What can we learn from a decade of promoting safe embryo transfer practices? A comparative analysis of policies and outcomes in the UK and Australia, 2001-2010.

STUDY QUESTION: Given similar socio-demographic profiles and costs of healthcare, why has Australia been significantly more successful than the UK in reducing the assisted reproductive technology (ART) multiple birth rate? SUMMARY ANSWER: The Australian model of supportive public ART funding, permissive clinical guidelines and an absence of published clinic league tables has enabled Australian fertility specialists to act collectively to achieve rapid and widespread adoption of single embryo transfer (SET). WHAT IS KNOWN ALREADY: There are striking differences in ART utilization and clinical practice between Australia and the UK. The ART multiple birth rate in Australia is <8% compared with slightly <20% in the UK. The role played by public funding, clinical guidelines, league tables and educational campaigns deserves further evaluation. STUDY DESIGN, SIZE, DURATION: Parallel time-series analysis was performed on ART treatment and outcome data sourced from the Human Fertilisation and Embryology Authority (HFEA) ART Registry and the Australian and New Zealand Assisted Reproduction Database (ANZARD). Funding arrangements, clinical practice guidelines and key professional and public education campaigns were mapped to trends in clinical practice and ART treatment outcomes between 2001 and 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 425 360 and 422 003 autologous treatment cycles undertaken between 2001 and 2010 in the UK and Australia were analysed. MAIN RESULTS AND THE ROLE OF CHANCE: From 2001 to 2010, the most striking difference in clinical practice was the increase in SET cycles in Australia from 21 to 70% of cycles, compared with an increase from 8.4 to 31% in the UK. In 2004-2005, both countries introduced clinical guidelines encouraging safe embryo practices, however, Australia has a history of supportive funding for ART, while the National Health Service has a more restrictive and fragmented approach. While clinical guidelines and education campaigns have an important role to play, funding remains a key element in the promotion of SET. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive population study and therefore quantifying the independent effect of differential levels of public funding was not possible. WIDER IMPLICATIONS OF THE FINDINGS: With demand for ART continuing to increase worldwide, it is imperative that we remove barriers that impede safe embryo transfer practices. This analysis highlights the importance of supportive public funding in achieving this goal.

Are US results for assisted reproduction better than the rest? Is it a question of competence or policies?

A comparison of nationally published 2006 data from the USA, UK and Australia and New Zealand (ANZ) was performed. Although live births/cycle was higher in USA, live birth/embryo transferred was significantly higher in ANZ (18.2%) compared with both USA and UK (13.8%) (P<0.001). The multiple rates were significantly lower in ANZ (12.0%) compared with USA (30.7%) and UK (25.2%) (P<0.001). The incidence of oocyte donation was significantly higher in the USA (11.1%) than in ANZ (2.8%) and UK (3.9%) (P<0.001). There was significantly higher cycle cancellation in USA (11.5%) compared with the UK (6.8%) and ANZ (9.5%) (P<0.001). The incidence of frozen embryo transfer cycles was significantly higher in ANZ (59%) compared with both UK (24%) and USA (22%) (P<0.001). The total live birth rate from fresh and frozen cycles for the same year was significantly higher in ANZ at 32.0% compared with the UK at 28.8% (P<0.001) with half the multiple rate. It is argued that the USA's higher success rates are explained by policy (transferring higher number of embryos) and selection issues (cancelling or avoiding poor responders) rather than being a matter of clinical competence.

Is meaningful reporting of national IVF outcome data possible?

The traditional use of live birth per IVF cycle started as the sole indicator of success can be potentially misleading. Different policies regarding reporting IVF cycles started, variations in the number of embryos transferred and associated multiple births have a profound effect on success, such that results from clinics or countries with similar expertise may appear significantly different. To account for these differences, we recommend the use of live birth per embryo-calculated as the number live birth events per 100 embryos transferred-as an outcome measure. This method of reporting can correct for under reported cycles started, adjust for differences in embryo transfer policies and provides an objective and reproducible international benchmark. Combining live birth outcomes from fresh and frozen cycles in the same reporting period per oocyte collection is also recommended. These data should be published as a range related to the national average without a mean or central point. Furthermore, for proper interpretation of results, it would be helpful if the policies regarding patient inclusion and cycle cancellation at all clinics are published.

Prednisolone suppresses NK cell cytotoxicity in vitro in women with a history of infertility and elevated NK cell cytotoxicity.

PROBLEM: To evaluate the effect of prednisolone on NK cell cytotoxicity in vitro environment and also to compare the effect of prednisolone versus immunoglobulin-G (IVIG) on NK cell cytotoxicity using in vitro co-culture with K562 cells. METHOD OF STUDY: The following is a prospective observational study, between August 2006 and February 2007, was carried out on blood samples from 110 patients with a history of recurrent miscarriage or recurrent failed implantation. Peripheral blood mononuclear cells containing NK cells were isolated and co-cultured with target cell K562 in three different effector-to-target (E:T) ratios of 50:1, 25:1 and 12.5:1. Prednisolone or IVIG was then added to the tube with E:T ratio of 50:1 to assess suppressive effect. The percentage killing was recorded and statistical analysis performed using Student's t-test. RESULTS: In the experiments with an E:T ratio of 50:1 without prednisolone or IVIG in the co-culture, the mean target cell killing percentage was 26.4%. In cultures using the same E:T ratio, this killing percentage was significantly reduced in the presence of IVIG (9.9%) or prednisolone (13.6%), (P<0.001 in both analyses). On comparing the reduction in killing percentage of target cells by prednisolone versus IVIG, a slightly lower reduction in the prednisolone co-culture was noted but this was not statistically significant (P>0.05). CONCLUSION: The results of this study show that prednisolone is able to suppress the cytolytic activity of the NK cell. Prednisolone and IVIG are almost equally effective in suppressing in vitro NK cell cytolytic activity.

