Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Pediatr. Aug 8, 2015; 4(3): 41-44
Published online Aug 8, 2015. doi: 10.5409/wjcp.v4.i3.41
Prevention of neural tube defects with folic acid: The Chinese experience
Ai-Guo Ren
Ai-Guo Ren, Institute of Reproductive and Child Health and Ministry of Health Key Laboratory of Reproductive Health, Peking University, Beijing 100191, China
Author contributions: Ren AG solely contributed to this work.
Conflict-of-interest statement: The author declares no competing financial or no-financial conflict of interests.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ai-Guo Ren, MD, PhD, Institute of Reproductive and Child Health and Ministry of Health Key Laboratory of Reproductive Health, Peking University, 38 College Road, Haidian District, Beijing 100191, China. renag@bjmu.edu.cn
Telephone: +86-10-82801140 Fax: +86-10-82801141
Received: March 25, 2015
Peer-review started: March 31, 2015
First decision: May 13, 2015
Revised: May 21, 2015
Accepted: June 18, 2015
Article in press: June 19, 2015
Published online: August 8, 2015


Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system that are caused by the closure failure of the embryonic neural tube by the 28th day of conception. Anencephaly and spina bifida are the two major subtypes. Fetuses with anencephaly are often stillborn or electively aborted due to prenatal diagnosis, or they die shortly after birth. Most infants with spina bifida are live-born and, with proper surgical treatment, can survive into adulthood. However, these children often have life-long physical disabilities. China has one of the highest prevalence of NTDs in the world. Inadequate dietary folate intake is believed to be the main cause of the cluster. Unlike many other countries that use staple fortification with folic acid as the public health strategy to prevent NTDs, the Chinese government provides all women who have a rural household registration and who plan to become pregnant with folic acid supplements, free of charge, through a nation-wide program started in 2009. Two to three years after the initiation of the program, the folic acid supplementation rate increased to 85% in the areas of the highest NTD prevalence. The mean plasma folate level of women during early and mid-pregnancy doubled the level before the program was introduced. However, most women began taking folic acid supplements when they knew that they were pregnant. This is too late for the protection of the embryonic neural tube. In a post-program survey of the women who reported folic acid supplementation, less than a quarter of the women began taking supplements prior to pregnancy, indicating that the remaining three quarters of the fetuses remained unprotected during the time of neural tube formation. Therefore, staple food fortification with folic acid should be considered as a priority in the prevention of NTDs.

Key Words: Neural tube defects, Folic acid, Folate, Supplementation, Fortification

Core tip: Neural tube defects are severe congenital malformations of the central nervous system. The prevalence of these defects in China is among the highest in the world. Low intake of dietary folate is to be blamed. The provision of free-of-charge folic acid supplements to all women who live in rural areas and plan to become pregnant has been implemented since 2009. However, fortification of staple foods with folic acid has not been planned. It is time to consider fortification since many pregnancies are unplanned and therefore it is difficult for a woman to take folic acid supplements from before pregnancy.


Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system that are caused by the failure of the embryonic neural tube to close by the 28th day of conception[1,2]. Anencephaly and spina bifida are the two major subtypes of NTDs. A closure failure that occurs in the cranial region of the neural tube leads to anencephaly, which is characterized by the absence of the cranial vault and absent or markedly reduced cerebral hemispheres. Fetuses with anencephaly are often stillborn or electively aborted due to prenatal diagnosis, or they die shortly after birth. A closure defect occurring in the caudal region of the neural tube is referred to as spina bifida or meningomyelocele. This condition is characterized by bony defects in the spine through which the meninges and/or spinal cord tissue protrude to the body surface. Most infants with spina bifida are live-born and, with proper surgical treatment and management, can survive into adulthood. However, these children often have life-long physical disabilities, including leg paralysis, absence of control of urine and bowel, and learning difficulties. In addition, a large proportion of infants with spina bifida are complicated with hydrocephalus, which may lead to intellectual impairment and even premature death.


