Received: 20 July 2018 Accepted: 29 July 2018

DOI: 10.1002/bdr2.1380

REVIEW ARTICLE

Overview on neural tube defects: From development to physical

characteristics
Laura Avagliano1 | Valentina Massa1 | Timothy M. George2 | Sarah Qureshy3 |
Gaetano Pietro Bulfamante1 | Richard H. Finnell3,4

1
Dipartimento di Scienze della Salute, Università
degli Studi di Milano, Milan, Italy Neural tube defects (NTDs) are the second most common congenital malformations
2
Pediatric Neurosurgery, Dell Children’s Medical in humans affecting the development of the central nervous system. Although NTD
Center, Department of Neurosurgery, The pathogenesis has not yet been fully elucidated, many risk factors, both genetic and
University of Texas at Austin Dell Medical
environmental, have been extensively reported. Classically divided in two main
School, Austin, Texas
3
sub-groups (open and closed defects) NTDs present extremely variable prognosis
Department of Pediatrics, The University of
Texas at Austin Dell Medical School, Austin, mainly depending on the site of the lesion. Herein, we review the literature on the
Texas histological and pathological features, epidemiology, prenatal diagnosis, and prog-
4
Center for Precision Environmental Health, nosis, based on the type of defect, with the aim of providing important information
Department of Molecular and Cellular Biology and based on NTDs classification for clinicians and scientists.
Medicine, Baylor College of Medicine, Houston,
Texas
KEYWORDS
Correspondence
Valentina Massa, Dipartimento di Scienze della anencephaly, neural tube defects, spina bifida
Salute, Università degli Studi di Milano, Via A. Di
Rudini’, 8, Milano, Italy.
valentina.massa@unimi.it
Funding information
March of Dimes Foundation, Grant/Award
Number: 16-FY16-169; NIH, Grant/Award
Numbers: HD067244HD081216HD083809,
HD083809, HD067244, HD081216; Università
degli Studi di Milano, Grant/Award Numbers:
Linea2-2017, Linea 2-2017; March of Dimes,
Grant/Award Number: 16-FY16-169

1 | DE VEL O PMEN T O F N EUR AL TU BE folate supplementation campaigns, bringing the prevalence

D E F E CTS
Neural tube defects (NTDs) arise secondary to abnormal
embryonic development of the future central nervous sys-
tem. The two most common types of NTDs are spina bifida
and anencephaly, affecting different levels of the brain and
spine, normally reflecting alterations of the embryonic pro-
cesses that form these structures. Birth defects such as NTDs
are relatively uncommon, with a global prevalence among
live births in the United States of 1 in 1,200 and a worldwide
prevalence ranging from 1 in 1,000 (in Europe and the Mid-
dle East) to 3–5 in 1,000 (in northern China as of 2014 with
Laura Avagliano and Valentina Massa contributed equally to this study.
down from 10 per 1,000 for years 2000–2004) (Blencowe,
Kancherla, Moorthie, Darlison, & Modell, 2018; Khoshnood
et al., 2015; Liu et al., 2016; Salih, Murshid, & Seidahmed,
2014). Despite their public health significance, surprisingly
little is known about the etiology of NTDs in humans.
The central nervous system (brain and spinal cord) is
formed in vertebrates during a process known as neurulation.
This process occurs in human embryos between Days
17 and 28 postfertilization. In the previous developmental
phase (gastrulation), the ectoderm is formed, which will
thicken in response to specific molecular signals released by
the underlying notochord, giving rise to the neural plate.
This plate of ectodermal cells will form the neural tube by
elevating, juxtaposing and fusing along the midline (primary

Birth Defects Research. 2019;111:1455–1467. wileyonlinelibrary.com/journal/bdr2 © 2018 Wiley Periodicals, Inc. 1455
1456
FIGURE 1 (a) Transverse section of normal fetal vertebra with typical spinal cord section. (b) Craniorachischisis. Note the absence of the cranial vault, the
defect extends to vertebral arch into upper dorsal area, resulting in anencephaly and spina bifida
neurulation) of the body axis. In the caudal region, neurula-
tion (secondary) involves cellular condensation and
mesenchymal-to-epithelial transition to close the neural tube
(Saitsu, Yamada, Uwabe, Ishibashi, & Shiota, 2004). In
mammals, primary neurulation is a multisite process and
recent evidence suggest that in humans two closure sites are
recognizable (one at the prospective cervical region and one
over the mesencephalon-rombencephalic boundary; Copp,
Stanier, & Greene, 2013; Nakatsu, Uwabe, & Shiota, 2000).
Mammalian neurulation is tightly regulated and energetically
highly demanding, involving the formation of an anterior
and posterior neuropore. These neuropores or openings will
progressively reduce in size until final fusion completes the
process of neural tube closure (Figure 1).
Different types of NTDs reflect the site of the interrupted
neurulation. For example, craniorachischisis, which affects
the brain and spinal cord, results from a failure of the initial
closure site resulting in an open brain and spine, while anen-
cephaly arises from abnormalities in the cranial neurulation
process, and spina bifida results from incomplete caudal
neurulation.
2 | EPIDEMIOL O GY AND R ISK FACT O RS
Chromosomal anomalies such as trisomy 13, trisomy
18, and triploidy represent less than 10% of all NTDs cases
(Kennedy, Chitayat, Winsor, Silver, & Toi, 1998), while
nonsyndromic-isolated cases represent the vast majority of
NTDs, exhibiting a sporadic pattern of occurrence (Copp
et al., 2015). The prevalence of the different types of NTDs
is not always reported in publications, given the difficulties
in data ascertainment following legal pregnancy terminations
and spontaneous abortions. The prevalence of NTDs in mis-
carriage or stillbirths appears higher than in term pregnancies
(Padmanabhan, 2006), and the estimated prevalence reflects
temporal, regional, and ethnic variations (Blom, Shaw, den
AVAGLIANO ET AL.
Heijer, & Finnell, 2006; Wallingford, Niswander, Shaw, &
Finnell, 2013). For example, the NTD prevalence in Mexico
(~3.2 in 2,000 births) is higher than in the United States
(CDC in 2000), while the prevalence in some regions of
China are 20 times higher than in the United States (Li et al.,
2006). Interestingly, the different prevalence of NTD cases
between ethnic groups persists after migration of the racial
groups to other geographical areas, indicating a genetic con-
tribution to NTD susceptibility (Leck, 1974; Shaw, Velie, &
Wasserman, 1997).
In terms of genetic predisposition, women who have had
an affected fetus have an empirical recurrence risk of 3% in
any subsequent pregnancy, yet this risk only rises to approx-
imately 10% after conceiving a second NTD embryo (Copp
et al., 2015). This underscores the fact that while genetic fac-
tors are important, one cannot ignore the impact of the envi-
ronment on the development of the NTD phenotype. In
twins, the NTDs’ concordance rates among monozygotics is
reported to be 7.7%, significantly higher than the rate for
dizygotic twins (4.4%).
Finally, a gender predisposition has been reported for
some types of NTDs: a female excess has been reported for
neural tube defects, possibly because of a sex-related genetic
or epigenetic effect. Despite the decades long attempts to
elucidate genetic factors causative of NTDs in humans, no
conclusive evidence has been identified. In studies based on
vertebrate animal models, a great number of genes have been
implicated in the causation of NTDs. In the mouse, for
example, more than 400 genes have been found responsible
for failed NTC (Harris & Juriloff, 2010; Wallingford et al.,
2013). Some of these genes are highly evolutionarily con-
served, and their role in neurulation has been shown in mul-
tiple vertebrate animal models (Wallingford, 2005). In
humans, cohort studies of NTDs, genetic variants have been
associated with increased risk (Greene, Stanier, & Copp,
2009). However, some variants are present in different
AVAGLIANO ET AL. 1457

