Folic acid supplementation and the occurrence of congenital heart
defects, orofacial clefts, multiple births, and miscarriage1–3
Lynn B Bailey and Robert J Berry
ABSTRACT
Key research findings relative to the question of whether maternal
use of folic acid before and during pregnancy reduces the chance that
offspring will be born with a congenital heart defect or an orofacial
cleft are reviewed in this paper. Observational studies in general
support an association between maternal use of multivitamins con-
taining folic acid and a reduction in the occurrence of congenital
heart defects and orofacial clefts. Results from one randomized
controlled trial (RCT) provide the strongest evidence that multivi-
tamins prevent congenital heart defects, but this RCT did not provide
evidence that multivitamins prevent orofacial clefts. In addition,
most observational and interventional studies are not designed to
detect an independent effect from folic acid. Early studies suggested
that periconceptional multivitamin use was associated with an in-
creased occurrence of both miscarriages and multiple births, which
has resulted in a great deal of controversy about the safety of folic
acid use during pregnancy. We also review reports that were de-
signed to answer these questions with more definitive data. When
more substantial evidence about the effect of periconceptional folic
acid on the occurrence of congenital heart defects and orofacial clefts
is reported, we will have additional support for promoting folic acid
intervention programs. All women capable of becoming pregnant
should continue to consume 400 ␮g/d of folic acid in addition to a
healthy diet as advised. Am J Clin Nutr 2005;81(suppl):
1213S–7S.
KEY WORDS Folic acid, heart defects, orofacial clefts, mis-
carriages, multiple births
INTRODUCTION
Periconceptional consumption of folic acid, or multivitamins
containing folic acid, has been shown in intervention studies to
reduce the risk for neural tube defects (NTDs) (1–3). The suc-
cessful translation of these scientific data related to folic acid and
NTD risk reduction into public health policy provides the ratio-
nale for evaluating evidence for an association between pericon-
ceptional folic acid and other common congenital anomalies
including heart defects and orofacial clefts. In this paper, key
findings related to periconceptional use of multivitamins con-
taining folic acid and a reduced occurrence of both congenital
heart defects and orofacial clefts are briefly reviewed.
The controversial claims that periconceptional folic acid use
will increase the occurrence of both multiple births (4 – 6) and
miscarriages (7, 8) are of concern to women of reproductive age
and their health care providers. Most of these studies analyzed
Am J Clin Nutr 2005;81(suppl):1213S–7S. Printed in USA. © 2005 American Society for Clinical Nutrition
data collected for other purposes which introduced many poten-
tial flaws. More recent findings from a large-scale intervention
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study fail to confirm an increased risk for either multiple births or
miscarriages associated with maternal use of folic acid before
and during early pregnancy (3).
An RCT testing whether different doses of folic acid or folic
acid plus other vitamins reduce the risk for other birth anomalies
including heart defects and orofacial clefts is needed before spe-
cific public health recommendations are made. The appropriate
advice to women capable of becoming pregnant is to follow the
current folic acid recommendation designed to reduce the occur-
rence of NTDs.
CONGENITAL HEART DEFECTS
Heart defects affect 1 in 110 newborns and account for a third
or more of infant deaths due to birth defects, more than that for
any other congenital anomaly including NTDs (9 –12). In the
United States alone the number of deaths attributed to heart
defects is estimated to be 앒6000/y (13). There has been an
extensive investigation of potential causes and risk factors for
heart defects; however, only a very small percentage of cases can
be definitively linked to known etiology (10).
The strongest evidence that multivitamins containing folic
acid taken periconceptionally will significantly reduce the risk of
congenital heart defects is supported by data from a Hungarian
RCT (2) and from 2 population-based case-control (PCC) studies
in the United States (14, 15). The Hungarian RCT was designed
to evaluate the efficacy of a prenatal multivitamin containing 800
␮g of folic acid in reducing the occurrence of NTDs (2). Further
analysis of this RCT and subsequent data from Hungary showed
that prenatal multivitamins were associated with an impressive
overall 50% reduction in risk for a broad range of heart defects
(Figure 1) (16, 17). In an Atlanta PCC study, use of periconcep-
tional multivitamins containing folic acid was associated with a
24% reduction in the odds for congenital heart defects in general
1
From the Food Science and Human Nutrition Department, University of
Florida, Gainesville, FL (LBB), and the National Center on Birth Defects and
Developmental Disabilities, Centers for Disease Control and Prevention,
Department of Health and Human Services, Atlanta, GA (RJB).
