The Beer Treatment Protocol for Recurrent Pregnancy Failure: A Retrospective Cohort Analysis
Main Article Content
Abstract
Backgound: Over the past 15 years we have learned much about recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) in otherwise healthy women. These women repeatedly fail to achieve successful pregnancy even when high-grade embryos are produced following in vitro fertilization. We have performed a retrospective cohort analysis to determine whether a careful clinical history, specific laboratory testing and targeted treatment can achieve pregnancy success in these women.
Methods: From 2007-2022, we collected data from 1,414 RPL/RIF patients who were evaluated according to the Beer treatment protocol. The Beer protocol uses a multivariate evaluation tool to identify immunological, metabolic and coagulation abnormalities that contribute to RPL and RIF. We examined 13 factors that may interfere with pregnancy, and we tailored our treatment to address these factors.
Results: The mean patient age was 37.8 ± 4.9 years and the mean number of pregnancy failures was 4.0 ± 2.6. The pregnancy success rate with the Beer protocol was 70% overall and even higher when egg quality issues were eliminated. Women who were age matched and untreated served as historical controls, and their pregnancy success rate was 23%. The difference in pregnancy success between treated versus untreated women was significant (P=0.0001).
Conclusion: The Beer treatment protocol for RPL/RIF was associated with significant pregnancy success in this cohort. Future approaches to improve pregnancy outcomes in women with RPL and RIF warrant investigation.
Article Details
How to Cite
STRICKER, Raphael B.; FESLER, Melissa C..
The Beer Treatment Protocol for Recurrent Pregnancy Failure: A Retrospective Cohort Analysis.
Medical Research Archives, [S.l.], v. 13, n. 11, dec. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7117>. Date accessed: 06 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i11.7117.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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28. Clark DA. Anti-TNFalpha therapy in immune-mediated subfertility: state of the art. J Reprod Immunol. 2010;85:15-24.
29. Gharesi-Fard B, Zolghadri J, Kamali-Sarvestani E. Effect of leukocyte therapy on tumor necrosis factor-alpha and interferon-gamma production in patients with recurrent spontaneous abortion. Am J Reprod Immunol. 2008;59:242-50.
30. Kwak-Kim JY, Chung-Bang HS, Ng SC, et al. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod. 2003;18:767-73.
31. 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.
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46. Clark DA, Coulam CB, Stricker RB. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF). J Assist Reprod Genet. 2006; 23:1-13.
47. Jafarzadeh S, Ahmadi M, Dolati S, et al. Intravenous immunoglobulin G treatment increases live birth rate in women with recurrent miscarriage and modulates regulatory and exhausted regulatory T cells frequency and function. J Cell Biochem. 2019;120:5424-5434.
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51. Stricker RB, Winger EE. Update on treatment of immunologic abortion with low-dose intravenous immunoglobulin. Am J Reprod Immunol. 2005;54: 390-6.
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53. Coulam CB. Intralipid treatment for women with reproductive failures. Am J Reprod Immunol. 2021;85:e13290.
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3. Bashiri A, Halper KI, Orvieto R. Recurrent implantation failure-update overview on etiology, diagnosis, treatment and future directions. Reprod Biol Endocrinol 2018;16:121.
4. Mekinian A, Cohen J, Alijotas-Reig J, Carbillon L, Nicaise-Roland P, Kayem G, Daraï E, Fain O, Bornes M. Unexplained recurrent miscarriage and recurrent implantation failure: Is there a place for immunomodulation? Am J Reprod Immunol. 2016; 76:8-28.
5. Busnelli A, Somigliana E, Cirillo F, Baggiani A, Levi-Setti PE. Efficacy of therapies and interventions for repeated embryo implantation failure: a systematic review and meta-analysis. Sci Rep. 2021;11:1747.
