Publications by authors named "Stephen Tong"

149 Publications

DAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia.

Sci Rep 2021 Mar 10;11(1):5540. Epub 2021 Mar 10.

Therapeutics Discovery and Vascular Function in Pregnancy Group, Mercy Hospital for Women, Heidelberg, VIC, 3084, Australia.

Previously, we identified increased maternal circulating DAAM2 mRNA in pregnancies complicated by preterm fetal growth restriction (FGR). Here, we assessed whether circulating DAAM2 mRNA could detect FGR, and whether the DAAM2 gene, known to play roles in the Wnt signalling pathway is expressed in human placenta and associated with dysfunction and FGR. We performed linear regression analysis to calculate area under the ROC curve (AUC) for DAAM2 mRNA expression in the maternal circulation of pregnancies complicated by preterm FGR. DAAM2 mRNA expression was assessed across gestation by qPCR. DAAM2 protein and mRNA expression was assessed in preterm FGR placenta using western blot and qPCR. DAAM2 expression was assessed in term cytotrophoblasts and placental explant tissue cultured under hypoxic and normoxic conditions by qPCR. Small interfering RNAs were used to silence DAAM2 in term primary cytotrophoblasts. Expression of growth, apoptosis and oxidative stress genes were assessed by qPCR. Circulating DAAM2 mRNA was elevated in pregnancies complicated by preterm FGR [p < 0.0001, AUC = 0.83 (0.78-0.89)]. Placental DAAM2 mRNA was detectable across gestation, with highest expression at term. DAAM2 protein was increased in preterm FGR placentas but demonstrated no change in mRNA expression. DAAM2 mRNA expression was increased in cytotrophoblasts and placental explants under hypoxia. Silencing DAAM2 under hypoxia decreased expression of pro-survival gene, BCL2 and oxidative stress marker, NOX4, whilst increasing expression of antioxidant enzyme, HMOX-1. The increased DAAM2 associated with FGR and hypoxia implicates a potential role in placental dysfunction. Decreasing DAAM2 may have cytoprotective effects, but further research is required to elucidate its role in healthy and dysfunctional placentas.
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http://dx.doi.org/10.1038/s41598-021-84785-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946951PMC
March 2021

Aspirin to prevent pre-eclampsia.

Drug Ther Bull 2021 Apr 3;59(4):56-59. Epub 2021 Mar 3.

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Victoria, Australia.

Topics for DTB review articles are selected by DTB's editorial board to provide concise overviews of medicines and other treatments to help patients get the best care. Articles include a summary of key points and a brief overview for patients. Articles may also have a series of multiple choice CME questions.
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http://dx.doi.org/10.1136/dtb.2020.000009DOI Listing
April 2021

Circulating Tissue Factor Pathway Inhibitor (TFPI) is increased preceding preeclampsia diagnosis and in established preeclampsia.

Placenta 2021 Feb 22;105:32-40. Epub 2021 Jan 22.

The Department of Obstetrics and Gynaecology, University of Melbourne, Australia; Mercy Perinatal, Mercy Hospital for Women, Victoria, Australia; Translational Obstetrics Group, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia. Electronic address:

Introduction: Tissue Factor Pathway Inhibitor (TFPI) is a part of the extrinsic coagulation pathway, and highly expressed in the placenta. We aimed to assess its potential as a preeclampsia biomarker.

Methods: Maternal plasma was prospectively collected at 36 weeks' gestation. Circulating TFPI was measured in a nested case-control group (39 women who developed preeclampsia, 98 controls), before being measured in a larger independent cohort along with Placental Growth Factor (PlGF; 41 who developed preeclampsia, 954 controls). Circulating TFPI was then measured in women with underlying vascular disease, and also assessed in the plasma and placentas from women with preterm preeclampsia (delivered at <34 weeks).

Results: Circulating TFPI was significantly increased in women destined to develop preeclampsia in the case-control study, a finding that validated in Cohort 2, with median TFPI in the preeclampsia group being 42.3 ng/ml (IQR 30-51 ng/ml) compared to 30 ng/ml (IQR 23.1-38.6 ng/ml) in controls (p < 0.0001). The area under the receiver operator characteristic curve (AUC) was 0.70. PlGF was significantly reduced in the preeclampsia group, and a ratio of TFPI/PlGF had an improved AUC of 0.78. In women with underlying vascular disease who were later diagnosed with early onset preeclampsia, circulating TFPI was significantly increased with a 0.29 (95% CI 0.13-0.44) increase in logTFPI (adjusted for gestation and hypertensive status). Circulating and placental TFPI were significantly increased in women with preterm preeclampsia.

Discussion: Circulating TFPI is increased in women preceding diagnosis of preeclampsia (at 36 weeks) and in women with preterm disease. TFPI may beneficially contribute to a multi-marker blood test to predict preeclampsia.
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http://dx.doi.org/10.1016/j.placenta.2021.01.018DOI Listing
February 2021

Reduced growth velocity from the mid-trimester is associated with placental insufficiency in fetuses born at a normal birthweight.

BMC Med 2020 12 24;18(1):395. Epub 2020 Dec 24.

Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, VIC, 3084, Australia.

Background: Fetal growth restriction (FGR) due to placental insufficiency is a major risk factor for stillbirth. While small-for-gestational-age (SGA; weight < 10th centile) is a commonly used proxy for FGR, detection of FGR among appropriate-for-gestational-age (AGA; weight ≥ 10th centile) fetuses remains an unmet need in clinical care. We aimed to determine whether reduced antenatal growth velocity from the time of routine mid-trimester ultrasound is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency among term AGA infants.

Methods: Three hundred and five women had biometry measurements recorded from their routine mid-trimester (20-week) ultrasound, at 28 and 36 weeks' gestation, and delivered an AGA infant. Mid-trimester, 28- and 36-week estimated fetal weight (EFW) and abdominal circumference (AC) centiles were calculated. The EFW and AC growth velocities between 20 and 28 weeks, and 20-36 weeks, were examined as predictors of four clinical indicators of placental insufficiency: (i) low 36-week cerebroplacental ratio (CPR; CPR < 5th centile reflects cerebral redistribution-a fetal adaptation to hypoxia), (ii) neonatal acidosis (umbilical artery pH < 7.15) after the hypoxic challenge of labour, (iii) low neonatal body fat percentage (BF%) reflecting reduced nutritional reserve and (iv) placental weight < 10th centile.

