孕期增补叶酸对子代生长发育影响的出生队列研究
发布时间：2018-07-18 11:20
【摘要】：目的围孕期增补叶酸预防先天神经管畸形已被研究所证实并付诸实践,但不同孕期增补叶酸对胎儿生长及出生后神经行为发育的影响目前尚不清楚,且引起越来越多的关注。本研究目的是阐明孕妇不同孕期增补叶酸对胎儿生长及出生后6月龄、18月龄神经行为发育的影响,并探讨胎盘在二者关联中的作用。方法采用前瞻性出生队列研究设计,自2013年5月到2014年9月,选取在马鞍山市妇幼保健院首次建立孕产妇保健手册并意愿在该医院进行定期产检和分娩的孕妇为研究对象,建立马鞍山优生优育出生队列(MABC)。共纳入孕妇3 474人,162例孕妇出现不良妊娠结局、39名孕妇分娩双胎、13人糖尿病合并妊娠、6人高血压合并妊娠、婴儿出生体重缺失者8人,3 246对单胎活产亲子纳入本研究。制订三个孕期的《孕产妇保健信息问卷》,分别在孕早、中、晚期收集孕妇人口统计学指标、孕产史、妊娠合并症与并发症,分别收集孕前、孕早期、孕中期、孕晚期叶酸及其它营养补充剂的增补情况;分娩时记录胎龄、出生体重、身长、头围、胸围、胎盘的长径、宽径、厚度、脐带长度及羊水量,收集新鲜胎盘组织液氮保存,半年内提取胎盘组织RNA,采用RT-PCR检测胎盘炎性相关因子的m RNA表达水平;出生后收集婴儿喂养方式、辅食添加、家庭环境等,运用年龄与发育进程量表(中国版)(ASQ-C)评定儿童6月龄、18月龄时的发育行为。运用Epi Data 3.0建立数据库,运用SPSS 16.0与STATA 10.0进行统计分析。组间比较:分类变量采用χ2检验,连续型资料服从正态分布使用方差分析(ANOVA)、服从偏态分布采用非参数Kruskal-Wallis H检验;应用单因素、多因素二分类Logistic回归分析不同孕期增补叶酸对大于胎龄儿(LGA)、小于胎龄儿(SGA)及6月龄、18月龄各能区发育迟缓的危险度,应用线性回归分析不同孕期增补叶酸对分娩时新生儿大小、胎盘大小及胎盘炎性相关因子表达的影响;在多元回归分析的基础上,采用倾向值加权调整以增加不同叶酸补充组间的可比性。结果本研究队列孕早期叶酸的补充率最高,每天补充者2 365人,占72.9%,每周补充3~6次者434人,占13.4%,合计占86.3%;其次是孕前一个月内;孕中、晚期叶酸的补充率较低。叶酸补充剂量为医生推荐的每天400μg。围孕期(包括孕前与孕早期)增补叶酸与新生儿出生体重、身长、头围、胸围、胎龄无统计学关联;在孕早期补充叶酸的基础上,孕12周后持续增补叶酸促进胎儿的生长,增加LGA发生的风险(RR=1.75,95%CI:1.13~2.62),该关联在调整了母亲怀孕时年龄、孕前体质指数(BMI)、母亲文化程度、家庭人均月收入、居住地、母亲吸烟、饮酒及补钙情况、妊娠糖尿病及妊娠期高血压、胎儿性别及产次后依然存在。采用倾向值加权调整的多元线性回归表明:在调整了各种混杂因素后,孕中期增补叶酸增加新生儿出生体重68.19(95%CI:15.43~120.96,P=0.011)g、头围0.226(95%CI:0.008~0.443,P=0.042)cm和胸围0.257(95%CI:0.070~0.445,P=0.007)cm,孕晚期增补叶酸增加新生儿出生体重57.31(95%CI:14.34~100.28,P=0.009)g、身长0.253(95%CI:0.093~0.413,P=0.002)cm、头围0.168(95%CI:0.015~0.320,P=0.031)cm和胸围0.169(95%CI:0.008~0.331,P=0.039)cm。MABC亲子队列中,儿童6月龄、18月龄儿童行为发育状况良好,发育迟缓率较低。孕前增补叶酸显著增加6月龄儿童沟通(CM)及个人-社会(PS)两个能区的得分(P0.05),采用倾向值加权调整的多因素分析发现:与孕前、孕早期均不补充叶酸组比较,围孕期规范增补叶酸显著降低儿童18月龄CM能区可能发育迟缓风险(a RR=0.478,95%CI:0.264~0.864;P=0.015),该效应主要是由于孕前叶酸的补充;孕早期增补叶酸显著增加18月龄儿童解决问题(GC)能区的得分(P=0.007)。孕中、晚期持续补充叶酸显著降低6月龄儿童精细动作(FM)能区与GC能区的发育迟缓风险,这种保护作用在采用倾向值分析后依然存在(RR=0.31,95%CI:0.12~0.82,P=0.019;RR=0.20,95%CI:0.05~0.79,P=0.022);孕中、晚期持续补充叶酸与儿童18月龄ASQ各能区的得分及发育迟缓率关联均无统计学意义。以未补充叶酸组为对照,采用倾向值加权调整后,孕前增补叶酸增加胎盘的宽径0.241(95%CI:0.052~0.429;P=0.013)cm、面积6.398(95%CI:1.407~11.389;P=0.012)cm2,孕早期、孕中期增补叶酸显著增加胎盘的厚度(0.061,95%CI:0.004~0.117,P=0.036;0.066,95%CI:0.004~0.129,P=0.038)cm,孕晚期增补叶酸与胎盘相关指标间关联无统计学意义。较大的胎盘长、宽、面积、厚度(最高三分位数)对6月龄儿童FM能区发育迟缓有保护作用,较大的胎盘厚度对6月龄儿童GC能区发育迟缓有保护作用,较大的胎盘宽径、面积对6月龄儿童PS能区发育迟缓有保护作用;较大的胎盘长径对18月龄儿童CM能区发育迟缓有保护作用,较大胎盘厚度对18月龄儿童粗大动作(GM)能区发育迟缓有保护作用孕前增补叶酸与胎盘血红素加氧酶-1(HO-1)、低氧诱导因子-1(HIF-1a)、葡萄糖调节蛋白78(GRP78)的表达增加有关,与白细胞介素-4(IL-4)、巨细胞表型因子206(CD206)的表达减低有关;孕晚期增补叶酸与GRP78、肿瘤坏死因子(TNF-α)、白细胞介素-8(IL-8)、巨细胞表型因子68(CD68)的表达减低相关;未发现孕早期、孕中期补充叶酸对胎盘炎症因子表达的影响。结论围孕期规范增补叶酸显著降低了18月龄儿童CM能区可能发育迟缓风险,孕中、晚期持续增补叶酸与显著提高的胎儿体格生长及出生后显著降低的6月龄儿童FM、GC能区可能发育迟缓相关,二者间的关联一方面由于增补叶酸对胎儿生长发育的直接作用,另一方面胎盘在其中起到一定的中介作用。有关孕12周后持续增补叶酸对子代生长发育的优势已引起关注,孕期叶酸的增补是否需要从现在的围孕期延长至整个孕期尚需要大规模人群随机对照试验来验证。
