Commentary on two recently published formal guidelines on management of "mosaic" embryos after preimplantation genetic testing for aneuploidy (PGT-A).

Two professional societies recently published opinions on the clinical management of "mosaic" results from preimplantation genetic testing for aneuploidy (PGT-A) in human blastocyst-stage embryos in associations with in vitro fertilization (IVF). We here point out three principal shortcomings: (i) Though a most recent societal opinion states that it should not be understood as an endorsement of the use of PGT-A, any discussion of how PGT-A should be clinically interpreted for all practical purposes does offer such an endorsement. (ii) The same guideline derived much of its opinion from a preceding guidance in favor of utilization of PGT-A that did not follow even minimal professional requirements for establishment of practice guidelines. (iii) Published guidelines on so-called "mosaic" embryos from both societies contradict basic biological characteristics of human preimplantation-stage embryos. They, furthermore, are clinically unvalidated and interpret results of a test, increasingly seen as harmful to IVF outcomes for many infertile women. Qualified professional organizations, therefore, should finally offer transparent guidelines about the utilization of PGT-A in association with IVF in general.

Should we still offer elective freezing of all embryos in all IVF cycles?

Elective 'freeze all', also called 'freeze only', refers to an IVF cycle where all embryos are frozen for later embryo transfer in a non-stimulated cycle, with the promise of increased success rates and prevention of ovarian hyperstimulation syndrome (OHSS) in most patients. However, 'freeze all' is associated with significantly higher perinatal complications including eclampsia, preeclampsia, chronic hypertension and large-for-gestational-age infants, without the demonstrated advantages of providing better results, except for a decrease in the incidence of OHSS, which should matter to women with polycystic ovary syndrome (PCOS) and high responders to ovarian stimulation but not to all patients. 'Freeze all' is also suggested for all simulated IVF cycles, due to the alleged 'faulty endometrium' caused by ovarian stimulation. However, there is no direct evidence that asynchronous endometrium exists, and only if preovulatory progesterone level increase, can 'freeze all' confer an advantage. We conclude that an alleged diagnosis of 'faulty endometrium' should not be used as an indication for 'freeze all'. To offset the risk of OHSS more simply, less costly and less risky solutions such as mild ovarian stimulation, to dampen the number of oocytes and to aim for transfer of a single blastocyst, should be the preferred solution to treat women with PCOS and high responders for oocyte retrieval.

Repeated implantation failure (RIF): an iatrogenic meaningless definition that generates unnecessary and costly use of add-on procedures.

This opinion paper addresses the literature regarding repeated implantation failure (RIF) in IVF embryo transfer programmes. We provide several lines of discussion as to why such diagnosis might be wrong, why it should not be a call for action or a reason to change the course of treatment, and how RIF biases the quality of the publications and leads to the use of unnecessary and costly adjuvant procedures beyond basic IVF. We argue that these costly add-on procedures are being offered to patients in this highly privatized sector to prevent them from quitting the programme and as a by-product to increase the clinic income. The patients, on the other hand, often equate lucrative hi-tech procedures with possible success and request them despite the lack of proof of the efficacy of most of the procedures.

The dilemma of social oocyte freezing: usage rate is too low to make it cost-effective.

Delayed childbearing in affluent countries and the financial crisis of the Y-generation have contributed to the dramatic decline in birth rate. Social oocyte freezing (SOF) has fuelled the imagination of patients and doctors to offer it as a solution to single, presumably fertile, women to preserve their fertility potential by egg banking at an early age. Some are calling on governments to support large-scale 'fertility preservation', but is it cost-effective? Social oocyte freezing is effectively expensive insurance, where future utilization is unknown. Theoretical studies have suggested that SOF is only cost-effective with a usage rate of 50% or over, and when getting married is not set as a condition. Maximal possible utilization of frozen eggs, however, is much lower. Recent studies have found usage rates of 3.1-9.3%, which sets the cost of each extra live birth between $600,000 and 1,000,000. As IVF is being privatized and business-driven, it is hard for experts to decipher scientific- from business-oriented claims. The cost-effectiveness of SOF for individuals or society unclear. These facts place the burden of responsibility on the treating physician, who should inform patients about the true likelihood of using their eggs, the age at which to freeze and possible alternatives.

Recommendations on the management of fragility fracture risk in women younger than 70 years.

The risk for fragility fracture represents a problem of enormous magnitude. It is estimated that only a small fraction of women with this risk take the benefit of preventive measures. The relationship between estrogen and bone mass is well known as they are the other factors related to the risk for fracture. There are precise diagnostic methods, including a tool to diagnose the risk for fracture. Yet there continues to be an under-diagnosis, with the unrecoverable delay in instituting preventive measures. Women under the age of 70 years, being much more numerous than those older, and having risk factors, are a group in which it is essential to avoid that first fragility fracture. Today it is usual not to differentiate between the treatment and the prevention of osteoporosis since the common aim is to prevent fragility fractures. Included in this are women with osteoporosis or with low bone mass and increased risk for fracture, for whom risk factors play a primary role. There is clearly controversy over the type of treatment and its duration, especially given the possible adverse effects of long-term use. This justifies the concept of sequential treatment, even more so in women under the age of 70, since they presumably will need treatment for many years. Bone metabolism is age-dependent. In postmenopausal women under 70 years of age, the increase in bone resorption is clearly predominant, related to a sharp drop in estrogens. Thus a logical treatment is the prevention of fragility fractures by hormone replacement therapy (HRT) and, in asymptomatic women, selective estradiol receptor modulators (SERMs). Afterwards, there is a period of greater resorption, albeit less intense but continuous, when one could utilise anti-resorptive treatments such as bisphosphonates or denosumab or a dual agent like strontium ranelate. Bone formation treatment, such as parathyroid hormone (PTH), in women under 70 years will be uncommon. That is because it should be used in cases where the formation is greatly diminished and there is a high risk for fracture, something found in much older women.