Results: Declining 20-36-week fetal growth velocity was associated with all indicators of placental insufficiency. Each one centile reduction in EFW between 20 and 36 weeks increased the odds of cerebral redistribution by 2.5% (odds ratio (OR) = 1.025, P = 0.001), the odds of neonatal acidosis by 2.7% (OR = 1.027, P = 0.002) and the odds of a < 10th centile placenta by 3.0% (OR = 1.030, P < 0.0001). Each one centile reduction in AC between 20 and 36 weeks increased the odds of neonatal acidosis by 3.1% (OR = 1.031, P = 0.0005), the odds of low neonatal BF% by 2.8% (OR = 1.028, P = 0.04) and the odds of placenta < 10th centile by 2.1% (OR = 1.021, P = 0.0004). Falls in EFW or AC of > 30 centiles between 20 and 36 weeks were associated with two-threefold increased relative risks of these indicators of placental insufficiency, while low 20-28-week growth velocities were not.

Conclusions: Reduced growth velocity between 20 and 36 weeks among AGA fetuses is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency. These fetuses potentially represent an important, under-recognised cohort at increased risk of stillbirth. Encouragingly, this novel fetal assessment would require only one additional ultrasound to current routine care, and adds to the potential benefits of routine 36-week ultrasound.
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http://dx.doi.org/10.1186/s12916-020-01869-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758928PMC
December 2020

Measuring circulating miRNAs in early pregnancy could identify fetuses' destined to undergrow and be at increased risk of stillbirth.

EBioMedicine 2021 Jan 16;63:103172. Epub 2020 Dec 16.

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal, Mercy Hospital for Women, Level 4, Mercy Hospital for Women, 163 Studley Rd., Heidelberg 3084, Victoria, Australia.

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http://dx.doi.org/10.1016/j.ebiom.2020.103172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750576PMC
January 2021

Nanoparticles in pregnancy: the next frontier in reproductive therapeutics.

Hum Reprod Update 2021 Feb;27(2):280-304

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia.

Background: Nanotechnology involves the engineering of structures on a molecular level. Nanomedicine and nano-delivery systems have been designed to deliver therapeutic agents to a target site or organ in a controlled manner, maximizing efficacy while minimizing off-target effects of the therapeutic agent administered. In both reproductive medicine and obstetrics, developing innovative therapeutics is often tempered by fears of damage to the gamete, embryo or developing foetus or of negatively impacting a woman's reproductive potential. Thus, nanomedicine delivery systems may provide alternative targeted intervention strategies, treating the source of the disease and minimizing long-term consequences for the mother and/or her foetus.

Objective And Rationale: This review summarizes the current state of nanomedicine technology in reproductive medicine and obstetrics, including safety, potential applications, future directions and the hurdles for translation.

Search Methods: A comprehensive electronic literature search of PubMed and Web of Science databases was performed to identify studies published in English up until February 2020. Relevant keywords were used to obtain information regarding use of nanoparticle technology in fertility and gene therapy, early pregnancy complications (ectopic pregnancy and gestational trophoblastic disease) and obstetric complications (preeclampsia, foetal growth restriction, preterm birth and gestational diabetes) and for selective treatment of the mother or foetus. Safety of specific nanoparticles to the gamete, embryo and foetus was also investigated.

Outcomes: Pre-clinical research in the development of nanoparticle therapeutic delivery is being undertaken in many fields of reproductive medicine. Non-hormonal-targeted nanoparticle therapy for fibroids and endometriosis may provide fertility-sparing medical management. Delivery of interventions via nanotechnology provides opportunities for gene manipulation and delivery in mammalian gametes. Targeting cytotoxic treatments to early pregnancy tissue provides an alternative approach to manage ectopic pregnancies and gestational trophoblastic disease. In pregnancy, nanotherapeutic delivery offers options to stably deliver silencing RNA and microRNA inhibitors to the placenta to regulate gene expression, opening doors to novel genetic treatments for preeclampsia and foetal growth restriction. Restricting delivery of teratogenic drugs to the maternal compartment (such as warfarin) may reduce risks to the foetus. Alternatively, targeted delivery of drugs to the foetus (such as those to treat foetal arrythmias) may minimize side effects for the mother.

Wider Implications: We expect that further development of targeted therapies using nanoparticles in a reproductive setting has promise to eventually allow safe and directed treatments for conditions impacting the health and reproductive capacity of women and for the management of pregnancy and serious pregnancy complications.
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http://dx.doi.org/10.1093/humupd/dmaa049DOI Listing
February 2021

MicroRNAs 363 and 149 are differentially expressed in the maternal circulation preceding a diagnosis of preeclampsia.

Sci Rep 2020 10 22;10(1):18077. Epub 2020 Oct 22.

Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Road, Heidelberg, VIC, 3084, Australia.

Preeclampsia is a pregnancy complication associated with angiogenic dysbalance, maternal endothelial dysfunction and end-organ injury. A predictive test to identify those who will develop preeclampsia could substantially decrease morbidity and mortality. MicroRNAs (miRs) are small RNA molecules involved in post-transcriptional gene regulation. We screened for circulating miRs differentially expressed at 36 weeks' gestation in pregnancies before the development of preeclampsia. We used a case-control group (198 controls, 34 pre-preeclampsia diagnosis) selected from a prospective cohort (n = 2015) and performed a PCR-based microarray to measure the expression of 41 miRs. We found six circulating miRs (miRs 363, 149, 18a, 1283, 16, 424) at 36 weeks' had significantly reduced expression (p < 0.0001-0.04). miR363 was significantly downregulated at 28 weeks' gestation, 10-12 weeks before the onset of clinical disease. In the circulation of another cohort of 34 participants with established preterm preeclampsia (vs 23 controls), we found miRs363, 18a, 149 and 16 were significantly down regulated (p < 0.0001-0.04). Combined expression of miRs149 and 363 in the circulation at 36 weeks' gestation provides a test with 45% sensitivity (at a specificity of 90%) which suggests measuring both miRs may have promise as part of a multi-marker test to predict preeclampsia.
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http://dx.doi.org/10.1038/s41598-020-73783-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583242PMC
October 2020

Novel approaches to combat preeclampsia: from new drugs to innovative delivery.

