147 results on '"Hui L."'
Search Results
2. Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies
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Pynaker, C, Norris, F, Hui, L, Halliday, J, Pynaker, C, Norris, F, Hui, L, and Halliday, J
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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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- 2023
3. AI, Governance and Ethics: Global Perspectives.
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Micklitz, H-W, Pollicino, O, Reichman, A, Simoncini, A, Sartor, G, De Gregorio, G, Daly, A, Hagendorff, T, Hui, L, Mann, Monique, Marda, V, Wagner, B, Wei Wang, W, Micklitz, H-W, Pollicino, O, Reichman, A, Simoncini, A, Sartor, G, De Gregorio, G, Daly, A, Hagendorff, T, Hui, L, Mann, Monique, Marda, V, Wagner, B, and Wei Wang, W
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- 2022
4. Assessing women's preferences towards tests that may reveal uncertain results from prenatal genomic testing: Development of attributes for a discrete choice experiment, using a mixed-methods design.
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Marshall, AT, Hammond, J, Klapwijk, JE, Riedijk, S, Lou, S, Ormond, KE, Vogel, I, Hui, L, Sziepe, E-J, Buchanan, J, Ingvoldstad-Malmgren, C, Soller, MJ, Harding, E, Hill, M, Lewis, C, Marshall, AT, Hammond, J, Klapwijk, JE, Riedijk, S, Lou, S, Ormond, KE, Vogel, I, Hui, L, Sziepe, E-J, Buchanan, J, Ingvoldstad-Malmgren, C, Soller, MJ, Harding, E, Hill, M, and Lewis, C
- Abstract
Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the likelihood of receiving a diagnosis when fetal structural anomalies are identified. However, some parents will receive uncertain results such as variants of uncertain significance and secondary findings. We aimed to develop a set of attributes and associated levels for a discrete-choice experiment (DCE) that will examine parents' preferences for tests that may reveal uncertain test results. A two phase mixed-methods approach was used to develop attributes for the DCE. In Phase 1, a "long list" of candidate attributes were identified via two approaches: 1) a systematic review of the literature around parental experiences of uncertainty following prenatal testing; 2) 16 semi-structured interviews with parents who had experienced uncertainty during pregnancy and 25 health professionals who return uncertain prenatal results. In Phase 2, a quantitative scoring exercise with parents prioritised the candidate attributes. Clinically appropriate levels for each attribute were then developed. A final set of five attributes and levels were identified: likelihood of getting a result, reporting of variants of uncertain significance, reporting of secondary findings, time taken to receive results, and who tells you about your result. These attributes will be used in an international DCE study to investigate preferences and differences across countries. This research will inform best practice for professionals supporting parents to manage uncertainty in the prenatal setting.
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- 2022
5. eLearning significantly improves maternity professionals' knowledge of the congenital cytomegalovirus prevention guidelines
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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, 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, and Shand, A
- Abstract
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.
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- 2022
6. Factor's that impact on women's decision-making around prenatal genomic tests: An international discrete choice survey
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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, 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, and Lewis, C
- Abstract
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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- 2022
7. Placental OLAH Levels Are Altered in Fetal Growth Restriction, Preeclampsia and Models of Placental Dysfunction
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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, 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, and Hannan, NJ
- Abstract
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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- 2022
8. RNA-Seq of amniotic fluid cell-free RNA: a discovery phase study of the pathophysiology of congenital cytomegalovirus infection
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Hui, L, De Catte, L, Beard, S, Maksimovic, J, Vora, NL, Oshlack, A, Walker, SP, Hannan, NJ, Hui, L, De Catte, L, Beard, S, Maksimovic, J, Vora, NL, Oshlack, A, Walker, SP, and Hannan, NJ
- Abstract
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 sa
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- 2022
9. Estimation of neonatal body fat percentage predicts neonatal hypothermia better than birthweight centile
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Banting, SA, Dane, KM, Charlton, JK, Tong, S, Hui, L, Middleton, AL, Gibson, LK, Walker, SP, MacDonald, TM, Banting, SA, Dane, KM, Charlton, JK, Tong, S, Hui, L, Middleton, AL, Gibson, LK, Walker, SP, and MacDonald, TM
- Abstract
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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- 2022
10. Final report on the CCPR Key Comparison CCPR-K3.2014 Luminous Intensity
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Gaertner, A.A., Côté, É., Campos Acosta, Joaquín, Obein, G., Blattner, P., Schafer, R., Hui, L., Xiaomei, J., Miller, C., Zong, Y., Atkinson, E., Thorvaldson, E., Kinoshita, K., Sieberhagen, R., Rabe, I., Goodman, T., Scott, B., Sperling, A., Lindner, D., Khlevnoy, B., Ivashin, E., Gaertner, A.A., Côté, É., Campos Acosta, Joaquín, Obein, G., Blattner, P., Schafer, R., Hui, L., Xiaomei, J., Miller, C., Zong, Y., Atkinson, E., Thorvaldson, E., Kinoshita, K., Sieberhagen, R., Rabe, I., Goodman, T., Scott, B., Sperling, A., Lindner, D., Khlevnoy, B., and Ivashin, E.
- Abstract
Main text The metrological equivalence of national measurement standards in the field of photometry and radiometry is determined by a set of key comparisons chosen and organised by the Consultative Committee of Photometry and Radiometry (CCPR) of the Comité international des poids et mesures (CIPM), working closely with the Regional Metrology Organisations (RMOs). In September 2009 the CCPR decided that a second round of the key comparison K3 Luminous Intensity be commenced. The National Research Council of Canada (NRC) was chosen to pilot this comparison. A total of 12 participants were selected from the three RMO group members: EURAMET&COOMET (6: IO-CSIC, LNE-CNAM, METAS, NPL, PTB, VNIIOFI), APMP&AFRIMETS (4: NMISA, NIM, NMIA, NMIJ), and SIM (2: NIST, NRC). The comparison was organised as a star comparison (NMI-Pilot-NMI) using incandescent standard lamps supplied by each NMI (National Metrology Institute) as the travelling comparison artifact. This report describes the comparison organisation (Section 2), the measurement methods and uncertainties achieved at all the participants and at the pilot (Sections 3 and 4), and the method for analysis and the results of the comparison according to this method (Section 4). It includes a comparison of the results of this comparison with the 1999 first round key comparison (Section 5). Section 6 presents a summary of the comparison. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/. The final report has been peer-reviewed and approved for publication by the CCPR, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
