围孕期补充叶酸预防神经管缺陷对策分析

于宏杰+孙思飞+袁红+张黎明+邵月琴+付朝伟

神经管缺陷（Neural-tube defects，NTDs）是是新生儿最常见、最严重的先天性中枢神经系统发育异常，大约占全部出生缺陷的三分之一，死亡率极高。国内外大量研究已经证实，妇女在围孕期补充叶酸可以有效地预防大多数神经管缺陷病例的发生。然而，每年通过补充叶酸实际预防的神经管缺陷病例数只占到全部病例数的10%左右[1-3 ]，预防效果不甚理想。本文拟从叶酸补充方法、补充剂量及预防效果等方面对妇女在围孕期补充叶酸预防神经管缺陷的对策进行分析和探索。

1 补充叶酸对神经管缺陷的预防

一项在中国开展的大规模人群研究显示，妇女在孕前1个月和孕期前3个月每天补充0.4 mg叶酸可以使神经管缺陷的发生率降低41%~79 % [4]。目前关于中国妇女围孕期补充叶酸预防神经管缺陷的效果尚无更多的研究。国外的大量研究证实，围孕期补充叶酸能有效地降低神经管缺陷的发病率，Cochrane对4项增补叶酸预防神经管缺陷初发的随机/准随机试验进行的Meta分析结果显示，增补叶酸对神经管缺陷初发的预防率为72%（RR = 0.28，95% CI：0.13～0.58）[5]。此外，围孕期补充叶酸还能降低神经管缺陷复发的风险，英国的一项多中心随机对照研究表明，围孕期补充叶酸使神经管缺陷的复发率降低了72%[6]。

除常规补充叶酸外，部分国家还在全国范围内启动了食品强化叶酸项目。美国食品和药品管理局（FDA）于1996年规定，在每100 g谷类食品中强化0.14 mg叶酸。随后美国CDC公布的数据显示，与食品强化叶酸前（1995-1996年）相比，强化叶酸后（1999-2000年）美国神经管缺陷的发生率降低了26%[7]。加拿大自1998年开始实施食品强化叶酸计划，强化后神经管缺陷的发生率从之前的1.58/1000降到了0.86/1000，降低了46%（95% CI：40～51）[8]。同样的叶酸强化效果也被南非的研究所证实[9]。

2 补充含叶酸的多维元素对神经管缺陷的预防

部分神经管缺陷的发生与孕妇体内过高的同型半胱氨酸水平有关。叶酸是同型半胱氨酸解毒过程中的关键因子，因此补充叶酸也有利于预防此类神经管缺陷的发生。而维生素B2是亚甲基四氢叶酸还原酶（Methylenetetrahydrofolate reductase，MTHFR）的辅因子，与MTHFR活性密切相关，体内维生素B2不足会导致MTHFR活性的降低，使5-四氢叶酸（5-Methyltetrahydrofolate，5-MTHF）的产生减少，同时增加血浆同型半胱氨酸的水平。而维生素B6和B12是同型半胱氨酸代谢过程中不可或缺的辅助因子，其缺乏也会引起体内同型半胱氨酸水平的升高，从而导致神经管闭合延迟，并间接导致神经管缺陷的发生。因此，服用含叶酸和维生素B2、B6 、B12的多维元素比单纯服用叶酸能更有效地预防神经管缺陷的发生。匈牙利的一项队列研究显示，妇女在围孕期服用含叶酸的多种维生素对初发神经管缺陷的预防率可达89%（OR = 0.11，95% CI：0.01～0.91) [10]。

3 补充叶酸的剂量及安全性

基于大量观察性研究结果，美国最早开始推荐围孕期妇女每日补充0.4 mg叶酸以预防神经管缺陷的发生，这一推荐剂量很快被包括中国在内的众多国家所采纳。Daily等经过研究发现，当孕妇体内红细胞叶酸浓度达到或超过906 nmol/L时才能使神经管缺陷的发生风险降到最低[11]，但每日补充0.4 mg叶酸的妇女其红细胞叶酸水平需要经过8-12周才能达到906 nmol/L，而每日补充0.8 mg叶酸的妇女在4.2周内可达到这一水平[12,13]。从这方面来讲，每日补充较高剂量的叶酸比低剂量更合理。

