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Genomic newborn screening raises practical and ethical issues. Evidence is required to build a framework to introduce this technology safely and effectively. We investigated the choices made by a diverse group of parents with newborns when offered tiered genomic information from exome sequencing. This population-derived cohort comprised infants with congenital deafness. Parents were offered exome sequencing and choice regarding the scope of analysis. Options were choice A, diagnostic analysis only; choice B, diagnostic analysis plus childhood-onset diseases with medical actionability; or choice C, diagnostic analysis plus childhood-onset diseases with or without medical actionability. Of the 106 participants, 72 (68%) consented to receive additional findings with 29 (27.4%) selecting choice B and 43 (40.6%) opting for choice C. Family size, ethnicity, and age of infant at time of recruitment were the significant predictors of choice. Parents who opted to have additional findings analysis demonstrated less anxiety and decisional conflict. These data provide evidence from a culturally diverse population that choice around additional findings is important and the age of the infant when this choice is offered impacts on their decision. We found no evidence that offering different levels of genomic information to parents of newborns has a negative psychological impact.

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

To analyze population-based trends in the prenatal diagnosis of sex chromosome aneuploidy (SCA) since the availability of non-invasive prenatal testing (NIPT).Retrospective state-wide data for all prenatal diagnoses performed25 weeks gestation from 2005 to 2020 in Victoria, Australia. Non-invasive prenatal testing became locally available from 2012. The prenatal diagnosis rates of SCA as proportions of all prenatal diagnostic tests and all births were calculated. Statistical significance was assessed with the χ46,518 amniocentesis and chorionic villus sampling were performed during the study period, detecting 617 SCAs. There was a significant increase in the rate of prenatal SCAs from 5.8 per 10,000 births in 2005 to 8.7 per 10,000 births in 2020 (p 0.0001). This increase was predominantly due to 47,XXY cases, 91% of which were ascertained via positive NIPT for this condition in 2020. The prenatal diagnosis rate of 47,XXY significantly increased from 0.8 per 10,000 births in 2005 to 4.3 per 10,000 births in 2020 (p 0.0001).Screening for SCAs using NIPT has directly led to an increase in their prenatal diagnosis on a population-wide basis, especially 47,XXY. This has implications for clinician education, genetic counselling, and pediatric services.

Background: Binge-level prenatal alcohol exposure (PAE) causes developmental abnormalities, which may be mediated in part by epigenetic mechanisms. Despite this, few studies have characterised the association of binge PAE with DNA methylation in offspring. Methods: We investigated the association between binge PAE and genome-wide DNA methylation profiles in a sex-specific manner in neonatal buccal and placental samples. Results: We identified no differentially methylated CpGs or differentially methylated regions (DMRs) at false discovery rate

Abstract Background The implementation of genomic testing in pregnancy means that couples have access to more information about their child’s genetic make-up before birth than ever before. One of the resulting challenges is the management of genetic variations with unclear clinical significance. This population-based study will help to close this critical knowledge gap through a multidisciplinary cohort study of children with and without genomic copy number variants (CNVs) diagnosed before birth. By comparing children with prenatally-ascertained CNVs to children without a CNV, we aim to (1) examine their developmental, social-emotional and health status; (2) measure the impact of prenatal diagnosis of a CNV on maternal perceptions of child health, behavior and development; and (3) determine the proportion of prenatally-ascertained CNVs of unknown or uncertain significance that are reclassified as benign or pathogenic after 2 or more years. Methods This study will establish and follow up a cohort of mother-child pairs who have had a prenatal diagnosis with a chromosomal microarray from 2013-2019 in the Australian state of Victoria. Children aged 12 months to 7 years will be assessed using validated, age-appropriate measures. The primary outcome measures will be the Wechsler Preschool and Primary Scale of Intelligence IV (WPSSI-IV) IQ score (2.5 to 7 year old’s), the Ages and Stages Questionnaire (12-30 months old), and the Brief Infant- Toddler Social and Emotional Assessment (BITSEA) score. Clinical assessment by a pediatrician will also be performed. Secondary outcomes will be scores obtained from the: Vineland Adaptive Behavior Scale, Maternal Postnatal Attachment Questionnaire, the Vulnerable Child Scale, Profile of Mood States, Parent Sense of Competence Scale. A descriptive analysis of the reclassification rates of CNVs after ≥2 years will be performed. Discussion This study protocol describes the first Australian cohort study following children after prenatal diagnostic testing with chromosomal microarray. It will provide long-term outcomes of fetal genomic variants to guide evidence-based pre-and postnatal care. This, in turn, will inform future efforts to mitigate the negative consequences of conveying genomic uncertainty during pregnancy. Trial registration ACTRN12620000446965p; Registered on April 6, 2020.

