Fetal vasculitis in preterm newborns: interrelationships, modifiers, and antecedents.

Histologic expressions of the fetal inflammatory response predict preterm delivery and neonatal disorders. We examined 1146 placentas in the Developmental Epidemiology Network data set for histologic evidence of membrane inflammation (subchorionitis, chorionitis, and chorioamnionitis) and fetal vasculitis (acute umbilical vasculitis or chorionic vasculitis). Our main findings are that (1) in the presence of membrane inflammation, fetal vasculitis is common, (2) duration of membrane rupture and gestational age appear to modify the risk of fetal vasculitis, (3) this risk modification differs for the different components of fetal vasculitis, i.e. umbilical and chorionic vasculitis, and (4) antecedents can be identified that appear to increase or decrease the risk of fetal vasculitis among births with membrane inflammation. We conclude that fetal vasculitis, the morphologic component of the fetal inflammatory response, might not be a homogeneous entity and deserves further study.

Very low birthweight placenta: clustering of morphologic characteristics.

Our objective was to use factor analysis as a data reduction tool to organize a large number of placental pathologic features into useful aggregates. We examined 1146 placentas of live-born infants with a birth weight of 500-1500 g. We then conducted analyses of pairs of characteristics and multiple characteristics to identify "associated groups" and "factors," respectively. We found an associated group and factor that had placental features associated with acute inflammation and another associated group and factor that had features associated with vasculopathy. Acute umbilical vasculitis had the strongest correlation with other features of the acute inflammation associated group and factor. Gross evidence of acute inflammation (opacification and green appearance of membrane) was eliminated in the reduction from associated group to factor. Infarcts and syncytial knots were strongly dissociated with features of acute inflammation. The multiple pathologic features of the very low birthweight placenta can be aggregated into two associated groups or two factors. Lack of membrane opacification cannot be used as a criterion for declining microscopic examination. The absence of infarcts and syncytial knots should prompt a search for features of acute inflammation. If a placenta has two or more findings from the acute inflammation factor or the vasculopathy factor, it is unlikely to demonstrate features from the other factor.

Umbilical vein interleukin 6 and tumor necrosis factor alpha plasma concentrations in the very preterm infant.

OBJECTIVE: To examine the relationship between umbilical vein plasma concentrations of interleukin 6 (IL-6) and tumor necrosis factor (TNF)-alpha and early neonatal sepsis in the very preterm infant, and the histopathologic findings of chorioamnionitis in the placentas from these pregnancies. METHODS: A prospective study was conducted in 43 very preterm, singleton infants delivered at or before 32 weeks of gestation. IL-6 and TNF-alpha were measured by enzyme-linked immunoassay. Placentas from these pregnancies were histologically examined for the presence of chorioamnionitis. Infants were prospectively classified as confirmed sepsis group, clinical sepsis group or control group. IL-6 and TNF-alpha plasma concentrations were not normally distributed, so they were transformed to their natural log values for statistical analysis. RESULTS: The enrolled infants had a mean gestational age of 27.2 +/- 2.7 weeks and a mean birth weight of 956 +/- 325 g. Three (7%) infants had confirmed sepsis, 18 (42%) were in the clinical sepsis group and 22 (51%) were in the control group. IL-6 concentrations but not TNF-alpha were significantly higher (P < 0.05) in the confirmed (8.9 +/- 1.7) and clinical sepsis (5.5 +/- 2.4) groups in comparison with the control group (2.1 +/- 1.6). We examined 42 placentas. Twenty-three (55%) had no evidence of chorioamnionitis, 1 (2%) had mild grade, 8 (19%) had a moderate grade and 10 (24%) had a severe grade of chorioamnionitis. IL-6 was significantly elevated in the moderate (5.9 +/- 1.6 vs. 1.9 +/- 1.6) and severe grade (7.2 +/- 2.3 vs. 1.9 +/- 1.6) of chorioamnionitis, in the presence of acute deciduitis (6.0 +/- 2.7 vs. 2.1 +/-1.8), chorionic vasculitis (6.8 +/- 2.1 vs. 2.2 +/- 1.9) and funisitis (7.3 +/- 1.9 vs. 2.7 +/- 2.3) (P < 0.05) TNF-alpha plasma concentrations were not significantly different. CONCLUSION: An elevated umbilical vein IL-6 concentration is a good indicator of sepsis syndrome in the very preterm infant and also correlates with histologic chorioamnionitis in these pregnancies.

