Chronic Villitis Research Articles

Biological Markers of Stress in Pregnancy: Associations with Chronic Placental Inflammation at Delivery

To estimate the association between biomarkers of chronic stress during pregnancy and chronic placental inflammation. African-American and Caucasian pregnant women were recruited between May 2008 and July 2009. Blood samples were collected between 14 and 226/7 weeks and between 28 and 326/7 weeks of gestation. Samples were analyzed for serum C-reactive protein (CRP), Epstein-Barr virus (EBV) antibody, corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH). Placentas were collected at delivery and evaluated for chronic inflammation. Placentas were available from 88 of the 112 women enrolled in the study. EBV antibody levels were significantly higher during both the second and third trimester in women whose placentas demonstrated chronic villitis. CRP values also were significantly higher during the third trimester when chronic villitis was present. No association between placental chronic inflammation and CRH or ACTH was found. Chronic placental inflammation is associated with elevated serum EBV antibody and CRP levels during pregnancy.

Specific infiltration pattern of FOXP3+ regulatory T cells in chronic histiocytic intervillositis of unknown etiology

IntroductionChronic histiocytic intervillositis of unknown etiology (CIUE) is a rare placental lesion characterized by an intervillous mononuclear inflammatory infiltrate of maternal origin. Although the mechanism and origin of these lesions are currently not understood, they appear to be related to an immune conflict between mother and fetus cells. AimTo clarify the inflammatory cell profile and evaluate the T regulatory lymphocyte (Treg) status in CIUE. Materials and methodsAll cases of CIUE that occurred over an 8-year period were analyzed using immunohistochemistry. ResultsThe inflammatory profile of CIUE was characterized by a clearly predominant component of histiocytic cells (80% ± 6.9) associated with some T cells (24% ± 5.7). The ratio of CD4+ versus CD8+ T cells was close to 1. This profile differs from infectious disease and chronic histiocytic villitis, the main differential diagnoses of CIUE. As for normal pregnancies most regulatory T cells were localized in the decidua basalis. Nevertheless, their appearance was also noted in the intervillous space. In both the intervillous space and the deciduas the number of Tregs gradually increased from grade 1 to 3. ConclusionWe found that CIUE is associated with an increase in Treg lymphocytes in the decidua basalis and the intervillous space. Contrary to previously published data on human miscarriage, this result appears to be specific to CIUE and would support the hypothesis of an immunopathological disorder for CIUE.

Relationship between placental pathology and small-for-gestational age neonates

To investigate the relationship between pathological abnormalities of placenta and small-for-gestational-age neonates. One hundred placentas of small-for-gestational-age (SGA group) and 200 appropriate-for-gestational-age (AGA group) with single living birth in third trimester were investigated by gross and microscopic examination. The AGA placentas were collected from 2 cases following every SGA placenta. All cases were collected from Shanghai Changning District Maternity and Infant Health Hospital from January 2010 to December 2011. The gestational week, neonatal birth weight, full-term neonatal birth weight, the preterm birth rate and vaginal spontaneous delivery rate were significantly lower in SGA group than that in AGA group (P < 0.002). Full-term placental volume, placental weight and fetal placental weight ratio were lower in SGA group than that in AGA group (P < 0.05). Unusual insertion and torsion of umbilical cord were more common in SGA group (P < 0.05). Syncytial knots increase, avascular villi and villous infarcts were significantly higher in SGA group (P < 0.005), but there were no significant difference between SGA group and AGA group in intervillous thrombi, chronic villitis and chorangiosis (P > 0.05). Gestational hypertension disease and abnormality of fetal monitoring were more common in SGA group (P < 0.05). Gestational hypertension disease is the main clinical cause of SGA. Some placental abnormality can affect the growth and development of intrauterine fetus.

