The use of preimplantation genetic testing for aneuploidy: a committee opinion (2024)
The use of preimplantation genetic testing for aneuploidy (PGT-A) in the United States has been increasing steadily. Moreover, the underlying technology used for 24-chromosome analysis continues to evolve rapidly. The value of PGT-A as a routine screening test for all patients undergoing in vitro fertilization has not been demonstrated. Although some earlier single-center studies reported higher live-birth rates after PGT-A in favorable-prognosis patients, recent multicenter, randomized control trials in women with available blastocysts concluded that the overall pregnancy outcomes via frozen embryo transfer were similar between PGT-A and conventional in vitro fertilization. The value of PGT-A to lower the risk of clinical miscarriage is also unclear, although these studies have important limitations. This document replaces the document of the same name, last published in 2018. (Fertil Steril® 2024;122: 421–34. ©2024 by American Society for Reproductive Medicine.)
Traditionally, morphology-based grading had been the primary technique used in in vitro fertilization (IVF) to evaluate and select the most competent embryo for transfer. Technologies have been developed in the fields of genomics, transcriptomics, proteomics, metabolomics, time-lapse imaging, and artificial intelligence to try to assist in the selection of the best embryos. However, the primary focus has been on analysis of 24-chromosome copy number for evaluation and transfer of only euploid embryos, also known as preimplantation genetic testing for aneuploidy (PGT-A). Several molecular techniques have been used during IVF cycles to determine ploidy including fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), array CGH (aCGH), digital polymerase chain reaction, singlenucleotide polymorphism (SNP) array, real-time quantitative PCR (qPCR), and next-generation sequencing (NGS). These technologies vary in terms of methodology, the number of chromosomes analyzed, algorithms used, cost, and time to completion.
The earliest iterations of PGT-A evaluated a subset of the chromosomes primarily using FISH to examine 5–10 unique chromosomes. Despite the hypothesis that exclusion of aneuploid embryos from transfer should improve IVF outcomes, all but one randomized controlled trial (RCT) of this initial approach failed to demonstrate a benefit (1, 2). Since 24-chromosome techniques have become available, there have been few well-designed studies providing high-quality evidence regarding IVF pregnancy outcomes in select populations with these techniques (3, 4).
The use of PGT among patients undergoing IVF in the United States has been increasing steadily. On the basis of national data from the Society for Assisted Reproductive Technology (SART), the proportion of IVF cycles using PGT has increased from 14% in 2014 to 44% in 2019 (5, 6). The aim of this communication is to review the current evidence and provide guidance for the continued use of PGT-A in IVF.
Another group of investigators from a single center performed 2 RCTs, comparing pregnancy rates after transfer of morphologically graded embryos (controls) vs. euploid embryos, using rapid qPCR-based PGT-A (8). First, they hypothesized that SET with a euploid embryo would result in an equivalent pregnancy rate compared with double-embryo transfer (DET) of morphologically graded embryos. There were 175 patients (mean age 35.1 and 34.5 years for the study and control groups, respectively) who were eligible for randomization on the basis of having at least 2 expanded blastocysts (most were randomized on day 5, but some did not have adequate blastocysts until day 6 of embryo development). The overall rate of aneuploidy was 31% (162/521) in the study group (mean maternal age 35.1 ± 3.9 years). The primary outcome of ongoing pregnancy beyond 20 weeks per transfer was similar between the study and control groups (60.7% [54/89] vs. 65.1% [56/86]). The secondary outcome of clinical miscarriage was similar also between the study and control groups, although the study was not powered to address this outcome. The multiple pregnancy rate for patients in the study group was significantly lower than that in the control group (0% [0/54] vs. 53.4% [31/56]). The investigators concluded that transfer of a single euploid blastocyst was noninferior in terms of ongoing pregnancy rates (OPRs) compared with transfer of 2 blastocysts with an unknown chromosome status.
A second study by the same group randomized women with 2 or more blastocysts on day 5 to biopsy with rapid qPCR-based PGT-A on day 5 and transfer on day 6 (n = 72) or the control group with morphologic grading and embryo transfer on day 5 (n = 83) (9). There was no significant difference in the mean maternal age or the number of high-quality blastocysts between the subjects and controls (7.1 and 6.2 blastocysts for the study and control groups, respectively). Patients in the control group had significantly more embryos transferred than the PGT-A group (2.0 vs. 1.86, P<.001), and the investigators explain that this was due to 10 patients in the study group having only 1 euploid embryo for transfer whereas all patients in the control group underwent DET. They report that clinical implantation rates were significantly higher in the PGT-A vs. control group (79.8% [107/134] vs. 63.2% [103/163], P =.002). In addition, the proportion of PGT-A screened embryos that progressed to delivery was significantly higher than the control group embryos (66.4% [89/134] vs. 47.9% [78/163], P =.001). Analysis of secondary outcomes demonstrated a higher delivery rate per cycle in the PGT-A vs. control group (84.7% [61/72] vs. 67.5% [56/83], P =.01). On the basis of the reported data, the calculated spontaneous abortion rates for the PGT-A and control groups were 8.9% and 21.1%, respectively, and twin rates were approximately 59.7% and 45.1%. The investigators concluded that trophectoderm biopsy with rapid qPCR-based PGT-A improves the chance of sustained implantation and delivery rates over traditional embryo selection.
It is worth noting that there are significant limitations to these RCTs. Specifically, randomization occurred only for patients who had a number of good-quality blastocyst embryos, which likely means that these are favorable-prognosis patients. If randomization occurred at the start of the cycle, some percentage of those in the PGT-A group would not have had embryos to biopsy or transfer, thus likely altering the success rates in that cohort, on the basis of intent-to-treat analysis. In addition, 2 of these studies were performed at a high-volume PGT-A clinic, which may limit generalizability to smaller programs. Another limitation is that these studies may not be reflective of current clinical practice, as most clinics biopsy embryos on day 5 and 6 vitrify and thaw in a later cycle. Although vitrified and thawed cycles have been postulated to have some benefits, there are likely to be some embryos that do not survive the thaw. In addition, instead of qPCR or aCGH that was used in these RCTs, many clinics now use the NGS technology owing to its potential increased efficiency and precision along with a lower cost (10).
A 2019 multicenter, RCT (STAR) evaluated the impact of PGT-A with NGS on frozen embryo transfers (FETs) (3). The study was conducted at 34 clinics in 9 laboratories for PGTA testing. The genetic laboratories followed their own internally validated criteria for identification of PGT-A results. The trial excluded patients over 40 years of age, those who had multiple miscarriages, and those who had multiple IVF failures. The trial randomized 661 patients aged 25–40 years (average age: 33.7) with at least 2 blastocysts that could be biopsied, to either PGT-A (n = 330) or morphology alone (n = 331). The OPR at 20 weeks’ gestation was similar between the PGT-A and the control arms, with no significant difference per embryo transfer (50% [137/274] vs. 46% [143/313], PGT-A vs. control, respectively) or per intention to treat (ITT) at randomization (41.8% [138/330] vs. 43.5% [144/331], PGT-A vs. control, respectively). Post hoc analysis of women aged 35–40 years showed a significant increase in OPR per embryo transfer (51% [62/122] vs. 37% [54/145]) but not per ITT. For women <35 years of age, 52.0% of embryos were aneuploid whereas for women of 35–40 years, 64.5% of embryos were aneuploid. Of the abnormal embryos, 31.0% were found to have a whole or partial chromosome mosaic aneuploidy for 1 or more chromosomes. Mosaic embryos were excluded from embryo transfer in this study which resulted in exclusion of 25 patients with 1 or more mosaic embryo results. There was a wide range in the percentage of euploid embryos on the basis of the laboratory involved. The small number of patients enrolled per laboratory prevented statistical comparison. The investigators concluded that PGT A did not improve pregnancy outcomes in all women, as analyzed per embryo transfer or per ITT.
Another multicenter randomized controlled noninferiority trial from 2021 randomized women in China between age 20 and 37 with 3 or more good-quality blastocysts to undergo PGT-A with NGS (n = 606) vs. conventional IVF (n = 606) (4). Patients underwent up to 3 sequential embryo transfers up to 1 year after randomization. A total of 1,212 patients underwent randomization. Live births occurred in 468 women (77.2%) in the PGT-A group and in 496 (81.8%) in the conventional IVF group (absolute difference, -4.6 percentage points; 95% confidence interval [CI], -9.2 to -0.0; P<.001). The cumulative frequency of clinical pregnancy loss was 8.7% and 12.6%, respectively (absolute difference, -3.9 percentage points; 95% CI, -7.5 to -0.2). The average age of patients undergoing PGT-A was 29.1. Of the embryos analyzed, 69.8% were euploid, 17.2% were aneuploid, 11.7% were mosaic, and 1.4% did not yield an interpretable result. Mosaic embryos were not transferred in the study protocol. The investigators concluded that conventional IVF resulted in a cumulative live-birth rate that was noninferior to that with PGT-A. Although the frequency of pregnancy loss among clinical pregnancies appeared to be lower in the PGT-A group, this differential did not translate into a higher cumulative live-birth rate or shorter mean time until a live birth. Unlike typical clinical practice where all good-quality blastocysts undergo biopsy for PGT-A, the study group only had 3 blastocysts biopsied, even if more were available. Therefore, some patients in the study group had fewer than 3 embryo transfers performed. Thus, rather than a true noninferiority trial, the study was more of a safety study and there was no decrease in the cumulative pregnancy rate with PGT-A.
Analysis of data from the SART from 2019 has found that the use of PGT-A is associated with higher implantation rates and lower miscarriage rates, particularly in older age groups. Implantation rates with and without PGT-A, respectively, in the SART age groups are as follows: <35: 62.7% vs. 54%; 35–37: 60.7% vs. 44.9%, 38–40: 59.5% vs. 30.0%; 41–42: 56.1% vs. 17.9%; and 43+: 53.7% vs. 7.4%. The miscarriage rates with and without PGT-A, respectively, are as follows: <35: 11.2% vs. 15.4%; 35–36: 13.0% vs. 20.3%; 38–40: 13.6% vs. 27.7%; 41–42: 13.9% vs. 37.9%; and 43: 18.3% vs. 51.5% (11). PGT-A of embryos appeared to improve the likelihood of having a live birth among women >37 years, with 1 study showing that 21 cycles (or 35 embryo transfers) as the number needed to treat with PGT-A to have 1 additional live birth (12). In this study, cycles that were intending PGT-A were more likely to reach embryo transfer in all age groups, but more significantly in women aged >37. This likely indicates that these women are from a patient cohort with a better prognosis and makes it difficult to isolate the benefit of PGT-A vs. the intrinsic likelihood for success in these patients. A retrospective study from a large US clinic from 2010 to 14 found similar results with autologous fresh non-PGT-A cycles vs. frozen cycles with PGT-A tested euploid embryos (13). When looking at clinical pregnancy, miscarriage, or live-birth rates, there was no difference between PGT-A and non-PGT-A cycles for women aged ≤37 years, and for women aged >37 years, there was no difference when comparing on a per cycle basis.
A Cochrane Database systematic review was performed and it included 13 trials involving 2,794 patients. The quality of evidence was low to moderate. Only 1 trial was included utilizing blastocyst stage biopsy analyzing 24 chromosomes with NGS. The remainder looked at polar body biopsy or cleavage-stage biopsy utilizing FISH or 24-chromosome testing or blastocyst biopsy utilizing FISH. It was concluded that there was insufficient good-quality evidence of a difference in cumulative live-birth rate, live-birth rate after the first embryo transfer, or miscarriage rate with and without PGT-A (14).
Retrospective studies suggest a benefit of PGT-A testing in older patient cohorts, particularly in women up to age 43 years (improved live-birth rate per cycle start seen in women aged 38–40 years with PGT-A) (16) and improved implantation rates in women of 40–43 years (implantation rate was 50.9% in euploid embryos compared with unscreened fresh [23.8%] and FET [25.4%] cycles) (17). The retrospective nature, inclusion criteria, and small numbers limit these studies; in particular, 1 study stratified groups by age, thus comparing only 8 cycles per group in the oldest age cohort (12), whereas another only included women with euploid embryos to transfer (only 76 of 145 patients had euploid blastocysts to transfer [52.4%]) (13). Furthermore, there is potential bias because only good-prognosis patients who were able to have a biopsy would have been included in the PGT-A group. The investigators in both groups believe that the improved pregnancy success demonstrates a benefit of PGT-A; however, the study methodologies leave questions regarding these conclusions. An observational prospective cohort study of patients aged 38–44 years from a single center demonstrated that PGT-A use is associated with a higher per transfer but not cumulative live-birth rates and lower multiple pregnancy and miscarriage rates compared with controls. However, a significant number of patients (106/414) withdrew consent to PGT-A after fertilization results became available (most having less than 5 normally fertilized oocytes), which introduces a selection bias in the PGT-A group toward more favorable prognosis (18). Given these data, PGT-A may have a beneficial role in patients of advanced maternal age, especially those with good ovarian reserve.
