Efficacy of Periconceptional High-Dose Folic Acid in Isolated Orofacial Cleft Prevention: A Systematic Review

Abstract

Background The effectiveness of folic acid in prevention of neural tube defects has been well established. Periconceptional supplementation of folic acid in low doses has been shown to be effective in some studies on its efficacy in prevention of occurrence of clefts. There are few studies on high-dose folic acid for prevention of occurrence and recurrence of clefts in high risk cases and the overall consensus based on these is not available.

Objectives The aim of this review is to assess whether high-dose folic acid supplementation during the periconceptional period reduces the risk of occurrence of nonsyndromic clefts and recurrence in high-risk cases.

Search Methods Search was conducted in the various databases and trial registers. There were no restrictions in the search with regards to language, study setting, or date of publication.

Results The search yielded four studies—one randomized control trial, two prospective control trials, and a case–control surveillance on screening 401 articles. The three case–control studies were specifically on recurrence of clefts in high risk cases. The heterogeneity of the studies prevented conduction of a meta-analysis. But results of the studies demonstrate a strong association between high-dose folic acid and isolated nonsyndromic cleft lip with or without cleft palate (CL±CP). But such an effect is weak with regards to isolated cleft palate (CP).

Conclusions With the limited evidence available, our conclusion is that high-dose folic acid probably has a role in prevention of recurrence of isolated CL±CP in high-risk individuals, but not CP.

Keywords

periconception - high-dose folic acid - cleft lip - cleft palate

• References

• 1 Wehby GL, Ohsfeldt RL, Murray JC. Health professionals’ assessment of health-related quality of life values for oral clefting by age using a visual analogue scale method. Cleft Palate Craniofac J 2006; 43 (04) 383-391
• 2 Wehby GL, Cassell CH. The impact of orofacial clefts on quality of life and healthcare use and costs. Oral Dis 2010; 16 (01) 3-10
• 3 Stuppia L, Capogreco M, Marzo G. et al. Genetics of syndromic and nonsyndromic cleft lip and palate. J Craniofac Surg 2011; 22 (05) 1722-1726
• 4 Little J, Gilmour M, Mossey PA. et al. ITS MAGIC Collaboration. Folate and clefts of the lip and palate—a U.K.-based case-control study: Part II: Biochemical and genetic analysis. Cleft Palate Craniofac J 2008; 45 (04) 428-438
• 5 Shaw GM, Todoroff K, Finnell RH, Rozen R, Lammer EJ. Maternal vitamin use, infant C677T mutation in MTHFR, and isolated cleft palate risk. Am J Med Genet 1999; 85 (01) 84-85
• 6 Jugessur A, Wilcox AJ, Lie RT. et al. Exploring the effects of methylenetetrahydrofolate reductase gene variants C677T and A1298C on the risk of orofacial clefts in 261 Norwegian case-parent triads. Am J Epidemiol 2003; 157 (12) 1083-1091
• 7 Chevrier C, Perret C, Bahuau M. et al. Fetal and maternal MTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts. Am J Med Genet A 2007; 143A [phone]
• 8 MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338 (8760): 131-137
• 9 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 (7591): 464
• 10 Little J, Gilmour M, Mossey PA. et al. ITS MAGIC collaboration. Folate and clefts of the lip and palate—a U.K.-based case-control study: Part I: Dietary and supplemental folate. Cleft Palate Craniofac J 2008; 45 (04) 420-427
• 11 van Rooij IALM, Ocké MC, Straatman H, Zielhuis GA, Merkus HM, Steegers-Theunissen RP. Periconceptional folate intake by supplement and food reduces the risk of nonsyndromic cleft lip with or without cleft palate. Prev Med 2004; 39 (04) 689-694
• 12 De-Regil LM, Peña-Rosas JP, Fernández-Gaxiola AC, Rayco-Solon P. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2015; 2015 (12) CD007950
• 13 Jahanbin A, Shadkam E, Miri HH, Shirazi AS, Abtahi M. Maternal folic acid supplementation and the risk of oral clefts in offspring. J Craniofac Surg 2018; 29 (06) e534-e541
• 14 Czeizel AE, Dobó M, Vargha P. Hungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities. Birth Defects Res A Clin Mol Teratol 2004; 70 (11) 853-861
• 15 Czeizel AE. The primary prevention of birth defects: Multivitamins or folic acid?. Int J Med Sci 2004; 1 (01) 50-61
• 16 Johnson CY, Little J. Folate intake, markers of folate status and oral clefts: is the evidence converging?. Int J Epidemiol 2008; 37 (05) 1041-1058
• 17 Wehby GL, Félix TM, Goco N. et al. High dosage folic acid supplementation, oral cleft recurrence and fetal growth. Int J Environ Res Public Health 2013; 10 (02) 590-605
• 18 Tolarova M, Harris J. Reduced recurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology 1995; 51 (02) 71-78
• 19 Briggs RM. Vitamin supplementation as a possible factor in the incidence of cleft lip/palate deformities in humans. Clin Plast Surg 1976; 3 (04) 647-652
• 20 Czeizel AE, Tímár L, Sárközi A. Dose-dependent effect of folic acid on the prevention of orofacial clefts. Pediatrics 1999; 104 (06) e66
• 21 Bortolus R, Blom F, Filippini F. et al. Italian and Dutch folic acid trial study groups. Prevention of congenital malformations and other adverse pregnancy outcomes with 4.0 mg of folic acid: community-based randomized clinical trial in Italy and the Netherlands. BMC Pregnancy Childbirth 2014; 14 (01) 166
• 22 Peer LA, Gordon HW, Bernhard WG. Effects of vitamins on human teratology. Plast Reconstr Surg 1964; 34: 358-362