Theonia K. Boyd

Maternal Vascular Underperfusion: Nosology and Reproducibility of Placental Reaction Patterns

Placental examination can be a useful tool for specifying the etiology, prognosis, and recurrence risk of pregnancy disorders. The purpose of this study was to test the reliability of a predetermined set of placental reaction patterns seen with maternal vascular underperfusion in the hope that this might provide a useful diagnostic framework for practicing pathologists. Study cases (14 with clinical and pathologic evidence of maternal underperfusion plus 6 controls) were evaluated for the presence or absence of 11 lesions by eight perinatal pathologists. After analysis of initial results, diagnostic criteria were refined and a second, overlapping set of cases was reviewed. The collective sensitivity, specificity, and efficiency of individual assessments for the 11 lesions relative to the group consensus ranged from 74–93% (22/33 > 90%). Reproducibility was measured by unweighted kappa-values and interpreted as follows: < 0.2 poor, 0.2–0.6 fair/moderate, > 0.6 substantial. Kappa values for lesions affecting villi and the intervillous space were increased syncytial knots (any −0.42, severe −0.50), villous agglutination (0.42), increased intervillous fibrin (0.25), and distal villous hypoplasia (0.57). Individual estimates of percent involvement for syncytial knots, intervillous fibrin, and distal villous hypoplasia were correlated with placental and fetal weight for gestational age. Extent of increased intervillous fibrin showed the strongest correlation with both placental weight (R = −0.64) and fetal weight (R = −0.45). Kappa values for lesions affecting maternal vessels and the implantation site were acute atherosis (0.50), mural hypertrophy of membrane arterioles (0.43), muscularized basal plate arteries (0.48), increased placental site giant cells (0.54), and immature intermediate trophoblast (0.36). Correlation of maternal vessel and implantation site lesions with the clinical diagnosis of preeclampsia showed that excessive placental site giant cells and immature intermediate trophoblast were more sensitive and efficient predictors, whereas atherosis and muscularized basal plate arteries were more specific. Kappa value for a thin umbilical cord, a possible indicator of fetal volume depletion, was 0.61. Reproducibility for a global impression of maternal vascular underperfusion, taking into account all of the above lesions, was moderate (kappa 0.54) and improved after inclusion of additional pathologic and clinical data (kappa 0.68). Adoption of this clearly defined, clinically relevant, and pathologically reproducible terminology could enhance clinicopathologic correlation and provide a more objective framework for future clinical research.

WT1 regulates the expression of the major glomerular podocyte membrane protein Podocalyxin

The WT1 tumor suppressor gene encodes a zinc finger transcription factor expressed in differentiating glomerular podocytes. Complete inactivation of WT1 in the mouse leads to failure of mesenchymal induction and renal agenesis, an early developmental phenotype that prevents analysis of subsequent stages in glomerular differentiation [1]. In humans with Denys-Drash Syndrome, a heterozygous germline mutation in WT1 is associated with specific defects in glomeruli and an increased risk for developing Wilms Tumor [2,3]. WT1 target genes implicated in cell cycle regulation and cellular proliferation have been proposed [4], but the link between WT1 function and glomerular differentiation is unexplained. Here, we show that inducible expression of WT1 in rat embryonic kidney cell precursors leads to the induction of endogenous Podocalyxin, the major structural membrane protein of glomerular podocytes, which is implicated in the maintenance of filtration slits. Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself. These observations support a role for WT1 in the specific activation of a glomerular differentiation program in renal precursors and provide a molecular basis for the glomerulonephropathy that is characteristic of Denys-Drash Syndrome.

Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement

CONTEXT -The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories. OBJECTIVE -To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community. DATA SOURCES -Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible. CONCLUSIONS -The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.

Chronic histiocytic intervillositis: a placental lesion associated with recurrent reproductive loss

Chronic (histiocytic) intervillositis (CHIV), defined for the purposes of this study as diffuse histiocytic infiltration of the intervillous space without villitis, is an idiopathic lesion seen in the chorionic sacs of some spontaneous abortion specimens and placentas. In this retrospective study, we evaluated all patients diagnosed with CHIV from 2 hospitals between 1993 and 2000, plus 1 additional patient from 1977. Histopathology, phenotype of the leukocytic infiltrate, perinatal outcome, and other associated clinical features were assessed by review of clinical records and all available pathology specimens plus immunohistochemical staining. CHIV was found in 31 of 45 specimens examined from 21 patients (23 of 31 first trimester, 3 of 5 second trimester, and 5 of 9 third trimester). Recurrence rate was 67% for patients with more than one specimen reviewed. Overall perinatal mortality rate was 77%, and only 18% of pregnancies reached 37 weeks. Eight of 19 patients with 3 or more pregnancies had recurrent spontaneous abortion (RSA); 5 with primary RSA (> or = 3 consecutive spontaneous abortions (SAB) with no living children) and 3 with secondary RSA (> or = 3 consecutive SAB with 1 or more living children). Severe intrauterine growth restriction was seen in 5 of 8 second- and third-trimester placentas with CHIV. Patients were generally not of advanced maternal age (mean, 29.8 +/- 6.2 years), and there was no obvious racial predisposition. Autoimmune or allergic phenomena were identified in 11 patients. Immunohistochemical staining of the intervillous infiltrate showed a near uniform population of monocyte-macrophages at varying stages of maturity and activation: more than 90% CD45Rb and CD68 positive, 30% to 40% MAC387 positive, less than 5% CD3 positive, and CD1a, CD20, CD30, and CD56 negative. We conclude that CHIV is an uncommon but important cause of recurrent spontaneous abortion and, in some cases, loss at later gestational ages. HUM PATHOL 31:1389-1396.

