Periconceptional folic acid-containing multivitamin
supplementation for prevention of neural-tube defects and
Andrew E. Czeizel
Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary
The number of words: 1,200
No conflict of interest
Short title: Folic acid and cardiovascular malformations
1028 Budapest, Törökvész lejtő, 32, Hungary
Tel/Fax: 36 1 3944 712, e-mail:firstname.lastname@example.org
Key words: Folic acid, folic acid-containing multivitamins, neural-tube defects,
The prevention of neural-tube defects with periconceptional folic acid or folic acid-
containing multivitamin supplementation is accepted by the scientific community;
here the possible prevention of cardiovascular malformations is discussed. The aim
of this presentation is to show the main findings of trials and studies that resulted in
the prevention of neural-tube defects and particularly cardiovascular malformations
by folic acid-containing multivitamins or folic acid supplementation in order to
stimulate the incorporation of folic acid-containing multivitamins or folic acid in the
prevention of cardiovascular malformations.
Folic acid-containing multivitamins (MVs) and folic acid (FA) can reduce significantly
the total (birth + fetal) prevalence of neural-tube defects (NTD). The aim of this
publication is to discuss seven debated questions mainly based on the results of two
Hungarian intervention trials, however, here only the first debated question is
The findings of five intervention trials are available for general evaluation. The
reduction of first occurrence of NTD (about 90%) was proved after the
periconceptional MV (containing 0.8 mg folic acid) supplementation in the Hungarian
randomized controlled trial (RCT)  and cohort controlled trial (CCT) , in addition
periconceptional FA (0.4 mg) supplementation (41-79%) in a public health project in
China . The reduction of recurrent NTD was shown first after periconceptional MV
(containing 0.36 mg folic acid) supplementation (about 90%) in a non-RCT
intervention trial  and later after FA (4.0 mg) supplementation (71%) in the RCT
MRC Vitamin Study , in the latter 43% of participants had Hungarian origin.
Question is whether MVs or FA can prevent other structural birth defects,
i.e. congenital abnormalities (CAs) beyond NTD?
Both the Hungarian RCT (RR with 95% CI: 0.42, 0.19-0.98) [1, 6, 7] and CCT (OR
with 95% CI: 0.60, 0.38-0.96)  resulted in a significant reduction in the birth
prevalence of cardiovascular malformations (CVMs) after MV supplementation. The
combination of the results of these two intervention trials [OR 95% CI: 0.57, 0.39-
0.85) associated with a 43% reduction in the risk for CVMs. However, CVMs include
heterogeneous manifestations and origins of different CVM entities. The most
obvious reduction was found in the incidence of ventricular septal defects and
The population-based observational Atlanta study [8-10] showed that the use
of periconceptional folic acid-containing MVs reduced the risk of CVM by 24 % (OR
with 95% CI: 0.76, 0.60-97). When evaluating the association with specific types of
CVMs, these data also suggested that the association was strongest for ventricular
septal defect and some conotruncal defects such as tetralogy of Fallot and D-
transposition of the great vessels . The birth prevalence of conotruncal defects
was reduced about 50% in the Hungarian intervention trials and Atlanta observational
study. The data of another US observational study also supported the conclusion that
periconceptional MVs were associated with a reduction (30%) in the birth prevalence
of CVMs . The Hungarian observational study evaluated the effect FA (high
doses: 3 and 6 mg) during the critical period of CVMs (i.e. in the second and third
gestational months) in the Hungarian Case-Control Surveillance of Congenital
Abnormalities and a significant reduction was found in the occurrence of CVMs [OR
with 95% CI: 0.86, 0.77-0.98) . In contrast, two other US observational studies did
not find association between periconceptional MV supplementation and the reduction
of two types of CVMs (ventricular septal defect and outflow tract defects)  or
outflow tract defects .
On the other hand a recent population-based observational Dutch Study 
evaluated FA intake (without mentioning FA alone or MVs), and a significant
reduction in the rate of CVMs (OR with 95% CI: 0.82, 0.68-0.98) was found. The
major reduction was observed in septal defects. Finally a significant reduction was
reported in the birth prevalence of severe CVMs in Quebec, Canada after FA
fortification of grain products .
