| Coverage Policy Manual | |
| Policy #: | 2005021 |
| Category: | Laboratory |
| Initiated: | August 2017 |
| Last Review: | December 2023 |
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| Preimplantation Genetic Diagnosis, Testing or Treatment | |
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| Description: |
Preimplantation genetic testing (PGT) describes a variety of adjuncts to an assisted reproductive procedure (See policy No. 2014008) in which either maternal or embryonic DNA is sampled and genetically analyzed, thus permitting deselection of embryos harboring a genetic defect prior to implantation of the embryo into the uterus. The ability to identify preimplantation embryos with genetic defects before the initiation of pregnancy provides an attractive alternative to amniocentesis or chorionic villous sampling (CVS) with selective pregnancy termination of affected fetuses.
Preimplantation genetic testing can be viewed as either diagnostic (PGD) or screening (PGS). Preimplantation genetic diagnosis (PGD) is used to detect genetic evidence of a specific inherited disorder, in the oocyte or embryo derived from mother or couple respectively, that has a high risk of transmission. Preimplantation genetic screening (PGS) is not used to detect a specific abnormality but instead uses similar techniques to identify genetic abnormalities in the absence of a known heritable disorder. This terminology, however, is not used consistently (eg, some authors use preimplantation genetic diagnosis when testing for a number of possible abnormalities in the absence of a known disorder), following a terminology change from 'preimplantation genetic screening' to 'preimplantation genetic testing' in 2017 (Cornelisse, 2020).
Biopsy for preimplantation genetic diagnosis can take place at 3 stages: the oocyte, cleavage stage embryo, or the blastocyst. In the earliest stage, both the first and second polar bodies are extruded from the oocyte as it completes the meiotic division after ovulation (first polar body) and fertilization (second polar body). This strategy thus focuses on maternal chromosomal abnormalities. If the mother is a known carrier of a genetic defect and genetic analysis of the polar body is normal, then it is assumed that the genetic defect was transferred to the oocyte during meiosis.
Biopsy of cleavage stage embryos or blastocysts can detect genetic abnormalities arising from either the maternal or paternal genetic material. Cleavage stage biopsy takes place after the first few cleavage divisions when the embryo is composed of 6 to 8 cells (ie, blastomeres). Sampling involves aspiration of 1 and sometimes 2 blastomeres from the embryo. Analysis of 2 cells may improve diagnosis but may also affect the implantation of the embryo. In addition, a potential disadvantage of testing at this phase is that mosaicism might be present. Mosaicism refers to genetic differences among the cells of the embryo that could result in an incorrect interpretation if the chromosomes of only a single cell are examined.
The third option is sampling the embryo at the blastocyst stage when there are about 100 cells. Blastocysts form 5 to 6 days after insemination. Three to 10 trophectoderm cells (outer layer of the blastocyst) are sampled. A disadvantage is that not all embryos develop to the blastocyst phase in vitro and, when they do, there is a short time before embryo transfer needs to take place. Blastocyst biopsy has been combined with embryonic vitrification to allow time for test results to be obtained before the embryo is transferred.
The biopsied material can be analyzed in a variety of ways. Polymerase chain reaction (PCR) or other amplification techniques can be used to amplify the harvested DNA with subsequent analysis for single genetic defects. This technique is most commonly used when the embryo is at risk for a specific genetic defect, such as Tay Sach’s disease or cystic fibrosis. Fluorescent in situ hybridization (FISH) is a technique that allows direct visualization of specific chromosomes to determine the number or absence of chromosomes. This technique is most commonly used to screen for aneuploidy, gender determination, or to identify chromosomal translocations. FISH cannot be used to diagnose single genetic defect disorders. However, molecular techniques can be applied with FISH (eg, microdeletions, duplications) and, thus, single-gene defects can be recognized with this technique. Performing preimplantation genetic screening using FISH is known as version 1.
Another more recent approach is with array comparative genome hybridization testing at either the 8-cell or more often, the blastocyst stage, also known as version 2. Unlike FISH analysis, hybridization allows for 24 chromosome aneuploidy screening, as well as more detailed screening for unbalanced translocations or inversions and other types of abnormal gains or losses of chromosomal material. Other preimplantation genetic screening version 2 methods include single nucleotide variant microarrays and quantitative polymerase chain reaction (Treff, 2013; Martin, 2013). Next-generation sequencing such as massively parallel signature sequencing has potential applications to prenatal genetic testing and is grouped with version 2 techniques in some literature and referred to as version 3 in other literature.
Three general categories of patients have undergone PGT:
1. Embryos at risk for a specific inherited single genetic defect
Inherited single gene defects fall into 3 general categories: autosomal recessive, autosomal dominant, and X-linked. When either the mother or father is a known carrier of a genetic defect, embryos can undergo PGT to deselect embryos harboring the defective gene. Gender selection of a female embryo is another strategy when the mother is a known carrier of an X-linked disorder for which there is not yet a specific molecular diagnosis. The most common example is female carriers of fragile X syndrome. In this scenario, PGT is used to deselect male embryos, half of which would be affected. PGT could also be used to deselect affected male embryos. While there is a growing list of single genetic defects for which molecular diagnosis is possible, the most common indications include cystic fibrosis, B thalassemia, muscular dystrophy, Huntington's disease, hemophilia, and fragile X disease. It should be noted that when PGT is used to deselect affected embryos, the treated couple is not technically infertile, but are undergoing an assisted reproductive procedure for the sole purpose of PGT. In this setting, PGT may be considered as an alternative to selective termination of an established pregnancy after diagnosis by amniocentesis or chorionic villus sampling.
