CAM 110

Pre-implantation Genetic Testing

Category:Laboratory   Last Reviewed:April 2021
Department(s):Medical Affairs   Next Review:April 2022
Original Date:October 2015    

Disclaimer:  Many benefit plans exclude or limit services related to in-vitro fertilization (IVF), which would include services detailed in this policy. Refer to the individual document plan to determine if coverage is available.

Description
Preimplantation genetic testing (PGT) involves the biopsy of a single cell, or a few cells of embryos to facilitate genetic testing for various genetic conditions. These conditions range from aneuploidies to monogenic disorders to structural deformities of the chromosomes themselves.

Policy

  1. Genetic counseling is considered MEDICALLY NECESSARY and is required when preimplantation genetic testing is being contemplated.
  2. Preimplantation genetic testing is considered MEDICALLY NECESSARY when BOTH conditions mentioned below are met:    
    1. Specific mutation(s) or chromosomal changes have been defined to be associated with a specific disorder, AND
    2. One of the following conditions are met:
      1. Both biological parents are known carriers of an autosomal recessive disorder with early onset, OR
      2. One biological parent is a known carrier of an autosomal dominant early onset disorder, OR
      3. One biological parent is a known carrier of an X-linked early onset disorder, OR
      4. One biological parent carries a balanced or unbalanced chromosomal translocation
  3. Preimplantation genetic testing for sex selection, in the absence of a sex-linked early onset disease, DOES NOT MEET COVERAGE CRITERIA.
  4. Preimplantation genetic testing in the following situations is investigational and/or unproven therefore considered NOT MEDICALLY NECESSARY:
    1. Preimplantation genetic testing for adult-onset disorders.
    2. Preimplantation HLA genotyping for purposes of identifying potential tissue or organ donors.
    3. Routine preimplantation screening for chromosomal abnormalities including testing based on advanced maternal age.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

  1. Preimplantation genetic testing for all other indications is considered NOT MEDICALLY NECESSARY.

Policy Guidelines
The American College of Obstetricians and Gynecologists (ACOG) recommendations state, “Current data does not support a recommendation for preimplantation genetic screening for aneuploidy using fluorescence in situ hybridization solely because of maternal age. Preimplantation genetic screening for aneuploidy does not improve in vitro fertilization success rates and may be detrimental. At this time there are no data to support preimplantation genetic screening for recurrent unexplained miscarriage and recurrent implantation failures; its use for these indications should be restricted to research studies with appropriate informed consent.” 

The Society of Obstetricians and Gynecologists of Canada (SOGC) recommendations note:

  1. “Before preimplantation genetic diagnosis is performed, genetic counselling must be provided to ensure that patients fully understand the risk of having an affected child, the impact of the disease on an affected child, and the benefits and limitations of all available options for preimplantation and prenatal diagnosis.
  2. “Couples should be informed that preimplantation genetic diagnosis can reduce the risk of conceiving a child with a genetic abnormality carried by one or both parents if that abnormality can be identified with tests performed on a single cell.
  3. “Invasive prenatal testing to confirm the results of preimplantation genetic diagnosis is encouraged because the methods used for preimplantation genetic diagnosis have technical limitations that include the possibility of a false negative result.
  4. “Before preimplantation genetic screening is performed, thorough education and counselling must be provided to ensure that patients fully understand the limitations of the technique, the risk of error, and the lack of evidence that preimplantation genetic screening improves live-birth rates.
  5. "Available evidence does not support the use of preimplantation genetic screening as currently performed to improve live-birth rates in patients with advanced maternal age, recurrent implantation failure, or recurrent pregnancy loss.” 

European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium has issued detailed guidelines related to technical aspects of PGD, specifically for the use of amplification techniques and for FISH.  The ESHRE recommends that “misdiagnosis rates should be calculated for each type of assay and for all assays from a particular Centre.”  Additionally, they note that “Follow-up of pregnancies (including multiple pregnancy rate and outcome), deliveries, and the health of children at birth and beyond should be attempted and maintained along with the cycle data.”

Rationale 
Preimplantation genetic testing (PGT) in conjunction with assisted reproductive technology (ART) was developed to allow couples at risk of transmitting a genetic condition to their offspring to have an unaffected child without facing prenatal diagnosis and termination of pregnancy (PGDIS, 2008). Initially offered for diagnosis in couples at-risk for single gene genetic disorders, such as cystic fibrosis, spinal muscular atrophy and Huntington disease, preimplantation genetic diagnosis (PGD) has most frequently been employed in assisted reproduction as preimplantation genetic screening (PGS) for detection of chromosome aneuploidy from advancing maternal age or structural chromosome rearrangements. The Preimplantation Genetic Diagnosis International Society (PGDIS) estimates that nearly 80% of PGT cycles have been performed for aneuploidy screening, 12% for single gene disorders, 6% for chromosome rearrangements and 2% for sibling human leukocyte antigen (HLA) matching. Both this and the European Society of Human Reproduction and Embryology (ESHRE) surveys confirm that aneuploidy testing is the major indication for PGT.

Embryonic genetic material used for PGT can be obtained from any of three sources: polar bodies from oocytes, blastomeres from day two or three, or trophectoderm cells from blastocysts. Polar bodies are typically analyzed if the embryo cannot be biopsied. However, polar body analysis is only useful for finding maternally inherited mutations or a cell division error during oocyte development. Furthermore, since genetic changes occur after the polar body develops, test results are of limited use. More, as many as 30% of oocytes will not fertilize successfully, causing the test to fail.

Blastomeres from day two or three (cleavage stage) were once the preferred practice in in-vitro-fertilization (IVF) as more embryos survived in culture by day three compared to days five or six (blastocyst stage). Despite the greater survival rate of day three embryos, these embryos were found to have a lower survival rate in a sustained implantation compared to day five embryos. Overall, trophectoderm biopsy on day five is preferred as it has no measurable impact on embryo development. Up to two or three dozen cells can be removed without disrupting development; although, common practice is to remove five to eight cells. Day five and later embryos also provide more DNA for testing compared to other stages of development. Improved results have been seen with decreasing use of day three blastomere biopsy in favor of day five trophectoderm biopsy.

