Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation.

OBJECTIVE: This study was undertaken to determine whether preeclampsia and intrauterine growth retardation are associated with an increase in placental apoptosis. STUDY DESIGN: Tissue specimens from 7 normal term placentas and each of 7 term placentas complicated by severe preeclampsia or intrauterine growth retardation were analyzed. Fas antigen and Bcl-2 protein expression were examined by the avidin/biotin immunoperoxidase method, whereas apoptosis was assessed by the terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling (TUNEL) method and transmission electron microscopy. RESULTS: Fas antigen was immunolocalized in syncytiotrophoblasts in all placentas examined. No changes in the intensity of Fas antigen immunostaining in syncytiotrophoblasts were apparent among those placentas. Bcl-2 protein was abundantly immunolocalized in syncytiotrophoblasts in normal term placentas, but least abundant in term placentas complicated by severe preeclampsia or intrauterine growth retardation. Apoptosis was apparent in the nuclei of both cytotrophoblasts and syncytiotrophoblasts. The apoptosis positive rate of syncytiotrophoblast nuclei in severe preeclamptic and intrauterine growth retardation term placentas was significantly higher than that in normal term placentas (severe preeclampsia, P <.001; intrauterine growth retardation, P <.01). Transmission electron microscopy revealed the appearance of apoptotic nuclei in trophoblasts in severe preeclamptic term placenta. CONCLUSION: Decreased expression of Bcl-2 protein in syncytiotrophoblasts in severe preeclamptic and intrauterine growth retardation placentas may result in the increase in apoptosis in syncytiotrophoblasts in those placentas.     

Comparative analysis of the maternal and umbilical interleukin-8 levels in normal pregnancies and in pregnancies complicated by preeclampsia with intrauterine normal growth and intrauterine growth retardation

Objectives.?The aim of this study was to determine the maternal and umbilical cord serum levels of interleukin-8 (IL-8) in pregnancies complicated by preeclampsia with intrauterine normal growth and intrauterine growth retardation (IUGR), and in normotensive pregnancies.

Patients and methods.?The study was carried out on 15 patients with singleton pregnancies complicated by preeclampsia with appropriate for gestational age weight infants and 12 pregnant patients with preeclampsia complicated by IUGR. The control group consisted of 10 healthy normotensive delivering patients with singleton uncomplicated pregnancies. Maternal and umbilical serum IL-8 concentrations were estimated using the ELISA method.

Results.?There were no statistically significant differences in patient profiles between the groups. Systolic and diastolic blood pressure and mean arterial blood pressure were higher in the study groups in comparison with the control group. Lower birth weight and lower gestational age at birth were observed in the group of patients with preeclampsia complicated by IUGR. Increased maternal and umbilical serum levels of IL-8 were found in both preeclamptic patient groups in comparison with the control group. The umbilical cord blood concentrations of IL-8 in all groups of patients tended to be higher in comparison with the maternal blood.

Conclusions.?It seems that these higher IL-8 concentrations may be associated with apoptosis, inflammation, neutrophil activation, endothelial cell damage and dysfunction, and increased endothelial permeability. They may also participate in an attempt to compensate for the imbalanced apoptosis and vascular resistance. Our findings suggest a possible significant role of IL-8 in the pathogenesis and sequelae of preeclampsia, especially in preeclamptic pregnancies complicated by IUGR.     

Increased placental apoptosis in intrauterine growth restriction

OBJECTIVES: Our purpose was to investigate a possible role for apoptosis in the pathophysiologic mechanisms of intrauterine growth restriction. STUDY DESIGN: Placental samples were obtained from 43 uncomplicated third-trimester pregnancies and from 26 pregnancies complicated by intrauterine growth restriction. The definition used to identify cases of intrauterine growth restriction depended on three criteria: clinical evidence of suboptimal growth, ultrasonographic evidence of deviation from an appropriate growth percentile, and individualized birth weight ratios <10th percentile. Light microscopy was used to quantify the incidence of apoptosis. Electron microscopy and TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling) staining were used to confirm the occurrence of apoptosis. RESULTS: Quantification of apoptosis (medians and interquartile ranges) resulted in the following values: normal third trimester (n = 43) 0.14% of cells (0.08% to 0.20%) and intrauterine growth restriction third trimester (n  = 26) 0.24% of cells (0.16% to 0.29%). The incidence of apoptosis was significantly higher in placentas from pregnancies with intrauterine growth restriction compared with normal third-trimester placentas (p < 0.01, Mann Whitney U test). CONCLUSIONS: These results suggest that apoptosis may play a role in the pathophysiologic mechanisms of intrauterine growth restriction.(Am J Obstet Gynecol 1997;177:401)     

