Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.
NOTE: Carefully check the member’s benefit plan, summary plan description or contract for language specific to assisted reproductive technologies (ART) and related services (including, but not limited to, in vitro fertilization [IVF], preimplantation genetic diagnosis [PGD], etc.). If ART and its related services are determined to be eligible for member benefits then the following services that are listed as medically necessary should be considered for benefit coverage.
Preimplantation genetic diagnosis (PGD) may be considered medically necessary as an adjunct to in vitro fertilization (IVF) in couples who meet any one of the following criteria subject to careful consideration of the technical and ethical issues involved:
- For evaluation of an embryo at an identified elevated risk of a genetic disorder, such as when:
- Both partners are known carriers of a single-gene autosomal recessive disorder; or
- One partner is a known carrier of a single-gene autosomal recessive disorder and the partners have one offspring that has been diagnosed with that recessive disorder; or
- One partner is a known carrier of a single-gene autosomal dominant disorder; or
- One partner is a known carrier of a single X-linked disorder; OR
- For evaluation of an embryo at an identified elevated risk of chromosomal abnormality, e.g., unbalanced translocation, such as for a parent with balanced or unbalanced chromosomal translocation.
NOTE: It is recommended that the provider and patient should carefully consider the technical and ethical issues involved in preimplantation genetic testing (PGT).
Preimplantation genetic diagnosis (PGD) as an adjunct to IVF is considered experimental, investigational and unproven in patients or couples who are undergoing IVF in all situations other than those specified above.
Preimplantation genetic screening (PGS) as an adjunct to IVF is considered experimental, investigational and unproven in patients or couples who are undergoing IVF in all situations.
Diagnostic or screening preimplantation genetic testing (PGD or PGS) utilizing human leukocyte antigen (HLA) matching or other markers is considered not medically necessary to establish whether the embryo is a potential donor for a future stem cell transplantation.
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 83890-83913).
If the technique is performed to detect aneuploidy or translocations, CPT codes for molecular cytogenetics will be used (CPT codes 88271-88275).
This policy was originally created in 2013. The most recent literature search was performed through September 2011. Issues addressed in the literature review include the technical feasibility of preimplantation genetic testing (PGT) to deselect embryos for different indications and the impact of the procedure on implantation rates, pregnancy and birth outcomes. Following is a summary of the key literature to date.
Preimplantation genetic diagnosis (PGD) has been shown to be a feasible 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. However, this policy is not designed to perform a separate analysis on every possible genetic defect. Therefore, the determination of medical necessity will require a case by case approach to address the many specific technical and ethical considerations inherent in testing for 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 PGT has expanded to a broader variety of conditions that have not been considered as an indication for genetic testing via amniocentesis or chorionic villus sampling (CVS). The report of PGT 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 PGT 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.” A representative sample of case series and reports on the technical feasibility of PGT to deselect embryos for different indications follows.
The European Society of Hormone Reproduction and Embryology (ESHRE) created a registry for PGD. In 1999, the registry reported that PGD had been performed on 51 genetic defects with the most common diseases being cystic fibrosis (CF), beta thalassemia, myotonic dystrophy, muscular dystrophy (MD), hemophilia, and fragile X syndrome. In this database pre- and postnatal confirmation of PGD was performed in 70 of 110 (64%) of the conceptuses, either through amniocentesis, CVS, or genetic testing on the live-birth. Among these 70 conceptuses, there was one misdiagnosis, which was detected by an amniocentesis followed by pregnancy termination. These registry data suggest that PGD, using PCR or fluorescence in situ hybridization (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 CF. 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 atrophy, and phenylketonuria (PKU).
Efficacy and Safety
PGD with IVF in otherwise fertile couples:
An area of clinical concern is the impact of PGD on overall IVF success rates. For example, is the use of PGT 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 PGT associated with IVF based on these two data sources.
