于宏杰+孫思飛+袁紅+張黎明+邵月琴+付朝偉

神經(jīng)管缺陷（Neural-tube defects，NTDs）是是新生兒最常見、最嚴(yán)重的先天性中樞神經(jīng)系統(tǒng)發(fā)育異常，大約占全部出生缺陷的三分之一，死亡率極高。國內(nèi)外大量研究已經(jīng)證實(shí)，婦女在圍孕期補(bǔ)充葉酸可以有效地預(yù)防大多數(shù)神經(jīng)管缺陷病例的發(fā)生。然而，每年通過補(bǔ)充葉酸實(shí)際預(yù)防的神經(jīng)管缺陷病例數(shù)只占到全部病例數(shù)的10%左右[1-3 ]，預(yù)防效果不甚理想。本文擬從葉酸補(bǔ)充方法、補(bǔ)充劑量及預(yù)防效果等方面對婦女在圍孕期補(bǔ)充葉酸預(yù)防神經(jīng)管缺陷的對策進(jìn)行分析和探索。

1 補(bǔ)充葉酸對神經(jīng)管缺陷的預(yù)防

一項(xiàng)在中國開展的大規(guī)模人群研究顯示，婦女在孕前1個(gè)月和孕期前3個(gè)月每天補(bǔ)充0.4 mg葉酸可以使神經(jīng)管缺陷的發(fā)生率降低41%~79 % [4]。目前關(guān)于中國婦女圍孕期補(bǔ)充葉酸預(yù)防神經(jīng)管缺陷的效果尚無更多的研究。國外的大量研究證實(shí)，圍孕期補(bǔ)充葉酸能有效地降低神經(jīng)管缺陷的發(fā)病率，Cochrane對4項(xiàng)增補(bǔ)葉酸預(yù)防神經(jīng)管缺陷初發(fā)的隨機(jī)/準(zhǔn)隨機(jī)試驗(yàn)進(jìn)行的Meta分析結(jié)果顯示，增補(bǔ)葉酸對神經(jīng)管缺陷初發(fā)的預(yù)防率為72%（RR = 0.28，95% CI：0.13～0.58）[5]。此外，圍孕期補(bǔ)充葉酸還能降低神經(jīng)管缺陷復(fù)發(fā)的風(fēng)險(xiǎn)，英國的一項(xiàng)多中心隨機(jī)對照研究表明，圍孕期補(bǔ)充葉酸使神經(jīng)管缺陷的復(fù)發(fā)率降低了72%[6]。

除常規(guī)補(bǔ)充葉酸外，部分國家還在全國范圍內(nèi)啟動了食品強(qiáng)化葉酸項(xiàng)目。美國食品和藥品管理局（FDA）于1996年規(guī)定，在每100 g谷類食品中強(qiáng)化0.14 mg葉酸。隨后美國CDC公布的數(shù)據(jù)顯示，與食品強(qiáng)化葉酸前（1995-1996年）相比，強(qiáng)化葉酸后（1999-2000年）美國神經(jīng)管缺陷的發(fā)生率降低了26%[7]。加拿大自1998年開始實(shí)施食品強(qiáng)化葉酸計(jì)劃，強(qiáng)化后神經(jīng)管缺陷的發(fā)生率從之前的1.58/1000降到了0.86/1000，降低了46%（95% CI：40～51）[8]。同樣的葉酸強(qiáng)化效果也被南非的研究所證實(shí)[9]。

