American Journal of Medical Genetics Part C (Semin. Med. Genet.

) 135C:88 94 (2005)

A R T I C L E

Epidemiology of Neural Tube Defects

LAURA E. MITCHELL*
The epidemiological investigation of the common open neural tube defects (NTDs), anencephaly, and spina
bifida, has a long history. The most significant finding from these past studies of NTDs was the identification of the
protective effect of maternal, periconceptional supplementation with folic acid. Fortuitously, the association
between folic acid and NTDs became widely accepted in the early 1990s, at a time when genetic association
studies of complex traits were becoming increasingly feasible. The confluence of these events has had a major
impact on the direction of epidemiological, NTD research. Association studies to evaluate genes that may
influence the risk of NTDs through their role in folate-related processes, or through other metabolic or
developmental pathways are now commonplace. Moreover, the study of genetic as well as non-genetic, factors
that may influence NTD risk through effects on the nutrient status of the mother or embryo has emerged as a
major research focus. Research efforts over the past decade indicate that genegene, geneenvironment, and
higher-order interactions, as well as maternal genetic effects influence NTD risk, highlighting the complexity of
the factors that underlie these conditions. The challenge for the future is to design studies that address these
complexities, and are adequately powered to detect the factors or combination of factors that influence the
development of NTDs. 2005 Wiley-Liss, Inc.
KEY WORDS: anencephaly; epideimology; neural tube; myelomeningocele; spina bifida

INTRODUCTION
Neural tube defects (NTDs) are generally believed to result from failure of
fusion of the neural tube during early
embryogenesis. The most common
NTDs are anencephaly, which results
from failure of fusion of the cranial
neural tube, and myelomeningocele
(commonly called spina bifida), which
results from failure of fusion in the spinal
region of the neural tube. Anencephaly
and myelomeningocele are often referred to as open NTDs because the
affected region of the neural tube is
exposed to the body surface. Cranior-

Laura Mitchell, Ph.D., is an Associate

Professor in the Center for Environmental
and Genetic Medicine of the Institute of
Biosciences and Technology, Texas A&M
University System Health Science Center in
Houston, Texas. Her research interests include genetic epidemiology of birth defects,
and methods for evaluating the genetic
contribution to complex human diseases.
Grant sponsor: National Institutes of
Health;
Grant
numbers:
HD39195,
HD39081, ES11658.
*Correspondence to: Laura E. Mitchell,
Ph.D., Center for Environmental and Genetic
Medicine, Institute of Biosciences and Technology, 2121 W. Holcombe Blvd., Houston,
TX 77030. E-mail: lmitchell@ibt.tamhsc.edu
DOI 10.1002/ajmg.c.30057

2005 Wiley-Liss, Inc.

achischisis, which results from failure of

fusion of the neural tube over the entire
body axis, is an additional, relatively rare
form of open NTD.
In addition to the open NTDs,
there are also a number of closed or
skin-covered conditions that involve the
neural tube, including: encephalocele,
meningocele (also called closed spina
bifida), iniencephaly, lipomeningocele,
sacral agensis, and occult spinal dysraphisms (also referred to as spina bifida
occulta) [Lemire, 1988]. The relationship between these skin-covered conditions and open NTDs has not been
firmly established. However, families
segregating both open and closed malformations have been reported (for
example, [Fellous et al., 1982; Fineman
et al., 1982; Moore et al., 1990]), and a
decline in the prevalence of encephalocele, as well as anencephaly and spina
bifida, was reported following folic acid
fortification of the food supply in Chile
[Castilla et al., 2003]. These observations
suggest that there may be an overlap in
the factors that influence the development of open and closed NTDs.
Epidemiological investigations of
NTDs have tended to focus on anencephaly and spina bifida (i.e., myelomeningocele). The focus on these two

