Reacción a "There is insufficient evidence that most complementary treatments for in vitro fertilization improve fertility"

The press release reflects the study fairly accurately, but it simplifies some important nuances and, above all, presents certain conclusions as more definitive than they are in the article, where they remain uncertain or model-dependent.

The press release gets the essentials right: the meta-analysis included 85 reliable randomized clinical trials (RCTs). Of 157 potentially eligible trials, it excluded 72 and concluded that most add-ons have no proven benefit or insufficient evidence. It is also correct in highlighting that there are three interventions with weak signs of benefit: endometrial scratching, which could be described as “a minor scraping of the uterine lining to try to promote implantation,” EmbryoGlue (an embryo culture medium containing a component that is supposed to increase embryo implantation), and PICSI (a microinjection of sperm selected using a special, more physiologically similar culture medium).

Where the article becomes somewhat more optimistic than the original paper is in its language regarding these three add-ons, because the original paper emphasizes that the effect of EmbryoGlue on live births was not robust under the random-effects model, and that the evidence for PICSI and scratching is of moderate or low certainty depending on the outcome. Furthermore, the article summarizes the limitations well but does not emphasize enough that the paper itself discusses heterogeneity, publication bias, imprecision, and risk of bias across various sets of studies.

The overall methodological quality is good for a review on this topic: a comprehensive search across multiple databases, double screening, duplicate data extraction, assessment using Cochrane RoB 1 and GRADE, and sensitivity and heterogeneity analyses. A key strength is that the authors did not merely count studies; rather, they excluded trials with serious reliability issues, which is particularly relevant in assisted reproduction.

Even so, the article itself makes clear that many trials were small, outdated, or at high risk of bias, and that for several outcomes, the certainty was low or very low. Thus, while the quality of the study is high, the quality of the available evidence for some interventions remains limited.

Overall, the main conclusions are supported by the presented data. The assertion that most add-ons show no clear benefit is consistent with the pooled results for acupuncture, corticosteroids, endometrial receptivity testing, intralipid therapy, PRP (platelet-rich plasma), and PGT-A (preimplantation genetic testing for aneuploidies) in their usual use as it relates to the outcome of live birth or cumulative outcomes.

However, statements regarding “possible benefit” should be read with caution. In the case of EmbryoGlue, for example, the positive effect was not consistent across statistical models, and the article explicitly acknowledges this. For PGT-A, the reduction in miscarriage does not clearly translate into more cumulative live births, which means that its actual clinical utility remains debatable.

The authors took several methodological confounding factors into account, primarily through subgroup comparisons, sensitivity analyses, and the GRADE approach, and they also attempted to minimize bias by excluding studies with reliability issues. However, in this type of review, “confounders” are not only clinical; there is also confounding due to study design: different populations, different indications, different IVF protocols, and outcomes measured at non-equivalent time points.

There are several significant limitations: the TRACT checklist has not been validated; some excluded studies might have been reliable; many trials were small or outdated; and some of the evidence comes from populations or practices that may not reflect current IVF practices. In the second study—the website trial—generalizability is also limited because all participants lived in Australia.

This study aligns well with the previous literature and, in part, refines it. The article itself notes that previous Cochrane reviews were outdated, included retracted or problematic studies, and that this meta-analysis incorporated 28 new trials. In other words, it does not radically contradict previous evidence but rather makes it more rigorous by filtering based on reliability.

The practical conclusion is quite consistent with the well-known trend in assisted reproduction: many add-ons are used more for marketing, habit, or biological plausibility than for proven clinical benefit. What is new here is the combination of a more rigorous review with a parallel trial on patient information, which reinforces the idea that the problem is not only therapeutic but also informational.

For clinical practice, the message is that most add-ons should be offered with great caution—if at all—and only with a clear explanation that the benefit is unproven or uncertain. This is especially relevant in private settings, where financial costs and information asymmetry can be high.

For patients, the study supports a more transparent shared-decision-making approach: distinguishing between standard interventions, experimental interventions, and interventions with weak evidence. For research, the priority should be large, pre-registered, and methodologically sound trials, as this field continues to be affected by reliability issues in primary studies.

The Spanish Fertility Society (SEF) has published two monographs specifically aimed at assisted reproduction professionals. One is titled “ADD-ONS” Adjuvant Treatments in Andrology and Assisted Reproduction Laboratories, prepared by the Clinical Embryology Interest Group, and the other is “ADD-ONS” Adjuvant Treatments in Assisted Reproduction, prepared by the Reproductive Endocrinology Interest Group. These guidelines contain a series of evidence-based recommendations reviewed and drafted by leading professionals in our country, which can serve as a reference for the add-ons included in the article and others. We are fortunate to be a country recognized worldwide as a leader in assisted reproduction.