A Cohort Study On The Association Of Maternal TPOAb Positivity During Pregnancy With Adverse Pregnancy Outcomes And Developmental Delay Of Their Offsprings

ObjectivesTo describe the dynamic changes of maternal thyroid peroxidase antibody(TPOAb)and thyroid function parameters during pregnancy.And to examine the associations of maternal TPOAb positivity during pregnancy with the risk of adverse pregnancy outcomes and the risk of early childhood development delay of their children.MethodsThis study was embedded in a prospective birth cohort,the Ma’anshan Birth Cohort study(the MABC study).A total of 3 474 pregnant women were enrolled in the MABC study during their first prenatal visit to Ma’anshan Maternal and Child Health(MCH)clinics.Pregnant women without singletons live births(n=201),women with a history of family or personal disease(n=49)and women with thyroid disease during pregnancy(n=49)were all excluded.And 3 175 mother-child pairs were included in the final analysis.All participants were asked to fill out a series of questionnaires and to provide blood for the biomarker study at their first(10.45±2.14 weeks),second(26.02±1.04weeks)and third(34.37±1.08 weeks)trimesters.Clinical and demographic information of mothers and their children were collected by a series of questionnaires.Maternal and paternal demographic information,history of disease and history of gestation,life style and behavior and pregnancy related information,including age,degree of education,level of household income,history of thyroid disease and family history of thyroid disease,smoking and alcohol use during or before pregnancy,pregnancy related anxiety symptoms and result of maternal intelligence quotient assessment,were all collected by a series of perinatal questionnaire and Wechsler Adult Intelligence Scale-Revised by China(WAIS-RC).Children’s neuropsychological assessments were performed by the Chinese validated version of Ages and Stages Questionnaires third edition(ASQ-C)at18 months of age and the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition(WPPSI-Ⅳ).ASQ-C is a valid screening scale to early identify children’s development delays in early childhood.ASQ-C failing scores were defined as scores of each domain 2 SDs below the mean for the child’s age per ASQ instructions,and was used to indicate developmental delay.WPPSI-Ⅳ was used to assess children’s intellectual ability and full scale intelligence quotient(FSIQ)was used to indicate children’s intellectual ability.Serum concentrations of TPOAb,TSH,FT4 were measured using electrochemiluminescence immunoassay(ECLIA)on Cobas Elecsys411(Roche Diagnostics Gmb H,Mannheim,Germany).Based on manufacturer cut-offs,a TPOAb concentration of 34.0 IU/m L or more was considered as positive.Women were categorized into different thyroid function groups according to TSH and FT4 levels as defined by our population-based and trimester-specific reference ranges,which were calculated from the 2.5th to 97.5th percentiles of TSH or FT4 in a reference population.Normal reference ranges of maternal FT4 at the first,second and the third trimesters of pregnancy were 13.20-23.85 pmol/L,9.18-15.24 pmol/L and 9.53-17.34pmol/L,respectively;And normal reference ranges of maternal TSH were 0.02-4.94μIU/m L,0.79-6.22 μIU/m L and 0.63-5.18 μIU/m L,respectively.Placental m RNA levels of 14 cytokines,including IL-1β,IL-4,IL-6,IL-8,IL-10,TNF-α,IFN-γ,HIF-1α,MCP-1,CRP,HO-1,GRP78,CD206 and CD68,were measured by RT-PCR.Statistical analyses were performed by Pearson’s chi-square test,independent samples t-tests,one-way ANOVA,generalized estimating equations(GEE),Spearman correlation tests,multivariate Logistic regression models and linear regression analysis,as appropriate.Maternal serum TPOAb concentration and placental m RNA levels of cytokines were skewed and need a logarithmic conversion before statistical analysis.Briefly,multivariate Logistic regression models were constructed to evaluated the associations of TPOAb positivity with thyroid dysfunction,gestational hypertension,GDM,mode of delivery,gestational week at delivery and SGA,ASQ-C failure,respectively.And linear regression analysis models were used to evaluate the associations among TPOAb levels(lg TPOAb)with gestational week at delivery,children’s FSIQ and placental m RNA levels of cytokines,respectively.In part three,firstly,Pearson correlations were estimated among TPOAb level in the first trimester,levels of 14 placental cytokines’ m RNA and FSIQ values of children at preschool age.Secondly,linear regression analysis were conducted to assess the