Skip to main content Accessibility help

Folic acid supplementation, dietary folate intake and risk of small for gestational age in China

  • Huaqi Guo (a1) (a2) (a3), Baohong Mao (a1), Meng Wang (a1) (a3), Qing Liu (a1), Liping Yang (a4), Yahui Xie (a1), Yanxia Wang (a1), Xiaochun He (a1), Hongmei Cui (a1), Xiaojuan Lin (a1), Ling Lv (a1), Min Zhou (a1), Xiaoying Xu (a1), Jie Qiu (a1) (a3) and Yawei Zhang (a5)...



To investigate the hypothesis that folic acid supplementation and dietary folate intake before conception and during pregnancy reduce the risk of small for gestational age (SGA) and to examine the joint effect of folic acid supplementation and dietary folate intake on the risk of SGA.


Participants were interviewed by trained study interviewers using a standardized and structured questionnaire. Information on birth outcomes and maternal complications was abstracted from medical records and dietary information was collected via a semi-quantitative FFQ before conception and during pregnancy.


A birth cohort data analysis using the 2010–2012 Gansu Provincial Maternity and Child Care Hospital.


Women (n 8758) and their children enrolled in the study.


Folic acid supplementation was associated with a reduced risk of SGA (OR = 0·72, 95 % CI 0·60, 0·86), with the reduced risk seen mainly for SGA at ≥37 weeks of gestational age (OR = 0·70, 95 % CI 0·58, 0·85) and nulliparous SGA (OR = 0·67, 95 % CI 0·54, 0·84). There was no significant association between dietary folate intake and SGA risk.


Our study suggested that folic acid supplementation was associated with a reduced risk of SGA and the risk varied by preterm status and parity.


Corresponding author

*Corresponding authors: Email,


Hide All

Huaqi Guo, Baohong Mao and Meng Wang contributed equally to the present study and should be regarded as co-first authors.