French Retrospective Multicentric Study of Neonatal Hemochromatosis: Importance of Autopsy and Autoimmune Maternal Manifestations

Neonatal hemochromatosis is a rare disease that causes fetal loss and neonatal death in the 1st weeks of life and is one of the most common causes of liver failure in the neonate. The diagnosis is mostly made retrospectively, based on histopathologic features of severe liver fibrosis associated with hepatic and extrahepatic siderosis. Several etiologies may underlie this phenotype, including a recently hypothesized gestational alloimmune disease. Fifty-one cases of liver failure with intrahepatic siderosis in fetuses and neonates were analyzed retrospectively. Maternal and infant data were collected from hospitalization and autopsy reports. All available slides were reviewed independently by 3 pathologists. Immunologic studies were performed on maternal sera collected immediately after delivery. The diagnosis of neonatal haemochromatosis was retained in 33 cases, including 1 case with Down syndrome and 1 case with myofibromas. Liver siderosis was inversely proportional to fibrosis progression. In fetuses, iron storage was more frequent in the thyroid than in the pancreas. Perls staining in labial salivary glands was positive in 1 of 5 cases. Abnormal low signal intensity by magnetic resonance imaging was detected in the pancreas in 2 of 7 cases. Renal tubular dysgenesis was observed in 7 of 23 autopsy cases. Chronic villitis was seen in 7 of 15 placentas. Half of the mothers presented with an autoimmune background and/or autoantibodies in their sera. Our work highlights the importance of autopsy in cases of neonatal hemochromatosis and marshals additional data in support of the hypothesis that neonatal hemochromatosis could reflect maternal immune system dysregulation.

An Immunologic Basis for Placental Insufficiency in Fetal Growth Restriction

We sought to determine whether chronic villitis, an immunologic disease of the placenta, was related to fetal growth restriction. Beginning in October 1999, a protocol was instituted that required placentas of high-risk births be submitted for standardized histological examination. Chronic villitis was diagnosed when a lymphohistiocytic infiltrate involving placental villi was present and was graded according to the extent and location of the infiltrate. Fetal growth restriction was defined as weight less than 3rd, 5th, and 10th percentiles. Placental hypoplasia was defined as weight less than 10th percentile. In the 10,204 placental examinations that were performed, low-grade and high-grade chronic villitis was associated with hypoplastic placentas and fetal growth restriction. Infants with placentas with low-grade and high-grade chronic villitis were more likely to require cesarean delivery for nonreassuring fetal heart rate compared with controls (27% and 25% versus 21%; p < 0.05). Fetal acidemia (umbilical artery pH < 7.0) was associated with high-grade chronic villitis compared with controls (4% versus 2%; p < 0.05). Chronic villitis was associated with anatomic and functional placental insufficiency manifested as placental hypoplasia, growth restriction, increased risk of cesarean for nonreassuring fetal heart rate, and fetal acidemia. These findings support an immunologic basis for fetal growth restriction.

Both Acute and Chronic Placental Inflammation Are Overrepresented in Term Stillbirths: A Case-Control Study

Objective. To elucidate differences in the frequency and severity of acute chorioamnionitis (CAM) and chronic villitis in placentas from stillborns compared with liveborns at term and to evaluate other risk factors and placental findings. Design. Case-control study. Setting. All delivery wards in major Stockholm area. Population or Sample. Placentas from stillborn/case (n = 126) and liveborn/control (n = 273) neonates were prospectively collected between 2002 and 2005. Methods. CAM was assessed on a three-grade scale based on the presence and distribution of polymorphonuclear leucocytes in the chorion/amnion. The presence of vasculitis and funisitis was recorded separately. Chronic villitis was diagnosed by the presence of mononuclear cells in the villous stroma. Relevant clinical data were collected from a specially constructed, web-based database. The statistic analyses were performed using multivariable logistic regression. Results. CAM (especially severe, AOR: 7.39 CI: 3.05–17.95), villous immaturity (AOR: 7.17 CI: 2.66–19.33), villitis (<1 % AOR: 4.31 CI: 1.16–15.98; ≥1 %, AOR: 3.87 CI: 1.38–10.83), SGA (AOR: 7.52 CI: 3.06–18.48), and BMI >24.9 (AOR: 2.06 CI: 1.21–3.51) were all connected to an elevated risk of term stillbirth. Conclusions. We found that CAM, chronic villitis, villous immaturity, SGA, and maternal overweight, but not vasculitis or funisitis are independently associated with risk for stillbirth at term.

