TEKRARLAYAN GEBELİK KAYIPLARINDA ETİYOLOJİNİN AÇIKLANMASINA YÖNELİK YENİ YAKLAŞIMLAR

Tekrarlayan gebelik kayıpları tüm dünyada yaklaşık %1-3 oranında görülmekte olup, yıllardır üzerinde çalışılan bir konudur. Gebelik, üreme hücrelerinin üretiminden başlayarak, fertilizasyon, implantasyon, embriyolojik gelişim süreçleri, plasentanın oluşumu, feto-maternal kan dolaşımının sağlanması ve gebeliğin devamını kapsayan oldukça geniş ve farklı süreçleri içermektedir. Bu süreçlerden herhangi birinde, ilişkili bir yolağı etkileyen faktörler gebelik kayıplarında altta yatan sebep olabilir. Yeni teknolojiler ile birlikte gebelik kayıplarında etiyolojide yer alan genetik faktörlerin sadece kromozom anomalileri değil, tek gen mutasyonları ya da farklı genetik faktörlerin de olduğu gösterilmektedir. Yeni gen/lerin tanımlanması ve yolakların aktivitesinin anlaşılması sebebi açıklanamayan olgu grubunda tanı ve tedavi yaklaşımlarını değiştirebilecek güçtedir.

Anahtar Kelimeler:

Tekrarlayan gebelik kayıpları, yeni nesil dizileme, genetik

NEW APPROACHES TO EXPLAINING THE ETIOLOGY IN RECURRENT PREGNANCY LOSSES

Recurrent pregnancy losses are seen in approximately 1-3% of the world’s pregnancies and it has been a subject that has been studied for years. Pregnancy includes the production of fertile cells, fertilization, implantation, embryological development processes, the formation of the placenta, the provision of feto-maternal blood circulation and the continuity of pregnancy. Factors affecting an associated pathway in any of these processes may be the underlying cause of pregnancy loss. With the new technologies, it has started to be shown that genetic factors in etiology in pregnancy losses are not only chromosome anomalies, but also single-gene mutations or different genetic factors. The identification of new gene/s and the understanding of the activity of the pathways are compelling enough to change the diagnosis and treatment approaches in the unexplained cases group.

Keywords:

Recurrent pregnancy loss, next generation sequencing, genetics,

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1. Practice Committee Opinion of the American Society for Reproductive Medicine (ASRM). Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012;98(5):1103-11. [CrossRef]
2. Hacettepe Üniversitesi Nüfus Etütleri Enstitüsü (2014). 2013 Türkiye Nüfus ve Sağlık Araştırması. Hacettepe Üniversitesi Nüfus Etütleri Enstitüsü, T.C. Kalkınma Bakanlığı ve TÜBİTAK, Ankara, Türkiye.
3. Hacettepe Üniversitesi Nüfus Etütleri Enstitüsü (2019). 2018 Türkiye Nüfus ve Sağlık Araştırması. Hacettepe Üniversitesi Nüfus Etütleri Enstitüsü, T.C. Cumhurbaşkanlığı Strateji ve Bütçe Başkanlığı ve TÜBİTAK, Ankara, Türkiye.
4. Kolte AM, van Oppenraaji RH, Quenby S, Farquharson RG, Stephenson M, Goddijn M. Eshre, S.I.G.E.P. Nonvisualized pregnancy loses are prognostically important for unexplained recurrent miscarriage. Human Reproduction 2014;29:931-7. [CrossRef]
5. Kutteh WH. Novel strategies for the management of Recurrent Pregnancy Loss. Semin Reprod Med 2015;33:161-8. [CrossRef]
6. Yatsenko AN, Turek PJ. Reproductive genetics and the aging male. J Ass Rep Gen 2018;35:933-41. [CrossRef]
7. Goddijn M, Christiensen OB, Elson J. Recurrent Pregnancy Loss, Guideline of European Society of Human Reproduction and Embriology; 2017 (November).
8. Royal College Obstetricians and Gynecologists (RCOG). The Investigation and Treatment of Couples with Recurrent first Trimester and Second Trimester Miscarriage. R Coll Obstet Gynaecol 2011;17:1-18.
9. Lee S-K, Na BJ, Kim JY, Hur SE, Lee M, Gilman-Sachs A, et al. Determination of Clinical Cellular Immune Markers in Women with Recurrent Pregnancy Loss. Am J Reprod Immunol 2013;70(5):398-411. [CrossRef]
10. 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(1):157-65. [CrossRef]
11. Ford HB, Schust DJ, Recurrent pregnancy loss: etiology, diagnosis and therapy. Rev Obstet Gyneacol 2009;2(2):76-83.
12. Rote NS, Lyden TW, Vogt E, Ng AK. Chapter 18: Antiphospolipid antibodies and placental development. In: Hunt JS, editor. Immunobiology of Reproduction. New York: Springer-Verlag; 1994:285-302. [CrossRef]
13. Katsuragawa H, Kazaki H, Inoue T, Hirano T, Mori T, Rote NS. Monoclonal antibody against phosphotidyl serine inhibits in vitro human trophoblastic hormone production and invasion. Biol Reprod 1997;56:50-8. [CrossRef]
14. DiSimone N, Costelleie R, Caliandro D, Caruso A, Monoclonal anti-annexin V antibody inhibits trophoblast gonadotrophin secretion and induces syncytiotrophoblast apoptosis. Biol Reprod 2011;65:1766-70. [CrossRef]
15. Girardi G, Bulla R, Salmon JE, Tedesco F. The complement system in the pathophysiology of pregnancy. Mole Immunol 2006;43:68-77. [CrossRef]
16. Laskin CA, Bombardier C, Hannah ME, Mandel FP, Ritchie JW, Farewell V, et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N. Engl J Med 1997;337(3):148-53. [CrossRef]
17. Gur C, Diav-Citrin O, Shechtman S, Arnon J, Ornay A. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 2004;18(1):93-101. [CrossRef]
18. Stephenson MD, Kutteh WH, Purkiss S, Librach C, Schultz P, Houlihan E, et al. Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial. Hum Reprod 2010;25(9):2203-2209. [CrossRef]
19. Mehta S, Gupta B editors. Recurrent Pregnancy Loss. Springer Nature Singapore Pte Ltd; 2018. [CrossRef]
20. Grimbizis GF, Camus M, Tarlatzis BC, Bontis JN, Devroey P. Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update 2001;7:161-74. [CrossRef]
21. Jaslow C. Uterin factor. Obstet Gynecol Clin North Am 2014;41(1):57-86. [CrossRef]
22. Salim S, Won H, Nesbitt-Hawes E, Campbell N, Abbott J. Diagnosis and management of endometrial polyps: a critical review of the literature. J Minim Invasive Gynecol 2011;18(5):569-81. [CrossRef]
23. Leitich H, Kiss H. Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome. Best Pract Res Clin Obstet Gynaecol 2007;21:37590. [CrossRef]
24. Sheekohi S, Mojarrad M, Raoofian R, Ahmadzadeh S, Mirzaie S, Hassanzadeh-Nazarabadi M. Chromosomal study of couples with the history of recurrent spontaneous abortions with diagnosed blighted ovum. Int J Mol Cell Med 2013;2(4):164-8.
