Anencephaly
Anencephaly is a profound and devastating birth defect where a major portion of the brain, skull, and scalp fails to develop during the earliest stages of pregnancy. It highlights the incredible complexity of human development and the critical role even tiny cellular processes play. While often a somber topic, understanding anencephaly reveals both the fragility of life and the immense advancements in prenatal care and medical ethics. Anencephaly results from a neural tube defect early in embryonic development, primarily causing the absence of the cerebral hemispheres. Folic acid supplementation before and during early pregnancy can significantly reduce the risk of anencephaly, though genetic and environmental factors also play a role. The diagnosis of anencephaly raises complex ethical dilemmas, particularly concerning end-of-life care, organ donation, and pregnancy termination.
AI Summary
Anencephaly is a profound and devastating birth defect where a major portion of the brain, skull, and scalp fails to develop during the earliest stages of pregnancy. It highlights the incredible complexity of human development and the critical role even tiny cellular processes play. While often a somber topic, understanding anencephaly reveals both the fragility of life and the immense advancements in prenatal care and medical ethics.
- Anencephaly results from a neural tube defect early in embryonic development, primarily causing the absence of the cerebral hemispheres.
- Folic acid supplementation before and during early pregnancy can significantly reduce the risk of anencephaly, though genetic and environmental factors also play a role.
- The diagnosis of anencephaly raises complex ethical dilemmas, particularly concerning end-of-life care, organ donation, and pregnancy termination.
A Glimpse into Early Development
Anencephaly is a severe cephalic disorder, meaning it affects the head. It arises from a crucial misstep during embryonic development, specifically a neural tube defect that occurs very early—between the 23rd and 26th day after conception, often before a woman even knows she's pregnant.
What Does 'Without a Brain' Truly Mean?
The term 'anencephaly' literally means 'without a brain' in Greek. However, it's a bit more nuanced: infants with this condition typically lack the telencephalon, the largest part of the brain that includes the cerebral hemispheres and neocortex—the seat of consciousness and cognition. What remains is usually a rudimentary brain stem, covered only by a thin membrane, with no skull or scalp protecting it.
Due to the absence of these vital brain structures, babies born with anencephaly are usually blind, deaf, and unable to feel pain or be aware of their surroundings. While some reflex actions like breathing or responses to sound or touch might occur, the lack of a functioning cerebrum means there is no possibility of gaining consciousness. Tragically, most infants with anencephaly do not survive beyond a few hours or days after birth.
Unraveling the Causes
The Power of Folic Acid
One of the most significant discoveries related to neural tube defects, including anencephaly, is the role of folic acid. Since at least 1991, studies have consistently shown that this B vitamin is crucial for proper neural tube formation during early development.
Supplementing the diet of women of child-bearing age with folic acid can dramatically reduce the incidence of these defects. It is recommended that all women who could become pregnant consume 0.4 mg of folic acid daily. For women who have previously had a pregnancy affected by a neural tube defect, physicians often prescribe a higher dosage of 5 mg per day to further reduce the risk.
Genetic Predispositions and Other Factors
Anencephaly can also have a genetic component, sometimes following patterns of autosomal recessive inheritance. Research has identified specific genes, like homozygous inactivation of the NUAK2 kinase, that can lead to anencephaly in humans. Animal models also point to a possible link with deficiencies in the TEAD2 transcription factor.
Beyond genetics, certain external factors can increase risk. Women taking specific anticonvulsant medications or those with insulin-dependent diabetes have a higher chance of having a child with a neural tube defect. For families with a history of such defects, genetic counseling is often recommended to discuss risks and available testing options.
Anencephaly as a Ciliopathy
Remarkably, anencephaly is now recognized as part of an emerging class of genetic disorders called ciliopathies. These are conditions that, despite varied symptoms, share a common root cause: dysfunctional primary cilia—tiny, hair-like organelles found on nearly all human cells.