conditions is likely to be explained by

their prevalence relative to other NTDs,
as well as their dramatic clinical appearance and consequences. Anencephaly is
a lethal condition and, in the absence of
adequate medical and surgical interventions, mortality rates for spina bifida also
approach 100%. With appropriate treatment, the majority of individuals with
spina bifida will survive. Recent population-based data from Atlanta, Georgia
(USA) indicate that survival among
individuals with spina bifida is approximately 87% at 1 year, and 78% at 17 years
[Wong and Paulozzi, 2001]. However,
affected individuals are at risk for a
range of physical and developmental
disabilities [Althouse and Wald, 1980;
Casari and Farrall, 1998; Buccimazza
et al., 1999; Singhal and Mathew, 1999;
Bowman et al., 2001], and experience
excess mortality into the adult years
[Hunt, 1999; Singhal and Mathew,
1999; McDonnell and McCann, 2000;
Bowman et al., 2001].

PREVALENCE
Geographic and temporal variation in
the prevalence of anencephaly and spina
bifida is well documented [Olney and
Mulinare, 1998, 2002]. In addition,

ARTICLE

within a given geographic location and

time period, the prevalence of these
conditions varies by race and ethnicity.
For example, in California, the prevalence of NTDs was reported to be
highest in Hispanics (1.12/1,000), lowest in Blacks and Asians (0.75/1,000),
and intermediate in non-Hispanic Caucasians (0.96/1,000) [Feuchtbaum et al.,
1999].
The relative contribution of genetic
and environmental (e.g., social, dietary)
differences between racial and ethnic
groups, to the observed differences
in NTD prevalence, has not been
established. Some studies of Mexican-

The relative contribution

of genetic and environmental
(e.g., social, dietary)
differences between racial
and ethnic groups,
to the observed differences
in NTD prevalence,
has not been established.
Hispanics residing in the United States
have reported that the risk of NTDs is
higher in the offspring of women who
were born in Mexico than in those born
in the United States [Shaw et al., 1997;
Hendricks et al., 1999]. Such observations suggest that environmental differences are likely to contribute to the
variation in NTD prevalence between
groups. However, other studies in Mexican-Hispanic populations have found
no relationship between maternal birth
place (Mexico vs. United States) and the
risk of having a child with a NTD
[Canfield et al., 1996].
The birth prevalence of NTDs is
influenced by the availability of prenatal
diagnosis and elective pregnancy termination [Chan et al., 1993; CDC, 1995;
Velie and Shaw, 1996; Palomaki et al.,
1999; Forrester and Merz, 2000; Rankin
et al., 2000]. Termination rates are
generally higher for anencephalic than
for spina bifida affected fetuses [Chan
et al., 1993; CDC, 1995; Velie and Shaw,
1996; Palomaki et al., 1999; Forrester

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

and Merz, 2000; Rankin et al., 2000]. In

addition, termination rates exhibit both
temporal [Rankin et al., 2000] and
regional [CDC, 1995] variation. These
factors complicate surveillance efforts,
since electively terminated fetuses with
NTDs must be ascertained in order to
monitor trends in NTD prevalence
across or between populations, and to
reduce the effects of selection bias in
studies of potential risk factors [Borman
and Cryer, 1990; Velie and Shaw, 1996].
A womans risk of having a child
with a NTD can be significantly reduced
by periconceptional, folic acid supplementation [MRC, 1991; Czeizel and
Dudas, 1992]. However, public health
campaigns promoting daily use of multivitamins with folic acid have not had an
appreciable impact on the prevalence
of NTDs [Abramsky et al., 1999; Olney
and Mulinare, 2002]. In contrast, data
from countries that have implemented
mandatory folic acid food fortification programs indicate a 30%50% reduction in the prevalence of NTDs
post-fortification [Honein et al., 2001;
Erickson, 2002; Persad et al., 2002; Ray
et al., 2002; Castilla et al., 2003; De Wals
et al., 2003; Mersereau et al., 2004].

