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ORIGINAL RESEARCH |
From the Tornblad Institute, and the Department of Obstetrics and Gynecology, University of Lund, Lund, Sweden.
Address reprint requests to: Bengt Källén, MD, Tornblad Institute, Biskopsgatan 7, S-223 62 Lund, Sweden, E-mail: embryol{at}embryol.lu.se
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Abstract |
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Methods: Using the Swedish Medical Birth Registry, congenital malformations were studied in 2014 infants whose mothers had used inhaled budesonide for asthma in early pregnancy. The presence of congenital malformations was checked further with auxilliary registries.
Results: No increase in the general rate of congenital malformations was observed: 3.8% (95% confidence interval [CI] 2.9, 4.6) of the infants had a congenital malformation diagnosed, which is similar to the population rate (3.5%). After exposure to budesonide, four infants were born with orofacial clefts; this also is similar to the expected number (3.3).
Conclusion: Even though a specific teratogenic effect of use of budesonide in early pregnancy cannot be ruled out, it is unlikely that a clinically significant teratogenic risk exists.
Asthma is relatively common among pregnant women, and antiasthmatic drugs often are used in early pregnancy. This may cause concern because of the possibility that such medication may cause birth defects. It is generally supposed that ß-stimulators are nonteratogenic, but little information is available on the possible teratogenicity of inhaled glucocorticoids. In Sweden, budesonide, like other inhaled glucocorticoids, is labelled with a pregnancy warning (category B:3), which means that not enough human data are available and that animal experiments may indicate a hazard, based on evidence for corticosteroids producing cleft lip/palate or cleft palate in many species.1,2 In contrast, the teratogenic potential of systemic glucocorticoid drugs in man is very uncertain.3,4 The amounts of absorbed steroids at inhalation therapy are low. In spite of this, in the United States, budesonide is classified as category C, indicating a teratogenic risk in animal experiments and a lack of sufficient human data.
We have studied the problem of a possible teratogenic effect of budesonide using prospectively collected information on drug usage in early pregnancy, available in the Swedish Medical Birth Registry.
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Material and Methods |
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Since July 1, 1994, when the record forms were modified, it has been possible to centrally store information on drug use reported by women in early pregnancy. At the first visit to the antenatal care center (usually about week 10 after the last menstrual period), the woman is interviewed by a midwife. Among other things, she is asked if she has used any drugs during pregnancy and if so, the name of the drug; if possible, the dosage and the week of use are recorded. Drug names are given as proprietary names, but these are later transferred to codes for data storage, using the Anatomical Therapeutic Chemical Classification system. For the present study, women who reported the use of budesonide (defined as code R03 A02) were identified.
Information on possible congenital malformations was obtained from codes from the International Classification of Diseases (ICD), Injuries and Causes of Death, Chapter 14 in ICD-9, and Chapter 17 in ICD-10, which was recorded at the pediatric examination of the newborn and from the more detailed Registry of Congenital Malformations (a surveillance register concentrating on serious defects)6 and the Child Cardiology Registry (containing reports from Child Cardiology Centers of cardiac defects identified before the age of 1)7 by record linkage with the aid of the personal identification number given to each person living in Sweden. It is thought that the various sources together identify 80–90% of all infants with a severe malformation. There is no reason to suspect that the recording of malformations is affected by the fact that the woman had asthma or used inhaled corticoids.
The expected number of infants with a malformation or a certain type of malformation was calculated from all births, and comparisons between observed and expected numbers were based on Poisson distributions. The inclusion of infants in multiple births theoretically invalidates this, as independence between infants in such births is not complete. In practice, concordance of malformations is an exception and not a rule in multiple births. In the present material, only one twin had a congenital malformation (hydronephrosis).
Risks were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). No standardization for maternal age, parity, or smoking was made, as these variables little affect malformation rate, with the exception of some chromosomal anomalies that are not relevant for the present study. Table 1
presents data on maternal age, parity, and smoking habits in the presence and absence of infant malformations. Chi-square analyses for heterogeneity between groups failed to show significant differences.
