Role of genetic factors in recurrent miscarriages - A review

Constant Ndjapa-Ndamkou, Logie Govender, Lawrence Chauke

Abstract

Recurrent miscarriage is classically defined as three or more consecutive pregnancy losses in about 1–5% of couples trying to conceive. However, several researchers have amended this to two or more because of the recent increase in childless miscarriages. Recurrent miscarriage is a clinical challenge for clinicians because there are many possible causes, and diagnostic testing is expensive and time-consuming. Established causes of recurrent miscarriage are antiphospholipid antibodies, uterine anomalies, and abnormal chromosomes in either partner, particularly translocations. Uterine anatomical abnormalities, endocrine abnormalities, infections, immunologic factors, environmental factors, metabolic or hormonal disorders, sperm quality, and maternal and paternal age have each been linked. Among them, the genetic factor plays a significant role in recurrent miscarriage. Approximately 70% of miscarriage conceptions with sporadic spontaneous miscarriage reveal some chromosome abnormality. Specifically, recurrent miscarriage can be caused by a structural or numerical defect in the parents' or fetus' chromosomes. Recurrent miscarriage has been linked to several genes, including those involved in oxidative stress, angiogenesis, clotting, and inflammation. Despite several well-known etiologic factors, the etiology of recurrent miscarriage is unknown in over half of all instances. The current review aims to analyse the role of the genetic basis of recurrent miscarriages. (Afr J Reprod Health 2022; 26[10]: 72-82).

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Sugiura-Ogasawara M, Ozaki Y and Kitaori, T. Diagnosis and treatment methods for recurrent miscarriage cases. Reprod Med Biol 2009, 8, 141–144.

Coomarasamy A, Dhillon-Smith RK, Papadopoulou A, Al-Memar M, Brewin J, Abrahams VM, Maheshwari A, Christiansen OB, Stephenson MD, Goddijn M, Oladapo OT, Wijeyaratne CN, Bick D, Shehata H, Small R, Bennett PR, Regan L, Rai R, Bourne T, Kaur R, Pickering O, Brosens JJ, Devall AJ, Gallos ID and Quenby S. Recurrent miscarriage: evidence to accelerate action. Lancet, 2021, 397, 1675–1682.

Homer HA. Modern management of recurrent miscarriage. Aust New Zeal J Obstet Gynaecol , 2019, 36–44.

Vomstein K, Feil K, Strobel L, Aulitzky A, Hofer-Tollinger S, Kuon RJ and Toth B. Immunological Risk Factors in Recurrent Pregnancy Loss: Guidelines Versus Current State of the Art. J Clin Med 10, 2021, 869.

Christiansen OB. Special Issue Recurrent Pregnancy Loss: Etiology, Diagnosis, and Therapy. J Clin Med, 2021, 10, 5040.

Ford HB and Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol, 2009, 2, 76.

Alijotas-Reig J and Garrido-Gimenez C. Current Concepts and New Trends in the Diagnosis and Management of Recurrent Miscarriage. Obstet Gynecol Surv, 2013 68, 445–466.

van Dijk MM, Kolte AM, Limpens J, Kirk E, Quenby S, van Wely M and Goddijn M. Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? A systematic review of the literature and meta-analysis. Hum Reprod Update. 2020, 26, 356–367.

Sugiura-Ogasawara M, Ozaki Y, Sato T, Suzumori N and Suzumori K. Poor prognosis of recurrent aborters with either maternal or paternal reciprocal translocations. Fertil Steril. 2004, 81, 367–373.

Sierra S and Stephenson M. Genetics of Recurrent Pregnancy Loss. Semin Reprod Med. 2006, 24, 017–024.

Sugiura Ogasawara, M. et al. The polycystic ovary syndrome does not predict further miscarriage in Japanese couples experiencing recurrent miscarriages. Am J Reprod Immunol. 2009, 61, 62–67.

Magnus MC, Hockey RL, Håberg SE and Mishra GD. Pre-pregnancy lifestyle characteristics and risk of miscarriage: the Australian Longitudinal Study on Women’s Health. BMC Pregnancy Childbirth. 2022, 22, 169.

Roepke ER, Christiansen OB, Matthiesen L and Rylance R. Is the incidence of recurrent pregnancy loss increasing? A retrospective register-based study in Sweden. J Reprod Immunol. 2018, 128, 58.

Magnus MC, Wilcox AJ, Morken NH, Weinberg CR and Håberg SE. Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study. BMJ l869 2019. doi:10.1136/bmj.l869.

Risch HA, Weiss NS, Aileen CE and Miller Ab. Risk factors for spontaneous abortion and its recurrence. Am J Epidemiol. 1988, 128, 420–430.

