Chronic histiocytic intervillositis: diagnosis and recurrence

What chronic histiocytic intervillositis is

A lesion of the intervillous space

The placenta links the mother to the fetus during pregnancy. Maternal blood circulates there in a cavity called the intervillous space, around the chorionic villi, that is, the branched structures of fetal origin through which oxygen and nutrients pass. Chronic histiocytic intervillositis is defined by the accumulation, in that space, of macrophages of maternal origin, also called histiocytes.

The review by Brady et al., published in 2021 in the American Journal of Reproductive Immunology, describes the lesion as an infiltration of maternal macrophages in the intervillous space. It is often accompanied by perivillous fibrin deposits. The series of four patients published in 2024 by the Saint-Antoine and Trousseau team defines it in the same terms, as a diffuse infiltration of monocytes in the intervillous space.

The FAI²R rare disease network devotes to this condition a page whose summary is signed by Prof. Estibaliz Lazaro, in August 2025. It specifies that these cells accumulate between the chorionic villi without direct involvement of the trophoblast or of the fetus. That point distinguishes the lesion from other placental abnormalities.

Several names coexist for the same lesion, and it is useful to know them all in order to find the literature. In English one reads chronic histiocytic intervillositis (CHI) and chronic intervillositis of unknown etiology (CIUE). In French one reads intervillite chronique histiocytaire and intervillite chronique d'étiologie indéterminée, whose acronym ICEI is the one used by the FAI²R network.

What the word histiocytic does not designate

The word histiocytic describes here the type of cell observed in the placenta, the macrophage, also called a histiocyte. The histiocytoses, such as Langerhans cell histiocytosis or Erdheim-Chester disease, are proliferative diseases of the histiocytic lineage, unrelated to pregnancy and to this placental lesion. The closeness of the two terms sustains a frequent confusion in literature searches.

Inflammation of the placenta may also arise from an identified infectious cause. It is the absence of an identified cause that defines chronic intervillositis of unknown etiology. The FAI²R page includes among its histological criteria the absence of villitis, that is, of inflammation of the villous stroma, and the absence of infection.

The diagnosis is made on the placenta alone

Pathological examination

The review by Brady et al. in 2021 writes that the diagnosis can only be made after delivery, on examination of the placenta, for want of a diagnostic marker, and that the criteria vary from one publication to another. That constraint governs the whole approach: without pathological examination of the placenta after a pregnancy loss or a severe obstetric complication, the diagnosis is not made.

The FAI²R page sets out the following histological criteria: an intervillous infiltrate composed mainly of CD68 positive macrophages of maternal origin, the presence at times of a CD3 positive lymphocytic component, the absence of villitis and the absence of infection. It states that immunohistochemistry is necessary for confirmation, with the CD68 and CD3 markers, sometimes CD4 and CD8.

The heterogeneity of the definitions is documented. The systematic review by Bos et al., published in 2018 in Placenta by teams from Leiden and Utrecht, included eighteen studies. The authors note that the only inclusion criterion common to all these studies was the presence of an intervillous infiltrate. They propose diagnostic criteria and suggest that a Delphi study be used to settle the points that remain controversial.

The consensus statement of the Amsterdam Placental Workshop Group was published in 2016 in Archives of Pathology and Laboratory Medicine. It set out a placental sampling protocol and diagnostic criteria. The French study of 2024 of which Arsène Mekinian is last author cites this consensus. It reports that the consensus lists chronic intervillositis and high-grade villitis among the lesions that it is important to identify. The reason given is their risk of recurrence and their association with adverse obstetric events. The full text of the consensus not having been reviewed for this page, this wording is attributed to the 2024 article and not to the consensus itself.

What the pathology report does not yet allow to be graded

The French review of 2018 notes that the determination of the extent and intensity of intervillositis is not standardised. That absence of a shared grading has a practical consequence, because the severity of the lesion is the only element that the literature associates significantly with the outcome of the pregnancy. The meta-analysis by Moar et al. in 2022 examined this link over 231 pregnancies. Less severe lesions were associated there with a lower probability of pregnancy loss, with an odds ratio of 0.17 (95 % CI 0.03 to 0.80; p = 0.03).

