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STUDY QUESTION Is cord blood DNA methylation associated with having been conceived by medically assisted reproduction? SUMMARY ANSWER This study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation. WHAT IS KNOWN ALREADY Medically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes. STUDY DESIGN, SIZE, DURATION We investigated the association of DNA methylation and medically assisted reproduction using a case–control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort). PARTICIPANTS/MATERIALS, SETTINGS, METHODS We assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls). MAIN RESULTS AND THE ROLE OF CHANCE The ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling. LIMITATIONS, REASONS FOR CAUTIONS While insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction. WIDER IMPLICATIONS OF THE FINDINGS Newborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health. STUDY FUNDING/COMPETING INTERESTS(S) This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union’s Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700. D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

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. METHODS: 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 12 months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . RESULTS: During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and

More than 7 million individuals have been conceived by Assisted Reproductive Technologies (ART) and there is clear evidence that ART is associated with a range of adverse early life outcomes, including rare imprinting disorders. The periconception period and early embryogenesis are associated with widespread epigenetic remodeling, which can be influenced by ART, with effects on the developmental trajectory in utero, and potentially on health throughout life. Here we profile genome-wide DNA methylation in blood collected in the newborn period and in adulthood (age 22–35 years) from a unique longitudinal cohort of ART-conceived individuals, previously shown to have no differences in health outcomes in early adulthood compared with non-ART-conceived individuals. We show evidence for specific ART-associated variation in methylation around birth, most of which occurred independently of embryo culturing. Importantly, ART-associated epigenetic variation at birth largely resolves by adulthood with no direct evidence that it impacts on development and health., Use of Assisted Reproductive Technologies (ART) is increasing globally but their impact on long term health remains unclear. Here the authors show that ART-conceived individuals show variation in epigenetic profile at birth that largely resolves by adulthood, with no evidence of an impact on long term outcomes.

Objective To determine the health outcomes for adults aged 22–35 years old who were conceived via assisted reproduction technology (ART) compared with adults of the same age conceived without use of ART. Design Cohort study. Setting Not applicable. Patient(s) Adult men and women aged 22–35 years who were conceived with and without use of ART. Intervention(s) Questionnaire and clinical review. Main Outcome Measure(s) Vascular structure (carotid artery intima-media thickness, pulse wave velocity), vascular function (blood pressure), metabolic markers (fasting blood glucose, insulin, and standard lipid profiles), anthropometric measurements, and respiratory function (spirometry). Result(s) The mean age of the 193 ART and 86 non-ART participants was 27.0 and 26.9 years, respectively. There were no substantial intragroup differences in demographics or vascular intermediate phenotypes, metabolic parameters, or anthropometric measures, before or after adjusting for perinatal factors and a quality of life measure with four domains. Diastolic blood pressure was lower in the ART men than the non-ART men (adjusted mean difference −4.4 mm Hg, 95% CI, −8.7 to −0.1). The ART group reported a higher prevalence of ever having asthma, (40.8% vs. 28.6%; odds ratio 1.7; 95% CI, 1.0–3.0), but expiratory flow rates were similar. Conclusion(s) This study of the health of 193 adults conceived via ART, the largest to date globally, found no evidence of increased vascular or cardiometabolic risk, or growth or respiratory problems in the ART group compared with a non-ART group from the same source population. Follow-up observation for reproductive and later-onset adverse health effects remains important.

To assess trends in ultrasound-indicated prenatal diagnostic testing performed over the past two decades in the Australian state of Victoria, in the context of rapidly changing practices in aneuploidy screening and chromosome analysis.This was a retrospective analysis of all ultrasound-indicated prenatal diagnostic testing (amniocentesis and chorionic villus sampling) performed in the state of Victoria between 1994 and 2016. Ultrasound indications for testing included: fetal structural abnormality, fetal death, fetal growth restriction, abnormal amniotic fluid volume, genetic 'soft marker' and unspecified ultrasound abnormality. Maternal age, indication for testing, type of diagnostic procedure, gestational age, type of chromosome analysis (G-banded karyotyping or chromosomal microarray (CMA)) and test results were obtained. Diagnostic yield (i.e. percentage of tests yielding a major abnormality) was analyzed by year, maternal age and gestational age. Statistical analysis was performed using the χDuring the 23-year study period, 1 533 317 births were recorded and 16 152 diagnostic procedures were performed for the primary indication of ultrasound abnormality. In recent years, ultrasound abnormality became the most common indication for prenatal invasive testing (29.4% of diagnostic tests between 2013 and 2016) due to a steep decline in testing for other indications such as positive result on combined first-trimester screening or advanced maternal age alone. In 2016, over 95% of ultrasound-indicated procedures were performed with CMA; among these, pathogenic copy number variant (CNV) was the most common (3.5%) abnormality detected, followed by trisomy 21 (2.8%). The diagnostic yield of ultrasound-indicated tests performed 16 weeks was significantly higher than that of tests performed after 20 weeks (31.5% vs 9.0%).Ultrasound-indicated invasive testing is contributing to prenatal diagnosis in new ways in the genomic era. A pathogenic CNV is now the most likely diagnosis after ultrasound-indicated testing, rather than trisomy 21 or other whole-chromosome aneuploidy. Despite steady improvements in first-trimester screening for aneuploidy, the diagnostic yield of ultrasound-indicated tests 20 weeks has remained stable due to increased utilization of CMA. Procedures performed for structural abnormalities 16 weeks continue to have the highest diagnostic yield, supporting the benefits of early fetal structural assessment at 11-13 weeks. Copyright © 2018 ISUOG. Published by John WileySons Ltd.

Background During the coronavirus disease 2019 (COVID-19) pandemic, concerns have been raised regarding the increased risk of perioperative mortality for patients with COVID-19, and the transmission risk to healthcare workers, especially during endonasal neurosurgical operations. The Pituitary Society has produced recommendations to guide management during this era. We sought to assess contemporary neurosurgical practice and the effects of COVID-19. Methods A multicenter prospective observational cohort study was conducted at 12 tertiary neurosurgical units (United Kingdom and Ireland). Data were collected from March 23 to July 31, 2020, inclusive. The data points collected included patient demographics, preoperative COVID-19 test results, operative modifications, and 30-day COVID-19 infection rates. Results A total of 124 patients were included. Of the 124 patients, 116 (94%) had undergone COVID-19 testing preoperatively (transsphenoidal approach, 97 of 105 [92%]; expanded endoscopic endonasal approach, 19 of 19 [100%]). One patient (1 of 116 [0.9%]) had tested positive for COVID-19 preoperatively, requiring a delay in surgery until the infection had been confirmed as resolved. Other than transient diabetes insipidus, no other complications were reported for this patient. All operating room staff had worn at least level 2 personal protective equipment. Adaptations to surgical techniques included minimizing drilling, draping modifications, and the use of a nasal iodine wash. At 30 days postoperatively, no evidence of COVID-19 infection (symptoms or positive formal testing results) were found in our cohort and no mortality had occurred. Conclusions Preoperative screening protocols and operative modifications have facilitated endonasal neurosurgery during the COVID-19 pandemic, with the Pituitary Society guidelines followed for most of these operations. We found no evidence of COVID-19 infection in our cohort and no mortality, supporting the use of risk mitigation strategies to continue endonasal neurosurgery in subsequent pandemic waves.