2
Presented at the conference “Women and Micronutrients: Addressing the
Gap Throughout the Life Cycle,” held in New York, NY, June 5, 2004.
3
Address correspondence to Lynn B Bailey, Food Science and Human
Nutrition Department, POB 110370, University of Florida, Gainesville, FL
32611. E-mail: lbbailey@mail.ifas.ufl.edu.
1213S
1214S BAILEY AND BERRY
FIGURE 1. Maternal use of multivitamins/folic acid and risk of cardiac defects: summary of findings from reports published in 1995–2000. Adapted from
reference 14 with permission.
[odds ratio (OR), 0.76] (see Figure 1) (14). Although the ob-
served association was less than that observed in the Hungarian
RCT (2, 17), data from the Atlanta PCC study also support the
conclusion that periconceptional use of multivitamins signifi-
cantly reduces the occurrence of congenital heart defects (14).
When evaluating the association with specific types of heart
defects, the data suggest that the association may be strongest for
ventricular septal defects (VSD) and some conotruncal defects
(tetralogy of Fallot and D-transposition of the great arteries) (18).
In both the Atlanta PCC study and the Hungarian RCT (14, 17),
the occurrence of conotruncal defects was reduced 앑50% (Fig-
ure 1). Data from a different PCC study (15) also support the
conclusion that periconceptional multivitamins are associated
with a reduction (30%) in the occurrence of conotruncal defects.
In contrast, Werler et al (19) detected no association between 2
types of congenital heart defects (VSD and outflow tract) and
periconceptional multivitamin use in a hospital-based case-
control study. Also, Scanlon et al (20) detected no association
between outflow tract defects and periconceptional multivitamin
use in the Baltimore-Washington Infant Study. The majority of
evidence supports the conclusion that periconceptional multivi-
tamins containing folic acid may reduce the risk for congenital
heart defects.
Which nutrient or combination of nutrients in multivitamins
that is responsible for the apparent reduction in congenital heart
defects has not been established. No direct evidence that folic
acid alone is responsible has been published. However, some
indirect evidence does exist. Analysis of a large case-control
study (21) evaluated, among women who took drugs that inhibit
dihydrofolate reductase, which is required for normal DNA syn-
thesis, whether taking these folic acid antagonists during early
pregnancy increased a woman’s risk of having an infant with a
congenital heart defect and whether concomitant use of multivi-
tamins influenced this risk. The relative risk associated with the
use of the folic acid antagonists when no multivitamin supple-
ment containing folic acid was taken was 7.7 [95% confidence
interval (CI), 2.8 to 21.7]. In contrast, when multivitamins were
taken in addition to the drugs (trimethoprim, triamterine, and
sulfasalazine), the relative risk associated with the use of both the
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drugs plus supplement was reduced to 1.5 (95% CI, 0.6 to 3.8).
These findings indicate that the use of folic acid antagonists in
early pregnancy increases the risk of heart defects particularly
among the infants of women who did not take multivitamins, but
that multivitamins could attenuate this increased risk. These data
support the conclusion that folic acid is the active ingredient in
multivitamins, that folic acid is essential for normal fetal cardiac
development during early embryogenesis, and that periconcep-
tional folic acid use may reduce the risk for congenital cardiac
anomalies.
