CETIRIZINE

Fetal Risk Summary

The antihistamine, cetirizine, is a second-generation, orally active, selective peripheral H1-receptor antagonist. It is indicated for the relief of seasonal and perennial allergic rhinitis and for the treatment of chronic urticaria. The agent is a human metabolite of hydroxyzine.

Reproduction studies in mice, rats, and rabbits at oral doses up to 40, 180, and 220 times the maximum recommended human daily dose on a body surface area basis (MRHD), respectively, revealed no teratogenic effects (1).

It is not known if cetirizine crosses the human placenta to the fetus. The molecular weight (about 462 for the dihydrochloride salt) is low enough, however, that transfer to the fetus should be expected.

A prospective controlled study published in 1997 evaluated the teratogenic risk of cetirizine and hydroxyzine (see also Hydroxyzine) in human pregnancy (2). A total of 120 pregnancies (2 sets of twins) exposed to either cetirizine (N=39) or hydroxyzine (N=81) during pregnancy were identified and compared to 110 controls. The control group was matched for maternal age, smoking, and alcohol use. The drugs were taken during the 1st trimester in 37 (95%) of the cetirizine exposures and in 53 (65%) of the hydroxyzine cases for a variety of indications (e.g., rhinitis, urticaria, pruritic urticarial papules and plaques of pregnancy, sedation, and other nonspecified reasons). Fourteen spontaneous abortions (cetirizine 6, hydroxyzine 3, controls 5) and 11 induced abortions (hydroxyzine 6, controls 5) occurred in the three groups. Among the live births, there were no statistical differences among the groups in birth weight, gestational age at delivery, rate of cesarean section, or neonatal distress. Two minor anomalies were observed in live-borne infants exposed to cetirizine during organogenesis; one had an ectopic kidney and one had undescended testes. No major abnormalities were seen in this group. In the hydroxyzine group, two of the live births had major malformations; one had a ventricular septal defect and one a complex congenital heart defect (also exposed to carbamazepine). A third infant, exposed after organogenesis, also had a ventricular septal defect. Minor abnormalities were observed in four hydroxyzine-exposed infants: one case each of hydrocele, inguinal hernia, hypothyroidism (mother also taking propylthiouracil), and strabismus. In the control group, no major malformations were observed, but five infants had minor defects (dislocated hip, growth hormone deficiency, short lingual frenulum, and two unspecified defects). Statistically, there were no differences between the groups in outcome (2).

A recent review compared the published pregnancy outcomes in terms of congenital malformations of various first and second generation antihistamines (3). Based on the one study above, the authors calculated a relative risk for cetirizine of 1.2 (95% confidence interval 0.1, 11.7). They concluded that in pregnancy, chlorpheniramine is the oral antihistamine of choice and that diphenhydramine should be used if a parenteral antihistamine is required (3).

A 1998 noninterventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (4). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Cetirizine was taken during the 1st trimester in 20 pregnancies. The outcomes of these pregnancies included 4 spontaneous abortions, 1 elective abortion, and 16 normal, term infants (1 set of twins) (4). Although this study found no major birth defects, it lacked the sensitivity to identify minor anomalies because of the absence of standardized examinations. Further, late-appearing major defects may also have been missed because of the timing of the questionnaires.

A 2000 publication reported the antiemetic effects of cetirizine in 60 women who were using the antihistamine (10 mg/day) for the treatment of allergies during pregnancy (5). A control group of pregnant women, matched for the use of pyridoxine (vitamin B6) but who were not taking an antihistamine, was used for comparison. The cetirizine group had a significantly lower rate of nausea and vomiting (7% vs 37%, p=0.0001). No pregnancy outcome data were provided.

In summary, cetirizine is not an animal teratogen, and there is no evidence in human pregnancy that the antihistamine presents a significant risk to the fetus. However, the number of human pregnancy exposures is too few to adequately assess the potential risk. Although cetirizine appears unlikely to be a major human teratogen, an oral first generation agent, such as chlorpheniramine or tripelennamine, should be considered if antihistamine therapy during pregnancy (especially in the 1st trimester) is required. Cetirizine or loratadine were considered acceptable alternatives, except during the 1st trimester, if a first generation agent was not tolerated (6,7 and 8). The use of cetirizine as an antiemetic needs further study.

Breast Feeding Summary

No published reports describing the use of cetirizine during human lactation have been located, but the manufacturer states that the antihistamine is excreted into human milk. This would be consistent with the relatively low molecular weight (about 462 for the dihydrochloride salt). Retarded pup weight gain was observed when lactating mice were given an oral dose (approximately 40 times the MRHD) of cetirizine (1). Moreover, in beagle dogs, about 3% of a cetirizine dose was excreted into milk (1). The effects, if any, on a nursing infant exposed to cetirizine in milk are unknown, but sedation is a possibility.

References

1. Product information. Zyrtec. Pfizer, 2001.
2. Einarson A, Bailey B, Jung G, Spizzirri D, Baillie M, Koren G. Prospective controlled study of hydroxyzine and cetirizine in pregnancy. Ann Allergy Asthma Immunol 1997;78:183–6.
3. Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 1997;78:157–9.
4. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.
5. Einarson A, Levichek Z, Einarson TR, Koren G. The antiemetic effect of cetirizine during pregnancy. Ann Pharmacol 2000;34:1486–7.
6. Mazzotta P, Loebstein R, Koren G. Treating allergic rhinitis in pregnancy. Safety considerations. Drug Saf 1999;20:361–75.
7. Horak F, Stubner UP. Comparative tolerability of second generation antihistamines. Drug Saf 1999;20:385–401.
8. Position statement of a joint committee of the American College of Obstetricians and Gynecologists and the American College of Allergy, Asthma and Immunology. The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000;84:475–80.