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.

This figure depicts the analytic framework that outlines the key questions addressed and the evidence covered in this research plan, including populations, interventions, and outcomes. On the left, the population of interest is specified as persons capable of pregnancy. Moving from left to right, the figure illustrates the overarching question: To what extent does folic acid supplementation reduce the risk for neural tube defects (first occurrence) in persons capable of becoming pregnant (Key Question 1)? The figure then depicts the pathway from folic acid supplementation to neural tube defects operating through folate levels in the body. Folic acid supplementation may result in harms (Key Question 2).

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.

  Included Excluded
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
  • Folic acid supplementation*, with or without food fortification or naturally occurring folate, for the prevention of NTDs and other birth defects
  • Supplementation with micronutrients (e.g., multivitamins, iron) in combination with folic acid
  • Food fortification only
  • Naturally occurring folate only
  • Counseling to improve dietary supplementation  
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:
  • Colorectal cancer or other reported types of cancer
  • Inability to diagnose vitamin B6 or B12 adequately (masking of vitamin B6 or B12 deficiency)
  • Autism
  • Asthma or allergies
  • Other reported child, neonatal, fetal, or maternal harms
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
Sample size All None
Quality Good and fair quality Poor quality
Language English Non-English studies

Abbreviations: KQ=key question; NTD=neural tube defect; RCT=randomized, controlled trial

* Terms for folic acid are broad and include folate, folic acid, folvite, folacin, vitamin B, and methyltetrahydrofolate, among others.

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.