Neural tube defect | |
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Illustration of a child with spina bifida, the most common NTD | |
Specialty | Medical genetics |
Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo begin to change shape and form the neural tube. When the neural tube does not close completely, an NTD develops.
Specific types include: spina bifida which affects the spine, anencephaly which results in little to no brain, encephalocele which affects the skull, and iniencephaly which results in severe neck problems. [1]
NTDs are one of the most common birth defects, affecting over 300,000 births each year worldwide. [2] For example, spina bifida affects approximately 1,500 births annually in the United States, or about 3.5 in every 10,000 (0.035% of US births), [1] [3] which has decreased from around 5 per 10,000 (0.05% of US births) since folate fortification of grain products was started. [3] The number of deaths in the US each year due to neural tube defects also declined from 1,200 before folate fortification was started to 840. [4]
There are two classes of NTDs: open, which are more common, and closed. Open NTDs occur when the brain and/or spinal cord are exposed at birth through a defect in the skull or vertebrae (spinal column). Open NTDs include anencephaly, encephaloceles, hydranencephaly, iniencephaly, schizencephaly, and the most common form, spina bifida. Closed NTDs occur when the spinal defect is covered by skin. Types of closed NTDs include lipomeningocele, lipomyelomeningocele, and tethered cord. [5]
Anencephaly (without brain) is a severe neural tube defect that occurs when the anterior-most end of the neural tube fails to close, usually during the 23rd and 26th days of pregnancy. This results in an absence of a major portion of the brain and skull. Infants born with this condition lack the main part of the forebrain and are usually blind, deaf and display major craniofacial anomalies. The lack of a functioning cerebrum will prevent the infant from even gaining consciousness. Infants are either stillborn or usually die within a few hours or days after birth. [6] For example, anencephaly in humans can result from mutations in the NUAK2 kinase. [7]
Encephaloceles are characterized by protrusions of the brain through the skull that are sac-like and covered with membrane. They can be a groove down the middle of the upper part of the skull, between the forehead and nose, or the back of the skull. [8] Due to the range in its location, encephaloceles are classified by the location as well as the type of defect it causes. Subtypes include occipital encephalocele, encephalocele of the cranial vault, and nasal encephaloceles (frontoethmoidal encephaloceles and basal encephaloceles), with approximately 80% of all encephaloceles occurring in the occipital area. [9] Encephaloceles are often obvious and diagnosed immediately. Sometimes small encephaloceles in the nasal and forehead are undetected. [10] Despite the wide range in its implications, encephaloceles are most likely to be caused by improper separation of the surface ectoderm and the neuroectoderm after the closure of the neural folds in the fourth week of gastrulation. [11]
Hydranencephaly is a condition in which the cerebral hemispheres are missing and instead filled with sacs of cerebrospinal fluid. People are born with hydranencephaly, but most of the time, the symptoms appear in a later stage. Newborns with hydrancephaly can swallow, cry, sleep and their head is in proportion to their body. [12] However, after a few weeks, the infants develop increased muscle tone and irritability. After a few months, the brain start to fill with cerebrospinal fluid (hydrocephalus). This has several consequences. Infants start to develop problems with seeing, hearing, growing, and learning. The missing parts of the brain and the amount of cerebrospinal fluid can also lead to seizures, spasm, problems with regulating their body temperature, and breathing and digestion problems. Besides problems in the brain, hydranencephaly can also be seen on the outside of the body. Hydrocephalus leads to more cerebrospinal fluid in the brain, which can result in an enlarged head. [13] [14]
The cause of hydranencephaly is not clear. Hydranencephaly is a result of an injury of the nervous system or an abnormal development of the nervous system. The neural tube closes in the sixth week of the pregnancy, [15] so hydranencephaly develops during these weeks of the pregnancy. The cause of these injuries/development is not clear. [16]
Theories regarding the causes of hydrancephaly include:
Iniencephaly is a rare neural tube defect that results in extreme bending of the head to the spine. The diagnosis can usually be made on antenatal ultrasound scanning, but if not will undoubtedly be made immediately after birth because the head is bent backwards and the face looks upwards. Usually the neck is absent. The skin of the face connects directly to the chest and the scalp connects to the upper back. Individuals with iniencephaly generally die within a few hours after birth. [17]
Spina bifida is further divided into two subclasses, spina bifida cystica and spina bifida occulta. [18]
