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Horne A.W.,Queens Medical Research Institute | Brown J.K.,Queens Medical Research Institute | Tong S.,Translational Obstetrics Group | Kaitu'u-Lino T.,Translational Obstetrics Group
PLoS ONE | Year: 2012

Background: Ectopic pregnancy (EP) remains the most life-threatening acute condition in modern gynaecology. It remains difficult to diagnose early and accurately. Women often present at emergency departments in early pregnancy with a 'pregnancy of unknown location' (PUL) and diagnosis/exclusion of EP is challenging due to a lack of reliable biomarkers. Recent studies suggest that serum levels of a disintegrin and metalloprotease protein-12 (ADAM-12) can be used differentiate EP from viable intrauterine pregnancy (VIUP). Here we describe a prospective study evaluating the performance of ADAM-12 in differentiating EP from the full spectrum of alternative PUL outcomes in an independent patient cohort. Methodology/Principal Findings: Sera were collected from 120 patients at their first clinical presentation with a PUL and assayed for ADAM-12 by ELISA. Patients were categorized according to final pregnancy outcomes. Serum ADAM-12 concentrations were increased in women with histologically-confirmed EP (median 442 pg/mL; 25%-75% percentile 232-783 pg/mL) compared to women with VIUP (256 pg/mL; 168-442 pg/mL) or miscarriage (192 pg/mL; 133-476 pg/mL). Serum ADAM-12 did not differentiate histologically-confirmed EP from spontaneously resolving PUL (srPUL) (416 pg/mL; 154-608 pg/mL). The diagnostic potential of ADAM-12 was only significant when 'ambiguous' PUL outcomes were excluded from the analysis (AROC = 0.6633; P = 0.03901). Conclusions/Significance: When measured in isolation, ADAM-12 levels had limited value as a diagnostic biomarker for EP in our patient cohort. The development of a reliable serum biomarker-based test for EP remains an ongoing challenge. © 2012 Horne et al. Source

Whitehead C.L.,Translational Obstetrics Group | Teh W.T.,University of Melbourne | Walker S.P.,University of Melbourne | Leung C.,Monash Medical Center | And 2 more authors.
PLoS ONE | Year: 2013

Stillbirth affects 1 in 200 pregnancies and commonly arises due to a lack of oxygen supply to the fetus. Current tests to detect fetal hypoxia in-utero lack the sensitivity to identify many babies at risk. Emerging evidence suggests that microRNAs derived from the placenta circulate in the maternal blood during pregnancy and may serve as non-invasive biomarkers for pregnancy complications. In this study, we examined the expression of miRs known to be regulated by hypoxia in two clinical settings of significant fetal hypoxia: 1) labour and 2) fetal growth restriction. Six miRs (miR 210, miR 21, miR 424, miR 199a, miR 20b, and miR 373) were differentially expressed in pregnancies complicated by fetal hypoxia. In healthy term pregnancies there was a 4.2 fold increase in miR 210 (p<0.01), 2.7 fold increase in miR 424 (p<0.05), 2.6 fold increase in miR 199a (p<0.01) and 2.3 fold increase in miR 20b (p<0.05) from prior to labour to delivery of the fetus. Furthermore, the combined expression of miR 21 and miR 20b correlated with the degree of fetal hypoxia at birth determined by umbilical cord lactate delivery (r = 0.79, p = 0.03). In pregnancies complicated by severe preterm fetal growth restriction there was upregulation of the hypoxia-regulated miRs compared to gestation-matched controls: 3.6 fold in miR 210 (p<0.01), 3.6 fold in miR 424 (p<0.05), 5.9 fold in miR 21 (p<0.01), 3.8 fold in miR 199a (p<0.01) and 3.7 fold in miR 20b (p<0.01). Interestingly, the expression of miR 373 in gestation matched controls was very low, but was very highly expressed in FGR (p<0.0001). Furthermore, the expression increased in keeping with the degree of in-utero hypoxia estimated by fetal Doppler velocimetry. We conclude quantifying hypoxia-regulated miRs in the maternal blood may identify pregnancies at risk of fetal hypoxia, enabling early intervention to improve perinatal outcomes. © 2013 Whitehead et al. Source

Whitehead C.L.,Translational Obstetrics Group | Walker S.P.,University of Melbourne | Mendis S.,University of Melbourne | Lappas M.,University of Melbourne | Tong S.,Translational Obstetrics Group
American Journal of Obstetrics and Gynecology | Year: 2013

