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The status of preimplantation genetic testing in the UK and USA

The status of preimplantation genetic testing in the UK and USA Human Reproduction, Vol.35, No.4, pp. 986–998, 2020 Advance Access Publication on April 24, 2020 doi:10.1093/humrep/deaa034 ORIGINAL ARTICLE Reproductive genetics The status of preimplantation genetic testing in the UK and USA 1 1 1,2, Rachel Theobald , Sioban SenGupta , and Joyce Harper 1 2 Institute for Women’s Health, 86-96 Chenies Mews, University College London, London, WC1E 6HX, UK Institute for Women’s Health, University College London, 86-96 Chenies Mews, London, WC1E 6HX, UK *Correspondence. E-mail: [email protected] Submitted on November 27, 2018; resubmitted on October 24, 2019; editorial decision on January 7, 2020 STUDY QUESTION: Has the number of preimplantation genetic testing (PGT) cycles in the UK and USA changed between 2014 and 2016? SUMMARY ANSWER: From 2014 to 2016, the number of PGT cycles in the UK has remained the same at just under 2% but in the USA has increased from 13% to 27%. WHAT IS KNOWN ALREADY: PGT was introduced as a treatment option for couples at risk of transmitting a known genetic or chromosomal abnormality to their child. This technology has also been applied as an embryo selection tool in the hope of increasing live birth rates per transfer. ART cycles are monitored in the UK by the Human Fertilisation and Embryology Authority (HFEA) and in the USA by the Society for Assisted Reproductive Technology (SART). Globally, data are monitored via the ESHRE PGT Consortium. STUDY DESIGN, SIZE, DURATION: This cross-sectional study used the HFEA and SART databases to analyse PGT cycle data and make comparisons with IVF data to examine the success of and changes in patient treatment pathways. Both data sets were analysed from 2014 to 2016. The UK data included 3385 PGT cycles and the USA data included 94 935 PGT cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Following an extensive review of both databases, filters were applied to analyse the data. An assessment of limitations of each database was also undertaken, taking into account data collection by the ESHRE PGT Consortium. In the UK and USA, the publicly available information from these datasets cannot be separated into different indications. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of PGT cycles as a total of ART procedures has remained the same in the UK but increased annually in the USA from 13% to 27%. Between 2014 and 2016 inclusive, 3385 PGT cycles have been performed in the UK, resulting in 1074 PGT babies being born. In the USA 94 935 PGT cycles have been performed, resulting in 26 822 babies being born. This gave a success rate per egg collection for PGT of 32% for the UK and 28% for the USA. Analysis of the data by maternal age shows very different patient populations between the UK and USA. These differences may be related to the way PGT is funded in the UK and USA and the lack of HFEA support for PGT for aneuploidy. LIMITATIONS, REASONS FOR CAUTION: Data reported by the HFEA and SART have different limitations. As undertaken by the ESHRE PGT Consortium, both data sets should separate PGT data by indication. Although the HFEA collects data from all IVF clinics in the UK, SART data only represent 83% of clinics in the USA. WIDER IMPLICATIONS OF THE FINDINGS: Worldwide, a consistent reporting scheme is required in which success rates can convey the effectiveness of PGT approaches for all indications. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained and there are no competing interests to declare that are directly related to this project. Joyce Harper is the director of the Embryology and PGD Academy, which offers education in these fields. Key words: preimplantation genetic testing / PGS / PGD / ART / reproductive genetics / UK / USA . Preimplantation genetic testing (PGT) is an ART procedure that Introduction is used to investigate the genetic make-up of embryos produced by Since the birth of Louise Brown, the world’s first ‘test-tube baby’ in IVF (Zhang et al., 2016). PGT-M (monogenic disease) and PGT-SR 1978 (Steptoe and Edwards, 1978), the use of ART has increased (structural rearrangements) are treatment options for couples whose dramatically. With over 6 million births worldwide, this global industry children are at high risk of inheriting a known genetic or chromosomal is now estimated to be worth £20–30 billion (Weinerman, 2018). abnormality (Harper and SenGupta, 2012). Although most couples © The Author(s) 2020. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which per- mits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] PGT in the UK and USA, 2014–2016 987 undergoing PGT-M tend to be fertile, success rates are similar to those . format and allowed a treatment cycle for IVF and PGT to be followed undergoing routine IVF (De Rycke et al., 2017). Patients undergoing up to a live birth occurrence. Only cycles where the patients used their PGT-SR are generally phenotypically normal, but often their infertility own eggs were analysed. issues make them aware they are balanced carriers of chromosomal The fields that were available for both databases were assessed, rearrangements. . and the appropriate filters were chosen. Filters were applied to both PGT-A (aneuploidy) is an IVF adjunct and its use is controversial sets of data to undertake the analysis. In cases where there were (Harper et al., 2017; Wilkinson et al., 2019). PGT-A is carried out . spurious results, data were excluded from analysis and highlighted for selection of a euploid embryo, which will be used for transfer in where necessary. the hope of increasing live birth rates (LBRs) (Brezina and Kutteh, 2015). PGT-A has been applied to women of advanced maternal HFEA data collection age, couples who have had repeated miscarriages but have a normal The HFEA presents treatment data as cycles. PGT-A, PGT-M/SR and karyotype, those with repeated implantation failure, egg donors and IVF treatment cycles could be separated to allow a better understand- good prognosis patients (Mastenbroek et al., 2011). . The first reports of PGT world data were published by Harper and ing of the demographics of each ART technique. These treatments Handyside (1994) and Harper (1996). This led to establishment of the could be further separated into fresh and frozen cycles. The HFEA data ESHRE PGT Consortium, which has been reporting annual PGT data include patient age at treatment, the number of treatment cycles and since 1997 (Harper et al., 2012). The Consortium reports the IVF and . outcomes such as LBR PET and LBR PTC. biopsy method, analysis details, embryology and clinical outcomes per . The HFEA PGT databases are fixed and closed. The full database egg collection and per embryo transfer (ET) procedure and collects that was used is not currently publicly available. In the HFEA reports, detailed data on individual PGT cycles separated into PGT-A, PGT-M, they separate out the PGT-M/SR data but leave the PGT-A data with PGT-SR, PGT using sexing only and PGT for social sexing. The outcome the IVF data. For this study, the PGT-A data had to be extracted from of individual embryos following an ART treatment can be tracked from . the IVF data. The HFEA sent the PGT-M/SR data to the authors on 6 start to finish in the newer databases (De Rycke et al., 2017). This gives January 2018 and the PGT-A data on 22 January 2018. a very rich picture of the use of PGT but the main limitation is that the . In order to collect relevant data from the HFEA database, the ‘Year majority of clinics worldwide do not report data to the Consortium. It of Treatment’ field was filtered to separate out the individual years is therefore not possible to work out the global use of PGT. in which treatment cycle data were available. Once separated, data Since 1991 the Human Fertilisation and Embryology Authority collection for each year was grouped into the following categories: (HFEA), an independent regulator of fertility treatments in the UK, has ‘Fresh IVF’, ‘Frozen IVF’, ‘Fresh PGT’ and ‘Frozen PGT’. provided information to the public about licensed fertility treatments Throughout this report the success rates are reported in different (HFEA, 2017). All UK clinics have a statutory duty to record and submit . . ways (Table I). The LBRs were measured in line with the HFEA annual data to the HFEA. The HFEA data are reported as LBR per treatment report by using LBR PTC and LBR PET. cycle (PTC) and per embryo transferred (PET) for fresh and frozen cycles. In their annual report, the HFEA gives detailed data of PGT-M . SART data collection and PGT-SR cycles, but since the HFEA does not recognize PGT-A as an evidence-based procedure and it is considered an IVF add-on, . The SART data showed the outcome from one egg collection. A cycle PGT-A cycles are not reported separately but instead are included in was counted when a woman started fertility drugs for the purpose of the overall IVF data. an ART procedure (SART, 2018), or, for a natural cycle, the first day In the USA, the American Society for Assisted Reproductive Tech- of the woman’s menstrual cycle for a procedure that month. Following nology (SART) provides reports on IVF and PGT success rates. Unlike an egg collection, most patients underwent an ET procedure (fresh or the HFEA, SART only requires data from SART-registered clinics, frozen) within 1 year. The outcome of this first ET was the ‘primary out- which includes 375 clinics, accounting for 83% of all American clinics . come’. The ‘subsequent outcome’ was the thawing of eggs/embryos (Toner et al., 2016). SART has continued to review the data, with after the primary outcome had been determined. This also included detailed reports being completed annually since 1988. PGT data are . ET procedures that occurred 1 year after the egg collection date. reported per cycle-started, per egg collection and per embryo transfer In the case of multiple egg collection cycles being performed, each procedure. PGT-A, PGT-M and SR data cannot be separated. collection was counted in the denominator when calculating outcomes Data reported by the ESHRE PGT Consortium, HFEA and SART all (see below). have limitations. In this study we have analysed the HFEA and SART . . A filter on the ‘Reporting year’ field was used to separate out IVF and PGT data in detail to determine if PGT has increased, identify the individual years. Data collection was grouped into the following key information regarding PGT (including LBR) and suggest ways of categories: ‘IVF primary outcome’, ‘IVF subsequent outcome’, ‘PGT improving PGT data collection. primary outcome’, and ‘PGT subsequent outcome’. Statistics Materials and Methods Significance was calculated using repeated measures ANOVA when Data collection . assessing two factors of interest, or two-way repeated ANOVA when The two databases were obtained from the HFEA and SART and data there were three factors of interest. This enabled comparisons to analysed from 2014 to 2016. Both databases were in an electronic be drawn between two or more groups for a dependent variable . 