Estimating the impact of bias in causal epidemiological studies: the case of health outcomes following assisted reproduction.

Researchers interested in causal questions must deal with two sources of error: random error (random deviation from the true mean value of a distribution), and bias (systematic deviance from the true mean value due to extraneous factors). For some causal questions, randomization is not feasible, and observational studies are necessary. Bias poses a substantial threat to the validity of observational research and can have important consequences for health policy developed from the findings. The current piece describes bias and its sources, outlines proposed methods to estimate its impacts in an observational study, and demonstrates how these methods may be used to inform debate on the causal relationship between medically assisted reproduction (MAR) and health outcomes, using cancer as an example. In doing so, we aim to enlighten researchers who work with observational data, especially regarding the health effects of MAR and infertility, on the pitfalls of bias, and how to address them. We hope that, in combination with the provided example, we can convince readers that estimating the impact of bias in causal epidemiologic research is not only important but necessary to inform the development of robust health policy and clinical practice recommendations.

Scale-up of Direct-Acting Antiviral Treatment in Prisons Is Both Cost-effective and Key to Hepatitis C Virus Elimination.

Background: The Surveillance and Treatment of Prisoners With Hepatitis C (SToP-C) study demonstrated that scaling up of direct-acting antiviral (DAA) treatment reduced hepatitis C virus (HCV) transmission. We evaluated the cost-effectiveness of scaling up HCV treatment in statewide prison services incorporating long-term outcomes across custodial and community settings. Methods: A dynamic model of incarceration and HCV transmission among people who inject drugs (PWID) in New South Wales, Australia, was extended to include former PWID and those with long-term HCV progression. Using Australian costing data, we estimated the cost-effectiveness of scaling up HCV treatment in prisons by 44% (as achieved by the SToP-C study) for 10 years (2021-2030) before reducing to baseline levels, compared to a status quo scenario. The mean incremental cost-effectiveness ratio (ICER) was estimated by comparing the differences in costs and quality-adjusted life-years (QALYs) between the scale-up and status quo scenarios over 40 years (2021-2060) discounted at 5% per annum. Univariate and probabilistic sensitivity analyses were performed. Results: Scaling up HCV treatment in the statewide prison service is projected to be cost-effective with a mean ICER of A$12 968/QALY gained. The base-case scenario gains 275 QALYs over 40 years at a net incremental cost of A$3.6 million. Excluding DAA pharmaceutical costs, the mean ICER is reduced to A$6 054/QALY. At the willingness-to-pay threshold of A$50 000/QALY, 100% of simulations are cost-effective at various discount rates, time horizons, and changes of treatment levels in prison and community. Conclusions: Scaling up HCV testing and treatment in prisons is highly cost-effective and should be considered a priority in the national elimination strategy. Clinical Trials Registration: NCT02064049.

Declining global fertility rates and the implications for family planning and family building: an IFFS consensus document based on a narrative review of the literature.

BACKGROUND: Family-planning policies have focused on contraceptive approaches to avoid unintended pregnancies, postpone, or terminate pregnancies and mitigate population growth. These policies have contributed to significantly slowing world population growth. Presently, half the countries worldwide exhibit a fertility rate below replacement level. Not including the effects of migration, many countries are predicted to have a population decline of >50% from 2017 to 2100, causing demographic changes with profound societal implications. Policies that optimize chances to have a child when desired increase fertility rates and are gaining interest as a family-building method. Increasingly, countries have implemented child-friendly policies (mainly financial incentives in addition to public funding of fertility treatment in a limited number of countries) to mitigate decreasing national populations. However, the extent of public spending on child benefits varies greatly from country to country. To our knowledge, this International Federation of Fertility Societies (IFFS) consensus document represents the first attempt to describe major disparities in access to fertility care in the context of the global trend of decreasing growth in the world population, based on a narrative review of the existing literature. OBJECTIVE AND RATIONALE: The concept of family building, the process by which individuals or couples create or expand their families, has been largely ignored in family-planning paradigms. Family building encompasses various methods and options for individuals or couples who wish to have children. It can involve biological means, such as natural conception, as well as ART, surrogacy, adoption, and foster care. Family-building acknowledges the diverse ways in which individuals or couples can create their desired family and reflects the understanding that there is no one-size-fits-all approach to building a family. Developing education programs for young adults to increase family-building awareness and prevent infertility is urgently needed. Recommendations are provided and important knowledge gaps identified to provide professionals, the public, and policymakers with a comprehensive understanding of the role of child-friendly policies. SEARCH METHODS: A narrative review of the existing literature was performed by invited global leaders who themselves significantly contributed to this research field. Each section of the review was prepared by two to three experts, each of whom searched the published literature (PubMed) for peer reviewed full papers and reviews. Sections were discussed monthly by all authors and quarterly by the review board. The final document was prepared following discussions among all team members during a hybrid invitational meeting where full consensus was reached. OUTCOMES: Major advances in fertility care have dramatically improved family-building opportunities since the 1990s. Although up to 10% of all children are born as a result of fertility care in some wealthy countries, there is great variation in access to care. The high cost to patients of infertility treatment renders it unaffordable for most. Preliminary studies point to the increasing contribution of fertility care to the global population and the associated economic benefits for society. WIDER IMPLICATIONS: Fertility care has rarely been discussed in the context of a rapid decrease in world population growth. Soon, most countries will have an average number of children per woman far below the replacement level. While this may have a beneficial impact on the environment, underpopulation is of great concern in many countries. Although governments have implemented child-friendly policies, distinct discrepancies in access to fertility care remain.

