Clinical UM Guideline

Preimplantation genetic testing (PGT) encompasses a variety of adjunctive techniques to assisted reproductive procedures, in which 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. This document addresses the use of preimplantation embryo biopsy and genetic testing for aneuploidies (PGT-A), monogenic disorders (PGT-M) or structural rearrangements (PGT-SR). These procedures may be performed as part of an assisted reproductive procedure (ART). The conditions for which ART may be warranted are addressed in the documents noted below.

Note: For additional information regarding the use of perinatal genetic testing, please see:

• CG-GENE-10 Chromosomal Microarray Analysis (CMA) for Developmental Delay, Autism Spectrum Disorder, Intellectual Disability and Congenital Anomalies
• CG-GENE-13 Genetic Testing for Inherited Diseases
• CG-GENE-21 Cell-Free Fetal DNA-Based Prenatal Testing

Note: For the purposes of this document, the term “genetic testing” refers to direct embryo biopsy.

Note: For the purposes of this document, the term “partners” indicates the individuals from whom the sperm and ova originated. That may include the individual members themselves or a gamete donor.

Note: The use of IVF services is subject to separate Benefit Determination, independent of this position statement. Not all benefit contracts or  certificates include benefits for IVF services, including preimplantation genetic testing (PGT). PGT is only covered when IVF services are covered benefits. Benefit language supersedes this document.

Medically Necessary:

1. Preimplantation genetic testing for aneuploidies (PGT-A) by embryo biopsy is considered medically necessary when the following criteria have been met:
   1. PGT-A is being used as a technique to improve the implantation rate of in vitro fertilization (IVF) procedures in infertile couples; and
   2. There is documentation in the clinical record of genetic counseling (see Definitions) as appropriate; and
   3. Either of the following:
      1. A history of at least three prior IVF cycles when there was a failed embryo transfer or egg retrieval without embryos to freeze or transfer; or
      2. There is a history of any aneuploidy in a previous pregnancy.
2. Preimplantation genetic testing for monogenic disorders (PGT-M) is considered medically necessary when the following criteria have been met:
   1. PGT-M is being used to deselect embryos with genetic mutations; and
   2. A specific mutation, or set of mutations, has been identified, that identifies the genetic disorder with a high degree of reliability; and
   3. The genetic disorder is associated with severe disability or has a lethal natural history; and
   4. There is documentation in the clinical record of genetic counseling (see Definitions) as appropriate; and
   5. At LEAST ONE of the following:
      1. Both partners are known carriers of the same autosomal recessive disorder; or
      2. One partner is a known carrier of an autosomal recessive disorder, and the couple have previously produced offspring affected by that disorder; or
      3. One partner is a known carrier of a single gene autosomal dominant disorder; or
      4. One partner is a known carrier of a single gene X-linked disorder.
3. Preimplantation genetic testing for structural chromosomal rearrangements (PGT-SR) is considered medically necessary when the following criteria have been met:
   1. PGT-SR is being used to deselect embryos with genetic mutations; and
   2. There is documentation in the clinical record of genetic counseling (see Definitions) as appropriate; and
   3. At LEAST ONE of the following:
      1. One of the partners is known to harbor a structural chromosomal abnormality; or
      2. Male parent is a carrier of a sex chromosome abnormality.
4. Preimplantation genetic testing when used to determine the sex of an embryo is considered medically necessary when the following criteria have been met:
   1. 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; and
   2. There is documentation in the clinical record of genetic counseling (see Definitions) as appropriate.
5. Preimplantation genetic testing is considered medically necessary when used to evaluate human leukocyte antigen (HLA) status alone when the following criteria have been met:
   1. A sibling with a bone marrow disorder requires a hematopoietic cell transplant; and
   2. There is no other source of a compatible donor other than an HLA-matched sibling; and
   3. There is documentation in the clinical record of genetic counseling (see Definitions) as appropriate.

Preimplantation embryo biopsy is considered medically necessary when any of the preimplantation genetic testing criteria above are met.

Not Medically Necessary:

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

Preimplantation genetic screening, including preimplantation genetic testing for aneuploidy (PGT-A), is considered not medically necessary as an adjunct to IVF, except when specified above (Section A), including but not limited to the following circumstances:

• To identify the presence or absence of conditions for which an embryo has no known risk factors.

Preimplantation embryo biopsy is considered not medically necessary when any of the preimplantation genetic testing criteria above have not been met.

