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Exposure to alcohol-containing medications during pregnancy
Facundo Garcia-Bournissen, MD, Yaron Finkelstein, MD, Massoud Rezvani, MD, Gideon Koren, MD, FRCPC
A pregnant patient consulted her physician after discovering that a diphenhydramine preparation (Benadryl elixir) she used for allergy symptoms during the first trimester of her pregnancy contained 15% alcohol. Should she be concerned about fetal alcohol spectrum disorder in her baby?
Most ethanol-containing medical preparations are safe during pregnancy. Adult doses of some elixirs with high ethanol concentrations might produce blood levels similar to those achieved by drinking 1 alcoholic beverage. Caution is advisable when prescribing ethanol-containing elixirs to pregnant women, as is informing them about the alcohol content.
Une patiente enceinte a consulté son médecin après avoir découvert qu’une préparation de diphenhydramine (l’élixir Bénadryl), qu’elle prenait durant le premier trimestre de sa grossesse pour des symptômes d’allergie, contenait 15% d’alcool. Devrait-elle s’inquiéter de la possibilité du syndrome d’intoxication fœtale à l’alcool chez son bébé?
La plupart des préparations médicales contenant de l’éthanol sont sécuritaires durant la grossesse. Une dose pour adulte de certains élixirs à forte concentration d’éthanol pourrait produire des taux d’alcool dans le sang semblables à ceux produits après avoir bu 1 consommation d’alcool. Il est conseillé d’être prudents lorsqu’on prescrit des élixirs contenant de l’éthanol aux femmes enceintes et de bien les renseigner sur le contenu en alcool.
Ethanol is used widely in pharmaceutical formulations and cosmetics as an antimicrobial preservative or as a solvent. Some common ethanol-containing medications are listed in Table 1. More than 130 preparations containing ethanol are listed in the 2006 Canadian Compendium of Pharmaceuticals and Specialties.1
If the above patient used Benadryl elixir containing 15% alcohol at an adult dose of 50 mg 4 times daily (80 mL of elixir daily), she would have ingested about 10 g of ethanol daily, equivalent to the amount of alcohol in a glass of wine.
Ethanol is a potent animal and human teratogen. A dose-dependent risk of malformation has been demonstrated repeatedly in animal experiments.2-4 Epidemiologic studies in humans have provided strong evidence for dose-dependent toxicity, with babies of heavy-drinking pregnant women having a higher risk of fetal alcohol spectrum disorder than those of moderate drinkers.5-7
A threshold level of exposure for fetal toxicity (ie, a level below which there is no toxicity) of ethanol has not been identified so far.8,9 Some authors have suggested, based on animal studies, that this threshold level could be exceeded with very low levels of exposure.9
Data obtained from animal studies suggest that serum ethanol concentrations are the best risk marker for fetal toxicity. On the other hand, the toxicologic definition of a threshold level of exposure in which no adverse effect is observed must be based on studies evaluating exposure of the most sensitive indicator of toxicity, the brain. Direct measurements of alcohol concentrations in the human fetal brain and correlation with neurotoxicity are not feasible, which precludes a precise estimation of dose-related risk.9
Most human data come from studies evaluating fetal ethanol exposure among alcohol-drinking pregnant women. Some experts consider the developmental outcomes observed to be irrelevant to the low blood alcohol concentrations resulting from physicians’ recommending use of consumer products containing ethanol.10,11 Small quantities of ethanol in the blood are metabolized rapidly, unlike the medium-to-large amounts ingested in beverages, which saturate alcohol-metabolizing enzymes and lead to disproportionally high blood alcohol concentrations.12-14
Experiments in primates have established that the threshold level of exposure for ethanol blood concentration is 400 mg/L,10 a level higher than most ethanol-containing medications would produce. Elixir formulations taken in adult doses would lead to exposures similar to those following 1 average alcoholic drink (9 to 14 g of ethanol), which produces serum levels around 150 mg/L.10 Most of these medications would be used for only short periods and would be divided into several (eg, 3 or 4) small doses throughout the day, unlike most alcohol exposures among alcholic beverage drinkers enrolled in epidemiologic studies. Yet the prospect of pregnant patients’ unknowingly consuming alcohol at a dose equivalent to 1 drink a day is troubling.
While most medical, industrial, and domestic uses of ethanol-containing products might be safe during pregnancy, women should still be made aware that they contain alcohol. Adult doses of some elixirs with high ethanol concentrations might produce blood alcohol levels similar to those observed after 1 alcoholic drink.10 It is important to use caution when prescribing ethanol-containing elixirs to pregnant women.
1. Repchins C, Editor-in-Chief. Compendium of Pharmaceuticals and Specialties. The Canadian drug reference for health professionals. Ottawa, Ont: Canadian Pharmacists Association; 2006.
2. Vaglenova J, Petkov VV. Fetal alcohol effects in rats exposed pre- and postnatally to a low dose of ethanol. Alcohol Clin Exp Res 1998;22(3):697-703.
3. Streissguth AP, Landesman-Dwyer S, Martin JC, Smith DW. Teratogenic effects of alcohol in humans and laboratory animals. Science 1980;209(4454):353-61.
4. Becker HC, Diaz-Granados JL, Randall CL. Teratogenic actions of ethanol in the mouse: a minireview. Pharmacol Biochem Behav 1996;55(4):501-13.
5. Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, Frias JL. Risk for congenital anomalies associated with different sporadic and daily doses of alcohol consumption during pregnancy: a case-control study. Birth Defects Res A Clin Mol Teratol 2004;70(4):194-200.
6. Jacobson JL, Jacobson SW. Drinking moderately and pregnancy. Effects on child development. Alcohol Res Health 1999;23(1):25-30.
7. Sood B, Delaney-Black V, Covington C, Nordstrom-Klee B, Ager J, Templin T, et al. Prenatal alcohol exposure and childhood behavior at age 6 to 7 years: I. dose-response effect. Pediatrics 2001;108(2):E34.
8. Ernhart CB, Sokol RJ, Martier S, Moron P, Nadler D, Ager JW, et al. Alcohol teratogenicity in the human: a detailed assessment of specificity, critical period, and threshold. Am J Obstet Gynecol 1987;156(1):33-9.
9. Sampson PD, Streissguth AP, Bookstein FL, Barr HM. On categorizations in analyses of alcohol teratogenesis. Environ Health Perspect 2000;108(Suppl 3):421-8.
10. Irvine LF. Relevance of the developmental toxicity of ethanol in the occupational setting: a review. J Appl Toxicol 2003;23(5):289-99.
11. Abel EL, Hannigan JH. Maternal risk factors in fetal alcohol syndrome: provocative and permissive influences. Neurotoxicol Teratol 1995;17(4):445-62.
12. Jones AW. Aspects of in-vivo pharmacokinetics of ethanol. Alcohol Clin Exp Res 2000;24(4):400-2.
13. Shoaf SE. Pharmacokinetics of intravenous alcohol: two compartment, dual Michaelis-Menten elimination. Alcohol Clin Exp Res 2000;24(4):424-5.
14. Holford NH. Clinical pharmacokinetics of ethanol. Clin Pharmacokinet 1987;13(5):273-92.