What is the question?

• What is the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and lactation and micronutrient status?
• What is the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and risk of gestational diabetes?
• What is the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and risk of hypertensive disorders during pregnancy?
• What is the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and lactation and human milk composition?
• What is the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and lactation and developmental milestones, including neurocognitive development, in the child?

What is the answer to the question?

Micronutrient status during pregnancy and lactation:

Folic acid intake before and during pregnancy:

• Strong evidence indicates that folic acid supplements consumed before and/or during pregnancy are positively associated with folate status (serum, plasma, and/or red blood cell folate).
• Insufficient evidence is available to determine the relationship between folic acid from supplements consumed before and/or during pregnancy and hemoglobin, mean corpuscular volume, and serum vitamin B₁₂.
• No evidence is available to determine the relationship between folic acid from supplements consumed before and/or during pregnancy and red blood cell distribution width. 
• No evidence is available to determine the relationship between folic acid from fortified foods consumed before and/or during pregnancy and micronutrient status.

Folic acid intake during lactation:

• Moderate evidence indicates that folic acid supplements consumed during lactation are positively associated with red blood cell folate, and may be positively associated with serum or plasma folate.
• Insufficient evidence is available to determine the relationship between folic acid from supplements consumed during lactation and hemoglobin, mean corpuscular volume, and serum vitamin B₁₂.
• No evidence is available to determine the relationship between folic acid from supplements consumed during lactation and red blood cell distribution width.
• No evidence is available to determine the relationship between folic acid from fortified foods consumed during lactation and micronutrient status. 

Gestational diabetes:

• Insufficient evidence is available to determine the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and the risk of gestational diabetes.

Hypertensive disorders of pregnancy:

• Limited evidence suggests that folic acid supplements consumed during early pregnancy may have a beneficial effect on reducing the risk of hypertensive disorders during pregnancy among women at high-risk (e.g., history of preeclampsia or prepregnancy BMI ≥25 kg/m2) compared to no folic acid supplementation.
• Moderate evidence indicates that higher levels of folic acid supplements consumed during pregnancy compared to lower levels (including no folic acid supplementation) does not affect the risk of hypertensive disorders during pregnancy among women at low-risk. 
• No evidence is available to determine the relationship between folic acid from fortified foods consumed before and during pregnancy and the risk of hypertensive disorders during pregnancy. 

Human milk composition:

Folic acid intake before and during pregnancy:

• No evidence is available to determine the relationship between folic acid from supplements or fortified foods consumed before and during pregnancy and human milk folate.

Folic acid intake during lactation:

• Moderate evidence indicates that folic acid supplements consumed during lactation does not influence folate levels in human milk. 
• No evidence is available to determine the relationship between folic acid from fortified foods consumed during lactation and human milk folate.

Developmental milestones in children:

Folic acid intake before and during pregnancy:

• Insufficient evidence is available to determine the relationship between folic acid supplementation before and/or during pregnancy and cognitive, language, and social-emotional development, and risk of autism spectrum disorder in the child.
• No evidence is available to determine the relationship between folic acid from supplements consumed before and during pregnancy and movement and physical development, academic performance, anxiety, depression, or the risk of attention-deficit disorder or attention-deficit/hyperactivity disorder in the child.
• No evidence is available to determine the relationship between folic acid from fortified foods consumed before and during pregnancy and developmental milestones, including neurobehavioral development, in the child.

Folic acid intake during lactation:

• No evidence is available to determine the relationship between folic acid from supplements or fortified foods consumed during lactation and developmental milestones, including neurobehavioral development, in the child.

Why was this question asked?

• This important public health question was identified by the U.S. Departments of Agriculture (USDA) and Health and Human Services (HHS) to be examined by the 2020 Dietary Guidelines Advisory Committee.

How was this question answered?

• The 2020 Dietary Guidelines Advisory Committee, Pregnancy and Lactation Subcommittee conducted a systematic review to answer this question with support from the Nutrition Evidence Systematic Review (NESR) team.

What is the population of interest? 

• The population of interest for folic acid intake is generally healthy women up to 6 months before pregnancy, during pregnancy, and during lactation.

