Oral Cleft Prevention Program

Cleft lip and palate is a common and burdensome birth defect that has large health
ramifications and requires surgical, speech, behavioral, dental, and medical interventions.
There is some evidence suggesting that taking folic acid particularly at large doses during
preconception and first trimester of pregnancy may decrease the risk of oral cleft
recurrence, which is the risk of having a child with an oral cleft for women who have an
oral cleft or who have had a child with a cleft. However this evidence is based on study
designs that are incapable of contributing the preventive effects to folic acid with
adequate confidence, and the real effect of folic acid on cleft recurrence prevention
remains to be identified. Taking 4 mg of folic acid per day at preconception and first
trimester of pregnancy has also been shown to prevent the recurrence of neural tube defects
by up to 70%, providing further support to evaluate this intervention for oral cleft
recurrence.

This study evaluates the effects of supplementation with 4 versus 0.4 mg of folic acid per
day at preconception and during the first three months of pregnancy on recurrence of cleft
lip and palate. Up to 6000 women will be randomly assigned to 4 versus 0.4 mg groups. The
primary aim is to compare the recurrence rates in the offspring of trial mothers in the two
groups. Secondary aims are to compare the two groups on several outcomes including
miscarriage, twinning, pre-eclampsia, serum and red cell folate levels, severity of oral
clefts and occurrence of other birth defects in the offspring of trial mothers, and birth
weight and gestational age of trial babies, and to compare the recurrence in the two groups
to that in historic controls.

Inclusion Criteria:

- Women with cleft lip with/out palate (CLP), 16 to 45 years of age registered at the
study clinics in Brazil or Women (16 to 45 years of age) with at least one natural
child of any age with CLP registered at the study clinics.

- Women must reside in the catchment area of the study, which includes the states where
the study clinics are located and surrounding states.

Exclusion Criteria:

- Consanguineous couples (up to third degree, i.e. first cousins or closer).

- Pregnany at the time of recruitment. Women will be recontacted later at an
appropriate time for participation in the study.

- Couples either one of which have been sterilized.

- Taking any form of seizure medication.

- Planning to move outside of the study catchment area within the next year.

- B12 deficiency (<174 pg/mL or 129.15 pmol/L).

- Being allergic to folic acid.