Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses before 24 weeks of gestation. It affects 3-5% of women who are attempting to conceive. RPL can stem from a variety of causes and is frequently associated with psychological distress and a diminished quality of life. By contrast, recurrent implantation failure (RIF) refers to the inability to achieve a successful pregnancy after three or more high-quality embryo transfers or at least two instances of egg donation. RIF shares several causative factors with RPL. The immunological underpinnings of these conditions involve alterations in uterine NK cells, reductions in M2 macrophages and myeloid-derived suppressor cells, an increased Th1/Th2 ratio, a decreased Treg/Th17 ratio, the presence of shared ≥3 HLA alleles between partners, and autoimmune disorders. Various therapeutic approaches have been employed to address these immunological concerns, achieving varying degrees of success, although some therapies remain contentious within the medical community. This review intends to explore the immunological factors implicated in RPL and RIF and to analyze the immunological treatments employed for these conditions, which may include steroids, intravenous immunoglobulins, calcineurin inhibitors, anti-TNF antibodies, intralipid infusions, granulocyte colony-stimulating factor, and lymphocyte immunotherapy.

Czech Advanced Technologies and Research Institute Institute of Molecular and Translational Medicine 779 00 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University 779 00 Olomouc Czech Republic

Laboratory of Experimental Medicine University Hospital Olomouc 779 00 Olomouc Czech Republic

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Tomkiewicz J., Darmochwał-Kolarz D. The Diagnostics and Treatment of Recurrent Pregnancy Loss. J. Clin. Med. 2023;12:4768. doi: 10.3390/jcm12144768. PubMed DOI PMC

The ESHRE Guideline Group on RPL. Bender Atik R., Christiansen O.B., Elson J., Kolte A.M., Lewis S., Middeldorp S., Nelen W., Peramo B., Quenby S., et al. ESHRE guideline: Recurrent pregnancy loss. Hum. Reprod. Open. 2018;2018:hoy004. doi: 10.1093/hropen/hoy004. PubMed DOI PMC

Practice Committee of the American Society for Reproductive Medicine Evaluation and treatment of recurrent pregnancy loss: A committee opinion. Fertil. Steril. 2012;98:1103–1111. doi: 10.1016/j.fertnstert.2012.06.048. PubMed DOI

Who: Recommended Definitions, Terminology, and Format for Statistical Tables Related to The Perinatal Period And Use of A New Certificate For the Cause of Perinatal Deaths. Acta Obstet. Gynecol. Scand. 1977;56:247–256. doi: 10.3109/00016347709162009. PubMed DOI

Dimitriadis E., Menkhorst E., Saito S., Kutteh W.H., Brosens J.J. Recurrent pregnancy loss. Nat. Rev. Dis. Primers. 2020;6:98. doi: 10.1038/s41572-020-00228-z. PubMed DOI

Dong P., Wen X.Z., Liu J., Yan C., Yuan J., Luo L., Hu Q.F., Li J. Simultaneous detection of decidual Th1/Th2 and NK1/NK2 immunophenotyping in unknown recurrent miscarriage using 8-color flow cytometry with FSC/Vt extended strategy. Biosci. Rep. 2017;37:BSR20170150. doi: 10.1042/BSR20170150. PubMed DOI PMC

Kohl Schwartz A.S., Wölfler M.M., Mitter V., Rauchfuss M., Haeberlin F., Eberhard M., von Orelli S., Imthurn B., Imesch P., Fink D., et al. Endometriosis, especially mild disease: A risk factor for miscarriages. Fertil. Steril. 2017;108:806–814.e2. doi: 10.1016/j.fertnstert.2017.08.025. PubMed DOI

Harb H.M., Ghosh J., Al-Rshoud F., Karunakaran B., Gallos I.D., Coomarasamy A. Hydrosalpinx and pregnancy loss: A systematic review and meta-analysis. Reprod. Biomed. Online. 2019;38:427–441. doi: 10.1016/j.rbmo.2018.12.020. PubMed DOI

Zhang L., Li H., Han L., Zhang L., Zu Z., Zhang J. Association between semen parameters and recurrent pregnancy loss: An umbrella review of meta-analyses. J. Obstet. Gynaecol. Res. 2024;50:545–556. doi: 10.1111/jog.15886. PubMed DOI

Deshmukh H., Way S.S. Immunological Basis for Recurrent Fetal Loss and Pregnancy Complications. Annu. Rev. Pathol. 2019;14:185–210. doi: 10.1146/annurev-pathmechdis-012418-012743. PubMed DOI PMC

Bagkou Dimakou D., Lissauer D., Tamblyn J., Coomarasamy A., Richter A. Understanding human immunity in idiopathic recurrent pregnancy loss. Eur. J. Obstet. Gynecol. Reprod. Biol. 2022;270:17–29. doi: 10.1016/j.ejogrb.2021.12.024. PubMed DOI

Bashiri A., Halper K.I., Orvieto R. Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions. Reprod. Biol. Endocrinol. 2018;16:121. doi: 10.1186/s12958-018-0414-2. PubMed DOI PMC

Comins Boo A., Segovia A.G., del Prado N.N., de la Fuente L., Alonso J., Ramon S.S. Evidence-based Update: Immunological Evaluation of Recurrent Implantation Failure. Reprod. Immunol. Open Access. 2016;1:24. doi: 10.21767/2476-1974.100024. DOI

Wu Y., Li L., Liu L., Yang X., Yan P., Yang K., Zhang X. Autologous peripheral blood mononuclear cells intrauterine instillation to improve pregnancy outcomes after recurrent implantation failure: A systematic review and meta-analysis. Arch. Gynecol. Obstet. 2019;300:1445–1459. doi: 10.1007/s00404-019-05275-w. PubMed DOI

Wu H., You Q., Jiang Y., Mu F. Tumor necrosis factor inhibitors as therapeutic agents for recurrent spontaneous abortion. Mol. Med. Rep. 2021;24:847. doi: 10.3892/mmr.2021.12487. PubMed DOI

Saadaoui M., Singh P., Ortashi O., Al Khodor S. Role of the vaginal microbiome in miscarriage: Exploring the relationship. Front. Cell. Infect. Microbiol. 2023;13:1232825. doi: 10.3389/fcimb.2023.1232825. PubMed DOI PMC

Mrozikiewicz A.E., Ożarowski M., Jędrzejczak P. Biomolecular Markers of Recurrent Implantation Failure—A Review. Int. J. Mol. Sci. 2021;22:10082. doi: 10.3390/ijms221810082. PubMed DOI PMC

Wang Q., Sun Y., Fan R., Wang M., Ren C., Jiang A., Yang T. Role of inflammatory factors in the etiology and treatment of recurrent implantation failure. Reprod. Biol. 2022;22:100698. doi: 10.1016/j.repbio.2022.100698. PubMed DOI

Ma J., Gao W., Li D. Recurrent implantation failure: A comprehensive summary from etiology to treatment. Front. Endocrinol. 2023;13:1061766. doi: 10.3389/fendo.2022.1061766. PubMed DOI PMC

Fathi M., Omrani M.A., Kadkhoda S., Ghahghaei-Nezamabadi A., Ghafouri-Fard S. Impact of miRNAs in the pathoetiology of recurrent implantation failure. Mol. Cell Probes. 2024;74:101955. doi: 10.1016/j.mcp.2024.101955. PubMed DOI

Liu L., Liu Y., Tian Y., Cao Y., Wang T., Mi S., Yang R., Liu S., Ma X., Wang J. Identification of Differentially Expressed mRNAs and lncRNAs Contributes to Elucidation of Underlying Pathogenesis and Therapeutic Strategy of Recurrent Implantation Failure. Reprod. Sci. 2024 doi: 10.1007/s43032-024-01630-8. PubMed DOI

Zahir M., Tavakoli B., Zaki-Dizaji M., Hantoushzadeh S., Majidi Zolbin M. Non-coding RNAs in Recurrent implantation failure. Clin. Chim. Acta. 2024;553:117731. doi: 10.1016/j.cca.2023.117731. PubMed DOI

Colamatteo A., Fusco C., Micillo T., D’Hooghe T., de Candia P., Alviggi C., Longobardi S., Matarese G. Immunobiology of pregnancy: From basic science to translational medicine. Trends Mol. Med. 2023;29:711–725. doi: 10.1016/j.molmed.2023.05.009. PubMed DOI

Zhao F., Hu X., Ying C. Advances in Research on the Relationship between Vaginal Microbiota and Adverse Pregnancy Outcomes and Gynecological Diseases. Microorganisms. 2023;11:991. doi: 10.3390/microorganisms11040991. PubMed DOI PMC

Moreno I., Codoñer F.M., Vilella F., Valbuena D., Martinez-Blanch J.F., Jimenez-Almazán J., Alonso R., Alamá P., Remohí J., Pellicer A., et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am. J. Obstet. Gynecol. 2016;215:684–703. doi: 10.1016/j.ajog.2016.09.075. PubMed DOI

Garmendia J.V., De Sanctis C.V., Hajdúch M., De Sanctis J.B. Microbiota and Recurrent Pregnancy Loss (RPL); More than a Simple Connection. Microorganisms. 2024;12:1641. doi: 10.3390/microorganisms12081641. PubMed DOI PMC

Jia D., Sun F., Han S., Lu L., Sun Y., Song Q. Adverse outcomes in subsequent pregnancies in women with a history of recurrent spontaneous abortion: A meta-analysis. J. Obstet. Gynaecol. Res. 2024;50:281–297. doi: 10.1111/jog.15848. PubMed DOI

Field K., Murphy D.J. Perinatal outcomes in a subsequent pregnancy among women who have experienced recurrent miscarriage: A retrospective cohort study. Hum. Reprod. 2015;30:1239–1245. doi: 10.1093/humrep/dev044. PubMed DOI

Fang Y., Jingjing F., Tiantain C., Huanhuan X., Qiaohua H. Impact of the number of previous embryo implantation failures on IVF/ICSI-ET pregnancy outcomes in patients younger than 40 years: A retrospective cohort study. Front. Endocrinol. 2023;14:1243402. doi: 10.3389/fendo.2023.1243402. PubMed DOI PMC

Cimadomo D., Rienzi L., Conforti A., Forman E., Canosa S., Innocenti F., Poli M., Hynes J., Gemmell L., Vaiarelli A., et al. Opening the black box: Why do euploid blastocysts fail to implant? A systematic review and meta-analysis. Hum. Reprod. Update. 2023;29:570–633. doi: 10.1093/humupd/dmad010. PubMed DOI

Nitu R., Neamtu R., Lordache O., Stelea L., Dahma G., Sacarin G., Socol G., Boarta A., Silaghi C., Puichita D., et al. Cross-Sectional Analysis of Intimacy Problems, Stress Levels, and Couple Satisfaction among Women with Thrombophilia Affected by Recurrent Pregnancy Loss. Int J Environ Res Public Health. 2023;20:1208. doi: 10.3390/ijerph20021208. PubMed DOI PMC

Chen S., Chang S., Kuo P., Chen C. Stress, anxiety and depression perceived by couples with recurrent miscarriage. Int J Nurs Pract. 2020;26:e12796. doi: 10.1111/ijn.12796. PubMed DOI

Quenby S., Gallos I.D., Dhillon-Smith R.K., Podesek M., Stephenson M.D., Fisher J., Brosens J.J., Brewin J., Ramhorst R., Lucas E.S., et al. Miscarriage matters: The epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021;397:1658–1667. doi: 10.1016/S0140-6736(21)00682-6. PubMed DOI

Voss P., Schick M., Langer L., Ainsworth A., Ditzen B., Strowitzki T., Wischmann T., Kuon R.J. Recurrent pregnancy loss: A shared stressor---couple-orientated psychological research findings. Fertil Steril. 2020;114:1288–1296. doi: 10.1016/j.fertnstert.2020.08.1421. PubMed DOI

Mínguez-Alarcón L., Williams P.L., Souter I., Ford J.B., Hauser R., Chavarro J.E. Women’s preconception psychological stress and birth outcomes in a fertility clinic: The EARTH study. Front Glob Womens Health. 2024;5:1293255. doi: 10.3389/fgwh.2024.1293255. PubMed DOI PMC

Marshall J.S., Warrington R., Watson W., Kim H.L. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2018;14((Suppl. 2)):49. doi: 10.1186/s13223-018-0278-1. PubMed DOI PMC

Garmendia J.V., De Sanctis J.B. A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation. Immuno. 2021;1:174–193. doi: 10.3390/immuno1030011. DOI

Lanier L.L. Five decades of natural killer cell discovery. J. Exp. Med. 2024;221:e20231222. doi: 10.1084/jem.20231222. PubMed DOI PMC

Rao V.A., Kurian N.K., Rao K.A. Cytokines, NK cells, and regulatory T cell functions in normal pregnancy and reproductive failures. Am. J. Reprod. Immunol. 2023;89:e13667. doi: 10.1111/aji.13667. PubMed DOI

Cavalcante M.B., da Silva P.H.A., Carvalho T.R., Sampaio O.G.M., Câmara F.E.A., Cavalcante C.T.M.B., Barini R., Kwak-Kim J. Peripheral blood natural killer cell cytotoxicity in recurrent miscarriage: A systematic review and meta-analysis. J. Reprod. Immunol. 2023;158:103956. doi: 10.1016/j.jri.2023.103956. PubMed DOI

Sacks G., Yang Y., Gowen E., Smith S., Fay L., Chapman M. Detailed Analysis of Peripheral Blood Natural Killer Cells in Women with Repeated IVF Failure. Am. J. Reprod. Immunol. 2012;67:434–442. doi: 10.1111/j.1600-0897.2012.01105.x. PubMed DOI

Cai J.Y., Tang Y.Y., Deng X.H., Li Y.J., Liang G., Meng Y.Q., Zhou H. Recurrent Implantation Failure May Be Identified by a Combination of Diagnostic Biomarkers: An Analysis of Peripheral Blood Lymphocyte Subsets. Front. Endocrinol. 2024;13:865807. doi: 10.3389/fendo.2022.865807. PubMed DOI PMC

Sacks G. Enough! Stop the arguments and get on with the science of natural killer cell testing. Hum. Reprod. 2015;30:1526–1531. doi: 10.1093/humrep/dev096. PubMed DOI

Dons’koi B.V. Accentuated hypo- and hyper-NK lymphocyte CD8 expression is a marker of NK subsets’ misbalance and is predictive for reproductive failures. Immunobiology. 2015;220:649–655. doi: 10.1016/j.imbio.2014.11.015. PubMed DOI

Dons’koi B.V., Chernyshov V.P., Sirenko V.Y., Strelko G.V., Osypchuk D.V. Peripheral blood natural killer cells activation status determined by CD69 upregulation predicts implantation outcome in IVF. Immunobiology. 2014;219:167–171. doi: 10.1016/j.imbio.2013.09.002. PubMed DOI

Gothe J.P., de Mattos A.C., Silveira C.F., Malavazi K.C. Exploring Natural Killer Cell Testing in Embryo Implantation and Reproductive Failure: An Overview of Techniques and Controversies. Reprod. Sci. 2024;31:603–632. doi: 10.1007/s43032-023-01372-z. PubMed DOI

Zhang J., Lye S.J. The immune potential of decidua-resident CD16+CD56+ NK cells in human pregnancy. Hum. Immunol. 2021;82:332–339. doi: 10.1016/j.humimm.2021.01.014. PubMed DOI

Salazar M.D., Wang W.J., Skariah A., He Q., Field K., Nixon M., Reed R., Dambaeva S., Beaman K., Gilman-Sachs A., et al. Post-hoc evaluation of peripheral blood natural killer cell cytotoxicity in predicting the risk of recurrent pregnancy losses and repeated implantation failures. J. Reprod. Immunol. 2022;150:103487. doi: 10.1016/j.jri.2022.103487. PubMed DOI

Singh N., Dogra Y., Kumar P., Mathur S., Sharma A., Patel G. Establishment of Cut-off Values for Uterine and Peripheral Blood Natural Killer Cells During the Peri-implantation Period in Fertile Controls and Women with Unexplained Recurrent Implantation Failure. J. Reprod. Infert. 2023;24:248–256. doi: 10.18502/jri.v24i4.14152. PubMed DOI PMC

Santillán I., Fernández Lozano I., Illán J., Verdú V., Coca S., Bajo-Arenas J., Martinez F. Where and when should natural killer cells be tested in women with repeated implantation failure? J. Reprod. Immunol. 2015;108:142–148. doi: 10.1016/j.jri.2014.12.009. PubMed DOI

Sfakianoudis K., Rapani A., Grigoriadis S., Pantou A., Maziotis E., Kokkini G., Tsirligkani C., Bolaris S., Nikolettos K., Chronopoulou M., et al. The Role of Uterine Natural Killer Cells on Recurrent Miscarriage and Recurrent Implantation Failure: From Pathophysiology to Treatment. Biomedicines. 2021;9:1425. doi: 10.3390/biomedicines9101425. PubMed DOI PMC