However, public health

campaigns promoting daily
use of multivitamins with folic
acid have not had an appreciable
impact on the prevalence
of NTDs. In contrast, data
from countries that have
implemented mandatory
folic acid food fortification
programs indicate a 30%50%
reduction in the prevalence of
NTDs post-fortification.
HETEROGENEITY
Syndromes
NTDs can occur as part of malformation
syndromes resulting from known chro-

89

mosomal abnormalities (e.g., trisomy

13, 18, and 21) and single gene disorders
(e.g., Meckel-Gruber and Waadenburg
syndromes) [Hall and Solehdin, 1998].
In addition, rare families, segregating
anencephaly and/or spina bifida (with
or without other forms of NTDs) in
patterns consistent with X-linked and
autosomal recessive inheritance have
also been reported [Baraitser and Burn,
1984; Toriello and Higgins, 1985; Farag
et al., 1986; Jennson et al., 1988]. However, the vast majority of cases cannot be
attributed to either chromosomal aberrations or the effects of a single genetic
locus.
In a small proportion of cases,
anencephaly and spina bifida occur as
part of malformation syndromes that
result from teratogenic exposures. The
teratogenic potential of maternal pregestational diabetes is well established
and includes a two- to tenfold increase in
the risk of central nervous system malformations (including NTDs) among
the offspring of affected women, relative
to the general population [McLeod and
Ray, 2002]. In addition, maternal use of
valproic acid and/or carbamazepine is
associated with an increased risk of spina
bifida [Lammer et al., 1987; HernandezDiaz et al., 2001; Matalon et al., 2002].
Among women taking these medications, the risk of having a pregnancy
affected with spina bifida may be as high
as 1%2% [Koren, 1999], whereas the
risk of anencephaly does not appear to be
increased.

In addition, maternal use

of valproic acid and/or
carbamazepine is associated
with an increased risk of spina
bifida. Among women taking
these medications, the risk of
having a pregnancy affected
with spina bifida may be as
high as 1%2%, whereas the
risk of anencephaly does not
appear to be increased.

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AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

Malformation Level
In studies of the non-syndromic forms
of anencephaly and spina bifida, these
two conditions are often considered as
a single entity. The legitimacy of such
grouping is supported on embryological
grounds (i.e. anencephaly and spina
bifida are both neural tube closure defects [Lemire, 1988]), as well as by family
studies that demonstrate that the sibs of
individuals with spina bifida or anencephaly are at increased risk for both spina
bifida and anencephaly (e.g., [Laurence
et al., 1967; Carter and Evans, 1973;
Nevin and Johnston, 1980]), and other
similarities in the characteristics of these
two conditions (e.g., the prevalence of
both anencephaly and spina bifida is
increased in Hispanics compared to nonHispanic Caucasians [Canfield et al.,
1996; Shaw et al., 1997]). However,
there is also evidence that the factors
influencing the development of anencephaly and spina bifida may not overlap
completely. For example, although
anencephaly and spina bifida co-occur
within families, affected sib pairs are
more likely to be concordant (e.g.,
anencephalyanencephaly) than discordant (e.g., anencephalyspina bifida)
[Laurence et al., 1967; Carter and Evans,
1973; Nevin and Johnston, 1980]. In
addition, exposure to valproic acid is
associated with an increased risk of spina
bifida, but not anencephaly.
It has also been suggested that there
may be heterogeneity in the factors that
influence the development of upper
and lower NTDs. This subdivision
has been justified on embryological
grounds: the upper portion of the neural
tube is formed by folding and fusion (i.e.,
neurulation), whereas the lower portion
is formed by a different process (i.e.,
canalization). During the 1980s and
early 1990s several studies that evaluated
concordance for upper and lower NTDs
among related individuals were published. These studies based their definitions of upper and lower defects on work
that suggested canalization was responsible for neural tube development posterior to the 25th somite. Some of these
studies reported complete concordance
for upper or lower defects among