Knudsen UB, Hansen V, Juul S and Secher NJ. Prognosis of a new pregnancy following previous spontaneous abortions. Eur J Obstet Gynecol Reprod Biol. 1991, 39, 31–36.

Kling C, Hedderich J and Kabelitz D. Fertility after recurrent miscarriages: results of an observational cohort study. Arch Gynecol Obstet. 2018, 297, 205–219.

Andersen AMN. Maternal age and fetal loss: population based register linkage study. BMJ. 2020, 320, 1708–1712.

Saravelos SH and Li TC. Unexplained recurrent miscarriage: how can we explain it? Hum Reprod. 2012, 27, 1882–1886.

Hassold T and Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet. 2001, 2, 280–291.

Gabriel AS, Hassold TJ, Thornhill AR, Affara NA, Handyside AH and Griffin DK. An algorithm for determining the origin of trisomy and the positions of chiasmata from SNP genotype data. Chromosom Res. 2011, 19, 155–163.

Nagaoka SI, Hassold TJ and Hunt PA. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat Rev Genet. 2012, 13, 493–504.

Capalbo A, Hoffmann ER, Cimadomo D, Maria Ubaldi F and Rienzi L. Human female meiosis revised: new insights into the mechanisms of chromosome segregation and aneuploidies from advanced genomics and time-lapse imaging. Hum Reprod Update. 2017, 23, 706–722.

Gruhn JR, Zielinska AP, Shukla V, Blanshard R, Capalbo A, Cimadomo D, Nikiforov D, Chan AC, Newnham LJ, Vogel I, Scarica C, Krapchev M, Taylor D, Kristensen SG, Cheng J, Ernst E, Bjørn AB, Colmorn LB, Blayney M, Elder K, Liss J, Hartshorne G, Grøndahl ML, Rienzi L, Ubaldi F, McCoy R, Lukaszuk K, Andersen CY, Schuh M and Hoffmann ER. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science. 2019, (80- ) 365, 1466–1469.

Maconochie N, Doyle P, Prior S and Simmons R. Risk factors for first trimester miscarriage-results from a UK-population-based case-control study. BJOG An Int J Obstet Gynaecol. 2007, 114, 170–186.

Ogasawara M, Aoki K, Okada S and Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril. 2000, 73, 300–304.

Coomarasamy A, Devall AJ, Brosens JJ, Quenby S, Stephenson MD, Sierra S, Christiansen OB, Small R, Brewin J, Roberts TE, Dhillon-Smith R, Harb H, Noordali H, Papadopoulou A, Eapen A, Prior M, Di Renzo GC, Hinshaw K, Mol BW, Lumsden MA, Khalaf Y, Shennan A, Goddijn M, van Wely M, Al-Memar M, Bennett P, Bourne T, Rai R, Regan L and Gallos ID. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. Am J Obstet Gynecol. 2020, 223, 167–176.

Pereza N, Ostojić S, Kapović M and Peterlin B. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril. 2017, 107, 150-159.e2.

Colley E, Hamilton S, Smith P, Morgan NV, Coomarasamy A and Allen S. Potential genetic causes of miscarriage in euploid pregnancies: a systematic review. Hum Reprod Update. 2019, 25, 452–472.

Kolte AM, Nielsen HS, Moltke I, Degn B, Pedersen B, Sunde L, Nielsen FC and Christiansen OB. A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic linkage. MHR Basic Sci Reprod Med. 2011, 17, 379–385.

Woolner AMF, Nagdeve P, Raja E, Bhattacharya S and Bhattacharya S. Family history and risk of miscarriage: A systematic review and meta‐analysis of observational studies. Acta Obstet Gynecol Scand. 2020, 99, 1584–1594.

Krieg SA, Shahine LK and Lathi RB. Environmental exposure to endocrine-disrupting chemicals and miscarriage. Fertil Steril. 2016, 106, 941–947.

Xue T, Zhu T, Geng G and Zhang Q. Association between pregnancy loss and ambient PM2•5 using survey data in Africa: a longitudinal case-control study, 1998–2016. Lancet Planet Heal. 2019, 3, e219-ee225.

ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, Nelen W, Peramo B, Quenby S, Vermeulen N and Goddijn M. Recurrent pregnancy loss. Hum Reprod Open 2018.

Braekeleer MD and Dao TN. Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod. 1990, 5, 519–528.

Sugiura-Ogasawara M, Aoki K, Fujii T, Fujita T, Kawaguchi R, Maruyama T, Ozawa N, Sugi T, Takeshita T and Saito S. Subsequent pregnancy outcomes in recurrent miscarriage patients with a paternal or maternal carrier of a structural chromosome rearrangement. J Hum Genet. 2008, 53, 622–628.