Relationship between women's age and basal follicle-stimulating hormone levels with aneuploidy risk in in vitro fertilization treatment.

OBJECTIVE: To assess the relationship of age and basal FSH level to the genetic quality of the embryo and the association with IVF treatment outcome. DESIGN: Prospective observation study. SETTING: A major inner London fertility clinic in the United Kingdom. PATIENT(S): One hundred fifty-one women who underwent IVF treatment cycles in conjunction with preimplantation genetic diagnosis for aneuploidy screening before fresh embryo transfer, between July 2003 and July 2005. INTERVENTION(S): Basal FSH levels (days 2-4) were determined at an earlier cycle, and women were divided into two groups: high basal FSH (>or=10 IU/L) and low basal FSH (<10 IU/L). Chromosome analysis was performed on a single blastomere by using fluorescence in situ hybridization. MAIN OUTCOME MEASURE(S): Percentage of aneuploid embryos. RESULT(S): The percentage of aneuploid embryos was not statistically significantly different between the high- (50.0%, n = 32) and low- (50.2%, n = 119) basal FSH groups. However, the percentage of aneuploid embryos was statistically significantly higher (56.2%, n = 109) for women aged >or=38 years, as compared with women <38 years of age (37.5%, n = 42), independent of basal FSH levels. CONCLUSION(S): Elevated basal FSH levels reflect lower ovarian reserve but have no association with genetic quality of embryos. The percentage of aneuploid embryos is increased with advanced maternal age.

The relationship of systemic TNF-alpha and IFN-gamma with IVF treatment outcome and peripheral blood NK cells.

BACKGROUND: To evaluate the association of serum tumour necrotic factor (TNF)-alpha and interferon (IFN)-gamma levels with IVF treatment outcome and peripheral blood NK cells. METHODS: Prospective observational study of 126 randomly selected women who underwent IVF treatment. The serum levels of TNF-alpha and IFN-gamma were determined by multiplex suspension beads array system. RESULTS: There were no significant differences with regard to the systemic TNF-alpha and IFN-gamma levels between the pregnant (n = 51, TNF-alpha: 53.5 pg/mL; IFN-gamma: 4.6 pg/mL) and not pregnant (n = 75, TNF-alpha: 63.0; IFN-gamma: 7.5) women after IVF treatment. For those women with a positive pregnancy after IVF treatment, the systemic TNF-alpha and IFN-gamma levels were higher in those women who miscarried (n = 13, TNF-alpha: 67.4; IFN-gamma: 9.1) when compared with those who had a live birth (n = 38, TNF-alpha: 48.7; IFN-gamma: 1.4), however this difference was not statistically significant. Interestingly, the systemic TNF-alpha and IFN-gamma levels were significantly higher in women who had a higher level of activated (CD69(+)) NK cells (n = 39, TNF-alpha: 86.8; IFN-gamma: 4.7) when compared with women who had a low level of activated NK cells (n = 87, TNF-alpha: 46.9; IFN-gamma: 1.7 P = 0.028 and 0.045 respectively). CONCLUSION: The systemic levels of TNF-alpha and IFN-gamma have no association with implantation rate or miscarriage rate in women undergoing IVF treatment. However, high levels of TNF-alpha and IFN-gamma are associated with elevated levels of activated NK cells and this may subsequently exert a negative impact on reproduction.

The effect of serum concentration of leukaemia inhibitory factor on in vitro fertilization treatment outcome.

PROBLEM: To evaluate the association of peripheral leukaemia inhibitory factor (LIF) levels on implantation and miscarriage rates after in vitro fertilization (IVF) treatment. METHODS: Prospective observational study of 120 randomly selected women who underwent IVF treatment. The concentration of LIF in serum was determined by enzyme-linked immunosorbent assay. RESULTS: There was no significant differences with regard to the systemic mean LIF concentration between the pregnant (42 patients, LIF: 11.55 pg/mL +/- 5.3 S.D.) and non-pregnant (66 patients, LIF: 13.47 pg/mL +/- 5.1 S.D.) women after IVF treatment. Likewise, for those women who have positive pregnancy after IVF treatment, the systemic mean LIF levels were not significantly different between women who have an ongoing pregnancy (34 ongoing pregnancy, LIF: 11.26 pg/mL +/- 5.2 S.D.) and those who had miscarriage (eight miscarriage, LIF: 12.78 pg/mL +/- 5.6 S.D.). CONCLUSION: The systemic levels of LIF concentration have no association with implantation rate or miscarriage rate in women undergoing IVF treatment. Measuring serum LIF concentration prior to embryo transfer in IVF treatment has no predictive value of implantation rate or miscarriage rate.