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Conclusion(s): Local endometrial immunity appears to be a new and important parameter able to influence the prognosis of pregnancy. Targeted medical care in case of local immune dysregulation resulted in significantly higher pregnancy rates in RIF and RM patients.

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Chromosomal translocations and other balanced rearrangements, although usually associated with a normal phenotype, can lead to the transmission of an abnormal unbalanced genome to the offspring. Balanced and unbalanced spermatozoa, being indistinguishable, cannot be selected or deselected for prior to IVF and pre-implantation genetic diagnosis. Spermatozoa from 16 chromosomal rearrangement carriers were studied. After incubation in a hypo-osmotic solution (hypo-osmotic swelling test, or HOST), spermatozoa were fixed on microscope slides. The chromosomally balanced or unbalanced status corresponding to each observed class of flagellar conformation was evaluated through fluorescent in-situ hybridization (FISH). We show here a specific type of spermatozoa, with a distinct flagellar conformation that was associated with a balanced genetic content. HOST is a simple, low-cost and time-honoured procedure initially developed to distinguish immotile viable from non-viable spermatozoa. We demonstrate that it can also be used to identify genetically balanced spermatozoa in chromosomal rearrangement carriers, with a 96% decrease in the proportion of unbalanced spermatozoa after selection. This may potentially improve reproductive prognosis in affected couples if used prior to pre-implantation genetic diagnosis (PGD), and clinical utility and efficacy should be evaluated in further studies.

IntroductionThe endometrial immune profiling is an innovative approach based on the analysis of the local immune reaction occurring in the endometrium at the time of the embryo implantation. By documenting the local immune activation during the period of uterine receptivity, we aim to detect and correct potential imbalances before and at the very beginning of placentation. The main objective of the study was to analyze in women with a history of repeated pregnancy loss (RPL) the association of personalized strategies based on immune dysregulations with live birth rates. The secondary objective was to highlight the main prognostic factors for live births.MethodsThis is an observational retrospective analysis of 104 patients with RPL, included between January 2012 and December 2019. Inclusion criteria included a spontaneous fertility with at least three miscarriages, an assessment including a three-dimension ultrasound scan, an endometrial biopsy for uterine immune profiling and a follow-up over at least 6 months with personalized care if indicated after the complete assessment. We defined as a success if the patients had a live birth after the suggested plan, as a failure if the patient either did not get pregnant or experienced a new miscarriage after the targeted therapies.ResultsUterine immune profiling was the only exploration to be significantly associated with a higher live birth rate (LBR) if a dysregulation was identified and treated accordingly (55% vs 45%, p=0.01). On the contrary, an absence of local dysregulation (resulting in an apparently balanced immune environment) was associated with a higher risk of a new miscarriage, suggesting that the cause inducing RPL still needed to be identified. Independently of age and AMH level, dysregulated immune profile is significatively associated with 3 times higher LBR than a non-deregulated profile (OR=3.4 CI 95%1.27-9.84) or five times in case of an overactive profile treated by immunotherapy (OR=5 CI 95% 1.65-16.5). The usage of ART was significantly associated with lower LBR regardless of the presence of a subfertility factor (p=0.012). Personalization of medical care using natural cycle or simple hormonal stimulation is associated with a significantly higher LBR than personalization including ART treatments regardless of maternal age and AMH level (OR= 2.9 CI 95% 1.03-8.88).ConclusionOur study suggests that some endometrial immune profiles with targeted management of RPL are associated with a higher rate of LBR. ART may be negatively associated with LBR.