Immunohistochemical Analysis Reveals an Influx of Regulatory T Cells and Focal Trophoblastic STAT-1 Phosphorylation in Chronic Villitis of Unknown Etiology

Maternal T cells and fetal macrophages constitute the primary infiltrate of chronic villitis of unknown etiology (CVUE), but the role of CD25(+)/FOXP3(+) regulatory T (Treg) cells in CVUE has not been examined. Moreover, little is known about the expression of immune markers, such as the major histocompatibility complex (MHC) class II antigen, human leukocyte antigen-DR (HLA-DR), in trophoblasts in this disease. We, therefore, examined CVUE placentas for the presence of Treg cells and aberrant activation of HLA-DR in trophoblasts. Sequential formalin-fixed, paraffin-embedded tissue sections from 8 CVUE placentas and 10 control placentas were stained by immunohistochemistry with antibodies for CD3, CD4, CD8, CD20, CD25, FOXP3, CD56, CD68, HLA-DR, STAT-1, and phosphorylated STAT-1 [P-(Y701)-STAT-1]. T cells and histiocytes were confirmed as the inflammatory infiltrate in CVUE. In areas of CVUE, histiocytes strongly expressed HLA-DR and nuclear P-(Y701)-STAT-1, and the relative numbers of CD25(+)/FOXP3(+) Treg cells were increased, compared with control placentas. In 5 of 8 CVUE cases, there was patchy nuclear expression of P-(Y701)-STAT-1 in syncytiotrophoblast most extensively involved by villitis, but no other marker examined was detected in the trophoblast cell layer. We confirmed the influx of T cells and histiocytes in CVUE. Our results are the 1st, to our knowledge, to identify increased numbers of Treg cells in CVUE vs noninflamed placentas. However, we were unable to verify HLA-DR expression in trophoblasts of placentas with CVUE, suggesting that this does not contribute to the influx of T cells. Our observation that P-(Y701)-STAT-1 expression in a syncytiotrophoblast is restricted to regions of inflammation suggests that the JAK-STAT-1 pathway is aberrantly activated in these cells.

Histopathological analysis of the placental lesions in pregnancies complicated with IUGR and stillbirths in comparison with noncomplicated pregnancies

Placental factors and hypoxemia are the keys to intrauterine growth restriction (IUGR) and stillbirth. The aim of the study is to analyze histological changes in placentas of IUGR fetuses in pregnancies with no apparent etiologic factor and unexplained intrauterine fetal deaths. A total of 110 placentas were collected; 26 placentas of IUGR fetuses with no apparent cause, 58 placentas from unexplained intrauterine deaths over 20 weeks of gestation, and 26 placentas from uncomplicated pregnancies who delivered a healthy live baby. Microscopic examinations of placentas were performed for histopathological analyzes. Gestational age at delivery was 33.67±4.37 weeks, 29.15±8.36 weeks, and 39.0±1.52 weeks in women in group I, group II and group III, respectively (p<0.01). Infarction and intervillous thrombosis are significantly more frequent in placentas of Group I and group II. Chronic villitis occurred in 69%, 63% and 30% of group I, group II, and group III, respectively. Placental intravascular thrombi (Group I, 31% and group II, 26%), perivillous fibrin deposition and fibrinoid necrosis (65% in Group I and 53% in group II), infarction, intervillous thrombosis, chronic villitis, hemorrhagic endovasculitis, placental intravascular thrombi, perivillous fibrin deposition, fibrinoid necrosis, erythroblastosis and villous edema were found in the study group. The results reported here indicate that a relationship exists between morphological changes in the placentas of IUGR and intrauterine fetal deaths.

Relationship between placental morphology and histological findings in an unselected population near term

Whilst individual histological features are well described, there are no universally agreed criteria as to what constitutes a clinically significant histological lesion of the placenta in an uncomplicated pregnancy, nor has the presence of such histological findings been systematically related to quantitative morphological characteristics of the placenta (such as placental shape, cord insertion and cord coiling). This study aims to explore this relationship and further to describe the incidence of predefined categories of histological lesions of the placenta in an unselected obstetric population recruited prior to delivery. The study is based upon the placental examination of 1,156 women with singleton pregnancies recruited prospectively in a single unit. Placentas were analysed where deliveries occurred between 34-43weeks. The incidence of normal histological findings and specific histological categories, such as ascending genital tract infection, chronic placental underperfusion, intervillous thrombus and villitis of unknown aetiology, were noted. The relationship between placental morphological indices: coiling index, cord centrality index (distance of cord insertion on the chorionic plate from the centre) and eccentricity (shape of the placenta) and histological lesions was investigated. There were no significant differences between cord centrality and eccentricity between placentas with and without histological lesions except an association between hypercoiling of the umbilical cord and intervillous thrombosis and villitis of unknown aetiology (p = 0.024 and p = 0.009, respectively). The macroscopic morphological features of the placenta cannot predict the presence or absence of the histological placental lesions, nor are these lesions in general associated with differences in cord centrality, placental eccentricity or cord coiling.

