High-dose folic acid and cancer risk; unjustified concerns by von Wrede and colleagues regarding our paper.

Women using antiseizure medication in pregnancy are often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that have emerged.

Cancer Risk in Children of Mothers With Epilepsy and High-Dose Folic Acid Use During Pregnancy.

Importance: 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. Objective: 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. Exposures: Maternal prescription fills for high-dose folic acid tablets (≥1 mg daily) between 90 days before pregnancy start and birth. Main Outcomes and Measures: 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. Results: 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%). Conclusions and Relevance: Prenatal exposure to high-dose folic acid was associated with increased risk of cancer in children of mothers with epilepsy.

Sociodemographic predictors are associated with compliance to a vaccination-reminder in 9692 girls age 14, Denmark 2014-2015.

We aimed to identify sociodemographic predictors of compliance after receiving a personalised reminder on lacking vaccinations against MMR (Measles, Mumps, Rubella) and/or HPV (Human Papilloma Virus) among parents of Danish adolescent girls. A nationwide register-based study, including all 14-year-old girls (15 May 2014-14 May 2015) lacking either MMR, HPV-vaccination or both. Vaccination-compliance following a postal reminder was modelled using multivariable logistic regression and included the following socio-demographic predictors: maternal age, education, employment and ethnicity. Birth order, number of siblings, family-structure, location of residence, and household income. The parents of 9692 girls received a reminder. Out of 4940 exclusively lacking an HPV-vaccine, 15.3% were subsequently vaccinated. Among 2026 only lacking an MMR vaccination, 8.5% were vaccinated. Among 2726 girls lacking both, 5% received an HPV, 4.4% an MMR and 5.4% received both vaccinations. We identified sociodemographic differences between reminderletter-compliers and non-compliers, also according to vaccination types. Non-western descendants were more likely to receive HPV-vaccination, although the association was only significant for those who only lacked HPV (OR 2.02, 95% 1.57-2.59). For girls only lacking an MMR, regional differences were identified. Among girls lacking both vaccines, girls of mothers with intermediate (OR 0.63, 0.42-0.95) or basic education (OR 0.43, 0.24-0.75) were less likely to be vaccinated compared to girls of higher educated mothers. Reminders were in particular effective in increasing HPV uptake among immigrants of non-Western ethnicity. We found reminders to be less effective among less educated mothers whose daughters lacked both vaccines. To increase the coverage in this group, additional interventions are needed.

Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring.

BACKGROUND AND OBJECTIVE: Fever during pregnancy has been suspected to harm the developing fetus. However, until now, no systematic analysis of the available evidence has been undertaken to assess the impact of maternal fever on health outcomes in the child. The goal of this study was to systematically review evidence from epidemiologic studies on adverse health outcomes of the offspring in relation to exposure to maternal fever during pregnancy. METHODS: Systematic searches in PubMed, Web of Science, and the Cochrane Library were performed by using Medical Subject Headings, Boolean operators, and truncation, and references of references were reviewed. Cohort and case-control studies addressing health outcomes of prenatal fever exposure in humans were eligible for inclusion. Studies with no direct reference to fever, studies in selected populations (eg, preterm births), and studies published before 1990 were excluded. RESULTS: The available literature supported an increased risk of adverse offspring health in association with fever during pregnancy. The strongest evidence was available for neural tube defects, congenital heart defects, and oral clefts, in which meta-analyses suggested between a 1.5- and nearly 3-fold increased risk with fever exposure in the first trimester. We did not find strong evidence of a dose-response relationship, but there was some evidence that antipyretic medications may have a protective effect when used in relation to febrile episodes. CONCLUSIONS: We found substantial evidence to support the contention that maternal fever during pregnancy may negatively affect offspring health. The harmful effects seemed to cover both short- and longer-term health outcomes; however, for several outcomes, the evidence was insufficient to judge any association.