Abstract
Background:
We investigated the association between supplemental folic acid in pregnancy and childhood cancer in a nation-wide study of 687 406 live births in Norway, 1999–2010, and 799 children diagnosed later with cancer.
Methods:
Adjusted hazard ratios (HRs) compared cancer risk in children by approximated periconceptional folic acid levels (folic acid tablets and multivitamins (0.6 mg), only folic acid (0.4 mg), only multivitamins (0.2 mg)) and cancer risk in unexposed.
Results:
Any folic acid levels were not associated with leukemia (e.g., high-level folic acid HR 1.25; 95% CI 0.89–1.76, PTrend 0.20), lymphoma (HR 0.96; 95% CI 0.42–2.21, PTrend 0.51), central nervous system tumours (HR 0.68; 95% CI 0.42–1.10, PTrend 0.32), neuroblastoma (HR 1.05; 95% CI 0.53–2.06, PTrend 0.85), Wilms' tumour (HR 1.16; 95% CI 0.52–2.58, PTrend 0.76), or soft-tissue tumours (HR 0.77; 95% CI 0.34–1.75, PTrend 0.90).
Conclusions:
Folic acid supplementation was not associated with risk of major childhood cancers.
Keywords: folic acid supplementation, pregnancy, childhood cancer, cohort study
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.
| Characteristics | Cohort (n) | Person-years | % | Cancer cases (n) |
|---|---|---|---|---|
| Children | 687 406 | 4 052 679 | 100 | 799 |
|
Sex | ||||
| Boys | 352 604 | 2 077 322 | 51 | 423 |
| Girls | 334 802 | 1 975 357 | 49 | 376 |
|
Gestational age (weeks) | ||||
| <37 | 46 682 | 271 770 | 7 | 60 |
| 37–41 | 587 197 | 3 447 416 | 85 | 670 |
| ⩾42 | 48 830 | 307 613 | 8 | 62 |
| Missing | 4697 | 25 881 | 1 | 7 |
|
Birth weight (g) | ||||
| <2500 | 33 804 | 191 809 | 5 | 39 |
| 2500–3999 | 516 075 | 3 008 163 | 74 | 587 |
| ⩾4000 | 136 760 | 847 264 | 21 | 173 |
| Missing | 767 | 5443 | 0 | 0 |
|
Birth order | ||||
| 1 | 284 468 | 1 651 442 | 41 | 339 |
| 2 | 244 834 | 1 446 964 | 36 | 281 |
| ⩾3 | 158 104 | 954 274 | 24 | 179 |
|
Maternal age at child birth, years | ||||
| <25 | 117 065 | 697 604 | 17 | 133 |
| 25–34 | 452 481 | 2 709 049 | 67 | 539 |
| ⩾35 | 117 860 | 646 026 | 16 | 127 |
|
Paternal age at child birth, years | ||||
| <25 | 52 776 | 312 202 | 8 | 65 |
| 25–34 | 396 496 | 2 406 027 | 59 | 468 |
| ⩾35 | 231 836 | 1 307 428 | 32 | 257 |
| Missing | 6298 | 27 023 | 1 | 9 |
|
Maternal educationa | ||||
| Compulsory | 128 452 | 782 418 | 19 | 148 |
| Intermediate | 232 745 | 1 475 123 | 36 | 288 |
| Tertiary | 299 871 | 1 662 622 | 41 | 340 |
| Missing | 26 338 | 132 516 | 3 | 23 |
|
Paternal educationa | ||||
| Compulsory | 129 537 | 779 208 | 19 | 142 |
| Intermediate | 301 918 | 1 842 424 | 45 | 373 |
| Tertiary | 227 910 | 1 297 762 | 32 | 251 |
| Missing | 28 041 | 133 286 | 3 | 33 |
|
Maternal smoking | ||||
| Did not smoke | 459 617 | 2 678 139 | 66 | 529 |
| Smoked sometimes | 17 222 | 106 380 | 3 | 15 |
| Smoked ⩽10 cigarettes daily | 69 270 | 455 935 | 11 | 103 |
| Smoked >10 cigarettes daily | 25 210 | 144 005 | 4 | 30 |
| Smoked daily, unknown amount | 5331 | 33 502 | 1 | 4 |
| Missing | 110 756 | 634 718 | 16 | 118 |
|
Maternal supplementationb | ||||
| No use | 325 706 | 2 307 683 | 57 | 424 |
| Multivitamins only | 46 598 | 309 597 | 8 | 61 |
| Folic acid only | 145 856 | 675 461 | 17 | 154 |
| Folic acid and multivitamin use | 169 246 | 759 938 | 19 | 160 |
Compulsory education length was 9 years until 1996 and 10 years from 1997 onwards.
