Oral Vitamin C (500 mg/d) to Pregnant Smokers Improves Infant Airway Function at 3 Months (VCSIP). A Randomized Trial

Cindy T McEvoy, Lyndsey E Shorey-Kendrick, Kristin Milner, Diane Schilling, Christina Tiller, Brittany Vuylsteke, Ashley Scherman, Keith Jackson, David M Haas, Julia Harris, Robert Schuff, Byung S Park, Annette Vu, Dale F Kraemer, Julie Mitchell, Jill Metz, David Gonzales, Carol Bunten, Eliot R Spindel, Robert S Tepper, Cynthia D Morris, Cindy T McEvoy, Lyndsey E Shorey-Kendrick, Kristin Milner, Diane Schilling, Christina Tiller, Brittany Vuylsteke, Ashley Scherman, Keith Jackson, David M Haas, Julia Harris, Robert Schuff, Byung S Park, Annette Vu, Dale F Kraemer, Julie Mitchell, Jill Metz, David Gonzales, Carol Bunten, Eliot R Spindel, Robert S Tepper, Cynthia D Morris

Abstract

Rationale: We reported a randomized trial demonstrating daily supplemental vitamin C to pregnant smokers significantly improved newborn pulmonary function tests. The current study tests these results in a new cohort using infant pulmonary function tests. Objectives: To determine if infants of pregnant smokers randomized to daily supplemental vitamin C would have improved forced expiratory flows (FEFs) at 3 months of age compared with those randomized to placebo, and to investigate the association of the α5 nicotinic acetylcholine receptor. Methods: A randomized, double-blind, placebo-controlled trial was conducted at three centers. Two hundred fifty-one pregnant smokers were randomized at 13-23 weeks of gestation: 125 randomized to vitamin C (500 mg/d) and 126 to placebo. Measurements and Main Results: The primary outcome was FEF75 at 3 months of age performed with the raised volume rapid thoracic compression technique (Jaeger/Viasys). FEF50 and FEF25-75 obtained from the same expiratory curves were prespecified secondary outcomes. The infants of pregnant smokers randomized to vitamin C (n = 113) had the following FEFs at 3 months of age compared with those randomized to placebo (n = 109) as measured by FEF75 (200.7 vs. 188.7 ml/s; adjusted 95% confidence interval [CI] for difference, -3.33 to 35.64; P = 0.10), FEF50 (436.7 vs. 408.5 ml/s; adjusted 95% CI for difference, 6.10-61.30; P = 0.02), and FEF25-75 (387.4 vs. 365.8 ml/s; adjusted 95% CI for difference, 0.92-55.34; P = 0.04). Infant FEFs seemed to be negatively associated with the maternal risk alleles for the α5 nicotinic acetylcholine receptor (rs16969968). Conclusions: Although the primary outcome of FEF75 was not improved after vitamin C supplementation to pregnant smokers, the predetermined secondary outcomes FEF50 and FEF25-75 were significantly improved. These results extend our previous findings and demonstrate improved airway function (FEF50 and FEF25-75) at 3 months of age in infants after vitamin C supplementation to pregnant smokers. Clinical trial registered with www.clinicaltrials.gov (NCT01723696).

Keywords: forced expiratory flows; infant pulmonary function; smoking in pregnancy; vitamin C; wheezing.

Figures

Figure 1.
Figure 1.
Consolidated Standards for Reporting Trials diagram for randomized smokers. Enrollment, randomization, and follow-up of randomized smokers and their infants through the 3-month pulmonary function tests/forced expiratory flows. BMI = body mass index; FEF = forced expiratory flow; PFT = pulmonary function test.

