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FMR1-Associated Diminished Ovarian Reserve: Reduced Oocyte Yield Without Loss of Per-Embryo Ploidy
Yuval Fouks1, Brittany Morse2, Catharyn Stern1
1Melbourne IVF, 36 Wellington Street, Collingwood, VIC 3066, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Australia; Reproductive Services Unit, The Royal Women's Hospital, Melbourne, Australia.
Objective:
To determine whether diminished ovarian reserve in FMR1 premutation carriers reflects a purely quantitative deficit or is also associated with impaired per-embryo chromosomal competence, including embryo aneuploidy risk.
Design:
Identification of FMR1 premutation patients from a clinic database. Subsequent retrospective cohort study with two analytic frameworks: (1) a carrier PGT subcohort analysis characterizing ovarian-reserve markers and per-embryo ploidy across PGT modalities; (2) a 1:1 matched-cohort analysis of FMR1 premutation-carrier PGT-A cycles (n=33) versus non-carrier PGT-A controls (n=33) matched on age, BMI and oocyte yield.
Setting:
Single private academically affiliated IVF center, January 2014-December 2023.
Subjects:
173 fresh IVF/ICSI cycles from FMR1 premutation carriers formed the carrier cohort; 142 underwent PGT (PGT-A and/or PGT-M) and formed the PGT subcohort. For the matched-cohort analysis, 33 carrier PGT-A cycles were matched 1:1 to 33 controls drawn from 5,376 non-carrier PGT-A cycles.
Exposure:
FMR1 premutation carrier status.
Main Outcome Measures:
Quantitative metrics: AMH, oocyte yield, mature oocytes, normal fertilizations, and usable blastocysts. The primary embryo-competence outcome was euploidy per embryo biopsied (Poisson incidence-rate ratio with log-offset for embryos biopsied) in PGT-A-only cycles; secondary outcomes were the proportion of cycles with ≥1 euploid embryo and the all-aneuploid proportion.
Results:
Quantitative ovarian-reserve markers (AMH, oocyte yield, mature oocytes, fertilisations, usable blastocysts) were lower in carriers, with a graded descriptive relationship to CGG repeat length (most evident for AMH and oocyte/mature-oocyte yield) in the subset with available CGG data. Of 173 carrier cycles, 142 underwent PGT, with at least one blastocyst biopsied in 124. In the carrier PGT subcohort, the odds of obtaining ≥1 euploid embryo were lower with advancing maternal age and in co-tested PGT-A+M versus PGT-A cycles, with no independent association for AMH or BMI; the usable-blastocyst rate per oocyte was not associated with PGT modality, age or BMI (AMH trend p=0.07). In the matched cohort, 84.8% of carriers versus 75.8% of controls achieved ≥1 euploid embryo; the three-category biopsy-outcome distribution did not differ between groups (p=0.67). Poisson regression confirmed no significant difference in per-embryo euploidy rate between groups (rate ratio 1.01, 95% CI 0.82-1.25, p=0.91). An IPTW sensitivity analysis was concordant with the matching results (IRR 0.996, 95% CI 0.83-1.19).
Conclusion:
FMR1 premutation carriers exhibit quantitative reductions in ovarian reserve and early embryology outcomes, but do not demonstrate impaired embryo ploidy once blastocysts reach biopsy stage. Although premutation carriers may yield fewer eggs, their per-embryo euploidy risk remains comparable to age-, BMI- and yield-matched non-carriers. These findings are restricted to clinically ascertained, PGT-A-eligible premutation carriers and to per-embryo ploidy among biopsied blastocysts, and should not be generalised to unscreened carriers, diminished ovarian reserve of other aetiologies, or non-chromosomal aspects of embryo competence.