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Introduction: Syncytiotrophoblasts are the major components of the human placenta involved in fetal maternal exchange and hormone secretion. The syncytiotrophoblasts arise from the fusion of villous cytotrophoblasts. The cell cycle suppressor p57 KIP2 is known to be an essential molecule for proper trophoblast differentiation during placental formation., Methods: We generated p57 KIP2 -expressing BeWo transfectant cells. Proliferation assay and matrigel invasion assay were used to characterize p57 KIP2 -expressing BeWo transfectant cells. To reveal the role of p57 KIP2 in syncytialization, we proceeded syncytium formation analysis and qRT-PCR for detection of the expression levels Syncytin-1, Syncytin-2 and their receptors., Results: The human choriocarcinoma cell line, BeWo has undetectable levels of p57 KIP2 expression. Expression of p57 KIP2 reduced cell proliferation rate and extracellular matrix invasion activity. p57 KIP2 expressing cells displayed multinucleated cells associated with syncytiotrophoblast differentiation. In the syncytialization event, p57 KIP2 was found to potentiate forskolin-induced upregulation of Syncytin-2 in a cAMP-independent manner., Discussion: These results indicate that the expression of p57 KIP2 may act on the proliferation/invasion inhibitory factor and enhance the expression of Syncytin-2, which are associated with syncytialization in cytotrophoblasts., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim: The difference of placental weight (PW) and fetal/placental weight ratio (F/P) Z scores by mode of delivery is unclear. To investigate such differences and the actual conditions underlying the imbalance between fetal and placental growth., Methods: The data from Japanese database 2013 were assessed. Light-for-dates (LFD, n = 12 884), appropriate-for-dates (n = 114 464) and heavy-for-dates (n = 13 164) from 140 512 placentas/infants of mothers delivered a singleton infant. Using Z scores of PW and F/P based on the standard curves of a sex-, parity- and gestational-age-specific PW and F/P, the rate of inappropriately heavy placenta according to the mode of delivery (vaginal [VD] vs cesarean [CS]) was investigated., Results: (i) The PW and F/P were heavier and bigger in VD than in CS, in each subgroup. In the LFD groups, the PW Z score in VD was higher than that in CS, whereas the F/P Z score was lower than in VD than that in CS. (ii) Data of single regression analyses between the PW Z score and F/P Z score in VD groups were different from those in CS, especially in LFD infants. (iii) In the LFD subgroups, the rates of inappropriately heavy placenta in VD (n = 7781) and CS (n = 5103) were 0.54% and 0.86%, respectively., Conclusion: Difference in the mode of delivery influenced the PW and F/P, and the rate of inappropriately heavy placenta is associated with mode of delivery among LFD infants. This methodology might give us a clue to search a useful way for identifying the high-risk groups requiring postnatal counseling., (© 2019 Japan Society of Obstetrics and Gynecology.)