• This review examines several health outcomes in different populations of interest:
  • Micronutrient status in women during pregnancy and lactation, 
  • Gestational diabetes in women during pregnancy, 
  • Hypertensive disorders in women during pregnancy, 
  • Human milk composition in women during lactation, and 
  • Developmental milestones including neurocognitive development in offspring from birth to age 18 years. 

What evidence was found? 

Micronutrient status during pregnancy and lactation:

• This review includes 14 articles that present evidence about folic acid supplementation before/during pregnancy (9 articles) or during lactation (5 articles). No articles present evidence about folic acid intake from fortified foods. Folic acid is the form of folate in supplements and fortified foods. Folate is found naturally in foods and is also the form that is measured in blood.
• The outcomes are all measures of folate and vitamin B₁₂ status. Most of the evidence is about folate status. Consistent evidence indicates that taking folic acid supplements before/during pregnancy or during lactation is associated with higher measures of folate status. The evidence included studies with strong designs (e.g. randomized controlled trials). 
• Due to inconsistent results or an insufficient number of studies, a conclusion could not be drawn on the association between folic acid supplementation and hemoglobin, mean corpuscular volume (MCV), or vitamin B₁₂. 

Gestational diabetes:

• One non-randomized controlled trial (NRCT) was included in this body of evidence.
• Due to an insufficient number of studies, a conclusion could not be drawn on the association between folic acid supplementation before/during pregnancy and risk of gestational diabetes.

Hypertensive disorders of pregnancy:

• Eight articles are included in the evidence about folic acid supplementation before and during pregnancy. No articles present evidence about folic acid intake from fortified foods.
• All articles were about the risk of hypertensive disorders during pregnancy, including high blood pressure, preeclampsia, and eclampsia. The evidence was different for women with a high risk of developing hypertensive disorders (e.g. women who had preeclampsia in a previous pregnancy; women who began pregnancy with over weight or obesity) compared to women with a low risk of developing hypertensive disorders:
  • For women with high risk: A few studies suggest that taking folic acid supplements during early pregnancy may be associated with a lower risk of hypertensive disorders. The evidence is somewhat inconsistent and is limited because it is based on a few studies, including studies with weak study designs.
  • For women with low risk: The evidence suggests that taking more folic acid from supplements compared to taking smaller amounts of folic acid supplements or not taking any folic acid supplements during pregnancy does not affect the risk of hypertensive disorders. The evidence is somewhat consistent and is based on a variety of studies, including studies with a strong study design (e.g. randomized controlled trials).

Human milk composition:

• Four articles are included in the evidence about folic acid supplementation during lactation. No articles present evidence about folic acid supplementation before or during pregnancy or about folic acid intake from fortified foods.
• None of the studies found that folic acid supplementation during lactation was associated with folate levels in human milk. The evidence was consistent and included studies with strong designs (e.g. randomized controlled trials). 
• All of the studies included women who likely had adequate folate status, so the evidence may be different for women who are folate deficient.

Developmental milestones in children:

• This review includes 6 articles that present evidence about folic acid supplementation before/during pregnancy. No articles present evidence about folic acid supplementation during lactation or about folic acid intake from fortified foods.
• The evidence included studies about outcomes in children, such as cognitive development (2 articles), language/communication development (2 articles), social-emotional development (1 article), and autism spectrum disorder (ASD; 1 article). Generally, folic acid supplementation before or during pregnancy was either not associated with or was associated with better had a beneficial association with these outcomes. However, due to inconsistent results or an insufficient number of studies, a conclusion could not be drawn for cognitive development, language/communication development, social-emotional development, or risk of ASD.
• There was no evidence about whether folic acid supplementation before/during pregnancy was associated with movement/physical development, academic performance, attention deficit disorder (ADD) or attention-deficit/hyperactivity disorder (ADHD), anxiety, or depression.

How up-to-date is this systematic review?

