This document addresses the use of preimplantation genetic diagnosis (PGD) which is performed as part of an assisted reproductive procedure.

Note: For the purposes of this document, the term "partners" indicates the individuals from whom the sperm and ova originated, whether the individuals themselves or a donor.

Medically Necessary:

1. Preimplantation genetic diagnosis, when used as a technique to improve the implantation rate of in vitro fertilization (IVF) procedures in otherwise infertile couples, is considered medically necessary when either of the following criteria are met:
   • There have been three prior failed attempts at IVF; or
   • One of the partners is known to harbor a balanced translocation.
     
2. Preimplantation genetic diagnosis, when used to deselect embryos with genetic mutations, is considered medically necessary in partners who meet any of the first set of criteria and all of the second set of criteria:
   • Criteria Set 1: (must meet at LEAST ONE of the following)
     • Both partners are known carriers of the same autosomal recessive disorder; or
     • One partner is a known carrier of an autosomal recessive disorder, and the couple have previously produced offspring affected by that 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; and
   • Criteria Set 2: (must meet ALL of the following)
     • A specific mutation, or set of mutations, has been identified, that specifically identifies the genetic disorder with a high degree of reliability; and
     • The genetic disorder is associated with severe disability or has a lethal natural history; and
     • Testing is accompanied by genetic counseling.
       
3. Preimplantation genetic diagnosis when used to determine the sex of an embryo is considered medically necessary only when there is a documented history of an X-linked disorder, such that deselection of an affected embryo can be made on the basis of sex alone.
   
4. Preimplantation genetic diagnosis when used to evaluate human leukocyte antigen (HLA) status alone is considered medically necessary in families with a child with a bone marrow disorder requiring a stem cell transplant, and in whom there is no other source of a compatible bone marrow donor other than an HLA matched sibling.

Investigational and Not Medically Necessary: 

Preimplantation genetic diagnosis is considered investigational and not medically necessary for all other indications, including when the criteria above have not been met.

At this time, there is adequate evidence to support the use of preimplantation genetic testing (PGD) for individuals undergoing assisted reproductive technology (ART) procedures who are known to be carriers of balanced translocation genetic mutations or are at risk for aneuploidy.  These types of mutations are known to negatively affect the outcome of ART procedures.  The identification and exclusion of embryos harboring these mutations has been demonstrated to improve implantation and birthrates for individuals undergoing ART procedures (Kuliev, 2005; Munne, 2005; Shenfeld, 2003).

The evidence demonstrates that PGD identifies embryos harboring specific genetic mutations known to cause various diseases.  Furthermore, there is adequate evidence from case series studies that PGD identification of genetic mutations permits deselection of affected embryos and allows successful live birth of healthy unaffected offspring (Kuliev, 2005; Shenfeld, 2003).

The addition of human leukocyte antigen (HLA) typing to the PGD procedure is a relatively new innovation.  For example, PGD may be performed when a prior child has an inherited disorder, such as Fanconi-anemia, which might be treated by a stem cell transplant.  The couple may opt for PGD during the next pregnancy in order to deselect an affected embryo, but at the same time select an embryo that is HLA compatible with their affected child.  Therefore, the resulting child could serve as a stem cell donor for his/her affected sibling.  Additionally, preimplantation diagnosis may be performed solely to select an HLA compatible donor for a sibling requiring a stem cell transplant.  For example, a sibling may have a leukemia requiring stem cell transplant, and the parents undergo an assisted reproductive procedure solely for the purposes of creating a suitable sibling as a stem cell donor.  While these applications create many ethical issues, they have been shown to be technically feasible (Verlinsky, 2004; Kuliev, 2004).

Specific selection criteria for PGD for otherwise fertile couples are difficult, and must be treated on a case-by-case basis.  While PGD has been shown to be technically feasible in general (i.e., the biopsy procedure, implantation and subsequent pregnancy), the diagnostic performance of the individual laboratory tests used to analyze the biopsied genetic material is rapidly evolving.  Evaluation of each specific genetic test for each abnormality is beyond the scope of this document.  However, in general, in order to assure adequate sensitivity and specificity for the genetic test guiding the embryo deselection process, the genetic defect must be well characterized.  For example, the gene or genes responsible for some genetic disorders may be quite large with mutations spread along the entire length of the gene.  The ability to detect all or some of these genes, and an understanding of the clinical significance of each mutation (including its penetration, i.e., whether or not it is expressed in an individual) will affect the diagnostic performance of the test.  An ideal candidate for genetic testing would be a condition that is associated with a single well-characterized mutation for which a reliable genetic test has been established.  In some situations, PGD may be performed in couples in which the mother is a carrier of an X-linked disease, such as fragile X syndrome.  In this case, the genetic test could focus on merely deselecting male embryos (Robertson, 2003).

