PSEUDOEPHEDRINE

Fetal Risk Summary

Pseudoephedrine is a sympathomimetic used to alleviate the symptoms of allergic disorders or upper respiratory infections. It is a common component of proprietary mixtures containing antihistamines and other ingredients. Thus, it is difficult to separate the effects of pseudoephedrine on the fetus from those of other drugs, disease states, and viruses.

Sympathomimetic amines are teratogenic in some animal species, but human teratogenicity has not been suspected (1). The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 3,082 of which had 1st trimester exposure to sympathomimetic drugs (2, pp. 345–356). For use anytime during pregnancy, 9,719 exposures were recorded (2, p. 439). An association in the 1st trimester was found between the sympathomimetic class of drugs as a whole and minor malformations (not life-threatening or major cosmetic defects), inguinal hernia, and clubfoot (2, pp. 345–356). However, independent confirmation of these results is required (2, pp. 345–356).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 940 newborns had been exposed to pseudoephedrine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 37 (3.9%) major birth defects were observed (40 expected). Specific data were available for six defect categories, including (observed/expected) 3/9 cardiovascular defects, 2/2 oral clefts, 0/0 spina bifida, 3/3 polydactyly, 0/2 limb reduction defects, and 0/2 hypospadias. These data do not support an association between the drug and congenital defects.

A case-controlled surveillance study published in 1992 reported a significantly elevated relative risk of 3.2 (95% confidence interval, 1.3–7.7) for the use of pseudoephedrine during the 1st trimester and 76 exposed cases with gastroschisis (3). A total of 2142 infants with other malformations formed a control group. Relative risks for other drugs were salicylates 1.6, acetaminophen 1.7, ibuprofen 1.3, and phenylpropanolamine 1.5. Because some of these drugs are vasoactive substances, and because the cause of gastroschisis is thought to involve vascular disruption of the omphalomesenteric artery (3), the investigators compared the use of 1st trimester pseudoephedrine and other drugs in relation to a heterogeneous group of malformations, other than gastroschisis, suspected of also having a vascular origin. In this case, however, the relative risk for the drugs approximated unity. These data suggested that the association between pseudoephedrine and the other drugs and gastroschisis may have been caused by an underlying maternal illness (3).

A 1981 report described a woman who consumed, throughout pregnancy, 480–840 mL/day of a cough syrup (4). The potential maximum daily doses based on 840 mL of syrup were 5.0 g of pseudoephedrine, 16.8 g of guaifenesin, 1.68 g of dextromethorphan, and 79.8 mL of ethanol. The infant had features of the fetal alcohol syndrome (see Ethanol) and displayed irritability, tremors, and hypertonicity. It is not known whether the ingredients, other than the ethanol, were associated with the adverse effects observed in the infant.

Breast Feeding Summary

Pseudoephedrine is excreted into breast milk (5). Three mothers, who were nursing healthy infants, were given an antihistamine-decongestant preparation containing 60 mg of pseudoephedrine and 2.5 mg of triprolidine as the hydrochloride salts. Two of the mothers had been nursing for 14 weeks, and one had been nursing for 18 months. Milk concentrations of pseudoephedrine were higher than plasma levels in all three patients, with peak milk concentrations occurring at 1.0–1.5 hours. The milk:plasma ratios at 1, 3, and 12 hours in one subject were 3.3, 3.9, and 2.6, respectively. The investigators calculated that 1000 mL of milk produced during 24 hours would contain 0.25–0.33 mg of pseudoephedrine base, approximately 0.5–0.7% of the maternal dose (5). The American Academy of Pediatrics considers the drug to be compatible with breast feeding (6).

References

1. Nishimura H, Tanimura T. Clinical Aspects of the Teratogenicity of Drugs. Amsterdam: Excerpta Medica, 1976:231.
2. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
3. Werler MM, Mitchell AA, Shapiro S. First trimester maternal medication use in relation to gastroschisis. Teratology 1992;45:361–7.
4. Chasnoff IJ, Diggs G. Fetal alcohol effects and maternal cough syrup abuse. Am J Dis Child 1981;135:968.
5. Findlay JWA, Butz RF, Sailstad JM, Warren JT, Welch RM. Pseudoephedrine and triprolidine in plasma and breast milk of nursing mothers. Br J Clin Pharmacol 1984;18:901–6.
6. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.