A retrospective analysis of the SART-CORS database compared couples with recurrent pregnancy loss (RPL) undergoing FET with or without PGT-A and found a significantly higher live-birth rate with PGT-A with an adjusted OR of 1.31 (95% CI 1.12, 1.52) for age <35, 1.45 (95% CI 1.21, 1.75) for ages 35–37, 1.89 (95% CI 1.56, 2.29) for ages 38–40, 2.62 (95% CI 1.94–3.53) for ages 41–42, and 3.8 (95% CI 2.52, 5.72) for ages >42 (42). After adjusting for covariates, no difference in rates of spontaneous abortions were seen. This study was restricted to couples already undergoing FET, limiting generalizability to couples pursuing IVF with PGT-A as a primary treatment of RPL. These studies are limited by their 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 reserves in patients with RPL and found that in women younger than 38 years, decreased ovarian reserve (defined as a cycle day-3 follicle-stimulating hormone level >10 mIU/mL and/or anti-mullerian 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 (43). These studies can assist in personalizing the counseling for patients considering PGTA, 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 (44). However, to date, definitive evidence of the benefit of PGT-A in this patient population is lacking.
The relatively recent application of culture through day 7 in some centers increases the pool of transferable embryos for patients who may otherwise have no usable embryos if culture was terminated on day 6. However, embryos that reach blastocyst stage on day 7 may have a higher risk of aneuploidy and lower implantation potential if euploid. A retrospective study by Tiegs et al. (49) of 229 NGS-tested euploid day 7 blastocysts found that pregnancy rates were slightly but not significantly reduced compared with day 5 and day 6 blastocysts. The sustained implantation rate for day 7 euploid blastocysts was 52.6% compared with 68.9% and 66.8% in day 5 and day 6 blastocysts with P=.29 and P=.14, respectively. A separate retrospective study by Hernandez-Nieto et al. (50) found a significant reduction ineuploidy and implantation rates for day 7 blastocysts compared with day 5 and day 6 blastocysts. The euploidy rate was 40.5% in day 7 blastocysts compared with 54.7% in day 5 blastocysts and 52.9% in day 6 blastocysts (P<.0001). In this study, 116 day 7 euploid blastocysts (by PGT-A) were transferred, resulting in a significant decrease in implantation (OR, 0.32; P<.001), clinical pregnancy (OR, 0.28; P<.001), and live birth (OR, 0.28; P<.001). These data support the selection of day 5 and day 6 blastocysts over day 7 blastocysts when available.
An inconclusive result is reported to occur after biopsy for PGT-A in 0.86% to 3.8% of cases (55). The option to re-biopsy a no-result blastocyst requires warming, followed by a second round of biopsy and vitrification. There are mixed data on the impact of multiple vitrification and biopsy cycles on clinical outcomes. One retrospective cohort study analyzed the impact of 2 rounds of vitrification with 1 or more rounds of biopsy (56). This study found comparable clinical pregnancy rates in embryos that underwent double vitrification with a single biopsy (44%) to controls that underwent single vitrification and single biopsy (46%). However, there was a trend toward lower clinical pregnancy rates in the double vitrification and double biopsy group (35%), which was not statistically significant. These findings were corroborated by another group (57), who did see a detrimental effect of double vitrification and double biopsy. A third group found that embryos that underwent 2 vitrifications and 1 biopsy (n = 3,452) had an ongoing pregnancy and clinical loss rate of 63.2% and 9.8%, respectively, compared with 50% and 21.7% in embryos that underwent double vitrification and double biopsy (n = 36) (P=.08) (58). This was further corroborated by another group that found that double vitrified and double biopsied embryos had a significantly reduced clinical pregnancy rate (31% vs. 54.3%) compared with single vitrification single biopsy embryos (P=.13) (59). On the other hand, 2 studies found that blastocysts can tolerate a second round of biopsy without compromising clinical pregnancy and live-birth rates (55, 60). Although the data are mixed, it appears that at least multiple rounds of vitrification and biopsy may impact the implantation of euploid blastocysts, and this should be balanced against the necessity of obtaining a PGT-A result.
Mosaic embryos can implant and generate apparently euploid offspring; however, they may implant at a lower success rate (85, 87–89). These data suggest a need for additional investigation of the validity and accuracy of a mosaic diagnosis. The fact embryos with a mosaic diagnosis can result in apparently euploid offspring is due to either inaccurate classification or from a correction process such as post-zygotic chromosome loss, chromosome gain, mitotic nondisjunction, or trisomic rescue (90–92). Further details surrounding the clinical management of mosaicism are provided in the ASRM committee opinion (86).
There are potential disadvantages to using PGT-A, such as the need for increased resources and up to 8 cumulative hours of labor for the embryology team for each biopsy case (102). Furthermore, not all embryos will survive in culture to the blastocyst stage for biopsy, although hypothetically they may have resulted in a healthy live birth if they had been transferred in the cleavage or early blastocyst stage. Given the uncertainty about self-correction, false-positive PGT-A results, and/or accuracy of a mosaic diagnosis, there is concern that one may be discarding embryos that may have resulted in healthy neonates (98). Potential variations in aneuploidy rates in same age groups between laboratories also need further investigation. In addition, more data are needed about cumulative pregnancy rates from 1 retrieval cycle, effects of PGT-A on miscarriage rates, and defining which patient groups could benefit from this technology.
Subjects participating in these RCTs are generally favorable-prognosis patients who have produced blastocysts for biopsy and analysis. A broader selection of patients with randomization at cycle start rather than blastulation would more appropriately address the applicability of wider use of this technology. Furthermore, the randomized trials were performed in centers with broad and deep experience in embryo biopsy and specimen preparation. The ability to expand reliably these techniques to centers with less experience has yet to be established.
Other important considerations about PGT-A that must be addressed by further research include cost-effectiveness, use of mosaic embryos, false-positive results, risk of embryo damage, the role and effect of cryopreservation, time to pregnancy, utility in specific subgroups (such as RPL, prior implantation failure, advanced maternal age, and so on), use of sex selection, and total reproductive potential per intervention.
Large, prospective, well-controlled studies evaluating the combination of multiple approaches (genomics, time-lapse imaging, transcriptomics, proteomics, metabolomics, artificial intelligence, and so on) for enhanced embryo selection applicable in a more inclusive patient population are needed to determine not only the effectiveness, but also the safety and potential risks of these technologies. PGT-A will likely remain part of a multidimensional approach to embryo screening and selection. At present, however, the routine use of blastocyst biopsy with aneuploidy testing in all infertile patients undergoing IVF treatment cannot be recommended.
The earliest iterations of PGT-A evaluated a subset of the chromosomes primarily using FISH to examine 5–10 unique chromosomes. Despite the hypothesis that exclusion of aneuploid embryos from transfer should improve IVF outcomes, all but one randomized controlled trial (RCT) of this initial approach failed to demonstrate a benefit (1, 2). Since 24-chromosome techniques have become available, there have been few well-designed studies providing high-quality evidence regarding IVF pregnancy outcomes in select populations with these techniques (3, 4).
The use of PGT among patients undergoing IVF in the United States has been increasing steadily. On the basis of national data from the Society for Assisted Reproductive Technology (SART), the proportion of IVF cycles using PGT has increased from 14% in 2014 to 44% in 2019 (5, 6). The aim of this communication is to review the current evidence and provide guidance for the continued use of PGT-A in IVF.
CLINICAL OUTCOMES IN FAVORABLE-PROGNOSIS PATIENTS
Literature search revealed 5 RCTs, several retrospective cohort studies, meta-analyses, and a systematic review. A 2012 pilot study randomized 112 favorable prognosis patients (age <35 years, tubal or male factor infertility, and no prior IVF treatment) to either day-5 aCGH after trophectoderm biopsy plus morphology assessment or traditional morphology assessment alone for selection of the single best embryo on day 6 (7). Ongoing per transfer pregnancy rates after fresh D6 single-embryo transfer (SET) were significantly higher in the aCGH group compared with the traditional morphology group (69.1%vs. 41.7%, P=.009). Of note, time to pregnancy was not reported, nor was the total reproductive potential of the cycle. There was no statistically significant difference in miscarriages or multiples between the groups, although the study was not powered to address these outcomes. Biopsy for aCGH could not be completed in 32 blastocysts in the study group because of embryo degeneration or poor morphology and failure of amplification resulting in ‘‘no signal’’ after biopsy was performed in 8 blastocysts. Interestingly, for these favorable-prognosis patients, the investigators found a blastocyst aneuploidy rate of 44.9% (191/425 biopsied blastocysts). The investigators acknowledged their small numbers and limited study population but concluded that outcomes with elective single-embryo transfer (eSET) are substantially improved with the addition of aCGH testing to the traditional screening methodology.Another group of investigators from a single center performed 2 RCTs, comparing pregnancy rates after transfer of morphologically graded embryos (controls) vs. euploid embryos, using rapid qPCR-based PGT-A (8). First, they hypothesized that SET with a euploid embryo would result in an equivalent pregnancy rate compared with double-embryo transfer (DET) of morphologically graded embryos. There were 175 patients (mean age 35.1 and 34.5 years for the study and control groups, respectively) who were eligible for randomization on the basis of having at least 2 expanded blastocysts (most were randomized on day 5, but some did not have adequate blastocysts until day 6 of embryo development). The overall rate of aneuploidy was 31% (162/521) in the study group (mean maternal age 35.1 ± 3.9 years). The primary outcome of ongoing pregnancy beyond 20 weeks per transfer was similar between the study and control groups (60.7% [54/89] vs. 65.1% [56/86]). The secondary outcome of clinical miscarriage was similar also between the study and control groups, although the study was not powered to address this outcome. The multiple pregnancy rate for patients in the study group was significantly lower than that in the control group (0% [0/54] vs. 53.4% [31/56]). The investigators concluded that transfer of a single euploid blastocyst was noninferior in terms of ongoing pregnancy rates (OPRs) compared with transfer of 2 blastocysts with an unknown chromosome status.
A second study by the same group randomized women with 2 or more blastocysts on day 5 to biopsy with rapid qPCR-based PGT-A on day 5 and transfer on day 6 (n = 72) or the control group with morphologic grading and embryo transfer on day 5 (n = 83) (9). There was no significant difference in the mean maternal age or the number of high-quality blastocysts between the subjects and controls (7.1 and 6.2 blastocysts for the study and control groups, respectively). Patients in the control group had significantly more embryos transferred than the PGT-A group (2.0 vs. 1.86, P<.001), and the investigators explain that this was due to 10 patients in the study group having only 1 euploid embryo for transfer whereas all patients in the control group underwent DET. They report that clinical implantation rates were significantly higher in the PGT-A vs. control group (79.8% [107/134] vs. 63.2% [103/163], P =.002). In addition, the proportion of PGT-A screened embryos that progressed to delivery was significantly higher than the control group embryos (66.4% [89/134] vs. 47.9% [78/163], P =.001). Analysis of secondary outcomes demonstrated a higher delivery rate per cycle in the PGT-A vs. control group (84.7% [61/72] vs. 67.5% [56/83], P =.01). On the basis of the reported data, the calculated spontaneous abortion rates for the PGT-A and control groups were 8.9% and 21.1%, respectively, and twin rates were approximately 59.7% and 45.1%. The investigators concluded that trophectoderm biopsy with rapid qPCR-based PGT-A improves the chance of sustained implantation and delivery rates over traditional embryo selection.
It is worth noting that there are significant limitations to these RCTs. Specifically, randomization occurred only for patients who had a number of good-quality blastocyst embryos, which likely means that these are favorable-prognosis patients. If randomization occurred at the start of the cycle, some percentage of those in the PGT-A group would not have had embryos to biopsy or transfer, thus likely altering the success rates in that cohort, on the basis of intent-to-treat analysis. In addition, 2 of these studies were performed at a high-volume PGT-A clinic, which may limit generalizability to smaller programs. Another limitation is that these studies may not be reflective of current clinical practice, as most clinics biopsy embryos on day 5 and 6 vitrify and thaw in a later cycle. Although vitrified and thawed cycles have been postulated to have some benefits, there are likely to be some embryos that do not survive the thaw. In addition, instead of qPCR or aCGH that was used in these RCTs, many clinics now use the NGS technology owing to its potential increased efficiency and precision along with a lower cost (10).
A 2019 multicenter, RCT (STAR) evaluated the impact of PGT-A with NGS on frozen embryo transfers (FETs) (3). The study was conducted at 34 clinics in 9 laboratories for PGTA testing. The genetic laboratories followed their own internally validated criteria for identification of PGT-A results. The trial excluded patients over 40 years of age, those who had multiple miscarriages, and those who had multiple IVF failures. The trial randomized 661 patients aged 25–40 years (average age: 33.7) with at least 2 blastocysts that could be biopsied, to either PGT-A (n = 330) or morphology alone (n = 331). The OPR at 20 weeks’ gestation was similar between the PGT-A and the control arms, with no significant difference per embryo transfer (50% [137/274] vs. 46% [143/313], PGT-A vs. control, respectively) or per intention to treat (ITT) at randomization (41.8% [138/330] vs. 43.5% [144/331], PGT-A vs. control, respectively). Post hoc analysis of women aged 35–40 years showed a significant increase in OPR per embryo transfer (51% [62/122] vs. 37% [54/145]) but not per ITT. For women <35 years of age, 52.0% of embryos were aneuploid whereas for women of 35–40 years, 64.5% of embryos were aneuploid. Of the abnormal embryos, 31.0% were found to have a whole or partial chromosome mosaic aneuploidy for 1 or more chromosomes. Mosaic embryos were excluded from embryo transfer in this study which resulted in exclusion of 25 patients with 1 or more mosaic embryo results. There was a wide range in the percentage of euploid embryos on the basis of the laboratory involved. The small number of patients enrolled per laboratory prevented statistical comparison. The investigators concluded that PGT A did not improve pregnancy outcomes in all women, as analyzed per embryo transfer or per ITT.
