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Impact of urinary FSH price: a cost-effectiveness analysis of recombinant and urinary FSH in assisted reproduction techniques in the USA.

This study compares the cost-effectiveness of recombinant human FSH (r(h)FSH, Gonal-F) and urinary FSH (uFSH) in assisted reproduction techniques in the USA, using several hypothetical prices for uFSH. A specifically designed Markov model and Monte-Carlo simulation techniques were used to model the possible outcomes during three treatment cycles. Data included in the model were derived from randomized clinical trials and databases. An expert panel determined probability distributions for each decision point throughout each virtual treatment cycle. The assumed unit cost of r(h)FSH was $58.52 (based on the average retail cost) and three unit prices ($49, $45, $40) were used for uFSH. A total of 5000 simulations was performed on a virtual cohort of 100,000 patients. The mean number of assisted reproduction treatment cycles/success (ongoing pregnancy at 12 weeks) was 4.34 with r(h)FSH and 4.75 with uFSH. The total number of pregnancies achieved was 40,665 and 37,890, respectively. The mean cost per successful pregnancy with r(h)FSH was $40 688. For uFSH at unit costs of $40, $45 and $49, the mean costs per successful pregnancy were $43,500, $44,400 and $45,000, respectively (each P < 0.0001 versus r(h)FSH). Thus, despite its greater cost per unit dose, r(h)FSH is more cost-effective than uFSH over a wide range of uFSH prices, reflecting the greater clinical efficacy of r(h)FSH.

Cost-Benefit Analysis↗

The results of aneuploidy screening in 276 couples undergoing assisted reproductive techniques.

Preimplantation genetic diagnosis for aneuploidy screening (PGD-AS) using sequential in situ hybridization was applied for aneuploidy testing in 276 couples with 282 ART cycles. Patients with advanced maternal age (AMA, n = 147), recurrent implantation failure (RIF, n = 48), repeated early spontaneous abortion (RSA, n = 32) and abnormal gamete cell morphology (AGCM, n = 55) including macrocephal sperm forms or cytoplasmic granular oocytes were included. Embryo biopsy was performed on day 3 in a calcium-magnesium-free medium by using a noncontact diode laser system. After fixation and enzymatic treatment, fluorescent in situ hybridization (FISH) was carried out on 1147 blastomeres with specific probes for chromosomes 13, 16, 18, 21 and 22 for AMA group, 13, 18, 21, X and Y for AGCM group and 13, 16, 18, 21, 22, X and Y for RIF and RSA groups respectively. The overall chromosomal abnormality rate in analyzed embryos was 40.9%, with no significant difference between AMA, RIF and RSA groups (p > 0.05). However, AGCM group presented a higher rate of chromosomal aneuploidies (57.4%) than the other three groups (p < 0.01). A total of 84% biopsied embryos presented cleavage in 24 h and embryo transfer was realized in 278 cycles. In four cycles, no chromosomally normal embryo was found for embryo transfer. A total of 88 pregnancies (31.6%) were achieved, 19.3% resulted in abortion and 63 healthy births were obtained, with a total of 93 babies born. Aneuploidy testing in couples with poor prognosis undergoing ART cycles is a useful tool to increase the chance of ART success. Furthermore, abnormal gamete cell morphology should be considered one of the major indications for PGD in ART programs as high aneuploidy rates were observed in this group.

Abortion, Habitual↗

[How to improve assisted reproductive techniques results? Biological aspects].

In spite of recent improvements in IVF, pregnancy rates remained dramatically low. Better criteria are therefore necessary to establish the viability of a transferable top quality embryo. Observation of both pronuclei patterns at the zygote stage and early cleavage appears to offer an additional prognostic tool, correlating with chromosomal status and IVF outcome. Developmental ability and morphological evaluation of the embryo on days 2-3 remains the most used and valid method of selection, even though it is not sufficient to select embryos with the higher implantation potential. Blastocyst culture is another possible strategy for selecting the ideal embryo with theoretical, reduced risk of aneuploidies, though not all major chromosomal aberrations are excluded by prolonged in-vitro-culture. Concerning micro-manipulation of embryo such as hatching or cleaning or cytoplasm transfer, only controversial data are still available. In the field of ART, recent meta-analysis could not conclude to a positive effect concerning hatching, blastocyst culture or systematic PGD-AS (preimplantation genetic diagnosis with aneuploidy screening). Beside the technological aspect, Quality Management System is of great importance. Staff development and monitoring of staff performance in the IVF laboratory has to be considered in the next future.

Blastocyst↗

[DNA sperm methylation in assisted reproductive techniques].

