Immunomodulation for unexplained recurrent implantation failure: where are we now?

In brief: Immune dysfunction may contribute to or cause recurrent implantation failure. This article summarizes normal and pathologic immune responses at implantation and critically appraises currently used immunomodulatory therapies. Abstract: Recurrent implantation failure (RIF) may be defined as the absence of pregnancy despite the transfer of ≥3 good-quality blastocysts and is unexplained in up to 50% of cases. There are currently no effective treatments for patients with unexplained RIF. Since the maternal immune system is intricately involved in mediating endometrial receptivity and embryo implantation, both insufficient and excessive endometrial inflammatory responses during the window of implantation are proposed to lead to implantation failure. Recent strategies to improve conception rates in RIF patients have focused on modulating maternal immune responses at implantation, through either promoting or suppressing inflammation. Unfortunately, there are no validated, readily available diagnostic tests to confirm immune-mediated RIF. As such, immune therapies are often started empirically without robust evidence as to their efficacy. Like other chronic diseases, patient selection for immunomodulatory therapy is crucial, and personalized medicine for RIF patients is emerging. As the literature on the subject is heterogenous and rapidly evolving, we aim to summarize the potential efficacy, mechanisms of actions and side effects of select therapies for the practicing clinician.

Aspirin for Endometrial Preparation in Patients Undergoing IVF: A Systematic Review and Meta-analysis.

OBJECTIVE: To investigate the effect of aspirin on IVF success rates when used as an adjuvant treatment for endometrial preparation. DATA SOURCES: Relevant publications were comprehensively selected from PubMed, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to November 15, 2020. STUDY SELECTION: Randomized controlled trials (RCTs) and retrospective cohort studies that used aspirin as an adjuvant treatment for endometrial preparation and reported subsequent pregnancy outcomes were included. Studies were excluded if aspirin was used before and/or during ovarian stimulation. DATA EXTRACTION AND SYNTHESIS: This systematic review and meta-analysis included a total of 7 studies. Risk of bias assessment was based on the methodology and categories listed in the Cochrane Handbook for the RCTs and the Newcastle-Ottawa scale for the retrospective studies. The primary outcome was live birth rate. Summary measures were reported as odds ratios (ORs) with 95% confidence intervals (CIs). There was significant evidence that aspirin for endometrial preparation improved live birth rates (OR  1.52; 95% CI   1.15-2.00). No effect was noted for clinical pregnancy rates (OR  1.37; 95% CI   1.00-1.87); however, aspirin was associated with improved pregnancy rates in a subgroup analysis of patients receiving oocyte donation (OR 2.53; 95% CI 1.30-4.92) and in the sensitivity analysis (OR 1.3; 95% CI   1.02-1.66). No effect of aspirin was found for implantation or miscarriage rates (OR 1.31; 95% CI  0.51-3.36 and OR 0.41; 95% CI  0.02-7.42, respectively). CONCLUSION: These findings support a beneficial effect of aspirin for endometrial preparation on IVF success rates, mainly live birth rates, outside the context of ovarian stimulation. However, this evidence is based on poor quality data and needs to be confirmed with high-quality RCTs.

Evidence-based clinical prioritization of embryos with mosaic results: a systematic review and meta-analysis.

PURPOSE: The purpose of this review and meta-analysis is to standardize the practice of mosaic embryo transfer, based on the current available evidence. METHODS: This is a systematic review and meta-analysis. Relevant studies published were comprehensively selected using PubMed, Medline, Embase, and CENTRAL until 5 March 2021. Prospective and retrospective studies reporting the genetic analysis and clinical outcomes of mosaic embryo transfer were included. Risk of bias assessment was based on the Newcastle-Ottawa scale for the non-randomized studies. The primary and secondary outcomes were combined ongoing pregnancy and live birth rate and miscarriage rate, respectively. RESULTS: There were no differences between low and high mosaic embryos when a cut-off of 40% was used in terms of OP/LBR and SAB. However, low mosaics with a cut-off of 50% compared to high mosaics showed a significantly higher OP/LBR in the NGS but not in the a-CGH group, and a significantly lower risk of SAB. No differences were noted between mosaic monosomies versus trisomies and single versus double mosaics for both OP/LBR and SAB. Finally, segmental mosaics showed a higher OP/LBR and a lower SAB compared to whole chromosomes, and single and double mosaics had a higher OP/LBR compared to complex mosaics. CONCLUSIONS: A cut-off of 50% in defining low versus high mosaic embryos is preferable to a threshold of 40% when using NGS platform. No priority was established for mosaic trisomies over monosomies. Single and double mosaics must be preferred over complex mosaics and segmental mosaics must be preferred over whole chromosome mosaics. These results should be interpreted in the context of specific chromosomes involved in the mosaicism.

