Research question: What are the health outcomes of individuals aged 27-38 years conceived with and without assisted reproductive technology (ART)? Design: An online survey, hosted in REDCap, was used to collect information on self-reported physical, psychological and reproductive health from an established cohort of people conceived with and without ART who were now aged 27-38 years. Questions included lists of common conditions and required tick-box responses to determine prevalence. A validated scale was used to assess psychological well-being. Results: There were 313 ART-conceived (236 IVF and 77 gamete intrafallopian transfer [GIFT]) and 153 non-ART conceived respondents. No marked differences between the ART and non-ART groups were observed in physical or psychological health measures. Similar proportions in both groups had had children and reported using medically assisted reproduction to conceive. More women in the ART than the non-ART group reported at least one reproductive health disorder (P = 0.01). Male reproductive health disorders were rare in both groups. Conclusions: Subjective indicators of health were no different between ART-and non-ART-conceived individuals, except for a slight increase in adverse reproductive health disorders reported by ART-conceived female participants. This warrants closer clinical scrutiny. Overall, a larger sample and objective measures in individuals beyond 30 years of age would provide the ultimate reassurance that ART is not associated with long-term health problems. This study is the first of its kind and may provide some reassurance of safety for people conceived with ART and those who contemplate using it.

Use of intracytoplasmic sperm injection (ICSI) continues to increase as the most common mode of oocyte insemination during in vitro fertilisation (IVF), sometimes in the absence of clear indications (i.e. male factor infertility). Several studies suggest an increased risk of congenital abnormalities after ICSI. The association between the ICSI technique and long-term childhood development remains unclear. Our population-based study included singleton infants conceived via IVF and born between 2005 and 2013. The cohort included state-wide linked maternal and childhood administrative data from Victoria, Australia. The primary exposure was conception via ICSI (without severe male factor infertility), with those born following standard IVF as controls. Childhood development was examined using the Australian Early Development Census (AEDC), a broad assessment of childhood development across five domains of health and neurodevelopment performed in Australian schools every triennium at school entry (age 4–6 years). Our primary outcome used a validated global measure—developmental vulnerability—defined as scoring less than the 10th percentile in two or more of the five developmental domains (DV2). Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The adjustment variable set was determined a priori via a modified Delphi procedure. Given the use of observational data, there were missing data and inherent differences in the covariate profile between exposure cohorts. Multiple imputation, bootstrapping and doubly robust inverse probability weighted regression adjustment modelling was utilised to allow a causal interpretation of results. Our cohort (N = 3656) included 1489 IVF and 2167 ICSI-conceived children. We found no causal effect of ICSI on the risk of AEDC-defined developmental vulnerability at school-entry age compared with children conceived via standard IVF; adjusted risk difference − 1.11

Numerous studies have investigated the physical health and development of children and adolescents conceived with assisted reproductive technology (ART). Less is known about the quality of life of ART-conceived adults. This study explores the contributions of being conceived with ART and psychosocial cofactors present in young adulthood to the quality of life of adults aged 22-35 years. Young adults conceived through ART or natural conception (NC) completed questionnaires which included a standardized measure of quality of life (World Health Organization Quality of Life - Brief assessment (WHOQoL-BREF)) when aged 18-28 years (T1) and again when aged 22-35 years (T2). The WHOQoL-BREF has four domains: (i) Physical, (ii) Psychological, (iii) Social relationships and (iv) Environment. A total of 193 ART-conceived and 86 NC individuals completed both questionnaires. When accounting for other cofactors in multivariable analyses, being ART-conceived was strongly associated with higher scores (better quality of life) on the Social relationships, and Environment WHOQoL-BREF domains at T2. In addition, less psychological distress, a better relationship with parents, a better financial situation, and perceptions of being about the right weight at T1 were associated with higher scores on one or more of the WHOQoL-BREF domains at T2. In conclusion, being ART-conceived can confer advantages in quality of life in adulthood, independent of psychosocial cofactors.

