ORCID Profile
0000-0002-1439-7016
Current Organisations
Mercy Hospital for Women
,
University of Melbourne
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Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.PLACENTA.2016.10.013
Abstract: Preecl sia is a serious complication affecting 5-8% of pregnancies. Central to its pathogenesis is placental hypoxia and inflammation which leads to secretion of soluble fms-like tyrosine kinase 1 (sFlt-1). sFlt-1 causes widespread endothelial dysfunction. The molecular mechanisms regulating sFlt-1 production remain poorly understood. Recently, a binding site for the nuclear factor activated T cells (NFAT) transcription factor has been found on fms-like tyrosine kinase 1 (FLT-1) promoter. We assessed whether inhibiting NFAT impacts FLT-1, sFlt-1 and cytokine expression, as well as sFlt-1 secretion in primary cytotrophoblasts, placental explants and human umbilical vein endothelial cells (HUVECs). We investigated whether NFAT is regulated by hypoxia in primary cytotrophoblasts. We characterised the expression of NFAT1-4 in preterm preecl tic compared to gestationally matched placentas. Inhibiting NFAT reduced FLT-1 and sFlt-1 splice variant e15a transcription, concordant with reduced total sFlt-1 and sFlt-1 e15a secretion from primary human cytotrophoblasts. This effect appeared tissue specific as inhibiting NFAT did not change sFlt-1 secretion from endothelial cells. Inhibiting NFAT also reduced transcription of inflammatory cytokines IL-1β and IL-10 in primary cytotrophoblasts. NFAT1 and NFAT3 mRNA expression were significantly increased under hypoxia (1% O NFAT positively regulates placental FLT-1 and sFlt-1 e15a, secretion of sFlt-1 and inflammatory cytokine expression. It may be involved in the pathophysiology of preecl sia.
Publisher: MDPI AG
Date: 25-08-2023
DOI: 10.3390/BIOENGINEERING10091007
Abstract: The measurement and analysis of fetal heart rate (FHR) and uterine contraction (UC) patterns, known as cardiotocography (CTG), is a key technology for detecting fetal compromise during labour. This technology is commonly used by clinicians to make decisions on the mode of delivery to minimise adverse outcomes. A range of computerised CTG analysis techniques have been proposed to overcome the limitations of manual clinician interpretation. While these automated techniques can potentially improve patient outcomes, their adoption into clinical practice remains limited. This review provides an overview of current FHR and UC monitoring technologies, public and private CTG datasets, pre-processing steps, and classification algorithms used in automated approaches for fetal compromise detection. It aims to highlight challenges inhibiting the translation of automated CTG analysis methods from research to clinical application and provide recommendations to overcome them.
Publisher: IEEE
Date: 11-2021
Publisher: Springer Science and Business Media LLC
Date: 12-05-2017
DOI: 10.1038/S41598-017-01993-W
Abstract: Preecl sia is a disease of pregnancy associated with placental oxidative stress, inflammation and elevated release of anti-angiogenic factors sFlt-1 and soluble endoglin. These placental factors cause generalized maternal endothelial dysfunction. There are no treatments to halt disease progression delivery is the only cure. Resveratrol modulates pathways involved in inflammation and oxidative stress and may offer a potential therapeutic for preecl sia. Resveratrol reduced sFlt-1, sFlt-1 e15a and soluble endoglin secretion from primary trophoblasts and HUVECs and reduced mRNA expression of pro-inflammatory molecules NFκB, IL-6 and IL-1β in trophoblasts. IL-6, IL-1β and TNFα secretion were also significantly reduced. In HUVECs, resveratrol significantly increased mRNA of anti-oxidant enzymes HO-1, NQO1, GCLC and TXN but did not significantly alter HO-1 protein expression, whilst reducing HO-1 protein in trophoblast. Endothelial dysfunction was induced in HUVECs using TNFα, increasing expression of cell adhesion molecule VCAM1 and adhesion of peripheral blood mononuclear cells, both of which were increased further by resveratrol. In contrast, resveratrol significantly reduced TNFα-induced Endothelin-1 (a vasoconstrictor) and significantly increased the phosphorylation of endothelial nitric oxide synthase (eNOS). In summary, resveratrol decreases secretion of anti-angiogenic factors however its effects on the endothelium are mixed. Overall, it may have potential as a treatment for preecl sia.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.PREGHY.2017.07.138
Abstract: Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are increased in the circulation of women with preecl sia. We examined whether they differ in concentration between plasma and serum s les. Maternal blood was collected and processed for serum and plasma, from 28 women with preterm preecl sia and 18 gestation matched controls (<34weeks). Significantly higher sFlt-1 was detected in preecl tic serum compared to plasma. Significantly higher levels of sENG were identified in serum compared to plasma from control pregnancies. Thus these data show the s le type (serum or plasma) needs to be consistent within comparisons for both sFlt-1 and sENG.