The work-up proposed after the diagnosis

The search for a maternal autoimmune disease rests on two French series. The first is a retrospective study published in 2015 in Archives of Gynecology and Obstetrics. It reviewed all the pregnancies of patients who had had, between 2004 and 2011 in a university hospital, at least one adverse obstetric event associated with chronic intervillositis. Twelve patients and thirty-eight pregnancies were included, the median age being 30 years. An autoimmune disease or autoantibodies were found in 7 of the 12 patients: four cases of primary antiphospholipid syndrome, one case of Sjögren syndrome, one case of pernicious anaemia and one case of coeliac disease.

In the multicentre prospective study published in 2015 in Autoimmunity, an autoimmune disease was present in 7 of the 24 women included, that is 29 %.

The FAI²R page proposes several additional investigations. It includes a maternal immunological work-up with testing for antinuclear antibodies and antiphospholipid antibodies, a thrombophilia work-up and HLA investigation. It also mentions HLA typing of the mother and the child, within studies or in complex cases.

Frequency and obstetric prognosis

The lesion is rare. Brady et al. put it in 2021 at 6 pregnancies in 10,000 beyond twelve weeks of gestation. The FAI²R page gives an estimate of another nature, between 6 and 10 % in unexplained miscarriages or recurrent intrauterine fetal deaths. It notes that the condition is probably underdiagnosed, for want of systematic placental examination after a fetal loss. These two figures do not measure the same thing: the first is an incidence across all pregnancies, the second a proportion in a population already selected by repeated obstetric failures.

The prospective study published in 2024 in AJOG Global Reports, of which Arsène Mekinian is last author, gives an order of magnitude in everyday practice. Out of 4,398 pregnancies delivered in a university department, 208 placental analyses, that is 4.7 %, were carried out because of an obstetric complication. Table 2 records isolated chronic intervillositis in 1 case (0.5 %) and an association of villitis and intervillositis in 7 cases (3.3 %). Inflammatory lesions represent in total 16 placentas, that is 8 %. Its authors note that the absence of normal pregnancies in the study is its main limitation.

The obstetric prognosis is severe. The systematic review by Bos et al. in 2018, over eighteen studies, records a miscarriage in 24 % of cases, about half of them late. It gives a proportion of 32.4 % of pregnancies carried to term and a live birth rate of 54.9 %. The French review of 2018 lists the events observed: intrauterine growth restriction, recurrent early miscarriage, intrauterine death and prematurity from placental insufficiency.

The risk of recurrence

The risk of recurrence is the point on which the sources diverge most. Six values circulate, and they bear neither on the same lesions, nor on the same numbers of patients, nor on the same definition of recurrence, histological or clinical. They are presented here side by side, and they must not be averaged.

Two of these values call for careful reading. The range of 25 to 50 % bears on high-grade villitis of unknown etiology, a neighbouring but distinct lesion. The authors of the 2021 review take it from the literature and did not measure it themselves. The range of 30 to 60 % appears in the discussion of the 2024 article, carries no reference call, which makes it impossible to trace its origin, and mixes intervillositis and villitis.

None of these values makes it possible to tell a given patient what her personal risk is. The French review of 2018 writes that high recurrence rates have been described, but that there is no reliable predictive marker.

The factors associated with failure of the next pregnancy have, on the other hand, been identified in the prospective study of 2015. On univariate analysis, three elements were associated with the absence of a live birth. They are a history of intrauterine fetal death, a history of intrauterine growth restriction, and the presence of intervillositis on the placenta of the pregnancy under follow-up.