Evaluation of the maternal and umbilical vein serum sFas/sFasL system in pregnancies complicated by preeclampsia with intrauterine growth retardation

OBJECTIVE: The aim of this study was to determine the maternal and umbilical vein soluble Fas and its ligand (sFasL) serum levels in pregnancies complicated by preeclampsia with intrauterine growth retardation (IUGR). PATIENTS AND METHODS: The study was carried out on 11 preeclamptic delivering patients in the third trimester of pregnancy with severe preeclampsia complicated by intrauterine growth retardation. The control group consisted of 12 healthy normotensive delivering patients with singleton uncomplicated pregnancies, without any renal, heart and vascular diseases and with normal laboratory tests. Maternal and umbilical serum soluble Fas and FasL concentrations were estimated using a sandwich ELISA assay. RESULTS AND CONCLUSIONS: Increased maternal and umbilical vein serum sFas and increased umbilical vein serum sFasL levels were found in the study group in comparison with the control group. In our study in both groups of patient higher maternal sFas values were observed in comparison with the umbilical cord blood. Further studies are necessary to evaluate the role of Fas/FasL pathway in pregnancies complicated by preeclampsia and intrauterine growth retardation.     

Fetal blood flow in pregnancies complicated by intrauterine growth retardation

A noninvasive pulsed Doppler ultrasound technique was used to characterize blood flow in the descending thoracic aorta and the intra-abdominal part of the umbilical vein in 159 fetuses suspected of intrauterine growth retardation (IUGR) on the basis of ultrasound fetometry. From this group, 74 infants with IUGR (defined as gestational age-related birth weight of 2 standard deviations [SD] or more below the population mean) were born. The blood flow results were not available to the clinicians managing the pregnancies. Blood flow mean velocity in the fetal aorta was lower, pulsatility index and rising slope higher, and umbilical volume flow and umbilical flow per 100 g placental tissue were lower in the pregnancies with IUGR than in 21 normal pregnancies. The waveform of the maximum aortic velocity envelope was related to operative delivery for fetal distress, Apgar score, and umbilical cord blood pH. The pulsatility index and the configurational assessment of the diastolic part of the waveform were combined to form a new concept, the blood flow class. The blood flow class was abnormal in 57% of the fetuses classified as having IUGR at birth and in 93% of those growth-retarded fetuses who subsequently developed signs of fetal distress requiring operative delivery. Waveform analysis, in terms of blood flow class, seems to be a useful tool in the surveillance of fetuses when IUGR is suspected. Abnormal blood flow class is a marker of fetal distress and probably gives an earlier indication than antenatal nonstressed cardiotocography. The results of this study point to a strong association between IUGR and impaired fetal blood flow. The aortic volume blood flow, unlike waveform analysis, does not seem to be a variable sensitive enough to predict fetal outcome in the individual pregnancy.     

Expression of inflammatory cytokines in placentas from pregnancies complicated with preeclampsia and HELLP syndrome

Abstract

Objective: To investigate the expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) in villous trophoblast, syncytial knots and decidua placentas from pregnancies complicated with preeclampsia (PE), Hemolysis, Elevated Liver enzymes and Low Platelet count (HELLP) syndrome and gestational age-matched controls.

Methods: Study group included 35 placentas from pregnancies complicated with PE and 35 placentas from pregnancies with HELLP syndrome. Control group included 35 placentas from idiopathic preterm labor. Placentas were matched according to the gestational age. Expression of TNF-α, IL-6 and IL-10 was determined by immunohistochemistry and semi-quantitative HSCORE method in villous trophoblast, syncytial knots and decidua. Non-parametric statistics were used for analyses.

Results: There was no difference in the expression of TNF-α, IL-6 and IL-10 in all the studied placental segments between PE, HELLP and gestational age-matched control group. TNF-α (F?=?32, 41, p?<?0.001), IL-6 (F?=?58, 53, p?<?0.001) and IL-10 (F?=?17, 62, p?<?0.001) expression was significantly different in different placental cell types, the highest expression of cytokines was in decidua.

Conclusion: There was no difference in cytokine expression in villous trophoblast, syncytial knots and decidua among the studied placental groups. The expression of cytokines was highest in decidua in all the studied placental groups.     