A Signature of Maternal Anti-Fetal Rejection in Spontaneous Preterm Birth: Chronic Chorioamnionitis, Anti-Human Leukocyte Antigen Antibodies, and C4d

BackgroundChronic chorioamnionitis is found in more than one-third of spontaneous preterm births. Chronic chorioamnionitis and villitis of unknown etiology represent maternal anti-fetal cellular rejection. Antibody-mediated rejection is another type of transplantation rejection. We investigated whether there was evidence for antibody-mediated rejection against the fetus in spontaneous preterm birth.Methods and FindingsThis cross-sectional study included women with (1) normal pregnancy and term delivery (n = 140) and (2) spontaneous preterm delivery (n = 140). We analyzed maternal and fetal sera for panel-reactive anti-HLA class I and class II antibodies, and determined C4d deposition on umbilical vein endothelium by immunohistochemistry. Maternal anti-HLA class I seropositivity in spontaneous preterm births was higher than in normal term births (48.6% vs. 32.1%, p = 0.005). Chronic chorioamnionitis was associated with a higher maternal anti-HLA class I seropositivity (p<0.01), significant in preterm and term birth. Villitis of unknown etiology was associated with increased maternal and fetal anti-HLA class I and II seropositivity (p<0.05, for each). Fetal anti-HLA seropositivity was closely related to maternal anti-HLA seropositivity in both groups (p<0.01, for each). C4d deposition on umbilical vein endothelium was more frequent in preterm labor than term labor (77.1% vs. 11.4%, p<0.001). Logistic regression analysis revealed that chronic chorioamnionitis (OR = 6.10, 95% CI 1.29–28.83), maternal anti-HLA class I seropositivity (OR = 5.90, 95% CI 1.60–21.83), and C4d deposition on umbilical vein endothelium (OR = 36.19, 95% CI 11.42–114.66) were associated with preterm labor and delivery.ConclusionsA major subset of spontaneous preterm births has a signature of maternal anti-fetal cellular and antibody-mediated rejections with links to fetal graft-versus-host disease and alloimmune reactions.

Placental vascular lesion differences in pregnancy-induced hypertension and normotensive fetal growth restriction

Pregnancy-induced hypertension/preeclampsia (PIH) and fetal growth restriction (FGR) share a common placental origin. The pathologic classification that divides placental lesions to maternal or fetal origin was compared between these disorders. Placentas from pregnancies that were complicated by PIH, normotensive FGR, or by both (combined) were analyzed, and lesions were classified as those consistent with maternal under-perfusion and with fetal thromboocclusive disease. Maternal vascular lesions were more common in the PIH group and combined group (61% and 59%, respectively), compared with the FGR group (16.2%; P < .001), and villous lesions were more common in the combined group, compared with the FGR and PIH groups (79.5%, 53.5%, and 46.9%, respectively; P = .004). Fetal villous changes were observed in 16.2% in the FGR group, compared with 3.1% in the PIH group (P = .03), and chronic villitis was 15.2% in the FGR group vs 1.6% in the PIH group (P = .004). Placental lesions correspond with different clinical presentations.

