High-dose folic acid use and cancer risk in women who have given birth: A register-based cohort study

Objective

This study was undertaken to study whether high-dose folic acid (>1 mg daily) use is associated with an increased risk of cancer in all women who have given birth and in women with epilepsy. High-dose folic acid supplementation during pregnancy has been linked to increased cancer risk in children born to mothers with epilepsy.

Methods

We identified women with their first pregnancy in Denmark (1997–2017), Norway (2005–2017), and Sweden (2006–2017) using medical birth registers, linking individual data across nationwide health registers and statistical agencies. Exposure was defined as filled prescriptions for high-dose folic acid, considered time-varyingly. The primary outcome was the first malignant cancer diagnosis. Hazard ratios (HRs) of cancer after high-dose folic acid exposure were estimated using Cox proportional hazard models with 95% confidence intervals (CIs), adjusted for confounders including antiseizure medication (ASM) use, and stratified by maternal epilepsy diagnosis. A 6-month time lag was applied, as cancer is unlikely to develop immediately.

Results

With up to 21 years of follow-up, we identified 1 465 785 women who gave birth, including 64 485 (4.4%) exposed to high-dose folic acid. In the exposed group, 755 cancer cases were observed (208 per 100 000 person-years, 95% CI = 193.8–223.5), compared with 18 702 cases in the unexposed group (164 per 100 000 person-years, 95% CI = 161.5–166.2), yielding a 20% increased cancer risk overall (adjusted HR = 1.2, 95% CI = 1.1–1.2). This risk was attenuated after the 6-month lag analysis (adjusted HR = 1.1, 95% CI = 1.04–1.2). The risk for non-Hodgkin lymphoma was increased in all analyses (n = 28, adjusted HR = 2.0, 95% CI = 1.3–2.9). The association between high-dose folic acid use and overall cancer risk was similar in those with epilepsy regardless of ASM use (adjusted HR = 1.3, 95% CI = 1.0–1.8).

Significance

High-dose folic acid use was associated with increased overall cancer risk in women who have given birth, with a consistent association with non-Hodgkin lymphoma, including those with epilepsy, regardless of ASM use.