The Safety of Dextromethorphan in Pregnancy: Results of a Controlled Study

; ; and , Motherisk Program, Division of Clinical Pharmacology, The Hospital for Sick Children, University Of Toronto, Ontario, Canada.

Disclosures

CHEST. 2001;119(2) 

In This Article

Discussion

Although DM has been on the market for many years, this is the first controlled study to specifically examine this particular cough medicine for its safety during pregnancy. The rates of malformations in the DM and the control groups were comparable, with no specific pattern of defects emerging in either group. Of particular interest, there were no cases of neural tube defects in the study group, as was suggested by the in ovo study.[2]

The inappropriate extrapolation from the chick embryo model to humans and the subsequent publicity in the lay press caused many women and their health professionals undue alarm. In fact, one woman in our study group reported that the Toronto Star article with the headline "Pregnant women urged to shun cough remedies" was posted in her doctor's office.[10]

It is crucial to examine the relevance of the teratogenicity in a chick embryo in humans. Animal studies can but do not always predict whether a drug will be teratogenic in humans; the main role of animal studies is to understand the mechanisms of teratogenicity. When thalidomide was first tested on rats and mice, it did not produce birth defects.[13] Conversely, some drugs have been found to be teratogenic in animals, but were not in clinically relevant doses in humans.[5,12] Today, when new drugs are screened for teratogenicity, three different animal models are required for testing.[5] Consequently, it can happen quite frequently that when certain drugs are tested on different animal species, birth defects will occur, such as in the DM study.[2]

The situation is much more complex when in ovo or other in vitro methods are used. As delineated by Polifka and Shepard,[14] Brent,[15] and Holmes,[16] in vitro studies cannot be used to identify a human teratogen, due to an absence of normal absorption, distribution and metabolism, the excessive dose used, the very short duration of the in vivo experiment, and the lack of epidemiologic evidence for human teratogenicity.

There are several limitations to this study. It is a known fact that DM is metabolized by cytochrome P450, with 1 in 10 of the population deficient in the enzyme, resulting in the ingestion of DM in some women leading to higher plasma levels. However, we do not really believe this is important, because dosage does not appear to be crucial.

Another limitation is we cannot define the exact amount of DM used; however, we do know that the dose of DM in over-the-counter preparations is either 15 mg or 30 mg per dose.

Finally, the biggest limitation is the sample size, as is always the case in these types of studies in pregnant women. For obvious reasons, women are not going to volunteer to participate in a study if they are asked to take a drug to investigate if it causes birth defects. These are women who were either unaware they were pregnant, or were suffering from such a bad cough that they took the drug regardless. This sample size has an 80% power to detect a 3.5-fold increase in the rate of malformations, with an of 0.05 and a 95% confidence interval.

In summary, our study of 184 women who were exposed to DM during their pregnancy (128 exposures in the first trimester) did not reveal an increase in the rates of major malformations above the baseline rate of 1% to 3%.

These results suggest that the use of DM in pregnancy does not pose a risk to the fetus; however, because of the size of this study, we are unable to rule out an increased risk for rare malformations.

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