2. Identification of aneuploid embryos
Implantation failure of fertilized embryos is common in assisted reproductive procedures; aneuploidy of embryos is thought to contribute to implantation failure and may also be the cause of recurrent spontaneous abortion. The prevalence of aneuploid oocytes increases in older women. These age-related aneuploidies are mainly due to nondisjunction of chromosomes during maternal meiosis. Therefore, preimplantation genetic screening has been explored as a technique to deselect aneuploid oocytes in older women and is also known as preimplantation genetic diagnosis for aneuploidy screening. Analysis of extruded polar bodies from the oocyte or no blastomeres at day 3 of embryo development using Fish was initially used to detect aneuploidy (preimplantation genetic screening version 1). A limitation of FISH is that analysis is restricted to a number of proteins. More recently, newer preimplantation genetic screening methods have been developed (version 2). These methods allow for all chromosomes' analysis with genetic platforms including array comparative genomic hybridization and single nucleotide variant chain reaction analysis. Moreover, in addition to older women, preimplantation genetic screening has been proposed for women with repeated implantation failures.
3. Embryos at a higher risk of translocations
Balanced translocations occur in 0.2% of the neonatal population but at a higher rate in infertile couples or in those with recurrent spontaneous abortions. PGT can be used to deselect those embryos carrying the translocations, thus leading to an increase in fertility or a decrease in the rate of spontaneous abortion.
The complicated technical and ethical issues associated with preimplantation genetic diagnosis, testing or treatment will frequently require case by case consideration. For example, such consideration may be required particularly for couples who are known carriers of potentially lethal or disabling genetic mutations and are seeking preimplantation genetic diagnosis as an alternative to conventional conception, with the possibility of an elective abortion if a subsequent amniocentesis identifies an affected fetus. The diagnostic performance of the individual laboratory tests used to analyze the biopsied genetic material is rapidly evolving, and evaluation of each specific genetic test for each abnormality is beyond the scope of this policy. However, in general, to assure adequate sensitivity and specificity for the genetic test guiding the embryo deselection process, the genetic defect must be well characterized. For example, the gene or genes responsible for some genetic disorders may be quite large, with mutations spread along the entire length of the gene. The ability to detect all or some of these genes, and an understanding of the clinical significance of each mutation (including its penetration, i.e., whether or not it is expressed in an individual) will affect the diagnostic performance of the test. An ideal candidate for genetic testing would be a person who has a condition that is associated with a single well-characterized mutation for which a reliable genetic test has been established. In some situations, PGD may be performed in couples in which the mother is a carrier of an X-linked disease, such as fragile X syndrome. In this case, the genetic test could focus on merely deselecting male embryos.
The severity of the genetic disorder is also a consideration. At the present time many cases of PGD have involved lethal or severely disabling conditions with limited treatment opportunities, such as Huntington's chorea or Tay Sach's disease. Cystic fibrosis is another condition for which PGD has been frequently performed. However, cystic fibrosis has a variable presentation and can be treatable. The range of genetic testing that is performed on amniocentesis samples as a possible indication for elective abortion may serve as a guide.
This policy does not attempt to address the myriad ethical issues associated with PGT that, it is hoped, have involved careful discussion between the treated couple and the physician. For some couples, the decision may involve the choice between the risks of an IVF procedure and deselection of embryos as part of the PGT treatment versus normal conception with the prospect of amniocentesis and an elective abortion.
Coding Issues
In 2004, specific CPT codes were issued describing the embryo biopsy procedure (89290-89291). Additional CPT codes will be required for the genetic analysis. The CPT codes used will vary according to the technique used to perform the genetic analysis. If performed to evaluate a specific genetic defect, a variable combination of CPT codes for molecular diagnostics will be used (CPT codes 83890-83912). If the technique is performed to detect aneuploidy or translocations, CPT codes for molecular cytogenetics will be used (CPT codes 88271-88275).
Assisted reproductive techniques may be subject to specific contractual restrictions that supersede this policy. Plans may consider reviewing their contract language to determine if such restrictions would apply to those patients undergoing preimplantation genetic diagnosis, not as an adjunct to treatment for infertility but as an alternative to selective termination of an established pregnancy. This latter group of patients is not infertile.
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Policy/ Coverage: |
Effective November 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
For those members who have in vitro fertilization benefits and have no express contract exclusion, Preimplantation Genetic Diagnosis, Testing or Treatment meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness provided that one of the following criteria are met:
For members of non-grandfathered plans, allowances for these services will be applied to the lifetime in vitro fertilization benefit of $15,000.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Preimplantation Genetic Diagnosis, Testing or Treatment for any other reason does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, Preimplantation Genetic Diagnosis, Testing or Treatment for any other reason is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to November 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
For those members who have in vitro fertilization benefits and have no express contract exclusion, Preimplantation Genetic Diagnosis, Testing or Treatment meets member benefit Primary Coverage Criteria that there be scientific evidence of effectiveness provided that one of the following criteria are met:
For members of non-grandfathered plans, allowances for these services will be applied to the lifetime in vitro fertilization benefit of $15,000.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Preimplantation Genetic Diagnosis, Testing or Treatment for any other reason does not meet member benefit Primary Coverage Criteria that there be scientific evidence of effectiveness.
