Impact of ovarian stimulation with gonadotrophins on embryo aneuploidy.

Sir, We have read the article published in your journal by Taylor et al. (2014) with much interest. In this review the authors properly summarize the mechanisms, origins and incidence of chromosomal mosaicism in humans. The review is rigorous, exhaustive and very well-documented, and therefore we congratulate the authors for their work. Nevertheless, we find that some relevant information about the external influences that could contribute to mosaicism and/or embryo aneuploidy is missing. Authors state that ‘hyperstimulation has been implicated in increased rates of cleavage stage aneuploidy’. We consider that this statement should not be so categorical as the potential deleterious effect of ovarian stimulation on oocyte and embryo quality is still the subject of lively debate. We conducted the first prospective cohort study by comparing unstimulated and stimulated cycles in the same woman (Labarta et al., 2012). The intrasubject comparison showed a rate of aneuploidy of 34.8% (95% CI 1⁄4 20.5–49.1) in the unstimulated cycle and 38.2% (95% CI 1⁄4 30.5–45.8) in the stimulated cycle (risk difference 1⁄4 3.4 (95% CI 1⁄4 217.9 to 11.2)). No differences were observed for embryo quality and type of chromosomal abnormalities.We concluded that ovarian stimulation does not significantly raise the embryo aneuploidy rate in IVF-derived human embryos when compared with an unstimulated cycle. The study was conducted in egg donors, younger than 35 years old with no previous ovarian stimulation treatments. The time frame between both unstimulated and stimulated cycles was a maximum of 3 months. The design of this study avoided some biases, such as impact of age on aneuploidy, intersubject variability, infertility background and different lab conditions between distinct IVF centres, such that we could analyse the net impact of gonadotrophins on embryo aneuploidy. We were also able to analyse the largest sample of IVF-derived embryos from unstimulated cycles, and we observed an aneuploidy rate of 34.8%, which is in agreement with previously published data (Verpoest et al., 2008). These results suggest that embryo aneuploidies are present in human beings, even in the absence of ovarian stimulation, and that this could be the reason why fertility in humans is so ineffective. These findings are supported by previous data showing that when comparing natural and stimulated cycles, no differences were observed in terms of cleavage capacity, embryo quality or incidence of aneuploidy in aborted fetuses. Other studies have compared the effect of different doses of gonadotrophins—instead of natural versus stimulated cycles—on the rate of mosaicism and embryo aneuploidy. In infertile patients, it has been suggested that the use of gonadotrophins might raise the chromosomal abnormality rate in a dose-dependent manner, mainly due to an increased incidenceofmosaicism (Baart et al., 2007). Yet in oocyte donors, our groupobserved that the incidenceofmosaicismwassimilar, regardlessof the doses of gonadotrophins used. However, the same study showed that when doses are small, but the number of oocytes obtained is similar to higher doses in the sameegg donor, the incidenceofmosaicism lowers (Rubio et al., 2010). In summary, according to recent literature, it cannot be stated that ovarian stimulation with gonadotrophins may significantly increase the rate of embryo aneuploidy in patients without the negative effect of age acting as a confounding factor. Moreover, embryo aneuploidy is present even in unstimulated cycles, suggesting that either this is the real incidence in human beings or there are factors other than ovarian stimulation related with the IVF procedure which may increase this incidence in comparison with in vivo fertilization. Finally, mosaicism could be related with doses of gonadotrophins and this effect should be further studied.