Reproductive immunology

Reproductive immunology studies the interactions between the maternal immune system, the endometrium, the trophoblast and the placenta, from embryo implantation through to the development of pregnancy.

It is concerned in particular with the possible contribution of immune mechanisms in certain situations of repeated reproductive failure: recurrent miscarriage, repeated implantation failure, inflammatory placental disease, obstetric antiphospholipid syndrome, and also pregnancy in autoimmune and autoinflammatory disease. Each of these five situations is the subject of a page on this site. They do not share the same definition, the same mechanism, or the same level of evidence. What they have in common is the question asked: in some women, is the repetition of failure due to a defect of immune tolerance, and do we know how to measure it and correct it?

What establishes his expertise in this field

What he coordinates or directs.

• The diplôme d'université d'immunologie de la reproduction (university diploma in reproductive immunology) of Sorbonne Université. The page that Sorbonne Université Formation Continue devotes to him states that he has directed this diploma since 2024, and the page for the diploma itself gives him as academic lead.
• The FALCO registry, NCT05557201, whose public ClinicalTrials.gov entry declares him principal investigator.
• The CERTIFY trial, NCT05930613, whose registry entry gives him as principal investigator; the page of the AP-HP trials registry names a coordinating investigator and does not cite him.
• The réunion de concertation pluridisciplinaire nationale « Infertilité » ("national multidisciplinary team meeting on infertility") of the FAI²R rare disease health network. Arsène Mekinian states that he provides its coordination; the network publishes the meeting and cites him among its experts, without publicly naming a coordinator.

His position in the publications cited here. Of the 10 references cited at the end of this page, Arsène Mekinian is first author of 4, last author of 5, and corresponding author of 4. An eleventh reference cited at the end of the page is not his, the randomised trial of prednisone against placebo published in JAMA in 2023, and it is there because the section on what research has still to establish relies on it.

In biomedical research, the first author is generally the person who carried out the work day to day, and the last author the one who designed and supervised the study. The literature describes this as an informal practice rather than a rule: international recommendations leave the order of authors to the authors themselves, and reading seniority from position becomes unreliable as the list of authors grows. [How to read author position](/en/method/author-position/)

A particular immunological interface

Pregnancy requires a complex adaptation of maternal immunity allowing, at the same time, tolerance of antigens of fetal origin and maintenance of the body's defence functions. The embryo carries half the father's genetic material, and the maternal organism must durably accept this half-foreign tissue, first at the level of the uterine mucosa, then at the placenta.

This regulation involves many actors of innate and adaptive immunity, in particular uterine NK cells, regulatory T cells, macrophages, dendritic cells, cytokines and HLA molecules, in close interaction with the trophoblast and the endometrial environment.

The French review that Arsène Mekinian co-authored in January 2026 in La Revue de médecine interne, where he is 4th of the five named authors, describes this system: the role of uterine NK cells, macrophages and dendritic cells at the maternal-fetal interface, the balance between pro-inflammatory and anti-inflammatory cytokines, the expression of particular HLA molecules, and the alterations of endometrial receptivity observed in endometriosis, adenomyosis and chronic endometritis. Its concluding sentence is that the efficacy of the immunomodulatory treatments explored, corticosteroids, intravenous immunoglobulins and intralipid, remains to be confirmed by large studies. [Ref. 2]

Changes in these mechanisms have been described in several complications of reproduction. However, the existence of a biological abnormality or of a statistical association is not enough to demonstrate its causal role or its usefulness in guiding treatment. This is why this page states, for each piece of work cited, the number of participants it covers and the result obtained, including when that result is negative.

The field lies at the meeting point of internal medicine, clinical immunology, obstetrics and gynaecology, reproductive medicine and placental pathology, and none of these disciplines is sufficient on its own. The immunological tests offered in practice in this area, their interpretation and the treatments that follow from them are not the subject of international consensus, and this page presents none of them as validated.

Lines of research

The work carried out in this field seeks mainly to answer three questions.