Placenta 2020 12 5;102:10-16. Epub 2020 Sep 5.

Therapeutics Discovery and Vascular Function, Australia; Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia. Electronic address:

Preeclampsia is a complex disease affecting 2-8% of pregnancies worldwide. It poses significant risk of maternal and perinatal morbidity and mortality. Despite the rising research interest to discover new therapeutic approaches to prevent and treat preeclampsia, options remain limited. Identifying the important pathological stages in the progression of this disease allows us to evaluate effective candidate therapeutics. Three important stages in the pathophysiology are: 1) placental hypoxia and oxidative stress, 2) excess release of anti-angiogenic and pro-inflammatory factors, and 3) widespread systemic endothelial dysfunction and vasoconstriction. Repurposing drugs already safe for use in pregnancy is an attractive option for discovery of novel therapeutics. There are many drugs currently being assessed to treat preeclampsia, including proton pump inhibitors (PPIs), metformin, statins, sulfasalazine, sofalcone, resveratrol, melatonin, and sildenafil citrate. These drugs show positive effects in preclinical studies, targeting placental and endothelial dysfunction. However, using novel therapeutics can raise safety concerns for the developing fetus. Therefore, innovative targeted delivery systems are being developed to safely administer these therapeutics directly to the placenta and/or endothelium. These include nanoparticle delivery systems, developed and used by the oncology field, now being adapted for obstetrics. This technology is currently being assessed in animal models and shows promise for treating preeclampsia. Combining effective therapeutics with targeted drug delivery could be the future of preeclampsia treatment.
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http://dx.doi.org/10.1016/j.placenta.2020.08.022DOI Listing
December 2020

Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia.

Am J Obstet Gynecol 2020 Sep 16. Epub 2020 Sep 16.

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia.

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.
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http://dx.doi.org/10.1016/j.ajog.2020.09.014DOI Listing
September 2020

Appropriate-for-gestational-age infants who exhibit reduced antenatal growth velocity display postnatal catch-up growth.

PLoS One 2020 8;15(9):e0238700. Epub 2020 Sep 8.

Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia.

Background: Postnatally, small-for-gestational-age (SGA; birthweight <10th centile) infants who are growth restricted due to uteroplacental insufficiency (UPI) demonstrate 'catch-up growth' to meet their genetically-predetermined size. Infants who demonstrate slowing growth during pregnancy are those that cross estimated fetal weight centiles at serial ultrasound examinations. These infants that slow in growth but are born appropriate-for-gestational-age (AGA; ≥10th centile), exhibit antenatal, intrapartum and postnatal indicators of UPI. Here, we examine if and when these infants (labelled as AGA-FGR) also demonstrate catch-up growth like SGA infants, when compared with AGA infants with normal antenatal growth velocity (AGA-NG).

Methods: We followed-up the infants of women who had previously undergone ultrasound assessment of fetal size at 28- and 36-weeks' gestation, enabling calculation of antenatal growth velocity. To assess postnatal growth, we asked parents to send their infant's growth measurements, up to two years post-birth, which are routinely collected through the state-wide Maternal-Child Health service. Infants with medical conditions affecting postnatal growth were excluded from the analysis. From the measurements obtained we calculated age-adjusted z-scores for postnatal weight, length and body mass index (BMI; weight(kg)/height(m2)) at birth and 4, 8, 12, 18 and 24 months. We used linear spline regression modelling to predict mean weight, length and BMI z-scores at intervals post birth. Predicted mean age-adjusted z-scores were then compared between three groups; SGA, AGA with low antenatal growth (AGA-FGR; loss of >20 customised estimated fetal weight centiles), and AGA-NG to determine if catch-up growth occurred. In addition, we compared the rates of catch-up growth (defined as an increase in weight age-adjusted z-score of ≥0.67 over 1 year) between the groups with Fisher's exact tests.

Results: Of 158 (46%) infant growth records received, 146 were AGA, with low antenatal growth velocity occurring in 34/146 (23.2%). Rates of gestational diabetes and SGA birthweight were higher in those lost to follow-up. Compared to AGA-NG infants, AGA-FGR infants had significantly lower predicted mean weight (p<0.001), length (p = 0.04) and BMI (p = 0.001) z-scores at birth. These significant differences were no longer evident at 4 months, suggesting that catch-up growth had occurred. As expected, the catch-up growth that occurred among the AGA-FGR was not as great in magnitude as that demonstrated by the SGA. When assessed categorically, there was no significant difference between the rate of catch-up growth among the AGA-FGR and the SGA. Catch-up growth was significantly more frequent among both the AGA-FGR and the SGA groups compared to the AGA-NG.

Conclusions: AGA infants that have exhibited reduced antenatal fetal growth velocity also exhibit significant catch-up growth in the first 12 months of life. This finding represents further evidence that AGA fetuses that slow in growth during pregnancy do so due to UPI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238700PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478563PMC
October 2020

Esomeprazole and sulfasalazine in combination additively reduce sFlt-1 secretion and diminish endothelial dysfunction: potential for a combination treatment for preeclampsia.

Pregnancy Hypertens 2020 Oct 28;22:86-92. Epub 2020 Jul 28.

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Hospital for Women, Australia; Therapeutics Discovery and Vascular Function, Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Hospital for Women, Australia; Mercy Perinatal 163 Studley Rd, Heidelberg 3084, Victoria, Australia. Electronic address:

Development and repurposing of therapies that show promise in the prevention or treatment of preeclampsia would be a major advance for the obstetrics field. We recently identified esomeprazole and sulfasalazine as potential candidates for the treatment of preeclampsia. Both reduce placental and endothelial secretion of sFlt-1 and sENG and mitigate endothelial dysfunction in vitro. Here we assessed whether esomeprazole and sulfasalazine in combination would additively attenuate the elevated release of anti-angiogenic factors and markers of endothelial dysfunction, key characteristics of preeclampsia. Primary placental tissue and cells, and primary endothelial cells were treated with esomeprazole and sulfasalazine alone and in combination. We assessed secretion of sFlt-1 and sENG and performed in vitro assays of endothelial dysfunction. Combining esomeprazole and sulfasalazine in lower concentrations caused an additive reduction in sFlt-1 secretion in primary cytotrophoblasts, placental explants and endothelial cells. No additive reduction was observed in sENG secretion when esomeprazole and sulfasalazine were combined. Together, esomeprazole and sulfasalazine additively reduced TNF-α-induced VCAM and ET-1 mRNA expression, and monocyte adhesion to endothelial cells. In conclusion, combining esomeprazole and sulfasalazine additively reduced secretion of sFlt-1 and markers of endothelial dysfunction. Combined administration of esomeprazole and sulfasalazine may provide a more effective treatment or prevention for preeclampsia compared to either as single agents.
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http://dx.doi.org/10.1016/j.preghy.2020.07.013DOI Listing
October 2020

Aspirin use during pregnancy and the risk of bleeding complications: a Swedish population-based cohort study.