Gender inequality and utilization of ART: an international cross-sectional and longitudinal analysis.

STUDY QUESTION: What is the association between a country's level of gender equality and access to ART, as measured through ART utilization? SUMMARY ANSWER: ART utilization is associated with a country's level of gender equality even after controlling for the level of development. WHAT IS KNOWN ALREADY: Although gender equality is recognized as an important determinant of population health, its association with fertility care, a highly gendered condition, has not been explored. STUDY DESIGN, SIZE, DURATION: A longitudinal cross-national analysis of ART utilization in 69 countries during 2002-2014 was carried out. PARTICPANTS/MATERIALS, SETTING, METHODS: The Gender Inequality Index (GII), Human Development Index (HDI), and their component indicators were modelled against ART utilization using univariate regression models as well as mixed-effects regression methods (adjusted for country, time, and economic/human development) with multiple imputation to account for missing data. MAIN RESULTS AND THE ROLE OF CHANCE: ART utilization is associated with the GII. In an HDI-adjusted analysis, a one standard deviation decrease in the GII (towards greater equality) is associated with a 59% increase in ART utilization. Gross national income per capita, the maternal mortality ratio, and female parliamentary representation were the index components most predictive of ART utilization. LIMITATIONS, REASONS FOR CAUTION: Only ART was used rather than all infertility treatments (including less costly and non-invasive treatments such as ovulation induction). This was a country-level analysis and the results cannot be generalized to smaller groups. Not all modelled variables were available for each country across 2002-2014. WIDER IMPLICATIONS OF THE FINDINGS: Access to fertility care is central to women's sexual and reproductive health, to women's rights, and to human rights. As gender equality improves, so does access to ART. This relation is likely to be reinforcing and bi-directional, with progress towards global, equitable access to fertility care also improving women's status and participation in societies. STUDY FUNDING/COMPETING INTEREST(S): External funding was not provided for this study. G.D.A. declares consulting fees from Labcorp and CooperSurgical. G.D.A. is the founder and CEO of Advanced Reproductive Care, Inc., as well as the Chair of the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) and the World Endometriosis Research Foundation, both of which are unpaid roles. G.M.C. is an ICMART Board Representative, which is an unpaid role, and no payments are received from ICMART to UNSW, Sydney, or to G.M.C. to undertake this study. O.F., S.D., F.Z.-H., and E.K. report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Risk for Congenital Anomalies in Children Conceived With Medically Assisted Fertility Treatment : A Population-Based Cohort Study.

BACKGROUND: More than 2 million children are conceived annually using assisted reproductive technologies (ARTs), with a similar number conceived using ovulation induction and intrauterine insemination (OI/IUI). Previous studies suggest that ART-conceived children are at increased risk for congenital anomalies (CAs). However, the role of underlying infertility in this risk remains unclear, and ART clinical and laboratory practices have changed drastically over time, particularly there has been an increase in intracytoplasmic sperm injection (ICSI) and cryopreservation. OBJECTIVE: To investigate the role of underlying infertility and fertility treatment on CA risks in the first 2 years of life. DESIGN: Propensity score-weighted population-based cohort study. SETTING: New South Wales, Australia. PARTICIPANTS: 851 984 infants (828 099 singletons and 23 885 plural children) delivered between 2009 and 2017. MEASUREMENTS: Adjusted risk difference (aRD) in CAs of infants conceived through fertility treatment compared with 2 naturally conceived (NC) control groups-those with and without a parental history of infertility (NC-infertile and NC-fertile). RESULTS: The overall incidence of CAs was 459 per 10 000 singleton births and 757 per 10 000 plural births. Compared with NC-fertile singleton control infants (n = 747 018), ART-conceived singleton infants (n = 31 256) had an elevated risk for major genitourinary abnormalities (aRD, 19.0 cases per 10 000 births [95% CI, 2.3 to 35.6]); the risk remained unchanged (aRD, 22 cases per 10 000 births [CI, 4.6 to 39.4]) when compared with NC-infertile singleton control infants (n = 36 251) (that is, after accounting for parental infertility), indicating that ART remained an independent risk. After accounting for parental infertility, ICSI in couples without male infertility was associated with an increased risk for major genitourinary abnormalities (aRD, 47.8 cases per 10 000 singleton births [CI, 12.6 to 83.1]). There was some suggestion of increased risk for CAs after fresh embryo transfer, although estimates were imprecise and inconsistent. There were no increased risks for CAs among OI/IUI-conceived infants (n = 13 574). LIMITATIONS: This study measured the risk for CAs only in those children who were born at or after 20 weeks' gestation. Observational study design precludes causal inference. Many estimates were imprecise. CONCLUSION: Patients should be counseled on the small increased risk for genitourinary abnormalities after ART, particularly after ICSI, which should be avoided in couples without problems of male infertility. PRIMARY FUNDING SOURCE: Australian National Health and Medical Research Council.

