What is Rescue ICSI?

Rescue ICSI was introduced in the year 1993.⁴ Experiencing total fertilization failure is a challenging situation for couples going through the in vitro fertilization process. To minimize the occurrence of this issue, intracytoplasmic sperm injection (ICSI) has become the preferred option over conventional in vitro fertilization (IVF) methods. However, the effectiveness of ICSI remains a topic of debate, and its application in cases where male factor infertility is not present is not recommended.²

To overcome this barrier of fertilization failure, intracytoplasmic sperm injection (ICSI) on day 1 of an unfertilized mature oocyte, the so called "rescue ICSI is recommended. This involves performing ICSI 18–24 hours after conventional insemination on eggs that have not exhibited signs of fertilization.⁴

When is rescue ICSI recommended? ⁴

• defective oocyte
• abnormal sperms
• improper stimulation protocol
• environmental factors or combination of any of these

Steps in rescue ICSI:

Prior to the availability of ICSI, it was common practice to perform a second insemination on oocytes that had not fertilized after day 1 of conventional IVF.¹

According to various research and observations it was identified, the initial sign of oocyte fertilization is the expulsion of the second polar body. Research indicates that second polar body is released within 2- 4 hours after ICSI in ~22% of oocytes and 66% at 4 hours. Pronuclei appear by 6 hours and 80% oocytes exhibiting two pronuclei by 8 hours.

For the oocytes which do not show any sign of fertilization, rescue ICSI can be performed 4-24h from conventional insemination.²

• When rescue ICSI is performed after 6 hours of fertilization failure, it results in higher fertilization rates and better-quality grade I embryos are formed. ⁵
• When rescue ICSI is performed after 22 hours of fertilization failure, their ability to undergo fertilization decreases due to aging on oocytes in culture, which results in increased cytogenetic abnormalities, fewer normal viable embryos and resulting in low pregnancy rates. ⁵

 Time sequence in rescue ICSI: ¹

Advantages and Disadvantages of using rescue ICSI:

Advantages:

• Rescue ICSI performed 6 hours post fertilization failure, results in in higher fertilization rates and better-quality grade I embryos are formed. ⁵
• Rescue ICSI has been observed to be better when compared to simple re-insemination, partial zona dissection, or subzonal insertion. Nevertheless, if fertilization fails because of poor oocyte quality, rescue ICSI cannot compensate for this defect.¹
• The transfer of cryopreserved rescue ICSI embryos has the potential to give rise to higher implantation rate and pregnancy rate per embryo transferred. ²
• It was also reported that blastocysts transferred from the rescue ICSI showed a higher implantation potential compared to cleavage stage embryo transfer from rescue ICSI cycle.²

Disadvantages:

• Rescue ICSI performed 22 hours post fertilization failure, their ability to undergo fertilization decreases due to aging on oocytes in culture.⁵
• The incidence of pregnancy following rescue ICSI is reduced compared to fresh ICSI, attributed to in vitro aging of oocytes, suboptimal embryo quality, and increased occurrences of cytogenetic abnormalities in embryos when there is a prolonged time interval between oocyte retrieval and fertilization, as reported in the literature.³
• Conducting rescue intracytoplasmic sperm injection (ICSI) on oocytes which is already undergoing fertilization may result in the development of zygotes with 3PN.⁵
• Performing rescue ICSI on certain oocytes which undergoes initial polar body fragmentation is quiet challenging as it may result in the formation of 3PN zygotes when it cannot be distinguished with the second polar body. It is recommended to promptly observe the emergence of pronuclei in such cases to enable the timely identification of 3PN zygotes.⁵

Conclusion:

In a standard IVF cycle, unexpected complete fertilization failure can occur in 10-25% of infertile women. While the use of a late rescue ICSI after 24 hours may have a low success rate due to factors like time-dependent oocyte quality deterioration and a mismatch between endometrial growth and embryo development, it has been considered a valuable option for rescuing cycles with total or partial fertilization failure. However, the challenges in implementing this technique in a laboratory setting have led to its current unpopularity.

A recent advancement in addressing this issue involves transferring embryos derived from late rescue ICSI after cryopreservation in a frozen-thawed cycle, leading to improved results. According to Beck-Fruchter et al.'s review, the application of the early rescue ICSI procedure in cases of total fertilization failure can achieve a pregnancy rate of 44%.

The major drawback of this procedure is when conducting rescue ICSI on oocytes undergoing fertilization it may result in the development of 3PN zygotes. In such cases, it is recommended to promptly observe the emergence of pronuclei to facilitate the identification of 3PN zygotes. Ultimately, the challenge lies in foreseeing IVF fertilization failure, given the multitude of influencing factors. Therefore, it becomes crucial to identify the earliest signs of fertilization.⁵

To carefully monitor these stages one can, use the time-lapse imaging technology for the continuous monitoring of the gametes.

References:

1. Yuzpe, A. A., Liu, Z., & Fluker, M. R. (2000). Rescue intracytoplasmic sperm injection (ICSI)—salvaging in vitro fertilization (IVF) cycles after total or near-total fertilization failure. Fertility and Sterility, 73(6), 1115–1119.
2. Paffoni, A., Reschini, M., Pisaturo, V. et al. Should rescue ICSI be re-evaluated considering the deferred transfer of cryopreserved embryos in in-vitro fertilization cycles? A systematic review and meta-analysis. Reprod Biol Endocrinol 19, 121 (2021).
3. Moon, J.H., Henderson, S., Garcia-Cerrudo, E. et al. Successful live birth after transfer of blastocyst and frozen blastocyst from rescue ICSI with application of polarized light microscopy for spindle examination on unfertilized eggs. J Ovarian Res 8, 22 (2015).
4. Singh N, Malhotra N, Shende U, Tiwari A. Successful live birth after rescue ICSI following failed fertilization. J Hum Reprod Sci. 2013 Jan;6(1):77-8.
5. Chen C, Kattera S. Rescue ICSI of oocytes that failed to extrude the second polar body 6 h post-insemination in conventional IVF. Hum Reprod. 2003 Oct;18(10):2118-21.