Letters

RESEARCH LETTER exception of race; 19 of 171 participants (11.1%) in the high-

Comparing Folic Acid Dosage Strengths to Prevent
Reduction in Fetal Size Among Pregnant Women
Who Smoked Cigarettes: A Randomized Clinical Trial
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
Supplemental content
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
dose group vs 38 of 174 participants (21.8%) in the low-dose
group were of other race (neither white and black). This vari-
able 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.
Infants born to mother 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 re-
ceiving 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
Figure. Enrollment and Follow-up of Trial Participants
860 Assessed for eligibility

entry; and (4) residency in Tampa, Florida. (The trial protocol

is available in Supplement 1.) Data analyses took place from 515 Excluded
January 2017 to July 2018. 484 Not meeting inclusion
criteria
Eligible women were enrolled and underwent randomiza- 31 Refused to participate
tion after written informed consent was obtained. The trial pro-
tocol was approved by the institutional review board of the Uni-
versity of South Florida and was registered at ClinicalTrials 345 Participants randomized

.gov (identifier: NCT01248260).

Eligible participants were randomly assigned in a 1:1 ratio
171 Participants randomized to 174 Participants randomized to
to receive either 4 mg of folic acid per day (the higher-dose receive 4 mg of folic acid receive 0.8 mg of folic acid
group) or 0.8 mg of folic acid per day (the standard-dose group).
In addition, both study arms received smoking cessation coun- 153 Participants attended visit 2 156 Participants attended visit 2
seling. Folic acid is considered safe for pregnant women across 19 Were lost to follow-up 18 Were lost to follow-up
7 Experienced fetal loss 7 Experienced fetal loss
a range of recommended dosages (0.4-4.0 mg/d).4 The pri-
mary outcomes were infant birth weight, infant status as small
for gestational age (SGA),5 and fetal growth restriction (FGR).6 145 Participants attended visit 3 152 Participants attended visit 3
8 Were lost to follow-up 4 Were lost to follow-up
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 129 Participants delivered 137 Participants delivered
in study center in study center
version 9.3 (SAS Institute) for analyses, and all tests were 11 Were lost to follow-up 13 Were lost to follow-up
2-sided with P values set at .05. or delivered elsewhere or delivered elsewhere
4 Experienced fetal loss 7 Had children with congenital
2 Had multiple gestation anomaly
Results | A total of 345 smoking pregnant women were 1 Had child with congenital 2 Experienced fetal loss
anomaly 2 Had multiple gestation
enrolled and randomized. The Figure describes the enroll-
ment and follow-up of the participants. We excluded 26
women (7.5%), including 20 who experienced fetal loss, 33 Participants’ birth weight 33 Participants’ birth weight
data were retrieved during data were retrieved during
2 whose children had congenital anomalies, and 4 who had postnatal follow-up postnatal follow-up
multiple gestations. In addition, 7 women who were lost to
follow-up (2.0%). Hence, the intention-to-treat analysis was
152 Participants had birth weight 160 Participants had birth weight
based on 312 study participants. The baseline characteristics data included in the analysis data included in the analysis
in both treatment groups were well matched, with the

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 Letters

Korede K. Yusuf, MBBS, PhD

Table. Unadjusted and Adjusted Effects of Higher-Dose Folic Acid
Treatment on Study Outcomes Among Trial Population Hamisu M. Salihu, MD, PhD
Roneé Wilson, PhD
Outcome Statistics (95% CI)
Alfred Mbah, PhD
Birth weight, mean difference, g
William Sappenfield, MD, MPH
Adjusted 140.39 (1.63-279.15)
Lindsey M. King, PhD, MPH
Unadjusted 144.77 (2.78-286.77)
Karen Bruder, MD
Small for gestational agea
Relative risk Author Affiliations: College of Nursing and Public Health, Adelphi University,
Adjusted 0.69 (0.46-1.03) Garden City, New York (Yusuf); Department of Family and Community
Medicine, Baylor College of Medicine, Houston, Texas (Salihu); College of Public
Unadjusted 0.71 (0.47-1.07)
Health, University of South Florida, Tampa (Wilson, Mbah, Sappenfield, King);
Risk difference Department of Obstetrics and Gynecology, University of South Florida, Tampa
Adjusted −0.09 (−0.18 to −0.01) (Bruder).

