Publications by authors named "Teresa M MacDonald"

17 Publications

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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

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

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

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

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

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

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

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

Assessing the sensitivity of placental growth factor and soluble fms-like tyrosine kinase 1 at 36 weeks' gestation to predict small-for-gestational-age infants or late-onset preeclampsia: a prospective nested case-control study.

BMC Pregnancy Childbirth 2018 Aug 31;18(1):354. Epub 2018 Aug 31.

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

Background: Fetal growth restriction is a disorder of placental dysfunction with three to four-fold increased risk of stillbirth. Fetal growth restriction has pathophysiological features in common with preeclampsia. We hypothesised that angiogenesis-related factors in maternal plasma, known to predict preeclampsia, may also detect fetal growth restriction at 36 weeks' gestation. We therefore set out to determine the diagnostic performance of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and the sFlt-1:PlGF ratio, measured at 36 weeks' gestation, in identifying women who subsequently give birth to small-for-gestational-age (SGA; birthweight <10th centile) infants. We also aimed to validate the predictive performance of the analytes for late-onset preeclampsia in a large independent, prospective cohort.

Methods: A nested 1:2 case-control study was performed including 102 cases of SGA infants and a matched group of 207 controls; and 39 cases of preeclampsia. We determined the diagnostic performance of each angiogenesis-related factor, and of their ratio, to detect SGA infants or preeclampsia, for a predetermined 10% false positive rate.

Results: Median plasma levels of PlGF at 36 weeks' gestation were significantly lower in women who subsequently had SGA newborns (178.5 pg/ml) compared to normal birthweight controls (326.7 pg/ml, p < 0.0001). sFlt-1 was also higher among SGA cases, but this was not significant after women with concurrent preeclampsia were excluded. The sensitivity of PlGF to predict SGA infants was 28.8% for a 10% false positive rate. The sFlt-1:PlGF ratio demonstrated better sensitivity for preeclampsia than either analyte alone, detecting 69.2% of cases for a 10% false positive rate.

Conclusions: Plasma PlGF at 36 weeks' gestation is significantly lower in women who subsequently deliver a SGA infant. While the sensitivity and specificity of PlGF currently limit clinical translation, our findings support a blood-based biomarker approach to detect late-onset fetal growth restriction. Thirty-six week sFlt-1:PlGF ratio predicts 69.2% of preeclampsia cases, and could be a useful screening test to triage antenatal surveillance.
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http://dx.doi.org/10.1186/s12884-018-1992-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119271PMC
August 2018

Prospective longitudinal assessment of the fetal left modified Myocardial Performance Index.

J Matern Fetal Neonatal Med 2019 Mar 24;32(5):760-767. Epub 2017 Oct 24.

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

Introduction: The fetal left modified Myocardial Performance Index (Mod-myocardial performance index (MPI)) is a measure of systolic versus diastolic time intervals obtained from a single cardiac cycle with ultrasound. It is a measure of global ventricular function and has been investigated for potential utility in fetal conditions associated with cardiac dysfunction.

Objectives: The objective of this study is to compare values from a precisely replicated fetal left Mod-MPI technique to published reference ranges.

Methods: Three hundred and sixty-five nulliparae prospectively underwent fetal left Mod-MPI measurement at 27-29 and 35-37 weeks' gestation. Measurements from pregnancies complicated by gestational diabetes mellitus, preeclampsia, or a small-for-gestational-age (<10th centile) infant were excluded. Mod-MPI values were compared with three published references created using similar measurement techniques.

Results: Compared with one selected reference, at 29 and 35-37 weeks' gestation, 90-100% of our values fell within the 5th-95th percentile range as expected. Thus, this reference range was validated for our population in late pregnancy. However, the expected level of concordance was not seen at 27-28 weeks'. The other two references to which we compared our Mod-MPI values demonstrated poor concordance, especially at 27-29 weeks'. Pearson interobserver correlation was also improved at 35-37 weeks' at 0.434, compared with 0.083 at 27-29 weeks' gestation.

Conclusions: Concordance and interobserver variability between our cohort and similar populations were both improved at 35-37 weeks' compared with 27-29 weeks' gestation. Overall, variable Mod-MPI reproducibility across gestations limits clinical application, especially earlier in pregnancy. Manual Mod-MPI measurement should be considered most reliable in late pregnancy until automated MPI measurement is possible.
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http://dx.doi.org/10.1080/14767058.2017.1391777DOI Listing
March 2019

Reduced growth velocity across the third trimester is associated with placental insufficiency in fetuses born at a normal birthweight: a prospective cohort study.

BMC Med 2017 08 31;15(1):164. Epub 2017 Aug 31.

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

Background: While being small-for-gestational-age due to placental insufficiency is a major risk factor for stillbirth, 50% of stillbirths occur in appropriate-for-gestational-age (AGA, > 10th centile) fetuses. AGA fetuses are plausibly also at risk of stillbirth if placental insufficiency is present. Such fetuses may be expected to demonstrate declining growth trajectory across pregnancy, although they do not fall below the 10th centile before birth. We investigated whether reduced growth velocity in AGA fetuses is associated with antenatal, intrapartum and neonatal indicators of placental insufficiency.

Methods: We performed a prospective cohort study of 308 nulliparous women who subsequently gave birth to AGA infants. Ultrasound was utilised at 28 and 36 weeks' gestation to determine estimated fetal weight (EFW) and abdominal circumference (AC). We correlated relative EFW and AC growth velocities with three clinical indicators of placental insufficiency, namely (1) fetal cerebroplacental ratio (CPR; CPR < 5th centile reflects placental resistance, and blood flow redistribution to the brain - a fetal response to hypoxia); (2) neonatal acidosis after the hypoxic challenge of labour (umbilical artery (UA) pH < 7.15 at birth); and (3) low neonatal body fat percentage (BF%, measured by air displacement plethysmography) reflecting reduced nutritional reserve in utero.

Results: For each one centile reduction in EFW growth velocity between 28 and 36 weeks' gestation, there was a 2.4% increase in the odds of cerebral redistribution (CPR < 5th centile, odds ratio (OR) (95% confidence interval) = 1.024 (1.005-1.042), P = 0.012) and neonatal acidosis (UA pH < 7.15, OR = 1.024 (1.003-1.046), P = 0.023), and a 3.3% increase in the odds of low BF% (OR = 1.033 (1.001-1.067), P = 0.047). A decline in EFW of > 30 centiles between 28 and 36 weeks (compared to greater relative growth) was associated with cerebral redistribution (CPR < 5th centile relative risk (RR) = 2.80 (1.25-6.25), P = 0.026), and a decline of > 35 centiles was associated with neonatal acidosis (UA pH < 7.15 RR = 3.51 (1.40-8.77), P = 0.030). Similar associations were identified between low AC growth velocity and clinical indicators of placental insufficiency.

Conclusions: Reduced growth velocity between 28 and 36 weeks' gestation among fetuses born AGA is associated with antenatal, intrapartum and neonatal indicators of placental insufficiency. These fetuses potentially represent an important unrecognised cohort at increased risk of stillbirth and may warrant more intensive antenatal surveillance.
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http://dx.doi.org/10.1186/s12916-017-0928-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577811PMC
August 2017

Re. Shining light in dark corners: Diagnosis and management of late-onset fetal growth restriction. ANZJOG 2015; 55(1):3-10. Author response (II).

Aust N Z J Obstet Gynaecol 2015 Aug;55(4):406-7

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

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http://dx.doi.org/10.1111/ajo.12384DOI Listing
August 2015

Re. Shining light in dark corners: Diagnosis and management of late-onset fetal growth restriction. ANZJOG 2015; 55(1):3-10. Author response (I).

Aust N Z J Obstet Gynaecol 2015 Aug;55(4):404-5

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

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http://dx.doi.org/10.1111/ajo.12383DOI Listing
August 2015

Shining light in dark corners: diagnosis and management of late-onset fetal growth restriction.

Aust N Z J Obstet Gynaecol 2015 Feb 3;55(1):3-10. Epub 2015 Jan 3.

The Northern Hospital, Melbourne, Victoria, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia.

Fetal growth restriction (FGR) is the single biggest risk factor for stillbirth. In the absence of any effective treatment for fetal growth restriction, the mainstay of management is close surveillance and timely delivery. While such statements are almost self-evident, the daily clinical challenge of late-onset fetal growth restriction remains; the competing priorities of minimising stillbirth risk, while avoiding excessive obstetric intervention and the neonatal sequelae of iatrogenic preterm birth. This dilemma is made harder because the tools for late-onset FGR diagnosis and surveillance compare poorly to those used in early-onset FGR; screening tests in early pregnancy have limited predictive value; most cases escape clinical detection, a phenomenon set to worsen given the obesity epidemic; there is a failure of consensus on the definition of small for gestational age, and ancillary tools, such as umbilical artery Doppler--of value in identification of preterm FGR--are less useful in the late-preterm period and at term. Most importantly, the problem is common; 96% of all births occur after 32 weeks. This means a poor noise/signal ratio of any test or management algorithm will inevitably have large clinical consequences. Into such a dark corner, we cast some light; a summary on diagnostic criteria, new developments to improve the diagnosis of late-onset FGR and a suggested approach to management.
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http://dx.doi.org/10.1111/ajo.12264DOI Listing
February 2015