The following codes for treatments and procedures applicable to this guideline 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 Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for situations designated in the Clinical Indications section as not medically necessary.

There are two general categories of individuals who may undergo PGT.

Embryos at risk for a specific inherited single gene defect:
When either parent is a known carrier of a genetic defect, embryos can undergo PGT-M or PGT-SR to deselect embryos harboring the defective gene or chromosome. Sex 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, PGT is used to deselect male embryos, half of which would be affected. Another strategy, when available, is to test for specific gene mutations such as . Tay-Sachs disease, cystic fibrosis, Lesch-Nyhan syndrome, and Duchenne muscular dystrophy. It should be noted that when PGT-M or PGT-SR are used to deselect affected embryos, the treated couple may not be infertile, but are undergoing an assisted reproductive procedure for the sole purpose of PGT-M or PGT-SR. In this setting, PGT-M or PGT-SR 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, PGT-A of the extruded polar bodies from the oocyte can be used to deselect aneuploid oocytes in older women, with the goal of permitting transfer of those embryos with a higher chance of successful implantation.

Genetic Counseling
According to the National Society of Genetic Counselors (NSGC), genetic counseling is the process of assisting individuals to understand and adapt to the medical, psychological and familial ramifications of a genetic disease. This process typically includes the guidance of a specially trained professional who:

1. Integrates the interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
2. Provides education about inheritance, genetic testing, disease management, prevention and resources; and
3. Provides counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
4. Provides counseling for the psychological aspects of genetic testing (NSGC, 2006).

Rationale
There is adequate evidence to support the use of PGT for individuals that are known to be carriers of structural chromosomal abnormalities or are at risk for aneuploidy and who are undergoing assisted reproductive technology (ART) procedures. 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 (Kato, 2016; Kuliev, 2005; Munné, 2005; Scriven, 2013; Shenfeld, 2003).

The impact of PGT on obstetric and neonatal outcomes has also been considered. In a systematic review with meta-analysis, Hou and colleagues (2021) investigated whether PGT increases the risk of adverse obstetric and neonatal outcomes. The study involved 785,445 participants, across 19 studies, who underwent either PGT (n=54,294) or IVF/intracytoplasmic sperm injection (ICSI; n=731,151). The PGT pregnancies had lower rates of low birth weight (risk ratio [RR] 0.85; 95% confidence interval [CI], 0.75 to 0.98), very low birth weight (RR 0.52; 95% CI, 0.33 to 0.81), and very preterm births (RR 0.55; 95% CI, 0.42 to 0.70) compared to those of IVF/ICSI pregnancies. However, the PGT group had a higher rate of hypertensive disorders of pregnancy (RR 1.30; 95% CI, 1.08 to 1.57). The PGT did not increase the risk of other adverse obstetric and neonatal outcomes, such as those associated with mean birth weight, mean gestational age at birth, birth defects, IUGR, sex ratio, cesarean section, gestational diabetes mellitus, placental disorders, or preterm premature rupture of membranes. A subgroup analysis which included only blastocyst biopsies found that PGT with blastocyst biopsies was associated with a lower rate of very low birth weight (RR 0.55; 95% CI, 0.31 to 0.95) and did not increase the risk of other adverse obstetric and neonatal outcomes. Additionally, a subgroup analysis of only frozen-thawed embryo transfer cycles revealed that PGT pregnancies were associated with a lower rate of very low birth weight (RR 0.55; 95% CI, 0.31 to 0.97), a lower rate of cesarean birth (RR 0.90, 95% CI, 0.82 to 0.99), but a higher rate of preterm birth (RR 1.10; 95% CI, 1.02 to 1.18) and a higher rate of intrauterine growth restriction (RR 1.21; 95% CI, 1.06 to 1.38) than those of IVF/ICSI pregnancies. The PGT with frozen-thawed embryo transfer did not increase the risk of other adverse obstetric and neonatal outcomes. The pooled analysis suggests that neonatal and obstetric outcomes of PGT pregnancies are comparable to those of IVF/ICSI pregnancies. However, further assessment of the impact on intrauterine growth restriction is necessary. The authors noted that the quality of studies included in the analysis was generally low and none were RCTs.

