Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset.

Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 × 10-40, N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 × 10-7, N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies.

The potential contribution of stromal cell-derived factor 2 (SDF2) in endoplasmic reticulum stress response in severe preeclampsia and labor-onset.

Endoplasmic reticulum (ER) stress occurs when the protein folding machinery in the cell is unable to cope with newly synthesized proteins, which results in an accumulation of misfolded proteins in the ER lumen. In response, the cell activates a cellular signaling pathway known as the Unfolded Protein Response (UPR), aiming to restore cellular homeostasis. Activation and exacerbation of the UPR have been described in several human pathologies, including cancer and neurological disorders, and in some gestational diseases such as preeclampsia and gestational diabetes. This review explores the participation of stromal cell-derived factor 2 (SDF2) in UPR pathways, shows new information and discusses its exacerbation regarding protein expression in severe preeclampsia and labor, both of which are associated with ER stress.

RKIP is decreased in laboring myometrium and modulates inflammation-induced pro-labor mediators.

Nuclear factor-kappa B (NF-κB)-induced inflammation plays a central role in the terminal process of human labor and delivery. Our previous studies show that IL1B induces NF-κB signaling through extracellular signal-regulated kinase (ERK; official gene symbol MAPK1), whereas TNF induces NF-κB-driven transcription of pro-labor mediators via an MAPK1-independent mechanism. Raf kinase inhibitor protein (RKIP) negatively regulates inflammation by inhibiting NF-κB activation directly or indirectly by inhibiting MAPK1. The role of RKIP in the processes of human labor and delivery is not known. The present study was performed to investigate the expression of RKIP in laboring and non-laboring human myometrium and determine the effect of siRNA knockdown of RKIP (siRKIP) on pro-labor mediators in human myometrial primary cells. Term labor was associated with a decrease in RKIP expression. Furthermore, RKIP expression was decreased in myometrial cells treated with IL1B and TNF, two likely factors contributing to preterm birth. The effect of siRKIP in primary myometrial cells was a significant augmentation of IL1B- and TNF-induced CXCL1 and CXCL8 mRNA abundance and secretion; PTGS2 mRNA levels and prostaglandin PGF2α release and MMP9 mRNA abundance and pro-MMP9 secretion. There was no effect of siRKIP on MAPK1 activation. On the other hand, RKIP knockdown was associated with increased activation of NF-κB RELA in the presence of IL1B and TNF. In conclusion, in human primary myometrial cells, RKIP negatively regulates IL1B- and TNF-induced expression and or secretion of pro-inflammatory and pro-labor mediators by inhibiting NF-κB RELA activation.

SLIT3 is increased in supracervical human foetal membranes and in labouring myometrium and regulates pro-inflammatory mediators.

PROBLEM: Inflammation is associated with preterm birth, a worldwide healthcare issue. SLIT3 has a role in inflammation, and thus, the purpose of this study was to determine the effect of SLIT3 on labour mediators in human gestational tissues. METHOD OF STUDY: SLIT3 protein expression was performed using immunohistochemistry in foetal membranes and myometrium with no labour and after labour. Foetal membranes were also obtained from a distal site (DS) and supracervical site (overlying the cervix; SCS). SLIT3 gene silencing was achieved using siRNA in primary amnion and myometrial cells. Pro-inflammatory and pro-labour mediators were evaluated by qRT-PCR, ELISA and gelatin zymography. RESULTS: SLIT3 expression was greater in foetal membranes from the SCS compared with DS and in myometrium after term spontaneous labour onset. SLIT3 siRNA in primary amnion and myometrial cells decreased IL-1ß-induced pro-inflammatory cytokine gene expression and release (IL-6 and IL-8) and MMP-9 gene expression and release. In amnion cells, SLIT3 siRNA knockdown decreased IL-1ß-induced COX-2 expression and prostaglandin PGE2 release. There was no effect of SLIT3 siRNA on IL-1ß-induced NF-κB transcriptional activity. CONCLUSION: Our results demonstrate that SLIT3 is increased with labour, and both our amnion and our myometrial studies describe a pro-inflammatory effect of SLIT3 in these tissues.