OROFACIAL CLEFTS
Orofacial clefts including cleft lip with or without cleft palate
(CLP) and cleft palate alone (CP) affect 앑 1 in 1000 and 앑1 in
2500 infants, respectively (22). Studies have resulted in mixed
findings related to the protective effect of maternal multivitamins
containing folic acid on the occurrence of orofacial clefts. Ma-
ternal use of multivitamins was associated with a significant
reduction in the occurrence of orofacial clefts in a PCC study
based on an analysis of data from the California Birth Defects
Monitoring Program (23). In this study, a 50% reduction in the
occurrence of CLP and a 27% reduction in the occurrence of CP
was associated with maternal use of multivitamins (23). A sim-
ilar finding for CLP (48%) was reported by Itikala et al (22)
among women who used multivitamins during the periconcep-
tional period or who started multivitamin use during the first
postconception month. In contrast, no association was observed
in a hospital-based case control study in the Boston, Philadel-
phia, and Toronto areas (24). However, in a subsequent investi-
gation in this same area, Werler et al (19) found significantly
lower odds for CP, but not CLP, among mothers who took mul-
tivitamins containing folic acid during pregnancy and gave birth
to healthy infants compared with case mothers. Recently
periconceptional folic acid supplement use was reported to halve
the risk of CLP (25). The findings from this investigation support
the previously reported 50% reduction in occurrence of CLP with
periconceptional folic acid-containing multivitamin use (22, 23).
The fact that 93% of the women took supplements containing
 FOLIC ACID AND OCCURRENCE OF SELECT BIRTH OUTCOMES
only folic acid strengthen the direct evidence that the association
between maternal use of periconceptional folic acid and a reduc-
tion in the occurrence of CLP is true (25).
A significant protection against recurrence of CLP was re-
ported in response to supplementation with multivitamins con-
taining a very high dose of folic acid (10 mg) in a Hungarian study
(26). In contrast, no protection against the occurrence of CLP was
detected in a cohort study with lower doses (800 ␮g) of folic acid
in a multivitamin supplement (27). In addition, data from the
Hungarian RCT do not support the conclusion that periconcep-
tional use of multivitamins containing folic acid may reduce the
risk for orofacial clefts (28).
Indirect evidence that the folic acid component of multivita-
mins taken periconceptionally reduces the risk for orofacial
clefts is supported by findings from a large case-control study in
which folic acid antagonists were shown to increase the risk for
orofacial clefts (21). The relative risk of orofacial clefts in infants
whose mothers were exposed to dihydrofolate reductase inhibi-
tors during early pregnancy as compared with infants whose
mothers had no such exposure was 2.6 (95% CI, 1.1 to 6.1). In
contrast, the relative risk of orofacial clefts associated with the
use of dihydrofolate reductase inhibitors with no multivitamins
containing folic acid was 4.9 (95% CI, 1.5 to 16.7). These find-
ings support the conclusion that the folic acid component of
multivitamins may reduce the risk for orofacial clefts.
MULTIPLE BIRTHS
A number of reports have suggested the possibility of a sig-
nificant increase in the occurrence of multiple births among
women who take multivitamins containing folic acid during
early pregnancy (4 – 6). Since multiple births result in more preg-
nancy complications, are more likely to result in preterm delivery
and are associated with an estimated sevenfold increase in mor-
tality compared with singleton pregnancies (29 –32), these re-
ports warrant careful evaluation. An analysis of data from an
RCT by Czeizel et al indicated a 40% increase in the number of
infants resulting from multiple births among women who re-
ceived multivitamins containing 800 ␮g folic acid compared
with the number of infants resulting from multiple births of
women who received only trace elements (4). In this study ovar-
ian stimulating drugs were used by 6.5% of the women from
whom 42% of the multiple pregnancies were produced. Among
these women the rate of multiple pregnancies was 10.92%, 11
times higher than the rate of 1.03% among women who did not
use ovarian stimulation. When women who used ovarian stim-
ulation are excluded, and the appropriate comparison is made, the
increased risk estimate is unchanged, but the statistical signifi-
cance disappears [risk ratio (RR), 1.45; 95% CI, 0.78 to 2.67]. In
1997, Werler et al retrospectively analyzed data on multiple and
singleton births collected from 3 separate birth defect programs
and reported a nonsignificant 30% to 60% greater prevalence of
periconceptional vitamin supplementation among mothers of
multiple births (5). Information about supplement use in these
studies was collected retrospectively by interview and did not
differentiate among types of vitamin supplements used. Only 2
programs could evaluate the occurrence of multiple births among
women who delivered normal infants. Among these women,
those who took multivitamins any time during pregnancy
showed no increase in the rates of twinning when compared with
those who did not take multivitamins, both in Atlanta (OR, 0.92;
1215S
95% CI, 0.46 to 1.45) and in California (OR, 0.80; 95% CI, 0.22
to 2.82).