In the last few years, many tests were developed to study the fertilizing properties of the spermatozoa. However none of them was useful to obtain a prognostic factor. Indeed, the integrity of the spermatic DNA is also necessary to a successful fertilization for obtaining a pregnancy. DNA integrity could be evaluated by the measurement of the level of DNA methylation. Indeed, in the mammals, the methylation of the ADN is involved in diverse processes amongst them the regulation of the genome expression during the embryonic development. The objective of this study is to evaluate the impact of the level of methylation of the spermatic DNA in the success of in vitro fertilization (IVF), in terms of rate of fertilization, quality of the embryos and rate of pregnancy. The immunostaining of the 5-methylecytosine, then the quantification by image analysis or with flow cytometry, allowed an objective evaluation of the level of total methylation of spermatic DNA. Our data show that the level of DNA methylation influences neither the fertilization rate nor the embryos quality. On the other hand, the rate of pregnancy is decreased if the total level of DNA methylation is lower than a threshold value. The level of spermatic DNA methylation represents a new parameter of spermatic maturation.

5-Methylcytosine↗

Is there a place for immunomodulation in assisted reproduction techniques?

We briefly review the history of the concepts of the materno foetal relationship, and the (various) rationales which have been used to justify lymphocyte alloimmunisation (LA) as a treatment for recurrent spontaneous abortion of putative immune origins. The effectiveness of the treatment is at best dubious and limited to a small number of women for which there is no real positive selection rationale, at worst it is not efficient. The rationales themselves are rather "evolutive". The present one is to use the Th1:Th2 paradigm and, thus, to propose to "dampen NK activity" in abortion prone women and this concept has been extended by some to implantation failure. We briefly review why the Th1:Th2 paradigms is no longer fully valid, describe briefly why it is inappropriate for implantation, and conclude that alloimmunisation should no longer be proposed for RSA, hence, more for implantation failure. We, however, do not reject immunotherapy, but we believe that molecular and cellular defects specific approaches should be used, tailored for the specific pathway whose disruption cause the clinical symptom.

Abortion, Spontaneous↗

[Contribution of ovarian and uterine color Doppler in medically assisted reproduction techniques (ART)].

Along the menstrual cycle and during pregnancy, small blood vessels proliferate within the uterus and the ovulating ovary. Angiogenic factors such as VEGF are involved in this phenomenon. In the ovulating ovary, neo-angiogenesis spreads progressively inside the dominant follicle wall and plays a role in the maintenance of the corpus luteum, under the influence of LH (or HCG during pregnancy). In ART, the measure of the blood flow is interesting since it correlates to the number and quality of harvested oocytes. Follicle hypoxia may impair chromosomal organization and separation within the oocyte. This neo-angiogenesis is also important in endometrium, in particular for embryo implantation. Ultrasounds with Doppler allow to estimate the endometrial receptivity, especially in IVF cycles. It is assumed that chance for ongoing pregnancy is almost zero if: endometrial thickness is < 8 mm; uterine pulsatility index (PI) is > 3. Doppler ultrasounds are a useful and even mandatory complement to standard vaginal ultrasonoghraphy in ART. It can be viewed as an indicator of the endometrial and follicular "well-being".

Endometrium↗

GnRH antagonists: do they open new pathways to safer treatment in assisted reproductive techniques?

GnRH antagonists (GnRHnt) induce a rapid decrease in LH and FSH, preventing and interrupting LH surges. Their properties do not require a desensitization period and allow their use in the late follicular phase. GnRHnt could replace GnRH agonists (GnRHa) in ovarian stimulation without their side-effects and their long period of desensitivity. Both protocols using GnRHnt were associated with a smaller amount of gonadotrophin, a shorter stimulation period and a lower incidence of ovarian hyperstimulation syndrome (OHSS) with statistically comparable pregnancy rates. There is room for improvement of both protocols concerning the programming, the antagonist dose and the timing of antagonist administration. Luteal support should be maintained until the results of further studies. The perinatal outcome appears to be similar to that of other stimulation regimens. Triggering of ovulation can be facilitated by GnRHa for patients at risk of OHSS. Provided that pregnancy rates equivalent to those obtained with GnRHa are confirmed in larger series, GnRHnt will clearly represent a safer alternative to GnRHa protocols in IVF.

Female↗

Assisted reproductive techniques for hybridization of camelids.

The camelid family comprises the Old World camelids (or dromedary and Bactrian camels) and the New World camelids (namely the llamas, alpacas, guanacos and vicunas). Although the species within each group can hybridize among themselves to produce fertile offspring, it is only recently that a hybrid between New and Old World camelids has been reported. To create this hybrid, semen was collected from male camels by artificial vagina (AV) and inseminated into female guanacos (n = 9) and llamas (n = 3) at the appropriate stage of their follicular wave cycle. Similarly, guanaco and llama semen was collected, also by AV, and inseminated into female camels (n = 42). Although several conceptions occurred, only one hybrid (camel sire x guanaco dam) continued to term and was born alive after 328 days of gestation, and another is pregnant at the time of writing (camel sire x llama dam). Further studies are presently being carried out using extraspecific embryo transfer to try and improve the success rate of live offspring being born. Female guanacos (n = 4) are treated with hormones to stimulate their ovaries to produce several follicles before being inseminated with camel semen. Of the 12 camel recipients that have to date received hybrid embryos (camel sire x guanaco dam), 10 conceived, but 9 of these subsequently aborted between 30 and 365 days and only one recipient was still pregnant at the time of writing.

Abortion, Veterinary↗