ICSI should not be used in PGT-A – unless indicated for male infertility factor ICSI

According to the authors of a large retrospective cohort study (1) which has found that the fertility treatment offers no benefit over conventional IVF (cIVF) for embryo quality and live birth rates (LBRs).

Based on more than 30,000 PGT-A cycles carried out in the USA for non-male factor infertility, the main findings show that embryos suitable for transfer and LBRs ‘are not significantly different’ in cIVF vs ICSI. In addition, ICSI did not improve secondary outcomes such as gestational age at delivery, birth weight and unexplained infertility.

The study which used data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SARS CORS) adds to the debate around the overuse of ICSI outside its primary indication for male infertility. While acknowledging that ICSI has enabled ‘countless’ infertile men to have genetically-related children, the authors say the fertility treatment is ‘not without its limitations’ including increased cost and controversy over adverse neonatal outcomes.

The use of ICSI for PGT-A has arisen out of concerns that results could be affected by contamination from residual cumulus cells and from surplus sperm attached to the zona pellucida because of cIVF. On this basis, ESHRE good practice recommendations have suggested ICSI is preferable for PGT (2) as have those from the American Society of Reproductive Medicine (ASRM) (3).

However, the authors of this retrospective cohort study say that advancements in PGT-A mean genomic contamination has been ‘drastically reduced’. They say this calls into question ‘the necessity of ICSI for PGT-A tested embryos ’, a conclusion which has been backed up by other studies. Moreover, the authors argue that the use cIVF for non-male factor PGT-A cycles could lead to a decrease in costs and in ‘embryology labor’ for fertility clinics. The results also question clinics’ rising use of ICSI for unexplained fertility in the belief that couples will benefit by increasing their chance of having a baby.

The authors used data from the SART CORS database) relating to all cIVF/ICSI cycles involving PGT-A from January 2014 to December 2017. SART CORS holds information from fertility clinics in the USA who are SART members. All frozen thawed embryo transfer (FET) cycles linked to PGT-A cycles were also evaluated for LBRs.

The primary outcomes were percentage of embryos suitable for transfer and LBRs. Secondary outcomes included subgroup analysis for embryos suitable for transfer on cycles from patients aged 35 years (y/o) or above vs those aged under 35 years; 6 or fewer oocytes retrieved vs more than 6; and cycles with the diagnosis of unexplained infertility. Additionally, gestational age at delivery and birthweight between cIVF and ICSI were evaluated.

Additional secondary outcomes included rates of pregnancy loss, average gestational age at delivery, birthweight, and sub-analysis of first FET cycles.

Exclusion criteria included PGT cycles where either parent was a carrier for a genetic disease, use of frozen oocytes and cycles with more than 10 embryos biopsied; and potential confounding variables included maternal age, maximum FSH level and number of oocytes retrieved.

A total of 30,446 non-male factor PGT-A cycles (n=4,867 cIVF cycles; n=25,579 ICSI) met the inclusion criteria. Results showed no significant differences in rate of embryos suitable for transfer between cIVF vs ICSI (41.6% vs 42.5% respectively, p=0.12) or within the patient subgroups (≥35 y/o=35.7% vs 36.5%, p=0.25; <35 y/o=57.6% vs 58.6%, p=0.21; ≤6 oocytes retrieved=32.9% vs 35.3%, p=0.12; >6 oocytes retrieved=43.9% vs 44.2%, p=0.66; and unexplained infertility=46.4% vs 48.8%, p=0.09).

Analysis of single FET (n=3,412 IVF; n=16,358 ICSI) found no significant differences for LBRs (50.1% vs 50.8% respectively, p=0.51) and pregnancy loss rates (16.6% vs 15.5, p=0.11); and sub-analysis of first FET transfers only in cIVF vs ICSI revealed a similar trend for LBRs (53.4% vs 53%, p=0.78) and pregnancy loss rates (15.7% vs 15.5%, p=0.84).

In addition, no significant differences were found in cIVF vs ICSI for gestational age in days (265.8 vs 265.6, p=0.73) and birth weight in grams at delivery (3,376.7 vs 3,363.5, p value=0.42).

Limitations of the study include the fact data may be biased towards larger centres, and that ICSI requires technical skill which may differ among embryologists and between centres.

Several areas of research were not covered by this SART CORs analysis: these are recommended for further study by the authors. In their paper, they write that evaluation of the incidence of mosaic embryos is important ‘given the ability’ for these embryos to lead to live births; and suggest that evidence is needed on whether ICSI decreases paternal contamination during PGT-A cycles.

1 Tozour J, Arnott A, Akerman M, Sung L, Vintzileos A and Fritz R. Comparison of Outcomes Between Intracytoplasmic Sperm Injection and In Vitro Fertilization with Pre-implantation Genetic Testing for Aneuploidy, Analysis of SART CORS Data. Fertility and Sterility (2024); https://doi.org/10.1016/j.fertnstert.2023.12.041
2 Georgia Kokkali et al. ESHRE PGT Consortium and SIG-Embryology Biopsy Working Group. ESHRE PGT Consortium and SIG Embryology good practice recommendations for polar body and embryo biopsy for PGT. HR Open 2020 (3); https://doi.org/10.1093/hropen/hoaa020
3 Intracytoplasmic sperm injection (ICSI) for non–male factor indications: a committee opinion Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Fert and Steril 2020; vol 114 (2); https://doi.org/10.1016/j.fertnstert.2020.05.032