Dose-dependent Effect of Folic Acid on the Prevention of Orofacial Clefts

Abstract

ABSTRACT. Objective. In 1982, Tolarova 4 found a reduction in the recurrence rate of isolated cleft lip (CL) with or without cleft palate (CP; CL ؎ CP) after periconceptional supplementation with a multivitamin including a very high dose (10 mg) of folic acid. The Hungarian randomized, double-blind, controlled trial of periconceptional supplementation with a multivitamin including a physiologic dose (.8 mg) of folic acid did not show any preventive effect on the first occurrence of isolated CL ؎ CP and CP. However, the general evaluation of congenital abnormalities in the Hungarian Case-Control Surveillance of Congenital Abnormalities indicated, among others, a reduction of isolated CL ؎ CP and CP after the use of high doses of folic acid in the critical period for the development of these congenital abnormalities in the 12-year dataset between 1980 and 1991. We hypothesized that the prevention of orofacial clefts by folic acid has a dose-dependent effect, and this hypothesis was tested in 2 recent Hungarian datasets.Design. In a prospective cohort study, the occurrence of isolated CL ؎ CP and CP was studied in the newborn infants born to mothers with or without periconceptional folic acid-containing (.8 mg) multivitamin supplementation. Supplemented women with confirmed pregnancy were recruited from the participants of the periconceptional service. Unsupplemented women were invited to take part in the study after the first visit between the 8th and 12th week of gestation in the antenatal care. Supplemented and unsupplemented women were matched based on age, socioeconomic status, and residence. In contrast, the occurrence of high-dose (in general daily 6 mg) folic acid supplementation was evaluated in the case-control pairs of CL ؎ CP and CP, particularly during the critical period of these 2 types of orofacial clefts in the 17 years dataset of the Case-Control Surveillance of Congenital Abnormalities, between 1980 and 1996. Cases were selected from the population-based Hungarian Congenital Abnormality Registry, whereas population controls without congenital abnormality were ascertained from the national birth registry. Two population controls were matched to every case according to sex, week of birth, and district of parental residence. The drug uses, including pregnancy supplements as folic acid, were evaluated based on retrospective self-reported maternal questionnaire and prospective medically documented data of antenatal care logbook.Results. In the prospective cohort study, of 3019 informative offspring (termination of pregnancies in the second and third trimesters because of fetal defect, stillborn fetuses, and liveborn infants) in the supplemented group, 3 had CL ؎ CP and 1 was affected with CP, whereas of 3432 informative offspring in the unsupplemented group, 2 had CL ؎ CP and 1 had CP. The lack of preventive effect was in agreement with the result of the previous Hungarian randomized double-blind controlled trial; thus, these 2 datasets were combined. The preventive effect of a folic acid containing m...

Orofacial Clefts: A Worldwide Review of the Problem

“…Several studies have reported decreased rates of cleft lip and palate with folic acid use [82][83][84][85]. Some ambiguity of the studies may be explained by a recent study that found that oral cleft risk can be reduced only by high doses of folic acid consumed at the time of lip and palate formation [86]. Maternal multivitamin use has also been found to result in a significant reduction in cleft palate risk and a nonsignificant reduction in cleft lip risk [87].…”

Folate modulates Hox gene‐controlled skeletal phenotypes

“…Folate deficiency has long been recognized as an important contributor to susceptibility for birth defects (Lewis et al, 1998;Lucock, 2000) and epidemiological studies have demonstrated a beneficial effect of folate supplementation on prevention of birth defects (Berry and Li, 2002;Czeizel et al, 1999;Molloy and Scott, 2001;Ray et al, 2002). These studies have focused on neural tube defects and craniofacial abnormalities, due to their ease of detection at birth and visual ascertainment criteria (Berry and Li, 2002).…”

Pregnancy in epileptic patients: comparison between well-established therapeutic strategies and opportunities coming from new drugs

“…Risultano significativamente ridotti anche i casi di malformazioni cardiache, labiopalatoschisi e difetti degli arti [7,8]. La riduzione del rischio relativo è stimata intorno al 36% se si assumono almeno 0,4 mg/die di acido folico.…”