Folic acid supplements and risk of facial clefts: national population based case-control studyBMJ 2007; 334 doi: https://doi.org/10.1136/bmj.39079.618287.0B (Published 01 March 2007) Cite this as: BMJ 2007;334:464
- Allen J Wilcox, senior investigator1,
- Rolv Terje Lie, professor2,
- Kari Solvoll, retired3,
- Jack Taylor, senior investigator1,
- D Robert McConnaughey, senior programmer4,
- Frank Åbyholm, professor5,
- Hallvard Vindenes, consultant plastic surgeon6,
- Stein Emil Vollset, professor2,
- Christian A Drevon, professor3
- 1Epidemiology Branch, National Institute of Environmental Health Sciences/NIH, Durham, NC 27709, USA
- 2Department of Public Health and Primary Health Care, Section for Epidemiology and Medical Statistics, University of Bergen, Norway
- 3Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
- 4WESTAT, Durham, NC
- 5Department of Plastic Surgery, Rikshospitalet, Oslo
- 6Department of Plastic Surgery, Haukeland University Hospital, Bergen
- Correspondence to: A J Wilcox
- Accepted 18 December 2006
Objective To explore the role of folic acid supplements, dietary folates, and multivitamins in the prevention of facial clefts.
Design National population based case-control study.
Setting Infants born 1996-2001 in Norway.
Participants 377 infants with cleft lip with or without cleft palate; 196 infants with cleft palate alone; 763 controls.
Main outcome measures Association of facial clefts with maternal intake of folic acid supplements, multivitamins, and folates in diet.
Results Folic acid supplementation during early pregnancy (≥400 µg/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96). Independent of supplements, diets rich in fruits, vegetables, and other high folate containing foods reduced the risk somewhat (adjusted odds ratio 0.75, 0.50 to 1.11). The lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins (0.36, 0.17 to 0.77). Folic acid provided no protection against cleft palate alone (1.07, 0.56 to 2.03).
Conclusions Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third. Other vitamins and dietary factors may provide additional benefit.
We are indebted to the dedicated staff who did the fieldwork for this study (Maria Acuero, Nina Hovland, Aase Gunn Mjaatvedt, Gunnar Åmlid, and Lil Stallone). We thank Donna Baird, Olga Basso, Freya Kamel, Matthew Longnecker, Ron Munger, Ruby Nguyen, Dale Sandler, Min Shi, and Clarice Weinberg for useful criticisms of earlier drafts of this paper.
Contributors: All authors made substantial contributions to the intellectual content of the manuscript and all have approved the final version. AJW originated the study, designed the field work, analysed the data, contributed critical insights in interpretation of data, and had primary responsibility for writing the paper. RTL originated the study, designed and supervised the field work, helped in analysis of data, and contributed critical insights in interpretation of data. KS contributed to the design of the field study, supervised the scanning and interpretation of the food frequency questionnaire, and participated in the interpretation of data. JT contributed substantially to the design of the field study. DRMcC made substantial contributions to the cleaning of the data, did the programming for data analysis, and contributed critical insights in interpretation. FÅ contributed to the design of the field study, provided clinical access to cases, and contributed critical insights in interpretation of data. HV contributed to the design of the field study, provided clinical access to cases, and contributed critical insights in interpretation of data. SEV contributed to the design of the field study and participated in the interpretation of data. CAD contributed to the design of the field study, designed the food frequency questionnaire, and participated in the interpretation of data. AJW is the guarantor.
Funding: Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (NIEHS), the Johan Throne Holst Foundation for Nutrition Research, and the Thematic Area of Perinatal Nutrition at the Medical Faculty of University of Oslo, Norway.
Competing interests: None declared.
Ethical approval: Norwegian Data Inspectorate and Regional Medical Ethics Committee of Western Norway.
- Accepted 18 December 2006