Introduction
Background
Anencephaly is a serious developmental defect of the central nervous system in which the brain and cranial vault are grossly malformed. The cerebrum and cerebellum are reduced or absent, but the hindbrain is present. Anencephaly is a part of the neural tube defect (NTD) spectrum. This defect results when the neural tube fails to close during the third to fourth weeks of development, leading to fetal loss, stillbirth, or neonatal death.
Anencephaly, like other forms of NTDs, generally follows a multifactorial pattern of transmission, with interaction of multiple genes as well as environmental factors, although neither the genes nor the environmental factors are well characterized. In some cases, anencephaly may be caused by a chromosome abnormality, or it may be part of a more complex process involving single-gene defects or disruption of the amniotic membrane. Anencephaly can be detected prenatally with ultrasonography and may first be suspected as a result of an elevated maternal serum alpha-fetoprotein (MSAFP) screening test. Folic acid has been shown to be an efficacious preventive agent that reduces the potential risk of anencephaly and other NTDs by approximately two thirds.
Pathophysiology
In the normal human embryo, the neural plate arises approximately 18 days after fertilization. During the fourth week of development, the neural plate invaginates along the embryonic midline to form the neural groove. The neural tube is formed as closure of the neural groove progresses from the middle toward the ends in both directions, with completion between day 24 for the cranial end and day 26 for the caudal end. Disruptions of the normal closure process give rise to NTDs. Anencephaly results from failure of neural tube closure at the cranial end of the developing embryo. Absence of the brain and calvaria may be partial or complete.
Most cases of anencephaly follow a multifactorial pattern of inheritance, with interaction of multiple genes as well as environmental factors. The specific genes that are most important in NTDs have not yet been identified, although genes involved in folate metabolism are believed to be important. One such gene, methylenetetrahydrofolate reductase (MTHFR), has been shown to be associated with the risk of NTDs. In 2007, a second gene, a membrane-associated signaling complex protein called VANGL1, was also shown to be associated with the risk of neural tube defects.1
A variety of environmental factors appear to be influential in the closure of the neural tube. Most notably, folic acid and other naturally occurring folates have a strong preventive effect. Folate antimetabolites, maternal diabetes, maternal obesity, mycotoxins in contaminated corn meal, arsenic, and hyperthermia in early development have been identified as stressors that increase the risk of NTDs, including anencephaly.
Frequency
United States
Average birth prevalence of anencephaly is approximately 1.2 per 10,000 births, with a gradient of increasing frequency from the West Coast to the East Coast. The frequency during pregnancy is considerably higher than the birth prevalence, with estimates as high as 1 case per 1000 pregnancies. Such pregnancies often end in early pregnancy loss, spontaneous abortion, fetal death, or pregnancy termination. Within the United States, South Carolina has historically reported the highest birth prevalence of NTDs, with a rate that has been approximately double that of the national average. The rate of NTDs in South Carolina has fallen dramatically over the past decade following the introduction of aggressive campaigning for periconceptional folic acid supplementation, fortification of wheat flour, and increased periconceptional vitamin supplementation. The reason for a higher occurrence of NTDs in South Carolina compared with other areas of the country is not known.
In 1990-1991, a cluster of NTDs was reported in Brownsville, Texas.2 This primarily Hispanic population was targeted for surveillance as well as an intensive folic acid supplementation campaign directed at prevention of recurrences. Since that time, it has been generally accepted that the Hispanic population has an increased risk of anencephaly and other NTDs compared with other racial/ethnic populations in the United States, although the reasons have not been identified.
In families that have previously experienced a pregnancy affected with anencephaly, the use of folic acid supplements at a dose 10 times higher than what is generally advised for the general population (4 mg/d vs 400 mcg/d) is recommended. In the South Carolina study, more than 300 pregnancies have been followed from women with a prior NTD-affected pregnancy who received the higher dose of folic acid supplements as part of the follow-up program with no recurrences of NTDs observed.
Study of NTDs in the United States by the Centers for Disease Control and Prevention shows a significant reduction of anencephaly and other NTDs following the introduction of fortification of wheat flour with folic acid.
International
Considerable geographical variation in NTD rates exists, with noted hotspots in Guatemala, northern China, Mexico, and parts of the United Kingdom.
Mortality/Morbidity
- Anencephaly is lethal in all cases because of the severe brain malformation that is present.
- A significant proportion of all anencephalic fetuses are stillborn or are aborted spontaneously.
Race
Hispanic and non-Hispanic whites are affected more frequently than women of African descent.
Sex
Females are affected more frequently than males.
Age
Anencephaly is determined by the 28th day of conception and is therefore invariably present at the time of birth.
Clinical
History
Anencephaly is readily apparent at birth because of the absence of the cranial vault and portions of the cerebrum and cerebellum. Facial structures are generally present and appear relatively normal. The cranial lesion occasionally is covered by skin, but usually it is not. When the lesion is covered with skin, prenatal screening using MSAFP is ineffective. Babies are frequently stillborn, and spontaneous abortion during pregnancy is common.