Hide All
1. McIntire, DD, Bloom, SL, Casey, BM et al. (1999) Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 340, 12341238.
2. Pallotto, EK & Kilbride, HW (2006) Perinatal outcome and later implications of intrauterine growth restriction. Clin Obstet Gynecol 49, 257269.
3. Hack, M, Taylor, HG, Drotar, D et al. (2005) Chronic conditions, functional limitations, and special health care needs of school-aged children born with extremely low-birth-weight in the 1990s. JAMA 294, 318325.
4. Hille, ET, den Ouden, AL, Saigal, S et al. (2001) Behavioural problems in children who weigh 1000 g or less at birth in four countries. Lancet 357, 16411643.
5. Nafee, TM, Farrell, WE, Carroll, WD et al. (2008) Epigenetic control of fetal gene expression. BJOG 115, 158168.
6. Schlotz, W & Phillips, DI (2009) Fetal origins of mental health: evidence and mechanisms. Brain Behav Immun 23, 905916.
7. Tosh, DN, Fu, Q, Callaway, CW et al. (2010) Epigenetics of programmed obesity: alteration in IUGR rat hepatic IGF1 mRNA expression and histone structure in rapid vs. delayed postnatal catch-up growth. Am J Physiol Gastrointest Liver Physiol 299, G1023G1029.
8. Waterland, RA (2009) Is epigenetics an important link between early life events and adult disease? Horm Res 71, 1316.
9. Weinstock, M (2005) The potential influence of maternal stress hormones on development and mental health of the offspring. Brain Behav Immun 19, 296308.
10. Lockwood, CJ (2002) Predicting premature delivery – no easy task. N Engl J Med 346, 282284.
11. Krishnaswamy, K & Madhavan Nair, K (2001) Importance of folate in human nutrition. Br J Nutr 85, Suppl. 2, S115S124.
12. Baker, BC, Mackie, FL, Lean, SC et al. (2017) Placental dysfunction is associated with altered microRNA expression in pregnant women with low folate status. Mol Nutr Food Res 61, 1600646.
13. Bergen, NE, Jaddoe, VW, Timmermans, S et al. (2012) Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: the Generation R Study. BJOG 119, 739751.
14. Bukowski, R, Malone, FD, Porter, FT et al. (2009) Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study. PLoS Med 6, e1000061.
15. Catov, JM, Bodnar, LM, Olsen, J et al. (2011) Periconceptional multivitamin use and risk of preterm or small-for-gestational-age births in the Danish National Birth Cohort. Am J Clin Nutr 94, 906912.
16. Chen, S, Zhu, R, Zhu, H et al. (2017) The prevalence and risk factors of preterm small-for-gestational-age infants: a population-based retrospective cohort study in rural Chinese population. BMC Pregnancy Childbirth 17, 237.
17. Dwarkanath, P, Barzilay, JR, Thomas, T et al. (2013) High folate and low vitamin B-12 intakes during pregnancy are associated with small-for-gestational age infants in South Indian women: a prospective observational cohort study. Am J Clin Nutr 98, 14501458.
18. Furness, DL, Yasin, N, Dekker, GA et al. (2012) Maternal red blood cell folate concentration at 10–12 weeks gestation and pregnancy outcome. J Matern Fetal Neonatal Med 25, 14231427.
19. Goldenberg, RL, Tamura, T, Cliver, SP et al. (1992) Serum folate and fetal growth retardation: a matter of compliance? Obstet Gynecol 79, 719722.
20. Hodgetts, VA, Morris, RK, Francis, A et al. (2015) Effectiveness of folic acid supplementation in pregnancy on reducing the risk of small-for-gestational age neonates: a population study, systematic review and meta-analysis. BJOG 122, 478490.
21. Kim, MW, Ahn, KH, Ryu, KJ et al. (2014) Preventive effects of folic acid supplementation on adverse maternal and fetal outcomes. PLoS One 9, e97273.
22. Li, N, Li, Z, Ye, R et al. (2017) Impact of periconceptional folic acid supplementation on low birth weight and small-for-gestational-age infants in China: a large prospective cohort study. J Pediatr 187, 105110.
23. Navarrete-Munoz, EM, Gimenez Monzo, D, Garcia de La Hera, M et al. (2010) Folic acid intake from diet and supplements in a population of pregnant women in Valencia, Spain. Med Clin (Barc) 135, 637643.
24. Navarrete-Munoz, EM, Valera-Gran, D, Garcia-de-la-Hera, M et al. (2019) High doses of folic acid in the periconceptional period and risk of low weight for gestational age at birth in a population based cohort study. Eur J Nutr 58, 241251.
25. Nilsen, RM, Vollset, SE, Monsen, AL et al. (2010) Infant birth size is not associated with maternal intake and status of folate during the second trimester in Norwegian pregnant women. J Nutr 140, 572579.
26. Papadopoulou, E, Stratakis, N, Roumeliotaki, T et al. (2013) The effect of high doses of folic acid and iron supplementation in early-to-mid pregnancy on prematurity and fetal growth retardation: the mother–child cohort study in Crete, Greece (Rhea study). Eur J Nutr 52, 327336.
27. Pastor-Valero, M, Navarrete-Munoz, EM, Rebagliato, M et al. (2011) Periconceptional folic acid supplementation and anthropometric measures at birth in a cohort of pregnant women in Valencia, Spain. Br J Nutr 105, 13521360.
28. Rolschau, J, Kristoffersen, K, Ulrich, M et al. (1999) The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part I. Eur J Obstet Gynecol Reprod Biol 87, 105110.
29. Ronnenberg, AG, Goldman, MB, Chen, D et al. (2002) Preconception homocysteine and B vitamin status and birth outcomes in Chinese women. Am J Clin Nutr 76, 13851391.
30. Timmermans, S, Jaddoe, VW, Hofman, A et al. (2009) Periconception folic acid supplementation, fetal growth and the risks of low birth weight and preterm birth: the Generation R Study. Br J Nutr 102, 777785.
31. Wang, S, Ge, X, Zhu, B et al. (2016) Maternal continuing folic acid supplementation after the first trimester of pregnancy increased the risk of large-for-gestational-age birth: a population-based birth cohort study. Nutrients 8, 493.
