in progress

Draft Research Plan

Folic Acid Supplementation to Prevent Neural Tube Defects: Preventive Medication

July 22, 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 proposed 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 serum folate levels. Folic acid supplementation may result in harms (Key Question 2).

Abbreviations: KQ=key question; NTD=neural tube defect.

  1. a. To what extent does folic acid supplementation reduce the risk for neural tube defects (first occurrence) in persons capable of becoming pregnant?
    b. Does the effect of folic acid supplementation on neural tube defects (first occurrence) differ by race/ethnicity?
    c. Do the benefits of folic acid supplementation differ by dosage, timing, or duration of therapy?
  2. a. Are harms associated with folic acid supplementation to the pregnant person, fetus, neonate, or child?
    b. Do the harms of folic acid supplementation differ by dosage, timing, or duration of therapy?

The proposed 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.

  Include Exclude
Populations KQ 1: Persons capable of becoming pregnant

KQ 2: Persons capable of becoming pregnant; fetus, neonate, or child from index pregnancy

KQ 1: Persons not capable of becoming pregnant (i.e., biological male sex, prepubertal persons, postmenopausal persons, sterilized persons, or persons with medical conditions rendering them sterile); persons with history of NTDs
Interventions 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 supplementation without folic acid (when compared with iron supplementation with folic acid)

KQs 1c, 2b (dose): Different doses of folic acid or micronutrient plus folic acid supplementation

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:
  • Twins
  • Colorectal cancer or other reported types of cancer
  • Vitamin B12 deficiency
  • Vitamin B6 deficiency
  • Autism
  • Asthma or allergies
  • Other reported child, neonatal, fetal, or maternal harms
Benefits not specified in inclusion criteria
Timing KQs 1a, 1b: Supplementation initiated before index pregnancy or in the first trimester

KQs 1c, 2a, 2b: All timing

KQs 1a, 1b: Supplementation initiated after the first trimester of pregnancy
Study designs KQ 1 (efficacy): Randomized, controlled trials; controlled clinical trials; cohort or case-control studies

KQ 2 (harms): Randomized, controlled trials; controlled clinical trials; observational studies (case-control, cohort, registry data)

Commentaries, editorials, or case reports
Sample size All None
Quality Good- and fair-quality studies Poor-quality studies
Language English Non-English studies

Abbreviations: KQ=key question; NTD=neural tube defect.