Am J Obstet Gynecol 2021 01 17;224(1):95.e1-95.e12. Epub 2020 Jul 17.

Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden; Center for Clinical Research, Falun, Sweden; Department of Obstetrics and Gynecology, Stellenbosch University, Stellenbosch, South Africa; Department of Obstetrics and Gynecology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Aspirin is offered to pregnant women to prevent preeclampsia, a severe obstetrical complication. Large studies of nonpregnant populations have consistently shown that aspirin prophylaxis increases the risk of hemorrhagic complications. However, there have not been any population-based studies investigating this in a pregnant population.

Objective: This study aimed to investigate whether aspirin use during pregnancy is associated with an increased risk of bleeding complications.

Study Design: We performed a register-based cohort study using the Swedish Pregnancy Register wherein we examined 313,624 women giving birth between January 2013 and July 2017. Logistic regression was used to assess the risk of antepartum, intrapartum, and postpartum hemorrhage. A propensity score and inverse probability treatment weighting was used to generate an odds ratio that corrects for differences in baseline characteristics.

Results: Aspirin use was registered in 4088 (1.3%) women during pregnancy. Compared with women who did not take aspirin, aspirin use was not associated with bleeding complications during the antepartum period (adjusted odds ratio, 1.22; 95% confidence interval, 0.97-1.54). However, aspirin users had a higher incidence of intrapartum bleeding (2.9% aspirin users vs 1.5% nonusers; adjusted odds ratio, 1.63; 95% confidence interval, 1.30-2.05), postpartum hemorrhage (10.2% vs 7.8%; adjusted odds ratio, 1.23; 95% confidence interval, 1.08-1.39), and postpartum hematoma (0.4% vs 0.1%; adjusted odds ratio, 2.21; 95% confidence interval, 1.13-4.34). The risk of a neonatal intracranial hemorrhage was also increased (0.07% vs 0.01%; adjusted odds ratio, 9.66; 95% confidence interval, 1.88-49.48). After stratifying by mode of birth, a higher incidence of bleeding among aspirin users was present for those who had a vaginal birth but not those who had a cesarean delivery.

Conclusion: Using aspirin during pregnancy is associated with increased postpartum bleeding and postpartum hematoma. It may also be associated with neonatal intracranial hemorrhage. When offering aspirin during pregnancy, these risks need to be weighed against the potential benefits.
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http://dx.doi.org/10.1016/j.ajog.2020.07.023DOI Listing
January 2021

Combining metformin and sulfasalazine additively reduces the secretion of antiangiogenic factors from the placenta: Implications for the treatment of preeclampsia.

Placenta 2020 06 25;95:78-83. Epub 2020 Apr 25.

Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, University of Melbourne. Mercy Perinatal, Mercy Hospital for Women, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia.

Introduction: The antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are elevated in preeclampsia and have been implicated in its pathogenesis. We have previously demonstrated metformin and sulfasalazine independently reduce antiangiogenic factor secretion. Here we examined whether combining metformin and sulfasalazine may be more effective than either alone in reducing placental expression and secretion of antiangiogenic and angiogenic factors and the expression of markers of endothelial dysfunction.

Methods: We performed functional experiments using primary human placenta to explore the effect of metformin and sulfasalazine, at lower doses than previously explored, individually and in combination, on sFlt-1 and sENG secretion and placental growth factor (PlGF) and vascular endothelial growth factor (VEGFα) expression. Using primary endothelial cells we induced dysfunction using cytokine tumor necrosis factor-α (TNF-α) and assessed the effect of low dose combination treatment on the expression of vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (a potent vasoconstrictor).

Results: We demonstrated combination metformin and sulfasalazine was additive in reducing sFlt-1 secretion from cytotrophoblasts and placental explants. Combination treatment was also additive in reducing sENG secretion from placental explants. Furthermore, combination treatment increased cytotrophoblast VEGFα mRNA expression. Whilst combination treatment increased PlGF mRNA expression this was similar to treatment with sulfasalazine alone. Combination therapy reduced TNFα induced endothelin-1 mRNA expression however did not change VCAM expression.

Discussion: Low dose combination metformin and sulfasalazine reduced cytotrophoblast sFlt-1 and sENG secretion, increased VEGFα expression and reduced TNFα induced endothelin-1 expression in primary endothelial cells. Combination therapy has potential to treat preeclampsia.
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http://dx.doi.org/10.1016/j.placenta.2020.04.010DOI Listing
June 2020

Aurora kinase mRNA expression is reduced with increasing gestational age and in severe early onset fetal growth restriction.

Placenta 2020 06 26;95:53-61. Epub 2020 Apr 26.

Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Victoria, Australia. Electronic address:

Introduction: Oxidative damage and biochemical ageing are implicated in placental dysfunction and potentially fetal death. Cellular senescence may play a role in the pathophysiology of fetal growth restriction (FGR) and preeclampsia (PE). Aurora kinases (AURKA, B and C) are important regulators of cellular division in mitosis and meiosis with implications in cellular senescence. We aimed to investigate whether aurora kinase expression is altered with placental dysfunction or placental ageing.

Methods: Placenta and blood was obtained across gestation from pregnancies complicated by PE, FGR or both PE and FGR, as well as gestation-matched control samples. Expression of AURKA, B and C mRNA was examined using real time qPCR in both the placenta and maternal circulation.