These cilia play a critical role in cellular signaling pathways essential for development. Defects in cilia can adversely affect these pathways, offering a plausible explanation for the often multi-symptom nature of many genetic syndromes and diseases, including anencephaly. Other known ciliopathies include Bardet-Biedl syndrome and polycystic kidney disease.
Early Detection and Specific Forms
Diagnosing Anencephaly
Fortunately, anencephaly can often be diagnosed before birth, typically through a routine prenatal ultrasound examination. Blood tests, specifically maternal serum alpha-fetoprotein (AFP screening), can also be useful screening tools for neural tube defects like anencephaly or spina bifida, alerting doctors to the need for further investigation.
Types of Anencephaly
Meroanencephaly
Meroanencephaly is a rarer form characterized by malformed cranial bones and a median cranial defect. Instead of a complete absence, there's a cranial protrusion called 'area cerebrovasculosa'—an abnormal, spongy, vascular tissue mixed with glial tissue that can range from a simple membrane to a large mass.
Holoanencephaly
The most common type is holoanencephaly, where the brain has almost entirely failed to form, with only the brain stem typically present. Infants with this severe form rarely survive more than a single day after birth.
Craniorachischisis
Craniorachischisis is the most severe form, combining anencephaly with bony defects in the spinal column. Here, both cranial and spinal defects are filled with neural tissue, as the skull and spine fail to close, exposing delicate neural structures. This extremely severe condition occurs in about 1 in 1000 live births.
Life Expectancy and Treatment
The prognosis for anencephaly is exceedingly poor. There is no cure or standard treatment, and many affected fetuses do not survive to term. Infants born alive typically succumb to cardiorespiratory arrest within hours or a few days, making prolonged survival exceptionally rare.
Global Patterns: Epidemiology
Anencephaly rates vary across the globe. In the United States, it occurs in approximately 1 out of every 4600 births. However, rates can be significantly higher in certain regions, such as parts of Nigeria, Ghana, and China, where estimates have ranged from 3 to 8 per 10,000 births.
A notable cluster of cases occurred in Brownsville, Texas, in the early 1990s, prompting a major public health investigation. This research highlighted a higher incidence among Mexican-American women and identified several risk factors beyond folic acid deficiency, including low vitamin B12, high homocysteine levels, and obesity.
Interestingly, research has also suggested that, overall, female babies are slightly more likely to be affected by anencephaly than males, though the reasons for this disparity are not fully understood.
Navigating Ethical Waters
The Complexities of Organ Donation
Anencephaly presents profound ethical challenges, particularly regarding organ donation. Infant organs are in extremely high demand, with many children dying before a suitable organ becomes available. The case of Baby Theresa in 1992 brought these difficult questions to the forefront of medical and legal debate.
Within the medical community, concerns include the possibility of misdiagnosis, the 'slippery slope' argument—that allowing donation from anencephalic infants could open the door to involuntary donation from other vulnerable populations—and the practical reality that few anencephalic infants would actually be suitable donors.
To address these issues, various proposals have been made: waiting for natural death before organ procurement, expanding the legal definition of death, or even creating a special legal category for anencephalic infants. Each approach carries its own set of ethical implications and vigorous debate.
A powerful example of compassionate organ donation occurred in the UK with Teddy Houlston in 2014. Diagnosed with anencephaly at 12 weeks gestation, his parents chose to carry the pregnancy to term specifically for organ donation. Teddy lived for 100 minutes after birth, and his kidneys were successfully transplanted into an adult, making him the UK's youngest organ donor.
Defining Brain Death
The ethical discussions surrounding anencephaly are closely intertwined with the definition of 'brain death.' Modern medical and legal frameworks typically define death as either irreversible cessation of circulatory and respiratory functions, or irreversible cessation of all functions of the entire brain, including the brain stem.
A more controversial concept, neocortical death—similar to a persistent vegetative state where only cognitive functions are lost—has been proposed as a legal equivalent to brain death. However, this idea has faced significant criticism, partly due to the difficulty of definitively confirming such a state, even with advanced imaging techniques like PET scans.
