Obstetrics and Gynaecology - Research Publications
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ItemEffects of Maternal Obstructive Sleep Apnoea on Fetal Growth: A Prospective Cohort Study(PUBLIC LIBRARY SCIENCE, 2013-07-24)OBJECTIVE: The objective of this study is to determine whether obstructive sleep apnea (OSA) is associated with reduced fetal growth, and whether nocturnal oxygen desaturation precipitates acute fetal heart rate changes. STUDY DESIGN: We performed a prospective observational study, screening 371 women in the second trimester for OSA symptoms. 41 subsequently underwent overnight sleep studies to diagnose OSA. Third trimester fetal growth was assessed using ultrasound. Fetal heart rate monitoring accompanied the sleep study. Cord blood was taken at delivery, to measure key regulators of fetal growth. RESULTS: Of 371 women screened, 108 (29%) were high risk for OSA. 26 high risk and 15 low risk women completed the longitudinal study; 14 had confirmed OSA (cases), and 27 were controls. The median (interquartile range) respiratory disturbance index (number of apnoeas, hypopnoeas or respiratory related arousals/hour of sleep) was 7.9 (6.1-13.8) for cases and 2.2 (1.3-3.5) for controls (p<0.001). Impaired fetal growth was observed in 43% (6/14) of cases, vs 11% (3/27) of controls (RR 2.67; 1.25-5.7; p = 0.04). Using logistic regression, only OSA (OR 6; 1.2-29.7, p = 0.03) and body mass index (OR 2.52; 1.09-5.80, p = 0.03) were significantly associated with impaired fetal growth. After adjusting for body mass index on multivariate analysis, the association between OSA and impaired fetal growth was not appreciably altered (OR 5.3; 0.93-30.34, p = 0.06), although just failed to achieve statistical significance. Prolonged fetal heart rate decelerations accompanied nocturnal oxygen desaturation in one fetus, subsequently found to be severely growth restricted. Fetal growth regulators showed changes in the expected direction- with IGF-1 lower, and IGFBP-1 and IGFBP-2 higher- in the cord blood of infants of cases vs controls, although were not significantly different. CONCLUSION: OSA may be associated with reduced fetal growth in late pregnancy. Further evaluation is warranted to establish whether OSA may be an important contributor to adverse perinatal outcome, including stillbirth.
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ItemQuantifying mRNA coding growth genes in the maternal circulation to detect fetal growth restriction(MOSBY-ELSEVIER, 2013-08)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.
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ItemNo Preview AvailableSkeletal Muscle MnSOD, Mitochondrial Complex II, and SIRT3 Enzyme Activities Are Decreased in Maternal Obesity During Human Pregnancy and Gestational Diabetes Mellitus(ENDOCRINE SOC, 2013-10)CONTEXT: Insulin resistance and systemic oxidative stress are prominent features of pregnancies complicated by maternal obesity or gestational diabetes mellitus (GDM). The role of skeletal muscle oxidative stress or mitochondrial capacity in obese pregnant women or obese women with GDM is unknown. OBJECTIVE: We investigated whether obese pregnant women, compared with normal weight (NW) pregnant women, demonstrate decreased skeletal muscle mitochondrial enzyme activity and elevated markers of oxidative stress, and if these differences are more severe in obese women diagnosed with GDM. DESIGN: We measured mitochondrial enzyme activity and markers of oxidative stress in skeletal muscle tissue from NW pregnant women (n = 10), obese pregnant women with normal glucose tolerance (NGT; n = 10), and obese pregnant women with GDM (n = 8), undergoing cesarean delivery (∼37 wk gestation). RESULTS: Electron transport complex-II and manganese superoxide dismutase (MnSOD) enzyme activities were decreased in obese-NGT and obese-GDM, compared with NW women. The glutathione redox ratio (GSH:GSSG) was decreased in obese-NGT and obese-GDM, indicative of increased oxidative stress. Mitochondrial sirtuin (SIRT)3 mRNA content and enzyme activity were lower in skeletal muscle of obese-NGT and obese-GDM women. Importantly, acetylation of MnSOD, a SIRT3 target, was increased in obese-NGT and obese-GDM vs NW women and was inversely correlated with SIRT3 activity (r = -0.603), suggesting a mechanism for reduced MnSOD activity. CONCLUSIONS: These data show that obese pregnant women demonstrate decreased skeletal muscle mitochondrial respiratory chain enzyme activity and decreased mitochondrial antioxidant defense. Furthermore, reduced skeletal muscle SIRT3 activity may play a role in the increased oxidative stress associated with pregnancies complicated by obesity.