Expression of tumor necrosis factor-alpha and vascular endothelial growth factor in different zones of fetal membranes: a possible relation to onset of labor.

This study aimed to explore whether the altered expression of tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF) and apoptotic changes in mid zone (MZ) and rupture zone (RZ) of fetal membranes (FM) are regulatory mechanisms associated with labor at term. Fifteen FM specimens were collected after vaginal deliveries and 13 specimens after elective caesarian section. Histological and immunohistochemical analysis were employed. Area percent of TNF-α and VEGF immunostaining and apoptotic index (AI) were evaluated using image analysis. The statistical data revealed significantly higher area % for TNF-α, VEGF immunoexpression and AI in labor compared to non-labor specimens (p < 0.0001). There was a significantly higher percentage of TNF-α immunoexpressed area in MZ compared with RZ in both groups (p < 0.0001). VEGF expression in RZ of both groups proved nearly double or triple the area % of expression relative to MZ with highly significant difference (p < 0.0001). quantitative analysis revealed near two fold increase in the AI in RZ (13.42% ± 1.2 in labor; 11.20% ± 0.96 in non-labor groups) when compared to MZ (7.20% ± 0.6 in labor; 5.08% ± 0.76 in non-labor groups) with highly significant zonal difference (p < 0.0001). Correlation analysis revealed significant correlation between apoptotic indices and area % of TNF-α (r = 0.575, p = 0.002 in non-labor; r = 0.652, p < 0.0001 in labor) and VEGF (r = 0.795, p < 0.0001 in non-labor; r = 0.668, p < 0.0001 in labor). In conclusion, Apoptosis may be regulated by TNF-α and VEGF expression in FM at labor. MZ is a step back from RZ and could participate actively in rupture of the FM during labor. TNF-α and VEGF increase with onset of labor and differentially expressed in the RZ and the MZ. These findings call for further study with tissue cultures or animal models.

Is vitamin D binding protein a novel predictor of labour?

Vitamin D binding protein (VDBP) has previously been identified in the amniotic fluid and cervicovaginal fluid (CVF) of pregnant women. The biological functions of VDBP include acting as a carrier protein for vitamin D metabolites, the clearance of actin that is released during tissue injury and the augmentation of the pro-inflammatory response. This longitudinal observational study was conducted on 221 healthy pregnant women who spontaneously laboured and delivered either at term or preterm. Serial CVF samples were collected and VDBP was measured by ELISA. Binary logistic regression analysis was performed to assess the utility of VDBP as a predictor of labour. VDBP in the CVF did not change between 20 and 35 weeks' gestation. VDBP measured in-labour was significantly increased 4.2 to 7.4-fold compared to 4-7, 8-14 and 15-28 days before labour (P<0.05). VDBP concentration was 4.3-fold significantly higher at 0-3 days compared to 15-28 days pre-labour (P<0.05). The efficacy of VDBP to predict spontaneous labour onset within 3 days provided a positive and negative predictive value of 82.8% and 95.3% respectively (area under receiver operator characteristic curve  = 0.974). This longitudinal study of pregnant women suggests that VDBP in the CVF may be a useful predictor of labour.

Early onset pre-eclampsia is associated with altered DNA methylation of cortisol-signalling and steroidogenic genes in the placenta.

Placental cortisol is inactivated in normotensive pregnancies, but is frequently present in pre-eclampsia associated placentae. Since glucocorticoids are strongly associated with the programming of long-term health, we assessed DNA methylation of genes involved in cortisol signalling and bioavailability, and hormonal signalling in the placenta of normotensive and hypertensive pregnancies. Candidate genes/CpG sites were selected through analysis of Illumina Infinium HumanMethylation450 BeadChip array data on control (n = 19) and early onset pre-eclampsia (EOPET; n = 19) placental samples. DNA methylation was further quantified by bisulfite pyrosequencing in a larger cohort of control (n = 111) cases, in addition to EOPET (n = 19), late onset pre-eclampsia (LOPET; n = 18) and normotensive intrauterine growth restriction (nIUGR; n = 13) cases. DNA methylation (percentage points) was increased at CpG sites within genes encoding the glucocorticoid receptor (NR3C1 exon 1D promoter; +8.46%; P<0.01) and corticotropin releasing hormone (CRH) binding protein (CRHBP intron 3; +9.14%; P<0.05), and decreased within CRH (5' UTR; -4.30%; P = 0.11) in EOPET-associated placentae, but not in LOPET nor nIUGR cases, compared to controls. Differential DNA methylation was not observed among groups at the 11ß-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene promoter. Significant hypomethylation was observed in pre-eclampsia but not nIUGR placentae for steroidogenic genes, including CYP11A1 (exon1; EOPET; -9.66%; P<0.00001, and LOPET; -5.77%; P<0.001), 3ß-hydroxy-delta-5-steroid dehydrogenase type 1 (HSD3B1 exon 2; EOPET; -12.49%; P<0.00001, and LOPET; -6.88%; P<0.001), TEA domain family member 3 (TEAD3 intron 1; EOPET; -12.56%; P<0.00001) and CYP19 (placental-specific exon 1.1 promoter; EOPET; -10.62%, P<0.0001). These data represent dysregulation of the placental epigenome in pre-eclampsia related to genes involved in maintaining the hormonal environment during pregnancy and highlights particular susceptibility in the early onset syndrome.

Differential proteolysis of insulin-like growth factor binding protein-1 (IGFBP-1) in pregnancy.

The insulin-like growth factors and their binding proteins are important for placental and foetal growth. In this study, we have investigated the presence of proteolytic activity directed against insulin-like growth factor binding protein-1 (IGFBP-1) in pregnancy. In addition, the effect of protease activity on IGFBP-1 immunoreactivity and IGF binding was characterised. 125I-IGFBP-1 was incubated with maternal and foetal serum, amniotic fluid and placental extracts. Breakdown of 125I-IGFBP-1 was determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and autoradiography. The size distribution of endogenous IGFBP-1 was determined by Western immunoblotting. Protease inhibitor studies characterised the proteolytic activity, and Western ligand blotting with 125I-IGF-I was used to determine IGF binding capacity of proteolysed IGFBP-1. Amniotic fluid samples collected after labour onset contained proteolytic activity that generated 12- and 19-kDa IGFBP-1 fragments that did not bind to 125I-IGF-I. This activity was not detected in amniotic fluid collected prior to labour onset or in other tissues. Activity was blocked by aprotinin, leupeptin, phenyl methyl sulphonyl fluoride, and Kunitz soybean trypsin inhibitor but not by ethylene diamine tetraacetic acid or pepstatin. Incubation of IGFBP-1 with trypsin generated fragments of a similar size to the amniotic fluid protease. In conclusion, we have demonstrated the presence in vivo of a trypsin-like proteolytic activity that alters the IGF-binding function of IGFBP-1 in pregnancy.

Labour induction at term: clinical, biophysical and molecular predictive factors.

PURPOSE: The aim of this multicentric study is to compare clinical, biophysical and molecular parameters in the prediction of the success of labour induction with prostaglandins. METHODS: We included 115 women, who underwent to labour induction at term with vaginal prostaglandin gel. We evaluated the diagnostic efficiency of endocervical phosphorylated insulin-like growth factor-binding protein (phIGFBP-1), cervicovaginal interleukins 6 (IL-6) and 8 (IL-8). We analyzed the transvaginal sonographic measurement of cervical length. A receiver-operating characteristics (ROC) curve was used to determine the most useful cut-off point. A multivariate logistic regression model was used to analyze the combination of significant predictive variables following univariate analysis. We analyzed all the data searching for the parameters that best predict the beginning of the active phase of labour within 12 h. RESULTS: 36.5 % of the patients delivered within 12 h. The Bishop score was >4 in the 43 % of patients with an active phase. The best cut-off values at ROC curves for cervical length, IL-6 and IL-8 were respectively 22 mm, 5 mg/dl and 20,237 mg/dl. At univariate analysis, all predictors of success, with the exception of IL-6, were significantly associated with the beginning of the active phase. Multivariate analysis of the Bishop score (OR 2.3), phIGFBP-1 test (OR 11.2) and IL-8 (OR 6.6) showed that the variables were independent and therefore useful in combination to predict the success of labour induction. CONCLUSION: The phIGFBP-1 test is a fast and easy test that can be used with Bishop score and IL-8 to reach an high positive predictive value in the prediction of the success of labour induction with prostaglandins.

15-Hydroxyprostaglandin dehydrogenase expression and localization in guinea pig gestational tissues during late pregnancy and parturition.

Prostaglandins are key components of the parturition cascade; however, the mechanisms that regulate prostaglandin concentrations in the uterus during pregnancy are largely unknown. The purpose of this study was to determine the intrauterine expression of the chief prostaglandin-inactivating enzyme, 15-hydroxyprostaglandin dehydrogenase (PGDH), during gestation and labor in the guinea pig, an animal model in which the endocrine control of pregnancy and parturition is analogous to that of women. PGDH messenger RNA (mRNA) abundance decreased significantly in the visceral yolk sac membrane (VYS, the anatomical equivalent of the human chorion laeve) and the amnion throughout the last third of pregnancy. PGDH protein was robustly expressed in the VYS epithelium and mesoderm, correlated strongly with PGDH mRNA levels and exhibited a nadir at term prior to labor onset. PGDH protein was not detected in the amnion. PGDH mRNA and protein levels in the placenta and myoendometrium were variable throughout late gestation. In the placenta, PGDH protein was concentrated in the parietal yolk sac membrane (PYS) lining the placental surface and in placental blood vessels. We observed strong expression of PGDH protein in the endometrial epithelium with comparably little expression in the myometrium. These data indicate that metabolic inactivation of prostaglandins in the pregnant guinea pig uterus takes place in the VYS, PYS, and endometrium. Decreased PGDH expression in the fetal membranes may contribute to the increase in intrauterine prostaglandin concentrations at term, stimulating the onset of labor.

Term myometrium is characterized by increased activating epigenetic modifications at the progesterone receptor-A promoter.

Term human myometrial expression of progesterone receptor (PR)-A is increased relative to PR-B, and as PR-A is a repressor of progesterone action mediated through PR-B, this increase may mediate the withdrawal of progesterone action and precipitate the onset of labour. PR-A and PR-B expression is regulated by two separate promoters of the PR gene. We hypothesized that epigenetic histone modifications at the two promoters contribute to the labour-associated regulation of PR-A and PR-B expression in term myometrium. PR total, PR-B and PR-A mRNA levels were determined using quantitative real-time PCR, and chromatin immunoprecipitation was used to determine the levels of activating and repressive histone modifications at the PR-A and PR-B promoters in human myometrial samples not in labour (n = 4) and in labour (n = 4). Chromatin extracts were immunoprecipitated with antibodies against activating (histone H3 and H4 acetylation and histone H3 lysine 4 trimethylation), and repressive (histone H3 lysine 9 trimethylation, histone H3 lysine 27 trimethylation and asymmetrical histone H3 arginine 2 dimethylation) histone modifications. PR-A mRNA levels increased during labour, while PR-B mRNA levels remained constant resulting in an increase of PR-A/PR-B mRNA ratio, as expected. Regardless of labour status, significantly higher levels of the activating histone modifications were found at the PR-A promoter compared with the PR-B promoter (P <0.001). H3K4me3 increased significantly at both promoters with labour onset (P =0.001). Low levels of the repressive histone modifications were also present at both promoters, with no labour-associated changes observed. Our data indicate that the PR-A promoter is epigenetically marked for activation in term myometrium more extensively than the PR-B promoter, and that labour is associated with an increase in H3K4me3 activating modification, consistent with the previously described increase in PR protein at this time.

Prevention of preterm labour via the modulation of inflammatory pathways.

Pregnancy is characterized by a complex interplay of inflammatory events regulated by both the innate and acquired immune systems. Similarly, parturition can be viewed as the activation of "pro-labour" inflammatory pathways, which drive cervical ripening and myometrial activation. Premature activation of these pathways, for example, by infection, can lead to preterm labour and birth. Nuclear factor κß is a key modulator of these pathways and functions by regulating the expression of prostaglandins, chemokines and pro-inflammatory cytokines involved in both term and preterm labour. Future design of therapeutics that target key mediators of inflammation and immune activation would therefore be a rational approach for preventing preterm labour and immune-mediated neonatal brain damage.

