What is the recommended protocol for frozen embryo transfer?

Frozen Embryo Transfer Protocol Recommendations

For frozen embryo transfer (FET) cycles, elective single embryo transfer (eSET) should be applied regardless of the quality of the vitrified blastocyst to minimize multiple pregnancy risks and associated complications. 1

Endometrial Preparation Methods

There are three main protocols for endometrial preparation in FET cycles:

1. Natural Cycle (NC-FET)

   • Preferred for women with regular ovulatory cycles
   • Two variations:
     • True NC-FET: Monitors natural LH surge through blood/urine tests
     • Modified NC-FET: Uses hCG trigger to induce ovulation
   • Advantages: May have higher pregnancy rates, lower cycle cancellation rates 2, 3
   • Timing: Blastocyst transfer at hCG+7 or LH+6 4

2. Artificial/Programmed Cycle

   • Sequential administration of estrogen and progesterone
   • Preferred for women with irregular cycles
   • Requires continued supplementation of both estradiol and progesterone
   • Luteal support should continue for 3-4 weeks, with gradual reduction over 2 weeks after pregnancy confirmation 5
   • Timing: Start progesterone on theoretical day of oocyte retrieval 4

3. Stimulated Cycle

   • Uses medications like letrozole, clomiphene citrate, or FSH
   • May improve clinical pregnancy rates compared to programmed cycles 2

Embryo Cryopreservation Recommendations

• Cryopreserve one embryo per device to facilitate single embryo transfer practice and ensure traceability 1
• For vitrified-warmed blastocyst transfer cycles, SET should be applied regardless of blastocyst quality 1
• The transfer of more than two embryos is not recommended under any circumstances 1

Monitoring and Support

• Luteal Phase Support:

  • Artificial cycles: Continue progesterone for 3-4 weeks after transfer 5
  • Modified natural cycles: Continue for 1-3 weeks after pregnancy confirmation 5
  • Measuring serum progesterone at 3 weeks post-FET helps assess adequacy of luteal support 5

• Pregnancy Confirmation:

  • Blood hCG test typically performed 10-14 days post-transfer 5
  • Home pregnancy tests may be accurate from day 12-14 post-transfer but can give false negatives if performed too early 5

Special Considerations

• For patients with BRCA mutations or other cancer-related concerns, careful attention should be paid to ovarian stimulation regimens as these may increase cancer risk 1
• For patients with rheumatic and musculoskeletal diseases, ensure disease stability before proceeding with ART 1

Potential Complications to Monitor

• Severe abdominal pain
• Heavy bleeding
• Severe dizziness or fainting
• Signs of ovarian hyperstimulation syndrome (OHSS) 5

Recent Evidence on Safety Considerations

Recent evidence suggests an increased risk of hypertensive disorders in pregnancies achieved through FET without an existing corpus luteum (i.e., in artificial cycles) 6. This adds another dimension to protocol selection beyond just pregnancy rates, highlighting the importance of considering both efficacy and safety outcomes.

Pitfalls to Avoid

• Avoid transferring multiple embryos to prevent multiple pregnancies and associated complications 1
• Avoid transferring more than two embryos with the intention of performing fetal reduction, as this is not recommended due to high risks 1
• Don't base decisions on embryo criteria alone when deciding between single embryo transfer (SET) and double embryo transfer (DET) in cryopreserved-warmed cleavage-stage embryo transfer cycles 1
• Don't restrict sexual intercourse after embryo transfer as current evidence does not support increased miscarriage risk 5

While all three endometrial preparation protocols show comparable reproductive outcomes, natural cycle protocols may offer advantages in terms of pregnancy rates and reduced cycle cancellation rates. The final protocol selection should consider the patient's menstrual cycle regularity, convenience, and optimization of clinical outcomes.