988 Theobald et al. Table I Live birth rate calculations used to assess the HFEA IVF and PGT data. Live birth rate calculations ...................................................................................................................................................................................... Live birth rate per treatment cycle (LBR PTC) The number of live birth occurrences (a multiple birth is counted as a single birth occurrence) divided by the sum of treatment cycles multiplied by 100. Live birth rate (LBR) per cycle that reached a successful egg The number of live birth occurrences (a multiple birth is counted as a single collection (PEC) birth occurrence) divided by the number of cycles that reached a successful egg collection multiplied by 100. Live birth rate (LBR) per cycle that reached warming The number of live birth occurrences (a multiple birth is counted as a single birth occurrence) divided by the number of cycles that reached warming for frozen cycles. Live birth rate per cycle to ET procedure (LBR PCET) The number of live birth occurrences (a multiple birth is counted as a single birth occurrence) divided by cycles to embryo transfer (ET) procedure multiplied by 100. Live birth rate per embryo transferred (LBR PET) The number of live birth occurrences (a multiple birth is counted as a single birth occurrence) divided by the sum of embryos transferred multiplied by 100. HFEA: Human Fertilisation and Embryology Authority, PGT: preimplantation genetic testing HFEA Table II A summary of the IVF and PGT cycles per- . For the HFEA data, a total of 281 IVF cycles and 18 PGT-M/SR cycles formed in the UK and USA between 2014 and 2016 . had to be excluded due to the inability to distinguish between fresh and inclusive. frozen cycles. Over the 3 years, there were a total of 199 498 IVF cycles and 3385 UK USA ................................................................................... . PGT cycles (2%). A total of 1074 babies were born (32% LBR per egg Total IVF cycles 199 498 458 541 collection) (Table II). Total PGT cycles 3385 94 935 Table III shows the HFEA data for the proportion of IVF and PGT PGT cycles as a % of IVF cycles 2% 21% . cycles of a total of ART procedures for 2014–2016. The number of Number PGT babies 1074 26 822 PGT cycles has not increased. PGT-M/SR account for more cycles that PGT-A. PGT LBR per egg collection 32% 28% LBR over the years. Assumptions of normality and constant variance were checked by a study of residuals. If there was concern regarding assump- The LBRs for fresh PGT-A cycles decreased from 2014 to 2016 tions, a square root transformation was taken for counts or the (Fig. 1A). From 2015, the LBRs for frozen cycles exceeded those of function ‘Arsin(SQRT(percentage/100))’ was taken for percentages. . fresh cycles. These transformations did not appear to improve the constant variance In 2016, for PGT M/SR, LBRs for frozen treatments were higher than assumption so the analysis was performed on the raw data, recognizing LBRs for fresh cycles (Fig. 1B). the fact the P values may have been incorrect. However, as P values Age profile were extreme, the conclusions drawn were probably correct. Results were classed as significant if the P value was less than 0.05. Significant The maternal age profile for PGT-A treatment has remained broadly differences in groups with more than three categories allowed post- . the same over time (P > 0.999) (Fig. 2A). The 40–42 years age category hoc tests to be performed for each dependent variable so further was significantly higher than all other age categories (P < 0.001). The comparisons could be made. Specifically the Bonferroni’s test was over 44 years age group made up the lowest percentage of PGT-A used to adjust the P value to avoid spuriously significant results arising . cycles (P < 0.05). from multiple comparisons. Regression analysis was also performed to In 2016, 60% (424/708) of those receiving PGT-M/SR were infer a linear relationship between variables of interest. After checking . aged18–34 years (Fig. 2B). Post-hoc tests showed the percentages normality assumptions, the raw data were used. SPSS Statistics for of women in the 18–34, 35–37 and 38–39 year age groups were Windows, Version 24.0. Released 2016 (IBM Corp., Armonk, NY, significantly higher than all other age groups (P < 0.001). USA) was used for all statistical analysis. PGT-A LBRs were assessed by patient age (Fig. 3A). For the first . time in 2016, frozen cycles resulted in higher LBRs for patients in both age categories (less than or over 38 years) when compared to fresh Results cycles. Statistical analysis showed no evidence for differences between LBR PTC and PET in terms of age groups (P = 0.146 and P = 0.823, Table II summarizes the number of cycles and babies born from the UK respectively) or frozen cycles (P = 0.555) but there was a significant and USA data. . difference in fresh cycles ( P = 0.023). . PGT in the UK and USA, 2014–2016 989 Table III HFEA data—the proportion of IVF and PGT cycles of total of ART procedures. Year Number of IVF and Number of IVF Number of PGT-M/SR Number of PGT-A Total PGT (%) PGT treatment cycles treatment cycles (%) treatment cycles (%) treatment cycles (%) ..................................................................................................................................................................................... 2014 64 395 63 404–98.5% 608–0.9% 383–0.6% 991 (1.5%) 2015 66 183 64 903–98.1% 687–1% 593–0.9% 1280 (1.9%) 2016 68 920 67 806–98.4% 708–1% 406–0.6% 1114 (1.6%) PGT-A: PGT-aneuploidy, PGT-M/SR: PGT-monogenic defects/chromosomal structural rearrangements For PGT-M/SR, for all years the LBR PTC for both fresh and frozen In this paper we have presented a unique analysis of the UK and USA cycles was higher in patients under 38 years than over 38 years PGT data for 2014–2016, including 1382 PGT-A and 2003 PGT-M/SR (P = 0.002), whereas the LBR PET did not differ by age ( P = 0.077) . cycles from the UK and 94 935 PGT cycles from the USA. Therefore, (Fig. 3B). The LBR PTC and PET did not differ for frozen cycles the USA has performed more cycles in 3 years than all of the ESHRE (P = 0.158) but there was a difference between LBR PTC and PET in Consortium data collected since 1997. In the UK, PGT-A and PGT- fresh cycles (P−0.002). M/SR make up less than 2% of the total ART cycles performed each . year. In the USA, PGT makes up 21% of ART cycles (27% in 2016). . Even though the USA data cannot be separated into PGT-A, PGT-M SART and PGT-SR, it is likely that the majority of cycles performed are for Over the 3 years, there were a total of 458 541 IVF cycles and 94 935 PGT-A as the ESHRE PGT Consortium data have consistently shown PGT cycles (21%) (Table IV). A total of 26 822 PGT babies were born that PGT cycles account for the majority of cycles (De Rycke et al., (28% LBR per egg collection) (Table II). 2017). From 2014 to 2016, the number of cryopreserved PGT treatment . One key question is why is there such a difference in the use of PGT cycles (after the primary ET had been determined) increased by 237% . in the UK and USA? (6986/2949). Across the 3 years, an average of 61 thaw procedures Approximately 40% of ART in the UK is funded by the National had no embryos suitable for transfer. Health Service and they do not fund PGT-A. In the UK, the addi- The number of cryopreserved cycles started for PGT increased over tional cost of PGT-A can be over £3000 but in the USA it can be the 3 years (P = 0.007). The number of thaw procedures did not differ . as high as $12 000. The HFEA does not report the PGT-A data in between years (P = 0.091). . their annual report as they consider it an unproven add-on. They have produced a patient web page called IVF add-ons, which uses a LBR traffic light system to rate the treatments ( HFEA, 2018a). A green The LBR per egg collection and per transfer procedure for PGT signal indicates that there is more than one good quality random- remained unchanged in 2014–2016 (Fig. 4). . ized controlled trial (RCT) that shows the procedure is effective . and safe. An amber signal indicates that there is a very small or conflicting body of evidence, which means further research is still Age profiles required and the technique cannot be recommended for routine The PGT treatment age profile has remained constant from 2014 to use. A red signal indicates that there is no evidence to show that 2016 (Fig. 5). Cycles are most commonly performed in women under . the technique is effective or safe: this may be because no studies 35 years of age. The over 42 years age group makes up the lowest have been conducted, or because studies have been conducted but percentage, accounting for just 7% (2391/33 718) of treatment cycles . they show no evidence of an improvement in success rates. PGT- in 2016. A using cleavage stage biopsy and using blastocyst biopsy are both The LBRs were shown to be higher in patients under 38 years of age rated red. than over 38 years for PGT (Fig. 6)(P < 0.001 for LBR per cycle started A group of stakeholders, including the HFEA, ESHRE, British Fertility and per collection, and P = 0.008 per transfer). . Society and the Association of Clinical Embryologists, has published a consensus document, urging clinics to think carefully before using non- evidence-based add-ons and to ensure that the information they give Discussion to the patients is accurate (HFEA et al., 2018b). Currently, it is unknown how many PGT-A, PGT-M and PGT-SR cycles . In the USA, the Practice Committee of the American Society of are performed globally each year. The latest report from the ESHRE Reproductive Medicine and the Society for Assisted Reproductive PGT Consortium shows that from data I-XV (1997–2013) a total of Technology has recently stated ‘The value of preimplantation genetic 56 093 PGT cycles have been reported to the Consortium, which . testing for aneuploidy (PGT-A) as a screening test for in vitro fertilization includes 32 832 PGT-A, 14 340 PGT-M (12 712 single gene disorders, (IVF) patients has yet to be determined’ (Penzias et al., 2018). However, 1628 PGT for sexing only for X linked disease), and 8921 PGT-SR (De ART is offered under very different principles with little regulation of Rycke et al., 2017). The latest ESHRE PGT Consortium paper contains . the use of add-ons. There is a more commercial ART market in the data from five UK and two US clinics (De Rycke et al., 2017). USA as all treatments are self-funded so women may be more willing 990 Theobald et al. Figure 1 Data from the HFEA on the use of PGT for the years 2014–2016.