Should early cleavage (EC) be assessed in routine practice?

To the Editor:

In a recent study (1), an important question has been mooted, namely, “Should we assess early cleavage between 25 to 27 hours after insemination, with the aim of yielding any benefit in the clinical outcomes?” The message I have been delivered by the results has been, “There was not any benefit of early cleavage assessment, unless all transfer embryos were of sub-optimal quality.” Promoted by ASEBIR with a clear aim to conclude with a scientifically based recommendation to embryologists, I think the results need to be evaluated under scrutiny.

Response to editorial entitled “Biomarkers of endometrial receptivity through a minimally invasive approach”

To the Editor:

The editorial by Dr. Robert Norman in this issue of Fertility and Sterility (1) succinctly summarizes the various approaches currently used to identify biomarkers of endometrial receptivity toward development of a viable predictive/assessment test for clinical application. As Dr. Norman points out, multiple approaches have been applied to identify candidate biomarkers, including proteomic and lipidomic assessments of uterine aspirate fluid and gene expression profiling of endometrial biopsies. In this editorial, Dr. Norman introduces our paper in which we demonstrate the feasibility of performing genome-wide gene expression profiling on uterine aspirations (2). Using unsupervised hierarchical clustering, we demonstrate that the phase of sampling (LH+2 versus LH+7) affects gene expression more so than individual differences in gene expression between patients. We identified and verified robust differences in expression of 245 genes due to phase of sampling and determined that expression of 53 of these genes efficiently separated our two groups and those of a publically available dataset of gene expression signatures obtained from endometrial biopsy samples. Since LH+2 coincides with a pre-receptive phase and LH+7 coincides with a receptive phase in fertile women, the differentially expressed genes identified in our study encode for candidate biomarkers of endometrial receptivity. This 53-gene list overlaps significantly with those indicated in other studies, including the 238-gene list comprising the endometrial receptivity assay used by Diaz-Gimeno et al. (3) in their algorithm for predicting the receptive period from endometrial biopsy samples. We are excited by the potential of our approach because uterine aspiration is less traumatic to the endometrium than biopsy. Unlike endometrial biopsy, uterine aspiration is compatible with evaluation within an active IVF or natural cycle in which a patient is attempting pregnancy (4, 5), enabling us and other researchers to directly associate altered gene expression with implantation success. This approach will facilitate our future identification of those candidate biomarkers for further development of point-of-care assays for clinical use. While our 53-gene cassette includes several interesting candidate biomarkers, including those encoding secreted products, we do not propose these as a clinical test. Rather, we propose that our approach enables further testing and reduction of this signature to identify those genes most predictive. We agree with Dr. Norman that protein-based assays will be preferable to transcript measurements for clinical assays; however, gene expression data are necessary to direct proteomic discovery assays to improve these approaches.

Concerning “The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and meta-analysis”

To the Editor:

With great interest we read the article by Hill et al. (1) on the use of recombinant luteinizing hormone (r-LH) in patients of 35 years and older undergoing assisted reproductive techniques. The use of r-LH supplementation during ovarian stimulation as part of assisted reproduction treatment is controversial and literature shows conflicting results in women of 35 years and older. The available evidence does not support the hypothesis that the addition of r-LH increases the pregnancy rate in unselected patients treated in an IVF/ICSI protocol with recombinant FSH and a GnRH agonist or antagonist. But there might be a potential benefit of the use of r-LH supplementation during ovarian stimulation in women with a poor response and women of advanced age (2). An update and systematic review and meta-analysis focused on women of 35 years and older is therefore timely and of great value with regard to possibilities to individualize treatments to improve outcomes.

Progesterone level and progesterone/estradiol ratio on the day of hCG administration: detrimental cutoff levels and new treatment strategy?

To the Editor:

I read the paper by Elgindy (1) on the detrimental role of progesterone levels on the day of hCG administration in pregnancy rates.

The detrimental effect of the high steroid levels on endometrial receptivity is a matter of debate. The advances in the study of endometrial receptivity are providing us with deeper knowledge of the possible mechanisms (2). The advances in cryopreservation are helping to propose new strategies to make up for the endometrium-embryo desynchronization (3).

However, Elgindy’s article raises two points:

Firstly, the authors find through ROC analysis that the levels of P > 1.5 ng/mL and the rate of P/E > 0.55 on the day of hCG administration had a detrimental effect on the pregnancy rates in the cleave-stage embryo transfer compared with blastocyst-stage embryo transfer. However, in an earlier study (4), using the same kind of analysis and with a population of similar characteristics (normal response and long protocol) we did not identify a cut-off level that had prognostic value, for which reason we disagree with their conclusions.

Letter regarding “The role of low molecular weight heparin in recurrent implantation failure.”

To the Editor:

We read with interest the article titled “The role of low molecular weight heparin in recurrent implantation failure: A prospective quasi-randomised, controlled study” by Berker et al. (1). This study addresses the important clinical question of the role of heparin in women with recurrent implantation failure following IVF treatment. This is the second study to evaluate the role of heparin in recurrent implantation failure in the absence of coagulation disorders.

Coasting resulting in a sharp decline in serum estradiol does not compromise implantation

To the Editor:

We read the retrospective analysis of Abdalla and Nicopoullos (1) with great interest. We agree with the results, especially regarding the effects of estradiol drop (E₂d). As was previously mentioned in the early studies, no strict, evidence-based criteria were established regarding the initial estradiol level (E₂i) to start coasting that would not compromise oocyte/embryo quality or implantation capacity of the embryos.

Evidence of absence or absence of evidence? A reanalysis of the effects of low-dose aspirin in in-vitro fertilization

To the Editor:

We read with respect the article by Ruopp et al. (1) that has questioned the methodological approach of our previously published review (2) on the use of aspirin in in vitro fertilization cycles. We disagree with the authors in that random-effects models should only be used in the absence of inter-study heterogeneity. With fixed-effects models, it is assumed that there is a sole common effect estimates for all studies, i.e., the true effect of treatment, in both magnitude and direction, is the same value in every study.