Epilepsy and pregnancy: folic acid reduces the risk of cognitive delay in children of women taking antiepileptics

Folic acid intake during the periconceptional period promotes cognitive development in children born to women taking epilepsy medications.

The neuropsychological effects of vitamin B9 on the fetus seem to positively influence verbal abilities, global, linguistic, non-verbal, and executive functions. These results confirm those of a previous study, which demonstrated how folic acid use in the early stages of pregnancy can have a preventive effect on language delay in children, a condition associated with the use of antiepileptic drugs during pregnancy.

This was demonstrated by a team of researchers from several American universities in a study recently published in Neurology, the medical journal of the American Academy of Neurology.

Folic acid prevents congenital malformations and supports neurocognitive development 

A diet rich in folates is recommended for all women of childbearing age to prevent  congenital malformations in newborns. However, consumption of folate-containing foods is often insufficient; therefore, the use of folic acid (or vitamin B9) supplements is strongly recommended for women of childbearing age. Folate deficiency in pregnant women increases the risk of Neural Tube Defects, a group of malformations, more or less severe, including Spina Bifida and the so-called Cleft Lip. 

Few studies have so far examined whether folic acid supplementation can also protect against neurological development alterations after fetal exposure to antiepileptic drugs. Some research has indicated that folic acid supplements may have a positive effect on Intelligence Quotient (IQ) and verbal abilities in children exposed to epilepsy medications during the fetal phase. 

Other studies suggest that folic acid intake during the periconceptional period, that is the time from about one month before conception to the third month of pregnancy, may have a protective effect against language deficits induced by epilepsy treatment drugs. These medications, if taken during pregnancy, can have a teratogenic effect, i.e., negatively interfere with child development. In particular, some antiepileptic drugs have been associated with neurological and behavioral developmental disorders. 

Unfortunately, these drugs are often necessary for young women of childbearing age to treat epilepsy, pain, or psychiatric disorders, and therapy cannot be discontinued during pregnancy because epileptic seizures could harm both fetus and mother. 

Folic acid supplementation improves cognitive performance of children born to women with epileptic seizures

In the current study, researchers further analyzed data collected in a previous work, finding a positive association between fetal exposure to folic acid and better neurological development in children of women taking anticonvulsant drugs. Results showed that at 6 years of age, children exposed to folic acid during the fetal period scored better in tests assessing non-verbal development, expressive language, and executive function. 

At 3 years, positive associations were found between the amount of folic acid consumed by the mother and some tests used to define language disorders in children: Verbal Index, Receptive Language Index. Non-significant effects were found for the Non-Verbal Index and Expressive Index. These data suggest that vitamin B9 effects involve multiple areas of neuropsychological function, including linguistic, non-verbal, and executive activities, extending into school age, and predictive of adult cognitive abilities. 

Some study details

This work, named NEAD (Neurodevelopmental Effects of Antiepileptic Drugs), involved pregnant women with epilepsy being treated with one of the most common antiepileptic drugs: carbamazepine, lamotrigine, phenytoin, or valproate. A total of 305 women were followed between October 1999 and February 2004 in 25 epilepsy centers in the United States and the United Kingdom.

Most importantly, their children were observed: 311 children underwent a “battery” of tests designed to evaluate various neuropsychological functions at ages 3 and 6. Test results were correlated with maternal folic acid supplement use during the preconception weeks and early pregnancy months. The group of children exposed to low folic acid doses (0-0.4 milligrams per day) showed an intermediate IQ between the “no folic acid” group and those exposed to higher doses over 0.4 mg per day. 

However, only 6 children were in the low-dose group (0-0.4 mg), limiting the exploration of dose-dependent effects. Potential confounding variables for participant selection were also considered: maternal IQ, age, education, occupation, ethnicity, alcohol, tobacco or other drug use during pregnancy, unwanted pregnancies, etc. 

The effect of folic acid on language: the Norwegian study

The results are consistent with those of a Norwegian study published about a year and a half earlier online in Neurology. In this work, also conducted among children of women taking epilepsy drugs during pregnancy, researchers collected information on antiepileptic drug use and folic acid supplementation. Parents completed questionnaires about their children’s language development at 18 months and three years of age. 

Results showed that children whose mothers did not take folic acid supplements had a fourfold greater likelihood of language deficits at 18 months compared to children of mothers without epilepsy who did not take folic acid supplements. At about three years, children of epileptic women on drug therapy who did not take folic acid supplements had an almost fivefold increased risk of language delays compared to children of healthy women. 

Among children whose mothers used folic acid during pregnancy, only 17% of children of women with epilepsy had language delay at 18 months, compared to 11% in the healthy control group. Results remained the same after researchers adjusted statistical analyses for other factors potentially influencing language abilities, such as parental education level, smoking and alcohol use during pregnancy, and gestational age. 

Norwegian researchers from the University of Bergen also observed that mothers of children exposed to epilepsy drugs with language delays had started taking folic acid rather late; on average after the sixth week of pregnancy. Women with children exposed to epilepsy drugs without language delays had started folic acid three weeks before conception. 

This suggests that the positive effect of folic acid supplementation is significant only if used between the fourth week before pregnancy and the end of the first trimester, indicating this as the most important period to prevent language delays. 

The protective action of folic acid supplementation in the periconceptional period remains to be further investigated.

These two studies, conducted on different populations of women and children, highlighted the need for folic acid supplementation for women of childbearing age who are required to take antiepileptic drugs. 

The American study investigated the relationship between fetal folic acid exposure and cognitive development through multiple neuropsychological assessments, while the Norwegian study focused only on language via parent questionnaires. 

Both studies suggest a role for folic acid in reducing the risk of language deficits and other neurocognitive impairments that may result from the teratogenic action of certain substances. The mechanisms underlying folic acid’s effect on the developing brain are poorly understood. A combination of basic and clinical research is essential to fully delineate the effects of vitamin B9 and medications on the developing fetus and optimize care for epileptic women during pregnancy. 

Source:

1. Kimford J. Meador et. al.,“Effects of periconceptional folate on cognition in children of women with epilepsy: NEAD study”. Neurology, 2020 2) Husebye, Elisabeth Synnøve Nilsenet.,Verbal abilities in children of mothers with epilepsy: Association to maternal folate status. Neurology, 2018