Pre-implantation genetic screening (PGS) is emerging as one of the most valuable tools to enhance pregnancy success with assisted reproductive technologies by assessing embryos for aneuploidy. PGS using comprehensive chromosome screening technology on blastocyst biopsy has now been accepted in the latest technical update to increase implantation rates and even improves embryo selection in ART cycles in patients with a good prognosis.

As the genetic basis of more disorders are identified, increasing demand for and acceptance of the use of PGT for adult-onset disorders, such as Huntington disease, hereditary breast and ovarian cancer and Alzheimer disease, have occurred. Using PGD to screen embryos for diseases or mutations that confer an increased risk for developing a particular disease raises issues of how to weigh the benefits of PGD to the future child against the risks of PGD and ART. The Ethics committee for the American Society of Reproductive Medicine (ASRM) found that PGD for adult-onset conditions is ethically justifiable when the conditions are serious and when there are no known interventions for the conditions or the available interventions are either inadequately effective or significantly burdensome. The use of PGT for nonmedical sex selection or family balancing continues to be controversial, and the ethics committee has stated that it is acceptable for facilities to offer this service; however, employees wishing to decline participation in these procedures should be allowed to do so.

Women recommended for pre-implantation genetic diagnosis for aneuploidy testing (PGD-A) or PGT for aneuploidy (PGT-A) are those of advanced reproductive age with a history of recurrent miscarriages and/or IVF failures; PGD-A is currently performed on trophectoderm biopsies by 24 different chromosome screening techniques. Trophectoderm biopsies are a safe and extensively validated approach with a low margin of error and miscarriage rate as well as a suspected high sustained pregnancy rate. However, Alteri et al. (2019) state that while PGT-A allows for an increased implantation rate, current data does not show an increase in successful pregnancy rates. Researchers agree that this technology is imperfect as Ledger (2019) reports that PGD-A can incorrectly designate an euploid embryo as an aneuploid embryo, leading to the unnecessary waste of embryos. These researchers also suggest that this type of screening may only be necessary in women between the ages of 35 and 44, as embryonic aneuploidy rates are low below 37 years of age and “costly screening for aneuploid seems pointless for women over 44 years of age, as almost all embryos are aneuploid.”

The development of whole genome amplification and genomic tools, such as single nucleotide polymorphism (SNP) microarrays and comparative genomic hybridization microarrays, has led to faster, more accurate diagnoses that lead to improved pregnancy and live birth rates. Next-generation sequencing has also been used to distinguish between normal and abnormal embryos. PGD-polymerase chain reaction (PCR) is often used to amplify the obtained DNA from the blastomere biopsy for further analysis. Fluorescence In-situ Hybridization (FISH) has also been used for PGD and is an efficient method that may help to decrease IVF failure in infertile patients.

Other researchers are attempting to develop a non-invasive pre-implantation genetic testing technique. Farra, Choucair, and Awwad (2018) state that circulating cell-free embryonic DNA can be obtained from used culture media from blastocysts and in blastocoel fluid; this can then be used as a non-invasive method to evaluate genetic embryonic properties.

Companies, such as Natera, have developed a preimplantation genetic test for aneuploidy (PGT-A) determination and for the identification of single inherited gene mutations to improve IVF pregnancy outcomes. This PGT-A uses SNP microarray technology. Simon et al. (2018) studied IVF outcomes with this test when measuring PGT-A and euploid embryo transfer in day five or six embryos. An implantation rate and live birth rate of 69.9% and 64.5%, respectively, was identified. The authors concluded that “SNP-based PGT-A can mitigate the negative effects of maternal age on IVF outcomes in cycles with transfer, and that pregnancy outcomes from SET [single embryo transfer] cycles are not significantly different from those of double-embryo transfer cycles, and support the use of SET when transfers are combined with SNP-based PGT-A.”

Clinical Validity and Utility 
Dreesen et al. (2014) performed a study assessing the accuracy of diagnoses made based on PGD. A total of 940 cases covering 53 genetic disorders were re-evaluated using a PCR-based test. Of the 940 embryos, 881 (93.7%) of these embryos had two agreeing diagnoses. The first evaluation breakdown was 234 unaffected embryos, 590 affected, and 116 aberrant whereas the re-evaluation’s breakdown was 283 unaffected embryos, 578 affected, and 79 aberrant. The sensitivity of this method was 99.2%, and its specificity was 80.2%. Allelic drop-out, mosaicism, and human error were the three most common causes of error.

A study focusing on couples’ decisions based on expanded carrier screening was performed by Ghiossi, Goldberg, Haque, Lazarin, and Wong (2018); Forty-five couples took a survey of their reproductive decision making after receiving their results, and of those 45, 28 said they would plan IVF with PGD or a prenatal diagnosis in future pregnancies. Of the 19 pregnant respondents, eight chose a prenatal diagnosis route, two planned amniocentesis but miscarried, and nine considered the condition insufficiently severe to warrant invasive testing. Three of the eight that chose the prenatal diagnosis route were affected by a condition, and two pregnancies were terminated. Disease severity was found to be a significant association with changes in decision making. Thirteen respondents did not plan to use the results from the carrier screening and four responses were unclear.

Kamath, Antonisamy, and Sunkara (2019) analyzed 207,697 data sets from women undergoing single-embryo transfer after PGT or IVF without PGT between the year 2000 and 2016. Results showed a significantly higher incidence of zygotic splitting following PGT (2.4%) compared to following non-PGT IVF (1.5%); this shows “a likely increased risk of monozygotic splitting following embryo biopsy”  and highlights a potential risk with PGT embryonic biopsies.