Inadequate levels of folate (vitamin B9) and vitamin B12 during pregnancy have been found to lead to increased risk of NTDs. [23] [24] Although both are part of the same biopathway, folate deficiency is much more common and therefore more of a concern. [23] [24] Folate is required for the production and maintenance of new cells, for DNA synthesis and RNA synthesis. Folate is needed to carry one carbon groups for methylation and nucleic acid synthesis. It has been hypothesized that the early human embryo may be particularly vulnerable to folate deficiency due to differences of the functional enzymes in this pathway during embryogenesis combined with high demand for post translational methylations of the cytoskeleton in neural cells during neural tube closure. [25] Failure of post-translational methylation of the cytoskeleton, required for differentiation has been implicated in neural tube defects. [26] Vitamin B12 is also an important receptor in the folate biopathway such that studies have shown deficiency in vitamin B12 contributes to risk of NTDs as well. [27] There is substantial evidence that direct folic supplementation increases blood serum levels of bioavailable folate even though at least one study have shown slow and variable activity of dihydrofolate reductase in human liver. [28] [29] A diet rich in natural folate (350 μg/d) can show as much increase in plasma folate as taking low levels of folic acid (250 μg/d) in individuals [30] However a comparison of general population outcomes across many countries with different approaches to increasing folate consumption has found that only general food fortification with folic acid reduces neural tube defects. [31] While there have been concerns about folic acid supplementation being linked to an increased risk for cancer, a systematic review in 2012 shows there is no evidence except in the case of prostate cancer which indicates a modest reduction in risk. [32]
There have been studies showing the relationship between NTDs, folate deficiency and the difference of skin pigmentation within human populations across different latitudes. There are many factors that would influence the folate levels in human bodies: (i) the direct dietary intake of folic acid through fortified products, (ii) environmental agents such as UV radiation. In concern with the latter, the UV radiation-induced folate photolysis has been shown via in vitro and in vivo studies to decrease the folate level and implicate in etiology of NTDs not only in humans but other amphibian species. Therefore, a protection against the UV radiation-induced photolysis of folate is imperative for the evolution of human populations living in tropical regions where the exposure to UV radiation is high over the year. One body natural adaptation is to elevate the concentration of melanin inside the skin. Melanin works as either an optical filter to disperse the incoming UV radiation rays or free radical to stabilize the hazardous photochemical products. Multiple studies have demonstrated the highly melanized integument as a defense against folate photolysis in Native Americans or African Americans correlates with lower occurrence of NTDs in general. [33] [34]
As reported by Bruno Reversade and colleagues, the inactivation of the NUAK2 kinase in humans leads to anencephaly. [7] This fatal birth defect is believed to arise as a consequence of impaired HIPPO signalling. [7] Other genes such as TRIM36 have also been associated with anencephaly in humans. [35]
A deficiency of folate itself does not cause neural tube defects. The association seen between reduced neural tube defects and folic acid supplementation is due to a gene-environment interaction such as vulnerability caused by the C677T methylenetetrahydrofolate reductase (MTHFR) variant. Supplementing folic acid during pregnancy reduces the prevalence of NTDs by not exposing this otherwise sub-clinical mutation to aggravating conditions. [36] Other potential causes can include folate antimetabolites (such as methotrexate), mycotoxins in contaminated corn meal, arsenic, hyperthermia in early development, and radiation. [37] [38] [39] Maternal obesity has also been found to be a risk factor for NTDs. [40] Studies have shown that both maternal cigarette smoking and maternal exposure to secondhand smoke increased the risk for neural tube defects in offspring. [41] A mechanism by which maternal exposure to cigarette smoke could increase NTD risk in offspring is suggested by several studies that show an association between cigarette smoking and elevations of homocysteine levels. [42] Cigarette smoke during pregnancy, including secondhand exposure, can increase the risk of neural tube defects. [43] All of the above may act by interference with some aspect of normal folic acid metabolism and folate linked methylation related cellular processes as there are multiple genes of this type associated with neural tube defects. [44]
Folic acid supplementation reduces the prevalence of neural tube defects by approximately 70% of neural tube defects indicating that 30% are not folate-dependent and are due to some cause other than alterations of methylation patterns. [45] Multiple other genes related to neural tube defects exist which are candidates for folate insensitive neural tube defects. [44] There are also several syndromes such as Meckel syndrome, and triploid syndrome which are frequently accompanied by neural tube defects that are assumed to be unrelated to folate metabolism [46]