Publisher: Elsevier BV
Date: 11-2019
Publisher: Informa UK Limited
Date: 26-09-2017
DOI: 10.1080/14767058.2017.1378338
Abstract: The optimal oxytocin infusion regimen to induce labour with the lowest caesarean section rate, instrumental delivery rate and length of active labour is unclear. We compared the effect of a low-dose to high-dose oxytocin regimen to induce labour. We conducted a retrospective study of nulliparous women induced at term in a single tertiary centre from 2009 to 2015. The oxytocin induction protocol changed from a high to low-dose regimen in November 2012, affording us the opportunity to compare outcomes 3 years prior to, and following the change in protocol. Main outcome measures were caesarean section rate, instrumental delivery rate and length of active labour. Four thousand eight hundred and eighty-five participants were included, 2211 were induced via the low-dose regimen, and 2674 using the high-dose regimen. There was no difference in caesarean section rate (adjusted OR 0.99 95% CI 0.87-1.13) or instrumental delivery rates once adjusted for regional anaesthesia (adjusted OR 1.16 95% CI 0.99-1.36) between the different regimens. Surprisingly, the length of labour was longer in the high-dose oxytocin group (adjusted mean difference 0.60 h 95%CI 0.81-0.12). There were significantly more postpartum haemorrhage ≥1000 ml (10.5% versus 7.8%, p < .001) and regional anaesthesia use (55.8% versus 52.1%, p = .03) in the low-dose cohort. There were no differences in neonatal outcomes. Outcomes between high- and low-dose oxytocin induction regimens are relatively comparable with similar caesarean section and instrumental delivery rates. Therefore, either regimen is acceptable for use for induction of labour.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.PREGHY.2018.04.011
Abstract: To examine the effect of sildenafil on level of antiangiogenic proteins of preecl sia. Firstly to examine the effect of sildenafil on serum biomarkers in a patient with preterm preecl sia. Secondly, to examine the effect of sildenafil on sFlt-1 and soluble endoglin secretion from primary trophoblasts and placental explants. The clinical team administered 50 mg tds sildenafil to a 26-year-old primigravid woman with severe preecl sia at the threshold of viability (24 3/7 weeks gestation) and we collected bloods to examine the effect of slidenafil on antiangiogenic factors sFlt-1 and soluble endoglin (sENG), pro-angiogenic factor PlGF and vascular cell adhesion molecule 1 (VCAM-1) and endothelin-1 (ET1). We administered sildenafil to human primary trophoblasts and placental explants and explored its effect on sFlt-1 and sENG secretion. We examined serum anti-angiogenic factors sFlt-1 and sENG, pro-angiogenic factor PlGF, the potent vasoconstrictor ET1 and VCAM-1 by ELISA. We explored the effect of sildenafil on sFlt-1 secretion from primary trophoblasts and sFlt-1 and sENG secretion from placental explants. We found a reduction in serum sFlt-1, stabilisation in sENG and PlGF in a patient with peri-viable preterm preecl sia administered oral sildenafil 50 mg three times daily (tds). Furthermore there was an initial stabilisation in serum VCAM-1 and a decline in ET1 with sildenafil administration. This was concordant with stabilisation of clinical and biochemical features of preecl sia. Interestingly, treating placental cells and tissues in vitro with sildenafil did not appear to change sFlt-1 or sENG secretion. Sildenafil administration was associated with a reduction in serum sFlt-1 and sENG secretion and increase in PlGF secretion in a patient with preterm preecl sia, potentially via increasing placental perfusion rather than acting directly on the placenta.
Publisher: Public Library of Science (PLoS)
Date: 23-11-2022
Publisher: BMJ
Date: 22-09-2021
DOI: 10.1136/BMJ.N2103
Abstract: To evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-ecl sia. Randomised, double blind, placebo controlled trial. Referral hospital in Cape Town, South Africa. 180 women with preterm pre-ecl sia between 26+0 to 31+6 weeks’ gestation undergoing expectant management: 90 were randomised to extended release metformin and 90 to placebo. 3 g of oral extended release metformin or placebo daily, in ided doses, until delivery. The primary outcome was prolongation of gestation. Of 180 participants, one woman delivered before taking any trial drug. The median time from randomisation to delivery was 17.7 days (interquartile range 5.4-29.4 days n=89) in the metformin arm and 10.1 (3.7-24.1 n=90) days in the placebo arm, a median difference of 7.6 days (geometric mean ratio 1.39, 95% confidence interval 0.99 to 1.95 P=0.057). Among those who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 (interquartile range 5.4-28.7 n=76) days compared with 7.9 (3.0-22.2 n=74) days in the placebo arm, a median difference of 9.6 days (geometric mean ratio 1.67, 95% confidence interval 1.16 to 2.42). Among those who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 (interquartile range 4.8-28.8 n=40) days compared with 4.8 (2.5-15.4 n=61) days in the placebo arm, a median difference of 11.5 days (geometric mean ratio 1.85, 95% confidence interval 1.14 to 2.88). Composite maternal, fetal, and neonatal outcomes and circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin did not differ. In the metformin arm, birth weight increased non-significantly and length of stay decreased in the neonatal nursery. No serious adverse events related to trial drugs were observed, although diarrhoea was more common in the metformin arm. This trial suggests that extended release metformin can prolong gestation in women with preterm pre-ecl sia, although further trials are needed. It provides proof of concept that treatment of preterm pre-ecl sia is possible. Pan African Clinical Trial Registry PACTR201608001752102 pactr.samrc.ac.za/ .
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2017
DOI: 10.1161/HYPERTENSIONAHA.117.09548
Abstract: Preecl sia is a major pregnancy complication associated with poor placental perfusion and placental hypoxia. Systemic and placental inflammation and elevated placental secretion of the antiangiogenic factors sFlt-1 (soluble fms-like tyrosine kinase 1) and sEng (soluble endoglin) are hallmarks of preecl sia, causing endothelial dysfunction and multiorgan injury. A molecule that links placental hypoxia, inflammation, and antiangiogenic factor release has not been described. ATF3 (activating transcription factor 3) is highly expressed in placenta. We assessed whether placental ATF3 is dysregulated in preterm preecl sia, is altered by hypoxia, and regulates proinflammatory cytokine and antiangiogenic factor production. ATF3 mRNA and protein expression was significantly reduced in preterm preecl tic placentas compared with gestation-matched controls. Hypoxia reduced ATF3 expression in primary cytotrophoblast and placental explants. Silencing ATF3 in primary cytotrophoblast increased proinflammatory cytokine (IL-6 [interleukin 6], TNF-α [tumor necrosis factor α]) and NF-κB (nuclear factor κB) expression. In silico analysis identified an ATF3–binding site in the promoter of Flt-1 (the transcript from which sFlt-1 is produced). Silencing ATF3 increased sFlt-1 and sEng secretion from primary cytotrophoblast possibly by increasing Rab11a and Arf1, cargo proteins that facilitate exosomal release of sFlt-1. ATF3 knockout mice did not have a preecl sia phenotype, suggesting that these pathways may be specific to humans (preecl sia is a uniquely human condition). To conclude, we have shown that ATF3 is decreased in preecl tic placentas and that this decrease is likely to occur after prolonged hypoxia. We show that ATF3 is a regulator of placental proinflammatory cytokines and antiangiogenic factors sFlt-1 and sEng. Therefore, reduced ATF3 may be centrally involved in the pathology of preecl sia.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.PREGHY.2016.02.002
Abstract: Preecl sia is a serious pregnancy complication for which there are no medical treatments. Soluble endoglin is an anti-angiogenic factor implicated in the pathogenesis of the disease, however little is known about its molecular regulation. The PI3K/Akt pathway is down regulated in preecl tic placentas and decreased PI3K/Akt signaling has been linked to increased soluble endoglin release from endothelial cells. MMP14 is a key protease that functions to release soluble endoglin from the placental surface. This study aimed to determine whether reduced placental PI3K/Akt causes elevated release of soluble endoglin via MMP14. Akt mRNA and protein expression were assessed in early onset preecl tic and preterm control placentas (delivered <34weeks gestation). PI3K/Akt inhibition was achieved by administering PI3K inhibitor wortmannin, a specific Akt inhibitor or Akt siRNA to primary human umbilical vein endothelial cells, primary trophoblast and placental explants. The effect of PI3K/Akt inhibition on soluble endoglin release, MMP14, endoglin and TIMP-3 mRNA expression was determined. We identified significantly reduced pAkt and total Akt in preecl tic placentas relative to preterm control. Inhibition of PI3K/Akt resulted in significantly elevated soluble endoglin release from HUVECs, had no effect on MMP14 mRNA expression but resulted in significantly reduced TIMP3. In contrast inhibiting PI3K/Akt in placental explants or primary trophoblast did not change soluble endoglin release. This study confirms that the PI3K/Akt cell protection pathway is down regulated in preecl sia, but demonstrates that this dysregulation is unlikely to be responsible for the excessive placental soluble endoglin release characteristic of preecl sia.
