Key points

Introduction

Corticosteroids are administered in pregnancy for their immunosuppressive and anti-inflammatory effects. They are used to treat symptoms of autoimmune conditions, because many standard immunosuppressive drugs and biologic agents are regarded as riskier in pregnancy or as having unknown effects on fetal development. Synthetic corticosteroids are often used to manage patients’ disease severity and flares. These corticosteroids were developed to have amplified glucocorticoid activity and reduced mineralocorticoid activity compared with naturally occurring cortisol and have significantly more potent anti-inflammatory activity. Although it is considered optimal to use prednisone at less than 20 mg/d in pregnancy, it is generally accepted that higher doses are allowable for aggressive disease. Inflammation from uncontrolled autoimmune activity is potentially more harmful to maternal and fetal health than high-dose steroids.

Introduction

Corticosteroids are administered in pregnancy for their immunosuppressive and anti-inflammatory effects. They are used to treat symptoms of autoimmune conditions, because many standard immunosuppressive drugs and biologic agents are regarded as riskier in pregnancy or as having unknown effects on fetal development. Synthetic corticosteroids are often used to manage patients’ disease severity and flares. These corticosteroids were developed to have amplified glucocorticoid activity and reduced mineralocorticoid activity compared with naturally occurring cortisol and have significantly more potent anti-inflammatory activity. Although it is considered optimal to use prednisone at less than 20 mg/d in pregnancy, it is generally accepted that higher doses are allowable for aggressive disease. Inflammation from uncontrolled autoimmune activity is potentially more harmful to maternal and fetal health than high-dose steroids.

Corticosteroids and the placenta

Cortisol, a naturally occurring glucocorticoid in humans, is critical for embryogenesis. However, in most species, maternal glucocorticoid levels are much higher than those in the developing fetus. The passage of natural and synthetic glucocorticoids is regulated primarily by 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2). This enzyme is expressed in aldosterone-selective tissues and the placenta and encoded by the HSD11B2 gene. 11βHSD2 converts active glucocorticoids such as cortisol and prednisolone to their inactive metabolites: cortisone and prednisone. Approximately 90% of cortisol is converted into cortisone. However, 11βHSD2 is less efficient at metabolizing synthetic corticosteroids, resulting in greater fetal exposure to active corticosteroids. There remains, however, a significant conversion of synthetic short-acting corticosteroids to inactive metabolites. Clinical studies have reported 8- to 10-fold lower concentrations of fetal prednisolone to maternal prednisolone following maternal intravenous administration. Endogenous fetal glucocorticoid levels are maintained at significantly lower levels than maternal levels; thus, even small transfers of synthetic corticosteroids across the placenta could have adverse developmental effects. It is important to evaluate the potential for adverse pregnancy or birth outcomes during this critical time in human development.

Adverse pregnancy and birth outcomes

Autoimmune conditions are more prevalent in women than men and often occur during a woman’s reproductive years. Generally, autoimmune conditions are not thought to substantially affect fertility, and thus, many women and their clinicians are confronted with concerns about how autoimmune disease and the associated treatments may affect pregnancy and birth outcomes. Concerns about the safety of corticosteroids in pregnancy arose in the 1950s following reports of oral clefts in the offspring of pregnant mice treated with corticosteroids. The association between corticosteroids and oral clefts was also observed in epidemiologic studies, although estimates have varied widely and results have been inconsistent. Additional findings suggested that oral corticosteroids (specifically prednisone) were associated with intrauterine growth restriction in humans and mice; these outcomes were reported to be independent of maternal disease. Finally, a parallel body of literature has noted the increased risks for numerous adverse pregnancy and birth outcomes in women with autoimmune diseases, including preterm birth, preeclampsia, and gestational diabetes mellitus. These articles generally conclude with an unanswered question: is the increased risk for adverse outcomes associated with the disease or the treatment?

In an effort to address this question, this review focuses on systemic corticosteroids and the associations with oral clefts, low birth weight (<2500 g), preterm birth (<37 weeks’ gestation), preeclampsia, and gestational diabetes mellitus. This review focuses on systemic corticosteroids, rather than inhaled or topical treatments, given the greater systemic bioavailability and systemic effects of these forms, and consequently, the potential for greater fetal exposure. Careful consideration is given to study design and statistical analysis, with emphasis on the comparison group and mitigation of confounding by disease indication or severity.

Literature review

Studies for this narrative review were identified from PubMed, with the search terms “glucocorticoids” or “corticosteroids” or “prednisone” and “pregnancy outcomes,” “birth outcomes,” “oral clefts,” “preeclampsia,” “preterm birth,” “birth weight,” or “gestational diabetes.” Additional searches were performed for “pregnancy or birth outcomes” and “rheumatoid arthritis,” “Crohn disease,” “inflammatory bowel disease,” “systemic lupus erythematosus,” “autoimmune disease,” and “rheumatic diseases.” Search results were narrowed to focus on oral or systemic corticosteroids, and whenever possible, limited to indications for autoimmune conditions.

Oral clefts

Clefts of the lip and palate affect approximately 1.7 in 1000 live births, with lifelong effects on speech and hearing. Development of the lip and palate require a highly coordinated series of events that are completed by the fifth or sixth week for closure of the lip and the eighth or ninth week for closure of the palate. Typically, the causes of disruption in this process are unknown. Oral clefts can be categorized into those that affect the palate only, the lip only, or the lip and the palate. Given the low prevalence, researchers often group the latter 2 into one category (cleft lip with or without cleft palate). Cleft palate alone has a lower prevalence than cleft lip (with or without cleft palate) and the 2 are thought to have different genetic and etiologic risk factors. Following earlier findings that corticosteroids caused cleft palate in mice, several epidemiologic studies have investigated the association in humans ( Table 1 ).