Physical
Although the features of anencephaly are readily evident, physical examination for anomalies not related directly to the anencephaly is indicated to evaluate the possible need for cytogenetic studies. When additional malformations are present, the likelihood of cytogenetic abnormalities is increased.
Causes
Anencephaly is usually an isolated birth defect and not associated with other malformations or anomalies. The vast majority of isolated anencephaly cases are multifactorial in their inheritance pattern, implicating multiple genes interacting with environmental agents and chance events.
- Adequate folic acid consumption during pregnancy is protective against anencephaly. Exposure to agents that interfere with normal folate metabolism during the critical period of neural tube development (up to 6 wk after last menstrual period) increases the likelihood of an NTD.
- Valproic acid, an anticonvulsant, and other antimetabolites of folic acid have been shown to increase the chance of an NTD when exposure occurs in early development. While these induced NTDs are usually spina bifida, the chance of anencephaly is probably increased as well.
- Maternal type 1, or pregestational insulin-dependent diabetes mellitus (IDDM) confers a significant increase in the risk for NTDs, and it also delays production of alpha-fetoprotein (AFP) during pregnancy. Maternal serum AFP is used as a screening test to detect NTDs, and adjustment of the expected values for AFP in maternal serum must be made if the patient is known to have IDDM. Presumably, well-controlled IDDM confers a lower risk for NTDs, while gestational diabetes does not appear to be associated with any significant increase in NTD risk. The degree of diabetic control is generally monitored using hemoglobin A1c levels.
- Maternal hyperthermia has been associated with an increased risk for NTD; therefore, pregnant women should avoid hot tubs and other environments that may induce transient hyperthermia. Similarly, maternal fever in early gestation also has been reported as a risk factor for anencephaly and other NTDs.
- While most NTDs are associated with a multifactorial model of inheritance, rare cases of NTDs are transmitted in an autosomal dominant or autosomal recessive manner in certain families. Such families may have children or fetuses with spina bifida, anencephaly, or other subtypes of NTDs. In families with a pedigree suggestive of autosomal dominant inheritance, reproduction is clearly only possible for the individuals with spina bifida since death occurs early in the life of individuals with anencephaly.
- Anencephaly may be associated with the unbalanced form of a structural chromosome abnormality in some families. In these cases, other malformations and birth defects that are not usually found in isolated cases of anencephaly may be present.
- Amniotic band disruption sequence is a condition resulting from rupture of the amniotic membranes. This can cause disruption of normally formed tissues during development, including the structures of the head and brain. Anencephaly caused by amniotic band disruption sequence is frequently distinguishable by the presence of remnants of the amniotic membrane. Recurrence risk for anencephaly caused by this mechanism is lower and the risk is not modified by the use of folic acid.
More on Anencephaly |
 Overview: Anencephaly |
| Differential Diagnoses & Workup: Anencephaly |
| Treatment & Medication: Anencephaly |
| Follow-up: Anencephaly |
| References |
| Next Page » |
References
Kibar Z, Torban E, McDearmid JR, Reynolds A, Berghout J, Mathieu M. Mutations in VANGL1 associated with neural-tube defects. N Engl J Med. Apr 5 2007;356(14):1432-7. [Medline].
Missmer SA, Suarez L, Felkner M, Wang E, Merrill AH Jr, Rothman KJ. Exposure to fumonisins and the occurrence of neural tube defects along the Texas-Mexico border. Environ Health Perspect. Feb 2006;114(2):237-41. [Medline].
Berry RJ, Li Z, Erickson JD, et al. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med. Nov 11 1999;341(20):1485-90. [Medline].
Botto LD, Moore CA, Khoury MJ, Erickson JD. Neural-tube defects. N Engl J Med. Nov 11 1999;341(20):1509-19. [Medline].
Brent RL, Oakley GP, Md J. The unnecessary epidemic of folic acid-preventable spina bifida and anencephaly. Pediatrics. Oct 2000;106(4):825-7. [Medline].
Campbell LR, Dayton DH, Sohal GS. Neural tube defects: a review of human and animal studies on the etiology of neural tube defects. Teratology. Oct 1986;34(2):171-87. [Medline].
Philipp T, Philipp K, Reiner A, et al. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod. Aug 2003;18(8):1724-32. [Medline].
Stevenson RE, Allen WP, Pai GS, et al. Decline in prevalence of neural tube defects in a high-risk region of the United States. Pediatrics. Oct 2000;106(4):677-83. [Medline].
Further Reading
Keywords
neural tube defect, NTD, neural tube defect spectrum, absent cerebellum, absent cerebrum, brain malformation, elevated maternal serum alpha-fetoprotein level, genetic defect, folic acid, failure of neural tube closure, developmental defect, folate metabolism, folic acid supplementation, fortification of wheat flour, stillbirth, neonatal death, early pregnancy loss, spontaneous abortion, fetal loss, termination of pregnancy