TABLE 1 Modifiable risk factors for NTDs

Risk factor Action Risk References

Maternal diabetes Teratogenic effect as a result of embryonic
exposure to high glucose concentrations leading
to increased cell death in the neuroepithelium
Maternal obesity Teratogenic effect as a result of embryonic
exposure to hyperinsulinemia, metabolic
syndrome, and oxidative stress related to
adiposity
Maternal hyperthermia Teratogenic effect due to embryonic exposure to
(sauna, hot water tube, heat stress
fever)
Drugs (particularly Teratogenic effect as a result of embryonic
valproate) exposure to valproate action as inhibitor of
histone deacetylases, disturbing the balance of
protein acetylation and deacetylation, leading to
neurulation failure
Inadequate maternal Teratogenic effect as a result of embryonic
nutritional status exposure to low folate intake, low methionine
intake, low zinc intake, low serum vitamin B12
level, low vitamin C level, caffeine abuse,
alcohol use, smoking, all conditions disturbing
the folate-related metabolism
2- to 10-fold increase
1.5-to 3.5-fold increase.
The risk increases with increased
maternal body mass index
2-fold increase
10-fold increase
Undetermined
Ray (2001), Shaw et al. (2003), and
Yazdy, Mitchell, Liu, and Werler
(2011)
Anderson et al. (2005), Carmichael,
Rasmussen, Lammer, Ma, and
Shaw (2010), Dietl (2005),
Hendricks, Nuno, Suarez, and
Larsen (2001), Shaw, Velie, and
Schaffer (1996), and Werler, Louik,
Shapiro, and Mitchell (1996)
(Moretti, Bar-Oz, Fried, & Koren,
2005; Suarez, Felkner, &
Hendricks, 2004; Waller et al.,
2017)
Kanai, Sawa, Chen, Leeds, and
Chuang (2004), Lammer, Sever,
and Oakley (1987), Meador
et al. (2006), Pai et al. (2015), and
Yildirim et al. (2003)
Grewal, Carmichael, Ma, Lammer,
and Shaw (2008), Kirke
et al. (1993), Ray and Blom (2003),
Schmidt et al. (2009), Suarez,
Hendricks, Felkner, and Gunter
(2003), and Velie et al. (1999))

NTDs subtypes and some have also been reported in healthy
patients, highlighting the difficulties of finding a clear geno-
type/phenotype association in humans.
Many factors, both genetic and non-genetic, are
involved in the abnormal closure of the neural tube, sug-
gesting that multifactorial causes lead to the development
of NTDs (Copp et al., 2015). It is likely that each factor
individually is insufficient to disrupt normal NTC; how-
ever, together these genetic and nongenetic factors produce
synergistic effects leading to failed NTC and the abnormal
embryonic phenotype. This working hypothesis represents
the so-called “multifactorial threshold model” (Harris &
Juriloff, 2007).
Nongenetic risk factors include exposure to a broad
range of environmental exposures such as air pollution
(Brender, Felkner, Suarez, Canfield, & Henry, 2010; Carmi-
chael et al., 2014; Cordier et al., 1997; Hutchins et al., 1996;
Zhiwen Li et al., 2011; Lupo et al., 2011; Padula et al.,
2013; Ren et al., 2011; Righi et al., 2012) and maternally
toxic factors including disease, nutrition, exposure to occu-
pational chemicals or physical agents and abuse of substance
(Table 1).
3 | PHYSICAL CHARACTERISTICS OF
N EUR AL TU BE D EFE CTS
NTDs have been classically divided into open defects such
as craniorachischisis, exencephaly-anencephaly, and myelo-
meningoceles, and closed defects, including encephalocele,
meningocele, and spina bifida occulta (Copp & Greene,
2013; McComb, 2015). In general, open defects are
characterized by the external protrusion and/or exposure of
neural tissue. Closed defects have an epithelial covering
(either full or partial skin thickness) without exposure of
neural tissue (McComb, 2015). Biochemically, during preg-
nancy, open defects are detectable because of the high levels
of amniotic fluid α-fetoprotein and amniotic fluid acetylcho-
linesterase, whereas closed defects do not deviate from nor-
mal levels of amniotic fluid α-fetoprotein or
acetylcholinesterase. Clinically, open defects trend toward
having worse functional neurological outcomes in children,
compared to closed defects.
3.1 | Open neural tube defects
3.1.1 | Craniorachischisis
Definition
Craniorachischisis is a defect of NTC that involves both
the cranial and spinal portions of the neural tube (Golden &
Harding, 2004). It is the most severe expression of an
open NTD.
Epidemiology
This is a very rare congenital malformation of the central
nervous system whose actual prevalence is not known.
Reported prevalence is about 0.1 per 10,000 live births for
cases of 20 weeks gestation or greater in Atlanta, a preva-
lence that had been adjusted upward 30% to account for pre-
natal terminations (Moore et al., 1997); 0.51 per 10,000
births in a Texas–Mexico border population whose preva-
lence ascertainment included prenatal terminations (Johnson,
Suarez, Felkner, & Hendricks, 2004); 10.7 per 10,000 births
in Northern China; and 0.9 per 10,000 births in Southern
China (Moore et al., 1997).
1458
Gross dysmorphology
The neural tube is open from the midbrain to the spine.
The defect of the skull and vertebral arch results both in
anencephaly and an open spina bifida (Figure 1). Fetuses
show absence of the cranial vault, with the defect extending
with various degree to the vertebrae. The neck may be short
or absent, facial dysmorphisms may be present and include a
broad nose, exopthalamos, low-set and folded ears. Typi-
cally, posterior telencephalon, hindbrain, and spinal cord tis-
sue are externally exposed.
Histology
In these cases, both the brain and the spinal cord are
exposed to the intra-amniotic environment resulting in
destruction of the nervous tissues because of the inherent
toxicity of the amniotic fluid. The same histological charac-
teristics of anencephaly and myelomeningocele are detect-
able in these specimens (see below).
Prenatal diagnosis
Absence of the cranial vault and spinal dysraphism is
detectable by ultrasound. A disorganized mass of cerebral
tissue is visible and cervical hyperextension may also be
observed. Differential diagnosis includes: nuchal tumors
(such as teratomas and lymphangiomas), Klippel–Feil syn-
drome (a disease caused by a failure of segmentation of the
cervical vertebrae during early fetal development), and
Jarcho–Levin syndrome, also known as spondylocostal dys-
ostosis, an autosomal recessive disorder characterized by a
shortened trunk, opisthotonus position of the head, short
neck, barrel-shaped thorax, multiple wedge-shaped and
block vertebrae, spina bifida, and rib anomalies
(Chen, 2007).
Prognosis
Craniorachischisis is a lethal condition: there is no cure
or surgical intervention and the death of the newborn is
unavoidable.
3.1.2 | Anencephaly
Definition
When the primary defect involves failure to close just
the cranial portion of the neural tube, the defect is refered to
as exencephaly (anencephaly). The degeneration of the
cerebral-neural tissues because of the destructive exposure
of the brain to the intra-amniotic environment converts the
exencephaly defect to anencephaly (Golden & Harding,
2004; Timor-Tritsch, Greenebaum, & Monteagudo, 1996;
Wilkins-Haug & Freedman, 1991).
Epidemiology
The Center for Disease Control and preventin (CDC)
estimates that each year, about 3 pregnancies per every
10,000 births in the United States will be affected by
anencephaly.
Gross dysmorphology
Anencephaly is a defect in which there is absence of the
structures derived from the forebrain and the skull. The
AVAGLIANO ET AL.
calvarium is generally absent, the parietal, frontal, and
squama of the temporal and occipital bones appears as rudi-
mentary fragments; the base of the skull is nearly normal
(Goldstein & Filly, 1988) but is thick and flattened; the
sphenoidal bone is abnormally shaped (Golden & Harding,
2004) resembing a “bat with folded wings” (Marin-Padilla,
1965). The facial bones appear normal, and the face is gener-
ally normally structured (Figure 2), although the eyes often
appear to protrude because of the shallowness of the orbits
and the forehead is absent or shortened. Moreover, other
associated facial abnormalities have been reported such as
flattened nasal bridge and low-set ears (Stumpf et al., 1990).
The brain remnants is called the area cerebrovasculosa
(Figure 2). Its macroscopic aspect appears as a dark-brown
undifferentiated mass (Anand, Javia, & Lakhani, 2015); the
residual amount of brain tissues varies, generally there is an
absence of the structures of the forebrain (both diencephalon
and telencephalon structures including thalamus and cere-
brum) and midbrain, whereas the brainstem may appear to
have been spared, or less severely involved. The pituitary is
present but it is hypoplastic and without the intermediate and
posterior lobes.
Histology
The residual cerebral tissue appears as an irregular mass
containing vascular tissue, glia, and some neuroblasts or
neurons surrounded by meninges (Golden & Harding, 2004)
although some authors failed to find neurons in the area cer-
ebrovasculosa (Ashwal et al., 1990). The overview shows a
poorly structured mass consisting of blood vessels (Figure 2)
scattered with connective tissue and islets of nervous tissue
including interspersed astroglial cells, nerve cells, and cavi-
ties surrounded by the epithelium (Anand et al., 2015). The
exposed cerebral area is covered by nonkeratinizing squa-
mous epithelium that laterally is continuous with epidermis
(Figure 2) (Golden & Harding, 2004). Interestingly, even
though there is a severe rostral neural tube abnormality, the
spinal cord in the anencephalic foetuses appears structurally
normal (Anand et al., 2015).
Prenatal diagnosis
The diagnosis is primarily based on the absence of a nor-
mally formed calvarium and the brain above the orbital line
(Goldstein & Filly, 1988). The area cerebrovasculosa may
be detected as fluctuant echogenic tissue. Often polyhydram-
nios are present. The differential diagnosis between anen-
cephaly and other causes of an absence of the cranial vault
may include cases of head destruction related to amniotic
bands (Stumpf et al., 1990). This distinction is very impor-
tant for counseling families, because the destruction related
to amniotic bands represents a sporadic event which would
have a very low recurrence risk, whereas the presence of
anencephaly increases the risk of occurrence of another
NTD in any subsequent pregnancy. The differential diagno-
sis between these two entity with an of absence of the cranial
vault relies on the presence or absence of othe malformations
AVAGLIANO ET AL. 1459