Higher maternal pre-pregnancy body mass index (ppBMI) is associated with increased neonatal morbidity, as well as with pregnancy complications and metabolic outcomes in offspring later in life. The placenta is a key organ in fetal development and has been proposed to act as a mediator between the mother and different health outcomes in children. The overall aim of the present work is to investigate the association of ppBMI with epigenomewide placental DNA methylation (DNAm) in 10 studies from the PACE consortium, amounting to 2631 mother-child pairs. We identify 27 CpG sites at which we observe placental DNAm variations of up to 2.0% per 10 ppBMI-unit. The CpGs that are differentially methylated in placenta do not overlap with CpGs identified in previous studies in cord blood DNAm related to ppBMI. Many of the identified CpGs are located in open sea regions, are often close to obesity-related genes such as GPX1 and LGR4 and altogether, are enriched in cancer and oxidative stress pathways. Our findings suggest that placental DNAm could be one of the mechanisms by which maternal obesity is associated with metabolic health outcomes in newborns and children, although further studies will be needed in order to corroborate these findings., French Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences de l'Univers (INSU), Swiss National Science Foundation (SNSF), European Commission, Ministry of Science and Innovation, Spain (MICINN), Spanish Government FJC2018-036729, European Development Fund, European Social Fund (ESF)

Accurate information on dose, frequency and timing of maternal alcohol consumption is critically important when investigating fetal risks from prenatal alcohol exposure. Identification of distinct alcohol use behaviours can also assist in developing directed public health interventions to prevent adverse child outcomes, including Fetal Alcohol Spectrum Disorder. We aimed to determine group-based trajectories of time-specific, unit-level, alcohol consumption using data from 1458 pregnant women in the Asking Questions about Alcohol in Pregnancy (AQUA) longitudinal study in Melbourne, Australia. Six alcohol consumption trajectories were identified incorporating four timepoints across gestation. Labels were assigned based on consumption in trimester one and whether alcohol use was continued throughout pregnancy: abstained (33.8%); low discontinued (trimester one) (14.4%); moderate discontinued (11.7%); low sustained (13.0%); moderate sustained (23.5%); and high sustained (3.6%). Median weekly consumption in trimester one ranged from 3 grams (low discontinued) to 184 grams of absolute alcohol (high sustained). Alcohol use after pregnancy recognition decreased dramatically for all sustained drinking trajectories, indicating some awareness of fetal risk. Improved understanding of factors that contribute to alcohol consumption in pregnancy in specific sub-populations is critical when developing prevention strategies. Maternal characteristics associated with different trajectories can inform the strategic development of such initiatives.

We would like to thank all the families that participated in these studies for their generous contribution. Detailed acknowledgements and funding can be found in Sup plementary Material., Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41467-021-24558-y, Maternal smoking during pregnancy contributes to poor birth outcomes. Here the authors perform a meta-analysis of the associations between maternal smoking during pregnancy and placental DNA methylation and identify links between these and poor birth outcomes, which may better inform the mechanisms through which smoking impacts placental function and fetal growth. Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth., Canadian Institutes of Health Research (CIHR) MOP 115071, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Environmental Health Sciences (NIEHS) P30 ES019776 - R01 ES022223 - P01 ES022832, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of General Medical Sciences (NIGMS) P20 GM104416, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) R01 MH094609

Data on the prognostic impact of pretherapy 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) in follicular lymphoma (FL) is conflicting. The predictive utility of pretherapy total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) on outcome appears to vary between regimens. Chemoimmunotherapies vary in the extent of T-cell depletion they induce. The role of intratumoral T cells on pretherapy FDG-PET parameters is undefined. We assessed pretherapy FDG-PET parameters and quantified intratumoral T cells by multiple methodologies. Low intratumoral T cells associated with approximately sixfold higher TMTV, and FL nodes from patients with high TMTV showed increased malignant B-cell infiltration and fewer clonally expanded intratumoral CD8+ and CD4+ T-follicular helper cells than those with low TMTV. However, fluorescently labeled glucose uptake was higher in CD4+ and CD8+ T cells than intratumoral B cells. In patients with FDG-PET performed prior to excisional biopsy, SUVmax within the subsequently excised node associated with T cells but not B cells. In summary, TMTV best reflects the malignant B-cell burden in FL, whereas intratumoral T cells influence SUVmax. This may contribute to the contradictory results between the prognostic role of different FDG-PET parameters, particularly between short- and long-term T-cell–depleting chemoimmunotherapeutic regimens. The impact of glucose uptake in intratumoral T cells should be considered when interpreting pretherapy FDG-PET in FL.

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.