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- 2022
11. Pregnancy in the Time of COVID-19: What Are the Challenges for Maternity Care?
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Moderator, Hui, L, Experts, Knight, M, Edlow, A, Homer, C, Danchin, M, Moderator, Hui, L, Experts, Knight, M, Edlow, A, Homer, C, and Danchin, M
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- 2022
12. Context Dependency of Epithelial-to-Mesenchymal Transition for Metastasis
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Blanpain, Cédric, Remmelink, Myriam, Gilles, Christine, Fuks, François, Rothé, Françoise, Del Marmol, Véronique, Lien, Wen-Hui L., Revenco, Tatiana, Blanpain, Cédric, Remmelink, Myriam, Gilles, Christine, Fuks, François, Rothé, Françoise, Del Marmol, Véronique, Lien, Wen-Hui L., and Revenco, Tatiana
- Abstract
We questioned whether EMT is required for metastasis, and we have analyzed metastasis formation in two distinct SCC models, different in terms of SCC ability to undergo EMT. We demonstrated that in spontaneous mouse model in which tumors presented a wide range of EMT (from well differentiated to fully EMT-like) presented high metastatic incidence: 49% (20/70) of mice presented LN metastasis and 28% (34/70) of mice presented lung metastases. Importantly, metastatic incidence was always associated with EMT-like tumors. However, in the second mouse model, that develops mostly well-differentiated tumors, the metastatic incidence was very low: 12% (5/42) of mice developed lung metastases and 10% (4/42) developed lymph node metastases. Importantly, the rare metastases were associated with tumors presenting some degree of EMT, supporting that EMT is needed for metastases arising from skin SCC.To understand whether EMT can occur at the intermediate step between primary tumor and distant metastasis, we analyzed blood from mice based on YFP reporter. We uncovered that most CTCs were EMT-like: 80% of CTCs were EpCAM-negative. This finding suggests that EpCAM marker, a gold standard used to detect CTCs, is not optimal as it doesn’t detect CTCs of EMT phenotype thus underestimating the real number of CTCs. Importantly, we noticed that the presence of CTCs was always associated with lung metastases and indeed can be used to predict prognosis of oncologic disease. Our immunofluorescent analysis of lung and lymph nodes showed that the majority of metastases were of differentiated phenotype. For the lung metastases, 71% (36/51) of them presented epithelial phenotype YFP+/K14+/Vim-, 14% (7/51) presented differentiated epithelial features but did not express K14 or Vimentin, 12% (6/51) presented an EMT hybrid epithelial phenotype YFP+/K14+/Vim+, whereas only 4% (2/51) were purely mesenchymal YFP+/K14-/Vim+. Histological analyses were confirmed by FACS analysis showing that lung metast, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished
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- 2022
13. The international Perinatal Outcomes in the Pandemic (iPOP) study: Protocol
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Stock, SJ, Zoega, H, Brockway, M, Mulholland, RH, Miller, JE, Been, JV, Wood, R, Abok, II, Alshaikh, B, Ayede, AI, Bacchini, F, Bhutta, ZA, Brew, BK, Brook, J, Calvert, C, Campbell-Yeo, M, Chan, D, Chirombo, J, Connor, KL, Daly, M, Einarsdóttir, K, Fantasia, I, Franklin, M, Fraser, A, Håberg, SE, Hui, L, Huicho, L, Magnus, MC, Morris, AD, Nagy-Bonnard, L, Nassar, N, Nyadanu, SD, Iyabode Olabisi, D, Palmer, KR, Pedersen, LH, Pereira, G, Racine-Poon, A, Ranger, M, Rihs, T, Saner, C, Sheikh, A, Swift, EM, Tooke, L, Urquia, ML, Whitehead, C, Yilgwan, C, Rodriguez, N, Burgner, D, Azad, MB, Stock, SJ, Zoega, H, Brockway, M, Mulholland, RH, Miller, JE, Been, JV, Wood, R, Abok, II, Alshaikh, B, Ayede, AI, Bacchini, F, Bhutta, ZA, Brew, BK, Brook, J, Calvert, C, Campbell-Yeo, M, Chan, D, Chirombo, J, Connor, KL, Daly, M, Einarsdóttir, K, Fantasia, I, Franklin, M, Fraser, A, Håberg, SE, Hui, L, Huicho, L, Magnus, MC, Morris, AD, Nagy-Bonnard, L, Nassar, N, Nyadanu, SD, Iyabode Olabisi, D, Palmer, KR, Pedersen, LH, Pereira, G, Racine-Poon, A, Ranger, M, Rihs, T, Saner, C, Sheikh, A, Swift, EM, Tooke, L, Urquia, ML, Whitehead, C, Yilgwan, C, Rodriguez, N, Burgner, D, and Azad, MB
- Abstract
Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread 'natural experiment' of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide cr
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- 2021
14. DAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia
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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, Hui, L, Tong, S, Hannan, NJ, 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, Hui, L, Tong, S, and Hannan, NJ
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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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- 2021
15. State-Wide Utilization and Performance of Traditional and Cell-Free DNA-Based Prenatal Testing Pathways: The Victorian Perinatal Record Linkage (PeRL) Study.
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Lindquist A., Hui L., Poulton A., Kluckow E., Hutchinson B., Pertile M.D., Bonacquisto L., Gugasyan L., Kulkarni A., Harraway J., Howden A., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., Nisbet D., Martin N., Bethune M., Poulakis Z., Halliday J., Lindquist A., Hui L., Poulton A., Kluckow E., Hutchinson B., Pertile M.D., Bonacquisto L., Gugasyan L., Kulkarni A., Harraway J., Howden A., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., Nisbet D., Martin N., Bethune M., Poulakis Z., and Halliday J.
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- 2021
16. Collaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: A protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia.
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Hui L., Marzan M.B., Potenza S., Rolnik D.L., Said J.M., Palmer K.R., Whitehead C.L., Sheehan P.M., Ford J., Pritchard N., Mol B.W., Walker S.P., Hui L., Marzan M.B., Potenza S., Rolnik D.L., Said J.M., Palmer K.R., Whitehead C.L., Sheehan P.M., Ford J., Pritchard N., Mol B.W., and Walker S.P.
- Abstract
Background The COVID-19 pandemic has resulted in a range of unprecedented disruptions to maternity care with documented impacts on perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne has endured one of the longest and most stringent lockdowns in globally. This paper presents the protocol for a multicentre study to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic. Methods Multicentre observational study analysing monthly deidentified maternal and newborn outcomes from births >20 weeks at all 12 public maternity services in Melbourne. Data will be merged centrally to analyse outcomes and create run charts according to established methods for detecting non-random signals' in healthcare. Perinatal outcomes will include weekly rates of total births, stillbirths, preterm births, neonatal intensive care admissions, low Apgar scores and fetal growth restriction. Maternal outcomes will include weekly rates of: induced labour, caesarean section, births before arrival to hospital, postpartum haemorrhage, length of stay, general anaesthesia for caesarean birth, influenza and COVID-19 vaccination status, and gestation at first antenatal visit. A prepandemic median for all outcomes will be calculated for the period of January 2018 to March 2020. A significant shift is defined as >=6 consecutive weeks, all above or below the prepandemic median. Additional statistical analyses such as regression, time series and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests. Ethics and dissemination Ethics approval for the collaborative maternity and newborn dashboard project has been obtained from the Austin Health (HREC/64722/Austin-2020) and Mercy Health (ref. 2020-031). Trial registration number ACTRN12620000878976; Pre-results.Copyright ©
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- 2021
17. Business as usual during the COVID-19 pandemic? Reflections on state-wide trends in maternity telehealth consultations during lockdown in Victoria and New South Wales.
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Potenza S., Marzan M.B., Rolnik D.L., Palmer K., Said J., Whitehead C., Sheehan P., Mol B.W., Walker S., Hui L., Potenza S., Marzan M.B., Rolnik D.L., Palmer K., Said J., Whitehead C., Sheehan P., Mol B.W., Walker S., and Hui L.
- Abstract
COVID-19 has resulted in unprecedented changes to maternity care across Australia. This study aims to analyse trends in maternity consultations and the uptake of telehealth in Victoria and New South Wales (NSW) since the first restrictions to reduce COVID-19 transmission were implemented. From March 2020 to April 2021, a higher proportion of antenatal care consultations was delivered via telehealth in Victoria compared to NSW (13.8% vs 7.4%, P < 0.0001). Uptake of telehealth and a shift from in-person care has been a major contributor to maintaining pregnancy care during pandemic restrictions. However, further research is required to understand women's perspectives and health outcomes.Copyright © 2021 Royal Australian and New Zealand College of Obstetricians and Gynaecologists
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- 2021
18. State-Wide Utilization and Performance of Traditional and Cell-Free DNA-Based Prenatal Testing Pathways: The Victorian Perinatal Record Linkage (PeRL) Study.
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Lindquist A., Hui L., Poulton A., Kluckow E., Hutchinson B., Pertile M.D., Bonacquisto L., Gugasyan L., Kulkarni A., Harraway J., Howden A., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., Nisbet D., Martin N., Bethune M., Poulakis Z., Halliday J., Lindquist A., Hui L., Poulton A., Kluckow E., Hutchinson B., Pertile M.D., Bonacquisto L., Gugasyan L., Kulkarni A., Harraway J., Howden A., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., Nisbet D., Martin N., Bethune M., Poulakis Z., and Halliday J.
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- 2021
19. Collaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: A protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia.
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Hui L., Marzan M.B., Potenza S., Rolnik D.L., Said J.M., Palmer, Kirsten R., Whitehead C.L., Sheehan P.M., Ford J., Pritchard N., Mol B.W., Walker S.P., Hui L., Marzan M.B., Potenza S., Rolnik D.L., Said J.M., Palmer, Kirsten R., Whitehead C.L., Sheehan P.M., Ford J., Pritchard N., Mol B.W., and Walker S.P.
- Abstract
Background The COVID-19 pandemic has resulted in a range of unprecedented disruptions to maternity care with documented impacts on perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne has endured one of the longest and most stringent lockdowns in globally. This paper presents the protocol for a multicentre study to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic. Methods Multicentre observational study analysing monthly deidentified maternal and newborn outcomes from births >20 weeks at all 12 public maternity services in Melbourne. Data will be merged centrally to analyse outcomes and create run charts according to established methods for detecting non-random signals' in healthcare. Perinatal outcomes will include weekly rates of total births, stillbirths, preterm births, neonatal intensive care admissions, low Apgar scores and fetal growth restriction. Maternal outcomes will include weekly rates of: induced labour, caesarean section, births before arrival to hospital, postpartum haemorrhage, length of stay, general anaesthesia for caesarean birth, influenza and COVID-19 vaccination status, and gestation at first antenatal visit. A prepandemic median for all outcomes will be calculated for the period of January 2018 to March 2020. A significant shift is defined as >=6 consecutive weeks, all above or below the prepandemic median. Additional statistical analyses such as regression, time series and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests. Ethics and dissemination Ethics approval for the collaborative maternity and newborn dashboard project has been obtained from the Austin Health (HREC/64722/Austin-2020) and Mercy Health (ref. 2020-031). Trial registration number ACTRN12620000878976; Pre-results.Copyright ©
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- 2021
20. Increased macrosomia and maternal obesity during COVID-19 lockdown in Melbourne, Australia.
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Hui L., Marzan M., Potenza S., Said J., Palmer K., Whitehead C., Rolnik D., Sheehan P., Ford J., Mol B., Walker S., Hui L., Marzan M., Potenza S., Said J., Palmer K., Whitehead C., Rolnik D., Sheehan P., Ford J., Mol B., and Walker S.
- Abstract
Objective Women living in the Australian city of Melbourne endured some of the most stringent pandemic restrictions in the world, while continuing to give birth to > 5000 babies/month. International studies have reported significant changes in perinatal outcomes such as preterm birth and stillbirths in association with pandemic restrictions. In response to these reports, maternity health services in Melbourne formed a research collaboration to monitor the impacts of lockdown restrictions on perinatal outcomes (the 'Collaborative Maternity and Newborn Dashboard'). Design Multi-centre maternity data collection of birth outcomes in Melbourne for weekly run chart displays of perinatal performance indicators during pandemic restrictions. Methods We collected outcomes of births >= 20 weeks' gestation in public maternity services in metropolitan Melbourne. Weekly rates of perinatal indicators were used to create run charts according to established methods for detecting non-random signals in health care. Pre-pandemic median rates for each indicator were calculated using births from Jan 2018 to March 2020. A significant shift was defined as >= six consecutive weeks all above or below the pre-pandemic median occurring after the onset of Stage 3 restrictions on March 31, 2020.1 Results Outcomes on 97 105 births (median 719 births/ week) from 1 Jan 2018 to 31 July 2020 were analysed. After the imposition of Stage 3 restrictions, we observed significant upwards shifts in the rates of macrosomia (birthweight >= 90th centile, and >=4000 g), and maternal overweight/obesity (BMI >= 25 and >=30 kg/m2). We also observed a decrease in exclusively breast milk-fed infants. There were small temporary increases in total preterm births and inductions of labour. There were no significant shifts in weekly rates of total births, stillbirths, neonatal intensive care admissions, fetal growth restriction, total antenatal visits, elective Cesarean sections, or low Apgar scores. Conclusion A three
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- 2021
21. Business as usual during the COVID-19 pandemic? Reflections on state-wide trends in maternity telehealth consultations during lockdown in Victoria and New South Wales.
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Potenza S., Marzan M.B., Rolnik D.L., Palmer K., Said J., Whitehead C., Sheehan P., Mol B.W., Walker S., Hui L., Potenza S., Marzan M.B., Rolnik D.L., Palmer K., Said J., Whitehead C., Sheehan P., Mol B.W., Walker S., and Hui L.
- Abstract
COVID-19 has resulted in unprecedented changes to maternity care across Australia. This study aims to analyse trends in maternity consultations and the uptake of telehealth in Victoria and New South Wales (NSW) since the first restrictions to reduce COVID-19 transmission were implemented. From March 2020 to April 2021, a higher proportion of antenatal care consultations was delivered via telehealth in Victoria compared to NSW (13.8% vs 7.4%, P < 0.0001). Uptake of telehealth and a shift from in-person care has been a major contributor to maintaining pregnancy care during pandemic restrictions. However, further research is required to understand women's perspectives and health outcomes.Copyright © 2021 Royal Australian and New Zealand College of Obstetricians and Gynaecologists
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- 2021
22. Business as usual during the COVID-19 pandemic? Statewide trends in maternity care during lockdown in Victoria and New South Wales.
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Potenza S., Marzan M., Said J., Palmer K., Whitehead C., Rolnik D., Mol B., Walker S., Hui L., Potenza S., Marzan M., Said J., Palmer K., Whitehead C., Rolnik D., Mol B., Walker S., and Hui L.
- Abstract
Introduction: The COVID-19 pandemic has resulted in unprecedented changes to the delivery of maternity care across Australia, including RANZCOG-endorsed measures to reduce antenatal visits, and implement telehealth. We analysed trends in maternity consultations and the uptake of telehealth in VIC and NSW since the first COVID-19 pandemic restrictions were introduced in late March 2020. Method(s): Episodes of outpatient antenatal and post-natal consultations and obstetric ultrasounds from January 2018 to September 2020 were obtained using Australian Government Medicare Statistics data from NSW and VIC. Run charts using pre-pandemic median from January 2018 were generated. A significant trend was defined as five consecutive months of numbers all going up or down.1 Utilisation of telehealth consultations was compared between VIC and NSW using the z-test for difference in proportions. Result(s): Despite a decline in monthly face-to-face consultations in Victoria and NSW (16% and 12% decline from pre-COVID medians of 32,413 and 41,848, respectively), there was no significant downward trend in total attendances during the first lockdown. A higher proportion of antenatal and post-natal care was delivered via telehealth/telephone in Victoria compared to NSW (19.4% vs 9.4%, respectively, p < 0.0001). From March 2020 in Victoria, the run chart showed a trend towards increased ultrasound examinations for women with a singleton pregnancy after 22 weeks. Discussion(s): Widespread uptake of telehealth has been a major contributor to maintaining maternity consultations during Victorian pandemic restrictions. Further research is required to understand the increase in ultrasound billings during lockdown in Victoria.
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- 2021
23. Transcriptomic analysis of patient plasma reveals circulating miR200c as a potential biomarker for high-grade serous ovarian cancer
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Hannan, NJ, Cohen, PA, Beard, S, Bilic, S, Zhang, B, Tong, S, Whitehead, C, Hui, L, Hannan, NJ, Cohen, PA, Beard, S, Bilic, S, Zhang, B, Tong, S, Whitehead, C, and Hui, L
- Abstract
BACKGROUND: High-grade serous tubo-ovarian cancer (HGSC) is the most common histological subtype of epithelial ovarian cancer, and highly lethal. Currently there is no effective screening test and prognosis is poor as the majority of cases are diagnosed at the advanced stage. Cell free RNAs including microRNAs (miRNAs) are dysregulated in ovarian cancer tissue and are detectable in the circulation. This study aimed to determine whether circulating cell free miRNAs may be potential biomarkers for the detection of HGSC. METHODS: Plasma was collected from women with HGSC (Grade 3, n = 24), and benign ovarian masses (n = 24). RNA was extracted from patient plasma and subjected to miRNA targeted next generation sequencing (NGS). A subsequent validation cohort was assessed using plasma collected from women with HGSC (n = 14) and controls (with a benign ovarian mass; n = 15). RNA was extracted and assessed using quantitative RT-PCR. RESULTS: Differential gene expression (DGE) of the NGS data revealed a significant increase in the miRNA, miR200c, in the circulation of women with HGSC (p less than 0.05) compared to controls. In the validation cohort miR200c expression by qPCR was found to also be increased in the circulation of women with HGSC compared to controls (p = 0.0023). CONCLUSIONS: Circulating miR200c may be a promising candidate biomarker for the detection of HGSC. Further larger cohort studies exploring earlier stages are needed to determine whether circulating miR200c may be a sensitive and specific biomarker of tubo-ovarian cancer.
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- 2021
24. Increased nuchal translucency after low-risk noninvasive prenatal testing: What should we tell prospective parents?
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Kelley, J, McGillivray, G, Meagher, S, Hui, L, Kelley, J, McGillivray, G, Meagher, S, and Hui, L
- Abstract
Three decades ago, the observation that first trimester fetuses with excess fluid accumulation at the back of the neck were more likely to be aneuploid, gave rise to a new era of prenatal screening. The nuchal translucency (NT) measurement in combination with serum biomarkers and maternal age, resulted in the first trimester combined screening (FTCS) program. The introduction of noninvasive prenatal testing (NIPT) over the past decade has introduced the option for parents to receive highly sensitive and specific screening information for common trisomy from as early as 10 weeks gestation, altering the traditional pathway FTCS pathway. The retention of the 11-13-week NT ultrasound remains important in the detection of structural anomalies; however, the optimal management of pregnancies with a low-risk NIPT result and an isolated increased NT measurement in an era of advanced genomic testing options is a new dilemma for clinicians. For parents, the prolonged period between the initial diagnosis in first trimester, and prognostic information at each successive stage of investigations up to 22-24 weeks, can be emotionally challenging. This article addresses the common questions from parents and clinicians as they navigate the uncertainty of having a fetus diagnosed with an increased NT after a low-risk NIPT result and presents suggested approaches to management.
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- 2021
25. Increase in preterm stillbirths and reduction in iatrogenic preterm births for fetal compromise: a multi-centre cohort study of COVID-19 lockdown effects in Melbourne, Australia
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Hui, L, Marzan, MB, Potenza, S, Rolnik, D, Pritchard, N, Said, J, Palmer, K, Whitehead, C, Sheehan, P, Ford, J, Mol, B, Walker, S, Hui, L, Marzan, MB, Potenza, S, Rolnik, D, Pritchard, N, Said, J, Palmer, K, Whitehead, C, Sheehan, P, Ford, J, Mol, B, and Walker, S
- Abstract
ABSTRACT
Objectives
The COVID-19 pandemic has been associated with a worsening of perinatal outcomes in many settings due to the combined impacts of maternal COVID-19 disease, disruptions to maternity care, and overloaded health systems. In 2020, Melbourne endured a unique natural experiment where strict lockdown conditions were accompanied by very low COVID-19 case numbers and the maintenance of health service capacity. The aim of this study was to compare stillbirth and preterm birth rates in women who were exposed or unexposed to lockdown restrictions during pregnancy.Design
Retrospective multi-centre cohort study of perinatal outcomes before and during COVID-19 lockdownSetting
Birth outcomes from all 12 public maternity hospitals in metropolitan MelbourneInclusion criteria
Singleton births without congenital anomalies from 24 weeks’ gestation. The lockdown-exposed cohort were those women for whom weeks 20- 40 of gestation would have occurred during the lockdown period of 23 March 2020 to 14 March 2021. The control cohort comprised all pregnancies in the corresponding periods one and two years prior to the exposed cohort.Main outcome measures
Odds of stillbirth, preterm birth (PTB), birth weight < 3 rd centile, and iatrogenic PTB for fetal compromise, adjusting for multiple covariates.Results
There were 24,017 births in the exposed and 50,017 births in the control group. There was a significantly higher risk of preterm, but not term, stillbirth in the exposed group compared with the control group (0.26% vs 0.18%, aOR 1.49, 95%CI 1.08 to 2.05, P = 0.015). There was also a significant reduction in preterm birth < 37 weeks (5.93% vs 6.23%, aOR 0.93, 95%CI 0.87 to 0.99, P=0.03), largely mediated by a reduction in iatrogenic PTB for live births (3.01% vs 3.27%, aOR 0.89, 95%CI 0.81 to 0.98, P = 0.015), including iatrogenic PTB for suspected fetal compromise (1.25% vs 1.51%, aOR 0.79, 95%CI 0.69 to 0.9- Published
- 2021
26. Dealing with uncertain results from chromosomal microarray and exome sequencing in the prenatal setting: An international cross-sectional study with healthcare professionals
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Lewis, C, Hammond, J, Klapwijk, JE, Harding, E, Lou, S, Vogel, I, Szepe, EJ, Hui, L, Ingvoldstad-Malmgren, C, Soller, MJ, Ormond, KE, Choolani, M, Hill, M, Riedijk, S, Lewis, C, Hammond, J, Klapwijk, JE, Harding, E, Lou, S, Vogel, I, Szepe, EJ, Hui, L, Ingvoldstad-Malmgren, C, Soller, MJ, Ormond, KE, Choolani, M, Hill, M, and Riedijk, S
- Abstract
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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- 2021
27. DAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia
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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, Hui, L, Tong, S, Hannan, NJ, 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, Hui, L, Tong, S, and Hannan, NJ
- Abstract
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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- 2021
28. The international Perinatal Outcomes in the Pandemic (iPOP) study: protocol.
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Stock, SJ, Zoega, H, Brockway, M, Mulholland, RH, Miller, JE, Been, JV, Wood, R, Abok, II, Alshaikh, B, Ayede, AI, Bacchini, F, Bhutta, ZA, Brew, BK, Brook, J, Calvert, C, Campbell-Yeo, M, Chan, D, Chirombo, J, Connor, KL, Daly, M, Einarsdóttir, K, Fantasia, I, Franklin, M, Fraser, A, Håberg, SE, Hui, L, Huicho, L, Magnus, MC, Morris, AD, Nagy-Bonnard, L, Nassar, N, Nyadanu, SD, Iyabode Olabisi, D, Palmer, KR, Pedersen, LH, Pereira, G, Racine-Poon, A, Ranger, M, Rihs, T, Saner, C, Sheikh, A, Swift, EM, Tooke, L, Urquia, ML, Whitehead, C, Yilgwan, C, Rodriguez, N, Burgner, D, Azad, MB, iPOP Study Team, Stock, SJ, Zoega, H, Brockway, M, Mulholland, RH, Miller, JE, Been, JV, Wood, R, Abok, II, Alshaikh, B, Ayede, AI, Bacchini, F, Bhutta, ZA, Brew, BK, Brook, J, Calvert, C, Campbell-Yeo, M, Chan, D, Chirombo, J, Connor, KL, Daly, M, Einarsdóttir, K, Fantasia, I, Franklin, M, Fraser, A, Håberg, SE, Hui, L, Huicho, L, Magnus, MC, Morris, AD, Nagy-Bonnard, L, Nassar, N, Nyadanu, SD, Iyabode Olabisi, D, Palmer, KR, Pedersen, LH, Pereira, G, Racine-Poon, A, Ranger, M, Rihs, T, Saner, C, Sheikh, A, Swift, EM, Tooke, L, Urquia, ML, Whitehead, C, Yilgwan, C, Rodriguez, N, Burgner, D, Azad, MB, and iPOP Study Team
- Abstract
Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread "natural experiment" of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide cr
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- 2021
29. Accelerated fetal growth velocity across the third trimester is associated with increased shoulder dystocia risk among fetuses who are not large-for-gestational-age: A prospective observational cohort study
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Fujioka, K, MacDonald, TM, Robinson, AJ, Hiscock, RJ, Hui, L, Dane, KM, Middleton, AL, Kennedy, LM, Tong, S, Walker, SP, Fujioka, K, MacDonald, TM, Robinson, AJ, Hiscock, RJ, Hui, L, Dane, KM, Middleton, AL, Kennedy, LM, Tong, S, and Walker, SP
- Abstract
OBJECTIVE: To investigate whether fetuses with accelerated third trimester growth velocity are at increased risk of shoulder dystocia, even when they are not large-for-gestational-age (LGA; estimated fetal weight (EFW) >95th centile). METHODS: Fetal growth velocity and birth outcome data were prospectively collected from 347 nulliparous women. Each had blinded ultrasound biometry performed at 28 and 36 weeks' gestation. Change in EFW and abdominal circumference (AC) centiles between 28-36 weeks were calculated, standardised over exactly eight weeks. We examined the odds of shoulder dystocia with increasing EFW and AC growth velocities among women with 36-week EFW ≤95th centile (non-LGA), who went on to have a vaginal birth. We then examined the relative risk (RR) of shoulder dystocia in cases of accelerated EFW and AC growth velocities (>30 centiles gained). Finally, we compared the predictive performances of accelerated fetal growth velocities to 36-week EFW >95th centile for shoulder dystocia among the cohort planned for vaginal birth. RESULTS: Of the 226 participants who had EFW ≤95th centile at 36-week ultrasound and birthed vaginally, six (2.7%) had shoulder dystocia. For each one centile increase in EFW between 28-36 weeks, the odds of shoulder dystocia increased by 8% (odds ratio (OR [95% Confidence Interval (CI)]) = 1.08 [1.04-1.12], p<0.001). For each one centile increase in AC between 28-36 weeks, the odds of shoulder dystocia increased by 9% (OR[95%CI] = 1.09 [1.05-1.12], p<0.001). When compared to the rest of the cohort with normal growth velocity, accelerated EFW and AC velocities were associated with increased relative risks of shoulder dystocia (RR[95%CI] = 7.3 [1.9-20.6], p = 0.03 and 4.8 [1.7-9.4], p = 0.02 respectively). Accelerated EFW or AC velocities predicted shoulder dystocia with higher sensitivity and positive predictive value than 36-week EFW >95th centile. CONCLUSIONS: Accelerated fetal growth velocities between 28-36 weeks' gestation are
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- 2021
30. Study protocol: childhood outcomes of fetal genomic variants: the PrenatAL Microarray (PALM) cohort study
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Hui, L, Pynaker, C, Kennedy, J, Lewis, S, Amor, DJ, Walker, SP, Halliday, J, Hui, L, Pynaker, C, Kennedy, J, Lewis, S, Amor, DJ, Walker, SP, and Halliday, J
- Abstract
BACKGROUND: The implementation of genomic testing in pregnancy means that couples have access to more information about their child's genetic make-up before birth than ever before. One of the resulting challenges is the management of genetic variations with unclear clinical significance. This population-based study will help to close this critical knowledge gap through a multidisciplinary cohort study of children with and without genomic copy number variants (CNVs) diagnosed before birth. By comparing children with prenatally-ascertained CNVs to children without a CNV, we aim to (1) examine their developmental, social-emotional and health status; (2) measure the impact of prenatal diagnosis of a CNV on maternal perceptions of child health, behavior and development; and (3) determine the proportion of prenatally-ascertained CNVs of unknown or uncertain significance that are reclassified as benign or pathogenic after 2 or more years. METHODS: This study will establish and follow up a cohort of mother-child pairs who have had a prenatal diagnosis with a chromosomal microarray from 2013-2019 in the Australian state of Victoria. Children aged 12 months to 7 years will be assessed using validated, age-appropriate measures. The primary outcome measures will be the Wechsler Preschool and Primary Scale of Intelligence IV (WPSSI-IV) IQ score (2.5 to 7 year old's), the Ages and Stages Questionnaire (12-30 months old), and the Brief Infant- Toddler Social and Emotional Assessment (BITSEA) score. Clinical assessment by a pediatrician will also be performed. Secondary outcomes will be scores obtained from the: Vineland Adaptive Behavior Scale, Maternal Postnatal Attachment Questionnaire, the Vulnerable Child Scale, Profile of Mood States, Parent Sense of Competence Scale. A descriptive analysis of the reclassification rates of CNVs after ≥2 years will be performed. DISCUSSION: This study protocol describes the first Australian cohort study following children after prenatal diagno
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- 2021
31. Collaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia
- Author
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Hui, L, Marzan, MB, Potenza, S, Rolnik, DL, Said, JM, Palmer, KR, Whitehead, CL, Sheehan, PM, Ford, J, Pritchard, N, Mol, BW, Walker, SP, Hui, L, Marzan, MB, Potenza, S, Rolnik, DL, Said, JM, Palmer, KR, Whitehead, CL, Sheehan, PM, Ford, J, Pritchard, N, Mol, BW, and Walker, SP
- Abstract
BACKGROUND: The COVID-19 pandemic has resulted in a range of unprecedented disruptions to maternity care with documented impacts on perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne has endured one of the longest and most stringent lockdowns in globally. This paper presents the protocol for a multicentre study to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic. METHODS: Multicentre observational study analysing monthly deidentified maternal and newborn outcomes from births >20 weeks at all 12 public maternity services in Melbourne. Data will be merged centrally to analyse outcomes and create run charts according to established methods for detecting non-random 'signals' in healthcare. Perinatal outcomes will include weekly rates of total births, stillbirths, preterm births, neonatal intensive care admissions, low Apgar scores and fetal growth restriction. Maternal outcomes will include weekly rates of: induced labour, caesarean section, births before arrival to hospital, postpartum haemorrhage, length of stay, general anaesthesia for caesarean birth, influenza and COVID-19 vaccination status, and gestation at first antenatal visit. A prepandemic median for all outcomes will be calculated for the period of January 2018 to March 2020. A significant shift is defined as ≥6 consecutive weeks, all above or below the prepandemic median. Additional statistical analyses such as regression, time series and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests. ETHICS AND DISSEMINATION: Ethics approval for the collaborative maternity and newborn dashboard project has been obtained from the Austin Health (HREC/64722/Austin-2020) and Mercy Health (ref. 2020-031). TRIAL REGISTRATION NUMBER: ACTRN12620000878976; Pre-results.
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- 2021
32. Evidence and advocacy in Melbourne maternity care during the COVID-19 pandemic
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Hui, L, Whitehead, C, Walker, SP, Hui, L, Whitehead, C, and Walker, SP
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- 2021
33. Business as usual during the COVID-19 pandemic? Reflections on state-wide trends in maternity telehealth consultations during lockdown in Victoria and New South Wales
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Potenza, S, Marzan, MB, Rolnik, DL, Palmer, K, Said, J, Whitehead, C, Sheehan, P, Mo, BW, Walker, S, Hui, L, Potenza, S, Marzan, MB, Rolnik, DL, Palmer, K, Said, J, Whitehead, C, Sheehan, P, Mo, BW, Walker, S, and Hui, L
- Abstract
COVID-19 has resulted in unprecedented changes to maternity care across Australia. This study aims to analyse trends in maternity consultations and the uptake of telehealth in Victoria and New South Wales (NSW) since the first restrictions to reduce COVID-19 transmission were implemented. From March 2020 to April 2021, a higher proportion of antenatal care consultations was delivered via telehealth in Victoria compared to NSW (13.8% vs 7.4%, P < 0.0001). Uptake of telehealth and a shift from in-person care has been a major contributor to maintaining pregnancy care during pandemic restrictions. However, further research is required to understand women's perspectives and health outcomes.
- Published
- 2021
34. Pre-natal and post-natal diagnosis of congenital upper limb differences: The first 3 years of the Australian Hand Difference Register
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O'Keefe, D, Kennedy, J, McCombe, D, Coombs, C, Hui, L, Wilks, D, Halliday, J, O'Keefe, D, Kennedy, J, McCombe, D, Coombs, C, Hui, L, Wilks, D, and Halliday, J
- Abstract
AIMS: Children with a congenital upper limb difference (CoULD) are a diverse group who often require multidisciplinary care and long-term support for functional and social impacts. The Australian Hand Difference Register (AHDR) provides a national database of children born with a CoULD and aims to facilitate research and improve health care for affected children. Using data from the first 3 years of its operation, we analysed the demographic and clinical features of participating families, including type of CoULDs and the frequency of pre-natal and syndromic diagnoses. METHODS: Families were recruited from tertiary plastic surgery, orthopaedic and genetics clinics, as well as by self-referral. Hand differences were classified by the consulting physician according to the Oberg-Manske-Tonkin classification system. Primary carers were invited to complete an online questionnaire covering demographic information, pregnancy and newborn outcomes and diagnostic details. RESULTS: Between August 2017 and September 2020, 822 families consented and 320 questionnaires were reviewed. CoULDs were detected pre-natally in 66 (20.6%) and post-natally in 248 children (77.5%); data for 6 (1.9%) children were missing. The most common CoULDs were radial polydactyly, symbrachydactyly with ectodermal elements and radial longitudinal deficiency, hypoplastic thumb. Twenty-seven children (8.4%) had an associated syndrome, 7 diagnosed pre-natally and 19 post-natally; the most common were VACTERL association, Poland anomaly, Holt-Oram and ectrodactyly-ectodermal dysplasia-clefting syndromes. CONCLUSIONS: The AHDR is a valuable resource for understanding the relative frequencies of CoULDs. Participation will assist future research into the diagnostic journeys of children with CoULDs, including risk factors, diagnosis and psychosocial impacts.
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- 2021
35. A systematic review of maternal TORCH serology as a screen for suspected fetal infection
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Fitzpatrick, D, Holmes, NE, Hui, L, Fitzpatrick, D, Holmes, NE, and Hui, L
- Abstract
BACKGROUND: The acronym 'TORCH' refers to well-recognised causes of perinatal infections: toxoplasmosis, rubella, cytomegalovirus (CMV) and herpes simplex virus (HSV). A TORCH serology panel is often used to test for maternal primary infection following detection of ultrasound abnormalities in pregnancy. AIM: This review aims to estimate the diagnostic yield of maternal TORCH serology in pregnancy following fetal ultrasound abnormalities. MATERIALS AND METHODS: Primary studies published since 2000 that assessed maternal TORCH serology for suspected fetal infection and included information on indications for testing, definition of positive TORCH serology results, and perinatal outcomes were included. RESULTS: Eight studies with a total of 2538 pregnancies were included. The main indications for testing were polyhydramnios, fetal growth restriction and hyperechogenic bowel. There were 26 confirmed cases of congenital CMV, of which 15 had multiple ultrasound abnormalities. There were no cases of congenital toxoplasmosis, rubella or HSV confirmed in any of the eight studies. CONCLUSIONS: The clinical utility of TORCH serology for non-specific ultrasound abnormalities such as isolated fetal growth restriction or isolated polyhydramnios is low. It is time to retire the TORCH acronym and the reflex ordering of 'TORCH' panels, as their continued use obscures, rather than illuminates, appropriate investigation for fetal ultrasound abnormalities.
- Published
- 2021
36. The predicted clinical workload associated with early post-term surveillance and inductions of labour in south Asian women in a non-tertiary hospital setting
- Author
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Green, B, Howat, P, Hui, L, Green, B, Howat, P, and Hui, L
- Abstract
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.
- Published
- 2021
37. A minimum estimate of the prevalence of 22q11 deletion syndrome and other chromosome abnormalities in a combined prenatal and postnatal cohort.
- Author
-
Martin N., Howden A., McCoy R., Costa F.D.S., Menezes M., Palma-Dias R., Nisbet D., Bethune M., Halliday J., Poulakis Z., Hui L., Poulton A., Kluckow E., Lindquist A., Hutchinson B., Pertile M.D., Bonacquisto L., Gugasyan L., Kulkarni A., Harraway J., Martin N., Howden A., McCoy R., Costa F.D.S., Menezes M., Palma-Dias R., Nisbet D., Bethune M., Halliday J., Poulakis Z., Hui L., Poulton A., Kluckow E., Lindquist A., Hutchinson B., Pertile M.D., Bonacquisto L., Gugasyan L., Kulkarni A., and Harraway J.
- Abstract
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 performe
- Published
- 2020
38. Whole Exome Sequencing (WES) enhances the diagnostic rate of perinatal autopsy: A prospective clinical utility trial with implications for prenatal diagnosis.
- Author
-
Teoh M., Dao C., Davis T., Hui L., Rowlands S., Walker S., Lynch E., Martyn M., Chong B., Gaff C., Lunke S., Collett J., McGillivray G., Chan F., Yeung A., Vasudevan A., Stark Z., Prystupa S., Chan Y., Leong T., Ireland-Jenkin K., Fawcett S., Graetz M., Rose K., Ayres S., Jarmolowicz A., Brett G., Prawer Y., Chalinor H., Teoh M., Dao C., Davis T., Hui L., Rowlands S., Walker S., Lynch E., Martyn M., Chong B., Gaff C., Lunke S., Collett J., McGillivray G., Chan F., Yeung A., Vasudevan A., Stark Z., Prystupa S., Chan Y., Leong T., Ireland-Jenkin K., Fawcett S., Graetz M., Rose K., Ayres S., Jarmolowicz A., Brett G., Prawer Y., and Chalinor H.
- Abstract
Genomic classification is rapidly becoming a routine and integral part of diagnosis in pathology. Perinatal pathology is following this trend. The aims of this study were to determine the utility of WES in perinatal autopsy for congenital anomalies and to model the outcome of WES as a prenatal test. A total of 131 probands with congenital anomalies who underwent post mortem examination were referred by pathologists to the study. 82 probands were considered suitable for sequencing. The parents of 5 declined enrolment and 10 could not be consented. 67 probands were enrolled. Autopsy identified specific diagnoses in 11 cases (17%). WES identified specific diagnoses ('pathogenic' or 'likely pathogenic' variants) in 23 cases - a diagnostic rate of 35%. The combined diagnostic rate of autopsy and sequencing was 38%. A geneticist blinded to the autopsy findings reviewed the probands' antenatal imaging reports and recommended a gene list to model the clinical utility of prenatal WES. The use of antenatal sequencing in this cohort would have identified a specific diagnosis in 18 of the 23 cases with positive sequencing findings. In conclusion, WES doubles the diagnostic rate of autopsy for congenital anomalies and our data supports the prenatal use of genomic sequencing.Copyright © 2020
- Published
- 2020
39. Statewide performance of traditional and cell-free DNA-based prenatal testing pathways: The Victorian Perinatal Record Linkage (PeRL) study.
- Author
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Martin N., Poulton A., Lindquist A., Kluckow E., Hutchinson B., Pertile M., Bonacquisto L., Gugasyan L., Kulkarni A., Harraway J., Howden A., Hui L., Halliday J., Poulakis Z., Bethune M., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., Nisbet D., Martin N., Poulton A., Lindquist A., Kluckow E., Hutchinson B., Pertile M., Bonacquisto L., Gugasyan L., Kulkarni A., Harraway J., Howden A., Hui L., Halliday J., Poulakis Z., Bethune M., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., and Nisbet D.
- Abstract
Introduction: This study aimed to ascertain the real-world utilisation and performance of various prenatal screening pathways, and to report the numbers of major chromosome abnormalities detected after a low-risk screening result. Method(s): Retrospective study of women resident in Victoria, Australia, undergoing screening or prenatal diagnosis in 2015. Patient-funded cell-free (cf) DNA referrals were merged with statewide results for combined frst-trimester screening (CFTS), second-trimester serum screening (STSS) and invasive diagnostic procedures. Postnatal cytogenetic were used to ascertain cases of false-negative screening results. Individual record linkage was performed with LinkageWizTM. Result(s): In 2015, 66146 women accessed at least one form of aneuploidy screening. Of the 61810 (94.6%) women with complete linkage data, 20.1% used cfDNA as their primary screen; 73.2% used CFTS alone; 5.3% had STSS, and 1.3% used both CFTS and cfDNA. CFTS had a combined sensitivity for trisomies 21/13/18 of 85.29% (95% CI 77.15-90.88) for a screen-positive rate (SPR) of 2.94%; cfDNA screening had 100% (95% CI 93.47-100.0) sensitivity and a 1.21% SPR for trisomies 21/13/18. The risk of any major chromosome abnormality after a low risk screening result was 1 in 1188 for CFTS and 1 in 717 for cfDNA (p = 0.08). Discussion(s): In 2015, 1 in 5 Victorian women chose self-funded cfDNA as a frst-line test. While the sensitivity of cfDNA for trisomies 21/18/13 was superior to CFTS, there was no statistically signifcant diference in the risk of any major chromosome abnormality after low-risk CFTS or cfDNA result.
- Published
- 2020
40. State-wide performance of traditional and cell-free DNA based prenatal testing pathways: The Victorian Perinatal Record Linkage (PeRL) study.
- Author
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Poulakis Z., Pertile M.D., Gugasyan L., Kulkarni A., Harraway J., Howden A., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., Nisbet D., Martin N., Bethune M., Halliday J., Hui L., Lindquist A., Poulton A., Kluckow E., Hutchinson B., Bonacquisto L., Poulakis Z., Pertile M.D., Gugasyan L., Kulkarni A., Harraway J., Howden A., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., Nisbet D., Martin N., Bethune M., Halliday J., Hui L., Lindquist A., Poulton A., Kluckow E., Hutchinson B., and Bonacquisto L.
- Abstract
Objectives: To perform individual record-linkage of women undergoing prenatal screening and/or prenatal and postnatal diagnosis to analyse the performance of different screening strategies, and report the residual risks of any major chromosome abnormality following a low risk result. Method(s): Retrospective study of women resident in Victoria, Australia, undergoing screening or prenatal diagnosis in 2015. Patientfunded cell-free (cf) DNA referrals from multiple providers were merged with statewide results for combined first trimester screening (CFTS), second trimester serum screening (STSS) and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain cases of false negative screening results. Individual record-linkage was performed with LinkageWizTM and statistical analyses with STATA v14.0. Result(s): In 2015, 66,146 women (83.6% total births) accessed at least one form of aneuploidy screening. Of the 61,810 (94.6%) women with complete linkage data, 20.1% used cfDNA as their primary screen; 73.2% used CFTS alone; 5.3% had STSS, and 1.3% used both CFTS and cfDNA. Of women with a high risk CFTS result (>1 in 300), 11.6% (178) had additional screening with cfDNA and of these, 10 had fetal aneuploidy confirmed on prenatal diagnosis. CFTS had a combined sensitivity for trisomies 21/13/18 of 87.95% (95% CI 79.22-93.32) for a screen positive rate (SPR) of 2.94%; cfDNA screening had 100% (95% CI 93.47-100.0) sensitivity and a 1.21% SPR for trisomies 21/13/18. When high risk cfDNA results for any chromosome abnormality and failed cfDNA tests were treated as screen positives, the SPR increased to 2.42%. The risk of any major chromosome abnormality after a low risk screening result was 1 in 1188 for CFTS and 1 in 717 for cfDNA (p = 0.08). Conclusion(s): In a population with primary screening with government-subsidized CFTS or self-funded cfDNA available, approximately 1 in 5 women chos
- Published
- 2020
41. Association between timing of diagnosis of trisomy 21, 18, and 13 and maternal socioeconomic status in Victoria, Australia: A population-based cohort study from 2015 to 2016.
- Author
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Nisbet D., Menezes M., Palma-Dias R., Hui L., Kluckow E., Halliday J., Poulton A., Lindquist A., Hutchinson B., Bethune M., Bonacquisto L., Da Silva Costa F., Gugasyan L., Harraway J., Howden A., Kulkarni A., Martin N., Poulakis Z., Pertile M.D., McCoy R., Nisbet D., Menezes M., Palma-Dias R., Hui L., Kluckow E., Halliday J., Poulton A., Lindquist A., Hutchinson B., Bethune M., Bonacquisto L., Da Silva Costa F., Gugasyan L., Harraway J., Howden A., Kulkarni A., Martin N., Poulakis Z., Pertile M.D., and McCoy R.
- Abstract
Objectives: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age and socioeconomic status (SES). Method(s): Retrospective study of all prenatal and postnatal cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13) in Victoria, Australia, in 2015-16, stratified by timing of diagnosis (prenatal <17 weeks gestation, prenatal > 17 weeks gestation, postnatal <12 months of age), maternal age and SES region (as assigned by postcode). Utilisation of prenatal testing following a liveborn T21 infant was ascertained via record linkage. Result(s): There were 160,230 total births and 817 diagnoses of T21 (n = 571), T18 (n = 139) and T13 (n = 107). The overall and livebirth prevalences of T21 were 3.56 and 0.47 per 1000 births, respectively. Compared with women from disadvantaged SES regions, women from advantaged SES regions were more likely to have a prenatal diagnosis of a trisomy before 17 weeks than after 17 weeks (p < 0.01) and less likely to have a liveborn T21 infant than a prenatal diagnosis (p < 0.01). There was a significant trend to higher livebirth rates of T21 with lower SES (p = 0.004). The majority (68.5%) of women who gave birth to a live infant with T21 did not utilise any prenatal screening or diagnostic testing. Conclusion(s): There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher livebirth rate of T21 in Victoria, Australia. The majority of livebirths with T21 were not preceded by any prenatal screening, suggesting significant disparities in utilization according to maternal SES.
- Published
- 2020
42. 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.
- Author
-
Nisbet D., Hui L., Poulakis Z., Pertile M.D., Kluckow E., Halliday J., Poulton A., Palma-Dias R., Lindquist A., Hutchinson B., Bethune M., Bonacquisto L., Da Silva Costa F., Gugasyan L., Harraway J., Howden A., Kulkarni A., Martin N., McCoy R., Menezes M., Nisbet D., Hui L., Poulakis Z., Pertile M.D., Kluckow E., Halliday J., Poulton A., Palma-Dias R., Lindquist A., Hutchinson B., Bethune M., Bonacquisto L., Da Silva Costa F., Gugasyan L., Harraway J., Howden A., Kulkarni A., Martin N., McCoy R., and Menezes M.
- Abstract
Objectives: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age, and socio-economic status (SES). Design(s): 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. Result(s): 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(s): There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher live birth rate of T21 in Victoria.Copyright © 2019 John Wiley & Sons, Ltd.
- Published
- 2020
43. Exome sequencing enhances the diagnostic rate of perinatal autopsy: A prospective multicentre clinical utility trial with implications for prenatal diagnosis.
- Author
-
Belinda C., Martyn M., Gaff C., Collett J., Lunke S., McGillivray G., Chan F., Yeung A., Anand V., Stark Z., Prystupa S., Chan Y., Trishe L., Ireland-Jenkin K., Fawcett S., Graetz M., Rose K., Ayres S., Jarmolowicz A., Brett G., Prawer Y., Chalinor H., Dao C., Davis T., Hui L., Teoh M., Rowlands S., Walker S., Lynch E., Belinda C., Martyn M., Gaff C., Collett J., Lunke S., McGillivray G., Chan F., Yeung A., Anand V., Stark Z., Prystupa S., Chan Y., Trishe L., Ireland-Jenkin K., Fawcett S., Graetz M., Rose K., Ayres S., Jarmolowicz A., Brett G., Prawer Y., Chalinor H., Dao C., Davis T., Hui L., Teoh M., Rowlands S., Walker S., and Lynch E.
- Abstract
Objectives: To determine the utility of exome sequencing as an adjunct to perinatal post mortem for congenital anomalies. To model the likely outcome of exome sequencing as a prenatal test in the same setting. Method(s): Probands with congenital anomalies were referred by perinatal pathologists. They were enrolled for sequencing if their microarray analysis was negative and their anomalies were considered to have a monogenic cause. Singleton or trio exome sequencing was performed as an adjunct to routine perinatal autopsy and the diagnostic outcomes were compared. A geneticist independently reviewed the probands' antenatal imaging findings and recommended a phenotype specific gene list to model the clinical utility of prenatal exome sequencing. Result(s): A prospective cohort of 131 probands was referred. Fortynine (37%) were unsuitable for inclusion. The parents of five (4%) declined enrolment and 10 (8%) could not be consented. Sixty-seven probands (52%) were enrolled. One proband could not be sequenced due to a degraded DNA sample. Results are available for 65 probands (32 singletons and 33 trios). Specific diagnoses were identified at autopsy in 11 cases (17%) including two cases with negative sequencing. Sequencing identified specific diagnoses ("pathogenic" or "likely pathogenic" variants) in 23 cases giving a diagnostic rate of 35%. The combined diagnostic rate of autopsy and exome was 38%. The individual autopsy and genomic diagnostic rates were highest in probands with significant skeletal findings (39% and 61% respectively, n = 18). Genomic diagnoses were obtained from 34% of singleton exomes, with segregation when required, and 36% of trio exomes. Variants of uncertain significance (VUS) were reported in 13 cases (20%). In four, a strong phenotype-genotype match together with plausible candidate variants indicated a need for additional studies. The combined rate of diagnostic or suspicious variants was 42%. The use of antenatal sequencing in this cohort u
- Published
- 2020
44. A minimum estimate of the prevalence of 22q11 deletion syndrome and other chromosome abnormalities in a combined prenatal and postnatal cohort.
- Author
-
Martin N., Howden A., McCoy R., Costa F.D.S., Menezes M., Palma-Dias R., Nisbet D., Bethune M., Halliday J., Poulakis Z., Hui L., Poulton A., Kluckow E., Lindquist A., Hutchinson B., Pertile M.D., Bonacquisto L., Gugasyan L., Kulkarni A., Harraway J., Martin N., Howden A., McCoy R., Costa F.D.S., Menezes M., Palma-Dias R., Nisbet D., Bethune M., Halliday J., Poulakis Z., Hui L., Poulton A., Kluckow E., Lindquist A., Hutchinson B., Pertile M.D., Bonacquisto L., Gugasyan L., Kulkarni A., and Harraway J.
- Abstract
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 performe
- Published
- 2020
45. Whole Exome Sequencing (WES) enhances the diagnostic rate of perinatal autopsy: A prospective clinical utility trial with implications for prenatal diagnosis.
- Author
-
Teoh M., Dao C., Davis T., Hui L., Rowlands S., Walker S., Lynch E., Martyn M., Chong B., Gaff C., Lunke S., Collett J., McGillivray G., Chan F., Yeung A., Vasudevan A., Stark Z., Prystupa S., Chan Y., Leong T., Ireland-Jenkin K., Fawcett S., Graetz M., Rose K., Ayres S., Jarmolowicz A., Brett G., Prawer Y., Chalinor H., Teoh M., Dao C., Davis T., Hui L., Rowlands S., Walker S., Lynch E., Martyn M., Chong B., Gaff C., Lunke S., Collett J., McGillivray G., Chan F., Yeung A., Vasudevan A., Stark Z., Prystupa S., Chan Y., Leong T., Ireland-Jenkin K., Fawcett S., Graetz M., Rose K., Ayres S., Jarmolowicz A., Brett G., Prawer Y., and Chalinor H.
- Abstract
Genomic classification is rapidly becoming a routine and integral part of diagnosis in pathology. Perinatal pathology is following this trend. The aims of this study were to determine the utility of WES in perinatal autopsy for congenital anomalies and to model the outcome of WES as a prenatal test. A total of 131 probands with congenital anomalies who underwent post mortem examination were referred by pathologists to the study. 82 probands were considered suitable for sequencing. The parents of 5 declined enrolment and 10 could not be consented. 67 probands were enrolled. Autopsy identified specific diagnoses in 11 cases (17%). WES identified specific diagnoses ('pathogenic' or 'likely pathogenic' variants) in 23 cases - a diagnostic rate of 35%. The combined diagnostic rate of autopsy and sequencing was 38%. A geneticist blinded to the autopsy findings reviewed the probands' antenatal imaging reports and recommended a gene list to model the clinical utility of prenatal WES. The use of antenatal sequencing in this cohort would have identified a specific diagnosis in 18 of the 23 cases with positive sequencing findings. In conclusion, WES doubles the diagnostic rate of autopsy for congenital anomalies and our data supports the prenatal use of genomic sequencing.Copyright © 2020
- Published
- 2020
46. Statewide performance of traditional and cell-free DNA-based prenatal testing pathways: The Victorian Perinatal Record Linkage (PeRL) study.
- Author
-
Martin N., Poulton A., Lindquist A., Kluckow E., Hutchinson B., Pertile M., Bonacquisto L., Gugasyan L., Kulkarni A., Harraway J., Howden A., Hui L., Halliday J., Poulakis Z., Bethune M., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., Nisbet D., Martin N., Poulton A., Lindquist A., Kluckow E., Hutchinson B., Pertile M., Bonacquisto L., Gugasyan L., Kulkarni A., Harraway J., Howden A., Hui L., Halliday J., Poulakis Z., Bethune M., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., and Nisbet D.
- Abstract
Introduction: This study aimed to ascertain the real-world utilisation and performance of various prenatal screening pathways, and to report the numbers of major chromosome abnormalities detected after a low-risk screening result. Method(s): Retrospective study of women resident in Victoria, Australia, undergoing screening or prenatal diagnosis in 2015. Patient-funded cell-free (cf) DNA referrals were merged with statewide results for combined frst-trimester screening (CFTS), second-trimester serum screening (STSS) and invasive diagnostic procedures. Postnatal cytogenetic were used to ascertain cases of false-negative screening results. Individual record linkage was performed with LinkageWizTM. Result(s): In 2015, 66146 women accessed at least one form of aneuploidy screening. Of the 61810 (94.6%) women with complete linkage data, 20.1% used cfDNA as their primary screen; 73.2% used CFTS alone; 5.3% had STSS, and 1.3% used both CFTS and cfDNA. CFTS had a combined sensitivity for trisomies 21/13/18 of 85.29% (95% CI 77.15-90.88) for a screen-positive rate (SPR) of 2.94%; cfDNA screening had 100% (95% CI 93.47-100.0) sensitivity and a 1.21% SPR for trisomies 21/13/18. The risk of any major chromosome abnormality after a low risk screening result was 1 in 1188 for CFTS and 1 in 717 for cfDNA (p = 0.08). Discussion(s): In 2015, 1 in 5 Victorian women chose self-funded cfDNA as a frst-line test. While the sensitivity of cfDNA for trisomies 21/18/13 was superior to CFTS, there was no statistically signifcant diference in the risk of any major chromosome abnormality after low-risk CFTS or cfDNA result.