Objective: To demonstrate the differences in intrauterine fetal deaths and neonatal deaths between small for date (SFD) and Non-SFD neonates by applying a novel classification from both Z scores of placental weight (PW) and fetal/placental weight ratio (F/P) to small for gestational age (SGA) neonates. Methods: From 93,034 placentas/infants of mothers who vaginally delivered a singleton infant (Japan Perinatal Registry Network database 2013), SGA (n=7,780) was chosen according to the reference to Japanese neonatal growth chart. They were divided into two subgroups: SFD (body weight and height less than the 10 th percentile, n=3,379) and Non-SFD (only body weight less than the 10 th percentile, n=4,401). Z scores of PW and F/P based on the standard curves for sex-, parity-, and gestational-age-specific PW and F/P were calculated. The population was classified into 9 groups according to the combination of 'low vs. middle vs. high' i) PW Z score and ii) F/P Z score. In both i) and ii), ± 1.28 standard deviations in the Z scores were used for classifying low vs. middle vs. high, with 3×3 making 9 groups. From top-left to bottom-right, we labeled the groups as Group A to Group I. Results: SFD and Non-SFD neonates distributed in the same 6 groups (A, D, E, G, H, I). In group E, which was considered to be balanced placental and infant growth, the incidence of intrauterine fetal death was significantly higher in Non-SFD neonates than in SFD neonates. In group D, which was considered to be small placenta and balanced infant growth, the incidence of neonatal death was significantly higher in SFD neonates than in Non-SFD neonates. Conclusion: Assessment of SGA neonates by dividing them into SFD and Non-SFD neonates and application of a 9-group classification by PW and F/P Z scores were informative to understand the pathophysiological involvement of an imbalance between placental and fetal sizes., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The present study aimed to investigate the relationship between placental pathological findings and physiological development during the neonate and infantile periods. Study participants were 258 infants from singleton pregnancies enrolled in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study) whose placentas were stored in our pathological division. They were followed up from birth to 18 months of age. Physiological development (body weight and the ponderal index [PI]) was assessed at 0, 1, 4, 6, 10, 14, and 18 months. Placental blocks were prepared by random sampling and eleven pathological findings were assessed, as follows: 'Accelerated villous maturation', 'Decidual vasculopathy', 'Thrombosis or Intramural fibrin deposition', 'Avascular villi', 'Delayed villous maturation', 'Maternal inflammatory response', 'Fetal inflammatory response', 'Villitis of unknown etiology (VUE)', 'Deciduitis', 'Maternal vascular malperfusion', and 'Fetal vascular malperfusion'. Mixed model analysis with the use of the xtmixed command by the generic statistical software, Stata version 13.1., identified 'Accelerated villous maturation' and 'Maternal vascular malperfusion' as significant predictors of a lower body weight and 'Deciduitis' as a significant predictor of a small PI, throughout the first 18 months of life. In conclusion, the present study is the first to demonstrate that some pathological findings of the placenta are associated with changes in infantile physical development during the initial 18 months of life in the Japanese population.

Objective: To classify the infants into 9 blocks based on the deviation of both placental weight (PW) and fetal/placental weight ratio (F/P) Z score and compared the incident rate of perinatal death in each of the small for date (SFD) vs. appropriate for date (AFD) vs. heavy for date (HFD) groups. Methods: The study population consisted of 93,034 placentas/infants from women who vaginally delivered a singleton infant. They were classified into 3 groups according to infants' weight: SFD (n=3,379), AFD (n=81,143) and HFD (n=8,512). The population was classified into 9 blocks according to the combination of i) low vs. middle vs. high placental weight (PW: a sex-, parity- and gestational-age-specific placental weight) and ii) low vs. middle vs. high F/P. In both i) and ii), ± 1.28 standard deviations in the in the Z scores was used for classifying low vs. middle vs. high, with 3x3 making 9 blocks. We then determined whether or not the perinatal death in each block differed among the three groups (SFD vs. AFD vs. HFD). Results: (1) The proportions of 'balanced growth of placenta and infant' (appropriate PW and F/P based on Z-score) were 37.6% in the SFD group, 78.8% in the AFD group, and 51.2% in HFD group. (2) The proportion of 'inappropriately heavy placenta' in the SFD group and that of 'inappropriately light placenta' in the HFD group were 0.3 and 0.4%, respectively, a very rare phenomenon. The proportions of 'inappropriately heavy placenta' and 'inappropriately light placenta' accounted for 4.1 and 5.5% in AFD group, respectively. (3) The rates of perinatal death in those with 'balanced growth of placenta and infant' were lowest in the SFD and AFD groups. Conclusion: By showing the fact that perinatal death was lowest in cases with balanced fetal/ placental growth, we conclude that 9-block categorization of PW and F/P based on deviation in the Z-score may be a candidate factor employable for understanding fetal and placental growth and perinatal deaths., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Placental villi play pivotal roles in feto-maternal transportation and phospholipids constitute a major part of the villous membrane. We have been developing and optimizing an imaging system based on a matrix-assisted laser desorption/ionization (MALDI)-based mass spectrometer, which provides clear two-dimensional molecular distribution patterns using highly sensitive mass spectrometry from mixtures of ions generated on tissue surfaces. We recently applied this technology to normal human uncomplicated term placentas and detected the specific distribution of sphingomyelin (SM) (d18:1/16:0) in stem villi and phosphatidylcholine (PC) (16:0/20:4) in terminal villi. In the present study, we applied this technology to nine placentas with maternal or fetal complications, and determined whether a relationship existed between these specific distribution patterns of phospholipid molecules and the six representative pathological findings of placentas, i.e., villitis of unknown etiology (VUE), thrombus, atherosis, chorioamnionitis (CAM), immature terminal villi, and multiple branched terminal villi. In two placentas with the first and second largest total number of positive pathological findings, i.e., five and three positive findings, the specific distribution of SM (d18:1/16:0) in stem villi and PC (16:0/20:4) in terminal villi disappeared. The common pathological findings in these two placentas were atherosis, immature terminal villi, and multiple branched terminal villi, suggesting the possible involvement of the underperfusion of maternal blood into the intervillous space. On the other hand, the number of pathological findings were two or less in the seven other placentas, in which no specific relationships were observed between the differential expression patterns of these two phospholipids in stem and terminal villi and the pathological findings of the placentas; however, the specific distribution pattern of SM (d18:1/16:0) in stem villi disappeared in four placentas, while that of PC (16:0/20:4) in terminal villi was preserved. These results suggested that the absence of the specific distribution of PC (16:0/20:4) in terminal villi, possibly in combination with the absence of SM (d18:1/16:0) in stem villi, was linked to placental morphological changes in response to maternal underperfusion of the placenta.

