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14th October 2022
Could prenatal high-dose folic acid use among pregnant women prescribed anti-epileptic medication increase the risk of childhood cancer was the subject addressed in a recent observational study by a team of Norwegian researchers.
In a report from the International League Against Epilepsy Task Force on Women and Pregnancy, it was recommended that women of childbearing potential taking anti-epileptic drugs should be on at least 0.4 mg/day of folate.
Nevertheless, concerns have been expressed that the use of folic acid, particularly in association with vitamin B12 is associated with increased cancer outcomes and all-cause mortality in patients with ischaemic heart disease. Despite these findings, there is also evidence that maternal use of folate supplementation in pregnancy reduces the risk of common acute lymphoblastic leukaemia in the child.
As prenatal folate use is a recommendation in women prescribed anti-epileptic medication during pregnancy, it is uncertain whether the drug, especially prenatal high dose folic acid (i.e., > 1 mg daily) impacts on the incidence of childhood cancer.
For the present study, the Norwegian researchers undertook an observational study in the Nordic countries between 1997 and 2107 and looked at pregnant women who were prescribed a range of anti-epileptic medicines and who also used folic acid. They turned to data collected as part of the Nordic Register-Based Study of Anti-epileptic Drugs in Pregnancy (SCAN-AED) collaboration project. For the purposes of the study, prenatal high-dose folic acid use was defined as at least 1 filled prescription of either 1 mg or 5 mg folic supplementation between 90 days before the first day of the last menstrual period and birth. To identify cases of childhood cancer, they used data held in a national cancer registry and in their analysis, they also adjusted for covariates known to be risk factors for childhood cancer.
Prenatal high-dose folic acid and childhood cancers
A total of 3,379,171 children were included in the analysis with 27784 were born to mother with epilepsy. These children were followed for a median of 7.3 years.
Overall, 21.4% of children had been exposed to prenatal high-dose folic acid. The incidence of cancer in children whose mothers had taken high-dose folic acid was 42.5 per 100,000 person-years compared to 18.4 per 100,000 person-years in mothers who did not take prenatal high-dose folic acid. This translated into a higher risk of cancer compared to the children of mothers with epilepsy not exposed to high-dose folic acid (adjusted hazard ratio, aHR = 2.7, 95% CI 1.2 – 6.3).
In a separate analysis, among epileptic mothers who continued with anti-epileptic medication and prenatal high-dose folic acid, the risk of childhood cancer was three-times higher than those who did not use high-dose folic acid (aHR = 3.0, 95% CI 1.1 – 7.9). Moreover, there was no association between childhood cancer risk among epileptic mothers prenatally exposed to anti-epileptic medicines but not folic acid (absolute risk = 0.6%, 95% CI 0.20 – 1.3%).
The authors concluded that there was an association between an increased childhood cancer risk and epileptic maternal use of high-dose folic acid.
Vegrim HM et al. Cancer Risk in Children of Mothers With Epilepsy and High-Dose Folic Acid Use During Pregnancy JAMA Neurol 2022