JBRA Assist. Reprod. 2026 2026;00(0):00-00
LETTER TO THE EDITOR
doi: 10.5935/1518-0557.20260075
1Centro de Reprodução Humana Monteleone - São Paulo, Brazil
I thank Cavalcante and colleagues for their careful reading and constructive response. Open debate on methodologically complex topics is essential for responsible scientific progress. To move this discussion forward, however, the central point of disagreement must be clearly defined. Our position challenges neither reproductive immunology as a field of research nor the biological plausibility of its proposed mechanisms. Rather, it concerns the evidentiary threshold that must be met before biological plausibility can justify routine clinical intervention.
In discussing the ESHRE guideline (ESHRE Guideline Group on RPL, 2023), for example, the authors state that the society "acknowledges that intravenous immunoglobulin (IVIG) may be beneficial in selected cases." This interpretation overlooks an important distinction. The guideline acknowledges the limitations of the available evidence, recognizes a possible benefit in specific subgroups, and calls for further investigation. That position does not support the routine or generalized use of IVIG, nor its extrapolation beyond the specific population and treatment regimen evaluated. There is a substantial difference between considering a therapy a legitimate subject of research and endorsing it for routine clinical practice.
The same methodological concern applies to biomarkers. Meta-analyses reporting an association between peripheral natural killer (NK) cell cytotoxicity and recurrent miscarriage document an epidemiologic association-an important initial observation, but one that remains insufficient to guide treatment. Two questions remain unresolved: Are these assays sufficiently reproducible and reliable across laboratories? Does treatment guided by their results increase live birth rates in randomized controlled trials? Without affirmative answers, the claim that interventions are reserved for "carefully selected patients" becomes circular. If the selection tool- the biomarker itself-has not been prospectively validated as a predictor of treatment response, patients are effectively selected using an unvalidated test to receive an equally unvalidated therapy.
This issue also raises a bioethical question regarding the burden of proof. The argument that clinicians should not "withhold potentially beneficial interventions" assumes the very premise that evidence-based medicine is intended to test. Under the same conditions of uncertainty, however, the concern can be framed in the opposite direction: clinicians may be "offering potentially ineffective and financially burdensome interventions to emotionally vulnerable patients." Both positions arise from the absence of robust evidence, and only rigorous clinical evaluation can distinguish between them. The economic implications also warrant greater attention. The cumulative costs of immunophenotyping, IVIG, intralipid therapy, and repeated treatment over multiple cycles remain largely peripheral to the debate.
Finally, describing the current state of reproductive immunology as "precision medicine" is inconsistent with the technical meaning of the term. Precision medicine requires a clearly defined biological subtype, a prospectively validated predictive biomarker, and clinical trials demonstrating a differential benefit in the biomarkerdefined group. Applying this label in the absence of those elements weakens, rather than strengthens, the argument.
I agree with the authors that reproductive immunology is a compelling field that merits continued investigation. Precisely because of its potential, however, proposed therapies should be subjected to the same methodological scrutiny applied in every other medical specialty. Biological plausibility and epidemiologic associations mark the beginning of scientific inquiry, not its endpoint. Our patients deserve that distinction.
REFERENCE
ESHRE Guideline Group on RPL; Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, Mcheik S, Peramo B, Quenby S, Nielsen HS, van der Hoorn ML, Vermeulen N, Goddijn M. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023;2023:hoad002. PMID: 36873081 DOI: 10.1093/hropen/hoad002
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