The use of high-dose folic acid during pregnancy in woman with epilepsy did not seem to affect the long-term neurodevelopmental outcome of their children a decade or longer after birth, according to a new study reported at the American Epilepsy Society meeting in Nashville in December.
“In this nationwide study of Danish school-aged children, we found no evidence that maternal use of high-dose folic acid supplements in pregnancy reduces the negative influence of prenatal valproate exposure on performance in standardized language and mathematics tests or modifies the association with other ASMs [antiseizure medications]," said study investigator Julie Dreier, PhD, a senior researcher at Aarhus University in Denmark who presented the findings.
“ASMs are increasingly used by pregnant women worldwide, not only for the treatment of epilepsy but also for mood disorders, migraine, and pain. Today, between 0.5 and 2 percent of all children are born to women who are using ASMs during pregnancy."
Dr. Dreier noted that some ASMs, such as valproate and phenobarbital, negatively affect children's developing brains, but the evidence of cognitive risks of in utero exposure remains limited for most of these medications. Valproic acid, however, has been linked to serious birth defects in 10 percent of babies born to women taking ASMs during pregnancy.
“Recently it has been proposed that supplementation with high doses of folic acid may reduce the potential adverse effects of some ASMs, but the evidence remains scarce, and studies with long-term follow-up in the children are lacking," she added.
Studies have shown that folic acid supplementation taken before pregnancy reduces the risk for neural tube defects in the developing fetus, and it also is recommended for use in pregnant woman with epilepsy taking ASMs to prevent ASM-associated birth defects, Dr. Dreier said.
Doctors caring for patients with epilepsy during the childbearing years know of the serious risks of many ASMs related to the developing fetus, and that guides decisions for birth control and use of safer antiepileptic drugs in patients wanting children. Contraceptive drugs can impact seizure medications, and women of childbearing age should be educated on the risks of the medications they take or switch to safer ones.
To determine whether folic acid reduced some of the neurodevelopmental effects associated with ASMs that have been observed in children exposed to ASMs in utero, the researchers tapped into the Danish National Prescription Registry and the Danish National Test Program (which measures students' academic knowledge) to compare test scores of children exposed and not exposed to ASM monotherapy in utero. They also determined whether mothers had taken high doses of folic acid supplementation during pregnancy.
The data came from over 550,000 children born between 1997 and 2009; 2,452 women (0.4 percent) used an ASM during their pregnancy, 685 (27.9 percent) of whom took high-dose folic acid supplements.
Researchers estimated the difference in mean standardized scores between children with no prenatal ASM exposure and those whose mothers took ASM monotherapy with and without concurrent high-dose folic acid supplementation. The mean score for all children was 56.3 for all language tests and 57.2 for all math tests. For children unexposed to any ASM, the mean score also was 56.3 for all language tests and 57.3 for all math tests. Children exposed to any ASM, meanwhile, had a mean score of 50.8 for all language tests and 51.2 for all math tests. The folic acid doses ranged from 1 to 5 mg.
The researchers found that children with prenatal valproate monotherapy exposure performed worse on standardized tests from elementary to high school “regardless of whether the mother used high-dose folic acid supplements in pregnancy." They also reported that high folic acid supplementation in utero did not modify school performance in children whose mothers took other ASMs during pregnancy.
Paul C. Van Ness, MD, director of the Baylor/St. Luke's Comprehensive Epilepsy Center at Baylor College of Medicine and head of the Peter Kellaway Neurophysiology Laboratory, advocates for doses of less than 1 mg. Dr. Van Ness and many of his colleagues also have tried to stop prescribing valproic acid to females of childbearing age in case they do become pregnant and during pregnancy.
“This study shows that doses over 1 mg a day do not effect cognitive outcomes on the testing done when the children were older," Dr. Van Ness said.
While the Denmark study looked at school-aged children exposed in utero, Dr. Van Ness said it is possible that children with developmental delays or learning disabilities did not participate in the Danish National Test Program or were not included in the study. He also said that the abstract does not differentiate between women on the 1 mg dose versus higher doses.
Dr. Van Ness does not believe in giving high doses of folic acid because the B vitamin is involved with cell division, and recent studies suggest a risk of malignancy in children exposed to high doses in utero.
The study was supported by the Danish Epilepsy Association, the Central Denmark Region, the Novo Nordisk Foundation.