Anti-Müllerian hormone (AMH): a reliable biomarker of oocyte quality in IVF.

PURPOSE: To evaluate the impact of serum AMH levels on stimulated IVF implantation and clinical pregnancy rates. METHODS: • DESIGN: Retrospective study with multivariate analysis. • SETTING: Clinique ovo (Montreal University affiliated Center). • PATIENT(S): Six hundred and thirty seven patients undergoing a stimulated IVF protocol were included. Only non-polycystic ovary patients at their first IVF attempt were considered for the analysis. • INTERVENTION(S): None. • MAIN OUTCOME MEASURES(S): Implantation and ongoing pregnancy rates. RESULT(S): Cycle outcomes were analysed according to AMH percentiles based on the AMH normogram per patient's age of our infertile population. Multivariate analyses were done to adjust for potential confounding factors such as age, total exogenous FSH dosage and number of eggs retrieved. Compared to the reference population, a significant lower mean implantation rate (0.26 vs 0.45) was observed in patients under 35 years of age with AMH < 1 ng/ml. Women with AMH < 25th percentile had less chances of having an embryo transferred, lower chances of having an ongoing pregnancy per started IVF cycle and a lower embryo freezing rate compared to the reference population. CONCLUSION(S): Patients with AMH < 0.47 ng/ml should be advised before starting a stimulated IVF cycle of the poorer prognosis compared to our reference population independently of their age, total exogenous FSH dosage and number of eggs retrieved. Therefore, AMH could enable a more individualized number of embryo transfer policy based on oocyte quality.

Intravenous immunoglobulin for patients with unexplained recurrent implantation failure: a 6-year single center retrospective review of clinical outcomes.

The effectiveness of intravenous immunoglobulin (IVIg) for patients with unexplained recurrent implantation failure (uRIF) remains debated. We retrospectively analysed outcomes of uRIF patients treated with IVIg compared to a separate control uRIF cohort within our center (01/2014-12/2021). Primary outcomes included live birth, miscarriage, or transfer failure. We documented IVIg side effects and maternal/fetal outcomes. Logistic regression analysis was used to assess for association of IVIg exposure with outcomes and adjust for confounders. The study included 143 patients, with a 2:1 ratio of controls to patients receiving IVIg treatment. Patient characteristics were similar between groups. There was higher live birth rate (LBR) in patients receiving IVIg (32/49; 65.3%) compared to controls (32/94; 34%); p < 0.001). When stratifying patients into moderate and severe uRIF (respectively 3-4 and [Formula: see text] 5 previous good quality blastocyst transfer failures), only patients with severe uRIF benefited from IVIg (LBR (20/29 (69%) versus 5/25 (20%) for controls, p = 0.0004). In the logistic regression analysis, IVIg was associated with higher odds of live birth (OR 3.64; 95% CI 1.78-7.67; p = 0.0004). There were no serious adverse events with IVIg. IVIg can be considered in well selected patients with [Formula: see text] 5 previous unexplained, high quality blastocyst transfer failures. A randomized controlled trial is needed to confirm these findings.

Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss.

