Folic Acid and Neural Tube Defects

127 Pages·2017·5.52 MB·English

Folic Acid and Neural
Tube Defects
Effective Primary Prevention or
Wishful Thinking?
Bengt Källén
Monograph Series
Avid Science Monograph Series
Monograph
Folic Acid and Neural Tube Defects:
Effective Primary Prevention or Wishful
Thinking?
Bengt Källén*
Tornblad Institute, Lund University, Sweden
*Corresponding Author: Bengt Källén, Tornblad Institute,
Lund University, Galjevångsvägen 26, SE-224 65 Lund, Swe-
den, Tel: [phone]; Email: [email protected]
First Published July 20, 2017
Copyright: © 2017 Bengt Källén.
This article is distributed under the terms of the Creative Com-
mons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s)
and the source.
Statements and opinions expressed in the book are these of the
individual contributors and not necessarily those of the editors or
publisher. No responsibility is accepted for the accuracy of infor-
mation contained in the published chapters. The publisher assumes
no responsibility for any damage or injury to persons or property
arising out of the use of any materials, instructions, methods or
ideas contained in the book.
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Contents
Preface
Chapter 1: Neural tube defects
Chapter 2: Genes and neural tube defects. The role of
folic acid metabolism.
Chapter 3: Different approaches to influence neural
tube defect rates with folic acid or other vitamins: Gen-
eral comments.
Chapter 4: Efforts to influence the risk of recurrence of
neural tube defects with folic acid.
Chapter 5: Efforts to affect occurrence risk of neural
tube defects with folic acid.
Chapter 6: Effects of food fortification with folic acid.
Chapter 7: Summary and concluding remarks.

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Preface
Numerous hazards during pregnancy are known or suspect-
ed, causing pregnancy complications, miscarriage, congeni-
tal malformations, stillbirths, neonatal deaths, or neonatal
or long term morbidity of the child. The degree of certainty
in these causalities vary from generally accepted risks like
that associated with maternal use of some anticonvulsants
or abuse of alcohol to statements of associations which have
so far not been verified by high quality independent data.
On the contrary rather few external factors have been
ascribed a beneficial effect on pregnancy outcome. Pre-
pregnancy and early pregnancy care has been said to reduce
complications which is definitely the case for women with
diseases like diabetes but is more uncertain for normal,
healthy women. The most wide-spread idea is the positive
effect of folic acid on pregnancy outcome, notably on the
rate of neural tube defects in the offspring. As we will see in
this book, the idea grew from observations on differences in
the rate of such malformations according to maternal social
class. Many alternative explanations to such an association
can be suggested but the main line of thought which was
followed was nutrition and notably inadequate amounts of
vitamins, among them folic acid, one of the many factors
which are necessary for a normal embryonic development.
Accumulating evidence supporting this association increased
the conviction that folic acid was the ultimate answer to
the prevention of neural tube defects, some other congeni-
tal malformations, and pregnancy complications. Studies
pointing in another direction were usually disregarded. It has
resulted in a general recommendation that women who plan
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pregnancy should take extra folic acid and in many countries
to food fortification with folic acid.
The majority of people including the majority of scientists
and health administrators are convinced about the beneficial
effect of folic acid (e.g., 1). This does not necessarily mean
that this is true. We can remember the general “knowledge”
that it was beneficial to put the young infant on its stomach
until it was proved that this habit increased the risk of sud-
den infant death and the recommendation had resulted in a
substantial number of such deaths around the world.
For this reason I think it is necessary to scrutinize the avail-
able evidence that folic acid actually reduces the risk of
neural tube defects. Is this at all true and, if so, is it valid for
all populations or only for some special ones, e.g., those with
a high background rate of the malformations? This is what I
have tried to do in the present book.
Lund, May 2017
Bengt Källén
Professor emeritus in embryology
Reference:
1. Viswanathan M, Treiman KA, Dolo JK, Middleton JC,
Coker.Schwimmer EJL, et al. Folic acid supplementation
for the prevention of neural tube defects: an updated
evidence report and systematic review for the US Pre-
ventive Services Task Force. JAMA. 2017; 317: 190-203.
No financial support was obtained for the preparation of this
book. The author declares no conflict of interest.
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Chapter 1
Neural Tube Defects
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Abstract
The basic neural tube defect rate varies between pop-
ulations and races within populations, possibly mainly be-
cause of genetics. There are marked temporal changes in
neural tube defect rate. There is a significantly increased
recurrence rate after a neural tube defect occurrence,
varying in strength with the population rate of the defect.
Relatively few non-genetic factors are definitively shown
to affect the neural tube defect rate. In areas with large so-
cioeconomic differences, there is an association between
a low such level and an increased neural tube defect rate.
Neural tube defects consist of three main types, some-
times occurring together: anencephaly, spina bifida, and
encephalocele. They are all serious malformations. The
rate of anencephaly and spina bifida is usually about the
same while encephalocele is rarer.
Anencephaly means absence of brain – but the basal
structures remain and mainly the hemispheres are miss-
ing (Figure 1:1). If an infant is born with anencephaly it
has a short life expectancy, survival beyond two weeks is
rare. Other malformations often also exist. In one study,
25% had another unrelated malformation [1]. The true
rate may be higher because the anencephaly is such a
dominating malformation that other less impressive mal-
formations may go unnoticed or be neglected.
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Figure 1:1: Stillborn infant with anencephaly and a closure defect of
the upper spinal cord [2].
Encephalocele consists of a midline defect of the skull
through which brain tissue and meninges are herniated,
often in the occipital region. It is usually skin-covered
and is often combined with a reduced head size with mi-
crocephaly (Figure 1:2). The infant may survive but will
often become mentally subnormal and have neurological
sequels. The condition may be part of a genetic syndrome,
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Meckel-Gruber syndrome, with polycystic kidneys. This
condition is autosomal recessive with 25% recurrence risk
in a future pregnancy. Encephalocele is often combined
with other malformations. In one study over 40% had an-
other unrelated malformation [1].
Figure 1:2: Newborn infant with a large encephalocele and micro-
cephaly [2].
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Spina bifida consists of a dorsal defect of the spine
with protruding meninges and often spinal cord (Figure
1:3). In most cases (over 90%) it is a myelomeningocele
with the spinal cord herniated – other forms are menin-
gocele or lipomeningocele where the spinal cord may be
intact. It may be located anywhere along the spine but the
most common location is in the lower spine. The defect
can be surgically closed (even prenatally) but remaining
neurological sequels are common and hydrocephaly may
develop and also foot deformities as a result of nerve dam-
ages.
Figure 1:3: Newborn infant with spina bifida. Note positional defects
of foot [2].
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