Background In vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception. Methods and findings Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring <10th percentile in ≥2/5 developmental domains (physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, communication skills, and general knowledge). The second, educational outcome at age 7 to 9, was assessed using National Assessment Program–Literacy and Numeracy (NAPLAN) data (n = 342,311) and defined by overall z-score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Inverse probability weighting with regression adjustment was used to estimate population average causal effects. The study included 412,713 children across the 2 outcome cohorts. Linked records were available for 4,697 IVF-conceived cases and 168,503 controls for AEDC, and 8,976 cases and 333,335 controls for NAPLAN. There was no causal effect of IVF-conception on the risk of developmental vulnerability at school-entry compared with spontaneously conceived children (AEDC metrics), with an adjusted risk difference of −0.3% (95% CI −3.7% to 3.1%) and an adjusted risk ratio of 0.97 (95% CI 0.77 to 1.25). At age 7 to 9 years, there was no causal effect of IVF-conception on the NAPLAN overall z-score, with an adjusted mean difference of 0.030 (95% CI −0.018 to 0.077) between IVF- and spontaneously conceived children. The models were adjusted for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education. Study limitations included the use of observational data, the potential for unmeasured confounding, the presence of missing data, and the necessary restriction of the cohort to children attending school. Conclusions In this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians.

Background: We have an established cohort of singleton adults conceived by IVF and GIFT born from January 1982 to December 1992, and matched controls conceived without assisted reproduction (non-ART). They have participated in two previous studies: 1) a telephone interview study when aged 21 years on average and 2) a clinical review 6 years later. As these adults are reaching the average age of first-time parents, it is important to determine their reproductive health. Aim: To examine the reproductive health of IVF/GIFT-conceived adults compared to non-ART controls. Method: Contact details were confirmed via email or the Australian Electoral Roll. Participants were asked to complete a 15-minute online questionnaire hosted in REDCap with questions about fertility and reproductive health, well-being, self-reported health status, demographics and important potential outcome modifiers. Data were analysed using chi-squared and [Formula: see text]-tests. Results: 231 IVF (60%), 74 GIFT (65%) and 153 non-ART (41%) control participants completed the questionnaire. As there were no outcome differences between IVF and GIFT, their results are combined. The overall median age of the IVF/GIFT group and controls was 31.3 years, and 63% were female in both groups. In both groups just over a third had already given birth, with 15% and 18% respectively reporting having had medical advice for fertility concerns. Endometriosis was the only condition more common in IVF/GIFT-conceived females compared to female controls (16% versus 8%, p=0.07). There were no differences between IVF/GIFT and non-ART conceived women on other female reproductive conditions such as PCOS (18% and 16% respectively) and painful periods (26% and 30% respectively). All male conditions such as undescended testes, sperm parameters or erectile disorders were rare in both groups. Conclusion: As IVF/GIFT-conceived individuals reach the average childbearing age of 31 years, they appear to have no substantial adverse outcomes related to their reproductive health or fertility.

Background: Use of ICSI has escalated globally. Concerns include: 1) heritability of infertility, 2) effects of poor-quality spermatozoa on offspring health, 3) epigenetic effects of ICSI procedure. Aim: Compare reproductive and metabolic health of ICSI-conceived men to IVF-conceived and spontaneously conceived (SC) controls. Method: This study is part of a larger project investigating the health and development, reproductive and metabolic health, and epigenetic profiles of ICSI-conceived men (aged 18-25 years). Age-matched IVF-conceived controls were sourced from the Clinical review of the Health of 22–35-year-olds conceived with and without ART (CHART) study; SC controls were derived from the Western Australian Pregnancy Cohort (Raine) study. In subgroup analyses, ICSI-conceived men of fathers with spermatogenic failure (STF-ICSI) were compared with ICSI-conceived men whose fathers had an obstructive cause of infertility, and IVF- and SC controls. Semen parameters and serum reproductive hormones were compared between 120 ICSI-conceived men and 356 SC controls. Resting systolic and diastolic blood pressure (BP), height, weight, BMI, body surface area, and serum metabolic markers were compared between 121 ICSI-conceived men, and 74 IVF-conceived and 688 SC controls. Results: We found no compelling evidence of poorer reproductive health in ICSI-conceived men compared to age-matched SC controls, including a subgroup of STF-ICSI-conceived men. There was no correlation in any of the semen parameters between ICSI fathers and sons, including STF-ICSI father-son pairs. ICSI-conceived men compared with SC controls had higher resting diastolic BP and higher homeostasis model assessment for insulin resistance (HOMA-IR), but a similar proportion had insulin resistance. Metabolic parameters of ICSI-conceived men and IVF-conceived controls were comparable. Conclusion: This study is the largest to date and indicates comparable reproductive health of ICSI-conceived men, including men whose fathers had STF, to a similarly aged population-representative cohort of SC men. It shows few metabolic differences between ICSI-conceived men, and IVF-conceived and SC controls.

