|MP 4.02.05||Preimplantation Genetic Testing|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/7:2013
|Return to Medical Policy Index|
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Preimplantation genetic testing (PGT) involves analysis of biopsied cells as part of an assisted reproductive procedure. It is generally considered to be divided into two categories. Preimplantation genetic diagnosis (PGD) is used to detect a specific inherited disorder and aims to prevent the birth of affected children in couples at high risk of transmitting a disorder. Preimplantation genetic screening (PGS) uses similar techniques to screen for potential genetic abnormalities in conjunction with in vitro fertilization for couples without a specific known inherited disorder.
Preimplantation genetic testing (PGT) describes a variety of adjuncts to an assisted reproductive procedure (see policy No. 4.02.04) 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 alternative to amniocentesis or chorionic villus sampling (CVS), with selective pregnancy termination of affected fetuses. Preimplantation genetic testing is generally categorized as either diagnostic (PGD) or screening (PGS). 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. PGS is not used to detect a specific abnormality but instead uses similar techniques to identify genetic abnormalities to identify embryos at risk. This terminology, however, is not used consistently e.g., some authors use the term preimplantation genetic diagnosis when testing for a number of possible abnormalities in the absence of a known disorder.
Biopsy for PGD can take place at 3 stages; the oocyte, the 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 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 6-8 cells (i.e., 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, if 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 disorder such as Tay-Sachs disease or cystic fibrosis. Fluorescent in situ hybridization (FISH) is a technique that allows direct visualization of specific (but not all) 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 (such as microdeletions and duplications) and thus, single-gene defects can be recognized with this technique.
Another approach that is becoming more common is array comparative genome hybridization testing at either the 8-cell or more often, the blastocyst stage. Unlike FISH analysis, this allows for 24 chromosome aneuploidy screening, as well as more detailed screening for unbalanced translocations and inversions and other types of abnormal gains and losses of chromosomal material.
Next-generation sequencing such as massively parallel signature sequencing has potential applications to prenatal genetic testing, but use of these techniques is in a relatively early stage of development compared to other methods of analyzing biopsied material. (1, 2)
Three general categories of embryos 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 PGD 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, PGD is used to deselect male embryos, half of which would be affected. PGD 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, beta thalassemia, muscular dystrophy, Huntington's disease, hemophilia, and fragile X disease. It should be noted that when PGD is used to deselect affected embryos, the treated couple is not technically infertile but is undergoing an assisted reproductive procedure for the sole purpose of PGD. In this setting, PGD may be considered an alternative to selective termination of an established pregnancy after diagnosis by amniocentesis or chorionic villus sampling.
2. 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. PGD can be used to deselect those embryos carrying the translocations, thus leading to an increase in fecundity or a decrease in the rate of spontaneous abortion.
3. Identification of aneuploid embryos
Implantation failure of fertilized embryos is a common cause for failure of 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, PGS of the extruded polar bodies from the oocyte has been explored as a technique to deselect aneuploid oocytes in older women. The FISH technique is most commonly used to detect aneuploidy.
Preimplantation genetic diagnosis (PGD) may be considered medically necessary as an adjunct to in vitro fertilization (IVF) in couples not known to be infertile who meet one of the following criteria:
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
- 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
- One partner is a known carrier of a single-gene autosomal dominant disorder
- One partner is a known carrier of a single X-linked disorder, or
For evaluation of an embryo at an identified elevated risk of structural chromosomal abnormality,.., such as for a
- Parent with balanced or unbalanced chromosomal translocation
Preimplantation genetic diagnosis (PGD) as an adjunct to IVF is considered investigational in patients/couples who are undergoing IVF in all situations other than those specified above.
Preimplantation genetic screening (PGS) as an adjunct to IVF is considered investigational in patients/couples who are undergoing IVF in all situations.
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.
The severity of the genetic disorder is also a consideration. At the present time, many cases of preimplantation genetic diagnosis (PGD) have involved lethal or severely disabling conditions with limited treatment opportunities, such as Huntington's chorea or Tay-Sachs 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.
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. As appropriate, specific codes from the CPT molecular pathology section (81200-81479) or molecular cytogenetics section (88271-88275) would be reported.
BlueCard/National Account Issues
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.
This policy was originally created in 1998 and was updated regularly with searches of the MEDLINE database. The most recent literature search was performed for the period May 2012 through June 10, 2013.
Note: The complicated technical and ethical issues associated with preimplantation genetic testing (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 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 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 embryos.
Following is a summary of the key literature to date.