Background CRANIAL (CSF Rhinorrhoea After Endonasal Intervention to the Skull Base) is a prospective multicenter observational study seeking to determine 1) the scope of skull base repair methods used and 2) corresponding rates of postoperative cerebrospinal fluid (CSF) rhinorrhea in the endonasal transsphenoidal approach (TSA) and the expanded endonasal approach (EEA) for skull base tumors. We sought to pilot the project, assessing the feasibility and acceptability by gathering preliminary data. Methods A prospective observational cohort study was piloted at 12 tertiary neurosurgical units in the United Kingdom. Feedback regarding project positives and challenges were qualitatively analyzed. Results A total of 187 cases were included: 159 TSA (85%) and 28 EEA (15%). The most common diseases included pituitary adenomas (n = 142/187), craniopharyngiomas (n = 13/187). and skull base meningiomas (n = 4/187). The most common skull base repair techniques used were tissue glues (n = 132/187, most commonly Tisseel), grafts (n = 94/187, most commonly fat autograft or Spongostan) and vascularized flaps (n = 51/187, most commonly nasoseptal). These repairs were most frequently supported by nasal packs (n = 125/187) and lumbar drains (n = 20/187). Biochemically confirmed CSF rhinorrhea occurred in 6/159 patients undergoing TSA (3.8%) and 2/28 patients undergoing EEA (7.1%). Four patients undergoing TSA (2.5%) and 2 patients undergoing EEA (7.1%) required operative management for CSF rhinorrhea (CSF diversion or direct repair). Qualitative feedback was largely positive (themes included user-friendly and efficient data collection and strong support from senior team members), demonstrating acceptability. Conclusions Our pilot experience highlights the acceptability and feasibility of CRANIAL. There is a precedent for multicenter dissemination of this project, to establish a benchmark of contemporary practice in skull base neurosurgery, particularly with respect to patients undergoing EEA.

To determine the effect of pooling of patients for elective non-instrumented lumbar decompression on patient satisfaction and waiting times.We performed a retrospective review of Spine Tango and Theatre Databases of our Neurosurgical unit for patients who underwent elective primary non-instrumented lumbar decompression between January 2012 and 2016. Patient satisfaction scores at 3 and 12 months post-surgery were collected from the Spine Tango Registry, and patients categorised as pooled/non-pooled by searching theatre databases to determine their named listing and operating consultants. Results were analysed numerically and by performing chi-squared testing to determine if pooling affected patient satisfaction. Theatre records were analysed between January 2004-2006, January 2009-2011 and 2014-2016 to determine what effect implementation of the 18-week wait target system (2009) and of our pooled system (2012) had on waiting times to operation for patients undergoing elective primary non-instrumented lumbar decompression.There is no significant difference in patient satisfaction levels between pooled and non-pooled patients at 3 (p = .052) and 12 months (p = .5) post primary elective lumbar decompression (significance p .05). There was no difference in average waiting time between the pooled and non-pooled groups. Both setting of 18-week targets and pooling improved waiting times. Setting of 18-week targets affected average waiting times markedly while pooling most notably reduced the variability in waiting times between patients for the same procedure.Pooling of patients for elective non-instrumented lumbar decompression in our unit has improved waiting times, particularly the variability in them, with no detriment to patient satisfaction. We would recommend other units to consider developing a system of pooling such as ours, to help maximise use of their current resources and avoid highly variable waiting times for patients for the same procedure within the same department.

OBJECTIVE: To assess the impact of non-invasive prenatal testing (NIPT) on trends in the prenatal diagnosis of sex chromosome aneuploidy (SCA) in a population with >73,000 annual births. METHOD: Retrospective population-based cohort study from 1986-2016 of all women undergoing prenatal diagnosis before 25 weeks gestation in the Australian state of Victoria. Statistical significance was tested using the chi-square test for trend or proportions. RESULTS: There were 2,043,345 births and 842 SCA diagnoses from 1986-2016. The percentage of prenatal diagnostic tests leading to a SCA diagnosis increased significantly from 0.95% in 2010 to 2.93% in 2016 (p

The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recently recommended offering genetic counseling and diagnostic testing for enlarged nuchal translucency at ≥3.0 mm, regardless of previous negative screening with noninvasive prenatal testing.This study aimed to perform a population-based, individual record linkage study to determine the optimal definition of an enlarged nuchal translucency for the detection of atypical chromosome abnormalities.This was a retrospective study of women resident in Victoria, Australia, undergoing combined first-trimester screening during the 24-month period from January 2015 to December 2016. Linkages between statewide results for combined first-trimester screening, prenatal diagnostic procedures, and postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain the frequency and type of chromosome abnormality by gestation and nuchal translucency measurement. An atypical chromosome abnormality was defined as any major chromosome abnormality other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X, and Y.Of the 81,244 singleton pregnancies undergoing combined first-trimester screening, 491 (0.60%) had a nuchal translucency of ≥3.5 mm, 534 (0.66%) had a nuchal translucency of 3.0 to 3.4 mm, and 80,219 (98.74%) had a nuchal translucency of3.0 mm. When grouped by nuchal translucency multiples of the median (MoM), 192 (0.24%) had a nuchal translucency of ≥3.0 MoM, 513 (0.63%) had a nuchal translucency of 1.9 to 2.9 MoM, and 80,539 (99.13%) had a nuchal translucency of1.9 MoM. A total of 1779 pregnancies underwent prenatal or postnatal diagnostic testing, of which 89.60% were performed by whole-genome single-nucleotide polymorphism chromosomal microarray. The frequency of total major chromosome abnormalities was significantly higher in the group with a nuchal translucency of ≥3.5 mm (147 of 491, 29.94%) than the group with a nuchal translucency of 3.0 to 3.4 mm (21 of 534, 3.93%) or a nuchal translucency of3.0 mm (71 of 80,219, 0.09%) (P.001). There were 93 atypical chromosome abnormalities in the total screened cohort. The frequency of an atypical chromosome abnormality was 4.07% (95% confidence interval, 2.51-6.22), 0.37% (95% confidence interval, 0.05-1.35), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.5 mm, 3.0 to 3.4 mm, and3.0 mm, respectively. The frequency of atypical chromosome abnormalities was 4.69% (95% confidence interval, 2.17-8.71), 2.53% (95% confidence interval, 1.36-4.29), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.0 MoM, 1.9 to 2.9 MoM, and1.9 MoM, respectively. When defining thresholds for offering diagnosis with chromosomal microarray at 11 to 13 weeks, both a nuchal translucency threshold of 1.9 MoM and a fixed threshold of 3.0 mm captured 22 of 93 fetuses (23.7%) with an atypical chromosome abnormality. Of these, 50.0% had a coexisting fetal abnormality on ultrasound. However, the gestation-specific threshold of 1.9 MoM had a better specificity than 3.0 mm. The positive predictive value of an enlarged nuchal translucency for any atypical chromosome abnormality was 1 in 47 for nuchal translucency of3.0 mm and 1 in 32 for nuchal translucency of1.9 MoM. Our nuchal translucency threshold of 1.9 MoM captured 0.87% of fetuses, thus approximating the 99th centile.A gestational age-adjusted nuchal translucency threshold of 1.9 MoM or 99th centile is superior to the fixed cutoff of 3.0 mm for the identification of atypical chromosome abnormalities. The risk of an atypical chromosome abnormality in a fetus with an enlarged nuchal translucency is more than tripled in the presence of an additional ultrasound abnormality.

STUDY QUESTION Is ART related with the association of American Heart Association (AHA) ideal cardiovascular health score and markers of subclinical atherosclerosis? SUMMARY ANSWER The associations between AHA score and markers of subclinical atherosclerosis in ART and non-ART groups were similar in magnitude. WHAT IS KNOWN ALREADY Long-term consequences of ART on cardiovascular health are unknown. STUDY DESIGN, SIZE, DURATION The study cohort for the cross-sectional analyses consisted of 172 ART-conceived and 78 non-ART conceived individuals of same age (range 22–35 years). PARTICIPANTS/MATERIALS, SETTING, METHODS Cardiovascular risk factor status was evaluated with American Heart Association (AHA) ideal cardiovascular health score consisting of seven factors (body mass index, blood pressure, total cholesterol, glucose, diet and physical activity, non-smoking). Carotid artery intima-media thickness (cIMT), arterial pulse-wave velocity (PWV) and retinal microvascular parameters were evaluated as markers of early atherosclerosis. Group comparisons in continuous variables were performed with t-tests. For categorical variables, comparisons were performed with chi-square tests. The relationships between AHA score and the markers of atherosclerosis were examined with linear regression analyses adjusted for age and sex. MAIN RESULTS AND THE ROLE OF CHANCE There was no difference in AHA ideal health score between the ART and non-ART groups; mean (SD) scores were 4.1(1.4) versus 4.0(1.5), respectively, P = 0.65. No differences were observed between groups for any individual ideal health metric (P always >0.2). AHA score was not associated with cIMT or retinal measures in either group (P always >0.05). An inverse association was observed between AHA score and PWV in the ART group (beta (95% CI) −0.18(−0.26 to −0.10)). A numerically similar relationship was observed in the smaller non-ART group (−0.19(−0.39 to 0.01)). LIMITATIONS, REASONS FOR CAUTION Even though this cohort is among the largest ART studies with extensive cardiovascular data, the sample is still relatively small and the statistical power is limited. As the study population was still in early adulthood, we were not able to evaluate the associations with clinical cardiovascular events, but utilized non-invasive methods to assess early markers of subclinical atherosclerosis. WIDER IMPLICATIONS OF THE FINDINGS These findings suggest that ART-conceived individuals do not have increased vulnerability for cardiovascular risk factors. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by a National Health & Medical Research Council Project Grant (APP1099641), The Royal Children’s Hospital Research Foundation, Monash IVF Research and Education Foundation, and Reproductive Biology Unit Sperm Fund, Melbourne IVF. The authors have no conflicts of interest relevant to this article to disclose.

