Abstract
Introduction/objectives
Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever, serositis, and arthritis, but some patients may experience long-term complications of disease such as infertility/subfertility. The published data about FMF-associated infertility is still limited. The aim of this study is to investigate the frequency and to determine potential factors for FMF-associated infertility/subfertility.
Methods
We enrolled 971 adult patients with FMF. We defined infertility as the failure to conceive after 12 months of regular, unprotected intercourse. All patients fulfilled Tel Hashomer criteria. Demographic data, FMF disease characteristics and genotype data (if available), disease complications, laboratory parameters, and treatment features were recorded.
Results
There were 582 subjects eligible for the present study (mean age 41.05 ± 10.6 years, 65.8% female). MEFV mutations were available in 482 subjects, and 74.9% of subjects were harboring M694 V mutation (25.1% homozygous for M694 V). Infertility was present in 64 patients (14.6% of females and 4% of males). Multivariate analysis showed female sex [odds ratio (OR), 4.47; 95% confidence interval (CI95%) 1.75–11.42; p = 0.002], FMF disease onset < 20 years [OR, 2.99; (CI95% 1.04–8.61);p = 0.04], disease severity (ISSF) [OR, 4.81; (CI95% 2.28–10.17); p < 0.001], and colchicine nonresponse [OR, 2.80; (CI95% 1.17–6.74) p = 0.021] were the independent predictors of infertility. We also observed reversal of infertility in five patients who were treated with IL-1 β antagonists.
Conclusion
Disease severity, FMF disease onset < 20 years, colchicine nonresponse, and female sex were found to be the independent predictors of infertility. The value of effective therapeutic interventions must be determined to treat infertility in these patients.
Key Points •The prevalence of infertility increased in female patients with FMF. • Female sex, FMF disease onset < 20 years, disease severity, and colchicine nonresponse were risk factors for FMF-associated infertility. • With effective treatment of FMF, reversal of infertility was observed in five patients. |
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References
Gafni J, Ravid M, Sohar E (1968) The role of amyloidosis in familial Mediterranean fever. A population study. Isr J Med Sci 4(5):995–999
Onen F (2006) Familial Mediterranean fever. Rheumatol Int 26(6):489–496. https://doi.org/10.1007/s00296-005-0074-3
van der Hilst JC, Simon A, Drenth JP (2005) Hereditary periodic fever and reactive amyloidosis. Clin Exp Med 5(3):87–98. https://doi.org/10.1007/s10238-005-0071-6
Barut K, Sahin S, Adrovic A, Sinoplu AB, Yucel G, Pamuk G, Aydın AK, Dasdemir S, Turanlı ET, Buyru N, Kasapcopur O (2018) Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int 38(1):67–74. https://doi.org/10.1007/s00296-017-3796-0
Berkun Y, Ben-Chetrit E, Klar A, Ben-Chetrit E (2007) Peritoneal adhesions and intestinal obstructions in patients with familial Mediterranean fever--are they more frequent? Semin Arthritis Rheum 36(5):316–321. https://doi.org/10.1016/j.semarthrit.2006.11.002
Ben-Chetrit E, Levy M (2003) Reproductive system in familial Mediterranean fever: an overview. Ann Rheum Dis 62(10):916–919
Mijatovic V, Hompes PG, Wouters MG (2003) Familial Mediterranean fever and its implications for fertility and pregnancy. Eur J Obstet Gynecol Reprod Biol 108(2):171–176
Practice Committee of tAmerican Society for Reproductive, M (2008) Definitions of infertility and recurrent pregnancy loss. Fertil Steril 90(5 Suppl):S60. https://doi.org/10.1016/j.fertnstert.2008.08.065
Sarac M, Koc I (2018) Prevalence and risk factors of infertility in Turkey: evidence from demographic and health surveys, 1993-2013. J Biosoc Sci 50(4):472–490. https://doi.org/10.1017/S0021932017000244
Ismajovich B, Zemer D, Revach M, Serr DM, Sohar E (1973) The causes of sterility in females with familial Mediterranean fever. Fertil Steril 24(11):844–847
Ehrenfeld M, Brzezinski A, Levy M, Eliakim M (1987) Fertility and obstetric history in patients with familial Mediterranean fever on long-term colchicine therapy. Br J Obstet Gynaecol 94(12):1186–1191
Ehrenfeld EN, Polishuk WZ (1970) Gynecological aspects of recurrent polyserositis (familial Mediterrranean fever, periodic disease). Isr J Med Sci 6(1):9–13
Granat M, Tur-Kaspa I, Zylber-Katz E, Schenker JG (1983) Reduction of peritoneal adhesion formation by colchicine: a comparative study in the rat. Fertil Steril 40(3):369–372
Mamou H (1970) Periodic disease and endocrine disorders. Sem Hop 46(29):2024–2029
Ben-Chetrit A, Ben-Chetrit E, Nitzan R, Ron M (1993) Colchicine inhibits spermatozoal motility in vitro. Int J Fertil Menopausal Stud 38(5):301–304
Yanmaz MN, Ozcan AJ, Savan K (2014) The impact of familial Mediterranean fever on reproductive system. Clin Rheumatol 33(10):1385–1388. https://doi.org/10.1007/s10067-014-2709-9
Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40(10):1879–1885. https://doi.org/10.1002/1529-0131(199710)40:10<1879::AID-ART23>3.0.CO;2-M
Ter Haar NM, Annink KV, Al-Mayouf SM, Amaryan G, Anton J, Barron KS et al (2017) Development of the autoinflammatory disease damage index (ADDI). Ann Rheum Dis 76(5):821–830. https://doi.org/10.1136/annrheumdis-2016-210092
Demirkaya E, Acikel C, Hashkes P, Gattorno M, Gul A, Ozdogan H, Turker T, Karadag O, Livneh A, Ben-Chetrit E, Ozen S, FMF Arthritis Vasculitis and Orphan disease Research in pediatric rheumatology (FAVOR) (2016) Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF). Ann Rheum Dis 75(6):1051–1056. https://doi.org/10.1136/annrheumdis-2015-208671
Tufan A, Babaoglu MO, Akdogan A, Yasar U, Calguneri M, Kalyoncu U et al (2007) Association of drug transporter gene ABCB1 (MDR1) 3435C to T polymorphism with colchicine response in familial Mediterranean fever. J Rheumatol 34(7):1540–1544
Berkun Y, Padeh S, Reichman B, Zaks N, Rabinovich E, Lidar M, Shainberg B, Livneh A (2007) A single testing of serum amyloid a levels as a tool for diagnosis and treatment dilemmas in familial Mediterranean fever. Semin Arthritis Rheum 37(3):182–188. https://doi.org/10.1016/j.semarthrit.2007.03.005
Aksentijevich I, Centola M, Deng Z, Sood R, Balow JE, Wood G et al (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 90(4):797–807
Park H, Bourla AB, Kastner DL, Colbert RA, Siegel RM (2012) Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol 12(8):570–580. https://doi.org/10.1038/nri3261
Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, Ozdogan H, Abu I, Gattorno M, Hawkins PN, Yuce S, Kallinich T, Bilginer Y, Kastner D, Carmona L (2016) EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 75(4):644–651. https://doi.org/10.1136/annrheumdis-2015-208690
Varan O, Kucuk H, Babaoglu H, Guven SC, Ozturk MA, Haznedaroglu S et al (2018) Efficacy and safety of interleukin-1 inhibitors in familial Mediterranean fever patients complicated with amyloidosis. Mod Rheumatol 1–4. https://doi.org/10.1080/14397595.2018.1457469
Dimitriadis E, White CA, Jones RL, Salamonsen LA (2005) Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod Update 11(6):613–630. https://doi.org/10.1093/humupd/dmi023
Prutsch N, Fock V, Haslinger P, Haider S, Fiala C, Pollheimer J, Knöfler M (2012) The role of interleukin-1beta in human trophoblast motility. Placenta 33(9):696–703. https://doi.org/10.1016/j.placenta.2012.05.008
Knofler M, Pollheimer J (2012) IFPA award in placentology lecture: molecular regulation of human trophoblast invasion. Placenta 33(Suppl):S55–S62. https://doi.org/10.1016/j.placenta.2011.09.019
Kauma SW, Walsh SW, Nestler JE, Turner TT (1992) Interleukin-1 is induced in the human placenta by endotoxin and isolation procedures for trophoblasts. J Clin Endocrinol Metab 75(3):951–955. https://doi.org/10.1210/jcem.75.3.1517391
Fazleabas AT, Kim JJ, Strakova Z (2004) Implantation: embryonic signals and the modulation of the uterine environment--a review. Placenta 25(Suppl A):S26–S31. https://doi.org/10.1016/j.placenta.2004.01.014
Karagouni EE, Chryssikopoulos A, Mantzavinos T, Kanakas N, Dotsika EN (1998) Interleukin-1beta and interleukin-1alpha may affect the implantation rate of patients undergoing in vitro fertilization-embryo transfer. Fertil Steril 70(3):553–559
Krussel JS, Simon C, Rubio MC, Pape AR, Wen Y, Huang HY, Bielfeld P, Polan ML (1998) Expression of interleukin-1 system mRNA in single blastomeres from human preimplantation embryos. Hum Reprod 13(8):2206–2211
Romero R, Gotsch F, Pineles B, Kusanovic JP (2007) Inflammation in pregnancy: its roles in reproductive physiology, obstetrical complications, and fetal injury. Nutr Rev 65(12 Pt 2):S194–S202
D'Ippolito S, Tersigni C, Marana R, Di Nicuolo F, Gaglione R, Rossi ED et al (2016) Inflammosome in the human endometrium: further step in the evaluation of the “maternal side”. Fertil Steril 105(1):111–118 e111-114. https://doi.org/10.1016/j.fertnstert.2015.09.027
Ozcakar ZB, Ozdel S, Yilmaz S, Kurt-Sukur ED, Ekim M, Yalcinkaya F (2016) Anti-IL-1 treatment in familial Mediterranean fever and related amyloidosis. Clin Rheumatol 35(2):441–446. https://doi.org/10.1007/s10067-014-2772-2
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This work was supported by grants from Hacettepe Rheumatology Association. Grant No. HRD2018-001.
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Atas, N., Armagan, B., Bodakci, E. et al. Familial Mediterranean fever-associated infertility and underlying factors. Clin Rheumatol 39, 255–261 (2020). https://doi.org/10.1007/s10067-019-04773-1
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DOI: https://doi.org/10.1007/s10067-019-04773-1