Vitamin C to Pregnant Smokers Persistently Improves Infant Airway Function to 12 Months of Age: A Randomised 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, Byung S Park, Annette Vu, Dale F Kraemer, David Gonzales, Carol Bunten, Eliot R Spindel, Cynthia D Morris, Robert S Tepper, Cindy T McEvoy, Lyndsey E Shorey-Kendrick, Kristin Milner, Diane Schilling, Christina Tiller, Brittany Vuylsteke, Ashley Scherman, Keith Jackson, David M Haas, Julia Harris, Byung S Park, Annette Vu, Dale F Kraemer, David Gonzales, Carol Bunten, Eliot R Spindel, Cynthia D Morris, Robert S Tepper

Abstract

Background: Vitamin C (500 mg·day-1) supplementation for pregnant smokers has been reported to increase newborn pulmonary function and infant forced expiratory flows (FEFs) at 3 months of age. Its effect on airway function through 12 months of age has not been reported.

Objective: To assess whether vitamin C supplementation to pregnant smokers is associated with a sustained increased airway function in their infants through 12 months of age.

Methods: This is a prespecified secondary outcome of a randomised, double-blind, placebo-controlled trial that randomised 251 pregnant smokers between 13 and 23 weeks of gestation: 125 to 500 mg·day-1 vitamin C and 126 to placebo. Smoking cessation counselling was provided. FEFs performed at 3 and 12 months of age were analysed by repeated measures analysis of covariance.

Results: FEFs were performed in 222 infants at 3 months and 202 infants at 12 months of age. The infants allocated to vitamin C had significantly increased FEFs over the first year of life compared to those allocated to placebo. The overall increased flows were: 40.2 mL·sec-1 for FEF75 (adjusted 95% CI for difference 6.6 to 73.8; p=0.025); 58.3 mL·sec-1 for FEF50 (95% CI 10.9 to 105.8; p=0.0081); and 55.1 mL·sec-1 for FEF25-75 (95% CI, 9.7 to 100.5; p=0.013).

Conclusions: In offspring of pregnant smokers randomised to vitamin C versus placebo, vitamin C during pregnancy was associated with a small but significantly increased airway function at 3 and 12 months of age, suggesting a potential shift to a higher airway function trajectory curve. Continued follow-up is underway.

Copyright ©ERS 2020.

Figures

Figure 1.. CONSORT Diagram for Randomized Smokers.
Figure 1.. CONSORT Diagram for Randomized Smokers.
Enrollment, randomization, and follow-up of randomized smokers and their infants through the 3 and 12 month measurements of airway function / forced expiratory flows (FEFs). In addition, 237 of the infants had respiratory questionnaires completed as per protocol.
Figure 2.. Effect of Vitamin C Supplementation…
Figure 2.. Effect of Vitamin C Supplementation During Pregnancy on Infant Airway Function Tests at 3 and 12 Months of Age.
Plots of unadjusted means (expressed as Means ± SEM) for FEF75 (the measurement of FEF at 75% of the expired volume), FEF50 (FEF at 50% of expired volume), FEF25–75, (FEF between 25 and 75% of expired volume), FVC (forced vital capacity). Vitamin C treated is solid line, closed square and placebo is dotted line, closed circle. FEF75, FEF50, and FEF25–75, were significantly improved in the vitamin C versus placebo group through 12 months of age by repeated measures analysis of covariance. There were no significant interactions for treatment group by study visit (3 and 12-month), suggesting effectively parallel differences between the treatment groups. See Table 2 legend and text.