PROBLEM: Recurrent pregnancy loss (RPL) affects up to 4% of couples attempting to conceive. RPL is unexplained in over 50% of cases and no effective treatments exist. Due to the immune system's pivotal role during implantation and pregnancy, immune-mediated RPL may be suspected and immunomodulatory treatments like intravenous immunoglobulin (IVIg) have been administered but remain controversial. The goal of our study was to evaluate our center's 6 year-outcomes and to develop a framework for IVIg use in RPL. METHOD OF THE STUDY: Retrospective, single-center cohort study. All patients having received IVIg for unexplained RPL at the McGill Reproductive Immunology Clinic (MRIC) from January 2014 to December 2020 were included if maternal age was <42 years, body mass index (BMI) < 35 kg/m2 , non-smoker and having had ≥3 consecutive RPL despite previous treatment with aspirin and progesterone. IVIg 0.6-0.8 g/kg was given prior to conception and monthly during pregnancy until 16-20 weeks' gestation. We compared IVIg treated patient's outcomes to a separate "natural history cohort". This cohort was composed of patients consulting at the McGill recurrent pregnancy loss clinic and the MRIC over a 2-year period (January 2020 to December 2021) with similar inclusion criteria as the treatment cohort but did not receive IVIg or other immunomodulatory treatments. The association of IVIg with outcomes (compared to no IVIg) was evaluated among the groups of patients with primary RPL and secondary RPL. The primary outcome was live birth rate (LBR), secondary outcomes included IVIg safety, obstetrical, and neonatal complications. RESULTS: Among 169 patients with unexplained RPL that were included in the study, 111 had primary RPL (38 exposed to IVIg and 83 controls) and 58 had secondary RPL (nine exposed to IVIG and 49 controls). Among patients with primary RPL (n = 111), the LBR was 64.3% (18/28) among patient exposed to IVIg compared to 43.4% (36/83) in controls (p = 0.079); regression analysis adjusting for BMI and number of previous miscarriages showed benefit favoring the use of IVIg (OR = 3.27, CI 95% (1.15-10.2), p = 0.03) when evaluating for live birth. In the subgroup of patients with ≥5 previous RPL and primary RPL (n = 31), IVIg was associated with higher LBR compared to control (10/15 (66.7%) vs. 3/16 (18.8%); p = 0.0113) but not the in the sub-group of patients with <5 miscarriages and primary RPL (8/13 (61.5%) vs. 33/67 (49.3%); p = 0.548). IVIG treatment did not improve LBR in patients with secondary RPL in our study (3/9 (33.3%) vs. 23/49 (47%); p = 0.495). There were no serious adverse events in the IVIg treatment group, obstetrical/neonatal complications were similar between groups. CONCLUSION: IVIg may be an effective treatment for patients with RPL if appropriately used in specific groups of patients. IVIg is a blood product and subject to shortages especially with unrestricted off-label use. We propose considering IVIg in well-selected patients with high order RPL who have failed standard medical therapy. Further mechanistic studies are needed to understand immune-mediated RPL and IVIg's mode of action. This will enable further refinement of treatment criteria and the development of standardized protocol for its use in RPL.

Surgically retrieved spermatozoa versus ejaculated spermatozoa in modified natural IVF-ICSI cycles.

A retrospective cohort study was performed to evaluate the outcome of modified natural IVF-intracytoplasmic sperm injection (mnIVF-ICSI) cycles to compare 81 mnIVF-ICSI first cycles using ejaculated spermatozoa with 44 mnIVF-ICSI first cycles using surgically retrieved spermatozoa. There were no differences between the two groups in terms of number of oocytes retrieved, oocyte maturity or female age. However, male age was significantly higher in the surgically retrieved compared with the ejaculated group (41.5 versus 36.5 years, P=0.001). There were no significant differences in fertilization rate or cleavage rate between the ejaculated and the surgically retrieved groups; however the prevalence of embryo transfer was higher in the surgically retrieved group (65.9% versus 45.7%, P=0.03). Only single-embryo transfer was performed. Biochemical (34.5% versus 37.8%) and clinical (31.0% versus 35.1%) pregnancy rates per embryo transfer were similar between the ejaculated and the surgically retrieved groups. The data suggest that mnIVF-ICSI is an alternative treatment option in couples with severe male factor infertility where surgical sperm retrieval is required. The aim of the present study was to evaluate and compare the outcomes of modified natural IVF-intracytoplasmic sperm injection (mnIVF-ICSI) with surgically retrieved spermatozoa (in male partners with obstructive azoospermia) and ejaculated spermatozoa (in couples with mild-to-moderate male factor). Eighty-one mnIVF-ICSI first cycles using ejaculated spermatozoa were compared with forty-four mnIVF-ICSI first cycles using surgically retrieved spermatozoa. There were no differences between the two groups in terms of number of oocytes retrieved, oocyte maturity or female age. However, male age was significantly higher in the surgically retrieved compared with the ejaculated group. There were no significant differences in fertilization rate, or cleavage rate between the two groups; however, there were more patients having embryo transfers in the surgically retrieved group. Only single-embryo transfer was performed. Biochemical and clinical pregnancy rates per embryo transfer were similar between both groups. The data suggest that mnIVF-ICSI is an alternative treatment option in couples with severe male factor infertility where surgical sperm retrieval is required.