Endometrial Receptivity Analysis (ERA) test: an unproven technology.

This article addresses the limitations of the endometrial receptivity array (ERA) methodology to increase implantation. Such limitations vary from the assumed inconsistency of the endometrial biopsy, the variable number of genes found to be dysregulated in endometrium samples without the embryonal-induced effect, the failure to account for the simultaneous serum progesterone level, and the expected low percentage of patients who may need this add-on procedure, to the difficulties in synchronising the endometrium with hormone replacements in successive cycles and the inherent perinatal risks associated with routine cryopreservation of embryos. Without a gold standard to compare, the claim that the window of implantation (WOI) might be off by ±12 h only requires a good argument for the advantage it provides to human procreation, knowing that embryos can linger for days before actual embedding starts and that the window is actually a few days. The intra-patient variations in the test need to be addressed. In summary, like all other add-ons, it is doubtful whether the ERA test use can significantly enhance implantation success rates.

Comparison of leuprolide acetate and triptorelin in assisted reproductive technology cycles: a prospective, randomized study.

OBJECTIVE: To compare the use of two depot GnRH-a, leuprolide and triptorelin, in long-suppression GnRH-a protocols. DESIGN: Prospective, randomized study. SETTING: An IVF unit of an academic medical center.Fifty-two women who underwent controlled ovarian hyperstimulation and IVF. INTERVENTION(S): Patients were prospectively randomized to receive 3.75 mg depot formulations of either leuprolide or triptorelin on days 21-23 of the menstrual cycle. Stimulation with gonadotropins was initiated after pituitary desensitization was achieved. MAIN OUTCOME MEASURE(S): The stimulation pattern and cycle outcomes were compared between the two groups. RESULT(S): Twenty-six patients were included in each group. No significant differences were observed in the patient age, estrogen, and P levels on day of hCG administration, gonadotropin dosage, number of oocytes retrieved, fertilization rate, percentage of high-quality embryos, and number of embryos transferred. However, significantly higher clinical implantation and pregnancy rates were found in the leuprolide group compared with the triptorelin group. CONCLUSION(S): A depot preparation of leuprolide is associated with higher implantation and pregnancy rates than a depot preparation of triptorelin when it is used in the midluteal phase as part of the long-suppression GnRH-a protocol in IVF.

Effect of betamethasone administration on fetal heart rate tracing: a blinded longitudinal study.

OBJECTIVE: Computerized fetal heart rate (FHR) analysis revealed that antenatal corticosteroids transiently suppress multiple parameters of fetal well-being, potentially leading to the erroneous diagnosis of fetal distress and to unnecessary iatrogenic delivery of premature infants. Our aim was to determine whether clinicians who visually analyze FHR tracings detect these suppressive effects, thereby potentially affecting their clinical management decisions. METHODS: Singleton pregnancies admitted for preterm labor between 26 and 34 weeks' gestation received two doses of betamethasone, 24 h apart, and were monitored daily between 16:00 and 19:00 h for 5 days. FHR tracings were randomly coded and presented in a non-consecutive order to four clinicians, who were unaware of the time of steroid administration. FHR baseline, FHR variability, number of accelerations and amplitude of maximal FHR acceleration were determined. Variability was scored semiquantitatively based on a modified Hon score. Analysis of variance (ANOVA) with repeated measures was used for primary analysis and followed up with the Wald test of significance. Corrections for multiple comparisons were made and only p < 0.005 considered significant. ANOVA was also used to assess the uniformity of trend in the interpretation by the four examiners for each given day. RESULTS: Baseline FHR was elevated, FHR variability was decreased, and the number of accelerations decreased on day 1 (p < 0.0001; p < 0.0001; p < 0.0001) and day 2 (p > 0.0001; p < 0.0001; p < 0.0001) in comparison to day 0. On day 3, the FHR baseline, variability and number of accelerations returned to pre-exposure values (p = NS). The maximal amplitude of FHR accelerations showed a trend towards reduction (p = 0.08). Subgroup analysis by gestational age (group I = 26-30 weeks and group II = 30-34 weeks) showed the same response patterns and significance levels for both groups. CONCLUSIONS: Betamethasone causes profound, but transient, suppression of FHR parameters, which can mimic fetal distress. This effect is clinically recognized by visual FHR analysis. Clinicians need to be aware of this phenomenon, in order to avoid unwarranted iatrogenic delivery.