A new study was published which compared the live birth rates of embryos fertilized without chromosome analysis compared to those analyzed via PGT-A and comprehensive chromosome screening of the first and second polar body. All mothers were of advanced maternal age between 36 and 40 years old. A total of 396 women enrolled in this multicenter, randomized clinical trial. Two hundred and five women had chromosomal screening, and 50 (24%) had a live birth within a year; in the group without intervention, which was comprised of 191 women, 45 (24%) had a live birth within a year. It is important to note that the groups had a slightly different number of participants. This study shows that PGT-A allows for similar birth rates when compared to embryos fertilized without chromosome analysis via intracytoplasmic sperm injection (ICSI). “Whether these benefits outweigh drawbacks such as the cost for the patient, the higher workload for the IVF lab and the potential effect on the children born after prolonged culture and/or cryopreservation remains to be shown.”

A meta-analysis focusing on evaluating the effectiveness and safety of PGT-A in women undergoing an IVF treatment was conducted in 2020. 13 randomized controlled trials—involving a total of 2,794 women—reporting data on clinical outcomes were included. The meta-analysis concluded that there existed insufficient evidence for preimplantation genetic testing for abnormal chromosomes numbers to provide a difference in cumulative live birth rate, live birth rate after the first embryo transfer, or miscarriage rate between IVF with and IVF without PGT‐A as currently performed, and therefore “the effect of PGT‐A on clinical pregnancy rate is uncertain.” The evidence evinced that though the observed cumulative live birth rate (cLBR) was 24% in the control group, the chance of live birth following the results of one IVF cycle with PGT‐A is between 17% and 34%. Similarly, trials focusing on IVF with addition of PGT‐A boasted an average cLBR of 29% in the control group, but the chance of live birth following the results of one IVF cycle with PGT‐A was between 12% and 29%. When PGT‐A is performed with FISH, the chance of live births after the first transfer in the control group (31%) fell to between 16% and 29% for those tested. Thus, the authors caution that “Women need to be aware that it is uncertain whether PGT‐A with the use of genome‐wide analyses is an effective addition to IVF, especially in view of the invasiveness and costs involved in PGT‐A”, going so far as to state that “PGT‐A using FISH for the genetic analysis is probably harmful”.

Next generation sequencing can be used for PGS to screen for aneuploidies in IVF scenarios. A study by Yap and colleagues analyzed results from a total of 391 IVF pregnancies whose embryos were cultured to the blastocyst stage; a total of 1,361 blastocysts were analyzed. Of the 1,361 blastocysts, 423 were identified as aneuploid, 723 as euploid and 216 as mosaic (contained varying cell lines). These results show that next generation sequencing can be used to identify mosaic and aneuploid blastocysts and is an effective PGS tool.

American College of Obstetricians and Gynecologists
In 2017, the ACOG noted that if a carrier couple (carriers for the same condition) is identified, genetic counselling is encouraged so that options such as preimplantation genetic diagnosis or prenatal diagnosis may be discussed.

In 2020, the ACOG published a series of recommendations in their “ACOG Committee Opinion” Number 799. These recommendations are shortened for brevity and reported below: 

  • “Preimplantation genetic testing-monogenic uses only a few cells from the early embryo, usually at the blastocyst stage, and misdiagnosis is possible but rare with modern techniques. Confirmation of preimplantation genetic testing-monogenic results with chorionic villus sampling (CVS) or amniocentesis should be offered.”
  • “To detect structural chromosomal abnormalities such as translocations, preimplantation genetic testing-structural rearrangements (known as PGT-SR) is used. Confirmation of preimplantation genetic testing-structural rearrangements results with CVS or amniocentesis should be offered.”
  • “The main purpose of preimplantation genetic testing-aneuploidy (known as PGT-A) is to screen embryos for whole chromosome abnormalities. Traditional diagnostic testing or screening for aneuploidy should be offered to all patients who have had preimplantation genetic testing-aneuploidy, in accordance with recommendations for all pregnant patients”

The Society of Obstetricians and Gynecologists of Canada (SOGC)
The SOGC recommendations on PGD are as follows: 

  • “Before preimplantation genetic diagnosis is performed, genetic counselling must be provided to ensure that patients fully understand the risk of having an affected child, the impact of the disease on an affected child, and the benefits and limitations of all available options for preimplantation and prenatal diagnosis.
  • Couples should be informed that preimplantation genetic diagnosis can reduce the risk of conceiving a child with a genetic abnormality carried by one or both parents if that abnormality can be identified with tests performed on a single cell.
  • Invasive prenatal testing to confirm the results of preimplantation genetic diagnosis is encouraged because the methods used for preimplantation genetic diagnosis have technical limitations that include the possibility of a false negative result.
  • Before preimplantation genetic screening is performed, thorough education and counselling must be provided to ensure that patients fully understand the limitations of the technique, the risk of error, and the lack of evidence that preimplantation genetic screening improves live-birth rates.
  • Available evidence does not support the use of preimplantation genetic screening as currently performed to improve live-birth rates in patients with advanced maternal age, recurrent implantation failure, or recurrent pregnancy loss.”

