Noriyuki Suehara

Placental interleukin-6 production is enhanced in intrauterine infection but not in labor

OBJECTIVE Because interleukin-6 is an important mediator in the host defense mechanism against infection and tissue damage, we studied the capacity of placentas with or without either labor or chorioamnionitis in the third trimester to produce interleukin-6. STUDY DESIGN The placental blocks were cultured, and their interleukin-6 titers were measured by a bioassay. RESULTS Placentas with labor produced a similar amount of interleukin-6 to placentas without labor. In contrast, placentas with chorioamnionitis produced much more interleukin-6 than the placentas with or without labor (p < 0.0001). CONCLUSION Placental interleukin-6 is thus surmised to participate in potentiation of the placental and fetomaternal defense mechanisms together with placental interleukin-1 during chorioamnionitis.

Value of the Maternal Interleukin 6 Level for Determination of Histologic Chorioamnionitis in Preterm Delivery

The present study examined whether maternal serum cytokine levels are useful for the diagnosis of histologic chorioamnionitis. The blood samples of 29 women who delivered preterm between 22 and 34 weeks of gestation were collected at delivery, and placentas were histopathologically examined for chorioamnionitis. The interleukin (IL) 6 titer was higher in 18 mothers with histologic chorioamnionitis (median 12.0 pg/ml, range 4.9-63.5 pg/ml) than that in 11 mothers without histologic chorioamnionitis (median 3.5 pg/ml, range 1.7-14.9 pg/ml; p < 0.0001). The C-reactive protein (CRP) titer also differed significantly between these two groups (chorioamnionitis group: median 5.2 mg/dl, range 0.1-12.3 mg/dl; no chorioamnionitis group: median 0.2 mg/dl, range 0.1-0.5 mg/dl; p = 0.0001). The IL-6 titer showed better clinical diagnostic indices and a higher odds ratio (9.78, 95% confidence interval 1.50-63.82) than did CRP (3.26, 95% confidence interval 1.22-8.67). The levels of IL-8, monocyte chemotactic and activating factor, and soluble IL-6 receptor did not differ between the two groups. These data suggest that the level of maternal serum IL-6 is more useful than other markers, including CRP, for the identification of women at risk of impending preterm labor with histologic chorioamnionitis.

Up-Regulation of α5-Integrin by E-Cadherin Loss in Hypoxia and Its Key Role in the Migration of Extravillous Trophoblast Cells during Early Implantation

During early pregnancy, cytotrophoblast cells differentiate into extravillous trophoblast (EVT) cells and invade the uterine spiral arteries. This physiological process is essential for the development of maternal-fetal circulation. Because EVT cells are exposed to a low-oxygen environment during this process, we investigated the role of hypoxia in the mechanism that regulates the invasive behavior of EVT cells. Real-time PCR and immunofluorescent analysis were performed to investigate how hypoxia influences the expression of E-cadherin in villous explants cultures and in trophoblast-derived BeWo cells. We determined that hypoxia induced E-cadherin down-regulation through Snail up-regulation in villous explant cultures. The influence of E-cadherin loss was examined by analyzing the expression of alpha(5)-integrin and phosphorylated focal adhesion kinase (FAK) by Western blot and evaluating trophoblast invasion using a matrigel invasion assay. E-cadherin loss induced the up-regulation of alpha(5)-integrin, which leads to the tyrosine phosphorylation of FAK, resulting in an increase in the invasive activity of EVT cells. An alpha(5)-integrin neutralizing antibody inhibited the invasion of EVT cells by attenuating FAK tyrosine phosphorylation. Immunohistochemical analysis using clinical placental bed biopsies revealed that alpha(5)-integrin was up-regulated and FAK tyrosine phosphorylated (Try(861)) as EVT cells invade the uterine myometrium, whereas E-cadherin expression was down-regulated. These results suggest that alpha(5)-integrin up-regulation induced by E-cadherin loss under hypoxia has a crucial role in regulating the migration of EVT cells. This finding should help us reach a better understanding of the pathogenesis of critical gestational diseases, such as preeclampsia.