In a systematic review with meta-analysis, Zheng and colleagues (2021) investigated whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or those conceived after IVF/ICSI. The study involved 3682 births from PGT pregnancies, 127,719 from IVF/ICSI pregnancies, and 915,222 from SC pregnancies across 15 studies. The relative risk of low birth weight was higher in PGT pregnancies compared to SC pregnancies (3.95; 95% CI, 2.32 to 6.72), but the risk of congenital malformations was not different between the two groups. The relative risks of preterm delivery (3.12; 95% CI, 2.67 to 3.64) and hypertensive disorders of pregnancy (3.12; 95% CI, 2.18 to 4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age and birth weight were also noted for PGT pregnancies compared to SC pregnancies. However, compared with IVF/ICSI pregnancies, the risks of very preterm delivery and very low birth weight in PGT pregnancies were significantly decreased by 41% and 30%, respectively. The risk of hypertensive disorders of pregnancy was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The results of this meta-analysis indicate that PGT pregnancies may be associated with increased risks of low birth weight, preterm delivery, and hypertensive disorders of pregnancy compared with SC pregnancies. Except for the higher risk of hypertensive disorders of pregnancy, the overall obstetric and neonatal outcomes of PGT pregnancies are favorable compared with those of IVF/ICSI pregnancies.

The evidence demonstrates that PGT-M identifies embryos harboring specific genetic mutations known to cause various diseases. Furthermore, there is adequate evidence from case series studies that PGT-M identification of genetic mutations permits deselection of affected embryos and allows successful live birth of healthy unaffected offspring (Chow, 2015; Iacobelli, 2003; Kuliev, 2005; Lee, 2013; Shenfeld, 2003; Vriesen, 2022).

The addition of human leukocyte antigen (HLA) typing to the PGT procedure is a relatively new innovation. PGT 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 PGT during the next pregnancy in order to deselect an affected embryo, and 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, PGT 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 to select a suitable sibling as a stem cell donor. While these applications create many ethical issues, they have been shown to be technically feasible (Kuliev, 2004; Verlinsky, 2004).

Specific selection criteria for PGT for otherwise fertile couples are difficult, and must be treated on a case-by-case basis. While PGT 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, 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 (Robertson, 2003).

One area of research has been the use of preimplantation genetic testing for aneuploidy (PGT-A) for the screening of embryos with aneuploidy in mothers with advanced maternal age. This use of PGT-A has been the topic of several randomized controlled trials with mixed results (Debrock, 2010; Hardarson, 2008; Mastenbroek, 2007; Rubio, 2013; Schoolcraft, 2009; Staessen, 2004). In the trial conducted by Staessen and colleagues, it was reported that there were no differences between the control group (n=141) which received standard care, and the PGT-A 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 PGT-A 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 PGT-A 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.” Hardarson led a group that set out to enroll 320 subjects with advanced maternal age; however, the study was ended prematurely (2008). The final report included only 56 subjects in the PGT-A group and 53 in the control group, which received no preimplantation diagnostic testing. The clinical pregnancy rate in the PGT-A group was reported to be 8.9% compared with 24.5% in the control group, a difference of 15.6% (p=0.039). However, due to the early termination of the study these results cannot be generalized to a wider population. Rubio and colleagues described a randomized controlled trial (RCT) involving 274 subjects with either three or more failed IVF cycles (FIVF group; n=91) or advanced maternal age defined as 41-44 years of age (AMA group; n=183). Subjects were assigned to undergo treatment with standard intracytoplasmic sperm injection (ICSI; n=43 FIVF subjects and 90 AMA subjects) or PGT-A with fluorescence in situ hybridization (FISH; n=48 FIVF subjects and 93 AMA subjects). The authors reported a significant increase in live birth rates per individual in the PGT-A group compared with the ICSI group for the subjects with AMA (30/93 subjects [32.3%] vs. 14/90 subjects [15.5%]; odds ratio [OR], 2.585; p=0.0099). In FIVF subjects, no significant differences were reported for any outcome measures as a result of PGT-A. They concluded that PGT-A with FISH was shown to be beneficial for the AMA group. A systematic review and meta-analysis by Checa and others looked at 10 RCTs involving 1512 subjects undergoing IVF with and without PGT-A for aneuploidy (2009). The authors reported significantly poorer results for the PGT-A group compared to controls with regard to rate of live births (relative risk [RR], 0.76), ongoing pregnancy (RR, 0.73), and clinical pregnancy (RR, 0.72).

Chromosomal analysis techniques have evolved, and FISH has been supplanted by newer comprehensive chromosome screening (CCS) platforms including array comparative genomic hybridization (aCGH), single-nucleotide polymorphism (SNP) array, quantitative polymerase chain reaction (qPCR) and, most recently, next-generation sequencing (NGS). Studies discussed below using these techniques have all shown favorable outcomes (for example, increased ongoing pregnancy rates and delivery rates, and fewer miscarriages) for individuals of advanced maternal age who have undergone PGT-A prior to embryo transfer.