Are there reproducible immunological phenotypes in some patients with repeated reproductive failure?

Can biomarkers be identified that would better characterise these situations or clarify their prognosis?

Can certain immunomodulatory strategies improve pregnancy outcome, and in which patients?

The studies conducted or coordinated by Arsène Mekinian thus combine clinical and immunological characterisation, prospective cohorts, translational studies and therapeutic trials.

His body of work has had a constant shape for ten years: describing cohorts of women in whom the validated work-up finds nothing, measuring in them the immune markers that practice offers, and assessing the immunomodulatory treatments given outside trials.

The starting text is a review with meta-analysis published in July 2016 in the American Journal of Reproductive Immunology, of which he is 1st of the nine named authors. It deals jointly with recurrent miscarriage and implantation failure, based on a search of Medline, Embase and the Cochrane Library, and reviews corticosteroids, progesterone, intralipid, TNF alpha antagonists, G-CSF, hydroxychloroquine, intravenous immunoglobulins and endometrial scratching. The only favourable meta-analysis finding it identifies is a modest benefit of progesterone on live birth, with an odds ratio of 1.38, 95% confidence interval 1.07 to 1.77, and strong heterogeneity between studies, p = 0.01 and I² = 78%. Its conclusion is that the efficacy of these medicines remains to be demonstrated and that it remains to be defined which subgroups of patients might derive benefit from them. [Ref. 1] Ten years later, the January 2026 review cited above states the same reservation in the same terms [Ref. 2]: between these two texts, the status of the question has not changed.

The work carried out on circulating lymphocyte populations, NK cells, cytokines and certain parameters of endometrial immunity illustrates the difficulty of identifying a biomarker robust and reproducible enough to be used on its own in clinical practice. Here is which ones, in what numbers, and with what result.

The first of these studies addresses the test most often offered to the women concerned, the measurement of NK cells in blood, and it is negative. Published in August 2019 in Archivum Immunologiae et Therapiae Experimentalis, it combines a case-control study and a meta-analysis of the literature. One hundred and fifteen women were recruited consecutively from December 2015 to October 2017 in three university hospitals: 54 with recurrent miscarriage, 41 with repeated implantation failure, and 20 controls who had had at least two term births. The proportions of CD3-CD56+ NK cells and of CD8+CD57+ T-cell large granular lymphocytes measured before conception did not differ between cases and controls, and did not differ either between the women who subsequently miscarried and those who had a live birth. The meta-analysis of the literature did find higher proportions of NK cells in recurrent miscarriage, mean difference 3.47 with a 95% confidence interval of 2.94 to 4.00, and in implantation failure, mean difference 1.64 with an interval of 0.82 to 2.45, both significant at p below 0.001, but with high heterogeneity between studies. The authors write that the proportion of these cells in blood in the preconception period does not reflect the risk of implantation failure or of miscarriage and should not be used as an indicator for management, and that large prospective studies are needed to develop a reliable blood marker of immune dysregulation. Arsène Mekinian is 16th and last of the 16 named authors, and the corresponding author. [Ref. 3]

The same finding emerges from the multicentre cohort of 101 women published in 2021, in which none of the immune markers measured, NK cells, lymphocytes, gammaglobulins, blood cytokines and activation status of uterine NK cells, differed according to pregnancy outcome; he is 21st and last named author. [Ref. 5] The implantation failure side of this question is the subject of a French multicentre observational study published the same year in the Journal of Reproductive Immunology, of which he is 15th and last named author and the corresponding author, without randomisation [Ref. 6]; its numbers and results are set out on the page on repeated implantation failure.

