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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Asthma; Pulmonary Function; Wheezing; In Utero Nicotine
• Intervention / Treatment: Other: No current intervention

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 420

Contacts and Locations

• Study Contact: Name: Cindy McEvoy, MD, MCR; Phone Number: 503-494-0085; Email: mcevoyc@ohsu.edu
• Study Contact Backup: Name: Kristin Milner, BA, CMA; Phone Number: 971-404-8667; Email: milner@ohsu.edu

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 47405
      • Recruiting
      • Indiana University
      • Contact: Rob Tepper, MD; Email: rtepper@iu.ed
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • Oregon Health and Science University
      • Contact: Cindy McEvoy, MD, MCR; Phone Number: 503-494-0085; Email: mcevoyc@ohsu.edu
      • Contact: Kristin Milner, BA, CMA; Phone Number: 971-404-8667; Email: milner@ohsu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 11 years (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

This study is a follow-up of women and their offspring who previously participated in NCT00632476 and/or NCT01723696.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
smokers who received Vitamin C	Other: No current intervention; This is a follow-up of two randomized trials. No active intervention is being given in the follow-up
smokers who received placebo	Other: No current intervention; This is a follow-up of two randomized trials. No active intervention is being given in the follow-up
control group non-smokers	Other: No current intervention; This is a follow-up of two randomized trials. No active intervention is being given in the follow-up

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Oregon Health and Science University
• Collaborators: National Institutes of Health (NIH); Indiana University

Publications and helpful links

General Publications

• McEvoy CT, Schilling D, Clay N, Jackson K, Go MD, Spitale P, Bunten C, Leiva M, Gonzales D, Hollister-Smith J, Durand M, Frei B, Buist AS, Peters D, Morris CD, Spindel ER. Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial. JAMA. 2014 May;311(20):2074-82. doi: 10.1001/jama.2014.5217.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2017
• Primary Completion (Actual): December 1, 2023
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: June 27, 2017
• First Submitted That Met QC Criteria: June 30, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: nicotine; ascorbic acid; pulmonary function testing; vitamin C; wheeze; smoke exposure; long term follow up; forced expiratory flows
• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Respiratory Sounds
• Other Study ID Numbers: VCSIP ECHO; UG3OD023288 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No