Recent Papers Commenting on Important Issues in IVF and Infertility in General
Today’s posting is a good, old-fashioned presentation of some recent and mostly clinical papers about issues relating to in vitro fertilization (IVF) and/or general infertility.
The CHR’s Editorial Staff
We are here presenting a potpourri of recently published articles in the medical literature which we feel have a message for patients as well as fertility service providers. They are short commentaries, - hopefully motivating some of our readers interested in a given subject to look up the respective reference. If you have comments to make regarding any of the here presented manuscripts, - we are very much looking forward to receiving them. Among others, the subjects are: Is a conception through IVF predictive of increased endometriosis and adenomyosis risks? Does the new “fashion” of re-biopsying embryos – and, yes, medicine also has its “fashions of the moment” - make sense if a first biopsy failed because of insufficient DNA or the result is questioned for other reasons? Is repeated implantation failure associated with dyslipidemia, and several other interesting mostly clinically-relevant issues. Let us know what you think!
These short commentaries originally appeared in the January issue of the CHRVOICE but were updated and reedited.
Have Female Children Conceived by IVF Increased Risk of Endometriosis, Adenomyosis, and Related Symptoms?
According to a study by Norwegian investigators, the answer was YES!1 But this is one of those studies which we usually describe as “self-fulfilling prophecy studies” because everybody, of course, knows that endometriosis is an especially familial condition.
The authors, of course, knew this and claimed to have adjusted the data based on the women’s endometriosis and adenomyosis histories. But we also, of course know how inaccurate patients’ endometriosis and adenomyosis medical histories are. In short, not a very credible and, therefore, valuable study!
REFERENCE
Magnus et al., Fertil Steril 2025;. 0015-0282, https://doi.org/10.1016/j.fertnstert.2025.10.002; ahead of print.
Why Would Anybody Re-biopsy an Embryo After PGT-A and Especially After a “Simple” Segmental Deletion?
And here is another paper that basically makes little sense, - this time by Chinese colleagues who concluded in their study that an embryo at PGT-A diagnosed with what the authors called “simple” segmental deletions (in contrast to not so “simple” deletions?) had “low predictive value.”1
That is, of course, not a surprise because if a first embryo biopsy is considered “inaccurate,” why would anybody believe that a repeat biopsy would -suddenly – be more accurate? Moreover, the literature by now has clearly demonstrated that embryos with segmental “aneuploidies” (the “-“ here have a
purpose!) have similar pregnancy and live birth rates (45.5%) to “euploid” embryos (50.0%). These are even better rates than (low) mosaic embryos (34.3%)2 which an increasing number of IVF clinics already have started transferring. One more thing that makes absolutely no sense in PGT-A practice.
REFERENCES
Wang et al., Reprod Biol Endocrnol 2025;23:156
Spinella et al., Hum Reprod 2025;40(Suppl 1).deaf097.266 (abstract)
Is Dyslipidemia a Risk Factor for Repeated Implantation failure?
This is at least the conclusion that another group of Chinese investigators recently reached (Chinese investigators are slowly dominating submissions to medical and science journals and more on that in the near future in these pages) in a paper in JCEM.1 Epidemiological observational studies have indicated an association between type 1 diabetes (T1DM) and systemic sclerosis (SSc, also called scleroderma). The reasons have, however, remained unclear.
Here a Mendelian randomization (MR) investigated the bidirectional causal relationship between the two. through a bidirectional two-sample analysis and revealed such a causal link between genetic susceptibility to T1DM and an increased risk of SSc, though not vice versa. This example, therefore, emphasizes the need for validation across diverse populations. Further exploration of underlying mechanisms, moreover, could offer interesting results with relevance beyond just SSc.
REFERENCE
Huang et al., J Diabetol & Metab Syndrome2025;17:195
Have You Ever Thought About Transferring Zona-free Blastocysts in an IVF cycle?
If you did and believe colleagues from Charlotte, NC, it does not seem to work very well: pregnancy rates in frozen-thawed cycles were lower and chemical pregnancies and miscarriages were higher in comparison to transfers with intact zonas. But what does that mean?