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

STUDY QUESTION What is the frequency of major chromosome abnormalities in a population-based diagnostic data set of genomic tests performed on miscarriage, fetal and infant samples in a state with >73 000 annual births? SUMMARY ANSWER The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826), with a significant decrease in the detection of major chromosome abnormalities with later developmental stage, from 50.9% to 21.3% to 15.6% of tests in the miscarriage, prenatal and postnatal cohorts, respectively. WHAT IS KNOWN ALREADY Over the past decade, technological advances have revolutionized genomic testing at every stage of reproduction. Chromosomal microarrays (CMAs) are now the gold standard of chromosome assessment in prenatal diagnosis and pediatrics. STUDY DESIGN, SIZE, DURATION A population-based cohort study including all chromosome analysis was performed in the Australian state of Victoria during a 24-month period from January 2015 to December 2016. All samples obtained via invasive prenatal diagnosis and postnatal samples from pregnancy tissue and infants ≤12 months of age were included. PARTICIPANTS/MATERIALS, SETTING, METHODS A research collaboration of screening and diagnostic units in the Australian state of Victoria was formed (the Perinatal Record Linkage collaboration), capturing all instances of prenatal and postnatal chromosome testing performed in the state. Victoria has over 73 000 births per annum and a median maternal age of 31.5 years. We analyzed our population-based diagnostic data set for (i) chromosome assessment of miscarriage, prenatal diagnosis and postnatal samples; (ii) testing indications and diagnostic yields for each of these cohorts; (iii) and the combined prenatal/infant prevalence of 22q11.2 deletion syndrome (DS) as a proportion of all births ≥20 weeks gestation. MAIN RESULTS AND THE ROLE OF CHANCE During the 24-month study period, a total of 8826 chromosomal analyses were performed on prenatal and postnatal specimens in Victoria. The vast majority (91.2%) of all chromosome analyses were performed with CMA. The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826). There was a significant decreasing trend in the percentage of chromosome abnormalities with later developmental stage from 50.9% to 21.3% to 15.6% in the miscarriage, prenatal and postnatal cohorts, respectively (χ2 trend = 790.0, P LIMITATIONS, REASONS FOR CAUTION Clinical information was missing on 11.6% of postnatal samples, and gestational age was rarely provided on the miscarriage specimens. We were unable to obtain rates of termination of pregnancy and stillbirth in our cohort due to incomplete data provided by clinical referrers. We therefore cannot make conclusions on pregnancy or infant outcome following diagnostic testing. Childhood and adult diagnoses of 22q11 DS were not collected. WIDER IMPLICATIONS OF THE FINDINGS Our study marks a complete transition in genomic testing from the G-banded karyotype era, with CMA now established as the first line investigation for pregnancy losses, fetal diagnosis and newborn/infant assessment in a high-income setting. Integration of prenatal and postnatal diagnostic data sets provides important opportunities for estimating the prevalence of clinically important congenital syndromes, such as 22q11 DS. STUDY FUNDING/COMPETING INTEREST(S) L.H. is funded by a National Health and Medical Research Council Early Career Fellowship (1105603); A.L. was funded by a Mercy Perinatal Research Fellowship; J.H. was funded by a National Health and Medical Research Council Senior Research Fellowship (10121252). The funding bodies had no role in the conduct of the research or the manuscript. Discretionary funding from the Murdoch Children’s Research Institute has supported the prenatal diagnosis data collection and reporting over the years. Dr Ricardo Palma-Dias reports a commercial relationship with Roche Diagnostics, personal fees from Philips Ultrasound, outside the submitted work. Debbie Nisbet reports a commercial relationship with Roche Diagnostics, outside the submitted work. TRIAL REGISTRATION NUMBER NA

Background Access to information about prenatal screening is important particularly in light of new techniques such as non-invasive prenatal testing (NIPT). This study aimed to develop and examine the acceptability of a low literacy decision aid (DA) about Down syndrome screening among pregnant women with varying education levels and GPs. Methods We developed a DA booklet providing information about first-trimester combined testing, maternal serum screening, and NIPT. GPs and women participated in a telephone interview to examine the acceptability of the DA and measure screening knowledge before and after reading the DA. The knowledge measure was designed to assess whether women had understood the gist of the information presented in the decision aid. It comprised conceptual questions (e.g. screening tells you the chance of having a baby with Down syndrome) and numeric questions (e.g. the accuracy of different screening tests). Results Twenty-nine women and 18 GPs participated. Regardless of education level, most women found the booklet ‘very’ clearly presented (n = 22, 76%), and ‘very’ informative (n = 23, 80%). Overall, women’s conceptual and numeric knowledge improved after exposure to the DA, from 4% having adequate knowledge to 69%. Women’s knowledge of NIPT also improved after receiving the decision aid, irrespective of education. Most GPs found it ‘very’ clearly presented (n = 13, 72%), and that it would ‘very much’ facilitate decision-making (n = 16, 89%). Conclusions The DA was found to be acceptable to women as well as GPs. A comprehensive evaluation of the efficacy of the decision aid compared to standard information is an important next step. Strategies are needed on how to implement the tool in practice. Electronic supplementary material The online version of this article (10.1186/s12884-018-2135-0) contains supplementary material, which is available to authorized users.

Reproductive genetic carrier screening identifies couples with an increased chance of having children with autosomal and X-linked recessive conditions. Initially only offered for single conditions to people with a high priori risk, carrier screening is becoming increasingly offered to individuals/couples in the general population for a wider range of genetic conditions. Despite advances in genomic testing technology and greater availability of carrier screening panels, there is no consensus around which types of conditions to include in carrier screening panels. This study sought to identify which types of conditions parents of children with a genetic condition believe should be included in carrier screening. Participants (n = 150) were recruited through Royal Children's Hospital (RCH) Melbourne outpatient clinics, the Genetic Support Network of Victoria (GSNV) and a databank of children with hearing loss (VicCHILD). This study found that the majority of participants support offering carrier screening for: neuromuscular conditions (n = 128/134, 95.5%), early fatal neurodegenerative conditions (n = 130/141, 92.2%), chronic multi-system disorders (n = 124/135, 91.9%), conditions which cause intellectual disability (n = 128/139, 92.1%) and treatable metabolic conditions (n = 120/138, 87.0%). Views towards the inclusion of non-syndromic hearing loss (n = 88/135, 65.2%) and preventable adult-onset conditions (n = 75/135, 55.6%) were more mixed. Most participants indicated that they would use reproductive options to avoid having a child with the more clinically severe conditions, but most would not do so for clinically milder conditions. A recurring association was observed between participants’ views towards carrier screening and their lived experience of having a child with a genetic condition.\ud \ud

ObjectiveTo examine overall micronutrient intake periconceptionally and throughout pregnancy in a population-based cohort of Australian women.DesignIn a prospective cohort study, micronutrient dosages were extracted from self-reported maternal supplement use, recorded pre-conception, and for each trimester of pregnancy. A food frequency scale (DQESv2) captured usual maternal diet for gestational weeks 14–26. The influence of sociodemographic and lifestyle factors associated with supplement use was examined using logistic regression, and changes in micronutrient intakes prior to and throughout pregnancy were assessed using repeated-measures ANOVA analyses.SettingMetropolitan hospital sites in Melbourne, Australia.SubjectsWomen with a viable singleton pregnancy were recruited at less than 19 weeks’ gestation (n2146).ResultsCompared with non-users, women using supplements during pregnancy were more likely to have planned their pregnancy, be >25 years old, primiparous, Caucasian, non-smokers, have a tertiary education and be consuming a folate-rich diet. Intakes of folate, Fe and Zn were significantly lower in the periconceptional period, compared with other periods (PConclusionsThe study highlights the need for improved public health education on nutritional needs during pregnancy, especially among women with lower educational achievements and income.