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| Rationale: |
Although some aspects of the genetic analysis performed as part of preimplantation genetic testing (PGT) are similar to those performed in chorionic villus sampling or amniocentesis, there are significant differences related to the small size and source of the sample. For example, chromosomal mosaicism is not uncommon in preimplantation embryos, creating the possibility of false results when only a single cell is biopsied; i.e., when testing for a dominant genetic disorder, if a haploid cell is biopsied from a heterozygous embryo and the haploid cell contains the unaffected allele, the embryo will be misdiagnosed as normal. Accurate interpretation of the maternal polar body (in cases where the mother is the known carrier of a genetic defect) assumes that no crossing between homologous chromosomes has taken place during meiotic division. If crossing over occurs during the first meiotic division, both the first polar body and the oocyte will be heterozygous for the genetic defect. The incidence of crossing over increases with the distance from the telomere (i.e., middle of the chromosome), therefore gene location on the chromosome becomes important.
Genetic analysis relies on two general techniques, PCR or fluorescent in situ hybridization (FISH); each has its own limitations. For detection of specific genetic defects, polymerase chain reaction or a related procedure is used to expand the limited genetic material. PCR is always associated with a risk of contamination of the biopsy sample and resulting misdiagnosis. The PCR technique may be inefficient when using limited material. For example, allelic dropout, in which only 1 of the 2 alleles on a chromosome is amplified, has been recognized as a possible source of false negative results using the PCR technique. Once PCR has been performed, the actual genetic analysis depends on the availability of specific DNA probes for the genetic defect or other sophisticated molecular genetic techniques.
The FISH technique may be used to assess aneuploidy or for gender selection when the mother is a carrier of an X-linked disorder. Limitations of the FISH technique include criteria-defining positive signals, signal overlap of chromosomes, or signal dropout. Technical failure of the FISH technique in up to 20% of cases may result in the discarding of potentially normal oocytes.
There have been numerous small case series and anecdotal reports regarding the technical feasibility of PGT to deselect embryos for different indications. A representative sample of these reports is reviewed below.
Embryos at risk for a specific inherited single genetic defect
The European Society of Hormone Reproduction and Embryology (ESHRE) has created a registry for PGD. In 1999, the registry reported that PGD had been performed on some 51 genetic defects with the most common diseases being cystic fibrosis, thalassemia, myotonic dystrophy, muscular dystrophy, hemophilia, and fragile X syndrome. In this database pre- and postnatal confirmation of the PGD was performed in 70/110 (64%) of the conceptuses, either through amniocentesis, chorionic villus sampling, or genetic testing on the live birth. Among these 70 conceptuses was one misdiagnosis, which was detected by an amniocentesis followed by pregnancy termination. These registry data suggest that PGD, using either PCR or FISH, can be used to deselect affected embryos.
Several smaller case series have reported on individual diseases. For example, Goossens and colleagues reported on 48 cycles of PGD in 24 couples at risk for cystic fibrosis. Thirteen patients became pregnant, and 12 healthy babies have been born. Other anecdotal studies have reported successful PGD in patients with osteogenesis imperfecta, Lesch-Nyhan syndrome, bulbar muscular dystrophy, and phenylketonuria.
Identification of aneuploid embryos
Some authors have suggested aneuploidy detection be routinely performed in women over the age of 35 undergoing IVF, due to the increasing risk of nonviable aneuploid embryos with increasing age. In this setting, the most relevant outcome is the live birth rate per cycle or per embryo transfer. A 1997 report summarized the worldwide experience in using PGD in diagnosing age-related aneuploidies. A total of 523 PGD cycles were reported in 413 couples, with most women over age 35 years. This resulted in 115 clinical pregnancies from which 56 normal babies have been born, for a live birth rate per cycle of 10.7%. Munne and colleagues performed a study in which 117 women undergoing PGD for aneuploidy were retrospectively matched with a control group of 117 according to maternal age and number of mature follicles, among other parameters. The clinical pregnancy rate per embryo transferred was not significantly different between the 2 groups; however, the spontaneous abortion rate decreased from 23% in the control group to 9% in the PGD group. The rate of live births increased from 10.5% in the control group to 16.1% in the PGD group. While these data suggest that deselecting aneuploid embryos is associated with an increase in the live birth rate, the effect is relatively modest, considering that in patients 35–42 years there is a 30%–50% reduction in clinical pregnancy rates compared to patients younger than 34. Therefore, PGD does not entirely correct the low pregnancy rate associated with IVF in older women. Gianaroli and colleagues reported on a study that randomized women over the age of 35, or with 3 or greater previous IVF failures or an abnormal karyotype, to undergo IVF with or without PGD. In the PGD group, the clinical pregnancy rate was 37% compared to 27% in the control group. The "ongoing implantation rate" was 22.5% in the PGD group compared to 10.2% in the control group.
Identification of translocations
In the setting of couples with known translocations, the most relevant outcome of PGD is the live birth rate per cycle or embryo transfer. Munne and colleagues reviewed 35 couples in which 1 partner was known to carry a translocation. Of the 47 cycles of PGD, there were 13 completed or ongoing pregnancies (27%). There was no embryo transfer in 14 of the cycles; thus the pregnancy rate per embryo transfer was 39%. A total of 15 patients in this group had 16 pregnancies, only 2 of which ended in spontaneous abortion. Prior to PGD, this same group of patients had 38 previous pregnancies, of which 35 ended in spontaneous abortion.
Another area of clinical concern is the impact of PGD on overall IVF success rates. For example, is the use of PGD associated with an increased number of IVF cycles required to achieve pregnancy or a live birth? The Centers for Disease Control and Prevention (CDC) routinely collects and reports on IVF success rates; these data may be compared to the ESHRE registry data. The following table summarizes the success rates for IVF overall and PGD associated with IVF based on these 2 data sources.