2 補(bǔ)充含葉酸的多維元素對神經(jīng)管缺陷的預(yù)防

部分神經(jīng)管缺陷的發(fā)生與孕婦體內(nèi)過高的同型半胱氨酸水平有關(guān)。葉酸是同型半胱氨酸解毒過程中的關(guān)鍵因子，因此補(bǔ)充葉酸也有利于預(yù)防此類神經(jīng)管缺陷的發(fā)生。而維生素B2是亞甲基四氫葉酸還原酶（Methylenetetrahydrofolate reductase，MTHFR）的輔因子，與MTHFR活性密切相關(guān)，體內(nèi)維生素B2不足會導(dǎo)致MTHFR活性的降低，使5-四氫葉酸（5-Methyltetrahydrofolate，5-MTHF）的產(chǎn)生減少，同時(shí)增加血漿同型半胱氨酸的水平。而維生素B6和B12是同型半胱氨酸代謝過程中不可或缺的輔助因子，其缺乏也會引起體內(nèi)同型半胱氨酸水平的升高，從而導(dǎo)致神經(jīng)管閉合延遲，并間接導(dǎo)致神經(jīng)管缺陷的發(fā)生。因此，服用含葉酸和維生素B2、B6 、B12的多維元素比單純服用葉酸能更有效地預(yù)防神經(jīng)管缺陷的發(fā)生。匈牙利的一項(xiàng)隊(duì)列研究顯示，婦女在圍孕期服用含葉酸的多種維生素對初發(fā)神經(jīng)管缺陷的預(yù)防率可達(dá)89%（OR = 0.11，95% CI：0.01～0.91) [10]。

3 補(bǔ)充葉酸的劑量及安全性

基于大量觀察性研究結(jié)果，美國最早開始推薦圍孕期婦女每日補(bǔ)充0.4 mg葉酸以預(yù)防神經(jīng)管缺陷的發(fā)生，這一推薦劑量很快被包括中國在內(nèi)的眾多國家所采納。Daily等經(jīng)過研究發(fā)現(xiàn)，當(dāng)孕婦體內(nèi)紅細(xì)胞葉酸濃度達(dá)到或超過906 nmol/L時(shí)才能使神經(jīng)管缺陷的發(fā)生風(fēng)險(xiǎn)降到最低[11]，但每日補(bǔ)充0.4 mg葉酸的婦女其紅細(xì)胞葉酸水平需要經(jīng)過8-12周才能達(dá)到906 nmol/L，而每日補(bǔ)充0.8 mg葉酸的婦女在4.2周內(nèi)可達(dá)到這一水平[12,13]。從這方面來講，每日補(bǔ)充較高劑量的葉酸比低劑量更合理。

Wald等人將13項(xiàng)關(guān)于服用葉酸后血清濃度的研究進(jìn)行了分析，結(jié)果表明，每日服用0.4 mg葉酸可以預(yù)防36%的神經(jīng)管缺陷病例發(fā)生，每日補(bǔ)充1.0 mg葉酸可以預(yù)防57%的病例，而每日補(bǔ)充5.0 mg葉酸可以預(yù)防85%的病例[14]。因此，葉酸補(bǔ)充劑量越大，預(yù)防神經(jīng)管缺陷的效果越好。

但對于圍孕期婦女來說，每日補(bǔ)充葉酸的劑量不僅需要考慮其預(yù)防神經(jīng)管缺陷的效果，還要考慮其安全性。盡管葉酸本身是無毒的，但有證據(jù)顯示，每日補(bǔ)充葉酸超過5 mg有可能會掩蓋維生素B12缺乏癥的血液學(xué)指征，導(dǎo)致維生素B12缺乏癥不能被及時(shí)發(fā)現(xiàn)，如果每日補(bǔ)充葉酸的劑量低于5 mg則不會發(fā)生這種情況。據(jù)美國CDC研究數(shù)據(jù)顯示，維生素B12缺乏癥在年齡4～50歲之間的人群中并不常見，發(fā)病率低于1%。鑒于以上原因，美國國家醫(yī)學(xué)研究院（IOM）在其營養(yǎng)素推薦攝入量指南中指出，“使用達(dá)到或超過攝入上限(1 mg/d)的葉酸補(bǔ)充劑不會產(chǎn)生副作用”。

