Keywords
autistic spectrum disorder - folic acid - pregnancy - supplementation
Palavras-chave
transtorno do espectro autista - ácido fólico - gravidez - suplementação
Introduction
Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social interaction
and communication, with the presence of repetitive interests and activities. Considered
as a neurodevelopmental disorder, it can manifest with extremely variable phenotypes,
from severely compromised individuals to independent individuals.[1]
[2]
The World Health Organization estimates that 1 in 160 children has ASD. The use of
preconception folic acid (FA) should be indicated at least 2 months before conception
and in the 1st 2 months of pregnancy, as it has a protective effect against open defects of the
neural tube.[3]
Since 2004, in Brazil, the Ministry of Health, through the National Health Surveillance
Agency (ANVISA, in the Portuguese acronym), adopted the Collegiate Directorate Resolution
(RDC, in the Portuguese acronym) No. 344 of December 13, 2002, establishing mandatory
FA fortification in wheat flour and corn to reduce the prevalence of maternal anemia
and defects of the neural tube. This fortification of synthetic FA may have generated
a population group with high serum levels of nonmetabolized FA. This finding occurs
when > 200mg/day is ingested.[4]
The theme has great importance in the social context because it involves the patient,
their family, the state, and the multiprofessional action, which makes its study fundamental
to guarantee the practice of evidence-based health care. The objective of the present
review is to describe the relationship between maternal FA supplementation and ASD,
according to scientific publications.
Methods
This is a qualitative exploratory study, of the metasynthesis type. The search for
data was performed between February 2018 and February 2020, based on the BIREME virtual
bank, the Virtual Health Library (VHL), and the Medical Literature Analysis and Retrieval
System Online (MEDLINE/PubMed) databases.
The inclusion criteria were: original articles, systematic reviews, available in full,
free of charge, studies with human beings, published in English, Spanish, and Portuguese,
which addressed the use of FA related to the occurrence of ASD.
The exclusion criteria used in this study start with free availability, that is, studies
published on non-free platforms were excluded from this research. The year of publication
was also one of the criteria used in this review, these were strictly maintained between
the years 2013 to 2020, another criterion used was the thematic, to exclude all works
in which their title and later their summary dealt with a different theme of the association
between maternal FA supplementation and ASD.
Studies that depict ASD associated with other drugs or other factors that do not correspond
to consumption of supplemental FA were excluded from the study, or those that deal
with the consumption of FA without associating it with ASD. The period in which FA
is used was also one of the criteria used in the present review, and all those dealing
with the consumption of FA at different periods of the periconceptional and gestational
period were excluded. Studies with animals and those that portrayed other subjects
outside the area of interest of the present research were excluded.
The operationalization of the search for data collection was performed in the BIREME
database using Health Science Descriptors (DeCS) linked to Boolean operators and using
quotation marks in compound words, (autistic OR autism) AND (“autism spectrum disorder”) AND (“folic acid”). In the PubMed database, the search was performed in English using Medical Subject
Headings (MeSH) linked to Boolean operators and quotes in compound words, (autistic OR autism) AND (“autistic
spectrum
disorder”) AND (“folic acid”).
The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P)
was used based on a checklist with 27 items and a 4-step flowchart.[5] In the present review, the acronym PICO (Patients; Intervention; Comparison; Outcome)
was also used to construct the guiding question of the study and to perform the bibliographic
search. For the presentation of eligibility criteria, the PRISMA and the table containing
information such as authors, year of publication, place and results were used ([Fig. 1]).
Fig. 1 Flowchart of eligible items. Source: Flowchart prepared according to PRISMA recommendations.
Results
According to the search strategy adopted, 220 articles were found at BIREME and 164
at PubMed, totaling 384 selected articles, as seen in [Fig. 1], and the studies are presented in tabular form, as seen in [Table 1].