Objective: To determine the semen quality and reproductive hormones of men conceived by in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) compared with men conceived without assisted reproductive technology (ART). Design: Cohort study. Setting: IVF centers in Victoria and the Western Australian Raine Study. Patient(s): Men conceived with IVF/ICSI and men conceived without ART aged 18-25 years. Intervention(s): Clinical review. Main Outcome Measure(s): The primary outcome was the prevalence of severe oligozoospermia (sperm concentration, <5 million/ mL). The secondary outcomes were total sperm count, total and progressive motility, total motile count, normal morphology, and serum testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Results: There was no difference in the prevalence of severe oligozoospermia between 120 men conceived with IVF/ICSI and 356 men conceived without ART (9% vs. 5.3%). Men conceived with IVF/ICSI had similar sperm concentration, total sperm count, and total motile count but lower mean total (55.3% vs. 60.6%) and progressive (44.7% vs. 53.9%) sperm motility with higher mean normal morphology (8.5% vs. 5.4%). Differences in progressive motility (beta, -9.9; 95% confidence interval [CI], -16.7 similar to -3.0), normal morphology (beta, 4.3; 95% CI, 3.0-5.7), and proportion with abnormal morphology (adjusted odds ratios, 0.1; 95% CI, 0.04-0.5) remained significant after adjusting for confounders. Men conceived with IVF/ICSI had lower mean FSH (3.3 IU/L) and LH (3.9 IU/L) levels and higher mean testosterone levels (19.1 nmol/L) than controls (4.2 IU/L, 11.0 IU/L, and 16.8 nmol/L). Conclusion: This study of men conceived with IVF/ICSI found similar sperm output to men conceived without ART. Overall, the results are reassuring. ((C) 2021 by American Society for Reproductive Medicine.) El resumen esta disponible en Espanol al final del articulo.

Background: There has been increasing interest in assessing longer term developmental and health outcomes in IVF-conceived offspring compared with those born after natural conception. So far, the findings have been conflicting. The Australian Early Developmental Consensus (AEDC) assesses children in their first year of primary school across five domains; physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, and communication skills and general knowledge. Aim: To compare school entry (5-7 years of age) outcomes in IVF-conceived children in Victoria with naturally conceived controls. Method: We undertook a statewide data linkage study, with perinatal data (births 2005-2014) linked to data from major IVF providers in Victoria and the AEDC. Our approach to analysis included: complete case analysis, multiple imputation of missing data, consideration of clustering (siblings) and inverse probability weighted modeling to adjust for covariates. Our primary outcome was an AEDC score indicative of developmental vulnerability in two or more domains. We adjusted for the child’s age at assessment, sex, highest level of maternal education, maternal age, parity, SEIFA (Socio-Economic Indexes for Areas) quintile, language background other than English, and Aboriginal and Torres Strait Islander (ATSI) status. Results: The linked dataset comprised 163,418 children, including 4,441 IVF-conceived children. The IVF conceived population had older, more highly educated mothers who lived in more affluent areas and were less likely to be from non-English speaking backgrounds or identify as ATSI. IVF-conceived children were less likely to be developmentally vulnerable, in both unadjusted (RR 0.59, 95%CI: 0.52-0.67, p<0.001) and adjusted analyses (aRR 0.72, 95%CI: 0.58-0.88, p<0.001). Conclusion: Children conceived by IVF were less likely to be developmentally vulnerable in their first year of schooling, compared with peers conceived naturally. Further research should aim to understand if similar patterns are seen in other education and health domains and the potential mechanisms for these differences.

