First Trimester Miscarriage Evaluation

Ruth B. Lathi, M.D.; Florette K. Gray Hazard, M.D.; Amy Heerema-McKenney, M.D.; Joanne Taylor, M.S., C.G.C.; Jane Tsung Chueh, M.D.


Semin Reprod Med. 2011;29(6):463-469. 

In This Article

Pathological Evaluation of the Miscarriage and Placenta

The pathological evaluation of the first trimester miscarriage includes assessment of the morphological features of the gestational sac, embryo or fetus, and placenta. An empty gestational sac does not allow for embryo/fetal assessment; however, when embryo or fetal examination is possible, developmental anomalies, growth restriction or embryonic disorganization, and isolated morphological defects may be detected. Pre-evacuation imaging techniques such as embryoscopy or high-resolution sonography can successfully augment this evaluation. Whereas the initial pathologic assessment should be used to confirm the presence or absence of pregnancy tissue and identification of a molar pregnancy, perinatal pathologists have strived to add more than a diagnosis of "products of conception."[21–23] Histopathology of the placental tissue commonly adds little to determining an etiology of first trimester loss, with a few rare but important exceptions. Diagnoses associated with an increased recurrence risk include chronic intervillositis, villitis, massive perivillous fibrin deposition/maternal floor infarction, and plasma cell deciduitis.

Chronic Intervillositis

Chronic intervillositis is a very rare disorder, present in <1% of first trimester miscarriage specimens and even more rarely in the second and third trimester.[24] Patients with this disorder tend to have recurrent miscarriage or pregnancies complicated by severe growth restriction or fetal demise. The etiology of this disorder is unknown.[25,26] The pathological hallmark is the presence of dense sheeting aggregates of histiocytes in the maternal blood space between villi, with or without the presence of perivillous fibrin deposition. The absence of villous inflammation and large number of histiocytes in chronic intervillositis distinguishes this lesion from chronic lymphohistiocytic villitis with perivillous extension and fibrin deposition. The intensity of the intervillous histiocytic burden increases with gestational age. In a recent series of 69 pregnancies complicated by chronic intervillositis, 21 had liveborn infants, 13 of whom weighed less than the 3rd percentile for age. These 69 pregnancies occurred in 50 patients, 9 of whom had at least one recurrence of chronic intervillositis.[25]

Massive Perivillous Fibrin Deposition/Maternal Floor Infarction

Massive perivillous fibrin deposition/maternal floor infarction has some overlap with changes from prolonged retention of the conceptus after embryo-fetal demise. The diagnosis of massive perivillous fibrin deposition/maternal floor infarction is made in the mature placenta when the parenchyma is firm and marbled appearing on gross examination because of markedly increased fibrin or there is a thick rind of fibrin on the maternal surface. This disorder has significant recurrent potential in subsequent pregnancies with complications of fetal growth retardation and demise.[27] In some cases it may be due to a maternal thrombophilia leading to increased fibrin deposition at the villous maternal–fetal interface. In addition, compromised villous trophoblast integrity exposes tissue factor and activates the clotting cascade locally on the villous surface. Various disorders could damage syncytiotrophoblast including extrinsic factors like antiphospholipid antibodies or intrinsic factors such as fetal long chain fatty acid deficiency.[28] Cases of massive perivillous fibrin deposition can be identified in midgestation, but the specificity of this finding in first trimester miscarriages is not entirely clear. Placental pathologists look for an extravillous trophoblast proliferation embedded within the fibrin in true cases of massive perivillous fibrin deposition/maternal floor infarction, to help distinguish the entity.[29] However, the presence of diffuse increased perivillous fibrin with a similar histologic appearance might also reflect prolonged bleeding or the presence of a severely macerated fetus.[30,31]

Also difficult to interpret is the significance of hemorrhage and ischemic necrosis at the implantation margins and the decidua basalis. Although one might like to speculate about a possible disorder of coagulation, the mechanism of miscarriage always involves separation of the conceptus from the decidua and hemorrhage. The various clinical associations with this finding suggest that the morphology is a final common pathway of syncytiotrophoblast injury or degeneration, with subsequent activation of the coagulation pathway at the villous surface, or possibly a balance that favors excessive coagulation at the villous surface due to an inherited thrombophilia.

