Effect of Vitamin C Supplementation for Pregnant Smokers on Offspring Airway Function and Wheeze at Age 5 Years: Follow-up of a Randomized Clinical Trial

Abstract

Importance: Vitamin C supplementation (500 mg/d) for pregnant smokers has been reported to increase offspring airway function as measured by forced expiratory flow (FEF) through age 12 months; however, its effects on airway function at age 5 years remain to be assessed.

Objective: To assess whether vitamin C supplementation in pregnant smokers is associated with increased and/or improved airway function in their offspring at age 5 years and whether vitamin C decreases the occurrence of wheeze.

Design, setting, and participants: This study followed up the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP) double-blind, placebo-controlled randomized clinical trial conducted at 3 centers in the US (in Oregon, Washington, and Indiana) between 2012 and 2016. Investigators and participants remain unaware of the treatment assignments. Forced expiratory flow measurements at age 5 years were completed from 2018 to 2021.

Interventions: Pregnant smokers were randomized to vitamin C (500 mg/d) or placebo treatment.

Main outcomes and measures: The primary outcome was the prespecified measurement of FEF between 25% and 75% expired volume (FEF25-75) by spirometry at age 5 years. Secondary outcomes included FEF measurements at 50% and 75% of expiration (FEF50 and FEF75), forced expiratory volume in 1 second (FEV1), and occurrence of wheeze.

Results: Of the 251 pregnant smokers included in this study, 125 (49.8%) were randomized to vitamin C and 126 (50.2%) were randomized to placebo. Of 213 children from the VCSIP trial who were reconsented into this follow-up study, 192 (90.1%) had successful FEF measurements at age 5 years; 212 (99.5%) were included in the analysis of wheeze. Analysis of covariance demonstrated that offspring of pregnant smokers allocated to vitamin C compared with placebo had 17.2% significantly higher mean (SE) measurements of FEF25-75 at age 5 years (1.45 [0.04] vs 1.24 [0.04] L/s; adjusted mean difference, 0.21 [95% CI, 0.13-0.30]; P < .001). Mean (SE) measurements were also significantly increased by 14.1% for FEF50 (1.59 [0.04] vs 1.39 [0.04] L/s; adjusted mean difference, 0.20 [95% CI, 0.11-0.30]; P < .001), 25.9% for FEF75 (0.79 [0.02] vs 0.63 [0.02] L/s; 0.16 [95% CI, 0.11-0.22]; P < .001), and 4.4% for FEV1 (1.13 [0.02] vs 1.09 [0.02] L; 0.05 [95% CI, 0.01-0.09]; P = .02). In addition, offspring of pregnant smokers randomized to vitamin C had significantly decreased wheeze (28.3% vs 47.2%; estimated odds ratio, 0.41 [95% CI, 0.23-0.74]; P = .003).

Conclusions and relevance: In this follow-up study of offspring of pregnant smokers randomized to vitamin C vs placebo, vitamin C supplementation during pregnancy resulted in significantly increased airway function of offspring at age 5 years and significantly decreased the occurrence of wheeze. These findings suggest that vitamin C supplementation for pregnant smokers may decrease the effects of smoking in pregnancy on childhood airway function and respiratory health.

Trial registration: ClinicalTrials.gov Identifier: NCT03203603.

Figure 1.. Study Flow Diagram

Enrollment, randomization, and follow-up of pregnant smokers randomized to supplemental vitamin C (500 mg/d) or placebo and their offspring at age 5 years. ADHD indicates attention-deficit/hyperactivity disorder; FEF, forced expiratory flow.

Figure 2.. Airway Function Test Results Obtained by Spirometry Measurements at Age 5 Years in Children Born to Pregnant Smokers Randomized to Vitamin C Supplementation (500 mg/d) vs Placebo

Spirometry measurements are shown for offspring of 93 and 99 pregnant smokers in the vitamin C and placebo treatment groups, respectively. P values were adjusted for trial stratification variables of study site and gestational age at randomization, sex, race and ethnicity, and height at testing. All forced expiratory flow (FEF) and forced expiratory volume in 1 second (FEV₁) measurements increased significantly in offspring of vitamin C–treated pregnant smokers. Of note, the ratio of FEF between 25% and 75% expired volume to forced vital capacity (FEF_25-75/FVC), an indicator of increased airway growth relative to lung volume (dysanapsis), was also significantly increased in the offspring of vitamin C–treated smokers. FEF₅₀ indicates FEF at 50% of expiration; FEF₇₅, FEF at 75% of expiration; and NS, not significant. ^aP < .01. ^bP < .05.

Figure 3.. Any Occurrence of Wheeze Between the Fourth and Sixth Birthday in Offspring of Pregnant Smokers Randomized to Vitamin C Supplementation (500 mg/d) vs Placebo During Pregnancy, Overall, and by Gestational Age at Randomization

A, Multiple logistic regression was used to compare the occurrence of wheeze between offspring in the vitamin C and placebo treatment groups, adjusting for trial design factors of study site and gestational age at randomization and covariates of race and ethnicity and sex, and significant 2-way interactions of all of these variables. The analysis included 212 children (106 each in the vitamin C and placebo treatment groups). Children born to vitamin C–treated pregnant smokers had a significant decrease in current wheeze (28.3% vs 47.2%; estimated odds ratio, 0.41 [95% CI, 0.23-0.74]; P = .003). B, There was a significant interaction between treatment group and gestational age at randomization (P = .04), with children born to pregnant smokers randomized at 18 weeks of gestational age or earlier demonstrating the largest benefit from vitamin C treatment (odds ratio, 0.22 [95% CI, 0.09-0.54]). NS indicates not significant. ^aP = .001.