Villitis of unknown etiology (VUE), also known as chronic villitis, is a placental injury. VUE is an inflammatory condition involving the chorionic villi (placental villi). VUE is a recurrent condition and can be associated with

intrauterine growth restriction Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...

(IUGR). IUGR involves the poor growth of the foetus,

stillbirth Stillbirth is typically defined as fetal death at or after 20 or 28 weeks of pregnancy, depending on the source. It results in a baby born without signs of life. A stillbirth can result in the feeling of guilt or grief in the mother. The term ...

miscarriage Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemical lo ...

, and

premature delivery Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between 2 ...

. VUE recurs in about 1/3 of subsequent pregnancies. VUE is a common lesion characterised by inflammation in the placental chorionic villi. VUE is also characterised by the transfer of maternal lymphocytes across the

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...

. VUE is diagnosed in 7–10% placentas in pregnancies. Roughly 80% of the VUE cases are in term placentas (greater than 37 weeks of pregnancy). A case of VUE in a placenta less than 32 weeks old should be screened for infectious villitis.

Pathogenesis

Inflammatory cells of maternal origin could access the foetal villous stoma in multiple ways: The villous

trophoblast The trophoblast (from Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the p ...

barrier could be damaged. In the third trimester, syncytial knots (nucleated clusters formed in the syncytiotrophoblast) break off and are shed from the foetal placental villi. The shedding can strip the villous stroma. The barrier could breakdown either by upstream foetal

thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...

ischemic Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems w ...

damage from maternal

infarction Infarction is tissue death (necrosis) due to inadequate blood supply to the affected area. It may be caused by artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as an infarct (from the ...

. The necrosis of

syncytiotrophoblasts Syncytiotrophoblast (from the Greek 'syn'- "together"; 'cytio'- "of cells"; 'tropho'- "nutrition"; 'blast'- "bud") is the epithelial covering of the highly vascular embryonic placental villi, which invades the wall of the uterus to establish nut ...

could arise as a result of the activation of coagulation components,

complement system The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...

platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...

antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

or antiphospholipids. Syncytiotrophoblasts can be made to exhibit

adhesion molecules Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...

(intracellular adhesion molecule 1,

E-selectin E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial ...

) in VUE, although in normal conditions adhesion molecules are not expressed. Maternal lymphocytes can enter the foetal stroma by passing the villous trophoblastic barrier via the anchoring villi. The anchoring villi lose their layer of continuous epithelial syncytiotrophoblast as the villi mature into invasive intermediate trophoblasts through the developmental course of the placenta. A trophic factor, IL-15, for CD8+ memory T-cells is expressed by

decidual The decidua is the modified mucosal lining of the uterus (that is, modified endometrium) that forms every month, in preparation for pregnancy. It is shed off each month when there is no fertilised egg to support. The decidua is under the influ ...

stromal cells. The trafficking of maternal lymphocytes responding to an antigen in the

chronic deciduitis Chronic deciduitis is a type of long-lasting inflammation that arises in pregnancy and affects the endometrial stromal tissue (decidua). It is associated with preterm labour. The diagnosis rests primarily on the presence of plasma cells. Image ...

could activate and enter via the

decidua The decidua is the modified mucosal lining of the uterus (that is, modified endometrium) that forms every month, in preparation for pregnancy. It is shed off each month when there is no fertilised egg to support. The decidua is under the influ ...

. VUE is a

T-cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

mediated, CD8+ dominating inflammatory reaction. VUE develops in the foetal fibrovasculature stroma of the placenta villi usually towards the end of pregnancy (term placentas). The lymphocytes in VUE are of maternal origin. VUE is a host-derived inflammatory response happening within a donor

allograft Allotransplant (''allo-'' meaning "other" in Greek) is the transplantation of cells, tissues, or organs to a recipient from a genetically non-identical donor of the same species. The transplant is called an allograft, allogeneic transplant, o ...

tissue. The non-T-cell component of the inflammatory infiltrate originates both from the maternal and placental side. Majority of the antigen-presenting cells were Hofbauer cells (macrophages) were of foetal origin. Perivillous monocyte-macrophages and histiocytic giant cells were of maternal origin. Foetal macrophages in VUE proliferate and are activated as a result of the up-regulation of MHC class 2 antigen expression. Examination of a male placenta with VUE demonstrated that 11.2% of the intravillous CD3+ lymphocytes were foetal, and 88.8% were maternal. Macrophages, intervillous lymphocytes, multinucleated

giant cells A giant cell (also known as multinucleated giant cell, or multinucleate giant cell) is a mass formed by the union of several distinct cells (usually histiocytes), often forming a granuloma. Although there is typically a focus on the pathological ...

were maternal; 10.5% of intravillous

CD68 CD68 ( Cluster of Differentiation 68) is a protein highly expressed by cells in the monocyte lineage (e.g., monocytic phagocytes, osteoclasts), by circulating macrophages, and by tissue macrophages (e.g., Kupffer cells, microglia). Structure a ...

