Diagnosis: Recurrent pregnancy loss.
Treatment: Infertility treatment.
The insurer denied the infertility treatment.
The denial is upheld.

The patient is a female G2 P0 Ab2 (two miscarriages) with a history of recurrent pregnancy loss, with two first trimester losses. The second loss was a confirmed aneuploid gestation. The patient consulted a Reproductive Endocrinologist. Expanded carrier testing revealed that the patient and her male partner are both carriers for Usher Syndrome Type IIA. The patient was offered preimplantation genetic testing for aneuploidy (PGT-A) and preimplantation genetic testing for monogenic disorder (PGT-M). In vitro fertilization (IVF) with preimplantation genetic testing (PGT) was performed.

The patient underwent combined preimplantation genetic testing for aneuploidy (PGT-A) and preimplantation genetic testing for monogenic disorder (PGT-M), the latter for Usher syndrome.

Usher syndrome is a ciliopathy. Ciliopathies are a group of disorders caused by a defect in ciliogenesis, ciliary protein trafficking. Because nearly every cell in the body (including the photoreceptors) contains cilia, defects in ciliary proteins typically affect multiple organ systems. Usher syndrome is the most common syndromic cause of retinitis pigmentosa (RP) and accounts for 10-20% of cases of retinitis pigmentosa. Inheritance is autosomal recessive, and the retinal dystrophy is usually rod-cone dystrophy. These patients have retinitis pigmentosa with sensorineural hearing loss (partial or complete) since birth; some may have vestibular dysfunction. Most patients retain central vision of about 20/40 until about age 40.

Usher Syndrome 1 (USH1): Profound congenital sensorineural hearing loss on audiometry, absent vestibular function, and typical RP (onset by 10 years of age); accounts for about 70% of all Usher cases. Patient may benefit from a cochlear implant. The retinitis pigmentosa occurs at an early age (childhood onset) and progresses slowly. Usher Syndrome 2 (USH2): Moderate to severe congenital sensorineural hearing loss on audiometry (predominantly for higher frequencies), normal vestibular function, and typical RP (onset by 20 years of age); accounts for about 26% of all Usher cases. Usher Syndrome 3 (USH3): Progressive sensorineural hearing loss and typical RP (onset in second decade); accounts for about 4% of all Usher cases. Vestibular function is normal in about half of patients, but abnormal in the other half.

Combined preimplantation genetic testing for aneuploidy (PGT-A) and preimplantation genetic testing for monogenic disorder (PGT-M) testing was performed. Traditionally, morphology-based grading had been the primary technique used for in vitro fertilization (IVF) to evaluate and select the most competent embryos for transfer. Technologies have been developed in the fields of genomics, transcriptomics, proteomics, metabolomics, and time-lapse imaging to try to assist in the selection of the best embryos. However, a focus has been on analysis of 24-chromosome copy number for evaluation and transfer of only diagnosed euploid embryos, also known as preimplantation genetic testing for aneuploidy (PGT-A). Several molecular techniques have been utilized during in vitro fertilization (IVF) cycles to determine ploidy including fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), array comparative genomic hybridization (aCGH), digital polymerase chain reaction (dPCR), single-nucleotide polymorphism (SNP) array, real-time quantitative PCR (qPCR), and next-generation sequencing (NGS). These technologies vary in terms of cost and time to completion, and few of these methods allow for fresh embryo transfer.

In both the United States and Europe, preimplantation genetic diagnosis for monogenic disorders (PGT-M) has been used with increasing frequency for preconception management. Prenatal diagnosis and pregnancy termination are also employed for the management of serious single-gene diseases. In 2018, the Practice Committee of the American Society for Reproductive Medicine (ASRM) recommended preimplantation genetic diagnosis for monogenic disorders (PGT-M) with in vitro fertilization as a significant advance over post-conception diagnosis and pregnancy termination in the case of single-gene (monogenic) disorders. The American Society for Reproductive Medicine (ASRM), in its Practice Committee Opinion, states: "Preimplantation genetic testing for monogenic disorders (PGT-M) predates PGT-A for embryo aneuploidy. With improvements in deoxyribonucleic acid (DNA) amplification techniques, it became possible to perform simultaneous PGT-M/PGT-A. One study compared outcomes of PGT-M/PGT-A vs PGT-M alone, and found that about 50% of PGT-M-unaffected embryos were aneuploid (mean maternal age 32.4 years). Accordingly, the authors reported an implantation rate of 75% vs 53% and live-birth rates of (59.4% vs 37.5%) in the PGT-M/PGT-A group, with miscarriage rates of 20% vs 40%. Patients undergoing PGT-M/PGT-A ultimately will have fewer embryos remaining for transfer after testing, but potentially will have a better assessment and higher reproductive potential with those remaining embryos, though further studies are needed in this population". The American Society for Reproductive Medicine (ASRM) states that this technique requires further study for this population. Therefore, the American Society for Reproductive Medicine Committee Opinion does not support co-testing of preimplantation genetic testing for aneuploidy (PGT-A) and preimplantation genetic testing for monogenic disorder (PGT-M) at this time. Therefore, the testing does not meet the standard of care.

