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Abstract Background There are no established guidelines for the follow up of infants born after a prenatal diagnosis of a genomic copy number variant (CNV), despite their increased risk of developmental issues. The aims of this study were (i) to determine the perinatal outcomes of fetuses diagnosed with and without a CNV, and (ii) to establish a population-based paediatric cohort for long term developmental follow up. Methods An Australian state-wide research database was screened for pregnant individuals who had a prenatal chromosomal microarray (CMA) between 2013–2019 inclusive. Following linkage to laboratory records and clinical referrer details, hospital records were manually reviewed for study eligibility. Eligible participants were mother–child pairs where the pregnancy resulted in a livebirth, the mother was able to provide informed consent in English (did not require a translator) and the mother was the primary caregiver for the child at hospital discharge after birth. Research invitations were sent by registered post at an average of six years after the prenatal diagnostic test. Statistical analysis was performed in Stata17. Results Of 1832 prenatal records examined, 1364 (74.5%) mother–child pairs were eligible for recruitment into the follow up cohort. Of the 468 ineligible, 282 (60.3%) had ‘no live pregnancy outcome’ (209 terminations of pregnancy (TOP) and 73 miscarriages, stillbirths, and infant deaths), 157 (33.5%) required a translator, and 29 (6.2%) were excluded for other reasons. TOP rates varied by the type of fetal CNV detected: 49.3% (109/221) for pathogenic CNVs, 18.2% (58/319) for variants of uncertain significance and 3.3% (42/1292) where no clinically significant CNV was reported on CMA. Almost 77% of invitation letters were successfully delivered (1047/1364), and the subsequent participation rate in the follow up cohort was 19.2% (201/1047). Conclusions This study provides Australia’s first population-based data on perinatal outcomes following prenatal diagnostic testing with CMA. The relatively high rates of pregnancy loss for those with a prenatal diagnosis of a CNV presented a challenge for establishing a paediatric cohort to examine long term outcomes. Recruiting a mother–child cohort via prenatal ascertainment is a complex and resource-intensive process, but an important step in understanding the impact of a CNV diagnosis in pregnancy and beyond. Trial registration ACTRN12620000446965p; Registered on April 6, 2020.

Plain language summary Approximately 1 in 20 men are sub-fertile or infertile yet very little is known about the causes of male infertility. Research has suggested that lifestyle choices and environmental factors contribute to infertility, but more needs to be done to identify and verify the full suite of associations. We will recruit up to 1000 Australian male partners within couples who are seeking help from fertility clinics to get pregnant. They will be asked about their general health, lifestyle and environmental exposures at home or work over their lifespan. We will compare findings between men who are sub- or infertile with men who are not. Any differences will help us understand what factors may be associated with risk of infertility in men. This study will provide important information to clinicians and to inform public policy that will lead to prevention and improved treatment strategies for infertile men. The data gathered from this study will enable future research including the genetic and epigenetic basis of male infertility.

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.

Abstract 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.

Abstract Background Recruitment of pregnant women to population health research can be challenging, especially if the research topic is sensitive. While many pregnant women may be inherently interested in research about pregnancy, there is the possibility that the nature and timing of the project may give rise to anxiety in some women, especially if the topic is sensitive or it brings about new awareness of potential pregnancy complications. Research staff undertaking recruitment need to be skilled at strategies to manage the environment, and have well developed communication and interpersonal skills to explain and promote the study and facilitate each woman’s informed decision-making regarding participation. However, the skills needed by recruitment staff to successfully engage pregnant women with a research topic are not well understood. This study aimed to address this evidence gap by providing insight into the dynamics between a pregnant woman and recruitment staff at the time of the offer to participate in an observational study about alcohol use in pregnancy. Methods Naturalistic inquiry guided a qualitative exploratory descriptive approach. Experienced recruitment staff from the Asking Questions about Alcohol in Pregnancy (AQUA) study (Muggli et al., BMC Pregnancy Childbirth 14:302, 2014) participated in individual semi-structured interviews and were asked about their experiences and approaches to engaging pregnant women. Interviews were transcribed verbatim and analysed using inductive content analysis. Results Pregnant women brought with them an inherent interest or disinterest in alcohol research, or in research in general, which formed the basis for engagement. Women responded favourably to the invitation to participate being delivered without pressure, and as part of a two-way conversation. Engagement with a sensitive topic such as alcohol use in pregnancy was facilitated by a non-judgmental and non-targeted approach. Influences such as privacy, distractions, partner’s opinion, time factors and level of clinical support either facilitated or hindered a woman’s engagement with the research. Conclusions These results provide an in-depth explanation of barriers and enablers to recruitment of pregnant women in antenatal clinics to studies that may inform strategies and the training of recruitment staff.

Abstract 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.

Abstract 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 ).

Abstract Background This paper presents drinking patterns in a prospective study of a population-based cohort of 1570 pregnant women using a combination of dose and timing to give best estimates of prenatal alcohol exposure (PAE). Novel assessments include women’s special occasion drinking and alcohol use prior to pregnancy recognition. Methods Information on up to nine types of alcoholic drink, with separate frequencies and volumes, including drinking on special occasions outside a ‘usual’ pattern, was collected for the periconceptional period and at four pregnancy time points. Weekly total and maximum alcohol consumption on any one occasion was calculated and categorised. Drinking patterns are described in the context of predictive maternal characteristics. Results 41.3 % of women did not drink during pregnancy, 27 % drank in first trimester only; most of whom stopped once they realised they were pregnant (87 %). When compared to women who abstained from alcohol when pregnant, those who drank in the first trimester only were more likely to have an unplanned pregnancy and not feel the effects of alcohol quickly. Almost a third of women continued to drink alcohol at some level throughout pregnancy (27 %), around half of whom never drank more than at low or moderate levels. When compared with abstainers and to women who only drank in trimester one, those who drank throughout pregnancy tended to be in their early to mid-thirties, smoke, have a higher income and educational attainment. Overall, almost one in five women (18.5 %) binge drank prior to pregnancy recognition, a third of whom were identified with a question about ‘special occasion’ drinking. Women whose age at first intoxication was less than 18 years (the legal drinking age in Australia), were significantly more likely to drink in pregnancy and at binge levels prior to pregnancy recognition. Conclusions We have identified characteristics of pregnant women who either abstain, drink until pregnancy awareness or drink throughout pregnancy. These may assist in targeting strategies to enhance adherence to an abstinence policy and ultimately allow for appropriate follow-up and interpretation of adverse child outcomes. Our methodology also produced important information to reduce misclassification of occasional binge drinking episodes and ensure clearly defined comparison groups.