One study done in the United Kingdom, for instance, identified 727 adults with surgically modified major heart defects and their 393 live offspring. Of these infants, 16 were born with cardiac malformations, representing a total recurrence risk of 4.1%. Recurrence risk in offspring ranged from 3.1% for tetralogy of Fallot to 7.8% for atrioventricular septal defect (Lancet 1998;351:311-6).
CHD occurred more often in offspring of affected mothers (5.7%) than affected fathers (2.2%). Compared with offspring, sibling risk was significantly lower: 2.1% overall.
A much larger and more recent study done in Denmark again showed strong familial clustering in first-degree relatives for CHDs, particularly for recurrences of the same heart defect. (Very few families experience a second heart defect, the study found.)
The study – a national cohort study of more than 1.7 million people born during a 29-year period – also is one of the largest studies, if not the largest study, to document a decreasing risk as family history gets more distant.
The relative risks of any CHD in singletons were 3.21 for a family history of any CHD in first-degree relatives, 1.78 for a family history involving second-degree relatives, and 1.10 for a family history in third-degree relatives (Circulation 2009;120:295-301).
Only with a history of affected first- and second-degree relatives was there a statistically greater chance of having an affected fetus.
In twins, the relative risks of any CHD were 12.5 for same-sex twins and 6.93 for twins of both sexes, the Danish investigators noted.
And in looking at the contribution of CHD family history to the total number of CHD cases in the population, they found that 2.2% of heart defect cases in the population were attributed to CHD family history in first-degree relatives.
Another notable finding from other studies is that women with cyanotic heart disease have a higher risk of having a baby with CHD than do women with noncyanotic heart disease.
Maternal Risks
Just as we've learned much about inherited causes of congenital heart disease over the past 15 years, there is a growing body of epidemiologic literature on potential fetal exposures – from maternal illnesses to maternal drug exposures – that can alter the risk of CHD.
The risk factors for CHD maternal teratogen exposure are numerous. They include lithium, alcohol, isotretinoin, and various anticonvulsant drugs, and many are well-appreciated by ob.gyns.
Other factors for which risk has been well determined, and can be better appreciated, include:
▸ High vitamin A intake. Findings are not completely consistent, but we have enough data now to suggest that women who take extra-large doses of vitamin A may actually be putting their fetuses at risk of birth defects.
One study worth noting found that among more than 22,000 pregnant women, those who took more than 10,000 IU of vitamin A from supplements were 4.8 times more likely to have babies with birth defects associated with cranial-neural-crest tissue than were women who consumed 5,000 IU or less per day (N. Engl. J. Med. 1995;333:1369-73).
Typical prenatal vitamins have 5,000 IU in each dose. This is one reason that women with twin pregnancies can take extra folic acid, but should not double up on their prenatal multivitamins.
▸ Folate antagonists. Common drugs such as trimethoprim, triamterene, sulfasalazine, phenytoin, phenobarbital, primidone, carbamazepine, and cholestyramine may increase the risk not only of neural-tube defects, but of cardiovascular defects as well, in addition to oral clefts and urinary tract defects.
Fortunately, studies such as one published in 2000 involving thousands of infants show that the folic acid component of prenatal multivitamin supplements can reduce the risks of these defects, just as it reduces the risk of neural-tube defects (N. Engl. J. Med. 2000;343:1608-14).
▸ Paxil (paroxetine). This is the only antidepressant that has been shown in some studies to increase the risk of CHD. Its manufacturer, GlaxoSmithKline, changed the label's pregnancy precaution in 2005 from a Pregnancy Category C to Category D. If a patient becomes pregnant while taking the drug, she should be advised of potential harm to the fetus.
One epidemiologic study showed that women taking Paxil were two times more likely to have an infant with CHD, and 2.2 times more likely to have an infant with any congenital malformation, than were women taking other antidepressants.
▸ Diabetes. The risk of fetal anomalies with maternal diabetes and elevated hemoglobin A1c in early pregnancy has been known for some time.
In a study published in 1981, for instance, the risk of CHD and other fetal anomalies rose from 5% to 22% as maternal HbA1c rose from a range of 7%–8.5% to greater than 8.5% (N. Engl. J. Med. 1981;304:1331-4).