IVIG Shows Promise as Therapy in Patients With Recurrent Implantation Failure

A systematic review and meta-analysis found a large swath of evidence indicating that intravenous immunoglobulin (IVIG) infusions can improve health outcomes in patients with otherwise unexplained recurrent implantation failure (RIF), according to results published in the Journal of Reproductive Immunology.¹

IVIG could act as a new treatment for those with RIF. © Krakenimages.com | stock.adobe.com

RIF is complex and poorly understood. There is a lack of consensus in the health care community on how to effectively manage or diagnose the condition, with several definitions proposed. Overall, the condition is defined by a failure to achieve a clinical pregnancy following the transfer of embryos considered to be viable.¹

IVIG has been reported to suppress NK cell activity both in vivo and in vitro, leading to an interest for treating RIF. Furthermore, across multiple occasions, IVIG has demonstrated effectiveness as a treatment for recurrent pregnancy loss (RPL).^1,2

Most recently, in a study conducted by Mu et al, IVIG was observed to significantly improve live birth rates (LBRs) in patients with unexplained RPL compared with patients in the control arm. In that study, those treated with IVIG were observed to have a 20% increase in LBR compared with the control group.²

Still, identifying RIF in advance of multiple treatment failures remains impossible, as a diagnosis would be retrospective. This fact, plus the lack of accepted screening tests or treatment options, led the investigators to investigate the utilization and impact of IVIG on implantation through a systematic review and meta-analysis of specific, confirmed RIF cases.¹

After an extensive search for full-text articles, the investigators narrowed the results down to 12 eligible studies, collectively assessing a total of 1023 cases with IVIG administered as a treatment for RIF and 2276 patients in control groups.¹

One important primary outcome measure, clinical pregnancy rate (CPR), was analyzed by 10 included studies. A statistically significant improvement in CPR among those treated with IVIG compared to controls was observed. Furthermore, the effect of IVIG on LBR was also significant, with an overall response (OR) of 4.60 (95% CI, 2.44 to 8.68, p < 0.001), aligning with results previously reported by Mu et al.^1,2

Moving to an analysis of miscarriage rate (MR), of which data was available in 7 included studies, the investigators found a statistically significant reduction in MR in the IVIG group compared to controls. OR was determined to be 0.60 (95% CI, 0.37 to 0.97, p = .036), with low heterogeneity observed, suggesting consistency in the effect of IVIG on reducing miscarriages.¹

Lastly, the researchers analyzed the effect of IVIG on implantation rate (IR), which is the number of gestational sacs divided by the number of embryos transferred. Through data available from 5 studies, they found that IVIG was associated with a significant improvement in IR, with an OR of 2.35 (95% CI, 1.04 to 5.29, p = .039). However, notable heterogeneity was found among the studies, suggesting variations in protocols or demographics.¹

There have been no dose comparison studies performed to directly compare outcomes against the prescribed amount of IVIG in a fertility setting. Variable doses of IVIG have been used in the reproductive setting; they typically range from 200 to 800 mg/Kg, but higher doses have been used for treating autoimmune disorders. Available data indicates that a positive effect from IVIG can be seen at both the upper and lower ends of the quantities used.¹

The investigators deemed that the subgroup of patients best considered for reproductive immunotherapy should be those with identified alloimmune/autoimmune abnormalities, where poor embryo quality is excluded, and all other tests are normal. At the same time, for patients where aneuploidy, abnormal receptivity, or systemic activity is identified, the investigators caution the use of immunomodulation.¹

“The findings are insufficient to establish IVIG as a routine intervention for RIF yet suggest a role for strong consideration in selected cases, especially when standard treatment has failed and identifiable immunological risk factors or immune disorders are present,” the investigators concluded.¹

REFERENCES

1. Kumar P, Philip CE, Eskandar K, et al. Effect of intravenous immunoglobulin therapy in recurrent implantation failure: a systematic review and meta-analysis. Journ Repro Immuno. 2024. Published online. doi:10.1016/j.jri.2024.104323

2. Halpern L. Intravenous immunoglobulin demonstrates effectiveness as treatment for unexplained recurrent pregnancy loss. Pharmacy Times. Published September 2, 2024. Accessed September 5, 2024.