發(fā)布時(shí)間：2018-07-18 11:20

【摘要】：目的圍孕期增補(bǔ)葉酸預(yù)防先天神經(jīng)管畸形已被研究所證實(shí)并付諸實(shí)踐,但不同孕期增補(bǔ)葉酸對(duì)胎兒生長及出生后神經(jīng)行為發(fā)育的影響目前尚不清楚,且引起越來越多的關(guān)注。本研究目的是闡明孕婦不同孕期增補(bǔ)葉酸對(duì)胎兒生長及出生后6月齡、18月齡神經(jīng)行為發(fā)育的影響,并探討胎盤在二者關(guān)聯(lián)中的作用。方法采用前瞻性出生隊(duì)列研究設(shè)計(jì),自2013年5月到2014年9月,選取在馬鞍山市婦幼保健院首次建立孕產(chǎn)婦保健手冊(cè)并意愿在該醫(yī)院進(jìn)行定期產(chǎn)檢和分娩的孕婦為研究對(duì)象,建立馬鞍山優(yōu)生優(yōu)育出生隊(duì)列(MABC)。共納入孕婦3 474人,162例孕婦出現(xiàn)不良妊娠結(jié)局、39名孕婦分娩雙胎、13人糖尿病合并妊娠、6人高血壓合并妊娠、嬰兒出生體重缺失者8人,3 246對(duì)單胎活產(chǎn)親子納入本研究。制訂三個(gè)孕期的《孕產(chǎn)婦保健信息問卷》,分別在孕早、中、晚期收集孕婦人口統(tǒng)計(jì)學(xué)指標(biāo)、孕產(chǎn)史、妊娠合并癥與并發(fā)癥,分別收集孕前、孕早期、孕中期、孕晚期葉酸及其它營養(yǎng)補(bǔ)充劑的增補(bǔ)情況;分娩時(shí)記錄胎齡、出生體重、身長、頭圍、胸圍、胎盤的長徑、寬徑、厚度、臍帶長度及羊水量,收集新鮮胎盤組織液氮保存,半年內(nèi)提取胎盤組織RNA,采用RT-PCR檢測(cè)胎盤炎性相關(guān)因子的m RNA表達(dá)水平;出生后收集嬰兒喂養(yǎng)方式、輔食添加、家庭環(huán)境等,運(yùn)用年齡與發(fā)育進(jìn)程量表(中國版)(ASQ-C)評(píng)定兒童6月齡、18月齡時(shí)的發(fā)育行為。運(yùn)用Epi Data 3.0建立數(shù)據(jù)庫,運(yùn)用SPSS 16.0與STATA 10.0進(jìn)行統(tǒng)計(jì)分析。組間比較:分類變量采用χ2檢驗(yàn),連續(xù)型資料服從正態(tài)分布使用方差分析(ANOVA)、服從偏態(tài)分布采用非參數(shù)Kruskal-Wallis H檢驗(yàn);應(yīng)用單因素、多因素二分類Logistic回歸分析不同孕期增補(bǔ)葉酸對(duì)大于胎齡兒(LGA)、小于胎齡兒(SGA)及6月齡、18月齡各能區(qū)發(fā)育遲緩的危險(xiǎn)度,應(yīng)用線性回歸分析不同孕期增補(bǔ)葉酸對(duì)分娩時(shí)新生兒大小、胎盤大小及胎盤炎性相關(guān)因子表達(dá)的影響;在多元回歸分析的基礎(chǔ)上,采用傾向值加權(quán)調(diào)整以增加不同葉酸補(bǔ)充組間的可比性。結(jié)果本研究隊(duì)列孕早期葉酸的補(bǔ)充率最高,每天補(bǔ)充者2 365人,占72.9%,每周補(bǔ)充3~6次者434人,占13.4%,合計(jì)占86.3%;其次是孕前一個(gè)月內(nèi);孕中、晚期葉酸的補(bǔ)充率較低。葉酸補(bǔ)充劑量為醫(yī)生推薦的每天400μg。圍孕期(包括孕前與孕早期)增補(bǔ)葉酸與新生兒出生體重、身長、頭圍、胸圍、胎齡無統(tǒng)計(jì)學(xué)關(guān)聯(lián);在孕早期補(bǔ)充葉酸的基礎(chǔ)上,孕12周后持續(xù)增補(bǔ)葉酸促進(jìn)胎兒的生長,增加LGA發(fā)生的風(fēng)險(xiǎn)(RR=1.75,95%CI:1.13~2.62),該關(guān)聯(lián)在調(diào)整了母親懷孕時(shí)年齡、孕前體質(zhì)指數(shù)(BMI)、母親文化程度、家庭人均月收入、居住地、母親吸煙、飲酒及補(bǔ)鈣情況、妊娠糖尿病及妊娠期高血壓、胎兒性別及產(chǎn)次后依然存在。采用傾向值加權(quán)調(diào)整的多元線性回歸表明:在調(diào)整了各種混雜因素后,孕中期增補(bǔ)葉酸增加新生兒出生體重68.19(95%CI:15.43~120.96,P=0.011)g、頭圍0.226(95%CI:0.008~0.443,P=0.042)cm和胸圍0.257(95%CI:0.070~0.445,P=0.007)cm,孕晚期增補(bǔ)葉酸增加新生兒出生體重57.31(95%CI:14.34~100.28,P=0.009)g、身長0.253(95%CI:0.093~0.413,P=0.002)cm、頭圍0.168(95%CI:0.015~0.320,P=0.031)cm和胸圍0.169(95%CI:0.008~0.331,P=0.039)cm。