(A) PGT-A live birth rates per year. For fresh PGT-A the live birth rate (LBR) per treatment cycle for the years 2014, 2015 and 2016 was 22.0% (72/327), 15.8% (63/400) and 14.3% (19/133) respectively. For fresh PGT-A the LBR per embryo transferred for the years 2014, 2015, 2016 was 30.6% (72/235), 27.8% (63/227) and 23.5% (9/81), respectively. For frozen PGT-A the LBR per treatment cycle for the years 2014, 2015, 2016 was 26.8% (15/56), 31.6% (61/193) and 36.6% (100/273), respectively. For frozen PGT-A the LBR per embryo transferred for the years 2014, 2015, 2016 was 23.1% (15/65), 30.2% (61/202) and 37.0% (100/270), respectively. (B) PGT-M/SR LBRss per year. For fresh PGT-M/SR the LBR per treatment cycle for the years 2014, 2015 and 2016 was 22.7% (58/256), 30.3% (46/152) and 18.9% (25/132), respectively. For fresh PGT-M/SR the LBR per embryo transferred for the years 2014, 2015 and 2016 was 29.7% (58/195), 37.1% (46/124) and 29.8% (25/84), respectively. For frozen PGT-M/SR the LBR per treatment cycle for the years 2014, 2015 and 2016 was 32.7% (115/352), 38.2% (204/535) and 37.5% (216/576), respectively. For the PGT-M/SR the LBR per embryo transferred was 30.2% (115/381), 34.9% (204/584) and 36.5% (216/592), respectively. HFEA: Human Fertilisation and Embryology Authority, PGT-A: preimplantation genetic testing aneuploidy, PTC: per treatment cycle, PET: per embryo transferred, PGT-M/SR monogenic defects/chromosomal structural rearrangements. to use IVF add-ons, such as PGT-A, on the basis that they are already . which is no longer recommended for PGT) did not show a significant paying for fertility treatment. difference in LBR ( Harper et al., 2010). This procedure was limited by The evidence for the use of PGT-A to increase LBR for any particular the analysis of a single cell from a cleavage stage embryo and by the group of patients is still conflicting. Eleven RCTs carried out up to use of an inefficient technique (FISH). Since 2010, four small RCTs 2010 using PGT-A version 1 (mainly cleavage stage biopsy and FISH, have been published using comprehensive chromosome testing for . PGT in the UK and USA, 2014–2016 991 Figure 2 Data from the HFEA on PGT treatment cycles for the years 2014–2016.(A) PGT-A treatment cycles by age, per year. For 18–34 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 16.5% (63/383), 18.0% (107/593) and 18.5% (75/406), respectively. For 35–37 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 17.0% (65/383), 16.0% (95/593) and 20.7% (84/406), respectively. For 38–39 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 14.6% (56/383), 16.5% (98/593) and 18.0% (73/406), respectively. For 40–42 years olds this was 31.9% (122/383), 31.5% (187/593), 28.1% (114/406), respectively. For 43–44 year olds this was 15.9% (61/383), 13.2% (78/593) and 13.1% (53/406), respectively. For the over 44 year olds for the percentage of women in the age group from 2014, 2015 and 2016 this was 4.2% (16/383), 4.7% (28/593) and 1.7% (7/406), respectively. Post-hoc tests were performed to show the 40–42 years age category was significantly higher than all other age categories (P < 0.001). The over 44 years age group made up the lowest percentage of PGT-A cycles (P < 0.05). (B) PGT-M/SR treatment cycles by age, per year. For 18–34 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 60.9% (371/609), 60.7% (417/687) and 59.9% (424/708), respectively. For 35–37 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 23.8% (145/609), 22.7% (156/687) and 25.7% (182/708), respectively. For 38–39 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 9.9% (60/609), 11.5% (79/687) and 10.0% (71/708), respectively. For 40–42 years olds this was 4.8% (29/609), 4.2% (29/687), 3.8% (27/708), respectively. For 43–44 year olds this was 0.2% (1/609), 0.9% (6/687) and 0.6% (4/708), respectively. For the over 44 year olds for the percentage of women in the age group from 2014, 2015 and 2016 this was 0.5% (3/609), 0% (0/687) and 0% (0/708), respectively. Post-hoc tests showed the percentages of women in the 18–34, 35–37 and 38–39 year age groups were significantly higher than all other age groups (P < 0.001). good and poor prognosis patients and have shown a benefit of the However, the two multicentre RCTs on PGT-A published in so called PGT-A version 2 (Yang et al., 2012; Scott et al., 2013; Forman . 2018 have shown no improvement in LBR/ongoing pregnancy rate et al., 2013; Rubio et al., 2017). Rubio (2019) has reported that when (Verpoest et al., 2018; Munne et al., 2019). The positive outcomes of adding in the cumulative LBR the difference seen by PGT-A is reduced. the ESHRE multicentre RCT (ESTEEM study) are that PGT-A patients A systematic analysis evaluated the three RCTs performed on good had fewer transfers, fewer miscarriages, fewer cryopreserved embryos prognosis patients and concluded that it is yet to be determined if the but the same LBR as the control group (Verpoest et al., 2018). The data on good prognosis patients can be extrapolated to poor prognosis results of the multicentre STAR trial showed that there was no overall patients (Dahdouh et al., 2015). . improvement in ongoing pregnancy rates at 20 weeks. Subgroup 992 Theobald et al. Figure 3 Data from the HFEA on the use of PGT, by age group, for the years 2014–2016.(A) PGT-A LBRs per year by age. The fresh PET LBR for under 38 s for the years 2014, 2015 and 2016 was 29.9% (32/107), 36.8% (35/95) and 20.0% (5/25), respectively. The fresh PET LBR for 38 and over for the years 2014, 2015 and 2016 was 31.3% (40/128), 21.2% (28/132) and 25.0% (14/56), respectively. The fresh PTC LBR for under 38 s for the years 2014, 2015 and 2016 was 31.1% (32/103), 30.4% (35/115) and 12.5% (5/40), respectively. The fresh PTC LBR over 38 and over for the year 2014, 2015 and 2016 was 17.9% (40/224), 9.8% (28/285) and 15.1% (14/93), respectively. The frozen PET LBR for under 38 s for the years 2014, 2015 and 2016 was 23.3% (7/30), 29.0% (29/100) and 35.9% (47/131). The frozen PET LBR for ages 38 and over for the years 2014, 2015 and 2016 was 22.8% (8/35), 31.4% (32/102), and 38.1% (53/139), respectively. The frozen PTC LBR for ages under 38 for the years 2014, 2015 and 2016 was 28.0% (7/25), 33.3% (29/87) and 39.5% (47/119), respectively, and the frozen PTC LBR for ages 38 and over for the years 2014, 2015 and 2016 was 25.8% (8/31), 30.2% (32/106) and 34.4% (53/154), respectively. Statistical analysis via an ANOVA test showed no evidence for differences between LBR PTC and PET in terms of age groups ( P = 0.146 and P = 0.823, respectfully) or frozen cycles (P = 0.555) but there was a significant difference in fresh cycles ( P = 0.023). (B) PGT-M/SR LBRs per year by age. The LBR for fresh PET for under 38 s for the years 2014, 2015 and 2016 were 30.1% (49/163), 44.1% (41/93) and 31.4% (21/67), respectively. The LBR for fresh PET for ages 38 and over for the years 2014, 2015 and 2016 were 9.8% (3/32), 16.1% (5/31) and 23.5% (4/17), respectively. The LBR for fresh PTC under 38 for the years 2014, 2015 and 2016 was 23.2% (49/211), 34.5% (41/119) and 20.0% (21/105), respectively. The LBR for fresh PTC ages 38 and over for the years 2014, 2015, and 2016 was 6.5% (3/46), 15.2% (5/33) and 14.8% (4/27), respectively. The LBR for frozen PET for under 38 s for the years 2014, 2015 and 2016 was 32.5% (107/329), 37.2% (182/489) and 27.2% (191/514). The LBR for frozen PET ages 38 and over for the years 2014, 2015 and 2016 was 42.1%, (8/19), 23.2% (22/95), 32.5% (25/77), respectively. The LBR for frozen PTC for ages under 38 for the years 2014, 2015 and 2016 was 35.1% (107/305), 40.1% (182/454), and 38.1% (191/501), respectively. The LBR for frozen PTC for ages 38 and over for the years 2014, 2015 and 2016 was 17.0% (8/47), 27.2% (22/81) and 33.3% (25/75), respectively. ANOVA analysis was carried out and showed the LBR PTC for both fresh and frozen cycles was higher in patients under 38 years than over 38 years (P = 0.002), whereas the LBR PET did not differ by age ( P = 0.077). The LBR PTC and PET did not differ for frozen cycles ( P = 0.158) but there was a difference between LBR PTC and PET in fresh cycles ( P−0.002). PGT in the UK and USA, 2014–2016 993 Table IV SART data—the proportion of IVF and PGT cycles of total of ART procedures. Year Number of IVF and PGT treatment Number of IVF treatment cycles Number of PGT treatment cycles cycles (cumulative) (cumulative) (%) (cumulative) (%) ..................................................................................................................................................................................... 2014 140 561 121 786–87% 18 775–13% 2015 154 001 121 494–79% 32 507–21% 2016 163 979 120 326–73% 43 653–27% SART: Society for Assisted Reproductive Technology Figure 4 SART data—PGT LBRs per year (fresh and frozen cycles). The LBR per egg collection for the years 2014, 2015 and 2016 was 33.6% (5311/15 826), 30.7% (8102/26 393) and 30.1% (10 158/33 718) and the LBR per embryo transfer procedure for the years 2014, 2015 and 2016 was 52.8% (5311/10 058), 51.1% (8102/15 862) and 54.9% (10 158/18 512), respectively. SART: Society for Assisted Reproductive Technology. analysis of the women aged 35–40 years did show an increase in PGT-M/SR treatment was aged 18–34 years (Fig. 2B). These age ongoing pregnancy rate if two or more embryos were biopsied, but demographics were similar to those found in other studies (Chang these data were not significant when analysed by intention-to-treat and . et al., 2016; De Rycke et al., 2017). there was no effect on miscarriage rates ( Munne et al., 2019). For both In the USA, for PGT treatment cycles the majority of women the ESHRE and STAR trials, the additional births from frozen embryos undergoing treatment were under 35 years of age and the smallest have not been included and may result in a lower live birth rate in the group was over 42 years (Fig. 5). It should be noted that a higher PGT-A group. Some authors argue that PGT will not increase LBR as percentage of younger women had a subsequent cryopreservation in it does not change the embryos but it will decrease miscarriages, is a comparison to a primary cycle. This was expected as older women are reduced cost compared to multiple ART cycles and reduces the time to . less likely to have embryos frozen. pregnancy (Rubio et al., 2017). Only the ESHRE study on polar body biopsy has shown an effect on miscarriages ( Verpoest et al., 2018); . LBR the STAR trial did not (Munne et al., 2019). Clinics need to think carefully what they tell their patients regarding the benefit of PGT-A Over the 3 years from the HFEA data for PGT-A there was no in relation to live birth rate, cumulative live birth rate and miscarriage . difference in LBR PTC and PET between age groups ( Fig. 3A). This rates. finding agrees with the hypothesis that PGT-A is used to balance out LBRs across age groups (Munné and Cohen, 2017) but the same result was not seen for the SART data. Patient characteristics . For the HFEA data on PGT-M/SR, the LBR PTC for both fresh and For the HFEA data, the majority of patients receiving PGT-A treatment frozen cycles was significantly higher in patients under 38 years of were aged 40–42 years and those aged over 44 years were the smallest . age than over 38 years (Fig. 3B). The HFEA LBR PET and PTC were group receiving PGT-A (Fig. 2A). The majority of those undergoing calculated in line with the HFEA annual report (HFEA, 2017). PET gives 994 Theobald et al. Figure 5 SART data—PGT treatment cycles (fresh and frozen) by age, per year. For under 35 