Specific SSRIs and Birth Defects: New Data
Using data from the US National Birth Defects Prevention Study (NBDPS), we confirmed previously reported associations between right ventricular outflow tract obstruction cardiac defects in infants and maternal use of fluoxetine or paroxetine early in pregnancy, and between anencephaly or atrial septal defects in infants and maternal use of paroxetine. This analysis also confirmed associations between gastroschisis or omphalocele and paroxetine and between craniosynostosis and fluoxetine that were reported in the analysis of an earlier subset of NBDPS data; however, these still require corroboration in an independent data source. It is reassuring that none of the five previously reported associations between sertraline and birth defects were confirmed in this analysis, particularly since about 40% of women reporting use of an SSRI in early pregnancy used sertraline. In addition, we did not find support for nine other previously reported associations between maternal SSRI treatment and selected birth defects in the child.
Although our analysis strongly supports the validity of the associations that were observed, the increase in the absolute risks, if the associations are causal, is small. The two strongest posterior odds ratios were seen for maternal paroxetine treatment and anencephaly (3.2) or right ventricular outflow tract obstruction cardiac defects (2.4) in the infant. If these associations are causal, the absolute risks in the children of women who are treated with paroxetine early in pregnancy would increase for anencephaly from 2 per 10 000 to 7 per 10 000, and for right ventricular outflow tract obstruction cardiac defects from 10 per 10 000 to 24 per 10 000. The absolute risks for these birth defects are still low.
This analysis confirms the need to assess the association between specific SSRIs and specific birth defects rather than combining an entire drug class or heterogeneous group of birth defects. Although SSRIs are similar pharmacologically, there are chemical differences, and if any of them do have teratogenic activity, it may be completely unrelated to the inhibition of serotonin receptors. SSRIs also differ pharmacokinetically, and this could account for differences in teratogenic activity, whether or not the mechanism involved inhibition of serotonin receptors.
This analysis does not address whether the birth defect associations we observed were caused by maternal SSRI treatment, underlying maternal disease, or some other factor. Since there was no specific question on depression and we cannot identify all participants with untreated depression, there is the possibility of confounding by indication.
A recent publication by Furu and colleagues combined data from five Nordic countries. Some overlap occurred between the data included in this recent study and the three Nordic studies we included in our meta-analysis, but this study also included data from Norway and Iceland that is not included in our analyses. Many of the associations we assessed for septal heart defects and right ventricular outflow tract obstruction cardiac defects showed similar risk estimates in our analysis and the recent study. One clear different finding is the association reported by Furu and colleagues for anal atresia and sertraline that was also reported by Louik and colleagues but is not evident in the NBDPS data.
Additional limitations of this analysis need to be acknowledged. Periconceptional exposure was based on maternal self report, with interviews conducted six weeks to 24 months after the expected date of delivery. However, Kwon and colleagues reported good concordance between self report of antidepressants and claims data.
We made 21 comparisons between exposure and outcome using five different models, and it is possible that some statistically significant findings occurred owing to the occurrence of false positive associations expected with multiple comparisons. Another limitation is that the small numbers for some of the individual birth defects and some of the specific exposures resulted in unstable estimates. Finally, exposure ascertainment is known to be more complete when women are specifically asked about their use of drugs by name; the interview did not include a specific question about use of escitalopram.
This analysis also has some important strengths. The bayesian analysis enabled consideration of evidence both for and against an association between use of SSRIs and risk of birth defects from previous epidemiological studies in the analyses and used relatively homogenous and discrete classes of birth defects and SSRI monotherapy. As a result, our study provides strong evidence for the reproducibility and validity of the associations that were observed. The sensitivity assessment showed that missing data were unlikely to have affected the results. The association between SSRIs and heart defects is biologically plausible; Sadler has suggested that the association may be a result of the key role that the neurotransmitter serotonin (5-hydroxytryptamine) plays in embryonic development of the heart.
A major advantage of this analysis over some previous reports is the ability to assess individual SSRIs and individual birth defects, while accounting for earlier reported associations. Although the data are self reported, they do represent reported use of the medications and not just filling of the prescription. Approximately 30% of mothers stop taking SSRIs during pregnancy, and this might not be captured if we relied on prescription information or medical records, since prescriptions might have been filled but not taken after the pregnancy was recognized. We have previously used NBDPS data to show that antidepressant prescription patterns have changed over time, making it more challenging to study these associations.
Our analyses of a large population based case-control dataset combined with prior odds ratios based on the literature allowed us to show and refine associations between maternal fluoxetine or paroxetine treatment during pregnancy and right ventricular outflow tract obstruction cardiac defects and between maternal use of paroxetine and anencephaly or atrial septal defects. In contrast, we found no evidence to support 14 other previously reported associations between maternal SSRI use and birth defects. Continued scrutiny of the association between SSRIs and birth defects is warranted, and additional studies of specific SSRI treatments during pregnancy and birth defects are needed to enable women and their healthcare providers to make more informed decisions about treatment. Meanwhile, the current analysis can help guide healthcare providers and women to the safest options for treatment during early pregnancy to minimize the risk of major birth defects, while providing adequate treatment of maternal depression.
