Risk category
Description
A
Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters)
B
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women
C
Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks
D
There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks
X
Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits
N
Not classified
Table 16.2
FDA risk categories of various potentially cardio-teratogenic drugs
Risk category | Drugs |
|---|---|
A | Folate |
B | Amoxicillin (±clavulanic acid), ampicillin, cefotaxime, metronidazole |
C | Acetaminophen, beta-carotene, bupropion, caffeine, cocaine (topical), codeine, fluconazole, fluoxetine, ibuprofen, Marinol, naproxen, rifampicin, sertraline, sulfamethoxazole/trimethoprim, theophylline, tretinoin topical, zidovudine |
D | Aspirin (in the third trimester), lithium, paroxetine, phenytoin, valproic acid |
X | Retinoic acid agents (alitretinoin, etretinate, isotretinoin), thalidomide |
N | Acetaminophen, aspirin, diazepam, marijuana |
16.2.3 Risks Assessment
The risk of developing CHD after different exposures can be defined in a number of ways, depending on the methods. Generally, odds ratios (ORs) are derived from case-control studies, while relative risks (RR) are derived from randomized control trials or cohort studies. As the following sections will summarize data from various studies, OR and RR will be combined. The range of OR/RR without confidence intervals will be noted in some cases, and the reader is referred to excellent reviews for more details [1, 5, 6].
The relative importance of any particular environmental factor is a combination of the prevalence of exposure, the relative risk of associated CHD, and the clinical severity of the CHD. For example, the extremely low prevalence of uncontrolled phenylketonuria during pregnancy mitigates the high risk of CHD in these pregnancies. In contrast, although the risk for CHD after in utero exposure to diabetes, fever, tobacco smoking, ethanol ingestion, seizures, or obesity may (or may not) be low, the relative importance to society may be high due to the high prevalence of these exposures.
16.3 Environmental Signals During Cardiac Development
The following sections review data from human studies of potential cardiac teratogens. Please note that studies of the risk and etiology of congenital defects in conditions such as those listed below are complicated by the association of some of these conditions with each other, making accurate assignment of any single risk factor difficult.
16.3.1 Human Demographics
16.3.1.1 Age
Younger and older age in both parents is associated with increased risk for all CHD or specific types of CHD, although these associations are inconsistent between studies. Men older than 25 years and women older than 30 years and both men and women under 20 years of age may have increased risk.
16.3.1.2 Race
Race may alter risk for CHD. Some studies suggest that Caucasian infants are more likely to have left-sided obstructive lesions, septal defects, Ebstein’s anomaly, and some conotruncal defects and are less likely to have atrial septal defects (ASD) and valvular pulmonary stenosis (PS) than African American infants. One study showed equal risk for Hispanic women compared to Caucasian women. Eastern Asian infants are also more likely to have a supracristal/outlet ventricular septal defect (VSD).
16.3.1.3 Socioeconomic Status
Lower socioeconomic status may be associated with increased risk for CHD, with significant OR/RR of 1.6 and 3.4 in two studies.
16.3.2 Human Conditions and Diseases
16.3.2.1 Diabetes
Pregestational and gestational maternal diabetes can cause many cardiac and noncardiac defects, particularly when it is uncontrolled in the early stages of pregnancy. Lesions include laterality defects, conotruncal defects, atrioventricular septal defects (AVSD), VSDs, and left-sided obstructive lesions. The OR/RR of any form of CHD in infants of diabetic mothers ranges from 1.8 to 18. This risk is decreased with good glycemic control. In addition, obstructive and nonobstructive hypertrophic cardiomyopathy can occur in infants of diabetic mothers. At any risk above baseline, the increasing rate of diabetes in the general population has worrisome implications for the global incidence of CHD.
16.3.2.2 Fever/Maternal Infections
Maternal fever is teratogenic in animal models. Human gestational fever in the first trimester increases risk for all CHDs, although data are inconsistent among studies. A variety of CHD types may be associated with fever, with the most common being conotruncal defects. However, interpreting data in humans is complicated by the effects of the infectious sources of and the therapies for fever. For example, the relationship between maternal rubella infection and a patent ductus arteriosus (PDA), PS, peripheral pulmonic stenosis (PPS), and VSDs is well documented. Influenza exposure during pregnancy may also increase risk for CHD, and gestational HIV exposure increases risk for dilated cardiomyopathy.