Another line concerns inflammatory disease of the placenta, in particular chronic histiocytic intervillositis, for which the work seeks to define more precisely the mechanisms, the risk of recurrence and preventive strategies. This is the line in which he signs in first position. The prospective multicentre study published in 2015 in Autoimmunity, of which he is 1st of the 18 named authors and the corresponding author, prospectively included between 2011 and 2013 all patients with a history of chronic histiocytic intervillositis and an ongoing pregnancy, that is 24 women. An autoimmune disease was present in seven cases, that is 29%. The number of live births was higher than in the same women's previous pregnancies, 16 of 24 against 24 of 76, p = 0.003, which the authors express as a move from 32% to 67% in the treated pregnancies, no difference being observed between the treatment regimens used; they write in the same discussion that the risk of preterm delivery remained at 30% and that the recurrence rate of an adverse obstetric event remained at 30% despite the intervention. [Ref. 7] The 2018 French review, of which he is 1st of the 11 named authors and the corresponding author, sets out the four limitations of the field: the lesion is rare and carries a severe obstetric prognosis, the measurement of its extent and intensity is not standardised, there is no reliable predictive marker of recurrence, and no treatment is validated. [Ref. 8] The detail of this work, together with the work devoted to chronic villitis and to massive perivillous fibrin deposition, appears on the page on inflammatory placental disease. Likewise, his work on obstetric antiphospholipid syndrome and on pregnancy in autoimmune disease is dealt with on their respective pages, with their numbers and their results.

Clinical research programmes

Several programmes currently give this activity its structure. The exact status of each, as declared by its public entry consulted on 8 September 2026 on clinicaltrials.gov, is stated here, because it cannot be deduced from any other source.

FALCO, NCT05557201

A prospective cohort devoted to recurrent miscarriage and unexplained reproductive failure, aimed in particular at characterising their clinical and biological determinants more precisely.

The public entry describes it as a prospective observational cohort devoted to unexplained recurrent miscarriage and to the identification of factors for early recurrence, sponsored by Assistance Publique-Hôpitaux de Paris, and declares Arsène Mekinian principal investigator. It shows an actual start on 24 October 2022, a planned enrolment of 700 participants, an estimated primary completion in October 2027, a recruiting status and a last update posted on 19 December 2025; the entry declares only one location, the department of internal medicine at Saint-Antoine Hospital, whereas the 2024 publication describes a registry established since 2017 and recruiting in several university hospitals.

Its first published analysis appeared in September 2024 in Human Reproduction and covers 100 pregnancies occurring in 74 women with recurrent pregnancy loss and exposed to hydroxychloroquine before conception or at the very beginning of pregnancy. Sixty-two of these pregnancies, that is 62%, ended before twelve weeks of gestation, and 38, that is 38%, continued beyond. The only factor significantly predictive of a pregnancy going beyond twelve weeks, after adjustment for age and for duration of exposure before conception, was having had four or fewer previous miscarriages, with an adjusted odds ratio of 3.13, 95% confidence interval 1.31 to 7.83, p = 0.01. The presence of at least one positive autoantibody did not change the outcome, 18 of 51 pregnancies going beyond twelve weeks against 18 of 45, p = 0.63. The authors conclude that exposure to hydroxychloroquine in early pregnancy in these women does not appear to prevent further miscarriages, and they themselves cite the absence of a control group as the first limitation of their work. Arsène Mekinian is 14th and last of the 14 named authors. [Ref. 4] The notable point is that the only factor found is not a treatment but the previous obstetric history, and that this result is published by the team that prescribes that treatment. The 2025 French review he co-authored, of which he is 5th and last named author, states it in the same terms: current data do not support the use of hydroxychloroquine in unexplained recurrent pregnancy loss, and no randomised controlled trial has assessed its addition to conventional treatment of refractory obstetric antiphospholipid syndrome. [Ref. 9]

FaCIL-2, NCT03970954

A phase 1/2 study which assessed low-dose interleukin-2 in unexplained recurrent early miscarriage, sponsored by AP-HP. The first results were released as a preprint and must be read as such.

