The placenta in preterm birth.

Rates of preterm birth range from 5% to 13% of deliveries in developed countries. About two-thirds of preterm deliveries are due to spontaneous onset of preterm labour or preterm premature rupture of membranes. Approximately one-third follow induction of labour or caesarean section performed for maternal or fetal indications such as preeclampsia, haemorrhage, non-reassuring fetal heart rate or intrauterine growth restriction. Thus, pathologists are frequently called on to evaluate preterm placentas, to determine the cause of the spontaneous preterm birth and/or correlate placental findings with the clinical history. This review provides pathologists with an overview of the recent clinical research in the pathogenesis of preterm birth and relates these to the correlative placental pathologies of the major causes of spontaneous preterm birth. A brief summary of the placental gross and histopathological findings in indicated preterm birth is also included.

Pulmonary atresia with intact ventricular septum associated with congenitally corrected transposition.

We present a rare case of pulmonary atresia with intact septum associated with congenitally corrected transposition. The patient was a nondysmorphic female infant. Despite a right Blalock-Taussig shunt on day 13 of life and a balloon atrial septostomy on day 23, she remained ventilator dependent with poor systemic ventricular function. The patient died at the age of 160 days, and postmortem findings are presented. The literature on this condition is reviewed, and the possibility that the left-sided morphologic right ventricle could not sustain the systemic circulation is discussed.

Lethal pulmonary hypoplasia after in-utero myelomeningocele repair.

BACKGROUND: In-utero surgical repair of fetal myelomeningocele has been performed as a means to improve the postnatal condition of affected infants. CASE: A nulliparous woman underwent in-utero surgical repair of a fetal lumbosacral myelomeningocele at 24 weeks' gestation. Her postoperative convalescence was complicated by pulmonary edema, abdominal pain, chronic oligohydramnios, and preterm labor. The infant was delivered by cesarean at 33 weeks' gestation, but expired from respiratory distress caused by pulmonary hypoplasia at 9 hours of age. CONCLUSION: Until the benefits of in-utero repair of fetal myelomeningoceles are determined by well-controlled clinical trials, this technique remains investigational. Physicians and their patients who are considering this procedure must be fully aware of the potential risks that can occur.

Value of perinatal autopsy.

OBJECTIVE: To determine how often a perinatal autopsy identified the cause of death, and how frequently this information changed recurrence risk estimates or altered parental counseling. METHODS: We reviewed all autopsies of fetal stillbirths and briefly viable neonates performed by one perinatal pathologist at the University of Alabama Hospital from 1992 to 1994. RESULTS: Four hundred sixteen fetal and early neonatal deaths occurred at our hospital from January 1, 1992, to June 1, 1994. Consent for an autopsy examination was granted for 139 of these (33%), and all autopsies were performed by a single perinatal pathologist. Abnormalities likely to be the cause of death were identified in 130 of 139 cases (94%). Ninety-one subjects did not have structural anomalies: In 14 cases autopsy revealed previously unsuspected pathology that altered parental counseling; in 68 cases autopsy findings were consistent with the clinical obstetrical diagnosis; and in nine cases the cause of death could not be identified. Forty-eight subjects were anomalous. Thirty-seven of these (79%) had been evaluated by antenatal ultrasonography, and autopsy identified additional abnormalities in 51% (19 of 37). In the 11 deaths evaluated neonatally, a previously unsuspected diagnosis likely to be the cause of death was identified in three. Overall, autopsy findings changed recurrence risk estimates and/or parental counseling in 36 of 139 cases (26%). CONCLUSION: The cause of fetal or perinatal death was determined by autopsy in 94% of cases in our series. Counseling and recurrence risk estimates were altered by autopsy findings in 26%.

Fetal membrane histology in preterm premature rupture of membranes: comparison to controls, and between antibiotic and placebo treatment. The National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network, Bethesda, MD, USA.

