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Dose-dependent effect of folic acid on the prevention of orofacial clefts.

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 multivitamin used in the periconceptional period for the first occurrence of isolated CL +/- CP and CP was estimated by the Mantel-Haenszel test. Of 5488 supplemented women, 6 had CL +/- CP, and of 5821 unsupplemented women, 4 had CL +/- CP. Of 5489 supplemented women, 1 had CP, and of 5823 unsupplemented pregnant women, 3 had CP. The Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996, included 38 151 population controls (1.8% of the Hungarian births) and 22 865 cases with congenital abnormalities. Within the latter group, 1368 had isolated CL +/- CP, and 596 had CP. A significantly more frequent use of high-dose folic acid (in general daily 6 mg) supplementation was found in controls than in cases of 1246 case-control pairs of CL +/- CP group and of 537 case-control pairs of CP group, respectively. (ABSTRACT TRUNCATED)

journal_name

Pediatrics

journal_title

Pediatrics

authors

Czeizel AE,Tímár L,Sárközi A

doi

10.1542/peds.104.6.e66

subject

Has Abstract

pub_date

1999-12-01 00:00:00

pages

e66

issue

eissn

0031-4005

issn

1098-4275

journal_volume

104

pub_type

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Dose-dependent effect of folic acid on the prevention of orofacial clefts.