Publications by authors named "Susan P Walker"

141 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

The Irie Classroom Toolbox, a universal violence-prevention teacher-training programme, in Jamaican preschools: a single-blind, cluster-randomised controlled trial.

Lancet Glob Health 2021 04 22;9(4):e456-e468. Epub 2021 Feb 22.

Caribbean Institute for Health Research, University of the West Indies, Mona, Kingston, Jamaica.

Background: Violence is a leading global public health problem, and interventions in early childhood are important in the primary prevention of violence. We tested whether the Irie Classroom Toolbox, a violence-prevention teacher-training programme reduced violence against children by teachers and reduced class-wide child aggression in Jamaican preschools (catering to children aged 3-6 years).

Methods: We did a single-blind, cluster-randomised controlled trial in 76 preschools in Kingston and St Andrew, randomly selected, using simple randomisation, from 120 eligible preschools. Inclusion criteria were two to four classes of children; at least ten children per class; and located in an urban area. We randomly assigned preschools (1:1) to either the Irie Classroom Toolbox intervention or waiting-list control that received no intervention, using a computer-generated randomisation sequence by an independent statistician masked to school identity. The Toolbox involved training teachers in classroom behaviour management and promoting child social-emotional competence. All assessors were masked to group assignment. All teachers and classrooms in the selected schools participated in the study. Within each school, we used simple randomisation to randomly select up to 12 children aged 4 years for evaluation of child outcomes. The Toolbox intervention was implemented from August to April the following year. Teacher and classroom measures were done at baseline (the summer school term; ie, May to June), post-intervention (after 8 months of intervention; ie, May to June of the following year), and 1-year follow-up (ie, May to June 2 years later). The primary outcomes were observations of violence against children (including physical violence and psychological aggression) by teachers occurring across one full school day, and class-wide child aggression occurring over five 20-min intervals on another school day, all measured at post-intervention and 1-year follow-up and analysed by intention to treat. This trial is registered with ISRCTN, number ISRCTN11968472.

Findings: Between June 22, 2015, and April 29, 2016, (after baseline measurements were completed), we assigned 38 preschools (with 119 teachers) to the Toolbox intervention and 38 preschools (with 110 teachers) to control. 441 children in the intervention schools and 424 in the control schools were included in the evaluation. All schools were included in the post-intervention and follow-up analyses. There were fewer counts of violence against children by teachers in the intervention schools compared with control schools at post-intervention (median counts 3 [IQR 0-11] vs 15 [3-35]; effect size -67·12%, 95% CI -80·71 to -53·52, p<0·0001) and 1-year follow-up (median counts 3 [IQR 0-9] vs 6 [1-16]; effect size -53·86, 95% CI -71·08 to -36·65, p<0·0001). No differences between groups were found for class-wide child aggression at post-intervention (effect size 0·07, 95% CI -0·16 to 0·29, p=0·72) or 1-year follow-up (-0·14, -0·42 to 0·16, p=0·72).

Interpretation: In Jamaican preschools, the Irie Classroom Toolbox effectively reduced violence against children by teachers. The Toolbox was designed for use with undertrained teachers working in low-resource settings and should be effective with early childhood practitioners in other LMICs. Additional research is needed to further develop the Toolbox to reduce class-wide child aggression.

Funding: Medical Research Council, Wellcome Trust, UK Aid, and the National Institute of Health Research.
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http://dx.doi.org/10.1016/S2214-109X(21)00002-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966677PMC
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

Are Benefits From a Parenting Intervention Delivered Through the Health Services Sustainable? Follow-Up of a Randomized Evaluation in Jamaica.

Acad Pediatr 2021 Jan 9. Epub 2021 Jan 9.

Caribbean Institute for Health Research, The University of the West Indies (JA Smith, SM Chang, and SP Walker), Kingston, Jamaica.

Objective: An innovative low-cost parenting intervention, implemented through health services in Jamaica showed benefits to children's cognitive development at 18 months and parent's attitudes concerning childcare. We assessed the impact of the intervention on child and parent outcomes at 6 years of age.

