Literature Review

The Etiopathogenic and Morphological Spectrum of Anencephaly

Abstract
One of the most prevalent types of neural tube anomalies is anencephaly, a severe central nervous system (CNS) abnormality.
It is described as a complete or partial absence of the calvarium and brain absence. The mortality rate for anencephaly is
100% during intrauterine life or within hours or days after birth, with a prevalence of 1 to 5 cases per 1000 births. The etiologi
of anencephaly is still unknown. However, some maternal associated environmental and genetic risk factors have been
identified, including diabetes, obesity, exposure to various medicines or toxins, genetic polymorphisms and mutations, and
positive family history of neural tube anomalies. Folate insufficiency is one of the most significant nutritional variables in the
emergence of anencephaly. The maternal serum alpha-fetoprotein level and ultrasonography (US) test are examples of
screening testing. Anencephaly is now always found during the first trimester of US screening. Still, to lower the risk of
complications during pregnancy termination, the diagnosis should be made as soon as feasible during the pregnancy
confirmation US. Since anencephaly is a serious CNS abnormality, morphological characterization could enhance first-
trimester US screening to plan the best, safest, and earliest management.

Keywords: anencephaly, folic acid, genetic polymorphism

Definition
The most frequent form neural tube defect is anencephaly, a severe central nervous system malformation (CNS). The Greek
terms "an," which means "without," and "enkephalos," which means "encephalon," are the source of the derivation. It
symbolizes the brain's whole or partial disappearance along with the calvarium's lack. Usually present are the brainstem,
cerebellum, and diencephalon [1]. Meroacrania refers to anencephaly without foramen magnum involvement, holoacrania
refers to anencephaly with rachischisis or spina bifida, and holoacrania without rachischisis refers to anencephaly without
foramen magnum involvement [2]. The neural tube goes through several stages of development. Therefore, the interplay of
genes and environmental variables is the etiology of neural tube abnormalities [3].

Epidemiology
As anencephaly affects 1–5 of every 1000 births, neural tube defects frequently occur in neonates. About one in every 4600
infants in the US is born anencephalic [4]. Geographical variance is an issue that should be considered; the incidence is higher
in places like Mexico, China, Turkey, and the British Isles [5]. The mortality rate is 100% during intrauterine life or in the first
few days or hours following birth, and more than 83% of pregnancies are terminated [6]. Genetic abnormalities can be
identified in 1–5% of cases, and other structural malformations can be related in 12–25 percent of cases [7].

Etiopathogenesis
Although the cause of anencephaly is still unknown, some environmental and genetic risk factors for mothers have been
identified. Folate deficiency is one of the most significant nutritional variables in the etiology of anencephaly. Numerous
factors could be to blame, and folic acid supplementation poses a severe public health risk by lowering the likelihood of
neural tube abnormalities [8]. One of the most significant environmental influences is the use of antiepileptic medications.
According to Kashif et al., neurologists may consider various recommendations to prevent neural tube abnormalities, such as
folic acid supplements or checking the levels of lamotrigine, carbamazepine, and phenytoin. Since valproate is regarded as the
most teratogenic drug, it should never be used as the first course of treatment [13]. Additionally, selective serotonin reuptake
inhibitors and the dermatological medication isotretinoin are linked to a higher likelihood of having an anencephalic fetus
[13]. Women who deal with cleaning solutions, spray paint, or paint thinners are twice as likely to be exposed to neural tube
abnormalities as men [11].
Additionally, farming villages with private wells that may be tainted by fertilizers and animal manure are where nitrate
exposure is discovered [11]. Pesticide exposure at home, work, or in the community has been linked to an increased incidence
of anencephaly and other neural tube problems in offspring [11]. Organic solvents, including halogenated hydrocarbons,
aliphatic alcohols, glycols, methoxy-ethanol, aromatic hydrocarbons, and their halogenated derivatives, are linked to the
development of anencephaly in babies whose mothers were exposed five years before delivery [12]. Given that organic
solvents and pesticides have a toxic effect on male gametes, changing the migration and transfer of deoxyribonucleic acid
(DNA) during meiosis, even the father's exposure to these substances during the peri-conceptional period was linked to an
increased risk of having a child with anencephaly [12]. Organic solvents produce polymers, colorants, colorants and
explosives, natural and synthetic rubber, leather and shoe industry, enamels, adhesives, lacquers and putty, and industrial
machinery cleaning and degreasing [12]. Early-pregnancy hot tub or sauna users will likely get neural tube abnormalities. This
also holds for pregnant women with a high temperature during that time [11].