The SOGC released a technical update in 2015, which reaffirm the first three recommendations and include the following statements: 

  • Trophectoderm biopsy has no measurable impact on embryo development, as opposed to blastomere biopsy. Therefore, whenever possible, trophectoderm biopsy should be the method of choice in embryo biopsy and should be performed by experienced hands. (I-B)
  • “Preimplantation genetic diagnosis of single-gene disorders should ideally be performed with multiplex polymerase chain reaction coupled with trophectoderm biopsy whenever available. (II-2B)
  • The use of comprehensive chromosome screening technology coupled with trophectoderm biopsy in preimplantation genetic diagnosis in couples carrying chromosomal translocations is recommended because it is associated with favorable clinical outcomes. (II-2B)
  • Before preimplantation genetic screening is performed, thorough education and counselling must be provided by a certified genetic counsellor to ensure that patients fully understand the limitations of the technique, the risk of error, and the ongoing debate on whether preimplantation genetic screening is necessary to improve live birth rates with in vitro fertilization. (III-A)
  • Preimplantation genetic screening using fluorescence in situ hybridization technology on day-3 embryo biopsy is associated with decreased live birth rates and therefore should not be performed with in vitro fertilization. (I-E)
  • Preimplantation genetic screening using comprehensive chromosome screening technology on blastocyst biopsy, increases implantation rates and improves embryo selection in IVF cycles in patients with a good prognosis (I-B) (Dahdouh et al., 2015).”

In the 2016 joint SOGC-CCMG (Canadian College of Medical Geneticists) opinion for reproductive genetic carrier screening, they state, “Women and their partners will be able to obtain appropriate genetic carrier screening information and possible diagnosis of AR (autosomal recessive), AD (autosomal dominant), or XL (X-linked) disorders (preferably pre-conception), thereby allowing an informed choice regarding genetic carrier screening and reproductive options (e.g., prenatal diagnosis, preimplantation genetic diagnosis, egg or sperm donation, or adoption).”

European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium
In 2010, the ESHRE  issued detailed guidelines related to technical aspects of PGD, specifically for the use of amplification techniques and for FISH. The ESHRE recommends that “misdiagnosis rates should be calculated for each type of assay and for all assays from a particular Centre.” Additionally, they note that “Follow-up of pregnancies (including multiple pregnancy rate and outcome), deliveries, and the health of children at birth and beyond should be attempted and maintained along with the cycle data.”

In 2020, the ESHRE expanded upon their practice recommendations for preimplantation genetic testing. For the organization of PGT, the ESHRE provided patient inclusion/exclusion criteria. In general, “It is recommended that PGT is only applied when genetic diagnosis is technically feasible, and the reliability of the diagnosis is high. Current procedures in most IVF/PGT centres allow for overall error rates (resulting in misdiagnosis) as low as 1 to 3%. Each centre should be aware of their error rates and include this information in their informed consents and reports in an open communication with the patient.

When considering PGT, safety issues, female age, impossibility to retrieve male or female gametes, body mass index (BMI) and other contraindications for IVF should be considered as possible exclusion criteria.

Furthermore, exclusion from PGT should be considered if the woman has serious signs and symptoms of an autosomal dominant or X-linked disorder (for which PGT is requested), which could introduce medical complications during ovarian stimulation, oocyte retrieval or pregnancy or medical risks at birth. PGT should be carefully considered if one of the partners has serious physical or psychological problems, either linked to the tested disease or due to other conditions.”

Different preimplantation genetic testing for specific defects and disorders carried their own caveats and recommendations in terms of inclusion and exclusion of patients:

For PGT-M, mitochondrial disorders and HLA: “Cases of genetic variants of unknown significance that are not predictive of a phenotype should be excluded from PGT. PGT testing is inappropriate in case of uncertain genetic diagnosis (for example genetic/molecular heterogeneity), or in case of uncertain mode of inheritance.

For autosomal recessive disorders, where a single pathogenic variant has been diagnosed in the proband and only one parent, it is acceptable to offer PGT if the pathogenic genotype is attributed to a single gene and sufficient evidence from the family pedigree allows identification of the disease-associated haplotypes. Similarly, it is acceptable to offer PGT for known X-linked recessive single gene disorders with a clear unequivocal clinical diagnosis where no pathogenic variant was found in the proband but low- and high-risk haplotypes can be identified based on the family history.

Exclusion or non-disclosure testing can be indicated for late-onset disorders, such as Huntington’s disease, to avoid pre-symptomatic testing of the partner with a family history of the disease. Exclusion testing is preferred over PGT with non-disclosure of the direct test results to the couple.”

For PGT for mitochondrial disorders: “PGT is not indicated in case of homoplasmy. In cases where the causative pathogenic variant of the mitochondrial disease is encoded by nuclear DNA, testing is the same as for other monogenic disorders”.

For HLA Typing: “When all other clinical options have been exhausted, selection of HLA-matched embryos via PGT is acceptable for couples who already have a child affected with a malignant, acquired disorder or a genetic disorder where the affected child is likely to be cured or life expectancy is substantially prolonged by transplantation with stem cells from an HLA-matched sibling. Testing can be performed for HLA typing alone, if the recurrence risk of the disease is low, or in combination with autosomal dominant/recessive or X-linked disorders”.

For PGT-SR: “Depending on the technology used (FISH, quantitative real-time PCR (qPCR), comprehensive testing methods (array-based comparative genomic hybridisation (aCGH), single nucleotide polymorphism (SNP) array or next generation sequencing (NGS))), different inclusion/exclusion criteria may apply. In general, PGT-SR is only recommended if the technique applied is able to detect all expected unbalanced forms of the chromosomal rearrangement. When comprehensive testing strategies are applied, it is acceptable to use information on copy number of nonindication chromosomes to refine embryo transfer strategies.”

For PGT-A: “For all, but in particular for RIF, RM and SMF couples, a previous karyotype of both partners is recommended since there is a higher chance of structural rearrangements for these indications. If an abnormal karyotype is identified, the technology for the detection of unbalanced abnormalities can differ from the regular PGT-A”.

Ethics Committee of the American Society for Reproductive Medicine (ASRM)
The ASRM ethics committee has published several opinion guidelines over the years.

In 2013, the ASRM published a committee opinion on the use of preimplantation genetic testing for monogenic defects (PGT-M) for adult-onset conditions. These guidelines stated the following: 

  • “Preimplantation genetic testing for monogenic disease (PGT-M) for adult-onset conditions is ethically justifiable when the conditions are serious and when there are no known interventions for the conditions, or the available interventions are either inadequately effective or are perceived to be significantly burdensome.
  • For conditions that are less serious or of lower penetrance, PGT-M for adult onset conditions is ethically acceptable as a matter of reproductive liberty.”

