Hum. Reprod. Advance Access originally published online on April 15, 2008
Human Reproduction 2008 23(7):1639-1643; doi:10.1093/humrep/den102
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Success rates and cost of a live birth following fresh assisted reproduction treatment in women aged 45 years and older, Australia 2002–2004
1 Perinatal and Reproductive Epidemiology and Research Unit, School Women's and Children's Health, University of New South Wales, McNevin Dickson Building, Randwick Hospitals Campus, Randwick, NSW 2031, Australia 2 Discipline of Obstetrics and Gynaecology, School Women's and Children's Health, University of New South Wales, Royal Hospital for Women, Locked Bag 2000, Randwick, NSW 2031, Australia
3 Correspondence address. Tel: +61-2-9382-1014; Fax: +61-2-9382-1025; E-mail: e.sullivan{at}unsw.edu.au
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Abstract |
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BACKGROUND: The aim of this study was to calculate assisted reproductive technology (ART) success rates for fresh autologous and donor cycles in women aged
45 and the resultant cost per live birth.
METHODS: We performed a retrospective population-based study of 2339 ART cycles conducted in Australia, 2002–2004 to women aged 45 years. The cost-outcome study was performed on fresh autologous treatment cycles.
RESULTS: There were 1101 fresh autologous cycles initiated in women aged 45, with a pregnancy rate of 1.9 per 100 initiated cycles. There were 21 women who achieved a clinical pregnancy with 15 (71%) ending in early pregnancy loss and 6 in live singleton births. The live birth rate following fresh autologous initiated cycles was 0.5% [95% confidence interval (CI): 0.1–1.0%]. Fresh donor recipients had an higher live birth rate of 19.1% (95% CI: 15.1–23.2) (odds ratio 43.2; 95% CI: 18.6–100.3) compared with women having fresh autologous cycles. The average cost of a live birth following fresh autologous cycles was 
753 107.
CONCLUSIONS: The success rate of fresh autologous treatment for women aged 45 years was <1%. The very high cost of a live birth reflects a treatment failure rate of >99%. The ART profession should counsel patients of the reality of the technology before the patients consent to treatment.
Key words: donor cycle/maternal age/cost/autologous cycle/assisted reproductive technology
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Introduction |
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Births to women aged 45 years and older in Australia remain uncommon reflecting both previous social prohibitions and the age-related decline in fertility (Laufer et al., 2004
). Since 1991, the proportion of women aged 45 years and older giving birth in Australia has risen from 0.05% of all confinements to 0.13% in 2004. Although rare, with only 340 women older than 45 giving birth in 2004, the overall trend in deferring childbirth has seen a change in the make-up of this population with higher rates of primiparity. In 2004, 1 in every 1159 first time births was to a woman aged 45 years and older compared with 1 in every 4583 in 1991 (Lancaster et al., 1994; Laws et al., 2006).
Concurrently, the utilization of assisted reproduction technology (ART) services in Australia has risen to almost 39 000 treatment cycles per year across all ages (Wang et al., 2006). There has been an increase in utilization of ART treatment by women aged 40 years and older worldwide. For example, in Australia, 11.2% of all treatment cycles undertaken in 2002 were to women aged 40 years, rising to 20.8% in 2004. Similarly, in the UK, the proportion of cycles to women aged 40 years has risen from 9.1% in 1991 to 15.7% in 2006 (Wang et al., 2006; HFEA, 2007).
In this context of rising birth rates at the margins of normal fertility, Australia offers a setting to investigate the true impact of ART utilization and treatment success in older women. Australia is unique in terms of funding and access to ART services, with no lifetime restriction to government reimbursement of ART treatment based on maternal age, number of treatment cycles offered or number of previously conceived children (Hughes and Giacomini, 2001). Medical procedures, monitoring and laboratory services relating to ART that are deemed to be legal and clinically relevant attract a partial rebate through the National Medicare Benefits Scheme. In addition, the majority of pharmaceuticals associated with ART treatment are funded by the National Pharmaceuticals Benefits Scheme. A government-funded ‘safety net’ also reimburses 80% of out-of-pocket expenses for Medicare funded services provided outside of hospital once an annual threshold is met. Many patients become eligible for this safety net in the first ART cycle (Department of Health and Ageing, 2004). Therefore, the financial disincentives for accessing ART services are limited to patient out-of-pocket expenses which we estimate to be 
20% of the 4493 total cost of a fresh ART cycle in Australia (Chambers et al., 2006).