• This review searched for studies:
  • Micronutrient status: from January 1980 to June 2019
  • Gestational diabetes: from January 1980 to July 2019
  • Hypertensive disorders of pregnancy: from January 1980 to July 2019
  • Human milk composition: from January 1980 to June 2019
  • Developmental milestones: from January 1980 to July 2019

Background

• This important public health question was identified by the U.S. Departments of Agriculture (USDA) and Health and Human Services (HHS) to be examined by the 2020 Dietary Guidelines Advisory Committee.
• The 2020 Dietary Guidelines Advisory Committee, Pregnancy and Lactation Subcommittee conducted a systematic review to answer this question with support from the Nutrition Evidence Systematic Review (NESR) team.
• The goal of this systematic review was to examine the following questions: 
  • What is the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and lactation and micronutrient status?
  • What is the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and risk of gestational diabetes?
  • What is the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and risk of hypertensive disorders during pregnancy?
  • What is the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and lactation and human milk composition?
  • What is the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and lactation and developmental milestones, including neurocognitive development, in the child?

Conclusion statements and grades

Micronutrient status

Pregnancy

• Strong evidence indicates that folic acid supplements consumed before and/or during pregnancy are positively associated with folate status (serum, plasma, and/or red blood cell folate). (Grade: Strong)
• Insufficient evidence is available to determine the relationship between folic acid from supplements consumed before and/or during pregnancy and hemoglobin, mean corpuscular volume, and serum vitamin B₁₂. (Grade: Grade not assignable)
• No evidence is available to determine the relationship between folic acid from supplements consumed before and/or during pregnancy and red blood cell distribution width. (Grade: Grade not assignable)
• No evidence is available to determine the relationship between folic acid from fortified foods consumed before and/or during pregnancy and micronutrient status. (Grade: Grade not assignable)

Lactation

• Moderate evidence indicates that folic acid supplements consumed during lactation are positively associated with red blood cell folate, and may be positively associated with serum or plasma folate. (Grade: Moderate)
• Insufficient evidence is available to determine the relationship between folic acid from supplements consumed during lactation and hemoglobin, mean corpuscular volume, and serum vitamin B₁₂. Grade: Grade not assignable
• No evidence is available to determine the relationship between folic acid from supplements consumed during lactation and red blood cell distribution width. (Grade: Grade not assignable)
• No evidence is available to determine the relationship between folic acid from fortified foods consumed during lactation and micronutrient status. (Grade: Grade not assignable) 

Gestational diabetes

• Insufficient evidence is available to determine the relationship between folic acid from supplements and/or fortified foods consumed before and during pregnancy and the risk of gestational diabetes. (Grade: Grade not assignable)

Hypertensive disorders of pregnancy

• Limited evidence suggests that folic acid supplements consumed during early pregnancy may have a beneficial effect on reducing the risk of hypertensive disorders during pregnancy among women at high-risk (e.g., history of preeclampsia or prepregnancy BMI ≥25 kg/m2) compared to no folic acid supplementation. (Grade: Limited)
• Moderate evidence indicates that higher levels of folic acid supplements consumed during pregnancy compared to lower levels (including no folic acid supplementation) does not affect the risk of hypertensive disorders during pregnancy among women at low-risk. (Grade: Moderate)
• No evidence is available to determine the relationship between folic acid from fortified foods consumed before and during pregnancy and the risk of hypertensive disorders during pregnancy. (Grade: Grade not assignable)

Human milk composition

Pregnancy

• No evidence is available to determine the relationship between folic acid from supplements or fortified foods consumed before and during pregnancy and human milk folate. (Grade: Grade not assignable)

Lactation

• Moderate evidence indicates that folic acid supplements consumed during lactation does not influence folate levels in human milk. (Grade: Moderate)
• No evidence is available to determine the relationship between folic acid from fortified foods consumed during lactation and human milk folate. (Grade: Grade not assignable)

Developmental milestones

Pregnancy

• Insufficient evidence is available to determine the relationship between folic acid supplementation before and/or during pregnancy and cognitive, language, and social-emotional development, and risk of autism spectrum disorder in the child. (Grade: Grade not assignable)
• No evidence is available to determine the relationship between folic acid from supplements consumed before and during pregnancy and movement and physical development, academic performance, anxiety, depression, or the risk of attention-deficit disorder or attention-deficit/hyperactivity disorder in the child. (Grade: Grade not assignable)
• No evidence is available to determine the relationship between folic acid from fortified foods consumed before and during pregnancy and developmental milestones, including neurobehavioral development, in the child. (Grade: Grade not assignable)