Results: Placental aurora kinase expression decreased as gestation progressed: AURKA and AURKB were significantly reduced at 37-40 weeks, whereas AURKC was significantly reduced at 34-37 weeks, when compared to <34 weeks. In the maternal circulation, the mRNA level of AURKB was significantly reduced at >40 weeks compared to <34 weeks gestation. A significant reduction in AURKC was seen in FGR pregnancies <34 weeks compared to gestation-matched controls.

Conclusion: Placental AURK expression is reduced with increased gestation. Circulating AURKB mRNA reduces at >40 weeks gestation, when compared to <34 weeks. AURKC is significantly reduced in placentas from pregnancies complicated by severe early onset (<34 weeks) FGR compared with gestation-matched controls. The functional role of aurora kinase in the placenta and in gestational age warrants further investigation.
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http://dx.doi.org/10.1016/j.placenta.2020.04.012DOI Listing
June 2020

Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth.

BMC Med 2020 05 22;18(1):145. Epub 2020 May 22.

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4, Studley Rd, Heidelberg, Victoria, 3084, Australia.

Background: Fetuses affected by placental insufficiency do not receive adequate nutrients and oxygenation, become growth restricted and acidemic, and can demise. Preterm fetal growth restriction is a severe form of placental insufficiency with a high risk of stillbirth. We set out to identify maternal circulating mRNA transcripts that are differentially expressed in preterm pregnancies complicated by very severe placental insufficiency, in utero fetal acidemia, and are at very high risk of stillbirth.

Methods: We performed a cohort study across six hospitals in Australia and New Zealand, prospectively collecting blood from 128 pregnancies complicated by preterm fetal growth restriction (delivery < 34 weeks' gestation) and 42 controls. RNA-sequencing was done on all samples to discover circulating mRNAs associated with preterm fetal growth restriction and fetal acidemia in utero. We used RT-PCR to validate the associations between five lead candidate biomarkers of placental insufficiency in an independent cohort from Europe (46 with preterm fetal growth restriction) and in a third cohort of pregnancies ending in stillbirth.

Results: In the Australia and New Zealand cohort, we identified five mRNAs that were highly differentially expressed among pregnancies with preterm fetal growth restriction: NR4A2, EMP1, PGM5, SKIL, and UGT2B1. Combining three yielded an area under the receiver operative curve (AUC) of 0.95. Circulating NR4A2 and RCBTB2 in the maternal blood were dysregulated in the presence of fetal acidemia in utero. We validated the association between preterm fetal growth restriction and circulating EMP1, NR4A2, and PGM5 mRNA in a cohort from Europe. Combining EMP1 and PGM5 identified fetal growth restriction with an AUC of 0.92. Several of these genes were differentially expressed in the presence of ultrasound parameters that reflect placental insufficiency. Circulating NR4A2, EMP1, and RCBTB2 mRNA were differentially regulated in another cohort destined for stillbirth, compared to ongoing pregnancies. EMP1 mRNA appeared to have the most consistent association with placental insufficiency in all cohorts.

Conclusions: Measuring circulating mRNA offers potential as a test to identify pregnancies with severe placental insufficiency and at very high risk of stillbirth. Circulating mRNA EMP1 may be promising as a biomarker of severe placental insufficiency.
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http://dx.doi.org/10.1186/s12916-020-01605-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243334PMC
May 2020

Circulating SPINT1 is a biomarker of pregnancies with poor placental function and fetal growth restriction.

Nat Commun 2020 05 15;11(1):2411. Epub 2020 May 15.

Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, 3084, Victoria, Australia.

Placental insufficiency can cause fetal growth restriction and stillbirth. There are no reliable screening tests for placental insufficiency, especially near-term gestation when the risk of stillbirth rises. Here we show a strong association between low circulating plasma serine peptidase inhibitor Kunitz type-1 (SPINT1) concentrations at 36 weeks' gestation and low birthweight, an indicator of placental insufficiency. We generate a 4-tier risk model based on SPINT1 concentrations, where the highest risk tier has approximately a 2-5 fold risk of birthing neonates with birthweights under the 3, 5, 10 and 20 centiles, whereas the lowest risk tier has a 0-0.3 fold risk. Low SPINT1 is associated with antenatal ultrasound and neonatal anthropomorphic indicators of placental insufficiency. We validate the association between low circulating SPINT1 and placental insufficiency in two other cohorts. Low circulating SPINT1 is a marker of placental insufficiency and may identify pregnancies with an elevated risk of stillbirth.
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http://dx.doi.org/10.1038/s41467-020-16346-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228948PMC
May 2020

Pravastatin as the statin of choice for reducing pre-eclampsia-associated endothelial dysfunction.

Pregnancy Hypertens 2020 Apr 4;20:83-91. Epub 2020 Mar 4.

Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Australia; Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg 3084, Victoria, Australia. Electronic address:

Objectives: There is avid interest in pravastatin as a therapeutic intervention for pre-eclampsia, however little is known on statin action on endothelial dysfunction. This study aimed to evaluate the ability of pravastatin, simvastatin and rosuvastatin to reduce pre-eclampsia-associated markers of endothelial dysfunction in human endothelial cells.

Study Design: Primary human umbilical vein endothelial cells (HUVECs) and uterine microvascular cells (UtMVs) were isolated and treated with 0.2, 2, 20 and 200 µM pravastatin, simvastatin and rosuvastatin for 24 h, either with or without pre-treatment with TNF-α to induce endothelial dysfunction.

Main Outcome Measures: Cell viability (MTS) assays were performed and cells were visually inspected. Expression of endothelial dysfunction markers, endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were assessed by qPCR (n=3). Intracellular VCAM-1 protein was examined by Western Blotting (n=5). ET-1 and soluble fms-like tyrosine kinase-1 (sFLT-1) protein secretion was assessed by ELISA in HUVEC conditioned media (n=3).

Results: High doses of simvastatin and rosuvastatin significantly compromised HUVEC survival. 200 µM simvastatin significantly reduced UtMV survival. Abnormal cell structure was observed with these doses and thus were excluded from further analysis. The statins did not mitigate TNF-α induced ET-1 or VCAM-1 expression in either HUVECs or UtMVs, nor VCAM-1 protein expression in HUVECs. 0.2 µM pravastatin and simvastatin significantly reduced ET-1 and sFLT-1 protein secretion.

