Publications by authors named "Lisa Hui"

69 Publications

Is it time to adopt routine CMV screening in pregnancy? No!

Am J Obstet Gynecol MFM 2021 Mar 22:100355. Epub 2021 Mar 22.

Child Population and Translational Health Research, Children's Hospital at Westmead Clinical School, The University of Sydney, Sydney NSW, Australia; Department of Maternal Fetal Medicine Royal Hospital for Women, Randwick NSW Australia; Department of Maternal Fetal Medicine, Royal North Shore Hospital, St Leonards NSW, Australia.

Congenital cytomegalovirus (cCMV) is caused by maternal primary or nonprimary infection during pregnancy and is a major preventable cause of neurodisability. Proposed strategies to reduce cCMV include primary prevention with maternal hygiene measures and secondary prevention by serological screening for the detection of maternal primary infection. A recent randomised trial found that high dose valaciclovir treatment resulted in a significant reduction in fetal infection after first trimester maternal primary infection, leading to calls to commence routine serological screening in pregnancy. Previously, observational studies have found a reduction in fetal infection with primary CMV with hyperimmune globulin (HIG) when given 2 weekly commenced in the first trimester, however this has not been replicated in randomised trials, which have used different regimens. However, evidence from a single intervention trial and observational studies does not provide us with all the necessary data required for rolling out an appropriate screening program. All screening tests may be associated with harm; in the case of cCMV, there is the well-recognised potential for increasing terminations of pregnancy without diagnostic confirmation of fetal infection or sequalae. While valaciclovir therapy and HIG may significantly reduce fetal infection rates, they do not prevent severe CMV-related fetal brain damage in all pregnancies. Therefore, it is not clear that the offer of a prenatal intervention will provide sufficient reassurance to screen positive women. In addition, the effectiveness of a prenatal screening and treatment strategy is predicated on a high rate of maternal primary infection, which is limited to regions with low CMV seroprevalence, such as Western Europe. In some countries, such as the USA, Finland, and Brazil, nonprimary maternal infections are responsible for the majority of the cCMV health burden, limiting the potential impact of pregnancy screening. In this invited clinical opinion, we review the evidence and outline the steps that need to be taken prior to determining if the benefits of routine screening for CMV in pregnancy outweigh the harms. Until we have the necessary evidence, we should follow the current advice of multiple national health authorities and focus on promoting primary prevention through maternal hygiene precautions.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100355DOI Listing
March 2021

Dealing with uncertain results from chromosomal microarray and exome sequencing in the prenatal setting: An international cross-sectional study with healthcare professionals.

Prenat Diagn 2021 Mar 16. Epub 2021 Mar 16.

Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.

Objectives: To conduct qualitative interviews with healthcare providers working in different countries to understand their experiences of dealing with uncertain results from prenatal chromosome microarray analysis (CMA) and exome sequencing (ES).

Methods: Semi-structured interviews with 31 healthcare providers who report or return prenatal CMA and/or ES results (clinicians, genetic counsellors and clinical scientists) in six countries with differing healthcare systems; Australia (4), Denmark (5), Netherlands (6), Singapore (4), Sweden (6) and United Kingdom (6). The topic guide explored the main sources of uncertainty and their management.

Results: There was variation in reporting practices both between and across countries for variants of uncertain significance, however, there was broad agreement on reporting practices for incidental findings. There was also variation in who decides what results are reported (clinical scientists or clinicians). Technical limitations and lack of knowledge (to classify variants and of prenatal phenotypes) were significant challenges, as were turnaround times and lack of guidelines.

Conclusion: Health professionals around the globe are dealing with similar sources of uncertainty, but managing them in different ways, Continued dialogue with international colleagues on ways of managing uncertain results is important to compare and contrast the benefits and limitations of the different approaches.
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http://dx.doi.org/10.1002/pd.5932DOI Listing
March 2021

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

40 years of prenatal diagnosis in 2020.

Prenat Diagn 2020 12;40(13):1623-1626

Perinatal Diagnostic Center, Inova Alexandria Hospital, Alexandria, Virginia, USA.

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http://dx.doi.org/10.1002/pd.5867DOI Listing
December 2020

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

Right or wrong? Looking through the retrospectoscope to analyse predictions made a decade ago in prenatal diagnosis and fetal surgery.