The Ross Sea, Antarctica, is amongst the least human-impacted marine environments, and the site of the world’s largest Marine Protected Area. We present research on two components of the Ross Sea benthic fauna: mega-epifauna, and macro-infauna, sampled using video and multicore, respectively, on the continental shelf and in previously unsampled habitats on the northern continental slope and abyssal plain. We describe physical habitat characteristics and community composition, in terms of faunal diversity, abundance, and functional traits, and compare similarities within and between habitats. We also examine relationships between faunal distributions and ice cover and productivity, using summaries of satellite-derived data over the decade prior to our sampling. Clear differences in seafloor characteristics and communities were noted between environments. Seafloor substrates were more diverse on the Slope and Abyss, while taxa were generally more diverse on the Shelf. Mega-epifauna were predominantly suspension feeders across the Shelf and Slope, with deposit feeder-grazers found in higher or equal abundances in the Abyss. In contrast, suspension feeders were the least common macro-infaunal feeding type on the Shelf and Slope. Concordance between the mega-epifauna and macro-infauna data suggests that non-destructive video sampling of mega-epifauna can be used to indicate likely composition of macro-infauna, at larger spatial scales, at least. Primary productivity, seabed organic flux, and sea ice concentrations, and their variability over time, were important structuring factors for both community types. This illustrates the importance of better understanding bentho-pelagic coupling and incorporating this in biogeographic and process-distribution models, to enable meaningful predictions of how these ecosystems may be impacted by projected environmental changes. This study has enhanced our understanding of the distributions and functions of seabed habitats and fauna inside and outside the Ross Sea MPA boundaries, expanding the baseline dataset against which the success of the MPA, as well as variability and change in benthic communities can be evaluated longer term.

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.

Craniopharyngiomas represent a unique management challenge. Aggressive surgical management has traditionally been associated with high rates of morbidity. Modern surgical techniques, and increasing practice of subtotal resection followed by radiosurgery, have reduced morbidity and mortality rates. One cause of postoperative morbidity, and indeed mortality, is aseptic meningitis from spill-out of craniopharyngioma cyst contents. We have developed a surgical technique for the management of large craniopharygngioma cysts extending into the third ventricle, to reduce this risk. We describe a technique of using an epidural catheter, inserted into the working channel of a neuroendoscope, to decompress the cystic portion of a craniopharyngioma cyst before opening the cyst wall widely, preventing spill-out of large volumes of cyst content into the ventricular system. We have had no cases of aseptic meningitis, nor any complications, from use of the described technique. We believe that this is a safe and effective technique of decompression and fenestration of large suprasellar craniopharyngioma cysts that reduces rates of aseptic meningitis and the associated morbidity and mortality from this.

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.

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

PurposeThe Asking Questions about Alcohol in Pregnancy (AQUA) study, established in 2011, is a pre-birth cohort of 1570 mother and child pairs designed to assess the effects of low to moderate prenatal alcohol exposure and sporadic binge drinking on long-term child development. The current follow-up of the children, now aged 6 to 8 years, aims to strengthen our understanding of the relationship between these levels of prenatal alcohol exposure and neuropsychological functioning, facial dysmorphology, and brain structure & function.Findings to dateOver half (59%) of mothers consumed some alcohol during pregnancy, with one in five reporting at least one binge drinking episode prior to pregnancy recognition. Children’s craniofacial shape was examined at 12 months of age, and low to moderate prenatal alcohol exposure was associated with subtle midface changes. At two years of age, formal developmental assessments showed no evidence that cognitive, language or motor outcome was associated with any of the prenatal alcohol exposures investigated.ParticipantsBetween June 2018 and April 2021, 802 of the 1342 eligible AQUA study families completed a parent-report questionnaire (60%). Restrictions associated with COVID-19 pandemic disrupted recruitment, but early school-age neuropsychological assessments were undertaken with 696 children (52%), and 482 (36%) craniofacial images were collected. A pre-planned, exposure-representative subset of 146 random children completed a brain MRI. The existing AQUA study biobank was extended through collection of 427 (32%) child buccal swabs.Future plansWe will investigate the relationship between prenatal alcohol exposure and specific aspects of neurodevelopment at 6-8 years, including brain structure & function. We will also determine whether craniofacial changes identified at 12 months of age are predictive of later developmental impairments. The contribution of genetics and epigenetics to individual variations in outcomes will be examined in conjunction with established and future national and international collaborations.STRENGTHS AND LIMITATIONSThe Asking Questions about Alcohol in Pregnancy (AQUA) cohort study was specifically designed to prospectively collect high-quality data on low to moderate prenatal alcohol exposure and relevant confounders to investigate the risk to offspring neurodevelopment.The children are being followed up for the third time at 6-8 years, using sensitive measures of neuropsychological function, 3D craniofacial photography, and brain MRI.A biobank of birth samples and maternal and child buccal DNA enables investigation of the contribution of genetic and epigenetic factors to neurodevelopmental outcomes.Despite carefully designed questions, reporting bias will need to be considered in the interpretation of findings, especially around alcohol use.The generalisability of some findings will be limited to a general antenatal population of Caucasian women, from middle-income backgrounds and with a low-risk pregnancy.

This annual report from the Victorian Prenatal Diagnosis Database (VPDD) summarises the results of fetal chromosome testing in Victoria during 2019. Victoria has approximately 76,111 confinements annually, and a median maternal age of 32 years (Australian Bureau of Statistics; https://www.abs.gov.au/).The VPDD has been collecting state-wide data on prenatal diagnostic procedures since 1976. We acknowledge our long-standing collaborators - the Victorian Clinical Genetics Service (VCGS) and Monash Medical Centre (current contributors), Melbourne Pathology and Australian Clinical Labs (former contributors).