Lactation

• No evidence is available to determine the relationship between folic acid from supplements or fortified foods consumed during lactation and developmental milestones, including neurobehavioral development, in the child. (Grade: Grade not assignable)

Methods

• Three literature searches were conducted using 4 databases (PubMed, Cochrane, Embase, and CINAHL) to identify articles that evaluated:
  • the intervention or exposure of folic acid from supplements and/or fortified foods consumed before and during pregnancy and lactation and the outcomes of 1) micronutrient status and 2) human milk composition
  • the intervention or exposure of folic acid from supplements and/or fortified foods consumed before and during pregnancy and the outcomes of 1) gestational diabetes and 2) hypertensive disorders during pregnancy
  • the intervention or exposure of folic acid from supplements and/or fortified foods consumed before and during pregnancy and lactation and the outcomes of developmental milestones, including neurocognitive development, in the child

A manual search was conducted to identify articles that may not have been included in the electronic databases searched. Articles were screened by two NESR analysts independently for inclusion based on pre-determined criteria 

• Data extraction and risk of bias assessment were conducted for each included study, and both were checked for accuracy. The Committee qualitatively synthesized the body of evidence to inform development of a conclusion statement(s), and graded the strength of evidence using pre-established criteria for risk of bias, consistency, directness, precision, and generalizability.

Summary of the evidence

Micronutrient status

Pregnancy

• Nine studies were identified through a literature search from 1980 to 2019 which met the criteria for inclusion in this systematic review. Studies included in this review assessed interventions and exposures before and/or during pregnancy: 6 randomized controlled trials (RCTs), 2 prospective cohort studies (PCSs), and 1 retrospective cohort study.
• Studies varied in intervention details, including: 
  • Folic acid supplement type (folic acid or 5-methyl tetrahydrofolate [5-MTHF]). 
  • Dose and comparator:
    • Three RCTs and 2 cohort studies compared no folic acid supplementation to folic acid supplementation (RCTs: 350 µg/d to 1.0 mg/d; cohorts: 400 µg/d or dose unknown).
    • Two RCTs compared different levels of folic acid supplementation (330 µg/d vs 730 µg/d; 1.1 mg/d vs 5.0 mg/d).
    • One RCT compared folic acid to 5-MTHF supplementation at the same dose (1.0 mg/d).
  • Duration (2, 3, 5.5, 7, or 12 months).
• Of the 5 outcome measures defined in the analytic framework, all but red blood cell (RBC) distribution width were reported in the body of evidence. 
• All but 1 study found a significant association between folic acid supplementation and at least one outcome measure.
• All 9 studies (6 RCTs; 3 PCSs) assessed plasma or serum folate. 
  • Of those, 6 found that supplementation was associated with higher values on at least 1 measure of plasma or serum folate and 2 found no association. Another study compared supplementation with folic acid vs 5-MTHF and found that both groups increased over time. 
• Six studies (4 RCTs; 2 PCSs) assessed RBC folate.
  • Five found that supplementation was associated with higher values on at least 1 measure of RBC folate and 1 found no association.
• Three studies (2 RCTs; 1 retrospective cohort) assessed hemoglobin. The findings were inconsistent; therefore a conclusion statement could not be drawn.
• Of the 2 RCTs that assessed mean corpuscular volume (MCV), neither found a significant effect on MCV, but study limitations and the small number of studies provided insufficient evidence to draw a conclusion. 
• Only 1 RCT assessed the effect of supplementation on vitamin B₁₂; therefore, a conclusion could not be drawn.
• The body of evidence had important limitations:
  • None of the studies preregistered data analysis plans, indicating a risk of bias due to selectivity in results presented.
  • The cohort studies did not adequately account for potential confounding.
  • Risk of bias due to classification of exposures or deviations from intended exposures was a concern for the cohort studies.
  • The study populations did not fully represent the racial/ethnic or socioeconomic diversity of the U.S. population. 
  • No studies met the inclusion criteria that examined the effect of intake of folic acid from fortified foods on the outcome of interest.

