A 32-year-old woman with corrected tetralogy of Fallot is pregnant at 18
weeks’ gestation with a male fetus. She inquires as to the chance that her
son has congenital heart disease.
The majority of birth defects (70%) are multifactorial or polygenic in origin,
which means there is an interaction of multiple genes with environmental
factors. Characteristic Mendelian patterns are not found, but there is an
increased frequency of the disorder or phenotype in families. Overall
recurrence rate is 2–3%.
Examples of multifactorial inheritance include the following:
Neural tube defects Cleft lip and palate
Congenital heart disease Pyloric stenosis
As the number of genes for a multifactorial trait increases, the liability for the
The more severe the malformation, the higher the risk for recurrence.
Neural tube defects (NTD) (1–2 per 1,000 births): The spectrum ranges from
anencephaly to very slight vertebral defects. Result from failure of neural tube
closure by day 22–28 postconception. Anencephaly and spina bifida occur
with equal frequency. Polyhydramnios is frequently seen.
Women at high risk for NTD should take 4 mg of folic
acid. Preconception folic acid supplementation may decrease incidence
All women should take 0.4 mg of folic acid.
Congenital heart disease (CHD) (1% of births): The majority of isolated
CHD are multifactorial with an overall recurrence risk of 2%. However, the
specific recurrence risk depends on the defect and family history details. It is
important to distinguish isolated defects from those that are part of a
syndrome with a higher recurrence risk. Preconception folate reduces the risk
of congenital CHD, as well as NTD.
Cleft lip and palate (1 per 1,000 births): The risk of cleft lip in a second
child of unaffected parents is 4%. If two children are affected, the risk of the
third child being affected is 10%.
Pyloric stenosis (more common in males): The risk of the condition in the
offspring of an affected parent is much greater if that parent is female.