+ cells and 96.4% of perivillous CD68+ cells were maternal. Lymphocytes were predominantly maternal T-cells. Maternal cells can enter the placental villi and the foetus as well.

Diagnosis

VUE can be of 2 types, low grade chronic villitis or high grade chronic villitis. Low grade chronic villitis involves less than 10 villi containing lymphocytes. Low grade chronic villitis can be either focal or multifocal. Focal has involved villi on only one glass slide, while multifocal has involved villi on at least two slides. High grade chronic villitis has more than 10 inflamed villi per focus. High grade chronic villitis is differentiated into diffuse and patchy. The term patchy is used if less than 30% of distal villi are involved. The term diffuse is used if more than 30% of distal villi are involved. VUE has 2 prominent distinct patterns. Approximately 50% of the cases only involve the distal villi (mature intermediate and terminal villi) and do not involve the proximal stem villi, the anchoring villi embedded in the basal plate, and the chorionic plate. The second most common pattern (roughly 30% of VUE cases) involves the proximal stem villi (and possibly the chorionic plate) and the distal villi usually. This type of VUE is linked with foetal vascular obtrusive lesions (Obliterative Foetal Vasculopathy). VUE does not have specific clinical signs and symptoms suggesting diagnosis; but an analysis of the inflammatory filtrate can aid in diagnosis. The composition of inflammatory infiltrate in VUE on a cellular level is primarily

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

and lymphocytes. The relative proportions of cells vary case by case. The lymphocytes present in VUE are predominantly CD8+ T-cells then CD4. There is usually a ratio of 0.1 to 0.5 for CD4/CD8. The macrophages present are mainly Mac387-, followed by CD68 and HAM56+. Class 2

major histocompatibility complex The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...

(MHC) antigens on macrophages are up-regulated at sites of VUE. Neutrophils should not be present at sites of VUE. VUE is a condition involving inflammation and not infection. High numbers of neutrophils are present in infectious villitis and not VUE.

Histopathology

Histomorphologically, VUE is characterized by a

lymphocytic A lymphocyte is a type of white blood cell (leukocyte) in the immune system of gnathostomata, most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated immunity, cell-mediated, cytotoxicity, cytotoxic innate imm ...

infiltrate of the chorionic villi without a demonstrable cause. Plasma cells should be absent; the presence of

plasma cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...

s suggests an infective etiology, e.g. CMV infection. Image: Villitis of unknown etiology - intermed mag.jpg , Intermed. mag. Image: Villitis of unknown etiology - high mag.jpg , High mag.

Differential diagnosis

VUE is often confused with infectious villitis. They can be differentiated by the following characteristics: There are no signs of infection in either the mother or the infant with VUE. Infectious villi there is both maternal and foetal infection. VUE is more common than infectious villitis; Infectious villitis is present in approximately 1–4 births per 1000 births. VUE is present in approximately 76–136 births per 1000 births. VUE occurs in the term placenta, in the late

third trimester Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but can ...

of pregnancy. Infectious villitis occurs at the early-third to late-

second trimester Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

of the pregnancy. Infectious villitis involves a greater part of the placenta (

umbilical cord In placental mammals, the umbilical cord (also called the navel string, birth cord or ''funiculus umbilicalis'') is a conduit between the developing embryo or fetus and the placenta. During prenatal development, the umbilical cord is physiologic ...

, chorionic plate,

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...

s) compared to VUE (terminal and stem villi). Histologically VUE is characterised with more lymphocytes present than infectious villitis. Recurrence of infectious villitis is rare. VUE has a 10% to 15% recurrence rate.

Prevention

There are no known prevention methods for VUE, but it is predicted that it could be due to infection by ''

Treponema pallidum ''Treponema pallidum'', formerly known as ''Spirochaeta pallida'', is a spirochaete bacterium with various subspecies that cause the diseases syphilis, bejel (also known as endemic syphilis), and yaws. It is transmitted only among humans. It is ...

'', '' Toxoplasma gondi'', and

cytomegalovirus ''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Betaherpe ...

Epidemiology

In New Zealand VUE is more common in Caucasians than in Maori and

Asia Asia (, ) is one of the world's most notable geographical regions, which is either considered a continent in its own right or a subcontinent of Eurasia, which shares the continental landmass of Afro-Eurasia with Africa. Asia covers an area ...

n ancestry.

Obese Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

women are more likely to develop VUE; this could be due to obese women having larger placentas, thus having a greater number of villous macrophages which could increase the efficiency of antigen presentation resulting in VUE.

References

External links

{{Medical resources , DiseasesDB = , ICD10 = , ICD9 = , ICDO = , OMIM = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = Health issues in pregnancy Ailments of unknown cause