Obstetrics and Gynaecology - Research Publications
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ItemCOVID-19 pandemic 2020: a tertiary Melbourne hospital's experience(WILEY, 2022-07)BACKGROUND: The COVID-19 pandemic has affected different parts of Australia in distinct ways across 2020 and 2021. In 2020, Melbourne was the epicentre of COVID-19. As one of the key tertiary centres caring for the patients affected by the outbreaks, the Royal Melbourne Hospital (RMH) managed the majority of the Victorian inpatient caseload. AIMS: To review the demographics, management and outcomes of patients with COVID-19 cared for by the RMH services in 2020. METHODS: A single health service retrospective cohort analysis of demographics, interventions and outcomes was conducted to characterise the RMH experience in 2020. RESULTS: From January to December 2020, 433 patients required admission more than 24 h. The demographics of affected patients and outcomes changed over the course of the study. Overall, 47% (203/433) required oxygen, most frequently (36%; 154/433) with low-flow devices (nasal prongs or hudson mask), and 11% (47/433) of patients required admission to intensive care. We recorded a 30-day mortality of 24% (104/433) mortality overall, rising to over 50% in patients aged over 80 years. CONCLUSIONS: The experience of this health service in 2020 demonstrated changing demographics over time, with associated differences in outcomes; notably marked mortality in older populations, frequent complications and limited inter-site transfer possible with mobilised resources.
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ItemRisk of obstetric anal sphincter injury among women who birth vaginally after a prior caesarean section: A state-wide cohort study(WILEY, 2022-07)OBJECTIVE: Vaginal birth after caesarean (VBAC) has been suggested to be associated with an increased risk of obstetric anal sphincter injury (compared with primiparous women who birth vaginally). However, prior studies have been small or have used outdated methodology. We set out to validate whether the risk of obstetric anal sphincter injury among women having their first VBAC is greater than that among primiparous women having a vaginal birth. DESIGN: State-wide retrospective cohort study. SETTING: Victoria, Australia. POPULATION: All births (455 000) between 2009 and 2014. METHODS: The risk of severe perineal injury between the first vaginal birth and the first VBAC was compared, after adjustment for potential confounding variables. Covariates were examined using logistic regression for categorical data and the Wilcoxon rank-sum test for continuous data. Missing data were handled using multiple imputation; the analysis was performed using regression adjustment and stata 16 multiple imputation and suite of effects commands. RESULTS: Women having a VBAC (n = 5429) were significantly more likely than primiparous women (n = 123 353) to sustain a third- or fourth-degree tear during vaginal birth (7.1 versus 5.7%, p < 0.001). After adjustment for mode of birth, body mass index, maternal age, infant birthweight, episiotomy and epidural, there was a 21% increased risk of severe perineal injury (RR 1.21, 95% CI 1.07-1.38). CONCLUSIONS: Women having their first VBAC have a significantly increased risk of sustaining a third- or fourth-degree tear, compared with primiparous women having a vaginal birth. Patient counselling and professional guidelines should reflect this increased risk.
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ItemMaternal factors during pregnancy influencing maternal, fetal, and childhood outcomes.(Springer Science and Business Media LLC, 2022-11-01)Enhancing pregnancy health is known to improve the mother's and offspring's life-long well-being. The maternal environment, encompassing genetic factors, impacts of social determinants, the nutritional/metabolic milieu, and infections and inflammation, have immediate consequences for the in utero development of the fetus and long-term programming into childhood and adulthood. Moreover, adverse pregnancy outcomes such as preterm birth or preeclampsia, often attributed to the maternal environmental factors listed above, have been associated with poor maternal cardiometabolic health after pregnancy. In this BMC Medicine article collection, we explore a broad spectrum of maternal characteristics across pregnancy and postnatal phenotypes, anticipating substantial cross-fertilization of new understanding and shared mechanisms around diverse outcomes. Advances in the ability to leverage 'omics across different platforms (genome, transcriptome, proteome, metabolome, microbiome, lipidome), large high-dimensional population databases, and unique cohorts are generating exciting new insights: The first articles in this collection highlight the role of placental biomarkers of preterm birth, metabolic influences on fetal and childhood growth, and the impact of common pre-existing maternal disorders, obesity and smoking on pregnancy outcomes, and the child's health. As the collection grows, we look forward to seeing the connections emerge across maternal, fetal, and childhood outcomes that will foster new insights and preventative strategies for women.
