Health implications resulting from the timing of elective cesarean delivery

<p>Abstract</p> <p>Background</p> <p>The literature is nearly unanimous in recommending elective cesarean delivery at 39 weeks of gestation because of the lower rates of neonatal respiratory complications compared to 38 weeks. However, elective cesarean delivery at 39 weeks or more may have maternal and other fetal consequences compared to delivery at 38 weeks, which are not always addressed in these studies.</p> <p>Discussion</p> <p>Between 38 and 39 weeks of gestation, approximately 10% - 14% of women go into spontaneous labor; meaning that a considerable number of women scheduled for an elective cesarean delivery at 39 weeks will deliver earlier in an unscheduled, frequently emergency, cesarean delivery. The incidence of maternal morbidity and mortality is higher among women undergoing non-elective cesarean deliveries than among those undergoing elective ones. Complications may be greater among women after numerous repeat cesarean deliveries and among older women. Other than reducing the frequency of non-elective cesarean deliveries, bringing forward the timing of elective cesarean delivery to 38 weeks, may occasionally prevent intrauterine fetal demise which has been shown to increase with increasing gestational age and to avoid other fetal consequences related to the emergency delivery. All these considerations need to be weighed against the medical and the economic impact of the increase in neonatal morbidity resulting from births at 38 weeks compared to 39 weeks.</p> <p>Summary</p> <p>Until prospective randomized trials are conducted, we are unlikely to be able to precisely answer all risk:benefit questions as to the best timing of scheduled elective cesarean delivery. Older women, and women with numerous prior cesarean deliveries, are of particular concern. It is reasonable to inform the pregnant women of the risk of each of the above options and to respect her autonomy and decision-making.</p

Human trophoblast function during the implantation process

The implantation process involves complex and synchronized molecular and cellular events between the uterus and the implanting embryo. These events are regulated by paracrine and autocrine factors. Trophoblast invasion and migration through the uterine wall is mediated by molecular and cellular interactions, controlled by the trophoblast and the maternal microenvironment. This review is focused on the molecular constituents of the human trophoblast, their actions and interactions, including interrelations with the uterine endometrium

Progesterone receptor A and c-Met mediates spheroids-endometrium attachment

<p>Abstract</p> <p>Background</p> <p>Implantation in humans involves cross talk between an active blastocyst and receptive endometrium. The role of the endometrial receptors in this complex embryo-maternal interaction is still unclear. We tested gene and protein expression of endometrial receptors (Progesterone receptor (PR) and c-Met) and the effect of theses receptors in endometrial receptivity.</p> <p>Methods</p> <p>Two endometrial cell lines were used: HEC-1A and RL95-2 considered as being of low and high receptivity, respectively. Western blot and RT-PCR analysis were utilized to study the receptor expression profile.</p> <p>The role of endometrial receptors in endometrial receptivity was studied by attachment and invasion assays of JAR spheroids (made of a trophoblast cell line) on endometrial cells. Different manipulations of inhibition and stimulation of the endometrial receptors were used including: inhibition by specific antibodies against the receptors, or antagonist of the receptors, as well as transfection with antisense for the endometrial receptors, stimulation by specific ligands for the receptors and transfection with the gene for endometrial receptors.</p> <p>Results</p> <p>Different protein expression patterns of endometrial receptors were observed between the tested endometrial cell lines. The expression levels of PRA ratio to PRB, and the 50 kDa c-MET isoform were significantly lower in HEC-1A as compared with RL95-2. Attachment rates and growth of JAR spheroids into HEC-1A were significantly lower as compared with RL95-2. Stimulation of PR with progesterone altered attachment rates to HEC-1A. Inhibition of PR with RU-486 mildly increased attachment rate to HEC-1A whereas it slightly decreased attachment rate to RL95-2. c-Met inhibition decreased attachment rates only to HEC-1A cells that expressing high levels of Plexin-B1 (PB1). Immunoprecipitation studies revealed that c-Met and PB1 associate in complexes in the endometrial cell lines.</p> <p>Conclusion</p> <p>Differential endometrial receptor profiles are expressed during the receptivity period. The attachment and invasion processes are separately regulated. We suggest a biologically functional role for PRA in endometrial receptivity and in the attachment process. c-Met contribution is minor and related with creation of a complex with PB1.</p

