Proteomic biomarkers that predict the clinical success of rescue cerclage
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland, Baltimore, Baltimore, Maryland, United States American Journal of Obstetrics and Gynecology
(Impact Factor: 4.7).
04/2005; 192(3):710-8. DOI: 10.1016/j.ajog.2004.10.588
The origin of incompetent cervix is multifactorial, and the success of rescue cerclage is unpredictable. We tested amniotic fluid from women who were preparing to undergo rescue cerclage for proteomic biomarkers and correlated their presence with clinical outcome.
Amniocentesis was performed to facilitate rescue cerclage in 37 consecutive women with painless dilation (> 2 cm) and no detectable uterine activity for 4 hours (range, 1-24 hours) before cerclage. Thirty-nine consecutive women with a sonographically normal pregnancy and cervix who underwent amniocentesis for chromosomal testing during the same study interval at the same clinical site provided the control samples. A proteomic fingerprint was generated with the discarded sample and the Mass-Restricted score (MR score) for inflammation calculated. Peaks corresponding to free hemoglobin chains were sought as evidence of decidual hemorrhage or intra-amniotic bleeding.
Amniocentesis was performed at 23.5 weeks in cerclage (mean dilation, 4 cm) versus 19.5 weeks in control subjects. Cerclage subjects were delivered at 28.8 weeks; control subjects were delivered at 39.2 weeks. Thirty-two of 37 of cerclage subjects (86%) were delivered prematurely. Ten of 37 of cerclage subjects (27%), but no control subject, had a MR score that was indicative of inflammation (P < .001). Hemoglobin peaks were present in 12 of 37 of cerclage subject (32%), but no control subjects. Among cerclage subjects, those with a MR score of 3 to 4 were delivered earlier than those with a MR score of 0 to 2 (P < .001). Women with a MR score of 3 to 4 had a shorter latency period (days from amniocentesis to delivery; 3 days) and a shorter percentage of prolongation (1.8%) than women with a MR score of 0 to 2 (35 days; P < .05; 17.9%; P < .05). Women with hemoglobin had a shorter latency period (6 days) and a shorter percentage of prolongation (3.8%) than women without hemoglobin (38 days; P < .05; 21.8%; P < .05). Hemoglobin was present in 7 of 10 of the cerclage subjects (70%) with a MR score of 3 to 4. Women with both a MR score of 3 to 4 and hemoglobin had the shortest intervals to delivery.
These findings illustrate 2 pathologic mechanisms that are associated with preterm delivery are also associated with incompetent cervix. Either an intrauterine inflammatory response or decidual hemorrhage predates surgery in one half the women whose condition requires rescue cerclage. The activation of either mechanism predicts cerclage failure.
Available from: Keun Young Lee
- "Lee et al (Lee et al., 2004) reported that elevated interleukin-6 in amniotic fluid was adversely associated with interval between physicalexamination cerclage and delivery. Weiner et al. (Weiner et al., 2005) found intrauterine inflammatory responses and decidual hemorrhage were correlated with adverse pregnancy outcome after physical-examination cerclage. A physical-examination cerclage could be considered in women with dilated cervix and bulging membrane after conization. "
Available from: PubMed Central
- "A comprehensive mapping of the proteome and microarray analysis was provided by several investigators [6–15]. Recent studies demonstrated associations between elevated levels of circulating proinflammatory cytokines, particularly interleukin (IL) 6, IL-1beta, and tumor necrosis factor alpha (TNF-alpha), and preterm birth [1, 5]. "
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ABSTRACT: Individuals with inflammation have a myriad of pregnancy aberrations including increasing their preterm birth risk. Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE) and their ligands were all found to play a key role in inflammation. In the present study, we reviewed TLR and RAGE expression, their ligands, and signaling in preterm birth.
A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2010, combining the keywords "preterm birth," "TLR", "RAGE", "danger signal", "alarmin", "genomewide," "microarray," and "proteomics" with specific expression profiles of genes and proteins.
This paper provides data on TLR and RAGE levels and critical downstream signaling events including NF-kappaB-dependent proinflammatory cytokine expression in preterm birth. About half of the genes and proteins specifically present in preterm birth have the properties of endogenous ligands "alarmin" for receptor activation. The interactions between the TLR-mediated acute inflammation and RAGE-mediated chronic inflammation have clear implications for preterm birth via the TLR and RAGE system, which may be acting collectively.
TLR and RAGE expression and their ligands, signaling, and functional activation are increased in preterm birth and may contribute to the proinflammatory state.
Available from: Carl P Weiner
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ABSTRACT: Four proteomic biomarkers (human neutrophil peptide 1 [HNP1], HNP2 [defensins], calgranulin C [Cal-C], and Cal-A) characterize the fingerprint of intra-amniotic inflammation (IAI). We compared proteomic technology using surfaced-enhanced laser desorption-ionization-time of flight (SELDI-TOF) mass spectrometry to enzyme-linked immunosorbent assay (ELISA) for detection of these biomarkers. Amniocentesis was performed on 48 women enrolled in two groups: those with intact membranes (n = 27; gestational age [GA], 26.0 +/- 0.8 weeks) and those with preterm premature rupture of the membranes (PPROM; n = 21; GA, 28.4 +/- 0.9 weeks). Paired abdominal amniotic fluids (aAFs)-vaginal AFs (vAFs) were analyzed in PPROM women. Quantitative aspects of HNP1-3, Cal-C, Cal-A, and calprotectin (a complex of Cal-A with Cal-B) were assessed by ELISA. SELDI-TOF mass spectrometry tracings from 16/48 (33.3%) aAFs and 13/17 (88.2%) vAFs were consistent with IAI (three or four biomarkers present). IAI (by SELDI-TOF mass spectrometry) was associated with increased HNP1-3 and Cal-C measured by ELISA. However, immunoassays detected Cal-A in only 4 of the AFs even though its specific SELDI-TOF mass spectrometry peak was identified in 19/48 AFs. Calprotectin immunoreactivity was decreased in AFs retrieved from women with IAI (P = 0.01). In conclusion, IAI is associated with increased HNP1-3 levels. In the absence of isoform-specific ELISAs, mass spectrometry remains the only way to discriminate the HNP biomarker isoforms. Monomeric Cal-A is not reliably estimated by specific ELISA as it binds to Cal-B to form the calprotectin complex. Cal-C was reliably measured by SELDI-TOF mass spectrometry or specific ELISA.
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