Leukemia Inhibitory Factor (LIF) and LIF Receptor (LIFR) Gene Polymorphisms and Implantation and Pregnancy Outcomes After Assisted Reproduction: A Systematic Review and Meta-Analysis
Abstract
Background: Leukemia inhibitory factor (LIF) signals through the LIF receptor (LIFR)–gp130 complex, and mice that lack uterine LIF cannot implant their embryos. Whether variants in LIF or LIFR shape the outcome of assisted reproductive technology (ART) is still debated. Methods: PubMed and supplementary sources were searched up to 29 September 2026 for studies that genotyped LIF or LIFR in women treated with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), including women with recurrent implantation failure (RIF). Genotype counts were taken from the original tables, quality was scored with the Newcastle–Ottawa scale, and odds ratios (ORs) were pooled under six genetic models. Results: Eleven studies (4,556 genotyped women) were included and six entered meta-analyses. Poolable ART-outcome data existed only for LIF rs929271, a 3′ untranslated region variant. In three cohorts (742 women), the GG genotype was linked to lower odds of failing to reach an ongoing pregnancy or live birth (GG vs TT+TG: OR 0.50, 95% CI 0.29–0.86; I2 = 19%), and in two cohorts G carriers had fewer miscarriages (OR 0.49, 0.28–0.86). The signal lost significance with the Hartung–Knapp–Sidik–Jonkman correction, rested mainly on one Brazilian center, and was absent when women with IVF failure were compared with fertile women (G vs T: OR 1.26, 0.91–1.75). Rare LIF variants showed no consistent effect, and no study has tested LIFR against ART outcomes. Conclusions: Certainty of evidence is very low. LIF or LIFR genotyping should not guide IVF practice until larger, ancestry-aware studies with clear outcome definitions confirm these findings.
Keywords:
Leukemia inhibitory factor, LIFR, rs929271, recurrent implantation failure, in vitro fertilization, genetic polymorphism, meta-analysis
References
1. Chambers GM, Dyer S, Zegers-Hochschild F, de Mouzon J, Ishihara O, Banker M, et al. International Committee for Monitoring Assisted Reproductive Technologies world report: assisted reproductive technology, 2014. Hum Reprod. 2021;36(11):2921–2934. doi:10.1093/humrep/deab198
2. Coughlan C, Ledger W, Wang Q, Liu F, Demirol A, Gurgan T, et al. Recurrent implantation failure: definition and management. Reprod Biomed Online. 2014;28(1):14–38. doi:10.1016/j.rbmo.2013.08.011
3. Polanski LT, Baumgarten MN, Quenby S, Brosens J, Campbell BK, Raine-Fenning NJ. What exactly do we mean by 'recurrent implantation failure'? A systematic review and opinion. Reprod Biomed Online. 2014;28(4):409–423. doi:10.1016/j.rbmo.2013.12.006
4. ESHRE Working Group on Recurrent Implantation Failure; Cimadomo D, de los Santos MJ, Griesinger G, Lainas G, Le Clef N, McLernon DJ, et al. ESHRE good practice recommendations on recurrent implantation failure. Hum Reprod Open. 2023;2023(3):hoad023. doi:10.1093/hropen/hoad023
5. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345(19):1400–1408. doi:10.1056/NEJMra000763
6. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the 'black box' of early pregnancy loss. Hum Reprod Update. 2002;8(4):333–343. doi:10.1093/humupd/8.4.333
7. Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18(12):1754–1767. doi:10.1038/nm.3012
8. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Köntgen F, et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992;359(6390):76–79. doi:10.1038/359076a0
9. Chen JR, Cheng JG, Shatzer T, Sewell L, Hernandez L, Stewart CL. Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis. Endocrinology. 2000;141(12):4365–4372. doi:10.1210/endo.141.12.7855
10. Charnock-Jones DS, Sharkey AM, Fenwick P, Smith SK. Leukaemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA for the receptor at this time. J Reprod Fertil. 1994;101(2):421–426. doi:10.1530/jrf.0.1010421
11. Cullinan EB, Abbondanzo SJ, Anderson PS, Pollard JW, Lessey BA, Stewart CL. Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proc Natl Acad Sci U S A. 1996;93(7):3115–3120. doi:10.1073/pnas.93.7.3115
12. Hu W, Feng Z, Teresky AK, Levine AJ. p53 regulates maternal reproduction through LIF. Nature. 2007;450(7170):721–724. doi:10.1038/nature05993
13. Kang HJ, Feng Z, Sun Y, Atwal G, Murphy ME, Rebbeck TR, et al. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci U S A. 2009;106(24):9761–9766. doi:10.1073/pnas.0904280106
14. Steck T, Giess R, Suetterlin MW, Bolland M, Wiest S, Poehls UG, et al. Leukaemia inhibitory factor (LIF) gene mutations in women with unexplained infertility and recurrent failure of implantation after IVF and embryo transfer. Eur J Obstet Gynecol Reprod Biol. 2004;112(1):69–73. doi:10.1016/S0301-2115(03)00315-4
15. Oliveira JBA, Vagnini LD, Petersen CG, Renzi A, Oliveira-Pelegrin GR, Mauri AL, et al. Association between leukaemia inhibitory factor gene polymorphism and pregnancy outcomes after assisted reproduction techniques. Reprod Biomed Online. 2016;32(1):66–78. doi:10.1016/j.rbmo.2015.09.018
16. Paskulin DD, Cunha-Filho JS, Souza CAB, Bortolini MC, Hainaut P, Ashton-Prolla P. ESR1 rs9340799 is associated with endometriosis-related infertility and in vitro fertilization failure. Dis Markers. 2013;35(6):907–913. doi:10.1155/2013/796290