In 2017, Ubaldi and others published the results of a case series study involving 137 subjects aged greater than 43 years who underwent IVF with PGT-A for aneuploidy and advanced maternal age. All subjects were highly screened and had at least 3 antral follicles on the day prior to starting the stimulation protocol, and no history of failed response to controlled ovarian stimulation. All subjects underwent a single cycle, with an additional 13 undergoing a second, for a total of 150 cycles. Only 21 cycles obtained a transferable embryo. Chromosomal analysis was performed using qPCR. The overall euploidy rate was 11.8% (22/187 blastocysts). This resulted in 12 deliveries (57.1% per transfer, 8.0% per cycle, and 8.8% per subject, respectively). Maternal age was negatively associated with live birth (OR, 0.78), and the number of Metaphase 2 collected at oocyte pickup as positively associated (OR, 1.24). Furthermore, in an ad hoc analysis, fertilization rate was associated with age (44.0-44.9 years of age vs. 46.0-46.9 years of age, p=0.003). No euploidy blastocysts were reported in the eight PGT-A cycles in subjects older than 46, vs. 14.4% in subjects 44.0-44.9 years of age and 4.5% in subjects vs. 45.0-45.9 years of age. The delivery rate was 10% (11/104) in subjects 44.0-44.9 years of age vs. 2.6% (1/38) in subjects 45.0-45.9 years of age. The authors concluded that their results demonstrated low miscarriage and good delivery rates in women with good ovarian reserve aged 44, which supports the use of PGT-A for aneuploidy in this population.

Rubio and colleagues (2017) published results of a multicenter RCT of PGT-A in women of advanced maternal age (between 38-41 years). The study had two arms: a PGT-A group with blastocyst transfer, and a control group with blastocyst transfer without PGT-A. A total of 205 subjects completed the study (100 in the PGT-A group and 105 in the control group). Chromosomal analysis was performed using aCGH. The PGT-A group had significantly fewer cycles reaching embryo transfer (68.0% vs. 90.5% for control) but the delivery rate after the first transfer attempt was significantly higher in the PGT-A group per transfer (52.9% vs. 24.2%) and per patient (36.0% vs. 21.9%) due to lower miscarriage rates in the PGT-A group (2.7% vs. 39.0% for control). The mean number of embryo transfers needed per live birth was lower in the PGT-A group compared with control (1.8 vs. 3.7), as was the time to pregnancy (7.7 vs. 14.9 weeks). The authors concluded that these results emphasize the clinical utility of PGT-A in individuals of advanced maternal age by showing improved likelihood of successful pregnancy and live birth.

In 2018, Verpoest and colleagues reported on the results of a multinational, multicenter, pragmatic RCT involving 396 women aged 36-40 years of age undergoing intracytoplasmic sperm injection (ICSI). CCS as part of a PGT-A procedure was done for 205 subjects and 191 subjects were allocated to ICSI treatment without CCS. While significantly more control group subjects had a minimum of one positive pregnancy vs. the PGT-A group, (45% versus 34%, p=0.03), clinical pregnancy rates were not significantly different (37% versus 31%, p=0.25). Live birth within 1 year was not significantly different (50 vs. 45, p=0.71). There were significantly fewer subjects in the PGT-A group with a transfer (177 vs. 249; RR, 0.81; no p-value reported) and fewer with a miscarriage (14 vs. 27; RR=0.48; p=0.02). The authors concluded that there is a clinical benefit from PGT-A for aneuploidy in the form of a significant reduction of interventions and miscarriages. Similar live birth rates were achieved with less embryo cryopreservation, fewer transfers, fewer double embryo transfers and fewer miscarriages. They stated that this points to a greater efficiency of transfers with PGT-A.

In 2019, Lee and others investigated PGT-A for aneuploidy of blastocysts through aCGH and its impact on live birth rates in subjects who underwent IVF and had a high prevalence of aneuploidy. Their study included 1389 blastocysts. aCGH results derived from 296 PGT-A cycles in subjects who underwent IVF for advanced maternal age (n=87, group A), subjects with repeated implantation failure (n=82, group B), subjects with recurrent miscarriage (n=82, group C), and young healthy oocyte donors (n=45). Another 61 subjects with advanced maternal age without PGT-A procedures were used as a control group for group A. For the advanced maternal age group who underwent PGT-A, a significant increase in live birth rates was reported vs. the non-PGT-A subjects (54.1% vs. 32.8%, p=0.018). Consistent live birth rates were obtained for all the indications (54.1%, 51.6%, 55.9%, and 57.1%, respectively, in group A, B, C, and young age group).

