Obstetrics and Gynaecology - Research Publications
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ItemSystematic review of areca (betel nut) use and adverse pregnancy outcomes(WILEY, 2019-12)BACKGROUND: 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. OBJECTIVE: To perform a systematic review of studies investigating prenatal betel nut use and adverse perinatal outcomes. SEARCH STRATEGY: Pubmed, Embase, and Cochrane databases were searched from inception until July 2018 using the terms areca, betel nut, pregnancy, pregnancy complications, and infection. SELECTION CRITERIA: Eligible studies included case-control, cohort, and randomized control studies involving pregnant women. DATA COLLECTION AND ANALYSIS: Where appropriate, bivariate meta-analysis was performed, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. MAIN RESULTS: 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). CONCLUSIONS: 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.
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ItemBlood-based biomarkers in the maternal circulation associated with fetal growth restriction(WILEY, 2019-10)Fetal growth restriction (FGR) is associated with threefold to fourfold increased risk of stillbirth. Identifying FGR, through its commonly used surrogate-the small-for-gestational-age (SGA, estimated fetal weight and/or abdominal circumference <10th centile) fetus-and instituting fetal surveillance and timely delivery decrease stillbirth risk. Methods available to clinicians for antenatal identification of SGA fetuses have surprisingly poor sensitivity. About 80% of cases remain undetected. Measuring the symphysis-fundal height detects only 20% of SGA fetuses, and even universal third trimester ultrasound detects, at best, 57% of those born SGA. There is an urgent need to find better ways to identify this at-risk cohort. This review summarises efforts to identify molecular biomarkers (proteins, metabolites, or ribonucleic acids) that could be used to better predict FGR. Most studies examining potential biomarkers to date have utilised case-control study designs without proceeding to validation in independent cohorts. To develop a robust test for FGR, large prospective studies are required with a priori validation plans and cohorts. Given that current clinical care detects 20% of SGA fetuses, even a screening test with ≥60% sensitivity at 90% specificity could be clinically useful, if developed. This may be an achievable aspiration. If discovered, such a test may decrease stillbirth.
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ItemSTRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction(WILEY, 2019-07)OBJECTIVE: To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction. DESIGN: A randomised placebo-controlled trial. SETTING: Thirteen maternal-fetal medicine units across New Zealand and Australia. POPULATION: Women with singleton pregnancies affected by fetal growth restriction at 22+0 to 29+6 weeks. METHODS: Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32+0 weeks, birth or fetal death (whichever occurred first). MAIN OUTCOME MEASURES: The primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia. RESULTS: Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23-1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80-7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84-4.45); and new-onset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26-1.75). CONCLUSIONS: Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing. TWEETABLE ABSTRACT: Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.
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ItemA survey of opinion and practice regarding prenatal diagnosis of vasa previa among obstetricians from Australia and New Zealand(WILEY, 2019-03)OBJECTIVES: To define current obstetric opinion and clinical practice regarding the prenatal diagnosis of vasa previa in Australia and New Zealand. METHODS: A population-based cross-sectional survey of Fellows of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists was conducted from April to May, 2016. Descriptive analysis was used to define factors influencing opinion and practice regarding definition of vasa previa, attributable risk factors, and the value of screening. RESULTS: Overall, 453 respondents were included in the study. Two-thirds (304/453; 67.1%) defined vasa previa as exposed fetal vessel(s) running over or within 2 cm of the internal os. A higher proportion of ultrasound specialists (30/65; 46.2%) preferred a broader definition as compared with generalists (115/388; 29.6%; P<0.001). Overall, Fellows were supportive (342/430; 79.5%) of both reporting ultrasound-based risk factors at the 20-week anomaly scan and targeted screening (298/430; 69.3%). Only 77/453 (17.0%) respondents recognized all five "known" risk factors for vasa previa. CONCLUSIONS: There was a lack of consensus regarding the definition and diagnosis process for vasa previa. There was also a knowledge gap in risk factors for vasa previa that would inform a targeted screening policy. Nevertheless, support for targeted screening was strong from obstetricians who responded.
