Budesonide

Name: BUDESONIDE
Class: Corticosteroid
Risk Factor: CM

Fetal Risk Summary

Budesonide is an antiinflammatory corticosteroid used in the maintenance treatment of asthma as prophylactic therapy (Pulmicort Turbuhaler) or for the management of symptoms of allergic rhinitis (Rhinocort Nasal Inhaler). Pulmicort Turbuhaler delivers approximately 160 µg of micronized budesonide per actuation, whereas Rhinocort Nasal Inhaler delivers approximately 32 µg of micronized budesonide per actuation (1,2). The latter dose is suspended in a mixture of propellants (dichlorodifluoromethane, trichloromonofluoromethane, and dichlorotetrafluoroethane) and sorbitan trioleate.
Budesonide has potent glucocorticoid but weak mineralocorticoid, activity. Compared to hydrocortisone (cortisol), budesonide is 40 times more potent when administered SC and 25 times more potent when given orally (1,2). Approximately 34% of the delivered dose of Pulmicort and 21% of Rhinocort are absorbed systemically (1,2).
Similar to other glucocorticoid agents, budesonide administered to pregnant rabbits at a SC dose of 25 mg/kg/day (about 1/3 the maximum recommended human daily inhalation dose on a mg/m2 basis [MRHD]) produced fetal loss, intrauterine growth retardation (IUGR), and skeletal anomalies (mostly delayed ossification of the vertebra and skull) (1,2 and 3). In pregnant rats, a SC dose of 500 mg/kg/day (about 3 times the MRHD) resulted in similar outcomes (1,2). No teratogenic or embryocidal effects were observed in pregnant rats administered inhalation doses up to 250 mg/kg/day (approximately 2 times the MRHD) (1,2).
No reports describing the placental transfer of budesonide have been located. The relatively low molecular weight (about 431 for the butyraldehyde formulation) and high lipid solubility predict substantial placental transfer. The actual amount of active budesonide reaching the fetus, however, may be small because of the low systemic bioavailability after inhalation (see above) and the observation that other corticosteroids undergo extensive placental metabolism to inactive compounds (e.g., see Hydrocortisone, Betamethasone, and Dexamethasone).
Data from the Swedish Medical Birth Registry involving 2,014 infants whose mothers had inhaled budesonide for asthma during early pregnancy were reported in 1999 (4). Drug exposures were identified prospectively, before the pregnancy outcomes were known. Among the mothers of the 2,014 infants, 1,675 also used b2-adrenergic agonists, 16 used other inhaled corticosteroids in addition to budesonide, and 316 used no other antiasthmatic drug. A total of 76 infants (3.8%) in the exposed group had a congenital malformation, compared with 3.5% for all infants born in 1995-1997. Major structural defects were observed in 41 of the infants, whereas 35 infants had minor and/or variable conditions. Five of the major defects were chromosomal anomalies. It is unlikely that these were due to drug therapy (4). Four (expected 3.3) of the major anomaly group had an orofacial cleft (median cleft palate [N=2], unilateral cleft lip [N=1], and unilateral cleft lip and palate [N=1]) (relative risk 1.2, 95% Confidence Interval 0.3–3.1) (4). Among the major and minor defects, 18 (expected 17-18) involved the heart, including two premature infants with patent ductus arteriosus (both categorized as minor defects). The other cardiac malformations were: ventricular septal defects (VSD) with or without other anomalies (N=11); atrial septal defects with or without other anomalies (N=4); and unspecified cardiac defect (N=1). Only two of the cases with VSD, one with transposition of the great vessels and another with tricuspidal atresia (both successfully repaired), were reported to the Swedish Child Cardiology Registry (expected number 5.6). Because the other 16 cases were not reported, the authors concluded that the defects were mild and of little clinical significance (4).
Twenty-one pregnancies in which the woman received an active drug were reported to the manufacturer during clinical trials of Pulmicort Turbuhaler (A. Marants, personal communication, Astra Pharmaceuticals, 1999). Two of the pregnancies were terminated voluntarily, one woman had a miscarriage, three had unknown outcomes, 13 delivered normal infants, and two delivered infants with congenital malformations. In one case, the 27-year-old mother was receiving budesonide 1600 µg/day at conception. She was also taking prednisone 10 mg/day and a combination oral contraceptive (levonorgestrel + ethinyl estradiol). Although the reason for early delivery was not specified, a female infant with coarctation of the aorta was delivered by cesarean section at 30 weeks' gestation. The infant was scheduled for surgical repair of the defect. In the second case, a 41-year-old mother used budesonide inhaler for 22 days (dosage unknown) before discontinuing it because of her pregnancy. Seven months later, she delivered a female infant with double-sided maxillary clefts, double digits of the left hand, and persistent fetal circulation (i.e., patent ductus arteriosus). The infant died at 8 days of age.
The infant outcomes of five asthmatic women who used budesonide during pregnancy were described in retrospective postmarketing reports to the manufacturer (A. Marants, personal communication, Astra Pharmaceuticals, 1999). Only limited data were available for each pregnancy. The first case involved a 36-year-old woman, treated with an unknown dose of budesonide combined with a b2-adrenergic agonist (albuterol), who delivered an anencephalic infant. In the second case, a 32-year-old woman administering budesonide 1600 µg/day gave birth to a healthy, 2.65-kg baby. A 33-year-old woman was treated with four antiasthmatic agents during gestation, including budesonide 1600 µg/day, an oral corticosteroid (name not specified), a b2-adrenergic agonist (not specified), and theophylline. She gave birth to a female infant with agenesis of the left foot who was otherwise healthy. Another 33-year-old woman being treated with budesonide 1600 µg/day, phenobarbital, and terbutaline (a b2-adrenergic agonist) delivered an infant with cleft palate, an unspecified cardiac defect, and hydrocephalus. Finally, IUGR and oligohydramnios were noted in a pregnancy of a 36-year-old woman who was being treated with budesonide 400 µg/day, salmeterol (an inhaled b2-adrenergic agonist), and terfenadine (an antihistamine). She gave birth to a growth-retarded infant (2.0 Kg) who had multiple malformations, including a diaphragmatic hernia, renal hypoplasia, and a VSD. The infant died on the day of birth.
In summary, inhaled budesonide is not teratogenic or embryocidal in rats dosed at twice the MRHD. In humans, the use of inhaled budesonide as the sole antiasthmatic agent is less frequent than multiple drug therapy, occurring in only 16% (316/2,014) of the patients in one published study. Combination with b2-adrenergic agonists (83%) was the prevalent therapy. In that study, the rate of major congenital malformations in exposed pregnancies was similar to the non-exposed population rate. Thus, budesonide does not appear to present a major teratogenic risk. A small, but statistically significant, increased risk for cleft lip with or without cleft palate has been reported for corticosteroids (see Hydrocortisone). In the Swedish Medical Birth Registry study, the relative risk for orofacial clefts was 1.2, but it was not statistically significant. The number of exposed infants, however, was too small to demonstrate a significant increase in this risk, if indeed there is a causative association between corticosteroids and oral clefts. The incidence of VSD (1:183) in the Swedish Medical Birth Registry study is also higher than expected. One source reports the rate as 1:400 in full-term live births (5). The relationship of this defect to budesonide is unknown.
The data from the manufacturer's postmarketing surveillance do not show a clustering of defects and thus in themselves cannot be used as evidence of an increased risk for birth defects. Surveillance reports of this type are important for detecting early signals of major teratogens, but they have several difficulties. The primary problems with these voluntary reports are their retrospective nature (reported after the outcome is known), their selection bias (mainly adverse outcomes are reported), and their lack of sufficient details on the mother, her family history, her disease, and her pregnancy. Moreover, these data cannot be used to determine true rates of outcomes.
During pregnancy, the benefits of treating allergic rhinitis with any product, including budesonide, must be carefully weighed against the potential risks of therapy. Consideration should be given to limiting corticosteroid exposure, especially during the 1st trimester. In contrast, poorly controlled asthma may result in adverse maternal, fetal, and neonatal outcomes (6). Maternal complications include an increased risk of preeclampsia, pregnancy-induced hypertension, hyperemesis gravidarum, vaginal hemorrhage, and induced and difficult labors. Fetal and neonatal adverse effects may be an increased risk of perinatal mortality, IUGR, prematurity, lower birth weight, and neonatal hypoxia. Because controlling maternal asthma can ameliorate or prevent all of these complications (6), the benefits of therapy appear to outweigh the potential risks of drug-induced teratogenicity or toxicity. Therefore, pregnant women who require an inhaled corticosteroid, such as budesonide, for control of their asthma should be counseled as to the risks and benefits of therapy, but treatment should not be withheld because of their pregnancy.

Breast Feeding Summary

No reports describing the use of inhaled budesonide during human lactation have been located. The relatively low molecular weight (about 431 for the butyraldehyde formulation) and the high lipid solubility predict substantial excretion of systemic budesonide into milk. However, the systemic bioavailability of budesonide following inhalation therapy is relatively low (see section above), so that the actual amount in milk also may be low. Small amounts of other corticosteroids are excreted into milk (e.g., see Prednisone), and if the mother is inhaling budesonide, the presence of the corticosteroid in her milk should be anticipated. Because of the oral potency of budesonide (about 25 times more glucocorticoid activity than hydrocortisone), the clinical significance of this potential exposure on a nursing infant is unknown. The manufacturer recommends stopping breast feeding if the mother must use the Pulmicort Turbuhaler (1).

References

1. Product information. Pulmicort Turbuhaler. AstraZeneca, 2000.
2. Product information. Rhinocort. AstraZeneca, 2000.
3. Kihlstrom I, Lundberg C. Teratogenicity study of the new glucocorticosteroid budesonide. Arzneim-Forsch/Drug Res 1987;37:43–6.
4. Kallen B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999;93:392–5.
5. Center for Birth Defects Information Services, Inc., Buyse ML, Editor-in-Chief. Birth Defects Encyclopedia. Volume 2. Cambridge, Mass:Blackwell Scientific Publications, 1990:1763–4.
6. Report of the Working Group on Asthma and Pregnancy, National Institutes of Health. Management of Asthma During Pregnancy. NIH Publication No. 93-3279, September 1993.

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