Fetal Thrombotic Vasculopathy: Perinatal Stroke, Growth Restriction, and Other Sequelae.

Clots in the fetal circulation of the placenta may occlude or narrow the lumens of fetal vessels sufficiently to diminish the placental oxygen and nutritional exchange, causing significant reduction in placental function. When extensive, growth restriction, neonatal encephalopathy, and stillbirth may occur. Propagation of clots in other organs, such as brain, kidney, and liver, may affect the function of these organs, resulting in infarcts and neonatal stroke. This article presents an account of the placental pathology and clinical sequelae of this condition, called fetal thrombotic vasculopathy.

Umbilical artery Doppler indices in small for gestational age fetuses: correlation with adverse outcomes and placental abnormalities.

OBJECTIVE: The purpose of this study was to compare the screening efficiency of the umbilical artery systolic to diastolic ratio (S/D), pulsatility index (PI), and absent end-diastolic flow (AEDF) for adverse pregnancy outcomes and placental abnormalities in small for gestational age (SGA) fetuses. METHODS: We conducted a retrospective cohort study of Doppler examinations of 161 nonanomalous SGA fetuses. The reliability of the S/D and PI were quantified by intraclass correlation coefficients. The association of the S/D, PI, and AEDF with adverse outcomes and placental abnormalities was compared by the chi(2) test. RESULTS: There was a simple association of Doppler results with adverse outcomes, which was mitigated when controlled for gestational age. For all measures of adverse outcomes, the specificity of abnormal Doppler results exceeded the sensitivity, and the negative predictive value was greater than the positive predictive value. Comparing the S/D with the PI, there was no significant difference in the sensitivity; however, the specificity of the PI was at least 90% and exceeded that of the S/D for all outcomes. The intraclass correlation coefficients of the S/D and PI were similar, indicating no difference in reliability. Placental abnormalities were significantly more common in cases with abnormal Doppler values (positive predictive value, 94%) with no overlap in the types of placental lesions in most cases. CONCLUSIONS: As an initial screen for adverse outcomes in SGA fetuses, the umbilical artery Doppler S/D, PI, and AEDF were imprecise. However, these measures were all strongly and similarly predictive of placental abnormalities, especially lesions of maternal underperfusion and fetal vascular obstruction.

Introduction: the importance of timely and complete placental and autopsy reports.

Poor communication, delayed communication, and failure to identify or evaluate significant placental lesions are major causes of failure to explain the cause of severe injuries in newborns. Families coping with stillbirth or a child with cerebral palsy need to have a sense that their bereavement deserves and is receiving major attention, and that a determined effort to explain the cause is being made and will be presented in a timely fashion. They are coping with long-lasting and devastating financial and emotional burdens. The obstetrician, neonatologist, and pathologist who have accepted the role of physician to these patients have a duty to cooperate as fully as they can to make those burdens as bearable as possible.

Clinical syndromes with variable pathologic features.

Frequently, placentas sent for pathologic examination include a clinical diagnosis that does not suggest a specific placental lesion. Pathologists who do not have great experience in this field may need some assistance with selecting the pertinent placental lesions to look for. This brief outline is included to define these conditions and present a list of the specific placental lesions that deserve consideration. The placental examination should be directed with the goal of identifying or noting and recording specifically the presence or absence of the relevant pathologic lesions. The syndromes or conditions considered in this context include neonatal encephalopathy, preterm birth, fetal growth restriction, maternal diabetes mellitus, thrombophilias, HELLP syndrome, and fetal hydrops.

Fetal vascular obstructive lesions: nosology and reproducibility of placental reaction patterns.

