Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial

Abstract

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.

Figure 1. Consort Diagram for Randomized Smokers

Enrollment, randomization, and follow-up of randomized smokers and their offspring through the newborn PFTs. * 131 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 were prospectively followed 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 TPTEF:TE or the Crs/kg due to inability to meet the testing criteria as outlined by the American Thoracic Society and European Respiratory Society (see text under methods for details of testing acceptance criteria). Exact numbers of successful measurements for TPTEF:TE and Crs/kg are noted in final boxes of each arm of treatment.

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 nAChR is changed from Asp to Asn showed the largest decrease in TPTEF:TE comparing placebo to vitamin C treatment. Values presented are means and 95% confidence intervals. Asp/Asp indicates mothers homozygous for non-risk allele, Asp/Asn indicates heterozygous mothers, Asn/Asn indicates mothers homozygous for risk allele. P values comparing TPTEF:TE values from newborns of mothers randomized to vitamin C versus placebo are 0.02, 0.32, 0.07, and < 0.0001 for mothers of all genotypes, Asp/Asp, Asp/Asn and Asn/Asn respectively. P values are from linear mixed models (used to allow for unequal variance) adjusting for gestational age at randomization (≤ 16 versus > 16 weeks), birthweight, and gestational age < 37 weeks, and allowing for different SD's within each genotype.