Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jun 4:16:1546602.
doi: 10.3389/fendo.2025.1546602. eCollection 2025.

Efficacy of intravenous immunoglobulin in recurrent pregnancy loss: a retrospective analysis of patients with abnormal cellular immunity

Jae Won Han  1 , Jin Sol Park  1 , Jong-Seok Kim  2 , Sung Ki Lee  1   2
Affiliations

Efficacy of intravenous immunoglobulin in recurrent pregnancy loss: a retrospective analysis of patients with abnormal cellular immunity

Jae Won Han et al. Front Endocrinol (Lausanne). .

Abstract

Introduction: Various causes of recurrent pregnancy loss (RPL) have been identified, but even with a detailed evaluation, almost half of the cases have unidentified etiologies. Immune imbalance is one of the proposed potential etiologies of these idiopathic RPL. To regulate abnormal cellular immunity, intravenous immunoglobulin (IVIG), a type of immunotherapy, is proposed to improve pregnancy outcomes. However, the efficacy of IVIG in RPL is still controversial.

Methods: RPL was defined as women with two or more spontaneous abortions and in total, 987 RPL women visited Department of Obstetrics and Gynecology, Konyang University Hospital from January 2007 to December 2020. Only those with a full evaluation and known treatment outcome were included. Idiopathic RPL(n=215) and women with known etiology (n=251) were enrolled. Both the idiopathic and known etiology groups were subsequently stratified into subgroups based on the presence of at least one abnormal cellular immunity (n=100 and n=97, respectively). We investigated the pregnancy outcome by sorting the patients into seven subgroups depending on abnormal cellular immunity including natural killer (NK) cell level, NK cell cytotoxicity and Th1/Th2 ratio.

Results: Patients with older age and higher body mass index had negative effect on pregnancy outcomes whereas the number of previous miscarriages did not show significant difference in pregnancy outcomes. Among all RPL women with at least one abnormal cellular immunity were treated with IVIG and the overall live birth rate (LBR) was 82.7%. The group which did not have IVIG treatment showed an overall LBR of 80.7%. Among the seven groups of idiopathic RPL women with abnormal cellular immunity, the group with both high NK cell level and NK cell cytotoxicity showed the highest LBR, 90.5%, and the group with both high NK cell level and Th1/Th2 ratio showed the lowest LBR, 75%.

Discussion: IVIG treatment appears to improve LBRs in women with RPL and abnormal cellular immunity. These findings support the potential benefit of IVIG in selected RPL patients with immune imbalances. Further studies are needed to refine patient selection criteria and optimize treatment protocols for improving pregnancy outcomes in this population.

Keywords: TH1/TH2 ratio; immunity; intravenous immunoglobulin; natural killer cell cytotoxicity; natural killer cells; recurrent pregnancy loss.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Patient enrollment. Among the RPL patients who visited our clinic, those meeting the exclusion criteria were excluded, and only patients with documented pregnancy outcomes were included. All RPL patients underwent a full evaluation of cellular immunity tests, and the outcome of the first pregnancy following this assessment was analyzed. The patients were then categorized into two groups: those with a known etiology and idiopathic RPL. Each group was further subdivided based on abnormal cellular immunity, patients with abnormal immunity received IVIG treatment.
Figure 2
Figure 2
The prevalence of abnormal cellular immunity in each group of enrolled patients. (A) The known etiology group. (B) The idiopathic group. Determination of cellular immunity was based on the cutoff values that were previously reported; NK cell level, >16.1% of lymphocytes; high NK cell cytotoxicity at the effector-to-target cell ratio of 50:1, 25:1 and 12.5:1, >34.3%, 23.8%, and 9.6% respectively; TNF-α producing CD4+ T cell to IL-10 producing CD4+ T cell ratio, >36.2%.
Figure 3
Figure 3
Pregnancy outcomes following etiology-based treatment. (A) The comparison of live birth rate between normal cellular immunity group and IVIG treated group. The live birth rate between two groups were not significant. (B) Live birth rate according to the types of abnormal cellular immunity. We compared the LBR between the known etiology and idiopathic groups by further subdividing the patients based on the diagnosed type of abnormal cellular immunity. The LBR among patients without abnormal cellular immunity was not significantly different between the known etiology and idiopathic groups. Additionally, no statistically significant differences in LBR were observed among the different types of abnormal cellular immunity. However, no patients presented with both elevated NK cell cytotoxicity and an abnormal Th1/Th2 ratio, precluding analysis of this specific combination. N-S, Not significant.
Figure 4
Figure 4
The live birth rate according to number of previous miscarriages. The LBR among all RPL patients showed a plateau up to the group with four or more miscarriages, and a similar pattern was observed in both the known etiology and idiopathic groups.
Figure 5
Figure 5
The prevalence of RPL women with at least one abnormal cellular immunity according to previous number of miscarriages. Both the all RPL group and the known etiology group demonstrated a significant increasing trend (p = 0.032 and 0.026, respectively). In contrast, no significant trend was observed in the idiopathic group.
Figure 6
Figure 6
Correlation between each type of cellular immunity and number of previous miscarriages. (A) known etiology group. The prevalence of an elevated Th1/Th2 ratio was significantly higher in the group with four or more miscarriages. However, neither NK cell levels nor NK cell cytotoxicity showed a significant correlation with the number of miscarriages. (*P<0.05). (B) Idiopathic group. None of the abnormal cellular immunity showed correlation with the number of miscarriages. N-S, Not significant.
Figure 7
Figure 7
Fetal aneuploidy rate according to previous number of miscarriages. When miscarriage was confirmed in the index pregnancy, a fetal chromosomal test was performed with patient consent. The results were analyzed across three groups. In the all RPL group, there was a trend suggesting that the aneuploidy rate decreased as the number of previous miscarriages increased, although this trend was not statistically significant. Neither the known etiology group nor the idiopathic group showed any correlation between the number of miscarriages and the aneuploidy rate. N-S, Not significant.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Berek JS. Berek&Novak’s gynecology. 16 ed. Berek JS, editor. Wolters Kluwer at Philadelphia, PA: Lippincott Williams & Wilkins; (2019).
    1. Yamada H, Deguchi M, Saito S, Takeshita T, Mitsui M, Saito T, et al. Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial. EClinicalMedicine. (2022) 50:101527. doi: 10.1016/j.eclinm.2022.101527 - DOI - PMC - PubMed
    1. Practice Committee of the American Society for Reproductive Medicine . Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. (2020) 113:533–5. doi: 10.1016/j.fertnstert.2019.11.025 - DOI - PubMed
    1. RPL EGGo. Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, et al. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. (2023) 2023:hoad002. doi: 10.1093/hropen/hoad002 - DOI - PMC - PubMed
    1. Practice Committee of the American Society for Reproductive M . Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. (2012) 98:1103–11. doi: 10.1016/j.fertnstert.2012.06.048 - DOI - PubMed

Substances

LinkOut - more resources