Munné and others (2019) published the results of an RCT involving 661 subjects ages 25-40 years of age undergoing IVF. Subjects were assigned to single embryo transfer based on morphology alone (n=331) vs. NGS-based PGT-A (n=330). The ongoing pregnancy rate was reported to be equivalent between the two groups, with no significant difference per embryo transfer (50% vs. 46%) or per intention to treat at randomization (41.8% vs. 43.5%). The authors concluded that PGT-A for aneuploidy did not improve overall pregnancy outcomes. However, there was a significant increase in ongoing pregnancy rate at 20 weeks gestation per embryo transfer with the use of PGT-A in the subgroup of women aged 35–40 years.

In a systematic review with meta-analysis, Shi and colleagues (2021) evaluated the outcomes of IVF with or without PGT-A in individuals of advanced maternal age (defined as age ≥ 35 years) across 9 RCTs involving 2113 participants. The authors reported that IVF/ICSI with PGT-A performed with CCS resulted in a significantly higher live birth rate (RR=1.30, 95% CI, 1.03 to 1.65), which was not observed in studies using FISH. They also found that blastocyst biopsy was associated with a higher live birth rate in individuals with PGT-A (RR=1.36, 95% CI, 1.05 to 1.79). Additionally, in a systematic review with meta-analysis, Simopoulou and colleagues (2021) aimed to identify an age group that benefits from PGT-A and the best day to perform biopsy. The study involved 11 RCTs employing PGT-A with CCS on Day-3 or Day-5. The authors found that PGT-A did not improve clinical outcomes for the general population. PGT-A improved live-birth rates in individuals over the age of 35 (RR=1.29; 95% CI, 1.05 to 1.60; n=692), whereas it appeared to be ineffective in younger individuals (RR=0.92; 95% CI, 0.62 to 1.39; n=666). Regarding optimal timing, only day-5 biopsy practice presented with improved live-birth rate per embryo transfer. In a similar systematic review and meta-analysis of nine trials with 3,334 participants, Cheng and colleagues (2022) also found PGT-A raised the live-birth rate and decreased the miscarriage rate in women of advanced maternal age but not in women of nonadvanced age.

Tiegs and colleagues (2021) published the results of a prospective, blinded, multicenter, nonselection study aimed at determining the predictive value of an aneuploid diagnosis with a PGT-A assay in predicting the failure of a successful delivery. The study involved 402 participants undergoing their first IVF cycle without recurrent pregnancy loss. All usable blastocysts were biopsied, and the single best morphologic blastocyst was transferred before genetic analysis. PGT for aneuploidy using NGS was performed after clinical outcome was determined. Clinical outcomes were compared to PGT-A results to calculate the predictive value of a PGT-A aneuploid diagnosis. There was a total of 484 single, frozen, blastocyst transfers. Overall, it was determined that 100% of embryos labeled aneuploid failed to progress to sustained implantation or delivery. There was no difference in sustained implantation between the study group (47.9%) and an age-matched control group (45.8%) where biopsy was not performed. The results indicate that the PGT-A assay evaluated in this study was highly prognostic of failure to deliver when an aneuploid result was obtained. Additionally, the trophectoderm biopsy had no detectable adverse impact on sustained implantation.

The American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (ASRT) released a committee opinion regarding the use of PGT-A in 2019. That document concluded the following:

The value of preimplantation genetic diagnosis for aneuploidy (PGT-A) as a screening test for in vitro fertilization (IVF) patients has yet to be determined. Several studies demonstrating higher birth rates after aneuploidy testing and elective single-embryo transfers (eSET) suggest the potential for this testing to decrease the risk of multiple gestations, though these studies have important limitations.