Clinical Pregnancy Rate Per: IVF (%) PGD + IVF (%)
Cycle 30.5 17
Egg retrieval 35 18
Transfer 37.7 22
Although this table provides only a very rough estimation, the data suggest that use of PGD lowers the success rate of an in vitro fertilization cycle potentially due to any of a variety of reasons such as inability to biopsy an embryo, inability to perform genetic analysis, lack of transferable embryos, and effect of PGD itself on rate of clinical pregnancy or live birth. In addition, the CDC database presumably represents couples who are predominantly infertile compared to the ESHRE database, which primarily includes couples who are not necessarily infertile but are undergoing IVF strictly for the purposes of PGD.
Another important general clinical issue is whether PGD is associated with adverse obstetric outcomes, specifically fetal malformations related to the biopsy procedure. Strom and colleagues addressed this issue in an analysis of 102 pregnant women who had undergone PGD with genetic material from the polar body. All preimplantation genetic diagnoses were confirmed postnatally; there were no diagnostic errors. The incidence of multiple gestations was similar to that seen with IVF. Preimplantation genetic diagnosis did not appear to be associated with an increased risk of obstetric complications compared to data reported for obstetric outcomes for in vitro fertilization. However, it should be noted that biopsy of the polar body is extra-embryonic material, and thus one might not expect an impact on obstetric outcomes. The patients in this study had undergone PGD for both unspecified chromosomal disorders and various disorders associated with a single gene defect (i.e., cystic fibrosis, sickle cell disease, and others).
Summary
PGD has been shown to be technically feasible in detecting single gene defects, structural chromosomal abnormalities, and aneuploid embryos, using a variety of biopsy and molecular diagnostic techniques. There do not appear to be adverse obstetric outcomes, particularly in terms of fetal malformations, although the reported data focus on PGD using polar body biopsy and not biopsy of the embryo itself. Further data are required to confirm this preliminary finding, both for PGD involving biopsy of extra-embryonic and embryonic material. In terms of health outcomes, small case series have suggested that PGD is associated with the birth of unaffected fetuses when performed for detection of single genetic defects, and a decrease in spontaneous abortions for patients with structural chromosomal abnormalities or those at increased risk of aneuploid embryos due to maternal age (i.e., >35 years). For couples with single genetic defects, these beneficial health outcomes are balanced against the probable overall decreased success rate of the PGD procedure compared to in vitro fertilization alone. However, the alternative for couples at risk for single genetic defects is prenatal genetic testing, i.e., amniocentesis or chorionic villus sampling, with pregnancy termination contemplated for affected fetuses. (It should be noted that many patients undergoing PGD will also undergo a subsequent amniocentesis or chorionic villus sampling to verify PGD accuracy.)
Ultimately, the choice is one of the risks (both medical and psychologic) of undergoing IVF with PGD, compared to the option of normal fertilization and pregnancy with the possibility of a subsequent elective abortion. Since patients with structural chromosome abnormalities or aneuploid embryos have a high risk of spontaneous abortion, the most relevant outcome is the live birth rate, not the clinical pregnancy rate discussed above. The ESHRE database is not structured to permit even a crude comparison with the overall IVF success rates reported by the CDC. However, smaller studies have suggested that PGD results in a decrease in spontaneous abortion in both of these groups.
Finally, the majority of the data is reported from a few centers specializing in PGD. It is well known that the success rates of IVF alone vary from center to center; the CDC data were specifically collected to address this issue. Similarly, selection of a clinic offering PGD should be preceded by careful questioning regarding the success rate in terms of live birth rate and incidence of unaffected infants.
In 2001, the American Society of Reproductive Medicine issued a practice committee report on preimplantation genetic diagnosis. This reports recommends that, "PGD appears to be a viable alternative to post conception diagnosis and pregnancy termination. PGD should be regarded as an established technique with specific and expanding applications for standard clinical practice."
Reconsideration of the data regarding the role of PGD in infertile couples suggests that this technique may result in a reduction in the rate of spontaneous abortion. Therefore, the policy statement has been revised to indicate that this technique would be considered medically necessary in those women at high risk for spontaneous abortion or infertility who are undergoing IVF; i.e., women over the age of 35 or those with a prior history of 3 previous failed IVF cycles, or in couples in which one is known to have a balanced translocation. Similarly, PGD has been shown to be technically feasible as a technique to detect genetic defects and to deselect affected embryos. A straightforward example is the ability to use PGD to distinguish male and female embryos as a technique to deselect male embryos at risk for X-linked disorders. In recognition of this technical feasibility, the policy statement has been revised to suggest that PGD may be considered medically necessary in patients/couples who have a known genetic disorder. However, this policy is not designed to perform a separate analysis on every possible genetic defect. Therefore, implementation of this policy will require a case by case approach to address the many specific technical and ethical considerations inherent in testing for different genetic disorders, based on an understanding of the penetrance and natural history of the genetic disorder in question, and the technical capability of genetic testing to identify affected embryos. For example, several studies suggest that the role of PGD has expanded to a broader variety of conditions that have not been considered as an indication for genetic testing via amniocentesis or chorionic villous sampling. The report of PGD used to deselect embryos at risk for early-onset Alzheimer’s disease prompted considerable controversy, both in lay and scientific publications. Other reports focus on other applications of PGD for predispositions to late-onset disorders. This contrasts with the initial use of PGD in deselecting embryos with genetic mutations highly predictive of lethal diseases. PGD has also been used for gender selection and “family balancing.”