The registry gives it as completed: start on 5 January 2021, end on 20 March 2024, actual enrolment of 18 participants, status "completed", last update posted on 12 September 2025. It declares Prof. David Klatzmann, of the Pitié-Salpêtrière, as principal investigator, and two study directors, Arsène Mekinian for the Saint-Antoine site and Prof. Gilles Kayem for the Trousseau site; three locations are declared, Saint-Antoine, Tenon and Trousseau, and one industry collaborator, Iltoo Pharma. The first results exist as a preprint posted on medRxiv on 16 June 2025, of which Arsène Mekinian is 1st of the eight named authors, and which is a preprint, not peer-reviewed: they must be read as such. [Ref. 10]

CERTIFY, NCT05930613

A randomised phase 3 trial assessing certolizumab pegol against placebo in unexplained repeated implantation failure.

The public entry declares it phase 3, double-blind against placebo, sponsor AP-HP. It plans 161 participants, its actual start is dated 30 November 2023, its primary completion is estimated in April 2029, and the registry entry gives Arsène Mekinian as principal investigator. No results are posted there, and the entry has not been updated since 11 December 2023.

The aim of these programmes is to move from immunological hypotheses and observational studies to a prospective and controlled assessment of biomarkers and treatment strategies.

Clinical and multidisciplinary organisation

This work is developed within the department of internal medicine and clinical immunology at Saint-Antoine Hospital, AP-HP – Sorbonne Université, in collaboration with the obstetrics and gynaecology, reproductive medicine, pathology, immunology and laboratory medicine teams.

The records of his publications carry the form "service de médecine interne de l'hôpital Saint-Antoine", AP-HP, Sorbonne Université, attached to the medical and university department devoted to inflammation, immunopathology and biotherapies, designated DHU i2B until about 2019, then DMU 3iD and DMU i3 in the affiliations of his publications. That is the affiliation Arsène Mekinian carries on all the MEDLINE records cited below, and it is the recruitment site declared on the FALCO registry entry. The Sorbonne Université Continuing Education page devoted to him states that he has been professor of internal medicine and clinical immunology at Sorbonne Université, in this department, since 2019: "médecine interne et immunologie clinique" is the name of his university discipline, not that of the department as the MEDLINE records write it.

None of this work is the doing of an isolated department, and the addresses carried on the records show it: the department of obstetrics, gynaecology and reproductive medicine at Tenon Hospital, the department of obstetrics and gynaecology and the fetal pathology department at Armand-Trousseau Hospital, the immunology and laboratory haematology departments at Saint-Antoine Hospital for the flow cytometry measurements, the obstetrics department at Jean-Verdier Hospital in Bondy for the oldest work, and, on the French reviews, internal medicine departments in Cochin, Nantes, Pessac and Amiens. It is this organisation by associated professions, obstetrics and gynaecology, reproductive medicine, pathology, immunology and laboratory medicine, and not a single location, that his publications describe.

Complex cases may be discussed within the FAI²R network national Infertility multidisciplinary team meeting, which brings together internists, obstetrician-gynaecologists and pathologists. It deals in particular with unexplained recurrent miscarriage and implantation failure, with villitis and intervillositis and with certain unexplained obstetric complications.

This meeting is one of the national multidisciplinary team meetings of that rare disease network. Arsène Mekinian states that he coordinates it; the network publishes the meeting and lists him among its experts, without publicly naming a coordinator. Its page states that these sessions are organised in partnership with the network, with a quorum of experts bringing together Prof. Gilles Kayem and Dr Meryam Cheloufi, obstetricians and gynaecologists, Prof. Coulomb-Lhermine, pathologist, and Prof. Arsène Mekinian, Dr Noémie Abisror, Dr Belhomme and Dr Grobost, internists. The cases discussed are unexplained recurrent miscarriage and implantation failure, villitis and intervillositis, and unexplained intrauterine fetal death and intrauterine growth restriction. The network page states that sessions are generally held on Thursdays from 1 pm to 2 pm, by videoconference, and that the presence of the physician following the patient is required in order to present the case in person. It names no coordinator for this meeting.

Teaching

Arsène Mekinian is the academic lead of the university diploma in reproductive immunology at Sorbonne Université. The date of 2024 rests on a single source, cited below.