Franssen MT, Korevaar JC, van der Veen F, Leschot NJ, Bossuyt PM and Goddijn M. Reproductive outcome after chromosome analysis in couples with two or more miscarriages: case-control study. BMJ. 2006, 332, 759–763.

Ocak Z, Özlü T and Ozyurt O. Association of recurrent pregnancy loss with chromosomal abnormalities and hereditary thrombophilias. Afr Health Sci. 2013, 13.

Gaboon NEA, Mohamed AR, Elsayed SM, Zaki OK and Elsayed MA. Structural chromosomal abnormalities in couples with recurrent abortion in Egypt. TURKISH J Med Sci, 2015, 45, 208–213.

Dong Y, Li LL, Wang RX, Yu XW, Yun X and Liu RZ. Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of chromosome abnormalities or polymorphisms. Genet Mol Res. 2014 13, 2849–2856.

Liao Y, Wang L, Zhang D and Liu C. Identification of a balanced complex chromosomal rearrangement involving chromosomes 3, 18 and 21 with recurrent abortion: case report. Mol Cytogenet. 2014, 7, 39.

Nonaka T, Ooki I, Enomoto T and Takakuwa K. Complex chromosomal rearrangements in couples affected by recurrent spontaneous abortion. Int J Gynecol Obstet 2015, 128, 36–39.

Laissue P, Burgio G, l'Hôte D, Renault G, Marchiol-Fournigault C, Fradelizi D, Fellous M, Serres C, Montagutelli X, Monget P and Vaiman D. Identification of Quantitative Trait Loci responsible for embryonic lethality in mice assessed by ultrasonography. Int J Dev Biol 2009, 53, 623–629.

Yildirim ME, Karakus S, Kurtulgan HK, Baser B and Sezgin I. The type and prevalence of chromosomal abnormalities in couples with recurrent first trimester abortions: A Turkish retrospective study. J Gynecol Obstet Hum Reprod 2019, 48, 521–525.

Alonso López AG, Bermejo Huerta S, Hernández Galván R, AyalaPosadas R, González del Angel A and González PG. [Cytogenetic diagnosis of first trimester spontaneous abortion]. Ginecol Obstet Mex 2011, 79, 779–84.

Bombell S and McGuire W. Cytokine polymorphisms in women with recurrent pregnancy loss: Meta-analysis. Aust New Zeal J Obstet Gynaecol 2008, 48, 147–154.

Choi YK and Kwak-Kim J. Review Article: Cytokine Gene Polymorphisms in Recurrent Spontaneous Abortions: A Comprehensive Review. Am J Reprod Immunol 2008, 60, 91–110.

Levrant S, Coulam CB and Jeyendran RS. Original Article: Interleukin 1 Receptor Antagonist Gene Polymorphisms Are Not Risk Factors for Recurrent Pregnancy Loss: Evaluation of Couples. Am J Reprod Immunol 2008, 60, 224–228.

Faridi RM, Das V, Tripthi G, Talwar S, Parveen F and Agrawal S. Influence of activating and inhibitory killer immunoglobulin-like receptors on predisposition to recurrent miscarriages. Hum Reprod 2009, 24, 1758–1764.

Kaare M, Ulander VM, Painter JN, Ahvenainen T, Kaaja R, and Aittomäki K. Variations in the thrombomodulin and endothelial protein C receptor genes in couples with recurrent miscarriage. Hum Reprod 2007, 22, 864–868.

Kupferminc MJ. Thrombophilia and pregnancy. Reprod Biol Endocrinol 2003, 1, 1–22.

Kutteh WH and Triplett DA. Thrombophilias and Recurrent Pregnancy Loss. Semin Reprod Med 2006, 24, 054–066.

Goodman C, Goodman CS, Hur J, Jeyendran RS and Coulam C. The association of Apoprotein E polymorphisms with recurrent pregnancy loss. Am J Reprod Immunol 2009, 61, 34–8.

Bogdanova N, Horst J, Chlystun M, Croucher PJ, Nebel A, Bohring A, Todorova A, Schreiber S, Gerke V, Krawczak M and Markoff A. A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss. Hum Mol Genet 2007, 16, 573–578.

Rull K, Nagirnaja L, Ulander VM, Kelgo P, Margus T, Kaare M, Aittomäki K and Laan M. Chorionic Gonadotropin β-Gene Variants Are Associated with Recurrent Miscarriage in Two European Populations. J Clin Endocrinol Metab 2008, 93, 4697–4706.

Kaare M, Götz A, Ulander VM, Ariansen S, Kaaja R, Suomalainen A and Aittomäki K. Do mitochondrial mutations cause recurrent miscarriage? Mol Hum Reprod 2009, 15, 295–300.