Background Advances in genetic technologies and ultrasound screening techniques have increased the ability to predict and diagnose congenital anomalies during pregnancy. As a result more prospective parents than ever before will receive a prenatal diagnosis of a fetal abnormality. Little is known about how Australian women and men experience receiving a prenatal diagnosis and how they make their decision about whether or not to continue the pregnancy. Aims This qualitative study aims to describe parental experiences and examine how best to provide support after a prenatal diagnosis. Results Individual in-depth interviews were conducted with 102 women and men approximately six weeks post-diagnosis of fetal abnormality. Data were elicited using a narrative, chronological approach and women (n = 75) and a sample of male partners (n = 27) were separately interviewed. Thematic analysis, involving a rigorous process of qualitative coding, enabled iterative development and validation of emergent themes. Participants identified that the shock of the diagnosis can be lessened when good care is delivered, by provision of: clear, accurate and respectful communication; empathic, non-judgemental, professional support; timely access to further testing and appointments; seamless interactions with services and administration; appropriate choices about invasive testing; acknowledgment of the enormity and unexpected nature of the diagnosis, and of the subsequent decision-making challenges; and discussion of the myriad feelings likely to emerge throughout the process. Conclusions This study has demonstrated the importance of providing timely access to accurate information and supportive, non-judgemental care for women and their partners following prenatal diagnosis of a fetal abnormality.

Aim: To compare Australian and French perceptions of genetics and preferences regarding the return of incidental findings. Methods: Participants from the International Sarcoma Kindred Study received a survey at intake to cancer referral units. A total of 1442 Australian and 479 French individuals affected by sarcoma and their unaffected family members responded to four hypothetical scenarios depicting hereditary conditions of varying treatability and severity. Results: Australians’ preference for the return of incidental findings was consistently higher than French for all scenarios. Country group differences were significant for two scenarios when individual characteristics were controlled through multivariable analyses. Conclusion: Findings support the need for guidelines that are sensitive to sociocultural context and promote autonomous decision-making.

Objective To compare the dietary intake of pregnant women to the 2013 Australian Dietary Guidelines and explore factors associated with inadequate intake. Design Dietary intake data were collected between July 2011 and July 2012 (n = 1570) using a 74-item food frequency questionnaire. Setting Metropolitan public health hospitals in Melbourne, Australia. Participants Pregnant women, at least 16 years of age, with a singleton pregnancy, and literate in English. Measurements and Findings The highest proportion of women met the recommended daily servings for fruit (65.7%), followed by dairy products (55.2%), meat/meat alternatives (31.1%), vegetables (10.3%), and then grain foods (1.8%). A majority of women (83.8%) regularly consumed up to 2.5 serves of discretionary foods per day. Only one woman met the minimum recommended daily servings for all five food groups. Women who were obese were more likely to consume an inadequate diet (Adj. OR 2.13, 95% CI 1.53, 2.95); and having a university degree was associated with a lower odds of consuming an inadequate diet (Adj. OR 0.63, 95% CI 0.50, 0.78). Key Conclusions and Implications for Practice Pregnancy care providers need to be aware of women’s low compliance with the national dietary guidelines, particularly regarding the poor intake of vegetables and grain foods; targeted as well as population-based approaches may be required.

Objective To analyse population-based trends over the entire history of prenatal testing for aneuploidy. Design Retrospective analysis of state-wide data sets. Setting Australian state of Victoria with ~70 000 annual births. Population All pregnant women undergoing invasive prenatal testing at

Background pregnancy alcohol research relies on self-reports of alcohol consumption. Reporting bias may contribute to ambiguous and conflicting findings on fetal effects of low to moderate pregnancy alcohol exposure. Objective this study aimed to identify the determinants which would enable women to provide accurate data in surveys of alcohol use in pregnancy. Design and participants six focus groups were held with a total of 26 pregnant women and new mothers. Participants reviewed a set of alcohol survey questions followed by a guided discussion. Transcripts were analysed using inductive content analysis. Setting public hospital antenatal clinics and Mother & Child Health Centres, Melbourne, Victoria, Australia. Findings women׳s emotional responses were generally favourable, although the potential for anxiety and fear of judgement was acknowledged. Barriers to accurate self-report were recall, complexity and use of subjective language. Facilitators were appropriate drink choices, occasional drinking options and contextualising of questions. Confidentiality and survey method, including a preference for methods other than face-to face, were also important factors. Key conclusions and implications for practice questions embedded in clear context may reduce anxiety around questions about alcohol use in pregnancy. Methods using shorter recall periods, a list of drinks choices, measures of special occasion drinking and minimising complex and subjective language will increase accurate self-report. A setting perceived as confidential and anonymous may reduce a desire to provide socially acceptable answers.

To investigate by means of a population-based analysis of a cohort of women who underwent combined first-trimester screening (CFTS), changes in uptake of invasive prenatal diagnosis according to risk of trisomy 21 (T21) on CFTS, and prevalence and methods for ascertainment of atypical chromosome abnormalities.This was a retrospective cohort study using state-wide prenatal datasets from Victoria, Australia. A three-step approach was taken to analyze the data: (1) linkage of records between serum screening and diagnostic results; (2) comparison of rates of diagnostic testing according to CFTS T21 risk result category in a 2014-2015 cohort with those of a historical 2002-2004 cohort; (3) detailed analysis of atypical abnormalities in the 2014-2015 group according to CFTS T21 risk result, individual serum analyte level and other indications for invasive diagnostic testing.In 2014-2015, there were 100 418 CFTS results issued for 146 776 births (68.4%). The overall prevalence of atypical chromosome abnormalities in the entire CFTS cohort was 0.10% and was highest in those with CFTS T21 risk 1 in 10 (4.6%), or serum analyte levels 0.2 multiples of the median (MoM) (6.9% for pregnancy-associated plasma protein-A (PAPP-A) and 5.2% for beta-human chorionic gonadotropin (β-hCG)). Almost half (49.2%) of women with PAPP-A 0.2 MoM had a risk for T21 on CFTS of less than 1 in 100. The majority (55%) of atypical abnormalities occurred in women with CFTS T21 risk below 1 in 300, and were most commonly detected on ultrasound examination (47.1%).Concerns regarding missed diagnoses of atypical chromosome abnormalities when non-invasive prenatal testing is offered after a result of high risk on CFTS can be mitigated if invasive diagnostic testing is offered to those women with CFTS T21 risk of 1 in 100, serum PAPP-A or β-hCG 0.2 MoM, or ultrasound-detected abnormality. This has implications for contingent models of screening. Copyright © 2017 ISUOG. Published by John WileySons Ltd.

This study aimed to examine the choice pregnant women make about the amount of fetal genetic information they want from chromosome microarray. Women having invasive prenatal testing in the absence of fetal structural abnormality were recruited in Victoria, Australia. A decision aid for women described ‘targeted’ analysis as reporting only copy number variants implicated in a highly penetrant and well-described phenotype and ‘extended’ as additionally reporting variants of uncertain or unknown significance. Participant’s choice and demographics were collected by survey before chorionic villus sampling or amniocentesis; psychological data were also collected then and again about 10 days after receiving results. High-resolution single-nucleotide polymorphism array analysis was performed, and a clinical review committee assessed variants for reporting before returning results to participants. Sixty-six participants (59.5%) chose extended analysis and 45 (40.5%) targeted. Choosing extended information was associated with (1) indication for prenatal diagnosis: maternal age alone (adjusted odds ratio (adjOR) 9.6, 95% confidence interval (CI): 1.4–66.0, p= 0.02), or ‘other’ indication (adjOR 7.1, 95% CI: 1.5–33.1, p= 0.01)); (2) >12 months to conceive (adjOR 4.1, 95% CI: 1.0–17.7, p= 0.05); and (3) Asian background (adjOR 4.67, 95% CI: 1.0–21.0, p= 0.04). No adverse psychological impact occurred in either group. We conclude that offering pregnant women different levels of fetal genetic analysis is warranted, alongside decision support.