The Canadian Fertility and Andrology Society (Chan, 2021) published guidance on the use of PGT-A. The guidelines concluded that available data does not support the use of PGT-A for all individuals undergoing IVF. They included the following recommendations:

• In patients aged 35-40 years undergoing IVF with at least two blastocysts, clinicians may consider the use of PGT-A to improve [ongoing pregnancy rate] OPR per embryo transfer. (Strength: weak; Quality of evidence: low)
• In patients aged 35-40 years undergoing IVF with at least two blastocysts, there is insufficient evidence for the use of PGT-A to reduce the risk of [early pregnancy loss] EPL. (Strength: weak; Quality of evidence: low)
• In patients with [recurrent pregnancy loss] RPL, there is insufficient evidence to recommend PGT-A over expectant management to improve [live birth rate] LBR. (Strength: weak; Quality of evidence: very low)
• In patients with RPL, there is insufficient evidence to recommend PGT-A to decrease EPL rates. (Strength: weak; Quality of evidence: very low)
• In patients with RPL, there is insufficient evidence to recommend PGT-A to decrease time to live birth.  (Strength: weak; Quality of evidence: very low)
• PGT-A should be undertaken only after thorough counseling and the provision of written informed consent from patients.

Despite this uncertain evidence, the use of PGT-A for the identification of embryos with aneuploidy has been accepted, and it is believed that PGT-A may serve a role specifically in identifying trisomy 21, 18, and 13 in individuals undergoing IVF procedures.

PGT-A has also been proposed as a method of improving IVF outcomes in individuals with no known risk factors. Yang and others (2012) enrolled subjects who were scheduled to undergo first-time IVF. Subjects had a good prognosis, with age under 35, no prior miscarriage, and normal karyotype seeking elective single embryo transfer. All subjects were prospectively randomized to have embryos selected either on the basis of morphology and comprehensive chromosomal screening by aCGH (n=55) or by morphology only (n=48). All subjects had a single fresh blastocyst transferred on day 6. For aCGH group subjects, 425 blastocysts were biopsied and analyzed (average 7.7 blastocysts/subject). Aneuploidy was detected in 191/425 (44.9%) of blastocysts in this group. For the control group, 389 blastocysts were microscopically examined (average 8.1 blastocysts/ subject). The clinical pregnancy rate was significantly higher in the aCGH group vs. the control group (70.9% vs. 45.8%, respectively; p=0.017); ongoing pregnancy rates were likewise significantly better in the aCGH group (69.1% vs. 41.7%, respectively; p=0.009). There were no twin pregnancies. The miscarriage rate was low for both groups and no significant differences were reported (2.6 vs. 9.2; p=0.0597). Live birth rates were not reported.

Forman (2013) reported the result of an RCT noninferiority trial investigating the benefits of CCS during elective single embryo transfer. The study involved 205 infertile couples with a female partner less than 43 years old and a serum anti-Müllerian hormone level ≥ 1.2 ng/mL and day 3 FSH < 12 IU/L. Subjects were assigned to undergo real-time CCS biopsy for embryo selection prior to implantation of a single embryo (n=89) or standard selection methodology of two best-quality embryos for implantation (n=86). The authors reported an ongoing pregnancy rate per randomized subject after the first embryo transfer was similar between groups (60.7% in the CCS group vs. 65.1% control group; RR, 0.9). The risk of multiple gestation was reduced after CCS (53.4% to 0%), and subjects were nearly twice as likely to have an ongoing singleton pregnancy (60.7% vs. 33.7%; RR, 1.8). No data regarding live birth rates were provided. The authors used a 20% noninferiority margin which may not be the most appropriate approach to evaluating the impact of PGT-A on health outcomes.

Scott and others (2013) reported the results of an RCT designed to determine whether blastocyst biopsy and CCS improved IVF implantation and delivery rates. Subjects were infertile couples in whom the female partner was between 21 and 42 years of age and undergoing IVF, and were assigned to treatment with CCS (134 blastocysts, n=72) or routine care (163 blastocysts, n=83). Sustained implantation rates were statistically significantly higher in the CCS group (66.4% vs. 47.9%). Delivery rates were also statistically significantly higher in the CCS group with 84.7% vs. 67.5% in the control group (RR, 1.26, p=0.001). The authors concluded that blastocyst biopsy with rapid qPCR-based CCS results in statistically significantly improved IVF outcomes, as evidenced by meaningful increases in sustained implantation and delivery rates.