Abstract Background There is interest in longer term outcomes in IVF-conceived offspring compared with those conceived naturally. So far, the findings have been conflicting. The Australian Early Developmental Consensus (AEDC) assesses children in their first year of primary school across five domains. Methods To compare school entry outcomes in IVF-conceived children with naturally conceived controls, we undertook a statewide data linkage study, with perinatal data (2005-2014) linked to data from IVF providers in Victoria and the AEDC. Our approach to analysis included: complete case analysis, multiple imputation of missing data, consideration of clustering (siblings) and inverse probability weighted modeling to adjust for covariates. Our primary outcome was an AEDC score indicative of developmental vulnerability in two or more domains. We adjusted for confounders: child’s age at assessment, sex, highest level of maternal education, maternal age, parity, SEIFA (Socio-Economic Indexes for Areas) quintile, language background other than English, and Aboriginal and Torres Strait Islander (ATSI) status. Results The linked dataset comprised 163,418 children, including 4,441 IVF-conceived children. The IVF-conceived population had older, more highly educated mothers who lived in more affluent areas and were less likely to be from non-English speaking backgrounds or identify as ATSI. IVF-conceived children were less likely to be developmentally vulnerable, in both unadjusted (RR 0.59, 95%CI:0.52-0.67, p < 0.001) and adjusted analyses (aRR 0.72, 95%CI:0.58-0.88, p < 0.001). Conclusions IVF-conceived were less likely to be developmentally vulnerable in their first year of schooling, compared with peers conceived naturally.

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.

Background: Studies have suggested that embryo-endometrial developmental asynchrony caused by slow-growing embryos can be corrected by freezing the embryo and transferring it back in a subsequent cycle. Therefore, we hypothesized that live birth rates (LBR) would be higher in frozen embryo transfer (FET) compared with fresh embryo transfers. Objective: To compare LBR between fresh and FET cycles. Materials and Methods: A cross-sectional analysis of 10,744 single autologous embryo transfer cycles that used a single cleavage stage embryo was performed. Multivariate analysis was performed to compare LBR between FET and fresh cycles, after correcting for various confounding factors. Sub-analysis was also performed in cycles using slow embryos. Results: Both LBR (19.13% vs 14.13%) and clinical pregnancy (22.48% vs 16.25%) rates (CPR) were higher in the fresh cycle group (p < 0.00). Multivariate analysis for confounding factors also confirmed that women receiving a frozen-thawed embryo had a significantly lower LBR rate compared to those receiving a fresh embryo (OR 0.76, 95% CI 0.68-0.86, p < 0.00). In the sub-analysis of 1,154 cycles using slow embryos, there was no statistical difference in LBR (6.40% vs 6.26%, p = 0.92) or CPR (8.10% vs 7.22%, p = 0.58) between the two groups. Conclusion: This study shows a lower LBR in FET cycles when compared to fresh cycles. Our results suggest that any potential gains in LBR due to improved embryo-endometrial synchrony following FET are lost, presumably due to freeze-thaw process-related embryo damage.