Background Children conceived by assisted reproductive technologies (ART) currently comprise 4% of Australian births. The manipulation of biological parameters related to fertilization and implantation are integral to successful ART but potentially pose a risk to the longer-term health of the offspring. There is consensus that many common adult health problems (particularly cardiovascular, metabolic and respiratory conditions) have their origins in early life, possibly before birth, and that risk trajectories track through childhood until clinical disease manifests in adulthood. Early life epigenetic variation may play a role in this process. However little is known about the long-term health of individuals conceived by ART. In a previous study, based on telephone-interviews, we found that young adults conceived by in vitro fertilization (IVF) had significantly more maternal reported atopic respiratory, endocrine, nutritional, and metabolic conditions than non-IVF conceived matched controls. Here we outline the protocol for a follow-up biomedical assessment of this cohort and a questionnaire to obtain information on potential confounders. Methods We are conducting a clinical review of an existing, well characterised cohort comprising 547 IVF-conceived adults and 549 matched controls. We are measuring cardiovascular intermediate phenotypes, metabolic parameters and respiratory function, complemented by epigenome-wide DNA methylation analysis. A pilot study demonstrated the feasibility of our proposed protocol and its acceptability to participants. Participants attend a 2–3 h clinical assessment and complete a study-specific online questionnaire. Measurements include: 1) cardiovascular phenotypes: carotid artery intima-media thickness and distensibility, retinal vascular calibre, resting blood pressure, pulse wave velocity and pulse wave analysis; 2) respiratory function: spirometry, plethysmography, multiple breath washout; 3) auxology: height, weight, waist circumference, bio-impedance. Blood is collected for 4) biomarkers of cardiometabolic profile including inflammatory markers and 5) epigenetic analysis. Discussion Recruitment for this clinical review is challenging as many of the participants have moved to regional, interstate or international locations. Additionally, many female participants are pregnant or breastfeeding, and are therefore ineligible. Nevertheless, comprehensive strategies have been developed to optimize recruitment. Given the increasing use of IVF and related technologies, the potential long-term consequences for risk of common adult diseases is an important clinical and public health issue.

BackgroundPrenatal alcohol exposure (PAE) is a community health problem with up to 50% of pregnant women drinking alcohol. The relationship between low or sporadic binge PAE and adverse child outcomes is not clear. This study examines the association between PAE in the general antenatal population and child neurodevelopment at 2 years, accounting for relevant contributing factors.MethodsThis prospective population-based cohort recruited 1570 pregnant women, providing sociodemographic, psychological and lifestyle information and alcohol use for five time periods. PAE categories were ‘low’, ‘moderate/high’, ‘binge’, in trimester 1 or throughout pregnancy. Measures of cognitive, language and motor development (Bayley Scales of Infant and Toddler Development) were available for 554 children, while measures of sensory processing (Infant/Toddler Sensory Profile) and social–emotional development (Brief Infant Toddler Social Emotional Assessment) were available for 948.ResultsA positive association in univariate analysis with low-level PAE throughout pregnancy and cognition (β=4.1, 95% CI −0.02 to 8.22, p=0.05) was attenuated by adjusting for environmental/social deprivation risk factors (β=3.06 (−1.19 to 7.30), p=0.16). Early binge drinking, plus continued PAE at lower levels, was associated with the child being more likely to score low in sensation avoidance (adjusted OR 1.88 (1.03 to 3.41), p=0.04).ConclusionEarly binge exposure, followed by lower-level PAE, demonstrated an increase in sensation-avoiding behaviour. There were, however, no significant associations between PAE and neurodevelopment following adjustment for important confounders and modifiers. Follow-up is paramount to investigate subtle or later onset problems.

Background The ‘common variant, common disease’ model predicts that a significant component of hereditary breast cancer unexplained by pathogenic variants in moderate or high-penetrance genes is due to the cumulative effect of common risk variants in DNA (polygenic risk). Assessing a woman’s breast cancer risk by testing for common risk variants can provide useful information for women who would otherwise receive uninformative results by traditional monogenic testing. Despite increasing support for the utility of common risk variants in hereditary breast cancer, research findings have not yet been integrated into clinical practice. Translational research is therefore critical to ensure results are effectively communicated, and that women do not experience undue adverse psychological outcomes. Methods In this prospective study, 400 women with a personal and/or high risk family history of breast cancer will be recruited from six familial cancer centers (FCCs) in Australia. Eligible women will be invited to attend a FCC and receive their personal polygenic risk result for breast cancer. Genetic health professionals participating in the study will receive training on the return of polygenic risk information and a training manual and visual aids will be developed to facilitate patient communication. Participants will complete up to three self-administered questionnaires over a 12-months period to assess the short-and long-term psychological and behavioral outcomes of receiving or not receiving their personal polygenic risk result. Discussion This is the world’s first study to assess the psychological and behavioral impact of offering polygenic risk information to women from families at high risk of breast cancer. Findings from this research will provide the basis for the development of a new service model to provide polygenic risk information in familial cancer clinics. Trial registration The study was retrospectively registered on 27th April 2017 with the Australian and New Zealand Clinical Trials Group (Registration no: ACTRN12617000594325; clinical trial URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372743). Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3485-0) contains supplementary material, which is available to authorized users.

Objective To compare obstetric and perinatal outcomes of singleton births after assisted reproductive technology (ART) with blastocyst transfer (days 5 to 6) versus nonblastocyst transfer (days 2 to 4). Design Retrospective cohort study. Setting Monash IVF. Patient(s) 4,202 women who conceived using in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) between 2004 and 2009. Intervention(s) Records analysis of fresh and frozen-thawed embryo transfers resulting in singleton births of at least 20 weeks' gestation. Main Outcome Measure(s) Perinatal outcomes: preterm birth, low birthweight, very low birthweight, small for gestational age, large for gestational age, preeclampsia, antepartum hemorrhage, placental abruption, placenta previa, and postpartum hemorrhage; and covariates: maternal age, year of birth of the baby, private health insurance status, maternal body mass index, smoking status, parity, gender of baby, and variations in treatment procedures. Result(s) Multivariate analysis found no statistically significant difference between transfers on days 5 and 6 and days 2 and 4 for all maternal and perinatal outcomes. There were modest increases in the adjusted odds ratios for preeclampsia (adjusted odds ratio 1.72, 99% confidence interval 0.93–3.20) and placenta previa (1.65, 0.92–2.98). Conclusion(s) Obstetric and perinatal outcomes after blastocyst transfer on days 5 to 6 are similar when compared with embryo cleavage-stage transfers on days 2 to 4.

Acardia is a severe, complex malformation of monozygotic twinning, but beyond clinical case series, very few epidemiologic data are available. The goals of this study were to assess the epidemiologic characteristics of acardia from birth defect registries in the International Clearinghouse for Birth Defects Surveillance and Research (Clearinghouse), and compare these findings to current literature. The study included 17 surveillance programs of the Clearinghouse representing 23 countries from North and South America, Europe, China, and Australia. Anonymized individual records with clinical and demographic data were reviewed centrally by clinical geneticists. A literature search was performed. A total of 164 cases of acardia were reported from an underlying cohort of 21.2 million births. Of these, 23% were elective pregnancy terminations. Rates did not vary significantly by maternal age. For many cases, information on pregnancy exposures and genetic testing was missing. However, these limited data did not suggest high rates of chronic illnesses (diabetes, seizure disorders) or lifestyle factors such as smoking. One case had trisomy 13. Major malformations were reported in 2.4% of co-twins. With some basic assumptions, the total prevalence of acardia was estimated at 1 in 50,000-70,000 births, and 1 in 200-280 monozygotic twins. In summary, acardia is a dramatic, probably underreported, and incompletely understood malformation. Studies on its epidemiology and etiology are challenging and still rare. An international collaboration of epidemiologists, clinicians, and geneticists is necessary to understand the etiology, pathogenesis, and occurrence of this severe malformation complex. (C) 2011 Wiley Periodicals, Inc.