Methods: A cluster randomized trial of 2 parenting interventions was conducted through 20 health centers in Jamaica. Interventions were implemented from age 3 to 18 months and each intervention benefited cognitive development at 18 months (effect size 0.34-0.38 standard deviation). Children were reassessed at 6 years (n = 262, 80.1% of those assessed at 18 months) to determine any benefits to cognition, behavior, and parenting behavior. Loss to follow-up was not significantly different by treatment. Inverse probability weighting and Lee bounds were used to adjust for loss to follow-up, and multilevel regression analyses conducted with random effects at the health center level.

Results: There were no significant benefits to any child outcomes at age 6 years or to parenting behavior. Results are robust using the wild cluster bootstrap procedure and using Lee bounds for attrition. The initial trial benefits were reproduced with the current sample and methods.

Conclusion: Lack of sustained benefits may be related to the initial effect size and low intensity of the intervention that ended very young at age 18 months. It may also be related to lack of initial impact on home environment and fade-out of effects in a country with near universal preschool. The findings have implications for intervention design and targeting.
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http://dx.doi.org/10.1016/j.acap.2021.01.003DOI Listing
January 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

The historical aspects of vaccination in pregnancy.

Best Pract Res Clin Obstet Gynaecol 2020 Oct 13. Epub 2020 Oct 13.

Mercy Perinatal, Mercy Hospital for Women, Level 3, 163 Studley Rd, Heidelberg, Victoria 3084, Australia; Department of Obstetrics and Gynaecology, The University of Melbourne, Level 4, 163 Studley Rd, Heidelberg, Victoria 3084, Australia. Electronic address:

As we live through the history-making pandemic of coronavirus disease 2019 (COVID-19), it is timely to consider the lessons that history has taught us about vaccine-preventable disease in pregnancy. Vaccinations have earned an established place in pregnancy care to prevent communicable disease in the mother, fetus and newborn. The improvements in maternal and perinatal outcome have been achieved through the evolution and application of new knowledge in many areas. These include recognition of the unique pathogenic consequences of diseases in pregnancy; improved understanding of the maternal immune system and its interplay with the fetus; optimizing safe vaccine development; ensuring pregnant women are included in appropriately designed trials of efficacy, and public health engagement to optimize uptake. As the world eagerly awaits an effective vaccine for COVID 19, these lessons of history help signpost the way, to ensure the potential of vaccinations to reduce morbidity for pregnant women and their newborns is fully realized.
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http://dx.doi.org/10.1016/j.bpobgyn.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550856PMC
October 2020

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

Evidence for Better Lives Study: a comparative birth-cohort study on child exposure to violence and other adversities in eight low- and middle-income countries - foundational research (study protocol).

BMJ Open 2020 10 10;10(10):e034986. Epub 2020 Oct 10.

Institute of Criminology, University of Cambridge, Cambridge, UK.

Introduction: Violence against children is a health, human rights and social problem affecting approximately half of the world's children. Its effects begin at prenatal stages with long-lasting impacts on later health and well-being. The (EBLS) aims to produce high-quality longitudinal data from cities in eight low- and middle-income countries-Ghana, Jamaica, Pakistan, the Philippines, Romania, South Africa, Sri Lanka and Vietnam-to support effective intervention to reduce violence against children. EBLS-Foundational Research (EBLS-FR) tests critical aspects of the planned EBLS, including participant recruitment and retention, data collection and analysis. Alongside epidemiological estimates of levels and predictors of exposure to violence and adversity during pregnancy, we plan to explore mechanisms that may link exposure to violence to mothers' biological stress markers and subjective well-being.

Methods And Analyses: EBLS-FR is a short longitudinal study with a sample of 1200 pregnant women. Data are collected during the last trimester of pregnancy and 2 to 6 months after birth. The questionnaire for participating women has been translated into nine languages. Measures obtained from mothers will include, among others, mental and physical health, attitudes to corporal punishment, adverse childhood experiences, prenatal intimate partner violence, substance use and social/community support. Hair and dry blood spot samples are collected from the pregnant women to measure stress markers. To explore research participation among fathers, EBLS-FR is recruiting 300 fathers in the Philippines and Sri Lanka.