6. Carp H. Immunotherapy for recurrent pregnancy loss. Best Pract Res Clin Obstet Gynaecol. 2019; 60:77-86.
7. Kling C, Steinmann J, Westphal E, Magez J, Kabelitz D. Adverse effects of intradermal allogeneic lymphocyte immunotherapy: acute reactions and role of autoimmunity. Hum Reprod. 2006;21:429-35.
8. Nonaka T, Takakuwa K, Ooki I, et al. Results of immunotherapy for patients with unexplained primary recurrent abortions–prospective non-randomized cohort study. Am J Reprod Immunol. 2007;58:530-6.
9. Liu Z, Xu H, Kang X, Wang T, He L, Zhao A. Allogenic lymphocyte immunotherapy for unexplained recurrent spontaneous abortion: A meta-analysis. Am J Reprod Immunol. 2016;76:443-453.
10. Cavalcante MB, Sarno M, Araujo Júnior E, Da Silva Costa F, Barini R. Lymphocyte immunotherapy in the treatment of recurrent miscarriage: systematic review and meta-analysis. Arch Gynecol Obstet. 2017;295:511-518.
11. Hajipour H, Nejabati HR, Latifi Z, et al. Lymphocytes immunotherapy for preserving pregnancy: Mechanisms and challenges. Am J Reprod Immunol. 2018;80:e12853.
12. Raut MK, Raut MM. Role of lymphocyte immunization therapy (LIT) in repeated miscarriages - A review. Am J Reprod Immunol. 2023;89:e13629.
13. Beer AE, Kwak JY, Ruiz JE. Immunophenotypic profiles of peripheral blood lymphocytes in women with recurrent pregnancy losses and in infertile women with multiple failed in vitro fertilization cycles. Am J Reprod Immunol. 1996;35:376-82.
14. King K, Smith S, Chapman M, Sacks G. Detailed analysis of peripheral blood natural killer (NK) cells in women with recurrent miscarriage. Hum Reprod. 2010;25:52-8.
15. Thum MY, Bhaskaran S, Abdalla HI, et al. An increase in the absolute count of CD56dimCD16+CD69+ NK cells in the peripheral blood is associated with a poorer IVF treatment and pregnancy outcome. Hum Reprod. 2004;19: 2395-400.
16. Ntrivalas EI, Kwak-Kim JY, Gilman-Sachs A, et al. Status of peripheral blood natural killer cells in women with recurrent spontaneous abortions and infertility of unknown aetiology. Hum Reprod. 2001; 16:855-61.
17. Emmer PM, Nelen WL, Steegers EA, Hendriks JC, Veerhoek M, Joosten I. Peripheral natural killer cytotoxicity and CD56(pos)CD16(pos) cells increase during early pregnancy in women with a history of recurrent spontaneous abortion. Hum Reprod. 2000; 15:1163-9.
18. Hao F, Zhou X, Jin L. Natural killer cells: functional differences in recurrent spontaneous abortion. Biol Reprod. 2020;102:524-531.
19. Kwak-Kim J, Gilman-Sachs A. Clinical implication of natural killer cells and reproduction. Am J Reprod Immunol. 2008;59:388-400.
20. Guan D, Chen Z, Zhang Y, Sun W, Li L, Huang X. Dual role of natural killer cells in early pregnancy: Immunopathological implications and therapeutic potential in recurrent spontaneous abortion and recurrent implantation failure. Cell Prolif. 2025;58: e70037.
21. Wu H, You Q, Jiang Y, Mu F. Tumor necrosis factor inhibitors as therapeutic agents for recurrent spontaneous abortion (Review). Mol Med Rep. 2021;24:847.
22. Clark DA. Anti-TNFalpha therapy in immune-mediated subfertility: State of the art. J Reprod Immunol. 2010;85:15-24.
23. Gharesi-Fard B, Zolghadri J, Kamali-Sarvestani E. Effect of leukocyte therapy on tumor necrosis factor-alpha and interferon-gamma production in patients with recurrent spontaneous abortion. Am J Reprod Immunol. 2008;59:242-50.