Tuberous Sclerosis Complex with Diffuse Cytomegalovirus Fetal Infection: Case Report and Review of the Literature

We report a case of a stillborn female fetus with combined stigmata of Tuberous Sclerosis Complex (TSC) and cytomegalovirus (CMV) infection. The baby was premature and small for gestational age (1625g). The heart showed multiple cardiac rhabdomyomas. The brain showed cortical tubers and subependymal nodule. Renal cysts are present. Autopsy also revealed multiple organ infected by CMV including lungs, liver and kidneys. The mother was 24 year old. The placental gross findings show multiple hematoma and infarction on maternal side, acute chorionitis with cytomegalovirus infection, chronic deciduitis and focal chronic villitis, might be the cause of the intrauterine demise of the fetus

Diagnosis of placental abruption: relationship between clinical and histopathological findings

Objective We evaluated the extent to which histologic lesions bearing a diagnosis of abruption conform to a diagnosis based on established clinical criteria. We further examined the profile of chronic and acute histologic lesions associated with clinical abruption. Methods Data from the New Jersey-Placental Abruption Study – a multi-center, case-control study – were utilized to compare the clinical and histologic criteria for abruption. The study was based on 162 women with clinically diagnosed abruption and 173 controls. We examined the concordance between clinical indicators for abruption with those of a histopathological diagnosis. The clinical criteria for a diagnosis of abruption included (i) evidence of retroplacental clot(s); (ii) abruption diagnosed on prenatal ultrasound; or (iii) vaginal bleeding accompanied by nonreassuring fetal status or uterine hypertonicity. The pathological criteria for abruption diagnosis included hematoma, fibrin deposition, compressed villi, and hemosiderin-laden histiocytes in cases with older hematomas. Acute lesions included chorioamnionitis, funisitis, acute deciduitis, meconium stained membranes, villous stromal hemorrhage, and villous edema. Chronic lesions included chronic deciduitis, decidual necrosis, decidual vasculopathy, placental infarctions, villous mal-development (delayed or accelerated maturation), hemosiderin deposition, intervillous thrombus, and chronic villitis. Results Of clinically diagnosed cases, the sensitivity and specificity for a histologic confirmation of abruption were 30.2% and 100%, respectively. Presence of retroplacental clots remained the single most common finding (77.1%) among clinically diagnosed cases. Among the acute lesions, chorioamnionitis and funisitis were associated with abruption. The only chronic histologic lesion associated with abruption was placental infarctions. Conclusions The concordance between clinical and pathologic criteria for abruption diagnosis is poor. The criteria for diagnosing a clinical abruption should include sonographic visualization of abruption, evidence of retroplacental clots, or vaginal bleeding accompanied by nonreassuring fetal status or uterine hypertonicity.

Brain damage in fetuses congenitally infected by Cytomegalovirus

Background: Cytomegalovirus (CMV) is the major infectious cause of congenital abnormalities in the central nervous system due to intrauterine infection in humans. Design and population: Twenty-seven fetuses with congenital CMV infection documented at 20–21 weeks' gestation by invasive prenatal diagnosis (amniotic fluid culture and PCR positive with a viral load > 10 5 copies/ml) underwent histological examination. We focused our attention on brain and placenta to understand the histopathogenesis of cerebral damage and to find a possible correlation between placental infection and ischemic brain damage. Material and methods: Fetal sections were studied with haematoxylin and eosin staining, immunohistochemistry for CMV early (ppUL44) and leukocyte common antigen CD45 to detect the inflammatory cells. Results: CMV-positivity was detected in all placentas and 55% (15/27) of brains. Six out of 15 CMV-positive brains showed mild inflammatory response without necrosis and only mild telencephalic leukencephalopathy. Four out of 15 CMV-positive brains showed a moderate CD45-positive inflammatory response associated with focal microglial nodules and telencephalic leukencephalopathy. The CD45-positive inflammatory response in the remaining five of the 15 CMV-positive brains was severe and associated with diffuse cerebral damage such as cortical necrosis, polymicrogyria and periventricular leukomalacia. No damage was observed in CMV-negative brains. Conclusions: Diffuse chronic villitis with necrosis was found in all the placentas of fetuses with severe brain damage. In other placentas, chronic villitis and necrosis were only focal. Brain damage may be caused not only by CMV infection but also by inflammatory infiltration and hypoxia due to severe placentitis.