OBJECTIVES/HYPOTHESIS: To assess the relative cost-effectiveness of exome sequencing for isolated congenital deafness compared with standard care. STUDY DESIGN: Incremental cost-effectiveness and cost-benefit analyses were undertaken from the perspective of the Australian healthcare system using an 18-year time horizon. METHODS: A decision tree was used to model the costs and outcomes associated with exome sequencing and standard care for infants presenting with isolated congenital deafness. RESULTS: Exome sequencing resulted in an incremental cost of AU$1,000 per child and an additional 30 diagnoses per 100 children tested. The incremental cost-effectiveness ratio was AU$3,333 per additional diagnosis. The mean societal willingness to pay for exome sequencing was estimated at AU$4,600 per child tested relative to standard care, resulting in a positive net benefit of AU$3,600. Deterministic and probabilistic sensitivity analyses confirmed the cost-effectiveness of exome sequencing. CONCLUSIONS: Our findings demonstrate the cost-effectiveness of exome sequencing in congenital hearing loss, through increased diagnostic rate and consequent improved process of care by reducing or ceasing diagnostic investigation or facilitating targeted further investigation. We recommend equitable funding for exome sequencing in infants presenting with isolated congenital hearing loss. LEVEL OF EVIDENCE: N/A. Laryngoscope, 131:E2371-E2377, 2021.

Objectives: Safe provision of transsphenoidal surgery for pituitary tumors (TSS) has been significantly disrupted by theCOVID-19 pandemic. We assess whether there was any compromise to patient and staff safety from COVID-19 fromundertaking TSS during the COVID-19 pandemic in our institution. Methods: We retrospectively review all the cases performed between the March 1 and September 11, 2020 and comparedour findings to the cases performed between March 1 and September 11, 2019. In doing so, we aim to assess the impact ofthe COVID-19 pandemic on our service. We review individual patient records to identify any COVID-19 relatedcomplications during or after their inpatient stay and evaluate any COVID-19 confirmed cases among staff involved in theseoperations. Results: Twenty-seven patients had TSS since March 2020 versus 39 during the same period in 2019. Of the patientstreated during the COVID-19 pandemic, 10 required urgent TSS for apoplexy or visual compromise, 10 needed expeditedsurgery and seven had elective procedures. Average duration of GA was 43 minutes (vs. 25 minutes in 2019), surgery 78minutes (vs. 79 minutes in 2019). The length of stay postsurgery was 2 days on average ([range: 1-9 days] vs. 3.6 days in2019 [range: 1-27 days]). No COVID-19 related complications were seen, no new infections developed and no staffinvolved contracted COVID-19. Measures taken to minimize risk included patients self-isolating prior to surgery andpreoperative COVID-19 testing with all patients operated on after April 2020 having received a COVID-19 antigen test at 1to 4 days before the date of their surgery. Theater and anesthetic process followed Trust COVID-19 guidance and physicalmeasures to reduce the spread of aerosols generated were used (clear sheet applied over the patient with small openingsfor instruments and endoscope ([ Fig. 1 ]), nasal latex slits ([ Fig. 2 ]), and full PPE (whenever necessary). Conclusion: We did not see any patient or staff COVID-19 complications or have any new COVID-19 cases contracted byundertaking transphenoidal surgery during the COVID-19 pandemic for pituitary tumors (TSS), with appropriate testing andprecautions in place. Anesthetic time did increase for these cases but there again were no compromises to patient safety orrecovery from this.

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.

Background: The endonasal transsphenoidal approach (TSA) has emerged as the preferred approach in order to treat pituitary adenoma and related sellar pathologies. The recently adopted expanded endonasal approach (EEA) has improved access to the ventral skull base whilst retaining the principles of minimally invasive surgery. Despite the advantages these approaches offer, cerebrospinal fluid (CSF) rhinorrhoea remains a common complication. There is currently a lack of comparative evidence to guide the best choice of skull base reconstruction, resulting in considerable heterogeneity of current practice. This study aims to determine: (1) the scope of the methods of skull base repair; and (2) the corresponding rates of postoperative CSF rhinorrhoea in contemporary neurosurgical practice in the UK and Ireland. Methods: We will adopt a multicentre, prospective, observational cohort design. All neurosurgical units in the UK and Ireland performing the relevant surgeries (TSA and EEA) will be eligible to participate. Eligible cases will be prospectively recruited over 6 months with 6 months of postoperative follow-up. Data points collected will include: demographics, tumour characteristics, operative data), and postoperative outcomes. Primary outcomes include skull base repair technique and CSF rhinorrhoea (biochemically confirmed and/or requiring intervention) rates. Pooled data will be analysed using descriptive statistics. All skull base repair methods used and CSF leak rates for TSA and EEA will be compared against rates listed in the literature. Ethics and dissemination: Formal institutional ethical board review was not required owing to the nature of the study–this was confirmed with the Health Research Authority, UK. Conclusions: The need for this multicentre, prospective, observational study is highlighted by the relative paucity of literature and the resultant lack of consensus on the topic. It is hoped that the results will give insight into contemporary practice in the UK and Ireland and will inform future studies.

