Folic acid to reduce neonatal mortality from neural tube disorders

Abstract

Background: Neural tube defects (NTDs) remain an important, preventable cause of mortality and morbidity. High-income countries have reported large reductions in NTDs associated with folic acid supplementation or fortification. The burden of NTDs in low-income countries and the effectiveness of folic acid fortification/supplementation are unclear.

Objective: To review the evidence for, and estimate the effect of, folic acid fortification/supplementation on neonatal mortality due to NTDs, especially in low-income countries.

Methods: We conducted systematic reviews, abstracted data meeting inclusion criteria and evaluated evidence quality using adapted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Where appropriate, meta-analyses were performed.

Results: Meta-analysis of three randomized controlled trials (RCTs) of folic acid supplementation for women with a previous pregnancy with NTD indicates a 70% [95% confidence interval (CI): 35-86] reduction in recurrence (secondary prevention). For NTD primary prevention through folic acid supplementation, combining one RCT with three cohort studies which adjusted for confounding, suggested a reduction of 62% (95% CI: 49-71). A meta-analysis of eight population-based observational studies examining folic acid food fortification gave an estimated reduction in NTD incidence of 46% (95% CI: 37-54). In low-income countries an estimated 29% of neonatal deaths related to visible congenital abnormalities are attributed to NTD. Assuming that fortification reduces the incidence of NTDs, but does not alter severity or case-fatality rates, we estimate that folic acid fortification could prevent 13% of neonatal deaths currently attributed to congenital abnormalities in low-income countries.

Discussion: Scale-up of periconceptional supplementation programmes is challenging. Our final effect estimate was therefore based on folic acid fortification data. If folic acid food fortification achieved 100% population coverage the number of NTDs in low-income countries could be approximately halved.

Conclusion: The evidence supports both folic acid supplementation and fortification as effective in reducing neonatal mortality from NTDs.

Figure 1

Synthesis of study identification in the review of the effect of folic acid on neonatal mortality form neural tube disorders. Detailed Pubmed search terms: ("folic acid"[MeSH Terms] OR ("folic"[All Fields] AND "acid"[All Fields]) OR "folic acid"[All Fields]) AND ("neural tube defects"[MeSH Terms] OR ("neural"[All Fields] AND "tube"[All Fields] AND "defects"[All Fields]) OR "neural tube defects"[All Fields] OR ("neural"[All Fields] AND "tube"[All Fields] AND "defect"[All Fields]) OR "neural tube defect"[All Fields]) AND ("infant, newborn"[MeSH Terms] OR ("infant"[All Fields] AND "newborn"[All Fields]) OR "newborn infant"[All Fields] OR "neonate"[All Fields]) OR ("infant mortality"[MeSH Terms] OR ("infant"[All Fields] AND "mortality"[All Fields]) OR "infant mortality"[All Fields] OR ("neonatal"[All Fields] AND "mortality"[All Fields]) OR "neonatal mortality"[All Fields]) OR ("women"[MeSH Terms] OR "women"[All Fields] OR "female"[MeSH Terms] OR "female"[All Fields] OR "pregnancy"[MeSH Terms] OR "pregnancy"[All Fields] OR periconceptual[All Fields] OR "peri conceptual"[All Fields]) Embase/ WHO regional databases: ‘neural tube defects’ ‘folic acid’

Figure 2

Meta analysis of the effect of folic acid supplementation. (a) Prevention of recurrent neural tube disorders (secondary prevention), Relative Risk (95% Confidence Interval); Heterogeneity χ² = 0.28 (degrees of freedom (df = 2) P = 0.867, I² (variation in RR attributable to heterogeneity) = 0%, Test of RR = 1: z = 3.06, P = 0.002. (b) Primary prevention of neural tube disorders, Relative Risk (95% Confidence Interval), Heterogeneity χ² = 4.16 (df = 3) P = 0.244, I² (variation in RR attributable to heterogeneity) = 27.9%, Test of RR = 1: z = 6.59, P < 0.001

Figure 3

Meta-analysis (random effects) of the effect of folic acid fortification on primary prevention of neural tube defects. Heterogeneity χ² = 22.73 (df = 7), P = 0.002, I² (variation in RR attributable to heterogeneity) = 69.2%; Estimate of between-study variance τ² = 0.0295, Test of RR = 1: z = 8.01, P < 0.001

Figure 4

Sensitivity analyses of the estimate of the effect folic acid fortification using different inclusion criteria and meta-analysis methods