Obstetrics and Gynaecology - Research Publications

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    Position statement from the International Society for Prenatal Diagnosis on the use of non-invasive prenatal testing for the detection of fetal chromosomal conditions in singleton pregnancies
    Hui, L ; Ellis, K ; Mayen, D ; Pertile, MDD ; Reimers, R ; Sun, L ; Vermeesch, J ; Vora, NLL ; Chitty, LSS ; SPD, BOD (WILEY, 2023-06)
    Key points What is already known about this topic? In 2015, the International Society for Prenatal Diagnosis (ISPD) published its first position statement on the use of non‐invasive prenatal testing (NIPT) to screen for aneuploidy. Widespread uptake across the globe and subsequent published research has shed new light on test performance and implementation issues. What does this study add? This new position statement replaces the 2015 statement with updated information on the current technologies, clinical experience, and implementation practices. As an international organization, ISPD recognizes that there are important population‐specific considerations in the organization of prenatal screening and diagnosis. These opinions are designed to apply to high income settings where prenatal screening for aneuploidy is an established part of antenatal care. This position statement is not a clinical practice guideline but represents the consensus opinion of the current ISPD Board based on the current state of knowledge and clinical practice.
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    Ethical issues associated with prenatal screening using non-invasive prenatal testing for sex chromosome aneuploidy
    Johnston, M ; Warton, C ; Pertile, MD ; Taylor-Sands, M ; Delatycki, MB ; Hui, L ; Savulescu, J ; Mills, C (WILEY, 2023-02)
    Prenatal screening for sex chromosome aneuploidies (SCAs) is increasingly available through expanded non-invasive prenatal testing (NIPT). NIPT for SCAs raises complex ethical issues for clinical providers, prospective parents and future children. This paper discusses the ethical issues that arise around NIPT for SCAs and current guidelines and protocols for management. The first section outlines current practice and the limitations of NIPT for SCAs. It then outlines key guidelines before discussing the ethical issues raised by this use of NIPT. We conclude that while screening for SCAs should be made available for people seeking to use NIPT, its implementation requires careful consideration of what, when and how information is provided to users.
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    A decade of non-invasive prenatal screening in Australia: National impact on prenatal screening and diagnostic testing
    Hui, L ; Halliday, J (WILEY, 2023-04-01)
    Prenatal screening for aneuploidy has undergone immense changes over the past two decades. In 2013 cell-free DNA-based non-invasive prenatal testing (NIPT) became a new self-funded option primarily for Down syndrome screening, but also other aneuploidies and genetic conditions. The numbers of Medicare item claims for prenatal diagnostic procedures have halved since the introduction of NIPT, while billings for serum screening fell by 40% over the same period, on a background of steady births. Australia is now observing historically low rates of prenatal diagnostic testing. These data provide an informative snapshot of historic changes in prenatal screening and diagnosis, as our sector prepares for the impending impacts of other advances in genomics on maternity care. They also highlight the need to address equity and quality issues that arise when consumers must bear the full costs of improved genomic tests in the absence of Medicare funding.
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    Estimation of neonatal body fat percentage predicts neonatal hypothermia better than birthweight centile
    Banting, SA ; Dane, KM ; Charlton, JK ; Tong, S ; Hui, L ; Middleton, AL ; Gibson, LK ; Walker, SP ; MacDonald, TM (TAYLOR & FRANCIS LTD, 2022)
    INTRODUCTION: PEA POD™ air displacement plethysmography quickly and noninvasively estimates neonatal body fat percentage (BF%). Low PEA POD™ BF% predicts morbidity better than classification as small-for-gestational-age (SGA; <10th centile), but PEA PODs are not widely available. We examined whether skinfold measurements could effectively identify neonates at risk; comparing skinfold BF%, PEA POD™ BF% and birthweight centiles' prediction of hypothermia - a marker of reduced in utero nutrition. METHODS: Neonates had customized birthweight centiles calculated, and BF% prospectively estimated by: (i) triceps and subscapular skinfolds using sex-specific equations; and (ii) PEA POD™. Medical record review identified hypothermic (<36.5 °C) episodes. RESULTS: 42/149 (28%) neonates had hypothermia. Skinfold BF%, with an area under the curve (AUC) of 0.66, predicted hypothermia as well as PEA POD™ BF% (AUC = 0.62) and birthweight centile (AUC = 0.61). Birthweight <10th centile demonstrated 11.9% sensitivity, 38.5% positive predictive value (PPV) and 92.5% specificity for hypothermia. At equal specificity, skinfold and PEA POD™ BF% more than doubled sensitivity (26.2%) and PPV increased to 57.9%. CONCLUSION: Neonatal BF% performs better to predict neonatal hypothermia than birthweight centile, and may be a better measure of true fetal growth restriction. Estimation of neonatal BF% by skinfold measurements is an inexpensive alternative to PEA POD™.
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    RNA-Seq of amniotic fluid cell-free RNA: a discovery phase study of the pathophysiology of congenital cytomegalovirus infection
    Hui, L ; De Catte, L ; Beard, S ; Maksimovic, J ; Vora, NL ; Oshlack, A ; Walker, SP ; Hannan, NJ (MOSBY-ELSEVIER, 2022-10)
    BACKGROUND: Congenital cytomegalovirus infection is the most common perinatal infection and a significant cause of sensorineural hearing loss, cerebral palsy, and neurodevelopmental disability. There is a paucity of human gene expression studies examining the pathophysiology of cytomegalovirus infection. OBJECTIVE: This study aimed to perform a whole transcriptomic assessment of amniotic fluid from pregnancies with live fetuses to identify differentially expressed genes and enriched Gene Ontology categories associated with congenital cytomegalovirus infection. STUDY DESIGN: Amniotic fluid supernatant was prospectively collected from pregnant women undergoing amniocentesis for suspected congenital cytomegalovirus infection because of first-trimester maternal primary infection or ultrasound features suggestive of fetal infection. Women who had received therapy to prevent fetal infection were excluded. Congenital cytomegalovirus infection was diagnosed via viral polymerase chain reaction of amniotic fluid; cytomegalovirus-infected fetuses were paired with noninfected controls, matched for gestational age and fetal sex. Paired-end RNA sequencing was performed on amniotic fluid cell-free RNA with the Novaseq 6000 at a depth of 30 million reads per sample. Following quality control and filtering, reads were mapped to the human genome and counts summarized across genes. Differentially expressed genes were identified using 2 approaches: voomWithQualityWeights in conjunction with limma and RUVSeq with edgeR. Genes with a false discovery rate <0.05 were considered statistically significant. Differential exon use was analyzed using DEXSeq. Functional analysis was performed using gene set enrichment analysis and Ingenuity Pathway Analysis. Manual curation of differentially regulated genes was also performed. RESULTS: Amniotic fluid samples were collected from 50 women; 16 (32%) had congenital cytomegalovirus infection confirmed by polymerase chain reaction. After excluding 3 samples without matched controls, 13 cytomegalovirus-infected samples collected at 18 to 23 weeks and 13 cytomegalovirus-negative gestation-matched controls were submitted for RNA sequencing and analysis (N=26). Ten of the 13 pregnancies with cytomegalovirus-infected fetuses had amniocentesis because of serologic evidence of maternal primary infection with normal fetal ultrasound, and 3 had amniocentesis because of ultrasound abnormality suggestive of cytomegalovirus infection. Four cytomegalovirus-infected pregnancies ended in termination (n=3) or fetal death (n=1), and 9 resulted in live births. Pregnancy outcomes were available for 11 of the 13 cytomegalovirus-negative controls; all resulted in live births of clinically-well infants. Differential gene expression analysis revealed 309 up-regulated and 32 down-regulated genes in the cytomegalovirus-infected group compared with the cytomegalovirus-negative group. Gene set enrichment analysis showed significant enrichment of multiple Gene Ontology categories involving the innate immune response to viral infection and interferon signaling. Of the 32 significantly down-regulated genes, 8 were known to be involved in neurodevelopment and preferentially expressed by the brain. Six specific cellular restriction factors involved in host defense to cytomegalovirus infection were up-regulated in the cytomegalovirus-infected group. Ingenuity Pathway Analysis predicted the activation of pathways involved in progressive neurologic disease and inflammatory neurologic disease. CONCLUSION: In this next-generation sequencing study, we revealed new insights into the pathophysiology of congenital cytomegalovirus infection. These data on the up-regulation of the intraamniotic innate immune response to cytomegalovirus infection and the dysregulation of neurodevelopmental genes may inform future approaches to developing prognostic markers and assessing fetal responses to in utero therapy.
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    Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies
    Pynaker, C ; Norris, F ; Hui, L ; Halliday, J (WILEY, 2023-04)
    OBJECTIVE: To determine the perinatal outcomes of fetuses diagnosed with a pathogenic copy number variant (CNV) or variant of uncertain significance (VUS); and to characterize these variants in terms of testing indication, genomic location, size, and inheritance. METHODS: Retrospective study of singleton pregnancies with a pathogenic CNV or VUS from a single laboratory during 2012-2018. Probabilistic record linkage between the prenatal diagnosis dataset and perinatal outcome data for births from 20 weeks gestation was performed. If no birth record was found, this implied a pregnancy loss <20 weeks. RESULTS: We included 6945 prenatal microarray results; a pathogenic CNV was detected in 230 (3.3%, 95% CI: 2.9%-3.8%) and a VUS in 483 (7.0%, 95% CI: 6.4%-7.6%). Of pregnancies with a pathogenic CNV, 20.0% (95% CI: 15.3%-25.6%) had a live birth, 3.0% (95% CI: 1.5%-6.2%) had a perinatal death (stillbirth or neonatal death), and 77% (95% CI: 71.1%-81.9%) had no birth record. Of those with a VUS, 64.4% (95% CI: 60.0%-68.5%) had a live birth, 1.8% (95% CI: 1.0%-3.5%) had a perinatal death, and no birth record was found for 33.7% (95% CI: 29.7%-38.1%). Most pathogenic CNVs (61.1%) were <7 Mb in size. The most common microdeletion syndromes were DiGeorge, Wolf-Hirschhorn, and Cri-du-chat syndromes. CONCLUSION: This study provides an overview of perinatal outcomes and frequency of recurrent CNVs observed in the prenatal microarray era.
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    Placental OLAH Levels Are Altered in Fetal Growth Restriction, Preeclampsia and Models of Placental Dysfunction
    de Alwis, N ; Beard, S ; Binder, NK ; Pritchard, N ; Kaitu'u-Lino, TJ ; Walker, SP ; Stock, O ; Groom, K ; Petersen, S ; Henry, A ; Said, JM ; Seeho, S ; Kane, SC ; Tong, S ; Hui, L ; Hannan, NJ (MDPI, 2022-09)
    Previously, we identified elevated transcripts for the gene Oleoyl-ACP Hydrolase (OLAH) in the maternal circulation of pregnancies complicated by preterm fetal growth restriction. As placental dysfunction is central to the pathogenesis of both fetal growth restriction and preeclampsia, we aimed to investigate OLAH levels and function in the human placenta. We assessed OLAH mRNA expression (qPCR) throughout pregnancy, finding placental expression increased as gestation progressed. OLAH mRNA and protein levels (Western blot) were elevated in placental tissue from cases of preterm preeclampsia, while OLAH protein levels in placenta from growth-restricted pregnancies were comparatively reduced in the preeclamptic cohort. OLAH expression was also elevated in placental explant tissue, but not isolated primary cytotrophoblast cultured under hypoxic conditions (as models of placental dysfunction). Further, we discovered that silencing cytotrophoblast OLAH reduced the expression of pro- and anti-apoptosis genes, BAX and BCL2, placental growth gene, IGF2, and oxidative stress gene, NOX4. Collectively, these findings suggest OLAH could play a role in placental dysfunction and may be a therapeutic target for mitigating diseases associated with this vital organ. Further research is required to establish the role of OLAH in the placenta, and whether these changes may be a maternal adaptation or consequence of disease.
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    Factor's that impact on women's decision-making around prenatal genomic tests: An international discrete choice survey
    Buchanan, J ; Hill, M ; Vass, CM ; Hammond, J ; Riedijk, S ; Klapwijk, JE ; Harding, E ; Lou, S ; Vogel, I ; Hui, L ; Ingvoldstad-Malmgren, C ; Soller, MJ ; Ormond, KE ; Choolani, M ; Zheng, Q ; Chitty, LS ; Lewis, C (WILEY, 2022-06)
    OBJECTIVE: We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. METHODS: Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. RESULTS: Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. CONCLUSION: Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable.
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    State-Wide Utilization and Performance of Traditional and Cell-Free DNA-Based Prenatal Testing Pathways: The Victorian Perinatal Record Linkage (PeRL) Study
    Norton, ME (LIPPINCOTT WILLIAMS & WILKINS, 2021-01)
    (Abstracted from Ultrasound Obstet Gynecol 2020;56:215–224) In recent years, the use of combined first-trimester screening (CFTS) and cell-free DNA (cfDNA) screening has increased. With the rise of CFTS and cfDNA prenatal testing, there has been a dramatic decrease in the number of invasive diagnostic tests performed during pregnancy.
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    eLearning significantly improves maternity professionals' knowledge of the congenital cytomegalovirus prevention guidelines
    Smithers-Sheedy, H ; Swinburn, K ; Waight, E ; King, R ; Hui, L ; Jones, CA ; Daly, K ; Rawlinson, W ; Mcintyre, S ; Webb, A ; Badawi, N ; Bowen, A ; Britton, PN ; Palasanthiran, P ; Lainchbury, A ; Shand, A (WILEY, 2022-06)
    AIMS: Cytomegalovirus (CMV) is a preventable cause of neurodevelopmental disability. Australian guidelines recommend that pregnant women are informed about CMV to reduce their risk of infection; however, less than 10% of maternity health professionals routinely provide prevention advice. The aim was to develop and evaluate the effectiveness of an eLearning course for midwives to improve knowledge and confidence about CMV. MATERIALS AND METHODS: Participants undertaking the course between March and November 2020 were invited to complete an evaluation questionnaire: before the course (T1), immediately after (T2) and three months post completion (T3). A linear mixed model was used to evaluate change in participant scores; P < 0.05 was considered statistically significant. RESULTS: Midwives (316/363, 87%), midwifery students (29/363, 8%) and nurses (18/363, 5%) participated. At T1 80% indicated they had not received education about CMV. Total adjusted mean scores for questionnaires completed between T1 (n = 363) and T2 (n = 238) increased significantly (from 17.2 to 22.8, P < 0.001). Limited available T3 scores (n = 27) (-1.7, P < 0.001), while lower than T2, remained higher than at T1 (+3.6, P < 0.001). Participants' awareness of CMV information resources improved from 10 to 97% from T1 to T2. Confidence in providing CMV advice increased from 6 to 95% between T1 and T2 (P < 0.001) and was maintained at T3. Almost all (99%) participants indicated they would recommend the course to colleagues. CONCLUSION: Participants who completed the eLearning course had significantly improved knowledge and confidence in providing advice about CMV. Programs targeting other maternity health professionals should be considered, to further support the implementation of the congenital CMV prevention guidelines.