Similar guidelines were also published in 2013 by the ASRM regarding the use of PGD for serious adult onset conditions: 

  • “Preimplantation genetic diagnosis (PGD) for adult-onset conditions is ethically justifiable when the conditions are serious and when there are no known interventions for the conditions or the available interventions are either inadequately effective or significantly burdensome.
  • For conditions that are less serious or of lower penetrance, PGD for adult onset conditions is ethically acceptable as a matter of reproductive liberty. It should be discouraged, however, if the risks of PGD are found to be more than merely speculative.
  • Physicians and patients should be aware that much remains unknown about the long-term effects of embryo biopsy on any developing fetus. Though thought to be without serious side effects, PGD for adult onset diseases of variable penetrance should only be considered after patients are carefully and thoroughly counseled to weigh the risks of what is unknown about the technology and the biopsy itself against the expected benefit of its use.
  • It is important to involve the participation of a genetic counselor experienced in such conditions before patients undertake PGD. Counseling should also address the patient specific prognosis for achieving pregnancy and birth through in vitro fertilization (IVF) with PGD.”

Additional guidelines were published in 2008 which stated the following: 

  • “Before PGD is performed, genetic counseling must be provided to ensure that patients fully understand the risk for having an affected child, the impact of the disease on an affected child, and the limitations of available options that may help to avoid the birth of an affected child.
  • Prenatal diagnostic testing to confirm the results of PGD is encouraged strongly because the methods used for PGD have technical limitations that include the possibility for a false negative result.
  • Available evidence does not support the use of PGS as currently performed to improve live-birth rates in patients with advanced maternal age.
  • Available evidence does not support the use of PGS as currently performed to improve live-birth rates in patients with previous implantation failure.
  • Available evidence does not support the use of PGS as currently performed to reduce miscarriage rates in patients with recurrent pregnancy loss related to aneuploidy.”

Preimplantation Genetic Diagnosis International Society (PGDIS)
The PGDIS has stated that PGD is appropriate for the following purposes: 

  • “For carriers of Mendelian disorders in order to have an unaffected offspring without facing prenatal diagnosis and clinical termination of pregnancy.
  • For HLA typing with the purpose of conceiving a sibling that is a match to an older sibling who requires stem cell therapy. 
  • For carriers of translocations or other structural chromosome abnormalities in order to have an unaffected offspring without facing prenatal diagnosis and termination of pregnancy, to reduce the risk of miscarriages, and/or to improve the chance of unaffected conception in infertile carrier couples This indication includes recurrent pregnancy loss (RPL) caused by translocations. 
  • For idiopathic RPL. Although the prognosis to conceive a child after standard treatment is good, couples wanting to reduce the trauma, pain and side effects of recurrent miscarriages can use PGD to reduce the risk of miscarriage. 
  • For infertile patients. Several sub indications have been proposed: PGD has been shown to significantly reduce trisomic conceptions. Thus, PGDIS considers this a valid indication regardless of maternal age and number of embryos produced. 
  • PGD has also been shown to reduce significantly spontaneous abortions in infertile couples undergoing IVF” Thus, for couples wanting to prevent the risk of miscarriages, PGDIS considers this a valid indication regardless of maternal age and number of embryos produced. 
  • PGD has been proposed as a method to increase take-home baby rates in certain subgroups of IVF patients (see Appendix A.2). Although there have been contradictory studies, rigorous analysis of methodology used in those studies (see Appendix A.2) has led PGDIS to nonetheless consider that the procedure, if performed adequately, is not detrimental.” 

Appendix A.2 subgroups: women 35 and older with a minimum of six biopsiable embryos.

The PGDIS has also published recent 2019 recommendations for clinicians: 

  • “Patients should continue to be advised that any genetic test based on sampling one or small number of cells biopsied from a preimplantation embryo cannot be 100% accurate for a combination of technical and biological factors, including chromosome mosaicism. 
  • The patient information and consent forms for aneuploidy testing (if used) should be modified to include the possibility of mosaic results and any potential risks in the event of transfer and implantation. This needs to be explained to patients by the person recommending PGT-A. 
  • Transfer of blastocysts with a normal euploid result should generally be prioritized over those with mosaic results. 
  • In the event of considering the transfer of a mosaic blastocyst, the following options should be discussed with the patient:
    • (i) Initiation of a further PGT-A cycle to increase the chance of identifying a euploid blastocyst for transfer
    • (ii) Transfer of a blastocyst with lower level mosaicism, after appropriate counselling.”

American College of Medical Genetics and Genomics
The ACMG has released guidelines on prenatal/preconception carrier screening, primarily when to test: 

  • “Disorders should be of a nature that most at-risk patients and their partners identified in the screening program would consider having a prenatal diagnosis to facilitate making decisions surrounding reproduction.
  • For each disorder, the causative gene(s), mutations, and mutation frequencies should be known in the population being tested, so that meaningful residual risk in individuals who test negative can be assessed.”
  • There must be validated clinical association between the mutation(s) detected and the severity of the disorder.”

British Fertility Society (BFS) Policy and Practice Guidelines
The BFS have published guidelines regarding PGS. These guidelines state that “It remains possible that PGS may be of benefit under certain circumstances. However at present patients should be informed that there is no robust evidence that PGS for advanced maternal age improves live birth rate per cycle started, and PGS should preferably be offered within the context of robustly designed randomised trials performed in suitably experienced centres.”

