Download Commentary by: Matthew Baral, ND Reference: Schlotz W, Jones A

Commentary by: Matthew Baral, ND
Reference: Schlotz W, Jones A, Phillips DI, Gale CR, Robinson SM, Godfrey KM.
Lower maternal folate status in early pregnancy is associated with childhood
hyperactivity and peer problems in offspring. J Child Psychol Psychiatry. 2010
May;51(5):594-602.
Design: Prospective cohort study.
Participants: The authors tested 100 mothers for red cell folate levels at the end of the
first trimester and folate intake was assessed throughout their pregnancies. Head
circumference of the newborns was measured and weight was measured at birth and 9
months of age. At 8.7 years of age, the mothers were then asked to complete a
questionnaire on the behavior of their children covering hyperactivity, emotional
symptoms, conduct problems, and peer problems. The authors controlled for maternal
smoking, alcohol consumption and gender.
Key Findings:
Red cell folate levels and total folate intake levels were both found to be lower in the
mothers of those children later reported to have high levels of hyperactivity and peer
problems. The range of folate intake for mothers was 328.5mcg-624.4mcg in early
pregnancy and 269.9-410.0mcg in late pregnancy. Controlling for mother's smoking and
drinking alcohol during pregnancy did not change the results.
Practice Implications:
This study is the first to show an association between folate status of the mothers and
behavioral outcomes in their children. In addition, they also found that decreased head
growth velocity was also associated with lower folate levels during pregnancy. It should
be noted that head growth is a rough indicator of brain growth. However, there was an
association here, indicating that in-utero folate status does affect neurodevelopment and
decreased fetal brain growth is one of the results. It is well known that inadequate
prenatal folate intake will affect other aspects of nervous system development, evidenced
by its relationship to spina bifida and other spinal dysraphisms. This study also provides
information as to when folate status may be more important. In this case, the evidence
points to the first trimester. In fact, other studies have shown that nutritional status in
early pregnancy is more influential than later.1 It is concerning that nutrition could play
such a significant role in the growing fetus at a time that many mothers may not even
know they are pregnant, or not thinking that prenatal nutrition it particularly important.
What is even more concerning is that the range of folate intake for the mothers in this
study did not fall that far out of the recommended minimum prenatal dose of 400 mcg. It
is possible that other confounding factors will affect the folate status and usable folate
that is consumed such as tobacco smoke, oral contraceptives, trimethoprim, methotrexate,
or sulfasalazine. Therefore, maternal use before pregnancy may create a further
disadvantage when compared to other women not using these substances. Folate
deficiency is known to decrease fetal cellular replication2, especially in the brain,34
leading to smaller brain size5 and behavioral problems.6 It is possible that prenatal folate
deficiency affects the risk of later hyperactivity through its influence on dopaminergic
system development,7 but this has yet to be studied. Other research makes a fairly solid
connection between folate and ADHD; Pediatric leukemia survivors that have mutations
in 5,10-methylenetetrahydroreductase (MTHFR), a crucial enzyme that provides usable
folate for DNA synthesis, show ADHD symptoms later in life.8 This could be further
affected by chemotherapeutic folate antagonists commonly used in these patients, in
particular, methotrexate. The authors themselves state that there are many confounding
factors here, especially after the child is born. However, when one looks at the past
literature, it makes sense that behavior would be affected. It might not be the only factor,
but certainly an important one to consider when counseling mothers for their family
planning. This might be even more important in those mothers who suffer themselves
from ADD, ADHD or depression. In addition, it is important to note that those mothers
who have a past history of delivering a child with a neural tube defect, have a much
increased risk for it to reoccur. Therefore, those mothers need much higher levels of
folate intake, up to 4 mg, starting at one month before they even become pregnant.
1
Neugebauer R, Hoek HW, Susser E. Prenatal exposure to wartime famine and development of antisocial
personality disorder in early adulthood. JAMA. 1999 Aug 4;282(5):455-62.
2
Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr. 2000
May;71(5 Suppl):1295S-303S.
3
Xiao S, Hansen DK, Horsley ET, Tang YS, Khan RA, Stabler SP, Jayaram HN, Antony AC. Maternal
folate deficiency results in selective upregulation of folate receptors and heterogeneous nuclear
ribonucleoprotein-E1 associated with multiple subtle aberrations in fetal tissues. Birth Defects Res A Clin
Mol Teratol. 2005 Jan;73(1):6-28.
4
Craciunescu CN, Brown EC, Mar MH, Albright CD, Nadeau MR, Zeisel SH. Folic acid deficiency during
late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain. J Nutr.
2004 Jan;134(1):162-6.
5
Middaugh LD, Grover TA, Blackwell LA, Zemp JW.Neurochemical and behavioral effects of diet related
perinatal folic acid restriction. Pharmacol Biochem Behav. 1976 Aug;5(2):129-34.
6
Castellanos FX, Lee PP, Sharp W, Jeffries NO, Greenstein DK, Clasen LS, Blumenthal JD, James RS,
Ebens CL, Walter JM, Zijdenbos A, Evans AC, Giedd JN, Rapoport JL. Developmental trajectories of
brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder.
JAMA. 2002 Oct 9;288(14):1740-8.
7
Schlotz W, Jones A, Godfrey KM, Phillips DI. Effortful control mediates associations of fetal growth
with hyperactivity and behavioural problems in 7- to 9-year-old children. J Child Psychol Psychiatry. 2008
Nov;49(11):1228-36.
8
Krull KR, Brouwers P, Jain N, Zhang L, Bomgaars L, Dreyer Z, Mahoney D, Bottomley S, Okcu MF.
Folate pathway genetic polymorphisms are related to attention disorders in childhood leukemia
survivors. J Pediatr. 2008 Jan;152(1):101-5. Epub 2007 Oct 24.