Obstetrics and Gynaecology - Research Publications
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ItemAccuracy of second trimester prediction of preterm preeclampsia by three different screening algorithms(WILEY, 2018-04)AIM: To compare the performance of three different screening methods (National Institute for Health and Clinical Excellence (NICE) guidelines, American College of Obstetricians and Gynecologists (ACOG) recommendations and Fetal Medicine Foundation (FMF) algorithm) for second trimester prediction of preeclampsia. METHODS: This was a prospective non-intervention study in singleton pregnancies, including women attending for second trimester morphologic ultrasound at 19-22 weeks. Maternal characteristics, medical history, mean arterial pressure and mean uterine artery Doppler pulsatility index were recorded and used for risk assessment. Outcomes measured were preeclampsia with delivery before 34, before 37 and after 37 weeks gestation. Detection rates, false positive rates and positive likelihood ratios were calculated, and receiver operating characteristic curves were produced. RESULTS: We screened 543 women during the study. The incidence of preeclampsia before 34, before 37 and after 37 weeks was 0.5, 1.4 and 3.4%, respectively. Detection rates for prediction of preterm preeclampsia were 75% (95% CI 34.9-96.8), 87% (95% CI 47.3-99.6), 100% (95% CI 63.0-100) and 100% (95% CI 63.0-100) for NICE guidelines, ACOG recommendations, FMF algorithm with a 1:100 cut-off and FMF algorithm at 1:60 cut-off, respectively. False positive rates were, 22, 67, 19 and 12% for NICE guidelines, ACOG recommendations, FMF algorithm with a 1:100 cut-off and FMF algorithm at 1:60 cut-off, respectively. CONCLUSION: Second trimester combined screening for preterm preeclampsia by maternal history, mean arterial pressure and mean uterine artery Doppler pulsatility index (FMF algorithm) was superior to screening by maternal factors alone (NICE guidelines and ACOG recommendations).
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ItemMother Nature versus Father Time(WILEY, 2017-03-15)
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ItemOptic nerve sonography and ophthalmic artery Doppler velocimetry in healthy pregnant women: an Australian cohort study(WILEY, 2019-11)PURPOSE: Maternal ocular sonography offers a window into cerebrovascular and intracranial pressure changes in pregnancy. This study aimed to determine the Doppler velocimetric variables of the ophthalmic artery, and the mean diameter of the optic nerve sheath (ONSD), in an Australian cohort of healthy pregnant women. METHODS: A prospective observational cohort study of healthy women with uncomplicated singleton pregnancies in the third trimester was undertaken in a tertiary maternity service. A single prenatal ultrasonographic examination was performed on all participants, with a postnatal examination performed on a subgroup with uncomplicated deliveries. RESULTS: Fifty women were examined at a mean gestation of 35 weeks. The mean ± SD Doppler variables in the ophthalmic artery were peak systolic velocity (PSV) 41.89 ± 13.13 cm/s, second peak velocity 20.63 ± 8.97 cm/s, end diastolic velocity 9.29 ± 5.13 cm/s, pulsatility index 1.97 ± 0.53, resistive index 0.78 ± 0.07, peak ratio (second peak velocity/PSV) 0.49 ± 0.12, while the mean ONSD was 4.34 ± 0.4 mm. None of these variables had a demonstrable relationship with gestation or mean arterial pressure (MAP), nor did the sheath diameter have a relationship with any of the Doppler variables. CONCLUSIONS: The ocular sonographic variables observed in this population are similar to those reported in other cohorts. No clear relationship could be identified in this cohort between ophthalmic artery Doppler variables and the ONSD, and between each of these variables and gestation or MAP.
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ItemSetting the pace for labour(WILEY, 2018-07-15)
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ItemGenome-Wide Association Scan Identifies a Risk Locus for Preeclampsia on 2q14, Near the Inhibin, Beta B Gene(PUBLIC LIBRARY SCIENCE, 2012-03-14)Elucidating the genetic architecture of preeclampsia is a major goal in obstetric medicine. We have performed a genome-wide association study (GWAS) for preeclampsia in unrelated Australian individuals of Caucasian ancestry using the Illumina OmniExpress-12 BeadChip to successfully genotype 648,175 SNPs in 538 preeclampsia cases and 540 normal pregnancy controls. Two SNP associations (rs7579169, p = 3.58×10(-7), OR = 1.57; rs12711941, p = 4.26×10(-7), OR = 1.56) satisfied our genome-wide significance threshold (modified Bonferroni p<5.11×10(-7)). These SNPs reside in an intergenic region less than 15 kb downstream from the 3' terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. They are in linkage disequilibrium (LD) with each other (r(2) = 0.92), but not (r(2)<0.80) with any other genotyped SNP ±250 kb. DNA re-sequencing in and around the INHBB structural gene identified an additional 25 variants. Of the 21 variants that we successfully genotyped back in the case-control cohort the most significant association observed was for a third intergenic SNP (rs7576192, p = 1.48×10(-7), OR = 1.59) in strong LD with the two significant GWAS SNPs (r(2)>0.92). We attempted to provide evidence of a putative regulatory role for these SNPs using bioinformatic analyses and found that they all reside within regions of low sequence conservation and/or low complexity, suggesting functional importance is low. We also explored the mRNA expression in decidua of genes ±500 kb of INHBB and found a nominally significant correlation between a transcript encoded by the EPB41L5 gene, ∼250 kb centromeric to INHBB, and preeclampsia (p = 0.03). We were unable to replicate the associations shown by the significant GWAS SNPs in case-control cohorts from Norway and Finland, leading us to conclude that it is more likely that these SNPs are in LD with as yet unidentified causal variant(s).