Cervical insulin-like growth factor binding protein-1 (IGFBP-1) to predict spontaneous onset of labor and induction to delivery interval in post-term pregnancy.

OBJECTIVE: To evaluate whether insulin-like growth factor binding protein-1 (IGFBP-1) assessed in cervical secretion can predict successful induction and spontaneous onset of labor in post-term pregnancy, compared to ultrasound measurement of cervical length and Bishop score. DESIGN: Cohort study, originating from a randomized controlled trial. SETTING: Obstetric department of a university and tertiary referral hospital, Norway. POPULATION: Five hundred and eight post-term women who had been randomized to induction of labor or expectant management 1 week beyond estimated day of delivery (289 [±2] days of gestation). METHODS: Time to delivery was related to presence of IGFBP-1 in cervical secretion, Bishop score and ultrasound measurement of cervical length recorded at inclusion. MAIN OUTCOME MEASURES: Spontaneous onset of labor and delivery within 3 days in the expectant management, and delivery within 24 hours of induction in the induction group. Test characteristics (sensitivity, specificity and negative and positive values and likelihood ratios) for IGFBP-1, Bishop score and cervical length were calculated. Logistic regression and Cox regression were used to account for parity and body mass index. RESULTS: With expectant management, IGFBP-1 predicted spontaneous labor onset and delivery within 72 hours with low sensitivity and high specificity (0.45 and 0.80, respectively), as did Bishop score (0.24, 0.92). Cervical length was more sensitive (0.67, 0.58). IGFBP-1 predicted successful induction within 24 hours with low sensitivity and high specificity (0.30, 0.85), such as Bishop score (0.06, 1.00) and cervical length (0.45, 0.76). Parity enhanced successful induction. CONCLUSION: IGFBP-1 predicts both spontaneous labor onset and successful induction in post-term pregnancy. Bishop score and cervical length performed equally well.

Surfactant protein-A (SP-A) selectively inhibits prostaglandin F2alpha (PGF2alpha) production in term decidua: implications for the onset of labor.

CONTEXT: Labor is characterized by "decidual activation" with production of inflammatory mediators. Recent data suggest that surfactant protein-A (SP-A) may be critical to the onset of labor in mice. Whether this is also true in humans is unclear. OBJECTIVES: The aim was to investigate: 1) the expression of SP-A at the maternal-fetal interface; 2) the effect of SP-A on the production of inflammatory mediators by human decidua; and 3) the association between single nucleotide polymorphisms in maternal SP-A genes and spontaneous preterm birth. RESEARCH DESIGN AND METHODS: In situ expression of SP-A was investigated by immunohistochemistry and quantitative RT-PCR. Term decidual stromal cells were isolated, purified, and treated with/without SP-A (1-100 µg/ml), IL-1ß, and/or thrombin. Levels of inflammatory mediators [IL-6, IL-8, TNFα, matrix metalloproteinase-3, monocyte chemotactic protein-1, IL-1ß, PGE(2), prostaglandin F(2α) (PGF(2α))] and angiogenic factors (soluble fms-like tyrosine kinase-1, vascular endothelial growth factor) were measured in conditioned supernatant by ELISA and corrected for protein content. The effect of SP-A on eicosanoid gene expression was measured by quantitative RT-PCR. RESULTS: SP-A localized to endometrium/decidua. High-dose SP-A (100 µg/ml) inhibited PGF(2α) by term decidual stromal cells without affecting the production of other inflammatory mediators, and this effect occurred at a posttranscriptional level. Decidual SP-A expression decreased significantly with labor. Single nucleotide polymorphisms in the SP-A genes do not appear to be associated with preterm birth. CONCLUSIONS: SP-A is produced by human endometrium/decidua, where it significantly and selectively inhibits PGF(2α) production. Its expression decreases with labor. These novel observations suggest that decidual SP-A likely plays a critical role in regulating prostaglandin production within the uterus, culminating at term in decidual activation and the onset of labor.

[Expression of Calponin-1 and Transgelin in human uterine smooth muscles in non-labor and labor situation].