I thank the College for the honour it shows me here as my 43-year career in reproductive medicine draws to its close. Dr Wilson was of Scottish descent and the Wilson family motto seems fitting for the pre-eminent obstetrician of his day…Semper Vigilans, always watchful! A comprehensive account of Dr Wilson’s life has been published.1 For my Oration, I have been charged with the task of describing how in vitro fertilisation (IVF) has evolved from no chance to better than natural fertility rates, matched for age, in 20 minutes. I had better be quick and of necessity highly selective so I will choose Forrest Gump as my avatar, for in the movie he ran everywhere and it was all about him…so, with the Oration I shall restrict my observations to advances I have initiated or been closely involved in. In Dr Wilson’s day, indeed up until the mid-1970s, there was really no demand for infertility treatment. Adoption was readily available, reaching its peak in 1971 when just under 10 000 babies were relinquished and placed for adoption in an Australia of 12 million souls. The description of how the tension between baby supply and demand ebbed and flowed is well set out in ‘The Market in Babies’.2 I suggest that at peak supply time, couples were encouraged to adopt early in their infertility with spontaneous conception commonly happening in the year after placement which one would expect in 30% of young women with poorly explained infertility3…the infertile woman was assumed to have ‘relaxed’. I believe that we are seeing a modern parallel in spontaneous conception post-IVF birth where increasingly available and affordable IVF has been offered earlier in the infertility than it once was.4 The rapid fall in babies available to adopt was due to a combination of the progressive Whitlam Government’s supporting mothers’ pension (previously they received not a penny), Judge Law as to when abortion was not unlawful and unmarried women being prescribed the pill. So suddenly demand for babies outstripped supply and fertility treatment took off just as I was parachuting into Melbourne on my 10 pound fare! Our successful treatments then, tubal microsurgery, donor insemination for male infertility and gonadotrophin ovulation induction are seldom practised now, replaced in the main by IVF which, in 1976, was experimental, in a joint program between The Queen Vic and The Women’s. The woman we treated in 1976 had a mean age of 28 with a body mass index (BMI) of 25. Now in 2019, she won’t, on average, see 37 again and her BMI is 29.2! 5 I believe that the Australian Fertility Community should continue to have a bias against helping women, particularly nulliparous women, aged 50 or more conceive as the consequences of pregnancy are concerning 6 but they should never be put at risk of multiple pregnancy, an occasional risk of travelling overseas to access treatment refused in Australia…a dilemma! Nothing it seems can be done to persuade women to start their family earlier. But surely it is worthwhile attacking the obesity epidemic! In Adelaide, Rob Norman’s group led the way7 with a lifestyle modification and weight loss program which Kate Stern and I copied in Melbourne with similar short-term success in the public system. We applied it in the private sector and lost 1 million dollars each over the two years 2008–2009 unsupported by colleagues who wouldn’t refer and by patients wanting a quick fix. Only bariatric surgery helps and even then we see that subverted with the vitamised pizza. Back to 1976…Carl Wood at the Queen Vic and Ian Johnston at The Women’s had asked for Melbourne University’s and my doctoral supervisor, Professor James B. Brown’s help in monitoring the rising oestrogen levels of human pituitary gonadotropin ovarian stimulation in urine. He was too busy but said that I could do it…all I had to do was ignore the carefully crafted rules for mono-follicular development with that follicle-stimulating hormone (FSH)/luteinising hormone human preparation. My work in 1977, published years later,8 on 83 women having laparoscopic oocyte retrieval, 71 at The Women’s and 12 at The Queen Vic, yielded no pregnancy with culture in what was essentially a basic salt solution with bovine albumin supplementation. Modern culture conditions with basically the same ovarian stimulation came too late for these brave early participants and we were not allowed by law to experiment so as to discover what the early embryo in culture needed. However, our work that year did show for the first time, the timing of sperm penetration and pronuclear formation.9 Ovarian stimulation often led to multiple cleavage stage embryo development so, in those days before embryo freezing it was common to transfer up to four embryos at a time. The usual result of four-embryo transfer was a failure but when pregnancy did occur the outcome was: singleton 65%, twins 25%, triplets 8% and quadruplets 2%. Mrs Helen Muir’s delivery in 1984 of four live boys at 34 weeks was celebrated as a triumph but it soon became clear to us that quadruplet pregnancy was a treatment failure. As confidence in embryo freezing increased over the remainder of the 1980s we gradually decreased the mode transfer number from four to three then to two. Single embryo transfer was not supported by the clinical results and was restricted to women where twin pregnancy was judged unwise for medical or past obstetrical history reasons. Nonetheless, at that time at The Women’s, we led the world in reducing embryo transfer numbers and tried to eliminate gamete intrafallopian transfer from our program due to its inherently high multiple pregnancy rate, banking on the serial transfer, two at a time