Prenatal detection of ischemic changes in the placenta of the growth-retarded fetus by Doppler flow velocimetry of the maternal uterine artery

Objective: To determine the relationships among the pregnancy outcomes of growth‐retarded fetuses, Doppler flow velocimetry of the fetomaternal circulation, and pathologic changes in the placenta. Methods: Forty‐seven fetuses confirmed to be growth‐retarded by ultrasonographic biometry were monitored during pregnancy in terms of the resistance indexes of the maternal uterine, fetal umbilical, and fetal middle cerebral arteries. After delivery, the placentas were examined for pathologic changes such as infarction and villous ischemia. Results: Compared with 23 fetuses with nonischemic placentas, 24 growth‐retarded fetuses whose placentas showed ischemic lesions were more frequently delivered preterm (P < .001) and by cesarean for fetal distress (P < .01), and they also had lower mean pH, higher carbon dioxide pressure, and lower oxygen pressure values (P < .05). Compared with the fetal umbilical and middle cerebral artery resistance indexes, the uterine artery resistance index showed the highest sensitivity (91.7%), specificity (78.3%), and positive predictive value (81.5%) for detecting placental ischemic changes. Linear discriminative analysis also showed that the uterine artery resistance index had the strongest correlation (P < .00001) with the placental ischemic changes. Conclusion: Ischemia of the placenta is associated with an adverse pregnancy outcome in growth‐retarded fetuses. The placental ischemic changes can be detected using Doppler flow velocimetry. Measurement of the uterine artery resistance index might be useful for determining the clinical management of growth‐retarded fetuses. (Obstet Gynecol 1993;82:494‐9)

Clinical Significance and Treatment of Massive Intervillous Fibrin Deposition Associated with Recurrent Fetal Growth Retardation

Retrospective examinations of 8,139 placentae were performed to clarify the relationship between placental disorders with massive intervillous fibrin deposition (MIFD) and intrauterine growth retardation (IUGR). Although the incidence of MIFD was low (0.4%), the small-for-date (SFD) birth rate in the MIFD group was significantly higher than that in the control group (62.9 vs. 8.3%; p < 0.001). Seventeen of 35 patients in the MIFD group had no clinical complications. MIFD itself was thought to be the main cause of IUGR in these patients. 78.4% of multiparae in the MIFD group have unsuccessful obstetrical histories such as intrauterine fetal death and fetal growth retardation. Four of 6 patients with a history of MIFD and SFD delivery in a previous pregnancy repeated the same episode. These data indicate that the MIFD recurrence rate in subsequent pregnancies must be high. Patients with a history of both SFD delivery and MIFD in previous pregnancies were defined as high-risk patients and they were given orally 30 mg of aspirin and 150 mg of dipyridamole daily and/or daily intravenous injection of 10,000 IU heparin during pregnancy. As a result, MIFD did not recur in all cases of the treated group and 87.5% (7/8) of the treated group could deliver approximate-for-date infants compared with 33.3% (2/6) of the untreated group (p < 0.05). These results indicate that anticoagulant and antiplatelet therapies are extremely effective for prevention of MIFD and IUGR due to MIFD.

Hydatidiform Mole in a Triplet Pregnancy Following Gonadotropin Therapy

A first case is reported of complete hydatidiform mole with two coexistent fetuses in a triple pregnancy following human menopausal gonadotropin human chorionic gonadotropin (hMG‐hCG) therapy. the molar mass and two fetuses were delivered separately at 17 weeks of gestation. the fetuses were female (155 g) and male (160 g) with individual placentae (85 g, 90 g). the hydatidiform mole (650 g) had a normal 46, XX karyotype. the sexes of the two fetuses and the karyotype of the mole are consistent with previous reports that the chromosomes of fetuses and moles are derived from both parents and the father, respectively.