Recently, Ericson and colleagues described an increase in the
occurrence of dizygotic twin deliveries among women reporting
the use of folic acid during early pregnancy in Sweden, compared
with the rate of twin births in the entire Swedish population (OR,
2.13; 95% CI, 1.64 to 2.74) (6). The overall rate of reported folic
acid consumption in this study was 쏝 1% which is markedly
different from the consumption in the United States, where
앒40% of women of childbearing age take multivitamins con-
taining folic acid (33). In addition, the authors state that their
results were highly confounded by increasing maternal age and
the length of involuntary childlessness, which raises questions
about whether most of the women who reported folic acid use in
this study were also using assisted reproductive technologies.
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If the occurrence of multiple births were influenced by con-
sumption of folic acid, the effect might be expected to be greater
with increasing folic acid dose; however, this has not been ob-
served. In 1999, Mathews et al analyzed data from the United
Kingdom Medical Research Council (MRC) Vitamin Study (1)
in which women consumed a multivitamin containing 4000 ␮g
folic acid per day and did not detect a significant difference in the
rates of multiple birth between supplemented and unsupple-
mented women (34).
Most of the reports suggesting that the periconceptional use of
multivitamins containing folic acid increased the occurrence of
multiple births have focused on the use of folic acid as the pur-
ported cause of the increase despite the fact that most women in
these studies took folic acid combined with multivitamins, not
folic acid alone. For example, the multivitamins taken by women
in the Hungarian study (4) contained 10 other components, in-
cluding 4000 – 6000 international units (IU) of vitamin A, which
has been reported to be associated with an increased rate of twin
births in a randomized controlled trial in Nepal (35, 36).
Evaluation of data from a large-scale (앑250,000 women) in-
tervention study in China where women took 400 ␮g/d of folic
acid daily before and during early pregnancy to prevent NTDs (3)
provides strong evidence that periconceptional folic acid use
does not increase the occurrence of multiple births (37). Overall,
the rate of multiple births was not different among women who
took folic acid daily compared with those who did not (0.59% and
0.65%, respectively). This study has important strengths includ-
ing the fact that the results were not confounded by other factors
that may have increased occurrence of multiple births. For ex-
ample, other studies have been conducted in populations where
the rates of multiple births may have been affected by increasing
maternal age and the use of ovarian stimulation or assisted re-
productive technologies (4, 6). In the China study, the study
population comprised a cohort of young women, most of whom
were experiencing their first pregnancy, and in whom the treat-
ment for subfertility was extremely low. For this reason, the
young Chinese women represented an excellent group for study-
ing the occurrence of multiple births because it was not necessary
to control for the presence of these factors. Another strength of
the China study was that precise records of supplement-taking
were collected prospectively, before the outcome of pregnancy
was known, minimizing the potential for recall bias. Possibly the
most important aspect of this study was that unlike others, the
women consumed a supplement containing only 400 ␮g of folic
acid. This large population-based study provided strong evi-
dence that consumption of 400 ␮g of folic acid alone before and
1216S BAILEY AND BERRY
during early pregnancy did not increase a woman’s likelihood of
having a multiple birth.
In the United States, the rate of multiple births has been re-
cently evaluated before and following the mandatory introduc-
tion of folic acid fortification in 1998. After adjusting for both
increasing maternal age and use of assisted reproductive tech-
nology, no evidence that multiple births have increased since the
start of folic acid fortification was detected (38 – 40).
MISCARRIAGE
In 1997, Hook and Czeizel analyzed data from the Hungarian
RCT (2) and concluded that periconceptional use of a multivi-
tamin containing 800 ␮g folic acid was associated with a signif-
icant 16% increase in miscarriage rates compared with women
who received trace elements (7). In addition, these investigators
analyzed data from the MRC (1) study including all women
assigned periconceptional folic acid treatment (4000 ␮g) and
reported a nonsignificant 15% increase in miscarriage rates (7).