Bagkou Dimakou D., Tamblyn J., Justin C., Coomarasamy A., Richter A. Diagnosis and management of idiopathic recurrent pregnancy loss (RPL): Current immune testing and immunomodulatory treatment practice in the United Kingdom. J. Reprod. Immunol. 2022;153:103662. doi: 10.1016/j.jri.2022.103662. PubMed DOI

Seshadri S., Sunkara S.K. Natural killer cells in female infertility and recurrent miscarriage: A systematic review and meta-analysis. Hum. Reprod. Update. 2013;20:429–438. doi: 10.1093/humupd/dmt056. PubMed DOI

Lachapelle M., Miron P., Hemmings R., Roy D. Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion. Altered profile and pregnancy outcome. J. Immunol. 1996;156:4027–4034. doi: 10.4049/jimmunol.156.10.4027. PubMed DOI

Ho Y.K., Chen H.H., Huang C.C., Lee C.I., Lin P.Y., Lee M.S., Lee T.H. Peripheral CD56+CD16+ NK Cell Populations in the Early Follicular Phase Are Associated With Successful Clinical Outcomes of Intravenous Immunoglobulin Treatment in Women With Repeated Implantation Failure. Front. Endocrinol. 2020;10:937. doi: 10.3389/fendo.2019.00937. PubMed DOI PMC

Fukui A., Fujii S., Yamaguchi E., Kimura H., Sato S., Saito Y. Natural Killer Cell Subpopulations and Cytotoxicity for Infertile Patients Undergoing In Vitro Fertilization. Am. J. Reprod. Immunol. 1999;41:413–422. doi: 10.1111/j.1600-0897.1999.tb00456.x. PubMed DOI

Strobel L., Vomstein K., Kyvelidou C., Hofer-Tollinger S., Feil K., Kuon R.J., Ebner S., Troppmair J., Toth B. Different Background: Natural Killer Cell Profiles in Secondary versus Primary Recurrent Pregnancy Loss. J. Clin. Med. 2021;10:194. doi: 10.3390/jcm10020194. PubMed DOI PMC

Fukui A., Kwak-Kim J., Ntrivalas E., Gilman-Sachs A., Lee S.K., Beaman K. Intracellular cytokine expression of peripheral blood natural killer cell subsets in women with recurrent spontaneous abortions and implantation failures. Fertil. Steril. 2008;89:157–165. doi: 10.1016/j.fertnstert.2007.02.012. PubMed DOI

Díaz-Peña R., de Los Santos M.J., Lucia A., Castro-Santos P. Understanding the role of killer cell immunoglobulin-like receptors in pregnancy complications. J. Assist. Reprod. Genet. 2019;36:827–835. doi: 10.1007/s10815-019-01426-9. PubMed DOI PMC

Lin Q.D., Qiu L.H. Pathogenesis, diagnosis, and treatment of recurrent spontaneous abortion with immune type. Front. Med. China. 2010;4:275–279. doi: 10.1007/s11684-010-0101-y. PubMed DOI

Dambaeva S.V., Lee D.H., Sung N., Chen C.Y., Bao S., Gilman-Sachs A., Kwak-Kim J., Beaman K.D. Recurrent Pregnancy Loss in Women with Killer Cell Immunoglobulin-Like Receptor KIR2DS1 is Associated with an Increased HLA-C2 Allelic Frequency. Am. J. Reprod. Immunol. 2016;75:94–103. doi: 10.1111/aji.12453. PubMed DOI

Akbari S., Shahsavar F., Karami R., Yari F., Anbari K., Ahmadi S.A.Y. Recurrent Spontaneous Abortion (RPL) and Maternal KIR Genes: A Comprehensive Meta-Analysis. JBRA Assist. Reprod. 2020;24:197–213. doi: 10.5935/1518-0557.20190067. PubMed DOI PMC

Yang X., Yang E., Wang W., He Q., Jubiz G., Katukurundage D., Dambaeva S., Beaman K.D., Kwak-Kim J. Decreased HLA-C1 alleles in couples of KIR2DL2 positive women with recurrent pregnancy loss. J. Reprod. Immunol. 2020;142:103186. doi: 10.1016/j.jri.2020.103186. PubMed DOI

Feyaerts D., Benner M., Comitini G., Shadmanfar W., van der Heijden O.W.H., Joosten I., van der Molen R.G. NK cell receptor profiling of endometrial and decidual NK cells reveals pregnancy-induced adaptations. Front. Immunol. 2024;15:1353556. doi: 10.3389/fimmu.2024.1353556. PubMed DOI PMC

Maftei R., Doroftei B., Popa R., Harabor V., Adam A.M., Popa C., Harabor A., Adam G., Nechita A., Vasilache I.A., et al. The Influence of Maternal KIR Haplotype on the Reproductive Outcomes after Single Embryo Transfer in IVF Cycles in Patients with Recurrent Pregnancy Loss and Implantation Failure—A Single Center Experience. J. Clin. Med. 2023;12:1905. doi: 10.3390/jcm12051905. PubMed DOI PMC

Nowak I., Wilczyńska K., Wilczyński J.R., Malinowski A., Radwan P., Radwan M., Kuśnierczyk P. KIR, LILRB and their Ligands’ Genes as Potential Biomarkers in Recurrent Implantation Failure. Arch. Immunol. Ther. Exp. 2017;65:391–399. doi: 10.1007/s00005-017-0474-6. PubMed DOI PMC

Braun A.S., Vomstein K., Reiser E., Tollinger S., Kyvelidou C., Feil K., Toth B. NK and T Cell Subtypes in the Endometrium of Patients with Recurrent Pregnancy Loss and Recurrent Implantation Failure: Implications for Pregnancy Success. J. Clin. Med. 2023;12:5585. doi: 10.3390/jcm12175585. PubMed DOI PMC

Morin S.J., Treff N.R., Tao X., Scott R.T., 3rd, Franasiak J.M., Juneau C.R., Maguire M., Scott R.T. Combination of uterine natural killer cell immunoglobulin receptor haplotype and trophoblastic HLA-C ligand influences the risk of pregnancy loss: A retrospective cohort analysis of direct embryo genotyping data from euploid transfers. Fertil. Steril. 2017;107:677–683.e2. doi: 10.1016/j.fertnstert.2016.12.004. PubMed DOI

Khalaf W.S., Mahmoud M.R.A., Elkhatib W.F., Hashem H.R., Soliman W.E. Phenotypic characterization of NKT-like cells and evaluation of specifically related cytokines for the prediction of unexplained recurrent miscarriage. Heliyon. 2021;7:e08409. doi: 10.1016/j.heliyon.2021.e08409. PubMed DOI PMC

Xu Q.H., Liu H., Wang L.L., Zhu Q., Zhang Y.J., Muyayalo K.P., Liao A.H. Roles of γδT cells in pregnancy and pregnancy-related complications. Am. J. Reprod. Immunol. 2021;86:e13487. doi: 10.1111/aji.13487. PubMed DOI

Li L., Liu Y., Zhou W., Yang C., Feng T., Li H. Human chorionic gonadotrophin indirectly activates peripheral γδT cells to produce interleukin-10 during early pregnancy. Immun. Inflamm. Dis. 2024;12:e1119. doi: 10.1002/iid3.1119. PubMed DOI PMC

Zhang D., Yu Y., Duan T., Zhou Q. The role of macrophages in reproductive-related diseases. Heliyon. 2022;8:e11686. doi: 10.1016/j.heliyon.2022.e11686. PubMed DOI PMC

Nagamatsu T., Schust D.J. The Contribution of Macrophages to Normal and Pathological Pregnancies. Am. J. Reprod. Immunol. 2010;63:460–471. doi: 10.1111/j.1600-0897.2010.00813.x. PubMed DOI

Tsao F.Y., Wu M.Y., Chang Y.L., Wu C.T., Ho H.N. M1 macrophages decrease in the deciduae from normal pregnancies but not from spontaneous abortions or unexplained recurrent spontaneous abortions. J. Formos. Med. Assoc. 2018;117:204–211. doi: 10.1016/j.jfma.2017.03.011. PubMed DOI

Robertson S.A., Moldenhauer L.M., Green E.S., Care A.S., Hull M.L. Immune determinants of endometrial receptivity: A biological perspective. Fertil. Steril. 2022;117:1107–1120. doi: 10.1016/j.fertnstert.2022.04.023. PubMed DOI

Wang W.J., Hao C.F., Lin Q.D. Dysregulation of macrophage activation by decidual regulatory T cells in unexplained recurrent miscarriage patients. J. Reprod. Immunol. 2011;92:97–102. doi: 10.1016/j.jri.2011.08.004. PubMed DOI

Quenby S., Bates M., Doig T., Brewster J., Lewis-Jones D.I., Johnson P.M., Vince G. Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum. Reprod. 1999;14:2386–2391. doi: 10.1093/humrep/14.9.2386. PubMed DOI

Krop J., Tian X., van der Hoorn M.L., Eikmans M. The Mac Is Back: The Role of Macrophages in Human Healthy and Complicated Pregnancies. Int. J. Mol. Sci. 2023;24:5300. doi: 10.3390/ijms24065300. PubMed DOI PMC

Tremellen K.P., Russell P. The distribution of immune cells and macrophages in the endometrium of women with recurrent reproductive failure. II: Adenomyosis and macrophages. J. Reprod. Immunol. 2012;93:58–63. PubMed

Wei R., Lai N., Zhao L., Zhang Z., Zhu X., Guo Q., Chu C., Fu X., Li X. Dendritic cells in pregnancy and pregnancy-associated diseases. Biomed. Pharmacother. 2021;133:110921. doi: 10.1016/j.biopha.2020.110921. PubMed DOI

Saito S. Role of immune cells in the establishment of implantation and maintenance of pregnancy and immunomodulatory therapies for patients with repeated implantation failure and recurrent pregnancy loss. Reprod. Med. Biol. 2024;23:e12600. doi: 10.1002/rmb2.12600. PubMed DOI PMC

Liu S., Wei H., Li Y., Huang C., Lian R., Xu J., Chen L., Zeng Y. Downregulation of ILT4+dendritic cells in recurrent miscarriage and recurrent implantation failure. Am. J. Reprod. Immunol. 2018;80:e12998. doi: 10.1111/aji.12998. PubMed DOI

Zhu X.X., Yin X.Q., Hei G.Z., Wei R., Guo Q., Zhao L., Zhang Z., Chu C., Fu X.X., Xu K., et al. Increased miR-6875-5p inhibits plasmacytoid dendritic cell differentiation via the STAT3/E2-2 pathway in recurrent spontaneous abortion. Mol. Hum. Reprod. 2021;27:gaab044. doi: 10.1093/molehr/gaab044. PubMed DOI PMC

Huang C., Zhang H., Chen X., Diao L., Lian R., Zhang X., Hu L., Zeng Y. Association of peripheral blood dendritic cells with recurrent pregnancy loss: A case-controlled study. Am. J. Reprod. Immunol. 2016;76:326–332. doi: 10.1111/aji.12550. PubMed DOI

Kwiatek M., Gęca T., Krzyżanowski A., Malec A., Kwaśniewska A. Peripheral Dendritic Cells and CD4+CD25+Foxp3+ Regulatory T Cells in the First Trimester of Normal Pregnancy and in Women with Recurrent Miscarriage. PLoS ONE. 2015;10:e0124747. doi: 10.1371/journal.pone.0124747. PubMed DOI PMC

Sivridis E., Giatromanolaki A., Agnantis N., Anastasiadis P. Mast cell distribution and density in the normal uterus--metachromatic staining using lectins. Eur. J. Obstet. Gynecol. Reprod. Biol. 2001;98:109–113. doi: 10.1016/S0301-2115(00)00564-9. PubMed DOI

Norrby K. On Connective Tissue Mast Cells as Protectors of Life, Reproduction, and Progeny. Int. J. Mol. Sci. 2024;25:4499. doi: 10.3390/ijms25084499. PubMed DOI PMC

Lampiasi N. Interactions between Macrophages and Mast Cells in the Female Reproductive System. Int. J. Mol. Sci. 2022;23:5414. doi: 10.3390/ijms23105414. PubMed DOI PMC

Derbala Y., Elazzamy H., Bilal M., Reed R., Salazar Garcia M.D., Skariah A., Dambaeva S., Fernandez E., Germain A., Gilman-Sachs A., et al. Mast cell-induced immunopathology in recurrent pregnancy losses. Am J Reprod Immunol. 2019;82:e13128. doi: 10.1111/aji.13128. PubMed DOI

McCallion A., Nasirzadeh Y., Lingegowda H., Miller J.E., Khalaj K., Ahn S., Monsanto S.P., Bidarimath M., Sisnett D.J., Craig A.W., et al. Estrogen mediates inflammatory role of mast cells in endometriosis pathophysiology. Front Immunol. 2022;13:961599. doi: 10.3389/fimmu.2022.961599. PubMed DOI PMC

Dunn T.N., Cope D.I., Tang S., Sirupangi T., Parks S.E., Liao Z., Yuan F., Creighton C.J., Masand R.P., Alpuing Radilla L., et al. Inhibition of CSF1R and KIT With Pexidartinib Reduces Inflammatory Signaling and Cell Viability in Endometriosis. Endocrinology. 2024;165:bqae003. doi: 10.1210/endocr/bqae003. PubMed DOI PMC

Blumenthal R.D., Samoszuk M., Taylor A.P., Brown G., Alisauskas R., Goldenberg D.M. Degranulating eosinophils in human endometriosis. Am. J. Pathol. 2020;156:1581–1588. doi: 10.1016/S0002-9440(10)65030-4. PubMed DOI PMC

Hornung D., Dohrn K., Sotlar K., Greb R.R., Wallwiener D., Kiesel L., Taylor R.N. Localization in tissues and secretion of eotaxin by cells from normal endometrium and endometriosis. J. Clin. Endocrinol. Metab. 2000;85:2604–2608. doi: 10.1210/jc.85.7.2604. PubMed DOI

Naseri S., Rosenberg-Hasson Y., Maecker H.T., Avrutsky M.I., Blumenthal P.D. A cross-sectional study comparing the inflammatory profile of menstrual effluent vs. peripheral blood. Health Sci. Rep. 2023;6:e1038. doi: 10.1002/hsr2.1038. PubMed DOI PMC

Wang X., Jia Y., Li D., Guo X., Zhou Z., Qi M., Wang G., Wang F. The Abundance and Function of Neutrophils in the Endometriosis Systemic and Pelvic Microenvironment. Mediat. Inflamm. 2023;2023:1481489. doi: 10.1155/2023/1481489. PubMed DOI PMC

Hebeda C.B., Savioli A.C., Scharf P., de Paula-Silva M., Gil C.D., Farsky S.H.P., Sandri S. Neutrophil depletion in the pre-implantation phase impairs pregnancy index, placenta and fetus development. Front. Immunol. 2022;13:969336. doi: 10.3389/fimmu.2022.969336. PubMed DOI PMC

Ghafourian M., Abuhamidy A., Karami N. Increase of peripheral blood TCD8+cells in women with recurrent miscarriage. J. Obstet. Gynaecol. 2013;34:36–39. doi: 10.3109/01443615.2013.817980. PubMed DOI

Morita K., Tsuda S., Kobayashi E., Hamana H., Tsuda K., Shima T., Nakashima A., Ushijima A., Kishi H., Saito S. Analysis of TCR Repertoire and PD-1 Expression in Decidual and Peripheral CD8+ T Cells Reveals Distinct Immune Mechanisms in Miscarriage and Preeclampsia. Front. Immunol. 2020;11:1082. doi: 10.3389/fimmu.2020.01082. PubMed DOI PMC

Carbone J., Sarmiento E., Gallego A., Lanio N., Navarro J., Garcia S., Fernández-Cruz E. Peripheral blood T- and B-cell immunophenotypic abnormalities in selected women with unexplained recurrent miscarriage. J. Reprod. Immunol. 2016;113:50–53. doi: 10.1016/j.jri.2015.11.003. PubMed DOI

Huang C., Xiang Z., Zhang Y., Li Y., Xu J., Zhang H., Zeng Y., Tu W. NKG2D as a Cell Surface Marker on γδ-T Cells for Predicting Pregnancy Outcomes in Patients With Unexplained Repeated Implantation Failure. Front. Immunol. 2021;12:631077. doi: 10.3389/fimmu.2021.631077. PubMed DOI PMC

Yu L., Wang L., Wang L., Yan S., Chen S., Xu Q., Su D., Wang X. Identification and validation of immune cells and hub genes alterations in recurrent implantation failure: A GEO data mining study. Front. Genet. 2023;13:1094978. doi: 10.3389/fgene.2022.1094978. PubMed DOI PMC

Wang X., Ma Z., Hong Y., Zhao A., Qiu L., Lu P., Lin Q. The Skewed TCR-BV Repertoire Displayed at the Maternal-Fetal Interface of Women with Unexplained Pregnancy Loss. Am. J. Reprod. Immunol. 2005;54:84–95. doi: 10.1111/j.1600-0897.2005.00291.x. PubMed DOI

Robertson S.A., Care A.S., Moldenhauer L.M. Regulatory T cells in embryo implantation and the immune response to pregnancy. J. Clin. Investig. 2018;128:4224–4235. doi: 10.1172/JCI122182. PubMed DOI PMC

