Methylenetetrahydrofolate Reductase Polymorphisms and Pregnancy Outcome

Abstract

Introduction Aim of the study was to evaluate the effect of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on pregnancy outcome.

Materials and Methods A total of 617 pregnancies of women who were investigated for MTHFR C677T and A1298C polymorphisms prior to pregnancy were included in the study. Cases were classified into “homozygous polymorphisms” (Group I), “heterozygous polymorphisms” (Group II), and patients without polymorphisms who functioned as controls (Group III). Patients with polymorphisms were assigned to a specific protocol at least 3 months before becoming pregnant. Administration of low molecular weight heparin (LMWH) was started very early during pregnancy. The Beksac Obstetrics Index (BOI) was used to estimate the obstetric risk levels for the different groups.

Results We found that the early pregnancy loss (EPL) rate increased as MTHFR polymorphism complexity increased and that the early EPL rate was significantly higher in patients with MTHFR C677T polymorphism compared to patients with MTHFR A1298C polymorphism (p = 0.039). There were significant differences between the previous pregnancies of the patients in the 3 study groups in terms of perinatal complications and EPLs (p = 0.003 and p = 0.019). The BOI decreased as the severity of polymorphisms increased. An association between MTHFR polymorphisms and congenital malformations and chromosomal abnormalities was observed. We could not demonstrate any statistically significant difference between study groups when the 3 groups were compared with regard to the pregnancy outcomes under specific management protocols.

Conclusion MTHFR polymorphisms are potential risk factors for adverse pregnancy outcomes.

Zusammenfassung

Einleitung Ziel dieser Studie war es, die Auswirkungen von Methylentetrahydrofolatreduktase-(MTHFR-)Polymorphismen auf das Schwangerschafts-Outcome zu untersuchen.

Material und Methoden Es wurden insgesamt 617 Schwangerschaften von Frauen, bei denen vor der aktuellen Schwangerschaft eine Untersuchung auf MTHFR-C677T- und -A1298C-Polymorphismen durchgeführt wurde, in die Studie aufgenommen. Die Frauen wurden in 3 Gruppen eingeteilt: „homozygote Polymorphismen“ (Gruppe I), „heterozygote Polymorphismen“ (Gruppe II) sowie Frauen ohne Polymorphismen, die als Kontrolle fungierten (Gruppe III). Patientinnen mit Polymorphismen wurden mindestens 3 Monate vor ihrer Schwangerschaft einem spezifischen Protokoll zugeordnet. Mit der Verabreichung von niedermolekularem Heparin (LMWH) wurde bereits sehr früh während der Schwangerschaft begonnen. Der Beksac Obstetrics Index (BOI) wurde zur Schätzung des geburtshilflichen Risikos der 3 Gruppen verwendet.

Ergebnisse Es zeigte sich, dass der Anstieg der Frühabortrate mit einem Anstieg an MTHFR-Polymorphismus-Komplexität einherging und dass die Frühabortrate bei Frauen mit MTHFR-C677T-Polymorphismen signifikant höher war als bei Frauen mit MTHFR-A1298C-Polymorphismen (p = 0,039). Es gab signifikante Unterschiede zwischen den früheren Schwangerschaften der Patientinnen in den 3 Untersuchungsgruppen in Bezug auf perinatale Komplikationen und Frühaborte (p = 0,003 bzw. p = 0,019). Der BOI nahm mit zunehmendem Schweregrad der Polymorphismen ab. Es wurde auch eine Assoziation zwischen MTHFR-Polymorphismen und angeborenen Fehlbildungen sowie Chromosomenanomalien beobachtet. Beim Vergleich der 3 Studiengruppen in Bezug auf Schwangerschafts-Outcome und Managementprotokoll konnten wir keinen statistisch signifikanten Unterschied feststellen.

Schlussfolgerung MTHFR-Polymorphismen sind ein potenzieller Risikofaktor für einen ungünstigen Schwangerschaftsverlauf.

Key words

pregnancy loss - placenta - preeclampsia - MTHFR

Schlüsselwörter

Abort - Plazenta - Präeklampsie - MTHFR

• References

• 1 Lykke J, Bare L, Olsen J. et al. Thrombophilias and adverse pregnancy outcomes: results from the Danish National Birth Cohort. J Thromb Haemost 2012; 10: 1320-1325
• 2 Nurk E, Tell GS, Refsum H. et al. Associations between maternal methylenetetrahydrofolate reductase polymorphisms and adverse outcomes of pregnancy: the Hordaland Homocysteine Study. Am J Med 2004; 117: 26-31
• 3 Pitkin RM. Folate and neural tube defects. Am J Clin Nutr 2007; 85: 285S-288S
• 4 Pan X, Wang P, Yin X. et al. Association between maternal MTHFR polymorphisms and nonsyndromic cleft lip with or without cleft palate in offspring, a meta-analysis based on 15 case-control studies. Inter J Fertil Steril 2015; 8: 463
• 5 Burke G, Robinson K, Refsum H. et al. Intrauterine growth retardation, perinatal death, and maternal homocysteine levels. N Engl J Med 1992; 326: 69-70
• 6 Goddijn-Wessel TA, Wouters MG, van de Molen EF. et al. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 1996; 66: 23-29
• 7 Tiwari D, Bose PD, Das S. et al. MTHFR (C677T) polymorphism and PR (PROGINS) mutation as genetic factors for preterm delivery, fetal death and low birth weight: A Northeast Indian population based study. Meta Gene 2015; 3: 31-42
• 8 Rady PL, Szucs S, Grady J. et al. Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A. Am J Med Genet 2002; 107: 162-168
• 9 Sazci A, Ergul E, Kaya G. et al. Genotype and allele frequencies of the polymorphic methylenetetrahydrofolate reductase gene in Turkey. Cell Biochem Funct 2005; 23: 51-54
• 10 Angeline T, Jeyaraj N, Granito S. et al. Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians. Exp Mol Pathol 2004; 77: 85-88
• 11 Perez ABA, DʼAlmeida V, Vergani N. et al. Methylenetetrahydrofolate reductase (MTHFR): incidence of mutations C677T and A1298C in Brazilian population and its correlation with plasma homocysteine levels in spina bifida. Am J Med Genet 2003; 119: 20-25
• 12 Esfahani ST, Cogger EA, Caudill MA. Heterogeneity in the prevalence of methylenetetrahydrofolate reductase gene polymorphisms in women of different ethnic groups. J Am Diet Assoc 2003; 103: 200-207
• 13 Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene 2014; 533: 11-20
• 14 Bhargava S, Tyagi S. Nutriepigenetic regulation by folate–homocysteine–methionine axis: a review. Mol Cell Biochem 2014; 387: 55-61
• 15 Şahin TG, Sayal B, Coşgun E. et al. Methylenetetrahydrofolate Reductase Enzyme Mutations and Relationship of Homocysteine Vitamin B12 and Folate Blood Levels. Gynecol Obstet Reprod Med 2016; 19: 1-6
• 16 Stover PJ. One-carbon metabolism–genome interactions in folate-associated pathologies. J Nutr 2009; 139: 2402-2405
• 17 Aydın E, Ceylan AC, Beksaç MS. The Relationship Between Methylation Defects and Different Genetic Disorders: Two Case Reports. Gynecol Obstet Reprod Med 2016; 22: 110-112 doi:10.21613/GORM.2016.484
• 18 Frederiksen J, Juul K, Grande P. et al. Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study. Blood 2004; 104: 3046-3051
• 19 Harpel PC, Zhang X, Borth W. Homocysteine and hemostasis: pathogenetic mechanisms predisposing to thrombosis. J Nutr 1996; 126 (Suppl. 04) 1285S
