To assess effects of periconceptional multivitamin and folic-acid supplementation on recurrence of cleft lip with or without cleft palate (CL +/- P), we prospectively evaluated 221 pregnancies in women at risk of a child with CL +/- P. The 10-step protocol included multivitamin supplementation with SPOFAVIT (A, B1, B2, B6, C, D3, E, nicotinamide, calcium pantothenicum) and folic acid (10 mg/day), beginning > or = 2 months before planned conception and continuing for > or = 3 months thereafter. A comparison group comprised 1,901 women at risk of a child with CL +/- P who received no supplementation and gave birth within the same period as the study group. In the supplemented group, 3 of 214 informative pregnancies ended with infants with CL +/- P, a 65.4% decrease (observed versus expected value -5.67; P = 0.031, Fisher's exact test); the expected value of 8.7 was calculated based on the incidence of cleft among first-degree relatives among the comparison group. Subset analysis by proband's sex, severity of CL +/- P, and both variables showed highest supplementation efficacy in probands with unilateral cleft (82.6% decrease, P = 0.024, Fisher's exact test). No efficacy was observed for female probands with bilateral CL +/- P. Generally, efficacy was greater for subgroups with unilateral than with bilateral cleft and for male than female probands.(ABSTRACT TRUNCATED AT 250 WORDS)