SLR - May 2015 - Clark Johnson

Use of Selective Serotonin-Reuptake Inhibitors During Pregnancy and the Risk of Clubfoot

Reference: Yazdy MM, Mitchell AA, Louik C, Werler MM.  Use of Selective Serotonin-reuptake Inhibitors Puring Pregnancy and the Risk of Clubfoot. Epidemiology. 2014 Nov;25(6):859-65.

Scientific Literature Review

Reviewed By: Clark Johnson, DPM
Residency Program: North Colorado Podiatric Medicine and Surgery Residency, Greeley, CO

Podiatric Relevance: Talipes equinovarus (clubfoot) is a structural malformation which occurs when the lower limbs fail to rotate correctly during early fetal development. The prevalence of clubfoot is approximately 1 per 1000 live births. Several studies have evaluated the underlying etiologies of clubfoot. These include environmental factors such as maternal smoking, chromosomal abnormalities and intra-uterine positioning. However, the majority of clubfoot cases are of unknown etiology. Currently, two studies have independently evaluated the risk of clubfoot in relation to the use of Selective Serotonin-Reuptake Inhibitors (SSRIs) during pregnancy. Identifying specific risk factors associated with fetal malformation will allow the physician and expectant mother to evaluate risk-benefit profiles when selecting appropriate treatment for depression. This is a level 3 retrospective case control study with the primary goal to evaluate whether SSRI use in early pregnancy increased the risk of structural clubfoot in the fetus. The authors also assessed the role of depression and the risk of clubfoot, independent of SSRI use.

Methods: Data was collected as part of a population-based case control study between 2006 and 2011 in Massachusetts, North Carolina and New York. The study groups were established as eligible case and control infants based on the following criteria. Case infants were less than 1 year of age, with a diagnosis of clubfoot without any other known congenital abnormality such as chromosomal anomaly, Potter syndrome, bilateral renal agenesis, amniotic bands, arthrogryposis or neural tube defects. Control infants were without diagnosis of major malformations or foot problems, drawn from the same birth population as the case infants. There were 622 case infants included in the final results; 2002 non-malformed control infants were included.  The important exposure window was defined as the 2nd and 3rd lunar months of pregnancy, when the lower limbs are in the process of intrauterine rotation. Included mothers were divided into 6 groups: 1) no depression and no SSRI use during pregnancy; 2) diagnosed depression with SSRI use for greater than 30 days within the exposure window; 3) diagnosed depression with SSRI use for less than 30 days within the exposure window; 4) diagnosed depression with SSRI use outside the exposure window; 5) diagnosed depression and non-SSRI use within the exposure window; 6) diagnosed depression and no medication use during pregnancy.

Results: The six groups of mothers were evaluated for the rate of clubfoot diagnosis and their odds ratios calculated. Among women who reported depression and use of SSRI for greater than 30 days during the exposure window, the odds ratio was 1.8, indicating a significantly increased risk of clubfoot. Odds ratios for mothers who used SSRI for less than 30 days within the exposure window, used SSRI outside the exposure window, and used non-SSRI medication within the exposure window were found to be near 1.0, indicating no increased risk of clubfoot. Depression without drug therapy did show a 1.3 odds ratio, a slightly increased risk of clubfoot. Specific SSRI medications were evaluated, unfortunately the number of evaluated cases were so small that no broad conclusions could be obtained. Of interest, case mothers were found to be more likely to be overweight, nulliparous, to smoke and to have affected male infants. These findings are consistent with the body of current literature available.

Conclusions: Diagnosis of depression, paired with consistent exposure to SSRI during the second and third lunar months of pregnancy increases the risk of clubfoot. While this study is the largest population-based study of idiopathic clubfoot cases to date, it is of limited clinical influence as the total number of evaluated patients was limited. Women of child bearing age, especially those with previously diagnosed depression who are currently using SSRI, should be counseled on the current body of literature, and reminded of the other known risk factors for clubfoot, i.e. obesity and smoking.

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