Another multicenter randomized controlled noninferiority trial from 2021 randomized women in China between age 20 and 37 with 3 or more good-quality blastocysts to undergo PGT-A with NGS (n = 606) vs. conventional IVF (n = 606) (4). Patients underwent up to 3 sequential embryo transfers up to 1 year after randomization. A total of 1,212 patients underwent randomization. Live births occurred in 468 women (77.2%) in the PGT-A group and in 496 (81.8%) in the conventional IVF group (absolute difference, -4.6 percentage points; 95% confidence interval [CI], -9.2 to -0.0; P<.001). The cumulative frequency of clinical pregnancy loss was 8.7% and 12.6%, respectively (absolute difference, -3.9 percentage points; 95% CI, -7.5 to -0.2). The average age of patients undergoing PGT-A was 29.1. Of the embryos analyzed, 69.8% were euploid, 17.2% were aneuploid, 11.7% were mosaic, and 1.4% did not yield an interpretable result. Mosaic embryos were not transferred in the study protocol. The investigators concluded that conventional IVF resulted in a cumulative live-birth rate that was noninferior to that with PGT-A. Although the frequency of pregnancy loss among clinical pregnancies appeared to be lower in the PGT-A group, this differential did not translate into a higher cumulative live-birth rate or shorter mean time until a live birth. Unlike typical clinical practice where all good-quality blastocysts undergo biopsy for PGT-A, the study group only had 3 blastocysts biopsied, even if more were available. Therefore, some patients in the study group had fewer than 3 embryo transfers performed. Thus, rather than a true noninferiority trial, the study was more of a safety study and there was no decrease in the cumulative pregnancy rate with PGT-A.
Analysis of data from the SART from 2019 has found that the use of PGT-A is associated with higher implantation rates and lower miscarriage rates, particularly in older age groups. Implantation rates with and without PGT-A, respectively, in the SART age groups are as follows: <35: 62.7% vs. 54%; 35–37: 60.7% vs. 44.9%, 38–40: 59.5% vs. 30.0%; 41–42: 56.1% vs. 17.9%; and 43+: 53.7% vs. 7.4%. The miscarriage rates with and without PGT-A, respectively, are as follows: <35: 11.2% vs. 15.4%; 35–36: 13.0% vs. 20.3%; 38–40: 13.6% vs. 27.7%; 41–42: 13.9% vs. 37.9%; and 43: 18.3% vs. 51.5% (11). PGT-A of embryos appeared to improve the likelihood of having a live birth among women >37 years, with 1 study showing that 21 cycles (or 35 embryo transfers) as the number needed to treat with PGT-A to have 1 additional live birth (12). In this study, cycles that were intending PGT-A were more likely to reach embryo transfer in all age groups, but more significantly in women aged >37. This likely indicates that these women are from a patient cohort with a better prognosis and makes it difficult to isolate the benefit of PGT-A vs. the intrinsic likelihood for success in these patients. A retrospective study from a large US clinic from 2010 to 14 found similar results with autologous fresh non-PGT-A cycles vs. frozen cycles with PGT-A tested euploid embryos (13). When looking at clinical pregnancy, miscarriage, or live-birth rates, there was no difference between PGT-A and non-PGT-A cycles for women aged ≤37 years, and for women aged >37 years, there was no difference when comparing on a per cycle basis.
A Cochrane Database systematic review was performed and it included 13 trials involving 2,794 patients. The quality of evidence was low to moderate. Only 1 trial was included utilizing blastocyst stage biopsy analyzing 24 chromosomes with NGS. The remainder looked at polar body biopsy or cleavage-stage biopsy utilizing FISH or 24-chromosome testing or blastocyst biopsy utilizing FISH. It was concluded that there was insufficient good-quality evidence of a difference in cumulative live-birth rate, live-birth rate after the first embryo transfer, or miscarriage rate with and without PGT-A (14).
OTHER SUBSETS OF PATIENTS
Advanced maternal age
The aforementioned studies were performed in either young or overall favorable-prognosis patients without stratified analysis for age in most cases. However, post hoc analysis of the STAR trial showed increased OPR per embryo transfer in patients 35–40 years old (3). Given the increased aneuploidy rates in older women, pragmatic trials with ITT analysis specifically addressing this patient population are needed. There was 1 RCT that focused on women with advanced maternal age (38–41 years old), randomizing before cycle start to routine blastocyst transfer vs. a PGT-A group that had a biopsy of a single blastomere on day 3 with transfer on day 5 (15). The live-birth rate was significantly higher in the PGT-A group when analyzed per transfer (52.9% vs. 24.2%, P=.0002) and per cycle (36% vs. 21.9%, P=.031). Of note, only 68% of the PGT-A patients had a transfer vs. 95% in the control group (P=.001). The miscarriage rate was significantly lower in the PGT-A group (2.7% vs. 39%, P=.0007). Of all cleavage embryos that were biopsied, they got results for 97.2%, and 78.6% of embryos were aneuploid. There was no statistically significant difference in live-birth rates when they included outcomes for FET cycles for the 6 months after the study (37% vs. 33.3% in controls) and the time to pregnancy was 4.5 weeks with PGT-A and 5.8 weeks with controls (P is not significant). Time to pregnancy resulting in live birth was estimated at 7.7 weeks for the PGT-A group vs. 14.9 weeks for controls.Retrospective studies suggest a benefit of PGT-A testing in older patient cohorts, particularly in women up to age 43 years (improved live-birth rate per cycle start seen in women aged 38–40 years with PGT-A) (16) and improved implantation rates in women of 40–43 years (implantation rate was 50.9% in euploid embryos compared with unscreened fresh [23.8%] and FET [25.4%] cycles) (17). The retrospective nature, inclusion criteria, and small numbers limit these studies; in particular, 1 study stratified groups by age, thus comparing only 8 cycles per group in the oldest age cohort (12), whereas another only included women with euploid embryos to transfer (only 76 of 145 patients had euploid blastocysts to transfer [52.4%]) (13). Furthermore, there is potential bias because only good-prognosis patients who were able to have a biopsy would have been included in the PGT-A group. The investigators in both groups believe that the improved pregnancy success demonstrates a benefit of PGT-A; however, the study methodologies leave questions regarding these conclusions. An observational prospective cohort study of patients aged 38–44 years from a single center demonstrated that PGT-A use is associated with a higher per transfer but not cumulative live-birth rates and lower multiple pregnancy and miscarriage rates compared with controls. However, a significant number of patients (106/414) withdrew consent to PGT-A after fertilization results became available (most having less than 5 normally fertilized oocytes), which introduces a selection bias in the PGT-A group toward more favorable prognosis (18). Given these data, PGT-A may have a beneficial role in patients of advanced maternal age, especially those with good ovarian reserve.
Use of donor oocytes
Regarding donor oocyte IVF cycles, the benefit of PGT-A was considered in a cohort study of 31 PGT-A cycles compared with 39 control cycles. PGT-A cycles showed no statistically significant difference in ongoing/live-birth rates (64.4% vs. 54%) or in miscarriage rates (19.2% vs. 9.5%) (19). The small numbers likely explain the heterogeneity of the study, thus limiting statistical power. Another group demonstrated a 15% aneuploidy rate in PGT-A tested embryos from donor oocyte cycles; yet clinical pregnancy rates decreased when PGT-A tested embryos were used (20). Studies demonstrate that the euploidy rates of donor oocyte-derived embryos vary by the fertility center, embryology and genetic testing laboratory (21–23). A retrospective cohort study on the basis of the SART database (2005–2013) suggested that the use of PGT-A is associated with reduced live-birth rates in donor oocyte cycles (odds ratio [OR], 0.65, 95% CI, 0.53–0.80; P<.001) (24). However, this study did not account for embryos derived from frozen vs. fresh oocytes, slow freeze or vitrification, or cleavage vs. blastocyst biopsies. Another retrospective cohort study analyzed the outcomes of fresh donor oocyte-derived embryos and compared euploid SET to fresh and frozen untested embryo transfers, and no difference was found in pregnancy and live-birth rates (25). Fresh embryo transfers showed higher implantation rates in this study, which is consistent with the evidence that fresh embryo transfers from fresh donor eggs are associated with higher live-birth rates compared with frozen and thawed embryos (26). Given that most PGT-A cycles require cryopreservation, the potential impact of freezing and thawing on embryos derived from donor oocytes needs to be considered in decision-making. Similar to the previous study, an additional retrospective cohort study showed no benefit of PGT-A in donor oocyte cycles (27). A retrospective paired cohort study of vitrified donor oocytes from an egg bank allowed the comparison of outcomes between PGT-A tested and untested embryos from the same donor (i.e., a single donor served as her own control because of the use of multiple egg lots from the same patient) and did not show a difference in live-birth rates after first embryo transfer (53.8% in the PGT-A group vs. 55.8% in the no PGT-A group, P=.44) and live-birth rate per transfer when all transfers from the same egg lot were analyzed (48.4% in the PGT-A group and 47.2% in the non-PGT-A group, P=.700). The median euploidy rate per recipient was 75% (22). Given the high probability of multiple pregnancy if more than 1 embryo (with or without PGT-A testing) derived from donor oocytes is transferred, SET should be the approach in most (if not all) cases, especially when the gestational carrier is used (28, 29). In addition, the use of PGTA in fresh donor oocyte cycles does not appear to be cost-effective (30). Overall, the totality of evidence argues against the routine use of PGT-A in donor egg cycles.Advanced paternal age
The impact of advanced age on semen parameters is well established and the mean paternal age is increasing (31). Advanced paternal age (APA) has been associated with stillbirth, congenital anomalies, single gene defects, and adverse neurodevelopmental outcomes (32). Approximately 10% of Down syndrome cases are paternal in origin; however, the impact of APA on the incidence of trisomy 21 and other aneuploidies is controversial because of lack of controls for maternal age in most cases (32). The use of donor oocytes accounts for this confounder. One multicenter retrospective case series with 1,202 oocyte donor intracytoplasmic sperm injection (ICSI) cycles, blastocyst biopsy, and PGT-A with NGS failed to demonstrate any association between embryo aneuploidy and paternal age (33). These data were corroborated by a similar study which assessed the aneuploidy rates in 3,118 embryos derived from oocyte donors and showed no association between paternal age and the embryo chromosomal status (34). However, age ≥50 years was associated with increased segmental aneuploidy rate according to this study. Similarly, meta-analysis of 3 retrospective studies did not demonstrate an association between the paternal age and embryo aneuploidy when oocyte donors were used (35). It is not clear whether adverse effects of APA on embryo ploidy manifest itself when superimposed on advanced maternal age (i.e., higher quality donor oocytes may have compensatory mechanisms that counteract genetic and epigenetic defects in sperm). However, the available evidence suggests that routine PGT-A testing should not be performed for APA.Elective single-embryo transfer
Live-birth rates after eSET of a euploid embryo from women across the reproductive aging spectrum are similar or only slightly decreased (but still >50%) with advancing age (36, 37). ASRM recommends the transfer of a single euploid embryo regardless of age in effort to promote singleton and reduce multiple gestations (38). Therefore, use of PGT-A may increase the utilization of eSET. In a retrospective analysis of 382 embryo transfers, similar live-birth rates were observed in good-prognosis patients (<38 years old, at least 2 frozen blastocysts) with eSET of a euploid embryo compared with the transfer of 2 euploid embryos (56% vs. 57%). However, multiple pregnancy rates were significantly higher with DET (0% vs. 65%). Live-birth rates following DET of untested blastocysts were not significantly different from eSET of a euploid embryo (66% vs. 56%, respectively); however, the multiple pregnancy rate was significantly higher in the DET group (45% vs. 0%) (39). A 2015 study compared IVF success before and after a change in the clinical protocol designed to decrease the number of embryos transferred in patients older than 35 years. eSET was offered in patients with fewer than 2 implantation failures if favorable embryo morphology and/or PGT-A screening occurred. There were no significant differences in clinical pregnancy rates per transfer before and after the change in protocol, but there was a significant increase in live-birth rates per embryo transfer cycle for the eSET/PGT-A recipients. However, only 43.6% of PGT-A cycles had at least 1 euploid embryo to transfer. When comparing live-birth rates per cycle, there was no significant difference between groups (20.9% without PGT-A vs. 24.4% with PGT-A) (40).RECURRENT PREGNANCY LOSS
The mechanism of first-trimester pregnancy loss is largely due to aneuploidy, providing biologic plausibility for PGTA. An analysis of a retrospective cohort study (118 PGT-A vs. 188 expectant management) demonstrated similar clinical pregnancy rates and miscarriage rates between the 2 groups (41), although the 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 1 euploid embryo to transfer.A retrospective analysis of the SART-CORS database compared couples with recurrent pregnancy loss (RPL) undergoing FET with or without PGT-A and found a significantly higher live-birth rate with PGT-A with an adjusted OR of 1.31 (95% CI 1.12, 1.52) for age <35, 1.45 (95% CI 1.21, 1.75) for ages 35–37, 1.89 (95% CI 1.56, 2.29) for ages 38–40, 2.62 (95% CI 1.94–3.53) for ages 41–42, and 3.8 (95% CI 2.52, 5.72) for ages >42 (42). After adjusting for covariates, no difference in rates of spontaneous abortions were seen. This study was restricted to couples already undergoing FET, limiting generalizability to couples pursuing IVF with PGT-A as a primary treatment of RPL. These studies are limited by their 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 reserves in patients with RPL and found that in women younger than 38 years, decreased ovarian reserve (defined as a cycle day-3 follicle-stimulating hormone level >10 mIU/mL and/or anti-mullerian 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 (43). These studies can assist in personalizing the counseling for patients considering PGTA, 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 (44). However, to date, definitive evidence of the benefit of PGT-A in this patient population is lacking.