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ItemDecreased Seizure Threshold in an Eclampsia-Like Model Induced in Pregnant Rats with Lipopolysaccharide and Pentylenetetrazol Treatments(PUBLIC LIBRARY SCIENCE, 2014-02-20)OBJECTIVE: Eclampsia is a poorly understood but potentially fatal complication of pregnancy. Research to date on this disorder has been hampered by the lack of a suitable animal model. To correct this deficiency, this report describes the generation of a rat eclampsia-like model using pentylenetetrazol (PTZ) in a previously established rat preeclampsia model. METHOD: Rats were administered lipopolysaccharide (1.0 µg/kg) by tail vein injection on gestational day 14 to establish preeclampsia (PE). PE and control rats (non-pregnant, NP; normal-pregnant, P) were injected intraperitoneally (i.p.) with PTZ (40 mg/kg) to induce seizures. In separate experiments, MgSO4 (270 mg/kg IP) was injected in advance of PTZ into PE rats to observe its effect on PTZ-induced seizures. RESULTS: PE conditions were verified in rats after LPS administration by significantly higher blood pressure (P<0.01) and urinary albumin excretion (P<0.05), elevated sFlt-1 (P<0.05) and decreased PlGF serum levels (P<0.05), and evidence of hepatic dysfunction compared to control groups. PTZ successfully induced seizure activity in all groups studied. Latency to seizure was significantly (P<0.01) less in the PE-PTZ group (73.2 ± 6.6 sec.) than in PTZ-treated controls (107.0 ± 7.4 sec.). Pretreatment with MgSO4 prolonged (P<0.05) latency to seizure, shortened seizure duration and decreased seizure rates. Significant increased (P<0.05) in the serum levels of the inflammatory cytokines TNF-α and IL-1β in PE and PE-PTZ groups, and decreased (P<0.05) in their levels following MgSO4 administration. CONCLUSION: This PTZ-induced eclampsia-like rat model is comparable to the human condition of eclampsia and may serve as a useful research tool for future studies of this disease. The increased inflammatory cytokines in preeclampsia are coincident with a decreased threshold for PTZ-induced seizures, suggesting that an inflammatory mechanism may contribute to the susceptibility to seizure activity and inflammation might have an important role in eclampsia.
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ItemImplications of the introduction of new criteria for the diagnosis of gestational diabetes: a health outcome and cost of care analysis(BMJ PUBLISHING GROUP, 2019-06)OBJECTIVE: To identify effects on health outcomes from implementing new criteria diagnosing gestational diabetes mellitus(GDM) and to analyse costs-of-care associated with this change. DESIGN: Quasi-experimental study comparing data from the calendar year before (2014) and after (2016) the change. SETTING: Single, tertiary-level, university-affiliated, maternity hospital. PARTICIPANTS: All women giving birth in the hospital, excluding those with pre-existing diabetes or multiple pregnancy. MAIN OUTCOME MEASURES: Primary outcomes were caesarean section, birth weight >90th percentile for gestation, hypertensive disorder of pregnancy and preterm birth less than 37 weeks. A number of secondary outcomes reported to be associated with GDM were also analysed.Care packages were derived for those without GDM, diet-controlled GDM and GDM requiring insulin. The institutional Business Reporting Unit data for average occasions of service, pharmacy schedule for the costs of consumables and medications, and Medicare Benefits Schedule ultrasound services were used for costing each package. All costs were estimated in figures from the end of 2016 negating the need to adjust for Consumer Price Index increases. RESULTS: There was an increase in annual incidence of GDM of 74% without overall improvements in primary health outcomes. This incurred a net cost increase of AUD$560 093. Babies of women with GDM had lower rates of neonatal hypoglycaemia and special care nursery admissions after the change, suggesting a milder spectrum of disease. CONCLUSION: New criteria for the diagnosis of GDM have increased the incidence of GDM and the overall cost of GDM care. Without obvious changes in short-term outcomes, validation over other systems of diagnosis may require longer term studies in cohorts using universal screening and treatment under these criteria.
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ItemAnalysis of the Epigenome in Multiplex Pre-eclampsia Families Identifies SORD, DGKI, and ICA1 as Novel Candidate Risk Genes(FRONTIERS MEDIA SA, 2019-03-19)Pre-eclampsia is a serious heritable disorder that affects 5-8% of pregnancies worldwide. While classical genetic studies have identified several susceptibility genes they do not fully explain the heritability of pre-eclampsia. An additional contribution to risk can be quantified by examining the epigenome, in particular the methylome, which is a representation of interactions between environmental and genetic influences on the phenotype. Current array-based epigenetic studies only examine 2-5% of the methylome. Here, we used whole-genome bisulfite sequencing (WGBS) to determine the entire methylome of 13 individuals from two multiplex pre-eclampsia families, comprising one woman with eclampsia, six women with pre-eclampsia, four women with uncomplicated normotensive pregnancies and two male relatives. The analysis of WGBS profiles using two bioinformatics platforms, BSmooth and Bismark, revealed 18,909 differentially methylated CpGs and 4157 differentially methylated regions (DMRs) concordant in females. The methylation patterns support the involvement of previously reported candidate genes, including COL4A1, SLC2A4, PER3, FLT1, GPI, LCT, DDAH1, TGFB3, DLX5, and LRP1B. Statistical analysis of DMRs revealed three novel genes significantly correlated with pre-eclampsia: sorbitol dehydrogenase (SORD, p = 9.98 × 10-6), diacylglycerol kinase iota (DGKI, p = 2.52 × 10-5), and islet cell autoantigen 1 (ICA1, 7.54 × 10-3), demonstrating the potential of WGBS in families for elucidating the role of epigenome in pre-eclampsia and other complex diseases.