[Abstract]:Objective the effect of supplementation of folic acid in the perinatal period to prevent congenital neural tube malformation has been confirmed and put into practice. However, the effect of supplementation of folic acid on fetal growth and postnatal neurobehavioral development in different pregnancy is not clear and arouses more and more attention. The purpose of this study is to elucidate the growth and production of folic acid in pregnant women at different stages of pregnancy. The effect of postnatal 6 month old, 18 month old neurobehavioral development, and the role of placenta in the association of two persons. Methods using prospective birth cohort study and design, from May 2013 to September 2014, the first birth and maternal health care manual in Ma'anshan Maternal and Child Health-Care Hospital was selected and pregnant women who were willing to have regular delivery and delivery in the hospital were selected for the first time. A total of 3474 pregnant women were included in the study. 3474 pregnant women were included in the cohort (MABC). 162 pregnant women had adverse pregnancy outcomes, 39 pregnant women had twins, 13 had diabetes combined with pregnancy, 6 had hypertension combined with pregnancy, 8 babies were born with loss of birth weight, and 3246 pairs of single births were included in this study. The demographic indicators of pregnant women, the history of pregnancy, pregnancy complications and complications were collected, and the supplementation of folic acid and other nutritional supplements before pregnancy, in the early pregnancy, in the middle of the pregnancy, in the late pregnancy, and in the birth weight, body length, head circumference, chest circumference, and the length, width and thickness of the placenta were recorded in the pregnancy, pregnancy, pregnancy, pregnancy and complications respectively. Degree, umbilical cord length and amniotic fluid amount, collect fresh placenta tissue liquid nitrogen, extract placental tissue RNA in half a year, use RT-PCR to detect m RNA expression level of placental inflammatory related factors, collect infant feeding mode, supplement food and family environment after birth, and evaluate children 6 month old, 18 months by age and development process scale (ASQ-C). Age development behavior. Using Epi Data 3 to establish a database, using SPSS 16 and STATA 10 for statistical analysis. Group comparison: the classification variables were tested by chi 2, continuous data were subordinate to normal distribution analysis of variance (ANOVA), nonparametric Kruskal-Wallis H test was subordinate to partial distribution, and single factor and multiple factors two classification Logist were applied. IC regression analysis was used to analyze the effects of supplementation of folic acid on the risk degree of developmental delay in fetal age (LGA), less than fetal age (SGA) and 6 month old, 18 month old, by linear regression analysis of the effects of supplementation of folic acid on the size of the newborn, the size of placenta and the expression of inflammatory factors associated with placenta at different stages of pregnancy; based on multiple regression analysis The percentage of folic acid supplementation was adjusted to increase the comparability between different