What has been tried to prevent recurrence

What the French review of 2018 says

The review published in La Revue de médecine interne in 2018 sets out four findings. Chronic intervillositis is a rare disease associated with a severe obstetric prognosis and a high recurrence rate. The adverse obstetric events observed are intrauterine growth restriction, recurrent early miscarriage, intrauterine death and prematurity from placental insufficiency. The determination of the extent and intensity of intervillositis is not standardised, and there is no reliable predictive marker of recurrence. No treatment is validated. Recourse to an immunomodulatory treatment may be justified by a possible autoimmune or alloimmune origin, in particular in patients with repeated and severe obstetric events and massive histological lesions.

The strategies described and the published series

The FAI²R page lists the treatments used empirically. It includes prednisone at 10 to 20 mg per day from the start of pregnancy and low-dose aspirin, at 100 to 160 mg per day. It adds low molecular weight heparin at a preventive or intermediate dose, and hydroxychloroquine in patients with autoimmunity. In case of failure or recurrence despite treatment, it mentions the possible addition of intravenous immunoglobulins. It also mentions the use of biologic therapies in selected cases, after specialist advice. It writes that there is to date no treatment validated by randomised clinical trials.

The multicentre prospective study published in 2015 in Autoimmunity included all patients with a history of chronic histiocytic intervillositis and an ongoing pregnancy between 2011 and 2013. Twenty-four women, of mean age 34 years plus or minus 5 years, were analysed. Twenty-one prospective pregnancies were treated, that is 88 %, against 13 % of the previous pregnancies of the same women. The number of live births was higher than in the previous pregnancies, 16 of 24 against 24 of 76 (p = 0.003). The authors express this result as a move from 32 % to 67 % live births in treated pregnancies. No difference was observed between the various treatment regimens. The authors themselves give two quantified limits to this result. The risk of preterm delivery remained at 30 %. The rate of recurrence of an adverse obstetric event remained at 30 % despite the therapeutic intervention.

Two short series document refractory situations. Two cases published in 2019 in the European Journal of Obstetrics and Gynecology and Reproductive Biology illustrate the use of a tumour necrosis factor alpha antagonist, adalimumab. The situations reported are refractory recurrent chronic intervillositis and unexplained miscarriages. The text recalls that the combination of hydroxychloroquine and prednisone had been described earlier by the same team in the forms with repeated obstetric events and intrauterine deaths.

In 2024, in the American Journal of Reproductive Immunology, four patients with recurrent chronic histiocytic intervillositis after failure of glucocorticoids and hydroxychloroquine are reported. All had at least four pregnancy losses, with histological confirmation of intervillositis for at least one of them, and a negative aetiological and immunological work-up. In three patients, intravenous immunoglobulins were started as soon as beta-HCG became positive, at a dose of 1 g/kg every fifteen days until delivery. In the fourth, already on combined treatment from the start of pregnancy, they were introduced at 20 weeks of gestation because of severe growth restriction. Two patients delivered a live child at 36 weeks and one at 39 weeks. The fourth, who had first-trimester hypertension and severe placental lesions, lost her pregnancy at 15 weeks. The authors describe this result as a potential benefit and write that larger studies are needed to confirm it.

The overall level of evidence

The systematic review and meta-analysis by Moar et al., published in 2022 in Frontiers in Endocrinology by a team from King's College London, gives the measure of that level of evidence. No randomised trial was identified. Over a population of 659 pregnancies, the treatments used were aspirin, prednisone, prednisolone, low molecular weight heparin, hydroxychloroquine and adalimumab. The quantitative synthesis covers 38 pregnancies. It gives a non-significant improvement in the live birth rate under targeted treatment, with an odds ratio of 1.79 (95 % CI 0.33 to 9.61; p = 0.50). The authors conclude that the data remain insufficient and that aspirin, low molecular weight heparin, prednisolone, hydroxychloroquine and adalimumab are candidates supported by a low to moderate level of evidence.

The treatments mentioned on this page are therefore used without any validation by a comparative trial. They are presented here as the literature describes them, and not as a course of action to follow.

The mechanisms under discussion

The origin of the lesion is not established. The review of 2018 writes that an autoimmune or alloimmune origin is possible, without asserting that it is demonstrated.

