圍孕期補充葉酸預防神經管缺陷對策分析

于宏杰+孫思飛+袁紅+張黎明+邵月琴+付朝偉

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

1 補充葉酸對神經管缺陷的預防

一項在中國開展的大規模人群研究顯示，婦女在孕前1個月和孕期前3個月每天補充0.4 mg葉酸可以使神經管缺陷的發生率降低41%~79 % [4]。目前關于中國婦女圍孕期補充葉酸預防神經管缺陷的效果尚無更多的研究。國外的大量研究證實，圍孕期補充葉酸能有效地降低神經管缺陷的發病率，Cochrane對4項增補葉酸預防神經管缺陷初發的隨機/準隨機試驗進行的Meta分析結果顯示，增補葉酸對神經管缺陷初發的預防率為72%（RR = 0.28，95% CI：0.13～0.58）[5]。此外，圍孕期補充葉酸還能降低神經管缺陷復發的風險，英國的一項多中心隨機對照研究表明，圍孕期補充葉酸使神經管缺陷的復發率降低了72%[6]。

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

2 補充含葉酸的多維元素對神經管缺陷的預防

部分神經管缺陷的發生與孕婦體內過高的同型半胱氨酸水平有關。葉酸是同型半胱氨酸解毒過程中的關鍵因子，因此補充葉酸也有利于預防此類神經管缺陷的發生。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，體內維生素B2不足會導致MTHFR活性的降低，使5-四氫葉酸（5-Methyltetrahydrofolate，5-MTHF）的產生減少，同時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同型半胱氨酸水平的升高，從而導致神經管閉合延遲，并間接導致神經管缺陷的發生。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防神經管缺陷的發生。匈牙利的一項隊列研究顯示，婦女在圍孕期服用含葉酸的多種維生素對初發神經管缺陷的預防率可達89%（OR = 0.11，95% CI：0.01～0.91) [10]。

3 補充葉酸的劑量及安全性

基于大量觀察性研究結果，美國最早開始推薦圍孕期婦女每日補充0.4 mg葉酸以預防神經管缺陷的發生，這一推薦劑量很快被包括中國在內的眾多國家所采納。Daily等經過研究發現，當孕婦體內紅細胞葉酸濃度達到或超過906 nmol/L時才能使神經管缺陷的發生風險降到最低[11]，但每日補充0.4 mg葉酸的婦女其紅細胞葉酸水平需要經過8-12周才能達到906 nmol/L，而每日補充0.8 mg葉酸的婦女在4.2周內可達到這一水平[12,13]。從這方面來講，每日補充較高劑量的葉酸比低劑量更合理。

Wald等人將13項關于服用葉酸后血清濃度的研究進行了分析，結果表明，每日服用0.4 mg葉酸可以預防36%的神經管缺陷病例發生，每日補充1.0 mg葉酸可以預防57%的病例，而每日補充5.0 mg葉酸可以預防85%的病例[14]。因此，葉酸補充劑量越大，預防神經管缺陷的效果越好。

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

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

綜上所述，關于通過補充葉酸來預防神經管缺陷的研究已取得了新的較大進展，補充含葉酸的多維元素的預防效果優于單純補充葉酸。但鑒于隨機對照試驗（Randomized Controlled Trial，RCT）證據的缺乏，各國對于圍孕期婦女服用葉酸的具體劑量仍未達成完全一致。基于目前的研究結果，圍孕期婦女可適當增加服用葉酸的劑量，同時提高服用的依從性，以更好地預防神經管缺陷的發生。

參考文獻

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[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管缺陷的預防效果[J]. 中華醫學雜志, 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] 中華醫學會婦產科學分會產科學組.孕前及孕期保健指南（第1版）.中華婦產科雜志,2011,46(2):150-153.

作者簡介：于宏杰（1982—），男，漢族，研究生，醫師，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管缺陷的預防效果[J]. 中華醫學雜志, 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] 中華醫學會婦產科學分會產科學組.孕前及孕期保健指南（第1版）.中華婦產科雜志,2011,46(2):150-153.

作者簡介：于宏杰（1982—），男，漢族，研究生，醫師，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管缺陷的預防效果[J]. 中華醫學雜志, 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] 中華醫學會婦產科學分會產科學組.孕前及孕期保健指南（第1版）.中華婦產科雜志,2011,46(2):150-153.

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