What are the next steps after a failed fertilization following Intracytoplasmic Sperm Injection (ICSI)?

Failed Fertilization After ICSI: Literature and Management Approach

Understanding Failed Fertilization

Complete fertilization failure after ICSI occurs in 1-3% of cycles and is most commonly caused by oocyte activation failure (71% of cases), not technical errors or sperm ejection. 1, 2

Primary Causes of Failed Fertilization

The cytological examination of 428 unfertilized oocytes revealed the following distribution of causes 2:

• Oocyte activation failure (71%): The spermatozoon was correctly injected and present as a swollen sperm head among metaphase chromosomes, but the oocyte failed to complete meiosis II 2
• Sperm ejection from oocyte (19%): The injected spermatozoon was expelled after injection 2
• Failed sperm head decondensation (10%): The sperm head remained completely undecondensed despite proper injection 2
• Premature chromosome condensation (6.6%): Sperm chromosomes condensed prematurely before oocyte activation 2

Contributing Factors

Analysis of 76 total fertilization failure cycles identified three major contributing factor categories 3:

• Sperm-related factors: Only immotile spermatozoa available, round-headed spermatozoa (globozoospermia), or poor sperm viability 3
• Oocyte-related factors: Low number of mature oocytes, abnormal oocyte morphology, or oocyte damage during ICSI 3
• Technical factors: ICSI procedural issues, though less common than biological causes 1, 4

Prognosis and Next Steps

Repeated ICSI attempts are strongly recommended, as 85% of couples who experience complete fertilization failure will achieve fertilization in subsequent cycles. 1

Evidence for Repeat Attempts

• Of 26 couples with initial total fertilization failure, 22 (85%) achieved fertilization in subsequent ICSI cycles 3
• Natural conception can occasionally occur even after total ICSI failure, particularly in cases of unexplained infertility 5
• Failed ICSI does not indicate a hopeless prognosis for future treatment 5

Management Algorithm

Immediate Post-Failure Assessment

ICSI is generally recommended for all PGT cycles to minimize interference from granulosa cells and residual spermatozoa, which can affect diagnostic accuracy 6:

1. Review cycle parameters: Examine ovarian stimulation protocol, oocyte number and quality, sperm parameters on injection day 3
2. Assess oocyte maturity: Document the number of metaphase II oocytes available for injection 1, 3
3. Evaluate sperm quality: Specifically assess sperm motility, morphology (particularly for round-headed spermatozoa), and viability 3, 4

Modifications for Subsequent Cycles

For poor ovarian responders where oocyte retrieval fails after routine stimulation, alternative protocols including natural cycle retrieval, minimal ovarian stimulation, or luteal phase stimulation can be considered 6:

• Patients must be counseled about risks of low oocyte numbers, no transferable embryos, or testing failure 6
• For normal responders, standard stimulation protocols remain appropriate 7

Advanced Interventions

When oocyte activation failure is suspected (the most common cause), artificial oocyte activation methods may be employed 4:

• Chemical activation techniques can be considered for repeated activation failure 4
• Morphologically selective ICSI should be used when sperm malformations are identified 4

Counseling Recommendations

Physicians should provide comprehensive counseling about all available options following repeated ICSI failure 1:

• Repeated ICSI attempts: First-line recommendation given 85% success rate in subsequent cycles 1, 3
• Donor oocytes or embryos: For persistent oocyte-related failure 1
• Donor sperm insemination: For persistent severe sperm-related failure 1
• Adoption or remaining childless: If other options are unacceptable due to religious or ethical reasons 1

Important Caveats

Single embryo transfer (eSET) should remain the standard even after failed cycles, as there is no evidence that double embryo transfer improves cumulative live birth rates 7:

• The ESHRE guideline found no clear indication to favor double embryo transfer over single embryo transfer based on previous failed treatments 6
• Each unsuccessful ART cycle decreases odds of ongoing implantation, but transferring multiple embryos increases risks without improving cumulative outcomes 6
• Multiple embryo transfer significantly increases risks of ectopic pregnancy (up to 20-fold), multiple gestation complications, and neonatal morbidity 6

Key Literature for Presentation

The most comprehensive analysis comes from the 1995 study examining 76 total fertilization failures among 2,732 ICSI cycles, which established the 3% failure rate and identified primary causative factors 3. The cytological study by the same group definitively demonstrated that oocyte activation failure, not technical errors, accounts for the majority of cases 2.