OBJECTIVE: To investigate the expression of Calponin-1 and Transgenlin in the uterine smooth muscles during normal labor on-sets, and to evaluate their effect on initiating the normal labor. METHODS: A total of 14 uterine bodies and lower segments of human pregnancy were divided to a non-labor group (NIL) and a labor group(IL). Immunohistochemical technology and Western blot were used to determine the expression of Calponin-1 and Transgelin in the 2 groups. RESULTS: Immunohistochemical detection and Western blot showed that Calponin-1 protein in the uterine smooth muscle tissue of the body and the lower uterine segment of smooth muscle tissues had significant difference (P<0.05). The expression of Transgelin in the uterine body smooth muscle tissue in the IL was higher than that in the NIL(P<0.05). In the lower uterine segments of the smooth muscle, the expression of Transgelin was not significantly different in the 2 groups (P>0.05). CONCLUSION: Calponin-1 of the uterine smooth muscle and Transgelin of the uterine body smooth muscle may involve in the regulation of uterine smooth muscle contractility, which is closely related to child birth launch.

Global gene expression changes induced in the human placenta during labor.

OBJECTIVES: To gain insight into the process of labor and the effects of labor on placental gene expression, we performed a microarray analysis to identify the differentially expressed transcripts that may participate in labor onset and progression. METHODS: We compared expression profiles in placentas from 16 women who underwent elective non-labored cesarean section and from seven women who underwent vaginal delivery. Oligonucleotide probes representing 55,000 genes were used to measure gene expression. Differential gene expression was evaluated using the Student's t-test and fold change assessment and reverse transcription PCR was used to validate the differentially expressed genes. RESULTS: A total of 351 genes were found to be differentially expressed between the two groups. Among these differentially expressed genes, 344 genes were up-regulated and seven were down-regulated. These differentially expressed genes involved 15 categories including genes involved in stress response, immune response, cell death, coagulation, and blood vessel development which are considered to be most closely associated with the inflammatory response that characterizes labor. CONCLUSION: A total of 351 differentially expressed genes of 15 categories were found in the placentas of the vaginal delivery group, indicating a diversity of gene expression alteration and complexity in the labor process. These gene expression changes could be a cause of labor onset and progress or simply an effect of labor.

Temporal expression of antioxidants in human cervicovaginal fluid associated with spontaneous labor.

Proteomic analysis of human cervicovaginal fluid (CVF) by 2D electrophoresis revealed significant differential expression of several major antioxidant enzymes during late pregnancy and term labor. Temporal quantitative changes of total antioxidant capacity (TAC), Cu,Zn superoxide dismutase (Cu,Zn SOD) and thioredoxin-1 (Trx-1) with impending term labor were investigated, and the potential of these biomarkers as individual and multiple predictors of labor was determined. The TAC of CVF (n = 193) was 8-fold significantly lower in labor, and approximately 2-fold significantly lower at 0-7, 8-14, 15-21, and 22-28 days, compared with >or=29 days prior to labor onset (p < 0.001). The expression of Cu,Zn SOD (n = 170) was 1.5- to 1.9-fold significantly decreased in labor (p < 0.001). Trx-1 (n = 163) was 2.8- to 5.1-fold significantly lower in labor (p = 0.002). The combination of TAC and Cu,Zn SOD produced the best predictive efficacy with 74% sensitivity and 95% specificity to predict term labor within 3 days of onset. These findings suggest that labor is associated with increased oxidative stress well before its onset and is reflected in the human CVF. The biomarkers identified in this study could serve as predictors of labor and offer potential strategies for novel therapeutics.

Is maternal progesterone actually independent of the fetal steroids?

