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Studies of the Fetal Effects of Dextromethorphan in Ovo Introduction The identification of new human teratogens is a priority of the members of the Teratology Society. One of our editorial goals is to use the original articles and the letters-to-the-editor to reflect the discussion of the merits of each proposal. In the January 1998 issue of Pediatric Research, Andaloro, Monaghan, and Rosen- quist suggested that exposure of the human pregnancy to dextromethorpham, an ingredient in cough medi- cines, could be a human teratogen. This article had a wider impact than the usual article in a basic science journal because the findings were reported in a press conference at the University of Nebraska where the related research studies had been carried out. The headlines developed from this event included ‘‘cough syrup linked to birth defects.’’ Many concerned women and their doctors called counselors for advice. Unfortu- nately, the published information available was lim- ited. One part of any reasoned response by a concerned individual was a review of the basis for this interpreta- tion. Experienced teratologists—Drs. Janine Polifka, Thomas Shepard, and Dr. Robert Brent—did this in two letters-to-the-editor submitted to Pediatric Research. They focus, in part, on the difficulty of extrapolating from the findings in studies in ovo to a human preg- nancy. We asked the editor of Pediatric Research for permission to reproduce these letters, and appreciate their willingness for us to do so. We believe an open discussion of the basis for identi- fying a human teratogen will inform the student and test the reasoning of the experienced teratologist. It is unlikely everyone will agree on all conclusions. We would welcome a discussion of this hypothesis and any others. This process will make us all better at what we do. Lewis B. Holmes, M.D. Editor REFERENCES Andaloro VJ, Monaghan DT, Rosenquist TH. 1998. Dextromethorphan and other N-methyl-D-aspartate receptor antagonists are terato- genic in the avian embryo model. Pediatr Res 43:1–7. Brent, RL. 1998. Letter to the editor. Pediatr Res 44:415–416. Polifka JE, Shepard TH. 1998. Letter to the editor. Pediatr Res 44:415. Rosenquist TH. 1998. Letter to the editor. Pediatr Res 44:416–417. Letters to the Editor To the Editor: In their recently published chick embryo study, An- daloro et al. 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 (Andaloro et al., ’98). We are concerned about the extrapolations to the human embryo that Andaloro et al. (’98) made on the basis of their avian study. The authors defend their extrapola- tions by stating that the genes regulating early embry- onic 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 con- sumes cough syrup containing this drug. The limita- tions of avian embryo studies in predicting human teratogenicity were eloquently discussed in a previ- ously published article (Rosenquist et al., ’98), 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 fre- These Letters to the Editor were previously published in Pediatric Research, 1998, Volume 44, pages 415–417, published by Lippincott Williams & Wilkins, Baltimore, MD. Reprinted with permission from Lippincott Williams & Wilkins. All rights reserved. TERATOLOGY 60:56–60 (1999) r 1999 WILEY-LISS, INC.

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Studies of the Fetal Effects of Dextromethorphanin Ovo

IntroductionThe identification of new human teratogens is a

priority of the members of the Teratology Society. Oneof our editorial goals is to use the original articles andthe letters-to-the-editor to reflect the discussion of themerits of each proposal. In the January 1998 issue ofPediatric Research, Andaloro, Monaghan, and Rosen-quist suggested that exposure of the human pregnancyto dextromethorpham, an ingredient in cough medi-cines, could be a human teratogen. This article had awider impact than the usual article in a basic sciencejournal because the findings were reported in a pressconference at the University of Nebraska where therelated research studies had been carried out. Theheadlines developed from this event included ‘‘coughsyrup linked to birth defects.’’ Many concerned womenand their doctors called counselors for advice. Unfortu-nately, the published information available was lim-ited.

One part of any reasoned response by a concernedindividual was a review of the basis for this interpreta-tion. Experienced teratologists—Drs. Janine Polifka,Thomas Shepard, and Dr. Robert Brent—did this in twoletters-to-the-editor submitted to Pediatric Research.

They focus, in part, on the difficulty of extrapolatingfrom the findings in studies in ovo to a human preg-nancy. We asked the editor of Pediatric Research forpermission to reproduce these letters, and appreciatetheir willingness for us to do so.

We believe an open discussion of the basis for identi-fying a human teratogen will inform the student andtest the reasoning of the experienced teratologist. It isunlikely everyone will agree on all conclusions. Wewould welcome a discussion of this hypothesis and anyothers. This process will make us all better at whatwe do.

Lewis B. Holmes, M.D.Editor

REFERENCES

Andaloro VJ, Monaghan DT, Rosenquist TH. 1998. Dextromethorphanand other N-methyl-D-aspartate receptor antagonists are terato-genic in the avian embryo model. Pediatr Res 43:1–7.

Brent, RL. 1998. Letter to the editor. Pediatr Res 44:415–416.Polifka JE, Shepard TH. 1998. Letter to the editor. Pediatr Res 44:415.Rosenquist TH. 1998. Letter to the editor. Pediatr Res 44:416–417.