folic acid supplementation groups. Results the rate of folic acid supplementation in the early pregnancy cohort was the highest, 2365 people were supplemented daily, 72.9%, 434 supplemental 3~6 times a week, 13.4%, and 86.3%. The second was in the first month of pregnancy; the supplementation rate of late folic acid was lower. Folic acid supplementation was in the middle of pregnancy. There is no statistical correlation between supplementation of folic acid and newborn birth weight, body length, head circumference, chest circumference and fetal age, which is recommended by doctors at 400 g. per day (including pre pregnancy and early pregnancy). On the basis of folic acid supplementation in the early pregnancy, 12 weeks after pregnancy, supplementation of folic acid to promote the growth of the fetus and increase the risk of LGA (RR=1.75,95%CI:1.13~2.62), which is associated with The maternal age, pre pregnancy body mass index (BMI), mother's health index (BMI), mother's education level, family per capita income, residence, mother smoking, drinking and calcium supplement, gestational diabetes and pregnancy hypertension, fetal sex and birth were still existing. Multivariate linear regression using the tendency plus weight adjustment showed that various confounding factors were adjusted. After the second trimester, the mid-term supplementation of folic acid increased the birth weight of the newborn 68.19 (95%CI:15.43~120.96, P=0.011) g, 0.226 (95%CI:0.008~0.443, P=0.042) cm and 0.257 (95%CI:0.070~0.445, P=0.007) cm in the head circumference, and added folic acid in the late pregnancy to increase the birth weight of the newborn 57.31 (95%CI:14.34~100.28, P=0.009) g, and 0.253 In the 0.168 (95%CI:0.015~0.320, P=0.031) cm and chest circumference 0.169 (95%CI:0.008~0.331, P=0.039) cm.MABC parentage cohort, children 6 month old, 18 month old children had good behavioral development and low growth retardation rate. Pre pregnancy supplementation of folic acid significantly increased the score of 6 month old children communication (CM) and individual social (PS) two energy areas (P0.05), with a tendency value added. The multiple factor analysis of the right adjustment found that compared with the folic acid group before pregnancy and early pregnancy, the perinatal standard supplementation of folic acid significantly reduced the risk of possible developmental retardation (a RR=0.478,95%CI:0.264~0.864; P=0.015) in the 18 month old CM area of children. This effect was mainly due to the supplementation of folic acid before pregnancy; the increase of folic acid in the early pregnancy was significantly increased by 18 month old children. GC energy zone score (P=0.007). During pregnancy, late continuous supplementation of folic acid significantly reduced the growth retardation risk of 6 month old children's fine movement (FM) and GC areas. This protective effect still exists after the use of tendency analysis (RR=0.31,95%CI:0.12~0.82, P =0.019; RR=0.20,95%CI:0.05~0.79, P=0.022); during