Conclusions: Pravastatin significantly reduced secretion of both ET-1 and sFLT-1, key mediators of endothelial dysfunction. Importantly, pravastatin had no toxic effects, in contrast to rosuvastatin and simvastatin. This further supports selection of pravastatin for clinical applications to combat pre-eclampsia.
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http://dx.doi.org/10.1016/j.preghy.2020.03.004DOI Listing
April 2020

Circulating Delta-like homolog 1 (DLK1) at 36 weeks is correlated with birthweight and is of placental origin.

Placenta 2020 02 8;91:24-30. Epub 2020 Jan 8.

Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Road, Heidelberg, 3084, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Victoria, Australia. Electronic address:

Introduction: Recently, Delta-like homolog 1 (DLK1) was identified as a potential marker of small-for-gestational-age (SGA; <10th centile) fetuses; mouse studies suggest reduced levels may represent a fetal stress signal. We sought to measure DLK1 in a large independent cohort of maternal blood samples, correlate levels with measures of placental insufficiency and assess whether DLK1 might be placental derived.

Methods: The Fetal Longitudinal Assessment of Growth (FLAG) study was a prospective blood collection from 2000 women. We assessed a case-control cohort at 28 and 36 weeks from the first 1000 FLAG women, before validating changes in the entire second 1000. A subgroup of FLAG participants underwent ultrasound examinations, and 137 neonates, body composition assessment (PEAPOD). DLK1 secretion was assessed from human placentas ex vivo.

Results: Circulating DLK1 was significantly reduced at 28 and 36 weeks' gestation in women destined to deliver a SGA fetus and associated with birthweight centile (n = 999, p < 0.0001), and placental weight (n = 96, p = 0.0064). Ex vivo, DLK1 was abundantly released from human placenta and significantly reduced under hypoxia (n = 7, p < 0.05). We found no relationship between circulating DLK1 and estimated fetal weight, cerebroplacental ratio, uterine artery or umbilical artery pulsatility index. Nor was there a relationship between DLK1 and neonatal fat or lean mass (n = 137).

Conclusion: We confirmed circulating DLK1 is reduced at both 28 and 36 weeks' gestation preceding delivery of a SGA infant, shown that it is not significantly associated with clinical measures of placental insufficiency, and provide new data demonstrating it may be placenta-derived in humans.
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http://dx.doi.org/10.1016/j.placenta.2020.01.003DOI Listing
February 2020

Accuracy of clinical suspicion of growth restriction at term despite a normal growth ultrasound: A retrospective cohort study.

Aust N Z J Obstet Gynaecol 2020 08 9;60(4):568-573. Epub 2020 Jan 9.

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Melbourne, Victoria, Australia.

Background: 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.

Aims: 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.

Materials And Methods: 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.

Results: 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.

Conclusions: A reassuring ultrasound with EFW ≥10th centile in the late third trimester should not override clinical concerns of impaired fetal growth at term.
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http://dx.doi.org/10.1111/ajo.13111DOI Listing
August 2020

The incidence of hypertensive disorders of pregnancy following sperm donation in IVF: an Australian state-wide retrospective cohort study.

Hum Reprod 2019 12;34(12):2541-2548

Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Australia.

Study Question: Does IVF using donor sperm increase the risk of hypertensive disorders of pregnancy and fetal growth restriction (FGR)?

Summary Answer: IVF conceptions arising from sperm donation are not associated with an increased risk of hypertensive disorders of pregnancy or FGR.

What Is Known Already: It has been hypothesized that the absence of prior exposure to factors within the paternal ejaculate increases the risk of preeclampsia and FGR among nulliparous women or women with a new partner-the concept of 'primipaternity'. It remains unclear which element of the ejaculate is responsible: the sperm cell or the constituents of seminal fluid. IVF pregnancies arising from donor sperm where the seminal fluid is absent provide a unique opportunity to test the theory of primipaternity and the relative contribution of the sperm cell. Pregnancies conceived via artificial reproductive technology are at increased risk of preeclampsia and FGR.

Study Design, Size, Duration: Theories about the development of preeclampsia and the relative contribution of spermatic factors were explored by comparing the risk of hypertensive disorders of pregnancy and FGR among IVF pregnancies conceived with autologous gametes (own eggs and partner sperm) and those conceived with donor sperm, donor egg (and partner sperm) and donor embryo. To do this, we performed a retrospective cohort analysis of pregnancy outcomes among singleton pregnancies (n = 15 443) conceived through fertility clinics within Australia between 2009 and 2017.

Participants/materials, Setting, Methods: All pregnancies resulting in a singleton pregnancy delivering after 20 weeks' gestation were included. The cohort was divided into donor sperm, donor egg and donor embryo (where both gametes came from a donor to create an embryo, or in a surrogate pregnancy) groups. We also compared the data with a control group, defined as IVF-conceived pregnancies from autologous cycles. A multivariable regression model was used to calculate an adjusted odds ratio (aOR).

Main Results And The Role Of Chance: The final cohort contained 1435, 578 and 239 pregnancies conceived by donor sperm, donor egg and donor embryo, respectively, and 13 191 controls. There were a very small number of women lost to follow-up (31 women; 0.2% of total cohort). Compared to control pregnancies, there was no increase in the risk of hypertensive disorders among pregnancies conceived via donor sperm (aOR 0.94; 95% CI 0.73-1.21). Subgroup analysis was performed for a cohort where parity was known (n = 4551), and of these, 305 multigravida pregnancies were conceived via donor sperm. Among this cohort, no increased risk of preeclampsia or pregnancy-induced hypertension was found (aOR 1.18; 95% CI: 0.69-2.04) as a result of primipaternity (new sperm donor).A significantly increased risk for hypertensive disorders of pregnancy was associated with the use of donor eggs (but partner sperm; aOR 2.34; 95% CI 1.69-3.21). However, the association was no greater among pregnancies conceived with donor embryos (i.e. donated egg and sperm; aOR 2.0; 95% CI 1.25-3.17) than among the donor oocyte group. The overall incidence of FGR (defined as birthweight <10th centile) was 18%. There were no significant differences observed between donor sperm, or donor embryo pregnancies; however, egg donation was associated with a 1.5-fold increase in FGR.