Letters to the Editor

To the Editor:In their recently published chick embryo study, An-

daloro et al. investigated the teratogenicity of N-methyl-D-aspartate (NMDA) receptor antagonists. They foundthat all classes of NMDA receptor antagonists inducedembryonic death and congenital defects of the neuralcrest and neural tube. Particularly, they found thatchannel blockers, such as dextromethorphan, were themost potent teratogens. They regarded their results tobe ‘‘alarming’’ given the increased clinical use of NMDAreceptor antagonists, and concluded that of these drugs,dextromethorphan posed ‘‘perhaps the greatest threat tohuman embryos’’ because of its widespread use as anover-the-counter medication (Andaloro et al., ’98). Weare concerned about the extrapolations to the humanembryo that Andaloro et al. (’98) made on the basis oftheir avian study. The authors defend their extrapola-

tions by stating that the genes regulating early embry-onic development have been found to be similar acrossspecies. Still, chicks are very different from humans!Furthermore, applying dextromethorphan directly onthe inner embryonic membrane of the chick does notcompare with the indirect way a human embryo isexposed to dextromethorphan when the mother con-sumes cough syrup containing this drug. The limita-tions of avian embryo studies in predicting humanteratogenicity were eloquently discussed in a previ-ously published article (Rosenquist et al., ’98), but asimilar caveat was missing in the present study. Alsomissing from their discussion were the results from twoepidemiological studies that found no increased fre-

These Letters to the Editor were previously published in PediatricResearch, 1998, Volume 44, pages 415–417, published by LippincottWilliams & Wilkins, Baltimore, MD. Reprinted with permission fromLippincott Williams & Wilkins. All rights reserved.

TERATOLOGY 60:56–60 (1999)

r 1999 WILEY-LISS, INC.

quency of congenital anomalies among the infants of359 women who used dextromethorphan during thefirst trimester of pregnancy (Heinonen et al., ’97;Aselton et al., ’97). It is noteworthy that the TERISdatabase assigns a risk assessment of ‘‘None’’ whenrating the magnitude of teratogenic risk to an infantwhose mother took dextromethorphan during preg-nancy, based on these two negative epidemiologicalstudies (Friedman and Polifka, et al., ’97). TERIS is acomputerized database that provides informationre-garding the teratogenic effects of drugs and chemicalson the human embryo or fetus. An advisoryboard comprised of six experts in clinical teratologyreviews the published scientific literature and assessesthe teratogenic risk for each of the agents on thesystem.

Using the avian embryo, Andaloro et al. (1998)provide important insight into some of the mechanismsunderlying embryonic development; however, more epi-demiological studies need to be conducted before we canconclude that maternal exposure to usual doses ofdextromethorphan will have a similar effect on humanembryos. The nationally-televised announcements ofthe authors’ broad extrapolation to humans have re-sulted in a flood of calls to teratogen informationservices from concerned physicians and pregnant pa-tients who feared that they had harmed their fetuses by

taking over-the-counter cough medications containingdextromethorphan. Scientists need to take more respon-sibility in communicating scientific uncertainty to thelay public and help them put the results of their studiesinto the proper clinical perspective. Andaloro et al. (’98)were remiss in this respect.

Janine E. PolifkaThomas H. ShepardDepartment of PediatricsUniversity of WashingtonSeattle, Washington

LITERATURE CITEDAndaloro VJ, Monaghan DT, Rosenquist TH. 1998. Dextromethorphan

and other N-methyl-D-aspartate receptor antagonists are terato-genic in the avian embryo model. Pediatr Res 43:1–7.

Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. 1985.First-trimester drug use and congenital disorders. Obstet Gynecol65:451–455.

Friedman JM, Polifka JE. 1997. TERIS: the teratogen informationsystem [database online]. Seattle: University of Washington, 1984[updated 2/97]. Available from: University of Washington (Seattle,WA).

Heinonen OP, Slone D, Shapiro S. 1977. Birth defects and drugs inpregnancy. Littleton, MA: John Wright-PSG. p 379–496.

Rosenquist TH, Ratashak SA, Selhub J. 1996. Homocysteine inducescongenital defects of the heart and neural tube: effect of folic acid.Proc Natl Acad Sci USA 93:15227–15232.

To the Editor:I read the article by Andaloro et al. (’98) and was

dismayed by its news media coverage, which quoted theauthors as claiming, ‘‘It can be predicted that the effectsdextromethorphan had on the chicken embryos alsowould occur in human babies.’’

However, over 30 years ago, the Food and DrugAdministration and the teratology scientific commu-nity abandoned the chick embryo for teratogenic screen-ing and more certainly for determining teratogenicrisks in humans (Warkany et al., ’63; Christian, ’83;Kimmel et al., ’87; Brent, ’88; Schardein, ’88). (Thechick embryo is an elegant tool for developmentalbiology research and for studying mechanisms of terato-genicity (Brent, ’88). The chick embryo is a poor modelbecause it is very susceptible to environmental pertur-bations that do not affect the mammal. Second, themetabolism, pharmacokinetics, and accessibility of thedrug can be markedly different in chick and mamma-lian models because of the presence of the maternalliver and chorioplacenta in mammals. Third, priorstudies demonstrated discordance between teratologystudies in the chick and mammalian models.

The essence of the demonstration of a teratogeniceffect is the presence of an increased incidence of

congenital malformations at the end of the period ofdevelopment-term in the mammal and hatching in thechick. The authors of this study terminated their ‘‘teratol-ogy’’ study at 72 hr of development. Those embryos hadcompleted only 15% of their development, and there is noway to determine whether the administration of those‘‘powerful’’ teratogens were teratogenic, i.e., whether anyviable defective embryos would have been present athatching. The authors infer that the 50-nmol exposure tothe chick embryo is equivalent to a 30-mg therapeutic doseof dextromethorphan in the human, but they present nodata or pharmacokinetics to support this conclusion.

They justify using the chick embryo for estimatingrisks to mammals because ‘‘the genes regulating earlyembryonic developmental events (e.g., neural tube clo-sure and neural crest migration) are highly conserved. . . therefore, data derived from experiments with earlyembryos may perhaps be applied broadly to the ex-pected results for other species, when they are exposedto the same teratogens, including the human embryo’’(Andaloro et al., ’98).

Commonality of genes in different species does notgive you commonality of results. There are numerousexamples within mammalian species in which a drug

LETTERS TO THE EDITOR 57