Maternal supplement intake before and/or during pregnancy, categorised by folic acid content: No use; multivitamins (approximately 0.2 mg); folic acid supplements (0.4 mg); and folic acid and multivitamins (approximately 0.6 mg).
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.
| Cancer cases | % | |
|---|---|---|
|
Age at cancer diagnosis (years) | ||
| <2 | 326 | 41 |
| 2–3 | 211 | 26 |
| 4–5 | 150 | 19 |
| ⩾6 | 112 | 14 |
|
Year of cancer diagnosis | ||
| 1999–2001 | 59 | 7 |
| 2002–2004 | 172 | 22 |
| 2005–2007 | 239 | 30 |
| 2008–2010 | 329 | 41 |
|
Cancer types (ICCC-3) | ||
| I Leukemias, myeloproliferative diseases, and myelodysplastic diseases | 268 | 34 |
| Lymphoid leukemia | 208 | |
| Acute myeloid leukemias | 45 | |
| II Lymphomas and reticuloendothelial neoplasms | 42 | 5 |
| III CNS and miscellaneous intracranial and intraspinal neoplasms | 185 | 23 |
| Ependymoma | 26 | |
| Astrocytoma | 79 | |
| Intracranial and intraspinal embryonal tumours | 50 | |
| IV Neuroblastoma and other peripheral nervous cell tumours | 72 | 9 |
| Neuroblastoma and ganglioneuroblastoma | 71 | |
| VI Renal tumours | 53 | 7 |
| Wilms' tumour | 52 | |
| IX Soft tissue and other extraosseous sarcomas | 64 | 8 |
| Rhabdomyosarcoma | 24 | |
| Other specified soft tissue sarcomas | 28 | |
| Other cancers | 115 | 14 |
| Total | 799 | 100 |
Abbreviations: CNS=central nervous system; ICCC-3=International Classification of Childhood Cancer, third edition (Steliarova-Foucher et al, 2005).
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.
| Cancer types | Supplementsa | Cancer cases | HRb | 95% CI | PTrend |
|---|---|---|---|---|---|
| All cancers | No supplements | 424 | 1.00 | Reference | |
| Multivitamins only | 61 | 1.05 | 0.78–1.42 | ||
| Folic acid only | 154 | 1.13 | 0.92–1.38 | ||
| Folic acid and multivitamins | 160 | 1.02 | 0.83–1.25 | 0.60 | |
|
I Leukemias, myeloproliferative diseases, and myelodysplastic diseases | |||||
| No supplements | 135 | 1.00 | Reference | ||
| Multivitamins only | 21 | 1.23 | 0.75–2.01 | ||
| Folic acid only | 50 | 1.13 | 0.79–1.63 | ||
| Folic acid and multivitamins | 62 | 1.25 | 0.89–1.76 | 0.20 | |
| (a) Lymphoid leukemia | |||||
| No supplements | 100 | 1.00 | Reference | ||
| Multivitamins only | 16 | 1.30 | 0.75–2.27 | ||
| Folic acid only | 42 | 1.30 | 0.87–1.95 | ||
| Folic acid and multivitamins | 50 | 1.31 | 0.89–1.94 | 0.12 | |
| (b) Acute myeloid leukemia | |||||
| No supplements | 28 | 1.00 | Reference | ||
| Multivitamins only | 3 | 0.97 | 0.29–3.27 | ||
| Folic acid only | 5 | 0.59 | 0.22–1.60 | ||
| Folic acid and multivitamins | 9 | 0.96 | 0.43–2.17 | 0.67 | |
|
II Lymphomas and reticuloendothelial neoplasms | |||||
| No supplements | 25 | 1.00 | Reference | ||
