Efficacy of Intravenous Immunoglobulin for Patients with Recurrent Miscarriage: A Meta-analysis
Abstract
Background: This study aimed to evaluate the efficacy and safety of intravenous immunoglobulin (IVIG) therapy for recurrent miscarriage (RMC) using meta-analysis.
Methods: Literature from Jan 1990 to Feb 2024 was searched in PubMed, etc., using keywords such as “IVIG”, “repetitive miscarriage”, and “RMC”. Two authors independently assessed the literature quality and risk of via Cochrane handbook, and extracted basic information and outcome indicator data. Meta-analysis was performed employing Review Manager 5.3.
Results: Eleven studies were involved, comprising 842 patients, of which 391 received IVIG therapy and 451 received placebo treatment. Relative to placebo group, IVIG group had a notably higher overall live birth rate (OR=2.24, 95% CI=1.68~2.98, Z=5.51, P<0.00001) and a greatly lower miscarriage rate (OR=0.46, 95% CI=0.22~0.95, Z=2.09, P=0.04). Subgroup analysis revealed that both primary and secondary RMC patients in IVIG group had markedly higher live birth rates versus placebo group (OR=2.13, 95% CI=1.18~3.83, Z=2.51, P=0.01; OR=1.50, 95% CI=0.98~2.30, Z=1.96, P=0.04). Nevertheless, the adverse reaction (AR) rate in IVIG group was superior to that in placebo group (OR=4.47, 95% CI=1.01~19.81, Z=1.97, P=0.05).
Conclusion: IVIG can markedly increase the live birth rate, reduce the miscarriage rate, and enhance pregnancy outcomes in patients with RMC. Nevertheless, the rate of ARs with IVIG therapy is relatively high, thus large-scale, multicenter, randomized controlled trials are needed for validation.
1. Vejerslev LO, Dissing J, Hansen HE, et al (1987). Hydatidiform mole: genetic markers in diploid abortuses with mac-roscopic villous enlargement. Cancer Genet Cytogenet, 26(1):143-155.
2. Coomarasamy A, Dhillon-Smith RK, Papa-dopoulou A, et al (2021). Recurrent mis-carriage: evidence to accelerate action. Lancet, 397(10285):1675-1682.
3. Melo P, Dhillon-Smith R, Islam MA, et al (2023). Genetic causes of sporadic and recurrent miscarriage. Fertil Steril, 120(5):940-944.
4. Coomarasamy A, Devall AJ, Brosens JJ, et al (2020). Micronized vaginal progester-one to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol, 223(2):167-176.
5. Devall AJ, Coomarasamy A (2020). Sporad-ic pregnancy loss and recurrent miscar-riage. Best Pract Res Clin Obstet Gynaecol, 69:30-39.
6. Gonçalves CCRA, Feitosa BM, Cavalcante BV, et al (2023). Obesity and recurrent miscarriage: the interconnections be-tween adipose tissue and the immune system. Am J Reprod Immunol, 90(3):e13757.
7. Rewald E, Francischetti MM, Barberis L (2002). High dose intravenous immuno-globulin repertoire versus anti-D. Dis-proportions in quantity and quality. Cell Mol Biol (Noisy-le-grand), 48(3):265-9.
8. Banjar S, Kadour E, Khoudja R, et al (2023). Intravenous immunoglobulin use in pa-tients with unexplained recurrent preg-nancy loss. Am J Reprod Immunol, 90(2):e13737.
9. Dernoncourt A, Hedhli K, Abisror N, et al (2024). Hydroxychloroquine in recurrent pregnancy loss: data from a French pro-spective multicenter registry. Hum Re-prod, 39(9):1934-1941.
10. Yamada H, Deguchi M, Saito S, et al (2023). High doses of intravenous immuno-globulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss. J Reprod Immunol, 158:103977.
11. Jiang M, Kimber JS, Gupta A, et al (2023). Adverse Reactions Associated with In-travenous Immunoglobulin Administra-tion in the Treatment of Neurological Disorders: A Systematic Review. Int Arch Allergy Immunol, 184(6):513-528.
12. Jiang M, Lam L, Kovoor JG, et al (2023). In-travenous immunoglobulin alteration in response to adverse reactions in neuro-logical conditions: A retrospective co-hort study. Transfus Med, 33(6):478-482.
13. Martimbianco ALC, Sá KMM, Santos GM, et al (2023). Most cochrane systematic reviews and protocols did not adhere to the Cochrane’s risk of bias 2.0 tool. Rev Assoc Med Bras (1992), 69(3):469-472.