Teaching in the field is organised at Sorbonne Université in the form of a university diploma in reproductive immunology, lasting seventy hours, entirely at a distance, open to physicians and to trainees whatever their specialty. The page for this diploma on the Sorbonne Université Continuing Education site, updated on 28 July 2026, gives Prof. Arsène Mekinian as academic lead and publishes a calendar of ten sessions, from 2 October 2026 to 18 June 2027. The page that the same continuing education service devotes to Arsène Mekinian writes that he has directed this diploma since 2024; that is the only source found carrying this date.

This multidisciplinary teaching is devoted to the immunological bases of pregnancy, to reproductive failure, to placental disease, to autoimmune disease and pregnancy, and to the critical appraisal of the immunological investigations and treatments offered in this area.

What research has still to establish

The exact contribution of immune mechanisms to unexplained reproductive failure remains incompletely defined. Many biomarkers and treatments have been proposed, but their level of validation is heterogeneous. To date, no single immunological profile makes it possible to characterise robustly enough the whole group of patients liable to have a dysimmune mechanism, or to predict their response to immunomodulation.

This is not a reservation of principle, it is the result of his own work: the proportions of circulating NK cells and of T-cell large granular lymphocytes measured before conception distinguished neither the 115 cases from the controls, nor the pregnancies that went to term from those that ended, and the article concludes that these measurements should not serve as an indicator for management [Ref. 3]; none of the immune markers measured in the 2021 cohort of 101 women differed according to outcome [Ref. 5].

The only randomised trial of sufficient size published to date on an immunomodulatory treatment in reproductive failure is negative, and it is not his. Conducted in eight fertility centres in China, with inclusions from November 2018 to August 2020, it randomised 715 women with at least two unsuccessful embryo transfers: 357 received 10 mg of prednisone per day and 358 a placebo. Live birth occurred in 37.8% of the women in the prednisone group, that is 135 of 357, against 38.8% in the placebo group, that is 139 of 358, absolute difference -1.0%, 95% confidence interval -8.1% to 6.1%, relative risk 0.97, interval 0.81 to 1.17, p = 0.78. Two secondary outcomes are against prednisone: biochemical pregnancy loss 17.3% against 9.9%, relative risk 1.75, interval 1.03 to 2.99, p = 0.04, and preterm delivery 11.8% against 5.5%, relative risk 2.14, interval 1.00 to 4.58, p = 0.04. The authors write that their results call into question the use of prednisone in clinical practice in this indication. This trial is signed by a Chinese team, Sun Y et al., 30 named authors, and Arsène Mekinian is not a signatory of it. [Ref. 11] Its population is not exactly that of every page in this family, since it concerns implantation failure in in vitro fertilisation, but it bears on the very principle of immunomodulatory treatment in reproductive failure, and its result is negative on live birth. No observational series, whatever its success rate, carries the same weight as a trial of this size, and this page does not claim otherwise.

The limitations of his own work are of three kinds and they are stated by their authors. They are first of all methodological: this work is observational, retrospective or prospective without a randomised control group, and the decision to treat is made by the physician. The 2015 prospective study of chronic intervillositis compares the pregnancies followed with the same women's previous pregnancies, a comparison in which the selection of patients and the general evolution of care cannot be separated from the effect of treatment [Ref. 7]. The FALCO registry has no control group, its authors say so first, it has produced only one publication to date and its primary data collection is not complete [Ref. 4]. They are then limitations of size: the series in this field are counted in tens of patients, not in hundreds. They are finally limitations of status: the CERTIFY trial has posted no results and its registry entry has not been updated since December 2023, so that continued recruitment in September 2026 cannot be presented here as an established fact; the FaCIL-2 trial was open-label, without a control group, with 18 participants included, its primary endpoint was immunological and not obstetric, and its results are available only as a preprint, not peer-reviewed, whose authors themselves conclude that a controlled trial is needed [Ref. 10].

