Peter Illingworth

The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review

STUDY QUESTION Is preimplantation genetic diagnosis for aneuploidy (PGD-A) with analysis of all chromosomes during assisted reproductive technology (ART) clinically and cost effective? SUMMARY ANSWER The majority of published studies comparing a strategy of PGD-A with morphologically assessed embryos have reported a higher implantation rate per embryo using PGD-A, but insufficient data has been presented to evaluate the clinical and cost-effectiveness of PGD-A in the clinical setting. WHAT IS KNOWN ALREADY Aneuploidy is a leading cause of implantation failure, miscarriage and congenital abnormalities in humans, and a significant cause of ART failure. Preclinical evidence of PGD-A indicates that the selection and transfer of euploid embryos during ART should improve clinical outcomes. STUDY DESIGN, SIZE AND DURATION A systematic review of the literature was performed for full text English language articles using MEDLINE, EMBASE, SCOPUS, Cochrane Library databases, NHS Economic Evaluation Database and EconLit. The Downs and Black scoring checklist was used to assess the quality of studies. Clinical effectiveness was measured in terms of pregnancy, live birth and miscarriage rates. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Nineteen articles meeting the inclusion criteria, comprising three RCTs in young and good prognosis patients and 16 observation studies were identified. Five of the observational studies included a control group of patients where embryos were selected based on morphological criteria (matched cohort studies). MAIN RESULTS AND ROLE OF CHANCE Of the five studies that included a control group and reported implantation rates, four studies (including two RCTs) demonstrated improved implantation rates in the PGD-A group. Of the eight studies that included a control group, six studies (including two RCTs) reported significantly higher pregnancy rates in the PGD-A group, and in the remaining two studies, equivalent pregnancies rates were reported despite fewer embryos being transferred in the PGD-A group. The three RCTs demonstrated benefit in young and good prognosis patients in terms of clinical pregnancy rates and the use of single embryo transfer. However, studies relating to patients of advanced maternal age, recurrent miscarriage and implantation failure were restricted to matched cohort studies, limiting the ability to draw meaningful conclusions. LIMITATIONS, REASONS FOR CAUTION Relevant studies may have been missed and findings from RCTs currently being undertaken could not be included. WIDER IMPLICATIONS OF THE FINDINGS Given the uncertain role of PGD-A techniques, high-quality experimental studies using intention-to-treat analysis and cumulative live birth rates including the comparative outcomes from remaining cryopreserved embryos are needed to evaluate the overall role of PGD-A in the clinical setting. It is only in this way that the true contribution of PGD-A to ART can be understood.

Immunolocalization of bcl-2 in the human corpus luteum

The mechanisms of luteal regression and rescue in women are unknown but forms of programmed cell death may be involved. The proto-oncogene bcl-2 is an important inhibitor of apoptosis but has not previously been described in the human corpus luteum. Immunohistochemical localization of bcl-2 protein was investigated in human corpora lutea obtained from women undergoing surgery during endocrine monitored menstrual cycles as well as from women who had been treated with human chorionic gonadotrophin (HCG) to prolong the luteal phase. Bcl-2 was found to be localized in granulosa-lutein, theca-lutein (as identified by co-localization of P450(17)alpha-hydroxylase) and the endothelial cells around some blood vessels. Immunoblotting demonstrated the presence of a single band of approximately MW 26 kDa. There was no apparent change in either the intensity of immunostaining or the histological localization during the normal luteal phase or following treatment with human chorionic gonadotrophin. The product of the proto-oncogene bcl-2 is present in the human corpus luteum. It is unlikely that bcl-2 expression alone is responsible for prolongation of the lifespan of the corpus luteum in early pregnancy although it is possible that the action of the bcl-2 gene present is modified by changes in other members of the bcl-2 family.

Assisted reproductive technology: public funding and the voluntary shift to single embryo transfer in Australia

Objectives: To calculate cost savings to the Australian federal and state governments from the reduction in twin and triplet birth rates for infants conceived by assisted reproductive technology (ART) since 2002, and to determine the number of ART treatment programs theoretically funded by means of these savings.

Socioeconomic disparities in access to ART treatment and the differential impact of a policy that increased consumer costs

STUDY QUESTION What was the impact on access to assisted reproductive technology (ART) treatment by different socioeconomic status (SES) groups after the introduction of a policy that increased patient out-of-pocket costs? SUMMARY ANSWER After the introduction of a policy that increased out-of-pocket costs in Australia, all SES groups experienced a similar percentage reduction in fresh ART cycles per 1000 women of reproductive age. Higher SES groups experienced a progressively greater reduction in absolute numbers of fresh ART cycles due to existing higher levels of utilization. WHAT IS KNOWN ALREADY Australia has supportive public funding arrangements for ARTs. Policies that substantially increase out-of-pocket costs for ART treatment create financial barriers to access and an overall reduction in utilization. Data from the USA suggests that disparities exist in access to ART treatment based on ethnicity, education level and income. STUDY DESIGN, SIZE, DURATION Time series analysis of utilization of ART, intrauterine insemination (IUI) and clomiphene citrate by women from varying SES groups before and after the introduction of a change in the level of public funding for ART. PARTICIPANTS/MATERIALS, SETTING, METHODS Women undertaking fertility treatment in Australia between 2007 and 2010. MAIN RESULTS AND THE ROLE OF CHANCE Women from higher SES quintiles use more ART treatment than those in lower SES quintiles, which likely reflects a greater ability to pay for treatment and a greater need for ART treatment as indicated by the trend to later childbearing. In 2009, 10.13 and 5.17 fresh ART cycles per 1000 women of reproductive age were performed in women in the highest and lowest SES quintiles respectively. In the 12 months after the introduction of a policy that increased out-of-pocket costs from ∼

A reduction in public funding for fertility treatment - an econometric analysis of access to treatment and savings to government

1500 Australian dollars (€1000) to ∼

Gonadotropin Control of Inhibin Secretion and the Relationship to Follicle Type and Number in the hpg Mouse

2500 (€1670) for a fresh IVF cycle, there was a 21-25% reduction in fresh ART cycles across all SES quintiles. The absolute reduction in fresh ART cycles in the highest SES quintile was double that in the lowest SES quintile. LIMITATIONS, REASONS FOR CAUTION In this study, SES was based on the average relative socioeconomic advantage and disadvantage of small geographic areas, and therefore may not reflect the SES of an individual. Additionally, the policy impact was limited to the 12 months following its introduction, and may not reflect longer term trends in ART treatment. WIDER IMPLICATIONS OF THE FINDINGS While financial barriers are an important obstacle to equitable access to ARTs, socioeconomic differences in utilization are likely to persist in countries with supportive public funding, due in part to differences in childbearing patterns and treatment seeking behaviour. Policy makers should be informed of the impact that changes in the level of cost subsidization have on access to ART treatment by different socioeconomic groups. STUDY FUNDING/COMPETING INTEREST(S) G.M.C. receives grant support to her institution from the Australian Government, Australian Research Council (ARC) Linkage Grant No LP1002165; ARC Linkage Grant Partner Organisations are IVFAustralia, Melbourne IVF and Queensland Fertility Group. V.P.H. is employed as an Economics Research Associate on the same grant. P.J.I. is Medical Director of the IVF Clinic, IVFAustralia and has a financial interest in the parent group, Virtus. TRIAL REGISTRATION NUMBER N/A.

Value of single and paired serum human chorionic gonadotropin measurements in predicting outcome of in vitro fertilisation pregnancy

BackgroundAlmost all assisted reproductive technology (ART) and intrauterine insemination (IUI) treatments performed in Australia are subsidized through the Australian Government’s universal insurance scheme, Medicare. In 2010 restrictions on the amount Medicare paid in benefits for these treatments were introduced, increasing patient out-of-pocket payments for fresh and frozen embryo ART cycles and IUI. The aim of this study was to evaluate the impact of the policy on access to treatment, savings in Medicare benefits and the number of ART conceived children not born.MethodsPooled quarterly cross-sectional Medicare data from 2007 and 2011 where used to construct a series of Ordinary Least Squares (OLS) regression models to evaluate the impact of the policy on access to treatment by women of different ages. Government savings in the 12 months after the policy was calculated as the difference between the predicted and observed Medicare benefits paid.ResultsAfter controlling for underlying time trends and unobserved factors the policy change reduced the number of fresh embryo cycles by almost 8600 cycles over 12 months (a 16% reduction in cycles, p < 0.001). The policy effect was greatest on women aged 40 years and older (38% reduction in cycles, p < 0.001). Younger women engaged in relatively more anticipatory behaviour by bringing forward their fresh cycles to 2009. Frozen embryo cycles, which are approximately one quarter of the cost of a fresh cycle, were only marginally impacted by the policy. Utilisation of IUI cycles were not impacted by the policy. After adjusting for anticipatory behaviour,

Assisted reproductive technology (ART) cumulative live birth rates following preimplantation genetic diagnosis for aneuploidy (PGD-A) or morphological assessment of embryos: A cohort analysis

76 million in Medicare benefits was saved in the 12 months after the policy change (0.47% of annual Medicare benefits). Between 1200 and 1500 ART conceived children were not born in 2010 as a consequence of the policy.ConclusionsThe introduction of the policy resulted in a significant reduction in fresh ART cycles in the first 15 months after its introduction. Further evaluation on the long term impact of the policy with regard access to treatment and on clinical practice, particularly the number of embryos transferred, is crucial to ensuring equitable access to fertility treatment and the health and welfare of ART children.

Reply: Preimplantation genetic screening using comprehensive chromosome screening: evidence and remaining challenges

Abstract Inhibin is secreted in two distinct heterodimeric forms, A and B, but the mechanism for the differential control of these two forms is unclear. To evaluate the relationship between secretion of inhibin forms and folliculogenesis, the effects of gonadotropins on inhibin concentrations were studied in parallel with stereological enumeration of ovarian follicle types in gonadotropin-deficient hypogonadal (hpg) female mice treated with recombinant human FSH (10 IU/day), hCG (1 IU/day), or both for 20 days. Treatment with FSH alone significantly increased blood concentrations of both inhibin A and inhibin B, whereas hCG alone had no effect on either inhibin. The combination of FSH and hCG further increased the concentration of inhibin A but had no effect on the concentration of inhibin B beyond that of FSH. The number of primordial follicles per ovary was significantly reduced in FSH-treated hpg mice, but was not affected by hCG treatment. Antral follicles were absent in the untreated hpg mice, present following treatment with FSH, and were present in only limited numbers following hCG treatment alone. Preovulatory follicles were observed only in the wild-type and combined FSH and hCG treatment groups. These results demonstrate that secretion of both inhibins is associated with the presence of antral follicles. Inhibin A secretion is increased by the presence of preovulatory follicles, whereas the concentration of inhibin B is not affected. The observed effects of gonadotropins on inhibin A and B secretion may be explained by corresponding gonadotropin effects on follicle development.

Monitoring of controlled ovarian stimulation to limit twin pregnancy

Objectives:  To assess whether paired human chorionic gonadotropin (hCG) measurements in early pregnancy are more effective than a single measurement, in predicting the outcome for an in vitro fertilisation pregnancy.