FIGURE 2 Macroscopic and histologic features of anencephaly. The cranial vault is absent, the brain is not covered with the bones, the skin is in continuity
with the nervous tissue, and the nervous tissue, called area cerebrovasculosa, is a mass of degenerated tissue. Histologically the typical aspect of area
cerebrovasculosa are shown with the enlarged venous vessels with various dimension immersed in nervous tissues

as anencephalic infants are usually isolated with no other
associated malformations. Moreover, the cranial defect in
cases of amniotic bands syndrome is asymmetric, whereas in
the case of anencephaly it is symmetric (Goldstein & Filly,
1988; Keeling & Kjaer, 1994).
Prognosis
Anencephaly is a lethal condition. Detection of anen-
cephaly during early gestation is generally followed by legal
interruption of the pregnancy. In cases of pregnancies that
continue to term, most anencephalic newborns die within the
first day or two postparturition (Stumpf et al., 1990).
3.1.3 | Myelomeningocele
Definition
In myelomeningocele, the developmental defect involves
the failure to close the posterior spinal portion of the neural
tube, more frequently the lumbar portion is the region which
fails to fuse. In this defect, the meningeal sac herniates
through a bony defect of the vertebral arch (Figures 3 and
4). In some cases, a clear open defect that involves the spinal
cord, but without a protruding meningeal sac, is defined as a
myelocele. Therefore, a myelocele is an open defect without
the cystic component (Figure 3 and 4).
Epidemiology
It is the most common form of spina bifida aperta in
humans, with an estimated incidence according to the CDC
of 1.8 per 10,000 live births in the United States.
Gross dysmorphology
In myelomeningocele, a cystic mass protruding though a
bony defect in the vertebral arches is detectable. The size
and shape of the lesion can vary significantly and may
include cerebrospinal fluid drainage. The neural tissues
appears translucent through the protruded meningeal sac and
the neural placode, a segment of flat, nonneurulated embry-
onic neural tissue, is externally shown and protrudes above
skin surface (Figure 4). In case of myelocele, the cystic mass
is absent and the neural tissue is clearly detectable though
the vertebral cleft and the placode is flush with the surface
of the skin (Figure 4). The spinal cord above the defect may
be distorted in position and shape, but it is not overtly mal-
formed (Emery & Lendon, 1973; Naik & Emery, 1968).
Myelomeningocele and myelocele are usually associated
with Chiari malformation Type II (Figures 4 and 5) because
1460 AVAGLIANO ET AL.

FIGURE 3 Macroscopic and histologic aspect of myelocele (upper panel) and myelomeningocele (lower panel). In myelocele, the foetus presented a clear
open defect in the lumbar-sacral region. The spinal cord is displayable in the depth of the cleft. The defect is open, and no meningeal sac is protruding. The
histological sections show the bone defect of the vertebral arches and the exposed spinal cords. In this case, the spinal cord is not closed in its typical shape
but is divided in two halves appearing as an “open book.” The remnant of the ependymal layer is visible at the surface, covering the center of the two halves.
In myelomeningocele, the foetus presented a clear meningeal cystic sac that contains cerebro-spinal fluid and nervous tissue. Note the translucent appearance
of the nervous tissue. The histological sections show the protrusion of the medulla through the bone defect of the vertebral arches. Meninges are also
herniated forming the cystic mass

FIGURE 4 Schematic representations of central nervous system appearance in normal foetus, meningocele, myelomeningocele, and myelocele. In
meningocele, meninges are displaced through a bone defect of the vertebral arches; spinal cord is not involved in the protrusion and the brain is normal. In
cases with myelocele and myelomeningocele, the neural tube defect is associated with Chiari malformation Type II, characterized by the herniation of
cerebellar vermis through the foramen magnum
AVAGLIANO ET AL. 1461

FIGURE 5 Prenatal signs of open neural tube defects. Differences between the normal fetus and fetus affected by open neural tube defects are shown. Note
the appearance of the transverse section of cerebellum at the ultrasound scan in normal fetus (typical butterfly shape) and the appearance of the herniated
cerebellum in Chiari malformation Type II (characteristic banana shape, asterisk). Note also the appearance of the transverse section of the skull comparing
the shape of the normal fetus with the lemon shaped skull of the NTD fetus. Lemon sign represents the scalloping of the frontal bones (arrows)

of the traction of the brain stem from below as a result of
tethering of the open spinal cord through the vertebral
defect. Indeed, the brain stem is elongated, there is caudal
elongation of the medulla and the fourth ventricle, cerebellar
vermis is displaced into the foramen magnum (Figures 4
and 5). As a result, the normal flow of cerebrospinal fluid
through the ventricles is compromized, resulting secondarily
in hydrocephalus. There is also an abnormal orientation of
the cervical nerve roots that lack their usual downward obli-
que orientation. Moreover, in these cases, the cerebellum
appears smaller than the normal dimension and presents an
altered contour (Del Bigio, 2010).
Histology
The meningeal cystic sac contains cerebrospinal fluid,
nerve roots and spinal cord. Both spinal cord and meninges
are damaged and displaced through the bony opening
(Figure 3). Histologically, the medulla is generally hyper-
vascularized and abnormal: in some cases the spinal cord
could be closed with dilated central canal, while in other
cases the spinal cord appears open as a flat mass
(Golden & Harding, 2004). In Chiari malformation Type
II, the cerebellar structure appears modified because of its
flattened elongation that extend downward below the level
of the foramen magum: the structure may be atrophied
with decreased neurons and chronic astroglial changes
(Del Bigio, 2010). Historical studies based on cell count
demonstrated that in these cases, the central lobes of the
cerebellum develop normally but subsequently acquire an
irregular degeneration and arrest of growth (Emery &
Gadsdon, 1975). This cerebellar local atrophy might
depend on local ischemia (Poretti, Prayer, & Boltshau-
ser, 2009).
Prenatal diagnosis
The detection rate of this type of open spina bifida by
ultrasound is very high (virtually 100%) thanks to the indi-
rect cranial signs including the “lemon” and the “banana”
sign (Figure 5) (Nicolaides, Gabbe, Campbell, & Guidetti,
1986). The lemon sign describes the shape of the skull and
represents the scalloping of the frontal bones: loss of the
convex outward shape of the frontal bones with mild flatten-
ing. It is present in virtually all fetuses with myelomeningo-
cele between 16 and 24 weeks of gestation. The banana sign
describes the shape of the cerebellum and is because of the
downward traction of the cerebellum, most likely related to
the leakage of spinal fluid from the open spinal defect. Foe-
tal repair of myelomeningocele has been shown to reverse
the cerebellar and brainstem displacement (Adzick
et al., 2011).
Direct findings of open spina bifida may be also detected
by ultrasound or fetal MRI: sections of the spine demon-
strates vertebral dysraphism with an associated fluid-filled
posterior bulging of meninges forming the cystic sac often
containing internal septations. Sometimes spinal dysraphism
without posterior cyst may be observed; this is the case of
myelocele. During pregnancy, a progressive deterioration of
leg movements may be observed due to the damage of the
spinal cord and nerves. Clubfoot, which is a deformity char-
acterized by abnormal foot position in which the foot is
internally rotated, is virtually always detectable.
Prognosis
In the absence of other additional serious congenital mal-
formations, newborns with myelomeningocele or myelocele
survive with various degree of neurological impairment.
Although controversial, cesarean section may be indicated to
1462 AVAGLIANO ET AL.

