Folic Acid and
Neural Tube Defects
Yongling Xiao
Neural Tube Defects (NTD)

NTD are birth defects of the
brain and spinal cord. Normally,
in human embryos, the closure
of the neural tube occurs
around the 30th day after
fertilization. However, if
something interferes and the
tube fails to close properly, a
NTD will occur.
Neural Tube Defects
 The
two most common NTD are:
Spina bifida (Latin: "split spine" ): incomplete
closure of the embryonic neural tube results in an
incompletely formed spinal cord during the first
month of pregnancy. There is usually nerve
damage that causes at least some paralysis of the
legs.
 Anencephaly, when the head end of the neural
tube fails to close, resulting in the absence of a
major portion of the brain, skull, and scalp. Babies
with anencephaly are either stillborn or die shortly
after birth.

Folic Acid

Folic acid (FA) is a water-soluble
Vitamin B9, also called Folate.



Foods with folic acid include leafy green
vegetables, fruits, dried beans, peas and
nuts
Dietary supplement
Folate deficiency


In adults, anemia is a sign of advanced
folate deficiency.
A deficiency of folate can occur when



need for folate is increased,
dietary intake of folate is inadequate,
body excretes (or loses) more folate than
usual
First observation

Connection between FA and congenital malformations
began with animal studies of aminopterin, an
antimetabolite of FA, in 1949 by Nelson.


The invariable effect of aminopterin on pregnant rats was
prenatal death, but not malformations.
This outcome led Thiersch, a pathologist, to use
aminopterin as a means of interrupting pregnancy in
women



12 women were given aminopterin during the 1st trimester.
Abortion occurred in only 10 /12. One of the ten and the other
two had offspring possessing various malformations.
For the first time, human embryos were shown to be capable
of being malformed by chemical substances.
Smithells’ study

In 1964, Smithells et al. conducted a study in
Liverpool to investigate a possible relationship
between fetal malformations & defective folate
metabolism in mother
 Of
98 mothers of severe malformed (principally of the
central nervous system) infants in 1964, 54 were
matched satisfactorily with controls, those who gave a
normal infant in the same hospital and were selected
with respect to age, parity and the time of conception
and gestation.
 A FIGLU excretion test was used to test FA
Smithells’ study
Mother
Of all malformed infants
Of all infants with C.N.S.
malformations
Matched pairs
Mothers of malformed infants
Mothers of normal infants
Mother of infants
with C.N.S. malformation
Mothers of normal infants
FIGLU excretion
Total
test
Positive Negative
61
37
98
% FIGLU
positive
48
25
73
66
35
8
24
19
46
11
54
54
35
65
17
69
6
29
35
17
62
Smithells’ study


A significant relationship between malformation
of the fetus and defective folate metabolism in
the mother.
However,
 The
results were based on the investigation of a
metabolic defect present in late pregnancy, thus, did
not indicate necessarily that such a defect was
present at the time of embryogenesis.
 A positive FIGLU test may indicate defective
metabolism rather than deficient intake of folate.
Evidence


A retrospective study of FA and NTD occurrence
conducted as part of Metropolitan Atlanta Birth Defects
Program found that multivitamin use was twice as great
in control women, with infants without malformation or
with other non-NTD malformations, as in case women
who had NTD births in 1968 through 1980, with the
respective estimated overall NTD risk being 0.4.
The Boston prospective study performed in 1984 to
1987 showed that the frequency of offspring with NTD of
those who replied negatively of vitamin use was 3.0 per
1000 and replying positively 0.9 per 1000, a reduction of
70%.
Evidence


Contradictive finding in a NIH study: no significant
difference was found in the rate of use of multivitamin
between case group (women with infants or fetuses with
a NTD diagnosed in 1985 – 1987) and 2 control groups
(women with normal offspring and another with non-NTD
major malformations).
In 1980, a multicenter intervention project undertaken in
Leeds, reported that 1/178 offspring of the treated (i.e. a
commercial multivitamin) women had a NTD, whereas
13/260 offspring of the control (already pregnant or
refused ) women had a NTD (0.6% vs 5.0%).
Medical Research Council RCT