Two methodological difficulties run through the whole field and make these limitations structural. The first is the heterogeneity of definitions: the number of pregnancy losses required varies between learned societies, there is no single international definition of repeated implantation failure, and studies therefore compare poorly with each other. The second is that a substantial proportion of the women concerned achieve an ongoing pregnancy at the next attempt with no particular treatment: a series without a control group, even with a high live birth rate, does not allow the conclusion that a treatment works.

The main research questions are therefore now to determine:

• which subgroups of patients have a clinically relevant immunological mechanism;

• which biomarkers are reproducible enough to contribute to identifying them;

• and which interventions genuinely improve the relevant obstetric outcomes, in particular live birth.

This distinction between mechanistic plausibility, associated biomarker and proof of clinical efficacy is central to the interpretation of work in reproductive immunology. It is the reason why the FALCO registry and the CERTIFY trial were built, and it is what the articles cited below say themselves. Until this work has come to fruition, immunomodulatory treatments in these situations belong to clinical research or to a decision taken case by case with the team following the patient.

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References

Published work he has taken part in, on this subject.

• Unexplained Recurrent Miscarriage and Recurrent Implantation Failure: Is There a Place for Immunomodulation? — American Journal of Reproductive Immunology, 2016 Arsène Mekinian 1st of 9 named authors. Review and meta-analysis of the literature.cited 117 times
• Immunology of fertilization, implantation and pregnancy: Key interactions and therapeutic perspectives (MEDLINE title in English; article published in French, original title: Immunologie de la fécondation, de l'implantation et de la grossesse : interactions clés et perspectives thérapeutiques) — La Revue de médecine interne, 2026 4th of 5 named authors. Review of the literature, in French.
• Proportion of Cytotoxic Peripheral Blood Natural Killer Cells and T-Cell Large Granular Lymphocytes in Recurrent Miscarriage and Repeated Implantation Failure: Case-Control Study and Meta-analysis — Archivum Immunologiae et Therapiae Experimentalis, 2019 16th of 16 named authors, corresponding author. Case-control study and meta-analysis.cited 24 times
• Hydroxychloroquine in recurrent pregnancy loss: data from a French prospective multicenter registry — Human Reproduction, 2024 14th of 14 named authors. FALCO registry, NCT05557201. Figures cited from the MEDLINE abstract. free full textcited 11 times
• Unexplained recurrent miscarriages: predictive value of immune biomarkers and immunomodulatory therapies for live birth — American Journal of Reproductive Immunology, 2021 21st of 21 named authors. Multicentre cohort, treatment not randomised. Comment letter published on this work: PMID 34921698.
• Unexplained recurrent implantation failures: Predictive factors of pregnancy and therapeutic management from a French multicentre study — Journal of Reproductive Immunology, 2021 15th of 15 named authors, corresponding author. Multicentre observational study, without randomisation.
• Chronic histiocytic intervillositis: outcome, associated diseases and treatment in a multicenter prospective study — Autoimmunity, 2015 1st of 18 named authors, corresponding author; consortium "SNFMI and the European Forum of APS" in the CN field, outside the count.cited 60 times
• Chronic histiocytic intervillositis: Diagnosis and management (MEDLINE title in English; article published in French, original title: Intervillites chroniques histiocytaires : bilan et prise en charge) — La Revue de médecine interne, 2018 1st of 11 named authors, corresponding author.
• Utilisation de l'hydroxychloroquine dans les pathologies obstétricales récurrentes à médiation immune (en dehors du lupus systémique) : fondements et preuves scientifiques (article published in French) — La Revue de médecine interne, 2025 5th of 5 named authors.
• Low-dose interleukin-2 for recurrent early pregnancy loss: a proof-of-concept study — preprint posted on medRxiv on 16 June 2025, 2025 1st of 8 named authors preprint, not peer-reviewed. The preprint page displays "Now published in La Revue de Médecine Interne, DOI 10.1016/j.revmed.2026.03.355"; that reference corresponds to a contribution in a conference supplement and not to an original peer-reviewed article.

General information only. This page does not replace individual medical advice. Updated: 19 September 2026.