Study questionIs DNA methylation at birth associated with having been conceived by assisted reproductive technologies (ART)?Summary answerThis study shows does not provide strong evidence of an association of conception by ART with variation in infant blood cell DNA methylation.What is known alreadyAssisted reproductive technologies (ART) are procedures used to help infertile/subfertile couples conceive. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with ART could reveal new insights into the biological effects of ART and potential adverse offspring outcomes.Study designWe investigated the association of DNA methylation and ART using a case-control study design (N=205 ART cases and N=2439 non-ART controls in discovery cohorts; N=149 ART cases and N=58 non-ART controls in replication cohort).Participants/materials, settings, methodWe assessed the association between ART and DNA methylation at birth in cord blood (205 ART conceptions and 2439 naturally conceived controls) at >450000 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 chanceThe ALSPAC and MoBa meta-analysis revealed evidence of association between conception by ART and DNA methylation (false-discovery-rate-corrected p-value < 0.05) at 5 CpG sites which are annotated to 2 genes. Methylation at 3 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 ART-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling.Limitations, reasons for cautionsWhile insufficient power is likely, heterogeneity in types of ART and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to ART.Wider implications of the findingsART-conceived newborns 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.

Blockade of the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+ regulatory T cells (Tregs) and was also highly expressed on CD8+ T cells compared with CD4+ non-Tregs (both P = .008). LAG3high TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P = .03). LAG3high gene expression was associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high were fivefold more likely to be LAG3high (P < .0001). Patients who were LAG3high/PD-L1high had an inferior progression-free survival (P = .011) and overall survival (P = .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high expression is associated with poor outcome independent of conventional prognosticators.

STUDY QUESTIONS What are the long-term health and reproductive outcomes for young men conceived using ICSI whose fathers had spermatogenic failure (STF)? Are there epigenetic consequences of ICSI conception? WHAT IS KNOWN ALREADY Currently, little is known about the health of ICSI-conceived adults, and in particular the health and reproductive potential of ICSI-conceived men whose fathers had STF. Only one group to date has assessed semen parameters and reproductive hormones in ICSI-conceived men and suggested higher rates of impaired semen quality compared to spontaneously conceived (SC) peers. Metabolic parameters in this same cohort of men were mostly comparable. No study has yet evaluated other aspects of adult health. STUDY DESIGN, SIZE, DURATION This cohort study aims to evaluate the general health and development (aim 1), fertility and metabolic parameters (aim 2) and epigenetic signatures (aim 3) of ICSI-conceived sons whose fathers had STF (ICSI study group). There are three age-matched control groups: ICSI-conceived sons whose fathers had obstructive azoospermia (OAZ) and who will be recruited in this study, as well as IVF sons and SC sons, recruited from other studies. Of 1112 ICSI parents including fathers with STF and OAZ, 78% (n = 867) of mothers and 74% (n = 823) of fathers were traced and contacted. Recruitment of ICSI sons started in March 2017 and will finish in July 2020. Based on preliminary participation rates, we estimate the following sample size will be achieved for the ICSI study group: mothers n = 275, fathers n = 225, sons n = 115. Per aim, the sample sizes of OAZ-ICSI (estimated), IVF and SC controls are: Aim 1—OAZ-ICSI: 28 (maternal surveys)/12 (son surveys), IVF: 352 (maternal surveys)/244 (son surveys), SC: 428 (maternal surveys)/255 (son surveys); Aim 2—OAZ-ICSI: 12, IVF: 72 (metabolic data), SC: 391 (metabolic data)/365 (reproductive data); Aim 3—OAZ-ICSI: 12, IVF: 71, SC: 292. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible parents are those who underwent ICSI at one of two major infertility treatment centres in Victoria, Australia and gave birth to one or more males between January 1994 and January 2000. Eligible sons are those aged 18 years or older, whose fathers had STF or OAZ, and whose parents allow researchers to approach sons. IVF and SC controls are age-matched men derived from previous studies, some from the same source population. Participating ICSI parents and sons complete a questionnaire, the latter also undergoing a clinical assessment. Outcome measures include validated survey questions, physical examination (testicular volumes, BMI and resting blood pressure), reproductive hormones (testosterone, sex hormone-binding globulin, FSH, LH), serum metabolic parameters (fasting glucose, insulin, lipid profile, highly sensitive C-reactive protein) and semen analysis. For epigenetic and future genetic analyses, ICSI sons provide specimens of blood, saliva, sperm and seminal fluid while their parents provide a saliva sample. The primary outcomes of interest are the number of mother-reported hospitalisations of the son; son-reported quality of life; prevalence of moderate-severe oligozoospermia (sperm concentration STUDY FUNDING/COMPETING INTERESTS This study is funded by an Australian National Health and Medical Research Council Partnership Grant (NHMRC APP1140706) and was partially funded by the Monash IVF Research and Education Foundation. L.R. is a minority shareholder and the Group Medical Director for Monash IVF Group, and reports personal fees from Monash IVF group and Ferring Australia, honoraria from Ferring Australia, and travel fees from Merck Serono, MSD and Guerbet; R.J.H. is the Medical Director of Fertility Specialists of Western Australia and has equity in Western IVF; R.I.M. is a consultant for and a shareholder of Monash IVF Group and S.R.C. reports personal fees from Besins Healthcare and non-financial support from Merck outside of the submitted work. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER Not applicable. TRIAL REGISTRATION DATE Not applicable. DATE OF FIRST PATIENT’S ENROLMENT Not applicable.

