A prospective cohort study

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encephaloceles, or macroglossia occurred.1, 3 The terato- genic effects of high doses of this drug in rats have been attributed to its action on the adrenal gland ...

Pregnancy outcome after in utero exposure to itraconazole: A prospective cohort study Benjamin Bar-Oz, MD,a, b Myla E. Moretti, MSc,a, b Raafat Bishai, MD,a, b Guy Mareels, PhD,c Tony Van Tittelboom, MD,c Johan Verspeelt, MD,c and Gideon Koren, MDa, b Toronto, Ontario, Canada, and Beerse, Belgium OBJECTIVE: This study was undertaken to determine whether itraconazole use during the first trimester of pregnancy was associated with increased risks of major malformations, spontaneous abortions, premature deliveries, and neonatal complications. STUDY DESIGN: In a prospective cohort study pregnant women exposed to oral itraconazole were matched with control subjects not exposed to any known teratogens. Primary outcome was the rate of major malformations. Secondary outcomes were live birth rate, rates of spontaneous abortion and therapeutic abortion, gestational age at delivery, birth weight, and neonatal complications. RESULTS: A total of 229 women exposed to itraconazole were reported to the manufacturer, 198 of whom used the drug during the first trimester of pregnancy. The rate of major malformations in the study group (156 live births) was 3.2%, compared with 4.8% in the control group (187 live births; relative risk, 0.67; 95% confidence interval, 0.23-1.95). The rate of any pregnancy loss was higher in the exposed group (relative risk, 1.75; 95% confidence interval, 1.47-2.09). Birth weight was lower in the itraconazole group, although that difference may not be clinically significant. Gestational age at birth, rate of preterm delivery, Apgar scores at 1 and 5 minutes, and neonatal complications were comparable between the groups. CONCLUSION: Our study supports the hypothesis that the use of itraconazole during pregnancy is safe. Further surveillance and reporting of pregnancy outcomes will help to support this conclusion. (Am J Obstet Gynecol 2000;183:617-20.)

Key words: Itraconazole, malformations, pregnancy

Itraconazole (Sporanox) is a systemic antifungal agent of the triazole group, as is fluconazole. It is indicated for the treatment of various fungal infections in both immunocompetent and immunocompromised patients.1 Itraconazole has been shown to produce embryotoxicity and to be teratogenic in both rats and mice.1-3 Major skeletal and secondary soft tissue defects in the offspring were reported when the drug was given in high doses to pregnant rats. In mice given 10 times the maximum recommended human dose maternal toxicity, fetal toxicity, encephaloceles, or macroglossia occurred.1, 3 The teratogenic effects of high doses of this drug in rats have been attributed to its action on the adrenal gland by blocking the activity of phospholipase A2 or cyclooxygenase and thus blocking the formation of various biologic media-

From the Motherisk Program, Division of Clinical Pharmacology/Toxicology, Hospital for Sick Children,a The Wood Gundy Children’s Miracle Foundation Chair in Child Health Research, The University of Toronto,b and Janssen Pharmaceutica Products, LP.c Supported by the Janssen Research Foundation, Beerse, Belgium. Received for publication June 29, 1999; revised November 8, 1999; accepted January 24, 2000. Reprint requests: Gideon Koren, MD, The Motherisk Program, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. Copyright © 2000 by Mosby, Inc. 0002-9378/2000 $12.00 + 0 6/1/105962 doi:10.1067/mob.2000.105962

tors.2 Because these adrenal effects do not occur in human beings at clinical doses of itraconazole, such adverse pregnancy outcomes would not be expected. The available human data about first-trimester exposure to itraconazole are limited. Inman et al4 reported on prescription event monitoring in England that revealed 56 cases of exposed pregnancies, 53 during the first trimester. Within the first-trimester exposures there were 40 normal live births, including that of 1 infant with a minor anomaly of one ear. Seven pregnancies were terminated and 2 spontaneously aborted.4 In 70 cases reported to the US Food and Drug Administration singledose exposure to itraconazole or fluconazole was followed by normal births.3, 5 The US Food and Drug Administration has also received 14 case reports of malformations after in utero exposure to itraconazole during the first trimester, 4 of which involved limb defects.5 Itraconazole is used more frequently in the clinical setting because of its improved side effect profile and broader spectrum than ketoconazole. The need for safety data on the use of this drug during human pregnancy is important. We conducted a prospective controlled study of pregnancy outcome after exposure to itraconazole. The potential teratogenic effect of the drug in human pregnancies was assessed by comparing the incidence of major malformations among patients exposed 617

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Table I. Maternal characteristics Itraconazole group Age 30.1 ± 5.0 (y, mean ± SD) Gravidity (No.) 1 59/138 (42.8%) 2 40/138 (29.0%) 3 25/138 (18.1%) 4 10/138 (7.2%) ≥5 4/138 (2.9%) Parity (No.) 0 70/137 (51.1%) 1 40/137 (29.2%) 2 21/137 (15.3%) 3 5/137 (3.6%) 4 1/137 (0.7%) Alcohol use (No.) Yes 12/136 (8.8%) No 124/136 (91.2%) Smoking (No.) Yes 19/124 (15.3%) No 105/124 (84.7%)