The objectives of this study were to test the hypotheses that antibiotic therapy will alter the histologic appearance of fetal membranes in preterm premature rupture of membranes (pPROM), and that the membrane histology will demonstrate distinct differences between term and preterm rupture of membranes. We also wished to test interobserver variability of pathologists. Placental membranes were sampled from 268 women participating in a randomized placebo-controlled trial of antibiotic therapy for pPROM at 24-32 weeks of gestation (cases) and from 4 control groups who were not in the randomized trial: (1) preterm labor without pPROM (n = 21), (2) term labor (n = 65), (3) term PROM (n = 21), and (4) term cesarean section (n = 27). The cases and controls were scored for 40 histologic features by pathologists blinded to the identity of each sample (case or control). pPROM histology of samples from patients receiving antibiotics and those receiving placebo was compared using a chi-squared test and with control groups using logistic regression. There were no histological differences between pPROM cases treated with antibiotic and those receiving placebo, nor with respect to duration of membrane rupture greater or less than 48 h. Concordance among pathologists was low for features other than acute inflammation. Logistic regression analysis controlled for race and pathologist, and demonstrated that all of the control groups had significantly fewer common markers of acute inflammation when compared with the pPROM cases. This study suggests that histopathologic evidence of infection is seen more frequently with pPROM than in preterm or term controls. The histologic features used in this study cannot be used to determine the effectiveness of antibiotic therapy.

Surrogate light chain production during B cell differentiation: differential intracellular versus cell surface expression.

Expression of the surrogate light (psi L) chain genes encoding the VpreB and lambda 5/14.1 proteins is restricted to B-lineage cells. Pro-B and pre-B cells produce psi L chains, but whether both employ these as cell surface receptor components remains enigmatic. Recombinant human VpreB protein was used to generate a large panel of monoclonal anti-VpreB Abs to examine this issue. Native psi L chain proteins within pro-B cells as well as those serving as receptor components on pre-B cells were precipitated by 16 of the 26 anti-VpreB Abs. Surrogate light chains were easily detected on pre-B cell lines, whereas these anti-VpreB Abs reacted with pro-B cell lines only after plasma membrane permeabilization. The subpopulation of normal bone marrow cells bearing pre-B receptors included large and small pre-B cells exclusively, although pro-B cells also contained intracellular VpreB. VpreB proteins were not detected on or within B cells in bone marrow or the circulation, but a subpopulation of B cells in germinal centers was found to express the VpreB proteins intracellularly. Surrogate L chains are thus intermittently produced during human B-lineage differentiation, while their role as receptor components appears limited to the pre-B cell stage.

Two fetal deaths associated with maternal sepsis and with thrombosis of the intervillous space of the placenta.

The placental pathology in two second trimester fetal losses associated with mild maternal disseminated intravascular coagulation are reported. Case one had a dental abscess, a leukocytosis of 36300 white blood cells/m, and evidence of mild consumptive coagulopathy at 20 weeks. Case two had septic findings including disseminated intravascular thrombosis associated with pyelonephritis. The placentae had extensive intervillous thrombosis at the periphery of spiral arterial flow. It is hypothesized that in mild disseminated intravascular coagulation, the trophoblast inhibits fibrinolysis, favouring thrombosis perhaps due to production of plasminogen activator inhibitor.

Effects of ACTH and cytokines on dehydroepiandrosterone sulfotransferase messenger RNA in human adrenal cells.

Dehydroepiandrosterone sulfate (DS) is the major adrenal androgen produced in the fetal and adult human; its formation is dependent upon the action of dehydroepiandrosterone sulfotransferase (DST). Since the factors that regulate DST are poorly characterized, we investigated the effects of ACTH, which stimulates DS production, and the cytokines transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) , both of which are inhibitory to adrenal steroidogenesis, on cultured human fetal adrenal cells. Cellular levels of DST mRNA were increased in a dose dependent fashion in response to ACTH; DST mRNA was less responsive to ACTH stimulation than was 17 hydroxylase (CYP 17) mRNA. The stimulatory effects of ACTH on DST mRNA levels were blunted by both TGF-beta and TNF-alpha; the inhibitory effects of TNF-alpha on DST mRNA were more striking than were those on CYP 17 mRNA. These data suggest that DS production can be altered by several agents acting on the DST gene.

Histologic features of chorioamnion membrane rupture: development of methodology.