The aim of the present study was to investigate the relationship between assisted reproductive technology procedures, the morphology of the basal plate of placentas, and amount of bleeding in deliveries. Fifty-five whole placentas (fresh-embryo transfer in the in vitro fertilization cycle [n = 6], frozen-thawed embryo transfer in the natural cycle [n = 13] or in the hormonal cycle [n = 10], and age-matched spontaneously conceived pregnancies [n = 26]) were retrospectively enrolled and histologically analyzed. The whole placentas were stored in our pathological division among 512 singleton pregnancies with vaginal deliveries (34-41 weeks of gestation) at Hamamatsu University Hospital. The morphology of the placental basal plate was examined using Azan staining. A total of 20 digital images (each 0.53 mm(2)) of microscopic fields were analyzed per placenta to measure the mean values of the vertical maximum thickness of Rohr and Nitabuch fibrinoid layers and % loss of decidua. The thickness of Rohr fibrinoid layer and % loss of decidua were significantly higher in the frozen-thawed embryo transfer in the hormonal cycle group than in the frozen-thawed embryo transfer in the natural cycle and spontaneously conceived pregnancy groups (each P < .01). The z scores for both the thickness of Rohr fibrinoid layer and % loss of decidua positively correlated with those for the amount of bleeding in deliveries (P < .05 each). Assisted reproductive technology procedures changed the morphology of the placental basal plate, suggesting a possible association with an increase in the amount of bleeding in deliveries., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: The local expression of two isoenzymes of 11β-hydroxysteroid dehydrogenase, type 1 (11βHSD-1) and type 2 (11βHSD-2), regulates the access of glucocorticoid hormones to their target cells. Reports on the association between the placental expression of 11βHSD and infantile growth are limited. The aim of the present study was to investigate if the placental gene expression of 11βHSD affects infantile growth at 10 months of age., Methods: Placentas and umbilical venous cord blood were obtained from 42 singleton cases of cesarean deliveries between 31 and 40 weeks of gestation at Hamamatsu University Hospital between March 2009 and June 2010. The gene expression of both 11βHSD-1 and 11βHSD-2 was measured by quantitative reverse transcription polymerase chain reaction. Adiponectin and leptin levels in umbilical cord blood were measured using enzyme-linked immunoassay., Results: 11βHSD-1 and 11βHSD-2 gene expression in human placentas did not correlate with bodyweight or the ponderal index (PI) at 10 months of age, whereas the gene expression of 11βHSD-1, but not 11βHSD-2, correlated with birthweight as well as PI at birth. Adiponectin levels in umbilical cord blood significantly correlated with the placental gene expression of 11βHSD-1 as well as bodyweight and PI at 10 months of age, although no direct correlation was observed between them., Conclusion: No direct correlation was observed between the placental gene expression of 11βHSD and infantile growth at 10 months of age. However, the placental gene expression of 11βHSD-1 may be indirectly connected with infantile growth via adiponectin-associated metabolic regulation represented by adiponectin levels in umbilical cord blood., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

