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Health authorities in many countries recommend women planning pregnancy to take folic acid before and during pregnancy to reduce offspring risk of neural tube defects (SACN, 2006). A large number of countries also fortify flour with folic acid (CDC, 2008). Mandatory food fortification with folic acid is debated in some countries because of the suggested cancer risk in adults (Kim, 2004; Mason et al, 2007; Smith et al, 2008). However, in case–control studies on children, cancer risks (leukemia, brain tumours) were reduced if the mother had been exposed to perigestational maternal folic acid supplementation (Thompson et al, 2001; Milne et al, 2010; Milne et al, 2012; Metayer et al, 2014). And, in ecological studies from Canada and the United States of America, the childhood cancer incidence (Wilms’ tumour, primitive neuroectodermal tumours, neuroblastoma) has been reduced after mandatory folic acid flour fortification (French et al, 2003; Grupp et al, 2011; Linabery et al, 2012).

The aim of our study was to investigate the association between maternal intake of folic acid supplementation in pregnancy and offspring risk of childhood cancer in a nation-wide cohort study in Norway.

Materials and methods

Data sources

The unique personal identification number assigned to all Norwegian residents enabled linkage of information between the Medical Birth Registry of Norway (MBRN) (Irgens, 2000), the Cancer Registry of Norway (CRN) (Larsen et al, 2009), and the Norwegian National Education Database that holds information on all individuals’ education (Kinge et al, 2015).

Folic acid and multivitamin supplementation exposure

Folic acid and multivitamin supplementation use has been registered in the MBRN since December 1998. The registration form uses check boxes with the items ‘folic acid before pregnancy’, ‘folic acid during pregnancy’, ‘multivitamins before pregnancy’, and ‘multivitamins during pregnancy’. During the study period, the folic acid content was 0.4 mg in folic acid supplements and approximately 0.2 mg in multivitamin supplements. Children were defined as exposed to folic acid if their mothers used folic acid supplements and/or multivitamins before and/or during pregnancy. Maternal folic acid intake was categorised by increasing folic acid content; no supplement use (0 mg), only multivitamins (approximately 0.2 mg), only folic acid supplements (0.4 mg), or intake of both folic acid supplements and multivitamins (approximately 0.6 mg).

Childhood cancer

Childhood cancer cases were identified through linkage with CRN. For each child, the first cancer diagnosis was used. The childhood cancers were categorised according to the International Classification of Childhood Cancer, version 3, which is based on ICD-O-3 (Steliarova-Foucher et al, 2005).

Study cohort

The study cohort consisted of all live births in Norway, 1 January 1999 through 31 December 2010 (excluding children with mothers with a prebirth cancer diagnosis (3371)), with follow-up until a cancer diagnosis, emigration, death, or 31 December 2010.

Statistical analysis

Risk of childhood cancers in children exposed to maternal folic acid and/or multivitamin supplements was compared with cancer risk in unexposed children and estimated with hazard ratios (HRs) using Cox proportional hazards regression models with time since birth as the time variable, adjusting for a priori selected covariates associated with maternal folic acid use and childhood cancer risk; that is, birth order (1, 2, ⩾3), maternal smoking (never, sometimes, ⩽10 cigarettes daily, >10 cigarettes daily, daily smoking of unknown amount), maternal and paternal age (<25, 25–34, ⩾35 years), and maternal and paternal education (compulsory, intermediate, tertiary). P-values for linear trend were calculated for folic acid exposure levels (0 mg, 0.2 mg, 0.4 mg, 0.6 mg). Statistical analyses were performed in STATA version 14 (STATA, 2015).

Ethics

The Regional Committee for Medical and Health Research Ethics of Western Norway approved the study.

Results

Among 687 406 children included in the study, 799 developed cancer. The mean follow-up time was 6 years (range 0.04–12 years), constituting 4 052 679 person-years (Table 1). Among all births, 4% were multiple births, and 2% were born after assisted reproductive technology. Mean maternal age at childbirth was 29 years (range 13–55 years). The proportion of children exposed to perigestational supplementation increased in the study period, 1999–2010; intake of folic acid changed from 18% to 69% and multivitamins from 19% to 42%.