This study developed a set of histologic features that will allow subclassification of placentas with preterm premature rupture of membranes. Placentas were obtained from patients participating in a multi-institutional NICHD Maternal-Fetal Medicine Unit Network study of antimicrobial therapy after preterm premature rupture of membranes. The rupture site was sampled by inking the open sac margin and rolling a membrane strip in four quadrants from the ink to the placental margin. Independently, four pathologists used a provisional feature list to score the slides from 15 placentas. A concordance analysis was performed on those results. With those results, the slides were reviewed concurrently to discover the source of disagreements and to revise the feature list. The sampling method frequently demonstrated a rupture site with histology distinct from that of the remainder of the membranes. After review of the preliminary scoring results, 29 features of membrane histology present in preterm premature rupture could be objectively described with agreement among four pathologists. The feature list allows both novel and commonly recognized histologic features of fetal membranes to be recorded with objectivity. This list, with the described sampling technique, is presented as a tool for clinical correlation in studies of membrane rupture, especially in preterm, premature rupture.

Stage-specific expression of integrin alphaVbeta3 in neuroblastic tumors.

The ligand specificity of the integrin cell adhesion receptors probably determines the ability of specific integrins to promote tumor cell proliferation and metastasis. Therefore, we compared the expression of integrin alphaVbeta3, a promiscuous receptor that binds with high affinity to numerous cell matrix proteins, with the expression of integrin alphaVbeta5 and the integrin beta 1 subunit (which pairs with multiple alpha subunits) in neuroblastic tumors at various stages of differentiation. Undifferentiated neuroblastoma tumors rapidly invade and metastasize, whereas ganglioneuroblastomas rarely metastasize. Differentiating neuroblastomas are associated with an intermediate prognosis. Paraffin sections of neuroblastic tumors at various stages of differentiation obtained at biopsy from 17 patients were hybridized with antisense integrin subunit-specific alphaV, beta3, beta1, and beta5 riboprobes. All neuroblastic tumors and seven adrenal glands obtained at autopsy were analyzed immunohistochemically with antibodies directed toward the alphaV, beta3, beta1, and beta5 subunits. The alphaV subunit was expressed in neuroblastic tumors independent of the stage of differentiation, although mRNA and protein expression were generally weak in ganglioneuroblastomas, and was also detected in adrenal gland medullae. The beta1 subunit was detected in most neuroblastic tumors independent of the stage of differentiation as well as in adrenal gland medullae. In contrast, the beta3 subunit, which was not expressed in adrenal gland medullae, was expressed at the protein and mRNA levels in undifferentiated neuroblastomas (six of seven and seven of seven, respectively) but was not expressed in neuroblasts or ganglion cells in ganglioneuroblastomas (one case weakly positive out of five). The beta 5 subunit was expressed at the protein (five of five) and mRNA (four of five) levels in the ganglion cells of ganglioneuroblastomas and, although mRNA for this subunit was detectable in undifferentiated tumors, the protein was not detectable. The expression of integrin alphaVbeta3 in undifferentiated neuroblastomas may contribute to the rapid growth of these tumors and their tendency to metastasize.

Prostaglandin E1-induced hyperostosis: clinicopathologic correlations and possible pathogenetic mechanisms.

Prostaglandin E1 (PGE1) causes skeletal hypertrophy, a phenomenon noted when it is administered for several weeks to maintain ductus arteriosus patency in neonates with congenital heart disease. This effect, a dose-dependent and reversible hyperostosis, was described radiologically as bone within bone, but skeletal histopathology was not studied. We compared postmortem gross, radiological, and histological bone findings for untreated controls and term gestation infants after 4, 27, and 56 days of continuous 0.1-0.2 microgram/kg/min PGE1. Bone was not significantly different from controls after 4 days of PGE1. Radiographs were negative after 27 days, but femoral cortex showed early periosteal osteoblast proliferation. At 56 days of PGE1, there was severe, radiologically apparent neocortex formation in tubular, rib, and scapular bones. Corresponding sections of femoral shaft revealed distinctive histopathology with thickened periosteum and fibrocartilage-like tissue covering an exuberant neocortex of closely aligned, gracile, woven bone trabeculae. Paratrabecular stroma contained ectatic capillaries orthogonally oriented to the periosteum, suggesting that a vascular reaction to PGE1 is important in the observed effect. The native cortex was partially resorbed; because it is stress shielded by the neocortex and no inflammation was present, this was interpreted as a secondary effect. We conclude that PGE1-associated paracortical bone hypertrophy is distinct from inflammatory processes and that its early stages may not be apparent radiologically. Moreover, the time course of PGE1-induced osteoblast proliferation and mineralization suggests that experimental use for 4-8 weeks may benefit conditions such as ununited fractures.

Lymphoplasmacytic aortitis and acute aortic dissection. An uncommon association.

A 43-year-old white man with a history of cigarette smoking, hypertension, nephrolithiasis, and cervical degenerative arthritis was hospitalized for sudden-onset severe, substernal, and pleuritic chest pain with epigastric radiation. Despite evaluation, the cause remained unclear and the patient expired on hospital day 5. Autopsy revealed acute Stanford type A aortic dissection, hemopericardium, and hemothorax. Grossly, the aorta and its branches, including uninvolved medium-sized arteries, displayed extreme mural fragility. Microscopic examination showed a primary lymphoplasmacytic aortitis-periaortitis without giant cells. Rents within the tunica media, medial-adventitial inflammation, and elastic fiber disruption were limited to sites of gross aortic dissection. Muscular arteries showed patchy, chronic arteritis-periarteritis without giant cell infiltrate or aneurysm formation. This case documents an unusual association of primary lymphoplasmacytic aortitis and aortic dissection.

Immunocytochemical analyses of dehydroepiandrosterone sulfotransferase in cultured human fetal adrenal cells.

Dehydroepiandrosterone sulfate is the major steroid secretory product of the human fetal adrenal gland. Several factors have been shown to modulate the secretion of this steroid by cultured fetal adrenal cells. In addition to the cytochrome P450 enzymes that are important in steroid biosynthesis, dehydroepiandrosterone sulfotransferase (DST) is likely to be a key regulated enzyme in the formation of sulfated steroids, which are characteristic of the human adrenal cortex, particularly that of the fetus and the adult zona reticularis. In the present investigation, we sought to evaluate the cellular localization of DST in cultures derived from the fetal zone, neocortex, and adrenal capsule and to determine the effects of ACTH and other agonists of the protein kinase-A pathway on the abundance of DST in such cells. Cells derived from the fetal zone, neocortex, and adrenal capsule were either precultured for 3-13 days in plastic flasks followed by culture on coverslips or were cultured directly on coverslips in control medium (McCoy's 5A medium that contained 5% fetal bovine serum) or control medium plus ACTH, forskolin, or dibutyryl cAMP for 1-4 days. Cells were fixed in buffered formalin and then immunostained for DST by use of a rabbit polyclonal antiserum prepared against human liver DST. DST immunoreactivity was abundant in freshly isolated cortical cells derived from fetal zone and neocortex. DST immunoreactivity was still observable in fetal zone and neocortex cells as well as in cells prepared from enzymatic digests of adrenal capsule after scraping off adherent neocortex cells following culture for 9-14 days in control medium. Adrenal fibroblasts were negative for DST. DST abundance in cortical cells was increased in cultures supplemented with ACTH, forskolin, or dibutyryl cAMP compared to that in cultures grown in control medium alone. The results of Western blot analyses of DST in these cells were consistent with the immunocytochemical data. These results suggest that DST is present in both fetal zone and neocortex cells of the human fetal adrenal at midgestation and that the production of DST is stimulated by ACTH and agonists of the protein kinase-A signal transduction pathway in the human fetal adrenal gland.

Immunocytochemical analyses of dehydroepiandrosterone sulfotransferase in cultured human fetal adrenal cells.

