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

Description
Pre-implantation 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 pre-implantation genetic testing is being contemplated.
2. Pre-implantation 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. Pre-implantation genetic testing for sex selection, in the absence of a sex-linked early onset disease, DOES NOT MEET COVERAGE CRITERIA.
4. Pre-implantation genetic testing in the following situations is investigational and/or unproven therefore considered NOT MEDICALLY NECESSARY:
1. Pre-implantation genetic testing for adult-onset disorders.
2. Pre-implantation HLA genotyping for purposes of identifying potential tissue or organ donors.
3. Routine pre-implantation 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.

5. Pre-implantation 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 pre-implantation genetic screening for aneuploidy using fluorescence in situ hybridization solely because of maternal age. Pre-implantation 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 pre-implantation 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 pre-implantation 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 pre-implantation and prenatal diagnosis.
2. “Couples should be informed that pre-implantation 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 pre-implantation genetic diagnosis is encouraged because the methods used for pre-implantation genetic diagnosis have technical limitations that include the possibility of a false negative result.
4. “Before pre-implantation 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 pre-implantation genetic screening improves live-birth rates.
5. "Available evidence does not support the use of pre-implantation 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 
Pre-implantation 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, pre-implantation genetic diagnosis (PGD) has most frequently been employed in assisted reproduction as pre-implantation genetic screening (PGS) for detection of chromosome aneuploidy from advancing maternal age or structural chromosome rearrangements. The Pre-implantation 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 (PGDIS, 2008). Both this and the European Society of Human Reproduction and Embryology (ESHRE) surveys confirm that aneuploidy testing is the major indication for PGT (Stern, 2014).

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 (Scott, Hong, & Scott, 2013). 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 (Schattman, 2020).

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 (Scott, Upham, Forman, Zhao & Treff, 2013). Overall, trophectoderm biopsy on day five is preferred as it has no measurable impact on embryo development (Dahdouh et al., 2015). 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 (Schattman, 2020). Improved results have been seen with decreasing use of day three blastomere biopsy in favor of day five trophectoderm biopsy (K. L. Scott, K. H. Hong & R. T. Scott, Jr., 2013).

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 (Brezina, Anchan & Kearns, 2016). 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 (Dahdouh et al., 2015).

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 (Stern, 2014). 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 (ASRM, 2013a). 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 (ASRM, 2015).

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 (Vaiarelli et al., 2016). 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 (Vaiarelli et al., 2016). 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 (Ledger, 2019).”

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 (Sullivan-Pyke & Dokras, 2018). Next-generation sequencing has also been used to distinguish between normal and abnormal embryos (García-Herrero et al., 2019). PGD-polymerase chain reaction (PCR) is often used to amplify the obtained DNA from the blastomere biopsy for further analysis (Feldman et al., 2017). 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 (Montazeri, Foroughmand, Kalantar, Aflatoonian, & Khalilli, 2018).

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.

Proprietary Testing
Companies, such as Natera, have developed a pre-implantation genetic test for aneuploidy (PGT-A) determination and for the identification of single inherited gene mutations to improve IVF pregnancy outcomes (Natera, 2020). 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 (Simon et al., 2018). 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 (Simon et al., 2018).”

iGLS Reproductive Genetics developed a PGT-A that uses next generation sequencing (NGS) to  analyze thousands of DNA sequences that are unique to each chromosome allowing for the accurate identification of extra or missing chromosomes (iGLS, 2022).

PacGenomics has developed several PGT’s for aneuploidies (PGT-A), structural chromosomal rearrangements (PGT-SR) with a subsequent PGT-SR Plus^® which is used to differentiate between normal and balanced translocation carrier embryos in translocation cases, and for monogenic/single gene disorders (PGT-M). PGT-A for aneuploidies is performed on embryos created through IVF to screen for chromosomal abnormalities. PGT-SR is a genetic test performed on embryos created through IVF to screen for chromosomal structural rearrangements caused by balanced translocations and inversions. PGT-SR-Plus^® can be added to PGT-SR which helps identify translocation carriers in patients who are not initially suspected to be at significant risk. PGT-M is performed on embryos created through IVF that is designed for individuals who know they are at an increased risk of having a child with a specific genetic disorder (PacGenomics, 2022).