Human Cytomegalovirus Interacts with Toll-like Receptor 2 and CD14 on Syncytiotrophoblasts to Stimulate Expression of TNFα mRNA and Apoptosis

Placentae from newborns with congenital human cytomegalovirus (HCMV) infection often display shallow implantation, chronic villitis and disruptions of the syncytiotrophoblast. Little is known about how HCMV infection induces inflammation in the placenta and loss of the trophoblast. We propose that the inflammation is initiated with innate defense responses of mature syncytiotrophoblast (ST) to virus. Previously we have shown that ultraviolet irradiation-inactivated (UV-) HCMV interacts with toll-like receptor 2 (TLR2) on primary placental cytotrophoblasts (CT) differentiated into ST-like cells thereby stimulating the release of tumor necrosis factor alpha (TNFα) and inducing apoptosis of neighboring cells (Chan et al, J. Pathol. 210: 111, 2006). We now determine whether known co-factors of the interaction of HCMV and TLR2 (TLR1 and CD14) bind to UV-HCMV to stimulate expression of TNFα and apoptosis in ST-like cells but not CT. We show that CT both fail to express detectable TLR1 and express much less CD14 than ST and that ST express CD14 but not TLR1 both in vivo and in cultured cells. The interaction of UV-HCMV and HCMV with CD14 on the surface of ST-like cells increases TNFα expression and induces apoptosis in the population. Antibody to CD14 also inhibits infectious HCMV induction of HCMV immediate early (HCMV IE) expressing ST-like cells. We conclude that primary villous CT express low levels of CD14 and no TLR1 but that ST strongly expresses CD14 which acts upstream of TLR2 to collect even transcriptionally inactive virus particles to stimulate TNFα expression and villous trophoblast damage.

The Prevalence of Chronic Deciduitis in Cases of Preterm Labor without Clinical Chorioamnionitis

Preterm labor is a major cause of perinatal mortality and morbidity, and in approximately 30% of cases a clinical cause is not identified. Acute chorioamnionitis is found histologically in a significant percentage of placentas from preterm deliveries, and the mother is often asymptomatic. Although such subclinical acute chorioamnionitis is known to play a role in preterm labor, this study explores the hypothesis that chronic deciduitis with plasma cells is seen more frequently in cases of preterm labor than in control placentas. Thirty-nine singleton placentas from patients with idiopathic preterm labor were examined microscopically and compared in a blinded fashion with 39 gestational age-matched control placentas. Cases of clinical acute chorioamnionitis and known chronic maternal diseases were excluded. Thirty-nine control singleton placentas were obtained from patients undergoing induction of labor for fetal structural abnormalities, excluding aneuploidy. The presence or absence of acute chorioamnionitis, acute fetal inflammatory response, chronic deciduitis, chronic villitis, infarction, and decidual vasculopathy was noted. Immunohistochemical staining was undertaken to further define leukocyte subtypes. Forty-one percent of cases and 15% of controls showed chronic deciduitis (P = 0.022). Forty-six percent of cases and 18% of controls showed histologic acute chorioamnionitis (P = 0.015). There were 8 cases demonstrating acute fetal inflammatory response but only 1 control (P = 0.029). Little difference was seen in the distribution of lymphocyte subsets between cases and control placentas. Our findings suggest that chronic deciduitis plays a role in the etiology of some cases of preterm labor.

Risk factors for uteroplacental vascular compromise and inflammation

The purpose of this study was to identify potentially modifiable risk factors of placental injury that reflect maternal uteroplacental vascular compromise (UPVC) and acute and chronic placental inflammation. A prospective epidemiologic study was conducted. A total of 1270 placentas were characterized by gross and microscopic examination. Placental pathologic condition was coded for features of amniotic fluid infection syndrome (AFIS), chronic villitis, UPVC, and fetal vascular obstructive lesions. Odds ratios between UPVC, the acute and the chronic inflammatory lesions, and risk factors of interest were calculated. After adjustment for confounders, we found that women with a history of preterm birth had 1.60 times the odds of chronic inflammation (95% CI, 1.10, 2.55). Women with a previous elective termination had 3.28 times the odds of acute inflammation (95% CI, 1.89, 5.70). The odds of chronic villitis increased with parity; the odds of AFIS decreased with parity. We have identified several predictors of UPVC, AFIS, and chronic villitis. Further studies are needed to examine whether interventions to alter UPVC, AFIS, and chronic villitis will lead to improved pregnancy outcomes.