FROZEN EMBRYO TRANSFER CYCLES
Because of logistical, technical, and cost requirements, currently, most clinics performing PGT-A do not process cells for ploidy assessment in-house. In addition, blastocysts can be biopsied on day 5, 6, or 7, and therefore, most euploid blastocysts are transferred in cryopreservation (vs. fresh) cycles. Data from 1 retrospective cohort study support equal or superior reproductive potential for frozen euploid blastocyst transfers (vs. fresh euploid blastocyst transfers) with higher implantation and live-birth rates, and lower miscarriage rates (45). Additional plausible benefits may include a lower incidence of both ovarian hyperstimulation syndrome and multiple gestation if eSET is used. Limitations include the retrospective nature of the study and potential limited generalizability because of the need for good-quality blastocysts for inclusion in this study. One prospective single-center RCT randomized 179 patients planning PGT-A with NGS at the time of hCG to either ‘‘freeze-all’’ or fresh day 6 embryo transfer (46). ITT analysis demonstrated a significantly higher ongoing pregnancy rate (PR) (50.9% vs. 62.2%; p < 0.1) and live birth rate (LBR) (39.8 vs. 61.5%; p < 0.1) for the freeze-all group. A per protocol analysis included 46 patients who underwent a fresh euploid blastocyst transfer and 61 patients who underwent a frozen and thawed euploid blastocyst transfer. Ongoing PR and LBR were significantly higher for the FET group (ongoing PR 80% vs. 61%; P=.03; LBR 77% vs. 59%; P=.04). Logistic regression analysis of LBR adjusting for female age and number of MII oocytes did not show a statistically significant difference between fresh and frozen strategies (OR 2.1, 95% CI 0.95–4.68; P=.68). The investigators concluded that the strategy was reasonable for patients, with a trend toward favoring the freeze-all option (46). Potential risks of a ‘‘freeze-all’’ strategy include increased risk of maternal hypertensive disorders of pregnancy and having a large-for-gestational-age infant (47).DAY OF EMBRYO BIOPSY
When comparing the outcomes for blastocysts biopsied on day 5 (n = 730) vs. day 6 (n = 441), the aneuploidy rate was not significantly different in the day-6 group (69.9% vs. 61.9%) (48). The age of the women in the 2 groups was not significantly different (mean age 38.5 years). Embryos biopsied on day 5 could be transferred fresh on day 6 or frozen, but all day-6 embryos were frozen for future FET. The implantation rate, clinical pregnancy rate, and live-birth rates were not significantly different. This study suggests that the developmental rate of euploid blastocysts that form on day 6 may be approximately as likely to result in live birth as those that form on day 5, although day-6 blastocysts may require cryopreservation for future transfer in an FET cycle.The relatively recent application of culture through day 7 in some centers increases the pool of transferable embryos for patients who may otherwise have no usable embryos if culture was terminated on day 6. However, embryos that reach blastocyst stage on day 7 may have a higher risk of aneuploidy and lower implantation potential if euploid. A retrospective study by Tiegs et al. (49) of 229 NGS-tested euploid day 7 blastocysts found that pregnancy rates were slightly but not significantly reduced compared with day 5 and day 6 blastocysts. The sustained implantation rate for day 7 euploid blastocysts was 52.6% compared with 68.9% and 66.8% in day 5 and day 6 blastocysts with P=.29 and P=.14, respectively. A separate retrospective study by Hernandez-Nieto et al. (50) found a significant reduction ineuploidy and implantation rates for day 7 blastocysts compared with day 5 and day 6 blastocysts. The euploidy rate was 40.5% in day 7 blastocysts compared with 54.7% in day 5 blastocysts and 52.9% in day 6 blastocysts (P<.0001). In this study, 116 day 7 euploid blastocysts (by PGT-A) were transferred, resulting in a significant decrease in implantation (OR, 0.32; P<.001), clinical pregnancy (OR, 0.28; P<.001), and live birth (OR, 0.28; P<.001). These data support the selection of day 5 and day 6 blastocysts over day 7 blastocysts when available.
PGT-A WITH PREIMPLANTATION GENETIC TESTING FOR MONOGENETIC DISORDERS
Preimplantation genetic testing for monogenic disorders (PGT-M) predates PGT-A for embryo aneuploidy. With improvements in embryo biopsy and deoxyribonucleic acid (DNA) amplification techniques, it became possible to perform simultaneous PGT-M/PGT-A in the same biopsy sample. One study compared outcomes of PGT-M/PGT-A vs. PGT-M alone and found that 50% of PGT-M-unaffected embryos were aneuploid (mean maternal age 32.4 years) (51). Accordingly, the investigators reported an implantation rate of 75% vs. 53% (P=.19) and live-birth rates of 59.4% vs. 37.5% in the PGT-M/PGT-A group, with miscarriage rates of 20% vs. 40% (P=.56). Patients undergoing PGT-M/PGT-A ultimately will have fewer embryos remaining for transfer after testing, but potentially will have a better assessment of their overall reproductive potential. It is possible that some potentially viable embryos will be discarded because of mosaicism and false-positive aneuploidy after PGT-A. In one study, retrospective NGS-based PGT-A testing of stored genetic material from PGT-M cases that resulted in unremarkable live birth of 76 infants revealed that 1 in 6 embryos (17.1%) with reproductive potential would have been discarded because of mosaicism or false aneuploidy if PGT-A was used before transfer (52). However, the whole-genome amplification method used and relatively long time (~2 to 3 years) from the time of TE biopsy and PGT-A may have affected these results. Therefore, further studies on the use of PGT-A in the setting of PGT-M are needed in this population, and the counseling needs to be individualized.THAWING AND WARMING, BIOPSY, AND RE-CRYOPRESERVATION FOR PGT-A
Patients with previously cryopreserved unbiopsied embryos may wish to thaw or warm their embryos for biopsy and testing followed by use or repeat cryopreservation. Reasons for this include previous miscarriage, disease discovery, family balancing, or desire to use new technology. Although fresh biopsy is preferable, reproductive outcomes did not seem significantly compromised with respect to the implantation rate, clinical pregnancy rate, or biochemical loss in 1 study on surviving euploid embryos after a sequence of warming and thawing, biopsy, (re)vitrification, and (re)warming (53). There was no comparison of live-birth rates in this group. One study found that the survival rate was lower for the second warming (87.5% vs. 98.3% in first thawing and warming, P .035), but some of the embryos had been slowly frozen on the first freeze. In contrast to embryos that were warmed for an initial biopsy, embryos warmed for a second biopsy (i.e., after initial ‘‘no read,’’ n = 3) did not perform well; in fact, none implanted in this study. Another study with a small sample size (under-powered) reported that for blastocysts that were warmed, biopsied, and transferred within 2 days (day 6 or day 7 of progesterone), the OPRs were 35.3% for age %35 (n = 17), 40% for age 36–44 (n = 16), and 100% for donor egg (n = 2) (54). Some patients may benefit from warming embryos for preimplantation screening, although, again, they may expect a reduction in the number of embryos available for transfer.An inconclusive result is reported to occur after biopsy for PGT-A in 0.86% to 3.8% of cases (55). The option to re-biopsy a no-result blastocyst requires warming, followed by a second round of biopsy and vitrification. There are mixed data on the impact of multiple vitrification and biopsy cycles on clinical outcomes. One retrospective cohort study analyzed the impact of 2 rounds of vitrification with 1 or more rounds of biopsy (56). This study found comparable clinical pregnancy rates in embryos that underwent double vitrification with a single biopsy (44%) to controls that underwent single vitrification and single biopsy (46%). However, there was a trend toward lower clinical pregnancy rates in the double vitrification and double biopsy group (35%), which was not statistically significant. These findings were corroborated by another group (57), who did see a detrimental effect of double vitrification and double biopsy. A third group found that embryos that underwent 2 vitrifications and 1 biopsy (n = 3,452) had an ongoing pregnancy and clinical loss rate of 63.2% and 9.8%, respectively, compared with 50% and 21.7% in embryos that underwent double vitrification and double biopsy (n = 36) (P=.08) (58). This was further corroborated by another group that found that double vitrified and double biopsied embryos had a significantly reduced clinical pregnancy rate (31% vs. 54.3%) compared with single vitrification single biopsy embryos (P=.13) (59). On the other hand, 2 studies found that blastocysts can tolerate a second round of biopsy without compromising clinical pregnancy and live-birth rates (55, 60). Although the data are mixed, it appears that at least multiple rounds of vitrification and biopsy may impact the implantation of euploid blastocysts, and this should be balanced against the necessity of obtaining a PGT-A result.