Wald等人将13项关于服用叶酸后血清浓度的研究进行了分析，结果表明，每日服用0.4 mg叶酸可以预防36%的神经管缺陷病例发生，每日补充1.0 mg叶酸可以预防57%的病例，而每日补充5.0 mg叶酸可以预防85%的病例[14]。因此，叶酸补充剂量越大，预防神经管缺陷的效果越好。

但对于围孕期妇女来说，每日补充叶酸的剂量不仅需要考虑其预防神经管缺陷的效果，还要考虑其安全性。尽管叶酸本身是无毒的，但有证据显示，每日补充叶酸超过5 mg有可能会掩盖维生素B12缺乏症的血液学指征，导致维生素B12缺乏症不能被及时发现，如果每日补充叶酸的剂量低于5 mg则不会发生这种情况。据美国CDC研究数据显示，维生素B12缺乏症在年龄4～50岁之间的人群中并不常见，发病率低于1%。鉴于以上原因，美国国家医学研究院（IOM）在其营养素推荐摄入量指南中指出，“使用达到或超过摄入上限(1 mg/d)的叶酸补充剂不会产生副作用”。

美国家庭医师学会（AAFP）和美国预防医学工作组（USPSTF）分别于2008年和2009年推荐计划怀孕或可能怀孕的妇女每日补充0.4～0.8 mg叶酸或含叶酸的多维元素补充剂以预防神经管缺陷的发生[15,16]。考虑到美国从1996年就开始实施了食品强化叶酸计划（每100 g谷类食品中强化0. 14 mg叶酸），美国孕妇每日实际摄入叶酸的量已经达到甚至超过了1 mg。与美国一样，加拿大也已实施了食品强化叶酸的计划，在此基础上，加拿大妇产科医师学会（SOGC）推荐孕前、孕中及哺乳期妇女每天补充含0.4～1.0 mg叶酸的多维元素补充剂[17]，因此，加拿大孕妇每日实际摄入叶酸的量也在1 mg左右。中华医学会妇产科学分会产科学组于2011年发布了《孕前及孕期保健指南》，建议孕妇每日补充0.4～0.8 mg叶酸来预防神经管缺陷的发生[18]。由于中国目前并未推动食品强化叶酸的计划，因此，与西方国家相比，中国孕妇每日实际摄入叶酸的量相对较低。

综上所述，关于通过补充叶酸来预防神经管缺陷的研究已取得了新的较大进展，补充含叶酸的多维元素的预防效果优于单纯补充叶酸。但鉴于随机对照试验（Randomized Controlled Trial，RCT）证据的缺乏，各国对于围孕期妇女服用叶酸的具体剂量仍未达成完全一致。基于目前的研究结果，围孕期妇女可适当增加服用叶酸的剂量，同时提高服用的依从性，以更好地预防神经管缺陷的发生。

参考文献

[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. 中国妇女妊娠前后单纯服用叶酸对神经管缺陷的预防效果[J]. 中华医学杂志, 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] 中华医学会妇产科学分会产科学组.孕前及孕期保健指南（第1版）.中华妇产科杂志,2011,46(2):150-153.

作者简介：于宏杰（1982—），男，汉族，研究生，医师，Email：jiecky2002@163.com

[4] 李竹，Robert J Berry，李松，等. 中国妇女妊娠前后单纯服用叶酸对神经管缺陷的预防效果[J]. 中华医学杂志, 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] 中华医学会妇产科学分会产科学组.孕前及孕期保健指南（第1版）.中华妇产科杂志,2011,46(2):150-153.

作者简介：于宏杰（1982—），男，汉族，研究生，医师，Email：jiecky2002@163.com

[4] 李竹，Robert J Berry，李松，等. 中国妇女妊娠前后单纯服用叶酸对神经管缺陷的预防效果[J]. 中华医学杂志, 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] 中华医学会妇产科学分会产科学组.孕前及孕期保健指南（第1版）.中华妇产科杂志,2011,46(2):150-153.

作者简介：于宏杰（1982—），男，汉族，研究生，医师，Email：jiecky2002@163.com