Limitations, Reasons For Caution: This study was limited by a lower than expected rate of hypertensive disorders of pregnancy (n = 862, 5.6%), which is contrary to the well-established increased risk among women using IVF. However, this is likely to be evenly distributed across the study groups and, therefore, unlikely to have introduced significant bias.

Wider Implications Of The Findings: These findings suggest that exposure to new sperm may not be implicated in the pathogenesis of preeclampsia. The mechanism of increased risk seen in conceptions arising from egg or embryo donation remains unclear. Further investigation is required to elucidate these mechanisms and, ultimately, improve pregnancy outcomes following IVF.

Study Funding/competing Interest(s): This study was supported by the Australian Commonwealth Government-Graduate Research Scheme (A.K.). Salary support was provided by the National Health and Medical Research Council of Australia (S.T.), Mercy Foundation (A.L.), and the Department of Obstetrics and Gynaecology at the University of Melbourne (R.H.). There are no competing interests.
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http://dx.doi.org/10.1093/humrep/dez198DOI Listing
December 2019

Combination methotrexate and gefitinib: A potential medical treatment for inoperable nontubal ectopic pregnancy.

J Obstet Gynaecol Res 2020 Mar 9;46(3):531-535. Epub 2019 Dec 9.

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Victoria, Australia.

Nontubal ectopic pregnancies present as a therapeutic challenge. A 35-year-old primigravida at 7 weeks gestation had a live interstitial ectopic pregnancy and contraindications to surgery. The patient was treated with a multidose methotrexate regimen combined with oral gefitinib (250 mg daily for 7 days). The peak human chorionic gonadotropin (hCG) of the patient was recorded at 19 510 IU/L and began declining from day 4 of combination therapy (day 6 of initial treatment). Successful resolution of the ectopic was demonstrated by cessation of the fetal heart by day 15 and hCG falling to 23 IU/L by day 42. A 10-year review of all nontubal ectopic pregnancies treated with methotrexate identified 46 cases, which had a comparable time to resolution to combination therapy. However, for cases where cardiac activity was present, the median time to resolution following methotrexate treatment was 64 days (47-87 days), 22 days longer than combination therapy. Combination therapy may provide a safe medical treatment for inoperable nontubal ectopic pregnancy.
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http://dx.doi.org/10.1111/jog.14169DOI Listing
March 2020

Death associated protein kinase 1 (DAPK-1) is increased in preeclampsia.

Placenta 2019 12 24;88:1-7. Epub 2019 Sep 24.

Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Road, Heidelberg, 3084, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Victoria, Australia.

Introduction: Death associated protein kinase-1 (DAPK-1) is highly expressed in the placenta relative to all other human tissues. We examine whether it is differentially expressed with preeclampsia.

Methods: We examined samples from a large prospective collection of plasma from 2002 women. We split the samples into two cohorts: Cohort 1 (n = 1000) and Cohort 2 (n = 1002). We first measured circulating DAPK-1 at 36 weeks' gestation in a nested case-control group (from Cohort 1) of 39 women who developed preeclampsia and 98 controls. We then validated our findings by measuring circulating levels in all samples from both cohorts. We also measured DAPK-1 in the circulation and placentas of women who were diagnosed with preterm preeclampsia or delivered a growth restricted infant at <34 weeks' gestation.

Results: In the case-control study, circulating DAPK-1 was significantly increased in women destined to develop preeclampsia (p < 0.01). We validated this by measuring circulating levels in Cohorts 1 and 2. Again, circulating DAPK-1 was significantly higher (p < 0.001) among women destined to develop preeclampsia (Cohort 1, Area under the receiver operator characteristic curve (AUC) = 0.66; Cohort 2 AUC = 0.67). Circulating DAPK-1 was also significantly elevated in women with established preterm preeclampsia. Placental DAPK-1 mRNA and protein expression were elevated in women with established preeclampsia.

Discussion: DAPK-1 is a novel placenta-enriched molecule that is elevated in the circulation of women preceding the diagnosis of preeclampsia and is likely to be secreted from the placenta.
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http://dx.doi.org/10.1016/j.placenta.2019.09.010DOI Listing
December 2019

Sulfasalazine decreases soluble fms-like tyrosine kinase-1 secretion potentially via inhibition of upstream placental epidermal growth factor receptor signalling.

Placenta 2019 11 10;87:53-57. Epub 2019 Sep 10.

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, 3084, Australia; Mercy Perinatal, Mercy Hospital for Women, Victoria, Australia.

Objectives: Preeclampsia 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 preeclampsia. 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 preeclampsia. 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.

Methods And Results: 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.

Conclusion: 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 preeclampsia.
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http://dx.doi.org/10.1016/j.placenta.2019.09.004DOI Listing
November 2019

Prediction of adverse maternal outcomes in preeclampsia at term.

Pregnancy Hypertens 2019 Oct 20;18:75-81. Epub 2019 Sep 20.

Department of Obstetrics and Gynaecology, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia; Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia. Electronic address:

Preeclampsia 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 preeclampsia 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 preeclampsia 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 preeclampsia at term and included in our study. After admission, 44.4% progressed to preeclampsia 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 preeclampsia with severe features. Almost half of the women presenting with preeclampsia at term will progress to preeclampsia with severe features. Admission characteristics can be used to predict those at risk of disease progression.
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http://dx.doi.org/10.1016/j.preghy.2019.09.004DOI Listing
October 2019

Screening circulating proteins to identify biomarkers of fetal macrosomia.

BMC Res Notes 2019 Sep 18;12(1):587. Epub 2019 Sep 18.

Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.

Objective: Fetal macrosomia is a major risk factor for shoulder dystocia, which can lead to birth asphyxia, maternal and neonatal traumatic injuries, and perinatal death. If macrosomia is diagnosed in the antenatal period, labour can be induced to decrease shoulder dystocia. But current clinical methods to diagnose fetal macrosomia antenatally perform with poor accuracy. Therefore, improved methods to accurately diagnose fetal macrosomia are required. Blood biomarkers that predict fetal macrosomia could be one such novel diagnostic strategy. We undertook a nested case-control study from a prospective collection of 1000 blood samples collected at 36 weeks' gestation. We analysed plasma samples from 52 women who subsequently delivered a macrosomic (> 95th centile for gestational age) infant and 106 controls. Circulating concentrations of the proteins COBLL1, CSH1, HSD3B1, EGFL6, XAGE3, S100P, PAPPA-1, ERBB2 were assessed for their ability to predict macrosomic infants.