Scanning of post-operative meningioma patients to detect tumour recurrence is common practice. There are however no guidelines for how often this should be performed for meningiomas of differing Simpson Grades of surgical removal and World Health Organisation (WHO) histological grades. A literature search reveals no studies investigating its role in post-operative care. The objective of this study was to determine current post-operative scanning use, in particular its timing and frequency in relation to meningioma recurrence rate. We performed a retrospective analysis of the surgical records of patients that underwent meningioma excision between 1998 and 2003 in Addenbrookes Hospital, and their follow-up scans up to 9 years post-surgery. Age at surgery, Simpson grade of surgical removal, tumour location, WHO histological grade, post-surgical radiotherapy, dates of meningioma recurrences, and dates of post-operative CT and MRI scans up to present, were recorded for each patient. A total of 283 records were analysed. Using logistic regression we found that WHO grade and post-surgical radiotherapy were the strongest predictors of meningioma recurrence. We found that timing and frequency of scans between patients of the same stage and grade is highly variable. Data suggests that the role for regular short term post-operative scanning of WHO grade 1 meningioma patients, a group that form the bulk of meningioma patients, is limited, and should only be performed in select, clinically indicated cases. A time and cost analysis reveals that significant savings can be made by adopting this policy. Data from a greater number of patients with WHO grade 2 and 3 meningiomas needs to analysed before definite conclusions can be made about the regularity of post-operative scanning in these patients. Our audit study has revealed an opportunity for significant monetary and time savings to be made without any compromise of patient care.

To examine utilization of genetic counseling after diagnosis of a birth defect in 2004, and trends in utilization from 1991 to 2004.Birth defects data for births in 2004 were linked to genetic counseling data to determine utilization of genetic counseling in Victoria, Australia. Variability in utilization was determined according to the need for genetic counseling (as indicated by the particular birth defect), and demographic and perinatal variables. Trends in utilization were determined by comparing 2004 data with that of earlier studies using the same data sources for birth defects cohorts in 1991, 1993, and 1995.Frequency of overall utilization was 20% and was not affected by maternal country of birth, socioeconomic advantage/disadvantage, or region of residence. Higher-than-average utilization was strongly predicted by "high-need" (48.4%), infant death (stillbirth 50%, postnatal death 50.4%), or birth in a tertiary level hospital (28.5%). There was an upward trend in the proportion of the high-need group using genetic counseling, progressively increasing from 39.7% in the 1991 cohort to 42.5% in the 1993 cohort, 46.5% in the 1995 cohort, to a high of 48.4% in the 2004 cohort.Utilization by those who most need it has gradually increased from 1991 to 2004, with no inequity of access apparent in the most recent cohort. Further studies are needed to determine whether high-need families not using genetic counseling are not doing so because of chance or choice.

Objective To report preterm birth and small for gestational age (SGA) rates from assisted reproduction technologies (ART) patients with ovarian endometriomata compared with control groups. Design Retrospective cohort study. Setting Tertiary university affiliated ART center and Perinatal Data Collection Unit (PDCU). Patient(s) Every woman who had an ART singleton baby born between 1991 and 2004 had her database record assessed (N = 4382). Control groups included 1201 singleton babies from ART patients without endometriosis and 2400 randomly selected women from the PDCU database of 850,000 births. Intervention(s) There were 95 singleton ART babies from patients with ovarian endometriomata and 535 ART singleton babies from patients who had endometriosis but no ovarian endometriomata. Main Outcome Measure(s) Preterm birth rates and SGA birth rates. Result(s) Preterm birth rate increased only in the ovarian endometriomata group when compared with community birth records (n = 850,000). Furthermore, ART patients with ovarian endometriomata had a statistically significantly increased likelihood of having a SGA baby when compared with other forms of endometriosis. Conclusion(s) Rates of preterm birth and SGA babies doubled in infertility patients with ovarian endometriomata who required ART.

To describe the prevalence of neural tube defects (NTDs) in Victoria, and to evaluate women's knowledge and awareness of the importance of folate after the introduction of voluntary food fortification.Descriptive study, set in Victoria, Australia, based on routinely collected data from the Victorian Birth Defects Register (VBDR) for 1998-2006, and responses by women aged 18-50 years to five questions relating to folate on the 2005 and 2006 Victorian Population Health Surveys (2314 and 2488 women, respectively).Prevalence of NTDs, and extent of women's knowledge of the importance of folate in NTD prevention, comparing the period before and since voluntary food fortification and a folate awareness campaign.The total prevalence of pregnancies affected by NTDs declined from approximately 17 to 14 per 10,000 births from 1997 to 1999 (coinciding with the period when voluntary food fortification was introduced, and a 1-year folate awareness campaign was held). It has since remained static. Over the 9-year study period, the termination of pregnancy rate was 79%, resulting in three NTD-affected babies per 10,000 livebirths. Compared with women aged 30-34 years (the reference group), those aged 20-24 years had the greatest likelihood of having a baby with an NTD (adjusted odds ratio, 1.70; 95% CI, 1.33-2.18; P0.001). Women aged 18-24 years had the lowest rate of folate supplement use (15.9% in 2006), while women aged 30-34 years had the highest rate (30.3% in 2006).There has been no further reduction in prevalence of NTDs in Victoria since 1999, and this prevalence remains well above that achievable through adequate folate intake. Accurate knowledge of folate consumption, population-based NTD prevalence data and folate awareness data are essential in monitoring the effectiveness of the mandatory fortification program to be implemented in Australia in the next 2 years.

Objective To evaluate the effectiveness of a decision aid for prenatal testing of fetal abnormalities compared with a pamphlet in supporting women’s decision making. Design A cluster randomised controlled trial. Setting Primary health care. Population Women in early pregnancy consulting a GP. Methods GPs were randomised to provide women with either a decision aid or a pamphlet. The decision aid was a 24-page booklet designed using the Ottowa Decision Framework. The pamphlet was an existing resource available in the trial setting. Main outcome measures Validated scales were used to measure the primary outcomes, informed choice and decisional conflict, and the secondary outcomes, anxiety, depression, attitudes to the pregnancy/fetus and acceptability of the resource. Outcomes were measured at 14 weeks of gestation from questionnaires that women completed and returned by post. Findings Women in the intervention group were more likely to make an informed decision 76% (126/165) than those in the control group 65% (107/165) (adjusted OR 2.08; 95% CI 1.14–3.81). A greater proportion of women in the intervention group 88% (147/167) had a ‘good’ level of knowledge than those in the control group 72% (123/171) (adjusted OR 3.43; 95% CI 1.79–6.58). Mean (SD) decisional conflict scores were low in both groups, decision aid 1.71 (0.49), pamphlet 1.65 (0.55) (adjusted mean difference 0.10; 95% CI −0.02 to 0.22). There was no strong evidence of differences between the trial arms in the measures of psychological or acceptability outcomes. Conclusion A tailored prenatal testing decision aid plays an important role in improving women’s knowledge of first and second trimester screening tests and assisting them to make decisions about screening and diagnostic tests that are consistent with their values.

Objective The objective of this study was to follow up and evaluate the statewide first-trimester combined screening programme for Down syndrome and trisomy 18 at Genetic Health Services Victoria, Australia. Design Retrospective population cohort. Setting Maternal Serum Screening Laboratory records. Sample All women screened between February 2000 and June 2002 (16 153 pregnancies). Methods Screening results were matched to Victorian perinatal and birth defect data via record linkage, with an ascertainment of 96.8% of pregnancy outcomes. Manual follow up with health professionals increased ascertainment to more than 99%. Main outcome measures Fetal Down syndrome or trisomy 18, and combined screen results, to calculate test characteristics. Results Using a risk threshold of 1 in 300 at time of ultrasound, the sensitivities for standard first-trimester combined screening and augmented 13-week combined screening for Down syndrome were 87.3 and 90.5% and the false-positive rates (FPR) were 4.1 and 3.9%, respectively. The sensitivity for trisomy 18 was 66.7% (10/15, 95% CI 42.8–90.5%) with a 0.4% FPR and 15.2% positive predictive value (1 in 250 risk threshold). Conclusions The combined use of record linkage and manual follow-up techniques was effective in ascertaining more than 99% of pregnancy outcomes for calculations of accurate test characteristics of the combined screen. The sensitivity for Down syndrome at Genetic Health is comparable to similar populations. However, the sensitivity for trisomy 18 is lower than that elsewhere, which may reflect the overall low birth prevalence of trisomy 18 and associated small numbers in this particular cohort.