Background A significant increase in the use of intracytoplasmic sperm injection (ICSI) since its introduction in 1992 has been observed worldwide, including beyond its original intended use for severe male factor infertility. Concerns regarding ICSI include the effects of poor quality spermatozoa on offspring health and future fertility, and of the technique itself. The health and development of ICSI-conceived children beyond early infancy have not been comprehensively assessed. Objective A systematic review of health outcomes of ICSI-conceived offspring beyond the neonatal period compared to spontaneously conceived (SC) offspring. Design PubMed, OVID Medline/Embase, InformIT, Web of Science, and ProQuest databases were searched for studies reporting on health outcomes in ICSI-conceived offspring beyond 28 days after birth. Main outcomes measure(s) Physical and psychosocial health. Results The search strategy yielded 2826 articles. Of these, 2580 were not relevant or did not meet inclusion criteria and 138 were duplicates. One hundred and eight full-text papers were evaluated further, and 48 satisfied the inclusion criteria. Most studies reported on neurodevelopment during early infancy and childhood with reassuring results. Growth, vision, and hearing of ICSI and SC offspring also appear comparable, although important differences in general physical health, and particularly metabolic and reproductive health have been described, including recently poorer semen quality among ICSI-conceived young adult men compared to SC peers. Conclusion Whilst neurodevelopment, growth, vision, and hearing appear similar between ICSI and SC children, evidence suggests differences in general physical health, and metabolic and reproductive endpoints. The clinical significance of many findings, however, remains unclear, and further prospective, large, and good quality studies with a focus on all these health outcomes in ICSI-conceived young adults are required.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare central nervous system inflammatory disorder primarily affecting the brainstem and cerebellum. We report a case of CLIPPERS in a 45-year-old man presenting with left facial numbness and dizziness. Imaging studies were conducted repeatedly over an 8-year follow-up period. Given diagnostic uncertainty in the early stages of the disease, three serial biopsies were obtained, which together with the clinical and radiological findings, led to the diagnosis. This case highlights the diagnostic challenges regarding the rare entity of CLIPPERS and discusses the main differential diagnoses that are necessary to consider. Additionally, some of the atypical features of this case, including the presenting finding of a large, solidly enhancing lesion on radiological imaging and prominent plasma cells on pathology, contribute to expanding the spectrum of appearances for CLIPPERS.

Congenital hearing impairment (HI) is the most common sensory impairment and can be isolated or part of a syndrome. Diagnosis through newborn hearing screening and management through early intervention, hearing aids and cochlear implantation is well established in the Australian setting; however understanding the genetic basis of congenital HI has been missing. This population-derived cohort comprised infants with moderate-profound bilateral HI born in the 2016-2017 calendar years, detected through newborn hearing screening. Participants were recruited through an integrated paediatric, otolaryngology and genetics HI clinic and offered whole exome sequencing (WES) on a HiSeq4000 or NextSeq500 (Illumina) platform with a targeted average sequencing depth of 100x and chromosome microarray on the Illumina Infinium core exome-24v1.2 platform. Of those approached, 68% (106/156) consented to participate. The rate of genetic diagnosis was 56% (59/106), significantly higher than standard of care (GJB2/6 sequencing only), 21% (22/106). There were clinical implications for the 106 participants: 36% required no further screening, 9% had tailored screening initiated, 2% were offered treatment and 4% had informed care for a complex neurodevelopmental syndrome. WES in this cohort demonstrates the range of diagnoses associated with congenital HI and confirms the genetic heterogeneity of congenital HI. The high diagnostic yield and clinical implications emphasises the need for genomic sequencing to become standard of care.