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ItemNo Preview AvailableNOD1 and NOD2 Regulate Proinflammatory and Prolabor Mediators in Human Fetal Membranes and Myometrium via Nuclear Factor-Kappa B(OXFORD UNIV PRESS INC, 2013-07)Preterm birth remains one of the most important issues facing perinatal medicine today, with chronic inflammation and/or infection being the biggest etiological factor. The nucleotide oligomerization domain (NOD) intracellular molecules recognize a wide range of microbial products as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor KB (NFKB), a central regulator of the terminal processes of human labor and delivery. The aims of this study were to determine the effect of 1) human labor, proinflammatory cytokines, and bacterial endotoxin LPS on NOD1 and NOD2 expression and 2) NOD1 and NOD2 activation on the expression of prolabor mediators in human fetal membranes and myometrium. NOD1 and NOD2 expression was significantly higher in fetal membranes and myometrium after spontaneous labor when compared to nonlaboring tissues. Bacterial endotoxin LPS and the proinflammatory cytokines TNF and IL1B significantly increased NOD2, but not NOD1, expression. Furthermore, LPS-induced NOD2 expression was decreased by the NFKB inhibitor BAY 11-7082. In both fetal membranes and myometrium, the NOD1 ligand bacterial iE-DAP and the NOD2 ligand bacterial MDP significantly increased the expression and secretion of proinflammatory cytokines (IL6 and IL8), cyclooxygenase (PTGS2) expression and subsequent release of prostaglandins PGE2 and PGF2alpha, and the expression and activity of MMP9. The effects of these NOD1 and NOD2 ligands were mediated via NFKB, as 1) both iE-DAP and MDP significantly increased NFKB activation and 2) the NFKB inhibitor BAY 11-7082 attenuated iE-DAP- and MDP-induced expression and secretion of prolabor mediators. In conclusion, NOD1 and NOD2 are increased in laboring fetal membranes and myometrium and with bacterial infection. Agonist activation of NOD1 and NOD2 by bacterial products leads to NFKB activation and transcription of NFKB induced prolabor genes. NOD1 and NOD2 may thus represent therapeutic targets for the treatment and/or management of preterm birth.
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ItemNo Preview AvailableDietary phytophenols curcumin, naringenin and apigenin reduce infection-induced inflammatory and contractile pathways in human placenta, foetal membranes and myometrium(OXFORD UNIV PRESS, 2013-07)A tenet of contemporary obstetrics is that a significant proportion of preterm births involve bacterial infection. Bacterial endotoxin induces pro-inflammatory cytokines, prostaglandins and proteases via the pro-inflammatory pathway nuclear factor-κB (NF-κB), which plays a key role in initiating uterine contractions and rupture of foetal membranes. In non-gestational tissues, the phytophenols curcumin, naringenin and apigenin exert anti-inflammatory properties via inhibition of NF-κB. The aim of this study was to determine whether these treatments regulate pro-inflammatory and pro-labour mediators in human gestational tissues. Placenta, foetal membranes and myometrium were treated with curcumin, naringenin and apigenin in the presence of lipopolysaccharide (LPS) or interleukin (IL)-1β. In placenta and foetal membranes, all treatments significantly reduced LPS-stimulated release and gene expression of pro-inflammatory cytokines IL-6 and IL-8; placenta decreased cyclooxygenase (COX-2) mRNA expression, subsequent release of prostaglandins PGE2 and PGF2α and expression and activity of matrix-degrading enzyme matrix metalloproteinase (MMP)-9. In myometrial cells, all treatments attenuated IL-1β-induced COX-2 expression, release of PGE2 and PGF2α and expression and activity of MMP-9. Although naringenin significantly attenuated IL-1β-induced IL-6 and IL-8 mRNA expression and release, there was no effect of curcumin and apigenin. LPS-stimulated release of 8-isoprostane, a marker of oxidative stress, was attenuated by all treatments. NF-κB p65 DNA-binding activity was also decreased using these treatments. In conclusion, curcumin, naringenin and apigenin exert anti-inflammatory properties in human gestational tissues by inhibiting the transcriptional activity of NF-κB. Further studies should be undertaken to define a possible implication of these natural spices in the management of preterm labour and delivery.