References

    1. Agusti A, Faner R. Lung function trajectories in health and disease. Lancet Respir Med 2019; 7:358–64.
    1. Svanes C, Sunyer J, Plana E, Dharmage S, Heinrich J, Jarvis J, deMarco R, Norback D, Raherison C, Villani S, Wjst M, Svanes K, Anto JM. Early life origins of chronic obstructive pulmonary disease. Thorax 2010;65(1):14–20.
    1. Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD. Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet 2007;370(9589):758–764.
    1. Martinez FJ, Han MK, Allinson JP, Barr RG, BOucher RC, Calverley PMA, Celli BR, Christenson SA, Crystal RG, Fageras M, Freeman CM, Groenke L, Hoffman EA, Kesimer M, Kstikas K, Paine R, Rafi S, Rennard SI, Segal LN, Shaykhiev R, Stevenson C, Tal-Singer R, Vestbo J, Woodruff PG, Curtis JL, Wedzchia JA. At the root: defining and halting progression of early chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2018;197(12):1540–1551.
    1. Best D. From the American Academy of Pediatrics: Technical report--Secondhand and prenatal tobacco smoke exposure. Pediatrics 2009;124(5):e1017–e1044.
    1. Neuman A, Hohmann C, Orsini N, Pershagen G, Eller E, Kjaer JF, Gehring U, Granell R, Henderson J, Heinrich J, Lau S, Nieuwenhuijsen M, Sunyer J, Tischer C, Torrent M, Wahn U, Wijga AH, Keil T, Bergstrom A. Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med 2012;186(10):1037–1043.
    1. Tong VT, Dietz PM, Morrow B, D’Angela DV, Farr SL, TOckhill KM, England LJ. Trends in smoking before, during, and after pregnancy--Pregnancy Risk Assessment Monitoring System, United States, 40 sites, 2000–2010. MMWR Surveill Summ 2013;62(6):1–19.
    1. Lange S, Probst C, Rehm J, Popova S. National, regional, and global prevalence of smoking during pregnancy in the general population: a systematic review and meta-analysis. Lancet Glob Health 2018;6(7):e769–e776.
    1. Spindel ER, McEvoy CT. The role of nicotine in the effects of maternal smoking during pregnancy on lung development and childhood respiratory disease. Implications for dangers of e-cigarettes. Am J Respir Crit Care Med 2016;193(5):486–494.
    1. McEvoy CT, Schilling D, Clay N, Jackson K, Go MD, Spitale P, Bunten C, Leiva M, Gonzales D, Hollister-Smith J, Durand M, Frei B, Buist AS, Peters D, Morris CD, Spindel ER. Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial. JAMA 2014;311(20):2074–2082.
    1. McEvoy CT, Shorey-Kendrick LE, Milner K, Schilling D, Tiller C, Vuylsteke B, Scherman A, Jackson K, Haas DM, Harris J, Schuff R, Park BS, Vu A, Kraemer DF, Mitchell J, Metz J, Gonzalez D, Bunten C, Spindel Er, Tepper RS, Morris CD. Oral vitamin C (500 mg/day) to pregnant smokers improves infant airway function at 3 months (VCSIP): A randomized trial. Am J Respir Crit Care Med 2019; 199:1139–1147.
    1. McEvoy CT, Milner KF, Schiling DG, Scherman A, TIller A, Buylsteke B, Jackson K, Haas D, Bunten C, Harris J, Vu A, Schuff R, Kraemer D, Mitchell J, Metz J, Shorey-Kendrick L, Spindel ER, Tepper RS, Morris CD. Improved forced expiratory flows in infants of pregnant smokers randomized to daily vitamin C versus placebo. Am J Respir Crit Care Med 2018:A4192.
    1. McEvoy CT, Milner KF, Scherman AJ, Schilling DG, TIller CJ, Vuylsteke B, Shorey-Kendrick LE, Spindel ER, Schuff R, Mitchell J, Peters D, Metz J, Haas D, Jackson K, Tepper RS, Morris CD. 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. ATS/ERS statement: raised volume forced expirations in infants: guidelines for current practice. Am J Respir Crit Care Med 2005;172(11):1463–1471.
    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(3):791–795.
    1. Ferris BG. Epidemiology Standardization Project (American Thoracic Society). Am Rev Respir Dis 1978;118(6 Pt 2):1–120.
    1. Litonjua AA, Lange NE, Carey VJ, Brown S, Laranjo N, Harshfield BJ, O’Connor GT, Sandel M, Strunk RC, Bacharier LB, Zeiger RS, Schatz M, Hollis BW, Weiss ST. The Vitamin D Antenatal Asthma Reduction Trial (VDAART): rationale, design, and methods of a randomized, controlled trial of vitamin D supplementation in pregnancy for the primary prevention of asthma and allergies in children. Contemp Clin Trials 2014;38(1):37–50.
    1. Hibbs AM, Ross K, Kerns LA, Wagner CL, Fuloria M, Groh-Wargo S, Zimmerman T, Minich N, Tatsuoka C. Effect of vitamin D supplementation on recurrent wheezing in black infants who were born preterm: The D-Wheeze randomized clinical trial. JAMA 2018;319 (20):2086–2094.