Yang H., Qiu L., Chen G., Ye Z., Lü C., Lin Q. Proportional change of CD4+CD25+ regulatory T cells in decidua and peripheral blood in unexplained recurrent spontaneous abortion patients. Fertil. Steril. 2008;89:656–661. doi: 10.1016/j.fertnstert.2007.03.037. PubMed DOI

Li Q.H., Zhao Q.Y., Yang W.J., Jiang A.F., Ren C.E., Meng Y.H. Beyond Immune Balance: The Pivotal Role of Decidual Regulatory T Cells in Unexplained Recurrent Spontaneous Abortion. J. Inflamm. Res. 2024;17:2697–2710. doi: 10.2147/JIR.S459263. PubMed DOI PMC

Wang W.J., Hao C.F., Qu Q.L., Wang X., Qiu L.H., Lin Q.D. The deregulation of regulatory T cells on interleukin-17-producing T helper cells in patients with unexplained early recurrent miscarriage. Hum. Reprod. 2010;25:2591–2596. doi: 10.1093/humrep/deq198. PubMed DOI

Garmendia J.V., Blanca I., Peña M.J., De Sanctis C.V., De Sanctis J.B. Unlocking the Puzzle: Investigating the Role of Interleukin 17 Genetic Polymorphisms, Circulating Lymphocytes, and Serum Levels in Venezuelan Women with Recurrent Pregnancy Loss. Immuno. 2024;4:301–311. doi: 10.3390/immuno4040019. DOI

Heitmann R.J., Weitzel R.P., Feng Y., Segars J.H., Tisdale J.F., Wolff E.F. Maternal T Regulatory Cell Depletion Impairs Embryo Implantation Which Can Be Corrected With Adoptive T Regulatory Cell Transfer. Reprod. Sci. 2017;24:1014–1024. doi: 10.1177/1933719116675054. PubMed DOI PMC

Granne I., Shen M., Rodriguez-Caro H., Chadha G., O’Donnell E., Brosens J.J., Quenby S., Child T., Southcombe J.H. Characterisation of peri-implantation endometrial Treg and identification of an altered phenotype in recurrent pregnancy loss. Mucosal Immunol. 2022;15:120–129. doi: 10.1038/s41385-021-00451-1. PubMed DOI PMC

Moldenhauer L.M., Foyle K.L., Wilson J.J., Wong Y.Y., Sharkey D.J., Green E.S., Barry S.C., Hull M.L., Robertson S.A. A disrupted FOXP3 transcriptional signature underpins systemic regulatory T cell insufficiency in early pregnancy failure. iScience. 2024;27:108994. doi: 10.1016/j.isci.2024.108994. PubMed DOI PMC

Winger E.E., Reed J.L. 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;66:320–328. doi: 10.1111/j.1600-0897.2011.00992.x. PubMed DOI

Jin L.P., Chen Q.Y., Zhang T., Guo P.F., Li D.J. The CD4+CD25 bright regulatory T cells and CTLA-4 expression in peripheral and decidual lymphocytes are down-regulated in human miscarriage. Clin. Immunol. 2009;133:402–410. doi: 10.1016/j.clim.2009.08.009. PubMed DOI

Tang C., Hu W. The role of Th17 and Treg cells in normal pregnancy and unexplained recurrent spontaneous abortion (URSA): New insights into immune mechanisms. Placenta. 2023;142:18–26. doi: 10.1016/j.placenta.2023.08.065. PubMed DOI

Farshchi M., Abdollahi E., Saghafi N., Hosseini A., Fallahi S., Rostami S., Rostami P., Rafatpanah H., Habibagahi M. Evaluation of Th17 and Treg cytokines in patients with unexplained recurrent pregnancy loss. J. Clin. Transl. Res. 2022;8:256–265. PubMed PMC

Franasiak J.M., Alecsandru D., Forman E.J., Gemmell L.C., Goldberg J.M., Llarena N., Margolis C., Laven J., Schoenmakers S., Seli E. A review of the pathophysiology of recurrent implantation failure. Fertil. Steril. 2021;116:1436–1448. doi: 10.1016/j.fertnstert.2021.09.014. PubMed DOI

Berdiaki A., Vergadi E., Makrygiannakis F., Vrekoussis T., Makrigiannakis A. Repeated implantation failure is associated with increased Th17/Treg cell ratio, during the secretory phase of the human endometrium. J. Reprod. Immunol. 2024;161:104170. doi: 10.1016/j.jri.2023.104170. PubMed DOI

Niafar M., Samaie V., Soltani-Zangbar M.S., Motavalli R., Dolati S., Danaii S., Mehdizadeh A., Yousefi M. The association of Treg and Th17 cells development factors and anti-TPO autoantibodies in patients with recurrent pregnancy loss. BMC Res. Notes. 2023;16:302. doi: 10.1186/s13104-023-06579-6. PubMed DOI PMC

Wang W.J., Salazar Garcia M.D., Deutsch G., Sung N., Yang X., He Q., Jubiz G., Bilal M., Dambaeva S., Gilman-Sachs A., et al. PD-1 and PD-L1 expression on T-cell subsets in women with unexplained recurrent pregnancy losses. Am. J. Reprod. Immunol. 2020;83:e13230. doi: 10.1111/aji.13230. PubMed DOI

Wang W., Sung N., Gilman-Sachs A., Kwak-Kim J. T Helper (Th) Cell Profiles in Pregnancy and Recurrent Pregnancy Losses: Th1/Th2/Th9/Th17/Th22/Tfh Cells. Front. Immunol. 2020;11:2025. doi: 10.3389/fimmu.2020.02025. PubMed DOI PMC

Weng J., Couture C., Girard S. Innate and Adaptive Immune Systems in Physiological and Pathological Pregnancy. Biology. 2023;12:402. doi: 10.3390/biology12030402. PubMed DOI PMC

Muzzio D., Zenclussen A.C., Jensen F. The Role of B Cells in Pregnancy: The Good and the Bad. Am. J. Reprod. Immunol. 2013;69:408–412. doi: 10.1111/aji.12079. PubMed DOI

Eblen A.C., Gercel-Taylor C., Shields L.B.E., Sanfilippo J.S., Nakajima S.T., Taylor D.D. Alterations in humoral immune responses associated with recurrent pregnancy loss. Fertil. Steril. 2000;73:305–313. doi: 10.1016/S0015-0282(99)00505-1. PubMed DOI

Marron K., Walsh D., Harrity C. Detailed endometrial immune assessment of both normal and adverse reproductive outcome populations. J. Assist. Reprod. Genet. 2019;36:199–210. doi: 10.1007/s10815-018-1300-8. PubMed DOI PMC

Vujisić S., Lepej S.Ž., Akšamija A., Jerković L., Sokolić B., Kupešić S., Vince A. B- and T-cells in the Follicular Fluid and Peripheral Blood of Patients Undergoing IVF/ET Procedures. Am. J. Reprod. Immunol. 2004;52:379–385. doi: 10.1111/j.1600-0897.2004.00238.x. PubMed DOI

Liu J.C., Zeng Q., Duan Y.G., Yeung W.S.B., Li R.H.W., Ng E.H.Y., Cheung K.W., Zhang Q., Chiu P.C.N. B cells: Roles in physiology and pathology of pregnancy. Front. Immunol. 2024;15:1456171. doi: 10.3389/fimmu.2024.1456171. PubMed DOI PMC

Danaii S., Ghorbani F., Ahmadi M., Abbaszadeh H., Koushaeian L., Soltani-Zangbar M.S., Mehdizadeh A., Hojjat-Farsangi M., Kafil H.S., Aghebati-Maleki L., et al. IL-10-producing B cells play important role in the pathogenesis of recurrent pregnancy loss. Int. Immunopharmacol. 2020;87:106806. doi: 10.1016/j.intimp.2020.106806. PubMed DOI

Bronte V., Brandau S., Chen S.H., Colombo M.P., Frey A.B., Greten T.F., Mandruzzato S., Murray P.J., Ochoa A., Ostrand-Rosenberg S., et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 2016;7:12150. doi: 10.1038/ncomms12150. PubMed DOI PMC

Ostrand-Rosenberg S., Sinha P., Figley C., Long R., Park D., Carter D., Clements V.K. Frontline Science: Myeloid-derived suppressor cells (MDSCs) facilitate maternal–fetal tolerance in mice. J. Leukoc. Biol. 2016;101:1091–1101. doi: 10.1189/jlb.1HI1016-306RR. PubMed DOI PMC

Köstlin N., Hofstädter K., Ostermeir A.L., Spring B., Leiber A., Haen S., Abele H., Bauer P., Pollheimer J., Hartl D., et al. Granulocytic Myeloid-Derived Suppressor Cells Accumulate in Human Placenta and Polarize toward a Th2 Phenotype. J. Immunol. 2016;196:1132–1145. doi: 10.4049/jimmunol.1500340. PubMed DOI

Bartmann C., Junker M., Segerer S.E., Häusler S.F., Krockenberger M., Kämmerer U. CD33+/HLA-DRnegand CD33+/HLA-DR+/−Cells: Rare Populations in the Human Decidua with Characteristics of MDSC. Am. J. Reprod. Immunol. 2016;75:539–556. doi: 10.1111/aji.12492. PubMed DOI

Pan T., Zhong L., Wu S., Cao Y., Yang Q., Cai Z., Cai X., Zhao W., Ma N., Zhang W., et al. 17β-Oestradiol enhances the expansion and activation of myeloid-derived suppressor cells via signal transducer and activator of transcription (STAT)-3 signalling in human pregnancy. Clin. Exp. Immunol. 2016;185:86–97. doi: 10.1111/cei.12790. PubMed DOI PMC

Li C., Zhang X., Kang X., Chen C., Guo F., Wang Q., Zhao A. Upregulated TRAIL and Reduced DcR2 Mediate Apoptosis of Decidual PMN-MDSC in Unexplained Recurrent Pregnancy Loss. Front. Immunol. 2020;11:1345. doi: 10.3389/fimmu.2020.01345. PubMed DOI PMC

Jiang H., Zhu M., Guo P., Bi K., Lu Z., Li C., Zhai M., Wang K., Cao Y. Impaired myeloid-derived suppressor cells are associated with recurrent implantation failure: A case-control study. J. Reprod. Immunol. 2021;145:103316. doi: 10.1016/j.jri.2021.103316. PubMed DOI

Marin N.S., Fuente-Muñoz E., Gil-Laborda R., Villegas Á., Alonso-Arenilla B., Cristóbal I., Pilar-Suárez L., Jiménez-Huete A., Calvo M., Sarria B., et al. Myeloid-derived suppressor cells as a potential biomarker for recurrent pregnancy loss and recurrent implantation failure. Am. J. Reprod. Immunol. 2023;90:e13783. doi: 10.1111/aji.13783. PubMed DOI

Pantos K., Grigoriadis S., Maziotis E., Pistola K., Xystra P., Pantou A., Kokkali G., Pappas A., Lambropoulou M., Sfakianoudis K., et al. The Role of Interleukins in Recurrent Implantation Failure: A Comprehensive Review of the Literature. Int. J. Mol. Sci. 2022;23:2198. doi: 10.3390/ijms23042198. PubMed DOI PMC

Dong X., Zhou M., Li X., Huang H., Sun Y. Gene profiling reveals the role of inflammation, abnormal uterine muscle contraction and vascularity in recurrent implantation failure. Front. Genet. 2023;14:1108805. doi: 10.3389/fgene.2023.1108805. PubMed DOI PMC

Kalu E., Bhaskaran S., Thum M.Y., Vishwanatha R., Croucher C., Sherriff E., Ford B., Bansal A.S. Serial Estimation of Th1:Th2 Cytokines Profile in Women Undergoing In-Vitro Fertilization-Embryo Transfer. Am. J. Reprod. Immunol. 2008;59:206–211. doi: 10.1111/j.1600-0897.2007.00565.x. PubMed DOI

Piekarska K., Dratwa M., Radwan P., Radwan M., Bogunia-Kubik K., Nowak I. Pro- and anti-inflammatory cytokines and growth factors in patients undergoing in vitro fertilization procedure treated with prednisone. Front. Immunol. 2023;14:1250488. doi: 10.3389/fimmu.2023.1250488. PubMed DOI PMC

Mukherjee N., Sharma R., Modi D. Immune alterations in recurrent implantation failure. Am. J. Reprod. Immunol. 2022;89:e13563. doi: 10.1111/aji.13563. PubMed DOI

Guo L., Guo A., Yang F., Li L., Yan J., Deng X., Dai C., Li Y. Alterations of Cytokine Profiles in Patients With Recurrent Implantation Failure. Front. Endocrinol. 2022;13:949123. doi: 10.3389/fendo.2022.949123. PubMed DOI PMC

Yang X., Tian Y., Zheng L., Luu T., Kwak-Kim J. The Update Immune-Regulatory Role of Pro- and Anti-Inflammatory Cytokines in Recurrent Pregnancy Losses. Int. J. Mol. Sci. 2023;24:132. doi: 10.3390/ijms24010132. PubMed DOI PMC

Kwak-Kim J.Y.H., Chung-Bang H., Ng S., Ntrivalas E., Mangubat C., Beaman K., Beer A., Gilman-Sachs A. 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;18:767–773. doi: 10.1093/humrep/deg156. PubMed DOI

Sereshki N., Gharagozloo M., Ostadi V., Ghahiri A., Roghaei M., Mehrabian F., Andalib A., Hassanzadeh A., Hosseini H., Rezaei A.A. Variations in T-helper 17 and Regulatory T Cells during The Menstrual Cycle in Peripheral Blood of Women with Recurrent Spontaneous Abortion. Int. J. Fertil. Steril. 2014;8:59–66. PubMed PMC

Inagaki N., Stern C., McBain J., Lopata A., Kornman L., Wilkinson D. Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase activity in women with recurrent failed embryo transfer. Hum. Reprod. 2003;18:608–615. doi: 10.1093/humrep/deg139. PubMed DOI

Wang W.J., Zhang H., Chen Z.Q., Zhang W., Liu X.M., Fang J.Y., Liu F.J., Kwak-Kim J. Endometrial TGF-β, IL-10, IL-17 and autophagy are dysregulated in women with recurrent implantation failure with chronic endometritis. Reprod. Biol. Endocrinol. 2019;17:2. doi: 10.1186/s12958-018-0444-9. PubMed DOI PMC

Sheikhansari G., Soltani-Zangbar M.S., Pourmoghadam Z., Kamrani A., Azizi R., Aghebati-Maleki L., Danaii S., Koushaeian L., Hojat-Farsangi M., Yousefi M. Oxidative stress, inflammatory settings, and microRNA regulation in the recurrent implantation failure patients with metabolic syndrome. Am. J. Reprod. Immunol. 2019;82:e13170. doi: 10.1111/aji.13170. PubMed DOI

O’Hern Perfetto C., Fan X., Dahl S., Krieg S.A., Westphal L.M., Lathi R.B., Nayak N.R. Expression of interleukin-22 in decidua of patients with early pregnancy and unexplained recurrent pregnancy loss. J. Assist. Reprod. Genet. 2015;32:977–984. doi: 10.1007/s10815-015-0481-7. PubMed DOI PMC

Wang W.J., Liu F.J., Qu H.M., Hao C.F., Qu Q.L., Bao H.C., Wang X.R. Regulation of the expression of Th17 cells and regulatory T cells by IL-27 in patients with unexplained early recurrent miscarriage. J. Reprod. Immunol. 2013;99:39–45. doi: 10.1016/j.jri.2013.04.002. PubMed DOI

Ma Y., Ma M., Ye S., Liu Y., Zhao X., Wang Y. Association of IL-17 and IL-27 polymorphisms with susceptibility to recurrent pregnancy loss and pre-eclampsia: A systematic review and meta-analysis. Immun. Inflamm. Dis. 2023;11:e1057. doi: 10.1002/iid3.1057. PubMed DOI PMC

Zhao L., Fu J., Ding F., Liu J., Li L., Song Q., Fu Y. IL-33 and Soluble ST2 Are Associated With Recurrent Spontaneous Abortion in Early Pregnancy. Front. Physiol. 2021;12:789829. doi: 10.3389/fphys.2021.789829. PubMed DOI PMC

Yue C., Zhang B., Ying C. Elevated Serum Level of IL-35 Associated with the Maintenance of Maternal-Fetal Immune Tolerance in Normal Pregnancy. PLoS ONE. 2015;10:e0128219. doi: 10.1371/journal.pone.0128219. PubMed DOI PMC

Karaer A., Cigremis Y., Celik E., Urhan Gonullu R. Prokineticin 1 and leukemia inhibitory factor mRNA expression in the endometrium of women with idiopathic recurrent pregnancy loss. Fertil. Steril. 2014;102:1091–1095.e1. doi: 10.1016/j.fertnstert.2014.07.010. PubMed DOI

Raghupathy R., Al-Mutawa E., Al-Azemi M., Makhseed M., Azizieh F., Szekeres-Bartho J. Progesterone-induced blocking factor (PIBF) modulates cytokine production by lymphocytes from women with recurrent miscarriage or preterm delivery. J. Reprod. Immunol. 2009;80:91–99. doi: 10.1016/j.jri.2009.01.004. PubMed DOI