prevent additional neurological defects related to the mode

of delivery (Thompson, 2009). Clinical characteristics
depend on the level of the lesion: motor and sensorial deficit
occur at levels below the spinal lesion and may be associated
with bladder and rectal incontinence (Golden & Harding,
2004) and sexual dysfunction (Thompson, 2009). Intellec-
tual disability is relatively infrequent (20%–25% of cases)
and generally related to hydrocephalus (Copp et al., 2015).
According to the results of the Management of Myelomenin-
gocele Study (MOMS) trial, to improve the prognosis of the
affected foetuses, predelivery surgical solutions may be
offered in selected cases, performing an in utero surgical
intervention. In fact, the results of the MOMS study show
that surgery performed prior to 26 weeks of gestation may
preserve neurologic function, reverse the hindbrain hernia-
tion of Chiari II malformation, and decrease the need to
place postnatally a ventriculo-peritoneal shunt (Adzick et al.,
2011). However, the prenatal surgery increases the risk of
premature rupture of the membranes and preterm delivery
(Adzick et al., 2011).

3.2 | Closed neural tube defects

3.2.1 | Encephalocele
Definition
Encephalocele is a herniation such as a sac-like protru-
sion of the brain and/or the meninges through an opening in
the skull. According to the type of tissue involved in the her-
niation, cephaloceles are classified as meningocele (hernia-
tion of meninges), encephalomeningocele (herniation of
meninges and brain), and encephalomeningocystocele (her-
niation of meninges, brain, and ventricle) (Figure 6; Pilu,
Buyukkurt, Youssef, & Tonni, 2014).
Epidemiology
CDC estimates that each year about 1 out of every
10,000 babies are born with an encephalocele in the United
FIGURE 6 Type and site of cephalocele. Upper panel shows a schematic
States.
representation of possible cephalocele localization. Middle panel shows a
Gross dysmorphology
schematic representation of different type of cephalocele classified
Encephaloceles can occur in any part of the cranial vault; according to the content of the herniated mass. Lower panel shows
cystic mass passes through a cleft of the calvarium squamae macroscopic aspect of human fetuses affect by cephalocele
and approximately 90% of cases involve the midline.
According to the site of the herniation, encephaloceles are types. Basal encephaloceles are internal lesions which occur
classified as: anterior, with lesion located between the within the nose, the pharynx, or the orbit. They are normally
bregma and the anterior aspect of the ethmoid bone; parietal, classified into three types: spheno-orbital, spheno-maxillary,
with lesion located between the bregma and the lambdoid and spheno-pharyngeal (Pilu et al., 2014).
suture; and occipital, with lesion located between the lamb- The occipital encephalocele may occur in association
doid suture and foramen magnum (Figure 6). This location with a Chiari III malformation. The Chiari Type III malfor-
is the most common, involving almost 75% of all mation is characterized by occipital and/or high cervical
encephaloceles. encephalocele associated with caudal displacement of the
The anterior encephalocele is further subclassified into lower brain stem into the spinal canal and herniation of the
frontal, sincipital, and basal varieties, according to the locali- cerebellar tissues into the herniated sac.
zation of the defect. The frontal encephaloceles are external The macroscopic aspect of the encephalocele is a round,
lesions that cause craniofacial abnormalities and are typi- soft, compressible nodule with subscalp localization
cally found near the glabella, the root of the nose. They are (Figure 6; Gao, Massimi, Rogerio, Raybaud, & Di Rocco,
subdivided into naso-frontal, naso-ethmoid, and naso-orbital 2014). The mass may appear solid or cystic according to the
AVAGLIANO ET AL.
content of the herniation, and it is generally covered by alo-
pecic skin that could be surrounded by a ring of hair deter-
mining the so called “hair collar signs” (Gao et al., 2014),
although sometimes hypertrichosis may be present over the
lesion (Sewell, Chiu, & Drolet, 2015). Sometimes the sur-
face of encephalocele appears bluish, translucent or glisten-
ing, and capillary malformations are detectable (Sewell
et al., 2015)
As a result of its patent intracranial communication,
encephaloceles modify its dimension (enlargement/reduc-
tion) with the modification of intracranial pressure: it
enlarges during increase of pressure such as during Valsalva
maneuver (Sewell et al., 2015) including crying and suction.
Histology
Solid variants results from the proliferation of neuroglial
and fibrous tissues and hyperplasia of the meningeal cells.
The herniated mass may contain various types of tissues
including cerebral and cerebellar portion, ventricles with
choroid plexus, gray matter heterotopias. Brain tissues
involved in the herniation are generally nonfunctional and
appears abnormal with gliosis, necrosis, reactive astrocyto-
sis. Meningeal inflammation has been detectable (Castillo,
Quencer, & Dominguez, 1992; Isik, Elmaci, Silav, Celik, &
Kalelioglu, 2009; Ivashchuk, Loukas, Blount, Tubbs, &
Oakes, 2015). Aberrant deep veins and ectopic venous
sinuses are also often observed (Ivashchuk et al., 2015).
Cystic variants contain cerebro-spinal fluid (Gao
et al., 2014).
Prenatal diagnosis
A sac protruding through a bony defect may be detected
by ultrasound. Associated brain abnormalities may include
cerebral ventriculomegaly and microcephaly (Cameron &
Moran, 2009). In case of a Chiari III malformation, a pro-
trusion through a defect of the occipital squama and or the
arch of the first cervical vertebra may be observed, associ-
ated with a small posterior cranial fossa with low tentorial
attachment, scalloping of the clivus and herniation of the
cerebellum into the defect and hydrocephalus (Caldarelli,
Rea, Cincu, & Di Rocco, 2002; Ivashchuk et al., 2015). In
the absence of identifying a skull defect, the differential
diagnosis includes a wide range of craniofacial mass,
according to the site of the lesion, such as a teratoma, a lyn-
phangiona, a haemangioma, nasolacrimal duct cyst, neuro-
glia heterotopia, lipoma (Cameron & Moran, 2009;
Connor, 2010).
Prognosis
Clinical characteristic depends on the localization and
content of the herniated mass. The more rostral the site, the
better the prognosis (Thompson, 2009). Moreover, the
underlying brain involvement and hydrocephalus affects the
prognosis. In cases with mechanical effects of distortion and
traction of the brain stem thought the herniation, various
degree of developmental delay, epilepsy and motor and sen-
sorial nerve dysfunction may occur (Caldarelli et al., 2002;
1463
Gao et al., 2014). The treatment of encephaloceles requires a
surgical correction.
3.2.2 | Meningocele
Definition
Although macroscopically similar to a myeolomeningo-
cele (Figure 3), meningocele is a closed spina bifida, compa-
rable to encephalocele, whereby the defect consists in
herniation of meninges through the vertebral column.
Although the herniation of the meninges through the verte-
bral arch defect, the spinal cord resides within the spinal
canal (McComb, 2015). Differences between meningocele,
myeolomeningocele and myelocele are summarized in
Table 2.
Epidemiology
The actual incidence of meningoceles is unknown.
Gross dysmorphology
In meningocele, the dura and the arachnoid herniate
through the vertebral arch defect whereas the spinal cord
remains in the normal position into the spinal canal. The her-
niated mass is covered by skin that is characterized by atro-
phic epidermis without skin appendages (Golden & Harding,
2004). Sometimes the skin may display different degree of
dysplasia (McComb, 2015). The lesion is peduncolated to
varying degrees and is generally easily compressible and
well transilluminable.
Histology
A protrusion in continuity with epidermal tissue is
detectable. The protruded mass is formed by extremely thick
meninges and generally contains vascularized stromal tissue.
The surface of the herniated mass generally does not pre-
sented skin appendages.
Prenatal diagnosis
By ultrasound may be seen spinal dysraphism with an
associated cystic mass. The characteristics of the cystic mass
are comparable with that of the myelomeningocele, although
they lack septa in the herniated mass, and the cranial anat-
omy is unremarkable (Ghi et al., 2006).
Prognosis
Cases with meningocele generally have normal neuro-
logic examination without deformity of the lower extremities
or sphincter dysfunction (McComb, 2015). The treatment of
meningocele is a surgical correction.
3.2.3 | Spina bifida occulta
Definition
Spina bifida occulta represents a spectrum of a spinal
cord abnormalities related to abnormal development of the
embryonic tail bud. The defect involves the low lumbar
and sacral regions, and results in closed defects with
incomplete vertebral arches. Spina bifida occulta is often
associated with other skeletal defects including sacral
agenesis.
1464 AVAGLIANO ET AL.

