Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss.
immunomodulatory therapy
intravenous immunoglobulin
unexplained recurrent pregnancy loss
Journal
American journal of reproductive immunology (New York, N.Y. : 1989)
ISSN: 1600-0897
Titre abrégé: Am J Reprod Immunol
Pays: Denmark
ID NLM: 8912860
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
revised:
30
04
2023
received:
20
02
2023
accepted:
02
06
2023
medline:
27
7
2023
pubmed:
26
7
2023
entrez:
26
7
2023
Statut:
ppublish
Résumé
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. 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/m 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. 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.
Substances chimiques
Immunoglobulins, Intravenous
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13737Informations de copyright
© 2023 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.
Références
Mahmood I, Tegenge MA, Golding B. Considerations for optimizing dosing of immunoglobulins based on pharmacokinetic evidence. Antibodies (Basel). 2020;9(2):24. https://doi.org/10.3390/antib9020024
RPL EGGo, Bender Atik R, Christiansen OB, et al, RPL EGGo. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):hoy004.
Dimitriadis E, Menkhorst E, Saito S, Kutteh WH, Brosens JJ. Recurrent pregnancy loss. Nat Rev Dis Primers. 2020;6(1):98.
Quenby S, Gallos ID, Dhillon-Smith RK, et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021;397(10285):1658-1667.
Lin L, Li J. The analysis of recurrent miscarriage: etiology, immunotherapy and observation. Jilin Med J. 2015:2733-2734.
Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368(9535):601-611.
Genest G, Banjar S, Almasry W, et al. Immunomodulation for recurrent implantation failure: where are we now? Reproduction. 2023;165(2):R39-R60.
Genest G, Almasri W, Banjar S, et al. Immunotherapy for recurrent pregnancy loss: a reappraisal. F&S Reviews. 2021.
Brinker KA, Silk HJ. Common variable immune deficiency and treatment with intravenous immunoglobulin during pregnancy. Ann Allergy Asthma Immunol. 2012;108(6):464-465.
Feldman AG, Whitington PF. Neonatal hemochromatosis. J Clin Exp Hepatol. 2013;3(4):313-320.
Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2013;368(8):777.
Hutton B, Sharma R, Fergusson D, et al. Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review. BJOG. 2007;114(2):134-142.
Wang SW, Zhong SY, Lou LJ, Hu ZF, Sun HY, Zhu HY. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis. Reprod Biomed Online. 2016;33(6):720-736.
PrabhuDas M, Bonney E, Caron K, et al. Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat Immunol. 2015;16(4):328-334.
Yang X, Meng T. Is there a role of intravenous immunoglobulin in immunologic recurrent pregnancy loss? J Immunol Res. 2020;2020:6672865.
Marron K, Walsh D, Harrity C. Detailed endometrial immune assessment of both normal and adverse reproductive outcome populations. J Assist Reprod Genet. 2019;36(2):199-210.
Yamada H, Deguchi M, Saito S, 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.
Rachid R, Bonilla FA. The role of anti-IgA antibodies in causing adverse reactions to gamma globulin infusion in immunodeficient patients: a comprehensive review of the literature. J Allergy Clin Immunol. 2012;129(3):628-634.
Gorczynski RM, Maqbool T, Hoffmann G. Mechanism(s) of prolonged attenuation of allergic responses after modulation of idiotypic regulatory network. Allergy Asthma Clin Immunol. 2019;15:79.
Piccinni MP, Raghupathy R, Saito S, Szekeres-Bartho J. Cytokines, hormones and cellular regulatory mechanisms favoring successful reproduction. Front Immunol. 2021;12:717808.
Negishi Y, Shima Y, Takeshita T, Morita R. Harmful and beneficial effects of inflammatory response on reproduction: sterile and pathogen-associated inflammation. Immunol Med. 2021;44(2):98-115.
Sung N, Khan SA, Yiu ME, et al. Reproductive outcomes of women with recurrent pregnancy losses and repeated implantation failures are significantly improved with immunomodulatory treatment. J Reprod Immunol. 2021;148:103369.
Parhizkar F, Motavalli-Khiavi R, Aghebati-Maleki L, et al. The impact of new immunological therapeutic strategies on recurrent miscarriage and recurrent implantation failure. Immunol Lett. 2021;236:20-30.
Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012;367(21):2015-2025.
Christiansen OB, Mathiesen O, Husth M, et al. Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin. Hum Reprod. 1995;10(10):2690-2695.
Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group. Br J Obstet Gynaecol. 1994;101(12):1072-1077.
Perino A, Vassiliadis A, Vucetich A, et al. Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study. Hum Reprod. 1997;12(11):2388-2392.
Stephenson MD, Dreher K, Houlihan E, Wu V. Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial. Am J Reprod Immunol. 1998;39(2):82-88.
Stephenson MD, Kutteh WH, Purkiss S, et al. Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial. Hum Reprod. 2010;25(9):2203-2209.
Jablonowska B, Selbing A, Palfi M, Ernerudh J, Kjellberg S, Lindton B. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study. Hum Reprod. 1999;14(3):838-841.
Christiansen OB, Larsen EC, Egerup P, Lunoee L, Egestad L, Nielsen HS. Intravenous immunoglobulin treatment for secondary recurrent miscarriage: a randomised, double-blind, placebo-controlled trial. BJOG. 2015;122(4):500-508.
Christiansen OB, Pedersen B, Rosgaard A, Husth M. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage. Hum Reprod. 2002;17(3):809-816.
