In a large nationwide cohort of live births, general use of corticosteroids during pregnancy was not significantly associated with an increased risk of orofacial clefts. However, the use of dermatologic corticosteroids was associated with an increased risk of cleft lip with or without cleft palate. In contrast, the use of oral corticosteroids, nasal sprays, inhalants or other topical forms was not associated with an increased risk of clefts.
Systemic corticosteroids have been associated with cleft palate and other adverse events in the fetus in rodents.1,25–28
Topical corticosteroids are assumed to be safer than systemic corticosteroids. However, corticosteroids have been detected in the fetal blood of some animals after topical application,29
and topical use of diflorasone diacetate has been associated with cleft palate in rabbits.30
Preparations that contain corticosteroids are among the most frequently prescribed dermatologic treatments. They are commonly used during pregnancy for various skin conditions such as eczema and psoriasis. In humans, topical corticosteroids cross the skin barrier. In a study involving young adults with atopic dermatitis, percutaneous application of 1.0% hydrocortisone cream yielded median serum cortisol levels of 125 nmol/L during the acute phase of the condition and 16 nmol/L during remission.31
Furthermore, it has been shown that even for a low-potency corticosteroid such as hydrocortisone, 15.0% of the dose crosses the placenta unmetabolized.32
These studies suggest fetal serum cortisol levels in the range of 2.4–18.75 nmol/L after the application of 1.0% hydrocortisone cream to the mother’s skin.
Many previous epidemiologic studies, though not all,7
have reported increased risks of orofacial clefts primarily after the use of oral corticosteroids.3–6,8–10
However, many of the previous studies were limited by a lack of statistical power. The largest study to date, an American case–control study, included 39 instances of orofacial clefts associated with exposure to corticosteroids,4
whereas our study included 84 instances associated with exposure during the first trimester. In addition, many of the previous studies determined corticosteroid use through postnatal interviews, which introduced the potential for recall bias.
Studies specifically evaluating topical corticosteroids and orofacial clefts are uncommon.4–6,8,9
A recent Cochrane review of the safety of topical corticosteroids during pregnancy concluded that the current studies were limited and inconclusive and that cohort studies with very large samples were needed.33
We relied on national health registers to find infants with orofacial clefts as defined by ICD-10 codes. The predictive value of the diagnosis of birth defects in the National Hospital Discharge Registry has previously been evaluated as being high (88.0%).34
We would expect these numbers to be higher for clefts alone, and any misclassification would likely bias our results toward no effect.
Our study did not include abortions. This could introduce bias in a study of drug use during pregnancy and the risk of birth defects, if the birth defect itself increases the risk of planned or spontaneous abortion. It is unlikely that such a bias played a role in a study of birth defects such as isolated orofacial clefts.
We relied on a national prescription drug registry to determine corticosteroid use with the assumption that a filled prescription would lead to use of the drug. However, some divergence with respect to use and timing of use is to be expected, and this divergence would bias our results toward no effect. We were not able to include information on over-the-counter use or hospital use of corticosteroids in this study. Again, we expect that any misclassification would bias our results toward no effect.
Confounding by indication is not obvious in our study; the indications for corticosteroid use are many, and none has been associated with orofacial clefts. That no association was seen between corticosteroid use during late pregnancy and risk of orofacial clefts, despite the apparent increase in risk seen with the use of dermatologic corticosteroids during early pregnancy, also supports the minimal impact of confounding by indication.
The absence of risk associated with corticosteroids taken orally or as inhalants seen in our study should be evaluated in the context of the study’s statistical power, which was limited, particularly for oral forms of the drug. However, moderate to high risks can be excluded. For example, for inhalants, we can exclude an increase in the risk of cleft lip with or without cleft palate that is higher than 68%.
The observed association between dermatologic corticosteroids and orofacial clefts in our study may be a result of multiple statistical comparisons. Given that exploratory analyses of the dose–response and potency–response relations between the use of dermatologic corticosteroids and cleft lip with or without cleft palate did not support a causal association, we cannot exclude that the observed results are non-causal random effects. The overall association between dermatologic corticosteroids and orofacial clefts appeared to be carried by hydrocortisone butyrate alone, a corticosteroid on the lower end of the potency scale.
Our results add to the safety information for a class of drugs commonly used during pregnancy. Our study did not show an adverse effect of corticosteroid use during pregnancy on the risk of orofacial clefts. However, the absence of risk associated with corticosteroids taken orally or as inhalants seen in our study does not necessarily show that these products are safe for use during pregnancy.
If the observed association between dermatologic corticosteroids and orofacial clefts seen in our study is causal, it is in contrast to the lack of association seen for corticosteroids taken orally or as inhalants. Since indepth investigation of the pattern of association between orofacial clefts and use of dermatologic corticosteroids during pregnancy indicated that this result did not signify a causal connection, it is likely that this association arose from multiple statistical comparisons.