There could be a variety of reasons why Hispanic women have births that result in neural tube abnormalities over twice as
frequently as non-Hispanic white women [11]. First, Hispanics frequently eat cornmeal and grits made from corn masa flour
and don't contain folic acid in tortillas and other goods (11). Second, commercial corn supply may include mycotoxins called
fumonisins, formed by a mold and may cause anencephaly. However, their impact may be mitigated by the administration of
folic acid [11].
The likelihood of having a kid with neural tube abnormalities increases with diabetes, hyperinsulinemia, and a body mass
index (BMI) of 30 kg/m2 or higher [11]. On the other hand, weight loss diets and supplements quadrupled the risk of neural
tube abnormalities in the early stages of pregnancy and even before [11], likely due to poor nutrient intake, including folic
acid. In women who used diuretics during the first trimester as part of a weight-loss plan, the incidence of neural tube
abnormalities was virtually tripled [11].
Because neural tube defects, such as anencephaly and spina bifida, cause perinatal, neonatal, infant, and under-five mortality,
folic acid fortification of wheat flour and maize flour became required in some nations, such as the United States. Since this
method has been used since January 1998, 1300 new cases of anencephaly and spina bifida have been prevented annually
[17]. In addition to folic acid consumption, weight loss in obese women of reproductive age may be used to avoid neural tube
abnormalities [16].
However, less than 50% of neural tube abnormalities have standard risk factors implicated [16]. With a positive family
history, the probability of having another child with anencephaly ranges from 2 to 10 percent, vs 0.006 percent in women
without a past. Compared to the general population, siblings of those affected have a higher chance of recurrence [16]. Given
that most anencephalic fetuses are female, even the infant's gender is mentioned as a risk factor [16]. Chromosome
abnormalities like trisomy 18 in Edwards syndrome have also been linked to anencephaly [14].
Additionally, research indicates that many anencephalic fetuses have concomitant anomalies, such as spina bifida, cleft palate,
clubfoot, clubhands, and gastroschisis, indicating the predominance of heredity in neural tube defects [18]. These
characteristics [11, 14, 15] emphasize the significance of genetic variables in the etiopathogenetic of neural tube
abnormalities. This is the rationale behind the increasing number of research that has examined the role of other nongenetic
risk variables and genetic risk factors in the emergence of anencephaly during the past several years [16].
Numerous genes, including those involved in folate metabolism and planar cell polarity (PCP) pathways, may contribute to
the etiopathogenesis of neural tube abnormalities and, consequently, anencephaly [19].

The interplay of genetic and dietary variables is unquestionably a component of the etiopathogenesis of anencephaly [20]. The
enzyme that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the circulating form of folate, is known as
methylenetetrahydrofolate reductase (MTHFR) and is encoded by the MTHFR gene (11, 15, 20, 21). Methionine synthase
catalyzes this process, which uses vitamin B12 as a cofactor [20]. Methionine is involved in some intricate chemical
processes, including DNA synthesis, cell division, tissue growth, and DNA methylation, which is crucial for chromatin
structure and gene expression [20]. The presence of two frequent polymorphisms, namely 677C-T and 1298A-C, can decrease
the enzyme's activity [20]. Because of alanine to valine substitution brought on by the 677C-T polymorphism, the enzyme
becomes thermolabile, and exhibits decreased enzymatic activity, increasing the risk for neural tube abnormalities in
homozygous patients by 2-4 times [15, 20]. This risk factor is influenced by folic acid levels [15]. The 1298A-C
polymorphism, brought on by a missense mutation, specifies the replacement of an adenine with a cytosine, turning a
glutamate residue into an alanine residue. However, the relative risk is more negligible in this situation than in the case of the
677C-T mutation [15, 20]. Given that decreased enzyme activity results in low active folate form, which is required for
appropriate neural tube development, it was discovered that the connection between MTHFR 677C-T polymorphism and
folate status is implied in the etiology of anencephaly [9, 11, 20]. But especially in the population of Mexico, the 677C-T
polymorphism is implicated in the etiopathogenesis of anencephaly [20, 22].