14. Carp HJ, Toder V, Gazit E, et al (2001). Fur-ther experience with intravenous immu-noglobulin in women with recurrent miscarriage and a poor prognosis. Am J Reprod Immunol, 46(4):268-273.
15. Christiansen OB, Mathiesen O, Husth M, et al (1995). Placebo-controlled trial of treatment of unexplained secondary re-current spontaneous abortions and re-current late spontaneous abortions with i.v. immunoglobulin. Hum Reprod, 10(10):2690-2695.
16. Christiansen OB, Pedersen B, Rosgaard A, et al (2002). A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with sec-ondary recurrent miscarriage. Hum Re-prod, 17(3):809-816.
17. Christiansen OB, Larsen EC, Egerup P, et al (2015). Intravenous immunoglobulin treatment for secondary recurrent mis-carriage: a randomised, double-blind, placebo-controlled trial. BJOG, 122(4):500-508.
18. Coulam CB, Krysa L, Stern JJ, et al (1995). Intravenous immunoglobulin for treat-ment of recurrent pregnancy loss. Am J Reprod Immunol, 34(6):333-337.
19. Jablonowska B, Selbing A, Palfi M, et al (1999). Prevention of recurrent sponta-neous abortion by intravenous immuno-globulin: a double-blind placebo-controlled study. Hum Reprod, 14(3):838-841.
20. Jafarzadeh S, Ahmadi M, Dolati S, et al (2019). Intravenous immunoglobulin G treatment increases live birth rate in women with recurrent miscarriage and modulates regulatory and exhausted reg-ulatory T cells frequency and function. J Cell Biochem, 120(4):5424-5434.
21. Jørgensen MM, Bæk R, Sloth J, et al (2020). Treatment with intravenous immuno-globulin increases the level of small EVs in plasma of pregnant women with re-current pregnancy loss. J Reprod Immunol, 140:103128.
22. Peero EK, Banjar S, Khoudja R, et al (2024). Intravenous immunoglobulin for pa-tients with unexplained recurrent im-plantation failure: a 6-year single center retrospective review of clinical out-comes. Sci Rep, 14(1):3876.
23. Stephenson MD, Kutteh WH, Purkiss S, et al (2010). Intravenous immunoglobulin and idiopathic secondary recurrent mis-carriage: a multicentered randomized placebo-controlled trial. Hum Reprod, 25(9):2203-2209.
24. Yamada H, Deguchi M, Saito S, et al (2022). Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, ran-domised, placebo-controlled trial. EClinicalMedicine, 50:101527.
25. Quenby S, Gallos ID, Dhillon-Smith RK, et al (2021). Miscarriage matters: the epi-demiological, physical, psychological, and economic costs of early pregnancy loss. Lancet, 397(10285):1658-1667.
26. Wang F, Jia W, Fan M, et al (2021). Single-cell immune landscape of human recur-rent miscarriage. Genomics Proteomics Bioin-formatics, 19(2):208-222.
27. Jiang Y, Cheng Y, Ma S, et al (2022). System-ic lupus erythematosus-complicating immune thrombocytopenia: From path-ogenesis to treatment. J Autoimmun, 132:102887.
28. Noval Rivas M, Arditi M (2020). Kawasaki disease: pathophysiology and insights from mouse models. Nat Rev Rheumatol, 16(7):391-405.
29. Kwapisz D, Bogusławska J (2023). Intrave-nous immunoglobulins (IVIG) in se-vere/critical COVID-19 adult patients. Biomed Pharmacother, 163:114851.
30. Dalakas MC (2021). Update on intravenous immunoglobulin in neurology: modulat-ing neuro-autoimmunity, evolving fac-tors on efficacy and dosing and chal-lenges on stoppingchronic IVIg therapy. Neurotherapeutics,18(4):2397-2418.
31. Abdolmohammadi-Vahid S, Pashazadeh F, Pourmoghaddam Z, et al (2019). The ef-fectiveness of IVIG therapy in pregnan-cy and live birth rate of women with re-current implantation failure (RIF): A sys-tematic review and meta-analysis. J Re-prod Immunol, 134-135:28-33.
32. Shi Y, Tan D, Hao B, Zhang X, et al (2022). Efficacy of intravenous immunoglobu-lin in the treatment of recurrent sponta-neous abortion: A systematic review and meta-analysis. Am J Reprod Immunol, 88(5):e13615.
33. Yang X, Meng T (2020). Is there a Role of Intravenous Immunoglobulin in Immu-nologic Recurrent Pregnancy Loss? J Immunol Res, 2020:6672865.