Results: We did not identify any significant changes in the plasma concentrations of COBLL1, CSH1, HSD3B1, EGFL6, XAGE3, S100P, PAPPA-1, ERBB2 from women who subsequently delivered macrosomic neonates relative to control samples. Although we have not identified any potential biomarkers of fetal macrosomia, we have ruled out these particular eight protein candidates.
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http://dx.doi.org/10.1186/s13104-019-4625-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749776PMC
September 2019

Systematic review of areca (betel nut) use and adverse pregnancy outcomes.

Int J Gynaecol Obstet 2019 Dec 3;147(3):292-300. Epub 2019 Oct 3.

Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Vic., Australia.

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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http://dx.doi.org/10.1002/ijgo.12971DOI Listing
December 2019

Maternal mortality at the National Referral Hospital in Honiara, Solomon Islands over a five-year period.

Aust N Z J Obstet Gynaecol 2020 04 11;60(2):183-187. Epub 2019 Sep 11.

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia.

Background: The Solomon Islands is a developing country facing significant barriers to the provision of quality antenatal and obstetric care. The maternal mortality rate is 114/100 000 live births, ranking the Solomon Islands 113th globally. Investigating maternal mortality may yield valuable insight into improving these numbers.

Aim: The objective of this study was to review all cases of maternal mortality at the National Referral Hospital, Solomon Islands over a five-year period.

Materials And Methods: This was a retrospective review of maternal deaths occurring at the National Referral Hospital, Solomon Islands from 2013 to 2017. Data on maternal demographics, characteristics and cause of death were collected.

Results: There were 39 maternal deaths at the National Referral Hospital from 2013 to 2017. The maternal mortality rate of the National Referral Hospital (139/100 000) is higher than the national rate (114/100 000). Most deaths were direct, with 28% attributed to haemorrhage. Overall, 79% of the total maternal deaths had elements that may be considered preventable, with laboratory delays present in 54% and medication shortages present in 29% of cases.

Conclusion: Maternal mortality is high in the Solomon Islands, with many potentially preventable deaths occurring at the National Referral Hospital. Continued focus on improving data collection, access to resources, and training is vital to reduce maternal mortality in the Solomon Islands.
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http://dx.doi.org/10.1111/ajo.13050DOI Listing
April 2020

Predictive Value of the Signs and Symptoms Preceding Eclampsia: A Systematic Review.

Obstet Gynecol 2019 10;134(4):677-684

Translational Obstetrics Group, Department of Obstetrics and Gynecology, and Mercy Perinatal, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia; the Department of Obstetrics and Gynecology, Stellenbosch University, Cape Town, South Africa; the Department of Women's and Children's Health, Uppsala University, Uppsala, and the Center for Clinical Research, Uppsala University, Falun, Sweden.

Objective: To estimate the predictive value of signs and symptoms that occur before onset of eclampsia among pregnant women.

Data Sources: Electronic databases, including MEDLINE, EMBASE, Cochrane, and ClinicalTrials.gov were searched from inception to 2018. Search terms included eclampsia, predict, likelihood ratio, predictive value, and risk.

Methods Of Study Selection: Abstracts and later full texts were selected for review if a diagnosis of eclampsia was made, a comparator arm included (women without a diagnosis of eclampsia), and predictors of imminent eclampsia 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).

Tabulation, Integration, And Results: 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 eclampsia nor rule out eclampsia in their absence, with moderate specificity (83-94%) and poor sensitivity (29-56%).

Conclusion: There is a dearth of high-quality studies investigating the predictive value of imminent signs and symptoms of eclampsia. 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 eclampsia. Of the most commonly reported symptoms-visual disturbances, epigastric pain, and headache-none were able to accurately predict, nor rule out, imminent eclampsia.

Systematic Review Registration: PROSPERO, CRD42018095076.
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http://dx.doi.org/10.1097/AOG.0000000000003476DOI Listing
October 2019

Blood-based biomarkers in the maternal circulation associated with fetal growth restriction.

Prenat Diagn 2019 10 22;39(11):947-957. Epub 2019 Jul 22.

Mercy Perinatal, Mercy Hospital for Women, Melbourne, Victoria, Australia.

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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http://dx.doi.org/10.1002/pd.5525DOI Listing
October 2019

Circulating adrenomedullin mRNA is decreased in women destined to develop term preeclampsia.

Pregnancy Hypertens 2019 Apr 10;16:16-25. Epub 2019 Feb 10.

Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Road, Heidelberg 3084, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women, Victoria, Australia.

Preeclampsia is a pregnancy complication associated with elevated placental secretion of anti-angiogenic factors, maternal endothelial dysfunction and end-organ injury. Adrenomedullin (ADM) is a pro-angiogenic peptide hormone which regulates blood pressure and vascular integrity. It is highly expressed in both the placenta and vascular endothelial cells. We performed a nested case-control study, selected from a large prospective cohort of over 2000 participants. Circulating ADM mRNA was reduced at both 28 (n = 39 vs 248 controls, p = 0.005) and 36 weeks' of pregnancy (n = 39 vs 205 controls, p < 0.0001) in those destined to develop term preeclampsia. It was also significantly reduced in the circulation of women with established early-onset preeclampsia (n = 34 vs 21 controls, p = 0.01). ADM mRNA (n = 34 vs 12 controls) and protein (n = 53 vs 17 controls) were significantly decreased in placental tissue from women with early-onset preeclampsia (p = 0.02, p = 0.0002 respectively), suggesting the placenta is a possible source of the reduced circulating mRNA. Functional studies in primary endothelial cells revealed significantly reduced ADM mRNA expression when cells were exposed to cytotrophoblast conditioned media (derived from normotensive pregnancies, p < 0.0001) or TNFα (p < 0.0001), suggesting another possible source of reduced circulating ADM mRNA is the endothelium. Circulating ADM mRNA, but not protein, is reduced 10-12 weeks before the diagnosis of term preeclampsia. It may be of endothelial or placental origin. Whole blood mRNA is a rich source of potential biomarker discovery in the prediction of preeclampsia.
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http://dx.doi.org/10.1016/j.preghy.2019.02.003DOI Listing
April 2019