Risk Factor: C
Fetal Risk Summary
Hydroxyzine belongs to the same class of compounds as buclizine, cyclizine, and meclizine. The drug is teratogenic in mice and rats, but not in rabbits, at high doses (1,2,3,4 and 5). One report suggested that hydroxyzine teratogenicity was mediated by a metabolite (norchlorcyclizine) that was common to four antihistamines (hydroxyzine, buclizine, meclizine, and chlorcyclizine) (3). High- dose hydroxyzine (612 mg/kg/day) resulted in abortions in rhesus monkeys (6). The manufacturer considers hydroxyzine to be contraindicated in early pregnancy because of the lack of clinical data (1,2).
In 100 patients treated in the 1st trimester with oral hydroxyzine (50 mg daily) for nausea and vomiting, no significant difference from nontreated controls was found in fetal wastage or anomalies (7). A woman treated with 60 mg/day of hydroxyzine during the 3rd trimester gave birth to a normal infant (8).
The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 50 of which had 1st trimester exposure to hydroxyzine (9, pp. 335337, 341). For use anytime during pregnancy, 187 exposures were recorded (9, p. 438). Based on 5 malformed children, a possible relationship was found between 1st trimester use and congenital defects.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 828 newborns had been exposed to hydroxyzine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 48 (5.8%) major birth defects were observed (42 expected). Specific data were available for six defect categories, including (observed/expected) 9/8 cardiovascular defects, 1/0.4 spina bifida, 0/2 polydactyly, 2/1 limb reduction defects, 0/2 hypospadias, and 3/1 oral clefts. Only with the latter defect is there a suggestion of a possible association, but other factors, including the mother’s disease, concurrent drug use, and chance, may be involved.
Withdrawal in a newborn exposed to hydroxyzine 600 mg/day throughout gestation has been reported (10). The mother, who was being treated for severe eczema and asthma, was also treated with phenobarbital, 240 mg/day for 4 days then 60 mg/day, for mild preeclampsia during the 3-week period before delivery. Symptoms in the newborn, some beginning 15 minutes after birth, consisted of a shrill cry, jitteriness with clonic movements of the upper extremities, irritability, and poor feeding. The presumed drug-induced withdrawal persisted for approximately 4 weeks and finally resolved completely after 2 weeks of therapy with phenobarbital and methscopolamine. The infant was apparently doing well at 9 months of age. Although phenobarbital withdrawal could not be excluded, and neonatal withdrawal is a well-known complication of phenobarbital pregnancy use, the author concluded the symptoms in the infant were primarily caused by hydroxyzine (10).
A 1996 report described the use of hydroxyzine, droperidol, diphenhydramine, and metoclopramide in 80 women with hyperemesis gravidarum (11). The mean gestational age at the start of treatment was 10.9 3.9 weeks. All women received approximately 200 mg/day of hydroxyzine in divided dosage for up to a week after discharge from the hospital, and 12 (15%) required a second course of therapy for recurrence of their symptoms. Three of the mothers (all treated in the 2nd trimester) delivered offspring with congenital defects: Poland’s syndrome, fetal alcohol syndrome, and hydrocephalus and hypoplasia of the right cerebral hemisphere. Only the latter anomaly is a potential drug effect, but the most likely cause was thought to be the result of an in utero fetal vascular accident or infection (11).
A 2001 study, using a treatment method similar to the above study, described the use of droperidol and diphenhydramine in 28 women hospitalized for hyperemesis gravidarum (12). Pregnancy outcomes in the study group were compared to a historical control of 54 women who had received conventional antiemetic therapy. Oral metoclopramide and hydroxyzine were used after discharge from the hospital. Therapy was started in the study and control groups at mean gestational ages of 9.9 and 11.1 weeks’, respectively. The study group appeared to have more severe disease then controls as suggested by a greater mean loss from the prepregnancy weight, 2.07 kg vs. 0.81 kg (n.s.), and a slightly lower serum potassium level, 3.4 vs. 3.5 mmol/L (n.s.). Compared to controls, the droperidol group had a shorter duration of hospitalization (3.53 vs. 2.82 days, p=0.023), fewer readmissions (38.9% vs. 14.3%, p=0.025), and lower average daily nausea and vomiting scores (both p0.05) in outcomes (study vs controls) in terms of spontaneous abortions (N=0 vs. N=2 [4.3%]), elective abortions (N=3 [12.0%] vs. N=3 [6.5%]), Apgar scores at 1, 5, and 10 minutes, age at birth (37.3 vs. 37.9 weeks’), and birth weight (3114 vs. 3347 g) (12). In controls, there was one (2.4%) major malformation of unknown cause, an acardiac fetus in a set of triplets, and one newborn with a genetic defect (Turner syndrome). There was also one unexplained major birth defect (4.4%) in the droperidol group (bilateral hydronephrosis), and two genetic defects (translocation of chromosomes 3 and 7; tyrosinemia) (12).