Kashyap N., Begum A., Ray Das C., Datta R., Verma M.K., Dongre A., Husain S.A., Ahmad Khan L., Deka Bose P. Aberrations in the progesterone pathway and the Th1/Th2 cytokine dichotomy—An evaluation of RPL predisposition in the northeast Indian population. Am. Reprod. Immunol. 2023;90:e13745. doi: 10.1111/aji.13745. PubMed DOI

Amjadi F., Zandieh Z., Mehdizadeh M., Aghajanpour S., Raoufi E., Aghamajidi A., Aflatoonian R. The uterine immunological changes may be responsible for repeated implantation failure. J. Reprod. Immunol. 2020;138:103080. doi: 10.1016/j.jri.2020.103080. PubMed DOI

Laitinen T. A Set of MHC Haplotypes Found Among Finnish Couples Suffering From Recurrent Spontaneous Abortions. Am. J. Reprod. Immunol. 1993;29:148–154. doi: 10.1111/j.1600-0897.1993.tb00580.x. PubMed DOI

Hsiao T.W., Chung M.T., Wen J.Y., Lin Y., Lin L.Y., Tsai Y. HLA sharing and maternal HLA expression in couples with recurrent pregnancy loss in Taiwan. Taiwan J. Obstet. Gynecol. 2022;61:854–857. doi: 10.1016/j.tjog.2021.11.039. PubMed DOI

Gharesi-Fard B., Askarinejad-Behbahani R., Behdin S. The effect of HLA-DRB1 sharing between the couples with recurrent pregnancy loss on the pregnancy outcome after leukocyte therapy. Iran. J. Immunol. 2014;11:13–20. PubMed

Wang X.P., Lin Q., Peng L., Ma Z., Zhao A. Association of HLA-DQB1 coding region with unexplained recurrent spontaneous abortion. Chin. Med. J. 2004;117:492–497. PubMed

Ho H.N., Yang Y.S., Hsieh R.P., Lin H.R., Chen S., Huang S., Lee T.Y., Gill T.J. Sharing of human leukocyte antigens in couples with unexplained infertility affects the success of in vitro fertilization and tubal embryo transfer. Am. J. Obstet. Gynecol. 1994;170:63–71. doi: 10.1016/S0002-9378(94)70385-X. PubMed DOI

Weckstein L.N., Patrizio P., Balmaceda J.P., Asch R.H., Branch D.W. Human leukocyte antigen compatibility and failure to achieve a viable pregnancy with assisted reproductive technology. Acta Eur. Fertil. 1991;22:103–107. PubMed

Balasch J., Jové I., Martorell J., Gayà A., Vanrell J.A. Histocompatibility in in vitro fertilization couples. Fertil Steril. 1993;59:456–458. doi: 10.1016/S0015-0282(16)55687-8. PubMed DOI

Hiby S.E., Regan L., Lo W., Farrell L., Carrington M., Moffett A. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum. Reprod. 2008;23:972–976. doi: 10.1093/humrep/den011. PubMed DOI

Hiby S.E., Apps R., Sharkey A.M., Farrell L.E., Gardner L., Mulder A., Claas F.H., Walker J.J., Redman C.W., Morgan L., et al. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J. Clin. Investig. 2010;120:4102–4110. doi: 10.1172/JCI43998. PubMed DOI PMC

Yang X., Meng T. Killer-cell immunoglobulin-like receptor/human leukocyte antigen-C combination and ‘great obstetrical syndromes’ (Review) Exp Ther Med. 2021;22:1178. doi: 10.3892/etm.2021.10612. PubMed DOI PMC

Gil Laborda R., de Frías E.R., Subhi-Issa N., de Albornoz E.C., Meliá E., Órdenes M., Verdú V., Vidal J., Suárez E., Santillán I., et al. Centromeric AA motif in KIR as an optimal surrogate marker for precision definition of alloimmune reproductive failure. Sci. Rep. 2024;14:3354. doi: 10.1038/s41598-024-53766-x. PubMed DOI PMC

Dahl M., Djurisic S., Hviid T.V. The many faces of human leukocyte antigen-G: Relevance to the fate of pregnancy. J. Immunol. Res. 2014;2014:591489. doi: 10.1155/2014/591489. PubMed DOI PMC

Fan W., Huang Z., Li S., Xiao Z. The HLA-G 14-bp polymorphism and recurrent implantation failure: A meta-analysis. J. Assist. Reprod. Genet. 2017;34:1559–1565. doi: 10.1007/s10815-017-0994-3. PubMed DOI PMC

Hu L., He D., Zeng H. Association of parental HLA-G polymorphisms with soluble HLA-G expressions and their roles on recurrent implantation failure: A systematic review and meta-analysis. Front. Immunol. 2022;13:988370. doi: 10.3389/fimmu.2022.988370. PubMed DOI PMC

Nowak I., Wilczyńska K., Radwan P., Wiśniewski A., Krasiński R., Radwan M., Wilczyński J.R., Malinowski A., Kuśnierczyk P. Association of Soluble HLA-G Plasma Level and HLA-G Genetic Polymorphism With Pregnancy Outcome of Patients Undergoing in vitro Fertilization Embryo Transfer. Front. Immunol. 2020;10:2982. doi: 10.3389/fimmu.2019.02982. PubMed DOI PMC

Zych M., Roszczyk A., Kniotek M., Dąbrowski F., Zagożdżon R. Differences in Immune Checkpoints Expression (TIM-3 and PD-1) on T Cells in Women with Recurrent Miscarriages-Preliminary Studies. J. Clin. Med. 2021;10:4182. doi: 10.3390/jcm10184182. PubMed DOI PMC

Zych M., Roszczyk A., Dąbrowski F., Kniotek M., Zagożdżon R. Soluble Forms of Immune Checkpoints and Their Ligands as Potential Biomarkers in the Diagnosis of Recurrent Pregnancy Loss-A Preliminary Study. Int. J. Mol. Sci. 2023;25:499. doi: 10.3390/ijms25010499. PubMed DOI PMC

Esparvarinha M., Madadi S., Aslanian-Kalkhoran L., Nickho H., Dolati S., Pia H., Danaii S., Taghavi S., Yousefi M. Dominant immune cells in pregnancy and pregnancy complications: T helper cells (TH1/TH2, TH17/Treg cells), NK cells, MDSCs, and the immune checkpoints. Cell Biol. Int. 2023;47:507–519. doi: 10.1002/cbin.11955. PubMed DOI

Qian C., Pan C., Liu J., Wu L., Pan J., Liu C., Zhang H. Differential expression of immune checkpoints (OX40/OX40L and PD-1/PD-L1) in decidua of unexplained recurrent spontaneous abortion women. Hum. Immunol. 2024;85:110745. doi: 10.1016/j.humimm.2023.110745. PubMed DOI

Zych M., Kniotek M., Roszczyk A., Dąbrowski F., Jędra R., Zagożdżon R. Surface Immune Checkpoints as Potential Biomarkers in Physiological Pregnancy and Recurrent Pregnancy Loss. Int. J. Mol. Sci. 2024;25:9378. doi: 10.3390/ijms25179378. PubMed DOI PMC

Opatrny L., David M., Kahn S.R., Shrier I., Rey E. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: A metaanalysis. J. Rheumatol. 2006;33:2214–2221. PubMed

Thangaratinam S., Tan A., Knox E., Kilby M.D., Franklyn J., Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: Metaanalysis of evidence. BMJ. 2011;342:1–8. doi: 10.1136/bmj.d2616. PubMed DOI PMC

Cavalcante M.B., Cavalgante C.T., Sarno M., Da Silva A., Barini R. Antinuclear antibodies and recurrent miscarriage: Systematic review and meta-analysis. Am. J. Reprod. Immunol. 2020;83:13215. doi: 10.1111/aji.13215. PubMed DOI

Chen S., Yang G., Wu P., Sun Y., Dai F., He Y., Qian H., Liu Y., Shi G. Antinuclear antibodies positivity is a risk factor of recurrent pregnancy loss: A meta-analysis. Semin. Arthritis Rheum. 2020;50:534–543. doi: 10.1016/j.semarthrit.2020.03.016. PubMed DOI

Alijotas-Reig J., Esteve-Valverde E., Ferrer-Oliveras R., Llurba E., Gris J.M. Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review. Clin. Rev. Allergy Immunol. 2017;53:40–53. doi: 10.1007/s12016-016-8596-x. PubMed DOI

Lockwood C.J., Romero R., Feinberg R.F., Clyne L.P., Coster B., Hobbins J.C. The prevalence and biologic significance of lupus anticoagulant and antic ardiolipin antibodies in a general obstetric population. Am. J. Obstet. Gynecol. 1989;161:369–373. doi: 10.1016/0002-9378(89)90522-X. PubMed DOI

Bahar A.M., Kwak J.Y.H., Beer A.E., Kim J.H., Nelson L.A., Beaman K.D., Gilman-Sachs A. Antibodies to phospholipids and nuclear antigens in non-pregnant women with unexplained spontaneous recurrent abortions. J. Reprod. Immunol. 1993;24:213–222. doi: 10.1016/0165-0378(93)90076-T. PubMed DOI

Kwak J.Y.H., Beer A.E., Cubillos J., Muñoz Sandoval P., Mendoza J., Espinel F. Biological Basis of Fetoplacental Antigenic Determinants in the Induction of the Antiphospholipid Antibody Syndrome and Recurrent Pregnancy Loss. Ann. N. Y. Acad. Sci. 1994;731:242–245. doi: 10.1111/j.1749-6632.1994.tb55776.x. PubMed DOI

Rai R.S., Regan L., Clifford K., Pickering W., Dave M., Mackie I., McNally T., Cohen H. Immunology: Antiphospholipid antibodies and β2-glycoprotein-I in 500 women with recurrent miscarriage: Results of a comprehensive screening approach. Hum. Reprod. 1995;10:2001–2005. doi: 10.1093/oxfordjournals.humrep.a136224. PubMed DOI

Del Porto F., Ferrero S., Cifani N., Sesti G., Proietta M. Antiphospholipid antibodies and idiopathic infertility. Lupus. 2022;31:347–353. doi: 10.1177/09612033221076735. PubMed DOI

D’Ippolito S., Ticconi C., Tersigni C., Garofalo S., Martino C., Lanzone A., Scambia G., Di Simone N. The pathogenic role of autoantibodies in recurrent pregnancy loss. Am. J. Reprod. Immunol. 2019;83:e13200. doi: 10.1111/aji.13200. PubMed DOI

Gibbins K.J., Mumford S.L., Sjaarda L.A., Branch D.W., Perkins N.J., Ye A., Schisterman E.F., Silver R.M. Preconception antiphospholipid antibodies and risk of subsequent early pregnancy loss. Lupus. 2018;27:1437–1445. doi: 10.1177/0961203318776089. PubMed DOI PMC

Papadimitriou E., Boutzios G., Mathioudakis A.G., Vlahos N.F., Vlachoyiannopoulos P., Mastorakos G. Presence of antiphospholipid antibodies is associated with increased implantation failure following in vitro fertilization technique and embryo transfer: A systematic review and meta-analysis. PLoS ONE. 2022;17:e0260759. doi: 10.1371/journal.pone.0260759. PubMed DOI PMC

Jarne-Borràs M., Miró-Mur F., Anunciación-Llunell A., Alijotas-Reig J. Antiphospholipid antibodies in women with recurrent embryo implantation failure: A systematic review and meta-analysis. Autoimmun. Rev. 2022;21:103101. doi: 10.1016/j.autrev.2022.103101. PubMed DOI

Tan X.F., Xu L., Li T.T., Wu Y.T., Ma W.W., Ding J.Y., Dong H.L. Serum antiphospholipid antibody status may not be associated with the pregnancy outcomes of patients undergoing in vitro fertilization. Medicine. 2022;101:e29146. doi: 10.1097/MD.0000000000029146. PubMed DOI PMC

Tan X., Ding J., Pu D., Wu J. Anti-phospholipid antibody may reduce endometrial receptivity during the window of embryo implantation. J. Gynecol. Obstet. Hum. Reprod. 2021;50:101912. doi: 10.1016/j.jogoh.2020.101912. PubMed DOI

Matalon S.T., Blank M.B., Ornoy A., Shoenfeld Y. The Association Between Anti-Thyroid Antibodies and Pregnancy Loss. Am. J. Reprod. Immunol. Microbiol. 2001;45:72–77. doi: 10.1111/j.8755-8920.2001.450202.x. PubMed DOI

Valeff N.J., Ventimiglia M.S., Diao L., Jensen F. Lupus and recurrent pregnancy loss: The role of female sex hormones and B cells. Front. Endocrinol. 2023;14:1233883. doi: 10.3389/fendo.2023.1233883. PubMed DOI PMC

Gao R., Zeng X., Qin L. Systemic autoimmune diseases and recurrent pregnancy loss: Research progress in diagnosis and treatment. Chin. Med. J. 2021;134:2140–2142. doi: 10.1097/CM9.0000000000001691. PubMed DOI PMC

Mankee A., Petri M., Magder L.S. Lupus anticoagulant, disease activity and low complement in the first trimester are predictive of pregnancy loss. Lupus Sci. Med. 2015;2:e000095. doi: 10.1136/lupus-2015-000095. PubMed DOI PMC

Ticconi C., Inversetti A., Logruosso E., Ghio M., Casadei L., Selmi C., Di Simone N. Antinuclear antibodies positivity in women in reproductive age: From infertility to adverse obstetrical outcomes—A meta-analysis. J. Reprod. Immunol. 2023;155:103794. doi: 10.1016/j.jri.2022.103794. PubMed DOI

Hardy C.J., Palmer B.P., Morton S.J., Muir K.R., Powell R.J. Pregnancy outcome and family size in systemic lupus erythematosus: A case-control study. Rheumatology. 1999;38:559–563. doi: 10.1093/rheumatology/38.6.559. PubMed DOI

Singh M., Fayaz F.F.A., Wang J., Wambua S., Subramanian A., Reynolds J.A., Nirantharakumar K., Crowe F., MuM-PreDiCT Pregnancy complications and autoimmune diseases in women: Systematic review and meta-analysis. BMC Med. 2024;22:339. doi: 10.1186/s12916-024-03550-5. PubMed DOI PMC

Motak-Pochrzest H., Malinowski A. Does autoimmunity play a role in the risk of implantation failures? Neuro Endocrinol. Lett. 2018;38:575–578. PubMed

Salmeri N., Gennarelli G., Vanni V.S., Ferrari S., Ruffa A., Rovere-Querini P., Pagliardini L., Candiani M., Papaleo E. Concomitant Autoimmunity in Endometriosis Impairs Endometrium-Embryo Crosstalk at the Implantation Site: A Multicenter Case-Control Study. J. Clin. Med. 2023;12:3557. doi: 10.3390/jcm12103557. PubMed DOI PMC

Ballester C., Grobost V., Roblot P., Pourrat O., Pierre F., Laurichesse-Delmas H., Gallot D., Aubard Y., Bezanahary H., Fauchais A.L. Pregnancy and primary Sjögren’s syndrome: Management and outcomes in a multicentre retrospective study of 54 pregnancies. Scand. J. Rheumatol. 2017;46:56–63. doi: 10.3109/03009742.2016.1158312. PubMed DOI

Gupta S., Gupta N. Sjögren Syndrome and Pregnancy: A Literature Review. Perm J. 2017;21:16-047. doi: 10.7812/TPP/16-047. PubMed DOI PMC

Imbroane M.R., LeMoine F., Gibson K.S. Autoimmune Condition Diagnosis Following Recurrent Pregnancy Loss. Am. J. Reprod. Immunol. 2024;92:e70006. doi: 10.1111/aji.70006. PubMed DOI

Masucci L., D’Ippolito S., De Maio F., Quaranta G., Mazzarella R., Bianco D.M., Castellani R., Inversetti A., Sanguinetti M., Gasbarrini A., et al. Celiac Disease Predisposition and Genital Tract Microbiota in Women Affected by Recurrent Pregnancy Loss. Nutrients. 2023;15:221. doi: 10.3390/nu15010221. PubMed DOI PMC

Arvanitakis K., Siargkas A., Germanidis G., Dagklis T., Tsakiridis I. Adverse pregnancy outcomes in women with celiac disease: A systematic review and meta-analysis. Ann. Gastroenterol. 2023;36:12–24. doi: 10.20524/aog.2022.0764. PubMed DOI PMC

Tersigni C., Castellani R., de Waure C., Fattorossi A., De Spirito M., Gasbarrini A., Scambia G., Di Simone N. Celiac disease and reproductive disorders: Meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum. Reprod. Update. 2014;20:582–593. doi: 10.1093/humupd/dmu007. PubMed DOI

Saccone G., Berghella V., Sarno L., Maruotti G.M., Cetin I., Greco L., Khashan A.S., McCarthy F., Martinelli D., Fortunato F., et al. Celiac disease and obstetric complications: A systematic review and meta-analysis. Am. J. Obstet. Gynecol. 2016;214:225–234. doi: 10.1016/j.ajog.2015.09.080. PubMed DOI