References

    1. US Department of Health and Human Services. The health consequences of involuntary exposure to tobacco smoke: a report of the Surgeon General—Executive Summary. Atlanta, GA: Centers for Disease Control and Prevention; 2006.
    1. Hayatbakhsh MR, Sadasivam S, Mamun AA, Najman JM, Williams GM, O’Callaghan MJ. Maternal smoking during and after pregnancy and lung function in early adulthood: a prospective study. Thorax. 2009;64:810–814.
    1. Best D Committee on Environmental Health; Committee on Native American Child Health; Committee on Adolescence. From the American Academy of Pediatrics: technical report: secondhand and prenatal tobacco smoke exposure. Pediatrics. 2009;124:e1017–e1044.
    1. Filion KB, Abenhaim HA, Mottillo S, Joseph L, Gervais A, O’Loughlin J, et al. The effect of smoking cessation counselling in pregnant women: a meta-analysis of randomised controlled trials. BJOG. 2011;118:1422–1428.
    1. Schneider S, Huy C, Schütz J, Diehl K. Smoking cessation during pregnancy: a systematic literature review. Drug Alcohol Rev. 2010;29:81–90.
    1. Tong VT, Dietz PM, Morrow B, D’Angelo DV, Farr SL, Rockhill KM, et al. Centers for Disease Control and Prevention (CDC) Trends in smoking before, during, and after pregnancy: Risk Assessment Monitoring System, United States, 40 sites, 2000-2010. MMWR Surveill Summ. 2013;62:1–19.
    1. Stoddard JJ, Gray B. Maternal smoking and medical expenditures for childhood respiratory illness. Am J Public Health. 1997;87:205–209.
    1. McEvoy CT, Schilling D, Clay N, Jackson K, Go MD, Spitale P, et al. Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial. JAMA. 2014;311:2074–2082.
    1. Bierut LJ. Convergence of genetic findings for nicotine dependence and smoking related diseases with chromosome 15q24-25. Trends Pharmacol Sci. 2010;31:46–51.
    1. Chen LS, Baker T, Hung RJ, Horton A, Culverhouse R, Hartz S, et al. Genetic risk can be decreased: quitting smoking decreases and delays lung cancer for smokers with high and low CHRNA5 risk genotypes. A meta-analysis. EBioMedicine. 2016;11:219–226.
    1. Sekhon HS, Jia Y, Raab R, Kuryatov A, Pankow JF, Whitsett JA, et al. Prenatal nicotine increases pulmonary alpha7 nicotinic receptor expression and alters fetal lung development in monkeys. J Clin Invest. 1999;103:637–647.
    1. Sekhon HS, Keller JA, Benowitz NL, Spindel ER. Prenatal nicotine exposure alters pulmonary function in newborn rhesus monkeys. Am J Respir Crit Care Med. 2001;164:989–994.
    1. Sekhon HS, Keller JA, Proskocil BJ, Martin EL, Spindel ER. Maternal nicotine exposure upregulates collagen gene expression in fetal monkey lung. Association with alpha7 nicotinic acetylcholine receptors. Am J Respir Cell Mol Biol. 2002;26:31–41.
    1. Proskocil BJ, Sekhon HS, Clark JA, Lupo SL, Jia Y, Hull WM, et al. Vitamin C prevents the effects of prenatal nicotine on pulmonary function in newborn monkeys. Am J Respir Crit Care Med. 2005;171:1032–1039.
    1. Tager IB, Hanrahan JP, Tosteson TD, Castile RG, Brown RW, Weiss ST, et al. Lung function, pre- and post-natal smoke exposure, and wheezing in the first year of life. Am Rev Respir Dis. 1993;147:811–817.
    1. Martinez FD, Morgan WJ, Wright AL, Holberg CJ, Taussig LM. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. N Engl J Med. 1988;319:1112–1117.
    1. Dezateux C, Stocks J, Dundas I, Fletcher ME. Impaired airway function and wheezing in infancy: the influence of maternal smoking and a genetic predisposition to asthma. Am J Respir Crit Care Med. 1999;159:403–410.
    1. Jones MH, Davis SD, Grant D, Christoph K, Kisling J, Tepper RS. Forced expiratory maneuvers in very young children. Assessment of flow limitation. Am J Respir Crit Care Med. 1999;159:791–795.
    1. Martinez FD. The origins of asthma and chronic obstructive pulmonary disease in early life. Proc Am Thorac Soc. 2009;6:272–277.
    1. McEvoy CT, Milner KF, Schilling DG, Scherman A, Tiller A, Vuylsteke B, et al. Improved forced expiratory flows in infants of pregnant smokers randomized to daily vitamin C versus placebo [abstract] Am J Respir Crit Care Med. 2018;197:A4192.