Although this table only provides a very rough estimate, the data suggest that use of PGT lowers the success rate of an IVF 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 PGT 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 represents couples who are not necessarily infertile but are undergoing IVF strictly for the purposes of PGD.
An 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 PGDs were confirmed postnatally; there were no diagnostic errors. The incidence of multiple gestations was similar to that seen with IVF. PGD did not appear to be associated with an increased risk of obstetric complications compared to the risk of obstetric outcomes reported in data for IVF. However, it should be noted that biopsy of the polar body is considered biopsy of 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., CF, sickle cell disease, and others).
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 one partner was known to carry a translocation. Of the 47 cycles of PGD, there were 13 completed or ongoing pregnancies. 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 two of which ended in spontaneous abortion. Prior to PGD, this same group of patients had 38 previous pregnancies, 35 of which ended in spontaneous abortion.
PGS with IVF:
Several meta-analyses of randomized controlled trials (RCTs) on PGS have been published. A meta-analysis published in 2009 by Checa and colleagues identified ten trials with a total of 1,512 women. PGS was performed for advanced maternal age in four studies, for previous failed IVF cycles in one study, and for single embryo transfer in one study; the remaining four studies included the general IVF population. A pooled analysis of data from seven trials (346 events) found a significantly lower rate of live-birth in the PGS group compared to the control group. The unweighted live-birth rates were 151 of 704 (21%) in the PGS group and 195 of 715 (27%) in the control group, p=0.003. Findings were similar in subanalyses including only studies of the general IVF population and only the trials including women in higher-risk situations. The continuing pregnancy rate was also significantly lower in the PGS group compared to the control group in a meta-analysis of eight trials. The unweighted rates were 160 of 707 (23%) in the PGS group and 210 of 691 (30%) in the control group, p=0.004. Again, findings were similar in subgroup analyses.
Another meta-analysis was published in 2011 by Mastenbroek and colleagues. They included RCTs that compared the live-birth rate in women undergoing IVF with and without PGS for aneuploidies. Fourteen potential trials were identified; five trials were excluded after detailed inspection, leaving nine eligible trials with 1,589 women. All trials used FISH to analyze the aspirated cells. Five trials included women of advanced maternal age, three included “good prognosis” patients, and one included women with repeated implantation failure. When data from the five studies including women with advanced maternal age were pooled, the live-birth rate was significantly lower in the PGS group (18%) compared to the control group (26%), p=0.0007. There was not a significant difference in live-birth rates when data from the three studies with good prognosis patients were pooled; rates were 32% in the PGS group and 42% in the control group, p=0.12. The authors concluded that there is no evidence of a benefit of PGS as currently applied in practice; they stated that potential reasons for inefficacy include possible damage from the biopsy procedure and the mosaic nature of analyzed embryos.
Technical and Ethical Issues
The complicated technical and ethical issues associated with PGT 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 PGD 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 penetrance, i.e., the probability that an individual with the mutation will express the associated disorder), 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, PGT 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 embyros.
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 Sachs disease. CF is another condition for which PGD has been frequently performed. However, CF 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. In some cases involving a single X-linked disorder, determination of the gender of the embryo provides sufficient information for excluding or confirming the disorder; thus guiding the couple in their decision making process.