We recently found a significant elevation in placental tissue oxygen index (TOI) values in cases of fetal growth restriction using near-infrared spectroscopy (NIRS), indicating high oxygenation in the placental tissue. We hypothesized that insufficient fetoumbilical blood flow is causatively associated with high oxygenation levels in placental tissue. We transiently (for 15 sec) ligated the whole umbilicus, umbilical arteries, or veins of pregnant Clawn miniature pigs (102-113 days of gestation) and assessed the changes in TOI values of the placenta and fetus. The ligation significantly increased placental TOI values (p<0.01, respectively), but concomitantly decreased fetal TOI values (p<0.01, respectively), suggesting a decline in oxygen inflow from the maternal to fetal circulation in the placental tissue to be causative of the elevated placental TOI values. These observations suggest the promising clinical use of placental TOI values measured noninvasively by the transabdominal application of NIRS to assess the fetoplacental circulation.

Objective: To develop the immunohistochemistry specific for meconium in the placenta, fetal membrane and umbilical cord., Study Design: We previously reported the specific presence of zinc coproporphyrin I (ZnCP-I) in human meconium and demonstrated the possible diagnostic use of an elevation in maternal plasma ZnCP-I levels in cases of amniotic fluid embolism. In this study, we developed a new specific monoclonal antibody for ZnCP-I and applied it to the immunostaining of meconium in the placenta, fetal membrane, and umbilical cord., Results: Immunoreactivity of ZnCP-I clearly and specifically identified meconium in the placenta, fetal membrane, and umbilical cord. It was especially useful in cases of severe chorioamnionitis to detect meconium in the macrophages surrounded by numerous neutrophils. In more than half of the cases, meconium was detected in clear amniotic fluid at delivery, suggesting previous exposure., Conclusions: Immunohistochemical detection of ZnCP-I is a highly sensitive histological diagnosis of meconium., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We evaluated the clinical usefulness of near-infrared spectroscopic quantitative measurement of placental oxygenation for the noninvasive estimation of uteroplacental function in pregnant women. We performed a prospective, observational clinical study. Women without complications (N = 15), women with threatened preterm delivery (TPD; N = 6), and women with intrauterine fetal growth restriction (IUGR; N = 6) were enrolled. Measurements of placental tissue oxygenation index (TOI) using the NIRO-300 (Hamamatsu Photonics, Hamamatsu City, Japan) were recorded. Mean TOI was 72.3 +/- 5.3% in women without complications, 72.9 +/- 5.6% in pregnant women with TPD, and 78.7 +/- 3.0% in pregnant women with IUGR. Mean TOI in pregnant women with IUGR was significantly higher than that of the other two groups (P < 0.05). In the IUGR group, although gestational age at measurement on admission was less than that made during hospitalization (P < 0.05), there were no differences in the TOI in relation to gestational age at measurement. Higher TOIs in pregnant women suggest decreased placental function. Monitoring the TOI by near-infrared spectroscopic quantitative measurement may have a high potential for clinical application, particularly in prenatal management., (Thieme Medical Publishers.)

Placental lakes are sonolucent or hypoechoic areas in images of the placenta, usually considered a physiological dilation of intervillous space with a rather good obstetrical outcome. However, diagnostic criteria for and the clinical significance of placental lakes are yet to be completely established, because of a wide variety of ultrasound findings, especially on color Doppler examination. We experienced a case of a huge placental lake, larger than the total placental area, located in an entire retroplacental space, concomitant with several penetrations of artery type blood flow. The antenatal differential diagnosis and course of clinical management are reported.