34. Yuan X, Zhang W, Wang T, et al (2024). Use of intravenous immunoglobulin in antiphospholipid antibody positive pa-tients with high risk of miscarriage: a systematic review and meta-analysis. PeerJ, 12: e18419.
35. Hao F, Zhou X, Jin L (2020). Natural killer cells: functional differences in recurrent spontaneous abortion†. Biol Reprod, 102(3):524-531.
36. Shi JW, Lai ZZ, Zhou WJ, et al (2024). TNFSF14+ natural killer cells prevent spontaneous abortion by restricting leu-cine-mediated decidual stromal cell se-nescence. EMBO J, 43(21):5018-5036.
37. Lapides L, Klein M, Belušáková V, et al (2022). Uterine Natural Killer Cells in the Context of Implantation: Immuno-histochemical Analysis of Endometrial Samples from Women with Habitual Abortion and Recurrent Implantation Failure. Physiol Res, 71(Suppl 1):S99-S105.
38. Li T, Li X, Guo Y, et al (2020). Distinct mRNA and long non-coding RNA ex-pression profiles of decidual natural killer cells in patients with early missed abortion. FASEB J, 34(11):14264-14286.
39. Ahmadi M, Ghaebi M, Abdolmohammadi-Vahid S, et al (2019). NK cell frequency and cytotoxicity in correlation to preg-nancy outcome and response to IVIG therapy among women with recurrent pregnancy loss. J Cell Physiol, 234(6):9428-9437.
40. Tao Y, Huang F, Zhang Z, et al (2020). Pro-biotic enterococcus faecalis symbioflor 1 ameliorates pathobiont-induced mis-carriage through bacterial antagonism and Th1-Th2 modulation in pregnant mice. Appl Microbiol Biotechnol, 104(12):5493-5504.
41. Esparvarinha M, Madadi S, Aslanian-Kalkhoran L, et al (2023). Dominant immune cells in pregnancy and preg-nancy complications: T helper cells (TH1/TH2, TH17/Treg cells), NK cells, MDSCs, and the immune checkpoints. Cell Biol Int, 47(3):507-519.
42. Winger EE, Reed JL, Ashoush S, et al (2011). Elevated preconception CD56+ 16+ and/or Th1:Th2 levels predict ben-efit from IVIG therapy in subfertile women undergoing IVF. Am J Reprod Immunol, 66(5):394-403.
43. Ahmadi M, Abdolmohammadi-Vahid S, Ghaebi M, et al (2017). Effect of Intra-venous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent preg-nancy loss (RPL). Biomed Pharmacother, 92:1095-1102.
44. Jiang Y, Zou Q, Zhang N, et al (2022). Tu-mour necrosis factor inhibitor com-bined with intravenous immunoglobulin and heparin for treatment of recurrent spontaneous abortion: A two-centre, ret-rospective, cohort study. J Clin Pharm Ther, 47(12):2320-2324.
45. Nain E, Kıykım A, Kasap NA, et al (2020). Immediate adverse reactions to intrave-nous immunoglobulin in primary im-mune deficiencies: a single center expe-rience. Turk J Pediatr, 62(3):379-386.
2. Coomarasamy A, Dhillon-Smith RK, Papa-dopoulou A, et al (2021). Recurrent mis-carriage: evidence to accelerate action. Lancet, 397(10285):1675-1682.
3. Melo P, Dhillon-Smith R, Islam MA, et al (2023). Genetic causes of sporadic and recurrent miscarriage. Fertil Steril, 120(5):940-944.
4. Coomarasamy A, Devall AJ, Brosens JJ, et al (2020). Micronized vaginal progester-one to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol, 223(2):167-176.
5. Devall AJ, Coomarasamy A (2020). Sporad-ic pregnancy loss and recurrent miscar-riage. Best Pract Res Clin Obstet Gynaecol, 69:30-39.
6. Gonçalves CCRA, Feitosa BM, Cavalcante BV, et al (2023). Obesity and recurrent miscarriage: the interconnections be-tween adipose tissue and the immune system. Am J Reprod Immunol, 90(3):e13757.
7. Rewald E, Francischetti MM, Barberis L (2002). High dose intravenous immuno-globulin repertoire versus anti-D. Dis-proportions in quantity and quality. Cell Mol Biol (Noisy-le-grand), 48(3):265-9.
8. Banjar S, Kadour E, Khoudja R, et al (2023). Intravenous immunoglobulin use in pa-tients with unexplained recurrent preg-nancy loss. Am J Reprod Immunol, 90(2):e13737.
9. Dernoncourt A, Hedhli K, Abisror N, et al (2024). Hydroxychloroquine in recurrent pregnancy loss: data from a French pro-spective multicenter registry. Hum Re-prod, 39(9):1934-1941.
