This is a application for a double blind, placebo-controlled study to determine if vitamin C supplementation (500 mg daily) can decrease the effect of maternal smoking in pregnancy on offspring pulmonary function (VC-SIP). Smoking during pregnancy remains a major public health problem as at least 12% of pregnant women cannot quit smoking during pregnancy. This addiction is the largest preventable cause of childhood respiratory illness, including asthma, and children whose mothers smoked during pregnancy show lifetime decreases in pulmonary function. Smoking is a unique morbidity in that it is addictive, heavily advertised and recent genome studies show there are genotypes that significantly increase the likelihood of being unable to quit. Teen pregnancy, low income, low education, and living with another smoker are important factors increasing the odds of smoking during pregnancy. Pulmonary function tests done shortly after birth in babies born to mothers who smoked during pregnancy show decreased pulmonary function as measured by decreased respiratory flows and compliance and altered tidal breathing patterns. These changes can still be measured even after the infants have reached adulthood. Multiple epidemiologic studies show that these decreases in pulmonary function lead to increased respiratory disease and costs of hundreds of millions of dollars per year. The primary aim of this multi-site study is to demonstrate improved pulmonary function testing at 3 months of age, in infants delivered to smoking mothers who are randomized to 500 mg/day of supplemental vitamin C versus placebo prior to 22 weeks of pregnancy. Patients will meet with research personnel at each prenatal visit and smoking cessation will be actively encouraged. Patients will be monitored with a set of serial biomarkers to assess smoking and medication compliance, including urine cotinines levels, smoking questionnaires, pill counts and fasting plasma ascorbic acid levels. Pulmonary function tests will be done at 3 months of age and will measure forced expiratory flows. Success of this study is supported by strong pilot data from Dr. McEvoy's K23 showing statistically significant improvements in pulmonary function tests in infants born to smoking mothers who received vitamin C, and preliminary data showing a lower incidence of wheezing at 1 year of age in these infants. Key genetic polymorphisms shown to increase sensitivity to in utero smoke exposure will also be measured. The success of this study is also supported by animal models showing the effectiveness of vitamin C to preserve pulmonary function and genetic and epidemiologic studies linking the effects of smoking during pregnancy to oxidant mechanisms. Given nicotine's addictive nature, the underserved socio-economic nature of the patient population, and the constant advertising by tobacco companies, smoking during pregnancy will continue to adversely victimize millions of babies worldwide. This research has great public health significance to potentially alter the fetal origins of respiratory disease by blocking some of the effects of in-utero smoke exposure on lung development.

Public Health Relevance

Maternal smoking during pregnancy is the largest preventable cause of childhood respiratory illness, and children whose mothers smoked during pregnancy show lifetime decreases in pulmonary function and increased respiratory illnesses and asthma. Maternal smoking is estimated to cause 10% of direct medical expenditures in the first year of life and approximately 20% of expenditures for childhood respiratory illness are caused by maternal smoking. The findings from this project will support the addition of a simple, safe, and inexpensive adjunct to current smoking cessation counseling that would significantly decrease the impact of smoking during pregnancy on child respiratory health both in the US and world-wide.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical Trials Review Committee (CLTR)
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Blaisdell, Carol J
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Oregon Health and Science University
Schools of Medicine
United States
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MacDonald, Kelvin D; Moran, Aurelia R; Scherman, Ashley J et al. (2017) Maternal high-fat diet in mice leads to innate airway hyperresponsiveness in the adult offspring. Physiol Rep 5:
McEvoy, Cindy T; Spindel, Eliot R (2017) Pulmonary Effects of Maternal Smoking on the Fetus and Child: Effects on Lung Development, Respiratory Morbidities, and Life Long Lung Health. Paediatr Respir Rev 21:27-33
Aschner, Judy L; Bancalari, Eduardo H; McEvoy, Cindy T (2017) Can We Prevent Bronchopulmonary Dysplasia? J Pediatr 189:26-30
Shorey-Kendrick, Lyndsey E; McEvoy, Cindy T; Ferguson, Betsy et al. (2017) Vitamin C Prevents Offspring DNA Methylation Changes Associated with Maternal Smoking in Pregnancy. Am J Respir Crit Care Med 196:745-755
McEvoy, Cindy T; Park, Byung S; Spindel, Eliot R (2017) Sensitive Windows for In Utero Exposures and Asthma Development. Layers of Complexity. Am J Respir Crit Care Med 196:1362-1364
McEvoy, Cindy; Schilling, Diane; Spitale, Patricia et al. (2017) Pulmonary function and outcomes in infants randomized to a rescue course of antenatal steroids. Pediatr Pulmonol 52:1171-1178
McEvoy, Cindy T; Milner, Kristin F; Scherman, Ashley J et al. (2017) Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP): Rationale, design, and methods of a randomized, controlled trial of vitamin C supplementation in pregnancy for the primary prevention of effects of in utero tobacco Contemp Clin Trials 58:66-77
Peterson-Carmichael, Stacey; Seddon, Paul C; Cheifetz, Ira M et al. (2016) An Official American Thoracic Society/European Respiratory Society Workshop Report: Evaluation of Respiratory Mechanics and Function in the Pediatric and Neonatal Intensive Care Units. Ann Am Thorac Soc 13:S1-11
Spindel, Eliot R; McEvoy, Cindy T (2016) Reply: Why Pregnant Women Should Avoid Any Form of Nicotine during Pregnancy: An Elastin-based Perspective. Am J Respir Crit Care Med 194:247-8
MacDonald, Kelvin D; Vesco, Kimberly K; Funk, Kristine L et al. (2016) Maternal body mass index before pregnancy is associated with increased bronchodilator dispensing in early childhood: A cross-sectional study. Pediatr Pulmonol 51:803-11

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