Apicobasal and planar cell divisions are the two forms of neuroepithelial cell division found in the vertebrate embryo [23].
Since the neural tube closes during the process of neurulation, the establishment of cell polarity is essential [23]. Early
embryogenesis' neural tube creation process is represented by neurulation. The neural plates give rise to the neural tube. The
neural folds (at the lateral edges) and the neural groove will be formed at the end of the third week by the neural plates (in the
midline). The midline of the neural folds will unite to produce the neural tube. The cranial and caudal areas communicate with
the amniotic cavity through cranial and caudal neuropores until fusion. These neuropores will close on the 25th to 28th day of
pregnancy, concluding neurulation [24]. In transitioning from the neural plate to the neural tube, where cells are polarized
along the apical-basal axis, PCP is a chemical process that gives cells a coordinated polarized orientation [23, 25]. The cells'
basal surfaces define the neural tube, while their apical surfaces face the lumen of the neural tube. Polarity proteins, which
regulate cell-to-cell adhesion, make this process feasible [23]. Vanglike 1 (VANGL1) and Vang-like 2 (VANGL2), two genes
involved in the PCP pathway, have some nonsynonymous mutations and single nucleotide polymorphisms (SNPs) [23]. The
etiopathogenesis of neural tube abnormalities may also be influenced by mutations in other genes, including platelet-derived
growth factor receptor alpha (PDGFRA), cadherin epidermal growth factor (EGF), laminin G (LAG), and seven-pass G-type
receptor 1 (CELSR1), which are implied in PCP [17, 19].
According to Sudiwala et al., Pax3 gene mutations cause problems in the neural tube because Pax3 is necessary for
neurulation to occur. Folic acid supplements enhance the cell cycle, which makes up for Pax3 loss, and prevent cranial neural
tube defects like anencephaly [26]. Folic acid supplements restore proliferation in the cranial neuroepithelium.
PDGFRA is a gene that codes for a cell-surface tyrosine kinase receptor involved in cell proliferation and embryonic
development [19]. In one investigation, a patient with anencephaly was found to have the PDGFRA frameshift variant c.3029
3030delAG, which resulted in a premature stop codon [19]. Two further anencephalic fetuses with the uncommon c.236G>A
missense mutation of the same gene were discovered [19]. The aminomethyltransferase (AMT) and glycine decarboxylase
(dehydrogenase) (GLDC) genes, which are a part of the mitochondrial glycine cleavage system (GCS), were also shown to
have variations in the same study [19].

