Pregnancy Outcome following Administration of Intravenous Immunoglobulin in Women with Unexplained Recurrent Implantation Failure: A Retrospective Cohort Study.

Currently, there’s no single definition universally accepted to diagnose recurrent implantation failure (RIF). Although there is a lack of consistency in the clinical definition of RIF, the 2023 European Society of Human Reproduction and Embryology (ESHRE) guideline on RIF defined it as the inability to achieve pregnancy after two to three transfers with good-quality embryos ( 1 ). Additionally, to precisely define RIF, several factors beyond the number of embryo transfer attempts must be considered. These factors include maternal age, the quality of the embryos, whether aneuploidy screening was performed, and the total number of embryos transferred ( 2 ). Around 10% of couples undergoing in vitro fertilization (IVF) are estimated to experience RIF ( 3 ). Even with thorough investigation, up to half of these cases remain unexplained, categorized as unexplained RIF ( 4 ). The intricate interplay of the immune system during pregnancy is essential for a healthy gestation and its proper coordination facilitates placentation and the establishment of maternal-fetal tolerance, a state that permits the fetus to develop ( 5 , 6 ). Disruptions in the normal inflammatory response during pregnancy, can contribute to implantation failure, miscarriage, premature birth, and intrauterine growth restriction ( 7 ). With this knowledge, immune modulation treatments are being investigated as a possible approach to improve pregnancy outcomes in women with RIF. During pregnancy, a shift towards a T helper cell type 2 (Th2)-dominant response is desired ( 8 ). Intravenous immunoglobulin (IVIg) therapy is an immunomodulatory strategy that targets the Th1/Th2 lymphocyte ratio and does this through potentially reducing the cytotoxic and inflammatory activity of Th1 cells ( 8 ). Nevertheless, the exact mechanism by which IVIg benefits RIF patients is yet to be fully understood ( 9 ). Although recent reviews analyzing IVIg’s effectiveness for RIF show promise ( 9 - 12 ), the studies are quite inconsistent, making it difficult to draw definitive conclusions. There's no consistent definition of RIF and crucial factors like stage and ploidy of transferred embryo aren't reported consistently across studies. This study aims to investigate whether IVIg has a positive effect on pregnancy and live birth rate of women with unexplained RIF in a 5 year period at our clinics.

Between April 2019 and March 2024 we reviewed medical records of infertile women aged 18-45 who had diagnosed as unexplained RIF and received IVIg at Yazd Reproductive Sciences Research Institute and reproductive medicine department of Madar Hospital, Yazd, Iran. Out of the 134 patients who received IVIg treatment at these centers during the above period, 66 were not included in the study due to abnormal immunologic assays, recurrent miscarriages, or fresh embryo transfers. We analyzed the data from the remaining 68 cycles, categorized as the IVIg group. Sixty-eight patients with unexplained RIF who underwent FET and did not receive IVIg between April 2019 and March 2024 were chosen for the control group using a systematic sampling method. Baseline characteristics of patients presented in Table 1, including age, anti-mullerian hormone (AMH) level, duration and ethiology of infertility, were analyzed and found no statistically significant difference between the groups. The IVIg group had a higher number of previous failed embryo transfers than the control group (4.72 vs. 3.76, P=0.013) in study groups. The control group had a lower body mass index (BMI) compared to IVIg group (27.14 vs. 25.94, P=0.048). Pregnancy outcomes of study groups are presented in Table 2. Baseline characteristics of study groups Data presented as mean ± SD and median and IQR. IVIg; Intravenous immune-globulin, BMI; Body mass index, PCOS; Polycystic ovary syndrome, DOR; Diminished ovarian reserve, AMH; Anti-mullerian hormone, IQR; Inter-quartile range, **; Independent samples t tests, ***; Chi-Square tests, and ****; Mann-Whitney test. Pregnancy outcomes in study groups Data are presented as n (%). *; Chi-square tests and **; Fisher’s exact test.