The severity of the genetic disorder of concern 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.  Cystic fibrosis is another.  PGD raises many ethical concerns and issues.  While some parties may consider that PGD should be allowed to avoid the birth of a baby with diseases that have an immediate effect, such as cystic fibrosis, there are other diseases like Huntington's disease, which occur in the fifth or sixth decade of life and may or may not be appropriate qualifying conditions for PGD.  Even though such conditions are unavoidable and untreatable, the offspring with such a genetic predisposition may still have a normal and productive life through their mid to late 40s before the onset of disease. 

One area of research has been the use of PGD for the screening of embryos with aneuploidy in mothers with advanced maternal age.  The use of PGD has been the topic of two randomized controlled trials in recent years (Staessen, 2004; Mastenbroek, 2007).  In the trial reported by Staessen and colleagues it was reported that there were no differences between the control group (n=141) which received standard care, and the PGD group (n=184) in implantation rate, positive serum HCG per transfer and per cycle.  They also note that there were significantly fewer embryos to transfer in the PGD group.  In the report by Mastenbroek and others, they found a significantly better ongoing pregnancy rate, live birth rate, and biochemical and clinical pregnancy rate in the control group (n=184) when compared to the PGD group (n=195).  In an accompanying editorial by Collins, the author states "Given the findings of Mastenbroek, et al. preimplantation genetic diagnosis for aneuploidy screening should not be performed solely because of advanced maternal age."

In conclusion, the use of PGD involves a wide variety of complicated scientific, ethical and legal issues.  Any application of this technology should be thoroughly and thoughtfully considered with these issues in mind.  Decisions regarding PGD should involve careful discussion between the treated couple and the physician.  For some couples, the decision may involve the choice between the risks of an in-vitro fertilization (IVF) procedure and deselection of embryos as part of the PGD treatment vs. normal conception with the prospect of amniocentesis and an elective abortion.

Preimplantation genetic diagnosis (PGD) describes a variety of adjunctive techniques to assisted reproductive procedures, 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.  

Two general categories of individuals have undergone PGD:

Embryos at risk for a specific inherited single gene defect:
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.  However, in this way half of the normal males will also be deselected.  Another strategy, when available, is to perform single diagnosis for specific gene mutations.  Single genetic defects for which molecular diagnosis is possible include Tay-Sach's disease, cystic fibrosis, Lesch-Nyhan syndrome, and Duchenne muscular dystrophy.  It should be noted that when PGD is used to deselect affected embryos, the treated couple may not be infertile, but are undergoing an assisted reproductive procedure for the sole purpose of PGD.  In this setting, PGD may be considered as an alternative to selective termination of an established pregnancy after diagnosis by amniocentesis or chorionic villus sampling.

Embryos at a higher risk of aneuploidy:
Implantation failure of fertilized embryos is a common cause for failure of assisted reproductive procedures; only 20% of morphologically normal embryos implant and produce a viable offspring.  Aneuploidy, a condition where there are an abnormal number of chromosomes in an embryo, is thought to contribute to implantation failure.  The prevalence of aneuploid oocytes increases in older women, thus explaining the decreased implantation rate in this population.  These age-related aneuploidies are mainly due to nondisjunction of chromosomes during maternal meiosis.  Therefore, PGD of the extruded polar bodies from the oocyte has been explored as a technique to deselect aneuploid oocytes in older women, with the goal of permitting transfer of those embryos with a higher chance of successful implantation.  The evidence regarding the use of this technique has been shown to have a negative effect on pregnancy outcomes when used for women whose only indication is advanced maternal age.  However, there are other indications where this technique is beneficial.  

Aneuploidy: A condition where there are either fewer or more than the normal number of chromosomes present in cells of a person's body.

Autosomal dominant: A gene mutation located on a non-sex chromosome that is expressed when present as part of a heterozygotic gene pair.

Autosomal recessive: A gene mutation located on a non-sex chromosome that is only expressed when present in homozygous pairs.

Balanced translocation: A chromosomal mutation, where a segment of DNA becomes abnormally attached to the wrong chromosome, which results in two nonhomologous chromosomes being able to cross over, something which normally can occur only between homologous chromosomes.

Genetic counseling: A process involving the guidance of a specially trained professional in the evaluation of family history, medical records, and genetic test results, in assessing the risk of genetic diseases.

HLA typing: Human leukocyte antigen (HLA) typing is the name given to the system used to identify the unique cell markers (antigens) that the immune system recognizes.

In vitro fertilization (IVF): A type of assisted reproductive procedure where an egg is fertilized outside a woman's body and then implanted into the womb.