TABLE 2 Differential diagnosis among meningocele, myelomeningocele, and myelocele

Meningocele Myelomeningocele Myelocele

Type of defect Closed Open Open
Ultrasound aspects
Posterior anechogenic cystic mass (sac-like protrusion) from the spine + + −
Presence of septa in the sac − + //
Abnormality of vertebral bones (absence of the arches) + + +
Abnormal shape of skull (lemon sign) − + +
Abnormal shape of cerebellum (banana sign) − + +
Association with Chiari type II malformation − + +
Association with hydrocephalus − + +
Association with clubfoot − + +
Macroscopic aspects of the lesion
Absence of vertebral arches + + +
Meningeal herniation though the bones defect + + −
Presence of neural tissues in the meningeal sac (medulla and/or nerves) − + //
External exposition of placode − + +
Covered by skin + − −

Although macroscopically similar, meningocele and myelomeningocele represent two opposite types of spina bifida, a closed and open defect, respectively, with differ-
ent prognosis. Because of the similar macroscopic aspect of the herniated sac, prenatal ultrasound differentiation of the cystic lesion may be difficult. In contrast, myelo-
meningocele and myelocele are macroscopically different but they represent the same type of spina bifida, an open defect, with the same clinical implications. The
macroscopic distinction between myelomeningocele and myelocele is based on the location of the neural placode. When the placode is pushed out of the confines of the
canal and through the vertebra, and a cutaneous defect is created by expansion of the subarachnoid space, a myelomeningocele is present. Otherwise, in case of myelo-
cele, the subarachnoid space is not expanded, the placode remains in plane with or deep to the cutaneous surface

