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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]

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] NUTRITIONAL FACTORS 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: Medications that block folate absorption Malabsorption of folate Increased bodily demand for folate 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] ENVIRONMENTAL FACTORS 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]

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]