Commentary by: Matthew Baral, ND

8143280_mlReference:  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 replication[2], especially in the brain,[3][4] leading to smaller brain size[5] 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.

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