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants. Developmental Epidemiology Network Investigators.

Echolucent images (EL) of cerebral white matter, seen on cranial ultrasonographic scans of very low birth weight newborns, predict motor and cognitive limitations. We tested the hypothesis that markers of maternal and feto-placental infection were associated with risks of both early (diagnosed at a median age of 7 d) and late (median age = 21 d) EL in a multi-center cohort of 1078 infants <1500 x g. Maternal infection was indicated by fever, leukocytosis, and receipt of antibiotic; fetoplacental inflammation was indicated by the presence of fetal vasculitis (i.e. of the placental chorionic plate or the umbilical cord). The effect of membrane inflammation was also assessed. All analyses were performed separately in infants born within 1 h of membrane rupture (n = 537), or after a longer interval (n = 541), to determine whether infection markers have different effects in infants who are unlikely to have experienced ascending amniotic sac infection as a consequence of membrane rupture. Placental membrane inflammation by itself was not associated with risk of EL at any time. The risks of both early and late EL were substantially increased in infants with fetal vasculitis, but the association with early EL was found only in infants born > or =1 after membrane rupture and who had membrane inflammation (adjusted OR not calculable), whereas the association of fetal vasculitis with late EL was seen only in infants born <1 h after membrane rupture (OR = 10.8; p = 0.05). Maternal receipt of antibiotic in the 24 h just before delivery was associated with late EL only if delivery occurred <1 h after membrane rupture (OR = 6.9; p = 0.01). Indicators of maternal infection and of a fetal inflammatory response are strongly and independently associated with EL, particularly late EL.

Clinical chorioamnionitis and histologic placental inflammation.

OBJECTIVE: To estimate the rate of histologic chorioamnionitis in the presence of diagnosed clinical chorioamnionitis and determine whether clinical markers of maternal and neonatal infection are associated with histologic chorioamnionitis. METHODS: We identified singleton pregnancies from 1996 in which discharge diagnoses included clinical chorioamnionitis and reviewed maternal and neonatal records for clinical evidence of chorioamnionitis and suspected or confirmed neonatal infections. Placentas were examined for acute histologic chorioamnionitis. RESULTS: One hundred thirty-nine pregnancies with the discharge diagnosis of maternal clinical chorioamnionitis were included. Eighty-six (61.9%) had the clinical diagnosis supported by histologic chorioamnionitis. Histologic chorioamnionitis was associated with an earlier gestational age at delivery (35.7+/-6.5 weeks versus 38.6+/-2.9 weeks, P = .002), lower epidural usage (72.1% versus 92.5%, P = .004), less internal monitoring (47.7% versus 75.5%, P = .001), and possible neonatal sepsis (60.5% versus 35.8%, P = .005). For 19 of 71 (26.8%) infants with possible neonatal sepsis, placentas did not show histologic chorioamnionitis. CONCLUSION: Clinical chorioamnionitis and possible neonatal infection were not supported by histologic evidence for infection in 38.1% and 26.8% of cases, respectively, suggesting other noninflammatory causes of signs and symptoms.

The relationship between placental histology and cervical ultrasonography in women at risk for pregnancy loss and spontaneous preterm birth.