The review by Brady et al. in 2021 puts forward the hypothesis of an inappropriate maternal immune response, directed against the semi-allogeneic fetus. It rests on the presence of maternal macrophages and on the reported increase in incidence among women with autoimmune disease. The authors note similarities between the histological features of intervillositis and those of acute rejection of a transplanted organ, and propose that this comparison be explored. They write that therapeutic approaches remain experimental and rest on limited reasoning, for want of an understanding of the mechanism.

The association with a maternal autoimmune disease is documented without being constant, in 7 of the 12 patients of the retrospective series of 2015 and in 7 of the 24 women of the prospective study of the same year. The FAI²R page states that the condition occurs mainly in patients with no known autoimmune disease, while noting that a significant proportion of women have an autoimmune history or immune abnormalities.

What is not known

The diagnosis remains retrospective. No investigation currently makes it possible to identify the lesion during the ongoing pregnancy, and Brady et al. attribute that limitation to the absence of a diagnostic marker.

The histological criteria are not unified. The review by Bos et al. in 2018 notes that the only criterion common to the eighteen studies included was the presence of an intervillous infiltrate. The review of 2018 notes that the extent and intensity of intervillositis are not graded in a standardised way.

Recurrence is not predictable in the individual case. The six published values range from 25 % to 100 %, they do not measure the same thing, and the review of 2018 writes that no reliable predictive marker exists.

The efficacy of treatments is not established. The meta-analysis of 2022 found no randomised trial and its quantitative result is not significant. The prospective study of 2015 has no control group treated in parallel. It compares the pregnancies followed with the previous pregnancies of the same women. In that comparison, the selection of the patients included and the general evolution of care cannot be separated from the effect of the treatment itself. The series of tumour necrosis factor alpha antagonists and of intravenous immunoglobulins cover two and four patients respectively.

The choice between the available treatments is not settled. No published data make it possible to say which one to use, in which patients, in what combination or for how long. The prospective study of 2015 found no difference between the treatment regimens used.

The mechanism remains hypothetical. The alloimmune hypothesis and the comparison with transplant rejection are put forward in the literature as lines of research, not as demonstrated facts.

The work of Arsène Mekinian on this subject

Arsène Mekinian has been publishing on this lesion since 2012. The two works of 2015 carry the affiliation of Jean-Verdier Hospital in Bondy; those that follow carry that of Saint-Antoine Hospital, AP-HP, Sorbonne Université.

The starting point is a letter published in 2012 in Rheumatology (Oxford), of which he is first author among six named authors. It reports a fetal death occurring in a patient with primary Sjögren syndrome, with chronic intervillositis on the placenta. He is second author among nine of the retrospective study of 2015 on the associated autoimmune diseases, of which Aurélie Revaux is first author; the MEDLINE record of that work carries no correspondence address.

He is first author among eighteen named authors of the multicentre prospective study published in 2015 in Autoimmunity. The MEDLINE record of that work carries no correspondence address: this page therefore designates none. It was carried out with the support of the Société nationale française de médecine interne and of the European Forum of APS. That group appears as a collective signature and does not enter the count of named authors.

He is first author among eleven named authors and corresponding author of the review published in 2018 in La Revue de médecine interne. His co-authors come from internal medicine, obstetrics and fetal pathology, in Paris, Nantes and Pessac. The FAI²R page devoted to chronic intervillositis of unknown etiology cites only one bibliographic reference, this review.

He is first author among eight named authors and corresponding author of the two cases treated with adalimumab published in 2019. He is tenth and last named author of the series of intravenous immunoglobulins published in 2024, whose MEDLINE record carries no correspondence address. He is finally last author among nine named authors of the study of the prevalence of placental lesions published in 2024 in AJOG Global Reports, where the PMC page designates him as corresponding author.

Where care is organised

In France, these lesions fall within the FAI²R rare disease network, the network for rare autoimmune and autoinflammatory diseases, which publishes a page devoted to chronic intervillositis of unknown etiology. That page states that the pregnancy is classed as very high risk, that it calls for follow-up in a specialist multidisciplinary centre, and that monitoring includes closely spaced growth ultrasound scans from the second trimester onwards.