pregnancy, late continuous supplement Folic acid was not associated with the score of 18 month old ASQ and the growth retardation rate in children. With the non supplemental folic acid group as the control, the supplementation of folic acid before pregnancy was used to add folic acid to increase the width of the placenta by 0.241 (95%CI:0.052~0.429; P=0.013) cm, 6.398 (95%CI:1.407~11.389; P=0.012) cm2, early pregnancy, and mid trimester of pregnancy. Folic acid significantly increased the thickness of the placenta (0.061,95%CI:0.004~0.117, P=0.036; 0.066,95%CI:0.004~0.129, P=0.038) cm. There was no statistical significance in the correlation between the supplemental folic acid and placental related indexes in the late pregnancy. The larger placental length, width, area, and thickness (the highest three digits) had protective effects on the developmental retardation of 6 month old children's FM area, and the larger placental thickness The degree has protective effect on the developmental retardation in the GC area of 6 month old children. The larger placental width and area have protective effect on the development retardation of 6 month old children, and the larger placental length has protective effect on the development retardation of 18 month old children's CM area, and the larger placental thickness has protective effect on the development of 18 month old children's rough movement (GM). Supplementation of folic acid with placenta heme oxygenase -1 (HO-1), hypoxia inducible factor -1 (HIF-1a), glucose regulation protein 78 (GRP78) expression increased, related to the decrease of the expression of interleukin -4 (IL-4), giant cell phenotype factor 206 (CD206), and the supplementation of folic acid and GRP78, tumor necrosis factor (TNF- alpha), -8 (IL-8), giant cells, and giant cells in the late pregnancy. The expression of phenotypic factor 68 (CD68) was associated with a decrease in expression; the effect of folic acid supplementation on the expression of placental inflammatory factors in the early pregnancy was not found. Conclusion the perinatal standard supplementation of folic acid significantly reduced the risk of possible developmental delay in the CM energy area of children, during pregnancy, late continuous supplementation of folic acid and significantly increased fetal physical growth and postnatal significance. The reduction of 6 month old children, FM, and the possible developmental delay in the GC area, the relationship among the two groups is due to the direct effect of supplementation of folic acid on the growth and development of the fetus. On the other hand, the placenta plays a mediating role in it. The advantages of supplementing folic acid for the growth and development of the offspring after 12 weeks of pregnancy have attracted attention and supplementation of folic acid during pregnancy. The need for large population randomized controlled trials is needed to extend pregnancy from the present pregnancy to the whole pregnancy.