Prenat Diagn 2020 12;40(13):1627-1635

Division of Prenatal Genomics and Fetal Therapy, Medical Genomics and Metabolic Genetics Branch, National Human Genome Institute, National Human Genome Institute, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1002/pd.5870DOI Listing
December 2020

Assessing maternal clotting function with novel global coagulation assays: A prospective pilot study.

Int J Lab Hematol 2020 Nov 10. Epub 2020 Nov 10.

Department of Obstetrics and Gynaecology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Vic., Australia.

Introduction: Women are at higher risk of venous thromboembolism (VTE) during pregnancy and the puerperium. Global coagulation assays (GCAs), including thromboelastography (TEG), thrombin generation using the calibrated automated thrombogram (CAT) and fibrin generation using the overall haemostatic potential assay (OHP), provide a more comprehensive assessment of the coagulation process than conventional coagulation assays. We aimed to evaluate the ability of these GCAs to analyse the coagulability among pregnant women of varying VTE risk profile.

Methods: Women undergoing term elective caesarean delivery provided a single predelivery blood sample for conventional and novel coagulation testing (TEG, CAT and OHP). Data from 47 healthy nonpregnant women aged 18-45 years were used as controls.

Results: Sixty women with term singleton pregnancies were included. Samples from pregnant women were hypercoagulable on most GCA parameters compared to nonpregnant controls, demonstrating increased maximum amplitude (clot strength) (71.5 vs 60.6 mm, P < .001) on whole blood TEG and increased endogenous thrombin potential (1895.22 vs 1399.33 nmol/L·min, P < .001) and overall coagulation potential (fibrin generation) (57.58 vs 36.21 units, P < .001) on platelet-poor plasma. Pregnant women with booking BMI ≥ 30 kg/m had significantly higher maximum amplitude compared to pregnant women of normal BMI (18.5-25 kg/m ) (73.2 vs 66.1 mm, P < .001).

Conclusions: Global coagulation assays reliably detect the physiological hypercoagulability of pregnancy. Thromboelastography in particular appears to correlate with obesity in the pregnant population. GCAs may be potential adjuncts to risk factor-based criteria to guide VTE thromboprophylaxis during pregnancy and the puerperium.
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http://dx.doi.org/10.1111/ijlh.13389DOI Listing
November 2020

The predicted clinical workload associated with early post-term surveillance and inductions of labour in south Asian women in a non-tertiary hospital setting.

Aust N Z J Obstet Gynaecol 2020 Nov 2. Epub 2020 Nov 2.

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

Background: Stillbirth increases steeply after 42 weeks gestation; hence, induction of labour (IOL) is recommended after 41 weeks. Recent Victorian data demonstrate that term stillbirth risk rises at an earlier gestation in south Asian mothers (SAM).

Aims: To determine the impact on a non-tertiary hospital in Melbourne, Australia, if post-dates IOL were recommended one week earlier at 40 + 3 for SAM; and to calculate the proportion of infants with birthweight < 3rd centile that were undelivered by 40 weeks in SAM and non-SAM, as these cases may represent undetected fetal growth restriction.

Materials And Methods: Singleton births ≥ 37 weeks during 2017-18 were extracted from the hospital Birthing Outcomes System. Obstetric and neonatal outcomes for pregnancies that birthed after spontaneous onset of labour or IOL were analysed according to gestation and country of birth.

Results: There were 5408 births included, and 24.9% were born to SAM (n = 1345). SAM women had a higher rate of IOL ≥ 37 weeks compared with non-SAM women (42.5% vs 35.0%, P < 0.001). If all SAM accepted an offer of IOL at 40 + 3, there would be an additional 80 term inductions over two years. There was no significant difference in babies < 3rd centile undelivered by 40 weeks in SAM compared with non-SAM (29.6% vs 37.7%, P = 0.42).

Conclusions: Earlier IOL for post-term SAM would only modestly increase the demand on birthing services, due to pre-existing high rates of IOL. Our current practices appear to capture the majority at highest risk of stillbirth in our SAM population.
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http://dx.doi.org/10.1111/ajo.13268DOI Listing
November 2020

Towards systematic nomenclature for cell-free DNA.

Hum Genet 2021 Apr 29;140(4):565-578. Epub 2020 Oct 29.

IRCM, Institute of Research in Oncology of Montpellier, Montpellier, France.

Cell-free DNA (cfDNA) has become widely recognized as a promising candidate biomarker for minimally invasive characterization of various genomic disorders and other clinical scenarios. However, among the obstacles that currently challenge the general progression of the research field, there remains an unmet need for unambiguous universal cfDNA nomenclature. To address this shortcoming, we classify in this report the different types of cfDNA molecules that occur in the human body based on its origin, genetic traits, and locality. We proceed by assigning existing terms to each of these cfDNA subtypes, while proposing new terms and abbreviations where clarity is lacking and more precise stratification would be beneficial. We then suggest the proper usage of these terms within different contexts and scenarios, focusing mainly on the nomenclature as it relates to the domains of oncology, prenatal testing, and post-transplant surgery surveillance. We hope that these recommendations will serve as useful considerations towards the establishment of universal cfDNA nomenclature in the future. In addition, it is conceivable that many of these recommendations can be transposed to cell-free RNA nomenclature by simply exchanging "DNA" with "RNA" in each acronym/abbreviation. Similarly, when describing DNA and RNA collectively, the suffix can be replaced with "NAs" to indicate nucleic acids.
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http://dx.doi.org/10.1007/s00439-020-02227-2DOI Listing
April 2021

Opportunities and challenges for international societies in the COVID-19 era.

Prenat Diagn 2020 12;40(13):1753-1754

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

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http://dx.doi.org/10.1002/pd.5843DOI Listing
December 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

Identification and management of congenital parvovirus B19 infection.

Prenat Diagn 2020 12 30;40(13):1722-1731. Epub 2020 Sep 30.

Department of Perinatal Medicine, Mercy Hospital for Women, Melbourne, Victoria, Australia.

Parvovirus B19 (B19V) infection is well known for its mild, self-limiting clinical presentations in children, such as erythema infectiosum. Approximately 40% of women of childbearing age are susceptible to B19V infection. While maternal B19V infection usually has a good prognosis, B19V can cause severe fetal anaemia and pregnancy loss due to its ability to suppress erythroid progenitor cells. Non-invasive ultrasound monitoring for fetal anaemia is usually performed if maternal seroconversion occurs in the first 20 weeks of gestation, with amniocentesis for fetal infection reserved for those who first present with fetal anaemia or hydrops of unknown cause. Intrauterine transfusion is the standard treatment for severe fetal anaemia and is associated with a significant improvement in survival. However, survivors of hydrops fetalis may have a higher rate of long-term neurodevelopmental complications compared with non-hydropic survivors. This review aims to synthesise published data on the diagnosis, surveillance and outcomes of congenital parvovirus infection to assist clinicians in diagnosing and managing this important condition.
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http://dx.doi.org/10.1002/pd.5819DOI Listing
December 2020

The intimate connection between maternal health and fetal development.

Authors:
Lisa Hui

Prenat Diagn 2020 08;40(9):1045-1046

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

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http://dx.doi.org/10.1002/pd.5775DOI Listing
August 2020

Lumbosacral myelomeningocele before and after in utero repair.

Am J Obstet Gynecol 2021 01 26;224(1):108-109. Epub 2020 Jun 26.

Department of Maternal Fetal Medicine, Mater Misericordiae Health Services Brisbane, Queensland, Australia.

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http://dx.doi.org/10.1016/j.ajog.2020.06.046DOI Listing
January 2021

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

Potential medication interactions with paroxetine use for cough in cancer patients.

J Oncol Pharm Pract 2020 07 11;26(5):1296. Epub 2020 Apr 11.

Department of Pharmacy, Austin Hospital, Melbourne, Australia.

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http://dx.doi.org/10.1177/1078155220915941DOI Listing
July 2020

Evolution of fetal acrania from 7 to 10 weeks gestation.

Prenat Diagn 2020 12;40(12):1515-1516

Monash Ultrasound for Women, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1002/pd.5688DOI Listing
December 2020

A minimum estimate of the prevalence of 22q11 deletion syndrome and other chromosome abnormalities in a combined prenatal and postnatal cohort.

Hum Reprod 2020 03;35(3):694-704

Reproductive Epidemiology Group, Murdoch Children's Research Institute, Parkville 3052, Victoria, Australia.

Study Question: What is the frequency of major chromosome abnormalities in a population-based diagnostic data set of genomic tests performed on miscarriage, fetal and infant samples in a state with >73 000 annual births?

Summary Answer: The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826), with a significant decrease in the detection of major chromosome abnormalities with later developmental stage, from 50.9% to 21.3% to 15.6% of tests in the miscarriage, prenatal and postnatal cohorts, respectively.

What Is Known Already: Over the past decade, technological advances have revolutionized genomic testing at every stage of reproduction. Chromosomal microarrays (CMAs) are now the gold standard of chromosome assessment in prenatal diagnosis and pediatrics.

Study Design, Size, Duration: A population-based cohort study including all chromosome analysis was performed in the Australian state of Victoria during a 24-month period from January 2015 to December 2016. All samples obtained via invasive prenatal diagnosis and postnatal samples from pregnancy tissue and infants ≤12 months of age were included.

Participants/materials, Setting, Methods: A research collaboration of screening and diagnostic units in the Australian state of Victoria was formed (the Perinatal Record Linkage collaboration), capturing all instances of prenatal and postnatal chromosome testing performed in the state. Victoria has over 73 000 births per annum and a median maternal age of 31.5 years. We analyzed our population-based diagnostic data set for (i) chromosome assessment of miscarriage, prenatal diagnosis and postnatal samples; (ii) testing indications and diagnostic yields for each of these cohorts; (iii) and the combined prenatal/infant prevalence of 22q11.2 deletion syndrome (DS) as a proportion of all births ≥20 weeks gestation.

Main Results And The Role Of Chance: During the 24-month study period, a total of 8826 chromosomal analyses were performed on prenatal and postnatal specimens in Victoria. The vast majority (91.2%) of all chromosome analyses were performed with CMA.The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826). There was a significant decreasing trend in the percentage of chromosome abnormalities with later developmental stage from 50.9% to 21.3% to 15.6% in the miscarriage, prenatal and postnatal cohorts, respectively (χ2 trend = 790.0, P < 0.0001). The total frequency of abnormalities in the live infant subgroup was 13.4% (244/1816). The frequencies of pathogenic copy number variants (CNVs) detected via CMA for the miscarriage, prenatal and postnatal cohorts were 1.9% (50/2573), 2.2% (82/3661) and 4.9% (127/2592), respectively. There was a significant increasing trend in the frequency of pathogenic CNVs with later developmental stage (χ2 trend = 39.72, P < 0.0001). For the subgroup of live infants, the pathogenic CNV frequency on CMA analysis was 6.0% (109/1816). There were 38 diagnoses of 22q11.2 DS, including 1 miscarriage, 15 prenatal and 22 postnatal cases. After excluding the miscarriage case and accounting for duplicate testing, the estimated prevalence of 22q11 DS was 1 in 4558 Victorian births.

Limitations, Reasons For Caution: Clinical information was missing on 11.6% of postnatal samples, and gestational age was rarely provided on the miscarriage specimens. We were unable to obtain rates of termination of pregnancy and stillbirth in our cohort due to incomplete data provided by clinical referrers. We therefore cannot make conclusions on pregnancy or infant outcome following diagnostic testing. Childhood and adult diagnoses of 22q11 DS were not collected.

Wider Implications Of The Findings: Our study marks a complete transition in genomic testing from the G-banded karyotype era, with CMA now established as the first line investigation for pregnancy losses, fetal diagnosis and newborn/infant assessment in a high-income setting. Integration of prenatal and postnatal diagnostic data sets provides important opportunities for estimating the prevalence of clinically important congenital syndromes, such as 22q11 DS.

Study Funding/competing Interest(s): L.H. is funded by a National Health and Medical Research Council Early Career Fellowship (1105603); A.L. was funded by a Mercy Perinatal Research Fellowship; J.H. was funded by a National Health and Medical Research Council Senior Research Fellowship (10121252). The funding bodies had no role in the conduct of the research or the manuscript. Discretionary funding from the Murdoch Children's Research Institute has supported the prenatal diagnosis data collection and reporting over the years.Dr Ricardo Palma-Dias reports a commercial relationship with Roche Diagnostics, personal fees from Philips Ultrasound, outside the submitted work. Debbie Nisbet reports a commercial relationship with Roche Diagnostics, outside the submitted work.

Trial Registration Number: NA.
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http://dx.doi.org/10.1093/humrep/dez286DOI Listing
March 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

Maternity health care professionals' views and experiences of fetal genomic uncertainty: A review.

Prenat Diagn 2020 05 20;40(6):652-660. Epub 2020 Apr 20.

London North Genomic Laboratory Hub, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, UK.

The field of prenatal screening and diagnosis for fetal anomalies has been marked by a rapid succession of technological advances, including most notably, chromosomal microarray analysis, and next generation sequencing. Despite the diagnostic advantages of these technologies, their incorporation into prenatal testing has created additional challenges of revealing genomic variants of unknown or uncertain significance, and secondary findings. While detailed posttest counseling about uncertain variants is best performed by medical geneticists, many of the screening and diagnostic tests that lead to this information are actually ordered by general maternity health care professionals (HCPs), such as obstetricians, midwives, and family physicians. Maternity HCPs support pregnant women through to the conclusion of their pregnancy and the postpartum period, and thus are close observers of the psychosocial impart of fetal genomic uncertainty on women and their families. While there have been many studies exploring the handling of genomic uncertainty by genetics HCPs, there has been relatively less attention paid to maternity HCPs without speciality training in genetics. This review explores the current literature surrounding nongenetic maternity HCPs' views and experiences of genomic uncertainty and returning uncertain results in the prenatal setting.
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http://dx.doi.org/10.1002/pd.5673DOI Listing
May 2020

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

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

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

Background: Small for gestational age (SGA) is a major determinant of poor perinatal outcome. Detecting SGA at term using ultrasound is challenging and we often plan birth based on clinical assessment.

Aims: To determine the incidence of SGA infants with birthweight <10th centile among women undergoing planned birth at term for suspected SGA despite a normal estimated fetal weight (EFW) on ultrasound at 35-37 weeks.

Materials And Methods: We performed a retrospective study including all women with a fetal growth ultrasound at ≥35 weeks reporting an EFW ≥ 10th centile (appropriate for gestational age, AGA) who subsequently had an induction of labour or caesarean birth at ≥37 weeks due to ongoing clinical suspicion of SGA between 2012-2014. The primary outcome was the incidence of SGA newborns using customised centiles.

Results: There were 532 women who had a planned birth for clinical suspicion of SGA during the study period. Of these, 205 (38.5%) had an AGA fetus on ultrasound ≥35 weeks but were subsequently delivered because of a persisting clinical suspicion of SGA on abdominal assessment. Sixty-eight percent (n = 139/205) delivered an SGA infant. Furthermore, almost half of these SGA infants (47.5%) had a birthweight <3rd centile. Neonatal outcomes were worse for the SGA infants, with 15.1% (n = 21/205) requiring special care nursery compared to 1.5% (n = 1/205) of those AGA at birth.

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

Fetal fraction and noninvasive prenatal testing: What clinicians need to know.

Prenat Diagn 2020 01 10;40(2):155-163. Epub 2019 Dec 10.

Prenatal Genomics and Therapy Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

The fetal fraction (FF) is a function of both biological factors and bioinformatics algorithms used to interpret DNA sequencing results. It is an essential quality control component of noninvasive prenatal testing (NIPT) results. Clinicians need to understand the biological influences on FF to be able to provide optimal post-test counseling and clinical management. There are many different technologies available for the measurement of FF. Clinicians do not need to know the details behind the bioinformatics algorithms of FF measurements, but they do need to appreciate the significant variations between the different sequencing technologies used by different laboratories. There is no universal FF threshold that is applicable across all platforms and there have not been any differences demonstrated in NIPT performance by sequencing platform or method of FF calculation. Importantly, while FF should be routinely measured, there is not yet a consensus as to whether it should be routinely reported to the clinician. The clinician should know what to expect from a standard test report and whether reasons for failed NIPT results are revealed. Emerging solutions to the challenges of samples with low FF should reduce rates of failed NIPT in the future. In the meantime, having a "plan B" prepared for those patients for whom NIPT is unsuccessful is essential in today's clinical practice.
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http://dx.doi.org/10.1002/pd.5620DOI Listing
January 2020

Association between timing of diagnosis of trisomy 21, 18, and 13 and maternal socio-economic status in Victoria, Australia: A population-based cohort study from 2015 to 2016.

Prenat Diagn 2019 12 6;39(13):1254-1261. Epub 2019 Nov 6.

Reproductive Epidemiology Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia.

Objectives: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age, and socio-economic status (SES).

Design: Retrospective study of cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13) in Victoria, Australia, in 2015 to 2016, stratified by timing (prenatal less than 17 weeks gestation, prenatal including or greater than or 17 weeks gestation, and postnatal before 12 months of age), maternal age, and SES region. Utilisation of prenatal testing following a live-born T21 infant was ascertained via record linkage.

Results: Among 160 230 total births were 571 diagnoses of T21 and 246 of T18/T13. The overall and live birth prevalences of T21 were 3.56 and 0.47 per 1000 births, respectively. Compared with women from disadvantaged SES regions, women from high SES regions were more likely to have a prenatal diagnosis of a trisomy before 17 weeks than after (P < .01) and less likely to have a live-born T21 infant than a prenatal diagnosis (P < .01). There was a significant trend to higher live birth rates of T21 with lower SES (P = .004). The majority (68.5%) of women who gave birth to a live infant with T21 did not utilise prenatal testing.

Conclusion: There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher live birth rate of T21 in Victoria.
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http://dx.doi.org/10.1002/pd.5577DOI Listing
December 2019

Maternal and perinatal outcomes for women with body mass index ≥50 kg/m in a non-tertiary hospital setting.

Aust N Z J Obstet Gynaecol 2020 06 3;60(3):361-368. Epub 2019 Oct 3.

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

Background: Obesity is prevalent in the Australian antenatal population, but there are scarce data on the prevalence and associated outcomes of body mass index (BMI) ≥50 kg/m .

Aims: To examine the prevalence and outcomes for women with BMI ≥50 kg/m delivering in a non-tertiary hospital.

Materials And Methods: Retrospective cohort study of women delivering a singleton pregnancy in a non-tertiary Victorian hospital during 2011-2016. Women >180 kg were excluded as their care was managed in a tertiary centre. Maternal and perinatal outcomes were analysed by BMI group. Statistical analysis was performed using χ , Kruskal-Wallis and logistic regression with a significance level of 0.05.

Results: Of the 18 518 births between 2011 and 2016, 99.4% had a maternal BMI recorded. The prevalence of BMI ≥50 kg/m was 0.5%. Highest complication rates were observed among women with BMI ≥50 kg/m , including gestational diabetes (29%), hypertensive disorders of pregnancy (20%) and caesarean section (48%). Of infants born to women with BMI ≥50 kg/m , 12% were late-pre-term, 23% required special or intensive care and 20% had birth weight ≥4.0 kg. When compared with obese women with BMI 30-49 kg/m , women with BMI ≥50 kg/m were significantly more likely to develop a hypertensive disorder of pregnancy (preeclampsia adjusted odds ratio (aOR) 3.98 (1.93-8.18), pregnancy-induced hypertension aOR 3.55 (1.79-7.03)) and deliver a late pre-term infant (aOR 2.45 (1.31-4.58)).

Conclusions: The prevalence of severe maternal obesity in our non-tertiary setting is higher than previous national estimates. Women with BMI ≥50 kg/m are an important subgroup of the obese obstetric population who experience high rates of complications and interventions. Health services need to respond to evolving needs of the antenatal population to achieve the best outcomes for mothers and babies.
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http://dx.doi.org/10.1111/ajo.13064DOI Listing
June 2020

The 2018 Malcolm Ferguson-Smith Young Investigator Award.

Prenat Diagn 2019 09 15;39(10):835-837. Epub 2019 Aug 15.

John Wiley and Sons, Oxford, UK.

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http://dx.doi.org/10.1002/pd.5533DOI Listing
September 2019

Is there a role for proton pump inhibitor prophylaxis in haematology patients?

