Maternal corticosteroid use and risk of orofacial clefts

1. Maternal corticosteroid use and risk of orofacial clefts SL Carmichael, GM Shaw, C Ma, MM Werler, SA Rasmussen, EJ Lammer National Birth Defects Prevention Study

2. Corticosteroids: Background • Anti-inflammatory and immune-suppressive properties • Treat asthma, rheumatoid arthritis, allergic reactions, eczema, lupus • Varied types, route of administration, absorption

3. Corticosteroids: Background • Associated with adverse pregnancy outcomes – e.g., growth retardation • Teratogenic in animal models • Several case-control studies suggest increased risk of clefts

4. Objective • Examine whether mothers who used corticosteroids during pregnancy were at increased risk of delivering infants with orofacial clefts • Build on previous studies by analyzing • Route of administration • Type of medication • Specific time windows of exposure

5. Methods: Study Design • National Birth Defects Prevention Study • Population-based case-control study • Births from 1997-2002 in 8 states • Controls: 4,143 Non-malformed, live born infants • Cases: • Multiple records; standard clinical guidelines and review; exclude syndromes • 1,141 CLP (cleft lip with or without cleft palate) • 628 CP (cleft palate without cleft lip)

6. Methods: Exposure Assessment • Maternal telephone interviews 6 wk - 24 mo after birth • Questions from interview: • Multiple questions about illnesses and injuries, and medications used to treat them • Final question about any other medication use (without indication) • Time period: • 12 weeks before conception through delivery • Mothers reported start and stop date, and frequency of intake, for each medication exposure

7. Analysis • Logistic regression to estimate risks • Time windows: • Broad: 4 weeks before through 12 weeks after conception • Specific: Timing more specific to lip and palate development • After lip and palate development: >12 weeks after conception • Covariates: Maternal race-ethnicity, education, smoking, folic acid supplement, study site

8. Description of Study Participants

9. Description of Study Participants

10. Corticosteroid use & risk of clefts – 4 weeks before through 12 weeks after conception * Reference = 1,108 CLP, 622 CP, and 4,071 controls with no exposure from 4 weeks before through 12 weeks after conception

11. Corticosteroid use & risk of clefts –4 weeks before through 12 weeks after conception * Reference = 1,108 CLP, 622 CP, and 4,071 controls with no exposure from 4 weeks before through 12 weeks after conception

12. Corticosteroid use & risk of CLP –Specific time periods from “B1 to P3” * Reference = 1,108 CLP, 622 CP, and 4,071 controls with no exposure from 4 weeks before through 12 weeks after conception

13. Corticosteroid use & risk of clefts – Use that began after lip & palate formation * Reference = 1,094 CLP, 609 CP, and 4,021 controls with no exposure from 12 weeks before conception through delivery

14. Corticosteroid use & risk of clefts • Adjustment for potential covariates did not alter results • Exclusion of cases with other major malformations or with family history of clefts did not alter results

15. Summary of Results • Corticosteroid use during early pregnancy associated with moderately increased risk of CLP, but not CP • Results relatively similar for most routes of administration & specific component medications, but sample sizes were small

16. Conclusions • Evidence points toward more cautious use of corticosteroids during early pregnancy • Data on specific types of corticosteroids, timing of exposure, & other birth defects is limited - further studies are needed to provide this information • Improved understanding of corticosteroid teratogenicity will enable more informed decisions about use of these important, commonly prescribed drugs during pregnancy