Progesterone and estradiol are the foremost steroid hormones in human pregnancy. However, the origin of maternal progesterone has still not been satisfactorily explained, despite the generally accepted opinion that maternal LDL-cholesterol is a single substrate for placental synthesis of maternal progesterone. The question remains why the levels of progesterone are substantially higher in fetal as opposed to maternal blood. Hence, the role of the fetal zone of fetal adrenal (FZFA) in the synthesis of progesterone precursors was addressed. The FZFA may be directly regulated by placental CRH inducing an excessive production of sulfated 3beta-hydroxy-5-ene steroids such as sulfates of dehydroepiandrosterone (DHEAS) and pregnenolone (PregS). Due to their excellent solubility in plasma these conjugates are easily transported in excessive amounts to the placenta for further conversion to the sex hormones. While the significance of C19 3beta-hydroxy-5-ene steroid sulfates originating in FZFA for placental estrogen formation is mostly recognized, the question "Which maternal and/or fetal functions may be served by excessive production of PregS in the FZFA?" - still remains open. Our hypothesis is that, besides the necessity to synthesize de novo all the maternal progesterone from cholesterol, it may be more convenient to utilize the fetal PregS. The activities of sulfatase and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) are substantially higher than the activity of cytochrome P450scc, which is rate-limiting for the placental progesterone synthesis from LDL-cholesterol. However, as in the case of progesterone synthesis from maternal LDL-cholesterol, the relative independence of progesterone levels on FZFA activity may be a consequence of substrate saturation of enzymes converting PregS to progesterone. Some of the literature along with our current data (showing no correlation between fetal and maternal progesterone but significant partial correlations between fetal and maternal 20alpha-dihydroprogesterone (Prog20alpha) and between Prog20alpha and progesterone within the maternal blood) indicate that the localization of individual types of 17beta-hydroxysteroid dehydrogenase is responsible for a higher proportion of estrone and progesterone in the fetus, but also a higher proportion of estradiol and Prog20alpha in maternal blood. Type 2 17beta-hydroxysteroid dehydrogenase (17HSD2), which oxidizes estradiol to estrone and Prog20alpha to progesterone, is highly expressed in placental endothelial cells lining the fetal compartment. Alternatively, syncytium, which is directly in contact with maternal blood, produces high amounts of estradiol and Prog20alpha due to the effects of type 1, 5 and 7 17?-hydroxysteroid dehydrogenases (17HSD1, 17HSD5, and 17HSD7, respectively). The proposed mechanisms may serve the following functions: 1) providing substances which may influence the placental production of progesterone and synthesis of neuroprotective steroids in the fetus; and 2) creating hormonal milieu enabling control of the onset of labor.

Fetal membranes as an interface between inflammation and metabolism: increased aquaporin 9 expression in the presence of spontaneous labor at term and chorioamnionitis.

OBJECTIVE: Aquaporin 9 (AQP9) is a water channel protein characterized by its high permeability to nutrients such as lactate and glycerol, as well as urea and other small solutes. These unique properties of AQP9 suggest that this molecule may play a role in the modulation of nutrient flux through the fetal membranes in conditions associated with increased metabolic demand, such as spontaneous labor and inflammation. The objective of this study was to determine the expression of AQP9 in the chorioamniotic membranes from women with and without term labor, as well as those with preterm prelabor rupture of membranes (PPROM) with and without histologic chorioamnionitis. STUDY DESIGN: A cross-sectional study was performed which included patients in the following groups: (1) term not in labor (TNL; n = 14); (2) term, spontaneous labor (n = 14); and (3) PPROM with (n = 20) and without (n = 17) histologic chorioamnionitis. AQP9 mRNA expression in fetal membranes was quantified using quantitative real-time reverse transcription-polymerase chain reaction and analyzed with a linear model including gestational age as a covariate. RESULTS: (1) AQP9 mRNA expression was identified in all chorioamniotic membrane specimens; (2) AQP9 expression in fetal membranes was significantly higher in spontaneous term labor when compared with TNL (fold change 3.6; p = 0.01); and (3) Among patients with PPROM, the presence of histologic chorioamnionitis was associated with a higher expression of AQP9 in the chorioamniotic membranes compared with those from women without histologic chorioamnionitis (fold change 8.7; p < 0.001). CONCLUSION: Aquaporin 9 mRNA expression is higher in the fetal membranes from patients with spontaneous term labor and those with PPROM and histologic chorioamnionitis. These findings are novel, and suggest a role for aquaporin 9 in membrane-mediated transfer of nutrients to support the increased metabolic demands associated with the host immune response of the terminal pathway of parturition and histologic chorioamnionitis.