Is sperm DNA damage associated with IVF embryo quality? A systematic review.

PURPOSE: Sperm DNA damage is common amongst infertile men and may adversely impact natural reproduction, IUI-assisted reproduction and to a lesser degree IVF pregnancy. The objective of this study was to examine the influence of sperm DNA damage on embryo quality and/or development at IVF and ICSI. METHODS: We conducted a systematic review of studies that evaluated sperm DNA damage and embryo development and/or quality after IVF and/or ICSI. RESULTS: We identified 28 studies (8 IVF, 12 ICSI and 8 mixed IVF-ICSI studies) that evaluated the relationship between sperm DNA damage and embryo quality. These 28 studies evaluated 3226 treatment cycles (1033 IVF and 873 ICSI, 1320 mixed IVF-ICSI cycles) and demonstrated highly variable characteristics. In 11 of the 28 studies (1/8 IVF, 5/12 ICSI and 5/8 mixed IVF-ICSI studies), sperm DNA damage was associated with poor embryo quality and/or development, whereas the remaining 17 studies showed no relationship between sperm DNA damage and embryo quality and/or development. CONCLUSIONS: This systematic review indicates that the evaluable studies are heterogeneous and that overall, there is no consistent relationship between sperm DNA damage and embryo quality and/or development. The data also suggest that the influence of sperm DNA damage on embryo quality/development may be more significant in ICSI compared to IVF cycles.

Successful pregnancy in an ovarian agenesis patient after modified natural cycle IVF oocyte donation.

The recovery of a mature oocyte from a modified natural cycle followed by in-vitro fertilization (nIVF) is an attractive alternative to conventional IVF, involving ovarian stimulation, in the treatment of female infertility. Ovarian agenesis is a rare disorder resulting in primary amenorrhoea and infertility in affected females. A couple sought help for infertility due to ovarian agenesis of the female partner and decided to pursue treatment utilizing oocyte donation. Modified natural-cycle egg retrieval was carried out on the donor; one mature oocyte was retrieved and underwent IVF using a sperm sample from the male partner. A good-quality embryo was transferred, A viable pregnancy was confirmed by ultrasound scan and resulted in the delivery of a healthy baby boy at 36 weeks' gestation. This is the second published report of an ongoing clinical pregnancy and subsequent birth resulting from oocyte donation recovered during a modified natural cycle. The use of less invasive assisted reproduction techniques such as nIVF can be used in oocyte donation cycles successfully.

Successful pregnancy following novel IVF protocol and transmyometrial embryo transfer after radical vaginal trachelectomy.

Radical vaginal trachelectomy in patients with early-stage cervical cancer is an oncologically safe procedure in well-selected patients. Successful pregnancy in a patient with radical vaginal trachelectomy is possible, with two-thirds of pregnancies resulting in live birth. However, it presents a great challenge for assisted reproductive techniques and reproductive medicine in cases with subsequent severe cervical stenosis. This is a report of a 38-year-old patient who underwent radical vaginal trachelectomy at the age of 33 years for early stage (IA2) adenocarcinoma and subsequently presented with infertility due to cervical factors. The patient underwent ovarian stimulation using a novel SMART (Stimulation with Minimal Adverse effects, Retrieval and Transfer)-IVF protocol. As it was impossible to perform transcervical embryo transfer with an almost absent severely stenotic cervical opening, a transmyometrial embryo transfer under ultrasound guidance was performed. This resulted in a successful singleton full-term pregnancy delivered by Caesarean section at gestational age 37 weeks. As far as is known, this is the first reported case of successful pregnancy conceived by IVF with transmyometrial embryo transfer for a patient who had previously undergone radical vaginal trachelectomy.