Lactation

• Five articles from 4 studies were identified through a literature search from 1980 to 2019, which met the criteria for inclusion in this systematic review. Studies included in this review assessed interventions and exposures during lactation: 3 RCTs, 1 uncontrolled before-and-after study, and 1 PCS that was nested within one of the RCTs.
• Studies varied in intervention details. including: 
  • Folic acid supplement type (folic acid or 5-methyltetrahydrofolate [5-MTHF]) 
  • Dose and comparator 
    • Three RCTs and 1 PCS compared no folic acid supplementation to folic acid supplementation (300 µg/d to 1.0 mg/d)
    • One RCT also compared folic acid to 5-MTHF supplementation at the same dose (400 µg/d)
    • One uncontrolled before-and-after study compared folate levels before to after supplementation of 1.0 mg/d synthetic folic acid 
    • Duration (1 month, 3 months, 4 months) 
• Of the 5 outcome measures defined in the analytic framework, all but RBC distribution width were reported in the body of evidence.
• All studies found a significant association between folic acid supplementation and at least 1 outcome measure.
• All 4 studies assessed plasma or serum folate: 
  • Four studies (5 articles: 3 RCTs; 1 PCS; 1 uncontrolled before-and-after study) assessed the relationship between folic acid from supplements during lactation. Two found that supplementation was associated with higher values on at least 1 measure of plasma/serum folate and two found no association.
• All 4 studies assessed RBC folate.
  • All 4 studies (5 articles: 3 RCTs; 1 PCS; 1 uncontrolled before-and-after study) that assessed supplementation during lactation found that supplementation was associated with higher values on at least one measure of RBC folate.
• Two RCTs assessed hemoglobin. The findings were inconsistent and therefore a conclusion statement could not be drawn.
• One RCT each assessed the effect of supplementation on MCV or vitamin B₁₂ status; therefore, conclusions could not be drawn.
• This body of evidence had important limitations: 
  • None of the studies preregistered data analysis plans, indicating a potential risk of bias due to selectivity in results presented. 
  • Neither the PCS nor the uncontrolled before-and-after study adequately accounted for potential confounding.
  • Risk of bias due to classification of exposures or deviations from intended exposures was a concern for the cohort study and the uncontrolled before-and-after study.
  • The study populations did not fully represent the racial/ethnic or socioeconomic diversity of the U.S. population. 
  • No studies that examined the effect of intake of folic acid from fortified foods on the outcome of interest met the inclusion criteria. 

Gestational diabetes

• One non-RCT (NRCT) that met the criteria for inclusion in this systematic review was identified through a literature search from 1980 to 2019.
• This study found that women who consumed folic acid supplementation based on genotype and stage of pregnancy had significantly fewer cases of gestational diabetes compared to women who did not consume folic acid supplements before or during pregnancy.
• The evidence had several limitations:
  • No baseline data on study groups were provided for comparison.
  • Intervention methods and adherence were not clear.
  • Results by subgroup were not reported.
  • Consistency could not be assessed with only 1 study.