Discussion
Using data from the US National Birth Defects Prevention Study (NBDPS), we confirmed previously reported associations between right ventricular outflow tract obstruction cardiac defects in infants and maternal use of fluoxetine or paroxetine early in pregnancy, and between anencephaly or atrial septal defects in infants and maternal use of paroxetine. This analysis also confirmed associations between gastroschisis or omphalocele and paroxetine and between craniosynostosis and fluoxetine that were reported in the analysis of an earlier subset of NBDPS data; however, these still require corroboration in an independent data source. It is reassuring that none of the five previously reported associations between sertraline and birth defects were confirmed in this analysis, particularly since about 40% of women reporting use of an SSRI in early pregnancy used sertraline. In addition, we did not find support for nine other previously reported associations between maternal SSRI treatment and selected birth defects in the child.
Although our analysis strongly supports the validity of the associations that were observed, the increase in the absolute risks, if the associations are causal, is small. The two strongest posterior odds ratios were seen for maternal paroxetine treatment and anencephaly (3.2) or right ventricular outflow tract obstruction cardiac defects (2.4) in the infant. If these associations are causal, the absolute risks in the children of women who are treated with paroxetine early in pregnancy would increase for anencephaly from 2 per 10 000 to 7 per 10 000, and for right ventricular outflow tract obstruction cardiac defects from 10 per 10 000 to 24 per 10 000. The absolute risks for these birth defects are still low.
This analysis confirms the need to assess the association between specific SSRIs and specific birth defects rather than combining an entire drug class or heterogeneous group of birth defects. Although SSRIs are similar pharmacologically, there are chemical differences, and if any of them do have teratogenic activity, it may be completely unrelated to the inhibition of serotonin receptors. SSRIs also differ pharmacokinetically, and this could account for differences in teratogenic activity, whether or not the mechanism involved inhibition of serotonin receptors.
Limitations of This Study
This analysis does not address whether the birth defect associations we observed were caused by maternal SSRI treatment, underlying maternal disease, or some other factor. Since there was no specific question on depression and we cannot identify all participants with untreated depression, there is the possibility of confounding by indication.
A recent publication by Furu and colleagues combined data from five Nordic countries. Some overlap occurred between the data included in this recent study and the three Nordic studies we included in our meta-analysis, but this study also included data from Norway and Iceland that is not included in our analyses. Many of the associations we assessed for septal heart defects and right ventricular outflow tract obstruction cardiac defects showed similar risk estimates in our analysis and the recent study. One clear different finding is the association reported by Furu and colleagues for anal atresia and sertraline that was also reported by Louik and colleagues but is not evident in the NBDPS data.
Additional limitations of this analysis need to be acknowledged. Periconceptional exposure was based on maternal self report, with interviews conducted six weeks to 24 months after the expected date of delivery. However, Kwon and colleagues reported good concordance between self report of antidepressants and claims data.
We made 21 comparisons between exposure and outcome using five different models, and it is possible that some statistically significant findings occurred owing to the occurrence of false positive associations expected with multiple comparisons. Another limitation is that the small numbers for some of the individual birth defects and some of the specific exposures resulted in unstable estimates. Finally, exposure ascertainment is known to be more complete when women are specifically asked about their use of drugs by name; the interview did not include a specific question about use of escitalopram.
Strengths of This Study
This analysis also has some important strengths. The bayesian analysis enabled consideration of evidence both for and against an association between use of SSRIs and risk of birth defects from previous epidemiological studies in the analyses and used relatively homogenous and discrete classes of birth defects and SSRI monotherapy. As a result, our study provides strong evidence for the reproducibility and validity of the associations that were observed. The sensitivity assessment showed that missing data were unlikely to have affected the results. The association between SSRIs and heart defects is biologically plausible; Sadler has suggested that the association may be a result of the key role that the neurotransmitter serotonin (5-hydroxytryptamine) plays in embryonic development of the heart.
A major advantage of this analysis over some previous reports is the ability to assess individual SSRIs and individual birth defects, while accounting for earlier reported associations. Although the data are self reported, they do represent reported use of the medications and not just filling of the prescription. Approximately 30% of mothers stop taking SSRIs during pregnancy, and this might not be captured if we relied on prescription information or medical records, since prescriptions might have been filled but not taken after the pregnancy was recognized. We have previously used NBDPS data to show that antidepressant prescription patterns have changed over time, making it more challenging to study these associations.
Our analyses of a large population based case-control dataset combined with prior odds ratios based on the literature allowed us to show and refine associations between maternal fluoxetine or paroxetine treatment during pregnancy and right ventricular outflow tract obstruction cardiac defects and between maternal use of paroxetine and anencephaly or atrial septal defects. In contrast, we found no evidence to support 14 other previously reported associations between maternal SSRI use and birth defects. Continued scrutiny of the association between SSRIs and birth defects is warranted, and additional studies of specific SSRI treatments during pregnancy and birth defects are needed to enable women and their healthcare providers to make more informed decisions about treatment. Meanwhile, the current analysis can help guide healthcare providers and women to the safest options for treatment during early pregnancy to minimize the risk of major birth defects, while providing adequate treatment of maternal depression.
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