Background: To fully assess predictive genetic testing programs, it is important to assess outcomes over periods of time longer than the 1-year follow-up reported in the literature. Methods: We conducted a 3-year study of individuals who received predictive genetic test results for previously identified familial mutations in Australian Familial Cancer Clinics. Questionnaires were sent before attendance at the familial cancer clinic and 2 weeks, 4 months, 1 year, and 3 years after receiving test results. Psychological measures were included each time, and preventive behaviors were assessed at baseline and 1 and 3 years. Psychological measures were adjusted for age, gender, and baseline score. Results: The study included 19 carriers and 54 non-carriers. We previously reported an increase in mean cancer-specific distress in carriers at 2 weeks with a return to baseline levels by 12 months. This level was maintained until 3 years. Non-carriers showed sustained decreases after testing with a significantly lower level at 3 years compared with baseline (P < 0.001). These scores tended to be lower than those for carriers at 3 years (P = 0.09). Mean depression and anxiety scores did not differ between carriers and non-carriers and, at 3 years, were similar to baseline. All carriers and 7% of non-carriers had had a colonoscopy by 3 years, and 69% of 13 female carriers had undergone gynecological screening in the previous 2 years. Prophylactic surgery was rare. Conclusion: This report of long-term data indicates appropriate screening and improved psychological measures for non-carriers with no evidence of undue psychological distress in carriers of hereditary nonpolyposis colorectal cancer mutations.

Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in Large 11001 of international data, to identify malformation patterns, and to evaluate the role of maternal age in non-isolated cases. Case-by-case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), WERE evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated: (h) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non-isolated cases were registered (14.1%): 41 chromosomal syndromes. 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardiovascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb-body wall complex and OEIS. In both of them the gastroschisis could he however misclassified. Chromosomal trisomies and possibly non-syndromic MCA are associated, with,in older Maternal age more than isolated cases. On consideration of our Data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non-isolted cases and a thorough case-by-case review. (c) 2007 Wiley-Liss, Inc.

Objective: To investigate geodemographic characteristics of women having prenatal diagnosis for Down syndrome and other fetal chromosome abnormalities in Victoria, Australia. Methods: A descriptive analysis of population-based data on all confinements, amniocenteses and chorionic villus sampling for 1998 and 2002 was undertaken. Multivariate logistic regression analysis of 2002 data investigated geographical differences, including selected maternal features and a socioeconomic status measure that may be associated with uptake of diagnostic testing. Results: After adjusting for age, parity of three or more children was associated with a significantly decreased likelihood of testing (P

Objective:To describe patterns of uptake of prenatal diagnostic testing and prenatal detection rates for Down syndrome in Victoria with regard to mater nal age and prenatal screening practices. Methods: Analysis of routinely collected statewide datasets for 1992 to 2002, containing detailed information on all prenatal diagnoses, births and birth defects. Results: Utilisation of prenatal diagnosis in women less than 37 years has increased significantly (p

Background: More than half of Victorian pregnant women are undergoing prenatal testing for birth defects, although little is known about the factors that are influencing their decisions. Aims: To examine whom women perceived as influencing their decision about prenatal testing for birth defects, with whom they would have liked to talk more, and what sources of information they preferred. Methods: A total of 737 pregnant women aged 37 years and over, who either had or had not undergone prenatal testing (screening and/or diagnosis) completed a questionnaire in 18 hospitals throughout Victoria. Results: Over 90% reported that they themselves had a strong influence on their decision, and 70% reported their partner as strongly influencing their decision. Approximately 30% of women who had both screening and diagnosis and more than 20% of women who had no prenatal testing, would like to have discussed prenatal testing with women who had previously had testing. Face-to-face counselling with a doctor or counsellor was the preferred source of information, followed by a pamphlet as the second choice. Conclusions: Given that both tested and untested women felt so strongly that they were responsible for their own decisions about prenatal testing, it is unlikely that universal acceptance and uptake will occur, even in this group of women of advanced maternal age. A support network of women who have already had testing could supplement existing sources of support. However, there continues to be a need for face-to-face sessions with a doctor or counsellor in combination with printed material.

This study was undertaken to document the phenotype of Kabuki (Niikawa-Kuroki) syndrome in patients from Australia and New Zealand, with particular emphasis on growth patterns, behavior, and relationship between head circumference and intellectual level. Data on 27 children and adults with Kabuki (Niikawa-Kuroki) syndrome from Australia and New Zealand were collected by questionnaire and clinical assessment. The patients ranged in age from 7 months to 36 years with a mean age of 7 years and 2 months. The mean age at diagnosis was 3(5/6) years, but in most cases, the facial phenotype was evident from infancy. The minimum birth prevalence was calculated at 1 in 86,000. Three of our patients died. Parents reported a behavior phenotype characterized by an excellent long-term memory and avoidance of eye contact. No correlation was found between head circumference and severity of intellectual disability. Eight of 14 patients over the age of 5 years were overweight or obese. Six of these eight patients had failure to thrive in infancy. One patient developed insulin-dependent diabetes mellitus in adolescence. Some individuals with Kabuki (Niikawa-Kuroki) syndrome show a characteristic growth profile with failure to thrive in infancy progressing to obesity or overweight in middle childhood or adolescence. A behavior phenotype was noted which requires further investigation. Head size is not a predictor of degree of intellectual disability.

In this paper, we examine reasons for declining both prenatal screening, and diagnosis among a small group of pregnant women in Victoria, Australia. Semi-structured questionnaires were used to elicit women's account of their refusals of offers during pregnancy. Previous literature suggests that women decline prenatal screening and diagnosis because they are against abortion and the medicalisation of pregnancy, and have conoerns about the health and well-being of their fetuses. Women in this study had similar reasons but they also had other reasons for declining. Most clearly was that related to 'risk' brought about by the prospect of knowledge gained from undertaking prenatal screening and diagnostic tests, which would cause emotional distress and lead to further difficult decisions. The results have implications for the development and expansion of prenatal screening and diagnosis for pregnant women in Australia and elsewhere. We are not suggesting that prenatal screening and diagnosis is a problem for all women or even most women. However, health service providers must provide information about prenatal screening and diagnosis that is appropriate for all pregnant women, presenting all options, including that of not having any screening or diagnostic test. In doing so we will be facilitating the opportunity for women to make an informed choice and acknowledging the existence and importance of this small, but concerned group of women.

Contrasting opinions exist regarding the disclosure of incidental findings detected through clinical genomic testing. This study used a discrete choice experiment to investigate genetic health professionals' preferences for the disclosure of incidental findings in an Australian paediatric setting. Four attributes of conditions relating to incidental findings were investigated: availability of prevention and treatment, chance of symptoms ever developing, age of onset and severity. Questionnaires from 59 Australian genetic health professionals were analysed. Results show that when evaluating incidental findings for disclosure, these professionals value the availability of prevention and treatment for the condition above all other characteristics included in the study. The framework of this discrete choice experiment can be used to investigate the preferences of other stakeholders such as paediatricians and parents about disclosure of incidental findings. The results of this study may be considered when assessing which categories of incidental findings are most suitable for disclosure in clinical practice.

Forty percent of pregnant women aged 37 years and over do not have prenatal diagnosis despite being eligible for a free test. The present study aimed to determine how often, and which, untested women were making a choice about this, how many declined an offer and why. A questionnaire was given to untested women, aged 37 years and over, at no less than 24 weeks gestation. A total of 375 (81.5%) women declined, 72 (16%) were not offered a test and 13 presented too late antenatally. There was a three-fold increased likelihood (OR 3.10 95% CI 1.44, 6.65) of no offer for urban non-English speaking background women, compared with the reference group (metropolitan, English speaking). Unpartnered women were also significantly less likely to receive an offer (OR 3.18, 95% CI 1.19, 8.46). Risk to the baby was the main reason for declining. When offered non-invasive prenatal screening, most decliners of prenatal diagnosis accepted, even those who declined because they were opposed to abortion. We estimate that overall 33% of older pregnant women were being offered and declining amniocentesis and/or chorion villus sampling (CVS). Only 6% were not offered a test, but this small proportion is over-represented by minority groups who must be given equal opportunity to make this choice.