Pregnancy Termination
Given the high accuracy of prenatal diagnosis and the universally fatal nature of anencephaly, pregnancy termination becomes a significant ethical and legal consideration. The legality of abortion, however, varies widely across different jurisdictions and is often a deeply contested issue influenced by religious and moral viewpoints.
Legal Frameworks in the US
The case of Baby Theresa in 1992 became a cornerstone of moral philosophy debates. Her parents wished to donate her organs, but Florida law prohibited organ removal while she was still alive. By the time she died naturally nine days later, her organs had deteriorated too much to be viable for transplant, highlighting the conflict between medical need and legal definitions of life and death.
In the United States, model bills like the Uniform Determination of Death Act (UDDA) and the Uniform Anatomical Gift Act (UAGA) guide states on defining death and organ donation. The UDDA defines death as irreversible cessation of either circulatory/respiratory functions or entire brain function. The UAGA grants individuals and families the right to decide on organ donation post-mortem.
These acts, however, haven't fully resolved the anencephaly debate. Some state bills have proposed changes—for instance, a California bill sought to define anencephalic infants as already dead, while a New Jersey bill aimed to allow them to be organ sources even if not legally deceased. These proposals reflect ongoing societal struggles to reconcile medical realities with established legal and ethical boundaries.
Ongoing Research
Genetic research continues to shed light on the origins of anencephaly. Studies have explored genes like CART1 (cartilage homeoprotein 1), finding it selectively expressed in cartilage cells. Mouse models with a deficiency in the Cart1 gene have exhibited conditions like acrania and meroanencephaly, and importantly, prenatal treatment with folic acid in these models was shown to suppress these defects, reinforcing folic acid's crucial role.
Article
Anencephaly
Photos of anencephalic baby at first (A) and second years (B) of age.
Photos of an anencephalic newborn.
Anencephaly is the absence of a major portion of the brain, skull, and scalp that occurs during embryonic development. It is a cephalic disorder that results from a neural tube defect that occurs when the rostral (head) end of the neural tube fails to close, usually between the 23rd and 26th day following conception. Strictly speaking, the Greek term translates as "without a brain", but it is accepted that children born with this disorder usually only lack a telencephalon, the largest part of the brain consisting mainly of the cerebral hemispheres, including the neocortex, which is responsible for cognition. The remaining structure is usually covered only by a thin layer of membrane—skin, bone, meninges, etc., are all lacking. With very few exceptions, infants with this disorder do not survive longer than a few hours or days after birth.
Anencephaly is a severe neural tube defect typically considered incompatible with prolonged postnatal survival, and as such, surgical intervention is not commonly indicated.
Signs and symptoms
Anencephaly
The National Institute of Neurological Disorders and Stroke (NINDS) describes the presentation of this condition as follows: "A baby born with anencephaly is usually blind, deaf, unaware of its surroundings and unable to feel pain. Although some individuals with anencephaly may be born with a main brain stem, the lack of a functioning cerebrum permanently rules out the possibility of ever gaining awareness of their surroundings. Reflex actions such as breathing and responses to sound or touch may occur."
Causes
Anencephaly
Folic acid has been shown to be important in neural tube formation since at least 1991, and as a subtype of neural tube defect, folic acid may play a role in anencephaly. Studies have shown that the addition of folic acid to the diet of women of child-bearing age may significantly reduce, although not eliminate, the incidence of neural tube defects. Therefore, it is recommended that all women of child-bearing age consume 0.4 mg of folic acid daily, especially those attempting to conceive or who may possibly conceive, as this can reduce the risk to 0.03%. It is not advisable to wait until pregnancy has begun, since, by the time a woman knows she is pregnant, the critical time for the formation of a neural tube defect has usually already passed. A physician may prescribe even higher dosages of folic acid (5 mg/day) for women having had a previous pregnancy with a neural tube defect.