A gene called Partitioning Defective 3 Homolog (PARD3) produces a protein that plays a role in cell polarity [23]. In a study
conducted in an area of China, six SNPs that created five haplotypes were found to be associated with an increased incidence
of neural tube abnormalities [23]. All SNPs were found in intronic regions except for rs118153230, an SNP found in exon 16
[23]. It encodes for a protein domain that interacts with aPKC, which is suggested in junctional structures unique to epithelia
[23]. Within the aPKC binding region, this mutation substitutes asparagine for serine [23].
In the Chinese population, maternal mutations in the protein carboxyl methyltransferase 1 (PCMT1) gene may be a risk factor
for anencephaly [21]. Although the study only had a small sample size of patients, the rs4816 SNP might be implicated in
solitary anencephaly [21].
Micro-ribonucleic acids (miRNAs) are small, single-stranded, non-coding RNA molecules with post-transcriptional regulatory
roles in messenger RNA activity [27, 28]. The miRNAs have the potential to control a wide range of genes and are implicated
in the regulation of cell cycle, apoptosis, and cell differentiation [27, 28]. MTHFR, transcobalamin receptor, transcobalamin 2,
solute carrier family 19 members 1, methionine adenosyltransferase 2A, methylenetetrahydrofolate dehydrogenase
[nicotinamide adenine dinucleotide phosphate (NADP+) dependent] 2, and methylenetetrahydrofolate dehydrogenase
[nicotinamide adenine dinu MiR-22 was reported to be markedly increased in cells cultured at low folate concentrations [27].
Through the mitogen-activated protein kinase (MAPK) signaling pathway, the miRNA is implicated in the etiopathogenesis of
anencephaly [27]. Given that miRNAs are dynamically controlled during neurodevelopment, there are variations between
healthy fetal brain tissues and tissues from anencephalic fetuses regarding miRNA up- and down-regulation [28]. MiRNAs
miR-22, miR-23a, miR-34a, miR103, miR-125a, miR-126, miR-132, miR-134, miR-138, miR-185, miR-198, and miR-451
were up-regulated, and miR-9, miR-212, miR-124, miR-138, miR-103/107, and miR-149 were down-regulated in the tissue
taken from the anencephalic The etiopathogenesis of anencephaly may be influenced by aberrant nucleotide synthesis and
biological methylation, which are implied by folate deprivation [28].
Embryology
The ectodermal germ layer is disc-shaped at the start of the third week, on day 18, with the cephalic portion being more
expansive than the caudal part [10, 29]. The notochord and prechordal mesoderm located below stimulate the thickening of
the embryonic ectoderm that lies above, creating an extended neural plate [10, 29, 30]. This significant inductive process
occurs during gastrulation [10, 29]. The neural plate and peripheral surface ectoderm will thus form from the ectoderm [29].
The initial stage of neurulation is the process of neural induction, and the caudal neuropore will close by the end of the fourth
week [10, 29, 30]. Around days 22–23, close to the fourth to sixth pairs of somites, neurulation forms the neural plate and tube
[30]. The neural plate is a slipper-shaped structure that develops from the cranial extremity toward the primitive streak and is
located on the back of the trilaminar embryo. It is the first CNS rudiment [10, 29, 30]. Since day 19, primordia for the three
prominent brain vesicles—the prosencephalon (or forebrain), mesencephalon (of the midbrain), and rhombencephalon (or
hindbrain)—are delineated by indentations on the neural plate [10, 29]. The future brain will be formed by the cranial two-
thirds of the neural plate and tube, which extend from the cranial extremity to the fourth pair of somites, whereas the future
spinal cord will be created by the caudal one-third [30].
The neural plate begins to fold up gradually so that by the third week's end (or roughly the 18th day), its central area will
create a depression known as the neural groove, and its lateral borders will elevate to form the neural folds [10, 29, 30]. In the
cranial end of the embryo, the lateral boundaries of the neural plate will grow peculiarly prominent [30]. The neural folds will
eventually merge in the midline when they come together, first in the cervical area at the 5th somite and then cranially and
caudally [10, 30]. The neural tube will eventually form during the fourth week, and its lumen will develop into the neural
canal [10, 29, 30]. The surface ectoderm, which differentiates into the epidermis, will be separated from the neural tube [10,
29, 30]. Neural crest cells will create the neural crest, which will lie between the neural tube and the developing epidermis
[30]. The neuroepithelial cells that make up the neural tube's wall will divide just before and right after it closes, determining
the development of a pseudostratified columnar epithelium with cells joined by junctional complexes, which will become the
neuroepithelium (neuroectoderm). The neural canal will develop into the ventricular system and the central canal of the spinal
cord. At the same time, the neuro progenitor cells will multiply, migrate, and differentiate to produce the CNS components
[30].