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ItemSystematic evaluation of the pre-eclampsia drugs, dietary supplements and biologicals pipeline using target product profiles(BMC, 2022-11-04)BACKGROUND: The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five pregnancy-related conditions, including pre-eclampsia. In parallel, we published target product profiles (TPPs) that describe optimal characteristics of medicines for use in preventing/treating pre-eclampsia. The study objective was to use systematic double screening and extraction to identify all candidate medicines being investigated for pre-eclampsia prevention/treatment and rank their potential based on the TPPs. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched (Jan-May 2021). The AIM database was screened for all candidates being investigated for pre-eclampsia. Candidates in clinical development were evaluated against nine prespecified criteria from TPPs identified as key for wide-scale implementation, and classified as high, medium or low potential based on matching to the TPPs. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 153 candidates for pre-eclampsia. Of the 87 candidates in clinical development, seven were classified as high potential (prevention: esomeprazole, L-arginine, chloroquine, vitamin D and metformin; treatment: sulfasalazine and metformin) and eight as medium potential (prevention: probiotic lactobacilli, dalteparin, selenium and omega-3 fatty acid; treatment: sulforaphane, pravastatin, rosuvastatin and vitamin B3). Sixty-six candidates were in preclinical development, the most common being amino acid/peptides, siRNA-based medicines and polyphenols. CONCLUSIONS: This is a novel, evidence-informed approach to identifying promising candidates for pre-eclampsia prevention and treatment - a vital step in stimulating R&D of new medicines for pre-eclampsia suitable for real-world implementation.
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ItemAdjusting growth standards for fetal sex improves correlation of small babies with stillbirth and adverse perinatal outcomes: A state-wide population study(PUBLIC LIBRARY SCIENCE, 2022-10-10)OBJECTIVES: Sex impacts birthweight, with male babies heavier on average. Birthweight charts are thus sex specific, but ultrasound fetal weights are often reported by sex neutral standards. We aimed to identify what proportion of infants would be re-classified as SGA if sex-specific charts were used, and if this had a measurable impact on perinatal outcomes. METHODS: Retrospective cohort study including all infants born in Victoria, Australia, from 2005-2015 (529,261 cases). We applied GROW centiles, either adjusted or not adjusted for fetal sex. We compared overall SGA populations, and the populations of males considered small by sex-specific charts only (SGAsex-only), and females considered small by sex-neutral charts only (SGAunadjust-only). RESULTS: Of those <10th centile by sex-neutral charts, 39.6% were male and 60.5% female, but using sex-specific charts, 50.3% were male and 49.7% female. 19.2% of SGA females were reclassified as average for gestational age (AGA) using sex-specific charts. These female newborns were not at increased risk of stillbirth, combined perinatal mortality, NICU admissions, low Apgars or emergency CS compared with an AGA infant, but were at greater risk of being iatrogenically delivered on suspicion of growth restriction. 25.0% male infants were reclassified as SGA by sex-specific charts. These male newborns, compared to the AGAall infant, were at greater risk of stillbirth (RR 1.94, 95%CI 1.30-2.90), combined perinatal mortality (RR 1.80, 95%CI 1.26-2.57), NICU admissions (RR 1.38, 95%CI 1.12-1.71), Apgars <7 at 5 minutes (RR 1.40, 95%CI 1.25-1.56) and emergency CS (RR 1.12, 95%CI 1.06-1.18). CONCLUSIONS: Use of growth centiles not adjusted for fetal sex disproportionately classifies female infants as SGA, increasing their risk of unnecessary intervention, and fails to identify a cohort of male infants at increased risk of adverse outcomes, including stillbirth. Sex-specific charts may help inform decisions and improve outcomes.
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ItemNo Preview AvailableEndothelial protein C receptor is increased in preterm preeclampsia and fetal growth restriction(WILEY, 2022-12)Placental dysfunction is the leading cause of both preeclampsia and fetal growth restriction. This study aimed to characterize endothelial protein C receptor (EPCR) in preterm preeclampsia, term preeclampsia, and fetal growth restriction (defined by delivery of a small for gestational age [SGA] infant [<10% birthweight centile]) and examine its regulation in primary syncytiotrophoblast. Placental EPCR mRNA and protein were significantly increased in patients with preterm preeclampsia (<34 weeks gestation) compared to gestation-matched controls (p < .0001). In the plasma, EPCR was also significantly elevated (p = .01) in established preterm preeclampsia while its substrate, protein C (PC) was significantly reduced (p = .0083). Placentas from preterm small for gestational age (SGA) cases, had elevated EPCR mRNA expression (p < .0001) relative to controls. At 36 weeks, no significant changes in plasma EPCR were detected in samples from patients destined to develop preeclampsia or deliver an SGA infant at term. In terms of syncytiotrophoblast, hypoxia significantly increased EPCR mRNA expression (p = .008), but Tumor Necrosis Factor Alpha (TNF-α) decreased EPCR mRNA. Interleukin-6 (IL-6) had no significant effect on EPCR mRNA expression. When isolated syncytiotrophoblast was treated with metformin under hypoxia (1% O2 ) or normoxia (8% O2 ), EPCR mRNA expression was significantly reduced (p = .008) relative to control. In conclusion, EPCR is markedly elevated in the placenta and the circulation of patients with established preterm preeclampsia and placental increases may be associated with hypoxia. Additionally, fetal growth-restricted pregnancies (as defined by the delivery of an SGA infant) also demonstrated elevated placental EPCR.