Di Simone N., Silano M., Castellani R., Di Nicuolo F., D’Alessio M.C., Franceschi F., Tritarelli A., Leone A.M., Tersigni C., Gasbarrini G., et al. Anti-tissue transglutaminase antibodies from celiac patients are responsible for trophoblast damage via apoptosis in vitro. Am. J. Gastroenterol. 2010;105:2254–2261. doi: 10.1038/ajg.2010.233. PubMed DOI

Di Simone N., De Spirito M., Di Nicuolo F., Tersigni C., Castellani R., Silano M., Maulucci G., Papi M., Marana R., Scambia G., et al. Potential new mechanisms of placental damage in celiac disease: Anti-transglutaminase antibodies impair human endometrial angiogenesis. Biol. Reprod. 2013;89:88. doi: 10.1095/biolreprod.113.109637. PubMed DOI

D’Ippolito S., Gasbarrini A., Castellani R., Rocchetti S., Sisti L.G., Scambia G., Di Simone N. Human leukocyte antigen (HLA) DQ2/DQ8 prevalence in recurrent pregnancy loss women. Autoimmun. Rev. 2016;15:638–643. doi: 10.1016/j.autrev.2016.02.009. PubMed DOI

Królik M., Wrześniak M., Jezela-Stanek A. Possible effect of the HLA-DQ2/DQ8 polymorphism on autoimmune parameters and lymphocyte subpopulation in recurrent pregnancy losses. J. Reprod. Immunol. 2022;149:103467. doi: 10.1016/j.jri.2021.103467. PubMed DOI

Huang C., Liang P., Diao L., Liu C., Chen X., Li G., Chen C., Zeng Y. Thyroid Autoimmunity is Associated with Decreased Cytotoxicity T Cells in Women with Repeated Implantation Failure. Int. J. Environ. Res. Public Health. 2015;12:10352–10361. doi: 10.3390/ijerph120910352. PubMed DOI PMC

Huisman P., Krogh J., Nielsen C.H., Nielsen H.S., Feldt-Rasmussen U., Bliddal S. Thyroglobulin antibodies in women with recurrent pregnancy loss: A Systematic Review and Meta-Analysis. Thyroid. 2023;33:1287–1301. doi: 10.1089/thy.2023.0292. PubMed DOI

Zhong Y., Ying Y., Wu H., Zhou C., Xu Y., Wang Q., Li J., Shen X., Jin L. Relationship between Antithyroid Antibody and Pregnancy Outcome following in Vitro Fertilization and Embryo Transfer. Int. J. Med. Sci. 2012;9:121–125. doi: 10.7150/ijms.3467. PubMed DOI PMC

Abdolmohammadi-Vahid S., Danaii S., Hamdi K., Jadidi-Niaragh F., Ahmadi M., Yousefi M. Novel immunotherapeutic approaches for treatment of infertility. Biomed. Pharmacother. 2016;84:1449–1459. doi: 10.1016/j.biopha.2016.10.062. PubMed DOI

Stewart-Akers A.M., Krasnow J.S., Brekosky J., Deloia J.A. Endometrial Leukocytes Are Altered Numerically and Functionally in Women with Implantation Defects. Am. J. Reprod. Immunol. 1998;39:1–11. doi: 10.1111/j.1600-0897.1998.tb00326.x. PubMed DOI

Dhillon-Smith R.K., Middleton L.J., Sunner K.K., Cheed V., Baker K., Farrell-Carver S., Bender-Atik R., Agrawal R., Bhatia K., Edi-Osagie E., et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. N. Engl. J. Med. 2019;380:1316–1325. doi: 10.1056/NEJMoa1812537. PubMed DOI

van Dijk M.M., Vissenberg R., Fliers E., van der Post J.A.M., van der Hoorn M.P., de Weerd S., Kuchenbecker W.K., Hoek A., Sikkema J.M., Verhoeve H.R., et al. Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10:322–329. doi: 10.1016/S2213-8587(22)00045-6. PubMed DOI

Leng T., Li X., Zhang H. Levothyroxine treatment for subclinical hypothyroidism improves the rate of live births in pregnant women with recurrent pregnancy loss: A randomized clinical trial. Gynecol. Endocrinol. 2022;38:488–494. doi: 10.1080/09513590.2022.2063831. PubMed DOI

Rao M., Zeng Z., Zhao S., Tang L. Effect of levothyroxine supplementation on pregnancy outcomes in women with subclinical hypothyroidism and thyroid autoimmunity undergoing in vitro fertilization/intracytoplasmic sperm injection: An updated meta-analysis of randomized controlled trials. Reprod. Biol. Endocrinol. 2018;16:92. doi: 10.1186/s12958-018-0410-6. PubMed DOI PMC

Yu M., Long Y., Wang Y., Zhang R., Tao L. Effect of levothyroxine on the pregnancy outcomes in recurrent pregnancy loss women with subclinical hypothyroidism and thyroperoxidase antibody positivity: A systematic review and meta-analysis. J. Matern.-Fetal Neonatal Med. 2023;36:2233039. doi: 10.1080/14767058.2023.2233039. PubMed DOI

[(accessed on 19 January 2025)]. Available online: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Recurrent-pregnancy-loss.

Gaál Z. Role of microRNAs in Immune Regulation with Translational and Clinical Applications. Int. J. Mol. Sci. 2024;25:1942. doi: 10.3390/ijms25031942. PubMed DOI PMC

Dong J., Warner L.M., Lin L.L., Chen M.C., O’Connell R.M., Lu L.F. miR-155 promotes T reg cell development by safeguarding medullary thymic epithelial cell maturation. J. Exp. Med. 2021;218:e20192423. doi: 10.1084/jem.20192423. PubMed DOI PMC

Zolfaghari M.A., Motavalli R., Soltani-Zangbar M.S., Parhizkar F., Danaii S., Aghebati-Maleki L., Noori M., Dolati S., Ahmadi M., Samadi Kafil H., et al. A new approach to the preeclampsia puzzle; MicroRNA-326 in CD4+ lymphocytes might be as a potential suspect. J. Reprod. Immunol. 2021;145:103317. doi: 10.1016/j.jri.2021.103317. PubMed DOI

Winger E.E., Reed J.L., Ji X. First-trimester maternal cell microRNA is a superior pregnancy marker to immunological testing for predicting adverse pregnancy outcome. J. Reprod. Immunol. 2015;110:22–35. doi: 10.1016/j.jri.2015.03.005. PubMed DOI

Patronia M.M., Potiris A., Mavrogianni D., Drakaki E., Karampitsakos T., Machairoudias P., Topis S., Zikopoulos A., Vrachnis D., Moustakli E., et al. The Expression of microRNAs and Their Involvement in Recurrent Pregnancy Loss. J. Clin. Med. 2024;13:3361. doi: 10.3390/jcm13123361. PubMed DOI PMC

Xu N., Zhou X., Shi W., Ye M., Cao X., Chen S., Xu C. Integrative analysis of circulating microRNAs and the placental transcriptome in recurrent pregnancy loss. Front. Physiol. 2022;13:893744. doi: 10.3389/fphys.2022.893744. PubMed DOI PMC

Wang X., Li B., Wang J., Lei J., Liu C., Ma Y., Zhao H. Evidence that miR-133a causes recurrent spontaneous abortion by reducing HLA-G expression. Reprod. Biomed. Online. 2012;25:415–424. doi: 10.1016/j.rbmo.2012.06.022. PubMed DOI

Li L., Feng T., Zhou W., Liu Y., Li H. miRNAs in decidual NK cells: Regulators worthy of attention during pregnancy. Reprod. Biol. Endocrinol. 2021;19:150. doi: 10.1186/s12958-021-00812-2. PubMed DOI PMC

Guo C., Yin X., Yao S. The effect of MicroRNAs variants on idiopathic recurrent pregnancy loss. J. Assist. Reprod. Genet. 2023;40:1589–1595. doi: 10.1007/s10815-023-02827-7. PubMed DOI PMC

Thapliyal A., Tomar A.K., Naglot S., Dhiman S., Datta S.K., Sharma J.B., Singh N., Yadav S. Exploring Differentially Expressed Sperm miRNAs in Idiopathic Recurrent Pregnancy Loss and Their Association with Early Embryonic Development. Noncoding RNA. 2024;10:41. doi: 10.3390/ncrna10040041. PubMed DOI PMC

Odendaal J., Black N., Bennett P.R., Brosens J., Quenby S., MacIntyre D.A. The endometrial microbiota and early pregnancy loss. Hum. Reprod. 2024;39:638–646. doi: 10.1093/humrep/dead274. PubMed DOI PMC

Gao X., Louwers Y.V., Laven E., Schoenmakers S. Clinical Relevance of Vaginal and Endometrial Microbiome Investigation in Women with Repeated Implantation Failure and Recurrent Pregnancy Loss. Int. J. Mol. Sci. 2024;25:622. doi: 10.3390/ijms25010622. PubMed DOI PMC

Soyer Caliskan C., Yurtcu N., Celik S., Sezer O., Kilic S.S., Cetin A. Derangements of vaginal and cervical canal microbiota determined with real-time PCR in women with recurrent miscarriages. J. Obstet. Gynaecol. 2022;42:2105–2114. doi: 10.1080/01443615.2022.2033183. PubMed DOI

Al-Memar M., Bobdiwala S., Fourie H., Mannino R., Lee Y.S., Smith A., Marchesi J.R., Timmerman D., Bourne T., Bennett P.R., et al. The association between vaginal bacterial composition and miscarriage: A nested case-control study. BJOG. 2020;127:264–274. doi: 10.1111/1471-0528.15972. PubMed DOI PMC

Grewal K., Lee Y.S., Smith A., Brosens J.J., Bourne T., Al-Memar M., Kundu S., MacIntyre D.A., Bennett P.R. Chromosomally normal miscarriage is associated with vaginal dysbiosis and local inflammation. BMC Med. 2022;20:38. doi: 10.1186/s12916-021-02227-7. PubMed DOI PMC

Peuranpää P., Holster T., Saqib S., Kalliala I., Tiitinen A., Salonen A., Hautamäki H. Female reproductive tract microbiota and recurrent pregnancy loss: A nested case-control study. Reprod. BioMed. Online. 2022;45:1021–1031. doi: 10.1016/j.rbmo.2022.06.008. PubMed DOI

Vomstein K., Reider S., Böttcher B., Watschinger C., Kyvelidou C., Tilg H., Moschen A.R., Toth B. Uterine microbiota plasticity during the menstrual cycle: Differences between healthy controls and patients with recurrent miscarriage or implantation failure. J. Reprod. Immunol. 2022;151:103634. doi: 10.1016/j.jri.2022.103634. PubMed DOI

Moreno I., Garcia-Grau I., Perez-Villaroya D., Gonzalez-Monfort M., Bahçeci M., Barrionuevo M.J., Taguchi S., Puente E., Dimattina M., Lim M.W., et al. Endometrial microbiota composition is associated with reproductive outcome in infertile patients. Microbiome. 2022;10:1. doi: 10.1186/s40168-021-01184-w. PubMed DOI PMC

Shi Y., Yamada H., Sasagawa Y., Tanimura K., Deguchi M. Uterine endometrium microbiota and pregnancy outcome in women with recurrent pregnancy loss. J. Reprod. Immunol. 2022;152:103653. doi: 10.1016/j.jri.2022.103653. PubMed DOI

Wang L., Chen J., He L., Liu H., Liu Y., Luan Z., Li H., Liu W., Luo M. Association between the vaginal and uterine microbiota and the risk of early embryonic arrest. Front. Microbiol. 2023;14:1137869. doi: 10.3389/fmicb.2023.1137869. PubMed DOI PMC

[(accessed on 19 January 2025)]. Available online: https://www.asrm.org/practice-guidance/practice-committee-documents/evaluation-and-treatment-of-recurrent-pregnancy-loss-a-committee-opinion-2012.

Quenby S., Kalumbi C., Bates M., Farquharson R., Vince G. Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Fertil. Steril. 2005;84:980–984. doi: 10.1016/j.fertnstert.2005.05.012. PubMed DOI

Gomaa M.F., Elkholy A.G., El-Said M.M., Abdel-Salam N.E. Combined oral prednisolone and heparin versus heparin: The effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Arch. Gynecol. Obstet. 2014;290:757–762. doi: 10.1007/s00404-014-3262-0. PubMed DOI PMC

Rezayat F., Esmaeil N., Rezaei A., Sherkat R. Contradictory Effect of Lymphocyte Therapy and Prednisolone Therapy on CD3+CD8+CD56+ Natural Killer T Population in Women with Recurrent Spontaneous Abortion. J. Hum. Reprod. Sci. 2023;16:246. doi: 10.4103/jhrs.jhrs_8_23. PubMed DOI PMC

Tang A.W., Alfirevic Z., Turner M.A., Drury J.A., Small R., Quenby S. A feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant. Hum. Reprod. 2013;28:1743–1752. doi: 10.1093/humrep/det117. PubMed DOI

Boomsma C.M., Kamath M.S., Keay S.D., Macklon N.S. Peri-implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane Database Syst. Rev. 2022;6:CD005996. doi: 10.1002/14651858.CD005996. PubMed DOI PMC

Cooper S., Laird S.M., Mariee N., Li T.C., Metwally M. The effect of prednisolone on endometrial uterine NK cell concentrations and pregnancy outcome in women with reproductive failure. A retrospective cohort study. J. Reprod. Immunol. 2019;131:1–6. doi: 10.1016/j.jri.2018.10.001. PubMed DOI

Dan S., Wei W., Yichao S., Hongbo C., Shenmin Y., Jiaxiong W., Hong L. Effect of Prednisolone Administration on Patients with Unexplained Recurrent Miscarriage and in Routine Intracytoplasmic Sperm Injection: A Meta-Analysis. Am. J. Reprod. Immunol. 2015;74:89–97. doi: 10.1111/aji.12373. PubMed DOI

He Y., Tang R., Yu H., Mu H., Jin H., Dong J., Wang W., Wang L., Chen S., Wang X. Comparative effectiveness and safety of 36 therapies or interventions for pregnancy outcomes with recurrent implantation failure: A systematic review and network meta-analysis. J. Assist. Reprod. Genet. 2023;40:2343–2356. doi: 10.1007/s10815-023-02923-8. PubMed DOI PMC

Huang Q., Wu H., Li M., Yang Y., Fu X. Prednisone improves pregnancy outcome in repeated implantation failure by enhance regulatory T cells bias. J. Reprod. Immunol. 2021;143:103245. doi: 10.1016/j.jri.2020.103245. PubMed DOI

Hasegawa I., Yamanoto Y., Suzuki M., Murakawa H., Kurabayashi T., Takakuwa K., Tanaka K. Prednisolone plus low-dose aspirin improves the implantation rate in women with autoimmune conditions who are undergoing in vitro fertilization. Fertil. Steril. 1998;70:1044–1048. doi: 10.1016/S0015-0282(98)00343-4. PubMed DOI

Fan J., Zhong Y., Chen C. Combined treatment of prednisone and aspirin, starting before ovulation induction, may improve reproductive outcomes in ANA-positive patients. Am. J. Reprod. Immunol. 2016;76:391–395. doi: 10.1111/aji.12559. PubMed DOI

Ando T., Suganuma N., Furuhashi M., Asada Y., Kondo I., Tsutsumi Y. Successful glucocorticoid treatment for patients with abnormal autoimmunity on in vitro fertilization and embryo transfer. J. Assist. Reprod. Genet. 1996;13:776–781. doi: 10.1007/BF02066497. PubMed DOI

Sun Y., Cui L., Lu Y., Tan J., Dong X., Ni T., Yan J., Guan Y., Hao G., Liu J.Y., et al. Prednisone vs Placebo and Live Birth in Patients With Recurrent Implantation Failure Undergoing In Vitro Fertilization. JAMA. 2023;329:1460. doi: 10.1001/jama.2023.5302. PubMed DOI PMC

Bramham K., Thomas M., Nelson-Piercy C., Khamashta M., Hunt B.J. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117:6948–6951. doi: 10.1182/blood-2011-02-339234. PubMed DOI

Riancho-Zarrabeitia L., Lopez-Marin L., Cacho P.M., López-Hoyos M., Barrio R.D., Haya A., Martínez-Taboada V.M. Treatment with low-dose prednisone in refractory obstetric antiphospholipid syndrome: A retrospective cohort study and meta-analysis. Lupus. 2022;31:808–819. doi: 10.1177/09612033221091401. PubMed DOI

Forges T., Monnier-Barbarino P., Guillet-May F., Faure G.C., Béné M.C. Corticosteroids in patients with antiovarian antibodies undergoing in vitro fertilization: A prospective pilot study. Eur. J. Clin. Pharmacol. 2006;62:699–705. doi: 10.1007/s00228-006-0169-0. PubMed DOI

Bandoli G., Palmsten K., Forbess Smith C.J., Chambers C.D. A review of systemic corticosteroid use in pregnancy and the risk of select pregnancy and birth outcomes. Rheum. Dis. Clin. N. Am. 2017;43:489–502. doi: 10.1016/j.rdc.2017.04.013. PubMed DOI PMC