Ethics And Dissemination: The study received ethical approvals at all recruiting sites and universities in the project. Results will be disseminated through journal publications, conferences and seminar presentations involving local communities, health services and other stakeholders. Findings from this work will help to adjust the subsequent stages of the EBLS project.
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http://dx.doi.org/10.1136/bmjopen-2019-034986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552842PMC
October 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

The effect of body position on maternal cardiovascular function during sleep and wakefulness in late pregnancy.

J Matern Fetal Neonatal Med 2020 Jul 16:1-10. Epub 2020 Jul 16.

Melbourne School of Psychological Sciences, University of Melbourne, Parkville, Australia.

Introduction: An association between the increased risk of late stillbirth and the maternal supine sleeping position has been recently established. The risk of stillbirth following supine sleep has been suspected to occur as a result of aortocaval compression by the gravid uterus. A number of studies conducted during wakefulness have reported compromised cardiovascular function during supine rest, as demonstrated by reductions in cardiac output, blood pressure and utero-placental blood flow. It remains unclear whether similar effects are also present during sleep, due to the presence of key sleep-specific changes in cardiovascular function.

Objective: To investigate the changes in maternal cardiovascular function between the supine and left-lateral positions during wakefulness and non-rapid eye movement (NREM) sleep in late pregnancy.

Methods: Twenty-nine women with a singleton pregnancy between 24.7 and 36.7 weeks' gestation participated in a single overnight sleep study. Physiological measures (blood pressure, heart rate, heart rate variability - HRV, and pulse arrival time - PAT) were measured and recorded throughout the night using standard polysomnography equipment and the Portapres Model-2 device. As the present study evaluated cardiovascular changes during natural rest and sleep in pregnancy, participants were not given explicit instructions on which position to adopt. Body position was continuously recorded using a position monitor and verified with video recording.

Results: No changes in systolic, diastolic or mean arterial blood pressure were observed between the left-lateral and supine positions during wakefulness or sleep. However, heart rate was significantly higher in the supine position compared to the left during wakefulness ( .03), with a similar trend present during sleep (= .11). A significantly shorter PAT was measured in the supine position (compared to the left) during wakefulness ( .01) and sleep ( .01). No change in HRV measures was observed between the left and supine positions in either state.

Conclusion: Blood pressure did not appear to differ significantly between the left-lateral and supine positions during wakefulness and sleep. The lack of blood pressure differences may reflect elevated sympathetic activity during rest and sleep in the supine position (compared to the left), suggesting that some degree of compensation for aortocaval compression may still be possible during sleep.
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http://dx.doi.org/10.1080/14767058.2020.1789583DOI Listing
July 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

Consider pregnancy in COVID-19 therapeutic drug and vaccine trials.

Lancet 2020 05 13;395(10237):e92. Epub 2020 May 13.

Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC, Australia.

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http://dx.doi.org/10.1016/S0140-6736(20)31029-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220166PMC
May 2020

Sleep-disordered breathing does not impact maternal outcomes in women with hypertensive disorders of pregnancy.

PLoS One 2020 27;15(4):e0232287. Epub 2020 Apr 27.

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

Objective: Sleep-disordered breathing (SDB) is characterised by intermittent hypoxemia, sympathetic activation and widespread endothelial dysfunction, sharing pathophysiologic features with the hypertensive disorders of pregnancy. We sought to determine whether coexisting SDB would adversely impact the outcomes of women with gestational hypertension (GH) and preeclampsia (PE), and healthy matched controls.

Study Design: Women diagnosed with GH or PE along with BMI- and gestation-matched normotensive controls underwent polysomnography in late pregnancy to establish the presence or absence of SDB (RDI ≥ 5). Clinical outcomes of hypertensive disease severity were compared between groups, and venous blood samples were taken in the third trimester and at delivery to examine for any impact of SDB on the anti-angiogenic markers of PE.

