| ObjectivePrenatal exposure to adversity,such as overweight/obesity,gestation diabetes mellitus(GDM),hypertension disorders in pregnancy(HDP),anxiety/depression,drinking and smoking,could increase the risk of adverse birth outcomes and autism spectrum disorder(ASD)in offspring.Previous studies have explored the effect of a single type of prenatal adversity on birth outcomes and the risk of ASD in offspring,ignoring the interaction of different types of perinatal adversity.Inflammatory cytokines have been proposed to play a mediating role in the relationship between prenatal adversity and birth outcomes and ASD risk;however,population cohort studies are still lacking.The purpose of this study were as follows:(1)To explore the occurrence patterns of maternal prenatal adversity and its effects on birth outcomes and ASD-related behavioral characteristics in early life of offspring;(2)To elucidate the relationship between maternal inflammatory cytokines and birth outcomes and ASD-related behavioral characteristics in early life of offspring and the critical period of the effects of maternal inflammatory cytokines;(3)To clarify the relationship between maternal prenatal adversity and maternal inflammation;(4)To explore the role of maternal inflammatory cytokines in the relationship between prenatal adversity and birth outcomes and ASD-related behavioral characteristics in early life of offspring.The findings are important for further understanding the relationship between prenatal adversity and offspring health and the risk of ASD,as well as for improving understanding of the etiology of ASD and providing clues for early intervention.Methods1.Based on a birth cohort design,evaluations of the cohort were conducted in the maternal and child health care centers of Heping and Hebei Districts in Tianjin,respectively.We prospectively collect information of mothers’ prenatal adversity,including overweight/obesity during early pregnancy,GDM,HDP,depression and anxiety during early pregnancy and smoking/drinking.Blood samples of the pregnant woman were collected in three maternal study visits during early(12.24±1.34 weeks ofgestation),middle(20.31±1.22 weeks of gestation),and late pregnancy(30.13±1.23 weeks of gestation).Four inflammatory cytokines,C-reactive protein(CRP),interleukin-6(IL-6),interleukin-8(IL-8),monocyte chemoattractant protein 1(MCP-1)and an anti-inflammatory cytokine—interleukin-10(IL-10)were selected based on the literature.Maternal serum levels of those five cytokines were measured by using enzyme-linked immunosorbent assay.2.Birth outcomes of the newborns were collected,including delivery model,gestational age,birth body length and birthweight.The Griffith Neurodevelopment Scale and eye tracking experiment were used to evaluate the social development and ASD-related behavior characteristics at 6-12 months of the newborns.The social development of the newborns was evaluated by using the personal-social quotient(BQ).ASD-related behavior characteristics were measured by using the indexes of fixation time of social and geometry images,and percentage of fixation time of social/geometric images.3.Mplus 6.0 and SPSS 22.0 were used for statistical analysis.A latent class analysis(LCA)was performed to explore the occurrence patterns of prenatal adversity by using Mplus 6.0.Chi-square tests,t-test,one-way analysis of variance,logistic regression model and multiple linear regression model were used for statistical analysis according to the distribution characteristics of the data by using SPSS 22.0.SPSS MACRO Process 3.2.1 was used to explore the mediating role of maternal serum levels of inflammatory cytokines in the relationship between prenatal adversity and ASDrelated behavior characteristics in offspring.Results1.In this study,the incidence of seven types of common prenatal adversity were as follows: overweight/obesity in early pregnancy was the highest(99/311,31.8%),followed by anxiety in early pregnancy(52/311,16.7%),GDM(50/311,16.1%),depression in early pregnancy(40/311,12.9%),smoking(21/311,6.8%),drinking(14/311,4.5%),and HDP(11/311,3.5%).Four occurrence patterns of prenatal adversity were identified by using LCA,including the low prenatal adversity group(214/311,68.8%)and the emotional problems group(46/311,12.5%),the overweight/obesity+GDM group(46/311,14.8%),and the somking+drinking group(12/31,3.8%).The overweight/obesity+GDM group was associated with an increased risk of cesarean section(OR=2.91,P=0.007).No significant relationships between patterns of prenatal adversity and gestational age,birth weight and body length were observed.The emotional problems group(β=10.40,P=0.001),overweight/obesity+GDM group(β=-11.33,P<0.001),and somking+drinking group(β=-9.84,P=0.037)were associated with lower BQ in offspring.The overweight/obesity+GDM group was related to lower percentage of fixation time of social/geometric images(β=0.35,P=0.005).2.Increased maternal serum CRP concentration during gestation was associated with shorter gestational age(β=-0.18,P<0.001)and lower birth body length(β=-0.21,P<0.001).During gestation,higher anti-inflammatory principal component score was related to longer gestational age(β=-0.16,P=0.046).Increased maternal serum IL-6during gestation were associated with decreased BQ(β=-6.59,P=0.012),decreased fixation time in social images(β=-0.16,P=0.025)and lower percentage of fixation time of social/geometric images(β=-0.24,P=0.045).Elevated maternal serum IL-8 levels were associated with an increased percentage of fixation time of social/geometric images(β=0.42,P=0.030).In pregnant women who provided with three blood samples,increased CRP concentration at the second trimester was associated with shorter gestational age at delivery(β=-0.12,P=0.031).CRP concentration at the third trimester was linked to lower birth weight(β=-40.04,P=0.022).Increased maternal serum levels of MCP-1 concentration in the first,second and third trimesters were associated with increased fixation time of social images(β=0.19,0.002,0.002,all P values<0.05),and increased percentage of fixation time of social/geometric images(β=0.35,0.003,0.003,all P values<0.05).Increased maternal serum IL-8 concentration in the third trimester was associated with higher percentage of fixation time of social/geometric images(β=0.25,P<0.05).3.The overweight/obesity+GDM group is associated with increased serum levels of CRP(β=1.81,P<0.001)and IL-6(β=0.27,P=0.001)and inflammatory factor scores(β=0.73,P<0.001).Maternal serum IL-6 level plays a partial mediation effect in the association between the overweight/obesity+GDM group and BQ in offspring,and the effect coefficient was 2.01(95% CI: 4.22～0.35).Maternal serum IL-6 level could explain 22.4% of the effect of the overweight/obesity+GDM group on BQ in offspring.Maternal serum IL-6 levels played a partial mediating role in the relationship between the overweight/obesity+GDM group and the percentage of fixation time of social/geometric images,the effect coefficient was-0.09(95%CI:-0.19～-0.02).Maternal serum IL-6 level could explain 25.7% of the effect of overweight/obesity+GDM on the percentage of fixation time of social/geometric images.Conclusions1.Overweight/obesity is the most common type of prenatal adversity,and prenatal adversity presents certain occurrence patterns.The occurrence pattern of prenatal adversity can influence the birth outcome and ASD-related behavior characteristics in early life of offspring.2.Maternal inflammation can influence birth outcomes and ASD-related behavior characteristics in early life of offspring,and this effect may exist during a critical period.3.Mother prenatal adversity can promote maternal systematic chronic inflammation.4.Maternal serum IL-6 levels mediates the association between maternal prenatal overweight/obesity+GDM and personal-social development,and the percentage of looking time of social/geometric images in early life of offspring,supporting the notion that maternal inflammation during pregnancy play a role in the connection of prenatal adversity and risk of neurodevelopmental disorders in offspring. |
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