Vitamin C Supplementation Among Pregnant Smokers and Airway Function Trajectory in Offspring

Abstract

This secondary analysis of a randomized clinical trial analyzes the association of vitamin C supplementation in women who smoked during pregnancy with airway function trajectory in their offspring at 4 to 6 years of age.

In a randomized clinical trial (RCT), McEvoy et al^1,2 demonstrated that vitamin C supplementation among women who smoked during pregnancy significantly increased their offspring’s forced expiratory flows (FEFs) at 3 and 12 months of age (the VCSIP [Vitamin C to Decrease Effects of Smoking in Pregnancy on Infant Lung Function] trial). A longitudinal follow-up study³ demonstrated that, at 60 months of age, the offspring continued to have significantly higher FEFs between 25% and 75% expired volume (FEF_25%-75%) and a significantly lower wheeze occurrence.

We performed new longitudinal analyses of the FEF_25%-75% obtained at 3, 12, and 60 months of age in the offspring of the randomized women who smoked during pregnancy in the VCSIP trial and new mediation analyses to assess the association of FEF_25%-75% with wheeze occurrence at 4 to 6 years of age. We hypothesized that offspring of women receiving vitamin C supplements would have an increased FEF_25%-75% trajectory with an association between the increased FEF_25%-75% and decreased occurrence of wheeze compared with offspring of placebo-treated women.

Methods

The study design details for this secondary analysis of an RCT have been published previously.^1,2,3 The VCSIP trial was a double-blind RCT of women who smoked during pregnancy randomized to vitamin C (500 mg/d) or placebo at Oregon Health & Science University, PeaceHealth Southwest Washington Medical Center, and Indiana University, with institutional review board approval at each site. Written informed consent was obtained. We followed the CONSORT reporting guideline. All participants and clinical investigators remain currently blinded to treatment allocation. We measured FEFs using spirometry at 3, 12, and 60 months of age and wheeze by quarterly standardized respiratory questionnaires.^1,2,3 General linear mixed-model, repeated-measures analysis of covariance was used to evaluate longitudinal treatment differences in FEF_25%-75%. A model-based mediation analysis determined whether FEF_25%-75% quartile mediated the association between vitamin C treatment and wheeze. Two-sided P < .05 indicated statistical significance. Statistical analysis used SAS, release 9.4.

Results

Of 243 offspring delivered, 233 (116 [49.8%] female and 117 [50.2%] male) had an FEF measurement performed at 1 of the 3 times, and 80% with data at 60 months had data at 3 or 12 months of age.³ Race included 3 (1.3%) American Indian or Alaska Native, 29 (12.4%) Black or African American, 1 (0.4%) Native Hawaiian or Other Pacific Islander, 185 (79.4%) White, and 15 (6.4%) more than 1 race. For each studied age, there were no significant differences between the randomized groups for length, sex, race (White or other), or postnatal smoke exposure by report or hair nicotine levels.⁴ Longitudinal FEF_25%-75% analyses demonstrated significantly higher values for the offspring of the vitamin C group (P < .001) and a greater increase in FEF_25%-75% with increasing age (Figure 1). Wheeze occurrence was significantly lower (30 [28.3%] vs 50 [47.2%]; odds ratio,  0.41 [95% CI, 0.23-0.74]; P = .003) in the vitamin C group (Figure 2A). Mediation analysis demonstrated most of the vitamin C association with wheeze was mediated through the vitamin C association with increased FEF_25%-75% (total proportion, 54.2%; P = .03) (Figure 2B).

Figure 1. Longitudinal Airway Function in Offspring Through 5 Years of Age.

A, The temporal changes of forced expiratory flows between 25% and 75% expired volume (FEF_25%-75%) are shown, along with the percentage difference between vitamin C and placebo groups at the 3-, 12-, and 60-month follow-up spirometric testing. Spirometric values and P values are adjusted for the trial design factors of gestational age at randomization, study site, race, sex, normalized child height, and their significant 2-way interactions. B, The temporal changes for forced vital capacity (FVC) showed no significant difference between the vitamin C and placebo groups by longitudinal analysis. Repeated-measures analysis of variance with heterogeneous compound symmetry as an intraparticipant covariance structure was used. Data are presented as mean (SEM).

Figure 2. Wheeze Occurrence and Mediation Analysis for Airway Function at 5 Years of Age and Wheeze Between 4 and 6 Years of Age.

A, Offspring born to women who smoked during pregnancy and received vitamin C supplementation had a significant decrease in wheeze at 4 to 6 years of age (30 [28.3%] vs 50 [47.2%]; estimated odds ratio, 0.41 [95% CI, 0.23-0.74]; P = .003). Multiple logistic regression was used to compare the occurrence of wheeze between offspring in the vitamin C and placebo groups, adjusting for trial design factors of study site and gestational age at randomization and covariates of maternal race and child sex, and significant 2-way interactions of all of these variables. Data are presented as proportion (SEM), with 106 offspring in each group. B, A model-based mediation analysis was performed to determine whether airway function mediates the association between vitamin C supplementation effect and wheeze. We binned forced expiratory flows between 25% and 75% expired volume (FEF_25%-75%) values into quartiles after adjusting for sex and height at pulmonary function testing. Age- and sex-adjusted FEF_25%-75% quartiles were used in mediation models accounting for potential confounding factors, including clinical site, gestational age at randomization, child sex, and maternal race.

Discussion

Vitamin C supplementation to women who smoked during pregnancy resulted in an increased FEF_25%-75% trajectory in offspring through 5 years of age. The difference in FEF_25%-75% between the treated groups increased with increasing age despite no postnatal supplementation. The vitamin C group had a lower wheeze occurrence at 4 to 6 years of age, and this improved clinical outcome appears to be mediated through the effect of vitamin C on improved airway function at 5 years of age. Our findings provide evidence for a direct association between maternal smoking during pregnancy and wheeze occurrence in the offspring.

Strengths include an RCT, continued blinded follow-up to minimize bias, and longitudinal airway function assessment from infancy to 5 years of age using the same FEF_25%-75% outcome. Limitations include report of wheeze, which can be difficult for caregivers to assess. However, we used a standardized respiratory questionnaire, and participants and research personnel remain blinded to treatment group. Since the vitamin C group had a greater increase in FEF_25%-75% from 3 months to 5 years of age, follow-up is required to determine whether FEF_25%-75% continues to increase beyond 5 years of age.

Supplement.

Data Sharing Statement