| Objective Conclusive evidence highlighted that periconceptional folic acid(FA)supplementation substantially reduced the risk of neural tube defects(NTDs)in offspring.Such evidence has led to a clear recommendation for women who are planning a pregnancy to take 400μg FA/day from preconception until the end of the first trimester,but the effects of FA supplements use in different periods of pregnancy on fetal growth and postnatal neurobehavioral development remain unclear.Therefore the objective of this study is to investigatet the effects of FA supplementation in different periods of pregnancy on fetal growth and postnatal neurobehavioral development.Methods The Ma’anshan Birth Cohort Study(MABC)is a prospective population-based cohort study designed to investigate the effects of prenatal exposure on adverse pregnant outcomes,child health and development.Pregnant women were consecutively recruited from antenatal clinics of the Maternal and Child Health Care Center in Ma’anshan city of Anhui Province in China from May 2013 to September 2014,when they came to the Center for their first prenatal examination in early pregnancy.A total of 3 474 pregnant women were recruited for this cohort.Data were collected via a face-to-face interview by trained investigators in the first,second and third trimester of pregnancy,respectively.The information on maternal useof FA supplements was assessed by asking if they have used these supplements in different periods(one month before pregnancy,the first/second/third trimester of pregnancy).Information regarding the date supplement use began,the frequency of use(times/week),dose and brand names of supplements were also collected.Anthropometric parameters at birth were obtained from the hospital delivery logs.Birth weight,length,head circumference,chest circumference of all neonates,and placental long diameter,wide diameter,thickness,amniotic fluid volume of all neonates were measured by midwife at birth.Gestational age was calculated based on the last menstruation period.Fresh placenta tissue was collected and preserved in liquid nitrogen.Infant’ breast feeding at 3 months and 6 months old was collected,and their neurobehavioral development at 6 months and 18 months were assessed using Ages and Stages Questionnaires(ASQ-C).Data analyses were performed using the Statistical Package for the Social Sciences software(SPSS 16.0)and STATA 10.0.For continuous variables,ANOVA and Non-parametric Kruskal-Wallis H test were used to determine differences among different groups and Student t test was used to determine differences between two groups.For categorical variables,differences were examined by using chi-square test.In order to adjust for pre-pregnancy BMI,maternal age,newborn’s sex and average monthly income,etc.,a multivariable logistic regression model was used to estimate relative risk(RR)with 95% confidence intervals(95%CI)with respect to large for gestational age(LGA),small for gestational age(SGA),and possible developmental delay.In addition,given that the possible selective bias in receiving FA supplements,we performed a propensity score analysis to adjust for those factors related to selecting FA use in the second and third trimesters of pregnancy.Propensity scores were calculated using logistic regression with FA supplementation as the outcome variable and allavailable variables as predictors.Weighted logistic regression using the inverse of the propensity scores as weights to assess the effect of FA supplementation on risk of SGA and LGA was conducted.All quantified data were expressed as means ± SD.All statistical tests were performed at the two-sided 0.05 level of significance.Results Among 3246 mother-and-singleton live births,2 365 mothers took FA supplements everyday,and 434 mothers took FA supplements 3-6 times/week in the first trimester.Fewer mothers took FA supplements in the second and third trimesters.There was not statistical relationship between periconceptional FA supplementation and neonatal birth weight,body length,head circumference,chest circumference,gestational age.Our results supported the hypothesis that continued supplementation with FA after the first trimester was associated with higher birth weight,body length,head circumference,and chest circumference,and continuing FA supplementation at a dose of 400 μg/day in the second and third trimesters significantly increased the risk of LGA in Chinese women,and this relation was strong or monotonic even after adjusting for known relevant confounders.However,it did not significantly decrease the risk of SGA.In MABC cohort,infants had a good behavioral development at the age of 6 months and18 months,and the prevalence of delayed development of 5 ASQ-C domains was low.Periconceptional FA supplementation was associated with increased scores in CM and PS domains among 6-month-old infants(P < 0.05),and was a protective factor for possible delayed development of CM domain for 18-month-old infants(a RR=0.478,95%CI: 0.264-0.864,P=0.015).FA supplements use in early pregnancy was associated with increased scores in GC domain among 18-month-old infants(P=0.007).Continuedsupplementation with FA after the first trimester was associated with decreased risk of delayed development of FM and GC domains among 6-month-old infants(RR=0.31,95%CI: 0.12-0.82,P=0.019;RR=0.20,95%CI: 0.05-0.79,P=0.022).Continued FA supplementation after the first trimester was not associated with infant behavioral development at the age of 18 months.FA supplements use before pregnancy was associated with increased placental width(0.241 cm,95%CI: 0.052-0.429,P=0.013)and increased placental surface area(6.398cm2,95%CI: 1.407-11.389,P=0.012).FA supplements use in early/ middle pregnancy was respectively related with increased placental thickness(0.061 cm,95%CI:0.004-0.117,P=0.036;0.066 cm,95%CI: 0.004-0.129,P=0.038).FA supplements use in late pregnancy was not associated with placental related parameters.FA supplements use before pregnancy was associated with increased expression of placental inflammatory cytokines(HO-1,HIF-1 and GRP78),and with decreased expression of placental inflammatory cytokines(IL-4,CD208).FA supplements use in late pregnancy was related with decreased expression of placental inflammatory cytokines(GRP78,TNF-α,IL-8,CD68).Conclusions Periconceptional FA supplementation was associated with decreased risk of delayed development of CM domain for 18-month-old infants,and continued FA supplements use in middle and late pregnancy was associated with improved intrauterine growth of fetus and postnatal behavior developments for 6-month-old infants.Placental development might mediate the effects partly.The advantages of prolonged maternal FA supplementation throughout pregnancy on offspring development need to be confirmed by large-scale randomized controlled trial. |
PDF Full Text Request