usually, of the frozen-thawed excess embryos in subsequent natural cycles to give an improved cumulative outcome from that index stimulated cycle. My presentation Reducing Success Rates in a Fresh Cycle to Improve Pregnancy Outcome in 199010 fell on deaf ears for quite some time. Legislation to govern IVF practice in Victoria in 1984 and repeated and strengthened in subsequent Acts, in addition to criminalising much needed research, made it an offence to treat an unmarried heterosexual couple let alone a same sex couple or a single woman…these were forced to travel interstate (reproductive tourism). I challenged that marriage requirement in the Federal Court in 2000 and won.11 The Catholic Bishops Conference saw this victory as a threat to the institution of the family and obtained writs of Mandamus and Certiorari to sue me in the High Court12, seeking a prohibition to my practice, essentially seeking to deny me the ‘fruits of my decision’ in legalese! My solicitor cautioned me on the financial peril which lay ahead for me if the Bishops won…fortunately they didn’t. So the stage was prepared for safe donor treatment for women who wished to have a family but had no male partner and I believe that such families have become normalised in Australia. In Australia, in its early days, the Fertility Community got two things right without needing the dead hand of government upon us. First, we measured and reported everything we did through the National Perinatal Epidemiology and Statistics Unit (NPESU) and second, we established a voluntary Code of Practice, enforced by a sub-committee of The Fertility Society of Australia, RTAC. I thank Professors Michael Chapman and Georgina Chambers of the NPESU for permission to quote from the recently published 2017 results.13 Essentially, 89% of embryo transfers in Australia and New Zealand now are single and as a consequence, the twin pregnancy rate in IVF births is four percent, half the twin rate from Clomid treatment and a third of what we see with even the most careful gonadotrophin ovulation induction and without the higher multiples of FSH-stimulated intrauterine insemination. A major frustration in IVF lies in the transfer of apparently normal embryos for no pregnancy. Aneuploidy accounts for a substantial amount of unrecognised and early pregnancy loss. Embryo biopsy and five probe fluorescent in situ hybridisation in the late ’90s said nothing about the other 19 untested chromosomes, although for a while we fooled ourselves that it did! Finding a way to test all 24 chromosomes in a single biopsied cell became one of the two major research themes for Melbourne IVF during my Chairmanship. The other, which I shall shortly discuss was ovarian tissue freezing and transplantation. By 1998, in collaboration with colleagues at the then Murdoch Institute, we found a way of using comparative genomic hybridisation, a technique developed to test milligram quantities of cancer cells to show, after amplification, a result for the karyotype of a single cell obtained from cleavage stage embryo biopsy.14 Years later, this is the standard test for normality on embryos from women aged 38 or more where high aneuploidy rates justify the invasive embryo biopsy procedure.15 Embryo biopsy for the detection of a heritable condition was first performed for the cystic fibrosis gene over 20 years ago. At Melbourne IVF we have tested embryos for over 350 separate heritable conditions. There is as yet no Medicare rebate for this condition and to have an affected child survive is commonly an impoverishing event. Our College changed its guidelines this year from ‘may’ recommend to ‘should’ recommend carrier screening. I suspect that our legal friends will tell Her Honour that we should have followed our College guidelines when the first affected child whose condition could have been detected brings an action against us or our hospital. The second theme where my team had world-first success16 lay in setting the science for ovarian tissue harvesting and freezing in women soon to have life-saving but fertility-compromising or destroying treatment. The birth of children from frozen-thawed then heterotopically transplanted ovarian tissue has been truly amazing. The hazard in replacing pre-chemo-treated tissue is that it might contain micro amounts of malignant cells which might lead to a return of the cancer. Ideally, for this reason, follicle culture should be performed in vitro but we have been waiting a long time for this to work! The risk of cancer recurrence could be avoided by xenografting ovarian tissue into the severe combined immunodeficiency pig for repeated oocyte recovery but discussions with our regulators have been fruitless because of fears of retrovirus contamination. In conclusion, I am pleased to be able to report that the long-term follow-up of young IVF-conceived adults shows no deleterious effect of spending the first few days of life in the laboratory or subsequent months or indeed years at minus 198°C! The only significant finding was that as a group they were happier than controls.17-19 This article is a heavily edited version of the Arthur Wilson Memorial Oration: The Changing Landscape of Fertility Management given in Melbourne on 16 October 2019 at the Royal Australian and New Zealand College of Obstetricians and Gynaecologists 2019 Annual Scientific Meeting. The complete oration together with a slide pack may be found at Supporting Information. Supporting Information. The changing landscape of fertility treatment Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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. ((C) 2019 by American Society for Reproductive Medicine.)

