Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Preimplantation Genetic Testing (Independence Administrators)

Policy #:06.02.24j

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.


This policy only applies to members for whom Independence Administrators serves as the claims administrator. For all other Independence members, refer to the policy entitled eviCore Lab Management Program.

The intent of this policy is to communicate the coverage positions for preimplantation genetic testing.

PREIMPLANTATION GENETIC DIAGNOSIS

MEDICALLY NECESSARY
PGD testing is considered medically necessary and, therefore, covered as an adjunct to in vitro fertilization (IVF) in otherwise fertile individuals/couples who meet at least 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 autosomal recessive gene (e.g., cystic fibrosis, phenylketonuria).
    • One partner is a known carrier of a single gene autosomal recessive disorder and the partners have one offspring that has been diagnosed with the recessive disorder (e.g., Tay-Sachs disease).
    • One partner is a known carrier of a single gene autosomal dominant disorder (e.g., myotonic dystrophy, neurofibromatosis, Huntington's chorea).
    • One partner is a known carrier of a single X-linked disorder (e.g., fragile X syndrome, hemophilia, Lesch-Nyhan syndrome, Fabry disease).
  • For evaluation of an embryo at an identified elevated risk for chromosomal abnormality (e.g., unbalanced translocation, microdeletion/duplication, aneuploidy) such as when:
    • One of the partners is known to harbor a balanced or unbalanced chromosomal translocation (i.e., a rearrangement of chromosome material with either no extra or missing material, or the exchange of chromosomal material is unequal, resulting in extra or missing genes).
    • Prior parental history of a child with aneuploidy or the change in the number of chromosomes that can lead to a chromosomal abnormality.

NOT MEDICALLY NECESSARY
PGD is considered not medically necessary and, therefore, not covered as an adjunct to IVF in individuals and/or couples undergoing IVF due to infertility when any of the following conditions are present:
  • When used as a substitute for usual genetic testing for women at higher risk based solely on maternal age (i.e., ovum used from mother or egg donor older than 35 years) when the medical necessity criteria stated above are not met.
  • There is no identified elevated risk of genetic disorder or chromosomal abnormality in the embryo (as stated in the above criteria).

EXPERIMENTAL/INVESTIGATIONAL
Preimplantation genetic diagnosis (PGD) as an adjunct to IVF in all other uses is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

PREIMPLANTATION GENETIC SCREENING

EXPERIMENTAL/INVESTIGATIONAL
Preimplantation genetic screening (PGS) as an adjunct to IVF is considered experimental/investigational and, therefore, not covered, for use due to advanced maternal age or in the absence of a known genetic or chromosomal defect because the safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the health care professional's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.
Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, preimplantation genetic diagnosis (PGD) testing is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in the medical policy are met. There are some procedures, (e.g., egg retrieval, IVF), and services associated with PGD testing that precede this testing, which require an infertility rider or mandate in order to be covered by the Company. Individual member benefits must be verified for these associated procedures and services.

However, services that are identified in this policy as not medically necessary or experimental/investigational are not eligible for coverage or reimbursement by the Company.

Description

Preimplantation genetic testing (PGT) involves analysis of biopsied cells used in an assisted reproductive procedure. PGT can be divided into two categories: preimplantation genetic diagnosis (PGD) and preimplantation genetic screening. The terminology is used inconsistently, however. PGD is sometimes used to test for specific abnormalities, as well as unknown abnormalities.

PREIMPLANTATION GENETIC DIAGNOSIS (PGD)

Preimplantation genetic diagnosis (PGD) testing describes a variety of adjuncts to an assisted reproductive procedure in which single-cell embryonic biopsies are obtained and deoxyribonucleic acid (DNA) material is retrieved and analyzed to determine if a defective gene is present. PGD testing identifies genetic defects prior to uterine implantation, which makes it a desirable alternative to the more invasive procedures typically performed to diagnose chromosomal abnormalities during pregnancy (e.g., chorionic villus sampling [CVS], genetic amniocentesis). If these studies reveal a genetic defect, the parent(s) are then faced with the decision of either having a child with a genetic disease or terminating the pregnancy.

PGD testing on single cells can diagnose specific, detectable single-gene mutations (e.g., molecular diagnosis of cystic fibrosis when parents are known mutation carriers). PGD testing also identifies sex-linked disorders (e.g., Rett syndrome, hemophilia, neuromuscular dystrophies), single gene defects (e.g., cystic fibrosis, Tay-Sachs disease, sickle cell anemia, Huntington disease), and chromosomal disorders (eg, DiGeorge syndrome, Down syndrome [Trisomy 21], Edwards syndrome [Trisomy 18]). However, PGD testing is unable to detect all genetic diseases, and it cannot determine if the embryo is at risk for developing birth defects unrelated to genetic mutation.