The purpose of this study was to assemble and test the reliability of a complete set of the placental reaction patterns seen with chronic fetal vascular obstruction in the hope that this might provide a standardized diagnostic framework useful for practicing pathologists. Study cases (14 with fetal vascular obstructive lesions, 6 controls) were reviewed blindly by seven pathologists after agreement on a standard set of diagnostic criteria. Majority vote served as the gold standard and 80% of the 180 diagnoses rendered (9 diagnoses each for 20 cases) were agreed upon by at least six of the seven scores. The sensitivity of individual diagnosis relative to the group consensus averaged 83% (range, 69-100%) and specificity averaged 91% (range, 86-100%). 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 of distal villi were generally superior to those for lesions involving large fetal vessels: avascular villi (0.49), villous stromal-vascular karyorrhexis (0.58), and villitis of unknown etiology (VUE) with stem villitis and avascular villi (0.65) versus large vessel thrombi (any vessel, 0.34; chorionic plate vessel, 0.40) and intimal fibrin cushions (recent, 0.47; remote, 0.78). Reproducibility for a global impression of any villous change consistent with chronic fetal vascular obstruction was substantial (0.63), while that for a more severe subgroup was moderate (0.44). Three points are worthy of emphasis. Our system separately recognizes, but later combines, uniformly avascular villi and villous stromal-vascular karyorrhexis as manifestations of the same underlying process. We propose that this combined group of villous lesions be dichotomized with the terms fetal thrombotic vasculopathy or extensive avascular villi (and/or villous stromal-vascular karyorrhexis) being reserved for the group with 15 or more affected terminal villi per section. Scattered foci of avascular villi (and/or villous stromal-vascular karyorrhexis) could be used to describe less severe cases. Finally, we distinguish VUE with stem villitis and avascular villi (obliterative fetal vasculopathy) as a distinct process with substantial perinatal morbidity.

Myocytes of chorionic vessels from placentas with meconium-associated vascular necrosis exhibit apoptotic markers.

Meconium-associated vascular necrosis (MAVN) is a histological abnormality of human placental chorionic vessels that is associated with poor neonatal outcome. We tested the hypothesis that MAVN shows apoptosis in the walls of chorionic vessels. Archival placental specimens with MAVN (n = 5) were compared with specimens from uncomplicated pregnancies at term (n = 5) and from placentas with intense chorionic vasculitis associated with acute chorioamnionitis with (n = 5) or without (n = 5) a clinical history of meconium in the amniotic fluid. Sections from all placentas were processed by the TUNEL method, and 2 observers who were blinded to specimen diagnosis quantified the immunofluorescent TUNEL staining in both the amnion-facing and villous-facing walls of the larger chorionic vessels in each specimen. Compared with the other 3 groups, only the amnion-facing wall of chorionic vessels in MAVN showed a significantly greater number of apoptotic cells. This was verified by morphological criteria and caspase 3 staining. There were limited or no detectable TUNEL-stained cells in either the villous-facing walls of vessels in the MAVN specimens or in any of the vessels of the placentas from uncomplicated pregnancies. There was a negligible level of apoptosis in chorionic vessels of placentas with intense chorionic vasculitis, with or without meconium, despite the inflammatory response or presence of meconium. We conclude that apoptosis contributes to the pathophysiology of MAVN.

Trophoblast apoptosis from pregnancies complicated by fetal growth restriction is associated with enhanced p53 expression.

OBJECTIVE: We tested the hypothesis that apoptotic trophoblasts from pregnancies associated with fetal growth restriction caused by preeclampsia or cigarette use exhibit enhanced expression of the proapoptotic proteins p53 and Bax and diminished expression of the antiapoptotic protein Bcl-2. STUDY DESIGN: Placentas were obtained from women with uncomplicated pregnancies (n = 4) or from women with pregnancies complicated by fetal growth restriction associated with preeclampsia, cigarette use, or both (n = 7). Placental sections were examined by means of hematoxylin and eosin and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining, as well as by detection of cytokeratin 18 cleavage products indicative of apoptosis. The expression of p53 was examined by means of Western immunoblotting and immunohistochemistry. The expression of Bax, Bcl-2, Bak, and Bcl-X(L) was analyzed by immunoblotting. RESULTS: More apoptosis was found in the trophoblast layer of villi from pregnancies complicated by fetal growth restriction than in the trophoblast layer of villi from control pregnancies. The enhanced apoptosis correlated with up-regulation of p53, primarily in cytotrophoblast nuclei. There was no difference between the two groups in expression of the proteins from the Bcl-2 family. CONCLUSIONS: The expression of p53, but not members of the Bcl-2 family of proteins is up-regulated in human placental villi from pregnancies complicated by fetal growth restriction. We speculate that conditions predisposing to placental hypoxia lead to p53-mediated apoptosis in trophoblasts and thereby contribute to placental dysfunction.