16.3.2.3 Folate Deficiency
Data supporting a risk for CHD in pregnancies complicated by folate deficiency are largely derived from studies showing that folate supplementation during early stages of pregnancy decreases risk for CHD. Although results among these studies are inconsistent, the potential benefit of folate supplementation during pregnancy on the risk of CHD strengthens the recommendation for this therapy. Additional studies suggest that hyperhomocysteinemia, which can result from folate and vitamin B12 deficiency, may also increase risk for CHD. Finally, multivitamin/folate use may ameliorate the effects of fever, alcohol, lithium, and hyperhomocysteinemia on the risk for CHD [8].
16.3.2.4 High Altitude/Hypoxia
Being born at high altitude causes maternal hypoxia and increases risk for ASDs and PDAs, but this has not been extensively studied.
16.3.2.5 Hypertension
Hypertension may increase the risk of CHD up to twice that of controls, but no specific lesion stands out.
16.3.2.6 Maternal Stress
Increased maternal stress has been associated with an increased risk (OR/RR = 1.4–2.7) for CHD, particularly conotruncal defects, in some studies.
16.3.2.7 Obesity
The association of obesity with CHD has been inconsistent among various studies, and OR/RR ranges between <1 and 3. However, increased risk is observed with increasing levels of obesity.
16.3.2.8 Phenylketonuria
There is a strong association of phenylketonuria with CHD, with an RR of ≥6 and a rate of up to 14 % of pregnancies with high levels of phenylketonuria having newborns with CHD. However, good dietary control can reduce or eliminate this risk. The most likely CHD lesions to be seen are left-sided obstructive lesions, tetralogy of Fallot (TOF), VSDs, and PDAs.
16.3.2.9 Reproductive History
Multiparous women are more likely to have children with CHD, while nulliparous women may have increased risk for children with ASDs, TOF, and VSDs. A history of reproductive problems carries increased risk for ASDs, AVSDs, Ebstein’s anomaly, and TOF. Assisted reproductive technology is associated with increased risk for congenital lesions, including CHD such as aortic valve stenosis, ASDs, coarctation of the aorta (CoA), TOF, and VSDs.
16.3.3 Dietary and Recreational Drug Exposures
16.3.3.1 Alcohol
The original description of fetal alcohol syndrome included CHD. However, heavy maternal alcohol consumption during pregnancy is inconsistently associated with CHD, particularly ASDs, conotruncal defects, and VSDs. It is difficult to gauge the exact level of exposure required to increase risk in these studies.
16.3.3.2 Caffeine
Caffeine has not been shown to cause CHD in humans, although animal models of in utero exposure to caffeine may alter cardiac function in adults [9].
16.3.3.3 Tobacco Smoke
Active, and, possibly, passive, exposure to tobacco smoking appears to increase risk for CHD, particularly conotruncal defects, although the risk is relatively low and inconsistent in a number of studies.
16.3.3.4 Other Recreational Drugs
Maternal cocaine use may increase risk for CHD, such as ASDs, AVSDs, looping defects, PPS, and VSDs. Marijuana use by the mother may increase risk for Ebstein’s anomaly, tricuspid atresia, and VSDs. Paternal cocaine use increases risk for ASDs, looping defects, VSDs, and/or tricuspid atresia, and paternal marijuana use increased risk for VSDs in the BWIS [3, 10].
16.3.4 Medications
16.3.4.1 Antibiotics
In general, antibiotic use during pregnancy is not thought to increase risk for CHD. However, sulfonamide-containing antibiotics inhibit folate metabolism and may increase risk for CHD (OR/RR = no risk or 1.8–3.4), such as CoA and hypoplastic left heart syndrome, and this risk may be decreased by folate supplementation. In addition, the antifungal agent metronidazole was associated with CHD in the BWIS, but this finding has not been validated by other studies. In contrast, fluconazole appears to be safe during pregnancy. The risk of antiretroviral therapy (e.g., zidovudine) during pregnancy appears to be low for causing CHD. Antibiotics are generally listed under FDA Risk Category B or C, and a few common antibiotics are listed in Table 16.2.
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