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ItemNo Preview AvailableA Novel Role for FOXO3 in Human Labor: Increased Expression in Laboring Myometrium, and Regulation of Proinflammatory and Prolabor Mediators in Pregnant Human Myometrial Cells(OXFORD UNIV PRESS INC, 2013-06)Preterm birth is the leading factor causing neonatal mortality and morbidity. Inflammation plays a central role in stimulating uterine contractility, which is responsible for approximately one-third of all preterm births. Recent studies have shown that the transcription factor Forkhead box O3 (FOXO3) regulates inflammation in nongestational tissues such as adipocytes and hepatocytes. Thus, in this study, we sought to determine the effect of 1) human term labor on myometrial FOXO3 expression and 2) FOXO3 inhibition and FOXO3 overexpression on proinflammatory and prolabor mediators in human myometrial cells. Higher FOXO3 gene and protein expression were detected in myometrium obtained from women in labor when compared to samples taken from nonlaboring women. Myometrial cells were isolated from pregnant human myometrium, and FOXO3 silencing was achieved using siRNA and overexpression using a cDNA clone. We found that the loss of FOXO3 in myometrial cells was associated with a significant decrease in IL1B-induced IL6 and IL8 expression and production, cyclooxygenase ([COX]-2, official symbol PTGS2) expression and subsequent prostaglandin (PGE2 and PGF2alpha) release, and matrix metalloproteinase 9 (MMP9) and mRNA expression and activity. Conversely, FOXO3 overexpression increased cytokine expression and secretion, prostaglandin production, and MMP9 expression in myometrial cells treated with IL1B. In summary, we have identified FOXO3 as an upstream mediator of inflammation in human myometrium. Thus, FOXO3 may present an alternative therapeutic target for preventing preterm birth and its associated morbidity and mortality.
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ItemNo Preview AvailablePlacental Specific mRNA in the Maternal Circulation Are Globally Dysregulated in Pregnancies Complicated by Fetal Growth Restriction(ENDOCRINE SOC, 2013-03)CONTEXT: Fetal growth restriction (FGR) is a leading cause of perinatal mortality, yet no reliable screening test exists. Placental specific mRNA in the maternal circulation may reflect changes in the placental transcriptome in FGR and could be a novel biomarker for FGR. OBJECTIVE: The aim of the study was to identify placental specific RNA detectable in the maternal circulation and examine whether they are differentially expressed in severe preterm FGR. DESIGN: In silico screening was used to identify placental specific RNAs. Their expression in cases of severe FGR vs controls was examined in both maternal blood and placenta by microarray, RT-PCR, and in situ hybridization. RESULTS: Via in silico analysis, we identified 137 genes very highly expressed in the placenta relative to other tissues. Using microarray, we found that they were detectable in the maternal blood and were globally dysregulated with preterm FGR; 75 genes (55%) had a ≥1.5-fold differential expression compared to controls. Eight genes (ERVWE-1, PSG1, PLAC4, TAC3, PLAC3, CRH, CSH1, and KISS1) were validated by RT-PCR to be significantly increased in both maternal blood and placenta in a larger cohort of severe FGR compared to controls. In situ hybridization confirmed PAPPA2 and ERVWE-1 localized to the syncytiotrophoblast. CONCLUSION: There is global differential expression of placental specific mRNA in the maternal blood in pregnancies complicated by severe preterm FGR. Placental specific mRNA in maternal blood may represent a new class of biomarkers for preterm FGR.
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ItemNo Preview AvailableSIRT6 Is Decreased with Preterm Labor and Regulates Key Terminal Effector Pathways of Human Labor in Fetal Membranes(OXFORD UNIV PRESS INC, 2013-01)Preterm birth is a major determinant of neonatal mortality and morbidity, affecting approximately one-third of preterm births as a result of prelabor rupturing of membranes. Infection and inflammation have strong causal links to preterm delivery, resulting in the activation of nuclear factor-kappaB (NFKB) and its downstream targets. Human sirtuin (SIRT) 6, which has ADP-ribosyl transferase and deacetylase activity, exhibits anti-inflammatory actions. The aims of this study were to determine the effect of 1) human preterm labor on SIRT6 expression in human gestational tissue and 2) the effect in primary amnion cells of SIRT6 inhibition, using small interfering RNA (siRNA) on prolabor mediators. To determine the effect of human preterm labor on SIRT6 expression, human fetal membranes were collected from women at preterm at the time of Cesarean section (no labor; n = 9) and from women after spontaneous labor and delivery (n = 9). SIRT6 mRNA and protein expression were significantly lower in fetal membranes after spontaneous preterm labor. Transfection of primary amnion cells with SIRT6 siRNA was associated with an increase in IL-1beta-induced proinflammatory cytokine gene expression and release (IL6, IL8, TNF [TNF-alpha]), cyclooxygenase ([COX]-2; official symbol PTGS2) expression and subsequent prostaglandin (PGE(2) and PGF(2alpha)) release, and MMP9 gene expression and release of pro-MMP9. To determine whether SIRT6 affects NFKB transcriptional activity, primary amnion cells were transfected with NFKB tagged with luciferase and stimulated with IL1B. As expected, IL1B induced NFKB transcriptional activity. However, when cells were also cotransfected with a vector expressing SIRT6, there was a decrease in NFKB transcriptional activity. In conclusion, SIRT6 plays a role in regulating the terminal effector pathways of human labor and delivery via the NFKB pathway.