MALE FACTOR INFERTILITY
One study compared rates of blastocyst aneuploidy for men with normal semen analyses to men with oligozoospermia and reported a threefold increase in sex chromosome abnormalities in the oligozoospermia group, regardless of oocyte age (61). The investigators hypothesized that ICSI, which is used traditionally for PGT-A and PGT-M cycles, could increase aneuploidy by affecting sperm nuclear decondensation or by destabilizing the oocyte spindle apparatus, but reported no difference in blastocyst aneuploidy rates for men with normal semen analyses who underwent IVF or PGT-A using conventional vs. ICSI fertilization. In oligozoospermic men, ICSI did not increase the overall aneuploidy (vs. conventional) but did increase aneuploidy in chromosomes 1, 2, 11, and 18. Similarly, comparison of aneuploidy rates in predominantly non-male factor infertility population in conventional IVF and ICSI split insemination cycles showed no differences in overall aneuploidy, sex chromosome aneuploidy, and embryo mosaicism between these insemination groups (62). Two retrospective cohort studies did not demonstrate an improved pregnancy and/or live-birth rates with the use of PGT-A for severe male factor infertility (63, 64), and additional studies show that the euploidy rates also do not appear to be affected in these cases (65, 66). Very limited evidence suggests that embryo chromosomal abnormality rate maybe increased when testicular sperm from azoospermic patients is used; however, the patients in these studies either had high rate of karyotypic abnormalities or FISH was used for aneuploidy analysis (65–68). In summary, male factor infertility does not appear to be associated with increased embryo aneuploidy according to the available studies, and PGT-A should not be used for this purpose only. The evidence is insufficient to make recommendation for cases when testicular sperm is used, and more studies are needed on this subject.USE OF ICSI
There is theoretical concern that conventional insemination of oocytes may produce a higher risk of genetic contamination during PGT because of the presence of lysed DNA from granulosa cells and excess sperm being adherent to the zona pellucida. The risk of such contamination has not been demonstrated and recent studies suggest that genetic material from sperm may not amplify using PGT methods (69, 70). Although ICSI may be preferred by some laboratories offering PGT-A and mandatory when PGT-M is being used, there is insufficient evidence to support this recommendation. Data reassure that the use of ICSI for non-male factor infertility in PGT-M does not increase the risk of birth defects (71). Given the importance of obtaining a reliable PGT-M result, it is reasonable to recommend ICSI in these cases, but it is not needed routinely for PGT-A.ETHNICITY
Although IVF outcomes have been reported to vary by ethnicity (72), a 2016 study found no difference in aneuploidy rates on the basis of maternal ethnicity as defined by ancestry informative markers (AIMs) (73). Limitations include the lack of data around paternal AIMs and the current AIMs’ inability to identify ethnicity subgroups, and most of the study population was of European descent. A wider group is needed for future study, but aneuploidy risk stratification by ethnicity is not indicated currently.NEONATAL AND CHILDHOOD OUTCOMES
Obstetric, neonatal, and early childhood outcome data seem reassuring thus far, although much has focused on PGT-M (single gene) rather than PGT-A (aneuploidy). The PGT-M vs. PGT-A parental groups are often inherently different in that most patients undergoing PGT-M do not have concomitant infertility. Nonetheless, kindergarten-aged PGT-M offspring perform as well as their IVF and ICSI and naturally conceived peers on measures of cognition (Wechsler Preschool and Primary Scale of Intelligence), motor skills (Movement ABC), psychosocial development (Child Behavior Checklist and Caregiver-Teacher Report Form) (74, 75), and body composition and blood pressure measurements (76). A prospective, assessor blinded, multicenter follow-up evaluation of a RCT of cleavage-stage PGT-A evaluated the neurodevelopment of children born after randomization to PGT-A or no PGT-A at age 9. The investigators found no difference in neurological optimality score (Touwen test), global cognition (Wechsler Abbreviated Scale of Intelligence, Dutch version of the Neuro Psychological Assessment-II), behavior (Child Behavior Checklist and Teacher Report Form), blood pressure, and anthropometrics (total body fat, BMI, and head circumference) between PGT-A and non-PGT-A offspring, although prevalence of minor neurological dysfunction was judged as high across both groups (PGT-A group 17/43 [40%], control group 19/56 [34%]) (77). A cohort study from Denmark noted that adverse obstetric and neonatal outcomes seemed more related to the parental condition than the technology used to treat the condition, although PGT-M pregnancies had more placenta previa than spontaneously conceived pregnancies. PGT-M pregnancies tested for monogenic disorders demonstrated more low birth weight, preterm premature rupture of membranes, placenta previa, cesarean delivery, and neonatal intensive care unit stays than both IVF or ICSI and spontaneously conceived pregnancies; however, the PGT-M offspring did not differ in these variables when compared with their unaffected siblings who were not from PGT-M cycles, suggesting an underlying familial or parental risk milieu (78). A retrospective cohort study linking Massachusetts maternal and neonatal hospitalization discharge diagnoses to SART-CORS data for singleton births after frozen and thawed single-embryo transfers compared outcomes for 585 cycles having embryo biopsy vs. 2,191 cycles having no embryo biopsy. There were no differences in preeclampsia, pregnancy-induced hypertension, placental disorders, preterm birth, low birthweight, cesarian delivery, gestational diabetes mellitus, or prolonged hospitalization for mothers or infants (79). In contrast, an observational cohort study compared pregnancy and neonatal outcomes of trophectoderm biopsy for PGT pregnancies and IVF without PGT pregnancies and found threefold higher odds of preeclampsia with trophectoderm biopsy while controlling for mode of conception (fresh vs. frozen ET, NC FET vs. programmed FET) (10.5% vs. 4.1%, aOR 3.02; 95% CI 1.1, 8.29). Other measured outcomes of placenta previa, gestational diabetes mellitus, preterm premature rupture of membranes, and post-partum hemorrhage were not statistically significantly different. Neonatal outcomes of gestational age at delivery, rate of preterm birth, low birth weight, NICU admission, neonatal morbidities, or birth defects were also not found to be different between the 2 groups (80). A prospective RCT studying PGT-A vs. conventional IVF included obstetric and neonatal outcomes as secondary outcomes. No differences in pregnancy or newborn complications were found between the 2 groups (4). In summary, most studies do not show a negative impact of PGT on obstetric, neonatal, and childhood outcomes.COST-EFFECTIVENESS
Cost-effectiveness for PGT-A is difficult to quantify, because cycle costs and insurance coverage vary considerably. It is difficult to quantify the intangible costs of miscarriage and failed implantation, and many studies do not consider all obstetric, neonatal, and ongoing costs of disease or aneuploidy. One study using a theoretical model found that applying PGTA to patients with unexplained RPL (n = 232) was not cost-effective when compared with expectant management (n = 302); although PGT-A decreased miscarriage rates (7% vs. 24%), the live-birth rate was not improved (40% vs. 55%) (81). Another study used a decision analytic model utilizing actual clinical data and assumptions about PGT-A from the literature applied to 8,998 patients from 74 IVF centers. As expected, once all embryos were exhausted, the cumulative live-birth rate was equivalent. However, PGT-A reduced time in treatment by 4 months and patients experienced fewer failed embryo transfers and clinical miscarriages (82). A third study applied a theoretical cost-effectiveness model utilizing costs from the regional public health system provider. They found that cost-effectiveness improves with female age and number of available blastocysts. They determined that, in theory, PGT-A can be cost-effective in specific clinical settings and population groups (83). Another theoretical cost-effectiveness study looked at the use of PGT-A with fresh oocyte donors and did not find it to be cost-effective (84). More research is needed, particularly as costs for PGT-A decrease, and clinicians should tailor their recommendations to the preference and situation of the individual patient (30).CONCERNS WITH INTERMEDIATE COPY NUMBER (MOSAICISM), TESTING PLATFORMS, AND ACCURACY
Mosaicism refers to 2 or more cell populations with different chromosomal complements being present within the same embryo. Mosaicism was first identified as a common phenomenon in cleavage-stage embryos, although the exact prevalence of mosaicism in embryos is unknown. Mosaicism is diagnosed with PGT-A on the basis of intermediate copy number results. It is important to recognize that, aside from mosaicism, other proposed explanations for intermediate copy number results include statistical variation, amplification bias, contamination, mitotic state, variation in embryo biopsy technique, and embryology laboratory conditions (85, 86). With more recent and sensitive assays such as NGS, it has become increasingly common to report identification and quantification of mosaicism within a trophectoderm biopsy sample. The rate of mosaic diagnoses in clinical testing of trophectoderm can vary depending on the specific NGS platform used, the cutoffs used to classify results as mosaic, technician and software interpretation, and individual PGTA testing laboratory classification schemes.Mosaic embryos can implant and generate apparently euploid offspring; however, they may implant at a lower success rate (85, 87–89). These data suggest a need for additional investigation of the validity and accuracy of a mosaic diagnosis. The fact embryos with a mosaic diagnosis can result in apparently euploid offspring is due to either inaccurate classification or from a correction process such as post-zygotic chromosome loss, chromosome gain, mitotic nondisjunction, or trisomic rescue (90–92). Further details surrounding the clinical management of mosaicism are provided in the ASRM committee opinion (86).
Testing platforms
Originally limited to subsets of chromosomes with FISH analysis, more recent platforms evaluate all 24 chromosomes. Early platforms for comprehensive chromosome screening included aCGH and qPCR. qPCR had the advantages of low cost and quick turnaround time; however, it is not able to detect segmental aneuploidies or mosaicism. At present, NGS and SNP microarray are the primarily used platforms. SNP microarray has the ability to indicate if the source of aneuploidy is from the sperm or egg and reliably detect triploidy and tetraploidy. Recently, NGS has become increasingly used in PGT-A because of its high throughput, ability to detect mosaicism and segmental mutation, and capability of concomitant PGT-A and PGT-M. PGT-A platforms are evolving rapidly and it is important that providers understand them in appropriate detail to counsel patients and select suitable platforms to meet the specific needs. Because of differences in laboratory protocols and quality controls, current data do not exist to conclusively determine the superiority of any platform.Accuracy
One of the items which requires clarification with PGT-A is how likely the portion of the embryo which is biopsied represents the entire embryo and accurately predicts the clinical outcomes. Although most published studies report the negative predictive value – the chance that a euploid embryo will produce a euploid pregnancy – very limited studies report the positive predictive value – the chance that an aneuploid embryo will not produce a pregnancy. The only study design that can do this adequately is a prospective nonselection study. One study analyzed cleavage-stage and blastocyst embryos utilizing SNP-microarray PGT-A (93). The investigators found the positive predictive value of PGT-A utilizing SNP microarray to be 96%. Positive predictive values were never established for qPCR or aCGH. A multicenter nonselection study utilizing NGS has also been published and of the 102 aneuploid embryos ultimately transferred, there were no ongoing pregnancies. The binomial proportion 95% CI of aneuploid diagnosis clinical error rate was calculated between 0% and 2.43% (94). In a recently published case series, 50 patients (average age at retrieval 41.4 years) underwent 57 FET cycles of 141 PGT-A abnormal (including mosaic) embryos, resulting in 11 miscarriages and 8 live births (95). Among the 141 abnormal embryos, 76 were aneuploid resulting in 4 first-trimester miscarriages and 1 live birth. Of 30 embryos transferred with complex (>2 chromosomal abnormalities), 28 had no evidence of implantation and 2 resulted in a first-trimester loss. Because new technology evolves which allows for diagnoses such as mosaicism, segmental duplications, and deletions, it will be important to understand the reproductive potential of embryos assigned these results before wide-spread utilization.EMBRYO DAMAGE
There are few data on embryo biopsy techniques used in PGT-A; however, it is generally accepted that trophectoderm biopsy has less impact on embryo viability than cleavage stage biopsy. This is because although more cells are removed during trophectoderm biopsy, it represents a smaller percentage of embryo mass and, by definition, trophectoderm biopsy removes only trophectoderm cells and not cells that have any fetal fate. Conversely, cleavage-stage biopsy occurs at a time when cell lineage has not yet been established and the cell removed could potentially impact viability of the embryo and the fate of the fetus. Available data evaluating the impact of cleavage-stage embryo biopsy show a significant developmental insult that is associated with the biopsy process itself, thereby inflicting trauma to the developing embryo and relative reduction in embryo implantation and progression to delivery (96, 97). There was potential selection bias in this study, given that only poorly developing embryos were biopsied on day 3, whereas normally developing embryos were allowed to grow until day 5 or 6 before biopsy. In a multicenter nonselection study, trophectoderm biopsy had no detectable impact on sustained implantation after embryo transfer (97). The impact of biopsy of the trophectoderm is not well understood and given the importance of the trophectoderm for implantation, damage to the trophectoderm may impact this critical event (98).Pretest counseling of patients or informed consent regarding clinical policy for abnormal test results
Informed consent before use of genetic testing, to include PGT-A, should include a thorough discussion of risks, benefits, and limitations of the technology used. In the case of PGT-A, possible outcomes including no result, embryos with results consistent with mosaicism or segmental aneuploidy, and misdiagnosis are important to discuss before testing. The counseling ought to include the alternate option of not performing PGT-A. In addition, clinics should strive to implement a written policy on disposition of abnormal embryos, including those with mosaic results and segmental aneuploidy. This policy should be disclosed to the patient before testing. Ready access to genetic counseling at any point in patients’ decision-making process is also consistent with best practice regarding the use of PGT-A. Comprehensive post-test counseling is also warranted in many cases, and referral to a genetic counselor can aid patient decision-making regarding the use of PGT-A tested embryos (99).SEX SELECTION
The use of PGT-A may give patients the choice to select the sex of their embryo, which may in effect allow for elective sex selection. In the United States, such potential choices and decisions are left between individual patients and their providers. With increasing use of PGT, there is potential for such elective sex selection leading to gender bias and skewing of the sex ratio. Two recent analyses of national SART data from 2014 to 2016 found that IVF cycles with PGT for any indication were much more likely to have a male offspring (5, 100). Between 2014 and 2016, the overall sex ratio (male/female) from all IVF live births was 107. In context, the overall sex ratio in the US population is estimated to be 105 (101). The sex ratio was however significantly higher (favoring male) among IVF live births from any PGT use compared with IVF live births without PGT use (115 vs. 105, respectively, P<.001). Among IVF live births using PGT specifically for sex selection, the sex ratio was 164. Such findings are concerning, and further research to monitor such utilization patterns is recommended.GAPS IN KNOWLEDGE
Other potential advantages and disadvantages exist with PGT-A, although 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. In addition, 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, those who want large families or those using gestational carriers to conceive. Another consideration is that identification and discarding of aneuploid embryos could potentially lessen the burden of excess embryos cryopreserved. On the other hand, patients using PGT-A may be left with the potential dilemma of how to handle excess mosaic embryos. In addition, the time to pregnancy may be faster in patients who conceive after a fresh transfer without PGT-A, because only those who did not conceive would pursue subsequent FETs with tested euploid embryos. Ideally, more RCTs that randomize patients at cycle start and evaluate cumulative live-birth rates are needed to elucidate some of these answers.There are potential disadvantages to using PGT-A, such as the need for increased resources and up to 8 cumulative hours of labor for the embryology team for each biopsy case (102). Furthermore, not all embryos will survive in culture to the blastocyst stage for biopsy, although hypothetically they may have resulted in a healthy live birth if they had been transferred in the cleavage or early blastocyst stage. Given the uncertainty about self-correction, false-positive PGT-A results, and/or accuracy of a mosaic diagnosis, there is concern that one may be discarding embryos that may have resulted in healthy neonates (98). Potential variations in aneuploidy rates in same age groups between laboratories also need further investigation. In addition, more data are needed about cumulative pregnancy rates from 1 retrieval cycle, effects of PGT-A on miscarriage rates, and defining which patient groups could benefit from this technology.