We evaluated the clinical usefulness of near-infrared spectroscopic quantitative measurement of placental tissue oxygenation for noninvasive estimation of uteroplacental function in pregnant women. We performed a prospective observational clinical study. Women without complications (N = 15) and women with pregnancy-induced hypertension (PIH; N = 6) were enrolled. Measurements of placental tissue oxygenation index (TOI) using NIRO-300 (Hamamatsu Photonics, Hamamatsu City, Japan) were recorded. The mean TOI in women without complications was 72.36 +/- 5.36% and 80.28 +/- 2.78% in pregnant women with PIH. The mean TOI in pregnant women with PIH was higher than that of pregnant women without complications. There were no differences in the TOI in relation to gestational age at onset of PIH, forms of PIH, or severity of hypertension. Higher TOIs in pregnant women suggest the reduced ability of the placental function. Monitoring the TOI by near-infrared spectroscopic quantitative measurement may have a high potential for clinical application, particularly in prenatal management., (Thieme Medical Publishers.)

Trophoblast giant cells in the mouse placentas are polyploid cells that form as a result of endoreduplication. The giant cells form the outermost layer of the extraembryonic compartment and produce a number of pregnancy-specific hormones, including prolactin family members. Here we demonstrate that trophoblast giant cells are increased, and display upregulation of prolactin releasing peptide (PrRP) receptor in the p53-null (p53(-/-)) embryonic placentas. At day 13.5 of gestation, the weight of p53(-/-) placentas was less than that of both wild-type and p53(+/-) placentas. In p53(-/-) placentas, the spongiotrophoblast layer was significantly decreased in thickness, and the trophoblast giant cells were observed not only in the outer layer of placentas but in both the spongiotrophoblast layer and the labyrinthine layer. The giant cells spread over the spongiotrophoblast and labyrinthine layer in p53(-/-) placentas displayed more intensive expression of immunoreactive PrRP receptor than in wild-type placentas. Previous studies indicated that the association between PrRP and PrRP receptor physiologically involves in the expression and secretion of the peptide hormones, including prolactin and growth hormones. These results suggest that p53 may regulate the differentiation of trophoblast giant cells, and may control the physiological PrRP stimuli in mouse placentas.

The uteroplacental circulation in the placenta can have a major impact on the fetus. Near infrared spectroscopy (NIRS) is the noninvasive method of measuring changes in blood volumes and oxygen concentrations in living tissue. The purpose of this study is to monitor changes in placental tissue oxygen index (TOI) levels, in patients with intrauterine fetal growth restriction during pregnancy, using NIRS. We measured placental TOI values of 15 normal pregnant woman and 15 patients with intrauterine growth restriction admitted to our hospital. The placenta was assessed by ultrasound examination and NIRS was performed on all patients. The TOI values of the IUGR group when hospitalized was 78.6 +/- 1.6 (SD). This value was significantly higher than that of the controls (78.6 +/- 1.6 [SD] versus 70.2 +/- 0.4 [SD]). And the TOI values of the IUGR group, when measured before delivery, were 77.8 +/- 1.6 (SD). The TOI values of the IUGR group before delivery were significantly higher than those of the control group (77.8 +/- 1.6 [SD] versus 70.3 +/- 0.4 [SD]). We propose that NIRS is a candidate, noninvasive method for assessing placental oxygen dynamics on a real-time basis. In the near future it may contribute to perinatal medical practice.

Olfactory receptors are G-protein coupled receptors and are encoded by an extremely large and diverse family of genes in mammals. There is increasing evidence that olfactory receptors are widely distributed in many organs, suggesting that olfactory receptors do not only recognize airborne odorants but also play important roles in chemotaxis or organ construction in embryo. In this study, we investigated whether olfactory receptors and their transduction molecule, Golf are expressed in the rat placenta. By RT-PCR, we identified 11 different olfactory receptor genes, which are all members of class II, in the rat placenta cDNAs, and our results suggested that particular members of the olfactory receptor gene family might be preferentially expressed in the placenta. By western blot analysis, we demonstrated that Golf protein is expressed in the placenta and its expression levels are developmentally regulated. We found that Golf immunoreactivity is exclusively localized to giant cell trophoblasts and spongiotrophoblast cells. These findings raised a possibility that a particular subset of olfactory receptors might be coupled with Golf and function in giant cell trophoblasts and spongiotrophoblast cells.

