Systemic

The concerns surrounding the use of glucocorticoids in pregnancy began more than 50 years ago following the publication of various studies which showed that large doses of glucocorticoids administered to pregnant rabbits, mice and rats during organogenesis lead to a higher incidence of cleft palate in the exposed offspring [3–6]. This was followed by the publication of two case reports of neonates with isolated cleft palate after pregnancy exposure to cortisone [7,8]. However, several subsequent case reports in which pregnant women were treated with prednisone throughout the first trimester [9–17] for various medical conditions (including renal transplantation, Hodgkin’s disease, steroid-dependent asthma and systemic lupus ery thematosus) did not reveal a consistent pattern of embryopathy. The increased incidence of low birthweight, miscarriages and stillbirths that is noted in some studies is difficult to discriminate from the effects of the underlying maternal conditions for which the glucocorticoids were being administered.

Two large prospective cohort studies published over the past decade have shown that there is, firstly, no risk of major congenital anomalies with first-trimester use of glucocorticoids and, secondly, either only a very small (odds ratio of 3.35; 95% confidence interval (CI) 1.97–5.69) [18] or no increased rate [19] of cleft lip or palate. Although the latter prospective study was only powered to detect a risk of 2.5-fold or greater, a pooling of the prospective data from these two studies describes a total of 499 pregnancies exposed to glucocorticoids with no cases of cleft lip or palate in any of the exposed offspring. It seems safe to say that glucocorticoids at therapeutic doses do not represent a major teratogenic risk in humans. Given the serious nature of the conditions treated with glucocorticoids and the fact that fetal well-being is dependent on maternal well-being, it would be difficult to envisage a situation where it would be justifiable to cease or withhold these agents during pregnancy on the basis of concerns about their teratogenic risk. This concept has made it much easier for clinicians to consider using glucocorticoids to treat a wide range of conditions, including hyperemesis gravidarum or migraines, which may be refractory to conventional treatments in early pregnancy.

Whilst systemic glucocorticoids are not significant teratogens, long-term use of the equivalent of 30 mg of prednisone per day has been shown in several studies to increase the risk of premature preterm rupture of membranes and this is consistent with the authors’ experience [20–22]. However, this again needs to be interpreted in the context of the very serious maternal and fetal implications of untreated inflammatory conditions such as asthma, systemic lupus erythematosus and inflammatory bowel disease.

Studies examining the effects of high-dose betamethasone given repeatedly to women with preterm labor do suggest an increased risk of intrauterine growth restriction [23–25] despite the marked advantage they confer to premature infants with respect to decreasing the risk of neonatal respiratory distress syndrome, intraventricular hemorrhage and necrotizing enterocolitis. Concern also exists about the long-term neurodevelopmental effects of high-dose steroids on premature infants [26,27] but it should be remembered that these concerns refer to supraphysiologic doses of glucocorticoids administered with the intention of getting most of the medication to the fetus and the applicability of these data to the use of prednisone in pregnancy is doubtful. Numerous other studies, in any case, have found that there are no significant differences in neurocognitive development of infants who were exposed to antenatal high-dose glucocorticoid therapy [28–31].

Glucocorticoids can cause insulin resistance and may unmask some impaired glucose tolerance in women at risk. Consideration of early or additional screening for gestational diabetes may be warranted in women receiving glucocorticoids in pregnancy, particularly if they have additional risk factors for gestational diabetes mellitus. It should be noted that betamethasone administered up to 7 days prior to a glucose challenge test or a formal glucose tolerance test may cause a spurious elevation in the result [32].

Topical

Patients and clinicians have also expressed concerns about the effects of topical steroids used on the skin, nasopharynx, airways and rectal mucosa for conditions such as eczema, aller gic rhinitis, asthma and ulcerative colitis. Systemic absorption of these agents does occur to some degree and varies with the medication, its formulation, the condition being treated, thickness of exposed skin (scalp and feet absorbing much less than the face or genitals) and whether an occlusive dressing is used. The large number of preparations available on the market also makes it difficult to develop meaningful pregnancy safety data for any one of them.