Talipes equinovarus or clubfoot occurs in approximately one of every 1000 live births. Although it is one of the most common structural malformations, little is known about its etiology. There are many lines of evidence that suggest vascular disruption in early development plays an etiologic role. Thus, maternal exposure to vasoactive agents during pregnancy may be associated with increased clubfoot risk. Decongestants and non-steroidal anti-inflammatory drugs are vasoactive and use of each has been associated with other malformations that are similarly thought to arise from vascular disruption. Maternal cigarette smoking, which is also vasoactive, has been found to increase clubfoot risk in three previous studies. We propose to examine maternal use of vasoactive medications and cigarette smoking in relation to clubfoot risk, with particular attention to timing of exposure. We will conduct a population-based case-control study of clubfoot in Massachusetts, New York, and North Carolina. Within each state, newly diagnosed cases with clubfoot will be identified from the birth defect registry. A random sample of controls will be identified from birth certificate records in each state. Over a four year period, we will enroll 800 cases and 1600 controls. Mothers of cases and controls will be interviewed by telephone within 12 months after delivery. Detailed questions will be asked about vasoactive exposures in pregnancy, including use of decongestants and non-steroidal anti-inflammatory drugs and cigarette smoking. Medication use will be ascertained with help of a medication identification booklet that includes color pictures of over 350 over-the-counter cough, cold, and analgesic products. Medical record review will be conducted to confirm clubfoot diagnoses. The separate and combined effects of cigarette smoking and maternal use of vasoactive medications will be studied in relation to clubfoot risk, while controlling for potential confounding factors. Findings from this study will be useful in counseling women of childbearing age. In addition, findings will help further understanding of the vascular disruption pathway. Buccal cell swabs will be collected from cases, controls, and their mothers. DNA will be extracted and stored for the purpose of studying genetic risk factors in future studies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IRAP-Q (01))
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Javois, Lorette Claire
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Boston University
Public Health & Prev Medicine
Schools of Medicine
United States
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Yazdy, Mahsa M; Werler, Martha M (2015) Comparison of web versus interview participants in a case-control study. Ann Epidemiol 25:794-6
Werler, Martha M; Yazdy, Mahsa M; Kasser, James R et al. (2015) Maternal cigarette, alcohol, and coffee consumption in relation to risk of clubfoot. Paediatr Perinat Epidemiol 29:3-10
Yazdy, Mahsa M; Mitchell, Allen A; Louik, Carol et al. (2015) The authors respond. Epidemiology 26:e35-6
Yazdy, Mahsa M; Mitchell, Allen A; Louik, Carol et al. (2014) Use of selective serotonin-reuptake inhibitors during pregnancy and the risk of clubfoot. Epidemiology 25:859-65
Werler, Martha M; Yazdy, Mahsa M; Kasser, James R et al. (2014) Medication use in pregnancy in relation to the risk of isolated clubfoot in offspring. Am J Epidemiol 180:86-93
Mahan, Susan T; Yazdy, Mahsa M; Kasser, James R et al. (2014) Prenatal screening for clubfoot: what factors predict prenatal detection? Prenat Diagn 34:389-93
Mahan, Susan T; Yazdy, Mahsa M; Kasser, James R et al. (2013) Is it worthwhile to routinely ultrasound screen children with idiopathic clubfoot for hip dysplasia? J Pediatr Orthop 33:847-51
Werler, Martha M; Yazdy, Mahsa M; Mitchell, Allen A et al. (2013) Descriptive epidemiology of idiopathic clubfoot. Am J Med Genet A 161A:1569-78
Werler, Martha M; Louik, Carol; Mitchell, Allen A (2011) Case-control studies for identifying novel teratogens. Am J Med Genet C Semin Med Genet 157:201-8
Werler, Martha M; Bosco, Jaclyn L F; Shapira, Stuart K et al. (2009) Maternal vasoactive exposures, amniotic bands, and terminal transverse limb defects. Birth Defects Res A Clin Mol Teratol 85:52-7

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