Prenatal exposure to high doses of folic acid associated with increased cancer risk in children of mothers with epilepsy

1. The risk of cancer was higher among children of mothers with epilepsy who were exposed to high doses of folic acid in utero compared to controls in this retrospective study.

2. There was no association between maternal antiepileptic drug use and cancer risk.

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Study rundown: Patients with epilepsy are often warned about the possible teratogenic side effects of their medications. Common agents such as valproic acid and carbamazepine may cause neural tube defects in babies of mothers who take these prescribed medications. Next, women are advised to take high doses of folic acid before and during pregnancy to mitigate this risk. However, folic acid is known to interfere with DNA methylation, and it has recently been speculated that exposure to this factor in utero may be associated with an increased risk of cancer. The current study by Magne Vegrim et al. He sought to describe this relationship.

In all, 3,379,171 children were included in this study. Of this group 27,784 (0.8%) were born to mothers with epilepsy, 5934 (21.4%) of whom were exposed to high doses of folic acid in utero. Among the children of mothers without epilepsy, 46,646 (1.4%) were exposed to high doses of folic acid. The incidence of childhood cancer in children born to mothers with epilepsy who took high doses of folic acid was 42.5 per 100 000 person-years compared to 18.4 per 100 000 in those who were not exposed to high doses of folic acid.

The current study by Magne Vegrim et al. determined that there was an increased risk of childhood cancer in children of mothers with epilepsy who used high doses of folic acid during pregnancy. These findings require further investigation, although if confirmed, this information is likely to change current practices. The main drawback of this study is the inability to exclude confounding factors due to the retrospective study design. However, the study results are supported by the large sample size and large-scale data collection. Future studies should seek to address and rule out potential confounding effects and confirm these findings in an alternative setting.

Click here to read this study in JAMA Neurology

Related reading: Cancer risk with folic acid supplementation: a systematic review and meta-analysis

in depth [retrospective cohort]: A retrospective study was conducted in Denmark, Norway and Sweden using data from 1997-2017. The final study population included more than 3.3 million children. Prescription exposure data for either 1 or 5 mg of folic acid supplement during pregnancy have been verified. Outcome data on pediatric cancer diagnoses were obtained using the national cancer registry in each country. Finally, maternal epilepsy was assessed using diagnostic codes and/or a prescription of anticonvulsant medication prior to pregnancy. The following agents were the most commonly used antispasmodics: carbamazepine, lamotrigine, levetiracetam, and valproate.

The incidence of childhood cancer in maternal patients with epilepsy who used high doses of folic acid was 42.5 (95% confidence interval). [CI], 26.8-67.5) per 100,000 person-years and was 18.4 (95% CI, 12.8-26.5) per 100,000 person-years among children of mothers with epilepsy who were not exposed to folic acid. The adjusted hazard ratio for childhood cancer between these two groups was 2.7 (95% CI, 1.2-6.3). The absolute risk of developing cancer was 1.5% (95% CI, 0.5%-3.5%) in children of mothers with epilepsy who were exposed to high doses of folic acid. The absolute risk of cancer among children of women who took anti-seizure medication but did not use high-dose folic acid was 0.6% by comparison (95% CI, 0.2%-1.3%). These risk estimates were robust to sensitivity analyses, including excluding children with significant congenital or chromosomal abnormalities.

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