Publisher: Wiley
Date: 03-10-2019
DOI: 10.1002/IJGO.12971
Abstract: Betel nut is the fourth most commonly abused substance worldwide and has been associated with significant adverse health outcomes. Little is known about its effects on the fetus. To perform a systematic review of studies investigating prenatal betel nut use and adverse perinatal outcomes. Pubmed, Embase, and Cochrane databases were searched from inception until July 2018 using the terms areca, betel nut, pregnancy, pregnancy complications, and infection. Eligible studies included case-control, cohort, and randomized control studies involving pregnant women. Where appropriate, bivariate meta-analysis was performed, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. In total, 28 studies were screened and eight studies (including 15 270 women) were included in the review and meta-analysis. Preterm birth, low birthweight, and anemia were most commonly investigated. Meta-analysis revealed a significant association between betel nut use and low birthweight, with a pooled OR of 1.75 (95% CI, 1.35-2.27). The review identified only eight eligible studies, all based in the Asia-Pacific region. There was a significant association between low birthweight and betel nut exposure in pregnancy. Further prospective studies are needed to confirm this association.
Publisher: Frontiers Media SA
Date: 29-03-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2017
DOI: 10.1161/HYPERTENSIONAHA.116.08408
Abstract: Preecl sia is a severe complication of pregnancy. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. Oxidative stress and vascular inflammation exacerbate the endothelial injury. A drug that can block these pathophysiological steps would be an attractive treatment option. Proton pump inhibitors (PPIs) are safe in pregnancy where they are prescribed for gastric reflux. We performed functional studies on primary human tissues and animal models to examine the effects of PPIs on sFlt-1 and soluble endoglin secretion, vessel dilatation, blood pressure, and endothelial dysfunction. PPIs decreased sFlt-1 and soluble endoglin secretion from trophoblast, placental explants from preecl tic pregnancies, and endothelial cells. They also mitigated tumor necrosis factor-α–induced endothelial dysfunction: PPIs blocked endothelial vascular cell adhesion molecule-1 expression, leukocyte adhesion to endothelium, and disruption of endothelial tube formation. PPIs decreased endothelin-1 secretion and enhanced endothelial cell migration. Interestingly, the PPI esomeprazole vasodilated maternal blood vessels from normal pregnancies and cases of preterm preecl sia, but its vasodilatory effects were lost when the vessels were denuded of their endothelium. Esomeprazole decreased blood pressure in a transgenic mouse model where human sFlt-1 was overexpressed in placenta. PPIs upregulated endogenous antioxidant defenses and decreased cytokine secretion from placental tissue and endothelial cells. We have found that PPIs decrease sFlt-1 and soluble endoglin secretion and endothelial dysfunction, dilate blood vessels, decrease blood pressure, and have antioxidant and anti-inflammatory properties. They have therapeutic potential for preecl sia and other diseases where endothelial dysfunction is involved.
Publisher: The Endocrine Society
Date: 22-02-2021
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.AJOG.2015.12.019
Abstract: Preecl sia is associated with placental ischemia/hypoxia and secretion of soluble fms-like tyrosine kinase 1 and soluble endoglin into the maternal circulation. This causes widespread endothelial dysfunction that manifests clinically as hypertension and multisystem organ injury. Recently, small molecule inhibitors of hypoxic inducible factor 1α have been found to reduce soluble fms-like tyrosine kinase 1 and soluble endoglin secretion. However, their safety profile in pregnancy is unknown. Metformin is safe in pregnancy and is also reported to inhibit hypoxic inducible factor 1α by reducing mitochondrial electron transport chain activity. The purposes of this study were to determine (1) the effects of metformin on placental soluble fms-like tyrosine kinase 1 and soluble endoglin secretion, (2) to investigate whether the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion are regulated through the mitochondrial electron transport chain, and (3) to examine its effects on endothelial dysfunction, maternal blood vessel vasodilation, and angiogenesis. We performed functional (in vitro and ex vivo) experiments using primary human tissues to examine the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion from placenta, endothelial cells, and placental villous explants. We used succinate, mitochondrial complex II substrate, to examine whether the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion were mediated through the mitochondria. We also isolated mitochondria from preterm preecl tic placentas and gestationally matched control subjects and measured mitochondrial electron transport chain activity using kinetic spectrophotometric assays. Endothelial cells or whole maternal vessels were incubated with metformin to determine whether it rescued endothelial dysfunction induced by either tumor necrosis factor-α (to endothelial cells) or placenta villous explant-conditioned media (to whole vessels). Finally, we examined the effects of metformin on angiogenesis on maternal omental vessel explants. Metformin reduced soluble fms-like tyrosine kinase 1 and soluble endoglin secretion from primary endothelial cells, villous cytotrophoblast cells, and preterm preecl tic placental villous explants. The reduction in soluble fms-like tyrosine kinase 1 and soluble endoglin secretion was rescued by coadministration of succinate, which suggests that the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin were likely to be regulated at the level of the mitochondria. In addition, the mitochondrial electron transport chain inhibitors rotenone and antimycin reduced soluble fms-like tyrosine kinase 1 secretion, which further suggests that soluble fms-like tyrosine kinase 1 secretion is regulated through the mitochondria. Mitochondrial electron transport chain activity in preterm preecl tic placentas was increased compared with gestation-matched control subjects. Metformin improved features of endothelial dysfunction relevant to preecl sia. It reduced endothelial cell messenger RNA expression of vascular cell adhesion molecule 1 that was induced by tumor necrosis factor-α (vascular cell adhesion molecule 1 is an inflammatory adhesion molecule up-regulated with endothelial dysfunction and is increased in preecl sia). Placental conditioned media impaired bradykinin-induced vasodilation this effect was reversed by metformin. Metformin also improved whole blood vessel angiogenesis impaired by fms-like tyrosine kinase 1. Metformin reduced soluble fms-like tyrosine kinase 1 and soluble endoglin secretion from primary human tissues, possibly by inhibiting the mitochondrial electron transport chain. The activity of the mitochondrial electron transport chain was increased in preterm preecl tic placenta. Metformin reduced endothelial dysfunction, enhanced vasodilation in omental arteries, and induced angiogenesis. Metformin has potential to prevent or treat preecl sia.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.PLACENTA.2016.10.008