Impact of prepregnant body mass index and maternal weight gain on the risk of pregnancy complications in Japanese women

Background. To analyze the association of pregnancy complications with prepregnant body mass index and weight gain during pregnancy in Japanese women. Methods. A retrospective cohort study was conducted with 21,718 Japanese women with a singleton pregnancy. Pregnant women were grouped by prepregnant body mass index and evaluated for association with pregnancy complications using multivariate logistic regression analysis. The women in each body mass index group were then divided into groups by weight gain during pregnancy using intervals of 0.05 kg/week to analyze the relationship between the weight gain and pregnancy complications by multivariate logistic regression association analysis. Results. In both nulliparous and parous women, the least pregnancy complications were found among women with medium prepregnant body mass indexes (18–23.9). Significant risks of pregnancy complications were associated with low (<18) and high (≥24) prepregnant body mass indexes, particularly high prepregnant body mass indexes. In nulliparous women, the optimal weight gain was 0.25–0.4 kg/week for low (<18) prepregnant body mass index, 0.20–0.30 kg/week for medium (18–23.9) prepregnant body mass index, and ≥0.05 kg/week for high (≥24) prepregnant body mass index. In parous women, the corresponding values were ≥0.20, 0.20–0.30, and 0.05–0.30 kg/week. Conclusions. Japanese women with prepregnant body mass indexes from 18 to 23.9 are least associated with pregnancy complications, although there is a broad range of prepregnant body mass indexes associated with few pregnancy complications. Optimal weight gain is roughly inversely related to prepregnant body mass index.

Changed expression of heat shock proteins in various pathological findings in placentas with intrauterine fetal growth restriction.

Heat shock proteins (HSPs) are activated in the cells of most organisms in response to sublethal heat shock and other stressors. It has been reported that HSP27, HSP60, HSP70, and HSP90 are expressed in normal human placenta, and it was thought that these HSPs play a role in the demonstration of cell viability and function. In this study, we performed an immunohistochemical (IHC) study of these HSPs for 27 placentas that had complicated intrauterine fetal growth restriction (IUGR) and compared the IHC findings with the pathological findings. To quantify HSP27, HSP60, HSP70, and HSP90, immunoreacted cells in the chorionic villi, syncytiotrophoblasts (ST), and cytotrophoblasts (CT) were counted. In thrombus, excessive syncytial knots, and avascular villi, the expression of HSPs was higher in the pathological sections compared to control in both ST and CT. In contrast, all HSPs decreased in both ST and CT around the infarction region. The data suggested that chorionic villi cells locally responded to some stresses, e.g., hypoxia and increase or decrease in the expression of HSPs. Although the villous cells around the infarction histologically appear viable, they may have received lethal damage, and as a result the expression of HSPs was decreased. These results are expected to improve our understanding of the pathological findings of IUGR in placentas, including the quality, damage, and function of the chorionic villi.

Prenatal diagnosis of Cockayne syndrome using assay of colony-forming ability in ultraviolet light irradiated cells.

The analysis of colony‐forming ability after ultraviolet light exposure is described with amniotic fluid cells from a pregnancy at risk for Cockayne syndrome. The amniotic fluid cells were considerably more sensitive to ultraviolet light than normal amniotic fluid cells and skin fibroblasts from normal donors. It took about 5 weeks from amniocentesis to identify the affected fetus by this colony assay. The diagnosis was confirmed in fibroblast cultures from both skin and lung of the aborted fetus.

Congenital Cervical Rhabdomyosarcoma Arising in One Fetus of a Twin Pregnancy

Objective: To describe a huge congenital cervical rhabdomyosarcoma. Methods: We were recently confronted with a case of fetal solid neck mass arising in one fetus of a twin pregnancy. Prenatally, the cervical tumor was consistent with teratoma, but it was diagnosed histologically as a rhabdomyosarcoma. Genetic amniocentesis showed a mosaic pattern consisting of 46,XY/46,XY,t(2;8)(q35;q21.2). Results: EXIT procedure was proposed to the parents but declined. The twin with huge cervical tumor died in utero at 35 weeks’ gestation due to hydrops fetalis. Conclusion: Fetal cervical rhabdomyosarcoma is an extremely rare condition that has not been previously reported, but should be considered in the presentation of fetal solid neck mass.