Preimplantation Genetic Diagnosis (PGD)
PGD has been shown to be a feasible technique to detect genetic defects and to deselect affected embryos. Recent reviews continue to state that PGD, using either polymerase chain reaction (PCR) or fluorescent in situ hybridization (FISH), can be used to identify numerous single gene disorders and unbalanced chromosomal translocation. (3, 4) According to the most recent data from a PGD registry initiated by the European Society of Hormone Reproduction and Embryology (ESHRE) in 1997, the most common indications for PGD were thalassemia, sickle cell syndromes, cystic fibrosis, spinal muscular disease, and Huntington’s disease. (5)
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 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. (Guidance is provided in the Policy Guidelines section.)
Efficacy and Safety
Preimplantation genetic diagnosis with in vitro fertilization in couples not known to be infertile
An 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 in vitro fertilization (IVF) cycles required to achieve pregnancy or a live birth? There is a lack of direct evidence comparing IVF success rates with and without PGD. A rough estimate can be obtained by comparing data from the Centers for Disease Control and Prevention (CDC) on IVF success rates overall and ESHRE registry data reporting on success rates after PGD. The most recent CDC data were collected in 2010. (6) Using fresh embryos from nondonor eggs, the percentage of cycles resulting in pregnancies was 47.6% for women younger than 35 years-old, 38.8% for women aged 35-37 and 29.9% for women aged 38-40. (These 3 age groups comprised approximately 85% of cycles.) The percentage of cycles resulting in live births was 41.5% for women younger than 35 years-old, 31.9% for women aged 35-37, and 22.1% for women aged 38-40. According to ESHRE data from 2007, with PGD the clinical pregnancy rate was 23% per oocyte retrieval and 32% per embryo transfer. (5) The delivery rate was 19% per oocyte retrieval and 26% per embryo transfer. Although this comparison only provides a very rough estimate, 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 PGT itself on rate of clinical pregnancy or live birth. It is important to note that 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. (7) All preimplantation genetic diagnoses 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., cystic fibrosis, 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. In 2011, Franssen and colleagues published a systematic review of literature on reproductive outcomes in couples with recurrent miscarriage (at least 2) who had a known structural chromosome abnormality; the review compared live birth rates after PGD or natural conception. (8) No controlled studies were identified. The investigators identified 4 observational studies on reproductive outcome in 469 couples after natural conception and 21 studies on reproductive outcome of 126 couples after PGD. The live birth rate per couple ranged from 33-60% (median 55.5%) after natural conception and between 0 and 100% (median 31%) after PGD. Miscarriage rate was a secondary outcome. After natural conception, miscarriage rates ranged from 21% to 40% (median 34%) and after PGD, miscarriage rates ranged from 0 to 50% (median 0%). Findings of this study apply only to couples with both recurrent miscarriage and a known structural chromosome abnormality.
Several additional studies have been published since the 2011 systematic review. In 2012, Keymolen and colleagues in Belgium reported clinical outcomes of 312 cycles performed for 142 couples with reciprocal translocations. (9) Data were collected at one center over 11 years. Seventy-five of 142 couples (53%) had PGD due to infertility, 40 couples (28%) due to a history of miscarriage, and the remainder due to a variety of other reasons. Embryo transfer was feasible in 150 of 312 cycles and 40 women had a successful singleton or twin pregnancy. The live birth rate per cycle was thus 12.8% (40 of 312), and the live birth rate per cycle with embryo transfer was 26.7% (40 of 150). A 2013 study by Scriven and colleagues in the United Kingdom evaluated PGD for couples carrying reciprocal translocations. (10) 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.
No studies were identified that specifically addressed PGD for evaluation of embryos when parents have a history of aneuploidy in a previous pregnancy.
Section summary: Studies have shown that PGD for evaluation of an embryo at identified risk of a genetic disorder or structural chromosomal abnormality is feasible and does not appear to increase the risk of obstetric complications, including fetal malformations related to the biopsy procedure.
Preimplantation Genetic Screening (PGS) With In Vitro Fertilization
A number of randomized controlled trials (RCTs) and several meta-analyses on PGS have been published. Meta-analyses have included studies using PGS for a variety of indications. In 2009, Checa and colleagues identified 10 trials with a total of 1,512 women. (11) PGS was performed for advanced maternal age in 4 studies, for previous failed IVF cycles in 1 study, and for single embryo transfer in 1 study; the remaining 4 studies included the general IVF population. A pooled analysis of data from 7 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 8 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. (12) The investigators included RCTs that compared the live birth rate in women undergoing IVF with and without PGS for aneuploidies. Fourteen potential trials were identified; 5 trials were excluded after detailed inspection, leaving 9 eligible trials with 1,589 women. All trials used FISH to analyze the aspirated cells. Five trials included women of advanced maternal age, 3 included “good prognosis” patients, and 1 included women with repeated implantation failure. When data from the 5 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 3 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.
Several of the recent trials on PGS are summarized below.