To determine the prevalence and sociodemographic and hospitalization history of genetic conditions in a sample of inpatients in a pediatric hospital in 2017, and to compare results with unpublished studies from 1985, 1995, and 2007. Two weeks of admissions were classified according to a pre-existing categorization, based on genetic etiology, encompassing chromosomal and monogenic conditions, multifactorial (MF) conditions, and no known genetic cause. In 2017, 299 (16%) patients had chromosomal or monogenic conditions, 6–7% more than 2007 and 1995, but similar to 1985. Autosomal dominant (AD) conditions increased from

The Department of Neurosurgery in Oxford University Hospitals NHS Foundation Trust is a tertiary referral centre which treats approximately 1500 neurosurgery inpatients per year. Feedback from junior doctors in the General Medical Council (GMC) National Training Survey 2018 revealed low rates of trainee satisfaction. To investigate the underlying cause, an anonymous online questionnaire was designed which collected data on various aspects of junior doctors’ experience in the department. Questionnaire responses from 12 out of 16 junior doctors identified problems with frequent overtime work, excessive administrative tasks, lack of protected training opportunities and variable levels of senior supervision on the ward.To reduce overtime working, the rota was re-designed to improve staffing levels in afternoons/evenings and a formal handover meeting was introduced. A departmental teaching programme with weekly seminars on the management of neurosurgical conditions and neuroanatomy was developed. This was supported by the introduction of a neurosurgery curriculum aimed specifically at junior doctors.The role of a ‘Ward Registrar’ was enhanced to provide structured support, supervision and training to junior doctors. This project has highlighted the value of a local questionnaire in seeking anonymised, honest feedback from junior doctors and encouraging engagement in the QI process. We anticipate that the frequent turnover of junior doctors in the department will pose a challenge for the project. It is therefore being linked to formal quality improvement training and a local peer support hub to ensure sustainability. Low levels of trainee satisfaction are likely to be multifactorial in nature and can be effectively investigated with a structured online questionnaire. By identifying key areas of concern at a local level, targeted QI projects can be designed and led by trainees, with an overall improvement in satisfaction, working hours and training opportunities.

Aim: Epigenetic changes, in particular in the placenta, may mediate the effects of prenatal alcohol exposure (PAE) on children's health. We examined the relationship between PAE patterns, based on dose and timing, and placental global DNA methylation. Methods: Using linear regression analysis, we examined the association between different PAE categories and placental global DNA methylation (n = 187), using the proxy measure of Alu-interspersed repeats. Results: Following adjustment for important covariates, we found no evidence of an association between PAE and placental global DNA methylation overall. However, when stratifying by newborn sex, PAE throughout pregnancy was associated with higher placental global DNA methylation (1.5%; p = 0.01) of male newborns. Conclusion: PAE may have sex-specific effects on placental global DNA methylation if alcohol is consumed throughout pregnancy.

BACKGROUND: Advances in technology can bring great benefits to human health, but their implementation may be influenced by socioeconomic factors, particularly in the field of prenatal screening for Down syndrome. AIM: To analyse screening test indications for, and diagnostic yield of, invasive prenatal diagnostic testing (PNDx) according to socioeconomic status. METHODS: Retrospective analysis of population-based data on PNDx and karyotype results for 2014-2015 in the Australian state of Victoria. Women having PNDx

Objective 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. Methods 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 χ2 tests for trend or difference in proportions, as appropriate. Results During 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 Conclusions 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

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.

PurposePopulation-based carrier screening for fragile X syndrome (FXS) is still not universally endorsed by professional organizations due to concerns around genetic counseling for complex information and potential for psychosocial harms.MethodsWe determined uptake levels, decision making, and psychosocial impact in a prospective study of pregnant and nonpregnant Australian women offered FXS carrier screening in clinical settings. Women received pretest genetic counseling, and completed questionnaires when deciding and one month later.ResultsOf 1,156 women recruited, 83.1% returned the first questionnaire with 70.6% nonpregnant and 58.8% pregnant women choosing testing (χ2=16.98, P

Introduction: Vestibular schwannomas (VS) account for approximately 85% of tumors in the cerebello-pontine angle, with a lifetime incidence of approximately 1 in 1000. Most are sporadic, with approximately 5% related to the tumor predisposition syndrome Neurofibromatosis Type 2 (NF2). The mainstays of management strategies are: observation, surgery, radiosurgery/radiotherapy and, for patients with NF2 and rapidly growing tumors or deteriorating neurologic function the targeted therapy bevacizumab. While morbidity and mortality rates related to treatment of VS have improved dramatically over the last decades, there are still significant improvements that could be made, in particular with regards to long-term facial nerve and hearing outcomes.Areas covered: The epidemiology and diagnosis of VS are discussed, followed by the different management strategies and outcomes of those for both sporadic and NF2 related tumors. An extensive literature review has been performed to inform this review article using PubMed and Google Scholar.Expert commentary: The future direction of VS management lies in obtaining longer-term follow-up data for patients with treated VS, and in improved understanding of cellular pathways and targeted therapies.

The use of donor sperm is increasing, yet limited information is available about the health and development of children conceived from donor sperm. This retrospective descriptive study aimed to assess health and development in a cohort of school-aged children who were conceived using donor sperm. Participants included 224 children, aged 5-11 years, who were conceived using donor sperm. Participants' mothers completed a questionnaire comprising validated scales examining their child's current and past physical, psychosocial and mental health, healthcare needs and child development, as well as the mothers' health and wellbeing. At the conclusion of the study, the response rate was 296 out of 407 (72.7%), with a participation rate of 224 out o 407 (55.0%). Compared with the normative Australian population, sperm donor-conceived children had similar physical, psychosocial and mental health and development. A modest increase in healthcare needs was evident. The study concludes that in school-aged children conceived using donor sperm, most aspects of child health and wellbeing are similar to the general population.