Semaphorin-4D (Sema-4D), the Plexin-B1 ligand, is involved in mouse ovary follicular development

BACKGROUND: Human Plexin-B1 is expressed in two truncated forms. The long form encodes a trans-membranal protein, while the short form, which is bound to the cell surface and partially secreted, possibly serves as a decoy receptor. Plexin receptors are trans-membrane proteins. The sema domain, found in the extracellular region, is common to all plexins, semaphorins, and the scatter factor receptors and is crucial for the biological activity and plexin receptor specificity. Semaphorin-4D/Plexin-B1 binding provides attractive and repulsive cues for the navigation of axonal growth cones, and new studies suggest that this system also plays a role in the regulation of the biological functions of endothelial cells, specifically in the control of angiogenesis. In a previous study, we have demonstrated the expression and possible role of Plexin-B1 in the mouse ovary. The present study was designed to test the hypothesis that Plexin-B1 effects are mediated by Semaphorin-4D. METHODS: In vivo expression and localization of mouse ovarian Sema-4D were tested by immunohisto-chemistry. The role of Sema-4D in follicular development was examined by in vitro growth of preantral follicles in the presence or absence of Semaphorin-4D, with or without neutralizing antibodies against Plexin-B1. Follicular growth and steroid hormone secretion rates were tested. RESULTS: Semaphorin-4D is expressed in the mouse ovary in vivo mostly in the granulosa cells and and its expression is modulated by PMSG and hCG. In the presence of Semaphorin-4D, in-vitro constant growth was observed as indicated by follicular diameter during the culture period and elevated steroid hormone secretion rates compared with control. These effects were abolished after addition of neutralizing antibodies against Plexin-B1. CONCLUSION: In the ovarian follicle, the effect of Plexin-B1 is mediated by sema-4D

Mechanisms of matrix metalloproteinase-2 (mmp-2) transcriptional repression by progesterone in jar choriocarcinoma cells

<p>Abstract</p> <p>Background</p> <p>Although the MMP-2 promoter lacks a canonical progesterone response element (PRE), the hormone inhibits MMP-2 expression and is part of treatment protocols in gynecological invasive pathologies, including endometriosis and endometrial hyperplasia. This study aimed to explore the mechanism by which progesterone inhibits MMP-2 expression.</p> <p>Methods</p> <p>The effect of progesterone on MMP-2 expression in the JAR human choriocarcinoma cell line was analyzed by gelatin zymography. MMP-2 transcript expression was studied using Northern blot and semi-quantitative RT-PCR. Rat promoter deletion analysis, electrophoretic mobility shift and chromatin immuno-precipitation assays were performed in order to locate the DNA binding site and the transcription factors involved in MMP-2 regulation.</p> <p>Results</p> <p>Progesterone significantly decreased secretion of pro-MMP-2 and MMP-2 transcript expression level in a dose-dependent manner. Progesterone (1 microM) significantly decreased both human and rat MMP-2 promoter activity (80.1% +/- 0.3 and 81.3% +/- 0.23, respectively). Progesterone acts through the SP1 family transcription factors-binding site, located between -1433 and -1342 bp region from the transcriptional start site of the rat MMP-2 promoter, which are present in the orthologous human MMP-2 promoter. Progesterone receptor (PR), SP2, SP3 and SP4 proteins are constitutively bound to this consensus sequence.</p> <p>Conclusion</p> <p>Progesterone reducesPR and SP4 binding to the MMP-2 promoter, thereby suppressing transcription. Progesterone also promotes SP4 degradation. These novel mechanisms of MMP-2 regulation by progesterone provide the biological rationale for the use of progesterone in clinical settings associated with increased MMP-2 expression.</p

Ets-2 and p53 mediate cAMP-induced MMP-2 expression, activity and trophoblast invasion