Abstract: Preecl sia is a serious complication of pregnancy affecting 5% of pregnancies. Our team identified 137 genes highly expressed in placenta relative to other human tissues. Here, we have explored a role for steroid sulfatase (STS) in preecl sia by characterising STS expression and the functional effects of STS on primary placental trophoblasts. Characterisation of STS was performed on preterm preecl tic and gestation-matched normotensive preterm controls who delivered at <34 weeks gestation. We characterised placental and maternal whole blood STS mRNA and placental protein expression via qRT-PCR, immunohistochemistry and Western Blot. To assess whether STS is involved in sFlt1 secretion and syncytialisation, we administered siRNA to silence STS in primary trophoblasts before measuring sFlt1 and hCG secretion and E-Cadherin expression. A custom array containing 45 placental specific genes identified 10 genes significantly altered in the placentas of preecl tic patients relative to normotensive gestation-matched controls. Of these genes, qRT-PCR and western blot on a larger cohort confirmed that the expression of STS was significantly elevated in preecl tic placentas (n = 44) relative to gestation matched controls (n = 26). Given placental RNA leaks in to the maternal circulation, we also assessed STS mRNA expression in the whole blood of patients with preecl sia and found it was significantly increased relative to normotensive controls. siRNA knockdown of STS in primary trophoblast resulted in a modest but significant reduction in sFlt1 secretion, but had no affect on hCG secretion or E-Cadherin protein expression. STS is increased in preecl tic placentas and maternal whole blood. Our data suggests that STS may affect sFlt1 secretion by regulating sFlt1-i13 transcription, and not via alterations in syncytialisation.
Publisher: Springer Science and Business Media LLC
Date: 20-05-2016
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.PLACENTA.2021.04.007
Abstract: Preecl sia is a serious pregnancy complication associated with elevated antiangiogenic markers and endothelial dysfunction. Recently nicotinamide (vitamin B3) was shown to reduce high blood pressure and proteinuria in mice models of the disease. Using primary human pregnancy tissue we show nicotinamide did not change antiangiogenic factor secretion including soluble fms-like tyrosine kinase 1 or soluble endoglin from primary cytotrophoblasts and placental explants. Furthermore, it did not reverse markers of endothelial dysfunction. Therefore, we did not demonstrate an effect of nicotinamide on reducing markers of preecl sia from primary human placental tissues and vascular cells.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.PREGHY.2018.09.001
Abstract: Preecl sia is a severe complication of pregnancy, and likely arises from abnormal placental development in early pregnancy. Persistent placental hypoxia is thought to trigger the release of anti-angiogenic factors into the maternal circulation leading to widespread endothelial dysfunction. Epidermal growth factor-like domain 7 (EGFL7) is a secreted angiogenic factor that may play a key role in the disrupted angiogenesis seen in response to placental hypoxia that characterizes preecl sia. Primary trophoblasts were isolated and cultured in both normoxic and hypoxic conditions. Under hypoxia HIF1α was silenced and EGFL7 mRNA expression was assessed. EGFL7 mRNA expression was measured in placentas obtained from women with early ( 2-fold, p < 0.0001), however this was not regulated via a HIF1α dependent manner. EGFL7 mRNA expression was not altered in placenta from women with early or late onset preecl sia. Circulating EGFL7 protein levels were not different in women with severe preecl sia. In contrast, EGFL7 mRNA expression was increased in maternal blood in women with early onset preecl sia (∼1.6-fold, p < 0.05). EGFL7 mRNA expression is increased with hypoxia in human trophoblast and is increased in the maternal circulation in women with preecl sia. Further studies aimed at understanding the role and regulation of EGLF7 in the pathophysiology of preecl sia are required.
Publisher: MDPI AG
Date: 09-02-2022
DOI: 10.3390/JCM11040901
Abstract: Fetal growth restriction (FGR), when undetected antenatally, is the biggest risk factor for preventable stillbirth. Maternal circulating SPINT1 is reduced in pregnancies, which ultimately deliver small for gestational age (SGA) infants at term (birthweight < 10th centile), compared to appropriate for gestational age (AGA) infants (birthweight ≥ 10th centile). SPINT1 is also reduced in FGR diagnosed before 34 weeks' gestation. We hypothesised that circulating SPINT1 would be decreased in co-existing preterm preecl sia and FGR. Plasma SPINT1 was measured in s les obtained from two double-blind, randomised therapeutic trials. In the Preecl sia Intervention with Esomeprazole trial, circulating SPINT1 was decreased in women with preecl sia who delivered SGA infants (
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.PLACENTA.2019.09.004
Abstract: Preecl sia is a hypertensive disorder of pregnancy with no available medical treatment. We recently reported sulfasalazine, an anti-inflammatory medication, to be a candidate therapeutic for preecl sia. We showed sulfasalazine decreases placental secretion of soluble Fms-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic factor strongly implicated in the pathogenesis of preecl sia. However, the cellular mechanism(s) by which sulfasalazine reduces placental sFlt-1 are yet to be determined. Recently we also reported that both the mitochondria and the epidermal growth factor receptor (EGFR) signalling pathways regulate secretion of placental sFlt-1. In this study we sought to assess directly whether sulfasalazine's capacity to reduce sFlt-1 secretion may be mediated via EGFR or the mitochondria. Using primary cytotrophoblast cells, we confirmed sulfasalazine reduced sFlt-1 secretion. Interestingly, when we measured the mRNA expression of EGFR, we found a reduction in EGFR expression which closely mirrored the changes in sFlt-1 secretion. At the protein level, sulfasalazine significantly reduced phosphorylated and active EGFR (phosphorylated/total) expression. Additionally, sulfasalazine significantly reduced the protein expression of ERK1/2 and STAT3 which are key adaptor molecules downstream of EGFR. Next, we assessed mitochondrial respiration following sulfasalazine treatment and found no effect on basal respiration, ATP production, proton leak or maximal respiration. Sulfasalazine reduces EGFR and down-stream signalling molecule expression coincident with reduced sFlt-1 secretion. EGFR signalling is a potential mechanism by which sulfasalazine decreases placental secretion of sFlt-1. Further interrogation of the EGFR may identify new candidate treatments for preecl sia.
