Oral Cleft Prevention Trial in Brazil

NICHD Global Network for Women's and Children's Health2,200 enrolled

Overview

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 versus 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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

DOUBLE

Enrollment

2,200

Conditions

Cleft Lip Cleft Palate

Interventions

Folic acid (0.4mg vs. 4.0mg)DRUG

Eligibility

Sex: FEMALEMin age: 16 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * All women must reside in the state where the clinic is located. * Women with NSCL/P who attend the craniofacial clinics, who are 16 to 45 years of age (after age 45 fecundity decreases substantially)who attend the craniofacial clinic for their care. * Women (ages 16 to 45 years of age) who have at least one natural child of any age with NSCL/P who receives care at the participating craniofacial clinics. 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. * Women who are planning to move outside of the state where the clinic is located within the next year. * Women who are planning to move outside of Sao Paulo state within the next year. * Women who have B12 deficiency (B12 level is below 174 pg/ml or 134.328 pmol/L). * Women who have an allergy to folic acid.

Locations (3)

Hospital de Reabilitação de Anomalias Craniofaciais (HRAC)

Bauru, São Paulo, Brazil

Hospital de Clinicas de Porto Alegre (HCPA)

Porto Alegre, Brazil

Hospital Santo Antonio-Centrinho: Obras Sociais Irma Dulce

Salvador, Brazil

Outcomes

Primary Outcomes

Recurrence of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in offspring of trial mothers

Secondary Outcomes

Recurrence of NSCL/P compared to a historical control group; Overall and high versus 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

Data from ClinicalTrials.gov

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