JBRA Assist. Reprod. 2026 2026;00(0):00-00
LETTER TO THE EDITOR
doi: 10.5935/1518-0557.20260101
1Graduate Program in Medical Sciences, University of Fortaleza (UNIFOR), Fortaleza, Brazil
2CONCEPTUS - Reproductive Medicine, Fortaleza, Brazil
3Department of Obstetrics and Gynecology, Federal University of Bahia (UFBA), Salvador, Brazil
4Department of Obstetrics and Gynecology, Campinas University (UNICAMP), Campinas, Brazil
CONFLICT OF INTEREST
The authors declare no conflict.
To the Editor,
We read with great interest the opinion article by Monteleone, which raises important concerns regarding the scientific robustness and clinical application of reproductive immunology (Monteleone, 2026). The call for stricter methodological standards and the emphasis on avoiding unvalidated interventions are both timely and necessary. However, we believe that the article presents an overly restrictive interpretation of the current state of evidence, potentially overlooking meaningful advances and the nuanced position adopted by major international societies.
Reproductive immunology is indeed a complex and evolving field, characterized by heterogeneity in study design, biomarkers, and patient populations. Nevertheless, it is precisely this complexity that justifies continued investigation and cautious clinical integration, rather than categorical skepticism. As highlighted in recent guidelines from the American Society for Reproductive Immunology (ASRI), immunological interventions are not presented as universally effective therapies, but rather as conditional, evidence-graded options to be applied in carefully selected patients (Cavalcante et al., 2025).
Importantly, the assertion that immunological approaches lack validation is not fully aligned with current guideline-based recommendations. The 2022 update of the European Society of Human Reproduction and Embryology (ESHRE) acknowledges that intravenous immunoglobulin (IVIG) may be beneficial in selected cases of recurrent pregnancy loss (RPL) (ESHRE Guideline Group on RPL, 2023). Furthermore, ESHRE supports the investigation of immune biomarkers, recognizing their potential role in identifying subgroups of patients who may benefit from targeted therapies. While these recommendations are appropriately cautious, they reflect a growing consensus that immunological factors are clinically relevant in at least a subset of patients.
The critique of biomarkers, such as uterine natural killer (NK) cells and Th1/Th2 balance, also warrants a more balanced interpretation. Although standardization remains a challenge, these markers have been consistently associated with adverse reproductive outcomes across multiple studies (Cavalcante et al., 2023; Kargar et al., 2025). As emphasized in the ASRI guidelines, their use should not be indiscriminate but rather confined to specialized settings, where expertise allows for appropriate interpretation and minimizes the risk of overdiagnosis or overtreatment.
We fully agree with the author that the indiscriminate use of costly and insufficiently validated therapies poses ethical concerns, particularly in a vulnerable patient population. However, it is equally important to avoid the opposite risk: withholding potentially beneficial interventions from patients with identifiable immunological dysfunctions, especially when conventional approaches have failed. Rather than dismissing reproductive immunology as a field driven primarily by weak evidence, we advocate for a more balanced and evidence-based perspective. This includes: (i) continued investment in well-designed randomized controlled trials, (ii) standardization of immunological assays, and (iii) the development of clear clinical pathways that incorporate both reproductive and immunological expertise.
In conclusion, while we commend Monteleone for highlighting critical gaps in the field, we emphasize that reproductive immunology should not be framed solely as a domain of unproven interventions. Instead, it represents an emerging area of precision medicine, where careful patient selection, biomarker-guided approaches, and adherence to evolving guidelines can offer meaningful clinical benefit.
REFERENCES
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