Objective: To examine whether mRNA circulating in maternal blood coding genes regulating fetal growth are differentially expressed in (1) severe preterm fetal growth restriction (FGR) and (2) at 28 weeks' gestation in pregnancies destined to develop FGR at term. Study Design: mRNA coding growth genes were measured in 2 independent cohorts. The first was women diagnosed with severe preterm FGR (<34 weeks' gestation; n = 20) and gestation matched controls (n = 15), where the mRNA was measured in both maternal blood and placenta. The second cohort was a prospective longitudinal study (n = 52) of women whom had serial ultrasound assessments of fetal growth. mRNA coding growth genes in maternal blood were measured at 28 and 36 weeks in pregnancies with declining growth trajectories (ending up with term FGR; n = 10 among the 52 recruited) and controls who maintained normal growth trajectory (n = 15). Results: In women with severe preterm FGR, there was increased expression of placental growth hormone (6.3-fold), insulin-like growth factors (IGF1, 3.4-fold; IGF2, 5.0-fold), IGF receptors (2.1-fold) and IGF binding proteins (3.0-fold), and reduced expression of ADAM12 (0.5-fold) in maternal blood (and similar trends in placenta) compared with controls (P <.05). Notably, at 28 weeks' gestation there was increased IGF2 (3.9-fold), placental growth hormone (2.7-fold), and IGF BP2 (2.1-fold) expression in maternal blood in women destined to develop FGR at term (P <.05). Conclusion: Measuring mRNA coding growth genes in maternal blood may detect unsuspected severe preterm FGR already present in utero, and predict term FGR when measured at 28 weeks' gestation. © 2013 Mosby, Inc. All rights reserved. Source

MacDonald T.M.,Translational Obstetrics Group | MacDonald T.M.,University of Melbourne | Kaitu'u-Lino T.J.,Translational Obstetrics Group | Kaitu'u-Lino T.J.,University of Melbourne | And 8 more authors.
Journal of Maternal-Fetal and Neonatal Medicine | Year: 2016

Background: It is not known whether fasting affects levels of circulating placenta-specific transcripts. Objective: To assess whether a glucose load affects circulating placenta-specific transcripts. Method: RNA was extracted from paired blood samples (fasting and 1-h post 75 g oral glucose) from 22 women. Placenta-specific genes were measured by RT-qPCR. Results: There was no change in ADM, CSH1, PAPPA2, PSG1 or TAC3 expression between fasting and post-glucose states. However, HTRA1 decreased after glucose load. Conclusion: Maternal fasting state does not influence expression of the majority of placenta-specific genes but may need to be accounted for when validating biomarkers of placental disease. © 2016 Informa UK Limited, trading as Taylor & Francis Group. Source

Paiva P.,Monash Institute of Medical Research | Whitehead C.,Monash Institute of Medical Research | Whitehead C.,Translational Obstetrics Group | Saglam B.,Monash Institute of Medical Research | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: mRNA of placental origin in maternal blood shows potential as a clinical biomarker of obstetric diseases such as preeclampsia (PE). We hypothesized that mRNA transcripts very highly expressed in the placenta relative to other tissues will be differentially expressed in PE and be useful as mRNA biomarkers in maternal blood. Objective: Our objective was to identify a panel of genes highly expressed in the placenta and compare their expression in placenta and maternal whole blood from PE vs. control pregnancies. Setting: Placental tissue and maternal whole blood specimens were obtained from normotensive controls (n = 15) and pregnancies complicated by severe preterm PE (n = 21). Intervention: mRNA expression was evaluated by quantitative real-time RT-PCR. Results: We identified 20 genes exhibiting highest to fourth highest expression in the placenta relative to all other tissues. All genes were detectable in placenta. Nine of the 20 genes were detectable in maternal whole blood. Four of the nine genes detectable in blood (i.e. PLAC3, PLAC4, CRH, and ERVWE1) were significantly increased in both maternal blood and placenta from PE pregnancies. The remaining five genes detectable in maternal blood were unchanged in both blood and placenta from PE pregnancies. Thus, there was complete correlation of gene expression between maternal blood and placenta. Conclusions: Circulating mRNA coding genes of high placental expression show strong correlation with transcript levels in preeclamptic placenta. Such transcripts may be promising candidates to screen as mRNA biomarkers of PE in maternal whole blood. Copyright © 2011 by The Endocrine Society. Source

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