Food, Nutrition and Health, Faculty of Land and Food Systems, The University of British Columbia, 2205 East Mall, Vancouver, BC, V6T 1Z4, Canada.
BC Children's Hospital Research Institute, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
Trials. 2020 May 5;21(1):380. doi: 10.1186/s13063-020-04320-3.
North American health authorities recommend 0.4 mg/day folic acid before conception and throughout pregnancy to reduce the risk of neural tube defects. Folic acid is a synthetic form of folate that must be reduced by dihydrofolate reductase and then further metabolized. Recent evidence suggests that the maximal capacity for this process is limited and unmetabolized folic acid has been detected in the circulation. The biological effects of unmetabolized folic acid are unknown. A natural form of folate, (6S)-5-methyltetrahydrofolic acid (Metafolin®), may be a superior alternative because it does not need to be reduced in the small intestine. Metafolin® is currently used in some prenatal multivitamins; however, it has yet to be evaluated during pregnancy.
METHODS/DESIGN: This double-blind, randomized trial will recruit 60 pregnant women aged 19-42 years. The women will receive either 0.6 mg/day folic acid or an equimolar dose (0.625 mg/day) of (6S)-5-methyltetrahydrofolic acid for 16 weeks. The trial will be initiated at 8-21 weeks' gestation (after neural tube closure) to reduce the risk of harm should (6S)-5-methyltetrahydrofolic acid prove less effective. All women will also receive a prenatal multivitamin (not containing folate) to ensure adequacy of other nutrients. Baseline and endline blood samples will be collected to assess primary outcome measures, including serum folate, red blood cell folate and unmetabolized folic acid. The extent to which the change in primary outcomes from baseline to endline differs between treatment groups, controlling for baseline level, will be estimated using linear regression. Participants will have the option to continue supplementing until 1 week postpartum to provide a breastmilk and blood sample. Exploratory analyses will be completed to evaluate breastmilk and postpartum blood folate concentrations.
This proof-of-concept trial is needed to obtain estimates of the effect of (6S)-5-methyltetrahydrofolic acid compared to folic acid on circulating biomarkers of folate status during pregnancy. These estimates will inform the design of a definitive trial which will be powered to assess whether (6S)-5-methyltetrahydrofolic acid is as effective as folic acid in raising blood folate concentrations during pregnancy. Ultimately, these findings will inform folate supplementation policies for pregnant women.
ClinicalTrials.gov, ID: NCT04022135. Registered on 14 July 2019.
北美卫生当局建议在受孕前和整个孕期每天摄入 0.4 毫克叶酸，以降低神经管缺陷的风险。叶酸是叶酸的合成形式，必须由二氢叶酸还原酶还原，然后进一步代谢。最近的证据表明，这个过程的最大能力是有限的，并且未代谢的叶酸已在循环中被检测到。未代谢的叶酸的生物学效应尚不清楚。一种天然形式的叶酸，（6S）-5-甲基四氢叶酸（Metafolin®），可能是一种更好的替代物，因为它不需要在小肠中还原。Metafolin®目前用于一些产前多种维生素中；然而，它在怀孕期间尚未得到评估。
方法/设计：这项双盲、随机试验将招募 60 名年龄在 19-42 岁的孕妇。这些女性将每天服用 0.6 毫克叶酸或等量（0.625 毫克/天）的（6S）-5-甲基四氢叶酸，持续 16 周。试验将在 8-21 周妊娠（神经管关闭后）开始，以降低（6S）-5-甲基四氢叶酸效果较差时对孕妇造成伤害的风险。所有女性还将服用产前多种维生素（不含叶酸），以确保其他营养素充足。将收集基线和终点的血样，以评估主要结局指标，包括血清叶酸、红细胞叶酸和未代谢的叶酸。使用线性回归估计从基线到终点的主要结局变化在治疗组之间的差异，控制基线水平。参与者将可以选择继续补充叶酸，直到产后 1 周，以提供母乳和血液样本。将完成探索性分析，以评估母乳和产后血液叶酸浓度。
这项概念验证试验是必要的，以获得（6S）-5-甲基四氢叶酸与叶酸相比对妊娠期间叶酸状态循环生物标志物的影响的估计。这些估计将为设计一项更有力的试验提供信息，该试验将评估（6S）-5-甲基四氢叶酸在提高妊娠期间血液叶酸浓度方面是否与叶酸一样有效。最终，这些发现将为孕妇的叶酸补充政策提供信息。
ClinicalTrials.gov，ID：NCT04022135。于 2019 年 7 月 14 日注册。
