Efavirenz is not a Known Teratogen

Abstract

Reply: Drs. Ford and Calmy take exception to the reference to efavirenz as a known teratogen in our report on the prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals.1 A teratogenic agent may be defined as one that is “of, relating to, or causing developmental malformations.”2 Ford and Calmy assert that we were “led to state” that efavirenz is a teratogen based upon the anomalies we reported. On the contrary, this characterization is based upon previously reported data relating efavirenz to developmental malformations.3–5 Efavirenz is considered to have “positive evidence of fetal risk” (Pregnancy Category D) according to the Food and Drug Administration based upon teratogenic effects associated with its use. We clearly state in our first paragraph that the teratogenicity risk is “based upon evidence from nonhuman primate data and case reports of neural tube defects.” Ford and Calmy erroneously state that we reported 6 abnormalities in 48 exposures to efavirenz in the first trimester: we reported 6 events/47 exposures in the first trimester and 0 events/9 exposures in the second and third trimesters. Ford and Calmy point out that only a single case of a neural tube defect has been reported in an infant exposed to efavirenz in utero and that this case has been reported “at least three times.” We clearly state that the neural tube defect in our study was the same case from the 219/219C study, which had also been previously reported.5,6 We do not suggest that our data indicate an association between efavirenz use and neural tube defects in particular, but rather that our data support previous findings of an association between efavirenz and congenital anomalies in general. We agree that association does not imply causation. Furthermore, we clearly indicate that not all studies (ie, the National Institute of Child Health and Human Development International Site Development Initiative analysis from Argentina and Brazil) have found an association between efavirenz exposure and congenital anomalies.7 Our results are consistent with those of other cohort studies, suggesting a higher prevalence of congenital anomalies among infants born to HIV-infected women when compared with the general population. We acknowledge that further research is needed to evaluate possible confounding factors and encourage voluntary prospective reporting to the Antiretroviral Pregnancy Registry. Katherine M. Knapp, MD St. Jude Children’s Research Hospital Memphis, TN Jennifer S. Read, MD Pediatric, Adolescent, and Maternal AIDS (PAMA) Branch Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda, MD NVPO/OASH/OS/DHHS Washington DC