Association Between Maternal Weight During Pregnancy And Neurodevelopment Of Infants On 6 Months Of Age And The Mechanism Of Inflammation

ObjectiveOverweight and obesity of women of childbearing age has become a major global public health problem due to its increasing prevalence.Overweight and obesity before pregnancy and excessive weight gain during pregnancy not only increase the shortterm health risk of the mother and offspring,but also have a long-term impact on the physical growth and neurological development of offspring.The potential mechanism of the effect of maternal overweight and obesity on the neurodevelopment of offspring before pregnancy is still unclear,and inflammation secondary to obesity is considered to be an important mechanism of this association.At present,longtitudinal studies are still lack on the relationship between maternal weight during pregnancy and specific domains of neurodevelopment in childhood in China,and there is limited evidence on potential mechanism.The purpose of this study includes the following four aspects:(1)to explore the effects of pre-pregnancy overweight and obesity on birth outcome and the specific domains of neurodevelopment of offspring through a birth cohort study;(2)to analyze the longitudinal changes of maternal inflammatory markers dring pregnancy to verify the effect of overweight and obesity dering pregnancy on systemic inflammation in normal pregnancy;(3)to study the role of maternal inflammatory markers in the effect of maternal obesity on the specific neurodevelopment of offspring during pregnancy,so as to provide clues for the etiological study of neurodevelopmental disorders in offspring,so as to provide a basis for scientific intervention in view of adverse birth outcome and neurodevelopmental disorders of offspring.Methods1.Based on the population-based birth cohort study,this study studied the independent effects and interactions of pre-pregnancy body mass index(BMI)and gestational weight gain(GWG)on the birth outcome and neural development of offspring.In the early stage of pregnancy,a questionnaire was used to collect the mother’s basic information,activities,living habits,emotional state,sleep status and other related information.The blood samples of the mother were collected during the whole pregnancy(first,second and third trimester).After delivery,the birth outcome information such as delivery mode,gestational age,birth length and weight were collected,and the Griffiths Development Scales-Chinese(GDS-C)was used to evaluate the neurological development of the baby at 6 months.2.In order to explore the short-term and long-term effects of maternal prenatal environment on mothers and infants,we compared the differences of birth outcome and neurodevelopment of offspring in different pre-pregnancy BMI group and GWG group.3.Four inflammatory markers,monocyte chemoattractant protein 1(MCP-1),interleukin-1 β(IL-1 β),interleukin-6(IL-6)and interleukin-10(IL-10),were screened to reflect the maternal pro-inflammatory and anti-inflammatory effects.Four inflammatory markers of 100 mothers were detected by double antibody sandwich enzyme-linked immunosorbent assay(ELISA).The levels of inflammatory markers in different pre-pregnancy BMI group and GWG group were compared,and the longitudinal changes of inflammatory markers in different pre-pregnancy BMI groups were further compared.4.The method established by Hayes et al was used to control age,weight gain during pregnancy,anxiety during pregnancy,depression,diabetes,hypertension during pregnancy,sex of infants and birth weight.The mediating effect of IL-6 level during pregnancy on the relationship between pre-pregnancy BMI classification and neurodevelopment at 6 months old.The purpose of this study is to provide clues for further formulating targeted prevention strategies and promoting the best development in the field of neurodevelopment of offspring.5.The statistical analysis was performed by SPSS 24.0.The Chi-square tests,ttests,logistic regression models,multiple linear regression models and mixed linear models were used to analyze the data,and SPSS macro PROCESS 3.2.1 was used to analyze the mediating effect of IL-6 level on the relationship between pre-pregnancy BMI classification and neonatal neurodevelopment.The test level is α = 0.05.Results1.The average pre-pregnancy BMI of female was 22.31 ±3.80 kg m2,the rate of pre-pregnancy overweight and obesity was 24.5%,and 50.6% of mothers gained excessive weight during pregnancy.Pre-pregnancy underweight,overweight and obesity had higher rates of excessive weight gain during pregnancy(64.3%,67.5%,66.7%).The risk factors for the increase of pre-pregnancy BMI were age(P=0.005),smoking history before pregnancy(P=0.007),irregular diet before pregnancy(P=0.016),sitting time before pregnancy(P=0.003),and sleep time>9 hours per night before pregnancy(P=0.033),while regular exercise(P=0.005)was the protective factor of pre-pregnancy BMI