Parveen F, Faridi RM, Das V, Tripathi G and Agrawal S. Genetic association of phase I and phase II detoxification genes with recurrent miscarriages among North Indian women. Mol Hum Reprod 2010, 16, 207–214.

Rey E, Kahn SR, David M and Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003, 361, 901–908.

Bolor H, Mori T, Nishiyama S, Ito Y, Hosoba E, Inagaki H, Kogo H, Ohye T, Tsutsumi M, Kato T, Tong M, Nishizawa H, Pryor-Koishi K, Kitaoka E, Sawada T, Nishiyama Y, Udagawa Y and Kurahashi H. Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss. Am J Hum Genet 2009, 84, 14–20.

Hunt PA and Hassold TJ. Sex Matters in Meiosis. Science (80- ) 2002, 296, 2181–2183.

Yuan L, Liu JG, Zhao J, Brundell E, Daneholt B and Höög C. The Murine SCP3 Gene Is Required for Synaptonemal Complex Assembly, Chromosome Synapsis, and Male Fertility. Mol Cell 2000, 5, 73–83.

Yuan L, Liu JG, Hoja MR, Wilbertz J, Nordqvist K and Höög C. Female Germ Cell Aneuploidy and Embryo Death in Mice Lacking the Meiosis-Specific Protein SCP3. Science (80- ) 2002, 296, 1115–1118.

Revenkova E, Eijpe M, Heyting C, Hodges CA, Hunt PA, Liebe B, Scherthan H and Jessberger R. Cohesin SMC1β is required for meiotic chromosome dynamics, sister chromatid cohesion and DNA recombination. Nat Cell Biol 2004, 6, 555–562.

Hodges CA, Revenkova E, Jessberger R, Hassold TJ and Hunt PA. SMC1β-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction. Nat Genet 2005, 37, 1351–1355.

Kuznetsov S, Pellegrini M, Shuda K, Fernandez-Capetillo O, Liu Y, Martin BK, Burkett S, Southon E, Pati D, Tessarollo L, West SC, Donovan PJ, Nussenzweig A and Sharan SK. RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. J Cell Biol 2007, 176, 581–592.

Sugiura-Ogasawara M and Suzumori K. Can preimplantation genetic diagnosis improve success rates in recurrent aborters with translocations? Hum Reprod 2005, 20, 3267–3270.

Lee HS, Jun JH, Choi HW, Lim CK, Yoo HW, Koong MK and Kang IS. Preimplantation Genetic Diagnosis for Ornithine Transcarbamylase Deficiency by Simultaneous Analysis of Duplex-nested PCR and Fluorescence In Situ Hybridization: A Case Report. J Korean Med Sci 2007, 22, 572.

Kyu Lim C, Hyun Jun J, Mi Min D, Lee HS, Young Kim J, Koong MK and Kang IS. Efficacy and clinical outcome of preimplantation genetic diagnosis using FISH for couples of reciprocal and Robertsonian translocations: the Korean experience. Prenat Diagn 2004, 24, 556–561.

Platteau P, Staessen C, Michiels A, Van Steirteghem A, Liebaers I and Devroey P. Preimplantation genetic diagnosis for aneuploidy screening in patients with unexplained recurrent miscarriages. Fertil Steril 2005, 83, 393–397.

Rubio C, Bellver J, Rodrigo L, Castillón G, Guillén A, Vidal C, Giles J, Ferrando M, Cabanillas S, Remohí J, Pellicer A and Simón C. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study. Fertil Steril 2017, 107, 1122–1129.

Tur-Torres MH, Garrido-Gimenez C and Alijotas-Reig J. Genetics of recurrent miscarriage and fetal loss. Best Pract Res Clin Obstet Gynaecol 2017, 42, 11–25.

Martín J, Cervero A, Mir P, Martinez-Conejero JA, Pellicer A and Simón C. The impact of next-generation sequencing technology on preimplantation genetic diagnosis and screening. Fertil Steril 2013, 99, 1054-1061.e3.

Treff NR, Fedick A, Tao X, Devkota B, Taylor D and Scott RT Jr. Evaluation of targeted next-generation sequencing–based preimplantation genetic diagnosis of monogenic disease. Fertil Steril 2013, 99, 1377-1384.e6.

Yin X, Tan K, Vajta G, Jiang H, Tan Y, Zhang C, Chen F, Chen S, Zhang C, Pan X, Gong C, Li X, Lin C, Gao Y, Liang Y, Yi X, Mu F, Zhao L, Peng H, Xiong B, Zhang S, Cheng D, Lu G, Zhang X, Lin G and Wang W. Massively Parallel Sequencing for Chromosomal Abnormality Testing in Trophectoderm Cells of Human Blastocysts1. Biol Reprod 2013, 88.

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