Cleft lip and/or palate (CL/P) are common and burdensome birth defects with a complex etiology of genetic, behavioral and environmental contributors. CL/P impose significant burden on the health, quality of life and economics of affected individuals individual and families. Several studies have suggested that maternal risk behaviors during pregnancy such as smoking, alcohol use, and obesity play a role in the etiology of CL/P. However, these studies that do not account for unobserved or unmeasured factors that may influence maternal self-selection into risk behaviors but are related to CL/P risks, such as maternal preferences for health and risk tolerance and maternal perceptions of health risks. These factors induce correlations between several maternal risk and health behaviors and are themselves correlated with biologic, environmental and maternal health risk factors. It is virtually impossible to observe all relevant behaviors and risk factors in available data samples. Ignoring these unobserved yet relevant factors may confound the estimates of the effects of maternal risk behaviors on CL/P, including estimates of average effects and interactive effects with genetic risk factors. Accurate estimation of the effects of maternal risk behaviors is needed for developing effective counseling and prevention programs for CL/P. The objective of this study is to estimate the effects of maternal risk behaviors during pregnancy including smoking, alcohol, and obesity on CL/P risks using a genetic instrumental variable (IV) model that accounts for unobserved confounders. The IV model will estimate these effects using variation in the risk behaviors that is predicted by genetic variants (instruments) that are significantly correlated with these risk behaviors but are otherwise unrelated to CL/P through unobserved confounders. Using appropriate instruments, the IV model will provide consistent (asymptotically unbiased) estimates of the "causal" effects of these risk behaviors on CL/P. The study will include a unique and large international consortium of population-level samples of about 8917 mothers of children with CL/P and mothers of unaffected children. The study will select and genotype genetic variants that are strong candidates for use as instruments for the study maternal risk behaviors, evaluate the utility of these variants as instruments, and estimate the effects of the maternal risk behaviors on CL/P using an IV model with the genetic instruments that fit the IV conditions. The employed IV model will estimate the average effects of these risk behaviors on CL/P as well as their interactive effects with genetic risk factors for CL/P. The study will provide consistent estimates of the "causal" effects of major maternal risk behaviors on CL/P which are highly needed for developing effective and cost-effective programs for prevention of CL/P and counseling at risk women. Further, the study utilizes a novel analytical approach that can be applied to study the effects of maternal risk behaviors on other birth defects and perinatal outcomes and has the potential for advancing this research field significantly.

Public Health Relevance

This project will help to identify the effects of several maternal risk behaviors during pregnancy including smoking, alcohol and obesity on the risks of cleft lip and/or palate, which are common and burdensome birth defects. Accurate estimates of the effects of these risk behaviors are needed for developing effective interventions and policies to prevent cleft lip and/or palate.

National Institute of Health (NIH)
Research Project (R01)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Harris, Emily L
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University of Iowa
Public Health & Prev Medicine
Schools of Public Health
Iowa City
United States
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Wehby, George L; Prater, Kaitlin N; Ryckman, Kelli K et al. (2015) Candidate gene study for smoking, alcohol use, and body weight in a sample of pregnant women. J Matern Fetal Neonatal Med 28:804-11
von Hinke Kessler Scholder, Stephanie; Wehby, George L; Lewis, Sarah et al. (2014) Alcohol Exposure In Utero and Child Academic Achievement. Econ J (London) 124:634-667
Wehby, George L; Scholder, Stephanie von Hinke Kessler (2013) Genetic instrumental variable studies of effects of prenatal risk factors. Biodemography Soc Biol 59:4-36
Wehby, George L (2013) Advancing and prioritizing research on oral clefts in Brazil. J Pediatr (Rio J) 89:112-5
Wehby, George L; Wilcox, Allen; Lie, Rolv T (2013) The Impact of Cigarette Quitting during Pregnancy on Other Prenatal Health Behaviors. Rev Econ Househ 11:211-233
Wehby, G L; Tyler, M C; Lindgren, S et al. (2012) Oral clefts and behavioral health of young children. Oral Dis 18:74-84
Wehby, George L; Murray, Jeffrey C; Wilcox, Allen et al. (2012) Smoking and body weight: evidence using genetic instruments. Econ Hum Biol 10:113-26
Guarnizo-Herreno, Carol Cristina; Wehby, George L (2012) Explaining racial/ethnic disparities in children's dental health: a decomposition analysis. Am J Public Health 102:859-66
Wehby, George L; Fletcher, Jason M; Lehrer, Steven F et al. (2011) A genetic instrumental variables analysis of the effects of prenatal smoking on birth weight: evidence from two samples. Biodemography Soc Biol 57:3-32
Wehby, George; Jugessur, Astanand; Murray, Jeffrey C et al. (2011) GENES AS INSTRUMENTS FOR STUDYING RISK BEHAVIOR EFFECTS: AN APPLICATION TO MATERNAL SMOKING AND OROFACIAL CLEFTS. Health Serv Outcomes Res Methodol 11:54-78