Gross Abnormalities of the Umbilical Cord: Related Placental Histology and Clinical Significance

OBJECTIVE To evaluate umbilical cord abnormalities predisposing to mechanical cord compression and determine their relationship to adverse clinical outcomes and stasis-associated histologic changes in the placenta. METHODS Placental slides of 224 singleton pregnancies with gross cord abnormality (true knots, long cords, nuchal/body cords, abnormal cord insertion, hypercoiled cords, narrow cords with diminished Whartons jelly), delivered on or after 28 weeks gestational age, and 317 gestational age-matched controls, were reviewed and specifically evaluated for the following histologic changes: (1) fetal vascular ectasia, (2) fetal vascular thrombosis, (3) and fetal thrombotic vasculopathy/avascular villi. These changes were analyzed in relation to both clinical information and findings at gross pathologic examination. RESULTS Gross cord abnormalities were associated with stillbirth, intrauterine growth restriction, non-reassuring fetal tracing, meconium-stained amniotic fluid, and increased rate of emergency Cesarean section. At microscopic evaluation, cases with gross cord abnormalities showed a statistically significant association with both ectasia and thrombosis in the fetal vasculature, as well as changes of fetal thrombotic vasculopathy in the terminal villi. When considering individual gross cord abnormalities, long cord and nuchal cord had the highest rates of thrombosis-related histopathology. Finally, cases with both abnormal cords and histologic thrombosis had significantly higher rates of adverse outcomes, including IUGR and stillbirth. CONCLUSION Gross cord abnormalities predispose the fetus to stasis-induced vascular ectasia and thrombosis, thus leading to vascular obstruction and adverse neonatal outcome, including IUGR and stillbirth. We recommend a thorough histopathologic evaluation of all placentas with gross cord abnormalities predisposing to cord compression.

Findings From aCGH in Patients With Congenital Diaphragmatic Hernia (CDH): A Possible Locus for Fryns Syndrome

Congenital diaphragmatic hernia (CDH) is a common and often devastating birth defect that can occur in isolation or as part of a malformation complex. Considerable progress is being made in the identification of genetic causes of CDH. We applied array‐based comparative genomic hybridization (aCGH) of ∼1Mb resolution to 29 CDH patients with prior normal karyotypes who had been recruited into our multi‐site study. One patient, clinically diagnosed with Fryns syndrome, demonstrated a de novo 5Mb deletion at chromosome region 1q41–q42.12 that was confirmed by FISH. Given prior reports of CDH in association with cytogenetic abnormalities in this region, we propose that this represents a locus for Fryns syndrome, a Fryns syndrome phenocopy, or CDH.

Acute Histologic Chorioamnionitis at Term: Nearly Always Noninfectious

Background The link between histologic acute chorioamnionitis and infection is well established in preterm deliveries, but less well-studied in term pregnancies, where infection is much less common. Methodology/Principal Findings We conducted a secondary analysis among 195 low-risk women with term pregnancies enrolled in a randomized trial. Histologic and microbiologic evaluation of placentas included anaerobic and aerobic cultures (including mycoplasma/ureaplasma species) as well as PCR. Infection was defined as ≥1,000 cfu of a single known pathogen or a ≥2 log difference in counts for a known pathogen versus other organisms in a mixed culture. Placental membranes were scored and categorized as: no chorioamnionitis, Grade 1 (subchorionitis and patchy acute chorioamnionitis), or Grade 2 (severe, confluent chorioamnionitis). Grade 1 or grade 2 histologic chorioamnionitis was present in 34% of placentas (67/195), but infection was present in only 4% (8/195). Histologic chorioamnionitis was strongly associated with intrapartum fever >38°C [69% (25/36) fever, 26% (42/159) afebrile, P<.0001]. Fever occurred in 18% (n = 36) of women. Most febrile women [92% (33/36)] had received epidural for pain relief, though the association with fever was present with and without epidural. The association remained significant in a logistic regression controlling for potential confounders (OR = 5.8, 95% CI = 2.2,15.0). Histologic chorioamnionitis was also associated with elevated serum levels of interleukin-8 (median = 1.3 pg/mL no histologic chorioamnionitis, 1.5 pg/mL Grade 1, 2.1 pg/mL Grade 2, P = 0.05) and interleukin-6 (median levels = 2.2 pg/mL no chorioamnionitis, 5.3 pg/mL Grade 1, 24.5 pg/mL Grade 2, P = 0.02) at admission for delivery as well as higher admission WBC counts (mean = 12,000cells/mm3 no chorioamnionitis, 13,400cells/mm3 Grade 1, 15,700cells/mm3 Grade 2, P = 0.0005). Conclusion/Significance Our results suggest histologic chorioamnionitis at term most often results from a noninfectious inflammatory process. It was strongly associated with fever, most of which was related to epidural used for pain relief. A more ‘activated’ maternal immune system at admission was also associated with histologic chorioamnionitis.

Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia

OBJECTIVE We sought to describe placental findings in asphyxiated term newborns meeting therapeutic hypothermia criteria and to assess whether histopathologic correlation exists between these placental lesions and the severity of later brain injury. STUDY DESIGN We conducted a prospective cohort study of the placentas of asphyxiated newborns, in whom later brain injury was defined by magnetic resonance imaging. RESULTS A total of 23 newborns were enrolled. Eighty-seven percent of their placentas had an abnormality on the fetal side of the placenta, including umbilical cord lesions (39%), chorioamnionitis (35%) with fetal vasculitis (22%), chorionic plate meconium (30%), and fetal thrombotic vasculopathy (26%). A total of 48% displayed placental growth restriction. Chorioamnionitis with fetal vasculitis and chorionic plate meconium were significantly associated with brain injury (P = .03). Placental growth restriction appears to significantly offer protection against the development of these injuries (P = .03). CONCLUSION Therapeutic hypothermia may not be effective in asphyxiated newborns whose placentas show evidence of chorioamnionitis with fetal vasculitis and chorionic plate meconium.

Obstetric and Perinatal Complications in Placentas with Fetal Thrombotic Vasculopathy

Fetal thrombotic vasculopathy (FTV) is a placental lesion characterized by regionally distributed avascular villi and is often accompanied by upstream thrombosis in placental fetal vessels. Previous studies, using preselected populations, have shown associations of this lesion with adverse neurodevelopmental outcomes and potentially obstructive lesions of the umbilical cord. We investigated the prevalence of obstetric complications, perinatal disease, and placental abnormalities in cases with FTV. One hundred thirteen cases of placentas with FTV were identified in our pathology database over an 18-year period. Two hundred sixteen placentas without the diagnosis of FTV, frequency matched on year of birth, were selected as controls. Electronic medical records and pathology reports were used to extract maternal and gestational age, method of delivery, neonatal outcome, lesions of the umbilical cord, obstetric complications, and fetal abnormalities. Placentas with FTV were associated with a 9-fold increase in rate of stillbirth and a 2-fold increase in intrauterine growth restriction. The increase in pregnancy-induced hypertension/preeclampsia was not significant when adjusted for maternal and gestational age. Although the rate of potentially obstructive cord lesions was similar in both groups, there was an almost 6-fold increase in the presence of oligohydramnios in FTV placentas, compared with controls. Finally, FTV was associated with a 6-fold increase in fetal cardiac abnormalities. Fetal thrombotic vasculopathy is associated with a significantly higher rate of obstetric and perinatal complications. This study points to abnormal fetal circulation, either in the form of congenital heart disease or oligohydramnios predisposing to cord compression, as a risk factor for FTV.

Severe perinatal liver disease associated with fetal thrombotic vasculopathy.

Three neonates with fetal thrombotic vasculopathy in the placenta and severe neonatal liver disease are described. Symptoms included a bleeding disorder on the first day of life, followed by direct hyperbilirubinemia and elevated liver transaminases. All patients also had evidence of thrombosis outside the placenta, including cerebral infarct in two infants and thrombosis of the inferior vena cava in one infant. Liver disease was demonstrated to be thrombotic in one infant who died with Budd-Chiari syndrome. Two infants survived and had liver biopsy with cholestasis, bile duct proliferation, and portal fibrosis demonstrated at 4 weeks and 11 weeks of age, respectively. The etiology of thrombosis is unknown, though in one patient an excessively long and coiled umbilical cord may be implicated. The prenatal onset of thrombosis suggests an inherited or acquired thrombophilic state. In cases of enigmatic neonatal liver disease, an association with thrombosis should be considered and thrombi sought in placenta, umbilical cord, major blood vessels, and other organs. Evaluation for a hypercoagulable state is also suggested.