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 maternal age (aged 35 through 41 years). (13) 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). Beukers and colleagues reported morphological abnormalities in surviving children at 2 years. (14) 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. (15) 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: 9.8-11.3) and non-PGS group (mean score: 12.3, 95% CI: 11.5-13.1). 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. (16) 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.
Debrock and colleagues published a trial in 2010 that included women of advanced maternal age (at least 35 years) who were undergoing in vitro fertilization. (17) Randomization was done by cycle; 52 cycles were randomized to a PGS group and 52 to a control group that did not undergo PGS. Cycles were excluded if 2 or fewer fertilized oocytes were available on day 1 after retrieval or if 2 or fewer embryos of 6 or more cells were available on day 3. 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 7 of 47 (14.9%) in the PGS group and 10 of 49 (20.4%) in the control group, p=0.60.
Section summary: Most RCTs and meta-analyses of RCTs tended to find similar or lower ongoing pregnancy and/or live birth rates after IVF with PGS compared to IVF without PGS. One recent RCT found a significantly higher live birth rate after IVS with PGS among women of advanced maternal age and no significant difference between groups among couples with repeated implantation failure. There is a lack of consistent evidence of benefit of PGS.
Preimplantation genetic testing 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 preimplantation genetic diagnosis 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 preimplantation genetic diagnosis (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 in vitro fertilization (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 policy statements, 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 a lack of consistent evidence from RCTs that preimplantation genetic screening improves ongoing and live birth rates in any patient population. Thus, preimplantation genetic screening as an adjunct to in vitro fertilization is considered investigational.
Practice Guidelines and Position Statements
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. (18) 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.
In 2009, the American College of Obstetricians and Gynecologists (ACOG) issued an opinion on preimplantation genetic screening for aneuploidy. (19) They state that current data do not support the use of preimplantation genetic screening to screen for aneuploidy due solely to maternal age. ACOG also does not recommend PGS for recurrent unexplained miscarriage and recurrent implantation failures in the clinical setting; they recommended that use be limited to research studies.
A 2007 practice committee opinion issued by the American Society for Reproductive Medicine 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. (20)
Medicare National Coverage
No national coverage determination.
- Treff NR, Fedick A, Tao X et al. Evaluation of targeted next-generation sequencing-based preimplantation genetic diagnosis of monogenic disease. Fertil Steril 2013; 99(5):1377-84 e6.
- Martin J, Cervero A, Mir P et al. The impact of next-generation sequencing technology on preimplantation genetic diagnosis and screening. Fertil Steril 2013; 99(4):1054-61 e3.
- Chang LJ, Chen SU, Tsai YY et al. An update of preimplantation genetic diagnosis in gene diseases, chromosomal translocation, and aneuploidy screening. Clin Exp Reprod Med 2011; 38(3):126-34.
- Harper JC, Sengupta SB. Preimplantation genetic diagnosis: state of the art 2011. Hum Genet 2012; 131(2):175-86.
- Harper JC, Coonen E, De Rycke M et al. ESHRE PGD Consortium data collection X: cycles from January to December 2007 with pregnancy follow-up to October 2008. Hum Reprod 2010; 25(11):2685-707.
- Centers for Disease Control. Assisted Reproductive Technology: Success Rates: National Summary and Fertility Clinic Reports. 2009. Available online at: http://www.cdc.gov/art/ARTReports.htm. Last accessed June, 2013.
- Strom CM, Strom S, Levine E et al. Obstetric outcomes in 102 pregnancies after preimplantation genetic diagnosis. Am J Obstet Gynecol 2000; 182(6):1629-32.
- Franssen MT, Musters AM, van der Veen F et al. Reproductive outcome after PGD in couples with recurrent miscarriage carrying a structural chromosome abnormality: a systematic review. Hum Reprod Update 2011; 17(4):467-75.
- Keymolen K, Staessen C, Verpoest W et al. Preimplantation genetic diagnosis in female and male carriers of reciprocal translocations: clinical outcome until delivery of 312 cycles. Eur J Hum Genet 2012; 20(4):376-80.
- Scriven PN, Flinter FA, Khalaf Y et al. Benefits and drawbacks of preimplantation genetic diagnosis (PGD) for reciprocal translocations: lessons from a prospective cohort study. Eur J Hum Genet 2013.
- Checa MA, Alonso-Coello P, Sola I et al. IVF/ICSI with or without preimplantation genetic screening for aneuploidy in couples without genetic disorders: a systematic review and meta-analysis. J Assist Reprod Genet 2009; 26(5):273-83.
- Mastenbroek S, Twisk M, van der Veen F et al. Preimplantation genetic screening: a systematic review and meta-analysis of RCTs. Hum Reprod Update 2011; 17(4):454-66.
- Mastenbroek S, Twisk M, van Echten-Arends J et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med 2007; 357(1):9-17.