Chronic Villitis

Chronic villitis is a histologic pattern of chronic inflammation of the villous parenchyma most commonly seen in the third trimester, less commonly seen in the second or first trimester placenta. Approximately 10% of cases are associated with a known infectious etiology, most commonly cytomegalovirus, Treponema pallidum, and Toxoplasma gondii in the United States. Rubella-associated chronic villitis is rarely seen due to vaccination. In the vast majority of cases, no infectious etiology can be identified and the inflammation is termed villitis of unknown etiology (VUE). Most authors now consider these cases an aberrant maternal cell-mediated immune response to fetal villous antigens. Chronic villitis is rarely manifested in the first trimester spontaneous abortion with very rare exceptions.[32] In some women, VUE appears to have no clinical significance. In others, the disorder gets progressively worse in subsequent pregnancies and is associated with recurrent pregnancy loss.[33,34] Earlier studies describing VUE and recurrent pregnancy loss did not distinguish between chronic intervillositis and chronic villitis. Patterns with chronic intervillositis were associated with recurrent loss, as expected. Also, chronic villitis with increased perivillous fibrin deposition was more frequently associated with recurrent loss. The increased perivillous fibrin deposition suggests more chronicity to the lesions, but whether or not this is a distinct pathogenetic category of chronic villitis is unclear. In the Redline study,[33] a significant number of the women had associated abnormalities of uterine anatomy or placentation, suggesting an important role of the decidua in mediating proper immunostasis.

Plasma Cell Deciduitis

Lymphocytes and natural killer cells are normal constituents of the gestational endometrium, but plasma cells are not. Detection of plasma cells in the endometrium on endometrial biopsy is a diagnostic marker of chronic endometritis. Chronic endometritis has been associated with recurrent pregnancy loss. It is assumed that chronic endometritis in the nonpregnant endometrium and chronic deciduitis of the decidua basalis or parietalis are a continuum of the same process.[35] However, a definite association has not been proven. The presence of plasma cells in the decidua of an early pregnancy loss remains an abnormal finding, not known to be associated with prolonged retention. Plasma cell deciduitis should be documented and further clinical correlation done. Their presence may indicate the presence of chronic endometritis with or without bacterial vaginosis, which are potentially treatable risk factors for recurrent miscarriage.

Acute Inflammation and Other Histopathological Changes of Unclear Significance

The significance of acute inflammation is unclear in this setting. Infection could be a mechanism of loss when acute inflammation is present.[23] However, one rarely sees acute inflammation of the villous parenchyma or chorion. The acute infiltrates are often adjacent to necrotic foci in the decidua, and they may be part of the miscarriage process. One early study demonstrated an association of acute inflammation of the decidua and placenta in first trimester miscarriages with the presence of genital Mycoplasma organisms. Although all cases with a positive culture had inflammation present, not all cases with inflammation present had a positive culture.[36] The presence of acute inflammation is worth noting in the pathology report, with clinical consideration given to a possible infectious process. It is unclear what percentage of recurrent pregnancy loss is associated with infections, but some reports suggest the number is significant.[37,38] However, the mechanism may be more complex than an active infection damaging the pregnancy or decidua.

Embryo Evaluation

The evaluation of an intact embryo by the pathologist following uterine evacuation is rare. Most embryos are submitted to the pathologist fragmented following endometrial curettage. This fragmentation may preclude definitive assessment of the CRL and other subtle external features. The use of pre-evacuation embryoscopy enables visualization of the intact miscarried embryo in situ before manipulation. With this technique, an endoscope is inserted through either the uterine cervix or the abdomen and the chorion is incised; the embryo is then viewed directly through the amnion.[39] Phillip and colleagues reported a series of embryoscopic observations of abnormal miscarried embryos under a variety of clinical circumstances. They report growth disorganization in 48 of 154 (31%) missed miscarriages from unassisted pregnancies[40] and 11 of 22 (50%) visualized missed miscarriages from in vitro fertilization.[41] Embryoscopy can also be used to detect isolated developmental anomalies such as neural tube defects, microcephaly, and craniorachischisis.[42] It has also been successfully used to characterize the embryonic features of various chromosomal abnormalities such as 45,X,[43] triploidies,[44] and a variety of syndromes.[39] The use of embryoscopy allows for a more complete examination of the intact embryo, particularly its external features. It also underscores the fact that miscarriage can result from a variety of causes including, but not limited to, growth disorganization, isolated developmental defects, and chromosomal anomalies.

Like the embryo, when a fetus is evaluated following miscarriage, the CRL and the crown-heel length can provide a useful guide to the overall growth (i.e., whether it is normal or restricted). The external fetal examination should focus on developmental anomalies and dysmorphisms that provide insight into the cause of the miscarriage. Although these anomalies may occur in isolation, they may also arise as part of a constellation of anomalies and possible genetic syndromes. Cytogenetic testing is complementary to the autopsy because there may be fetuses affected by chromosomal abnormalities even when external examination does not reveal typical stigmata.[45]


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