Adina Lapine HNSC 7211 Professor Caviglia

Folic Acid Supplementation Beyond the First Trimester

Introduction

Hopeful mothers to be dutifully take a prenatal vitamin containing folic acid each day. Folic acid has long
been touted as the cure for neural tube defects due to its high bioavailability (folate is unique in that it is
one of the few vitamins where the man made form is more bioavailable than the natural form), ease of
use and low cost. Women have been told they can stop taking folic acid a month into the pregnancy
because the critical period for preventing neural tube defects has passed. Now, researchers are
questioning why expectant mothers do not take folic acid throughout pregnancy.

General background: The Importance of Maternal Folate Status

Folate is a water-soluble vitamin important for the transfer of methyl groups. It is vital in purine and
pyrimidine synthesis and in methylation reactions (such as in the epigenetic regulation of embryonic
development). Folate is also important in the formation of myelin 1, the synthesize of some
neurotransmitters1 and in the reduction of homocysteine levels. A high plasma homocysteine level has
been shown to result in neural destruction in animal studies 2.

Folate supplementation, in the form of folic acid, has been recommended for decades to prevent NTDs
(neural tube defects) in infants. NTDs are found in mothers with inadequate diets and people with
polymorphisms in the MTFHR (methylenetetrahydrofolate reductase) enzyme that converts folate to its
active form, 5 methyl THF. One common polymorphism is C677T, found in 10-15% of Caucasian
populations1. Folic acid supplementation prevents NTDs because a large amount of folate is needed to
synthesize the purine and pyrimidines that will fuel the growth of embryonic cells. The formation of the
neural tube during week three is a critical period because the tube will not close properly if key players,
including folate, are missing. This can result in anencephaly or spina bifida. Methylation may also play a
role in neural tube development: Studies of humans with NTD’s have observed decreased methylation in
the subjects’ neural tissues1. Since the FDA mandated fortification of grain products with folic acid, NTD
prevalence has decreased by 30%1.

Since folate plays such important roles in brain formation, researchers question if folate
supplementation might be important even after the neural tube has closed. The review of studies of
folate by Naninck et al2 brings in many preclinical trials that illustrate how it influences neural formation
in animals. There are few clinical trials in humans, and observational studies have provided mixed
results. Half of the reviewed observational studies found low maternal folate status in association with
lower IQ scores, behavioral problems and Autism Spectrum Disorder while the other half did not 2. One
study found that mothers who supplemented with less than the recommended amount of folic acid had
children with improved mental development compared to those who supplemented at or above the
recommended amount, with between 400 and 1000 mcg 2.

A review and meta analysis3 on folic acid supplementation, neurocognitive outcomes and Autism
Spectrum Disorder was published in 2019. The researchers looked for papers in Pubmed, Scopus, and
the Cochrane Library until June 2018. They found a total of 647 papers, which they checked for
applicability and quality. The final analysis included two randomized control trials, three case control
studies, and eleven cohort studies, for a total of 16 papers. This resulted in a cohort of 756,365 children
aged 11 months to 15 years. The researchers grouped the subjects by folic acid intake: less than 400
Adina Lapine HNSC 7211 Professor Caviglia

mcg, 400-999 mcg, 1,000 – 5,000 mcg, and over 5,000 mcg. The results were that prenatal folic acid
supplementation at any amount was not associated with improved neurocognitive development.
Furthermore, three studies found an association of better neurocognitive outcomes with doses of less
than 400 mcg per day. Prenatal folic acid supplementation (compared to no supplementation) was
associated with a 58% reduction in Autism Spectrum Disorder (95% CI 0.46–0.75). The authors conclude
that mothers should take supplements prior to and in the first three months of pregnancy to prevent
Autism Spectrum Disorder. Limitations of this study include confounding factors (diet and environmental
and genetic factors) and heterogeneity in several characteristics of the study, including the types of
studies included, the ages of subjects and how the data was collected and reported.

Several papers state that folic acid supplementation can have health risks: More well known is the risk of
folic acid supplementation masking a B12 deficiency 2. Another possibility, though not well studied, is
that over-supplementation of folic acid (1,000 mcg) may lead to high levels of folic acid in the blood 3.
Increased levels of folate in cells may lead to decreased activity of folate dependant enzymes through
substrate inhibition or competitive inhibition with THF (tetrahydrofolate) 2. Over supplementation of folic
acid in mice resulted in anxious behavior2 while supplementation with greater than 5000 mcg per day
was associated with reduced psychomotor development in offspring in one prospective cohort study 2.

Background of the study

FASTT (Folic Acid Supplementation in the Second and Third Trimesters) was a randomized control trial
conducted between 2006-2007 to study the impact of late gestation maternal folic acid
supplementation on offspring4. In the first iteration of the study, 119 participants were recruited from
clinics in Northern Ireland. Inclusion criteria included being a pregnant woman before the 14 th week of
gestation, of good health, age 18-35 years, and having taken 400 micrograms of folic acid daily in the
first trimester. The women were allocated to a treatment group or a control group for 26 weeks. The
treatment group received a 400 mcg/day folic acid supplement while the control group received a
placebo. The results were that the placebo group had higher plasma homocysteine and lower
RBC/plasma folate compared to the treatment group. Offspring of the treatment group received more
folate, as measured in cord blood. The conclusion of this study was that folic acid supplements should
be taken in the second and third trimesters to maintain maternal folate concentrations and prevent an
increase in homocysteine levels. An advantage of this study was that it was a double blind randomized
control trial, compliance was high, and that it accounted for dietary folate and MTHF polymorphisms.
Limitations of the study included that the population was 100% Caucasian so generalizability was
limited, and that it experienced high attrition rates.