Intern Med J 2019 06;49(6):694-701

Department of Clinical Haematology, Austin Hospital, Melbourne, Victoria, Australia.

While proton pump inhibitors (PPI) are widely prescribed as prophylaxis in selected haematology inpatient and outpatients, an informal survey of haematology units around Australia found wide variations in the specific indications for their use. This is consistent with a literature review which showed a paucity of robust evidence to support their use, specifically in chemotherapy-induced mucositis, thrombocytopenia or administration of high dose glucocorticosteroids in the absence of additional risk factors. Rationalising PPI prescribing is clinically important from both a cost and safety perspective, given the emerging evidence of adverse events associated with prolonged PPI administration. A review of prescribing practices at our institution over a 14-month period found that approximately 60% of myeloma, lymphoma and autograft patients received PPI prophylaxis during and beyond chemotherapy without an accepted indication. We encourage institutions to review their PPI prescribing practices with the intent of rationalising their use, and to conduct studies aiming to fill the substantial gaps in our knowledge.
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http://dx.doi.org/10.1111/imj.14241DOI Listing
June 2019

Alobar holoprosencephaly detected in a 9-week embryo.

Am J Obstet Gynecol 2019 07 6;221(1):73-74. Epub 2019 Jan 6.

Department of Perinatal Medicine, Mercy Hospital for Women, Heidelberg, Australia.

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http://dx.doi.org/10.1016/j.ajog.2018.12.019DOI Listing
July 2019

Noninvasive Approaches to Prenatal Diagnosis: Historical Perspective and Future Directions.

Authors:
Lisa Hui

Methods Mol Biol 2019 ;1885:45-58

Department of Perinatal Medicine, Mercy Hospital for Women, Heidelberg, VIC, Australia.

The field of prenatal screening and diagnosis has undergone enormous progress over the past four decades. Most of this period has been characterized by gradual improvements in the technical and public health aspects of prenatal screening for Down syndrome. Compared to the direct analysis of fetal cells from amniocentesis or chorionic villus sampling, noninvasive approaches using maternal blood or ultrasound have the great advantage of posing no risk of miscarriage to the pregnancy. Recent advances in molecular genetics and DNA sequencing have revolutionized both the accuracy and the range of noninvasive testing for genetic abnormalities using cell-free DNA in maternal plasma. Many of these advances have already been incorporated into clinical care, including diagnosis of fetal blood group and aneuploidy screening. The accelerated pace of these recent developments is creating not just technical and logistical challenges, but is also magnifying the ethical and public policy issues traditionally associated with this field.
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http://dx.doi.org/10.1007/978-1-4939-8889-1_3DOI Listing
June 2019

Population-based trends in the prenatal diagnosis of sex chromosome aneuploidy before and after non-invasive prenatal testing.

Prenat Diagn 2018 12 30;38(13):1062-1068. Epub 2018 Oct 30.

Murdoch Children's Research Institute, Public Health Genetics Group, Parkville, Victoria, Australia.

Objective: To assess the impact of non-invasive prenatal testing (NIPT) on trends in the prenatal diagnosis of sex chromosome aneuploidy (SCA) in a population with >73,000 annual births.

Method: Retrospective population-based cohort study from 1986-2016 of all women undergoing prenatal diagnosis before 25 weeks gestation in the Australian state of Victoria. Statistical significance was tested using the chi-square test for trend or proportions.

Results: There were 2,043,345 births and 842 SCA diagnoses from 1986-2016. The percentage of prenatal diagnostic tests leading to a SCA diagnosis increased significantly from 0.95% in 2010 to 2.93% in 2016 (p < 0.001) but due to a concurrent decline in testing, the annual prenatal diagnosis rate of SCA remained stable at 4.4/10,000 births. Among confirmed fetal SCAs the most common indication for testing in 1986 was advanced maternal age (63%); in 2016 it was high risk NIPT (49%).

Conclusion: SCAs now make up an increasing proportion of prenatal diagnostic results but due to the overall decline in diagnostic testing, the prenatal prevalence as a percentage of births remained steady. The ascertainment of fetal SCA has evolved from an incidental finding after testing for increased risk of trisomy 21, to a diagnosis obtained after suspected SCA on NIPT.
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http://dx.doi.org/10.1002/pd.5363DOI Listing
December 2018