- Beukers F, van der Heide M, Middelburg KJ et al. Morphologic abnormalities in 2-year-old children born after in vitro fertilization/intracytoplasmic sperm injection with preimplantation genetic screening: follow-up of a randomized controlled trial. Fertil Steril 2013; 99(2):408-13.
- Schendelaar P, Middelburg KJ, Bos AF et al. The effect of preimplantation genetic screening on neurological, cognitive and behavioural development in 4-year-old children: follow-up of a RCT. Hum Reprod 2013; 28(6):1508-18.
- Rubio C, Bellver J, Rodrigo L et al. Preimplantation genetic screening using fluorescence in situ hybridization in patients with repetitive implantation failure and advanced maternal age: two randomized trials. Fertil Steril 2013; 99(5):1400-7.
- Debrock S, Melotte C, Spiessens C et al. Preimplantation genetic screening for aneuploidy of embryos after in vitro fertilization in women aged at least 35 years: a prospective randomized trial. Fertil Steril 2010; 93(2):364-73.
- Ethics Committee of the American Society for Reproductive M. Use of preimplantation genetic diagnosis for serious adult onset conditions: a committee opinion. Fertil Steril 2013; 100(1):54-7.
- ACOG Committee Opinion No. 430: preimplantation genetic screening for aneuploidy. Obstet Gynecol 2009; 113(3):766-7.
- Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril 2007; 88(6):1497-504.
Molecular pathology code range
|88271 - 88275||Molecular cytogenetics (i.e., FISH), code range|
|88384 - 88386||Array-based evaluation of multiple molecular probes, code range|
|89290 - 89291||Biopsy, oocyte polar body or embryo blastomere, microtechnique (for preimplantation genetic diagnosis), less than or equal to, or greater than 5 embryo(s), respectively|
Genetic counseling and testing
|ICD-10-CM (effective 10/1/14)||Z31.430; Z31.438||Encounter for genetic testing of female for procreative management; code list|
|Z31.440; Z31.448||Encounter for genetic testing of male for procreative management; code list|
|Z31.49||Encounter for other procreative investigation and testing|
|ICD-10-PCS (effective 10/1/14)||Not applicable. No ICD-10-PCS codes for laboratory tests.|
Type of Service
Place of Service
Preimplantation Genetic Diagnosis
|11/01/98||Add to OB/Gyn Reproduction||New policy|
|05/15/02||Replace policy||Policy updated; policy unchanged, but additional information provided regarding potential patient selection criteria if individual case consideration is considered|
|07/17/03||Replace policy||Policy revised; policy statement revised to indication that PGD may be considered investigational in certain situations, but individual consideration is still recommended|
|12/17/03||Replace policy||Policy updated with new 2004 CPT codes only|
|3/15/05||Replace policy||Policy updated with literature search; references added (26-29); no change in policy statement|
|03/7/06||Replace policy||Policy updated with literature review; no change in policy statement, reference numbers 26–28 added (references renumbered)|
|09/18/07||Replace policy||Policy updated with literatur review up to August 2007. Policy statement changed to indicate the PGD is not medically necessary in thos undergoing IVF for infertility with maternal age greater than 35 years. Policy statement modified to clarify medical necessity role in detecting both genetic and chromosomal abnormalities. Reference numbers 33 and 34 added.|
|05/14/09||Replace policy||Policy updated with literature search, references 34 – 36 added. Policy statements modified to reflect preimplantation genetic diagnosis (PGD) as medically necessary and preimplantation genetic screening (PGS) as investigational. “Diagnosis” replaced with “Testing” in title.|
|7/14/11||Replace policy||Policy updated with literature search through May 2011. Changes made to the policy statements for clarifications. New policy statement added that preimplantation genetic diagnosis is considered investigational in all situations other than those specified in the medically necessary policy statement. In addition, the phrase “in all situations” added to the policy statement on preimplantation genetic screening.|
|07/12/12||Replace policy||Policy updated with literature search through May 2011. . In Medically Necessary statement, parent with documented history of aneuploidy in a previous pregnancy added as example of reason for evaluating an embryo at elevated risk of chromosomal abnormality. References 1, 2, 3, 4, 6 and 7 added; other references renumbered or removed.|
|7/11/13||Replace policy||Policy updated with literature search through June 10, 2013. The following changes were made to the medically necessary statement: 1) Parent with documented history of aneuploidy in a previous pregnancy removed as example of reason for evaluating an embryo at elevated risk of chromosomal abnormality; 2) “otherwise fertile” couples changed to couples “not known to be infertile”; 3) “structural” was added to “chromosomal abnormality” for clarification; and 4) “e.g., unbalanced translocation” was removed because it was repetitive. References 1, 2, 10, 14-16, and 18 added; other references renumbered or removed|