Investigators from multiple institutions conducted a retrospective study to assess the risk of cancer in children born to women with epilepsy who were prescribed high doses of folic acid during pregnancy to reduce the risk of congenital anomalies associated with exposure to anti-seizure medications (ASM).1 For the study, they reviewed national medical birth registries in Denmark (1997–2017), Norway (2005–2017), and Sweden (2006–2017). Personal individual numbers in these countries allowed linkage between birth registries and multiple health, pharmacy, cancer, and demographic databases. Study participants were children identified in the birth registries during the study periods. ICD-10 codes were used to identify children with cancer from birth until 2017 and to classify mothers as having epilepsy. Pharmacy databases were reviewed to abstract information on folic acid and ASM prescriptions beginning 90 days before pregnancy until birth. The primary outcome was diagnosis of cancer before the age of 20 years, and the exposure of interest was high-dose folic acid, defined as ≥1 prescription of ≥1 mg daily during pregnancy. Cox regression was used to compare the risk of cancer among children of mothers with epilepsy who received prescriptions for high-dose folic acid and those whose mothers with epilepsy didn’t receive high doses of folic acid. The model included multiple demographic characteristics, maternal conditions, other cancer risk factors, and prescriptions for ASM. The analysis was repeated in children of mothers without epilepsy. A secondary analysis limited to children of mothers with epilepsy who had ≥1 prescriptions for ASM during pregnancy also was performed.
Data on 3,379,171 children were analyzed, including 27,784 born to mothers with epilepsy. Median follow-up in study participants was 7.3 years. Among the mothers with epilepsy, 5,934 (21.4%) had prescriptions for high-dose folic acid, with a mean daily dose of 4.3 ±4.1 mg. The incidence rate (per 100,000 person years) was 42.5 (95% confidence interval [CI], 26.8, 67.5) in the children of these mothers vs 18.4 (95% CI, 12.8, 26.5) in those whose mothers with epilepsy were not prescribed high-dose folic acid (adjusted hazard ratio [aHR], 2.7; 95% CI, 1.2, 6.3). Among women without epilepsy, 46,646 were prescribed high-dose folic acid (mean daily dose 2.9 ±2.9 mg), but there was not an increased risk of cancer in their children compared to those of mothers not taking high doses (aHR, 1.1; 95% CI, 0.9, 1.4). When the analysis was limited to mothers with epilepsy who were prescribed ASM during pregnancy, the risk of cancer in children exposed to high-dose folic acid remained significantly increased (aHR, 3.0; 95% CI, 1.1, 7.9).
The authors conclude that prenatal exposure to high-dose folic acid in children of mothers with epilepsy was associated with an increased risk of childhood cancer.
Dr Doolittle has disclosed no financial relationship relevant to...