32. Yan, SQ, Xu, YQ, Su, PY et al. (2013) Relationship between folic acid supplements during peri-conceptional period and the adverse pregnancy outcomes: a cohort study. Zhonghua Liu Xing Bing Xue Za Zhi 34, 14.
33. Yang, T, Gu, Y, Wei, X et al. (2017) Periconceptional folic acid supplementation and vitamin B12 status in a cohort of Chinese early pregnancy women with the risk of adverse pregnancy outcomes. J Clin Biochem Nutr 60, 136142.
34. Zheng, JS, Guan, Y, Zhao, Y et al. (2016) Pre-conceptional intake of folic acid supplements is inversely associated with risk of preterm birth and small-for-gestational-age birth: a prospective cohort study. Br J Nutr 115, 509516.
35. Policy and Research Team, Save the Children China Programme (n.d.) Laws and Policies for Maternal and Young Child Health Care in China. (accessed November 2019).
36. Kloosterman, GJ (1970) On intrauterine growth. Int J Gynecol Obstet 8, 895912.
37. Shaw, GM, Carmichael, SL, Nelson, V et al. (2004) Occurrence of low birthweight and preterm delivery among California infants before and after compulsory food fortification with folic acid. Public Health Rep 119, 170173.
38. de Bree, A, van Dusseldorp, M, Brouwer, IA et al. (1997) Folate intake in Europe: recommended, actual and desired intake. Eur J Clin Nutr 51, 643660.
39. Scholl, TO & Johnson, WG (2000) Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 71, 5 Suppl., 1295S1303S.
40. World Health Organization & Food and Agriculture Organization of the United Nations (2004) Folate and folic acid. In Vitamin and Mineral Requirements in Human Nutrition, 2nd ed., pp. 289302. Rome: FAO.
41. Ren, AG (2015) Prevention of neural tube defects with folic acid: the Chinese experience. World J Clin Pediatr 4, 4144.
42. Liu, J, Jin, L, Meng, Q et al. (2015) Changes in folic acid supplementation behaviour among women of reproductive age after the implementation of a massive supplementation programme in China. Public Health Nutr 18, 582588.
43. Zeng, Z & Zhu, J (2010) Low folic acid supplement intake rate among women in northern China with a high-prevalence of neural tube defects, 2008. Prev Med 51, 338339.
44. Zhang, L, Ren, A, Li, Z et al. (2006) Folate concentrations and folic acid supplementation among women in their first trimester of pregnancy in a rural area with a high prevalence of neural tube defects in Shanxi, China. Birth Defects Res A Clin Mol Teratol 76, 461466.
45. Liu, X, Lv, L, Zhang, H et al. (2016) Folic acid supplementation, dietary folate intake and risk of preterm birth in China. Eur J Nutr 55, 14111422.
46. Qiu, J, He, X, Cui, H et al. (2014) Passive smoking and preterm birth in urban China. Am J Epidemiol 180, 94102.
47. Wang, Y, Zhao, N, Qiu, J et al. (2015) Folic acid supplementation and dietary folate intake, and risk of preeclampsia. Eur J Clin Nutr 69, 11451150.
48. Zhao, N, Qiu, J, Zhang, Y et al. (2015) Ambient air pollutant PM10 and risk of preterm birth in Lanzhou, China. Environ Int 76, 7177.
49. Dai, L, Deng, C, Li, Y et al. (2014) Birth weight reference percentiles for Chinese. PLoS One 9, e104779.
50. Duryea, EL, Hawkins, JS, McIntire, DD et al. (2014) A revised birth weight reference for the United States. Obstet Gynecol 124, 1622.
51. Institute of Nutrition and Food Hygiene, Chinese Academy of Preventive Medicine (1999) Table of Food Components (National Representative Values). Beijing: People’s Hygiene Press.
52. Tamura, T & Picciano, MF (2006) Folate and human reproduction. Am J Clin Nutr 83, 9931016.
53. Timmermans, S, Jaddoe, VW, Silva, LM et al. (2011) Folic acid is positively associated with uteroplacental vascular resistance: the Generation R study. Nutr Metab Cardiovasc Dis 21, 5461.
54. Bailey, LB & Gregory, JF , 3rd (1999) Folate metabolism and requirements. J Nutr 129, 779782.
55. Bleker, OP, Buimer, M, van der Post, JA et al. (2006) Ted (G.J.) Kloosterman: on intrauterine growth. The significance of prenatal care. Studies on birth weight, placental weight and placental index. Placenta 27, 10521054.
56. Pennisi, E (2005) Environmental epigenomics meeting. Supplements restore gene function via methylation. Science 310, 1761.
57. Waterland, RA & Jirtle, RL (2004) Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 20, 6368.
58. Steegers-Theunissen, RP & Steegers, EA (2003) Nutrient–gene interactions in early pregnancy: a vascular hypothesis. Eur J Obstet Gynecol Reprod Biol 106, 115117.
59. Rolschau, J (1978) A prospective study of the placental weight and content of protein, RNA and DNA. Acta Obstet Gynecol Scand 57, 2843.
60. Cikot, RJ, Steegers-Theunissen, RP, Thomas, CM et al. (2001) Longitudinal vitamin and homocysteine levels in normal pregnancy. Br J Nutr 85, 4958.
61. Thaler, CJ (2014) Folate metabolism and human reproduction. Geburtshilfe Frauenheilkd 74, 845851.
62. McPartlin, J, Halligan, A, Scott, JM et al. (1993) Accelerated folate breakdown in pregnancy. Lancet 341, 148149.
63. Scholl, TO, Hediger, ML, Schall, JI et al. (1996) Dietary and serum folate: their influence on the outcome of pregnancy. Am J Clin Nutr 63, 520525.


Type Description Title
Supplementary materials

Guo et al. supplementary material
Table S1

 Word (52 KB)
52 KB

Folic acid supplementation, dietary folate intake and risk of small for gestational age in China

  • Huaqi Guo (a1) (a2) (a3), Baohong Mao (a1), Meng Wang (a1) (a3), Qing Liu (a1), Liping Yang (a4), Yahui Xie (a1), Yanxia Wang (a1), Xiaochun He (a1), Hongmei Cui (a1), Xiaojuan Lin (a1), Ling Lv (a1), Min Zhou (a1), Xiaoying Xu (a1), Jie Qiu (a1) (a3) and Yawei Zhang (a5)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed