Sympathomimetic (Adrenergic)
PREGNANCY RECOMMENDATION: Human Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Although the limited human data suggest there may be a risk of gastroschisis and small intestinal atresia (SIA) from 1st trimester exposure to pseudoephedrine, the risk is low and may only be identifiable in case–control studies. Moreover, the risk may only be present when pseudoephedrine is combined with other agents, not when it used alone. Confirmation of these findings is required. Until such data are available, the best course is to avoid pseudoephedrine during the 1st trimester.
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, 3082 of whom had 1st trimester exposure to sympathomimetic drugs (2, pp. 345–356). For use anytime during pregnancy, 9719 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–control surveillance study published in 1992 reported a significantly elevated relative risk of 3.2 (95% confidence interval [CI] 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).
In a 2002 retrospective case–control study, conducted in 1995–1999, mothers of 206 gastroschisis cases, 126 SIA cases, and 798 controls were interviewed about medication use and illnesses (4). The interval of between birth and interview was <6 months for all cases. The risk of gastroschisis was increased for aspirin (odds ratio [OR] 2.7, 95% CI 1.1–5.9), all pseudoephedrine (OR 1.8, 95% CI 1.0–3.2), all acetaminophen (OR 1.5, 95% CI 1.1–2.2), and pseudoephedrine plus acetaminophen (OR 4.2, 95% CI 1.9–9.2). The risk for SIA was increased for all pseudoephedrine (OR 2.0, 95% CI 1.0–4.0), and pseudoephedrine plus acetaminophen (OR 3.0, 95% CI 1.1–9.0). However, when pseudoephedrine was used as a single agent, the ORs and 95% CIs for gastroschisis and SIA were 0.7 (0.2–2.1) and 1.1 (0.5–2.9), respectively. Fever (as reported by the patient), upper respiratory infection, and allergy were not associated with increased risks of gastroschisis or SIA. There were also no significant associations with phenylpropanolamine, ibuprofen, antihistamines, guaifenesin, or dextromethorphan. The results confirmed the association of an increased risk of gastroschisis with aspirin shown in previous studies. However, the data for pseudoephedrine raised questions concerning interactions between drugs and possible confounding by underlying illness (4).
A 2005 abstract reviewed the fetal effects of pseudoephedrine after 1st trimester exposure (5). Two analyses of pharmacy data from health maintenance organizations revealed 9 malformed infants among 902 exposures, suggesting no association with congenital malformations overall. However, case–control studies have shown that 1st trimester exposure to decongestants is associated with small to moderate increases in the risk of gastroschisis, SIA, and hemifacial microsomia. Moreover, these risks are increased if the mother also smokes cigarettes (5).
Data from the Swedish Medical Birth Registry regarding pregnancy exposure to oral decongestants were reported in 2006 (6). The 1st trimester pregnancy exposures reported by 2474 women were 2304 phenylpropanolamine alone, 136 phenylpropanolamine plus cinnarizine, 23 pseudoephedrine alone, and 11 used 2 of these preparations. Compared with 1771 women who were prescribed an oral decongestant later in pregnancy, the risk ratio for any congenital malformation among the 2474 subjects was 0.96, 95% CI 0.80–1.16 (6).
A 1981 report described a woman who consumed, throughout pregnancy, 480–840 mL/day of a cough syrup (7). 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 (7). It is not known whether the ingredients, other than the ethanol, were associated with the adverse effects observed in the infant.
BREASTFEEDING SUMMARY
Pseudoephedrine is excreted into breast milk (8,9). Three mothers, who were nursing healthy infants, were given an antihistamine-decongestant preparation containing 60 mg of pseudoephedrine and 2.5 mg of triprolidine (8). 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 (8).
A single-blind, cross-over study of pseudoephedrine 60 mg vs. placebo was conducted in eight lactating women (9). The mean milk volume was significantly reduced by pseudoephedrine, falling from 784 mL/day (placebo period) to 623 mL/day (pseudoephedrine period). The effect on milk volume was not due to breast blood flow, but the slightly reduced (ns) serum prolactin concentrations in the women may have contributed. The mean average milk concentration was 829 mcg/L. Assuming a pseudoephedrine 60 mg 4 times daily dose (maximum recommended dose), the estimated infant dose, based on AUC and 150 mL/kg/day, was 4.3% of the mother’s weight-adjusted dose (9).
The American Academy of Pediatrics classifies pseudoephedrine as compatible with breastfeeding (10).
References
1.Nishimura H, Tanimura T. Clinical Aspects of the Teratogenicity of Drugs. Amsterdam, The Netherlands: 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.Werler MM, Sheehan JE, Mitchell AA. Maternal medication use and risks of gastroschisis and small intestinal atresia. Am J Epidemiol 2002;155:26–31.
5.Werler MM. Teratogen update: pseudoephedrine. Birth Defects Res A Clin Mol Teratol 2005;73:328.
6.Kallen BAJ, Olausson PO. Use of oral decongestants during pregnancy and delivery outcome. Am J Obstet Gynecol 2006;194:480–5.
7.Chasnoff IJ, Diggs G. Fetal alcohol effects and maternal cough syrup abuse. Am J Dis Child 1981;135:968.
8.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.
9.Aljazaf K, Hale TW, Hett KF, Hartmann PE, Mitoulas LR, Kritensen JH, Hackett LP. Pseudoephedrine: effects on milk production in women and estimation of infant exposure via breastmilk. Br J Clin Pharmacol 2003;56:18–24.
10.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.