Publisher: Wiley
Date: 09-01-2020
DOI: 10.1111/AJO.13111
Abstract: Small for gestational age (SGA) is a major determinant of poor perinatal outcome. Detecting SGA at term using ultrasound is challenging and we often plan birth based on clinical assessment. To determine the incidence of SGA infants with birthweight <10th centile among women undergoing planned birth at term for suspected SGA despite a normal estimated fetal weight (EFW) on ultrasound at 35-37 weeks. We performed a retrospective study including all women with a fetal growth ultrasound at ≥35 weeks reporting an EFW ≥ 10th centile (appropriate for gestational age, AGA) who subsequently had an induction of labour or caesarean birth at ≥37 weeks due to ongoing clinical suspicion of SGA between 2012-2014. The primary outcome was the incidence of SGA newborns using customised centiles. There were 532 women who had a planned birth for clinical suspicion of SGA during the study period. Of these, 205 (38.5%) had an AGA fetus on ultrasound ≥35 weeks but were subsequently delivered because of a persisting clinical suspicion of SGA on abdominal assessment. Sixty-eight percent (n = 139/205) delivered an SGA infant. Furthermore, almost half of these SGA infants (47.5%) had a birthweight <3rd centile. Neonatal outcomes were worse for the SGA infants, with 15.1% (n = 21/205) requiring special care nursery compared to 1.5% (n = 1/205) of those AGA at birth. A reassuring ultrasound with EFW ≥10th centile in the late third trimester should not override clinical concerns of impaired fetal growth at term.
Publisher: Public Library of Science (PLoS)
Date: 21-02-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2019
DOI: 10.1161/HYPERTENSIONAHA.118.12300
Abstract: Preecl sia is a hypertensive disorder of pregnancy characterized by maternal endothelial dysfunction and end-organ damage. The antiangiogenic factor, sFlt-1 (soluble FMS-like tyrosine kinase-1) has been strongly implicated in the pathogenesis of preecl sia. sFlt-1 is secreted into the maternal circulation where it antagonizes VEGF (vascular endothelial growth factor) and ultimately disrupts vascular homeostasis. However, the upstream mechanisms regulating release of sFlt-1 are poorly characterized. We investigated the roles of key prosurvival pathways, EGFR (epidermal growth factor receptor) signaling, and the mitochondria, in regulating sFlt-1 production. We initially found that the mRNA and protein of EGFR and downstream adaptor molecules were significantly increased in preecl tic placental tissue relative to normotensive controls. Inhibiting the EGFR signaling cascade using siRNA (small interfering ribonucleic acid) or small molecule inhibitors significantly reduced sFlt-1 release from primary cytotrophoblast (placental cells). Additionally, inhibiting the mitochondrial electron transport chain or activating downstream energy-sensing molecules (AMPK [AMP-activated kinase], SIRT1 [sirtuin 1 ], and PGC1α [PPAR-γ co-activator 1]) also significantly reduced sFlt-1 secretion from cytotrophoblast cells, without affecting EGFR signaling. In vivo, treating pregnant mice with gefitinib (an EGFR inhibitor) or resveratrol (perturbs mitochondrial function) significantly reduced circulating murine sFlt-1 compared with vehicle control. Furthermore, treating primary cytotrophoblasts with therapeutics which have been previously found to reduce sFlt-1 secretion, either reduced EGFR signaling (esomeprazole and statins) or perturbed mitochondrial function (esomeprazole, resveratrol, and metformin). Additionally, targeting both pathways simultaneously produced additive reductions in sFlt-1 secretion. Thus, we have identified 2 key survival pathways that seem to be overactive in preecl sia and involved in the regulation of placental sFlt-1 secretion.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.PREGHY.2018.09.005
Abstract: Preecl sia is associated with intermittent placental hypoxia, inflammation and the release of antiangiogenic factors, namely sFLT-1 and sEng. These factors cause maternal endothelial dysfunction and the manifestation of clinical disease. Disulfiram is a dehydrogenase inhibitor used to treat alcoholism and has been suggested as a proteasome inhibitor. Inhibiting the proteasome has been previously shown to reduce FLT-1 gene expression. Thus, we aim to investigate whether disulfiram alters the secretion of sFLT-1 and sEng and reduces endothelial dysfunction. METHODS AND RESULTS: We assessed the effects of disulfiram on primary cytotrophoblast and human umbilical vein endothelial cells (HUVECs). Disulfiram significantly reduced mRNA expression of membrane bound FLT-1 and sFLT-1 variants in primary cytotrophoblasts, which translated into a significant reduction in the protein secretion of sFLT-1. Additionally, sFLT-1 was reduced in primary HUVECs treated with disulfiram, whilst sEng was only reduced in primary cytotrophoblasts. Next, we investigated the effect of disulfiram on endothelial dysfunction using primary HUVECs treated with 5% preecl tic serum ± disulfiram. Serum from preecl tic women induced endothelial dysfunction evidenced by increased mRNA expression of vascular cell adhesion molecule-1 (VCAM-1) and adhesion of peripheral blood mononuclear cells (PBMCs) to HUVECs. The addition of disulfiram reduced VCAM-1 mRNA expression, however did not affect the adhesion of PBMCs to endothelial cells. Lastly, we assessed the effects of disulfiram on the 20S subunit of the proteasome and found disulfiram did not inhibit this subunit in either primary cytotrophoblast or HUVECs. CONCLUSIONS: Disulfiram quenches sFLT-1 and sEng via mechanisms independent of the 20S subunit of the proteasome. Understanding of the mechanisms by which disulfiram inhibits antiangiogenic secretion may reveal insights into the pathogenesis and potential therapeutic targets for preecl sia.