PATIENT PRIORITIES AND INDIVIDUAL CONSIDERATION
Despite the lack of evidence in support of universal use of PGT-A, uptake of this technology continues to grow. Factors that may contribute to patients and clinicians selecting this option include but are not limited to: insurance coverage (5) that mandates use of all embryos before additional retrievals or that limits the number of covered transfers such that knowledge that transferrable embryos are euploid may outweigh the risk of having fewer transferrable embryos or even losing some viable embryos in the process; consideration of banking extra embryos with a high likelihood of success to achieve ideal family size in older women, RPL with proven aneuploid conceptions, and the desire to limit recurrences. Older patients at a higher risk for aneuploid pregnancy may also be motivated to request PGT-A, especially in cases in which anticipated embryo yield is high, to reduce the likelihood of miscarriage or an ongoing aneuploid pregnancy. It is important to counsel patients on the published success and outcomes of PGT-A and discuss any social and financial concerns so that patients can make informed decisions around care.CONCLUSIONS
Adoption and use of PGT-A as part of IVF treatment has been increasing in the United States. The underlying technology used for 24-chromosome analysis also continues to evolve rapidly. The value of PGT-A as a universal screening test for all patients undergoing IVF has not been demonstrated. Some earlier single-center studies reported higher birth rates after PGT-A and eSET in the primary embryo transfer of favorable-prognosis patients, suggesting the potential for this testing to increase eSET utilization and minimize the incidence of multiple gestations. However, 2 recent, multicenter, randomized control trials in women with available blastocysts concluded that overall pregnancy outcomes via FET were similar between conventional IVF vs. PGT-A. The value of PGT-A to lower the risk of clinical miscarriage is also unclear. However, these studies have important limitations and there remain questions about appropriate patient selection and testing platforms.Subjects participating in these RCTs are generally favorable-prognosis patients who have produced blastocysts for biopsy and analysis. A broader selection of patients with randomization at cycle start rather than blastulation would more appropriately address the applicability of wider use of this technology. Furthermore, the randomized trials were performed in centers with broad and deep experience in embryo biopsy and specimen preparation. The ability to expand reliably these techniques to centers with less experience has yet to be established.
Other important considerations about PGT-A that must be addressed by further research include cost-effectiveness, use of mosaic embryos, false-positive results, risk of embryo damage, the role and effect of cryopreservation, time to pregnancy, utility in specific subgroups (such as RPL, prior implantation failure, advanced maternal age, and so on), use of sex selection, and total reproductive potential per intervention.
Large, prospective, well-controlled studies evaluating the combination of multiple approaches (genomics, time-lapse imaging, transcriptomics, proteomics, metabolomics, artificial intelligence, and so on) for enhanced embryo selection applicable in a more inclusive patient population are needed to determine not only the effectiveness, but also the safety and potential risks of these technologies. PGT-A will likely remain part of a multidimensional approach to embryo screening and selection. At present, however, the routine use of blastocyst biopsy with aneuploidy testing in all infertile patients undergoing IVF treatment cannot be recommended.
Acknowledgments
This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. The Practice Committee and the Board of Directors of the American Society for Reproductive Medicine have approved this report. This document was reviewed by ASRM members and their input was considered in the preparation of the final document. The following members of the ASRM Practice Committee participated in the development of this document: Alan Penzias, M.D.; Jacob Anderson; Paula Amato, M.D.: Kristin Bendikson, M.D.; Clarisa Gracia, M.D., M.S.C.E.; Tommaso Falcone, M.D.; Rebecca Flyckt, M.D.; Jessica Goldstein, R.N.; Karl Hansen, M.D., Ph.D.; Micah Hill, D.O.; Sangita Jindal, Ph.D.; Suleena Kalra, M.D., M.S.C.E.; Tarun Jain, M.D.; Bruce Pier, M.D.; Michael Thomas, M.D.; Richard Reindollar, M.D.; Jared Robins, M.D.; Chevis N Shannon, Dr.P.H., M.B.A., M.P.H.; Anne Steiner, M.D., M.P.H.: Cigdem Tanrikut, M.D.; and Belinda Yauger, M.D. The Practice Committee acknowledges the special contribution of Tarun Jain, M.D.; Elnur Babayev, M.D.; Nicole Banks, M.D.; Jake Anderson; Eric Forman, M.D.; and Jason Franasiak, M.D., in the preparation of this document. All Committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the Committee who were found to have conflicts of interest based on the relationships disclosed did not participate in the discussion or development of this document.REFERENCES
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- Somigliana E, Busnelli A, Paffoni A, Vigano P, Riccaboni A, Rubio C, et al. Cost-effectiveness of preimplantation genetic testing for aneuploidies. Fertil Steril 2019;111:1169–76.
- Lee E, Costello MF, Botha WC, Illingworth P, Chambers GM. A cost-effectiveness analysis of preimplantation genetic testing for aneuploidy (PGT-A) for up to three complete assisted reproductive technology cycles in women of advanced maternal age. Aust N Z J Obstet Gynaecol 2019; 59:573–9.
- Viotti M, Victor AR, Barnes FL, Zouves CG, Besser AG, Grifo JA, et al. Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use. Fertil Steril 2021;115: 1212–24.
- Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org. Clinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion. Fertil Steril 2020;114:246–54.
- Capalbo A, Poli M, Rienzi L, Girardi L, Patassini C, Fabiani M, et al. Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial. Am J Hum Genet 2021;108:2238–47.
- Munne S, Weier HU, Grifo J, Cohen J. Chromosome mosaicism in human embryos. Biol Reprod 1994;51:373–9.
- Gutierrez-Mateo C, Colls P, S'anchez-García J, Escudero T, Prates R, Ketterson K, et al. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril 2011;95:953–8.
- Gleicher N, Vidali A, Braverman J, Kushnir VA, Barad DH, Hudson C, et al. Accuracy of preimplantation genetic screening (PGS) is compromised by degree of mosaicism of human embryos. Reprod Biol Endocrinol 2016; 14:54.
- Kung A, Munn'e S, Bankowski B, Coates A, Wells D. Validation of next generation sequencing for comprehensive chromosome screening of embryos. Reprod Biomed Online 2015;31:760-9.
- Wells D, Kaur K, Grifo J, Glassner M, Taylor JC, Fragouli E, et al. Clinical utilisation of a rapid low-pass whole genome sequencing technique for the diagnosis of aneuploidy in human embryos prior to implantation. J Med Genet 2014;51:553–62.
- Scott RT Jr, Ferry K, Su J, Tao X, Scott K, Treff NR. Comprehensive chromosome screening is highly predictive of the reproductive potential of human embryos: a prospective, blinded, nonselection study. Fertil Steril 2012;97: 870–5.
- Tiegs AW, Tao X, Zhan Y, Whitehead C, Kim J, Hanson B, et al. A multi-center, 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;115:627–37.
- Barad DH, Albertini DF, Molinari E, Gleicher N. IVF outcomes of embryos with abnormal PGT-A biopsy previously refused transfer: a prospective cohort study. Hum Reprod 2022;37:1194-206.
- De Vos A, Staessen C, De Rycke M, Verpoest W, Haentjens P, Devroey P, et al. Impact of cleavage-stage embryo biopsy in view of PGD on human blastocyst implantation: a prospective cohort of single embryo transfers. Hum Reprod 2009;24:2988–96.
- Scott RT Jr, Upham KM, Forman EJ, Zhao T, Treff NR. Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial. Fertil Steril 2013;100:624–30.
- Paulson RJ. Preimplantation genetic screening: what is the clinical efficiency? Fertil Steril 2017;108:228–30.
- Counseling about genetic testing and communication of genetic test results. Committee Opinion No. 693. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017;129:771–2.
- Shaia K, Truong T, Pieper C, Steiner A. Pre-implantation genetic testing alters the sex ratio: an analysis of 91,805 embryo transfer cycles. J Assist Reprod Genet 2020;37:1117–22.
- United States Census Bureau. Age and sex composition: 2010. Available at: https://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf. Accessed October 24, 2020.
- Alikani M, Go KJ, McCaffrey C, McCulloh DH. Comprehensive evaluation of contemporary assisted reproduction technology laboratory operations to determine staffing levels that promote patient safety and quality care. Fertil Steril 2014;102:1350–6.
Practice Documents
ASRM Practice Documents have been developed to assist physicians with clinical decisions regarding the care of their patients.
The use of preimplantation genetic testing for aneuploidy: a committee opinion (2024)
PGT-A use in the U.S. is rising, but its value as a routine IVF screening test is unclear, with mixed results from various studies.
Evidence-based diagnosis and treatment for uterine septum: a guideline (2024)
To provide evidence-based recommendations regarding the diagnosis and effectiveness of surgical treatment of a uterine septum.
The use of hormonal contraceptives in fertility treatments: a committee opinion (2024)
Hormonal contraception aids in the timing of ART cycles, reduce ovarian cysts at IVF cycle initiation, and optimize visualization before hysteroscopy.
Current evaluation of amenorrhea: a committee opinion (2024)
Amenorrhea is the absence or abnormal cessation of the menses.More Resources
ASRM Academy on the Go
ASRM MAC Tool 2021
The ASRM Müllerian Anomaly Classification 2021 (MAC2021) includes cervical and vaginal anomalies and standardize terminology within an interactive tool format.
Practice Guidance
EMR Shared Phrases/Template Library
This resource includes phrases shared by ASRM physician members to provide a template for individuals to create their own EMR phrases.
ASRM Practice Documents
These guidelines have been developed by the ASRM Practice Committee to assist physicians with clinical decisions regarding the care of their patients.
ASRM Ethics Opinions
Ethics Committee Reports are drafted by the members of the ASRM Ethics Committee on the tough ethical dilemmas of reproductive medicine.
Practice Guidance
Coding Corner Q & A
The Coding Corner Q & A is a list of previously submitted and answered questions from ASRM members about coding. Answers are available to ASRM Members only.
Practice Guidance
COVID-19 Resources
A compendium of ASRM resources concerning the Novel Corona virus (SARS-COV-2) and COVID-19.
Patient Resources
ReproductiveFacts.org provides a wide range of information related to reproductive health and infertility through patient education fact sheets, infographics, videos, and other resources.
Topic Resources
View more on the topic of genetic screening/testing
Genetics: Counseling Fertility Couples About Their Evaluation
Caitlin Hebert discusses fertility counseling, the importance of carrier screening, and overcoming barriers for patients while highlighting the role of genetic counseling. View the ASRMed Talk VideoUse of preimplantation genetic testing for monogenic adult-onset conditions: an Ethics Committee opinion (2024)
Preimplantation genetic testing for monogenic diseases for adult-onset conditions is ethically permissible for various conditions, including when the condition is fully penetrant or confers disease predisposition. View the Committee Opinion
Codes for Embryo Biopsy
When doing a preimplantation genetic test (PGT) biopsy, can you bill for each day a biopsy is performed or can you only bill once for the cycle? View the Answer
The use of preimplantation genetic testing for aneuploidy: a committee opinion (2024)
PGT-A use in the U.S. is rising, but its value as a routine IVF screening test is unclear, with mixed results from various studies. View the Committee Opinion
Fertility and Sterility On Air - TOC: July 2024
Articles this month include: predicting ART complications, laser assisted hatching on vitrified blastocysts, predictive models of miscarriage and more.Listen to the Episode
Fertility and Sterility On Air - TOC: May 2024
Topics this month include Iatrogenic and demographic determinants of the national plural birth increase, outcomes between ICSI and IVF with PGT-A. Listen to the Episode
Journal Club Global: Recent clinical trials in Fertility and Sterility from the Asia Pacific region
Join ASPIRE 2024 for a Journal Club Global on PGT-A and IVF. Learn from top experts discussing recent clinical trial data and pregnancy outcomes View the Video
Coding for an endometrial biopsy/Mock cycle
We had patients request us to bill their insurance for the two monitoring visits and the Endo BX and change the diagnosis code to something that is payable. View the Answer
Journal Club Global: Cost effectiveness analyses of PGT-A
Infertility treatments can be financially burdensome, often without insurance coverage, making understanding the cost effectiveness of PGT-A crucial. View the Video
Coding PGT requisitions to the PGT lab
Do you have any recommended codes to use for PGT requisitions to the PGT lab? View the Answer
Genetics: Is Expanded Carrier Screening the Standard of Care?
Hannah Green, a genetic counselor at NYU, discusses the benefits and limitations of expanded carrier screening, highlighting its impact on clinical practice and patient care. View the ASRMed Talk Video
Clinical management of mosaic results from preimplantation genetic testing for aneuploidy of blastocysts: a committee opinion (2023)
This document incorporates studies about mosaic embryo transfer and provides evidence-based considerations for embryos with mosaic results on PGT-A. View the Committee Opinion
Journal Club Global - Revisiting the STAR trial: The Fellows debate PGT-A
We are excited to host a debate covering the pros and cons of PGT-A and how new technologies should be validated before clinical implementation. View the Video
Sperm DNA Fragmentation
Is there a CPT code for HALO DNA Fragmentation for sperm? View the Answer
Results Review
What CPT code is most appropriate to submit for Physician Time to review CCS/PGS/PGD results? View the Answer
ICSI and Embryo Biopsy
How to bill for ICSI or embryo biopsies that occur in different days? View the Answer
Embryo Biopsy
Have any new codes been introduced for the lab portion of PGT? View the Answer
Embryo Biopsy Embryologist Travel Costs
Can we bill insurance for the biopsy procedure? Can we bill for travel expenses? View the Answer
Embryo Biopsy PGS Testing
What codes are appropriate for PGS testing? View the Answer
Genetic Counseling
Does ASRM have any guidance for how to bill for genetic counseling services provided by a genetic counselor?View the Answer
Assisted Zona Hatching
Can assisted hatching and embryo biopsy for PGT-A; PGT-M or PGT-SR be billed during the same cycle? View the Answer
Indications and management of preimplantation genetic testing for monogenic conditions: a committee opinion (2023)
ASRM has updated its opinion on PGT for monogenic conditions, providing guidance on clinical and technical complexities. View the Committee Opinion
Journal Club Global - PGT-A - Can non-invasive approaches based on spent medium analysis
PGT-A by trophectoderm biopsy aims to select available euploid embryos for transfer. View the Video
ASRM müllerian anomalies classification 2021
The Task Force set goals for a new classification and chose to base it on the iconic AFS classification from 1988 because of its simplicity and recognizability. View the Committee Opinion
Journal Club Global - Accuracy of Preimplantation Genetic Testing for Aneuploidies
One of the highest aspirations in reproductive medicine is to develop a technology allowing for ID of embryos that have true reproductive potential.
