Oral Cleft Prevention Trial in Brazil

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.

Study Overview

• Status: Completed
• Conditions: Cleft Palate; Cleft Lip
• Intervention / Treatment: Drug: Folic acid (0.4mg vs. 4.0mg)

Detailed Description

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
• Enrollment (Anticipated): 2200
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Porto Alegre, Brazil
    • Hospital de Clinicas de Porto Alegre (HCPA)
  • Salvador, Brazil
    • Hospital Santo Antonio-Centrinho: Obras Sociais Irma Dulce
  • Sao Paulo
    • Bauru, Sao Paulo, Brazil
      • Hospital de Reabilitação de Anomalias Craniofaciais (HRAC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Birth weight
Miscarriage rate
Gestational age
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
Preeclampsia
Rates of other birth defects

Collaborators and Investigators

• Sponsor: NICHD Global Network for Women's and Children's Health
• Collaborators: National Cancer Institute (NCI); University of Iowa; National Institute of Dental and Craniofacial Research (NIDCR); Bill and Melinda Gates Foundation; National Center for Complementary and Integrative Health (NCCIH); Fogarty International Center of the National Institute of Health; RTI International; Global Network for Women's and Children's Health Research; Hospital de Reabilitação de Anomalias Craniofaciais (HRAC) - Brazil
• Investigators: Principal Investigator: Jeff Murray, M.D., University of Iowa

Publications and helpful links

Helpful Links

• RTI International
• Global Network for Women's and Children's Health Research

Study record dates

Study Major Dates

• Study Start: January 1, 2004
• Study Completion (Actual): April 1, 2007

Study Registration Dates

• First Submitted: December 6, 2004
• First Submitted That Met QC Criteria: December 6, 2004
• First Posted (Estimate): December 7, 2004

Study Record Updates

• Last Update Posted (Estimate): December 17, 2013
• Last Update Submitted That Met QC Criteria: December 16, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Pregnancy; Folic acid; International; Maternal and child health; Brazil; Cleft palate; Global Network; Women's health; Latin America; Cleft lip; Brasil; ECLAMC; Congenital defects
• Additional Relevant MeSH Terms: Congenital Abnormalities; Musculoskeletal Diseases; Stomatognathic Diseases; Mouth Diseases; Lip Diseases; Mouth Abnormalities; Stomatognathic System Abnormalities; Jaw Abnormalities; Jaw Diseases; Maxillofacial Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Cleft Palate; Cleft Lip; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Hematinics; Folic Acid
• Other Study ID Numbers: GN 04 Aim III