References

  1. ACMG. (2013). ACMG position statement on prenatal/preconception expanded carrier screening. Retrieved from https://www.acmg.net/docs/Prenatal_Preconception_Expanded_Carrier_Screening_Statement_GiM_June_2013.pdf
  2. ACOG. (2017). Carrier Screening in the Age of Genomic Medicine. Retrieved from https://www.acog.org/-/media/Committee-Opinions/Committee-on-Genetics/co690.pdf?dmc=1&ts=20170328T2033175160
  3. ACOG, Klugman, S., & Rollene, N. (2020). Preimplantation Genetic Testing. Obstetrics & Gynecology, 135(3). Retrieved from https://www.acog.org/-/media/project/acog/acogorg/clinical/files/committee-opinion/articles/2020/03/preimplantation-genetic-testing.pdf
  4. Alteri, A., Corti, L., Sanchez, A. M., Rabellotti, E., Papaleo, E., & Vigano, P. (2019). Assessment of pre-implantation genetic testing for embryo aneuploidies: A SWOT analysis. Clin Genet, 95(4), 479-487. doi:10.1111/cge.13510
  5. Anderson, R. A., & Pickering, S. (2008). The current status of preimplantation genetic screening: British Fertility Society Policy and Practice Guidelines. Hum Fertil (Camb), 11(2), 71-75. doi:10.1080/14647270802041607
  6. ASRM. (2008). Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril, 90(5 Suppl), S136-143. doi:10.1016/j.fertnstert.2008.08.062
  7. ASRM. (2013a). Use of preimplantation genetic diagnosis for serious adult onset conditions: a committee opinion. Fertil Steril, 100(1), 54-57. doi:10.1016/j.fertnstert.2013.02.043
  8. ASRM. (2013b). Use of preimplantation genetic testing for monogenic defects (PGT-M) for adult-onset conditions: an Ethics Committee opinion. Retrieved from https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/ethics-committee-opinions/use-of-pgt-for-monogenic-defects-foradult-onset-conditions.pdf
  9. ASRM. (2015). Use of reproductive technology for sex selection for nonmedical reasons. Fertil Steril, 103(6), 1418-1422. doi:10.1016/j.fertnstert.2015.03.035
  10. ASRM, E. C. o. t. A. S. f. R. M. (2013). Use of preimplantation genetic diagnosis for serious adult onset conditions: a committee opinion. Fertil Steril, 100(1), 54-57. doi:10.1016/j.fertnstert.2013.02.043
  11. Audibert, F., Wilson, R. D., Allen, V., Blight, C., Brock, J. A., Desilets, V. A., . . . Wyatt, P. (2009). Preimplantation genetic testing. J Obstet Gynaecol Can, 31(8), 761-775.
  12. Brezina, P. R., Anchan, R., & Kearns, W. G. (2016). Preimplantation genetic testing for aneuploidy: what technology should you use and what are the differences? J Assist Reprod Genet, 33(7), 823-832. doi:10.1007/s10815-016-0740-2
  13. Committee, E. P. C. S., Carvalho, F., Coonen, E., Goossens, V., Kokkali, G., Rubio, C., . . . De Rycke, M. (2020). ESHRE PGT Consortium good practice recommendations for the organisation of PGT†. Human Reproduction Open, 2020(3). doi:10.1093/hropen/hoaa021
  14. Cornelisse, S., Zagers, M., Kostova, E., Fleischer, K., Wely, M., & Mastenbroek, S. (2020). Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation. Cochrane Database of Systematic Reviews(9). doi:10.1002/14651858.CD005291.pub3
  15. Cram, D. S., Leigh, D., Handyside, A., Rechitsky, L., Xu, K., Harton, G., . . . Kuliev, A. (2019). PGDIS Position Statement on the Transfer of Mosaic Embryos 2019. Reprod Biomed Online, 39 Suppl 1, e1-e4. doi:10.1016/j.rbmo.2019.06.012
  16. Dahdouh, E. M., Balayla, J., Audibert, F., Wilson, R. D., Brock, J. A., Campagnolo, C., . . . Vallee-Pouliot, K. (2015). Technical Update: Preimplantation Genetic Diagnosis and Screening. J Obstet Gynaecol Can, 37(5), 451-463. Retrieved from https://www.jogc.com/article/S1701-2163(15)30261-9/fulltext
  17. Dreesen, J., Destouni, A., Kourlaba, G., Degn, B., Mette, W. C., Carvalho, F., . . . Traeger-Synodinos, J. (2014). Evaluation of PCR-based preimplantation genetic diagnosis applied to monogenic diseases: a collaborative ESHRE PGD consortium study. Eur J Hum Genet, 22(8), 1012-1018. doi:10.1038/ejhg.2013.277
  18. Farra, C., Choucair, F., & Awwad, J. (2018). Non-invasive pre-implantation genetic testing of human embryos: an emerging concept. Hum Reprod, 33(12), 2162-2167. doi:10.1093/humrep/dey314
  19. Feldman, B., Aizer, A., Brengauz, M., Dotan, K., Levron, J., Schiff, E., & Orvieto, R. (2017). Pre-implantation genetic diagnosis-should we use ICSI for all? J Assist Reprod Genet, 34(9), 1179-1183. doi:10.1007/s10815-017-0966-7
  20. García-Herrero, S., Martínez-Fernández, A., Marin, L., Nieto, J., Campos-Gallindo, I., Peinado, V., . . . Simón, C. (2019). New high-throughput semiautomated Next Generation Sequencing (NGS) platform for Pre- implantation Genetic Testing for aneuploidies (PGT-A). Reprod Biomed Online, 38. Retrieved from https://www.sciencedirect.com/science/article/abs/pii/S1472648319301543