25. Annan JJK, Gudi A, Bhide P, Shah A, Homburg R. Biochemical pregnancy during assisted conception: a little bit pregnant. J Clin Med Res 2013;5(4):269-74. [CrossRef]
26. Wang J, Fan HC, Behr B, Quake SR. Genome-wide single cell analysis of recombination activity and de novo mutation rates in human sperm. Cell 2012;150(2):402-12.
27. van den Boogard E, Hermens RPMG, Verhoeve HR, Kremer JAM, van der Veen F, Knegt AC, et al. Selective karyotyping in recurrent miscarriage: are recommended guidelines adopted in daily practice?. Hum Reprod 2011;26:1965-70.
28. Levy B, Wapner R. Prenatal Diagnosis by Chromosomal Microarray Analysis. Fertil Steril 2018;109(2):201-12. [CrossRef]
29. Lindqvist PG. Debate: Should thromboprophylaxis be used in hereditary thrombophilias with recurrent pregnancy loss? No. Editör: Carp H.J.A. Recurrent pregnancy loss, causes, controversies, and treatment, second edition. CRC Press. Florida: 2015.
30. Sullivan AE, Lewis T, Stephenson M, Odem R, Schreiber J, Ober C,et al. Pregnancy outcome in recurrent miscarriage patients with skewed X chromosome inactivation. Obstet Gynecol 2003;101(6):1236-42. [CrossRef]
31. Moghbeli M. Genetics of recurrent pregnancy loss among Iranian population. Mol Genet Genomic Med. 2019;7:e891. [CrossRef]
32. Kolte AM, Nielsen HS, Moltke I, Degn B, Pedersen B, Sunde L,et al. A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggest genetic linkage. Mol Hum Reprod 2011;17(6):379-85. [CrossRef]
33. Su M-T, Lin S-H, Chen Y-C. Genetic association studies of angiogenesis and vasoconstriction related genes in women with recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod Update 2011;17:803-12. [CrossRef]
34. Suzuki T, Behnam M, Ronasian F, Salehi M, Shiina M, Koshimizu E,et al. A homozygous NOP14 variant is likely to cause recurrent pregnancy loss. J Hum Genet 2018;63:42530. [CrossRef]
35. Shehab O, Tester DJ, Ackerman NC, Cowchock FS, Ackerman MJ. Whole genome sequencing identifies etiology of recurrent male intrauterine fetal death. Prenat Diagn 2017;37:1040-5. [CrossRef]
36. Spellicy CJ, Norris J, Bend R, Bupp C, Mester P, Reynolds T,et al. Key apoptotic genes APAF1 and CASP9 implicated in recurrent folate-resistant neural tube defects. Eur J Hum Genet 2018;26(3):420-7. [CrossRef]
37. Shamseldin HE, Swaid A, Alkuraya FS. Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing. Genet Med 2013;15:307-9.
38. Docherty LE, Rezwan FI, Poole RL, Turner CL, Kivuva E, Maher ER, et al. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans. Nat Commun 2015;6:8086. [CrossRef]
39. Quintero-Ronderos P, Mercier E, Fukuda M, Gonzalez R, Suarez CF, Patarroyo MA, et al. Novel genes and mutations in patients affected by recurrent pregnancy loss. PLoS One 2017;12:e0186149. [CrossRef]
40. Cristofoli F, de Keersmaecker B, de Catte L, Vermeesch JR, Van Esch H. Novel STIL compund heterozygous mutations cause severe fetal microcephaly and centriolar lengthening. Mol Syndromol 2017;8:282-93. [CrossRef]
41. Qiao Y, Wen J, Tng F, Martell S, Shomer N, Leung PC, et al. Whole exome sequencing in recurrent early pregnancy loss. Mol Hum Reprod 2016;22(5):364-72. [CrossRef] 42. Tsurusaki Y, Yonezawa R, Furuya M, Nishimura G, Pooh RK, Nakashima M, et al. Whole exome sequencing revealed biallelic IFT122 mutations in a family with CED1 and recurrent pregnancy loss. Clin Genet 2014;85:592-4. [CrossRef]
43. Qian J, Nguyen NMP, Rezaei M, Huang B, Tao Y, Zhang X, et al. Biallelic PADI6 variants linking infertility, miscarriages and hydatidiform moles. Eur J Hum Genet 2018;26:1007-13. [CrossRef]
44. Pan H, Xiang H, Wang J, Wei Z, Zhou Y, Liu B, et al. CAPS mutations are potentially associated with unexplained recurrent pregnancy loss. Am J Pathol 2019;189(1):124-31. [CrossRef]
45. Wilbe M, Ekvali S, Eurenius K, Ericson K, Casar-Borota O, Klar J, et al. MuSK: a new target for lethal fetal akinesia deformation sequence (FADS). J Med Genet 2015;52:195202. [CrossRef]
46. Begemann M, Rezwan FI, Beygo J, Docherty LE, Kolarova J, Schroeder C, et al. Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring. J Med Genet 2018;55:497-504.