| Multivitamins only | 3 | 0.55 | 0.13–2.33 | ||
| Folic acid only | 5 | 0.40 | 0.12–1.34 | ||
| Folic acid and multivitamins | 9 | 0.96 | 0.42–2.21 | 0.51 | |
|
III CNS and miscellaneous intracranial and intraspinal neoplasms | |||||
| No supplements | 107 | 1.00 | Reference | ||
| Multivitamins only | 14 | 1.08 | 0.60–1.94 | ||
| Folic acid only | 37 | 1.18 | 0.78–1.78 | ||
| Folic acid and multivitamins | 27 | 0.68 | 0.42–1.10 | 0.32 | |
| (b) Astrocytoma | |||||
| No supplements | 44 | 1.00 | Reference | ||
| Multivitamins only | 8 | 1.57 | 0.72–3.40 | ||
| Folic acid only | 15 | 1.31 | 0.70–2.45 | ||
| Folic acid and multivitamins | 12 | 0.86 | 0.43–1.73 | 0.97 | |
| (c) Intracranial and intraspinal embryonal tumours | |||||
| No supplements | 28 | 1.00 | Reference | ||
| Multivitamins only | 2 | 0.61 | 0.14–2.59 | ||
| Folic acid only | 12 | 1.28 | 0.60–2.76 | ||
| Folic acid and multivitamins | 8 | 0.69 | 0.27–1.74 | 0.69 | |
|
IV Neuroblastoma and other peripheral nervous cell tumours | |||||
| (a) Neuroblastoma and ganglioneuroblastoma | |||||
| No supplements | 37 | 1.00 | Reference | ||
| Multivitamins only | 5 | 0.99 | 0.35–2.82 | ||
| Folic acid only | 15 | 1.08 | 0.54–2.15 | ||
| Folic acid and multivitamins | 14 | 1.05 | 0.53–2.06 | 0.85 | |
|
VI Renal tumours | |||||
| (a) Wilms' tumour | |||||
| No supplements | 28 | 1.00 | Reference | ||
| Multivitamins only | 5 | 1.60 | 0.60–4.25 | ||
| Folic acid only | 9 | 1.01 | 0.42–2.40 | ||
| Folic acid and multivitamins | 10 | 1.16 | 0.52–2.58 | 0.76 | |
|
IX Soft tissue and other extraosseous sarcomas | |||||
| No supplements | 32 | 1.00 | Reference | ||
| Multivitamins only | 5 | 1.12 | 0.39–3.22 | ||
| Folic acid only | 18 | 1.72 | 0.90–3.29 | ||
| Folic acid and multivitamins | 9 | 0.77 | 0.34–1.75 | 0.90 | |
Abbreviation: CNS=central nervous system.
Maternal supplement intake before and/or during pregnancy, categorised by folic acid content: No use; multivitamins (approximately 0.2 mg); folic acid supplements (0.4 mg); and folic acid and multivitamins (approximately 0.6 mg).
Hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for birth order (1, 2, ⩾3), 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) comparing cancer risk in children exposed to periconceptional folic acid (multivitamins, folic acid, folic acid and multivitamins) and cancer risk in children without perigestational folic acid exposure (reference).
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.
Acknowledgments
This study was supported by the Norwegian Cancer Society and the Western Norway Regional Health Authority (911629) to Dr Nina Øyen.
The authors declare no conflict of interest.
Footnotes
This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License.
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