17. Palomares AR, Castillo-Domínguez AA, Ruiz-Galdón M, Rodriguez-Wallberg KA, Reyes-Engel A. Genetic variants in the p53 pathway influence implantation and pregnancy maintenance in IVF treatments using donor oocytes. J Assist Reprod Genet. 2021;38(12):3267–3275. doi:10.1007/s10815-021-02324-9
18. Bhatt H, Brunet LJ, Stewart CL. Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc Natl Acad Sci U S A. 1991;88(24):11408–11412. doi:10.1073/pnas.88.24.11408
19. Song H, Lim H, Das SK, Paria BC, Dey SK. Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice. Mol Endocrinol. 2000;14(8):1147–1161. doi:10.1210/mend.14.8.0498
20. Kelleher AM, Milano-Foster J, Behura SK, Spencer TE. Uterine glands coordinate on-time embryo implantation and impact endometrial decidualization for pregnancy success. Nat Commun. 2018;9(1):2435. doi:10.1038/s41467-018-04848-8
21. Hu W. The role of p53 gene family in reproduction. Cold Spring Harb Perspect Biol. 2009;1(6):a001073. doi:10.1101/cshperspect.a001073
22. Feng Z, Zhang C, Kang HJ, Sun Y, Wang H, Naqvi A, et al. Regulation of female reproduction by p53 and its family members. FASEB J. 2011;25(7):2245–2255. doi:10.1096/fj.10-180166
23. Gearing DP, Thut CJ, VandeBos T, Gimpel SD, Delaney PB, King J, et al. Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. EMBO J. 1991;10(10):2839–2848. doi:10.1002/j.1460-2075.1991.tb07833.x
24. Gearing DP, Comeau MR, Friend DJ, Gimpel SD, Thut CJ, McGourty J, et al. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992;255(5050):1434–1437. doi:10.1126/science.1542794
25. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003;374(1):1–20. doi:10.1042/BJ20030407
26. Nicola NA, Babon JJ. Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev. 2015;26(5):533–544. doi:10.1016/j.cytogfr.2015.07.001
27. Suman P, Malhotra SS, Gupta SK. LIF-STAT signaling and trophoblast biology. JAKSTAT. 2013;2(4):e25155. doi:10.4161/jkst.25155
28. Sun X, Bartos A, Whitsett JA, Dey SK. Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses. Mol Endocrinol. 2013;27(9):1492–1501. doi:10.1210/me.2013-1086
29. Lee JH, Kim TH, Oh SJ, Yoo JY, Akira S, Ku BJ, et al. Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus. FASEB J. 2013;27(7):2553–2563. doi:10.1096/fj.12-225664
30. Cheng JG, Chen JR, Hernandez L, Alvord WG, Stewart CL. Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation. Proc Natl Acad Sci U S A. 2001;98(15):8680–8685. doi:10.1073/pnas.151180898
31. Ware CB, Horowitz MC, Renshaw BR, Hunt JS, Liggitt D, Koblar SA, et al. Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development. 1995;121(5):1283–1299. doi:10.1242/dev.121.5.1283
32. Li M, Sendtner M, Smith A. Essential function of LIF receptor in motor neurons. Nature. 1995;378(6558):724–727. doi:10.1038/378724a0
33. Dagoneau N, Scheffer D, Huber C, Al-Gazali LI, Di Rocco M, Godard A, et al. Null leukemia inhibitory factor receptor (LIFR) mutations in Stüve-Wiedemann/Schwartz-Jampel type 2 syndrome. Am J Hum Genet. 2004;74(2):298–305. doi:10.1086/381715
34. Chen DB, Hilsenrath R, Yang ZM, Le SP, Kim SR, Chuong CJ, et al. Leukaemia inhibitory factor in human endometrium during the menstrual cycle: cellular origin and action on production of glandular epithelial cell prostaglandin in vitro. Hum Reprod. 1995;10(4):911–918. doi:10.1093/oxfordjournals.humrep.a136060
35. Laird SM, Tuckerman EM, Dalton CF, Dunphy BC, Li TC, Zhang X. The production of leukaemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Hum Reprod. 1997;12(3):569–574. doi:10.1093/humrep/12.3.569
36. Aghajanova L, Stavreus-Evers A, Nikas Y, Hovatta O, Landgren BM. Coexpression of pinopodes and leukemia inhibitory factor, as well as its receptor, in human endometrium. Fertil Steril. 2003;79:808–814. doi:10.1016/S0015-0282(02)04830-6
37. Sharkey AM, Dellow K, Blayney M, Macnamee M, Charnock-Jones S, Smith SK. Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos. Biol Reprod. 1995;53(4):974–981. doi:10.1095/biolreprod53.4.974
38. Hambartsoumian E. Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation. Am J Reprod Immunol. 1998;39(2):137–143. doi:10.1111/j.1600-0897.1998.tb00345.x
39. Tawfeek MA, Eid MA, Hasan AM, Mostafa M, El-Serogy HA. Assessment of leukemia inhibitory factor and glycoprotein 130 expression in endometrium and uterine flushing: a possible diagnostic tool for impaired fertility. BMC Womens Health. 2012;12:10. doi:10.1186/1472-6874-12-10
40. Mariee N, Li TC, Laird SM. Expression of leukaemia inhibitory factor and interleukin 15 in endometrium of women with recurrent implantation failure after IVF; correlation with the number of endometrial natural killer cells. Hum Reprod. 2012;27(7):1946–1954. doi:10.1093/humrep/des134
41. Wu M, Yin Y, Zhao M, Hu L, Chen Q. The low expression of leukemia inhibitory factor in endometrium: possible relevant to unexplained infertility with multiple implantation failures. Cytokine. 2013;62(2):334–339. doi:10.1016/j.cyto.2013.03.002
42. Margioula-Siarkou C, Prapas Y, Petousis S, Milias S, Ravanos K, Kalogiannidis I, et al. LIF and LIF-R expression in the endometrium of fertile and infertile women: a prospective observational case-control study. Mol Med Rep. 2016;13(6):4721–4728. doi:10.3892/mmr.2016.5142