Table 1 Characteristics of the study population of 687 406 live births, Norway, 1999–2010
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About 67% of all cancers were diagnosed within the first 3 years of life (Table 2). Leukemia and central nervous system (CNS) tumours accounted for 57% of the cases. We performed analyses for the six most frequent childhood cancer types (leukemia, lymphoma, CNS tumours, neuroblastoma, Wilms’ tumour, soft tissue tumours) (Table 3). There was no change in childhood leukemia risk by maternal use of multivitamins only (HR 1.23; 95% CI 0.75–2.01), folic acid use only (HR 1.13; 95% CI 0.79–1.63), or combined folic acid and multivitamin use (HR 1.25; 95% CI 0.89–1.76), as compared with no supplement use (PTrend 0.20). Similarly, there were no associations between CNS tumours and different levels of maternal folic acid intake; multivitamins only (HR 1.08; 95% CI 0.60–1.94), folic acid use only (HR 1.18; 95% CI 0.78–1.78), or combined folic acid and multivitamin use (HR 0.68; 95% CI 0.42–1.10), as compared with no supplement use (PTrend 0.32). The HRs of the other frequent childhood cancer types (lymphoma, neuroblastoma, Wilms’ tumour, soft tissue tumours) did not change for different levels of folic acid exposure. Adding birth year to adjustment models showed no substantial changes in the risk estimates for neither cancer types. And excluding 867 children with Down syndrome from the analyses did not change the HR estimates for specific cancers.

Table 2 Children with first-time childhood cancer (n=799) by age at diagnosis, year of diagnosis, and major cancer types (ICCC-3), identified among 687 406 livebirths, Norway, 1999–2010
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Table 3 Hazard ratios (HRs) with 95% confidence intervals (95% CI) of childhood cancer by perigestational supplementation of folic acid and/or multivitamins, among 687 406 children, Norway, 1999–2010
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Discussion

In a nation-wide cohort study of all live births, estimated maternal intakes of multivitamins, folic acid, or combined intake of these supplements were not associated with childhood cancer.

Our results of no association between periconceptional folic acid supplementation and major childhood cancers are in discordance with case–control studies showing inverse associations between self-reported folic acid use and acute lymphoblastic leukemia (ALL) (Thompson et al, 2001; Milne et al, 2010; Metayer et al, 2014) and CNS tumours (Milne et al, 2012).

A recent large international collaborating study, including >7000 children with acute leukemia and 11 000 controls, found reduced risks of ALL and acute myeloid leukemia (AML) after maternal intake of folic acid supplements. And these reduced risks of ALL and AML did not vary by timing of the supplementation exposure (preconception, pregnancy, or pregnancy trimester) (Metayer et al, 2014). However, an Australian study found weak evidence of a reduced risk of ALL from folate supplementation before pregnancy, but no reduced risk from use during pregnancy (Milne et al, 2010). Also, another Australian study reported on an inverse association of childhood brain tumours and folic acid supplementation before and possibly also during pregnancy (Milne et al, 2012). In our study, a further stratification of the exposure data into preconceptional use and use during pregnancy was not feasable due to the limited statistical power of the analyses.

The strengths of our study include using comprehensive data from population-based registries covering the entire Norwegian population. To our knowledge, Norway is the only country where individual-level information on periconceptional folic acid and multivitamin intake has been collected for the entire birth population since 1999. All incident cancer cases have been reported to the Cancer Registry of Norway since 1952 (Larsen et al, 2009). And information on supplement use was collected before cancer diagnosis precluding recall bias.

The study had some limitations. Even though our cohort was large, the numbers of several childhood cancer types were relatively low, which may limit the statistical power of our findings. The follow-up time of study participants were on average 6 years, and our results could only be generalised to younger children. Maternal folic acid intake could have been misclassified; in the beginning of the study period, folic acid users were under-reported to the MBRN (Nilsen et al, 2009). A possible misclassification of folic acid dose (independent of cancer risk) would bias risk estimates towards the null value and, in theory, could have concealed an association between folic acid intake and childhood cancer risk. Information on maternal smoking was missing for 16% of the births; however, HR estimates adjusting for maternal smoking were similar to HRs without smoking adjustments. Although we did not have information on dietary folate, residual confounding by dietary folate is less likely. In pregnant women, maternal plasma levels of serum folate is strongly related to intake of folic acid supplements (Bjorke-Monsen et al, 2013). And in other studies of maternal intake of folic acid supplements and offspring outcomes (oral clefts, autism), adjustment for dietary folate did not change overall risk estimates (Wilcox et al, 2007; Suren et al, 2013). We could not adjust for mother’s weight and height, physical activity, diet, use of alcohol, or use of contraceptive pills, as these covariates were not available in the MBRN.

In conclusion, we found no association between maternal supplemental folic acid intake before and/or during pregnancy and risk of leukemia, lymphomas, CNS tumours, neuroblastoma, Wilms’ tumour, or soft tissue tumours among younger children.