【学位授予单位】：安徽医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R17
本文编号：2131747
[Abstract]:Objective the effect of supplementation of folic acid in the perinatal period to prevent congenital neural tube malformation has been confirmed and put into practice. However, the effect of supplementation of folic acid on fetal growth and postnatal neurobehavioral development in different pregnancy is not clear and arouses more and more attention. The purpose of this study is to elucidate the growth and production of folic acid in pregnant women at different stages of pregnancy. The effect of postnatal 6 month old, 18 month old neurobehavioral development, and the role of placenta in the association of two persons. Methods using prospective birth cohort study and design, from May 2013 to September 2014, the first birth and maternal health care manual in Ma'anshan Maternal and Child Health-Care Hospital was selected and pregnant women who were willing to have regular delivery and delivery in the hospital were selected for the first time. A total of 3474 pregnant women were included in the study. 3474 pregnant women were included in the cohort (MABC). 162 pregnant women had adverse pregnancy outcomes, 39 pregnant women had twins, 13 had diabetes combined with pregnancy, 6 had hypertension combined with pregnancy, 8 babies were born with loss of birth weight, and 3246 pairs of single births were included in this study. The demographic indicators of pregnant women, the history of pregnancy, pregnancy complications and complications were collected, and the supplementation of folic acid and other nutritional supplements before pregnancy, in the early pregnancy, in the middle of the pregnancy, in the late pregnancy, and in the birth weight, body length, head circumference, chest circumference, and the length, width and thickness of the placenta were recorded in the pregnancy, pregnancy, pregnancy, pregnancy and complications respectively. Degree, umbilical cord length and amniotic fluid amount, collect fresh placenta tissue liquid nitrogen, extract placental tissue RNA in half a year, use RT-PCR to detect m RNA expression level of placental inflammatory related factors, collect infant feeding mode, supplement food and family environment after birth, and evaluate children 6 month old, 18 months by age and development process scale (ASQ-C). Age development behavior. Using Epi Data 3 to establish a database, using SPSS 16 and STATA 10 for statistical analysis. Group comparison: the classification variables were tested by chi 2, continuous data were subordinate to normal distribution analysis of variance (ANOVA), nonparametric Kruskal-Wallis H test was subordinate to partial distribution, and single factor and multiple factors two classification Logist were applied. IC regression analysis was used to analyze the effects of supplementation of folic acid on the risk degree of developmental delay in fetal age (LGA), less than fetal age (SGA) and 6 month old, 18 month old, by linear regression analysis of the effects of supplementation of folic acid on the size of the newborn, the size of placenta and the expression of inflammatory factors associated with placenta at different stages of pregnancy; based on multiple regression analysis The percentage of folic acid supplementation was adjusted to increase the comparability between different folic acid supplementation groups. Results the rate of folic acid supplementation in the early pregnancy cohort was the highest, 2365 people were supplemented daily, 72.9%, 434 supplemental 3~6 times a week, 13.4%, and 86.3%. The second was in the first month of pregnancy; the supplementation rate of late folic acid was lower. Folic acid supplementation was in the middle of pregnancy. There is no statistical correlation between supplementation of folic acid and newborn birth weight, body length, head circumference, chest circumference and fetal age, which is recommended by doctors at 400 g. per day (including pre pregnancy and early pregnancy). On the basis of folic acid supplementation in the early pregnancy, 12 weeks after pregnancy, supplementation of folic acid to promote the growth of the fetus and increase the risk of LGA (RR=1.75,95%CI:1.13~2.62), which is associated with The maternal age, pre pregnancy body mass index (BMI), mother's health index (BMI), mother's education level, family per capita income, residence, mother smoking, drinking and calcium supplement, gestational diabetes and pregnancy hypertension, fetal sex and birth were still existing. Multivariate linear regression using the tendency plus weight adjustment showed that various confounding factors were adjusted. After the second trimester, the mid-term supplementation of folic acid increased