Reproductive Genetic Innovations (RGI) developed several PGT tests including PGT-A, PGT-SR, and PGT-M which has similar functions to the other proprietary tests. RGI provides an additional test, PGT-HLA, which identifies embryos that are HLA compatible with a child who needs a bone marrow or cord blood transplant to help treat blood disorders (RGI, 2022).

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 reevaluation’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 (Dreesen et al., 2014).

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 amniocenteses 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 (Ghiossi et al., 2018).

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” (Kamath et al., 2019) 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 (Verpoest et al., 2018). 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 (Verpoest et al., 2018). 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 (Verpoest et al., 2018).”

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 2794 women—reporting data on clinical outcomes were included. The meta-analysis concluded that there existed insufficient evidence for pre-implantation 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” (Cornelisse et al., 2020).

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 1361 blastocysts were analyzed (Yap, Lee, Chan, & Lim, 2019). Of the 1361 blastocysts, 423 were identified as aneuploid, 723 as euploid and 216 as mosaic (contained varying cell lines) (Yap et al., 2019). These results show that next generation sequencing can be used to identify mosaic and aneuploid blastocysts and is an effective PGS tool.

Zeevi studied the clinical validity of Haploseek, a method for pre-implantation genetic testing and compared the results to polymerase chain reaction (PCR)-based PGT case results. 151 embryo biopsies from 27 PGT cases were obtained and sequenced using Haploseek to predict the chromosome copy-number variants (CNVs) and relevant variant-flanking haplotypes in each embryo. For each of the 151 embryo biopsies, all Haploseek-derived haplotypes and CNVs were concordant with clinical PGT results. The authors conclude that “Haploseek is clinically accurate and fit for all standard clinical PGT applications” (Zeevi et al., 2021).

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 pre-implantation genetic diagnosis or prenatal diagnosis may be discussed (ACOG, 2017).

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:

• “Pre-implantation 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 pre-implantation genetic testing-monogenic results with chorionic villus sampling (CVS) or amniocentesis should be offered.”
• “To detect structural chromosomal abnormalities such as translocations, pre-implantation genetic testing-structural rearrangements (known as PGT-SR) is used. Confirmation of pre-implantation genetic testing-structural rearrangements results with CVS or amniocentesis should be offered.”
• “The main purpose of pre-implantation 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 pre-implantation genetic testing-aneuploidy, in accordance with recommendations for all pregnant patients” (ACOG, Klugman, & Rollene, 2020)

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

• “Before pre-implantation 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 pre-implantation and prenatal diagnosis.
• Couples should be informed that pre-implantation 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 pre-implantation genetic diagnosis is encouraged because the methods used for pre-implantation genetic diagnosis have technical limitations that include the possibility of a false negative result.
• Before pre-implantation 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 pre-implantation genetic screening improves live-birth rates.
• Available evidence does not support the use of pre-implantation genetic screening as currently performed to improve live-birth rates in patients with advanced maternal age, recurrent implantation failure, or recurrent pregnancy loss (Audibert et al., 2009).”

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)
• “Pre-implantation 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 pre-implantation genetic diagnosis in couples carrying chromosomal translocations is recommended because it is associated with favorable clinical outcomes. (II-2B)
• Before pre-implantation 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 pre-implantation genetic screening is necessary to improve live birth rates with in vitro fertilization. (III-A)
• Pre-implantation 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)
• Pre-implantation 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, pre-implantation genetic diagnosis, egg or sperm donation, or adoption) (Wilson et al., 2016).”

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 (Harton et al., 2010).”

In 2020, the ESHRE expanded upon their practice recommendations for pre-implantation 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 pre-implantation 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” (Committee et al., 2020).

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 pre-implantation genetic testing for monogenic defects (PGT-M) for adult-onset conditions. These guidelines stated the following:

• “Pre-implantation 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 (ASRM, 2013b).”

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

• “Pre-implantation 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 (E. C. o. t. A. S. f. R. M. ASRM, 2013).”

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 (ASRM, 2008).”

Pre-implantation 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 (Colls et al., 2007). 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 (P. G. D. I. S. PGDIS, 2008).” 

Appendix A.2 subgroups: women 35 and older with a minimum of six biopsiable embryos (P. G. D. I. S. PGDIS, 2008). 

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 pre-implantation 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 (Cram et al., 2019).” 

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 (ACMG, 2013).”

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 (Anderson & Pickering, 2008).” 

