Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4–5 y of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study,,§

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ABSTRACT

Background

The benefits of the use of folic acid supplements (FASs) during the periconception period to prevent neural tube defects and to ensure normal brain development in offspring are well known. There is concern, however, about the long-term effects of the maternal use of high dosages of FASs that exceed the Tolerable Upper Intake Level (UL) (≥1000 μg/d) on child neurocognitive outcomes.

Objective

The objective of the study was to examine the association between the use of high dosages of FASs during pregnancy and child neuropsychological development at ages 4–5 y.

Design

The multicenter prospective mother-child cohort study, the Infancia y Medio Ambiente (INMA) Project, was conducted in 4 regions of Spain: Asturias, Sabadell, Gipuzkoa, and Valencia. Pregnant women were recruited between 2003 and 2008. Data on 1682 mother-child pairs were included in the final analyses. The pregnant women completed an interviewer-administered questionnaire that was validated to estimate typical dietary folate intake and the use of FASs at 10–13 and 28–32 wk of gestation. Neuropsychological development scores at 4–5 y of age were estimated with the use of the McCarthy Scales of Children's Abilities. Multiple linear regression and meta-analysis were used to obtain combined-effect estimates.

Results

During the periconception period, one-third of the women (n = 502) took FAS dosages ≥1000 μg/d. The use of FAS dosages ≥1000 μg/d in this period was negatively associated with several neuropsychological outcomes scores in children: global verbal (β = −2.49; 95% CI: −4.71, −0.27), verbal memory (β = −3.59; 95% CI: −6.95, −0.23), cognitive function of posterior cortex (β = −2.31; 95% CI: −4.45, −0.18), and cognitive function of left posterior cortex (β = −3.26; 95% CI: −5.51, −1.01).

Conclusions

The use of FAS dosages exceeding the UL (≥1000 μg/d) during the periconception period was associated with lower levels of cognitive development in children aged 4–5 y. The use of FAS dosages ≥1000 μg/d during pregnancy should be monitored and prevented as much as possible, unless medically prescribed.

Key Words

folic acid supplements
folate
pregnancy
periconception period
child neurocognitive development

ABBREVIATIONS

CFLPC
cognitive function of left posterior cortex
CFPC
cognitive function of posterior cortex
FA
folic acid
FAS
folic acid supplement
FFQ
food-frequency questionnaire
INMA
Infancia y Medio Ambiente
MSCA
McCarthy Scales of Children's Abilities
UL
Tolerable Upper Intake Level

Cited by (0)

This study was funded by grants from Instituto de Salud Carlos III and the Spanish Ministry of Health (Red INMA G03/176, CB06/02/0041, FIS 97/0588, 00/0021-2, PI061756, PS0901958, FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02647, FIS-PI041436, FIS-PI081151, FIS-PI06/0867, FIS-PS09/00090, FIS-PI042018, FIS-PI09 02311, FIS PI11/01007, and FISPI13/02429), University of Oviedo, Conselleria de Sanitat Generalitat Valenciana, Generalitat de Catalunya-CIRIT 1999SGR 00241, Department of Health of the Basque Government (2005111093 and 2009111069), and the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001).

The funders had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

§

DV-G and EMN-M contributed equally to the article.