43. Choi Y, Kim HR, Lim EJ, Park M, Yoon JA, Kim YS, et al. Integrative analyses of uterine transcriptome and microRNAome reveal compromised LIF-STAT3 signaling and progesterone response in the endometrium of patients with recurrent/repeated implantation failure (RIF). PLoS One. 2016;11(6):e0157696. doi:10.1371/journal.pone.0157696
44. Subramani E, Madogwe E, Ray CD, Dutta SK, Chakravarty B, Bordignon V, et al. Dysregulated leukemia inhibitory factor and its receptor regulated signal transducers and activators of transcription 3 pathway: a possible cause for repeated implantation failure in women with dormant genital tuberculosis? Fertil Steril. 2016;105(4):1076–1084.e5. doi:10.1016/j.fertnstert.2015.12.015
45. Serafini PC, Silva IDCG, Smith GD, Motta ELA, Rocha AM, Baracat EC. Endometrial claudin-4 and leukemia inhibitory factor are associated with assisted reproduction outcome. Reprod Biol Endocrinol. 2009;7:30. doi:10.1186/1477-7827-7-30
46. Lédée-Bataille N, Laprée-Delage G, Taupin J, Dubanchet S, Frydman R, Chaouat G. Concentration of leukaemia inhibitory factor (LIF) in uterine flushing fluid is highly predictive of embryo implantation. Hum Reprod. 2002;17(1):213–218. doi:10.1093/humrep/17.1.213
47. Brinsden PR, Alam V, de Moustier B, Engrand P. Recombinant human leukemia inhibitory factor does not improve implantation and pregnancy outcomes after assisted reproductive techniques in women with recurrent unexplained implantation failure. Fertil Steril. 2009;91(4):1445–1447. doi:10.1016/j.fertnstert.2008.06.047
48. Aghajanova L. Leukemia inhibitory factor and human embryo implantation. Ann N Y Acad Sci. 2004;1034:176–183. doi:10.1196/annals.1335.020
49. Kimber SJ. Leukaemia inhibitory factor in implantation and uterine biology. Reproduction. 2005;130(2):131–145. doi:10.1530/rep.1.00304
50. Salleh N, Giribabu N. Leukemia inhibitory factor: roles in embryo implantation and in nonhormonal contraception. ScientificWorldJournal. 2014;2014:201514. doi:10.1155/2014/201514
51. Rosario GX, Stewart CL. The multifaceted actions of leukaemia inhibitory factor in mediating uterine receptivity and embryo implantation. Am J Reprod Immunol. 2016;75(3):246–255. doi:10.1111/aji.12474
52. Dimitriadis E, White CA, Jones RL, Salamonsen LA. Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod Update. 2005;11(6):613–630. doi:10.1093/humupd/dmi023
53. Paiva P, Menkhorst E, Salamonsen L, Dimitriadis E. Leukemia inhibitory factor and interleukin-11: critical regulators in the establishment of pregnancy. Cytokine Growth Factor Rev. 2009;20(4):319–328. doi:10.1016/j.cytogfr.2009.07.001
54. Martin FJ, Amode MR, Aneja A, Austine-Orimoloye O, Azov AG, Barnes I, et al. Ensembl 2023. Nucleic Acids Res. 2023;51(D1):D933–D941. doi:10.1093/nar/gkac958
55. UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 2023;51(D1):D523–D531. doi:10.1093/nar/gkac1052
56. Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46(D1):D1062–D1067. doi:10.1093/nar/gkx1153
57. 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526(7571):68–74. doi:10.1038/nature15393
58. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–443. doi:10.1038/s41586-020-2308-7
59. Okahisa Y, Ujike H, Kunugi H, Ishihara T, Kodama M, Takaki M, et al. Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(1):172–176. doi:10.1016/j.pnpbp.2009.10.020
60. Moudi M, Sargazi S, Heidari Nia M, Saravani R, Shirvaliloo M, Shakiba M. Polymorphism in the 3′-UTR of LIF but not in the ATF6B gene associates with schizophrenia susceptibility: a case-control study and in silico analyses. J Mol Neurosci. 2020;70(12):2093–2101. doi:10.1007/s12031-020-01616-6
61. Ucisik-Akkaya E, Davis CF, Do TN, Morrison BA, Stemmer SM, Amadio WJ, et al. Examination of genetic polymorphisms in newborns for signatures of sex-specific prenatal selection. Mol Hum Reprod. 2010;16(10):770–777. doi:10.1093/molehr/gaq047
62. Jacovas VC, Rovaris DL, Peréz O, de Azevedo S, Macedo GS, Sandoval JR, et al. Genetic variations in the TP53 pathway in Native Americans strongly suggest adaptation to the high altitudes of the Andes. PLoS One. 2015;10(9):e0137823. doi:10.1371/journal.pone.0137823
63. Alipour M, Mashayekhi F, Salehi Z. Association of leukemia inhibitory factor gene polymorphism and in vitro fertilization outcome in a population in northern Iran. Cell Mol Biol (Noisy-le-grand). 2017;63(3):58–61. doi:10.14715/cmb/2017.63.3.11
64. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71
65. Little J, Higgins JPT, Ioannidis JPA, Moher D, Gagnon F, von Elm E, et al. STrengthening the REporting of Genetic Association Studies (STREGA): an extension of the STROBE statement. PLoS Med. 2009;6(2):e1000022. doi:10.1371/journal.pmed.1000022
66. Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, et al. The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod. 2017;32(9):1786–1801. doi:10.1093/humrep/dex234
67. Wigginton JE, Cutler DJ, Abecasis GR. A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet. 2005;76(5):887–893. doi:10.1086/429864
68. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–605. doi:10.1007/s10654-010-9491-z
