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Final Research Plan

Folic Acid for the Prevention of Neural Tube Defects: Preventive Medication

October 16, 2014

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.

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The final Research Plan is used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Review will form the basis of the USPSTF Recommendation Statement on this topic.

The draft Research Plan was available for comment from July 10 until August 6, 2014 at 5:00 p.m., ET.

Go to text description below.

Text Description.

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 women of childbearing age. 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 women of childbearing age (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).

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

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

  1. What is the current intake of folic acid and natural folates from diet and other sources in women of childbearing age?
  2. Does intake of folic acid and natural folates from diet and other sources differ by pregnancy intention, age, race or ethnicity, or access to foods?
  3. Does folic acid supplementation outside of the periconceptional period reduce the risk for neural tube defects?
  4. Does the effect of folic acid supplementation in the periconceptional period on neural tube defects differ by medical risk factors (i.e., obesity, poorly controlled diabetes, seizure medications, methotrexate or other folate antagonist therapies, and previous pregnancies with a neural tube defect)?
  5. Are there other potential fetal, neonatal, or maternal benefits from folic acid supplementation in the periconceptional period?

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 specific to each of the key questions (KQs).

  Include Exclude
Populations KQ 1: Women of childbearing age (postmenarchal and premenopausal; women with the potential for or planning childbearing)

KQ 2: Women of childbearing age (postmenarchal and premenopausal; women with the potential for or planning childbearing); fetus, neonate, or child from index pregnancy

 KQ 1: Prepubertal girls; men; women without the potential for childbearing (e.g., women who are postmenopausal or have genetic uterine or ovarian abnormalities)
Interventions
  • Folic acid supplementation, with or without food fortification or naturally occurring folate, for the prevention of neural tube defects and other birth defects
  • Supplementation with micronutrients (e.g., multivitamins, iron) in combination with folic acid for the prevention of neural tube defects only

 
  • Food fortification only
  • Naturally occurring folate only
  • Counseling to improve dietary supplementation
  • Supplementation with micronutrients (e.g., multivitamin, iron) in combination with folic acid for the prevention of harms only
Comparisons KQs 1a, 1b, 2a: Placebo or no treatment; dietary supplementation only; supplementation with prenatal vitamins without folic acid; iron supplements without folic acid

KQs 1b, 1c, 2b: All of the above plus folic acid supplementation of varying dosages

 KQs 1a, 1b, 2a: Lower or higher dose of folic acid supplementation; folic acid vs. other active comparators

KQs 1c, 2b: Folic acid vs. other active comparators (e.g., multivitamins)
Outcomes Neonatal outcomes: Neural tube defects

Harms from treatment:

  • Multifetal pregnancy
  • Colorectal cancer or other reported types of cancer
  • Vitamin B12 deficiency
  • Vitamin B6 deficiency
  • 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

KQs 1c, 2a, 2b: No restrictions
Settings Developed countries categorized as “Very High” on the Human Development Index (as defined by the United Nations Development Programme) Countries not categorized as “Very High” on the Human Development Index
Study designs Efficacy (KQ 1): Randomized, controlled trials; controlled clinical trials; cohort or case-control studies

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

 Commentaries, editorials, case reports
Sample size More than 50 participants 50 participants or less
Quality Good and fair quality Poor quality
Language English Non-English studies

 

The draft Research Plan was posted for public comment on the U.S. Preventive Services Task Force (USPSTF) Web site from July 10 to August 6, 2014. The USPSTF received several comments requesting clarification on the inclusion and exclusion criteria and key questions related to populations, interventions, timing, and outcomes. The Research Plan was revised in response to these comments. The USPSTF revised the inclusion and exclusion criteria to include 5-methyltetrahydrofolate (the metabolically active form of folic acid) and expanded the eligible study designs for assessing harms. The USPSTF also made the following clarifications: various sources of folic acid and natural folate intake are included in the contextual questions; the outcomes include B12 status; assessed harms are specific to women exposed to folic acid supplementation during their reproductive years and children from the index pregnancy following folic acid intake; the key questions relate to the first occurrence of neural tube defects; and periconceptional timing refers only to key questions 1a and 1b.