Hypertensive disorders of pregnancy

• Eight studies, including 3 RCTs, 2 NRCTs, and 3 PCSs, met the criteria for inclusion in this systematic review, which were identified through a literature search from 1980 to 2019.  
• The 3 RCTs compared 5.0 mg/d of folic acid supplementation to a lower-dose of either 0.5 mg/d (2 studies) or 1.0 mg/d (1 study) from early pregnancy through delivery. The folic acid supplementation dose had no effect on incidence of gestational hypertension, preeclampsia, or eclampsia. None of the studies compared folic acid supplementation to a control group with no folic acid supplementation. 
• The 2 NRCTs found a statistically significant association of folic acid supplementation (15 mg/d of 5-MTHF in one study; 400-800 µg/d in another study) from early pregnancy through delivery on risk of gestational hypertension or preeclampsia compared to a control group with no folic acid supplementation. One NRCT was among a high-risk population (women who had preeclampsia in their preceding pregnancy); the other had methodological limitations related to exposure, outcome assessment, and analysis. 
• The 3 PCSs reported mixed results. One study found an association between folic acid use in the first trimester and lower incidence of preeclampsia in the full study sample, and specifically among those with a BMI ≥25 kg/m2; another study found a statistically significant association between folic acid use at 12 to 20 weeks gestation and lower incidence of preeclampsia among high-risk women. A third study did not find a significant association between folic acid supplementation pre and/or post-conception (Four weeks before to 8 weeks after last menstrual period) and preeclampsia. In addition to problems related to confounding, these studies did not account for potential changes in folic acid supplementation during pregnancy.
• No articles were identified that met the inclusion criteria related to folic acid intake from fortified foods and risk of hypertensive disorders during pregnancy.

Human milk composition

Pregnancy

• No studies related to folic acid intake from supplements during pregnancy which met the criteria for inclusion in this systematic review were identified through a literature search from 1980 to 2019.

Lactation

• Four studies were identified through a literature search from 1980 to 2019, which met the criteria for inclusion in this systematic review: 3 RCTs and 1 uncontrolled before-and-after study. 
• Studies varied in intervention details, including folic acid supplement type (folic acid, 5-methyltetrahydrofolate, or pteroylmonoglutamate), dose (300 µg/d, 400 µg/d, or 1 mg/d), time of initiation (1 to 25 weeks postpartum), duration (4 weeks, 12 weeks, or 16 weeks), and sample characteristics. 
• As defined by the inclusion criteria, all studies took place in high or very high Human Development Index countries; therefore, the participants were likely to be folate replete. 
• None of the studies found an association between folic acid supplementation in women who were lactating and milk folate levels. 
• This body of evidence had important limitations: 
  • In one of the 3 RCTs, the reference group was not recruited and randomized with the other 2 study groups. In another study, milk folate was significantly different between the control and intervention groups at baseline, and this was not controlled for in the analyses. 
  • Only 1 study reported a power calculation and that study did not reach the target sample size. 
• The study populations did not fully represent the racial/ethnic or socioeconomic diversity of the U.S. population. 

Neurocognitive development of the child
Pregnancy

• Six articles that met the criteria for inclusion in this systematic review were identified through a literature search from 1980 to 2019. The articles report findings from 4 studies representing 4 outcome domains: 
  • Cognitive development: 1 RCT; 2 articles.
  • Language and communication development: 1 PCS; 2 articles.
  • Social-emotional development: 1 RCT; 1 article.
  • ASD: 1 nested case-control study; 1 article.
• Generally, folic acid supplementation before or during pregnancy was either not associated with or had a beneficial association with the included outcomes.
• For cognitive development, findings were inconsistent; therefore a conclusion statement could not be drawn.
• For social-emotional development, only 1 study was available and it had some limitations; therefore, a conclusion could not be drawn. 
• For language development, 2 articles were included from the Norwegian Mother and Child (MoBa) cohort. These articles reported a lower risk of severe language delay in children age 3 years whose mothers had taken folic acid supplements during early pregnancy compared to children whose mothers either did not take folic acid during pregnancy or took folic acid supplements later in pregnancy. 
• For ASD, 1 nested case-control found a significant association between folic acid supplementation before pregnancy and during pregnancy and lower risk of ASD in children ages 8 to 12 years, compared to no folic acid supplementation. This was true for a number of subgroups within the sample, including children without siblings, males, females, children with low socioeconomic status, children with both parents with psychiatric diagnosis, and children without intellectual disabilities. 
• No evidence was found on whether folic acid supplementation before and/or during pregnancy was associated with other included outcomes: movement and physical development, academic performance, ADD or ADHD, anxiety, or depression.
• No evidence was found on folic acid from supplements or fortified foods consumed before and during pregnancy and lactation and developmental milestones, including neurocognitive development.

Lactation

• The search identified 0 studies published between 1980 and 2019 that met the inclusion criteria.