What is the recommended cycle plan for a patient with multiple failed Frozen Embryo Transfers (FETs)?

Frozen Embryo Transfer Protocol After Multiple Failed Attempts

Continue with single embryo transfer (SET) regardless of the number of previous failed cycles, as the decision to transfer multiple embryos should never be based on prior unsuccessful treatments. 1, 2, 3

Core Transfer Strategy

• Maintain SET for all frozen blastocyst transfers, even after multiple failures, as this is a strong recommendation from ESHRE that explicitly states the number of previous unsuccessful ART treatments should not influence the decision to perform double embryo transfer 1, 2
• Transferring multiple embryos does not improve outcomes and creates a 30-fold increased risk of multiple pregnancy (OR 30.54,95% CI 7.46-124.95) 3
• The cumulative live birth rate with repeated SET equals that of double embryo transfer while avoiding twin-related complications 3

Optimal Endometrial Preparation Protocol

Consider switching to a natural cycle (NC-FET) or modified natural cycle protocol rather than continuing artificial cycles (AC-FET) after multiple failures. 4, 5

Natural Cycle Advantages:

• Natural cycles demonstrate superior endometrial receptivity at the molecular level compared to artificial cycles, with better expression of genes crucial for implantation including ESR2, FSHR, LEP, and key interleukins 5
• NC-FET is associated with better maternal and perinatal outcomes, particularly lower preeclampsia risk, due to the presence of corpus luteum 4
• Endometrial transcriptome analysis shows artificial cycles negatively affect expression of pathways essential for endometrial receptivity 5

Modified Natural Cycle with Letrozole:

• For patients with previous cycle cancellations or suboptimal responses, letrozole-stimulated FET cycles significantly improve clinical pregnancy rates and live birth rates compared to artificial cycles 6
• This approach is particularly beneficial for patients with uterine peristalsis issues that caused prior cycle cancellations 6

Personalized Timing Strategy

Implement personalized embryo transfer timing based on individual hormonal response rather than fixed protocols. 7

• Personalized FET timing (adjusting transfer day based on serum progesterone levels and endometrial thickness) achieves 59.62% clinical pregnancy rate versus 35.42% with routine fixed-day protocols in recurrent implantation failure patients 7
• Monitor serum progesterone and E2/P ratio on transfer day to optimize timing 7
• Allow for delayed endometrial trigger and luteal support initiation based on individual patient response rather than calendar days 7

Transfer Timing After Failed Cycle

Proceed with immediate FET in the next available cycle rather than postponing transfer. 8

• Immediate FET (in the first cycle following failed transfer) shows superior outcomes with pooled adjusted OR of 1.20 (95% CI 1.01-1.44) for live birth rate compared to postponed FET 8
• Clinical pregnancy rate is also higher with immediate transfer: pooled aOR 1.22 (95% CI 1.07-1.39) 8
• The standard practice of waiting at least one menstrual cycle is not supported by evidence and unnecessarily delays time to pregnancy 8

Critical Counseling Points

• Emphasize that transferring multiple embryos will not improve success rates after failed cycles and significantly increases risks of preeclampsia, gestational diabetes, preterm birth, and emergency cesarean section 3
• Discuss that even singleton pregnancies after double embryo transfer carry higher risks of neonatal death and complications compared to SET 3
• Explain that the strategy focuses on optimizing the endometrial environment and transfer timing rather than increasing embryo number 7, 5

Common Pitfalls to Avoid

• Do not increase embryo number based on failed attempts—this is explicitly contraindicated by ESHRE guidelines and does not improve outcomes 1, 2
• Do not routinely postpone the next FET cycle, as immediate transfer shows better results 8
• Do not continue the same artificial cycle protocol if multiple failures have occurred—consider switching to natural or modified natural cycles 4, 5
• Avoid fixed-day transfer protocols—personalize timing based on hormonal monitoring 7