- Published
- 2020
47. 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.
- Author
-
Nisbet D., Hui L., Poulakis Z., Pertile M.D., Kluckow E., Halliday J., Poulton A., Palma-Dias R., Lindquist A., Hutchinson B., Bethune M., Bonacquisto L., Da Silva Costa F., Gugasyan L., Harraway J., Howden A., Kulkarni A., Martin N., McCoy R., Menezes M., Nisbet D., Hui L., Poulakis Z., Pertile M.D., Kluckow E., Halliday J., Poulton A., Palma-Dias R., Lindquist A., Hutchinson B., Bethune M., Bonacquisto L., Da Silva Costa F., Gugasyan L., Harraway J., Howden A., Kulkarni A., Martin N., McCoy R., and Menezes M.
- Abstract
Objectives: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age, and socio-economic status (SES). Design(s): 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. Result(s): 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(s): There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher live birth rate of T21 in Victoria.Copyright © 2019 John Wiley & Sons, Ltd.
- Published
- 2020
48. Association between timing of diagnosis of trisomy 21, 18, and 13 and maternal socioeconomic status in Victoria, Australia: A population-based cohort study from 2015 to 2016.
- Author
-
Nisbet D., Menezes M., Palma-Dias R., Hui L., Kluckow E., Halliday J., Poulton A., Lindquist A., Hutchinson B., Bethune M., Bonacquisto L., Da Silva Costa F., Gugasyan L., Harraway J., Howden A., Kulkarni A., Martin N., Poulakis Z., Pertile M.D., McCoy R., Nisbet D., Menezes M., Palma-Dias R., Hui L., Kluckow E., Halliday J., Poulton A., Lindquist A., Hutchinson B., Bethune M., Bonacquisto L., Da Silva Costa F., Gugasyan L., Harraway J., Howden A., Kulkarni A., Martin N., Poulakis Z., Pertile M.D., and McCoy R.
- Abstract
Objectives: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age and socioeconomic status (SES). Method(s): Retrospective study of all prenatal and postnatal cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13) in Victoria, Australia, in 2015-16, stratified by timing of diagnosis (prenatal <17 weeks gestation, prenatal > 17 weeks gestation, postnatal <12 months of age), maternal age and SES region (as assigned by postcode). Utilisation of prenatal testing following a liveborn T21 infant was ascertained via record linkage. Result(s): There were 160,230 total births and 817 diagnoses of T21 (n = 571), T18 (n = 139) and T13 (n = 107). The overall and livebirth prevalences of T21 were 3.56 and 0.47 per 1000 births, respectively. Compared with women from disadvantaged SES regions, women from advantaged SES regions were more likely to have a prenatal diagnosis of a trisomy before 17 weeks than after 17 weeks (p < 0.01) and less likely to have a liveborn T21 infant than a prenatal diagnosis (p < 0.01). There was a significant trend to higher livebirth rates of T21 with lower SES (p = 0.004). The majority (68.5%) of women who gave birth to a live infant with T21 did not utilise any prenatal screening or diagnostic testing. Conclusion(s): There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher livebirth rate of T21 in Victoria, Australia. The majority of livebirths with T21 were not preceded by any prenatal screening, suggesting significant disparities in utilization according to maternal SES.
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- 2020
49. State-wide performance of traditional and cell-free DNA based prenatal testing pathways: The Victorian Perinatal Record Linkage (PeRL) study.
- Author
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Poulakis Z., Pertile M.D., Gugasyan L., Kulkarni A., Harraway J., Howden A., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., Nisbet D., Martin N., Bethune M., Halliday J., Hui L., Lindquist A., Poulton A., Kluckow E., Hutchinson B., Bonacquisto L., Poulakis Z., Pertile M.D., Gugasyan L., Kulkarni A., Harraway J., Howden A., McCoy R., Da Silva Costa F., Menezes M., Palma-Dias R., Nisbet D., Martin N., Bethune M., Halliday J., Hui L., Lindquist A., Poulton A., Kluckow E., Hutchinson B., and Bonacquisto L.
- Abstract
Objectives: To perform individual record-linkage of women undergoing prenatal screening and/or prenatal and postnatal diagnosis to analyse the performance of different screening strategies, and report the residual risks of any major chromosome abnormality following a low risk result. Method(s): Retrospective study of women resident in Victoria, Australia, undergoing screening or prenatal diagnosis in 2015. Patientfunded cell-free (cf) DNA referrals from multiple providers were merged with statewide results for combined first trimester screening (CFTS), second trimester serum screening (STSS) and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain cases of false negative screening results. Individual record-linkage was performed with LinkageWizTM and statistical analyses with STATA v14.0. Result(s): In 2015, 66,146 women (83.6% total births) accessed at least one form of aneuploidy screening. Of the 61,810 (94.6%) women with complete linkage data, 20.1% used cfDNA as their primary screen; 73.2% used CFTS alone; 5.3% had STSS, and 1.3% used both CFTS and cfDNA. Of women with a high risk CFTS result (>1 in 300), 11.6% (178) had additional screening with cfDNA and of these, 10 had fetal aneuploidy confirmed on prenatal diagnosis. CFTS had a combined sensitivity for trisomies 21/13/18 of 87.95% (95% CI 79.22-93.32) for a screen positive rate (SPR) of 2.94%; cfDNA screening had 100% (95% CI 93.47-100.0) sensitivity and a 1.21% SPR for trisomies 21/13/18. When high risk cfDNA results for any chromosome abnormality and failed cfDNA tests were treated as screen positives, the SPR increased to 2.42%. The risk of any major chromosome abnormality after a low risk screening result was 1 in 1188 for CFTS and 1 in 717 for cfDNA (p = 0.08). Conclusion(s): In a population with primary screening with government-subsidized CFTS or self-funded cfDNA available, approximately 1 in 5 women chos
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- 2020
50. Exome sequencing enhances the diagnostic rate of perinatal autopsy: A prospective multicentre clinical utility trial with implications for prenatal diagnosis.
- Author
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Belinda C., Martyn M., Gaff C., Collett J., Lunke S., McGillivray G., Chan F., Yeung A., Anand V., Stark Z., Prystupa S., Chan Y., Trishe L., Ireland-Jenkin K., Fawcett S., Graetz M., Rose K., Ayres S., Jarmolowicz A., Brett G., Prawer Y., Chalinor H., Dao C., Davis T., Hui L., Teoh M., Rowlands S., Walker S., Lynch E., Belinda C., Martyn M., Gaff C., Collett J., Lunke S., McGillivray G., Chan F., Yeung A., Anand V., Stark Z., Prystupa S., Chan Y., Trishe L., Ireland-Jenkin K., Fawcett S., Graetz M., Rose K., Ayres S., Jarmolowicz A., Brett G., Prawer Y., Chalinor H., Dao C., Davis T., Hui L., Teoh M., Rowlands S., Walker S., and Lynch E.
- Abstract
Objectives: To determine the utility of exome sequencing as an adjunct to perinatal post mortem for congenital anomalies. To model the likely outcome of exome sequencing as a prenatal test in the same setting. Method(s): Probands with congenital anomalies were referred by perinatal pathologists. They were enrolled for sequencing if their microarray analysis was negative and their anomalies were considered to have a monogenic cause. Singleton or trio exome sequencing was performed as an adjunct to routine perinatal autopsy and the diagnostic outcomes were compared. A geneticist independently reviewed the probands' antenatal imaging findings and recommended a phenotype specific gene list to model the clinical utility of prenatal exome sequencing. Result(s): A prospective cohort of 131 probands was referred. Fortynine (37%) were unsuitable for inclusion. The parents of five (4%) declined enrolment and 10 (8%) could not be consented. Sixty-seven probands (52%) were enrolled. One proband could not be sequenced due to a degraded DNA sample. Results are available for 65 probands (32 singletons and 33 trios). Specific diagnoses were identified at autopsy in 11 cases (17%) including two cases with negative sequencing. Sequencing identified specific diagnoses ("pathogenic" or "likely pathogenic" variants) in 23 cases giving a diagnostic rate of 35%. The combined diagnostic rate of autopsy and exome was 38%. The individual autopsy and genomic diagnostic rates were highest in probands with significant skeletal findings (39% and 61% respectively, n = 18). Genomic diagnoses were obtained from 34% of singleton exomes, with segregation when required, and 36% of trio exomes. Variants of uncertain significance (VUS) were reported in 13 cases (20%). In four, a strong phenotype-genotype match together with plausible candidate variants indicated a need for additional studies. The combined rate of diagnostic or suspicious variants was 42%. The use of antenatal sequencing in this cohort u
- Published
- 2020
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