An evidence-based policy for the provision of subsidised fertility treatment in California: Integration of array comparative genomic hybridisation with IVF and mandatory single embryo transfer to lower multiple gestation and preterm birth rates

Common to other practice settings, standard in vitro fertilisation (IVF) in California strongly skews the multiple gestation/preterm birth rate upward to approximately 50% of all deliveries, while unassisted conceptions yield this outcome in only 3% of births. Preterm/multiple gestation babies from IVF are “super-utilisers” and consume a disproportionate share of healthcare resources, particularly during the first year of life. However, early experience with molecular cytogenetic techniques has shown that single embryo transfer (SET) with IVF can now lift pregnancy rates to an acceptable level while not altering the normal multiple gestation rate. This approach would effectively solve the preterm and multiple gestation problem historically associated with IVF. Building on the author’s previous research in medically assisted reproduction, the current proposal describes a new public health policy to incentivise SET by modifying the California Insurance Code (benchmark health plan), when it may next be revised in 2015. The proposal would partially cover IVF costs for qualified California residents with the proviso that only one embryo is transferred per procedure after comprehensive chromosomal screening of embryos with array comparative genomic hybridisation (aCGH). This investigation considers the interconnected problems of preterm birth and multiple gestation in a demographic context, showing that although the contribution made by conventional IVF to these adverse outcomes in California is numerically minor, substantial costs can still be recovered by redirecting expenditures away from high-risk IVF deliveries when the increased multiple gestation/preterm birth rate from standard IVF is corrected. This analysis is the first to examine costs calculated for all delivery types in California as a function of antecedent IVF treatment vs. unassisted conception, based on 2009 birth records, and apply this to a new model of comprehensive embryo testing and mandatory SET. These data reveal that even if partially subsidised IVF with aCGH and SET were provided for every California IVF cycle initiated in 2009 (n=18,405), the state would still realise a net surplus of at least $20M per year by stabilising the IVF multiple birth rate at ~3.2%. Thus, California can avoid up to 4,810 iatrogenic preterm/multiple gestation births by shifting the prevailing approach to IVF away from multiple embryo transfers. The proposal is net revenue positive for California because although IVF with aCGH and SET is expensive, the price to obtain this technology is always lower than the cost for one high-risk preterm/multiple birth. While a compelling primary interest exists to lower the multiple birth rate with IVF, this proposal also yields a socially valuable secondary public health benefit by improving general access to this advanced reproductive treatment for all Californians

Follow-up analysis of federal process of care data reported from three acute care hospitals in rural Appalachia

BACKGROUND: This investigation evaluated standardized process of care data collected on selected hospitals serving a remote rural section of westernmost North Carolina. METHODS: Centers for Medicare and Medicaid Services data were analyzed retrospectively for multiple clinical parameters at Fannin Regional Hospital, Murphy Medical Center, and Union General Hospital. Data were analyzed by paired t-test for individual comparisons among the three study hospitals to compare the three facilities with each other, as well as with state and national average for each parameter. RESULTS: Centers for Medicare and Medicaid Services "Hospital Compare" data from 2011 showed Fannin Regional Hospital to have significantly higher composite scores on standardized clinical process of care measures relative to the national average, compared with Murphy Medical Center (P = 0.01) and Union General Hospital (P = 0.01). This difference was noted to persist when Fannin Regional Hospital was compared with Union General Hospital using common state reference data (P = 0.02). When compared with national averages, mean process of care scores reported from Murphy Medical Center and Union General Hospital were both lower but not significantly different (-3.44 versus -6.07, respectively, P = 0.54). CONCLUSION: The range of process of care scores submitted by acute care hospitals in western North Carolina is considerable. Centers for Medicare and Medicaid Services "Hospital Compare" information suggests that process of care measurements at Fannin Regional Hospital are significantly higher than at either Murphy Medical Center or Union General Hospital, relative to state and national benchmarks. Further investigation is needed to determine what impact these differences in process of care may have on hospital volume and/or market share in this region. Additional research is planned to identify process of care trends in this demographic and geographically rural area

Balancing selected medication costs with total number of daily injections: a preference analysis of GnRH-agonist and antagonist protocols by IVF patients

