Rapid Responses to:

RESEARCH: Allen J Wilcox, Rolv Terje Lie, Kari Solvoll, Jack Taylor, D Robert McConnaughey, Frank Åbyholm, Hallvard Vindenes, Stein Emil Vollset, and Christian A Drevon Folic acid supplements and risk of facial clefts: national population based case-control study BMJ 2007; 334: 464 [Abstract] [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Data-driven post-hoc choices

Johannes C. van der Wouden, Tjerk Wiersma, Sten P. Willemsen   (22 March 2007)

Lack of evidence of a protective effect of folic acid against cleft lip.

Fionnuala Cooney   (21 October 2007)

The authors respond.

Allen J Wilcox, Rolv Terje Lie   (25 October 2007)

Data-driven post-hoc choices 22 March 2007
Johannes C. van der Wouden, senior lecturer Dept. of General Practice, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands, Tjerk Wiersma, Sten P. Willemsen Send response to journal: Re: Data-driven post-hoc choices	In the abstract of this paper, folic acid supplementation (at least 400 microgram/day) is reported to reduce the risk of isolated cleft lip with or without cleft palate, with a (statistically significant) adjusted odds ratio of 0.61.(1) This is misleading, because the reader would expect the comparator for this figure to be no supplementation. However, in the table, none of the adjusted risks do attain statistical significance, and the significance of the result in the abstract appears to have been constructed by combining the group using less than 400 micrograms of folic acid daily (and their surprisingly elevated adjusted odds ratio of 1.17!) with the group taking no folic acid at all, and contrasting this to the group using 400 micrograms or more. Surprisingly, the editorial by Bille et al (2) critiquelessly accepts this, resulting in a plea for strategies to implement worldwide implementation. In our view, the results of this study are flawed by data- driven post-hoc choices which do not allow such firm conclusions. 1. Wilcox AJ, Lie RT, Solvoll K, et al. Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ 2007; 334: 464-7. 2. Bille C, Murray JC, Olsen SF. Folic acid and birth malformations. BMJ 2007; 334: 433-4. Competing interests: None declared
Lack of evidence of a protective effect of folic acid against cleft lip. 21 October 2007
Fionnuala Cooney, SpR Public Health Medicine Public Health Department, HSE West, Ireland Send response to journal: Re: Lack of evidence of a protective effect of folic acid against cleft lip.	There is not enough evidence presented in this paper to support the assertion that folic acid supplementation in early pregnancy is protective against cleft lip. Despite this, the paper is being cited as providing such evidence. It has been correctly pointed out in a Rapid Response by Johannes C. van der Wouden, Tjerk Wiersma, Sten P. Willemsen (22 March 2007) that none of the adjusted ORs reported in the Results Section actually attain statistical significance. It is also clear from the Figure presented in the Results that of the eight different categories of women only one group attain a statistically significant reduction in odds, OR 0.36 (95% CI 0.17, 0.77), this being the category of expectant mothers who had taken at least 400 microgram of folic acid supplements/day in combination with multivitamins and had a dietary folate intake above the median. The three other categories of women who had all taken at least 400 microgram of folic acid supplements/day had ORs that did not attain statistical significance. Crucially, there is no report of a sample size calculation in this paper. Also there is an absence of any information on some of the known risk factors for cleft palate, such as family history of facial clefts, epilepsy or maternal intake of anti-convulsant medication in early preganancy. A more powerful study that incorporates data on the known risk factors is needed to fully answer this important question on the possible protective effect of folic acid on cleft lip. Competing interests: None declared
The authors respond. 25 October 2007
Allen J Wilcox, Senior Investigator NIEHS, Durham NC 27709, USA, Rolv Terje Lie Send response to journal: Re: The authors respond.	The two letter writers express concerns about our data describing a protective role of folic acid supplementation in cleft lip. Dr van der Wouden is correct that an adjusted odds ratio for the highest level of folic acid is not by itself statistically significant. However, it would be wrong to suggest that there is anything misleading in these analyses, which are fully laid out in the paper. Table 2 provides a complete breakdown of the crude and adjusted odds ratios for three levels of folic acid. The three crude estimates for the highest level of folic acid are strongly statistically significant, and statistical adjustment has little impact on the risk. The pooling of the two lower categories of folic acid was explicitly described and justified in the paper. Dr. Cooney asks about further adjustments for family history of clefts, epilepsy, and anti-convulsant medications. We did collect this information; there were few affected mothers, and these factors had no effect on our estimates. Regarding sample size, most experts agree that once a study is completed, confidence intervals are much better than crude sample size calculations in describing the power of the study. We are surprised that the letter writers focus on such small points and dismiss the bigger picture. If we take into account the supporting animal studies, the strengths of the present study design (constructed specifically to test the folic acid hypothesis), and the specificity of the folic acid association with cleft lip but not cleft palate (consistent with prior studies), there is a striking convergence of evidence to suggest that folic acid protects against cleft lip. This convergence seems worth taking seriously. Competing interests: None declared