The neural tube's cephalic and caudal open ends communicate with the amniotic cavity through the rostral and caudal
neuropores. The posterior neuropore closes around two days after the cranial neuropore, during the 18- to the 20-somite stage
(i.e., around the 25th day), starting from the initial closure site in the cervical region (i.e., 27th day). When the neuropores
close, a vascular circulation of the neural tube will manifest [30].
The prominent brain cysts are located in the cephalic section of the newly created tubular structure, whereas the spinal cord is
located in the caudal portion, which is narrower [10, 29]. The prosencephalon, also known as the forebrain, mesencephalon,
and rhombencephalon, also known as the back brain, are the three prominent brain vesicles [10, 29, 30]. In the fifth week, the
prosencephalon splits into the telencephalon and diencephalon, while the rhombencephalon splits into the metencephalon and
myelencephalon [29]. Together with the mesencephalon, these four vesicles will become five secondary brain vesicles [29].
The cephalic flexure will develop in the midbrain, the cervical flexure between the spinal cord and the hindbrain, and the
pontine flexure will be dorsally directed [10, 29, 30]. These flexures are all ventrally oriented.
When several circumstances impact neurulation, birth abnormalities of the CNS may develop [30]. Exencephaly will manifest
if the rostral neuropore of the neural tube does not shut by the end of the fourth week [10, 30]. This could display due to issues
with cell adhesion, cell fate, and neural tube closure mechanisms [30].
The absence of the calvaria causes anencephaly, which is invariably accompanied by acrania. The brain is not protected and
degenerates without the calvaria, while the brainstem is undamaged [10, 30]. However, the aberrant brain structure and
vascularization, shown by the development of new blood vessels, also contribute to the damaging process [30]. On
macroscopic examination, the remaining portion of the brain seems spongy and forms a vascular mass almost entirely made
up of structures from the hindbrain [30].
The development of neural tube defects may also suggest additional mechanisms, such as aberrant processes that take place at
the places where neural tubes are formed, which may number five [30]. Site 2 failure leads to anencephaly, whereas spina
bifida cystica causes problems in site 1 closure [30]. Sites 2, 4, and 1 will experience craniorachischisis if they do not shut
down. It is unusual for site 3 fusion not to occur [30].

Clinical and morphological features

One of the most critical phases in detecting prenatal CNS abnormalities in imaging diagnosis by US examination.
Anencephaly can be identified in all cases during the first-trimester screening, which occurs between 11 and 13 plus 6 weeks
of pregnancy [31, 32]. The present difficulty in clinical practice is the early diagnosis when the risk of complications from
abortion is lower. The transvaginal US can diagnose anencephaly that presents with acrania and different levels of cerebral
degeneration. This calls for in-depth familiarity with every morphological trait that exists in the early fetal stage before
mechanical and chemical harm from extended contact to amniotic fluid affects the encephalon's development.
At the typical 8–10 week US scan, a focused search for the sonographic indicators of this illness is essential for a conclusive
diagnosis of anencephaly. Due to the lack of the skull and the degradation of the brain, the gestational age determined by the
crown-rump length is severely lowered in all affected fetuses by an average of two weeks less than anticipated (Figure 1).
However, in anencephaly, the hemispheres are replaced by masses of connective and vascular tissue with spread islands of
neural tissue, known as area cerebrovascular or angiomatous stroma, as opposed to exencephaly, which has varying amounts
of recognizable cerebral tissue as seen on sonography and in pathology. The "Mickey Mouse" indication was described as the
irregular masses above the fetal orbits floating into the amniotic fluid in the coronal view of the head [33].
In light of the fetus's failure to develop a functioning swallowing mechanism, the clinical correlation of abnormal brain
development is represented by the occurrence of hydramnios in the final two months of pregnancy. Another sonographic
feature is polyhydramnios, which can occur in up to 50% of cases but does not typically appear until the second or third
trimester [10, 34].
Anencephaly is linked to problems in other organs and tissues in addition to the CNS. While it is impossible to make a
diagnosis in the first trimester for associated malformations like cervical rachischisis (failure in the fusion of neural arches),
cleft palate, cardiac and pulmonary defects, club foot, overlapping fingers, rocker-bottom feet, hexadactyly and other
musculoskeletal defects, adrenal and pulmonary hypoplasia, microphthalmia, enlarged pinnae, kidney agenesis, and
omphalocele, parietal, and significant sections of the occipital bones may frequently be affected by ossification, which is
detectable as early as the 11th week of pregnancy [35].