Does a public online IVF prediction tool help set patient expectations? A mixed methods evaluation study.

STUDY QUESTION: Does a public online IVF success prediction calculator based on real-world data help set patient expectations? SUMMARY ANSWER: The YourIVFSuccess Estimator aided consumer expectations of IVF success: one quarter (24%) of participants were unsure of their estimated IVF success before using the tool; one half changed their prediction of success after using the tool and one quarter (26%) had their expectations of IVF success confirmed. WHAT IS KNOWN ALREADY: Several web-based IVF prediction tools exist worldwide but have not been evaluated for their impact on patient expectations, nor for patient perceptions of usefulness and trustworthiness. STUDY DESIGN, SIZE, DURATION: This is a pre-post evaluation of a convenience sample of 780 online users of the Australian YourIVFSuccess Estimatorhttps://yourivfsuccess.com.au/ between 1 July and 31 November 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were eligible if they were over 18 years of age, Australian residents, and considering IVF for themselves or their partner. Participants filled in online surveys before and after using the YourIVFSuccess Estimator. MAIN RESULTS AND THE ROLE OF CHANCE: The response rate of participants who completed both surveys and the YourIVFSuccess Estimator was 56% (n = 439). The YourIVFSuccess Estimator aided consumer expectations of IVF success: one quarter (24%) of participants were unsure of their estimated IVF success before using the tool; one half changed their prediction of success after using the tool (20% increased, 30% decreased), bringing their predictions in line with the YourIVFSuccess Estimator, and one quarter (26%) had their IVF success expectations confirmed. One in five participants claimed they would change the timing of IVF treatment. The majority of participants found the tool to be at least moderately trustworthy (91%), applicable (82%), and helpful (80%), and would recommend it to others (60%). The main reasons given for the positive responses were that the tool is independent (government funded, academic) and based on real-world data. Those who did not find it applicable or helpful were more likely to have had a worse-than-expected prediction, or to have experienced non-medical infertility (e.g. single women, LGBTQIA+), noting that at the time of evaluation the Estimator did not accommodate these patient groups. LIMITATIONS, REASONS FOR CAUTION: Those who dropped out between the pre- and post-surveys tended to have a lower education status or have been born outside of Australia or New Zealand, therefore there may be issues with generalizability. WIDER IMPLICATIONS OF THE FINDINGS: With consumers demanding increasing levels of transparency and participation in decisions around their medical care, public-facing IVF predictor tools based on real-world data are useful for aligning expectations about IVF success rates. Given differences in patient characteristics and IVF practices internationally, national data sources should be used to inform country-specific IVF prediction tools. STUDY FUNDING/COMPETING INTEREST(S): The YourIVFSuccess website and evaluation of the YourIVFSuccess Estimator are supported by the Medical Research Future Fund (MRFF) Emerging Priorities and Consumer Driven Research initiative: EPCD000007. BKB, ND, and OF have no conflicts to declare. DM holds a clinical role at Virtus Health. His role did not influence the analysis plan or interpretation of results in this study. GMC is an employee of the UNSW Sydney, and Director of the UNSW NPESU. UNSW receives research funding on behalf of Prof Chambers from the MRFF to develop and manage the Your IVF Success website. Grant ID: MRFF Emerging Priorities and Consumer Driven Research initiative: EPCD000007. TRIAL REGISTRATION NUMBER: N/A.

Childbirth timing and completed family size by the mode of conception-the role of medically assisted reproduction: a population-based cohort study in Australia.

Background: With declining total fertility rates to below replacement levels amongst all high-, middle- and low-income countries, coupled with increasing use of medically assisted reproduction (MAR) treatments globally, we describe the impact of these treatments on completed family size and childbearing timing in a country with unlimited publicly funded access to MAR. Methods: We utilised a unique longitudinal propensity score-weighted population-based birth cohort that included nulliparous mothers who gave birth after all major forms of MAR treatments (assisted reproductive technologies [ART], ovulation induction [OI], and intrauterine insemination [IUI]) and after natural conception (reference category) in Australia, 2003-2017. We followed first-time mothers over their reproductive lifespan (15-50 years). The primary outcome was completed family size (i.e., the mean cumulative number of children per mother of our cohort) and the fertility gap (i.e., adjusted difference in completed family size between MAR conceptions and the reference). Findings: Our cohort includes 481,866 first-time mothers, mean follow-up of 13.8 years. ART mothers (n = 25,296) were six years older (mean age: 34.6 years) than mothers who conceived naturally (28.7 years (reference)) while OI/IUI mothers were only 2.2 years older (31.0 years) than the reference. ART mothers had up to 27% smaller completed family size (2.54 children) compared to OI/IUI mothers (2.98 children) and natural conception mothers (3.23 children). ART mothers who resided in the lower socioeconomic areas were less likely to reach a similar family size to the natural conception mothers (fertility gap of 0.83 fewer children per ART mother compared to natural conception mothers) than ART mothers who resided in the higher socioeconomic areas (0.43 fewer children). Interpretation: Greater awareness of the limitations of MAR treatment to resolve childlessness and achieve desired family size is needed. Furthermore, with policymakers increasingly turning to MAR treatment as a tool to reverse declining fertility rates, their potential impact should not be overestimated. Funding: Australian National Health and Medical Research Council.