  21. Ghiossi, C. E., Goldberg, J. D., Haque, I. S., Lazarin, G. A., & Wong, K. K. (2018). Clinical Utility of Expanded Carrier Screening: Reproductive Behaviors of At-Risk Couples. J Genet Couns, 27(3), 616-625. doi:10.1007/s10897-017-0160-1
  22. Harton, G. L., De Rycke, M., Fiorentino, F., Moutou, C., SenGupta, S., Traeger-Synodinos, J., & Harper, J. C. (2010). ESHRE PGD consortium best practice guidelines for amplification-based PGD†. Human Reproduction, 26(1), 33-40. doi:10.1093/humrep/deq231
  23. Kamath, M. S., Antonisamy, B., & Sunkara, S. K. (2019). Zygotic splitting following embryo biopsy: a cohort study of 207 697 single-embryo transfers following IVF treatment. Bjog. doi:10.1111/1471-0528.16045
  24. Ledger, W. (2019). Preimplantation genetic screening should be used in all in vitro fertilisation cycles in women over the age of 35 years: AGAINST: Pre-implantation genetic screening should not be used in all IVF cycles in women over the age of 35 years. Bjog, 126(13), 1555. doi:10.1111/1471-0528.15942
  25. Montazeri, F., Foroughmand, A. M., Kalantar, S. M., Aflatoonian, A., & Khalilli, M. A. (2018). Tips and Tricks in Fluorescence In-situ Hybridization (FISH)-based Preimplantation Genetic Diagnosis/Screening (PGD/PGS). International Journal of Medical Laboratory, 5, 84-98. Retrieved from https://pdfs.semanticscholar.org/961d/7648113976ca31c7655e29b471078bd1026b.pdf
  26. Natera. (2020). Spectrum®. Retrieved from https://www.natera.com/spectrum-pgt
  27. PGDIS. (2008). Guidelines for good practice in PGD: programme requirements and laboratory quality assurance. Reprod Biomed Online, 16(1), 134-147. Retrieved from https://www.rbmojournal.com/article/S1472-6483(10)60567-6/pdf
  28. PGDIS, P. G. D. I. S. (2008). Guidelines for good practice in PGD: programme requirements and laboratory quality assurance. Reprod Biomed Online, 16(1), 134-147. Retrieved from https://www.rbmojournal.com/article/S1472-6483(10)60567-6/pdf
  29. Schattman, G. (2020). Preimplantation genetic testing. Retrieved from https://www.uptodate.com/contents/preimplantation-genetic-testing#H16
  30. Scott, Hong, & Scott. (2013). Selecting the optimal time to perform biopsy for preimplantation genetic testing. Fertil Steril, 100(3), 608-614. doi:10.1016/j.fertnstert.2013.07.004
  31. Scott, Upham, Forman, Zhao, & Treff, N. R. (2013). Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial. Fertil Steril, 100(3), 624-630. doi:10.1016/j.fertnstert.2013.04.039
  32. Scott, K. L., Hong, K. H., & Scott, R. T., Jr. (2013). Selecting the optimal time to perform biopsy for preimplantation genetic testing. Fertil Steril, 100(3), 608-614. doi:10.1016/j.fertnstert.2013.07.004
  33. Simon, A. L., Kiehl, M., Fischer, E., Proctor, J. G., Bush, M. R., Givens, C., . . . Demko, Z. P. (2018). Pregnancy outcomes from more than 1,800 in vitro fertilization cycles with the use of 24-chromosome single-nucleotide polymorphism-based preimplantation genetic testing for aneuploidy. Fertil Steril, 110(1), 113-121. doi:10.1016/j.fertnstert.2018.03.026
  34. Stern, H. J. (2014). Preimplantation Genetic Diagnosis: Prenatal Testing for Embryos Finally Achieving Its Potential. J Clin Med, 3(1), 280-309. doi:10.3390/jcm3010280
  35. Sullivan-Pyke, C., & Dokras, A. (2018). Preimplantation Genetic Screening and Preimplantation Genetic Diagnosis. Obstet Gynecol Clin North Am, 45(1), 113-125. doi:10.1016/j.ogc.2017.10.009
  36. Vaiarelli, A., Cimadomo, D., Capalbo, A., Orlando, G., Sapienza, F., Colamaria, S., . . . Ubaldi, F. M. (2016). Pre-implantation genetic testing in ART: who will benefit and what is the evidence? J Assist Reprod Genet, 33(10), 1273-1278. doi:10.1007/s10815-016-0785-2
  37. Verpoest, W., Staessen, C., Bossuyt, P. M., Goossens, V., Altarescu, G., Bonduelle, M., . . . Sermon, K. (2018). Preimplantation genetic testing for aneuploidy by microarray analysis of polar bodies in advanced maternal age: a randomized clinical trial. Hum Reprod, 33(9), 1767-1776. doi:10.1093/humrep/dey262
  38. Wilson, R. D., De Bie, I., Armour, C. M., Brown, R. N., Campagnolo, C., Carroll, J. C., . . . Zwingerman, R. (2016). Joint SOGC & CCMG Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to-Consumer Testing. Journal of Obstetrics and Gynaecology Canada, 38(8), 742-762.e743. doi:10.1016/j.jogc.2016.06.008
  39. Yap, W., Lee, C., Chan, W., & Lim, Y. (2019). Detection of Mosaicism in Blastocyst using High Resolution Next Generation Sequencing Preimplantation Genetic Screening (hr-NGS). Reprod Biomed Online, 38. Retrieved from https://www.sciencedirect.com/science/article/abs/pii/S1472648319301671

