How can controlled ovarian stimulation be optimized to minimize the risk of aneuploidy?

Optimizing Controlled Ovarian Stimulation to Minimize Aneuploidy Risk

GnRH antagonist protocols are recommended as the first-line approach for controlled ovarian stimulation to minimize the risk of aneuploidy, particularly in patients at high risk for ovarian hyperstimulation syndrome. 1

Optimal Stimulation Protocol Selection

• GnRH antagonist protocols are preferred over long GnRH agonist protocols as they may reduce OHSS risk without compromising live birth rates 2
• For patients with normal ovarian reserve, routine ovarian stimulation is recommended to obtain more embryos for genetic testing and transfer 1
• For poor responders, alternative protocols such as natural cycle, minimal ovarian stimulation, or luteal phase stimulation can be considered to increase the number of oocytes retrieved 1
• Individualized gonadotropin dosing is essential, taking into account the patient's age, body mass, antral follicle count, and previous response to gonadotropins 3

Stimulation Duration and Gonadotropin Exposure

• Prolonged stimulation beyond 12 days should be avoided as it significantly increases the odds of embryonic aneuploidy 4
• There is a 16.4% increase in the odds of aneuploidy for each 1000-unit increase in cumulative gonadotropin exposure in patients requiring prolonged stimulation 4
• In patients with normal ovarian response (not requiring stimulation beyond day 12), the cumulative gonadotropin dose does not significantly affect aneuploidy rates 4

Special Considerations for High-Risk Patients

• For patients at high risk of OHSS (young age, PCOS, prior hyper-response), using GnRH antagonist protocols with GnRH agonist trigger for final oocyte maturation is recommended 3, 5
• In patients with antiphospholipid antibodies, prophylactic anticoagulation with low molecular weight heparin should be started at the beginning of ovarian stimulation 1
• For BRCA mutation carriers, special attention should be paid to the stimulation regimen as ovarian stimulation may potentially increase cancer risk 1

Laboratory Procedures to Reduce Aneuploidy Risk

• ICSI is generally recommended for PGT cycles to minimize interference from maternal granulosa cells and paternal spermatozoa in embryo genetic testing accuracy 1
• Trophectoderm biopsy at the blastocyst stage is the preferred method for genetic testing, with 5-8 cells being the optimal number for biopsy 1
• A "freeze-all" embryo strategy is recommended, particularly for patients at high risk of OHSS 1, 3

Embryo Transfer Strategy

• Single embryo transfer is strongly recommended for patients at high risk of OHSS 3
• Progesterone rather than hCG should be used for luteal phase support to reduce OHSS risk 3
• Transferring more than one embryo should be avoided as it increases risks without improving cumulative live birth rates 6

Common Pitfalls and Caveats

• Avoid high cumulative gonadotropin doses, especially in patients requiring prolonged stimulation, as this increases aneuploidy risk 4
• Do not continue stimulation beyond day 12 if possible, as this is associated with increased aneuploidy rates 4
• For patients with antiphospholipid antibodies, do not forget to withhold anticoagulation 24-36 hours before oocyte retrieval and resume afterward 1
• Consider ovarian stimulation protocols that yield lower peak serum estrogen levels (such as those incorporating aromatase inhibitors) for patients at risk for thrombosis or OHSS 1

By following these evidence-based recommendations, clinicians can optimize controlled ovarian stimulation protocols to minimize the risk of aneuploidy while maintaining good clinical outcomes in assisted reproductive technology.