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

Consumption of folic acid in the periconceptional period promotes the cognitive development of babies born to women taking epilepsy drugs.

The neuropsychological effects of vitamin B9 on the fetus appear to act positively on verbal skills, global, language, nonverbal and executive functions. These findings confirm those of a previous study, which showed that the use of folic acid early in pregnancy may have a preventive effect on language delay in children, a condition associated with the use of antiepileptic drugs in pregnancy

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

Folic acid prevents birth defects and promotes neurocognitive development 

A diet rich in folate is recommended for all women of childbearing age to prevent birth defects in newborns. However, the consumption of folate-containing foods is often insufficient; and for this reason, the use of folic acid (or vitamin B9) supplements is strongly recommended for women of childbearing age. Folic acid deficiency in pregnant women increases the risk of Neural Tube Defects, a group of malformations, more or less severe, to which Spina Bifida and the so-called Labbro Leporino belong. 

Few studies to date have examined whether folic acid supplementation can also protect against neurodevelopmental changes after fetal exposure to antiepileptic drugs. Some research has indicated that folic acid supplements may have a positive effect on Intellectual Quotient (IQ) and verbal skills in children exposed to epilepsy drugs during the fetal stage. 

Other studies suggest that consumption of folic acid at the periconceptional age, that is, the period from about month before conception to the 3rd month of pregnancy, may have a protective effect against speech deficits induced by drugs to treat epilepsy. This group of drugs, in fact, if taken during gestation may have a teratogenic effect, that is, they may negatively interfere with the development of the child. In particular, some antiepileptic drugs have been associated with neurodevelopmental and behavioral disorders. 

Such drugs, unfortunately, are often needed by young and childbearing-age women for treatment of epilepsy, pain, or psychiatric disorders, and during pregnancy therapy cannot be stopped because seizures could cause harm to the fetus and mother. 

Folic acid supplementation improves cognitive performance of children of women with seizures

In the current study, the researchers expanded on data collected in their previous work, finding a positive association between fetal exposure to folic acid and better neurological development, in children of women taking anticonvulsant drugs. The results showed that at 6 years of age, children who had been exposed to folic acid in the fetal period performed better on tests assessing nonverbal development, expressive language, and executive function. 

At age 3, however, positive associations were found between the amount of folic acid taken by the mother and some tests used to define language disorders in children: Verbal Index, Receptive Language Index. In contrast, non-significant effects were found for the Nonverbal Index and the Expressive Language Index. These data suggest that the effects of Vitamin B9 involve multiple areas of neuropsychological function, including language, nonverbal, and executive activities, extending over the school-age years, and are predictive of cognitive abilities as adults. 

Some details of the study

To conduct this work, named NEAD (Neurodevelopmental Effects of Antiepileptic Drugs), pregnant women with epilepsy who were being treated with only one of the most common antiepileptic drugs; that is, carbamazepine, lamotrigine, phenytoin, or valproate, were involved. The women, 305 in all, were followed between October 1999 and February 2004, at 25 epilepsy centers in the United States and the United Kingdom.

Most importantly, their children were observed: as many as 311 children took a "battery" of tests, made to assess various neuropsychological functions at ages 3 and 6. Test results were correlated with mothers' use of folic acid supplements in the preconception weeks and early months of pregnancy. The group of children exposed to a low dose of folic acid (0-0.4 milligrams per day) had shown IQs intermediate between those in the "no folic acid" group and those exposed to the higher doses of 0.4 mg per day. 

However, only 6 children were in the low-dose group (0-0.4 mg), which limited the exploration of dose-dependent effects. Potentially confounding variables were also taken into account in selecting study subjects: maternal IQ, age, education, occupation, ethnicity, use of alcohol, tobacco or other drugs during pregnancy, unwanted pregnancies, etc. 

The effect of folic acid on language: the Norwegian study

Their findings are consistent with those of a Norwegian study published about a year and a half earlier in the online issue of Neurology. In that work, also conducted among children of women who were taking epilepsy medication during pregnancy, the researchers collected information on the use of antiepileptic drugs and folic acid supplements. Parents completed a questionnaire on their children's language development at 18 months and three years of age. 

The results showed that children whose mothers were not taking folic acid supplements were four times more likely to have deficits in their language skills at the age of 18 months, compared with children of mothers without epilepsy who were not taking folic acid supplements. By the age of about three years, on the other hand, children of epileptic women on drug therapy who were not taking folic acid supplements had an almost five times greater risk of language delays, compared with children of healthy women. 

In contrast, among children whose mothers had used folic acid during pregnancy, only 17 percent of children of women with epilepsy had a language delay at 18 months, compared with 11 percent in the healthy control group. The results remained the same after the researchers accounted in their statistical analysis for other factors that might influence language abilities, such as parental education level, smoking and alcohol use during pregnancy, and gestational age. 

The 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. In contrast, women with children exposed to epilepsy drugs without delays in language skills had started taking folic acid three weeks before conception. 

This would show that the positive effect of using the supplement is significant only when used in the period between the fourth week before pregnancy and the end of the first trimester, suggesting how this is the most important time to prevent speech delays. 

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

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

In the American study, the relationship between exposure to folic acid in the fetal environment and cognitive development was investigated through the multiple measures of neuropsychological assessments, whereas in the Norwegian study, only the aspect of language was assessed through questionnaires provided to parents. 

Both studies, however, suggest a role for folic acid in reducing the risk of deficits in language and other neurocognitive abilities that may result from the teratogenic action of certain substances. The mechanisms underlying the action of folic acid on the untrained brain are poorly understood. A combination of basic and clinical research is essential to fully delineate the effects of vitamin B9 and drugs on the developing fetus and maximize the care of women with epilepsy 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