Neural tube defects can follow patterns of heredity, with direct evidence of autosomal recessive inheritance. As reported by Bruno Reversade and colleagues, the homozygous inactivation of the NUAK2 kinase leads to anencephaly in humans. Animal models indicate a possible association with deficiencies of the transcription factor TEAD2. A woman who has had one child with a neural tube defect such as anencephaly has about a 3% risk of having another child with a neural tube defect, as opposed to the background rate of 0.1% occurrence in the population at large. Genetic counseling is usually offered to women at a higher risk of having a child with a neural tube defect to discuss available testing.
An infant with anencephaly and acrania
It is known that people taking certain anticonvulsants and people with insulin-dependent diabetes have a higher risk of having a child with a neural tube defect.
Relation to genetic ciliopathy
Until recently, medical literature did not indicate a connection among many genetic disorders, both genetic syndromes and genetic diseases, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause despite the widely varying set of medical symptoms that are clinically visible in the disorders. Anencephaly is one such disease, part of an emerging class of diseases called ciliopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and, thus, offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome, and some forms of retinal degeneration.
Diagnosis
Anencephaly
Ultrasound image of fetus with anencephaly
Anencephaly can often be diagnosed before birth through an ultrasound examination. The maternal serum alpha-fetoprotein (AFP screening) and detailed fetal ultrasound can be useful for screening for neural tube defects such as spina bifida or anencephaly.
Meroanencephaly
Meroanencephaly is a rare form of anencephaly characterized by malformed cranial bones, a median cranial defect, and a cranial protrusion called area cerebrovasculosa. Area cerebrovasculosa is a section of abnormal, spongy, vascular tissue admixed with glial tissue ranging from simply a membrane to a large mass of connective tissue, hemorrhagic vascular channels, glial nodules, and disorganized choroid plexuses.
Holoanencephaly
The most common type of anencephaly, where the brain has entirely failed to form, except for the brain stem. Infants rarely survive more than one day after birth with holoanencephaly.
Craniorachischisis
The most severe type of anencephaly where area cerebrovasculosa and area medullovasculosa fill both cranial defects and the spinal column. Craniorachischisis is characterized by anencephaly accompanied by bony defects in the spine and the exposure of neural tissue as the vault of the skull fails to form. Craniorachischisis occurs in about 1 of every 1000 live births, but various physical and chemical tests can detect neural tube closure during early pregnancy.
Prognosis
Anencephaly
There is no cure or standard treatment for anencephaly. Prognosis is extremely poor, as many anencephalic fetuses do not survive birth and infants that are not stillborn will usually die within a few hours or days after birth from cardiorespiratory arrest.
In 2023, Menekse and colleagues reported what they described as the first surgical procedure performed on an infant with anencephaly who survived beyond the neonatal period. The case involved a multidisciplinary approach and neurosurgical intervention aimed at improving the patient's quality of life.
Epidemiology
Anencephaly
As of 2024, anencephaly occurs in about 1 out of every 5250 births (1.9‱) in the United States. In 1990, rates in Nigeria were estimated at 3 per 10,000 (3.0‱). Meanwhile, rates in Ghana were estimated at 8 per 10,000 (8.0‱) in 1992, and rates in China were estimated at 5 per 10,000 (5.0‱) in 2005.
A high anencephaly rate of 19.7 per 10,000 live births was found in 1990/1991 in Brownsville, Texas. A cluster of cases made national headlines and prompted a public health investigation and the Texas Neural Tube Defect Project. It was found, that neural tube defects in general, including spina bifida, and encephalocele had been occurring in Mexican-American women undetected for years in the area. Subsequently, multiple risk factors were found, foremost folic acid deficiency, low serum vitamin B12, high serum homocysteine levels, and obesity independently contributed to risk. Increasing dietary folate intake had a protective effect.
Research has suggested that, overall, female babies are more likely to be affected by the disorder.
Ethical issues
Organ donation
One issue concerning anencephalic newborns is organ donation. Initial legal guidance came from the case of Baby Theresa in 1992, in which the boundaries of organ donation were tested for the first time. Infant organs are scarce, and the high demand for pediatric organ transplants poses a major public health issue. In 1999, it was found that for American children under the age of two who are waiting for a transplant, 30–50% die before an organ becomes available.