Does in vitro fertilization (IVF) treatment provide good value for money? A cost-benefit analysis.

Background: Using traditional health technology assessment (HTA) outcome metrics, such as quality-adjusted life-years, to assess fertility treatments raises considerable methodological challenges because the objective of fertility treatments is to create new life rather than extend, save, or improve health-related quality of life. Objective: The aim of this study was to develop a novel cost-benefit framework to assess value for money of publicly funded IVF treatment; to determine the number of cost-beneficial treatment cycles for women of different ages; and to perform an incremental cost-benefit analysis from a taxpayer perspective. Methods: We developed a Markov model to determine the net monetary benefit (NMB) of IVF treatment by female age and number of cycles performed. IVF treatment outcomes were monetized using taxpayers' willingness-to-pay values derived from a discrete choice experiment (DCE). Using the current funding environment as the comparator, we performed an incremental analysis of only funding cost-beneficial cycles. Similar outputs to cost-effectiveness analyses were generated, including net-benefit acceptability curves and cost-benefit planes. We created an interactive online app to provide a detailed and transparent presentation of the results. Results: The results suggest that at least five publicly funded IVF cycles are cost-beneficial in women aged <42 years. Cost-benefit planes suggest a strong taxpayer preference for restricting funding to cost-beneficial cycles over current funding arrangements in Australia from an economic perspective. Conclusions: The provision of fertility treatment is valued highly by taxpayers. This novel cost-benefit method overcomes several challenges of conventional cost-effectiveness methods and provides an exemplar for incorporating DCE results into HTA. The results offer new evidence to inform discussions about treatment funding arrangements.

Projecting the Contribution of Assisted Reproductive Technology to Completed Cohort Fertility.

Assisted reproductive technology (ART) is increasingly influencing the fertility trends of high-income countries characterized by a pattern of delayed childbearing. However, research on the impact of ART on completed fertility is limited and the extent to which delayed births are realized later in life through ART is not well understood. This study uses data from Australian fertility clinics and national birth registries to project the contribution of ART for cohorts of women that have not yet completed their reproductive life and estimate the role played by ART in the fertility 'recuperation' process. Assuming that the increasing trends in ART success rates and treatment rates continue, the projection shows that the contribution of ART-conceived births to completed fertility will increase from 2.1% among women born in 1968 to 5.7% among women born in 1986. ART is projected to substantially affect the extent to which childbearing delay will be compensated at older ages, suggesting that its availability may become an important factor in helping women to achieve their reproductive plans later in life. Supplementary Information: The online version contains supplementary material available at 10.1007/s11113-023-09765-3.

Freeze-all embryos during treatment with assisted reproduction: Health economic aspects.

Assisted reproductive technologies are evolving, with the most recent example being the introduction of the freeze-all policy during which a fresh embryo transfer does not take place and all embryos of good quality are cryopreserved to be used in future frozen embryo transfers. As the freeze-all policy is becoming more prevalent, it is important to review the economic aspects of this approach, along with considerations of efficacy and safety, and the role of emerging freeze-all-specific ovarian stimulation strategies. Based on the available evidence, the freeze-all policy presents distinct clinical advantages, particularly for high responders. Available health economic evaluations are limited. Two good-quality cost-effectiveness analyses based on randomized controlled trials suggest that the freeze-all strategy is unlikely to be cost-effective in non-polycystic ovarian syndrome (non-PCOS), normally responding patients. However, the cost-effectiveness of the freeze-all strategy in different populations of patients and in different settings has not been evaluated, nor has the clinical and economic efficacy of modern freeze-all-specific ovarian stimulation protocols that are likely to simplify treatment and make it more affordable for patients. Economic evaluations that incorporate good practice health technology assessment (HTA) methods are needed to compare freeze-all with conventional embryo transfer strategies. Furthermore, future research should address the unique limitation of traditional HTA methods in valuing a life conceived through fertility treatment.

Maternal asthma in Australian indigenous women and perinatal outcomes: A whole population-linked study.