The existence of fibrous amniotic bands is another US characteristic to be taken into account. The "Turkish turban" sign,
which develops as a result of an amniotic band forming around the exterior base of the developing calvarium, was initially
identified by Sepulveda et al. in a research based on transvaginal and three-dimensional (3D) US examination in the first
trimester of pregnancy [36]. The pregnancy was terminated in the 18th week, and the fetus displayed several congenital
disabilities, including anencephaly, due to the amniotic band, as described by Kostadinov & Shapiro [37].
Anencephaly is an "always detectable" malformation, which means it must be identified in the first trimester as early as
possible [38]. Although some structural anomalies can be missed depending on the examiner's experience, the quality of the
US machines, or maternal characteristics like a high BMI, anencephaly is a malformation that is "always detectable" by
definition.
As previously mentioned, second-trimester ultrasonography consistently finds anencephaly. The diagnosis cannot be made in
the first trimester since the corpus callosum and cerebellum are not yet fully matured, but in the second trimester, they can be
found. The term "anencephaly" refers to a failure of the midbrain and forebrain to fuse together, whereas the cerebellum, pons,
and medulla oblongata usually are fused [39]. The "frog eye" indication, which can be detected, denotes that aberrant cortical
development is linked to projecting orbital structures [33].
The obstetrician can use the following criteria to make a macroscopic diagnosis after delivery quickly: lack of the calvarium
and scalp, external presence of a hemorrhagic or fibrotic mass, and absence of cerebral hemispheres (Figures 2-4) [40]. In
cases of live births, spontaneous abortions, intrauterine fetal deaths, and terminated pregnancies, the macroscopic diagnosis
can also be verified through autopsies. A thorough postmortem examination is necessary to support the US findings and
provide a more precise diagnosis [39]. Malformations of the cerebellum, brainstem, optic nerves, and spinal cord may be
apparent, and the hypothalamus is often absent. Adrenal hypoplasia results from the absence or underdevelopment of the
pituitary and is permanent.
The following factors make it simple for the obstetrician to create a macroscopic diagnosis as soon as after delivery:
The calvarium and scalp are absent, there is an exterior hemorrhagic or fibrotic mass, and the cerebral hemispheres are absent
(Figures 2-4). [40]. In cases of live births, spontaneous abortions, intrauterine fetal deaths, and terminated pregnancies, the
macroscopic diagnosis can also be verified at autopsies. A thorough postmortem examination is necessary to support the US
findings and provide a more precise diagnosis [39]. Malformations of the cerebellum, brainstem, optic nerves, and spinal cord
may be apparent, and the hypothalamus is often absent. Adrenal hypoplasia results from the absence or underdevelopment of
the pituitary and is permanent. External examination at autopsy may reveal any of the following morphological changes:
entire or partial lack of the skull bones, delayed development of the ossification center, prominence of the orbit, and area
cerebrovasculosa (section of abnormal hypervascular tissue admixed with neuroglial tissue and disorganized choroid plexuses
located at the base of the skull). The hypoplastic brainstem, underdeveloped hypophysis, and superficial sella turcica are
typically seen at the bottom of the head. The retina may only have a few ganglion cells or none at all, and the optic nerves
may be undeveloped upon examination of the visual system. Brain tissue may aspirate into the lungs. Examining the cephalic
region under a microscope reveals either a complete lack of or aberrant hypothalamic tissue. Additionally, neurohypophysis
may be entirely gone or still exist but be dysfunctional. If it is present, adenohypophysis is often tiny and made up of cells
with normal morphology. Corticotrophs have decreased and deteriorated, as seen by immunohistochemistry and electron
microscopy.
Unusual placental attachment to the location of the skull defect is a rare anencephaly presentation. These infants
could also have low-set ears, cleft lips, cleft palates, or bilateral congenital talipes equinovarus, among other congenital
deformities [41].
It is currently accepted that the transformation of an undifferentiated population of cells underlies the growth and maturation
of the placenta and other organs. Of those, the majority develop into an end-stage, vastly differentiated cell population that
typically does not divide further. Nevertheless, the placenta linked to anencephaly seems to have some issues with this
process. Although the conclusion drawn from this finding is very speculative, it suggests that the intact fetus is involved in
regulating placental growth. Batson et al. compared a group of 12 control cases from healthy pregnancies to a series of 12
placentas from anencephalic newborns. They came to a conclusion that, when systematically observed under light microscopy
and supported by morphometric analysis, the placenta of anencephalic newborns was strikingly less developed in all 12 cases.
This was demonstrated by the prominent persistence of cytotrophoblast with sporadic mitoses in the placenta of newborns
with anencephaly [42].