美國家庭醫(yī)師學(xué)會（AAFP）和美國預(yù)防醫(yī)學(xué)工作組（USPSTF）分別于2008年和2009年推薦計(jì)劃懷孕或可能懷孕的婦女每日補(bǔ)充0.4～0.8 mg葉酸或含葉酸的多維元素補(bǔ)充劑以預(yù)防神經(jīng)管缺陷的發(fā)生[15,16]。考慮到美國從1996年就開始實(shí)施了食品強(qiáng)化葉酸計(jì)劃（每100 g谷類食品中強(qiáng)化0. 14 mg葉酸），美國孕婦每日實(shí)際攝入葉酸的量已經(jīng)達(dá)到甚至超過了1 mg。與美國一樣，加拿大也已實(shí)施了食品強(qiáng)化葉酸的計(jì)劃，在此基礎(chǔ)上，加拿大婦產(chǎn)科醫(yī)師學(xué)會（SOGC）推薦孕前、孕中及哺乳期婦女每天補(bǔ)充含0.4～1.0 mg葉酸的多維元素補(bǔ)充劑[17]，因此，加拿大孕婦每日實(shí)際攝入葉酸的量也在1 mg左右。中華醫(yī)學(xué)會婦產(chǎn)科學(xué)分會產(chǎn)科學(xué)組于2011年發(fā)布了《孕前及孕期保健指南》，建議孕婦每日補(bǔ)充0.4～0.8 mg葉酸來預(yù)防神經(jīng)管缺陷的發(fā)生[18]。由于中國目前并未推動食品強(qiáng)化葉酸的計(jì)劃，因此，與西方國家相比，中國孕婦每日實(shí)際攝入葉酸的量相對較低。

綜上所述，關(guān)于通過補(bǔ)充葉酸來預(yù)防神經(jīng)管缺陷的研究已取得了新的較大進(jìn)展，補(bǔ)充含葉酸的多維元素的預(yù)防效果優(yōu)于單純補(bǔ)充葉酸。但鑒于隨機(jī)對照試驗(yàn)（Randomized Controlled Trial，RCT）證據(jù)的缺乏，各國對于圍孕期婦女服用葉酸的具體劑量仍未達(dá)成完全一致?；谀壳暗难芯拷Y(jié)果，圍孕期婦女可適當(dāng)增加服用葉酸的劑量，同時(shí)提高服用的依從性，以更好地預(yù)防神經(jīng)管缺陷的發(fā)生。

參考文獻(xiàn)

[1] Bell KN, Oakley GP Jr. Update on prevention of folic acid-preventable spina bifida and anencephaly [J]. Birth Defects Res A Clin Mol Teratol, 2009, 85 (1): 102-107.

[2] Oakley GP Jr. Elimination of folic acid-preventable neural tube defects [J]. A m J Prev Med, 2008, 35(6): 606-607.

[3] Oakley GP Jr, Bell KN, Weber MB. Recommendations for accelerating globle action to prevent folic acid2preventable birth defects and other folate-deficiency diseases: meeting of experts on preventing folic acid-preventable neural tube defects [J]. Birth Defects Res A Clin Mol Teratol, 2004, 70(11): 835-837.

[4] 李竹，Robert J Berry，李松，等. 中國婦女妊娠前后單純服用葉酸對神經(jīng)管缺陷的預(yù)防效果[J]. 中華醫(yī)學(xué)雜志, 2000, 80(7): 493-498.

[5] Lumley J, Watson L, Watson M, et al. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects[J]. Cochrane Database Syst Rev, 2001, ( 3 ): CD001056.

[6] MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet, 1991, 338: 131-7.

[7] Centers for Disease Control and Prevention(CDC). Use of dietary supplements containing folic acid among women of child bearing age——United States, 2005 [J]. MMWR Morb Mortal Wkly Rep, 2005, 54(38): 955-958.

[8] De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural tube defects after folic acid fortification in Canada [J]. N Engl J Med, 2007, 357(2): 135-142.

[9] Sayed AR, Bourne D, Pattinson R, et al. Decline in the prevalence of neural tube defects following folic acid fortification and its cost-benefit in South Africa [J]. Birth Defects Res A Clin Mol Teratol, 2008, 82(4): 211-216.