OBJECTIVE: To assess the association between maternal asthma and adverse perinatal outcomes in an Australian Indigenous population. METHODS: This prospective cohort study included all Indigenous mother and baby dyads for births from 2001 to 2013 in Western Australia (n = 25 484). Data were linked from Western Australia Births, Deaths, Midwives, Hospital, and Emergency Department collections. Maternal asthma was defined as a self-reported diagnosis at an antenatal visit or hospitalization or emergency visit for asthma during pregnancy or less than 3 years before pregnancy. Associations with birth, labor, and pregnancy outcomes were assessed using generalized estimating equations. Asthma exacerbation during pregnancy and stratification by remoteness was also assessed. RESULTS: Maternal asthma was associated with placental abruption (adjusted odds ratio [aOR], 1.59 [95% confidence interval (CI), 1.07-2.35]), threatened preterm labor (aOR, 1.58 [95% CI, 1.39-1.79]), and emergency cesarean sections (aOR, 1.27 [95% CI, 1.13-1.44]). These risks increased further with an asthma exacerbation during pregnancy or if the mother was from a remote area. No associations were found for low birth weight, preterm birth, small for gestational age, or perinatal mortality. CONCLUSION: Maternal asthma in Indigenous women is associated with an increased risk of emergency cesarean sections, placental abruption, and threatened preterm labor. These risks may be mitigated by improved management of asthma exacerbations during pregnancy.

What Features of Fertility Treatment do Patients Value? Price Elasticity and Willingness-to-Pay Values from a Discrete Choice Experiment.

BACKGROUND: Infertility is a medical condition affecting an estimated 186 million people worldwide. Medically assisted fertility treatments allow many of these individuals to have a baby. Insights about preferences of patients who have experienced fertility treatment should be used to inform funding policies and treatment configurations that best reflect the patients' voice and the value of fertility treatment to patients. OBJECTIVE: To explore the preferences for fertility treatment attributes of infertile women who had previously undergone or were undergoing fertility treatments-ex post perspective. METHODS: We used data from a stated-preference discrete choice experiment (DCE) among 376 Australian women who had undergone or were undergoing fertility treatment. Respondents chose their preferred treatment choices in 12 hypothetical treatment choice scenarios described by seven attributes (success rates, side effects, counselling/peer support, treatment journey, continuity of care, availability of experimental treatment and out-of-pocket cost). We estimated random parameter logit (RPL) and latent class (LC) models that accounted for preference heterogeneity. The results were used to derive price elasticities of demand and marginal willingness-to-pay (WTP) values for the treatment attributes explored within the DCE survey. RESULTS: Income level did not have a significant effect on marginal WTP for fertility treatment attributes. The demand for fertility treatment from an ex post perspective was found to be highly inelastic (treatment cost changes had almost no impact on demand). Success rates and out-of-pocket costs were significant and important predictors of individuals' treatment choices conditional on the attributes and levels included in the study. These were followed by counselling/peer support, side effects, treatment journey, continuity of care, and availability of experimental treatment, in that order. Respondents were willing to pay $383-$524 per one percentage point increase in the treatment success rate and over $2000 and over $3500 to avoid moderate and significant side effects, respectively (values are reported in AU$). Latent class models revealed that the majority of respondents (51%) were risk-averse success-rate seekers. CONCLUSION: Infertile women who had previously undergone or were undergoing fertility treatment valued fertility treatment highly as reflected by highly price-inelastic demand. Success rate of treatment and out-of-pocket costs were the most important attributes and largely determined patients' WTP for fertility treatment relative to the attributes and levels used in the study. While further research should investigate the price sensitivity of women who have not experienced fertility treatment, these results might explain why women continue fertility treatment once they have commenced despite their financial capacity to pay. Future research should also determine patients' price elasticities for a fertility treatment program with multiple treatment cycles.

Residential proximity to a fertility clinic is independently associated with likelihood of women having ART and IUI treatment.