On first impulse, one could conclude that it is the absence of a zona that is responsible for observed poorer outcomes. But hold on for a moment: Why would 12.6% of the authors’ frozen embryos have been zona-free. Maybe, they were just – for whatever reason - lousy embryos that hatched earl. Or, maybe, they hatched early because they were frozen too late. We basically don’t know why such a large percentage of embryos ended up zona-free; but we know that this is not normal.
This paper, therefore, does not suggest whether absence of a zona - in itself - represents a poor prognostic sign regarding embryo quality and/or chance of implantation. This question can only be answered by prospectively randomized study with embryos randomized to zona removal or not before embryo transfer. So, don’t try it yet (unless, of course, there is no choice)
REFERENCE
Ying et al. J Assist Reprod Genet 2025; 42:4301-4307
Is Systemic Sclerosis Associated with Risk of Premature Ovarian Insufficiency (POI) (also called Primary Ovarian Insufficiency)
Using data of 61,569,984 women, - claiming that there was no data in the literature on a possible association between systemic sclerosis (SSc) and occurrence of primary ovarian insufficiency (POI), Chinese investigators explored this question and concluded that SSc was, indeed, associated with a 1.6-times increased risk for POI. But for anybody familiar with the very strong association of autoimmunity with POI, this does not come as a surprise. If anything, we would have expected an even stronger association. Since, except in women with Addison’s disease, when autoimmune oophoritis demonstrates an obvious ovarian epitope for an autoimmune response against the ovary, no other ovarian epitope for an autoimmune response has been identified in decades of research, the important question that remains unanswered is, what associates autoimmunity so strongly with POI?
As we have noted in these pages repeatedly, the most likely explanation is that the autoimmune response causing POI is not directed against an ovarian epitope but against and extraovarian epitope, with the autoimmune response against that epitope demonstrating cross reactivity with a functional ovarian epitope. Our strong suspicion is that it may be an adrenal epitope because ovaries and adrenals share a common embryological primordium.
REFERENCE
Dai et al., Rheumatology 2025; keaf479 (abstract)
A new Marker for Recurrent Miscarriage Risk?
Australian investigators recently published an interesting paper in Human Reproduction which was based on observations in a mouse model. The study implicated abnormally low concentrations of nicotinamide adenine dinucleotide (NAD) in repeat miscarriages. More specifically, perturbations of NAD synthesis due to genetic and/or environmental factors causes NAD deficiency, implicated in so-called congenital NAD deficiency disorder (CNDD) which, in turn, is characterized by recurrent pregnancy loss and congenital anomalies.
In CNDD mouse models, fetal anomalies and embryo loss are prevented if NAD levels are raised by - during pregnancy - supplementing the mother’s diet with a NAD precursor, such as vitamin B3,.
The investigators, therefore, executed a prospective pilot cohort study of 88 non-pregnant women between 20 and 40 years of age, 37 with and 51 without a history of recurrent miscarriages, who served as controls. Recurrent miscarriage patients were defined as a history of two or more consecutive spontaneous miscarriages before 20 weeks’ gestation, with the last miscarriage between 6 weeks and 2 years prior to recruitment.
And women with a history of recurrent miscarriage indeed demonstrated higher blood, plasma, and urine concentrations of NAD Salvage Pathway excretion products. Moreover, urinary excretion of nicotinamide (NAM) was also elevated, compared to control women.
So, what is then the meaning of these findings: (i) Elevated excretion of Nam and its derivatives appears linked to differences in NAD synthesis pathways; and (ii) also in some ways appears linked to higher miscarriage risk.
But there also exist other adverse pregnancy outcomes that are associated with effects in NAD metabolism based on the secretion of elevate metabolites, raising the question whether elevation of these markers (the authors identified three specific metabolites) is, indeed, suggestive of miscarriage risk or of a more general poor pregnancy outcome risk. Despite these remaining uncertainties, nevertheless, a potentially important paper!
REFERENCE
Cuny et al., Hum Reprod 2025;40(12):2247-2259