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ItemCustomised growth charts in large-for-gestational-age infants and the association with emergency caesarean section rate(WILEY, 2019-06)BACKGROUND AND AIM: Large-for-gestational-age (LGA) infants are at increased risk of intrapartum complications. However, some infants classified as LGA may be appropriate-for-gestational-age (AGA) if adjusted for maternal stature. We determined whether customisation of birthweight centiles by maternal height, or height and weight, improves the detection of LGA infants at risk of complications. METHODS: We conducted a retrospective analysis of 38 246 term, singleton nulliparous women. We compared population birthweight centiles to those customised by height, or height and weight for complications including intrapartum caesarean section, instrumental delivery, postpartum haemorrhage, anal sphincter injury and neonatal outcomes. RESULTS: Those considered LGA when customised for height but AGA by population centiles (LGA-ht-only) were at increased risk of intrapartum emergency caesarean section compared with infants AGA on all charts (AGA-all); odds ratio (OR) 4.64, 95% CI 3.22-6.76. In contrast, infants considered LGA on population charts, but AGA when customised by height (LGA-pop-only) were not at increased risk compared to the AGA-all group (OR 1.43, 95% CI 0.70-1.88). Infants classified as LGA-ht-only compared to LGA-pop-only remained at significantly higher risk after adjustment for potential confounders (aOR 3.27; 95% CI 2.02-5.31). No difference was seen for any other outcomes. No benefit was seen with customisation by both maternal height and weight. CONCLUSION: Women with an infant classified as AGA on population centiles but LGA when customised for height are at increased risk of intrapartum caesarean section. This is a population unrecognised in current practice. Fetal growth should be customised for maternal height when making assessments regarding the LGA infant.
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ItemIncreased expression and phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoforms in urinary exosomes in pre-eclampsia(BMC, 2019-02-28)BACKGROUND: Glycolysis is altered in various kidney diseases, but little is known about glycolysis in pre-eclampsia, a multi-system disorder with major pathological effects on the kidney. Urinary exosomes provide a non-invasive alternative for studying changes in kidney metabolism. This study aims to characterise the expression and phosphorylation of isozymes of the key glycolytic regulatory protein, 6-phosphofructokinase-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2), in urinary exosomes of subjects with pre-eclampsia (PE), compared to normotensive non-pregnant (NC) and normotensive pregnant (NP) controls. METHODS: A cross-sectional study of NC (n = 19), NP (n = 23) and PE (n = 29) subjects was performed. Exosomes were isolated from urine samples by differential ultracentrifugation, and then analyzed by Western blot and densitometry for expression of PFK-2/FBPase-2 isozymes (PFKFB2, PFKFB3 and PFKFB4) and phosphorylation of PFKFB2 at residues Ser483 and Ser466 and PFKFB3 at Ser461. RESULTS: PFKFB2 expression was increased 4.7-fold in PE compared to NP (p < 0.001). PFKFB2 phosphorylation at Ser483 was increased 2.6-fold in PE compared to NP (p = 0.002). Expression of phosphorylated PFKFB2/PFKFB3 at Ser466/Ser461 was increased in PE, being present in 77.4% (95% CI 59.9-88.9%) of PE and 8.3% (95% CI 1.2-27.0%) of NP samples (p < 0.001). PFKFB3 was more commonly expressed in PE, detected in 90.3% (95% CI 74.3-97.4%) of PE and 8.3% (95% CI 1.2-27.0%) of NP samples (p < 0.001). PFKFB4 had a 7.2-fold increase in expression in PE compared to NP (p < 0.001). No significant differences between NP and NC groups were observed. CONCLUSION: Regulatory proteins that increase glycolysis are increased in the urinary exosomes of subjects with pre-eclampsia, suggesting that renal glycolysis may be increased in this condition.
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ItemCirculating GATA2 mRNA is decreased among women destined to develop preeclampsia and may be of endothelial origin(NATURE PORTFOLIO, 2019-01-18)Preeclampsia is a pregnancy complication associated with elevated placental secretion of anti-angiogenic factors, maternal endothelial dysfunction and organ injury. GATA2 is a transcription factor expressed in the endothelium which regulates vascular homeostasis by controlling transcription of genes and microRNAs, including endothelial miR126. We assessed GATA2 and miR126 in preeclampsia. Whole blood circulating GATA2 mRNA and miR126 expression were significantly decreased in women with established early-onset preeclampsia compared to gestation-matched controls (p = 0.002, p < 0.0001, respectively). Using case-control groups selected from a large prospective cohort, whole blood circulating GATA2 mRNA at both 28 and 36 weeks' gestation was significantly reduced prior to the clinical diagnosis of preeclampsia (p = 0.012, p = 0.015 respectively). There were no differences in GATA2 mRNA or protein expression in preeclamptic placentas compared to controls, suggesting the placenta is an unlikely source. Inducing endothelial dysfunction in vitro by administering either tumour necrosis factor-α or placenta-conditioned media to endothelial cells, significantly reduced GATA2 mRNA expression (p < 0.0001), suggesting the reduced levels of circulating GATA2 mRNA may be of endothelial origin. Circulating GATA2 mRNA is decreased in women with established preeclampsia and decreased up to 12 weeks preceding onset of disease. Circulating mRNAs of endothelial origin may be a novel source of biomarker discovery for preeclampsia.
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ItemA double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol(BMJ PUBLISHING GROUP, 2019-06)INTRODUCTION: Pre-eclampsia 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-eclampsia, 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-eclampsia. Here, we describe a phase II clinical trial to examine whether administering extended-release metformin may be effective in treating women with preterm pre-eclampsia (PI2 Trial). METHODS: The PI2 Trial is a phase II, double blind, randomised controlled trial that aims to recruit 150 women with preterm pre-eclampsia (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. ETHICS AND DISSEMINATION: 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. TRIAL REGISTRATION NUMBER: PACTR201608001752102; Pre-results.
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ItemIdentification of the optimal growth charts for use in a preterm population: An Australian state-wide retrospective cohort study(PUBLIC LIBRARY SCIENCE, 2019-10)BACKGROUND: Preterm infants are a group at high risk of having experienced placental insufficiency. It is unclear which growth charts perform best in identifying infants at increased risk of stillbirth and other adverse perinatal outcomes. We compared 2 birthweight charts (population centiles and INTERGROWTH-21st birthweight centiles) and 3 fetal growth charts (INTERGROWTH-21st fetal growth charts, World Health Organization fetal growth charts, and Gestation Related Optimal Weight [GROW] customised growth charts) to identify which chart performed best in identifying infants at increased risk of adverse perinatal outcome in a preterm population. METHODS AND FINDINGS: We conducted a retrospective cohort study of all preterm infants born at 24.0 to 36.9 weeks gestation in Victoria, Australia, from 2005 to 2015 (28,968 records available for analysis). All above growth charts were applied to the population. Proportions classified as <5th centile and <10th centile by each chart were compared, as were proportions of stillborn infants considered small for gestational age (SGA, <10th centile) by each chart. We then compared the relative performance of non-overlapping SGA cohorts by each chart to our low-risk reference population (infants born appropriate size for gestational age [>10th and <90th centile] by all intrauterine charts [AGAall]) for the following perinatal outcomes: stillbirth, perinatal mortality (stillbirth or neonatal death), Apgar <4 or <7 at 5 minutes, neonatal intensive care unit admissions, suspicion of poor fetal growth leading to expedited delivery, and cesarean section. All intrauterine charts classified a greater proportion of infants as <5th or <10th centile than birthweight charts. The magnitude of the difference between birthweight and fetal charts was greater at more preterm gestations. Of the fetal charts, GROW customised charts classified the greatest number of infants as SGA (22.3%) and the greatest number of stillborn infants as SGA (57%). INTERGROWTH classified almost no additional infants as SGA that were not already considered SGA on GROW or WHO charts; however, those infants classified as SGA by INTERGROWTH had the greatest risk of both stillbirth and total perinatal mortality. GROW customised charts classified a larger proportion of infants as SGA, and these infants were still at increased risk of mortality and adverse perinatal outcomes compared to the AGAall population. Consistent with similar studies in this field, our study was limited in comparing growth charts by the degree of overlap, with many infants classified as SGA by multiple charts. We attempted to overcome this by examining and comparing sub-populations classified as SGA by only 1 growth chart. CONCLUSIONS: In this study, fetal charts classified greater proportions of preterm and stillborn infants as SGA, which more accurately reflected true fetal growth restriction. Of the intrauterine charts, INTERGROWTH classified the smallest number of preterm infants as SGA, although it identified a particularly high-risk cohort, and GROW customised charts classified the greatest number at increased risk of perinatal mortality.