Results: Data was available for 17 women with PE, 24 women with GH and 44 controls. SDB was diagnosed in 41% of the PE group, 63% of the GH group and 39% of the control group. Women with PE and co-existing SDB did not have worse outcomes in terms of gestation at diagnosis of PE (SDB = 29.1 (25.9, 32.1) weeks vs. no SDB = 32.0 (29.0, 33.9), p = n.s.) and days between diagnosis of PE and delivery (SDB = 20.0 (4.0, 35.0) days vs. no SDB = 10.5 (9.0, 14.0), p = n.s.). There were also no differences in severity of hypertension, antihypertensive treatment and biochemical, haematological and anti-angiogenic markers of PE between SDB and no SDB groups. Similar results were observed among women with GH. Healthy control women with SDB were no more likely to develop a hypertensive disorder of pregnancy in the later stages of pregnancy (SDB = 5.9% vs. no SDB = 7.4%, p = n.s.). Increasing the threshold for diagnosis of SDB to RDI ≥ 15 did not unmask a worse prognosis.

Conclusion: The presence of SDB during pregnancy did not worsen the disease course of GH or PE, and was not associated with high blood pressure or anti-angiogenic markers of hypertensive disease amongst healthy pregnant women. Given the numerous reports of the relationship between SDB and diagnosis of hypertensive disorders of pregnancy, it appears more work is required to distinguish causal, versus confounding, pathways.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232287PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185691PMC
July 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

The presence of coexisting sleep-disordered breathing among women with hypertensive disorders of pregnancy does not worsen perinatal outcome.

PLoS One 2020 26;15(2):e0229568. Epub 2020 Feb 26.

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

Objective: To determine whether the presence of co-existing sleep-disordered breathing (SDB) is associated with worse perinatal outcomes among women diagnosed with a hypertensive disorder of pregnancy (HDP), compared with normotensive controls.

Study Design: Women diagnosed with HDP (gestational hypertension or preeclampsia) and BMI- and gestation-matched controls underwent polysomnography in late pregnancy to determine if they had coexisting SDB. Fetal heart rate (FHR) monitoring accompanied the sleep study, and third trimester fetal growth velocity was assessed using ultrasound. Cord blood was taken at delivery to measure key regulators of fetal growth.

Results: SDB was diagnosed in 52.5% of the HDP group (n = 40) and 38.1% of the control group (n = 42); p = .19. FHR decelerations were commonly observed during sleep, but the presence of SDB did not increase this risk in either the HDP or control group (HDP group-SDB = 35.3% vs. No SDB = 40.0%, p = 1.0; control group-SDB = 41.7% vs. No SDB = 25.0%, p = .44), nor did SDB affect the total number of decelerations overnight (HDP group-SDB = 2.7 ± 1.0 vs. No SDB = 2.8 ± 2.1, p = .94; control group-SDB = 2.0 ± 0.8 vs. No SDB = 2.0 ± 0.7, p = 1.0). Fetal growth restriction was the strongest predictor of fetal heart rate events during sleep (aOR 5.31 (95% CI 1.26-22.26), p = .02). The presence of SDB also did not adversely affect fetal growth; in fact among women with HDP, SDB was associated with significantly larger customised birthweight centiles (43.2% ± 38.3 vs. 16.2% ± 27.0, p = .015) and fewer growth restricted babies at birth (30% vs. 68.4%, p = .026) compared to HDP women without SDB. There was no impact of SDB on measures of fetal growth for the control group. Cord blood measures of fetal growth did not show any adverse effect among women with SDB, either in the HDP or control group.

Conclusion: We did not find that the presence of mild SDB worsened fetal acute or longitudinal outcomes, either among women with HDP or BMI-matched normotensive controls. Unexpectedly, we found the presence of SDB conferred a better prognosis in HDP in terms of fetal growth. The fetus has considerable adaptive capacity to withstand in utero hypoxia, which may explain our mostly negative findings. In addition, SDB in this cohort was mostly mild. It may be that fetal sequelae will only be unmasked in the setting of more severe degrees of SDB and/or underlying placental disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229568PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043804PMC
June 2020

Multimedia in improving informed consent for caesarean section: A randomised controlled trial.

Aust N Z J Obstet Gynaecol 2020 10 28;60(5):683-689. Epub 2020 Jan 28.