Coulam CB, Krysa L, Stern JJ, Bustillo M. Intravenous immunoglobulin for treatment of recurrent pregnancy loss. Am J Reprod Immunol. 1995;34(6):333-337.
Morita K, Ono Y, Takeshita T, Sugi T, Fujii T, Yamada H, et al. Risk factors and outcomes of recurrent pregnancy loss in Japan. J Obstet Gynaecol Res. 2019;45(10):1997-2006.
Norgaard-Pedersen C, Nielsen K, Steffensen R, et al. Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open. 2022;12(9):e064780.
Eapen A, Hayes ET, McQueen DB, Beestrum M, Eyck PT, Boots C. Mean differences in maternal body mass index and recurrent pregnancy loss: a systematic review and meta-analysis of observational studies. Fertil Steril. 2021;116(5):1341-1348.
Marquard K, Westphal LM, Milki AA, Lathi RB. Etiology of recurrent pregnancy loss in women over the age of 35 years. Fertil Steril. 2010;94(4):1473-1477.
Huri M, Noferi V, Renda I, Piazzini F, Benemei S, Coccia ME. The COVID-19 pandemic impact on the outcome of medically assisted reproduction pregnancies. Front Reprod Health. 2022;4:860425.
Yildiz Y, Gurlek B, Yildiz IE, Aydin T, Kanburoglu MK, Yilmaz B. The effects of Coronavirus disease-2019 (COVID-19) pandemic on routine antenatal care visits and complications of pregnancy. Rev Assoc Med Bras (1992). 2021;67(6):833-838.
Schwab I, Mihai S, Seeling M, Kasperkiewicz M, Ludwig RJ, Nimmerjahn F. Broad requirement for terminal sialic acid residues and FcgammaRIIB for the preventive and therapeutic activity of intravenous immunoglobulins in vivo. Eur J Immunol. 2014;44(5):1444-1453.
N'Kaoua E, Attarian S, Delmont E, et al. Immunoglobulin shortage: practice modifications and clinical outcomes in a reference centre. Rev Neurol (Paris). 2022;178(6):616-623.
De Groot AS, Moise L, McMurry JA, et al. Activation of natural regulatory T cells by IgG Fc-derived peptide “Tregitopes”. Blood. 2008;112(8):3303-3311.
Kwak JY, Quilty EA, Gilman-Sachs A, Beaman KD, Beer AE. Intravenous immunoglobulin infusion therapy in women with recurrent spontaneous abortions of immune etiologies. J Reprod Immunol. 1995;28(3):175-188.
Ahmadi M, Abdolmohammadi-Vahid S, Ghaebi M, et al. Effect of Intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL). Biomed Pharmacother. 2017;92:1095-1102.
Bunk S, Ponnuswamy P, Trbic A, et al. IVIG induces apoptotic cell death in CD56(dim) NK cells resulting in inhibition of ADCC effector activity of human PBMC. Clin Immunol. 2019;198:62-70.
Higuchi K, Aoki K, Kimbara T, Hosoi N, Yamamoto T, Okada H. Suppression of natural killer cell activity by monocytes following immunotherapy for recurrent spontaneous aborters. Am J Reprod Immunol. 1995;33(3):221-227.
Krop J, Heidt S, Claas FHJ, Eikmans M. Regulatory T cells in pregnancy: it is not all about FoxP3. Front Immunol. 2020;11:1182.
Kim DJ, Lee SK, Kim JY, et al. Intravenous immunoglobulin G modulates peripheral blood Th17 and Foxp3(+) regulatory T cells in pregnant women with recurrent pregnancy loss. Am J Reprod Immunol. 2014;71(5):441-450.
Tjon AS, Tha-In T, Metselaar HJ, et al. Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells. Clin Exp Immunol. 2013;173(2):259-267.
Kessel A, Ammuri H, Peri R, et al. Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol. 2007;179(8):5571-5575.
Elluru S, Duong Van Huyen JP, Prost F, et al. Comparative study of the anti-inflammatory effect of two intravenous immunoglobulin preparations manufactured by different processes. Immunol Lett. 2006;107(1):58-62.
Esen F, Orhun G, Ozcan PE, et al. Neuroprotective effects of intravenous immunoglobulin are mediated through inhibition of complement activation and apoptosis in a rat model of sepsis. Intensive Care Med Exp. 2017;5(1):1.
Burns JC, Franco A. The immunomodulatory effects of intravenous immunoglobulin therapy in Kawasaki disease. Expert Rev Clin Immunol. 2015;11(7):819-825.
Kedzierska AE, Lorek D, Slawek A, Chelmonska-Soyta A. Tregitopes regulate the tolerogenic immune response and decrease the foetal death rate in abortion-prone mouse matings. Sci Rep. 2020;10(1):10531.
Massoud AH, Yona M, Xue D, Chouiali F, Alturaihi H, Ablona A, et al. Dendritic cell immunoreceptor: a novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells. J Allergy Clin Immunol. 2014;133(3):853-63 e5.
Zhao X, Shen Y, Hu W, et al. DCIR negatively regulates CpG-ODN-induced IL-1beta and IL-6 production. Mol Immunol. 2015;68(2 Pt C):641-647.
Seno A, Maruhashi T, Kaifu T, et al. Exacerbation of experimental autoimmune encephalomyelitis in mice deficient for DCIR, an inhibitory C-type lectin receptor. Exp Anim. 2015;64(2):109-119.