s the percentage of women in the age group from 2014, 2015 and 2016 was 30.1% (4754/15 826), 30.7% (8099/26 393) and 32.6% (10 991/33 718), respectively. For 35–37 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 21.3% (3365/15 826), 22.9% (6041/26 393) and 22.7% (7655/33 718), respectively. For 38–40 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 26.0% (4111/15 826), 25.2% (6643/26 393) and 25.1% (8458/33 718), respectively. For 41–42 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 14.6% (2304/15 826), 13.7% (3604/26 393) and 12.5% (4223/33 718), respectively. For over 42 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 8.2% (1292/15 826), 7.6% (2006/26 393) and 7.1% (2391/33 718), respectively. patients an estimate of the number of transferable embryos required Frozen embryos are used for PGT as it is almost essential for to achieve a live birth. This may lead patients to want multiple embryos blastocyst biopsy. Blastocyst vitrification provides an unconstrained transferred per transfer procedure. Patients should be made aware of . time frame for genetic diagnosis to be completed. Blastocyst biopsy the risks associated with such procedures, such as multiple pregnancies, means there are more cells for testing, reducing the chance of a ‘no so informed consent can be given regarding single embryo transfer result’ (Chang et al., 2011). The high proportion of frozen PGT cycles (Forman et al., 2013). is also likely to reflect the trends towards next generation sequencing In the SART data, the LBR per cycle started, per egg collection and (Rodriguez-Purata et al., 2016; Coates et al., 2017). Owing to resource per embryo transfer procedure was significantly higher in the under 38- . and finance limitations, most clinics performing PGT do not carry year olds for all 3 years compared to older women (Fig. 6). The LBR for out diagnostics in-house; it is therefore easier and cheaper to batch the subsequent PGT cycles was also significantly higher for the under frozen samples (Penzias et al., 2018). The use of vitrified embryos 35 years age group than for patients over 41 years old. may lead to improved health of patients and babies, a reduced risk of ESHRE and SART success measures focus on transfer procedures ovarian hyperstimulation syndrome and a reduced number of multiple in which at least one embryo is transferred (De Rycke et al., 2017). pregnancies (Li et al., 2014; Rienzi et al., 2017). Additionally, policies This gives a patient who reaches the ET stage a success rate that could . set in the UK requiring a lower ET order to reduce the multiple birth be easier to understand. IVF has created new challenges for reporting rate have subsequently led to an increase in embryos available for outcomes, in which it is difficult for one success rate alone to convey cryopreservation, which has gradually become the trend since 2009 both the effectiveness and safety of a procedure ( Braakhekke et al., (Rienzi et al., 2017). 2015). However, LBRs of PGT could be inflated due to the exclusion of embryo banking cycles, a factor highlighted in other studies (Kushnir Limitations et al., 2016, 2017). . Globally, the IVF LBR is decreasing in some countries, with Canada This was a retrospective report looking at data, and its major limitations and Japan seeing the most dramatic effect ( Gleicher et al., 2019). arose from the data itself. Overall, the HFEA data were poorly collated. Gleicher et al. (2019) suggest that IVF add-ons, including PGT-A, have A total of 299 cases were excluded from analysis as it was unclear been partly to blame for this. In the USA, the decrease in IVF LBR whether they were classified as a fresh or frozen cycle. This calls started in 2011 and has continued. In 2010, the LBR was 30%, and by . for consistent reporting on what is classified as a fresh or frozen 2016 it had dropped to just over 20%. cycle. PGT in the UK and USA, 2014–2016 995 Figure 6 SART data—PGT LBRs per year by age group. The LBR per cycle started under age 38 for the years 2014, 2015 and 2016 were 42.3% (3436/8119), 38.2% (5400/14 140) and 38.9% (7253/18 646), respectively. The LBR per cycle started 38 years and over for the years 2014, 2015 and 2015 and 2016 was 24.3% (1874/7707), 22.1% (2702/12 253) and 19.3% (2905/15 072) respectively. The LBR per egg collection under 38 for the years 2014, 2015 and 2016 was 42.3% (3436/8119), 38.2% (5400/14 140) and 38.9% (7253/18 646), respectively. The LBR per egg collection age 38 and over for the years 2014, 2015 and 2016 was 24.3% (1874/7707), 22.1% (2702/12 253) and 19.3% (2905/15 072), respectively. The LBR per embryo transfer procedure for ages under 38 for the years 2014, 2015 and 2016 was 54.0% (3435/6364), 55.4% (5855/10 576) and 56.3% (72 481/12 887), respectively. The LBR per embryo transfer procedure for ages 38 and over for the years 2014, 2015 and 2016 was 50.7% (1874/3694), 51.1% (2702/5286) and 51.0% (2902/5625), respectively. Additionally, it was unclear whether a cycle-started had been form that clinics submit to the HFEA to include a section for the recorded if they did not reach egg collection. This can be related to the number of collections performed and allowing cycles to be linked. early Consortium reports in which cycle-started was abandoned, as . LBRs per egg collection, as per SART and Consortium data, could then clinics rarely reported accurate data (Geraedts et al., 2000). If today’s . be calculated. clinics are not submitting these data to the HFEA, this report may not Likewise, the number of HFEA PGT cycles that were due to be provide an accurate view on the total number of ART procedures. fresh but had no normal embryos available for transfer could not be Furthermore, by excluding cancelled and failed cycles, the chances identified. This is a problem specifically for many PGT-M/SR treatment of success for prospective patients are exaggerated by assuming that . cycles as the probability of creating an affected embryo that is not stimulation, fertilization, thawing etc. will be successful (Wilkinson . suitable for transfer is high (Lewis et al., 2001). If these cycles were et al., 2017). In comparison, the SART data include all intended not recorded, the number of PGT cycles would be much larger than collections when assessing outcomes. Any cancelled or failed cycles those reported in this study. are hence taken into account when assessing treatment numbers or Owing to the possibility of cycle inflation, only those with an indi- outcomes per cycle-started (Wilkinson et al., 2017). . cated ‘treatment now’ in the ‘main reason for producing embryos The HFEA reporting system does not adequately capture embryo storing eggs’ were included in this analysis. These ensured patients cryopreservation and genetic testing. For PGT treatments, patients . were not counted twice for the same cycle. This filter excluded patients may go through multiple egg collections in order to cryopreserve and going through an ART procedure for egg sharing or donation, which bank embryos (Chamayou et al., 2017). However, the data for these would have reduced the chance of pregnancy and affected the overall cases are not currently linked, although the HFEA are developing this. outcomes. Depending on how clinics fill out HFEA treatment forms, those egg . Unlike the HFEA, SART PGT data could not be separated into collection procedures could appear as ‘for embryo storage’ or for PGT-M/SR and PGT-A. Therefore, age profile and LBRs were not ‘treatment now and embryo storage’. Therefore, the egg collection . adequately captured. In addition, as the primary and subsequent cycles cannot be followed to the final outcome. When reporting such data, it were linked it was difficult to infer whether the age at a subsequent is unclear whether embryologists are mindful that these data are part cycle was the age of the women at egg collection or the age at the of a person’s full treatment, or if a form is filled in as an individual . transfer procedure. If age was only recorded at the ET procedure date, cycle. However, as per the SART data, all collections should be counted . the success rates of older groups may be artificially raised, especially in when calculating the outcomes. This allows the wider picture of cases of embryos/oocytes being cryopreserved several years earlier. fertility treatments to be more accurately captured (Wilkinson et al., It would therefore be valuable for clinics to report on both, especially 2017). This inaccuracy would easily be corrected by amending the for patients using IVF for fertility preservation. . 996 Theobald et al. Although the Consortium is not able to collect data from . Authors’ roles many of the clinics that SART and the HFEA report on (De Joyce Harper and Rachel Theobald designed the methods. Rachel Rycke et al., 2017), the Consortium has an important role in . Theobald carried out the data collection and wrote the initial draft of collecting data. A much better follow-through of an embryo is the paper. All three authors edited the final paper. reported. The effect of such a technology-driven approach is the impact of accuracy and later complications with increasing ART procedures. Unlike the Consortium, both the HFEA and . SART data do not separate PGT-M and PGT-SR data, making Funding it difficult to show the impact of new technologies. It could be No specific funding was used. that the PGT-SR cycle numbers have stayed static over time, if older technologies were used. In contrast, PGT-M cycle numbers may have increased, as most diseases can now be tested by new technologies. Therefore, it would have been interesting to see if . Conflict of interest technological advancements had increased the proportion of PGT- M over PGT-SR or vice versa. The ESHRE data can validate these None relating to this project. Joyce Harper is the director of the hypotheses, which has been useful for future planning of the patient Embryology and PGD Academy, which offers education in these fields. pathway and determining the types of treatments required for patients. Like the Consortium, the HFEA and SART should separate . PGT-M, PGT-SR and PGT-A to identify the type of technologies References used and the resulting impact on the delivery of the service (De Rycke et al., 2015). Recording these nuances in LBR PTC and Braakhekke M, Kamphuis EI, Mol F, Norman RJ, Bhattacharya S, Van PET will allow assessment and thereby improvement in approaches Der Veen F, Mol BW. Effectiveness and safety as outcome measures to PGT. in reproductive medicine. Hum Reprod 2015;30:2249–2251. . Brezina PR, Kutteh WH. Clinical applications of preimplantation genetic testing. BMJ 2015;350:g7611. Chamayou S, Sicali M, Alecci C, Ragolia C, Liprino A, Nibali D, Storaci Conclusion G, Cardea A, Guglielmino A. The accumulation of vitrified oocytes This report has demonstrated that there is an increasing number of is a strategy to increase the number of euploid available blastocysts patients using PGT in the USA at a time when the USA LBR has for transfer after preimplantation genetic testing. J Assist Reprod Genet decreased. 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S, Jackson E, Harper J, Mol B. Do à la carte menus serve infertility Mol Cytogenet 2012;5:24. patients? The ethics and regulation of IVF add-ons. . Zhang Y, Li N, Wang L, Sun H, Ma M, Wang H, Xu X, Zhang W, Yang Z, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, Peck AC, Sills Liu Y, Cram DS et al. Molecular analysis of DNA in blastocoele ES, Salem RD. Selection of single blastocysts for fresh transfer via fluid using next-generation sequencing. J Assist Reprod Genet 2016;33: standard morphology assessment alone and with array CGH for 637–645. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Reproduction (Oxford, England) Pubmed Central

