Advanced paternal age affects miscarriages and live birth outcomes in oocyte donation cycles

Does advanced paternal age affect miscarriage and/or live birth outcomes following the first transfer attempt in oocyte donation cycles?

Paternal age has a gradual but cumulative effect that becomes apparent above 45 years of age, where it evidently increases miscarriage rates and decreases live birth rates following the first transfer in oocyte donation cycles.

Donor oocyte cycles are becoming a common strategy for addressing female age-related infertility, offering high success rates (∼60% ongoing pregnancies) attributed to superior oocyte quality. However, male age-related effects on the success of ART have received less attention. In autologous cycles, advanced paternal age has been associated with poor clinical outcomes. However, disentangling its effects from female factors remains challenging. Oocyte donation cycles offer a useful model for studying the impact of male factors on ART outcomes, eliminating biases related to female age and underlying diagnoses.

Multicentric, retrospective study of 1606 first oocyte donation cycles performed between January 2019 and December 2023, across seven IVF centers. Only ICSI cycles with fresh donor oocytes, inseminated with partner sperm were included. Only the first single blastocyst transfers (fresh or frozen) were considered. Cycles with abnormal male karyotypes, sperm obtained from testicular biopsy, donor sperm, frozen oocytes, in vitro matured oocytes or preimplantation genetic testing (PGT) were excluded.

Paternal age was assessed as a continuous variable, in multiple age strata (<35, 35-40, 40-45, and >45 years) and dichotomized into ≤45 and >45 years. Fertilization rates, the number of usable blastocysts and blastocyst utilization rates were assessed. Clinical outcomes included clinical pregnancy, miscarriage, and live birth rates. P < 0.05 was considered statistically significant after univariate tests and a multivariable logistic analysis adjusting for recipient and oocyte age, male and recipient BMI, fresh/frozen semen for insemination, number of mature (MII) oocytes injected, embryo morphology grade, and fresh/frozen embryo transfer. An exploratory analysis comparing Kaplan-Meier curves for subsequent embryo transfers was performed.

Within the cohort of 1606 patients who underwent a first oocyte donation cycle, the mean female recipient age (±SD) was 43.2 (±4.1) years, the mean oocyte donor age (±SD) was 26.2 (±4.2) years, and the mean paternal age (±SD) was 43.1 (±6.0). Paternal age as a continuous variable showed a modest but gradual reduction in live birth without a discrete transition at any specific age. Stratifying paternal age (<35, 35-40, 40-45, and >45 years) showed a trend to reduced odds of live birth when comparing the >45 years group to the <35 years group (aOR = 0.66; 95% CI 0.43-1.02; P = 0.06). To explore cumulative effects of paternal age in ART outcomes, we decided to compare in more detail two groups: ≤45 and >45 years. In the ≤45 years group (n = 1031), the mean paternal age (±SD) was 39.7 (±4.1) years, while in the >45 years group (n = 575), it was 49.1 (±3.7). No differences were observed in oocyte donor age, number of oocytes fertilized, or number of blastocysts obtained among paternal age groups. Interestingly, miscarriage rate was 25.4% (67/264) in the >45 years group and 15.6% (81/518) in the ≤45 years group. The differences were statistically significant (P = 0.001). Consequently, the live birth rate was also reduced to 34.3% in >45 years versus 42.4% in ≤45 years (197/575 vs 437/1031; P = 0.001). These results were further confirmed in the adjusted analysis, where >45 years of paternal age remained associated with a statistically significant higher miscarriage rate (aOR = 1.86, [95% CI: 1.25-2.76], P = 0.002) and a statistically significant lower live birth rate (aOR = 0.72, [95% CI: 0.57-0.91], P = 0.005). In an exploratory analysis, the >45 years group also showed a lower probability of achieving a live birth in subsequent embryo transfers compared to the ≤45 years old group (P = 0.003).

This study is limited by its retrospective nature. No data on the chromosomal status of the blastocysts transferred was available. Caution is warranted when generalizing results to different embryo transfer strategies or other patient populations.

Our results indicate that paternal age can affect clinical outcomes in oocyte donation cycles. If confirmed in a larger cohort of patients, these results would suggest considering patient counseling in relation to advanced paternal age when delaying childbearing.

No funding was received from agencies in the public, commercial, or not-for-profit sectors.

The authors declare no conflict of interest related to the current study.

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