Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model

Abstract

Objective: To determine an optimal population red blood cell (RBC) folate concentration for the prevention of neural tube birth defects.

Design: Bayesian model.

Setting: Data from two population based studies in China.

Participants: 247,831 participants in a prospective community intervention project in China (1993-95) to prevent neural tube defects with 400 μg/day folic acid supplementation and 1194 participants in a population based randomized trial (2003-05) to evaluate the effect of folic acid supplementation on blood folate concentration among Chinese women of reproductive age.

Intervention: Folic acid supplementation (400 μg/day).

Main outcome measures: Estimated RBC folate concentration at time of neural tube closure (day 28 of gestation) and risk of neural tube defects.

Results: Risk of neural tube defects was high at the lowest estimated RBC folate concentrations (for example, 25.4 (95% uncertainty interval 20.8 to 31.2) neural tube defects per 10,000 births at 500 nmol/L) and decreased as estimated RBC folate concentration increased. Risk of neural tube defects was substantially attenuated at estimated RBC folate concentrations above about 1000 nmol/L (for example, 6 neural tube defects per 10,000 births at 1180 (1050 to 1340) nmol/L). The modeled dose-response relation was consistent with the existing literature. In addition, neural tube defect risk estimates developed using the proposed model and population level RBC information were consistent with the prevalence of neural tube defects in the US population before and after food fortification with folic acid.

Conclusions: A threshold for "optimal" population RBC folate concentration for the prevention of neural tube defects could be defined (for example, approximately 1000 nmol/L). Population based RBC folate concentrations, as a biomarker for risk of neural tube defects, can be used to facilitate evaluation of prevention programs as well as to identify subpopulations at elevated risk for a neural tube defect affected pregnancy due to folate insufficiency.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

© Crider et al 2014.

Figures

Fig 1 Relation between folic acid intake, blood folate concentration, and risk of neural tube defects. a: Many studies have shown that folic acid intake from multivitamin and folic acid only supplements (common doses between 200 and 5000 µg/day) in the periconceptional period (before neural tube closure at day 28) reduces risk of neural tube defects in those pregnancies. b: Controlled folic acid intake studies show that folic acid increases blood folate concentrations; these studies have shown that absolute concentration after folic acid intake is dependent on dose of folic acid supplements, length of time supplement is consumed, baseline folate concentration, and genetic variation in folate metabolism (notably MTHFR677). c: Single study of blood folate concentration (red blood cell (RBC) and plasma) during pregnancy (mean gestational age 15 weeks) showed inverse dose-response with risk of neural tube defects in offspring. Study reported here used information from existing data sources to build a statistical model to predict association between RBC folate concentration at time of neural tube closure (embryologic day 28) and risk of neural tube defects

Fig 2 Genotype, concentration, and risk model components used to assess association between red blood cell (RBC) folate concentration and risk of neural tube defects among Community Intervention Project participants. Genotype model: MTHFR genotype frequencies have been shown to be different in northern (36% TT in Folic Acid Dosing Trial) and southern Chinese populations (8% TT). Each person was assigned a probability of having a specific genotype. RBC folate concentration model: RBC folate concentration at time of neural tube closure was estimated on basis of region of residence (northern v southern), probable genotype, and folic acid supplementation history. Substantial regional differences in diet have been previously described, with northern regions having less natural folate intake and lower RBC folate concentrations. As a result, the concentration model included a term reflecting regional differences in baseline RBC concentration. Neural tube defect risk model: risk of neural tube defects associated with RBC folate concentrations was estimated for Community Intervention Project participants on basis of observed neural tube defect occurrence and estimated RBC folate concentration

Fig 3 Estimated risk of neural tube defect per 10 000 births by red blood cell (RBC) folate concentration (nmol/L) at time of neural tube closure among participants in Community Intervention Project and observed values of neural tube defect risk at measured RBC folate concentrations (nmol/L) reported by Daly et al (1995). Estimates were derived using estimated parameters of neural tube defect risk model to predict neural tube defect risk at specified RBC folate concentrations. Solid blue line is median of posterior distribution of possible values of neural tube defect risk at given concentration; dashed blue lines reflect 95% uncertainty interval for estimate. Lower value of this interval is 2.5th centile of posterior distribution of possible values for neural tube defect risk; upper value is 97.5th centile. Estimated time of closure of fetal neural tube was date of initiation of last reported menstrual cycle plus 42 days

Fig 4 Using model developed with Chinese data to predict prevalence of neural tube defects from population level red blood cell (RBC) folate concentrations in US population before and after mandatory folic acid fortification. *RBC folate concentrations from Pfeiffer et al (supplementary table D, female participants 4 years and older during pre-fortification period, NHANES 1988-94; supplementary table F, total female participants aged 4 years and older, NHANES 2005-10). Published RBC folate concentration centiles were normalized to method used in papers by both Daly and Hao, using standardizing equations generated from Pfeiffer 2011: NHANES RBC folate (nmol/L)=(Dublin RBC folate (nmol/L)×0.7876)+34.2802 (nmol/L) (personal communication). These adjusted RBC folate concentrations were used to generate a modeled population with a similar distribution of RBC folate concentration; modeled associations in Chinese data were then used to predict risk in that modeled US population. †Neural tube defect prevalence for US (1994-95) just before start of mandatory folic acid fortification. ‡Neural tube defect prevalence for US (2004-06) after implementation of mandatory folic acid fortification