24. Kwak-Kim JY, Chung-Bang HS, Ng SC, et al. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod. 2003;18:767-73.
25. 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.
26. Winger EE, Reed JL. Low Circulating CD4(+)CD25(+)Foxp3(+) T Regulatory cell levels predict miscarriage risk in newly pregnant women with a history of failure. Am J Reprod Immunol. 2011;66:320-8
27. Wu H, You Q, Jiang Y, Mu F. Tumor necrosis factor inhibitors as therapeutic agents for recurrent spontaneous abortion (Review). Mol Med Rep. 2021 Dec;24(6):847.
28. Clark DA. Anti-TNFalpha therapy in immune-mediated subfertility: state of the art. J Reprod Immunol. 2010;85:15-24.
29. Gharesi-Fard B, Zolghadri J, Kamali-Sarvestani E. Effect of leukocyte therapy on tumor necrosis factor-alpha and interferon-gamma production in patients with recurrent spontaneous abortion. Am J Reprod Immunol. 2008;59:242-50.
30. Kwak-Kim JY, Chung-Bang HS, Ng SC, et al. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod. 2003;18:767-73.
31. 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.
32. Min Y, Wang X, Chen H, Yin G. The exploration of Hashimoto's thyroiditis related miscarriage for better treatment modalities. Int J Med Sci. 2020; 17:2402-2415.
33. Cellini M, Santaguida MG, Stramazzo I, et al. Recurrent pregnancy loss in women with Hashimoto's thyroiditis with concurrent non-endocrine autoimmune disorders. Thyroid. 2020;30:457-462.
34. Gumusoglu S, Scroggins S, Vignato J, Santillan D, Santillan M. The serotonin-immune axis in preeclampsia. Curr Hypertens Rep. 2021;23:37.
35. Mao J, Kinkade JA, Bivens NJ, Roberts RM, Rosenfeld CS. Placental changes in the serotonin transporter (Slc6a4) knockout mouse suggest a role for serotonin in controlling nutrient acquisition. Placenta. 2021;115:158-168.
36. Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology. 2011;36:2452-9.
37. Maryam K, Bouzari Z, Basirat Z, Kashifard M, Zadeh MZ. The comparison of insulin resistance frequency in patients with recurrent early pregnancy loss to normal individuals. BMC Res Notes. 2012; 5:133.
38. Cai WY, Luo X, Lv HY, Fu KY, Xu J. Insulin resistance in women with recurrent miscarriage: a systematic review and meta-analysis. BMC Pregnancy Childbirth. 2022;22:916.
39. Wartena R, Matjila M. Polycystic ovary syndrome and recurrent pregnancy loss, a review of literature. Front Endocrinol (Lausanne). 2023;14:1183060.
40. Barut MU, Bozkurt M, Kahraman M, et al. Thrombophilia and recurrent pregnancy loss: The enigma continues. Med Sci Monit. 2018;24:4288-4294.
41. Joksic I, Mikovic Z, Filimonovic D, Munjas J, Karadzov ON, Egic A, Joksic G. Combined presence of coagulation factor XIII V34L and plasminogen activator inhibitor 1 4G/5G gene polymorphisms significantly contribute to recurrent pregnancy loss in Serbian population. J Med Biochem. 2020;39: 199-207.
42. Wen Y, He H, Zhao K. Thrombophilic gene polymorphisms and recurrent pregnancy loss: a systematic review and meta-analysis. J Assist Reprod Genet. 2023;40:1533-1558.
43. Murvai VR, Galiș R, Panaitescu A, et al. Antiphospholipid syndrome in pregnancy: a comprehensive literature review. BMC Pregnancy Childbirth. 2025;25:337.
44. Vinatier D, Dufour P, Cosson M, Houpeau JL. Antiphospholipid syndrome and recurrent miscarriages. Eur J Obstet Gynecol Reprod Biol. 2001;96:37-50.