    1. Lum S, Bountziouka V, Wade A, Hoo AF, Kirby 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. MacDonald KD, Vesco KK, Funk KL, Donovan J, Nguyen T, Chen Z, Lapidus JA, Stevens VJ, McEvoy CT. Maternal body mass index before pregnancy is associated with increased bronchodilator dispensing in early childhood: A cross-sectional study. Pediatr Pulmonol 2016;51(8):803–811.
    1. Friedrich L, Pitrez PM, Stein RT, Goldani M, Tepper R, Jones MH. Growth rate of lung function in healthy preterm infants. Am J Respir Crit Care Med 2007;176(12):1269–1273.
    1. Belgrave DCM, Granell R, Turner SW, Curtin JA, Buchan IE, LeSouef PN, Simpson A, Henderson AJ, Custovic A. Lung function trajectories from pre-school age to adulthood and their associations with early life factors: a retrospective analysis of three population-based birth cohort studies. Lancet Respir Med 2018; 6 (7): 526–534.
    1. Jones M, Castile R, Davis S, Kisling J, Filburn D, Flucke R, Goldstein A, Emsley C, Ambrosius W, Tepper RS. Forced expiratory flows and volumes in infants. Normative data and lung growth. Am J Respir Crit Care Med 2000;161(2 Pt 1):353–359.
    1. Hanrahan JP, Tager IB, Segal MR, Tosteson TD, Castile RG, Van Vunakis J, Weiss ST, Speizer FE. The effect of maternal smoking during pregnancy on early infant lung function. Am Rev Respir Dis 1992;145(5):1129–1135.
    1. Hayatbakhsh MR, Sadasivam S, Mamun AA, Najman JM, O’callaghan MJ. Maternal smoking during and after pregnancy and lung function in early adulthood: A prospective study. Thorax 2009;64(9):810–814.
    1. Sekhon HS, Jia Y, Raab R, Kuryatov A, Pankow JF, Whitsett JA, Lindstrom J, Spindel ER. Prenatal nicotine increases pulmonary alpha7 nicotinic receptor expression and alters fetal lung development in monkeys. J Clin Invest 1999;103(5):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(6):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(1):31–41.
    1. Proskocil BJ, Sekhon HS, Clark JA, Lupo SL, Jia Y, Hull WM, Whitsett JA, Starcher BC, Spindel ER. 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. Wongtrakool C, Wang N, Hyde DM, Roman J, Spindel ER. Prenatal nicotine exposure alters lung function and airway geometry through α7 nicotininc receptors. Am J Respir Crit Care Med 2012;46:695–702.
    1. Haland G, Carlsen KC, Sandvik L, Devulapalli CS, Munthe-Kaas MC, Pettersen M, Carlsen KH. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med 2006;355(16):1682–1689.
    1. Martinez FD, Morgan WJ, Wright AL, Holberg C, Taussig LM. Initial airway function is a risk factor for recurrent wheezing respiratory illnesses during the first three years of life. Group Health Medical Associates. Am Rev Respir Dis 1991;143(2):312–316.
    1. Rosenfeld M, Allen J, Arets BH, Aurora P, Beydon N, Calogero C, Castile RG, Davis SD, Fuchs S, Gappa M, Gustaffson PM, Hall GL, Jones MH, Kirkby JC, Kraemer R, Lombardi E, Lum S, Mayer OH, Merkus P, Nielsen KG, Oliver C, Oostveen E, Ranganathan S, Ren CL, Robinson PD, Seddon PC, Sly PD, Sockrider MM, Sonnappa S, STocks J, Subbarao P, Tepper RS, Vilozni D. An official American Thoracic Society workshop report: optimal lung function tests for monitoring cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheezing in children less than 6 years of age. Ann Am Thorac Soc 2013;10(2):S1–S11.
    1. Ly NP, Gold DR, Weiss ST, Celedon JC. Recurrent wheeze in early childhood and asthma among children at risk for atopy. Pediatrics 2006;117(6):e1132–e1138.
    1. Sarria EE, Mattiello R, Yao W, Chakr V, Tiller CJ, Kisling J, Tabbey R, Yu Z, Kaplan MH, Tepper RS. Atopy, cytokine production, and airway reactivity as predictors of pre-school asthma and airway responsiveness. Pediatr Pulmonol 2014;49(2):132–139.
    1. Filion KB, Abenhaim HA, Mottillo S, Joseph L, Gervais A, O’Loughlin J, Paradis G, Pihl R, Pilote L, Rinfret S, Tremblay M, Eisenberg MJ. The effect of smoking cessation counselling in pregnant women: a meta-analysis of randomised controlled trials. BJOG 2011;118(12):1422–1428.
    1. Schneider S, Huy C, Schutz J, Diehl K. Smoking cessation during pregnancy: a systematic literature review. Drug Alcohol Rev 2010;29(1):81–90.
    1. Yieh L, McEvoy CT, Hoffman SW, Caughey AB, MacDonald KD, Dukhovny D. Cost effectiveness of vitamin c supplementation for pregnant smokers to improve offspring lung function at birth and reduce childhood wheeze/asthma. J Perinatol 2018;38(7):820–827.

Source: PubMed

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