NTDs are the second most common birth defect after congenital heart defects. It has been estimated that every year more than 320000 infants are born with NTDs worldwide[3]. However, the prevalence of infants born with NTDs varies widely between countries and also within countries. In China, NTD epidemiology is characterized by a higher prevalence in the North than in the South and a higher prevalence in rural areas than in cities. A nationwide survey conducted in 1986-1987 showed an overall prevalence of 45.5 per 10000 births in the 15 northern provinces, compared with 11.3 per 10000 births in 12 Southern provinces[4]. Of the northern provinces, Shanxi had the highest prevalence, with 68.5 per 10000 births for males and 144 per 10000 births for females. During the same period, the prevalence of NTDs was 6 per 10000 births in the United States[5]. Ireland is well known for its high prevalence of NTDs. East Ireland had a prevalence rate about 23 per 10000 births in 1986-1987[6]. These data indicate that the prevalence of NTDs in Northern China is among the highest in the world. It has been estimated that around 100000 fetuses are affected annually in China. In recent years, the prevalence of NTDs in China has been declining consistently, but no national data are available to clarify how much of this trend is attributable to fewer NTD occurrences or to avoidance through pregnancy termination after prenatal diagnosis. This is because the national birth defects monitoring system includes only pregnancies of 28 wk’ gestation or greater, thus not counting any pregnancies that are terminated before 28 wk’ gestation. One study showed that more than two-thirds of NTD-affected pregnancies were terminated before 28 wk of gestation in the Shanxi rural population in early 2000s[7]. This proportion is expected to be over 90% in urban populations. Surveillance data from 5 counties in Shanxi Province show that NTD prevalence declined from a peak of 120 per 10000 births in 2004 to 31.5 per 10000 births in 2014 (unpublished data). The latter remains much higher than the current prevalence of NTDs (5-7 per 10000 births) in the United States[8].


It has long been known that low blood folate during the periconceptional period is associated with an increased risk that a pregnancy will be affected by an NTD[9]. Folate is the natural form of folic acid contained in food and in the body. Folic acid is the synthetic form that is used in supplements and fortified foods. Folate cannot be synthesized in the body and therefore can only be obtained from food. The typical diet of northern China is characterized by low amounts of fresh vegetables and fruits; this results in low blood folate. An investigation among women in Shanxi’s rural population who were planning to become pregnant showed that the mean (± SD) and median (interquartile range) daily folate intake values were 114.3 ± 59.7 μg/d and 102.8 (69.3-146.8) μg/d, respectively. Virtually all (99%) of the women had an intake level below 320 μg/d, the estimated average requirement for non-pregnant women, and only 1% and 7% of the women consumed 75% and 50%, respectively, of the recommended daily folate intake of 400 μg for non-pregnant women[10]. As a result of this low dietary folate intake, people living in the North have less than half the blood folate level of people living in the South. During early to mid-pregnancy, women living in the North had plasma and erythrocyte folate concentrations of 12.2 nmol/L and 440.0 nmol/L, respectively, compared to 33.5 nmol/L and 910.4 nmol/L, respectively, for women living in the south[11]. Low dietary folate intake and low blood folate concentration lead to a high risk of an NTD-affected pregnancy.


Although folate may be taken in naturally via the diet, folate intake from the diet alone cannot meet the needs of pregnant women and their growing fetuses. Folic acid supplements and consumption of folic acid-fortified cereals or staples are two alternatives to increase folate intake. In the late 1980s, a multicenter randomized controlled trial demonstrated that supplementation with 4 mg of daily folic acid during the periconceptional period could reduce the risk of NTD recurrence (i.e., a subsequent NTD baby) by as much as 83%[12]. A later randomized controlled trial conducted in Hungary showed that periconceptional supplementation with an 0.8 mg folic acid-containing multivitamin every day could prevent the first occurrence of NTDs[13]. In the early 1990s, Peking University conducted a large-scale community interventional trial on the prevention of NTDs with folic acid with 247831 women of reproductive age, in collaboration with the Centers for Disease Control and Prevention of the United States. The results confirmed that periconceptional supplementation with only 0.4 mg of folic acid per day can reduce NTD risk by as much as 81%[14]. However, science discoveries are not easy to translate into public health or clinical practice. For example, between 2002 and 2004, only 15% of pregnant women in Shanxi Province reported that they had ever taken folic acid supplements during the periconceptional period, and only one-third of these women took the supplements prior to pregnancy[15]. To tackle this problem, the Chinese government launched a program that provides folic acid supplements, free of charge, to all women with a rural household registration who plan to become pregnant (estimated total number, 8 million) in 2009. The supplements are procured by provincial governments, but paid in total or in part by the central government. Local maternal health care workers are responsible for the distribution of the supplements. In 2011, the perinatal (28 gestational weeks to 4 wk of life) prevalence of NTDs decreased by 22.4% in rural areas compared to that in 2009[16]. In 2011 and 2012, 2 to 3 years after the initiation of the supplementation program, the folic acid supplementation rate had increased to 85% in the areas of highest NTD prevalence[17]. The mean plasma folate concentration of women during early and mid-pregnancy increased to 33.4 nmol/L (range, 18.7-58.4 nmol/L), double the level before the program was introduced[18]. However, the proportion of women who began taking folic acid prior to pregnancy did not increase. In a post-program survey of the women who reported folic acid supplementation, 23.2% had begun taking supplements prior to pregnancy, compared to 27.3% in the pre-program survey in the high NTD prevalence population[17], indicating that many fetuses/embryos remained unprotected during the time of neural tube formation.