Detection of cytomegalovirus, parvovirus B19 and herpes simplex viruses in cases of intrauterine fetal death: Association with pathological findings

There are previous indications that transplacental transmission of cytomegalovirus (CMV), parvovirus B19 (PB19) and herpes simplex virus types 1 and 2 (HSV-1/2) cause fetal infections, which may lead to fetal death. In a prospective case-control study we examined the incidence of these viruses in intrauterine fetal death and their association with fetal and placenta pathological findings. Molecular assays were performed on placenta tissue extracts of 62 fetal deaths and 35 controls for the detection of CMV, PB19 and HSV-1/2 genomes. Formalin-fixed, paraffin-embedded liver, spleen and placenta tissues of fetal death cases were evaluated histologically. Thirty-four percent of placental specimens taken from intrauterine fetal deaths were positive for any of the three viruses (16%, 13%, and 5% positive for CMV, PB19, and HSV-1/2, respectively), whereas only 6% of those taken from full term newborns were positive (P = 0.0017). No dual infection was observed. This difference was also observed when fetal deaths with a gestational age <20 weeks or a gestational age >20 weeks were compared with the controls (P = 0.025 and P = 0.0012, respectively). Intrauterine death and the control groups differed in the detection rate of CMV DNA (16% and 3%, respectively; P = 0.047), which was more pronounced in a gestational age >20 weeks (P = 0.03). Examination of the pathological findings among the PCR-positive and PCR-negative fetal deaths revealed that hydrops fetalis and chronic villitis were more common among the former group (P = 0.0003 and P = 0.0005, respectively). In conclusion, an association was detected between viral infection and fetal death, which was more pronounced in the advanced gestational age. Fetal hydrops and chronic villitis were evidently associated with viral DNA detection in cases of intrauterine death.

Elevated circulating fetal nucleated red blood cells and placental pathology in term infants who develop cerebral palsy

An elevated circulating fetal nucleated red blood cell count has long been recognized as an indicator of significant intrauterine stress. However, the nature of the causative events and their timing remain controversial. In this study, subacute and chronic placental lesions known to be associated with neurodisability were used as surrogates for antenatal stress. Mother-infant pairs with complete blood counts within 2 hours of delivery (n = 81) were drawn from a larger database of 152 term infants with cerebral palsy. An elevated nucleated red blood cell count (2.5 x 10(3)/mm(3)) in these infants was associated with a significantly increased prevalence of subacute or chronic placental lesions, whereas clinical findings did not significantly differ. The number of nucleated red blood cells per 10 high-power fields of villous parenchyma was directly correlated with the nucleated red blood cell count, and a threshold of 10 or more nucleated red blood cells predicted a nucleated red blood cell count greater than 2.5 x 10(3)/mm(3). Among individual placental lesions, multiple foci of avascular villi and chronic villitis were significantly associated with an elevated nucleated red blood cell count, whereas meconium-associated vascular necrosis showed a borderline association. Acute chorioamnionitis was the only placental lesion more common in the group without elevated nucleated red blood cell count. The presence of significant placental lesions was associated with an elevated nucleated red blood cell count in infants with or without either acidosis (cord pH <7.0) or birth asphyxia (American College of Obstetrics and Gynecology criteria). Acidosis and birth asphyxia were not significantly related to an elevated nucleated red blood cell count in infants without these placental lesions.

The fetus, not the mother, elicits maternal immunologic rejection: lessons from discordant dizygotic twin placentas

Our objective was to elucidate the pathogenesis of twin discordance in four dizygotic pregnancies where only one of the twins had IUGR due to chronic villitis. We identified four cases of dizygotic twin placentas over a period of four years with evidence of chronic villitis. There was no clinical or pathologic evidence of TORCH, bacterial infection, preeclampsia or autoimmune disorders. Placentas were weighed, processed for histologic examination and stained with CD45RO (clone UCHL1) mouse monoclonal antibody, which identifies T-cells. All placentas were dichorionic, with two being fused. Birth weight differences were 29%, 41%, 17% and 10%. Villitis was more marked in the placenta of the twin that weighed less and correlated with the degree of weight discordance. On examining the junction between the fused dichorionic placentas, the chorionic villi from the smaller twin contained numerous T-cells, whereas the villi associated with the less affected twin, showed little to no T-cells. We describe a series of dizygotic twin placentas where the more severe the chronic villitis, the more affected the placenta and fetus. Since the maternal environment was constant for each of these twins, differences in villitis severity appears to be attributable to differences in the ability of each placenta to induce a maternal immune response.