The aim of this study was to calculate success rates for fresh autologous and donor recipient cycles in women aged 45 years and older; and to calculate the cost per live birth for fresh autologous cycles.
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Materials and Methods |
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Study population
A retrospective population-based study was conducted of all ART cycles among women aged
45 years. Data were extracted from the Australia and New Zealand Assisted Reproduction Database (ANZARD) for treatment cycles initiated in Australia from 1 January 2002 to 31 December 2004. ANZARD contains treatment and pregnancy outcome data of all assisted reproductive technology (ART) cycles conducted in Australia and New Zealand. ART treatment included stimulated and natural cycles using in vitro fertilization (IVF) and intracytoplasmic sperm injection procedures and involved both fresh and frozen embryo transfers. Surrogate cycles, GIFT and artificial insemination cycles were excluded. The study population consisted of women aged 45 years that underwent ART procedures during the study period 2002–2004. Because ANZARD is a treatment based collection, individual women could be included in the data set more than once.
Definition of exposure and outcome
Maternal age was defined as the age of the mother in completed years at the time of ART treatment. Donor cycles were defined as cycles in which donated oocytes or embryos from another woman/couple were used in the cycle by a recipient woman. Autologous cycles were defined as cycles in which the oocytes originated from the woman undergoing the embryo transfer cycle. An initiated cycle was defined as a cycle in which treatment was commenced with the intention to transfer embryos. Transfer cycles included only those cycles where an embryo(s) were injected into the uterus. Early pregnancy loss was defined as pregnancy loss of <20 weeks gestation and included ectopic and heterotopic pregnancy. A clinical pregnancy was defined as satisfying one or more of the following criteria: visualization of a gestational sac by ultrasound; presence of chorionic villi on examination of products of conception; or diagnosis of ectopic pregnancy by laparoscope or ultrasound. A live birth was defined as the birth of at least one live born infant of 20 weeks' gestation. The birth of twins or triplets was counted as one live birth. Treatment success rates were calculated as the proportion of initiated cycles resulting in a live birth, and the proportion of embryo transfer cycles resulting in a live birth. The main outcome measures were clinical pregnancy and live birth rates by donor status. The main economic outcome measure was the cost per live birth resulting from autologous ART treatment cycles.
Statistical analysis
Treatment success rates, expressed as clinical pregnancies and live births per initiated cycles and embryo transfer cycles, were compared by donor status for fresh cycles. Odds ratios (OR) and 95% confidence intervals (CIs) for live births associated with donor status were estimated using unconditional multiple logistic regression models. All data were analysed using SPSS statistical software version 14.0.
Economic analysis of autologous treatment cycles
The average cost per live birth resulting from fresh autologous cycles was calculated using a decision analysis model of ART treatment and Australian cost data. The model was constructed to represent each possible outcome from an initiated treatment cycle, including cycles discontinued before oocyte retrieval and embryo transfer. Additional procedures, such as surgical sperm collection, intracytoplasmic sperm injection, assisted hatching, blastocyst culture and cryopreservation of embryos were also included. Costs reflected the direct healthcare costs of ART treatment including public and private sector costs and patient out-of-pocket expenses. The number of cycles reaching each stage of the decision analysis model was multiplied by the corresponding average cost of each type of partial and complete cycle to calculate the average cost per live birth. Costs were captured in 2005 Australian dollars and expressed in 2005 Euros. Detailed methods are described elsewhere (Chambers et al., 2006). The costs per live birth were compared with previously published age-specific estimates for autologous ART treatments undertaken in Australia in 2002 (Chambers et al., 2006).
Ethics approval
This study was approved by the Human Research Ethics Advisory Panel I, University of New South Wales.
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Results |
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Overall, there were 102 900 initiated cycles reported for the period 2002–2004, with 2339 (2.3%) cycles being reported in women aged
45 years. Of these cycles in older women, <1.0% (162/16 501) of embryo transfer cycles resulted in a live birth. Approximately one-fifth (22.8%) of all donor recipient cycles were to women aged 45 years, ranging from 21.4% to 24.1% over the period 2002–2004. Of the 2339 treatment cycles reported in women aged 45 years, 1467 (62.7%) were fresh treatment cycles, comprising 1101 autologous cycles and 366 donor cycles. There were 872 frozen embryo transfer comprising 308 (35.3%) autologous and 564 donor frozen embryo transfers. Only data on fresh treatment cycles are presented.
