Cleft lip and palate are a significant component of morbid human birth defects in the developing world. By supplementing a high-risk group of women with folic acid (4.0 mg vs. 0.4 mg) from preconception and continuing throughout the first 3 months of pregnancy in the state of Sao Paulo, Brazil, this study aims to reduce the recurrence of cleft lip and palate.

Condition	Treatment or Intervention	Phase
Cleft Lip Cleft Palate Congenital Defects Pregnancy	Drug: Folic acid 0.4mg vs. 4.0mg	Phase III

Further Study Details: 

Primary Outcomes: Recurrence of nonsyndromic cleft lip with or without clef palate (NSCL/P) in offspring of trial mothers
Secondary Outcomes: Recurrence of NSCL/P compared to a historical control group; Overall and high vs. low dose; Serum and red cell folate levels; Severity of NSCL/P in offspring of trial mothers; Twinning rate; Miscarriage rate; Preeclampsia; Rates of other birth defects; Birth weight; Gestational age
Expected Total Enrollment:  2200

Craniofacial anomalies and cleft lip with or without cleft palate (CL/P) are a model for the impact of birth defects on fetal and neonatal health directly and maternal health indirectly. Craniofacial anomalies comprise a significant component of morbid human birth defects. The primary hypothesis is that folic acid supplementation of 4mg/day at preconception and during the first three months of pregnancy will decrease the recurrence of nonsyndromic cleft lip with or without clef palate (NSCL/P) in a high-risk group of women when compared to women taking 0.4 mg per day of folic acid. The total sample will include 2,000 women (that either have NSCL/P or that have at least one child with NSCL/P) randomly assigned to the 4 mg versus the 0.4 mg folic acid study groups. The study will also compare the recurrence rates of NSCL/P in the total sample of subjects as well as the two study groups (4mg, 0.4 mg) to that of a historical control group.

The primary outcome assessed is the rate of recurrences of NSCL/P in offspring of the trial mothers in each of the two study groups. Secondary outcomes include recurrence of NSCL/P compared to a historical control group; serum and red cell folate levels; severity of NSCL/P in offspring of trial mothers; twinning rate; miscarriage rate; preeclampsia; rates of other birth defects; birth weight; and gestational age. The sample size was based on historic tables of birth rates and the rates of cleft occurrences. The study hypothesizes that a total of 2000 subjects will be enrolled during a 2.5 year period; a dropout rate of 10%; birth rate for group A (women with NSCL/P) of 10% and a rate of 12% for group B (women with at least one child with NSCL/P); risk of cleft for group A is 7% and for group B is 4%; one-sided test with continuity correction.

Ages Eligible for Study:  16 Years   -   36 Years,  Genders Eligible for Study:  Female

Accepts Healthy Volunteers

Criteria

Inclusion criteria:

• All women must reside in the state of São Paulo, Brazil.
• Women with NSCL/P registered at Hospital de Reabilitação de Anomalias Craniofaciais (HRAC) and/or its branches, 16 to 36 years of age (16 is the age of consent, after age 36 fecundidity decreases substantially).
• Women (age 16 to 36) who have at least one natural child (under 10 years of age) with NSCL/P registered at HRAC and/or its branches.

Exclusion Criteria:

• Cases resulting from consanguineous couples (first, second, and third degree, i.e., first cousins or closer).
• Couples where at least one of the two is definitely sterilized.
• Women on anti-epileptic drugs.
• Women who are pregnant.
• Couples not wanting to have additional children.
• Women who are planning to move outside of Sao Paulo state within the next year.
• Women who have B12 deficiency (B12 level is below 175 pg/ml or 129.15 pmol/L).
• Women who have an allergy to folic acid.

Lorette Javois, Ph.D       javoisl@mail.nih.gov

Brazil, Sao Paulo
      Hospital de Reabilitação de Anomalias Craniofaciais (HRAC), Bauru,  Sao Paulo,  Brazil; Recruiting

Study chairs or principal investigators

Jeff Murray, M.D.,  Principal Investigator,  University of Iowa   

Study ID Numbers:  GN 04 Aim III
Record last reviewed:  December 2004
Last Updated:  December 6, 2004
Record first received:  December 6, 2004
ClinicalTrials.gov Identifier:  NCT00098319
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08