A prospective controlled study published in 1997 evaluated the teratogenic risk of hydroxyzine and cetirizine (see also Cetirizine) in human pregnancy (13). A total of 120 pregnancies (2 sets of twins) exposed to either hydroxyzine (N=81) or cetirizine (N=39) 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 53 (65%) of the hydroxyzine cases and in 37 (95%) of the cetirizine exposures for a variety of indications (e.g., rhinitis, urticaria, pruritic urticarial papules and plaques of pregnancy, sedation, and other nonspecified reasons). Fourteen spontaneous abortions (hydroxyzine 3, cetirizine 6, controls 5) and 11 induced abortions (hydroxyzine 6, controls 5) occurred in the three groups. Among the live births, there were no statistical differences between the groups in birth weight, gestational age at delivery, rate of cesarean section, or neonatal distress. In the hydroxyzine group, two of the live births had major malformations, one with a ventricular septal defect and one with 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. Two minor anomalies were observed in liveborn infants exposed to cetirizine during organogenesis, one with an ectopic kidney and one with undescended testes. No major abnormalities were seen in this group. 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 (13).
A 1997 article compared the published pregnancy outcomes, in terms of congenital malformations, of various first- and second-generation antihistamines (14). Based on 995 hydroxyzine-exposed liveborn infants, the authors calculated a relative risk for any congenital malformation that ranged from 1.2 to 3.4 (95% confidence interval 0.4 to 0.9, 1.6 to 17.9). Based on their analysis of published reports, the authors concluded that, in pregnancy, chlorpheniramine is the oral antihistamine of choice and that diphenhydramine should be used if a parenteral antihistamine is required (14).
During labor, hydroxyzine has been shown to be safe and effective for the relief of anxiety (15,16). No effect on the progress of labor or on neonatal Apgar scores was observed. In a study published in 1978, however, a 75-mg IM dose administered during labor caused a statistically significant decrease in FHR variability in 10 of 16 cases (17). Maximal effects on the FHR were observed within 25 minutes after which they returned to normal values. Administration of hydroxyzine close to delivery reduces newborn platelet aggregation, but the clinical significance of this is unknown (18).
Breast Feeding Summary
No reports describing the use of hydroxyzine during lactation, or measuring the amount of the drug in breast milk, have been located. The molecular weight (about 448) is low enough that excretion into breast milk should be expected. The effects, if any, on the nursing infant are unknown.
- Product information. Vistaril. Pfizer, 1997.
- Product information. Atarax. Pfizer, 1997.
- King CTG, Howell J. Teratogenic effect of buclizine and hydroxyzine in the rat and chlorcyclizine in the mouse. Am J Obstet Gynecol 1966;95:10911.
- Posner HS, Darr A. Fetal edema from benzhydrylpiperazines as a possible cause of oral-facial malformations in rats. Toxicol Appl Pharmacol 1970;17:6775.
- Walker BE, Patterson A. Induction of cleft palate in mice by tranquilizers and barbiturates. Teratology 1974;10:15964.
- Steffek AJ, King CTG, Wilk AL. Abortive effects and comparative metabolism of chlorcyclizine in various mammalian species. Teratology 1968;1:399406.
- Erez S, Schifrin BS, Dirim O. Double-blind evaluation of hydroxyzine as an antiemetic in pregnancy. J Reprod Med 1971;7:579.
- Romero R, Olsen TG, Chervenak FA, Hobbins JC. Pruritic urticarial papules and plaques of pregnancy. A case report. J Reprod Med 1983;28:6159.
- Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977.
- Prenner BM. Neonatal withdrawal syndrome associated with hydroxyzine hydrochloride. Am J Dis Child 1977;131:52930.
- Nageotte MP, Briggs GG, Towers CV, Asrat T. Droperidol and diphenhydramine in the management of hyperemesis gravidarum. Am J Obstet Gynecol 1996;174:18016.
- Turcotte V, Ferreira E, Duperron L. Utilit du dropridol et de la diphenhydramine dans l’hyperemesis gravidarum. J Soc Obstet Gynaecol Can 2001;23:1339.
- 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;78:1836.
- Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 1997;78:1579.
- Zsigmond EK, Patterson RL. Double-blind evaluation of hydroxyzine hydrochloride in obstetric anesthesia. Anesth Analg (Cleve) 1967;46:27580.
- Amato G, Corsini D, Pelliccia E. Personal experience with a combination of Althesin and Atarax in caesarean section. Minerva Anesteriol 1980;46:6714.
- Petrie RH, Yeh S-Y, Murata Y, Paul RH, Hon EH, Barron BA, Johnson RJ. The effects of drugs on fetal heart rate variability. Am J Obstet Gynecol 1978;130:2949.
- Whaun JM, Smith GR, Sochor VA. Effect of prenatal drug administration on maternal and neonatal platelet aggregation and PF4 release. Haemostasis 1980;9:22637.