Residency 2014-15

Residency 2014-15
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Tuesday, September 14, 2010

Resident Journal Club




The resident Journal Club featured a recent article in NEJM regarding Valproic Acid Exposure and the risk of Congenital Malformations.

The article was presented by R3 Shayna Norman and the discussion led by R4 Dan Czarnecki. The highlights of the article are listed below and the discussion questions follow the summary. Big thanks to Dr. Norman and Dr. Czarnecki for doing a great job!

NEJM Study Summary:

Objective: This was a retrospective case control study performed to investigate if the use of valproic acid monotherapy in the first trimester infers an increased risk for congenital malformations other than spina bifida.

Study design/Results: Utilizing the EUROCAT antiepileptic database ,and previously identified 14 malformations from prior cohort studies, the authors found that in comparison to no antiepileptic drug (AED) exposure, valproic acid leads to significant increase in the risk for spina bifida, ASD, cleft palate, hypospadias, polydactyly, and craniosynostosis. The associations persisted when comparing exposure to monotherapy of a different AED, except craniosynostosis.

Strengths: Minimally affected by recall bias, large study population, type of antiepileptic used was known in 99.9% of cases, and monotherapy was well delineated, diverse study population (14 countries), able to control for chromosomal abnormalities.

Weaknesses: Basis for defining cases (14 malformations) dependent on literature review, no information on type or severity of epilepsy, dosage, or outcome data, could cause confounding, no baseline comparison between cases and controls, difficult to apply to general population given all cases and controls had congenital malformations.

Impact: Valproic acid use in the first trimester should be avoided if possible due to its known teratogenic effects. Valproic Acid is pregnancy category D, illustrating that there are some cases in which the benefits may outweigh the risks of congenital anomalies. This study has reaffirmed this classification. Further study on dosage and indication is warranted as well as investigation into long term outcomes

Discussion questions:

1. How were Valproic Acid-associated malformations chosen from the literature? Was this the best way to choose outcomes? How would you characterize their method? Why do you think they did it this way?
2. Essentially, what type of study was this? Who were the cases? Who were the controls?
3. Were these the most appropriate control groups? Do we know if cases and controls were similar-appearing groups? Could there be confounders?
4. What are the main issues when using databases as the foundation for your study design? Did these issues affect this study?
5. Is any Valproic Acid exposure the same? Do we have the necessary information in this study to draw a cause/effect relationship?
6. Are all the results this study reports as significantly different actually statistically and/or clinically significant? What does an odds ratio of 12.7 mean in table 3? How can some of the wide confidence intervals be explained?
7. What is the difference between risk associated with elevated odds ratios and absolute risk?
8. How should we counsel a patient who is well-controlled on Valproic Acid for her epilepsy and would like to conceive? Should we offer first trimester terminations for exposures?

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