Importance Genomic newborn screening (gNBS) may optimize the health and well-being of children and families. Screening programs are required to be evidence based, acceptable, and beneficial. Objectives To identify what has been discovered following the reporting of the first gNBS pilot projects and to provide a summary of key points for the design of gNBS. Evidence Review A systematic literature review was performed on April 14, 2021, identifying 36 articles that addressed the following questions: (1) what is the interest in and what would be the uptake of gNBS? (2) what diseases and genes should be included? (3) what is the validity and utility of gNBS? and (4) what are the ethical, legal, and social implications? Articles were only included if they generated new evidence; all opinion pieces were excluded. Findings In the 36 articles included, there was high concordance, except for gene disease inclusion, which was highly variable. Key findings were the need for equitable access, appropriate educational materials, and informed and flexible consent. The process for selecting genes for testing should be transparent and reflect that parents value the certainty of prediction over actionability. Data should be analyzed in a way that minimizes uncertainty and incidental findings. The expansion of traditional newborn screening (tNBS) to identify more life-threatening and treatable diseases needs to be balanced against the complexity of consenting parents of newborns for genomic testing as well as the risk that overall uptake of tNBS may decline. The literature reflected that the right of a child to self-determination should be valued more than the possibility of the whole family benefiting from a newborn genomic test. Conclusions and Relevance The findings of this systematic review suggest that implementing gNBS will require a nuanced approach. There are gaps in our knowledge, such as the views of diverse populations, the capabilities of health systems, and health economic implications. It will be essential to rigorously evaluate outcomes and ensure programs can evolve to maximize benefit.

Summary The use of intra-cytoplasmic sperm injection (ICSI) has increased significantly worldwide, often chosen instead of in vitro fertilization (IVF), yet long-term health outcomes are unknown and health differences between ICSI and IVF conceptions have not been comprehensively assessed. A systematic review of health outcomes of ICSI-conceived offspring beyond the neonatal period compared to IVF-conceived offspring was carried out. PubMed, OVID Medline/Embase, Informit, Web of Science and Proquest databases were searched on 9 November 2016 for studies reporting on health outcomes in ICSI-conceived offspring beyond 28 days after birth. Physical and psychosocial health were the main outcome measures. The search strategy yielded 2781 articles; 2539 were not relevant or did not meet inclusion criteria and 137 were duplicates. One hundred and five full-text papers were evaluated further and 34 satisfied the inclusion criteria. Studies comparing ICSI- and IVF-conceived children suggest their neurodevelopment is comparable. Growth and aspects of physical health are also similar; however, studies are few and limited to childhood. ICSI-conceived children may be at increased risk of autism and intellectual impairment. No difference in risk of childhood cancer was reported in one study. Whilst the neurodevelopment of ICSI-conceived children appears comparable to those of IVF conception, data relating to neurodevelopmental disorders, growth, physical health and childhood cancer are inconclusive. Further research into health outcomes in adolescence and adulthood is required before conclusions can be drawn about the long-term safety of ICSI compared to IVF. Until then, ICSI might be better reserved for its original intended use, male-factor infertility.

BACKGROUND: Since the 1970s, a range of facial, neurostructural and neurocognitive adverse effects have been shown to be associated with prenatal alcohol exposure. Typically, these effects are studied individually and not in combination. Our objective is to improve the understanding of the teratogenic effects of prenatal alcohol exposure by simultaneously considering face-brain morphology and neurocognitive measures. METHODS: Participants were categorized as control (n=47), fetal alcohol syndrome (FAS, n=22) or heavily exposed prenatally, but not eligible for a FAS diagnosis (HE, n=50). Structural brain MRI images and high-resolution 3D facial images were analyzed using dense surface models of features of the face and surface shape of the corpus callosum and caudate nucleus. Asymmetry of the caudate nucleus was evaluated for correlations with neurocognitive measures. RESULTS: i. Facial growth delineations for FAS, HE and controls are replicated for the caudate nucleus and the corpus callosum. ii. Concordance of clinical diagnosis and face based control-FAS discrimination improves when the latter is combined with specific brain regions. In particular, midline facial regions discriminate better when combined with midsagittal profile of the corpus callosum. iii. A subset of HE individuals was identified with FAS-like caudate nucleus dysmorphism. The average of this HE subset was FAS-like in its facial dysmorphism. iv. Right-left asymmetry found in the caudate nuclei of controls is not apparent for FAS, is diminished for HE and correlates with neurocognitive measures in the combined FAS and HE population. CONCLUSIONS: Combined morphology analysis of the caudate nucleus, and the corpus callosum, with the face, better identify those with FAS. Caudate nucleus asymmetry was reduced for FAS compared to controls and is strongly associated with general cognitive ability, verbal learning and recall in those with prenatal alcohol exposure. This study further extends the brain-behavior relationships known to be vulnerable to alcohol teratogenesis.

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