The status of preimplantation genetic testing in the UK and USA

Theobald, Rachel; SenGupta, Sioban; Harper, Joyce
Human Reproduction (Oxford, England) , Volume 35 (4) – Apr 24, 2020
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10.1093/humrep/deaa034
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Human Reproduction, Vol.35, No.4, pp. 986–998, 2020 Advance Access Publication on April 24, 2020 doi:10.1093/humrep/deaa034 ORIGINAL ARTICLE Reproductive genetics The status of preimplantation genetic testing in the UK and USA 1 1 1,2, Rachel Theobald , Sioban SenGupta , and Joyce Harper 1 2 Institute for Women’s Health, 86-96 Chenies Mews, University College London, London, WC1E 6HX, UK Institute for Women’s Health, University College London, 86-96 Chenies Mews, London, WC1E 6HX, UK *Correspondence. E-mail: [email protected] Submitted on November 27, 2018; resubmitted on October 24, 2019; editorial decision on January 7, 2020 STUDY QUESTION: Has the number of preimplantation genetic testing (PGT) cycles in the UK and USA changed between 2014 and 2016? SUMMARY ANSWER: From 2014 to 2016, the number of PGT cycles in the UK has remained the same at just under 2% but in the USA has increased from 13% to 27%. WHAT IS KNOWN ALREADY: PGT was introduced as a treatment option for couples at risk of transmitting a known genetic or chromosomal abnormality to their child. This technology has also been applied as an embryo selection tool in the hope of increasing live birth rates per transfer. ART cycles are monitored in the UK by the Human Fertilisation and Embryology Authority (HFEA) and in the USA by the Society for Assisted Reproductive Technology (SART). Globally, data are monitored via the ESHRE PGT Consortium. STUDY DESIGN, SIZE, DURATION: This cross-sectional study used the HFEA and SART databases to analyse PGT cycle data and make comparisons with IVF data to examine the success of and changes in patient treatment pathways. Both data sets were analysed from 2014 to 2016. The UK data included 3385 PGT cycles and the USA data included 94 935 PGT cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Following an extensive review of both databases, filters were applied to analyse the data. An assessment of limitations of each database was also undertaken, taking into account data collection by the ESHRE PGT Consortium. In the UK and USA, the publicly available information from these datasets cannot be separated into different indications. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of PGT cycles as a total of ART procedures has remained the same in the UK but increased annually in the USA from 13% to 27%. Between 2014 and 2016 inclusive, 3385 PGT cycles have been performed in the UK, resulting in 1074 PGT babies being born. In the USA 94 935 PGT cycles have been performed, resulting in 26 822 babies being born. This gave a success rate per egg collection for PGT of 32% for the UK and 28% for the USA. Analysis of the data by maternal age shows very different patient populations between the UK and USA. These differences may be related to the way PGT is funded in the UK and USA and the lack of HFEA support for PGT for aneuploidy. LIMITATIONS, REASONS FOR CAUTION: Data reported by the HFEA and SART have different limitations. As undertaken by the ESHRE PGT Consortium, both data sets should separate PGT data by indication. Although the HFEA collects data from all IVF clinics in the UK, SART data only represent 83% of clinics in the USA. WIDER IMPLICATIONS OF THE FINDINGS: Worldwide, a consistent reporting scheme is required in which success rates can convey the effectiveness of PGT approaches for all indications. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained and there are no competing interests to declare that are directly related to this project. Joyce Harper is the director of the Embryology and PGD Academy, which offers education in these fields. Key words: preimplantation genetic testing / PGS / PGD / ART / reproductive genetics / UK / USA . Preimplantation genetic testing (PGT) is an ART procedure that Introduction is used to investigate the genetic make-up of embryos produced by Since the birth of Louise Brown, the world’s first ‘test-tube baby’ in IVF (Zhang et al., 2016). PGT-M (monogenic disease) and PGT-SR 1978 (Steptoe and Edwards, 1978), the use of ART has increased (structural rearrangements) are treatment options for couples whose dramatically. With over 6 million births worldwide, this global industry children are at high risk of inheriting a known genetic or chromosomal is now estimated to be worth £20–30 billion (Weinerman, 2018). abnormality (Harper and SenGupta, 2012). Although most couples © The Author(s) 2020. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which per- mits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] PGT in the UK and USA, 2014–2016 987 undergoing PGT-M tend to be fertile, success rates are similar to those . format and allowed a treatment cycle for IVF and PGT to be followed undergoing routine IVF (De Rycke et al., 2017). Patients undergoing up to a live birth occurrence. Only cycles where the patients used their PGT-SR are generally phenotypically normal, but often their infertility own eggs were analysed. issues make them aware they are balanced carriers of chromosomal The fields that were available for both databases were assessed, rearrangements. . and the appropriate filters were chosen. Filters were applied to both PGT-A (aneuploidy) is an IVF adjunct and its use is controversial sets of data to undertake the analysis. In cases where there were (Harper et al., 2017; Wilkinson et al., 2019). PGT-A is carried out . spurious results, data were excluded from analysis and highlighted for selection of a euploid embryo, which will be used for transfer in where necessary. the hope of increasing live birth rates (LBRs) (Brezina and Kutteh, 2015). PGT-A has been applied to women of advanced maternal HFEA data collection age, couples who have had repeated miscarriages but have a normal The HFEA presents treatment data as cycles. PGT-A, PGT-M/SR and karyotype, those with repeated implantation failure, egg donors and IVF treatment cycles could be separated to allow a better understand- good prognosis patients (Mastenbroek et al., 2011). . The first reports of PGT world data were published by Harper and ing of the demographics of each ART technique. These treatments Handyside (1994) and Harper (1996). This led to establishment of the could be further separated into fresh and frozen cycles. The HFEA data ESHRE PGT Consortium, which has been reporting annual PGT data include patient age at treatment, the number of treatment cycles and since 1997 (Harper et al., 2012). The Consortium reports the IVF and . outcomes such as LBR PET and LBR PTC. biopsy method, analysis details, embryology and clinical outcomes per . The HFEA PGT databases are fixed and closed. The full database egg collection and per embryo transfer (ET) procedure and collects that was used is not currently publicly available. In the HFEA reports, detailed data on individual PGT cycles separated into PGT-A, PGT-M, they separate out the PGT-M/SR data but leave the PGT-A data with PGT-SR, PGT using sexing only and PGT for social sexing. The outcome the IVF data. For this study, the PGT-A data had to be extracted from of individual embryos following an ART treatment can be tracked from . the IVF data. The HFEA sent the PGT-M/SR data to the authors on 6 start to finish in the newer databases (De Rycke et al., 2017). This gives January 2018 and the PGT-A data on 22 January 2018. a very rich picture of the use of PGT but the main limitation is that the . In order to collect relevant data from the HFEA database, the ‘Year majority of clinics worldwide do not report data to the Consortium. It of Treatment’ field was filtered to separate out the individual years is therefore not possible to work out the global use of PGT. in which treatment cycle data were available. Once separated, data Since 1991 the Human Fertilisation and Embryology Authority collection for each year was grouped into the following categories: (HFEA), an independent regulator of fertility treatments in the UK, has ‘Fresh IVF’, ‘Frozen IVF’, ‘Fresh PGT’ and ‘Frozen PGT’. provided information to the public about licensed fertility treatments Throughout this report the success rates are reported in different (HFEA, 2017). All UK clinics have a statutory duty to record and submit . . ways (Table I). The LBRs were measured in line with the HFEA annual data to the HFEA. The HFEA data are reported as LBR per treatment report by using LBR PTC and LBR PET. cycle (PTC) and per embryo transferred (PET) for fresh and frozen cycles. In their annual report, the HFEA gives detailed data of PGT-M . SART data collection and PGT-SR cycles, but since the HFEA does not recognize PGT-A as an evidence-based procedure and it is considered an IVF add-on, . The SART data showed the outcome from one egg collection. A cycle PGT-A cycles are not reported separately but instead are included in was counted when a woman started fertility drugs for the purpose of the overall IVF data. an ART procedure (SART, 2018), or, for a natural cycle, the first day In the USA, the American Society for Assisted Reproductive Tech- of the woman’s menstrual cycle for a procedure that month. Following nology (SART) provides reports on IVF and PGT success rates. Unlike an egg collection, most patients underwent an ET procedure (fresh or the HFEA, SART only requires data from SART-registered clinics, frozen) within 1 year. The outcome of this first ET was the ‘primary out- which includes 375 clinics, accounting for 83% of all American clinics . come’. The ‘subsequent outcome’ was the thawing of eggs/embryos (Toner et al., 2016). SART has continued to review the data, with after the primary outcome had been determined. This also included detailed reports being completed annually since 1988. PGT data are . ET procedures that occurred 1 year after the egg collection date. reported per cycle-started, per egg collection and per embryo transfer In the case of multiple egg collection cycles being performed, each procedure. PGT-A, PGT-M and SR data cannot be separated. collection was counted in the denominator when calculating outcomes Data reported by the ESHRE PGT Consortium, HFEA and SART all (see below). have limitations. In this study we have analysed the HFEA and SART . . A filter on the ‘Reporting year’ field was used to separate out IVF and PGT data in detail to determine if PGT has increased, identify the individual years. Data collection was grouped into the following key information regarding PGT (including LBR) and suggest ways of categories: ‘IVF primary outcome’, ‘IVF subsequent outcome’, ‘PGT improving PGT data collection. primary outcome’, and ‘PGT subsequent outcome’. Statistics Materials and Methods Significance was calculated using repeated measures ANOVA when Data collection . assessing two factors of interest, or two-way repeated ANOVA when The two databases were obtained from the HFEA and SART and data there were three factors of interest. This enabled comparisons to analysed from 2014 to 2016. Both databases were in an electronic be drawn between two or more groups for a dependent variable . 