Publisher: Wiley
Date: 03-2018
DOI: 10.1002/UOG.19016
Publisher: Elsevier BV
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 16-08-2021
DOI: 10.1038/S41598-021-96077-1
Abstract: Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts a large prospective cohort collected around 36 weeks’ gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women s led at 24–34 weeks’ gestation) two prospective cohorts collected on the day of delivery (36 + 3–41 + 3 weeks’ gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR ( 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Wiley
Date: 29-08-2013
Publisher: Wiley
Date: 29-12-2015
Abstract: To assess whether routinely weighing women at each antenatal visit leads to a difference in gestational weight gain and weight gain within the Institute of Medicine (IOM) recommendation. A randomised controlled trial. Antenatal clinics in a tertiary obstetric hospital in Melbourne, Australia. Healthy women were enrolled during their antenatal booking visit if they were between 18 and 45 years of age, were <21 weeks' gestation with a singleton pregnancy. The intervention was weighing at each antenatal clinic appointment followed by counselling by their treating clinician according to IOM gestational weight gain guidelines. The control group had standard antenatal care comprising recording weight at booking and then at 36 weeks. Primary analysis was by intention-to-treat. The primary outcome was difference in mean weight gain between groups. An important secondary outcome was gestational weight gain within IOM recommendations. Secondary outcomes also included maternal or neonatal morbidity. Seven hundred and eighty two women consented to take part and 386 were randomised to the intervention group and 396 to the control group. There was no significant difference in weight gain between the intervention group (0.54 kg/week) compared with the control group (0.53 kg/week) (P = 0.63). A similar proportion of women gained more weight than the IOM recommended range: 75% in the intervention group and 71% in the control group (P = 0.21). There were no significant differences in secondary outcomes between the two groups. We found no evidence that regular weighing in antenatal clinics changed weight gain or was effective at reducing excessive gestational weight gain.
Publisher: Springer London
Date: 16-10-2013
Publisher: Informa UK Limited
Date: 09-09-2021
DOI: 10.1080/14767058.2021.1974835
Abstract: To assess the growth trajectory of preterm small-for-gestational-age (SGA) neonates compared to preterm non-small-for-gestational age neonates in the neonatal intensive care unit and special care nursery. We conducted a retrospective cohort study at a large tertiary hospital in Victoria, Australia, examining neonates ≤34 weeks' gestation admitted to the neonatal intensive care unit or special care nursery between 2013 and 2017. We categorized neonates according to their birth weight centile: <10th centile (small-for-gestational age) and ≥10th centile (non-small-for-gestational age). Growth trajectory was tracked based on serial weights obtained in the neonatal intensive care unit and special care nursery, using Of the 910 babies included, 88 were small-for-gestational age and 822 were appropriate-for gestational age. Both groups had a reduction in their weight Preterm SGA babies experience a smaller reduction in their weight trajectory compared to their appropriately grown counterparts in the neonatal intensive care unit or special care nursery.
Publisher: BMJ
Date: 04-2019
DOI: 10.1136/BMJOPEN-2018-025809
Abstract: Pre-ecl sia is a major complication of pregnancy, globally responsible for 60 000 maternal deaths per year, and far more fetal losses. There is no definitive treatment other than delivery. A therapeutic that could quench the disease process would be useful to treat preterm pre-ecl sia, as it could allow these pregnancies to safely continue to a gestation where fetal outcomes are significantly improved. We have published preclinical data to show that metformin, a drug known to be safe in pregnancy and commonly used to treat gestational diabetes, has potent biological effects making it another promising candidate to treat pre-ecl sia. Here, we describe a phase II clinical trial to examine whether administering extended-release metformin may be effective in treating women with preterm pre-ecl sia (PI2 Trial). The PI2 Trial is a phase II, double blind, randomised controlled trial that aims to recruit 150 women with preterm pre-ecl sia (gestational age 26+0 to 31+6 weeks) who are being managed expectantly. Participants will be randomised to receive either 3 g of metformin or placebo daily. The primary outcome is time from randomisation until delivery. A delay in delivery of 5 days is assumed to be clinically relevant. The secondary outcomes will be a maternal composite and neonatal composite outcome. All other outcomes will be exploratory. We will record adverse events. This study has ethical approval (Protocol number M16/09/037 Federal Wide Assurance Number 00001372, Institutional Review Board Number IRB0005239), is registered with the Pan African Clinical Trial Registry (PACTR201608001752102) and the South African Medicine Control Council (20170322). Data will be presented at international conferences and published in peer-reviewed journals. PACTR201608001752102 Pre-results.
Publisher: Wiley
Date: 29-12-2015
Abstract: To assess the opinions of pregnant women regarding their weight gain and to assess the level of satisfaction and anxiety provoked by being weighed in clinic. Questionnaires were given to women participating in a randomised controlled trial comparing routine weighing in the antenatal clinic with standard care. A tertiary hospital antenatal clinic in Melbourne, Australia. In all, 782 healthy pregnant women participated in the randomised controlled trial and 586 responded to the questionnaire. A questionnaire was offered to all participants at 36 weeks of gestation gauging their satisfaction with their weight gain during pregnancy. The intervention group was asked about their level of satisfaction and anxiety provoked by being weighed in clinic. The control group was asked whether they would have liked to be weighed in clinic. Both groups were questioned about the influences on their weight gain. Women in both groups were satisfied with their weight gain during pregnancy. Seventy-three percent of women in the intervention group were very comfortable with being weighed in clinic. Approximately half of those in the control group would have favoured being weighed. Twenty-one percent of women said other people influenced their weight gain mostly family members and two-thirds of them encouraged weight gain. Less than half of the women in the study used weighing scales at home. Women were satisfied with being weighed antenatally and it did not cause anxiety. Pregnant women accepted the re-introduction of weighing in the antenatal clinic.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2015
DOI: 10.1161/HYPERTENSIONAHA.115.05847