<p>Abstract</p> <p>Background</p> <p>We have previously shown that Matrix metalloproteinase (MMP) -2 is a key-enzyme in early trophoblast invasion and that Protein Kinase A (PKA) increases MMP-2 expression and trophoblast invasion. The aim of this study was to examine MMP -2 regulation by PKA in invasive trophoblasts: JAR choriocarcinoma cell-line and 6-8 w first trimester trophoblasts.</p> <p>Methods</p> <p>The effect of Forskolin (PKA) on MMP-2 expression was assessed by Northern Blot and RT-PCR. Possible transcription factors binding to consensus MMP-2 promoter sequences in response to Forskolin, were detected by EMSA binding assay and their expression assessed by western blot analysis. Antisense transfection of relevant transcription factors was performed and the inhibitory effect assessed on MMP-2 expression (RT-PCR), secretion (zymography) and trophoblast invasiveness (transwell migration assay).</p> <p>Results</p> <p>We found that Forskolin increased MMP-2 mRNA in JAR cells within 24 hours, and induced binding to p53, Ets, C/EBP and AP-2. Transcription factors Ets-2, phospho- p53, C/EBP epsilon, C/EBP lambda and AP-2 alpha bound to their respective binding sequences in response to Forskolin and the expressions of these transcription factors were all elevated in Forskolin- treated cells. Inhibition of Ets-2 and p53 reduced MMP-2 expression, secretion and invasiveness of Forskolin treated cells.</p> <p>Conclusion</p> <p>MMP-2 is regulated by PKA through several binding sites and transcription factors including Ets-2, p53, C/EBP, C/EBP lambda and AP-2 alpha. Ets-2 and p53 mediate cAMP- induced trophoblast invasiveness, through regulation of MMP-2.</p

Plexin-B1, glycodelin and MMP7 expression in the human fallopian tube and in the endometrium

<p>Abstract</p> <p>Background</p> <p>To study the expression of Plexin-B1, Glycodelin, and MMP7 during the menstrual cycle in the endometrium and in the fallopian tube.</p> <p>Methods</p> <p>The research included women undergoing hysterectomy, tubal sterilization or salpingo-oophoerectomy. Total RNA from endometrial and fallopian tube tissues was extracted using a total RNA isolation kit. Semi-quantitative RT-PCR was performed to examine mRNA relative expression.</p> <p>Results</p> <p>Plexin-B1 expression in the endometrium was significantly higher on days 19 - 23 compared to days 12 - 14 (1.166 +/- 0.42 versus 0.523 +/- 0.299), P < 0.005. In the fallopian tube the level of plexin-B1 did not change significantly throughout the menstrual cycle. Glycodelin expression was significantly higher on days 19 - 23 compared with days 12-14, both in the endometrium (0.819 +/- 0.564 versus 0.072 +/- 0.343, P < 0.05) and the fallopian tube (0.796 +/- 0.196 versus 0.329 +/- 0.398, P < 0.05). Although the level of MMP7 secretion was the highest in the secretory phase the difference from the proliferative phase did not reach statistical significance, neither in the endometrium nor in the fallopian tube. This could result from a lack of power.</p> <p>Conclusions</p> <p>In the endometrium, both Glycodelin and Plexin-B1 are exhibiting a cyclic pattern suggesting a possible steroid regulation and a role in endometrial receptivity.</p

The impact of non-significant variable decelerations appearing in the latent phase on delivery mode: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Variable decelerations are the most frequent fetal heart rate changes that are related to labor. The objective of the study was to estimate the impact of non-significant variable decelerations (NSV) appearing during the latent phase of labor on delivery mode and neonatal outcome.</p> <p>Methods</p> <p>Women at term, who were in the latent phase of labor and had a singleton pregnancy, were prospectively included. Women were divided into three groups. All had a fetal heart rate tracing with normal baseline and variability. The study group was composed of women who had in addition NSV, Category II, according to the National Institute of Child Health and Human Development categorization system. Women who had Category I tracings composed the control group. Women who had non-repetitive severe variables (SV) composed a second control group (Category II-SV). Main outcome compared was mode of delivery. Secondary outcome was cord pH. One-way analysis of variance was used to compare the continuous demographic and clinical variables of the three groups. Backwards stepwise logistic regression using significant univariables was performed to determine which predicted operative delivery. P < 0.05 was considered significant.</p> <p>Results</p> <p>Of 1005 women who delivered during the study period 186 had Category II- NSV tracings (study group), 76 had Category II-SV and 251 had Category I tracings. Mode of delivery and indications for operative delivery were similar between women in Category II-NSV compared to Category I. In addition mean cord pH did not differ between the two groups. Conversely, women in Category II-SV, had a higher rate of cesarean or vacuum deliveries compared to the other groups (p = 0.0001). Beside, they had a significantly higher number of neonates born with cord pH between 7.0 to 7.1 (p = 0.03).</p> <p>Conclusions</p> <p>Non-significant variable decelerations in early stages of labor are probably a non-ominous sign for neonatal outcome and have no impact on delivery mode.</p

