Graduation Year

2017

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Public Health

Major Professor

Roneé Wilson, Ph.D., MPH

Co-Major Professor

William Sappenfield, M.D., MPH

Committee Member

Alfred Mbah, Ph.D.

Committee Member

Hamisu M. Salihu, M.D., Ph.D.

Keywords

folic acid, cotinine, birth outcomes, small-for-gestational age, birth weight, randomized clinical trial

Abstract

The adverse effects of maternal smoking on infant mortality and morbidity has been well documented in the literature. Maternal tobacco use is causally associated with fetal growth restriction and correlates negatively with folate intake and metabolism. Studies have examined the association between smoking and folate levels during pregnancy, but very few have assessed this relationship using objective and accurate measures of both variables. Furthermore, despite evidence of a causal association between smoking in pregnancy and intrauterine growth restriction, and a plausible relationship between tobacco use and low maternal folate which is required for optimal fetal growth, no experimental study has investigated the potential benefit of folic acid in mitigating the adverse effects of maternal smoking on fetal outcomes.

The objectives of this study were to investigate the relationship between maternal smoking and folate levels and examine the efficacy of higher-strength folic acid supplementation, in combination with enrollment in a smoking cessation program, in promoting fetal body and brain growth. Our hypothesis was that women who smoke during pregnancy have lower peri-conceptional folic acid reserves than non-smoker pregnant women and that folic acid reserves will decrease with increasing cotinine level. Additionally, smoker pregnant women on higher-strength folic acid (4mg daily) in combination with smoking cessation programs will experience faster fetal brain growth and have infants with larger body size at birth compared to smokers on the standard dose of folic acid (0.8mg daily).

Participants were pregnant women (smokers and non-smokers) who received antenatal care between 2010-2014 at the Genesis Clinic of Tampa, a community health center affiliated with the Department of Obstetrics and Gynecology of the University of South Florida (USF). They were aged 18-44 years and had a gestational age of less than 21 weeks at study enrollment. To determine the peri-conceptional folic acid reserves in smoking versus nonsmoking women during pregnancy and associated sociodemographic factors, baseline (crosssectional) data from a double-blinded randomized controlled trial were analyzed using Tobit regression models (n=496). Smoking information was assessed using salivary cotinine, a sensitive and specific tobacco use biomarker. Folate reserve was measured using red blood cell folate. To investigate the efficacy of higher-strength folic acid on fetal body and brain size, baseline and follow-up data from pregnant smokers enrolled in the randomized controlled trial were utilized (n=345). All primary analyses of the clinical trial data were conducted on a modified intention-to-treat basis and included participants who completed the trial with an observed endpoint, irrespective of compliance to protocol. Multilevel modeling, linear regression, and log-binomial regression analyses were conducted.

A significant inverse association between salivary cotinine level and periconceptional red blood cell folate concentration was found among pregnant women in the early to midpregnancy period. Smokers on high-dose folate during pregnancy had infants with a 140.38g higher birth weight than infants of their counterparts on standard dose folate (P =0.047). Mothers who received higher strength folate had a 31.0% lower risk of having babies with SGA compared to their mothers on the standard-dose (adjusted relative risk-ARR=0.69, 95% CI: 0.46–1.03; (P =0.073)). High-dose folate had no significant effect on the intrauterine rate of growth in head circumference, and head circumference and brain weight at birth in our trial sample. However, the brain-body ratio of infants of mothers who received high-dose treatment was 0.33 percentage-point lower than that for infants of mothers who received the standard dose of folate (P =0.044).

Higher strength folic acid supplementation in pregnant women who smoke might be a cost-effective and safe option to improve birth outcomes and reduce low birth weight and SGA associated infant morbidity and mortality. Future studies with larger sample sizes and diverse populations are indicated to confirm or refute the results of this study. Randomized controlled trials starting during the preconception period and with follow-up until delivery are warranted, to identify the most folate-sensitive period of fetal growth and determine the optimal dose of folic acid supplement. Further research investigating several pathways through which the effects of prenatal smoking on adverse birth outcomes can be mitigated is needed.

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