The present study investigated the potential benefits of IVIg therapy on pregnancy outcomes in women with unexplained RIF undergoing FET. This is a retrospective study with a relatively large sample size (n=68 per group). The study controlled for potential confounding factors by including women with unexplained RIF and using a systematic sampling method for the control group. A significantly higher proportion of women in the IVIg group achieved a chemical pregnancy. Although not statistically significant, clinical pregnancy, ongoing pregnancy, and live birth rates were also higher in the IVIg group. There was no significant difference in miscarriage rates between the groups. Our findings align with recent reviews suggesting potential benefits of IVIg for unexplained RIF ( 9 - 12 , 14 - 18 ), but also the inconsistency across studies is present regarding dosing scheme and control groups. A systematic review examining IVIg treatment for RIF found that most included studies reported positive outcomes. These studies generally indicated increased pregnancy and live birth rates, as well as reduced implantation failures and miscarriages in patients treated with IVIg ( 9 ). A systematic review and meta-analysis focusing on effect of different therapies on RIF found positive effect of IVIg on both cumulative pregnancy rate and live birth rate ( 19 ). A study investigating immunotherapies effect on IVF outcome of women with RIF and recurrent pregnancy loss (RPL) showed that the pregnancy rate and live birth rate significantly improved in all women including the group which received IVIg ( 20 ). A study on women with immune dysregulation and RIF or RPL showed that IVIg administration enhances the pregnancy outcome in this group of women ( 11 ). The exact mechanism by which IVIg improves reproductive outcomes is not fully understood. IVIg exerts its immunomodulatory effects by neutralizing pro-inflammatory cytokines, chemokines, pathogenic autoantibodies, and complement components ( 4 ). High-dose IVIg during early pregnancy may reduce embryonic damage by inhibiting maternal peripheral blood natural killer (NK) cell activity ( 17 , 18 ). Additionally, IVIg can regulate the balance of Th1 and Th2 cytokines, promoting a more favorable immune environment for pregnancy ( 4 , 14 , 21 ). IVIg contains antibodies that can neutralize antiphospholipid antibodies, which are implicated in pregnancy complications such as antiphospholipid syndrome ( 11 ). Moreover, IVIg has been reported to expand the population of regulatory T cells (Tregs), which play a crucial role in establishing maternal-fetal immune tolerance ( 22 ). By enhancing Treg activity, IVIg may suppress excessive inflammatory responses that are detrimental to implantation and early placental development ( 23 ). In addition, IVIg has been shown to block Fc receptors on immune effector cells, thereby reducing antibody-dependent cellular cytotoxicity, which may otherwise contribute to embryo rejection ( 24 ). The main limitation of our study was it’s retrospective design. The retrospective nature of the study limits the ability to establish a cause-and-effect relationship between IVIg and improved pregnancy outcomes. Additionally, the control group was not matched to the intervention group and had a lower number of prior implantation failures. While this difference could suggest the controls had a better overall prognosis, it might also unintentionally strengthen the positive effect observed in the IVIg group by creating a comparison group with potentially lower baseline fertility. Another limitation of this study is that Information on embryo ploidy status is not included, which could influence implantation success. We were unable to assess the prevalence of aneuploidy in transferred embryos due to limited patient access to pre-implantation genetic testing for aneuploidy (PGTA) associated with cost constraints. To definitively understand how IVIg therapy works and its specific effects on patients experiencing implantation failure or recurrent pregnancy loss, we need well-designed prospective studies with larger participant groups.

Our findings suggest that IVIg treatment may increase biochemical pregnancy rates in women with unexplained RIF. However, larger prospective studies are needed to confirm these results and to assess the long-term effects of IVIg on pregnancy outcomes.

Between April 2019 and March 2024, we conducted a retrospective cohort study by reviewing the medical records of infertile women aged 18-45 who had diagnosed as unexplained RIF at Yazd Reproductive Sciences Research Institute and Reproductive Medicine Department of Madar Hospital, Yazd, Iran. Data was extracted from the electronic medical records of women with unexplained RIF who underwent frozen embryo transfer (FET) following endometrial preparation using hormonal therapy and received at least three doses of IVIg therapy. We excluded patients who received fewer than three IVIg doses. Patients with congenital uterine anomalies, abnormal karyotype, thrombophilia and abnormal immunologic assays were also excluded (IVIg group). In the control group, based on the systematic sampling method in the above time interval, and among the patients with unexplained RIF who did not receive IVIg, they were selected with the same number of samples as the intervention group. Patients were followed until livebirth. The Ethics Committee of Shahid Sadoughi University of Medical Sciences approved the study (IR. SSU.RSI.REC.1403.002). Patients received IVIg in multiple doses throughout their pregnancy. The first dose was 20 grams, given between 24 and 72 hours before the embryo transfer. If chemical pregnancy was confirmed by a beta-human chorionic gonadotropin (β-hCG) test, a second 20 g dose was administered. Following confirmation of a clinical pregnancy with a fetal heartbeat detected, another 20 g dose was given. If the pregnancy continued successfully, patients received monthly maintenance doses of 5 g until the 20th week of pregnancy ( 9 ). A chemical pregnancy was diagnosed if the level of serum β-hCG was at least 50 IU/L fourteen days after the embryo transfer. A clinical pregnancy was confirmed by detecting a fetal heart on ultrasound at four weeks after the embryo transfer. Ongoing pregnancy was defined as positive fetal cardiac activity on ultrasound 12 weeks after embryo transfer, Miscarriage was defined as loss of gestational sac or fetal heartbeat in clinically pregnant women till 12 weeks of gestational age ( 13 ). The statistical package for the SPSS version 26 for Windows (IBM Corp., Armonk, NY, USA) was applied for data analysis. For continuous variables, the Student’s independent t test was used to compare differences between groups assuming normal distribution. Alternatively, the Mann-Whitney U test was used if normality was not assumed. Categorical variables were analyzed using the Chi-square test for larger sample sizes or the Fisher’s exact test for smaller sample sizes or sparse data. Data were presented as mean ± SD and median and inter-quartile range (IQR) for continuous variables and number (%) for categorical variables. A P;#x003c;0.05 was considered statistically significant.