Reacción a "A large study finds genetic variants associated with pregnancy loss"

Overall, I find the article to be of high quality, both in terms of design and the study's scope in terms of sample size and analytical rigor. It is an ambitious, well-planned, and well-executed work that addresses a central question in human reproduction: why meiotic errors and aneuploidies occur, which are responsible for 50-60% of pregnancy losses. The authors conclude that these can be partly explained by maternal genetic factors that go beyond age.

Strengths include:

The sample size, clearly. It provides significant statistical power.

1. A specific computational method has been developed to relate crossovers and aneuploidies by tracing parental haplotypes.
2. The main results appear biologically consistent, given that the genes in which they identify common variants (especially SMC1B) are associated with recombination and aneuploidy due to alterations in maternal meiosis.
3. In summary, this is a suitable approach with a solid methodology and consistent results that would allow for establishing a link between advanced genetics and human embryology beyond the classical concepts of aneuploidy and maternal age.

The article confirms several previous findings. Above all, that aneuploidy is related to maternal age, primarily due to maternal meiotic origin. It was also known that insufficient or malpositioned crossovers have a higher risk of meiotic nondisjunction and, therefore, aneuploidy (although I believe there was some controversy here due to inconsistent findings among some studies). The results of this study tell us that embryos with aneuploidy tend to have fewer crossovers in disomic chromosomes, which would therefore be a global indicator of 'less efficient meiosis'.

Beyond this, the main contribution lies in the identification of alterations in specific genes involved in meiosis. However, I believe the clinical impact of this is currently limited, as it doesn't appear to be actionable at present, and furthermore, the causal contribution of these findings (individual risk of each variant) is very low. It might perhaps help to slightly better predict a woman's individual risk of having a meiotic abnormality, although maternal age would still remain the greatest contributor to aneuploidy risk.

On the other hand, in the current social context and reproductive landscape, these results reinforce the concept that there may be an individual susceptibility to aneuploidy beyond maternal age. In my opinion, this could be particularly helpful in interpreting some cases where we find higher-than-expected aneuploidy rates, especially in young women. It could also help guide translational research toward more specific diagnostic targets (precision medicine), which is often lacking in the context of reproductive medicine. And finally, it could open the door to more advanced reproductive genetics, although in my opinion this is still far from having clinical applicability. There's been a lot of talk lately about polygenic scores; this could be one avenue, especially if rare variants with greater impact could be identified.

Despite all of the above, and it's important to keep this in mind, and although I think it's a good article, there are inherent limitations in the design. First, it was conducted in a very specific population (infertile women undergoing IVF with PGT-A [Preimplantation Genetic Testing for Aneuploidies]). The authors don't report the IVF indication in much detail, as far as I can understand, and therefore, they don't represent the entire fertile population, nor even the subgroup of women with miscarriage or recurrent miscarriage. This does not diminish the value of the findings, given that they are likely to have long-term clinical implications in the context of assisted reproduction, but it is a limitation when generalizing the data to women or couples with spontaneous abortion, and even more so outside the context of assisted reproductive techniques.

On the other hand, it's important to remember that PGT-A involves a trophectoderm biopsy, which represents approximately six cells in a blastocyst that, logically, contains many more. Therefore, there is a risk of mosaicism, and furthermore, these cells actually represent what occurs in the placenta, not in the embryo (inner cell mass). So, again, caution is necessary. We also know that embryos have the capacity for 'repair,' and there are reported births of healthy (and euploid) children after transfers of embryos with aneuploid or mosaic PGT-A. This study focuses primarily on mechanisms that allow us to better understand aneuploidy, but we cannot conclude that this necessarily translates into pregnancy failure (although we logically know there is a relationship, it is not the focus of the study).

Finally, one detail that I consider essential: this article did not actually analyze cells obtained from spontaneous abortions or abortions following assisted reproductive technology. And yet, they extrapolate the data to the risk of miscarriage. These are results of aneuploidy detected by PGT-A prior to transfer, so they are not actually applicable to spontaneous abortion. Many of these embryos, if transferred, would not even implant, so they would not result in a miscarriage as such.

It makes sense that the authors refer to miscarriage, given that 50-60% of spontaneous abortions are due to chromosomal rearrangements, which is true. However, it should also be noted that this percentage decreases with a greater number of previous miscarriages. In other words, the more miscarriages, the lower the probability that they are due to genetic causes (this has been confirmed in previous articles). This implies that, in women with recurrent miscarriage, the mechanisms involved in pregnancy loss are not so much related to aneuploidy, but rather to metabolic disorders, uterine malformations, chronic inflammation, or thrombotic events, among others. This seems very relevant to me when considering the clinical application of these results, given that we see the impact is even more limited.

Therefore, I believe we must be cautious when interpreting these results and avoid conclusions such as the discovery of ‘a gene that predisposes to miscarriage,’ that ‘miscarriage is hereditary,’ or that miscarriage could be prevented with a genetic test. What I conclude from this study is that part of the risk of pregnancy loss due to aneuploidy could have a polygenic, small-effect, and multifactorial genetic component, and that this is a good piece of work that helps us understand the mechanisms of aneuploidy in infertile populations (the title of the article is ambitious because it implies that they have discovered the cause of aneuploidy, although the actual clinical contribution of the findings is limited, but at least it is correct in the sense that it is limited to talking about aneuploidy, without extrapolating to miscarriage).