STUDY QUESTION: Is geographic proximity to a fertility clinic associated with the likelihood of women of reproductive age undertaking different forms of medically assisted fertility treatment? SUMMARY ANSWER: After adjusting for socioeconomic status (SES) and other confounders including a proxy for the need for infertility treatment, women who lived within 15 km of a fertility clinic were 21% more likely to undergo ART treatment and 68% more likely to undergo IUI treatment than those who lived further than 60 km away. WHAT IS KNOWN ALREADY: In most countries, patients living outside of metropolitan areas are more likely to be more socio-economically disadvantaged and to have less equitable access to healthcare. However, how a woman's residential proximity to fertility clinics predicts utilization of high-cost/high-technology treatment (ART) and low-cost/low-technology treatment (IUI) is limited, and whether socio-economic disadvantage explains much of the hypothesized lower utilization is unknown. Australia's universal insurance scheme provides supportive reimbursement for almost all ART and IUI treatment regardless of age or number of cycles, providing a unique setting to investigate disparities in access to infertility treatment. STUDY DESIGN, SIZE, DURATION: National population-based observation study of ART and IUI treatment utilization by women across socio-economic gradients and Australian residential locations between August 2015 and December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Universal insurance claims information on female patients who underwent ART or IUI were provided by Services Australia, comprising 67 670 female patients who accessed 162 795 ART treatments, and 10 211 female patients who accessed 19 615 IUI treatments over a 29-month period. Incidence rates by SES and proximity to fertility clinics were calculated to describe the number of women undergoing at least one ART or IUI treatment cycle per 1000 women of reproductive age (25-44). Treatment frequencies were calculated to describe the average number of ART or IUI treatment cycles per woman of reproductive age who had undergone at least one ART or IUI treatment during the study period. Poisson regression analyses were used to estimate the independent effect on accessibility to infertility treatment by geographic proximity (based on small area locations) to the closest fertility clinic after adjusting for SES, childbearing delay, remoteness area, and marital status. MAIN RESULTS AND THE ROLE OF CHANCE: On average, 19.1 women per 1000 women of reproductive age underwent at least one fresh or frozen ART cycle, with an average 2.3 ART cycles each, while 3.0 women per 1000 women of reproductive age received at least one IUI cycle, with an average of 1.6 IUI cycles each. After adjusting for SES and other confounders including a proxy for the need for infertility treatment, women who lived within 15 km of a fertility clinic were 21% more likely to undergo ART treatment and 68% more likely to undergo IUI than those who lived over 60 km away. Regardless of geographic location, there was a steady and independent gradient in access to ART treatment based on increasing SES, with women residing in the most advantaged residential quartile having a 37% higher rate of receiving ART treatment compared to those in the most disadvantaged quartile. The negative effect of social disadvantage on ART use became more pronounced as distance from a fertility clinic grew, indicating that the barriers to access to ART care caused by distance were further compounded by the level of socioeconomic advantage of the women's residential location. In contrast, socioeconomic status did not modify the likelihood of using IUI over and above the distance from a fertility clinic. In relation to IUI treatment, differences in utilization by SES disappeared after adjusting for geographic proximity to a fertility clinic, childbearing delay, remoteness area, and marital status. LIMITATIONS, REASONS FOR CAUTION: Information is aggregated by small geographic areas and it therefore may not reflect individual characteristics. Australia provides partial but comparably supportive reimbursement for both ART and IUI through its universal healthcare system and thus the results may not be fully generalizable to other settings. WIDER IMPLICATIONS OF THE FINDINGS: Residential proximity to a fertility clinic is a persistent barrier to accessing ART and IUI treatment, regardless of SES, even in countries characterized by supportive public funding, such as Australia. SES is less of a barrier to accessing IUI than ART, presumably driven by the lower cost and fewer clinic visits required with IUI treatment. Safe and effective fertility treatment should be available to all women regardless of where they live. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Australian National University Research scholarship and by the Higher Degree Research Fee Merit Scholarship. The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Economic Evaluation of Newborn Screening for Severe Combined Immunodeficiency.

Evidence on the cost-effectiveness of newborn screening (NBS) for severe combined immunodeficiency (SCID) in the Australian policy context is lacking. In this study, a pilot population-based screening program in Australia was used to model the cost-effectiveness of NBS for SCID from the government perspective. Markov cohort simulations were nested within a decision analytic model to compare the costs and quality-adjusted life-years (QALYs) over a time horizon of 5 and 60 years for two strategies: (1) NBS for SCID and treat with early hematopoietic stem cell transplantation (HSCT); (2) no NBS for SCID and treat with late HSCT. Incremental costs were compared to incremental QALYs to calculate the incremental cost-effectiveness ratios (ICER). Sensitivity analyses were performed to assess the model uncertainty and identify key parameters impacting on the ICER. In the long-term over 60 years, universal NBS for SCID would gain 10 QALYs at a cost of US $0.3 million, resulting in an ICER of US$33,600/QALY. Probabilistic sensitivity analysis showed that more than half of the simulated ICERs were considered cost-effective against the common willingness-to-pay threshold of A$50,000/QALY (US$35,000/QALY). In the Australian context, screening for SCID should be introduced into the current NBS program from both clinical and economic perspectives.

Modelling the Cost-Effectiveness and Budget Impact of a Newborn Screening Program for Spinal Muscular Atrophy and Severe Combined Immunodeficiency.

Spinal muscular atrophy (SMA) and severe combined immunodeficiency (SCID) are rare, inherited genetic disorders with severe mortality and morbidity. The benefits of early diagnosis and initiation of treatment are now increasingly recognized, with the most benefits in patients treated prior to symptom onset. The aim of the economic evaluation was to investigate the costs and outcomes associated with the introduction of universal newborn screening (NBS) for SCID and SMA, by generating measures of cost-effectiveness and budget impact. A stepwise approach to the cost-effectiveness analyses by decision analytical models nested with Markov simulations for SMA and SCID were conducted from the government perspective. Over a 60-year time horizon, screening every newborn in the population and treating diagnosed SCID by early hematopoietic stem cell transplantation and SMA by gene therapy, would result in 95 QALYs gained per 100,000 newborns, and result in cost savings of USD 8.6 million. Sensitivity analysis indicates 97% of simulated results are considered cost-effective against commonly used willingness-to-pay thresholds. The introduction of combined NBS for SCID and SMA is good value for money from the long-term clinical and economic perspectives, representing a cost saving to governments in the long-term, as well as improving and saving lives.

Double jeopardy-pregnancy and birth during a catastrophic bushfire event followed by a pandemic lockdown, a natural experiment.

