Vitamin C to Decrease Effects of Smoking in Pregnancy on Infant Lung Function

Smoking during pregnancy remains a major public health problem as at least 12% of pregnant
women cannot quit smoking during pregnancy. This addiction is the largest preventable cause
of childhood respiratory illness, including asthma, and children whose mothers smoked during
pregnancy show lifetime decreases in pulmonary function. Smoking is a unique morbidity in
that it is addictive, heavily advertised and recent genome studies show there are genotypes
that significantly increase the likelihood of being unable to quit. Teen pregnancy, low
income, low education, and living with another smoker are important factors increasing the
odds of smoking during pregnancy. Pulmonary function tests done shortly after birth in babies
born to mothers who smoked during pregnancy show decreased pulmonary function as measured by
decreased respiratory flows and respiratory compliance and altered tidal breathing patterns.
These changes can still be measured even after the infants have reached adulthood. Multiple
epidemiologic studies show that these decreases in pulmonary function lead to increased
respiratory disease and costs of hundreds of millions of dollars per year.

The primary aim of this double-blind, placebo controlled, randomized, multi-site study is to
demonstrate improved pulmonary function testing at 3 months of age, in infants delivered to
smoking mothers who are randomized to 500 mg/day of supplemental vitamin C versus placebo at
less than or equal to 22 weeks of pregnancy. We will recruit 278 smoking pregnant women into
the study. Patients will meet with research personnel at each prenatal visit and smoking
cessation will be actively encouraged. Patients will be monitored with a set of serial
biomarkers to assess smoking and medication compliance, including urine cotinine levels,
smoking questionnaires, pill counts and fasting plasma ascorbic acid levels. Pulmonary
function tests will be done at 3 months of age and will measure forced expiratory flows. The
infants will also be followed through one year of age with monthly validated respiratory
questionnaires and a follow-up pulmonary function test at 12 months of age. Success of this
study is supported by strong pilot data showing statistically significant improvements at
about 48 hours of age in pulmonary function tests in infants born to smoking mothers who
received vitamin C versus placebo, and preliminary data showing a lower incidence of wheezing
at 12 months of age in these infants. Key genetic polymorphisms shown to increase sensitivity
to in-utero smoke exposure will also be measured. The success of this study is also supported
by animal models showing the effectiveness of vitamin C to preserve pulmonary function and
genetic and epidemiologic studies linking the effects of smoking during pregnancy to oxidant
mechanisms. The secondary aims of the study include: 1) to demonstrate a decreased incidence
of wheezing through 12 months of age in infants delivered to smoking mothers who are
randomized to 500mg/day of supplemental vitamin C versus placebo during pregnancy; 2) to
demonstrate improved pulmonary function tests at 12 months of age in these infants.

Inclusion Criteria: At randomization:

- Singleton gestation

- ≥ 15 years old

- Gestational age between 13 and 22 weeks

- Receiving prenatal care

- Current smoker

- English speaking

Exclusion Criteria:

- Gestational age ≥ 23 and 0/7 weeks

- Multiple gestation

- Major fetal congenital anomalies

- Current use of illicit drugs

- Current alcohol abuse

- Use of vitamin C (≥ 500 mg/day)>3 days per week since last menstrual period

- Refusal to abstain from vitamin or supplements containing significant vitamin C other
than those provided through or approved by study staff

- History of kidney stone in patient

- Insulin dependent diabetes

- Complex maternal medical conditions

- Participation in other conflicting research projects

- Unable to demonstrate stable method of communication

- Pregnancy by in-vitro fertilization

- Plan to terminate pregnancy

- Failure of medication compliance trial

- Failure to return in designated period during placebo run-in

- Body mass index > 50 at screening