[10] Czeizel AE, Dobo M, Vargha P. Haungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities [J]. Birth Def ects Res A Clin Mol Teratol, 2004, 70 (11): 853-861.

[11] Daily LE, Kirke PN, Molloy A, et al. Folate levels and neural tube defects. Implications for prevention. JAMA, 1993, 274: 1698-1702.

[12] Pietrzik K, Lamers Y, Bramswig S, et al. Calculation of red blood cell folate steady state conditions and elimination kinetics after daily supplementation with various folate forms and doses in women in childbearing age. Am J Clin Nutr, 2007, 86: 1414-1419.

[13] Bramswig S, Prinz-Langenohl R, Lamers Y, et al. Supplementation with a multivitamin containing 800 microg of folic acid shortens the time to reach the preventive red blood cell folate concentration in healthy women. Int J Vitam Nutr Res, 2009, 79: 61-70.

[14] Wald NJ, Law MR, Morris JK, et al. Quantifying the effect of folic acid. Lancet, 2001, 358(9298): 2069-2073.

[15] American Academy of Family Physicians. Summary of recommendations for clinical and preventive services. Leawood, Kansas. AAFP, 2008[2014-4-18]. http://www.aafp.org/online/en/home/clinical/exam.html.

[16] U.S. Preventive Services Task Force. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine, 2009, 150(9): 626-632.

[17] Wilson RD, et al. Pre-conceptional vitamin/folic acid supplementation 2007: The use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. Joint SOGC-motherisk clinical practice guideline, No.201, December 2007.

[18] 中華醫(yī)學(xué)會婦產(chǎn)科學(xué)分會產(chǎn)科學(xué)組.孕前及孕期保健指南（第1版）.中華婦產(chǎn)科雜志,2011,46(2):150-153.

作者簡介：于宏杰（1982—），男，漢族，研究生，醫(yī)師，Email：jiecky2002@163.com

[4] 李竹，Robert J Berry，李松，等. 中國婦女妊娠前后單純服用葉酸對神經(jīng)管缺陷的預(yù)防效果[J]. 中華醫(yī)學(xué)雜志, 2000, 80(7): 493-498.

[5] Lumley J, Watson L, Watson M, et al. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects[J]. Cochrane Database Syst Rev, 2001, ( 3 ): CD001056.

[6] MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet, 1991, 338: 131-7.

[7] Centers for Disease Control and Prevention(CDC). Use of dietary supplements containing folic acid among women of child bearing age——United States, 2005 [J]. MMWR Morb Mortal Wkly Rep, 2005, 54(38): 955-958.

[8] De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural tube defects after folic acid fortification in Canada [J]. N Engl J Med, 2007, 357(2): 135-142.

[9] Sayed AR, Bourne D, Pattinson R, et al. Decline in the prevalence of neural tube defects following folic acid fortification and its cost-benefit in South Africa [J]. Birth Defects Res A Clin Mol Teratol, 2008, 82(4): 211-216.

[10] Czeizel AE, Dobo M, Vargha P. Haungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities [J]. Birth Def ects Res A Clin Mol Teratol, 2004, 70 (11): 853-861.

[11] Daily LE, Kirke PN, Molloy A, et al. Folate levels and neural tube defects. Implications for prevention. JAMA, 1993, 274: 1698-1702.

[12] Pietrzik K, Lamers Y, Bramswig S, et al. Calculation of red blood cell folate steady state conditions and elimination kinetics after daily supplementation with various folate forms and doses in women in childbearing age. Am J Clin Nutr, 2007, 86: 1414-1419.

[13] Bramswig S, Prinz-Langenohl R, Lamers Y, et al. Supplementation with a multivitamin containing 800 microg of folic acid shortens the time to reach the preventive red blood cell folate concentration in healthy women. Int J Vitam Nutr Res, 2009, 79: 61-70.

