| Objective Studies have found that pregnancy-related anxiety during pregnancy can predict preschoolers’ emotional and behavioral development in a gender-dependent manner.This study aims to test for this gender-specific effect in a different cohort and investigate whether the gender difference was specific to placental methylation of genes regulating glucocorticoids.Methods This study was conducted based on the Ma’anshan Birth Cohort Study（MABC）.A total of 3474 baseline pregnant women were recruited in this cohort from May 2013 to September 2014 in Ma’anshan Women’s And Children’s Health Hospital,Anhui Province,After 162 cases of adverse pregnancy outcomes and 39 cases of twins were excluded,3273 pairs of single live births and their mothers were included in the cohort,and the growth and development of their offspring were followed up after delivery.The study included 2,405 mother-child pairs who completed an assessment of pregnancy-related anxiety in the third trimester and mood symptoms and hyperactivity symptoms at 4 years old.Using our research group made "Maternal child health record during pregnancy" pregnant women baseline information collection.The maternal pregnancy-related anxiety symptoms were evaluated with the Pregnancy-Related Anxiety Questionnaire in the third trimester of pregnancy.The height of pregnant women,blood pressure,blood sugar and weight before delivery shall be measured and recorded by specialized personnel,and medical records and birth records shall be extracted during delivery,and placental tissues shall be collected.“The babies and infants health record” was used to collect breastfeeding information,child emotional symptoms and hyperactivity was assessed with the Strengths and Difficulties Questionnaire（SDQ）at 4 years old and the Strengths and Difficulties Questionnaire.According to the score ranking of pregnancy-related anxiety symptoms in the third trimester evaluated by the Pregnancy-related Anxiety Questionnaire,a total of 300 placental tissues with higher and lower scores were selected for subsequent epigenetic studies.Placental methylation of CpGs in promoter regions of FKBP5,NR3C1 and HSD11B2 genes was quantified using the Methyl Target approach.Exploratory factor analysis was used to obtain significant orthogonal factors for the methylation level of glucocorticoid response gene（methylation factor for short）.Logistic regression models were used to estimate association of pregnancy-related anxiety in the third trimester with hyperactivity and emotional symptoms,association of methylation factor scores with hyperactivity and mood symptoms in children,a linear regression model was used to analyze the association between trimester pregnancy-related anxiety and methylation factor scores.The above Logistic regression and linear regression analyses were stratified by gender.Sensitivity analysis was performed in full term infants and normal birth weight infants.The mediating role of methylation factor scores between pregnancy-related anxiety in the third trimester and children’s hyperactivity and emotional symptoms was analyzed using the PROCESS procedure.Results The mean age of 2405 pregnant women was（26.63±3.60）years.713（29.6%）had pregnancy-related anxiety in the third trimester,with an average age of（26.21±3.32）years.There were statistically significant differences in maternal age,pregnancy weight gain,education level,smoking and delivery mode between the group without pregnancy related anxiety and the group with pregnancy related-anxiety in the third trimester（P < 0.05）.After controlling for confounding factors（maternal age,pre-pregnancy BMI,gestational weight gain,educational level,monthly family monthly income,smoking,drinking,gestational diabetes,pregnancy-induced hypertension,delivery mode,and exclusive breastfeeding in the first 6 months）,compared with the group without pregnancy-related anxiety,pregnancy-related anxiety in the third trimester increased the risk of hyperactivity in boys（OR = 1.54,95% CI = 1.13 ～ 2.11）and emotional symptoms in girls（OR = 1.61,95% CI = 1.15 ～2.24）.Five significant orthogonal factors were extracted by factor analysis（methylation factor）.A significant association between methylation factor and trimester anxiety and hyperactivity and emotional symptoms in preschoolers was found only in boys,with pregnancy-related anxiety in the third trimester negatively associated with methylation factor 5 scores（OR =-0.50,95%CI =-0.87 ～-0.13）,and factor 5 was significantly loaded with FKBP5.Factor 1 scores increased the risk of hyperactivity（OR = 1.80,95%CI = 1.15 ～ 2.83）and emotional symptoms（OR = 1.64,95%CI = 1.03 ～ 2.59）in boys,Factor 4 score reduced the risk of emotional symptoms（OR = 0.53,95% CI = 0.29 ～ 0.97）.Factor 1 significantly loaded NR3C1 and factor 4significantly loaded HSD11B2.The results were significant after sensitivity analysis.However,no mediating role of methylation factor scores was found in the gender-dependent association between pregnancy-related anxiety and hyperactivity and emotional symptoms in preschoolers.Conclusions Pregnancy-related anxiety in the third trimester predicts hyperactivity and emotional symptoms in preschoolers in a gender-dependent manner,further supporting previous findings.In addition,placental glucocorticoid response gene methylation was found to be gender-dependent in association with pregnancy-related anxiety and hyperactivity and emotional symptoms in preschoolers,but no mediating effect was found.The reason may be that the sample size used for mediating effect analysis in this study was not large enough（the power of all mediating effects was <80%）.Whether the methylation of placental glucocorticoid response genes is the epigenetic mechanism of gender differences in neurobehavioral development in children caused by pregnancy-related anxiety during pregnancy remains to be further explored. |
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