affected relatives [Toriello and Higgins,

1985; Hall et al., 1988], whereas other
studies reported both concordant and
discordant affected relatives [Frecker
et al., 1988; Seller, 1990; Drainer et al.,
1991; Torok and Papp, 1991]. The latter
studies indicate that the causes of upper
and lower defects (as defined in these
studies) are likely to be related. However, these studies may not have truly
addressed the issue of heterogeneity in
the causes of neurulation and canalization defects, since there is evidence that
canalization is limited to a more distal
segment of the neural tube (i.e., posterior to somites 3234) [Nievelstein et al.,
1993; ORahilly and Muller, 1999] than
was assumed.
Associated Malformations
It has also been suggested that there
may be etiological differences between
NTDs that occur with and without
additional malformations (after exclusion of cases with known chromosomal,
genetic or teratogenic syndromes)
[Khoury et al., 1982a,b]. However, the
presence of additional malformations
appears to be related to the location of
the NTD [Seller and Kalousek, 1986;
Davies and Duran, 2003], making it
difficult to determine which of these
characteristics may serve as a better
indictor for the subdivision of cases into
etiologically more homogenous subgroups. Given that anencephaly and
spina bifida, as well as upper and lower
NTDs co-segregate within families, it
would appear reasonable to study all
open NTDs as a single group. However,
it would also seem prudent to perform
subgroup analyses based on lesion level
and/or the presence of additional malformations when sample sizes permit.

RISK FACTORS
The epidemiological characteristics of
anencephaly and spina bifida have
been extensively studied, and numerous
review articles have been published
[Mitchell, 1997; Olney and Mulinare,
1998; Botto et al., 1999; Frey and
Hauser, 2003]. Although a number of
potential risk factors for NTDs have

ARTICLE

been identified, many of the reported associations have been weak and
have not been consistently replicated.
Maternal obesity has emerged as a
consistent risk factor for NTDs, with
women in the highest body mass index
categories (usually defined as a prepregnancy body mass index greater than
29 kg/m2) having a 1.5- to 3.5-fold
higher risk than women with lower
indices [Waller et al., 1994; Shaw et al.,
1996, 2000; Watkins et al., 1996, 2003;
Werler et al., 1996; Hendricks et al.,
2001]. There is also relatively strong

Maternal obesity has emerged

as a consistent risk factor
for NTDs, with women in
the highest body mass index
categories having a 1.5- to
3.5-fold higher risk than
women with lower indices.
evidence that maternal hyperthermia
increases the risk of having a child with
an NTD by up to twofold [Milunsky
et al., 1992; Lynberg et al., 1994;
Lapunzina, 1996; Chambers et al.,
1998; Shaw et al., 1998]. Other exposures that are currently of interest, but
which require further investigation to
establish their relationships with NTDs,
include: food contaminated with fumonisins (a class of myocotoxins) [Hendricks, 1999; Sadler et al., 2002],
chlorination disinfection by-products
in drinking water [Klotz and Pyrch,
1999; Dodds and King, 2001], electromagnetic fields [Blaasaas et al., 2002],
hazardous waste sites [Dolk et al., 1998;
Orr et al., 2002], pesticides [Shaw et al.,
1999], and maternal stress and social
support [Carmichael et al., 2003a;
Suarez et al., 2003a].
Undoubtedly, the most significant
epidemiological finding with respect
to NTDs is the protective effect of
maternal periconceptional folic acid
supplementation. This finding has been
translated into public health policies, including educational campaigns and food

ARTICLE

fortification programs. Initial reports

from countries that have implemented fortification programs indicate that
the population prevalence of NTDs has
declined following fortification [Honein
et al., 2001; Erickson, 2002; Persad et al.,
2002; Ray et al., 2002; Castilla et al.,
2003; De Wals et al., 2003; Mersereau
et al., 2004]. Hence, folic acid fortification of the food supply appears to
represent the first successful, population-based, strategy for the primary
prevention of a common congenital
malformation.