988 Theobald et al. Table I Live birth rate calculations used to assess the HFEA IVF and PGT data. Live birth rate calculations ...................................................................................................................................................................................... Live birth rate per treatment cycle (LBR PTC) The number of live birth occurrences (a multiple birth is counted as a single birth occurrence) divided by the sum of treatment cycles multiplied by 100. Live birth rate (LBR) per cycle that reached a successful egg The number of live birth occurrences (a multiple birth is counted as a single collection (PEC) birth occurrence) divided by the number of cycles that reached a successful egg collection multiplied by 100. Live birth rate (LBR) per cycle that reached warming The number of live birth occurrences (a multiple birth is counted as a single birth occurrence) divided by the number of cycles that reached warming for frozen cycles. Live birth rate per cycle to ET procedure (LBR PCET) The number of live birth occurrences (a multiple birth is counted as a single birth occurrence) divided by cycles to embryo transfer (ET) procedure multiplied by 100. Live birth rate per embryo transferred (LBR PET) The number of live birth occurrences (a multiple birth is counted as a single birth occurrence) divided by the sum of embryos transferred multiplied by 100. HFEA: Human Fertilisation and Embryology Authority, PGT: preimplantation genetic testing HFEA Table II A summary of the IVF and PGT cycles per- . For the HFEA data, a total of 281 IVF cycles and 18 PGT-M/SR cycles formed in the UK and USA between 2014 and 2016 . had to be excluded due to the inability to distinguish between fresh and inclusive. frozen cycles. Over the 3 years, there were a total of 199 498 IVF cycles and 3385 UK USA ................................................................................... . PGT cycles (2%). A total of 1074 babies were born (32% LBR per egg Total IVF cycles 199 498 458 541 collection) (Table II). Total PGT cycles 3385 94 935 Table III shows the HFEA data for the proportion of IVF and PGT PGT cycles as a % of IVF cycles 2% 21% . cycles of a total of ART procedures for 2014–2016. The number of Number PGT babies 1074 26 822 PGT cycles has not increased. PGT-M/SR account for more cycles that PGT-A. PGT LBR per egg collection 32% 28% LBR over the years. Assumptions of normality and constant variance were checked by a study of residuals. If there was concern regarding assump- The LBRs for fresh PGT-A cycles decreased from 2014 to 2016 tions, a square root transformation was taken for counts or the (Fig. 1A). From 2015, the LBRs for frozen cycles exceeded those of function ‘Arsin(SQRT(percentage/100))’ was taken for percentages. . fresh cycles. These transformations did not appear to improve the constant variance In 2016, for PGT M/SR, LBRs for frozen treatments were higher than assumption so the analysis was performed on the raw data, recognizing LBRs for fresh cycles (Fig. 1B). the fact the P values may have been incorrect. However, as P values Age profile were extreme, the conclusions drawn were probably correct. Results were classed as significant if the P value was less than 0.05. Significant The maternal age profile for PGT-A treatment has remained broadly differences in groups with more than three categories allowed post- . the same over time (P > 0.999) (Fig. 2A). The 40–42 years age category hoc tests to be performed for each dependent variable so further was significantly higher than all other age categories (P < 0.001). The comparisons could be made. Specifically the Bonferroni’s test was over 44 years age group made up the lowest percentage of PGT-A used to adjust the P value to avoid spuriously significant results arising . cycles (P < 0.05). from multiple comparisons. Regression analysis was also performed to In 2016, 60% (424/708) of those receiving PGT-M/SR were infer a linear relationship between variables of interest. After checking . aged18–34 years (Fig. 2B). Post-hoc tests showed the percentages normality assumptions, the raw data were used. SPSS Statistics for of women in the 18–34, 35–37 and 38–39 year age groups were Windows, Version 24.0. Released 2016 (IBM Corp., Armonk, NY, significantly higher than all other age groups (P < 0.001). USA) was used for all statistical analysis. PGT-A LBRs were assessed by patient age (Fig. 3A). For the first . time in 2016, frozen cycles resulted in higher LBRs for patients in both age categories (less than or over 38 years) when compared to fresh Results cycles. Statistical analysis showed no evidence for differences between LBR PTC and PET in terms of age groups (P = 0.146 and P = 0.823, Table II summarizes the number of cycles and babies born from the UK respectively) or frozen cycles (P = 0.555) but there was a significant and USA data. . difference in fresh cycles ( P = 0.023). . PGT in the UK and USA, 2014–2016 989 Table III HFEA data—the proportion of IVF and PGT cycles of total of ART procedures. Year Number of IVF and Number of IVF Number of PGT-M/SR Number of PGT-A Total PGT (%) PGT treatment cycles treatment cycles (%) treatment cycles (%) treatment cycles (%) ..................................................................................................................................................................................... 2014 64 395 63 404–98.5% 608–0.9% 383–0.6% 991 (1.5%) 2015 66 183 64 903–98.1% 687–1% 593–0.9% 1280 (1.9%) 2016 68 920 67 806–98.4% 708–1% 406–0.6% 1114 (1.6%) PGT-A: PGT-aneuploidy, PGT-M/SR: PGT-monogenic defects/chromosomal structural rearrangements For PGT-M/SR, for all years the LBR PTC for both fresh and frozen In this paper we have presented a unique analysis of the UK and USA cycles was higher in patients under 38 years than over 38 years PGT data for 2014–2016, including 1382 PGT-A and 2003 PGT-M/SR (P = 0.002), whereas the LBR PET did not differ by age ( P = 0.077) . cycles from the UK and 94 935 PGT cycles from the USA. Therefore, (Fig. 3B). The LBR PTC and PET did not differ for frozen cycles the USA has performed more cycles in 3 years than all of the ESHRE (P = 0.158) but there was a difference between LBR PTC and PET in Consortium data collected since 1997. In the UK, PGT-A and PGT- fresh cycles (P−0.002). M/SR make up less than 2% of the total ART cycles performed each . year. In the USA, PGT makes up 21% of ART cycles (27% in 2016). . Even though the USA data cannot be separated into PGT-A, PGT-M SART and PGT-SR, it is likely that the majority of cycles performed are for Over the 3 years, there were a total of 458 541 IVF cycles and 94 935 PGT-A as the ESHRE PGT Consortium data have consistently shown PGT cycles (21%) (Table IV). A total of 26 822 PGT babies were born that PGT cycles account for the majority of cycles (De Rycke et al., (28% LBR per egg collection) (Table II). 2017). From 2014 to 2016, the number of cryopreserved PGT treatment . One key question is why is there such a difference in the use of PGT cycles (after the primary ET had been determined) increased by 237% . in the UK and USA? (6986/2949). Across the 3 years, an average of 61 thaw procedures Approximately 40% of ART in the UK is funded by the National had no embryos suitable for transfer. Health Service and they do not fund PGT-A. In the UK, the addi- The number of cryopreserved cycles started for PGT increased over tional cost of PGT-A can be over £3000 but in the USA it can be the 3 years (P = 0.007). The number of thaw procedures did not differ . as high as $12 000. The HFEA does not report the PGT-A data in between years (P = 0.091). . their annual report as they consider it an unproven add-on. They have produced a patient web page called IVF add-ons, which uses a LBR traffic light system to rate the treatments ( HFEA, 2018a). A green The LBR per egg collection and per transfer procedure for PGT signal indicates that there is more than one good quality random- remained unchanged in 2014–2016 (Fig. 4). . ized controlled trial (RCT) that shows the procedure is effective . and safe. An amber signal indicates that there is a very small or conflicting body of evidence, which means further research is still Age profiles required and the technique cannot be recommended for routine The PGT treatment age profile has remained constant from 2014 to use. A red signal indicates that there is no evidence to show that 2016 (Fig. 5). Cycles are most commonly performed in women under . the technique is effective or safe: this may be because no studies 35 years of age. The over 42 years age group makes up the lowest have been conducted, or because studies have been conducted but percentage, accounting for just 7% (2391/33 718) of treatment cycles . they show no evidence of an improvement in success rates. PGT- in 2016. A using cleavage stage biopsy and using blastocyst biopsy are both The LBRs were shown to be higher in patients under 38 years of age rated red. than over 38 years for PGT (Fig. 6)(P < 0.001 for LBR per cycle started A group of stakeholders, including the HFEA, ESHRE, British Fertility and per collection, and P = 0.008 per transfer). . Society and the Association of Clinical Embryologists, has published a consensus document, urging clinics to think carefully before using non- evidence-based add-ons and to ensure that the information they give Discussion to the patients is accurate (HFEA et al., 2018b). Currently, it is unknown how many PGT-A, PGT-M and PGT-SR cycles . In the USA, the Practice Committee of the American Society of are performed globally each year. The latest report from the ESHRE Reproductive Medicine and the Society for Assisted Reproductive PGT Consortium shows that from data I-XV (1997–2013) a total of Technology has recently stated ‘The value of preimplantation genetic 56 093 PGT cycles have been reported to the Consortium, which . testing for aneuploidy (PGT-A) as a screening test for in vitro fertilization includes 32 832 PGT-A, 14 340 PGT-M (12 712 single gene disorders, (IVF) patients has yet to be determined’ (Penzias et al., 2018). However, 1628 PGT for sexing only for X linked disease), and 8921 PGT-SR (De ART is offered under very different principles with little regulation of Rycke et al., 2017). The latest ESHRE PGT Consortium paper contains . the use of add-ons. There is a more commercial ART market in the data from five UK and two US clinics (De Rycke et al., 2017). USA as all treatments are self-funded so women may be more willing 990 Theobald et al. Figure 1 Data from the HFEA on the use of PGT for the years 2014–2016.