Because of the low prevalence of oral clefts, most studies of systemic corticosteroids have been case-control, although at least 2 were retrospective cohort studies. All case-control studies relied on recall of medication exposure by parents after the birth, potentially biasing associations if parents of offspring with clefts report medication use with more or less accuracy than controls. Several case-control studies stratified exposure into oral or systemic corticosteroids, and a few focused on systemic use reported statistically significant associations of approximately 2- to 9-fold greater risk for cleft lip with or without cleft palate. Others found similar increases in odds with confidence intervals (CIs) slightly crossing the null (resulting in P >.05).

In general, early case-control studies (before 2000) reported stronger odds of cleft lip with or without cleft palate following corticosteroid exposure as summarized in a meta-analysis in 2000 (odds ratio [OR] any corticosteroid use during the first trimester: 3.4, 95% CI 2.0, 5.7). Of note, although previous studies separately estimated cleft lip and cleft palate, the meta-analysis grouped all outcomes into “oral clefts.” In more recent studies, the strength of the associations of corticosteroids and oral clefts has reduced to nonsignificant findings. Analyzing data from the National Birth Defect Prevention Study (NBDPS) in the time periods of 1997 to 2002 and 2003 to 2009, Skuladottir and colleagues reported weaker associations between systemic corticosteroids and cleft lip and palate in the latter years. The study followed the same protocol and procedures, case ascertainment, and recruitment practices during both time periods. The investigators note the increased use of corticosteroids among mothers of controls and the decreased use among mothers of cleft lip and palate cases in the latter time period. Overall, it is unclear what is driving the observed reduction in risk, but some possibilities include a temporal trend toward shorter durations or lower doses of systemic corticosteroids in favor of alternative treatments. In addition, the underlying medical conditions necessitating corticosteroid use may change over time, resulting in different risk estimates.

Two retrospective population-based cohorts have been reported. Both studies relied on medical records of corticosteroid exposure, mitigating risk of recall bias. Unfortunately, in both studies, the investigators were unable to estimate the risk of oral corticosteroids, specifically, because of no observed exposed cases. In the study by Hviid and Mølgaard-Nielsen using all live births in Denmark from 1996 to 2008 (n = 832,636), estimates for exposure to any corticosteroids during the first trimester did not correlate with increased risk for cleft lip or cleft palate. Only those exposed to topical corticosteroids had a higher risk of cleft lip with or without cleft palate (OR 1.45 [1.03, 2.05]), although it is unclear if the increased risk is due to systemic absorption from the topical treatment, the dermatologic condition for which the topical steroids were used (ie, eczema or psoriasis), or disease severity. Another study by Bay Bjørn and colleagues relied on live births from primiparous women in northern Denmark from 1999 to 2009 (n = 83,043). The unadjusted odds of oral clefts following exposure to any corticosteroids (inhaled or oral) in the first trimester was also null (OR 0.4 [0.1, 2.8]). Because of the relatively small sample, cleft lip and cleft palate were analyzed together.

A serious methodologic consideration for all studies in Table 1 is that none adjusted for underlying disease or disease severity. Confounding by disease or disease severity occurs when the underlying disease or severity of the disease is associated with the exposure, is not a result of the exposure, and is associated with the outcome. In the case of corticosteroids, the first 2 points are undisputable, that is, corticosteroids are taken as a result of the underlying disease and associated flares. Whether maternal disease or disease activity is associated with oral clefts, directly or through common causes, such as smoking, alcohol, interpregnancy interval, or obesity, remains unanswered. Consequently, studies that group any underlying indication for corticosteroids without statistical adjustment for the disease or severity are difficult to interpret. Furthermore, none of the studies considered systemic corticosteroid dose, which is necessary to evaluate potential teratogenicity.

Another methodologic consideration for the body of evidence is temporality of the corticosteroid exposure relative to the oral cleft. Several studies of oral clefts count exposure from a few weeks before estimated conception through the end of the first trimester. However, the critical periods for formation of the lip and palate encompass only specific weeks in the first trimester. This practice could lead to potential exposure misclassification, that is, for those exposures that took place only outside the biologically relevant time period in early gestation. This bias from misclassification would result in smaller effect estimates. Skuladottir and colleagues attempted to look at any corticosteroid use by small time intervals (1–4 weeks preconception, and 1–4 weeks, 5–8 weeks, and 9–12 weeks postconception). Even with 2372 cases of clefts, the number of pregnancies exposed to corticosteroids within specific gestational windows were very small. The small sample available for analysis led to inconsistent results, demonstrating the difficulty of defining risk periods for corticosteroid use in epidemiologic studies.

In summary, the evidence for cleft palate alone is not sufficient to summarize. The estimated risk of cleft lip with or without cleft palate from corticosteroid exposure has weakened over time, and no study published after 2003 has reported a statistically significant risk estimate. The largest case-control study to date (NBDPS) has estimated a modest (60%) increase in the odds of cleft lip with or without cleft palate, although the CI did slightly cross 1.0. Cohort studies, which are not subject to recall bias, have been limited by insufficient sample sizes to differentiate between routes of administration or type of oral cleft. Examining the evidence and methodological limitations in totality, systemic corticosteroids may be associated with small increases in the risk of cleft lip with or without palate. Assuming a causal OR of 1.6 (from the NBDPS), the risk of cleft lip with or without cleft palate among women using corticosteroids in the relevant time frame would increase from 1.7 per 1000 live births to 2.7 per 1000 live births. Ultimately, the sample sizes required to detect a relatively small risk of cleft lip and to address the contribution of specific maternal diseases, dose, and timing, are challenging to obtain.