BACKGROUND: During in vitro fertilization (IVF), fertility patients are expected to self-administer many injections as part of this treatment. While newer medications have been developed to substantially reduce the number of these injections, such agents are typically much more expensive. Considering these differences in both cost and number of injections, this study compared patient preferences between GnRH-agonist and GnRH-antagonist based protocols in IVF. METHODS: Data were collected by voluntary, anonymous questionnaire at first consultation appointment. Patient opinion concerning total number of s.c. injections as a function of non-reimbursed patient cost associated with GnRH-agonist [A] and GnRH-antagonist [B] protocols in IVF was studied. RESULTS: Completed questionnaires (n = 71) revealed a mean +/- SD patient age of 34 +/- 4.1 yrs. Most (83.1%) had no prior IVF experience; 2.8% reported another medical condition requiring self-administration of subcutaneous medication(s). When out-of-pocket cost for [A] and [B] were identical, preference for [B] was registered by 50.7% patients. The tendency to favor protocol [B] was weaker among patients with a health occupation. Estimated patient costs for [A] and [B] were $259.82 +/- 11.75 and$654.55 +/- 106.34, respectively (p < 0.005). Measured patient preference for [B] diminished as the cost difference increased. CONCLUSIONS: This investigation found consistently higher non-reimbursed direct medication costs for GnRH-antagonist IVF vs. GnRH-agonist IVF protocols. A conditional preference to minimize downregulation (using GnRH-antagonist) was noted among some, but not all, IVF patient sub-groups. Compared to IVF patients with a health occupation, the preference for GnRH-antagonist was weaker than for other patients. While reducing total number of injections by using GnRH-antagonist is a desirable goal, it appears this advantage is not perceived equally by all IVF patients and its utility is likely discounted heavily by patients when nonreimbursed medication costs reach a critical level

Medical student experiences in clinical reproductive medicine: dual-cohort assessment of a new learning module at the Royal College of Surgeons in Ireland

Aims: Exposure to a structured curriculum in reproductive medicine during medical school is helpful given the high frequency of fertility and pregnancy-related issues that future physicians will encounter. This study sought to evaluate a new reproductive medicine module for medical students. Study Design: Prospective cohort study. Place and Duration of Study: Dublin, Ireland; 2008-2010. Methodology: A new educational module in reproductive medicine for upper-level medical students was initiated in 2008 at the Royal College of Surgeons in Ireland (RCSI). The module included reproductive endocrinology lectures, laboratory sessions, and direct observation of clinical consultations as a required component of an obstetrics and gynaecology rotation. Students were assigned to this module on the basis of random allocation by departmental administration. The current investigation used an anonymous questionnaire and a MCQ exam to measure academic performance and student acceptance of this module, at launch and again two years later. The first sampling was from the pilot class in 2008 and a second group was evaluated in 2010. No student was in both groups. Results: 42 of 66 students completed the evaluation in 2008, and 71 of 98 did so in 2010. Mean±SD medical student age and average examination scores were comparable for the two groups. In both samples, most students (95.5%) had no prior lectures on reproductive endocrinology, and most indicated improvement in their level of understanding after the module. Both laboratory and clinical features were scored highly by students. Conclusion: At present, there is no standardised medical student curriculum for reproductive medicine in Ireland. This report is the first to describe a structured learning experience in this subspecialty area for medical students in Ireland. Additional studies are planned to track knowledge acquisition and career impact specific to reproductive medicine based on this module

Array comparative genomic hybridization screening in IVF significantly reduces number of embryos available for cryopreservation

Objective During IVF, non-transferred embryos are usually selected for cryopreservation on the basis of morphological criteria. This investigation evaluated an application for array comparative genomic hybridization (aCGH) in assessment of surplus embryos prior to cryopreservation. Methods First-time IVF patients undergoing elective single embryo transfer and having at least one extra non-transferred embryo suitable for cryopreservation were offered enrollment in the study. Patients were randomized into two groups: Patients in group A (n=55) had embryos assessed first by morphology and then by aCGH, performed on cells obtained from trophectoderm biopsy on post-fertilization day 5. Only euploid embryos were designated for cryopreservation. Patients in group B (n=48) had embryos assessed by morphology alone, with only good morphology embryos considered suitable for cryopreservation. Results Among biopsied embryos in group A (n=425), euploidy was confirmed in 226 (53.1%). After fresh single embryo transfer, 64 (28.3%) surplus euploid embryos were cryopreserved for 51 patients (92.7%). In group B, 389 good morphology blastocysts were identified and a single top quality blastocyst was selected for fresh transfer. All group B patients (48/48) had at least one blastocyst remaining for cryopreservation. A total of 157 (40.4%) blastocysts were frozen in this group, a significantly larger proportion than was cryopreserved in group A (p=0.017, by chi-squared analysis). Conclusion While aCGH and subsequent frozen embryo transfer are currently used to screen embryos, this is the first investigation to quantify the impact of aCGH specifically on embryo cryopreservation. Incorporation of aCGH screening significantly reduced the total number of cryopreserved blastocysts compared to when suitability for freezing was determined by morphology only. IVF patients should be counseled that the benefits of aCGH screening will likely come at the cost of sharply limiting the number of surplus embryos available for cryopreservation

Bivariate analysis of basal serum anti-Müllerian hormone measurements and human blastocyst development after IVF