Abstract: Elevated placental release of the antiangiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG), is central to the pathophysiology of preecl sia. It is widely accepted that heme oxygenase-1 (HO-1) is decreased in preecl tic placenta and negatively regulates sFlt-1 and sENG production. We set out to verify these contentions. There was no difference in HO-1 mRNA or protein levels in preterm preecl tic placentas (n=17) compared with gestationally matched controls (n=27). In silico analysis of microarray studies did not identify decreased placental HO-1 expression in preecl tic placenta. Silencing HO-1 in primary trophoblasts did not affect sFlt-1 protein secretion after 24 or 48 hours. Silencing nuclear factor (erythroid-derived 2)-like 2 (transcription factor that upregulates HO-1) in trophoblasts also did not affect sFlt-1 secretion. Administering tin protoporphyrin IX dichloride (HO-1 inhibitor) or cobalt protoporphyrin (HO-1 inducer) into placental explants did not affect sFlt-1 or sENG secretion. Silencing HO-1 in 2 types of primary endothelial cells (human umbilical vein endothelial and uterine microvascular endothelial cells) significantly increased sFlt-1 secretion but not sENG secretion. However, HO-1 silencing selectively increased mRNA expression of sFlt-1 i13 (generically expressed sFlt-1 variant) but not of sFlt-1 e15a (sFlt-1 variant mainly expressed in placenta). Furthermore, adding tin protoporphyrin IX dichloride decreased sFlt-1, whereas adding HO-1 inducers (cobalt protoporphyrin, dimethyl fumarate, and rosiglitazone) either had no effect or increased sFlt-1 or sENG secretion (these trends are opposite to what is expected). We conclude that HO-1 expression is not decreased in preecl tic placenta and HO-1 does not negatively regulate placental sFlt-1 and sENG secretion in placental or endothelial cells.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.PLACENTA.2021.08.002
Abstract: Preecl sia is associated with reduced pro-angiogenic Placental Growth Factor (PlGF) and increased levels of anti-angiogenic soluble FMS like tyrosine kinase-1 (sFlt-1). We have previously shown that sFlt-1 secretion is positively regulated via the Epidermal Growth Factor Receptor (EGFR) and mitochondrial respiration pathways. We assessed whether these pathways also regulate endothelial and placental secretion of PlGF. Primary cytotrophoblast cells and primary human umbilical vein endothelial cells (HUVECs) were treated with EGFR inhibitor gefitinib, or small molecules that inhibit down-stream pathways of the receptor: U0126, PD98059 (ERK/MEK pathway inhibitors), ZM336372 (JAK/STAT inhibitor) or AG490 (JAK inhibitor). We inhibited mitochondrial respiration in primary cytotrophoblasts using mitochondrial complex inhibitors rotenone (complex I), antimycin (complex III) or oligomycin (complex IV). We then measured PlGF secretion in the condition media. Three inhibitors of the EGFR pathway significantly increased PlGF secretion: gefitinib (p = 0.03), AG490 (p < 0.0001) and U0126 (p = 0.03) in primary cytotrophoblasts, while PD98059 reduced PlGF secretion (p = 0.002). In the same cells, neither gefitinib or UO126 altered PlGF mRNA expression, but AG490 significantly increased its expression (p = 0.02). Primary endothelial cell PlGF secretion was significantly reduced when treated with PD98059 and U0126 while ZM336372 had no effect. Rotenone significantly reduced cytotrophoblast PlGF secretion (p = 0.0005). Neither antimycin (p = 0.9) or oligomycin (p = 0.9) had an effect. We have shown that PlGF secretion from primary cytotrophoblast and HUVECs is altered by inhibiting EGFR signaling and potentially mitochondrial respiration, coincident with reduced sFlt-1 secretion. This suggests that common pathways are regulating both pro and anti-angiogenic molecules that are changed in association with preecl sia and provides insight into the pathogenesis of this serious disease.
Publisher: Informa UK Limited
Date: 09-02-2021
DOI: 10.1080/14767058.2021.1882980
Abstract: To investigate delivery indications for women with late preterm preecl sia and evaluate whether disease characteristics at presentation are predictive of delivery indication. We conducted a retrospective case-control study at the Mercy Hospital for Women (a tertiary hospital in Melbourne, Australia). Indication for delivery was assessed among women presenting with preecl sia between 30 173 women were diagnosed with preecl sia between 30 Women presenting with late preterm preecl sia primarily required delivery for maternal disease progression rather than fetal compromise.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2021
Publisher: SAGE Publications
Date: 27-05-2015
Abstract: Fetal persistent middle cerebral artery reversed end diastolic flow is a rare and ominous finding. Previous cases have been associated with intracranial hemorrhage, growth restriction, anaemia, and hepatic anomaly. Intrauterine demise or early neonatal death is a common outcome. We report the case of persistent middle cerebral artery reversed end diastolic flow in a well-grown fetus at 32 weeks’ gestation resulting from acute, severe anaemia due to a large feto-maternal hemorrhage. An emergency cesarean section was performed and the neonate required advanced resuscitation and immediate blood transfusion. Postnatal magnetic resonance imaging confirmed a hemorrhagic parietal infarct and bilateral ischaemic changes in the basal ganglia. This provides further evidence that persistent middle cerebral artery reversed end diastolic flow in any fetus is an ominous finding warranting urgent diagnostic evaluation and/or delivery.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.PREGHY.2019.09.004
Abstract: Preecl sia complicates 5-8% of all pregnancies and is associated with high rates of maternal and perinatal morbidity. The majority of cases occur at term gestations where the baby can be safely delivered. The preecl sia disease process however can progress in the mother resulting in significant morbidity. In this study we were interested in examining the number of patients developing preecl sia with severe features at term. We also investigated whether factors at admission might be predictive of disease progression. We performed a retrospective cohort study at a tertiary obstetric hospital in Melbourne, Australia from 2015 to 2017. There were 124 participants presenting with preecl sia at term and included in our study. After admission, 44.4% progressed to preecl sia with severe features. Disease features at admission associated with disease progression were chronic hypertension, elevated systolic blood pressure, reduced haemoglobin and elevated creatinine. Using predictive modelling, we determined that a combination of these features showed good discrimination (area under ROC = 0.88 (95% confidence interval 0.82-0.94)) with good performance (negative predictive value 80% and positive predictive value 87%) for predicting progression to preecl sia with severe features. Almost half of the women presenting with preecl sia at term will progress to preecl sia with severe features. Admission characteristics can be used to predict those at risk of disease progression.
Publisher: IEEE
Date: 07-2020
Publisher: IOP Publishing
Date: 28-02-2022
Abstract: Objective. Fetal arrhythmias are a life-threatening disorder occurring in up to 2% of pregnancies. If identified, many fetal arrhythmias can be effectively treated using anti-arrhythmic therapies. In this paper, we present a novel method of detecting fetal arrhythmias in short length non-invasive fetal electrocardiography (NI-FECG) recordings. Approach. Our method consists of extracting a fetal heart rate time series from each NI-FECG recording and computing an entropy profile using a data-driven range of the entropy tolerance parameter r . To validate our approach, we apply our entropy profiling method to a large clinical data set of 318 NI-FECG recordings. Main Results. We demonstrate that our method ( TotalS En ) provides strong performance for classifying arrhythmic fetuses (AUC of 0.83) and outperforms entropy measures such as S En (AUC of 0.68) and FuzzyEn (AUC of 0.72). We also find that NI-FECG recordings incorrectly classified using the investigated entropy measures have significantly lower signal quality, and that excluding recordings of low signal quality (13.5% of recordings) increases the classification performance of TotalS En (AUC of 0.90). Significance. The superior performance of our approach enables automated detection of fetal arrhythmias and warrants further investigation in a prospective clinical trial.