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.

Introduction Despite the considerable and increasing proportion of women of reproductive age with a chronic non-communicable disease (NCD) and the potential adverse implications of many NCDs for childbearing, little is known about the fertility management experiences of women with an NCD, including their contraceptive use, pregnancy experiences and outcomes, and reproductive health care utilisation. The aim of this study was to investigate the fertility management experiences of women with an NCD and draw comparisons with women without an NCD. Method A sample of 18–50 year-old women (n = 1543) was randomly recruited from the Australian electoral roll in 2013. Of these women, 172 women reported a physical, chronic non-communicable disease: diabetes, arthritis, asthma, hypertension, heart disease, thyroid disorders, and cystic fibrosis. Respondents completed an anonymous, self-administered questionnaire. Factors associated with fertility management were identified in multivariable analyses. Results Women who reported having an NCD were significantly more likely than women who did not report an NCD to have ever been pregnant (75.9 vs. 67.5%, p = 0.034), have had an unintended pregnancy (33.47 vs. 25.5%, p = 0.026), and have had an abortion (20.3 vs. 14.2%, p = 0.044); they were less likely to consult a healthcare provider about fertility management (45.0 vs. 54.4%, p = 0.024). Similar proportions were using contraception (48.8 vs. 54.5%, p = 0.138). Conclusion The findings have implications for healthcare providers and women with an NCD and highlight the importance of addressing possible assumptions about the inability of women with an NCD to become pregnant, and ensuring women receive information about suitable methods of contraception and pre-pregnancy care.

Background: Approximately 4% of babies born in Australia are conceived by assisted reproductive technologies (ART). The artificial procedures used during ART raises the risk profile of adult-onset chronic health problems, including respiratory conditions, compared with naturally conceived children. Our aim was to determine whether adults conceived by ART have altered lung function compared with age- and sex-matched controls. Methods: As part of a large cohort study in Victoria, Australia, participants performed spirometry and multiple breath nitrogen washout (MBNW) according to current ATS/ERS guidelines. These measures were done with the clinician blinded to the case or control status of the participant. Results: 165 ART-conceived participants (94 female) and 79 naturally conceived controls (53 female) completed spirometry and a subgroup of 71 (48 ART) completed MBNW. There were no differences in mean (sd) age (27.3 (2.9) vs 27.3 (2.5) years, p=0.97) or mean (sd) BMI (25.4 (5.1) vs 25.6 (4.9) kg/m2, p=0.77) between the ART and control groups. There were no significant differences between ART and control participants for any lung function measurements. ART and control participants had similar FEV1 z-scores (mean difference (95%CI) (-0.15 (-0.39 to 0.10)), FVC z-scores (-0.08 (-0.33 to 0.16)), lung clearance index (0.37 (-0.01 to 0.73)) and functional residual capacity (0.27 (-0.20 to 0.74)). Conclusions: ART-conceived adults have comparable lung function to age- and sex-matched controls.

Background: Women with polycystic ovary syndrome (PCOS) are usually told that the condition is associated with fertility difficulties. However, little is known about their fertility management including contraceptive use, childbearing desires, and pregnancy outcomes. Aim: To compare the fertility management experiences and outcomes of Australian women with and without PCOS. Method: The 2013 Australian electoral roll was used to identify a random sample of 18- to 50-year-old women who were sent the Understanding Fertility Management in Australia survey to be completed anonymously. Factors associated with fertility management and outcomes were identified in multivariable analyses. Results: Among the 1543 women who completed and returned the survey, 113 (7.3%) reported having PCOS. Women with PCOS reported a similar rate of current contraceptive use as women without PCOS (50.4% vs. 52.6%, p = .66). However, they were significantly younger at first pregnancy (24.9 vs. 26.8 years, p = .015), more likely to have consulted a health professional about fertility management (OR: 3.86, 95% CI: 2.50-5.96, p < .001), and perceive that it would be difficult to conceive (OR: 2.31, 95% CI: 1.41-3.79, p = .001) than women without PCOS. There were no significant differences in the number of desired children, unintended pregnancies, live births, abortions or miscarriages between women with and without PCOS. Conclusion: These findings indicate that women with PCOS need more nuanced information about their fertility potential. While they may experience fertility difficulties because of their condition, they should also be informed that they can conceive spontaneously and need reliable contraception to avoid pregnancy when it is not wanted.

