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Embryology, Anencephaly

Editor: Forshing Lui Updated: 5/1/2023 6:00:04 PM


Anencephaly is a pathology of development characterized by a fetus that has no calvarium, with a lack of most or all of the fetus' brain tissue.[1] Anencephaly belongs to a collective group known as neural tube defects (NTD) and is a result of the neural tube failing to close in its rostral end during fetal development.[2] While the central nervous system (CNS) is developing in a fetus, the neural plate becomes folded and fused, creating the neural tube. Any disturbance to the process of neural tube closure can result in structural abnormalities collectively called neural tube defects. Anencephaly is one of the two main types resulting from the failure of closure of the rostral end of the neural tube.[3] The other primary type is due to the failure of closure of the caudal end called spina bifida. The development of anencephaly is not believed to have one single origin but can be a result of many factors, including environmental and nutritional factors.[2]


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Neural tube defects emerge when there is a disturbance during neurulation.[4] Neurulation is a mechanical process that occurs during the early embryogenesis of a fetus. The main goal of the neurulation is to form the neural tube, which is a hollow structure that provides the basis for the central nervous system.[5]

Primary neurulation:

Neurulation is a series of systematic, morphologic, structural changes. The process begins with the Hensen node and the nascent ectoderm signaling to one another, which induces the neural plate to begin neurulation.[5] The neural plate is a flat, open neural epithelium that bends to form neural folds on each end.[4] The two neural folds begin to elevate and start to bend towards one another, both ends growing in the direction of the midline, forming the neural groove. The two bends continue elongating, meet in the middle, and fusing. The fusion creates the neural tube and marks the end of primary neurulation.[6][5] During the third week of gestation, the neural tube is developing from the neural plate. The fourth week is the time when the neural tube closes. Failure of the closure of the rostral end will result in anencephaly which occurs between days 23rd and 26th of gestation. Any insult to the fetus during the fourth gestational week may result in anencephaly in the developing fetus.

Secondary neurulation:

At the sacral and coccygeal level, the neural tube is referred to as the tailbud.[5] The tail bud gives rise to the neural tube and other non-epidermal tissues.[7] The tailbud cells begin to aggregate together and proliferate,[7] forming the medullary cord.[6] While the medullary cord is forming, intercellular junctions arise and join lateral cell surfaces.[5] Epithelization of the medullary cord results in the formation of many lumina.[6][5] The process of cavitation takes place and results in the creation of a central lumen. This singular lumen is the secondary neural tube, which eventually merges with the primary neural tube, forming one continuous structure. Regardless of successful anterior neural tube formation during primary neurulation, secondary neurulation can still be successful.[5]




The presence of anencephaly can be detected as early as the first trimester through fetal ultrasound. However, since some organ systems are still developing through the first trimester, screening for structural abnormalities is used to be delayed until the second trimester. Ultrasound remains the gold standard for diagnostic imaging in pregnant women due to its increased efficacy from technological advances and its safety for the fetus.[8] Upon ultrasound imaging, there is an absence of the superior portion of the cranial vault. In addition, there is an absence of brain tissue at the location of the cerebral hemispheres.[9]


Alpha-fetoprotein (AFP) is a protein normally found in human serum. During pregnancy, AFP concentrations rise quickly, reaching peak levels at the end of the first trimester. After the first trimester, AFP is continuously synthesized, but its presence becomes diluted due to increases in fetal blood volume.[10] In about 90-percent of Anencephaly cases, there is a substantial elevation in serum alpha-fetoprotein levels in the mother. Also, almost all cases are found to have a notable increase in the alpha-fetoprotein levels in the amniotic fluid, accompanied by a presence of acetylcholinesterase.[9]


In the postnatal period, diagnosis is by physical examination. All of the following criteria are required for a positive diagnosis[9]:

  1. No calvarium present
  2. Absence of scalp
  3. External presence of a hemorrhagic, fibrous mass or tissue 
  4. Lack of cerebral hemispheres


The pathogenesis and etiology of anencephaly remain poorly understood but are believed to have a multifactorial origin comprised of both nutritional and environmental risk factors.[2]


Folate is a coenzyme that facilitates the transfer of one-carbon units, which are then in various reactions, such as purine and pyrimidine synthesis, as well as methylation reactions.[11] Folate deficiency is an important nutritional risk factor known to contribute to the development of the disease.[12] A deficiency in folate can result from a variety of causes:

  1. Medications that block folate absorption
  2. Malabsorption of folate
  3. Increased bodily demand for folate
  4. Insufficient intake of dietary folate

Folate is involved in the process of methylating homocysteine and cytosine. It also contributes to the synthesis of purines and pyrimidines. Consequently, a lack of folate leads to an inability to properly build proteins and DNA and also alters the expression of some genes.[11] Although the role folate plays in reducing the risk of NTD is not well known, women of reproductive age are encouraged to incorporate a folate supplement into their diet.[11][13]


Anti-epileptic drugs (AEDs) are a known cause of NTDs. Use of AEDs, such as valproate, carbamazepine, and phenytoin, alters folate absorption, leading to decreased levels of folate in the blood. Of note, valproate is considered the most teratogenic AEDs, especially when combined with lamotrigine.[12] Other folic acid antagonists include trimethoprim (an antibiotic used to treat infections, such as malaria), triamterene (a potassium-sparing diuretic), and aspirin (an over-the-counter anti-coagulant).[12][14]

Diabetes complicates pregnancies by increasing the risk of the fetus developing congenital birth defects (diabetic embryopathy).[15] This complication is because high blood sugar causes dysfunction during organogenesis.[16][17] The mechanism behind this is that hyperglycemia causes a disturbance in protein folding and promotes apoptosis in embryonic cells. The misfolded proteins aggregate and are unable to be degraded properly. The aggregates then accumulate in the cytosol and disrupt organelle function, leading to the creation of reactive oxygen species (ROS). Oxidative stress causes intracellular signaling to become disrupted, and cells are unable to function properly.[15]

Hyperthermia during the first trimester can alter anterior neural tube closure and correlates with anencephaly. Possible causes of hyperthermia in the mother include the use of saunas or hot tubs, exercising in an environment with increased temperatures, and febrile illness.[18]

Excess Vitamin A has shown to be teratogenic in pregnant rats due to decreased protein synthesis.[12] Increases in Vitamin A prevent the anterior neural tube from closing, leading to the development of anencephaly or other NTDs.[19]

Clinical Significance

Anencephaly is not compatible with life. The most important aspect of the management of this condition is prevention. The simplest way to reduce the incidence of anencephaly is to advise women of childbearing age to take a supplement of folic acid. Any dose at or more than 0.4 mg a day is effective; this is especially important for any woman taking anticonvulsants. For a young female patient with epilepsy, counseling is essential about the risk of seizures during pregnancy to the developing fetus and the risk of teratogenicity. The patient and provider should develop a plan before she starts a family. The seizures should best be under optimal control with at all possible a single anti-epileptic agent at the lowest possible dose. Valproate should be avoided. The anticonvulsant with the best track record concerning teratogenicity is lamotrigine.

Maternal serum and fetal ultrasonography are diagnostic procedures during pregnancy for in utero diagnosis of any neural tube defect, including anencephaly. Early termination of pregnancy may be an option upon the diagnosis of anencephaly.



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