69. Attia J, Thakkinstian A, D'Este C. Meta-analyses of molecular association studies: methodologic lessons for genetic epidemiology. J Clin Epidemiol. 2003;56(4):297–303. doi:10.1016/S0895-4356(03)00011-8
70. Thakkinstian A, McElduff P, D'Este C, Duffy D, Attia J. A method for meta-analysis of molecular association studies. Stat Med. 2005;24(9):1291–1306. doi:10.1002/sim.2010
71. Minelli C, Thompson JR, Abrams KR, Thakkinstian A, Attia J. The choice of a genetic model in the meta-analysis of molecular association studies. Int J Epidemiol. 2005;34(6):1319–1328. doi:10.1093/ije/dyi169
72. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188. doi:10.1016/0197-2456(86)90046-2
73. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. doi:10.1136/bmj.327.7414.557
74. IntHout J, Ioannidis JPA, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med Res Methodol. 2014;14:25. doi:10.1186/1471-2288-14-25
75. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–634. doi:10.1136/bmj.315.7109.629
76. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–1101. doi:10.2307/2533446
77. Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002. doi:10.1136/bmj.d4002
78. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–926. doi:10.1136/bmj.39489.470347.AD
79. Fraga LR, Dutra CG, Boquett JA, Vianna FSL, Gonçalves RO, Paskulin DD, et al. p53 signaling pathway polymorphisms associated to recurrent pregnancy loss. Mol Biol Rep. 2014;41(3):1871–1877. doi:10.1007/s11033-014-3036-6
80. Králíčková M, Šíma R, Martínek P, Vaněček T, Ulčová-Gallová Z, Šíma P, et al. [The leukemia inhibitory factor gene mutations in the population of infertile women: the heterozygote transition G to A on the position 3400 does not affect the outcome of the infertility treatment]. Ceska Gynekol. 2007;72(4):293–298. Czech.
81. Novotný Z, Křížan J, Šíma R, Šíma P, Uher P, Zech N, et al. Leukaemia inhibitory factor (LIF) gene mutations in women diagnosed with unexplained infertility and endometriosis have a negative impact on the IVF outcome. A pilot study. Folia Biol (Praha). 2009;55(3):92–97.
82. Hussein ZF, Al-Musawi BJ, Aziz IH, Al-Dujaily SS. Role of leukemia inhibitory factor (LIF) gene variation on implantation rate following IVF program in PCOS and non PCOS women. Iraqi J Biotechnol. 2018;17(2):57–67.
83. Vagnini LD, Renzi A, Petersen B, Canas MCT, Petersen CG, Mauri AL, et al. Association between estrogen receptor 1 (ESR1) and leukemia inhibitory factor (LIF) polymorphisms can help in the prediction of recurrent implantation failure. Fertil Steril. 2019;111(3):527–534. doi:10.1016/j.fertnstert.2018.11.016
84. Liu YL, Lee CI, Liu CH, Cheng EH, Yang SF, Tsai HY, et al. Association between leukemia inhibitory factor gene polymorphism and clinical outcomes among young women with poor ovarian response to assisted reproductive technology. J Clin Med. 2023;12(3):796. doi:10.3390/jcm12030796
85. Vahdani S, Mashayekhi F, Bahadori MH, Salehi Z. Leukemia inhibitory factor Val64Met (rs41281637) genetic variation and circulating levels in risk prediction of in vitro fertilization and embryo transfer outcome. Middle East Fertil Soc J. 2025;30:36. doi:10.1186/s43043-025-00252-7
86. Králíčková M, Šíma R, Vaněček T, Šíma P, Rokyta Z, Ulčová-Gallová Z, et al. Leukemia inhibitory factor gene mutations in the population of infertile women are not restricted to nulligravid patients. Eur J Obstet Gynecol Reprod Biol. 2006;127(2):231–235. doi:10.1016/j.ejogrb.2006.02.008
87. Ali R, Iqbal MUN, Rehman R, Khan TA. Association of novel stop-gained leukaemia inhibitory factor receptor gene (rs121912501) variant, leukaemia inhibitory factor and ovarian steroids with unexplained infertility among Pakistani women. Int J Clin Pract. 2021;75(7):e14245. doi:10.1111/ijcp.14245
88. Ali R, Iqbal MUN, Rehman R, Khan TA. Interplay of “leukemia inhibitory factor receptor gene” (rs3099124) polymorphism, leukemia inhibitory factor and ovarian steroids with unexplained infertility. Nucleosides Nucleotides Nucleic Acids. 2023;42(9):718–730. doi:10.1080/15257770.2023.2188911
89. Tajeddin N, Ahadi AM, Javadi G, Ayat H. Investigation of polymorphisms in the upstream sequence of LIF and LIFR genes in the infertile women. Zahedan J Res Med Sci. 2021;23(1):e95239. doi:10.5812/zjrms.95239
90. Heydarzadeh MJ, Mehmannavaz Y. Effects of rs929271 SNP in leukemia inhibitory factor gene on recurrent pregnancy loss, placental location and fetal gender. Gene Cell Tissue. 2019;6(2):e86579. doi:10.5812/gct.86579
91. Giess R, Tanasescu I, Steck T, Sendtner M. Leukaemia inhibitory factor gene mutations in infertile women. Mol Hum Reprod. 1999;5(6):581–586. doi:10.1093/molehr/5.6.581
92. Ali R, Rehman R, Khan HN, Iqbal MUN, Khan TA. Association of glycoprotein GP130 polymorphisms (rs747379809, rs754547662) with unexplained infertility in women using TETRA-ARMS-PCR. J Coll Physicians Surg Pak. 2026;36(3):320. doi:10.29271/jcpsp.2026.03.320
93. Ioannidis JPA, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. Replication validity of genetic association studies. Nat Genet. 2001;29(3):306–309. doi:10.1038/ng749
94. Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N. Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst. 2004;96(6):434–442. doi:10.1093/jnci/djh075
95. Mrozikiewicz AE, Ożarowski M, Jędrzejczak P. Biomolecular markers of recurrent implantation failure—a review. Int J Mol Sci. 2021;22(18):10082. doi:10.3390/ijms221810082
96. Lessey BA, Young SL. What exactly is endometrial receptivity? Fertil Steril. 2019;111(4):611–617. doi:10.1016/j.fertnstert.2019.02.009
2. Coughlan C, Ledger W, Wang Q, Liu F, Demirol A, Gurgan T, et al. Recurrent implantation failure: definition and management. Reprod Biomed Online. 2014;28(1):14–38. doi:10.1016/j.rbmo.2013.08.011
3. Polanski LT, Baumgarten MN, Quenby S, Brosens J, Campbell BK, Raine-Fenning NJ. What exactly do we mean by 'recurrent implantation failure'? A systematic review and opinion. Reprod Biomed Online. 2014;28(4):409–423. doi:10.1016/j.rbmo.2013.12.006
4. ESHRE Working Group on Recurrent Implantation Failure; Cimadomo D, de los Santos MJ, Griesinger G, Lainas G, Le Clef N, McLernon DJ, et al. ESHRE good practice recommendations on recurrent implantation failure. Hum Reprod Open. 2023;2023(3):hoad023. doi:10.1093/hropen/hoad023
5. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345(19):1400–1408. doi:10.1056/NEJMra000763
6. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the 'black box' of early pregnancy loss. Hum Reprod Update. 2002;8(4):333–343. doi:10.1093/humupd/8.4.333
7. Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18(12):1754–1767. doi:10.1038/nm.3012
8. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Köntgen F, et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992;359(6390):76–79. doi:10.1038/359076a0
9. Chen JR, Cheng JG, Shatzer T, Sewell L, Hernandez L, Stewart CL. Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis. Endocrinology. 2000;141(12):4365–4372. doi:10.1210/endo.141.12.7855
10. Charnock-Jones DS, Sharkey AM, Fenwick P, Smith SK. Leukaemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA for the receptor at this time. J Reprod Fertil. 1994;101(2):421–426. doi:10.1530/jrf.0.1010421
11. Cullinan EB, Abbondanzo SJ, Anderson PS, Pollard JW, Lessey BA, Stewart CL. Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proc Natl Acad Sci U S A. 1996;93(7):3115–3120. doi:10.1073/pnas.93.7.3115
12. Hu W, Feng Z, Teresky AK, Levine AJ. p53 regulates maternal reproduction through LIF. Nature. 2007;450(7170):721–724. doi:10.1038/nature05993
13. Kang HJ, Feng Z, Sun Y, Atwal G, Murphy ME, Rebbeck TR, et al. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci U S A. 2009;106(24):9761–9766. doi:10.1073/pnas.0904280106
14. Steck T, Giess R, Suetterlin MW, Bolland M, Wiest S, Poehls UG, et al. Leukaemia inhibitory factor (LIF) gene mutations in women with unexplained infertility and recurrent failure of implantation after IVF and embryo transfer. Eur J Obstet Gynecol Reprod Biol. 2004;112(1):69–73. doi:10.1016/S0301-2115(03)00315-4
15. Oliveira JBA, Vagnini LD, Petersen CG, Renzi A, Oliveira-Pelegrin GR, Mauri AL, et al. Association between leukaemia inhibitory factor gene polymorphism and pregnancy outcomes after assisted reproduction techniques. Reprod Biomed Online. 2016;32(1):66–78. doi:10.1016/j.rbmo.2015.09.018
16. Paskulin DD, Cunha-Filho JS, Souza CAB, Bortolini MC, Hainaut P, Ashton-Prolla P. ESR1 rs9340799 is associated with endometriosis-related infertility and in vitro fertilization failure. Dis Markers. 2013;35(6):907–913. doi:10.1155/2013/796290
17. Palomares AR, Castillo-Domínguez AA, Ruiz-Galdón M, Rodriguez-Wallberg KA, Reyes-Engel A. Genetic variants in the p53 pathway influence implantation and pregnancy maintenance in IVF treatments using donor oocytes. J Assist Reprod Genet. 2021;38(12):3267–3275. doi:10.1007/s10815-021-02324-9
18. Bhatt H, Brunet LJ, Stewart CL. Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc Natl Acad Sci U S A. 1991;88(24):11408–11412. doi:10.1073/pnas.88.24.11408
19. Song H, Lim H, Das SK, Paria BC, Dey SK. Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice. Mol Endocrinol. 2000;14(8):1147–1161. doi:10.1210/mend.14.8.0498
20. Kelleher AM, Milano-Foster J, Behura SK, Spencer TE. Uterine glands coordinate on-time embryo implantation and impact endometrial decidualization for pregnancy success. Nat Commun. 2018;9(1):2435. doi:10.1038/s41467-018-04848-8
21. Hu W. The role of p53 gene family in reproduction. Cold Spring Harb Perspect Biol. 2009;1(6):a001073. doi:10.1101/cshperspect.a001073
22. Feng Z, Zhang C, Kang HJ, Sun Y, Wang H, Naqvi A, et al. Regulation of female reproduction by p53 and its family members. FASEB J. 2011;25(7):2245–2255. doi:10.1096/fj.10-180166
23. Gearing DP, Thut CJ, VandeBos T, Gimpel SD, Delaney PB, King J, et al. Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. EMBO J. 1991;10(10):2839–2848. doi:10.1002/j.1460-2075.1991.tb07833.x
24. Gearing DP, Comeau MR, Friend DJ, Gimpel SD, Thut CJ, McGourty J, et al. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992;255(5050):1434–1437. doi:10.1126/science.1542794
25. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003;374(1):1–20. doi:10.1042/BJ20030407
26. Nicola NA, Babon JJ. Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev. 2015;26(5):533–544. doi:10.1016/j.cytogfr.2015.07.001