Care brings together several skills, and none is sufficient alone. The pathologist identifies the lesion on the placenta and describes its extent. The obstetrician organises maternal and fetal monitoring and decides on the timing of delivery. The internist looks for an associated autoimmune or autoinflammatory disease, in particular antiphospholipid syndrome, and takes part in the discussion of strategies in complex forms.

The affiliations carried on the publications cited above outline this organisation. They name the department of internal medicine of Saint-Antoine Hospital, AP-HP, Sorbonne Université. To these are added the department of pathology and the obstetrics department of Armand-Trousseau Hospital, and the obstetrics and gynaecology department of Tenon Hospital. The earliest works are signed by the departments of internal medicine and obstetrics of Jean-Verdier Hospital in Bondy. Complex situations may be discussed in a multidisciplinary team meeting. Treatments given intravenously, immunoglobulins in particular, are administered in the day hospital.

Key points

• Other names: chronic intervillositis of unknown etiology (CIUE); in French, intervillite chronique d'étiologie indéterminée (ICEI).
• Lesion: accumulation of CD68 positive maternal macrophages in the intervillous space, without direct involvement of the trophoblast (FAI²R page, August 2025).
• Diagnosis: pathological examination of the placenta after the end of the pregnancy, with immunohistochemistry. No antenatal diagnosis, no biological marker (Brady 2021).
• Frequency: 6 pregnancies in 10,000 beyond twelve weeks of gestation (Brady 2021). From 6 to 10 % in unexplained miscarriages or recurrent intrauterine fetal deaths (FAI²R page).
• Obstetric outcome: miscarriage in 24 % of cases, 32.4 % of pregnancies carried to term, 54.9 % live births, over eighteen studies (Bos 2018).
• Recurrence: six published values, from 25 % to 100 %, bearing on different lesions, different numbers of patients and different definitions. See the table in the section "The risk of recurrence".
• Associated autoimmune disease: 7 patients of 12 in a retrospective series, 7 women of 24 in a prospective study, both published in 2015.
• Treatment: no validated treatment. No randomised trial identified over 659 pregnancies reviewed (Moar 2022). Odds ratio of live birth under targeted treatment 1.79 (95 % CI 0.33 to 9.61; p = 0.50) over 38 pregnancies.
• Treatments described empirically: prednisone 10 to 20 mg per day, aspirin 100 to 160 mg per day, low molecular weight heparin, hydroxychloroquine, then intravenous immunoglobulins and biologic therapies in case of failure (FAI²R page).
• Reference text in French: the review in Rev Med Interne 2018, the only bibliographic reference cited by the FAI²R page.
• No national diagnosis and care protocol is cited by the FAI²R page on this condition.

Sources

Author positions counted on the FAU fields of the complete MEDLINE records alone, in the ?format=pubmed view, reviewed on 13 September 2026; the CN, FIR and IR fields are never counted. The MEDLINE record has no correspondence field: "corresponding author" here means that the person concerned is the only signatory whose AD line carries an electronic address, except where another source is named.