This study aims to assess the impact of prenatal diagnosis of de novo apparently balanced chromosome rearrangements (ABCRs) on maternal stress, family functioning and maternal plans of disclosure of genetic information to their child.All liveborn children with prenatally detected de novo ABCRs in two Australian states over a 10-year period (1994-2003) were retrospectively ascertained. Of 39 eligible cases, 16 (41%) participated in the study. Mothers of these children completed a questionnaire using standardized measures to assess family functioning, parental distress, parent-child interaction and child characteristics, with open-ended questions regarding disclosure.The majority of mothers appeared to experience normal levels of parenting stress, quality of parent-child interaction and healthy family functioning. However, most mothers recalled experiencing a significant degree of worry at the time of receiving their prenatal test results, and some mothers (4/15) reported receiving uncertain or conflicting results. Most mothers (13/15) conveyed an understanding of the importance of disclosing this genetic information to their child, and 12/15 conveyed their intention to make this disclosure.Most mothers reported normal parenting stress and family functioning, despite experiencing significant worry upon receiving results. Some children are at risk of nondisclosure of their carrier status.

Objective To compare outcomes for young adults conceived by assisted reproductive technology (ART) with non-ART–conceived young adults. Design Cohort study. Setting Not applicable. Participant(s) Mothers and their offspring (aged 18–28 years) conceived by ART; mothers and their non-ART–conceived offspring, randomly selected from the same source population. Intervention(s) Structured telephone interviews, one with mothers and another with their young adult offspring. Main Outcome Measure(s) Maternal report on young adult offspring hospitalizations and chronic illness accumulated over the first 18 years of their lives; young adult self-report on perceived current quality of life, body mass index, pubertal development, and educational achievement. Result(s) Of 1,480 eligible ART mothers, 80% were traced and contacted. Of those, 656 (55%) participated, reporting on 705 ART-conceived offspring; 269 (23%) declined participation and 262 (22%) did not respond. Of the participants, 84% consented to contact with their young adult offspring, of whom 547 (92%) participated. Random-digit dialing recruited 868 non-ART mothers and 549 offspring. Compared with non-ART young adults, the ART group had significant increases in three maternally reported outcomes: 1) hospital admissions, including those in the secondary school years; 2) atopic respiratory conditions; and 3) combined endocrine, nutritional, and metabolic disease ICD-10 category. Young adult reported outcomes were similar for both groups. Conclusion(s) This study addresses gaps in knowledge of outcomes beyond adolescence for those conceived by ART. Results show few adverse outcomes in this large cohort of young adults, but additional assessment through clinical review is required to address issues unable to be examined in this study.

Objectives To examine alcohol-use disorders in pregnant women and the extent of under-reporting. Design Population-based cohort study. Setting Western Australia. Population Women with a birth recorded on the Western Australian Midwives Notification System (1985–2006). Methods Mothers with an International Classification of Diseases 9/10 alcohol-related diagnosis, indicating heavy alcohol consumption, recorded on population-based health datasets (non-Aboriginal n = 5839; Aboriginal n = 2583) were identified through the Western Australian data-linkage system. This ‘exposed’ cohort was frequency matched (on maternal age, year of birth of offspring, Aboriginal status) with comparison mothers without an alcohol-related diagnosis (non-Aboriginal n = 33 979; Aboriginal n = 8005). Main outcome measures Trends in maternal alcohol diagnoses in relation to pregnancy for non-Aboriginal and Aboriginal women. The proportion of children diagnosed with fetal alcohol syndrome (FAS) who had a mother with an alcohol diagnosis recorded during pregnancy. Results The proportion of Aboriginal mothers in Western Australia with an alcohol diagnosis (23.1%) is ten times greater than for non-Aboriginal mothers (2.3%). There has been a six-fold increase in the percentage of non-Aboriginal births with a maternal alcohol diagnosis recorded during pregnancy and a 100-fold increase for Aboriginal births. Around 70% of the mothers of children diagnosed with FAS did not have an alcohol diagnosis recorded during pregnancy and 18% of the mothers had no record of an alcohol diagnosis. Conclusions Maternal alcohol exposure during pregnancy is significantly under-ascertained. Given the severe risks to the fetus from heavy prenatal alcohol exposure, assessment and recording of alcohol use should be routinely undertaken in maternity and other health settings.

Background Use of assisted reproductive technologies (ART) continues to increase, yet little is known of the longer term health of ART conceived offspring. There are some adverse birth outcomes associated with ART conception but the subsequent developmental trajectory is unclear. Undertaking research in this area is challenging due the sensitive nature of the topic and the time elapsed since birth of the ART conceived young adults. The aim of this report is to describe a research protocol, including design and ethical considerations, used to compare the physical and psychosocial health outcomes of ART conceived young adults aged 18-28 years, with their spontaneously conceived peers. Design This is a retrospective cohort study of mothers who conceived with ART in Victoria, Australia and gave birth to a singleton child between 1982 and 1992. A current address for each mother was located and a letter of invitation to participate in the study was sent by registered mail. Participation involved completing a telephone interview about her young adult offspring’s health and development from birth to the present. Mothers were also asked for consent for the researcher to contact their son/daughter to invite them to complete a structured telephone interview about their physical and psychosocial health. A comparison group of women living in Victoria, Australia, who had given birth to a spontaneously conceived singleton child between 1982 and 1992 was recruited from the general population using random digit dialling. Data were collected from them and their young adult offspring in the same way. Regression analyses were used to evaluate relationships between ART exposure and health status, including birth defects, chronic health conditions, hospital admissions, growth and sexual development. Psychosocial wellbeing, parental relationships and educational achievement were also assessed. Factors associated with the age of disclosure of ART conception were explored with the ART group only. Discussion The conceptualization and development of this large project posed a number of methodological, logistical and ethical challenges which we were able to overcome. The lessons we learnt can assist others who are investigating the long-term health implications for ART conceived offspring.

This study aimed to determine if liveborn children with prenatally detected de novo apparently balanced chromosome rearrangements (ABCR) have more long-term health, developmental or behavioural concerns compared with children in a normal Australian population.This was a retrospective ascertainment of all liveborn children with prenatally detected de novo ABCRs in two Australian states over a 10-year period (1994-2003). Child health, development and behaviour were assessed by maternal report using standardised measures; educational ability and achievement were measured by direct child assessment. Data were compared with relevant population norms, and one sample t-test performed to test for statistical differences.Of 39 eligible cases, 16 (41%) participated in the study. One child (6%) was born with a congenital anomaly, and two children (12.5%) reported a chronic health concern. Compared with population norms, no significant differences were observed with respect to intelligence, mental health, child development and educational ability; children had significantly higher scores indicative of better functioning on bodily pain, social-emotional behaviour and physical functioning. No child satisfied the criteria for having a special health care need.Children in this study with a prenatally detected de novo ABCR have similar long-term health, developmental and behavioural outcomes compared with population norms.

Current measures of livebirth prevalence of Down syndrome are derived from data obtained up to 20 years ago, before the introduction of the prenatal diagnostic tests amniocentesis and chorionic villus sampling (CVS). For women aged 36-52 years, but who were not tested prenatally, we proposed to make a direct estimate of current livebirth prevalence of Down syndrome. We could also determine prevalence at the time of CVS and amniocentesis in women of the same age undergoing prenatal testing. Differences in these prevalences allow an estimation of the relative loss of Down syndrome during pregnancy. In Victoria, Australia, we identified 3041 women having CVS, 7504 having amniocentesis, and 13,139 having no test. Smoothed regression estimates of age-specific livebirth prevalence were found to be higher than in the early studies. The estimate of spontaneous loss was 17 per cent between the time of CVS and amniocentesis, and 18 per cent after the time of amniocentesis. The latter figure is lower than previous estimates and may be explained by a greater likelihood of a Down syndrome fetus surviving to be liveborn, given the modern approach to early obstetric intervention. These current risk estimates of livebirth may be useful updates for genetic counselling, but perhaps more importantly, may be used as precise maternal age-related risk figures, necessary in the design and implementation of prenatal screening programmes for Down syndrome.