Table 1
Characteristics of the articles that composed the body of analysis of the study according
to authors, year, place and main results
|
Authors
|
Year
|
Place
|
Main results
|
|
Steenweg-de-Graaff et al.[6]
|
2015
|
Rotterdam, Netherlands.
|
The concentration of folic acid at the beginning of pregnancy does not show a direct
relationship with autism in the offspring. However, it shows a decrease in traces
of childhood autism, related to early folic acid supplementation.
|
|
Neggers[14]
|
2014
|
Alabama, USA.
|
Autism may be related to the potential association between DNA methylation by high
folic acid intake, food fortification with folic acid, and it may also be pointed
out as a protective factor for autism. Therefore, the cause of autism could not be
affirmed, only possible relations with the problem, being necessary further studies
in this respect.
|
|
Braun et al.[7]
|
2014
|
Cincinnati, Ohio, USA
|
Among the mother-son pairs who used multivitamins with folic acid in the 2nd trimester of pregnancy, it was shown to have a beneficial effect in reducing autistic
characteristics. When the concentrations of folate in maternal whole blood alone were
seen, a protective relationship against the disorder was not observed.
|
|
Berry et al.[15]
|
2013
|
Atlanta, Georgia, USA.
|
The increasing number of ASD cases, together with the fortification of food folic
acid, leads to some aspects of ASD. It may be protective in relation to folic acid
supplementation and ASD or it may have an adverse effect of this excessive supplementation,
increasing the risk for the problem. As its role is not yet clear regarding its relationship
with ASD, future studies are needed.
|
|
Schmidt[8]
|
2013
|
California, USA.
|
The prevalence of ASD decreases as preconception folic acid is used and in early pregnancy.
A 40% decrease in the risk of developing the disorder is observed.
|
|
Gao et al.21
|
2016
|
Columbia, USA.
|
Although studies have been observed that indicate a relationship between folic acid
supplementation and autism, most of the articles studied in this review suggest that
folic acid supplementation in the pregnancy has a protective effect against ASD.
|
|
Raghavan et al.[18]
|
2018
|
Boston, USA.
|
Based on folate measured in the maternal blood plasma, there is a relationship between
increased and decreased folic acid consumption with an increased risk of ASD. However,
moderate intake of multivitamins indicates a decreased risk for ASD.
|
|
Strøm et al.22
|
2018
|
Denmark
|
The supplementary consumption of preconception folic acid and at the beginning of
pregnancy did not present ASD as an outcome. A detailed examination of genetic factors
and biomarkers of exposure is necessary.
|
|
Wang et al.[9]
|
2017
|
China
|
Maternal folic acid supplementation demonstrates protective action against ASD. The
consumption of folic acid could allow a significant reduction in the risk of the disorder
when compared with those who did not perform the supplementation.
|
|
Rangel-Rivera et al.[16]
|
2015
|
Colombia
|
Folic acid remains a major ally against structural defects of the central nervous
system. There are aspects that affirm its protective effect in relation to ASD, but
this study is inconclusive to affirm its protection.
|
|
Wiens et al.[13]
|
2017
|
Iowa, USA.
|
Excessive consumption of folic acid proves not to be innocuous, high levels of nonmetabolized
folic acid denote a negative effect on neurological development, being consequently
related to disorders such as ASD.
|
|
Moussa et al.[10]
|
2016
|
Houston, Texas, USA.
|
Preconception and early pregnancy folic acid consumption show a positive effect in
reducing the risk of ASD, but its effects are not known if used during the entire
pregnancy.
|
|
Neggers[17]
|
2014
|
Alabama, USA.
|
Fortification of folic acid associated with preconception folic acid supplementation
has shown a close relationship with the increase in the number of ASD cases. Further
studies in this area are needed to reach a conclusion.
|
|
DeVilbiss et al.[19]
|
2015
|
Philadephia, USA.
|
Folic acid consumption has shown a relationship with ASD, and this relationship is
both with risk, related to high consumption, and with insufficient intake, given its
necessity in neurodevelopment. The dosage of folic acid, vitamin B12 and homocysteine
is necessary for a more complete and conclusive evaluation of this relationship.