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ItemNo Preview AvailableEstimation of neonatal body fat percentage predicts neonatal hypothermia better than birthweight centile(TAYLOR & FRANCIS LTD, 2022)INTRODUCTION: PEA POD™ air displacement plethysmography quickly and noninvasively estimates neonatal body fat percentage (BF%). Low PEA POD™ BF% predicts morbidity better than classification as small-for-gestational-age (SGA; <10th centile), but PEA PODs are not widely available. We examined whether skinfold measurements could effectively identify neonates at risk; comparing skinfold BF%, PEA POD™ BF% and birthweight centiles' prediction of hypothermia - a marker of reduced in utero nutrition. METHODS: Neonates had customized birthweight centiles calculated, and BF% prospectively estimated by: (i) triceps and subscapular skinfolds using sex-specific equations; and (ii) PEA POD™. Medical record review identified hypothermic (<36.5 °C) episodes. RESULTS: 42/149 (28%) neonates had hypothermia. Skinfold BF%, with an area under the curve (AUC) of 0.66, predicted hypothermia as well as PEA POD™ BF% (AUC = 0.62) and birthweight centile (AUC = 0.61). Birthweight <10th centile demonstrated 11.9% sensitivity, 38.5% positive predictive value (PPV) and 92.5% specificity for hypothermia. At equal specificity, skinfold and PEA POD™ BF% more than doubled sensitivity (26.2%) and PPV increased to 57.9%. CONCLUSION: Neonatal BF% performs better to predict neonatal hypothermia than birthweight centile, and may be a better measure of true fetal growth restriction. Estimation of neonatal BF% by skinfold measurements is an inexpensive alternative to PEA POD™.
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ItemNo Preview AvailablePlacental DAAM2 is unaltered in preeclampsia, but upregulated by treatment with proton pump inhibitors(ELSEVIER SCI LTD, 2022-12)BACKGROUND: Dishevelled Associated Activator Of Morphogenesis 2 (DAAM2) levels are elevated in the maternal circulation and placenta in pregnancies complicated by fetal growth restriction. However, placental DAAM2 levels in cases of preeclampsia have not previously been explored. Here, we examined placental DAAM2 in pregnancies complicated by preterm preeclampsia, and whether candidate preeclampsia therapeutics altered its expression. METHODS: DAAM2 mRNA and protein levels were assessed in placental tissue from cases of preterm preeclampsia and gestation-matched controls (delivering ≤ 34 weeks; qPCR and western blot respectively). Short interfering RNAs were used to silence DAAM2 in isolated primary cytotrophoblast under normoxic (8 % O2) and hypoxic (1 % O2) conditions, and expression of anti-angiogenic sFLT-1, angiogenic PGF, antioxidant, fetal growth, and inflammatory genes assessed. DAAM2 expression was measured in placental explant tissue from pregnancies complicated by preeclampsia, treated with three proton pump inhibitors (100 µM esomeprazole, lansoprazole, and rabeprazole). RESULTS: DAAM2 expression was significantly reduced in preeclamptic placental tissue compared to controls, but protein production was unchanged. Silencing DAAM2 in hypoxic cytotrophoblast increased sFLT-i13 isoform expression, but did not alter sFLT-e15a or PGF expression, or sFLT-1 secretion. DAAM2 knockdown did not alter expression of antioxidant (NQO-1, TXN, GCLC), fetal growth (SPINT1), or inflammasome (NLRP3) genes. Esomeprazole and lansoprazole, but not rabeprazole, increased DAAM2 expression in placental explant tissue from cases of preeclampsia. CONCLUSION: Placental DAAM2 protein is not significantly altered in placental tissue in cases of preeclampsia, and its suppression does not alter sFLT-1 secretion. Hence, placental DAAM2 is unlikely to drive the pathogenesis associated with preeclampsia.
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ItemNo Preview AvailablePravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia(MOSBY-ELSEVIER, 2022-02)There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant.