Cord Blood Metabolomics In Women With Thyroid Autoimmune Or Hypothyroxinemia During Pregnancy

Objective: Thyroid hormones are essential for fetal neurological development,and maternal hypothyroxinemia can induce neurodevelopmental disorders in the developing fetus.Thyroid peroxidase antibodies(TPOAb)and thyroglobulin antibodies(Tg Ab)are the most common and representative autoantibodies in autoimmune thyroid disease.The positivity rate of these thyroid autoantibodies in the general population during the reproductive years is 10-20%.TPOAb positivity is one of the risk factors for hypothyroidism in pregnancy(GH),which is associated with a higher risk of subclinical hypothyroidism.Abnormal thyroid function during pregnancy is strongly associated with the development of various adverse pregnancy outcomes,as well as leading to a significantly higher risk of developing disorders of glucolipid metabolism during pregnancy.The metabolic status of the mother and fetus is closely related,and alterations in maternal metabolism often affect fetal levels of various metabolites and metabolic homeostasis,leading to an increased risk of various diseases such as macrosomia and respiratory distress syndrome.Metabolite levels in cord blood may be based on the transfer of maternal metabolites,as well as metabolites synthesized by the fetus in response to the intrauterine environment.Currently,metabolomics is increasingly used in maternal-fetal medicine to identify biological changes associated with fetal growth.However,to date,only two studies have investigated metabolic changes in cord blood in the context of gestational hypothyroidism and gestational TPOAb positivity,respectively.On this basis,this study intends to investigate the changes in metabolic profiles between the mother-infant interface in the context of abnormal maternal thyroid function through metabolomic analysis of cord blood in the context of thyroid autoimmunity and hypothyroxinemia states during pregnancy.Methods: This study was based on naturally pregnant women recruited from the Northeast Regional Maternal-Fetal-Child-Adolescent Cohort Project,excluding all pregnant women with abnormal blood tests and blood glucose tests,and screening 17 pregnant women with normal serum free triiodothyronine(FT3),free thyroxine(FT4),and thyroid stimulating hormone(TSH)in the third trimester of pregnancy but with Tg Ab and/or TPOAb above the normal range from the same geographic region as the thyroid autoimmune(TAI)group of this study;selecting age,body mass index Twenty-one pregnant women with normal thyroid functions(FT3,FT4,TSH,Tg Ab and TPOAb)matched with blood glucose were selected as the non-TAI euthyroid group(N group);six other pregnant women with reduced FT4 and normal FT3,TSH,Tg Ab and TPOAb in all three trimesters of pregnancy were selected as the hypothyroxinemia group(Hypo group)of this study.Metabolomic analysis of cord blood serum samples was performed by high performance liquid chromatography-mass spectrometry to find the differential metabolites and differential metabolic pathways in pregnant women with TAI and hypothyroxinemia in pregnancy compared with non-TAI euthyroid pregnant women.Results: 1.There were differences in cord blood metabolism in pregnant women with TAI,hypothyroxinemia and non-TAI euthyroid women during pregnancy.In this project,we used non-targeted metabolomics technology to carry out the subject study,and a total of 683 positive ion pattern metabolites and 331 negative ion pattern metabolites were identified in 44 samples.A total of 121 differential metabolites were identified in the TAI vs.N comparison group,of which 60 were up-regulated and 61 were down-regulated.73 differential metabolites were identified in the Hypo vs.40 metabolites were down-regulated.2.Screening for differential metabolic pathways was performed by KEGG pathway analysis according to the criteria of P-value< 0.05 and containing more than 2 differential metabolites.Four significantly different metabolic pathways were found between pregnant women with TAI in pregnancy and non-TAI euthyroid pregnant women,including upregulation of choline and downregulation of phosphatidylcholine in the choline metabolism pathway in glycerophospholipid metabolism and cancer,upregulation of arginine and choline and downregulation of c GMP and cortisol in the bile secretion metabolism pathway,and upregulation of levodopa and downregulation of acetoacetate in the tyrosine metabolism pathway.Betaine and L-histidine were found to be down-regulated in the ABC transporter protein metabolic pathway between pregnant women with gestational hypothyroxinemia and non-TAI euthyroid pregnant women.3.Intergroup comparisons of maternal pregnancy outcomes showed that five cases of fetal distress occurred in the TAI group,which was significantly higher than the non-TAI euthyroid group;birth weight was significantly higher in the Hypo group than the non-TAI metronomic group.The rest of the pregnancy outcomes showed no significant difference in the TAI and Hypo groups compared with the non-TAI euthyroid group.The alterations in cord blood differential metabolite abundance in the development of fetal distress were compared between the overall of TAI and non-TAI euthyroid pregnant women(n=38).The results showed that the abundance of multiple differential metabolites between TAI and N group,particularly multiple lipid metabolites,including1-stearoylglycerol,acetyl-L-carnitine,methyl palmitate,1-palmitoylglycerol,2-arachidonic acid glycerol,PC(19:2/18:3),PC(19:2/18:5),and PC(17:0/18:4)were also present in the cord blood of offspring who developed fetal distress.Additionally,the trend of change is consistent with the changes in TAI.Suggesting that the development of fetal distress in pregnant women with TAI may lead to disorders of lipid metabolism in the fetal cord blood.Conclusions: 1.This study suggests that the offspring of pregnant women with TAI and hypothyroxinemia during pregnancy have undergone metabolic alterations in utero compared with non-TAI euthyroid pregnant women,and cord blood showed multiple differential metabolites and metabolic pathways,suggesting that thyroid autoimmunity or hypothyroxinemia may affect maternal-fetal metabolism through metabolite alterations,which warrants in-depth study.2.Thyroid autoimmunity and hypothyroxinemia may affect lipid metabolism and other pathways leading to fetal dysplasia,and even become the early potential basis for FOAD in offspring,and the related mechanisms deserve further study.