An additional literature search for the period of 2003 through November 2004 reveals that PGD is an area of active research; many studies report PGD for a broadening variety of well-defined genetic mutations, and further document the role of PGD in older women or in those with prior failed IVF cycles. In addition, there is ongoing discussion of the ethical implications of PGD focusing on such issues as sex selection or selection of HLA-matched fetus for subsequent use as a stem cell donor for an affected sibling.
2007 Update
The policy was updated based on a literature review using MEDLINE in August 2007. Mastenbroek, in a randomized controlled trial, found that preimplantation genetic screening reduced the rates of ongoing pregnancies and live births after IVF in women of advanced (aged 35 through 41 years) maternal age (Mastenbroek et al, 2007). In this study, 408 women underwent 836 cycles of IVF. The ongoing-pregnancy rate was significantly lower in the women assigned to preimplantation genetic screening (25%) than in those not assigned to PGS (37%). The women assigned to preimplantation genetic screening also had a significantly lower live-birth rate (24% vs. 35%). A prior Cochrane review had concluded that available data on preimplantation testing for advanced maternal age showed no difference in live birth rate and ongoing pregnancy rates (Twisk et al, 2006).
2008-9 Update
The policy was updated based on a literature search using MEDLINE through February 2009. Since the last update, a number of randomized trials of preimplantation genetic screening have been published and results of the studies have been summarized.
In an editorial commentary, Fritz reviews 5 trials examining the impact of preimplantation genetic screening on outcomes in women of advanced maternal age and 4 trials in patients having a generally good prognosis, and notes that all studies have failed to demonstrate any clear benefit for preimplantation genetic screening (Fritz, 2008). Fritz comments that while preimplantation genetic screening should work, after a decade of experience there is no substantive evidence to indicate that it does work. Possible reasons for these findings include potential adverse effects of biopsy on implantation or developmental potential, transfer of presumed normal embryos that were aneuploid for one or more chromosomes that were not analyzed, and misdiagnoses due to interpretation errors or due to mosaicism. The commentary concludes that lack of technical prowess does not explain these findings.
In a second editorial commentary, Fauser notes that none of the reported randomized controlled trials (RCTs) demonstrate a benefit with preimplantation genetic screening, whereas 2 studies suggest worse outcomes. He notes that well-designed studies failed to demonstrate a clinical benefit of preimplantation genetic screening in IVF (Fauser, 2008). Issues that need to be addressed, in this author’s view, include better understanding of mosaicism, improving preimplantation genetic screening related to studying all chromosomes in a reliable manner, and determining the optimal timing for removal of one or more cells.
Summary of this evidence further supports a late 2007 practice committee opinion issued by the American Society for Reproductive Medicine. This opinion concluded that available evidence did not support the use of preimplantation genetic screening as currently performed to improve live birth rates in patients with advanced maternal age, previous implantation failure, or recurrent pregnancy loss, or to reduce miscarriage rates in patients with recurrent pregnancy loss related to aneuploidy.
2012 Update
A literature search was conducted through July 2012. There was no new information identified that would prompt a change in the coverage statement.
2013 Update
A literature search was conducted using the MEDLINE database through July 2013. There was no new literature identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
A 2013 study by Scriven and colleagues in the United Kingdom evaluated PGD for couples carrying reciprocal translocations (Scriven, 2013). This prospective analysis included the first 59 consecutive couples who completed treatment at a single center. Thirty-two out of the 59 couples (54%) had a history of recurrent miscarriages. The 59 couples underwent a total of 132 cycles. Twenty-eight couples (47%) had at least one pregnancy, 21 couples (36%) had at least 1 live birth and 10 couples (36%) had at least one pregnancy loss. The estimated live birth rate per couple was 30 of 59 (51%) after 3 to 6 cycles. The live birth rate estimate assumed that couples who were unsuccessful and did not return for additional treatment would have had the same success rate as couples who did return.
Beukers and colleagues reported morphological abnormalities in surviving children at 2 years Beukers, 2013). Data were available on 50 children born after PGS and 72 children born without PGS. Fourteen out of 50 children (28%) in the PGS group and 25 of 72 children (35%) in the group that did not receive PGS had at least one major abnormality; the difference between groups was not statistically significant, p=0.43. Skin abnormalities (e.g., capillary hemangioma and hemangioma plana) were the most common, affecting 5 children after PGS and 10 children in the non-PGS group. In a control group of 66 age-matched children born without assisted reproduction, 20 children (30%) had at least one major abnormality. Developmental outcomes at 2 and 4 years have also been reported. In 2013, Schendelaar and colleagues reported on outcomes when children were 4 years-old (Schendelaar, 2013). Data were available on 49 children (31 singletons, 9 sets of twins) born after IVF with PGS and 64 children (42 singletons, 11 sets of twins) born after IVF without PGS. The primary outcome of this analysis was the child’s neurological condition, as assessed by the fluency of motor behavior. The fluency score ranged from 0 to 15 and is a sub-scale of the neurological optimality score (NOS). In the sample as a whole, and among singletons, the fluency score did not differ among children in the PGS and non-PGS groups. However, among twins, the fluency score was significantly lower among those in the PGS group (mean score: 10.6, 95% CI: 9.8 to 11.3) and non-PGS group (mean score: 12.3, 95% CI: 11.5 to 13.1). Cognitive development, as measured by IQ score, and behavioral development, as measured by the total problem score, were similar between non-PGS and PGS groups.