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

Background: Multimedia modules have been used as an adjunct to improve patient knowledge and recall for various elective surgical procedures, but have been incompletely evaluated in patients undergoing caesarean section.

Aims: To compare the use of a supplementary multimedia module with written information in improving the informed consent process prior to elective caesarean section.

Materials And Methods: This was a prospective randomised controlled trial (ACTRN12616000430437). Primary outcomes were knowledge and anxiety scores immediately following the intervention and on the day of surgery. Secondary outcomes were patient satisfaction, length of stay, time to cessation of analgesia, and patient assessment of the consent types.

Results: Seventy-five patients completed the study. Both multimedia module and written information groups demonstrated a significant increase in knowledge scores with no difference between the groups. In the multimedia-assisted consent group, scores improved from baseline by +2.31 (P < 0.001) immediately after watching the multimedia module and by +2.41 (P < 0.001) on the day of surgery. In the written information group, scores improved by +1.76 (P < <0.001), and +2.31 (P < 0.001) respectively. There was no adverse impact on anxiety in either group. Patient-reported understanding (92.4% vs 78.5%, P = 0.001), and helpfulness (90.1% vs 73.3%, P = 0.001) was significantly higher in the multimedia module group than in the written information group. The multimedia module was assessed as 'slightly too long' and provided 'slightly too much information'.

Conclusions: Multimedia modules are a valuable adjunct to traditional processes of obtaining informed consent for elective caesarean section and should be offered and made available to patients prior to surgery.
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http://dx.doi.org/10.1111/ajo.13124DOI Listing
October 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

The D-score: a metric for interpreting the early development of infants and toddlers across global settings.

BMJ Glob Health 2019 19;4(6):e001724. Epub 2019 Nov 19.

Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Introduction: Early childhood development can be described by an underlying latent construct. Global comparisons of children's development are hindered by the lack of a validated metric that is comparable across cultures and contexts, especially for children under age 3 years. We constructed and validated a new metric, the Developmental Score (D-score), using existing data from 16 longitudinal studies.

Methods: Studies had item-level developmental assessment data for children 0-48 months and longitudinal outcomes at ages >4-18 years, including measures of IQ and receptive vocabulary. Existing data from 11 low-income, middle-income and high-income countries were merged for >36 000 children. Item mapping produced 95 'equate groups' of same-skill items across 12 different assessment instruments. A statistical model was built using the Rasch model with item difficulties constrained to be equal in a subset of equate groups, linking instruments to a common scale, the D-score, a continuous metric with interval-scale properties. D-score-for-age z-scores (DAZ) were evaluated for discriminant, concurrent and predictive validity to outcomes in middle childhood to adolescence.

Results: Concurrent validity of DAZ with original instruments was strong (average =0.71), with few exceptions. In approximately 70% of data rounds collected across studies, DAZ discriminated between children above/below cut-points for low birth weight (<2500 g) and stunting (-2 SD below median height-for-age). DAZ increased significantly with maternal education in 55% of data rounds. Predictive correlations of DAZ with outcomes obtained 2-16 years later were generally between 0.20 and 0.40. Correlations equalled or exceeded those obtained with original instruments despite using an average of 55% fewer items to estimate the D-score.

Conclusion: The D-score metric enables quantitative comparisons of early childhood development across ages and sets the stage for creating simple, low-cost, global-use instruments to facilitate valid cross-national comparisons of early childhood development.
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http://dx.doi.org/10.1136/bmjgh-2019-001724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882553PMC
November 2019

Identification of the optimal growth charts for use in a preterm population: An Australian state-wide retrospective cohort study.

PLoS Med 2019 10 4;16(10):e1002923. Epub 2019 Oct 4.

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

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.
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http://dx.doi.org/10.1371/journal.pmed.1002923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777749PMC
October 2019

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

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

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

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

A double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol.

BMJ Open 2019 04 24;9(4):e025809. Epub 2019 Apr 24.

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

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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http://dx.doi.org/10.1136/bmjopen-2018-025809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503454PMC
April 2019

The ROC Curve Redefined - Optimizing Sensitivity (and Specificity) to the Lived Reality of Cancer.