Epidemiology
The actual incidence of spina bifida occulta is unknown
(Hertzler, DePowell, Stevenson, & Mangano, 2010).
Gross dysmorphology
The presence of cutaneous stigmata of the low back may
be the only signs of occult spina bifida. Cutaneous markers
include nevi, lumps, depigmented region, subcutaneous lipo-
mas, capillary hemangiomas, hair tufts (localized hypetrico-
sis), and dermal sinus tract (Hertzler et al., 2010; Sewell
et al., 2015). Structural abnormalities may also been detected
such as an asymmetrical gluteal cleft, scoliosis, and leg
length discrepancy.
Prenatal diagnosis
No secondary cranial findings are detectable thus the pre-
natal diagnosis is hard and in such cases is a challenge
(Coleman, Langer, & Horii, 2014). The commonest form of
closed spinal dysraphism detectable in utero is the type asso-
ciated with intradural lipoma. Its aspect may affect the sensi-
tivity of differential diagnosis and the ability of the correct
identification during the prenatal diagnosis: during intra-
uterine life, meningoceles, and lipomas have a very similar
appearance and may be very difficult or impossible to distin-
guish (Pierre-Kahn & Sonigo, 2003). In fact, by ultrasound,
lipomas typically appear as echogenic masses (Ghi et al.,
2006) much like a meningocele. Postnatally, high-resolution
ultrasound may be employed until the sixth month of life,
before the ossification of the vertebral body, but the sensitiv-
ity is low, especially in cases of a subcutaneous mass (Sewell
et al., 2015). The more appropriate diagnostic technique is
magnetic resonance, but this procedure is limited by its cost,
availability, and the need for sedation for many children.
Prognosis
This group of defects represents a less severe form of
malformation: more often, this problem may be detected
only later in life, because nerves and the spinal cord are not
affected and therefore it does not usually result in disabil-
ities. In other cases, spinal cord anomalies may occur and
include hydromyelia (overdistension of the central canal),
diplomyelia (longitudinal duplication of the spinal cord),
diastematomyelia (longitudinal split of the spinal cord), and
tethering of the lower end of the cord (Golden & Harding,
2004). Neurological symptoms start when the damage and/or
traction of the cord occurs. During the intrauterine life, the
spinal cord grows slower than the spinal column. The caudal
spinal cord (also called conus medullaris) reaches its normal
level only after birth, and the symptoms may start through
the extrauterine life when the cord is insulted (Sewell et al.,
2015). Sometimes this occurs in childhood, other times this
occurs later in life, in case of thickening of filum terminale
(increased fibrosis leading to progressive loss of elasticity),
increased physical activity, development of spinal stenosis
or occurrence of lumbar trauma (Hertzler et al., 2010). Neu-
rosurgical intervention is the therapy of choice in cases of
symptomatic patients with neurological deterioration.
4 | P RE VE NT I O N O F N E U RA L T U B E
DE FEC TS
NTDs are known as one of the few birth defects in which
primary preventive strategies are available and effective.
Pioneering studies by Smithells and colleagues in the United
AVAGLIANO ET AL.
Kingdom (Smithells et al., 1980; Smithells, Sheppard, &
Schorah, 1976) showed the importance of vitamin intake
during pregnancy with respect to NTD outcome. Subse-
quently, a randomized double-blind, placebo-controlled trial
was initiated in 1991 by the U.K. Medical Council (MRC
Vitamin Study Research Group, 1991). This study demon-
strated that supplementation with 4 mg folic acid per day
resulted in a threefold reduction in NTD recurrence risk.
Together with several nonrandomized trials, these data indi-
cate that folic acid supplementation during pregnancy in a
dose range of ~0.4 to 5 mg/day prevents NTD births. The
biological and molecular mechanisms of this prevention are
yet to be elucidated, despite the large number of studies con-
ducted using animal studies to test various hypotheses mech-
anistically (Blom et al., 2006), as folate plays a pivotal role
in numerous cellular reactions, including purines and thymi-
dylate production and S-adenosyl-methionine synthesis,
which is the cellular methyl donor used in methylation reac-
tions for DNA, proteins including histones and lipids
(Crider, Yang, Berry, & Bailey, 2012).
Maternal folic acid periconceptional supplementation
strategies have been implemented in a number of countries
(Blom et al., 2006); however, epidemiological studies have
shown that not all NTDs are prevented and a subgroup of
“folic acid-resistant” NTDs still occur (Mosley et al., 2009;
MRC Vitamin Study Research Group, 1991). Among other
possible supplements fundamental for correct NTC, inositol
may represent a tool for those non folate responsive NTDs.
Indeed, in nonrandomszed studies supported by experimen-
tal evidence on animal models (Copp et al., 2013; Greene &
Copp, 1997), inositol supplementation appears to reduce
NTDs recurrence. In a recent randomized, placebo-
controlled trial no recurrence was observed in women sup-
plemented both with folic acid and inositol (Greene et al.,
2016). Larger and statistically powerful studies are expected
to investigate this possible new preventive strategy.
ACKNOWLEDGMENTS
The authors appreciate the financial support of the various
funding agencies that contributed to this effort. R.H.F. was
supported by NIH grants HD081216, HD067244,
HD083809, as well as support from the March of Dimes
(16-FY16-169). V.M. was supported by Università degli
studi di Milano grant (Linea 2-2017).
CONFLICT OF INTEREST
There is no conflict of interest to be disclosed.
ORCID
Valentina Massa https://orcid.org/0000-0003-2246-9515
1465
REFERENCES
Adzick, N. S., Thom, E. A., Spong, C. Y., Brock, J. W. 3rd, Burrows, P. K.,
Johnson, M. P., … Farmer, D. L. (2011). A randomized trial of prenatal ver-
sus postnatal repair of myelomeningocele. The New England Journal of
Medicine, 364(11), 993–1004. http://doi.org/10.1056/NEJMoa1014379
Anand, M. K., Javia, M. D., & Lakhani, C. J. (2015). Development of brain and
spinal cord in anencephalic human fetuses. Anatomy, 9(2), 60–65.
Anderson, J. L., Waller, D. K., Canfield, M. A., Shaw, G. M., Watkins, M. L., &
Werler, M. M. (2005). Maternal obesity, gestational diabetes, and central
nervous system birth defects. Epidemiology, 16(1), 87–92. http://doi.org/10.
1097/01.ede.0000147122.97061.bb
Ashwal, S., Peabody, J. L., Schneider, S., Tomasi, L. G., Emery, J. R., &
Peckham, N. (1990). Anencephaly: Clinical determination of brain death and
neuropathologic studies. Pediatric Neurology, 6(4), 233–239. http://doi.
org/10.1016/0887-8994(90)90113-F
Blencowe, H., Kancherla, V., Moorthie, S., Darlison, M. W., & Modell, B.
(2018). Estimates of global and regional prevalence of neural tube defects
for 2015: A systematic analysis. Annals of the New York Academy of Sci-
ences. http://doi.org/10.1111/nyas.13548
Blom, H. J., Shaw, G. M., den Heijer, M., & Finnell, R. H. (2006). Neural tube
defects and folate: case far from closed. Nature Reviews. Neuroscience, 7(9),
724–31. http://doi.org/10.1038/nrn1986
Brender, J. D., Felkner, M., Suarez, L., Canfield, M. A., & Henry, J. P. (2010).
Maternal pesticide exposure and neural tube defects in Mexican Americans.
Annals of Epidemiology, 20(1), 16–22. http://doi.org/10.1016/j.annepidem.
2009.09.011
Caldarelli, M., Rea, G., Cincu, R., & Di Rocco, C. (2002). Chiari type III mal-
formation. Child’s Nervous System, 18(5), 207–210. http://doi.org/10.1007/
s00381-002-0579-y
Cameron, M., & Moran, P. (2009). Prenatal screening and diagnosis of neural
tube defects. Prenatal Diagnosis. http://doi.org/10.1002/pd.2250
Carmichael, S. L., Rasmussen, S. A., Lammer, E. J., Ma, C., & Shaw, G. M.
(2010). Craniosynostosis and nutrient intake during pregnancy. Birth Defects
Research. Part A, Clinical and Molecular Teratology, 88(12), 1032–1039.
http://doi.org/10.1002/bdra.20717
Carmichael, S. L., Yang, W., Roberts, E., Kegley, S. E., Padula, A. M.,
English, P. B., … Shaw, G. M. (2014). Residential agricultural pesticide
exposures and risk of selected congenital heart defects among offspring in
the San Joaquin Valley of California. Environmental Research, 135,
133–138. http://doi.org/10.1016/j.envres.2014.08.030
Castillo, M., Quencer, R. M., & Dominguez, R. (1992). Chiari III malformation:
Imaging features. American Journal of Neuroradiology, 13(1), 107–113.
Chen, C. P. (2007). Prenatal diagnosis of iniencephaly. Taiwanese Journal of
Obstetrics and Gynecology. http://doi.org/10.1016/S1028-4559(08)60021-2
Coleman, B. G., Langer, J. E., & Horii, S. C. (2014). The diagnostic features of
spina bifida: The role of ultrasound. Fetal Diagnosis and Therapy, 37,
179–196. http://doi.org/10.1159/000364806
Connor, S. E. J. (2010). Imaging of skull-base cephalocoeles and cerebrospinal
fluid leaks. Clinical Radiology. http://doi.org/10.1016/j.crad.2010.05.002
Copp, A. J., Adzick, N. S., Chitty, L. S., Fletcher, J. M., Holmbeck, G. N., &
Shaw, G. M. (2015). Spina bifida. Nature Reviews, Disease Primers, 1.