Yan and colleagues (2021) published the results of a multicenter RCT investigating whether PGT-A improves the cumulative live-birth rate as compared with conventional IVF. The study involved 1212 participants between 20 and 37 years of age with 3 or more good-quality blastocysts. Participants were randomized to blastocyst screening by NGS in the PGT-A group or selection by morphological criteria in the conventional IVF group. The primary outcome was cumulative live-birth rate after up to three embryo-transfer procedures within 1 year after randomization. The authors hypothesized that the use of PGT-A would result in a cumulative live-birth rate that was no more than 7% higher than the rate after conventional IVF, which would constitute the noninferiority margin for conventional IVF as compared with PGT-A. Live births occurred in 468 participants (77.2%) in the PGT-A group and in 496 participants (81.8%) in the conventional IVF group (absolute difference, -4.6%; 95% CI, -9.2 to 0.0; p<0.001). The cumulative frequency of clinical pregnancy loss was 8.7% in the PGT-A group and 12.6% in the conventional IVF group (absolute difference, -3.9%; 95% CI, -7.5 to -0.2). The incidences of obstetrical or neonatal complications and other adverse events were similar in the two groups. The findings indicate that conventional IVF resulted in a cumulative live-birth rate that was noninferior to the rate with PGT-A in individuals with three or more good-quality blastocysts.

Altogether, the results of these four RCTs involving subjects with good prognosis were mixed. More substantial benefits could be observed in individuals of advanced maternal age who tend to have a higher baseline rate of aneuploidy. RCTs involving older individuals were consistent in showing lower rates of early pregnancy loss with PGT-A.

In conclusion, the use of PGT involves complicated scientific, ethical and legal issues. Any application of this technology should be thoroughly and thoughtfully considered with these issues in mind. Decisions regarding PGT should involve careful discussion between the treated couple and their providers.. 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.

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.

Embryo biopsy: A procedure conducted during an assisted reproduction process where, following the fertilization process, a single cell is removed from the developing embryo and used for genetic testing.

Genetic counseling: Guidance provided by a trained professional in the evaluation of the risk of genetic diseases based on family history, medical records, and genetic test results. It may also include education about inheritance, risks of genetic testing, disease management and resources, and counseling to promote informed choices, adaptation to the risk or presence of a genetic condition, and for the psychological aspects of genetic testing.

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.

Intracytoplasmic sperm injection (ICSI): A technique used during IVF in which a single live sperm is injected directly into the center of a human egg for the purpose of fertilization.

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.

Preimplantation genetic testing: A technique in which embryonic DNA is sampled via embryo biopsy and genetically analyzed to identify abnormal embryos and to select only genetically normal embryos for implantation.

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.