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ItemNo Preview Available2D-DIGE to identify proteins associated with gestational diabetes in omental adipose tissue(BIOSCIENTIFICA LTD, 2013-08)Gestational diabetes mellitus (GDM) is a significant risk factor for the type 2 diabetes epidemic in many populations. Maternal adipose tissue plays a central role in the pathophysiology of GDM. Thus, the aim of this study was to determine the effect of GDM on the proteome of adipose tissue. Omental adipose tissue was obtained at the time of term Caesarean section from women with normal glucose tolerance (NGT) or GDM. 2D-difference gel electrophoresis (DIGE), followed by mass spectrometry, was used to identify protein spots (n = 6 patients per group). Western blotting was used for confirmation of six of the spot differences (n = 6 patients per group). We found 14 proteins that were differentially expressed between NGT and GDM adipose tissue (≥ 1.4-fold, P < 0.05). GDM was associated with an up-regulation of four proteins: collagen alpha-2(VI) chain (CO6A2 (COL6A2)), fibrinogen beta chain (FIBB (FGB)), lumican (LUM) and S100A9. On the other hand, a total of ten proteins were found to be down-regulated in adipose tissue from GDM women. These were alpha-1-antitrypsin (AIAT (SERPINA 1)), annexin A5 (ANXA5), fatty acid-binding protein, adipocyte (FABP4), glutathione S-transferase P (GSTP (GSTP1)), heat-shock protein beta-1 (HSP27 (HSPB1)), lactate dehydrogenase B chain (LDHB), perilipin-1 (PLIN1), peroxiredoxin-6 (PRX6 (PRDX6)), selenium-binding protein 1 (SBP1) and vinculin (VINC (VCL)). In conclusion, proteomic analysis of omental fat reveals differential expression of several proteins in GDM patients and NGT pregnant women. This study revealed differences in expression of proteins that are involved in inflammation, lipid and glucose metabolism and oxidative stress and added further evidence to support the role of visceral adiposity in the pathogenesis of GDM.
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ItemEffect of Supracervical Apposition and Spontaneous Labour on Apoptosis and Matrix Metalloproteinases in Human Fetal Membranes(HINDAWI LTD, 2013)BACKGROUND: Apoptosis and matrix metalloproteinase (MMP-9) are capable of hydrolysing components of the extracellular matrix and weakening the fetal membranes which leads to eventual rupture, a key process of human parturition. The aim of this study was to determine the effect of supracervical apposition and spontaneous labour on apoptosis and MMP-9 in human fetal membranes at term. METHODS: Fetal membranes were obtained from term non-labouring supracervical site (SCS) and compared to (i) a paired distal site (DS) or (ii) site of rupture (SOR) after spontaneous labour onset. RESULTS: The expression of the proapoptotic markers Bax, Smac, Fas, FasL, caspase-3, and PARP, was significantly higher in the non-labouring SCS chorion compared to paired DS. Bax, Smac, FasL, caspase-3, and PARP staining was higher in the non-labouring SCS fetal membranes than that in the post-labour SOR. MMP-9 expression and activity were higher in the post-labour SOR fetal membranes compared to non-labouring SCS fetal membranes. CONCLUSION: Components of the apoptotic signalling pathways and MMP-9 may play a role in rupture and labour. Non-labouring SCS fetal membranes display altered morphology and altered apoptotic biochemical characteristics in preparation for labour, while the laboured SOR displays unique MMP characteristics.