Tests for neural tube defects include ultrasound examination and measurement of maternal serum alpha-fetoprotein (MSAFP). Second trimester ultrasound is recommended as the primary screening tool for NTDs, and MSAFP as a secondary screening tool. [47] This is due to increased safety, increased sensitivity and decreased false positive rate of ultrasound as compared to MSAFP. [47] Amniotic fluid alpha-fetoprotein (AFAFP) and amniotic fluid acetylcholinesterase (AFAChE) tests are also used to confirming if ultrasound screening indicates a positive risk. [48] Often, these defects are apparent at birth, but acute defects may not be diagnosed until much later in life. An elevated MSAFP measured at 16–18 weeks gestation is a good predictor of open neural tube defects, however the test has a very high false positive rate, (2% of all women tested in Ontario, Canada between 1993 and 2000 tested positive without having an open neural tube defect, although 5% is the commonly quoted result worldwide) and only a portion of neural tube defects are detected by this screen test (73% in the same Ontario study). [49] MSAFP screening combined with routine ultrasonography has the best detection rate although detection by ultrasonography is dependent on operator training and the quality of the equipment. [50] [51]
Incidence of neural tube defects has been shown to decline through maintenance of adequate folic acid levels prior to and during pregnancy. This is achieved through dietary sources and supplementation of folic acid. [52] In 1996, the United States Food and Drug Administration published regulations requiring the addition of folic acid to enriched breads, cereals, flour and other grain products. [53] Similar regulations made it mandatory to fortify selected grain products with folic acid in Canada by 1998. [54] During the first four weeks of pregnancy (when most women do not even realize that they are pregnant), adequate folate intake is essential for proper operation of the neurulation process. Therefore, any individuals who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risks of serious birth defects. [55] [56] [57] In Canada, mandatory fortification of selected foods with folic acid had been shown to reduce the incidence of neural tube defects by 46% compared to incidence prior to mandatory fortification. [58] However, relying on eating a folate-rich diet alone is not recommended for preventing neural tube defects when trying to conceive because a regular diet usually does not contain enough folate to reach pregnancy requirements. [59] [60] All individuals who have the ability to become pregnant are advised to get 400 micrograms of folic acid daily. [61] [62] This daily 400 mcg dose of folic acid can be found in most multivitamins advertised as for women. [63] Higher doses can be found in pre-natal multivitamins but those doses may not be necessary for everyone. [64] [65] Individuals who have previously given birth to a child with a neural tube defect and are trying to conceive again may benefit from a supplement containing 4.0 mg daily, following advice provided by their doctor. [63] In Canada, guidelines on folic acid intake when trying to conceive is based on a risk assessment of how likely they are to experience a neural tube defect during pregnancy. Risk is divided into high, moderate, and low risk categories. [62] High risk would include those that had a past experience with neural tube defects, either themselves or during another pregnancy. [62] Medium risk individuals are those with certain conditions that put them at higher risk for experiencing a neural tube defect. These include having a first or second degree relative or partner with a history of neural tube defects, having a gastrointestinal condition that affects normal absorption patterns, advanced kidney disease, kidney dialysis, alcohol over-use, or had another pregnancy resulting in a congenital abnormality that was folate sensitive. Medium risk individuals would also include those taking medications that can interfere with folate absorption such as anticonvulsants, metformin, sulfasalazine, triamterene, and trimethoprim. [62] Low risk would include everyone else that do not fall into either medium or high risk categories. Recommendations on when to start folic acid supplementation for all individuals looking to become pregnant is at least three months preconception. [60] [62] If an individual is in the high risk category, the recommended dose is 4–5 mg of folic acid daily until 12 weeks gestation and then decrease to 0.4–1 mg until 4–6 weeks postpartum or for however long breastfeeding lasts. [62] If an individual is in the medium risk category, the recommended dose is 1 mg of folic acid daily until 12 weeks gestation and then they can either continue at 1 mg or decrease to 0.4 mg daily until 4–6 weeks postpartum or however long breastfeeding lasts. [62] If the pregnancy is low risk to develop a neural tube defect then the recommendation for that individual is 0.4 mg daily until 4–6 weeks postpartum or however long breastfeeding lasts. [62] All dose recommendations and risk assessment should be done with the advice of a qualified health care provider. [61]
As of 2008, treatments of NTDs depends on the severity of the complication. No treatment is available for anencephaly and infants usually do not survive more than a few hours. Aggressive surgical management has improved survival and the functions of infants with spina bifida, meningoceles and mild myelomeningoceles. [66] The success of surgery often depends on the amount of brain tissue involved in the encephalocele. The goal of treatment for NTDs is to allow the individual to achieve the highest level of function, and independence. Fetal surgery in utero before 26 weeks gestation has been performed with some hope that there is benefit to the outcome including a reduction in Arnold–Chiari malformation and thereby decreases the need for a ventriculoperitoneal shunt but the procedure is very high risk for both mother and baby and is considered extremely invasive with questions that the positive outcomes may be due to ascertainment bias and not true benefit. Further, this surgery is not a cure for all problems associated with a neural tube defect. Other areas of research include tissue engineering and stem cell therapy but this research has not been used in humans. [67]