1. Mekinian A, Costedoat-Chalumeau N, Carbillon L, et al. Intervillites chroniques histiocytaires : bilan et prise en charge. Rev Med Interne. 2018;39(2):117-121. Indexed in PubMed under the translated title [Chronic histiocytic intervillositis: Diagnosis and management]. DOI 10.1016/j.revmed.2017.10.422. PMID 29146013. Article in French, 11 named authors, first author and corresponding author. Closed access.
2. Mekinian A, Costedoat-Chalumeau N, Masseau A, et al. Chronic histiocytic intervillositis: outcome, associated diseases and treatment in a multicenter prospective study. Autoimmunity. 2015;48(1):40-45. DOI 10.3109/08916934.2014.939267. PMID 25028066. Published online on 16 July 2014. 18 named authors, first author; no correspondence address in the MEDLINE record. Closed access.
3. Revaux A, Mekinian A, Nicaise P, et al. Antiphospholipid syndrome and other autoimmune diseases associated with chronic intervillositis. Arch Gynecol Obstet. 2015;291(6):1229-1236. DOI 10.1007/s00404-014-3536-6. PMID 25416199. 9 named authors, Arsène Mekinian second author. Closed access.
4. Mekinian A, Revaux A, Bucourt M, et al. Fetal death in primary SS associated with chronic intervillositis. Rheumatology (Oxford). 2012;51(6):1136-1137. DOI 10.1093/rheumatology/ker517. PMID 22337943. Letter, 6 named authors, first author. Closed access.
5. Mekinian A, Houfflin-Debarge V, Kolanska K, et al. Antagonists of TNFα for recurrent miscarriages: 2 illustrative cases. Eur J Obstet Gynecol Reprod Biol. 2019;236:263-264. DOI 10.1016/j.ejogrb.2019.02.036. PMID 30872045. 8 named authors, first author and corresponding author. Closed access.
6. Abisror N, Cheloufi M, Cohen J, et al. Intravenous immunoglobulins for recurrent chronic histiocytic intervillositis: a series of case studies. Am J Reprod Immunol. 2024;92(1):e13898. DOI 10.1111/aji.13898. PMID 38973779. 10 named authors, Arsène Mekinian last author.
7. Mekinian A, Kolanska K, Cheloufi M, et al. Chronic villitis of unknown etiology (VUE): obstetrical features, outcome and treatment. J Reprod Immunol. 2021;148:103438. DOI 10.1016/j.jri.2021.103438. PMID 34710823. 10 named authors, first author and corresponding author. Neighbouring lesion, cited here for its recurrence figure.
8. Boujenah J, Cohen J, Allouche M, et al. Prevalence and association of placental lesions with obstetrical features and outcome: data from French prospective study. AJOG Glob Rep. 2024;4(3):100374. DOI 10.1016/j.xagr.2024.100374. PMID 39188579. 9 named authors, Arsène Mekinian last author. Open access full text: PMC11345551.
9. Bos M, Nikkels PGJ, Cohen D, et al. Towards standardized criteria for diagnosing chronic intervillositis of unknown etiology: a systematic review. Placenta. 2018;61:80-88. DOI 10.1016/j.placenta.2017.11.012. PMID 29277275. Reference not by him.
10. Brady CA, Williams C, Sharps MC, et al. Chronic histiocytic intervillositis: a breakdown in immune tolerance comparable to allograft rejection? Am J Reprod Immunol. 2021;85(3):e13373. DOI 10.1111/aji.13373. PMID 33155353. Reference not by him.
11. Moar L, Simela C, Nanda S, et al. Chronic histiocytic intervillositis (CHI): current treatments and perinatal outcomes, a systematic review and a meta-analysis. Front Endocrinol (Lausanne). 2022;13:945543. DOI 10.3389/fendo.2022.945543. PMID 35937841. Reference not by him.
12. Khong TY, Mooney EE, Ariel I, et al. Sampling and definitions of placental lesions: Amsterdam Placental Workshop Group Consensus Statement. Arch Pathol Lab Med. 2016;140(7):698-713. DOI 10.5858/arpa.2015-0225-CC. PMID 27223167. Reference not by him.
13. FAI²R, the network for rare autoimmune and autoinflammatory diseases. Page "Intervillites chroniques d'étiologie indéterminée", Généralités subpage, summary signed by Prof. Estibaliz Lazaro, August 2025. fai2r.org

Sources last checked: 13 September 2026.

Disclosures

Statement required by article R.4113-110 of the French public health code. Eight of the thirteen sources cited on this page are works in which the author of this page took part, five of them as first author: that is the first interest to declare. The declaration relating to the subject covered is set out on the Disclosures page of this site.

Page written for professional information. It does not replace individual medical advice and does not constitute a treatment protocol.