Vitamin C Supplementation to Pregnant Smokers: Follow-up of 2 Randomized Trials Plus Changes in DNA Methylation

Study Overview
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Brief Summary
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In a randomized clinical trial (RCT) published in JAMA, the investigators have provided evidence that vitamin C supplementation (500 mg daily during pregnancy) ameliorates the effects of maternal smoking during pregnancy on offspring lung function and subsequent incidence of wheeze by 48% through 1 year of age. The investigators are currently completing a second RCT of vitamin C supplementation in pregnant smokers with more robust measures of pulmonary outcomes. The purpose of this ECHO application is to combine these 2 focused, interventional cohorts to allow critical longitudinal follow-up of respiratory outcomes in these children including the study of pulmonary function test (PFT) trajectories and incidence of recurrent wheeze/asthma from infancy through early adolescence in offspring of pregnant smokers randomized to vitamin C versus placebo.

Detailed Description
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In a randomized clinical trial (RCT) published in JAMA, the investigators have provided evidence that vitamin C supplementation (500 mg daily during pregnancy) ameliorates the effects of maternal smoking during pregnancy on offspring lung function and subsequent incidence of wheeze by 48% through 1 year of age. the investigators are currently completing a second RCT of vitamin C supplementation in pregnant smokers with more robust measures of pulmonary outcomes. The purpose of this ECHO application is to combine these 2 focused, interventional cohorts to allow critical longitudinal follow-up of respiratory outcomes in these children including the study of pulmonary function test (PFT) trajectories and incidence of recurrent wheeze/asthma from infancy through early adolescence in offspring of pregnant smokers randomized to vitamin C versus placebo. This will allow the investigators to study the duration of the protection vitamin C provides in the face of in-utero smoke, the relationship between PFTs and the development of recurrent wheeze and/or asthma. In addition we have preliminary data suggesting that, in parallel with the effects of vitamin C on the reduction of pulmonary harm, the supplementary vitamin C blocked the majority of significant changes in DNA methylation induced by maternal smoking in placentas, cord blood and offspring cheek cells. Thus this study will also study the association between the prevention of wheeze/asthma associated with maternal smoking during pregnancy and the prevention of epigenetic changes caused by maternal smoking during pregnancy. By linking the clinical outcomes of decreased wheeze/asthma and pulmonary function in offspring of smokers to epigenetic changes, this study has the potential to identify genes linked to the effects of maternal smoking on lung development and the protective effects of vitamin C.

Official Title
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Maternal Vitamin C Supplementation to Decrease Effects of Smoking During Pregnancy on Infant Lung Function and Health: Follow-up of 2 Randomized Trials and Association With Changes in DNA Methylation

Conditions
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Asthma, Wheezing, In Utero Nicotine, Pulmonary Function

Intervention / Treatment
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* Other: No current intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women and their offspring randomized to vitamin C versus placebo during pregnancy in VCSIP1 or VCSIP2 as well as pregnant nonsmokers and their offspring enrolled as the reference group in VCSIP 1 or VCSIP2 Exclusion Criteria: Patients specifically withdrawing consent from VCSIP1 or VCSIP2

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| smokers who received Vitamin C<br> | Other: No current intervention<br>* This is a follow-up of two randomized trials. No active intervention is being given in the follow-up<br>|
| smokers who received placebo<br> | Other: No current intervention<br>* This is a follow-up of two randomized trials. No active intervention is being given in the follow-up<br>|
| control group non-smokers<br> | Other: No current intervention<br>* This is a follow-up of two randomized trials. No active intervention is being given in the follow-up<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improved pulmonary function | The first primary aim of this study is to demonstrate improved pulmonary function trajectories as measured with forced expiratory flows through 15 years of age in the offspring of pregnant smokers randomized to vitamin C (500 mg/day) versus placebo. | through 15 years of age | 
| Decreased recurrent wheeze/asthma | The second primary aim of this study is to demonstrate a decreased incidence of recurrent wheeze/ asthma through 15 years of age in the offspring of pregnant smokers randomized to vitamin C (500 mg/day) versus placebo. | through 15 years of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Decreased incidence of recurrent wheeze/asthma | A secondary aim of this study is to demonstrate a decreased incidence of recurrent wheeze/asthma through 15 years of age in offspring of pregnant smokers randomized to vitamin C (500 mg/day) versus placebo | through 15 years of age | 
| Epigenetic changes | An additional secondary aim of the study is the analysis of epigenetic changes caused by maternal smoking and reversed by vitamin C at birth. DNA methylation will be measured in biologic samples and then followed longitudinally through ages 15. | through 15 years of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vitamin C, ascorbic acid, wheeze, nicotine, smoke exposure, long term follow up, pulmonary function testing, forced expiratory flows