10. Yamada H, Deguchi M, Saito S, et al (2023). High doses of intravenous immuno-globulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss. J Reprod Immunol, 158:103977.
11. Jiang M, Kimber JS, Gupta A, et al (2023). Adverse Reactions Associated with In-travenous Immunoglobulin Administra-tion in the Treatment of Neurological Disorders: A Systematic Review. Int Arch Allergy Immunol, 184(6):513-528.
12. Jiang M, Lam L, Kovoor JG, et al (2023). In-travenous immunoglobulin alteration in response to adverse reactions in neuro-logical conditions: A retrospective co-hort study. Transfus Med, 33(6):478-482.
13. Martimbianco ALC, Sá KMM, Santos GM, et al (2023). Most cochrane systematic reviews and protocols did not adhere to the Cochrane’s risk of bias 2.0 tool. Rev Assoc Med Bras (1992), 69(3):469-472.
14. Carp HJ, Toder V, Gazit E, et al (2001). Fur-ther experience with intravenous immu-noglobulin in women with recurrent miscarriage and a poor prognosis. Am J Reprod Immunol, 46(4):268-273.
15. Christiansen OB, Mathiesen O, Husth M, et al (1995). Placebo-controlled trial of treatment of unexplained secondary re-current spontaneous abortions and re-current late spontaneous abortions with i.v. immunoglobulin. Hum Reprod, 10(10):2690-2695.
16. Christiansen OB, Pedersen B, Rosgaard A, et al (2002). A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with sec-ondary recurrent miscarriage. Hum Re-prod, 17(3):809-816.
17. Christiansen OB, Larsen EC, Egerup P, et al (2015). Intravenous immunoglobulin treatment for secondary recurrent mis-carriage: a randomised, double-blind, placebo-controlled trial. BJOG, 122(4):500-508.
18. Coulam CB, Krysa L, Stern JJ, et al (1995). Intravenous immunoglobulin for treat-ment of recurrent pregnancy loss. Am J Reprod Immunol, 34(6):333-337.
19. Jablonowska B, Selbing A, Palfi M, et al (1999). Prevention of recurrent sponta-neous abortion by intravenous immuno-globulin: a double-blind placebo-controlled study. Hum Reprod, 14(3):838-841.
20. Jafarzadeh S, Ahmadi M, Dolati S, et al (2019). Intravenous immunoglobulin G treatment increases live birth rate in women with recurrent miscarriage and modulates regulatory and exhausted reg-ulatory T cells frequency and function. J Cell Biochem, 120(4):5424-5434.
21. Jørgensen MM, Bæk R, Sloth J, et al (2020). Treatment with intravenous immuno-globulin increases the level of small EVs in plasma of pregnant women with re-current pregnancy loss. J Reprod Immunol, 140:103128.
22. Peero EK, Banjar S, Khoudja R, et al (2024). Intravenous immunoglobulin for pa-tients with unexplained recurrent im-plantation failure: a 6-year single center retrospective review of clinical out-comes. Sci Rep, 14(1):3876.
23. Stephenson MD, Kutteh WH, Purkiss S, et al (2010). Intravenous immunoglobulin and idiopathic secondary recurrent mis-carriage: a multicentered randomized placebo-controlled trial. Hum Reprod, 25(9):2203-2209.
24. Yamada H, Deguchi M, Saito S, et al (2022). Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, ran-domised, placebo-controlled trial. EClinicalMedicine, 50:101527.
25. Quenby S, Gallos ID, Dhillon-Smith RK, et al (2021). Miscarriage matters: the epi-demiological, physical, psychological, and economic costs of early pregnancy loss. Lancet, 397(10285):1658-1667.
26. Wang F, Jia W, Fan M, et al (2021). Single-cell immune landscape of human recur-rent miscarriage. Genomics Proteomics Bioin-formatics, 19(2):208-222.
27. Jiang Y, Cheng Y, Ma S, et al (2022). System-ic lupus erythematosus-complicating immune thrombocytopenia: From path-ogenesis to treatment. J Autoimmun, 132:102887.
28. Noval Rivas M, Arditi M (2020). Kawasaki disease: pathophysiology and insights from mouse models. Nat Rev Rheumatol, 16(7):391-405.
29. Kwapisz D, Bogusławska J (2023). Intrave-nous immunoglobulins (IVIG) in se-vere/critical COVID-19 adult patients. Biomed Pharmacother, 163:114851.