• 20 Tsitsiou E, Sibley CP, DʼSouza SW. et al. Homocysteine transport by systems L, A and y+L across the microvillous plasma membrane of human placenta. J Physiol 2009; 587: 4001-4013
• 21 Jansson T. Novel mechanism causing restricted fetal growth: does maternal homocysteine impair placental amino acid transport?. J Physiol 2009; 587: 4123
• 22 Hoffer LJ. Homocysteine remethylation and trans-sulfuration. Metabolism 2004; 53: 1480-1483
• 23 Solanky N, Jimenez AR, DʼSouza S. et al. Expression of folate transporters in human placenta and implications for homocysteine metabolism. Placenta 2010; 31: 134-143
• 24 Beksaç K, Örgül G, Çagan M. et al. Retrospective evaluation of pregnant women with celiac disease. J Turk Ger Gynecol Assoc 2017; 18: 56
• 25 Kamudhamas A, Pang L, Smith SD. et al. Homocysteine thiolactone induces apoptosis in cultured human trophoblasts: a mechanism for homocysteine-mediated placental dysfunction?. Am J Obstet Gynecol 2004; 191: 563-571
• 26 Beksaç MS, Aydın E, Turgal M. et al. An Obstetrics Index for the Assessment of Risk Levels of “High Risk Pregnancy” Groups. Gynecol Obstet Reprod Med 2016; 21: 10-13
• 27 Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome?: A systematic review. Eur J Obstet Gynecol Reprod Bio 2002; 101: 6-14
• 28 da Silva LR, Vergani N, Galdieri Lde C. et al. Relationship between polymorphisms in genes involved in homocysteine metabolism and maternal risk for Down syndrome in Brazil. Am J Med Genet A 2005; 135: 263-267
• 29 Turgal M, Yazicioglu A, Ozyuncu O. et al. Impaired DNA methylation leading to heterotrisomy. J Obstet Gynaecol 2013; 33: 904-905
• 30 Wenstrom KD, Johanning GL, Owen J. et al. Amniotic fluid homocysteine levels, 5, 10-methylenetetrahydrafolate reductase genotypes, and neural tube closure sites. Am J Med Genet 2000; 90: 6-11
• 31 van Beynum IM, Kapusta L, den Heijer M. et al. Maternal MTHFR 677C> T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation. Eur Heart J 2006; 27: 981-987
• 32 Amorim MR, Lima MA, Castilla EE. et al. Non-Latin European descent could be a requirement for association of NTDs and MTHFR variant 677C> T. Am J Med Genet 2007; 143: 1726-1732
• 33 Botto LD, Yang Q. 5, 10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 2000; 151: 862-877
• 34 Wu X, Zhao L, Zhu H. et al. Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: a meta-analysis. Genet Test Mol Biomarkers 2012; 16: 806-811
• 35 Nair RR, Khanna A, Singh R. et al. Association of maternal and fetal MTHFR A1298C polymorphism with the risk of pregnancy loss: a study of an Indian population and a meta-analysis. Fertil Steril 2013; 99: 1311-1318.e4
• 36 Kosar A, Kasapoglu B, Kalyoncu S. et al. Treatment of adverse perinatal outcome in inherited thrombophilias: a clinical study. Blood Coagul Fibrinolysis 2011; 22: 14-18
• 37 Laskin CA, Spitzer KA, Clark CA. et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol 2009; 36: 279-287
• 38 Aracic N, Roje D, Drmic Hofman I. et al. Low molecular weight heparin treatment and impact of inherited thrombophilia type in pregnancies with previous adverse outcome. J Matern Fetal Neonatal Med 2015; 28: 306-310
• 39 Wang X, Fu J, Li Q. et al. Geographical and Ethnic Distributions of the MTHFR C677T, A1298C and MTRR A66G Gene Polymorphisms in Chinese Populations: A Meta-Analysis. PLoS One 2016; 11: e0152414