Statistical Control group significance 31.0 ± 4.3

P = .02* P = .92†

79/197 (40.1%) 62/197 (31.5%) 36/197 (18.3%) 12/197 (6.1%) 8/197 (4.1%) P = .77† 100/197 (50.8%) 63/197 (32.0%) 28/197 (14.2%) 6/197 (3.0%) 0/197 (0%) P = .36† 25/198 (12.6%) 173/198 (87.4%) P = .13† 18/198 (9.1%) 180/198 (90.9%)

*By Mann-Whitney rank sum test. †By χ2 test with or without Yates’ correction.

to itraconazole during first trimester of pregnancy with the incidence in a matched nonexposed group of mother-child pairs. Material and methods Exposed pregnancies were ascertained from reports to the international pharmacovigilance department of the manufacturer of itraconazole (Janssen Pharmaceutica Products, LP, Beerse, Belgium). Pregnancies were reported prospectively (before pregnancy outcome was known) between April 1989 and June 1998. Only those patients who were known to have first-trimester exposure were included in the study. Data were reported by the treating physician at the time of exposure. Data collected included the following: maternal age, gravidity, parity, maternal tobacco smoking or alcohol consumption, other drug exposures, maternal medical conditions, and details (timing and dose) of maternal drug therapy. Pregnancy outcome reports were also sent to the manufacturer by the treating physician and included the following: perinatal and neonatal complications, gestational age at delivery, birth weight, and the presence and identity of any birth defects. A control group consisted of pregnant women who contacted the Motherisk Program, a Canadian teratogen information service. The control group was not exposed to any known teratogens. Acceptable exposures included acetaminophen, dental radiography, penicillins, prenatal vitamins, or no exposures. Patients were followed up with standardized data collection forms that recorded information about the following: maternal demographic data; medical and obstetric histories; drug exposure; details on

the pregnancy, labor, and delivery; neonatal complications; and postnatal growth and development. The exposed patients and the control subjects were matched for maternal age (within 2 years), last menstrual period (within 6 months), gravidity, parity, and alcohol and smoking status. In cases in which the exposed group was missing the data needed for matching, a randomly selected control subject was used. The primary outcome of interest was the rate of major malformations (any structural abnormality with serious medical, surgical, or cosmetic consequences). Secondary outcomes of interest were the rate of live birth, the rates of spontaneous and therapeutic abortions, gestational age at delivery, birth weight, and perinatal and neonatal complications. Statistical analysis. Data for both groups are presented as mean ± SD. The χ2 analysis or the Fisher exact test was used to compare categoric variables whenever appropriate. Relative risks and 95% confidence intervals were also calculated. The Student t test (for normally distributed data) and the Mann-Whitney rank sum test (for nonnormally distributed data) were used to compare continuous variables. Results A total of 229 women exposed to itraconazole were reported to the manufacturer. We excluded 5 women with second-trimester exposures and 26 women for whom the timing of exposure was unknown. Not all data were available for the 198 women who were exposed to itraconazole during the first trimester of pregnancy. In cases in which data were available, however, the daily itraconazole doses ranged between 50 and 800 mg (median, 200 mg). The mean duration of drug therapy was 8.5 ± 12.4 days (range, 1-90 days; median, 3 days). The total itraconazole dose during the first trimester ranged from 200 to 18,600 mg (median, 800 mg). There were no differences between maternal characteristics of exposed women and those of the control group (Table I), with the exception of a difference in maternal age at conception (30.1 ± 5.0 years vs 31.0 ± 4.3 years, respectively; P = .02). Gravidity, parity, and rates of alcohol consumption and cigarette smoking were all similar. There was no difference in the rate of major malformations between the exposed group and the control group (3.2% vs 4.8%, respectively; P = .64; relative risk, 0.67; 95% confidence interval, 0.23-1.95; Table II). The reported major malformations in the itraconazole group included the following: microphthalmia, dysplasia of the right hand, pyloric stenosis, hip joint dysplasia, and congenital heart disease. In the control group there were 9 major birth defects: congenital heart disease (n = 2 cases with ventricular septal defect, n = 1, not specified), hypospadias requiring surgery (n = 2), oversized

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Table II. Pregnancy outcomes Itraconazole group

Control group

Pregnancy outcome (No.) Live birth 156/199 (78.4%) 187/198 (94.4%) Spontaneous abortion 25/199 (12.6%) 8/198 (4.0%) Therapeutic abortion 15/199 (7.5%) 1/198 (0.5%) Fetal death 3/199 (1.5%) 2/198 (1.0%) Major birth defects (No.) 5/156 (3.2%) 9/187 (4.8%) Delivery method (No.) Vaginal 76/99 (76.8%) 162/188 (86.2%) Cesarean 23/99 (23.2%) 26/188 (13.8%) Gestational age (No.) Term 103/119 (86.6%) 173/188 (92.0%) Preterm 10/119 (8.4%) 6/188 (3.2%) Postterm 6/119 (5.0%) 9/188 (4.8%) 1-min Apgar score (No.) High (8-10) 105/121 (86.8%) 57/66 (86.4%) Moderate (5-7) 13/121 (10.7%) 9/66 (13.6%) Low (