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Results |
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Seventy-five infants (3.8%, 95% CI 2.9, 4.6) had a congenital malformation recorded in the Medical Birth Registry. Among all infants born in 1995–1997, the corresponding rate is 3.5%. One other infant with a congenital malformation was identified from the Registry of Congenital Malformations, from which further diagnostic details were obtained for some other cases. The malformed infants were divided into two groups: one with relatively major structural defects (n = 41, Table 2), and one with minor and/or variable conditions (n = 35, Table 3). This division is to some extent arbitrary, but the inclusion of anomalies in each group appears in the tables.
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There were two slightly unusual malformations. One infant had Poland syndrome, and another had a unilateral lower jaw anomaly. The chromosomal anomalies are of various types: two infants had Turner syndrome, and one of them was a mosaic.
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Discussion |
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The information on drug use was collected prospectively relative to the identification of a congenital anomaly; therefore, the information cannot be biased by the outcome. It is likely, however, that all drug exposures were not recorded, but this should not affect the risk estimates. It is unlikely that a woman who reported the use of a specific drug did not use it, but she may have used it before or after the organogenetic period or at such a low dosage that the embryo was really not exposed. Such phenomena will result in a dilution of the material and a bias of the estimated risk ratios toward 1.0.
The inability to demonstrate a teratogenic effect may, however, not mean the absence of such effects. We have identified a little more than 2000 infants exposed in early pregnancy to inhaled budesonide. From animal experiments, the most likely effect would be on orofacial clefting. It is unclear whether even systemic administration of glucocorticoids in humans increases the risk of orofacial clefts, even though this has been suggested.8 In the present study, we observed a slightly increased risk ratio (1.2), but in spite of the large study population, the 95% CI of this estimate is wide and does not exclude 1.0. To have a reasonable chance to demonstrate a 20% increased risk for an orofacial cleft (
= .05, ß = .80) more than 100,000 exposures would have to be studied, and to demonstrate a doubling of the risk, close to 5000 exposures would be required. Even at a doubling of the risk for an orofacial cleft, the individual risk for a woman using inhaled budesonide is only 1:250 in Sweden (where the base rate is 1:500) and therefore negligible for the individual, compared with the 1:50 risk to have any serious malformation.
Two slightly unusual malformations were observed. Poland syndrome is reported at a rate of about 1:100,000 births in the Swedish Registry of Congenital Malformations. This condition is sometimes thought to have a vascular basis. The unilateral jaw malformation is an unusual condition, and no baseline can be given. In the present case, there was a marked asymmetry of the mandible lying at a 30° angle against the horizontal plane. These two rare conditions are probably coincidental to the use of budesonide. In any study of 2000 infants, one or two unusual malformations may occur. In further studies of the drug, however, one should look for the occurrence of these or related conditions.
Five infants had chromosomal anomalies. It is unlikely that drug therapy can cause such anomalies, even though two of them were mosaic, indicating origination during the cleavage period of the fertilized egg.
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Footnotes |
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Received June 1, 1998. Received in revised form September 8, 1998. Accepted September 17, 1998.
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References |
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2. Walker BE. Cleft palate produced in mice by human-equivalent dosage with triamcinolone. Science 1965;149:862–3.
3. Schardein JL. Chemically induced birth defects. New York: Marcel Dekker, Inc., 1985.
4. Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology 1997;56:335–40.[Medline]
5. Cnattingius S, Ericson A, Gunnarskog J, Källén B. A quality study of a medical birth registry. Scand J Soc Med 1990;18:143–8.[Medline]
6. Källén B. Search for teratogenic risks with the aid of malformation registries. Teratology 1987;35:47–52.[Medline]
7. Carlgren LE, Ericson A, Källén B. Monitoring of congenital cardiac defects. Pediatr Cardiol 1987;8:247–56.[Medline]
8. Rodríguez-Pinilla E, Martínez-Frías ML. Corticosteroids during pregnancy and oral clefts: A case-control study. Teratology 1998;58: 2–5.[Medline]
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