In 2013, Rubio and colleagues published findings of 2 RCTs evaluating PGS (Rubio, 2013). Studies’ designs were similar, but one included women of advanced maternal age (41-44 years-old) and the other included couples younger than 40 years-old with repetitive implantation failure (RIF), defined as failing 3 or more previous attempts at implantation. All couples were infertile and did not have a history of pregnancy or miscarriage with chromosomal abnormality. In all cases, blastocysts were transferred at day 5. In the groups receiving PGS, single-cell biopsies were done at the cleavage stage. A total of 91 patients enrolled in the RIF study (48 in the PGS group and 43 in the non-PGS group) and 183 patients in the advanced maternal age study (93 patients in the PGS group and 90 patients in the non-PGS group). Among RIF patients, the live birth rate did not differ significantly between groups. Twenty-three of 48 patients (48%) in the PGS group and 12 of 43 patients (28%) in the non-PGS groups had live births. (The exact p value was not provided). However, the live birth rate was significantly higher with PGS in the advanced maternal age study. Thirty of 93 patients (32%) in the PGS group and 14 of 90 patients (16%) in the non-PGS group had live births: The difference between groups was statistically significant, p=0.001.
In 2013, the Ethics Committee of the American Society for Reproductive Medicine published a committee opinion on use of PGD for serious adult onset conditions (ASRM, 2013). Main points include:
- "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.”
The committee opinion also stated that physicians and patients should be aware that much remains unknown about the long-term effects of embryo biopsy on the developing fetus and that experienced genetic counselors should be involved in the decision process.
2016 Update
A literature search conducted through November 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
A 2016 study Kato and colleagues included 52 couples with a reciprocal translocation (n=46) or Robersonian translocation (n=6) in at least 1 partner (Kato, 2016). All of the couples had a history of at least 2 miscarriages. The average live birth rate was 76.9% over 4.6 oocyte retrieval cycles. In the subgroups of young (<38 years) female carriers, young male carriers, older (≥38 years) female carriers and older male carriers, the live birth rate was 77.8%, 72.7%, 66.7% and 50.0%, respectively.
In 2015, Chow and colleagues reported on 124 cycles of PGD in 76 couples with monogenetic diseases (x-linked recessive, autosomal recessive or autosomal dominant) (Chow, 2015). The most common genetic conditions were alpha-thalassemia (64 cycles) and beta-thalassemia (23 cycles). Patients were not required to have a history of miscarriage. A total of 92 PGD cycles resulted in embryo transfer, with an ongoing pregnancy rate (beyond 8-10 weeks of gestation) in 28.2% of initiated cycles and an implantation rate of 35%. The live birth rate was not reported.
In a subsequent meta-analysis, Dahdouh and colleagues pooled findings of the above 3 RCTs (Dahdouh, 2015). Primary outcomes of the meta-analysis were implantation rates and ongoing pregnancy rates (ie, beyond 20 weeks). In pooled analyses, rates of both primary outcomes were significantly higher after use of the newer PGS techniques compared with standard care without PGS. For clinical implantation rate, there was a risk ratio [RR] of 1.29 (95% CI: 1.15 to 1.45). When findings on sustained implantation rate were pooled, RR: 1.30, 95% CI: 1.21 to 1.60. The meta-analysis did not address the live birth rate or adverse obstetric outcomes.
Another 2015 meta-analysis on newer PGS methods was published by Chen and colleagues (Chen, 2015). Four RCTs and 7 cohort studies were identified. In addition to the 3 RCTs described in Table 1, Chen et al included a 2012 that used SNP microarray analysis. A pooled analysis of the 4 RCTs found a significantly higher implantation rate with PGS than control (RR: 1.32, 95% CI: 1.18 to 1.47). However, in pooled analysis of RCTs, other outcomes were not significantly better with PGS than control. For example, for the ongoing pregnancy rate, a pooled analysis of 2 RCTs had an RR: 1.31, 95% CI: 0.64 to 2.66. Two RCTs reporting the miscarriage rate were included in a meta-analysis ((RR: 0.53: 95% CI: 0.24 to 1.15). Meta-analyses of the cohort studies found significantly improved ongoing pregnancy rates (RR: 1.61, 95% CI: 1.30 to 2.00, 6 studies) and miscarriage rates (RR: 0.31, 95% CI: 0.21 to 0.46, 5 studies), but not live birth rate (RR: 1.35, 95% CI: 0.85 to 2.13, 3 studies). The cohort studies are subject to limitations such as selection bias.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below:
Ongoing
(NCT02265614) PGS Using Microarray in IVF Patients with Repeated Implantation Failure; planned enrollment 130; projected completion date June 2016, recruiting patients in July 2016 status).
2017 Update
A literature search conducted using the MEDLINE database through November 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2017, Hasson et al published a meta-analysis of studies comparing obstetric and neonatal outcomes after intracytoplasmic sperm injection without PGD compared with intracytoplasmic sperm injection with PGD (Hasson, 2017). Studies focused on cases in which there were known parental genetic aberrations. Reviewers identified 6 studies, including data published by the investigators in the same article. Pooled analysis found no significant differences between the 2 groups for 4 of the 5 reported outcomes: mean birth weight, mean gestational age at birth, the rate of preterm delivery, and the rate of malformations. There was a significantly lower rate of low birth weight neonates (<2500 g) in the PGD group than in the non-PGD group (relative risk [RR], 0.84; 95% confidence interval [CI], 0.72 to 1.00; p=0.04).
