Association Of Genetic Polymorphisms Related To Folate Metabolism And Prenatal Maternal Serum Markers In The Second Trimester For Screening Adverse Pregnancy Outcomes

BackgroundAdverse pregnancy outcomes mainly include abortion,premature delivery,low birth weight infants,hypertension during pregnancy,etc.,which not only seriously affects the health quality of mother and child,but also causes heavy economic and mental burden to the family and society.At present,the causes of adverse pregnancy outcome is not clear,but some studies have shown that it is related to genetic factors and related gene mutations.Methylenetrahydrofolate reductase（MTHFR）and methionine synthase reductase（MTRR）are key enzymes of folic acid metabolism,which are involved in the metabolism and transport of folic acid.The genes of these enzymes have polymorphisms,which can change the activity of the enzyme.In recent years,the correlation between MTHFR and MTRR gene mutation sites and a variety of maternal and child diseases（such as infertility,hypertension during pregnancy,congenital heart disease,etc.）has become a hot topic.Serological screening indexes such as AFP,free estriol（UE₃）and Freeβ-human chorionic gonadotropin（β-HCG）were used to screen fetal aneuploidy such as trisomy 21 and trisomy 18 and open neural tube defects in the second trimester of pregnancy.A number of studies have shown that serum screening results can not only screen target diseases,but also are closely related to a variety of adverse pregnancy outcomes.However,the current studies on the specific prediction of adverse pregnancy outcomes due to abnormal changes in serum indicators are inconsistent,and no consistent diagnosis and treatment specifications have been reached for abnormal management of serum markers.This study mainly analyzed the correlation between adverse pregnancy outcomes,folate metabolism-related gene polymorphisms and serological indicators in the second trimester,so as to provide certain reference for clinical prediction and prevention of adverse pregnancy and strengthen the attention to prenatal examination.ObjectiveIn this study,by analyzing the relationship between MTHFR and MTRR gene polymorphisms and adverse pregnancy outcomes,we expected to find genetic risk factors for adverse pregnancy.To explore the correlation between serological prenatal screening indicators in the second trimester and adverse pregnancy outcomes,and to evaluate its predictive value,so as to provide clinical basis for early detection of adverse pregnancy and reduce the incidence of adverse pregnancy outcomes.Material and methodsFrom October 2018 to August 2020,500 pregnant women with adverse pregnancy outcomes who received folic acid metabolism related gene detection and serological prenatal screening in the second trimester of pregnancy in the Third Affiliated Hospital of Zhengzhou University were selected as the adverse pregnancy outcome group,adverse pregnancy outcomes including fetal loss（including unexplained abortion,stillbirth）,fetal deformity（including congenital heart disease,digestive system,and other system malformation）,premature birth,low birth weight,gestational hypertension disease and placental abruption.A total of 500 healthy full-term pregnant women with normal pregnancy outcome were randomly selected as the control group.Pregnancy outcome data were collected through electronic records of outpatient and inpatient systems of the Third Affiliated Hospital of Zhengzhou University,Down’s screening application form,and Birth Defects Registration Card in the delivery room.The genotypes and gene frequencies of folate metabolism-related genes MTHFR C677T,A1298C and MTRR A66G in pregnant women with adverse pregnancy outcome group and control group were compared retrospectively,in order to find out the genetic risk factors of adverse pregnancy.The levels of AFP,β-HCG and UE₃ in serum of pregnant women in the two groups were compared,and the correlation between serum indexes and adverse pregnancy outcomes was analyzed.The predictive value of single serum indexes and the combination of serum indexes on adverse pregnancy outcomes was compared.The experimental data were statistically analyzed using SPSS 25.0 and Graph Pad Prism9.0 software.Result1.Compared with the control group,there was no significant difference in the genotype frequencies of MTHFR C677T,A1298 and MTRR A66G gene loci in the adverse pregnancy outcome group（P>0.05）.The T allele frequency of MTHFR C677T locus in the adverse pregnancy group was higher than that in the control group with statistical significance.Compared with the control group,there were statistically significant differences in the polymorphism of MTHFR C677T gene in pregnant women with fetal loss,fetal structural abnormality and gestational hypertension in the adverse pregnancy outcome group（P<0.05）.The frequency of CC/AC,CT/AA,TT/AA combined genotype in the adverse pregnancy outcome group was higher than that in the control group（P<0.05）,while there was no significant difference in the risk of adverse pregnancy outcomes between the patients carrying CC/CC and CT/AC genotypes and those carrying CC/AA genotypes（P>0.05）.The number of patients with 1 to 2 gene mutations in the adverse pregnancy outcome group was higher than that in the control group,and the difference was statistically significant（P<0.05）.2.Compared with the control group,the median values of MOM of serum indexes AFP andβ-HCG were increased and the median values of MOM of UE3were decreased in the adverse pregnancy outcome group,with statistical significance （P<0.05）.The abnormal increase of MOM of AFP andβ-HCG and the abnormal decrease of MOM of UE3 in serum of the control group and the adverse pregnancy outcome group were statistically significant compared with the incidence of multiple abnormal indicators（P<0.05）.Group compared with control group,the adverse pregnancy outcome of fetal loss,premature birth,low birth weight,gestational hypertension disease with higher incidence of abnormal serum AFP level correlation（P<0.05）,low birth weight is associated with increased incidence of abnormal serum beta HCG levels（P<0.05）,fetal loss,premature birth,low birth weight,and reduce the incidence of abnormal serum uE3 level（P<0.05）,premature birth,low birth weight,the incidence of abnormal index is higher than the control group（P<0.05）.There was no significant difference in the incidence of abnormal serum indexes between the patients with fetal structural malformation and placental abruption and the control group（P>0.05）.3.The frequencies of different genotypes and alleles of MTHFRC677T,A1298C and MTRR A66G in the high-risk group and the low-risk group of Down syndrome were tested byχ² and only the genotype of MTHFR A1298C showed statistically significant differences（P<0.05）.4.Using serum indexes AFP,β-HCG,UE₃ and their combined predictors as test variables,the ROC curve was plotted and the results showed that serum AFP had a certain predictive value in predicting premature birth and low birth weight infants and UE₃ had a certain predictive value in predicting low birth weight infants.The areas under the curve were 0.706,0.739 and 0.702,respectively.The AUC of combined predictors for the diagnosis and prediction of fetal loss,premature delivery and low birth weight infants was 0.718,0.741 and 0.827,which had a certain predictive efficiency and the predictive efficiency was higher than that of the single index.Conclusions1.MTHFR C677T mutation has a certain impact on the occurrence of adverse pregnancy outcomes,which is closely related to fetal loss,fetal structural abnormalities and pregnancy induced hypertension.2.The abnormal levels of serum markers AFP,β-HCG and UE₃ during the second trimester of pregnancy are related to the occurrence of adverse pregnancy outcomes,which has a certain predictive value for the occurrence of fetal loss,premature delivery and low birth weight infants.3.The polymorphism of folate metabolism related gene MTHFR A1298C may be associated with the high risk of Down’s syndrome.