To The Editor: In their recently published chick embryo study, Andaloro et al.(1) investigated the teratogenicity of N-methyl-D-aspartate (NMDA) receptor antagonists. They found that all classes of NMDA receptor antagonists induced embryonic death and congenital defects of the neural crest and neural tube. Particularly, they found that channel blockers, such as dextromethorphan, were the most potent teratogens. They regarded their results to be "alarming" given the increased clinical use of NMDA receptor antagonists, and concluded that of these drugs, dextromethorphan posed "perhaps the greatest threat to human embryos" because of its widespread use as an over-the-counter medication(1). We are concerned about the extrapolations to the human embryo that Andaloro et al. have made on the basis of their avian study. The authors defend their extrapolations by stating that the genes regulating early embryonic development have been found to be similar across species. Still, chicks are very different from humans! Furthermore, applying dextromethorphan directly on the inner embryonic membrane of the chick does not compare with the indirect way a human embryo is exposed to dextromethorphan when the mother consumes cough syrup containing this drug. The limitations of avian embryo studies in predicting human teratogenicity were eloquently discussed in a previously published article by one of the authors(2), but a similar caveat was missing in the present study. Also missing from their discussion were the results from two epidemiological studies that found no increased frequency of congenital anomalies among the infants of 359 women who used dextromethorphan during the first trimester of pregnancy(3,4). It is noteworthy that the TERIS database assigns a risk assessment of "None" when rating the magnitude of teratogenic risk to an infant whose mother took dextromethorphan during pregnancy, based on these two negative epidemiological studies(5). TERIS is a computerized database that provides information regarding the teratogenic effects of drugs and chemicals on the human embryo or fetus. An Advisory Board comprised of six experts in clinical teratology review the published scientific literature and assess the teratogenic risk for each of the agents on the system.
Using the avian embryo, Andaloro et al. provide important insight into some of the mechanisms underlying embryonic development; however, more epidemiological studies need to be conducted before we can conclude that maternal exposure to usual doses of dextromethorphan will have a similar effect on human embryos. The nationally-televised announcements of the authors' broad extrapolation to humans have resulted in a flood of calls to teratogen information services from concerned physicians and pregnant patients who feared that they had harmed their fetuses by taking over-the-counter cough medications containing dextromethorphan. Scientists need to take more responsibility in communicating scientific uncertainty to the lay public and help them put the results of their studies into the proper clinical perspective. Andaloro et al. were remiss in this respect.
Andaloro VJ, Monaghan DT, Rosenquist TH 1998 Dextromethorphan and other N-methyl-D-aspartate receptor antagonists are teratogenic in the avian embryo model. Pediatr Res 43: 1–7.
Rosenquist TH, Ratashak SA, Selhub J 1996 Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci USA 93: 15227–15232.
Heinonen OP, Slone D, Shapiro S 1977 Birth Defects and Drugs in Pregnancy. John Wright-PSG, Littleton, MA, pp 379–496.
Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A 1985 First-trimester drug use and congenital disorders. Obstet Gynecol 65: 451–455.
Friedman JM, Polifka JE 1997 TERIS: the teratogen information system [database online]. University of Washington, Seattle, WA, 1984 [updated 2/97]. Available from: University of Washington, Seattle, WA
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Polifka, J., Shepard, T. Teratogenesis of Dextromethorphan in the Avian Embryo. Pediatr Res 44, 415 (1998). https://doi.org/10.1203/00006450-199809000-00025