OBJECTIVE: Our objective was to determine whether there were any differences in the placental lesions of high-risk patients with versus without ultrasonographic evidence of cervical shortening between 15 and 24 weeks' gestation. STUDY DESIGN: Women who were at risk for pregnancy loss and spontaneous preterm birth were followed by serial transvaginal cervical ultrasonography with transfundal pressure between 15 and 24 weeks' gestation. Two groups of women were identified: those in whom progressive cervical shortening developed to below 2 cm, either spontaneously or induced by transfundal pressure, and those in whom it did not. A perinatal pathologist who was blinded to the pregnancy outcome retrospectively examined placental histologic slides. The histologic placental lesions were categorized as acute or chronic inflammatory lesions, decidual vascular lesions, and coagulation-related lesions. RESULTS: There were 278 women who were followed during the study. Placentas were submitted for histologic examination in 189 cases (125 singleton, 45 twin, and 19 triplet gestations). There were 72 pregnancies with and 117 pregnancies without an ultrasonographic diagnosis of cervical shortening, respectively. Overall, there were significantly more acute inflammatory lesions in patients in whom cervical shortening developed, as determined by ultrasonographic examination. However, there were significantly more decidual vascular lesions in women in whom cervical shortening did not develop. When we examined the distribution of the placental histologic lesions in the 64 cases of multiple gestations, the only significant finding was again a greater frequency of acute inflammatory lesions in patients in whom cervical shortening developed. There was no difference in the distribution of the placental histologic lesion categories among women treated with bed rest versus cervical cerclage because of the ultrasound diagnosis of cervical shortening. CONCLUSION: Acute inflammatory lesions of the placenta were more frequent in patients with second-trimester cervical shortening. These findings support that patients with cervical shortening in the second trimester are prone to acute placental inflammation.

Maternal chorioamnionitis and umbilical vein interleukin-6 levels for identifying early neonatal sepsis.

OBJECTIVE: The purpose of this study was to determine whether elevated levels of umbilical vein IL-6 would be a better marker for early neonatal sepsis than the clinical signs of maternal chorioamnionitis. METHODS: Patients delivering preterm because of spontaneous preterm labor or premature rupture of the membranes were evaluated for clinical signs of chorioamnionitis, which was defined as a temperature of > or =100.4 degrees F along with > or =2 of the following: significant maternal tachycardia (> or = 120 bpm), fetal tachycardia (> or =160 bpm), purulent discharge, uterine tenderness, and leukocytosis (WBC > or =18,000 cells/mm3). Umbilical vein blood was assayed for interleukin-6. An elevated interleukin-6 level was determined to be 25 pg/mL. Infants were evaluated for evidence of early neonatal sepsis. The abilities of clinical chorioamnionitis and interleukin-6 levels > or =25 pg/mL to predict early neonatal sepsis were compared. RESULTS: There were 28 patients delivering 14 (50%) neonates with evidence for early neonatal sepsis. The incidence of suspected neonatal sepsis in women with and without clinical chorioamnionitis was 6/10 (60%) vs. 8/18 (44.4%), P = 0.43. Using receiver operator characteristic curves, the best cutoff for interleukin-6 was found to be 25 pg/mL. The compared sensitivity, specificity, and positive and negative predictive values of clinical chorioamnionitis vs. interleukin-6 levels > or =25 pg/mL for predicting early neonatal sepsis were 42.9% vs. 92.9%, 71.4% vs. 92.9%, 60% vs. 92.9%, and 55.6% vs. 92.9%, respectively. CONCLUSIONS: Elevated umbilical vein levels of interleukin-6 predict those preterm infants with early sepsis better than the presence of clinical chorioamnionitis.

Prenatal sonographic appearance of hemorrhagic cerebellar infarction.

To date, the prenatal diagnosis of cerebellar hemorrhage has been limited to isolated case reports, which have demonstrated either a hyperechoic cerebellar hemisphere or a hyperechoic mass within the cerebellum in near-term fetuses. We demonstrate the ultrasonographic findings of intracerebellar hemorrhagic infarction in a fetus at approximately 21 weeks' gestation. In contrast to previous case reports, the hemorrhagic infarcts seen in our case were hypoechoic.

Standards of birth weight in twin gestations stratified by placental chorionicity.