Essential fatty acids in pregnancies complicated by intrauterine growth retardation.

The relative fatty acid composition of lecithin was measured in maternal and cord blood serum in human pregnancies at risk for intrauterine growth retardation (IUGR) (n = 28) as compared to controls (n = 20). In the IUGR cases (n = 13) linoleic acid was lower in maternal samples but higher in cord blood, oleic acid was elevated in both whereas docosohexaenoic acid was lower. Essential fatty acid composition of lecithin was found to be different in IUGR.     

Fas and FasL expression in placentas complicated with intrauterine growth retardation with and without preeclampsia

Objective: To compare the level of Fas and FasL immunohistochemical expression in villous trophoblast (VT), extravillous trophoblast (EVT) cells, decidual cells (DC), endothelial cells (EC) of villous blood vessels and spiral arteries between the study groups of intrauterine growth retardation (IUGR) placentas with and without preeclampsia (PE).

Methods: The study included 17 placentas from pregnancies complicated by IUGR?+?PE and 17 placentas from pregnancies complicated by idiopathic IUGR (I-IUGR). Seventeen placentas from normal pregnancies served as a control group. CD31 was used to detect endothelial cells (EC). Immunohistochemical expression of Fas and FasL was assessed in all examined parts of placenta using the semi-quantitative HSCORE method.

Results: FasL expression was significantly higher in all examined parts of placenta in I-IUGR as compared to IUGR?+?PE and control group. Placentas with IUGR?+?PE had the significantly lowest expression of FasL in VT and EC of villi vessels. Expression of Fas did not differ significantly between the study groups.

Conclusion: Different expression of FasL in placentas from I-IUGR and IUGR?+?PE suggests that FasL probably has a different role in the etiology of these two syndromes.     

Expression of EGF,EGFR, and proliferation in placentas from pregnancies complicated with preeclampsia

Objective: To investigate proliferation, EGF and EGFR expression of villous trophoblast (VTB), decidual cells (DC), and extravillous trophoblast (EVTB) in the placentas from pregnancies complicated with preeclampsia (PE) and to compare them with placentas from normal pregnancies. Methods: Twenty-nine PE placentas and 19 control placentas were studied for EGF and EGFR immunohistochemical expression (noted as week, moderate or strong). Proliferation was expressed as the proliferation index. The CK7 antibody was used to distinguish DC from EVTB. Results: DC and EVTB proliferation was significantly higher in PE placentas. EGFR and EGF expression showed no significant difference. Conclusion: Higher DC and EVTB proliferation in PE could contribute to PE development.     

A piece in the puzzle of intrauterine fetal death: Pathological findings in placentas from term and preterm intrauterine fetal death pregnancies

Objective.?To compare pathological findings of placentas from term and preterm pregnancies complicated by intrauterine fetal death (IUFD).

Study design.?A retrospective cohort study was conducted including deliveries complicated by IUFD. A comparison was made between placentas from term and preterm (<37 weeks' gestation) pregnancies complicated by IUFD. A second analysis was undertaken comparing IUFD placentas delivered before and after 34 weeks' gestation. Uteroplacental insufficiency was defined when one or more of the following pathological features were found: placental infarct, poor vascularity of the chorionic villi, intravascular thrombi and vascular occlusion.

Results.?During the study period, 849 placentas of IUFD were examined. Gross and microscopic pathological finding were noted. When comparing gross and microscopic findings in term and preterm (<37 weeks) IUFD placentas, higher rates of calcifications, tissue congestion and cellular metaplasia were found in term vs. preterm placentas. Significantly increased rates of poor tissue vascularity, placental vascular occlusion and uteroplacental insufficiency were demonstrated in preterm IUFD placentas. When comparing pathological findings in IUFD placentas delivered before and after 34 weeks' gestation, higher rates of abnormal cord insertion, calcifications, tissue congestion, infarcts and intravascular thrombi as well as poor tissue vascularity and placental vascular occlusion were demonstrated in IUFD placentas delivered before 34 weeks. Regardless of gestational age at the time of IUFD in more than 90% of placentas vascular wall thickening was found. A third of both term and preterm placentas demonstrated histological chorioamionitis.

Conclusions.?A vast majority of IUFD placentas reveal numerous pathological findings that reflect uteroplacental insufficiency and abnormal blood supply. Different characteristics were noted in term and preterm placentas of pregnancies complicated by IUFD. Better definition of causes and associated placental pathological findings of IUFD might aid clinicians in counseling such patients regarding the reason and risk of recurrence in subsequent pregnancies.     

Expression of low density lipoprotein receptor messenger ribonuclein acid in placentas from pregnancies with preterm delivery and pregnancies with intrauterine growth retardation

The low density lipoprotein receptor plays an important role in the uptake of maternal plasma lipoproteins for placental steroid metabolism. Using an RNase protection assay, the expression of low density lipoprotein receptor mRNA was measured in human placentas from pregnancies in the second and third trimester and from pregnancies with intrauterine growth retardation. Pregnancies complicated by intrauterine growth retardation showed a significantly higher expression (1–28), compared with the term and preterm pregnancies (   P < 0.05  ). The increased low density lipoprotein receptor expression in placentas from pregnancies with intrauterine growth retardation could be a compensatory mechanism for the lower circulating low density lipoprotein concentrations in women with intrauterine growth retardation.     

Fetal movements and intrauterine growth retardation

Fetal Movement (FM) rate was evaluated in cases of symmetrical and asymmetrical intrauterine growth retardation (IUGR) and was compared to the FM rate in normal pregnancy. In the 25–36th week of gestation there was a significant decrease of FM rate in both groups of IUGR which was more pronounced in the symmetrical group. Also shown, was a gradual trend of increase of the FM rate with advancing gestational age in both groups of IUGR. Cases of asymmetrical IUGR were noted, who had markedly decreased FM until cessation. In this group of IUGR decreased FM demands prompt hospitalization and fetal heart rate monitoring so that possible respiratory failure and impending fetal death can be detected.     

Expression of low density lipoprotein receptor messenger ribonucleic acid in placentas from pregnancies with intrauterine growth retardation.

The low density lipoprotein receptor plays an important role in the uptake of maternal plasma lipoproteins for placental steroid metabolism. Using an RNase protection assay, the expression of low density lipoprotein receptor mRNA was measured in human placentas from pregnancies in the second and third trimester and from pregnancies with intrauterine growth retardation. Pregnancies complicated by intrauterine growth retardation showed a significantly higher expression (1.28), compared with the term and preterm pregnancies (P < 0.05). The increased low density lipoprotein receptor expression in placentas from pregnancies with intrauterine growth retardation could be a compensatory mechanism for the lower circulating low density lipoprotein concentrations in women with intrauterine growth retardation.     

Morphological characteristics of placentas associated with idiopathic intrauterine growth retardation: a clinicopathologic study

Objectives

To investigate histopathologic findings, placental diameters and characteristics of syncytial knots in the placentas from idiopathic intrauterine growth retardation (IUGR) pregnancies, and to compare them with a normal birth weight group.

Study design

Based on strict eligibility criteria, this prospective case-control study included 52 term placentas from idiopathic IUGR pregnancies and 69 term placentas from normal birth weight pregnancies. The study was carried out at the Clinical Hospital Centre, Split, where all placentas were collected and examined. For each placenta, diameters were measured and the following histopathologic findings were recorded: infarction, intervillous thrombosis, abruption, villous branching and maturation, chorioamnionitis, decidual vasculopathy and hemorrhagic endovasculitis for each placenta. In addition we assessed quantitative (number of syncytial knots and number of syncytial nuclei per syncytial knot) and qualitative (density and surface area) characteristics of syncytial knots in each placental sample. Statistical significance was tested using χ²-test, Student's t-test and Mann-Whitney U-test. Statistical significance was set at P ≤ 0.05.

Results

There was no difference in investigated histopathologic findings between idiopathic IUGR placentas and control group placentas. Placental diameters correlated significantly with neonatal birth weight (r = 0.64; P < 0.01); with higher birth weight there is an increase in placental diameters. Syncytial knots from idiopathic IUGR had significantly smaller surface area (Z = 2.637; P = 0.008) and higher density (Z = 3.225; P = 0.001) compared with the control group, while there is no difference in number of syncytial knots per individual villus, total number of syncytial knots in each placenta sample or number of syncytial nuclei per syncytial knot.

Conclusions

The investigated histopathologic findings in idiopathic IUGR placentas are incidental, with no higher frequency than in placentas from uncomplicated pregnancies, and should not be considered as possible causative factors for idiopathic IUGR. The demonstrated qualitative changes of syncytial knots in placentas associated with IUGR could represent a compensatory mechanism.