Neural tube defects resulted in 71,000 deaths globally in 2010. [68] It is unclear how common the condition is in low income countries. [69]
Prevalence rates of NTDs at birth used to be a reliable measure for the actual number of children affected by the diseases. [70] However, due to advances in technology and the ability to diagnose prenatally, the rates at birth are no longer reliable. [70] Measuring the number of cases at birth may be the most practical way, but the most accurate way would be to include stillbirths and live-births. [70] Most studies that calculate prevalence rates only include data from live births and stillborn children and normally exclude the data from abortions and miscarriages. [70] Abortions are a huge contributing factor to the prevalence rates; one study found that in 1986 only a quarter of the pregnancies with an identified NTD were aborted, but that number had already doubled by 1999. [70] Through this data, it is clear that excluding data from abortions could greatly affect the prevalence rates. This could also possibly explain why prevalence rates have appeared to drop. If abortions are not being included in the data but half of the identified cases are being aborted, the data could show that prevalence rates are dropping when they actually are not. However, it is unclear how much of an impact these could have on prevalence rates due to the fact that abortion rates and advances in technology vary greatly by country. [70]
There are many maternal factors that also play a role in prevalence rates of NTDs. [70] These factors include things like maternal age and obesity all the way to things like socioeconomic status along with many others. [70] Maternal age has not been shown to have a huge impact on prevalence rates, but when there has been a relationship identified, older mothers along with very young mothers are at an increased risk. [70] While maternal age may not have a huge impact, mothers that have a body mass index greater than 29 double the risk of their child having an NTD. [70] Studies have also shown that mothers with three or more previous children show moderate risk for their next child having an NTD. [70]
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is required for the body to make DNA and RNA and metabolise amino acids necessary for cell division and maturation of blood cells. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.
Spina bifida is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, meningocele and myelomeningocele. Meningocele and myelomeningocele may be grouped as spina bifida cystica. The most common location is the lower back, but in rare cases it may be in the middle back or neck.
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.
Iniencephaly is a rare type of cephalic disorder characterised by three common characteristics: a defect to the occipital bone, spina bifida of the cervical vertebrae and retroflexion of the head on the cervical spine. Stillbirth is the most common outcome, with a few rare examples of live birth, after which death invariably occurs within a short time.
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth defects are divided into two main types: structural disorders in which problems are seen with the shape of a body part and functional disorders in which problems exist with how a body part works. Functional disorders include metabolic and degenerative disorders. Some birth defects include both structural and functional disorders.
Prenatal testing is a tool that can be used to detect some birth defects at various stages prior to birth. Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of the zygote, embryo, or fetus, either before gestation even starts or as early in gestation as practicable. Screening can detect problems such as neural tube defects, chromosome abnormalities, and gene mutations that would lead to genetic disorders and birth defects, such as spina bifida, cleft palate, Down syndrome, trisomy 18, Tay–Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, muscular dystrophy, and fragile X syndrome. Some tests are designed to discover problems which primarily affect the health of the mother, such as PAPP-A to detect pre-eclampsia or glucose tolerance tests to diagnose gestational diabetes. Screening can also detect anatomical defects such as hydrocephalus, anencephaly, heart defects, and amniotic band syndrome.
Nutrition and pregnancy refers to the nutrient intake, and dietary planning that is undertaken before, during and after pregnancy. Nutrition of the fetus begins at conception. For this reason, the nutrition of the mother is important from before conception as well as throughout pregnancy and breastfeeding. An ever-increasing number of studies have shown that the nutrition of the mother will have an effect on the child, up to and including the risk for cancer, cardiovascular disease, hypertension and diabetes throughout life.
