his anticoagulant is a vitamin K antagonist with a long halflife. Because of its low molecular weight, it readily crosses the placenta and may cause embryotoxic and fetotoxic efects. Warfarin analogues, such as Coumadin, are considered contraindicated in pregnancy. An exception, as discussed in Chapter 49 (p. 954), is treatment of women with mechanical heart valves who are at high risk for thromboembolism (Bristol-Myers Squibb,i2017a).
Waarin embryopathy is characterized by stippled epiphyses and nasal hypoplasia (Fig. 12-6). In one review of 63 cases attributed to warfarin exposure, 80 percent displayed characteristic indings, which include depressed nasal bridge with nasal hypoplasia and choanal atresia, along with stippled epiphyses of the femur, humerus, calcanei, and distal phalanges (Van Driel, 2002). It may result from exposure between the 6th and 9th weeks' gestation (Hall, 1980). he prevalence of the warfarin embryopathy following exposure during this critical period is estimated to be 6 percent (van Driel, 2002). One metaanalysis of cases in which the warfarin dosage was ; 5 mg/ d identiied embryopathy in 1 percent of exposed fetuses. his suggests that risk may be dose dependent (Hassouna, 2014).
If used beyond the first trimester, warfarin may lead to hemorrhage into fetal structures, which can cause abnormal growth and deformation from scarring (Warkany, 1976). Nearly 50 percent of reported embryopathy cases also have CNS anomalies (van Driel, 2002). Abnormalities can include agenesis of the corpus callosum; cerebellar vermian agenesis, which is the Dandy-Walker malformation; microphthalmia; and optic atrophy (Hall, 1980). Afected infants are also at risk for blindness, deafness, and developmental delays.
With various herbal remedies, associated risks are more challenging to estimate because studies are few and because these compounds are not FDA-regulated. he European Committee of Herbal Medicinal Products provides assessment reports and
Teratology, Teratogens, and Fetotoxic Agents 247
FIGURE 12-6 Warfarin embryopathy or fetal warfarin syndrome: nasal hypoplasia and depressed nasal bridge seen in a fetal sonographic image (A) and in the same newborn (8).
monographs on selected herbal substances and preparations, but safety data are generally limited (Wiesner, 2017). Animal studies have not been conducted, and thus knowledge of complications often derives from reports of acute toxicity (Hepner, 2002; Sheehan, 1998). Further, the identity, quantity, and purity of each ingredient are usually unknown. Given these uncertainties, it seems prudent to counsel pregnant women to avoid these substances. A list of selected herbal compounds and their potential efects is shown in Table 12-5.
Not uncommonly, fetuses are exposed to one or more illicit drugs. Assessment of outcomes attributable to these drugs may be confounded by factors such as poor maternal health, malnutrition, infectious disease, and polysubstance abuse. Moreover, illegal substances may contain toxic contaminants such as lead, cyanide, herbicides, and pesticides. Impurities added as diluents may independently have serious adverse perinatal efects. As noted on page 239, alcohol is a significant teratogen. Because it is legally obtained and ubiquitous, its use also confounds the study of illicit drug teratogenicity.