Previous PGS Study Trials
In 2007, Mastenbroek et al., in an RCT, found that PGS reduced the rates of ongoing pregnancies and live-births after IVF in women of advanced (aged 35 through 41 years) maternal age. In this study, 408 women (206 assigned to PGD and 202 assigned to the control group) underwent 836 cycles of IVF (434 cycles with and 402 cycles without PGS). The ongoing pregnancy rate was significantly lower in the women assigned to PGS (52 of 206 women [25%]) than in those not assigned to PGS (74 of 202 women [37%]; rate ratio, 0.69; 95% confidence interval [CI]: 0.51–0.93). The women assigned to PGS also had a significantly lower live-birth rate (24% vs. 35%, respectively; rate ratio, 0.68; 95% CI: 0.50–0.92). In 2011, a follow-up study was published when surviving children were two years-old. Forty-nine pregnancies in the PGS group and 71 in the control group resulted in live-births of at least one child. Forty-five couples with 54 children (36 singletons and nine twins) in the PGS group and 63 couples with 77 children (49 singletons and 14 twins) in the control group were available for follow-up. The groups of children did not differ significantly in scores on an infant development scale and child development checklist variables. For example, median scores on the total Child Behavior Checklist were 43.0 among children born after PGS and 46.0 in control children, p=0.44. However, the neurologic optimality score (NOS) was significantly lower in the PGS group than the control group, p=0.20. In the PGS group, there were four children (7%) classified as having simple minor neurologic dysfunction (MND), two (4%) with complex MND and one (2%) with cerebral palsy. In the control group, three (4%) children had simple MND, one (1%) had complex MND, and there were no cases of cerebral palsy. Simple MND referred to the isolated presence of fine motor, gross motor of visuomotor dysfunction, or mild dysregulation of muscle tone and complex MND to dysfunction in two or more of these domains.
Debrock and colleagues, in Belgium, published a trial in 2010 that included women of advanced (at least 35 years) maternal age who were undergoing IVF to undergo PGS or implantation without PGS. Randomization was done by cycle; 52 cycles were randomized to the PGS group and 52 to the control group. Cycles were excluded if two or fewer fertilized oocytes were available on day one after retrieval or if two or fewer embryos of six or more cells were available on day three. Individuals could participate more than once, and there was independent randomization for each cycle. More cycles were excluded postrandomization in the control group; outcome data were available for 37 cycles (71%) in the PGS group and 24 cycles (46%) in the control group. Study findings did not confirm the investigators’ hypothesis that the implantation rate would be higher in the group receiving PGS. The implantation rate was 15.1% in the PGS group and 14.9% in the control group; p=1. Moreover, the live-birth rate per embryo transferred did not differ significantly between groups; rates were 9.4% in the PGS group and 14.9% in the control group; p=0.76. An intention-to-treat (ITT) analysis of all randomized cycles (included and excluded) did not find any significant differences in outcomes including the implantation rate which was 11 of 76 (14.5%) in the PGS group and 16 of 88 (18.2%) in the control group, p=0.67. In the ITT, the live-birth date per embryo transferred was seven of 47 (14.9%) in the PGS group and ten of 49 (20.4%) in the control group, p=0.60.
A randomized trial published in 2009 included good prognosis patients (similar to the general IVF population in the Checa et al. meta-analysis) undergoing IVF. This was defined as women with age younger than 39 years, normal ovarian reserve, body mass index (BMI) less than 30 kg/m2, presence of ejaculated sperm, normal uterus and no more than two previous failed IVF cycles. Women were randomly assigned to receive PGS (n=23) or implantation without PGS on day three (n=24) after oocyte retrieval. There was no significant difference between groups in PGS and control groups in terms of clinical pregnancy rate (52.4% vs. 72.7%, respectively). However, there was a significantly lower rate of embryo implantation in the PGS group than the control group (31.7% vs. 62.3%, respectively, p=0.004). There was also a significantly lower live-birth rate in the PGS group (28.6% vs. 68.2%, respectively, p=0.009). The investigators originally planned to enroll 100 women per group, but the study was terminated early because of results from a planned interim analysis.
In a 2008 editorial commentary, Fritz commented that while PGS should work, after a decade of experience, there is no substantive evidence to indicate that it does work. Possible reasons for this lack of benefit 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. In another commentary, Fauser noted that well-designed studies failed to demonstrate a clinical benefit of PGS in IVF. Issues that need to be addressed, in Fauser’s view, include better understanding of mosaicism, improving PGS related to studying all chromosomes in a reliable manner, and determining the optimal timing for removal of one or more cells.