Encephalocele is a neural tube defect characterized by sac-like protrusions of the brain and the membranes that cover it through openings in the skull. These defects are caused by failure of the neural tube to close completely during fetal development. Encephaloceles cause a groove down the middle of the skull, or between the forehead and nose, or on the back side of the skull. The severity of encephalocele varies, depending on its location.
Fetal surgery also known as antenatal surgery, prenatal surgery, is a growing branch of maternal-fetal medicine that covers any of a broad range of surgical techniques that are used to treat congenital abnormalities in fetuses who are still in the pregnant uterus. There are three main types: open fetal surgery, which involves completely opening the uterus to operate on the fetus; minimally invasive fetoscopic surgery, which uses small incisions and is guided by fetoscopy and sonography; and percutaneous fetal therapy, which involves placing a catheter under continuous ultrasound guidance.
Food fortification or enrichment is the process of adding micronutrients to food. It can be carried out by food manufacturers, or by governments as a public health policy which aims to reduce the number of people with dietary deficiencies within a population. The predominant diet within a region can lack particular nutrients due to the local soil or from inherent deficiencies within the staple foods; the addition of micronutrients to staples and condiments can prevent large-scale deficiency diseases in these cases.
Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. This may result in a type of anemia in which red blood cells become abnormally large and is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. Signs of folate deficiency are often subtle. Symptoms may include feeling tired, heart palpitations, shortness of breath, feeling faint, open sores on the tongue, loss of appetite, changes in the color of the skin or hair, irritability, and behavioral changes. Temporary reversible infertility may occur. Folate deficiency anemia during pregnancy may give rise to the birth of low weight birth premature infants and infants with neural tube defects.
A multiple of the median (MoM) is a measure of how far an individual test result deviates from the median. MoM is commonly used to report the results of medical screening tests, particularly where the results of the individual tests are highly variable.
Folate receptor 1 is a protein that in humans is encoded by the FOLR1 gene.
Methionine synthase reductase, also known as MSR, is an enzyme that in humans is encoded by the MTRR gene.
Rachischisis is a developmental birth defect involving the neural tube. This anomaly occurs in utero, when the posterior neuropore of the neural tube fails to close by the 27th intrauterine day. As a consequence the vertebrae overlying the open portion of the spinal cord do not fully form and remain unfused and open, leaving the spinal cord exposed. Patients with rachischisis have motor and sensory deficits, chronic infections, and disturbances in bladder function. This defect often occurs with anencephaly.
The MOMS Trial was a clinical trial that studied treatment of a birth defect called myelomeningocele, which is the most severe form of spina bifida. The study looked at prenatal and postnatal surgery to repair this defect. The first major phase concluded that prenatal surgery had strong, long-term benefits and some risks.
Women should speak to their doctor or healthcare professional before starting or stopping any medications while pregnant. Non-essential drugs and medications should be avoided while pregnant. Tobacco, alcohol, marijuana, and illicit drug use while pregnant may be dangerous for the unborn baby and may lead to severe health problems and/or birth defects. Even small amounts of alcohol, tobacco, and marijuana have not been proven to be safe when taken while pregnant. In some cases, for example, if the mother has epilepsy or diabetes, the risk of stopping a medication may be worse than risks associated with taking the medication while pregnant. The mother's healthcare professional will help make these decisions about the safest way to protect the health of both the mother and unborn child. In addition to medications and substances, some dietary supplements are important for a healthy pregnancy, however, others may cause harm to the unborn child.
Sir Nicholas John Wald FRS, FRCP, FMedSci, qualified in medicine from University College London in 1967. He is currently honorary professor of preventive medicine, University College London, honorary professor, Population Health Research Institute, St George's, University of London, visiting professor, University of Oxford, and honorary consultant and adjunct professor, Brown University, Rhode Island. He was professor of environmental and preventive medicine from 1983 to 2019 at Barts and The London School of Medicine and Dentistry. He was co-founder and director of the Wolfson Institute of Preventive Medicine.
The rostral neuropore or anterior neuropore is a region corresponding to the opening of the embryonic neural tube in the anterior portion of the developing prosencephalon. The central nervous system develops from the neural tube, which initially starts as a plate of cells in the ectoderm and this is called the neural plate, the neural plate then undergoes folding and starts closing from the center of the developing fetus, this leads to two open ends, one situated cranially/rostrally and the other caudally. Bending of the neural plate begins on day 22, and the cranial neuropore closes on day 24. giving rise to the lamina terminalis of the brain.