    1. McEvoy CT, Milner KF, Scherman AJ, Schilling DG, Tiller CJ, Vuylsteke B, et al. 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 smoke exposure on infant lung function and respiratory health. Contemp Clin Trials. 2017;58:66–77.
    1. Fiore MC, Jaen CR, Baker TB, Bailey WC, Benowitz NL, Curry SJ, et al. Treating tobacco use and dependence: 2008 update. Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services. Public Health Service; 2008.
    1. Ferris BG. Epidemiology Standardization Project (American Thoracic Society) Am Rev Respir Dis. 1978;118:1–120.
    1. American Thoracic Society; European Respiratory Society. ATS/ERS statement: raised volume forced expirations in infants: guidelines for current practice. Am J Respir Crit Care Med. 2005;172:1463–1471.
    1. Frei B. Efficacy of dietary antioxidants to prevent oxidative damage and inhibit chronic disease. J Nutr. 2004;134:3196S–3198S.
    1. Benowitz NL, Hukkanen J, Jacob P., III Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 2009;192:29–60.
    1. Jones M, Castile R, Davis S, Kisling J, Filbrun D, Flucke R, et al. Forced expiratory flows and volumes in infants. Normative data and lung growth. Am J Respir Crit Care Med. 2000;161:353–359.
    1. Lum S, Bountziouka V, Wade A, Hoo AF, Kirkby J, Moreno-Galdo A, et al. New reference ranges for interpreting forced expiratory manoeuvres in infants and implications for clinical interpretation: a multicentre collaboration. Thorax. 2016;71:276–283.
    1. Hanrahan JP, Tager IB, Segal MR, Tosteson TD, Castile RG, Van Vunakis H, et al. The effect of maternal smoking during pregnancy on early infant lung function. Am Rev Respir Dis. 1992;145:1129–1135.
    1. Hoo AF, Henschen M, Dezateux C, Costeloe K, Stocks J. Respiratory function among preterm infants whose mothers smoked during pregnancy. Am J Respir Crit Care Med. 1998;158:700–705.
    1. Tager IB, Weiss ST, Muñoz A, Rosner B, Speizer FE. Longitudinal study of the effects of maternal smoking on pulmonary function in children. N Engl J Med. 1983;309:699–703.
    1. Jones MH, Howard J, Davis S, Kisling J, Tepper RS. Sensitivity of spirometric measurements to detect airway obstruction in infants. Am J Respir Crit Care Med. 2003;167:1283–1286.
    1. Moshammer H, Hoek G, Luttmann-Gibson H, Neuberger MA, Antova T, Gehring U, et al. Parental smoking and lung function in children: an international study. Am J Respir Crit Care Med. 2006;173:1255–1263.
    1. Schleicher RL, Carroll MD, Ford ES, Lacher DA. Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES) Am J Clin Nutr. 2009;90:1252–1263.
    1. Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest. 2013;144:266–273.
    1. Litonjua AA, Carey VJ, Laranjo N, Harshfield BJ, McElrath TF, O’Connor GT, et al. Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age 3 years: the VDAART randomized clinical trial. JAMA. 2016;315:362–370.
    1. Manuck TA, Levy PT, Gyamfi-Bannerman C, Jobe AH, Blaisdell CJ. Prenatal and perinatal determinants of lung health and disease in early life: a National Heart, Lung, and Blood Institute workshop report. JAMA Pediatr. 2016;170:e154577.
    1. Martinez FJ, Han MK, Allinson JP, Barr RG, Boucher RC, Calverley PMA, et al. At the root: defining and halting progression of early chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;197:1540–1551.
    1. Taylor B, Wadsworth J. Maternal smoking during pregnancy and lower respiratory tract illness in early life. Arch Dis Child. 1987;62:786–791.
    1. Burke H, Leonardi-Bee J, Hashim A, Pine-Abata H, Chen Y, Cook DG, et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics. 2012;129:735–744.
    1. Neuman Å, Hohmann C, Orsini N, Pershagen G, Eller E, Kjaer HF, et al. ENRIECO Consortium. Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med. 2012;186:1037–1043.
    1. Stocks J, Hislop A, Sonnappa S. Early lung development: lifelong effect on respiratory health and disease. Lancet Respir Med. 2013;1:728–742.
    1. Ten Have-Opbroek AA. The development of the lung in mammals: an analysis of concepts and findings. Am J Anat. 1981;162:201–219.

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