(A) PGT-A live birth rates per year. For fresh PGT-A the live birth rate (LBR) per treatment cycle for the years 2014, 2015 and 2016 was 22.0% (72/327), 15.8% (63/400) and 14.3% (19/133) respectively. For fresh PGT-A the LBR per embryo transferred for the years 2014, 2015, 2016 was 30.6% (72/235), 27.8% (63/227) and 23.5% (9/81), respectively. For frozen PGT-A the LBR per treatment cycle for the years 2014, 2015, 2016 was 26.8% (15/56), 31.6% (61/193) and 36.6% (100/273), respectively. For frozen PGT-A the LBR per embryo transferred for the years 2014, 2015, 2016 was 23.1% (15/65), 30.2% (61/202) and 37.0% (100/270), respectively. (B) PGT-M/SR LBRss per year. For fresh PGT-M/SR the LBR per treatment cycle for the years 2014, 2015 and 2016 was 22.7% (58/256), 30.3% (46/152) and 18.9% (25/132), respectively. For fresh PGT-M/SR the LBR per embryo transferred for the years 2014, 2015 and 2016 was 29.7% (58/195), 37.1% (46/124) and 29.8% (25/84), respectively. For frozen PGT-M/SR the LBR per treatment cycle for the years 2014, 2015 and 2016 was 32.7% (115/352), 38.2% (204/535) and 37.5% (216/576), respectively. For the PGT-M/SR the LBR per embryo transferred was 30.2% (115/381), 34.9% (204/584) and 36.5% (216/592), respectively. HFEA: Human Fertilisation and Embryology Authority, PGT-A: preimplantation genetic testing aneuploidy, PTC: per treatment cycle, PET: per embryo transferred, PGT-M/SR monogenic defects/chromosomal structural rearrangements. to use IVF add-ons, such as PGT-A, on the basis that they are already . which is no longer recommended for PGT) did not show a significant paying for fertility treatment. difference in LBR ( Harper et al., 2010). This procedure was limited by The evidence for the use of PGT-A to increase LBR for any particular the analysis of a single cell from a cleavage stage embryo and by the group of patients is still conflicting. Eleven RCTs carried out up to use of an inefficient technique (FISH). Since 2010, four small RCTs 2010 using PGT-A version 1 (mainly cleavage stage biopsy and FISH, have been published using comprehensive chromosome testing for . PGT in the UK and USA, 2014–2016 991 Figure 2 Data from the HFEA on PGT treatment cycles for the years 2014–2016.(A) PGT-A treatment cycles by age, per year. For 18–34 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 16.5% (63/383), 18.0% (107/593) and 18.5% (75/406), respectively. For 35–37 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 17.0% (65/383), 16.0% (95/593) and 20.7% (84/406), respectively. For 38–39 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 14.6% (56/383), 16.5% (98/593) and 18.0% (73/406), respectively. For 40–42 years olds this was 31.9% (122/383), 31.5% (187/593), 28.1% (114/406), respectively. For 43–44 year olds this was 15.9% (61/383), 13.2% (78/593) and 13.1% (53/406), respectively. For the over 44 year olds for the percentage of women in the age group from 2014, 2015 and 2016 this was 4.2% (16/383), 4.7% (28/593) and 1.7% (7/406), respectively. Post-hoc tests were performed to show the 40–42 years age category was significantly higher than all other age categories (P < 0.001). The over 44 years age group made up the lowest percentage of PGT-A cycles (P < 0.05). (B) PGT-M/SR treatment cycles by age, per year. For 18–34 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 60.9% (371/609), 60.7% (417/687) and 59.9% (424/708), respectively. For 35–37 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 23.8% (145/609), 22.7% (156/687) and 25.7% (182/708), respectively. For 38–39 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 9.9% (60/609), 11.5% (79/687) and 10.0% (71/708), respectively. For 40–42 years olds this was 4.8% (29/609), 4.2% (29/687), 3.8% (27/708), respectively. For 43–44 year olds this was 0.2% (1/609), 0.9% (6/687) and 0.6% (4/708), respectively. For the over 44 year olds for the percentage of women in the age group from 2014, 2015 and 2016 this was 0.5% (3/609), 0% (0/687) and 0% (0/708), respectively. Post-hoc tests showed the percentages of women in the 18–34, 35–37 and 38–39 year age groups were significantly higher than all other age groups (P < 0.001). good and poor prognosis patients and have shown a benefit of the However, the two multicentre RCTs on PGT-A published in so called PGT-A version 2 (Yang et al., 2012; Scott et al., 2013; Forman . 2018 have shown no improvement in LBR/ongoing pregnancy rate et al., 2013; Rubio et al., 2017). Rubio (2019) has reported that when (Verpoest et al., 2018; Munne et al., 2019). The positive outcomes of adding in the cumulative LBR the difference seen by PGT-A is reduced. the ESHRE multicentre RCT (ESTEEM study) are that PGT-A patients A systematic analysis evaluated the three RCTs performed on good had fewer transfers, fewer miscarriages, fewer cryopreserved embryos prognosis patients and concluded that it is yet to be determined if the but the same LBR as the control group (Verpoest et al., 2018). The data on good prognosis patients can be extrapolated to poor prognosis results of the multicentre STAR trial showed that there was no overall patients (Dahdouh et al., 2015). . improvement in ongoing pregnancy rates at 20 weeks. Subgroup 992 Theobald et al. Figure 3 Data from the HFEA on the use of PGT, by age group, for the years 2014–2016.(A) PGT-A LBRs per year by age. The fresh PET LBR for under 38 s for the years 2014, 2015 and 2016 was 29.9% (32/107), 36.8% (35/95) and 20.0% (5/25), respectively. The fresh PET LBR for 38 and over for the years 2014, 2015 and 2016 was 31.3% (40/128), 21.2% (28/132) and 25.0% (14/56), respectively. The fresh PTC LBR for under 38 s for the years 2014, 2015 and 2016 was 31.1% (32/103), 30.4% (35/115) and 12.5% (5/40), respectively. The fresh PTC LBR over 38 and over for the year 2014, 2015 and 2016 was 17.9% (40/224), 9.8% (28/285) and 15.1% (14/93), respectively. The frozen PET LBR for under 38 s for the years 2014, 2015 and 2016 was 23.3% (7/30), 29.0% (29/100) and 35.9% (47/131). The frozen PET LBR for ages 38 and over for the years 2014, 2015 and 2016 was 22.8% (8/35), 31.4% (32/102), and 38.1% (53/139), respectively. The frozen PTC LBR for ages under 38 for the years 2014, 2015 and 2016 was 28.0% (7/25), 33.3% (29/87) and 39.5% (47/119), respectively, and the frozen PTC LBR for ages 38 and over for the years 2014, 2015 and 2016 was 25.8% (8/31), 30.2% (32/106) and 34.4% (53/154), respectively. Statistical analysis via an ANOVA test showed no evidence for differences between LBR PTC and PET in terms of age groups ( P = 0.146 and P = 0.823, respectfully) or frozen cycles (P = 0.555) but there was a significant difference in fresh cycles ( P = 0.023). (B) PGT-M/SR LBRs per year by age. The LBR for fresh PET for under 38 s for the years 2014, 2015 and 2016 were 30.1% (49/163), 44.1% (41/93) and 31.4% (21/67), respectively. The LBR for fresh PET for ages 38 and over for the years 2014, 2015 and 2016 were 9.8% (3/32), 16.1% (5/31) and 23.5% (4/17), respectively. The LBR for fresh PTC under 38 for the years 2014, 2015 and 2016 was 23.2% (49/211), 34.5% (41/119) and 20.0% (21/105), respectively. The LBR for fresh PTC ages 38 and over for the years 2014, 2015, and 2016 was 6.5% (3/46), 15.2% (5/33) and 14.8% (4/27), respectively. The LBR for frozen PET for under 38 s for the years 2014, 2015 and 2016 was 32.5% (107/329), 37.2% (182/489) and 27.2% (191/514). The LBR for frozen PET ages 38 and over for the years 2014, 2015 and 2016 was 42.1%, (8/19), 23.2% (22/95), 32.5% (25/77), respectively. The LBR for frozen PTC for ages under 38 for the years 2014, 2015 and 2016 was 35.1% (107/305), 40.1% (182/454), and 38.1% (191/501), respectively. The LBR for frozen PTC for ages 38 and over for the years 2014, 2015 and 2016 was 17.0% (8/47), 27.2% (22/81) and 33.3% (25/75), respectively. ANOVA analysis was carried out and showed the LBR PTC for both fresh and frozen cycles was higher in patients under 38 years than over 38 years (P = 0.002), whereas the LBR PET did not differ by age ( P = 0.077). The LBR PTC and PET did not differ for frozen cycles ( P = 0.158) but there was a difference between LBR PTC and PET in fresh cycles ( P−0.002). PGT in the UK and USA, 2014–2016 993 Table IV SART data—the proportion of IVF and PGT cycles of total of ART procedures. Year Number of IVF and PGT treatment Number of IVF treatment cycles Number of PGT treatment cycles cycles (cumulative) (cumulative) (%) (cumulative) (%) ..................................................................................................................................................................................... 2014 140 561 121 786–87% 18 775–13% 2015 154 001 121 494–79% 32 507–21% 2016 163 979 120 326–73% 43 653–27% SART: Society for Assisted Reproductive Technology Figure 4 SART data—PGT LBRs per year (fresh and frozen cycles). The LBR per egg collection for the years 2014, 2015 and 2016 was 33.6% (5311/15 826), 30.7% (8102/26 393) and 30.1% (10 158/33 718) and the LBR per embryo transfer procedure for the years 2014, 2015 and 2016 was 52.8% (5311/10 058), 51.1% (8102/15 862) and 54.9% (10 158/18 512), respectively. SART: Society for Assisted Reproductive Technology. analysis of the women aged 35–40 years did show an increase in PGT-M/SR treatment was aged 18–34 years (Fig. 2B). These age ongoing pregnancy rate if two or more embryos were biopsied, but demographics were similar to those found in other studies (Chang these data were not significant when analysed by intention-to-treat and . et al., 2016; De Rycke et al., 2017). there was no effect on miscarriage rates ( Munne et al., 2019). For both In the USA, for PGT treatment cycles the majority of women the ESHRE and STAR trials, the additional births from frozen embryos undergoing treatment were under 35 years of age and the smallest have not been included and may result in a lower live birth rate in the group was over 42 years (Fig. 5). It should be noted that a higher PGT-A group. Some authors argue that PGT will not increase LBR as percentage of younger women had a subsequent cryopreservation in it does not change the embryos but it will decrease miscarriages, is a comparison to a primary cycle. This was expected as older women are reduced cost compared to multiple ART cycles and reduces the time to . less likely to have embryos frozen. pregnancy (Rubio et al., 2017). Only the ESHRE study on polar body biopsy has shown an effect on miscarriages ( Verpoest et al., 2018); . LBR the STAR trial did not (Munne et al., 2019). Clinics need to think carefully what they tell their patients regarding the benefit of PGT-A Over the 3 years from the HFEA data for PGT-A there was no in relation to live birth rate, cumulative live birth rate and miscarriage . difference in LBR PTC and PET between age groups ( Fig. 3A). This rates. finding agrees with the hypothesis that PGT-A is used to balance out LBRs across age groups (Munné and Cohen, 2017) but the same result was not seen for the SART data. Patient characteristics . For the HFEA data on PGT-M/SR, the LBR PTC for both fresh and For the HFEA data, the majority of patients receiving PGT-A treatment frozen cycles was significantly higher in patients under 38 years of were aged 40–42 years and those aged over 44 years were the smallest . age than over 38 years (Fig. 3B). The HFEA LBR PET and PTC were group receiving PGT-A (Fig. 2A). The majority of those undergoing calculated in line with the HFEA annual report (HFEA, 2017). PET gives 994 Theobald et al. Figure 5 SART data—PGT treatment cycles (fresh and frozen) by age, per year. For under 35 s the percentage of women in the age group from 2014, 2015 and 2016 was 30.1% (4754/15 826), 30.7% (8099/26 393) and 32.6% (10 991/33 718), respectively. For 35–37 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 21.3% (3365/15 826), 22.9% (6041/26 393) and 22.7% (7655/33 718), respectively. For 38–40 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 26.0% (4111/15 826), 25.2% (6643/26 393) and 25.1% (8458/33 718), respectively. For 41–42 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 14.6% (2304/15 826), 13.7% (3604/26 393) and 12.5% (4223/33 718), respectively. For over 42 year olds the percentage of women in the age group from 2014, 2015 and 2016 was 8.2% (1292/15 826), 7.6% (2006/26 393) and 7.1% (2391/33 718), respectively. patients an estimate of the number of transferable embryos required Frozen embryos are used for PGT as it is almost essential for to achieve a live birth. This may lead patients to want multiple embryos blastocyst biopsy. Blastocyst vitrification provides an unconstrained transferred per transfer procedure. Patients should be made aware of . time frame for genetic diagnosis to be completed. Blastocyst biopsy the risks associated with such procedures, such as multiple pregnancies, means there are more cells for testing, reducing the chance of a ‘no so informed consent can be given regarding single embryo transfer result’ (Chang et al., 2011). The high proportion of frozen PGT cycles (Forman et al., 2013). is also likely to reflect the trends towards next generation sequencing In the SART data, the LBR per cycle started, per egg collection and (Rodriguez-Purata et al., 2016; Coates et al., 2017). Owing to resource per embryo transfer procedure was significantly higher in the under 38- . and finance limitations, most clinics performing PGT do not carry year olds for all 3 years compared to older women (Fig. 6). The LBR for out diagnostics in-house; it is therefore easier and cheaper to batch the subsequent PGT cycles was also significantly higher for the under frozen samples (Penzias et al., 2018). The use of vitrified embryos 35 years age group than for patients over 41 years old. may lead to improved health of patients and babies, a reduced risk of ESHRE and SART success measures focus on transfer procedures ovarian hyperstimulation syndrome and a reduced number of multiple in which at least one embryo is transferred (De Rycke et al., 2017). pregnancies (Li et al., 2014; Rienzi et al., 2017). Additionally, policies This gives a patient who reaches the ET stage a success rate that could . set in the UK requiring a lower ET order to reduce the multiple birth be easier to understand. IVF has created new challenges for reporting rate have subsequently led to an increase in embryos available for outcomes, in which it is difficult for one success rate alone to convey cryopreservation, which has gradually become the trend since 2009 both the effectiveness and safety of a procedure ( Braakhekke et al., (Rienzi et al., 2017). 2015). However, LBRs of PGT could be inflated due to the exclusion of embryo banking cycles, a factor highlighted in other studies (Kushnir Limitations et al., 2016, 2017). . Globally, the IVF LBR is decreasing in some countries, with Canada This was a retrospective report looking at data, and its major limitations and Japan seeing the most dramatic effect ( Gleicher et al., 2019). arose from the data itself. Overall, the HFEA data were poorly collated. Gleicher et al. (2019) suggest that IVF add-ons, including PGT-A, have A total of 299 cases were excluded from analysis as it was unclear been partly to blame for this. In the USA, the decrease in IVF LBR whether they were classified as a fresh or frozen cycle. This calls started in 2011 and has continued. In 2010, the LBR was 30%, and by . for consistent reporting on what is classified as a fresh or frozen 2016 it had dropped to just over 20%. cycle. PGT in the UK and USA, 2014–2016 995 Figure 6 SART data—PGT LBRs per year by age group. The LBR per cycle started under age 38 for the years 2014, 2015 and 2016 were 42.3% (3436/8119), 38.2% (5400/14 140) and 38.9% (7253/18 646), respectively. The LBR per cycle started 38 years and over for the years 2014, 2015 and 2015 and 2016 was 24.3% (1874/7707), 22.1% (2702/12 253) and 19.3% (2905/15 072) respectively. The LBR per egg collection under 38 for the years 2014, 2015 and 2016 was 42.3% (3436/8119), 38.2% (5400/14 140) and 38.9% (7253/18 646), respectively. The LBR per egg collection age 38 and over for the years 2014, 2015 and 2016 was 24.3% (1874/7707), 22.1% (2702/12 253) and 19.3% (2905/15 072), respectively. The LBR per embryo transfer procedure for ages under 38 for the years 2014, 2015 and 2016 was 54.0% (3435/6364), 55.4% (5855/10 576) and 56.3% (72 481/12 887), respectively. The LBR per embryo transfer procedure for ages 38 and over for the years 2014, 2015 and 2016 was 50.7% (1874/3694), 51.1% (2702/5286) and 51.0% (2902/5625), respectively. Additionally, it was unclear whether a cycle-started had been form that clinics submit to the HFEA to include a section for the recorded if they did not reach egg collection. This can be related to the number of collections performed and allowing cycles to be linked. early Consortium reports in which cycle-started was abandoned, as . LBRs per egg collection, as per SART and Consortium data, could then clinics rarely reported accurate data (Geraedts et al., 2000). If today’s . be calculated. clinics are not submitting these data to the HFEA, this report may not Likewise, the number of HFEA PGT cycles that were due to be provide an accurate view on the total number of ART procedures. fresh but had no normal embryos available for transfer could not be Furthermore, by excluding cancelled and failed cycles, the chances identified. This is a problem specifically for many PGT-M/SR treatment of success for prospective patients are exaggerated by assuming that . cycles as the probability of creating an affected embryo that is not stimulation, fertilization, thawing etc. will be successful (Wilkinson . suitable for transfer is high (Lewis et al., 2001). If these cycles were et al., 2017). In comparison, the SART data include all intended not recorded, the number of PGT cycles would be much larger than collections when assessing outcomes. Any cancelled or failed cycles those reported in this study. are hence taken into account when assessing treatment numbers or Owing to the possibility of cycle inflation, only those with an indi- outcomes per cycle-started (Wilkinson et al., 2017). . cated ‘treatment now’ in the ‘main reason for producing embryos The HFEA reporting system does not adequately capture embryo storing eggs’ were included in this analysis. These ensured patients cryopreservation and genetic testing. For PGT treatments, patients . were not counted twice for the same cycle. This filter excluded patients may go through multiple egg collections in order to cryopreserve and going through an ART procedure for egg sharing or donation, which bank embryos (Chamayou et al., 2017). However, the data for these would have reduced the chance of pregnancy and affected the overall cases are not currently linked, although the HFEA are developing this. outcomes. Depending on how clinics fill out HFEA treatment forms, those egg . Unlike the HFEA, SART PGT data could not be separated into collection procedures could appear as ‘for embryo storage’ or for PGT-M/SR and PGT-A. Therefore, age profile and LBRs were not ‘treatment now and embryo storage’. Therefore, the egg collection . adequately captured. In addition, as the primary and subsequent cycles cannot be followed to the final outcome. When reporting such data, it were linked it was difficult to infer whether the age at a subsequent is unclear whether embryologists are mindful that these data are part cycle was the age of the women at egg collection or the age at the of a person’s full treatment, or if a form is filled in as an individual . transfer procedure. If age was only recorded at the ET procedure date, cycle. However, as per the SART data, all collections should be counted . the success rates of older groups may be artificially raised, especially in when calculating the outcomes. This allows the wider picture of cases of embryos/oocytes being cryopreserved several years earlier. fertility treatments to be more accurately captured (Wilkinson et al., It would therefore be valuable for clinics to report on both, especially 2017). This inaccuracy would easily be corrected by amending the for patients using IVF for fertility preservation. . 996 Theobald et al. Although the Consortium is not able to collect data from . Authors’ roles many of the clinics that SART and the HFEA report on (De Joyce Harper and Rachel Theobald designed the methods. Rachel Rycke et al., 2017), the Consortium has an important role in . Theobald carried out the data collection and wrote the initial draft of collecting data. A much better follow-through of an embryo is the paper. All three authors edited the final paper. reported. The effect of such a technology-driven approach is the impact of accuracy and later complications with increasing ART procedures. Unlike the Consortium, both the HFEA and . SART data do not separate PGT-M and PGT-SR data, making Funding it difficult to show the impact of new technologies. It could be No specific funding was used. that the PGT-SR cycle numbers have stayed static over time, if older technologies were used. In contrast, PGT-M cycle numbers may have increased, as most diseases can now be tested by new technologies. Therefore, it would have been interesting to see if . Conflict of interest technological advancements had increased the proportion of PGT- M over PGT-SR or vice versa. The ESHRE data can validate these None relating to this project. Joyce Harper is the director of the hypotheses, which has been useful for future planning of the patient Embryology and PGD Academy, which offers education in these fields. pathway and determining the types of treatments required for patients. Like the Consortium, the HFEA and SART should separate . 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Journal

Human Reproduction (Oxford, England) – Pubmed Central

Published: Apr 24, 2020

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