BACKGROUND: From November 2019 to January 2020, eastern Australia experienced the worst bushfires in recorded history. Two months later, Sydney and surrounds were placed into lockdown for six weeks due to the COVID-19 pandemic, followed by ongoing restrictions. Many pregnant women at this time were exposed to both the bushfires and COVID-19 restrictions. OBJECTIVE: To assess the impact of exposure to bushfires and pandemic restrictions on perinatal outcomes. METHODS: The study included 60 054 pregnant women who gave birth between November 2017 and December 2020 in South Sydney. Exposure cohorts were based on conception and birthing dates: 1) bushfire late pregnancy, born before lockdown; 2) bushfires in early-mid pregnancy, born during lockdown or soon after; 3) conceived during bushfires, lockdown in second trimester; 4) conceived after bushfires, pregnancy during restrictions. Exposure cohorts were compared with pregnancies in the matching periods in the two years prior. Associations between exposure cohorts and gestational diabetes, preeclampsia, hypertension, stillbirth, mode of birth, birthweight, preterm birth and small for gestational age were assessed using generalised estimating equations, adjusting for covariates. RESULTS: A decrease in low birth weight was observed for cohort 1 (aOR 0.81, 95%CI 0.69, 0.95). Conversely, cohort 2 showed an increase in low birth weight, and increases in prelabour rupture of membranes, and caesarean sections (aOR 1.18, 95%CI 1.03, 1.37; aOR 1.21, 95%CI 1.07, 1.37; aOR 1.10 (1.02, 1.18) respectively). Cohort 3 showed an increase in unplanned caesarean sections and high birth weight babies (aOR 1.15, 95%CI 1.04, 1.27 and aOR 1.16, 95%CI 1.02, 1.31 respectively), and a decrease in gestational diabetes mellitus was observed for both cohorts 3 and 4. CONCLUSION: Pregnancies exposed to both severe climate events and pandemic disruptions appear to have increased risk of adverse perinatal outcomes beyond only experiencing one event, but further research is needed.

Population-wide contribution of medically assisted reproductive technologies to overall births in Australia: temporal trends and parental characteristics.

STUDY QUESTION: In a country with supportive funding for medically assisted reproduction (MAR) technologies, what is the proportion of MAR births over-time? SUMMARY ANSWER: In 2017, 6.7% of births were conceived by MAR (4.8% ART and 1.9% ovulation induction (OI)/IUI) with a 55% increase in ART births and a stable contribution from OI/IUI births over the past decade. WHAT IS KNOWN ALREADY: There is considerable global variation in utilization rates of ART despite a similar infertility prevalence worldwide. While the overall contribution of ART to national births is known in many countries because of ART registries, very little is known about the contribution of OI/IUI treatment or the socio-demographic characteristics of the parents. Australia provides supportive public funding for all forms of MAR with no restrictions based on male or female age, and thus provides a unique setting to investigate the contribution of MAR to national births as well as the socio-demographic characteristics of parents across the different types of MAR births. STUDY DESIGN, SIZE, DURATION: This is a novel population-based birth cohort study of 898 084 births using linked ART registry data and administrative data including birth registrations, medical services, pharmaceuticals, hospital admissions and deaths. Birth (a live or still birth of at least one baby of ≥400 g birthweight or ≥20 weeks' gestation) was the unit of analysis in this study. Multiple births were considered as one birth in our analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included a total of 898 084 births (606 488 mothers) in New South Wales and the Australian Capital Territory, Australia 2009-2017. We calculated the prevalence of all categories of MAR-conceived births over the study period. Generalized estimating equations were used to examine the association between parental characteristics (parent's age, parity, socio-economic status, maternal country of birth, remoteness of mother's dwelling, pre-existing medical conditions, smoking, etc.) and ART and OI/IUI births relative to naturally conceived births. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of MAR births increased from 5.1% of all births in 2009 to 6.7% in 2017, representing a 30% increase over the decade. The proportion of OI/IUI births remained stable at around 2% of all births, representing 32% of all MAR births. Over the study period, ART births conceived by frozen embryo-transfer increased nearly 3-fold. OI/IUI births conceived using clomiphene citrate decreased by 39%, while OI/IUI births conceived using letrozole increased 56-fold. Overall, there was a 55% increase over the study period in the number of ART-conceived births, rising to 56% of births to mothers aged 40 years and older. In 2017, almost one in six births (17.6%) to mothers aged 40 years and over were conceived using ART treatment. Conversely, the proportion of OI/IUI births was similar across different mother's age groups and remained stable over the study period. ART children, but not OI/IUI children, were more likely to have parents who were socio-economically advantaged compared to naturally conceived children. For example, compared to naturally conceived births, ART births were 16% less likely to be born to mothers who live in the disadvantaged neighbourhoods after accounting for other covariates (adjusted relative risk (aRR): 0.84 [95% CI: 0.81-0.88]). ART- or OI/IUI-conceived children were 25% less likely to be born to immigrant mothers than births after natural conception (aRR: 0.75 [0.74-0.77]). LIMITATIONS, REASONS FOR CAUTION: The social inequalities that we observed between the parents of children born using ART and naturally conceived children may not directly reflect disparities in accessing fertility care for individuals seeking treatment. WIDER IMPLICATIONS OF THE FINDINGS: With the ubiquitous decline in fertility rates around the world and the increasing trend to delay childbearing, this population-based study enhances our understanding of the contribution of different types of MARs to population profiles among births in high-income countries. The parental socio-demographic characteristics of MAR-conceived children differ significantly from naturally conceived children and this highlights the importance of accounting for such differences in studies investigating the health and development of MAR-conceived children. STUDY FUNDING/COMPETING INTEREST(S): This study was funded through Australian National Health and Medical Research Council (NHMRC) grant: APP1127437. G.M.C. is an employee of The University of New South Wales (UNSW) and Director of the National Perinatal Epidemiology and Statistics Unit (NPESU), UNSW. The NPESU manages the Australian and New Zealand Assisted Reproduction Database with funding support from the Fertility Society of Australia and New Zealand. C.V. is an employee of The University of New South Wales (UNSW), Director of Clinical Research of IVFAustralia, Member of the Board of the Fertility Society of Australia and New Zealand, and Member of Research Committee of School of Women's and Children's Health, UNSW. C.V. reports grants from Australian National Health and Medical Research Council (NHMRC), and Merck KGaA. C.V. reports consulting fees, and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript, writing or educational events or attending meeting or travel from Merck, Merck Sparpe & Dohme, Ferring, Gedon-Richter and Besins outside this submitted work. C.V. reported stock or stock options from Virtus Health Limited outside this submitted work. R.J.N. is an employee of The University of Adelaide, and Chair DSMC for natural therapies trial of The University of Hong Kong. R.J.N. reports grants from NHMRC. R.J.N. reports lecture fees and support for attending or travelling for lecture from Merck Serono which is outside this submitted work. L.R.J. is an employee of The UNSW and Foundation Director of the Centre for Big Data Research in Health at UNSW Sydney. L.R.J. reports grants from NHMRC. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The clinical performance and cost-effectiveness of two psychosocial assessment models in maternity care: The Perinatal Integrated Psychosocial Assessment study.

