Over-the-counter H1-antihistamines

H₁-antihistamines are commonly used by pregnant and lactating women. New information suggests that their mechanism of action is different from the initial characterization that they were competitive antagonists of H₁-histamine receptors. On the cellular surface, both active and inactive H₁-receptors exist in equilibrium, responding to histamines (agonists) and inverse agonists (antihistamines). Antihistamines bind and stabilize the inactive receptors, shifting the equilibrium to the inactive state and preventing or reducing the physiologic effects of histamine (Clin. Exp. Allergy 2002;32:489-98).

Antihistamines can be classified as either first-generation (nonselective) or second-generation (peripherally selective) agents. First-generation antihistamines bind nonselectively to central and peripheral inactive H₁-receptors. They have various indications, including allergic rhinitis (hay fever), allergic conjunctivitis, urticaria/angioedema, vasomotor rhinitis, sneezing, asthma, and hypersensitivity reactions. The four first-generation oral agents available over-the-counter (OTC) can be further classified, based on their chemical composition, into two groups: alkylamines (chlorpheniramine) and ethanolamines (clemastine, diphenhydramine, and doxylamine). This latter group has marked sedative properties, as well as anticholinergic and antiemetic actions.

Gerald G. Briggs

Chlorpheniramine

Brands include Aller-Chlor, Allergy Relief, Chlo-Amine, Chlor-Trimeton, and Efidac 24. More than 1,100 first-trimester exposures to this agent have been reported. In these cases, the number of congenital anomalies was not increased over the expected background risk (Collaborative Perinatal Project 1977 [CPP]; and Michigan Medicaid Data 1993 [MMD]).

Clemastine

Brands include Dayhist-1 and Tavist Allergy. More than 2,800 first-trimester exposures to clemastine have been reported. No increased risk of teratogenicity was noted in one study involving 1,230 exposures (J. Matern. Fetal Neonat. Med. 2002;11:146-52). In contrast, among the 1,617 exposures in the MMD, a possible association with limb reduction defects (5 observed/1.9 expected) was discovered, but a causal association cannot be determined from these data.

Diphenhydramine

Brands include AllerMax, Altaryl Children’s Allergy, Banophen, Benadryl, Diphenhist, Dormin, Genahist, Miles Nervine, Nytol, Siladryl, Sleep-eze 3, Sleepwell 2-nite, and Sominex. Commonly used to promote sleep, as well as to treat nausea and allergies, more than 2,300 first-trimester exposures have been reported in the literature.

Several possible associations with congenital defects have been observed in some of these reports, such as those from the CPP and MMD, but many other studies have not found these associations (Drugs in Pregnancy and Lactation, 9th ed. Riverwoods, Ill.: Wolters Kluwer Health, 2011). Withdrawal was observed in one infant whose mother took diphenhydramine 150 mg/day throughout pregnancy (J. Pediatr. 1974;85:580). A potential drug interaction, resulting in stillbirth, occurred when a mother took 50 mg of the antihistamine for itching and then, 1.5 hours later, a 30-mg dose of temazepam for sleep. Violent fetal movements occurred 3 hours later, followed in 4 hours by the stillbirth of a term female infant. The interaction was confirmed in rabbits with a fetal mortality rate of 81% (N. Engl. J. Med. 1985;313:1417-8).

Doxylamine

Brands include Unisom Nighttime Sleep Aid. This agent is a potent antiemetic and sedative and may be one of the most studied drugs in human pregnancy. Although some studies found associations with various defects, most studies have not (Drugs in Pregnancy and Lactation, 9th ed. Riverwoods, Ill.: Wolters Kluwer Health, 2011). These results suggest that other exposures, conditions, or chance were involved in the positive studies, and doxylamine is considered safe to use in pregnancy. The combination of doxylamine and pyridoxine (vitamin B₆) is recommended as a first-line therapy for nausea and vomiting of pregnancy (ACOG Practice Bulletin no. 52. Nausea and vomiting of pregnancy. April 2004. Obstet. Gynecol. 2004;103:803-15). The combination has been available for years as Diclectin in Canada but, in the United States, could only be obtained as individual OTC components. In April 2013, the doxylamine-pyridoxine combination (Diclegis) was approved by the U.S. Food and Drug Administration.

Second-generation antihistamines are selective for peripheral inactive H₁-receptors and, as a group, are less sedating. These agents are used for allergic rhinitis, sinusitis, seasonal allergic rhinitis, and chronic idiopathic urticaria, The three OTC agents in this class also can be divided into two subgroups: piperazines (cetirizine) and piperidines (fexofenadine and loratadine).

Cetirizine

It comes in various generic and Zyrtec formulations. Cetirizine is a human metabolite of hydroxyzine. Although the human pregnancy experience is limited (about 120 cases), there is no evidence that it is a significant risk to the embryo and/or fetus. In one report, pregnant women using the drug for allergies had a lower rate of nausea and vomiting than a control group (Ann. Pharmacother. 2000;34:1486-7).

Fexofenadine

There are various generic and Allegra formulations. There are no reports describing the use of this agent in human pregnancy. Animal data suggest moderate risk based on dose-related embryo and fetal toxicity in rats. The use of other antihistamines is recommended.