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Original Investigation |

Vitamin C Supplementation for Pregnant Smoking Women and Pulmonary Function in Their Newborn Infants:  A Randomized Clinical Trial

Cindy T. McEvoy, MD, MCR1; Diane Schilling, RRT1; Nakia Clay, BS1; Keith Jackson, RRT2; Mitzi D. Go, MD, MCR1; Patricia Spitale, MD2; Carol Bunten, MD3; Maria Leiva, MD4; David Gonzales, PhD1; Julie Hollister-Smith, PhD5; Manuel Durand, MD6; Balz Frei, PhD7; A. Sonia Buist, MD1; Dawn Peters, PhD1; Cynthia D. Morris, PhD1; Eliot R. Spindel, MD, PhD5
[+] Author Affiliations
1Oregon Health & Science University, Portland
2PeaceHealth Southwest Medical Center, Vancouver, Washington
3Vancouver Clinic, Vancouver, Washington
4Providence Maternal Care Clinic, Portland, Oregon
5Oregon National Primate Research Center, Beaverton
6University of Southern California, Keck School of Medicine, LAC-USC Medical Center, Los Angeles, California
7Linus Pauling Institute, Oregon State University, Corvallis
JAMA. 2014;311(20):2074-2082. doi:10.1001/jama.2014.5217.
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Importance  Maternal smoking during pregnancy adversely affects offspring lung development, with lifelong decreases in pulmonary function and increased asthma risk. In a primate model, vitamin C blocked some of the in-utero effects of nicotine on lung development and offspring pulmonary function.

Objective  To determine if newborns of pregnant smokers randomized to receive daily vitamin C would have improved results of pulmonary function tests (PFTs) and decreased wheezing compared with those randomized to placebo.

Design, Setting, and Participants  Randomized, double-blind trial conducted in 3 sites in the Pacific Northwest between March 2007 and January 2011. One hundred fifty-nine newborns of randomized pregnant smokers (76 vitamin C treated and 83 placebo treated) and 76 newborns of pregnant nonsmokers were studied with newborn PFTs. Follow-up assessment including wheezing was assessed through age 1 year, and PFTs were performed at age 1 year.

Interventions  Pregnant women were randomized to receive vitamin C (500 mg/d) (n = 89) or placebo (n = 90).

Main Outcomes and Measures  The primary outcome was measurement of newborn pulmonary function (ratio of the time to peak tidal expiratory flow to expiratory time [TPTEF:TE] and passive respiratory compliance per kilogram [Crs/kg]) within 72 hours of age. Secondary outcomes included incidence of wheezing through age 1 year and PFT results at age 1 year. A subgroup of pregnant smokers and nonsmokers had genotyping performed.

Results  Newborns of women randomized to vitamin C (n = 76), compared with those randomized to placebo (n = 83), had improved pulmonary function as measured by TPTEF:TE (0.383 vs 0.345 [adjusted 95% CI for difference, 0.011-0.062]; P = .006) and Crs/kg (1.32 vs 1.20 mL/cm H2O/kg [95% CI, 0.02-0.20]; P = .01). Offspring of women randomized to vitamin C had significantly decreased wheezing through age 1 year (15/70 [21%] vs 31/77 [40%]; relative risk, 0.56 [95% CI, 0.33-0.95]; P = .03). There were no significant differences in the 1-year PFT results between the vitamin C and placebo groups. The effect of maternal smoking on newborn lung function was associated with maternal genotype for the α5 nicotinic receptor (rs16969968) (P < .001 for interaction).

Conclusions and Relevance  Supplemental vitamin C taken by pregnant smokers improved newborn PFT results and decreased wheezing through 1 year in the offspring. Vitamin C in pregnant smokers may be an inexpensive and simple approach to decrease the effects of smoking in pregnancy on newborn pulmonary function and respiratory morbidities.

Trial Registration  clinicaltrials.gov Identifier: NCT00632476

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Figure 1.
CONSORT Diagram for Randomized Smokers

Enrollment, randomization, and follow-up of randomized smokers and their offspring through the newborn pulmonary function tests (PFTs).aOne hundred thirty-one participants were recorded as ineligible, but the specific frequency for each listed reason is unknown. Not shown is a reference group of 76 nonsmokers who underwent prospective follow-up in pregnancy similar to randomized smokers. Their offspring were studied with newborn PFTs. A few newborns did not have a successful measurement of either the ratio of time to peak tidal expiratory flow to expiratory time (TPTEF:TE) or passive respiratory compliance per kilogram (Crs/kg) because of inability to meet the testing criteria as outlined by the American Thoracic Society and European Respiratory Society (see Methods for details of testing acceptance criteria). Exact numbers of successful measurements for TPTEF:TE and Crs/kg are noted in the final boxes for each treatment group.

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Figure 2.
Effect of Maternal Smoking During Pregnancy on Newborn Pulmonary Function as Modulated by Maternal α5 Genotype (rs16969968)

Newborns whose mothers were homozygous for the risk allele in which amino acid 398 of the α5 nicotinic acetylcholine receptor is changed from Asp to Asn showed the largest decrease in ratio of time to peak tidal expiratory flow to expiratory time (TPTEF:TE) comparing placebo with vitamin C treatment. Data markers indicate means; error bars, 95% confidence intervals. Asp/Asp indicates mothers homozygous for nonrisk allele; Asp/Asn, heterozygous mothers; Asn/Asn, mothers homozygous for risk allele. P values comparing TPTEF:TE values from newborns of mothers randomized to receive vitamin C vs placebo are .02 for mothers of all genotypes, .32 for Asp/Asp, .07 for Asp/Asn, and <.001 for Asn/Asn. P values are from linear mixed models (used to allow for unequal variance), adjusting for gestational age at randomization (≤16 vs >16 weeks), birthweight, and gestational age younger than 37 weeks and allowing for different SDs within each genotype.

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