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The safety of astemizole in pregnancy

1996; Elsevier BV; Volume: 98; Issue: 4 Linguagem: Inglês

10.1016/s0091-6749(96)70122-7

1097-6825

A Pastuszak, Betsy Schick, Diana D'Alimonte, Alan E. Donnenfeld, Gideon Koren,

Asthma and respiratory diseases

Since the introduction of nonsedating selective H1 antagonists, they have been largely used by women of reproductive age for the treatment of seasonal allergic rhinitis, conjunctivitis, chronic urticaria, and other allergic conditions. However, because of lack of human studies on the reproductive safety of these compounds, their manufacturers either cannot support their use in pregnancy, through the product monographs,129th ed. Compendium of Pharmaceuticals and Specialties. The Canadian Pharmaceutical Association, Ottawa, Ontario, Canada1994: 556Google Scholar or label them as relatively safe even when no data exist to support such statements. The issue of documenting pregnancy outcome after exposure to new drugs is even more complex if one considers that over 50% of all pregnancies are unplanned, and therefore it may not be sufficient to advise women “not to use a compound in pregnancy.” Astemizole is a potent long-acting selective H1 blocker antihistamine, which does not produce the typical central nervous system depression and drowsiness. In animal studies, doses that were 200- to 800-fold the recommended human dose per kilogram did not induce teratogenic effects.2Schardein JL. Chemically induced birth defects.in: 2nd ed. Marcel Dekker, New York1993: 342Google Scholar We report on the first prospective, controlled, observational study of women who took astemizole during the first trimester of pregnancy and their offspring. We followed up pregnancy outcome of women who were counseled by two Teratogen Information Services between January 1989 and September 1994 after exposure to astemizole: The Motherisk Program in Toronto and the Pregnancy Healthline in Philadelphia, Pennsylvania. Both programs collect information by using a similar protocol including maternal age; gravidity; parity; medical, obstetric, and genetic backgrounds; cigarette smoking and alcohol use in pregnancy; dose of astemizole and length of use during pregnancy. Pregnancy outcome, including mode of delivery, weight gain, perinatal and maternal complications, gestational age, and major malformations were recorded through a follow-up interview with the mother conducted at least 6 months after delivery. Each woman exposed to astemizole was matched to the next woman calling Motherisk according to age (±2 years), smoking, and alcohol use. The control subjects were pregnant women consulted by the Motherisk Program after exposure to nonteratogens (e.g., dental x-rays, acetaminophen). Follow-up of control subjects was conducted in a similar way. The astemizole group was compared with the control group by means of Student’s t test or chi square test whenever appropriate. A total of 114 women, who were counseled during pregnancy on the use of astemizole, were recruited. The mean dose ingested by them (10 mg/day) was according to the recommended instructions for treatment of allergic reactions. Seventy-six women took the drug up to 16 weeks of gestation, whereas the rest (38) used it for longer periods. The astemizole and control groups were of similar ages and smoking and alcohol use patterns, because these were the criteria for matching (Table I). However, women taking astemizole had experienced significantly more pregnancies (Table I). The two groups did not differ in pregnancy weight gain, mode of delivery, percentage of live births, spontaneous or therapeutic abortions. Gestational age at birth was similar between the two groups, as was birth weight (Table II). There were two major malformations in the astemizole group (hypospadias and spina bifida occulta), and in both cases the drug was taken throughout the first trimester; and there were two major malformations in the control group (ventricular septal defect and ocular myopathy). Table IMaternal