The patient has a secondary diagnosis of recurrent pregnancy loss (RPL). The ASRM, in its Practice Committee Opinion, states: "Recurrent pregnancy loss is a disease distinct from infertility, defined by the spontaneous loss of two or more pregnancies". Therefore, according to the standard of care, the patient does not have a diagnosis of infertility.

Since 24 chromosome techniques have become available, there have been few well-designed studies providing Level-I evidence regarding in vitro fertilization pregnancy outcomes in select populations with these techniques. Several opinion pieces have discussed advantages and disadvantages of PGT-A. Other potential advantages and disadvantages exist with PGT-A, though there are limited data to support or refute these. For example, PGT-A testing may lower the risk of aneuploidy detected during pregnancy or after birth. Another consideration is that identification and discard of aneuploid embryos could potentially lessen the burden of excess embryos cryopreserved. Also, identifying euploid embryos may decrease the time to pregnancy by focusing embryo transfer cycles only using euploid embryos to select populations; this may be helpful in older women. One randomized controlled trial (RCT) in patients aged 38-41 demonstrated improved live-birth rates per cycle with a day three single-blastomere biopsy and PGT-A. Large, prospective, well-controlled studies evaluating the combination of multiple approaches (genomics, time-lapse imaging, transcriptomics, proteomics, metabolomics, etc.) for enhanced embryo selection applicable in a more inclusive in vitro fertilization (IVF) population are needed to determine not only the effectiveness, but also the safety and potential risks of these technologies. PGT-A will likely be part of a future multidimensional approach to embryo screening and selection. At present, however, there is insufficient evidence to recommend the routine use of blastocyst biopsy with aneuploidy testing in all infertile patients. Therefore, at this time PGT-A is considered unproven.

The American Society for Reproductive Medicine (ASRM), in its Practice Committee Opinion, states: "The mechanism of first-trimester pregnancy loss is largely due to aneuploidy, providing biologic plausibility for PGT-A. An analysis of a retrospective cohort study (118 PGT-A vs 188 expectant management) demonstrated similar clinical pregnancy rates and miscarriage rates between the two groups, though time to successful pregnancy was statistically shorter in the expectant-management group (3.0 vs 6.5 months, respectively). Of the PGT-A cohort, 77% were able to create embryos that were tested and, of those, 74% had at least one euploid embryo to transfer. This study is limited by its retrospective design, which makes it difficult to interpret potentially different clinical prognoses for those who did or did not pursue PGT-A. A prospective study explored the relationship between ovarian reserve in recurrent pregnancy loss (RPL) patients and found that in women younger than 38 years, decreased ovarian reserve (defined as a cycle day-3 follicle-stimulating hormone level >10 IU/mL and/or antimullerian hormone <1 ng/mL) resulted in a significantly lower likelihood of having a euploid embryo to transfer compared with women with normal ovarian reserve testing. These studies can assist in personalizing the counseling for patients considering PGT-A, regarding one's likelihood of successfully obtaining a euploid embryo from the technology. It is worth noting that the increased rate of aneuploidy with decreased ovarian reserve is likely not unique to the RPL population. However, to date, the literature has not suggested an improved live-birthrate using PGT-A in RPL patients".

In vitro fertilization is required to complete preimplantation genetic testing for aneuploidy (PGT-A) and preimplantation genetic testing for monogenic disorder (PGT-M). The service is not for the indication of infertility. Therefore, the service, for the proposed indication, is not currently within the standard of care and is not medically necessary. Therefore, the health plan acted reasonably, with sound medical judgment and in the best interest of the patient.