Final Research Plan
Folic Acid Supplementation to Prevent Neural Tube Defects: Preventive Medication
October 21, 2021
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Abbreviations: KQ=key question; NTD=neural tube defect.
1a. To what extent does folic acid supplementation reduce the risk for neural tube defects (NTDs) (first occurrence) in persons capable of getting pregnant?
1b. Does the effect of folic acid supplementation on NTDs (first occurrence) differ by race and ethnicity?
1c. Do the benefits of folic acid supplementation differ by dosage, timing, or duration of therapy?
2a. Are harms associated with folic acid supplementation to the pregnant person, fetus, neonate, or child?
2b. Do the harms of folic acid supplementation differ by dosage, timing, or duration of therapy?
The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the Key Questions.
|Populations||KQ 1: Persons capable of getting pregnant
KQ 2: Persons capable of getting pregnant; fetus, neonate, or child from index pregnancy
|KQ 1: Persons not capable of getting pregnant (i.e., persons of biological male sex, prepubertal persons, postmenopausal persons, sterilized persons or persons with medical conditions rendering them sterile, persons taking antiseizure medications); persons with history of NTDs|
|Comparisons||KQs 1a, 1b, 1c (timing, duration), 2a: Placebo or no treatment or diet only (when compared with folic acid supplementation); supplementation with prenatal vitamins without folic acid (when compared with prenatal vitamin supplementation with folic acid); iron supplements without folic acid (when compared with iron supplementation with folic acid)
Folic acid supplementation alone when compared with folic acid supplementation with food fortification
KQs 1c, 2b (dose): Different doses of folic acid or micronutrient plus folic acid supplementation
|All KQs: Folic acid vs. other active comparators (e.g., multivitamins)
KQs 1a, 1b, 1c (timing, duration), 2a: Lower vs. higher doses of folic acid supplementation
|Outcomes||Neonatal outcomes: NTDs
Harms from treatment:
|Benefits not specified in inclusion criteria|
|Timing||KQ 1a: Supplementation initiated before index pregnancy and in the first month of pregnancy
KQs 1b, 1c, 2a, 2b: All timing
|KQ 1a: Supplementation initiated after the first month of pregnancy|
|Study designs||Efficacy (KQ 1): RCTs; controlled clinical trials, cohort or case-control studies
Harms (KQ 2): RCTs, controlled clinical trials, or observational studies (case-control, cohort, registry data)
|Systematic reviews, case reports, or case series|
|Publication type||Original research||Commentaries or editorials|
|Setting||Countries categorized as “Very High” on the Human Development Index (as defined by the United Nations Development Programme in 2020)||All other countries|
|Quality||Good and fair quality||Poor quality|
Abbreviations: KQ=key question; NTD=neural tube defect; RCT=randomized, controlled trial
The draft Research Plan was posted for public comment on the U.S. Preventive Services Task Force (USPSTF) website from July 22, 2021, to August 18, 2021. Based on comments related to the scientific and conceptual scope of the review, the USPSTF replaced the term “serum folate” in the analytic framework with a more general term—“folate levels in the body”—to reflect the uncertainty around the specific mechanism of action of folic acid supplements. The USPSTF added search terms for salts of L-5-methyltetrahydrofolate and clarified several items in the inclusion and exclusion criteria. Specifically, the USPSTF excluded studies in which all participants were taking antiseizure medications, restricted inclusion to studies conducted in countries with a “Very High” Human Development Index, clarified that the vitamin B6 and B12 deficiency outcome has to do with the inability to accurately diagnose vitamin B6 or B12 deficiency, and removed twins from the list of harms.