The biopsied material can be analyzed in a variety of ways. Polymerase chain reaction (PCR) or other amplification techniques are commonly used to analyze the harvested DNA 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 their number or absence. FISH is most commonly used to screen for aneuploidy, gender determination, or chromosomal translocations; it cannot be used to diagnose single gene defects.

The literature suggests that PGD testing for infertile couples may result in a reduction in the rate of spontaneous abortion. In addition, PGD testing has been shown to be technically feasible for identifying male and female embryos for deselection when a sex-linked mutation is present.

A study published in 2007 by Mastenbroek revealed findings on the use of PGD testing in 408 women of advanced maternal age (35-41 years of age) who were undergoing in vitro fertilization (IVF). The randomized, controlled trial found that PGD testing reduced the rates of ongoing pregnancies and live births after IVF in women of advanced maternal age. The study compared 206 women who were given PGD after IVF with 202 women who did not receive PGD following their IVF procedures. The ongoing-pregnancy rate was significantly lower in the women assigned to PGD testing (52 of 206 women [25 percent]) than in those not assigned to PGD testing (74 of 202 women [37 percent]; rate ratio, 0.69; 95 percent confidence interval [CI]: 0.51–0.93). The women assigned to PGD testing also had a significantly lower live-birth rate (24 percent vs. 35 percent; rate ratio, 0.68; 95 percent CI: 0.50–0.92). Based on this study, there is no medical benefit in performing PGD testing as an adjunct to IVF in women of advanced maternal age.

In October 2007, the Practice Committee of the American Society for Reproductive Medicine (ASRM) issued the new practice committee opinion on the use of PGD testing. A careful review of the published studies led the ASRM Practice Committee to conclude at this time that the available evidence does not support the use of PGD testing to improve live-birth rates in women with advanced maternal age, previous implantation failure, or recurrent pregnancy loss; or to reduce miscarriage rate in women with recurrent pregnancy loss related to aneuploidy. PGD is generally used by women who know they are at risk of transmitting a genetic disease or chromosomal abnormality to their offspring. The committee concluded that for couples at risk of having children with a heritable genetic disease, IVF with PGD testing represents a major scientific advance.

In 2013, the Ethics Committee of the American Society for Reproductive Medicine (ASRM) published a committee opinion on use of PGD for serious adult onset conditions. The main points included:
  • "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.”

This 2013 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.

PREIMPLANTATION GENETIC SCREENING (PGS)

Preimplantation genetic screening (PGS), unlike PGD, does not detect a specific abnormality, but uses similar techniques to identify genetic abnormalities that help identify embryos at risk or embryos without a known disorder. Several meta-analyses of randomized controlled trials (RCTs) on PGS have been published.

A meta-analysis published in 2009 by Checa and colleagues identified 10 trials with a total of 1,512 women. 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 combined 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 published in 2011 by Mastenbroek and colleagues reviewed RCTs that compared the live birth rate in women undergoing IVF with and without PGS for aneuploidies (a type of chromosome abnormality). 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 combined together, 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.

The American Society for Reproductive Medicine (ASRM) issued a 2007 practice committee opinion that 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.

In 2009 (reaffirmed 2014), the American College of Obstetricians and Gynecologists (ACOG) issued an opinion on PGS for aneuploidy. They stated that current data do not support the use of PGS to screen for aneuploidy due solely to maternal age. ACOG also did not recommend PGS for recurrent unexplained miscarriage and recurrent implantation failures in the clinical setting; they recommended that use be limited to research studies.

SUMMARY

Preimplantation genetic testing (PGT) involves analysis of biopsied cells as part of an assisted reproductive procedure. It is generally considered to be divided into 2 categories. Preimplantation genetic diagnosis (PGD) is used to detect a specific inherited disorders in couples at high risk of transmitting those disorders. Preimplantation genetic screening (PGS) involves screening for potential genetic abnormalities in conjunction with in vitro fertilization for couples without a specific known inherited disorder.

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 PGD procedure compared with in vitro fertilization (IVF) alone. However, the alternative for couples at risk for single genetic defects is prenatal genetic testing, i.e., amniocentesis or chorionic villus sampling (CVS), with pregnancy termination contemplated for affected fetuses. (It should be noted that many individuals 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 with the option of normal fertilization and pregnancy with the possibility of a subsequent elective abortion.

Initial PGS methods were not found to improve pregnancy and live birth rates. There is insufficient high-quality evidence that newer PGS methods improve the net health outcome (including ongoing pregnancy and live birth rates), particularly in the populations of greatest interest, namely, women of advanced maternal age, women with a history of repeated implantation failure, or in the absence of a known genetic or chromosomal defect.
References


ACOG Committee Opinion No. 430: Preimplantation genetic screening for aneuploidy. Obstet Gynecol. 2009; Reaffirmed 2014;113(3):766-767.

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):408-413.

Centers for Disease Control. Assisted Reproductive Technology: Success Rates: National Summary and Fertility Clinic Reports. February 2016. Available at: http://www.cdc.gov/art/ARTReports.htm. Accessed June 13, 2016.

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):126-134.

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):273-283.

Dahdouh EM, Balayla J, Garcia-Velasco JA. Impact of blastocyst biopsy and comprehensive chromosome screening technology on preimplantation genetic screening: a systematic review of randomized controlled trials. Reprod Biomed Online. 2015;30(3):281-289.

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):54-57.

FDA C, FTC,. Federal Regulation of Genetic Tests. Available at: http://www.genome.gov/10002335#al-3. Accessed June 13, 2016.

Forman EJ, Hong KH, Ferry KM, et al. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013;100(1):100-107.

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):467-475.

Harper JC, Coonen E, De Rycke M, et al. ESHRE PGD Consortium data collection X: cycles from January toDecember 2007 with pregnancy follow-up to October 2008. Hum Reprod. 2010;25(11):2685-2707.

Harper JC, Sengupta SB. Preimplantation genetic diagnosis: state of the art 2011. Hum Genet. 2012;131(2):175-186.

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):376-380.

Lee E, Illingworth P, Wilton L, et al. The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review. Hum Reprod. 2015;30(2):473-483.

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):1054-1061.

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.

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):454-466.

Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril. 2007;88(6):1497-1504.

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):1508-1518.

Scott RT, Jr., Upham KM, Forman EJ, et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril. 2013;100(3):697-703.

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;21(10):1035-41.

Strom CM, Strom S, Levine E, et al. Obstetric outcomes in 102 pregnancies after preimplantation genetic diagnosis. Am J Obstet Gynecol. 2000;182(6):1629-1632.

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):1377-1384.

Yang Z, Liu J, Collins GS, et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet. 2012;5(1):24.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

88271, 88272, 88273, 88274, 88275, 88364, 88365, 88366, 89290, 89291


THE FOLLOWING CODE IS USED TO REPRESENT INTERPRETATION AND REPORT
88291

THE FOLLOWING CODE IS APPROPRIATE WHEN REPORTED BY A GENETIC COUNSELOR. WHEN PERFORMED BY A PHYSICIAN OR OTHER QUALIFIED HEALTH CARE PROFESSIONAL, THE PHYSICIAN OR OTHER QUALIFIED HEALTH CARE PROFESSIONAL SHOULD USE THE APPROPRIATE EVALUATION AND MANAGEMENT EXAM CODES
96040



Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

THE FOLLOWING CODES ARE USED TO REPRESENT PREIMPLANTATION GENETIC DIAGNOSIS (PGD) TESTING

Z31.430 Encounter of female for testing for genetic disease carrier status for procreative management

Z31.438 Encounter for other genetic testing of female for procreative management

Z31.440 Encounter of male for testing for genetic disease carrier status for procreative management

Z31.441 Encounter for testing of male partner of patient with recurrent pregnancy loss

Z31.448 Encounter for other genetic testing of male for procreative management

Z31.7 Encounter for procreative management and counseling for gestational carrier



HCPCS Level II Code Number(s)



THE FOLLOWING CODE IS USED TO REPRESENT INTERPRETATION AND REPORT

G0452 Molecular pathology procedure; physician interpretation and report

THE FOLLOWING CODE IS APPROPRIATE WHEN REPORTED BY A GENETIC COUNSELOR. WHEN PERFORMED BY A PHYSICIAN OR OTHER QUALIFIED HEALTH CARE PROFESSIONAL, THE PHYSICIAN OR OTHER QUALIFIED HEALTH CARE PROFESSIONAL SHOULD USE THE APPROPRIATE EVALUATION AND MANAGEMENT EXAM CODES

S0265 Genetic counseling, under physician supervision, each 15 minutes


Revenue Code Number(s)

N/A

Coding and Billing Requirements



Policy History

06.02.24j
11/21/2018This policy has been reissued in accordance with the Company's annual review process.
11/22/2017This policy has been reissued in accordance with the Company's annual review process.


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 10/01/2016
Version Issued Date: 09/30/2016
Version Reissued Date: 11/26/2018

Connect with Us        


2017 Independence Blue Cross.
Independence Blue Cross is an independent licensee of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.