Abstract
This randomized clinical trial examines the effect of folic acid supplementation in pregnant women who smoke tobacco on infant birth weight, infant status as small for gestational age, and fetal growth restriction.
Cumulative evidence supports a causal association between tobacco use in pregnancy and intrauterine growth restriction,1,2 and a plausible association between smoking and low levels of maternal folic acid.3 Given this evidence, we conducted a double-blind, randomized clinical trial to determine the efficacy of higher-dose folic acid in preventing a reduction in fetal body size among infants of women who smoked tobacco cigarettes during pregnancy.
Methods
This randomized clinical trial was conducted from March 2011 to October 2015 at the Department of Obstetrics and Gynecology at the University of South Florida in Tampa. Eligibility criteria were (1) status as currently active smokers per self-report and cotinine biomarker; (2) an age between 18 and 44 years; (3) a gestation of less than 21 weeks at study entry; and (4) residency in Tampa, Florida. (The trial protocol is available in Supplement 1.) Data analyses took place from January 2017 to July 2018.
Eligible women were enrolled and underwent randomization after written informed consent was obtained. The trial protocol was approved by the institutional review board of the University of South Florida and was registered at ClinicalTrials.gov (identifier: NCT01248260).
Eligible participants were randomly assigned in a 1:1 ratio to receive either 4 mg of folic acid per day (the higher-dose group) or 0.8 mg of folic acid per day (the standard-dose group). In addition, both study arms received smoking cessation counseling. Folic acid is considered safe for pregnant women across a range of recommended dosages (0.4-4.0 mg/d).4 The primary outcomes were infant birth weight, infant status as small for gestational age (SGA),5 and fetal growth restriction (FGR).6 We estimated the relative risk of SGA birth and FGR using a log-binomial regression model and the mean differences in birth weight using multiple linear regression model. We used SAS version 9.3 (SAS Institute) for analyses, and all tests were 2-sided with P values set at .05.
Results
A total of 345 smoking pregnant women were enrolled and randomized. The Figure describes the enrollment and follow-up of the participants. We excluded 26 women (7.5%), including 20 who experienced fetal loss, 2 whose children had congenital anomalies, and 4 who had multiple gestations. In addition, 7 women who were lost to follow-up (2.0%). Hence, the intention-to-treat analysis was based on 312 study participants. The baseline characteristics in both treatment groups were well matched, with the exception of race; 19 of 171 participants (11.1%) in the high-dose group vs 38 of 174 participants (21.8%) in the low-dose group were of other race (neither white and black). This variable was controlled for in the analyses. Overall, the mean (SD) birth weight was 3059.0 (640.2) g, and the incidence of SGA and FGR were 74 of 312 (23.7%) and 91 of 312 (29.2%), respectively.
Figure. Enrollment and Follow-up of Trial Participants.
Infants born to mothers who smoked and received higher-dose folic acid had a mean birth weight that was 140.39 (95% CI, 1.63-279.15) g greater than that of their counterparts receiving standard-dose folic acid (Table). Mothers in the higher-dose folic-acid arm had a 31.0% lower risk of infants with SGA status than those on the standard dose (adjusted relative risk [ARR], 0.69 [95% CI, 0.46-1.03]). Infants born to mothers who smoked who received higher-dose folic acid were also 35% less likely to have FGR (ARR, 0.65 [95% CI, 0.46-0.93]). We found no elevated risk of adverse effects associated with higher-dose folic acid.
Table. Unadjusted and Adjusted Effects of Higher-Dose Folic Acid Treatment on Study Outcomes Among Trial Population.
| Outcome | Statistics (95% CI) |
|---|---|
| Birth weight, mean difference, g | |
| Adjusted | 140.39 (1.63-279.15) |
| Unadjusted | 144.77 (2.78-286.77) |
| Small for gestational agea | |
| Relative risk | |
| Adjusted | 0.69 (0.46-1.03) |
| Unadjusted | 0.71 (0.47-1.07) |
| Risk difference | |
| Adjusted | −0.09 (−0.18 to −0.01) |
| Unadjusted | −0.08 (−0.17 to 0.01) |
| Fetal growth restrictionb | |
| Relative risk | |
| Adjusted | 0.65 (0.46-0.93) |
| Unadjusted | 0.66 (0.46-0.94) |
| Risk difference | |
| Adjusted | −0.12 (−0.22 to −0.03) |
| Unadjusted | −0.12 (−0.22 to −0.02) |
Infants who were small for gestational age were defined as those with weights at less than the 10th percentile of birth weight for their gestational age using normalized growth curves.5
Fetal growth restriction was defined as a fetal growth ratio less than 0.85, a validated cut point.6 The fetal growth ratio was estimated as the ratio of the observed birth weight to the expected mean birth weight for each gestational age.6
Discussion
To our knowledge, this is the first randomized clinical trial assessing the effect of higher-dose folic acid on improved fetal growth among the infants of women who smoked while pregnant. Higher-dose folic acid compared with standard-dose folic acid supplements resulted in a statistically significant increase in birth weight and a significant decrease in FGR. We also observed a 31% lower risk of SGA in the higher-dose arm; this is clinically substantial, although not statistically significant.
Higher-dose folic acid supplementation represents a safe and potential option that may offer women who continue to smoke during pregnancy an effective approach to minimize the risk of reduction in fetal size. The strengths of this study include the relatively low attrition rate of 2% and the use of the intention-to-treat principle as closely as possible. However, as with most randomized clinical trials, the generalizability of these results is an issue. These findings are new and could change current perinatal practice, if confirmed.
Trial Protocol.
Data Sharing Statement.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol.
Data Sharing Statement.