The evaluation of CVM reduction after supplementation of MVs in some
previously mentioned trials or studies [6-7, 8-10, 11, 13, 14] showed a reduction in
CVMs (OR = 0.76 and 0.42) and in conotruncal defects (OR = 1.00 and 0.46)
.The meta-analysis of both case-control studies (OR with 95% CIC: 0.78, 0.67-
0.92) and cohort or RCT (OR with 95% CI: 0.61, 0.40-0.92) confirmed the preventive
effect of MVs in the reduction of CVMs .
Unfortunately our knowledge is limited regarding the mechanism of MVs and/or
FA in the prevention of CVMs. However, FA antagonist drugs that inhibit
dihydrofolate reductase which is required for DNA synthesis increased the risk of
CVMs in the children of pregnant women . After trimethoprim-sulfamethazine
(cotrimoxazole) use during the second and third gestational month of pregnant
women, a higher risk of CVMs (OR with 95% CI: 2.1, 1.4-3.3]  was found in their
children. A higher risk of CVMs was also observed after the intake of certain
sulfonamides (OR with 95% CI: 3.5, 1.9-6.4). However, the most important
argument for the role of FA in the pathogenesis of CVMs was that the risk of CVMs
after the use FA antagonists without concomitant use of MVs was 7.7 (95% CI: 2.8-
21.7) while this risk was only 1.5 (95% CI: 0.6-3.8) after the parallel use of FA
antagonist drugs and MVs . On the other hand association was found between
higher plasma homocysteine level due to methylenetetrahydrofolate-reductase
(MTHFR) gene polymorphism and higher risk of CVMs  though the recent
evaluation of 13 eligible studies did not confirm this association between the risk of
CVMs and fetal (OR with 95% CI: 1.3, 0.97-1.73) or maternal (OR with 95% CI: 1.2,
0.83-1.74) MTHFR TT genotype . The interaction of folate-related genes,
maternal obesity and smoking habit resulted in a higher risk for CVMs .
In conclusion the available data support that FA or FA containing MVs are
essential for normal fetal cardiac development during early embryogenesis and FA
and/or MV supplementation during the periconceptional period or in very early
pregnancy reduce the risk for CVMs.
To my mind as a next step, it would be necessary to incorporate CVMs in our
public health action of CA prevention with periconceptional MVs or FA
supplementation with three arguments:
(i) Cases with CVM represent the most common CA-group, the birth prevalence
of CVMs was estimated 8 per 1000 in the USA , but the detailed personal
examination of all newborn infants in a Hungarian cohort showed a rate of 10.2 per
1000 in Hungary . CVMs account for a third or more of infant death .
(ii) Available findings indicate about 40 % efficacy of MVs in the reduction of
(iii) Obviously the efficacy of NTD by MVs or FA is much better, but we have to
consider the absolute numbers. The total prevalence of NTD is 2.8 per 1000 in
Hungary . The efficacy of MVs in the prevention of NTD is about 90 %, thus
theoretically the population-based rate of NTD can reduce to 0.3 per 1000, and this
reduction is equal to 252 cases per 100,000 births. However, the birth prevalence of
cases with CVM is 10.2 per 1000 and it can be reduced to 6.1 per 1000 on the basis
of 40% efficacy of MVs, thus the preventable absolute number of CVM cases is 408
for 100,000 births. This CVM : NTD ratio is 1.6:1.0, but if a lower rate of NTD is
considered (e.g. about 1 per 1000 in the USA ), this ratio may be higher.
In conclusion, there is no debate that the major part of NTD is preventable by
MVs or FA, but we have growing evidence for the prevention of certain proportion of
CVMs, the most common CAs. Thus about one-third of CAs are preventable by MVs
and FA supplementation in the periconception period , therefore the inertia on the
use of MVs or FA for the prevention of CAs is medical malpractice .
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