In 2017, Rubio et al published a randomized controlled trial (RCT) comparing outcomes in women of advanced maternal age who underwent PGD for aneuploidy before blastocyst transfer compared with blastocyst transfer without PGD (Rubio, 2017). The trial included women between 38 and 41 years old with normal karyotypes who were on their first or second cycle of intracytoplasmic sperm injection. A total of 138 patients were randomized to the PGD group and 140 to the non-PGD control group. Of these, 100 patients in the PGD group and 105 in the non-PGD group completed the intervention. In an intention-to-treat analysis, there was a significantly higher live birth rate in the PGD group (31.9%) than in the control group (18.6%; odds ratio [OR], 2.4; 95% CI, 1.3 to 4.2; p=0.003). In the per-protocol analysis, there was a
significantly higher rate of live birth in the PGD group than in the control group, both in the per transfer and per patient analyses. Per transfer, there were live births in 65% of the PGD group and 27% of the control group (OR=4.86; 95% CI, 2.49 to 9.53; p<0.001). Per patient, there were live births in 44% of the PGD group and 25% of the control group (OR=2.39; 95% CI, 1.32 to 4.32; p=0.005). In addition, the implantation rate was significantly higher in the PGD group (53%) than in the control group (43%; p<0.001) and the miscarriage rate was significantly lower in the PGD group (3%) than in the control group (39%; p=0.007).
2018 Update
A literature search was conducted through November 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
PRACTICE GUIDELINES AND POSITION STATEMENTS
American Society for Reproductive Medicine
The American Society for Reproductive Medicine issued an opinion on the use of preimplantation genetic testing (PGS) for aneuploidy in 2018 which was informed by a literature search for relevant trials. The committee concluded that “The value of preimplantation genetic testing for aneuploidy as a universal screening test for all IVF patients has yet to be determined” (ASRM, 2018).
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Natsuaki et al conducted a systematic review with meta-analysis to assess pregnancy and child development outcomes after the preimplantation genetic screening (Natsuaki, 2018). They included 26 studies (n=6192 women) for the clinical pregnancy outcome. Due to heterogeneity, a random-effects model was used in the analysis. Across all effect sizes, the average risk ratio (RR) suggested no statistically significant difference in pregnancy rates between embryos that had preimplantation genetic diagnosis or screening (PGD/S; RR = 1.08; 95% CI, 0.95 to 1.23; P =.24). No significant difference was found between mothers younger than 35 years and those 35 or older who had PGD/S (RR = 0.88; 95% CI, 0.61 to 1.26; P =.48). The screening method used—comprehensive chromosome testing vs FISH—also produced no significant differences in reporting a clinical pregnancy (RR = 0.80; 95% CI, 0.56 to 1.14; P =.22). Nineteen studies (n=4439 women) examined live birth rates and found that undergoing PGD/S made no significant difference in outcome (RR = 1.02; 95% CI, 0.85 to 1.24; P =.80). However, for live births, comprehensive chromosome testing was significantly favorable over FISH (RR = 0.61; 95% CI, 0.38 to 0.98; P =.03). Evidence from the 18 studies that assessed child development (up to age 9) suggested no significant differences in the areas of anthropometric, psychomotor, cognitive, or behavioral development; neurological functioning; or parent-child relationships between children who were conceived after PGD/S vs no genetic testing.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Several RCTs have been published (Yang, 2012; Forman, 2013; Scott, 2013; Rubio, 2017; Verpoest, 2018; Munne, 2019). Four trials conducted embryo biopsies on day 5 or 6 of development while the Rubio et al trial performed a biopsy in the PGS group on day 3. Two trials (Yang et al and Rubio et al) used aCGH, 2 used quantitative PCR, 1 (Verpoest et al) used comprehensive chromosome screening, and 1 used next-generation sequencing (NGS) (Veriseq PGS). The majority of trials did not target women of advanced maternal age or women with repeated implantation failure. Instead, the majority of trials targeted good prognosis patients. For example, Yang et al included good prognosis patients younger than age 35 with no history of spontaneous abortion, Forman et al included women younger than age 43, and Scott et al included women between the ages of 21 and 42 years with no more than 1 failed IVF attempt. The Rubio et al and Verpoest et al trial did target women of advanced maternal age (36-41 years). One of the trials (Forman et al) transferred 1 embryo in the intervention group and 2 embryos in the control group, which might have introduced bias. The majority of studies were superiority trials. Forman et al was a noninferiority trial using a 20% noninferiority margin.
Results were mixed for all outcomes reported across studies. Pregnancy rates were higher in 2 of the 6 RCTs with PGS compared with the control group. The pregnancy rate in PGS was 37% in the study including women of advanced maternal age and from 70% to 90% in the studies including good prognosis couples. Findings were mixed across 3 studies (Yang et al, Forman et al, and Munne et al) reporting ongoing pregnancy rate (≥ 20 or 24 weeks gestation). Yang et al reported higher rates in the PGS group compared with control (71% vs 46%) (Yang, 2012). Forman et al reported lower rates in the PGS group (61% vs 65%) but with a CI for the risk difference that excluded the noninferiority margin (Forman, 2013). Munne et al reported similar (50.0% versus 45.7%) ongoing pregnancy rates (≥ 20 weeks gestation) for NGS-based PGS versus morphology in good-prognosis patients (Munne, 2019). But, in Munne et al, in the subgroup of 267 women aged 35 to 40 years, NGS-based PGS improved ongoing pregnancy rates (50.8% versus 37.2%; P=.0349). Scott et al reported a statistically significantly higher delivery rate in the PGS compared with control (85% vs 68%). Similarly, Rubio et al reported a statistically significant higher live birth rate (32% vs 19%). None of the studies provided justification for clinically meaningful improvements in the outcomes reported. Few neonatal or postdelivery outcomes were reported.