View the Video
Reproductive and hormonal considerations in women at increased risk for hereditary gynecologic cancers: Society of Gynecologic Oncology and American Society for Reproductive Medicine Evidence-Based Review (2019)
Providers who care for women at risk for hereditary gynecologic cancers must consider the impact of these conditions. View the Joint Statement
Disclosure of sex when incidentally revealed as part of preimplantation genetic testing (PGT): an Ethics Committee opinion (2018)
Clinics may develop a policy to disallow selecting which embryos to transfer based on sex and choose to use only embryo quality as selection criteria. View the Committee Opinion
Use of preimplantation genetic testing for monogenic defects (PGT-M) for adult-onset conditions: an Ethics Committee opinion (2018)
Preimplantation genetic testing for monogenic diseases for adult-onset conditions is ethically permissible for a range of conditions including when the condition is serious and no safe, effective interventions are available. View the Committee Document
Transferring embryos with genetic anomalies detected in preimplantation testing: an Ethics Committee Opinion (2018)
Patient requests for transfer of embryos with genetic anomalies linked to serious health-affecting disorders detected in preimplantation testing are rare but do exist. View the Committee Document
Best practices of ASRM and ESHRE: a journey through reproductive medicine (2012)
ASRM and ESHRE are the two largest societies in the world whose members comprise the major experts and professionals working in reproductive medicine. View the Committee Joint Guideline
Preimplantation Genetic Testing Special Interest Group (PGTSIG)
The ASRM PGTSIG coordinates research, education, and training in preimplantation genetic diagnosis (PGT). Learn more about the PGTSIGTopic Resources
View more on the topic of in vitro fertilization (IVF)
Fertility and Sterility On Air - Unplugged: October 2024
Topics include: mechanical contractions and fibroid progression, endometriosis classification and risk of infertility, fertility coverage for military personnel and more. Listen to the Episode
ASRM Releases Congressional Scorecard
Discover ASRM's first Congressional scorecard, detailing positions of the 118th Congress on key reproductive legislation to guide ASRM members in elections.
View the Press Release
Fertility Care Gets Important Win in California
ASRM celebrates California's SB 729, expanding IVF coverage for same-sex couples and singles, advancing equitable fertility care access.
View the Press Release
ASRM Today: Equity, Access, and Innovation, Episode Five: Policy Matters
This episode covers ballot measures on reproductive rights, ASRM advocacy efforts, and Vot-ER’s push for civic engagement among healthcare workers ahead of elections. Listen to the Episode
Nation’s Leading Professional Group for Fertility Care Professionals Calls for Passage of Right to IVF Act
ASRM applauds Majority Leader Schumer’s decision to seek reconsideration of the Right to IVF Act.
View the Press Release
ASRM Today: Equity, Access, and Innovation, Episode Three: Innovation
Explore innovation in reproductive health with ASRM Today. Discover how AI, robotics, and new technologies are transforming fertility care and improving patient outcomes. Listen to the Episode
Fertility and Sterility On Air - Live from ESHRE 2024: Part 1
Discover the impact of embryo expansion post-biopsy and freezing time standardization on live births in this episode from ESHRE 2024. Listen to the Episode
Fertility and Sterility On Air - Live from ESHRE 2024: Part 2
Explore fresh embryo transfers, progesterone elevation, and day-seven embryo utility from experts at ESHRE 2024. Cutting-edge fertility insights await! Listen to the Episode
Fertility and Sterility On Air - ANZSREI 2024 Journal Club Global: "Should Unexplained infertility Go Straight to IVF?"
Join "Fertility and Sterility On Air" for insights from the ANXSREI conference on unexplained infertility, IVF, and expert debates. Listen now at ASRM.org. Listen to the Episode
The use of preimplantation genetic testing for aneuploidy: a committee opinion (2024)
PGT-A use in the U.S. is rising, but its value as a routine IVF screening test is unclear, with mixed results from various studies. View the Committee Opinion
Trump Calls for IVF Coverage, California Legislature Sends IVF Mandate Bill to Governor
The California General Assembly approved a bill mandating most private health insurance plans to provide coverage for In Vitro Fertilization (IVF).
View the Press Release
Journal Club Global from ANZSREI 2024: Debate Unexplained infertility; Straight to IVF?
ANZSREI 2024 debate: Should unexplained infertility go straight to IVF? Experts discuss pros, cons, and alternative treatments. No clear consensus reached. View the Video
Get Vot-ER Ready This National Patient Advocacy Day!
Celebrate National Patient Advocacy Day by boosting civic engagement! Order your free Vot-ER badge to help patients register to vote and promote healthy communities.
View the Press Release
Who to bill for gestational carrier services if intended parents have insurance?
I wanted to inquire about guidelines for billing services to a surrogate’s insurance company if intended parents purchased the insurance coverage. View the Answer
Performing MD is not the Doctor of Record
Currently we are billing the performing provider as the service provider and the Doctor of Record as the billing provider. View the Answer
ASRM marks World IVF Day by doing what we do best – advocating for access to reproductive health care by calling for a House floor vote on the Right to IVF Act
ASRM observed World IVF Day, the day marking the birth of the world’s first IVF baby in 1978, by continuing its advocacy for improvements in IVF policy.
View the Press Release
Journal Club Global: Oral Progestin For Ovulation Suppression During IVF
Live broadcast from the 2024 Midwest Reproductive SymposiumInternational in Chicago, IL View the Video
Order your FREE Vot-ER badge to encourage patients and colleagues to vote!
ASRM) is pleased to announce our partnership with Vot-ER, a grassroots organization dedicated to driving civic engagement among healthcare professionals.
View the Press Release
Fertility and Sterility On Air - Seminal Article: Ernest Ng and Zhi Chen
June issue Seminal Contribution: a randomized controlled trial studying the use of progestins for ovulation supression in predicted high responders. Listen to the Episode
ASRM Responds to Senate Vote on IVF Bill
ASRM is disappointed that a filibuster prevented the passage of the Right to IVF Act.
View the Press Release
ASRM Calls for Passage of Family Building Bill
It would increase access to IVF treatments for all Americans, including active-duty service members, veterans, and federal employees.
View the Press Release
Fertility and Sterility On Air - TOC: May 2024
Topics this month include Iatrogenic and demographic determinants of the national plural birth increase, outcomes between ICSI and IVF with PGT-A. Listen to the Episode
ASRM publishes IVF one-pagers for media use
The documents lay out the clinical IVF process, summarize oversight of IVF in the U.S., and explain how lawmakers can support access to IVF.
View the Press Release
Billing for assisted hatching at biopsy and transfer
We would also like to know if you can bill assisted hatching with biopsy and then assisted hatching again during the transfer cycle. View the Answer
ASRM Reacts to Cruz/Britt OPED
We are pleased to see Senators Cruz and Britt express their interest in protecting access to IVF.
View the Press Release
Fertility and Sterility On Air - Unplugged: April 2024
Topics include: IVF in film, a rat model of fallopian tube torsion, comparing letrozole regimens for PCOS, and a review of chronic endometritis. Listen to the Episode
ASRM Files Amicus Brief in Texas Embryo Case
ASRM has filed an amicus curiae (friend of the court) brief in the case of Antoun v Antoun, which is pending before the Texas Supreme Court.
View the Press Release
Financial ‘‘risk-sharing’’ or refund programs in assisted reproduction: an Ethics Committee opinion (2023)
Financial ‘‘risk-sharing’’ fee structures in programs charge patients a higher initial fee but provide reduced fees for subsequent cycles. View the Committee Document
Alabama Supreme Court Rules Frozen Embryos are “Unborn Children” and admonishes IVF’s “Wild West” treatment
Legally Speaking™ on presenting facts and reflecting on the impact and potential implications of legal developments in ART. View the Column
Billing IVF lab work
We typically bill our IVF Lab work under the rendering provider who performs the VOR. Who should be the supervising provider for embryology billing? View the Answer
Journal Club Global: IVM in Clinical Practice: An Idea Whose Time Has Come?
In vitro maturation (IVM) has the potential to make IVF cheaper, safer, and more widely accessible to patients with infertility. View the Video
Comparison of pregnancy rates for poor responders using IVF with mild ovarian stimulation versus conventional IVF: a guideline (2018)
Mild-stimulation protocols with in vitro fertilization (IVF) generally aim to use less medication than conventional IVF. View the Guideline
IVF cycle management and facility fees, an overview
How should IVF Cycle Management be coded? View the Answer
Limited ultrasound performed by RN
Would it be appropriate to bill a 99211 when an RN is doing a limited ultrasound and documenting findings during an IUI or IVF treatment cycle? View the Answer
CPT 89253 and 89254 for Assisted hatching
Can I bill CPT codes 89253 and 89254 together? If yes, do I need a modifier on any of the codes? View the Answer
Journal Club Global - What is the optimal number of oocytes to reach a live-birth following IVF?
The optimal number of oocytes necessary to expect a live birth following in vitro fertilization remains unclear. View the Video
Patient Education
What is the correct way to bill for the patient education sessions performed by registered nurses to individual patients prior to their IVF cycle? View the Answer
Pregnancy Ultrasound
Our practice does routine ultrasounds (sac check- 76817) at the end of an IVF cycle and bill with a diagnosis code O09.081, pregnancy resulting from ART. View the Answer
IVF Consent Counseling
When a patient is scheduled to undergo IVF and the provider schedules the patient for a 30-minute consultation is this visit billable? View the Answer
Lab Case Rates
What ICD-10 codes apply to case rates? View the Answer
In Vitro Maturation
Have CPT codes been established for maturation in vitro? View the Answer
IUI or IVF
Should other ovarian dysfunction (diagnosis code E28.8) or unspecified ovarian dysfunction (diagnosis code E28.9) can be used for an IUI or an IVF cycle View the Answer
IV Fluids During Egg Retrieval
Is it appropriate to bill the insurance company for CPT 96360, Under Hydration Infusion when being used in conjunction with IVF retrieval? View the Answer
IVF Billing Forms
I am seeking information on IVF insurance billing guidelines. View the Answer
IVF Billing Globally
Am I correct in assuming that it is duplicate billing for both the ambulatory center and embryology laboratory to bill globally? View the Answer
IVF Billing of Professional Charges
Are we allowed to bill professional charges under the physician for the embryologist who performs the IVF laboratory services? View the Answer
IVF Case Rates
What ICD-10 codes apply to case rates? View the Answer
Oocyte Denudation
Is there is a separate code for denudation of oocytes? View the Answer
Ovulation Induction Monitoring for IUI
We would like to clarify the correct ICD 10 diagnosis code for monitoring of an IUI cycle. View the Answer
Endometrial Biopsy/Scratch
What CPT code should be used for a “scratch test”? View the Answer
Endometriosis and Infertility
For treatment like IVF would we bill with N97.x first or an endometriosis diagnosis? View the Answer
Follicle Monitoring For Diminished Ovarian Reserve
If a patient has decreased ovarian reserve (ICD-10 E28.8) and patient is undergoing follicle tracking to undergo either an IUI cycle or IVF cycle... View the Answer
Global Billing Vs Billing Under Provider
For an IVF cycle (that is not being billed global to an insurance plan) is it appropriate to bill the charges under one “global” provider? View the Answer
Diagnosis of Infertility for IVF Procedure
How important is it to have accurate documentation of the type of infertility diagnosis for IVF procedures? View the Answer
Donor Embryos
Could you give guidance for the correct ICD-10 code(s) to use when a patient is doing an Anonymous Donor Embryo Transfer cycle? View the Answer
Egg Culture and Fertilization
We are billing for the technical component of 89250 and would like to also bill a professional component of the 89250. View the Answer
Egg Culture and Fertilization: Same Gender
A same-sex male couple requested half their donor eggs be fertilized with sperm from male #1 and the other half fertilized from male #2. View the Answer
Journal Club Global: Natural versus Programmed FET Cycles
A significant portion of IVF cycles now utilize frozen embryo transfer.