associations among TPOAb level in the first trimester of pregnancy,levels of 14 placental cytokines’ m RNA and FSIQ values of children at preschool age.Finally,the mediating effect of levels of placental cytokines’ m RNA between TPOAb level in the first trimester and FSIQ values of children at preschool age was assessed by Bootstraping method.Analysis were all adjusted for maternal age,prepregnancy body mass index(BMI),parity,maternal education,household income,cigarette smoking and alcohol consumption before or during pregnancy,and analysis were selectively adjusted for hypertensive disorders of pregnancy and gestational diabetes,gender of child,gestational week at delivery and birth weight,infant breastfeeding,education level of caregivers,paternal age,paternal smoking and alcohol use,and so on,as appropriate.ResultsA total of 3 175 mother-child pairs from the MABC study were included in the final analysis.Rates of TPOAb positivity in the first,second and third trimester of pregnancy were 12.0%,6.8% and 7.0%,respectively.GEE results showed that maternal TPOAb level was associated with increased risk of hyperthyroidism(OR=5.08,95%CI:2.36-10.92),hypothyroidism(OR=10.43,95%CI: 5.74-18.96),subclinical hypothyroidism(OR=3.59,95%CI: 2.49-5.17)and hypothyroxinemia(OR=1.68,95%CI:1.77-2.40).Results from Logistic regression models showed that maternal TPOAb positivity at the first,second and the third trimester were all associated with hyperthyroidism and subclinical hypothyroidism(P<0.05).And it was the maternal TPOAb positivity in the first trimester that associated with hypothyroxinemia during the first trimester(OR=1.95,95%CI: 1.20-3.17).Maternal TPOAb positivity in the first trimester was also associated with hypothyroidism in the first trimester(OR=13.34,95%CI: 6.40-27.80),subclinical hyperthyroidism in the third trimester(OR=2.26,95%CI:1.23-4.15)and hyperthyroxinemia in the third trimester(OR=2.05,95%CI:1.01-4.14).Maternal TPOAb positivity in the second trimester was also associated with subclinical hyperthyroidism in the third trimester(OR=2.54,95%CI:1.22-5.29).Maternal TPOAb positivity in the first,second and the third trimesters of pregnancy were associated with higher risk of hypertension of pregnancy,OR values were 1.65,2.05 and 1.97,respectively(P<0.05).There was no association between TPOAb positivity and gestational diabetes mellitus.Maternal TPOAb concentration in the first trimester of pregnancy was inversely association gestational week at delivery(β =﹣0.27,95%CI:﹣0.40-﹣0.14).TPOAb positivity in each trimester of pregnancy had a1.53 to 1.76 fold risk of early term births(P<0.05).TPOAb positivity in the first trimester of pregnancy had a 1.5 fold risk of umbilical cord around the neck(95%CI:1.16-1.98),and TPOAb positivity in the second trimester was associated with a 1.98 fold risk of SGA(95%CI: 1.26-3.12).In part two,18.5% of children were developmental delay with at least one domain.And rates of developmental delay at domain of communication,gross motor,fine motor,problem-solving and personal-social were 2.9%,4.9%,7.4%,6.3% and 3.7%,respectively.Maternal TPOAb positivity in the first,second and third trimester of pregnancy were associated with higher risk of developmental delay at domain of personal-social,OR values were 2.11,2.14,1.94,respectively(P<0.05).Moreover,maternal TPOAb level in the first trimester of pregnancy was inversely associated with children’s FSIQ(β=﹣1.55,95%CI:﹣2.80-﹣0.30),WMI(β=﹣1.82,95%CI:﹣3.17-﹣0.47)and FRI(β=1.89,95%CI:﹣2.80-﹣0.30).And maternal TPOAb level in the third trimester of pregnancy was also inversely association with children’s FSIQ value(β=﹣2.51,95%CI:﹣4.61-﹣0.40)and WMI(β=﹣2.69,95%CI:﹣4.99-﹣0.38).In part three,ln TPOAb in the first trimester was positively correlated with levels of m RNA of IL-6,TNF-α,MCP-1,CRP,HO-1,HIF-α,GRP and CD68(P<0.05).Levels of m RNA of IL-6,HIF-1α and CD68 were inversely correlated with children’s FSIQ values at preschool age.Expression levels of placental IL-6,HIF-1α and CD68 all partially mediated the association between maternal TPOAb and children’s FSIQ,and the proportion of the mediator effect of IL-6,HIF-1α and CD68 was 19.6%,10.7% and25.0%,respectively.ConclusionsOur results suggest that maternal TPOAb positivity during pregnancy is associated with adverse pregnancy outcomes,including thyroid dysfunction,hypertension during pregnancy,SGA and umbilical cord around the neck.Maternal TPOAb positivity during pregnancy is associated with suboptimal neuropsychologic development and the levels of placental inflammation maybe the mediator.