王敵，華麗，成晨，王少康

（1.東南大學(xué)公共衛(wèi)生學(xué)院營(yíng)養(yǎng)與食品衛(wèi)生系，環(huán)境醫(yī)學(xué)工程教育部重點(diǎn)實(shí)驗(yàn)室，江蘇 南京 210009；2.句容市婦幼保健院，江蘇 句容 212400）

孕婦葉酸補(bǔ)充情況對(duì)妊娠情況影響的研究進(jìn)展

王敵1，華麗2，成晨1，王少康1

（1.東南大學(xué)公共衛(wèi)生學(xué)院營(yíng)養(yǎng)與食品衛(wèi)生系，環(huán)境醫(yī)學(xué)工程教育部重點(diǎn)實(shí)驗(yàn)室，江蘇 南京 210009；2.句容市婦幼保健院，江蘇 句容 212400）

妊娠過(guò)程異常不僅威脅孕母的健康，而且對(duì)新生兒出生情況、生長(zhǎng)發(fā)育及生命后期都有著重要影響。隨著醫(yī)學(xué)技術(shù)的進(jìn)步，新生兒的生存率在不斷提高，早產(chǎn)兒以及低出生體重的新生兒逐漸增多。如何通過(guò)改變?cè)袐D營(yíng)養(yǎng)素?cái)z入情況來(lái)減少不良妊娠的發(fā)生是營(yíng)養(yǎng)學(xué)研究者的挑戰(zhàn)之一。已有多項(xiàng)研究證明孕婦在孕早期或整個(gè)孕期服用葉酸可以降低先兆子癇的發(fā)生率，同時(shí)也有研究證明葉酸可以降低胎盤早剝、自然流產(chǎn)、宮內(nèi)生長(zhǎng)遲緩和早產(chǎn)的發(fā)生率。本研究就近幾年國(guó)內(nèi)外關(guān)于孕期葉酸補(bǔ)充情況和葉酸相關(guān)代謝酶基因多態(tài)性與先兆子癇、胎盤早剝、自然流產(chǎn)、宮內(nèi)生長(zhǎng)遲緩、早產(chǎn)等不良妊娠關(guān)系進(jìn)行簡(jiǎn)要綜述。

葉酸；先兆子癇；胎盤早剝；自然流產(chǎn)；宮內(nèi)生長(zhǎng)遲緩；早產(chǎn)

葉酸是含有蝶酰谷氨酸結(jié)構(gòu)的一類化合物的統(tǒng)稱，是維持人體正常生命活動(dòng)必需的一種水溶性B族維生素，其主要生物學(xué)功能包括參與嘌呤和胸腺嘧啶的合成，進(jìn)一步合成DNA和RNA；參與氨基酸之間的相互轉(zhuǎn)化，充當(dāng)一碳單位的載體；參與血紅蛋白及重要的甲基化合物合成。美國(guó)食品藥品管理局在1996年作出決定，強(qiáng)制要求自1998年1月起糧食制品添加一定量的合成葉酸。我國(guó)的《中國(guó)居民膳食營(yíng)養(yǎng)素參考攝入量（2013版）》建議我國(guó)成人葉酸每日推薦攝入量為400 μg/DFE（dietary folate equivalent膳食葉酸當(dāng)量）。但妊娠期由于胃酸分泌減少，胃腸蠕動(dòng)減弱，影響孕母對(duì)葉酸的攝取。子宮和胎盤的快速增殖和生長(zhǎng)，胎兒在母體內(nèi)的生長(zhǎng)發(fā)育也會(huì)增加孕婦對(duì)葉酸攝入的需求，并且母體血容量的增加使得血液中葉酸濃度降低[1]，哺乳期由于泌乳而代謝旺盛，使得孕婦和母乳對(duì)葉酸的需求增加。因此孕婦、乳母葉酸每日推薦攝入量分別增加到600 μg/DFE、550 μg/DFE。

20世紀(jì)90年代，瑞典和英國(guó)醫(yī)學(xué)研究協(xié)會(huì)證實(shí)孕前期或孕早期補(bǔ)充葉酸可有效降低新生兒神經(jīng)管畸形的發(fā)生率[2-3]。隨后研究表明，孕期服用葉酸不僅可以降低神經(jīng)管畸形的發(fā)生，還可以降低圓錐動(dòng)脈干畸形、肢體缺失、唇腭裂、肛門閉鎖和臍膨出等多種出生缺陷的發(fā)生率[4]。研究的同時(shí)發(fā)現(xiàn)，孕期服用葉酸也可影響妊娠過(guò)程以及結(jié)局，包括先兆子癇、胎盤早剝、自然流產(chǎn)或死產(chǎn)、早產(chǎn)、低體重出生等。