STUDY QUESTION What are the reproductive experiences of women who cryopreserve oocytes for non-medical reasons? SUMMARY ANSWER One in three women had been pregnant at some stage in their lives and while most still wanted to have a child or another child, very few had used their stored oocytes, predominantly because they did not want to be single parents. WHAT IS KNOWN ALREADY The number of healthy women who freeze oocytes to avoid age-related infertility is increasing. Evidence about reproductive outcomes after oocyte cryopreservation for non-medical reasons is needed to help women make informed decisions. STUDY DESIGN SIZE, DURATION A cross-sectional survey was carried out. Study packs which included a self-administered questionnaire were mailed by clinic staff to 193 eligible women. PARTICIPANTS/MATERIALS, SETTING, METHODS Women who had stored oocytes for non-medical reasons at Melbourne IVF, a private ART clinic, between 1999 and 2014 were identified from medical records and invited to complete an anonymous questionnaire about their reproductive histories and experience of oocyte cryopreservation. MAIN RESULTS AND THE ROLE OF CHANCE A total of 10 survey packs were returned to the clinic marked 'address unknown'. Of the 183 potential respondents, 96 (53%) returned the questionnaire. One respondent provided only free-text comments, thus data from 95 respondents were compiled. The mean age at the time of freezing oocytes was 37.1 years (SD ± 2.6, range: 27-42) and the average number of oocytes stored was 14.2 (SD ± 7.9, range: 0-42); 2% had attempted to store oocytes but had none suitable for freezing, 24% had stored <8 oocytes, 35% had 8-15, 25% had 16-23 and 14% had stored >23 oocytes. About one-third of respondents (34%) had been pregnant at some point in their lives. Six women (6%) had used their stored oocytes and three of them had given birth as a result. The main reason for not using stored oocytes was not wanting to be a single parent. Of the 87 (91%) women who still had oocytes stored, 21% intended to use them while 69% indicated that their circumstances would determine usage. The mean number of children respondents would ideally have liked to have was significantly higher than the number of children they expected to have (2.11 versus 1.38, P < 0.001). LIMITATIONS, REASONS FOR CAUTION The limitations are inherent to any anonymously completed questionnaire: participation bias, missing data and the possibility that some questions or response alternatives may have been ambiguous. WIDER IMPLICATIONS OF THE FINDINGS The findings add to the very limited evidence about the reproductive outcomes experienced by women who freeze oocytes for non-medical reasons and can be used to help women make informed decisions about whether to store oocytes. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by Melbourne IVF. K.H. has received honoraria from Merck-Serono, J.M. is a clinician at Melbourne IVF, F.A. is a Melbourne IVF employee, J.F. is supported by a Monash Professorial Fellowship and the Jean Hailes Professorial Fellowship which receives funding from the L and H Hecht Trust, managed by Perpetual Trustees Pty Ltd. M.K., N.P., M.H., M.P. and C.B. have no competing interests. TRIAL REGISTRATION NUMBER Not applicable.

Abstract Objective: This study aimed to explore the characteristics and circumstances of women who cryopreserved their oocytes for non-medical indications and their reasons for cryopreservation. Background: Oocyte cryopreservation for non-medical reasons is becoming increasingly common. Little is known about women who freeze their oocytes in this context. Methods: All women who had cryopreserved oocytes for non-medical indications at a large Australian fertility treatment centre from 1999 to 2014 were invited to complete an anonymous postal survey. Results: Of the 193 questionnaires mailed, 10 were returned to sender; 96/183 (53%) were completed and returned. Most respondents had completed tertiary education (90%) and were employed in professional occupations (89%). At the time of oocyte cryopreservation, 48% of women were aged at least 38 years (range 28–44 years). Most (90%) women were single when their oocytes were frozen. The lack of a partner or having a partner unwilling to commit to fatherhood were the most common reasons for oocyte freezing, which was viewed as an investment in hope against the possibility of remaining in these predicaments. Some women reported that discussions in the media and interactions with peers influenced their decisions. A few women were influenced by tests indicating a low ovarian reserve. Conclusion: These data provide new evidence about women’s characteristics, circumstances, and reasons for oocyte cryopreservation for non-medical indications that do not support pejorative conceptualisations of these women as selfish and hedonistic.