The provision of folic acid supplements can be costly when manpower and the other logistical efforts involved in its distribution are taken into account. It is estimated that the Chinese central government needs 195 million RMB (about United States dollar 31 million) per year for supplement procurement. More important, many pregnancies are unplanned, meaning that supplementation with folic acid prior to pregnancy is impossible. On the other hand, staple fortification can supply folic acid “passively” to all women of reproductive age (and unintentionally to other segments of a population as well). Currently, about 80 countries have adopted or plan to implement staple fortification with folic acid[19]. Reported NTD prevalence has been reduced by 28% in the United States[8], by 46% in Canada[20], and by 50% in Chile[21] since fortification began. However, China has no plan to fortify staple foods in the foreseeable future. Perceived major barriers to the implementation of staple fortification include[22]: (1) a lack of consensus in the scientific community; (2) the absence of a centralized production and distribution system for staples; (3) a lack of public awareness and acceptance; and (4) a lack of political will. The author hopes that these problems can be solved so that fortified flour and/or rice will become commercially available.


Since the recent change in China’s family planning policy, more women wish to have a second baby. A proportion of these women are in their 30s or even 40s, meaning that they are at an increased risk of conceiving babies with down syndrome. In addition, advanced age is associated with a greater likelihood of obesity and diabetes, which are confirmed risk factors for NTD-affected pregnancies. This is an imminent challenge for the prevention of birth defects, including NTDs. In the battle to combat NTDs, physicians, including pediatricians, can play a critical role in every clinical encounter with women of reproductive age. For women who plan to have a second baby, pediatricians should advise them to take a 0.4-mg folic acid supplement daily beginning 3 mo prior to pregnancy or when there is a chance they may become pregnant. For women with a previous pregnancy affected by NTDs, it is recommended that they take 5 mg of folic acid daily, beginning from 3 mo before a pregnancy is planned. The ultimate goal is to protect each fetus from NTDs, which are preventable with folic acid.


P- Reviewer: Classen CF, Sergi CM, Urganci N S- Editor: Tian YL L- Editor: A E- Editor: Liu SQ

1.  Botto LD, Moore CA, Khoury MJ, Erickson JD. Neural-tube defects. N Engl J Med. 1999;341:1509-1519.  [PubMed]  [DOI]
2.  Wallingford JB, Niswander LA, Shaw GM, Finnell RH. The continuing challenge of understanding, preventing, and treating neural tube defects. Science. 2013;339:1222002.  [PubMed]  [DOI]
3.  March of Dimes global report on birth defects: the hidden toll of dying and disabled children. [Accessed May 23, 2014].  Available from: http://www.marchofdimes.org/mission/march-of-dimes-global-report-on-birth-defects.aspx.  [PubMed]  [DOI]
4.  Chinese Birth Defects Monitoring Collaborative Group Atlas of Birth Defects in China. Chengdu: Chengdu Map Publishing House 1992; .  [PubMed]  [DOI]
5.  Yen IH, Khoury MJ, Erickson JD, James LM, Waters GD, Berry RJ. The changing epidemiology of neural tube defects. United States, 1968-1989. Am J Dis Child. 1992;146:857-861.  [PubMed]  [DOI]
6.  McDonnell RJ, Johnson Z, Delaney V, Dack P. East Ireland 1980-1994: epidemiology of neural tube defects. J Epidemiol Community Health. 1999;53:782-788.  [PubMed]  [DOI]
7.  Li K, He XB, Zhang L, Li ZW, Ye RW, Liu JM, Zhai RQ, Duan XJ, Ren AG. [Impact of pregnancy terminations before 28 weeks of gestation on the overall prevalence of neural tube defects in two counties of Shanxi province]. Zhonghua Liuxing Bingxue Zazhi. 2012;33:509-512.  [PubMed]  [DOI]
8.  Williams J, Mai CT, Mulinare J, Isenburg J, Flood TJ, Ethen M, Frohnert B, Kirby RS. Updated estimates of neural tube defects prevented by mandatory folic Acid fortification - United States, 1995-2011. MMWR Morb Mortal Wkly Rep. 2015;64:1-5.  [PubMed]  [DOI]
9.  Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. JAMA. 1995;274:1698-1702.  [PubMed]  [DOI]
10.  Meng Q, Zhang L, Liu J, Li Z, Jin L, Zhang Y, Wang L, Ren A. Dietary folate intake levels in rural women immediately before pregnancy in Northern China. Birth Defects Res A Clin Mol Teratol. 2015;103:27-36.  [PubMed]  [DOI]
11.  Ren A, Zhang L, Hao L, Li Z, Tian Y, Li Z. Comparison of blood folate levels among pregnant Chinese women in areas with high and low prevalence of neural tube defects. Public Health Nutr. 2007;10:762-768.  [PubMed]  [DOI]
12.  Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991;338:131-137.  [PubMed]  [DOI]
13.  Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327:1832-1835.  [PubMed]  [DOI]
14.  Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, Mulinare J, Zhao P, Wong LY, Gindler J. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med. 1999;341:1485-1490.  [PubMed]  [DOI]
15.  Ren A, Zhang L, Li Z, Hao L, Tian Y, Li Z. Awareness and use of folic acid, and blood folate concentrations among pregnant women in northern China--an area with a high prevalence of neural tube defects. Reprod Toxicol. 2006;22:431-436.  [PubMed]  [DOI]
16.  Ministry of Health. Birth Defects Prevention and Control in China. [Accessed April 18, 2014].  Available from: http://www.gov.cn/gzdt/att/att/site1/20120912/1c6f6506c7f811bacf9301.pdf.  [PubMed]  [DOI]
17.  Liu J, Jin L, Meng Q, Gao L, Zhang L, Li Z, Ren A. Changes in folic acid supplementation behaviour among women of reproductive age after the implementation of a massive supplementation programme in China. Public Health Nutr. 2015;18:582-588.  [PubMed]  [DOI]
18.  Liu J, Gao L, Zhang Y, Jin L, Li Z, Zhang L, Meng Q, Ye R, Wang L, Ren A. Plasma folate levels in early to mid pregnancy after a nation-wide folic acid supplementation program in areas with high and low prevalence of neural tube defects in china. Birth Defects Res A Clin Mol Teratol. 2015;103:501-508.  [PubMed]  [DOI]
19.  Global Progress, 2014 . [Accessed March 28, 2014].  Available from: http://www.ffinetwork.org/global_progress/.  [PubMed]  [DOI]
20.  De Wals P, Tairou F, Van Allen MI, Uh SH, Lowry RB, Sibbald B, Evans JA, Van den Hof MC, Zimmer P, Crowley M. Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med. 2007;357:135-142.  [PubMed]  [DOI]
21.  Cortés F, Mellado C, Pardo RA, Villarroel LA, Hertrampf E. Wheat flour fortification with folic acid: changes in neural tube defects rates in Chile. Am J Med Genet A. 2012;158A:1885-1890.  [PubMed]  [DOI]
22.  Ren A. Neural tube defects prevention with folic acid. Beijing Daxue Xuebao. 2014;46:343-346.  [PubMed]  [DOI]