27. Suman P, Malhotra SS, Gupta SK. LIF-STAT signaling and trophoblast biology. JAKSTAT. 2013;2(4):e25155. doi:10.4161/jkst.25155
28. Sun X, Bartos A, Whitsett JA, Dey SK. Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses. Mol Endocrinol. 2013;27(9):1492–1501. doi:10.1210/me.2013-1086
29. Lee JH, Kim TH, Oh SJ, Yoo JY, Akira S, Ku BJ, et al. Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus. FASEB J. 2013;27(7):2553–2563. doi:10.1096/fj.12-225664
30. Cheng JG, Chen JR, Hernandez L, Alvord WG, Stewart CL. Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation. Proc Natl Acad Sci U S A. 2001;98(15):8680–8685. doi:10.1073/pnas.151180898
31. Ware CB, Horowitz MC, Renshaw BR, Hunt JS, Liggitt D, Koblar SA, et al. Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development. 1995;121(5):1283–1299. doi:10.1242/dev.121.5.1283
32. Li M, Sendtner M, Smith A. Essential function of LIF receptor in motor neurons. Nature. 1995;378(6558):724–727. doi:10.1038/378724a0
33. Dagoneau N, Scheffer D, Huber C, Al-Gazali LI, Di Rocco M, Godard A, et al. Null leukemia inhibitory factor receptor (LIFR) mutations in Stüve-Wiedemann/Schwartz-Jampel type 2 syndrome. Am J Hum Genet. 2004;74(2):298–305. doi:10.1086/381715
34. Chen DB, Hilsenrath R, Yang ZM, Le SP, Kim SR, Chuong CJ, et al. Leukaemia inhibitory factor in human endometrium during the menstrual cycle: cellular origin and action on production of glandular epithelial cell prostaglandin in vitro. Hum Reprod. 1995;10(4):911–918. doi:10.1093/oxfordjournals.humrep.a136060
35. Laird SM, Tuckerman EM, Dalton CF, Dunphy BC, Li TC, Zhang X. The production of leukaemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Hum Reprod. 1997;12(3):569–574. doi:10.1093/humrep/12.3.569
36. Aghajanova L, Stavreus-Evers A, Nikas Y, Hovatta O, Landgren BM. Coexpression of pinopodes and leukemia inhibitory factor, as well as its receptor, in human endometrium. Fertil Steril. 2003;79:808–814. doi:10.1016/S0015-0282(02)04830-6
37. Sharkey AM, Dellow K, Blayney M, Macnamee M, Charnock-Jones S, Smith SK. Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos. Biol Reprod. 1995;53(4):974–981. doi:10.1095/biolreprod53.4.974
38. Hambartsoumian E. Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation. Am J Reprod Immunol. 1998;39(2):137–143. doi:10.1111/j.1600-0897.1998.tb00345.x
39. Tawfeek MA, Eid MA, Hasan AM, Mostafa M, El-Serogy HA. Assessment of leukemia inhibitory factor and glycoprotein 130 expression in endometrium and uterine flushing: a possible diagnostic tool for impaired fertility. BMC Womens Health. 2012;12:10. doi:10.1186/1472-6874-12-10
40. Mariee N, Li TC, Laird SM. Expression of leukaemia inhibitory factor and interleukin 15 in endometrium of women with recurrent implantation failure after IVF; correlation with the number of endometrial natural killer cells. Hum Reprod. 2012;27(7):1946–1954. doi:10.1093/humrep/des134
41. Wu M, Yin Y, Zhao M, Hu L, Chen Q. The low expression of leukemia inhibitory factor in endometrium: possible relevant to unexplained infertility with multiple implantation failures. Cytokine. 2013;62(2):334–339. doi:10.1016/j.cyto.2013.03.002
42. Margioula-Siarkou C, Prapas Y, Petousis S, Milias S, Ravanos K, Kalogiannidis I, et al. LIF and LIF-R expression in the endometrium of fertile and infertile women: a prospective observational case-control study. Mol Med Rep. 2016;13(6):4721–4728. doi:10.3892/mmr.2016.5142
43. Choi Y, Kim HR, Lim EJ, Park M, Yoon JA, Kim YS, et al. Integrative analyses of uterine transcriptome and microRNAome reveal compromised LIF-STAT3 signaling and progesterone response in the endometrium of patients with recurrent/repeated implantation failure (RIF). PLoS One. 2016;11(6):e0157696. doi:10.1371/journal.pone.0157696
44. Subramani E, Madogwe E, Ray CD, Dutta SK, Chakravarty B, Bordignon V, et al. Dysregulated leukemia inhibitory factor and its receptor regulated signal transducers and activators of transcription 3 pathway: a possible cause for repeated implantation failure in women with dormant genital tuberculosis? Fertil Steril. 2016;105(4):1076–1084.e5. doi:10.1016/j.fertnstert.2015.12.015
45. Serafini PC, Silva IDCG, Smith GD, Motta ELA, Rocha AM, Baracat EC. Endometrial claudin-4 and leukemia inhibitory factor are associated with assisted reproduction outcome. Reprod Biol Endocrinol. 2009;7:30. doi:10.1186/1477-7827-7-30
46. Lédée-Bataille N, Laprée-Delage G, Taupin J, Dubanchet S, Frydman R, Chaouat G. Concentration of leukaemia inhibitory factor (LIF) in uterine flushing fluid is highly predictive of embryo implantation. Hum Reprod. 2002;17(1):213–218. doi:10.1093/humrep/17.1.213
47. Brinsden PR, Alam V, de Moustier B, Engrand P. Recombinant human leukemia inhibitory factor does not improve implantation and pregnancy outcomes after assisted reproductive techniques in women with recurrent unexplained implantation failure. Fertil Steril. 2009;91(4):1445–1447. doi:10.1016/j.fertnstert.2008.06.047
48. Aghajanova L. Leukemia inhibitory factor and human embryo implantation. Ann N Y Acad Sci. 2004;1034:176–183. doi:10.1196/annals.1335.020