Within the medical community, the main ethical issues with organ donation are a misdiagnosis of anencephaly, the slippery slope argument, that anencephalic neonates would rarely be a source of organs, and that it would undermine confidence in organ transplantation. Slippery slope concerns are a major issue in personhood debates, across the board. In regards to anencephaly, those who oppose organ donation argue that it could open the door for involuntary organ donors such as an elderly person with severe dementia. Another point of contention is the number of children who would actually benefit. There are discrepancies in statistics; however, it is known that most anencephalic children are stillborn.
Proposals have been made to bypass the legal and ethical issues surrounding organ donation. These include waiting for death to occur before procuring organs, expanding the definition of death, creating a special legal category for anencephalic infants, and defining them as non-persons.
In the United Kingdom, a child born with anencephaly was reported as the country's youngest organ donor. Teddy Houlston was diagnosed as anencephalic at 12 weeks of gestation. His parents, Jess Evans and Mike Houlston, decided against abortion and instead proposed organ donation. Teddy was born on 22 April 2014, in Cardiff, Wales, and lived for 100 minutes, after which his heart and kidneys were removed. His kidneys were later transplanted into an adult in Leeds. Teddy's twin, Noah, was born healthy.
Brain death
There are four different concepts used to determine brain death: failure of heart, failure of lungs, whole brain death, and neocortical death.
Neocortical death, similar to a persistent vegetative state (PVS), involves loss of cognitive functioning of the brain. A proposal by law professor David Randolph Smith, in an attempt to prove that neocortical death should legally be treated the same as brain death, involved PET scans to determine the similarities. However, this proposal has been criticized on the basis that confirming neocortical death by PET scan may risk indeterminacy.
Pregnancy termination
Anencephaly can be diagnosed before delivery with a high degree of accuracy. Although anencephaly is a fatal condition, the option of abortion is dependent on the abortion laws in the jurisdiction. According to a 2013 report, 26% of the world's population reside in a country where abortion is generally prohibited. In 2012, Brazil extended the right of abortion to mothers with anencephalic fetuses. This decision, however, received vocal disapproval from several religious groups.
Legal proceedings
The case of baby Theresa was the beginning of the ethical debate over anencephalic infant organ donation. The story of baby Theresa remains a focus of basic moral philosophy. Baby Theresa was born with anencephaly in 1992. Her parents, knowing that their child was going to die, requested that her organs be given for transplantation. Although her physicians agreed, Florida law prohibited the infant's organs from being removed while she was still alive. By the time she died nine days after birth, her organs had deteriorated past the point of being viable.
United States uniform acts
The Uniform Determination of Death Act (UDDA) is a model bill, adopted by many US states, stating that an individual who has sustained either 1) irreversible cessation of circulatory and respiratory functions or 2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead. This bill was a result of much debate over the definition of death and is applicable to the debate over anencephaly. A related bill, the Uniform Anatomical Gift Act (UAGA), grants individuals and, after death, their family members the right to decide whether or not to donate organs. Because it is against the law for any person to pay money for an organ, the person in need of an organ transplant must rely on a volunteer.
There have been two state bills that proposed to change current laws regarding death and organ donation. California Senate Bill 2018 proposed to amend the UDDA to define anencephalic infants as already dead, while New Jersey Assembly Bill 3367 proposed to allow anencephalic infants to be organ sources even if they are not dead.
Research
Anencephaly
Some genetic research has been conducted to determine the causes of anencephaly. It has been found that cartilage homeoprotein (CART1) is selectively expressed in chondrocytes (cartilage cells). The CART1 gene to chromosome 12q21.3–q22 has been mapped. Also, it has been found that mice homozygous for deficiency in the Cart1 gene manifested acrania and meroanencephaly, and prenatal treatment with folic acid will suppress acrania and meroanencephaly in the Cart1-deficient mutants.