characteristicsTreatmentControlgroupgroupp(n = 114)(n = 114)ValueAge (yr)31.0 ± 4.731 ± 4.70.9Gravidity0.01•G039 (34.2%)47 (41.2%)0.3•G122 (19.3%)35 (30.7%)0.07•G235 (30.7%)14 (12.3%)0.001•G311 (9.7%)12 (10.5%)1•≥G47 (6.1%)6 (5.3%)1Parity0.02•P048 (42.1%)63 (55.3%)0.06•P133 (28.9%)31 (27.1%)0.90•≥P233 (28.9%)20 (17.5%)0.06Spontaneous0.3 ± 0.60.3 ± 0.50.8abortionTherapeutic0.1 ± 0.40.2 ± 0.50.3abortionSmoking0.96(cigarettes per day)•Abstinence101/112 (90.2%)104 (91.2%)•≤22/112 (1.8%)1 (0.9%)•≤51/112 (1%)1 (0.9%)•≤102/112 (1.8%)2 (1.8%)•≥1 pack/day6/112 (5.4%)6 (5.3%)Alcohol0.8•Abstinence65/112 (58.0%)69 (60.5%)•1-4 gl/mo36/112 (32.1%)35 (30.7%)•5-10 gl/mo3/112 (2.7%)3 (2.6%)•>10 gl/mo8/112 (7.1%)7 (6.1%)gl, Glasses. Open table in a new tab gl, Glasses. Table IIPregnancy outcome dataControlTreatmentgroupp(n = 114)(n = 114)ValuePrepregnancy63.6 ± 12.059.6 ± 9.30.3weight (kg)Weight gain (kg)14.6 ± 6.214.9 ± 5.50.9Delivery0.8•Vaginal, vertex77/104 (74.0%)76/103 (73.8%)•Vaginal, breech0/104 (0%)2/103 (1.9%)•CS, emergency5/104 (4.8%)7/103 (6.8%)•CS, repeat8/104 (7.7%)10/103 (9.7%)•CS, scheduled14/104 (13.5%)8/103 (7.8%)Outcome0.8•Live birth104 (91.2%)104 (91.2%)•SA8 (7.0%)7 (6.1%)•TA1 (0.9%)3 (2.6%)•Stillbirth1 (0.9%)0 (0%)Gestational age39.6 ± 1.739.2 ± 2.60.3at birth (wk)Major malformations2 (1.9%)2 (1.9%)1.0CS, Caesarean section; SA, spontaneous abortion; TA, therapeutic abortion. Open table in a new tab CS, Caesarean section; SA, spontaneous abortion; TA, therapeutic abortion. Because many patients with allergies tend to treat their conditions with the new nonsedating antihistamines and because at least half of pregnancies are unplanned, it is imperative to establish the reproductive safety of these products. In two separate meta-analyses we have documented the safety of doxylamine (the antihistamine used in the antiemetic Bendectin),3Einarson T Leeder S Koren G. A method of meta-analysis of epidemiological studies.Drug Intell Clin Pharm. 1988; 22: 813-824PubMed Google Scholar and of all “old” H1 blockers.4Seto A, Einarson T, Koren G. Pregnancy outcome after first trimester use of antihistamines. Submitted for publication.Google Scholar At present, however, the reproductive safety of astemizole (Hismanal) has not been established. This is a long-acting nonsedating antihistamine with an elimination half-life of 1 to 3 days and an elimination half-life of 11 to 16 days for its active metabolite, desmethylastemizole.5Janssens MML. Astemizole: a nonsedating antihistamine with fast and sustained activity.Clin Rev Allergy. 1993; 11: 35-63PubMed Google Scholar Studies in Wistar rats revealed no teratogenic effect with oral doses as high as 160 mg/kg/day, given between days 6 and 15 of pregnancy.2Schardein JL. Chemically induced birth defects.in: 2nd ed. Marcel Dekker, New York1993: 342Google Scholar For comparison, the average human dose is 0.1 to 0.2 mg/kg/day. In a similar manner, New Zealand white rabbits did not exhibit teratogenicity with oral doses of 40 mg/kg/day between days 6 and 18 of gestation.2Schardein JL. Chemically induced birth defects.in: 2nd ed. Marcel Dekker, New York1993: 342Google Scholar Our prospective study is the first account of astemizole use in pregnancy. No similar reports have been published for other nonsedating antihistamines. The rate of major malformation in the astemizole group (1.9%) was identical to that of the control group and well within the expected range of 1% to 3% in the general population.6Koren G. Maternal-fetal toxicology: a clinician’s guide.2nd ed. Marcel Dekker, New York1994Google Scholar Similarly, the use of the drug was not associated with intrauterine growth retardation or perinatal complications. Our study suggests that astemizole can be used safely during pregnancy. Pregnant women with allergic conditions should not be told to discontinue effective H1 blockers, because this may have a major negative impact on their quality of life. In the case of rhinitis, effective topical compounds with minimal systemic absorption are presently available for use and should be considered.