The British double-blind randomized trial was
launched in July, 1983, and continued till 1991
33 centers ( 17 in UK and 16 in other countries:
Hungary, Israel, Australia, Canada, USSR and France)
1817 women at high risk of having a
pregnancy with a NTD (because of a previous
affected pregnancy) were allocated to one of
the four groups.
Group
A
B
C
D
Folic Acid(4mg/day)
yes
yes
no
no
Other vitamins
no
yes
no
yes
Medical Research Council RCT
Medical Research Council RCT




Relative risk for the women allocated to take FA was
0.28 compared with the control groups (72% of the NTD
were prevented)
No indication that the vitamins other than FA had any
preventive effect nor that they enhanced the effect of FA
MRC trial study has established the specific role of folic
acid in the prevention of NTD.
In MRC trial, FA supplementation had been shown to
reduce the NTD recurrence rate, whether the same
could be achieved for first time occurrence of these
abnormalities?
Another Randomized Trial

The results of Hungarian RCT was reported in
1992
 To
test the efficacy of periconceptional multivitamin
supplementation in reducing the incidence of a first
occurrence of NTD.
 Women planning a pregnancy were randomly
assigned to receive a single tablet of a vitamin
supplement (containing 12 vitamins, including 0.8 mg
of FA) or a placebo supplement daily for at least one
month before conception
 Significant difference was found: 6 cases of NTD in
the placebo group (n=2052), as compared with 0 in
the vitamin-supplement group (n=2104) (P = 0.029)
Folic Acid Fortification (FAF)


In 1992, U.S. Public Health Service
recommended that “All women of
childbearing age in the United States
who are capable of becoming pregnant
should consume 0.4 mg of folic acid per
day for the purpose of reducing their risk
of having a pregnancy affected with
spina bifida or other NTDs.”
However, a survey indicated that only
29% of US women were following this
recommendation.
Folic Acid Fortification (FAF)


In a further effort to reduce the occurrence of folatepreventable NTDs, the US FDA authorized the addition
of FA to enriched grain products at a level of 140µg/100g
flour in March 1996 and made compliance mandatory by
January 1998.
The Canadian milling industry started fortification early in
1997, to meet the US requirements for imported flour. On
November 11, 1998, fortification with FA of all types of
white flour, enriched pasta, and cornmeal became
mandatory in Canada.
Evaluation of Folic Acid Fortification

A study was conducted in Canada





To assess changes in the prevalence of NTD associated with
food fortification with FA throughout Canada.
To test the hypothesis that the magnitude of the effect of FA
fortification would vary with the baseline rate of the defect
Study population included live births, stillbirths, and
terminations of pregnancies because of fetal anomalies
among women residing in seven Canadian provinces
from 1993 to 2002
2446 subjects with NTD were recorded among 1.9
million births
Study periods:



Prefortification: Jan. 1, 1993, to Sept. 30, 1997
Partial-fortification: Oct.1, 1997 to Mar.31, 2000
Full-fortification: April 1, 2000 to Dec. 31, 2002
Evaluation of Folic Acid Fortification

The prevalence of NTD decreased from 1.58 per
1000 births before fortification to 0.86 per 1000 births
during the full-fortification period, a 46% reduction.
Evaluation of Folic Acid Fortification

The magnitude of the decrease was proportional to the
prefortification baseline rate in each province, and geographical
differences almost disappeared after fortification began.
Evaluation of Folic Acid Fortification

Conclusions:

Food fortification with FA was associated
with a significant reduction in the rate of
NTD in Canada.
 The decrease was greatest in areas in which
the baseline rate was high.
Concerns about possible adverse
effects of Folic Acid Fortafication

Possible adverse effects due to FA:




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Masking B12 deficiency and consequent neurologic damage
Intake in children
Decreased natural killer cell activity
Cancer promotion
The evidence available to date does not support the
conclusion that foods fortified with FA cause harm
However, the possibility that higher FA intake may pose
a risk to the general population must be taken into
consideration seriously.
Thanks!