Copp, A. J., & Greene, N. D. E. (2013). Neural tube defects-disorders of neurula-
tion and related embryonic processes. Wiley Interdisciplinary Reviews:
Developmental Biology. http://doi.org/10.1002/wdev.71
Copp, A. J., Stanier, P., & Greene, N. D. E. (2013). Neural tube defects: Recent
advances, unsolved questions, and controversies. The Lancet Neurology.
http://doi.org/10.1016/S1474-4422(13)70110-8
Cordier, S., Bergeret, A., Goujard, J., Ha, M.-C., Aymé, S., Bianchi, F., …
Scarpelli, A. (1997). Congenital malformations and maternal occupational
exposure to glycol ethers. Epidemiology, 8(4), 355–363. http://doi.org/10.
1097/00001648-199707000-00002
Crider, K. S., Yang, T. P., Berry, R. J., & Bailey, L. B. (2012). Folate and DNA
methylation: A review of molecular mechanisms and the evidence for
folate’s role. Advances in Nutrition (Bethesda, Md.), 3(1), 21–38. http://doi.
org/10.3945/an.111.000992
Del Bigio, M. R. (2010). Neuropathology and structural changes in hydrocepha-
lus. Developmental Disabilities Research Reviews. http://doi.org/10.1002/
ddrr.94
Dietl, J. (2005). Maternal obesity and complications during pregnancy. Journal
of Perinatal Medicine. http://doi.org/10.1515/JPM.2005.018
1466
Emery, J. L., & Gadsdon, D. R. (1975). A quantitative study of the cell popula-
tion of the cerebellum in children with myelomeningocele. Developmental
Medicine and Child Neurology. Supplement, (35), 20–25.
Emery, J. L., & Lendon, R. G. (1973). The local cord lesion in neurospinal dys-
raphism (meningomyelocele). The Journal of Pathology, 110(1), 83–96.
http://doi.org/10.1002/path.1711100110
Gao, Z., Massimi, L., Rogerio, S., Raybaud, C., & Di Rocco, C. (2014). Vertex
cephaloceles: A review. Child’s Nervous System. http://doi.org/10.1007/
s00381-013-2249-7
Ghi, T., Pilu, G., Falco, P., Segata, M., Carletti, a, Cocchi, G., … Rizzo, N.
(2006). Prenatal diagnosis of open and closed spina bifida. Ultrasound in
Obstetrics & Gynecology, 28(January), 899–903. http://doi.org/10.1002/uog.
3865
Golden, J. A., & Harding, B. N. (2004). Pathology and genetics: Developmental
neuropathology. Neuropathology and Applied Neurobiology, 31: 452-453.
Goldstein, R. B., & Filly, R. A. (1988). Prenatal diagnosis of anencephaly: Spec-
trum of sonographic appearances and distinction from the amniotic band syn-
drome. American Journal of Roentgenology, 151(3), 547–550. http://doi.
org/10.2214/ajr.151.3.547
Greene, N., & Copp, A. (1997). Inositol prevents folate-resistant neural tube
defects in the mouse. Nature Medicine, 3(1), 60–66. http://doi.org/10.1038/
nm0197-60
Greene, N. D. E., Leung, K.-Y., Gay, V., Burren, K., Mills, K., Chitty, L. S., &
Copp, A. J. (2016). Inositol for the prevention of neural tube defects: A pilot
randomised controlled trial. The British Journal of Nutrition, 1–10. http://
doi.org/10.1017/S0007114515005322
Greene, N. D. E., Stanier, P., & Copp, A. J. (2009). Genetics of human neural
tube defects. Human Molecular Genetics, 18(R2). http://doi.org/10.1093/
hmg/ddp347
Grewal, J., Carmichael, S. L., Ma, C., Lammer, E. J., & Shaw, G. M. (2008).
Maternal periconceptional smoking and alcohol consumption and risk for
select congenital anomalies. Birth Defects Research. Part A, Clinical and
Molecular Teratology, 82(7), 519–526. http://doi.org/10.1002/bdra.20461
Harris, M. J., & Juriloff, D. M. (2007). Mouse mutants with neural tube closure
defects and their role in understanding human neural tube defects. Birth
Defects Research. Part A, Clinical and Molecular Teratology. http://doi.
org/10.1002/bdra.20333
Harris, M. J., & Juriloff, D. M. (2010). An update to the list of mouse mutants
with neural tube closure defects and advances toward a complete genetic per-
spective of neural tube closure. Birth Defects Research. Part A, Clinical and
Molecular Teratology. http://doi.org/10.1002/bdra.20676
Hendricks, K. A., Nuno, O. M., Suarez, L., & Larsen, R. (2001). Effects of
hyperinsulinemia and obesity on risk of neural tube defects among Mexican
Americans. Epidemiology, 12(6), 630–635. http://doi.org/10.
1097/00001648-200111000-00009
Hertzler, D. A., DePowell, J. J., Stevenson, C. B., & Mangano, F. T. (2010).
Tethered cord syndrome: A review of the literature from embryology to adult
presentation. Neurosurgical Focus, 29(July), E1. http://doi.org/10.
3171/2010.3.FOCUS1079
Hutchins, G. M., Meuli, M., Meuli-Simmen, C., Jordan, M. A., Heffez, D. S., &
Blakemore, K. J. (1996). Acquired spinal cord injury in human fetuses with
myelomeningocele. Pediatric Pathology & Laboratory Medicine, 16(5),
701–712.
Isik, N., Elmaci, I., Silav, G., Celik, M., & Kalelioglu, M. (2009). Chiari malfor-
mation type III and results of surgery: a clinical study: Report of eight surgi-
cally treated cases and review of the literature. Pediatric Neurosurgery,
45(1), 19–28. http://doi.org/10.1159/000202620
Ivashchuk, G., Loukas, M., Blount, J. P., Tubbs, R. S., & Oakes, W. J. (2015).
Chiari III malformation: a comprehensive review of this enigmatic anomaly.
Child’s Nervous System. http://doi.org/10.1007/s00381-015-2853-9
Johnson, K. M. K., Suarez, L., Felkner, M. M., & Hendricks, K. (2004). Preva-
lence of craniorachischisis in a Texas-Mexico border population. Birth
Defects Research. Part A, Clinical and Molecular Teratology, 70(2), 92–94.
http://doi.org/10.1002/bdra.10143
Kanai, H., Sawa, A., Chen, R. W., Leeds, P., & Chuang, D. M. (2004). Valproic
acid inhibits histone deacetylase activity and suppresses
excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in
neurons. Pharmacogenomics Journal, 4(5), 336–344. http://doi.org/10.1038/
sj.tpj.6500269
AVAGLIANO ET AL.
Keeling, J. W., & Kjaer, I. (1994). Diagnostic distinction between anencephaly
and amnion rupture sequence based on skeletal analysis. Journal of Medical
Genetics, 31(11), 823–829.
Kennedy, D., Chitayat, D., Winsor, E. J. T., Silver, M., & Toi, A. (1998). Prena-
tally diagnosed neural tube defects: Ultrasound, chromosome, and autopsy or
postnatal findings in 212 cases. American Journal of Medical Genetics,
77(4), 317–321. http://doi.org/10.1002/(SICI)1096-8628(19980526)77:
4<317::AID-AJMG13>3.0.CO;2-L
Khoshnood, B., Loane, M., Walle, H. De, Arriola, L., Addor, M., Barisic, I., …
Dolk, H. (2015). Long term trends in prevalence of neural tube defects in
Europe: Population based study. British Medical Journal, 351, 1–6. http://
doi.org/10.1136/bmj.h5949
Kirke, P. N., Molloy, A. M., Daly, L. E., Burke, H., Weir, D. G., & Scott, J. M.
(1993). Maternal plasma folate and vitamin B12 are independent risk factors
for neural tube defects. The Quarterly Journal of Medicine, 86(11), 703–8.
Lammer, E. J., Sever, L. E., & Oakley, G. P. J. (1987). Teratogen update: Val-
proic acid. Teratology, 35(3), 465–473. http://doi.org/10.1002/tera.
1420350319
Leck, I. (1974). Causation of neural tube defects: Clues from epidemiology. Brit-
ish Medical Bulletin, 30(2), 158–163. http://doi.org/10.1093/oxfordjournals.
bmb.a071187
Li, Z., Ren, A., Zhang, L., Ye, R., Li, S., Zheng, J., … Li, Z. (2006). Extremely
high prevalence of neural tube defects in a 4-county area in Shanxi Province,
China. Birth Defects Research. Part A, Clinical and Molecular Teratology,
76(4), 237–240. http://doi.org/10.1002/bdra.20248
Li, Z., Zhang, L., Ye, R., Pei, L., Liu, J., Zheng, X., & Ren, A. (2011). Indoor
air pollution from coal combustion and the risk of neural tube defects in a
rural population in Shanxi Province, China. American Journal of Epidemiol-
ogy, 174(4), 451–458. http://doi.org/10.1093/aje/kwr108
Liu, J., Zhang, L., Li, Z., Jin, L., Zhang, Y., Ye, R., … Ren, A. (2016). Preva-
lence and trend of neural tube defects in five counties in Shanxi province of
Northern China, 2000 to 2014. Birth Defects Research. Part A, Clinical and
Molecular Teratology, 106(4), 267–274. http://doi.org/10.1002/bdra.23486
Lupo, P. J., Symanski, E., Kim Waller, D., Chan, W., Langlois, P. H.,
Canfield, M. A., & Mitchell, L. E. (2011). Maternal exposure to ambient
levels of Benzene and Neural tube defects among offspring: Texas,
1999-2004. Environmental Health Perspectives, 119(3), 397–402. http://doi.
org/10.1289/ehp.1002212
Marin-Padilla, M. (1965). Study of the skull in human cranioschisis. Acta Anato-
mica (Basel), 62, 1–20.
McComb, J. G. (2015). A practical clinical classification of spinal neural tube
defects. Child’s Nervous System, 31(10), 1641–1657. http://doi.org/10.1007/
s00381-015-2845-9
Meador, K. J., Baker, G. A., Finnell, R. H., Kalayjian, L. A., Liporace, J. D.,
Loring, D. W., … Wolff, M. C. (2006). In utero antiepileptic drug exposure:
Fetal death and malformations. Neurology, 67(3), 407–412. http://doi.org/10.
1212/01.wnl.0000227919.81208.b2
Moore, C. A., Li, S., Li, Z., Hong, S. X., Gu, H. Q., Berry, R. J., …
Erickson, J. D. (1997). Elevated rates of severe neural tube defects in a
high-prevalence area in northern China. American Journal of Medical Genet-
ics, 73(2), 113–118. http://doi.org/10.1002/(SICI)1096-8628(19971212)73:
2<113::AID-AJMG2>3.0.CO;2-V
Moretti, M. E., Bar-Oz, B., Fried, S., & Koren, G. (2005). Maternal hyperthermia
and the risk for neural tube defects in offspring: Systematic review and
meta-analysis. Epidemiology. http://doi.org/10.1097/01.ede.0000152903.