MABC親子隊(duì)列中,兒童6月齡、18月齡兒童行為發(fā)育狀況良好,發(fā)育遲緩率較低。孕前增補(bǔ)葉酸顯著增加6月齡兒童溝通(CM)及個(gè)人-社會(huì)(PS)兩個(gè)能區(qū)的得分(P0.05),采用傾向值加權(quán)調(diào)整的多因素分析發(fā)現(xiàn):與孕前、孕早期均不補(bǔ)充葉酸組比較,圍孕期規(guī)范增補(bǔ)葉酸顯著降低兒童18月齡CM能區(qū)可能發(fā)育遲緩風(fēng)險(xiǎn)(a RR=0.478,95%CI:0.264~0.864;P=0.015),該效應(yīng)主要是由于孕前葉酸的補(bǔ)充;孕早期增補(bǔ)葉酸顯著增加18月齡兒童解決問題(GC)能區(qū)的得分(P=0.007)。孕中、晚期持續(xù)補(bǔ)充葉酸顯著降低6月齡兒童精細(xì)動(dòng)作(FM)能區(qū)與GC能區(qū)的發(fā)育遲緩風(fēng)險(xiǎn),這種保護(hù)作用在采用傾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、晚期持續(xù)補(bǔ)充葉酸與兒童18月齡ASQ各能區(qū)的得分及發(fā)育遲緩率關(guān)聯(lián)均無統(tǒng)計(jì)學(xué)意義。以未補(bǔ)充葉酸組為對(duì)照,采用傾向值加權(quán)調(diào)整后,孕前增補(bǔ)葉酸增加胎盤的寬徑0.241(95%CI:0.052~0.429;P=0.013)cm、面積6.398(95%CI:1.407~11.389;P=0.012)cm2,孕早期、孕中期增補(bǔ)葉酸顯著增加胎盤的厚度(0.061,95%CI:0.004~0.117,P=0.036;0.066,95%CI:0.004~0.129,P=0.038)cm,孕晚期增補(bǔ)葉酸與胎盤相關(guān)指標(biāo)間關(guān)聯(lián)無統(tǒng)計(jì)學(xué)意義。較大的胎盤長、寬、面積、厚度(最高三分位數(shù))對(duì)6月齡兒童FM能區(qū)發(fā)育遲緩有保護(hù)作用,較大的胎盤厚度對(duì)6月齡兒童GC能區(qū)發(fā)育遲緩有保護(hù)作用,較大的胎盤寬徑、面積對(duì)6月齡兒童PS能區(qū)發(fā)育遲緩有保護(hù)作用;較大的胎盤長徑對(duì)18月齡兒童CM能區(qū)發(fā)育遲緩有保護(hù)作用,較大胎盤厚度對(duì)18月齡兒童粗大動(dòng)作(GM)能區(qū)發(fā)育遲緩有保護(hù)作用孕前增補(bǔ)葉酸與胎盤血紅素加氧酶-1(HO-1)、低氧誘導(dǎo)因子-1(HIF-1a)、葡萄糖調(diào)節(jié)蛋白78(GRP78)的表達(dá)增加有關(guān),與白細(xì)胞介素-4(IL-4)、巨細(xì)胞表型因子206(CD206)的表達(dá)減低有關(guān);孕晚期增補(bǔ)葉酸與GRP78、腫瘤壞死因子(TNF-α)、白細(xì)胞介素-8(IL-8)、巨細(xì)胞表型因子68(CD68)的表達(dá)減低相關(guān);未發(fā)現(xiàn)孕早期、孕中期補(bǔ)充葉酸對(duì)胎盤炎癥因子表達(dá)的影響。結(jié)論圍孕期規(guī)范增補(bǔ)葉酸顯著降低了18月齡兒童CM能區(qū)可能發(fā)育遲緩風(fēng)險(xiǎn),孕中、晚期持續(xù)增補(bǔ)葉酸與顯著提高的胎兒體格生長及出生后顯著降低的6月齡兒童FM、GC能區(qū)可能發(fā)育遲緩相關(guān),二者間的關(guān)聯(lián)一方面由于增補(bǔ)葉酸對(duì)胎兒生長發(fā)育的直接作用,另一方面胎盤在其中起到一定的中介作用。有關(guān)孕12周后持續(xù)增補(bǔ)葉酸對(duì)子代生長發(fā)育的優(yōu)勢(shì)已引起關(guān)注,孕期葉酸的增補(bǔ)是否需要從現(xiàn)在的圍孕期延長至整個(gè)孕期尚需要大規(guī)模人群隨機(jī)對(duì)照試驗(yàn)來驗(yàn)證。
[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.
【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R17

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