the birth weight of the newborn 68.19 (95%CI:15.43~120.96, P=0.011) g, 0.226 (95%CI:0.008~0.443, P=0.042) cm and 0.257 (95%CI:0.070~0.445, P=0.007) cm in the head circumference, and added folic acid in the late pregnancy to increase the birth weight of the newborn 57.31 (95%CI:14.34~100.28, P=0.009) g, and 0.253 In the 0.168 (95%CI:0.015~0.320, P=0.031) cm and chest circumference 0.169 (95%CI:0.008~0.331, P=0.039) cm.MABC parentage cohort, children 6 month old, 18 month old children had good behavioral development and low growth retardation rate. Pre pregnancy supplementation of folic acid significantly increased the score of 6 month old children communication (CM) and individual social (PS) two energy areas (P0.05), with a tendency value added. The multiple factor analysis of the right adjustment found that compared with the folic acid group before pregnancy and early pregnancy, the perinatal standard supplementation of folic acid significantly reduced the risk of possible developmental retardation (a RR=0.478,95%CI:0.264~0.864; P=0.015) in the 18 month old CM area of children. This effect was mainly due to the supplementation of folic acid before pregnancy; the increase of folic acid in the early pregnancy was significantly increased by 18 month old children. GC energy zone score (P=0.007). During pregnancy, late continuous supplementation of folic acid significantly reduced the growth retardation risk of 6 month old children's fine movement (FM) and GC areas. This protective effect still exists after the use of tendency analysis (RR=0.31,95%CI:0.12~0.82, P =0.019; RR=0.20,95%CI:0.05~0.79, P=0.022); during pregnancy, late continuous supplement Folic acid was not associated with the score of 18 month old ASQ and the growth retardation rate in children. With the non supplemental folic acid group as the control, the supplementation of folic acid before pregnancy was used to add folic acid to increase the width of the placenta by 0.241 (95%CI:0.052~0.429; P=0.013) cm, 6.398 (95%CI:1.407~11.389; P=0.012) cm2, early pregnancy, and mid trimester of pregnancy. Folic acid significantly increased the thickness of the placenta (0.061,95%CI:0.004~0.117, P=0.036; 0.066,95%CI:0.004~0.129, P=0.038) cm. There was no statistical significance in the correlation between the supplemental folic acid and placental related indexes in the late pregnancy. The larger placental length, width, area, and thickness (the highest three digits) had protective effects on the developmental retardation of 6 month old children's FM area, and the larger placental thickness The degree has protective effect on the developmental retardation in the GC area of 6 month old children. The larger placental width and area have protective effect on the development retardation of 6 month old children, and the larger placental length has protective effect on the development retardation of 18 month old children's CM area, and the larger placental thickness has protective effect on the development of 18 month old children's rough movement (GM). Supplementation of folic acid with placenta heme oxygenase -1 (HO-1), hypoxia inducible factor -1 (HIF-1a), glucose regulation protein 78 (GRP78) expression increased, related to the decrease of the expression of interleukin -4 (IL-4), giant cell phenotype factor 206 (CD206), and the supplementation of folic acid and GRP78, tumor necrosis factor (TNF- alpha), -8 (IL-8), giant cells, and giant cells in the late pregnancy. The expression of phenotypic factor 68 (CD68) was associated with a decrease in expression; the effect of folic acid supplementation on the expression of placental inflammatory factors in the early pregnancy was not found. Conclusion the perinatal standard supplementation of folic acid significantly reduced the risk of possible developmental delay in the CM energy area of children, during pregnancy, late continuous supplementation of folic acid and significantly increased fetal physical growth and postnatal significance. The reduction of 6 month old children, FM, and the possible developmental delay in the GC area, the relationship among the two groups is due to the direct effect of supplementation of folic acid on the growth and development of the fetus. On the other hand, the placenta plays a mediating role in it. The advantages of supplementing folic acid for the growth and development of the offspring after 12 weeks of pregnancy have attracted attention and supplementation of folic acid during pregnancy. The need for large population randomized controlled trials is needed to extend pregnancy from the present pregnancy to the whole pregnancy.
【学位授予单位】：安徽医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R17
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