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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

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.

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

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.

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.

Objectives: To create and analyse a population-based dataset of genomic tests performed on miscarriage, fetal, and infant samples in a state with >73,000 annual births. Method(s): Analysis of state-wide chromosome testing from Jan 2015 to Dec 2016, including all prenatal and postnatal samples including infants up to 12 months of age, was performed for: (i) the numbers and types of chromosome abnormalities present in miscarriage, prenatal diagnosis, and postnatal specimens; (ii) trends in chromosome abnormalities with advancing development; and (iii) the state-wide prevalence of the 22q11.2 deletion syndrome. Result(s): 8827 chromosomal analyses on 2573 miscarriage, 3661 prenatal, and 2593 postnatal samples were obtained. The majority (91.1%) were performed with whole genome SNP microarrays. The overall frequency of major chromosome abnormalities in the entire cohort was 28.4%. There was a significant decreasing trend in the percentage of chromosome abnormalities with later developmental stage from 51.0% to 21.3% to 16.2% in the miscarriage, prenatal and postnatal cohorts respectively (chi2 trend = 768.1, p < 0.0001). The total frequency of abnormalities in the live infant subgroup was 14.1%. The frequencies of pathogenic CNVs detected via CMA for the miscarriage and prenatal and postnatal cohorts were 2.8%, 2.3%, and 6.2%, respectively. There was a significant increasing trend in the frequency of pathogenic CNVs with later developmental stage (chi2 trend = 41.75, p < 0.0001). For the subgroup of live infants, the pathogenic CNV frequency on CMA analysis was 7.1%. There were 39 cases of 22q11.2 DS detected, including 1 miscarriage and 15 prenatal and 23 postnatal cases. After accounting for two cases of duplicate testing, and excluding the miscarriage case, the estimated prevalence of 22q11 DS was 1 in 4301 Victorian births. More than one third of diagnoses were confirmed during pregnancy. Conclusion(s): Our study marks a complete transition in genomic testing from t

OBJECTIVES: To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. METHOD(S): This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . RESULT(S): During the study period, there were 79140 births and 66166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n=61877) of women who underwent screening, and of these, 73.2% (n=45275) had CFTS alone, 20.2% (n=12486) had cfDNA alone; 5.3% (n=3268) had STSS alone, 1.3% (n=813) had both CFTS and cfDNA, and <0.1% (n=35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95%CI, 82.64-93.93%) for a screen-positive rate (SPR) of 2.94%. There were 12 false-negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95%CI, 95.00-100%) for a SPR of 1.21%. When high-risk cfDNA results for any chromosome (including the sex chromosomes) a

OBJECTIVES: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age, and socio-economic status (SES). DESIGN: Retrospective study of cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13) in Victoria, Australia, in 2015 to 2016, stratified by timing (prenatal less than 17 weeks gestation, prenatal including or greater than or 17 weeks gestation, and postnatal before 12 months of age), maternal age, and SES region. Utilisation of prenatal testing following a live-born T21 infant was ascertained via record linkage. RESULTS: Among 160 230 total births were 571 diagnoses of T21 and 246 of T18/T13. The overall and live birth prevalences of T21 were 3.56 and 0.47 per 1000 births, respectively. Compared with women from disadvantaged SES regions, women from high SES regions were more likely to have a prenatal diagnosis of a trisomy before 17 weeks than after (P < .01) and less likely to have a live-born T21 infant than a prenatal diagnosis (P < .01). There was a significant trend to higher live birth rates of T21 with lower SES (P = .004). The majority (68.5%) of women who gave birth to a live infant with T21 did not utilise prenatal testing. CONCLUSION: There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher live birth rate of T21 in Victoria.

OBJECTIVES: The purpose of this study was to determine whether measurement of the near-field lateral ventricular diameter can be reliably obtained within a practical time frame during second-trimester obstetric scans by angling the fetal head approximately 30degree away from the horizontal image axis such that the posterior aspect of the fetal head lies closer to the transducer. METHODS: Fifty consecutive singleton pregnancies presenting for a routine-second trimester scan were recruited for this study. The far-field lateral ventricular diameter was measured, followed by the near-field lateral ventricular diameter using the proposed technique. The measurements were repeated by a second operator who was blinded to the first measurement. Both operators recorded the measurements taken and scored the level of visibility of the near-field lateral ventricle. The difference between the two operators' measurements was compared by a kappa analysis. RESULTS: The near-field lateral ventricle was visualized in 49 of 50 cases (98%). There was no statistically significant difference in the measurement of the near-field lateral ventricular diameter by the two operators (P = .34). There was, however, a statistically significant difference in the time it took each operator to obtain the near-field measurement after the far-field measurement (P = .01). CONCLUSIONS: Manipulating the transducer to position the falx of the fetal head approximately 30degree away from the horizontal image axis allows the near-field lateral ventricle to be routinely visualized and measured with a high degree of interoperator agreement and within a practical time frame once the operator is experienced in performing the technique.

We report a rare case of large bilateral phaeochromocytomas in pregnancy, found coincidentally by ultrasonography at 26 weeks' gestation, in a woman with a family history of Von Hippel Lindau syndrome. Further, we report maternal and fetal serum and amniotic fluid phenoxybenzamine levels from this case.

Accurate determination of gestational age underpins good obstetric care. We assessed the performance of six existing ultrasound reference charts to determine gestational age in 1268 singleton IVF pregnancies, where "true" gestational age could be precisely calculated from date of fertilisation. All charts generated dates significantly different to IVF dates (P < 0.0001 all comparisons). Thus we generated a new reference chart, The Monash Chart, based on a line of best fit describing crown-rump length across 6 + 1 to 9 + 0 weeks of gestation (true gestational age) in the IVF singleton cohort. The Monash Chart, but none of the existing charts, accurately determined gestational age among an independent IVF twin cohort (185 twin pairs). When applied to 3052 naturally-conceived singletons scans, The Monash Chart generated estimated due dates that were different to all existing charts (P ≤ 0.004 all comparisons). We conclude that commonly used ultrasound reference charts have inaccuracies. We have generated a CRL reference chart based on true gestational age in an IVF cohort that can accurately determine gestational age at 6-9 weeks of gestation.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) target HIV-1 reverse transcriptase (RT) by binding to a pocket in RT that is close to, but distinct, from the DNA polymerase active site and prevent the synthesis of viral cDNA. NNRTIs, in particular, those that are potent inhibitors of RT polymerase activity, can also act as chemical enhancers of the enzyme's inter-subunit interactions. However, the consequences of this chemical enhancement effect on HIV-1 replication are not understood. Here, we show that the potent NNRTIs efavirenz, TMC120, and TMC125, but not nevirapine or delavirdine, inhibit the late stages of HIV-1 replication. These potent NNRTIs enhanced the intracellular processing of Gag and Gag-Pol polyproteins, and this was associated with a decrease in viral particle production from HIV-1-transfected cells. The increased polyprotein processing is consistent with premature activation of the HIV-1 protease by NNRTI-enhanced Gag-Pol multimerization through the embedded RT sequence. These findings support the view that Gag-Pol multimerization is an important step in viral assembly and demonstrate that regulation of Gag-Pol/Gag-Pol interactions is a novel target for small molecule inhibitors of HIV-1 production. Furthermore, these drugs can serve as useful probes to further understand processes involved in HIV-1 particle assembly and maturation.