49. Kimber SJ. Leukaemia inhibitory factor in implantation and uterine biology. Reproduction. 2005;130(2):131–145. doi:10.1530/rep.1.00304
50. Salleh N, Giribabu N. Leukemia inhibitory factor: roles in embryo implantation and in nonhormonal contraception. ScientificWorldJournal. 2014;2014:201514. doi:10.1155/2014/201514
51. Rosario GX, Stewart CL. The multifaceted actions of leukaemia inhibitory factor in mediating uterine receptivity and embryo implantation. Am J Reprod Immunol. 2016;75(3):246–255. doi:10.1111/aji.12474
52. Dimitriadis E, White CA, Jones RL, Salamonsen LA. Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod Update. 2005;11(6):613–630. doi:10.1093/humupd/dmi023
53. Paiva P, Menkhorst E, Salamonsen L, Dimitriadis E. Leukemia inhibitory factor and interleukin-11: critical regulators in the establishment of pregnancy. Cytokine Growth Factor Rev. 2009;20(4):319–328. doi:10.1016/j.cytogfr.2009.07.001
54. Martin FJ, Amode MR, Aneja A, Austine-Orimoloye O, Azov AG, Barnes I, et al. Ensembl 2023. Nucleic Acids Res. 2023;51(D1):D933–D941. doi:10.1093/nar/gkac958
55. UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 2023;51(D1):D523–D531. doi:10.1093/nar/gkac1052
56. Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46(D1):D1062–D1067. doi:10.1093/nar/gkx1153
57. 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526(7571):68–74. doi:10.1038/nature15393
58. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–443. doi:10.1038/s41586-020-2308-7
59. Okahisa Y, Ujike H, Kunugi H, Ishihara T, Kodama M, Takaki M, et al. Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(1):172–176. doi:10.1016/j.pnpbp.2009.10.020
60. Moudi M, Sargazi S, Heidari Nia M, Saravani R, Shirvaliloo M, Shakiba M. Polymorphism in the 3′-UTR of LIF but not in the ATF6B gene associates with schizophrenia susceptibility: a case-control study and in silico analyses. J Mol Neurosci. 2020;70(12):2093–2101. doi:10.1007/s12031-020-01616-6
61. Ucisik-Akkaya E, Davis CF, Do TN, Morrison BA, Stemmer SM, Amadio WJ, et al. Examination of genetic polymorphisms in newborns for signatures of sex-specific prenatal selection. Mol Hum Reprod. 2010;16(10):770–777. doi:10.1093/molehr/gaq047
62. Jacovas VC, Rovaris DL, Peréz O, de Azevedo S, Macedo GS, Sandoval JR, et al. Genetic variations in the TP53 pathway in Native Americans strongly suggest adaptation to the high altitudes of the Andes. PLoS One. 2015;10(9):e0137823. doi:10.1371/journal.pone.0137823
63. Alipour M, Mashayekhi F, Salehi Z. Association of leukemia inhibitory factor gene polymorphism and in vitro fertilization outcome in a population in northern Iran. Cell Mol Biol (Noisy-le-grand). 2017;63(3):58–61. doi:10.14715/cmb/2017.63.3.11
64. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71
65. Little J, Higgins JPT, Ioannidis JPA, Moher D, Gagnon F, von Elm E, et al. STrengthening the REporting of Genetic Association Studies (STREGA): an extension of the STROBE statement. PLoS Med. 2009;6(2):e1000022. doi:10.1371/journal.pmed.1000022
66. Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, et al. The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod. 2017;32(9):1786–1801. doi:10.1093/humrep/dex234
67. Wigginton JE, Cutler DJ, Abecasis GR. A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet. 2005;76(5):887–893. doi:10.1086/429864
68. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–605. doi:10.1007/s10654-010-9491-z
69. Attia J, Thakkinstian A, D'Este C. Meta-analyses of molecular association studies: methodologic lessons for genetic epidemiology. J Clin Epidemiol. 2003;56(4):297–303. doi:10.1016/S0895-4356(03)00011-8
70. Thakkinstian A, McElduff P, D'Este C, Duffy D, Attia J. A method for meta-analysis of molecular association studies. Stat Med. 2005;24(9):1291–1306. doi:10.1002/sim.2010
71. Minelli C, Thompson JR, Abrams KR, Thakkinstian A, Attia J. The choice of a genetic model in the meta-analysis of molecular association studies. Int J Epidemiol. 2005;34(6):1319–1328. doi:10.1093/ije/dyi169
72. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188. doi:10.1016/0197-2456(86)90046-2
73. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. doi:10.1136/bmj.327.7414.557
74. IntHout J, Ioannidis JPA, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med Res Methodol. 2014;14:25. doi:10.1186/1471-2288-14-25
75. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–634. doi:10.1136/bmj.315.7109.629
76. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–1101. doi:10.2307/2533446
77. Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002. doi:10.1136/bmj.d4002
78. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–926. doi:10.1136/bmj.39489.470347.AD
79. Fraga LR, Dutra CG, Boquett JA, Vianna FSL, Gonçalves RO, Paskulin DD, et al. p53 signaling pathway polymorphisms associated to recurrent pregnancy loss. Mol Biol Rep. 2014;41(3):1871–1877. doi:10.1007/s11033-014-3036-6
80. Králíčková M, Šíma R, Martínek P, Vaněček T, Ulčová-Gallová Z, Šíma P, et al. [The leukemia inhibitory factor gene mutations in the population of infertile women: the heterozygote transition G to A on the position 3400 does not affect the outcome of the infertility treatment]. Ceska Gynekol. 2007;72(4):293–298. Czech.
