Anti-thyroid drug use during the first trimester of pregnancy and the risk of birth defects in offspring: systematic review and meta-analysis of observational studies with methodological considerations

ABSTRACT Background Maternal anti-thyroid drug (ATD) use during the first trimester of pregnancy has been associated with an increased risk of birth defects in offspring. Uncertainty remains on the size of this risk and how it compares to untreated hyperthyroidism due to methodological limitations of previous studies. Methods Systematic review of MEDLINE and EMBASE identifying observational studies examining ATD use during the first trimester of pregnancy and risk of birth defects. Data were extracted on study characteristics, adjusted effect estimates and comparator groups. Effect estimates were pooled using a random-effects generic inverse variance method of analysis and absolute risk calculated. Results Seven cohort studies and one case–control study (involving 6212322 pregnancies and 388976 birth defects) were identified. Compared to unexposed women without hyperthyroidism, the association between ATD first trimester use and birth defects in offspring was: adjusted risk ratio [aRR] 1.16 95% CI 1.08-1.25 for propylthyoruacil (PTU); aRR 1.28 95% CI 1.06-1.54 for methimazole/carbimazole (MMI/CMZ); aRR 1.51, 95% CI 1.16-1.97 for both MMI/CMZ and PTU; and aRR 1.15 95%CI 1.02-1.29 for untreated hyperthyroidism. The risk of major birth defects per 1000 live births was: 9.6 for PTU; 16.8 for MMI/CMZ; 30.6 for both MMI/CMZ and PTU; and 9.0 for untreated hyperthyroidism. Conclusions When appropriately analysed this risk of birth defects associated with ATD use in the first trimester of pregnancy is attenuated. Although still elevated, the risk of birth defects is smallest with PTU compared to use of MMI/CMZ and may be similar to that of untreated hyperthyroidism.