Hooper A., Bacal V., Bedaiwy M.A. Does adding hydroxychloroquine to empiric treatment improve the live birth rate in refractory obstetrical antiphospholipid syndrome? A systematic review. Am. J. Reprod. Immunol. 2023;90:e13761. doi: 10.1111/aji.13761. PubMed DOI

Mekinian A., Lazzaroni M.G., Kuzenko A., Alijotas-Reig J., Ruffatti A., Levy P., Canti V., Bremme K., Bezanahary H., Bertero T., et al. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: Data from a European multicenter retrospective study. Autoimmun. Rev. 2015;14:498–502. doi: 10.1016/j.autrev.2015.01.012. PubMed DOI

Mekinian A., Alijotas-Reig J., Carrat F., Costedoat-Chalumeau N., Ruffatti A., Lazzaroni M.G., Tabacco S., Maina A., Masseau A., Morel N., et al. Refractory obstetrical antiphospholipid syndrome: Features, treatment and outcome in a European multicenter retrospective study. Autoimmun. Rev. 2017;16:730–734. doi: 10.1016/j.autrev.2017.05.006. PubMed DOI

Ye S.L., Gu X.K., Tao L.Y., Cong J.M., Wang Y.Q. Efficacy of Different Treatment Regimens for Antiphospholipid Syndrome-related Recurrent Spontaneous Abortion. Chin. Med. J. 2017;130:1395–1399. doi: 10.4103/0366-6999.207471. PubMed DOI PMC

Gerde M., Ibarra E., Mac Kenzie R., Fernandez Suarez C., Heer C., Alvarez R., Iglesias M., Balparda J., Beruti E., Rubinstein F. The impact of hydroxychloroquine on obstetric outcomes in refractory obstetric antiphospholipid syndrome. Thromb. Res. 2021;206:104–110. doi: 10.1016/j.thromres.2021.08.004. PubMed DOI

Ruffatti A., Tonello M., Hoxha A., Sciascia S., Cuadrado M.J., Latino J.O., Udry S., Reshetnyak T., Costedoat-Chalumeau N., Morel N., et al. Effect of Additional Treatments Combined with Conventional Therapies in Pregnant Patients with High-Risk Antiphospholipid Syndrome: A Multicentre Study. Thromb. Haemost. 2018;47:639–646. doi: 10.1055/s-0038-1632388. PubMed DOI

Sciascia S., Hunt B.J., Talavera-Garcia E., Lliso G., Khamashta M.A., Cuadrado M.J. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am. J. Obstet. Gynecol. 2016;214:273.e1–273.e8. doi: 10.1016/j.ajog.2015.09.078. PubMed DOI

Sadeghpour S., Ghasemnejad Berenji M., Nazarian H., Ghasemnejad T., Nematollahi M.H., Abroon S., Paktinat S., Heidari Khoei H., Ghasemnejad Berenji H., Ghaffari Novin M. Effects of treatment with hydroxychloroquine on the modulation of Th17/Treg ratio and pregnancy outcomes in women with recurrent implantation failure: Clinical trial. Immunopharmacol. Immunotoxicol. 2020;42:632–642. doi: 10.1080/08923973.2020.1835951. PubMed DOI

Dernoncourt A., Hedhli K., Abisror N., Cheloufi M., Cohen J., Kolanska K., McAvoy C., Selleret L., Ballot E., Mathieu d’Argent E., et al. Hydroxychloroquine in recurrent pregnancy loss: Data from a French prospective multicenter registry. Hum. Reprod. 2024;39:1934–1941. doi: 10.1093/humrep/deae146. PubMed DOI PMC

Halloran P.F. Molecular mechanisms of new immunosuppressants. Clin. Transplant. 1996;10:118–123. doi: 10.1111/j.1399-0012.1996.tb00657.x. PubMed DOI

Saad A.F., Pacheco L.D., Saade G.R. Immunosuppressant Medications in Pregnancy. Obstet. Gynecol. 2024;143:e94–e106. doi: 10.1097/AOG.0000000000005512. PubMed DOI

Cavalcante M.B., Tavares A.C.M., Rocha C.A., de Souza G.F., Lima E.M., Simões J.M.L., de Souza L.C., Martins M.Y.M., de Araújo N.O., Barini R. Calcineurin inhibitors in the management of recurrent miscarriage and recurrent implantation failure: Systematic review and meta-analysis. J. Reprod. Immunol. 2023;160:104157. doi: 10.1016/j.jri.2023.104157. PubMed DOI

Nakagawa K., Sugiyama R. Tacrolimus treatment in women with repeated implantation failures. Reprod. Med. Biol. 2024;23:e12558. doi: 10.1002/rmb2.12558. PubMed DOI PMC

Ling Y., Huang Y., Chen C., Mao J., Zhang H. Low dose Cyclosporin A treatment increases live birth rate of unexplained recurrent abortion—Initial cohort study. Clin. Exp. Obstet. Gynecol. 2017;44:230–235. doi: 10.12891/ceog3375.2017. PubMed DOI

Azizi R., Ahmadi M., Danaii S., Abdollahi-Fard S., Mosapour P., Eghbal-Fard S., Dolati S., Kamrani A., Rahnama B., Mehdizadeh A., et al. Cyclosporine A improves pregnancy outcomes in women with recurrent pregnancy loss and elevated Th1/Th2 ratio. J. Cell. Physiol. 2019;234:19039–19047. doi: 10.1002/jcp.28543. PubMed DOI

Fu J.H. Analysis of the use of cyclosporin A to treat refractory immune recurrent spontaneous abortion. Clin. Exp. Obstet. Gynecol. 2015;42:739–742. doi: 10.12891/ceog2006.2015. PubMed DOI

Qu D., Tian X., Ding L., Li Y., Zhou W. Impacts of Cyclosporin A on clinical pregnancy outcomes of patients with a history of unexplained transfer failure: A retrospective cohort study. Reprod. Biol Endocrinol. 2021;19:44. doi: 10.1186/s12958-021-00728-x. PubMed DOI PMC

Liu J., Li M., Fu J., Yuan G., Li N., Fu Y., Zhao L. Tacrolimus improved the pregnancy outcomes of patients with refractory recurrent spontaneous abortion and immune bias disorders: A randomized controlled trial. Eur. J. Clin. Pharmacol. 2023;79:627–634. doi: 10.1007/s00228-023-03473-9. PubMed DOI

Kuroda K., Ikemoto Y., Horikawa T., Moriyama A., Ojiro Y., Takamizawa S., Uchida T., Nojiri S., Nakagawa K., Sugiyama R. Novel approaches to the management of recurrent pregnancy loss: The OPTIMUM (OPtimization of Thyroid function, Thrombophilia, Immunity, and Uterine Milieu) treatment strategy. Reprod. Med. Biol. 2021;20:524–536. doi: 10.1002/rmb2.12412. PubMed DOI PMC

Nakagawa K., Kuroda K., Sugiyama R., Yamaguchi K. After 12 consecutive miscarriages, a patient received immunosuppressive treatment and delivered an intact baby. Reprod. Med. Biol. 2017;16:297–301. doi: 10.1002/rmb2.12040. PubMed DOI PMC

Shen P., Zhang T., Han R., Xie H., Lv Q. Co-administration of tacrolimus and low molecular weight heparin in patients with a history of implantation failure and elevated peripheral blood natural killer cell proportion. J. Obstet. Gynaecol. Res. 2022;49:649–657. doi: 10.1111/jog.15500. PubMed DOI

Nakagawa K., Kwak-Kim J., Hisano M., Kasahara Y., Kuroda K., Sugiyama R., Yamaguchi K. Obstetric and perinatal outcome of the women with repeated implantation failures or recurrent pregnancy losses who received pre- and post-conception tacrolimus treatment. Am. J. Reprod. Immunol. 2019;82:e13142. doi: 10.1111/aji.13142. PubMed DOI

Nakamura A., Tanaka Y., Amano T., Takebayashi A., Takahashi A., Hanada T., Tsuji S., Murakami T. mTOR inhibitors as potential therapeutics for endometriosis: A narrative review. Mol. Hum. Reprod. 2024;30:gaae041. doi: 10.1093/molehr/gaae041. PubMed DOI PMC

Li M.Y., Shen H.H., Cao X.Y., Gao X.X., Xu F.Y., Ha S.Y., Sun J.S., Liu S.P., Xie F., Li M.Q. Targeting a mTOR/autophagy axis: A double-edged sword of rapamycin in spontaneous miscarriage. Biomed. Pharmacother. 2024;177:116976. doi: 10.1016/j.biopha.2024.116976. PubMed DOI

Ahmadi M., Abdolmohamadi-Vahid S., Ghaebi M., Dolati S., Abbaspour-Aghdam S., Danaii S., Berjis K., Madadi-Javid R., Nouri Z., Siahmansouri H., et al. Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: A double-blind, phase II randomized clinical trial. Int. Immunopharmacol. 2019;74:105730. doi: 10.1016/j.intimp.2019.105730. PubMed DOI

Kwak J.Y.H., Kwak F.M.Y., Ainbinder S.W., Ruiz A.M., Beer A.E. Elevated Peripheral Blood Natural Killer Cells Are Effectively Downregulated by Immunoglobulin G Infusion in Women With Recurrent Spontaneous Abortions. Am. J. Reprod. Immunol. 1996;35:363–369. doi: 10.1111/j.1600-0897.1996.tb00495.x. PubMed DOI

Ahmadi M., Abdolmohammadi-Vahid S., Ghaebi M., Aghebati-Maleki L., Afkham A., Danaii S., Abdollahi-Fard S., Heidari L., Jadidi-Niaragh F., Younesi V., 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. doi: 10.1016/j.biopha.2017.06.001. PubMed DOI

Ahmadi M., Abdolmohammadi-Vahid S., Ghaebi M., Aghebati-Maleki L., Dolati S., Farzadi L., Ghasemzadeh A., Hamdi K., Younesi V., Nouri M., et al. Regulatory T cells improve pregnancy rate in RIF patients after additional IVIG treatment. Syst. Biol. Reprod. Med. 2017;63:350–359. doi: 10.1080/19396368.2017.1390007. PubMed DOI

Yamada H., Deguchi M., Saito S., Takeshita T., Mitsui M., Saito T., Nagamatsu T., Takakuwa K., Nakatsuka M., Yoneda S., et al. High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss. J. Reprod. Immunol. 2023;158:103977. doi: 10.1016/j.jri.2023.103977. PubMed DOI

Shi Y., Tan D., Hao B., Zhang X., Geng W., Wang Y., Sun J., Zhao Y. Efficacy of intravenous immunoglobulin in the treatment of recurrent spontaneous abortion: A systematic review and meta-analysis. Am. J. Reprod. Immunol. 2022;88:e13615. doi: 10.1111/aji.13615. PubMed DOI PMC

Christiansen O.B., Kolte A.M., Krog M.C., Nielsen H.S., Egerup P. Treatment with intravenous immunoglobulin in patients with recurrent pregnancy loss: An update. J. Reprod. Immunol. 2019;133:37–42. doi: 10.1016/j.jri.2019.06.001. PubMed DOI

Yamada H., Deguchi M., Saito S., Takeshita T., Mitsui M., Saito T. 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. PubMed DOI PMC

Ramos-Medina R., García-Segovia A., Gil J., Carbone J., Aguarón de la Cruz A., Seyfferth A., Alonso B., Alonso J., León J.A., Alecsandru D., et al. Experience in IVIg Therapy for Selected Women with Recurrent Reproductive Failure and NK Cell Expansion. Am. J. Reprod. Immunol. 2014;71:458–466. doi: 10.1111/aji.12217. PubMed DOI

Lee S.K., Kim J.Y., Han A.R., Hur S.E., Kim C.J., Kim T.H., Cho B.R., Han J.W., Han S.G., Na B.J., et al. Intravenous Immunoglobulin G Improves Pregnancy Outcome in Women with Recurrent Pregnancy Losses with Cellular Immune Abnormalities. Am J Reprod Immunol. 2016;75:59–68. doi: 10.1111/aji.12442. PubMed DOI

Banjar S., Kadour E., Khoudja R., Ton-Leclerc S., Beauchamp C., Beltempo M., Dahan M.H., Gold P., Jacques Kadoch I., Jamal W., et al. Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss. Am. J. Reprod. Immunol. 2023;90:e13737. doi: 10.1111/aji.13737. PubMed DOI

Kim J.H., Kim S.H., Yang N., Ko Y., Lee S.R., Chae H.D. Outcomes of Empirical Treatment With Intravenous Immunoglobulin G Combined With Low-Dose Aspirin in Women With Unexplained Recurrent Pregnancy Loss. J. Korean Med. Sci. 2022;37:e200. doi: 10.3346/jkms.2022.37.e200. PubMed DOI PMC

Habets D.H.J., Pelzner K., Wieten L., Spaanderman M.E.A., 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. doi: 10.1186/s13223-022-00660-8. PubMed DOI PMC

Clark D.A., Coulam C.B., Stricker R.B. 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. doi: 10.1007/s10815-005-9013-1. PubMed DOI PMC

Kumar P., Philip C.E., Eskandar K., Marron K., Harrity C. Effect of intravenous immunoglobulin therapy in recurrent implantation failure: A Systematic review and meta-analysis. J. Reprod. Immunol. 2024;166:104323. doi: 10.1016/j.jri.2024.104323. PubMed DOI

Park J.S., Song A.Y., Bae J.Y., Han J.W., Kim T.H., Kim C.J., Lee S.K. IL-17 Producing T to Foxp3+CD4+ Regulatory T Cell Ratio as a Diagnostic and Prognostic Marker in Women With Recurrent Pregnancy Loss and Its Implications for Intravenous Immunoglobulin Therapy. Am. J. Reprod. Immunol. 2024;92:e70020. doi: 10.1111/aji.70020. PubMed DOI

Velikova T., Sekulovski M., Bogdanova S., Vasilev G., Peshevska-Sekulovska M., Miteva D., Georgiev T. Intravenous Immunoglobulins as Immunomodulators in Autoimmune Diseases and Reproductive Medicine. Antibodies. 2023;12:20. doi: 10.3390/antib12010020. PubMed DOI PMC

Perricone R., De Carolis K.B., Greco E., Giacomelli R., Cipriani P., Fontana L., Perricone C. Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion. Rheumatology. 2008;47:646–651. doi: 10.1093/rheumatology/ken046. PubMed DOI

Wang S.W., Zhong S.Y., Lou L.J., Hu Z.F., Sun H.Y., Zhu H.Y. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: A meta-analysis. Reprod. BioMed. Online. 2016;33:720–736. doi: 10.1016/j.rbmo.2016.08.025. PubMed DOI

Winger E.E., Reed J.L., Ashoush S., El-Toukhy T., Ahuja S., Taranissi M. Elevated Preconception CD56+16+ and/or Th1:Th2 Levels Predict Benefit from IVIG Therapy in Subfertile Women Undergoing IVF. Am. J. Reprod. Immunol. 2011;66:394–403. doi: 10.1111/j.1600-0897.2011.01018.x. PubMed DOI

Sung N., Han A.R., Park C.W., Park D.W., Park J.C., Kim N.Y., Lim K.S., Shin J.E., Joo C.W., Lee S.E., et al. Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines. Clin. Exp. Reprod. Med. 2017;44:1–7. doi: 10.5653/cerm.2017.44.1.1. PubMed DOI PMC

Woon E.V., Day A., Bracewell-Milnes T., Male V., Johnson M. Immunotherapy to improve pregnancy outcome in women with abnormal natural killer cell levels/activity and recurrent miscarriage or implantation failure: A systematic review and meta-analysis. J. Reprod. Immunol. 2020;142:103189. doi: 10.1016/j.jri.2020.103189. PubMed DOI

Porter T.A., Lacoursiere Y., Scott J. Immunotherapy for recurrent miscarriage. Cochrane Database Syst. Rev. 2006:CD000112. doi: 10.1002/14651858.cd000112.pub2. PubMed DOI

Urban M.L., Bettiol A., Serena C., Comito C., Turrini I., Fruttuoso S., Silvestri E., Vannacci A., Ravaldi C., Petraglia F., et al. Intravenous immunoglobulin for the secondary prevention of stillbirth in obstetric antiphospholipid syndrome: A case series and systematic review of literature. Autoimmun. Rev. 2020;19:102620. doi: 10.1016/j.autrev.2020.102620. PubMed DOI

Perricone R., Di Muzio G., Perricone C., Giacomelli R., De Nardo D., Fontana L., De Carolis C. High Levels of Peripheral Blood NK Cells in Women Suffering from Recurrent Spontaneous Abortion are Reverted from High-Dose Intravenous Immunoglobulins. Am. J. Reprod. Immunol. 2006;55:232–239. doi: 10.1111/j.1600-0897.2005.00356.x. PubMed DOI

Elram T., Simon A., Israel S., Revel A., Shveiky D., Laufer N. Treatment of recurrent IVF failure and human leukocyte antigen similarity by intravenous immunoglobulin. Reprod. BioMed. Online. 2005;11:745–749. doi: 10.1016/S1472-6483(10)61694-X. PubMed DOI