81. Novotný Z, Křížan J, Šíma R, Šíma P, Uher P, Zech N, et al. Leukaemia inhibitory factor (LIF) gene mutations in women diagnosed with unexplained infertility and endometriosis have a negative impact on the IVF outcome. A pilot study. Folia Biol (Praha). 2009;55(3):92–97.
82. Hussein ZF, Al-Musawi BJ, Aziz IH, Al-Dujaily SS. Role of leukemia inhibitory factor (LIF) gene variation on implantation rate following IVF program in PCOS and non PCOS women. Iraqi J Biotechnol. 2018;17(2):57–67.
83. Vagnini LD, Renzi A, Petersen B, Canas MCT, Petersen CG, Mauri AL, et al. Association between estrogen receptor 1 (ESR1) and leukemia inhibitory factor (LIF) polymorphisms can help in the prediction of recurrent implantation failure. Fertil Steril. 2019;111(3):527–534. doi:10.1016/j.fertnstert.2018.11.016
84. Liu YL, Lee CI, Liu CH, Cheng EH, Yang SF, Tsai HY, et al. Association between leukemia inhibitory factor gene polymorphism and clinical outcomes among young women with poor ovarian response to assisted reproductive technology. J Clin Med. 2023;12(3):796. doi:10.3390/jcm12030796
85. Vahdani S, Mashayekhi F, Bahadori MH, Salehi Z. Leukemia inhibitory factor Val64Met (rs41281637) genetic variation and circulating levels in risk prediction of in vitro fertilization and embryo transfer outcome. Middle East Fertil Soc J. 2025;30:36. doi:10.1186/s43043-025-00252-7
86. Králíčková M, Šíma R, Vaněček T, Šíma P, Rokyta Z, Ulčová-Gallová Z, et al. Leukemia inhibitory factor gene mutations in the population of infertile women are not restricted to nulligravid patients. Eur J Obstet Gynecol Reprod Biol. 2006;127(2):231–235. doi:10.1016/j.ejogrb.2006.02.008
87. Ali R, Iqbal MUN, Rehman R, Khan TA. Association of novel stop-gained leukaemia inhibitory factor receptor gene (rs121912501) variant, leukaemia inhibitory factor and ovarian steroids with unexplained infertility among Pakistani women. Int J Clin Pract. 2021;75(7):e14245. doi:10.1111/ijcp.14245
88. Ali R, Iqbal MUN, Rehman R, Khan TA. Interplay of “leukemia inhibitory factor receptor gene” (rs3099124) polymorphism, leukemia inhibitory factor and ovarian steroids with unexplained infertility. Nucleosides Nucleotides Nucleic Acids. 2023;42(9):718–730. doi:10.1080/15257770.2023.2188911
89. Tajeddin N, Ahadi AM, Javadi G, Ayat H. Investigation of polymorphisms in the upstream sequence of LIF and LIFR genes in the infertile women. Zahedan J Res Med Sci. 2021;23(1):e95239. doi:10.5812/zjrms.95239
90. Heydarzadeh MJ, Mehmannavaz Y. Effects of rs929271 SNP in leukemia inhibitory factor gene on recurrent pregnancy loss, placental location and fetal gender. Gene Cell Tissue. 2019;6(2):e86579. doi:10.5812/gct.86579
91. Giess R, Tanasescu I, Steck T, Sendtner M. Leukaemia inhibitory factor gene mutations in infertile women. Mol Hum Reprod. 1999;5(6):581–586. doi:10.1093/molehr/5.6.581
92. Ali R, Rehman R, Khan HN, Iqbal MUN, Khan TA. Association of glycoprotein GP130 polymorphisms (rs747379809, rs754547662) with unexplained infertility in women using TETRA-ARMS-PCR. J Coll Physicians Surg Pak. 2026;36(3):320. doi:10.29271/jcpsp.2026.03.320
93. Ioannidis JPA, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. Replication validity of genetic association studies. Nat Genet. 2001;29(3):306–309. doi:10.1038/ng749
94. Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N. Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst. 2004;96(6):434–442. doi:10.1093/jnci/djh075
95. Mrozikiewicz AE, Ożarowski M, Jędrzejczak P. Biomolecular markers of recurrent implantation failure—a review. Int J Mol Sci. 2021;22(18):10082. doi:10.3390/ijms221810082
96. Lessey BA, Young SL. What exactly is endometrial receptivity? Fertil Steril. 2019;111(4):611–617. doi:10.1016/j.fertnstert.2019.02.009
Statistics
0 Views | 0 Downloads
How to Cite
Jabbar, D. K. (2026). Leukemia Inhibitory Factor (LIF) and LIF Receptor (LIFR) Gene Polymorphisms and Implantation and Pregnancy Outcomes After Assisted Reproduction: A Systematic Review and Meta-Analysis. Journal of Integral Sciences, 9(2), 114-130. https://doi.org/10.37022/jis.v9i2.160
Issue
Section
Research Article(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright © Author(s) retain the copyright of this article.
