Department of Clinical Medicine, University of Bergen, Bergen, Norway.
National Centre for Register-Based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark.
JAMA Neurol. 2022 Nov 1;79(11):1130-1138. doi: 10.1001/jamaneurol.2022.2977.
Women with epilepsy are recommended high doses of folic acid before and during pregnancy owing to risk of congenital anomalies associated with antiseizure medications. Whether prenatal exposure to high-dose folic acid is associated with increases in the risk of childhood cancer is unknown.
To assess whether high-dose folic acid supplementation in mothers with epilepsy is associated with childhood cancer.
DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study conducted with nationwide registers in Denmark, Norway, and Sweden from 1997 to 2017. Analyses were performed during January 10, 2022, to January 31, 2022. Mother-child pairs were identified in medical birth registers and linked with information from patient, prescription, and cancer registers, as well as with sociodemographic information from statistical agencies, and were categorized by maternal diagnosis of epilepsy. The study population consisted of 3 379 171 children after exclusion of 126 711 children because of stillbirth or missing or erroneous values on important covariates.
Maternal prescription fills for high-dose folic acid tablets (≥1 mg daily) between 90 days before pregnancy start and birth.
First onset of childhood cancer at younger than 20 years. Cox proportional hazards models were used to calculate adjusted hazard ratios with corresponding 95% CIs, adjusted for potential confounders. Cumulative incidence at aged 20 years was used as a measure of absolute risk.
The median age at the end of follow-up in the study population of 3 379 171 children was 7.3 years (IQR, 3.5-10.9 years). Among the 27 784 children (51.4% male) born to mothers with epilepsy, 5934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with 18 exposed cancer cases compared with 29 unexposed, producing an adjusted hazard ratio of 2.7 (95% CI, 1.2-6.3), absolute risk if exposed of 1.4% (95% CI, 0.5%-3.6%), and absolute risk if unexposed of 0.6% (95% CI, 0.3%-1.1%). In children of mothers without epilepsy, 46 646 (1.4%) were exposed to high-dose folic acid (mean dose, 2.9 mg), with 69 exposed and 4927 unexposed cancer cases and an adjusted hazard ratio of 1.1 (95% CI, 0.9-1.4; absolute risk, 0.4% [95% CI, 0.3%-0.5%]). There was no association between children born to mothers with epilepsy who were prenatally exposed to antiseizure medications, but not high-dose folic acid, and an increased risk of cancer (absolute risk, 0.6%; 95% CI, 0.2%-1.3%).
Prenatal exposure to high-dose folic acid was associated with increased risk of cancer in children of mothers with epilepsy.
由于抗癫痫药物与先天畸形相关，建议患有癫痫的女性在怀孕前和怀孕期间服用大剂量叶酸。然而，目前尚不清楚产前暴露于高剂量叶酸是否会增加儿童癌症的风险。
评估母亲在癫痫发作期间补充高剂量叶酸是否与儿童癌症有关。
设计、地点和参与者：在丹麦、挪威和瑞典的全国登记处进行的观察性队列研究，时间为 1997 年至 2017 年。分析于 2022 年 1 月 10 日至 1 月 31 日进行。在医疗出生登记处识别母婴对，并与来自患者、处方和癌症登记处的信息以及来自统计机构的社会人口学信息进行关联，根据母亲的癫痫诊断对其进行分类。研究人群包括 3379171 名儿童，排除了 126711 名因死产或重要协变量缺失或错误而不符合条件的儿童。
母亲在怀孕开始前 90 天至出生期间服用高剂量叶酸片（≥1 毫克/天）的处方记录。
20 岁前首次发生儿童癌症。使用 Cox 比例风险模型计算调整后的危险比及其相应的 95%置信区间，调整了潜在混杂因素。20 岁时的累积发病率作为绝对风险的衡量标准。
在 3379171 名儿童的研究人群中，中位随访结束时的年龄为 7.3 岁（IQR，3.5-10.9 岁）。在 27784 名（51.4%为男性）患有癫痫的儿童中，有 5934 名（21.4%）暴露于高剂量叶酸（平均剂量 4.3 毫克），18 名暴露于癌症病例，而 29 名未暴露于癌症，调整后的危险比为 2.7（95%CI，1.2-6.3），如果暴露，绝对风险为 1.4%（95%CI，0.5%-3.6%），如果未暴露，绝对风险为 0.6%（95%CI，0.3%-1.1%）。在没有癫痫的母亲所生的儿童中，有 46646 名（1.4%）暴露于高剂量叶酸（平均剂量 2.9 毫克），其中 69 名暴露，4927 名未暴露癌症病例，调整后的危险比为 1.1（95%CI，0.9-1.4；绝对风险，0.4%[95%CI，0.3%-0.5%]）。在产前暴露于抗癫痫药物但未暴露于高剂量叶酸的癫痫母亲所生的儿童中，癌症风险并未增加（绝对风险，0.6%；95%CI，0.2%-1.3%）。
产前暴露于高剂量叶酸与癫痫母亲所生儿童癌症风险增加有关。
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