PROBLEM: Although perinatal universal depression and psychosocial assessment is recommended in Australia, its clinical performance and cost-effectiveness remain uncertain. AIM: To compare the performance and cost-effectiveness of two models of psychosocial assessment: Usual-Care and Perinatal Integrated Psychosocial Assessment (PIPA). METHODS: Women attending their first antenatal visit were prospectively recruited to this cohort study. Endorsement of significant depressive symptoms or psychosocial risk generated an 'at-risk' flag identifying those needing referral to the Triage Committee. Based on its detailed algorithm, a higher threshold of risk was required to trigger the 'at-risk' flag for PIPA than for Usual-Care. Each model's performance was evaluated using the midwife's agreement with the 'at-risk' flag as the reference standard. Cost-effectiveness was limited to the identification of True Positive and False Positive cases. Staffing costs associated with administering each screening model were quantified using a bottom-up time-in-motion approach. FINDINGS: Both models performed well at identifying 'at-risk' women (sensitivity: Usual-Care 0.82 versus PIPA 0.78). However, the PIPA model was more effective at eliminating False Positives and correctly identifying 'at-risk' women (Positive Predictive Value: PIPA 0.69 versus Usual Care 0.41). PIPA was associated with small incremental savings for both True Positives detected and False Positives averted. DISCUSSION: Overall PIPA performed better than Usual-Care as a psychosocial screening model and was a cost-saving and relatively effective approach for detecting True Positives and averting False Positives. These initial findings warrant evaluation of longer-term costs and outcomes of women identified by the models as 'at-risk' and 'not at-risk' of perinatal psychosocial morbidity.

Patterns of psychiatric admission in Australian pregnant and childbearing women.

PURPOSE: The early postnatal period is a time of increased risk for psychiatric admission. However, there is scope to further examine if this increase in risk extends to the entire perinatal period (pregnancy and first postnatal year), and how it compares to admission outside of the perinatal period. METHODS: Data were linked across birth and hospital admission registers from July 2000 to December 2009. The study cohort, consisting of all pregnant and childbearing women with a psychiatric history, was divided into two groups: case women (at least one perinatal principal psychiatric admission in the study period) (38%) and comparison women (no perinatal principal psychiatric admissions) (62%). Outcomes were admission rate and length of stay adjusted for diagnosis, socio-demographic factors and timing of admission. RESULTS: Antenatal and postnatal admissions rates were both higher than non-perinatal admission rates for case women for all diagnoses. There was little evidence that women with perinatal admissions were at an increased risk of admissions at other times. Socially disadvantaged women had significantly fewer and shorter admissions than their respective counterparts. CONCLUSIONS: The entire perinatal period is a time of increased risk for admission across the range of psychiatric disorders, compared to other times in a woman's childbearing years. Reduced admission rate and length of stay for socially disadvantaged women suggest lack of equity of access highlighting the importance of national perinatal mental health policy initiatives inclusive of disadvantaged groups.