[14] Wald NJ, Law MR, Morris JK, et al. Quantifying the effect of folic acid. Lancet, 2001, 358(9298): 2069-2073.

[15] American Academy of Family Physicians. Summary of recommendations for clinical and preventive services. Leawood, Kansas. AAFP, 2008[2014-4-18]. http://www.aafp.org/online/en/home/clinical/exam.html.

[16] U.S. Preventive Services Task Force. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine, 2009, 150(9): 626-632.

[17] Wilson RD, et al. Pre-conceptional vitamin/folic acid supplementation 2007: The use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. Joint SOGC-motherisk clinical practice guideline, No.201, December 2007.

[18] 中華醫(yī)學(xué)會婦產(chǎn)科學(xué)分會產(chǎn)科學(xué)組.孕前及孕期保健指南（第1版）.中華婦產(chǎn)科雜志,2011,46(2):150-153.

作者簡介：于宏杰（1982—），男，漢族，研究生，醫(yī)師，Email：jiecky2002@163.com

[4] 李竹，Robert J Berry，李松，等. 中國婦女妊娠前后單純服用葉酸對神經(jīng)管缺陷的預(yù)防效果[J]. 中華醫(yī)學(xué)雜志, 2000, 80(7): 493-498.

[5] Lumley J, Watson L, Watson M, et al. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects[J]. Cochrane Database Syst Rev, 2001, ( 3 ): CD001056.

[6] MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet, 1991, 338: 131-7.

[7] Centers for Disease Control and Prevention(CDC). Use of dietary supplements containing folic acid among women of child bearing age——United States, 2005 [J]. MMWR Morb Mortal Wkly Rep, 2005, 54(38): 955-958.

[8] De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural tube defects after folic acid fortification in Canada [J]. N Engl J Med, 2007, 357(2): 135-142.

[9] Sayed AR, Bourne D, Pattinson R, et al. Decline in the prevalence of neural tube defects following folic acid fortification and its cost-benefit in South Africa [J]. Birth Defects Res A Clin Mol Teratol, 2008, 82(4): 211-216.

[10] Czeizel AE, Dobo M, Vargha P. Haungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities [J]. Birth Def ects Res A Clin Mol Teratol, 2004, 70 (11): 853-861.

[11] Daily LE, Kirke PN, Molloy A, et al. Folate levels and neural tube defects. Implications for prevention. JAMA, 1993, 274: 1698-1702.

[12] Pietrzik K, Lamers Y, Bramswig S, et al. Calculation of red blood cell folate steady state conditions and elimination kinetics after daily supplementation with various folate forms and doses in women in childbearing age. Am J Clin Nutr, 2007, 86: 1414-1419.

[13] Bramswig S, Prinz-Langenohl R, Lamers Y, et al. Supplementation with a multivitamin containing 800 microg of folic acid shortens the time to reach the preventive red blood cell folate concentration in healthy women. Int J Vitam Nutr Res, 2009, 79: 61-70.

[14] Wald NJ, Law MR, Morris JK, et al. Quantifying the effect of folic acid. Lancet, 2001, 358(9298): 2069-2073.

[15] American Academy of Family Physicians. Summary of recommendations for clinical and preventive services. Leawood, Kansas. AAFP, 2008[2014-4-18]. http://www.aafp.org/online/en/home/clinical/exam.html.

[16] U.S. Preventive Services Task Force. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine, 2009, 150(9): 626-632.

[17] Wilson RD, et al. Pre-conceptional vitamin/folic acid supplementation 2007: The use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. Joint SOGC-motherisk clinical practice guideline, No.201, December 2007.

[18] 中華醫(yī)學(xué)會婦產(chǎn)科學(xué)分會產(chǎn)科學(xué)組.孕前及孕期保健指南（第1版）.中華婦產(chǎn)科雜志,2011,46(2):150-153.

作者簡介：于宏杰（1982—），男，漢族，研究生，醫(yī)師，Email：jiecky2002@163.com