Unadjusted −0.08 (−0.17 to 0.01) Accepted for Publication: October 23, 2018.

Fetal growth restrictionb Corresponding Author: Hamisu M. Salihu, MD, PhD, Department of Family
and Community Medicine, Baylor College of Medicine, 3701 Kirby Dr,
Relative risk
Ste 600, Houston, TX 77098 (hamisu.salihu@bcm.edu).
Adjusted 0.65 (0.46-0.93)
Published Online: March 18, 2019. doi:10.1001/jamapediatrics.2019.0112
Unadjusted 0.66 (0.46-0.94)
Author Contributions: Drs Adegoke and Mbah had full access to all of the data
Risk difference in the study and take responsibility for the integrity of the data and the accuracy
Adjusted −0.12 (−0.22 to −0.03) of the data analysis.
Concept and design: Adegoke, Salihu, Wilson, Mbah, Sappenfield, King.
Unadjusted −0.12 (−0.22 to −0.02)
Acquisition, analysis, or interpretation of data: All authors.
a
Infants who were small for gestational age were defined as those with weights Drafting of the manuscript: Adegoke, Salihu, King.
at less than the 10th percentile of birth weight for their gestational age using Critical revision of the manuscript for important intellectual content: All authors.
normalized growth curves.5 Statistical analysis: Adegoke, Salihu, Mbah, Sappenfield.
b Obtained funding: Salihu, King.
Fetal growth restriction was defined as a fetal growth ratio less than 0.85,
Administrative, technical, or material support: Salihu, King, Bruder.
a validated cut point.6 The fetal growth ratio was estimated as the ratio of
Supervision: Salihu, Wilson, Mbah, King.
the observed birth weight to the expected mean birth weight for each
gestational age.6 Funding/Support: The study was supported by grants from the James and
Esther King Biomedical Research Program of the Florida Department of Health
(grants 4KB03 and 1KG14-33987).
Role of the Funder/Sponsor: The funder had no role in the design and conduct
no elevated risk of adverse effects associated with higher- of the study; collection, management, analysis, and interpretation of the data;
dose folic acid. preparation, review, or approval of the manuscript; and decision to submit the
manuscript for publication.

Discussion | To our knowledge, this is the first randomized clini-
cal trial assessing the effect of higher-dose folic acid on im-
proved fetal growth among the infants of women who smoked
while pregnant. Higher-dose folic acid compared with stan-
dard-dose folic acid supplements resulted in a statistically sig-
nificant 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 statisti-
cally 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 in-
clude 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.
Data Sharing Statement: See Supplement 2.
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prevalence, maternal characteristics, and pregnancy outcomes. Nicotine Tob Res.
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2. Salihu HM, Wilson RE. Epidemiology of prenatal smoking and perinatal
outcomes. Early Hum Dev. 2007;83(11):713-720. doi:10.1016/j.earlhumdev.
2007.08.002
3. Pfeiffer CM, Sternberg MR, Fazili Z, et al. Folate status and concentrations of
serum folate forms in the US population: National Health and Nutrition
Examination Survey 2011-2. Br J Nutr. 2015;113(12):1965-1977. doi:10.1017/
S0007114515001142
4. Wen SW, White RR, Rybak N, et al; FACT Collaborating Group. Effect of high
dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double
blind, phase III, randomised controlled, international, multicentre trial. BMJ.
2018;362:k3478. doi:10.1136/bmj.k3478
5. Alexander GR, Kogan M, Martin J, Papiernik E. What are the fetal growth
patterns of singletons, twins, and triplets in the United States? Clin Obstet Gynecol.
1998;41(1):114-125. doi:10.1097/00003081-199803000-00017
6. Kramer MS, McLean FH, Olivier M, Willis DM, Usher RH. Body proportionality
and head and length ‘sparing’ in growth-retarded neonates: a critical
reappraisal. Pediatrics. 1989;84(4):717-723.

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