Fresh autologous cycles
There were 1101 fresh autologous initiated treatment cycles in women aged 45 years. Almost three in five of these cycles were in women aged 45 years, with a further one-quarter (n = 278, 25.2%) in women aged 46 years (Table I). The age of women having fresh autologous treatment cycles ranged from 45 to 51 years. The rate of pregnancy per initiated cycle ranged from 2.5% in women aged 45 years to 0% in women aged 49 years and older (Table I).
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The fresh autologous treatment outcomes are detailed in Table II. Over 40% of initiated cycles did not proceed to embryo transfer. There were 21 women who achieved a clinical pregnancy with an overall pregnancy rate of 1.9 per 100 initiated cycles. Of clinical pregnancies following fresh autologous embryo transfers, 71% ended in early pregnancy loss. There were six live singleton births of which five were in women aged 45 years. The live birth rate following fresh autologous initiated cycles was 0.5 per 100 initiated cycles and 0.9 per 100 fresh autologous embryo transfer.
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Fresh recipient donor cycles
Treatment outcomes of the 366 recipient donor treatment cycles are also detailed in Table II. Of the initiated recipient donor cycles, 29% resulted in a clinical pregnancy. Almost one-third (32.0%) of clinical pregnancies ended in early pregnancy loss. Of the 70 live births, 58 were singleton births and 12 were twin births. The live birth rate following fresh recipient donor cycles was 19.1 per 100 initiated cycles.
Comparison of pregnancy outcomes of fresh autologous and recipient donor cycles
The live birth rate following fresh autologous initiated cycles was 0.5 per 100 initiated cycles (95% CI: 0.1–1.0) compared with that for fresh donor initiated cycles: 19.1 per 100 initiated cycle (95% CI: 15.1–23.2). Overall, fresh donor recipients had increased odds (OR 43.2; 95% CI: 18.6–100.3) of a live birth compared with women having fresh autologous cycles.
Cost per live birth resulting from autologous treatment cycles
The average cost of a live birth following fresh autologous cycles in women aged 45 years was 753 107 (Table III). The total direct healthcare costs of autologous ART treatment undertaken for women in Australia aged 45 years during 2002–2004 was 4 869 829 of which 92.7% 4 518 642 of costs were for fresh embryo transfer cycles. Using the same costing model and data sources, the cost per live birth following fresh autologous cycles for women aged 45 years was shown to be 28.9 times higher than for all women undergoing fresh autologous ART treatment in Australia (Chambers et al., 2006) (Table III).
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Discussion |
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The decline in fertility remains a complex issue for women who for a variety of reasons are attempting to have children at advanced age (Friese et al., 2006
). This national observational study reports an autologous treatment pregnancy success rate of 1.9%, or more accurately a treatment failure rate of 98% for all women aged 45 years or older. This high failure rate is consistent with published registry data from the UK, which recently reported 0–1.6% live birth success rates for fresh autologous cycles in older women (HFEA, 2007), and with clinic based studies that have reported consistently low to zero rates of pregnancies in women aged 45 years and older (Lass et al., 1998; Ron-El et al., 2000; Jansen 2003; Spandorfer et al., 2007; Tsafrir et al., 2007).
In an era of evidence based medicine, there would appear no clinical or economic evidence to continue fresh autologous ART treatment in women aged 45 years and older, with a conservative average cost of 753 107 per live birth. This is 29 times the overall national average cost for a live birth following fresh autologous ART treatment (Chambers et al., 2006). These findings are relevant to the provision and funding of ART treatment worldwide, as the cost and cost-effectiveness of ART treatment in Australia are comparable with a number of European countries but less costly and more cost-effective than reported in the USA (Collins 2002; Koivurova et al., 2004; National Collaborating Centre for Women's and Children's Health, 2004; Chambers et al., 2006).
However, if we look at access to fertility treatment in the broader context, research has shown that women have a strong sense of entitlement to choice and autonomy in reproductive decisions (Population Council, 2000) which in a developed country like Australia includes fertility treatment. Therefore, the approach taken by the Australian Government preserves the reproductive rights of these women by endorsing that ‘clinical appropriateness of ART services should be determined by the treating physician’ and places the onus on clinicians to ‘take into account relevant clinical practice guidelines when discussing treatment choices with patients to ensure that decisions made are fully informed’ (Commonwealth of Australia, 2006).
The recommendation by the Report of the Independent Review of Assisted Reproductive Technologies in Australia made in 2006 was ‘...that given the success rate of less than 2% ..., it is not clinically appropriate to initiate a new cycle of in-vitro fertilisation (IVF) treatment in women using their own eggs at 44 years and over’ (Assisted Reproductive Technologies Review Committee, 2006). The impact of this recommendation on ART practice in Australia will not be seen until 2007 registry data are available. Practice change and community acceptability will be reflected in both the number of fresh autologous cycles being undertaken by women aged 44 years and older and in the number of fertility centres where this treatment occurs.
The most critical statistic that couples contemplating fertility treatment need to understand is the odds of them taking home a healthy baby. A recent study by Spandorfer concluded that IVF was a ‘reasonable option’ for women aged 45 years with normal ovarian reserve and a production of at least five oocytes (Spandorfer et al., 2007). This conclusion was based on results from the study of a single IVF clinic with a highly selective study population where 19.8% (57) of the original 288 patients were ineligible due to elevated FSH or ovarian cyst and a further 30% (70/231) were excluded due to not proceeding to pick-up. These exclusions would have the effect of inflating the pregnancy rates which likely explains the 11-fold higher pregnancy rate of 21.1% and 4-fold higher live birth rate of 2.2% per initiated cycle reported in the clinic's study (Spandorfer et al., 2007). At a population level, there are no success rates similar to these data, rather failure rates ranging from 97.8% for a highly selected population to 99.5% in our Australia wide study.
In our study, 71.4% of the pregnancies resulting from fresh autologous ART treatment ended before 20 weeks gestation; this finding is similar to the 85.3% overall pregnancy loss reported by Spandorfer. For clinicians faced with counselling older women who wish to become pregnant using their own oocyte, these data will provide further evidence of the high treatment and pregnancy failure rates associated with fresh autologous treatment (Orvieto et al., 2004; Spandorfer et al., 2007; Tsafrir et al., 2007).
What treatment is in the patient's best interest? The most efficacious treatment model for women aged 45 years and older attempting to become pregnant is to undergo donor ART treatment. The live birth success rate per initiated cycle of almost one in five for fresh donor cycles contrasts starkly with autologous ART treatment. Donor ART treatment is both less physically invasive for the recipient and less expensive for the Australian health sector, as donor gametes are only legally available for use in Australia for ART treatment through altruistic donation.
Couples seeking donor oocytes or embryos in Australia are constrained by a lack of supply, with only 1659 donor cycles with embryo transfers in 2005, of which 24% were to women aged 45 years and older (Wang et al., 2007). The unmet demand for donor oocytes in Australia is demonstrated by advertisements found in the press from parents looking for altruistic donors. Likewise, the lack of donor embryos was confirmed in a 2007 national survey of Australian fertility clinics, which found that of 105 109 embryos in cryostorage, only 1.0% were for donation to other couples (Sullivan et al., 2007). This places infertile couples in an invidious situation where they are often powerless to access altruistic donor gametes and are too old to adopt. It could be argued that this lack of access to donor oocytes/embryos contributes to the decisions of many couples to attempt and persevere with fresh autologous ART. When this fails, the remaining option for couples still wanting a child are to become reproductive tourists and seek donor gametes and treatment outside of Australia (Pennings, 2002). However, the financial disincentives for reproductive tourism are high with extra costs for the gametes, ART services, travel and living expenses. Because of this Australian couples may persist with autologous ART treatment, an option, which is not encumbered with either age or cycle based restrictions, is affordable, and offers the small chance of a biological child.
As ART services continue to evolve, it is the responsibility of fertility organizations and the ART profession to provide clinical leadership on what is an acceptable success rate for ART related procedures to be acceptable practice. From an economic perspective, very small savings are made by restricting the services available to older women as they make up only 2.3% of all treatment cycles in Australia. Instead, better community education about fertility potential and the impact of advancing maternal age on both natural and assisted conception is needed (Friese et al., 2006). The widespread availability of such data will support better targeting of fertility education campaigns for both women and men. This information, in conjunction with financial costs and best practice guidelines for older women, will assist practitioners in counselling and educating couples.
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Funding |
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Georgina Chambers is the recipient of a Postgraduate Research Scholarship from the Australian Government National Health and Medical Research Council (NHMRC). The Fertility Society of Australia funds the ANZARD collection. The AIHW provides core funding for the AIHW National Perinatal Statistics Unit.
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Acknowledgements |
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The authors acknowledge the contribution of Australian fertility clinics in the provision of data to Australian and New Zealand Reproductive Technology Database (ANZARD).
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References |
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Submitted on October 31, 2007; resubmitted on February 13, 2008; accepted on February 26, 2008.
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