Publisher: Springer Science and Business Media LLC
Date: 09-2017
Abstract: Preecl sia is a hypertensive disorder of pregnancy, responsible for over 60 000 maternal deaths annually. Endothelial dysfunction is a central aspect to its pathophysiology, and currently, no medical therapeutic is available for its treatment. In this study, we aim to investigate the effect of epidermal growth factor (EGF) on endothelial dysfunction using primary human tissues. We performed a number of in vitro assays that mimic the vascular endothelial dysfunction that occurs in preecl sia. Epidermal growth factor reduced the expression of vascular cell adhesion molecule-1, a marker of endothelial dysfunction, after insult with tumor necrosis factor α (TNF-α) or serum from women with preecl sia. Additionally, after TNF-α insult, EGF reduced tube disruption and the adhesion of monocytes to primary human umbilical vein endothelial cells (HUVECs). Our findings suggest that EGF reduces endothelial dysfunction in primary HUVECs. Epidermal growth factor may have potential as a novel peptide treatment for preecl sia and other diseases where there is endothelial dysfunction.
Publisher: Informa UK Limited
Date: 03-03-2016
DOI: 10.3109/14767058.2016.1147555
Abstract: To examine the delivery indication (maternal or fetal) for patients with preterm preecl sia and assess whether disease characteristics at presentation are predictive of delivery indication. We conducted a retrospective cohort study at a tertiary hospital in Melbourne, Australia (Mercy Hospital for Women). We assessed indication for delivery for participants presenting with preecl sia from 23(+0) to 32(+6) weeks gestation. We compared baseline disease characteristics, disease features at delivery and postnatal outcomes between those delivered for maternal or fetal indications, or for both maternal and fetal indications. Two hundred sixty six participants presented with preterm preecl sia and 108 were eligible for inclusion in our study. More participants were delivered for maternal indications at 65.7% compared to those requiring delivery on fetal grounds at 19.4% or for both indications at 14.8% (p < 0.0001). Maternal disease characteristics at presentation were similar between groups however, there was a higher proportion of growth restriction and abnormal Dopplers among those delivered on fetal grounds. Participants delivered on maternal grounds gained less gestation, had higher blood pressure and higher incidence of abnormal liver function tests than those delivering for fetal indications at delivery. Participants with preterm preecl sia were predominantly delivered due to maternal disease progression compared to fetal compromise.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2019
DOI: 10.1097/AOG.0000000000003476
Abstract: To estimate the predictive value of signs and symptoms that occur before onset of ecl sia among pregnant women. Electronic databases, including MEDLINE, EMBASE, Cochrane, and ClinicalTrials.gov were searched from inception to 2018. Search terms included ecl sia, predict, likelihood ratio, predictive value, and risk. Abstracts and later full texts were selected for review if a diagnosis of ecl sia was made, a comparator arm included (women without a diagnosis of ecl sia), and predictors of imminent ecl sia reported. Of 2,791 retrieved records, 11 were selected. Significant heterogeneity existed between studies, with differing designs, settings, participants, and signs or symptoms. In total, 28 signs or symptoms were reported, with visual disturbances and epigastric pain most common (six studies), followed by headache (five studies), and any edema (four studies). Data on study characteristics and predictive value of signs or symptoms were extracted, and, where appropriate, bivariate mixed-effect meta-analysis was applied to raw data. None of the pooled estimates were able to accurately predict ecl sia nor rule out ecl sia in their absence, with moderate specificity (83–94%) and poor sensitivity (29–56%). There is a dearth of high-quality studies investigating the predictive value of imminent signs and symptoms of ecl sia. Owing to the small number of studies, heterogeneity, and inconsistent reporting, it is difficult to provide accurate estimates of the predictive value of prodromal symptoms of ecl sia. Of the most commonly reported symptoms—visual disturbances, epigastric pain, and headache—none were able to accurately predict, nor rule out, imminent ecl sia. PROSPERO, CRD42018095076.
Publisher: Oxford University Press (OUP)
Date: 03-2016
DOI: 10.1095/BIOLREPROD.115.134460
Abstract: The anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFLT-1), plays a central role in preecl tic pathophysiology. A splice variant of FLT-1 (VEGF receptor 1), sFLT-1 is released in excessive amounts from the preecl tic placenta into the maternal circulation, where it causes endothelial dysfunction manifesting as end-organ disease. However, the mechanisms regulating its production within the placenta remain poorly understood. Recently it was shown in endothelial cells that Jumonji domain containing protein 6 (JMJD6) hydroxylates U2 small nuclear ribonucleoprotein auxiliary factor 65-kDa subunit (U2AF65, a component of the splicesome). The hydroxylation by JMJD6 is oxygen dependent. Under hypoxia, JMJD6 is less able to hydroxylate U2AF65, and this unhydroxylated form of U2AF65 biases splicing of FLT-1 to sFLT-1. We assessed whether oxygen-sensing JMJD6 is differentially expressed in preecl tic placenta and regulates sFLT-1 splicing in placenta via U2AF65. JMJD6 protein expression was significantly reduced in preterm preecl tic placenta (P < 0.0001 n = 21) relative to preterm controls (n = 10). Exposing both placental and endothelial cells to hypoxia significantly reduced JMJD6 mRNA and increased sFLT-1 mRNA and protein expression. Silencing JMJD6 in primary endothelial and trophoblast cells significantly increased sFLT-1 secretion. Next, we examined whether these molecules may be directly interacting. We demonstrated that placental U2AF65 colocalized with JMJD6. In turn, we found JMJD6 directly interacts with U2AF65, which in turn produces sFLT-1 mRNA transcripts. Taken together, our findings provide evidence that JMJD6 may play a role in regulating the production of sFLT-1 in the preecl tic placenta. Decreased placental JMJD6 expression may be an important component to the pathophysiology of preecl sia.
Start Date: 2019
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2018
Funder: Society of Obstetric Medicine of Australia and New Zealand
View Funded ActivityStart Date: 2019
End Date: 2020
Funder: University of Melbourne
View Funded Activity