Coding Section 

Codes Number Description
CPT 89290 Biopsy, oocyte polar body or embryo blastomere, michrotechnique (for pre-implantation genentic diagnosis); less than or equal to 5 embryos;
  89291 greater than 5 embryos
  81161 DMD (dystrophin) (eg, Duchenne/Becker muscular dystrophy) deletion analysis, and duplication analysis, if performed
  81200 ASPA (aspartoacylase)(eg, Canavan disease) gene analysis, common variants (eg, E285A, Y231X)
  81201 – 81203 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence, known familial variants, duplication/deletion variants
  81205 BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, Maple syrup urine disease) gene analysis, common variants (eg, R183P, G278S, E422X)
  81209 BLM (Bloom syndrome, RecQ helicase-like) (eg, Bloom syndrome) gene analysis, 2281del6ins7 variant
  81220 CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; common variants (eg, ACMG/ACOG guidelines)
  81221 known familial variants
  81240 F2 (prothrombin, coagulation factor II) (eg, hereditary hypercoagulability) gene analysis, 20210G>A variant
  81242 FANCC (Fanconi anemia, complementation group C) (eg, Fanconi anemia, type C) gene analysis, common variant (eg, IVS4+4A>T)
  81243 FMR1 (Fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; evaluation to detect abnormal (eg, expanded) alleles
  81250 G6PC (glucose-6-phosphatase, catalytic subunit) (eg, Glycogen storage disease, Type 1a, von Gierke disease) gene analysis, common variants (eg, R83C, Q347X)
  81251 GBA (glucosidase, beta, acid) (eg, Gaucher disease) gene analysis, common variants (eg, N370S, 84GG, L444P, IVS2+1G>A)
  81252 – 81253 GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; full gene sequence, known familial variants
  81255 HEXA (hexosaminidase A [alpha polypeptide]) (eg, Tay-Sachs disease) gene analysis, common variants (eg, 1278insTATC, 1421+1G>C, G269S)
  81256 HFE (hemochromatosis) (eg, hereditary hemochromatosis) gene analysis, common variants (eg, C282Y, H63D)
  81257 HBA1/HBA2 (alpha globin 1 and alpha globin 2 (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (eg, Southeast Asian, Thai Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, and Constant Spring)
  81260 IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) (eg, familial dysautonomia) gene analysis, common variants (eg, 2507+6T>C, R696P)
  81280 Long QT syndrome gene analyses (eg, KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3. SCN4B, AKAP, SNTA1, and ANK2); ful sequence analysis
  81281 Long QT syndrome gene analyses (eg, KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3. SCN4B, AKAP, SNTA1, and ANK2); known familial sequence variant
  81282 Long QT syndrome gene analyses (eg, KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3. SCN4B, AKAP, SNTA1, and ANK2); duplication/deletion variants
  81288 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis
  81290 MCOLN1 (mucolipin 1)(eg, Mucolipidosis, type IV) gene analysis, common variants (eg, IVS3-2A>G, del6, 4kb)
  81292 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
  81293 known familial variants
  81294 duplication/deletion variants
  81295 MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
  81296 known familial variants
  81297 duplication/deletion variants
  81298 MSH6 (mutS homolog 6 [E. Coli]) )eg. jeredotaru mpm-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
  81299 known familial variants
  81300 duplication/deletion variants
  81301 Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed
  81302 MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; full sequence analysis
  81303  Mecp2 (methyl cpg binding protein 2) (eg, rett syndrome) gene analysis; known familial variant 
  81304  Mecp2 (methyl cpg binding protein 2) (eg, rett syndrome) gene analysis; duplication/deletion variants 
  81310 NPM1 (nucleophosmin) (eg, acute myeloid leukemia) gene analysis, exon 12 variants
  81317 PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
  81318 known familial variants
  81319 duplication/deletion variants
  81321 – 81323 PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; full sequence analysis, known familial variant, duplication/deletion variant
  81324 – 81326 PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis, full sequence analysis, known familial variant
  81330 SMPD1 (sphingomyelin phosphodiesterase 1, acid lysosomal) (eg, Niemann-Pick disease, Type A) gene analysis, common variants (eg, R496L, L302P, fsP330)
  81331 SNRPN/UBE3A (small nuclear ribonucleoprotein polypeptide N and ubiquitin protein ligase E3A)(eg, Prader-Willi syndrome and/or Angelman syndrome), methylation analysis
  81332 SERPINA1 (serpin peptidase inhibitor, clade A, alpha-1 antiproteinase, antitrypsin, member 1) (eg, alpha-1-antitrypsin deficiency), gene analysis, common variants (eg, *S and *Z)
  81413  Cardiac ion channelopathies (eg, Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia); genomic sequence analysis panel, must include sequencing of at least 10 genes, including ANK2, CASQ2, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, RYR2, and SCN5A 
  81414  Cardiac ion channelopathies (eg, Brugada syndrome, lon QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia); duplication/deletion gene analysis panel, must include analysis of at least 2 genes, including KCNH2 and KCNQ1 
  88245 – 88269 Chromosome analysis
  88271 – 88275 Molecular cytogenetics
  89290  Biopsy, oocyte polar body or embryo blastomere, microtechnique (for pre-implantation gentic diagnosis); less than or equal to 5 embryos 
  89291  greater than 5 embryos 
  96040 Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family
  S0265  Genetic counseling, under physician supervision, each 15 minutes 
HCPCS G9143 Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)
ICD-10-PCS (effective 10/01/15) Z84.81 Family history genetic disease carrier
  All Z14 codes Genetic carrier status
  All Z15 codes Genetic susceptibility

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2015 Forward     

04/08/2021 

Annual review, no change to policy intent. Updating description, rationale and references. 

04/08/2020 

Annual review, no change to policy intent. 

06/19/2019 

Interim review. Genetic counseling is required is replacing Genetic counseling is Medically necessary. No other changes made 

04/01/2019 

Annual review, no change to policy intent. 

04/18/2018 

Annual review, no change to policy intent. Rephrasing criteria number 4 for clarity. 

06/19/2017 

Interim review to remove cpt code 81422. No other changes.

04/26/2017 

Interim review to align with Avalon quarterly schedule. Updated category to Laboratory. 

03/08/2017 

Updated CPT codes.  

10/05/2016 

Annual review, no change to policy intent.

01/04/2016 

Updated CPT codes. No change to policy intent. 

10/05/2015

NEW POLICY


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