High Dosage Folic Acid Supplementation, Oral Cleft Recurrence and Fetal Growth

Abstract

Objectives: To evaluate the effects of folic acid supplementation on isolated oral cleft recurrence and fetal growth. Patients and Methods: The study included 2,508 women who were at-risk for oral cleft recurrence and randomized into two folic acid supplementation groups: 0.4 and 4 mg per day before pregnancy and throughout the first trimester. The infant outcome data were based on 234 live births. In addition to oral cleft recurrence, several secondary outcomes were compared between the two folic acid groups. Cleft recurrence rates were also compared to historic recurrence rates. Results: The oral cleft recurrence rates were 2.9% and 2.5% in the 0.4 and 4 mg groups, respectively. The recurrence rates in the two folic acid groups both separately and combined were significantly different from the 6.3% historic recurrence rate post the folic acid fortification program for this population (p = 0.0009 when combining the two folic acid groups). The rate of cleft lip with palate recurrence was 2.9% in the 0.4 mg group and 0.8% in the 4 mg group. There were no elevated fetal growth complications in the 4 mg group compared to the 0.4 mg group. Conclusions: The study is the first double-blinded randomized clinical trial (RCT) to study the effect of high dosage folic acid supplementation on isolated oral cleft recurrence. The recurrence rates were similar between the two folic acid groups. However, the results are suggestive of a decrease in oral cleft recurrence compared to the historic recurrence rate. A RCT is still needed to identify the effect of folic acid on oral cleft recurrence given these suggestive results and the supportive results from previous interventional and observational studies, and the study offers suggestions for such future studies. The results also suggest that high dosage folic acid does not compromise fetal growth.

Folic Acid Fortification and Women’s Folate Levels in Selected Communities in Brazil - A First Look

“…The OCPP was a randomized clinical trial aimed at assessing the effect of 4 mg versus 0.4 mg folic acid, taken daily during preconception and the first trimester of pregnancy, on oral cleft recurrence among women who themselves have or have had a child with an oral cleft without other birth defects [17, 21, 22]. The women included in our study were enrolled into the OCPP between January 29, 2004 and April 27, 2005, which covers the period before and after initiating the fortification program in Brazil.…”

“…In the state of Sao Paulo (where our study sample resides as explained below), NTD prevalence declined by 35% among live births [16]. Folic acid has been suggested to play a role in preventing other birth defects such as oral clefts [17], but the evidence for such effects remains controversial.…”

Maternal Intake of Folic Acid Supplementation and Non- syndromic Orofacial Clefts Risk: Systematic Review and Meta Analysis.

“…A randomized control trial found no difference in the recurrence rates of orofacial clefts among two groups of women assigned to high dose (4mg) and low dose (0.4mg) of folic acid intake, suggesting that potential ineffectiveness of the higher dose was possibly ineffective in further reducing recurrence of orofacial clefts relative to the lower dose [30] Limitations:-Our results were limited by relatively few number of studies included in the meta analysis (6 studies) which might affect the statistical power for estimating the combined effect.…”

“…A meta-analysis of studies that examined the association of fortification with orofacial clefts among the populations in United States and Canada have shown a reduction of about 7% of cleft lip and palate [30].…”

Estudo clínico e molecular em pacientes com fissuras orais para avaliação do efeito fenotípico de variantes do IRF6 e estimativa da contribuição genética nas fissuras palatinas

“…Até a presente data, além do IRF6, os loci mais corroborados como implicados na etiologia das FL±PNS foram a região 8q24.21 um deserto gênico inequivocamente implicado em suscetibilidade a FL±PNS e a região 10q25.3 (BIRNBAUN et al , 2009a, MANGOLD et al , 2009 (WEHBY & MURRAY, 2010;WEHBY et al , 2013). No entanto, os resultados dos estudos sobre programas de fortificação de alimentos com ácido fólico permanecem controversos (LOPEZ-CAMELO et al , 2010).…”