View the Video
Role of assisted hatching in in vitro fertilization: a guideline (2022)
There is moderate evidence that assisted hatching does not significantly improve live birth rates in fresh assisted reproductive technology cycles View the Committee Opinion
Journal Club Global - Best Practices of High Performing ART Clinics
This Fertility and Sterility Journal Club Global discusses February’s seminal article, “Common practices among consistently high-performing in vitro fertilization programs in the United States: a 10 year update.” View the Video
Guidance on the limits to the number of embryos to transfer: a committee opinion (2021)
ASRM's guidelines for the limits on the number of embryos to be transferred during IVF cycles have been further refined ... View the Committee Opinion
Journal Club Global Live from India - Adjuvants in IVF and IVF Add-Ons for the Endometrium
Many adjuvants have been utilized by IVF centers to improve their success rates. View the Video
Evidence-based outcomes after oocyte cryopreservation for donor oocyte in vitro fertilization and planned oocyte cryopreservation: a guideline (2021)
A review of success rates, factors that may impact success rates, and outcomes. View the Committee Opinion
Development of an emergency plan for in vitro fertilization programs: a committee opinion (2021)
All IVF programs and clinics should have a plan to protect fresh and cryopreserved human specimens (embryos, oocytes, sperm). View the Committee Opinion
In vitro maturation: a committee opinion (2021)
The results of in vitro maturation (IVM) investigations suggest the potential for wider clinical application. View the Committee Opinion
Fertility treatment when the prognosis is very poor or futile: an Ethics Committee opinion (2019)
The Ethics Committee recommends that in vitro fertilization (IVF) centers develop patient-centered policies regarding requests for futile treatment. View the Committee Opinion
Blastocyst culture and transfer in clinically assisted reproduction: a committee opinion (2018)
The purposes of this document is to review the literature regarding the clinical application of blastocyst transfer. View the Committee Opinion
The role of immunotherapy in in vitro fertilization: a guideline (2018)
Adjuvant immunotherapy treatments in in vitro fertilization (IVF) aim to improve the outcome of assisted reproductive technology (ART) in both the general ART population as well as subgroups such as patients with recurrent miscarriage or implantation failure. View the Committee Opinion
Performing the embryo transfer: a guideline (2017)
A systematic review of the literature was conducted which examined each of the major steps of embryo transfer. Recommendations made for improving pregnancy rates are based on interventions demonstrated to be either beneficial or not beneficial. (Fertil Steril® 2017;107:882–96. ©2017 by American Society for Reproductive Medicine.) View the Committee Guideline
Best practices of ASRM and ESHRE: a journey through reproductive medicine (2012)
ASRM and ESHRE are the two largest societies in the world whose members comprise the major experts and professionals working in reproductive medicine. View the Committee Joint Guideline
What support for IVF looks like
Bipartisan support for IVF, that is responsible for the birth of over 2% of all babies born in the USA each year, will ensure that families continue to grow. View the advocacy resource
It takes more than one
Why IVF patients often need multiple embryos to have a baby View the advocacy resource
Oversight of IVF in the US
In the US, medical care is regulated by a complex and comprehensive network of federal and state regulations and professional oversight. View the advocacy resource
In Vitro Maturation Special Interest Group (IVMSIG)
IVMSIG strives to define the best strategies to optimize IVM outcomes. Learn more about IVMSIG
Advocacy Resources
ASRM has prepared resources to help explain and advocate for reproductive rights and the continuation of in vitro fertilization and other fertility treatments. View the advocacy resourcesTopic Resources
View more on the topic of infertility
Use of preimplantation genetic testing for monogenic adult-onset conditions: an Ethics Committee opinion (2024)
Preimplantation genetic testing for monogenic diseases for adult-onset conditions is ethically permissible for various conditions, including when the condition is fully penetrant or confers disease predisposition. View the Committee Opinion
Fertility Care Gets Important Win in California
ASRM celebrates California's SB 729, expanding IVF coverage for same-sex couples and singles, advancing equitable fertility care access.
View the Press Release
Appropriate Use of Modifier -25
Is Modifier -25 appropriate in the monitoring cycle when an ultrasound View the Answer
Billing for E/M Visits
When billing Evaluation & Management (E/M) visits based on medical decision-making, would we View the Answer
Timed Intercourse Cycle Codes
Is it appropriate to utilize codes N97.8 or View the Answer
The use of preimplantation genetic testing for aneuploidy: a committee opinion (2024)
PGT-A use in the U.S. is rising, but its value as a routine IVF screening test is unclear, with mixed results from various studies. View the Committee Opinion
National Infertility Awareness Week
April 20-26, 2025, is National Infertility Awareness Week (NIAW)!
View the NIAW Toolkit
Fertility Support and AI: Help or Hinderance
Discover how fertility apps impact patient care and nursing staff. Explore the balance between tech and human touch in complex fertility treatments View the ASRMed Talk Video
Fertility and Sterility On Air - Seminal Article: Ernest Ng and Zhi Chen
June issue Seminal Contribution: a randomized controlled trial studying the use of progestins for ovulation supression in predicted high responders. Listen to the Episode
ASRM announces support for HOPE with Fertility Services Act
The American Society for Reproductive Medicine is proud to endorse the HOPE with Fertility Services Act (HR 8821).
View the Press Release
HyCoSy and CPT 74740
When Office HSG/HyCoSy is performed but no x-ray/fluoroscopic imaging is performed, only ultrasound is done, is it appropriate to bill CPT code 74740? View the Answer
Subclinical hypothyroidism in the infertile female population: a guideline (2024)
This guideline reviews the risks and benefits of treating subclinical hypothyroidism in female patients with a history of infertility and miscarriage. View the Committee Guideline
Tobacco or marijuana use and infertility: a committee opinion (2023)
In the United States, approximately 21% of adults report some form of tobacco use, although 18% report marijuana use. View Committee Opinion
Journal Club Global: The future of REI Fellowship training: debating opportunities and threats
This exciting collaboration discusses the controversy and future directions for the field of Reproductive Endocrinology and Infertility medicine. View the Video
Journal Club Global: Infertility and Subclinical Hypothyroidism
The impact of treating SCH on fertility, obstetric outcomes, and offspring neurocognitive development is debated in the literature. View the Video
Ethical considerations for telemedical delivery of fertility care: an Ethics Committee opinion (2024)
Telemedicine has the potential to increase access to and decrease the cost of care. View the Committee Opinion
Ethical obligations in fertility treatment when intimate partners withhold information from each other: an Ethics Committee opinion (2024)
Clinicians should encourage disclosure between intimate partners but should maintain confidentiality where there is no harm to the partner and/or offspring. View the Committee Opinion
Definition of infertility: a committee opinion (2023)
‘‘Infertility’’ is a disease, condition, or status characterized by several factors. View the Committee Opinion
Diagnostic evaluation of sexual dysfunction in the male partner in the setting of infertility: a committee opinion (2023)
It is the responsibility of the clinician to assess for erectile dysfunction, ejaculatory dysfunction, or diminished libido in men presenting for infertility. View the Committee Opinion
Journal Club Global - Actualización en la suplementación con progesterona en fase lútea para transferencias de embriones congelados
Efectividad del rescate de progesterona en mujeres que presentan niveles bajos de progesterona circulante alrededor del día de la transferencia de embriones View the Video
The International Glossary on Infertility and Fertility Care, 2017†‡§ (2017)
Terms and definitions currently used infertility care, infertility and medically assisted reproduction (MAR) can have different meanings that are dependent upon the setting, their usage in research or clinical interventions, or among diverse populations.View the Committee Joint Guideline
Endometriosis and infertility: a committee opinion (2012)
Women with endometriosis typically present with pelvic pain, infertility, or an adnexal mass, and may require surgery. View the Committee Opinion
Testing With No History of Infertility
What diagnosis codes should providers submit to insurance carriers while trying to evaluate fertility issues? View the Answer
Self-referred New Patient
A patient self-refers to our physician for an initial new patient consultation instead of referred by another physician, how do we code for the consult? View the Answer
Surgery Coding
I took the ASRM coding course, and in that course, coding for bilateral neosalpingostomies was coded using only a dx of N70.11 (hydrosalpinx). View the Answer
Telephone Consult
Does a physician need to speak directly to a patient to code for a telephone consult (99371-99373) or can a staff member relay physician notes to patients? View the Answer
Post Vasectomy Infertility
If a husband has had a vasectomy, does the sterilization code apply to the wife's visits? View the Answer
Pregnancy Of Uncertain Viability Ultrasound
My staff is telling me that I am getting reimbursed for the first sonogram and OB visit (using ICD 10 code for pregnancy of uncertain viability – O36.80X0. View the Answer
Pregnancy Ultrasound
Our practice does routine ultrasounds (sac check- 76817) at the end of an IVF cycle and bill with a diagnosis code O09.081, pregnancy resulting from ART. View the Answer
Psychological Evaluation
Many REs require patients (and their spouses/partners) who are considering using donor gametes to see an infertility counselor first. View the Answer
Infertility Consult
Does ASRM have any examples of evaluation and management documentation for patients being seen for an initial infertility evaluation? View the Answer
Infertility Consult by Nurse
What code is used for a nurse practitioner seeing a fertility patient for the first time? View the Answer
Initial Visit for Infertility With No Mandated Coverage
What code would be appropriate for an initial visit for infertility? View the Answer
IUI or IVF
Should other ovarian dysfunction (diagnosis code E28.8) or unspecified ovarian dysfunction (diagnosis code E28.9) can be used for an IUI or an IVF cycle View the Answer
Monitoring E&M
Our group would like to know if others are billing an evaluation and management code for ultrasound and blood draw visits? View the Answer
New vs Established Patient
How soon can you bill as a new infertility patient? View the Answer
General E&M Consult
Recently we have received a “re-code” on a new patient (we billed a 99203 and the insurance re-coded it to a 99213). View the Answer
Hysteroscopy Recurrent Implantation Failure
What is the appropriate ICD-10 code for recurrent implantation failure? View the Answer
D&C Under Ultrasound Guidance
What are the CPT codes and ICD-10 codes for coding a surgical case for a patient with history of Stage B adenocarcinoma of the cervix ... View the Answer
Diagnosis of Infertility for IVF Procedure
How important is it to have accurate documentation of the type of infertility diagnosis for IVF procedures? View the Answer
Diagnostic Testing of an Infertile Couple
The Z31.41 is or is not the correct code to use for diagnostic testing of an infertile couple? And If so can if be used as the primary and only code? View the Answer
Blood Draws
If a patient comes in only for a blood draw (venipuncture) and is seen only by the lab technician (not an MD, PA, or NP), may we bill for a (minimal) office visit? View the Answer
Blood Tests
Patients are requesting to have lab work drawn from the female patient moved to the males account due to the female fertility coverage being maxed out. View the Answer
Male Infertility
A summary of common codes for Male Infertility compiled by the ASRM Coding Committee. View the Coding Summary
ASRM müllerian anomalies classification 2021
The Task Force set goals for a new classification and chose to base it on the iconic AFS classification from 1988 because of its simplicity and recognizability. View the Committee Opinion
Intracytoplasmic sperm injection (ICSI) for non–male factor indications: a committee opinion (2020)
Intracytoplasmic sperm injection is frequently used in combination with assisted reproductive technologies. View the Committee Document
Moving innovation to practice: an Ethics Committee opinion (2021)
The introduction of new strategies, tests, and procedures into clinical practice raises challenging ethical issues. View the Committee Opinion
Fertility evaluation of infertile women: a committee opinion (2021)
Diagnostic evaluation for infertility in women should be conducted in a systematic, expeditious, and cost-effective manner. View the Committee Opinion
Fertility treatment when the prognosis is very poor or futile: an Ethics Committee opinion (2019)
The Ethics Committee recommends that in vitro fertilization (IVF) centers develop patient-centered policies regarding requests for futile treatment. View the Committee Opinion
Use of exogenous gonadotropins for ovulation induction in anovulatory women: a committee opinion (2020)
Pretreatment evaluation, indications, treatment regimens, and complications of gonadotropin treatment. View the Committee Opinion
Reproductive and hormonal considerations in women at increased risk for hereditary gynecologic cancers: Society of Gynecologic Oncology and American Society for Reproductive Medicine Evidence-Based Review (2019)
Providers who care for women at risk for hereditary gynecologic cancers must consider the impact of these conditions. View the Joint Statement
Guidance for Providers Caring for Women and Men Of Reproductive Age with Possible Zika Virus Exposure (Updated 2019)
This ASRM guidance specifically addresses Zika virus infection issues and concerns of individuals undergoing assisted reproductive technologies (ART). View the Guideline
American Society for Reproductive Medicine position statement on uterus transplantation: a committee opinion (2018)
Following the birth of the first child from a transplanted uterus in Gothenburg, Sweden, in 2014, other centers worldwide have produced scientific reports. View the Committee Opinion
Child-rearing ability and the provision of fertility services: an Ethics Committee opinion (2017)
Fertility programs may withhold services on the basis that patients will be unable to provide minimally adequate or safe care for offspring. View the Committee Opinion
Removal of myomas in asymptomatic patients to improve fertility and/or reduce miscarriage rate: a guideline (2017)
This review evaluates if uterine myomas impact likelihood of pregnancy and pregnancy loss, and if myomectomy influences pregnancy outcomes. View the Guideline