|
|
Surén et al.[11]
|
2013
|
Norway
|
Maternal folic acid supplementation between the 4th week and before the 8th week after the beginning of pregnancy is associated with a lower risk of ASD. However,
the inverse association observed represents a causal relationship, indicating that
folate deficiency around conception and early pregnancy, or reduced capacity to use
available folate, are important causes of ASD.
|
|
Tan et al.[12]
|
2019
|
China
|
The study demonstrates that maternal use of folic acid and/or micronutrients during
pregnancy offer reduced the risk of autistic characteristics in the offspring. Observing
characteristic signs regarding social cognition, media, autism behavioral mannerisms,
adaptive behavior, coarse motor behavior and problems in gastrointestinal tract of
children with ASD. There is also a relationship with the consumption of the micronutrient
in pregnancy and vitamin status in children with ASD.
|
|
Altamimi[20]
|
2018
|
Palestine
|
Through a systematic review, the relationship of ASD with maternal use of micronutrients
was evaluated, and it was observed that folic acid can be related to ASD due to its
relationship with glutathione, a product of the methionine cycle that depends on folic
acid and B12. This element is involved in neuroprotection against oxidative stress
and neuroinflammation in the brain. According to studies, glutathione is deficient
in children with autism compared with typically developed children.
|
Abbreviation: ASD, autism spectrum disorder.
Source: Own elaboration, 2020.
The main result of the present review is that the use of FA in the preconception period
and in the beginning of pregnancy is effective in preventing ASD. Therefore, early
supplementation with FA is beneficial for neurodevelopment and, consequently, acts
on the prevention of ASD. The consumption of additional FA at an early stage should
be indicated, because in addition to preventing ∼ 70% of neural tube defects cases,
it is associated with a protective effect in relation to ASD.
It was also found that excess FA consumption and the gestational period in which it
is used can have a negative influence on the occurrence of ASD. Too much intake can
be observed, since FA, in addition to being consumed in the usual diet, can also be
added in the form of oral supplementation, which, associated with the extended time
of use, demonstrates a causative effect for the disorder.
Many studies addressed in the present review bring inconclusive results regarding
the effect of FA in relation to ASD, indicating the need for future investigations
of maternal FA serum levels and also a detailed investigation regarding its consumption
from the 2nd trimester of pregnancy, a period considered a risk for its use, in relation to the
disorder. All this is relevant, so that optimal doses are indicated according to individual
needs and maternal nutritional deficiency.
Of the 15 studies evaluated, 8 were unable to safely determine the effects caused
by FA. The majority found that there is an effect on neurodevelopment and even observed
a relationship with ASD, but in a contradictory way, which may be protective or even
cause the problem. They also point out the need for further studies and that an evaluation
of FA in the blood plasma of the mother should be performed to analyze its possible
indication, in optimal dose and time.
Discussion
After the analysis of the eligible articles and following the already defined method,
three thematic categories emerged: FA as a protection to ASD, increased risk of ASD
in relation to excessive use of FA, and inconclusive association between FA consumption
and ASD.
Folic Acid as Protection against Autism Spectrum Disorder
Studies carried with children diagnosed with ASD whose mothers used FA in the 6 weeks
before and after conception pointed to the protective effect of preconception FA and
the occurrence of ASD.[6]
[7]
[8] Folic acid consumption is related to a decrease in the occurrence of ASD when compared
with other mothers who did not have the supplementation.[9]
[10] Corroborating in the study, the nonuse or deficiency in the folate metabolism in
this same period can be pointed out as a cause for the development of autism disorder.[11]
A study was conducted in a Chinese population with a total of 416 children with ASD
and 201 children with typical development (TD). It concluded that children born to
mothers without FA and micronutrient supplementation during pregnancy exhibited more
severe social cognitive impairment, such as social communication, behavioral mannerisms,
delays in developing raw and adaptive motor behavior, and gastrointestinal problems
than children born to mothers who used FA and micronutrient supplements, demonstrating
the need for micronutrient supplementation during pregnancy and periconception.[12]
In this category, it is clear that FA can be considered a protector for autism, especially
when used in the preconception period and at the beginning of pregnancy, since research
has shown that it reduces the risk of autism in the offspring. This beneficial effect
cannot be confirmed if consumed during the rest of the course of pregnancy. It should
be noted that many studies point to FA supplementation as having a beneficial effect
in relation to ASD, since 8 of the 15 analyzed studies point to this effect.
