Mothers who smoked cigarettes during pregnancy, but also took vitamin C supplements, had children with improved airway function and lower risk of wheeze later on, according to a follow-up study of a randomized trial.
At 5 years, kids born to mothers who smoked and took daily vitamin C during pregnancy had 17.2% higher average forced expiratory flow (FEF)25-75 measurements versus those whose mothers received a placebo (1.45 vs 1.24 L/s; P<0.001), reported Cindy McEvoy, MD, of Oregon Health & Science University in Portland, and colleagues.
Additionally, children of pregnant smokers who took vitamin C had nearly 60% lower likelihood of developing wheeze (OR 0.41, 95% CI 0.23-0.74), they wrote in JAMA Pediatrics.
Children whose mothers initiated vitamin C treatment at 18 weeks of pregnancy or earlier may have experienced an even greater reduction in the odds of wheeze (OR 0.22, 95% CI 0.09-0.54), the group noted.
“Airway function at age 5 years suggests that (1) an in utero intervention targeted for a specific toxin can provide lasting improvements in offspring respiratory health at least until preschool age and (2) the timing of the intervention during fetal lung development may be important,” McEvoy and colleagues stated.
They added that of all the phases of airway growth, childhood is the “least well investigated” yet potentially the most important to define whether early life factors influence airway function trajectories, including risk of chronic obstructive pulmonary disease (COPD). Future studies may demonstrate the effect of vitamin C on airway size relative to lung volume, they said.
Smoke exposure in utero is a known risk factor for impaired fetal lung development, decreased airway function, and increased risk of wheeze during childhood, McEvoy’s group wrote. Approximately 10% of people in the U.S. continue to smoke during pregnancy, which totals more than 400,000 exposed infants each year, they added.
Previous analyses conducted by the researchers showed that pregnant smokers who took vitamin C had newborns with significantly improved pulmonary function and FEF measurements in early childhood, but results after 12 months were mixed. In this current analysis, they aimed to assess whether the effects of vitamin C supplements in pregnancy could be observed in early childhood and maintained through preschool age.
McEvoy’s group analyzed participants of the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP) study, a double-blind, placebo-controlled randomized clinical trial performed at three sites in Oregon, Washington, and Indiana. Participants in the trial were randomized from December 2012 to June 2015, and the follow-up for the current analysis was from 2018 to 2021.
The researchers enrolled 251 trial participants who were ages 15 years or older with a singleton pregnancy between 13 and 22 weeks gestation. All participants were current cigarette smokers, smoking at least one cigarette in the week leading up to enrollment. Individuals were randomized to 500 mg/day of vitamin C (n=125) or placebo (n=126). At each prenatal visit, researchers collected data on smoking history and medication adherence, as well as provided counseling on smoking cessation.
In this follow-up study, respiratory technicians performed spirometry measurements to assess FEF25-75 among kids at 5 years, which can detect obstructive lung diseases. Prespecified secondary outcomes included FEF50, FEF75, and forced expiratory volume in 1 second (FEV1).
The researchers also assessed the presence of wheeze in kids, ages 4-6 years, via a standardized respiratory questionnaire administered to the child’s primary caretaker. They adjusted the analyses for infant sex, maternal race and ethnicity, and child height at testing.
Overall, 213 children re-consented for this analysis. Mothers were an average of 27 at enrollment, and kids were an average age of 3 when they entered the follow-up study. There were no significant differences in birth or postnatal characteristics between the vitamin C and placebo groups.
Mothers in both groups smoked around eight cigarettes a day in the week before enrollment, and around 10 a day when their offspring reached age 1 year.
Of all children who re-consented, 90% had successful FEF measurements at age 5 years. Children whose mothers received vitamin C treatment in pregnancy consistently had significantly better air function across all flow parameters, the researchers noted.
Kids in the vitamin C group had a 14% increased average measurement of FEF50 compared with the placebo group (1.59 vs 1.39 L/s; P<0.001), and a 26% increased measurement of FEF75 (0.79 vs 0.63 L/s; P<0.001). Those in the treatment cohort also had a 4% increased FEV1 compared to the placebo cohort (1.13 vs 1.09 L; P=0.02).
McEvoy and colleagues noted that both groups had a high occurrence of wheeze (28% in the vitamin C group and 47% in the placebo group), which highlights the “high respiratory morbidity associated with in utero smoke exposure.”
There was no significant difference in forced vital capacity (FVC) measurements between the vitamin C and placebo groups, showing that the effect was primarily observed in airway size rather than lung volume, they added.
McEvoy’s group acknowledged that cohort loss in this follow-up analysis may have biased findings. Additionally, they noted that wheeze is a complex clinical respiratory outcome, which they assessed via responses from a parent or the child’s primary caretaker. Finally, atopic and non-atopic mechanisms can contribute to airway obstruction and wheeze, but vitamin C may not modify both of these mechanisms. The researchers did not have an objective measure of atopy for most participants.
Disclosures
The study was funded by the National Heart, Lung, and Blood Institute and the NIH Office of Dietary Supplements.
McEvoy and co-authors disclosed support from the NIH. A co-author reported owning Pfizer shares.