Rutella S. Granulocyte Colony-Stimulating Factor for the Induction of T-Cell Tolerance. Transplantation. 2007;84((Supplement)):S26–S30. doi: 10.1097/01.tp.0000269611.66517.bf. PubMed DOI

Perobelli S.M., Mercadante A.C., Galvani R.G., Gonçalves-Silva T., Alves A.P., Pereira-Neves A., Benchimol M., Nóbrega A., Bonomo A. G-CSF-Induced Suppressor IL-10+ Neutrophils Promote Regulatory T Cells That Inhibit Graft-Versus-Host Disease in a Long-Lasting and Specific Way. J. Immunol. 2016;197:3725–3734. doi: 10.4049/jimmunol.1502023. PubMed DOI

Scarpellini F., Sbracia M. Use of granulocyte colony-stimulating factor for the treatment of unexplained recurrent miscarriage: A randomised controlled trial. Hum. Reprod. 2009;24:2703–2708. doi: 10.1093/humrep/dep240. PubMed DOI

Eapen A., Joing M., Kwon P., Tong J., Maneta E., Santo C.D., Mussai F., Lissauer D., Carter D., RESPONSE study group et al. Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: A randomized clinical trial. Hum. Reprod. 2019;34:424–432. doi: 10.1093/humrep/dey393. PubMed DOI PMC

Busnelli A., Somigliana E., Cirillo F., Baggiani A., Levi-Setti P.E. Efficacy of therapies and interventions for repeated embryo implantation failure: A systematic review and meta-analysis. Sci. Rep. 2021;11:1747. doi: 10.1038/s41598-021-81439-6. PubMed DOI PMC

Kamath M.S., Chittawar P.B., Kirubakaran R., Mascarenhas M. Use of granulocyte-colony stimulating factor in assisted reproductive technology: A systematic review and meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 2017;214:16–24. doi: 10.1016/j.ejogrb.2017.04.022. PubMed DOI

Arefi S., Fazeli E., Esfahani M., Borhani N., Yamini N., Hosseini A., Farifteh F. Granulocyte-colony stimulating factor may improve pregnancy outcome in patients with history of unexplained recurrent implantation failure: An RCT. Int. J. Reprod. Biomed. 2018;16:299–304. doi: 10.29252/ijrm.16.5.299. PubMed DOI PMC

Liu M., Yuan Y., Qiao Y., Tang Y., Sui X., Yin P., Yang D. The effectiveness of immunomodulatory therapies for patients with repeated implantation failure: A systematic review and network meta-analysis. Sci. Rep. 2022;12:18434. doi: 10.1038/s41598-022-21014-9. PubMed DOI PMC

Li J., Mo S., Chen Y. The effect of G-CSF on infertile women undergoing IVF treatment: A meta-analysis. Syst. Biol. Reprod. Med. 2017;63:239–247. doi: 10.1080/19396368.2017.1287225. PubMed DOI

Fu J., Li L., Qi L., Zhao L. A randomized controlled trial of etanercept in the treatment of refractory recurrent spontaneous abortion with innate immune disorders. Taiwan J. Obstet. Gynecol. 2019;58:621–625. doi: 10.1016/j.tjog.2019.07.007. PubMed DOI

Santiago K.Y., Porchia L.M., López-Bayghen E. Endometrial preparation with etanercept increased embryo implantation and live birth rates in women suffering from recurrent implantation failure during IVF. Reprod. Biol. 2021;21:100480. doi: 10.1016/j.repbio.2021.100480. PubMed DOI

Winger E.E., Reed J.L. Treatment with Tumor Necrosis Factor Inhibitors and Intravenous Immunoglobulin Improves Live Birth Rates in Women with Recurrent Spontaneous Abortion. Am. J. Reprod. Immunol. 2008;60:8–16. doi: 10.1111/j.1600-0897.2008.00585.x. PubMed DOI

Winger E.E., Reed J.L., Ashoush S., Ahuja S., El-Toukhy T., Taranissi M. Treatment with Adalimumab (Humira®) and Intravenous Immunoglobulin Improves Pregnancy Rates in Women Undergoing IVF. Am. J. Reprod. Immunol. 2008;61:113–120. doi: 10.1111/j.1600-0897.2008.00669.x. PubMed DOI

Alijotas-Reig J., Esteve-Valverde E., Anunciación-Llunell A., Marques-Soares J., Pardos-Gea J., Miró-Mur F. Pathogenesis, Diagnosis and Management of Obstetric Antiphospholipid Syndrome: A Comprehensive Review. J. Clin. Med. 2022;11:675. doi: 10.3390/jcm11030675. PubMed DOI PMC

Hajipour H., Nejabati H.R., Latifi Z., Hamdi K., Bahrami-Asl Z., Fattahi A., Nouri M. Lymphocytes immunotherapy for preserving pregnancy: Mechanisms and Challenges. Am. J. Reprod. Immunol. 2018;80:e12853. doi: 10.1111/aji.12853. PubMed DOI

Yang H., Qiu L., Di W., Zhao A., Chen G., Hu K., Lin Q. Proportional change of CD4+CD25+ regulatory T cells after lymphocyte therapy in unexplained recurrent spontaneous abortion patients. Fertil. Steril. 2009;92:301–305. doi: 10.1016/j.fertnstert.2008.04.068. PubMed DOI

Sarkesh A., Sorkhabi A.D., Parhizkar F., Soltani-Zangbar M.S., Yousefi M., Aghebati-Maleki L. The immunomodulatory effect of intradermal allogeneic PBMC therapy in patients with recurrent spontaneous abortion. J. Reprod. Immunol. 2023;156:103818. doi: 10.1016/j.jri.2023.103818. PubMed DOI

Liu S., Gu X., Weng R. Clinical effect of lymphocyte immunotherapy on patients with unexplained recurrent spontaneous abortion. Immun. Inflamm. Dis. 2021;9:1272–1278. doi: 10.1002/iid3.474. PubMed DOI PMC

Fainboim L., Belén S., González V., Fernández P. Evaluation of paternal lymphocyte immunotherapy and potential biomarker mixed lymphocyte reaction-blocking factor in an Argentinian cohort of women with unexplained recurrent spontaneous abortion and unexplained infertility. Am. J. Reprod. Immunol. 2021;86:e13422. doi: 10.1111/aji.13422. PubMed DOI

Sarno M., Cavalcante M.B., Niag M., Pimentel K., Luz I., Figueiredo B., Michelon T., Neumann J., Lima S., Machado I.N., et al. Gestational and perinatal outcomes in recurrent miscarriages couples treated with lymphocyte immunotherapy. Eur. J. Obstet. Gynecol. Reprod. Biol. X. 2019;3:100036. doi: 10.1016/j.eurox.2019.100036. PubMed DOI PMC

Chen J.L., Yang J.M., Huang Y.Z., Li Y. Clinical observation of lymphocyte active immunotherapy in 380 patients with unexplained recurrent spontaneous abortion. Int. Immunopharmacol. 2016;40:347–350. doi: 10.1016/j.intimp.2016.09.018. PubMed DOI

Gharesi-Fard B., Zolghadri J., Foroughinia L., Tavazoo F., Samsami Dehaghani A. Effectiveness of leukocyte immunotherapy in primary recurrent spontaneous abortion (RPL) Iran. J. Immunol. 2007;4:173–178. PubMed

Pandey M.K., Agrawal S. Induction of MLR-Bf and protection of fetal loss: A current double blind randomized trial of paternal lymphocyte immunization for women with recurrent spontaneous abortion. Int. Immunopharmacol. 2004;4:289–298. doi: 10.1016/j.intimp.2004.01.001. PubMed DOI

Ober C., Karrison T., Odem R.R., Barnes R.B., Branch D.W., Stephenson M.D., Baron B., Walker M.A., Scott J.R., Schreiber J.R. Mononuclear-cell immunisation in prevention of recurrent miscarriages: A randomised trial. Lancet. 1999;354:365–369. doi: 10.1016/S0140-6736(98)12055-X. PubMed DOI

Wong L.F., Porter T.F., Scott J.R. Immunotherapy for recurrent miscarriage. Cochrane Database Syst. Rev. 2014;2014:CD000112. doi: 10.1002/14651858.CD000112.pub3. PubMed DOI PMC

Günther V., Alkatout I., Meyerholz L., Maass N., Görg S., von Otte S., Ziemann M. Live Birth Rates after Active Immunization with Partner Lymphocytes. Biomedicines. 2021;9:1350. doi: 10.3390/biomedicines9101350. PubMed DOI PMC

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. doi: 10.1111/aji.12511. PubMed DOI

Rasmark Roepke E., Hellgren M., Hjertberg R., Blomqvist L., Matthiesen L., Henic E., Lalitkumar S., Strandell A. Treatment efficacy for idiopathic recurrent pregnancy loss—A systematic review and meta-analyses. Acta Obstet. Gynecol. Scand. 2018;97:921–941. doi: 10.1111/aogs.13352. PubMed DOI

Melo P., Thornton T., Coomarasamy A., Granne I. Evidence for the effectiveness of immunologic therapies in women with subfertility and/or undergoing assisted reproduction. Fertil. Steril. 2022;117:1144–1159. doi: 10.1016/j.fertnstert.2022.04.015. PubMed DOI

Yu N., Zhang B., Xu M., Wang S., Liu R., Wu J., Yang J., Feng L. Intrauterine administration of autologous peripheral blood mononuclear cells (PBMCs) activated by HCG improves the implantation and pregnancy rates in patients with repeated implantation failure: A prospective randomized study. Am. J. Reprod. Immunol. 2016;76:212–216. doi: 10.1111/aji.12542. PubMed DOI

Li S., Wang J., Cheng Y., Zhou D., Yin T., Xu W., Yu N., Yang J. Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J. Reprod. Immunol. 2017;119:15–22. doi: 10.1016/j.jri.2016.11.006. PubMed DOI

Maleki-Hajiagha A., Razavi M., Rezaeinejad M., Rouholamin S., Almasi-Hashiani A., Pirjani R., Sepidarkish M. Intrauterine administration of autologous peripheral blood mononuclear cells in patients with recurrent implantation failure: A systematic review and meta-analysis. J. Reprod. Immunol. 2019;131:50–56. doi: 10.1016/j.jri.2019.01.001. PubMed DOI

Pourmoghadam Z., Abdolmohammadi-Vahid S., Pashazadeh F., Aghebati-Maleki L., Ansari F., Yousefi M. Efficacy of intrauterine administration of autologous peripheral blood mononuclear cells on the pregnancy outcomes in patients with recurrent implantation failure: A systematic review and meta-analysis. J. Reprod. Immunol. 2020;137:103077. doi: 10.1016/j.jri.2019.103077. PubMed DOI

Yakin K., Oktem O. Urman B. Intrauterine administration of peripheral mononuclear cells in recurrent implantation failure: A systematic review and meta-analysis. Sci. Rep. 2019;9:3897. doi: 10.1038/s41598-019-40521-w. PubMed DOI PMC

Cai S., Dai S., Lin R., Huang C., Zeng Y., Diao L., Lian R., Tu W. The effectiveness and safety of intrauterine infusion of autologous regulatory T cells (Tregs) in patients with recurrent pregnancy loss and low levels of endometrial FoxP3+ cells: A retrospective cohort study. Am. J. Reprod. Immunol. 2023;90:e13735. doi: 10.1111/aji.13735. PubMed DOI

Ban Y., Yang X., Xing Y., Que W., Yu Z., Gui W., Chen Y., Liu X. Intrauterine Infusion of Leukocyte-Poor Platelet-Rich Plasma Is an Effective Therapeutic Protocol for Patients with Recurrent Implantation Failure: A Retrospective Cohort Study. J. Clin. Med. 2023;12:2823. doi: 10.3390/jcm12082823. PubMed DOI PMC

Kong X., Tang G., Liu Y., Zheng Z., Li Y., Yan F. Efficacy of intrauterine infusion therapy before embryo transfer in recurrent implantation failure: A systematic review and network meta-analysis. J. Reprod. Immunol. 2023;156:103819. doi: 10.1016/j.jri.2023.103819. PubMed DOI

Deng H., Wang S., Li Z., Xiao L., Mao Y. Effect of intrauterine infusion of platelet-rich plasma for women with recurrent implantation failure: A systematic review and meta-analysis. J. Obstet. Gynaecol. 2023;43:2144177. doi: 10.1080/01443615.2022.2144177. PubMed DOI

Mehrafza M., Pourseify G., Zare Yousefi T., Azadeh R., Saghati Jalali S., Hosseinzadeh E., Samadnia S., Habibdoost M., Tamimi A., Hosseini A. The Efficiency of Introducing Intrauterine Infusion of Autologous Platelet-Rich Plasma versus Granulocyte Colony-Stimulating Factor in Repeated Implantation Failure Patients: An Unblinded Randomised Clinical Trial. Int. J. Fertil. Steril. 2024;18((Suppl. 1)):30–34. doi: 10.22074/ijfs.2024.2013900.1557. PubMed DOI PMC

Kumar P., Marron K., Harrity C. Intralipid therapy and adverse reproductive outcome: Is there any evidence? Reprod. Fertil. 2021;2:173–186. doi: 10.1530/RAF-20-0052. PubMed DOI PMC

Roussev R.G., Acacio B., Ng S.C., Coulam C.B. Duration of Intralipid’s Suppressive Effect on NK Cell’s Functional Activity. Am. J. Reprod. Immunol. 2008;60:258–263. doi: 10.1111/j.1600-0897.2008.00621.x. PubMed DOI

Singh N., Davis A.A., Kumar S., Kriplani A. The effect of administration of intravenous intralipid on pregnancy outcomes in women with implantation failure after IVF/ICSI with non-donor oocytes: A randomised controlled trial. Eur. J. Obstet. Gynecol. Reprod. Biol. 2019;240:45–51. doi: 10.1016/j.ejogrb.2019.06.007. PubMed DOI

Dakhly D.M.R., Bayoumi Y.A., Sharkawy M., Gad Allah S.H., Hassan M.A., Gouda H.M., Hashem A.T., Hatem D.L., Ahmed M.F., El-Khayat W. Intralipid supplementation in women with recurrent spontaneous abortion and elevated levels of natural killer cells. Int. J. Gynecol. Obstet. 2016;135:324–327. doi: 10.1016/j.ijgo.2016.06.026. PubMed DOI

Han E.J., Lee H.N., Kim M.K., Lyu S.W., Lee W.S. Efficacy of intralipid administration to improve in vitro fertilization outcomes: A systematic review and meta-analysis. Clin. Exp. Reprod. Med. 2021;48:203–210. doi: 10.5653/cerm.2020.04266. PubMed DOI PMC

Rimmer M.P., Black N., Keay S., Quenby S., Al Wattar B.H. Intralipid infusion at time of embryo transfer in women with history of recurrent implantation failure: A systematic review and meta-analysis. J. Obstet. Gynaecol. Res. 2021;47:2149–2156. doi: 10.1111/jog.14763. PubMed DOI

Marchand G.J., Masoud A.T., Ulibarri H., Arroyo A., Coriell C., Goetz S., Moir C., Moberly A., Gonzalez D., Blanco M., et al. Effect of a 20% intravenous fat emulsion therapy on pregnancy outcomes in women with RPL or RIF undergoing IVF/ICSI: A systematic review and meta-analysis. J. Clin. Transl. Res. 2023;9:236–245. PubMed PMC

Ndukwe G. Recurrent embryo implantation failure after in vitro fertilisation: Improved outcome following intralipid infusion in women with elevated T Helper 1 response. Hum. Fertil. 2011;14:1–8.

Coulam C.B. Intralipid treatment for women with reproductive failures. Am. J. Reprod. Immunol. 2021;85:e13290. doi: 10.1111/aji.13290. PubMed DOI

Martini A., Jasulaitis S., Fogg L., Uhler M., Hirshfeld-Cytron J. Evaluating the utility of intralipid infusion to improve live birth rates in patients with recurrent pregnancy loss or recurrent implantation failure. J. Hum. Reprod. Sci. 2018;11:261. doi: 10.4103/jhrs.JHRS_28_18. PubMed DOI PMC

Carta G., Iovenitti P., Falciglia K. Recurrent miscarriage associated with antiphospholipid antibodies: Prophylactic treatment with low-dose aspirin and fish oil derivates. Clin. Exp. Obstet. Gynecol. 2005;32:49–51. PubMed

Mu F., Huo H., Wang M., Wang F. Omega-3 fatty acid supplements and recurrent miscarriage: A perspective on potential mechanisms and clinical evidence. Food Sci. Nutr. 2023;11:4460–4471. doi: 10.1002/fsn3.3464. PubMed DOI PMC

Canella P.R.B.C., Vinces S.S., Silva Á.A.R., Sanches P.H.G., Barini R., Porcari A.M., Razolli D.S., Carvalho P.O. Altered profile of plasma phospholipids in woman with recurrent pregnancy loss and recurrent implantation failure treated with lipid emulsion therapy. Am. J. Reprod. Immunol. 2023;89:e13673. doi: 10.1111/aji.13673. PubMed DOI

ESHRE Guideline Group on RPL. Bender Atik R., Christiansen O.B., Elson J., Kolte A.M., Lewis S., Middeldorp S., Mcheik S., Peramo B., Quenby S., et al. ESHRE guideline: Recurrent pregnancy loss: An update in 2022. Hum. Reprod. Open. 2023;2023:hoad002. doi: 10.1093/hropen/hoad002. PubMed DOI PMC

Royal College of Obstetricians and Gynaecologists The Investigation and Treatment of Couples with Recurrent First- trimester and Second-trimester Miscarriage Green-top Guideline No. 17. 2022. [(accessed on 8 December 2024)]. Available online: https://www.rcog.org.uk/media/3cbgonl0/gtg_17.pdf.