Based on an analysis of these data by MRC study researchers
including only data from women who became pregnant, there
was no association between periconceptional folic acid supple-
mentation and an increase in miscarriage rates (RR, 1.06; 95%
CI, 0.79 to 1.43, P ҃ 0.70) (41). More recently, Windham et al (8)
reported that data from a prospective study of women in Cali-
fornia interviewed during their first trimester of pregnancy sup-
ported the conclusion of Hook and Czeizel (7) that periconcep-
tional vitamins increased the occurrence of miscarriage. In this
study, a nonsignificant increase in the occurrence of miscarriage
among women who took vitamins during the prenatal period
(RR, 1.14; 95% CI, 0.96 to 1.35) was observed and attributed to
periconceptional folic acid use although the supplements
taken were a mixture of vitamins not folic acid alone (8). Other
investigators, however, disagreed that this report provided
evidence that folic acid increased the occurrence of miscar-
riage (42).
Data from a large-scale folic-acid intervention study con-
ducted in China provided strong evidence that periconceptional
folic acid use does not increase miscarriage rates (43). In this
study, the miscarriage rate was 9.0% for women who took folic
acid alone (400 ␮g) and 9.3% for women who did not take folic
acid during early pregnancy (RR, 0.97; 95% CI, 0.84 to 1.12).
The strengths of this study include the fact that the investigation
was larger than all of the previous studies combined (6, 8); the
study population was confined to women who were registered in
the program before they became pregnant for the first time
(avoiding confounding by previous miscarriages); supplement-
taking data were obtained during pregnancy (avoiding recall
bias); and supplements contained folic acid alone.
The association between folate status and the occurrence of
miscarriage was further evaluated in a recent large PCC study in
Sweden (44). Cases were women who had spontaneously
aborted a fetus with a gestational age of 6 –12 wk and controls
were women matched for gestational age of the fetus. Women
with low plasma folate concentrations (울4.9 nmol/L) were more
likely to have had a miscarriage than women with plasma folate
concentrations between 5.0 and 8.9 nmol/L. The occurrence of
miscarriage was not increased in women with higher plasma
folate concentrations (욷14.0 nmol/L) relative to women with
plasma folate concentrations between 5.0 and 8.9 nmol/L. Sup-
plement use was not associated with an increased occurrence of
miscarriage. A major strength of this study was the adjustment
for confounders (eg, maternal age, cigarette smoking, previous
miscarriages) providing data that further supports the conclusion
that a folate deficiency significantly increases the occurrence of
miscarriage as previous studies had suggested (45– 47).
APPLICATION AND FUTURE DIRECTION
Research findings to date suggest that periconceptional use of
multivitamins containing folic acid is associated with a reduction
in the occurrence of congenital heart defects and a possible re-
duced occurrence of orofacial clefts, although the data are less
convincing for orofacial clefts. Efforts to draw definitive con-
clusions from these studies are hampered by the difficulties in
interpreting and drawing conclusions due to heterogeneity be-
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tween studies including factors such as classification of the types
of defects and variation in exposure to numerous environmental
factors, including maternal use of multivitamins containing folic
acid (11, 18). The evolution of science related to folic acid and
NTD risk reduction required the careful evaluation of similar
types of complex and often conflicting data (48). Resolution of
the NTD/folic acid controversy was a direct result of RCTs,
which highlights the need for similar large well-designed studies
to specifically address whether maternal periconceptional use of
other vitamins or higher doses of folic acid will reduce the oc-
currence of other congenital anomalies, and, if so, whether the
protective effect of folic acid is limited to specific types of de-
fects. Collaborative multidisciplinary research endeavors that
address the complexities of these research issues are needed
before definitive public health recommendations can be imple-
mented (11).
The appropriate medical advice is that all women capable of
becoming pregnant should consume 400 ␮g/d of synthetic folic
acid in addition to a healthy diet (49). Although NTD risk reduc-
tion is the goal of this existing public health recommendation, if
future research confirms that periconceptional folic acid supple-
mentation also reduces the risk for other birth defects, this would
augment the benefit to a proven effective way to prevent infant
mortality and disability (18). It is reassuring that data do not
support the reports that folic acid supplements increase the oc-
currence of miscarriage or multiple births because women of
childbearing age in many countries are advised to take folic acid
supplements daily to prevent NTDs. Women of reproductive
age and their health care providers can support the pericon-
ceptional folic acid supplementation policy without concern
that this practice will increase the occurrence of multiple
births or miscarriages.
The authors have no conflict of interest.
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