Wald Nicholas J, Vale Stephen H, Bestwick Jonathan P, Morris Joan K
UCL Institute of Health Informatics, University College London, London, UK
Population Health Research Institute, City St George's University of London, London, UK.
Arch Dis Child. 2025 Jul 18;110(8):651-656. doi: 10.1136/archdischild-2024-328115.
Neural tube defects (NTDs) are a preventable folate deficiency disorder; increasing folic acid intake through food fortification increases serum and red blood cell folate and reduces the risk of an NTD pregnancy. There is controversy over the blood folate level needed to achieve the full preventive effect because of discrepant study conclusions.
Results from two published studies were used to determine the relationship between serum folate and NTD risk which was compared with the observed result in a randomised trial of folic acid that increased serum folate from 5 ng/mL to 44 ng/mL among women who took a 4 mg daily periconceptional folic acid supplement.
Both studies showed a proportional (logarithmic) relationship between serum folate and NTD risk without evidence of a folate threshold above which there is no further NTD risk reduction. The suggestion of a threshold is due to the incorrect interpretation of the folate-NTD risk association when plotted on arithmetic scales, which conceals the proportional relationship between the two. Also, both studies accurately estimated the observed result from the randomised trial that achieved a median serum folate level of 44 ng/mL and an 83% preventive effect. This is much higher than has been achieved with current levels of folic acid fortification with serum folate between 10 and 16 ng/mL, resulting in an approximate 20% preventive effect.
To achieve fully effective fortification, median population serum folate levels need to be about 44 ng/mL, which would globally prevent about 250 000 NTD cases every year.
神经管缺陷（NTDs）是一种可预防的叶酸缺乏症；通过食物强化增加叶酸摄入量可提高血清和红细胞叶酸水平，并降低NTD妊娠风险。由于研究结论存在差异，对于实现完全预防效果所需的血液叶酸水平存在争议。
两项已发表研究的结果用于确定血清叶酸与NTD风险之间的关系，并与一项叶酸随机试验的观察结果进行比较，该试验使每日服用4毫克孕前叶酸补充剂的女性血清叶酸水平从5纳克/毫升提高到44纳克/毫升。
两项研究均显示血清叶酸与NTD风险之间存在比例（对数）关系，没有证据表明存在一个叶酸阈值，超过该阈值NTD风险就不会进一步降低。关于阈值的建议是由于在算术尺度上绘制叶酸与NTD风险关联时的错误解释，这掩盖了两者之间的比例关系。此外，两项研究都准确估计了随机试验的观察结果，该试验的血清叶酸中位数水平为44纳克/毫升，预防效果为83%。这远高于目前叶酸强化水平所达到的效果，目前血清叶酸水平在10至16纳克/毫升之间，预防效果约为20%。
为实现完全有效的强化，人群血清叶酸中位数水平需要达到约44纳克/毫升，这将在全球范围内每年预防约25万例NTD病例。
