A cost-effectiveness analysis of preimplantation genetic testing for aneuploidy (PGT-A) for up to three complete assisted reproductive technology cycles in women of advanced maternal age.

BACKGROUND: Current evidence suggests that preimplantation genetic testing for aneuploidy (PGT-A) used during assisted reproductive technology improves per-cycle live-birth rates but cumulative live-birth rate (CLBR) was similar to a strategy of morphological assessment (MA) of embryos. No study has assessed the cost-effectiveness of repeated cycles with PGT-A using longitudinal patient-level data. AIM: To assess the cost-effectiveness of repeated cycles with PGT-A compared to MA of embryos in older women. MATERIALS AND METHODS: Micro-costing methods were used to value direct resource consumption of 2093 assisted reproductive technology-naïve women aged ≥37 years undergoing up to three 'complete assisted reproductive technology cycles' (fresh plus cryopreserved embryos) with either PGT-A or MA in an Australian clinic between 2011 and 2014. Incremental cost-effective ratios were calculated from healthcare and patient perspectives with uncertainty assessed using non-parametric bootstrap methods. Cost-effectiveness acceptability curves were constructed to evaluate the probability of PGT-A being cost-effective over a range of willingness-to-pay thresholds. RESULTS: The CLBR and mean healthcare costs per patient were 30.90% and $22 962 for the PGT-A group, and 26.77% and $21 801 for the MA group, yielding an incremental cost-effective ratio of $28 103 for an additional live birth with PGT-A. At a willingness-to-pay threshold of $50 000 and above, there is more than an 80% probability of PGT-A being cost-effective from the healthcare perspective and a 50% likelihood from a patient perspective. CONCLUSION: This is the first study to use real-world patient-level data to assess the cost-effectiveness of PGT-A in older women from the healthcare and patient perspectives. The findings contribute to the ongoing debate on the role of PGT-A in clinical practice.

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

BACKGROUND: Preimplantation genetic diagnosis for aneuploidy (PGD-A) for all 24 chromosomes improves implantation and clinical pregnancy rates per single assisted reproductive technology (ART) cycle. However, there is limited data on the live-birth rate of PGD-A over repeated cycles. AIM: To assess the cumulative live-birth rates (CLBR) of PGD-A compared with morphological assessment of embryos of up to three 'complete ART cycles' (fresh plus frozen/thaw cycles) in women aged 37 years or older. MATERIALS AND METHODS: A retrospective cohort study of ART treatments undertaken by ART-naïve women at a large Australian fertility clinic between 2011 and 2014. Cohorts were assigned based on the embryo selection method used in their first fresh cycle [PGD-A, n = 110 women (PGD-A group); morphological assessment of embryos, n = 1983 women (control group)]. CLBR, time to clinical pregnancy and cycles needed to achieve a live birth were measured over multiple cycles. RESULTS: Compared to the control group, the PGD-A group achieved a higher per cycle live-birth rate (14.47% vs 9.12%, P < 0.01), took a shorter mean time to reach a clinical pregnancy leading to a live-birth (104.8 days vs 140.6 days, P < 0.05) and required fewer cycles to achieve a live-birth (6.91 cycles vs 10.96 cycles, P < 0.01). However, after three 'complete ART cycles', the CLBR was comparable for the two groups (30.90% vs 26.77%, P = 0.34). CONCLUSION: This is the first study to assess the effectiveness of PGD-A over multiple ART cycles. These real-world findings suggest that PGD-A leads to better outcomes than using morphological assessment alone in women of advanced maternal age.

Recombinant LH supplementation in patients with a relative reduction in LH levels during IVF/ICSI cycles: A prospective randomized controlled trial.

PURPOSE: The aim of this study was to assess the use of recombinant luteinizing hormone (rLH) supplementation in patients who experience a reduction in LH concentration during controlled ovarian hyperstimulation (COH) for IVF/ICSI. METHODS: A multi-center prospective randomized controlled trial (RCT) was performed over three years. Two hundred and forty patients aged between 24 and 42 years undergoing IVF/ICSI treatment with a long down regulation (LDR) protocol were recruited. LH was measured on the day FSH was started and again 6days later. 100 patients had a 50% or greater reduction in LH levels and these were randomized to receive either recombinant LH (rLH) supplementation (group 1, n=43) or no additional rLH supplementation (group 2, n=57). Group 1 received rLH 75IU daily from day 7 of FSH stimulation to the day of HCG trigger. RESULTS: There were no differences in either live birth or clinical pregnancy rates per embryo transfer between the two groups (27.8% vs. 37.0%, p=0.39, RR=0.75, 95%CI 0.39-1.44 and 36.1% vs. 43.5% p=0.51, RR=0.84, 95%CI 0.5-1.48, respectively). CONCLUSION: In conclusion the addition of rLH in patients with a relative reduction in serum LH concentration during COH for IVF/ICSI did not improve live birth or clinical pregnancy rates. However the results were not conclusive and further large well-designed RCTs are required to confirm these findings.

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.

Single-arm, observational study of the ease of use of a redesigned pen device to deliver recombinant human follicle-stimulating hormone (follitropin alfa) for assisted reproductive technology treatment.

PURPOSE: Evaluation of patients' ease of use of the redesigned, disposable, ready-to-use follitropin alfa pen during controlled ovarian stimulation for assisted reproductive technology. METHODS: This single-center, observational, open-label, single-arm study recruited infertile normo-ovulatory women (aged 18-45 years). Nurses trained patients to self-administer recombinant human follicle-stimulating hormone daily using the follitropin alfa pen (300 IU, 450 IU, and 900 IU). Before treatment, patients completed Questionnaire A. Following self-administered treatment, on stimulation days 5-6 and 7-8 (within a day of receiving recombinant human chorionic gonadotropin), patients completed Questionnaire B. Nurses completed an ease-of-learning/teaching questionnaire. The primary endpoint was proportion of patients rating the pen as "easy/very easy" to use (Questionnaire B) on the final visit before recombinant human chorionic gonadotropin. Secondary endpoints included: proportion of patients rating the follitropin alfa pen as easy to learn, use, prepare, deliver, and dispose of (Questionnaires A and B). Proportions (95% confidence intervals [CIs]) were provided for primary and secondary endpoints. Adverse events were reported descriptively. RESULTS: Eighty-six patients received recombinant human follicle-stimulating hormone. Of the 72 patients who had completed the overall assessment questions, 66 (91.7%; 95% CI =82.7%-96.9%) found the pen "easy" to use. Also, 70/86 (81.4%) patients "strongly agreed/agreed" that, overall, it was easy to learn how to use the pen; 72/86 (83.7%) "strongly agreed/agreed" that easily understandable, verbal information was provided; and 70/86 (81.4%) were confident about using the pen correctly. In total, 24/26 nurses (92.3%; 95% CI =74.9%-99.1%) rated the pen as easy to use. Clinical pregnancy rate/patient/cycle/embryo transfer was 37%. Twenty-six ovarian hyperstimulation syndrome events were reported (none severe; 16 patients [19%]); of these, 13 occurred at embryo transfer. CONCLUSION: In this observational study, patients had a high acceptance of the redesigned follitropin alfa pen, with most finding it very easy/easy to use. Assisted reproductive technology nurses found the pen very easy/easy to teach.

Single embryo transfer reduces the risk of perinatal mortality, a population study.

STUDY QUESTION: Do births following single embryo transfers (SET) have a reduced risk of perinatal mortality compared with those following double embryo transfers (DET)? SUMMARY ANSWER: SET is associated with reduced risk of perinatal mortality compared with DET. WHAT IS KNOWN ALREADY: Fetal, neonatal and perinatal mortality are important indicators for monitoring pregnancy and childbirth, particularly for births following assisted reproductive technology (ART) treatments. Following the introduction of SET, there has been a decline in the perinatal mortality rate (PMR) among babies born after ART in Australia and New Zealand. STUDY DESIGN, SIZE, DURATION: This population study (census) included 50,258 births of ≥ 20 weeks gestation and/or ≥ 400 g of birthweight following embryos transfer cycles in Australia and New Zealand during the period 2004-2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: The PMR was calculated according to the number of embryos transferred and other demographic and treatment-related factors. Perinatal deaths were defined as the number of fetal deaths (stillbirths) plus the number of neonatal deaths (deaths that occur before 28 days after birth). MAIN RESULTS AND THE ROLE OF CHANCE: The PMR was 16.2 per 1000 births (n= 813). Of the 813 perinatal deaths, 630 were fetal deaths and 183 neonatal deaths. Twins had a significantly higher PMR (27.8 per 1000 births) than singletons (12.4 per 1000 births). The risk of perinatal mortality for all births following DET was 53% higher than for all births following SET (adjusted risk ratio 1.53, 95% confidence interval (95% CI): 1.29-1.80). Births following fresh DET had a 58% increased risk of perinatal mortality compared with births following fresh SET (risk ratio 1.58, 95% CI: 1.32-1.90). LIMITATIONS, REASONS FOR CAUTION: Information on outcomes was missing from <1% of clinical pregnancies recorded in Australian and New Zealand Assisted Reproduction Database for the study period. There are no data on the timing of fetal death, the cause of perinatal death or on late termination of pregnancy at ≥ 20 weeks' gestation. WIDER IMPLICATIONS OF THE FINDINGS: Double and higher order embryo transfer is associated with a higher risk of perinatal mortality when compared with SET. The number of embryos transferred is determined by the clinician with consent of the patient and is a modifiable treatment factor. SET should be advocated as the first-line management in ART as it is the single most effective public health intervention for preventing excess perinatal mortality among ART pregnancies. STUDY FUNDING/COMPETING INTEREST(S): Nil.

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

BACKGROUND: Almost 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. METHODS: Pooled 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. RESULTS: After 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, $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. CONCLUSIONS: The 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.

Elevated progesterone in GnRH agonist down regulated in vitro fertilisation (IVFICSI) cycles reduces live birth rates but not embryo quality.

OBJECTIVE: To assess the impact of pre-hCG elevated progesterone on live birth outcomes during GnRH agonist long down regulated protocol assisted reproduction cycles. DESIGN: Retrospective cohort study. SETTING: Single Centre Private IVF Clinic. PATIENTS: A total of 582 consecutive cycles of IVF/ICSI in 2003. INTERVENTIONS: All patients underwent a long down-regulation protocol, controlled ovarian stimulation and IVF/ICSI. Serum progesterone concentrations were measured just prior to HCG administration. 253 patients were followed to 2009 for outcomes of their frozen embryo cycles. MAIN OUTCOME MEASURE: Live birth rate in fresh and frozen cycles. RESULTS: Patients in the upper quartile pre-hCG progesterone concentration (≥ 5.4 pmol/L) had a higher final estradiol level, more oocytes collected and more usable embryos, when compared to those with lower quartiles. They also had lower live birth rates per cycle started (21.9% vs. 15%, P < 0.05). However, live birth rates from frozen embryo cycles were not significantly different between the groups. CONCLUSIONS: Pre-hCG progesterone elevation leads to lower live birth rates in stimulated IVF cycles. Live birth rates achieved with frozen embryos in the high progesterone cycles suggest, that pre-hCG progesterone elevation negatively affects endometrial receptivity without adversely affecting embryo quality.

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. DESIGN AND SETTING: Costing model using data from the Australia and New Zealand Assisted Reproduction Database, the National Perinatal Data Collection and Medicare Australia on ART treatment cycles undertaken in Australia between 2002 and 2008. MAIN OUTCOME MEASURES: Annual savings in maternal and infant inpatient birth-admission costs resulting from the reduction in ART multiple birth rate; theoretical number of ART treatment programs funded and infants born by means of these savings. RESULTS: The reduction in the ART multiple birth rate from 18.8% in 2002 to 8.6% in 2008 resulted in estimated savings to government of $47.6 million in birth-admission costs alone. Theoretically, these savings funded 7042 ART treatment programs comprising one fresh plus one frozen embryo transfer cycle, equating to the birth of 2841 babies. Fifty-five per cent of the increased use of ART services since 2002 has been theoretically funded by the reduction in multiple birth infants. CONCLUSIONS: Against a backdrop of supportive public funding of ART in Australia, a voluntary shift to single embryo transfer by fertility clinicians and ART patients has resulted in substantial savings in hospital costs. Much of the growth in ART use has been theoretically cross-subsidised by the move to safer embryo transfer practices.

Gonadotropin control of inhibin secretion and the relationship to follicle type and number in the hpg mouse.

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.

Value of single and paired serum human chorionic gonadotropin measurements in predicting outcome of in vitro fertilisation 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. DESIGN: Retrospective analysis. SETTING: Westmead Fertility Centre, Westmead Hospital, Sydney, Australia. MATERIALS AND METHODS: Serial hCG measurements in 143 patients at Westmead Fertility Centre, from August 1997 to April 2000, were studied retrospectively. The predictive value of single hCG measurements relative to the published assay reference ranges were evaluated. The predictive value of serial hCG levels in predicting pregnancy outcome was assessed separately. Normal daily rate of rise (ROR) of hCG was defined as the mean ROR for ongoing pregnancies +/- 1 SD. Abnormal daily ROR was defined as a daily increase in hCG less than the mean ROR for ongoing pregnancies--1 SD. MAIN OUTCOME MEASURES: Viability of the pregnancy at 20 weeks' gestation. RESULTS: An initial hCG measurement below the 5th centile reference limit for gestation has 85% (confidence interval (CI) 75-92%) positive predictive value for non-viability, with a sensitivity of 40% (CI 33-48). Serial testing of borderline samples for ROR did not improve positive predictive value (70%: CI 50-86%) or sensitivity (30%: CI 20-43%) in identifying non-ongoing pregnancies. CONCLUSIONS: In assisted reproductive technologies pregnancies, comparison of a single hCG value with appropriate reference ranges enables approximately 40% of non-viable pregnancies to be identified with a high positive predictive value. Repeated measurements did not contribute further to the predictive value.

Effect of progestin-only pill on pituitary-ovarian axis activity during lactation.

We have monitored effects of progestin-only pill (POP) on ovarian activity during breastfeeding. Twenty-one women, using barrier methods (BM) of contraception and 9 women on POP were enrolled 6 weeks postpartum (PP) and followed-up to 18 weeks PP. There was little change in plasma follicle-stimulating hormone and luteinizing hormone, and no differences between BM and POP. POP did not affect plasma estradiol. There was no difference between BM and POP in plasma inhibin B concentrations. The size of follicles was similar in both groups in all time points. There was an increase in the endometrial thickness from 6 weeks PP to 18 weeks PP in BM (3.7 +/- 0.5 vs. 5.4 +/- 0.6 mm, p < 0.05), but no differences within the POP group or between the treatment groups. POP does not suppress gonadotropins nor affect growth of ovarian follicles during breastfeeding. Thus, the contraceptive effect of POP is likely mediated through local actions at the endometrium and cervix in a manner similar to that in menstruating women.