Table of Terminology

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). Pre-implantation Genetic Testing. Obstetrics & Gynecology, 135(3). Retrieved from https://www.acog.org/-/media/project/acog/acogorg/clinical/files/committee-opinion/articles/2020/03/pre-implantation-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 pre-implantation genetic screening: British Fertility Society Policy and Practice Guidelines. Hum Fertil (Camb), 11(2), 71-75. doi:10.1080/14647270802041607
6. ASRM. (2008). Pre-implantation 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 pre-implantation 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 pre-implantation 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 pre-implantation 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). Pre-implantation genetic testing. J Obstet Gynaecol Can, 31(8), 761-775.
12. Brezina, P. R., Anchan, R., & Kearns, W. G. (2016). Pre-implantation 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). Pre-implantation 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: Pre-implantation 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 pre-implantation 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. iGLS. (2022). Pre-implantation Genetic Testing for Aneuploidy. Retrieved from https://www.igls.net/services/pgt-a/
24. 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
25. Ledger, W. (2019). Pre-implantation 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
26. Montazeri, F., Foroughmand, A. M., Kalantar, S. M., Aflatoonian, A., & Khalilli, M. A. (2018). Tips and Tricks in Fluorescence In-situ Hybridization (FISH)-based Pre-implantation Genetic Diagnosis/Screening (PGD/PGS). International Journal of Medical Laboratory, 5, 84-98. Retrieved from https://pdfs.semanticscholar.org/961d/7648113976ca31c7655e29b471078bd1026b.pdf
27. Natera. (2020). Spectrum®. Retrieved from https://www.natera.com/spectrum-pgt
28. PacGenomics. (2022). Pre-implantation Genetic Testing (PGT). Retrieved from https://pacgenomics.com/pgt/
29. 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
30. 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
31. RGI. (2022). What is PGT. Retrieved from https://rgiscience.com/
32. Schattman, G. (2020). Pre-implantation genetic testing. Retrieved from https://www.uptodate.com/contents/pre-implantation-genetic-testing#H16
33. Schattman, G. (2022). Pre-implantation genetic testing. Retrieved from https://www.uptodate.com/contents/pre-implantation-genetic-testing#H16
34. Scott, Hong, & Scott. (2013). Selecting the optimal time to perform biopsy for pre-implantation genetic testing. Fertil Steril, 100(3), 608-614. doi:10.1016/j.fertnstert.2013.07.004
35. 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
36. Scott, K. L., Hong, K. H., & Scott, R. T., Jr. (2013). Selecting the optimal time to perform biopsy for pre-implantation genetic testing. Fertil Steril, 100(3), 608-614. doi:10.1016/j.fertnstert.2013.07.004
37. 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 pre-implantation genetic testing for aneuploidy. Fertil Steril, 110(1), 113-121. doi:10.1016/j.fertnstert.2018.03.026
38. Stern, H. J. (2014). Pre-implantation Genetic Diagnosis: Prenatal Testing for Embryos Finally Achieving Its Potential. J Clin Med, 3(1), 280-309. doi:10.3390/jcm3010280
39. Sullivan-Pyke, C., & Dokras, A. (2018). Pre-implantation Genetic Screening and Pre-implantation Genetic Diagnosis. Obstet Gynecol Clin North Am, 45(1), 113-125. doi:10.1016/j.ogc.2017.10.009
40. 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
41. Verpoest, W., Staessen, C., Bossuyt, P. M., Goossens, V., Altarescu, G., Bonduelle, M., . . . Sermon, K. (2018). Pre-implantation 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
42. 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
43. Yap, W., Lee, C., Chan, W., & Lim, Y. (2019). Detection of Mosaicism in Blastocyst using High Resolution Next Generation Sequencing Pre-implantation Genetic Screening (hr-NGS). Reprod Biomed Online, 38. Retrieved from https://www.sciencedirect.com/science/article/abs/pii/S1472648319301671
44. Zeevi, D. A., Backenroth, D., Hakam-Spector, E., Renbaum, P., Mann, T., Zahdeh, F., . . . Altarescu, G. (2021). Expanded clinical validation of Haploseek for comprehensive pre-implantation genetic testing. Genetics in Medicine, 23(7), 1334-1340. doi:10.1038/s41436-021-01145-6

Coding Section 

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 Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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