Background To report on relationships among baseline serum anti-Müllerian hormone (AMH) measurements, blastocyst development and other selected embryology parameters observed in non-donor oocyte IVF cycles. Methods Pre-treatment AMH was measured in patients undergoing IVF (n = 79) and retrospectively correlated to in vitro embryo development noted during culture. Results Mean (+/- SD) age for study patients in this study group was 36.3 ± 4.0 (range = 28-45) yrs, and mean (+/- SD) terminal serum estradiol during IVF was 5929 +/- 4056 pmol/l. A moderate positive correlation (0.49; 95% CI 0.31 to 0.65) was noted between basal serum AMH and number of MII oocytes retrieved. Similarly, a moderate positive correlation (0.44) was observed between serum AMH and number of early cleavage-stage embryos (95% CI 0.24 to 0.61), suggesting a relationship between serum AMH and embryo development in IVF. Of note, serum AMH levels at baseline were significantly different for patients who did and did not undergo blastocyst transfer (15.6 vs. 10.9 pmol/l; p = 0.029). Conclusions While serum AMH has found increasing application as a predictor of ovarian reserve for patients prior to IVF, its roles to estimate in vitro embryo morphology and potential to advance to blastocyst stage have not been extensively investigated. These data suggest that baseline serum AMH determinations can help forecast blastocyst developmental during IVF. Serum AMH measured before treatment may assist patients, clinicians and embryologists as scheduling of embryo transfer is outlined. Additional studies are needed to confirm these correlations and to better define the role of baseline serum AMH level in the prediction of blastocyst formation

Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study

Background Single embryo transfer (SET) remains underutilized as a strategy to reduce multiple gestation risk in IVF, and its overall lower pregnancy rate underscores the need for improved techniques to select one embryo for fresh transfer. This study explored use of comprehensive chromosomal screening by array CGH (aCGH) to provide this advantage and improve pregnancy rate from SET. Methods First-time IVF patients with a good prognosis (age <35, no prior miscarriage) and normal karyotype seeking elective SET were prospectively randomized into two groups: In Group A, embryos were selected on the basis of morphology and comprehensive chromosomal screening via aCGH (from d5 trophectoderm biopsy) while Group B embryos were assessed by morphology only. All patients had a single fresh blastocyst transferred on d6. Laboratory parameters and clinical pregnancy rates were compared between the two groups. Results For patients in Group A (n=55), 425 blastocysts were biopsied and analyzed via aCGH (7.7 blastocysts/patient). Aneuploidy was detected in 191/425 (44.9%) of blastocysts in this group. For patients in Group B (n=48), 389 blastocysts were microscopically examined (8.1 blastocysts/patient). Clinical pregnancy rate was significantly higher in the morphology+aCGH group compared to the morphology-only group (70.9 and 45.8%, respectively; p=0.017); ongoing pregnancy rate for Groups A and B were 69.1 vs. 41.7%, respectively (p=0.009). There were no twin pregnancies. Conclusion Although aCGH followed by frozen embryo transfer has been used to screen at risk embryos (e.g., known parental chromosomal translocation or history of recurrent pregnancy loss), this is the first description of aCGH fully integrated with a clinical IVF program to select single blastocysts for fresh SET in good prognosis patients. The observed aneuploidy rate (44.9%) among biopsied blastocysts highlights the inherent imprecision of SET when conventional morphology is used alone. Embryos randomized to the aCGH group implanted with greater efficiency, resulted in clinical pregnancy more often, and yielded a lower miscarriage rate than those selected without aCGH. Additional studies are needed to verify our pilot data and confirm a role for on-site, rapid aCGH for IVF patients contemplating fresh SET

Prediction of individual probabilities of livebirth and multiple birth events following in vitro fertilization (IVF): a new outcomes counselling tool for IVF providers and patients using HFEA metrics

In vitro fertilization (IVF) has become a standard treatment for subfertility after it was demonstrated to be of value to humans in 1978. However, the introduction of IVF into mainstream clinical practice has been accompanied by concerns regarding the number of multiple gestations that it can produce, as multiple births present significant medical consequences to mothers and offspring. When considering IVF as a treatment modality, a balance must be set between the chance of having a live birth and the risk of having a multiple birth. As IVF is often a costly decision for patients—financially, medically, and emotionally—there is benefit from estimating a patient’s specific chance that IVF could result in a birth as fertility treatment options are contemplated. Historically, a patient’s “chance of success” with IVF has been approximated from institution-based statistics, rather than on the basis of any particular clinical parameter (except age). Furthermore, the likelihood of IVF resulting in a twin or triplet outcome must be acknowledged for each patient, given the known increased complications of multiple gestation and consequent increased risk of poor birth outcomes. In this research, we describe a multivariate risk assessment model that incorporates metrics adapted from a national 7.5-year sampling of the Human Fertilisation & Embryology Authority (HFEA) dataset (1991–1998) to predict reproductive outcome (including estimation of multiple birth) after IVF. To our knowledge, http://www.formyodds.com is the first Software-as-a-Service (SaaS) application to predict IVF outcome. The approach also includes a confirmation functionality, where clinicians can agree or disagree with the computer-generated outcome predictions. It is anticipated that the emergence of predictive tools will augment the reproductive endocrinology consultation, improve the medical informed consent process by tailoring the outcome assessment to each patient, and reduce the potential for adverse outcomes with IVF