The authors returned to gather data when the children were ages three and seven to study the effects
of maternal folic acid supplementation on neurocognitive development of the participants’ offspring 5.
The children’s cognitive function was examined using IQ tests. The researchers observed cognitive
differences between the offspring of the treatment group and the placebo group, especially in the area
of verbal reasoning5.

Maternal Folic Acid supplementation and neurocognitive development in children aged eleven years

The most current study took place from December 2017 to November 2018, when the offspring of the
FASTT trial participants were eleven years old 6. The authors hypothesized that the verbal IQ differences
seen between the treatment and control groups at ages three and seven would still be observable at age
Adina Lapine HNSC 7211 Professor Caviglia

eleven with IQ testing and MEG (magnetoencephalography) brain wave imaging. Study measures
included an IQ test and MEG brain imaging for a language task. Secondary measures included head
circumference, anthropometrics, socioeconomic status, nutrient intake from the diet and supplements,
serum and RBC folate, serum vitamin B12, plasma homocysteine, and riboflavin status.

The participants included 68 children, 31 in the placebo group and 37 in the treatment group. Only 33
participants underwent MEG imaging (14 in the placebo group, 19 in the treatment group). Children
from the treatment group had better processing speed scores than the placebo group (p = 0.03 and
0.04), and girls from the treatment group scored higher in verbal reasoning than girls from the placebo
group (p = 0.03). The researchers observed a correlation between children who scored above the
median IQ at age seven to those who scored above the median IQ at age eleven. The results of the MEG
were that children from the treatment group had higher powered responses at the beta (p = 0.01) and
high gamma bands (p = 0.04) when completing a language task than the placebo group. The researchers
conclude that maternal folic acid supplementation through the entire pregnancy has positive cognitive
effects on offspring up to age eleven. Advantages of the study include its double blind randomized
design and its use of MEG, a quick, noninvasive means to examine brain function in children. Limitations
of the study include a low response rate (57% of the original 119 participants), the MEG results not
being analyzed by sex, and the fact that the IQ tests were repeatedly measured. This increases the
possibility of the results being more from chance, and thus requires a very low p value for the results to
be considered significant.

Discussion

This information is relevant because it is the job of the dietitian to improve their client’s health while
considering multiple factors, including time and budget. Conscientious mothers want to ensure the best
health outcomes for their future child, but healthy foods can be expensive. With the information
gleaned from these articles, a dietitian can contrast the possible benefits of folic acid supplementation
throughout pregnancy with the conflicting observational evidence and dearth of significant causal
evidence. It is not possible to say definitively that a pregnant client should take folic acid supplements,
but one can say that folate in the diet is necessary due to an increased need for it during pregnancy. The
dietitian must ensure that the client is getting adequate folate intake of 600 mcg 7 of dietary folate
equivalent from either supplements, leafy greens, or fortified foods. I would recommend folic acid
supplements for a client with a poor diet and low socioeconomic status because the supplements are
relatively cheap and less time consuming to take. Since there is a concern for deleterious effects with
over-supplementation, dietitians need to ensure that clients are not taking more than 1,000 mcg of folic
acid per day7.

Conclusion

Folic acid has been widely used as a prenatal vitamin for decades. Folate is an essential part of the
human diet and its’ requirement increases 5-10 fold during pregnancy 2 due to increased DNA synthesis
and methylation. Multiple preclinical studies have demonstrated folate’s role in neural development.
Observational studies have provided conflicting associations between folate status, folate intake and
children’s neurocognitive development. Randomized control trials are scant and often of weak quality.
In such an environment, a dietitian must work with the unique needs of the client while ensuring
recommended dietary intakes are obtained.
Adina Lapine HNSC 7211 Professor Caviglia

References

1. Naninck EFG, Stijger PC, Brouwer-Brolsma EM. The Importance of Maternal Folate Status for
Brain Development and Function of Offspring. Adv Nutr. 2019;10(3):502-519.
doi:10.1093/advances/nmy120
2. Irwin RE, Pentieva K, Cassidy T, et al. The interplay between DNA methylation, folate and
neurocognitive development. Epigenomics. 2016;8(6):863-879. doi:10.2217/epi-2016-0003
3. Iglesias Vázquez L, Canals J, Arija V. Review and meta-analysis found that prenatal folic
acid was associated with a 58% reduction in autism but had no effect on mental and
motor development. Acta Paediatr. 2019;108(4):600-610. doi:10.1111/apa.14657
4. McNulty B, McNulty H, Marshall B, et al. Impact of continuing folic acid after the first trimester
of pregnancy: findings of a randomized trial of Folic Acid Supplementation in the Second and
Third Trimesters. Am J Clin Nutr. 2013;98(1):92-98. doi:10.3945/ajcn.112.057489
5. McNulty H, Rollins M, Cassidy T, et al. Effect of continued folic acid supplementation beyond the
first trimester of pregnancy on cognitive performance in the child: a follow-up study from a
randomized controlled trial (FASSTT Offspring Trial). BMC Med. 2019;17(1):196. Published 2019
Oct 31. doi:10.1186/s12916-019-1432-4
6. Caffrey A, McNulty H, Rollins M, et al. Effects of maternal folic acid supplementation during the
second and third trimesters of pregnancy on neurocognitive development in the child: an 11-
year follow-up from a randomised controlled trial. BMC Med. 2021;19(1):73. Published 2021
Mar 10. doi:10.1186/s12916-021-01914-9
7. U.S. Department of Health and Human Services, National Institutes of Health, Office of Dietary
Supplements. (2021). Folate (Fact Sheet for Consumers). Retrieved from
https://ods.od.nih.gov/factsheets/folate-Consumer/#disc