Increased Risk of ASD in Relation to Excessive Use of Folic Acid
Studies show that maternal FA supplementation, together with food fortification, has
resulted in a population with superior parameters of AF than expected, and with an
excess of nonmetabolized folate in the body. This may be associated with an increasing
number of ASD cases.[13]
Inconclusive Association between Folic Acid Consumption and Autism Spectrum Disorder
It is still too early to reach a conclusion on the association between FA consumption
and ASD. Studies show its protective effect against ASD, but others intrigue us with
their investigations of alterations in the metabolic pathways of maternal folate,
its potential role in DNA methylation through high maternal FA intake and its relationship
with autistic traits. Finding the optimal level of maternal FA intake is difficult,
but it may be the answer to these hypotheses.[14]
The beneficial or harmful effect of FA on ASD cannot be stated. This requires intensified
studies to discover the relationship of nutrition in different populations and the
association with food fortification and additional FA supplementation.[15]
[16] The increase in the number of ASD cases may be linked to several factors, such as
changing diagnostic criteria, increased information, and excess FA consumed by women
of childbearing age.[17]
Supplementation with periconceptional FA reduced neural tube defects by up to 70%
and resulted in fortification of cereal products in several countries. The recommendation
was that all women of childbearing age should consume 400µg/day of FA. It was also
observed that the metabolism of maternal folate can vary between women, which may
be involved with the increase in the number of cases of ASD.
Based on postpartum maternal blood samples, folate and vitamin B12 were analyzed in
mothers who reported multivitamin supplement consumption at least in the 3rd trimester of pregnancy. The diagnosis of ASD was observed through electronic medical
records. The results can be understood as a “U” format, where the increased risk for
ASD is at both extremes, when the supplement was consumed in excess and when it was
consumed in small amounts. In contrast, moderate supplementation showed a protective
effect in relation to ASD.[18]
The maternal folate status may be related to ASD. Insufficient FA consumption may
lead to hypomethylation of DNA, which is associated with neurodevelopment. It has
also been found in some studies that FA consumption can be considered protective for
autism.
The author indicates that repeated biological measurements of folate, vitamin B12
and homocysteine during the 1st trimester of pregnancy are necessary, as well as genetic variants relevant to folate
involved in carbon metabolism, and the epigenetic mechanisms.[19]
The relationship of ASD with maternal use of micronutrients such as iron, zinc, vitamin
D and AF were evaluated, and it was observed that the AF shows contradictory effects
in relation to the TEA, which, in some studies, is presented as a protective effect
and, in others, as causal effects. Thus, it was not possible to demonstrate whether
or not there is a relationship between PA supplementation and ASD. Another finding
in relation to ASD involves its relationship with glutathione, a product of the methionine
cycle that depends on FA and B12, this element is involved in neuroprotection against
oxidative stress and neuroinflammation in the brain. Research shows that glutathione
is deficient in children with autism when compared with children with typical development.[20]
Conclusion
The use of FA in the preconception period and in the beginning of pregnancy is effective
in preventing ASD. Therefore, early supplementation with FA is beneficial for neurodevelopment
and, consequently, acts on the prevention of ASD. The present study deals strictly
with the consumption of FA with the development of ASD, and the action of FA in the
treatment of other neurological problems has not been reviewed. The study also did
not aim to associate the use of FA with other drugs. The present study recommends
that new investigations be performed to identify optimal doses and identify whether
FA consumption from the 2nd trimester can really be associated with the increase in the number of new cases of
ASD as mentioned by some studies in the present review.
