Folate and global health umbrella review series, part 1: methodological framework and syntheses on anaemia and neural tube defects

Background: Folate is essential for normal growth and in human health throughout the lifecycle. Clinical deficiency of folate impairs DNA synthesis and results in megaloblastic anaemia, while suboptimal folate status before and in early pregnancy results in an elevated risk of neural tube defects (NTD). The evidence on the association of folate status with other health outcomes is largely fragmented and understudied. We conducted a series of umbrella reviews examining the association between folate and multiple health outcomes in various populations and settings. Methods: We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and DARE from inception to February 2024 for systematic reviews with or without meta-analyses examining an association between folate intake/status and any health outcome. We performed screening and data extraction in duplicate and assessed the risk of bias using the ROBIS tool. Evidence was then characterised into unique associations (unique exposure measure - unique outcome measure - unique setting). For each category of unique associations, we identified the evidence based on the statistical power, recency of publication and the potential risk of bias. All unique associations were evaluated for credibility using predefined criteria. Results: We retrieved 3565 records and included 283 in the final synthesis. The evidence on anaemia consisted of four intervention trials demonstrating effectiveness of folic acid supplementation during pregnancy in reducing the risk of megaloblastic anaemia (relative risk (RR) = 0.21; 95% CI = 0.11, 0.38; I2 = 15%). Maternal folic acid use was also significantly inversely related to the prevention of NTD at birth (RR = 0.31; 95% CI = 0.16, 0.60; I2 = 0%) and NTD recurrence (RR = 0.30; 95% CI = 0.14, 0.65; I2 = 0%). This relationship was supported by the inverse association reported between low maternal blood folate concentrations and the increased risk of NTD. Further evidence showed that fortification of food with folic acid was associated with the lower prevalence of NTD on a population-level. Conclusion: In NTDs and anaemia, we identified strong evidence supporting the protective role of folate status based on intervention trials and observational studies. More recent reviews examining the role of folate in other less well understood health conditions will be presented in the subsequent reports. Registration: PROSPERO: CRD42021265041.