OBJECTIVE: To establish fetal growth nomograms for twin gestations, categorized by placental chorionicity, and to compare them with those of published singleton and twin nomograms. METHODS: Computerized data files of live births of all twins delivered between January 1990 and October 1996 at Saint Peter's Medical Center were used. Birth weight curves corresponding to the fifth, tenth, 50th, 90th, and 95th percentiles were derived separately for twins with monochorionic and dichorionic placentation. We generated the curves by applying the method of generalized estimating equations, after adjusting for the potential intracluster correlation due to twinning. The curves were then smoothed on the basis of nonparametric restricted cubic splines to derive (smoothed) birth weight percentiles. We then compared our twin birth weight nomogram to six previously published singleton and two twin nomograms published previously for predicting small for gestational age infants (defined as birth weight below the tenth percentile). RESULTS: Among 1302 twin fetuses, 272 (21%) were monochorionic. Twins from monochorionic gestations weighed, on average, 66.1 g (standard deviation 28.4 g, P = .02) less than twins from dichorionic gestations after correcting for gestational age. Twin curves based on parity (nulliparity versus multiparity) were not different from each other. Analyses indicate that all previously published singleton nomograms approximate twin growth reasonably well between 32 and 34 weeks, but they underestimate twin growth at earlier gestational ages (between 25 and 32 weeks) and overestimate twin growth beyond 34 weeks' gestation. Similarly, a comparison of previously published twin nomograms with those of ours indicates that the growth standards in our population were similar to those in other published twin nomograms. CONCLUSION: We recommend that future epidemiologic and clinical studies use twin nomograms to identify growth-restricted twin fetuses. Moreover, because fetal growth is influenced by placental chorionicity, we recommend that fetal growth assessment in twin gestations consider placental chorionicity, whenever the information is available.

Observer reliability in assessing placental maturity by histology.

AIMS: To evaluate the ability of five experienced perinatal pathologists to assess placental maturity reliably by histology. METHODS: Twenty four haematoxylin and eosin slides, six each from placentas of 27, 31, 35, and 39 weeks' gestation, were circulated to five pathologists on three separate occasions. The slides were labelled with the correct or incorrect gestational ages. RESULTS: The mean absolute error over all 360 readings was 2.72 weeks. Only 54% of the slides were assessed within two weeks of the correct gestation. Pathologist tended to overestimate younger gestations and underestimate older gestations. Two, and possibly three, pathologist were influenced by the gestational age state on the label. One pathologist, who did not appear to be influenced by the label, was more accurate in diagnosing gestation of the placentas than other colleagues. CONCLUSIONS: Experienced pathologists can have difficulty in assessing the villous maturity of placentas by histology. They can also be influenced by clinical information provided, such as gestational age. Other observer reliability studies must address the issue of the influence of labelled information on observer variation. A difference in maturation would have to be of a six week magnitude to have a chance of being detected by current methods. This may limit the value of the histological diagnosis of placental dysmaturity as a surrogate marker for uteroplacental ischaemia.

Prenatal diagnosis of an unusual nuchal cord complication in monoamniotic twins.

BACKGROUND: Monoamniotic twin pregnancies are frequently associated with cord entanglement, but such entanglement rarely involves the co-twin's trunk, extremities, or neck. CASE: We report a set of monoamniotic twins in which color Doppler imaging revealed that the cord of twin B was wrapped around the neck of its dead co-twin. This knowledge allowed us to avoid clamping and dividing twin A's nuchal cord during vaginal delivery, preventing asphyxia of twin B. This is the fifth reported incidence of this particular monoamniotic complication and the first to be diagnosed prenatally. CONCLUSION: Color Doppler imaging facilitates the diagnosis of rare cord complications in monoamniotic twin pregnancies.

Pulmonary changes following extracorporeal membrane oxygenation: autopsy study of 23 cases.

Extracorporeal membrane oxygenation (ECMO) has become an established mode of therapy in many centers for potentially fatal neonatal respiratory failure refractory to conventional therapy. We reviewed the findings of 23 autopsies of patients placed on ECMO therapy during the period from 1988 to 1992 at our institution in order to document the pulmonary histopathologic changes and to correlate such changes with the duration of treatment. Interstitial and intra-alveolar hemorrhages, as well as hyaline membrane formation, were the most common findings during the first few days of therapy. Reactive epithelial hyperplasia (bronchial and type II pneumocytes), squamous metaplasia, and smooth muscle hyperplasia were observed as early as 2 to 3 days after initiation of ECMO therapy. Interstitial fibrosis was noted only after 7 days of ECMO therapy. In three patients treated for 15, 19, and 21 days there was replacement of the terminal airways and alveoli by tall columnar and mucin-producing epithelium. Alveolar and bronchiolar calcifications were noted in seven of the 23 cases in this series. Pulmonary vascular changes were seen in association with persistent fetal circulation, meconium aspiration, and respiratory distress syndrome. These changes are most likely due to the compounded effect of ECMO and the underlying pulmonary insult.

Genetics and biology of human ovarian teratomas. III. Cytogenetics and origins of malignant ovarian germ cell tumors.

This report presents cytogenetic data on three cases of malignant ovarian germ cell tumors. All were diagnosed as malignant teratoma; case 1 with yolk sac elements; case 2 with elements of endodermal sinus tumor, embryonal carcinoma, and choriocarcinoma; and case 3 with yolk sac elements and embryonal carcinoma. Metaphase cells from each tumor, and normal tissue from the host, were karyotyped and scored for centromeric heteromorphisms in an attempt to determine the mechanism of origin. The karyotypes were 79,XXX,+1,+3,-6,+8,+12,+14,-15,+17, +20,+21,+22;49,XX,+8,+12,+22; and 48,XX,+3,+14, respectively. The analysis of centromeric heteromorphisms and DNA fingerprints of host and teratoma using the M13 probe revealed that one case originated from a germ cell before the first meiotic division. Normal host tissue was not available in case 2, but several centromeric markers were heterozygous in the tumor, indicating either meiosis I error or complete failure of germ cell meiosis. In the third case the centromeric heteromorphisms that were heterozygous in the host appeared to be homozygous for certain chromosomes and heterozygous for others in the tumor. These results suggest that germ cell teratomas could arise by the fusion of two ova.

Multiple gastrointestinal atresias with imperforate anus: pathology and pathogenesis.

The syndrome of hereditary multiple gastrointestinal atresias is characterized by multiple and widespread atresias from pylorus to rectum, intraluminal calcifications on plain abdominal roentgenogram, and an invariably fatal course with an autosomal recessive mode of inheritance. We review 18 cases reported in the literature and one additional case in an infant with imperforate anus. The anatomical and histological characteristics of the atresias suggest a failure of recanalization of the embryonic intestinal lumen. The association between multiple atresias and imperforate anus supports the hypothesis that this disorder is a malformation syndrome caused by a defect in the development of the gastrointestinal tract.

Correlation between pathologic and ultrasound findings in first trimester spontaneous abortions.

We compared the pathologic and ultrasonographic findings of 31 first trimester spontaneous abortions to determine the benefits of such studies. The ultrasound diagnoses included empty gestational sac (n = 11), intrauterine fetal death (n = 11), abortion in progress or incomplete abortion (n = 8), and live embryo (n = 1). Two subgroups of empty sacs were identified by pathologic examination. Embryonic development appeared to be more advanced in one group as indicated by the presence of embryonic red blood cells (RBC's) in the placental vessels. Although an embryo or fetus was identified more frequently by sonar than by pathologic examination, we were able to diagnose developmental anomalies in small embryos that current ultrasound equipment cannot resolve. Such anomalies were identified even in the presence of fetal heart activity. Pathologic examination was also informative when heavy bleeding obscured the contents of the uterine cavity to sonar and was thus supplementary of a suboptimal ultrasound examination. Placental examination proved to be reliable in assessing gestational age at the time of embryonic/fetal death. There was a good correlation between RBC morphology and sonographic measurement of crown-rump length. First trimester ultrasound and pathologic examination of the embryo and placenta are informative and complement each other.

Placental abruption in the preterm gestation: an association with chorioamnionitis.

Thirty-seven women with acute severe preterm placental abruption were compared with a control group of 51 women requiring preterm delivery for a medical complication of pregnancy. Histologic chorioamnionitis and funisitis were present significantly more often in patients with abruption than in control patients (41 versus 4%; P less than .0001). No patient in either group had clinical evidence of chorioamnionitis. We conclude that a significant association exists between preterm placental abruption and histologic chorioamnionitis.