Expression and importance of matrix metalloproteinase 2 and 9 (MMP-2 and -9) in human trophoblast invasion

BACKGROUND: The aim of this study was to examine the invasiveness of first trimester trophoblasts according to the secretion profile of MMP-2 and -9 at different gestational stages, and to test the similarity between primary trophoblast cell-culture and the JAR choriocarcinoma cell-line. METHODS: First trimester trophoblasts were divided into two groups: 6–8 weeks (early) and 9–12 w (late) of gestation. The two trophoblast groups and JAR cells were cultured in medium, with various concentrations of forskolin and Epidermal Growth Factor (EGF). Proteolytic activity was detected by zymography and invasiveness was assessed by Matrigel invasion assay. Student's T-test was used for statistical analysis. RESULTS: In 6–8 w trophoblast, proMMP-2 was only slightly dominant over proMMP-9 (53.2% vs. 46.8% respectively), whereas in 9–12 w, proMMP-9 was clearly dominant over proMMP-2 (61.7% vs.38.3% respectively). In JAR cells proMMP-2 was strongly dominant (90.2% vs.9.8% respectively). In JAR cells forskolin significantly increased proMMP-2 and -9 secretion (128.5% +/- 12 and 183.2% +/- 27.9 of control, respectively). EGF had a dual effect on JAR cells: at 8 ng/ml both proMMP-2 and -9 were increased (133.5% +/-15 and 223.9% +/- 32.4 of control, respectively) while at 80 ng/ml both proMMP-2 and -9 were decreased (65.1% +/- 18.3 and 66.6% +/- 37 of control, respectively). Forskolin significantly increased both proMMP-2 and -9 secretion in 6–8 w and 9–12 w trophoblasts (125.9% +/- 6.3,128.4% +/- 6.4; 169.7% +/- 20.3, 120.3% +/- 4.5 of control, respectively). EGF also significantly increased both proMMP-2 and -9 secretion in 6–8 w and 9–12 w trophoblasts (141.22% +/- 14.8, 138.8% +/- 10.3; 168.3% +/- 18.2, 117.3 +/- 3.8 of control, respectively). Both forskolin and EGF increased trophoblast cells invasiveness in all groups. The invasive ability of trophoblast cells, induced by forskolin, was reduced by MMP-2 antibody in: JAR cells, 6–8 w and 9–12 w trophoblasts. Likewise trophoblast invasion induced by EGF was reduced by MMP-2 antibody in all groups. However the invasive ability induced by forskolin or EGF was inhibited by MMP-9 antibody only in trophoblasts from 9–12 w. CONCLUSIONS: First trimester trophoblasts express differential gelatinase secretion profile according to the gestational week. In JAR and early trophoblasts (6–8 w) MMP-2 is the main gelatinase and the key enzyme in trophoblast invasion. Thereafter in late first trimester trophoblasts (9–12 w), both MMP-2 and -9 participate in trophoblast invasion

Matrix metalloproteinase-2 is elevated in midtrimester amniotic fluid prior to the development of preeclampsia

<p>Abstract</p> <p>Objective</p> <p>To evaluate levels of matrix metalloproteinases (MMP) and their inhibitors (TIMP) in second trimester amniotic fluid of women with hypertensive disorders compared to normotensive women.</p> <p>Study Design</p> <p>Amniotic fluid was obtained from 133 women undergoing genetic second trimester amniocentesis. Zymography was performed for MMP characterization and an MMP-2 ELISA kit was used to determine MMP-2 levels. TIMP-2 expression was evaluated using western blot.</p> <p>Results</p> <p>Mean amniotic fluid MMP-2 and TIMP-2 levels were significantly higher in women who developed a hypertensive disorder compared to normotensive women (P < 0.0004 and P < 0.01, respectively). When subdivided into subgroups, amniotic fluid from women who eventually developed preeclampsia or superimposed preeclampsia showed significantly higher MMP-2 levels than normotensive women (P < 0.05). However, no statistical difference in MMP-2 levels was found between patients with gestational hypertension and normotensive patients.</p> <p>Conclusion</p> <p>Higher amniotic fluid MMP-2 and TIMP-2 levels are found in women who eventually develop preeclampsia.</p