In 2020, the American College of Obstetricians and Gynecologists issued Committee Opinion #799 on Preimplantation Genetic Testing (ACOG, 2020). Recommendations are as follows:
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A number of RCTs evaluating preimplantation genetic screening using FISH-based technology have been published, and these findings have been summarized in several systematic reviews and a meta-analysis. The most recent and comprehensive meta-analysis was a Cochrane review by Cornelisse et al, which included RCTs comparing participants undergoing IVF with preimplantation genetic testing for aneuploides (PGT-A) versus IVF without PGT-A (Cornelisse, 2020). A total of 13 trials were included (N=2794 women), of which 11 used FISH for the genetic analysis. The Cochrane review also included 2 studies that used genome-wide analysis (Verpoest et al 2018 and Munne et al 2019); however, pooled analyses were not performed due to heterogeneity in testing methods, and each study is discussed separately later in this review. Of the 13 included RCTs, studies included patients with advanced maternal age (n=7 studies) and repeated IVF failure (n=3 studies), as well as good prognosis patients (n=5 studies). In a pooled analysis of RCTs using FISH for genetic analysis, live birth rate after the first embryo transfer was lower in patients undergoing PGT-A compared to the control group (odds ratio [OR], 0.62; 95% CI, 0.43 to 0.91; 10 RCTs; n=1680; I2=54%). No difference in miscarriage rate per woman randomized was observed between PGT-A and control groups (OR, 1.03; 95% CI, 0.75 to 1.41; 10 RCTs; n=1680; I2=16%); however rate of miscarriage per clinical pregnancy was reduced in the control group (OR, 1.77; 95% CI, 1.10 to 2.86; 5 RCTs, n=288; I2=45%). Only 1 study utilizing FISH evaluated cumulative live birth rate per woman, which did not detect a difference in patients undergoing PGT-A compared with the control (OR, 0.59; 95% CI, 0.35 to 1.01; 1 RCT; n=408). Ongoing pregnancy rate (OR, 0.68; 95%0.51 to 0.90; 5 RCTs; n=1121; I2=60%) and clinical pregnancy rate (OR, 0.60; 95% CI, 0.45 to 0.81; 5 RCTs; n=1131; I2=0%) were also reported to be lower in patients undergoing PGT-A compared with the control group. The authors noted a risk of publication bias, a limited quantity of studies and events, inconsistency in estimates between studies, and high heterogeneity for certain analyses (considered I2 >50).
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Shi et al conducted a systematic review and meta-analysis of 9 RCTs (N=2113) evaluating IVF with or without PGT-A in women of advanced maternal age (Shi, 2021). Six of the included trials used FISH-based technology while comprehensive chromosomal screening was applied in 3 trials. Overall, PGT-A did not improve the live birth rate (risk ratio [RR], 1.01; 95% CI, 0.75 to 1.35); however, when the analysis was limited to the 3 trials evaluating comprehensive chromosomal screening (see Rubio et al 2017,, Verpoest et al 2018,, and Munne et al 2019 trials) the live birth rate was significantly higher in those randomized to IVF with PGT-A than those without PGT-A (RR, 1.30; 95% CI, 1.03 to 1.65). Clinical pregnancy and miscarriage rates were not significantly different between those receiving PGT-A and those without in the general population or subgroups. Although live birth rates were improved in advanced maternal age patients using comprehensive chromosomal screening for PGT-A, studies assessing the overall benefit of PGT-A with newer screening methods are needed.
In a meta-analysis limited to PGT-A with comprehensive chromosomal screening conducted on day 3 or day 5, Simopoulou et al identified 11 RCTs (Simopoulou, 2021). In the overall population PGT-A did not improve live birth rates (RR 1.11; 95% CI, 0.87 to 1.42; 6 trials; n=1513; I2=75%). However, in a subgroup of patients over 35 years of age, live birth rates improved with PGT-A (RR 1.29; 95% CI, 1.05 to 1.60; 4 trials; n=629). Clinical pregnancy rates were also not significantly improved in the overall population (RR 1.14; 95% CI, 0.95 to 1.37; 9 trials; n=1824); however, miscarriage rates were improved with PGT-A (RR 0.36; 95% CI, 0.17 to 0.73; 7 trials; n=912). The authors concluded that PGT-A with comprehensive chromosomal screening did not generally improve outcomes, but when performed on blastocyst stage embryos in women over 35 years of age live birth rates were improved.
Several RCTs evaluating comprehensive chromosomal screening in patients undergoing PGT-A have been published and are included in the above systematic reviews (Yang, 2012; Forman, 2013; Scott, 2013; Verpoest, 2018; Munne, 2019; Rubio, 2017). One additional RCT was published in 2021 and was not incorporated in the above reviews (Yan, 2021)., Two trials (Yang et al and Rubio et al) used array comparative genetic hybridization, 2 used quantitative PCR, 1 (Verpoest et al) used comprehensive chromosome screening, and 2 used next-generation sequencing (Munne et al and Yan et al). The majority of trials did not target women of advanced maternal age or women with repeated implantation failure. Instead, the majority of trials targeted good prognosis patients. For example, Yan et al included good prognosis patients undergoing their first IVF and who were 20 to 37 years of age, Yang et al included good prognosis patients younger than age 35 with no history of spontaneous abortion, Forman et al included women younger than age 43, and Scott et al included women between the 21 and 42 years of age with no more than 1 failed IVF attempt. The Rubio et al and Verpoest et al trials did target women of advanced maternal age (36 to 41 years). One of the trials (Forman et al) transferred 1 embryo in the intervention group and 2 embryos in the control group, which might have introduced bias. The majority of studies were superiority trials. Forman et al and Yan et al were noninferiority trials.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.
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Mol Cytogenet. May 02 2012; 5(1): 24. PMID 22551456 |
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