55579.15
Mosley, B. S., Cleves, M. A., Siega-Riz, A. M., Shaw, G. M., Canfield, M. A.,
Waller, D. K., … Hobbs, C. A. (2009). Neural tube defects and maternal
folate intake among pregnancies conceived after folic acid fortification in the
United States. American Journal of Epidemiology, 169(1), 9–17. http://doi.
org/10.1093/aje/kwn331
MRC Vitamin Study Research Group. (1991). Prevention of neural tube defects:
results of the Medical Research Council Vitamin Study. MRC Vitamin Study
Research Group. The Lancet, 338(8760), 131–137. http://doi.org/10.
1016/0140-6736(91)90133-A
NAIK, D. R., & EMERY, J. L. (1968). The position of the spinal cord segments
related to the vertebral bodies in children with meningomyelocele and hydro-
cephalus. Developmental Medicine & Child Neurology, 10, 62–68. http://
doi.org/10.1111/j.1469-8749.1968.tb04848.x
Nakatsu, T., Uwabe, C., & Shiota, K. (2000). Neural tube closure in humans ini-
tiates at multiple sites: Evidence from human embryos and implications for
AVAGLIANO ET AL.
the pathogenesis of neural tube defects. Anatomy and Embryology, 201(6),
455–466. http://doi.org/10.1007/s004290050332
Nicolaides, K. H., Gabbe, S. G., Campbell, S., & Guidetti, R. (1986). Ultrasound
screening for spina bifida: Cranial and cerebellar signs. The Lancet,
328(8498), 72–74. http://doi.org/10.1016/S0140-6736(86)91610-7
Padmanabhan, R. (2006). Etiology, pathogenesis and prevention of neural tube
defects. Congenital Anomalies. http://doi.org/10.1111/j.1741-4520.2006.
00104.x
Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Yang, W.,
Lurmann, F., & Shaw, G. M. (2013). Ambient air pollution and traffic expo-
sures and congenital heart defects in the san joaquin Valley of California.
Paediatric and Perinatal Epidemiology, 27(4), 329–339. http://doi.org/10.
1111/ppe.12055
Pai, Y. J., Leung, K. Y., Savery, D., Hutchin, T., Prunty, H., Heales, S., …
Greene, N. D. E. (2015). Glycine decarboxylase deficiency causes neural
tube defects and features of non-ketotic hyperglycinemia in mice. Nature
Communications, 6. http://doi.org/10.1038/ncomms7388
Pierre-Kahn, A., & Sonigo, P. (2003). Lumbosacral lipomas: In utero diagnosis
and prognosis. Child’s Nervous System, 19(7–8), 551–554. http://doi.org/10.
1007/s00381-003-0777-2
Pilu, G., Buyukkurt, S., Youssef, A., & Tonni, G. (2014). Cephalocele. Visual
Encyclopedia of Ultrasound in Obstetrics and Gynecology - VISUOG.
Poretti, A., Prayer, D., & Boltshauser, E. (2009). Morphological spectrum of pre-
natal cerebellar disruptions. European Journal of Paediatric Neurology.
http://doi.org/10.1016/j.ejpn.2008.09.001
Ray, J. G. (2001). Preconception care and the risk of congenital anomalies in the
offspring of women with diabetes mellitus: A meta-analysis. QJM, 94(8),
435–444. http://doi.org/10.1093/qjmed/94.8.435
Ray, J. G., & Blom, H. J. (2003). Vitamin B12 insufficiency and the risk of fetal
neural tube defects. QJM - Monthly Journal of the Association of Physicians,
96(4), 289–295. http://doi.org/10.1093/qjmed/hcg043
Ren, A., Qiu, X., Jin, L., Ma, J., Li, Z., Zhang, L., … Zhu, T. (2011). Association
of selected persistent organic pollutants in the placenta with the risk of neural
tube defects. Proceedings of the National Academy of Sciences of the United
States of America, 108(31), 12770–5. http://doi.org/10.1073/pnas.
1105209108
Righi, E., Bechtold, P., Tortorici, D., Lauriola, P., Calzolari, E., Astolfi, G., …
Aggazzotti, G. (2012). Trihalomethanes, chlorite, chlorate in drinking water
and risk of congenital anomalies: A population-based case-control study in
Northern Italy. Environmental Research, 116, 66–73. http://doi.org/10.1016/
j.envres.2012.04.014
Saitsu, H., Yamada, S., Uwabe, C., Ishibashi, M., & Shiota, K. (2004). Develop-
ment of the posterior neural tube in human embryos. Anatomy and Embryol-
ogy, 209(2), 107–117. http://doi.org/10.1007/s00429-004-0421-2
Salih, M. A., Murshid, W. R., & Seidahmed, M. Z. (2014). Epidemiology, prena-
tal management, and prevention of neural tube defects. Saudi Medical
Journal.
Schmidt, R. J., Romitti, P. A., Burns, T. L., Browne, M. L., Druschel, C. M., &
Olney, R. S. (2009). Maternal caffeine consumption and risk of neural tube
defects. Birth Defects Research. Part A, Clinical and Molecular Teratology,
85(11), 879–889. http://doi.org/10.1002/bdra.20624
Sewell, M. J., Chiu, Y. E., & Drolet, B. A. (2015). Neural tube dysraphism:
Review of cutaneous markers and imaging. Pediatric Dermatology. http://
doi.org/10.1111/pde.12485
Shaw, G. M., Quach, T., Nelson, V., Carmichael, S. L., Schaffer, D. M.,
Selvin, S., & Yang, W. (2003). Neural tube defects associated with maternal
periconceptional dietary intake of simple sugars and glycemic index. The
American Journal of Clinical Nutrition, 78(5), 972–8.
Shaw, G. M., Velie, E. M., & Schaffer, D. (1996). Risk of neural tube
defect-affected pregnancies among obese women. Journal of the American
Medical Association, 275(14), 1093–1096. http://doi.org/10.1001/jama.275.
14.1093
Shaw, G. M., Velie, E. M., & Wasserman, C. R. (1997). Risk for neural tube
defect-affected pregnancies among women of Mexican descent and White
women in California. American Journal of Public Health, 87(9), 1467–1471.
http://doi.org/10.2105/AJPH.87.9.1467
1467
Smithells, R. W., Sheppard, S., & Schorah, C. J. (1976). Vitamin deficiencies
and neural tube defects. Archives of Disease in Childhood, 51(12), 944–50.
http://doi.org/10.1136/adc.51.12.944
Smithells, R. W., Sheppard, S., Schorah, C. J., Seller, M. J., Nevin, N. C.,
Harris, R., … Fielding, D. W. (1980). Possible prevention of neural-tube
defects by periconceptional vitamin supplementation. The Lancet,
315(8164), 339–340. http://doi.org/10.1016/S0140-6736(80)90886-7
Stumpf, D. A., & The Medical Task Force on Anencephaly. (1990). The infant
with anencephaly. New England Journal of Medicine, 322(10), 669–674.
Suarez, L., Felkner, M., & Hendricks, K. (2004). The effect of fever, febrile ill-
nesses, and heat exposures on the risk of neural tube defects in a
Texas-Mexico border population. Birth Defects Research. Part A, Clinical and
Molecular Teratology, 70(10), 815–819. http://doi.org/10.1002/bdra.20077
Suarez, L., Hendricks, K., Felkner, M., & Gunter, E. (2003). Maternal serum
B12 levels and risk for neural tube defects in a Texas-Mexico border popula-
tion. Annals of Epidemiology, 13(2), 81–8. http://doi.org/10.1016/
S1047-2797(02)00267-3
Thompson, D. N. P. (2009). Postnatal management and outcome for neural tube
defects including spina bifida and encephalocoeles. Prenatal Diagnosis.
http://doi.org/10.1002/pd.2199
Timor-Tritsch, I. E., Greenebaum, E., & Monteagudo, A. (1996).
Exencephaly-anencephaly sequence: Proof by ultrasound imaging and amni-
otic fluid cytology. Journal of Maternal-Fetal Medicine, 5(4), 182–185.
http://doi.org/10.1002/(SICI)1520-6661(199607/08)5:4<182::
AID-MFM4>3.0.CO;2-G
Velie, E. M., Block, G., Shaw, G. M., Samuels, S. J., Schaffer, D. M., &
Kulldorff, M. (1999). Maternal supplemental and dietary zinc intake and the
occurrence of neural tube defects in California. American Journal of Epidemi-
ology, 150(6), 605–616. http://doi.org/10.1093/oxfordjournals.aje.a010059
Waller, D. K., Hashmi, S. S., Hoyt, A. T., Duong, H. T., Tinker, S. C.,
Gallaway, M. S., … Canfield, M. A. (2017). Maternal report of fever from
cold or flu during early pregnancy and the risk for noncardiac birth defects,
National Birth Defects Prevention Study, 1997-2011. Birth Defects Research
http://doi.org/10.1002/bdr2.1147
Wallingford, J. B. (2005). Neural tube closure and neural tube defects: Studies in
animal models reveal known knowns and known unknowns. In American
Journal of Medical Genetics, 135 C, 59–68). http://doi.org/10.1002/ajmg.c.
30054
Wallingford, J. B., Niswander, L. A., Shaw, G. M., & Finnell, R. H. (2013). The
continuing challenge of understanding, preventing, and treating neural tube
defects. Science, 339, 1048–1054. http://doi.org/10.1038/nrn1986
Werler, M. M., Louik, C., Shapiro, S., & Mitchell, A. A. (1996). Prepregnant
weight in relation to risk of neural tube defects. Journal of the American
Medical Association, 275(14), 1089–1092. http://doi.org/10.1001/jama.275.
14.1089
Wilkins-Haug, L., & Freedman, W. (1991). Progression of exencephaly to anen-
cephaly in the human fetus—An ultrasound perspective. Prenatal Diagnosis,
11(4), 227–233. http://doi.org/10.1002/pd.1970110404
Yazdy, M. M., Mitchell, A. A., Liu, S., & Werler, M. M. (2011). Maternal die-
tary glycaemic intake during pregnancy and the risk of birth defects. Paediat-
ric and Perinatal Epidemiology, 25(4), 340–346. http://doi.org/10.1111/j.
1365-3016.2011.01198.x
Yildirim, E., Zhang, Z., Uz, T., Chen, C. Q., Manev, R., & Manev, H. (2003).
Valproate administration to mice increases histone acetylation and
5-lipoxygenase content in the hippocampus. Neuroscience Letters, 345(2),
141–143. http://doi.org/10.1016/S0304-3940(03)00490-7
How to cite this article: Avagliano L, Massa V,
George TM, Qureshy S, Bulfamante GP, Finnell RH.
Overview on neural tube defects: From development to
physical characteristics. Birth Defects Research. 2019;
111:1455–1467. https://doi.org/10.1002/bdr2.1380