1 葉酸對(duì)妊娠過(guò)程的影響

1.1 葉酸對(duì)妊娠期先兆子癇發(fā)生的影響 先兆子癇是孕產(chǎn)婦和新生兒發(fā)病和死亡的主要原因，孕產(chǎn)婦中的發(fā)生比例約占5%[5]。美國(guó)的研究數(shù)據(jù)發(fā)現(xiàn)，先兆子癇或者子癇會(huì)增加胎盤早剝、血小板減少、彌散性血管內(nèi)凝血，肺水腫和吸入性肺炎發(fā)生[6]。研究結(jié)果發(fā)現(xiàn)，先兆子癇的發(fā)生與孕期飲食和營(yíng)養(yǎng)素補(bǔ)充劑的攝入情況有關(guān)[7]。

對(duì)印度婦女中的研究發(fā)現(xiàn)，控制孕期充分多樣化的膳食攝入和鐵及葉酸的補(bǔ)充與減少先兆子癇或子癇癥狀發(fā)生具有相關(guān)性[8]。產(chǎn)前體質(zhì)量過(guò)輕（BMI＜25）的孕婦在懷孕前口服葉酸補(bǔ)充劑可降低40%的先兆子癇的發(fā)生率，但對(duì)BMI進(jìn)行調(diào)整后保護(hù)作用差異無(wú)統(tǒng)計(jì)學(xué)意義[9]。隨后在加拿大的前瞻性隊(duì)列研究也發(fā)現(xiàn)孕期補(bǔ)充葉酸可降低先兆子癇發(fā)生的風(fēng)險(xiǎn)，尤其是對(duì)先兆子癇高發(fā)生風(fēng)險(xiǎn)的孕婦[10]。

1.2 葉酸對(duì)自然流產(chǎn)的影響 胚胎著床后30%會(huì)發(fā)生自然流產(chǎn)，而在特定的婦女中，自然流產(chǎn)會(huì)反復(fù)發(fā)生，約1%～2%的女性在生育年齡會(huì)經(jīng)歷3次或以上的自然流產(chǎn)[11]。在第二次護(hù)士健康研究中，對(duì)年齡在22～44歲之間的116 480名女性護(hù)士進(jìn)行18年的隨訪，結(jié)果顯示與未補(bǔ)充葉酸的婦女相比，服用葉酸較多的婦女（每天超過(guò)730 μg）可以降低自然流產(chǎn)的危險(xiǎn)度[12]。然而病例對(duì)照研究得出的結(jié)果是血清葉酸濃度與特發(fā)性復(fù)發(fā)性流產(chǎn)沒(méi)有相關(guān)性[13]。日本的前瞻性隊(duì)列研究也發(fā)現(xiàn)孕婦早期的血清葉酸濃度與流產(chǎn)沒(méi)有關(guān)聯(lián)[14]。

近幾年關(guān)于自然流產(chǎn)的研究多集中在葉酸代謝通路基因多態(tài)性的作用方面。杭州地區(qū)一項(xiàng)漢族人群葉酸代謝通路基因多態(tài)性的病例對(duì)照研究發(fā)現(xiàn)MTHFR677T等位基因和677T/1298A/2756A/66A/80G單倍型是不明原因反復(fù)流產(chǎn)（URPL）的危險(xiǎn)因素，而等位基因MTR2756G和677C/1298A/2756A/66A/80A單倍型則是保護(hù)因素[15]。

1.3 葉酸對(duì)胎兒宮內(nèi)生長(zhǎng)遲緩的影響 孕婦孕期營(yíng)養(yǎng)不良是宮內(nèi)生長(zhǎng)遲緩（IUGR）發(fā)生的重要因素。在嘉興的出生隊(duì)列研究發(fā)現(xiàn)孕前服用葉酸可減少19%的小于胎齡兒的發(fā)生率[16]。國(guó)內(nèi)樣本量為8 743的一項(xiàng)隊(duì)列研究發(fā)現(xiàn)持續(xù)服用葉酸的孕婦小于胎齡兒的發(fā)生率低于未服或偶服葉酸的孕婦[17]。采用巢式病例對(duì)照研究方法對(duì)1 368名育齡婦女納入隊(duì)列進(jìn)行隨訪跟蹤，孕母的葉酸水平與宮內(nèi)生長(zhǎng)遲緩的發(fā)生有關(guān)[18]。根據(jù)印度2005～2006年的全國(guó)家庭健康調(diào)查數(shù)據(jù)發(fā)現(xiàn)孕期服用鐵-葉酸補(bǔ)充劑的出生體質(zhì)量增加6.46克/月[19]。

孕婦在孕早期和孕中期每天補(bǔ)充5 mg葉酸可降低66%的宮內(nèi)生長(zhǎng)遲緩的發(fā)生率[20]。但同時(shí)有文獻(xiàn)報(bào)道孕期第一階段的母體的葉酸水平與胎兒宮內(nèi)生長(zhǎng)受限沒(méi)有相關(guān)性[14]。近幾年動(dòng)物實(shí)驗(yàn)多集中在母體葉酸補(bǔ)充可預(yù)防暴露于地塞米松引起的胎兒-胎盤生長(zhǎng)受限[21]。

1.4 葉酸對(duì)早產(chǎn)的影響 據(jù)估計(jì)，全球每年有1 500萬(wàn)例早產(chǎn)兒出生，早產(chǎn)是新生兒死亡的首要原因，每年超過(guò)100萬(wàn)例嬰兒死于早產(chǎn)并發(fā)癥，早產(chǎn)是繼肺炎之后五歲以下兒童死亡的第二大原因。在184個(gè)國(guó)家中，新生兒出生早產(chǎn)的比例在5%～18%[22]。

在嘉興的出生隊(duì)列研究發(fā)現(xiàn)，孕前開始服用葉酸可降低8%的早產(chǎn)發(fā)生率，但孕后開始補(bǔ)充對(duì)早產(chǎn)發(fā)生率沒(méi)有影響[16]。國(guó)內(nèi)的一個(gè)孕前保健服務(wù)機(jī)構(gòu)對(duì)172 206名產(chǎn)婦進(jìn)行調(diào)查發(fā)現(xiàn)，孕前補(bǔ)充葉酸是早產(chǎn)發(fā)生的保護(hù)因素，并且和孕婦產(chǎn)前的BMI具有交互作用[23]。在孟加拉國(guó)的一項(xiàng)前瞻性研究與之前的研究結(jié)果截然相反，研究結(jié)果顯示孕期補(bǔ)充鐵質(zhì)葉酸是早產(chǎn)發(fā)生的一個(gè)危險(xiǎn)因素，文章中給出的解釋是鐵誘導(dǎo)的大紅細(xì)胞癥可增加血液黏度在一定程度上會(huì)損害子宮胎盤血流量，降低胎盤灌注，增加胎盤梗死的危險(xiǎn)[24]。

2 討論

隨著二胎政策的落實(shí)，國(guó)內(nèi)生育二胎的夫婦逐漸增多，如何減少包括先兆子癇、胎盤早剝等多種復(fù)雜性妊娠疾病的發(fā)生率是對(duì)科研工作者的挑戰(zhàn)。國(guó)家對(duì)孕婦免費(fèi)發(fā)放葉酸使得妊娠期葉酸補(bǔ)充比例逐漸增高。懷孕前及懷孕早期或整個(gè)孕期服用葉酸不僅能夠預(yù)防妊娠期巨幼紅細(xì)胞貧血，而且可以減少先兆子癇、胎盤早剝、自然流產(chǎn)和早產(chǎn)的發(fā)生。近幾年研究重點(diǎn)逐漸轉(zhuǎn)移到葉酸的補(bǔ)充時(shí)機(jī)和補(bǔ)充劑量、葉酸相關(guān)酶的基因多態(tài)性與不良妊娠結(jié)局發(fā)生的相關(guān)性，為個(gè)體化補(bǔ)充葉酸提供證據(jù)。

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Impact of folic acid intake during pregnancy on abnormal pregnancy

Wang Di1,Hua Li2,Cheng Chen1,Wang Shao-kang1
(1.Department of nutrition and food hygiene,School of public health,Southeast University,Key Laboratory of environmental science and engineering of Ministry of Education Jiangsu Province,Nanjing,Jiangsu,210009,China;2.Maternal and child health care hospital of Jurong City,Jurong,Jiangsu,212400,China)

Abnormal pregnancy not only threatens maternal health,but also significantly impacts on the birth condition,growth and development and the quality of later life.With the advances in medical technology,neonatal survival rate continues to increase,and preterm children and low birth weight newborns gradually increase.How to reduce the incidence of adverse pregnancy by changing the nutrient intake of pregnant women is one of the challenges of nutrition researchers.Number of studies have proved that pregnant women who take in folic acid in the first trimester or throughout pregnancy can reduce the incidence of pre-eclampsia,while studies have shown that folic acid intake can also reduce the incidence of placental abruption,spontaneous abortion,intrauterine growth retardation,preterm birth

Folic acid;Preeclampsia;Placental abruption;Spontaneous abortion;Intrauterine growth retardation;Premature birth

10.3969/j.issn.1009-4393.2017.33.082

江蘇省婦幼保健協(xié)會(huì)科研課題（FYX201504）、鎮(zhèn)江市社會(huì)發(fā)展指導(dǎo)性項(xiàng)目及句容市民生科技計(jì)劃項(xiàng)目（FZ2015067）、東南大學(xué)兒童發(fā)展與學(xué)習(xí)科學(xué)教育部重點(diǎn)實(shí)驗(yàn)室開放基金項(xiàng)目（CDLS-2016-04）、東南大學(xué)科研訓(xùn)練計(jì)劃項(xiàng)目（201742017）

王少康，E-mail：shaokangwang@seu.edu.cn