Near-infrared spectroscopy (NIRS) has been used as a noninvasive method for monitoring the real-time oxygenation status in areas such as the brain and striated muscle. Because the oxygenation status of the placenta is closely related to the fetal condition, monitoring placental oxygenation through the maternal abdomen is desirable. We performed transabdominal monitoring of oxygenation of the placenta by NIRS in 11 women. We improved the conventional probe of the NIRO 300 system (Hamamatsu Photonics KK, Hamamatsu, Japan) to obtain placental oxygenation data. With this probe, we succeeded in obtaining oxyhemoglobin and deoxyhemoglobin data through the maternal abdomen. We believe NIRS will prove to be useful for intrapartum monitoring.

Invasion of the trophoblast into the decidua and the myometrium is very important for the establishment of a normal pregnancy. This invasion is regulated by the expression of integrins in the trophoblast. Recently, it has been shown that invasion of the trophoblast is impaired in preeclampsia. We report the effect of hypoxia on the expression of integrins and extracellular matrices at the mRNA level in early placenta and BeWo cells. Tissue RNA levels of fibronectin and integrin alpha5 were significantly higher in the hypoxic condition than under normoxic conditions. In contrast, tissue RNA levels of integrin alpha1 were significantly lower for the hypoxic condition than those under normoxic conditions. Alteration of the integrin components and increases in fibronectin expression were observed in early placenta and BeWo cells under hypoxic conditions. These results suggest that hypoxic stress regulates the synthesis of integrin and fibronectin mRNAs in early placenta., (Copyright 2004 S. Karger AG, Basel)

Placentas of mice lacking p57(Kip2) expression have trophoblastic hyperplasia. To elucidate the mechanism underlying this phenomenon, we studied expression of two angiogenic factors, vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). Immunohistochemical analysis with anti-VEGF antibodies indicated that VEGF expression was stronger and more clearly detectable in placentas of p57(Kip2) null embryos compared to wild-type placentas. PlGF showed no significant differences between placentas of p57(Kip2) null and wild-type embryos. In quantitative analysis, placentas of p57(Kip2) null embryos showed higher VEGF messenger (m)RNA and protein levels than did wild-type placentas. PlGF mRNA and protein levels were not significantly different. These findings suggest that VEGF is involved in the hyperplasia that occurs in placentas of p57(Kip2) null embryos.

The aim of this study was to investigate the effect of local cold stress to the soles on placental histology in rats. Pregnant rats were subjected to a cold provocation (0 degrees C, 12 degrees C) and room temperature (23 degrees C) for 15 and 30 minutes. During cold stimulation and at the control temperature, uterine blood flow and uterine contraction were measured simultaneously. Histological studies of the placentas of these rats were also performed. Cold stress at 0 degrees C and 12 degrees C significantly decreased uterine blood flow (P < .005, P < .02) compared with controls (23 degrees C). The decrease in uterine blood flow was greater at 0 degrees C than at 12 degrees C stress. Cold-induced stress (0 degrees C) also evoked an isometric tension with increased frequency and amplitude in the rat uterus (P < .003, P < .0002) compared with controls (23 degrees C). Stimulation at 12 degrees C did not induce any uterine contractions. Placental histology of rats stressed at 0 degreesC revealed hemorrhages into the decidua basalis. These findings suggest that local cold stress decreases uterine blood flow and increases uterine contraction, resulting in retroplacental hemorrhage in rats. This model may account for human abruptio placentae.

We investigated the clinical significance of annexin V in the placentae with preeclampsia and found: (1) annexin V was detected on trophoblasts in the placentae and the staining intensity of annexin V in the placentae from such patients was reduced when compared to normal placentae; (2) as expression of annexin V was reduced, the gestosis index from patients with preeclampsia was elevated and the standard deviation value in the infant's standard weight was decreased; plasma level of the fibrin degradation products and thrombin-antithrombin III complex from patients were elevated as the expression of anexin V was reduced. These results suggest that the reduced expression of annexin V in the placentae from patients with preeclampsia may lead to a hypercoagulable state in the intervillous space and may be associated with the development of intrauterine growth restriction., (Copyright 2000 S. Karger AG, Basel)