Current state of knowledge

The first trimester ultrasound is advised for determining gestational age, fetal viability, and fetal gross anatomy, according to
the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG). Therefore, during the first trimester, fetal
heads with the third ventricle, choroid plexus, thalamus, posterior fossa, and intracranial translucency should always be found.
While second trimester ultrasonography, performed between 18 and 23 weeks of gestation, is the "gold standard" for fetal
anatomy, the first trimester is sufficient for the early detection of anencephaly.
According to Santana et al., transvaginal and abdominal US are advised for enhancing diagnosis accuracy for various
disorders. They also stated that various structural defects were seen in 12–25 percent of the anencephalic fetuses [35].
According to Araujo Jnior et al., cranial defects can be examined in a sagittal plan as well as coronal imaging of the face,
which allows for a better understanding of the defect. The absence of the calvaria above the orbit in coronal slice suggests
anencephaly [43].
Although no studies have demonstrated that three-dimensional (3D) US is superior to two-dimensional (2D) US for the
evaluation of brain anomalies, Gonçalves et al. claimed that 3D US could pinpoint the exact location of normal anatomy and
pathological structures through simultaneous evaluation of three anatomical planes [44].
The pituitary-adrenal axis dysfunction seen in anencephalic pregnancies may change the gestational period. As a result,
pregnancies can be very long or unusually short [45]. Atypical growth patterns in anencephalic neonates with widespread
growth restriction have also been noted by several writers.
This pattern is brought about by hypoplastic adrenals, which produce insufficient cortisol and cause generalized atrophy of all
organs while spearing the lymphoid tissue, particularly the thymus, which may even appear to be relatively big [46]. Due to
the increased subcutaneous adiposity brought on by improper glucose management, these fetuses may also appear overweight.
Exogenous adrenocorticotropic hormone (ACTH) can counteract the excessively high insulin levels seen in decapitated rabbit
fetuses, a similar phenomenon [47].
According to a 2018 study, cleft palates and anencephaly are among the health problems that are more common in the
offspring of pregnant women who consume sprouting potatoes four or more times per week. With enough vitamin B intake,
this impact appeared less likely [48].
According to Tica et al., specific disorders, such as amniotic loop syndrome, large encephalocele, microcephaly, and
iniencephaly, must be considered for the differential diagnosis [49].
According to Edwards and Hui, fetal structural defects complicate 2-3% of all pregnancies, and early detection of a severe
problem gives doctors more options for treatment than discovery later in the pregnancy. They added that for fatal defects such
as anencephaly, a higher diagnosis rate in the first trimester is required [50]. In addition to this study, numerous other studies
assert that first-trimester ultrasonography is a crucial imaging technique for fetal anomaly detection [50, 51].
A definitive diagnosis in the first trimester will enable parents to receive counseling and terminate the pregnancy [43, 52]. If
the pregnancy cannot be ended, some maternal outcomes need to be taken into account. Continued pregnancies can result in
difficulties such as stillbirth, polyhydramnios, elective Caesarean delivery, redundant Caesarean delivery, labor induction,
shoulder dystocia, and ante/postpartum hemorrhage, according to Ekmekci & Gencdal [5].
The clinician must be aware of the mother's risk factors, such as obesity, diabetes, hypertension, and autoimmune illness, to
provide the best delivery option for women for whom abortion is not an option. Monitoring for the complications mentioned
above is essential [53].
Pregnancy termination rates in Japan are comparable to those in North American or European nations, and Kondo et al.
reported in a study conducted over two years (2014–2015) with more than 311 000 pregnant women that 50% of pregnancies
with neural tube defects and 80% of those with anencephaly were terminated [54].

Conclusions
The most common type of neural tube abnormality is anencephaly. The high occurrence of this deformity in neonates justifies
the significance of first-trimester US screening for it and enables the doctor to decide on the best course of treatment. We
stress the importance of a thorough prenatal examination even if individual anomalies in neural tube closure account for most
cases of anencephaly. Any severe facial asymmetry or clefts that cannot be explained from a developmental standpoint may be
linked to the sequence of an early amnion rupture.

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