1) Exposure to certain medications like anticonvulsants, lithium, angiotensin-converting enzyme inhibitors, and NSAIDs during pregnancy increases the risk of congenital heart disease in fetuses. 2) Anticonvulsants like carbamazepine have been associated with a 1.8% risk of cardiac malformations in exposed fetuses. Lithium exposure has been linked to a risk of up to 8% for cardiac anomalies, though more recent studies find a lower risk of 1.1%. 3) Angiotensin-converting enzyme inhibitor exposure in the first trimester is associated with increased risk of congenital heart disease.

1. Donofrio et al Diagnosis and Treatment of Fetal Cardiac Disease 7
autoantibody (anti-Ro/SSA or anti-La/SSB) positivity in the
general population is unknown. In prospectively examined preg-
nancies of mothers with known antibodies and no prior affected
child, the reported incidence of fetal CHB was between 1% and
5%. The number of affected pregnancies increases to 11% to
19% for those with a previously affected child with CHB.13–17
In
addition, women with both autoantibodies and hypothyroidism
are at a 9-fold increased risk of having an affected fetus or neo-
nate compared with those with SSA or SSB alone.18
In addition to abnormalities in the conduction system, up
to 10% to 15% of SSA-exposed fetuses with conduction sys-
tem disease may also develop myocardial inflammation, endo-
cardial fibroelastosis, or atrioventricular (AV) valve apparatus
dysfunction.94
Because of the perception that the inflammatory
effects resulting from antibody exposure may be preventable if
detected and treated at an early stage, it has been recommended
that SSA/SSB-positive women be referred for fetal echocar-
diography surveillance beginning in the early second trimes-
ter (16–18 weeks).14,16,95
The mechanical PR interval has been
measured in fetuses at risk with the use of a variety of M-mode
and pulsed Doppler techniques and compared with gestational
age–adjusted normal values.96
Although the value of serial
assessment for the detection of the progression of myocardial
inflammation or conduction system disease from first-degree
block (PR prolongation) to CHB has not been proved, serial
assessment at 1- to 2-week intervals starting at 16 weeks and
continuing through 28 weeks of gestation is reasonable to per-
form because the potential benefits outweigh the risks. For
women who have had a previously affected child, more fre-
quent serial assessment, at least weekly, is recommended.
Medication Exposure
Most of the current literature implicating maternal medications
in congenital abnormalities comes from retrospective patient
interviews and voluntary registries and therefore may be sub-
ject to bias. Nevertheless, a number of human teratogens are
used clinically in women of childbearing age, and exposure
to these medications in the period of cardiogenesis increases
the risk of CHD. Among the most studied include anticonvul-
sants, lithium, angiotensin-converting enzyme inhibitors, reti-
noic acid, selective serotonin reuptake inhibitors (SSRIs), and
nonsteroidal anti-inflammatory agents (NSAIDs).
Anticonvulsants
Anticonvulsants used in pregnancy include carbamazepine,
diphenylhydantoin, and valproate. In a meta-analysis including a
group of untreated epileptic women as control subjects, 1.8% of
1208 carbamazepine-exposed fetuses exhibited cardiac malfor-
mations.21
This proportion was similar whether the mothers were
taking carbamazepine alone or in combination with other anti-
epileptic drugs. The incidence of malformations in the unmedi-
cated epileptic control subjects was similar to that for the normal
population. Fetal echocardiogram may be considered, although
its usefulness has not been established if exposure occurs.
Lithium
Lithium has been reported to be associated with cardiac
malformations in up to 8% of offspring in a registry study.25
However, more recent prospective case-control studies22
and
literature analyses97
have suggested that the risk is not as high
as initially thought, with a risk ratio for cardiac anomalies of
1.1 (95% confidence interval [CI], 0.1–16.6).22
Fetal echocar-
diogram may be considered, although its usefulness has not
been established if exposure occurs.
Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme inhibitor exposure in the
first trimester is associated with increased risk for CHD, with
Table 3. Common Indications for Referral for Fetal
Echocardiogram
Indications with higher risk profile (estimated >2% absolute risk)
Maternal pregestational diabetes mellitus
Diabetes mellitus diagnosed in the first trimester
Maternal phenylketonuria (uncontrolled)
Maternal autoantibodies (SSA/SSB+
)
Maternal medications
ACE inhibitors
Retinoic acid
NSAIDs in third trimester
Maternal first trimester rubella infection
Maternal infection with suspicion of fetal myocarditis
Assisted reproduction technology
CHD in first degree relative of fetus (maternal, paternal or sibling with CHD)
First or second degree relative with disorder with Mendelian inheritance
with CHD association
Fetal cardiac abnormality suspected on obstetrical ultrasound
Fetal extracardiac abnormality suspected on obstetrical ultrasound
Fetal karyotype abnormality
Fetal tachycardia or bradycardia, or frequent or persistent irregular heart
rhythm
Fetal increased NT 95% (≥3 mm)
Monochorionic twinning
Fetal hydrops or effusions
Indications with lower risk profile (estimated 1% but 2% absolute risk)
Maternal medications
Anticonvulsants
Lithium
Vitamin A
SSRIs (only paroxetine)
NSAIDs in first/second trimester
CHD in second degree relative of fetus
Fetal abnormality of the umbilical cord or placenta
Fetal intra-abdominal venous anomaly
Not indicated (≤1% risk)
Maternal gestational diabetes mellitus with HbA1c
6%
Maternal medications
SSRIs (other than paroxetine)
Vitamin K agonists (Coumadin), although fetal survey is recommended
Maternal infection other than rubella with seroconversion only
Isolated CHD in a relative other than first or second degree
ACE indicates angiotensin-converting enzyme; CHD, congenital heart disease;
HbA1c
, hemoglobin A1c
; NSAID, nonsteroidal anti-inflammatory drug; NT, nuchal
translucency; and SSRI, selective serotonin reuptake inhibitor.
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