Hence, folic acid fortification

of the food supply appears
to represent the first
successful, population-based,
strategy for the primary
prevention of a common
congenital malformation.
Although evidence for an association between NTDs and folic acid
accumulated during the 1970s and
1980s, it was the results of the MRC
[MRC, 1991] and Hungarian trials
[Czeizel and Dudas, 1992] of folic acid
suplementation that fueled public health
efforts to reduce the prevalence of
NTDs. Fortuitously, publication of the
trial results occurred at a time when genetic studies of complex, non-Mendelian
conditions, such as NTDs, were becoming increasingly feasible. In combination, these events have had a substantial
influence on the direction of epidemiological studies on NTDs.
Given the observed association
between folic acid and NTDs, it is not
surprising that there has been substantial
interest in the relation between genes
involved in folate-related metabolic
pathways and NTDs. Variants of several
such genes have been found to be
significantly associated with the risk of
NTDs in one or more studies [Finnell
et al., 2003]. Moreover, there is evidence
that folate-related genes may exert their
influence on the risk of NTDs via gene

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

gene [Wilson et al., 1999; De Marco

et al., 2003; Zhu et al., 2003] and gene
environmental [Shaw et al., 2002; Volcik
et al., 2003] interactions, and that such
genes may act via either the maternal
[Doolin et al., 2002] or the embryonic
[Shields et al., 1999] genotype. However, firm conclusions regarding the
relationship between NTDs and variants
of specific folate-related genes are largely
precluded at this time.
In addition to genes involved in
folate-related metabolic pathways, there
is currently considerable interest in genes
that may influence the risk of NTDs
through other metabolic or developmental pathways. Studies to date have
not established any such gene as a risk
factor for NTDs [Harris, 2001]. However, in general, the relationship between NTDs and non-folate genes
has not been adequately studied.
There is also an interest in the
relationship between NTDs and nutrients, and factors that effect nutrients,
other than folic acid. There is an accumulating body of literature that supports an association between maternal
vitamin B12 levels and NTDs [Ray
and Blom, 2003; Suarez et al., 2003b].

There is also an interest in

the relationship between
NTDs and nutrients, and
factors that effect nutrients,
other than folic acid. There is
an accumulating body of
literature that supports
an association between
maternal vitamin B12
levels and NTDs.
In addition, recent studies have suggested potential associations between NTDs
and maternal myo-inositol, zinc, and
glucose levels [Groenen et al., 2003a,b],
maternal intake of sucrose and foods
with high glycemic index values [Shaw
et al., 2003], maternal dieting behavior

91

[Carmichael et al., 2003b] and physical

activity [Carmichael et al., 2002], and
maternal diarrhea [Felkner et al., 2003].

CONCLUSIONS
Although the identification of the relationship between folic acid and NTDs
should be heralded as one of the great
successes of epidemiological research,
the identification of additional NTD
risk factors has proven to be exceedingly
difficult. Interestingly, the initial experience with genetic association studies of
NTDs has largely mirrored the experience with association studies of environmental risk factors for NTDs, that is the
majority of the reported genetic associations have been weak and difficult to
replicate. This relative lack of success
has emerged as a characteristic common
to genetic association studies of complex, human traits [Hirschhorn et al.,
2002], and can be attributed to several
factors including: (a) small, underpowered studies, (b) narrowly focused studies
that consider only one or a few variants per gene, (c) lack of independent
studies, (d) non-replication in independent studies, (e) failure to adequately
address the influence of both the maternal and embryonic genotype, and (f)
failure to adequately address potential
effect modifiers.
The somewhat disappointing track
record of genetic association studies
of complex diseases has led some to
question the utility of this approach
[Gambaro et al., 2000; Holtzman, 2001;
Strohman, 2002]. However, others have
provided compelling arguments that
genetic association studies can be informative when they are appropriately
designed and analyzed [Ioannidis et al.,
2003; Lohmueller et al., 2003; Redden
and Allison, 2003; Zondervan and
Cardon, 2004]. The challenge now is
to design studies that minimize the
potential for confounding and bias, and
are adequately powered to detect the
associations of interest. More than ever,
this will require the collaboration of
epidemiologists and geneticists, as well as
individuals with expertise in nutrition,
biochemistry, and other areas of the
biomedical sciences.

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AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

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