDNA testing should always be balanced with the potential and risk of conventional karyotyping, with or without microarray analysis, following invasive sampling. More importantly, the role of cfDNA testing as an alternative to standard invasive testing in women considered to be at very high risk after combined screening (>1:10) but with no ultrasound anomaly should be evaluated in prospective studies. Expert opinion currently suggests that cfDNA testing should not replace routinely invasive testing in this group, based on the fact that, in this population, only 70% of the chromosomal abnormalities are trisomy 21, 18 or 13, and that chromosomal microarray analysis, if offered, is able to detect a large number of additional anomalies
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2.
cfDNA testing as a first-line screening test. Most current guidelines endorse cfDNA testing only for high- or intermediate-risk populations, for which comprehensive data exist. Experience in low-risk populations is increasing, apparently confirming the high detection rates published for high-risk populations. However, testing in low-risk women may impact on the quality of both pretest counselling and subsequent ultrasound screening. In particular, cfDNA testing should not replace first-trimester ultrasound and should not be offered when an ultrasound anomaly or markedly increased NT is detected. Using cfDNA in low-risk patients might be endorsed as a widely available option only when more data emerge and cfDNA costs decrease
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3.
Invasive testing based on a woman's preference or background risk (maternal age, previous history, fetal ultrasound anomaly) with no further individual risk calculation. An invasive test might be discussed in light of the recently reported reduction in the risk of invasive procedures as well as the increase in cytogenetic resolution provided by microarray techniques. However, the cost of this option is not usually covered by most national insurance policies and it should not be recommended beyond the context of clinical trials and until sufficient peer-reviewed data and validation studies have been published
cfDNA test results should always be interpreted and explained individually in relation to the a priori risk and the fetal fraction In the presence of a fetal structural anomaly, the indications for fetal karyotyping and/or microarray testing should not be modified by a previously normal cfDNA test result In the case of a failed cfDNA test, the patient should be informed about the increased risk of anomalies as well as alternative screening and testing strategies cfDNA testing is not diagnostic, and confirmatory invasive testing is required in the presence of an abnormal result. Whenever there is discordance between an abnormal cfDNA test result and a normal ultrasound examination, amniocentesis rather than chorionic villus sampling should be performed Accuracy of cfDNA testing in twin pregnancies should be investigated further Variations in cfDNA test performance by different providers should be investigated further It is becoming technically feasible to test non-invasively, not only for trisomies but also for other genetic syndromes. Both healthcare providers and women should be clearly aware of the tests being performed and of their performance, as having multiple tests increases the overall false-positive rate and failure rate. The detection rate for microdeletions has yet to be established and most national guidelines currently do not support testing for microdeletions on cfDNA. Screening for microdeletions also raises complex issues regarding pretest and post-test counseling Prospective, publicly funded studies assessing the cost-effectiveness of various screening strategies should be performed as a matter of urgency |
| Allyse et al, 201338
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Best ethical practices for clinicians
Medical providers offering noninvasive prenatal testing should:
Offer all women the opportunity to receive reliable, medically relevant prenatal tests that have demonstrated safety and effectiveness in their demographic Where possible, work with third party payors to help all patients access noninvasive prenatal testing, if medically appropriate Structure the informed consent process so that it is comprehensive, interactive and sensitive to the need to understand the subjective experience of disease and disability Ensure that patients are offered genetic counseling both before and after testing Give patients clear opportunities to decline testing, both in general and for specific disorders, and never pressure patients to undergo testing Encourage patients to make clear choices about which results they wish to receive, including paternity and sex testing, before testing is undergone
Best ethical practices for commercial test providers
Companies offering noninvasive prenatal testing should:
Offer testing only through licensed clinicians and not directly to consumers Seek oversight to validate the safety and effectiveness of genetic tests from relevant regulatory agencies Do their best to comply with national and international regulations and laws regarding the results that can legally be returned to patients Implement proficiency testing procedures verified independently by a third party to ensure analytic validity. Set transparent standards for data interpretation and error rates Require verification of comprehensive informed consent from clinicians before testing is conducted. Companies may wish to provide clinicians with appropriate informed consent forms in order to facilitate this process Obtain written consent for the storage of samples and genetic data and any research conducted using samples or test results. Samples should not be used for research without explicit consent separate from consent obtained to use samples for clinical purposes, and samples destroyed after clinical testing unless specific consent for future use has been obtained Provide the capacity to return selected results based on the wishes of the patient Provide genetic counseling resources to assist clinicians in facilitating the informed consent process Design marketing and advertising materials to promote values-based decision-making and avoid advocating for specific actions on the basis of test results
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