Safety of corticosteroids in pregnancy: Is it the drug or the disease?

 

Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.

Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.

Earlier studies that were incorporated into a meta-analysis published in 2000 suggested a 3.4-times increased odds of cleft lip with or without cleft palate following first trimester corticosteroid use (95% confidence interval, 2.0-5.7).¹ However, a 2014 update from the multisite U.S. National Birth Defects Prevention case-control study (NBDPS) demonstrated that, while data from 1997 to 2002 indicated an elevated risk for oral clefts, more recent data from 2003 to 2009 did not.² The authors speculated that typical doses of corticosteroids or duration of use in pregnancy could have declined over time as more disease modifying alternative treatments have become available for some conditions and that this could have resulted in attenuated risk estimates in recent years.

Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an 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 (odds ratio, 1.45; 95% CI, 1.03-2.05).³ Another, smaller Danish study covered primiparous births 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 null (OR, 0.4; 95% CI, 0.1-2.8).⁴

Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.

With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).⁵ In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.⁶ In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.⁷

Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).⁸ However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.

Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.

With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.

 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.

References

1. Teratology. 2000 Dec;62(6):385-92.

2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.

3. CMAJ. 2011 Apr 19;183(7):796-804.

4. Am J Ther. 2014 Mar-Apr;21(2):73-80.

5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.

6. Arthritis Rheum. 2009 Nov;60(11):3196-206.

7. Lupus. 2010 Dec;19(14):1665-73.

8. PLoS One. 2015 Jun 17;10(6):e0129567.

 

Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.

Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.

Earlier studies that were incorporated into a meta-analysis published in 2000 suggested a 3.4-times increased odds of cleft lip with or without cleft palate following first trimester corticosteroid use (95% confidence interval, 2.0-5.7).¹ However, a 2014 update from the multisite U.S. National Birth Defects Prevention case-control study (NBDPS) demonstrated that, while data from 1997 to 2002 indicated an elevated risk for oral clefts, more recent data from 2003 to 2009 did not.² The authors speculated that typical doses of corticosteroids or duration of use in pregnancy could have declined over time as more disease modifying alternative treatments have become available for some conditions and that this could have resulted in attenuated risk estimates in recent years.

Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an 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 (odds ratio, 1.45; 95% CI, 1.03-2.05).³ Another, smaller Danish study covered primiparous births 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 null (OR, 0.4; 95% CI, 0.1-2.8).⁴

Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.

With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).⁵ In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.⁶ In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.⁷

Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).⁸ However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.

Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.

With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.

 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.

References

1. Teratology. 2000 Dec;62(6):385-92.

2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.

3. CMAJ. 2011 Apr 19;183(7):796-804.

4. Am J Ther. 2014 Mar-Apr;21(2):73-80.

5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.

6. Arthritis Rheum. 2009 Nov;60(11):3196-206.

7. Lupus. 2010 Dec;19(14):1665-73.

8. PLoS One. 2015 Jun 17;10(6):e0129567.

 

Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.

Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.

Earlier studies that were incorporated into a meta-analysis published in 2000 suggested a 3.4-times increased odds of cleft lip with or without cleft palate following first trimester corticosteroid use (95% confidence interval, 2.0-5.7).¹ However, a 2014 update from the multisite U.S. National Birth Defects Prevention case-control study (NBDPS) demonstrated that, while data from 1997 to 2002 indicated an elevated risk for oral clefts, more recent data from 2003 to 2009 did not.² The authors speculated that typical doses of corticosteroids or duration of use in pregnancy could have declined over time as more disease modifying alternative treatments have become available for some conditions and that this could have resulted in attenuated risk estimates in recent years.

Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an 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 (odds ratio, 1.45; 95% CI, 1.03-2.05).³ Another, smaller Danish study covered primiparous births 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 null (OR, 0.4; 95% CI, 0.1-2.8).⁴

Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.

With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).⁵ In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.⁶ In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.⁷

Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).⁸ However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.

Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.

With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.

 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.

References

1. Teratology. 2000 Dec;62(6):385-92.

2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.

3. CMAJ. 2011 Apr 19;183(7):796-804.

4. Am J Ther. 2014 Mar-Apr;21(2):73-80.

5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.

6. Arthritis Rheum. 2009 Nov;60(11):3196-206.

7. Lupus. 2010 Dec;19(14):1665-73.

8. PLoS One. 2015 Jun 17;10(6):e0129567.