Ongoing Clinical Trials for PGS and PGD
PGS in women of advanced maternal age (NCT00795795): This non-blinded RCT is comparing the outcome of IVF cycles with and without PGS among women of advanced maternal age (38-44 years). Primary outcomes are ongoing implantation per embryo and per patient. The study is being conducted in Spain and is sponsored by the Instituto Valenciano de Infertilidad. The estimated study completion date is December 2011.
Implantation failure and PGD (NCT00547781): This non-blinded RCT will include patients with repetitive implantation failure (at least two previous failures). It will compare standard IVF with day five transfer with and without PGD. PGD will include aneuploidy screening. The study is being conducted in Spain and is sponsored by the Instituto Valenciano de Infertilidad. The expected completion date for data collection is July 2011.
PGD by array comparative genome hybridization (CGH) (NCT01332643): This RCT is comparing single embryo transfer with and without array CGH. The treatment group will undergo embryo biopsy at the blastocyst stage (day five) and analysis of the biopsied cells with a comprehensive chromosome analysis technique. The primary outcome is implantation rate, and secondary outcomes include miscarriage rate and live-birth rate. To be included, women need to be between 35 and 42 years-old. The study is being conducted in Peru; the expected date of study completion is May 2012.
Efficacy of 24 chromosome preimplantation genetic diagnosis (NCT01219283): This is a RCT comparing embryo transfer with and without 24-chromosome PGD. Embryos in the treatment group will undergo biopsy at day five and two normal embryos will be transferred. In the control group, the two morphologically best embryos will be transferred. Inclusion criteria include attempting conception through IVF and a maximum of one prior failed IVF cycle. The study is being conducted at several centers in the United States. The expected date of study completion is July 2012.
Practice Guidelines and Position Statements on PGS
In 2009, the American College of Obstetricians and Gynecologists issued an opinion on PGS for aneuploidy. They state that current data do not support the use of PGS to screen for aneuploidy due solely to maternal age.
A 2007 practice committee opinion issued by the American Society for Reproductive Medicine concluded that available evidence did not support the use of PGS 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.
Practice Guidelines and Position Statements on PGT with IVF for Donor Suitability
In 2009, the American Academy of Pediatrics (AAP) issued an opinion on utilizing PGT with IVF to ensure an HLA matched donor of stem cells, either by umbilical cord blood donation or future stem cell donations, for a sibling requiring stem cell rescue due to a disease, such as leukemia. The parents often request PGD to be done simultaneously to the HLA matching to avoid the birth of a child with a similar genetic defect, such as Fanconi anemia. The AAP site a 2005 study of five PGD centers in four countries that have performed HLA genotyping in 180 IVF cycles. In 122, the goal was to avoid a genetic condition. But in 58 cycles, PGD was done solely for HLA typing. The AAP further expressed the following statement, “The willingness of health care professionals to collect cord blood for stem cells in the delivery room must be ensured before delivery, although the pregnant woman and couple must also understand that the health of both the newborn infant and the pregnant woman have priority and that peripartum events may preclude collection. To avoid exposing the newborn infant to any risks from the donation, the delivery should not be modified to maximize the number of cells collected.”
PGT 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. 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. 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 IVF alone. However, the alternative for couples at risk for single genetic defects is prenatal genetic testing, i.e., amniocentesis or CVS, with pregnancy termination contemplated for affected fetuses. (It should be noted that many patients undergoing PGD will also undergo a subsequent amniocentesis or CVS 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. Thus, PGD is considered medically necessary, as noted in the coverage, when the evaluation is focused on a known disease or disorder, and the decision to undergo PGD is made upon careful consideration of the risks and benefits. There is insufficient evidence that PGS improves ongoing pregnancy and live-birth rates; thus, PGS as an adjunct to IVF is considered experimental, investigational and unproven. Since PGD or PGS testing for HLA typing is not required for the maintenance of a healthy embryo, PGD with IVF is not medically necessary to determine if the healthy embryo is a suitable potential donor for a sibling requiring stem cell transplantation.
Disclaimer for coding information on Medical Policies
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.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.