growth.Pre-pregnancy underweight(P=0.028)and obesity(P=0.002)are the risk factors for GWG growth.The rate of cesarean section was 48.3%.With the increasing of maternal age and the increasing of pre-pregnancy BMI and GWG,the rate of cesarean section showed an upward trend(c2age trend =8.580,P=0.003;c2BMI trend =19.411 P<0.001;c2GWG trend =5.932 P= 0.015).Pre-pregnancy overweight(P=0.047),obesity(P=0.030)and excessive GWG(P=0.006)were the risk factors for cesarean section.Pre-pregnancy overweight(P<0.001),obesity(P<0.001)and excessive GWG(P=0.047)were associated with birth weight gain,and below GWG was associated with birth weight loss(P<0.001).The rate of large for gestational age(LGA)was 13.8%.With the increasing of pre-pregnancy BMI,the rate of LGA gradually increased(c2BMI trend= 17.521,P<0.001).Pre-pregnancy overweight(P=0.002),obesity(P=0.049)were risk factors for LGA.Maternal pre-pregnancy obesity is an independent risk factor for the decrease of hand-eye coordination(DQ)in 6-month-old infants.2.The MCP-1 level of pre-pregnancy obese mothers in early pregnancy was higher than that in underweight,normal weight and overweight(P<0.001).There was no difference in maternal inflammatory markers in the second trimester of pregnancy.In the third trimester,the level of IL-6 in pre-pregnancy obese pregnant women in the third trimester was higher than that in underweight,normal weight and overweight(P <0.001).The levels of IL-1 β in pregnant women with pre-pregnancy underweight and obesity were higher than those in normal body weight in the third trimester of pregnancy(P=0.018,P=0.018,respectively).Among all pre-pregnancy BMI categories,the levels of MCP-1 and IL-10 in pregnant women had no significant change,however,the levels of IL-6 in the third trimester were significantly higher than those in the first and second trimester of pregnancy(P<0.001),and the rising trend of pre-pregnancy obese mothers was more obvious.The level of IL-1 β in the third trimester of pregnancy with pre-pregnancy normal weight was significantly lower than that in the first trimester(P=0.001),but there was no significant decrease in pre-pregnancy underweight and obese pregnant women(P>0.05).The levels of MCP-1 and IL-6 in pre-pregnancy obese mothers were higher(P<0.001),and mother with excessive GWG had higher levels of IL-6(P=0.018).However,there was no interaction between prepregnancy BMI and GWG on IL-6 levels.3.At the age of 6 months,DQ was negatively correlated with pre-pregnancy BMI(r=0.311,P=0.008),and negatively correlated with the average concentration of MCP-1 during pregnancy(P=0.047),and significantly negatively correlated with the average concentration of IL-6 during pregnancy(r=0.469,P<0.001).The method established by Hayes et al.was used to adjust the complications related to obesity in pregnancy and the adverse antenatal environment related to immune activation(such as anxiety and depression).The results showed that IL-6 played a mediating role in pre-pregnancy obesity and 6-month-old hand-eye coordination,with an effect coefficient of-6.5736(95%CI:-14.5997,-0.7492).Maternal serum IL-6 level could explain 35.0136% of the effect of pre-pregnancy obesity on hand-eye coordinated development at 6 months old.Conclusions1.In the current study found that the rate of pre-pregnancy overweight and obesity was 24.5%,moreover,50.6% of the mothers had excessive GWG during pregnancy.The rate of excessive GWG was higher in women who were underweight,overweight and obese before pregnancy(64.3%,67.5%,66.7%,respectively).Maternal prepregnancy overweight and obesity and excessive GWG were related to cesarean section;Pre-pregnancy overweight and obesity were related to LGA;Maternal pre-pregnancy obesity was an independent risk factor for the decrease of Eye-hand coordination developmental quotient(DQ)in 6-month-old infants.2.In the current study,we found that the change trend of inflammatory markers of pre-pregnancy normal weight was that IL-6 level increased,especially in prepregnancy obese mothers,and IL-1 β decreased with pregnancy in pre-pregnancy normal weight,but not in pre-pregnancy low weight and obese mothers.MCP-1 and IL-6 levels were higher in pre-pregnancy obese mothers,and IL-6 levels were higher in women with excessive GWG,indicating that systemic inflammation associated with normal pregnancy was exaggerated by obesity.3.The study found that there was a negative correlation between pre-pregnancy obesity and hand-eye coordination ability of 6-month-old offspring mediated by IL-6.It is suggested that the management of pregnancy weight should be advanced to before pregnancy,and adjusting the weight of women planning pregnancy to the normal range before pregnancy may be the safest and most effective way to reduce the neurodevelopmental and mental illnesses risks of offspring.In addition,this study was to provide a basis for further formulating preventive strategies and promoting the neural development of offspring.