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. Checa MA, Alonso-Coello P, Solà 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.
3. Cheng X, Zhang Y, Deng H, et al. Preimplantation genetic testing for aneuploidy with comprehensive chromosome screening in patients undergoing in vitro fertilization: a systematic review and meta-analysis. Obstet Gynecol. 2022; 140(5):769-777.
4. Chow JF, Yeung WS, Lee VC, et al. Experience of more than 100 preimplantation genetic diagnosis cycles for monogenetic diseases using whole genome amplification and linkage analysis in a single centre. Hong Kong Med J. 2015; 21(4):299-303.
5. Collins JA. Preimplantation genetic testing in older mothers. N Engl J Med. 2007; 357(1):61-63.
6. 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):364-373.
7. 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.
8. 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.
9. Garrisi JG, Colls P, Ferry KM, et al. Effect of infertility, maternal age, and number of previous miscarriages on the outcome of preimplantation genetic diagnosis for idiopathic recurrent pregnancy loss. Fertil Steril. 2009; 92(1):288-295.
10. 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.
11. Hou W, Shi G, Ma Y, et al. Impact of preimplantation genetic testing on obstetric and neonatal outcomes: a systematic review and meta-analysis. Fertil Steril. 2021; 116(4):990-1000.
12. Iacobelli M, Greco E, Rienzi L, et al. Birth of a healthy female after preimplantation genetic diagnosis for Charcot-Marie-Tooth type X. Reprod Biomed Online. 2003; 7(5):558-562.
13. 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.
14. Kato K, Aoyama N, Kawasaki N, et al. Reproductive outcomes following preimplantation genetic diagnosis using fluorescence in situ hybridization for 52 translocation carrier couples with a history of recurrent pregnancy loss. J Hum Genet. 2016; 61(8):687-692.
15. Kuliev A, Verlinsky Y. Preimplantation diagnosis: a realistic option for assisted reproduction and genetic practice. Curr Opin Obstet Gynecol. 2005; 17(2):179-183.
16. 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.
17. Lee CI, Wu CH, Pai YP, et al. Performance of preimplantation genetic testing for aneuploidy in IVF cycles for patients with advanced maternal age, repeat implantation failure, and idiopathic recurrent miscarriage. Taiwan J Obstet Gynecol. 2019; 58(2):239-243.
18. Lee HS, Kim MJ, Ko DS, et al. Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease. Clin Exp Reprod Med. 2013; 40(4):163-168.
19. 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.
20. 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.
21. 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.
22. Munné 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.
23. Munné S, Kaplan B, Frattarelli JL, et al.; STAR Study Group. Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial. Fertil Steril. 2019; 112(6):1071-1079.
24. 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.
25. 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):1400-1407.
26. Rubio C, Bellver J, Rodrigo L, et al. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study. Fertil Steril. 2017; 107(5):1122–1129.
27. Schoolcraft WB, Katz-Jaffe MG, Stevens J, et al. Preimplantation aneuploidy testing for infertile patients of advanced maternal age: a randomized prospective trial. Fertil Steril. 2009; 92(1):157-162.
28. 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.
29. 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):1035-1041.
30. 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.
31. Shenfield F, Pennings G, Devroey P, et al. Taskforce 5: preimplantation genetic diagnosis. Hum Reprod. 2003; 18(3):649-651.
32. Shi WH, Jiang ZR, Zhou ZY, et al. Different strategies of preimplantation genetic testing for aneuploidies in women of advanced maternal age: a systematic review and meta-analysis. J Clin Med. 2021; 10(17):3895.
33. Simopoulou M, Sfakianoudis K, Maziotis E, et al. PGT-A: who and when? Α systematic review and network meta-analysis of RCTs. J Assist Reprod Genet. 2021; 38(8):1939-1957.
34. 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.
35. 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.
36. 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.
37. Tiegs AW, Tao X, Zhan Y, et al. A multicenter, prospective, blinded, nonselection study evaluating the predictive value of an aneuploid diagnosis using a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy assay and impact of biopsy. Fertil Steril. 2021; 115(3):627-637.
38. 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.
39. Ubaldi FM, Cimadomo D, Capalbo A, et al. Preimplantation genetic diagnosis for aneuploidy testing in women older than 44 years: a multicenter experience. Fertil Steril. 2017; 107(5):1173-1180.
40. Verlinsky Y, Rechitsky S, Sharapova T, et al. Preimplantation HLA testing. JAMA. 2004; 291(17):2079-2095.
41. Verpoest W, Staessen C, Bossuyt PM, et al. Preimplantation genetic testing for aneuploidy by microarray analysis of polar bodies in advanced maternal age: a randomized clinical trial. Hum Reprod. 2018; 33(9):1767-1776.
42. Vriesen N, Carmany EP, Natoli JL. Clinical outcomes of preimplantation genetic testing for hereditary cancer syndromes: a systematic review. Prenat Diagn. 2022; 42(2):201-211.
43. 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.
44. Yan J, Qin Y, Zhao H, et al. Live birth with or without preimplantation genetic testing for aneuploidy. N Engl J Med. 2021; 385(22):2047-2058.
45. 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.
46. Zheng W, Yang C, Yang S, et al. Obstetric and neonatal outcomes of pregnancies resulting from preimplantation genetic testing: a systematic review and meta-analysis. Hum Reprod Update. 2021; 27(6):989-1012.

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. Committee Opinion Number 430. Preimplantation genetic screening for aneuploidy. March 2009.
3. American College of Obstetrics and Gynecology. Preimplantation Genetic Testing: ACOG Committee Opinion, Number 799. Obstet Gynecol. 2020; 135(3):e133-137.
4. American Society for Reproductive Medicine and Society for Assisted Reproductive Technology. Preimplantation genetic testing: a Practice Committee opinion. Fert Steril. 2008; 90(5 Suppl):S136-143.
5. Chan C, Ryu M, Zwingerman R. Preimplantation genetic testing for aneuploidy: a Canadian Fertility and Andrology Society guideline. Reprod Biomed Online. 2021; 42(1):105-116.
6. National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 15(2):77-83.
7. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion. Fertl Steril. 2018;109:429-436.
8. Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive Medicine. Clinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion (2020). Fertil Steril. 2020; 114:246–254.
9. 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 Syst Rev. 2006;(1):CD005291.
10. Zwingerman R, Langlois S. Committee Opinion No. 406: Prenatal Testing After IVF With Preimplantation Genetic Testing for Aneuploidy. J Obstet Gynaecol Can. 2020; 42(11):1437-1443.e1.