Dehydroepiandrosterone sulfate is the major steroid secretory product of the human fetal adrenal gland. Several factors have been shown to modulate the secretion of this steroid by cultured fetal adrenal cells. In addition to the cytochrome P450 enzymes that are important in steroid biosynthesis, dehydroepiandrosterone sulfotransferase (DST) is likely to be a key regulated enzyme in the formation of sulfated steroids, which are characteristic of the human adrenal cortex, particularly that of the fetus and the adult zona reticularis. In the present investigation, we sought to evaluate the cellular localization of DST in cultures derived from the fetal zone, neocortex, and adrenal capsule and to determine the effects of ACTH and other agonists of the protein kinase-A pathway on the abundance of DST in such cells. Cells derived from the fetal zone, neocortex, and adrenal capsule were either precultured for 3-13 days in plastic flasks followed by culture on coverslips or were cultured directly on coverslips in control medium (McCoy's 5A medium that contained 5% fetal bovine serum) or control medium plus ACTH, forskolin, or dibutyryl cAMP for 1-4 days. Cells were fixed in buffered formalin and then immunostained for DST by use of a rabbit polyclonal antiserum prepared against human liver DST. DST immunoreactivity was abundant in freshly isolated cortical cells derived from fetal zone and neocortex. DST immunoreactivity was still observable in fetal zone and neocortex cells as well as in cells prepared from enzymatic digests of adrenal capsule after scraping off adherent neocortex cells following culture for 9-14 days in control medium. Adrenal fibroblasts were negative for DST. DST abundance in cortical cells was increased in cultures supplemented with ACTH, forskolin, or dibutyryl cAMP compared to that in cultures grown in control medium alone. The results of Western blot analyses of DST in these cells were consistent with the immunocytochemical data. These results suggest that DST is present in both fetal zone and neocortex cells of the human fetal adrenal at midgestation and that the production of DST is stimulated by ACTH and agonists of the protein kinase-A signal transduction pathway in the human fetal adrenal gland.

Immunohistochemical evaluation of the cellular localization and ontogeny of 3 beta-hydroxysteroid dehydrogenase/delta 5-4 isomerase in the human fetal adrenal gland.

The enzyme, 3 beta-hydroxysteroid dehydrogenase/delta 5-4 isomerase (3 beta-HSD) is an essential element in the biosynthetic pathway for potent adrenal steroid hormones that appear to regulate maturation of many tissues in utero and are critical for homeostasis after birth. The results of prior studies are suggestive that 3 beta-HSD activity in the human fetal adrenal (HFA) is very low and restricted to the outer zone of cortical cells, the neocortex (NC), during mid-gestation. Near the time of birth, however, there must be enhanced expression of this enzyme to allow for adaptation to extrauterine life. In the present study, we sought to characterize, by use of immunohistochemical methods, the cellular localization and developmental changes of 3 beta-HSD in the HFA during the interval of 11-41 wks gestation. Early in gestation, 11-15 wks, we noted considerable 3 beta-HSD in NC and in occasional fetal zone (FZ) cells as well. Thereafter until 24-25 wks, 3 beta-HSD was very low in NC cells and virtually absent from the FZ. Throughout the third trimester, the outer 1/2-2/3 of the NC was increasingly immunostained and clusters of immunoreactive cells also appeared near the central medullary vein of the adrenal. The NC cells and those located in the cortical cuff region that expressed 3 beta-HSD resembled zona glomerulosa cells. Among many other fetal tissues studied, only testicular Leydig cells (18,19 wks) and hilar cells of the ovary (26 wks) were found to contain 3 beta-HSD in quantities sufficient to be detected by immunohistochemistry. These results are suggestive of a heretofore undocumented stimulus to 3 beta-HSD in the HFA in early gestation followed by a suppression of the adrenal concentration of this enzyme during mid-gestation. High levels of 3 beta-HSD in early development may facilitate cortisol production, which is believed to play a role in differentiation of the medullary precursors during this developmental period. The control of adrenal 3 beta-HSD during human fetal development may be more complex than initially envisioned and requires further study.

Lumbosacral neurenteric cyst in an infant. Case report.

The case of a combined intra- and extraspinal neurenteric cyst in an infant is reported. This case is unique because an intraspinal cyst was not suspected clinically until large numbers of squamous epithelial cells were obtained at lumbar puncture performed as part of a workup for a septic entity. The cyst extended from an intradural location ventral to the conus medullaris at L-1 through a ventrolateral defect in the S-4 vertebral body to communicate with a large presacral component. The entire cystic cavity was lined by stratified squamous epithelium. The possible pathogenesis of this lesion is discussed.

Radiologic-pathologic correlation. Capillary hemangioma of the meninges.

Hemangiomas are the most common tumor of the head and neck in children, including intracranial neoplasms. Capillary hemangioma in turn is the commonest type of hemangioma. Our case establishes that its anatomic distribution may include the intracranial compartment. We were unable to distinguish capillary hemangioma from meningioma based on imaging findings alone.