Authors:
Susan P Walker

N Engl J Med 2019 Apr;380(17):1594-1595

From the Department of Obstetrics and Gynaecology, University of Melbourne; and Mercy Hospital for Women - both in Melbourne, Australia.

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http://dx.doi.org/10.1056/NEJMp1814951DOI Listing
April 2019

Proton Pump Inhibitors and Preeclampsia Risk Among 157 720 Women.

Hypertension 2019 05;73(5):1097-1103

Department of Women's and Children's Health, Uppsala University, Sweden (R.H., L.B., A.W., A.-K.W., S.H.).

Preeclampsia is a hypertensive disorder of pregnancy with a high rate of maternal and neonatal morbidity and mortality. The only definite treatment is delivery. Preclinical investigations have identified proton pump inhibitors (PPIs), which are commonly used to treat reflux during pregnancy, as a potential treatment for preeclampsia. The aim of this study was to determine the association between PPI use during pregnancy and preeclampsia risk in a population-based register cohort. Using the Swedish Pregnancy Register, we conducted a cohort study of nulliparous pregnant women delivering from January 2013 to July 2017. Associations between PPI use and preeclampsia were investigated using logistic regression analyses with risk estimates presented as crude and adjusted odds ratios (aOR) with 95% CI. Of 157 720 nulliparous pregnant women, 6051 (3.8%) reported PPI use during pregnancy. PPI use during any point of pregnancy was associated with an increased risk of overall preeclampsia (aOR of 1.17; 95% CI, 1.04-1.32) and preeclampsia at term (aOR of 1.20; 95% CI, 1.04-1.39). However, PPI use recorded after 28 gestational weeks was associated with a reduced risk of preterm (delivery <37 weeks) preeclampsia (aOR of 0.63; 95% CI, 0.41-0.96) and early (delivery <34 weeks) preeclampsia (aOR of 0.41; 95% CI, 0.20-0.82). These findings highlight the heterogeneity of this disease, with a potential role PPIs for preventing preterm preeclampsia when used in close proximity to disease onset. Targeting PPI use to women at greatest risk of preterm preeclampsia may help prevent this severe form of disease.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12547DOI Listing
May 2019

The untapped potential of placenta-enriched molecules for diagnostic and therapeutic development.

Placenta 2019 09 4;84:28-31. Epub 2019 Feb 4.

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

Pregnancy complications such as fetal growth restriction and preeclampsia are diseases with limited biomarkers for prediction, and a complete lack of therapeutic options. We define placenta-enriched molecules as those that are highly expressed in the placenta relative to all other human tissues. Many exist including mRNAs, miRNAs and proteins. It is now well established that placenta-enriched mRNAs are found within the maternal circulation and are cleared rapidly after birth. Similarly, distinct clusters of miRNAs that are placenta-enriched have been identified and are measurable within the circulation. However, perhaps the most established potential diagnostics thus far are circulating placental proteins such as placental growth factor (PlGF), pregnancy associated pregnancy protein-A (PAPP-A) and soluble FMS-like tyrosine kinase 1 (sFlt-1). There has also been much interest in targeting placenta-enriched molecules as a means to treat diseases of pregnancy. We have shown promising results in targeting placenta-enriched epidermal growth factor receptor (EGFR) to treat ectopic pregnancy. Others have focused on using placenta-enriched molecules as a means of homing therapeutic-filled nanoparticles to the placenta, or to directly target sFlt-1 to improve disease outcomes. Importantly, many placenta-enriched molecules remain largely unstudied. We propose that a better understanding of their biology, and potential contribution to the pathogenesis of diseases, may yield more predictive diagnostic and therapeutic targets.
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http://dx.doi.org/10.1016/j.placenta.2019.02.002DOI Listing
September 2019

Circulating GATA2 mRNA is decreased among women destined to develop preeclampsia and may be of endothelial origin.

Sci Rep 2019 01 18;9(1):235. Epub 2019 Jan 18.

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

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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http://dx.doi.org/10.1038/s41598-018-36645-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338784PMC
January 2019