45. Dai YF, Lin LZ, Lin N, et al. APA scoring system: a novel predictive model based on risk factors of pregnancy loss for recurrent spontaneous abortion patients. J Obstet Gynaecol. 2022;42:2069-2074
46. Clark DA, Coulam CB, Stricker RB. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF). J Assist Reprod Genet. 2006; 23:1-13.
47. Jafarzadeh S, Ahmadi M, Dolati S, et al. Intravenous immunoglobulin G treatment increases live birth rate in women with recurrent miscarriage and modulates regulatory and exhausted regulatory T cells frequency and function. J Cell Biochem. 2019;120:5424-5434.
48. Habets DHJ, Pelzner K, Wieten L, Spaanderman MEA, Villamor E, Al-Nasiry S. Intravenous immunoglobulins improve live birth rate among women with underlying immune conditions and recurrent pregnancy loss: a systematic review and meta-analysis. Allergy Asthma Clin Immunol. 2022; 18:23.
49. Muyayalo KP, Li ZH, Mor G, Liao AH. Modulatory effect of intravenous immunoglobulin on Th17/Treg cell balance in women with unexplained recurrent spontaneous abortion. Am J Reprod Immunol. 2018;80:e13018.
50. Yuan X, Zhang W, Wang T, Jiang P, Wang ZK, Li CQ. Use of intravenous immunoglobulin in antiphospholipid antibody positive patients with high risk of miscarriage: a systematic review and meta-analysis. PeerJ. 2024;12:e18419.
51. Stricker RB, Winger EE. Update on treatment of immunologic abortion with low-dose intravenous immunoglobulin. Am J Reprod Immunol. 2005;54: 390-6.
52. Kumar P, Marron K, Harrity C. Intralipid therapy and adverse reproductive outcome: is there any evidence? Reprod Fertil. 2021;2:173-186.
53. Coulam CB. Intralipid treatment for women with reproductive failures. Am J Reprod Immunol. 2021;85:e13290.
54. Liu S, Shi L, Wang T, Shi J. Effect of low-dose dexamethasone on patients with elevated early follicular phase progesterone level and pregnancy outcomes in IVF-ET treatment: A randomized controlled clinical trial. Clin Endocrinol (Oxf). 2018; 89:771-778.
55. Bramham K, Thomas M, Nelson-Piercy C, Khamashta M, Hunt BJ. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117:6948-51.
56. Dernoncourt A, Hedhli K, Abisror N, et al. Hydroxychloroquine in recurrent pregnancy loss: data from a French prospective multicenter registry. Hum Reprod. 2024;39:1934-1941.
57. Lima J, Guerreiro J, Ângelo-Dias M, et al. Efficacy of therapeutic interventions for idiopathic recurrent pregnancy loss: a systematic review and network meta-analysis. Front Med (Lausanne). 2025;12:1569819.
58. Mak A, Cheung MW, Cheak AA, Ho RC. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford). 2010;49:281-8.
59. Yu X, He L. Aspirin and heparin in the treatment of recurrent spontaneous abortion associated with antiphospholipid antibody syndrome: A systematic review and meta-analysis. Exp Ther Med. 2021; 21:57.
60. Huang W, Yu Y, Chen L, et al. Comparative effectiveness of low molecular weight heparin on live birth for recurrent spontaneous abortion: systematic review and network meta-analysis. Am J Obstet Gynecol MFM. 2025;7:101572.
61. Vidmar Golja M, Šmid A, Karas Kuželički N, Trontelj J, Geršak K, Mlinarič-Raščan I. Folate insufficiency due to MTHFR deficiency is bypassed by 5-methyltetrahydrofolate. J Clin Med. 2020;9: 2836.
62. Nelson SM, Greer IA. The potential role of heparin in assisted conception. Hum Reprod Update. 2008;14:623-45.
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