30. Dalakas MC (2021). Update on intravenous immunoglobulin in neurology: modulat-ing neuro-autoimmunity, evolving fac-tors on efficacy and dosing and chal-lenges on stoppingchronic IVIg therapy. Neurotherapeutics,18(4):2397-2418.
31. Abdolmohammadi-Vahid S, Pashazadeh F, Pourmoghaddam Z, et al (2019). The ef-fectiveness of IVIG therapy in pregnan-cy and live birth rate of women with re-current implantation failure (RIF): A sys-tematic review and meta-analysis. J Re-prod Immunol, 134-135:28-33.
32. Shi Y, Tan D, Hao B, Zhang X, et al (2022). Efficacy of intravenous immunoglobu-lin in the treatment of recurrent sponta-neous abortion: A systematic review and meta-analysis. Am J Reprod Immunol, 88(5):e13615.
33. Yang X, Meng T (2020). Is there a Role of Intravenous Immunoglobulin in Immu-nologic Recurrent Pregnancy Loss? J Immunol Res, 2020:6672865.
34. Yuan X, Zhang W, Wang T, et al (2024). Use of intravenous immunoglobulin in antiphospholipid antibody positive pa-tients with high risk of miscarriage: a systematic review and meta-analysis. PeerJ, 12: e18419.
35. Hao F, Zhou X, Jin L (2020). Natural killer cells: functional differences in recurrent spontaneous abortion†. Biol Reprod, 102(3):524-531.
36. Shi JW, Lai ZZ, Zhou WJ, et al (2024). TNFSF14+ natural killer cells prevent spontaneous abortion by restricting leu-cine-mediated decidual stromal cell se-nescence. EMBO J, 43(21):5018-5036.
37. Lapides L, Klein M, Belušáková V, et al (2022). Uterine Natural Killer Cells in the Context of Implantation: Immuno-histochemical Analysis of Endometrial Samples from Women with Habitual Abortion and Recurrent Implantation Failure. Physiol Res, 71(Suppl 1):S99-S105.
38. Li T, Li X, Guo Y, et al (2020). Distinct mRNA and long non-coding RNA ex-pression profiles of decidual natural killer cells in patients with early missed abortion. FASEB J, 34(11):14264-14286.
39. Ahmadi M, Ghaebi M, Abdolmohammadi-Vahid S, et al (2019). NK cell frequency and cytotoxicity in correlation to preg-nancy outcome and response to IVIG therapy among women with recurrent pregnancy loss. J Cell Physiol, 234(6):9428-9437.
40. Tao Y, Huang F, Zhang Z, et al (2020). Pro-biotic enterococcus faecalis symbioflor 1 ameliorates pathobiont-induced mis-carriage through bacterial antagonism and Th1-Th2 modulation in pregnant mice. Appl Microbiol Biotechnol, 104(12):5493-5504.
41. Esparvarinha M, Madadi S, Aslanian-Kalkhoran L, et al (2023). Dominant immune cells in pregnancy and preg-nancy complications: T helper cells (TH1/TH2, TH17/Treg cells), NK cells, MDSCs, and the immune checkpoints. Cell Biol Int, 47(3):507-519.
42. Winger EE, Reed JL, Ashoush S, et al (2011). Elevated preconception CD56+ 16+ and/or Th1:Th2 levels predict ben-efit from IVIG therapy in subfertile women undergoing IVF. Am J Reprod Immunol, 66(5):394-403.
43. Ahmadi M, Abdolmohammadi-Vahid S, Ghaebi M, et al (2017). Effect of Intra-venous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent preg-nancy loss (RPL). Biomed Pharmacother, 92:1095-1102.
44. Jiang Y, Zou Q, Zhang N, et al (2022). Tu-mour necrosis factor inhibitor com-bined with intravenous immunoglobulin and heparin for treatment of recurrent spontaneous abortion: A two-centre, ret-rospective, cohort study. J Clin Pharm Ther, 47(12):2320-2324.
45. Nain E, Kıykım A, Kasap NA, et al (2020). Immediate adverse reactions to intrave-nous immunoglobulin in primary im-mune deficiencies: a single center expe-rience. Turk J Pediatr, 62(3):379-386.
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| Issue | Vol 54 No 6 (2025) | |
| Section | Review Article(s) | |
| Keywords | ||
| Intravenous immunoglobulin Recurrent miscarriage Pregnancy outcome Adverse reactions Meta-analysis | ||
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How to Cite
1.
Gao Y, Peng L, Yuan C, Zhang S. Efficacy of Intravenous Immunoglobulin for Patients with Recurrent Miscarriage: A Meta-analysis. Iran J Public Health. 2025;54(6):1193-1203.