X-linked disorder: A disease associated with a genetic mutation on the X-sex chromosome; X-linked genes are expressed in all males with the gene, but only in females when the same gene is on both X chromosomes.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary, when criteria are met: 

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Blockeel C, Schutyser V, De Vos A, et al. Prospectively randomized controlled trial of PGS in IVF/ICSI patients with poor implantation. Reprod Biomed Online. 2008; 17(6):848-854.
2. Collins JA. Preimplantation genetic testing in older mothers. N Engl J Med. 2007; 357(1):61-63. 
3. Feyereisen E, Steffann J, Romana S, et al. Five years' experience of preimplantation genetic diagnosis in the Parisian Center: outcome of the first 441 started cycles. Fertil Steril. 2007; 87(1):60-73. 
4. Hardarson T, Hanson C, Lundin K, et al. Preimplantation genetic screening in women of advanced maternal age caused a decrease in clinical pregnancy rate: a randomized controlled trial. Hum Reprod. 2008; 23(12):2806-2812.
5. Jansen RP, Bowman MC, de Boer KA, et al. What next for preimplantation genetic screening (PGS)? Experience with blastocyst biopsy and testing for aneuploidy. Hum Reprod. 2008; 23(7):1476-1478.
6. Kuliev A, Verlinksy Y. Preimplantation diagnosis: a realistic option for assisted reproduction and genetic practice. Curr Opin Obstet Gynecol. 2005; 17(2):179-183.
7. Kuliev A, Verlinsky Y. Preimplantation HLA typing and stem cell transplantation: Reports of International meeting, Cyprus, 27-8 March, 2004. Reprod Biomed Online. 2004; 9(2):205-209.
8. 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.
9. Mersereau JE, Pergament E, Zhang X, Milad MP. Preimplantation genetic screening to improve in vitro fertilization pregnancy rates: a prospective randomized controlled trial. Fertil Steril. 2008; 90(4):1287-1289.
10. Meyer LR, Klipstein S, Hazlett WD, et al. A prospective randomized controlled trial of preimplantation genetic screening in the "good prognosis" patient. Fertil Steril. 2009; 91(5):1731-1738.
11. Munne S, Chen S, Fischer J, et al.  Preimplantation genetic diagnosis reduces pregnancy loss in women aged 35 years and older with a history of recurrent miscarriages. Fertil Steril. 2005; 84(2):331-335.
12. Robertson JA. Extending preimplantation genetic diagnosis: the ethical debate. Ethical issues in new uses of preimplantation genetic diagnosis. Hum Reprod. 2003; 18(3):465-471.
13. Shahine LK, Cedars MI. Preimplantation genetic diagnosis does not increase pregnancy rates in patients at risk for aneuploidy. Fertil Steril. 2006; 85(1):51-56.
14. Shenfield F, Pennings G, Devroey P, et al. Taskforce 5: preimplantation genetic diagnosis. Hum Reprod. 2003; 18(3):649-651.
15. Staessen C, Platteau P, Van Assche E, et al. Comparison of blastocyst transfer with or without preimplantation genetic diagnosis for aneuploidy screening in couples with advanced maternal age: a prospective randomized controlled trial. Hum Reprod. 2004; 19(12):2849-2858.
16. Staessen C, Verpoest W, Donoso P, et al. Preimplantation genetic screening does not improve delivery rate in women under the age of 36 following single-embryo transfer. Hum Reprod. 2008; 23(12):2818-2825.
17. Stephenson MD, Sierra S. Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of a structural chromosome rearrangement. Hum Reprod. 2006; 21(4):1076-1082.
18. Twisk M, Mastenbroek S, Hoek A, et al. No beneficial effect of preimplantation genetic screening in women of advanced maternal age with a high risk for embryonic aneuploidy. Hum Reprod. 2008; 23(12):2813-2817.
19. Verlinsky Y, Rechitsky S, Sharapova T, et al. Preimplantation HLA testing. JAMA. 2004; 291(17):2079-2095.
20. Yakin K, Ata B, Ercelen N, et al. The effect of preimplantation genetic screening on the probability of live birth in young women with recurrent implantation failure; a nonrandomized parallel group trial. Eur J Obstet Gynecol Reprod Biol. 2008; 140(2):224-249.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Agency for Healthcare Research and Quality. Effectiveness of Assisted Reproductive Technology. Health Technology Assessments. 2008 May. No. 08-E012.
2. American College of Obstetrics and Gynecology.  Sex selection. In: Ethics In Obstetrics and Gynecology. 2004. Morales AJ, Saffold CE, eds. Washington, DC.
3. American Society for Reproductive Medicine and Society for Assisted Reproductive Technology. Preimplantation genetic diagnosis: A practice committee opinion. Fert Steril. 2008; 90:S136-143.
4. Twisk M, Mastenbroek S, van Wely M, et al. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005291.