Hamulyák E.N., Scheres L.J., Marijnen M.C., Goddijn M., Middeldorp S. Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss. Cochrane Database Syst. Rev. 2020;5:CD012852. doi: 10.1002/14651858.cd012852.pub2. PubMed DOI PMC

Liu X., Qiu Y., Yu E.D., Xiang S., Meng R., Niu K.F., Zhu H. Comparison of therapeutic interventions for recurrent pregnancy loss in association with antiphospholipid syndrome: A systematic review and network meta-analysis. Am. J. Reprod. Immunol. 2020;83:e13219. doi: 10.1111/aji.13219. PubMed DOI

Grandone E., Tiscia G.L., Mastroianno M., Larciprete G., Kovač M., Tamborini Permunian E., Lojacono A., Barcellona D., Bitsadze V., Khizroeva J., et al. Findings from a multicentre, observational study on reproductive outcomes in women with unexplained recurrent pregnancy loss: The OTTILIA registry. Hum. Reprod. 2021;36:2083–2090. doi: 10.1093/humrep/deab153. PubMed DOI

Aynıoglu O., Isik H., Sahbaz A., Alptekın H., Bayar U. Does anticoagulant therapy improve adverse pregnancy outcomes in patients with history of recurrent pregnancy loss? Ginekol. Pol. 2016;87:585–591. doi: 10.5603/GP.2016.0049. PubMed DOI

Shaaban O.M., Abbas A.M., Zahran K.M., Fathalla M.M., Anan M.A., Salman S.A. Low-Molecular-Weight Heparin for the Treatment of Unexplained Recurrent Miscarriage With Negative Antiphospholipid Antibodies: A Randomized Controlled Trial. Clin. Appl. Thromb. Hemost. 2016;23:567–572. doi: 10.1177/1076029616665167. PubMed DOI

Jiang F., Hu X., Jiang K., Pi H., He Q., Chen X. The role of low molecular weight heparin on recurrent pregnancy loss: A systematic review and meta-analysis. Taiwan J. Obstet. Gynecol. 2021;60:1–8. doi: 10.1016/j.tjog.2020.11.001. PubMed DOI

Li J., Gao Y.H., Xu L., Li Z.Y. Meta-analysis of heparin combined with aspirin versus aspirin alone for unexplained recurrent spontaneous abortion. Int. J. Gynaecol. Obstet. 2020;151:23–32. doi: 10.1002/ijgo.13266. PubMed DOI

Skeith L., Carrier M., Kaaja R., Martinelli I., Petroff D., Schleußner E., Laskin C.A., Rodger M.A. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood. 2016;127:1650–1655. doi: 10.1182/blood-2015-12-626739. PubMed DOI

de Jong P., Kaandorp S., Di Nisio M., Goddijn M., Middeldorp S. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst. Rev. 2014;2014:CD004734. doi: 10.1002/14651858.CD004734.pub4. PubMed DOI PMC

Schleussner E., Kamin G., Seliger G., Rogenhofer N., Ebner S., Toth B., Schenk M., Henes M., Bohlmann M.K., Fischer T., et al. Low-Molecular-Weight Heparin for Women With Unexplained Recurrent Pregnancy Loss. Ann. Intern. Med. 2015;162:601–609. doi: 10.7326/M14-2062. PubMed DOI

Karadağ C., Akar B., Gönenç G., Aslancan R., Yılmaz N., Çalışkan E. Aspirin, low molecular weight heparin, or both in preventing pregnancy complications in women with recurrent pregnancy loss and factor V Leiden mutation. J. Matern.-Fetal Neonatal Med. 2020;33:1934–1939. doi: 10.1080/14767058.2019.1671348. PubMed DOI

Lin T., Chen Y., Cheng X., Li N., Sheng X. Enoxaparin (or plus aspirin) for the prevention of recurrent miscarriage: A meta-analysis of randomized controlled studies. Eur. J. Obstet. Gynecol. Reprod. Biol. 2019;234:53–57. doi: 10.1016/j.ejogrb.2018.12.023. PubMed DOI

Wang G., Zhang R., Li C., Chen A. Evaluation of the effect of low molecular weight heparin in unexplained recurrent pregnancy loss: A meta-analysis of randomized controlled trials. J. Matern.-Fetal Neonatal Med. 2021;35:7601–7608. doi: 10.1080/14767058.2021.1957819. PubMed DOI

Scarrone M., Salmeri N., Buzzaccarini G., Canti V., Pasi F., Papaleo E., Rovere-Querini P., Candiani M., Alteri A., Busnelli A., et al. Low-molecular-weight heparin in the prevention of unexplained recurrent miscarriage: A systematic review and meta-analysis. Sci. Rep. 2024;14:14168. doi: 10.1038/s41598-024-62949-5. PubMed DOI PMC

Scarrone M., Canti V., Vanni V.S., Bordoli S., Pasi F., Quaranta L., Erra R., De Lorenzo R., Rosa S., Castiglioni M.T., et al. Treating unexplained recurrent pregnancy loss based on lessons learned from obstetric antiphospholipid syndrome and inherited thrombophilia: A propensity-score adjusted retrospective study. J. Reprod. Immunol. 2022;154:103760. doi: 10.1016/j.jri.2022.103760. PubMed DOI

Quenby S., Booth K., Hiller L., Coomarasamy A., de Jong P.G., Hamulyák E.N., Scheres L.J., van Haaps T.F., Ewington L., Tewary S., et al. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): An international open-label, randomised controlled trial. Lancet. 2023;402:54–61. doi: 10.1016/S0140-6736(23)00693-1. PubMed DOI

Giouleka S., Tsakiridis I., Arsenaki E., Kalogiannidis I., Mamopoulos A., Papanikolaou E., Athanasiadis A., Dagklis T. Investigation and Management of Recurrent Pregnancy Loss: A Comprehensive Review of Guidelines. Obstet. Gynecol. Surv. 2023;78:287–301. doi: 10.1097/OGX.0000000000001133. PubMed DOI

Kuroda K., Matsumura Y., Ikemoto Y., Segawa T., Hashimoto T., Fukuda J., Nakagawa K., Uchida T., Ochiai A., Horimoto Y., et al. Analysis of the risk factors and treatment for repeated implantation failure: OPtimization of Thyroid function, IMmunity, and Uterine Milieu (OPTIMUM) treatment strategy. Am. J. Reprod. Immunol. 2021;85:e13376. doi: 10.1111/aji.13376. PubMed DOI

Kuroda K., Horikawa T., Moriyama A., Ojiro Y., Takamizawa S., Watanabe H., Maruyama T., Nojiri S., Nakagawa K., Sugiyama R. Therapeutic efficacy of the optimization of thyroid function, thrombophilia, immunity and uterine milieu (OPTIMUM) treatment strategy on pregnancy outcomes after single euploid blastocyst transfer in advanced age women with recurrent reproductive failure. Reprod. Med. Biol. 2023;22:e12554. doi: 10.1002/rmb2.12554. PubMed DOI PMC

Mohammad-Akbari A., Mohazzab A., Tavakoli M., Karimi A., Zafardoust S., Zolghadri Z., Shahali S., Tokhmechi R., Ansaripour S. The effect of low-molecular-weight heparin on live birth rate of patients with unexplained early recurrent pregnancy loss: A two-arm randomized clinical trial. J. Res. Med. Sci. 2022;27:78. doi: 10.4103/jrms.jrms_81_21. PubMed DOI PMC

Dolitzky M., Inbal A., Segal Y., Weiss A., Brenner B., Carp H. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil. Steril. 2006;86:362–366. doi: 10.1016/j.fertnstert.2005.12.068. PubMed DOI

Naimi A.I., Perkins N.J., Sjaarda L.A., Mumford S.L., Platt R.W., Silver R.M., Schisterman E.F. The Effect of Preconception-Initiated Low-Dose Aspirin on Human Chorionic Gonadotropin-Detected Pregnancy, Pregnancy Loss, and Live Birth: Per Protocol Analysis of a Randomized Trial. Ann. Intern. Med. 2021;174:595–601. doi: 10.7326/M20-0469. PubMed DOI PMC

Mumford S.L., Silver R.M., Sjaarda L.A., Wactawski-Wende J., Townsend J.M., Lynch A.M., Galai N., Lesher L.L., Faraggi D., Perkins N.J., et al. Expanded findings from a randomized controlled trial of preconception low-dose aspirin and pregnancy loss. Hum. Reprod. 2016;31:657–665. doi: 10.1093/humrep/dev329. PubMed DOI PMC

Blomqvist L., Hellgren M., Strandell A. Acetylsalicylic acid does not prevent first-trimester unexplained recurrent pregnancy loss: A randomized controlled trial. Acta Obstet. Gynecol. Scand. 2018;97:1365–1372. doi: 10.1111/aogs.13420. PubMed DOI

Ikemoto Y., Kuroda K., Nakagawa K., Ochiai A., Ozaki R., Murakami K., Jinushi M., Matsumoto A., Sugiyama R., Takeda S. Vitamin D Regulates Maternal T-Helper Cytokine Production in Infertile Women. Nutrients. 2018;10:902. doi: 10.3390/nu10070902. PubMed DOI PMC

Ota K., Dambaeva S., Kim M.W., Han A.R., Fukui A., Gilman-Sachs A., Beaman K., Kwak-Kim J. 1,25-Dihydroxy-vitamin D3 regulates NK-cell cytotoxicity, cytokine secretion, and degranulation in women with recurrent pregnancy losses. Eur. J. Immunol. 2015;45:3188–3199. doi: 10.1002/eji.201545541. PubMed DOI

Ichikawa T., Toyoshima M., Watanabe T., Negishi Y., Kuwabara Y., Takeshita T., Suzuki S. Associations of Nutrients and Dietary Preferences with Recurrent Pregnancy Loss and Infertility. J. Nippon Med. Sch. 2024;91:254–260. doi: 10.1272/jnms.JNMS.2024_91-313. PubMed DOI

Chen X., Yin B., Lian R.C., Zhang T., Zhang H.Z., Diao L.H., Li Y.Y., Huang C.Y., Liang D.S., Zeng Y. Modulatory effects of vitamin D on peripheral cellular immunity in patients with recurrent miscarriage. Am. J. Reprod. Immunol. 2016;76:432–438. doi: 10.1111/aji.12585. PubMed DOI

Tamblyn J.A., Pilarski N.S.P., Markland A.D., Marson E.J., Devall A., Hewison M., Morris R.K., Coomarasamy A. Vitamin D and miscarriage: A systematic review and meta-analysis. Fertil. Steril. 2022;118:111–122. doi: 10.1016/j.fertnstert.2022.04.017. PubMed DOI

Raghupathy R., Szekeres-Bartho J. Progesterone: A Unique Hormone with Immunomodulatory Roles in Pregnancy. Int. J. Mol. Sci. 2022;23:1333. doi: 10.3390/ijms23031333. PubMed DOI PMC

Lee J.H., Lydon J.P., Kim C.H. Progesterone suppresses the mTOR pathway and promotes generation of induced regulatory T cells with increased stability. Eur. J. Immunol. 2012;42:2683–2696. doi: 10.1002/eji.201142317. PubMed DOI PMC

Green E.S., Moldenhauer L.M., Groome H.M., Sharkey D.J., Chin P.Y., Care A.S., Robker R.L., McColl S.R., Robertson S.A. Regulatory T cells are paramount effectors in progesterone regulation of embryo implantation and fetal growth. JCI Insight. 2023;8:e162995. doi: 10.1172/jci.insight.162995. PubMed DOI PMC

Haas D.M., Hathaway T.J., Ramsey P.S. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst. Rev. 2019;2019:CD003511. doi: 10.1002/14651858.CD003511.pub5. PubMed DOI PMC

Devall A.J., Papadopoulou A., Haas D.M., Price M.J., Coomarasamy A., Gallos I.D. Progestogens for preventing miscarriage: A network meta-analysis. Cochrane Database Syst. Rev. 2021;4:CD013792. doi: 10.1002/14651858.cd013792. PubMed DOI PMC

Zhao Y., D’Souza R., Gao Y., Hao Q., Kallas-Silva L., Steen J.P., Guyatt G. Progestogens in women with threatened miscarriage or recurrent miscarriage: A meta-analysis. Acta Obstet. Gynecol. Scand. 2024;103:1689–1701. doi: 10.1111/aogs.14829. PubMed DOI PMC

Xie H., Zeng H., He D., Liu N. Effect of intrauterine perfusion of human chorionic gonadotropin before embryo transfer after two or more implantation failures: A systematic review and meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 2019;243:133–138. doi: 10.1016/j.ejogrb.2019.10.039. PubMed DOI

Bakry M.S., Eldesouky E., Alghazaly M.M., Farag E., Sultan E.E.K., Elazzazy H., Mohamed A., Ali S.M.S., Anwar A., Elrashedy A.A., et al. Granulocyte colony stimulating factor versus human chorionic gonadotropin for recurrent implantation failure in intra cytoplasmic sperm injection: A randomized clinical trial. BMC Pregnancy Childbirth. 2022;22:881. doi: 10.1186/s12884-022-05098-9. PubMed DOI PMC

Amooee S., Shomali Z., Namazi N., Jannati F. Is There any Role for Granulocyte Colony Stimulating Factor in Improvement of Implantation in Intrauterine Insemination? A Prospective Double-Blind Randomized Control Trial. Int. J. Fertil. Steril. 2022;16:281–285. doi: 10.22074/ijfs.2021.537125.1171. PubMed DOI PMC

Bellver J., Marín C., Lathi R.B., Murugappan G., Labarta E., Vidal C., Giles J., Cabanillas S., Marzal A., Galliano D., et al. Obesity Affects Endometrial Receptivity by Displacing the Window of Implantation. Reprod. Sci. 2021;28:3171–3180. doi: 10.1007/s43032-021-00631-1. PubMed DOI

Gonnella F., Konstantinidou F., Donato M., Gatta D.M.P., Peserico A., Barboni B., Stuppia L., Nothnick W.B., Gatta V. The Molecular Link between Obesity and the Endometrial Environment: A Starting Point for Female Infertility. Int. J. Mol. Sci. 2024;25:6855. doi: 10.3390/ijms25136855. PubMed DOI PMC

Gonçalves C.C.R.A., Feitosa B.M., Cavalcante B.V., Lima A.L.G.S.B., de Souza C.M., Joventino L.B., Cavalcante M.B. Obesity and recurrent miscarriage: The interconnections between adipose tissue and the immune system. Am. J. Reprod. Immunol. 2023;90:e13757. doi: 10.1111/aji.13757. PubMed DOI

Ramidi G., Khan N., Glueck C.J., Wang P., Goldenberg N. Enoxaparin-metformin and enoxaparin alone may safely reduce pregnancy loss. Trans. Res. J. Lab. Clin. Med. 2009;153:33–43. doi: 10.1016/j.trsl.2008.11.003. PubMed DOI

Silverii G.A. Optimizing metformin therapy in practice: Tailoring therapy in specific patient groups to improve tolerability, efficacy and outcomes. Diabetes Obes. Metab. 2024;26((Suppl. 3)):42–54. doi: 10.1111/dom.15749. PubMed DOI

Rajeev D., MacIver N.J. Metformin as a Therapeutic Agent for Obesity-Associated Immune Dysfunction. J. Nutr. 2024;154:2534–2542. doi: 10.1016/j.tjnut.2024.07.001. PubMed DOI

Sola-Leyva A., Pathare A.D.S., Apostolov A., Aleksejeva E., Kask K., Tammiste T., Ruiz-Durán S., Risal S., Acharya G., Salumets A. The hidden impact of GLP-1 receptor agonists on endometrial receptivity and implantation. Acta Obstet. Gynecol. Scand. 2024 doi: 10.1111/aogs.15010. PubMed DOI PMC

Maslin K., Alkutbe R., Gilbert J., Pinkney J., Shawe J. What is known about the use of weight loss medication in women with overweight/obesity on fertility and reproductive health outcomes? A scoping review. Clin. Obes. 2024;14:e12690. doi: 10.1111/cob.12690. PubMed DOI

Dang D., Dearholt S., Bissett K., Ascenzi J., Whalen M. Johns Hopkins Evidence-Based Practice for Nurses and Healthcare Professionals: Model and Guidelines. 4th ed. Sigma Theta Tau International; Indianapolis, IN, USA: 2022.

Endometriosis: An Immunologist's Perspective